Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:8])[CH3:7])=[CH:2]1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>>[CH3:11][N:12]([CH3:14])/[CH:13]=[CH:7]/[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8]
Reactant: CC(=O)c1ccsc1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1ccsc1
Temperature: 25 °C
Yield: 70.1 %

Procedure:
Stir 1-thien-3-ylethanone (1.26 g, 10 mmol) with N,N-dimethylformamide dimethyl acetal (2.66 mL, 20 mmol) at reflux for 4 h. Cool to RT, concentrate and dry in a vacuum oven to give the title compound as a brown solid (1.27 g, 70%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][O:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])[CH:6]=[CH:5]2.[CH2:21]([C:23]1([CH2:30][CH3:31])[CH2:28][C:27](=[O:29])[O:26][C:24]1=[O:25])[CH3:22]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][O:13][C:14]1[CH:15]=[C:16]([NH:17][C:27](=[O:29])[CH2:28][C:23]([CH2:30][CH3:31])([CH2:21][CH3:22])[C:24]([OH:26])=[O:25])[CH:18]=[CH:19][CH:20]=1)[CH:6]=[CH:5]2
Reactant: Cc1ccc2nc(COc3cccc(N)c3)ccc2c1
Reactant: CCC1(CC)CC(=O)OC1=O
Solvent: c1ccncc1
Product: CCC(CC)(CC(=O)Nc1cccc(OCc2ccc3cc(C)ccc3n2)c1)C(=O)O
Reaction time: 0.5 h

Procedure:
2.05 g of 3-(6-methyl-2-quinolinylmethoxy)aniline and 2.42 g of 2,2-diethylsuccinic acid anhydride are stirred in 30 ml of pyridine for 72 hours at 20° and concentrated by evaporation. The residue is suspended in 25 ml of 2N aqueous hydrochloric acid and the suspension is stirred for 30 min. at 20° and filtered. The precipitate is washed with water and crystallised from ethanol to give the title compound in the form of crystals of m.p. 175°, IR (Nujol): inter alia 3600-2600, 3320, 1685, 1545 cm-1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]2[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[N:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N:49]1[CH2:54][CH2:53][CH:52]([NH:55][C:56](N2C=CN=C2)=[O:57])[CH2:51][CH2:50]1>C1(C)C=CC=CC=1.CC(O)C.ClCCl>[N:49]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][N:43]=2)[CH2:54][CH2:53][CH:52]([NH:55][C:56](=[O:57])[NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])[C@@H:18]([OH:26])[C@H:17]3[OH:27])=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)=[O:6])[CH2:51][CH2:50]1
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NC4CCN(c5ccccn5)CC4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
9-((1R,2S,3R,4S)-2,3-Dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-ethyl)-amide (25 mg, 0.044 mmol) is dissolved in toluene (2 ml) and iPrOH (1 ml). N-[1-(2-Pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide (prepared using the procedure described in international patent application WO 01/94368) (12 mg, 0.044 mmol) is added as a solution in dichloromethane. The reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 24 hours. The solvent is removed in vacuo. The title compound is obtained by flash column chromatography (Isolute™ C18, 0-100% acetonitrile in water). MS (ES+) m/e 388.7(MH+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].C(=O)(O)[O-].[Na+].[C:18](Cl)(=[O:20])[CH3:19]>>[Cl:1][C:2]1[N:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH:9][C:18](=[O:20])[CH3:19])=[N:6][C:7]=1[Cl:8]
Reactant: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]

Procedure:
To 1.0 g of 5,6-dichloro-3-nitropyrazinamine in 15 ml acetyl chloride under nitrogen atmosphere at room temperature is added 0.84 g anhydrous sodium bicarbonate. The reaction mixture is then stirred and heated at reflux for 4 days. Excess acetyl chloride is then removed in vacuo and the residue is chromatographed on silica gel. The desired product is eluted from the column with chloroform.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:12][CH2:13][C:14]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)([F:16])[F:15].C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[F:16][C:14]([F:15])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH2:13][CH2:12][S:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Fc1ccc(C(F)(F)CCBr)cc1
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccccc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 36.9 %

