Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[N:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Cl)[CH:26]=1.C(N(CC)C(C)C)(C)C.O>CN(C=O)C.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:7]=[N:8][C:9]=1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=2)[CH2:13][CH2:12]1
Reactant: CCOC(=O)/C=C/c1cnc(NC2CCNCC2)c(Cl)c1
Reactant: ClCc1cccc(Cl)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/c1cnc(NC2CCN(Cc3cccc(Cl)c3)CC2)c(Cl)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 46 %

Procedure:
To a solution of ethyl (2E)-3-[5-chloro-6-(4-piperidinylamino)-3-pyridinyl]acrylate dihydrochloride (500 mg) in DMF (5 ml) was added 1-chloro-3-(chloromethyl)benzene (0.173 ml) and N,N-diisopropylethylamine (0.91 ml), the mixture was stirred at 70° C. for 7 hour. The mixed solution was poured into a mixture of water (30 ml) and AcOEt (30 ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give ethyl (2E)-3-(5-chloro-6-{[1-(3-chlorobenzyl)-4-piperidinyl]amino}-3-pyridinyl)acrylate (261 mg, 46%).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[C:34](#[N:37])[CH:35]=[CH2:36]>>[CH3:1][N:2]1[C:10]([CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH2:36][CH2:35][C:34]#[N:37])[CH2:14][CH2:13]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:24]1[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]=[C:25]1[CH3:33])=[N:6][C:7]=2[N:18]1[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1
Reactant: C=CC#N
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(CCC#N)CC3)n(C)c2n1

Procedure:
Following General Procedure C, 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine and acrylonitrile were reacted to give 568. LCMS m/z: 250.7 (2M+H+)
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[CH:8](I)[CH2:7][CH2:6][C:5]2[C:12]([O:19][CH3:20])=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=[CH:15][C:4]1=2)[CH3:2].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O>[N:21]([CH:8]1[C:9](=[O:10])[N:3]([CH2:1][CH3:2])[C:4]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH3:20])[C:5]=2[CH2:6][CH2:7]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CCN1C(=O)C(I)CCc2c1ccc([N+](=O)[O-])c2OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)C(N=[N+]=[N-])CCc2c1ccc([N+](=O)[O-])c2OC

Procedure:
Combined (+/−)-1-ethyl-3-iodo-6-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (1.3 g), Sodium azide (2.17 g) and N,N-Dimethylformamide (20 mL) in flask under nitrogen and stirred overnight. Partitioned between EtOAc/water. The organic layers were further washed with water, brine, dried (MgSO4), filtered and concentrated. Stripped onto Celite and purified by ISCO chromatography (120 g SiO2, hexane to EtOAc gradient). (+/−)-3-Azido-1-ethyl-6-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one isolated as a clear oil (402 mgs). 1H-NMR (CDCl3, 400 MHz): 7.86 (d, J=8.8 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 4.33-4.25 (m, 1H), 3.98 (s, 3H), 3.78-3.71 (broad m, 2H), 3.35-3.23 (broad m, 1H), 2.65-2.35 (broad m, 3H), 1.25-1.21 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([Br:18])=[CH:4][N:3]=1.[NH2:19][C@@H:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)[CH2:21][OH:22].O.CCOC(C)=O>C1COCC1>[NH2:1][C:2]1[C:7]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:19][C@@H:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[CH2:21][OH:22])=[O:14])=[C:10]([F:17])[CH:9]=2)=[CH:6][C:5]([Br:18])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1-c1ccc(C(=O)O)c(F)c1
Reactant: N[C@H](CO)c1cccc(Cl)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ncc(Br)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Reaction time: 15 h

Procedure:
To a solution of 4-(2-amino-5-bromopyridin-3-yl)-2-fluorobenzoic acid (300 mg, 0.964 mmol) in THF (8.036 mL) was added (S)-2-amino-2-(3-chlorophenyl)ethanol (331 mg, 1.157 mmol). The reaction mixture was stirred for 15 h. After water was added, the reaction mixture was worked up with EtOAc, the organic layer was dried over anhydrous Na2SO4, filtered off and concentrated in vacuo. The crude (S)-4-(2-amino-5-bromopyridin-3-yl)-N-(1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide was used for the next step without further purification. LCMS (m/z): 464.1/466.1 (MH+), 0.69 min.
Reaction SMILES: CC1C=[CH:6][C:5]([CH:8]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[C:9](=O)[CH:10]([CH3:12])[CH3:11])=[CH:4]C=1.[CH2:21]([SiH](CC)CC)C.FC(F)(F)C(O)=O.BrC1C=CC=CC=1C1CCCCC=1.C1COCC1>CCOCC.C(O)(=O)C.ClCCl>[CH3:6][C:5]1[CH:4]=[CH:12][C:10]([CH3:11])=[CH:9][C:8]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=1
Reactant: Cc1ccc(C(C(=O)C(C)C)c2ccc(C)cc2)cc1
Reactant: CC[SiH](CC)CC
Agent: Brc1ccccc1C1=CCCCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: Cc1cccc(-c2cc(C)ccc2C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 40.4 %

