Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].ClN1C(=O)CCC1=O.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([C:29]([F:32])([F:31])[F:30])=[CH2:28])[CH:24]=[C:23]([Cl:33])[CH:22]=1.C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH2:28][C:27]([C:25]3[CH:24]=[C:23]([Cl:33])[CH:22]=[C:21]([Cl:20])[CH:26]=3)([C:29]([F:30])([F:32])[F:31])[O:8][N:7]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C=NO)ccc1Br
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 70 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 4-bromo-3-methyl-benzaldehyde oxime (2.600 g, 12.15 mmol) from example S.1 in DMF (40 mL) was added N-chloro succinimide (1.700 g, 12.73 mmol) and the mixture was heated at 70° C. (bath temperature) for 1 h. After cooling to 0° C., a solution of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (2.900 g, 12.03 mmol) in DMF (8 mL), followed by triethylamine (2.00 g, 2.75 mL, 19.8 mmol) was added. After 1 h at this temperature, the cooling bath was removed and the mixture was stirred over night. The mixture was separated between MTBE and aqueous NH4Cl solution. The organic layer was separated and the solvent was removed in vacuum. Column chromatography on SiO2 with heptane/CH2Cl2 gave the title compound (2.95 g, 54%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=O)=[C:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].N1CCCCC1>CCO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=[C:32]5[NH:26][C:27](=[O:28])[NH:29][C:30]5=[O:31])=[C:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(Nc3ccn4ncc(C=O)c4n3)cc2)CC1
Reactant: O=C1CNC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CN1CCN(c2ccc(Nc3ccn4ncc(C=C5NC(=O)NC5=O)c4n3)cc2)CC1
Temperature: 70 °C

Procedure:
To 5-(4-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (56 mg, 0.167 mmol) in EtOH was added hydantoin (17 mg, 0.167 mmol) and piperidine (17 μL, 0.167 mmol). The mixture was heated at 70° C. Solvent was removed under reduced pressure and then the solid was redissolved in MeOH and sonicated. Insolubilities were filtered off and the filtrate was purified by HPLC to yield 5-((5-(4-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=419)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[N:16]=[CH:17][CH:18]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.ClC1C=CC=CC=1>>[Br:19][C:18]1[CH:17]=[N:16][N:11]2[C:10]=1[CH:9]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1)[N:13]=[C:12]2[S:14][CH3:15]
Reactant: CSc1nc(-c2ccc(I)cc2)cc2ccnn12
Reactant: O=C1CCC(=O)N1Br
Solvent: Clc1ccccc1
Product: CSc1nc(-c2ccc(I)cc2)cc2c(Br)cnn12
Reaction time: 1 h

Procedure:
To a solution of 5-(4-iodo-phenyl)-7-methylsulfanyl-pyrazolo[1,5-c]pyrimidin (1000 mg) in chlorobenzene N-bromosuccinimide (730 mg) is added. The mixture is stirred for 1 hour then the chlorobenzene is evaporated. The residue is partitioned between ethylacetate and sodium-hydrogencarbonate (5%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].O.[CH2:6]([O:8][C:9](=[O:54])[C:10]([CH3:53])([CH3:52])[CH2:11][C:12]1[N:13]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[N:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:14]2[C:19]([C:20]=1SC(C)(C)C)=[CH:18][C:17]([O:26][CH2:27][C:28]1[S:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[N:32]=1)=[CH:16][CH:15]=2)[CH3:7]>C(Cl)Cl>[CH2:6]([O:8][C:9](=[O:54])[C:10]([CH3:53])([CH3:52])[CH2:11][C:12]1[N:13]([CH2:37][C:38]2[CH:43]=[CH:42][C:41]([C:44]3[CH:45]=[N:46][C:47]([O:50][CH3:51])=[CH:48][CH:49]=3)=[CH:40][CH:39]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:26][CH2:27][C:28]1[S:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[N:32]=1)=[CH:16][CH:15]=2)[CH3:7]
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(-c2ccc(OC)nc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C(C)(C)Cc1cc2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(-c2ccc(OC)nc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Aluminum chloride (0.18 g, 1.37 mmol) was suspended in CH2Cl2 (1 mL), and water (19 uL, 11.0 mmol) was added slowly at room temperature. The mixture was stirred for 5 minutes, and then cooled to 0° C. 3-{5-(Benzothiazol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid ethyl ester (0.12 g, 0.17 mmol) was added in CH2Cl2 (1 mL), and the reaction was stirred at room temperature for 2 hours. Once no starting material was observed by tlc, water was added and the mixture was extracted with CH2Cl2. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated. The residue was purified to give the desired product (H-1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.[OH-].[K+].CO.Cl[CH2:20][CH:21]([CH3:35])[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:14][CH2:20][CH:21]([CH3:35])[CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: CC(CCl)CN1CCC(c2ccccc2)CC1
Reactant: O=C1CCc2c(O)c(Cl)cc(Cl)c2N1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(COc1c(Cl)cc(Cl)c2c1CCC(=O)N2)CN1CCC(c2ccccc2)CC1
Yield: 35 %

