Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)[CH:6]=[N:5][CH:4]=1.[ClH:27].CO>>[ClH:27].[CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:6]=[N:5][CH:4]=1
Reactant: CSc1cncc2cccc(NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Agent: Cl
Solvent: CO
Product: CSc1cncc2cccc(NC3CCNCC3)c12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 74 (214 mg) and 10% hydrogen chloride/methanol solution (5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (2 ml) and diethyl ether (6 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (154 mg) as brown powdery solid.
Reaction SMILES: [F:1][CH:2]([CH2:17][CH2:18][CH2:19][CH3:20])[C:3](=[O:16])[CH2:4][CH2:5][C@H:6]1[C@H:13]([OH:14])[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9](=[O:15])[O:10]2.[C:21]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>>[F:1][CH:2]([C:3]1([O:16][CH3:21])[CH2:4][CH2:5][CH:6]2[CH:13]([CH2:12][CH:11]3[CH:7]2[CH2:8][C:9](=[O:15])[O:10]3)[O:14]1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Reactant: CCCCC(F)C(=O)CC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1O
Product: CCCCC(F)C1(OC)CCC2C(CC3OC(=O)CC32)O1

Procedure:
According to a similar manner as described in example 4, using (1S,5R,6R,7R)-6-[4(RS)-fluoro-3-oxo-1-octyl]-7-hydroxy-2-oxabicyclo[3.3.0]octane-3-one (0.263 g) and camphor sulfonic acid (0.021 g), the title compound was obtained (yields: 0.236 g, 86%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:38]([CH:35]3[CH2:37][CH2:36]3)=[O:39])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)C3CC3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, cyclopropanecarbonyl chloride.
Reaction SMILES: C(Cl)(Cl)Cl.[CH2:5]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[N+:19]([O-])=[CH:18][C:17]3[N:24]=[C:25]([CH2:28][CH3:29])[N:26]([CH3:27])[C:16]=3[C:15]=2[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.ClC(Cl)(Cl)C([N:34]=C=O)=O.C[O-].[Na+]>ClCCl.CO>[CH2:5]([O:12][C:13]1[CH:22]=[CH:21][C:20]2[N:19]=[C:18]([NH2:34])[C:17]3[N:24]=[C:25]([CH2:28][CH3:29])[N:26]([CH3:27])[C:16]=3[C:15]=2[CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1C
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCc1nc2c(N)nc3ccc(OCc4ccccc4)cc3c2n1C
Reaction time: 3.5 h
Yield: 73.3 %

Procedure:
A modification of the general method of Part C of Example 3 was used. Chloroform (10 mL) was added to the solution of 8-benzyloxy-2-ethyl-1-methyl-5-oxido-1H-imidazo[4,5-c]quinoline (1.30 g, 3.90 mmol) in dichloromethane (35 mL) to improve the solubility. After the addition of trichloroacetyl isocyanate (0.633 mL, 5.31 mmol), the reaction was stirred for 3.5 hours. In the second step, chloroform (10 mL) was also added to the suspension in methanol (30 mL). After the reaction with sodium methoxide, the reaction was stirred over two nights, and the precipitate was isolated by filtration, washed with hexanes, recrystallized from methanol (278 mL/g), isolated by filtration, washed with hexanes, and dried for two days in a vacuum oven. A second crop of crystals from the mother liquor was combined with the first to provide 0.95 g of 8-benzyloxy-2-ethyl-1-methyl-1H-imidazo[4,5-c]quinolin-4-amine as a white crystalline solid, mp 238.4-238.9° C.
Reaction SMILES: [CH3:1][C:2]1[CH:35]=[C:5]2[N:6]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1.C([Sn](=O)CCCC)CCC.[N:46]([Si](C)(C)C)=[N+:47]=[N-:48].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:35]=[C:5]2[N:6]([CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[C:7](=[O:28])[C:8]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:48][N:47]=[N:46][N:27]=4)=[CH:18][CH:19]=3)=[C:9]([CH2:10][CH2:11][CH3:12])[N:4]2[N:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2cc(C)nn12
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCOCC2)c2cc(C)nn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 32 %

Procedure:
A mixture of 4′-{[2-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.1 g), dibutyltin oxide (0.011 g), azidotrimethylsilane (0.74 g) and toluene (10 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.035 g, 31%).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[CH:12]2>CCOCC.C1COCC1>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([C:19]([O:21][CH3:1])=[O:20])=[CH:14][CH:13]=[CH:12]2
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cccc2cc(O)ccc12
Reaction time: 1.5 h
Yield: 56 %

