Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:9][OH:10])([CH2:7][OH:8])[C:4]([OH:6])=[O:5].[N+](=[CH2:13])=[N-].C(OCC)C>CO>[OH:1][CH2:2][C:3]([CH2:9][OH:10])([CH2:7][OH:8])[C:4]([O:6][CH3:13])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: O=C(O)C(CO)(CO)CO
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(CO)(CO)CO
Temperature: 25 °C

Procedure:
To a stirred solution of 3-hydroxy-2,2-bis(hydroxymethyl)propanoic acid, prepared according to EP 751223 A2, in MeOH at rt is added dropwise 2 M trimethylsilyl)diazomethane/diethyl ether (1-5 equivalents) and the mixture is stirred at rt until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is concentrated under reduced pressure and the residue is partitioned between saturated aq sodium bicarbonate solution and dichloromethane. The organic layer is separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel flash chromatography to afford methyl 3-hydroxy-2,2-bis(hydroxymethyl)propanoate.
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C:11]([CH3:33])([CH3:32])[CH2:12][N:13]1[C:25]2[C:24]3[N:23]=[CH:22][C:21]([Br:26])=[CH:20][C:19]=3[N:18]=[C:17]([NH2:27])[C:16]=2[N:15]=[C:14]1[CH2:28][O:29][CH2:30][CH3:31].[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[NH2:27][C:17]1[C:16]2[N:15]=[C:14]([CH2:28][O:29][CH2:30][CH3:31])[N:13]([CH2:12][C:11]([NH:10][S:35]([CH3:34])(=[O:37])=[O:36])([CH3:32])[CH3:33])[C:25]=2[C:24]2[N:23]=[CH:22][C:21]([Br:26])=[CH:20][C:19]=2[N:18]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(Br)cnc3c2n1CC(C)(C)NS(C)(=O)=O
Temperature: 4 °C
Reaction time: 24 h
Yield: 85.7 %

Procedure:
Triethylamine (13.02 g, 128.7 mmol) was added to a suspension of 1-(2-amino-2-methylpropyl)-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine dihydrochloride (6.00 g, 12.9 mmol) in dichloromethane (500 mL), and the reaction was cooled to 4° C. A solution of methanesulfonyl chloride (1.62 g, 14.2 mmol) in dichloromethane (10 mL) was then added dropwise. The reaction mixture was allowed to warm to room temperature, stirred for 24 hours, diluted with dichloromethane (200 mL), washed sequentially with water (200 mL), 4% aqueous sodium carbonate (2×200 mL), water (200 mL), and brine (200 mL), and concentrated under reduced pressure. The crude product was purified by automated flash chromatography (FLASH 40+M silica cartridge, eluting with 0 to 25% CMA in chloroform) followed by recrystallization from acetonitrile to provide 5.21 g of N-{2-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]-1,1-dimethylethyl}methanesulfonamide as a white solid, 211-212° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH2:7](O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:7]([O:5][C:4](=[O:6])[CH2:3][C:1]#[N:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CCC(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: N#CCC(=O)OCc1ccccc1

Procedure:
To a mixture of cyanoacetic acid (VII) 2.34 g (27.5 mmol) and benzyl alcohol (VIIIa) 2.70 g (25 mmol) in 60 mL of toluene 50 mg of p-TsOH was added and the mixture was refluxed in a flask with a Dean-Stark trap for 24 h. The mixture was cooled down and toluene was washed with H2O and toluene was evaporated. The residue was distilled in vacuo (Kugelrohr apparatus, 0.1 mm Hg, T. oven 170-180° C.). Yield 3.36 g (77%), a colorless oil. MS (m/z, rel. intensity, %): 167.0 ([M+NH4−CN]+, 27), 193.0 ([M+NH4]+, 100).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:16][CH3:17])[C:5]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[N:6][C:7]=1[CH2:8][CH3:9].[CH3:18][O:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][CH2:25][CH2:26]2)=[CH:22][C:21]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH2:16]([C:4]1[C:5]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[N:6][C:7]([CH2:8][CH3:9])=[C:2]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][C:20]=2[O:19][CH3:18])[CH2:26][CH2:25][CH2:24]3)[N:3]=1)[CH3:17]
Reactant: COc1cc2c(cc1B(O)O)CCC2
Reactant: CCc1nc(NC(CC)CC)c(CC)nc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCc1nc(-c2cc3c(cc2OC)CCC3)c(CC)nc1NC(CC)CC
Temperature: 80 °C
Yield: 66.1 %

