Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18])[CH2:6][OH:7].Cl[C:26]1[C:31]([C:32]#[N:33])=[CH:30][CH:29]=[CH:28][N:27]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18])[CH2:6][O:7][C:26]1[N:27]=[CH:28][CH:29]=[CH:30][C:31]=1[C:32]#[N:33]
Reactant: N#Cc1cccnc1Cl
Reactant: COc1cc(CO)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2ncccc2C#N)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
To a mixture of 3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyl alcohol (4.00 g), 2-chloro-3-cyanopyridine (1.62 g) and N,N-dimethylformamide (40 mL) was added sodium hydride (60%, oil, 515 mg) under ice-cooling. The reaction mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained crystals were recrystallized from ethyl acetate-hexane to give 2-[3-methoxy-4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinonitrile as pale-yellow crystals (4.50 g, 90%). melting point: 117-118° C.
Reaction SMILES: [CH3:1][N:2]([CH3:37])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12]/[N:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=4)[N:22]=3)=[CH:17][CH:16]=2)=[S:11])=[CH:5][CH:4]=1.I[CH3:39]>CCO>[CH3:1][N:2]([CH3:37])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH:12][N:13]=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:34])([F:36])[F:35])=[CH:28][CH:27]=4)[N:22]=3)=[CH:19][CH:20]=2)=[SH:11][CH3:39])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(NC(=S)N/N=C/c2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)cc1
Reactant: CI
Solvent: CCO
Product: C[SH]=C(NN=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)Nc1ccc(N(C)C)cc1
Temperature: 80 °C
Yield: 60.3 %

Procedure:
A solution containing (E)-N-(4-(dimethylamino)phenyl)-2-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (150 mg, 0.285 mmol) and iodomethane (0.054 mL, 0.856 mmol) in EtOH (5 mL) was heated at 80° C. for 3 h before the solvent was removed under reduced pressure. The residue was purified via normal phase flash chromatography (gradient elution with hexanes/EtOAc) to afford the title compound as an orange foam (93 milligrams (mg), 60%): 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.48 (s, 1H), 8.22 (d, J=8.24 Hz, 2H), 8.17 (s, 1H), 7.89 (d, J=8.24 Hz, 2H), 7.80 (d, J=8.28 Hz, 2H), 7.41 (d, J=8.28 Hz, 2H), 7.19 (d, J=8.24 Hz, 2H), 6.71 (d, J=8.24 Hz, 2H), 2.99 (s, 6H), 2.42 (s, 3H); EIMS m/z 540 (M+).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[C:2]1([C:9]23[CH2:12][CH:11]([CH2:8]2)[CH2:10]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC
Reactant: Ic1ccccc1
Product: c1ccc(C23CC(C2)C3)cc1

Procedure:
1.28 ml (0.5 e.g.) of iodobenzene were added to a solution of propellane (10 mmol) generated via Procedure B. The solution was transferred into a borosilicate tube and irradiated 1 hr, after which GC analysis of the solution showed three new major peaks. The reaction mixture was reduced in volume, high vacuum applied (40° C./0.2 mm Hg) to remove starting material and 1-iodobicyclo[1.1.1]pentane. After these products were removed, 1-iodo-3-phenylbicyclo[1.1.1]pentane sublimed out of the mixture (40°-50° C./0.2 mm Hg): 1H NMR 2.06 (s, 6H); EIMS, m/z (relative intensity) 77(24), 127(25), 128(100), 143(91). Resublimation produced an analytical sample having mp. 64°-65° C. Recrystallization from penfane at 0° C. gave a gummy solid. The liquid was diluted with pentane and recrystallization at -78° C., giving 1-phenylbicyclo[1.1.1]pentane: The solid, a mixture of 1-phenyl]2]staffane and 3-iodo-3'-phenyl[2]staffane by GCMS, was recrystallized from benzene.
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:14]([O:13][CH:12]([O:16][CH2:17][CH3:18])[CH2:11][NH:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])[CH3:15]
Reactant: CCOC(CBr)OCC
Reactant: C[C@@H](N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(CN[C@H](C)c1ccccc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.8 %

