Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]([S:30]([CH2:33][CH2:34][CH2:35]Cl)(=[O:32])=[O:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:35][CH2:34][CH2:33][S:30]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:31])=[O:32])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: O=S(=O)(CCCCl)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCS(=O)(=O)Cc2ccccc2)CC1
Yield: 41.3 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (8.00 g) as a starting compound, 3-benzylsulfonylpropyl chloride (6.03 g) and potassium carbonate (13.4 g) were reacted and purified in the same manner as in Example 199 to give 4.40 g of 4-amino-5-chloro-2-methoxy-N-((1-(3-benzylsulfonylpropyl)piperidin-4-yl)methyl)-benzamide, m.p. 166°-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>C(O)C>[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:10][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[CH3:9])=[CH:14][CH:13]=1
Reactant: C[C@@H](N)c1ccc(Br)cc1
Reactant: O=Cc1ccc(O)cc1
Solvent: CCO
Product: CC(N=Cc1ccc(O)cc1)c1ccc(Br)cc1
Yield: 100 %

Procedure:
4.44 g (0.0222 mole) of (R)-(+)-1-(p-bromophenyl)ethylamine and 2.85 g (0.0233 mole) of p-hydroxybenzaldehyde were dissolved in 30 ml of ethyl alcohol, and the solution thus formed was stirred under reflux for 3 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and refined by a column chromatography using 30 g of silica gel to give 6.75 g of (-)-N-(p-hydroxybenzylidene)-1-(p-bromophenyl)ethylamine.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](OCC)=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH2:40][O:41][CH3:42])[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39][CH2:40][O:41][CH3:42])[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OCOC)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COCOc1cc(COc2nn(Cc3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)benzyl)oxy]-1H-pyrazole-4-carboxylate (1.50 g) in tetrahydrofuran (30 mL) was added lithium aluminum hydride (0.15 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. Sodium sulfate decahydrate (1.26 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate and the precipitate was filtered off. The filtrate was concentrated to give {1-benzyl-3-([4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)benzyl]oxy)-1H-pyrazol-4-yl}methanol as colorless crystals (1.34 g, yield 97%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 98-99° C.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]([S:35]([C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[N:46]=[CH:45][CH:44]=[CH:43]2)(=[O:37])=[O:36])[C:8]1[CH:34]=[CH:33][C:11]2[N:12]([CH3:32])[C:13]([CH2:15][C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH2:29])=[N:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:18][CH:17]=3)=[N:14][C:10]=2[CH:9]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[C:4]([CH2:6][N:7]([S:35]([C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[N:46]=[CH:45][CH:44]=[CH:43]2)(=[O:37])=[O:36])[C:8]1[CH:34]=[CH:33][C:11]2[N:12]([CH3:32])[C:13]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([NH2:29])=[N:21][C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:30][CH:31]=3)=[N:14][C:10]=2[CH:9]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(Cc1ccc(C(N)=NC(=O)OC(C)(C)C)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(Cc2ccc(C(N)=NC(=O)OC(C)(C)C)cc2)nc2cc(N(CC(=O)O)S(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 13 from 4-[(5-(N-ethoxycarbonylmethylquinolin-8-yl-sulphonylamino)-1-methyl-1H-benzimidazol-2-yl)-methyl]-N'-tert.butyloxycarbonyl-benzamidine and sodium hydroxide in ethanol.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:34]([C:37]([CH3:39])=[CH2:38])[CH2:35][CH2:36][C@:5]1([NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)[CH2:4][CH2:3]2.C(N(C(C)C)C(C)C)C.[CH3:58][N:59]([CH3:65])[C:60](=[O:64])[C:61](O)=[O:62]>ClCCl.O>[CH3:58][N:59]([CH3:65])[C:60](=[O:64])[C:61]([N:46]1[CH2:45][CH2:44][N:43]([CH2:42][CH2:41][NH:40][C@:5]23[CH2:36][CH2:35][C@@H:34]([C:37]([CH3:39])=[CH2:38])[C@@H:6]2[C@@H:7]2[C@@:2]([CH3:1])([CH2:3][CH2:4]3)[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:33])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8]2)[CH2:48][CH2:47]1)=[O:62]
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN3CCNCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CN(C)C(=O)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(C(=O)C(=O)N(C)C)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 20 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
A mixture of methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (50 mg, 0.076 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (29.4 mg, 0.091 mmol), N-ethyl-N-isopropylpropan-2-amine (11.82 mg, 0.091 mmol) and 2-(dimethylamino)-2-oxoacetic acid (26.8 mg, 0.229 mmol) in dichloromethane (2 mL) was stirred at 20° C. for 2 hours. The reaction mixture was diluted with distilled water (5 mL), extracted with ethyl acetate (3×4 mL), the extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to provide the desired product as a yellow oil (40 mg, 70%). LCMS: m/e 755.68 (M+H)+, 2.42 min (method 11).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([N:9]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[S:16][CH:17]=[C:18](/[CH:20]=[CH:21]/[C:22]([NH:24][O:25]C4CCCCO4)=[O:23])[N:19]=3)[CH2:10]2)=[O:8])=[CH:5][CH:4]=1.C(OCC)C>CO>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[S:16][CH:17]=[C:18](/[CH:20]=[CH:21]/[C:22]([NH:24][OH:25])=[O:23])[N:19]=3)[CH2:10]2)=[O:8])=[CH:32][CH:33]=1
Reactant: O=C(/C=C/c1csc(NC2CCN(C(=O)c3ccc(Cl)cc3)C2)n1)NOC1CCCCO1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(/C=C/c1csc(NC2CCN(C(=O)c3ccc(Cl)cc3)C2)n1)NO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 155.5 %

