Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([OH:7])=O)[CH3:2].CCOC(OC(OCC)=O)=O.[N:30]1([C:35]2[CH:40]=[C:39]([CH2:41][NH2:42])[CH:38]=[C:37]([C:43]3[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=3)[N:36]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[CH2:1]([N:3]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:4](=[CH2:8])[C:5]([NH:42][CH2:41][C:39]1[CH:38]=[C:37]([C:43]2[CH:44]=[CH:45][C:46]([C:49]([F:52])([F:50])[F:51])=[CH:47][CH:48]=2)[N:36]=[C:35]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34]2)[CH:40]=1)=[O:7])[CH3:2]
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Reactant: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
A solution of acid 4B (0.15 g, 0.53 mmol) in THF (10 mL) was added with DEPC (0.10 mL, 1.3 mol eq) and the mixture was stirred at room temperature several minutes. Then [2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27A (0.17 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water was added to the residue that is extracted with EtOAc (3×25 mL) and washed with brine (1×40 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (1/1 EtOAc/Petroleum ether) to afford a white solid (90 mg) after crystallization from ethyl ether. Yield=32%. 1HNMR (DMSO, 200 MHz) δ 1.092 (t, 3H, J=5.6), 1.95 (m, 4H), 3.4-3.46 (m, 6H), 4.39 (d, 2H, J=6), 5.13 (s, 1H), 6.12 (s, 1H), 6.47 (s, 1H), 7.20 (s, 1H), 7.51 (t, 2H, J=7.9), 7.80-7.90 (m, 4H), 8.27 (d, 2H, J=8.1), 8.78 (bt, 1H). [M+1] 576.28 (C28H28F4N4O3S requires 576.60).
Reaction SMILES: Cl[CH2:2][C@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][C@@H:3]([CH3:13])[CH2:2][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:7][CH:8]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@@H](CCl)COc1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{[(2R)-3-chloro-2-methylpropyl]oxy}-4-fluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[N:18]1[CH:17]=[CH:16][C:15]([C:14]2[C:10]([C:6]3[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=3)=[N:11][NH:12][CH:13]=2)=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])c1cccc(-c2n[nH]cc2-c2ccncc2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(-c2n[nH]cc2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.6 %

Procedure:
1.27 g (4.77 mmol) of 4-[3-(3-nitro-phenyl)-1H-pyrazol-4-yl]-pyridine was suspended in methanol (200 mL). Pd/C 10% (250 mg) was added and the mixture was agitated under hydrogen pressure (50 psi) in a Parr apparatus at room temperature for 4 hours. The catalyst was then filtered on a Celite pad and washed with methanol. The filtrate was concentrated to dryness to obtain 1.1 g (98% yield) of 3-(4-pyridin-4-yl-1H-pyrazol-3-yl)-phenylamine as an off-white solid.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25](/[CH:28]=[CH:29]/[C:30]([O:32]C(C)(C)C)=[O:31])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14]([C:16]2[CH:17]=[CH:18][C:19]([C@H:22]3[CH2:27][CH2:26][C@H:25](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)=[O:15])=[N:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)/C=C/[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(Cc4ccccc4)s3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
35 mg of tert-butyl trans-(E)-3-{4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)phenyl]-cyclohexyl}acrylate (0.07 mmol, 1 eq.) are placed in 1 mL of dichloromethane. 0.5 mL of trifluoroacetic acid (6.73 mmol, 97 eq.) is added and the reaction medium is stirred for 3 hours at room temperature. The solvent is evaporated off. The resin is triturated in ethyl acetate to give 8 mg of trans-(E)-3-{4-[4-(5-benzyl[1.3.4]thiadiazol-2-ylcarbamoyl)-phenyl]cyclohexyl}acrylic acid.
Reaction SMILES: C[O:2][CH:3](OC)[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)[C:13]2=[O:29])=[CH:8][C:7]=1[O:30][CH3:31].C(O)(C(F)(F)F)=O.ClCCl.O>>[CH3:31][O:30][C:7]1[CH:8]=[C:9]([N:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][O:25]4)[CH:18]=3)[C:13]2=[O:29])[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH:3]=[O:2]
Reactant: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1OCC(OC)OC
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1OCC=O

