Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:4]([C:15](=[O:17])[CH3:16])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][C:10]([CH3:14])([CH3:13])[C:11]=2[CH:12]=1.B(Br)(Br)Br>ClCCl>[OH:2][C:3]1[C:4]([C:15](=[O:17])[CH3:16])=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][C:10]([CH3:13])([CH3:14])[C:11]=2[CH:12]=1
Reactant: COc1cc2c(cc1C(C)=O)CCCC2(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)c1cc2c(cc1O)C(C)(C)CCC2
Reaction time: 3 h

Procedure:
To 1-(3-methoxy-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (Compound A-86, 14.2 g, 61.2 mmol) in dichloromethane (350 mL) at −78° C. was added boron tribromide (1 M in hexane, 80 mL, 80 mmol). After stirring from −78° C. to room temperature over 3 h the reaction mixture was quenched with sodium bicarbonate at −10° C. and extracted with diethyl ether. Combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. Recrystallization from diethyl ether afforded the title compound as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][CH:17](OCC)[O:18][CH2:19][CH3:20].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:16]=[CH:17][O:18][CH2:19][CH3:20]
Reactant: CCOC(CBr)OCC
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC=CSc1ccccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromothiophenol (10.50 g, 55.87 mmol) in dry DMF (50 mL) under nitrogen is added cautiously potassium carbonate (9.2 mL, 61.46 mmol, 1.10 equiv.). Once bubbling has subsided, 2-bromo-1,1-diethoxyethane (8.46 g, 61.46 mmol, 1.10 equiv.) is added to the mixture and stirred for 2 h at room temperature. The resulting suspension is poured onto 200 mL of iced water and extracted with diethyl ether (3×50 mL). The organic layers are washed with brine, dried over MgSO4 to afford after solvent removal the title compound as a viscous orange oil, used without further purification.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]([CH2:8][CH2:9][OH:10])[C:6]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:5]=2[N:4]=1.CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:10][CH2:9][CH2:8][N:7]1[C:6]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:17])[F:16])=[CH:14][C:5]=2[N:4]=[C:3]1[C:2]([F:1])([F:19])[F:20])(=[O:31])=[O:30]
Reactant: OCCn1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCn1c(C(F)(F)F)nc2cc(C(F)(F)F)ccc21
Temperature: 0 °C

Procedure:
To a stirred solution of 2-[2,5-bis(trifluoromethyl)-1H-benzimidazol-1-yl]ethanol (5.36 g, 17 mmol) in CH2Cl2 (15 ml), Et3N (5.0 ml, 36 mmol) was added and cooled to 0° C. To the cooled solution, methanesulfonyl chloride (1.53 ml, 19.8 mmol) was added slowly.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7](=[S:22])[NH:9][CH3:10]
Reactant: CNC(=O)c1cc(Br)ccc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CNC(=S)c1cc(Br)ccc1F
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 99.6 %

Procedure:
A mixture of 5-bromo-2-fluoro-N-methylbenzamide (500 mg, 2 mmol) and Lawesson's reagent (872 mg, 2.16 mmol) in toluene (10 mL) was heated to 100° C. and stirred for 3.5 hours. The reaction was cooled to room temperature, diluted with toluene, and filtered. The filtrate was concentrated and purified by flash column chromatography (0-20% ethyl acetate/heptanes) to give the title compound (494 mg, 92%) as a yellow oil that solidified upon standing. +ESI (M+H+1) 250.1; 1H NMR (400 MHz, CDCl3, δ): 8.20 (dd, J=6.93, 2.63 Hz, 1H), 8.06 (br.s., 1H), 7.47 (ddd, J=8.73, 4.44, 2.63 Hz, 1H), 6.95 (dd, J=11.12, 8.78 Hz, 1H), 3.32 (dd, J=4.88, 0.78 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[OH:17])([O-:3])=[O:2].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:17][C:5]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]([C:10]([CH3:13])([CH3:11])[CH3:12])=[CH:7][C:6]=2[N+:14]([O-:16])=[O:15])(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)Oc2c([N+](=O)[O-])cc(C(C)(C)C)cc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,6-dinitro-4-t-butyl-phenol (80 mmol; 10) and tosyl chloride (80 mmol) were dissolved in 300 ml CH2Cl2. Diisopropylethylamine (DIEA, 80 mmol) was added to the solution. The mixture was stirred at room temperature for 2 hours. The solution was washed with 10% citric acid, saturated aqueous NaCl (sat. NaCl), and dried with MgSO4. The solvent was removed under reduced pressure, and the product was obtained as a bright yellow solid in quantitative yield. 1H NMR (500 MHz, CDCl3): δ=8.12 (s, 2H), 7.80 (d, 2H), 7.40 (d, 2H), 2.51(s, 3H), 1.41 (s, 9H). ESI-MS: m/z: 417.2 (M+Na+).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=O)[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=3)=[CH:12][C:3]1=2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>O>[CH3:1][C:2]1([CH3:20])[O:7][C:6](=[S:30])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[S:17][CH:16]=[C:15]([C:18]#[N:19])[CH:14]=3)=[CH:12][C:3]1=2
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(C#N)cs3)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Product: CC1(C)OC(=S)Nc2ccc(-c3cc(C#N)cs3)cc21

