Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH:11]=[CH:10]1.CO.[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([CH:33](O)[C:34]([OH:36])=[O:35])=[CH:32][C:27]=2[O:26][CH2:25]1>C(#N)C>[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([CH:33]([C:11]3[C:12]4[C:17](=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=4)[N:9]([CH3:8])[CH:10]=3)[C:34]([OH:36])=[O:35])=[CH:32][C:27]=2[O:26][CH2:25]1
Reactant: O=C(O)C(O)c1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc2ccn(C)c2c1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COC(=O)c1ccc2c(C(C(=O)O)c3ccc4c(c3)OCO4)cn(C)c2c1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
Trifluoroacetic acid (1.92 kg) was added portionwise to a stirred suspension of methyl 1-methyl-1H-indole-6-carboxylate (prepared by the same method as 1-methylindole-6-tert-butyl ester in Example 28, International Patent Application WO 97/43260, but using methanol in place of 6-tert-butanol; 1.63 kg) and 2-(1,3-benzodioxol-5-yl)-2-hydroxyacetic acid (1.67 kg) in acetonitrile (16.3 liters) at room temperature under a nitrogen atmosphere. The suspension was heated to reflux for 24 h and allowed to cool to room temperature. Filtration of the precipitated product gave the subtitle compound as a white crystalline solid (2.54 kg, 80.4%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7](=[O:10])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([OH:13])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>CN(C=O)C>[CH3:1][C:2]1[NH:6][C:5]2[C:7](=[O:10])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:13]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCC2=O
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1[nH]c2c(c1C(=O)N1CCC[C@H]1CN1CCCC1)CCC2=O
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
A mixture of 2-methyl-6-oxo-1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-3-carboxylic acid (Example B, 3.58 g, 20 mmol), HOBt (2.7 g, 20 mmol) and EDC (5.74 g, 30 mmol) in dry DMF (50 mL) was stirred at 0° C. to room temperature for 20 min. Then (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (24 mmol) was added and stirring was continued for 48 hours. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc, washed with sat. Na2CO3, dried, concentrated and purified on a silica gel column to give 5.1 g (81%) of the titled compound as a yellowish foam.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1.CN(C1C=CC=CN=1)C>[C:19]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C1CCNCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(C(C)=O)CC1
Yield: 98.6 %

Procedure:
To a solution of ethyl isonipecotate (8.0 g) in THF (100 mL) was added triethylamine (5.7 g), dimethylaminopyridine (0.6 g) and acetyl chloride (4.4 g) at 0° C. and the mixture was stirred for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl 1-acetylpiperidine-4-carboxylate (10 g) as a colorless oil. To a solution of acetonitrile (2.5 g) in THF (300 mL) was added n-BuLi (57 mmol) at −78° C. Further, ethyl 1-acetylpiperidine-4-carboxylate (10 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (7.5 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.17 g) and 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (0.4 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.49 g) as yellow crystals.
Reaction SMILES: [CH3:1][C@@H:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12][CH2:13][O:14][C:15]=2[N:16]=1)[CH2:3][CH3:4].[ClH:24].C(OCC)(=O)C>>[ClH:24].[CH3:1][C@@H:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][NH:11][CH2:12][CH2:13][O:14][C:15]=2[N:16]=1)[CH2:3][CH3:4]
Reactant: CC[C@@H](C)Oc1ccc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@@H](C)Oc1ccc2c(n1)OCCNC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
A mixture of the compound obtained in step 1 (0.70 g) and 4N hydrogen chloride/ethyl acetate (5 mL) was stirred at room temperature for 3 hr. The precipitate was collected by filtration, and the aqueous layer was basified and extracted with ethyl acetate and aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, and 4N hydrogen chloride/ethyl acetate was added. The precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.36 g, 60%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:7][C:8]=2O)[C:3]=1[S:17]([OH:20])(=[O:19])=[O:18].FC1N=NN=C(F)C=1F.C(N)CN.FC1N=NN=C(F)C=1>>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([S:13]([OH:16])(=[O:14])=[O:15])=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]=1[S:17]([OH:20])(=[O:19])=[O:18]
Reactant: Nc1ccc2c(O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O
Agent: Fc1cc(F)nnn1
Agent: Fc1nnnc(F)c1F
Solvent: NCCN
Product: Nc1ccc2c(S(=O)(=O)O)cccc2c1S(=O)(=O)O
Reaction time: 2.5 h
Yield: 100 %