Procedure:
To a solution of 2-mercapto-benzoic acid (0.10 g, 0.65 mmol) in acetone (30 ml) are added 1-(3-bromo-1,1-difluoro-propyl)-4-fluoro-benzene (0.16 g, 0.65 mmol) and potassium carbonate (0.27 g, 1.95 mmol) at RT. The reaction mixture is stirred at 70° C. for 2.5 h. The reaction mixture is diluted with water (20 ml), acidified with 2M hydrochloric acid and the aqueous layer is extracted with EtOAc (3×20 ml). The combined organic layers are washed with water (15 ml), brine (15 ml), dried over sodium sulfate and evaporated to dryness. The crude product is purified by column chromatography (silica gel, 80% EtOAc/hexane) to yield 2-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-benzoic acid (0.08 g, 0.24 mmol, 37%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[C:10]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])([CH:19]=O)[C:11]2[C:16]([CH2:17][CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH3:7][O:8][C:9]1[C:10]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])([CH:19]=[CH2:1])[C:11]2[C:16]([CH2:17][CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: CC(C)(C)[O-]
Reactant: COC1=CCc2ccccc2C1(C=O)CCC(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1(CCC(C)C)C(OC)=CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a suspension of methyltriphenylphosphonium bromide (0.62 g, 1.7 mmol) in tetrahydrofuran (3 mL) at 0° C. was added a solution of 1.0 M potassium t-butoxide in tetrahydrofuran (1.5 mL, 1.5 mmol). The mixture was allowed to warm to room temperature and stirred for 1 h. After which, the solution was cooled to 40° C. and a solution of Example 181A (0.15 g, 0.6 mmol) in tetrahydrofuran (3 mL) was added dropwise. The reaction mixture was stirred at −40° C. for 1 h, and then allowed to warm to room temperature and stirred for 2 h. The solution was quenched with saturated NH4Cl solution (15 mL) and extracted with ethyl acetate (3× 10 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. Column chromatography on silica (hexane) afforded product as a colorless oil (0.13 g, 87%). 1H NMR (300 MHz, CDCl3) δ ppm 0.63 (m, 1H), 0.77 (dd, J=12.87, 6.62 Hz, 6H), 0.90 (m, 1H), 1.40 (m, 1H), 1.79 (m, 1H), 2.17 (m, 1H), 3.50 (d, J=3.68 Hz, 2H), 3.59 (s, 3H), 4.99 (m, 3H), 6.00 (dd, J=17.65, 10.66 Hz, 1H), 7.16 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([CH2:50][CH3:51])=[C:48]=[O:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:48]([NH:47][CH2:50][CH3:51])=[O:49])[CH2:42][CH2:41]1)=[O:39]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: CCN=C=O
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)N1CCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 25 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and isocyanato-ethane as starting materials in 25% yield. LCMS for C27H31ClN7O2 (M+H)+: m/z=520.2.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O-:20][C:21]#[N:22].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[C:12]([C:3]1[NH:4][C:5]2[C:10]([C:2]=1[NH:1][C:21]([NH2:22])=[O:20])=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Reactant: N#C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 15.2 %

Procedure:
To a solution of 3-amino-2-benzoyl-6-chloroindole (step 1, 60 mg, 0.21 mmol) in acetic acid (10 ml) was added sodium cyanate (14 mg, 0.21 mmol) and the mixture was stirred for 1.5 h at 90° C. After cooling, the mixture was poured into a saturated sodium bicarbonate (50 ml) and extracted with ethyl acetate (40 ml×2), dried (MgSO4) and concentrated. The residual solids were purified by flash column chromatography eluting with hexane/ethyl acetate (1/1) to give 10 mg (15%) of the title compound as yellow solids.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:17](Cl)=[C:16]([CH:19]([CH3:21])[CH3:20])[C:14](=[O:15])[NH:13][C:11]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]1([SeH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC1C=C([SeH])C=C(C)C=1>>[CH2:1]([O:8][CH2:9][N:10]1[C:17]([Se:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([CH:19]([CH3:21])[CH3:20])[C:14](=[O:15])[NH:13][C:11]1=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [SeH]c1ccccc1
Reactant: CC(C)c1c(Cl)n(COCc2ccccc2)c(=O)[nH]c1=O
Agent: Cc1cc(C)cc([SeH])c1
Product: CC(C)c1c([Se]c2ccccc2)n(COCc2ccccc2)c(=O)[nH]c1=O
Yield: 92 %

