Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[C:5]#[N:6].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O.O.CO.O>[O:17]=[C:15]1[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12](=[O:22])[N:16]1[CH2:2][C:3]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: N#Cc1cc(F)ccc1CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: N#Cc1cc(F)ccc1CN1C(=O)c2ccccc2C1=O
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a stirred solution of intermediate 104, 2-(bromomethyl)-5-fluorobenzonitrile (29.72 g, 139 mmol) and phthalimide (32.69 g, 222 mmol) in dimethylformamide (300 mL) was added Cs2CO3 (67.87 g, 208 mmol). After stirring vigorously for 1 h, the reaction mixture was poured into water (1.2 L). The precipitated product was filtered, washed with water (600 mL) and methanol (150 mL) to give a white solid. The solid was taken up into 1L of water/methanol (2:1) to which was added K2CO3 (12 g) and the mixture stirred at 40° C. After 30 min., the mixture was cooled and filtered. The filter cake was washed with water (500 mL), and dried under vacuum to afford the title compound (38.91 g, 94% yield) as a white powder. 1H NMR (500 MHz, CDCl3) δ: 7.89 (2H, dd, J=5.5, 3.1 HZ), 7.76 (5.5, 3.1 Hz), 7.41 (1H, dd, J=8.6, 5.2 Hz), 7.38 (1H, dd, J=7.9, 2.8 Hz), 7.24 (1H, td, J=8.2, 2.8 Hz), 5.06 (2H, s). LCMS (M+H) calcd for C16H10FN2O2: 281.07; found: 281.15.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1([CH2:10][OH:11])[CH2:9][O:8][CH2:7]1.O[C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:33]#[C:34][CH3:35])[CH2:28][C:29]([O:31]C)=[O:30])=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]1([CH2:10][O:11][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([C:33]#[C:34][CH3:35])[CH2:28][C:29]([OH:31])=[O:30])=[CH:23][CH:22]=2)[CH2:7][O:8][CH2:9]1
Reactant: OCC1(COc2ccc(C(F)(F)F)cc2Cl)COC1
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Product: CC#CC(CC(=O)O)c1ccc(OCC2(COc3ccc(C(F)(F)F)cc3Cl)COC2)cc1

Procedure:
Analogously to example 1, [3-(2-chloro-4-trifluoromethylphenoxymethyl)oxetan-3-yl]-methanol and methyl 3-(4-hydroxyphenyl)hex-4-ynoate were used to obtain 3-{4-[3-(2-chloro-4-trifluoromethylphenoxymethyl)oxetan-3-ylmethoxy]phenyl}hex-4-ynoic acid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl
Product: Cc1sc2nc(-n3cncn3)nc(NCc3ccc(Cl)c(Cl)c3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2,5-dichloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5-chloro-6-methyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32](O)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=23)[CH2:3][CH2:2]1.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[C:20]([C:32]([NH:35][C@H:36]4[CH2:41][CH2:40][C@H:39]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:38][CH2:37]4)=[O:33])=[C:21]([CH3:31])[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:15]=23)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: COc1ccc(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c4) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)([CH2:14][NH2:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:1]([N:8]1[CH2:9][CH2:10][C:11]([CH2:14][NH:15][S:30]([CH3:29])(=[O:32])=[O:31])([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(C2CCCCC2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNS(C)(=O)=O)(C2CCCCC2)CC1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 92.8 %

Procedure:
A 15-mL, round-bottomed flask was purged with nitrogen and then charged with the amine from Step A (0.063 g, 0.213 mmol), 1.7 mL of methylene chloride, and triethylamine (0.045 mL, 0.320 mmol). The reaction mixture was cooled at 0° C. in an ice-water bath and then methanesulfonyl chloride (0.018 mL, 0.23 mmol) was added dropwise via syringe. The resulting mixture was stirred at 0° C. for 50 min, warmed to room temperature, and stirred for 16.5 h. The reaction mixture was then diluted with methylene chloride and washed with two portions of 1N HCl solution, saturated sodium bicarbonate solution, water, and saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography (1:1 methylene chloride-acetone) to give the desired product (0.074 g) as a white solid.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(OCC)(=O)C>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=2[O-:20])=[CH:4][N:3]=[CH:2]1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: [O-][n+]1ccccc1-c1cnco1
Temperature: 25 °C
Reaction time: 144 h
Yield: 35.7 %

