Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([N:40]([CH3:42])[CH3:41])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[CH3:41][N:40]([CH3:42])[CH:37]1[CH2:36][CH2:35][N:34]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:39][CH2:38]1
Reactant: CN(C)C1CCN(S(=O)(=O)c2ccccc2Br)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: CN(C)C1CCN(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)CC1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-N,N-dimethylpiperidin-4-amine. MS (ESI): mass calcd. for C23H26FN5O2S, 455.18; m/z found, 456.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38 (m, 1H), 8.20 (d, J=1.5, 1H), 8.14-8.10 (m, 1H), 7.99-7.94 (m, 1H), 7.76-7.71 (m, 1H), 7.66-7.61 (m, 1H), 7.47-7.43 (m, 1H), 7.36-7.30 (m, 2H), 3.52-3.45 (m, 2H), 3.26-3.16 (m, 1H), 2.78 (s, 6H), 2.55-2.44 (m, 2H), 1.93 (d, J=11.6, 2H), 1.48-1.36 (m, 2H).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH2:7][CH2:8][C:9]1[N:10]([CH3:25])[C:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][CH2:5][C@@:6]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH2:7][CH2:8][C:9]1[N:10]([CH3:25])[C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@](C)(CCc1ccc(C#CCCCc2ccccc2)n1C)COC(C)=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)N[C@](C)(CCc1ccc(CCCCCc2ccccc2)n1C)COC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
To a solution of (2R)-1-acetoxy-2-acetylamino-2-methyl-4-[1-methyl-5-(5-phenylpent-1-ynyl)pyrrol-2-yl]butane (77 mg, 0.19 mmol) obtained in Example (31a) in methanol (2 ml) was added 10% palladium-charcoal (50% wet with water) (4.3 mg), and the resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. After stirring, the internal atmosphere was replaced with nitrogen, and the palladium-charcoal in the reaction mixture was filtered off using celite, which was washed with ethyl acetate. The filtrate and the washings were combined and evaporated to dryness in vacuo to afford the title compound (75.5 mg, yield: 97%).
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH2:12])=[C:7]([Cl:13])[N:6]=1)=[O:4]>C(N)CN>[NH2:6][CH2:5][CH2:10][NH:9][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([NH2:12])=[C:7]([Cl:13])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Cl)c(N)nc1N
Solvent: NCCN
Product: NCCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 0 °C

Procedure:
3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid methyl ester (2.0 g, 9.88 mmol) in neat ethylene diamine (18 mL) is heated using microwave irradiation in a Personal Chemistry Emrys™ Optimizer microwave reactor at 130° C. for 1 h at 4 bar. The solvent is removed in vacuo, water (10 mL) is added to the orange solid and the suspension is then cooled to 0° C. The off-white solid is collected by filtration and dried under vacuum at 50° C. to afford the title compound. [M+H]+ 231.
Reaction SMILES: CO[C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25]>>[CH2:17]([C:13]1[C:12]([CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:25][CH2:24][C:23]([F:27])([F:26])[F:22])=[O:21])=[CH:5][N:6]=2)=[CH:16][O:15][N:14]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCc1nocc1COc1ccc(C(=O)OC)cn1
Reactant: NCC(F)(F)F
Product: CCCCc1nocc1COc1ccc(C(=O)NCC(F)(F)F)cn1
Yield: 69 %

