Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[C:3]([C:6]1[CH:11]=[N:10][CH:9]=[CH:8][N:7]=1)([OH:5])[CH3:4]>[Pt](=O)=O.CO>[CH3:1][CH:2]([CH3:12])[C:3]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1)([OH:5])[CH3:4]
Reactant: CC(C)C(C)(O)c1cnccn1
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)C(C)(O)C1CNCCN1
Reaction time: 24 h
Yield: 96.5 %

Procedure:
A PARR vessel was charged with platinum dioxide (1 g, 4.404 mmol), methanol (70 mL) and 3-methyl-2-pyrazin-2-yl-butan-2-ol (5 g, 30.08 mmol). The vessel was shaken in the PARR under a 60 psi H2 pressure for 24 hours. As the reaction did not go to completion, more platinum dioxide (˜300 mg) was added and the reaction mixture was shaken in the PARR for another 24 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo to give the title compound as a colourless oil (5 g; 97%). 1H NMR (CDCl3) 0.85-0.90 (3H, m), 0.97-1.06 (6H, m), 1.70-1.90 (3H, m), 2.60-2.70 (3H, m), 2.80-2.90 (2H, m), 3.05-3.10 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[Cl:29][CH2:30][C:31](Cl)=[O:32]>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=2[CH2:24][N:25]([C:31](=[O:32])[CH2:30][Cl:29])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CCl)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester and chloroacetyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.Br[CH2:10][C:11]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)=[O:12]>C(N(CC)CC)C.C(O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11](=[O:12])[C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=1
Reactant: O=c1ncc(Br)c[nH]1
Reactant: O=C(CBr)c1ccsc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(Cn1cc(Br)cnc1=O)c1ccsc1
Temperature: 25 °C
Yield: 39.7 %

Procedure:
A mixture of 5-bromopyrimidin-2-one (700 mg) and 3-bromoacetylthiophene (1.025 g) in triethylamine (0.84 ml) and ethanol (25 ml) was stirred at room temperature. After 1 h. the mixture was cooled to 3° C. and the precipitate collected. The dried solid was crystallised from ethanol to give the title pyrimidinone (475 mg), m.p. 180°-182° C. (dec), λmax (EtOH) 250.5 nm (ε 14,930), 334.5 nm (ε 3,260).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[NH:10][CH2:11][C:12](=[O:40])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH2:26][O:27]C(=O)C)=[O:23])=[CH:17][C:16]=1[C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(O)(=O)C>CO>[CH2:1]([O:8][C:9](=[O:41])[NH:10][CH2:11][C:12](=[O:40])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH2:25][CH2:26][OH:27])=[O:23])=[CH:17][C:16]=1[C:31](=[O:39])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[F:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OCCNC(=O)Nc1ccc(CNC(=O)CNC(=O)OCc2ccccc2)c(C(=O)c2ccccc2F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(CNC(=O)OCc1ccccc1)NCc1ccc(NC(=O)NCCO)cc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
250 mg of benzyl{[[2-(o-fluorobenzoyl)-4-[3-(2-acetoxyethyl)ureido]phenyl]methylcarbamoyl]methyl}carbamate dissolved in 10 ml of absolute methanol are treated with 50 mg of sodium methylate, stirred at room temperature for 1 hour and buffered with a small amount of acetic acid. The mixture is poured on to ice/10% sodium bicarbonate and extracted with methylene chloride. The organic solution is dried over sodium sulphate, filtered and concentrated. After crystallisation from ether/ethanol, there is obtained benzyl{[[2-(o-fluorobenzoyl)-4-[3-(2-hydroxyethyl)ureido]phenyl]methylcarbamoyl]methyl}carbamate which melts at 117°-120° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH2:12][CH2:11][Br:10])=[C:2]([NH2:1])[CH:7]=1
Reactant: BrCCBr
Reactant: Nc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(Br)ccc1OCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 31.9 %

Procedure:
A mixture of the product 2-amino-4-bromophenol (500 mg, 2.66 mmol), 1,2-dibromoethane (2.5 g, 13.3 mmol) and K2CO3 (1.84 g, 13.3 mmol) in DMF (10 mL) was stirred at room temperature for 4 h. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (3×50 mL) and brine (50 mL), concentrated and purified by column chromatography on silica gel (ethyl acetate in petroleum, 10% v/v) to give 5-bromo-2-(2-bromoethoxy)benzenamine (250 mg, 37%) as a yellow solid. LCMS: 294 [M+1]+. 1H NMR (400 MHz, DMSO-d6) δ 3.79 (t, J=6.0 Hz, 2H), 4.25 (t, J=5.6 Hz, 2H), 5.06 (s, 2H), 6.63 (dd, J1=2.4 Hz, J2=8.0 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.82 (d, J=2.4 Hz, 1H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11](B(O)O)=[C:10]([F:18])[CH:9]=1.Br[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[C:10]([F:18])[CH:9]=1
Reactant: OB(O)c1c(F)cc(CCC2OCCO2)cc1F
Reactant: N#Cc1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1ccc(-c2c(F)cc(CCC3OCCO3)cc2F)cc1
Yield: 51.9 %

