Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1C=CC=CC=1[S:8]([OH:11])(=[O:10])=[O:9].[N+](C1C=CC(N[C:22]2[C:31]3[C:26](=[CH:27][C:28](S(O)(=O)=O)=[CH:29][C:30]=3[OH:32])[CH:25]=[C:24]([S:37]([OH:40])(=[O:39])=[O:38])[CH:23]=2)=CC=1)([O-])=O.[S-2].[Na+].[Na+].[Cl-].[Na+]>>[OH:32][C:30]1[C:31]2[C:26](=[CH:25][C:24]([S:37]([OH:40])(=[O:38])=[O:39])=[CH:23][CH:22]=2)[C:27]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:28][CH:29]=1
Reactant: Nc1ccccc1S(=O)(=O)O
Reactant: O=[N+]([O-])c1ccc(Nc2cc(S(=O)(=O)O)cc3cc(S(=O)(=O)O)cc(O)c23)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [S-2]
Product: O=S(=O)(O)c1ccc2c(O)ccc(S(=O)(=O)O)c2c1

Procedure:
6.8 parts of 2,4,6-trifluoro-1,3,5-triazine are added dropwise to a solution of 13.4 parts of 1,4-diaminobenzene-2,5-disulphonic acid in 200 parts by volume of water at 0° C. and a pH value of 4 to 5 is maintained by constantly neutralising the hydrogen fluoride liberated. The course of the reaction is followed chromatographically. The resulting solution of the intermediate product is condensed, at a pH value of 7 to 8 and at 10° to 20° C. with 31 parts of the aminoazo dyestuff obtained by coupling diazotised 1-aminobenzene-2-sulphonic acid with 1-(4'-nitrophenylamino)-8-hydroxynaphthalene-3,6-disulphonic acid and subsequently reducing the nitro group with sodium sulphide. The dyestuff is salted out completely with sodium chloride, filtered off, washed and again converted to a neutral solution in 500 parts by volume of water. Further diazotisation of the resulting aminoazo dyestuff and coupling with 15 parts of 1-hydroxynaphthalene-4,6-disulphonic acid gives the dyestuff of the formula ##STR43## which is precipitated with sodium chloride, isolated and then washed and dried. It is a dark red powder which gives a red solution in water.
Reaction SMILES: C(O[C:4](=[O:10])[CH:5]([CH2:8]Br)[CH2:6]Br)C.[C:11]1(N2CCCC2)[CH2:15]C[CH2:13][CH:12]=1.CCN(C(C)C)C(C)C.CCOC(C)=O>CC#N>[O:10]=[C:4]1[CH:5]2[CH2:6][CH2:15][CH:11]1[CH2:12][CH2:13][CH2:8]2
Reactant: C1=C(N2CCCC2)CCC1
Reactant: CCOC(=O)C(CBr)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1C2CCCC1CC2

