Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.CO[C:14](=[O:32])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:16]=1[C:28]([O:30]C)=O.Cl.[NH2:34][CH:35]1[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:36]1=[O:37].O>CN(C=O)C>[CH2:26]([O:25][C:23](=[O:24])[NH:22][CH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]2[C:16]=1[C:28](=[O:30])[N:34]([CH:35]1[CH2:41][CH2:40][C:39](=[O:42])[NH:38][C:36]1=[O:37])[C:14]2=[O:32])[CH3:27]
Reactant: CCOC(=O)NCc1cccc(C(=O)OC)c1C(=O)OC
Reactant: NC1CCC(=O)NC1=O
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 120 °C
Yield: 46.8 %

Procedure:
1,8-Diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5 mmol) was added to a stirred suspension of methyl-3-[(ethoxycarbonylamino)methyl]-2-(methoxycarbonyl)benzoate (1.54 g, 5 mmol) and aminoglutarimide hydrochloride (0.86 g, 5 mmol) in DMF (15 ml). The mixture was heated to 120° C. for 24 hours. The mixture was cooled to room temperature and poured into water (150 ml). The mixture was extracted with ethyl acetate (3×30 ml) and the ethyl acetate solution was washed with water (30 ml), brine (30 ml) and dried. Solvent was removed and the residue was purified by flash chromatography (dichloromethane/ethyl acetate 7 to 3) to give 0.84 g (45%) of the product as a white solid: mp 187–189° C.; 1H NMR (DMSO-d6) δ 11.03 (s, 1H), 7.76–7.58 (m, 4H), 5.06–4.99 (dd, J=5.4 and 12.6 Hz, 1H), 4.52 (d, J=5.9 Hz, 2H), 3.91 (q, J=7.0 Hz, 2H), 2.79–2.70 (m, 1H), 2.51–2.38 (m, 2H), 1.96–1.86 (m, 1H), 1.06 (t, J=7.0 Hz, 3H); 13C NMR (DMSO-d6) δ 172.89, 169.93, 167.55, 167.05, 156.72, 139.69, 134.91, 132.90, 131.58, 127.04, 121.97, 60.15, 48.90, 39.34, 30.98, 22.04, 14.69; Anal. Calcd. For C17H17N3O6: C, 56.82; H, 4.77; N, 11.69. Found: C, 56.94; H, 4.81; N, 11.37.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1.[C:41](Cl)(=[O:43])[CH3:42].[Cl-].[NH4+]>C(Cl)Cl>[C:41]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[P:22]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:43])[CH3:42]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc2ccccc2c1-c1c(P(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.2 %

Procedure:
1.15 gram (2.54 mmol) of (−)-2-amino-2′-diphenylphosphino-1,1′-binaphthyl (the formula (1-1a)) was dissolved in 51 ml of methylene chloride, followed by the addition of 0.25 ml (3.04 mmol) of pyridine and 0.20 ml (2.78 mmol) of acetyl chloride under 0° C. The reaction mixture was stirred at room temperature for 3 hours. To the reaction solution, 30 ml of saturated aqueous solution of ammonium chloride was added and extracted with 100 ml of methylene chloride. The extract was washed with 70 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure. The residue was purified using a silica gel column chromatography (eluent: 1:3 mixture of ethyl acetate and hexane) to obtain 1.11 gram of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@@H:20]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=1)[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[CH:30]2)=[O:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8](=[O:9])[NH:10][N:11]([CH2:13][C:14]([NH:19][C@@H:20]([CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=2)[C:21]([N:23]([C@@H:35]([CH3:43])[CH:36]([O:37][CH2:38][CH3:39])[O:40][CH2:41][CH3:42])[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)=[O:22])=[O:16])[CH3:12])=[CH:17][CH:18]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 80 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxy-propan-2-yl)-N-(quinolin-8-ylmethyl)propanamide (Compound IV-3) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([NH:11][S:12]([C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[N:6]=[C:7](OC)[N:8]=1.[CH2:22]([NH2:25])[CH2:23][CH3:24]>C(O)C>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([NH:11][C:5]2[CH:4]=[C:3]([NH:25][CH2:22][CH2:23][CH3:24])[N:8]=[C:7]([NH:6][CH2:5][CH2:4][CH3:3])[N:6]=2)(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: COc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(OC)n1
Reactant: CCCN
Solvent: CCO
Product: CCCNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(NCCC)n1
Temperature: 140 °C
Reaction time: 65 h
Yield: 85.2 %

