Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:27][CH2:26][C:25]2[C:24]3[C:19](=[CH:20][C:21]([N:28]4[CH:33]=[CH:32][C:31]([C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=5[O:41][CH3:42])=[CH:30][C:29]4=[O:43])=[CH:22][CH:23]=3)[N:18]([CH3:44])[C:17]=2[CH2:16]1)=O)CCC>C(Cl)Cl>[ClH:40].[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([C:31]2[CH:32]=[CH:33][N:28]([C:21]3[CH:20]=[C:19]4[C:24]([C:25]5[CH2:26][CH2:27][NH:15][CH2:16][C:17]=5[N:18]4[CH3:44])=[CH:23][CH:22]=3)[C:29](=[O:43])[CH:30]=2)=[C:35]([O:41][CH3:42])[CH:36]=1
Reactant: CCCCOC(=O)N1CCc2c(n(C)c3cc(-n4ccc(-c5ccc(Cl)cc5OC)cc4=O)ccc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Cl)ccc1-c1ccn(-c2ccc3c4c(n(C)c3c2)CNCC4)c(=O)c1
Product: Cl
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1.0 mL) was added to a solution of ten-butyl-7-(4-(4-chloro-2-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (0.23 g, 0.44 mmol) in CH2Cl2 (2 mL) under argon and stirred for 1 h. The mixture was concentrated under reduced pressure, and the residue was partitioned between CH2Cl2 and saturated NaHCO3 solution. The organic phase was removed, and the aqueous phase was extracted with CH2Cl2 (10×25 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4, and concentrated under reduced pressure. Flash column chromatography (12 g ISCO CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes to 0:100 over 20 column volumes and hold for 10 column volumes) provided the free base of the title compound. The free base was converted to the HCl salt using 2 N HCl in Et2O as of Example 129 (step b), providing the title compound (0.13 g, 33%) as a yellow solid: mp 294-300° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.43 (br s, 2H), 7.65 (d, J=7.0 Hz, 1H), 7.61 (d, J=1.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 7.13 (dd, J=8.5, 2.0 Hz, 1H), 7.09 (dd, J=8.0, 2.0 Hz, 1H), 6.56 (d, J=2.0 Hz, 1H), 6.47 (dd, J=7.0, 1.5 Hz, 1H), 4.49-4.47 (m, 2H), 3.87 (m, 3H), 3.69 (s, 3H), 3.47-3.43 (m, 2H), 3.00-2.97 (m, 2H); ESI MS m/z 420 [M+H]+; HPLC (Method A) 96.7% (AUC), tR=15.5 min.
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[F:22])[NH2:18].C(N(CC)CC)C>C(OCC)C>[F:14][C:15]1[CH:16]=[C:17]([NH:18][C:11]([C:1]23[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]4)[CH2:2]2)[CH2:8]3)=[O:12])[CH:19]=[CH:20][C:21]=1[F:22]
Reactant: Nc1ccc(F)c(F)c1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)c(F)c1)C12CC3CC(CC(C3)C1)C2

Procedure:
Subject 2.29 g. of adamantane carboxylic acid chloride (11.5 mmoles) 1.29 g. of (10 mmoles) 3,4-difluoroaniline and 4.0 ml. of triethylamine to the process of Example 11. Crystallize the residue obtained thereby from ethyl ether to yield the title product, m.p. 168.5°-170° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH2:43]([OH:54])[C@@H:44]([OH:53])[C@@H:45]([OH:52])[C@H:46]([OH:51])[C@@H:47]([OH:50])[CH2:48]O>>[OH:50][C@H:47]([C@@H:46]([OH:51])[C@H:45]([OH:52])[C@H:44]([OH:53])[CH2:43][OH:54])[CH2:48][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Product: COc1cc(C(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with (2R,3R,4R,5S)-hexane-1,2,3,4,5,6-hexaol to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid (2S,3R,4R,5R)-2,3,4,5,6-pentahydroxy-hexyl ester. MS (ES+) m/z calcd. for C37H42Cl2F2N3O9: [(M+H)+]: 780. found: 780.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2C)[C@H:6]([OH:20])[C@@H:5]1[OH:21].ClC[C@H]1O[C@@H:27]([N:29]2C3N=CN=C(N)C=3N=C2NC)[C@H](O)[C@@H]1O>CN.C(O)C>[CH3:1][NH:2][CH2:3][C@H:4]1[O:8][C@@H:7]([N:9]2[C:18]3[N:17]=[CH:16][N:15]=[C:13]([NH2:14])[C:12]=3[N:11]=[C:10]2[NH:29][CH3:27])[C@H:6]([OH:20])[C@@H:5]1[OH:21]
