Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:29])([F:28])[F:27])[CH:4]=1.ClC1C=CC=C(C(OO)=[O:42])C=1>C(Cl)(Cl)Cl>[F:33][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([S:14]([CH2:15][C:16]([F:17])([F:18])[F:19])=[O:42])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[N:6]=[C:5]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:29])([F:28])[F:27])[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2C(F)F)cc1SCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)cc2C(F)F)cc1S(=O)CC(F)(F)F
Reaction time: 1 h
Yield: 97 %

Procedure:
0.35 g of 5-difluoromethyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 150 mg of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for one hour under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.35 g of 5-difluoromethyl-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](Cl)[N:3]=1.[OH-].[NH4+:11]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([NH2:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)nc(Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1cc(N)nc(Cl)c1
Yield: 51 %

Procedure:
A solution of 2,6-Dichloro-4-methylpyridine (Chem. Mater., 2004, 16, 1564-1572, 30 g, 0.185 mol) in ammonium hydroxide (200 mL, 25% solution in water) was heated at 200° C. in a pressure vessel for 10 h. The reaction mixture was then concentrated under reduced pressure. The brown solid obtained was suspended in DCM for 30 min at 25-26° C. and filtered. Filtrate was concentrated under reduced pressure. Purification of the crude thus obtained by flash chromatography (20% ethyl acetate in pet ether) afforded the title compound as off-white solid (13.5 g, Yield 51%). LC/MS: M+(ESI): 142.7; 1H NMR (DMSO d6: 400 MHz) δ 6.34 (1H, s), 6.23 (2H, s), 6.15 (1H, s), 2.1 (3H, s).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][CH2:13][C@H:14]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:15][C:16]([NH:18][CH2:19][C@@H:20]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[O:17])C1C=CC=CC=1>[Pd].C(O)C>[C:44]([O:43][C:41](=[O:42])[NH:40][C@H:14]([CH2:15][C:16]([NH:18][CH2:19][C@@H:20]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])=[O:17])[CH2:13][CH2:12][CH2:11][NH2:10])([CH3:45])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)C[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCC[C@@H](CNC(=O)C[C@H](CCCN)NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
20 mg of palladium on activated carbon (10%) are added to a mixture of 0.127 g (0.19 mmol) of the compound from Example 230A in 10 ml of ethanol, and the mixture is then hydrogenated under atmospheric pressure for 12 h. The reaction mixture is filtered through kieselguhr, and the filtrate is concentrated in vacuo and dried under high vacuum. The crude product is reacted without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][C:26]([C:31](O)=[O:32])=[CH:25][C:24]2=[O:34]>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:31]([C:26]1[O:27][C:28]2[C:23]([C:24](=[O:34])[CH:25]=1)=[CH:22][C:21]([CH3:20])=[CH:30][CH:29]=2)=[O:32]
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Reactant: Cc1ccc2oc(C(=O)O)cc(=O)c2c1
Product: Cc1ccc2oc(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)cc(=O)c2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 6-methyl-4-oxo-4H-chromene-2-carboxylic acid. MS: 446.4 (M+H).
Reaction SMILES: [C:1]([OH:18])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:19][C:20]1[N:21]=[C:22]([NH2:31])[S:23][C:24]=1[CH2:25][CH2:26][O:27][N+:28]([O-:30])=[O:29]>>[CH3:19][C:20]1[N:21]=[C:22]([NH:31][C:1](=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[S:23][C:24]=1[CH2:25][CH2:26][O:27][N+:28]([O-:30])=[O:29]
Reactant: Cc1nc(N)sc1CCO[N+](=O)[O-]
Reactant: CCCCCCCCCCCCCCCC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)Nc1nc(C)c(CCO[N+](=O)[O-])s1
Yield: 62 %