Procedure:
As described for example 25e, 6-(3-butyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (200 mg, 0.69 mmol) was converted, using 2,2,2,-trifluoroethylamine instead of isopropylamine, to the title compound (170 mg, 69%) which was obtained as a white solid after purification by chromatography (silica, 30 to 50% ethyl acetate in heptane). MS: m/e=358.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])#[CH:2].Cl[C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][N:18]=[C:17]([NH:25][C:26]2[CH:27]=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[N:16]=1>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:33][O:32][C:29]1[N:28]=[CH:27][C:26]([NH:25][C:17]2[N:16]=[C:15]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[CH:9]([CH3:13])[C:10]([NH2:12])=[O:11])[C:20]([C:21]([F:24])([F:22])[F:23])=[CH:19][N:18]=2)=[CH:31][CH:30]=1
Reactant: C#Cc1ccccc1C(C)C(N)=O
Reactant: COc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3C(C)C(N)=O)n2)cn1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-(2-ethynylphenyl)propanamide K7 (0.120 g, 0.693 mmol), 4-chloro-N-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)pyrimidin-2-amine A68 (0.211 g, 0.693 mmol), CuI (0.013 g, 0.069 mmol), t-Bu3PHBF4 (0.020 g, 0.069 mmol) and PdCl2(PPh3)2 (0.024 g, 0.035 mmol) in DMF (3 mL) was bubbled with N2 for 5 minutes. Et3N (1 mL) was added and the reaction mixture was stirred in the microwave at 120° C. for 15 minutes. The volatiles were removed in vacuo and the black residue was adsorbed onto silica. Purification by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) gave the title compound A69 as a yellow solid (0.198 g, 65%). LCMS-D: rt 3.43 min; m/z 442 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:14]I>C1COCC1>[Br:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:14])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Fc1c(Br)ccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1ccc2ccc(Br)c(F)c21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-bromo-7-fluoro-1H-indole (470 mg, 2.19 mmol) in THF (7 mL) at −10° C. was added sodium hydride (175 mg, 4.39 mmol, 60% dispersion) and the mixture was stirred at 0° C. for 30 min. Methyl iodide was added at 0° C. and the reaction was allowed to warm to at 10° C. and stirred for 2 h. The reaction was quenched with saturated ammonium chloride and extracted with DCM. The DCM extract was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography over silica gel eluting with EtOAc/hexane to afford 6-bromo-7-fluoro-1-methyl-1H-indole. 1H NMR (400 MHz, CDCl3) δ=3.95 (d, J=2.00 Hz, 1H), 6.42 (t, J=2.78 Hz, 1H), 6.94 (d, J=3.03 Hz, 1H), 7.09-7.15 (m, 1H) and 7.20 (d, J=8.34 Hz, 1H); MS (ES+): m/z 228.04 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[Pt]=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(OCC=Cc2ccc(Cl)cc2)CC1
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(OCCCc2ccc(Cl)cc2)CC1
Yield: 40.6 %

Procedure:
A mixture of tert-butyl 4-[3-(4-chlorophenyl)-2-propenyloxy]piperidine-1-carboxylate (0.37 g, 1.05 mmol) prepared in Reference example 112 and platinum oxide (37 mg) in ethanol (10 ml), was stirred at room temperature under atmospheric pressure of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to afford tert-butyl 4-[3-(4-chlorophenyl)propoxy]piperidine-1-carboxylate (0.151 g, yield 40%) as a yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:7]([CH3:9])[N:8]=1.[CH3:33][NH:34][CH3:35]>CCO>[CH3:33][N:34]([CH3:35])[CH2:2][CH2:3][C:4]1[NH:5][C:6]([C:10]2[CH:11]=[C:12]([CH:29]=[CH:30][C:31]=2[CH3:32])[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:7]([CH3:9])[N:8]=1
Reactant: CNC
Reactant: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CCCl)nc1C
Solvent: CCO
Product: Cc1ccc(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1-c1[nH]c(CCN(C)C)nc1C
Temperature: 100 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Into a vessel with condensor, was placed a solution of 4-(1-(3-(2-(2-chloroethyl)-4-methyl-1H-imidazol-5-yl)-4-methylbenzoyl)piperidin-4-yl)benzonitrile (compound 24.1, 26 mg, 0.06 mmol, 1.00 equiv) in EtOH (10 mL). Dimethylamine (1 M in THF, 0.3 mL, 0.3 mmol) was added and the mixture was sealed under a nitrogen balloon. The resulting solution was stirred overnight with a 100° C. oil bath. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure and the crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column,) (Bridge Shield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, WATER WITH 0.03% NH3H2O and CH3CN (31% CH3CN up to 43% in 7 min, up to 100% in 0.5 min, down to 31% in 3.5 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield 6.3 mg (24%) of the title compound as a white solid. m/z (ES+) 456 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.[O:27]=[C:28]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][C:30](=[O:39])[N:29]1[CH2:40][CH2:41][CH2:42][CH2:43][NH2:44]>ClCCl>[O:27]=[C:28]1[C:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:31][C:30](=[O:39])[N:29]1[CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: NCCCCN1C(=O)C=C(c2ccccc2)C1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(C=Cc1cccnc1)NCCCCN1C(=O)C=C(c2ccccc2)C1=O
Reaction time: 0.5 h