Procedure:
A solution of 2-[4-(2,2-dimethoxyethoxy)-3-methoxyphenyl]-6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]-2H-isoquinolin-1-one (94 mg) in 10:10:1 TFA/dichloromethane/water (2 mL) was stirred at room temperature for 2 h. The solvent was removed in vacuo. The product with the molecular weight of 409.44 (C23H23NO6) was obtained in this way; MS (ESI): 428 (M+water+H+).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[CH2:40]([NH2:44])[CH2:41][CH2:42][CH3:43]>>[CH2:40]([NH:44][CH2:1][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:38][CH:39]=1)[CH2:41][CH2:42][CH3:43]
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Reactant: CCCCN
Product: CCCCNCCc1ccc(CCCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1
Yield: 16.1 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (31 mg) and butylamine (6.8 mg) according to an analogous synthetic method to Example 806, the title compound (4.6 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O.[H][H]>O.[Pt](=O)=O>[NH2:1][C:4]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: [H][H]
Reactant: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC
Agent: O=[Pt]=O
Solvent: O
Product: COc1cc(N)c(C(N)=O)cc1OC

Procedure:
A suspension of 28 g of 2-nitro-4,5-dimethoxybenzamide was hydrogenated under normal pressure in the presence of 1.5 g of platinum dioxide hydrate until hydrogen was no longer absorbed. The catalyst was filtered off with suction, the filtrate was evaporated and the residue was dried under reduced pressure. Yield: 24.1 g. M.p.: 147° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1C(=O)N([Br:18])C(=O)C1>OS(O)(=O)=O>[Br:18][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][N:2]=[CH:1]2
Reactant: c1ccc2cnccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: Brc1cccc2cnccc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Into a 250 mL 3-necked round bottom flask was placed H2SO4 (150 mL). To the above was added isoquinoline (17 g, 131.62 mmol) in several batches, while cooling to a temperature of 0° C. To the above was added NBS (29.2 g, 164.04 mmol) in several batches, while cooling to a temperature of −25-−22° C. The resulting solution was allowed to react, with stirring, for 2 hours while the temperature was maintained at −25-−22° C. The resulting solution was allowed to react, with stirring, overnight while the temperature was maintained at room temperature. The reaction progress was monitored by TLC (ethyl acetate/petroleum ether=1:5). The reaction mixture was then quenched by the adding 1000 mL of H2O/ice. Adjustment of the pH to 8-10 was accomplished by the addition of NH3. H2O (30%). The resulting solution was extracted four times with 500 mL of ethyl acetate and the organic layers combined and dried over Na2SO4. The residue was purified by eluting through a column with a 1:5 ethyl acetate/petroleum ether solvent system. This resulted in 22.24 g (81%) of 5-bromoisoquinoline as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:18][C@H:19]4[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]4)[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:26]=1.[F:27][C:28]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:29]=1[NH2:30].P.O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:27][C:28]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:29]=1[NH:30][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:18][C@H:19]4[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]4)[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:26]=1
Reactant: CC1(C)OC[C@H](COc2cccc3c2CCc2cc(Cl)ccc2C3=O)O1
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CC1(C)OC[C@H](COc2cccc3c2CCc2cc(Nc4ccc(F)cc4F)ccc2C3=O)O1
Yield: 37 %

