Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[CH:17](OCC)(OCC)[O:18][CH2:19][CH3:20].C(OC(=O)C)(=O)C>>[Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:10](=[CH:17][O:18][CH2:19][CH3:20])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16]
Reactant: CCOC(=O)CC(=O)c1ccc(I)cc1Cl
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1ccc(I)cc1Cl
Yield: 89.8 %

Procedure:
md) 53.7 g of ethyl 3-(2-chloro-4-iodo-phenyl)-3-oxo-propionate are heated to boiling under reflux for 4 hrs. with 40 g of triethyl orthoformate and 46.1 g of acetic anhydride. The volatile constituents are distilled off in a water-jet vacuum and finally in a high vacuum. 55.9 g (90%) of ethyl 2-(2-chloro-4-iodo-benzoyl)-3-ethoxy-acrylate are obtained as a yellowish oil. Mass spectrum: peaks inter alia at 408 (M+, 4%), 373 (67%), 342 (14%), 335 (100%).
Reaction SMILES: [NH2:1][C@H:2]([CH2:23][F:24])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)[OH:4].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(OC(=O)C)C.O>[F:24][CH2:23][C@@H:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[C@H:3]([OH:4])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[N:15][C:14]([CH2:17][NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@H](N)CF)cc2)cn1
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NS(C)(=O)=O)cc2)cn1
Yield: 49.7 %

Procedure:
To a slurry of N-((5-(4-((1R,2S)-2-amino-3-fluoro-1-hydroxypropyl)phenyl)pyridin-2-yl)methyl)methanesulfonamide (100 mg, 0.28 mmol) in ethylacetate/aqueous NaHCO3 (1:1) (2 mL) is slowly added methanesulfonyl chloride (50 mg, 0.42 mmol) over a period of 20 minutes. Reaction is diluted with water (2 mL) and extracted with ethylacetate (3×5 mL). Combined organic solution is dried over Na2SO4 and concentrated. Crude product is purified using HPLC to give the title compound (60 mg): 1H NMR (400 MHz, DMSO-d6) 2.55 (s, 3H), 2.98 (s, 3H), 3.67-3.80 (m, 1H), 4.18-4.26 (m, 0.5H), 4.31-4.40 (m, 2.5H), 4.48-4.55 (m, 0.5H), 4.60-4.67 (m, 0.5H), 4.80-4.87 (m, 1H), 5.83-5.93 (m, 1H), 7.27 (d, 1H), 7.54 (d, 2H), 7.54 (d, 1H), 7.62 (d, 1H), 7.70-7.79 (m, 3H), 8.20-8.26 (m, 1H), 8.90 (d, 1H). m/z (Cl) M+H 432.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11].[OH-].[Na+]>ClCCl.C(O)C>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:10]([C:12]1[CH:32]=[CH:31][C:15]2[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=3)=[N:18][C:14]=2[CH:13]=1)=[O:11]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccc3F)ccc21
Yield: 45 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 45% of theory, C26H25FN6O3 (488.5); Rf value: 0.05 (silica gel; dichloromethane/ethanol=4:1); EKA mass spectrum: (M+H)+=489; (M+H+Na)++=267; (M+2H)++=256.
Reaction SMILES: [C:1]([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][C@:14]2([C:29]2[S:30][C:31]([C:34]#[N:35])=[CH:32][CH:33]=2)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C(#N)C.I[Si](C)(C)C>[C:34]([C:31]1[S:30][C:29]([C@:14]23[CH2:16][NH:17][CH2:18][C@H:13]2[CH2:12][S:11][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:15]3)=[CH:33][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc([C@]23CN(C(=O)OCc4ccccc4)C[C@H]2CSC(NC(=O)c2ccccc2)=N3)s1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: CC#N
Product: N#Cc1ccc([C@]23CNC[C@H]2CSC(NC(=O)c2ccccc2)=N3)s1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 117.5 %

