Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[N:16][C:17]=3[NH2:19])[N:12]([C@H:20]3[CH2:25][CH2:24][C@@H:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)[N:11]=2)=[CH:6][C:5]=1[F:33])[CH3:2].[C:34]1([CH3:43])[CH:39]=[CH:38][CH:37]=[C:36]([N:40]=[C:41]=[O:42])[CH:35]=1>N1C=CC=CC=1>[NH2:19][C:17]1[N:16]=[CH:15][N:14]=[C:13]2[N:12]([C@H:20]3[CH2:25][CH2:24][C@@H:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)[N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([N:3]([CH2:1][CH3:2])[C:41]([NH:40][C:36]4[CH:37]=[CH:38][CH:39]=[C:34]([CH3:43])[CH:35]=4)=[O:42])=[C:5]([F:33])[CH:6]=3)[C:18]=12
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCNc1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1F
Solvent: c1ccncc1
Product: CCN(C(=O)Nc1cccc(C)c1)c1ccc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
cis-3-[4-(Ethylamino)-3-fluorophenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (80 mg, 0.177 mmol) was dissolved in pyridine (3 mL) then cooled to 0° C. m-Tolylisocyanate (26 mg, 0.194 mmol) was added to the reaction and stirring was continued at 0° C. for 2.5 hours. The reaction mixture was warmed to room temperature and stirred overnight. Additonal m-tolylisocyanate (13 mg, 0.101 mmol) was added to the reaction mixture and stirring was continued for 1 week. The reaction mixture was concentrated under reduced pressure to give the crude product as a light yellow oil (110 mg). Purification was achieved by RP-HPLC (Waters PrepLC 4000, flow rate: 10 mL/min. λ=254 nm Gradient: 10% to 30% acetonitrile/0.1M aqueous ammonium acetate gradient over 40 minutes; Deltapak C18, 300 A, 15 μm, 40×100 mm column). cis-N-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-N-ethyl-N′-(3-methylphenyl)urea was collected as a white solid (10 mg). HPLC-RT: 13.18 min. (flow rate: 1 mL/min λ=254 mn Gradient: 5% to 85% acetonitrile/0.1M aqueous ammonium acetate gradient over 20 min.; Deltapak C18, 300 A, 5 μm, 150×3.9 mm column); m/z (MH+)=586.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][CH2:10][C@H:9]2[C:13]([N:15]2[CH2:24][C@@H:23]([N:25]([CH:32]3[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH2:33]3)[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:22][C@H:16]2[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[O:14])=[CH:4][CH:3]=1.C(O[C:43]1(O[Si](C)(C)C)[CH2:45][CH2:44]1)C.[Na].C([BH3-])#N.C(O)(=O)C>ClCCCl>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11]([CH:43]3[CH2:45][CH2:44]3)[CH2:10][C@H:9]2[C:13]([N:15]2[CH2:24][CH:23]([N:25]([CH:32]3[CH2:37][CH2:36][C:35]([CH3:39])([CH3:38])[CH2:34][CH2:33]3)[C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:22][C@H:16]2[C:17]([N:19]([CH3:21])[CH3:20])=[O:18])=[O:14])=[CH:4][CH:3]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CN(C)C(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(C)C(=O)[C@@H]1CC(N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)[C@@H]1CN(C2CC2)C[C@H]1c1ccc(Cl)cc1
Product: Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of (4S)-1-[(3S,4R)-4-(4-chlorophenyl)pyrrolidine-3-yl]carbonyl-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]-N,N-dimethyl-L-prolineamide (100 mg, 0.18 mmol) prepared in Example E1-1 in DCE (5 ml) was added 1-ethoxycyclopropoxytrimethylsilane (47 mg, 0.27 mmol) and sodium-cyanoborohydride (23 mg, 0.36 mmol), added a catalytic amount of acetic acid, and the solution was stirred at 80° C. for 2 h. After the reaction finished, the solvent was concentrated in vacuo, and extracted with a saturated NaHCO3 