Procedure:
For the synthesis of the title compound, 0.50 g (0.0013 mol) of (S)-8-chloro-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.17 g (0.0013 mol) of 2,4-difluoroaniline, 2 spatula tips of Pd(OAc)2, 0.14 g of phosphine ligand and 0.70 g (0.0073 mol) of NaOtert-Bu in 10 ml of toluene and 2 ml of tert-BuOH are reacted by method O.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:36])[NH:24][C@H:25]([CH2:33][NH:34][CH3:35])[CH2:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1>CO.[Pd]>[CH:27]1([CH2:26][C@H:25]([NH:24][C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:17]([C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=3)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH2:18]2)=[O:36])[CH2:33][NH:34][CH3:35])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CNC[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2)C1
Agent: [Pd]
Solvent: CO
Product: CNC[C@H](CC1CCCCC1)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of fumarate salt (0.120 g) of methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-1-cyclohexyl-3-(methylamino)propan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate, HCO2NH4 (1.200 g), and 10% Pd/C (0.150 g) in MeOH was stirred at rt for 3 d. The mixture was filtered off precipitates through Celite® 545 and washed with MeOH. After the solvent was evaporated under reduced pressure, the crude methyl 2-((R)—((R)-1-((S)-1-cyclohexyl-3-(methylamino)propan-2-ylcarbamoyl)piperidin-3-yl)(phenyl)methoxy)ethylcarbamate was directly used in the next step without further purification. MS ESI +ve m/z 489 (M+H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].C(OCC)C.CC(O[B:16]1[O:20][C@@H:19]2[CH2:21][C@@H:22]3[CH2:25][C@H:24]([C@:18]2([CH3:28])[O:17]1)[C:23]3([CH3:27])[CH3:26])C.[Na+].[Cl-]>O1CCCC1.S(=O)(=O)(O)O.C(OC(C)C)(C)C>[CH3:3][CH:2]([CH3:4])[CH2:1][B:16]1[O:20][C@@H:19]2[CH2:21][C@@H:22]3[CH2:25][C@H:24]([C@:18]2([CH3:28])[O:17]1)[C:23]3([CH3:27])[CH3:26]
Reactant: CC(C)OB1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Reactant: CC(C)C[Mg]Br
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CB1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Temperature: -78 °C
Yield: 62 %

Procedure:
A 2M solution of isobutyl magnesium bromide in diethyl ether (131.5 ml, 0.263 mol) was added dropwise, in 1 hour, to a solution of 2-(1-methylethoxy)-(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborole obtained in Step 1 (62.6 g, 0.263 mol), in anhydrous tetrahydrofuran (330 ml) while stirring at −78° C., under nitrogen. The mixture was then allowed to warm to room temperature, then transferred in a mixture of 2N sulfuric acid (150 ml) and diisopropyl ether (250 ml). After stirring for 10 minutes, a saturated solution of NaCl was added (100 ml) and the layers were separated. The organic phase was washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (silica gel) eluting with 5% diethyl ether in hexane. The product was obtained as a clear oil (38.45 g, 62% yield).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([Si](C)(C)C)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:19]I>O1CCCC1.F[B-](F)(F)F.[Ag+]>[I:19][C:10]1[N:9]=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11]=1[CH2:12][CH2:13][CH3:14]
Reactant: CCCc1c([Si](C)(C)C)nnn1-c1ccccc1
Reactant: II
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: CCCc1c(I)nnn1-c1ccccc1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
1-Phenyl-5-propyl-4-trimethylsilanyl-1H-[1,2,3]-triazole (260 mg) prepared in the above 1) was dissolved in 5.0 ml of tetrahydrofuran, 389 mg of silver tetrafluoroborate and 507 mg of iodine were added thereto and the mixture was stirred at room temperature for one night. The reaction solution was filtered through Celite, a saturated aqueous solution of sodium thiosulfate was added to the filtrate and the solvent was evaporated in vacuo. Water was added to the residue, the mixture was extracted with ethyl acetate and the ethyl acetate layer washed with a saturated saline solution and dried over sodium sulfate. After the solvent was evaporated in vacuo, the residue was separated and purified by a silica gel column chromatography (hexane/ethyl acetate=2/1) to give 180 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:10]2[S:14][C:13]([NH:15][CH2:16][C@@H:17]([NH:29]C(=O)OC(C)(C)C)[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:12][CH:11]=2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C@@H:17]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:21][CH:20]=1)[CH2:16][NH:15][C:13]1[S:14][C:10]([C:5]2[CH:6]=[CH:7][C:8]([F:9])=[C:3]([CH:4]=2)[C:1]#[N:2])=[CH:11][N:12]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1ncc(-c2ccc(F)c(C#N)c2)s1)Cc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(-c2cnc(NC[C@@H](N)Cc3ccc(C(F)(F)F)cc3)s2)ccc1F
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution of tert-butyl (S)-1-(5-(3-cyano-4-fluorophenyl)thiazol-2-ylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.18 g, 0.35 mmol) in 7 mL of DCM was added TFA (0.40 mL, 5.2 mmol). After 30 minutes, 2 mL of additional TFA was added. The mixture was stirred for 30 minutes and was then concentrated under reduced pressure. The residue was taken up in 30 mL of 1:1 EtOAc to 2 N aqueous Na2CO3. The mixture was partitioned in a separatory funnel, and the aqueous portion was extracted with 25 mL of EtOAc. The combined organic extracts were washed with brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (2.5% to 10% MeOH/DCM) afforded 5-(2-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propylamino)thiazol-5-yl)-2-fluorobenzonitrile (0.14 g, 0.33 mmol, 96% yield) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.83 (dd, J=5.8, 2.4 Hz, 1H), 7.76 (ddd, J=8.7, 5.0, 2.4 Hz, 1H), 7.68 (d, J=8.2 Hz, 2H), 7.52 (d, J=7.8 Hz, 2H), 7.48 (s, 1H), 7.35 (t, J=9.0 Hz, 1H), 3.84-3.78 (m, 1H), 3.68-3.63 (m, 1H), 3.55-3.47 (m, 1H), 3.14-3.04 (m, 2H) LCMS (M+H) 421 calc. for C20H19F3N4OS 420.43.
Reaction SMILES: [C:1]1(=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:6]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:3][CH2:2]1.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(O)C>[CH:1]1([CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)[C:6]=2[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(C=C2CC2)c2ccccc2n1Cc1cccc(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CCOC(=O)c1c(CC2CC2)c2ccccc2n1Cc1cccc(C(F)(F)F)c1

