Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH:35]=2)=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[CH:1]1([O:6][C:7]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:8]=2[C:9]([N:33]2[CH2:32][CH:31]=[C:30]([C:27]3[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=3)[CH2:35][CH2:34]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C2=CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(C2=CCN(C(=O)c3cc(S(C)(=O)=O)ccc3OC3CCCC3)CC2)cc1

Procedure:
According to the procedure described for the synthesis of example 4, step f, the title compound has been synthesized from 2-cyclopentyloxy-5-methanesulfonyl-benzoic acid and 4-(4-Methanesulfonyl-phenyl)-1,2,3,6-tetrahydro-pyridine. MS (m/e): 503.9 (M+, 100%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:12]=[CH:13]OCC)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH3:17][NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)C>>[OH:1][C:2]1[CH:3]=[C:4]([N:12]=[CH:13][N:18]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CNc1ccccc1
Reactant: CCOC=Nc1ccc(C(=O)OC)c(O)c1
Solvent: CCO
Product: COC(=O)c1ccc(N=CN(C)c2ccccc2)cc1O

Procedure:
A mixture of ethyl N-(3-hydroxy-4-methoxycarbonylphenyl)formimidate (6.6 g, 0.03 mol) and N-methylaniline (3.2 g, 0.03 mol) were heated at 150° until 1.7 mol of ethanol had been collected by distillation. The pale yellow oil was flash distilled to yield the desired product, bp≈200° C. (0.1 mm). ##STR16##
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].Cl[C:27]([O:29][CH3:30])=[O:28]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([C:27]([O:29][CH3:30])=[O:28])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COC(=O)Cl
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(F)cc1Cl
Product: COC(=O)n1c2c(c(=O)n(-c3cc(C(=O)OC(C)C)c(Cl)cc3F)c1=O)CCC2

Procedure:
using isopropyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and methyl chloroformate there is obtained isopropyl 2-chloro-4-fluoro-5-(1,2,4,5,6,7-hexahydro-1-methoxycarbonyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.84 ppm (d, 1H), 7.35 ppm (d, 1H), 5.24 ppm (m, 1H), 4.03 ppm (s, 3H), 3.02 ppm (m, 2H), 2.79 ppm (m, 2H), 2.16 ppm, (m, 2H), 1.36 ppm (d, 6H),
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([CH3:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc4c(c3)OCO4)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-methyl-4-(3,4-methylene dioxybenzylamino)-thieno-[2,3-d]-pyrimidine yields 2-(pyrazol-1-yl)-6-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[CH:2]([CH3:9])[C:3](=O)[C:4]([O:6][CH3:7])=[O:5].[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>C(OCC)(=O)C>[CH3:9][C:2]1[N:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]2=[N:10][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(=O)C(C)Br
Reactant: Nc1ccc([N+](=O)[O-])cn1
Solvent: CCOC(C)=O
Product: COC(=O)c1nc2ccc([N+](=O)[O-])cn2c1C

Procedure:
Operations similar to Production Example 1-(2) were conducted using methyl 3-bromo-2-oxobutanoate and 2-amino-5-nitropyridine. The resulting solid was suspended in ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to provide the title compound as yellow crystals.
Reaction SMILES: [C:1]1([CH:7]([CH3:21])[CH:8]([C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>Cl>[C:1]1([C:7]([CH3:21])=[CH:8][C:10]2[S:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(c1ccccc1)C(O)c1ccc(-c2ccccc2)s1
Agent: Cl
Product: CC(=Cc1ccc(-c2ccccc2)s1)c1ccccc1
Yield: 53.6 %

Procedure:
A stirred mixture of 8.0 grams (0.027 mole) of 2-phenyl-1-(5-phenylthien-2-yl)-1-propanol in 100 mL of concentrated hydrochloric acid was heated at reflux for 1.5 hours. The mixture was cooled and extracted with chloroform. The extract was washed with an aqueous solution saturated with sodium chloride and dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was evaporated under reduced pressure yielding a solid residue. Half of this residue was purified by column chromatography on silica gel, eluting with toluene:n-hexane (5:95). The remainder of the residue was purified by recrystallization from toluene and ethanol to yield a total of 4.0 grams of 2-phenyl-1-(5-phenylthien-2-yl)-1-propene as a solid, m.p. 115°-25° C.
Reaction SMILES: O[C:2]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][CH2:4][CH2:3]1>C1(C)C=CC=CC=1>[S:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:2]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][CH2:4]1
Reactant: CCOC(=O)C1(O)CCSc2ccccc21
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=CCSc2ccccc21
Yield: 104.1 %

