Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OCC)=O.[C:7]([O:11][C:12]([NH:14][C:15]([CH3:21])([CH3:20])[CH2:16][C:17](O)=[O:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.[Li].Cl>C1COCC1.CO>[C:7]([O:11][C:12](=[O:13])[NH:14][C:15]([CH3:21])([CH3:20])[CH2:16][CH2:17][OH:18])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [Li]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(CCO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 78.7 %

Procedure:
At 0° C., ethyl chloroformate (1.10 ml, 11.5 mmol) was given dropwise to a solution of 3-tert-butoxycarbonylamino-3-methylbutanoic acid (2.50 g, 11.5 mmol) and triethylamine (1.92 ml, 13.8 mmol) in THF (10 ml). The solution was stirred for 40 min at 0° C. The obtained precipitate was filtered off and washed with THF (20 ml). The liquid was immediately cooled to 0° C. A 2M solution of lithium boronhydride in THF (14.4 ml, 28.8 mmol) was added dropwise. The solution was stirred at 0° C. for 2 h, and then warmed to room temp. over a period of 4 h. It was cooled to 0° C. Methanol (5 ml) was added carefully. 1N Hydrochloric acid (100 ml) was added. The solution was extracted with ethyl acetate (2×100 ml, 3×50 ml). The combined organic layers were washed with saturated solution of sodium hydrogencarbonate (100 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was chromatographed on silica (110 g) with ethyl acetate/heptane 1:2 to give 1.84 g of 3-hydroxy-1,1-dimethylpropylcarbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1C(O)=O.ClC(O[C:21](=[O:27])[O:22][C:23](Cl)(Cl)Cl)(Cl)Cl.[OH2:28]>O1CCCC1>[Cl:11][C:9]1[C:10]2[C:23](=[O:28])[O:22][C:21](=[O:27])[NH:1][C:2]=2[CH:3]=[C:7]([C:12]([F:13])([F:14])[F:15])[CH:8]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(Cl)cc(C(F)(F)F)c1C(=O)O
Reactant: O
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(C(F)(F)F)cc(Cl)c2c(=O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-amino-4-chloro-6-trifluoromethylbenzoic acid (0.53 g, 2.2 mM) in dry tetrahydrofuran (6 mL) under a nitrogen atmosphere was added bis(trichloromethyl)carbonate (0.218 g, 0.734 mM). The resulting solution was stirred at room temperature for 2 hr, poured into water and the resulting mixture extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered and concentrated to leave the title compound as a tan solid; MS(CI): 266 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]1[CH2:16][C:17]([O:19]C)=[O:18].O[Li].O.Cl>C1COCC1.O>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:14])([F:13])[F:15])[CH:8]=2)[N:3]1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: COC(=O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a stirring solution of methyl 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetate (4.8 g, 16.8 mmol) in THF/water (25 mL/5 mL, 5:1) was added LiOH.H2O (3.52 g, 84.2 mmol). The resulting mixture was stirred overnight. The crude mixture was slowly acidified with 1N HCl and then extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated under vacuum to give 2-(2-oxo-6-(trifluoromethyl)quinolin-1(2H)-yl)acetic acid (4.3 g). Retention time (min)=3.005, method [7], MS(ESI) 272.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[F:9][C:10]([F:28])([F:27])[C:11]([N:13]1[CH2:22][CH2:21][C:20]2[C:15](=[CH:16][C:17]([S:23](Cl)(=[O:25])=[O:24])=[CH:18][CH:19]=2)[CH2:14]1)=[O:12]>>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([NH:8][S:23]([C:17]2[CH:16]=[C:15]3[C:20]([CH2:21][CH2:22][N:13]([C:11](=[O:12])[C:10]([F:28])([F:9])[F:27])[CH2:14]3)=[CH:19][CH:18]=2)(=[O:24])=[O:25])=[CH:4][CH:3]=1
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Reactant: Cc1ccc(N)cc1
Product: Cc1ccc(NS(=O)(=O)c2ccc3c(c2)CN(C(=O)C(F)(F)F)CC3)cc1

