Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([C:11](=[O:21])[C:12]3[C:18]([Br:19])=[C:17]([Br:20])[S:16][C:13]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CC(O)=O.C([O-])(O)=O.[Na+]>CO>[CH2:1]([N:8]1[CH2:15][CH:14]2[CH:10]([CH:11]([OH:21])[C:12]3[C:18]([Br:19])=[C:17]([Br:20])[S:16][C:13]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(sc(Br)c2Br)C2CN(Cc3ccccc3)CC12
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: OC1c2c(sc(Br)c2Br)C2CN(Cc3ccccc3)CC12
Temperature: 22 °C
Yield: 91 %

Procedure:
The product of step e) (325 mg, 0.76 mmol) was dissolved in MeOH (10 ml) and treated with NaBH4 (289 mg, 7.6 mmol) at 0° C. Next, the reaction was warmed to 22° C. and, after 2 hours, AcOH was added dropwise until gas evolution ceased. The quenched reaction mixture was slowly poured saturated NaHCO3 (100 ml). The aqueous mixture was extracted with EtOAc (2×50 ml), dried (MgSO4) and concentrated providing the subtitle product (298 mg, 91%). MS calculated for C16H15Br2NOS+H 430, observed 428, 430, 432.
Reaction SMILES: Cl[C:2]([N:4]1[CH2:7][CH:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH2:5]1)=[O:3].C(=O)([O-])[O-].[K+].[K+].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.C1C=CC=CC=1>[F:16][C:15]([F:18])([F:17])[C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH:6]1[CH2:7][N:4]([C:2]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:3])[CH2:5]1
Reactant: C1CCNCC1
Reactant: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: O=C(N1CCCCC1)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Temperature: -70 °C

Procedure:
A solution of 5.6 g (0.02 mole) of 1-chlorocarbonyl-3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml of tetrahydrofuran was treated with 3 g (0.022 mole) of potassium carbonate and while stirring, 1.9 g (0.022 mole) of piperidine was added dropwise. The mixture was then treated with 10 g of ice and stirred for 2 hr. The tetrahydrofuran was decanted then concentrated on a rotary evaporator to yield an amber oil, 6.0 g. The oil was dissolved in benzene, washed with dilute acid then water, dried over magnesium sulfate and concentrated in vacuo. This oil crystallized when cooled to -70° C. and was recrystallized from hexane with charcoal treatment at 0° C. yielding pale tan crystals, 4.5 g (68.5%), m.p. 50°-52° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]([C:14]1[C:18]2[N:19]=[C:20](Cl)[N:21]=[CH:22][C:17]=2[S:16][CH:15]=1)=[O:13].[C@@H:24]1([NH2:31])[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]1[NH2:30].ClCCl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12]([C:14]1[C:18]2[N:19]=[C:20]([NH:30][C@@H:25]3[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]3[NH2:31])[N:21]=[CH:22][C:17]=2[S:16][CH:15]=1)=[O:13]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: COc1ccc(NC(=O)c2csc3cnc(Cl)nc23)c(OC)c1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2csc3cnc(N[C@@H]4CCCC[C@@H]4N)nc23)c(OC)c1

Procedure:
To a solution of 0.047 g (0.134 mmole) 2-chloro-thieno[3,2-d]pyrimidine-7-carboxylic acid(2,4-dimethoxy-phenyl)-amide in 1.34 mL of dioxane was added 0.0967 mL (0.806 mmole) of (cis-cyclohexane-1,2-diamine. The mixture was heated at 100 degrees for over night. Dichloromethane was added and washed with aqueous sodium bicarbonate. The aqueous layer was washed twice with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-0.7 N ammonia solution in methanol (gradient 100:0-90:10) gave 0.052 g of 2-(cis-2-amino-cyclohexylamino)-thieno[3,2-d]pyrimidine-7-carboxylic acid (2,4-dimethoxy-phenyl)-amide as a yellow solid. MH+/Z=428
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:32]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:17]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)[N:12]3[N:11]=2)=[CH:5][CH:4]=1)#[N:2].BrC1N2N=C(NC3C=CC(C#N)=CC=3)N=C2C=CC=1.N[C@H]1CCCN(C(OC(C)(C)C)=[O:60])C1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.[Cl-].[Na+].O>[NH:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][C:17]2[N:12]3[N:11]=[C:10]([NH:9][C:6]4[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:60])=[CH:4][CH:5]=4)[N:32]=[C:13]3[CH:14]=[CH:15][CH:16]=2)[CH2:20]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](Nc2cccc3nc(Nc4ccc(C#N)cc4)nn23)C1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N#Cc1ccc(Nc2nc3cccc(Br)n3n2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)c1ccc(Nc2nc3cccc(N[C@H]4CCCNC4)n3n2)cc1
Temperature: 100 °C
Yield: 35 %