Procedure:
10% Metallic hydrogen chloride (1.4 mL) was added to the solution of (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (0.6 g) in MeOH (12 ml) and the mixture was stirred at ambient temperature for 3.5 hours. To the reaction mixture was added ethyl ether and isolated precipitate was collected by filtration to give (2E)-3-(2-{[1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-1,3-thiazol-4-yl)-N-hydroxyacrylamide hydrochloride (0.42 g)
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[Cl:15])[C:8]([NH:10][NH2:11])=[O:9])(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].[I-].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>C(O)(C)C>[CH2:23]([N:11]([C:5]1[CH:6]=[CH:7][CH:12]=[CH:13][CH:14]=1)[NH:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:14]([Cl:15])=[C:5]([S:2](=[O:4])(=[O:3])[NH2:1])[CH:6]=1)[CH:24]=[CH2:25]
Reactant: NNC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reactant: C=CCBr
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: C=CCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Yield: 80 %

Procedure:
A mixture of 3-aminosulfonyl-4-chloro-benzhydrazide (326.6g, 1.0 mole) sodium bicarbonate (420.0g, 2.0 mole), potassium iodide (16.6g, 0.1 mole) and allyl bromide (242.0g, 2.0 mole) in isopropanol (1,500 ml) was stirred at gentle reflux for 20 hours, then cooled to 50° and filtered by suction. The cake was washed twice with 100 ml portions of isopropanol. The washes and filtrate were combined and diluted with sufficient water to make a 70% isopropanol solution, then allowed to stir overnight to complete crystallization. The crude product was filtered and washed twice with 100 ml portions of isopropanol-water (70:30). One recrystallization from isopropanol-water (70:30) and clarification with activated charcoal gave pure compound in 80% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[OH-].[K+].[N+:11]([CH2:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:15])#[C-:12]>CO>[N:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[O:8][CH:12]=[N:11][C@H:13]2[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:3][CH:2]=1
Reactant: O=Cc1ccncc1
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccncc1)N1CCCC1
Yield: 98 %