Procedure:
A round bottomed flask was purged with argon and charged with alcohol 1 (1.78 g, 7.0 mmol), dichloromethane (28 mL), triethylsilane (1.5 mL, 9.1 mmol), and trifluoroacetic acid (1.1 mL, 14.7 mmol). The mixture was stirred at room temperature for 1.5 h, then was quenched with solid potassium carbonate (ca 2 g). The mixture was diluted with ether (50 mL) and transferred to a separatory funnel. The mixture was washed with saturated aqueous NaHCO3 (50 mL), and the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford a mixture of 2 and 1-(2-bromophenyl)cyclohexene. The crude material was placed into a round bottomed flask, and the flask was purged with argon. THF (2 mL) was added, and the mixture was cooled to 0° C. with stirring. A solution of BH3 in THF (7 mL, 1M, 7.0 mmol) was added dropwise to the mixture. The mixture was stirred at 0° C. for 1.5 h, then warmed to room temperature and stirred for 19 h. Acetic acid (4 mL) was added and the mixture was stirred at room temperature for 6h. The mixture was then diluted with ether (50 mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (50 mL), the layers were separated, and the aqueous phase was extracted with ether (50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel to afford 555 mg of 2 which was judged to be 93% pure by GC analysis. This material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:24])[CH2:11][CH2:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]([OH:24])[CH2:11][CH2:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C2=C(c3cc(F)cc(F)c3)C(=O)CC2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C2=C(c3cc(F)cc(F)c3)C(O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.7 %

Procedure:
To a -78° C. solution of 2-(3,5-Difluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-cyclopenten-1-one (98 mg, 0.28 mmol) in THF (5 mL) was added DIBAL (1.5M toluene solution, 0.4 mL, 0.6 mmol). The solution was warmed to 0° C. and stirred 15 min, then cooled to -78° C. and quenched with 0.5 mL acetone. The solution was warmed and poured into 1M sodium potassium tartrate. The mixture was extracted with EtOAc, washed with brine, and dried over MgSO4. Crystallization from ether/hexanes provided the title compound (90 mg).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][C:23]([CH3:26])=[CH:22]4)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.CCOCC>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][C:23]([CH3:26])=[CH:22]4)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2cccc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c2[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: NCCN
Solvent: CCOCC
Product: Cc1cc2cccc(-c3cnc4[nH]cc(C(=O)NC(C)(C)C)c4n3)c2[nH]1
Temperature: 60 °C
Reaction time: 20 h
Yield: 66.2 %

