Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[CH:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8](=O)[C:9](=[O:15])[NH:10]3)[CH2:4][CH2:3][CH2:2]1.IC1C=CC=C2C=1C(=O)C(=O)N2.C=C1CC=C1.[CH:34]1[C:39]([NH:40][NH2:41])=[CH:38][CH:37]=[C:36]([S:42]([NH2:45])(=[O:44])=[O:43])[CH:35]=1.Cl>>[C:1]1(=[CH:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8](=[N:41][NH:40][C:39]2[CH:38]=[CH:37][C:36]([S:42]([NH2:45])(=[O:43])=[O:44])=[CH:35][CH:34]=2)[C:9](=[O:15])[NH:10]3)[CH2:4][CH2:3][CH2:2]1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C1Nc2cccc(C=C3CCC3)c2C1=O
Agent: C=C1C=CC1
Agent: Cl
Agent: O=C1Nc2cccc(I)c2C1=O
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cccc(C=C4CCC4)c32)cc1
Yield: 76 %

Procedure:
By methods described in Procedure L, 4-cyclobutylidenemethyl-1H-indole-2,3-dione was prepared from 4-iodo-1H-indole-2,3-dione and methylene cyclobutene in 25% yield: 1H NMR (DMSO-d6): δ 2.08 (quintet, J=7.8 Hz, 2H), 2.91 (m, 2H), 3.06 (m, 2H), 6.67 (d, J=7.7 Hz, 1H), 6.94 (d, J=7.7 Hz, 1H), 6.96 (s, 1H), 7.47 (d, J=7.7 Hz, 1H), 11.00 (bs, 1H); APCI−MS m/z 211 (M−1)−. Condensation of 4-(cyclobutylidenemethyl)-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 76% yield: 1H NMR (DMSO-d6): δ 2.11 (quintet, J=7.8 Hz, 2H), 3.00 (t, J=7.8 Hz, 2H), 3.06 (t, J=7.8 Hz, 2H), 6.74 (d, J=7.7 Hz, 1H), 6.97 (d, J=7.7 Hz, 1H), 7.07 (s, 1H), 7.21 (t, J=7.7 Hz, 1H), 7.25 (s, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.81 (d, J=8.7 Hz, 2H), 11.12 (s, 1H), 13.03 (s, 1H); APCI−MS m/z 381 (M−1)−.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:11])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].Cl.C(OC(C)C)(=[O:21])C>C(O)(C)C>[CH3:11][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:1])[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].[CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:21]
Reactant: CC(=O)OC(C)C
Reactant: CC(C)(c1ccccn1)C(N)c1ccccc1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)(C(=O)c1ccccc1)c1ccccn1
Product: CC(C)(c1ccccn1)[C@@H](N)c1ccccc1

Procedure:
(S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine is prepared starting from racemic 2-methyl-1-phenyl-2-(pyridin-2-yl)propan-1-amine using chiral SFC chromatography. This oil is dissolved in isopropyl acetate and a solution of 5-6 N HCl in isopropyl alcohol is added. The mixture is concentrated, and triturated in ether to yield 4 as a white solid. M.p.=188° C. 1HNMR (300 MHz, CD3OD): δ 1.59 (s, 3H), 1.76 (s, 3H), 5.09 (s, 1H), 7.25-7.28 (m, 2H), 7.38-7.40 (m, 3H), 8.00 (t, J=6.6 Hz, 1H), 8.11 (d, J=6.9 Hz, 1H), 8.56 (t, J=7.8 Hz, 1H), 8.77 (d, J=5.7 Hz, 1H). MS: m/z 227.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O.[Cl-].[Mg+2].[Cl-].C(O)(=O)[CH2:26][C:27]([OH:29])=[O:28].[CH2:32]([K])[CH3:33].C(N(CC)CC)C>>[CH2:32]([O:29][C:27](=[O:28])[CH2:26][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[CH3:33]
Reactant: CC[K]
Reactant: O=C(O)CCCCCCCCCCCOC1CCCCO1
Reactant: O=C(O)CC(=O)O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)CCCCCCCCCCCOC1CCCCO1