Procedure:
To 150 ml of N,N-dimethyl formamide (hereinafter abbreviated as “DMF”) were added 7.0 g (27 mmol) of 4-(1,3-dioxolan-2-ylethyl)-2,6-diflurophenyl boronic acid obtained in Step 2, 5.0 g (27 mmol) of 4-bromobenzonitrile, 10 g (99 mmol) of triethyl amine, 0.20 g (0.89 mmol) of palladium acetate and 0.50 g (1.9 mmol) of triphenylphosphine and the mixture was refluxed for 4 hours. The solvent was distilled off under reduced pressure. To the residue of this distillation were added 500 ml of methylene chloride and 250 ml of a 10% aqueous ammonia and the mixture was stirred. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluting solvent: toluene/ethyl acetate=5/1) and then the solvent was distilled off under reduced pressure. The residue thus obtained was washed with ethanol and then dried under reduced pressure to afford 4.4 g (14 mmol) of 1-(1,3-dioxolan-2-ylethyl)-3,5-difluoro-4-(4-cyanophenyl)benzene. (Yield: 52%)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12](=[S:14])=[S:13]>C(O)C>[CH3:1][C:2]1[NH:3][CH:4]=[N:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12](=[S:13])[SH:14]
Reactant: S=C=S
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CCO
Product: Cc1[nH]cnc1CSCCNC(=S)S
Reaction time: 8 h

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (10.2 g) in ethanol (75 ml) was added slowly, with stirring, to carbon disulphide (200 ml). The mixture was set aside overnight at room temperature and the solid formed was collected and recrystallised from aqueous isopropyl alcohol to afford N-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]dithiocarbamic acid (9.8 g)., m.p. 127-129°.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[NH:4][N:3]=1.C([O-])(O)=O.[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>C1COCC1.C(O)C>[Cl:17][C:18]1[N:23]=[C:22]([NH:11][C:7]2[CH:6]=[C:5]3[C:10]([C:2]([CH3:1])=[N:3][NH:4]3)=[CH:9][CH:8]=2)[CH:21]=[CH:20][N:19]=1
Reactant: Cc1n[nH]c2cc(N)ccc12
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1n[nH]c2cc(Nc3ccnc(Cl)n3)ccc12
Reaction time: 4 h
Yield: 89.8 %

Procedure:
To a stirred solution of 3-methyl-6-aminoindazole (2.71 g, 0.015 mol) and NaHCO3 (1.26 g, 0.045 mol) in THF (15 mL) and ethanol (60 mL) was added 2,4-dichloropyrimidine (6.66 g, 0.045 mol) at room temperature. After the reaction was stirred for four hours, the suspension was filtered and washed thoroughly with ethanol. The filtrate was concentrated under reduced pressure, and the resulting solid was washed with ether to remove excess pyrimidine to yield 3.5 g (89% yield) of N-(2-chloro-4-pyrimidinyl)-N-(3-methyl-1H-indazol-6-yl)amine.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[C:12]([CH3:13])=[C:11]([C:14]2[Se:15][C:16]([Br:19])=[CH:17][CH:18]=2)[N:10]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[N:9]=1)=[O:7])C.O.Cl>CO>[Br:19][C:16]1[Se:15][C:14]([C:11]2[N:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])[N:9]=[C:8]([C:6]([OH:7])=[O:5])[C:12]=2[CH3:13])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Br)[se]2)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Br)[se]1
Yield: 95.4 %

