Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:34]1[CH:39]=[CH:38][C:37]([C:40]2([NH2:43])[CH2:42][CH2:41]2)=[N:36][CH:35]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:43][C:40]5([C:37]6[CH:38]=[CH:39][N:34]=[CH:35][N:36]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2ccncn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccncn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.096 g, 0.221 mmol, 1.0 eq), 1-(pyrimidin-4-yl)cyclopropanamine HCl (0.03 g, 0.221 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.12 g, 1.188 mmol, 5.0 eq) and BOP reagent (0.146 g, 0.330 mmol, 1.5 eq). The reaction mixture was stirred as RT overnight. The reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 3% MeOH/CHCl3 as eluent. Yield: 0.070 g (57.33%). 1H NMR (400 MHz, CD3OD): δ 8.99 (d, J=1.0 Hz, 1H), 8.61 (d, J=5.6 Hz, 1H), 7.99-7.93 (m, 2H), 7.79 (s, 1H), 7.69-7.54 (m, 3H), 7.39-7.23 (m, 3H), 7.16 (s, 1H), 4.08 (s, 3H), 2.96 (s, 3H), 2.34 (s, 3H), 1.85-1.82 (m, 2H), 1.61-1.49 (m, 2H). LCMS: (ES+) m/z=551.2 (M+H)+
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Br:18][Si](C)(C)C.O.[OH-].[Na+]>C(#N)CCC>[Br:18][C:2]1[N:7]=[CH:6][C:5]([C:8]2([C:16]#[N:17])[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Br
Reactant: N#CC1(c2ccc(Cl)nc2)CCC(F)(F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCC#N
Product: N#CC1(c2ccc(Br)nc2)CCC(F)(F)CC1
Temperature: 120 °C
Yield: 65.1 %

Procedure:
To a stirred solution of 1-(6-chloro-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (1.3 g, 5.1 mmol) in butyronitrile (100 mL) at room temperature under nitrogen atmosphere was added bromotrimethylsilane (1.55 g, 10.2 mmol). The reaction mixture was heated at 120° C. for 24 hours. The reaction mixture was then cooled to room temperature and poured into water (25 mL) and 10% aqueous NaOH solution (25 mL). The aqueous layer was extracted with diethyl ether (3×250 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was then purified by column chromatography on silica gel to afford 1-(6-bromo-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile as a white solid (1.0 g, 65%). LC-MS (m/z) 301.0 (MH+). 1H NMR (400 MHz, CDCl3) δ ppm 8.55 (d, J=2.7 Hz, 1 H), 7.69 (dd, J=8.4, 2.8 Hz, 1 H), 7.57 (d, J=8.4 Hz, 1 H), 2.09-2.41 (m, 8 H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[CH2:6]1[CH2:10][O:9][C:8]2[CH:11]=[CH:12][C:13]3[CH2:14][CH:15]=[C:16]([CH2:18][CH2:19][NH2:20])[C:17]=3[C:7]1=2.C(N(CC)CC)C>CN(C)C=O>[CH2:6]1[CH2:10][O:9][C:8]2[CH:11]=[CH:12][C:13]3[CH2:14][CH:15]=[C:16]([CH2:18][CH2:19][NH:20][C:1](=[O:3])[CH3:2])[C:17]=3[C:7]1=2
Reactant: NCCC1=CCc2ccc3c(c21)CCO3
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCC1=CCc2ccc3c(c21)CCO3
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
Acetyl chloride (0.24 g, 3.03 mmol) was slowly added dropwise to an ice-cooled solution of 2-(1,6-dihydro-2H-indeno[5,4-b]furan-8-yl)ethylamine hydrochloride (0.6 g, 2.52 mmol) and triethylamine (0.64 g, 6.31 mmol) in N,N-dimethylformamide (60 mL). After overnight stirring at room temperature, the reaction mixture was concentrated and poured into water, and the organic matter was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and water and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (ethyl acetate:methanol=98:2) and further recrystallized from ethyl acetate to give 425 mg (yield: 70%) of the target compound.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH2:17]([O:24][C:25]([NH:27][CH2:28][CH2:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]2[NH:42][CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38]2)[CH:34]=[CH:35][CH:36]=1)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)CC(C)C>[NH2:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=[C:2]([N:42]2[CH2:41][CH2:40][N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:47])[CH3:48])=[O:44])[CH2:38][CH:37]2[C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH2:29][CH2:28][NH:27][C:25]([O:24][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:26])[CH:32]=2)[N:11]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: CC(C)(C)OC(=O)N1CCNC(c2cccc(OCCNC(=O)OCc3ccccc3)c2)C1
Solvent: CC(C)CCO
Product: COc1cc2nc(N3CCN(C(=O)OC(C)(C)C)CC3c3cccc(OCCNC(=O)OCc4ccccc4)c3)nc(N)c2cc1OC