Procedure:
The title compound was prepared from 12-[(tetrahydro-2H-pyran-2-yl)oxy]-dodecanoic acid (10.0 g, 0.033 mol), 1,11-carbonyldiimidazole (6.47 g, 0.039 mol), magnesium chloride (6.02 g, 0.063 mol), ethyl potassium malonate (9.06 g, 0.053 mol), and triethylamine (7.40 g, 0.073 mol) using the procedure described in Example 3, Step A.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](Br)=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:4].[C:14]([CH:16]1[CH2:18][CH2:17]1)#[CH:15].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>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.[Cu]I.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]#[C:14][CH:16]2[CH2:18][CH2:17]2)=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:4]
Reactant: C#CC1CC1
Reactant: COC(=O)c1sc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1sc(C#CC2CC2)cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
Firstly bis(triphenylphosphine)palladium(II) chloride (17.6 mg) and then copper(I) iodide (19 mg) were added to a mixture of 5-bromo-3-nitrothiophene-2-carboxylic acid methyl ester (133 mg), ethynylcyclopropane (66 mg), triethylamine (51 mg), triphenylphosphine (3.3 mg) and THF (14 mL). After one hour, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The crude product was purified by preparative HPLC. The product with the molecular weight of 251.26 (C11H9NO4S) was obtained in this way; MS (ESI): 252 (M+H+).
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[C:8](C)[CH:7]=[CH:6][C:5]=1[O:11][S:12]([CH3:15])(=[O:14])=[O:13].[Li+].[BH4-].[CH3:19]O.Cl>C1COCC1.O.CCOC(C)=O>[OH:16][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:19])=[CH:6][C:5]=1[O:11][S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: COC(=O)c1cc(C)ccc1OS(C)(=O)=O
Reactant: CO
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(CO)c(OS(C)(=O)=O)c1
Reaction time: 0.25 h

Procedure:
To a solution of 2-methanesulfonyloxy-5-methylbenzoic acid methyl ester (15 g, 61.4 mmol) in THF (30 mL) at 0° C. is added portionwise LiBH4 (4.0 g, 184 mmol) and the mixture is stirred for 15 min. Then MeOH (8 mL, 196 mmol) is added dropwise over 30 min. The mixture is stirred under ice cooling for 30 min, then at RT for 18 h. EtOAc is added followed by ice and water. The mixture is acidified slowly with 1N HCl solution and organic phase is separated. The aqueous phase is extracted with EtOAc. The organic phases are combined, and washed with 1N HCl solution, and brine. It is then dried over Na2SO4 and MgSO4, and concentrated to give the title compound as an oil.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[N:16]1([C:21]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH3:7][N:6]1[C:2]([C:24]2[CH:23]=[CH:22][C:21]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:26][CH:25]=2)=[C:3]([C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[N:4]=[CH:5]1
Reactant: OB(O)c1ccc(N2CCCC2)cc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(N2CCCC2)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-pyrrolidinophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H19N5, 330. Found, 330.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:45]([O:47][C:48](=[O:60])[C@H:49]([OH:59])[C@H:50]([NH2:58])[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH3:46]>C(Cl)Cl>[CH2:45]([O:47][C:48](=[O:60])[C@H:49]([OH:59])[C@H:50]([NH:58][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([Br:1])[CH:3]=1)[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[CH3:46]
Reactant: CCOC(=O)[C@H](O)[C@H](N)Cc1ccccc1
Reactant: O=C(O)c1ccc(F)c(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)c1ccc(F)c(Br)c1
Reaction time: 1 h

Procedure:
3-Bromo-4-fluorobenzoic acid (109 mg, 497 μmol, 1.0 eq.), DIPEA (273 μL, 3.2 eq.), HATU (189 mg, 497 μmol, 1.0 eq.), and (2R,3R)-3-amino-2-hydroxy-4-phenyl-butyric acid ethyl ester (129 mg, 497 μmol, 1.0 eq.) were combined in DCM (2 mL) and stirred for 1 hour. The crude reaction was then chromatographed (0-80% EtOAc/hexanes gradient) to yield (2R,3R)-3-(3-bromo-4-fluoro-benzoylamino)-2-hydroxy-4-phenyl-butyric acid ethyl ester.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:16]O>>[CH3:2][C:3]1[NH:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH3:16])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CO
Reactant: Cc1nc2ccc(C(=O)O)cc2[nH]1
Agent: Cl
Product: COC(=O)c1ccc2nc(C)[nH]c2c1
Yield: 93.2 %