Procedure:
SLA 07092 was prepared in accordance with method D using pyridine-4-carbaldehyde (1.88 mL, 19.76 mmol), KOH (1.01 g, 18.00 mmol) in methanol (18 mL) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (2.73 g, 19.76 mmol). The residue was partitioned between ethyl acetate (200 mL) and water (150 mL). The organic layer was combined with additional ethyl acetate extracts (2×150 mL), washed with aqueous sodium chloride (2×150 mL) and dried over MgSO4, filtered and evaporated. Trans-(4,5-dihydro-5-(pyridin-4-yl)oxazol-4-yl)(pyrrolidin-1-yl)methanone Compound 19 was obtained as a white solid (4.32 g, 98% yield).
Reaction SMILES: C([O:8][CH:9]1[CH2:24][CH2:23][C:12]2([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]2)[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[OH:8][CH:9]1[CH2:10][CH2:11][C:12]2([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:13]2)[CH2:23][CH2:24]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC2(CCC(OCc3ccccc3)CC2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2(CCC(O)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of tert-butyl 7-(benzyloxy)-2-azaspiro[3.5]nonane-2-carboxylate (290 mg, 0.96 mmol, 1.0 equiv) in MeOH (8 mL) was added Pd(OH)2 (43.5 mg, 15 wt %). The mixture was carefully vacuumed and refilled with Hydrogen. The mixture was then stirred at room temperature under hydrogen balloon for 2 hrs. The mixture was passed through a pad of celite and eluted with MeOH (50 mL). The combined methanol solution was concentrated to afford 218 mg (yield 94%) of tert-butyl 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylate as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]([C:9]([CH:15]=[O:16])=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:7]#[N:8])[CH3:2].C(OCC)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([O:3][C:4]1[C:5]([F:17])=[C:6]([C:9]([CH2:15][OH:16])=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:7]#[N:8])[CH3:2]
Reactant: CCOc1cc(C=O)c(C#N)c(F)c1OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1cc(CO)c(C#N)c(F)c1OCC
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a reaction vessel, 3,4-diethoxy-2-fluoro-6-formylbenzonitrile (5.90 kg, 24.87 mol) and ethyl acetate (59.0 L) were added under a nitrogen atmosphere, followed by addition of sodium triacetoxyborohydride (NaB(OAc)3H) (11.70 kg) while stirring. After stirring for 30 min, the inside temperature was raised to 40° C., and the reaction solution was stirred for 2 hours. Then, the reaction solution was cooled. Water (2 L) was added thereto slowly and dropwise at the inside temperature of 15° C. to thereby decompose excessive sodium triacetoxyborohydride. Water (27.5 L) was further added thereto. The temperature of the external bath was raised to 40° C. to dissolve insoluble matter, followed by re-cooling and separation of liquid layers. The resultant organic layer was washed with aqueous sodium bicarbonate solution twice and then with saline. The thus obtained organic layer was cooled with the external bath temperature of 10° C. and left overnight.
Reaction SMILES: [Cl:1][CH2:2]CC1C2C(=CC=CC=2)CCO1.O.[ClH:15].Cl.[CH:17]1([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3OC)[CH2:31][CH2:30]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][O:18]1.C(N(C(C)C)CC)(C)C>C(O)CO>[ClH:1].[ClH:15].[CH:17]1([CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][N:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:2])[CH2:33][CH2:34]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][O:18]1
Reactant: COc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Reactant: ClCCC1OCCc2ccccc21
Agent: Cl
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccccc1N1CCN(CCC2OCCc3ccccc32)CC1
Reaction time: 72 h

Procedure:
A mixture of 1-(2-chloroethyl)isochroman (LXIV, PREPARATION 2, 0.2466 g, 1.25 mmol), 1-(2-methylphenyl)piperazine dihydrochloride (XI, 0.5327 g, 2.14 mmol), diisopropylethylamine (0.98 ml, 5.63 mmol) and ethylene glycol (2.5 ml) is stirred under nitrogen at 100° for 3 days. The reaction mixture is cooled and partitioned between aqueous sodium bicarbonate and ethyl acetate. The combined organic phase is washed with saline, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel eluting with methanol/dichloromethane (2/98). The appropriate fractions are pooled and concentrated to give the free base of the title compound. The dihydrochloride salt is formed using hydrochloric acid/methanol to give the title compound, mp 207.5°-210.5°; MS (m/z) 336; IR (mineral oil) 770, 2406, 2435, 2992, 2364 and 1489 cm-1.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:19][C:12]=3[CH2:11][CH2:10]2)=[O:8])[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.N1CC=CCC1.C(Cl)(Cl)=O.N1(C(Cl)=O)CC=CCC1.Cl.C1C2C=CC(S(N)(=O)=O)=CC=2CCNC1>>[CH:24]1([NH:30][C:31]([NH:23][S:20]([C:18]2[CH:17]=[CH:16][C:13]3[CH2:14][CH2:15][N:9]([C:7]([N:1]4[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]4)=[O:8])[CH2:10][CH2:11][C:12]=3[CH:19]=2)(=[O:22])=[O:21])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C=NC1CCCCC1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CC=CCC1)CC2
Agent: C1=CCNCC1
Agent: Cl
Agent: NS(=O)(=O)c1ccc2c(c1)CCNCC2
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc2c(c1)CCN(C(=O)N1CC=CCC1)CC2

