Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8](O)=[O:9])([O-:3])=[O:2].S(Cl)([Cl:30])=O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=2[Cl:27])=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8]([Cl:30])=[O:9])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)O
Solvent: Cc1ccccc1
Product: CC(Oc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-])C(=O)Cl
Temperature: 67 °C

Procedure:
2-[2-Nitro-5-(2-Chloro-4-trifluoromethylphenoxy)phenoxy]propionic acid (100 grams) and toluene (40 ml) were charged into a glass reaction vessel equipped with a magnetic stirrer. The mixture was heated on a steam bath until a solution was obtained. The solution was allowed to cool and thionyl chloride (100 ml) was added dropwise with stirring. After the addition was completed the mixture was warmed to 67° C. with continued stirring for a period of about 21/2 hours. After this time the mixture was stripped of solvent in a rotary evaporator under reduced pressure leaving as the residue 105 grams of the desired product, 2-[2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxy]propionyl chloride as a burgundy colored viscous oil.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:21][C@@H:22]1[C:28](=[O:29])[N:27]([CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])[C:26]2[CH:38]=[CH:39][CH:40]=[CH:41][C:25]=2[O:24][CH2:23]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])=O)(C)(C)C.C(OCC)(=O)C.[ClH:48]>>[ClH:48].[ClH:48].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:21][C@@H:22]1[C:28](=[O:29])[N:27]([CH2:30][C:31]([OH:33])=[O:32])[C:26]2[CH:38]=[CH:39][CH:40]=[CH:41][C:25]=2[O:24][CH2:23]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)[C@H](CCCCCCNC(=O)OC(C)(C)C)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCCN)N[C@H]1COc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3 h

Procedure:
In 10 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 1.1 g of tert-butyl 3(S)-[7-tert-butoxycarbonylamino-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained in Example 67 and the solution is allowed to stand at room temperature for 3 hours. Petroleum ether (100 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.9 g of 3(S)-[7-amino-1(S)-ethoxycarbonylheptyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetic acid dihydrochloride as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][C:12]([C:13](O)=[O:14])=[C:11]([CH2:20][C:21]#[N:22])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:16][C:17]=1[O:18][CH3:19])[C:13](=[O:14])[NH:22][C:21]([NH:23][C:24]1[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=1)=[CH:20]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: COc1cc(C(=O)O)c(CC#N)cc1OCc1ccccc1
Product: COc1cc2c(=O)[nH]c(Nc3cc(C)[nH]n3)cc2cc1OCc1ccccc1

Procedure:
Similar procedure as described in example 2c was used, starting from 4-Benzyloxy-2-cyanomethyl-5-methoxy-benzoic acid and 3-amino-5-methyl-1H-pyrazole to give 6-Benzyloxy-7-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-2H-isoquinolin-1-one. LC-MS: m/e 377 (MH+).
Reaction SMILES: [I-].CS[C:4]1[S:5][CH2:6][C@@H:7]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N+:8]=12.[NH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH:20]=[C:21]([CH3:28])[N:22]=[CH:23]2>N1C=CC=CC=1>[CH3:28][C:21]1[N:22]=[CH:23][C:24]2[C:19]([CH:20]=1)=[C:18]([N:17]=[C:4]1[N:8]3[CH2:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[CH2:16][C@H:7]3[CH2:6][S:5]1)[CH:27]=[CH:26][CH:25]=2
Reactant: Cc1cc2c(N)cccc2cn1
Reactant: CSC1=[N+]2Cc3ccccc3C[C@H]2CS1
Agent: [I-]
Solvent: c1ccncc1
Product: Cc1cc2c(N=C3SC[C@@H]4Cc5ccccc5CN34)cccc2cn1
Reaction time: 24 h
Yield: 84.6 %

