Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7](=O)[CH2:8][CH:9]2[C:14](=O)[CH2:13][CH2:12][S:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:19][N:20]([CH2:22][CH2:23][CH2:24][NH2:25])[CH3:21].C(O)C.[ClH:29]>Cl.CCOCC>[ClH:29].[CH3:19][N:20]([CH3:21])[CH2:22][CH2:23][CH2:24][N:25]1[C:7]([C:6]2[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:8][C:9]2[CH2:10][S:11][CH2:12][CH2:13][C:14]1=2
Reactant: COc1ccc(C(=O)CC2CSCCC2=O)cc1
Reactant: CN(C)CCCN
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(-c2cc3c(n2CCCN(C)C)CCSC3)cc1
Temperature: 25 °C

Procedure:
A solution of 3.09 g (0.012 mole) of 3-(4-methoxyphenacyl)-2,3,5,6-tetrahydrothiopyran-4-one, 1.22 g of dimethylaminopropylamine, 20 ml. of ethanol and one drop of concentrated hydrochloric acid is heated under reflux for 1.5 hours, cooled to ambient temperature, treated with 4 ml. of saturated ethereal hydrogen chloride, and diluted to the cloud point with ether. A brown solid precipitates. The solid is recrystallized from 2-propanol to give tan crystals of 1-(3-dimethylaminopropyl)-2-(4-methoxyphenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole hydrochloride, m.p. 193 to 194°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.Cl[C:12]1[CH:17]=[C:16]([NH:18][CH2:19][CH2:20][O:21][CH3:22])[C:15]([C:23]([F:26])([F:25])[F:24])=[CH:14][N:13]=1>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:12]2[CH:17]=[C:16]([NH:18][CH2:19][CH2:20][O:21][CH3:22])[C:15]([C:23]([F:24])([F:26])[F:25])=[CH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: COCCNc1cc(Cl)ncc1C(F)(F)F
Reactant: COc1ccc(CN)cc1
Product: COCCNc1cc(NCc2ccc(OC)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Reaction time: 18 h

Procedure:
4-Methoxybenzylamine (485 mg, 3.53 mmol) was added to 2-chloro-N-(2-methoxyethyl)-5-(trifluoromethyl)pyridin-4-amine (intermediate 86, 300 mg, 1.18 mmol) and heated in a MW in a septum sealed vial at 60° C. for 3 h. Conventional heating was then continued for 18 h at 80° C., the reaction mixture cooled, additional 4-methoxybenzylamine (162 mg, 1.18 mmol) added and heating continued at 100° C. for 22 h. The reaction mixture was then heated for 9 h at 120° C., cooled, partitioned between saturated aqueous NaHCO3 solution and DCM, extracted 3X with DCM, the organic layers dried over Na2SO4 and evaporated. The residue was applied to a 24 g RediSep® silica column as a DCM solution and purified by normal phase chromatography, eluting with a gradient from DCM to 20% EtOAc in DCM. Product containing fractions were combined and evaporated to give the title compound as a white solid. (UPLC-MS 6) tR 0.77; ESI-MS 356.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:4]=1[C:5]([O:7][CH3:8])=[O:6])#[N:2].[Br:14]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)Cl>[Br:14][CH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(C)cccc1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(C#N)cccc1CBr

Procedure:
To a solution of EXAMPLE 6B (2.37 g) in chloroform (30 mL) was added N-bromosuccinimide (2.41 g) and AIBN (4 mg), and the mixture was heated at reflux for 18 hours. After cooling, the solvent was removed, and the concentrate was partitioned between ethyl acetate and water. The extract was washed with brine and concentrated, and the concentrate was purified by flash chromatography on silica gel with 20% ethyl acetate in hexanes.
Reaction SMILES: CS[C:3]1[C:9]2=[N:10][N:11]=[N:12][N:8]2[CH2:7][C:6]2[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=2[N:4]=1.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1>>[CH3:24][N:21]1[CH2:22][CH2:23][CH:18]([NH:17][C:3]2[C:9]3=[N:10][N:11]=[N:12][N:8]3[CH2:7][C:6]3[CH:13]=[CH:14][CH:15]=[CH:16][C:5]=3[N:4]=2)[CH2:19][CH2:20]1
Reactant: CSC1=Nc2ccccc2Cn2nnnc21
Reactant: CN1CCC(N)CC1
Product: CN1CCC(NC2=Nc3ccccc3Cn3nnnc32)CC1
Yield: 49 %