Procedure:
To a stirred clear and colorless solution of the benzyl (4aR,7aR)-2-(benzoylamino)-7a-(5-cyanothiophen-2-yl)-4a,5,7,7a-tetrahydropyrrolo[3,4-d][1,3]thiazine-6(4H)-carboxylate (405 mg, 0.806 mmol) in acetonitrile (16 mL) under an atmosphere of nitrogen at room temperature is added iodotrimethylsilane (345 μL, 2.42 μmol). The resulting pale yellow solution is stirred at room temperature for 70 minutes. Methanol (391 μL, 9.67 mmol) is added and the pale yellow mixture is stirred for 5 minutes, and then concentrated under reduced pressure. The residue is partially purified by silica gel chromatography, eluting with a dichloromethane/methanol, gradient from 99:1 to 90:10, to give the title compound (349 mg, 118%) as a pale yellow solid (assume quantitative recovery and carry partially purified material into next step). MS/ES (m/z) 369.0 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][NH:11][C:10]2=[S:20])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:23](I)[CH3:24]>>[CH2:23]([S:20][C:10]1[N:9]([CH2:8][C:7]2[CH:21]=[CH:22][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:11]=1)[CH3:24]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc(Cn2c(-c3ccccc3)n[nH]c2=S)cc1
Product: CCSc1nnc(-c2ccccc2)n1Cc1ccc([N+](=O)[O-])cc1
Yield: 91 %

Procedure:
Reaction of 2,4-dihydro-4-(4-nitrobenzyl)-5-phenyl-3H-1,2,4-triazole-3-thione with ethyl iodide according to the procedure of Example 6, Part B, gave a 91% yield of the desired product as a solid, mp 107.5°-108.5° C., homogeneous by TLC in 97:3 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 341 (M+1)+.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([CH:22]=[CH2:23])=[N:11][C:12]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:13][C:14]=1[CH3:15])=[O:8].[OH-:26].[Na+].OO>C1COCC1>[CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([CH:22]([OH:26])[CH3:23])=[N:11][C:12]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[CH:13][C:14]=1[CH3:15])=[O:8]
Reactant: [OH-]
Reactant: C=Cc1nc(N2CCOCC2)cc(C)c1C(=O)NCCCC(C)(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)nc(C(C)O)c1C(=O)NCCCC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 750 mg, (2.17 mmol) N-(4,4-dimethylpentyl)-4-methyl-6-morpholino-2-vinyl-pyridine-3-carboxylic acid amide (synthesized according to the methods described for example 9) in THF (10 ml) was added dropwise 730 μl (7.6 mmol) at 0° C. and the resulting mixture was stirred at RT for 16 h. The reaction mixture was cooled to 0° C. and a 1N aq. NaOH sol (4 ml) was added dropwise over a period of 0.5 h, followed by the addition of H2O2 (30% in water, 4 ml). Then the reaction mixture was stirred at RT for 4 h and was then extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated in vacuo. After CC (hexane/EtOAc 3:7) a mixture of N-(4,4-dimethylpentyl)-2-(2-hydroxyethyl)-4-methyl-6-morpholino-pyridine-3-carboxylic acid amide and N-(4,4-dimethylpentyl)-2-(1-hydroxyethyl)-4-methyl-6-morpholino-pyridine-3-carboxylic acid amide was obtained. This mixture was dissolved in THF (6 ml) and benzene (6 ml) and 24 mg, 0.0716 mmol) TBAHS was added at RT followed by the addition of a 25% aq. NaOH sol (6 ml) and 0.450 μl (7.16 mmol) iodomethane. Then the reaction mixture was slowly heated to 70° C. and stirred at the same temperature for 3 h. The additional 0.450 μl (7.16 mmol) iodomethane was added and stirring was continued at 70° C. for another 3 h. Then the organic layer was separated and the aq. layer was extracted with EtOAc. The combined organic layer was washed with water, and brine, dried over Na2SO4 and concentrated in vacuo. Purification of this residue by CC (hexane/EtOAc 3:2) provided 60 mg (0.16 mmol, 6%) N-(4,4-Dimethyl-pentyl)-2-(2-methoxy-ethyl)-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 358). [M+H]+ 377.3
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1I.[CH2:10]([O:12][C:13]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])[C:14]#[CH:15])[CH3:11]>[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.C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:15]#[C:14][C:13]([O:16][CH2:17][CH3:18])([O:12][CH2:10][CH3:11])[O:19][CH2:20][CH3:21]
Reactant: C#CC(OCC)(OCC)OCC
Reactant: Clc1ccc(Br)c(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CCOC(C#Cc1cc(Cl)ccc1Br)(OCC)OCC
Temperature: 23 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A suspension of 1-bromo-4-chloro-2-iodobenzene (2.5 g, 7.9 mmol), 3,3,3-triethoxyprop-1-yne (2.4 g, 13.9 mmol), copper(I) iodide, (455 mg, 2.3 mmol), and trans-dichlorobis(triphenylphosphine)palladium(II) (559 mg, 0.79 mmol) was treated with ACN (30 mL). The reaction was capped, evacuated under vacuum, backfilled with argon, and treated with TEA (9.9 mL, 71.6 mmol). The reaction was stirred at 23° C. After 2 hours, the reaction mixture was concentrated in vacuo to remove all solvents, diluted with EtOAc (250 mL) and washed with brine (150 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 4% EtOAc/hexane+1% TEA), affording 2.6 g of 1-bromo-4-chloro-2-(3,3,3-triethoxyprop-1-ynyl)benzene.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:11][C:12]([OH:14])=[O:13].O>O1CCCC1>[CH:3]1([O:9][CH2:11][C:12]([OH:14])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCCCC1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COC1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 842.1 %

