Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH:15]=[CH:14][S:13][C:12]2([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)C(O)=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>N1C2C(=CC=CC=2)C=CC=1>[NH2:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:15]=[CH:14][S:13][C:12]=2[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: NS(=O)(=O)c1ccc(C2C=CSC2(C(=O)O)c2ccc(F)cc2)cc1
Solvent: c1ccc2ncccc2c1
Product: NS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
To a solution of 3-(4-(aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene-2-carboxylic acid (0.280 g) in quinoline (4.0 mL) was added Cu bronze (0.300 g). After 0.5 h at 180° C. under nitrogen, the reaction mixture was extracted with EtOAc and HCl 3N, dried over Na2SO4 and purified by flash chromatography (30% EtOAc in hexane) to give the title compound as a white solid (0.180 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]1([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([C:28](OC)=[O:29])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1.O>O1CCCC1>[N:7]1([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3([CH2:28][OH:29])[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 2.5 °C
Yield: 93.3 %

Procedure:
Anhydrous tetrahydrofuran (141 ml, 10 vol) was charged rapidly onto stirred and cooled (0-5° C.) lithium aluminium hydride (6.2 g, 0.1634 mol, 0.44 wt) under nitrogen. The resulting slurry was cooled to 0-5° C. and then a solution of methyl 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylate (14.1 g, 0.04058 mol) in tetrahydrofuran (99 ml, 7 vol) was added dropwise over 30 minutes maintaining 0-5° C. On complete addition the reaction was allowed to warm to room temperature over 30 minutes and stirred at 18-25° C. for 30 minutes, LC analysis showed the reaction to be complete. The mixture was cooled to 0 to 5° C., a 1:1 mixture of tetrahydrofuran and water (18.6 ml, 1.32 vol) was added very slowly. The mixture was further quenched with 20% w/v sodium hydroxide solution (6.2 ml, 0.44 vol) and water (18.6 ml, 1.32 vol) and the resulting white suspension stirred vigorously for 30 minutes at 18-25° C. The salts were removed by filtration and rinsed with tetrahydrofuran (3×150 ml). The combined filtrates were evaporated to dryness at 40° C. to yield {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methanol (12.1 g, 94%) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23].O>ClCCl>[C:22]([NH:1][CH2:2][CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)C(CCN)CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc2c(c1)C(CCNC(C)=O)CC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
To a solution of 1-(2-aminoethyl)-6-methoxyindan (0.80 g, 4.18 mmol) and triethylamine (0.44 g, 4.39 mmol) in dichloromethane (15 ml) was gradually added dropwise, under ice cooling, acetyl chloride (0.33 g, 4.18 mmol). The mixture was stirred for 10 minutes at room temperature. The reaction mixture was poured into water. The organic layer was subjected to extraction with chloroform. The extract solution was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and brine, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was recrystallized from ethyl acetate/isopropyl ether to give the above-titled compound (yield 0.68 g, 70%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1c[nH]c2nc(Br)ccc12
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cn(C)c2nc(Br)ccc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 6-bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.18 mmol) in DMF (6 mL) was added cesium carbonate (502 mg, 1.54 mmol). The reaction solution was stirred at room temperature for 5 minutes, then iodomethane (219 mg, 1.54 mmol) was added. The reaction solution was stirred for 30 minutes and quenched with water. The mixture was concentrated in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was washed with brine, dried (MgSO4) and concentrated to give crude which was purified by chromatographic column to afford the desired product. LCMS-ESI+: calc'd for C9H9BrN2 225.2 (M+H+); Found: 225.2 (M+H+).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]([CH:11]1[CH:24](O)[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:26][CH3:27])[CH:21]=3)[N:16]=[CH:15][C:14]=2[S:13][CH2:12]1)=[O:10])[CH3:7].C(N(CC)CC)C.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:6]([O:8][C:9]([C:11]1[CH2:12][S:13][C:14]2[CH:15]=[N:16][C:17]3[C:22]([C:23]=2[CH:24]=1)=[CH:21][C:20]([O:26][CH3:27])=[CH:19][CH:18]=3)=[O:10])[CH3:7]
Reactant: CCOC(=O)C1CSc2cnc3ccc(OC)cc3c2C1O
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)C1=Cc2c(cnc3ccc(OC)cc23)SC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 34.1 %