Procedure:
31.9 g of 2-amino-5-hydroxy-naphthalene-1,7-disulphonic acid are subjected to a condensation reaction with trifluorotriazine as described in Example 1. 5.0 g of ethylenediamine are added to the solution of the resulting difluorotriazine compound at 0°, a pH of 5.5-6.5 being maintained. The condensation has ended after 2 to 3 hours. A diazo compound obtained by the customary route by diazotisation of 30.3 g of 2-amino-naphthalene-1,5-disulphonic acid is added to the reaction product of the formula ##STR20## which is largely present as a suspension, the pH simultaneously being kept at pH 7.0-7.5 by sprinkling in sodium bicarbonate. When the coupling has ended, the dyestuff of the formula ##STR21## which has precipitated as a sparingly soluble product, is filtered off with suction and stirred in 1 l of water again. 16.9 g of 2,4,6-trifluoro-5-chloro-pyrimidine are added dropwise at 0°-5°, during which a pH of 7.5-8.0 is maintained with dilute sodium hydroxide solution. The dyestuff dissolves during the condensation reaction. When the condensation has ended (thin layer chromatogram), the dyestuff is salted out, filtered off with suction, dried and ground. The red powder dissolves readily in water and dyes cotton a clear scarlet (colour code number 6).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:15]=[C:16]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([NH:25][CH3:26])=[O:24])=[CH:21][CH:20]=1>>[Cl:32][C:30]1[CH:29]=[C:16]([CH:15]=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:31]=1)[O:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH3:26])=[O:24])=[CH:27][CH:28]=1
Reactant: CNC(=O)c1ccc(COc2cc(N)cc(Cl)c2)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: CNC(=O)c1ccc(COc2cc(Cl)cc(Nc3ccnc4nc(C)ccc34)c2)cc1

Procedure:
The product from Example 1d (100 mg, 0.56 mmol) was reacted with the product from Example 195d (160 mg, 0.56 mmol) for 15 h following the procedure from Example 1g giving the crude title compound which was purified by trituration with EtOAc providing the product (240 mg, 99%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.75 (s, 3H), 2.79 (d, J=4.4 Hz, 3H), 5.26 (s, 2H), 6.90 (d, J=7.0 Hz, 1H), 7.14 (br-t, J=1.9 Hz, 1H), 7.18 (br-t, J=1.9 Hz, 1H), 7.20 (br-t, J=1.9 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.8 Hz, 1H), 7.87 (d, J=8.5 Hz, 2H), 8.47 (br-s, 1H), 8.50 (d, J=7.0 Hz, 1H), 9.08 (d, J=8.8 Hz, 1H), 11.08 (br-s, 1H); MS (ESI+) m/z 433, 435 (M+H)+, (ESI−) m/z 431, 433 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:9]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:2]([Br:1])[CH:3]=1)(=[O:11])[CH3:10]
Reactant: COC(=O)CBr
Reactant: CC(=O)c1ccc(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(C(C)=O)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of 1-(3-bromo-4-hydroxyphenyl)ethanone (15) (963 mg, 4.48 mmol, 1 eq, Aldrich, Milwaukee, Wis., USA) in DMF (15 mL), was added methyl 2-bromoacetate (1.02 g, 6.72 mmol, 1.5 eq) and potassium carbonate (1.86 g, 13.5 mmol; 3 eq). The reaction mixture was stirred at room temperature for 18 h. Solvent was removed in vacuo, and the residue was dissolved in EtOAc, washed by water and brine, dried (Na2SO4), filtered, and concentrated in vacuo to give 1.05 g, (81%) of methyl 2-(4-acetyl-2-bromophenoxy)acetate (16) as a brown solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl.CCOCC>[O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 65.6 %

