Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].[C:17]([C:19]1[O:20][CH:21]=[CH:22][CH:23]=1)#[CH:18]>N1CCCC1.[Cu]I>[O:20]1[CH:21]=[CH:22][CH:23]=[C:19]1[C:17]#[C:18][C:2]#[C:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: C#Cc1ccco1
Reactant: COC(=O)CCCCCCCCCC#CBr
Agent: [Cu]I
Solvent: C1CCNC1
Product: O=C(O)CCCCCCC/C=C\C#CC#Cc1ccco1
Reaction time: 1 h

Procedure:
A mechanically stirred solution of bromoacetylene 5 (35 g, 121 mmol) and ethynylfuran 8 (23% w/w, 16.7 g, 182 mmol) in 400 mL of pyrrolidine under nitrogen was cooled via ice-water bath. Copper (I) iodide (3.69 g, 19 mmol) was added in one portion and after 5 min the cooling bath was removed and the homogeneous mixture was stirred an additional 1 h. The dark red reaction was quenched by addition of 850 mL of water with stirring. The orange-yellow suspension was extracted with 4×300 ml of diethyl ether. The combined organic layers were washed with 3×100 mL of water and 100 mL of brine, dried over sodium sulfate, and concentrated in vacuo to a dark red oil. The residue was resuspended in 100 mL of 10% ethyl acetate in hexanes and passed through a pad of silica gel in a flitted funnel. The pad was washed with an additional 4×50 mL of solvent and concentrated in vacuo to give 21.0 g of crude 9 as a dark red oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([NH2:15])[CH:11]=[CH:12][C:13]=2[F:14])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[H][H]>[Pd]>[F:14][C:13]1[CH:12]=[CH:11][C:10]([NH2:15])=[CH:9][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[CH:2][N:7]=1
Reactant: Nc1ccc(F)c(-c2ccnc(Cl)n2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Product: Nc1ccc(F)c(-c2ccncn2)c1

Procedure:
To the solution of 3-(2-chloro-pyrimidin-4-yl)-4-fluorophenylamine from above was added triethylamine (0.48 mL, 3.15 mmol) and palladium on active carbon (100 mg, 10% palladium) and the mixture was reduced under 40 p.s.i. hydrogen for 30 minutes. The mixture was filtered and the solvent removed to give 4-fluoro-3-pyrimidin-4-yl-phenylamine as a yellow solid: m/z (ES+) 190 (M++H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]2[C:30]3[C:25](=[N:26][CH:27]=[N:28][C:29]=3[NH2:31])[N:24]([C@H:32]3[CH2:37][CH2:36][C@H:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:23]=2)=[C:16]([F:45])[CH:15]=1>ClCCl.N1C=CC=CC=1>[NH2:31][C:29]1[N:28]=[CH:27][N:26]=[C:25]2[N:24]([CH:32]3[CH2:37][CH2:36][CH:35]([N:38]4[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]4)[CH2:34][CH2:33]3)[N:23]=[C:22]([C:17]3[C:16]([F:45])=[CH:15][C:14]([NH:13][C:10]([C@@H:8]4[CH2:9][C@H:7]4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:11])=[C:19]([O:20][CH3:21])[CH:18]=3)[C:30]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1N
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCC(N4CCN(C)CC4)CC3)c3ncnc(N)c23)c(F)cc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
trans-2-phenyl-1-cyclopropanecarbonyl chloride (32 mg, 0.176 mmol) in dichloromethane (0.3 mL) was added to a solution of trans-3-(4-amino-2-fluoro-5-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.176 mmol) in pyridine (1.5 mL) at 0° C. After 5 minutes the ice-water bath was removed and the reaction mixture was stirred at room temperature for 3 hours. More trans-2-phenyl-1-cyclopropanecarbonyl chloride (32 mg, 0.176 mmol) was added to ensure the reaction went to completion. Solvent was evaporated and the residue was purified by flash column chromatography to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-5-fluoro-2-methoxyphenyl)-2-phenyl-1-cyclopropanecarboxamide (93 mg, 88%). 1H NMR (DMSO-d6) δ 1.35 (m, 1H), 1.50 (m, 3H), 1.98 (m, 6H), 2.19 (s, 3H), 2.37-2.68 (m, 11H), 3.87 (s, 3H), 4.64 (m, 1H), 7.09 (m, 1H), 7.21 (m, 3H), 7.31 (m, 2H), 8.21 (m, 2H), 9.82 (m, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=599.3, Rt=1.97 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([O:27][CH:28]([F:30])[F:29])[C:11]([N:18]3[CH2:22][CH2:21][C@@H:20]([C:23]([NH2:26])([CH3:25])[CH3:24])[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:31]2[CH2:33][CH2:32]2)[C:7]=1[S:34](C)(=O)=O)=[O:5])[CH3:2].O.[SH-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([O:27][CH:28]([F:29])[F:30])[C:11]([N:18]3[CH2:22][CH2:21][C@@H:20]([C:23]([NH2:26])([CH3:25])[CH3:24])[CH2:19]3)=[C:12]([F:17])[CH:13]=2)[N:8]([CH:31]2[CH2:33][CH2:32]2)[C:7]=1[SH:34])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(S(C)(=O)=O)n(C2CC2)c2c(OC(F)F)c(N3CC[C@@H](C(C)(C)N)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [SH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(S)n(C2CC2)c2c(OC(F)F)c(N3CC[C@@H](C(C)(C)N)C3)c(F)cc2c1=O

