Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:6][NH:7][C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1.C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>O1CCCC1.O>[F:3][C:4]1[C:5]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:6][N:7]([S:48]([C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([F:41])[CH:43]=2)(=[O:50])=[O:49])[C:8]=1[C:9]1[C:10]([F:15])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.6 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) was added a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (323 mg) in tetrahydrofuran (5 mL) at 0° C., 15-crown-5 (330 mg) and 3-fluorobenzenesulfonyl chloride (292 mg) were added at the same temperature. The mixture was stirred at room temperature for 30 min, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous is sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:1→3:1) to give the title compound as a colorless oil (yield 527 mg, quantitative).
Reaction SMILES: C([O:4][C:5]1[C:6]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:7][C:8]2O[C:11]([CH2:14]I)([CH3:13])[CH2:10][C:9]=2[C:16]=1[C:17]([CH3:20])([CH3:19])[CH3:18])(=O)C.[C-:25]#[N:26].[K+].[OH2:28]>CS(C)=O>[C:17]([C:16]1[C:9]2[CH2:10][C:11]([CH2:13][C:25]#[N:26])([CH3:14])[O:28][C:8]=2[CH:7]=[C:6]([C:21]([CH3:22])([CH3:24])[CH3:23])[C:5]=1[OH:4])([CH3:19])([CH3:20])[CH3:18]
Reactant: O
Reactant: [C-]#N
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CI)O2
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(CC#N)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Temperature: 140 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
In 5 ml of dimethyl sulfoxide were dissolved 1.00 g of 5-acetoxy-4,6-di-t-butyl-2-iodomethyl-2-methyl-2,3-dihydrobenzofuran synthesized in Example 70-2) and 0.36 g of potassium cyanide and the mixture was heated with stirring at 140° C. under nitrogen overnight. After cooling to room temperature, the reaction solution was poured into water and extracted with ether, and the combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The residue was purified by silica gel column chromatography eluting with n-hexane containing 9-13% ethyl acetate to give 0.09 g of 4,6-di-t-butyl-2-cyanomethyl-5-hydroxy-2-methyl-2,3-dihydrobenzofuran as a colorless solid (yield 13%).
Reaction SMILES: C[I:2].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[OH:25][C:26]1[C:27]([CH3:41])=[C:28]([CH3:40])[C:29]2[O:33][CH:32]([CH2:34][CH2:35][CH2:36]O)[S:31][C:30]=2[C:38]=1[CH3:39]>CN(C)C=O>[OH:25][C:26]1[C:27]([CH3:41])=[C:28]([CH3:40])[C:29]2[O:33][CH:32]([CH2:34][CH2:35][CH2:36][I:2])[S:31][C:30]=2[C:38]=1[CH3:39]
Reactant: CI
Reactant: Cc1c(C)c2c(c(C)c1O)SC(CCCO)O2
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1O)SC(CCCI)O2
Reaction time: 1 h

Procedure:
2 ml of methyl iodide were added to 0.67 g of triphenyl phosphite, and then the temperature of the reaction mixture was raised to reflux temperature, after which the reaction was continued for 1 hour at a bath temperature of 100° C. The temperature of the reaction mixture was reduced to room temperature, and then 0.5 g of 3-(5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)propanol (prepared as described in Example 71), 1 ml of methyl iodide and 0.5 ml of dimethylformamide were added to the reaction mixture. The reaction was continued for 3 days at room temperature. At the end of this time, the title compound, having the same properties as the product of (a) above, was obtained by the same treatment and separation procedures as in (a).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7](C(=O)C)[N:6]=[CH:5]2.[OH-].[Na+]>C(O)C.Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][N:6]=[CH:5]2
Reactant: CC(=O)n1ncc2cc(Br)c(F)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Fc1cc2[nH]ncc2cc1Br
Reaction time: 0.08 h
Yield: 88.7 %