Procedure:
A solution of 2-chloro-6,7-dimethoxyquinazolin-4-amine (CAS#23680-84-4) (105 mg, 0.439 mmol) and (+) or (−)-tert-butyl 3-(3-(2-(((benzyloxy)carbonyl)amino)ethoxy)phenyl)piperazine-1-carboxylate (100 mg, 0.220 mmol) in isoamyl alcohol (5 ml) was stirred for 16 hr at 135° C. After evaporation, the crude was purified by preparative HPLC (Macherey-Nagel Nucleosil® 100-10 C18, CH3CN/H2O (0.1% TFA)) to give the title compound. MS (ESI+) m/z 659.2 (M+H).
Reaction SMILES: S(O[CH2:12][C:13]12[CH2:27][CH:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=31)[C:19]1[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=1)(C1C=CC(C)=CC=1)(=O)=O.[O-][C:29]#[N:30].[K+]>CN(C)C=O.O>[CH:15]1[C:14]2[C:13]3([CH2:12][C:29]#[N:30])[CH2:27][CH:20]([C:21]4[C:26]3=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: N#C[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC23CC(c4ccccc42)c2ccccc23)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC12CC(c3ccccc31)c1ccccc12
Temperature: 150 °C

Procedure:
A mixture of 9-tosyloxymethyl-9,10-dihydro-9,10-methanoanthracene (188 mg) and potassium cyanate (40 mg) in dimethylformamide (2 ml) was heated at 150° C. for 7 hours. The reaction mixture was diluted with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give crude crystals of (9,10-dihydro-9,10-methano-9-anthryl)acetonitrile, which was recrystallized from isopropanol to give pure crystals. M.P. 130°-131° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:22])[C:7]=1[NH:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:20]=[O:21])=[CH:16][NH:17]2)=[CH:13][CH:12]=1)=[O:10].[H-].[Na+].[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>CN(C)C=O>[Cl:22][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9]([C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH:20]=[O:21])=[CH:16][N:17]2[S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])=[CH:13][CH:12]=1)=[O:10]
Reactant: O=Cc1c[nH]c2cc(C(=O)Nc3c(Cl)cncc3Cl)ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccc(C(=O)Nc4c(Cl)cncc4Cl)cc32)cc1
Temperature: -40 °C
Reaction time: 0.25 h
Yield: 105.7 %

Procedure:
A stirred solution of N-(3,5-dichloro-pyridin-4-yl)-3-formyl-1H-indole-6-carboxamide (0.518 g, Example 18) in dimethylformamide at 0° C. was treated with sodium hydride (0.136 g). The mixture was stirred for 15 minutes, then cooled to −40° C. and then treated with 4-toluenesulphonyl chloride (0.325 g). The reaction mixture was gradually allowed to warm to −20° C. over a period of 90 minutes, then quenched with water (20 ml), then extracted three times with ethyl acetate (25 ml). The combined extracts were dried over sodium sulphate then evaporated to give the title compound (800 mg), which was used without firther purification as a white solid, m.p. 245° C. [Elemental analysis:—C,53.91; H,3.34; N,8.30%. Calculated for C22H15Cl2N3O4S:—C,54.11; H,3.10; N,8.60%].
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][C:5](OC)=[O:6].[CH3:11][NH2:12]>>[CH3:11][NH:12][C:5](=[O:6])[CH2:4][C:3]([NH2:2])([CH3:10])[CH3:9]
Reactant: CN
Reactant: COC(=O)CC(C)(C)N
Agent: Cl
Product: CNC(=O)CC(C)(C)N