Procedure:
(S)-tert-Butyl 3-(2-(4-cyanophenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)piperidine-1-carboxylate. To an orange solution of 4-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)benzonitrile (0.250 g, 0.796 mmol) in dioxane (10 mL) was added (5)-tert-butyl 3-aminopiperidine-1-carboxylate (0.319 g, 1.592 mmol), cesium carbonate (0.519 g, 1.592 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.092 g, 0.159 mmol) and tris(dibezylideneacetone)palladium (0.077 g, 0.084 mmol) at room temperature under nitrogen. The reaction mixture was heated at 100° C. for 1.5 h under nitrogen. Upon completion of the reaction as indicated by LCMS the reaction mixture was poured into brine, and extracted with ethyl acetate several times. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified by column chromatography (eluting with 0-80% ethyl acetate in hexanes) to give the title compound as a tan solid (0.122 g, 35% yield). MS (ESI) m/z 434.51 [M+1]+.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[C:7]([CH2:9][Br:10])[CH:6]=[C:5]([CH2:11][Br:12])[CH:4]=1.F[B-](F)(F)F.[O:18]=[N+:19]=[O:20].O>CC#N>[Br:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:11][Br:12])[CH:6]=[C:7]([CH2:9][Br:10])[C:8]=1[N+:19]([O-:20])=[O:18]
Reactant: BrCc1cc(CBr)cc(CBr)c1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1c(CBr)cc(CBr)cc1CBr
Reaction time: 0.33 h
Yield: 86.4 %

Procedure:
To a solution of 5 g (0.014 mole) of the tribromide 8 in 100 ml of CH3CN was added, at room temperature and under argon atmosphere, in a dropwise fashion 3.72 g (0.028 mole) of nitronium tetrafluoroborate in 200 ml of CH3CN. The solution was then stirred for 20 minutes longer, poured into water and the mixture extracted with CH2Cl2. The CH2Cl2 extracts were washed with 10% NaHCO3, dried (Na2SO4) and solvents removed to afford 4.86 g (86%) of the desired nitro compound 27: NMR (CDCl3) 4.5 (s,6,--CH2Br), 7.55 (s,--C6H2).
Reaction SMILES: [C:1]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([C:9]1[CH:33]=[CH:32][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Solvent: CO
Product: COC(=O)CCc1ccc(OCCn2c(=O)sc3cc(Cc4ccccc4)ccc32)cc1

Procedure:
The procedure is as in Example 48, starting from the compound obtained in Example 32. The recrystallisation solvent is methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[C:20]3[C:15](=[C:16]([F:22])[CH:17]=[CH:18][C:19]=3[F:21])[O:14][CH2:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Si](C)(C)[O:25][C:26](=[CH2:29])[CH:27]=[CH2:28]>FC(F)(F)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]23[CH2:28][CH2:27][C:26](=[O:25])[CH2:29][CH:12]2[CH2:13][O:14][C:15]2[C:20]3=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(C1=CCOc2c(F)ccc(F)c21)c1ccc(Cl)cc1
Reactant: C=CC(=C)O[Si](C)(C)C
Solvent: FC(F)(F)c1ccccc1
Product: O=C1CCC2(S(=O)(=O)c3ccc(Cl)cc3)c3c(F)ccc(F)c3OCC2C1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A mixture of 10.8 g (31.5 mmol) of the vinylsulphone product of step 3 of Example 17 and 24 g (165 mmol) of the 3-trimethylsiloxy-1,3-butadiene in 100 mL of trifluorotoluene in a sealed tube was heated at 150° C. for 15 h. It was concentrated, the residue was dissolved in 50 mL of THF. To this solution was added 3 mL of 1N HCl, the mixture was stirred at room temperature for 30 min. It was diluted with 300 mL of methylene chloride, washed with 50 mL of brine, and concentrated. The residue was recrystallized from ethyl acetate to give 6.8 g of the ketone. Chromatography of the mother liquid gave additional 3.4 g of the ketone.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH2:22][CH2:23][NH:24]C(=O)OC(C)(C)C)[CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([CH3:32])[CH:4]=1)#[N:2]>Cl>[NH2:24][CH2:23][CH2:22][N:10]1[CH:11]=[CH:12][C:13]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:9]1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:32]
Reactant: COc1ccc(-c2ccn(CCNC(=O)OC(C)(C)C)c2-c2ccc(C#N)cc2C)cc1
Agent: Cl
Product: COc1ccc(-c2ccn(CCN)c2-c2ccc(C#N)cc2C)cc1
Yield: 118.3 %

