Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH:11]=O)[CH2:3]1.C[C:15]1[NH:16]C2C(C=1C=O)=CC=CC=2>>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][NH:16][CH3:15])[CH2:3]1
Reactant: Cc1[nH]c2ccccc2c1C=O
Reactant: CC1(C)CC(C=O)c2ccccc21
Product: CNCC1CC(C)(C)c2ccccc21
Yield: 81 %

Procedure:
According to the procedure of Preparation 12, except substituting 1,1-dimethyl-3H-indene-3-carboxaldehyde for the 2-methylindole-3-carboxaldehyde, the title compound (3 g, 81%) was obtained as a reddish oil: MS (ES) m/e 188.2 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Cl[CH2:8][C:9]([O:11][C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16]1)([CH3:14])[CH3:13])=[O:10].[C:23]([OH:27])(=[O:26])[CH2:24][CH3:25].CCOCC>CC(C)=O>[C:23]([O:27][CH2:8][C:9]([O:11][C:12]([CH:15]1[CH2:20][CH2:19][CH2:18][C:17]([CH3:22])([CH3:21])[CH2:16]1)([CH3:14])[CH3:13])=[O:10])(=[O:26])[CH2:24][CH3:25]
Reactant: CC1(C)CCCC(C(C)(C)OC(=O)CCl)C1
Reactant: CCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCC(=O)OCC(=O)OC(C)(C)C1CCCC(C)(C)C1
Yield: 73.8 %

Procedure:
K2CO3 (6.2 g, 45 mmol) and 1-(3,3-dimethylcyclohexyl)-1-methylethyl chloroacetate (2,5 g, 10 mmol) are added successively to a solution of propionic acid (1.8 g, 30 mmol) in acetone (20 ml). After the suspension has been heated under reflux for 36 hours, it is allowed to cool and ether (80 ml) and 10% K2CO3 solution (50 ml) are added. After phase separation has taken place, the aqueous phase is freed from residual acetone and the aqueous phase is also extracted twice with 50 ml diethyl ether. The combined organic phases are also washed once with water and once with saturated NaCl solution, then dried, filtered off and freed from solvent in a rotary evaporator. After purification by flash chromatography (cyclohexane/EtOAc=10:1, Rf=0.23) and subsequent bulb tube distillation, (BTD: 215° C., 0.9 mbar) 2.1 g (78%) 2-[1-(3,3-dimethylcyclohexyl)-1-methylethoxy]-2-oxoethyl propionate is obtained as a colorless liquid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C[NH:15][C:16]([C:18]1[CH:22]=[C:21]([CH2:23][OH:24])[O:20][N:19]=1)=[O:17].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:24][CH2:23][C:21]1[O:20][N:19]=[C:18]([C:16](=[O:17])[NH2:15])[CH:22]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNC(=O)c1cc(CO)on1
Solvent: c1ccncc1
Solvent: ClCCl
Product: NC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
2.84 g (14.07 mmoles) of 4-nitrophenyl chloroformate are added in small portions to a solution of 2.0 g (14.07 mmoles) of 3-methylcarbamoyl-isoxazol-5-yl-methanol (commercial), 1.71 ml (21.11 mmoles) of pyridine and 0.17 g (1.41 moles) of N,N-dimethylaminopyridine in 15 ml of dichloromethane, cooled to about 0° C. The medium is maintained with stirring for 1 hr at 0° C. then for 1 hr at ambient temperature. The precipitate formed is filtered off then copiously rinsed with diisopropyl ether. After drying under vacuum at about 60° C., 3.12 g of the expected product are obtained in the form of a white solid used as such in the following stage.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1.[C:8](OC(=O)C)(=[O:10])[CH3:9]>C(Cl)Cl.N1C=CC=CC=1>[C:8]([NH:1][C:2]1[S:3][C:4]([Br:7])=[CH:5][N:6]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ncc(Br)s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ncc(Br)s1
Temperature: 25 °C

Procedure:
To a solution of 2-amino-5-bromothiazole (22.3 g, 85.9 mmol) in methylene chloride (100 mL) and pyridine (60 mL) was added acetic anhydride (11 mL) slowly with stirring. The mixture was allowed to stir for 2.5 hours, warmed to room temperature, and stirred for an additional 4 hours. Most of the solvent was removed in vacuo and the residue was washed with ethyl acetate and aqueous HCl. The organic solution was then washed with water, dried over MgSO4 and concentrated to give a crude solid. This solid was triturated with Et2O, filtered, washed with Et2O, and dried to give 2-acetamido-5-bromothiazole as a solid (15.1 g, 80%, C5H5BrN2OS, MS m/e 222 (M+H)+).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([NH:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:22]=3)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Br)c2)[C@H](c2ccccc2)C1
Reactant: Nc1ccccc1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2cccc(Nc3ccccc3)c2)[C@H](c2ccccc2)C1

