Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:15])=O>[NH4+].[OH-]>[Cl:15][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccc2cccc(O)c2n1
Agent: [NH4+]
Agent: [OH-]
Product: Oc1cccc2ccc(Cl)nc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 2,8-dihydroxyquinoline (4 g, 24.8 mmol, Fluka) and phosphorus oxychloride (20 mL, Aldrich) was stirred at 100° C. for 1 h. The clear solution was cooled to room temperature and poured slowly with stirring into a mixture of NH4OH (150 mL) and crushed ice (200 g). The white solid that precipitated was filtered, dissolved in concentrated HCl (200 mL) and stirred at 100° C. for 1 h. Neutralization of the cooled to room temperature acid solution with NH4OH afforded white precipitate, which was filtered, washed with water and dried to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 180 (M+1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][C:17]([CH3:22])([CH2:20][OH:21])[CH2:18][OH:19]>CO.O>[CH3:22][C:17]([NH:16][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([OH:9])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH2:20][OH:21])[CH2:18][OH:19]
Reactant: CC(N)(CO)CO
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: O
Solvent: CO
Product: CC(CO)(CO)NC(c1ccccc1)C(O)c1ccccc1
Temperature: 150 °C
Yield: 81.6 %

Procedure:
A mixture of trans-stilbene oxide (2.00 g, 0.010 mol) and 2-amino-2-methyl-1,3-propanediol (3.15 g, 0.030 mol) was heated at 150° C. for 3 hours. The reaction mixture was dissolved in 20 mL of methanol and diluted with water to form a white solid. The solid was collected, washed with water and dried for 18 hours under ambient conditions to obtain 2.46 g (82%) of the product. Recrystallization from toluene gave 2.38 g of material; mp 144°-145° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][C:8]=1[CH2:20][CH3:21].[B:22](OC)([O:25]C)[O:23]C.Cl>O1CCCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[C:8]([CH2:20][CH3:21])[C:7]([B:22]([OH:25])[OH:23])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1
Reactant: COB(OC)OC
Reactant: CCc1cc(-c2ccc(Cl)cc2)ccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(-c2ccc(Cl)cc2)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.1 %

Procedure:
A solution of n-butyl lithium in hexanes (1.6 M, 38.75 ml, 0.062 mol) is added dropwise to a solution of 4-bromo-4′-chloro-3-ethylbiphenyl (12.35 g, 0.041 mol) in tetrahydrofuran (125 ml) at −78° C., under an atmosphere of nitrogen, and the mixture is stirred at −78° C. for 30 minutes. Trimethyl borate (27.8 ml, 0.25 mol) is added slowly at −78° C. and the mixture is stirred for 1 hr. The reaction mixture is allowed to warm to room temperature over 2-3 hrs and then stirred at room temperature for 1 hr. 0.1N aqueous hydrochloric acid (343 ml) is added and the mixture is stirred at room temperature overnight. The reaction mixture is extracted with ethyl acetate (3×300 ml) and the organic extracts are combined, dried with anhydrous sodium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4′-chloro-3-ethylbiphen-4-ylboronic acid (4.5 g) as white solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:12][CH:11]3[C:13]([CH3:15])([CH3:14])[CH:7]([CH2:8][NH:9][CH2:10]3)[CH2:6]2)[CH2:3][CH2:2]1.[NH2-].[Li+].[C:18]1([CH:24](Br)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:18]1([CH:24]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:9]2[CH2:8][CH:7]3[C:13]([CH3:15])([CH3:14])[CH:11]([CH2:12][N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:6]3)[CH2:10]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CC1(C)C2CNCC1CN(CC1CC1)C2
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [NH2-]
Solvent: C1CCOC1
Product: CC1(C)C2CN(CC3CC3)CC1CN(C(c1ccccc1)c1ccccc1)C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
1 g 3-cyclopropylmethyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane was dissolved in 25 ml absolute tetrahydrofuran, and 0.2 g lithium amide was added to the solution and stirred for 1 hour at 60° C. and then left to cool. After cooling, a solution of 3 g diphenylmethyl bromide in 25 ml absolute tetrahydrofuran was added slowly in drops, and the reaction mixture was stirred further for 90 min at a temperature of 40° C. Then the reaction mixture was acidified with aqueous citric acid solution and worked up as described in Example 1. 1.5 g 7-diphenylmethyl-3-cyclopropylmethyl-9,9-dimethyl-3,7-diazabicyclo[3,3,1]nonane were obtained as an oleaginous base.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][OH:22])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:16][C@@H:15]([S:17][C:18](=[O:20])[CH3:19])[CH2:14][C@H:13]2[CH2:21][O:22][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:11])=[CH:23][CH:24]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)S[C@H]1C[C@@H](CO)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)OC[C@@H]1C[C@H](SC(C)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
(2S,4S)-1-(p-Nitrobenzyloxycarbonyl)-2-hydroxymethyl-4-acetylthiopyrrolidine (177 mg), 76 mg of triethylamine and 61 mg of 4-N,N-dimethylaminopyridine were dissolved in 2 ml of dry dichloromethane. Ethyl chloroformate (81 mg) was added thereto under ice-cooling in a nitrogen stream. The mixture was stirred under ice-cooling for 3.5 hours, washed successively with water, dilute hydrochloric acid, water, a saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and distilled to obtain (2S,4S)-1-(p-nitrobenzyloxycarbonyl)-2-ethoxycarbonyloxymethyl-4-acetylthiopyrrolidine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=O.[NH2:13][C:14]([NH2:16])=[S:15].CC([O-])=O.[Na+]>CCO>[NH2:16][C:14]1[S:15][CH:2]=[C:3]([C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[N:13]=1
Reactant: NC(N)=S
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(-c2csc(N)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(2-Bromo-acetyl)-benzonitrile (2.9 g, 12.9 mmol) was combined with 1.0 g (12.9 mmol) of thiourea. This mixture was suspended in 60 mL of EtOH. To this suspension was added NaOAc (1.4 g, 16.8 mmol). This suspension was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure to yield the desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[Cu]>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([O:17][C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 210 °C
Reaction time: 2 h

