Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=1)(=[O:25])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][CH2:6]2)#[N:2].[ClH:37]>>[ClH:37].[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:36])[CH2:14][CH:15]([NH:22][S:23]([C:26]1[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=1)(=[O:25])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH2:7][CH2:6]2
Reactant: N#Cc1ccc2c(c1)CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1
Agent: Cl
Product: NCc1ccc2c(c1)CCC2NC(=O)CC(NS(=O)(=O)c1ccc2ccccc2c1)c1ccccc1

Procedure:
The title compound was prepared from N-(5-cyano-indan-1-yl)-3-(naphthalen-2-yl-sulfonylamino)-3-phenyl-propionamide yielding the HCl salt as a white solid. MS (ESI) m/z 500 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:15]1[CH:27]=[CH:26][C:18]([C:19]([O:21]C(C)(C)C)=[O:20])=[CH:17][CH:16]=1)[C:11]([O:13][CH3:14])=[O:12].FC(F)(F)C(O)=O>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:15]1[CH:16]=[CH:17][C:18]([C:19]([OH:21])=[O:20])=[CH:26][CH:27]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(c1ccc(C(=O)OC(C)(C)C)cc1)c1nc2ccccc2o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(c1ccc(C(=O)O)cc1)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-[1-(1,3-benzoxazol-2-yl)-2-methoxy-2-oxoethyl]benzoate (90 mg, 0.25 mmol) in methylene chloride (2 mL) was added trifluoroacetic acid (0.5 mL) and the solution was stirred at ambient temperature for 1 hour. The reaction was evaporated to dryness to give the title compound as a clear oil. ESIMS calcd 312.1 (M++H), found 312.0 (M++M).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:18][CH2:17]2)[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]2[CH2:17][CH2:18]2)[CH3:15])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F)C1CC1
Agent: Cl[Sn]Cl
Solvent: O
Product: CN(c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F)C1CC1

Procedure:
The title compound was prepared from [5-(cyclopropyl-methyl-amino)-2-nitro-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example C3) (3.74 g, 9.96 mmol) by reduction with SnCl2.2H2O according to the general procedure J (method b). Obtained as an orange semisolid (2.00 g).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>O1CCOCC1>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:13]1[C:12]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1
Solvent: C1COCCO1
Product: Clc1ccccc1-n1nc2c(c1-c1ccccc1)CCNCC2
Yield: 26.4 %

Procedure:
The title compound (17.2 mg) was prepared from 199.8 mg of 2-(2-chloro-phenyl)-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (made from (2-chloro-phenyl)-hydrazine as in Example 176, Steps A and B), as described in Example 196 using 1,4-dioxane as the solvent. MS (ESI): exact mass calculated for C19H18ClN3, 323.12; found, m/z 324.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.37-7.34 (m, 2H), 7.29-7.24 (m, 5H), 7.14-7.10 (m, 2H), 3.12-3.09 (m, 2H), 3.04-2.99 (m, 4H), 2.74-2.71 (m, 2H), 2.13 (br s, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9](Cl)[N:8]=[C:7]([NH2:12])[N:6]=2)[CH2:3][CH2:2]1.[NH3:13]>O1CCOCC1>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([NH2:13])[N:8]=[C:7]([NH2:12])[N:6]=2)[CH2:3][CH2:2]1
Reactant: N
Reactant: Nc1nc(Cl)nc(NC2CC2)n1
Solvent: C1COCCO1
Product: Nc1nc(N)nc(NC2CC2)n1
Temperature: 140 °C
Yield: 55.8 %

Procedure:
A mixture of 100 g of 2-cyclopropylamino-4-chloro-6-amino-s-triazine, 51 g of anhydrous ammonia and 500 ml of dioxane is heated for 24 hours in an autoclave at 140° C. After cooling to room temperature the solvent is removed by water jet vacuum distillation. 300 ml of water are added to the residue. After stirring, the residue product is filtered off and recrystallised from boiling ethanol. 50 g of 2-cyclopropylamino-4,6-diamino-s-triazine are obtained. Melting point: 219°-222° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH:24]([Mg]Cl)([CH3:26])[CH3:25].C1C[O:32]CC1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([C:24]([OH:32])([CH3:26])[CH3:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=O
Reactant: CC(C)[Mg]Cl
Reactant: C1CCOC1
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1C(C)(C)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.2 %

