Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[O:6][C@@H:5]([C@H:7]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:8]([O:10]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[C:4](=[O:26])[O:3]1.ONC(=O)[C@@H](O)[C@@H](C(N1CCN(C2C=CC=CN=2)CC1)=O)CC(C)C.ONC(=O)[C@@H](O)[C@@H](C([N:64]1[CH2:69][CH2:68][N:67]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=2)[CH2:66][C@H:65]1[CH3:76])=O)CC(C)C.O>CN(C=O)C>[CH3:27][C:2]1([CH3:1])[O:3][C:4](=[O:26])[C@H:5]([C@@H:7]([C:8]([N:64]2[CH2:69][CH2:68][N:67]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=3)[CH2:66][C@@H:65]2[CH3:76])=[O:10])[CH2:22][CH:23]([CH3:24])[CH3:25])[O:6]1
Reactant: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)C[C@H]1C)[C@H](O)C(=O)NO
Reactant: CC(C)C[C@H](C(=O)Oc1c(F)c(F)c(F)c(F)c1F)[C@@H]1OC(C)(C)OC1=O
Agent: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)CC1)[C@H](O)C(=O)NO
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](C(=O)N1CCN(c2ccccn2)C[C@@H]1C)[C@@H]1OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 22 %

Procedure:
To a solution of a 55/45 diastereoisomeric mixture of pentafluorophenyl (2S)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate and pentafluorophenyl (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate (Intermediate 1, 198 mg; 0.50 mmol; 1.0 eq.) in DMF (4 mL) was added (3S)-3-methyl-1-pyridin-2-ylpiperazine (Intermediate 4, 88.6 mg; 0.50 mmol; 1.0 eq.) and the resulting reaction mixture was stirred 48 h at RT. Water was added and the mixture was extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4, filtered and evaporated to give an oil. Purification by chromatography (SiO2, gradient from 10% EtOAc in c-hex up to 40% EtOAc in c-hex in 15 min) gave the title compound as a colorless oil (43 mg; 22%) (mixture of 2 diastereoisomers). M+(ESI): 390.3.
Reaction SMILES: [OH:1][C:2]1([C:20](OC)=[O:21])[CH2:11][C:10]2([S:15][CH2:14][CH2:13][S:12]2)[C:9]2[C:4](=[C:5]([O:18][CH3:19])[CH:6]=[CH:7][C:8]=2[O:16][CH3:17])[CH2:3]1.[BH4-].[Na+]>O1CCCC1>[OH:1][C:2]1([CH2:20][OH:21])[CH2:3][C:4]2[C:9](=[C:8]([O:16][CH3:17])[CH:7]=[CH:6][C:5]=2[O:18][CH3:19])[C:10]2([S:12][CH2:13][CH2:14][S:15]2)[CH2:11]1
Reactant: COC(=O)C1(O)Cc2c(OC)ccc(OC)c2C2(C1)SCCS2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(OC)c2c1CC(O)(CO)CC21SCCS1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.8 %

Procedure:
2.0 g of methyl rac-1',2',3',4'-tetrahydro-2'-hydroxy-5',8'-dimethoxyspiro[1,3-dithiolane-2,4'-naphthalene]-2'-carboxylate, prepared as described in Example 4(iv), were dissolved in 200 ml of dry tetrahydrofuran and 2.0 g of sodium borohydride were added to the solution. The resulting mixture was stirred at room temperature under nitrogen for 20 hours. The solvent was removed by evaporation and 100 ml of 10% ammonium chloride solution were added. The mixture was extracted with three 30 ml portions of ethyl acetate. The extracts were dried and evaporated to give a colourless oil. Crystallisation of this oil from ethyl acetate/petroleum ether gave 1.6 g (87%) of rac-1',2',3',4'-tetrahydro-3'-hydroxy-3'-hydroxymethyl-5',8'-dimethoxyspiro[1,3-dithiolane-2,1'-naphthalene] of melting point 132.5°-133.5° C.
Reaction SMILES: Cl.[CH3:2][S:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)N)=[CH:6][CH:5]=1.C[O:22][C:23](=[O:32])[CH2:24][CH:25]([CH3:31])[CH2:26][C:27](=O)[CH2:28][CH3:29]>C(O)(C)(C)C>[CH3:2][S:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[C:11]3[C:16](=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[C:28]([CH3:29])=[C:27]2[CH2:26][CH:25]([CH3:31])[CH2:24][C:23]([OH:32])=[O:22])=[CH:6][CH:5]=1
Reactant: CCC(=O)CC(C)CC(=O)OC
Reactant: COc1ccc(N(N)Cc2ccc(SC)cc2)cc1
Agent: Cl
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)c(C)c(CC(C)CC(=O)O)n2Cc1ccc(SC)cc1

