Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:52]=[O:53])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.N12CCCN=C1CCCCC2.[C:67](OCC)(=[O:69])C>O1CCCC1.O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][C:48]([F:50])([F:51])[F:49])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:67][OH:69])[CH:52]=[O:53])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OC(F)(F)F)cc3)c2)O[C@](C=O)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(trifluoromethoxy) phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 15l (100 mg, 0.13 mmol) in tetrahydrofuran (5 mL) were added formaldehyde (72.3 mg, 2.47 mmol, 37 wt % solution) and 1,8-diazabicyclo[5.4.0]undec-7-ene (16.3 mg, 0.11 mmol) in turn at room temperature. The mixture was stirred at room temperature for 48 hours, and then ethyl acetate (20 mL) and water (5 mL) were added. The resulting mixture was partitioned. The aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (10 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 15m as yellow oil (108 mg, 100%). This material was not further purified.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1.O>O1CCCC1>[Br:6][C:7]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]([S:17]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:19])=[O:18])=[CH:9][CH:8]=1
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1ccc(Br)c2c1CCCC2
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccc(Br)c2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
tert-butyl amine [8.5 g, 12.32 ml, 116.0 mmol) was added dropwise to a stirred suspension of 4-bromo-5,6,7,8-tetrahydronaphthalene-1-sulfonyl chloride (59a, 12.0 g, 38.8 mmol) in 150 ml tetrahydrofuran at 0° C. The reaction mixture was then stirred at a temperature of about 25° C. for 2 hours. The progress of the reaction was monitored by TLC. Water (100 ml) was added to the reaction mixture, and the mixture so obtained was extracted with ethyl acetate (2×150 ml). The combined organic layer was then dried over sodium sulphate, and the dried organic layer was concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography over silica gel (100-200 mesh) using 15% ethyl acetate in hexanes as an eluent to obtain the title compound (2.34 g, 17.4%).
Reaction SMILES: [Cl:1]Cl.[CH3:3][N:4]([CH2:9][CH2:10][CH:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([CH3:8])([CH3:7])[CH3:6]>C(O)(=O)C>[CH3:3][N:4]([CH2:9][CH2:10][CH:11]([C:18]1[CH:23]=[C:22]([Cl:1])[CH:21]=[CH:20][C:19]=1[OH:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: ClCl
Reactant: CN(CCC(c1ccccc1)c1ccccc1O)C(C)(C)C
Solvent: CC(=O)O
Product: CN(CCC(c1ccccc1)c1cc(Cl)ccc1O)C(C)(C)C

Procedure:
A solution of chlorine (7,1 g, 0,10 mol) in acetic acid (500 ml) is added dropwise to a stirred solution of N-methyl-N-tert.butyl-3-(2-hydroxyphenyl)-3 -phenylpropylamine (29.7 g. 0.10 mol) in acetic acid (200 ml) with stirring. After 2 h the solvent is distilled off under reduced pressure and the crude hydrochloride left is recrystallized from 2-propanol. Melting point 260° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[C:13]2[CH2:20][CH2:21][CH2:22][C@@H:23]1[CH2:28][CH2:27][NH:26][CH2:25][C@@H:24]1[CH:29]=[CH2:30].[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>C(Cl)(Cl)Cl>[C:31]([N:26]1[CH2:27][CH2:28][C@@H:23]([CH2:22][CH2:21][CH2:20][C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH3:8])[CH:11]=3)[N:16]=[CH:15][CH:14]=2)[C@@H:24]([CH:29]=[CH2:30])[CH2:25]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=C[C@H]1CNCC[C@H]1CCCc1ccnc2ccc(OC)cc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=C[C@H]1CN(C(=O)c2ccccc2)CC[C@H]1CCCc1ccnc2ccc(OC)cc12

Procedure:
18.4 cm3 of triethylamine were added to a stirred solution of 20.8 g of (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]-3-vinylpiperidine in 270 cm3 of chloroform, followed, over 1 hour, by a solution of 7.2 cm3 of benzoyl chloride in 50 cm3 of chloroform. After stirring the mixture at a temperature in the region of 20° C. for 1 hour 30 minutes, 100 cm3 of distilled water were added to the reaction mixture. The chloroform phase was separated by settling, washed with 2 times 100 cm3 of water, and then dried over magnesium sulfate. After filtering through paper, the chloroform solution was concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 25 g of (3R,4R)-1-benzoyl-4-[3-(6-methoxyquinolin-4-yl)propyl]-3-vinylpiperidine were obtained in the form of a brown oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CCN(CC)CC.[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[N+:37]([O-:39])=[O:38])[C:31](Cl)=[O:32]>C(Cl)Cl>[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[N+:37]([O-:39])=[O:38])[C:31]([NH:2][C@H:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])=[O:32]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc([N+](=O)[O-])c(F)c1)C(=O)OC(C)(C)C