Procedure:
2.4 Grams of 6,8-dichloro-5-hydroxy-3,4-dihydrocarbostyril and 0.8 g of granular potassium hydroxide were mixed with 60 ml of methanol and concentrated under a reduced pressure to dryness. To the residue thus obtained was added 60 ml of dimethylformamide and mixed well, then 5 g of 1-chloro-2-methyl-3-(4-phenylpiperidyl)propane and heated at 70°-80° C. for 8 hours under stirring condition. The reaction mixture was concentrated under a reduced pressure to dryness, then 60 ml of 5% sodium hydrogencarbonate aqueous solution was added thereto and extracted with chloroform. The chloroform layer was washed with water and dried, then the chloroform was removed by distillation and thus obtained residue was purified by silica-gel column chromatography and recrystallized from ligroin to obtain 1.6 g (yield: 35%) of 6,8-dichloro-5-[2-methyl-3-(4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril as in the form of colorless needle-like crystals. Melting point 125°-126° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[C:5]([OH:12])=[N:4][CH:3]=1.[NH3:13]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH2:13])=[O:9])[C:5]([OH:12])=[N:4][CH:3]=1
Reactant: N
Reactant: COC(=O)c1nc(Cl)cnc1O
Product: NC(=O)c1nc(Cl)cnc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 5 mL of 25% aqueous ammonia is suspended 0.25 g of methyl 6-chloro-3-hydroxy-2-pyrazinecarboxylate obtained according to the method described in literature [J. Med. Chem., 285-287 (1969)]. The suspension is stirred at ambient temperature for 1 hour. The deposited crystals are collected by filtration to obtain 0.18 g of 6-chloro-3-hydroxy-2-pyrazinecarboxamide.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[CH:13][C:14]([F:20])=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:14]1[CH:13]=[CH:12][C:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:16][C:15]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1cc(-c2ccccc2)ccc1F
Yield: 96.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.8 g) was added to a mixture of 3.1 g of benzeneboronic acid, 5 g 5-bromo-2-fluoronitrobenzene and 22 mL 2 M sodium carbonate solution in 50 mL toluene and 50 mL ethanol. The mixture was refluxed for 2 hours, concentrated, and the residue extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and brine, dried, and concentrated to give a yellow oil. The oil was chromatographed on silica gel using 5% ethyl acetate in hexane to give 4.75 g (96% yield) of 4-fluoro-3-nitrobiphenyl as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2-].[Na+].C[N:17](C)C1C=CC=CC=1>>[NH2:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:9]=1
Reactant: CN(C)c1ccccc1
Reactant: c1ccc(Cc2ccccn2)cc1
Agent: [NH2-]
Agent: [Na+]
Product: Nc1cccc(Cc2ccccc2)n1

Procedure:
2-benzylpyridine (Aldrich, 2.5 g, 0.015 mole), sodium amide (780 mg, 0.02 mole) and N, N-dimethylaniline (25 mL) were refluxed overnight. The contents were allowed to cool and were partitioned between ether and water. The ether layer was dried (MgSO4) and concentrated in vacuo leaving an oil. The oil was purified by chromatography. The purified material was dissolved in 1N HCl, lyophilized, and triturated with EtOAc to give 2-amino-6-benzylpyridine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].O.[NH2:15][NH2:16]>N1C=CC=CC=1>[Cl:8][C:7]1[C:2]([Cl:1])=[C:3]([C:10]([F:13])([F:12])[F:11])[CH:4]=[CH:5][C:6]=1[NH:15][NH2:16]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1Cl
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NNc1ccc(C(F)(F)F)c(Cl)c1Cl
Yield: 79.4 %