Procedure:
1.50 g (0.00483 mol) of sulfadimethoxine were suspended in 20 ml of ethanol, treated with 16 ml (0.193 mol) of propylamine and stirred in an autoclave at 140° C. for 65 hours. The mixture was cooled and, after 24 hours., the crystals which separated were filtered off under suction. There was obtained 0.75 g (50%) of 4-amino-N-(2,6-bis-propylamino-pyrimidin-4-yl)-benzenesulfonamide as pale beige crystals; m.p. 211-215° C.
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:29]([NH:33][C:34](=[O:59])[C@H:35]([CH3:58])[CH2:36][C@@H:37]1[O:41][C:40]([CH3:43])([CH3:42])[N:39]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:38]1[CH2:51][C:52]([CH3:57])([CH3:56])[CH2:53][CH2:54]O)[CH2:30][CH2:31][CH3:32]>C(Cl)Cl>[CH2:29]([NH:33][C:34](=[O:59])[C@H:35]([CH3:58])[CH2:36][C@@H:37]1[O:41][C:40]([CH3:43])([CH3:42])[N:39]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:38]1[CH2:51][C:52]([CH3:57])([CH3:56])[CH2:53][CH2:54][I:1])[CH2:30][CH2:31][CH3:32]
Reactant: NC(=O)CCC(=O)NI
Reactant: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCNC(=O)[C@H](C)C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCI
Reaction time: 7 h

Procedure:
168 mg of N-iodosuccinamide and 196 mg of triphenylphosphine are added to a solution of 300 mg of 3-[3-tert-butoxycarbonyl-4(S)-(4-hydroxy-2,2-dimethylbutyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-methyl-propionic acid (N-butyl)amide (Example 1c)) in 5 ml of methylene chloride at 0° C. and the reaction mixture is stirred for 7 h. The crude product is purified, after customary working up, over 65 g of silica gel (mobile phase B) to give the title compound: Rf (B)=0.55.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[N+:16]([O-])([OH:18])=[O:17]>O>[Cl:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: Clc1nc2ccccc2s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2nc(Cl)sc2c1

Procedure:
Conc. sulfuric acid (50 mL) was added to 2-chlorobenzothiazole (10 g) under ice-cooling, and conc. nitric acid (5 mL) was added dropwise under ice-cooling. The mixture was stirred under ice-cooling for 1 hr, and iced water (600 mL) was added to the reaction mixture. The precipitated solid was collected by filtration, which was then recrystallized from acetone to give 2-chloro-6-nitrobenzothiazole (6.36 g) as a pale-yellow powder.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][CH2:9][CH3:10])[N:6]=[C:5]([C:11]#[N:12])[CH:4]=1)[CH3:2].C([O-])(=O)C.[K+].[Br:18]Br.S([O-])(O)=O.[Na+]>C(O)(=O)C>[Br:18][C:4]1[C:5]([C:11]#[N:12])=[N:6][N:7]([CH2:8][CH2:9][CH3:10])[C:3]=1[CH2:1][CH3:2]
Reactant: CCCn1nc(C#N)cc1CC
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: CC(=O)O
Product: CCCn1nc(C#N)c(Br)c1CC
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.3 %