Procedure:
Following the method of Example 2, but using 1-[4-methylthiobenzyl]-1-[4-methoxyphenyl]hydrazine hydrochloride and methyl-3-methyl-5-oxoheptanoate as starting materials, in t-butanol as solvent, the title compound was prepared
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18]3[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=3)=[C:9](S(C)(=O)=O)[CH:10]=[CH:11][C:12]=2C)C=CC=CC=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[C:28]1[C:36]([OH:38])=[O:37].Cl>C(O)C>[C:7]1([CH:8]([C:18]2[CH:19]=[CH:20][C:21]([N:24]([CH3:25])[CH3:26])=[CH:22][CH:23]=2)[C:29]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[NH:27][C:28]=2[C:36]([OH:38])=[O:37])[CH:1]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: Cc1ccc(S(C)(=O)=O)c(-c2ccc(N(C)C)cc2)c1-c1ccccc1
Agent: Cl
Solvent: CCO
Product: CN(C)c1ccc(C(c2ccccc2)c2c(C(=O)O)[nH]c3ccccc23)cc1

Procedure:
Proceeding in a manner similar to that described in Example 2 above, 20.5 g of [(phenyl)(4-dimethylaminophenyl)(4-methylphenylsulfonyl)]methane was interacted with 10.0 g of indole-2-carboxylic acid in the presence of 5.6 ml of concentrated hydrochloric acid in 140.0 ml of ethanol to obtain 3.34 g of [(phenyl)(4-dimethylaminophenyl)(2-carboxyindol-3-yl]methane (Formula XI: R1 =R2 =R3 =R4 =R11 =B"=H; R5 =N(CH3)2), a blue solid which melted at 213°-215° C. The nuclear magnetic resonance spectrum was consistent with the assigned structure. A toluene solution of the product spotted on an acid clay-coated paper slowly developed a purple-colored image and on a phenolic resin-coated paper slowly developed a dark blue-colored image.
Reaction SMILES: [CH2:1]([NH:5][C:6]([C:8]1([CH2:22][CH2:23][CH2:24][CH2:25]Br)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[N:27]1([C:33]2[CH:42]=[CH:41][C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([NH:5][C:6]([C:8]1([CH2:22][CH2:23][CH2:24][CH2:25][N:30]2[CH2:31][CH2:32][N:27]([C:33]3[CH:42]=[CH:41][C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=3)[CH2:28][CH2:29]2)[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: CCCCNC(=O)C1(CCCCBr)c2ccccc2Oc2ccccc21
Product: CCCCNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-butylamide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CC(C)=O.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Reaction time: 2.5 h
Yield: 93.5 %

Procedure:
A solution of 3-hydroxymethylpiperidine-1-carboxylic acid tert-butyl ester (15.0 g, 69.7 mmol) and triethylamine (14.6 mL, 104.5 mmol) in dichloromethane (270 mL) was stirred on a bath of ice and acetone. A solution of methanesulfonyl chloride (5.5 mL, 71.1 mmol) in dichloromethane (25 mL) was added dropwise at a rate which kept the internal temperature remained below 0° C. (the addition required about 20 minutes). The mixture was stirred on an ice bath for 2.5 hours, then was concentrated under vacuum. The residue was dissolved in ethyl acetate, and the mixture was filtered to remove a white crystalline solid. The filtrate was concentrated under vacuum to provide an orange gum. Purification by flash chromatography (50% ethyl acetate in hexane) provided a white solid (19.12 g, 93%). 1H NMR (300 MHz, CDCl3) δ4.10 (m, 2H), 3.95 (bd, J=13 Hz, 1H), 3.81 (dt, J=14, 4 Hz, 1H), 3.03 (s, 3H), 2.92 (ddd, J=14, 10, 3 Hz, 1H), 2.79 (dd, J=13, 10 Hz, 1H), 1.97 (m, 1H), 1.83 (m, 1H), 1.68 (m, 1H), 1.49 (m, 1H), 1.46 (s, 9H), 1.30 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24]>C(O)C.N1C=CC=CC=1.CC(=O)OCC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]2=[N:23][OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC1(C)CC(=O)c2cc(OCc3ccccc3)ccc2O1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1(C)CC(=NO)c2cc(OCc3ccccc3)ccc2O1