Procedure:
To a solution of (R)-(+)-1-phenylethylamine 66.6 g (550 mmol) in acetonitrile 300 ml, 2-bromo-1,1-diethoxyethane 41.3 ml (270 mmol) and potassium carbonate 70.7 g (405 mmol) were added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate 300 ml and washed with water 500 ml and brine 500 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified on silica gel column chromatography (n-hexane:ethyl acetate=5:1 and 1:1) to obtain the title compound 46.0 g (70%).
Reaction SMILES: C([O:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH3:14])[CH2:7]1)C=C.[OH-].[Na+]>Cl.O>[OH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH3:14])[CH2:7]1
Reactant: C=CCOCC1CN(CCC)CCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN1CCOC(CO)C1
Yield: 35 %

Procedure:
2-Allyloxymethyl-4-n-propylmorpholine (59.7 g.) is heated under reflux in hydrochloric acid (240 ml., 20%) for 18 hours. The solution is cooled, diluted with ice and water, and basified with sodium hydroxide and extracted with ether (3 × 200 ml.). The ethereal solution is dried (MgSO4) filtered and the ether evaporated to give recovered starting material. The aqueous layer is concentrated to a small volume and precipitated salt is removed by filtration and washed with ether. The filtrate is extracted with ether (3 × 100 ml.) and the combined extracts and ethereal wash are dried (MgSO4) filtered and the ether evaporated. 2-Hydroxymethyl-4-n-propylmorpholine (16.7 g.) is obtained as a viscous oil which forms a hydrogen oxalate, m.p. 133°-135°C. after crystallisation from a methanol/ether mixture.
Reaction SMILES: C([PH:5](=[O:7])[OH:6])CCC.C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:20]=[C:21]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35])[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>ClCCl>[CH2:25]([O:24][C:22]([CH:21]([CH2:32][CH2:33][C:34]([O:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:35])[CH2:20][PH:5](=[O:6])[OH:7])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCCC[PH](=O)O
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCC(C[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.4 %

Procedure:
Butylphosphinic acid (2.0 g, 16 mmol) in 80 mL of dry dichloromethane was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (6.7 g, 66 mmol) was added followed by trimethylsilyl chloride (58 mL, 58 mmol, 1.0 M in dichloromethane). The mixture was stirred at 0° C. for 10 minutes and dibenzyl 2-methylenepentanedioate (2)(6.4 g, 20 mmol) in 20 mL of dichloromethane was added. The cold bath was removed and the reaction warmed to room temperature and stirred overnight. The mixture was then cooled to 0° C. and quenched by the slow addition of 5% hydrochloric acid. The dichloromethane layer was then removed and washed with 5% hydrochloric acid and with brine. The organic layer was dried (MgSO4) and evaporated to give a clear light golden liquid. The liquid was purified by flash chromatography and eluted with 3:1 hexane/ethyl acetate containing 5% acetic acid. The desired fractions were combined and evaporated to give butyl[2,4-di(benzyloxycarbonyl)butylphosphinic acid (3,R=n-butyl, R1=H) (2.9 g, 40%) as a clear and colorless oil. Rf0.12 (3:1, Hex./EtOAc 5% AcOH). 1H NMR (d6-DMSO): 7.3 ppm (m, 10), 5.0 ppm (s,4H), 2.7 ppm (m, 1H) 2.3 ppm (y, 2H), 1.8 ppm (m, 2H), 1.3 ppm (m, 4H), 0.8 ppm (t, 3H)
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[N:5]([CH2:19][CH2:20][CH3:21])[C:4](=[O:22])[C:3]=1[N+:23]([O-])=O>CO.O.[Pd]>[NH2:23][C:3]1[C:4](=[O:22])[N:5]([CH2:19][CH2:20][CH3:21])[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)[C:2]=1[CH3:1]
Reactant: CCCn1c(=O)c([N+](=O)[O-])c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: CCCn1c(=O)c(N)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Yield: 103.7 %

Procedure:
To a solution of 6-methyl-5-nitro-3-propyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (200.0 mg) in methanol (10.0 ml) was added palladium hydrate (20.0 mg) and the resulting mixture was stirred at room temperature under catalytic hydrogenation condition for twelve hours. The reaction mixture was degassed and then filtered through Celite (trade mark), and then concentrated under reduced pressure to afford 5-amino-6-methyl-3-propyl-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (190.0 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl[S:13]([C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:15])=[O:14]>CN(C1C=CN=CC=1)C>[CH3:21][O:20][C:18](=[O:19])[C:17]1[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=1[S:13](=[O:14])(=[O:15])[NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: Nc1cccc2cccnc12
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 33.9 %

