Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1O)=[CH:15][CH:14]=[CH:13][CH:12]=2)([O-:7])=[O:6].CN(C=O)C.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28]>C(Cl)Cl>[N+:5]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:24][CH2:25][CH2:26][CH2:27][OH:28])=[CH:15][CH:14]=[CH:13][CH:12]=2)([O-:7])=[O:6]
Reactant: NCCCO
Reactant: O=[N+]([O-])c1cnc2ccccc2c1O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCO
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (6.3 mL) was added to a mixture of 3-nitroquinolin-4-ol (15 g) and DMF (6.9 mL) in DCM (200 mL). The mixture was heated under reflux for 3 h then cooled to 0° C. 3-Amino-1-propanol (7.3 mL) was added slowly followed by dropwise addition of TEA (36 mL) and the mixture stirred at rt for 3 h. The precipitate was filtered, washed with DCM then water. The DCM filtrate was washed with water and evaporated under reduced pressure then combined with the filtered solid. The combined solids were triturated with ether and filtered to give a yellow solid, 19.2 g
Reaction SMILES: [CH2:1]([NH:5][C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21].O>C1C=CC=CC=1>[CH2:1]([N:5]([C:6]1[O:7][CH:8]=[C:9]([CH3:11])[N:10]=1)[C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nc(C)co1
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Solvent: O
Product: CCCCN(C(=O)C(C)C)c1nc(C)co1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
2-(N-butylamino)-4-methyloxazole (106.7 g., 0.69 m.) and triethylamine (110 g., 0.77 m.) was stirred together in dry benzene (1500 c.c.) during the addition of isobutyrylchloride (81.0 g., 0.76 m.). The mixture was stirred at room temperature for 15 hours and then water (1 litre) was added. After stirring for a further hour the organic phase was separated, and the aqueous phase extracted twice in ether. The combined extract was washed successively with 2N hydrochloric acid (2 × 500 c.c.), 10% sodium carbonate solution (2 × 500 c.c.), and saturated brine (2 × 500 c.c.). Evaporation of the dried organic phase gave an oil, which was distilled to give 2-(N-butylisobutyramido)-4-methyloxazole, (118 g., 80%), b.p. 75-76° C./0.15 mm., which existed as an oil at room temperature but crystallised on cooling to 0° C.
Reaction SMILES: CC1(C)COC(C([C@@H]2[C@]3(C)[C@H](C4[C@H](CC3)[C@]3(C)C(C[C@@H](OC(OC)=O)C[C@@H]3O)=CC=4)CC2)C)OC1.CC1(C)CO[CH:40]([CH:43]([C@@H:45]2[C@:62]3([CH3:63])[C@H:48]([C:49]4[C@H:59]([CH2:60][CH2:61]3)[C@:57]3([CH3:58])[C:52]([CH2:53][C@@H:54]([O:69]C(OC)=O)[CH2:55][C@@H:56]3[O:64][C:65]([O:67][CH3:68])=[O:66])=[CH:51][CH:50]=4)[CH2:47][CH2:46]2)[CH3:44])[O:39]C1>>[OH:69][C@H:54]1[CH2:55][C@H:56]([O:64][C:65]([O:67][CH3:68])=[O:66])[C@@:57]2([CH3:58])[C:52](=[CH:51][CH:50]=[C:49]3[C@@H:59]2[CH2:60][CH2:61][C@@:62]2([CH3:63])[C@H:48]3[CH2:47][CH2:46][C@@H:45]2[CH:43]([CH:40]=[O:39])[CH3:44])[CH2:53]1
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Agent: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](O)C1
