Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16]S(C)(=O)=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH2:14][CH2:15][O:16][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)[N:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)Nc1nc(CCOS(C)(=O)=O)cs1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1nc(CCOc2ccc(F)cc2)cs1
Temperature: 80 °C
Yield: 42 %

Procedure:
To a mixture of Methanesulfonic acid 2-(2-tert-butoxycarbonylamino-thiazol-4-yl)-ethyl ester (6.0 g, 18 mmol) and 4-fluoro phenol (5.21 g, 46 mmol) in Toluene (60 ml) K2Co3 (7.7 g, 55 mmol) was added and heated at 80° C. for 18 h. The reaction mixture was filtered to remove solid residues, washed with ethyl acetate (50 ml) and combined organic layer washed with brine (20 ml) dried over Na2SO4. Solvent was removed under reduced pressure, crude product was purified by column chromatography using 1:10 EtOAC and Hexanes to obtain {4-[2-(4-Fluoro-phenoxy)-ethyl]-thiazol-2-yl}-carbamic acid tert-butyl ester (2.56 g, 40%). 1H NMR (400 MHz, CDCl3): 1.53 (s, 9H), 3.09 (t, J=6.4 Hz, 2H), 4.20 (t, J=6.4 Hz, 2H), 6.21 (s, 1H), 6.811-6.84 (m, 2H), 6.95 (t, J=8.8 Hz, 2H). 8.28 (brs, 1H). MS (EI) m/z: 338.89 (M+1).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>ClCCl>[CH3:26][S:23]([O:1][CH2:2][C@H:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CO)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCO[C@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
To a solution of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (3.0 g, 13.8 mmol) and triethylamine (4.2 g, 41.4 mmol) in dichloromethane (80 mL) at 0° C. was dropwise added mesyl chloride (1.9 g, 16.5 mmol). The reaction mixture was stirred at 0° C. for 2 hour, and then diluted with dichloromethane (100 mL). The organic layers were washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated to afford (S)-tert-butyl 2-((methylsulfonyloxy)methyl)morpholine-4-carboxylate as a purple oil (4.0 g, 98%), which was directly used in the next step without further purification. MS (ES+) C11H21NO6S requires: 295, found: 240 [M+H-56]+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][S:28](=[O:32])(=[O:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:30][CH2:29][S:28](=[O:31])(=[O:32])[CH2:27][CH2:26]2)=[O:24])=[CH:36][CH:35]=1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1ccc(Cl)cc1)N1CCN(C2CCCC2)CC1
Yield: 34 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxo-thiomorpholin-4-yl)-methanone (example 34), 4-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless solid (34%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1.[CH2:27]([OH:30])[CH2:28][OH:29]>>[OH:29][CH2:28][CH2:27][O:30][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1
Reactant: OCCO
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Product: CCCOc1ccc(COCCO)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 45 %

Procedure:
This compound was prepared from 5-(5-chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one and ethylene glycol following the procedure of Example 38 and was obtained as a white solid (45%), m.p. 101°-102° C. Found C,63.13; H,6.88; N,13.98. C21H28N4O4 requires C,62.98; H,7.05; N,13.99%.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[CH3:11][O:12][CH2:13][CH2:14]Br>C(O)C>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:14][CH2:13][O:12][CH3:11])[CH3:2]
Reactant: CCNCc1ccccc1
Reactant: COCCBr
Solvent: CCO
Product: CCN(CCOC)Cc1ccccc1
Yield: 47 %

Procedure:
The synthesis of BnEA was carried out in a manner similar to that of BnEO (process 2) using N-ethylbenzylamine (15 mL, 0.101 mol), bromoethyl methyl ether (0.101×1.2 mol), and ethanol (100 mL) as a solvent. BnEA (9.17 g, 47.46 mmol, yield 47%) was obtained as a yellow-orange clear liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:28]=[N:27][NH:26][C:5]2=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=[C:15]([Cl:17])[CH:16]=1)[O:8][C:7]2=[O:25].[CH:29]([NH2:32])([CH3:31])[CH3:30]>O1CCCC1>[CH:29]([NH:32][C:7]([C:6]1[C:11]([NH:10][C:9]([C:12]2[N:13]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:14]=[C:15]([Cl:17])[CH:16]=2)=[O:8])=[C:2]([Cl:1])[CH:3]=[C:4]2[C:5]=1[NH:26][N:27]=[CH:28]2)=[O:25])([CH3:31])[CH3:30]
Reactant: CC(C)N
Reactant: O=c1oc(-c2cc(Cl)nn2-c2ncccc2Cl)nc2c(Cl)cc3cn[nH]c3c12
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(Cl)nn2-c2ncccc2Cl)c(Cl)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.3 %

