Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1)=[O:9])=[O:4].[CH3:37][NH:38][CH3:39]>>[CH3:37][N:38]([CH3:39])[CH2:2][C:3]([NH:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][N:15]=[C:14]2[NH:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:30]=[N:31][C:32]([CH3:35])=[CH:33][CH:34]=2)=[C:24]([CH3:36])[CH:23]=1)=[O:9])=[O:4]
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)CCl)cc34)cc2C)cn1
Reactant: CNC
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(NC(=O)CCNC(=O)CN(C)C)cc34)cc2C)cn1
Yield: 50 %

Procedure:
The procedure of Example 62 was repeated except for using 0.08 g of the compound obtained in Example 67 and 0.24 ml of dimethylamine 2 M THF instead of the compound obtained in Example 61 to obtain the title compound (0.04 g, 50%).
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[Br:7][C:8]1[S:16][C:15]2[CH:14]=[CH:13][N:12]=[C:11](Cl)[C:10]=2[CH:9]=1.O>CN(C=O)C>[Br:7][C:8]1[S:16][C:15]2[CH:14]=[CH:13][N:12]=[C:11]([S:16][C:15]3[CH:14]=[CH:3][C:2]([CH3:5])=[CH:1][CH:10]=3)[C:10]=2[CH:9]=1
Reactant: Clc1nccc2sc(Br)cc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Sc2nccc3sc(Br)cc23)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Para-thiocresol (500 mg, 4 mmol) in DMF (10 mL) was treated with potassium t-butoxide (451 mg, 4 mmol) at room temperature, after 15 minutes cooled to 0° C., treated with 2-bromo-4-chlorothieno[3,2-c]pyridine (prepared in 6 steps according to the method of F. Eloy and A. Deryckere (Bull. Soc. Chim. Belg. 1970, 79,301) (1.0 g, 4.0 mmol), stirred at 0° C. for 2 hours and at room temperature for 12 hours, poured into water and extracted with diethyl ether. The extract was washed with water, dried (Na2SO4), and concentrated under vacuum. The residue was purified by flash chromatography on silica gel with 1:20 ethyl acetate-hexane to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:11]=2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.N1C=CC=CC=1.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>O1CCCC1>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([NH:1][S:54]([CH3:53])(=[O:56])=[O:55])[CH:3]=[C:4]([C:10]2[C:18]3[C:17]([NH:19][C@H:20]([C:22]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:26](=[O:34])[C:25]5=[C:35]([CH3:38])[CH:36]=[CH:37][N:24]5[N:23]=4)[CH3:21])=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH:11]=2)[CH:5]=1
Reactant: COc1cc(N)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(NS(C)(=O)=O)cc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1
Temperature: 45 °C
Yield: 67 %

Procedure:
(S)-2-(1-((5-(3-Amino-5-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with pyridine (22 μl, 0.27 mmol), methanesulfonyl chloride (18 μl, 0.23 mmol) and 0.75 ml tetrahydrofuran as a solvent according to the method described in Preparation 175 but heating at 45° C. during 48 h. The residue was purified using SP1® Purification System (0% to 70% hexane-ethyl acetate) to obtain 42 mg (67% yield, 89% purity) of the title compound.
Reaction SMILES: [CH3:1][S:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.[CH3:13][NH2:14]>CCO>[CH3:13][N:14]=[CH:8][C:7]1[CH:10]=[CH:11][CH:12]=[C:5]([O:4][CH2:3][S:2][CH3:1])[CH:6]=1
Reactant: CSCOc1cccc(C=O)c1
Reactant: CN
Solvent: CCO
Product: CN=Cc1cccc(OCSC)c1
Temperature: 40 °C