Procedure:
A mixture of 4-bromoanisole (35 ml, 0.28 mol), 4-chlorophenol (43 g, 0.33 mol), anhydrous K2CO3 (13 g, 0.09 mol) and copper bronze (0.38 g, 5.98 mmol) were stirred under a nitrogen atmosphere at 210° C. for 2 hours. After cooling to room temperature, the mixture was dissolved in methylene chloride, extracted two times with 1 N NaOH, dried (MgSO4) and the solvent removed under reduced pressure to give a brown liquid. Excess 4-bromoanisole was removed by distillation under reduced pressure (60°-73° C., 1 mm) and the residual crystalline solid was purified by HPLC (hexane-methylene chloride). 4-Methoxy-4'-chlorodiphenyl ether was isolated as a white crystalline solid (28.84 g, 44%), mp 49°-51° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][CH:3]=1.[C:8]12([C:18](Cl)=[O:19])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2.C(N(CC)CC)C>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([NH:7][C:18]([C:8]23[CH2:17][CH:12]4[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]4)[CH2:15]2)[CH2:9]3)=[O:19])=[N:4][CH:3]=1
Reactant: Nc1ncc(Br)s1
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ncc(Br)s1)C12CC3CC(CC(C3)C1)C2
Temperature: 80 °C

Procedure:
A mixture of 5-bromothiazol-2-amine (3.0 g, 11.5 mmol), adamantane-1-carbonyl chloride (2.74 g, 13.8 mmol), triethylamine (3.2 mL, 23 mmol) and 4-di(methylamino)pyridine (1.1 g) in tetrahydrofuran (100 mL) was heated at 80° C. for 48 hours. The mixture was cooled to ambient temperature, concentrated, diluted with water and extracted with ethyl acetate. The organic extract was dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (silica gel, 25% ethyl acetate/hexanes) afforded the title compound. MS (ESI) m/z 342 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH2:8]1.[NH3:27]>CO>[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C@@H:9]2[CH2:10][CH2:11][N:7]([CH2:6][CH2:5][CH2:4][C:3]([NH2:27])=[O:2])[CH2:8]2)=[CH:14][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N
Reactant: COC(=O)CCCN1CC[C@@H](Oc2ccc(Cc3ccccc3)cc2)C1
Solvent: CO
Product: NC(=O)CCCN1CC[C@@H](Oc2ccc(Cc3ccccc3)cc2)C1
Temperature: 100 °C
Yield: 75 %