Procedure:
prepared by reaction of p-tolylamine with 2-(2,2,2-trifluoro-acetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[CH2:12]([Sn:16]([CH2:22][CH2:23][CH2:24][CH3:25])([CH2:18][CH2:19][CH2:20][CH3:21])Cl)[CH2:13][CH2:14][CH3:15].C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[S:3][C:4]([Sn:16]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][N:6]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nccs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(C)s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To a cold (−78° C.) solution of 2-methylthiazole (2.80 g, 28.2 mmol) in anhydrous THF (100 mL) was added butyllithium (19.41 mL, 31.1 mmol) dropwise. After stirring for 60 min at −78° C., a solution of tributylchlorostannane (9.14 mL, 33.9 mmol) in anhydrous THF was added to the reaction mixture. The reaction mixture was stirred for 30 min at −78° C. and then allowed to warm to RT over a 2 to 3 h period. Saturated aq NaHCO3 was added and the aqueous phase was extracted with ether (3×200 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. The crude product was purified on a silica gel column eluting with 10-50% EtOAc in Hexane over a 60 min period. The fractions were collected and solvent was removed in vacuo to give the title compound as a yellow oil (72%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.71-0.92 (m, 9 H), 0.96-1.18 (m, 6 H), 1.23-1.38 (m, 6 H), 1.40-1.64 (m, 6 H), 2.69 (s, 3 H), 7.56 (d, J=12.69 Hz, 1 H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH3:16][NH2:17].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:14][C:9]1[C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:17][CH3:16])[CH:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Clc1cc(-c2cccnc2Cl)ncn1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(-c2cccnc2Cl)ncn1
Temperature: 80 °C

Procedure:
4-Chloro-6-(2-chloro-pyridin-3-yl)-pyrimidine (450 mg, 1.99 mmol), methylamine hydrochloride (202 mg, 2.99 mmol), K2CO3 (550 mg, 3.98 mmol) and DMSO (3.0 mL) were combined. The mixture was heated overnight at 80° C. in a sealed tube. The cooled mixture was diluted with water (300 mL) and the resulting solid was filtered, washed with water and dried to yield the title compound. MS m/z=221 [M+1]+. Calc'd for C10H9ClN4: 220.66.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:9])[NH:7][N:8]=2)[CH2:3][CH2:2]1.[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15](OCC)=[O:16])[CH3:11]>C(O)(=O)C>[CH2:10]([O:12][C:13]([C:14]1[C:15](=[O:16])[N:7]2[N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:5]=[C:6]2[NH:9][CH:20]=1)=[O:24])[CH3:11]
Reactant: Nc1cc(C2CC2)n[nH]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2cc(C3CC3)nn2c1=O
Temperature: 120 °C
Yield: 73.9 %

Procedure:
To a solution of 5-cyclopropyl-2H-pyrazol-3-ylamine (280 mg, 2.3 mmol, 1 eq) in acetic acid (3 mL) was added 2-ethoxymethylene-malonic acid diethyl ester (500 μL, 2.5 mmol, 1.1 eq). The mixture was heated at 120° C. for 2 h in a sealed tube. After cooling, the precipitate was filtered and washed with ethanol to afford the expected compound as white powder (420 mg, 75% yield).
Reaction SMILES: [C:1]([C:3]1[C:4](F)=[C:5]([CH:19]=[C:20]([F:23])[C:21]=1[F:22])[C:6]([C:8](=[CH:14][NH:15][CH:16]1[CH2:18][CH2:17]1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])#[N:2].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:3]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:5]2[C:4]=1[N:15]([CH:16]1[CH2:18][CH2:17]1)[CH:14]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:6]2=[O:7])#[N:2]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(F)c(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C2CC2)c2c(C#N)c(F)c(F)cc2c1=O
Temperature: 0 °C

Procedure:
The reaction product from stage f and 27.6 g of potassium carbonate are stirred at room temperature for 16 hours in 80 ml of dimethylformamide. The reaction mixture is then added to 750 ml of ice water, and the solid is filtered off with suction and washed with 80 ml of cold methanol. After drying, 47 g of ethyl 8-cyano-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate of melting point 209-211° C. are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)[OH:4].[OH-].[Na+].[Cl:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)Cl.O>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH2:2][NH:1][C:16](=[O:17])[CH2:15][Cl:14])=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: NCC(O)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)NCC(O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 68.4 %