Procedure:
3-Methylsulfanylmethoxy-benzaldehyde from step 1 (3.309 g, 18.16 mmol) was dissolved in EtOH (9 mL). MeNH2 (2.55 mL, 40% in H2O) was added and the mixture was heated to 40° C. for 30 min. Upon cooling, the mixture was concentrated in vacuo. The aqueous residue was diluted with isopropanol and then concentrated in vacuo. This was repeated twice more giving 3.55 g (quant) of a pale yellow oil.
Reaction SMILES: [OH-].[Na+].C([SiH2][O:8][C:9](C)(C)[C:10]1[CH:11]=[C:12]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:13][NH:14][C:15]([CH:17]1[CH2:19][CH2:18]1)=[O:16])(C)(C)C>CO>[Cl:23][C:22]1[CH:21]=[CH:20][C:12]([CH2:13][NH:14][C:15]([CH:17]2[CH2:18][CH2:19]2)=[O:16])=[CH:11][C:10]=1[CH2:9][OH:8]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(CNC(=O)C2CC2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1ccc(Cl)c(CO)c1)C1CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
Aq. 1M NaOH (111 mL) was added to a sol. of cyclopropanecarboxylic acid 3-(tert-butyl-dimethyl-silanyloxymethyl)-4-chloro-benzylamide (6.10 g, 17.2 mmol) in MeOH (222 mL). The mixture was heated to 80° C., and stirred at this temperature for 30 min. The mixture was allowed to cool to rt, and the solvents were partially removed under reduced pressure. The aq. residue was diluted with water, and was extracted with EtOAc (3×). The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC(CH2Cl2→MeOH/CH2Cl2 1:9) yielded the title compound (3.47 g, 84%). LC-MS: tR=0.71 min; ES+: 281.31.
Reaction SMILES: C([Si]([O:8][CH2:9][C@@H:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[CH3:11])(C)C)(C)(C)C.C([Li])(CC)C.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C>C1COCC1>[F:18][C:16]1[CH:17]=[C:12]([C@@H:10]([CH3:11])[CH2:9][OH:8])[C:13]([O:19][CH3:20])=[CH:14][C:15]=1[B:26]([OH:31])[OH:27]
Reactant: COc1ccc(F)cc1[C@@H](C)CO[Si](C)(C)C(C)(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)c(F)cc1[C@@H](C)CO
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 81.9 %

Procedure:
To a solution of 25B (1.12 g, 3.75 mmol) in THF (20 mL) was dropwise added sec-butyllithium (3.22 mL, 4.50 mmol) at −78° C. and stirred at −78° C. for 10 min. Triisopropyl borate (1.743 mL, 7.50 mmol) was added and the mixture was slowly warmed up to r.t. overnight. The reaction was quenched by 6.0 ml of 1N HCl and the mixture was stirred at r.t. for 4 h. TBS is ˜60% removed. Addition 4 ml of 1 N HCl was gassed and the mixture was heated at 50° C. for 1 h. The mixture was concentrated and purified by prep HPLC to yield 25C (700 mg, 3.07 mmol, 82% yield) as a white solid. MS (ESI) m/z: 227.5 (M−H)+. 1H NMR (400 MHz, methanol-d3) δ ppm 6.87-6.94 (2H, m), 3.81 (3H, s), 3.70 (1H, dd, J=10.77, 5.93 Hz), 3.51 (1H, dd, J=10.55, 7.47 Hz), 3.32-3.37 (1H, m), 1.22 (3H, d, J=7.03 Hz).
Reaction SMILES: I[C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[C:20]#[CH:21])[CH3:17]>CN(C=O)C.C(OCC)(=O)C.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>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[C:20]1[O:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:21]=1)[CH3:17]
Reactant: Oc1cccnc1I
Reactant: C#CC(OCC)OCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(OCC)c1cc2ncccc2o1
Reaction time: 17 h

Procedure:
2-Iodo-3-pyridinol (24 mmol), triethylamine (1.0 eq), 3,3-diethoxy-1-propyne (1.0 eq), bis(triphenylphosphine)palladium (II) chloride (0.02 eq), and copper(I) iodide (0.04 eq) were combined in DMF (14 mL) and allowed to stir for 17 hours. The mixture was diluted with ethyl acetate (100 mL) and filtered through a Celite pad. The filtrate was washed with saturated sodium bicarbonate (2×50 mls), dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to provide the title compound which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 1.28 (t, J=7.1 Hz, 6H), 3.70 (q, J=7.1 Hz, 4H), 5.68 (s, 1H), 7.05 (s, 1H), 7.23 (dd, J=8.5, 4.8 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 8.57 (br, 1H). MS (DCI/NH3) m/z 222 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1)=[O:4]>O=[Pt]=O.C(O)C>[CH3:1][NH:2][C:3]([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([OH:16])[CH2:8][CH2:7]1)=[O:4]
Reactant: CNC(=O)NC1CCC(=O)c2ccccc21
Agent: O=[Pt]=O
Solvent: CCO
Product: CNC(=O)NC1CCC(O)c2ccccc21