Procedure:
A solution of tert-butyl 2-(2-(4-cyano-2-methylphenyl)-3-(4-methoxyphenyl)-1H-pyrrol-1-yl)ethylcarbamate (6-1) (110 mg, 0.255 mmol) in methanolic hydrochloride solution (2 M, 5 mL) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to give the title compound 6-2 (100 mg), which was used directly in the next step.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([C:42]([NH:44][C:45]3[CH:50]=[CH:49][C:48]([C:51]4[CH:59]=[C:58]5[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[C:57]5=[O:60])=[CH:53][CH:52]=4)=[CH:47][CH:46]=3)=[O:43])=[CH:41][C:36]=2[O:35][CH2:34]1>>[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([C:42]([NH:44][C:45]3[CH:46]=[CH:47][C:48]([C:51]4[CH:59]=[C:58]5[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([OH:64])=[O:63])[C:57]5=[O:60])=[CH:53][CH:52]=4)=[CH:49][CH:50]=3)=[O:43])=[CH:41][C:36]=2[O:35][CH2:34]1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc5c(c4)OCO5)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc5c(c4)OCO5)cc3)cc2C1=O
Yield: 64.6 %

Procedure:
The compound of example 128 was prepared analogous to compound of example 98 by hydrolysis of compound of example 127.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)[C:10]([NH2:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:33]2)=CC=1>O1CCOCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([C:10](=[S:33])[NH2:12])[CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc2ccccc2c1)C(N)=S
Temperature: 60 °C
Reaction time: 12 h
Yield: 157.2 %

Procedure:
(2R)-2-tert-Butoxycarbonylamino-3-(2-naphthyl)propionic acid amide (1.058 g; 3.36 mmol) and 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) (0.71 g; 1.76 mmol) were dissolved in dioxane (6 ml). The reaction mixture was heated 30 min at 60° C. and stirred 12 hours at room temperature. The solvent was removed in vacuo and to the residue was added a mixture of water/sodium hydrogencarbonate (1:1; 15 ml) and stirred 30 min at room temperature. The mixture was filtered. The solid was washed with water (2×5 ml) and chromatographed on silica (2×15 cm) using ethyl acetate/heptane (2:1) to afford 0.914 g of ((1R)-2-(2-naphthyl)-1-thiocarbamoylethyl)carbamic acid tert-butylester.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[C:17]([O:24][CH3:25])[CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>B#[Ni]>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[C:17]([O:24][CH3:25])[CH:16]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(=O)O[C@H]2CCN(Cc3ccccc3)C2)ccc1[N+](=O)[O-]
Agent: B#[Ni]
Product: COc1cc(C(=O)O[C@H]2CCN(Cc3ccccc3)C2)ccc1N

Procedure:
The aniline was prepared by nickel boride reduction of 3-methoxy-4-nitro-benzoic acid (3S)-1-benzyl-pyrrolidin-3-yl ester analogously to the preparation of 4-[(Benzyl-methyl-amino)-methyl]-2-methoxy-phenylamine used in the synthesis of Compound 340. 1H-NMR (400 MHz, CDCl3) δ 7.54 (d, J=8.21 Hz, 1H), 7.44 (s, 1H), 7.2-7.4 (m, 5H) 6.65 (d, J=8.21 Hz, 1H), 5.38 (br.m, 1H), 4.22 (s, 1H), 3.90 (s, 3H), 3.69 (q, J=24.63 Hz, 1H), 3.0 (m, 1H), 2.7-2.9 (m, 2H), 2.5-2.6 (m, 1H), 2.3-2.4 (m, 1H), 1.9-2.1 (m, 1H). MS apci-pos (M+1=327.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1
Reactant: BrCCCCBr
Reactant: O=C1CCc2ccc(O)cc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1CCc2ccc(OCCCCBr)cc2N1
Yield: 68.4 %