Procedure:
To a suspension of 60% sodium hydride (8.79 g) in tetrahydrofuran (500 mL) was added cyclohexanol (10 g) and the mixture was stirred at 0° C. for 0.5 hour. To the mixture was added bromoacetic acid (13.9 g) under ice-water cooling and the mixture was heated under reflux for 2 hours. After adding water to the mixture and organic solvent was evaporated in vacuo. The aqueous solution was diluted with water, washed with ether, acidified with 1 N hydrochloric acid, and extracted with ether. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo to give (cyclohexyloxy)acetic acid as colorless oil (133 g).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH2:11]([C@H:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1)[CH3:12]>>[NH2:8][C:3]1[CH:4]=[N:5][N:6]([CH3:7])[C:2]=1[N:18]1[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:14][C@H:13]1[CH2:11][CH3:12]
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1c(N)cnn1C

Procedure:
Following the procedure for Intermediate 10 starting from 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 and (R)-tert-butyl 3-ethylpiperazine-1-carboxylate gave (R)-tert-butyl 4-(4-amino-1-methyl-1H-pyrazol-5-yl)-3-ethylpiperazine-1-carboxylate as an orange gum (118 mg, 67% over two steps). LCMS (ES+) m/z 310 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31]2)(=O)=O)=CC=1>>[CH:30]1([CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31]1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccccc32)cc1
Product: O=C(N[C@H]1CCN(CC2CCc3ccccc32)C1)C12CC3CC(CC(C3)C1)C2

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide and (2,3-dihydroinden-1-yl)methyl p-toluenesulfonate were reacted under the same conditions as in Example 6 to give (S)-N-(1-((2,3-dihydroinden-1-yl)methyl)pyrrolidin-3-yl)-1-adamantanecarboxamide.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1>C1COCC1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:1]([Cl:4])=[O:2])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCO
Solvent: C1CCOC1
Product: O=C(Cl)OCCc1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 2.5 h
Yield: 95 %

Procedure:
Phosgene was introduced in a solution of 2-(4-chloro-2-nitrophenyl)ethanol (6.8 g, 34 mmol) in THF (50 ml, dist. over CaH2) at room temperature. After 2.5 h, the excess phosgene and the solvent were removed by distillation in a high vacuum. 2-(4-chloro-2-nitrophenyl)ethoxycarbonyl chloride (8.53 g, 95%) was obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11]N(C)C)=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:15].[C-:16]#[N:17].[Na+]>C(OCC)(=O)C.CS(C)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:16]#[N:17])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:15]
Reactant: CN(C)Cc1c[nH]c2cc(Br)c(F)cc12
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CCc1c[nH]c2cc(Br)c(F)cc12
Temperature: 80 °C
Yield: 43.9 %