Procedure:
Pet-158 was prepared according to the general procedure described hereinabove and the procedure described above for the preparation of Pet-154, using hexadecanoic acid (palmitic acid) and 4-methyl-5-(2-nitrooxy-ethyl)-thiazol-2-ylamine (Pet-10) as the starting materials, in an overall yield of 62%.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26](Cl)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CC(C)([O-])C.[K+].C(O)(C)(C)C.[Cl:41][C:42]1[CH:47]=[C:46]([CH2:48][OH:49])[CH:45]=[CH:44][N:43]=1>CO>[F:28][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:26]([O:49][CH2:48][C:46]4[CH:45]=[CH:44][N:43]=[C:42]([Cl:41])[CH:47]=4)=[N:25][S:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2Cl)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)(C)O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2OCc2ccnc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.1 %

Procedure:
To a solution of 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide (103.7 mg, 0.226 mmol, prepared in Example 10b) and 1M solution of potassium tert-butoxide in tert-butanol (0.70 mL, 0.70 mmol) was added 2-chloro-4-pyridinemethanol (64.5 mg, 0.448 mmol, prepared in Example 16a). The resulting suspension was stirred at room temperature for 2 h. The crude reaction mixture was diluted with methanol and purified by preparative HPLC (0.1% TFA in water, 0.1% TFA in acetonitrile). The pure fractions were combined and the acetonitrile/TFA was removed in vacuo. The remaining aqueous solution was made basic with NaHCO3 and the free based product was extracted into EtOAc. The organic phase was concentrated in vacuo yielding pure product N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-chloropyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide (33.4 mg, 26.1% yield). 1H NMR (CDCl3) 8.43 (d, 1H), 7.90 (s, 2H), 7.55 (s, 1H), 7.38 (s, 1H), 6.68 (s, 1H), 5.49 (s, 2H), 3.66 (d, 8H) ppm.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14].C(Cl)(=O)C(Cl)=O.CN1C2C=C(C(Cl)=O)C=CC=2OC1=O.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[C:38]([Cl:44])[CH:37]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C.COCCOC.[Zn].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][C:11]([C:8]2[CH:9]=[CH:10][C:5]3[O:4][C:3](=[O:14])[N:2]([CH3:1])[C:6]=3[CH:7]=2)=[O:13])=[C:38]([Cl:44])[CH:37]=1
Reactant: Cn1c(=O)oc2ccc(C(=O)O)cc21
Reactant: Clc1cc(Br)ccc1CBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cn1c(=O)oc2ccc(C(=O)Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: COCCOC
Product: Cn1c(=O)oc2ccc(C(=O)Cc3ccc(Br)cc3Cl)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carboxylic acid (2.20 g) in CH2Cl2 (30 mL) were added five drops of DMF and oxalylchloride (1.57 mL). The mixture was stirred at room temperature for 1.5 hours and was then concentrated to dryness. 1,2-Dimethoxyethane (150 mL) was added and the solvent was evaporated again to give the crude acid chloride (3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carbonyl chloride). To a suspension of zinc powder (1.49 g) in 1,2-dimethoxyethane (15 mL) was added tetrakis(triphenylphosphine)palladium(0) (132 mg). A suspension of the acid chloride in 1,2-dimethoxyethane (20 mL) was added. The mixture was cooled in an ice bath and a solution of 4-bromo-1-bromomethyl-2-chloro-benzene (3.25 g, [CAS Reg. No. 89720-77-4]) in 1,2-dimethoxyethane (15 mL) was slowly added over a period of 30 minutes. The mixture was stirred for 10 minutes at 0° C. and then for 2 hours at r.t. The reaction mixture was poured into ice and basified with sat. NaHCO3. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. Ethyl acetate (50 mL) was added to the resulting precipitate and the suspension was stirred for 30 minutes at r.t. The solid was filtered off and dried in vacuo. The title compound was obtained as a light yellow solid (1.95 g, 40%). MS (neg. ion, m/e)=378.0 [(M−H)−].
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([NH2:10])[C:4]=2[CH:3]=[N:2]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1I>CCOC(C)=O.[Cu]I.C1(C)C=CC=CC=1>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([NH2:10])[C:4]=2[CH:3]=[N:2]1
Reactant: Fc1ccccc1I
Reactant: Nc1cccc2[nH]ncc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Nc1cccc2c1cnn2-c1ccccc1F
Yield: 52.4 %