aqueous solution and EtOAc. The organic solution was dried over MgSO4, concentrated in vacuo, and the residue was purified by HPLC. This TFA salt of the compound was treated according to the procedure described in Step G of Example A1 to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19](=[O:28])[CH:20]([NH2:27])[CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.ClCCl>[CH3:17][O:18][C:19](=[O:28])[CH:20]([NH:27][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)C(N)C1CCCCC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-tert.butoxycarbonylamino-3,3-dimethyl butyric acid (500 mg, 2.16 mmol), Amino-cyclohexyl-acetic acid methyl ester (444 mg, 2.59 mmol) and HATU (2 g, 5.40 mmol) in DMF (20 mL) was added diisopropylethylamine (1.88 mL, 10.8 mmol). The solution was stirred for 1 hrs at r.t. and diluted with dichloromethane (40 mL). This solution washed with aqueous. NaHCO3 (sat.) and water (×2), dried and concentrated. The product was >95% pure. M+H+385.4.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:37])[CH2:14][CH2:15][CH2:16][N:17]([C:24](=[O:36])[C@H:25]([NH:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)[CH3:26])[CH2:18][CH:19](OC)OC)(C)(C)C.C([SiH](CC)CC)C.C(N(CC)CC)C>ClCCl>[Cl:35][C:30]1[CH:29]=[C:28]([N:27]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][CH2:14][C:13]([OH:12])=[O:37])[C:24](=[O:36])[C@H:25]2[CH3:26])[CH:33]=[CH:32][C:31]=1[Cl:34]
Reactant: COC(CN(CCCC(=O)OC(C)(C)C)C(=O)[C@@H](C)Nc1ccc(Cl)c(Cl)c1)OC
Agent: CC[SiH](CC)CC
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1C(=O)N(CCCC(=O)O)CCN1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
0.69 ml (9.00 mmol) of trifluoroacetic acid was added to a cooled solution (0° C.) of 0.28 g (0.60 mmol) 4-[[(R)-2-(3,4-dichloro-phenylamino)-propionyl]-(2,2-dimethoxy-ethyl)-amino]-butyric acid tert-butyl ester (62% ee) in 6 ml of dichloromethane. After 30 min the ice bath was removed, then after 1 h, 0.49 ml (3.00 mmol) of triethylsilane was added. After 16 h the reaction mixture was cooled to 0° C. and treated with 1.25 ml (9.00 mmol) of triethylamine, then after 15 min partitioned between Et2O (3×)/aqueous 10% KHSO4, the organic phases were washed with aqueous 10% KHSO4 and aqueous 10% NaCl, dried over Na2SO4 and evaporated. The residue was precipitated (dichloromethane/n-pentane) to give 0.198 g (96%) of the titled compound as brown viscous oil. MS: 345.07 (MH+, 2Cl).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][OH:22])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].O[N:24]1[C:32](=[O:33])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]1=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.N#N>C(Cl)Cl.O>[Si:1]([O:8][C@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([CH2:21][O:22][N:24]2[C:32](=[O:33])[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]2=[O:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.0 g, 6.0 mmol) in CH2Cl2 (15.0 mL) was added 2-hydroxyisoindoline-1,3-dione (978 mg, 6.0 mmol) and triphenylphosphine (2.36 g, 9.0 mmol). The resultant mixture was cooled to 0° C. and diisopropylazodicarboxylate (1.78 ml, 9.0 mmol) was slowly added drop wise under N2 atmosphere. The reaction mixture was stirred at ambient temperature for 48 h. To the reaction mixture, H2O (100 mL) was added and extracted with CH2Cl2. The organic layers washed with brine. Dried over anhydrous Na2SO4, filtered and concentrated to provide yellow oil, which was purified by flash chromatography (50% EtOAc-hexane) to yield (2S,4R)-tert-butyl 