Procedure:
To a solution of 5.0 g. (22 mmol.) of 11-Methylthio-5H-tetrazolo[5,1-c][1,4]benzodiazepine in 15 ml. of 4-amino-1-methylpiperidine is heated at 115° C. for 18 hours. The excess amine is evaporated and the resulting solid is triturated with water. Recrystallization from ethanol-water gives the title product in 49% yield (m.p. 112°-114° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([OH:13])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc2cccc(O)c2n1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2ccc(OC)nc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 93.7 %

Procedure:
To a solution of 2-methoxyquinolin-8-ol (500 mg, 2.86 mmol) in MeCN (10 mL) was added ethyl 2-bromoacetate (501 mg, 3.0 mmol) and K2CO3 (789 mg, 5.72 mmol). The mixture was stirred at 80° C. for 5 h. The mixture was filtered and the filtrate evaporated to give the desired compound (700 mg, yield 94%). LCMS (m/z): 262.1 [M+H]+
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:14])[CH2:6][CH2:5]2)(=[O:31])=[O:30])=[CH:27][CH:28]=1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: COc1ccc(S(=O)(=O)NC2CCN(CCCC(=O)c3ccccc3)CC2)cc1

Procedure:
Using an analogous procedure to Example 2 4-amino-1-(4-phenyl-4-oxobutyl)piperidine dihydrochloride may be reacted with p-methoxybenzenesulphonyl chloride to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.[F:11][C:12]1[CH:31]=[CH:30][C:15]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=2)=[O:19])=[CH:14][CH:13]=1.CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([S:26]([C:23]2[CH:22]=[CH:21][C:20]([C:18]([NH:17][CH2:16][C:15]3[CH:30]=[CH:31][C:12]([F:11])=[CH:13][CH:14]=3)=[O:19])=[CH:25][CH:24]=2)(=[O:27])=[O:28])[N:3]=1
Reactant: Clc1n[nH]c2ccccc12
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2nc(Cl)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
Dissolve 3-chloro-1H-indazole (120 mg, 0.79 mmol) and 4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (114 mg, 0.35 mmol) in CH2Cl2 (2.0 mL) and treat with Et3N (50 L, 0.36 mmol). Stir the solution for 1 h at RT, then dilute with additional CH2Cl2 (20.0 mL) and wash with satd aq. NaHCO3 (15 mL). Dry, filter, and concentrate the organic phase and purify the crude material by flash chromatography (100% hexanes to 50% EtOAc/hexanes linear gradient) to give the title compound (129 mg, 83%) as a white foam. MS (ES+) 443.9 (M+1)+, (ES−) 442.0 (M−1)−. 1H NMR (400 MHz, CDCl3): δ 8.17 (d, 1H, J=8.3), 8.03 (d, 2H, J=8.2), 7.83 (d, 2H, J=8.9), 7.64 (m, 2H), 7.41 (t, 1H, J=7.4), 7.27 (m, 2H), 7.01 (t, 2H, J=8.9), 6.31 (br s, 1H), 4.57 (d, 2H, J=5.9).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=O)(C)(C)C.C(N(CC)CC)C.[O:29]1[C:34]2[CH:35]=[CH:36][C:37]([C:39](Cl)=[O:40])=[CH:38][C:33]=2[O:32][CH2:31][CH2:30]1>ClCCl>[S:19]1[CH2:20][CH2:21][N:17]([C:15]([C@H:9]2[NH:8][CH2:12][C@@H:11]([CH2:13][NH:14][C:39]([C:37]3[CH:36]=[CH:35][C:34]4[O:29][CH2:30][CH2:31][O:32][C:33]=4[CH:38]=3)=[O:40])[CH2:10]2)=[O:16])[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Reactant: O=C(Cl)c1ccc2c(c1)OCCO2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC[C@@H]1CN[C@H](C(=O)N2CCSC2)C1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 17D (31.6 mg, 0.1 mmol) in anhydrous dichloromethane (1 mL) was added triethylamine (0.021 mL, 0.15 mmol) followed by 2,3-dihydro-1,4-benzodioxine-6-carbonyl chloride (23.8 mg, 0.12 mmol). The mixture was shaken overnight at room temperature and concentrated under reduced pressure, MS (APCI) m/e 472 (M+H)+. The residue was dissolved in anhydrous dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL) was added. The mixture was allowed to stir for 5 hours at room temperature, concentrated under reduced pressure, and the residue purified by reverse-phase HPLC to provide the titled compound. MS (ESI) m/e 372 (M+H)+; 1H NMR (500 MHz, CD3OD): δ ppm 1.75-2.4 (m, 1 H), 2.74 (m, 2 H), 3.15 (m, 3 H), 3.33 (m, 1 H), 3.47 (m, 3 H), 3.75 (m, 1 H), 3.87 (m, 1 H), 4.28 (m, 4 H), 4.51 (m, 1H), 4.66 (m, 2 H), 6.90 (dd, 1 H), 7.33 (m, 2 H).
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH2:28]([NH2:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)(Cl)Cl>[CH2:28]([NH:35][C:12]([C:9]1[C:8](=[O:15])[N:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]2=[N:11][CH:10]=1)=[O:14])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCN
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCNC(=O)c1cnc2cccc(C)n2c1=O
Reaction time: 0.08 h
Yield: 70.5 %