Procedure:
By the reaction of 3-[3,6-dihydro-1(2H)-pyridinecarbonyl]-2,3,4,5-tetrahydro-1H-3benzazepine-7-sulfonamide with cyclohexylisocyanate in a manner analogous to that described in Example 1, there is obtained 1-cyclohexyl-3-{[3-[3,6-dihydro-1(2H)-pyridinecarbonyl]-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-sulfony(} urea, m.p. 173°-174° C. The starting material can be prepared by first reacting 1,2,3,6-tetrahydropyridine with phosgene and subsequently bringing the resulting 3,6-dihydro-1(2H)-pyridinecarbonyl chloride to reaction with 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride.
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[CH2:13]([O:15][C:16](=[O:35])[C@H:17]([OH:34])[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:31]=[CH:30][C:29](=[O:32])[CH2:28][CH2:27]2)=[C:22]([F:33])[CH:21]=1)[CH3:14]>C(#N)C>[CH2:13]([O:15][C:16]([CH:17]1[O:34][C:6](=[O:7])[N:19]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:27]=[CH:28][C:29](=[O:32])[CH2:30][CH2:31]3)=[C:22]([F:33])[CH:21]=2)[CH2:18]1)=[O:35])[CH3:14]
Reactant: CCOC(=O)[C@H](O)CNc1ccc(N2C=CC(=O)CC2)c(F)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CCOC(=O)C1CN(c2ccc(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
CDI (162.0 mg, 1.0 mmol) is added with stirring to a solution of 3-[3-fluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenylamino]-2(R)-hydroxypropionic acid ethyl ester (Step 5, 146.0 mg, 0.45 mmol) in acetonitrile (4.0 mL), and the mixture is stirred at room temperature overnight. Solvent is removed under vacuum, and the residue partitioned between EtOAc (30 mL) and aq. 3% citric acid (30 mL). The aqueous layer is extracted with EtOAc (2×30 mL), and the combined organic layers are washed with water and saline and dried (MgSO4). EtOAc is removed under vacuum to afford the crude 3-[3-fluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid ethyl ester which is used in the next step w/o further purification (MS (m/z): 349 [M+H]+). The ester intermediate is taken up in 2M methanolic ammonia (8.0 mL, 16.0 mmol), and the resulting solution heated in a closed vial at 60° C. for 1 h. Volatiles are removed under vacuum, and the crude material purified by silica gel chromatography (eluent: 2% MeOH in CH2Cl2) to afford the title compound (55.0 mg, 38% for two steps) as white crystals, MS for C15H14FN3O4 m/z 320 (M+H)+; 1H NMR (CD3CN): δ 2.51 (m, 2 H), 3.89 (m, 2 H), 4.05 (m, 1 H), 4.24 (dd, 1 H), 4.97 (m, 1 H), 5.03 (d, 1 H), 6.18 (br. s, 1 H), 6.72 (br. s, 1 H), 7.20-7.40 (m, 3 H), 7.57 (d, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=1.[CH3:23][O:24][C:25](=[O:32])[C@H:26]([CH2:28][CH2:29][S:30][CH3:31])[NH2:27]>>[CH3:23][O:24][C:25](=[O:32])[C@H:26]([CH2:28][CH2:29][S:30][CH3:31])[NH:27][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:9][C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc(Oc2ccccn2)cc1-c1ccccc1
Reactant: COC(=O)[C@@H](N)CCSC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(Oc2ccccn2)cc1-c1ccccc1