Procedure:
6-Methoxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (300 mg, 0.974 mmol) obtained in Example 1 was dissolved in THF and 1.5 equivalents of isopropylmagnesium chloride were added thereto, followed by stirring for 1 hr at 0° C. The resulting mixture washed with saturated saline and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4, and concentrated under a reduced pressure. Then, the resulting residue was purified by flash chromatography to obtain 155 mg of the titled compound (yield: 45.2%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.Cl[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCc1ccccn1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccccn3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Yield: 85.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 2-(chloromethyl)pyridine hydrochloride (0.49 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[1-(2-pyridylmethyl)pyrazol-4-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.74 g) was obtained.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#N)=[CH:7][N:6]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=[C:5]2[CH:4]=1.[OH:20]S(O)(=O)=O.[CH3:25][CH2:26][OH:27]>O>[CH2:26]([O:27][C:9]([C:8]1[C:3]([NH2:2])=[CH:4][C:5]2[N:6]([CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:13]=2)[CH:7]=1)=[O:20])[CH3:25]
Reactant: N#Cc1cn2cc(-c3ccccc3)nc2cc1N
Reactant: O=S(=O)(O)O
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCOC(=O)c1cn2cc(-c3ccccc3)nc2cc1N
Temperature: 25 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
To a stirred suspension of 7-amino-2-phenyl-imidazo[1,2-a]pyridine-6-carbonitrile hydrochloride (1.0 g, 3.7 mmol) at rt in EtOH (20 ml) under an argon atmosphere was added H2SO4 (1.5 ml, 27.7 mmol) in one portion. The mixture was heated to reflux and stirring was continued for 2 days. The mixture was cooled to rt and diluted with 10 ml H2O. The solid was collected by filtration, washed with H2O and dried. Then it was suspended in CH2Cl2/MeOH 9:1 and treated with triethylamine to give a yellow solution. The dissolved material was adsorbed on Isolute® Flash-NH2 silica gel (from Separtis) and purified by chromatographie on the same silica gel as stationary phase using a CH2Cl2/MeOH gradient as eluent, providing the title compound as off-white solid (642 mg, 62%).
Reaction SMILES: [CH3:1][C:2]1([OH:12])[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]=[CH2:9])[C:3]1([CH3:11])[CH3:10].[C:13](Cl)(=[O:15])[CH3:14]>>[CH3:1][C@@:2]1([O:12][C:13](=[O:15])[CH3:14])[CH2:6][CH2:5][C@@H:4]([CH2:7][CH:8]=[CH2:9])[C:3]1([CH3:11])[CH3:10]
Reactant: C=CCC1CCC(C)(O)C1(C)C
Reactant: CC(=O)Cl
Product: C=CC[C@@H]1CC[C@@](C)(OC(C)=O)C1(C)C

Procedure:
Using the procedure of Example 15, 1.6 g of 1,2,2-trimethyl-3-(2-propenyl)-cyclopentanol and 10 ml of acetyl chloride were reacted to obtain 1.3 of (1R,S) 1,2,2-trimethyl-1-acetyloxy-3-(2-propenyl)-cyclopentane.
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12]OS(C3C=CC(C)=CC=3)(=O)=O)[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][CH:29]([NH2:31])[CH3:30]>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][CH:8]([CH2:12][NH:31][CH:29]([CH3:30])[CH3:28])[O:7][C:6]=2[CH:5]=[C:4]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:3]=1
Reactant: CC(C)N
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CC(C)NCC1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 42 using [5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl-4-methylbenzenesulfonate (0.005 g, 0.012 mmol), propan-2-amine (0.5 ml), ACN (2.5 ml). MS m/z (rel. intensity, 70 eV) 303 (M+, 2), 288 (17), 84 (6), 72 (bp), 56 (6).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][NH2:5].[CH3:6][S:7][CH2:8][C:9](O)=[O:10].ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][S:2][CH2:3][CH2:4][NH:5][C:9](=[O:10])[CH2:8][S:7][CH3:6]
Reactant: CSCC(=O)O
Reactant: CSCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Product: CSCCNC(=O)CSC
Temperature: 25 °C

Procedure:
6 ml of 2-methylthio-ethylamine is dissolved in 250 ml of methylene chloride, mixed with 6.84 g of S-methyl-thioglycolic acid and with 7.42 g of N-hydroxysuccinimide and mixed drop by drop with 13.3 g of dicyclohexylcarbodiimide in 250 ml of methylene chloride under a cover-gas atmosphere. It is stirred, for 3 more hours at room temperature. The precipitate is filtered off, the filtrate is washed twice with semi-saturated sodium bicarbonate solution and once with water, dried with sodium sulfate and concentrated by evaporation. The residue is purified by chromatography with the mobile solvent system of methylene chloride/methanol: Yield 10 g=86.7% of theory.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[F:10]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[F:10]
Reactant: OCc1ccc(F)c(Br)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(F)c(Br)n1
Temperature: 70 °C
Yield: 40.9 %