Procedure:
A solution of (trimethylsilyl)diazomethane (4.0 mL of a 2.0 M solution in Et2O, 8.0 mmol) was added slowly to a solution of 6-hydroxy-1-naphthoic acid (commercially available from TCI, 1.50 g, 8.0 mmol) in THF (40 mL) at 0° C. After 1.5 h at 0° C., the reaction mixture was concentrated in vacuo and absorbed onto silica. The resulting residue was purified on 80 g silica gel (100% hexanes→100% EtOAc, gradient) to afford 910 mg (56%) of methyl 6-hydroxy-1-naphthoate.
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][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][C:42]=1B(O)O.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][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][C:42]=1[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
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(C)cc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1ccc(C)cc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Yield: 70.8 %

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 (60 mg, 0.10 mmol) was treated with (2-methoxy-5-methylphenyl)boronic acid (42 mg, 0.25 mmol), sodium carbonate (26 mg, 0.25 mmols) and bis(triphenylphosphine)palladium(II) dichloride (8 mg, 0.11 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 45 mg (70% yield) of the title compound. Purity 94%.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][O:44]S(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:49][O-].[Na+]>CN(C)C=O.CO.COC(C)(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][O:44][CH3:49])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCOS(C)(=O)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: C[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCOC)C[C@@H]3c3ccc(OC)cc3)cc21
Reaction time: 5 h

Procedure:
To a solution of 0.10 g of (2S,4R,5R)-2-(2-methanesulfonyloxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester in 2.0 ml of N,N-dimethylformamide are added 0.060 ml of a 5M solution of sodium methoxide in methanol at room temperature. The reaction mixture is stirred for 5 hours, diluted with tert-butyl methyl ether, washed with 1N hydrochloric acid and the organic phase is dried over sodium sulfate. The organic phase is concentrated under reduced pressure and the residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a slightly brown oil. Rf=0.25 (EtOAc-heptane 1:1); Rt=5.47.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])O.N1C(C)=CC=CC=1C.FC(F)(F)S(O)(=O)=O.[F:24][C:25]1[C:31]([F:32])=[C:30]([F:33])[CH:29]=[CH:28][C:26]=1[NH2:27].Cl>ClCCl>[F:24][C:25]1[C:31]([F:32])=[C:30]([F:33])[CH:29]=[CH:28][C:26]=1[NH:27][C@@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5]
Reactant: Nc1ccc(F)c(F)c1F
Reactant: COC(=O)[C@@H](C)O
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
Under ice-cooling, methyl D-lactate (8.5 g) and 2,6-lutidine (11.4 g) were dissolved in dichloromethane (100 ml). After dropping anhydrous trifluoromethanesulfonic acid (25.4 g), the mixture was heated to room temperature and stirred for 30 minutes. Then it was cooled to 0° C. again and a solution (30 ml) of 2,3,4-trifluoroaniline (12.0 g) in dichloromethane was dropped thereinto. The mixture was stirred at the same temperature for 17 hours. To the resultant solution, hydrochloric acid (0.5 mol/l) was added and the mixture was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and filtered. After evaporating the solvent, the residue thus obtained was subjected to silica gel column chromatography. Thus, 17.1 g (90%) of the title compound was obtained as an oily substance. The optical purity determined by HPLC was 97% ee.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20]([OH:22])=[O:21]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[Cl:26])[C:20]([OH:22])=[O:21])=[O:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cc(C(=O)O)ccc1Cl
Reactant: CC(C)(C)OC(=O)NCCCCC(=O)O
Product: CC(C)(C)OC(=O)NCCCCC(=O)Nc1cc(C(=O)O)ccc1Cl

Procedure:
For the preparation of the starting material, 5-[1-(t-butoxy)formamido]valeric acid and 3-amino-4-chlorobenzoic acid are coupled to give 3-[5-(1-t-butoxyformamido)valeramido]-4-chlorobenzoic acid, m.p. 203° C., and the latter is coupled with β-alanine t-butyl ester to give N-[3-[5-(1-t-butoxyformamido)valeramido]-4-chlorobenzoyl]-β-alanine t-butyl ester, MS: 498 (60, M+H).
Reaction SMILES: F[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:15][O:16][CH3:17])[CH:3]=1.[O:18]1[CH2:22][CH2:21][CH:20]([C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)[CH2:19]1.C(#N)C>C(N(CC)CC)C>[CH3:17][O:16][CH2:15][C:4]1[CH:3]=[C:2]([N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:20]2[CH2:21][CH2:22][O:18][CH2:19]2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: c1c[nH]c(C2CCOC2)n1
Reactant: COCc1cc(F)c([N+](=O)[O-])cc1C(=O)OC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCc1cc(-n2ccnc2C2CCOC2)c([N+](=O)[O-])cc1C(=O)OC
Temperature: 70 °C
Reaction time: 5.5 h
Yield: 74.6 %