Procedure:
(S)-3-Methylthio-1,5,10,10a-tetrahydrothiazolo-[3,4-b]isoquinolinium iodide (36.3 g) is added to a solution of 5-amino-3-methylisoquinoline (15.9 g) in pyridine (200 cc). The suspension obtained gradually goes into solution. After 24 hours at a temperature of about 20° C., the mixture is concentrated to dryness under reduced pressure (25 mm Hg) at 50° C. The residue is dissolved in a mixture of methylene chloride (600 cc) and N aqueous sodium hydroxide solution (400 cc). The organic phase is decanted, washed with water (200 cc), dried over magnesium sulphate, filtered and the filtrate is then concentrated to dryness under reduced pressure (40 mm Hg) at 40° C. The residue obtained is recrystallised from acetonitrile (500 cc). (S)-3-[(3-Methylisoquinol-5-yl)imino]-1,5,10,10a-tetrahydrothiazolo-[3,4-b]isoquinoline (29.2 g), which melts at 181° C., is thus obtained.
Reaction SMILES: C(N1[C:9]2=[N:10][CH:11]=[C:12]([N+]([O-])=O)[CH:13]=[C:8]2[C:7]([C:17](O)=O)=C1)(C)(C)C.CC(C)[N:22]=C=NC(C)C.CCN(C(C)C)C(C)C.N1C2C(=CC=CN=2)C=C1>C(Cl)Cl.CN(C=O)C>[NH:22]1[C:7]2[C:8](=[CH:13][CH:12]=[CH:11][CH:17]=2)[CH:9]=[N:10]1
Reactant: CC(C)(C)n1cc(C(=O)O)c2cc([N+](=O)[O-])cnc21
Reactant: CC(C)N=C=NC(C)C
Agent: c1cnc2[nH]ccc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To the AMEBA II resin (0.1 g, 1 mmol/g, 0.1 mmol) in DCM/DMF (1:1, 2 ml), 1-tert-butyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (3 eq), DIC (1.5 eq) DMAP (0.5 eq) and DIPEA (1 eq) were added. The reaction mixture was shaken at room temperature for 20 hours and then the resin was isolated by filtration. The resin was washed sequentially with DMF (2 ml), DCM (2 ml), DMF (2 ml), DCM (2 ml), MeOH (2 ml), DCM (2 ml), MeOH (2 ml), DCM (2 ml), MeOH (2 ml), DCM (2 ml) and dried in vacuo to give the resin bound 7-azaindole.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[NH2:13][CH:14]([CH3:17])[CH2:15][OH:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:13]([CH:14]([CH3:17])[CH2:15][OH:16])[CH2:11]2
Reactant: CC(N)CO
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Product: CC(CO)N1Cc2cc(Br)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from 4-bromo-2-(bromomethyl)benzoate and 2-aminopropanol (Aldrich Cat No. 192171). LCMS (M+H)+=270.1.
Reaction SMILES: CC([O-])(C)C.[K+].[CH2:7]1[O:15][C:14]2[CH:13]=[CH:12][C:11]([OH:16])=[CH:10][C:9]=2[O:8]1.[K].C(S([C:23]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH3:33])(=[O:31])=[O:30])=[CH:25][N:24]=1)(=O)=O)C>CS(C)=O.C1COCC1>[CH2:32]([S:29]([C:26]1[CH:27]=[CH:28][C:23]([O:16][C:11]2[CH:12]=[CH:13][C:14]3[O:15][CH2:7][O:8][C:9]=3[CH:10]=2)=[N:24][CH:25]=1)(=[O:30])=[O:31])[CH3:33]
Reactant: CCS(=O)(=O)c1ccc(S(=O)(=O)CC)nc1
Reactant: Oc1ccc2c(c1)OCO2
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [K]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Oc2ccc3c(c2)OCO3)nc1
Temperature: 0 °C
Yield: 80.8 %