Procedure:
In a manner similar to that described in Example 15, ethyl 3,4-dihydro-4-hydroxy-2H-1-benzothiopyran-4-carboxylate (16 g) was dehydrated in refluxing toluene to give in quantitative yield after chromatography the title compound as a mobil oil (15.4 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:21]2[N:22]=[CH:23][NH:24][CH:25]=2)(O)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.S([O-])(O)(=O)=O.[K+]>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:21]2[N:22]=[CH:23][NH:24][CH:25]=2)=[CH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: OC(CCCCc1ccccc1)(c1ccc(F)cc1)c1c[nH]cn1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCO
Product: Fc1ccc(C(=CCCCc2ccccc2)c2c[nH]cn2)cc1

Procedure:
4-[1-(4-fluorophenyl)-1-hydroxy-5-phenylpentyl]-1H-imidazole hydrochloride (5,0 g) and 30,0 g of anhydrous potassium hydrogen sulphate are heated at 150° C. for 4 hours. The mixture is cooled and 90 ml of ethanol is added to dissolve the product. The mixture is then filtered and the filtrate is evaporated to minor volume. Water is added and the mixture is made alkaline with sodium hydroxide. The product is extracted into methylene chloride, washed with water and evaporated to dryness. The product is then made to hydrochloride salt with dry hydrogen chloride in dry ethylacetate.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[O:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.CS[C:20]([N:24]([CH3:33])[N:25]=CC1C=CC=CC=1)=[N:21][C:22]#[N:23].Cl>CC(C)=O>[CH3:33][N:24]1[C:20]([NH:14][CH2:13][CH2:12][CH2:11][O:10][C:9]2[CH:15]=[CH:16][CH:17]=[C:7]([CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)=[N:21][C:22]([NH2:23])=[N:25]1
Reactant: CSC(=NC#N)N(C)N=Cc1ccccc1
Reactant: NCCCOc1cccc(CN2CCCC2)c1
Agent: Cl
Solvent: CC(C)=O
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCC2)c1
Yield: 14.6 %

Procedure:
A mixture of 3-[3-[1-pyrrolidinylmethyl]phenoxy]propanamine (0.97 g) and N-cyano-1-methyl-2-(phenylmethylene)hydrazine carboximidothioic acid methyl ester (0.97 g) was heated at 70° for 8 hr under a reduced pressure of 20 mm of mercury. Acetone was added and the solution was treated with hydrochloric acid at room temperature for one hour, washed with ether, basified with sodium carbonate and extracted with ethyl acetate. Evaporation of the ethyl acetate extracts gave a thick oil which crystallised from ethyl acetate/light petroleum (b.p. 60-80") to give the title compound as a white solid (0.2 g). TLC; silica/methanol/0.88 ammonia 80:1) Rf 0.5, m.p. 95°-95.5°.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][C:25](F)=[CH:24][CH:23]=2)[C:18]=1[C:29](Cl)=[O:30]>C(Cl)Cl.[N+](C)([O-])=O>[CH3:16][C:17]1[O:21][N:20]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:18]=1[C:29]([C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1)=[O:30]
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)Cl
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1C(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.7 %