Procedure:
The title compound, MS: m/e=569.2 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(3-bromo-phenyl)-3-phenyl-piperidin-1-yl]-methanone and aniline.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:24]([O:28][C:29](=[O:32])[CH2:30]Br)([CH3:27])([CH3:26])[CH3:25].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:24]([O:28][C:29]([C:30]1[O:17][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:16]=[CH:15][C:12]=2[CH:13]=1)=[O:32])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)c1cc2ccc(OCc3ccccc3)cc2o1
Temperature: 140 °C
Yield: 71.8 %

Procedure:
To a solution of 4-benzyloxy-2-hydroxy-benzaldehyde (5.56 g, 24.4 mmol) in DMF (20 mL) is added K2CO3 (6.73 g, 48.8 mmol), bromo-acetic acid tert-butyl ester (4.75 g, 24.4 mmol), and DBU (1.0 mL). The mixture is heated to 140° C. for 2 hours and cooled to room temperature. The mixture is quenched with water (200 mL) and extracted with EtOAc (100 mL). The organic layer is dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography cluting with 15% EtOAc/Hexanes to provide the title compound (5.68 g, 72%). LC-ES/MS m/e 269.0 (acid, M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8].C(O[CH2:21][CH3:22])(=O)C>C(O)C.[Cl-].[Na+].O>[CH2:21]([C:22]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]#[N:12])=[CH:3][C:2]=2[N:1]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#Cc1ccccc1-c1ccc2[nH]c(Cc3ccccc3)nc2c1