Procedure:
A solution of 2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (3.10 g, 12.6 mmol) in CH2Cl2 (25.0 mL) was added to a slurry of PCC (4.10 g, 19.0 mmol) in CH2Cl2 (15.0 mL) and stirred at room temperature for 3.5 hours. The reaction was diluted with Et2O (60.0 mL), decanted and the residue swirled with Et2O (2×40.0 mL). The combined ether layers were filtered through florisil and concentrated in vacuo to dryness, and the residue was recrystallized from ethyl acetate/hexane to give 2.01 g (65%) of 2-(4-oxocyclohexyl)-1H-isoindole-1,3(2H)-dione as colorless needles: mp 140.3-142.1° C.; 1H NMR (400 MHz, CDCl3) δ 7.84, 7.74, 4.64, 2.72, 2.54, 2.09; 13C NMR (100 MHz, CDCl3) δ 208.9, 168.1, 134.1, 131.9, 123.3, 48.4, 39.9, 28.6; IR (mull) 3062, 3031, 2958, 2949, 2919, 2885, 1775, 1762, 1721, 1708, 1611, 1465, 1436, 1419, 1393, 1379, 719 cm−1; HRMS (FAB) calcd for C14H14NO3: 244.0974, found 244.0976; Anal. Calcd for C-14H14NO3: C, 69.12; H, 5.39; N, 5.76. Found: C, 68.87; H, 5.47; N, 5.73.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][N:12]2[C:23]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([S:31][CH3:32])[N:26]=2)=O)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:10])[N:11]3[CH2:15][CH:14]([O:16][C:17](=[O:22])[C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:13][N:12]3[C:23]=2[C:25]2[CH:30]=[CH:29][N:28]=[C:27]([S:31][CH3:32])[N:26]=2)=[CH:6][CH:7]=1
Reactant: CSc1nccc(C(=O)N2CC(OC(=O)C(C)(C)C)CN2C(=O)Cc2ccc(F)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n3n2CC(OC(=O)C(C)(C)C)C3)n1
Temperature: 0 °C
Yield: 30 %

Procedure:
2,2-Dimethyl-propionic acid 1-[2-(4-fluorophenyl)acetyl]-2-(methylsulfanyl-pyrimidine-4-carbonyl)-pyrazolidin-4-yl ester, 33, (300 mg, 0.651 mmol) is dissolved in THF (6 mL). This solution is then added dropwise via cannula to a suspension of NaH (29 mg of a 60% dispersion in mineral oil, 0.716 mmol) at −30° C. The reaction is allowed to gradually warm to 0° C. over 3 hours. The reaction is quenched with NH4Cl (sat. aq.) (1 mL). The mixture is stirred at room temperature, then concentrated in vacuo. The residue is diluted with tetrahydrofuran (50 mL) and the mixture filtered through Celite. The filtrate is concentrated in vacuo to give an orange oil. The crude product is purified over silica (100% ethyl acetate to 5% to 10% to 20% methyl alcohol/ethyl acetate) to afford 87 mg (30% yield) of the desired product as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:28][S:29]([C:32]1[S:33][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:36]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[S:33][C:34]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=3)[CH:22]=2)=[CH:35][CH:36]=1)(=[O:30])=[O:31])([CH3:27])([CH3:25])[CH3:26]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)s1

Procedure:
5-{1-[4-(4-Chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide was prepared from 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.70) (0.68 g, 1.5 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example F.1) (0.62 g, 1.8 mmol) according to the general procedure VI. Obtained as a light brown solid (0.52 g), which was subsequently deprotected.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:2]1.CO[C:16](=[O:32])[C:17]([C:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[CH2:24][CH:23]([CH3:31])[CH2:22][N:21]3[CH:20]=1)=O>>[CH3:31][CH:23]1[CH2:24][C:25]2[C:30]3=[C:29]([C:19]([C:17]4[C:16](=[O:32])[NH:13][C:11](=[O:12])[C:10]=4[C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)=[CH:20][N:21]3[CH2:22]1)[CH:28]=[CH:27][CH:26]=2
Reactant: NC(=O)Cc1c[nH]c2ccccc12
Reactant: COC(=O)C(=O)c1cn2c3c(cccc13)CC(C)C2
Product: CC1Cc2cccc3c(C4=C(c5c[nH]c6ccccc56)C(=O)NC4=O)cn(c23)C1

Procedure:
Beginning with indole-3-acetamide and (5-methyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)oxoacetic acid methyl ester, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6](N)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])(=[O:3])[CH3:2].[BrH:14].O.N([O-])=O.[Na+]>>[C:1]([C:4]1[CH:5]=[C:6]([Br:14])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(N)ccc1[N+](=O)[O-]
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h

Procedure:
In the ice bath, the starting material, about 10 mmol of 3-acetyl-4-nitro-aminobenzene was added into HBr/H2O (about 100 mL, 1/2, v/v), and sodium nitrite solution was gradually added. The solution was stirred at about 60° C. for about 2 hours. After the reaction was completed, the precipitate was filtered. The filtered solution was neutralized with about 1N NaOH, and extracted with EtOAc. Then the extracted material was dried with sodium sulfate anhydride. Next, the dried material was distilled under reduced pressure. Then, 3-acetyl-4-nitro-bromobenzene was obtained in a form of about 75% yellow oil using silica gel column chromatography (Hexane/EtOAc=2/1).
Reaction SMILES: [OH:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].CO.I[CH2:16][CH2:17][CH2:18][CH3:19]>O.Cl>[CH2:16]([N:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]1=[O:1])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCI
Reactant: O=C(O)c1cccnc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCn1cccc(C(=O)O)c1=O
Temperature: 60 °C
Yield: 38.5 %