Procedure:
To a solution of 22.5 g of 1-(5-bromo-6-fluoro-indazol-1-yl)ethanone in 250 mL of ethanol was added 20.0 mL of 5N sodium hydroxide aqueous solution at room temperature, and stirred at this temperature for 5 minutes. After neutralizing in 5N hydrochloric acid aqueous solution, the solution was diluted with ethyl acetate. The organic layer was successively washed with water and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3), to afford 16.7 g of the title compound as pale brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33](O)=[O:34])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCN(C5C=CC(C(O)=O)=CC=5)C=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.[N:99]1([CH2:105][CH2:106][OH:107])[CH2:104][CH2:103][NH:102][CH2:101][CH2:100]1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:48]=[CH:49][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([C:33]([N:102]6[CH2:103][CH2:104][N:99]([CH2:105][CH2:106][OH:107])[CH2:100][CH2:101]6)=[O:34])[CH:36]=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)O)c3)cn2)cc1
Reactant: OCCN1CCNCC1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)N4CCN(CCO)CC4)c3)cn2)cc1
Yield: 93.6 %

Procedure:
Using 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (68.1 mg, 0.103 mmol) obtained in Step A in Example 1-D-53 instead of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid, and 1-piperazineethanol (26.0 μl, 0.211 mmol) instead of 3-(aminomethyl)pyridine, amidation was carried out in the same manner as Step B in Example 1-D-19, to obtain a crude product of {3-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone as a yellow solid (74.4 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-125) as a yellow powder (31.7 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.C([Li])CCC.CN([CH:18]=[O:19])C.Cl>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:18]=[O:19])=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(F)cc(Cl)c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1c(F)cc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 41.6 %

Procedure:
To a −78° C. solution of 1-chloro-3,5-difluoro-benzene (5.0 g, 34 mmol) in THF (70 mL) at was added n-butyl lithium (1.6 M in hexane, 19 mL). After 50 min, DMF (5.2 mL, 67 mmol) was added and the reaction was allowed to warm to rt over 18 h. After the addition of 0.5 M HCl (150 mL) and ether (150 mL), the aqueous layer was extracted with Et2O (3×). The combined organic extracts were dried and concentrated to provide a yellow solid. The crude material was dissolved in warm hexanes and a small amount of white solid formed upon cooling. This white solid was filtered off and discarded. The filtrate was concentrated to provide the title compound as a light yellow solid (2.5 g, 41%). 1H NMR (CDCl3): 10.3 (s, 1H), 7.06 (d, J=8.1 Hz, 2H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].[F:17][C:18]([F:39])([F:38])[C:19]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][C:26]=2[C:28]2[CH:29]=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:21][N:20]=1.O>CN1CCCC1=O>[CH3:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[N:21]1[C:22]2=[N:23][CH:24]=[CH:25][C:26]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:27]2[C:19]([C:18]([F:17])([F:39])[F:38])=[N:20]1)[C:6]#[N:7]
Reactant: Cc1cc(C#N)ccc1F
Reactant: FC(F)(F)c1n[nH]c2nccc(-c3cnc4ccccc4c3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C#N)ccc1-n1nc(C(F)(F)F)c2c(-c3cnc4ccccc4c3)ccnc21
Temperature: 120 °C
Reaction time: 60 h
Yield: 11 %

Procedure:
4-Fluoro-3-methylbenzonitrile (0.052 g) and cesium carbonate (0.150 g) were added to a solution of compound (1d) (0.092 g) in 1-methyl-2-pyrrolidone (hereinafter referred to as NMP) (1.0 mL), followed by stirring at 120° C. for 60 hr. Water was added to the reaction solution, and the precipitate was collected by filtration and was washed by sprinkling water to obtain 3-methyl-4-{4-(quinolin-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile (11%). According to Example 1(7), compound (82) (64%) was prepared as a white solid using 3-methyl-4-{4-(quinolin-3-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]3[N:17]=[C:16]([CH3:18])[O:15][C:13]3=[CH:14][C:7]=2[CH2:6][CH2:5]1.[CH3:19][N:20]1[C:24]([C:25]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:26]=2[CH:27]=[CH:28][C:29]([CH3:35])=[N:30]3)=[N:23][NH:22][C:21]1=[S:36]>>[ClH:1].[CH3:18][C:16]1[O:15][C:13]2[C:12]([N:17]=1)=[CH:11][C:8]1[CH2:9][CH2:10][N:4]([CH2:3][CH2:2][S:36][C:21]3[N:20]([CH3:19])[C:24]([C:25]4[CH:34]=[CH:33][CH:32]=[C:31]5[C:26]=4[CH:27]=[CH:28][C:29]([CH3:35])=[N:30]5)=[N:23][N:22]=3)[CH2:5][CH2:6][C:7]=1[CH:14]=2
Reactant: Cc1ccc2c(-c3n[nH]c(=S)n3C)cccc2n1
Reactant: Cc1nc2cc3c(cc2o1)CCN(CCCl)CC3
Product: Cc1ccc2c(-c3nnc(SCCN4CCc5cc6nc(C)oc6cc5CC4)n3C)cccc2n1
Product: Cl

