Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1(=[O:11])[O:10][C:8](=[O:9])[CH2:7][CH2:6]1.Cl.[Br:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:5](=[O:11])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:16][CH:15]=1
Reactant: Brc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCC(=O)c1ccc(Br)cc1
Temperature: -10 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
AlCl3 (26.7 g, 0.200 mol) was added in one portion to a stirred mixture of succinic anhydride (10.0 g, 0.100 mol) in bromobenzene (97.0 g) at −10° C. under N2 atmosphere. The reaction temperature was maintained at −10° C. for 1Hour and was then allowed to warm to room temperature. The mixture was stirred at room temperature overnight and poured into ice water. HCl (1M) was added slowly until pH 5. The mixture was extracted with ethyl acetate (150 mL×2). The combined organics were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was washed with ether to afford 4-(4-bromophenyl)-4-oxobutanoic acid (16.0 g, 62%) as a white solid. 1H NMR (300 MHz, DMSO) δ 12.15 (br s, 1H), 7.90 (d, J=8.7, 2H), 7.73 (d, J=8.7, 2H), 3.22 (t, J=6.0, 2H), 2.55 (t, J=6.0, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([S:13][CH3:14])[N:5]=[C:4]([CH3:15])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]([C:24]1[CH:37]=[CH:36][CH:35]=[CH:34][C:25]=1[O:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1)#[N:23].O>CN(C=O)C.[Cu](I)I>[CH3:15][C:4]1[N:5]=[C:6]([S:13][CH3:14])[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:2]([O:33][C:29]2[CH:30]=[CH:31][CH:32]=[C:27]([O:26][C:25]3[CH:34]=[CH:35][CH:36]=[CH:37][C:24]=3[C:22]#[N:23])[CH:28]=2)[N:3]=1
Reactant: N#Cc1ccccc1Oc1cccc(O)c1
Reactant: COC(=O)Cc1c(Cl)nc(C)nc1SC
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(Oc2cccc(Oc3ccccc3C#N)c2)nc(C)nc1SC

Procedure:
A solution of methyl 2-(4-chloro-2-methyl-6-methylthio-pyrimidin-5-yl)-acetate (5.5 g) in DMF (80 ml) is added to a suspension of anhydrous potassium carbonate (5.6 g) and 3-(2-cyanophenoxy)phenol (5.1 g) and copper iodide (1 g) in DMF at room temperature. The mixture was heated to +120° C. for 2 hours and then cooled. The mixture is poured into water and extracted successively with ethyl acetate (2×50 ml) and the organic phase dried over anhydrous sodium sulfate. Evaporation and drying under high vacuum gives the methyl 2-[2-methyl-4-methylthio-6-(3-(2-cyanophenoxy)-phenoxy)-pyrimidin-5-yl]-acetate, as a crude product in form of a yellow oil. NMR (CDCl3): 6.18-6.84 (m, 3H); 3.74 (s, 2H); 3.69 (s, 3H); 2.85 (m, 1H); 2.51 (s, 3H); 2.45 (s, 3H); 2.34 (s, 3H); 1.22 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]([F:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:14]1(C(N2C=CN=C2)N)C=CN=[CH:15]1>C1COCC1>[NH2:14][C:15]1[O:12][C:11]2[C:2](=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:8]([F:13])=[CH:9][CH:10]=2)[N:1]=1
Reactant: NC(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1c(F)ccc(O)c1N
Solvent: C1CCOC1
Product: COC(=O)c1c(F)ccc2oc(N)nc12
Temperature: 25 °C