Procedure:
By heating 11.3 g (40 mmol) of 6-benzyloxy-2,2-dimethylchroman-4-one with 3.1 g (44 mmol) of hydroxylamine hydrochloride in 27 ml of ethanol and 27 ml of pyridine for 3 h at 70° C., after distilling off the solvent in vacuo and precipitating with water, 12.5 g of product, m.p. 105-108° C., were obtained. The product was dissolved in EA, the solution was dried and concentrated, and the residue was crystallized using petroleum ether; m.p. 118-120° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14]>>[CH2:11]([NH:15][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Clc1ccn2nccc2n1
Reactant: CCCCN
Product: CCCCNc1ccn2nccc2n1

Procedure:
A solution of 5-chloro-pyrazolo[1,5-a]pyrimidine [29274-24-] (955.4 mg, 6.2 mmol) in butylamine [109-73-9] (6.2 mL, 62.7 mmol), under N2 blanket, was magnetically stirred at 65° C. for 17 h then partitioned between brine (pH adjusted to 10 with saturated aqueous sodium bicarbonate) and ethyl acetate. The phase separated extract was dried (MgSO4) and diluted with heptane to precipitate butyl-pyrazolo[1,5-a]pyrimidin-5-yl-amine as 1.2 g of yellow powder, mp. 75-76° C. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (t, J=7.33 Hz, 3 H) 1.37 (dq, J=15.00, 7.29 Hz, 2 H) 1.47-1.59 (m, 2 H) 3.24-3.34 (m, 2 H) 5.94 (d, J=1.52 Hz, 1 H) 6.22 (d, J=7.58 Hz, 1 H) 7.35 (br. s., 1 H) 7.74 (d, J=2.27 Hz, 1 H) 8.40 (d, J=7.58 Hz, 1 H). 13C NMR (100 MHz, DMSO-d6) δ ppm 13.69, 19.71, 30.65, 91.00, 99.95, 134.70, 143.45, 148.37, 155.43. LRMS (ESI) m/z 191.1 [(M+H)]+, calc'd for C10H14N4: 190.25
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].O.[N:12]#[C:13]Br.C(=O)([O-])O.[Na+]>C(#N)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:13]([NH2:12])=[N:10][C:4]=2[CH:3]=1
Reactant: N#CBr
Reactant: Nc1cc(F)c(F)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Nc1nc2cc(F)c(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 40 %

Procedure:
4,5-Difluorobenzene-1,2-diamine (0.651 g, 0.562 mmol, commercially available from Matrix Scientific) in acetonitrile (10 mL) and water (2 ml) at 0° C. was treated with cyanogen bromide (0.063 g, 0.6 mmol). The reaction mixture was allowed to warm to room temperature, and then stirred for 14 hours. The reaction mixture was then treated with saturated aqueous sodium hydrogen carbonate solution (50 ml) and shaken. The resulting solid was filtered off, washed with water and dried under reduced pressure to give 0.39 g of 5,6-difluoro-1H-benzo[d]imidazol-2-amine (yield, 40%). MS (EI): 186 (MH+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]([F:11])([F:10])[C:7](Cl)=[O:8].[C:12]([Cl:15])([Cl:14])=[CH2:13]>ClCCl.O>[Cl:14][C:12]([Cl:15])=[CH:13][C:7](=[O:8])[C:6]([F:11])([F:10])[F:5]
Reactant: O=C(Cl)C(F)(F)F
Reactant: C=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)C(F)(F)F
Temperature: -50 °C
Reaction time: 0.25 h

Procedure:
To a solution of aluminum chloride (3.0 g, 22.5 mmol) in dichloromethane (100 mL) was added dropwise a solution of trifluoroacetyl chloride (3 g, 22.6 mmol) in dichloro-methane (5 mL) while keeping the temperature of the reaction mixture below −30° C. The reaction mixture was stirred for 15 minutes at −50° C. Then a solution of vinylidene chloride (2.2 g, 22.7 mmol) in dichloromethane (10 mL) was added dropwise over 2 h to the reaction mixture. The reaction mixture was stirred an additional 2 h at −50° C. and then warmed gradually to room temperature. The reaction mixture was diluted with water, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, dried (MgSO4), and concentrated under reduced pressure to give 4,4-dichloro-1,1,1-trifluoro-3-buten-2-one as an oil which was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]CCCC)[C:8](Cl)=[O:9])([CH3:4])[CH3:3].[H-].[Na+].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][NH:38][C:39](=[O:41])[CH3:40])[CH:32]=1>O1CCCC1>[C:39]([N:38]([CH2:37][C:33]1[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=1)[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[CH:6]=1)(=[O:41])[CH3:40]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1C(C)(C)C
Reactant: CC(=O)NCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc(C(=O)N(Cc2cccnc2)C(C)=O)cc1C(C)(C)C
Yield: 176.3 %