Procedure:
Manganese dioxide (695 mg) was added to a solution of (6-bromo-5-fluoropyridin-2-yl)methanol (200 mg) in chloroform (3.00 mL) and the mixture was stirred while heating at 70° C. for 12 hr. After stirring at room temperature for 13 hr, the reaction mixture was filtered through Celite. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=98:2-82:18) to afford the title compound (81 mg).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:26]4[C:25](=[O:27])[N:24]([CH:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH2:23][C:22]([CH3:35])([CH3:34])[O:21][C:20]=4[N:19]=[C:18]([N:36]4[CH2:42][CH:41]5[O:43][CH:38]([CH2:39][CH2:40]5)[CH2:37]4)[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([NH2:51])=[N:47]1.CN(C=O)C>C1COCC1>[CH3:35][C:22]1([CH3:34])[O:21][C:20]2[N:19]=[C:18]([N:36]3[CH2:37][CH:38]4[O:43][CH:41]([CH2:40][CH2:39]4)[CH2:42]3)[N:17]=[C:16]([C:13]3[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:51][C:48]4[CH:49]=[CH:50][N:46]([CH3:45])[N:47]=4)=[O:7])=[CH:15][CH:14]=3)[C:26]=2[C:25](=[O:27])[N:24]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:23]1
Reactant: CC1(C)CN(C2CCOCC2)C(=O)c2c(nc(N3CC4CCC(C3)O4)nc2-c2ccc(NC(=O)Oc3ccccc3)cc2)O1
Reactant: Cn1ccc(N)n1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1ccc(NC(=O)Nc2ccc(-c3nc(N4CC5CCC(C4)O5)nc4c3C(=O)N(C3CCOCC3)CC(C)(C)O4)cc2)n1
Temperature: 100 °C

Procedure:
50 mg (83.4 μmol) of {4-[8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-6-(tetrahydropyran-4-yl)-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]phenyl}carbamic acid phenyl ester are placed in a microwave reactor and 25 mg (26 μmol) of 1-methyl-1H-pyrazol-3-ylamine are added. 1 ml of DMF and 2 ml of THF are added. The reactor is heated in a Biotage microwave machine for 30 minutes at 100° C. 100 mg (100 μmol) of 1-methyl-1H-pyrazol-3-ylamine are added and the mixture is heated for 2 hours at 110° C. The solvents are evaporated off. The residue is chromatographed on silica gel, eluting with an MeOH/DCM mixture from (0/100 v/v) up to (5/95 v/v) to give a solid, which is then washed with water and dried. 23 mg of 1-{4-[8,8-dimethyl-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5-oxo-6-(tetrahydropyran-4-yl)-5,6,7,8-tetrahydro-9-oxa-1,3,6-triazabenzocyclohepten-4-yl]phenyl}-3-(1-methyl-1H-pyrazol-3-yl)urea are recovered.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32][C:33](=O)[NH2:34])=[O:6])[CH:2]=[CH2:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>COCCOC.O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:9][C@@H:8]1[CH2:32][C:33](=[S:45])[NH2:34])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CC(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@@H]1CC(N)=S
Temperature: 50 °C
Reaction time: 4 h
Yield: 98.7 %

Procedure:
To a solution of (2R,4S)-1-allyloxycarbonyl-2-carbamoylmethyl-4-(triphenylmethylthio) pyrrolidine (255 mg) in ethylene glycol dimethyl ether (5 ml) was added Lawesson's reagent (106 mg). After stirring at 50° C. for 4 hours, the solution was poured into a mixture of ethyl acetate and water, and adjusted to pH 7.0 with aqueous sodium hydrogen carbonate solution. The separated organic layer was washed with aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residue was subjected to column chromatography on silica gel (eluent; n-hexane:ethyl acetate=2:1) to give (2R,4S)-1-allyloxycarbonyl-2-thiocarbamoylmethyl-4-(triphenyl-methylthio) pyrrolidine (130 mg).
Reaction SMILES: Cl[C:2]1[CH:28]=[CH:27][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]3[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=3)=[O:18])[CH2:14][OH:15])[CH2:8]2)=[CH:4][CH:3]=1.Cl.N[C@@H](CCN1CC(OC2C=CC=CC=2)C1)CO>>[O:6]([CH:7]1[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:16][C:17]([NH:19][C:20]2[S:21][C:22]([CH2:25][CH3:26])=[N:23][N:24]=2)=[O:18])[CH2:14][OH:15])[CH2:8]1)[C:5]1[CH:27]=[CH:28][CH:2]=[CH:3][CH:4]=1
Reactant: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccc(Cl)cc3)C2)s1
Agent: Cl
Agent: N[C@H](CO)CCN1CC(Oc2ccccc2)C1
Product: CCc1nnc(NC(=O)N[C@H](CO)CCN2CC(Oc3ccccc3)C2)s1