Procedure:
The title compound was prepared in analogy to General Procedure 1 from 7-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-5H-[1,3]oxazolo[4,5-h][3]benzazepine (0.11 mmol) and 4-methyl-5-(2-methyl-5-quinolinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (0.11 mmol) and was obtained in 40 mg yield.
Reaction SMILES: C1(C(C2C=CC=CC=2)=CC2CCNCC2)C=CC=CC=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)(O)[CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1.FC(F)(F)C(O)=O>CC1C=CC=CC=1>[F:43][C:40]1[CH:41]=[CH:42][C:37]([C:28]([C:25]2[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=2)=[CH:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:38][CH:39]=1
Reactant: OC(CC1CCNCC1)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: C(=C(c1ccccc1)c1ccccc1)C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: Fc1ccc(C(=CC2CCNCC2)c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared in the same manner as the compound of example 6, starting with 25 g of alpha,alpha-bis(4-fluorophenyl)-4-piperidineethanol, 0.25 molar methylbenzene solvate and 50 mL of trifluoroacetic acid. Crystallization from hexane gave 19.6 g (83%) of the hexane solvate of 4-[2,2-bis(4-fluorophenyl)ethenyl]-piperidine, mp 84°-86° C. Analysis Calculated for C19H19F2N.O.15C6H14 : C, 76.54; H, 6.81; N, 4.49; F, 12.17. Found: C, 76.87; H, 6.72; 4.65; F, 12.12.
Reaction SMILES: [CH3:1][Si:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([NH2:16])[N:15]=[C:10]2[CH:9]=[CH:8]1.[CH:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1(C)C=CC=CC=1>[CH:19]1([NH:25][C:26]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:18])([CH3:17])[CH3:1])[C:11]3=[N:12][CH:13]=2)=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(N)cnc21
Reactant: O=C=NC1CCCCC1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCCC3)cnc21
Temperature: 25 °C
Yield: 137.3 %

Procedure:
5-(2-Trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamine (1.32 g, 4.99 mmol) was dissolved in toluene (50 mL). Cyclohexylisocyanate (6.4 mL, 49.9 mmol) was added and the reaction mixture was heated to reflux for 88 hr, cooled to RT, and concentrated, and purified by SiO2 chromatography (150 g SiO2, DCM/MeOH 0 to 5% MeOH) to give 2.67 g of impure 1-cyclohexyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a yellow solid (31% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[Br:10]Br>C(O)(=O)C>[Br:10][C:6]1[C:5]([CH3:8])=[CH:4][C:3]([OH:9])=[C:2]([F:1])[CH:7]=1
Reactant: BrBr
Reactant: Cc1ccc(F)c(O)c1
Solvent: CC(=O)O
Product: Cc1cc(O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
2-fluoro-5-methylphenol (23.8 g, 0.19 mol) and bromine (9.7 ml, 0.19 mol) are combined in 50 ml of glacial acetic acid and stirred at RT for one hour. Acetic acid was removed under vacuum. The liquid was diluted with ethyl acetate and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 4-bromo-2-fluoro-5-methylphenol (38 g, 98% yield) as a colorless liquid. No [M+H] peak by LCMS. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.98 (s, 1 H) 2.22 (s, 3 H) 6.81 (dd, J=9.15, 0.54 Hz, 1 H) 7.17 (d, J=9.88 Hz, 1 H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:16])[N:19]([O:20][CH3:21])[CH3:18])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CCCCN1C(=O)OC(C)(C)C