Procedure:
The title compound is prepared by the procedure of Example 27, using 0.90 g of product from Example 33, 0.316 g of washed 50% sodium hydride, 2.57 g of product from Example 14 and 25 ml of dry tetrahydrofuran. The residue is purified by chromatography (silica gel: 40% ethyl acetate/hexane) to give 1.81 g of the desired product as a yellow oil which crystallizes on standing.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13]C1C=CC(N[C:19]2[C:28]3[C:23](=[CH:24][C:25](O)=[C:26](OC)[CH:27]=3)[N:22]=[CH:21][N:20]=2)=C(F)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(CCO)C1C=CN=NC=1.Cl>C(Cl)Cl.C(Cl)Cl.CO>[ClH:13].[N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[N:20][CH:21]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: CN(CCO)c1ccnnc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: c1ccc2ncncc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 165.1 %

Procedure:
Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (128 mg, 0.4 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (314 mg, 1.2 mmol) and 2-(N-methyl-N-(pyridazin-4-yl)amino)ethanol (80 mg, 0.52 mmol) in methylene chloride (5 ml) and the mixture stirred for 2 hours at ambient temperature. The solvent was removed by evaporation, the residue was triturated with ether and the resulting solid was collected by filtration. The solid was purified by column chromatography eluting with methylene chloride/methanol (9/1 followed by 8/2) to give a white solid. This solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (0.5 ml of a 4M solution) was added. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-N-methyl-N-(pyridazin-4-yl)amino)ethoxy)quinazoline hydrochloride (110 mg, 60%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[N:8][N:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]=2[CH:11]=[C:12]([C:14]#[N:15])[CH:13]=1)=[O:4].[OH-].[Na+].Cl>O.CO>[C:14]([C:12]1[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]2[CH:7]=[N:8][N:9]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:10]=2[CH:11]=1)#[N:15]
Reactant: COC(=O)c1cc(C#N)cc2c1cnn2-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1cc(C(=O)O)c2cnn(-c3ccc(F)cc3)c2c1
Temperature: 25 °C

Procedure:
To a stirred solution of 6-cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid methyl ester (0.30 g, 1.1 mmol) in water (10 mL) and methanol (10 mL) was added a 2 N aqueous sodium hydroxide (10 mL, 20 mmol). The mixture was warmed at reflux for 1 hour, cooled to room temperature, and acidified with 1 N aqueous HCl (pH=3-4). The white solid was collected by filtration, washed with MeOH (10 mL) and dried to afford 6-cyano-1-(4-fluoro-phenyl)-1H-indazole-4-carboxylic acid.
Reaction SMILES: P([O-])([O-])([O-])=O.[CH3:6]O.Cl(O)(=O)(=O)=O.[NH2:13][C@@H:14]([C:23]([OH:25])=[O:24])[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:6][O:24][C:23](=[O:25])[CH:14]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:13]
Reactant: N[C@H](CCc1ccccc1)C(=O)O
Reactant: CO
Agent: O=P([O-])([O-])[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)C(N)CCc1ccccc1
Reaction time: 2 h

Procedure:
In Example 30, a 20 g/l solution of DL-homophenylalanine methyl ester was prepared in a 0.2M phosphate buffer (pH 7.0). Then 10 g/l of a porcine pancreas lipase Sigma 3126 was also added. The mixture was caused to react at 30° C. The reaction conversion was measured by HPLC using an RP-18 column with a mobile phase consisting of 40:60 methanol/perchloric acid (pH 1.7) at an elution rate of 0.6 ml/min. The concentration of the eluent was detected at a wavelength of 215 nm. The optical purity of the product was measured using the CR(+) column with a mobile phase containing 15:85 methanol/perchloric acid (pH 1.7), at an elution rate of 0.7 ml/min. The concentration of the eluent was detected at the same wavelength of 215 nm. After 120 minutes, the reaction conversion was measured to be at 61.5%, and the e.e. value for the D-homophenylalanine and its methyl ester was measured to be 94.4%.
Reaction SMILES: C[O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[OH-].[Na+].Cl>C(O)C>[NH2:5][C@H:4]([C:3]([OH:13])=[O:2])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N[C@@H](Cc1ccccc1)C(=O)O
Yield: 179.3 %