Procedure:
This compound is prepared analogously to 1-{(S)-3-[3-(4-chloro-phenoxy)-azetidin-1-yl]-1-hydroxymethyl-propyl}-3-(5-ethyl-[1,3,4]-thiadiazol-2-yl)-urea in Example 99 except using (S)-2-amino-4-[3-phenoxy-azetidin-1-yl]-butan-1-ol hydrochloride in place of (S)-2-amino-4-[3-(4-chloro-phenoxy)-azetidin-1-yl]-butan-1-ol hydrochloride.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.Cl.[CH3:9][O:10][CH:11]1[CH2:14][NH:13][CH2:12]1>>[CH3:9][O:10][CH:11]1[CH2:14][N:13]([CH2:6][C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:12]1
Reactant: O=Cc1ncc[nH]1
Reactant: COC1CNC1
Agent: Cl
Product: COC1CN(Cc2ncc[nH]2)C1

Procedure:
The title compound was prepared from 2-imidazolecarboxaldehyde and 3-methoxyazetidine hydrochloride using the synthetic procedure described for Intermediate 5.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[CH3:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][NH:22]1>>[CH3:20][C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1
Reactant: C[C@@H]1CCCN1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: C[C@@H]1CCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B15 was prepared following the general procedure reported for B10 using A1 and (R)-2-methylpyrrolidine. Yield: 31.5 mg (9%), colorless amorphous solid. MS (ES) C15H20N6O2S requires: 348. found: 349 (M+H)+.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[Br:15][C:16]1[C:17]2[C:18]3[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=O)[C:19]=3[CH:26]=[CH:27][CH:28]=2.[N:29]1C=CC=CC=1>>[N:21]1[CH:28]=[CH:27][CH:26]=[C:19]([CH2:18][CH2:22][CH2:23][CH2:24][NH2:29])[CH:20]=1.[Br:15][C:16]1[C:17]2[C:18]3[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([SH:2])[C:19]=3[CH:26]=[CH:27][CH:28]=2
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: c1ccncc1
Reactant: O=C1Nc2ccc(Br)c3cccc1c23
Product: NCCCCc1cccnc1
Product: SC1=Nc2ccc(Br)c3cccc1c23

Procedure:
4-(3-Pyridinyl)butylamine was prepared by the procedure described in Helv. Chim. Acta. 65 1868-1883 (1982). 6-Bromobenz(cd)indol-2-thiol was prepared by the action of P2S5 upon 6-bromobenz(cd)indol-2-one in refluxing pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([OH:16])[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[C:22]([F:24])[CH:23]=1.CCN(CC)CC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[C:14]([O:16][C:20]2[CH:19]=[C:18]([F:17])[CH:23]=[C:22]([F:24])[CH:21]=2)[C:8]2[CH2:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(O)c2c(c1)OC(C)(C)C2
Reactant: OB(O)c1cc(F)cc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Oc2cc(F)cc(F)c2)c2c(c1)OC(C)(C)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 26.6 %