Procedure:
To a suspension of 210 mg (0.40 mmol) of the above 5-chloro-7-[5-chloro-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-1H-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalen-9-one in 4.2 mL of tetrahydrofuran is added 110 μl (1.3 mmol) of isopropylamine. The reaction mixture is stirred for 4 hours at ambient temperature and then concentrated in vacuo. The residue is Purification of the residue by reverse-phase chromatography affords 111 mg (52%) of the product as a white solid; LC/MS:514/516 (M+Na)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[OH:8].[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].CCOCC>CO.[Pt]=O>[C:20]([OH:27])(=[O:26])/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24].[CH3:2][C:3]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH:7]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)[OH:8]
Reactant: Cc1ccc(OCC(O)c2ccccn2)c(C)c1
Agent: O=[Pt]
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: CCOCC
Product: Cc1ccc(OCC(O)C2CCCCN2)c(C)c1
Reaction time: 8 h
Yield: 52.9 %

Procedure:
A solution of α-[(2,4-dimethylphenoxy)methyl]pyridine-2-methanol hydrochloride (10.0 g, 0.0347 mole) in 200 ml of methanol was hydrogenated at room temperature with 1.4 g of platinum oxide for 1/2 hr. The methanol solution was filtered and solvent removed on the rotary evaporator. The resulting material was dissolved in water, made basic with 10% sodium hydroxide and the free base was extracted into methylene chloride. Removal of methylene chloride on the rotary evaporator gave a yellow oil. While standing overnight the oil crystallized to give a white solid (softens 75°-78° C., 78°-90° C. m.p.). The free base was dissolved in methanol and treated with a methanol solution of an equimolar quantity of fumaric acid. A crystalline white solid was obtained by adding ether, and upon recrystallization from methanol-ethyl ether, 5.81 g (52.9%) of crystalline white product was obtained, m.p. 208°-212° C. with decomposition.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([NH2:18])=[O:17])[CH2:15][C@@:9]1([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:10]([O:19][CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:42][C:43](=O)[CH3:44].CN(C)C=O>C(OCC)C>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]3[O:17][CH:42]=[C:43]([CH3:44])[N:18]=3)[CH2:15][C@@:9]1([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C@H:10]([O:19][CH2:20][C:21]1[CH:22]=[C:23]([C:31]([F:32])([F:33])[F:34])[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: NC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1coc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 120 °C
Reaction time: 24 h
Yield: 12 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl) phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octan-6-carboxamide (Example 75; 250 mg, 0.44 mmol), chloroacetone (1 ml) and N,N-dimethylforamide (4 ml) was stirred at 120° C. for 24 hours. After cooling to room temperature the reaction mixture was diluted with diethyl ether (70 ml), washed with saturated aqueous NaHCO3, water and brine. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate) to give the title compound (53 mg, 12%).
Reaction SMILES: [OH:1][CH:2]([CH:6]([S:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([OH:5])=[O:4].[C:33]1([C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[N+]=[N-])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH:6]([S:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([O:5][CH:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:4]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: O=C(O)CCSC(c1ccccc1CCCCCCCCc1ccccc1)C(O)C(=O)O
Solvent: Cc1ccccc1
Product: O=C(O)CCSC(c1ccccc1CCCCCCCCc1ccccc1)C(O)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 45 °C