Reactant: CNC[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CNc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Agent: CN
Solvent: CCO
Product: CNC[C@H]1O[C@@H](n2c(NC)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 4c was prepared by the same procedure as described for the preparation of 4a using 3c (1.00 g, 3.17 mmol) and 33% methylamine/ethanol solution (30 mL). After column chromatography (elution with 7:1:0.4 chloroform:methanol:NH4OH), a yellow glassy solid was obtained: 505 mg (51%); MS m/z 310 (M+H)+; 1HNMR (DMSO-d6) δ 7.89 (bs and q, 2H, H-2 and 8CH3—NH), 6.44 (bs, 2H, 6-NH2), 5.84 (d, 1H, H-1′, J1′,2′=7.0 Hz), 5.22 (d, 1H, 2′-OH, J2′-2′OH=6.4 Hz), 5.12 (d, 1H, 3′-OH, J3′-3′OH=4.0 Hz), 4.66 (ddd, 1H, H-2′, J1′,2′=7.0 Hz, J2′,3′=5.4 Hz, J2′-2′OH=6.4 Hz), 4.14 (bm, 1H, H-3′), 3.94-4.0 (bm, 1H, H-4′), 2.90 (d, 3H, 8NH—CH3, J=4.4 Hz), 2.77-2.83 (m, 1H, 5′-CH2), 2.57-2.62 (m, 1H, 5′-CH2), 2.35 (s, 3H, 5′NH—CH3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+]([O-])=O)[CH:5]=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][SH:20])=[CH:15][CH:14]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>ClCCl>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][S:20][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=2)=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: COc1ccc(CS)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(CSc2ccnc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A flask was charged with 2-chloro-4-nitropyridine (12.75 g, 80.4 mmol), (4-methoxyphenyl)methanethiol (12.40 g, 80.4 mmol) and DMF (100 mL). Cesium carbonate (31.43 g, 96.48 mmol) was added in portions, and the mixture was stirred for 2 hours at ambient temperature. The solution was diluted with dichloromethane (250 mL) and washed with diluted sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. The resulting yellowish residue was triturated with hexanes and the solid was filtered to obtain the desired product (18.1 g, 85%) as a pale yellow powder.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.Cl[CH2:35][C:36](Cl)=[O:37].[OH-].[K+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:17]=2)[O:11][CH2:35][C:36]1=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CCCCCCCCOc1ccc(C(O)CNCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(C2CN(Cc3ccccc3)C(=O)CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of 2-benzylamino-1-(4-octyloxy-phenyl)-ethanol (22.50 g; 63.3 mmol) and Et3N (9.7 mL; 69.6 mmol) in CH2Cl2 (500 mL) was added dropwise a solution of chloroacetyl chloride (5.5 mL; 69.6 mmol) in CH2Cl2 (25 mL), at 0° C. After 1 hour at 0° C. the reaction mixture was quenched with 1M aqueous HCl (200 mL). The layers were separated and the organic layer washed with a 5% aqueous NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in 2-propanol (250 mL) and KOH (4.26 g; 76 mmol) was added. The resulting mixture was stirred at RT for 1 hour and subsequently concentrated in vacuo. The crude product was partitioned between EtOAc and 0.5 M aqueous HCl. The layers were separated and the organic layer was washed with 5% aqueous NaHCO3 solution, dried (Na2SO4) and evaporated in vacuo to afford 4-benzyl-6-(4-octyloxy-phenyl)-morpholin-3-one (22.30 g) which was used as such in the next step.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:11]#[C:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[N:14]=2)[CH:7]=[CH:8][C:9]=1[CH3:10])(=[O:3])[NH2:2]>CN(C=O)C.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:11][CH2:12][C:13]1[C:18]([C:19]([F:21])([F:22])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[CH2:34][CH2:35]3)=[CH:26][CH:25]=2)[N:14]=1)(=[O:3])[NH2:2]
