Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN1CCOCC1.[N:8]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3([C:22]([OH:24])=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[N:9]1.Cl.Cl.[NH:27]1[CH2:31][CH2:30][C:29]2([C:39]3[CH:38]=[CH:37][N:36]=[CH:35][C:34]=3[C:33](=[O:40])[O:32]2)[CH2:28]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(O)(C(F)(F)F)=O>CN(C=O)C>[N:8]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3([C:22]([N:27]4[CH2:31][CH2:30][C@@:29]5([C:39]6[CH:38]=[CH:37][N:36]=[CH:35][C:34]=6[C:33](=[O:40])[O:32]5)[CH2:28]4)=[O:24])[CH2:20][CH2:21]3)=[CH:17][CH:18]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: O=C(O)C1(c2ccc(-n3cccn3)cc2)CC1
Reactant: O=C1OC2(CCNC2)c2ccncc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(-n5cccn5)cc4)CC3)C2)c2ccncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
4-Methylmorpholine (55 μL, 0.50 mmol) was added to a mixture of 1-[4-(1H-pyrazol-1-yl)phenyl]cyclopropanecarboxylic acid (0.10 mmol), 3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one dihydrochloride (0.026 g, 0.10 mmol), and BOP (0.057 g, 0.11 mmol) in DMF (1 mL). The mixture was stirred at room temperature for 2 hours, then adjusted to be acidic (PH=2.0) with TFA, and then diluted with DMF (0.8 mL). The resulting solution was purified by a prep-LCMS followed by chiral HPLC to give (1R)-1′-({1-[4-(1H-pyrazol-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[furo[3,4-c]pyridine-1,3′-pyrrolidin]-3-one (30%). MS (ESI): (M+H)+=401.1
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:30]([O:33][CH2:34][C:35]1[C:40](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:38]=[CH:37][C:36]=1[N:50]1[CH2:62][CH2:61][N:53]2[C:54]3[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=3[CH:60]=[C:52]2[C:51]1=[O:63])(=[O:32])[CH3:31].C([O-])([O-])=O.[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl>[C:30]([O:33][CH2:34][C:35]1[C:36]([N:50]2[CH2:62][CH2:61][N:53]3[C:54]4[CH2:55][CH2:56][CH2:57][CH2:58][C:59]=4[CH:60]=[C:52]3[C:51]2=[O:63])=[CH:37][CH:38]=[CH:39][C:40]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, 301a (500 mg, 1.077 mmol), 2-(2-(hydroxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 114a (546 mg, 1.292 mmol), Pd(PPh3)4 (62 mg, 0.054 mmol), Na2CO3 aqueous solution (1.0 N, 3.55 mL, 3.55 mmol), 1,2-dimethoxyethane (4.3 mL) were added. The mixture was reacted in microwave at 130° C. for 10 min. Methylene chloride (200 mL) was added and the resulting mixture was washed with water (3×30 mL), brine (30 mL), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (methanol:methylene chloride=5:95) gave 301b.
Reaction SMILES: Br[CH2:2][CH:3]([C:5]1[C:6]([F:14])=[C:7]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:8]#[N:9])[OH:4].[C:15]([NH2:19])([CH3:18])([CH3:17])[CH3:16].CCO>C(Cl)Cl>[C:15]([NH:19][CH2:2][CH:3]([C:5]1[C:6]([F:14])=[C:7]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:8]#[N:9])[OH:4])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)N
Reactant: N#Cc1cc(F)cc(C(O)CBr)c1F
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)NCC(O)c1cc(F)cc(C#N)c1F