Procedure:
Mass spectrum (FAB, Pos): m/z 177 (M+ +1, as a free base). ##STR15## 2-Methylbenzimidazole-5-carboxylic acid hydrochloride, 6.6 g (32.5 mmols), was added to 200 ml of methanol and 5 ml of conc. hydrochloric acid was added to the mixture followed by heating to reflux for 8 hours. The solvent was distilled off under reduced pressure and 200 ml of water was added to the residue. After 1 N sodium hydroxide solution was added to the mixture to adjust pH to 9 to 10, the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off to give 5.5 g (93.2%) of methyl 2-methyl-benzimidazole-5-carboxylate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[CH3:33][C:34]1[C:38]([S:39](Cl)(=[O:41])=[O:40])=[C:37]([CH3:43])[O:36][N:35]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:39]([C:38]5[C:34]([CH3:33])=[N:35][O:36][C:37]=5[CH3:43])(=[O:41])=[O:40])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Product: Cc1noc(C)c1S(=O)(=O)NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}-3,5-dimethylisoxazole-4-sulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and 3,5-dimethylisoxazole-4-sulfonyl chloride following General Procedure U.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=2[CH:5]=[C:4]([F:14])[CH:3]=1.Cl.Cl.[NH2:17][C@@H:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[C@@H:18]([NH:17][C:11]([C:8]1[O:9][C:10]3[C:2]([Br:1])=[CH:3][C:4]([F:14])=[CH:5][C:6]=3[CH:7]=1)=[O:13])[CH2:19]2
Reactant: O=C(O)c1cc2cc(F)cc(Br)c2o1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(F)cc(Br)c2o1
Reaction time: 0.33 h

Procedure:
143 mg (0.55 mmol) of 5-fluoro-7-bromo-1-benzofuran-2-carboxylic acid (Example 4A), 100 mg (0.50 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 229.14 mg (0.6 mmol) of HATU, 234 mg (1.81 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF are reacted by general method C. DMF is removed under reduced pressure, and the crude product is dissolved in 1N sodium hydroxide solution. The aqueous phase is extracted with ethyl acetate, and the organic phase is washed with saturated aqueous sodium chloride solution. The combined organic phases are dried over magnesium sulphate, and the solvent is removed in a rotary evaporator under reduced pressure. The crude product is taken up in methanol and shaken together with acidic ion exchanger (Dowex® WX2-200) for about 20 min. The loaded ion exchanger is washed three times with 30 ml of methanol each time, then with water, again with methanol, with dichloromethane and finally again with methanol. The product is eluted with methanol/triethylamine 95:5. The solvent is removed in a rotary evaporator under reduced pressure. 181 mg (98% of theory) of the title compound are isolated.
Reaction SMILES: C1(C)C=CC(S(O[CH:11](C)[C:12](OC)(OC)[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][CH3:24])[CH:19]=3)[CH:14]=2)(=O)=O)=CC=1.[CH3:31]S(OC(C)C(OC)(OC)C1C=CC2C(=CC=C(OC)C=2)C=1)(=O)=O.[C:55](=[O:58])([O-])[O-:56].[Ca+2].CN(C)C=O>O>[CH3:24][O:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:12]([CH3:11])[C:55]([O:56][CH3:31])=[O:58])[CH:22]=[CH:21]2
Reactant: COc1ccc2cc(C(OC)(OC)C(C)OS(=O)(=O)c3ccc(C)cc3)ccc2c1
Reactant: COc1ccc2cc(C(OC)(OC)C(C)OS(C)(=O)=O)ccc2c1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)c1ccc2cc(OC)ccc2c1

Procedure:
A mixture of 3.07 grams of (S) 1,1-dimethoxy-1-(6-methoxy-2-naphthyl)prop-2-yl methanesulfonate, 1.0 gram of calcium carbonate, 100 ml. of dimethylformamide and 25 ml. of water is heated to 110° C. and maintained at that temperature for 5 hours. Then the mixture is cooled and the insolubles removed by filtration. The filtrate is poured into excess water and the solid which forms is collected by filtration. Separation by chromatography yields methyl 2-(6-methoxy-2-naphthyl)propionate, exhibiting an [α]25D =+77° in chloroform and an optical purity of greater than 99 percent.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][CH:7]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(Cl)Cl>[N:5]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][NH:11][C:12](=[O:17])[C:13]([CH3:15])([CH3:16])[CH3:14])=[CH:18][CH:19]=1)=[C:1]=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)C(=O)NCc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)C(=O)NCc1ccc(N=C=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of phosgene (24.1 ml of a 1.93 M solution in toluene, 46.5 mmol) in methylene chloride (50 ml) cooled to 0° C. is added dropwise a solution of N-(4-amino-benzyl)-2,2-dimethyl-propionamide (8 g, 38.8 mmol) and triethyl amine (13.5 ml, 97 mmol) in methylene chloride (80 ml). The reaction mixture is allowed to slowly warm to 25° C. and stirred at this temperature for 18 hrs. The reaction mixture is filtered on dry cellite, under an argon atmosphere and the filtrate is concentrated in vacuo. The residue is dissolved in methylene chloride (380 ml) to provide a 0.1 M solution of N-(4-isocyanato-benzyl)-2,2-dimethyl-propionamide in methylene chloride which is used as is.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34].C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1.O>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][C:30]1[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=1)[C:33]([O:35][CH3:36])=[O:34])=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cccc(Oc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1
Temperature: 120 °C

