Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.CO.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[C:18]1([C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cn1
Temperature: 70 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To a solution of 1B (7.65 g, 28 mmol) in THF (50 mL)-MeOH (50 mL) at RT was added phenylboronic acid (6.83 g, 56 mmol), PXPd (500 mg, 0.93 mmol), followed by K2CO3 (15.5 g, 112 mmol). The reaction mixture was stirred at 70° C. in a preheated oil bath for 1 h. After this time, the reaction mixture was cooled to RT. The reaction mixture was poured into water (100 mL), and the resultant mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with saturated NaCl. The organic layer was dried (Na2SO4), filtered and concentrated. The resulting residue was purified by silica gel (120 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as an off-white solid (5.4 g, 72%). LC/MS (method A): retention time=3.07 min, (M+H)+=271.
Reaction SMILES: [NH2:1][C@@H:2]([CH:8]([CH3:10])[CH3:9])[CH:3]([OH:7])[C:4]([OH:6])=[O:5].[OH-].[Na+].O1CCOCC1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O>[CH2:23]([O:22][C:20]([NH:1][C@@H:2]([CH:8]([CH3:10])[CH3:9])[CH:3]([OH:7])[C:4]([OH:6])=[O:5])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)[C@H](N)C(O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution under an atmosphere of nitrogen containing 1.0 g (6.8 mmol) of 3-(S)-amino-2-(R,S)-hydroxy-4-methylpentanoic acid in 9.5 ml, of 1 N NaOH and 10 mL of dioxane was added 1.43 g (8.4 mmol) of benzyl chloroformate. The pH was maintained above pH 8 with 1 N NaOH as needed. The reaction mixture was allowed to stir at room temperature overnight. The reaction was diluted with water and washed with ether. The aqueous layer was acidified with 1 N HCl to pH=2 and extracted with ether (2×). The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo to afford 1.75 g (92%) of 3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-hydroxy-4-methylpentanoic acid as a light yellow viscous oil. FAB MS [M+H]m/z; Calcd: 282, Found: 282.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[Cl:11].[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:9])=[CH:4][C:3]=1[Cl:11]
Reactant: CC(O)c1ccc(Br)c(Cl)c1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccccc1)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1-(4-bromo-3-chlorophenyl)ethanol (1.32 g, 5.6 mmol), phenol (525 mg, 5.6 mmol) and triphenylphosphine (2198 mg, 8.4 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature for 0.5 hour. Diisopropyl azodicarboxylate (1695 mg, 8.4 mmol) was dropwise to the reaction mixture and was stirred at room temperature for 12 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=5:1) to give 1-bromo-2-chloro-4-(1-phenoxyethyl)benzene as a colorless oil (882 mg 54%). 1H NMR (300 MHz, CDCl3): 7.37 (d, J=8.1, 1H), 7.27-7.20 (m, 4H), 6.92-6.82 (m, 3H), 5.30 (q, J=6.6, 1H), 1.62 (d, J=6.6, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(Cl)=[O:14]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(N)c(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c(=O)oc(=O)c2c1
Reaction time: 1.5 h

Procedure:
To a suspension of 2-amino-5-methoxy-benzoic acid (8.0 g, 47.8 mmol) in toluene (100 mL) was added a solution of phosgene (20%, 50.0 mL) in toluene and triethyl amine (13.40 mL). The reaction mixture was heated at 80 C. for 1.5 h. The precipitated product was filtered and washed with hexanes and toluene and dried to give 9.00 g of 6-methoxy-1H-benzo[d][1.3]oxazine-2,4-dione as a light brown solid. This was used directly for the next step.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH2:2]C.[Mn+2:6].[C:7]([O-:11])(=[O:10])[CH2:8]C.C(=O)([O-])[O-].[Mn+2].[OH-].[Na+]>C(O)(=O)C>[C:1]([O-:5])(=[O:4])[CH3:2].[Mn+2:6].[C:7]([O-:11])(=[O:10])[CH3:8]
Reactant: CCC(=O)[O-]
Agent: [Mn+2]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)[O-]

