Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][NH:30][C:29]4=[O:33])[CH:25]=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)[N:5]=1.[H-].[Na+].Cl.[Cl:37][CH2:38][C:39]1[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=1>CN(C=O)C>[ClH:37].[ClH:1].[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][N:30]([CH2:38][C:39]5[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=5)[C:29]4=[O:33])[CH:25]=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)[N:5]=1
Reactant: ClCc1ccncc1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCN(Cc6ccncc6)C5=O)c4)CC3)cccc2n1

Procedure:
The title compound was prepared according to the procedure described for Example 156 using 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (Example 85, 50 mg), DMF (1 mL), sodium hydride (60%, 14 mg) and 4-chloromethylpyridine hydrochloride (20 mg). Yield, 19 mg.
Reaction SMILES: [Si:1]([O:8][CH:9]([C:15]1[S:16][C:17]([C:20]2[N:25]=[C:24]([NH:26][C:27]3[CH:31]=[C:30]([CH:32]4[CH2:34][CH2:33]4)[NH:29][N:28]=3)[C:23]([Cl:35])=[CH:22][N:21]=2)=[CH:18][CH:19]=1)[C:10]([O:12]CC)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[Si:1]([O:8][CH:9]([C:15]1[S:16][C:17]([C:20]2[N:25]=[C:24]([NH:26][C:27]3[CH:31]=[C:30]([CH:32]4[CH2:33][CH2:34]4)[NH:29][N:28]=3)[C:23]([Cl:35])=[CH:22][N:21]=2)=[CH:18][CH:19]=1)[C:10]([OH:12])=[O:11])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(O[Si](C)(C)C(C)(C)C)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC(C(=O)O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
To a mixture of ethyl 2-(tert-butyldimethylsilyloxy)-2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)acetate (100 mg, 0.19 mmol, 1.0 eq.) in ethanol (10 mL) was added 1 N NaOH (0.8 mL, 0.76 mmol, 4.0 eq). The mixture was stirred at room temperature for 1 hour, then, concentrated and the residue was redissolved in water. To the solution was added 1N HCl (0.8 mL) and the mixture was stirred for 0.5 h at 23° C. The solution was filtered to give 2-(tert-butyldimethylsilyloxy)-2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophen-2-yl)acetic acid (60 mg, 63.3%). LC-MS (m/z): 506.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH:13]=C)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=C.O=[O+][O-].Cl.[NH2:19][C@@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22].C(N(CC)CC)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.O>[CH3:24][O:23][C:21](=[O:22])[C@@H:20]([N:19]1[CH2:2][CH2:1][N:4]([C:5]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:11])[CH2:12][CH2:13]1)[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: C=CCN(CC=C)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=[O+][O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cooled solution of tert-butyl diallylcarbamate (145 mg, 0.74 mmol) in DCM (15 mL) at −78° C. was bubbled ozone for about 5 minutes. The solution was light blue at that point. Excess ozone was removed by flushing nitrogen through the reaction. To the reaction was added methyl(2S)-2-amino-3-(4-nitrophenyl)propanoate hydrochloride and triethylamine (74 mg, 0.74 mmol), followed by NaB(OAc)3H (940 mg, 4.4 mmol). The reaction was allowed to warm to RT, and stir for an additional 4 hours. The mixture was poured into water, extracted with DCM. The organic layer was washed with brine, dried with MgSO4, and purified by prep-TLC (50% EtOAc and Hexanes) to afford 93 mg of the desired tert-butyl 4-[(1S)-2-methoxy-1-(4-nitrobenzyl)-2-oxoethyl]piperazine-1-carboxylate. LC-MS (IE, m/z): 394 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][OH:22])=[N:14][C:15]=1[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18].Cl[C:24]1[N:29]=[CH:28][N:27]=[C:26]([CH:30]([CH:37]2[CH2:39][CH2:38]2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:25]=1.[H-].[Na+]>C1COCC1.C(OCC)(=O)C.O>[CH:37]1([CH:30]([C:26]2[CH:25]=[C:24]([O:22][CH2:21][C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:15]([CH2:16][C:17]([CH3:19])([CH3:18])[CH3:20])[N:14]=3)[N:29]=[CH:28][N:27]=2)[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:39][CH2:38]1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ncn1)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77.5 %

Procedure:
To a solution of (5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)methanol (504 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (465 mg) in THF (5.0 mL) was added 60% sodium hydride (86 mg) at 0° C., and the mixture was stirred at room temperature for 14 hr. The reaction mixture was diluted with ethyl acetate, and water was added at room temperature. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (672 mg) as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([I:11])=[CH:9][N:10]=2)[N:7]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[I:11][C:8]1[N:6]2[N:7]=[C:2]([NH:15][CH2:14][CH2:12][OH:13])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: Clc1ccc2ncc(I)n2n1
Reactant: NCCO
Product: OCCNc1ccc2ncc(I)n2n1
Yield: 36.8 %