Reactant: Cc1ccc(C#Cc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cc1C(N)=O
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1ccc(CCc2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)ncc2C(F)(F)F)cc1C(N)=O
Yield: 31.5 %

Procedure:
A mixture of tert-butyl 4-(4-((4-((3-carbamoyl-4-methylphenyl)ethynyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (I72) (0.092 g, 0.16 mmol) and 10% Pd/C (0.116 g) in DMF (5 mL) was stirred over night under a H2 atmosphere. The mixture was filtered through Celite then concentrated under reduced pressure. The residue was then purified using silica gel column chromatography (0-100% EtOAc/petroleum benzine 40-60° C.) and the product triturated with methanol. The resulting precipitate was collected by vacuum filtration to give the title compound (I73) (29.5 mg, 32%); 1H NMR (400 MHz, d6-DMSO) δ 10.00 (s, 1H), 8.61 (s, 1H), 7.66 (s, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.33 (s, 1H), 7.25 (s, 1H), 7.16 (m, 2H), 6.94 (d, J=9.1 Hz, 2H), 3.46 (m, 4H), 3.04 (m, 8H), 2.32 (s, 3H), 1.42 (s, 9H). LCMS Method C: rt 6.18 min; m/z 585.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[S:9][C:10]([CH2:13][CH2:14][NH:15][C:16]2[C:17]3[S:24][CH:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][N:12]=1)([CH3:4])([CH3:3])C.Cl.C(N(CC)CC)C.ClC(O[C:38]1[CH:43]=CC=C[CH:39]=1)=O>O1CCOCC1.C1COCC1>[C:1]1([O:5][C:6](=[O:25])[NH:7][C:8]2[S:9][C:10]([CH2:13][CH2:14][NH:15][C:16]3[C:17]4[S:24][CH:23]=[CH:22][C:18]=4[N:19]=[CH:20][N:21]=3)=[CH:11][N:12]=2)[CH:3]=[CH:43][CH:38]=[CH:39][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(CCNc2ncnc3ccsc23)s1
Reactant: O=C(Cl)Oc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Nc1ncc(CCNc2ncnc3ccsc23)s1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of compound 14.2 (23.7 mmol) in 1,4-dioxane (100 mL) was added HCl (70 mL of a 4.0 M in 1,4-dioxane) at 0° C. The reaction was allowed to warm to room temperature, stirred for 2 hours and concentrated to dryness to give a tan solid. The crude solid was suspended in THF (200 mL) and cooled to 0° C. Triethylamine (33 mL) was added followed by phenyl chloroformate (26.1 mmol). The reaction mixture was allowed to slowly warm to room temperature and stirred for 2 hours. Volatiles were removed under reduced pressure at room temperature, water was added and the solid collected by vacuum filtration. The solid was washed with ethyl ether and dried under vacuum to give {5-[2-(thieno[3,2-d]pyrimidin-4-ylamino)-ethyl]-thiazol-2-yl}-carbamic acid phenyl ester (compound 16.1) in 80% yield as a tan solid.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:6]=1)C.Cl.C([O-])([O-])=O.[Na+].[Na+]>>[CH3:10][N:9]1[C:5]([CH:4]=[O:3])=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8]1
Reactant: CCOC(OCC)c1nc(-c2ccccn2)nn1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cn1nc(-c2ccccn2)nc1C=O
Reaction time: 8 h
Yield: 45.5 %

Procedure:
