Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][OH:44].O>CN(C)C=O>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][OH:44])=[CH:30][CH:31]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)cc1
Reactant: OCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCCCCCCOc1ccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
The obtained 3,6-diphenyl-9-(4-hydroxyphenyl)carbazole (1.54 g, 3.7 mmol) was dissolved in N,N-dimethylformamide (20 mL). Under cooling with ice water, 55% by mass sodium hydride (0.25 g, 5.7 mmol) was added to the resultant solution, followed by stirring for 1 hour. Next, 8-bromo-1-octanol (1.16 g, 5.5 mmol) was added thereto, and the resultant mixture was stirred for 3 hours at room temperature. In addition, the mixture was poured to water, followed by extraction with ethyl acetate. Next, the mixture was washed with water and dried and the solvent was evaporated, to thereby obtain 1.90 g of 8-[4-(3,6-diphenylcarbazol-9-yl)phenoxy]octan-1-ol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cnc3cc(C#N)ccc32)CC1
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)ncn2C1CCNCC1

Procedure:
tert-Butyl-4-(5-cyano-1H-benzimidazol-1-yl)piperidin-1-carboxylate (326 mg) was dissolved in DCM (10 ml) and silica gel (10 g) was added and the mixture evaporated to dryness. Toluene (100 ml) was added and the mixture refluxed for 15 hours. The mixture was evaporated to dryness and the silica was then washed with dichloromethane. The organics were evaporated to a gum which was purified by chromatography on silica eluting with NH3/MeOH/dichloromethane (2:18:80) to give the title compound as a solid. Yield 77 mg. NMR (d6 DMSO): 2.0 (m, 4H), 2.75 (m, 2H), 3.15 (m, 2H), 4.6 (m, 1H), 7.7 (d, 1H), 7.9 (d, 1H), 8.2 (s, 1H), 8.6 (s, 1H). MS 227 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2[CH:22]=[CH:23][CH:24]=[CH:25][C:16]1=2.C(N(CC)CC)C>C(Cl)Cl.O>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([N:15]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]3[CH:22]=[CH:23][CH:24]=[CH:25][C:16]2=3)(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=1[Cl:1])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: c1ccc2c(c1)CCCCN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To 4-chloro-3-nitrobenzenesulfonyl chloride (2.56 g, 10 mmol) in dry DCM (20 mL) was added 2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.54 g, 10.5 mmol) and triethylamine (3.3 mL, 25 mmol). The mixture was stirred at ambient temperature for 16 hrs. The mixture was then diluted with 40 mL of DCM and 30 mL of water. The organic layer was separated, washed with brine (2×20 mL), dried over MgSO4, and evaporated to afford 1-(3-nitro-4-chloro-benzenesulfonyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine as a yellow solid (3.6 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:44])([CH3:43])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:33])=[C:24]([N:27]3[C:31](=[O:32])[NH:30][N:29]=[N:28]3)[CH:25]=2)[NH:20][C:19](=[O:34])[C:18]=1[C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[CH:36]=1)=[O:7].[C:45](=O)([O-])[O-].[K+].[K+].IC>>[CH3:44][Si:2]([CH3:43])([CH3:1])[CH2:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:33])=[C:24]([N:27]3[C:31](=[O:32])[N:30]([CH3:45])[N:29]=[N:28]3)[CH:25]=2)[NH:20][C:19](=[O:34])[C:18]=1[C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[CH:36]=1)=[O:7]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(-n4nn[nH]c4=O)c(Cl)cc3[nH]c2=O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OCC[Si](C)(C)C)c3cc(-n4nnn(C)c4=O)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-(5-oxo-4,5-dihydro-tetrazol-1-yl) -1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid 2-trimethylsilanylethyl ester (35 mg in 2 mL dry N,N-dimethylformamide) was added 26 mg of finely powdered potassium carbonate followed by 0.011 mL iodomethane and the mixture stirred at room temperature. After 30 minutes, the reaction was quenched by the addition of saturated ammonium chloride and the mixture partitioned between ethyl acetate and water. The organic layer was isolated and washed with water and brine, then dried over sodium sulfate. Purification of the concentrate by preparative tlc on silica gel (hexane:ethyl acetate, 3:2) gave the title compound (21 mg).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:11](O)=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[CH3:1][NH:2][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:11][OH:12]
Reactant: CN[C@@H](Cc1ccccc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN[C@H](CO)Cc1ccccc1
Temperature: -10 °C
Yield: 95.6 %