Procedure:
A scintillation vial with a Teflon lined cap was charged with 5-bromo-3,6-diethyl-N-(1-ethylpropyl)pyrazin-2-amine (300.2 mg, 1 mmol), 6-methoxy-2,3-dihydro-1H-inden-5-ylboronic acid (211.2 mg, 1.1 mmol, Preparation 2), terakis(triphenylphosphine)palladium (0) (116 mg, 0.1 mmol), 2M Na2CO3 (1 mL, 2 mmol), and ethylene glycol dimethyl ether (6 mL). The reaction was heated on the orbital shaker to 80° C. for 30 hours. After cooling to ambient temperature, the reaction was partitioned between H2O and ethyl acetate. The aqueous layer was extracted one more time with ethyl acetate. The organics were combined, dried with Na2SO4, filtered and concentrated to 530 mg of a yellow crude oil. The crude was purified by Biotage MPLC (90 g column, 1.5% acetone in toluene) to give 243 mg (66%) of 3,6-diethyl-N-(1-ethylpropyl)-5-(6-methoxy-2,3-dihydro-1H-inden-5-yl)pyrazin-2-amine as a pale yellow oil. Rf 0.19 (10% ethyl acetate in heptane). IR (liq.) 2964, 2935, 2874, 1566, 1550, 1484, 1464, 1444, 1391, 1380, 1276, 1253, 1203, 1174, 1033 cm−1. OAMS supporting ions at: ESI+368.3. HRMS (ESI) calcd for C23H33N3O+H1 368.2702, found 368.2703. Anal. Calcd for C23H33N3O: C, 75.16; H, 9.05; N, 11.43. Found: C, 75.25; H, 9.15; N, 11.13.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[O:19])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:28])=[CH:7][CH:8]=2)[N:3]=1.[C:29]1([N:35]=[C:36]=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC#N.ClCCCl>[Cl:28][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([N:12]3[CH2:13][CH2:14][N:15]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)=[O:19])[CH2:16][CH2:17]3)=[CH:11][C:2]([NH:1][C:36]([NH:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:37])=[N:3]2)=[CH:8][CH:7]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1
Solvent: ClCCCl
Solvent: CC#N
Product: O=C(Nc1ccccc1)Nc1cc(N2CCN(C(=O)Nc3ccc(F)cc3)CC2)c2ccc(Cl)cc2n1

Procedure:
To a solution of 2-amino-7-chloro-4-[4-(4-fluorophenylaminocarbonyl)piperazin-1-yl]quinoline (20 mg, 0.05 mmol) in MeCN-1,2-dichloroethane 1:1 (12 mL) is added phenyl isocyanate (17 μL, 0.11 mmol). The reaction mixture is heated at reflux for 1 h. Upon cooling the title product precipitates and is collected by filtration.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>>[Br:1][C:2]1[S:6][C:5]([S:7]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: c1cc[nH]c1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Product: O=S(=O)(c1ccc(Br)s1)n1cccc1
Yield: 88 %