Procedure:
1H-Indazol-4-amine (1.83 g, 10 mmol), copper (I) iodide (95 mg. 0.5 mmol) and potassium phosphate (4.46 g, 21 mmol) were stirred together. The flask was evacuated and refilled with argon twice. To the flask was then added trans-N,N′-dimethyl-1,2-cyclohexanediamine (320 μL, 2 mmol), 2-fluoro-1-iodobenzene (2.66 g, 12 mmol) and toluene (30 mL) and the mixture was heated at 110° C. overnight. The reaction mixture was diluted with EtOAc, filtered through Celite to remove inorganics and the Celite pad was washed successively with EtOAc until the solvent ran clear. The reaction mixture was evaporated and the residue was purified by column chromatography eluting with dichloromethane then with dichloromethane:EtOAc 9:1 to give the title compound as a yellow oil (1.19 g) which solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.C(O[CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16])C>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:17]([NH2:18])=[C:14]([C:15]#[N:16])[CH:13]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOC=C(C#N)C#N
Reactant: NNc1ccc(Cl)nn1
Solvent: CCO
Product: N#Cc1cnn(-c2ccc(Cl)nn2)c1N

Procedure:
A mixture of 4.35 g. (30 mmoles) of 3-chloro-6-pyridazinylhydrazine, 3.96 g. (30 mmoles) of ethoxymethylenemalononitrile and 60 ml. of ethanol is heated and refluxed for 2 hours. After cooling the separated crystals are filtered, washed with ethanol and dried. Yield: 5.85 g. (88.5%); m.p.: 250°-252° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21]Br)[CH:7]=1)[CH3:2].[CH3:24][C@H:25]1[C@@H:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:28][C:27](=[O:36])[NH:26]1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH2:21][N:26]2[C@H:25]([CH3:24])[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:28][C:27]2=[O:36])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(Br)cc2CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Product: CCOC(=O)Cc1ccc(Cl)c(Oc2ccc(Br)cc2CN2C(=O)O[C@H](c3ccccc3)[C@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(4-bromo-2-bromomethyl-phenoxy)-4-chloro-phenyl]-acetic acid ethyl ester and (4S,5R)-(−)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:8]=[C:9]([C:13]([O:15][CH3:16])=[O:14])[NH:10][C:11]=1[CH3:12].CN(C)[CH:19]=[O:20].[OH-].[Na+]>>[CH:19]([C:8]1[C:7]([CH3:6])=[C:11]([CH3:12])[NH:10][C:9]=1[C:13]([O:15][CH3:16])=[O:14])=[O:20]
Reactant: COC(=O)c1cc(C)c(C)[nH]1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1[nH]c(C)c(C)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
15.0 g (0.0979 mole) of phosphorus oxychloride were dropwise added to a solution of 13.7 g (0.0898 mole) of methyl 4,5-dimethylpyrrole-2-carboxylate in 13 ml (0.17 mole) of dimethylformamide over a period of 1.3 hours with ice-cooling, and the resulting mixture was stirred at room temperature for 0.5 hour and then at 90-100° C. for 0.5 hour. The hot reaction mixture thus obtained was poured into ice-water and dissolved. The solution was adjusted to pH 5-6 with a 10% aqueous solution of sodium hydroxide. The solids precipitated were collected by filtration and then dissolved in 600 ml of ethyl acetate. The filtrate was extracted twice with 200 ml each of ethyl acetate. The combined extracts were washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was washed with a mixture of hexane and ethyl acetate and collected by filtration to give 10.6 g (0.0583 mole) of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate as a brown powder.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:20]([NH2:22])=[O:21].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31](Cl)=O)=[CH:26][CH:25]=1>>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[NH:22][C:20](=[O:21])[C:3]3[CH:4]=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:2]=3[N:1]=2)=[CH:26][CH:25]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: CC(O)C(CCCc1ccccc1)n1ncc(C(N)=O)c1N
Product: CC(O)C(CCCc1ccccc1)n1ncc2c(=O)[nH]c(Cc3ccc(Br)cc3)nc21