Procedure:
A stirred mixture of 10.2 g of 3-(2-bromo-1-hydroxyethyl)-2,5-difluorobenzonitrile, 100 mL of t-butylamine and 100 mL of EtOH is heated at reflux under N2 for 2 hours. The mixture is stripped in vacuo and the residue is partitioned between 50 mL of H2O and 100 mL of 10% NaOH and 3×100 mL of CH2Cl2. The CH2Cl2 layers are combined, washed with 2×50 mL of H2O, dried with Na2SO4 and evaporated in vacuo to afford 9.44 g of partly crystallized dark orange material. This material is dissolved in 100 mL of CH2Cl2 and extracted with 50 mL of 10% aqueous HCl, 50 mL of H2O, 50 mL of 10% HCl and 50 mL of H2O. The combined aqueous acidic extracts are basified with 10% aqueous NaOH in ice and extracted with 3×100 mL of CH2Cl2. The CH2Cl2 extracts are washed with 2×50 mL of H2O, dried with Na2SO4 and stripped in vacuo to give an off-white solid. Recrystallization from hexane gives 5.8 g of 3-[2-(tert-butylamino)-1-hydroxyethyl]-2,5-difluorobenzonitrile, m.p. 99°-101° C. The mass spectrum shows an M+1 ion at 255. Infrared and NMR spectral data are consistent.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8]2([C:19]4=[CH:20][C:21]5[O:25][CH2:24][O:23][C:22]=5[CH:26]=[C:18]4[O:17][CH2:16]2)[C:9](=[O:15])[NH:10]3)=[CH:2]1>CS(C)=O>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C@:8]2([C:19]4=[CH:20][C:21]5[O:25][CH2:24][O:23][C:22]=5[CH:26]=[C:18]4[O:17][CH2:16]2)[C:9](=[O:15])[NH:10]3)=[CH:2]1
Reactant: O=C1Nc2cccc(-c3ccoc3)c2C12COc1cc3c(cc12)OCO3
Solvent: CS(C)=O
Product: O=C1Nc2cccc(-c3ccoc3)c2[C@@]12COc1cc3c(cc12)OCO3
Yield: 40 %

Procedure:
4′-Furan-3-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.25 g) was resolved on a semi-preparative chiral column (CHIRALPAK-IA, Chiral Technologies, Inc.) and eluted with 5% acetonitrile in tert-butylmethylether at 30 mL/min. Each run consisted of 50 mg of the racemate dissolved first in dimethylsulfoxide (0.15 mL) and diluted with acetonitrile (0.85 mL) and tert-butylmethylether (1.00 mL). The product isolated was dissolved in dimethylsulfoxide (2.0 mL), precipitated with water (50.0 mL), filtered and air dried to afford (7R)-4′-furan-3-ylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.10 g, 75%) as a colorless solid. This enantiomer was the second to elute: mp 229-231° C. (water); 1H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H), 7.57 (dd, J=1.6, 1.6 Hz, 1H), 7.27 (dd, J=7.8, 7.8 Hz, 1H), 7.03 (s, 1H), 6.90 (dd, J=7.1, 7.1 Hz, 2H), 6.55 (s, 1H), 6.32 (s, 1H), 6.06 (d, J=0.8 Hz, 1H), 5.92 (d, J=4.8 Hz, 2H), 4.60 (d, J=9.4 Hz, 1H), 4.44 (d, J=9.4 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 179.2, 156.1, 148.8, 143.8, 143.3, 142.0, 140.5, 130.5, 129.6, 128.9, 124.3, 123.2, 121.4, 111.3, 109.7, 103.3, 101.9, 93.7, 77.6, 58.6; MS (ES+) m/z 347.9 (M+1).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.Br[C:24]1[CH:25]=[CH:26][C:27]([F:34])=[C:28]([CH:33]=1)[C:29]([O:31][CH3:32])=[O:30]>C(Cl)Cl>[F:34][C:27]1[CH:26]=[CH:25][C:24]([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=2)=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COC(=O)c1cc(Br)ccc1F
Solvent: ClCCl
Product: COC(=O)c1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)ccc1F