Procedure:
A solution of N-(2-chloro-6-methylbenzoyl)-4-[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester (1.31 g, 2,6 mmol) in ethanol (45 mL) and 1.0 N sodium hydroxide 45 mL, 45 mmol) was stirred over night at room temperature to give a clear solution. The mixture was neutralized with 1 N hydrochloric acid to precipitate 1.28 g of a white solid. The mother liquor was extracted with ethyl acetate (2×50 mL) and the combined extracts were washed with sat. brine, dried (Na2SO4) and evaporated to give 0.56 g. Recrystallization of the first crop from ethyl acetate afforded N-(2-chloro-6-methylbenzoyl)-4-[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine (0.77 g). Recrystallization of the second crop from ethyl acetate afforded an additional 0.20 g. FAB HRMS: obs. mass 505.0483. Calcd mass, 505.0488 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:14][CH3:15])=[C:7](C(O)=O)[NH:8]2)=[CH:4][C:3]=1[F:16].[H-].[Na+].[CH3:19][C@@H:20]1[CH2:22][O:21]1>C1(OC2C=CC=CC=2)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:14][CH3:15])=[CH:7][N:8]2[CH2:19][C@H:20]([OH:21])[CH3:22])=[CH:4][C:3]=1[F:16]
Reactant: CCc1c(C(=O)O)[nH]c2cc(Cl)c(F)cc12
Reactant: C[C@@H]1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1cn(C[C@@H](C)O)c2cc(Cl)c(F)cc12
Reaction time: 4 h
Yield: 79 %

Procedure:
A suspension of 1.16 g of 6-chloro-5-fluoro-3-ethyl-indole-2-carboxylic acid in 16 ml of diphenyl ether was stirred at 260° for 4 hours and, after cooling to 0°, diluted with 24 ml of tetrahydrofuran. 180 mg of sodium hydride dispersion were added and the mixture was stirred for one hour. Subsequently, 0.5 ml of (R)-methyloxirane was added and the reaction mixture was stirred at room temperature for 112 hours. The mixture was extracted with diethyl ether, water and saturated sodium chloride solution and the organic phase was dried over sodium sulfate. The solvent was removed and the residue was chromatographed over 120 g of silica gel with hexane-toluene (1:2) and subsequently with toluene-ethyl acetate (9:1). 0.97 g (79%) of (R)-1-(6-chloro-5-fluoro-3-ethylindol-1-yl)-propan-2-ol was obtained as pale brown crystals with m.p. 112°-114°.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:40])[C:21]([CH3:39])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:40])[C:21]([CH3:39])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@@H:33]([CH3:38])[C:34]([CH3:36])([CH3:35])[CH3:37])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)(C)C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@@H](C)C(C)(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 10 mg) dissolved in chloroform (0.1 ml) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide (Intermediate 15, 10 mg) in chloroform (2 ml) at 60° C. and the reaction maintained at 60° C. for 5 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (1 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1S)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:9][C:8]=1[N:21]([CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH3:22])[CH3:2].C(O)C.[BH4-].[Na+]>O1CCCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[N:21]([CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1)[CH3:22])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(COc2ccccc2)cc1N(C)CCc1ccc2ccccc2c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CCc1ccc(COc2ccccc2)cc1N(C)CCc1ccc2ccccc2c1
Reaction time: 0.25 h

Procedure:
To a solution of the compound prepared in Example 23 (135 mg) in tetrahydrofuran (1.2 ml)-ethanol (0.3 ml) were added portionwise nickel chloride hexahydrate (70 mg) and sodium borohydride (45 mg) at 0° C. The mixture was stirred for 15 minutes. The reaction mixture was extracted with diethyl ether. The organic layer was filtered. The filtrate was extracted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated to give the title compound having the following physical data.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([CH:7](O)[CH2:8][NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)=[CH:5][CH:4]=1.S(=O)(=O)(O)O>O>[ClH:2].[Cl:2][C:3]1[CH:23]=[CH:22][C:6]([CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][NH:9][CH2:8]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CNCC(O)c2ccc(Cl)cc2)cc1OC
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc2c(cc1OC)C(c1ccc(Cl)cc1)CNC2
Temperature: 25 °C

Procedure:
At room temperature with stirring, 7.12 g. of rac.-4-chloro-α-{[(3,4-dimethoxybenzyl)amino]methyl}benzyl alcohol hydrochloride are introduced into 100 ml. of a mixture of equal parts by volume of conc. sulfuric acid and water and heated of 80° for 30 minutes. After rendering alkaline, extraction of the base with methylene chloride, acidification with ethanolic hydrogen chloride and recrystallization from ethanol-ether there is obtained rac.-4-(4-chlorphenyl)-1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride of m.p. 186°-187°. The free base displays a m.p. of 118°-119° after recrystallization from ether.