Procedure:
To a solution of 4.06 g of potassium carbonate with 400 ml of water was added 40 g of 7-hydroxy-3,4-dihydrocarbostyril and 158 g of 1,4-dibromobutane, then the mixture was refluxed for 3 hours. The reaction mixture thus obtained was extracted with dichloromethane, dried with anhydrous magnesium sulfate, then the solvent was removed by evaporation. The residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane), and recrystallized from n-hexane-ethanol to yield 50 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:12]C(=O)N(C)C)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.[OH-].[Na+]>CO>[Cl:1][C:2]1[C:3]([SH:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2
Reactant: CN(C)C(=O)Sc1ccc2ccncc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Sc1ccc2ccncc2c1Cl

Procedure:
To a stirred solution (213 g., 0.08 m.) of 8-chloro-7-dimethylcarbamoylthioisoquinoline in 750 ml of methanol was slowly added 77 ml. of 10% aqueous sodium hydroxide under a nitrogen atmosphere. The resulting solution is refluxed 1.5 hours, cooled, concentrated at reduced pressure, diluted with 90 ml. of water and adjusted to pH 6-7 with glacial acetic acid. The resulting precipitate was collected by filtration, washed with cold water and dried to yield 8-chloro-7-mercaptoisoquinoline, m.p. 118°-122° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]3[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:9]=3[CH2:8][C:7]=2[CH:24]=1.COC1C=CC2CC(CC(OCC)=O)C3C=CC=CC=3CC=2C=1>CO>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:12][CH:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]3[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:9]=3[CH2:8][C:7]=2[CH:24]=1
Reactant: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2c(C)cccc21
Agent: CCOC(=O)CC1Cc2ccc(OC)cc2Cc2ccccc21
Solvent: CO
Product: CCOC(=O)CC1Cc2ccc(O)cc2Cc2c(C)cccc21