Procedure:
Ethyl 3-(cyclopropylidenemethyl)-1-[3-(trifluoromethyl)benzyl]-1H-indole-2-carboxylate (Example 182, 140 mg, 0.351 mmol) was stirred over Lindlar catalyst (28 mg) in ethanol (15 mL) under 1 atmosphere of hydrogen for 1 hour. The mixture was filtered through Celite with an excess of ethanol. The filtrate was concentrated, and the resulting crude oil was purified by flash chromatography on silica gel eluted with 20% Et2O/hexane. The title compound was collected as a yellow oil (95 mg, 67%). The product had: 1H NMR (300 MHz, acetone-d6) δ 7.78 (d, 1 H), 7.56-7.45 (m, 4 H), 7.34-7.32 (m, 1 H), 7.28-7.26 (m, 1 H), 7.16-7.13 (m, 1 H), 5.93 (s, 2 H), 4.32 (q, 2 H), 3.08 (d, 2 H), 1.31 (t, 3 H), 1.13-1.15 (m, 1 H), 0.42-0.38 (m, 2 H), 0.29-0.26 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][N:5]([CH:7]([F:9])[F:8])[CH:6]=1.Cl.[CH3:14][NH:15][O:16][CH3:17].CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH3:17][O:16][N:15]([CH3:14])[C:10]([C:3]1[C:2]([Cl:1])=[CH:6][N:5]([CH:7]([F:9])[F:8])[N:4]=1)=[O:12]
Reactant: O=C(O)c1nn(C(F)F)cc1Cl
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1nn(C(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid (880 mg, 4.5 mmol) and N,O-dimethylhydroxylamine hydrochloride (459 mg, 4.7 mmol) in dichloromethane (30 ml) was treated at room temperature with N-methylmorpholine (476 mg, 4.7 mmol). Thereafter, in three portions 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (901 mg, 4.7 mmol) was added. The solution was stirred at room temperature overnight. For the workup, the reaction mixture was treated dropwise with hydrochloric acid (1M, 30 ml) and stirred for 10 minutes. The organic layer was separated, washed with water, then dried over sodium sulphate and evaporated. The crude material was purified by chromatography on silica gel using a 2:1-mixture of cyclohexane and ethyl acetate as the eluent. The 4-chloro-1-difluoromethyl-1H-pyrazole-3-carboxylic acid methoxy-methyl-amide was obtained as a colourless oil (930 mg, 87%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Br[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38]>>[C:40]([O:39][C:37]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][O:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1)=[O:38])([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)OC(=O)CCCCCBr
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCCCCC(=O)OC(C)(C)C)C(C)(C)CCC2(C)C
Yield: 103.3 %