Procedure:
Methanesulfonyl chloride (745 μL, 9.63 mmol, 3.0 eq) is added at room temperature to a stirred solution of 4-hydroxy-6-methoxy-3,4-dihydro-2H-1-thia-9-aza-phenanthrene-3-carboxylic acid ethyl ester (1.02 g, 3.21 mmol, 1.0 eq) in dichloromethane (10 mL), followed by triethylamine (2.23 mL, 16.05 mmol, 5.0 eq) and 4-(dimethylamino)pyridine (392 mg, 3.21 mmol, 1.0 eq). After 20 minutes stirring at room temperature, solvent is removed and the crude product is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 10:1, v/v) to afford 6-methoxy-2H-1-thia-9-aza-phenanthrene-3-carboxylic acid ethyl ester as a yellow solid (330 mg, 34% yield).
Reaction SMILES: Br[C:2]1[N:3]2[N:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]2[S:5][CH:6]=1.[CH:20]1([O:24][CH2:25][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29](B(O)O)=[C:28]([O:37][CH3:38])[CH:27]=2)[CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.COCCOC>[CH:20]1([O:24][CH2:25][C:26]2[CH:27]=[C:28]([O:37][CH3:38])[C:29]([C:2]3[N:3]4[N:9]=[C:8]([O:10][CH3:11])[C:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:4]4[S:5][CH:6]=3)=[C:30]([O:32][CH3:33])[CH:31]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: COc1cc(COC2CCC2)cc(OC)c1B(O)O
Reactant: COc1nn2c(Br)csc2c1NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(COC2CCC2)cc(OC)c1-c1csc2c(NC(=O)OC(C)(C)C)c(OC)nn12
Temperature: 90 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
To a mixture of tert-butyl (3-bromo-6-methoxypyrazolo[5,1-b][1,3]thiazol-7-yl)carbamate (987 mg, 2.83 mmol), DME (80 mL) and water (28 mL) were added {4-[(cyclobutyloxy)methyl]-2,6-dimethoxyphenyl}boronic acid (904 mg, 3.4 mmol), potassium carbonate (785 mg, 5.68 mmol), triphenylphosphine (370 mg, 1.42 mmol) and palladium acetate (63.7 mg, 0.282 mmol) in that order, and the mixture was stirred at 90° C. (internal temperature) for 3 hours. Water was added to the reaction mixture, and then ethyl acetate was added. After thoroughly shaking the mixture, the organic layer was separated and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was filtered, and then the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (mixture of n-heptane and ethyl acetate: n-heptane/ethyl acetate=2/1) to obtain the title compound (1.24 g, 2.53 mmol).
Reaction SMILES: [C:1]([O:18][CH2:19][C@H:20]([CH2:25][O:26]P(OCC[N+](C)(C)C)(O)=O)[O:21][C:22](=[O:24])[CH3:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[C:1]([O:18][CH2:19][C@H:20]([CH2:25][OH:26])[O:21][C:22](=[O:24])[CH3:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(=O)(O)OCC[N+](C)(C)C)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H](CO)OC(C)=O
Temperature: 100 °C

Procedure:
An ester analog of PAF, 1-hexadecanoyl-2-acetyl-sn-glycero-3-phosphocholine, was made by acetylation of 1-hexadecanoyl-2-lyso-sn-glycero-3-phosphocholine in a reaction with 0.5 ml of acetic anhydride and 20 mg of 4-dimethylaminopyridine in 1.25 ml of toluene; the sealed tube was heated at 100° C. for 2 hours and, after evaporation of the solvents with a stream of N2, the products were extracted by the method of Bligh and Dyer as described in Canadian Journal of Biochemical Physiology, Vol. 3, pp. 911-917, 1959. The product, 1-hexadecanoyl-2-acetyl-sn-glycerol-3-phosphocholine, was then treated with phospholipase C to produce 1-hexadecanoyl-2-acetyl-sn-glycerol, which was estimated on the basis of TLC to have a purity >95%.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:7][N:6]=[C:5]([NH2:8])[CH:4]=1.C(N(CC)CC)C.[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1>CCO>[Cl:16][C:17]1[N:22]=[C:21]([NH:8][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[NH:7][N:6]=2)[C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1cc(N)n[nH]1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reaction time: 12 h