Procedure:
3-Bromo-2-bromomethyl-propionic acid ethyl ester (5.48 g, 20 mmol) was added to a mixture of 1-cyclopent-1-enyl-pyrrolidine (2.74 g, 20 mmol) and Hünig's base (3.5 mL) in MeCN (15 mL) with vigorous stirring. An exothermic reaction ensued, bringing the mixture to reflux. The mixture was refluxed for 16 h, cooled, and poured into 100 mL of EtOAc with stirring. The resulting solid (3.33 g) was collected by filtration, dissolved in 0.5 M aqueous HCl (100 mL) and stirred with EtOAc (100 mL) for 48 h. The organic layer was separated and concentrated to give 8-oxo-bicyclo[3.2.1]octane-endo-3-carboxylic acid ethyl ester (1.0 g, 5.1 mmol) as a colourless oil. This was dissolved in EtOH (50 mL),treated with a solution of hydroxylamine hydrochloride (1.04 g, 15 mmol) and sodium acetate trihydrate (2.04 g, 15 mmol) in water (10 mL) and heated at reflux for 16 h. The solution was cooled, concentrated, diluted with water (100 mL) and extracted with DCM. The DCM extracts were dried (MgSO4), concentrated and purified by flash chromatography (20→30% EtOAc/hexane) to give the oxime (270 mg) as a colourless oil. 1H NMR (CDCl3, 360 MHz) δ 9.85 (1 H, bs, N—OH), 4.20 (2 H, q, J=7.1 Hz, CH2—O), 3.36 (1 H, bs, bridgehead H), 2.63-2.56 (4 H, m), 2.15-2.04 (2 H, m), 1.76-1.69 (4 H, m), 1.30 (3 H, t, J=7.1 Hz, —Me). m/z 212 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][O:16][C:15]([CH3:20])([CH3:19])[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=1.[C:27]1([NH2:34])[C:28]([NH2:33])=[CH:29][CH:30]=[CH:31][CH:32]=1.[C:35](O)(=O)[CH3:36]>>[CH3:19][C:15]1([CH3:20])[O:16][CH2:17][CH2:18][N:13]([CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:3]=[C:2]([N:33]2[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:34]=[C:35]2[CH3:36])[N:10]=3)[CH2:14]1
Reactant: CC(=O)O
Reactant: Nc1ccccc1N
Reactant: Cn1c(CN2CCOC(C)(C)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCOC(C)(C)C3)n(C)c2n1

Procedure:
Following the procedures for 157 and General Procedure J, 4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-2,2-dimethylmorpholine and benzene-1,2-diamine were reacted, followed by condensation with acetic acid to give 196. LCMS m/z: 477.2 (MH+)
Reaction SMILES: [OH-].[Li+].[CH2:3]([S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[C:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[CH:21]=2)=[CH:13][C:12]=1[O:42][CH3:43])(=[O:9])=[O:8])[CH2:4][CH2:5][CH3:6].O.Cl>O1CCCC1>[CH2:3]([S:7]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[C:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=3)[CH:21]=2)=[CH:13][C:12]=1[O:42][CH3:43])(=[O:8])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)OC)c(OCc3cccc(OC)c3)c2)cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)Oc1ccc(CCCc2ccc(CCC(=O)O)c(OCc3cccc(OC)c3)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
0.62 ml (0.62 mmol) of 1M lithium hydroxide solution is added to a solution of 181.6 mg (0.31 mmol) of methyl 3-[4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-(3-methoxybenzyloxy)phenyl]propanoate in 5 ml of tetrahydrofuran. The reaction mixture is stirred overnight at room temperature. The reaction is treated by adding 10 ml of water, acidified with hydrochloric acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. After evaporating off the solvents, the residue is purified by chromatography on a column of silica eluted with a 95/5 dichloromethane/methanol mixture. 162 mg (92%) of 3-[4-{3-[4-(butane-1-sulfonyloxy)-3-methoxyphenyl]propyl}-2-(3-methoxybenzyloxy)phenyl]propanoic acid are obtained in the form of a yellow oil.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[NH2:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:49]=[C:48]3[C:44]([CH2:45][N:46]([C:51]([CH3:57])([CH3:56])[C:52]([O:54][CH3:55])=[O:53])[C:47]3=[O:50])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.[CH2:58]([C:63]1[CH:71]=[CH:70][C:66]([C:67](Cl)=[O:68])=[CH:65][CH:64]=1)[CH2:59][CH2:60][CH2:61][CH3:62]>>[CH3:56][C:51]([N:46]1[CH2:45][C:44]2[C:48](=[CH:49][C:41]([C:38]3[CH:37]=[CH:36][C:35]([NH:34][C:67](=[O:68])[C:66]4[CH:70]=[CH:71][C:63]([CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[CH:64][CH:65]=4)=[CH:40][CH:39]=3)=[CH:42][CH:43]=2)[C:47]1=[O:50])([CH3:57])[C:52]([O:54][CH3:55])=[O:53]
Reactant: COC(=O)C(C)(C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: CCCCCc1ccc(C(=O)Cl)cc1
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N(C(C)(C)C(=O)OC)C4)cc2)cc1
Yield: 93 %