Procedure:
A partially dissolved mixture of 2-hydroxy-3-[(2-carboxyethyl)thio]-3-[2-(8-phenyloctyl)phenyl]propanoic acid prepared as in Example 20(c) (2.3 g, 5 mmol) in 25 ml of toluene was heated in an oil bath at 45° C. and stirred under argon while a solution of diphenyldiazomethane (1.02 g, 5.26 mmol) in 25 ml of toluene was added dropwise over a period of 20 minutes. The solvent was evaporated and the residue was flash chromatographed on silica gel (30% EtOAc/hexane, 1% HCO2H) to give the product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1.[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([F:26])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:27][CH2:28][CH:29]=O.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([F:26])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH2:27][CH2:28][CH2:29][NH:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1
Reactant: NC1COc2ccc3c(c2C1)C(=O)NC3
Reactant: O=CCCc1c[nH]c2c(F)cc(F)cc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C1NCc2ccc3c(c21)CC(NCCCc1c[nH]c2c(F)cc(F)cc12)CO3
Reaction time: 2 h

Procedure:
To a mixture of (1) (202 mg, 0.99 mmol), 3-(5,7-difluoro-1H-indol-3-yl)propanal ((41), 247 mg, 1.09 mmol) in acetic acid (145 μl, 2.36 mmol) and methanol (10 ml) was added NaBH3CN (126 mg, 2.00 mmol) in portions. Resulting mixture was stirred for 2.0 hr. The solvent was removed in vacuo and the residue was dissolved in CH2Cl2 and washed with 1 N NaOH and saturated NaCl. The organic solution was dried over Na2SO4 and concentrated in vacuo. The compound was purified on silica gel eluting with 70% EtOAc/Hexane to give (18), which was treated with 1 equivalent of etherate HCl to form HCl salt. MS (ES) m/z 412.2.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[N:19]=[C:18]([C:20]([N:22]([CH2:28][CH2:29][CH3:30])[C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[O:21])[CH:17]=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:27][N:25]([CH3:26])[C:23]([N:22]([C:20]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([C:12]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:13]=2)[N:19]=1)=[O:21])[CH2:28][CH2:29][CH3:30])=[O:24]
Reactant: CCCN(C(=O)c1cccc(C#N)n1)C(=O)N(C)C
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCN(C(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1)C(=O)N(C)C
Yield: 73 %

Procedure:
A mixture of methyl thiosalicylate (1.6 g, 9.6 mmol), N-[(6-cyano-2-pyridyl)carbonyl]-N′,N′-dimethyl-N-propylurea (1.2 g, 4.7 mmol), triethylamine (2.0 ml, 14 mmol) and toluene (4 ml) was refluxed for 9 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-tetrahydrofuran to give the titled compound (1.36 g, 72%) as crystals.
Reaction SMILES: N#N.C(OC(=O)[NH:9][C:10]1[N:11]=[C:12]([CH2:15][C:16]2[S:17][C:18]([C:21](=[O:23])[CH3:22])=[CH:19][CH:20]=2)[S:13][CH:14]=1)(C)(C)C.[ClH:25]>C(Cl)Cl.O1CCOCC1>[ClH:25].[NH2:9][C:10]1[N:11]=[C:12]([CH2:15][C:16]2[S:17][C:18]([C:21](=[O:23])[CH3:22])=[CH:19][CH:20]=2)[S:13][CH:14]=1
Reactant: CC(=O)c1ccc(Cc2nc(NC(=O)OC(C)(C)C)cs2)s1
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)c1ccc(Cc2nc(N)cs2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-acetyl-thiophen-2-ylmethyl)-thiazol-4-yl]-carbamic acid tert-butyl ester (75 mg, 0.22 mmol) in dry CH2Cl2 (2.2 mL) was treated at 0° C. with HCl (0.55 mL of a 4M solution in dioxane, 2.22 mmol). After stirring at 0° C. for 1 h, the reaction mixture was stirred at rt for 16 h. The solvents were removed under reduced pressure to give the title compound as a light brown solid. LC-MS-conditions 02: tR=0.71 min, [M+AcCN+H]+=280.14.
Reaction SMILES: Cl.[NH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[C:12]([OH:14])=[O:13].[C:15]([S:18][CH2:19][CH:20]([CH2:24][S:25][C:26](=[O:28])[CH3:27])[C:21](Cl)=[O:22])(=[O:17])[CH3:16].Cl>N1C=CC=CC=1>[C:15]([S:18][CH2:19][CH:20]([CH2:24][S:25][C:26](=[O:28])[CH3:27])[C:21]([N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[C:12]([OH:14])=[O:13])=[O:22])(=[O:17])[CH3:16]
Reactant: O=C(O)C1CCc2ccccc2N1
Reactant: CC(=O)SCC(CSC(C)=O)C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)SCC(CSC(C)=O)C(=O)N1c2ccccc2CCC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (±)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid hydrochloride (14.52 g) in pyridine (150 ml) was treated dropwise with 3-acetylthio-2-(acetylthiomethyl)propanoyl chloride with vigorous stirring. After stirring overnight at room temperature, the mixture was added to ice (300 g) and the pH was adjusted to 2.5 with concentrated hydrochloric acid. The mixture was extracted with ether and the ether extract dried over sodium sulfate and evaporated to a syrup. This (±) 1-(3-acetylthio-2-acetylthiomethyl-1-oxopropyl)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid was further purified by column chromatography (silica gel, toluene:ethyl acetate:acetic acid, 6.5:3:0.5); yield 2.5 g, m.p. 149°-151°.
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>C(O)(=O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:5][CH2:6][C:2]([N:1]=[CH:24][C:23]3[CH:26]=[CH:27][C:20]([O:19][CH3:18])=[CH:21][CH:22]=3)=[N:3]2)=[CH:8][C:9]=1[C:14]([F:17])([F:15])[F:16]
Reactant: NC1=NN(c2ccc(Br)c(C(F)(F)F)c2)CC1
Reactant: COc1ccc(C=O)cc1
Solvent: CC(=O)O
Product: COc1ccc(C=NC2=NN(c3ccc(Br)c(C(F)(F)F)c3)CC2)cc1
Yield: 90.4 %