Procedure:
To a solution of compound 2-amino-1-(4-bromophenyl)ethanol (2.0 g, 10 mmol) in CH2Cl2 (40 mL) and water (40 mL) was added NaOH (0.48 g, 12 mmol) and chloroacetyl chloride (1.7 g, 15 mmol) at 0° C. After addition, the mixture was allowed to warm to room temperature and stirred for 6 hours. The layers were separated. The organic was washed with 3% HCl and saturated NaHCO3, dried over sodium sulfate, and concentrated to afford the title compound (2.0 g, 76% yield) as a yellow solid. 1H NMR: (400 MHz, CDCl3): δ 7.45 (d, 2H), 7.19 (d, 2H), 6.98 (br. s, 1H), 4.80 (m, 1H), 4.01 (s, 2H), 3.68 (m, 1H), 3.30 (m, 1H), 2.82 (br. s, 1H):
Reaction SMILES: [C:1]1([N:11]=[C:12]=[S:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1>>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:12]([NH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[S:13])=[CH:18][C:17]=1[N:23]1[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]1
Reactant: S=C=Nc1cccc2ccccc12
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Product: COc1ccc(NC(=S)Nc2cccc3ccccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from 1-naphthyl isothiocyanate and 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP0533268A1) using a similar procedure to Example 6.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:19]([O-:21])=[O:20])[C:10]=1[C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)[OH:23].N([O-])=O.[Na+]>O>[C:11]([C:10]1[C:9]([N+:19]([O-:21])=[O:20])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[OH:23])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1

Procedure:
To a solution of 3-amino-4-benzoyl-5--nitrobenzoic acid (100 g) in a mixture of conc. sulfuric acid (875 ml) and water (280 ml) is dropwise added a solution of sodium nitrite (45.0 g) in water (280 ml), while stirring at -5° C to 0° C. After additional stirring at -5° C to 0° C for about 15 minutes, the resulting diazoniumsolution is heated on a steam bath for 2-3 hours until the nitrogen evolution has ceased. After cooling, the resulting precipitate is collected by filtration and washed with water. After drying and recrystallization twice from aqueous ethanol, 4-benzoyl-3-hydroxy-5-nitrobenzoic acid is obtained as a monohydrate with a melting point of 264° -266° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH2:6]O.[ClH:12].C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH3:11])[CH2:6][Cl:12]
Reactant: Cl
Reactant: COc1cc(CO)ccc1C
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: COc1cc(CCl)ccc1C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 3-methoxy-4-methylbenzylalcohol (41.61 g), conc. hydrochloric acid (125 ml) and toluene (83 ml) was stirred at 90° C. for 1 hour. After cooling, ice-water (125 ml) and diisopropyl ether (80 ml) were added to the mixture, and the organic layer was separated, and the aqueous layer was extracted with diisopropyl ether (160 ml). The combined organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and evaporated in vacuo to give 3-methoxy-4-methylbenzyl chloride (46.35 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:5]2.[CH2:16]([NH:23][C:24]1[C:29]([CH:30]=O)=[CH:28][N:27]=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[CH2:16]([NH:23][C:24]1[CH:25]=[CH:26][N:27]=[CH:28][C:29]=1[CH2:30][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:5]2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=Cc1cnccc1NCc1ccccc1
Reactant: CCCCN1Cc2cc(N)ccc2C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCN1Cc2cc(NCc3cnccc3NCc3ccccc3)ccc2C1=O
Reaction time: 48 h
Yield: 16.9 %