Procedure:
1-Methyl-3-(1,2,3,4-tetrahydro-4-oxo-1-naphthyl)-urea (3.3 g.) is hydrogenated in the presence of 0.3 g. of PtO2 /0.05 mmole FeCl3 solution in 300 ml. of 95% ethanol using a low-pressure all-glass hydrogenator. After 615 ml. of hydrogen is absorbed, the excess hydrogen is removed by purging the system with nitrogen. The solution is filtered and evaporated to dryness in vacuo to afford 3.4 g. of an oil. The oil is stirred with about 20 ml. of acetone and the formed white solid is collected to afford 1.6 g. of the title compound as a cis/trans mixture, melting point 172°-180° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15]>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][CH:18]=[C:12]([O:11][CH3:10])[CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2ncc(F)c(Nc3cccc(OC)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-methoxyaniline were reacted to yield N2,N4-bis(3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.96 (d, 1H, J=5.4 Hz), 7.24 (m, 6H), 7.06 (t, 1H, J=2.4 Hz), 7.00 (dt, 1H, J=1.2 Hz), 6.79 (m, 1H), 3.72 (s, 3H), 3.70 (s, 3H); 19F NMR (CD3OD): δ−46112; LCMS: ret. time: 23.46 min.; purity: 99%; MS (m/e): 341 (MH+).
Reaction SMILES: C(=O)([O-])[O-:2].[Na+:5].[Na+].C(=O)=[O:8].[C:10](=[O:13])([O-:12])[O-:11].[OH-].[Na+]>>[OH2:2].[C:10](=[O:11])([O-:13])[O-:12].[Na+:5].[Na+:5].[OH-:8].[Na+:5]
Reactant: O=C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: O

Procedure:
In U.S. Pat. No. 3,628,919 to Beauchamp, there is described a process for crystallizing sodium carbonate (possibly monohydrated) starting from aqueous solutions containing organic materials. It aims more particularly at furnishing a process which avoids the unfavorable action of these organic materials on the sodium carbonate crystals. According to the Beauchamp process, sodium carbonate is crystallized onto seed crystals obtained under good crystallization conditions. The choice of the source of seed crystals is not however critical. Further, the Beauchamp patent is not concerned with the use of carbon dioxide (CO2) to carbonate an aqueous solution of sodium hydroxide and then evaporated to produce seed crystals of sodium carbonate monohydrate free of sodium hydroxide.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:17]=[CH:16][C:8]([CH2:9]P(=O)(OC)OC)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].C([O:23][CH2:24][CH2:25][N:26]([CH3:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)(=O)C>COCCOC>[OH:23][CH2:24][CH2:25][N:26]([CH3:35])[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[CH:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:17][CH:16]=2)=[CH:29][CH:28]=1
Reactant: CC(=O)OCCN(C)c1ccc(C=O)cc1
Reactant: COP(=O)(Cc1ccc(S(C)(=O)=O)cc1)OC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CN(CCO)c1ccc(C=Cc2ccc(S(C)(=O)=O)cc2)cc1
Temperature: 0 °C