Procedure:
Into a reaction flask was weighed 5.6 g of t-BuOK and then 50 ml of THF was added. In 50 ml of DMSO was dissolved 6.2 g of 3,4-methylenedioxyphenol which was then slowly added to the t-BuOK solution with stirring. To the resulting potassium phenate solution was added 10.5 g of 2,5-bis(ethylsulfonyl)pyridine and this mixture heated at 50°-55° C. for 3 hrs. After cooling, the reaction mixture was poured into 400 g of ice, stirred and then filtered. The solid which was recovered was dissolved in CH2Cl2, treated with charcoal, dried over MgSO4 and then filtered. The CH2Cl2 solution was concentrated to 50 ml, diluted with an equal volume of hexane and then chilled and a crystalline material recovered, which provided 9.9 g, (80% yield), of 5-(ethylsulfonyl)-2-(3,4-methylenedioxyphenoxy)pyridine, m.p. 97°-99° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31](=[O:35])[CH2:32][C:33]#[N:34])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH3:36][C:37]([N:41]1[CH2:46][CH2:45][N:44]([CH:47]2[CH2:50][O:49][CH2:48]2)[CH2:43][CH2:42]1)([CH3:40])[CH:38]=O.N1CCCC1.[Si](Cl)(C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([C:32](=[CH:38][C:37]([CH3:40])([N:41]4[CH2:46][CH2:45][N:44]([CH:47]5[CH2:50][O:49][CH2:48]5)[CH2:43][CH2:42]4)[CH3:36])[C:33]#[N:34])=[O:35])[CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Reactant: CC(C)(C=O)N1CCN(C2COC2)CC1
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1)N1CCN(C2COC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
To a cooled (0° C.) solution of 3-[(3R)-3-[4-amino-3-(2-fluoro-4-phenoxy-phenyl)-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidyl]-3-oxo-propanenitrile (80 mg, 0.17 mmol), was added 2-methyl-2-[4-(oxetan-3-yl)piperazin-1-yl]propanal (˜108 mg, 0.51 mmol) in DCM (10 mL) followed by pyrrolidine (0.08 mL, 1.02 mmol) and TMS-Cl (0.09 mL, 0.68 mmol.) The ice bath was removed, and the reaction stirred 1 hour. Most of the solvent was removed and the residues were purified by chromatography, using 95:5 CH2Cl2:MeOH to obtain 79 mg of (R)-2-(3-(4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]-pyrimidin-1-yl)piperidine-1-carbonyl)-4-methyl-4-(4-(oxetan-3-yl)piperazin-1-yl)pent-2-enenitrile as a white solid. MS (pos. ion) m/z: 666 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH3:2].[C:10]([O:17][CH2:18][CH3:19])(=[O:16])[C:11]([O:13]CC)=O.CC[O-].[Na+]>CCO>[CH2:18]([O:17][C:10](=[O:16])[C:11](=[O:13])[CH:5]([CH2:6][CH2:7][CH3:8])[C:4]([O:3][CH2:1][CH3:2])=[O:9])[CH3:19]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCCCC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCC(C(=O)OCC)C(=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At room temperature, a mixture of pentanoic acid ethyl ester (0.4 mol) and diethyl oxalate (compound 11 in Scheme 1) (73.1 g, 0.5 mol) is added to a solution of NaOEt (32.7 g, 0.48 mol) in EtOH (250 ml). The mixture is stirred at room temperature for 30 minutes and EtOH is distilled away. The residue is then purified by vacuum distillation, which provides the product (120) as a clear oil.
Reaction SMILES: O[C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(N(S(F)(F)[F:22])CC)C.[OH-].[Na+]>ClCCl.O>[F:22][C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: N#Cc1ccc(C2(O)CCOCC2)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(C2(F)CCOCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(4-hydroxytetrahydro-2H-pyran-4-yl)benzonitrile (Step 1 of Intermediate 1,300 mg, 1.48 mmol) in dichloromethane (28 mL) was added dropwise N-ethyl-N-(trifluoro-λ4-sulfanyl)ethanamine (586 mg, 1.77 mmol, dissolved in 2 mL dichloromethane) at a temperature of −78° C. After 30 minutes at this temperature, the reaction mixture was rapidly warmed to −20° C. by the aid of a water/ice bath for no longer than 30 seconds whereupon NaOH (1N aq., 10 mL) was added and the reaction mixture was allowed to warm to rt. The mixture was diluted with water (100 mL) and extracted with diethyl ether. The organic extract was dried with anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude product was purified by MPLC (silica, cyclohexane/ethyl acetate 20:1→4:1) to afford the title compound in pure form (267 mg, 88%): 1H NMR (400 MHz, CDCl3) δ 7.68 (d, 2H), 7.50 (d, 2H), 3.98-3.83 (m, 4H), 2.23-2.05 (m, 2H), 1.91-1.85 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:27])[C:9]=1[C:10]1[S:11][C:12]2[C:13]([NH:19][C:20]3[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=3)=[N:14][CH:15]=[CH:16][C:17]=2[N:18]=1)[C:5]#[N:6].[CH2:28]([CH2:30][NH2:31])[OH:29]>CN1C(=O)CCC1>[Cl:27][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[C:9]=1[C:10]1[S:11][C:12]2[C:13]([NH:19][C:20]3[CH:25]=[C:24]([NH:31][CH2:30][CH2:28][OH:29])[N:23]=[CH:22][N:21]=3)=[N:14][CH:15]=[CH:16][C:17]=2[N:18]=1)[C:5]#[N:6]
Reactant: N#Cc1cc(Cl)c(-c2nc3ccnc(Nc4cc(Cl)ncn4)c3s2)c(Cl)c1
Reactant: NCCO
Solvent: CN1CCCC1=O
Product: N#Cc1cc(Cl)c(-c2nc3ccnc(Nc4cc(NCCO)ncn4)c3s2)c(Cl)c1
Reaction time: 0.75 h
Yield: 43.6 %