Procedure:
A solution of potassium hydroxide (442 mg, 7.88 mmol) in methanol (7 mL) was added to a magnetically stirred solution of 5-(5-Bromo-selenophen-2-yl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (2.0 g, 3.94 mmol) in methanol (15 mL). The mixture was heated under reflux for 3 h. The reaction mixture was cooled, poured into water, and acidified with 10% hydrochloric acid. The precipitate was filtered out, washed with water, and dried under vacuum to yield the corresponding acid (1.8 g, 95%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:20][CH2:19][C:18]4[CH:21]=[C:22]([NH2:25])[CH:23]=[CH:24][C:17]=4[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.Cl[C:27]1[N:32]=[C:31]([NH:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]2[NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:30]([Cl:45])=[CH:29][N:28]=1>>[Cl:45][C:30]1[C:31]([NH:33][C@@H:34]2[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]2[NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[N:32][C:27]([NH:25][C:22]2[CH:23]=[CH:24][C:17]3[CH2:16][CH2:15][CH:14]([N:11]4[CH2:12][CH2:13][CH:8]([N:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)[CH2:9][CH2:10]4)[CH2:20][CH2:19][C:18]=3[CH:21]=2)=[N:28][CH:29]=1
Reactant: CS(=O)(=O)NC1CCCCC1Nc1nc(Cl)ncc1Cl
Reactant: CN1CCN(C2CCN(C3CCc4ccc(N)cc4CC3)CC2)CC1
Product: CN1CCN(C2CCN(C3CCc4ccc(Nc5ncc(Cl)c(N[C@@H]6CCCC[C@H]6NS(C)(=O)=O)n5)cc4CC3)CC2)CC1

Procedure:
The title compound was prepared from 7-[4-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and N-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to Example 179 heating at 140° C. Product was isolated as an off-white solid (10 mg, 9%). LCMS (m/e) 645 (M+1); 1H NMR (400 MHz, DMSO-d6) δ 9.32 (m, 2H), 7.97 (s, 1H), 7.57 (m, 1H), 7.42 (m, 1H), 7.17 (m, 1H), 7.06 (d, 1H, J=7.8 Hz), 6.95 (m, 1H), 3.38-2.82 (m, 8H), 2.94-3.02 (m, 8H), 2.67-2.77 (m, 8H), 2.33 (m, 2H), 1.95-2.06 (m, 4H), 1.72 (m, 4H), 1.15-1.44 (m, 8H).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][NH:10]C(OC(C)(C)C)=O)=[N:7][CH:8]=1.[Cl:20][C:21]1[C:26]([C:27]([N:29]=[C:30]=[O:31])=O)=[C:25]([F:32])[C:24]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:23][CH:22]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[C:25]([F:32])[C:26]=1[C:27]1[NH:29][C:30](=[O:31])[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[CH:8][N:7]=2)[N:10]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)N=C=O)c1F
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cn3)c(=O)[nH]2)c1F
Yield: 14.1 %

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(5-(trifluoromethyl)pyridin-2-yl)hydrazinecarboxylate (Intermediate-60, 0.050 g, 0.18 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoyl isocyanate (Intermediate-51, 0.120 g, 0.36 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.012 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 1.13 (s, 9H), 4.30 (d, J=5.6 Hz, 2H), 7.11 (br s, 1H), 7.46 (1, J=8 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 8.14 (m, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.35 (dd, J=7.2 Hz, 1H), 8.87 (s, 1H); MS (m/z): 472.24 (M+H+).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:9]#[N:10].[Na+]>C(#N)C>[C:2]1([CH2:1][C:9]#[N:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC#N
Product: N#CCc1ccccc1

Procedure:
A mixture of 0.635 g. (0.005 mole) benzyl chloride, O.50 g. sodium cyanide (0.010 mole), 0.53 g. (0.0005 mole) compound I (R = --CH2CH2 -O--2CH2CH3), and 15 ml. acetonitrile was stirred at reflux for 3.0 hours, at which time vapor-phase chromatographic analysis of the reaction mixture showed complete consumption of benzyl chloride and formation of phenylacetonitrile as the sole product. The reaction mixture was poured into water and extracted with petroleum ether to afford phenylacetonitrile and recovered catalyst I (82% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=2)=[CH:3]1.[OH:25][CH2:26][CH2:27][C:28](=O)[CH3:29].[BH3-]C#N.[Na+]>ClCCl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:24])[NH:13][C:14](=[O:23])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:28]([CH3:29])[CH2:27][CH2:26][OH:25])[CH:17]=2)=[CH:3]1
Reactant: Cn1cc(C2=C(c3cccc(N)c3)C(=O)NC2=O)c2ccccc21
Reactant: CC(=O)CCO
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Product: CC(CCO)Nc1cccc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (0.2 g, 0.6 mmol) and 4-hydroxy-2-butanone (80 mg, 1.5 eq) in dichloromethane (15 mL) was added NaCNBH3 (56 mg, 1.5 eq) and the reaction mixture was stirred at RT for three days. The product 3-(1-methylindol-3-yl)-4-[3-(3-hydroxy-1-methylpropylamino)phenyl]-1H-pyrrole-2,5-dione separated by preparatory TLC (8.9 mg, 3.6%). LC/mS: M+ 389.
Reaction SMILES: [BrH:1].C(S[C:5]1[NH:6][CH2:7][CH:8]([OH:11])[CH2:9][N:10]=1)C.O.[NH2:13][NH2:14].C(O)C.CO>CC(O)C>[BrH:1].[NH:13]([C:5]1[NH:6][CH2:7][CH:8]([OH:11])[CH2:9][N:10]=1)[NH2:14]
Reactant: NN
Reactant: CCSC1=NCC(O)CN1
Agent: Br
Solvent: CO
Solvent: CC(C)O
Solvent: O
Product: NNC1=NCC(O)CN1
Temperature: -10 °C