Procedure:
2-(1,3-Oxazol-5-yl)pyridine (2.8 g, 19 mmol) and 3-chloroperbenzoic acid (77%, 13.6 g, 58 mmol) were dissolved in ethyl acetate, and the mixture was stirred at room temperature for 6 days. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (1:4, v/v) were collected and concentrated to give the titled compound (1.1 g, 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH:18]1([C:23](=O)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:23]2[C:24]([C:25]#[N:26])=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:3]3[C:2](=[CH:7][C:6]([O:8][CH3:9])=[CH:5][CH:4]=3)[N:1]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1ccc(C(=O)c2ccccc2)c(N)c1
Reactant: N#CCC(=O)C1CCCC1
Product: COc1ccc2c(-c3ccccc3)c(C#N)c(C3CCCC3)nc2c1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-4-methoxy-phenyl)-phenyl-methanone (prepared as described in example 121 step A) and 3-cyclopentyl-3-oxo-propionitrile (prepared as described in example 105 step A). White solid. MS (ESI): 329.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]3)=[N:9][C:10]=2[C:11]2[CH:26]=[CH:25][C:14]([C:15]([NH:17][C:18]3[S:19][C:20]([CH2:23][CH3:24])=[CH:21][N:22]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:33][O:34][CH2:35]/[CH:36]=[CH:37]/[C:38](O)=[O:39]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][N:28]3[C:38](=[O:39])/[CH:37]=[CH:36]/[CH2:35][O:34][CH3:33])=[N:9][C:10]=2[C:11]2[CH:26]=[CH:25][C:14]([C:15]([NH:17][C:18]3[S:19][C:20]([CH2:23][CH3:24])=[CH:21][N:22]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCc1cnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCCN4)n4ccnc(N)c34)cc2)s1
Reactant: COC/C=C/C(=O)O
Product: CCc1cnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCCN4C(=O)/C=C/COC)n4ccnc(N)c34)cc2)s1
Yield: 47.6 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(5-ethylthiazol-2-yl)benzamide (intermediate 37) and (E)-4-methoxybut-2-enoic acid (Intermediate 3), to afford the title compound (11.7 mg, 47.6%). Data: UPLC(C) Rt: 2.59 min; m/z 546.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:11][C@H:12]([CH2:17][OH:18])[C@H:13]([CH2:15][CH3:16])[CH3:14].C(N(CC)CC)C.CCOC(C)=O.CCCCCC>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([S:7]([NH:11][C@H:12]([CH2:17][OH:18])[C@@H:13]([CH3:14])[CH2:15][CH3:16])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CC[C@H](C)[C@H](N)CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H](CO)NS(=O)(=O)c1ccc(Br)s1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
5-Bromothiophene-2-sulfonyl chloride (5.0 g, 19.11 mmol) was added dropwise (5 min) as a solution in CH2Cl2 (10 mL) to a 0° C. solution of L-isoleucinol (2.108 g, 18.16 mmol) in CH2Cl2 (15 mL) and triethylamine (3.77 mL, 27.24 mmol). The solution was allowed to warm to 25° C. overnight (19 h). An aliquot was taken and TLC (1:1 EtOAc-hexane) indicated that reaction was complete. It was diluted in methylene chloride (100 mL) and the organic layer was washed with 1N HCl (2×50 mL) and saturated aqueous NaCl (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated to obtain a crude off-yellow solid (5.2 g). The crude product was purified by column chromatography, silica gel 230-400 mesh, eluent: starting with 1:4 EtOAc-hexane and ending with 1:1 EtOAc-hexane to furnish 5-bromo-N-[(1S,2S)-1-(hydroxymethyl)-2-methylbutyl]-2-thiophenesulfonamide as an amorphous white solid (4.3 g, 70.49%). Mass Spectrum (−ESI): 246 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:16]([OH:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=O)=[C:5]([CH3:19])[O:4][N:3]=1.[CH3:20][C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:9]([C:29]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][C:21]=3[CH3:20])[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:16]2=[O:17])=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: Cc1noc(C)c1CN1C(=O)c2ccccc2C1O
Reactant: Cc1cc2ccccc2[nH]1
Product: Cc1noc(C)c1CN1C(=O)c2ccccc2C1c1c(C)[nH]c2ccccc12
Temperature: 180 °C