Procedure:
2.7 g (17.8 mmol) 3-(3-pyridyl)-acrylic acid and 1.8 g (17.8 mmol) TEA are suspended in 50 ml abs. dichloromethane and cooled to ca. 0° C. under moisture exclusion. 3.1 g (17.8 mmol) 88% HOBT and 3.4 g (17.8 mmol) EDC are added and the mixture is stirred for 30 min under ice cooling. 5.0 g (17.8 mmol) 4-(2,5-dioxo-3-phenyl-2,5-dihydropyrrol-1-yl)-butylamine hydrochloride are dissolved in 30 ml abs. dichloromethane and added dropwise under ice cooling. The mixture is stirred overnight at RT without further cooling. Subsequently, the batch is washed with 25 ml 1M NaOH and with 50 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The resinous residue is chromatography pre-purified over silica gel with CHCl3/CH3OH (95/5) and further purified by flash chromatography with CHCl3/CH3OH (95/5). After withdraw of the solvent, this is crystallized from acetic acid ethyl ester: Colorless crystals with MP. 141–143° C.; Yield 0.6 g (9%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[CH3:18][N:19](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([C:18]#[N:19])=[N:7][C:6]=1[O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1OC1CCOCC1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc([N+](=O)[O-])c(OC2CCOCC2)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 73 %

Procedure:
A mixture of 1.2 g (4.6 mmol) of 6-chloro-3-nitro-2-(tetrahydro-pyran-4-yloxy)-pyridine, 550 mg (4.7 mmol) zinc cyanide, 260 mg (0.47 mmol) 1,1′-bis(diphenylphosphino)-ferrocene, 215 mg (0.24 mmol) Pd2dba3 in DMF are stirred at 120° C. for 5 h and 100° C. over night. After cooling to RT, the reaction mixture is diluted with EtOAc, washed with 10% aq. K2CO3 solution, water and brine, dried and evaporated. The residual is purified by FC, giving rise to 840 mg (73%) 5-Nitro-6-(tetrahydro-pyran-4-yloxy)-pyridine-2-carbonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:20]([O-])=O)[C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[CH:10]=2)=[N:6][CH:7]=1.[CH2:23](O)C>>[Br:1][C:2]1[CH:3]=[C:4]2[N:20]=[CH:23][N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N:15]4[CH:19]=[CH:18][N:17]=[CH:16]4)[CH:10]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Nc1cccc(-n2ccnc2)c1
Reactant: CCO
Product: Brc1cnc2c(c1)ncn2-c1cccc(-n2ccnc2)c1

Procedure:
6-Bromo-3-[3-(imidazol-1-yl)phenyl]-3H-imidazo[4,5-b]pyridine was prepared from N-(5-bromo-3-nitropyridin-2-yl)-N-[3-(imidazol-1-yl)phenyl]amine as described in Example 1. Oxalate salt, cream-coloured powder, m.p. 236-238° C. (from ethanol); δH (400 MHz, d6-DMSO) 7.23 (1H, s), 7.75 (2H, m), 7.92 (1H, s), 8.01-8.03 (1H, m), 8.24 (1H, s), 8.51 (1H, s), 8.57 (2H, dd, J 6 and 2), 9.09 (1H, s); m/z (ES+) 340 and 342 (M++H).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH:5](=[O:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>[Cl-].[NH4+]>[CH2:1]=[CH:2][CH:5]([OH:16])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C=C[Mg]Br
Reactant: CCCCCCCCCCC=O
Agent: [Cl-]
Agent: [NH4+]
Product: C=CC(O)CCCCCCCCCC
Reaction time: 6 h

Procedure:
To a solution of vinyl magnesium bromide in tetrahydrofuiran (1M, 82.0 mL) at 0° C. was added a solution of undecanal i (7.00 g, 41.1 mmol) in tetrahydrofuiran (25 mnL) in about 10 min. After 6 h at 0° C., saturated ammonium chloride solution (50 mL) was added. The two layers were separated. The water layer was extracted with ether (2×50 mL). The combined organic solutions were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate in hexane) to give 7.94 g (98%) of i-a as a colorless oil: IR (neat) 3409, 3079, 1644, and 1463 cm-1 ; 1H NMR (CDCl3, 300 MHz) δ 5.80 (ddd, 1 H, J=6.3, 10.7, and 17.2 Hz, CH=CH2), 5.55 (dd, 1 H, J=17.2 and 1.4 Hz, CH=CH2), 5.05 (dd, 1 H, J=10.7 and 1.4 Hz, CH=CH2), 3.99 (q, 1 H, J=6.2 Hz, CHOH), 2.58 (br s, 1 H, OH, 1.46-1.22 [m, 18 H, C(4-12)H2 ], and 0.83 (t, J=6.4 Hz, CH2CH3); 13C NMR (CDCl3, 75.5 MHz) δ 141.61, 114.50, 73.33, 37.24, 32.12, 29.83, 29.55, 25.57, 22.87, and 14.26.
Reaction SMILES: [C:1]1(=O)[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([NH:15][CH:1]2[C:13]3[NH:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH2:4][CH2:3][CH2:2]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCCc2c1[nH]c1ccccc21
Product: c1ccc(NC2CCCc3c2[nH]c2ccccc32)cc1