4-(tert-butyldimethylsilyloxy)-2-((1,3-dioxoisoindolin-2-yloxy)methyl)pyrrolidine-1-carboxylate as light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH3:23])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]1[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C:26]1[C:27]([CH:33]=O)=[N:28][CH:29]=[C:30]([CH3:32])[CH:31]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:24])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:33][C:27]1[C:26]([CH3:25])=[CH:31][C:30]([CH3:32])=[CH:29][N:28]=1)[CH:13]1[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)[CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: CN(CCCCNC1CCCc2cccnc21)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCN(C)C(=O)OC(C)(C)C)C2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of methyl-[4-(5,6,7,8-tetrahydro-quinolin-8-ylamino)-butyl]-carbamic acid tert-butyl ester, 3,5-dimethyl-pyridine-2-carbaldehyde and NaBH(OAc)3 in CH2Cl2 gave {4-[(3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino}-butyl}-methyl-carbamic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.20-1.29 (m, 4H), 1.41 (s, 9H), 1.60-1.65 (m, 1H), 1.86 (s, 3H), 1.93-2.00 (m, 3H), 2.25 (s, 3H), 2.38 (s, 3H), 2.45-2.890 (m, 7H), 2.96-3.04 (m, 2H), 3.94-4.05 (m, 3H), 7.01 (dd, 1H, J=7.6, 4.6 Hz), 7.19 (s, 1H), 7.30 (d, 1H, J=7.8 Hz), 8.15 (s, 1H), 8.45 (d, 1H, J=3.8 Hz). Conversion to the HBr salt according to General Procedure D gave COMPOUND 370 as a white solid. 1H NMR (D2O) δ 1.39-1.49 (m, 4H), 1.78-1.85 (m, 1H), 2.03-2.21 (m, 2H), 2.40-2.55 (m, 8H), 2.62 (s, 3H), 2.71-2.80 (m, 1H), 2.86-2.91 (m, 2H), 3.00-3.04 (m, 2H), 4.13 (d, 1H, J=17.7 Hz), 4.38 (d, 1H, J=17.8 Hz), 4.47-4.51 (m, 1H), 7.84-7.89 (m, 1H), 8.21 (s, 1H), 8.35 (d, 1H, J=7.9 Hz), 8.46 (s, 1H), 8.60 (d, 1H, J=5.7 Hz); 13C NMR (D2O) δ 19.41, 19.92, 22.88, 23.03, 26.19, 27.77, 30.23, 35.44, 51.34, 54.26, 63.52, 128.25, 138.90, 139.74, 140.04, 141.74, 143.13, 150.52, 151.24, 151.60, 153.54; ES-MS m/z 353 (M+H). Anal Calcd. For C22H32N4.4.3(HBr).3.3(H2O).0.5(C4H10O): C, 36.17; H, 6.06; N, 7.03; Br, 43.11. Found: C, 36.31; H, 5.93; N, 6.95; Br, 42.84.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][C:12](=[O:17])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([S:32]([C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[CH:10]([CH2:11][C:12](=[O:17])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CC(=O)CC(C1)N2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CC(=O)CC(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.3 %

Procedure:
7-Oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester (11.7 g, 48.6 mmol) was dissolved in methylene chloride (100 mL). Et3N (13.5 mL, 97.3 mmol) and 4-chlorobenzenesulfonyl chloride (12.3 g, 58.4 mmol) were added and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with methylene chloride (50 mL) and washed with saturated NaHCO3 (50 mL). The aqueous phase was separated and extracted once with methylene chloride (50 mL). The combined organic phases were then dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified on a silica gel column (eluant hexane/EtOAc, 20/1 to 1/1) to give 16.6 g (82%) of 9-(4-chloro-benzenesulfonyl)-7-oxo-3,9-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester as a yellow oil. Retention time (min)=2.164, method [1], MS (ESI) 437.0 (M+Na); 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 4.40 (d, J=4.4 Hz, 2H), 4.18-3.95 (m, 2H), 2.95-2.81 (m, 2H), 2.59 (dd, J=15.9, 6.0 Hz, 2H), 2.38 (d, J=15.9 Hz, 2H), 1.40 (s, 9H).