Procedure:
A solution of dimethyl 4-methylsulfonylbenzylphosphonate prepared as described in Ulman et al U.S. Pat. No. 4,792,208 (6.29 g, 22.6 mmol), 60% sodium hydride dispersion (1.35 g, 33.9 mmol) and 50 mL of dry 1,2-dimethoxyethane (DME) under nitrogen was treated with a solution of 4-[(2-acetoxyethyl)methylamino]benzaldehyde (5.00 g, 22.6 mmol, Example 5) in 50 mL of DME. The resulting mixture was heated at reflux for 16 hr, then cooled and poured onto 300 g of ice. The resulting yellow solid was filtered, washed with water and air-dried. The solid was heated at reflux in a mixture of 10 g of NaOH, 90 mL of ethanol and 90 mL of water for 24 hr, then cooled and poured onto 200 mL of water. The resulting brown solid was filtered and air-dried. The product was recrystallized twice from a mixture of ethanol and pyridine to produce 4.46 g (60%) of yellow plates, m.p. 201°-204° C.
Reaction SMILES: C(Cl)(C(Cl)=O)=O.CS(C)=O.[CH2:11]([N:13]1[C:25]2[C:24]([CH2:26][OH:27])=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([N:13]1[C:25]2[C:24]([CH:26]=[O:27])=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH3:12]
Reactant: CCn1c2ccccc2c2cccc(CO)c21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCn1c2ccccc2c2cccc(C=O)c21
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
A 50-mL round-bottom flask was placed a solution of methyl 9-ethyl-9H-carbazole-1-carboxylate (1.3 g, 5.14 mmol, 1.00 equiv) in THF (50 mL). To the mixture was added LiAlH4 (840 mg, 22.11 mmol, 4.00 equiv) in several batches at 0° C. and allowed to stir at this temperature 30 minutes. Then, the reaction was quenched with aqueous NaOH (2M, 12 mL). The mixture was then extracted with ethyl acetate (3×50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (50:1) affording (9-ethyl-9H-carbazol-1-yl)methanol as white solid (1 g, (86%). Meanwhile, a 250-mL 3-necked round-bottom was charged with a solution of (COCl)2 (840 mg, 6.67 mmol, 1.50 equiv) in DCM (40 mL). To this was added DMSO (1 g, 12.80 mmol, 3.00 equiv)-78° C. and allowed to stir for 30 min at this temperature. To this solution was added a solution of (9-ethyl-9H-carbazol-1-yl)methanol (1 g, 4.44 mmol, 1.00 equiv) in DCM (5 mL) at −78° C. The resulting solution was stirred at −78° C. for 5 hours. Then, triethylamine (TEA) (10 mL) was added and allowed to stir an additional hour at −78° C. Upon completion, the reaction was quenched with water and extracted with DCM (3×50 mL). Combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (50:1) affording 9-ethyl-9H-carbazole-1-carbaldehyde as light yellow solid (0.9 g, 90.8%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:7]=[C:8]([CH:30]([C:44]3[CH:49]=[C:48]([O:50][CH2:51][CH3:52])[CH:47]=[C:46]([O:53][CH:54]([CH3:56])[CH3:55])[C:45]=3[F:57])[NH:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]4[N:42]=[C:41]([CH3:43])[O:40][N:39]=4)=[CH:34][CH:33]=3)[N:9]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:10]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH3:60]I>C1COCC1>[CH2:51]([O:50][C:48]1[CH:47]=[C:46]([O:53][CH:54]([CH3:56])[CH3:55])[C:45]([F:57])=[C:44]([CH:30]([C:8]2[N:9]([C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:10]=[C:6]([C:4]3[CH:5]=[N:1][N:2]([CH3:60])[CH:3]=3)[N:7]=2)[NH:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[N:42]=[C:41]([CH3:43])[O:40][N:39]=3)=[CH:34][CH:33]=2)[CH:49]=1)[CH3:52]
Reactant: CI
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3cn[nH]c3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3cnn(C)c3)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
To a solution of Intermediate 237.1 (30 mg, 0.04 mmol) in THF (1 mL) at 0° C. was added NaH (3.16 mg, 0.08 mmol), stirred at 0° C. for 30 min, then MeI was added and the reaction mixture was warmed up to rt over 1 h. The reaction mixture was then partitioned between EtOAc and sat. NH4Cl, the organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes, gradient) to afford 20 mg (62%) of Intermediate 237.2.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[N:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH2:32]Cl)([CH3:23])[CH3:22])[C:15]1=[O:34].[CH3:35][NH2:36]>C(#N)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[N:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH:20][C:21]([CH3:22])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH2:32][NH:36][CH3:35])[CH3:23])[C:15]1=[O:34]
Reactant: CN
Reactant: CC(C)(Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2Cl)c1=O)c1ccccc1OCCCl
Solvent: CC#N
Product: CNCCOc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2Cl)c1=O
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of 4-chloro-3-[3-({1-[2-(2-chloroethoxy)phenyl]-1-methylethyl}amino)-2-oxopyrazin-1(2H)-yl]-N-cyclopropylbenzamide (Example 3301, 0.22 g) dissolved in acetonitrile (3 mL) was treated with 40% aqueous methylamine (0.380 mL). The resulting mixture was stirred at 100° C. for 16 h in a sealed tube. The reaction mixture was filtered and purified by preparative HPLC (Phenominex Gemini column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent). The fractions containing the desired compound were evaporated to afford the title compound (0.087 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.C(OO)(=[O:17])C.OO>C(O)(=O)C.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:9]=[N+:10]([O-:17])[CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: CC(=O)OO
Reactant: Fc1ccc(Br)cc1-c1cccnc1
Agent: OO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: [O-][n+]1cccc(-c2cc(Br)ccc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
A mixture of 3-(5-bromo-2-fluorophenyl)pyridine (2.52 g, 10.0 mmol) and peracetic acid (3.37 ml of a 36-40 wt % solution in acetic acid) in tetrahydrofuran (40 ml) was stirred at ambient temperature for 1 h and then heated at 50° C. for 2 h. Hydrogen peroxide (35 wt % solution in water, 1 ml) was added and the mixture heated at 50° C. for a further hour. The solvent was removed in vacuo and the residue diluted with water and layered with ethyl acetate. Solid sodium hydrogencarbonate was added to pH 8. The layers were separated and the organic layer washed with water, brine, dried over anhydrous magnesium sulfate, filtered and pre-adsorbed onto silica. Purification by flash column chromatography on silica gel eluting with dichloromethane (containing 1% ammonia) on a gradient of methanol (2-5%) gave 3-(5-bromo-2-fluorophenyl)pyridine-1-oxide as a white solid (2.00 g, 75%): δH (400 MHz, CDCl3) 7.09-7.14 (1H, m), 7.35-7.43 (2H, m), 7.52-7.57 (2H, m), 8.22-8.25 (1H, m), 8.42 (1H, t, J 1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.O1[CH2:10][CH2:9][CH2:8][CH2:7]1>>[Br:1][CH2:2][CH2:3][CH2:4][CH:7]=[CH:8][C:9]1[CH:10]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CCOC1
Reactant: BrCCCBr
Product: BrCCCC=Cc1ccccc1
Reaction time: 2 h