Procedure:
To a solution of 2-hydroxy-nicotinic acid (0.50 g, 3.59 mmol) and potassium -hydroxide (0.40 g, 7.13 mmol) in 4:1 methanol: water (6 mL) at room temperature, was added 1-iodobutane (0.74 mL, 6.42 mmol). This solution was heated at 60° C. for 30 minutes, then cooled to room temperature and diluted with water and 1N HCl. The resulting solid was filtered and dried to give the title compound (0.27 g, 39%). MS (DCI/NH3) m/z 196 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 0.91 (m, 3 H) 1.30 (m, 2 H) 1.69 (m, 2 H) 4.10 (m, 2 H) 6.73 (m, 1 H) 8.27 (dd, J=6.62, 1.84 Hz, 1 H) 8.38 (dd, J=7.35, 2.21 Hz, 1 H) 14.68 (s, 1 H).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11](O)=[O:12])(=[O:5])[CH2:2][CH2:3][CH3:4].O=S(Cl)[Cl:19]>>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([O:15][CH3:16])=[C:10]([CH:14]=1)[C:11]([Cl:19])=[O:12])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCC(=O)c1ccc(OC)c(C(=O)O)c1
Product: CCCC(=O)c1ccc(OC)c(C(=O)Cl)c1
Temperature: 30 °C
Yield: 90 %

Procedure:
206 g of the acid obtained in Example 4 (0.927 mole), 1 liter of CHCl2, are introduced into a triple-tube flask and 1.11 mole of SOCl2 (80 ml) are added with care. The mixture is maintained for 24 hours at 30° C. and the solvents are then removed. Retreatment with 200 ml of benzene is carried out three times by removing the solvent in vacuo each time. 200 g of the product having a melting point of 65° C. (cyclohexane) are thus obtained with a yield of 90%. IR spectrum (KBr) CO: 1670 and 1780 cm-1.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:7]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[N:6]=1)(=O)=O.C([Li])CCC.[CH:38]1([CH2:42][OH:43])[CH2:41][CH2:40][CH2:39]1>>[CH:38]1([CH2:42][O:43][C:5]2[N:10]=[C:9]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[C:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[C:7]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])[N:6]=2)[CH2:41][CH2:40][CH2:39]1
Reactant: OCC1CCC1
Reactant: CS(=O)(=O)c1nc(Oc2cccnc2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: [Li]CCCC
Product: Clc1ccc(-c2c(Oc3cccnc3)nc(OCC3CCC3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylsulfonyl-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine from Example 86 (50 mg, 0.1 mmol) was reacted with 2 equivalents each of n-butyl lithium and cyclobutylmethanol by the procedure described in Reference Examples 6 and 7 to afford 2-cyclobutylmethoxy-4-(3-pyridyloxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine: HPLC/MS: m/e=512 (M++1); Rt=4.40 min. 1H-NMR 400 MHz (CDCl3): δ 1.80-1.98 (m, 4H), 2.10-2.11(m, 2H), 2.74(m, 1H), 4.20 (d, J=7 Hz, 2H), 7.00 (m, 1H), 7.13-7.18 (m, 2H), 7.20-7.30 (m, 5H), 7.63-7.68 (m, 1H), 8.11 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([S:14]C(=O)N(C)C)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1>CO>[CH3:1][O:2][C:3](=[O:20])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([SH:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1
Reactant: COC(=O)Cn1ccc2cc(SC(=O)N(C)C)ccc21
Solvent: CO
Product: COC(=O)Cn1ccc2cc(S)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 72D (4.04 g, 13.8 mmol) was dissolved in 200 ml methanol. Nitrogen was bubbled for 5 minutes followed by the addition of a 2N NaOH solution (1.4 g/17 ml water). The solution was heated at reflux and tuned brown after 10 minutes. The reaction was concentrated to ca. 50 ml under vacuum and acidified to pH<4 with 2N HCl. The product was extracted into ethyl acetate 2×100 ml, dried over anhydrous sodium sulfate, decanted and concentrated. The crude acid was dissolved into 100 ml anhydrous methanol followed by 5 drops concentrated sulfuric acid. This was heated at reflux for 3 h then cooled to room temp. 500 mg dithiothreitol was added followed by 100 mg sodium borohydride. This was stirred for 1 h and concentrated to an oil. The crude thiol ester was dissolved into 100 ml dichloromethane, filtered through silica and eluted with 300 ml dichloromethane. The filtrate was concentrated and purified by liquid chromatography to give the title product as a yellow oil. MS m/z 222 (M+1).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:25])[CH2:10][N:11]1[C:19]2[CH:18]=[CH:17][C:16]([F:20])=[C:15]([F:21])[C:14]=2[C:13]2[CH2:22][CH2:23][CH2:24][C:12]1=2)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39]>ClCCl.CC(O)C>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[F:20][C:16]1[CH:17]=[CH:18][C:19]2[N:11]([CH2:10][C@@H:9]([NH2:8])[CH3:25])[C:12]3[CH2:24][CH2:23][CH2:22][C:13]=3[C:14]=2[C:15]=1[F:21]
Reactant: C[C@@H](Cn1c2c(c3c(F)c(F)ccc31)CCC2)NC(=O)OC(C)(C)C
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)O
Product: C[C@H](N)Cn1c2c(c3c(F)c(F)ccc31)CCC2
Temperature: 25 °C
Yield: 220.8 %