Procedure:
A mixture of 11.5 g of 2-(ethylthio)-1,4,5,6-tetrahydro-5-pyrimidinol, hydrobromide, 2.5 ml of hydrazine hydrate and 50 ml of ethanol was stirred at reflux for 5 hours, taken to dryness in vacuo and suspended in 100 ml of 2-propanol at the boil. A 100 ml portion of methanol was added at the boil, then the solution was clarified and cooled to -10° C., giving 4.9 g of the desired intermediate, mp 163°-164° C.
Reaction SMILES: [F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:29][CH2:28][C:23]4(OCC[O:24]4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)=[C:12]2[C:7]([C:8]([C:30]([F:33])([F:32])[F:31])=[CH:9][CH:10]=[CH:11]2)=[N:6]1>C(O)=O>[F:1][C:2]1[CH:37]=[C:36]([F:38])[CH:35]=[C:34]([F:39])[C:3]=1[CH2:4][N:5]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:21][CH2:22][C:23](=[O:24])[CH2:28][CH2:29]3)=[CH:16][CH:15]=2)=[C:12]2[C:7]([C:8]([C:30]([F:33])([F:31])[F:32])=[CH:9][CH:10]=[CH:11]2)=[N:6]1
Reactant: Fc1cc(F)c(Cn2nc3c(C(F)(F)F)cccc3c2-c2ccc(N3CCC4(CC3)OCCO4)cc2)c(F)c1
Solvent: O=CO
Product: O=C1CCN(c2ccc(-c3c4cccc(C(F)(F)F)c4nn3Cc3c(F)cc(F)cc3F)cc2)CC1
Yield: 55.2 %

Procedure:
A solution of 8-{4-[2-(2,4,6-trifluorobenzyl)-7-(trifluoromethyl)-2H-indazol-3-yl]phenyl}-1,4-dioxa-8-azaspiro[4.5]decane (0.195 g, 0.36 mmol) in 2 mL of formic acid was heated at 70° C. for 2 hours. The solvent was evaporated and the residue purified by flash chromatography (CH2Cl2-EtOAc, 19:1) to give 0.1 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:31])[CH2:16][C:17]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:18]=2[C:19](N(CC)CC)=[O:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)CC.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[O:31][C:19](=[O:20])[C:18]3[C:17]([CH:16]=2)=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:30])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)c1c(Cl)cccc1CC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCC(=O)O
Product: O=c1oc(-c2ccc(OCc3ccccc3)cc2)cc2cccc(Cl)c12
Temperature: 165 °C
Yield: 72.8 %

Procedure:
In a 10 mL round bottomed flask equipped with a magnetic stir bar 2-[2-(4-benzyloxyphenyl)-2-oxo-ethyl]-6-chloro-N,N-diethylbenzamide (340 mg, 0.78 mmol) was treated with propionic acid (1.5 mL). The resulting mixture was stirred and heated to reflux in a 165° C. oil bath. As the reaction heated, the 2-[2-(4-benzyloxyphenyl)-2-oxo-thyl]-6-chloro-N,N-diethylbenzamide was dissolved in the propionic acid to afford a pale brown solution. After stirring at reflux for 88 hours, the reaction was analyzed by TLC, which showed no starting material remaining. The reaction was allowed to cool to ambient temperature during which time a mass of pale brown crystals were deposited on the walls of the reaction flask. The reaction mixture was diluted with ethyl acetate to dissolve the solids, and the resulting solution was washed with saturated aqueous NaHCO3 solution. The basic aqueous solution was then extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford an off-white solid. This material was quite clean by 1H NMR analysis and was further purified by recrystallization from EtOAc to afford 3-(4-benzyloxyphenyl)-8-chloro-isochromen-1-one (206 mg, 73% yield) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: CCc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: CCc1cc2c(NCc3ccc(F)cc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyridin-4-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(4-fluorobenzylamino)-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:25][CH2:24]3)=[O:22])[O:18][C:17]2=[O:34])=[CH:12][CH:11]=1)=O)(C)(C)C.C([O-])(=O)C.[ClH:39]>>[ClH:39].[ClH:39].[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([C:21]([N:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:27][CH2:28]3)=[O:22])[O:18][C:17]2=[O:34])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N2CC(C(=O)N3CCN(CCC(=O)O)CC3)OC2=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Product: NCc1ccc(N2CC(C(=O)N3CCN(CCC(=O)O)CC3)OC2=O)cc1