Procedure:
Compound 14 (1.6 g, 2.93 mmol) is dissolved in DMF (40 mL) under an atmosphere of argon. Sodium hydrosulfide hydrate crystals (Aldrich, 72.6% by titration, 330 mg, 5.88 mmol) are added to this solution. The resulting mixture is sparged slowly with argon for 30 min. The progress of the reaction is monitored by HPLC-MS, and judged to be complete (≦2% of 14 remains) after 5 h. Excess sodium hydrosulfide is quenched upon addition of aq. HCl (4.5 mL, 4 N). The resulting orange solution (pH ˜2) is sparged with argon (30 min) to remove the generated hydrogen sulfide. DMF is removed under reduced pressure to give orange oil.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1.[H-].[Na+].[O:25]1[CH2:29][CH2:28]OS1(=O)=O.O>CN(C)C=O>[OH:25][CH2:29][CH2:28][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:3]1
Reactant: O=S1(=O)OCCO1
Reactant: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCO)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.01 g of tert-butyl 3-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate in 40 ml of N,N-dimethylformamide is added at 0° C. to the suspension of 0.26 g of sodium hydride dispersion (60%) in 40 ml of N,N-dimethylformamide. After 30 minutes, the reaction mixture is admixed with 0.83 g of [1,3,2]dioxathiolane 2,2-dioxide and stirred at room temperature over 18 hours. The reaction mixture is cooled to 0° C., admixed with water and concentrated by evaporation. The residue is stirred in a 1:10 mixture of 0.1 M H2SO4/dioxane at 50° C. over 60 hours, neutralized with saturated aqueous sodium hydrogencarbonate solution and concentrated by evaporation. The residue is dissolved in ethyl acetate, washed with water and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (1:1 EtOAc-heptane); Rt=4.24.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[CH2:13]Br)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([NH:22][CH2:23][CH2:24][NH:25][CH3:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]1([S:7]([NH:10][CH:11]2[CH2:13][N:22]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23][CH2:24][N:25]([CH3:26])[CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)N1CC1CBr
Reactant: CNCCNCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN1CCN(Cc2ccccc2)CC(NS(=O)(=O)c2ccccc2)C1
Reaction time: 5 h
Yield: 22.3 %