Procedure:
tert-Butyl 4-[4-fluoro-3-(methoxycarbonyl)phenyl]-3,6-dihydropyridine-1(2H)-carboxylate was synthesized as described for INTERMEDIATE 32 using tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (prepared according to Eastwood, P. R. Tetrahedron Lett., 41, 19, 2000, 3705-3708) and methyl 5-bromo-2-fluorobenzoate as starting material and PdCl2dppf.CH2Cl2 as a catalyst.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.C1(CNC2C=CC(S(C)(=O)=O)=CC=2)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:27]1([CH2:26][N:15]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:32])=[O:3])=[CH:8][N:9]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)s1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Agent: CS(=O)(=O)c1ccc(NCC2CCCC2)cc1
Product: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(4-methanesulfonyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[C:14]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[CH:13][C:12]([C:22]([O:24]C(C)(C)C)=[O:23])=[C:11]2[CH3:29])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]2[C:14]([CH:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)=[CH:13][C:12]([C:22]([OH:24])=[O:23])=[C:11]2[CH3:29])=[CH:6][CH:7]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)cc(C2CCN(C)CC2)n1CCc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)O)cc(C2CCN(C)CC2)n1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 230 mg portion of tert-butyl 1-[2-(4-fluorophenyl)ethyl]-2-methyl-5-(1-methylpiperidin-4-yl)-1H-pyrrole-3-carboxylate was dissolved in 2 ml of dichloromethane, and 1 ml of trifluoroacetic acid was added under ice-cooling, followed by stirring at room temperature for 1.5 hours. The reaction liquid was concentrated under a reduced pressure, and a saturated sodium bicarbonate aqueous solution was added, followed by three times extractions with chloroform. After drying the organic layer with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (methanol:chloroform=10:90-15:85-20:80) to obtain 124 mg of 1-[2-(4-fluorophenyl)ethyl]-2-methyl-5-(1-methylpiperidin-4-yl)-1H-pyrrole-3-carboxylic acid as a colorless solid.
Reaction SMILES: [ClH:1].Cl.[CH2:3](OC1C=CC(C2(O)CCCCC2CCN2CCN(C)CC2)=CC=1F)C1C=CC=CC=1.Cl.Cl.[CH2:36]([O:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]([C:58]2([OH:64])[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]2)[CH2:51][N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)=[CH:46][C:45]=1[F:65])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[ClH:1].[ClH:1].[CH2:36]([O:43][C:44]1[CH:49]=[CH:48][C:47]([CH:50]([C:58]2([OH:64])[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]2)[CH2:51][N:52]2[CH2:57][CH2:56][N:55]([CH3:3])[CH2:54][CH2:53]2)=[CH:46][C:45]=1[F:65])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CN1CCN(CCC2CCCCC2(O)c2ccc(OCc3ccccc3)c(F)c2)CC1
Reactant: OC1(C(CN2CCNCC2)c2ccc(OCc3ccccc3)c(F)c2)CCCCC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(OCc3ccccc3)c(F)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 1-[1-[4-(benzyloxy)-3-fluorophenyl]-2-(4-methylpiperazin-1-yl)ethylcyclohexanol dihydrochloride was prepared from 1-{1-[4-(benzyloxy)-3-fluorophenyl]-2-piperazin-1-ylethyl}cyclohexanol dihydrochloride (See Example 413). MS (ES) m/z 427.1; HRMS: calcd for C26H35FN2O2+H+, 427.27553; found (ESI, [M+H]+), 427.2756.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5]([O-:7])=[O:6].[K+].[CH2:11](I)[CH3:12]>CN(C=O)C>[CH2:11]([O:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[CH2:3][CH2:2][OH:1])[CH3:12]
Reactant: CC(C)(CCO)C(=O)[O-]
Reactant: CCI
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)CCO
Reaction time: 2 h
Yield: 169 %

Procedure:
To a solution of potassium 4-hydroxy-2,2-dimethylbutyrate (1.92 mmol; 327 mg) in DMF (6 mL) is added ethyl iodide (2.30 mmol; 359 mg). The reaction mixture is stirred for 2 hours, and quenched with saturated ammonium chloride solution. The product is extracted three times with EtOAc. The combined organic layer is washed with aqueous 0.1 M HCl then brine, dried over Na2SO4, filtered, concentrated under reduced pressure to give 4-Hydroxy-2,2-dimethylbutyric acid ethyl ester (520 mg) contaminated with DMF.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([C@@H:49]5[CH2:53][CH2:52][CH2:51][N:50]5[CH3:54])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:8]([C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][Si](C(C)(C)C)(C)C)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:25][C:26]([NH:28][C@@H:29]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@H:32]([O:39][C:40]3[CH:41]=[CH:42][C:43]4[N:44]([C:46]([C@@H:49]5[CH2:53][CH2:52][CH2:51][N:50]5[CH3:54])=[N:47][N:48]=4)[CH:45]=3)[CH2:31][CH2:30]2)=[O:27])[N:8]([C:10]2[CH:11]=[C:12]([OH:17])[CH:13]=[C:14]([Cl:16])[CH:15]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cc(Cl)cc(O[Si](C)(C)C(C)(C)C)c4)c4ccccc43)cn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cc(O)cc(Cl)c4)c4ccccc43)cn12
Yield: 30 %