Procedure:
The compound of example 524 was prepared analogous to compound of example 97 by reaction of compound of example 515 with 4-(n-pentyl)-benzoyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[F:10][C:11]([F:39])([F:38])[C:12]1[CH:13]=[C:14]([CH:22]([NH2:37])[C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:37][CH:22]([C:14]2[CH:15]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:17]=[C:12]([C:11]([F:10])([F:38])[F:39])[CH:13]=2)[C:23]2[CH:24]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: NC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Fc1cnc(Cl)nc1NC(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine was reacted with di[3,5-di(trifluoromethyl)phenyl]methylamine to provide 2-chloro-N4-[[di(3,5-di(trifluoromethyl)phenyl)]methyl]-5-fluoro-4-pyrimidineamine. 1H NMR (CDCl3): δ 8.06 (d, 1H, J=2.3 Hz), 7.92 (s, 2H), 7.74 (s, 4H), 6.75 (d, 1H, J=7.6 Hz), 5.80 (d, 1H, J=7.0 Hz).
Reaction SMILES: IC.[CH3:3][C:4]1[C:5](=[O:10])[NH:6][CH:7]=[CH:8][CH:9]=1.[C:11](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[C:5]1=[O:10]
Reactant: Cc1ccc[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: Cc1cccn(C)c1=O
Temperature: 55 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
Iodomethane (10.62 mL, 111.6 mmol) was added to a mixture of 3-methyl-2-pyridone (4.06 g, 37.20 mmol) and potassium carbonate (15.43 g, 111.6 mmol) in acetone (150 mL) in a sealable flask. The mixture was vigorously stirred in an oil bath at 55° C. for 16 hours. The reaction mixture was cooled to ambient temperature then filtered through glass fiber filter paper and the filtrate was concentrated under vacuum until a solid formed (5.4 g). The solid was partitioned between water (50 mL) and dichloromethane (100 mL). The aqueous phase was extracted once more with dichloromethane (50 mL). The combined organic phases were dried over magnesium sulfate and concentrated under vacuum to give 1,3-dimethylpyridin-2(1H)-one as an oil (3.6 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:26])=[C:4]([C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])[C:5]([I:17])=[C:6]([C:9]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:10])[C:7]=1[I:8].[C:27](Cl)(Cl)=[O:28].C1(C)C=CC=CC=1>O1CCOCC1>[N:11]1([C:9]([C:6]2[C:5]([I:17])=[C:4]([C:18]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:19])[C:3]([I:26])=[C:2]([N:1]=[C:27]=[O:28])[C:7]=2[I:8])=[O:10])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: O=C(Cl)Cl
Reactant: Nc1c(I)c(C(=O)N2CCOCC2)c(I)c(C(=O)N2CCOCC2)c1I
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: O=C=Nc1c(I)c(C(=O)N2CCOCC2)c(I)c(C(=O)N2CCOCC2)c1I
Temperature: 50 °C

Procedure:
To a solution of [3-Amino-2,4,6-triiodo-5-(morpholine-4-carbonyl)-phenyl]-morpholin-4-yl-methanone (8 g, 11.4 mmol) in 1,4-dioxane (40 mL) was added ˜11 equivalents of 20% phosgene solution in toluene (60 mL, 120 mmol) at ambient temperature, the solution was heated at 50° C. for 15 hours. The reaction was allowed to cool to ambient temperature and then concentrated at reduced pressure to yield an off white, semi-crystalline solid. Dioxane (30 mL×2) was added and removed slowly at reduced pressure to give a light brown, semi-crystalline solid which was placed on a vacuum line to remove any residual solvent. The material was used without further purification.
Reaction SMILES: BrC1N(C2N=CN=C(N)C=2N=1)[C@@H]1O[C@H](CO)[C@@H](O)C1.[SnH](CCCC)(CCCC)CCCC.CC(N=NC(C#N)(C)C)(C#N)C.C[O:46][C:47]1[N:48]([C:56]2[N:57]=[CH:58][N:59]=[C:60]([NH2:63])[C:61]=2[N:62]=1)[C@@H:49]1[O:55][C@H:52]([CH2:53][OH:54])[CH2:51][CH2:50]1>>[OH:46][C:47]1[N:48]([C:56]2[N:57]=[CH:58][N:59]=[C:60]([NH2:63])[C:61]=2[N:62]=1)[C@@H:49]1[O:55][C@H:52]([CH2:53][OH:54])[CH2:51][CH2:50]1
Reactant: COc1nc2c(N)ncnc2n1[C@H]1CC[C@@H](CO)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: Nc1ncnc2c1nc(Br)n2[C@H]1C[C@H](O)[C@@H](CO)O1
Product: Nc1ncnc2c1nc(O)n2[C@H]1CC[C@@H](CO)O1