Procedure:
5-Ethyl-1-propyl-1H-pyrazole-3-carbonitrile (4.89 g, 30.0 mmol) was dissolved in glacial acetic acid (30 mL) and treated with potassium acetate (4.41 g, 44.9 mmol) and bromine (4.79 g, 30.0 mmol). During the slow addition of bromine, an exotherm occurred and ice bath was used to cool the reaction. After the addition of bromine was complete, the reaction was allowed to warm to ambient temperature and stir for 5 hours. Saturated aqueous sodium hydrogensulfite was added to reduce the residual bromine. The mixture was concentrated under reduced pressure and 2 M aqueous sodium carbonate was added to adjust the mixture to pH 9. The mixture was extracted with chloroform (3×100 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to yield 6.12 g of 4-bromo-5-ethyl-1-propyl-1H-pyrazole-3-carbonitrile as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][O:10][C@@H:9]1[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:33][C:27]1[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:26]=1[C@@H:9]1[C@@H:8]([NH2:7])[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:19]=3)[CH2:15]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(S(C)(=O)=O)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)n1cc2c(n1)CN([C@H]1CO[C@H](c3cc(F)ccc3F)[C@@H](N)C1)C2
Reaction time: 2 h

Procedure:
Removal of the BOC group in the product from Step A (13.78 g, 27.67 mmol) was accomplished with trifluoroacetic acid (100 ml) in dichloromethane (200 mL) at room temperature. After stirring for 2 h, the reaction was concentrated and neutralized with 25% MeOH and 2.5% ammonium hydroxide in dichloromethane. Solvents were removed under reduced pressure and the resulting crude material was purified on a 65i Biotage™ column eluting with 1.25-5% MeOH and 0.125-0.5% ammonium hydroxide in dichloromethane. The isolated material was further purified by recrystallization from 5:1 EtOAc/CH2Cl2 at 60° C. The crystalline product was washed with cold 2:1EtOAc/hexanes to give the title compound as a light brown solid. 1H NMR (500 MHz, CD3OD): 1.71 (q, 1H, J=12 Hz), 2.56-2.61 (m, 1H), 3.11-3.18 (m, 1H), 3.36-3.40 (m, 1H), 3.48 (t, 1H, J=12 Hz), 3.88-3.94 (m, 4H), 4.30-4.35 (m, 1H), 4.53 (d, 1H, J=12 Hz), 7.14-7.23 (m, 2H), 7.26-7.30 (m, 1H), 7.88 (s, 1H). LC-MS: 399.04 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][C:3]=1[S:12]([NH:15][CH2:16][CH2:17][OH:18])(=[O:14])=[O:13].S1C=CN=C1.ClC1C=CC(CC(=O)C)=CC=1S(N)(=O)=O.ClC1C=CC(C2SC(NC3C=NC=CN=3)=NC=2C)=CC=1S(N)(=O)=O.[NH:63]1[CH:67]=[CH:66][C:65]([NH:68][C:69]([NH2:71])=[S:70])=[N:64]1>>[OH:18][CH2:17][CH2:16][NH:15][S:12]([C:3]1[CH:2]=[CH:7][CH:6]=[C:5]([C:8]2[S:70][C:69]([NH:68][C:65]3[CH:66]=[CH:67][NH:63][N:64]=3)=[N:71][C:9]=2[CH3:10])[CH:4]=1)(=[O:14])=[O:13]
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)NCCO)c1
Reactant: NC(=S)Nc1cc[nH]n1
Agent: CC(=O)Cc1ccc(Cl)c(S(N)(=O)=O)c1
Agent: Cc1nc(Nc2cnccn2)sc1-c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: c1cscn1
Product: Cc1nc(Nc2cc[nH]n2)sc1-c1cccc(S(=O)(=O)NCCO)c1