Procedure:
N-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 2,3,4,9-tetrahydro-1H-carbazol-1-one (150 mg, 0.81 mmol) and aniline (1.0 g, 11 mmol) in a similar manner as described above to give 24 mg (11%) of a white solid; 1H-NMR (DMSO-d6): δ 10.83 (s, 1H), 7.40 (d, 1H), 7.28 (d, 1H), 7.09 (t, 2H), 7.03 (t, 1H), 6.94 (t, 1H), 6.72 (d, 2H), 6.54 (t, 1H), 5.91 (d, 1H), 4.79-4.75 (m, 1H), 2.73-2.67 (m, 1H), 2.64-2.57 (m, 1H), 2.01-1.73 (m, 4H); MS m/z (M−93) 170.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[NH:17][C:16]2=O)=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].P(Cl)(Cl)([Cl:33])=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([F:22])=[C:18]([C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[N:17]=[C:16]2[Cl:33])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)c1cc(-n2c(Cl)nc(C(F)(F)C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-5-[3,6-dihydro-2,6-dioxo-5-fluoro-4-pentafluoroethyl-1(2H)-pyrimidinyl]-4-fluorobenzoate with phosphorus oxychloride and pyridine within 6 hours at room temperature there is obtained isopropyl 2-chloro-5-[2-chloro-5-fluoro-6-oxo-4-pentafluoroethyl-1(6H) -pyrimidinyl]-4-fluorobenzoate, 1H-NMR (CDCl3, 400 MHz): 7.88 ppm (d,1H), 7.48 ppm (d,1H), 5.28 ppm (m,1H), 1.39 ppm (d,6H),
Reaction SMILES: [Br:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([C:6](=O)[C:7](=[O:23])[N:8]2[CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:4][CH:3]=1.O>O.NN>[Br:1][C:2]1[C:10]([CH3:11])=[C:9]2[C:5]([CH2:6][C:7](=[O:23])[N:8]2[CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1c(Br)ccc2c1N(Cc1ccc3ccccc3c1)C(=O)C2=O
Agent: NN
Solvent: O
Product: Cc1c(Br)ccc2c1N(Cc1ccc3ccccc3c1)C(=O)C2

Procedure:
6-Bromo-7-methyl-1-naphthalen-2-ylmethyl-1H-indole-2,3-dione (1.04 g, 2.58 mmol) was dissolved in 20 ml of hydrazine hydrate and refluxed for 120 minutes. The reaction mixture was poured into cold water, extracted in ethyl acetate, dried over MgSO4, filtered and concentrated under vacuum to give the crude product. It was chromatographed on flash silica gel eluting with 5% ethyl acetate in hexane to yield the title compound of 2C (0.592 g, 59% yield).
Reaction SMILES: Cl[C:2]([N:11]=[C:12]=[O:13])([C:7]([F:10])([F:9])[F:8])[C:3](Cl)([F:5])[F:4]>COCCOC.[Zn]>[F:4][C:3]([F:5])=[C:2]([N:11]=[C:12]=[O:13])[C:7]([F:9])([F:8])[F:10]
Reactant: O=C=NC(Cl)(C(F)(F)F)C(F)(F)Cl
Agent: [Zn]
Solvent: COCCOC
Product: O=C=NC(=C(F)F)C(F)(F)F
Reaction time: 1 h
Yield: 91.3 %