Procedure:
A preparation of manganese propionate is made by combining 114.95 grams of dry manganese carbonate, 300.30 grams of dry acetic acid, and 40.01 grams of sodium hydroxide. The mixture is heated to reflux with constant stirring. Water with some acetic acid is removed by fractional distillation. Heat is increased until the water and about 80 percent of the acetic acid liquid has been removed. Carbon dioxide is released through a vented condenser. The resulting composition of manganese acetate and sodium acetate in residual acetic acid is poured into a flat metal pan and placed in a freezer until cool. After cooling, the solution solidifies into a pink "glass". The "glass" is ground releasing the acetic acid. A white to slightly pink powder is collected containing manganese acetate and sodium acetate.
Reaction SMILES: [N:1]([C@@:4]1(/[CH:29]=[CH:30]/[P:31](=[O:34])([OH:33])[OH:32])[C@@H:8]([OH:9])[C@@H:7]([OH:10])[C@H:6]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][CH:14]=[N:15][C:16]=3[NH:20]C(=O)C2C=CC=CC=2)[O:5]1)=[N+:2]=[N-:3]>[NH4+].[OH-]>[NH2:20][C:16]1[N:15]=[CH:14][N:13]=[C:12]2[C:17]=1[N:18]=[CH:19][N:11]2[C@@H:6]1[O:5][C@@:4](/[CH:29]=[CH:30]/[P:31](=[O:32])([OH:34])[OH:33])([N:1]=[N+:2]=[N-:3])[C@@H:8]([OH:9])[C@H:7]1[OH:10]
Reactant: [N-]=[N+]=N[C@]1(/C=C/P(=O)(O)O)O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Agent: [NH4+]
Agent: [OH-]
Product: [N-]=[N+]=N[C@]1(/C=C/P(=O)(O)O)O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
Compound 36.6 (crude 233 mg) was dissovled in 10 mL concentrated NH4OH. The solution was stirred at r.t. for 24 h and then concentrated under reduced pressure. The residue was subjected to a reverse phase HPLC eluting with 0-15% CH3CN in water to give compound 36.7 (40 mg, 22% yield). 1H NMR (D2O, 300 MHz) 8.12 (s, 1H), 8.03 (s, 1H), 6.14 (br m, 3H), 4.66 (m, 1H), 4.40 (d, J=6.0 Hz, 1H),; 31P NMR (D2O 121.4 MHz) 7.1; MS (ESI) m/z 385 [M+H]+.
Reaction SMILES: [C:1]12([OH:13])[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[O:21]1C[CH2:24][CH2:23][CH2:22]1.C(Cl)(=O)C=C>O>[C:22]([O:13][C:1]12[CH2:10][C:5]3([OH:11])[CH2:6][CH:7]([CH2:9][C:3]([OH:12])([CH2:4]3)[CH2:2]1)[CH2:8]2)(=[O:21])[CH:23]=[CH2:24]
Reactant: OC12CC3CC(O)(C1)CC(O)(C3)C2
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)OC12CC3CC(O)(CC(O)(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
10 mmol of 1,3,5-adamantanetriol, 10 mmol of triethylamine, and 40 ml of tetrahydrofuran were mixed, and 10 mmol of acrylic acid chloride was added dropwise to this mixture for about 30 minutes. After completion of the dropwise addition, the mixture was stirred at room temperature for 6 hours. After the reaction had been completed, to the reaction mixture was added water and the resultant mixture was purified by column chromatography to give 1-acryloyloxy-3,5-dihydroxyadamantane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH2:15][C:14]([C:16]([O:18]C)=[O:17])=[C:13]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:12][C:11]=2[C:29]([O:31]C)=[O:30])=[CH:5][CH:4]=1.[Na].[N+](C1C=C(S(O)(=O)=O)C=CC=1)([O-])=O.[OH-].[Na+].Cl>O.C(O)C>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:13]2[CH:12]=[C:11]([C:29]([OH:31])=[O:30])[C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:15][C:14]=2[C:16]([OH:18])=[O:17])=[CH:22][CH:23]=1
Reactant: COC(=O)C1=C(Nc2ccc(OC)cc2)CC(C(=O)OC)=C(Nc2ccc(OC)cc2)C1
Agent: Cl
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(OC)cc3)cc2C(=O)O)cc1
Yield: 97.9 %