Procedure:
To a stirred solution of N-tert-butyl-2-(2-methyl-1H-indol-7-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (60 mg, 126 μmol) in DMF (4 mL) was added ethylenediamine (355 mg, 399 μL, 5.9 mmol) then tetrabutylammonium fluoride (389 μL, 389 μmol). The solution was heated to 60° C. with stirring under a nitrogen atmosphere for 20 h. The reaction mixture was cooled, diluted with ether, washed water and brine, then dried (MgSO4), filtered, and concentrated in vacuo to give an oil which slowly crystallized. The crystals were triturated with water twice then dried under vacuum to give N-tert-butyl-2-(2-Methyl-1H-indol-7-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (29 mg) as a yellow solid. MS (M+H)+=348.1; 1H NMR (CDCl3) δ: 8.87 (s, 1H), 8.35 (d, J=3.0 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.55-7.61 (m, 1H), 7.20-7.30 (m, 2H), 6.33-6.36 (m, 1H), 2.54 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10]2[O:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:11]=2)[CH:7]=[C:6]([CH3:25])[CH:5]=1.[Li+].[OH-]>C1COCC1.O.Cl>[CH3:25][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]2[O:18][C:17]3[C:12](=[N:13][CH:14]=[CH:15][C:16]=3[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:11]=2)[CH:7]=1)[C:3]([OH:26])=[O:2]
Reactant: COC(=O)c1cc(C)cc(-c2cc3nccc(-c4ccccc4)c3o2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C(=O)O)cc(-c2cc3nccc(-c4ccccc4)c3o2)c1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
3-Methyl-5-(7-phenyl-furo[3,2-b]pyridin-2-yl)-benzoic acid methyl ester (61.321 μmol) is dissolved in THF (300.00 μl) and LiOH 1M (122,600 μmol) is added. The reaction solution is stirred 26 h at RT and diluted with H2O (10 ml) and 1M HCl (122.6 μl) is added. The precipitate is filtered and washed with water and dried in vacuo. The product is obtained as colorless solid in quantitative yield; LCMS (ESI+) (method E): Rt 2.25 min, M+H+ 330.1 m/z.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:37])[C:32]=1[O:33]C(C)C)[CH2:5][N:6]1[C:14]2[CH:13]=[C:12]3[NH:15][C:16]([NH:18][C:19](=[O:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:17][C:11]3=[CH:10][C:9]=2[C:8]([CH3:28])([CH3:27])[C:7]1=[O:29].B(Br)(Br)Br.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:37])[C:32]=1[OH:33])[CH2:5][N:6]1[C:14]2[CH:13]=[C:12]3[NH:15][C:16]([NH:18][C:19](=[O:26])[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:17][C:11]3=[CH:10][C:9]=2[C:8]([CH3:27])([CH3:28])[C:7]1=[O:29]
Reactant: CC(C)Oc1c(F)cc(CN2C(=O)C(C)(C)c3cc4nc(NC(=O)c5ccccc5)[nH]c4cc32)cc1F
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: CC1(C)C(=O)N(Cc2cc(F)c(O)c(F)c2)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.3 %

Procedure:
N-[5-(3,5-Difluoro-4-isopropoxy-benzyl)-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl]-benzamide (90 mg; 0.18 mmol) is suspended in a BBr3 solution in CH2Cl2 (1 M; 600 μl ) and stirred at RT for 18 h. After addition of hydrochloric acid (300 μl; 1 N) the mixture is stirred at RT for another 1 h and then evaporated to dryness. The crude material is purified by preparative RP-HPLC, eluted with MeCN/water to yield the desired compound (27.7 mg).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:15][N:14]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[CH3:19][C:17]1[C:16]([O:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:15][N:14]=[C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH:18]=1
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ncc1OCCC(F)(F)F
Reactant: O=COc1ccccc1
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)ncc1OCCC(F)(F)F
Yield: 41 %

Procedure:
The title compound is prepared in 41% yield (30 mg, white solid) from 4-chloro-2-((4-methyl-5-(3,3,3-trifluoropropoxy)pyridin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (60 mg, 0.16 mmol, Intermediate-75) and phenyl formate (38 mg, 0.31 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: Cl[CH2:2][CH:3]([O:6][CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4]Cl.[CH3:20][NH2:21]>>[C:8]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:6][CH:3]2[CH2:4][N:21]([CH3:20])[CH2:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN
Reactant: ClCC(CCl)OC(c1ccccc1)c1ccccc1
Product: CN1CC(OC(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 244. g (0.83 mole) of 1,3-dichloro-2-diphenylmethoxypropane in 300 ml of methylamine was heated in a steel bomb to 100° for 18 hours. The mixture was concentrated, and the residue partitioned between chloroform and dilute hydrochloric acid. The acid solution was washed twice with chloroform, and the chloroform solutions combined. The chloroform was extracted with dilute sodium hydroxide, dried with sodium sulfate, and concentrated. The residue was distilled (b.p. 125°-130°/0.1 mm) to yield 104 g (40%). The distillate crystallizes on standing and can be recrystallized from isooctane, mp 44°-48°.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1([CH2:12][OH:13])[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][CH2:4]1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21]>N1C=CC=CC=1>[CH3:1][N:2]([CH3:14])[C:3]1([CH2:12][O:13][C:20](=[O:21])[C:19]2[CH:18]=[C:17]([O:16][CH3:15])[C:25]([O:26][CH3:27])=[C:24]([O:28][CH3:29])[CH:23]=2)[C:8]2[CH:9]=[CH:10][S:11][C:7]=2[CH2:6][CH2:5][CH2:4]1
Reactant: CN(C)C1(CO)CCCc2sccc21
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc(C(=O)OCC2(N(C)C)CCCc3sccc32)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 14 h