Procedure:
To a solution of di-tert butyl L-glutamate hydrochloride (20.0 g, 67.6 mol) in Et3N (19 ml, 136.0 mmol) was added dropwise a solution of 3-fluoro,4-nitro benzoyl chloride (13.8 g, 68.0 mmol) in CH2Cl2 (300 ml). Extractive workup gave an oil (13); yield (28.0 g, 97%); 1 H NMR (Me2SO-d6) δ1.40 (s, 9H, t-Bu), 1.42 (s, 9H, t-Bu), 1.99 (m, 2H, CH2CH2CO2 -t-Bu), 2.36 (t, 2H, J=7.45 Hz, CH2CH2CO2 -t-Bu), 4.35 (m, 1H, CH), 7.92 (dd, 1H, JH-6,H-5 =7.56 Hz, H-6), 8.01 (dd, 1H, JH-2,F =11.97 Hz, H-2), 8.29 (dd, 1H, JH-5,H-6 =7.83, JH-5,F =16.10 Hz, H-5), 8.97 (d, 1H, J=7.42 Hz, NH); 9F NMR (Me2SO-d6) δ-117.98 (dd, JF,H-2 =7.32, JF,H-5 =17.8 Hz); mass spectrum (CI) m/z 427 ([M+H+ ], 100); Anal: C20H27N2O7 F-0.25CH2Cl2 requires C-54.33, H-6.19, N-6.26, F-4.24, Cl-3.96, found C-54.22, H-6.38, N-6.05, F-4.34, Cl-4.15. (The presence of CH2 Cl2 noted in the elemental analysis was confirmed by NMR).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:3]=1.C(O[BH-](O[C:31](=O)[CH3:32])OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+].Cl[CH2:41][CH2:42]Cl>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH2:11][C:2]3[CH:1]=[C:42]4[C:41](=[CH:31][CH:32]=3)[N:18]=[CH:17][CH:16]=[N:15]4)[CH2:17][CH2:16]2)[N:3]=1
Reactant: Cc1ccc2c(OCCN3CCNCC3)cccc2n1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: ClCCCl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc2c(OCCN3CCN(Cc4ccc5nccnc5c4)CC3)cccc2n1
Temperature: 20 °C
Reaction time: 24 h
Yield: 61 %

Procedure:
A mixture of 2-methyl-5-(2-piperazin-1-ylethoxy)quinoline (0.054 g, 0.2 mmol) and quinoxaline-6-carboxyaldehyde (0.032 g, 0.2 mmol) in 1,2-dichloroethane (5 mL) was treated with sodium triacetoxyborohydride (64 mg, 0.2 mmol) and stirred at 20° C. under an atmosphere of argon for 24 h. The mixture was then treated with saturated aqueous NaHCO3 (20 mL) and the organic layer separated and purified directly by chromatography on silica (ethyl acetate to 10% methanol/ethyl acetate), to afford the title compound (0.05 g, 61%) as a solid.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:25])[NH:7][C:6]=2[CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[C:10]3[NH:9][C:8]([N:11]4[CH2:16][CH2:15][N:14]([C:17]5[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=5)[CH2:13][C@H:12]4[CH3:25])=[N:7][C:6]=3[CH:5]=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=2)=[CH:33][CH:32]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2c(Br)cc(C(F)(F)F)cc2[nH]1
Product: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(Cl)cc3)c2[nH]1