Procedure:
4-[(R)-3-(4-Benzyl-phenoxy)-pyrrolidin-1-yl]-butyric acid methyl ester (200 mg, 0.566 mmol) was taken into 7N ammonia in methanol solution (5 mL) in a pressure tube. The reaction was sealed and heated at 100° C. for 48 h. The mixture was then cooled to room temperature and concentrated to dryness. The resulting residue was then purified by silica gel flash chromatography (20:1 silica ratio, eluted with a gradient of 10% methanol in dichloromethane to 15% methanol in dichloromethane) to obtain the title product (145 mg, 75%); LCMS; m/z 340 (M+1); 1H NMR (400 MHz, DMSO); δ 1.58-1.74(m, 3H), 2.04-2.08 (m, 2H), 2.19-2.24 (m, 1H), 2.33-2.41 (m, 3H), 2.54-2.58 (m, 1H), 2.61-2.65 (m, 1H), 2.78-2.82 (m, 1H), 3.85 (s, 2H), 4.77-4.80 (m, 1H), 6.68 (s, 1H), 6.78 (d, J=8.8, 2H), 7.11 (d, J=8.4, 2H), 7.17-7.22 (m, 3H), 7.25-7.29 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[S:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2=[O:15])#[CH:2].I[C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1>CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:14][C:8]1([CH3:13])[CH2:7][C:6](=[O:15])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:1]#[C:2][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)[CH:4]=2)[S:9]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)C(=O)CC(C)(C)S2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CC(C)(C)S3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.2 %

Procedure:
A solution of 6-ethynyl-2,2-dimethylthiochroman-4-one (82.0 mg, 0.38 mmol) and ethyl 4-iodobenzoate (104.9 mg, 0.38 mmol) in 5.0 mL Et3N was purged with argon for 10 minutes. To this solution were added bis(triphenylphosphine)-palladium (II) chloride (88.0 mg, 0.12 mmol) and copper (I) iodide (22.9 mg, 0.12 mmol). After purging for an additional 5 minutes with argon, the solution was stirred overnight at room temperature. The reaction mixture was filtered through a pad of Celite using an Et2O wash. Concentration of the filtrate under reduced pressure, followed by column chromatography of the residual solid, afforded 100 mg (72%) of ethyl 4-[(2,2-dimethyl-4-oxo-thiochroman-6-yl)ethynyl]-benzoate as a yellow solid. 1H NMR (300 MHz, CDCl3) δ: 8.25 (1H, d, J=1.8 Hz), 8.00 (2H, d, J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.53 (1H, dd, J=1.8, 8.2 Hz), 7.21 (1H, d, J=8.2 Hz), 4.37 (2H, q, J=7.1 Hz), 2.88 (2H, s), 1.47 (6H, s), 1.39 (3H, t, J=7.1 Hz).
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH2:13])[CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[C:10]2[N:9]=[C:8]([C@@H:11]([NH:13][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:12])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1nc2c(F)cccc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2c(F)cccc2n1-c1ccccc1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of (S)-1-(4-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine from Example 15 (0.407 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (122 mg, 0.509 mmol) and DIPEA (0.444 mL, 2.55 mmol) in n-butanol (3 mL) was stirred in a sealed vial for 20 h at 100° C. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc). The product containing fractions were concentrated in vacuo and the resulting residue was dissolved in EtOAc (10 mL) and stirred with 2N HCl (10 mL) for 15 min. Volatiles were removed under reduced pressure and the residue was dissolved in MeOH (2 mL) and triturated with diethyl ether affording 136 as a beige powder (126 mg, 78%). LCMS: RT 3.47 min [M+H]+ 374.0. 1H NMR (DMSO, 400 MHz): δ 10.03 (1H, s), 8.66 (1H, s), 8.55 (1H, s), 7.68-7.38 (5H, m), 7.28-7.21 (1H, m), 7.13 (1H, dd, J=10.91, 7.98 Hz), 6.94 (1H, dd, J=8.11, 0.82 Hz), 5.68-5.59 (1H, m), 1.72 (3H, d, J=6.85 Hz)
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[N:9][N:10]=2)[N:7]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>>[N:19]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=4)=[N:9][N:10]=3)[N:7]=2)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: c1c[nH]cn1
Reactant: Oc1ccc(Cc2nnc3ccc(Cl)nn23)cc1
Product: Oc1ccc(Cc2nnc3ccc(-n4ccnc4)nn23)cc1