Procedure:
To a solution of methyl 2-amino-6-fluoro-3-hydroxybenzoate (0.4 g, 2.2 mmol) in THF (10 mL) was added di-(1H-imidazole-1-yl)methanamine (0.44 g, 2.75 mmol) at room temperature and the resulting reaction mixture was heated at reflux for 16 h. The reaction mixture cooled to room temperature and was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 mL), and the solution was treated with saturated aqueous ammonium chloride (25 mL). The organic layer was separated and the aqueous layer was extracted with additional CH2Cl2 (2×100 mL). The combined organic phase was washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford a yellow solid. The solid was triturated from ether to afford methyl 2-amino-5-fluorobenzoxazole-4-carboxylate. MS consistent.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][OH:7])#[N:2].[H-].[Na+].[F:10][C:11]([F:27])([F:26])[CH2:12][N:13]=[C:14]([NH2:25])[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18](S(C)=O)[N:17]=1>C(O)(C)(C)C>[F:27][C:11]([F:10])([F:26])[CH2:12][N:13]=[C:14]([NH2:25])[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[N:17]=1
Reactant: CS(=O)c1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: N#CCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: N#CCCCCOc1nccc(NC(N)=NCC(F)(F)F)n1
Reaction time: 2 h

Procedure:
4-Cyanobutanol (10 g.) was added to sodium hydride (2.75 g.) in t-butanol (95 ml.) and the solution warmed to 40°. 4-[2-(2,2,2-Trifluoroethyl)guanidino]-2-methylsulphinylpyrimidine (European patent publication No. 30092) was added over 10 minutes and the solution kept at 40° for 2 hours then at room temperature for 18 hours. The solvent was removed under vacuum and the residue washed with water, then ether, to give 5-[4-(2-[2,2,2-trifluoroethyl]guanidino)pyrimid-2-yloxy]valeronitrile (8.5 g.), m.p. 134°-136°.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][C:5]=12.S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[ClH:14].[Cl:14][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[N:4]([CH:3]=[CH:2][N:1]=2)[CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2nccn2c1
Solvent: ClC(Cl)Cl
Product: Cl
Product: ClCc1ccc2nccn2c1
Reaction time: 1 h

Procedure:
11.23 g of the (imidazo[1,2-a]pyridin-6-yl)methanol prepared in the Preparative Example 6 was dissolved in 170 ml of chloroform, followed by the dropwise addition of 11.1 ml of thionyl chloride at room temperature under stirring. After one hour, the solvent was distilled off. Thus, crude 6-chloromethylimidazo[1,2-a]pyridine hydrochloride was obtained as a light-brown powder.
Reaction SMILES: [C:1]1([C:7]2[NH:17][C:10]3=[N:11][CH:12]=[C:13]([C:15]#[N:16])[CH:14]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]=O.[NH:20]1[CH2:25][CH2:24][CH:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH2:21]1.Cl>C(O)(=O)C>[NH2:26][CH:23]1[CH2:22][CH2:21][N:20]([CH2:18][C:8]2[C:9]3[C:10](=[N:11][CH:12]=[C:13]([C:15]#[N:16])[CH:14]=3)[NH:17][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: N#Cc1cnc2[nH]c(-c3ccccc3)cc2c1
Reactant: C=O
Agent: Cl
Solvent: CC(=O)O
Product: N#Cc1cnc2[nH]c(-c3ccccc3)c(CN3CCC(N)CC3)c2c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of the compound prepared in Example 9 (22 mg, 0.1 mmol) in acetic acid (1 mL) were added formalin (0.1 mL) and tert-butyl piperidin-4-ylcarbamate (30 mg, 0.5 mmol). The reaction mixture was stirred at 80° C. for 1 h. The LC/MS showed a peak of m/e=462. Aqueous HCl (3N, 1 mL) was added and the resulting mixture was heated to 100° C. for 4 h. The LC/LC/MS; (M+H)+=analysis indicated the formation of the desired product. The mixture was cooled, concentrated and the residue was purified by preparative RP HPLC eluting with a mixture of methanol in water containing 0.1% TFA. The fractions containing the desired product were collected, concentrated and converted to HCl salt to afford the title compound (40 mg) as a solid. LC/MS; (M+H)+=332.
Reaction SMILES: [OH-].[OH:2][C:3]1[N+:7]2[CH2:8][CH2:9][C:10]3[C:15]([C:6]=2[S:5][C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:14][CH:13]=[CH:12][CH:11]=3.[C:22](#[N:25])[CH:23]=[CH2:24]>C1(C)C=CC=CC=1>[O:2]=[C:3]1[C:4]2([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:5][C:6]3([CH:23]([C:22]#[N:25])[CH2:24]2)[N:7]1[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=13
Reactant: C=CC#N
Reactant: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccccc1-2
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#CC1CC2(c3ccccc3)SC13c1ccccc1CCN3C2=O