Product: COC(=O)O[C@H]1C[C@H](O)CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@]21C
Yield: 74.7 %

Procedure:
The reaction and workup procedures of Example 156 were repeated except that 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(methoxycarbonyl)oxypregna-5,7-dien-1α-ol was used in lieu of 100 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene to give 55 mg of 3β-hydroxy-1α-(methoxycarbonyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])=[CH:4][C:3]=1[F:24].[C:25]([NH:28][C:29]1[NH:30][C:31](=[O:46])[C:32]([CH2:42][CH2:43][CH:44]=O)=[C:33]([N:35]([C:39](=[O:41])[CH3:40])[C:36](=[O:38])[CH3:37])[N:34]=1)(=[O:27])[CH3:26].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C.CO>[C:25]([NH:28][C:29]1[NH:30][C:31](=[O:46])[C:32]([CH2:42][CH2:43][CH2:44][NH:1][C:2]2[CH:23]=[CH:22][C:5]([C:6]([NH:8][C@H:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:7])=[CH:4][C:3]=2[F:24])=[C:33]([N:35]([C:36](=[O:38])[CH3:37])[C:39](=[O:41])[CH3:40])[N:34]=1)(=[O:27])[CH3:26]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)c(F)c1)C(=O)OCC
Reactant: CC(=O)Nc1nc(N(C(C)=O)C(C)=O)c(CCC=O)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCO
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NCCCc2c(N(C(C)=O)C(C)=O)nc(NC(C)=O)[nH]c2=O)c(F)c1)C(=O)OCC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Both diethyl N-(4-amino-3-fluorobenzoyl)-(L)-glutamate (2.21 g, 6.49 mmoles) and 3-(2-acetylamino-4-diacetylamino-1,6-dihydro-6-oxo-5-pyrimidinyl)propionaldehyde (2.00 g, 6.49 mmoles) were stirred in absolute ethanol (50 mL) under nitrogen while glacial acetic acid (3mL) was added dropwise during 1 minute. After solution was achieved (1 hour), activated 3 Å molecular sieves (10 mL) were added and stirring was continued 5 hours. The reaction mixture was chilled (ice bath) and sodium cyanoborohydride (408 mg, 6.49 mmoles) added in one portion. After stirring cold 0.5 hour, the bath was removed. The reaction mixture was allowed to warm to ambient temperature and stir 16 hours. The reaction mixture was filtered and the solids rinsed with ethanol (100 mL). The filtrate was spin evaporated to a brown residue that was partitioned between ethyl acetate and water (100 mL each). The organic phase was separated, washed (1×100 mL 1:1 water/brine), dried (MgSO4), filtered, and spin evaporated to a small volume (20 mL). The solution was chromatographed on silica gel (175 g) using an ethyl acetate rinse (450 mL) followed by elution of the product with 5% added methanol. Like fractions were combined by spin evaporation and dried to give a white solid; yield, 2.66 g (65%); mp 76°-84° C. (dec); 1H-NMR (DMSO-d6) δ 1.15 and 1.16 (2t overlapped, 6H), 1.64 (m, 2H), 2.00 (m, 2H), 2.11 (s, 3H), 2.20 (s, 6H), 2.27 (m, 2H), 2.40 (t, 2H), 3.10 (m, 2H), 3.9-4.1 (2q overlapped, 4H), 4.35 (m, 1H), 6.10 (m, 1H), 6.66 (t, JoH,H and JmF,H =9 Hz, 1H), 7.5-7.6 (m, 2H), 8.35 (d, 1H), 11.9 (v br d, 1H); uv (MeOH) 299 nm max (28000), 257 min (7500); mass spec (FAB) m/e 633 (23%), 430 (100), 388 (87).