Procedure:
A solution of (S)-4-[2-(tert-butoxycarbonylamino)propyl]-7,8-difluoro-1,2,3,4-tetrahydrocyclopent[b]indole (0.4 g, 1.1 mmol) and trifluoroacetic acid (5 mL) in dichloromethane (15 mL) was stirred at room temperature for 1 h. The mixture was made basic by the addition of aqueous sodium hydroxide solution (2 N), then extracted with dichloromethane (3×50 mL). The organic extracts were combined, dried (magnesium sulfate), filtered and concentrated in vacuo to give an orange oil. The oil was dissolved in 2-propanol (5 mL) and the solution was heated to boiling then fumaric acid (0.38 g, 3.3 mmol) was added. The mixture was cooled to room temperature and filtered The filter-cake was washed (2-propanol, ether) and dried in vacuo to give the title compound (0.89 g, 68%) as a pale orange solid. mp. 154-156° C. (dec.); NMR δH (400 MHz, DMSO-d6) 1.13 (3H, d, J 7 Hz), 2.43-2.52 (2H, m), 2.78-2.94 (4H, m), 3.5-3.57 (1H, m), 4.13 (1H, d, J 8 Hz), 4.29 (1H, dd, J 6.5 Hz), 6.55 (2H, s), 7.01-7.10 (1H, m) and 7.26-7.31 (1H, m).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[CH2:4][C@H:3]1[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12]1)=[O:10].C1([O:31][C:32](=O)[NH:33][C:34]2[S:35][C:36]([C:40](=[O:42])[CH3:41])=[C:37]([CH3:39])[N:38]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:40]([C:36]1[S:35][C:34]([NH:33][C:32]([NH:1][C@@H:2]2[C@@H:3]([C:9]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH2:12]3)=[O:10])[CH2:4][S:5](=[O:7])(=[O:8])[CH2:6]2)=[O:31])=[N:38][C:37]=1[CH3:39])(=[O:42])[CH3:41]
Reactant: N[C@@H]1CS(=O)(=O)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1
Reactant: CC(=O)c1sc(NC(=O)Oc2ccccc2)nc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)c1sc(NC(=O)N[C@H]2CS(=O)(=O)C[C@@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)nc1C
Temperature: 25 °C
Reaction time: 94 h
Yield: 54.2 %

Procedure:
[(3R,4S)-4-Amino-1,1-dioxo-tetrahydrothiophen-3-yl]-[(S)-3-(4-fluorobenzyl)-piperidin-1-yl]-methanone (50 mg, 141 μmol) and [5-acetyl-4-methylthiazol-2-yl]-carbamic acid phenyl ester (43 mg, 155 μmol) were dissolved in N,N-dimethylformamide (1 mL) and treated with triethylamine (22 μL, 155 μmol). The mixture was stirred at room temperature for 94 h , and then concentrated. The residue was purified by flash column chromatography (4% methanol/dichloromethane containing 0.4% aqueous ammonium hydroxide) to provide a white solid (41 mg, 55%). 1H NMR (300 mHz, CD3OD) δ7.16 (m, 2H), 6.95 (m, 2H), 4.74 (m, 1H), 4.32 (m, 1H), 4.1-3.8 (m, 2H), 3.6-3.5 (m, 2H), 3.4-3.2 (m, 2H), 3.2-2.8 (m, 2H), 2.54 (s, 3H), 2.5 (m, 2H), 2.46+2.44 (2s, 3H), 1.75 (m, 3H), 1.43 (m, 1H), 1.23 (m, 1H), ESI MS: (M+H)+=537.4.