Procedure:
To a mixture of 6.0 g of methyl 4-fluoro-2-(methoxymethyl)-5-nitrobenzoate, 3.5 g of 2-(tetrahydrofuran-3-yl)-1H-imidazole, and 60 mL of acetonitrile was added 6.9 mL of triethylamine, followed by stirring at 70° C. for 5.5 hours. The reaction mixture was concentrated, and water and ethyl acetate were added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 6.65 g of methyl 2-(methoxymethyl)-5-nitro-4-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]benzoate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1.C1C=CC2N(O)N=NC=2C=1.[Cl:20][CH2:21][CH2:22][CH2:23][C:24]([O-])=[O:25]>CN(C)C=O>[Cl:20][CH2:21][CH2:22][CH2:23][C:24]([CH:8]1[CH2:7][CH2:6][NH:5][CH:4]([CH2:3][CH2:2][OH:1])[CH2:9]1)=[O:25]
Reactant: O=C([O-])CCCCl
Reactant: OCCC1CCCCN1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCCl)C1CCNC(CCO)C1

Procedure:
2-(2-Hydroxyethyl)piperidine, HOBt and WSCI are added to N,N-dimethylformamide solution of 4-chlorobutyrate while being cooled with ice and the mixture is reacted at room temperature to obtain 1-(4-(chlorobutanoyl)-2-(2-hydroxyethyl)piperidine.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([OH:18])=[C:8]3[C:13](=[C:14]([OH:15])[C:4]2=[CH:3][CH:2]=1)[C:12]([NH2:16])=[CH:11][CH:10]=[C:9]3[NH2:17].[S:19](=O)(=[O:22])([OH:21])[OH:20].[OH:24][S:25]([OH:28])(=[O:27])=[O:26].O=S(=O)=O>>[NH2:17][C:9]1[C:8]2[C:7](=[O:18])[C:5]3[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=3)[C:14](=[O:15])[C:13]=2[C:12]([NH2:16])=[CH:11][C:10]=1[S:19]([OH:22])(=[O:21])=[O:20].[S:25](=[O:26])(=[O:24])([OH:28])[OH:27]
Reactant: Nc1ccc(N)c2c(O)c3ccccc3c(O)c12
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Nc1cc(S(=O)(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 110 °C
Reaction time: 4 h

Procedure:
80 parts of leuco-1,4-diaminoanthraquinone are added to 270 parts of 100% sulfuric acid over 30 minutes, the temperature rising to 65°-70° C. The solution is heated to 110° C. and then 90 parts of 66% oleum are added initially over 1 hour, followed by the dropwise addition of a further 80 parts of 66% oleum over the next 3 hours. The reaction mixture is then stirred for a further 4 hours at 110° C., cooled to room temperature and poured onto 255 parts of ice. The resultant brown suspension is filtered at room temperature, affording crude 1,4-diaminoanthraquinone-2-sulfonic acid which still contains sulfuric acid and is of sufficient purity that it can be used in this form direct for the dye synthesis, especially if the subsequent synthesis is carried out in sulfuric acid in any case.
Reaction SMILES: [CH:1]1([CH2:6][NH:7][C:8]([C:10]2[C:11]([C:17]([F:20])([F:19])[F:18])=[N:12][C:13](Cl)=[N:14][CH:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=1[NH2:24]>O1CCOCC1>[CH:1]1([CH2:6][NH:7][C:8]([C:10]2[C:11]([C:17]([F:20])([F:19])[F:18])=[N:12][C:13]([NH:24][C:23]3[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:22]=3[Cl:21])=[N:14][CH:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cc(F)ccc1Cl
Reactant: O=C(NCC1CCCC1)c1cnc(Cl)nc1C(F)(F)F
Solvent: C1COCCO1
Product: O=C(NCC1CCCC1)c1cnc(Nc2cc(F)ccc2Cl)nc1C(F)(F)F
Yield: 25.8 %