Procedure:
A mixture of 3,5-dichloro-4-[4-(6-chloropyrimidin-4-ylamino)-thiazolo[5,4-c]pyridin-2-yl]-benzonitrile (0.030 g, 0.07 mmol) and ethanolamine (12.6 μL, 0.21 mmol) in NMP (0.7 mL) was subjected to microwave irradiation at 150° C. for 75 minutes. Further ethanolamine (5.0 μL, 0.08 mmol) was added and the mixture subjected to microwave irradiation at 160° C. for 45 minutes then 190° C. for 45 minutes. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge that was washed with MeOH and the product eluted with 2M ammonia in MeOH. The relevant fractions were combined and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-5% MeOH in DCM) to give the desired compound as an off-white solid (0.014 g, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 8.40-8.34 (m, 3H), 8.16 (s, 1H), 7.73 (d, J=5.6 Hz, 1H), 7.22 (br s, 1H), 6.85 (br s, 1H), 4.72 (t, J=5.4 Hz, 1H), 3.52 (q, J=5.9 Hz, 3H). LCMS (Method C): RT=3.10 min, m/z: 458 [M+H+].
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]([CH2:22]C2C=CN=CC=2)[C:9](=[O:21])[NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][N:15]=2)[CH2:4][CH2:3]1.C([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)=O>>[CH3:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]([CH2:22][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:9](=[O:21])[NH:10][C:11]2[S:12][C:13]([S:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][N:15]=2)[CH2:6][CH2:7]1
Reactant: C[C@H]1CC[C@H](N(Cc2ccncc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=Cc1ccccn1
Product: C[C@H]1CC[C@H](N(Cc2ccccn2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[3-(trans-4-methyl-cyclohexyl)-3-pyridin-4-ylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 2-formyl-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([NH2:16])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][O:18][C:19]1[CH:30]=[CH:29][C:22]2[N:23]=[C:24]([C:26](N)=[O:27])[S:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[C:14]([CH3:15])=[C:13]([NH:16][C:26]([C:24]3[S:25][C:21]4[CH:20]=[C:19]([O:18][CH3:17])[CH:30]=[CH:29][C:22]=4[N:23]=3)=[O:27])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1c(N)nnn1Cc1ccc(Cl)c(Cl)c1
Reactant: COc1ccc2nc(C(N)=O)sc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2nc(C(=O)Nc3nnn(Cc4ccc(Cl)c(Cl)c4)c3C)sc2c1
Temperature: 45 °C
Reaction time: 48 h