Procedure:
The title compound was prepared in a manner similar to Example 16 using 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)thiophene-3-carbonitrile and Lawesson's reagent. The product was obtained in the form of yellow crystals: m.p. 258-259° C. 1H NMR (DMSO-d6) δ 12.3 (s, 1H), 8.54 (d, 1H, J=0.9 Hz), 7.96 (s, 1H), 7.69-7.62 (m, 2H), 7.11-7.08 (d, 1H, J=8.3 Hz), 1.69 (s, 6H); MS (ESI) m/z 299 [M−H]−; Anal. Calcd. For C15H12N2OS2.½ H2O: C, 58.0; H, 4.24; N, 9.05. Found: C, 58.33; H, 3.85; N, 8.39.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.Cl[C:22]1[CH:34]=[C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:35])[N:23]=1.[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:19][O:20][C:22]1[CH:34]=[C:26]2[N:27]([CH:31]([CH3:32])[CH3:33])[CH2:28][CH2:29][CH2:30][N:25]2[C:24](=[O:35])[N:23]=1
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Reactant: CC(C)N1CCCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCCn2c1cc(OCc1ccc(Oc3ccc(C(F)(F)F)nc3)c(F)c1)nc2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol (126 mg, 0.439 mmol) and 8-chloro-1-isopropyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one (20 mg, 0.088 mmol) in N,N-dimethylformamide (DMF) (8 mL), was added NaH (35.1 mg, 0.878 mmol) 25 and stirred for 1 h at rt. The reaction mixture was quenched by addition of sat. aq. NH4Cl solution and was filtered. The solution was purified by MDAP to afford the desired product as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[Cl:26][C:27]1[N:32]=[C:31](Cl)[CH:30]=[CH:29][N:28]=1>>[Cl:26][C:27]1[N:32]=[C:31]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)[CH:30]=[CH:29][N:28]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccnc(Cl)n4)c3n2)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 2,4-dichloropyrimidine (194 mg, 1.3 mmol) according to general procedure II. Obtained as an orange solid (220 mg, 47%). MS (ISP) 468.1 [(M+H)+]; mp 192-195° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH:27]=O)=[CH:21][CH:20]=1.[C:29]([CH2:31]P(=O)(OCC)OCC)#[N:30]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH:27]=[CH:31]/[C:29]#[N:30])=[CH:21][CH:20]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(/C=C/C=O)cc1
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(/C=C/C=C/C#N)cc1