Procedure:
15 ml of pyridine Containing 1.52 g of 4-dimethylamino-4-hydroxymethyl-4,5,6,7-tetrahydro-1-benzothiophene obtained in Example 1 was cooled with ice, and added with 1.82 g of 3,4,5-trimethoxybenzoylchloride. The reaction mixture was then stirred at room temperature for 14 hours. The solvent was removed under reduced pressure, and the residue was poured into water, followed by extracting with chloroform. The chloroform phase was washed with water and dried. The solvent was removed under reduced pressure, and the residue was crystallized from isopropyl ether to obtain 1.87 g of the title compound as colorless crystals.
Reaction SMILES: [F:1][CH:2]([F:11])[CH:3](C(F)F)[C:4]([F:7])([F:6])[F:5].ClC(Cl)(Cl)C(=[O:18])C(Cl)Cl>>[F:5][C:4]([F:7])([F:6])[C:3](=[O:18])[CH:2]([F:11])[F:1]
Reactant: O=C(C(Cl)Cl)C(Cl)(Cl)Cl
Reactant: FC(F)C(C(F)F)C(F)(F)F
Product: O=C(C(F)F)C(F)(F)F

Procedure:
As another preparation example, 2-difluoromethyl-1,1,1,3,3-pentafluoropropane may be prepared by fluorinating commercially available 1,1,1,3,3-pentachloro-2-propanone to form 1,1,1,3,3-pentafluoro-2-propanone which may then be reacted with CF2 carbene to form 2-difluoromethyl-1,1,3,3,3-tetrafluoro-1-propene. The 2-difluoromethyl-1,1,3,3,3-tetrafluoro-1-propene may then be hydrogenated to form 2-difluoromethyl-1,1,1,3,3-pentafluoropropane.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1([C:16](Br)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1.[K+].[Br-]>O>[C:10]1([C:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[CH:1])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C#CC(O)CCCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: C#CC(CCCCC)OC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 1.26 g. (10.0 mmoles) of 1-octyn-3-ol, 4.85 g. (15.0 mmoles) of triphenylmethyl bromide, and 50 ml. of dry pyridine is heated at 95° C. for 60 minutes with occasional swirling. The solution is cooled, treated with water, and extracted with ether. The extract is washed successively with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by chromatography on Florisil and recrystallization from petroleum ether to give white crystals, m.p. 65°-66.5°, νmax. (KBr) 3280 (acetylenic hydrogen), 1605, 1030, and 702 cm-1 (triphenylmethoxy group).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([C:10]1[CH:17]=[C:16]([CH3:18])[C:13]([C:14]#[N:15])=[C:12](I)[C:11]=1[O:20][CH2:21][CH3:22])(=[O:9])[CH3:8].[CH3:23][N:24]([CH3:36])[C:25]([C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].ClCCl>O.C(#N)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:7]([C:10]1[C:11]([O:20][CH2:21][CH3:22])=[C:12]([C:30]2[CH:29]=[CH:28][C:27]([C:25]([N:24]([CH3:36])[CH3:23])=[O:26])=[N:32][CH:31]=2)[C:13]([C:14]#[N:15])=[C:16]([CH3:18])[CH:17]=1)(=[O:9])[CH3:8]
Reactant: CN(C)C(=O)c1ccc(B(O)O)cn1
Reactant: CCOc1c(C(C)=O)cc(C)c(C#N)c1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCOc1c(C(C)=O)cc(C)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 100 °C
Yield: 74.4 %

Procedure:
Sodium carbonate (3 g, 30 mmol) in water (20 mL) was added to a mixture of 4-acetyl-3-ethoxy-2-iodo-6-methylbenzonitrile (3 g, 9 mmol) and {6-[(dimethylamino)carbonyl]pyridin-3-yl}boronic acid (1700 mg, 8.8 mmol, Example 313, Step 2) in acetonitrile (100 mL). The mixture was degassed with nitrogen and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (400 mg, 0.4 mmol) was added. The reaction was degassed again with nitrogen and was heated to 100° C. for 4 hrs. The reaction was allowed to cool to room temperature, diluted with water and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give the crude product. The product was purified by FCC on silica gel eluting (hexane/EtOAc, 0-100%) gradient to give 5-(3-acetyl-6-cyano-2-ethoxy-5-methylphenyl)-N,N-dimethylpyridine-2-carboxamide product as yellow solid (2.3 g, 75%). LCMS calculated for C20H22N3O3(M+H)+: m/z=352.1; found: 352.2.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH3:11])[CH2:7][C:6]2[CH:12]=[C:13]([C:16]([O:18]C(C)(C)C)=O)[CH:14]=[CH:15][C:5]=2[NH:4]1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[CH2:33][NH:34][CH3:35].CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.Cl>>[CH3:35][N:34]([CH2:33][C:25]1[N:24]([CH3:23])[C:32]2[C:27]([CH:26]=1)=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:16]([C:13]1[CH:14]=[CH:15][C:5]2[NH:4][C@H:3]([CH2:2][OH:1])[C:9](=[O:10])[N:8]([CH3:11])[CH2:7][C:6]=2[CH:12]=1)=[O:18]
Reactant: CNCc1cc2ccccc2n1C
Reactant: CN1Cc2cc(C(=O)OC(C)(C)C)ccc2N[C@H](CO)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccc2c(c1)CN(C)C(=O)[C@@H](CO)N2
Yield: 90.7 %