Procedure:
The resultant product from Example 6C is coupled to methionine methyl ester according to the procedure of Example 1C to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]([S:15][CH3:16])=[C:11]([CH2:13][CH3:14])[N:12]=1)(C)(C)C>Cl>[CH2:13]([C:11]1[N:12]=[C:8]([NH2:7])[S:9][C:10]=1[S:15][CH3:16])[CH3:14]
Reactant: CCc1nc(NC(=O)OC(C)(C)C)sc1SC
Agent: Cl
Product: CCc1nc(N)sc1SC
Temperature: 30 °C

Procedure:
The above prepared (4-ethyl-5-methylsulfanyl-thiazol-2-yl)-carbamic acid tert-butyl ester (1.067 g, 3.888 mmol) was treated with 20 mL of HCl (4 M in dioxane). After 48 h at RT the reaction mixture was evaporated to dryness and, since still some starting material was present, the procedure repeated, but this time the temperature was raised to 30° C. Careful evaporation and drying left 0.814 g of the title compound as hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(Cc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
To a solution of 4-(4-chloro-benzyl)-phenol (3.08 g, 14 mmol) in DMF (30 mL) at 0-5° C. was added 60% NaH (1.05 g, 26 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (S)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g, 14 mmol) in DMF (20 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to it and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (1.66 g, 30%).
Reaction SMILES: [I-].[CH3:2][O:3][C:4]1[C:9]([CH3:10])=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:5]=1[C:15]1[O:16]CC(C)(C)[N+]=1C.C[OH:24]>[OH-].[Na+]>[CH3:2][O:3][C:4]1[C:9]([CH3:10])=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:7]=[CH:6][C:5]=1[C:15]([OH:16])=[O:24]
Reactant: COc1c(C2=[N+](C)C(C)(C)CO2)ccc(C(F)(F)F)c1C
Reactant: CO
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C(=O)O)ccc(C(F)(F)F)c1C
Temperature: 25 °C

Procedure:
A solution of 515 mg (1.2 mmol) 2-(2-methoxy-3-methyl-4-trifluoromethyl-phenyl)-3,4,4-trimethyl-4,5-dihydro-oxazol-3-ium iodide in 5 ml methanol and 5 ml 20% NaOH was heated to 70° C. for 17 h. The yellow solution was cooled to rt, methanol was distilled off, the residue acidified with conc. HCl to pH 1 and extracted three times with tert-butyl methyl ether. The combined organic phases were washed twice with brine, dried over Na2SO4, filtered and evaporated: 2-Methoxy-3-methyl-4-trifluoromethyl-benzoic acid was obtained as yellow solid: MS (ISN): 233.04 ((M−H)−).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH2:5][CH2:6][NH:7][C:8](=[O:44])[CH:9]([NH:23][C:24](=[O:43])[C@@H:25]([S:33]CC1C=CC(OC)=CC=1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)=[O:11]>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][C:47]=1[Cl:48])[CH2:5][CH2:6][NH:7][C:8](=[O:44])[CH:9]([NH:23][C:24](=[O:43])[CH:25]([SH:33])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:10]([NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)=[O:11]
Reactant: COc1ccc(CS[C@@H](Cc2ccccc2)C(=O)NC(C(=O)NCCc2ccc(Cl)c(Cl)c2)C(=O)NCCc2ccc(Cl)c(Cl)c2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(NC(C(=O)NCCc1ccc(Cl)c(Cl)c1)C(=O)NCCc1ccc(Cl)c(Cl)c1)C(S)Cc1ccccc1

Procedure:
Prepare by the method of Example 15.2 using N,N′-di-(3,4-dichlorophenethyl)-2-((S)-2-(p-methoxybenzylmercapto)-3-phenylpropionylamino)malonamide (0.166 g, 0.222 mmol). Coevaporation with carbon tetrachloride gives the title compound.