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (2.4 mmoles, 0.50 g) was dissolved in 3 ml ethanol. Ethyl phenylacetamidate hydrochloride (2.88 mmoles, 0.573 g) (prepared from HCl gas bubbled through benzyl cyanide and ethanol) was added. The reaction was warmed on a steam bath for 10 minutes. Ethyl acetate and brine were added. The organic phase was separated dried and concentrated. The product was precipitated from ethyl acetate and hexane and filtered to yield 290 mg of 2-benzyl-5-(2-cyanophenyl)-1H-benzimidazole. (MS)
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]([OH:14])=O)=[CH:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N:16]1CCOCC1.ClC(OCC(C)C)=O.N.O1CCOCC1>COCCOC>[C:1]1([N:7]2[C:11]([C:12]([NH2:16])=[O:14])=[CH:10][N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cnnn1-c1ccccc1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: COCCOC
Solvent: C1COCCO1
Product: NC(=O)c1cnnn1-c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 1-phenyl-1H-1,2,3-triazole-5-carboxylic acid (1.0 g, 5.6 mmol) and 4-methylmorpholine (0.57 g, 5.6 mmol) in 1,2-dimethoxyethane (5 mL), isobutyl chloroformate (0.77, 5.6 mmol) was added to the mixture. After 30 minutes, ammonia in dioxane (16.8 mL, 8.4 mmol) was added to the reaction. Then it was stirred overnight. The solvent was removed and dissolved in 50 mL of ethyl acetate. The organic layer was washed with brine twice. The organic layer was dried with Na2SO4, filtered and concentrated and used without further purification. MS (m/z) 189 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30])#[N:25]>>[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:30])#[N:25]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(C#N)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Cyano-benzoic acid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3C(OC(C)(C)C)=O)[S:11][CH:12]=2)=[CH:4][C:3]1=[O:25].[ClH:26]>C(Cl)Cl.O1CCOCC1>[ClH:26].[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)[S:11][CH:12]=2)=[CH:4][C:3]1=[O:25]
Reactant: Cn1ccc(-c2csc([C@H]3CCCN3C(=O)OC(C)(C)C)n2)cc1=O
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cn1ccc(-c2csc([C@H]3CCCN3)n2)cc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(R)-tert-butyl 2-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)thiazol-2-yl)pyrrolidine-1-carboxylate (131 mg,) was dissolved in CH2Cl2 (5 mL) and 4 M HCl in dioxane (5 mL) was added. The mixture was stirred at rt for 3 h and concentrated to afford (R)-1-methyl-4-(2-(pyrrolidin-2-yl)thiazol-4-yl)pyridin-2(1H)-one HCl salt (127 mg) as an off-white solid. LC-MS Method 1 tR=0.40 min, m/z=262.
Reaction SMILES: [CH3:1][N:2]1[CH:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[C:28]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CCC12
Reactant: Clc1nc(-c2ccccc2)cc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc(-c5ccccc5)cc5ccccc45)cc3CC[C@@H]12
Yield: 41.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (86 mg, 0.33 mmol), potassium carbonate (158 mg, 1.14 mmol), 1-chloro-3-phenyl- isoquinoline (95 mg, 0.40 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 64 mg (42%) of the title compound as an off white solid. mp 183°-189°. FDMS: m/e=464. α[D]589 =+54.61 (c=0.53, chloroform).
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].[Li+].CC([N-]C(C)C)C.CN1C(=O)N(C)CCC1.I[CH2:25][C:26]1[S:30][C:29]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)=[N:28][C:27]=1[CH3:41]>O1CCCC1>[CH2:5]([O:4][C:1](=[O:3])[CH2:2][CH2:25][C:26]1[S:30][C:29]([C:31]2[CH:32]=[CH:33][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:35][CH:36]=2)=[N:28][C:27]=1[CH3:41])[CH3:6]
Reactant: CCOC(C)=O
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CI
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
A solution of ethyl acetate (2.24 ml, 22.8 mmol) in tetrahydrofuran (6 ml) was added to a −78° C. cold solution of LDA (2 M solution in tetrahydrofuran/n-heptane; 9.8 ml, 19.6 mmol) in tetrahydrofuran (15 ml) within 30 min under an argon atmosphere. The solution was stirred for 30 min at −78° C. and DMPU (3.9 ml, 32.6 mmol) was added within 20 min. A solution of 5-iodomethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole (2.5 g, 6.5 mmol) in tetrahydrofuran (15 ml) was added within 30 min and stirring was continued for additional 30 min. The mixture was naturally warmed to ambient temperature, stirred for one hour and poured onto aqueous ammonium chloride/ice water 1/1. Twofold extraction with ethyl acetate was followed by washing of the combined extracts with ice water/brine 1/1 (two times), drying over sodium sulfate and removal of the solvent under reduced pressure. The residue was purified by column chromatography (silica gel, heptane/AcOEt) and crystallized from heptane/dichloro-methane to yield 480 mg (1.4 mmol, 21%) of the title compound as light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][O:8][C:9]([C:11]2[N:16]3[C:17](=[O:29])[C@@H:18]([NH:19][C:20](=[O:28])[CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:15]3[S:14][CH2:13][C:12]=2[CH2:30]Cl)=[O:10])=[CH:5][CH:4]=1.[SH:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:22]1([CH2:21][C:20]([NH:19][C@@H:18]2[C:17](=[O:29])[N:16]3[C:11]([C:9]([O:8][CH2:7][C:6]4[CH:32]=[CH:33][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[O:10])=[C:12]([CH2:30][S:34][C:35]4[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=4)[CH2:13][S:14][C@H:15]23)=[O:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Reactant: Sc1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C2=C(CSc3ccncc3)CS[C@@H]3[C@H](NC(=O)Cc4ccccc4)C(=O)N23)cc1
Temperature: 0 °C
Yield: 93.5 %

Procedure:
To a stirred and ice cold solution of 7β-phenylacetamido-3-chloromethyl-3-cephem-4-carboxylic acid p-methoxybenzyl ester (1) (4.87 g; 10 mMol.) and 4-mercaptopyridine (1.45 g; 1.3 Eq.) in N,N-dimethylformamide (15 ml) is added sodium hydrogen carbonate (1.09 g; 1.3 Eq.), and the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with ice water and separating solidis collected by filtration, dissolved in ethyl acetate, washed with water, dried, and concentrated under reduced pressure. The residue is washed with ether to give p-methoxybenzyl 7β-phenylacetamido-3-(4-pyridyl)thiomethyl-3-cephem-4-carboxylate (2) (5.25 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[NH:11][C:12](=[O:19])[C:13]3[C:18]([C:9]=2[C:8]2[CH:7]=[C:6]([Cl:20])[CH:5]=[CH:4][C:3]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3.[H-].[Na+].[CH:23](Br)=[CH2:24]>>[CH:23]([O:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:8]3[CH:7]=[C:6]([Cl:20])[CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[C:10]=2[N:11]=1)=[CH2:24]
Reactant: C=CBr
Reactant: Cn1c2ccc(Cl)cc2c2c3ccccc3c(=O)[nH]c21
Agent: [H-]
Agent: [Na+]
Product: C=COc1nc2c(c3ccccc13)c1cc(Cl)ccc1n2C