Procedure:
3-Amino-1-(4-bromo-3-trifluoromethylphenyl)-2-pyrazoline (prepared in Example 39 of our European patent specification No. 22-578) (240 mg) in S.V.M. (5 ml) together with 4-methoxybenzaldehyde (160 mg) and 1 drop of glacial acetic acid were heated to reflux for 1 hour. A yellow product separated which was collected, washed with methanol and dried in vacuo to yield 300 mg 1-(4-bromo-3-trifluoromethylphenyl)-3-(4-methoxybenzylideneamino)-2-pyrazoline, m.p. 175°-176° (decomp).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].Br[CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]>>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: COC(=O)CCCCBr
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Product: COC(=O)CCCCOc1cccc(C(=O)OC)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Yield: 75.2 %

Procedure:
In the same manner as described in Example 38, 050 g (1.171 mmol) of the product of Example 37 and 0.419 mL (2.927 mmol) of methyl 5-bromovalerate provided 0.477 g (75%) of the desired product as a white solid. Electrospray Mass Spec: 542.3 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.[F:27][C:28]([F:46])([F:45])[C:29]1[CH:30]=[C:31]([CH:42]=[CH:43][CH:44]=1)[CH2:32][N:33]1[CH2:37][C@H:36]2[C@H:38]([NH2:41])[CH2:39][CH2:40][C@H:35]2[CH2:34]1.CN(C)CCCN=C=NCC>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([NH:41][C@H:38]1[C@H:36]2[C@H:35]([CH2:34][N:33]([CH2:32][C:31]3[CH:42]=[CH:43][CH:44]=[C:29]([C:28]([F:46])([F:27])[F:45])[CH:30]=3)[CH2:37]2)[CH2:40][CH2:39]1)=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H]1CC[C@H]2CN(Cc3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
N-(tert-Butoxycarbonyl)-L-leucine (180 mg, 0.778 mmol), hydroxybenzotriazole (119 mg, 0.778 mmol), and (3aS,4R,6aR)-2-(3-(trifluoromethyl)benzyl)octahydrocyclopenta[c]pyrrol-4-amine (201 mg, 0.707 mmol) from Example 154 Step A were combined in dichloromethane (1 mL). After 20 minutes, N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.138 mL, 0.778 mmol) was added and the reaction stirred at room temperature for 24 hours. The reaction was quenched with water, and the layers were separated. The aqueous layer extracted with 1 mL of dichloromethane. The combined organic layers were applied to a silica gel cartridge (Analogix®, Burlington, Wis., RS15-24) and eluted with 1-10% methanol (2 N ammonia)/dichloromethane to give N2-(tert-butyloxycarbonyl)-N1-{(3aS,4R,6aR)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}-L-leucinamide: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.66 (d, J=7.1, 1H), 7.97 (d, J=8.5, 1H), 7.73 (s, 1H), 7.56 (s, 2H), 7.44 (t, J=7.7, 1H), 4.70 (dd, J=5.9, 11.0, 1H), 4.40 (br s, 1H), 3.56 (d, J=13.5, 1H), 3.41 (d, J=13.5, 1H), 2.74 (d, J=8.9, 1H), 2.48 (s, 2H), 2.37-2.31 (m, 1H), 2.27 (d, J=8.4, 1H), 2.24-2.19 (m, 1H), 2.12 (dq, J=6.0, 12.0, 1H), 