Procedure:
83.16 g of p-chlorostyrene was reacted with metal magnesium at 35° C. for 5 hours under stirring in tetrahydrofuran flushed with nitrogen to obtain a magnesium composite. This composite was dropwise added to a solution mixture comprising tetrahydrofuran, 1,3-dibromopropane and Li2CuCl4 at 30° C. The reaction was continued at 30° C. for two hours. Then, the obtained product was fractionated by distillation. 3-bromopropylstyrene was obtained under 0.2 Torr at 110° C., and the yield based on the starting material pchlorostyrene was 47%. Identification of 3-bromopropylstyrene was conducted by the NMR method.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(C)=O)CC4)c[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A151) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][CH:2](O)[CH2:3][CH:4]=[CH2:5].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH2:1]=[CH:2][CH2:3][CH:4]([N:11]1[C:7](=[O:17])[C:8]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:9]2[C:10]1=[O:12])[CH3:5]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCC(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=CCC(C)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 70.1 %

Procedure:
To a stirred solution of 4-penten-2-ol (5.00 g, 58.1 mmol), phthalimide (8.55 g, 58.1 mmol), and triphenylphosphine (15.2 g, 58.1 mmol) in THF (40 mL), at 0° C. under nitrogen, was added a solution of diethyl azodicarboxylate (10.1 g, 58.1 mmol) in THF (20 mL) dropwise. The mixture was stirred at 0° C. (12 h) and then at 25° (12 h). The mixture was diluted with water and extracted three times with chloroform. The chloroform extracts were dried (Na2SO4), evaporated and column chromatographed on Merck silica gel 60 (70–230 mesh) with chloroform to give 8.77 g (70.2% yield) of colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH3:7].[CH3:8][C:9]1[N:10]=[C:11]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[S:12][C:13]=1[CH3:14]>CS(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([C:15]([C:11]2[S:12][C:13]([CH3:14])=[C:9]([CH3:8])[N:10]=2)([OH:20])[C:16]([F:19])([F:18])[F:17])[S:5][C:6]=1[CH3:7]
Reactant: Cc1ncsc1C
Reactant: Cc1nc(C(=O)C(F)(F)F)sc1C
Solvent: CS(C)=O
Product: Cc1nc(C(O)(c2nc(C)c(C)s2)C(F)(F)F)sc1C

Procedure:
From 4,5-dimethylthiazole and 4,5-dimethyl-2-trifluoroacetylthiazole. M.p. 122°-123.5° C. 13C Nmr (d6 -DMSO) 10.5, 14.4, 76.9 (g, J 30 Hz) 123.1 (q, J 286Hz), 129.0, 147.9 and 161.0 ppm.