The acetal from step 2, 2-[5-(diethoxymethyl)-1-methyl-1H-1,2,4-triazol-3-yl]pyridine (11.06 g, 0.042 mol) was dissolved in 1.5 equiv of 2 N HCl (aq) and stirred at 40–50° C., overnight. The mixture was concentrated, yielding a viscous oil, which was then basified to pH 10 using saturated aqueous Na2CO3. The mixture was then extracted using ethyl acetate (4×200 mL), the organic layer dried over Na2SO4, filtered and concentrated, to a yellow solid. The solid was dissolved in a minimal amount of hot ethyl acetate, scratched and diluted with hexanes to recrystallize the product, affording 3.6 g (45%) of the desired aldehyde as a yellow powder. 1H NMR (300 MHz, CDCl3): δ 4.28 (s, 3H), 7.46 (m, 1H), 7.82 (m, 1H), 8.15 (m, 1H), 8.78 (m, 1H), 10.08 (s, 1H). MS (APCI) calcd for C9H8N4O: 188.07, found (M+H+): 189.3.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:10])[C@H:4]([CH2:6][CH2:7][S:8][CH3:9])[NH2:5].CCCCC.O.[CH:17](=O)[C:18]([CH3:21])([CH3:20])[CH3:19]>>[CH3:1][NH:2][C:3](=[O:10])[C@H:4]([CH2:6][CH2:7][S:8][CH3:9])[N:5]=[CH:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)C=O
Reactant: CNC(=O)[C@@H](N)CCSC
Solvent: CCCCC
Solvent: O
Product: CNC(=O)[C@H](CCSC)N=CC(C)(C)C

Procedure:
There were added to 40.0 grams (247 mmoles) of (S)-methionine mono-methylamide dissolved in 100 ml of n-pentane 27.5 ml (250 mmoles) of pivalaldehyde. The reaction mixture was boiled on the water separator until the formation of water ended (3 hours). The solvent was removed under reduced pressure and there remained behind 52.2 grams (92% of theory) of (S)-N-(2', 2'- dimethylpropylidene)-methionine mono-methylamide which was further processed without further purification.
Reaction SMILES: CS[C:3]1[O:4][CH2:5][CH2:6][CH2:7][N:8]=1.[N+:9]([CH2:12][C:13]([O:15][CH3:16])=[O:14])([O-:11])=[O:10]>[Cl-].[Zn+2].[Cl-]>[N+:9]([C:12](=[C:3]1[NH:8][CH2:7][CH2:6][CH2:5][O:4]1)[C:13]([O:15][CH3:16])=[O:14])([O-:11])=[O:10]
Reactant: CSC1=NCCCO1
Reactant: COC(=O)C[N+](=O)[O-]
Agent: [Cl-]
Agent: [Zn+2]
Product: COC(=O)C(=C1NCCCO1)[N+](=O)[O-]

Procedure:
A mixture of 25 g of 5,6-dihydro-2-(methylthio)-4H-1,3-oxazine (Clapp, et al., J. Heterocyclic Chemistry, 5, 107 (1968)), 25 g of methyl nitroacetate and a catalytic amount of zinc chloride was heated to 90° over one hour and maintained at that temperature for an additional hour. The mixture then was cooled and triturated with ether to effect crystallization. The solid was recrystallized from ethanol to give methyl nitro(tetrahydro-2H-1,3-oxazin-2-ylidene)acetate (1A), as a yellow solid, m.p.: 132°-3°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12]>>[Cl:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:12]
Reactant: c1ccsc1
Reactant: O=C(Cl)CCCCCl
Product: O=C(CCCCCl)c1cccs1

Procedure:
Using thiophene (1.00 ml) and 5-chlorovaleryl chloride (1.63 ml) according to the same method as that of Reference Example 1, the title compound (2.20 g) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15]O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH2:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C(O)(=O)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[CH:15][NH:29][CH2:28][CH2:27][C:21]1[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=1
Reactant: COc1cc2c(cc1OC)C(=CO)C(=O)N2
Reactant: COc1ccc(CCN)cc1OC
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COc1ccc(CCNC=C2C(=O)Nc3cc(OC)c(OC)cc32)cc1OC

Procedure:
5.00 g. of 5,6-Dimethoxy-3-hydroxymethylene oxindole, 6.00 g. of 2(3,4-dimethoxyphenyl)ethylamine and 2.20 acetic acid in 40 ml. benzene was reacted as described in Example 5 to give 6.30 g. product, m.p. 164°-166° C.