Procedure:
100 g of 2,3,4-trichlorobenzotrifluoride are initially introduced, 200 ml of pyridine are added, followed by 100 g of hydrazine hydrate and the mixture is then heated to the reflux temperture for 12 hours. Thereafter, 90% of the pyridine is distilled off and the remaining residue is stirred into 250 ml of water. The crystalline product is filtered off under suction, washed with a little water and dried. 78 g of 2,3-dichloro-4-trifluoromethyl-phenylhydrazine having a melting point of 79° to 80° C. are obtained.
Reaction SMILES: CC1(C)O[C:6](=[O:8])[C:5](=[CH:9][NH:10][C:11]2[CH:15]=[CH:14][N:13]([CH3:16])[N:12]=2)C(=O)O1.C1(OC2C=CC=CC=2)C=CC=CC=1>CC(C)=O>[CH3:16][N:13]1[CH:14]=[C:15]2[C:11]([NH:10][CH:9]=[CH:5][C:6]2=[O:8])=[N:12]1
Reactant: Cn1ccc(NC=C2C(=O)OC(C)(C)OC2=O)n1
Solvent: CC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1cc2c(=O)cc[nH]c2n1
Yield: 40.4 %

Procedure:
A mixture of the product of Example 8a (1.50 g, 5.97 mmol) and diphenyl ether (25 mL) was heated under reflux for 1 h, with removal of the resultant acetone by distillation. The solvent was then decanted, and the remaining solid residue was dissolved in dichloromethane (5 mL) and purified by chromatography on silica gel, eluting with a 0-10% MeOH/CH2Cl2 gradient, to provide the title compound (0.360 g, 40% yield).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][CH2:16][C:17]1[N:25]=[C:24]2[C:20]([N:21]=[CH:22][N:23]2[C@H:26]2[C@H:30]([OH:31])[C@H:29]([OH:32])[C@@H:28]([CH2:33][O:34]C)[O:27]2)=[C:19]([NH:36][CH2:37][CH:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:18]=1.[CH3:51][N:52]1[CH2:57][CH2:56][C:55](=O)[CH2:54][CH2:53]1.C(O)(=O)C>O1CCCC1>[C:39]1([CH:38]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:37][NH:36][C:19]2[N:18]=[C:17]([CH2:16][NH:15][CH:55]3[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]3)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[C@H:26]2[C@H:30]([OH:31])[C@H:29]([OH:32])[C@@H:28]([CH2:33][OH:34])[O:27]2)[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Reactant: CN1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN1CCC(NCc2nc(NCC(c3ccccc3)c3ccccc3)c3ncn([C@@H]4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium triacetoxyborohydride (162 mg, 0.76 mmol) was added to a stirred solution of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (250 mg, 0.51 mmol) (example 1), 1-methyl-4-piperidinone (52 mg, 0.46 mmol) and acetic acid (30 mg, 0.5 mmol) in tetrahydrofuran (20 ml). The reaction mixture was stirred for 24 hr at room temperature. The solvent was then removed under reduced pressure and the residue partitioned between dichloromethane (30 ml) and saturated aqueous sodium hydrogen carbonate solution (10 ml). The aqueous layer was discarded and the organic layer washed with water (10 ml), separated and the solvent removed under reduced pressure to give a residue which was purified by column chromatography on silica gel eluting with a solvent gradient of dichloromethane:methanol:ammonia (90:10:0.5) increasing in polarity to (85:15:0.75) to give the title compound contaminated with example 1. The mixture was treated with diethyl ether (10 ml) and the solid filtered off. This solid was treated with diethyl ether (10 ml) and then filtered. The diethyl ether filtrates were combined and the solvent removed under reduced pressure to give the title compound (60 mg) as a solid. MS: 589 (MH+).
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[H-].[Na+].[CH3:13][C:14]([C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2)=[O:15]>C1COCC1>[CH2:9]([O:8][C:1](=[O:7])[C:2](=[O:4])[CH2:13][C:14]([C:16]12[CH2:25][CH:20]3[CH2:21][CH:22]([CH2:24][CH:18]([CH2:19]3)[CH2:17]1)[CH2:23]2)=[O:15])[CH3:10]
Reactant: CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)CC(=O)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Yield: 100.1 %