Procedure:
The title compound was prepared from 4-(6-Chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-phenol (Example 45: step a) and imidazole as described in Example 43. 1H-NMR (CD3OD): δ 9.78 (1H, t, J=1.3 Hz), 8.54 (1H, d, J=9.9 Hz), 8.38 (1H, t, J=1.8 Hz), 7.97 (1H, d, J=9.9 Hz), 7.83 (1H, dd, J=1.3, 1.8 Hz), 7.23 (2H, d, J=8.6 Hz), 6.72 (2H, d, J=8.6 Hz), 4.53 (s, 2H). ESI-MS (m/z): Calcd. for C15H12N6O: 292.1; found: 293.2 (M+H).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][OH:33])[CH:27]=3)[CH:24]=2)[NH:19][CH:18]=1)=O)C1C=CC=CC=1.C(Cl)(=O)C>C(O)C>[OH:33][CH2:32][C:28]1[CH:27]=[C:26]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[CH2:16][C@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)[CH:31]=[CH:30][CH:29]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(-c3cccc(CO)c3)cc12
Solvent: CCO
Solvent: CC(=O)Cl
Product: OCc1cccc(-c2ccc3[nH]cc(C[C@H]4CCCN4)c3c2)c1
Yield: 63.8 %

Procedure:
3-(1-Benzyloxycarbonylpyrrolidin-2(R)-ylmethyl)-5-(3-hydroxymethylphenyl)-1H-indole (1.030 g, 2.316 mmol) (see Preparation 38) in ethanol was reduced using catalytic hydrogenation as described in Example 35 except that no acetyl chloride was used in the reaction. This gave the title compound as an off-white foam (453 mg). Found: C,72.36; H,6.76; N,8.20; C20H22N2O.3/8CH2Cl2 requires: C,72.35; H,6.78; N,8.28%.
Reaction SMILES: [O:1]=[C:2]([C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH3:19][O:20][C:21]1[CH:22]=[C:23](O)[CH:24]=[CH:25][CH:26]=1.C(Cl)Cl>>[O:1]=[C:2]([C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)[CH2:3][C:4]([O:6][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:26]=1)=[O:5]
Reactant: COc1cccc(O)c1
Reactant: COc1cc(C(=O)CC(=O)O)cc(OC)c1OC
Solvent: ClCCl
Product: COc1cccc(OC(=O)CC(=O)c2cc(OC)c(OC)c(OC)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
To a mixture of 0.27 g (1.06 mmol) of the product of Step 1 and 0.13 g (1.06 mmol) of 3-methoxyphenol in 2 ml of anhydrous methylenechloride 0.16 ml (1.06 mmol) of diisopropylcarbondiimide was added at room temperature. The resulting mixture was stirred for 24 hours at room temperature and filtered off. The filtrate was evaporated to dryness and purified by flash column chromaytography (silica gel; methylene chloride) to give the title compound as a colorless crystals (0.185 g, 49%); 1H NMR (CDCl3) δ 3.77 (s, 3H, OMe); 3.91 (s, 6H, OMe); 4.17 (s, 3H, OMe); 4.173 (s, 2H, CH2); 6.6-6.8 (m, 3H, CH aromatic); 7.2-7.3 (m, 3H, CH aromatic).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:24])[C:12]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([CH3:15])[CH:14]=1)[NH2:5].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:26]([CH3:25])(=[O:28])=[O:27])[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:24])[C:12]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:13]([CH3:15])[CH:14]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(Cc2ccc(N)cc2F)n(C)c1C(=O)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(Cc2ccc(NS(C)(=O)=O)cc2F)n(C)c1C(=O)c1ccccc1
Temperature: -5 °C
Yield: 62.4 %