Procedure:
A mixture of (6-Bromo-5-fluoro-1H-indol-3-ylmethyl)-dimethyl-amine (1.0 g) and sodium cyanide (0.54 g, 11.02 mmol) in ethyl acetate (1.8 ml) and methylsulfoxide (16 ml) was heated at 80° C. for 24 hrs then partitioned between ethyl acetate and water. The organic extract was washed with brine, dried (anhydrous sodium sulfate), concentrated under reduced pressure. The residue was purified by flash column chromatography over silica gel eluting with 20% ethyl acetate in hexane to give (6-Bromo-5-fluoro-1H-indol-3-yl)-acetonitrile as a yellow solid (0.41 g, 44%). 1H NMR (CDCl3) d: 3.78 (d, 2H, J=1.0 Hz), 7.27 (dd, 1H, J=1.2 Hz), 7.31 (d, 1H, J=8.8 Hz, 7.58 (d, 1H, J=5.5 Hz), 8.23 (bs, 1H).
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][O:6][C:5](=[O:8])[N:4]1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)[CH3:2].Cl.[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([N:4]4[C@H:3]([CH2:1][CH3:2])[CH2:7][O:6][C:5]4=[O:8])=[CH:17][CH:16]=3)=[O:15])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: CC[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Agent: Cl
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Yield: 38.2 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using (R)-4-(4-ethyl-2-oxooxazolidin-3-yl)benzoic acid (470 mg) described in Preparation Example 78 and 1-(3,5-dimethylpyridin-2-yl)piperazine hydrochloride (455 mg) described in Preparation Example 64, the title compound (312 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2([CH:15]=[N:16]S(C(C)(C)C)=O)[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:23][Mg]Br.[Cl-].[NH4+]>ClCCl>[Cl:1][C:2]1[C:3]([C:12]2([CH:15]([NH2:16])[CH3:23])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: CC(C)(C)S(=O)N=CC1(c2ncc(C(F)(F)F)cc2Cl)CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CC(N)C1(c2ncc(C(F)(F)F)cc2Cl)CC1
Temperature: -48 °C
Reaction time: 18 h

Procedure:
412 mg of 2-methyl-propane-2-sulfinic acid 1-[1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropyl]-methylideneamide (step 3) was dissolved in 12 ml of dichloromethane and cooled to −48° C. 0.78 ml of methylmagnesium bromide (3M solution in diethyl ether) was added dropwise at −48° C. The reaction mixture was left to warm to ambient temperature and stirred for 18 hours. Then the mixture was poured into 30 ml of a saturated aqueous ammonium chloride solution. The aqueous phase was extracted with three 30 ml portions of ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in 12 ml of methanol and 0.6 ml of hydrochloric acid (4M solution in dioxane) was added. The mixture was stirred at ambient temperature for 2 hours, then concentrated. The residue was treated with aqueous 1N hydrochloric acid and washed with ethyl acetate. The aqueous phase was made basic by addition of aqueous sodium hydroxide solution, then extracted with ethyl acetate. The organic phase dried over sodium sulfate, filtered and concentrated. Thus, 262 mg of 1-[1-(3-chloro-5-trifluoromethyl-pyridin-2-yl)-cyclopropyl]-ethylamine was obtained as a yellow oil. 1H-NMR (CDCl3): 8.72 ppm (s, 1H), 7.90 ppm (s, 1H), 3.10 ppm (q, 1H), 1.34 ppm (s, 2H, broad), 1.06 ppm (d, 3H), 1.02 ppm (m, 2H), 0.93 ppm (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14](OCC)(OCC)(OCC)[CH3:15]>>[Cl:1][C:2]1[C:11]2[N:10]([C:14]([CH3:15])=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1nc2ccccc2nc1Cl
Product: Cc1nnc2c(Cl)nc3ccccc3n12
Temperature: 100 °C