Procedure:
The titled compound was prepared from N-(2-hydroxy-ethyl)-3-(2-oxo-propyl)-benzenesulfonamide (43b) following the two-step procedure (bromination, thiazole formation) described for the conversion of 2-chloro-5-(2-oxo-propyl)-benzene-sulfonamide (33a) to 2-chloro-5-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide (33c) replacing pyrazin-2-yl-thiourea (1a) in the final step with (1H-pyrazol-3-yl)-thiourea (35a).
Reaction SMILES: C(#N)C.N1C=CC=CC=1.F.[O:11]([C@H:19]1[C@H:33](/[CH:34]=[CH:35]/[C@@H:36]([O:44][Si](C(C)(C)C)(C)C)[CH2:37][C@H:38]([CH3:43])[CH2:39][CH2:40][CH2:41][CH3:42])[C:22]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH2:20]1)[Si](C(C)(C)C)(C)C>N1C=CC=CC=1>[OH:11][C@H:19]1[C@H:33](/[CH:34]=[CH:35]/[C@@H:36]([OH:44])[CH2:37][C@H:38]([CH3:43])[CH2:39][CH2:40][CH2:41][CH3:42])[C:22]([S:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH2:20]1
Reactant: CCCC[C@@H](C)C[C@@H](/C=C/[C@@H]1C(SCCCCCC(=O)OC)=CC[C@H]1O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCC[C@@H](C)C[C@H](O)/C=C/[C@@H]1C(SCCCCCC(=O)OC)=CC[C@H]1O
Reaction time: 15 h
Yield: 86.4 %

Procedure:
To a solution of ice-cooled acetonitrile (1.5 mL) and pyridine (0.15 mL) was added hydrogen fluoride-pyridine (0.15 mL). To this solution was added methyl (11R,12S,13E,15S,17R)-11,15-bis(tert-butyldimethylsiloxy)-17,20-dimethyl-7-thiaprosta-8,13-dienoate (150 mg, 0.238 mmol) in pyridine (0.15 mL). The ice bath was removed and the solution was agitated for 15 hours, while returning it to room temperature. The reaction solution was poured into a mixture of ethyl acetate and saturated aqueous sodium hydrogencarbonate. The desired product was extracted from this mixed solution with ethyl acetate. The extract was washed with brine, then dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure, then was purified by silica gel column chromatography (40 to 50% ethyl acetate/hexane) to obtain methyl (11R,12S,13E,15S,17R)-11,15-dihydroxy-17,20-dimethyl-7-thiaprosta-8,13-dienoate (82 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:37])[C:11]=1[O:12][CH2:13][C:14]1[N:15]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:16]([C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)([CH3:21])[CH3:20])=[CH:17][N:18]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:37])[C:11]=1[O:12][CH2:13][C:14]1[N:15]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[C:16]([C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)([CH3:21])[CH3:20])=[CH:17][N:18]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(F)c(OCc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)cc2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(c1ccc(Cl)c(Cl)c1)c1cnc(COc2c(F)cc(C(=O)O)cc2Cl)n1-c1ccc(F)cc1
Temperature: 65 °C
Yield: 38.8 %