Procedure:
Starting from 2.1 g (6.95 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-pyrazole-4-carboxamide and 4.05 mg (17.38 mmol) of 4-bromophenylacetyl chloride, the title compounds are prepared analogously to the protocol of Example 13. This gives 594 mg (18%) of the diastereomer which elutes more rapidly, M.p.: 117° C., and 372 mg (11%) of the diastereomer which elutes more slowly, M.p.: 116° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])[C:5]([Cl:20])=[CH:4][C:3]=1[CH2:21][OH:22].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>CN(C=O)C>[CH2:27]([O:22][CH2:21][C:3]1[C:2]([Br:1])=[CH:7][C:6]([CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:11]([CH3:12])[CH3:13])[CH:14]([CH3:15])[CH3:16])=[C:5]([Cl:20])[CH:4]=1)[CH:26]=[CH2:25]
Reactant: CC(C)[Si](OCc1cc(Br)c(CO)cc1Cl)(C(C)C)C(C)C
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCc1cc(Cl)c(CO[Si](C(C)C)(C(C)C)C(C)C)cc1Br
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.9 %

Procedure:
To a solution of alcohol 30 (31 g, 75.5 mmol) in DMF (300 mL) were added NaH (60% dispersion in mineral oil, 4.0 g, 98.2 mmol) at 0° C. The mixture was stirred at 0° C. for 15 min and allyl bromide (23 mL, 264 mmol) was added to the mixture at 0° C. The mixture was warmed up to room temperature and stirred at room temperature for 2 h. After dilution with water, the mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica column chromatography to provide the titled compound 31 (32.1 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Br:1])[CH:3]=1
Reactant: CO
Reactant: N#Cc1ccc(CC(=O)O)cc1Br
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(C#N)c(Br)c1
Temperature: 85 °C

Procedure:
(3-Bromo-4-cyanophenyl)acetic acid (1.0 g, 4.2 mmol) was dissolved in methanol (20 mL), and thionyl chloride (0.5 mL) was added drop wise to the solution. The reaction was heated to 85° C. for 4 h. Then it was cooled to room temperature and evaporated to dryness in vacuo. The residue was partitioned between ethyl acetate and sat. NaHCO3. The organic layer was dried over MgSO4, filtered, and the filtrate was evaporated to dryness under reduced pressure to yield the crude title compound as an off white solid. 1H NMR (500 MHz, CDCl3): δ 7.07 (d, J=7.07 Hz, 1H), 7.00-6.97 (m, 2H), 3.74 (s, 3H), 3.73 (s, 2H). LC-MS (IE, m/z): 195.2 [(M+1)−CO2CH3]+.
Reaction SMILES: [Br:1]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:22]([CH:26]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27]O)[CH2:23][CH2:24][CH3:25]>ClCCl>[CH2:22]([CH:26]([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:27][Br:1])[CH2:23][CH2:24][CH3:25]
Reactant: BrBr
Reactant: CCCCC(CO)CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCC(CBr)CCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromine (61.4 g, 384 mmol) was added into a solution of triphenylphosphine (100.7 g, 384 mmol) and 450 mL dichloromethane at room temperature under argon protection. Then 2-butylhexanol (60.8 g, 384 mmol) was added dropwise via additional funnel over 50 minutes, the reaction solution was kept to stir at room temperature overnight. Dichloromethane was evaporated, and the concentrate filtered with pentane wash. The filtrate was concentrated via rotary evaporation and the resulting crude yellow oil was purified via vacuum distillation. The title compound was collected as colorless oil (70.8 g, 83.3%). 1H NMR (CDCl3): δ 0.89-0.92 (6H, m), 1.21-1.45 (12H, m), 1.54-1.67 (1H, m), 3.45 (2H, d).
Reaction SMILES: [NH:1]([C:3]1[C:4]2[N:5]([CH:13]=[CH:14][N:15]=2)[C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)N>[Ni].O>[CH:13]1[N:5]2[C:6]3[C:11]([N:12]=[C:3]([NH2:1])[C:4]2=[N:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: NNc1nc2ccccc2n2ccnc12
Agent: [Ni]
Solvent: O
Product: Nc1nc2ccccc2n2ccnc12
Yield: 108.2 %