Procedure:
4.08 g of 5,6-dihydro-3-hydroxy-2-phenylthiazolo[2,3-a]isoquinolinium hydroxide (internal salt) and 1.95 ml of acrylonitrile were heated together under reflux overnight in 250 ml of toluene. After evaporation of the solvent in vacuo, the residue was recrystallized from acetonitrile. There was obtained 1,2,3,4,6,7-hexahydro-4-oxo-3-phenyl-3,11b-epithio-11bH-benzo[a]quinolizine-1-carbonitrile of m.p. 225°-226°.
Reaction SMILES: Cl[C:2]([O:5][C:6](Cl)=[O:7])(Cl)Cl.[F:9][C:10]1C=[CH:14][CH:13]=[CH:12][C:11]=1O.N1C2C(=CC=CC=2)C=CC=1.[F:27][C:28]1[CH:61]=[C:60]([F:62])[C:59]([F:63])=[CH:58][C:29]=1[CH2:30][O:31][CH2:32][C@@H:33]1[CH2:37][C@@H:36]([S:38][C:39]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:35][NH:34]1.N1C=CC=CC=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[O:5][C:6]([N:34]1[CH2:35][C@H:36]([S:38][C:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:37][C@H:33]1[CH2:32][O:31][CH2:30][C:29]1[CH:58]=[C:59]([F:63])[C:60]([F:62])=[CH:61][C:28]=1[F:27])=[O:7]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Oc1ccccc1F
Reactant: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: c1ccc2ncccc2c1
Solvent: ClCCl
Product: O=C(Oc1ccccc1F)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
A solution of 0.19 ml (1.58 mmol) trichloromethyl-chloroformate in 20 ml CH2Cl2 was treated at 0° C. with 0.28 ml (3 mmol) 2-fluorophenol and 0.35 ml (3 mmol) quinoline and then stirred for 3 h at room temperature. The reaction was then cooled (0° C.) and a solution of 0.52 g (1 mmol) (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine and 0.2 ml (2.5 mmol) pyridine in 3 ml CH2Cl2 was added, followed by 122 mg (1 mmol) DMAP. After 3 h at 0° C. the reaction was evaporated and poured into aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous 10% NaCl solution, dried over Na2SO4 and evaporated. Flash chromatography on silica gel (hexane/EtOAc 9:1) gave 0.39 g (60%) (2S,4R)-2-(2,4,5-trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid 2-fluoro-phenyl ester, MS: 658 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH3:24])(=[O:17])[CH2:13][C:14]([CH3:16])=O.[NH2:25][C:26]([CH3:31])=[CH:27][N+:28]([O-:30])=[O:29]>C(O)C>[CH3:31][C:26]1[NH:25][C:14]([CH3:16])=[C:13]([C:12]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][CH3:24])=[O:17])[CH:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:27]=1[N+:28]([O-:30])=[O:29]
Reactant: CCCOCCOC(=O)CC(C)=O
Reactant: CC(N)=C[N+](=O)[O-]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: CCCOCCOC(=O)C1=C(C)NC(C)=C([N+](=O)[O-])C1c1cccc([N+](=O)[O-])c1

Procedure:
15.1 g (0.1 mol) of 3-nitrobenzaldehyde, together with 18.8 g (0.1 mol) of β-n-propoxyethyl acetoacetate and 10.2 g (0.1 mol) of 2-amino-1-nitro-prop-1-ene in 150 ml of ethanol, were heated uder reflux for 6 hours. After cooling, the solvent was distilled off in vacuo, and the oily residue was taken up in a small amount of chloroform and was chromatographed on a silica gel column, using chloroform with the addition of methanol. The fractions containing the product were concentrated, the residue was taken up in a small amount of isopropanol, and the nitrodihydropyridine crystallized in yellow crystals of melting point 161° C.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23](=[O:26])([O-])[O-:24].[K+].[K+].O.ClCCl.CO.[C:35](#[N:37])[CH3:36]>>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:11][CH:10]([N:37]3[CH2:11][CH2:10][CH2:9][N:8]([C:23]([O:24][C:1]([CH3:7])([CH3:6])[CH3:2])=[O:26])[CH2:36][CH2:35]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 25 °C