Procedure:
A 244 g sample (1.0 mole) of 1,2-dichloro-2,2-difluoro-1-(trifluoromethyl)ethyl isocyanate was added dropwise to a stirred suspension of 98 g (1.5 gram atom) of powdered zinc in 1000 ml of glycol dimethyl ether at such a rate that the temperature warmed to 45° and remained between 45°-50°. The reaction mixture was stirred for 1 hr after the addition, and then the most volatile portion was distilled under reduced pressure (5 mm) into a trap cooled to -78°. The condensate in the trap was redistilled to give 158 g (91%) of 2,2-difluoro-1-(trifluoromethyl)vinyl isocyanate as a colorless liquid: bp 42.3°-42.5°, ir (liquid), 4.38 μ (NCO) and 5.67 μ (=CF2); 19F nmr (CCl3F) δ 66.6 ppm (d, J = 9 Hz to d, J = 23 Hz, 3F) δ 82.9 ppm (d, J = 21 Hz to q, J = 9 Hz, IF) and δ 89.7 ppm (d, J = 21 Hz to d, J = 23 Hz, IF).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.[CH3:12][Si:13](Cl)([CH3:15])[CH3:14]>C(OCC)C>[CH3:6][C:7]1[N:8]=[C:9]([Si:13]([CH3:15])([CH3:14])[CH3:12])[S:10][CH:11]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cscn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1csc([Si](C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5M solution in hexane, 1.1 equivalents) was added dropwise to a solution of 4-methylthiazole (1.0 equivalent) in dry diethyl ether at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, trimethylsilylchloride (1.0 equivalent) was added dropwise. The mixture was allowed to warm to room temperature and was then quenched by the addition of saturated aqueous sodium hydrogen carbonate. Work-up in the normal fashion and vacuum distillation then gave the title compound. B.p. 42° C. at 1 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[NH:32]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CO>[N:32]1([CH2:21][CH2:20][O:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)=[C:11]([C:8]3[CH:9]=[CH:10][C:4]4[O:3][C:2]([Cl:1])=[CH:6][C:5]=4[CH:7]=3)[CH2:30][CH3:31])=[CH:18][CH:17]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Reactant: C1CCCNCC1
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCN2CCCCCC2)cc1)c1ccc2oc(Cl)cc2c1
Yield: 41.9 %

Procedure:
According to the same procedure as example 1, step E described, 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)phenyl)but-1-enyl)phenol (220 mg, 1.0 eq, made by example 11, step D) was reacted with azepane (500 mg) in MeOH under reflux to give the desired product (105 mg, 48%, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J=1.6 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 6.97-7.01 (m, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 6.76 (d, J=8.8 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 6.45 (d, J=8.8 Hz, 1H), 6.43-6.44 (m, 1H), 4.46-4.48 (m, 1H), 4.25-4.27 (m, 1H), 3.00-3.71 (m, 6H), 2.44-2.51 (m, 2H), 1.73-2.00 (m, 8H), 0.91 (t, J=7.6 Hz, 3H); m/z=516[M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]([Li])[C:4]2[C:12]([C:13]=1[CH3:14])=[CH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH:5]=2.[Si:16]([CH3:20])([CH3:19])(Cl)[Cl:17]>C1COCC1>[Cl:17][Si:16]([CH3:20])([CH3:19])[CH:3]1[C:4]2[C:12](=[CH:11][C:10]3[CH2:9][CH2:8][CH2:7][C:6]=3[CH:5]=2)[C:13]([CH3:14])=[C:2]1[CH3:1]
Reactant: C[Si](C)(Cl)Cl
Reactant: [Li]C1C(C)=C(C)c2cc3c(cc21)CCC3
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Cl)c2cc3c(cc21)CCC3
Temperature: 22.5 °C
Yield: 76.7 %

Procedure:
(1,5,6,7-tetrahydro-2,3-dimethyl-s-indacen-1-yl)lithium (9.27 g, 0.04874 moles) in THF (90 mL) was added dropwise to a solution of Me2SiCl2 (18.90 g, 0.1463 moles) in THF (50 mL). This mixture was then allowed to stir at 20-25 ° C. 16 hours. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. The removal of the hexane resulted in the isolation of the desired product as an orange/brown oil (10.35 g, 76.7 percent).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:13]1[N:22]=[C:21]([C:23]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[O:24])[C:20]([OH:34])=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2)(C)(C)C.C(NCC)(C)C.[Cl:42][CH2:43][C:44](Cl)=[O:45]>O1CCOCC1>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][NH:25][C:23]([C:21]2[C:20]([OH:34])=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[N:18]3)=[C:13]([CH2:12][CH2:11][N:10]([CH2:9][CH2:8][NH2:7])[C:44](=[O:45])[CH2:43][Cl:42])[N:22]=2)=[O:24])=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)NCCNCCc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Reactant: O=C(Cl)CCl
Agent: CCNC(C)C
Solvent: C1COCCO1
Product: NCCN(CCc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12)C(=O)CCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-Butyl-2-{[2-(7-{[(4-fluorobenzyl)amino]carbonyl}-8-hydroxy[1,6]-naphthyridin-5-yl)ethyl]amino}ethylcarbamate (Example 150, Step 1) (0.10 g, 0.21 mmol), isopropylethylamine (0.11 mL, 0.62 mmol), and chloroacetyl chloride (18 μL, 0.23 mmol) in dioxane (10 mL) was stirred at room temperature for 1 hour. The resultant mixture was concentrated under vacuum. The residue was dissolved in dichloromethane (5 mL) and treated with trifluoroacetic acid (0.5 mL) and stirred at room temperature overnight. The resultant mixture was concentrated under vacuum and used in the following step without further purification. ES MS M+1=406