Procedure:
The starting compound for the synthesis of VIII was 8-bromo-2'-deoxyadenosine which was prepared by bromination of the corresponding deoxynucleoside. This starting compound was first converted to its azido derivative and then subjected to the deoxygenation procedure. During the nBu3SnH/AIBN step, reduction of the azido group occurred concomitantly with the deoxygenation. In a related procedure, 8-bromo-2'-deoxyadenosine was converted to the corresponding 8-methoxy compound and then deoxygenated to 2',3'-dideoxy-8-methoxyadenosine (IX). 2',3'-Dideoxy-8-thiomethyl- adenoxine (XI) can be similarly prepared from 8-thiomethyl- 2'-deoxyadenosine. Compound IX can be demethylated to give 2',3'-dideoxy-8-hydroxyadenosine (X).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH3:2].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCO.OS(O)(=O)=O>[Br:13][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:17])[N:14]=[CH:15]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1ccc(Br)cc1)NC=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc2ccc(Br)cc2cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.8 %

Procedure:
To a mixture of ethyl-3-(4-bromophenyl)-2-formamidopropanoate (23.5 g, 78 mmol) in DCM (200 mL) was added (CO)2Cl2 (8 ml, 84 mmol). The reaction mixture was stirred at r.t. for 30 mins. Then the reaction solution was cooled to 0° C. and FeCl3 (16 g, 98 mmol) was added into the solution, followed by stirring at r.t overnight. After the solution was extracted by CH2Cl2, the combined organic layers were concentrated in vacuo to afford a black oil. The oil was dissolved in the EtOH (100 ml), and concentrated H2SO4 was added into the solution and refluxed at 80° C. overnight. The solution was poured into saturated NaHCO3 and extracted by EA. After drying with anhydrous Na2SO4, the solution was concentrated in vacuo, and the residue was purified by silica gel chromatography (PE/EA=8:1 to 5:1) to afford ethyl 7-bromoisoquinoline-3-carboxylate as a yellow solid (5.2 g, yield: 23.8%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])=[N:6][N:5]2[CH:17]=1.[CH3:18][C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][N:20]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.O>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]2[N:5]([CH:17]=[C:2]([C:22]3[CH:21]=[N:20][C:19]([CH3:18])=[C:24]([N+:25]([O-:27])=[O:26])[CH:23]=3)[N:3]=2)[N:6]=1
Reactant: Fc1ccccc1-c1ccc2nc(Cl)cn2n1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1ncc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 11.4 %