Procedure:
To a suspension of N-methyl-L-phenylalanine (20 g, 112 mmol) in THF (1200 mL) cooled to −10° C. was added in small portions lithium aluminium hydride (6.35 g, 167 mmol). After ceasing of the initial exothermic reaction, the cooling bath was removed and the reaction mixture was heated at reflux overnight. Subsequently, another portion of lithium aluminium hydride (4.24 g, 112 mmol) was added after cooling to −10° C., followed by refluxing for an additional 3 h. The reaction mixture was cooled to −40° C., and aqueous 2 N sodium hydroxide was added cautiously. After warming up to r.t., the mixture was filtered, the residue was washed with MTB, and the filtrate was evaporated to give the crude target compound (17.7 g, 96% yield) which was used without further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([NH:10][CH:11]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:12]([OH:28])[C:13]([N:15]1[CH2:26][CH:25]([Cl:27])[CH2:24][C@H:16]1[C:17]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6].[N+:36]([C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[N:45]=[C:44]([C:49](O)=[O:50])[CH:43]=[N:42]2)([O-:38])=[O:37]>>[N+:36]([C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][CH:48]=1)[N:45]=[C:44]([C:49]([NH:2][C@H:3]([C:8]([NH:10][C@@H:11]([CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C@H:12]([OH:28])[C:13]([N:15]1[CH2:26][C@@H:25]([Cl:27])[CH2:24][C@H:16]1[C:17]([NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:14])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6])=[O:50])[CH:43]=[N:42]2)([O-:38])=[O:37]
Reactant: CC(C)(C)NC(=O)[C@@H]1CC(Cl)CN1C(=O)C(O)C(Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=C(O)c1cnc2cc([N+](=O)[O-])ccc2n1
Agent: Cl
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1cnc2cc([N+](=O)[O-])ccc2n1
Yield: 29.6 %

Procedure:
Following a procedure similar to that described in Example 14, but using 490 mg (0.92 mmol) of 1-[3-(L-asparaginyl)amino-2-hydroxy-4-phenylbutyryl]-4-chloro-N-t-butyl-L-prolinamide hydrochloride and 220 mg (1.01 mmol) of 6-nitroquinoxaline-2-carboxylic acid (prepared as described in Preparation 22), 190 mg of the title compound were obtained as a pale yellow powder, melting at 153°-156° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][Si:8]([O:13][CH3:14])([O:11][CH3:12])[O:9][CH3:10].Cl[CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21].C(N)CN>>[Si:8]([CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2][NH:1][CH2:16][CH2:17][CH2:18][Si:19]([O:24][CH3:25])([O:22][CH3:23])[O:20][CH3:21])([O:13][CH3:14])([O:9][CH3:10])[O:11][CH3:12]
Reactant: CO[Si](CCCNCCN)(OC)OC
Reactant: CO[Si](CCCCl)(OC)OC
Solvent: NCCN
Product: CO[Si](CCCNCCNCCC[Si](OC)(OC)OC)(OC)OC
Temperature: 140 °C
Yield: 972.3 %