Procedure:
To (RS)-1-(tert-butyloxycarbonyl)-2-piperidine carboxylic acid (5.32 g, 23.2 mmol) in dichloromethane (20 ml) was added sequentially N,O-dimethyl hydroxylamine hydrochloride (2.68 g, 27.5 mmol), triethylamine (12 ml, 86.0 mmol) and py-BOP (13.2 g, 25.4 mmol). The resultant mixture was stirred at ambient temperature for 6 h, then diluted with dichloromethane (350 ml) and poured into 1M HCl (50 ml).
Reaction SMILES: [CH2:1]([C:4]1([CH3:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][C:5]1=[O:14])[CH:2]=[CH2:3].[CH3:16]OC(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:16][O:14][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])([CH3:15])[C:13]2[C:8]([CH2:7][CH:6]=1)=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: COC(OC)OC
Reactant: C=CCC1(C)C(=O)CCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C=CCC1(C)C(OC)=CCc2ccccc21
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of Example 123A (10.1 g, 50.5 mmol), trimethylorthoformate (20 mL), p-toluenesulfonic acid monohydrate (60 mg, 0.315 mmol) in methanol (100 mL) was heated at 60 C for 2 hours. After cooling to room temperature, the solution was concentrated in vacuo, and the resultant residue was purified by column chromatography employing 70-230 mesh silica gel eluting with hexane to provide the title compound as a colorless oil (7.8 g, 73%). 1H NMR (300 MHz, DMSO-d6): δ 1.38 (s, 3 H), 2.44 (dd, J=13.8, 7.4 Hz, 1H), 2.65 (dd, J=13.6, 7.0 Hz, 1 H), 3.41 (d, J=3.7 Hz, 2 H), 3.54 (s, 3 H), 4.75 m, 2 H), 4.90 (t, J=3.7 Hz, 1 H), 5.24 m, 1 H), 7.10 m, 2 H), 7.19 m, 1 H), 7.40 (d, J=7.8 Hz, 1 H).
Reaction SMILES: [Ni:1].[CH2:2]([CH:4]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([OH:7])=[O:6])[CH3:3].[N+]([O-])([O-])=O.[NH4+].C([O-])(=O)C.[NH4+]>O>[CH2:2]([CH:4]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([O-:7])=[O:6])[CH3:3].[Ni+2:1].[CH2:2]([CH:4]([CH2:8][CH2:9][CH2:10][CH3:11])[C:5]([O-:7])=[O:6])[CH3:3]
Reactant: CCCCC(CC)C(=O)O
Reactant: [Ni]
Agent: CC(=O)[O-]
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: CCCCC(CC)C(=O)[O-]
Product: [Ni+2]
Temperature: 85 °C