Procedure:
2-Chloro-4-trifluoromethyl-pyrimidine-5-carboxylic acid cyclopentylmethyl-amide (100 mg Example 183a), 2-chloro-5-fluoroaniline (ex-Fluorochem, 237 mg), and 1,4-dioxan (1 ml) were stirred at 100° C. under nitrogen for 18 h. The cooled reaction mixture was evaporated in vacuo, treated with ethyl acetate (5 ml), washed with aqueous 2M hydrochloric acid (2×3 ml), followed by water (2×3 ml), and dried (Na2SO4). The solution was evaporated in vacuo and the residue purified by mass directed auto-preparative purification to give the title compound (35 mg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](OC)=[O:9])=[CH:6][N:5]=[C:4]([Cl:12])[C:3]=1[F:13].O.[NH2:15][NH2:16]>C(O)C>[Cl:12][C:4]1[N:5]=[CH:6][C:7]2[C:8](=[O:9])[NH:15][NH:16][C:2]=2[C:3]=1[F:13]
Reactant: NN
Reactant: COC(=O)c1cnc(Cl)c(F)c1Cl
Solvent: CCO
Solvent: O
Product: O=c1[nH][nH]c2c(F)c(Cl)ncc12
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Methyl 4,6-dichloro-5-fluoronicotinate (5.0 g, 22.32 mmol) and hydrazine monohydrate (1.7 mL, 22.32 mmol) were dissolved in ethanol (5 mL) and stirred at 80° C. for 1 h. The reaction mixture was filtered, dissolved in MeOH, and HCl (1 N, 0.5 mL) was added. The reaction was stirred at room temperature for 4 h. The reaction mixture was then filtered and washed with water to give 6-chloro-7-fluoro-1H-pyrazolo[4,3-c]pyridin-3(2H)-one, which was carried onto the next step without further purification. MS ESI calc'd. for C6H13ClFN3O [M+1]+ 188. found 188.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]=[O:11]>>[OH:11][CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccccc1
Reactant: C=O
Product: O=C(NCO)c1ccccc1
Yield: 84 %

Procedure:
The compound N-(hydroxymethyl)benzamide is prepared in 84% yield from benzamide and formaldehyde using the procedure described by Monti, Gazz. Chim., 50: 39 (1930).
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]([CH3:63])[C:41](=[O:62])[C:42]1[CH:47]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:45]=[C:44]([NH:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH:43]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:39][N:40]([CH3:63])[C:41](=[O:62])[C:42]1[CH:43]=[C:44]([NH:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH:45]=[C:46]([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:47]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CN(C)C(=O)c1cc(NS(C)(=O)=O)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc(C(=O)N(C)C)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 106.3 %

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 (170 mg, 0.29 mmol) was treated with N, N-dimethyl-3-(methylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (262 mg, 0.71 mmol), sodium carbonate (75 mg, 0.71 mmols) and bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (74 mg, 0.09 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, dichloromethane-ethyl acetate) to give 233 mg (99% yield) of the title compound. Purity 92%.
Reaction SMILES: [CH3:1][C:2]([C@@H:4]1[CH2:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)=[CH2:3].[H][H]>[Pt]=O.C(O)(=O)C>[CH:2]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:1]
Reactant: [H][H]
Reactant: C=C(C)[C@@H]1CC=C(C(=O)O)CC1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CC(C)C1CCC(C(=O)O)CC1
Yield: 93 %

Procedure:
Platinum oxide (200 mg) as a catalyst was suspended in acetic acid (20 ml), and then (s)-(-)perillic acid (2 g, 12 mmole) was added. The mixture thus obtained was stirred for 8 hours at room temperature under a current of hydrogen gas. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to a dryness. The matter was recrystallized from methanol-water to obtain 4-isopropyl cyclohexane carboxylic acid (1.9 g, yield 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].CC([O-])=O.[Na+].[Br:21]Br.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:21][C:8]1[C:3]([O:2][CH3:1])=[C:4]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([CH3:9])[CH:7]=1
Reactant: BrBr
Reactant: COc1ccc(C)cc1CCCC(=O)O
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1c(Br)cc(C)cc1CCCC(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 104.5 %

Procedure:
A solution of 4-(2-methoxy-5-methylphenyl)-butyric acid (74 g, 0.36 mole), NaOAc (29.8 g, anhydrous), and glacial acetic acid (710 mL) was stirred under N2 at room temperature. as a solution of bromine (22 mL, 0.43 mole) and glacial acetic acid (185 mL) was added dropwise. The reaction mixture was stirred at room temperature for 20 hours. 10% aqueous sodium bisulfite (400 mL) was added and the solution was extracted with CH2Cl2. The combined extracts were washed with water, 10% aqueous sodium thiosulfate, water, saturated aqueous. NaCl, dried (MgSO4), filtered, and evaporated to yield 108 g brown solid which was recrystallized from hexane to yield 76 g white solid, (74%); m+ 286.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([O:17][CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15]Br)[CH:7]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[OH:30].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][CH2:14][CH2:15][O:30][C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[CH:7]=1)[C:3]([OH:2])=[O:19]
Reactant: COC(=O)C(Cc1cccc(OCCCBr)c1)OC
Reactant: Oc1ccc2ccccc2c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COC(Cc1cccc(OCCCOc2ccc3ccccc3c2)c1)C(=O)O

Procedure:
The title compound was prepared from 3-[3-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid methyl ester (Example 323, Step 1) and 2-naphthol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1). The enatiomers were separated by chiral HPLC.