Procedure:
4-Bromo-2-[(2R)-4-(3,5-dichloro-pyridin-2-yl)-2-methyl-piperazin-1-yl]-6-trifluoromethyl-1H-benzoimidazole (204 mg, 0.4 mmol, Example 149b) and 4-chlorophenylboronic acid (124 mg, 0.8 mmol, Aldrich) reacted under the conditions of Example 158 to give the title compound. MS (ESI, pos. ion) m/z: 504 (M+1).
Reaction SMILES: BrC1CCOCC1.[OH-].[Na+].[CH:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([C:17]([O:19]O)=[O:18])[CH:11]=1>O>[Cl:16][C:14]1[CH:13]=[C:12]([CH:11]=[CH:10][CH:15]=1)[C:17]([OH:19])=[O:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: BrC1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc(Cl)c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
4-Bromotetrahydropyran (Frontier Scientific #B10197, 25.8 g, 156 mmol) was added to the solution of sodium hydroxide (16.0 g, 400 mmol) in 40 mL water. The biphase mixture was stirred in 90° C. with a condenser for 1 day. The mixture was cooled to RT and transferred to a small separatory funnel. The organic phase was carefully separated. It was a mixture of alkene J79 (major) and leftover 4-bromotetrahydropyran. This mixture was dissolved in 100 mL chloroform. To it was added MCPBA (77%, 26.8 g, 120 mmol) in small portions. The mixture was vigorously stirred at RT for overnight. The thick suspension was chilled in ice bath and filtered through celite. The solid cake was washed with ice-chilled chloroform 500 mL×3. All the filtrate and wash solutions were transferred into a big reparatory funnel. It was washed with saturated NaHCO3 solution twice. The organic phase was then dried over anhydrous Na2SO3 (30 g). The mixture was filtered and the filtrate was concentrated on a rotary instrument in ice-bath bath (<5° C.) to remove chloroform. A light liquid (J80) with some remaining meta-chlorobenzoic acid solid was obtained. This mixture was dissolved in 100 mL isopropanol. To it was added (S)-(−)-α-methylbenzylamine (15.2 mL, 120 mmol). A gel-like mixture was got initially. The mixture was slowly heated to 70° C. and stirred. A clean solution was then got. The clear solution was stirred for 2 days at 70° C. It was then concentrated in vacuo. The residue was taken into 500 mL EtAOc and washed with saturated Na2CO3 solution three times. The organic phase was dried, concentrated and subjected to flash column (0-40% EtOAc in DCM) to isolate desired product J81 (3.52 g) as a cream-colored solid. UV: 259 nm. M+H found for C13H19NO2: 222.2. NMR (DMSO-d6): 7.32-7.25 (4H, m), 7.18 (1H, t), 4.89 (1H, d), 3.86 (1H, m), 3.63 (1H, m), 3.45-3.37 (2H, m, partially obscured by water), 3.19 (1H, m), 2.66 (1H, m), 2.22 (1H, m), 1.92 (1H, m), 1.74 (1H, d), 1.35 (1H, m), 1.22 (3H, d, J=6.4 Hz) ppm.
Reaction SMILES: [N:1]1C=NC=N[CH:2]=1.[NH2:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[N:11]=[CH:10][C:9]=1[C:20](O)=O.B(F)(F)F.CCOCC>CS(C)=O.CCOC(C)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:8]3=[N:7][CH:2]=[N:1][CH:20]=[C:9]3[CH:10]=[N:11]2)=[CH:14][CH:15]=1
Reactant: Nc1c(C(=O)O)cnn1-c1ccc(Br)cc1
Reactant: c1ncncn1
Agent: FB(F)F
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Brc1ccc(-n2ncc3cncnc32)cc1
Temperature: 120 °C

Procedure:
To a solution of 1,3,5-triazine (0.575 g, 7.09 mmol) and 5-amino-1-(4-bromophenyl)-1H-pyrazole-4-carboxylic acid (22A) (2 g, 7.09 mmol) in DMSO (30 mL) was added boron trifluoride etherate (1.08 mL, 8.51 mmol). The resulting mixture was heated at 120° C. for 20 hours, cooled, diluted with EtOAc and washed with 1% NaOH and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was triturated with small amount of EtOAc and the precipitate was collected to provide the desired product 1-(4-bromophenyl)-1H-pyrazolo[3,4-d]pyrimidine (22B): 1H NMR (400 MHz, DMSO-D6) δ ppm 9.47 (1H, s), 9.16 (1H, s), 8.68 (1H, s), 8.22 (2H, d), 7.80 (2H, d).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([S:11]([Cl:14])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.BrC1C=CC=CC=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](C2C=CC(Br)=CC=2C2C=CC=CC=2)(=[O:31])=[O:30])=[C:25](C2C=CC=CC=2)[CH:24]=1.ClS(O)(=O)=O>C(Cl)Cl>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([C:7]2[CH:6]=[C:5]([S:11]([Cl:14])(=[O:13])=[O:12])[CH:10]=[CH:9][CH:8]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=S(=O)(c1ccc(Br)cc1-c1ccccc1)c1ccc(Br)cc1-c1ccccc1
Agent: O=S(=O)(O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: Brc1ccccc1
Product: O=S(=O)(Cl)c1cccc(S(=O)(=O)c2ccc(Br)cc2)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
From 200 g of anhydrous aluminum chloride, 153 ml of benzenesulfonyl chloride, 138 ml of bromobenzene, and 600 ml of methylene chloride was prepared 220 g of p-bromophenyl-phenyl-sulfone according to the method of Journal of Chem. Soc., p. 2508 (1960). To 100 ml of chlorosulfonic acid was added 100 g of p-bromophenylphenylsulfone, and after stirring the mixture for 4 hours at 130° to 140° C., the mixture was poured into ice water to provide 121 g of 3-(4-bromophenylsulfonyl)benzenesulfonyl chloride.
Reaction SMILES: [O:1]=O.[CH2:3]([C:5]1([CH2:9][OH:10])[CH2:8][O:7][CH2:6]1)[CH3:4]>>[CH2:3]([C:5]1([C:9]([OH:1])=[O:10])[CH2:8][O:7][CH2:6]1)[CH3:4]
Reactant: CCC1(CO)COC1
Reactant: O=O
Product: CCC1(C(=O)O)COC1
Reaction time: 2 h
Yield: 86.2 %