Procedure:
The product of example 22, step b) (230 mg, 0.89 mmol) was treated with 2-methyl indole (196 mg, 1.5 mmol) and heated (neat) to 180° C. for 1 h. The reaction was cooled and the sub-title product was purified by silica chromatography (EtOAc/Hex).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:23]=[C:22](B(O)O)[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:22]2[C:16]3[CH2:17][C:18]([CH3:20])([CH3:21])[O:19][C:15]=3[CH:14]=[C:13]([Cl:12])[CH:23]=2)=[CH:4][N:3]=1
Reactant: Cc1c(Br)cnc(N)c1C#N
Reactant: CC1(C)Cc2c(cc(Cl)cc2B(O)O)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(Cl)cc3c2CC(C)(C)O3)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 2.7 grams (0.012 mole) of 6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-ylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 mL (catalyst) of tetrakis(triphenylphosphine)palladium(O)in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-(6-chloro-2,3-dihydro-2,2-dimethylbenzofuran-4-yl)pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH3:13])=[C:8]([F:21])[CH:7]=1)=[CH2:5])[CH3:2].Cl[CH2:23]I.C([Zn]CC)C.[NH4+].[Cl-]>C1(C)C=CC=CC=1.CO.C(Cl)Cl>[CH2:1]([O:3][C:4]1([C:6]2[CH:11]=[CH:10][C:9]([C@@H:12]([NH:14][S@@:15]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:16])[CH3:13])=[C:8]([F:21])[CH:7]=2)[CH2:23][CH2:5]1)[CH3:2]
Reactant: ClCI
Reactant: C=C(OCC)c1ccc([C@H](C)N[S@](=O)C(C)(C)C)c(F)c1
Agent: CC[Zn]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC1(c2ccc([C@H](C)N[S@](=O)C(C)(C)C)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.2 %

Procedure:
To a round bottom flask containing (R)—N—((S)-1-(4-(1-ethoxyvinyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (0.49 g, 1.56 mmol) and chloroiodomethane (1.14 mL, 15.6 mmol) in toluene (15 mL) at 0° C. under argon was added diethylzinc (1.0M in hexanes) (15.6 mL, 15.6 mmol). Reaction mixture allowed to warm to room temperature and stirred for 1 hour. Reaction mixture was cooled to 0° C. in an ice bath and to the cold reaction mixture was slowly added a saturated solution of NH4Cl. The aqueous mixture was extracted with EtOAc. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated onto silica gel. Silica gel column chromatography (MeOH/CH2Cl2 0 to 10%) provided (R)—N—((S)-1-(4-(1-ethoxycyclopropyl)-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (145 mg, 0.44 mmol, 28% yield) as a viscous brown oil. 1H NMR (300 MHz, CDCl3) δ 0.93-0.99 (m, 2H) 1.14-1.20 (m, 3H) 1.21 (s, 9H) 1.22-1.27 (m, 2H) 1.57-1.61 (m, 4H) 3.35 (d, J=4.98 Hz, 1H) 3.45 (q, J=7.07 Hz, 2H) 4.77-4.87 (m, 1H) 6.98 (dd, J=7.58, 1.43 Hz, 3H) 7.00-7.03 (m, 4H) 7.28-7.32 (m, 1H). LCMS m/z 328.1 (M+H)+, Rt 0.95 min.
Reaction SMILES: O.O[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:16])[CH3:15])[CH2:4][CH2:5][CH3:6].Cl.[H][H]>[Pd].C(O)C>[CH2:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:16])[CH3:15])[CH2:4][CH2:5][CH3:6]
Reactant: [H][H]
Reactant: CCCC(O)c1ccccc1NC(C)=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCc1ccccc1NC(C)=O
Yield: 94 %

Procedure:
A suspension of 10% (w/w) palladium on carbon (7.8 g, wet with an additional 50% by weight of water) in absolute ethanol (625 ml) containing N-[2-(1-hydroxybutyl)phenyl]acetamide (156 g) was prepared, and concentrated hydrochloric acid (3.2 ml) was added. The mixture was shaken under a positive pressure of about 345,000 Pascals (50 pounds per square inch gauge reading) of hydrogen gas. When hydrogen uptake had ceased (in about 24 hours), the mixture was filtered through diatomaceous earth, and the filtrate was concentrated at reduced pressure to afford 135.3 grams (94% yield) of the title compound as a white solid, m.p. 96.5°-99.5°. This material was used in step (f) without further purification.
Reaction SMILES: F[B-](F)(F)F.[N:6]#[O+:7].[C:8]([O:12][C:13]([NH:15][CH:16]1[CH2:18][CH2:17]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].N1C=CC=CC=1.CCOC(C)=O>C(#N)C>[N:6]([N:15]([CH:16]1[CH2:18][CH2:17]1)[C:13]([O:12][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:14])=[O:7]
Reactant: CC(C)(C)OC(=O)NC1CC1
Reactant: N#[O+]
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N(N=O)C1CC1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 106.7 %