Procedure:
To a solution of 1-diphenylmethyl-3-methanesulphonyloxyazetidine (WO 96/05193) (25 g) in acetonitrile (800 mL) were added the compound of PREPARATION 24 (19 g) and potassium carbonate (33 g). The reaction mixture was heated to reflux for 12 h, then cooled to room temperature. Water was added to the resulting slurry, and the mixture extracted three times with ethyl acetate. The combined organics were washed with brine, dried over magnesium sulphate, filtered and dried in vacuo to yield crude product. Chromatography on silica gel eluting with dichloromethane:methanol (95:5) yielded the title compound (24.7 g).
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[S:7][CH:8]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]=1[O:11][C:12]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])(=[O:5])[CH3:4]>C(O)(=O)C>[Br:1][CH2:4][C:3]([C:6]1[S:7][CH:8]=[C:9]([C:20]([O:22][CH3:23])=[O:21])[C:10]=1[O:11][C:12]([CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13])=[O:5]
Reactant: COC(=O)c1csc(C(C)=O)c1OC(=O)C1CCCCC1
Reactant: BrBr
Solvent: CC(=O)O
Product: COC(=O)c1csc(C(=O)CBr)c1OC(=O)C1CCCCC1
Temperature: 0 °C
Yield: 29 %

Procedure:
A solution of 0.70 mL of bromine in 3.45 mL of acetic acid was added dropwise over a period of 60 minutes to a solution of 3.56 g of Compound 3A in 34.5 mL of acetic acid at 20-25° C. while stirring. After stirring further for 2.5 hours at 20-25° C., the mixture was poured into ice water and extracted with diethyl ether (2×80 mL). The combined organic layers were washed with water (2×80 mL), 10% aqueous sodium carbonate (100 mL) and water (3×80 mL), dried over sodium sulphate and evaporated to dryness in vacuo. The crude product was purified by flash chromatography in n-hexane/chloroform (6:4) to yield 1.31 g (29%) of Compound 3B.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH:20]([CH3:22])[CH3:21])[C:16](=[O:19])[NH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[CH3:25][C:26]([OH:43])([CH3:42])[CH2:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1>>[OH:43][C:26]([CH3:42])([CH3:25])[CH2:27][N:28]1[CH:32]=[C:31]([C:2]2[CH:24]=[CH:23][C:5]3[C:6]4[N:7]=[C:8]([C:14]5[N:15]([CH:20]([CH3:22])[CH3:21])[C:16](=[O:19])[NH:17][N:18]=5)[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:30]=[N:29]1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)n1c(-c2nc3c(s2)CCOc2cc(Br)ccc2-3)n[nH]c1=O
Product: CC(C)n1c(-c2nc3c(s2)CCOc2cc(-c4cnn(CC(C)(C)O)c4)ccc2-3)n[nH]c1=O

Procedure:
Similarly to as described in General Procedure C, 5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-4-isopropyl-2,4-dihydro-[1,2,4]triazol-3-one was reacted with 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol. Purification of the crude reaction mixture by reverse phase HPLC gave 447. LCMS: 467.1. 1H NMR (400 MHz, DMSO) δ 12.21 (s, 1H), 8.25 (d, J=8.3 Hz, 1H), 8.15 (s, 1H), 7.94 (s, 1H), 7.43 (dd, J=8.3, 1.8 Hz, 1H), 7.29 (d, J=1.8 Hz, 1H), 5.35-5.18 (m, 1H), 4.71 (s, 1H), 4.37 (t, J=5.0 Hz, 2H), 4.03 (s, 2H), 3.39 (dd, J=17.6, 12.4 Hz, 2H), 1.56 (d, J=6.9 Hz, 6H), 1.09 (s, 6H)
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:6][CH2:7][NH2:8].C([O:15][CH:16]([O:29]CC)[CH2:17][NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])C>C(O)CCC.O>[C:16]([OH:29])(=[O:15])[CH3:17].[CH2:22]([O:21][C:19]([NH:18][CH2:17][CH:16]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[C:11]([OH:12])[CH:10]=2)[CH2:6][CH2:7][NH:8]1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(CNC(=O)OCc1ccccc1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: CC(=O)O
Product: O=C(NCC1NCCc2cc(O)c(O)cc21)OCc1ccccc1
Yield: 41.3 %