Procedure:
N-(5-bromothiophene-2-sulfonyl)pyrrole was prepared in the same manner as described in Example 33A from 5-bromothiophene-2-sulfonyl chloride and pyrrole in 88% yield. This was purified by recrystallization using hexane/ethyl acetate as a solvent.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:26])([CH3:25])[O:6][CH2:7][C@H:8]([CH3:24])[C@@H:9]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C@@H:10]([CH3:13])[CH:11]=O)([CH3:4])[CH3:3].Br[CH:28]([Si](C)(C)C)[CH:29]=[CH2:30].CO.[OH-].[K+]>C1COCC1>[CH3:1][C:2]([Si:5]([O:6][CH2:7][C@H:8]([CH3:24])[C@@H:9]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)[C@@H:10]([CH3:13])/[CH:11]=[CH:30]\[CH:29]=[CH2:28])([CH3:26])[CH3:25])([CH3:4])[CH3:3]
Reactant: COc1ccc(CO[C@@H]([C@@H](C)C=O)[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc1
Reactant: C=CC(Br)[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C=C/C=C\[C@H](C)[C@H](OCc1ccc(OC)cc1)[C@@H](C)CO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A suspension consisting of CrCl2 (12.93 g, 105.38 mmol) and 700 mL anhydrous THF is cooled to 0° C. 2,4-dideoxy-5-O-[(1,1-dimethylethyl)dimethylsilyl]-3-O-[(4-methoxyphenyl)methyl]-2,4-dimethyl-L-lyxose (8.9 g, 23.42 mmol) in 40 mL THF is added dropwise. (1-Bromoallyl) trimethylsilane (22.61, 117.1 mmol) is added neat. After 3 h at room temperature, the reaction mixture is cooled to 10° C. Methanol (270 mL) and 6 N aqueous KOH (550 mL) are added in sequence, keeping the reaction temperature less than 20° C. during the addition. The mixture is stirred overnight at room temperature. The organic layer is separated. The aqueous layer is extracted with ether (3×400 mL). The combined organic phase is washed with brine, dried over NaSO4, and concentrated. Flash chromatography gives the desired compound (6.74 g, 71.2%) as a clear oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:7][C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2.[H-].[Li+].CN(C)C=O.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCc2c1ccc(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (5.0 g), lithium hydride (0.37 g), and dimethylformamide (200 ml) was stirred at 25° C. for 3 hrs. Benzyl bromide (5.5 g) was added and the mixture was stirred for 20 hrs. Water was added, and the mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The layers were separated and combined organic phase was washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was triturated with hexanes to provide 4.5 (58%) of 5,6,7,8-tetrahydro-5-oxo-1-phenylmethyl-2(1H)-quinolinone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH:12]CC2C=CC(OC)=CC=2OC)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C[Li].[CH3:26][C:27]([CH3:29])=[O:28].FC(F)(F)C(O)=O>C1COCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([S:9]([NH2:12])(=[O:10])=[O:11])[C:27]([OH:28])([CH3:29])[CH3:26])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: COc1ccc(CNS(=O)(=O)Cc2cccc(Cl)c2)c(OC)c1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(C)(O)C(c1cccc(Cl)c1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under inert gas, 1.65 g of C-(3-chlorophenyl)-N-(2,4-dimethoxybenzyl)methanesulfonamide were initially charged in 30 ml of THF, and then, at a temperature of −75° C., 6.67 ml of a 1.6 N methyllithium solution in diethyl ether were added dropwise and the mixture was stirred at constant temperature for 10 minutes. Subsequently, 1.86 ml of acetone were added. After stirring for 5 minutes, the reaction solution was admixed with 15 ml of trifluoroacetic acid and allowed to warm up to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in 10 ml of dichloromethane, and 2.5 ml of trifluoroacetic acid were added. After stirring at room temperature for 2 hours, the reaction solution was admixed with 50 ml of water, and the solid which precipitated out was filtered off with suction and washed with water. For drying, the product was coevaporated twice more with toluene. This gave the product (1.16 g) with a molecular weight of 263.7 g/mol (C10H14ClNO3S).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][N:4]=1.C([Li])CCC.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH:21]=[O:22].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[OH:22])=[CH:5][N:4]=1
Reactant: O=Cc1ccccn1
Reactant: COc1ccc(Br)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2ccccn2)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 44.6 %

Procedure:
50 ml of a tetrahydrofuran solution containing 3.00 g of 2-methoxy-5-bromopyridine was cooled to −78° C., followed by the dropwise addition of 10 ml of n-butyl lithium (1.6M hexane solution). After the completion of the dropwise addition, 1.70 g of picoline aldehyde was immediately added thereto, followed by stirring at −78° C. for 1 hour, to return the mixture slowly to room temperature. To the mixture was added a saturated aqueous solution of ammonium chloride, and then it was extracted with ethyl acetate. The ethyl acetate layer was washed with water and brine, and then dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel chromatography (ethyl acetate), to give 1.53 g of the title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH2:23])[C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][N:12]1[C:16]2[NH:17][C:18]([NH2:22])=[N:19][C:20](=[O:21])[C:15]=2[N:14]=[CH:13]1)=[O:6])[CH3:3].[CH:24]([O-])=[O:25].[NH4+]>CN1CCCC1=O>[CH3:3][CH:2]([C@H:4]([NH:23][CH:24]=[O:25])[C:5]([O:7][CH2:8][CH2:9][O:10][CH2:11][N:12]1[C:16]2[NH:17][C:18]([NH2:22])=[N:19][C:20](=[O:21])[C:15]=2[N:14]=[CH:13]1)=[O:6])[CH3:1]
Reactant: O=C[O-]
Reactant: CC(C)[C@H](N)C(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21
Agent: [NH4+]
Solvent: CN1CCCC1=O
Product: CC(C)[C@H](NC=O)C(=O)OCCOCn1cnc2c(=O)nc(N)[nH]c21
Temperature: 125 °C