Reaction SMILES: CO[C:3](=O)[C:4]([OH:9])(C)[CH2:5]C=C.[CH3:11][Mg+].[Br-].[CH2:14]1[CH2:18][O:17][CH2:16][CH2:15]1>>[CH3:3][C:4]([OH:9])([C:16]([CH3:11])([OH:17])[CH2:15][CH:14]=[CH2:18])[CH3:5]
Reactant: C=CCC(C)(O)C(=O)OC
Reactant: C[Mg+]
Reactant: C1CCOC1
Agent: [Br-]
Product: C=CCC(C)(O)C(C)(C)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 2-hydroxy-2-methylpent-4-enoic acid methyl ester (1.12 g, 7.77 mmol) in THF (8 mL) at 0° C. is added MeMgBr (10 mL, 30 mmol) drop wise. The mixture is stirred for 3 h at room temperature and then quenched with sat. NH4Cl. It is then extracted with Et2O (3×50 mL). The organic layers are washed with water and brine, dried and concentrated to afford 2,3-dimethylhex-5-ene-2,3-diol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][CH:9]1[CH:11]1[CH2:13][CH2:12]1.[CH2:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(C)(C)C.[Na+].C(OCC)(=O)C>C(COC)OC>[CH2:14]([NH:21][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][CH:9]1[CH:11]1[CH2:13][CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1ccccc1C1CC1C1CC1
Reactant: NCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: c1ccc(CNc2ccccc2C2CC2C2CC2)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
3.7 g of 2-(2-bromophenyl)bicyclopropyl (15.6 mmol, trans/cis ratio of about 3:1), 2.0 g of benzylamine (18.7 mmol), 2.1 g of sodium tert-butanolate (21.8 mmol), 3.5 mg of Pd(II) acetate (0.016 mmol) and 8.6 mg of R(−)-di-tert-butyl-[1-[(S)-2-(dicyclohexylphosphanyl)-ferrocenyl]ethyl]phosphine (0.016 mmol) are dissolved in 30 ml of dimethoxyethane. The reaction mixture is heated to 70° C. and stirred for 24 hours. After cooling, ethyl acetate is added. The organic phase is washed with water. The solvent is removed using a water jet vacuum and the residue is dried. The product is purified by column chromatography on silica gel (eluant:ethyl acetate/hexane 1:15). 3.47 g of benzyl(2-bicyclopropyl-2-yl-phenyl)amine (84% of theory) are obtained in the form of a brown oil (trans/cis ratio of about 3:1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH2:17][C:18]([OH:20])=O)=[CH:15][N:16]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:3]([CH3:21])=[C:4]([S:8]([NH:11][C:12]2[S:13][C:14]([CH2:17][C:18]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[O:20])=[CH:15][N:16]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Nc1ncc(CC(=O)O)s1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(Cl)cccc1S(=O)(=O)Nc1ncc(CC(=O)N2CCOCC2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
To a solution of (2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-5-yl)acetic acid (Example 3) (0.09 g, 0.25 mmol) in CH2Cl2 (5.0 mL) and DMF (0.5 mL) were added EDCI (0.05 g, 0.27 mmol), DMAP (0.02 g, 0.12 mmol), triethylamine (0.1 mL, 0.75 mmol) and morpholine (0.03 mL, 0.30 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was then washed with 1 M HCl (2×15 mL) and the organic layer was collected. The organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification using preparative HPLC afforded the desired product (0.01 g) in 10% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-])=O)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]>C(O)(=O)C.C(O)C.ClCCl.[Zn]>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(N)c1
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of [4-(3-nitro-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (390 mg, 0.96 mmol) in acetic acid (3 mL) and ethanol (15 mL) was added zinc powder portionwise. After being heated at reflux for 2 hours, the mixture was cooled to room temperature, diluted with dichloromethane (30 mL), filtered through a glass funnel and concentrated in vacuo. The residue was purified by flash column (gradient elution, 0-5% methanol in dichloromethane) to afford [4-(3-amino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (300 mg, 83%) as a semisolid. MS cald. for C17H22N4O4S 378, obsd. (ESI+) [(M+H)+] 379.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:12])[F:11])[NH2:5].[CH3:13][C:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1.N1C=CC=CC=1.Cl>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:17]([C:14]2([CH3:13])[CH2:16][CH2:15]2)=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([F:11])[F:12]
Reactant: Nc1ccc(OC(F)F)c(Br)c1
Reactant: CC1(C(=O)Cl)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC1(C(=O)Nc2ccc(OC(F)F)c(Br)c2)CC1