Procedure:
A solution of 3,4-dihydroxyphenethylamine hydrochloride (2.17 g) and N-benzyloxycarbonylaminoacetaldehyde diethyl acetal (4.0 g) in a mixture of n-butyl alcohol (20 ml) and water (3.5 ml) was refluxed for 4.5 hours. After the reaction, the solvent was distilled off under reduced pressure. To the residue were added water (15 ml) and sodium acetate. A precipitating oil was separated from the aqueous layer and chloroform was added thereto. The mixture was allowed to stand to give crystals. The crystals were collected by filtration, washed with chloroform and recrystallized twice from a mixture of methanol and ether to give 1(N-benzyloxycarbonylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline acetate (1.2 g), mp 158° to 162° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9]C(O)=O)=O)=[CH:4][CH:3]=1.[OH-:15].[K+].NN.Cl.[CH2:20]([OH:23])CO>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([CH2:8][CH3:9])[C:20]([OH:23])=[O:15])=[CH:13][CH:14]=1
Reactant: OCCO
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: [OH-]
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: O
Product: CCC(C(=O)O)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
A 5-liter, 3-neck flask is charged with 400 g (1.9 moles) of (I), 350 g potassium hydroxide, 2.47 liters of ethylene glycol and 155 g of 95% hydrazine diluted to 250 ml with water. The mixture is refluxed for 1.5 hours, after which the water is drained from the condenser and the internal temperature of the reaction mixture is allowed to rise to 190°. Refluxing is then continued for another 4 hours. The cooled solution is diluted with 2.5 liters of water and poured slowly into 2.0 liters of 6N hydrochloric acid. The precipitate is filtered and air-dried. Yield: 332.5 g, 88.1%, mp 54°-57°.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH:20]1([C:23]([NH2:31])([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)[CH3:24])[CH2:22][CH2:21]1>>[CH:20]1([C:23]([NH:31][C:10]([C:7]2[CH:6]=[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])([C:25]2[N:29]=[C:28]([CH3:30])[O:27][N:26]=2)[CH3:24])[CH2:22][CH2:21]1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Product: Cc1nc(C(C)(NC(=O)c2cc(O[C@@H](C)C(F)(F)F)c(C3CC3)cn2)C2CC2)no1

Procedure:
The mixture of epimers was synthesized in analogy to Example 63b, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) and 1-Cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (CAN 1155536-64-3) as starting materials and isolated (135 mg, 58%) as a light yellow oil. The mixture of epimers was separated into its epimers by preparative chiral HPLC (Chiralpak AD, ethanol/heptane) and the title compound was the first epimer collected and isolated as colorless oil; MS (ESI, m/z): 425.5 (M+H+).
Reaction SMILES: [CH:1]([N:4]([CH:28]([CH3:30])[CH3:29])[C:5](=[O:27])[O:6][C:7]1[C:15]2[C:14]3[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=3[CH2:12][CH2:11][C:10]=2[N:9]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:8]=1)([CH3:3])[CH3:2].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl.Cl.C(O)(C)C>[ClH:20].[CH:28]([N:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:27])[O:6][C:7]1[C:15]2[C:14]3[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:13]=3[CH:12]=[CH:11][C:10]=2[N:9]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:8]=1)([CH3:30])[CH3:29]
Reactant: CC(C)N(C(=O)Oc1nn(-c2ccncc2)c2c1-c1ccc(Cl)cc1CC2)C(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)O
Product: CC(C)N(C(=O)Oc1nn(-c2ccncc2)c2ccc3cc(Cl)ccc3c12)C(C)C
Yield: 153.8 %