Procedure:
A solution of Intermediate 62e (265 mg, 0.32 mmol) and TBAF (1M in THF, 0.38 mL, 0.38 mmol) in THF (3 mL) was stirred at RT for 1.3 h, then diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the impure product. This residue was purified further by HPLC (XBridge C18 column, 35-98% MeCN in H2O, 0.1% NH4OH) to give the product. This residue purified further by HPLC (XBridge C18 column, 20-98% MeCN in H2O, 0.1% NH4OH) to give the title compound (63 mg, 30%). LCMS (Method 5): Rt 3.61 min, m/z 655 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.93-2.12 (5H, m), 2.13 (3H, s), 2.14-2.25 (3H, m), 2.34-2.37 (1H, m), 3.12-3.15 (1H, m), 3.99 (1H, t, J=8.2 Hz), 4.80-4.83 (1H, m), 5.39 (1H, t, J=4.2 Hz), 6.31 (1H, s), 6.78 (1H, s), 6.89 (1H, s), 6.96 (1H, s), 7.15 (1H, d, J=8.6 Hz), 7.29-7.41 (5H, m), 7.75 (1H, dd, J=9.9, 0.8 Hz), 8.14 (1H, s), 8.25 (1H, d, J=2.1 Hz).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:17][F:18])([CH3:16])[C:4](=[O:15])[CH:5](Br)[O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.O.O.O.O.C1(S(O)(=O)=O)C2C=CC=C(S(O)(=O)=O)C=2C=CC=1>C(#N)C>[F:1][CH2:2][C:3]([CH2:17][F:18])([CH3:16])[C:4](=[O:15])[CH:5]([O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: CC(CF)(CF)C(=O)C(Br)Oc1ccc(Cl)cc1
Reactant: c1c[nH]cn1
Agent: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Solvent: O
Solvent: CC#N
Product: CC(CF)(CF)C(=O)C(Oc1ccc(Cl)cc1)n1ccnc1
Yield: 23.7 %

Procedure:
61.5 g (0.18 mol) of 3,3-bis-fluoromethyl-1-bromo-1-(4-chlorophenoxy)-butan-2-one were stirred with 27.2 g (0.4 mol) of imidazole in 500 ml of acetonitrile at 45° C. for 4 hours. The solvent was distilled off under a waterpump vacuum, the oil which remained was taken up in 500 ml of methylene chloride, the organic phase was washed twice with 1,000 ml of water and dried over sodium sulphate and the solvent was distilled off. The oil was taken up in acetone, 36 g (0.1 mol) of 1,5-naphthalenedisulphonic acid tetrahydrate were added and the precipitate formed was filtered off. The precipitate (the 1,5-naphthalenedisulphonate of the compound of Example 3) was treated with sodium bicarbonate solution. 14 g (24% of theory) of 3,3-bis-fluoromethyl-1-(4-chlorophenoxy)-1-(imidazol-1-yl)-butan-2-one were obtained as a viscous oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[CH:7]=[CH2:8])[CH3:2].B1C2CCCC1CCC2.C([O-])(O)=[O:27].[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][CH:6]([C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[N:13][CH:14]=1)[CH2:7][CH2:8][OH:27])[CH3:2]
Reactant: C=CC(CC(=O)OCC)c1cnc(C)nc1
Reactant: O=C([O-])O
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(CCO)c1cnc(C)nc1
Reaction time: 18 h

Procedure:
To a stirred solution of 4-4 (422 mg, 1.92 mmol) in THF was added 5.75 mL of 9-BBN (0.5 M/THF). After 18 hours, a slurry of NaBO3 (2.35 g) and NaHCO3 (2.42 g) in H20 (10 mL) was added and the mixture stirred vigorously for 1 hour. The mixture was extracted with CHCl3, washed with brine, and dried over MgSO4. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 3% EtOH/EtOAc) to give 4-5 as a clear oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[N:7]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][NH2:30]>CN1CCCC1=O>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][NH:30][C:2]1[C:3]2[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)[N:7]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: CCCc1nn(C)c2c(Cl)nc(-c3ccc(C(=O)OC)cc3)nc12
Solvent: CN1CCCC1=O
Product: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(-c3ccc(C(=O)OC)cc3)nc12
Yield: 87.8 %