Procedure:
0.43 g of 3-{1-[3-(4-tert-butoxycarbonylaminomethylphenyl)-2-oxo-5-oxazolidinylcarbonyl]-4-piperazinyl}propionic acid, acetate, is stirred in 30 ml of ethereal HCl solution at room temperature. The precipitate formed is filtered off with suction, washed with a little ether and dried. 3-{1-[3-(4-aminomethylphenyl)-2-oxo-5-oxazolidinylcarbonyl]-4-piperazinyl}propionic acid, dihydrochloride, is obtained, m.p. 184°-186°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([C:16](N(OC)C)=[O:17])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22]1([Mg]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH4+].[Cl-]>C1COCC1>[C:16]([CH:12]1[CH2:11][N:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C:14](=[O:15])[CH2:13]1)(=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(N2CC(C(=O)N(C)OC)CC2=O)cc1F
Reactant: Cl[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(N2CC(C(=O)c3ccccc3)CC2=O)cc1F
Temperature: 50 °C

Procedure:
To a solution of 1-(3-fluoro-4-methoxyphenyl)-N-methoxy-N-methyl-5-oxopyrrolidine-3-carboxamide (Step 1, 2 g, 6.75 mmol) in 30 mL of THF was added 2 M phenylmagnesium chloride in THF (6.75 mL) via syringe at RT. The solution was heated to 50° C. for 2 h. The solution was poured to 50 mL of satd. NH4Cl aq. soln. The resulting mixture was extracted with 100 mL of EtOAc. The organic phase was washed with 50 mL of brine, dried over Na2SO4 and concentrated in vacuo. The crude was purified by a silica gel column chromatography (10% to 80% EtOAc/hexane) to give white solid. MS (ESI pos. ion) m/z: 314.2 (M+H). Calc'd Exact Mass for C18H16FNO3: 313.32.
Reaction SMILES: C1(O[C:8](=[O:18])[NH:9][C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH3:17][O:16][C:11]1[C:10]([NH:9][C:8]([N:30]2[CH2:29][CH2:28][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[O:20][CH3:19])[CH2:32][CH2:31]2)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1ncccc1NC(=O)Oc1ccccc1
Product: COc1ccccc1N1CCN(C(=O)Nc2cccnc2OC)CC1
Yield: 86 %

Procedure:
Phenyl-N-(2-methoxypyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:16][C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[CH:9]=1)=[O:7])C>C(O)C>[NH:16]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[CH:9]=[C:8]1[C:6]([OH:7])=[O:5]
Reactant: CCOC(=O)c1cc2cnccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2cnccc2[nH]1

Procedure:
Aqueous sodium hydroxide solution (2.4 mL, 2M, 4.8 mmol) was added to a solution of 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (Preparation 11, 0.76 g, 4.0 mmol) in ethanol (40 mL) and the mixture heated under reflux for 2 h before being cooled and concentrated in vacuo. The residue was dissolved in a minimum amount of water, glacial acetic acid (1 mL) was added and the solution cooled in a refrigerator for 3 days. The resultant precipitate was collected by filtration washed with ether and dried in vacuo to give the title compound as a cream coloured solid. δH (D2O): 7.05 (1H, s), 7.63 (1H, d), 8.08 (1H, d), 8.94 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(N(CC)C(C)C)(C)C.Cl[CH2:23][O:24][CH3:25]>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH2:23][O:24][CH3:25])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCl
Reactant: COC(=O)c1cc(O)cc(O)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(O)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.8 %

Procedure:
With ice cooling, to a solution of methyl 3,5-dihydroxybenzoate (14.0 g, 83.3 mmol) and N,N-diisopropylethylamine (11.0 g, 85.0 mmol) in dichloromethane (100 mL) was added dropwise chloromethylmethyl ether (6.84 g, 85.0 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with dichloromethane (300 mL), and the organic layer was washed successively with a 3% aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution and saturated brine, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=4:6) to give the title compound (7.74 g, yield 44%) as an oily matter.