Procedure:
A mixture of 1-benzenesulfonyl-2-bromomethylethylenimine (27.2 g), N-benzyl-N'-methylethylenediamine (16.2 g), triethylamine (19.9 g) and chloroform (350 ml) is refluxed with stirring for 5 hours. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel chromatography to give the title compound (7.9 g) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C=O)C.O>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:8]2[C:9]3[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=3)[CH:6]=[N:7]2)=[CH:23][CH:22]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2ncc3c([N+](=O)[O-])cccc32)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a suspension of 4-nitro-1H-indazole (10 g, 61.30 mmol) and potassium carbonate (9.32 g, 67.43 mmol) in DMF (100 mL) at 25° C. was added 4-methoxybenzyl chloride (9.14 mL, 67.43 mmol). The resulting mixture was stirred at 110° C. for 2 hours. The reaction mixture was cooled and diluted with water. The aqueous layer was extracted with DCM (2×100 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0 to 2% ethyl acetate in dichloromethane. The solvent was evaporated to dryness to afford 1-(4-methoxybenzyl)-4-nitro-1H-indazole (9.00 g, 51.8%) as a orange solid. NMR Spectrum: (DMSOd6) 3.70 (s, 3H), 5.73 (s, 2H), 6.87 (d, 2H), 7.25 (d, 2H), 7.65 (dd, 1H), 8.17 (d, 1H), 8.34 (d, 1H), 8.54 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:16][CH3:17].Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[N:24][C:19]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:16][CH3:17])=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)c2OC
Yield: 45 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (75 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine (89 mgs) were converted to the title compound as an off-white solid (66 mgs). 1H-NMR (CDCl3): δ 10.30 (s, 1H), 8.52 (d, J=8.6 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.10 (s, 1H), 7.86 (d, J=15.7 Hz, 2H), 7.44-7.41 (m, 2H), 7.28-7.25 (m, 1H), 6.94 (d, J=9.1 Hz, 1H), 6.54 (s, 1H), 3.80 (s, 3H), 2.32 (broad S, 2H), 3.15-1.5 broad absorptions, 6H), 1.15 (t, J=7.3 Hz, 3H). LC/MS, found 504.17 (M+H)+; MP: 183-185° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH2:11][CH3:12].[F:13]C1C=CC(C(O)=O)=CC=1O>>[CH2:11]([O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[F:13])[CH:6]=[O:7])[CH3:12]
Reactant: CCOc1cc(C=O)ccc1Cl
Reactant: O=C(O)c1ccc(F)c(O)c1
Product: CCOc1cc(C=O)ccc1F

Procedure:
The title compound was prepared according to the procedure described for the synthesis of 4-chloro-3-ethoxy-benzaldehyde (intermediate B2) starting from 4-fluoro-3-hydroxy-benzoic acid in 73% overall yield after purification by flash column chromatography on silica eluting with hexane/ethyl acetate (10:1). 1H NMR (300 MHz, DMSO): δ 1.32 (t, J=7.0 Hz, 3H), 4.12 (q, J=7.0 Hz, 2H), 7.34-7.41 (m, 1H), 7.47-7.56 (m, 2H), 9.87 (s, 1H). MS (ISP): 186.1 [M+NH4]+.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:19]=[CH:18][CH:17]=[N:16][C:8]=3[NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:26][C:27]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])([C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1)[CH3:28].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:28][C:27]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:48])([CH3:49])[CH3:50])([C:29]1[CH:30]=[CH:31][C:32]([C:2]2[N:6]3[C:7]4[CH:19]=[CH:18][CH:17]=[N:16][C:8]=4[NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[C:5]3=[N:4][C:3]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:33][CH:34]=1)[CH3:26]
Reactant: Brc1c(-c2ccccc2)nc2n1-c1cccnc1Nc1ccccc1-2
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)c1ccc(-c2c(-c3ccccc3)nc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 80.2 %

Procedure:
A suspension of 3-bromo-2-phenyl-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepine (50 mg) and tert-butyl {1-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}carbamate (93 mg) and potassium phosphate (82 mg) and PdCl2(dppf)CH2Cl2 (11 mg) in dioxane (2.5 mL) and H2O (0.25 mL) was degassed for 5 min then stirred at 80° C. for 18 h. The reaction mixture was concentrated under reduced pressure. Purification by column chromatography (0-50% ethyl acetate in hexanes) gave the product (56 mg, 80%). 1HNMR (DMSO-d6) 400 MHz δ: 8.54 (s, 1H), 8.09-8.00 (m, 1H), 7.95 (dd, 1H, J=7.8, 1.4 Hz), 7.55-7.48 (m, 2H), 7.38-7.32 (m, 3H), 7.31-7.19 (m, 5H), 7.17-7.07 (m, 3H), 6.91-6.77 (m, 1H), 6.70-6.59 (m, 1H), 1.50 (br s, 6H), 1.41-1.05 (m, 9H). LCMS: 544 [M+H].
Reaction SMILES: CS[C:3](=[NH:22])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[S:13][C:12]3[N:14]=[CH:15][CH:16]=[N:17][C:11]=3[N:10]([CH2:18][O:19][CH3:20])[C:9]=2[CH:21]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.CO>[C:24]1([NH:23][C:3](=[NH:22])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]3[S:13][C:12]4[N:14]=[CH:15][CH:16]=[N:17][C:11]=4[N:10]([CH2:18][O:19][CH3:20])[C:9]=3[CH:21]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COCN1c2cc(CC(=N)SC)ccc2Sc2nccnc21
Reactant: Nc1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: COCN1c2cc(CC(=N)Nc3ccccc3)ccc2Sc2nccnc21