Reaction SMILES: [CH:1]1([NH2+:7]C2CCCCC2)CC[CH2:4][CH2:3][CH2:2]1.[CH2:14]([C@H:18]1[O:20][C@@H:19]1[C:21]([O-:23])=O)[CH2:15][CH2:16][CH3:17].C(Cl)(=O)C(C)(C)C.C(N)CCC>O1CCCC1>[CH2:1]([NH:7][C:21]([C@@H:19]1[C@@H:18]([CH2:14][CH2:15][CH2:16][CH3:17])[O:20]1)=[O:23])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[C@H]1O[C@@H]1C(=O)[O-]
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CC(C)(C)C(=O)Cl
Solvent: CCCCN
Solvent: C1CCOC1
Product: CCCCNC(=O)[C@H]1O[C@@H]1CCCC
Reaction time: 0.25 h
Yield: 99.8 %

Procedure:
Under ice-cooling, to 10 ml of an anhydrous tetrahydrofuran solution containing 299 mg (1.84 mmol) of (2S-trans)-3-butyl-oxiranecarboxylic acid-dicyclohexylammonium salt was added 2 ml of an anhydrous tetrahydrofuran solution containing 222 mg (1.84 mmol) of pivaloyl chloride, and the resulting mixture was stirred at the same temperature for 15 minutes. Moreover, the temperature of the reaction mixture was returned to room temperature, and the mixture was stirred for 2 hours. After filtering off insoluble materials in the reaction mixture, the filtrate was added to 10 ml of an anhydrous tetrahydrofuran solution containing 135 mg (1.84 mmol) of n-butylamine under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. Under reduced pressure, the reaction mixture was concentrated and ethyl acetate was added to the concentrate, and the resulting mixture was washed successively with a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution and then a saturated NaCl solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 366 mg (Yield: 100%) of the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18](OCC)=[O:19])=[CH:12]2)#[N:8].CO>C1COCC1>[OH:19][CH2:18][C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:7]#[N:8])=[CH:17][CH:16]=2
Reactant: CCOC(=O)c1cc2cc(C#N)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc2[nH]c(CO)cc2c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.6 %

Procedure:
LiAlH4 (1.0 M in THF, 5 mL) was added to a solution of ethyl 5-cyano-1H-indole-2-carboxylate (D21) (1 g) in THF (100 mL). The reaction mixture was stirred for 15 min at RT. MeOH was added to quench the reaction. The solvent was evaporated. EtOAc (500 mL) was added. The organic solution was washed with aqueous HCl (300 mL), then was dried over anhydrous magnesium sulfate. The dried solution was concentrated to afford 2-(hydroxymethyl)-1H-indole-5-carbonitrile (D24) (600 mg) as a pale orange oil. MS (ES): C10H8N2O requires 172; found 173.2 (M+H+)
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:6]2[CH:20]=1)#[N:2].C(=O)([O-])[O-:22].[K+].[K+].OO>CS(C)=O.O>[C:1]([C:3]1[N:4]=[C:5]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:10]=3[O:9][CH2:8][CH2:7][N:6]2[CH:20]=1)(=[O:22])[NH2:2]
Reactant: COC(=O)c1ccc2c(c1)OCCn1cc(C#N)nc1-2
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(c1)OCCn1cc(C(N)=O)nc1-2
Yield: 75.8 %

Procedure:
Methyl 2-cyano-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (0.46 g, 1.7 mmol) was stirred with potassium carbonate (469 mg, 3.4 mmol), water (1.2 mL) and hydrogen peroxide (408 mg, 6 mmol) in DMSO (7 mL) for 4 hours. The mixture was diluted with 70 mL of water and extracted with ethyl acetate. Ethyl acetate solution was washed with water, 5% Na2S2O3, water, brine, dried over MgSO4 and concentrated under vacuum to give methyl 2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate (0.37 g).
Reaction SMILES: [NH2:1][C@H:2]([C:24]([NH:26][C@H:27]([C:30]([NH:32][C@H:33]([C:38]([OH:40])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH2:28][OH:29])=[O:25])[CH2:3][S:4]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.O.[F:43][C:44]([F:49])([F:48])[C:45]([OH:47])=[O:46]>C(S)C>[NH2:1][C@H:2]([C:24]([NH:26][C@H:27]([C:30]([NH:32][C@H:33]([C:38]([OH:40])=[O:39])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:31])[CH2:28][OH:29])=[O:25])[CH2:3][SH:4].[F:43][C:44]([C:45]([OH:47])=[O:46])([F:49])[F:48]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCS
Product: CC(C)C[C@H](NC(=O)[C@H](CO)NC(=O)[C@@H](N)CS)C(=O)O
Reaction time: 0.5 h

Procedure:
564 mg (0.97 mmole) of H-Cys(Trt)-Ser-Leu-OH.H2O (Chem. Ber. 103, 2034 (1970)) are dissolved in a mixture of 2.5 ml of ethylmercaptan and 2.5 ml of trifluoroacetic acid. The mixture is left to stand for 30 minutes at room temperature and the batch is poured into 50 ml of water. The aqueous phase is extracted three times with ether and is freeze-dried.