Procedure:
To a solution of 2.1 g (10 mmol) of 2-trichloroacetyl-1H-pyrrole (commercially available) in CH2Cl2 (35 mL) and nitromethane (17.5 mL), 1.66 g (12.5 mmol) of AlCl3 was added in one portion. Then 2.96 g (12.5 mmol) of 5-methyl-3-(4-fluoro-phenyl)-isoxazole-4-carboxylic acid chloride (example 2, step 1) in 5 mL of CH2Cl2 was added dropwise. The reaction mixture was stirred at room temperature for 18 h before poured onto ice-water. The organic phase was separated, and the aqueous phase was extracted with diethyl ether. The combined organic solution was dried over Na2SO4, and evaporated to dryness. The obtained solid was washed extensively with petroleum ether to give 2.93 g 4-(5-methyl-3-phenyl-isoxazole-4-carbonyl)-2-trichloroacetyl-1H-pyrrole in 70% yield as yellow solid. (m/e): 414.8 (M+; 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[H-].[Na+].Cl[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[N:9]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=2)[N:7]=1
Reactant: CCOC(=O)CCl
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1nc2ccc(Cl)nn2c1=O
Temperature: 90 °C

Procedure:
To a solution of 6-chloro-2,3-dihydro-s-triazolo[4,3-b]pyridazin-3-one [P. Francavilla and F. Lauria, J. Het. Chem., 8, 415 (1971)] (1, 1.00 g., 5.9 m.mole) in dry DMF (30 ml.) was added sodium hydride (50% in paraffin, 0.3 g., 6.3 m.mole) under stirring with formation of yellow crystals. To the mixture was added ethyl chloroacetate (1.4 ml., 13 m.mole) and the mixture was heated at 90° C. for 8 hours with stirring. After cooling, the reaction mixture was poured into water (50 ml.) and extracted with toluene (5 × 40 ml.). The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated at reduced pressure. The residue was crystallized with benzene-n-hexane to give yellow needles (1.16 g., 77%), m.p. 114°-115° C. (lit. 110° C.).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[C:10]1[CH:31]=[CH:30][C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:18]=2)=[O:15])=[C:12]([CH3:32])[N:11]=1>CN(C=O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[C:13]2[CH:30]=[CH:31][C:10]([N:4]3[CH:5]=[N:6][C:2]([CH3:1])=[N:3]3)=[N:11][C:12]=2[CH3:32])=[CH:18][C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Cc1nc(Cl)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cc1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncn(-c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(C)n2)n1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
A mixture of 57 mg of 3-methyl-1,2,4-triazol and 16 mg of sodium hydride in 2 mL of DMF was stirred for 10 min. 80 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide was added. The reaction was heated to 140° C. for 16 h. The reaction mixture was quenched with MeOH and evaporated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methyl-1H-1,2,4-triazol-1-yl)nicotinamide. MS (Q1) 405.3 (M)+.
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.NN>C(O)C>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[CH:26][CH:27]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCOc1ccc(-n2cnnn2)cc1
Agent: NN
Solvent: CCO
Product: NCCCCOc1ccc(-n2cnnn2)cc1

Procedure:
A suspension of 19.4 g of 2-[4-[4-(1H-tetrazol-1-yl)phenoxy]butyl]-1H-isoindole-1,3(2H)-dione (Example 38) in 400 ml boiling ethanol is treated with 3 ml of anhydrous hydrazine, and the mixture stirred at reflux for 16 hours. The precipitate is collected, washed with 200 ml of hot 1.5N HCl, and 50 ml of H2O. The combined ethanol, hydrochloric acid, and water filtrates are taken to dryness in vacuo to give the hydrochloride salt of the title compound. A portion of the salt was recrystallized from hot ethanol, m.p. 197°-198° C. (dec.).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@@H:10]([N:13]([CH:15]([CH3:17])[CH3:16])[CH3:14])[CH2:9][C@H:8]2[C:18]([O:20][CH3:21])=[O:19])[C:3]1=[O:22].Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:37])([F:36])[F:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.CCN(CC)CC>CCO>[CH:15]([N:13]([CH3:14])[C@H:10]1[CH2:9][C@@H:8]([C:18]([O:20][CH3:21])=[O:19])[C@@H:7]([N:4]2[CH2:5][CH2:6][C@H:2]([NH:1][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[C:3]2=[O:22])[CH2:12][CH2:11]1)([CH3:17])[CH3:16]
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 100 °C
Yield: 0 %