Procedure:
1.65 g (3.38 mmol) of 7-chloro-4,5-dihydro-3-(pyrid-4-yl)-3H-benzo[e]indazol-1-yl N,N-diisopropylcarbamate, prepared according to the method described in Example 5, 1.105 g (6.21 mmol) of N-bromosuccinimide and 0.127 g (0.78 mmol) of 2,2′-azobis(2-methylpropionitrile) are added to a 100 ml reactor. The mixture, dissolved in 40 ml of carbon tetrachloride, is stirred at reflux for 24 h and is then concentrated under reduced pressure. The resulting product is taken up in 300 ml of dichloromethane and 2 ml of a concentrated aqueous ammonia solution. The organic phase is separated and washed with 200 ml of water and then with 200 ml of a saturated aqueous sodium chloride solution. The organic phase is subsequently dried over magnesium sulphate and then concentrated under reduced pressure. The resulting product is purified by chromatography on an alumina column (eluents: mixture of dichloromethane and of methanol) and then on a silica column (eluents: mixture of dichloromethane and of ethyl acetate). The product thus isolated is converted to the hydrochloride by dissolution in a 0.1 N solution of hydrochloric acid in isopropanol. The solution is concentrated to dryness under reduced pressure. After triturating from ethyl ether, filtering off and drying under reduced pressure, 1.2 g (2.6 mmol) of the final product are obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[C:7]([CH2:9]O)[CH:6]=[CH:5][CH:4]=1.S(Cl)([Cl:15])=O>C(Cl)Cl>[Cl:15][CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:12])([F:11])[F:1])[N:8]=1
Reactant: OCc1cccc(C(F)(F)F)n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: FC(F)(F)c1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(6-Trifluoromethylpyridin-2-yl)methanol (760 mg, 4.3 mmol) was dissolved in CH2Cl2 and thionyl chloride was added slowly at room temperature. The reaction mixture was stirred at room temperature for 4 h. Solvent was removed under the reduced pressure, the pH was adjusted to 5, and the product was extracted with EtOAc. Purification by flash column (5% EtOAc-Hexane) gave 2-chloromethyl-6-trifluoromethylpyridine (200 mg) as a white solid.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:23][C:24]1[C:25]([O:34][CH3:35])=[N:26][O:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN1CCCC1=O>[C:1]([NH:4][C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH2:23][C:24]1[C:25]([O:34][CH3:35])=[N:26][O:27][C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CCOC(=O)c1onc(OC)c1CBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1onc(OC)c1CC(NC(C)=O)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A mixture of diethyl acetamidomalonate (1.6 g, 7.4 mmol) and potassium tert-butoxide (0.9 g, 8.0 mmol) in N-methylpyrrolidone (30 mL) was stirred at room temperature for 30 min. Ethyl 4-(bromomethyl)-3-methoxyisoxazole-5-carboxylate (1.8 g, 6.8 mmol) in N-methylpyrrolidone (10 mL) was added (temp 22-28° C.) and the resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was poured onto an ice/water mixture (100 mL) and the aqueous phase was extracted with EtOAc (3×150 mL). The organic extracts were washed with an aqueous solution of potassium tert-butoxide, water (100 mL) and brine (100 mL), dried (MgSO4) and concentrated in vacuo. Flash chromatography (silica gel, eluent: EtOAc/heptane=1:1) afforded crude title compound (1.8 g, 66%). A small sample was recrystallized (EtOAc/heptane) to give colourless crystals: mp 78-80° C. The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:23]([O:25]CC)=O)=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN[CH2:30][CH2:31]NC.C([Al](CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:23](=[O:25])[CH2:30][CH3:31])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(-c2ccc(C(F)(F)F)cc2)n1
Reactant: CNCCNC
Agent: CC[Al](CC)CC
Solvent: Cc1ccccc1
Product: CCC(=O)c1ccc(-c2ccccc2)c(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
Following General Procedure O, 5-phenyl-6-(4-trifluoromethyl-phenyl)-pyridine-2-carboxylic acid ethyl ester (Compound 29, 292 mg, 0.71 mmol) in toluene (5 ml), N,N′-dimethylethylenediamine (DMEDA, 76 mg, 0.86 mmol) and triethylaluminum (2.4 ml, 0.35 mmol, 1 M in hexane) were reacted to produce the title compound as a oil.