Reaction SMILES: I.[N:2]1[NH:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]=1[C:8]1[S:12][C:11]2[CH2:13][CH2:14][CH:15]([NH2:17])[CH2:16][C:10]=2[CH:9]=1.C(N(CC)CC)C.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN1CCN(C)C1=O>[N:2]1[NH:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]=1[C:8]1[S:12][C:11]2[CH2:13][CH2:14][CH:15]([NH:17][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])[CH2:16][C:10]=2[CH:9]=1
Reactant: NC1CCc2sc(C3=NNC(=O)CC3)cc2C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: I
Solvent: CCN(CC)CC
Solvent: CN1CCN(C)C1=O
Product: O=C1CCC(c2cc3c(s2)CCC(NS(=O)(=O)c2ccccc2)C3)=NN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To 1.34 g of 2-[4,5-dihydropyridazin-3(2H)-on-6-yl]-5-amino-4,5,6,7-tetrahydrobenzo[b]thiophene.hydroiodide and 1.2 ml of triethylamine dissolved in 20 ml of 1,3-dimethyl-2-imidazolidinone was added 765 mg of benzenesulfonyl chloride, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. After the organic layer was washed and dried, the solvent was removed. The resulting crystals were recrystallized from nitromethane to obtain 1.22 g of 2-[4,5-dihydropyridazin-3(2H)-on-6-yl]-5-(phenylsulfonylamino)-4,5,6,7-tetrahydrobenzo[b]thiophene.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[O:12][C@H:13]([C:15](=[O:43])[NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]3[CH:35]=[CH:36][CH:37]=[CH:38][C:20]=3[C:19]3[CH:39]=[CH:40][CH:41]=[CH:42][C:18]2=3)[CH3:14])=CC=1)([O-])=O.[F:45][C:46]([F:53])([C:49]([F:52])([F:51])[F:50])[CH2:47][NH2:48]>>[CH2:28]([O:27][CH2:26][CH2:25][N:22]1[C:23](=[O:24])[C@@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:10])[NH:48][CH2:47][C:46]([F:53])([F:45])[C:49]([F:52])([F:51])[F:50])[CH3:14])=[O:43])[C:18]2[CH:42]=[CH:41][CH:40]=[CH:39][C:19]=2[C:20]2[CH:38]=[CH:37][CH:36]=[CH:35][C:21]1=2)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NCC(F)(F)C(F)(F)F
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: C[C@H](OC(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Carbonic acid (S)-1-[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl]-ethyl ester 4-nitro-phenyl ester (65 mg, 0.11 mmol) and 2,2,3,3,3-penta-fluoropropylamine (663 mg, 4.3 mmol) were stirred for 24 h at ambient temperature. After evaporation of all volatile components and chromatography on silica (gradient of heptane/ethyl acetate 0 to 80%), the title compound was obtained as white solid (>98%). MS: m/e=606(M+H+).