Procedure:
A mixture of methyl 3-chloro-4-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)methoxy)-5-fluorobenzoate (120 mg, 0.21 mmol) and 2N NaOH (0.31 mL, 0.63 mmol) in MeOH (3 mL) was heated 3 h at 65° C. After cooling, the reaction was neutralized to pH 3 with 3N HCl, concentrated under reduced pressure, diluted with water, and then extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by HPLC (MeCN/H2O, 10-99%) to give the title compound as an off-white solid (45 mg, 39%). MS (EI) m/z 553.5 [M+H]+.
Reaction SMILES: N#N.[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14](/[CH:17]=C/C2C=CC=CC=2)[O:15][CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[OH2:25]>CC(C)=O>[Si:3]([O:10][CH2:11][C:12]1[N:13]=[C:14]([CH:17]=[O:25])[O:15][CH:16]=1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OCc1coc(/C=C/c2ccccc2)n1
Reactant: O
Agent: N#N
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1coc(C=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of NaIO4 (726 mg, 3.33 mmol) in water (6.6) mL was slowly added to a vigorously stirred suspension of silica gel (4.46 g) in acetone (13.2 mL). The mixture was then concentrated under reduced pressure and the lumpy solid slurried in CH2Cl2 and the solvent was evaporated under reduced pressure. CH2Cl2 (16.5 mL) was added and the reaction mixture was treated at rt with (E)-4-(((tert-butyldimethylsilyl)oxy)methyl)-2-styryloxazole (350 mg, 1.1 mmol) and RuCl3 hydrate (7.8 mg, 0.03 mmol). The reaction mixture was stirred at rt in the dark overnight, filtered through silica gel and concentrated under reduced pressure to give the title compound as a red oil. TLC: rf (1:3 EA-Hept)=0.51. LC-MS-conditions 07: tR=0.64 min.
Reaction SMILES: [CH:1]1([N:4]=[C:5]=[O:6])[CH2:3][CH2:2]1.[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:30])=[C:17]([N:22]4[CH2:27][CH:26]([CH3:28])[NH:25][CH:24]([CH3:29])[CH2:23]4)[C:18]=3[O:20][CH3:21])[C:13](=[O:31])[C:12]([C:32]([NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=3[Cl:43])=[O:33])=[CH:11]2)[CH2:9][CH2:8]1>ClCCl>[CH:7]1([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:30])=[C:17]([N:22]4[CH2:23][CH:24]([CH3:29])[N:25]([C:5]([NH:4][CH:1]5[CH2:3][CH2:2]5)=[O:6])[CH:26]([CH3:28])[CH2:27]4)[C:18]=3[O:20][CH3:21])[C:13](=[O:31])[C:12]([C:32]([NH:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:37]=3[Cl:43])=[O:33])=[CH:11]2)[CH2:9][CH2:8]1
Reactant: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Reactant: O=C=NC1CC1
Solvent: ClCCl
Product: COc1c(N2CC(C)N(C(=O)NC3CC3)C(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Temperature: 25 °C

Procedure:
30 μl (24.3 mg, 0.29 mmol) of cyclopropylisocyanate are dissolved in dichloromethan, 80.0 mg (0.146 mmol) of the compound of Example 12 are added and the mixture is stirred over night at room temperature. For the work-up the solvent is removed completely and after fine purification by preparative RP-HPLC (Method 6) 55 mg of the target compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][C:13]([CH3:18])([CH3:17])[CH2:14][CH:15]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:15]/[CH2:14][C:13]([CH3:18])([CH3:17])[CH3:12])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CC(C)(C)CC=O
Solvent: CO
Solvent: C1CCNC1
Product: CC(C)(C)C/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 100 °C
Yield: 99.4 %

Procedure:
To the mixture of 6-chlorooxindole (0.26 g, 1.49 mmol) (Crescent) and 3,3-dimethyl-butyraldehyde (0.21 g, 2.09 mmol) (Aldrich) in methanol (20 mL) was added pyrrolidine (0.15 g, 2.09 mmol) (Aldrich) dropwise. The mixture was then heated at 100° C. for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried over Na2SO4, concentrated, and dried in vacuo to give the crude E/Z-6-chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one as a white solid (Yield 0.37 g, 100%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:52]([N:59]1[CH2:64][CH2:63][O:62][CH:61]([C:65]([NH2:68])=[N:66]O)[CH2:60]1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1>CN(C)C=O.O>[CH2:52]([N:59]1[CH2:64][CH2:63][O:62][CH:61]([C:65]2[N:68]=[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:9][N:66]=2)[CH2:60]1)[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1
Reactant: O=C(O)c1ccccc1
Reactant: NC(=NO)C1CN(Cc2ccccc2)CCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(CN2CCOC(c3noc(-c4ccccc4)n3)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
To a stirred solution of benzoic acid (2.30 g, 19.1 mmol) in N,N-dimethylformamide (20 ml) was added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (6.15 g, 19.1 mmol), 1-hydroxybenzotriazole hydrate (518 mg, 3.83 mmol) and N,N-diisopropylethylamine (11.0 ml, 63.8 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. After addition of 4-benzyl-N′-hydroxymorpholine-2-carboxamidine (intermediate 26, 3.0 g, 12.8 mmol), the reaction mixture was stirred at room temperature for one hour, and then heated to 110° C. When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by addition of water and the aqueous layer was extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluent: 30% ethyl acetate in hexane) to afford 4-benzyl-2-(5-phenyl-1,2,4-oxadiazol-3-yl)morpholine (intermediate 27, 3.08 g, 75%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: [H][H]
Reactant: CCN1CCN(c2cc([N+](=O)[O-])ccn2)CC1
Agent: [Pd]
Solvent: CO
Product: CCN1CCN(c2cc(N)ccn2)CC1