Procedure:
According to the procedure of Preparation 10 (g), except substituting ethyl (±)-10,11-dihydro-3-methoxy-6-methyl-5H-dibenzo[a,d]cycloheptene-10-acetate for the ethyl (±)-10,11-dihydro-3-methoxy-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was obtained as a white solid after trituration with MeOH: MS (ES) m/e 311.2 (M+H)+.
Reaction SMILES: [C:1]([CH2:9][C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:22])=[N-]>CO.C(O)(=O)C>[CH3:22][O:15][C:14](=[O:16])[C@@H:13]1[CH2:17][CH2:18][CH2:19][N:12]1[C:10](=[S:11])[CH2:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC(=S)N1CCC[C@H]1C(=O)O)c1ccccc1
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CCCN1C(=S)CC(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
1-(2-Benzoylthioacetyl)-L-proline obtained in Example 1, is dissolved in methanol and an ethereal solution of diazomethane is added until there is a persistent yellow color. After 15 minutes, a few drops of acetic acid are added and the solvent is removed in vacuo to obtain 1-(2-benzoylthioacetyl)-L-proline methyl ester.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13].O.[OH-].[Li+]>CO.O>[Cl:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][C:3]([OH:15])=[O:2])=[O:14]
Reactant: COC(=O)CNC(=O)c1ccccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CNC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of above (2-chloro-benzoylamino)-acetic acid methyl ester (6 g, 26 mmol) in 30 mL of methanol, was added three equivalents of lithium hydroxide hydrate in 10 mL of water. The solution was stirred at room temperature for 1 hour, concentrated and mixed with water. Citric acid was added until pH of the solution was adjusted to pH 2-3. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated to dryness to give (2-chloro-benzoylamino)-acetic acid as a solid. To a solution of (2-chloro-benzoylamino)-acetic acid in 40 mL of acetone at −20° C. was added excess of trifluoroacetic anhydride. The mixture was warmed up to room temperature and stirred overnight. The solvent was removed under vacuum. The residue was poured into 400 mL of water and stirred for 20 min. The solid was filtered out and washed with 2×100 mL of water, and dried under vacuum to give 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid as a red solid. This red solid was suspended in 80 mL of methanol, and heated to reflux for 30 min. The solvent was removed and the mixture was purified by flash chromatography using ethyl acetate/hexane to give 2-(2-chloro-benzoylamino)-4,4,4-trifluoro-3,3-dihydroxy-butyric acid methyl ester as a light yellow solid. The methyl ester was suspended in 100 g of phosphorus oxychloride, and stirred at 80° C. overnight. The reaction mixture was concentrated to remove excess POCl3. The remaining oil was diluted with toluene, and poured into a mixture of ice-water. The layers were separated and the organic layer was washed with water and diluted sodium bicarbonate and then concentrated to dryness. The solid was dissolved in 30 mL of methanol and treated with 2.5 equivalent of lithium hydroxide in 30 mL of water, and stirred for 30 min. Methanol was removed under vacuum, and the mixture was diluted with water. pH of the solution was adjusted to about 3 with 12 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by flash chromatography to give 1.67 g of 2-(2-chloro-phenyl)-5-trifluoromethyl-oxazole-4-carboxylic acid as a light yellow solid. LCMS calcd for C11H5ClF3NO3 (m/e) 291, obsd 292 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C(N(CC)CC)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[F:68][CH:69]1[CH2:74][CH2:73][N:72]([CH2:75][CH2:76][NH2:77])[CH2:71][CH2:70]1>CN(C=O)C>[F:68][CH:69]1[CH2:74][CH2:73][N:72]([CH2:75][CH2:76][NH:77][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:31])[CH2:71][CH2:70]1
Reactant: NCCN1CCC(F)CC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCC(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (151 mg, 0.3 mmol), triethylamine (0.084 mL, 0.6 mmol) and BOP reagent (199 mg, 0.45 mmol) in DMF (0.5 mL) was added 2-(4-fluoro-piperidin-1-yl)-ethylamine (48 mg, 0.32 mmol) in DMF (0.5 mL). The mixture was stirred at rt for overnight. After the usual workup, the residue was purified on a silica gel column to give 90 mg (47%) of the titled compound.
Reaction SMILES: [CH:1]([C:4]1[C:12]([C:13]2[NH:17][C:16]([CH2:18][CH2:19][O:20][CH3:21])=[N:15][N:14]=2)=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([CH3:22])[CH:5]=1)([CH3:3])[CH3:2].Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH:1]([C:4]1[C:12]([C:13]2[NH:17][C:16]([CH2:18][CH2:19][O:20][CH3:21])=[N:15][N:14]=2)=[CH:11][C:7]([C:8]([N:24]2[CH2:29][CH2:28][CH:27]([C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=3)[CH2:26][CH2:25]2)=[O:10])=[C:6]([CH3:22])[CH:5]=1)([CH3:2])[CH3:3]
Reactant: COCCc1nnc(-c2cc(C(=O)O)c(C)cc2C(C)C)[nH]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C(C)C)[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 4-mL vial was added 4-Isopropyl-5-(5-(2-methoxyethyl)-4H-1,2,4-triazol-3-yl)-2-methylbenzoic acid (compound 198.6, 31 mg, 0.10 mmol, 1.0 equiv), 4-(piperidin-4-yl)benzonitrile hydrochloride (compound 1.5, 23 mg, 0.10 mmol, 1.0 equiv), 1-hydroxybenzotriazole hydrate (20 wt % water) (22 mg, 0.13 mmol, 1.25 equiv), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (21.5 mg, 0.11 mmol, 1.1 equiv), DMF (1 mL) and DIEA (71 μL, 0.41 mmol, 4 equiv). The mixture was stirred at room temperature for 24 hours then diluted with ethyl acetate (10 mL) and washed with brine (10 mL). The aqueous was back extracted with ethyl acetate (3 mL) and the combined organics was washed with saturated NaHCO3 (5 mL), 1 M NaH2PO4 (5 mL), and brine (5 mL). The organics were dried (Na2SO4), filtered and removed in vacuo. The crude residue was purified by preparative TLC (DCM/8% MeOH) to obtain the title compound as an off white solid (23 mg, 48%). m/z (ES+) 472 (M+H)+.