Reaction SMILES: [CH3:1][C@@H:2]1[C:7](=O)[N:6]2[CH2:9][CH2:10][NH:11][CH2:12][CH:5]2[C:4](=O)[NH:3]1.B.C1COCC1>Cl>[CH3:1][C@@H:2]1[CH2:7][N:6]2[CH2:9][CH2:10][NH:11][CH2:12][CH:5]2[CH2:4][NH:3]1
Reactant: C[C@H]1NC(=O)C2CNCCN2C1=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: C[C@@H]1CN2CCNCC2CN1
Yield: 81.2 %

Procedure:
To a flask containing (3R)-3-methyltetrahydro-2H-pyrazino[1,2-a]pyrazine-1,4(3H,6H)-dione (D98, 353 mg, 1.927 mmol) was added 1M BH3-THF solution (20 mL) and it was heated to reflux for 20 h. MS analysis: m/z=156 (M+1 of the target product). To the reaction were added at 0° C. 10 mL of 6M HCl and it was heated to 90° C. for 20 h. The reaction mixture was purified by SCX, obtaining 243 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:3]=1[NH2:4].Br.Br[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Br.[OH-].[K+].[OH-].[Na+]>O>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:3]=1[N:4]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: COc1cccc(F)c1N
Reactant: BrCCNCCBr
Agent: Br
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: COc1cccc(F)c1N1CCNCC1
Temperature: 110 °C
Yield: 77 %

Procedure:
2-Fluoro-6-methoxyaniline (7.80 g) and 17.23 g of di-(2-bromoethyl)amine hydrobromide were dissolved in 5 ml of water and, by heating at about 110° C. on a bath, 10 ml of 30% potassium hydroxide solution was added thereto (each about 3.5 ml once an hour). Heating was further continued (7 hours in total). After cooled, the reaction solution was made alkaline with aqueous solution of sodium hydroxide to salt out and extracted with chloroform twice. The extract was washed with saturated sodium chloride solution, dried over sodium sulfate, the solvent was evaporated therefrom, and the residue was purified by a column chromatography to give 8.95 g of oily 1-(2-fluoro-6-methoxyphenyl)piperazine in 34.93 g yield or 94%.
Reaction SMILES: Br.[Br-].[CH3:3][N:4]([CH3:27])[CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.CCCCCC.[Br:39][C:40]1[CH:41]=[CH:42][C:43]2[CH2:49][CH2:48][C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3[C:45](=O)[C:44]=2[CH:55]=1.Cl>O.O1CCCC1>[Br:39][C:40]1[CH:41]=[CH:42][C:43]2[CH2:49][CH2:48][C:47]3[CH:50]=[CH:51][CH:52]=[CH:53][C:46]=3/[C:45](=[CH:7]/[CH2:6][CH2:5][N:4]([CH3:27])[CH3:3])/[C:44]=2[CH:55]=1
Reactant: O=C1c2ccccc2CCc2ccc(Br)cc21
Reactant: CN(C)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Br
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CN(C)CC/C=C1/c2ccccc2CCc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Anhydrous 3-(dimethylamino)propyltriphenylphosphonium bromide hydrobromide (21 g., 40.8 mmole) was suspended in 400 ml. of dry tetrahydrofuran and n-butyl lithium in hexane (82 mmole) was added dropwise at 0° C. under a nitrogen atmosphere during a period of 0.5 hour. After an additional 10 minutes, 9.0 g. (31.3 mmole) of 3-bromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one, prepared as described in C. A. Stone, J. M. Stavorski, H. C. Wenger and C. T. Ludden, J. Med. Chem. (1965) 8, 829, in 100 ml. dry tetrahydrofuran was added slowly to the deep red solution and the reaction was then refluxed for 18 hours. The solution was poured into ice-water and the mixture was extracted with diethyl ether. Evaporation of the ether under reduced pressure gave an oily residue which was suspended in water and the mixture was then acidified with 6N hydrochloric acid. The acidic aqueous solution was washed with hexanes, and then concentrated under reduced pressure. The residue was chromatographed on a silica gel Prep 500 column with methanol to provide an E/Z (1:1) stereoisomeric mixture of bromoamines. Recrystallization of the