Procedure:
A mixture of methyl 3-amino-3-methyl-butyrate hydrochloride (10.5 g; 62.6 mmoles) and methyl amine (33% solution in ethanol; 55 ml) is refluxed for 18 hours. The solvent is evaporated, the crude is dissolved in methylene chloride (100 ml) and washed with a saturate aqueous solution of sodium chloride (10 ml). After drying over sodium sulphate and evaporation of the solvent to dryness, N-methyl-3-amino-3-methyl-butyramide is obtained; chromatographically pure colorless oil (T.L.C., eluent--methylene chloride:methanol:NH4OH=80:15:1)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]1[CH2:7][OH:8].Cl[C:10]([O:12][CH3:13])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[OH:8][CH2:7][C@H:2]1[NH:1][CH2:6][CH2:5][N:4]([C:10]([O:12][CH3:13])=[O:11])[CH2:3]1
Reactant: COC(=O)Cl
Reactant: OC[C@@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)N1CCN[C@H](CO)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.4 %

Procedure:
A solution of the product of stage (ii) (0.080 g) in dry acetonitrile (10 ml) was treated with a solution of methyl chloroformate (71 mg; 0.75 mmol) in dry acetonitrile (3 ml) over a 5 min period. The mixture was stirred at ambient temperature for 30 min and aqueous sodium carbonate solution (1 ml) was added. The solvent was removed in vacuo and the aqueous residue was extracted with dichloromethane (3×25 ml) and chloroform (3×25 ml). The extract was washed with aqueous sodium carbonate solution (5 ml: 1M), and the combined extracts were dried and evaporated in vacuo to give the title compound as an oil (0.1 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][C:12]([NH2:14])=[O:13])[CH:4]=[CH:3]1.C[O:16][C:17](=O)[C:18]([C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[O:29][CH3:30])[NH:22][CH:21]=1)=O.CC(C)([O-])C.[K+].C1COCC1>CN(C=O)C>[CH3:30][O:29][C:27]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:28]=1[C:20]([C:18]1[C:17](=[O:16])[NH:14][C:12](=[O:13])[C:11]=1[C:9]1[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]3)=[CH:21][NH:22]2
Reactant: COC(=O)C(=O)c1c[nH]c2cccc(OC)c12
Reactant: Cn1ccc2cccc(CC(N)=O)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc2[nH]cc(C3=C(c4cccc5ccn(C)c45)C(=O)NC3=O)c12
Temperature: 60 °C
Yield: 39.7 %

Procedure:
To a solution of 2-(1-methyl-1H-indol-7-yl)-acetamide (0.539 g, 2.87 mmol) and (4-methoxy-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.656 g, 2.81 mmol) in DMF (40 mL) under N2 was added a 1.0 M solution of potassium-tert-butoxide in THF (10 mL, 10 mmol) dropwise over 5 minutes. The mixture was heated at 60° C. for 15 h, quenched with 1N HCl (excess) and poured into EtOAc. The organic layer was separated, washed with water (3×), saturated aq NaHCO3, and brine, dried (MgSO4), filtered and concentrated onto flash SiO2. Flash chromatography (30–40% hexane/EtOAc) gave the title compound (0.414 g, 40%) as a red solid, which was dried under vacuum overnight. 1H NMR (400 MHz, DMSO-d6) 11.49 (br s, 1H), 11.08 (s, 1H), 7.49 (dd, J=7, 3 Hz, 1H), 7.30 (d, J=3 Hz, 1H), 7.25 (d, J=3 Hz, 1H), 6.86–7.05 (m 4H), 6.39 (d, J=7 Hz, 1H), 6.42 (d, J=3 Hz, 1H), 3.76 (s, 3H), 3.34 (s, 3H). MS (electrospray, m/z) 372.1 (M++1), 370 (M−−1). HRMS 372.1347 (M++1, calcd for C22H18N3O3 372.1348).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH2:69]([NH:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1)[CH:70]=[CH2:71]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:14]([C:15](=[O:17])[N:72]([CH2:69][CH:70]=[CH2:71])[CH:73]2[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]2)[CH:13]=1)[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: C=CCNC1CCCCC1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.039 g), TBTU (0.064 g) and HOBt (0.027 g) in DMF (1 ml) was added DIPEA (0.036 ml) followed by N-allylcyclohexylamine (0.029 ml) after 15 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.032 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:9]1[NH:10][C:11](=[O:18])[CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])[CH2:6][CH2:7][CH3:8].[CH3:19]O>>[CH2:5]([C:9]1[NH:10][C:11](=[O:18])[CH:12]=[C:13]([C:14]([O:16][CH3:19])=[O:15])[CH:17]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CO
Reactant: CCCCc1cc(C(=O)O)cc(=O)[nH]1
Solvent: O=S(Cl)Cl
Product: CCCCc1cc(C(=O)OC)cc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12.5 ml (0.17 mol) of thionyl chloride are added dropwise to a suspension of 29.25 g (0.15 mol) of 6-butyl-2-oxo-1,2-dihydro-isonicotinic acid in 200 ml of methanol, while cooling with ice, and the mixture is stirred overnight at room temperature. It is concentrated to dryness and the residue is chromatographed over 450 g of silica gel (230-400 mesh) using methylene chloride→methylene chloride/methanol 10:1. Colourless crystals of melting point 106° C. crystallise from methylene chloride, ether and petroleum ether.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:17][CH:16]([O:18]C)[CH:15]([OH:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].O>N1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH:16]([O:18][S:2]([CH3:1])(=[O:4])=[O:3])[CH:15]([OH:20])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: COC1CN(C(=O)OC(C)(C)C)CC1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(O)C(OS(C)(=O)=O)C1
Reaction time: 8 h
Yield: 76.4 %