Procedure:
A solution of (1R,2S,5R)-methyl 2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(isopropyl(methyl)amino)-cyclohexanecarboxylate (50 mg, 0.16 mol), 4-chloro-6-(trifluoromethyl)quinazoline (48 mg, 0.20 mol) and Et3N (100 mg, 1.0 mol) in EtOH (2 ml) was added to a microwave reaction tube, sealed, and heated in a microwave oven at 100° C. for 60 minutes. The reaction mixture was concentrated in vacuo and the residue chromatographed on silica gel (3%-5% (NH4OH/MeOH)/CH2Cl2) to give 25 mg of the title product, (1R,2S,5R)-methyl 5-(isopropyl(methyl)amino)-2-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexanecarboxylate, as a white solid. MS found: (M+H)+=508.24.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[CH2:5][C:4]([CH3:20])([CH3:19])[NH:3]1.[CH3:22]SC[C@H](NC(CC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)C(O)=O.C=O.C(O)=O.C(=O)=O>>[CH3:22][N:8]([CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)[CH:6]1[CH2:7][C:2]([CH3:21])([CH3:1])[NH:3][C:4]([CH3:20])([CH3:19])[CH2:5]1
Reactant: CC1(C)CC(NC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CSC[C@H](NC(=O)CC1c2ccccc2-c2ccccc21)C(=O)O
Agent: C=O
Agent: O=C=O
Solvent: O=CO
Product: CN(C1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C
Yield: 49 %

Procedure:
1. A 200 ml sulfonation flask is charged with 40.48 g (0.14 mol) of bis(2,2,6,6-tetramethyl-piperidin-4-yl)amine [EP-A-336 895, Ciba-Geigy] and 11.4 g (0.14 mol) of a 36% aqueous solution of formaldehyde. 25.8 g (0.56 mol) of formic acid are added dropwise at room temperature. The temperature in the flask rises to 70° C. with evolution of CO2. The reaction mixture is stirred until it has cooled to room temperature. The aqueous phase is then saturated with potassium carbonate and the reaction mixture is extracted three times with chloroform. The organic phases are combined, dried over potassium carbonate and concentrated on a vacuum rotary evaporator. Chromatography of the residue over silica gel using the solvent system hexane/dichloromethane 9:1+5% triethylamine gives 21 g (49%) of the methyl-bis(2,2,6,6-tetramethyl-piperidin-4-yl)amine, m.p. 51°-53° C., in the form of a white powder.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37]>ClCCl>[CH2:1]([N:8]1[CH2:14][CH:13]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:36]([O:38][CH3:39])=[O:37])[N:19]=2)=[O:17])[CH2:12][N:11]([CH3:27])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(Cc2ccccc2)CC(NC(=O)c2n[nH]c3ccccc23)C1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)n1nc(C(=O)NC2CN(C)CCN(Cc3ccccc3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.6 %