Yield: 96 %

Procedure:
In the same manner as in Example 3 but using 3-bromo-4-difluoromethoxyaniline (2.4 g) and 1-methylcyclopropanecarbonyl chloride (1.2 g) with pyridine (0.8 g) as the hydrogen chloride-eliminating agent and ethyl acetate as the solvent, the operations were effected to give N-(3-bromo-4-difluoromethoxyphenyl)-1-methylcyclopropanecarboxamide (3.1 g). M.P., 71°-71.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(O)(C(F)(F)F)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:33][S:34][C:35]1[O:36][C:37]2[CH:43]=[C:42]([CH:44]=O)[CH:41]=[CH:40][C:38]=2[N:39]=1>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:44][C:42]2[CH:41]=[CH:40][C:38]3[N:39]=[C:35]([S:34][CH3:33])[O:36][C:37]=3[CH:43]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CSc1nc2ccc(C=O)cc2o1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1nc2ccc(CNc3ccc(Br)cc3[N+](=O)[O-])cc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 4-bromo-2-nitroaniline (400 mg, 1.84 mmol) and TFA (1.89 mL) in DCM (8 mL) at −5° C. was added NaBH(OAc)3 (1.17 g, 5.52 mmol). Then to the mixture at 0° C. was added a solution of 2-(methylthio)benzo[d]oxazole-6-carbaldehyde (391 mg, 2.03 mmol) in DCM (7 mL), and the mixture was stirred at 0° C. for 2 h. The mixture was diluted with DCM and washed with H2O, aq NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 20:1 to 10:1 petroleum ether/ethyl acetate to give 4-bromo-N-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)-2-nitroaniline as a yellow solid (704 mg, 97.4%). 1H NMR (300 MHz, DMSO-d6) δ 8.80 (t, 1H), 8.15 (s, 1H), 7.64 (s, 1H), 7.50-7.60 (m, 2H), 7.35 (d, J=8.4 Hz, 1H), 6.90 (d, J=9.3 Hz, 1H), 4.72 (d, J=6.6 Hz, 1H), 2.73 (s, 3H). LCMS (ESI) m/z 394 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10]2)=[C:5]([CH2:20][CH3:21])[CH:4]=1)#[CH:2].[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1)[CH3:23]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:29]3[CH:30]=[CH:31][C:26]([C:25]([O:24][CH2:22][CH3:23])=[O:33])=[CH:27][CH:28]=3)=[CH:4][C:5]=2[CH2:20][CH3:21])[CH2:11][CH2:10]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OCc3ccccc3)CC2)c(CC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(CC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90, 90.0 mg, 0.33 mmol) and ethyl-4-iodo benzoate (Reagent A, 100.0 mg, 0.36 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (77 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 100.0 mg (72%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]12[CH2:13][CH2:12]1.C([O-])(=O)C.[Na+].[Br:19]Br>C(Cl)Cl.CCOCC>[Br:19][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][C:8](=[O:11])[C:7]12[CH2:13][CH2:12]1
Reactant: O=C1Nc2c(F)cccc2C12CC2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: O=C1Nc2c(F)cc(Br)cc2C12CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
7′-Fluorospiro[cyclopropane-1,3′-indol]-2′(1′H)-one (0.54 g, 3.05 mmol) was dissolved in 20 mL of CH2Cl2 and sodium acetate (0.28 g, 3.36 mmol) was added followed by bromine (0.173 mL, 3.36 mmol). The mixture was stirred at 25° C. for 16 h then diluted with ether and washed with Na2S3O3, sodium bicarbonate, water, brine, dried over MgSO4, and concentrated. Purification by flash chromatography (15% acetone/hexane) afforded 5′-Bromo-7′-fluorospiro[cyclopropane-1,3′-indol]-2′(1′H)-one (0.64 g, 82%) as a white solid:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][NH:8][N:7]=1.Cl[CH2:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:27][CH:28]=2)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:29]1([C:26]2[O:27][CH:28]=[C:24]([CH2:23][O:22][C:21]3[CH:20]=[CH:19][C:18]([CH2:17][N:8]4[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)=[N:7]4)=[CH:36][CH:35]=3)[N:25]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1c[nH]nc1-c1cccs1
Reactant: ClCc1ccc(OCc2coc(-c3ccccc3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc(OCc3coc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
A mixture of ethyl 3-(2-thienyl)-1H-pyrazole-4-caboxylate (1.43 g), 4-(4-chloromethylphenoxy)methyl-2-phenyloxazole (1.88 g), potassium carbonate (1.30 g), and N,N-dimethylformamide (30 ml) was stirred at 80° C. for 8 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-[4-(2-phenyl-4-oxazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate as colorless crystals (2.81 g, yield: 92%) from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 114˜115° C.