Procedure:
11.5 g (0.1 mole) of methanesulfonyl chloride were added dropwise, whilst ice-cooling to a solution of 13.0 g (0.06 mole) of 1-t-butoxycarbonyl-3-hydroxy-4-methoxypyrrolidine [prepared as described in Step (c) above] in 100 ml of pyridine, and the mixture was stirred overnight whilst ice-cooling. The reaction mixture was then poured into 800 ml of water and extracted with diethyl ether. The extract was washed with water and dried, and the solvent was removed by evaporation under reduced pressure to afford 12.9 g of 1-t-butoxycarbonyl-3-hydroxy-4-methanesulfonyloxypyrrolidine as a brown oily substance. The whole of this oily substance was placed in a 100 ml stainless steel autoclave, and 50 ml of liquid ammonia was added thereto. The mixture was then heated with stirring at 140° C. under pressure for 8 hours. At the end of this time, the excess ammonia was removed by evaporation, and the residue was subjected to silica gel column chromatography eluted with ethanol, to afford 8.0 of cis-3-amino-1-t-butoxycarbonyl-4-methoxypyrrolidine as a brown oily substance.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:20]=[CH:19][C:13]([CH:14]([OH:18])[C:15]([OH:17])=O)=[CH:12][CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][CH:22]([NH2:39])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:27][CH:26]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([CH:14]([OH:18])[C:15](=[O:17])[NH:39][CH:22]([CH3:21])[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[CH:27][CH:26]=2)=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(N)CCc1ccc(OCc2ccccc2)cc1
Reactant: O=C(Oc1ccc(C(O)C(=O)O)cc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(CCc1ccc(OCc2ccccc2)cc1)NC(=O)C(O)c1ccc(OCc2ccccc2)cc1

Procedure:
As pointed out above, a preferred embodiment of this invention employs a mixture of all four optica isomers of the compound of Example 7. This racemic mixture can be prepared by the method described above by reaction of dl-4-(benzoyloxy)mandelic acid with dl-1-methyl-3-(4-benzyloxyphenyl)propylamine in the presence of DCC to give racemic 1-(4-benzyloxyphenyl)-2-oxo-2-[1-methyl-3-(4-benzyloxyphenyl)propylamino]ethanol. Reduction of the latter compound and subsequent removal of the benzyl groups provides racemic 1-(4-hydroxy-phenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]-ethanol. This compound is more preferably prepared by the following procedure.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)O1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27](I)=[CH:28][N:29]=2)[CH:26]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O>[Br:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([C:9]3[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=3)=[CH:28][N:29]=2)[CH:26]=1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1ccc2ncc(I)n2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cnc3ccc(Br)cn23)cc1
Yield: 67.8 %

Procedure:
2.3 g methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate prepared according to T. Ishiyama et al., J. Org. Chem., 60, 7508 (1995), 2.0 g 6-bromo-3-iodoimidazo[1,2-a]pyridine (compound in Production Example 49), 2.5 g potassium phosphate, 360 mg tetrakistriphenyl phosphine palladium and 30 mL N,N-dimethylformamide were heated at 100° C. under nitrogen atmosphere. Insolubles were filtered off, the solvent was removed, and the residue was purified by NH silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate to give 1.39 g of the title compound (colorless crystals).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[CH:20]=[CH:19][C:11](/[CH:12]=C/N2CCCC2)=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=1>C1COCC1.O>[Br:7][C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[O:2])=[C:10]([N+:21]([O-:23])=[O:22])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1/C=C/N1CCCC1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)cc1[N+](=O)[O-]
Reaction time: 15 h
Yield: 85.3 %