Procedure:
A mixture of 50 grams (0.852 mole) of powdered nickel (particle size 3 to 7 microns), 248 grams (1.710 moles) of 2-ethylhexanoic acid (acid number, 387), a catalyst solution prepared by dissolving 10 grams of ammonium nitrate and 5 grams of ammonium acetate in 30 grams of water, and 170 grams of mineral spirits was agitated and heated to 85° C. The reaction mixture was maintained at 80°-85° C. for 6 hours while it was sparged with air at the rate of 30 liters per hour. It was then heated to 135° C. under vacuum to remove water from it. After the reaction product had been filtered and diluted with mineral spirits, there was obtained a solution of nickel 2-ethylhexanoate in mineral spirits that contained l0% by weight of nickel and had an acid number of 21.7.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]([Cl:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:4]=1.C(N(CC)C(C)C)(C)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>CN(C)C=O>[C:30]([NH:1][CH2:2][C:3]1[C:12]([Cl:13])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[N:4]=1)(=[O:32])[CH3:31]
Reactant: COC(=O)c1cc(Cl)c(CN)nc1-c1cccc(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(CNC(C)=O)nc1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 6-(aminomethyl)-5-chloro-2-(3-fluorophenyl)nicotinate (0.35 g, 1,2 mmol) was stirred in N,N-dimethylformamide (5 mL) with N,N-diisopropylethylamine (0.41 mL, 2.4 mmol) and acetic anhydride (0.17 mL, 1.8 mmol) was added. The mixture was stirred for 30 minutes at room temperature. Evaporation gave the crude material which was contaminated with the corresponding dechlorinated byproduct (0.4 g, 100%). LCMS calculated for C16H15ClFN2O3 (M+H)+: m/z=337.1. found 336.9.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]=[C:8]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])OC3C=CC=CC=3)=[CH:20][CH:19]=2)[N:7]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:41][NH:42][CH2:43][CH2:44][OH:45]>CN1C(=O)CCC1>[OH:45][CH2:44][CH2:43][N:42]([CH3:41])[C:25]([NH:24][C:21]1[CH:20]=[CH:19][C:18]([C:8]2[N:7]=[C:6]([CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:9]=2)=[CH:23][CH:22]=1)=[O:33]
Reactant: CS(=O)(=O)Cc1cc(N2CCOCC2)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Reactant: CNCCO
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN(CCO)C(=O)Nc1ccc(-c2nc(CS(C)(=O)=O)cc(N3CCOCC3)n2)cc1
Temperature: 70 °C

Procedure:
A solution of phenyl N-[4-[4-(methylsulfonylmethyl)-6-morpholin-4-yl-pyrimidin-2-yl]phenyl]carbamate (94 mg, 2 mmol) and triethylamine (0.09 mL, 9.2 mmol) in NMP (1 mL) was added to 2-methylaminoethanol (10 mmol). The mixture was heated at 70° C. for 2 hours and the reaction purified by prep HPLC, to give the desired compound.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]2[CH2:7][C@@H:8]([O:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:9](/[CH:10]=[CH:11]/[C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C@H:4]2[CH2:3]1.CO>C1COCC1>[OH:21][C@@H:12]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)/[CH:11]=[CH:10]/[C@@H:9]1[C@@H:4]2[C@@H:5]([O:6][C:2](=[O:1])[CH2:3]2)[CH2:7][C@H:8]1[O:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(/C=C/[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC(=O)c1ccccc1)CCc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCc3ccccc3)[C@H](OC(=O)c3ccccc3)C[C@@H]2O1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
To a solution of 50 g of compound 20a (MW=406.8; 1.0 eq.; prepared as described in example 2) in 500 mL of dry THF was slowly added 190 mL of (−)-DIP-Cl solution (MW=320.76; 2.75 eq. 63% in heptane) at −30° C. After stirring for 6 h 180 mL of methanol were added and the mixture was warmed to room temperature. After removal of the solvent under reduced pressure, the residue was dissolved in methanol/water (10/1) and extracted twice with heptane. After concentration of the aqueous layer, ethyl acetate was added and the resulting mixture was consecutively extracted with an aqueous NaCl solution (9%) and with an aqueous NaHCO3 solution (8.6%). The organic solvents were removed under reduced pressure and the residue was recrystallized from ethyl acetate/n-heptane (1/7) to give 41 g of the title compound after drying (40° C., 10 mbar; yield=81.2%, de(S)=89.2%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1)[NH2:23]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)c(Cl)c1
Reactant: CCOCCOCCn1ccc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOCCOCCn1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c21
Temperature: 120 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a solution of 4-chloro-5-[2-(2-ethoxyethoxy)ethyl]-5H-pyrrolo[3,2-d]pyrimidine (150 mg) in 1-methyl-2-pyrrolidone (1.1 mL) was added 3-chloro-4-[(3-fluorobenzyl)oxy]aniline (189 mg), and the reaction mixture was stirred at 120° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (30 mL×3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (basic silica gel, eluent:ethyl acetate/methanol=100/0→95/5). The object fraction was concentrated under reduced pressure and dried to give the title compound (146 mg) as a colorless oil.