Procedure:
Dimethyl 2,5-bis{(4-methoxyphenyl)amino}cyclohexa-1,4-diene-1,4-dicarboxylate (6.58 gm, 15 mmol), the sodium salt of 3-nitrobenzenesulphonic acid (3.6 gm; 16 mmol), ethanol (90 ml) and 1.0M sodium hydroxide (50 ml) were heated to reflux overnight under a nitrogen atmosphere. The orange solution was allowed to cool and water (120 ml) was added. The mixture was acidified with conc. hydrochloric acid when a purple solid precipitated out. This material was filtered off, washed with water, then 25% ethanol/water and dried under vacuum over phosphorous pentoxide to give 6.0 gm (98%) of 2,5-bis{(4-methoxyphenyl)amino}terephthalic acid.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C@H:6]2[CH2:11][N:10]([S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH2:9][CH2:8][N:7]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:32])([CH3:31])[C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:3][CH2:2]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:1]1([N:4]([CH2:5][C@H:6]2[CH2:11][N:10]([S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH2:9][CH2:8][N:7]2[C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:32])([CH3:31])[C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[S:34]([CH3:33])(=[O:36])=[O:35])[CH2:2][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CNC2CC2)cc1)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN(C2CC2)S(C)(=O)=O)cc1)C(F)(F)F
Reaction time: 0.33 h
Yield: 68.3 %

Procedure:
To a solution of 2-(4-((2S)-2-((cyclopropylamino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (0.130 g, 0.258 mmol, Example 199) in CH2Cl2 (5.0 mL) was added 4-dimethylaminopyridine (0.006 g, 0.052 mmol), methanesulfonyl chloride (0.059 g, 0.516 mmol) and Hünig's base (0.135 mL, 0.774 mmol). After 20 min at room temperature, the solvent was concentrated and the crude product was purified by column chromatography (40 g of silica gel, 10 to 30% acetone in hexanes) to give N-cyclopropyl-N-(((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)methanesulfonamide (0.100 g) as a mixture of two isomers.
Reaction SMILES: [CH:1]1([CH2:4]CN)C[CH2:2]1.C[CH:8]([NH:11][CH2:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])CC>>[CH:1]1([CH2:8][NH:11][CH2:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])[CH2:4][CH2:2]1
Reactant: CCC(C)NCCC(=O)NC
Reactant: NCCC1CC1
Product: CNC(=O)CCNCC1CC1

Procedure:
Using 2-Cyclopropylethanamine—Aldrich and analogous conditions to Intermediate 89 the title compound was obtained as a pale yellow oil (590 mg)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:31])=[C:8]2[C:15]([C:16]#[N:17])=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:32]([Cu])#[N:33]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:31])=[C:8]2[C:15]([C:16]#[N:17])=[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:13]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:9]2=[C:10]([C:32]#[N:33])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1
Reactant: N#C[Cu]
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(C#N)c(-c1ccc(F)cc1)n2-c1ccccc1

Procedure:
Prepared in analogy to that of Example 105(a) from 7-bromo-3-cyano-2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 427 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13](=[O:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])([CH3:22])[C:13](=[O:21])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)C1(C)CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To the solution of N-benzyloxycarbonyl-4-ethoxycarbonylpyrrolidin-3-one (291 g) in acetone (1.5 l) was added potassium carbonate (200 g), followed by iodomethane (300 mL), and then the solution was refluxed for 3 hr. The reaction mixture was cooled at room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:6) to obtain the desired compound, (237.7 g, 80.7%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH:8]([CH2:11]O)[C:9]#[N:10])(=O)=O.[C:13](=[O:26])([O:19][NH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].C(=O)([O-])ON(C(C)(C)C)C(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:13](=[O:26])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[O:19][N:20]([CH2:6][CH2:7][C:8]([C:9]#[N:10])=[CH2:11])[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CS(=O)(=O)OCCC(C#N)CO
Reactant: CCOC(=O)NOC(=O)OC(C)(C)C
Agent: CCOC(=O)N(OC(=O)[O-])C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C#N)CCN(OC(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-methylsulfonyloxy-2-(hydroxymethyl) butanenitrile (i.e. the product of Step E) (6.87 g, 0.039 mol), 1,1-dimethylethyl (ethoxycarbonyl)azanyl carbonate (7.65 g, 0.037 mol) (i.e. the product of Step F) and potassium carbonate (10.21 g, 0.074 mol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 20 h. The reaction mixture was poured onto iced water (100 mL) and extracted with diethyl ether (3×50 mL). The combined organic layers were washed with water (50 mL) and concentrated to a pale-tan oil (10.05 g). The oil was adsorbed onto Celite® (diatomaceous filter aid), and then purified by silica gel chromatography (0-100% gradient of ethyl acetate in petroleum ether as eluant). The appropriate fractions were combined to provide the title compound as a yellow oil (3.78 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([C:17]([O:19]CC)=[O:18])[NH:14]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH:12]=[C:13]([C:17]([OH:19])=[O:18])[NH:14]3)=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc2ccc(-c3ccc(C)cc3)cc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc3cc(C(=O)O)[nH]c3c2)cc1
Reaction time: 64 h
Yield: 94.3 %