Procedure:
To a mixture of 2-chloro-6-(2-fluorophenyl)imidazo[1,2-b]pyridazine (0.100 g, 0.403 mmol), 2-methyl-3-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.605 mmol), Na2CO3 (2.01 mmol) in 2-propanol (3.75 mL) and water (1.25 mL) that has been degassed with N2 (5 minutes) is added PdCl2(PPh3)2(0.0403) mmol). The mixture is heated at 80° C. for 12 hours, then cooled, concentrated under reduced pressure, added sat. aqueous NaHCO3 (20 mL) and extracted with EtOAc (3×20 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography (hexanes to EtOAc) to afford the title compound (0.016 g, 11%) as a white solid: Rf 0.38 (1:1 EtOAc:hexanes); LCMS (m/z)=350.3 [M+H]+, tR=2.71 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si](C(C)(C)C)(C)C)[CH:6]=[CH:5]2.C([Li])CCC.C(=O)=O.[CH2:28]([O:35][CH:36]1[CH2:41][CH2:40][C:39](=[O:42])[CH:38]([CH2:43][N:44]([CH3:46])[CH3:45])[CH2:37]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1.CCCCCC.O>[CH2:28]([O:35][CH:36]1[CH2:41][CH2:40][C:39]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]3)([OH:42])[CH:38]([CH2:43][N:44]([CH3:46])[CH3:45])[CH2:37]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(C)CC1CC(OCc2ccccc2)CCC1=O
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(Br)ccc2c1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CC1CC(OCc2ccccc2)CCC1(O)c1ccc2cc(O)ccc2c1
Temperature: 0 °C
Yield: 70.9 %

Procedure:
3.87 g (6-bromonaphthalen-2-yloxy)-tert.-butyldimethylsilane were dissolved in 19 ml THF p.a., 6.0 ml 1.6 M butyl lithium solution in hexane added dropwise with dry ice cooling, briefly stirred, then a solution of 2.00 g 4-benzyloxy-2-dimethylaminomethylcyclohexanone in 20 ml THF p.a. added dropwise and stirred for 1 hour while slowly heating. For working up, 4 ml water were added to the ice bath, the organic phase separated, the aqueous phase extracted twice with diethyl ether, the combined organic phases dried by sodium sulphate, filtered and concentrated. The crude product obtained (5.00 g) was chromatographed with ethyl acetate/methanol (V/V=1:1) on silica gel. 2.20 g 6-(4-benzyloxy-2-dimethylaminomethyl-1-hydroxy-cyclohexyl)-naphthalen-2-ol were obtained and converted into the corresponding hydrochloride (1.33 g) in the same way as in AAV 1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][N:9]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([Cl:23])[CH:14]=1)[CH2:10][CH:11]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:25][O:26][C:27](=[O:43])[C@@H:28]([NH2:42])[CH2:29][CH2:30][C:31]([N:33]1[CH2:40][CH2:39][C:36]2([CH2:38][CH2:37]2)[C@H:35]([OH:41])[CH2:34]1)=[O:32]>>[ClH:23].[CH3:25][O:26][C:27](=[O:43])[C@@H:28]([NH:42][CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:24])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:22])[F:21])=[C:15]([Cl:23])[CH:14]=1)[CH2:29][CH2:30][C:31]([N:33]1[CH2:40][CH2:39][C:36]2([CH2:37][CH2:38]2)[C@H:35]([OH:41])[CH2:34]1)=[O:32]
Reactant: CC(C)(C)OC(=O)CCN(CC=O)c1ccc(C(F)(F)F)c(Cl)c1
Reactant: COC(=O)[C@@H](N)CCC(=O)N1CCC2(CC2)[C@H](O)C1
Product: COC(=O)[C@H](CCC(=O)N1CCC2(CC2)[C@H](O)C1)NCCN(CCC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)c(Cl)c1
Product: Cl