Procedure:
5-Amino-2-butylisoindolin-1-one (48.1 mg, 0.236 mmol) was added to a solution of 4-(benzylamino)nicotinaldehyde (50 mg, 0.236 mmol) in acetic acid (0.5 mL). Sodium triacetoxyborohydride (100 mg, 0.471 mmol) was added and the reaction mixture was stirred for 2 days. After the addition of more triacetoxyborohydride (50 mg, 0.235 mmol) and stirring for 6 h, water and sat aqueous NaHCO3 solution were added. The mixture was extracted with EtOAc, the combined org. layers washed with water and dried (MgSO4). Purification by HPLC provided 5-((4-(benzylamino)pyridin-3-yl)methylamino)-2-butylisoindolin-1-one (16 mg, 13%). ESI-MS [M+H+]=401.2.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]=[C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[Cl:27])=[C:4]([F:30])[CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[C:39](=[O:47])[C:40]([C:44](O)=[O:45])=[CH:41][NH:42][CH:43]=2)=[CH:34][CH:33]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:27][C:8]1[C:9]([N:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:10][CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:28]=[CH:29][C:2]([NH:1][C:44]([C:40]2[C:39](=[O:47])[C:38]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)=[CH:43][NH:42][CH:41]=2)=[O:45])=[CH:3][C:4]=1[F:30]
Reactant: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-3-chloro-N-(diphenylmethylene) pyridin-2-amine (836 mg, 2.0 mmol) and 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (490 mg, 2.0 mmol) in DMF (10 mL) at room temperature were added HATU (913 mg, 2.4 mmol) and DIPEA (1.05 ml, 6.0 mmol). The reaction mixture was stirred at room temperature for 3 h prior to being quenched by the addition of cold water (50 mL). The solid that formed was collected by filtration, and washed with water and ether. The solid was dissolved in DCM and purified by flash column chromatography (SiO2, DCM to 10% MeOH in DCM) to give the desired product (987 mg, 78%) as a light yellow solid. MS (ESI) m/z 633 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1.[CH3:15][Si]([N-][Si](C)(C)C)(C)C.[Na+].C([O-])(O)=O.[Na+].O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)CCc1cccc(C#N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
To a solution of 3-(3-cyano-phenyl)-propionic acid methyl ester of Step A (220 mg, 1.16 mmol) in THF (5 mL) at −78° C. was added sodium bis(trimethylsilyl)amide (1 M in THF, 1.2 mL, 1.2 mmol). The reaction was stirred for 0.5 h and Mel (0.08 mL, 1.28 mmol) was added. After 1 h, a solution of saturated NaHCO3:water (1:1) was added and the reaction was warmed to room temperature. The aqueous solution was washed with CH2Cl2 (3×) and the combined organic solutions were dried (MgSO4), filtered, and concentrated. Medium pressure chromatography (6:1 hexanes:EtOAc) provided the title compound of Step B as a colorless oil (62 mg). 1H NMR (400 MHz, CDCl3) δ 7.50-7.34 (m, 4H), 3.62 (s, 3H), 3.01 (m, 1H), 2.71 (m, 2H), 1.16 (d, 3H).
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][CH2:6][N:7]([CH3:14])[CH2:8][CH2:9][CH2:10][NH:11][CH:12]=[O:13])=[O:2].[CH2:15]([N:17]([CH2:24][CH2:25][Cl:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:16]>O>[Cl-:26].[CH3:14][N+:7]([CH2:16][CH2:15][N:17]([CH2:24][CH3:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH2:6][CH2:5][CH2:4][NH:3][CH:1]=[O:2])[CH2:8][CH2:9][CH2:10][NH:11][CH:12]=[O:13]
Reactant: CCN(CCCl)c1ccccc1
Reactant: CN(CCCNC=O)CCCNC=O
Solvent: O
Product: CCN(CC[N+](C)(CCCNC=O)CCCNC=O)c1ccccc1
Product: [Cl-]