Procedure:
Into a mixed solution of ethyl 6-(4-methylphenyl)-1H-indole-2-carboxylate (0.6 g) in ethanol/THF (10/10 ml) was added at room temperature a 2 N aqueous solution of sodium hydroxide (5 ml), and the resulting mixture was stirred for 64 hours. After addition of 1 N hydrochloric acid (15 ml), the reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration of the organic layer under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with hexane to obtain 6-(4-methylphenyl)-1H-indole-2-carboxylic acid (509 mg) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:5].[OH:13][CH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[OH:13][CH:14]1[CH2:19][CH2:18][CH:17]([NH:5][C@@H:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([O:2][CH3:1])=[O:12])[CH2:16][CH2:15]1
Reactant: COC(=O)[C@@H](N)c1ccccc1
Reactant: O=C1CCC(O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)[C@@H](NC1CCC(O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 35 %

Procedure:
(S)-(+)-2-Phenylglycine methyl ester (commercially available from Sigma-Aldrich, Milwaukee, Wis., 433 g, 2.146 mol) was added to a solution of 4-hydroxycyclohexanone (245 g, 2.146 mol) in DCE (8.5 L). Sodium triacetoxyborohydride was added (910 g, 4.292 mol), and the mixture was stirred at room temperature under nitrogen for 23 hours. Water (3 L) was added to quench the reaction, and the organic layer was separated. The aqueous phase was extracted with DCM (4 L×2) and the organic layers were combined, dried, filtered and concentrated. The residue was purified by column chromatography (gradient elution with 100% DCM to DCM/MeOH=25:1) to afford (S)-methyl 2-((4-hydroxycyclohexyl)amino)-2-phenylacetate (197 g, 35%) (mixture of cis and trans). m/z (ESI) 264 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH3:11][O:12]C(Cl)Cl>Cl[Ti](Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][C:5]([CH:11]=[O:12])=[C:6]([F:8])[CH:7]=1
Reactant: COC(Cl)Cl
Reactant: COc1ccc(F)cc1Br
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc(C=O)c(F)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a N2 purged flask is added TiCl4 (0.44 mL) followed by 2-Bromo-4-fluoro-1-methoxy-benzene (400 mg, 1.95 mmol). The stirred mixture is cooled in an ice water bath and treated dropwise with 1,1-dichloromethyl methyl ether (0.35 mL, 1.95 mmol). After stirring for 90 minutes, the resulting slurry is treated with CH2Cl2 (200 mL) and reaction is allowed to warm up to room temperature. After passing through a column, the title compound is isolated (220 mg, 48%). MS (ESI): 232.9 (M+1)+1.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[CH:19]=[CH:18][C:6]=1[C:7]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(=[O:3])[CH3:2].[CH3:25][N:26]([CH3:36])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]([CH3:35])[CH3:34])[CH:28]=1>>[CH3:34][N:33]([CH3:35])[C:29]1[CH:28]=[C:27]([N:26]([CH3:36])[CH3:25])[CH:32]=[CH:31][C:30]=1[C:7]1([C:6]2[CH:18]=[CH:19][C:20]([N:22]([CH3:24])[CH3:23])=[CH:21][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:13])[O:12]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: CC(=O)Nc1cc(N(C)C)ccc1C(=O)c1ccccc1C(=O)O
Product: CC(=O)Nc1cc(N(C)C)ccc1C1(c2ccc(N(C)C)cc2N(C)C)OC(=O)c2ccccc21