Procedure:
Nitrosonium tetrafluoroborate (9.32 g, 79.8 mmol) was added carefully in several portions to a cooled (−30° C.) solution of N-(tert-butoxycarbonyl)cyclopropylamine (9.57 g, 60.9 mmol) and anhydrous pyridine (11.7 mL) in dry acetonitrile (150 mL). The solution was stirred at −30° C. for 30 minutes, and then at 0° C. for 2 hours. Ice water and EtOAc were added and the organic phase was separated and washed quickly with 1N HCl to remove pyridine. The organic phase was washed with 1N NaHCO3 and brine, dried (MgSO4), filtered, and evaporated under high vacuum with a water bath temperature below 40° C. to give N-nitroso-N-(tert-butoxycarbonyl)amino-cyclopropane (12.1 g, quantitative) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29]OS(C)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCN(C)C1=O.O>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH2:29][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:7]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COS(C)(=O)=O
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 48 h
Yield: 45.4 %

Procedure:
A mixture of 2.2 g (8.7 mmol) 1-(6-chloro-1H-indol-3-yl)-2,2,2-trifluoro-ethanone, 3.7 g (13 mmol) (S)-2-methanesulfonyloxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (preparation described in Tetrahedron 2006, 62, 4584-4589) and 5.7 g (18 mmol) cesium carbonate in 44 ml dry 1,3-dimethyl-3,4,5,6-tetrahydropyrimidinone (DMPU) was stirred for 48 h at 80° C. The reaction mixture was diluted with 100 ml water and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over sodium sulfate and concentrated to dryness. Residual DMPU was removed by kugelrohrdistillation in high vacuo (ca. 1 mbar) at 120° C. Flash chromatography gave the title compound (1.7 g, 46%) as a light yellow solid.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][C:4]2N(O)N=N[C:3]=2C=1.FC(F)(F)C([O-])=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([CH2:37][C:38]([OH:40])=O)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]3=[NH+:34][CH:35]=[CH:36][N:26]23)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.N1CCCC1>CN(C=O)C.C(Cl)CCl>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2([CH2:37][C:38](=[O:40])[N:5]3[CH2:4][CH2:3][CH2:1][CH2:6]3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]3=[N:34][CH:35]=[CH:36][N:26]23)=[CH:23][CH:24]=1
Reactant: O=C(O)CC1(c2ccc(Br)cc2)c2ccccc2-c2[nH+]ccn21
Reactant: On1nnc2cccnc21
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC1(c2ccc(Br)cc2)c2ccccc2-c2nccn21)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of EDC (49.2 mg) and HOAT (17.5 mg) was added a solution of 5-(4-bromophenyl)-5-(carboxymethyl)-5H-imidazo[2,1-a]isoindol-1-ium trifluoroacetate (62 mg) and Hunig's base (0.134 mL) in DMF (1 mL) followed by pyrrolidine (22.8 mg). The reaction mixture was stirred overnight at room temperature and was then purified by reversed phase HPLC (21×100 mm Phenomenex Gemini, 15-70% MeCN/water containing 0.05% NH4OH over 20 min at 20 mL/min) to give title compound as a white solid. HRMS. Found, 422.0873; calcd for (M+H)+, 422.0863. 1H NMR (500 MHz, CDCl3): δ 7.84 (d, J=7.60 Hz, 1 H); 7.47 (d, J=1.30 Hz, 1 H); 7.42-7.39 (m, 3 H); 7.29-7.26 (m, 3 H); 6.91 (dd, J=21.03, 8.48 Hz, 2 H); 3.71 (d, J=16.82 Hz, 1 H); 3.42 (t, J=6.89 Hz, 2 H); 3.34 (dt, J=9.85, 6.85 Hz, 1 H); 3.18 (dt, J=9.89, 6.80 Hz, 1 H); 2.86 (d, J=16.81 Hz, 1 H); 1.95-1.79 (m, 4 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:31])[CH:28]([F:30])[F:29])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:11][C:10]=2[C:21]2[CH:26]=[CH:25][C:24]([CH:27]([OH:31])[CH:28]([F:29])[F:30])=[CH:23][CH:22]=2)=[CH:6][CH:7]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(C(=O)C(F)F)cc2)c1Sc1ccc(Cl)cc1
Solvent: CCO
Product: Cn1c(-c2ccccn2)nc(-c2ccc(C(O)C(F)F)cc2)c1Sc1ccc(Cl)cc1