Procedure:
In the similar fashion using route 14 general procedure 27, 8-aminoquinoline (100 mg, 0.69 mmol), methyl 2-chlorosulfonylbenzoate (160 mg, 0.69 mmol) and DMAP (cat.) gave the title compound (80 mg, 35%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([S:17][C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Sc1ccccc1
Product: Nc1ccc(Sc2ccccc2)cc1

Procedure:
The titled compound was prepared from 4-fluoronitrobenzene and thiophenol using the procedures in Steps 1 and 2 of Example 8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][C:15](=[O:25])[N:16]2[CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[C:12]([Cl:26])[N:11]=1.[CH3:27]OC(OC)OC>CO.CS(O)(=O)=O>[Cl:26][C:12]1[N:11]=[C:10]([N:9]2[C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[N:1]=[CH:27]2)[N:18]=[C:17]2[C:13]=1[NH:14][C:15](=[O:25])[N:16]2[CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1
Reactant: Nc1ccc(F)cc1Nc1nc(Cl)c2[nH]c(=O)n(C3CCOCC3)c2n1
Reactant: COC(OC)OC
Agent: CS(=O)(=O)O
Solvent: CO
Product: O=c1[nH]c2c(Cl)nc(-n3cnc4ccc(F)cc43)nc2n1C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
Pale yellow solid. Synthesized from 2-(2-amino-5-fluorophenylamino)-6-chloro-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (160 mg, 0.42 mmol) in anhydrous methanol (10 mL), using anhydrous trimethylorthoformate (1 mL) and methane sulfonic acid (5 drops) with stirring under Ar at room temperature for 2 h (HPLC monitoring). The solvent was removed in vacuo and the residue purified by column chromatography (silica gel, gradual elution with 2% methanol in methylene chloride to 10% methanol in methylene chloride) to afford the desired product (120 mg, 73% yield). 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.03 (s, 1H), 8.40-8.20 (m, 1H), 7.82-7.72 (m, 1H), 7.17-7.11 (m, 1H), 4.72-4.58 (m, 1H), 4.28-4.13 (m, 2H), 3.70-3.62 (m, 2H), 2.90-2.72 (m, 2H), 1.90-1.78 (m, 2H); MS (EI) m/z 389.2 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([O-:21])=[O:20])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([C:19]([OH:21])=[O:20])[CH:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(-c2c[nH]nc2-c2ccc(F)cc2)ccn1
Yield: 73 %

Procedure:
To a solution of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylate prepared as set forth in Example A-224 (0.90 g, 0.003 mol) in 10 mL of ethanol was added a solution of sodium hydroxide (0.24 g, 0.006 mol) in 5 mL of water. The reaction mixture was heated at reflux for 10 hours. After the removal of solvent, the residue was dissolved in water and acidified with citric acid solution to pH 5. Then the aqueous phase was extracted with ethyl acetate and the organic phase was dried over magnesium sulfate and concentrated. The crude was purified by treating with ether to give 0.62 g of 4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyridinecarboxylic acid as a white solid (73% yield), mp: 245° C.(dec). Anal Calc'd for C15H10FN3O+0.2 H2O: C, 62.80; H, 3.65; N, 14.65. Found: C, 62.77; H, 3.42; N, 14,58.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[CH2:22][CH:23]([OH:26])[CH2:24][OH:25]>O>[OH:26][CH:23]([CH2:24][OH:25])[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[O:7])=[CH:17][CH:18]=1
Reactant: OCC(O)CCl
Reactant: O=C(c1ccc(O)cc1)c1c[nH]c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(c1ccc(OCC(O)CO)cc1)c1c[nH]c2ccccc12
Reaction time: 3 h

Procedure:
11 g of 3-(p-hydroxybenzoyl)indole and 7.43 g of sodium hydroxide were dissolved in 10 ml of water. 20.51 g of 3-chloro-1,2-propandiol was added to the solution followed by reflux with stirring for 3 hours in oil bath. After cooling, the solution was evaporated to dryness. The residue was purified by column chromatography on silica gel. After recrystallization from ethyl acetate, 3-[p-(2,3-dihydroxypropoxy)benzoyl]indole (compound 16) was obtained in the form of white crystals. (Yield: 13.8%).
Reaction SMILES: C([Mg]Br)C.C(OCC)C.I[C:11]1[N:12]=[C:13]2[CH2:19][CH2:18][O:17][C:16]3[CH:20]=[C:21]([C:24]([O:26][CH3:27])=[O:25])[CH:22]=[N:23][C:15]=3[N:14]2[C:28]=1[I:29].O1CCCC1>[NH4+].[Cl-]>[I:29][C:28]1[N:14]2[C:15]3[N:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]2=[N:12][CH:11]=1
Reactant: COC(=O)c1cnc2c(c1)OCCc1nc(I)c(I)n1-2
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cnc2c(c1)OCCc1ncc(I)n1-2
Reaction time: 0.29 h