Procedure:
Preparation C13, Step 1: Diethyl oxalate (3.81 mL, 28 mmol, 1 eq.) was dissolved in THF (25 mL) at RT under nitrogen then taken to near-reflux. Sodium hydride (1.18 g, 29 mmol, 1.05 eq.) was added in 5 portions carefully. A solution of 1-adamantyl methyl ketone (5.00 g, 28 mmol, 1 eq.), in THF (10 mL) was added dropwise via an addition funnel. After the addition was complete, the mixture was refluxed for 1 hour. Cooled to RT and very carefully quenched with saturated NH4Cl (50 mL) then extracted 3 times with methylene chloride. The organic layers were combined, dried and stripped in vacuo to give 7.80 g of 4-adamantan-1-yl-2,4-dioxo-butyric acid ethyl ester as an amber oil. MS found: (M+H)+=279.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C([O:10][C:11]([N:13]1[CH2:25][C@@H:24]([CH3:26])[N:23]2[C:15](=[CH:16][C:17]3[C:22]2=[N:21][C:20]([Cl:27])=[CH:19][CH:18]=3)[CH2:14]1)=[O:12])(C)(C)C.CN(C)[CH:30]=[O:31]>>[Cl:27][C:20]1[N:21]=[C:22]2[C:17](=[CH:18][CH:19]=1)[C:16]([CH:30]=[O:31])=[C:15]1[N:23]2[C@H:24]([CH3:26])[CH2:25][N:13]([C:11]([OH:10])=[O:12])[CH2:14]1
Reactant: CN(C)C=O
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)Cc2cc3ccc(Cl)nc3n21
Solvent: O=P(Cl)(Cl)Cl
Product: C[C@@H]1CN(C(=O)O)Cc2c(C=O)c3ccc(Cl)nc3n21
Yield: 55.2 %

Procedure:
N,N-Dimethylformamide (10 ml) was cooled to 1 deg C. and treated dropwise with 5.1 ml (56.0 mmol) phosphorus oxychloride. After the addition the temperature was again cooled to 1 deg C. and a solution of 1.0 g (3.11 mmol) (R)-6-chloro-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in (Example 2, intermediate a) in 10 ml N,N-dimethylformamide was added. The cooling bath was removed and after 1.5 h at room temperature the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and was extracted three times with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel (0.032–0.063 mm) with ethyl acetate:n-hexane (1:3) as eluant to yield the desired compound as a yellow foam (55.2%).
Reaction SMILES: [CH2:1]1[NH:6][C:4](=[O:5])[NH:3][CH2:2]1.[CH2:7]([S:9](Cl)(=[O:11])=[O:10])[CH3:8]>>[CH2:7]([S:9]([N:3]1[CH2:2][CH2:1][NH:6][C:4]1=[O:5])(=[O:11])=[O:10])[CH3:8]
Reactant: CCS(=O)(=O)Cl
Reactant: O=C1NCCN1
Product: CCS(=O)(=O)N1CCNC1=O

Procedure:
The starting material required is prepared as follows: A mixture of 29.2 g of ethyleneurea and 43.7 g of ethane sulphonyl chloride is heated at 110° for 3 hrs under nitrogen. The reaction mixture is triturated with 30 ml methanol and filtered. The filtrate is evaporated off and the residue is dissolved in chloroform and chromatographed on a column of 750 g of silica gel. The fraction which eluted with 5% methanol in chloroform, is recrystallized from a mixture of methylene chloride and hexane to afford 1-ethylsulphonyl-2-oxo-tetrahydroimidazole which melts at 114°-116°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([OH:17])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][CH:20]([CH3:39])[CH:21]([C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1[CH3:38])O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[C:12]([O:17][CH:21]([C:23]3[S:27][C:26]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][CH:29]=4)=[N:25][C:24]=3[CH3:38])[CH:20]([CH3:39])[CH3:19])[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(C)C
Reactant: CC(C)(C)OC(=O)Cn1ccc2c(O)cccc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(Oc1cccc2c1ccn2CC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 14 h
Yield: 12 %