Procedure:
A reaction mixture of 5 g of 2-chloro-3-hydrazinoquinoxaline in 50 ml of triethyl orthoacetate was heated at 100° C. for three hours. Upon cooling, the precipitated solid was filtered, washed with cyclohexane, and dried affording 4.27 g of 4-chloro-1-methyl[1,2,4]triazolo[4,3-a]quinoxaline having a mp of 215°-218° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[OH-].[Na+].O.C(OCC)(=O)C.[CH3:20][C:21]([CH3:23])=[O:22]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:20][C:21](=[O:22])[CH3:23]
Reactant: COc1ccccc1C=O
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccccc1C=CC(C)=O
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
In a 250 ml single neck flask was charged 13.6 g (100 mmoles,1.0 eq) of o-methoxybenzaldehyde dissolved in 30 ml of acetone. To this was added 5 g of 10% aqueous sodium hydroxide solution (12.5 mmoles, 0.125 eq), dropwise and during the course of addition, temperature was kept no higher than 25° C., while the mixture was agitated continuously for 30 minutes. To the mixture was added 50 ml of water, followed by 100 ml of ethyl acetate, the phases were separated and the organic phase was washed with water three times and then dried, and concentrated to obtain 14.5 g of 4-(2-methoxyphenyl)-3-buten-2-one as a faintly yellow oil in 82.3% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][C@@H:13]([N:23]2[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]2)[CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])=[CH:4][CH:3]=1.[CH:31](=O)[CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Si:16]([O:15][CH2:14][C@H:13]([N:23]1[CH:27]=[C:26]([C:28]([NH2:30])=[O:29])[N:25]=[CH:24]1)[CH2:12][CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][CH2:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:10]=2)[CH:6]=[CH:7]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(N)cc21)n1cnc(C(N)=O)c1
Reactant: O=CCCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H](CCn1ccc2ccc(NCCCc3ccccc3)cc21)n1cnc(C(N)=O)c1
Reaction time: 0.5 h
Yield: 25.2 %

Procedure:
Under N2, to a stirred solution of 1-[(R)-4-(6-aminoindol-1-yl)-1-(tert-butyldimethylsilyloxy)-2-butyl]imidazole-4-carboxamide (164 mg, 0.383 mmol) in dichloromethane (10 ml) was added hydrocinnamaldehyde (51 mg, 0.383 mmol) at room temperature. The mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (114 mg, 0.536 mmol) was added to the mixture at room temperature and the resulting mixture was stirred for 5 hours. And then the reaction mixture was partitioned between dichloromethane and water. The organic layer was washed with brine, dried (sodium sulfate), and concentrated in vacuo. The residue was purified by silica gel (10 g) column chromatography eluted with chloroform/methanol (100:1 to 10:1) to give 1-[(R)-1-(tert-butyldimethylsilyloxy)-4-(6-(3-phenylpropylamino)indol-1-yl)-2-butyl]imidazole-4-carboxamide (52.6 mg, 25.2%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[S:23]1[CH:27]=[CH:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:31](B(O)O)[C:24]1=2>>[S:23]1[CH:27]=[CH:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:31]([C:2]3[CH:3]=[C:4]([C:9]4[N:13]5[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]5=[N:11][CH:10]=4)[CH:5]=[CH:6][C:7]=3[F:8])[C:24]1=2
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: OB(O)c1cccc2ccsc12
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cccc5ccsc45)c3)cnc2c1F
Yield: 3 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and benzo[b]thiophene-7-boronic acid were coupled in the same way as in Example 30 to give 2-{3-[3-(benzo[b]thien-7-yl)-4-fluorophenyl]-8-fluoroimidazo[1,2-α]pyridin-7-yl}propan-2-ol as an off-white solid (4 mg, 3%): m/z (ES+) 421 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[CH:21]#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>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.[Cu]I>[C:21]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])#[C:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: C#CCCCCC
Reactant: COC(=O)c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CCCCCC#Cc1cc(OC)ccc1C(=O)OC
Yield: 100.9 %

Procedure:
Coupling of methyl 4-(methyloxy)-2-{[(trifluoromethyl)sulfonyl]oxy}benzoate (77) (0.80 g, 2.55 mmol) with 1-heptyne (0.70 mL, 5.10 mmol) using Pd(PPh3)2Cl2 and CuI gave 0.67 g (˜100%) of compound 110 as a brown oil. 1H NMR (400 MHz, CDCl3): δ 0.92 (t, J=7.3 Hz, 3H), 1.30-1.50 (m, 4H), 1.60-1.70 (m, 2H), 2.47 (t, J=7.2 Hz, 2H), 3.83 (s, 3H), 3.87 (s, 3H), 6.82 (dd, J1=8.9 Hz, J2=2.7 Hz, 1H), 6.99 (d, J=2.7 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H).