Procedure:
The title compound was prepared from 1-(4-{5-[(4-chlorophenyl)thio]-1-methyl-2-pyridin-2-yl-1H-imidazol-4-yl}phenyl)-2,2-difluoroethanone (Example 56) following the procedure described for Example 55. 1H NMR (500 MHz, (CDCl3): 8.65 (d, 1H), 8.38 (d, 1H), 8.04 (d, 2H), 7.84 (t, 1H), 7.39 (d, 2H), 7.36 (t, 1H), 7.26 (d, 2H), 7.03 (d, 2H), 5.74 (dt, 1H), 4.58 (m, 1H), 4.12 (s, 3H). LCMS: m/z 458 (M+H)+. The racemic alcohol was resolved on a Chiral AD-H column (20% EtOH/80% hexanes, flow rate 1 mL/min) to give two enantiomers: faster enantiomer's retention time=17.8 min; slower enantiomer's retention time=20.4 min.
Reaction SMILES: Br.[S:2]1[CH2:5][CH:4]([NH2:6])[CH2:3]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:30][C:31]1[CH:39]=[C:38]([C:40]2[CH2:41][C:42]([C:49]3[CH:54]=[C:53]([Cl:55])[C:52]([Cl:56])=[C:51]([Cl:57])[CH:50]=3)([C:45]([F:48])([F:47])[F:46])[CH2:43][N:44]=2)[CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34]>CN(C)C=O.C(N(CC)CC)C.C(OC)(C)(C)C>[CH3:30][C:31]1[CH:39]=[C:38]([C:40]2[CH2:41][C:42]([C:49]3[CH:50]=[C:51]([Cl:57])[C:52]([Cl:56])=[C:53]([Cl:55])[CH:54]=3)([C:45]([F:46])([F:48])[F:47])[CH2:43][N:44]=2)[CH:37]=[CH:36][C:32]=1[C:33]([NH:6][CH:4]1[CH2:5][S:2][CH2:3]1)=[O:34]
Reactant: NC1CSC1
Reactant: Cc1cc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: Cc1cc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NC1CSC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of thietan-3-amine hydrobromide in N,N-dimethylformamide, triethylamine was added at 0° C. Then 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122 mg, 0.53 mmol), 1-hydroxybenzotriazole monohydrate (72 mg, 0.53 mmol), and 2-methyl-4-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]benzoic acid (200 mg, 0.44 mmol) were added to the solution. The reaction mixture was stirred overnight at room temperature and then diluted with t-BuOMe and washed with 2M HCl, and after that with H2O, saturated NaCl aq. and dried over MgSO4. After evaporation, the residue was purified with chromatography (220 mg, 95%).
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([CH:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=4)[NH:21][C:20]3=[O:30])[CH:12]=[CH:11][C:10]1=2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(OCC)(=O)C>[OH:8][CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([CH:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=4)[NH:21][C:20]3=[O:30])[CH:12]=[CH:11][C:10]1=2
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2nc(C3C(=O)Nc4ccc(C#N)cc43)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)C(c1ccc3c(n1)CCCC3O)C(=O)N2
Temperature: 0 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A suspension of 3-(5-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydroquinolin-2-yl)-2-oxoindoline-5-carbonitrile (26 mg, 0.062 mmol) in tetrahydrofuran (5 mL) was cooled to 0° C. To this mixture was added dropwise a 1.0M solution of TBAF in THF (0.124 ml, 0.124 mmol) resulting in a clear yellow solution. The reaction was stirred for 1 h at 0° C. and then warmed to RT. After 3 h another portion of TBAF (1.0M in THF, 0.124 ml, 0.124 mmol) was added and the reaction was stirred at RT for 16 h. The mixture was diluted with ethyl acetate and the organic layer was washed with water (2×) and brine (1×). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (silica gel, DCM/MeOH) yielding a yellow solid. Amount 11 mg. Yield 59%.