Procedure:
The procedure as in Example 10 is carried out, but at an oxidation temperature of 40° C. After 2 hours, 0.8 mol of oxygen have been taken up per mol of 3-ethyl-3-hydroxymethyl-oxetane. After working up, 3-ethyl-oxetane-3-carboxylic acid is obtained in a yield of 86.2% of theory.
Reaction SMILES: C1(C)C(S([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][NH:23]C(=O)C(F)(F)F)=[CH:18][CH:17]=2)(=O)=O)=CC=CC=1.[OH-].[K+]>CCO>[NH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:11]2[NH:10][CH:14]=[CH:13][CH:12]=2)=[O:30])=[CH:21][CH:20]=1
Reactant: Cc1ccccc1S(=O)(=O)n1cccc1C(=O)c1ccc(CNC(=O)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: NCc1ccc(C(=O)c2ccc[nH]2)cc1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a stirred EtOH (10 mL) solution containing N-toluenesulfonyl-2-(4-(trifluoroacetylaminomethyl)benzoyl)pyrrole (1.00 g, 2.20 mmol), was added 40% KOH solution (2 mL) and the mixture was heated at reflux until TLC analysis showed complete consumption of the starting material. The reaction mixture was then cooled to room temperature worked up as in Example 7. The crude product was suspended in H2O, filtered and dried to afford the purified product 2-(4-aminomethylbenzoyl)pyrrole (381 mg, 86%). 1H NMR (500 MHz, CD3OD, 25° C.) δ 2.43 (s, 3H), 4.53 (s, 2H), 6.42 (m, 1H), 6.77 (m, 1H), 7.41 (d, 2H), 7.72 (d, 2H), 7.85 (m, 1H), 7.95 (d, 2H), 8.39 (t, 1H); 13C NMR (100 MHz, CD3OD, 25° C.) δ 44.6, 109.7, 119.4, 125.6, 126.5, 128.4, 130.4, 136.8, 146.1, 184.6; HRMS (EI): m/z 200.0940 (100) {M}+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][NH:22]3)[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.I[CH3:27]>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][N:22]3[CH3:27])[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1cccc(Cl)c1)c1cn(CC2CCCN2)c2ncccc12
Reactant: CI
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCCC1Cn1cc(S(=O)(=O)c2cccc(Cl)c2)c2cccnc21
Product: Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 3-(3-chlorophenylsulfonyl)-1-(pyrrolidin-2-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (0.09 g, 0.24 mmol) in DMF under a nitrogen atmosphere at room temperature is treated with iodomethane (0.021 mL, 0.34 mmol), stirred at room temperature for 18 h, diluted with water and extracted with ethyl acetate. The extracts are combined, washed sequentially with water and brine and concentrated in vacuo. The resultant residue is purified by flash chromatography (5% methanol in CH2Cl2 as eluent) to afford the free amine of the title product. The amine is dissolved in Et2O, treated with an etheral solution of anhydrous HCl, stirred and concentrated in vacuo'to afford the title compound as a solid, 30 mg, mp 149-150° C., identified by HNMR and mass spectral analyses.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]>O1CCCC1>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:3]=1
Reactant: CC(C)(C)CN
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: CC(C)(C)CNc1nc(Cl)cc(Cl)n1