Procedure:
A mixture of 1.8 g of methyl 4-[7-chloro-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]phenylcarboxylate (“B”) and 1.5 g of 3-chloro-4-methoxybenzylamine in 20 ml of N-methylpyrrolidone is heated at 110° for 4 hours. After cooling, it is worked up in the customary manner. 2.2 g of methyl 4-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo-[4,3-d]pyrimidin-5-yl]benzoate are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=O)[CH:7]=1.C([SiH](CC)CC)C>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:17])=[C:6]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: Cc1ccc(Br)cc1C(=O)c1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: Cc1ccc(Br)cc1Cc1ccc(Cl)cc1
Temperature: 0 °C
Yield: 61.5 %

Procedure:
(5-Bromo-2-methylphenyl)(4-chlorophenyl)methanone (2, 37.0 g, 121 mmol) and triethylsilane (77.3 mL, 484 mmol) were dissolved in 300 mL of CH3CN and cooled to 0° C. BF3OEt2 (91 mL, 726 mmol) was added and the reaction was heated to 60° C. for 2 hours. GCMS was used to monitor the reaction. Upon completion, the reaction was cooled to 0° C. and quenched with 500 mL saturated aqueous NaHCO3. The aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4, filtered, and the solvent removed in vacuo. The crude solid was slurried in 20% EtOAc/hexanes and passed over a silica plug to remove residual salts. Concentration of the filtrate provided the title compound as a white solid (22.0 g, 62% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 (d, J=2.0 Hz, 1 H), 7.21-7.31 (m, 3 H), 7.04 (d, J=8.3 Hz, 2 H), 7.04 (d, J=8.1 Hz, 2 H), 3.91 (s, 2 H), 2.17 (s, 3 H). GCMS (CH4—Cl) [M+H]+=295.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=O)[O:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:22][NH:23][NH2:24]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:7])[N:24]([NH:23][CH3:22])[C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CNN
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Product: CNn1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
In the same manner as in Reference Example 6, 6-chloro-4-phenylisocoumarin-3-carboxylic acid and methylhydrazine were reacted to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[N:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)=O.CSC>C1COCC1>[CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[N:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)[CH2:9][CH2:10]1
Reactant: CC(C)(C)C(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Yield: 52.5 %

Procedure:
To a solution of 2,2-dimethyl-1-[4-(6-nitro-pyridin-3-yl)-piperazin-1-yl]-propan-1-one (1.0 g, 3.42 mmol) in THF (10 mL) was added BH3.DMS (0.6 mL, 6.84 mmol) at r.t. and the reaction was then heated to reflux for 6 h. The reaction was cooled, quenched with ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was purified by column chromatography over silica gel (60-120 mesh) using 20% ethyl acetate/petroleum ether as eluent to afford 1-(2,2-dimethyl-propyl)-4-(6-nitro-pyridin-3-yl)-piperazine (0.5 g, 52.5%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-])=O.[BH4-].[Na+]>C(O)C>[NH:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:4]([NH2:1])[C:5]=2[CH:6]=[N:7]1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75.1 %

Procedure:
4-Nitro-1H-indazole (1.63 g, 10 mmol) in ethanol (100 mL) was treated with BiCl3 (3.46 g, 11 mmol) followed by a portionwise addition of NaBH4. The reaction mixture was stirred at ambient temperature for 20 minutes and filtered through Celite. The filtrate was evaporated under reduced pressure and the residue was partitioned between ethyl acetate/dilute NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and the filtrate concentrated under reduced pressure to provide the title compound as a tan solid (1.0 g). 1H NMR (300 MHz, DMSO-d6) δ 5.64 (s, 2H), 6.1 (d, 1H), 6.6 (d, 1H), 6.98 (t, 1H), 8.03 (s, 1H), 12.6 (s, 1H).