Procedure:
In analogy to the procedure described for example 14C, 3-[(3-chloro-4-trifluoromethyl-phenyl)-(2-oxo-ethyl)-amino]-propionic acid tert-butyl ester and (S)-2-amino-5-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-5-oxo-pentanoic acid methyl ester; compound with HCl (intermediate 41) gave the title compound in 52% yield as light yellow foam. MS: 620.27 (MH+, Cl).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#N)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C1C[O:36]CC1>CCCCCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=[O:36])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(-c2cccc(OCc3ccccc3)c2)c1
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Product: O=Cc1cccc(-c2cccc(OCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a stirred solution of 75 (0.12 g, 0.42 mmol) in anhydrous THF (10 mL) at −78° C., under a nitrogen atmosphere was added diisobutylaluminum hydride (0.5 mL, 0-5 mmol, using a 1M solution in hexane) dropwise. The reaction mixture was stirred at the same temperature for 1 hour and then quenched by dropwise addition of potassium sodium tartrate (10% solution in water). The resulting mixture was warmed to room temperature, diluted with diethyl ether (20 mL) and stirred vigorously for 1 h. The organic phase was separated and the aqueous phase was extracted with diethyl ether. The combined organic layer was washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (20% diethyl ether-hexane) to give 76 (0.091 g, 75% yield) as a viscous liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:24]#[N:25])=[C:4]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)[CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:24]([C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[CH:6]=[N:7][C:2]([C:36]2[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=2)=[CH:3][C:4]=1[C:26]1[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=1)#[N:25]
Reactant: Cn1nccc1-c1cc(Cl)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(-c2ccc(F)cc2)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1C#N
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
10 mg (0.02 mmol) of 4-((6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)-3-cyano-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 4.4 mg (0.03 mmol) of (4-fluorophenyl)boronic acid was added thereto, and then 2.4 mg (10 mol %) of Pd(PPh3)4, 6.7 mg (0.6 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (45% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=1>CN(C=O)C>[F:36][C:35]([F:37])([F:38])[C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([C:39]([F:42])([F:40])[F:41])[CH:32]=1)[CH2:28][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[CH2:11][CH2:12][CH2:13][CH:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]1=[CH:5]2
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CC1CCCn2c1cc1cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1CCCn2c1cc1cc(OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)ccc12
Temperature: 75 °C
Yield: 83.4 %

Procedure:
To a mixture of ethyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (95 mg, 0.348 mmol) and cesium carbonate (170 mg, 0.521 mmol) in DMF (2 mL) was added 1-(bromomethyl)-3,5-bis(trifluoromethyl)benzene (128 mg, 0.417 mmol). The reaction mixture was heated at 75° C. for 15 h and cooled down. The solid was filtered and washed with ethyl acetate. The combined solvent was evaporated, and the residue was purified by silica gel column chromatography to give the title compound (145 mg). LCMS m/z=500.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.30 (t, J=7.1 Hz, 3H), 1.51-1.61 (m, 1H), 2.00-2.10 (m, 1H), 2.10-2.24 (m, 2H), 2.55 (dd, J=15.6, 8.6 Hz, 1H), 2.93 (dd, J=15.6, 5.4 Hz, 1H), 3.45-3.54 (m, 1H), 3.85-3.94 (m, 1H), 4.10-4.17 (m, 1H), 4.22 (q, J=7.1 Hz, 2H), 5.19 (s, 2H), 6.18 (s, 1H), 6.90 (dd, J=8.8, 2.4 Hz, 1H), 7.09 (d, J=2.4 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.83 (s, 1H), 7.94 (s, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[CH2:19]([C:21]1[N:25]=[C:24]([C:26](O)=[O:27])[O:23][N:22]=1)[CH3:20]>CC#N>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:26]([C:24]3[O:23][N:22]=[C:21]([CH2:19][CH3:20])[N:25]=3)=[O:27])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CCc1noc(C(=O)O)n1
Solvent: CC#N
Product: CCc1noc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)n1
Yield: 11.5 %

Procedure:
(S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (200 mg, 0.77 mmol) was coupled with 3-ethyl-1,2,4-oxadiazole-5-carboxylic acid (131 mg, 0.92 mmol) using the method of Example 34(d). Crude product was suspended in MeCN and the precipitation was filtered to yield 34 mg (11%) of the title compound. Filtrate was purified by CombiFlash (column: C-18, eluent: 0-100% MeCN) to yield additional 118 mg (40%) of title product. Combined total yield was 152 mg (51%). 1H-NMR (400 MHz; d6-DMSO): δ 1.18 (d, 3H), 1.26 (t, 3H), 2.81 (q, 2H), 4.31-4.37 (m, 2H), 4.40-4.52 (m, 1H), 6.95 (d, 1H), 7.85 (d, 1H), 7.92 (dd, 1H), 7.97 (d, 1H), 8.06 (d, 1H), 9.39 (broad d, 1H).