Procedure:
A 2 liter, 3-necked reaction flask equipped with a magnetic stirrer, electric heating mantle, dropping funnel and water condenser, containing 22.0 grams of NH2CH2CH2NH(CH2)3Si(OCH3)3 was heated to 140° C. whereupon the addition thereto of 198.0 grams of 3-chloropropyltrimethoxy silane (Cl(CH2)3Si(OCH3)3) was commenced. Cl(CH2)3Si(OCH3)3 was introduced dropwise to the reaction flask over a period of 1 hour while maintaining a temperature of 145° C. to 150° C. by the occasional application of a water bath. The resultant mixture was cooled to 75° C., and 90 grams of anhydrous ethylenediamine was added to the cooled mixture. Thereafter, the mixture was allowed to separate into layers with the upper product containing layer being separated therefrom and stripped by vacuum distillation of low boiling volatiles to yield 370 grams of (CH3O)3SiC3H6NHC2H4NHC3H6Si(OCH3)3. Amine titration and 13C NMR and 29Si NMR analysis verified the assigned structure of the resultant product.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=3[O:47][CH3:48])=[CH:30][CH:29]=2)[C@H:10]([O:49][CH2:50][C@H:51]([OH:55])[CH2:52][O:53][CH3:54])[CH2:9]1)=O)(C)(C)C.Cl>CO>[F:46][C:44]1[CH:43]=[CH:42][C:41]([O:47][CH3:48])=[C:40]([CH:45]=1)[CH2:39][O:38][CH2:37][CH2:36][CH2:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([C@@H:11]2[C@@H:12]([O:14][CH2:15][C:16]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH2:13][NH:8][CH2:9][C@H:10]2[O:49][CH2:50][C@H:51]([OH:55])[CH2:52][O:53][CH3:54])=[CH:29][CH:30]=1
Reactant: COC[C@@H](O)CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2cc(F)ccc2OC)cc1
Agent: Cl
Solvent: CO
Product: COC[C@@H](O)CO[C@@H]1CNC[C@H](OCc2cc(OC)c3ccccc3c2)[C@H]1c1ccc(OCCCOCc2cc(F)ccc2OC)cc1

Procedure:
In analogy to the procedure described in example 1(l) the (3S,4R,5R)-4-{4-[3-(5 fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl}-3-[(2R)-2-hydroxy-3-methoxy-propoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester was deprotected with hydrochloric acid in methanol to yield the (R)-1-[(3S,4R,5R)-4-[4-[3-(5-fluoro-2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidin-3-yloxy]-3-methoxy-propan-2-ol as colorless oil; MS: 664 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][NH2:3].Cl[C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1>CCOCC>[CH3:1][N:2]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1)[NH2:3]
Reactant: CNN
Reactant: Clc1nc2ccccc2o1
Solvent: CCOCC
Product: CN(N)c1nc2ccccc2o1
Temperature: 0 °C

Procedure:
To an ice cooled solution of 16.2 ml. of methylhydrazine in 100 ml. of dry ether is added 10.8 g. of 2-chlorobenzoxazole at a dropwise rate, keeping the temperature below 25° C. The mixture is stirred 30 min. in the ice bath and 2 hours at room temperature and then carefully evaporated. The residue is slurried with 200 ml. cold water, filtered, washed and dried to give 9.5 g. of 2-(1-methylhydrazine)benzoxazole, m.p. 128°-31°.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[CH:31][CH:30]=1)[CH:7]=[CH:6]2.[ClH:41].C(OCC)C.B(Br)(Br)Br>ClCCl>[ClH:41].[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:16][CH:15]=1)=[C:8]([C:29]1[CH:30]=[CH:31][C:32]([S:35]([N:38]([CH3:40])[CH3:39])(=[O:36])=[O:37])=[CH:33][CH:34]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2c(Oc3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(S(=O)(=O)N(C)C)cc3)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc(-c2ccc3cc(O)ccc3c2Oc2ccc(OCCN3CCCCC3)cc2)cc1
Yield: 77 %