Procedure:
According to the method described for Reference Example 35, (E)-3-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]-2-propen-1-al was allowed to react with diethyl cyanomethylphosphonate to give (E,E)-5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]-2,4-pentadienenitrile. Recrystallization from ethyl acetate--ether gave colorless prisms, m.p.159°-160° C.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[OH:23][CH2:24][CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Br:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[C:2]([N:29]4[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][OH:23])[CH2:27][CH2:28]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: Brc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Reactant: OCCN1CCNCC1
Product: OCCN1CCN(c2nnc3n2-c2ccc(Br)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In a manner given in Example 1, 1,8-dibromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess 1-(β-hydroxyethyl)piperazine to give 8-bromo-1-[4-(β-hydroxyethyl)piperazino]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10](F)[CH:9]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[N:27]=3)[CH2:18]2)[N:3]=1.[NH2:36][NH2:37]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]3[C:11]([C:12]([NH2:13])=[N:36][NH:37]3)=[CH:14][CH:15]=2)[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH:19]([C:23]3[NH:24][CH:25]=[C:26]([C:28]4[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=4)[N:27]=3)[CH2:18]2)[N:3]=1
Reactant: COc1ccc(-c2c[nH]c(C3CN(c4cc(-c5ccc(C#N)c(F)c5)nc(N)n4)CCO3)n2)cc1
Reactant: NN
Solvent: CCO
Product: COc1ccc(-c2c[nH]c(C3CN(c4cc(-c5ccc6c(N)n[nH]c6c5)nc(N)n4)CCO3)n2)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
A mixture of 4-[2-amino-6-(2-{4-[4-(methyloxy)phenyl]-1H-imidazol-2-yl}-4-morpholinyl)-4-pyrimidinyl]-2-fluorobenzonitrile (350 mg, 0.742 mmol) and hydrazine (1.18 mL, 37.1 mmol) in ethanol (4 mL) was heated under microwave conditions with stirring for 1 hour. The mixture was concentrated. Ethanol (15 mL) was added to the resulting residue, and the resulting mixture was heated to 85° C. for 20 minutes, and then filtered while hot and dried in vacuo to afford the title compound (115 mg) as a pale yellow solid. LC-MS (ES) m/z=484 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 3.09-3.15 (m, 1H), 3.19-3.25 (m, 1H), 3.69-3.77 (m, 4H), 4.02-4.05 (m, 1H), 4.29-4.36 (m, 1H), 4.56-4.62 (m, 1H), 4.72 (s, 1H), 5.39 (s, 2H), 6.21 (s, 2H), 6.71 (s, 1H), 6.89-6.98 (m, 2H), 7.21-7.68 (m, 1H), 7.60-7.65 (m, 1H), 7.68-7.72 (m, 3H), 7.99 (s, 1H), 11.52 (s, 1H), 12.22-12.48 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:14]=[C:6]2[N:7]=[C:8]([CH2:12][OH:13])[CH:9]=[C:10]([SH:11])[N:5]2[N:4]=1.CC(O[CH2:19][C:20]1[CH2:29][S:28][C@@H:23]2[C@H:24]([NH2:27])[C:25](=[O:26])[N:22]2[C:21]=1[C:30]([OH:32])=[O:31])=O.O.N>C(#N)C>[NH2:27][CH:24]1[C:25](=[O:26])[N:22]2[C:21]([C:30]([OH:32])=[O:31])=[C:20]([CH2:19][S:11][C:10]3[N:5]4[N:4]=[C:3]([CH2:2][OH:1])[N:14]=[C:6]4[N:7]=[C:8]([CH2:12][OH:13])[CH:9]=3)[CH2:29][S:28][C@H:23]12
Reactant: OCc1cc(S)n2nc(CO)nc2n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: N
Solvent: CC#N
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3cc(CO)nc4nc(CO)nn34)CS[C@H]12
Temperature: 50 °C
Reaction time: 3 h
Yield: 37.6 %

Procedure:
In 80 ml of acetonitrile were suspended 7.1 g of 2,5-bis -(hydroxymethyl)-7-mercapto-s-triazolo[1,5-a]pyrimidine and 9.1 g of 7-aminocephalosporanic acid, and 15 ml of boron trifluoride-ethyl ether complex was added to the suspension and the mixture was stirred at 50 ° C for 3 hours. After cooling the reaction mixture, 200 ml of water was added thereto and the mixture was adjusted to pH 2 with conc. aqueous ammonia. Precipitated crystal was collected by filtration, washed with water, washed with acetone and then dried to obtain 5.34 g of the title compound.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15]O)=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][N:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23]>>[CH3:17][N:18]1[CH2:22][CH2:21][N:20]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][N:13]=2)[C:19]1=[O:23]
Reactant: OCc1ccc(C#Cc2ccccc2)cn1
Reactant: CN1CCNC1=O
Product: CN1CCN(Cc2ccc(C#Cc3ccccc3)cn2)C1=O