Procedure:
To an ice cold solution of (4-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (49 mg, 0.2 mmol), [rac]-2-methyl-1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol [62 mg, 0.2 mmol; PCT Int. Appl. (2002), WO 02/062774 A1] and tributylphosphine (70 μl, 0.3 mmol) in tetrahydrofuran (3 ml) was added N,N,N′,N′-tetramethyl azodicarboxamide (51 mg, 0.3 mmol) under an argon atmosphere. The cooling bath was removed and stirring continued for 14 h. Filtration over celite and evaporation of the solvent under reduced pressure gave a yellow oil which was purified by column chromatography (silica gel, heptane/AcOEt) to give 13 mg (24 μmol, 12%) of the title compound as yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=1)=[O:14])[CH2:8]2)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C=O.O>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=1)=[O:14])[CH2:8]2
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)C1Cc2cccc([N+](=O)[O-])c2C1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cccc2c1CC(C(=O)Nc1ccc(N3CCOCC3)cc1)C2
Temperature: 90 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
To a solution of the crude nitro compound (3.5 g) in N,N-dimethylformamide (25 mL) and water (3 mL) was added, in portions, sodium dithionite (7.0 g, 40 mmol). The mixture was stirred at 90° C. for 3 hours. The solvent was evaporated in vacuo and water (200 mL) was added. The mixture was made alkaline with 2 M sodium hydroxide and extracted with chloroform. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give 1.1 g of the crude product (GC purity 89%): EIMS (70 eV) m/z (relative intensity) 337 (100, M+).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:19])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[C:10]([C:11]=1[NH2:12])=[CH:9][CH:8]=[CH:7][N:6]=2.[C:20](N1C=CN=C1)(N1C=CN=C1)=[S:21]>O1CCCC1>[SH:21][C:20]1[NH:1][C:2]2[C:3](=[O:19])[N:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]3[N:6]=[CH:7][CH:8]=[CH:9][C:10]=3[C:11]=2[N:12]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: Nc1c(N)c2cccnc2n(-c2ccccc2)c1=O
Solvent: C1CCOC1
Product: O=c1c2[nH]c(S)nc2c2cccnc2n1-c1ccccc1
Yield: 47.3 %

Procedure:
Compound 102 (2.0 g, 7.9 mmol) was then suspended in 80 ml of tetrahydrofuran, and 2.3 g (13 mmol) of thiocarbonyldiimidazole was added to the suspension. The mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, and the residue was triturated with ethanol. The formed crystals were taken by filtration. Recrystallization from DMF gave 1.1 g (yield 47%) of Compound 20 as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1.[CH2:45]([NH:47][CH3:48])[CH3:46]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][N:47]([CH2:45][CH3:46])[CH3:48])=[CH:12][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1
Reactant: CCNC
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2cccc(Cl)c2)cc1
Solvent: C1CCOC1
Product: CCN(C)CCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1cccc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.8 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.350 g, 0.541 mmol) and ethylmethylamine (1.0 mL, 12 mmol) in THF (8 mL) was stirred for 2 hours in a sealed tube at 70° C. Additional ethylmethylamine (1.0 mL, 12 mmol) was added, and the reaction mixture was stirred at 80° C. in sealed tube for 2 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. It was dried at 80° C. for 20 minutes in vacuo to yield {2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-ethyl-methyl-amine as a yellow semi-solid (0.268 g, 92.7%). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was then concentrated and dried in vacuo at 82° C. for 14 hours. The result was the hydrochloride as a light orange foam (0.266 g); Mass Spectrum (+EI, [M+H]+) m/z 534. 1HNMR (500 MHz, DMSO-d6): δ9.90-9.93 (s, br, 1H), 8.73-8.75 (m, 1H), 8.54-8.57 (m, 1H), 8.27 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.82 (d, 1H, J=9.27 Hz), 7.70-7.74 (m, 1H), 7.56-7.63 (m, 2H), 7.30 (d. 1H, J=2.20 Hz), 7.15-7.26 (m, 4H), 7.04 (d, 1H, J=7.57 Hz), 5.73 (s, 2H), 4.36-4.38 (m, 2H), 3.40-3.55 (m, 3H), 3.09-3.14 (br, 1H), 2.78 (s, 3H), 1.19-1.23 ppm (m, 3H). Elemental Analysis for C29H28ClN3O3S.1.00 HCl.0.75 mol H2O: Calcd: C, 59.64; H, 5.26; N, 7.19; Found: C, 59.24; H, 5.17; N, 6.89.
Reaction SMILES: [C:1]1([CH:7]2[NH:10][C:9](=[O:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[Si](C)(C)C.[C:17]([OH:21])([CH3:20])([CH3:19])[CH3:18]>>[C:1]1([CH:7]([NH2:10])[CH2:8][C:9]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)O
Reactant: O=C1CC(c2ccccc2)N1
Agent: C[Si](C)(C)Cl
Product: CC(C)(C)OC(=O)CC(N)c1ccccc1
Yield: 47 %

Procedure:
A solution of 10 g of 4-phenylazetidin-2-one and 15.2 g of chlorotrimethylsilane in 150 cm3 of anhydrous tert.-butanol are refluxed for 7 days. The solution is then evaporated and ethyl acetate and aqueous sodium bicarbonate at 5% are added. The organic phase is washed with water, dried on sodium sulphate and is then evaporated. 7 g of tert.- butyl 3-phenyl-3-amino-propanoate are obtained (yield 47%).