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1)([CH3:6])[C:3]([OH:5])=O.[CH3:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]([NH2:29])[CH3:28])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:6][C:2]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1)([CH3:1])[C:3]([NH:29][CH:27]([CH3:28])[CH:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=1)=[O:5]
Reactant: Cc1ccc(CC(c2ccccc2)C(C)N)cc1
Reactant: CC(C)(Oc1ccc(C(F)(F)F)cn1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CC(c2ccccc2)C(C)NC(=O)C(C)(C)Oc2ccc(C(F)(F)F)cn2)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanoic acid (Reference example 55, 250 mg, 1.04 mmol) and 4-(4-methylphenyl)-3-phenylbutan-2-amine (Reference example 102, 260 mg, 1.04 mmol, mixture of 4 isomers) in CH2Cl2 (5.5 mL) at RT was added diisopropylethylamine (272 μl, 1.56 mmol) followed by PyBOP (649 mg, 1.25 mmol) and the reaction mixture stirred overnight. The reaction was purified by loading the reaction mixture directly onto a silica gel column and eluting from 0-30% EtOAc/hexane to give the title compound as a mixture of 4 isomers. The diastereomers were separated by HPLC on a ZORBAX RxSi column eluting 97% hexane: 3% ethanol at 20 mL/min with retention times of:
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[CH:5][N:4]=1)#[N:2].[CH:12]1[C:17]([OH:18])=[CH:16][CH:15]=[C:14]([CH3:19])[CH:13]=1.[OH-].[Na+].O>CC(C)=O>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([O:18][C:17]2[CH:12]=[CH:13][C:14]([CH3:19])=[CH:15][CH:16]=2)=[CH:5][N:4]=1)#[N:2]
Reactant: N#Cc1ncc(Cl)nc1C#N
Reactant: Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(Oc2cnc(C#N)c(C#N)n2)cc1
Yield: 41.5 %

Procedure:
2,3-Dicyano-5-chloropyrazine (0.83 g; 0.005 mole) was dissolved in 25 ml of acetone. The solution was cooled to 0° to 5° C., and with stirring, a solution prepared from 0.54 g (0.005 mole) of p-cresol, 0.21 g (0.005 mole) of sodium hydroxide, 1 ml of water and 15 ml of acetone was added dropwise over the period of 15 minutes. The mixture was stirred at 0° to 5° C. for 1 hour. After the reaction, the solvent was removed by concentration under reduced pressure. The residue was extracted with 100 ml of chloroform. The chloroform solution was washed with 30 ml of a 1N aqueous solution of sodium hydroxide and 30 of water and dried over anhydrous calcium chloride. Then, the solvent was distilled off. Recrystallization of the crude product from ethanol afforded 0.49 g (yield 41%) of 2,3-dicyano-5-(p-methylphenoxy)pyrazine.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:6]=1.C([Mg]Cl)(C)C.[F:20][C:21]([F:31])([F:30])[C:22](N1CCCCC1)=[O:23]>O1CCCC1>[F:20][C:21]([F:31])([F:30])[C:22]([C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:23]
Reactant: O=C(N1CCCCC1)C(F)(F)F
Reactant: FC(F)(F)CCCCn1cc(I)cn1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1cnn(CCCCC(F)(F)F)c1)C(F)(F)F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a stirred solution of Intermediate 12A (460 mg, 1.446 mmol) in tetrahydrofuran (5 mL) at 0° C. was added isopropylmagnesium chloride (0.795 mL, 1.591 mmol) quickly. After 30 min, additional 0.25 eq of iPrMgCl was added and after 30 min, the mixture was cooled to −78° C. 2,2,2-Trifluoro-1-(piperidin-1-yl)ethanone (288 mg, 1.591 mmol) was added quickly and the reaction was warmed to rt and stirred for 3 h. The reaction was quenched with sat'd aq NH4Cl and diluted with EtOAc. The organic layer was washed with sat'd aq NH4Cl, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (40 g silica gel, eluted with 0-100% EtOAc in hexanes) to give the desired product (265 mg, 64%) as clear oil. 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 2H), 4.22 (t, J=7.0 Hz, 2H), 2.07-2.20 (m, 2H), 1.98-2.05 (m, 2H), 1.55-1.65 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]12(O)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[C:9]12([S:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc(SC23CC4CC(CC(C4)C2)C3)cc1
Yield: 91.2 %

Procedure:
3.78 g (20 mmol) of p-bromothiophenol, 3.04 g (20 mmol) of 1-adamantanol and 10 ml of trifluoroacetic acid are stirred at ambient temperature for 8 hours and then poured in water. Sodium bicarbonate is added until the mixture is neutral at which time it is extracted with methylene chloride. The organic phase is dried and evaporated. After crystallization in isooctane, 5.9 g of the expected product are obtained. Yield - 92%. Melting point: 121°-122° C.