Procedure:
The title compound, light brown solid, MS: m/e=293.1 (M+H+), can be prepared in accordance with the general method of example 31, step 2 from (5-phenylethynyl-pyridin-2-yl)-methanol (example 31, step 1) and 1-methyl-imidazolidin-2-one.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:17]=1.[C:20]([O:24][C:25]([C:27]1([CH2:30][CH:31]=O)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl>[C:20]([O:24][C:25]([C:27]1([CH2:30][CH2:31][N:14]2[CH2:13][CH2:12][N:11]([C:10]3[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:18])([F:1])[F:19])=[CH:17][C:7]=4[S:8][CH:9]=3)[CH2:16][CH2:15]2)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)C1(CC=O)CC1
Reactant: FC(F)(F)c1ccc2c(N3CCNCC3)csc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1(CCN2CCN(c3csc4cc(C(F)(F)F)ccc34)CC2)CC1
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
To a solution of 4.2 g (14.7 mmol) of 1-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazine in 100 mL of dichloromethane under nitrogen was added 3.5 g (19.1 mmol) of 1-(2-Oxo-ethyl)-cyclopropanecarboxylic acid tert-butyl ester. After stirring 10 minutes at room temperature 6.5 g (30.7 mmol) of sodium triacetoxyborohydride was added portion-wise. After 30 minutes 100 mL of 0.5 N aqueous sodium hydroxide was added and the reaction was stirred for 15 minutes. The organic layer was separated, dried and concentrated to deliver a paste. This was taken up in methanolic hydrogen chloride. The salt thus obtained was recrystallized from ethyl acetate/methanol to deliver 6.6 g (13.4 mmol) of the desired product as a white powder mp=187-9° C.
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]1[C:21]2[CH:22]=[CH:23]C=CC=2N=C1>>[O:17]1[CH2:21][CH:22]1[CH2:23][O:16][C:13]1[CH:14]=[CH:15][C:9]2[S:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][C:10]=2[CH:12]=1
Reactant: Oc1ccc2sc(-c3ccccc3)nc2c1
Reactant: c1ccc2ocnc2c1
Product: c1ccc(-c2nc3cc(OCC4CO4)ccc3s2)cc1

Procedure:
Compound 59 was prepared in the manner of compound 6 substituting compound 29 for compound 8 in partC-5 of Example 1.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[CH:20][C:10]=2[C:11]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.[C:33](=O)=O.C([O-])(O)=O.[Na+]>C(O)=O>[CH3:33][N:27]1[CH2:28][CH2:29][CH2:30][C@@H:26]1[CH2:25][O:24][C:21]1[CH:22]=[CH:23][C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:10]([CH:20]=1)[C:11]([NH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)=[O:12]
Reactant: O=C=O
Reactant: O=C(Nc1cccnc1)c1cc(OC[C@H]2CCCN2)ccc1OCc1ccccc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CN1CCC[C@@H]1COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1

Procedure:
2-[(Phenylmethyl)oxy]-N-3-pyridinyl-5-{[(2R)-2-pyrrolidinylmethyl]oxy}benzamide (may be prepared as described in Example 44; 250 mg, 0.62 mmol) was added to formic acid (4.5 ml) at 5° C., followed by 40% aqueous formaldehyde (2.4 ml). When the initial evolution of carbon dioxide had subsided, the mixture was refluxed for 2 h. After the solution was cooled, the pH of the solution was adjusted to 7-8 by adding aqueous NaHCO3 solution. The mixture was extracted with dichloromethane. The organic layer was dried over Na2SO4, and concentrated to obtain a crude product, which was purified by prep-HPLC to yield the title compound as a white solid. 47 mg.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:11]=3[N:12]=2)[CH2:4]1>C(O)(=O)C.O>[CH3:1][N:2]([CH3:20])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:11]=3[N:12]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2nc3cc([N+](=O)[O-])ccc3o2)C1
Solvent: O
Solvent: CC(=O)O
Product: CN(C)C1CCN(c2nc3cc(N)ccc3o2)C1
Yield: 86.2 %

Procedure:
Combine dimethyl-[1-(5-nitro-benzooxazol-2-yl)-pyrrolidin-3-yl]-amine (1.00 g, 3.62 mmol) and Fe0 (1.98 g, 35.4 mmol) in acetic acid (20 mL) and stir at 40° C. for 2 h. Dilute with water (50 mL) and filter through Celite®. Wash with copious amounts of water and MeOH. Make the filtrate alkaline with 5 N NaOH and extract twice with CH2Cl2 (2×). Concentrate in vacuo to afford the title compound (769 mg, 86%). 1H NMR (400 MHz, CDCl3): δ 7.00 (d, 1H, J=8.4 Hz), 6.70 (d, 1H, J=2.2 Hz), 6.32 (dd, 1H, J=8.4, 2.6 Hz), 3.88 (dd, 1H, J=9.9, 7.1 Hz), 3.81 (m, 1H), 3.62-3.50 (m, 3H), 3.39 (dd, 1H, J=10.1, 8.8 Hz), 2.83 (m, 1H), 2.30 (s, 6H), 2.21 (m, 1H), 1.93 (m, 1H).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9]2)=[O:7])[CH2:5]CC[CH2:2]1.[CH2:27](N(CC)CC)C.C(Cl)(=O)C(C)(C)C>ClCCl>[CH3:2][C:1]([CH3:5])([CH3:27])[C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:9]1)=[O:7]
Reactant: CCOC(=O)C1CC(c2ccc(OC)cc2)CN(C(=O)C2CCCC2)C1
Reactant: CCN(CC)CC
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)C1CC(c2ccc(OC)cc2)CN(C(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.0 g (18.99 mmol) of ethyl 1-(cyclopentylcarbonyl)-5-[4-(methoxy)phenyl]piperidine-3-carboxylate were dissolved in 50 ml of dichloromethane, and 2.88 g (28.48 mmol) of triethylamine were added at 0° C. 3.00 g (24.68 mmol) of pivaloyl chloride were then added dropwise. The reaction mixture was stirred at RT for 2 h. For work-up, the mixture was twice washed with water. The organic phase was dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: C(OC([N:11]1[CH2:17][C@H:16]([OH:18])[C@@H:15]([NH:19][C:20](=[O:34])[C@@H:21]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:14][CH2:13][C@H:12]1[CH3:35])=O)C1C=CC=CC=1.CO.[H][H]>CCOC(C)=O.[Pd]>[C:30]([O:29][C:27](=[O:28])[NH:26][C@H:21]([C:20](=[O:34])[NH:19][C@H:15]1[CH2:14][CH2:13][C@@H:12]([CH3:35])[NH:11][CH2:17][C@@H:16]1[OH:18])[CH2:22][CH:23]([CH3:25])[CH3:24])([CH3:32])([CH3:33])[CH3:31]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)N(C(=O)OCc2ccccc2)C[C@@H]1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)NC[C@@H]1O
Reaction time: 8 h