Procedure:
562 mg (2.0 mmol) of 6-chloro-3-iodoimidazo[1,2-b]pyridazine and 2.35 ml (39.2 mmol) of ethanolamine were stirred at 90° C. for 16 h. After cooling, the mixture was concentrated. The resulting residue was purified by chromatography (DCM/EtOH 9:1). 224 mg of the product were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=3)[C:16](Cl)=[O:17])=[N:9]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:14]=[C:15]([CH2:16][OH:17])[CH:19]=[CH:20][CH:21]=3)=[N:9]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(Cn2nnc(-c3cccc(C(=O)Cl)c3)n2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc(-c3cccc(CO)c3)n2)cc1
Temperature: 0 °C
Yield: 84.4 %

Procedure:
The acid chloride (2.5 g, 7.6 mmol) prepared in Step (d) of Example 1 was added to a suspension of lithium aluminum hydride (“LAH”) (0.58 g, 25 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. The reaction mixture gradually warmed to room temperature over two hours. Aqueous HCl was added dropwise to quench excess LAH. The mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was washed with brine, dried (MgSO4), and concentrated. The resulting viscous liquid was triturated with hexane/diethyl ether to yield a pale yellow solid (1.9 g, 84%). Mp 70–72° C.
Reaction SMILES: C(OC([NH:8][CH:9]([C:13]([F:29])([F:28])[CH2:14][CH2:15][CH:16]([NH:20]C(OC(C)(C)C)=O)[C:17]([OH:19])=[O:18])[C:10]([OH:12])=[O:11])=O)(C)(C)C>CCOCC.Cl>[F:28][C:13]([F:29])([CH:9]([C:10]([OH:12])=[O:11])[NH2:8])[CH2:14][CH2:15][C@@H:16]([C:17]([OH:19])=[O:18])[NH2:20]
Reactant: CC(C)(C)OC(=O)NC(CCC(F)(F)C(NC(=O)OC(C)(C)C)C(=O)O)C(=O)O
Agent: Cl
Solvent: CCOCC
Product: NC(C(=O)O)C(F)(F)CC[C@H](N)C(=O)O
Reaction time: 8 h

Procedure:
2,6-di-t-butoxycarbonylamino-3,3-difluoro-1,7-heptanedioic acid (34 mg, 0.08 mmoles) is dissolved in dry ether saturated with HCl gas. After standing overnight and filtration, the title compound is obtained as a white solid (9 mg, 38%, RF: 0.4 (ethanol, conc. ammonia: 70/30, RF: 0.1 (butanol/acetic acid/water: 4/2/2)
Reaction SMILES: [CH3:1][C:2]1[C:3]([Sn](CCCC)(CCCC)CCCC)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:21]([O:25][C:26](=[O:45])[N:27]([CH2:29][C:30]1[CH:34]=[C:33](Br)[N:32]([S:36]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)(=[O:38])=[O:37])[CH:31]=1)[CH3:28])([CH3:24])([CH3:23])[CH3:22]>C1(C)C=CC=CC=1.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>[CH3:28][N:27]([CH2:29][C:30]1[CH:34]=[C:33]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:32]([S:36]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)(=[O:38])=[O:37])[CH:31]=1)[C:26](=[O:45])[O:25][C:21]([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccnc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 25 °C
Yield: 22.3 %

Procedure:
A solution of 3-methyl-2-(tributylstannyl)pyridine (1.0 g), tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (563 mg) and tetrakis(triphenylphosphine)palladium (454 mg) in toluene was stirred under a nitrogen atmosphere at 120° C. for 30 hr. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent:hexane-ethyl acetate=4:1) to give the title compound as a colorless oil (yield 129 mg, 22%).
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:15]([Li])CCC.IC>C1COCC1>[C:1]1([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: O=C(O)Cc1cccc2ccccc12
Solvent: C1CCOC1
Solvent: CI
Product: CC(C(=O)O)c1cccc2ccccc12
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
1-Naphthylacetic acid (10 g, 53.7 mmol) is dissolved in dry THF (150 mL) under nitrogen. The solution is cooled to -10° C., treated with 1.6M butyl lithium in hexanes (72 mL, 115 mmol), and stirred for 15 minutes. A solution of iodomethane (3.7 mL, 59.4 mmol) in dry THF (50 mL) is added, and the mixture is allowed to warm to room temperature and stir for several hours. The solvent is removed in vacuo, and the residue dissolved in 5% sodium hydroxide solution (500 mL), washed with ether (3×200 mL), and then acidified by the addition of 6N hydrochloric acid. The aqueous is then extracted with dichloromethane (3×200 mL), the organic extracts are dried over sodium sulfate, and the solvent removed to leave 2-(1-naphthyl)propionic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:17]=[C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[NH:25]C(=O)OC(C)(C)C)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:33])[CH:14]=2)[N:9]=1)=[O:7].C(OCC)(=O)C.Cl.C(OCC)C>C(OCC)(=O)C>[NH2:25][C@@H:20]1[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:19]1[NH:18][C:16]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:33])[CH:14]=2)[N:9]=[C:8]([C:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])=[O:7])[N:17]=1
Reactant: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)c2cc(C)ccc2n1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COCCNC(=O)c1nc(N[C@H]2CCCC[C@H]2N)c2cc(C)ccc2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92 %