Procedure:
To a solution of sodium periodate (298 g, 1.40 mol) in THF—H2O (4 L, 1:1) at 0° C. was added (E)-1-(4-bromo-2-nitrostyryl)pyrrolidine (138 g, 464 mmol). The mixture was stirred for 15 h and then filtered to remove solid precipitates. The aqueous layer from the filtrate was separated and extracted with EtOAc (4×200 mL). The combined organic layers were washed with H2O (2×200 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product that was purified by silica gel flash column chromatography (5% EtOAc in hexanes) to afford 91 g (86%) of 4-bromo-2-nitrobenzaldehyde.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20]>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([F:10])=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH2:18][C:19]([O:21][CH:22]([CH3:24])[CH3:23])=[O:20]
Reactant: Nc1c(F)ccc(O)c1F
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)COc1ccc(F)c(N)c1F
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 70.6 %

Procedure:
To a stirred solution of 3-amino-2,4-difluoro-phenol (intermediate X(a)) (713 mg, 4.91 mmol, 1.0 eq) in DMF (20 mL) was added Na2CO3 (1.56 g, 14.8 mmol, 3.0 eq). The resulting mixture was stirred at room temperature for 35 min, then isopropyl bromoacetate (1.07 g, 5.90 mmol, 1.2 eq) was added and the reaction stirred at room temperature overnight. The reaction was diluted with water then extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by chromatography (EtOAc:petroleum ether, 0:1 to 1:6) to give the title compound (intermediate IV(b)) as an oil (850 mg, 71%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][NH:11][CH2:10][C:9]=2[C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[N:7]1.[CH3:28][N:29]1[C:33]([C:34](Cl)=[O:35])=[CH:32][N:31]=[CH:30]1.C(N(CC)CC)C>C(Cl)Cl>[F:2][C:3]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:34]([C:33]3[N:29]([CH3:28])[CH:30]=[N:31][CH:32]=3)=[O:35])[CH2:10][C:9]=2[C:8]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])=[N:7]1
Reactant: Cn1cncc1C(=O)Cl
Reactant: N#Cc1cccc(-c2nn(Cc3ccc(F)cc3F)c3c2CNCC3)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cncc1C(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2Cc2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
A mixture of 3-[1-(2,4-Difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (7c) (0.04 g, 0.114 mmol), 3-Methyl-3H-imidazole-4-carbonyl chloride (0.083 g, 0.457 mmol) and triethylamine (138 mg, 1.37 mmol) in CH2Cl2 was stirred at 25° C. for 16 h. The crude product was purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 43 mg of 3-[1-(2,4-Difluoro-benzyl)-5-(3-methyl-3H-imidazole-4-carbonyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (8w).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH2:14])=[S:13])=[N:9][CH:10]=1.Br[CH:16]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17](OC)OC.Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[C:22]1([C:16]2[S:13][C:12]([NH:11][C:8]3[N:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=3)=[N:14][CH:17]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(=S)Nc1ccc(CCCO)cn1
Reactant: COC(OC)C(Br)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCCCc1ccc(Nc2ncc(-c3ccccc3)s2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[5-(3-Hydroxy-propyl)-pyridin-2-yl]-thiourea (7-4), 2.20 g (10.4 mmol) was stirred in 20 mL EtOH. (1-Bromo-2,2-dimethoxy-ethyl)-benzene (3.83 g, 15.6 mmol)was added, dissolved in 12 mL EtOH. The reaction was heated to reflux. After 30 min, 8 mL of concentrated HCl (aq) was added. After 7 h the reaction was cooled to RT, and diluted with water. Na2CO3 (s) was added to pH 9. The resulting precipitate was filtered, and washed with water. To solid was added ether, the mixture was sonicated and filtered, washing with ether. Afford the titled compound as a white solid. 1H NMR (CDCl3): δ8.74 (bs, 1H), 8.25 (d, 1H, J=2.2 Hz), 7.57 (dd, 2H, J=1.7, 9.0 Hz)7.49 (dd, 1H, J=2.4, 8.4 Hz), 7.38 (t, 2H, J=7.7 Hz), 6.83 (d, 1H, J=8.2 Hz), 3.71 (m, 2H), 2.70 (t, 2H, J=6.7 Hz), 1.89 (m, 2H). Mp 153-154° C. MS [M+H]+=312.2.