Procedure:
According to the procedure of Example 8, except using tert-butyl (2R)-2-hydroxymethyl-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylate (0.50 g, 1.6 mmole), 1-methyl-2-(methylaminomethyl)indole (0.26 g, 1.6 mmole), Et3N (0.46 mL, 3.3 mmole), HOBt.H2O (0.22 g, 1.6 mmole), and EDC.HCl (0.31 g, 1.6 mmole), the title compound (0.59 g, 91%) was prepared as an off-white solid following flash chromatography on silica gel (gradient: 2-4% MeOH/CHCl3): MS (ES) m/e 407.1 (M+H)+.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:12][CH2:11]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[O:18]([CH2:17][CH2:16][N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH:8][C:1](=[O:3])[CH3:2])[CH2:11][CH2:12]1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: NCC1CCN(CCOc2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)NCC1CCN(CCOc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetic anhydride (8.72 g) was added with stirring to a mixture of 4-aminomethyl-1-(2-phenoxyethyl)piperidine (20.0 g) in pyridine (85 ml) containing 4-dimethylaminopyridine (catalytic amount) with cooling to maintain ambient temperature. The mixture was stirred overnight at ambient temperature and then evaporated to dryness. Water was removed by adding toluene and removing the toluene by distillation. The residue was dissolved in water (100 ml) and 2M hydrochloric acid (50 ml). The solution was washed with dichloromethane, basified with concentrated sodium hydroxide solution and extracted with dichloromethane to give N-[1-(2-phenoxyethyl)piperid-4-ylmethyl]acetamide as an oil which solidified on standing, m.p. 79°-80° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[N+:10]([O-])=O)=[CH:4][C:3]=1[Cl:13].[Li+].[BH4-].Cl[Si](C)(C)C>C1COCC1>[Cl:13][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][NH2:10])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])/C=C/c1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 96.3 %

Procedure:
Using an analogous procedure and workup as described for the preparation of intermediate I-15b, (E)-1,2-dichloro-4-(2-nitrovinyl)benzene (I-55a: 6.2 g, 28.97 mmol) in dry THF (62 mL) was reacted with LiBH4 (2.52 g, 115.887 mmol) and chlorotrimethylsilane (25.17 g, 231.768 mmol) at 0° C. The resulting mixture was stirred at room temperature for 40 hours to afford 5.3 g of the product (98% yield).
Reaction SMILES: I[C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][S:11][C:5]2=[N:4][C:3]=1[CH3:12].C([O-])([O-])=O.[Na+].[Na+].[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:26])[CH:25]=1>C1(C)C=CC=CC=1.O.C(O)C>[F:19][C:20]1[CH:21]=[C:22]([C:2]2[C:7](=[O:8])[N:6]3[CH:9]=[CH:10][S:11][C:5]3=[N:4][C:3]=2[CH3:12])[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Cc1nc2sccn2c(=O)c1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1

Procedure:
To a solution of Step 2 intermediate (0.300 g, 1.027 mmol) in toluene (10 ml) was added Pd[(C6H5)3P]4 [tetrakis(triphenylphosphine)palladium(0)] (0.048 g. 0.042 mmol) and a solution of Na2CO3 (0.653 g, 6.162 mmol) in water (4 ml). A solution of 3,5-difluorophenylboronic acid (6.5 g, 44.235 mmol) in ethanol (6 ml) was added to the reaction mixture and it was refluxed for 1.5 h. After completion of the reaction mixture, the solvent was concentrated in vacuo, the residue partitioned between ethyl acetate (200 ml) and water (50 ml). The organic layer was washed with brine (50 ml) and dried over anhydrous Na2SO4 to afford a crude product which was purified by silica gel column chromatography using 10% ethyl acetate in chloroform to give 280 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 2.19 (s, 3H), 7.53 (d, J=7.8 Hz, 3H), 7.88 (d, J=7.8 Hz, 1H) 8.02 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 276.31 (M−H)−.