Procedure:
To a suspension of 2.24 g of tert-butyl {(1R,2S)-2-[(2-{[(2-methoxyethyl)amino]carbonyl}-6-methylquinazolin-4-yl)amino]cyclohexyl}carbamate in 10 ml of ethyl acetate, 10 ml of a 4 N hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred at room temperature for 48 hours. To the reaction solution, 20 ml of diethyl ether was added, and the mixture was stirred for 30 minutes. Then, the deposited substance was collected by filtration, washed with diethyl ether and dried under reduced pressure. The resulting powder was purified by Fuji Silysia NH silica gel column chromatography (chloroform:methanol=20:1), whereby 1.61 g of a desired compound was obtained as a colorless powder.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[N:31](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:30]=[N:29][N:28]=4)=[CH:17][CH:16]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[CH:10][C:3]=12.C(Cl)Cl>CO.Cl.[NH4+].[OH-]>[CH2:11]([C:9]1[N:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:4]2=[N:5][CH:6]=[CH:7][CH:2]=[C:3]2[CH:10]=1)[CH2:12][CH3:13]
Reactant: CCCc1cc2c(C)ccnc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCc1cc2cccnc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
To a stirred solution of 4-methyl-2-propyl-1-[[2'-(1-triphenylmethyl-1H-tetrazol-5-yl)[1,1']-biphenyl-4-yl]methyl]-1H-pyrrolo[2,3-b]pyridine (68 mg, 0.11 mmol) in 30 mL of 2:1 MeOH--CH2Cl2 at rt was added 2 drops of conc HCl. After 30 min 3 drops of conc NH4OH were added. Concentration and purification by flash chromatography (SiO2, 25% EtOAc/hexanes) gave 2-propyl-1-[[2'-(1H-tetrazol-5-yl)-[1,1']-biphenyl-4-yl]methyl]-1H-pyrrolo[2,3-b]-pyridine as a solid. FAB MS M+ +1=395.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][N:40]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47](B2OC(C)(C)C(C)(C)O2)[CH:46]=1)[S:41]([CH3:44])(=[O:43])=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:39][N:40]([C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:46]=1)[S:41]([CH3:44])(=[O:42])=[O:43]
Reactant: CN(c1cccc(B2OC(C)(C)C(C)(C)O2)c1)S(C)(=O)=O
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc(N(C)S(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 93 %

Procedure:
(S)-2-(1-((5-Bromo-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 (131 mg, 0.22 mmol) was treated with N-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (170 mg, 0.55 mmol, prepared according to WO 2006015829 A1 20060216), sodium carbonate (62 mg, 0.58 mmols) and bis(triphenylphosphine)palladium(II) dichloride (55 mg, 0.07 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl ether) to give 143 mg (92% yield) of the title compound. Purity 99%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:26]1([CH2:32][S:33][CH:34]([C:38](O)=[O:39])[C:35](O)=[O:36])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[OH:39][C:38]1[CH:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[O:10][C:35](=[O:36])[C:34]=1[S:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1ccccc1C
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cc(O)c(SCc2ccccc2)c(=O)o1