isomeric mixture from methanol gave 0.5 g. of the pure E-isomer as its hydrochloric salt, m.p. 239°-240° C. The residue from the mother liquor was chromatographed on a reverse phase C18 semi-preparative column with 70% methanol in water (containing 0.1% triethylamine). The appropriate fractions were pooled and recrystallized from methanol/water to yield 1.13 g. of the Z-isomer (with the presence of 5% E-isomer) as the free base, m.p. 73°-75° C. Also, the fractions containing the E-isomer were pooled, evaporated and recrystallized from methanol/ethyl acetate to give 0.70 g. of the E-isomer as the free base. From other fractions 3.5 g. of E/Z (1:1) isomeric mixture was collected which could be used either for further separation or for carboxylation in the next step. pmr (E-isomer, free base) (CDCl3) δ: 7.43 (d, J=1.9 Hz, 1H, H4), 7.12-7.26 (m, 5H, aromatic), 6.89 (d, J=8.3 Hz, 1H, H1), 5.88 (t, J=7.3 Hz, 1H, CH=), 3.30 (m, 2H, CH2Ar), 2.84 (m, 2H, CH2Ar), 2.28-2.38 (m, 4H, NCH2CH2), 2.16 (s, 6H, NMe2). pmr (≥95% stereoisomeric pure Z-isomer, free base) (CDCl3) δ: 7.00-7.33 (m, 7H, aromatic), 5.86 (t, J=7.3 Hz, 1H, CH=), 3.30 (m, 2H, CH2Ar), 2.90 (m, 1H, CHAr), 2.70 (m, 1H, CHAr), 2.26-2.37 (m, 4H, NCH2CH2), 2.18 (s, 6H, NMe2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@H:13]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-])=O)[CH:22]=2)=[O:19])[CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@H:13]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][S:35]([CH3:34])(=[O:37])=[O:36])[CH:22]=2)=[O:19])[CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1
Reactant: CC(C)[C@H](CN1CCC(Cc2ccc(Cl)c(Cl)c2)CC1)NC(=O)Nc1cccc([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Agent: O=[Pt]=O
Product: CC(C)[C@H](CN1CCC(Cc2ccc(Cl)c(Cl)c2)CC1)NC(=O)Nc1cccc(NS(C)(=O)=O)c1

Procedure:
Proceeding as described in Example 13 above, but substituting 3-methoxyphenylisocyanate with 3-nitrophenylisocynate gave 1-{1-(R)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-nitrophenyl)urea which was then converted to the corresponding 1-{1-(R)-[4-(3,4-dichlorobenzyl)piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-aminophenyl)urea under catalytic hydrogenation conditions using PtO2 catalyst, followed by reaction with methylsulfonyl chloride to give 1-{1-(R)-[4-(3,4-dichlorobenzyl)-piperidin-1-ylmethyl]-2-methylpropyl}-3-(3-methylsulfonylaminophenyl)urea.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:31])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17][C:18]3[S:22][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26](Br)[N:25]=4)=[N:20][CH:19]=3)[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:31])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([S:17][C:18]3[S:22][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[N:25]=4)=[N:20][CH:19]=3)[CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: C1CCNCC1
Reactant: CC(=O)N1CCN(C(=O)c2cccc(Sc3cnc(Nc4cccc(Br)n4)s3)c2)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)N1CCN(C(=O)c2cccc(Sc3cnc(Nc4cccc(N5CCCCC5)n4)s3)c2)CC1
Yield: 83.1 %

Procedure:
A solution of Example 4 (30 mg, 0.058 mmol), piperidine (86 μL, 0.87 mmol), 4-dimethylaminopyridine (7.1 mg, 0.058 mmol) in pyridine (300 μL) was heated to 134° C. in a sealed vial under nitrogen for 8.75 h. Most of pyridine was removed on a speed-vac at 40° C. The residue was purified using reversed phase automated preparative HPLC (conditions: YMC S5 ODS A 20×100 mm column, 15 min gradient starting from 10% solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 90% solvent A (10% MeOH, 90% H2O, 0.1% TFA) to 90% solvent B and 10% solvent A, flow rate 20 mL/min, λ=220 nM) to obtain the