Procedure:
350 mg of methyl(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-yl)acetothioimidate was dissolved in a solvent mixture of tetrahydrofuran (7 ml) with methanol (15 ml). After adding 0.5 ml of aniline, the resulting mixture was heated under reflux for 5 hours. Then the reaction mixture was brought back to room temperature. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol/aqueous ammonia) to thereby give 250 mg of the title compound as yellow crystals.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([NH:20][C:21]2[CH:36]=[C:24]3[CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][N:23]3[N:22]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)(=[O:3])[CH3:2].Cl.O1CCOCC1>ClCCl>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[C:14]([NH:20][C:21]2[CH:36]=[C:24]3[CH2:25][NH:26][CH2:27][CH2:28][N:23]3[N:22]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C(=O)OC(C)(C)C)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCNC4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
A mixture of 205e (280 mg, 0.41 mmol), 4.0 M HCl/dioxane (4 mL), and dichloromethane (4 mL) was stirred at room temperature for 2 h. It was then concentrated under reduced pressure to afford 205f as a yellow solid (165 mg, 66%), which was used for the next step without further purification. MS-ESI: [M+H]+ 583.3.
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:1]([C:8](=[CH2:12])[C:9]([O:11][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Cc1ccccc1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 86.8 %

Procedure:
To a solution of 2-benzylacrylic acid (1.02 g, 6.3 mmol) in dimethylformamide (10 ml) was added potassium carbonate (1.04 g, 7.6 mmol) and water (0.25 ml) with stirring. After 10 minutes, benzyl bromide (0.9 ml, 7.6 mmol) was added. After 3 hours, water was added and the resulting mixture was extracted with ether. The ether layer was washed 3 times with water, dried over magnesium sulfate, filtered over silica gel, and concentrated under reduced pressure. The resulting oil was distilled (70° C., 0.2 torr) to remove any unreacted starting material, then distilled (125° C., 0.2 torr) to yield 1.38 g (87%) of clear oil. 1H NMR (CDCl3): δ 3.7 (s, 2H), 5.2 (s, 2H), 5.5 (s, 1H), 6.3 (s, 1H), 7.2-7.6 (m, 10H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][NH:22][CH2:23][CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=[O:28]>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[CH2:21][N:22]([C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)=[O:28])[CH2:23][CH3:24])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=C(Cl)OCc1ccc(Cl)cc1
Reactant: CCNCc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC
Product: CCN(Cc1ccc(OC)cc1-c1cc(CC(=O)OC)ccc1OC)C(=O)OCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6,5′-dimethoxy-biphenyl-3-yl)-acetic acid methyl ester and 4-chlorobenzyl chloroformate.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C1C=CC=CC=1>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:1][N:2]2[C:6]3[CH:7]=[C:8]([CH:11]=[CH2:12])[CH:9]=[CH:10][C:5]=3[N:4]=[N:3]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: C=Cc1ccc2nnn(O)c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=Cc1ccc2nnn(OS(=O)(=O)c3ccc(C)cc3)c2c1
Temperature: 10 °C
Yield: 64.5 %

Procedure:
In dry benzene (300 ml) are dissolved 1-hydroxy-6-vinyl-1,2,3-benzotriazole (4.83 g) and triethylamine (3.2 g) under stirring, and thereto is added dropwise a solution of p-toluenesulfonyl chloride (5.8 g) in benzene (50 ml) under cooling at 10° C. The mixture is stirred at room temperature for 2 hours. The reaction mixture is poured onto ice-water (200 ml) and extracted with ethyl acetate (60 ml, three times). The combined extracts are washed with an aqueous sodium hydrogen carbonate and then water, dried over anhydrous magnesium sulfate, treated with charcoal and then concentrated under a reduced pressure. The resulting residue is recrystallized from ethyl acetate-n-hexane to give colorless crystals of 1-(p-toluenesulfonyloxy)-6-vinyl-1,2,3-benzotriazole (6.1 g), melting point: 90°-91° C. The filtrate is further concentrated, and the resulting residue is recrystallized from benzene-n-hexane to give additionally the desired product (1.9 g).
Reaction SMILES: [ClH:1].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].[CH2:10]([OH:12])[CH3:11]>C(OCC)C>[ClH:1].[CH2:10]([O:12][C:2](=[NH:3])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:11]
Reactant: CCO
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)CC(=O)OCC
Reaction time: 72 h
Yield: 88 %