Procedure:
Proceeding in a manner similar to that described in C-1, 185.5 parts of N,N-bis(3-formamidopropyl)methylamine and 171 parts of N-ethyl-N-(2-chloroethyl)aniline were interacted in 140 parts of water to obtain a nearly quantitative yield of N-methyl-N-2-(N'-ethylanilino)ethyl-N,N-bis(3-formamidopropyl)ammonium chloride in the form of an aqueous solution.
Reaction SMILES: C[O-].[Na+].[N+](C(C)C)([O-])=[O:5].[Cl:10][C:11]1[C:12]([CH3:20])=[C:13]([C:16]([Cl:19])=[CH:17][CH:18]=1)[CH2:14]Br.Cl>CO.O>[Cl:10][C:11]1[C:12]([CH3:20])=[C:13]([C:16]([Cl:19])=[CH:17][CH:18]=1)[CH:14]=[O:5]
Reactant: Cc1c(Cl)ccc(Cl)c1CBr
Reactant: CC(C)[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1c(Cl)ccc(Cl)c1C=O
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
122.4 g (0.68 mol) of a 30% strength solution of sodium methoxide are dissolved in 1030 ml of methanol, and 56.4 g ( 0.57 mol) of 90% pure 2-nitropropane and 188.5 g (0.52 mol) of 61.6% pure 3,6-dichloro-2-methylbenzyl bromide are then added. The reaction is exothermic to 53° C., and the mixture is then stirred for 90 min. The reaction mixture is poured into 2.5 l of water, the pH is adjusted to pH 7.0 using 10% strength HCl, the mixture is extracted three times with 1 l of ethyl acetate, and the organic phases are combined, washed twice with 500 ml of saturated NaCl solution, dried over Na2SO4 and concentrated under reduced pressure: the 161.0 g of crude product are distilled using a 10 cm column packed with 10 mm Raschig rings. The crystals from the last fractions are filtered. This gives 9.8 g comprising 85.9% of the desired product and 4.5% and 6.9% of isomers. Yield: 9.7%. The residue is distilled over a Spaltrohr column, giving another 3.2 g of 94.3% pure product.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[C:7]1([CH3:23])[CH:12]=[CH:11][C:10]([S:13]([CH:16]2[S:20][C:19](=[O:21])[NH:18][C:17]2=[O:22])(=[O:15])=[O:14])=[CH:9][CH:8]=1>>[CH2:2]([C:16]1([S:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:23])=[CH:8][CH:9]=2)(=[O:14])=[O:15])[S:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[CH2:3][CH2:4][C:5]#[CH:6]
Reactant: Cc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Reactant: C#CCCCI
Product: C#CCCCC1(S(=O)(=O)c2ccc(C)cc2)SC(=O)NC1=O

Procedure:
In the manner of Example 100 above, 5-iodo-1-pentyne is created with 5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione to give the title compound, mp 226° C., THEORY: C,53.4, H, 4.48, N, 4.15 FOUND: C, 53.3, H, 4.58, N, 4.13.
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[C:15](=[N:22]O)[C:14]=2[CH:13]=[CH:12][CH:11]=1.C(O)C.O>C(O)(=O)C.[Zn]>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]([NH2:22])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: ON=C1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21
Agent: [Zn]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: NC1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21
Temperature: 25 °C
Yield: 26.7 %

Procedure:
In a 100 ml round-bottomed flask, a mixture of 200 mg of 5-(3H-imidazo[4,5-c]pyridin-2-yl)pyrrolo[1,2-a]indol-9-one oxime obtained according to the preceding stage, in 5 ml of glacial acetic acid, 5 ml of ethanol and 5 ml of water, is stirred at ambient temperature. 43 mg of powdered zinc are added and the stirring is maintained at ambient temperature for 2 hours. The reaction medium is filtered through clarcel, washing being carried out with methanol. The filtrate is evaporated to dryness under vacuum and the residue is chromatographed on silica gel (15-40 μm), elution being carried out with a mixture of dichloromethane and 5N ammoniacal methanol (95/5 v/v). 51 mg of 5-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-pyrrolo[1,2-a]indol-9-ylamine are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([Cl:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[N:31]=3)[CH:15]=2)[CH2:10][C@H:9]1[C:35]([OH:37])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH3:71][NH:72][CH2:73][CH2:74][CH2:75][CH2:76][CH:77]=[CH2:78].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:26][C:19]1[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[C:23]2[C:18]=1[N:17]=[C:16]([C:27]1[S:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[N:31]=1)[CH:15]=[C:14]2[O:13][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[C@H:9]([C:35](=[O:37])[N:72]([CH2:73][CH2:74][CH2:75][CH2:76][CH:77]=[CH2:78])[CH3:71])[CH2:10]1
Reactant: C=CCCCCNC
Reactant: COc1ccc2c(O[C@H]3C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@H](Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
Compound 133 (20.5 g) was dissolved in anhydrous DMF (48 mL) at room temperature. O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.25 eq.) was added at room temperature and the reaction mixture was stirred for 10 min. Compound 32a (1.1 eq.) was added and the reaction mixture was stirred for additional 10-15 min. After cooling to 5° C., diisopropylethylamine (3 eq.) was added. After warming to room temperature for 1 hr, the reaction mixture was diluted with ethyl acetate, washed with brine and ammonium chloride, dried over Na2SO4, and concentrated under vacuum to give crude 134 (22.09 g) as an orange foam. The crude product was crystallized from ethyl acetate and heptane to give compound 134 (20.55 g) as a white powder in 92% yield and 98% purity.