Procedure:
A 100 ml round bottom flask equipped with magnetic stir bar is charged with 7.25 gr Valacyclovir (20 mmol), 1.97 gr ammonium formate (31.2 mmol), NMP (N-Methyl-pyrrolidone) (15 ml) is added and stirring is started. The resulting mixture is placed in an oil bath that is heated to 125° C. for 2 hrs. The mixture is removed from the oil bath, allowed to cool to room temperature, and the solvent is removed under reduced pressure using high vac. pump. The residue is crystallized from 150 ml boiling water to give 6.0 gr at the purity of 80%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:5]=[C:6]([C:8]2([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.[CH3:27]I>>[F:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:5]=[C:6]([C:8]2([O:14][CH3:27])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1
Reactant: OC1(c2cc(F)cc(OCc3ccc4ccccc4c3)c2)CCOCC1
Reactant: CI
Product: COC1(c2cc(F)cc(OCc3ccc4ccccc4c3)c2)CCOCC1
Yield: 98 %

Procedure:
Using the procedure described in Example 3, 4-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-4-hydroxytetrahydropyran was reacted with methyl iodide to give 4-[5-fluoro-3-(naphth-2-ylmethoxy)phenyl]-4-methoxytetrahydropyran in 98% yield, m.p. 109°-111° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:13])=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].C1C(=O)N([Br:21])C(=O)C1>CN(C=O)C>[Br:21][C:9]1[C:10]([O:11][CH3:12])=[C:2]([F:1])[C:3]([OH:13])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C(=O)O)c(O)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COc1c(Br)cc(C(=O)O)c(O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-fluoro-2-hydroxy-4-methoxybenzoic acid (7.30 g) in DMF (70.0 mL) was added NBS, and the mixture was stirred at 25° C. for 2 hr. The solvent was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (8.86 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:9]=2[CH2:10]Cl)=[CH:4][C:3]=1[CH3:18].C([O:21][P:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C>>[C:23]1([P:22]([CH2:10][C:9]2[C:12]([CH3:17])=[CH:13][C:14]([CH3:16])=[CH:15][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:18])[CH:4]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:21])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOP(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)c(CCl)c(-c2ccc(F)c(C)c2)c1
Product: Cc1cc(C)c(CP(=O)(c2ccccc2)c2ccccc2)c(-c2ccc(F)c(C)c2)c1
Temperature: 150 °C

Procedure:
2.06 grams (7.84 mmol) of 2-(4-fluoro-3-methyl-phenyl)-4,6-dimethylbenzyl chloride was treated with ethyldiphenylphosphinite (2.08 grams, 9.01 mmol) and heated to 150° C. for 3 hrs. After cooling to room temperature, the crude mixture was purified by silicagel chromatography ((10% acetone/90% methylene chloride) and the appropriate fractions concentrated and recrystallized from ether/hexane to provide the title compound (MP 109-111° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:27]([O:29][CH2:30][C@@H:31]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[NH:32][C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])=[O:28])[CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:14]C1CCCCO1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH2:1]([O:8][C:9]([NH:11][CH:12]([C:27]([O:29][CH2:30][C@@H:31]([C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40])[NH:32][C:33](=[O:38])[C:34]([F:37])([F:35])[F:36])=[O:28])[CH:13]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC(C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1)C(OC1CCCCO1)c1ccccc1)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: O=C(NC(C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1)C(O)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
To a solution of benzyl O-(N-benzyloxycarbonyl-3-phenyl-O-tetrahydropyranyl-D,L-serinyl)-N-trifluoroacetyl-L-serinate (0.8 g) in methanol (10 ml) was added p-toluenesulfonic acid (45.6 mg) at room temperature. After stirring for an hour at room temperature, the reaction mixture was concentrated and the residue was chromatographed on preparative thin layer chromatography to give benzyl O-(N-benzyloxycarbonyl-3-phenyl-D,L-serinyl)-N-trifluoroacetyl-L-serinate (404 mg).
Reaction SMILES: C(OC(N([C@@H]1CCN(S([C:18]2[C:19]3[C:20](Br)=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=O)=O)C1)C)=O)(C)(C)C.C(O[C:34]([N:36]([C@@H:38]1CCN[CH2:39]1)C)=O)(C)(C)C>>[CH2:23]([N:22]1[CH2:21][CH2:20][C@@H:38]([NH:36][CH3:34])[CH2:39]1)[C:24]1[CH:19]=[CH:18][CH:27]=[CH:26][CH:25]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Product: CN[C@@H]1CCN(Cc2ccccc2)C1