Procedure:
A mixture containing 16.32 g (0.08 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 12.4 ml (0.088 mol) of triethylamine in 480 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 6.5 ml (0.08 mol) of methyl chloroformate in 40 ml of chloroform is dropped to the above mixture at a temperature between -12° C. and -15° C. during 20 minutes. After stirring for 5 minutes, 10.14 g (0.088 mol) of heptylamine dissolved in 80 ml of chloroform are dropped to the above solution at a temperature between -11° C. and -16° C. during 50 minutes. The reaction mixture is stirred at the same temperature for 1 hour and then allowed to stand under cooling by ice. For working up, the reaction mixture is washed 3 times with 150 ml of 5% sodium hydrogen carbonate solution each and then 3 times with 150 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to give 17.0 g (70.5%) of the named product as orange yellow crystals, m.p.: 118°-120° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1.CN(C=O)C.S(Cl)([Cl:26])=O>>[Cl:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[N:4][CH:3]=1
Reactant: COCCOc1cc2nncc(O)c2cc1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COCCOc1cc2nncc(Cl)c2cc1OC
Yield: 74 %

Procedure:
The starting material 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline was obtained by heating a solution of 4-hydroxy-6-methoxy-7-(2-methoxyethoxy)cinnoline (7.8 g, 0.031 mol) in thionyl chloride (130 ml) containing DMF (0.8 ml) at 80° C. for 2 hours. After dilution with toluene, the mixture was evaporated to dryness. The resulting solid was filtered off, washed with ether, and then dissolved in ethyl acetate. The ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate solution and then brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography using methylene chloride/ethyl acetate (1/9) as eluent to give 4-chloro-6-methoxy-7-(2-methoxyethoxy)cinnoline (6.2 g, 74%).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4]([Br:16])[CH:5]=[CH:6]3)[CH:2]=1)=O.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.C(O)(=O)C>O>[Br:16][C:4]1[CH:5]=[CH:6][C:7]2[C:14](=[O:15])[N:17]([C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=3)[C:11](=[O:13])[C:9]3[C:8]=2[C:3]=1[CH:2]=[CH:1][CH:10]=3
Reactant: O=C1OC(=O)c2ccc(Br)c3cccc1c23
Reactant: Cc1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(N2C(=O)c3cccc4c(Br)ccc(c34)C2=O)cc1
Reaction time: 10 h
Yield: 87 %

Procedure:
A mixture of 4-Bromo 1,8 naphthalic anhydride (10 g), p-toluidine (4.08 g) and acetic acid (75 ml) was refluxed with stirring for 10 hours. Water (200 ml) was added at room temperature, the separated solid was filtered, washed with acetic acid followed by water and dried at 100° C. for 8 hours to yield 11.5 g of the product.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:12][C:13]([CH3:15])=[CH2:14])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1.C(OCC)(=O)C>[OH:6][CH2:5][C:4]1[C:3]([CH2:12][C:13]([CH3:15])=[CH2:14])=[C:2]([OH:1])[CH:11]=[CH:10][CH:9]=1
Reactant: C=C(C)Cc1c(O)cccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)Cc1c(O)cccc1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 101.5 %