Procedure:
A solution of 2.03 g (9 mmol) 1-ethyl-4-(4-nitro-pyridin-2-yl)-piperazine in 30 ml methanol was hydrogenated over 0.052 g Pd/C with 1 bar hydrogen for 3 h at room temperature. The mixture was filtered and evaporated to dryness to yield the title compound as yellow solid which was used without further purification (m/e): 207.1 (MH+; 100%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C@H:16]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34]CC)=[O:33])[CH2:27][CH2:26]4)[CH2:21][CH2:20]3)=[O:18])=[O:14])[CH2:9][CH2:8]2)[N:5]=[C:4]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[NH:3]1.[Li+].[OH-]>>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C@H:16]([CH2:37][C:38]3[CH:43]=[C:42]([CH3:44])[C:41]([OH:45])=[C:40]([CH3:46])[CH:39]=3)[C:17]([N:19]3[CH2:24][CH2:23][CH:22]([N:25]4[CH2:26][CH2:27][N:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:29][CH2:30]4)[CH2:21][CH2:20]3)=[O:18])=[O:14])[CH2:11][CH2:12]2)[N:5]=[C:4]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[NH:3]1
Reactant: CCOC(=O)CN1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(n4nc(-c5ccccc5)[nH]c4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3nc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N2CCC(N3CCN(CC(=O)O)CC3)CC2)cc(C)c1O

Procedure:
Prepared analogously to Example 2.12 from 38 mg (0.05 mmol) (R)-2-[4-(4-ethoxycarbonylmethyl-piperazin-1-yl)-piperidin-1-yl]-1-(4-hydroxy-3,5-dimethyl-benzyl)-2-oxo-ethyl 4-(5-oxo-3-phenyl-4,5-dihydro-1,2,4-triazol-1-yl)-piperidine-1-carboxylate and 2.1 mg (0.09 mmol) LiOH.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([CH3:7])[C:3]([CH2:5][OH:6])=[O:4].C(N(C(C)C)CC)(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:7][C:2]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([CH3:1])[C:3]([CH2:5][O:6][S:29]([CH3:28])(=[O:31])=[O:30])=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)COS(C)(=O)=O
Temperature: 0 °C
Yield: 63 %

Procedure:
N-(1',1'-dimethyl-3'-hydroxyacetonyl)-3,5-dichlorobenzamide (1.0 gm, 0.00345 m) was dissolved in methylene chloride (25 ml) and diisopropylethylamine (0.44 gm, 0.0035 m) and cooled to about 5° C. under a nitrogen atmosphere. While the solution was stirred magnetically, methanesulfonylchloride (0.475 gm, 0.0041 m) was added dropwise. After its addition, the mixture was stirred about an hour longer while maintaining the temperature at 5°-10° C. The mixture was then poured into ice water (500 ml) containing methylene chloride (100 ml). The organic layer was separated and was washed with cold 1% hydrochloric acid, saturated sodium bicarbonate, water and brine, and then dried over anhydrous potassium carbonate. The solvent was removed and 800 mg of the desired product was obtained.