Procedure:
25 g (136.3 mmoles) of 2,4,6-trichloropyrimidine are dropwise added to a mixture of 23.84 g (273.5 mmoles) of 1-amino-2,2-dimethylpropane and 200 ml of tetrahydrofuran at a temperature between 10° C. and 15° C. while stirring and cooling. Thereafter, the reaction mixture is stirred at room temperature for an additional 30 minutes, then evaporated. After distributing the evaporation residue between 300 ml of chloroform and 50 ml of 10% sodium hydroxide solution, the organic phase is separated, washed 4 times with 100 ml of water each, then dried and evaporated. The evaporation residue is subjected to chromatography on a silica gel column. By using a 19:1 mixture of hexane and ethyl acetate, 4,6-dichloro-2-(2,2-dimethylpropylamino)pyrimidine is obtained, which is recrystallized from a mixture of ether and hexane to obtain a yield of 13.60 g (42.6%), m.p.: 63°-66° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([C:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH:32]=2)=[C:24]([CH3:26])[CH:25]=1)=[O:18].C[C:34]1N(C2C=CC(C(F)(F)F)=CN=2)N=[CH:36][C:35]=1[C:49](NC1C=NC(C2CCNCC2)=C(C)C=1)=[O:50]>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([C:27]2[CH2:28][CH2:29][N:30]([C:49](=[O:50])[CH:35]([CH3:36])[CH3:34])[CH2:31][CH:32]=2)=[C:24]([CH3:26])[CH:25]=1)=[O:18]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1CCNCC1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCN(C(=O)C(C)C)CC1

Procedure:
5-Methyl-N-[5-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide described in Reference Example 170 in place of 5-methyl-N-[5-methyl-6-(piperidin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)-pyridin-2-yl]-1H-pyrazole-4-carboxamide in Example K61, and reacted and treated in a similar manner to give the titled compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2OC)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:31]C1C=CC=CC=1C[Mg]Cl>>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:31])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccccc1C[Mg]Cl
Reactant: COc1ccccc1CC(O)(c1ccccc1)C1CN(Cc2ccccc2)CCO1
Product: OC(Cc1ccccc1F)(c1ccccc1)C1CN(Cc2ccccc2)CCO1

Procedure:
The procedure for the synthesis of example 1a, 1-(4-benzyl-morpholin-2-yl)-2-(2-methoxy-phenyl)-1-phenyl-ethanol, was followed using commercially available 2-fluoro-benzylmagnesium chloride (available from Rieke Metals) as starting material and making non-critical variations, to yield the title compound. FIA [M+H]+=392.1.
Reaction SMILES: C(O)C(O)C.[CH3:6][CH:7]([OH:11])[CH:8]([OH:10])[CH3:9].[CH2:12]([NH2:15])[CH2:13][NH2:14]>O>[CH3:6][CH:7]([OH:11])[CH:8]([OH:10])[CH3:9].[CH3:6][C:7]1[C:8]([CH3:9])=[N:15][CH:12]=[CH:13][N:14]=1
Reactant: NCCN
Agent: CC(O)C(C)O
Solvent: O
Solvent: CC(O)CO
Product: Cc1nccnc1C

Procedure:
The procedure in Example 2 was repeated except that propylene glycol was replaced by 2,3-butanediol, water was not used and the mixing (molar) ratio of the mixed gas was changed to ethylene diamine: 2,3-butanediol:nitrogen=1:1.2:0.7 to produce 2,3-dimethylpyrazine. The rate of conversion was 100% and the yield of 2,3-dimethylpyrazine was 72%.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][C:19]3[CH:22]=[CH:23][S:24][C:18]=3[CH:17]2[CH3:25])[N:13]=[C:12]([Cl:26])[CH:11]=1>CN(C)C=O>[ClH:26].[CH3:9][C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][C:19]3[CH:22]=[CH:23][S:24][C:18]=3[CH:17]2[CH3:25])[N:13]=[C:12]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH:11]=1
Reactant: Nc1ccc(F)cc1
Reactant: Cc1cc(Cl)nc(N2CCc3ccsc3C2C)n1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2ccc(F)cc2)nc(N2CCc3ccsc3C2C)n1
Product: Cl
Yield: 42.6 %

Procedure:
After 4-fluoroaniline(0.26 ml, 2.74 mmol) was added to a mixture solution of 6-methyl-2-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl)-4-chloropyrimidine(0.5 g, 1.8 mmol) and dimethylformamide(10 ml), 0.30 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: CO[CH:3](OC)[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(#N)C.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>C(OCC)(=O)C.O>[N:27]1[CH:3]=[C:4]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=12
Reactant: CCOC(=O)C=CC(OC)OC
Reactant: Nc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)Cc1cnc2ccccn12

Procedure:
Add ethyl 4,4-dimethoxybut-2-enoate (2.0 g, 11.48 mmol) and p-toluenesulfonic acid (catalytic) to 4:1 acetonitrile:water. Reflux for 1 hour and add 2-aminopyridine (1.08 g, 11.48 mmol). Reflux for 1 hour, dilute with ethyl acetate, and wash saturated aqueous sodium bicarbonate followed by saturated aqueous sodium chloride. Concentrate under reduced pressure to provide the desired compound as a brown oil.