Procedure:
Condensation of 2-(2-acetamido-4-(dimethylamino)benzoyl)benzoic acid and N,N,N',N'-tetramethyl-m-phenylenediamine by the method of part B of Example 1 affords 3-(2,4-bis(dimethylamino)phenyl)-3-(2-acetamido-4-(dimethylamino)-phenyl)phthalide, the compound of part A of this example.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].O.C(OC([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([N:26]1[CH:33]=[C:32]([F:34])[C:30](=[O:31])[NH:29][C:27]1=[O:28])=[O:25])=O)(C)(C)C.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([N:26]1[CH:33]=[C:32]([F:34])[C:30](=[O:31])[NH:29][C:27]1=[O:28])=[O:25].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)NCCCCCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: NCCCCCCNC(=O)n1cc(F)c(=O)[nH]c1=O
Reaction time: 8 h

Procedure:
In 10 ml of a mixed solution of anhydrous trifluoroacetic acid: water=9:1 was suspended 0.74 g (2 mmole) of 1-[6-(t-butoxycarbonylamino)-n-hexylcarbamoyl]-5-fluorouracil under ice-cooling. When the suspension was stirred under ice-cooling, it was gradually dissolved to form a uniform solution. After stirring about one hour, the mixture was condensed under reduced pressure. To the residue was added 50 ml of toluene, and azeotropically dehydrated by reduced pressure condensation. To the residue was again added 50 ml of toluene, the same procedure as mentioned above was carried out. When about 100 ml of chloroform was added to the residue and allowed to stand overnight, the residue crystallized. Chloroform was removed under reduced pressure and the residue was recrystallized from 20 ml of ethanol. The title compound can be obtained with an amount of 0.29 g (Yield: 37.5%) as a salt of trifluoroacetic acid with a molar ratio of 1:1.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:33])[C@@H:4]2[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]2[C:11]=1[CH2:12][O:13][C:14]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>CO>[I:1][C:2]1[C@H:3]([OH:33])[C@@H:4]2[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]2[C:11]=1[CH2:12][O:13][C:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC1(C)O[C@@H]2C(COC(c3ccccc3)(c3ccccc3)c3ccccc3)=C(I)C(=O)[C@@H]2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)O[C@@H]2[C@H](O1)C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)=C(I)[C@@H]2O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of compound 6 (from Example 6b) was added to the reactor and cooled to 0° C. 2.2 kg MeOH was added followed by addition of CeCl3.7H2O (355 g) and the mixture stirred for 1 h to result homogeneous solution. NaBH4 (8.8 g) was added in portions at 0° C., stirred for 30 min, IPC showed the reaction started and additional NaBH4 (30 g) was added in portions with stirring for 1 h at 0° C. IPC showed complete consumption of compound 6. Saturated NH4Cl (0.27 kg) was added followed by celite (266 g) and the mixture stirred for 30 min after which it was filtered, washed with water (12 L×3), and dried over Na2SO4 to give compound 7 in MTBE solution (5.5 kg), which was concentrated (below 40° C.) to furnish a residue. DMF (3 kg) was added and the solution was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][N:11]=[CH:10][C:9]=1[N+:13]([O-:15])=[O:14].[CH:16](=O)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[N+:13]([C:9]1[CH:10]=[N:11][N:12]2[C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH:16]2[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)([O-:15])=[O:14]
Reactant: Nc1ccccc1-c1[nH]ncc1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Product: COc1ccc(C2Nc3ccccc3-c3c([N+](=O)[O-])cnn32)cc1
Yield: 97 %

Procedure:
5-(o-Aminophenyl)-4-nitropyrazole is reacted with p-anisaldehyde as given in Example 11. 1-Nitro-5-(p-methoxyphenyl)-5,6-dihydropyrazolo[1,5-c]quinazoline is obtained with a yield of 97%. M.p.: 181°-183° C.