Procedure:
3-Fluoro-4-[5-benzoyl-1,4-dimethyl-1H-pyrrol-2-ylmethyl]aniline (1.0 g, 3.1 mmol) [prepared as described in Example 1] was dissolved in pyridine (10 ml) and the solution was cooled to -5° C. Methanesulfonyl chloride (0.39 g, 3.4 mmol) was added and after 1 h the reaction mixture was poured into 1M HCl/ice/water and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate and concentrated to dryness. The residue was crystallized from methylene chloride-methanol to give N-{3-fluoro-4-[5-benzoyl-1,4-dimethyl-1H-pyrrol-2-ylmethyl]phenyl}-methanesulfonamide (775 mg, 62%) as a solid, mp 165-167° C.
Reaction SMILES: [N:1]1([C:8]2[N:13]=[C:12]([NH2:14])[N:11]3[N:15]=[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:10]3[N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH:26]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[N:13]=[C:12]([NH2:14])[N:11]3[N:15]=[C:16]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:10]3[N:9]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccccc1Cl
Reactant: Nc1nc(N2CCCNCC2)nc2nc(-c3ccco3)nn12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1nc(N2CCCN(Cc3ccccc3Cl)CC2)nc2nc(-c3ccco3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-[1,4]Diazepan-1-yl-2-furan-2-yl-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-ylamine (0.15 mmol) was dissolved in 4 mL of CH2Cl2 along with 2 eq. of 2-chloro-benzaldehyde and 25 mL of glacial acetic acid. The reaction mixture was stirred at room temperature for 30 minutes and sodium triacetoxyborohydride (4 eq.) was added in a single portion. The resulting reaction mixture was then stirred at room temperature for 18 hours. It was then concentrated under a stream of N2 and purified by preparative HPLC using a mixture of aqueous CH3CN that has been buffered with 0.1% TFA. 1H NMR (PMSO-d6) δ 7.60 (d, J=1.0 Hz, 1H), 7.28 (br s, 2H), 7.22 (d, J=3.6 Hz, 1H), 6.9-7.2 (m, 4H), 6.68 (dd, J=3.6 Hz, 1.0 Hz, 1H), 3.8 (br s, 2H), 2.2-3.2 (m, 10 H). MS: m/z: 426 [M+H]+.
Reaction SMILES: O[C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:28]>[N+](CC)(CC)(CC)CC.[Cl-].C(#N)C>[Cl:28][C:2]1[N:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:3]=1
Reactant: CCCCCC(=O)OCc1cc(O)ncn1
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: CCCCCC(=O)OCc1cc(Cl)ncn1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 915 mg (4.08 mMol) hexanoic acid 6-hydroxy-pyrimidin-4-ylmethyl ester, 1.48 g (8.98 mMol) Et4NCl and 698 μl (5.44 mMol) N,N-dimethylaniline in 30 ml of acetonitrile, 3.73 ml (40.8 mMol) POCl3 are added. After stirring for 1 h at 60° C., the cooled solution is concentrated in vacuo. The residue is re-dissolved in EtOAc and water, the aq. layer separated off and extracted twice with EtOAc. The organic phases are washed with water, sat. NaHCO3 and brine, dried (Na2SO4) and concentrated, yielding the title compound as an oil: MS: [M+1]+=243/245; TLC(CH2Cl2): Rf=0.20.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][C:10]1[N:11]=[C:12]([NH:22][C:23](=[NH:27])SCC)[S:13][C:14]=1[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1>CC(O)C.C(OCC)(=O)C>[CH3:9][C:10]1[N:11]=[C:12]([NH:22][C:23]([NH:2][OH:3])=[NH:27])[S:13][C:14]=1[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1
Reactant: CCSC(=N)Nc1nc(C)c(-c2cc(C)ccn2)s1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Cc1ccnc(-c2sc(NC(=N)NO)nc2C)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 43.9 %

Procedure:
To a suspension of hydroxylamine hydrochloride (146 mg) and sodium acetate (172 mg) in 2-propanol (4 ml) was added N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-S-ethylisothiourea (205 mg), and the mixture was stirred at 90° C. for 1 hour. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, 3 to 4% methanol in dichloromethane) to give N-(4-methyl-5-(4-methylpyridin-2-yl)thiazol-2-yl)-N′-hydroxyguanidine (81 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.ClC1C=C(C=CC=1)C(OO)=[O:16].O.C(=O)([O-])[O-].[K+].[K+]>COCCOC>[CH3:1][C:2]1[NH:3][C:4]2=[N+:5]([O-:16])[CH:6]=[CH:7][CH:8]=[C:9]2[CH:10]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc2cccnc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc2ccc[n+]([O-])c2[nH]1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 2-methyl-7-azaindole (5 g, 37.8 mmol) in 1,2-dimethoxyethane (40 ml) is added m-chloroperoxybenzoic acid (10.4 g, of a 77% w/w solid, 46.6 mmol). The reaction mixture is stirred at 0° C. for 30 minutes, at room temperature for 3 hours and then poured into water (400 ml). The solution is basified to pH 9-10 using saturated potassium carbonate solution. The aqueous is extracted with DCM (2×100 ml) and the organic portions are combined, dried (MgSO4) and concentrated in vacuo. Purification of the resulting crude by chromatography on silica eluting firstly with neat ethyl acetate followed by DCM/MeOH (10:1) yields the titled compound as a yellow powder. (MH+ 297 appears as a dimer)