Procedure:
Methyl 3-hydroxy-2-(2-methylallyl)benzoate (Intermediate 168, 410 mg, 1.99 mmol) was dissolved in tetrahydrofuran (5 ml) to give a colourless solution. The reaction mixture was cooled at 0° C. A solution of LiAlH4 2M in THF (1.09 ml, 2.19 mmol) was added dropwise and the reaction mixture was stirred at 0° C. for 30 min. After this time the reaction mixture was poured into ice and diluted with 60 ml of ethyl acetate. Phases were separated, the organic phase was dried over Na2SO4 and evaporated under vacuum to afford the title compound (360 mg) as a colorless oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11](=O)[C:12]([OH:14])=[O:13])=[CH:2]1.CC1C(O)=C(CN)C(COP(O)(O)=O)=C[N:18]=1.P([O-])([O-])([O-])=O>O>[NH2:18][C@H:11]([C:12]([OH:14])=[O:13])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: Cc1ncc(COP(=O)(O)O)c(CN)c1O
Reactant: O=C(O)C(=O)Cc1c[nH]c2ccccc12
Agent: O=P([O-])([O-])[O-]
Solvent: O
Product: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Temperature: 37 °C
Reaction time: 2 h

Procedure:
To a solution containing 20.3 g (100 mmol) of indole-3-pyruvic acid and 26.5 g (100 mmol) of pyridoxamine-5-phosphate in 1000 ml of distilled water buffered at pH 6.5 with 0.5M phosphate buffer and maintained at 37° C., is added 50 mg of the monoclonal antibodies prepared according to Example 15. The reaction mixture is gently agitated for 2 hours. The monoclonal antibodies are then recovered by ultrafiltration. Dialysis of the reaction mixture followed by lyophilization yields the product L-tryptophan.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=1[O:26][CH3:27])=O>CC(C)=O>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[C:16]1[N:1]=[C:2]([C:3]2[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=2[CH3:8])[S:13][CH:15]=1
Reactant: COc1ccc(C(=O)CBr)c(OC)c1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccc(OC)cc3OC)cs2)c(C)s1
Yield: 54.8 %

Procedure:
99 mg (0.424 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-2′,4′-dimethoxyacetophenone (0.440 mmol; 114 mg) was added and the solution was allowed to reflux for 2.5 h. The solution was allowed to cool and the crude product was collected as a solid and washed with methanol and dried yielding 91 mg (56% yield) of methyl 4-[4-(2,4-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.[CH2:17]([OH:20])[CH:18]=[CH2:19].[H-].[Na+]>CN(C)C=O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=[C:2]([O:20][CH2:17][CH:18]=[CH2:19])[CH:7]=1
Reactant: Clc1cc(Cl)nc(OCc2ccccc2)n1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(Cl)nc(OCc2ccccc2)n1
Temperature: 25 °C

Procedure:
4,6-Dichloro-2-(phenylmethoxy)pyrimidine (Compound I-173) (1.5 g, 5.9 mmol) and allyl alcohol (0.342 g, 5.9×1.0 mmol) were introduced into a 50 ml eggplant type flask, to which dimethylformamide (20 ml) was added to form a solution. While cooling with ice, 60% sodium hydride (0.247 g, 5.9×1.05 mmol) which had been washed with hexane was added. After stirred for one night at room temperature, the reaction solution was poured into iced water and extracted with toluene (40 ml). The organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and thereafter, the solvent was distilled off to afford an oily product, which was then purified on silica gel column chromatography (Wakogel C300, 300 ml, hexane/ethyl acetate=25/1000(v/v)) to obtain the compound (I-343).
Reaction SMILES: [C:1]1([C@@H:7]([CH2:9][OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11](OCC)(=[O:15])[C:12]([CH3:14])=O>C(O)C(F)(F)F>[CH3:14][C:12]1[C:11](=[O:15])[O:10][CH2:9][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: CCOC(=O)C(C)=O
Reactant: N[C@H](CO)c1ccccc1
Solvent: OCC(F)(F)F
Product: CC1=N[C@@H](c2ccccc2)COC1=O
Yield: 44.2 %