1.91-1.81 (m, 4H), 1.66 (td, J=7.4, 14.7, 1H), 1.50 (s, 9H), 1.43-1.35 (m, 1H), 0.87 (d, J=5.9, 3H), 0.84 (d, J=5.6, 3H); MS (ESI+) m/z 498 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:23])([CH3:22])[C:7](=[O:21])[N:8]2[C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:36]([O:35][C:33](=[O:34])[CH2:32][N:18]1[CH2:19][CH2:20][CH:15]([CH2:14][NH:13][C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:10]=3)[C:6]([CH3:23])([CH3:22])[C:7]2=[O:21])=[O:12])[CH2:16][CH2:17]1)([CH3:39])([CH3:38])[CH3:37]
Reactant: CC1(C)C(=O)N(C(=O)NCC2CCNCC2)c2cc(F)ccc21
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCC(CNC(=O)N2C(=O)C(C)(C)c3ccc(F)cc32)CC1
Temperature: 35 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
A solution of 6-fluoro-3,3-dimethyl-2-oxo-N-(piperidin-4-ylmethyl)indoline-1-carboxamide (200 mg, 0.63 mmol, step 2 in Example 17) and triethylamine (114 μL, 0.82 mmol) in tetrahydrofuran (3 mL) was stirred at 0° C., it was slowly added tert-butyl bromoacetate (111 μL, 0.75 mmol). The reaction mixture was stirred at room temperature for 5 h and at 35° C. for 4 h. It was further added triethylamine (17 μL, 0.12 mmol) and tert-butyl bromoacetate (18 μL, 0.12 mmol). The solution was stirred at room temperature overnight. The resulting solution was added sat. sodium bicarbonate. It was extracted with ethyl acetate (10 mL×3). The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was chromatographed on a column of aminopropyl-silica gel eluting with ethyl acetate/hexane (1:10 to 1:6) to give 203 mg (74%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)(O)[C:13]([F:16])([F:15])[F:14])[C:6]3[CH2:25][CH2:26][N:27]([CH3:29])[CH2:28][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)\[C:13]([F:16])([F:15])[F:14])[C:6]3[CH2:25][CH2:26][N:27]([CH3:29])[CH2:28][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(c2ccc(F)cc2)C(F)(F)F)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CN1CCc2c(c3cc(Cl)ccc3n2/C=C(/c2ccc(F)cc2)C(F)(F)F)C1
Temperature: 5 °C

Procedure:
3-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1,1,1-trifluoro-2-(4-fluorophenyl)propan-2-ol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%).
Reaction SMILES: [N:1]([CH2:4][C:5]([CH2:7][O:8][C:9](=[O:11])[CH3:10])=[O:6])=[N+]=[N-].[N-]=[N+]=[N-]>C(OC(=O)C)C.[Pd]>[NH2:1][CH2:4][C:5]([CH2:7][O:8][C:9](=[O:11])[CH3:10])=[O:6]
Reactant: CC(=O)OCC(=O)CN=[N+]=[N-]
Agent: [Pd]
Agent: [N-]=[N+]=[N-]
Solvent: CCOC(C)=O
Product: CC(=O)OCC(=O)CN

Procedure:
1-Azido-3-acetoxyacetone (15.7 g.) is dissolved in ethylacetate (200 ml.). The 10% palladium on carbon catalyst (1.0 g.) is added; the mixture is reduced under hydrogen at atmospheric pressure until the infrared spectrum of an aliquot indicates the absence of the azide. The catalyst is filtered off and the filtrate is evaporated to afford 1-amino-3-acetoxy acetone.