Procedure:
To a solution of 5-methoxy-1H-pyrazol-3-amine (890 mg, 7.8 mmol) in absolute EtOH (20 ml) were added triethylamine (3.3 ml, 23.6 mmol), 2,4,5-trichloropyrimidine (1.4 g, 7.8 mmol) and the resulting solution was aged at room temperature for 12 hours. The mixture was partitioned between EtOAc and H2O, the organic layer was washed with brine and dried. The solvents were removed under reduced pressure to give the title compound as an oil which crystallized upon standing (1.8 g). m/z: 261.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[CH3:13][CH:14]1[O:19][C:18]2[CH:20]=[CH:21][C:22]([O:24][CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][C:17]=2[NH:16][C:15]1=[O:31]>>[CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:28]2[CH2:29][CH2:30][CH:25]([O:24][C:22]3[CH:21]=[CH:20][C:18]4[O:19][CH:14]([CH3:13])[C:15](=[O:31])[NH:16][C:17]=4[CH:23]=3)[CH2:26][CH2:27]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(F)cc1
Reactant: CC1Oc2ccc(OC3CCNCC3)cc2NC1=O
Product: CCNC(=O)c1ccc(N2CCC(Oc3ccc4c(c3)NC(=O)C(C)O4)CC2)cc1
Yield: 6 %

Procedure:
Using N-ethyl-4-fluorobenzamide 281 as the alkylating agent, the reaction with 394E was carried out as described for 395 providing the title compound as a tan solid (0.0051 g, 6.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3H) 1.40 (d, J=6.57 Hz, 3H) 1.59-1.74 (m, 2H) 1.92-2.07 (m, 1H) 3.08-3.34 (m, 3H) 3.54-3.69 (m, 2H) 4.36-4.50 (m, 1H) 4.58 (q, J=6.65 Hz, 1H) 6.50 (d, J=2.78 Hz, 1H) 6.52-6.63 (m, 1H) 6.88 (d, J=8.59 Hz, 1H) 6.92-7.04 (m, 2H) 7.72 (d, J=8.84 Hz, 2H) 8.18 (s, 1 H) 10.56 (s, 1H). ESI-MS: m/z 410.3 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:10]([Br:11])=[C:9]([Cl:12])[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:3]=1[CH:4]=[N:5]O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>O1CCCC1>[OH:1][C:2]1[C:10]([Br:11])=[C:9]([Cl:12])[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:7][C:3]=1[C:4]#[N:5]
Reactant: CC(C)(C)c1cc(C=NO)c(O)c(Br)c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)c1cc(C#N)c(O)c(Br)c1Cl
Yield: 86.8 %