Procedure:
The title compound was prepared by Method A using 2'-methylacetophenone (0.712 g, 5.31 mmol), lithium bis(trimethylsilyl)amide (0.977 g, 5.84 mmol), chlorotrimethylsilane (0.741 mL, 5.84 mmol), THF (58 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). 1H NMR (400 MHz, DMSO-d6) δ2.34 (s, 3 H), 4.01 (s, 2 H), 6.32 (s, 1 H), 7.32 (m, 9H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[N:8]=1)=O.[C:23]1([NH:33]N)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:33]([C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH:26]=[CH:25][CH:24]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)[CH:19]=[CH:18][CH:17]=1
Reactant: NNc1cccc2ccccc12
Reactant: COc1cccc(-n2ccc(=O)c(C(=O)/C=C/N(C)C)n2)c1
Product: COc1cccc(-n2ccc(=O)c(-c3ccnn3-c3cccc4ccccc34)n2)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-methoxy-phenyl)-1H-pyridazin-4-one (A-5) and naphthalen-1-yl-hydrazine according to the method described for example 91. MS: M=395.1 (M+H)+
Reaction SMILES: C([O:3][C:4](=[O:35])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[C:27]1[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:35])=[O:3])=[CH:14][CH:13]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccs4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1oc(-c2ccc(-c3cccs3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-thiophen-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4-thiophen-2-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl) 8.74 (2H, m), 8.39 (2H, d), 8.26 (1H, m), 8.16 (2H, m), 7.64 (2H, d), 7.55 (2H, d), 4.18 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.53 (6H, s)
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[S:13][CH:14]=[CH:15][C:4]=2[CH:3]1O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[S:13][CH:14]=[CH:15][C:4]=2[CH:3]=1
Reactant: CC1c2ccccc2Sc2sccc2C1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1=Cc2ccsc2Sc2ccccc21

Procedure:
24.8 g (0.1 mole) of 4,5-dihydro-5-methyl-benzo[f]thieno [2,3-b]thiepin-4-ol in 600 ml of benzene is boiled, with the addition of 0.57 g (0.03 mole) of p-toluenesulphonic acid hydrate, for one hour on a water separator. The solution is thereupon cooled to 20°, extracted by shaking with 2 N sodium bicarbonate solution, dried over sodium sulphate and concentrated in vacuo. The oily residue is chromatographed on a silica-gel column (300 g of silica gel, particle size 0.063-0.2 mm) with the use of cyclohexane as the eluant. Recrystallisation of the eluted substance from pentane yields 5-methyl-benzo[f]thieno[2,3-b]thiepin, m.p. 70°-71°.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=3)[N:10]([C:19]([NH:21][C:22]3[S:23][C:24]([Cl:27])=[CH:25][N:26]=3)=[O:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=3)[N:10]([C:19]([NH:21][C:22]3[S:23][C:24]([Cl:27])=[CH:25][N:26]=3)=[O:20])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(C=O)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(CO)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
The 1′-acetyl-N-(5-chlorothiazol-2-yl)-5-formylspiro[indoline-3,3′-pyrrolidine]-1-carboxamide (30.6 mg, 0.076 mmol) obtained in Step 2 of Example 401 was dissolved in methanol (1 mL). Thereafter, sodium borohydride (3.0 mg, 0.091 mmol) was added to the above obtained solution under cooling on ice, and the thus obtained mixture was then stirred at room temperature for 1 hour. Thereafter, the reaction solution was concentrated in vacuo, and the obtained residue was then purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the captioned compound (30.4 mg, 99%) in the form of a white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13](Cl)(=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[Na+].Cl>O.C(O)(C)C>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCC(=O)Cl
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCCCCCCCCCCCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
As in Synthetic Example 1, to 113 g of L-arginine were added 706 g of isopropyl alcohol and 302 g of water. Thereto were concurrently added dropwise 176 g of myristoyl chloride (manufactured by Nippon Oil and Fats Co., Ltd.) and 27 wt % NaOH aqueous solution over a period of 2 hours with the pH being maintained at 10.5 to 11.5 and the reaction temperature, at 10 to 13° C. After 1 hour of aging, the reaction mixture was warmed to 50° C. and adjusted to below pH 2.7 by adding concentrated hydrochloric acid to dissolve the reaction product completely. Thereafter, the pH was adjusted to 6.0 by adding 27 wt % NaOH aqueous solution to precipitate crystals and the resulting slurry was gradually cooled to 10° C. with stirring. When the slurry was cooled to 10° C., the crystals were collected by filtration and washed with 1,500 g of water and 492 g of isopropyl alcohol, successively. The resulting washed crystals were dried under reduced pressure to obtain 230 g of mono-Nα-myristoyl-L-arginine as flake-shaped crystals (yield 92.2%).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=O)[C:7]([CH3:10])([CH3:9])[CH3:8])(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>O1CCCC1>[C:7]([C:6]1[S:21][C:1]([CH3:2])=[N:4][N:5]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(=O)NNC(=O)C(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Cc1nnc(C(C)(C)C)s1

Procedure:
A mixture of the product from Example 50A (158 mg, 1 mmol) and Lawesson's reagent (808 mg, 2 mmol) in tetrahydrofuran (4 mL) was heated at reflux for 2 hours. The solution was concentrated, dissolved in dichloromethane (15 mL) and washed with saturated sodium bicarbonate solution (10 mL). The resulting organic layer was passed through a silica pad and washed with dichloromethane and ethyl acetate (10:1). The solvent was evaporated to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9 H) 2.67 (s, 3 H); MS (ESI) m/z 157 (M+H)+.