Procedure:
(S)-2-phenylglycinol (3.00 g, 21.9 mmol, 1.0 equiv.) and ethyl pyruvate (2.67 mL, 24.1 mmol, 1.1 equiv.) were refluxed in trifluoroethanol (50 mL) over activated 4 molecular sieves (8.00 g) for 24 hours. Filtration through a short pad of CELITE® diatomaceous earth and removal of solvent from the filtrate in vacuo generated the crude product which was purified by flash column chromatography on silica, eluting with petrol and diethyl ether (7:3) to furnish the title compound as a white solid (1.83 g, 44%); m.p. 70.0-71.0° C. (lit 71.0-72.0° C.); v(max)(KBr) 3007 (C—H), 1735 (C═O), 1640 (C═N) cm−1; δH, (250 MHz, CDCl3) 7.45-7.32 (5H, m, Ph), 4.88-4.81 (1H, m, PhCH), 4.56 (1H, dd, J 4.49 Hz, T 9.48 Hz, 6β-H), 4.25 (1H, dd/13.01 Hz, JT 14.99 Hz, 6α-H), 2.41 (3H, s, CH3); δc (62.5 MHz CDCl3) 160.7, 155.9, 137.2, 129.4, 128.7, 127.5, 71.9, 60.1, 22.2; m/z (CL, NH3), 189 (M+, 25%), 159 (12%), 130 (24%), 104 (100%), 90 (21%), and 78 (6%); HRMS for C11HnNO2 requires 189.0787 found 189.0782. [α]D20 +253.0 (c 0.98 CHCl3) (the enantiomer lit. [α]D20 −237.1 (c 1.11 CHCl3)).
Reaction SMILES: [I:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>O1CCCC1>[NH2:15][C:9]1[C:8]([O:7][C:6]2[CH:16]=[C:2]([I:1])[C:3]([O:20][CH3:21])=[CH:4][C:5]=2[CH:17]([CH3:19])[CH3:18])=[CH:13][N:12]=[C:11]([NH:14][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[N:10]=1
Reactant: CC(C)C(=O)Cl
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(Oc2cnc(NC(=O)C(C)C)nc2N)cc1I
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (1 g, 2.50 mmol), dissolved in anhydrous tetrahydrofuran, was added triethylamine (0.38 mL, 2.75 mmol) and isobutyryl chloride (0.29 mL, 2.75 mmol). After stirring 30 minutes, the reaction was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), and the dichloromethane layer was washed with water, dried using anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography eluting with 96/4/0.1 dichloromethane/methanol/ammonium hydroxide yielded 634 mg (54%) of N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-isobutyramide as pale yellow solid, MS (M+H)=471.
Reaction SMILES: C([NH:8][CH:9]([CH:11]=[CH:12][CH:13]1[C:17]([CH3:19])([CH3:18])[CH2:16][CH2:15][C:14]1([CH3:21])[CH3:20])[CH3:10])(OC(C)(C)C)=O.O.[OH-].[K+]>FC(F)(F)C(O)=O>[NH2:8][CH:9]([CH:11]=[CH:12][CH:13]1[C:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][C:17]1([CH3:18])[CH3:19])[CH3:10]
Reactant: CC(C=CC1C(C)(C)CCC1(C)C)NC(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(N)C=CC1C(C)(C)CCC1(C)C
Reaction time: 8 h

Procedure:
N-Boc-2-amino-4-(2,2,5,5-tetramethyl-1-cyclopentyl)-3-butene is dissolved in trifluoroacetic acid and the solution is stirred overnight. Water is added and the mixture is made basic with 20% KOH. The mixture is extracted with ether, and the organic layer is dried over Na2SO4 and evaporated to yield 2-amino-4-(2,2,5,5-tetramethyl-1-cyclopentyl)-3-butene.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].CO[CH:32]([N:35]([CH3:37])[CH3:36])OC>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:8][C:9]=1[N:10]=[CH:32][N:35]([CH3:37])[CH3:36])=[O:4]
Reactant: COC(=O)c1sc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1N
Reactant: COC(OC)N(C)C
Product: COC(=O)c1sc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1N=CN(C)C

Procedure:
3-Amino-5-(tert-butyldiphenylsilanyloxymethyl)thiophene-2-carboxylic acid methyl ester and dimethoxymethyldimethylamine were reacted by method B. The product with the molecular weight of 480.71 (C26H32N2O3SSi) was obtained in this way; MS (ESI): 481 (M+H+).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:12][CH:11]=1.C(O)(=O)C>CO>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:2][CH2:1][C:3]3[CH:8]=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: C=Cc1cnccn1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Solvent: CO
Solvent: CC(=O)O
Product: Fc1ccc(Cn2c(NC3CCN(CCc4cnccn4)CC3)nc3ccccc32)cc1

Procedure:
A mixture of 1.27 parts of 2-ethenylpyrazine, 6.48 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 0.3 parts of acetic acid and 40 parts of methanol was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (88:12 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was washed with 2,2'-oxybispropane and crystallized from 27 parts of methylbenzene, yielding 2.4 parts of 1-(4-fluorophenylmethyl)-N-[1-[2-(2-pyrazinyl)ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 165.3° C. (compound 101).