Procedure:
The titled compound was prepared in the same manner as described in Example 34 B by using 1-[(benzyloxy)methyl]-6-chloro-5-isopropyluracil and benzeneselenol in place of 6-chloro-1-(ethoxymethyl)-5-isopropyluracil and 3,5-dimethylphenyl selenol.
Reaction SMILES: Cl.C(OC(=O)[N:8]([CH2:12][C:13]1[CH:18]=[C:17]([CH2:19][C:20](=[O:25])[NH:21][CH:22]2[CH2:24][CH2:23]2)[CH:16]=[CH:15][C:14]=1[Cl:26])[CH:9]1[CH2:11][CH2:10]1)(C)(C)C.[OH-].[Na+]>C(Cl)Cl>[Cl:26][C:14]1[CH:15]=[CH:16][C:17]([CH2:19][C:20]([NH:21][CH:22]2[CH2:24][CH2:23]2)=[O:25])=[CH:18][C:13]=1[CH2:12][NH:8][CH:9]1[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CC(=O)NC2CC2)ccc1Cl)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Cc1ccc(Cl)c(CNC2CC2)c1)NC1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
HCl (4M in dioxane, 31 mL) was added to a sol. of (2-chloro-5-cyclopropylcarbamoylmethyl-benzyl)-cyclopropyl-carbamic acid tert-butyl ester (3.14 g, 8.29 mmol) in CH2Cl2 (31 mL) at 0° C. The mixture was stirred for 2 h at 0° C., and was carefully neutralized with aq. 1M NaOH. The layers were separated, and the aq. layer was extracted with CH2Cl2. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield the crude title compound (2.11 g, 91%) that was used further without purification. LC-MS: tR=0.59 min; ES+: 279.32.
Reaction SMILES: CCN=C=NCCCN(C)C.[CH2:12]([NH2:18])[C:13]1[O:17][CH:16]=[CH:15][CH:14]=1.[CH2:19]([O:21][C:22]([C:24]1[C:25]([C:46]2[CH:54]=[CH:53][C:49]([C:50](O)=[O:51])=[CH:48][CH:47]=2)=[C:26]2[C:41](=[O:42])[N:40]3[CH2:43][CH2:44][CH2:45][N:39]3[C:27]2=[N:28][C:29]=1[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)=[O:23])[CH3:20].C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][C:29]2[N:28]=[C:27]3[N:39]4[CH2:45][CH2:44][CH2:43][N:40]4[C:41](=[O:42])[C:26]3=[C:25]([C:46]3[CH:54]=[CH:53][C:49]([C:50]([NH:18][CH2:12][C:13]4[O:17][CH:16]=[CH:15][CH:14]=4)=[O:51])=[CH:48][CH:47]=3)[C:24]=2[C:22]([O:21][CH2:19][CH3:20])=[O:23])=[CH:33][CH:34]=1
Reactant: NCc1ccco1
Reactant: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)O)cc1)c(=O)n1n2CCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(CCc2ccc(F)cc2)nc2c(c1-c1ccc(C(=O)NCc3ccco3)cc1)c(=O)n1n2CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.3 %