Procedure:
A mixture of 2.20 g (7.18 mmol) of 2-hydroxy-3-bromo-4-chloro-5-(1,1-dimethylethyl)benzaldehyde oxime and 3.12 g (14.72 mmol) of trifluoroacetic anhydride in 15 ml of tetrahydrofuran was cooled in an ice-water bath. A solution of 2.18 g (21.54 mmol) of triethylamine in 10 ml of tetrahydrofuran was added After refluxing for 2 hours, the solvent was evaporated and the residue was partitioned between saturated aqueous sodium bicarbonate solution and ether. The organic phase was washed with 1N hydrochloric acid, followed by water and brine. The organic phase was dried and evaporated. The residue was chromatographed on 100 g of silica gel using a gradient from 5:95 to 50:50 (v/v) ether:hexane as eluent. There was obtained 1.80 g (6.23 mmol, 87%) of 2-hydroxy-3-bromo-4-chloro-5-(1,1-dimethylethyl)benzonitrile; mp 105°-107° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([N:14]2[CH2:20][CH2:19][CH2:18][N:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)[CH2:9]1)=O)(C)(C)C.O1CCOCC1>C(Cl)Cl>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([N:17]2[CH2:18][CH2:19][CH2:20][N:14]([C@@H:10]3[CH2:9][NH:8][CH2:12][C@H:11]3[OH:13])[CH2:15][CH2:16]2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N2CCCN(c3ccc(Cl)cc3)CC2)C1
Solvent: ClCCl
Solvent: C1COCCO1
Product: O[C@@H]1CNC[C@H]1N1CCCN(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 151.2 %

Procedure:
To a solution of trans-3-[4-(4-Chloro-phenyl)-[1,4]diazepan-1-yl]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (0.820 g, 2.08 mmol) in methylene chloride (1 mL) was added 4 N HO/dioxane (10 mL, 40 mmol). The solution was stirred at rt for 1 hour, upon which a brown precipitate formed. The reaction was concentrated in vacuo to yield 0.930 g (−100%) of the title compound. ESI-MS m/z: 296 (M+1), FAS method rt: 0.83 min.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@@:8]2([CH3:21])[N:17]=[C:16]([NH2:18])[C:11]3([CH2:15][CH:14]=[CH:13][CH2:12]3)[S:10](=[O:20])(=[O:19])[CH2:9]2)[CH:7]=1.N>CO.[Pd]>[F:22][C:5]1[CH:4]=[CH:3][CH:2]=[CH:7][C:6]=1[C@@:8]1([CH3:21])[N:17]=[C:16]([NH2:18])[C:11]2([CH2:12][CH2:13][CH2:14][CH2:15]2)[S:10](=[O:20])(=[O:19])[CH2:9]1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)C2(CC=CC2)C(N)=N1
Agent: [Pd]
Agent: N
Solvent: CO
Product: C[C@@]1(c2ccccc2F)CS(=O)(=O)C2(CCCC2)C(N)=N1
Temperature: 23 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a solution of (R)-8-(5-bromo-2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]deca-2,9-dien-10-ylamine (245 mg, 633 μmol, Eq: 1.00) in methanol (10 ml) and ammonia (7 N in MeOH) (271 μl, 1.9 mmol, Eq: 3.0) was added at 23° C. under inert atmosphere Pd/C 10% (67.3 mg, 63.3 μmol, Eq: 0.1). The suspension was set under hydrogen (balloon) and stirred at 23° C. for 2 hours. The catalyst was filtered off, washed three times with methanol and evaporated. The residue was extracted with dichloromethane and sat. NaHCO3-sol., the organic layer was dried over Na2SO4, filtered and evaporated to give the pure (R)-8-(2-fluoro-phenyl)-8-methyl-6,6-dioxo-6λ6-thia-9-aza-spiro[4.5]dec-9-en-10-ylamine (175 mg, 564 μmol, 89.1% yield) as a white solid. MS (ISP): m/z=311.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C@@H:23]2[C@@H:28]3[CH2:29][C@@H:25]([CH:26]=[CH:27]3)[C@@H:24]2[C:30]([NH2:32])=[O:31])=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)[CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>N1C=CC=CC=1>[C:33]([N:19]1[CH2:20][CH2:21][CH:16]([N:14]2[CH:15]=[C:11]([C:9]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([NH:22][C@@H:23]5[C@@H:28]6[CH2:29][C@@H:25]([CH:26]=[CH:27]6)[C@@H:24]5[C:30]([NH2:32])=[O:31])=[C:4]4[N:10]=3)[CH:12]=[N:13]2)[CH2:17][CH2:18]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4cnn(C5CCNCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: c1ccncc1
Product: CC(=O)N1CCC(n2cc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)c(Cl)cnc4[nH]3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
(1S,2S,3R,4R)-3-[6-Chloro-2-(1-piperidin-4-yl-1H-pyrazol-4-yl)-3H-imidazo[4,5-b]pyridine-7-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100 mg, 0.20 mmol) and acetic anhydride (45.1 mg, 0.442 mmol) were combined in pyridine (1 mL) and stirred at ambient temperature overnight. The mixture was concentrated and the crude product was purified employing reverse phase chromatography (Gilson) to afford following lyophilization of desired fractions a white lyophilate—the title compound (100%). 1H NMR (d-chloroform): 8.38 (d, J=8 Hz, 1H), 8.12 (s, 2H), 7.80 (s, 1H), 6.48 (m, 1H), 6.43 (m, 1H), 5.81 (br s, 1H), 5.40 (br s, 1H), 5.35 (m, 1H), 4.81 (m, 1H), 4.47 (m, 1H), 4.04 (m, 1H), 3.31 (t, J=8 Hz, 1H), 3.17 (s, 1H), 3.03 (s, 1H), 2.82 (m, 1H), 2.65 (m, 1H), 2.36-1.98 (m, 8H), 1.67 (d, J=8 Hz, 1H), 1.26 (d, J=8 Hz, 1H). MS: 494.9 (M+H). HPLC retention time: 1.88 minutes (G Method).
Reaction SMILES: C(OC([Cl:6])=O)C.[CH2:7]([NH:9][C:10]([CH:12]1[CH2:15][C:14]([F:29])([C:16]2[CH:21]=[CH:20][C:19]([CH2:22]N3CCCC3)=[C:18]([F:28])[CH:17]=2)[CH2:13]1)=[O:11])[CH3:8]>ClCCCl>[CH2:7]([NH:9][C:10]([CH:12]1[CH2:15][C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][Cl:6])=[C:18]([F:28])[CH:17]=2)([F:29])[CH2:13]1)=[O:11])[CH3:8]
Reactant: CCNC(=O)C1CC(F)(c2ccc(CN3CCCC3)c(F)c2)C1
Reactant: CCOC(=O)Cl
Solvent: ClCCCl
Product: CCNC(=O)C1CC(F)(c2ccc(CCl)c(F)c2)C1
Temperature: 25 °C
Yield: 72.4 %