Procedure:
Ethylmagnesium bromide in ethyl ether (3.0 M, 0.104 mL, 0.31 mmol)) was added dropwise to a suspension of methyl 9,10-diiodo-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carboxylate (130 mg, 0.26 mmol) in Tetrahydrofuran (5.0 mL, 62 mmol) at −15° C. The mixture was stirred for 15-20 min (a completion was monitored by LCMS), pour into 20 ml of sat. aq. NH4Cl and extracted with ethyl acetate. The organic extracts were washed with water (2×20 ml), brine, dried over MgSO4 and concentrated in vacuum. Weight 92 mg (94%). MS (ESI+): 372.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:9]([CH3:12])=[N:10][NH:11][C:3]=12.[CH3:13]OC(OC)N(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]2[C:4](=[C:9]([CH3:12])[N:10]([CH3:13])[N:11]=2)[N:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)c2[nH]nc(C)c2n1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)c2nn(C)c(C)c2n1
Yield: 15 %

Procedure:
7-Chloro-3,5-dimethyl-1H-pyrazolo[4,3-b]pyridine (900 mg) and dimethylformamide dimethyl acetal (1.06 ml) in dry toluene (10 ml) were heated at reflux for 4 hours. The solvent was removed under reduced pressure and the brown oily residue chromatographed on silica gel eluting with 50:50 ether/pentane to give the title compound (150 mg, 15%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([OH:13])=O)=[O:4].S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([Cl:16])=[O:13]
Reactant: COC(=O)c1ccncc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccncc1C(=O)Cl
Temperature: 25 °C

Procedure:
3-Chlorocarbonyl-isonicotinic acid methyl ester was prepared by refluxing a mixture of pyridine-3,4-dicarboxylic acid 4-methyl ester (100 mg) and thionyl chloride (75 μl) in chloroform (5 ml) for 3 h. After cooling to room temperature, volatiles were evaporated, and the residue was dried under high vacuum to give the product (100 mg).
Reaction SMILES: C(OC(=O)[NH:10][C:11]([CH3:22])([C:16]1[N:20]=[C:19]([CH3:21])[O:18][N:17]=1)[CH2:12][CH:13]1[CH2:15][CH2:14]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH:13]1([CH2:12][C:11]([NH2:10])([CH3:22])[C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)[CH2:15][CH2:14]1
Reactant: Cc1nc(C(C)(CC2CC2)NC(=O)OCc2ccccc2)no1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1nc(C(C)(N)CC2CC2)no1
Yield: 52.6 %

Procedure:
To a solution of [2-Cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethyl]-carbamic acid benzyl ester (Example 66d, 540 mg, 1.71 mmol) in ethanol (10 ml) under argon atmosphere was added palladium on charcoal 10% (54.7 mg, 514 μmol). The reaction was stirred at room temperature under a pressure of 2.5 bar hydrogen for 2 hours. The reaction mixture was filtered through a pad celite and the filter cake was washed two times with ethanol. The filtrate was evaporated down to dryness to yield the title compound (163 mg, 53%) as crude yellow oil which was used with any purification. MS (ESI, m/z): 182.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: CS(=O)(=O)Cl
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Product: CS(=O)(=O)NC1CCCc2c1[nH]c1ccc(Br)cc21

Procedure:
N-(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)methanesulfonamide was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine and methane sulfonyl chloride to give a tan solid (57% yield). 1H-NMR (CDCl3): δ 8.71 (s, 1H), 7.60 (m, 1H), 7.26 (m, 1H), 7.20 (d, 1H), 4.71A4.59 (m, 2H), 3.07 (s, 3H), 2.67 (m, 2H), 2.22 (m, 1H), 2.00-1.78 (m, 3H); MS m/z 343 (M−1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[CH2:13]([NH:15][CH2:16][CH2:17][OH:18])[CH3:14]>C(Cl)Cl.[OH-].[Na+]>[Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][OH:18])=[O:6]
Reactant: CCNCCO
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCN(CCO)C(=O)c1ccc(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.4 %