Procedure:
In a round bottom flask place the product of Example 64 (120 mg, 0.214 mmol), dichloromethane (5 mL) and a 1.0 M hydrochloric acid in diethyl ether solution (0.43 mL, 0.43 mmol). Shake this solution at ambient temperature for 2 minutes then evaporate it in vacuo. After drying on vacuum, add dichloromethane (10 mL) and place this solution in an ice bath with stirring. Add a solution of 1.0 M boron tribromide in dichloromethane (0.750 mL, 0.750 mmol) and stir the reaction for 3-4 hours, keeping the temperature between 0° C.-10° C. Quench the reaction over saturated aqueous sodium bicarbonate then extract it into ethyl acetate. Wash the combined extracts with saturated aqueous sodium bicarbonate, water and brine; then-dry (sodium sulfate) and evaporate them in vacuo. Purify the crude solid on a Chromatotron (silica gel; 5%-11% MeOH gradient in CH2Cl2; loaded with 7% MeOH/CHCl3). Dissolve the purified material in methanol (5 mL) and add a 1.0 M hydrochloric acid in diethyl ether solution (0.43 mL). Shake the resulting solution for two minutes at room temperature then evaporate it in vacuo to give 96 mg of the title compound (77%). MS (IS+) m/e 547 (M+1-HCl).
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:32])[C:18]=1[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)=[O:21]>>[Cl:32][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:12])[C:18]=1/[CH:19]=[C:20](\[O:21][C:8](=[O:9])[C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])/[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Reactant: C[C@H](C(=O)Cl)c1ccccc1
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)[C@@H](C)c2ccccc2)cc1OC

Procedure:
The compound was obtained starting from 2-(S)-phenyl-propionyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl) -ethanone, following the procedure of Example 7.
Reaction SMILES: [OH-].[Na+:2].C(O)C.O1CCCC1.Cl.[NH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:26]3[C:25](=[O:36])[N:24]([CH3:37])[C:23](=[O:38])[N:22]([CH3:39])[C:21]=3[C:20]=2[C:40]([O:42]C)=[O:41])[CH2:14]1>O>[NH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]2[N:27]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])[C:26]3[C:25](=[O:36])[N:24]([CH3:37])[C:23](=[O:38])[N:22]([CH3:39])[C:21]=3[C:20]=2[C:40]([O-:42])=[O:41])[CH2:14]1.[Na+:2]
Reactant: COC(=O)c1c(N2CCC[C@@H](N)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(=O)c2c(c(C(=O)[O-])c(N3CCC[C@@H](N)C3)n2Cc2ccccc2Cl)n(C)c1=O
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A 1N aqueous sodium hydroxide solution (1 ml), ethanol (1 ml) and tetrahydrofuran (1 ml) were added to methyl 6-[(3R)-3-aminopiperidin-1-yl]-5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidine-7-carboxylate hydrochloride (53 mg), and the resulting mixture was stirred at 80° C. for 3 hours. After the reaction solution was cooled to 25° C., water was added thereto, followed by washing with ethyl acetate, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered and the filtrate was concentrated under reduced pressure to obtain the title compound (41 mg) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[CH2:8][S:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([N:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O>C(N(CC)CC)C>[C:19]([C:16]1[CH:15]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:17]=1[OH:18])[CH2:8][S:9][CH2:10][CH2:11][C:12]([O:14][N:30]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:13])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(CSCCC(=O)O)cc(C(C)(C)C)c1O
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(CSCCC(=O)ON(Cc2ccccc2)Cc2ccccc2)cc(C(C)(C)C)c1O
Yield: 11.6 %

Procedure:
The compound is prepared using the method of Example II, with 16.20 g of 3-(3,5-di-tert-butyl-4-hydroxybenzylthio)propanoic acid, 10.66 g of N,N-dibenzylhydroxylamine, 5.06 g of triethylamine, and 6.35 g of oxalyl chloride. The residue is purified by preparative HPLC to give 3.0 g of a white solid: mp 84°-86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][O:10][C@@H:11]1[C@@H:17]([CH2:18][O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[O:16][C@H:13](OC)[C@:12]1([CH:30]=[CH2:31])[OH:29].Br.[Na].[Cl:34][C:35]1[N:40]=[CH:39][NH:38][C:37]2=[N:41][CH:42]=[CH:43][C:36]=12>ClCCl.NC1C2C=CN([C@@H]3O[C@H](CO)[C@@H](O)[C@@]3(C)O)C=2N=CN=1>[Cl:34][C:35]1[C:36]2[CH:43]=[CH:42][N:41]([C@@H:13]3[O:16][C@H:17]([CH2:11][O:10][CH2:9][C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])[C@@H:18]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[C@@:12]3([CH:30]=[CH2:31])[OH:29])[C:37]=2[N:38]=[CH:39][N:40]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: C=C[C@]1(O)[C@@H](OC)O[C@H](COCc2ccc(Cl)cc2Cl)[C@H]1OCc1ccc(Cl)cc1Cl
Agent: Br
Agent: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Agent: [Na]
Solvent: ClCCl
Product: C=C[C@@]1(O)[C@H](OCc2ccc(Cl)cc2Cl)[C@@H](COCc2ccc(Cl)cc2Cl)O[C@H]1n1ccc2c(Cl)ncnc21
Reaction time: 4 h
Yield: 22.1 %