Procedure:
To a solution of N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1H-indazole-3-carboxamide (0.92 g) and triethylamine (0.77 g) in dichloromethane (30 ml), methyl chloroformate (0.48 g) is added dropwise at 0° C., and the mixture is stirred at 25° C. for 16 hours. The reaction mixture is washed with saturated sodium bicarbonate and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (0.7 g) as an oil. The free base thus obtained is converted to the fumarate of the title compound in a usual manner, m.p. 158°-160° C. (recrystallized from ethanol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)([CH3:14])[CH2:9][CH2:10][C:11](O)=O)=[CH:4][CH:3]=1.[C:22]1([NH2:29])[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH2:28]>P(=O)(O)(O)O>[NH:28]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:29]=[C:11]1[CH2:10][CH2:9][C:8]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=1)[CH3:14]
Reactant: CC(CCC(=O)O)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Nc1ccccc1N
Agent: O=P(O)(O)O
Product: CC(CCc1nc2ccccc2[nH]1)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a four neck 250 mL reaction kettle equipped with an overhead stirrer, thermocouple, gas inlets adapter and condenser, were charged 30.01 gram 4,4-bis(4-hydroxyphenyl)pentanoic acid (0.1048 moles), 15.17 gram 1,2-phenylenediamine (0.1403 moles) and 150 gram polyphosphoric acid. The mixture was stirred at 250 rpm at room temperature for 15 minutes and heated up to 120° C. under argon atmosphere. The reaction was continued for 3 hours and the product was cooled to room temperature. The product obtained in phosphoric acid solution was isolated by precipitating in water followed by neutralization and filtration. The isolated product was dried in vacuum at 90° C. for 48 hours. The conversion of acid to benzimidazole functionality was confirmed by IR spectroscopy.
Reaction SMILES: [NH:1]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:31])[C@H:16]([C:20]([N:22]1[CH2:30][CH2:29][CH2:28][C@H:23]1[C:24]([O:26]C)=[O:25])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])[CH:3]([CH3:5])[CH3:4].O>CO>[NH:1]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:2]([C:6]([NH:8][C@H:9]([C:13]([N:15]([CH3:31])[C@H:16]([C:20]([N:22]1[CH2:30][CH2:29][CH2:28][C@H:23]1[C:24]([OH:26])=[O:25])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C(C)C)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(C)C
Solvent: CO
Solvent: O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N(C)[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
31.96 g (57 mmol) of Z-Val-Val-MeVal-Pro-OMe were dissolved in 250 ml of methanol. 102.6 ml of a 1N LIOH solution was added and the mixture stirred overnight at room temperature. After addition of 500 ml of water, the aqueous phase was washed three times with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness yielding 30.62 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:22])[CH2:7][C:6]=2[CH:23]=1.[BH4-].[Na+].O>CO>[OH:22][CH:8]1[C:9]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[C:15](=[C:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:23][C:6]=2[CH2:7]1
Reactant: O=C1Cc2cc(Cl)ccc2C(=C2CCNCC2)c2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1Cc2cc(Cl)ccc2C(=C2CCNCC2)c2ncccc21
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
Mix 8-Chloro-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-5-one (400 mg, 1.23 mmol) in CH3OH (20 mL) at 0° C. under an argon atmosphere, and add in 3 portions NaBH4 (total 231 mg, 6.10 mmol). After 30 minutes, pour the mixture into water and extract (3×) with ethyl acetate. Combine the organic portions, wash with brine, dry over sodium sulfate, filter and concentrate in vacuo. Triturate the solid with isopropyl ether/ethyl acetate to give the title compound as a white solid (351 mg, 87%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[Cl:10].[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12].C([O-])([O-])=O.[K+].[K+].Cl>C1COCC1.O>[C:11]([CH:13]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:4]=1[Cl:10])[C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]
Reactant: Clc1cccc(CBr)c1Cl
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C#N)Cc1cccc(Cl)c1Cl
Temperature: 60 °C
Reaction time: 16 h
Yield: 48.6 %

Procedure:
A mixture of 1-(bromomethyl)-2,3-dichlorobenzene (82 g, 0.34 mol), ethyl 2-cyanoacetate (82 g, 0.34 mol) and K2CO3 (187.7 g, 1.36 mol) in THF (1.5 L), was stirred at 60° C. for 16 h. The reaction mixture was cooled and adjusted pH to 2-3 with 4N aq. HCl. The mixture was diluted with water (1 L) and extracted with ethyl acetate (400 mL*3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography eluted with PE:EA=15:1 to provide the titled compound (45 g, 48%), as a white solid; 1H NMR (300 MHz, CDCl3) δ ppm 1.32 (t, J=7.2 Hz, 3H), 3.23 (dd, J=9.6, 13.8 Hz, 1H), 3.56 (dd, J=6.0, 13.8 Hz, 1H), 3.91 (dd, J=6.0, 9.6 Hz, 1H), 4.28 (q, J=7.2 Hz, 2H), 7.21 (t, J=7.8 Hz, 1H), 7.28 (dd, J=1.8, 7.5 Hz, 1H), 7.45 (dd, J=1.8, 7.8 Hz, 1H).
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=[C:3]([I:10])[CH:2]=1.[CH3:11][Si](C=[N+]=[N-])(C)C.CCCCCC>CO>[CH3:11][O:8][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([I:10])=[CH:2][CH:1]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
p-iodobenzoic acid (500 mg, 2.02 mmol) was dissolved in methanol (30 ml), to which was added 2M trimethylsilyl diazomethane/hexane solution (13 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to yield a crude product (500 mg) of the title compound. This was used as a raw material in the subsequent reaction without purification.