Procedure:
5-Vinyloxy-7-methyl-10-chloro-7H-indolo(2,3-c)isoquinoline (melting point 121°-124° C.) is prepared from 7-methyl-10-chloro-7H-indolo(2,3-c)isoquinolin-5(6H)-one, sodium hydride and vinyl bromide by the method described in Example 8.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=O.C(O)C.Cl.[NH2:19][OH:20]>CCCCCC>[OH:20]/[N:19]=[C:4](\[C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[CH3:1])/[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)c1ccccc1C
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Product: CCOC(=O)/C(=N/O)c1ccccc1C
Yield: 68 %

Procedure:
To a solution containing 19.2 g of ethyl 2-methylbenzoylformate (0.1 mol) and 100 ml of ethanol, 7.6 g of hydroxylamine hydrochloride (0.11 mol) was added and the resulting mixture was heated under reflux for 5 hours. Afterwards, the solvent was distilled off under reduced pressure as a work-up procedure to give a solid. The solid, to which hexane was added, was pulverized and 14.1 g of ethyl (E)-α-hydroxyimino-o-tolylacetate (yield; 68%) was filtered off. Furthermore, the concentrated residue of the filtrate, to which ethanol and a catalytic amount of thionyl chloride were added, was heated under reflux for 5 hours. The same work-up procedure as shown above was then employed to give 4.5 g of the objective product (yield; 21%). mp 88.0-89.0° C.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:22])[NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)=[O:3].[CH:23]1([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:25][CH2:24]1.[K+].[Br-].C(O)[C@H](O)[C@H]1OC(=O)C(O)=C1O>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][NH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][CH:23]4[CH2:25][CH2:24]4)[CH2:28][CH2:29]3)=[O:3])=[CH:6][CH:7]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: O=C(Cl)Oc1ccc(C(=O)NCCc2ccc(Cl)cc2)cc1
Reactant: C1CN(CC2CC2)CCN1
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Agent: [Br-]
Agent: [K+]
Product: O=C(NCCc1ccc(Cl)cc1)c1ccc(OC(=O)N2CCN(CC3CC3)CC2)cc1
Yield: 18 %

Procedure:
The title compound was prepared from 4-[2-(4-chloro-phenyl)-ethylcarbamoyl]-phenyl chloroformate and 1-cyclopropylmethyl-piperazine, yield 18%. White crystals, m.p. 225–226° C.; IR (KBr): ν 1710 (ester C═O), 1661 (amide C═O) cm−1.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[C:24]2[CH:23]=[C:22]([C:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=3)[S:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.C(O)C.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>C(OCC)(=O)C>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[Cl:15][C:16]1[C:24]2[CH:23]=[C:22]([C:25]3[CH2:26][CH2:27][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:29][CH:30]=3)[S:21][C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Clc1cccc2sc(C3=CCNCC3)cc12
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2cc3c(Cl)cccc3s2)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.129 g, 0.068 mmol) and 4-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl) benzo[b]thiophene (0.170 g, 0.068 mmol) using ethanol as reaction solvent. Yield 0.105 g (34%) of a tan powder. FDMS m/e=438 (M+ of free base). A sample was dissolved in ethyl acetate and treated with 1.0 equivalent of oxalic acid and evaporated to an orange powder. mp 138°-142° C. (dec) α[D]589 =-5.3 (c=1.13, dimethylsufoxide).
Reaction SMILES: I[C:2]1[C:3]([CH:11]([CH3:13])[CH3:12])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.O.[NH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(C1C(C2C=C(N)C=CC=2)=C2C=CC=CN2N=1)(C)C>>[CH:11]([C:3]1[C:2]([C:19]2[CH:20]=[CH:21][C:16]([NH2:15])=[CH:17][CH:18]=2)=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)([CH3:13])[CH3:12]
Reactant: Nc1ccc(B(O)O)cc1
Reactant: CC(C)c1nn2ccccc2c1I
Agent: CC(C)c1nn2ccccc2c1-c1cccc(N)c1
Solvent: O
Product: CC(C)c1nn2ccccc2c1-c1ccc(N)cc1