titled compound (25.2 mg, 68%) as a light tan solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15]([C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:14]3)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][CH:7]4[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:9][CH2:8]4)=[CH:19][CH:18]=3)[CH:14]=[C:15]2[C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCOCC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCOCC2)n3-c2ccc(Cl)cc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-morpholin-4-yl-methanone (intermediate 2) and 4-chlorophenylboronic acid. The title compound was obtained in 90% yield as yellow foam. MS (m/e): 482.3 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:20][CH:19]=2)=C)[C:11](=[O:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:32].[Na+]>C(#N)C.O.S([O-])([O-])(=O)=S.[Na+].[Na+].O.[Ru](Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:15][C:16](=[O:32])[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:20][CH:19]=2)[C:11](=[O:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CN2CCCC2)cc1
Agent: Cl[Ru](Cl)Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(Cn1ccc(OCc2ccccc2)cc1=O)c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 200 mg (0.50 mmol) 4-benzyloxy-1-[2-(4-pyrrolidin-1-ylmethyl-phenyl)-allyl]-1H-pyridin-2-one (example 26.1) in 6.0 mL acetonitrile is added at RT subsequently a solution of 4 mg (0.02 mmol) ruthenium(III)-trichloride hydrate in 1.0 mL water and then 214 mg (1.00 mmol) sodium metaperiodate in small portions. The reaction mixture is stirred 4 h at RT and is diluted with aqueous 10% sodium thiosulfate solution. The layers are separated and the aqueous phase is extracted with DCM. The combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Waters xbridge; water (15% NH4OH)/acetonitrile (15% NH4OH) 95:5 to 5:95).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([NH:19][CH:20]=[O:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:22]C1C=C(C=CC=1)C=O>>[Br:22][C:2]1[CH:3]=[C:4]([CH:8]([NH:19][CH:20]=[O:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(I)c2)cc1
Reactant: O=Cc1cccc(Br)c1
Product: Cc1ccc(S(=O)(=O)C(NC=O)c2cccc(Br)c2)cc1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 52 but using 3-bromobenzaldehyde in place of 3-iodobenzaldehyde. Solid (11 g, 28%);
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9]C#N)[CH:6]=[CH:5][C:3]=1[NH2:4].[ClH:12]>CCO>[ClH:12].[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([SH:9])=[CH:8][C:2]=1[F:1]
Reactant: N#CSc1ccc(N)c(F)c1
Agent: Cl
Solvent: CCO
Product: Nc1ccc(S)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Fluoroaniline (9.8 mL, 0.1 mol) and sodium thiocyanate (24.9 g, 0.3 mol) in MeOH (55 mL) were treated with a cold solution of bromine (5.7 mL, 0.11 mol) in saturated NaBr-MeOH solution (50 mL) added dropwise at −5-0° C. over 2 hours. After the addition, the reaction mixture was poured into cold water (200 mL) with stirring, adjusted to pH 8-9 with NaHCO3 (10 g), and stirred at 5° C. for 30 minutes. The resulting crystals were collected by filtration, washed with cold water, and dried at room temperature overnight in vacuum to give crude product 2-fluoro-4-thiocyanatoaniline (14.5 g) as slightly brown crystal. A mixture of the crude 2-fluoro-4-thiocyanatoaniline (14.5 g) and concentrated hydrochloric acid (58 mL) in EtOH (15 mL) was refluxed for 8 hours. The reaction mixture was cooled and stirred at room temperature overnight. The resulting crystals were collected by filtration, washed with cold EtOH and i-Pr2O, dried at room temperature overnight in vacuum to give the title compound as its hydrochloride salt (pale yellow crystal, 10.1 g, 56%).