Procedure:
A mixture of 1-[(3,4-dichlorophenyl)methyl]-5-methyl-1H-1,2,3-triazol-4-amine (Intermediate 19) (0.1 g, 0.39 mmol), 6-(methyloxy)-1,3-benzothiazole-2-carboxamide (81 mg, 1 eq), HATU (0.192 g, 1.3 eq) and DIPEA (0.12 mL, 1.3 eq) in DMF (5 mL) was stirred at 45° C. for 48 hours. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulphate, filtered and concentrated. The residue was purified by flash chromatography eluting with DCM/MeOH (99/1) to give after recrystallisation from acetonitrile the title compound as pink pale crystals (110 mg, 65%). HRMS calculated for C19H15Cl2N5O2S (M+H)+448.0402, found: 448.0406, Rt: 3.08 min. MP: 176° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([CH3:17])[C:12](OCC)=[O:13])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl-].[Ce+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[C:11]([CH3:17])[CH2:12][OH:13])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)=Cc1ccc(C(C)C)cc1
Agent: [Al+3]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=Cc1ccc(C(C)C)cc1)CO
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
To a suspension of ethyl 3-(4-isopropylphenyl)-2-methyl-2-propenoate (9.00 g, 38.7 mmol) and cerium chloride (1.00 g, 4.06 mmol) in tetrahydrofuran (50 ml) was added in four portions at −40° C. over a period of 30 minutes lithium aluminum hydride (1.47 g, 38.7 mmol) and the resulting mixture was stirred at the same temperature for 30 minutes. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexane-ethyl acetate 8:1) to obtain 6.30 g (86% yield) of the oily title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][C:30]=1[OH:31])[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[CH3:2].Cl.Cl.[CH3:34]OC(=O)C1C(C(F)(F)F)=CC(NC2CCNCC2)=NC=1.C(OC1C=C(C=CC=1OC)C=O)C>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][C:30]=1[O:31][CH3:34])[CH2:7][N:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:23]=[C:22]([C:24]([F:26])([F:25])[F:27])[C:18]([C:19]([OH:21])=[O:20])=[CH:17][N:16]=2)[CH2:12][CH2:13]1)[CH3:2]
Reactant: COC(=O)c1cnc(NC2CCNCC2)cc1C(F)(F)F
Reactant: CCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(=O)O)cn3)CC2)ccc1O
Agent: CCOc1cc(C=O)ccc1OC
Agent: Cl
Product: CCOc1cc(CN2CCC(Nc3cc(C(F)(F)F)c(C(=O)O)cn3)CC2)ccc1OC

Procedure:
The title compound was prepared in analogy to the synthesis of 6-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-4-trifluoromethyl-nicotinic acid (example 201) from 6-(piperidin-4-ylamino)-4-trifluoromethyl-nicotinic acid methyl ester dihydrochloride (intermediate B7) and 3-ethoxy-4-methoxy-benzaldehyde (commercially available) in a yield of 15.3 mg (22%). MS (ISP): 454.2 [M+H]+.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:8][CH3:9])[CH2:6][CH3:7].[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>O>[CH2:6]([N:5]([CH2:8][CH3:9])[CH2:4][CH2:3][O:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:7]
Reactant: CCN(CC)CCCl
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCOc1ccccc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
A solution of 108.5 g (0.630 mol; 1.2 eq.) of N-(2-chloroethyl)-N,N-diethylamine hydrochloride in 65 ml of water is added slowly (over about 55 minutes) to a mixture containing 50 g (0.531 mol) of phenol and 46.3 g (1.158 mol; 2.2 eq.) of NaOH in 270 ml of water. The mixture is stirred for 3 hours 30 minutes at 20° C. and then for 45 minutes at 55° C. The phases are separated by settling and the supernatant oil diluted in 100 ml of DCE is washed with (i) 100 ml of 2.5% sodium hydroxide and then (ii) with 100 ml of 5% sodium hydroxide. The product is dried over sodium sulfate and then concentrated. 81.4 g of crude N,N-diethyl-N-(phenoxyethyl)amine are obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[O:22][CH2:23][CH:24]([OH:26])[CH3:25].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(OCC)(=O)C.Cl>N1C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([NH:9][CH:10]=[C:11]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[O:22][CH2:23][CH:24]([O:26][S:33]([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34])[CH3:25]
Reactant: CCOC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)O)C(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C(=CNc1ccc(F)c(F)c1OCC(C)OS(=O)(=O)c1ccc(C)cc1)C(=O)OCC
Reaction time: 4 h
Yield: 94.7 %