Procedure:
4-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine was prepared from 3-iodo-2-isopropyl-pyrazolo[1,5-a]pyridine and 4-aminophenylboronic acid monohydrate following the method used in Step 3 of the synthesis of 3-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-phenylamine as in Example 59 above (134 mg, 18%). 1H-NMR (250 MHz, DMSO-d6) δ 8.58 (d, J=7.0 Hz, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.14-7.04 (m, 3H), 6.77 (t, J=7.0 Hz, 1H), 6.67 (d, J=8.5 Hz, 2H), 5.15 (s, 2H), 3.23 (sept, J=6.8 Hz, 1H), 1.26 (d, J=7.0 Hz, 6H). LC/MS 252.3 m/z (M+H+). Compound 1101.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=C(C#N)C=1.[OH:23]O>C[Re](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]2[CH2:14][O:23]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OO
Reactant: C=C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: C[Re](=O)(=O)=O
Agent: N#Cc1cccnc1
Product: CC(C)(C)OC(=O)N1CC[C@H](C2CO2)C1
Yield: 63.9 %

Procedure:
To (R)-3-vinylpyrrolidine-1-carboxylic acid t-butyl ester (6.1 g, 30.8 mmol) was added 3-pyridinecarbonitrile (320 mg, 3.1 mmol) and methyltrioxorhenium(VII) (192 mg, 769 μmol). The mixture was stirred until homogeneous. The mixture was placed in an ice water bath and 30% hydrogen peroxide (33:77, hydrogen peroxide:H2O, 4.08 mL, 40.0 mmol) was added, while keeping the temperature below 35° C. The mixture was stirred for 2 hours. Additional methyltrioxorhenium(VII) (50 mg) was added and the mixture was stirred for 2 hours. The organic layer was collected and washed with a saturated sodium metabisulfite solution (10 mL) under an ice bath. The material was then washed with saturated aqueous NaCl. The organic layer was collected, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography (0-100% EtOAc in hexanes) to give (S)-3-oxiranylpyrrolidine-1-carboxylic acid t-butyl ester as a yellowish oil (4.2 g).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)#[N:2].[CH2:18]([NH2:20])[CH3:19]>C(O)C>[C:1]([N:3]=[C:4]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[NH:20][CH2:18][CH3:19])#[N:2]
Reactant: CCN
Reactant: CSC(=NC#N)NC1CCCc2ccccc21
Solvent: CCO
Product: CCNC(=NC#N)NC1CCCc2ccccc21
Reaction time: 20 h

Procedure:
A solution of 6.13 g of N'-cyano-N-(1,2,3,4-tetrahydro-1-naphthyl)-S-methylisothiourea and 10 ml of 70% aqueous ethylamine in 90 ml of ethanol was heated at reflux with stirring for 20 hours. The reaction mixture was cooled in a refrigerator to give 2.44 g of N"-cyano-N-ethyl-N'-(1,2,3,4-tetrahydro-1-naphthyl)guanidine as a white, crystalline solid, mp 152°-153.5° C.
Reaction SMILES: [CH3:1][N:2]([CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[S:3]([N:6]1[C:11]2([CH2:13][CH2:12]2)[CH2:10][N:9]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[CH2:38]([S:41](Cl)(=[O:43])=[O:42])[CH2:39][CH3:40]>CS(C)=O>[CH3:1][N:2]([CH2:23][CH:24]1[CH2:28][CH2:27][N:26]([S:41]([CH2:38][CH2:39][CH3:40])(=[O:43])=[O:42])[CH2:25]1)[S:3]([N:6]1[C:11]2([CH2:13][CH2:12]2)[CH2:10][N:9]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5]
Reactant: CCCS(=O)(=O)Cl
Reactant: CN(CC1CCNC1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCCS(=O)(=O)N1CCC(CN(C)S(=O)(=O)N2CCN(c3ncnc4[nH]ccc34)CC23CC3)C1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
N-methyl-N-(pyrrolidin-3-ylmethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-5,8-diazaspiro[2.5]octane-8-sulfonamide (intermediate 25) (0.042 mmol) was dissolved in dry DMSO (0.5 mL), added DIPEA (0.25 mL) and propane-1-sulfonyl chloride (0.050 mmol) and then stirred at 40° C. for 1 h. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.