Procedure:
3-Chloro-2,4-difluorobenzoylchloride (211 mg, 1 mmol) in DCM (1 mL) was added to a stirred solution of 2-(ethylamino)ethanol (98 mg, 1.1 mmol) in a mixture of DCM (1 mL) and 10% sodium hydroxide solution (1 mL) at 0° C. After the addition of the acid chloride was complete, the mixture was warmed to RT and stirred for approximately 4 hours. The two layers were separated and the aqueous layer was extracted with DCM (3×30 mL). The organic layers were combined, dried (MgSO4), filtered and evaporated to give a colourless oil (220 mg). The material was used without further purification or analysis.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:29]([CH:38]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:40]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:39]2=[O:53])=[CH:30][C:31]2[CH2:32][CH2:33][CH2:34][CH2:35][C:36]=2[CH:37]=1>>[OH:16][CH2:5][C:38]1([C:29]2[C:28]([OH:27])=[CH:37][C:36]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=3[CH:30]=2)[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:39]1=[O:53]
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCOC(=O)CN1C(=O)C(c2cc3c(cc2O)CCCC3)c2ccccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc3c(cc2O)CCCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained: MS (ES+) m/z 378 (M−17), 418 (M+23).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[C:9]1([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]=[CH:26][C:27](Cl)=[O:28])(=[O:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:3][NH:2][C:27](=[O:28])[CH:26]=[CH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[S:16](=[O:18])(=[O:17])[NH:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NO
Reactant: O=C(Cl)C=Cc1ccccc1S(=O)(=O)Nc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1S(=O)(=O)Nc1ccccc1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.21 g, 3.01 mmol) in tetrahydrofuran (4.0 ml) a saturated NaHCO3 solution (2.6 ml) was added and the resultant mixture was stirred at ambient temperature for 25 min. To the reaction mixture a 3-(2-phenylsulfamoyl-phenyl)-acryloyl chloride (36a) (0.19 g, 0.59 mmol) solution in tetrahydrofuran (2.5 ml) was added and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, and the solvent was removed. The residue was washed with diethyl ether and crystallised from acetonitrile to give the title compound (0.056 g, 30%) as white crystals, m.p. 205-206.5° C. 1H NMR (DMSO-d6, HMDSO), δ: 6.37 (1H, d, J=16.0 Hz); 6.99-8.04 (10H, m); 8.23 (1H, d, J=16.0 Hz); 10.55 (1H, s), 10.83 (1H, br s). HPLC analysis on Symmetry C18 column: impurities 6.4% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer, pH 2.5, 30:70; sample concentration 0.2 mg/ml; flow rate 1.2 ml/min; detector UV 220 nm). Anal. Calcd for C15H14N2O4S*0.1 H2O, %: C 56.28, H 8.75, N 4.47. Found, %: C 55.63, H 9.07, N 4.36.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2([OH:33])[CH2:18][CH2:17][N:16]([C:19]3[C:28]4[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=4)[N:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)(=O)=O)=CC=1.[I-:35].[Na+]>CC(=O)CC>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][N:20]=[C:19]2[N:16]1[CH2:17][CH2:18][C:13]([OH:33])([CH2:12][CH2:11][I:35])[CH2:14][CH2:15]1
Reactant: COc1cc2ncnc(N3CCC(O)(CCOS(=O)(=O)c4ccc(C)cc4)CC3)c2cc1OC
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COc1cc2ncnc(N3CCC(O)(CCI)CC3)c2cc1OC

Procedure:
A mixture of 1-[4-toluenesulphonyloxy]-2-[1-(6,7-dimethoxyquinazolin-4-yl)-4-hydroxy-piperid-4-yl]ethane (0.6 g) and sodium iodide (1.84 g) in butan-2-one (10 cm3) was heated under reflux for 2.5 hours. Volatile material was removed in vacuo and the residue partitioned between chloroform (20 cm3) and water (20 cm3). The dried (MgSO4) organic phase was evaporated and the residue was crystallized from ethyl acetate to afford 6,7-dimethoxy-4-[4-hydroxy-4-(2-iodoethyl)piperid-1-yl]quinazoline, m.p. 179°-181°, (0.3 g).