Procedure:
In a manner similar to that of Example 1(a), by reaction of 2.36 g (5.8 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 1.6 g (6.3 mmol) of tert-butyl 6-bromohexanoate obtained above, 3.3 g (100%) of the expected compound were obtained in the form of a yellow oil.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([C:13]1[CH:18]=[C:17]([N:19]2[C:23]3[N:24]=[C:25]([N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)[N:26]=[C:27]([C:28]4[CH:29]=[N:30][C:31]([N:34]([CH2:44][C:45]5[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=5)[CH2:35][C:36]5[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=5)=[N:32][CH:33]=4)[C:22]=3[CH2:21][CH2:20]2)[CH:16]=[CH:15][N:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:9]([O:8][C:6](=[O:7])[N:5]([C:13]1[CH:18]=[C:17]([N:19]2[C:23]3[N:24]=[C:25]([N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)[N:26]=[C:27]([C:28]4[CH:29]=[N:30][C:31]([N:34]([CH2:35][C:36]5[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=5)[CH2:44][C:45]5[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=5)=[N:32][CH:33]=4)[C:22]=3[CH2:21][CH2:20]2)[CH:16]=[CH:15][N:14]=1)[CH2:4][CH2:3][OH:2])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1cc(N2CCc3c(-c4cnc(N(Cc5ccc(OC)cc5)Cc5ccc(OC)cc5)nc4)nc(N4CCOCC4)nc32)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(N(CCO)C(=O)OC(C)(C)C)c3)cn2)cc1
Temperature: 0 °C
Yield: 56 %

Procedure:
A THF solution (5 ml) of {[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-tert-butoxycarbonyl-amino}-acetic acid methyl ester (135 mg, 0.168 mmol) obtained in Step B was cooled to −40°, and 1.0M diethyl ether solution (0.20 ml, 0.20 mmol) of lithium aluminium hydride was added, which was gradually raised to 0° C. over 1 hour. The reaction mixture was quenched with aqueous potassium sodium tartrate solution, followed by extraction with dichloromethane (15 ml×2). The organic layers were combined, and washed with saturated aqueous sodium chloride solution. After the organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=50:1), to obtain [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester as a yellow solid (73 mg, 56%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]([CH3:19])=[C:13]2[C:9]=1[CH2:10][CH:11]([NH:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12]2>O1CCCC1>[CH2:21]([NH:20][CH:11]1[CH2:12][C:13]2[C:9](=[C:8]([CH3:7])[C:16]([CH3:17])=[C:15]([CH3:18])[C:14]=2[CH3:19])[CH2:10]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1c(C)c(C)c2c(c1C)CC(NC(=O)c1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(C)c(C)c2c(c1C)CC(NCc1ccccc1)C2
Temperature: 50 °C
Reaction time: 20 h

Procedure:
1M Lithium aluminium hydride (2.4 ml) in tetrahydrofuran is added dropwise to a solution of N-(4,5,6,7-tetramethyl-indan-2-yl)-benzamide (352 mg) in anhydrous THF (10 ml) under nitrogen at room temperature. The reaction mixture is allowed to stir at 50° C. for 20 hours. After 4 hours more 1M Lithium aluminium hydride (1.2 ml, 1.20 mmol) in THF is added. On cooling the reaction mixture is quenched with ice water. The aqueous phase is washed with diethyl ether (×3) and the organic layers combined, treated with magnesium sulphate, filtered and the solvent removed in vacuo.