Procedure:
To a solution of the compound from Step A (6.4 g, 12.6 mmol) in anhydrous dichloromethane (150 mL) at −20° C. was added HBr (30% solution in AcOH, 20 mL, 75.6 mmol) dropwise. The resulting solution was stirred between −10° C. and 0° C. for 4 h, evaporated in vacuo and co-evaporated with anhydrous toluene (3×40 mL). The oily residue was dissolved in anhydrous acetonitrile (100 mL) and added to a solution of the sodium salt of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (5.8 g, 37.8 mmol) in acetonitrile (generated in situ as described in Example 2) at −20° C. The resulting mixture was allowed to come to room temperature and stirred at room temperature for 24 h. The mixture was then evaporated to dryness, taken up in water and extracted with EtOAc (2×300 mL). The combined extracts were dried over Na2SO4, filtered and evaporated. The crude mixture was purified by flash chromatography (SiO2, 10% EtOAc in hexanes) and the title compound (1.75 g) isolated as a white foam.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nn1
Product: Cc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)nn1

Procedure:
The title compound was prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert-butyl ester [CAS-No. 335255-65-7] (227 mg, 0.75 mmol) and 3-[3-(6-methyl-pyridazin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K6) (234 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (330 mg).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:34]([C:31]5[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=5)(=[O:36])=[O:35])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=S(=O)(N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1)c1ccc(F)cc1

Procedure:
The title compound, white solid (84 mg, 69%), MS (ISP) m/z=487.4 [(M+H)+], mp 134° C., was prepared in accordance with the general method of example 47 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydro chloride (intermediate B) (100 mg, 0.25 mmol) and 4-fluoro-benzenesulfonyl chloride.
Reaction SMILES: [C:1]([C:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])=[CH:8][NH:7][CH:6]=1)([O:3]C)=[O:2].Cl>CO>[Cl:17][C:11]1[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]1[C:5]([C:1]([OH:3])=[O:2])=[CH:6][NH:7][CH:8]=1
Reactant: COC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Agent: Cl
Solvent: CO
Product: O=C(O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Temperature: 70 °C

Procedure:
3.2 g of the 3-carbomethoxy-4-(2,3-dichlorophenyl)pyrrole obtained in (a) and 40 ml of a 1:1 mixture of methanol and 5N HCl are stirred for hours at 70° C. After it has coled to room temperature, the reaction mixture is poured onto ice and extracted with ethyl acetate. The ester phase is in turn extracted with 10% sodium hydroxide solution. The aqueous extract is washed twice with ethyl acetate, acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and filtered. The filtrate is concentrated by evaporation and the resultant 4-(2,3-dichlorphenyl)pyrrole-3-carboxylic acid melts at 180°-182° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([OH:36])=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[OH:37]C1C=C(O)C=CC=1C(=O)C.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([C:6]2[CH:7]=[CH:2][C:3]([OH:37])=[CH:4][C:5]=2[OH:36])[CH:17]=[CH:16]3)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc(O)cc4O)ccc3c1)n2C1CCCCC1
Yield: 8 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(2,4-dihydroxy-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (9.5 mg, 8% yield).