Procedure:
To a solution of 747 mg of the compound obtained in Example 3 in 2 ml of pyridine was added 710 mg of p-toluenesulfonyl chloride and the mixture was stirred under cooling with ice for 24 hours, and then at room temperature for 4 hours. To the mixture were added ethyl acetate and 1 N hydrochloric acid. The mixture was shaken, and the organic layer was separated. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography to yield 1.0 g of the titled compound.
Reaction SMILES: [Na].Cl[C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1.[CH3:11][OH:12]>>[CH3:11][O:12][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CO
Agent: [Na]
Product: COc1cc(C#N)ccn1
Yield: 51 %

Procedure:
Sodium (20.8 g) was dissolved in methanol (285 ml), a solution of 2-chloro-4-cyanopyridine (115.53 g) in methanoldioxan (1:1, 850 ml) was added and the mixture was boiled under reflux for 21/2 hours and was allowed to cool. The mixture was filtered and the volume of the filtrate was reduced by evaporation in 200 ml and water (400 ml) was added. The solid which precipitated out was filtered off to give 2-methoxy-4-cyanopyridine (57.2 g, 51%), m.p. 93-95.5°.
Reaction SMILES: [Br:1][CH2:2][C:3]([N:5]([CH:12]([CH3:14])[CH3:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[F:15]C1C=CC(NC(C)C)=CC=1.BrCC(Br)=O>>[Br:1][CH2:2][C:3]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([F:15])=[CH:8][CH:7]=1)[CH:12]([CH3:14])[CH3:13])=[O:4]
Reactant: CC(C)Nc1ccc(F)cc1
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Agent: O=C(Br)CBr
Product: CC(C)N(C(=O)CBr)c1ccc(F)cc1

Procedure:
Following the procedure described for Preparation 1(A), (4-fluoro-phenyl)-isopropyl-amine (13.70 g, 89.54 mmol) was alkylated with bromoacetyl bromide (7.78 mL, 89.54 mmol) to provide 15.02 g of 2-bromo-N-(4-fluoro-phenyl)-N-isopropyl-acetamide as an oil. 1H NMR (CD2Cl2) δ 7.14-7.23 (m, 4H), 4.90 (m, 1H), 3.53 (s, 2H), 1.05 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.Cl.[NH:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])N>C(O)C.O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3[C:23]4[C:15](=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=[CH:21][CH:22]=4)[NH:13][C:8]=32)=[CH:4][CH:3]=1
Reactant: NNc1ccccc1C(=O)O
Reactant: O=C1CCc2ccc(Br)cc21
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c3c([nH]c12)-c1cc(Br)ccc1C3
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of 6-bromoindanone (0.447 g, 2.12 mmol) [Adamczyk, M. et al. J. Org. Chem. 1984, 49, 4226-4237] in ethanol (100 mL) was added a solution of 2-hydrazinobenzoic acid hydrochloride (0.800 g, 4.24 mmol) in deionized water (50 mL). The mixture was stirred for 1 h then cooled to 0° C. The precipitated hydrazone was vacuum filtered and dried in vacuo to afford 0.628 g (86%) of the title compound as a yellow solid: mp 186° C. (dec).