Procedure:
Ethylchloroformate (0.505 ml, 5.28 mmol) was added to a solution of Example 16, 3-fluoro-3-(3-fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-cyclobutanecarboxylic acid ethylamide (1.7 g, 5.28 mmol) in DCE (50 ml) After 1 hr stirring at rt. the reaction was quenched with saturated aq. NaHCO3 (150 ml) and extracted with CH2Cl2 (3×100 ml) to recover a residual oil. This was purified by flash column chromatography using a 120 g ISCO™ cartridge and 35% and 40% EtOAc/hexanes to obtain an intermediate 3-(4-chloromethyl-3-fluoro-phenyl)-3-fluoro-cyclobutanecarboxylic acid ethylamide (1.1 g, 75% yield).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]([O:18]C)=[O:17])=[CH:14][C:13]([S:20][CH3:21])=[N:12]2)=[CH:7][CH:6]=1>CO>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]([S:20][CH3:21])=[N:12]2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1cc(SC)nn1-c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(-n2nc(SC)cc2C(=O)O)cc1
Reaction time: 21 h
Yield: 98.9 %

Procedure:
A solution of lithium hydroxide (4.5 mL, 1.0 M, 4.5 mmol) was added to a suspension of methyl 1-(4-methoxyphenyl)-3-methylthio-1H-pyrazole-5-carboxylate (840 mg, 3.0 mmol) in MeOH (30 mL) and stirred at room temperatureerature for 21 hours. The resulting mixture was concentrated and partitioned between EtOAc and H2O. The organic layer was removed, and the aqueous layer was acidified with 1M HCl and extracted twice with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and evaporated to yield clean product (784 mg, 98%). 1H NMR (CDCl3): δ 7.33 (d, 2H, J=8.4), 6.97 (s, 1H), 6.95 (d, 2H, J=8.4), 3.85 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:31])([F:30])[F:29])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:29])([F:30])[F:31])=[O:22])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C2CCNCC2)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Yield: 92.7 %