Procedure:
(R)-3-[N-(tert-Butoxycarbonyl)-N-methylamino]-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine (Intermediate 20b) can be prepared by using (R)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine obtained from (R)-1-benzyl-3-(methylamino)pyrrolidine (Tokyo Kasei Kogyo) instead of (S)-3-[N-(tert-butoxycarbonyl)-N-methylamino]pyrrolidine according to the method described in a known literature (Barlocco et al., Tetrahedron, 1995, 51, 11547) in Example 1-3, Step A, and used in the method of Example 1-3, Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11]O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.P(Br)(Br)[Br:14]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][Br:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OCC1(c2ccc(Br)cc2)CC1
Reactant: BrP(Br)Br
Product: BrCC1(c2ccc(Br)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 1, using [1-(4-bromo-phenyl)-cyclopropyl]-methanol and phosphorus tribromide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25][OH:26])[S:23][CH:24]=1)=[CH:16][CH:15]=3.I[CH3:33]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:29](=[O:30])[N:28]([CH3:31])[C:12]2[N:13]([CH3:27])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:21]=[C:22]([CH2:25][O:26][CH3:33])[S:23][CH:24]=1)=[CH:16][CH:15]=3
Reactant: CI
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CO)n4)ccc3n(C)c21
Product: COCc1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cs1

Procedure:
The process is carried out as in Example 10 above, with the compound from Example 9, 3-(2,4-dichlorophenyl)-6-(2-hydroxymethylthiazol-4-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and iodomethane
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[CH2:5]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([CH3:19])[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[CH:6]=[CH2:7]>O>[CH2:1]([NH:4][C:13]1[N:14]=[C:9]([NH:8][CH2:5][CH:6]=[CH2:7])[C:10]2[S:18][CH:17]=[C:16]([CH3:19])[C:11]=2[N:12]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2c(C)csc12
Reactant: C=CCN
Solvent: O
Product: C=CCNc1nc(NCC=C)c2scc(C)c2n1
Temperature: 140 °C
Yield: 81.4 %

Procedure:
In 2.28 g (40.0 mmol) of allylamine was suspended 250 mg (1.1 mmol) of 4-allylamino-2-chloro-7-methylthieno[3,2-d]pyrimidine, and the resulting mixture was heated in a sealed tube at 140° C. for 24 hours. After the reaction mixture was cooled, 50 ml of water was added thereto, followed by extraction with ethyl acetate (50 ml×3). The organic layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=4/1) to give 233 mg (yield: 85.7%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:15]([CH2:16][N:17]([CH2:24][CH2:25][CH3:26])[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)=[O:7])=[CH:4][C:3]=1[Br:27].[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[NH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH2:43][C:44]([O-:46])=[O:45].[Na+]>>[NH2:1][C:2]1[C:15]([CH2:16][N:17]([CH2:24][CH2:25][CH3:26])[CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[CH:14][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:45][C:44](=[O:46])[CH2:43][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[NH:36][C:30]2[C:29]([Cl:28])=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:35])=[O:7])=[CH:4][C:3]=1[Br:27]
Reactant: CCCN(Cc1cc(C(=O)OCCCCCl)cc(Br)c1N)C1CCCCC1
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Agent: [Na+]
Product: CCCN(Cc1cc(C(=O)OCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc(Br)c1N)C1CCCCC1

Procedure:
This compound was prepared from 4-[4-amino-3-bromo-5-(N-cyclohexyl-n-propylaminomethyl)-benzoyloxy]-n-butyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8. Oil.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[C:13]([O-:16])(O)=O.[Na+].[CH3:18]S(C)=O>C(Cl)Cl>[CH3:18][O:8][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH:13]=[O:16])=[C:3]([O:11][CH3:12])[CH:4]=1
Reactant: O=C([O-])O
Reactant: CS(C)=O
Reactant: COc1cc(C(=O)O)ccc1Br
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(C=O)c(OC)c1
Temperature: 80 °C
Yield: 79 %

Procedure:
To a stirred solution of 4-bromo-3-methoxy-benzoic acid (15.0 g, 58 mmol) in DMSO (150 mL) was added NaHCO3 (20.0 g, 230 mmol). This was heated to 80° C. for 18 hours. The reaction was then cooled to room temperature and the solvent removed under reduced pressure. The crude reaction mixture was then dissolved in DCM (200 mL) and washed with 1N HCl (100 mL), water (100 mL), NaCl (sat.) (100 mL), dried over MgSO4 and then filtered. The solvent was removed under reduced pressure. The crude material was sufficiently pure to use without further purification. The product, 4-formyl-3-methoxybenzoic acid methyl ester, was obtained in 79% yield (8.9 g, 45.8 mmol).