Procedure:
A mixture of 0.17 g of 4-hydrazinoimidazo[1,2-a]quinoxaline and 3.4 ml of Raney nickel in 20 ml of water is refluxed for 1.5 h. After cooling down, the mixture is filtered on Celite, followed by washing with methanolic chloroform. The filtrate is concentrated under vacuum and extracted with ethyl acetate. The organic extracts are then washed with saturated NaCl, dried and evaporated, thereby obtaining 0.17 g of imidazo[1,2-a]quinoxalin-4-amine. M.p. (DSC)=205.3° C. (onset); IR (KBr): 3301, 3143, 1653, 1525 cm-1 ; 1 -NMR (CDCl3): δ8.0 (1H,s), 7.8÷7.45 (3H,m), 7.45÷7.2 (2H,m), 5.8 (2H,sb); UV (EtOH): λmax =229, 295, 331 nm. Elementary analysis for C10H3N4 (m.w. 184.20): calcd. C 65.21, H 4.38, N 30.42%; found C 65.48, H 4.71, N 30.10%;.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[CH:73]1([C:79]([C:81]2[CH:88]=[CH:87][C:84]([CH2:85][NH2:86])=[CH:83][CH:82]=2)=[O:80])[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:86][CH2:85][C:84]1[CH:87]=[CH:88][C:81]([C:79]([CH:73]2[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]2)=[O:80])=[CH:82][CH:83]=1
Reactant: NCc1ccc(C(=O)C2CCCCC2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C1CCCCC1
Temperature: 100 °C
Yield: 74.7 %

Procedure:
Use a method similar to the General Procedure 5-2 to react 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (150 mg, 0.353 mmol), tris(dibenzylideneacetone)dipalladium(0) (64 mg, 0.071 mmol), BINAP (88 mg, 0.141 mmol), 4-cyclohexanecarbonyl-benzylamine (125 mg, 0.576 mmol) and cesium carbonate (230 mg, 0.706 mmol) in degassed toluene (10 mL). Degas the mixture with vacuum/nitrogen purge and heat to 100° C. for 6 h. Cool the mixture to room temperature, dilute with EtOAc and filter through Celite®. Purify the crude mixture by chromatography on silica gel eluting with hexane and then hexane/EtOAc (90:10 and 85:15) to obtain 7-chloro-6-(4-cyclohexanecarbonyl-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (130 mg, 75%). MS (ES+) m/z: 493 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH:11](I)([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:12][CH:11]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH3:13]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)N1CCCc2ccccc21
Temperature: 60 °C
Yield: 74741.8 %

Procedure:
13.8 g (0.1 mmol) of 1,2,3,4-tetrahydroquinoline was dissolved in 60 ml of N,N-dimethylformamide, followed by the addition of 21.1 g (0.124 mmol) of isopropyl iodide and 20.6 g (0.208 mol) of potassium carbonate. The obtained mixture was stirred under heating at 60° C. for 5 hours. Water was added to the resulting reaction mixture, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was purified by silica gel column chromatography (3% ethyl acetate/n-hexane) to give 13.1 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11]CC2C=CC=CC=2)=[C:9]([O:19]CC2C=CC=CC=2)[CH:8]=[CH:7][C:3]=1[CH:4]1[O:6][CH2:5]1.[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28]>>[Cl:1][C:2]1[C:10]([OH:11])=[C:9]([OH:19])[CH:8]=[CH:7][C:3]=1[CH:4]([OH:6])[CH2:5][NH:31][C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: Clc1c(C2CO2)ccc(OCc2ccccc2)c1OCc1ccccc1
Reactant: CC(C)(C)N
Product: CC(C)(C)NCC(O)c1ccc(O)c(O)c1Cl

Procedure:
Reacting 2-chloro-3,4-dibenzyloxystyrene oxide with t-butylamine followed by hydrogenation furnishes the product 2-chloro-α-(t-butylaminomethyl)-3,4-dihydroxybenzyl alcohol.