Procedure:
4-{4-[(2-Phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (245 mg, 0.475 mmol) from above was dissolved in methylene chloride (2 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at room temperature and the solvents were evaporated. The residue was partitioned between methylene chloride and dilute sodium hydroxide solution. The organic layer was washed with brine and dried over sodium sulfate. Evaporation of solvents gave 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (4-piperidin-4-yl-phenyl)-amide (183 mg) as a white solid. LC-MS calcd for C22H20F3N3O2 (m/e) 415.41, obsd 416.0. The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]=[CH:9][C:5]2=[N+:6]([O-])[CH:7]=1.[C:13](#[N:15])C.C(N(CC)CC)C.C[Si](C#N)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH:10]=[CH:9][C:5]2=[N:6][C:7]=1[C:13]#[N:15]
Reactant: CC#N
Reactant: Cn1ccc2c1cc(Br)c[n+]2[O-]
Agent: C[Si](C)(C)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ccc2nc(C#N)c(Br)cc21
Temperature: 10 °C
Reaction time: 10 h
Yield: 77.1 %

Procedure:
A solution of 6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine 4-oxide (42.8 kg, 188 mol) in DCM from the previous step was distilled at 45° C. to a volume of about 85 L. Acetonitrile (100 kg) was added and the mixture was distilled at 45° C. to a volume of about 110 L (2.5 L/kg). More ACN (80 kg) was added and the mixture was again distilled at 45° C. to a volume of about 110 L. Triethylamine (80 kg, 791 mol) was added. The mixture was cooled to 10±5° C. and trimethylsilyl cyanide (81.6 kg, 822 mol) was added over the course of 15 minutes while maintaining the temperature of the mixture below 25° C. The reaction mixture was gradually heated to 70±5° C. After stirring for 10 hours at this temperature, the starting material was consumed. The reaction mixture was cooled to 10±5° C. A 20% aqueous K2CO3 solution (260 kg) was added and the mixture was stirred at 10±5° C. for 1 hour. The resulting precipitate was filtered. The reactor was rinsed with a 2.3% aqueous K2CO3 solution (133 kg). The rinse was used to wash the filter cake, which was slurried in water (180 kg) for 30 minutes and filtered. The filter cake was again slurried in water (180 kg) for 30 minutes and filtered. The filtered solids were dispersed in a solution of DCM (1166 kg) and THF (156 kg). The mixture was stirred for 2 hours at 30±5° C. Activated carbon (7.0 kg, 0.16 kg/kg) was added and the mixture was stirred at 30±5° C. for 2 hours and filtered through a pad of Celite under pressure. The reactor was rinsed with DCM (200 kg) and the rinse was used to wash the filter cake. The combined filtrate was distilled at 40±5° C. to a volume of about 170 L. Next, n-heptane (120 kg) was added to the mixture, which was concentrated by distillation at 40±5° C. to a volume of about 170 L. More n-heptane (238 kg) was added to the mixture. The slurry was cooled to 5±5° C. and stirred for 1 hour. The resulting precipitate was filtered under pressure and the filter cake was washed with n-heptane (68 kg) from the reactor rinse. The wet cake was dried under vacuum at 40° C. for 20 hours to give the title compound as an off-white solid (34.2 kg).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].I[CH2:25][CH:26]([CH3:28])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:22][CH:23]=1)#[N:2]
Reactant: CC(C)CI
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OCC(C)C)cc1F

Procedure:
In analogy to example 16.4, (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-hydroxy-phenyl)-2-methoxy-acetamide (example 70.4) was alkylated with 1-iodo-2-methylpropane and cesium carbonate in DMF to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-isobutoxy-phenyl)-2-methoxy-acetamide. Off-white, amorphous solid. MS 371.3 ([M+H]+)