Procedure:
EDCI (31 mg, 0.16 mmol) was added to a solution of furfuryl amine (14 mg, 0.15 mmol), the product from Step E (71 mg, 0.15 mmol) and HOBT.H2O (20 mg, 0.15 mmol) in DMF (2.5 mL). The reaction was stirred 4 h at rt and then concentrated at reduced pressure. The remaining material was dissolved in CH2Cl2, washed with water, dried, filtered and concentrated. Chromatography on silica gel afforded the title compound as a yellow solid (30 mg, 0.05 mmol, 33%): 1H NMR (400 MHz, DMSO-d6) δ 9.06 (t, 1H, J=6), 7.89 (d, 2H, J=8), 7.56 (br s, 1H), 7.38 (d, 2H, J=8), 7.22 (br t, 2H J˜8), 7.07 (t, 2H, J=9), 6.37 (br s, 1H), 6.26 (d, 1H, J=3), 4.46 (d, 2H, J=6), 3.90 (m, 4H), 3.77 (t, 2H, J=7), 3.06 (m, 2H), 2.99 (m, 2H), 2.54 (quint., 2H, J=7), 0.78 (t, 3H, J=7) ppm; ESI-MS m/z 569 (M+H)+;
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([O:32][CH2:33][CH3:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[O:30][CH3:31].[Li+].[OH-]>>[CH2:33]([O:32][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:28])[CH3:29])=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[O:30][CH3:31])[C:3]([OH:35])=[O:2])[CH3:34]
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1OC)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1OC)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionic acid methyl ester was treated with LiOH to obtain (S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methoxy-phenyl}-propionic acid as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=3[F:24])[CH:11]=[C:10]([C:25]([F:28])([F:27])[F:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:29]([NH:33][S:34]([C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1)(=[O:36])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([NH:33][S:34]([C:37]1[CH:42]=[C:41]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][C:15]=4[F:24])[CH:11]=[C:10]([C:25]([F:28])([F:26])[F:27])[N:9]=3)[CH:3]=2)[CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: Fc1cc(C(F)(F)F)ccc1-c1cc(C(F)(F)F)nc(-c2cccc(Br)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: CC(C)(C)NS(=O)(=O)c1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4F)cc(C(F)(F)F)n3)c2)c1

Procedure:
3′-[4-(2-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide was prepared from 2-(3-bromo-phenyl)-4-(2-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.105) (0.465 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as light yellow foam (0.54 g), which was subsequently deprotected.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH:11][C:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)=O)=[C:9]([C:25]#[N:26])[C:8]([CH2:27][CH3:28])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:29](C)[Na].OO.C(O)(=O)C>C(O)C.O>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH2:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=4)=[N:26][C:25](=[O:29])[C:9]3=[C:8]([CH2:27][CH3:28])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO[Na]
Reactant: CCc1nn(C2CCCC2)c(NC(=O)Cc2ccc(OC)c(OC)c2)c1C#N
Agent: OO
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(OC)c(OC)c3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
To a mixture of 1-cyclopentyl-3-ethyl-4-cyano-5-[(3,4-dimethoxyphenylmethyl)carbonylamino]-1H-pyrazole (1.0 g, 2.7 mmol), ethanol (500 ml), and NaOCH3 (0.3 g) was added 30% H2O2 (4 ml). The reaction mixture was stirred at room temperature overnight, additional 30% H2O2 (3 equivalents) was added and the reaction mixture was refluxed on a steam bath for 1 hour. Starting material was still present so an additional 3 equivalents of 30% H2O2 was added and the reaction mixture was refluxed for 4 hours. The reaction mixture was stripped to dryness, treated with acetic acid and ethanol and again was stripped to dryness. The oily residue was dissolved in ethanol, water was added and the solution was cooled in an ice-bath. A solid formed which was collected by filtration and dried at 90° C. to afford 0.3 g (30%) of 1-cyclopentyl-3-ethyl-6-(3,4-dimethoxyphenylmethyl)-pyrazolo[3,4-d)pyrimidin-4-one, 1/10 hydrate, as a light yellow solid, m.p. 148°-149° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](/[CH:8]=[CH:9]/[N+:10]([O-:12])=[O:11])[C:3]=1[CH3:13].[BH4-].[Na+]>C(O)(C)C.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][N+:10]([O-:12])=[O:11])[C:3]=1[CH3:13]
Reactant: Cc1c(F)cccc1/C=C/[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: Cc1c(F)cccc1CC[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Analogously to the procedure described in A. K. Sinhababu et al., Tetrahedron Lett. 24 (1983), 227, to a solution of the compound of step 1 (16.85 g, 93.01 mmol) in isopropanol (275 ml) and chloroform (825 ml) were added dry silica gel (110 g) and then in small portions sodium borohydride (7.038 g, 186.02 mmol). The mixture was stirred at room temperature for 0.5 h, then cooled to 0° C. and quenched by slow addition of 10 ml of 5 N hydrochloric acid. After stirring for 10 min, the silica gel was filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 150 ml of DCM and the solution washed with water (75 ml) and brine (75 ml), dried over magnesium sulfate, filtered and evaporated to dryness to give 15.02 g of the title compound as a thick orange oil.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[S:20][N:19]=[C:18]([CH3:21])[CH:17]=1>>[CH3:21][C:18]1[CH:17]=[C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[S:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: Cc1cc(Br)sn1
Product: Cc1cc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)sn1