Procedure:
A mixture of 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxy-lic acid methyl ester (3e) (1 g, 0.0045 mol), 3,5-difluorophenylboronic acid (1.07 g, 0.0068 mol), Cu(OAc)2 (0.9 g, 0.005 mol), freshly activated 4A molecular sieves (4g) and Et3N (4 mL) in CH2Cl2 (25 mL) was stirred at room temperature under N2 for 48 hrs. The mixture was filtered through Celite and the filter cake was washed with CH2Cl2. The filtrate was concentrated to give a dark liquid. The crude liquid was purified by column chromatography eluting with EtOAc/petroleum ether (1/5) to give the title compound (0.4 g, 26.6%) as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.18 (s, 1 H), δ 7.14 (s, 1 H), 6.47 (m, 1 H), δ 6.36 (dd, 2 H), 3.81 (s, 3 H), 2.83 (s, 2 H), 1.41 (s, 6 H).
Reaction SMILES: NC1N(CC2CCCCC2)C(=O)N(CC2CCCCC2)C(=O)C=1.[NH2:24][C:25]1[N:30]([CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:29](=[O:38])[N:28]([CH2:39][CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[C:27](=[O:46])[C:26]=1[N:47]=O.[CH:49]([C:51]1[CH:59]=[CH:58][CH:57]=[CH:56][C:52]=1[C:53]([OH:55])=[O:54])=O>>[CH:32]1([CH2:31][N:30]2[C:25]([NH2:24])=[C:26]([NH2:47])[C:27](=[O:46])[N:28]([CH2:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[C:29]2=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1.[CH:40]1([CH2:39][N:28]2[C:27](=[O:46])[C:26]3[N:47]=[C:49]([C:51]4[CH:59]=[CH:58][CH:57]=[CH:56][C:52]=4[C:53]([OH:55])=[O:54])[NH:24][C:25]=3[N:30]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:29]2=[O:38])[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=Cc1ccccc1C(=O)O
Reactant: Nc1c(N=O)c(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Agent: Nc1cc(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Product: Nc1c(N)n(CC2CCCCC2)c(=O)n(CC2CCCCC2)c1=O
Product: O=C(O)c1ccccc1-c1nc2c(=O)n(CC3CCCCC3)c(=O)n(CC3CCCCC3)c2[nH]1

Procedure:
1,3-Bis(cyclohexylmethyl)-5,6-diaminouracil was prepared as in part (d) of Example 1 by reduction of 1, 6-amino 1,3-bis(cyclohexylmethyl)-5-nitrosouracil (2.00 g) and immediately condensed with 2-formylbenzoic acid (Aldrich, 1.424 g) by the method of J. Perumattam (Synthetic Commun. 1989, 19: 3367-3370) to give title compound as an off-white solid off-white solid (1.22 g, 46%), m.p. 271-274° C.; 1H-NMR (DMSO-d6) consistent with structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[CH3:15][O:16][C:17]1[CH:44]=[CH:43][C:20]([CH2:21][NH:22][C:23]([C:25]2([CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:31]3[C:26]2=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:24])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23]([C:25]2([CH2:38][CH2:39][CH2:40][CH2:41][N:12]3[CH2:13][CH2:14][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=4)[CH2:10][CH2:11]3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=3[C:32]3[C:37]2=[CH:36][CH:35]=[CH:34][CH:33]=3)=[O:24])=[CH:43][CH:44]=1
Reactant: COc1cccc(N2CCNCC2)n1
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Product: COc1ccc(CNC(=O)C2(CCCCN3CCN(c4cccc(OC)n4)CC3)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 2 b from 1-(6-methoxy-pyridin-2-yl)-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxybenzyl-amide.
Reaction SMILES: [CH2:1]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.[H-].[Na+].[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22]Cl>>[CH3:18][N:19]([CH3:24])[CH2:20][CH2:21][CH2:22][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[CH2:1][CH2:2][S:3][CH2:4][CH2:5][CH2:6][C:7]1=2
Reactant: c1ccc2c3c([nH]c2c1)CCCSCC3
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Product: CN(C)CCCn1c2c(c3ccccc31)CCSCCC2

Procedure:
A mixture of 21.7g (0.1 mole) of 1,2,4,5,6,7-hexahydrothiocino-[5,4-b]indole, 4.29g (0.102 mole) of 57% dispersion sodium hydride and 12.16g (0.1 mole) of 3-dimethylaminopropyl chloride is treated according to the procedure in Example 6. Recrystallization from pentane affords 20.5g (68%) of an analytical sample, m.p. 70°-71° C.
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CO.[Pd]>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)CC1CCN(CCC=C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Solvent: CCO
Product: O=C(O)CC1CCN(CCCC(c2ccccc2)c2ccccc2)C1

Procedure:
A solution of 0.460 g. (1.37 mmole) of 1-(4,4-diphenyl-3-butenyl)-3-pyrrolidineacetic acid in 30 ml. of absolute ethanol was reduced, using 0.15 g. of 10% palladium-on-carbon, for 1.5 hours at ambient temperature. The mixture was filtered and concentrated. A portion of the oily residue and one equivalent of maleic acid were mixed in methanol and concentrated to yield a solid which was recrystallized from isopropanol/ether to give 1-(4,4-diphenylbutyl)-3-pyrrolidineacetic acid maleate, m.p. 85°-87° C.