Procedure:
Hydrogen chloride gas was bubbled through a stirred solution of ethyl cyanoacetate (900 g. 7.96 moles), ethanol (410 ml, 7.0 moles) and diethyl ether (2.4 liters). The temperature was kept below 15° C. by use of a cooling bath. After 3.5 hours 395 g (10.8 moles) of hydrogen chloride had been absorbed. The mixture was kept in a cold room for 72 hours. Then the resulting white, crystalline product was filtered off, washed first with diethyl ether, then with petroleum-ether (b.p. 60°-80° C.) and dried under vacuum. The product weighed 1210 g (88% yield).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:44])[CH2:30][CH2:31][N:32]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][C:37]=1[NH2:43])[C:33](=[O:35])[CH3:34]>>[CH3:44][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:36]1[CH:42]=[CH:41][C:39]([NH:40]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:38][C:37]=1[NH2:43])[C:33](=[O:35])[CH3:34]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CC(=O)N(CCN(C)C)c1ccc(N)cc1N
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(C)=O)c(N)c1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-3-amino-aniline Rf value: 0.5 (aluminium oxide, methylene chloride/methanol=20:1) C29H31N5O4
Reaction SMILES: [C:1]1([CH:7](O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C(Cl)=NC(Cl)=NC=1[Cl:12]>>[Cl:12][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: CC(O)c1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: CC(Cl)c1ccccc1

Procedure:
Using a procedure analogous to that of Example 1, 100 g (0.82 mol) of 1-phenylethane-1-ol is reacted with 97.6 g (0.529 mol) of cyanuric chloride over a period of 14 hours at a reaction temperature of 90° C. After phase separation, treatment with sodium hydroxide and purification by distillation, 1-chloro-1-phenylethane having a purity of>99% and containing<0.3% of isomeric alkyl chlorides is obtained.
Reaction SMILES: CO[N:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[O:7][CH2:6][CH2:5]1.CON=C1C2C(=CC=C(C)C=2)OCC1>>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[O:7][CH2:6][CH2:5][CH:4]2[NH2:3]
Reactant: CON=C1CCOc2ccc(F)cc21
Agent: CON=C1CCOc2ccc(C)cc21
Product: NC1CCOc2ccc(F)cc21

Procedure:
The title compound was prepared using the procedure as described in Example 7B, substituting the product of Example 10A for the product of Example 7A. 1H NMR (300 MHz, CDCl3) δ 7.03 (dd, 1H, J=9.1 and 3.1 Hz), 6.85 (m, 1H), 6.74 (m, 1H,), 4.15-4.29 (m, 2H), 4.02 (m, 1H), 2.10-2.20 (m, 1H), 1.79-1.89 (m, 1H). MS (DCI) m/e 168 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.[F:17][C:18]1([F:25])[CH2:22][NH:21][C@H:20]([C:23]#[N:24])[CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH2:2][C:3]([N:21]1[CH2:22][C:18]([F:25])([F:17])[CH2:19][C@H:20]1[C:23]#[N:24])=[O:4]
Reactant: N#C[C@@H]1CC(F)(F)CN1
Reactant: O=C(Br)CBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#C[C@@H]1CC(F)(F)CN1C(=O)CBr
Temperature: -10 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a CH2Cl2 solution (5 mL) containing bromoacetyl bromide (365 mg, 1.80 mmol) cooled to −10° C. was added dropwise (2S)-4,4-difluoro2-pyrrolidinecarbonitrile 4-methylbenzenesulfonate (described earlier) (500 mg, 1.64 mmol) and triethylamine (199 mg, 1.97 mmol) in CH2Cl2 (5 mL). After stirring for 2 hours at 10° C. the reaction was quenched with H2O and the organics extracted with CH2Cl2 and washed with 1.0 M HCl. After drying over MgSO4 the solvents were reduced in vacuo yielding 400 mg (1.57 mmol, 96% yield) of the title compound as a yellow oil.