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611) and 5-bromo-3-methylisothiazole, prepared as described in (U.S. Pat. No. 3,840,665) were coupled according to the procedure described in Example 1A to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)[C:9]([C:11]1[S:24][C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].C(Cl)Cl.C(O)(C(F)(F)F)=O>>[NH2:27][CH2:26][CH2:25][N:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:9]([C:11]1[S:24][C:14]2[C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: CC(C)(C)OC(=O)NCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCN(C(=O)c1cc2c(s1)-c1ccccc1OCC2)c1ccccc1Cl

Procedure:
To a solution of tert-butyl 2-(N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)ethylcarbamate (0.022 g, 0.36 mmol)/in DCM (0.400 mL, 4.93 mmol) was added a solution of 95% TFA/5% water. The reaction was monitored by LC/MS for desired product. Reaction mix concentrated in vacuo, taken into EA and washed with H2O, dried (Na2SO4), concentrated and crude purified by preparative RP-HLPC to give 131 (yield=98% of theoretical). MS: (ESI+) 400.1
Reaction SMILES: COC1NC(C)=C(C(OCC)=O)C(C2C=CC=C(Cl)C=2Cl)N=1.N1C=CC=CC=1.ClC(OCC)=O.Cl.[CH3:36][C:37]1[NH:38][C:39](=[O:61])[N:40]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH:41]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[C:42]=1[C:43]([O:45][CH2:46][CH3:47])=[O:44]>ClCCl.O1CCCC1CO>[CH3:36][CH:37]1[C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:41]([C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[C:49]=2[Cl:55])[N:40]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[C:39](=[O:61])[NH:38]1
Reactant: CCOC(=O)C1=C(C)NC(=O)N(C(=O)OCC)C1c1cccc(Cl)c1Cl
Agent: CCOC(=O)C1=C(C)NC(OC)=NC1c1cccc(Cl)c1Cl
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: OCC1CCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(c2cccc(Cl)c2Cl)N(C(=O)OCC)C(=O)NC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,4-dihydro-2-methoxy-6-methyl-4-(2,3-dichlorophenyl)-5-pyrimidinecarboxylic acid, ethyl ester (1.3 g., 3.8 mmole) in dichloromethane (10 ml.) is cooled to 0° and treated with pyridine (0.6 ml., 7.58 mmole) followed by ethyl chloroformate (0.4 ml., 4.0 mmole). The cooling bath is removed and the reaction is allowed to stir at room temperature overnight. The solvent is then stripped off to provide a colorless solid. This material is dissolved in tetrahydrofuran-methanol (10 ml. of 1:4 mixture) and treated with 2N hydrochloric acid (2 ml.). The reaction is allowed to stir at room temperature for 30 minutes and the solvent is then evaporated. The residue is extracted with ethyl acetate and the combined extracts are washed with sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent is stripped and the residue is crystallized from isopropyl ether to provide 1.25 g. of 3,6-dihydro-4-methyl-6-(2,3-dichlorophenyl)-2-oxo-1,5(2H)pyrimidinedicarboxylic acid, diethyl ester as a colorless solid; m.p. 139.5°-141°. TLC(silica gel; acetone/hexanes, 50:50) Rf =0.44.