Procedure:
(2R,5S,6S)-5-((S)-2-tert-Butoxycarbonylamino-4-methyl-pentanoylamino)-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (0.169 g, 0.344 mmol) was dissovled in EtOAc (3 ml), MeOH (1 ml). Then 10% Pd/C (0.183 g, 0.172 mmol) was added and the reaction was stirred overnight under a balloon filled with hydrogen gas. The reaction mixture was filtered through Celite, concentrated in vacuo by rotary evaporation and was used in the next reaction without further purification (0.126 g): Electrospray mass spec: M+H+=358.11.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][C@H:13]1[CH2:18][O:17][CH2:16][CH2:15][NH:14]1.C(N(CC)C(C)C)(C)C>C(O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][C@@H:13]2[CH3:12])[N:3]=1
Reactant: Clc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H]1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[C@H]1COCCN1c1nc(Cl)nc2[nH]cnc12
Yield: 52.6 %

Procedure:
An ethanol (5 ml) solution of 2,6-dichloro-9H-purine (187 mg, 0.99 mmol), (S)-3-methyl-morpholine (100 mg, 0.99 mmol), and N,N-diisopropylethylamine (252 μl, 1.48 mmol) was heated to reflux for 15 hours. The reaction mixture was returned to room temperature and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (methylene chloride:methanol=98:2 to 97:3) to give the title compound (132 mg, 53%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(Cl)(Cl)Cl.ClC1C=CC=C(C(OO)=[O:33])C=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[N+:4]([O-:33])[CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:11]=2[N:12]=1
Reactant: FC(F)(F)c1ccc2oc(-c3ccncc3Br)nc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: [O-][n+]1ccc(-c2nc3cc(C(F)(F)F)ccc3o2)c(Br)c1
Temperature: 50 °C
Yield: 70.7 %

Procedure:
To a mixture of 0.50 g of 2-(3-bromopyridin-4-yl)-5-(trifluoromethyl)benzoxazole and 5 ml of chloroform, 0.58 g of 65% m-chloroperbenzoic acid was added. The reaction mixture was stirred while heating at 50° C. for 1.5 hours. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate, and washed with a saturated aqueous solution of sodium hydrogencarbonate (twice) and a saturated sodium chloride solution, sequentially. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.37 g of 3-bromo-4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridine N-oxide (hereinafter, referred to as “active compound 28”).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH:14]([NH:17][CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([N:17]([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[S:10])=[CH:4][C:3]=1[NH:11][C:12]([N:17]([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15])=[S:13]
Reactant: CC(C)NC(C)C
Reactant: S=C=Nc1ccc(Cl)c(N=C=S)c1
Solvent: CC#N
Product: CC(C)N(C(=S)Nc1ccc(Cl)c(NC(=S)N(C(C)C)C(C)C)c1)C(C)C

Procedure:
A mixture of 11.1 g. of 4-chloro-1,3-diisothiocyanatobenzene and 10.2 g. of diisopropylamine is refluxed in 250 ml. of acetonitrile for 4 hours. The reaction mixture is cooled and the acetonitrile is removed in vacuo. The residue is crystallized twice from ether to yield 5.0 g. of the title compound, melting point 122°-123° C.