Procedure:
A mixture of 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol (2.65 g, 7.0 mmol), methyl 3-bromobenzoate (3.01 g, 14.0 mmol), CuO (1.01 g, 12.6 mol), and K2CO3 (1.93 g, 14.0 mmol) in dry pyridine (17.5 mL) are heated under nitrogen at 120° C. for 48 h. The cooled reaction is diluted with water (100 mL) and extracted with ether (2×100 mL). The dried (MgSO4) extracts are concentrated to a dark oil which is chromatographed on silica gel using 20:80 ethyl acetate:hexane as eluent isolating the title compound as a colorless tacky solid (Rf˜0.3, 1.53 g). MS (ESI) m/z 514; HRMS: calcd for C31H22F3NO3+H+, 514.16245; found (ESI, [M+H]+), 514.1638.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10](=[O:17])[C:9]3[CH2:18][C:19](=[O:22])[CH2:20][CH2:21][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].C(O)C>O>[C:1]1([N:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:10](=[O:17])[C:9]3[CH2:18][CH:19]([OH:22])[CH2:20][CH2:21][C:8]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCc2c(c(=O)c3cccnc3n2-c2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1c2c(n(-c3ccccc3)c3ncccc13)CCC(O)C2
Reaction time: 0.25 h

Procedure:
Reduce 6,8,9,10-tetrahydro-10-phenylbenzo[b][1,8]naphthyridin-5,7-dione (2 mmol) with sodium borohydride (50 mg) in a solvent of ethanol (30 ml) and water (0.25 ml). After 15 minutes, pour the reaction mixture over ice and collect the resulting precipitate on a filter. Reserve the precipitate, and extract the aqueous filtrate with chloroform. Dry the extracts, evaporate the chloroform, and combine the residue with the reserved precipitate to give the product, 10-phenyl-7-hydroxy-6,7,8,9-tetrahydro-benzo[b][1,8]naphthyridin-5(10H)-one, m.p. 283°-286° C. after crystallization from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[C:12]([CH3:17])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].I[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:17][C:12]1[CH:11]=[C:10]([N:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[C:28]2[CH:29]=[CH:30][C:25]([C:22]3[CH:23]=[CH:24][CH:19]=[CH:20][CH:21]=3)=[CH:26][CH:27]=2)[CH:15]=[CH:14][C:13]=1[CH3:16]
Reactant: Cc1ccc(Nc2ccc(C)c(C)c2)cc1C
Reactant: Ic1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: Cc1ccc(N(c2ccc(-c3ccccc3)cc2)c2ccc(C)c(C)c2)cc1C
Temperature: 120 °C
Reaction time: 3 h

Procedure:
In a 500 milliliter round bottomed flask equipped with mechanical stirrer and fitted with a Dean-Stark trap under a reflux condenser were placed 12.39 grams (0.055 mole) of bis(3,4-dimethylphenyl)amine, 14 grams (0.050 mole) of 4-iodobiphenyl, 0.25 gram (0.0025 mole) of cuprous chloride, 0.45 gram (0,0025 mole) of 1,10-phenanthroline, 22.44 grams (0.4 mole) of flake potassium hydroxide and 20 milliliters of toluene solvent. The reaction was heated quickly to a reflux temperature of 120° C. and maintained at this temperature for 4 hours after which time chromatographic analysis revealed the reaction to be complete. The reaction was cooled to room temperature, about 25° C., and partitioned between 200 milliliters of toluene and 150 milliliters of deionized water. The resulting organic layer was separated and water removed by azeotropic distillation of the solvent under a Dean-Stark trap. The product was decolorized by slurry treating the toluene solution with 10 grams of Filtrol-24™, an acid washed clay, and 10 grams of Alcoa CG-20 alumina. After 3 hours stirring at reflux, the solution was hot filtered to remove the clay and alumina, and cooled to room temperature. Evaporation of the solvent and recrystallization from octane provided the above product compound in a yield of 10.2 grams (76 percent) and which product melted at 113.8° C. This product of N,N-bis(3,4-dimethylphenyl)-4-biphenylamine was suitable for further purification by conventional means to afford electronic grade, about 99 percent pure, product. The above total reaction time was an accelerated 4 hours.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[O:25][C:26]([NH:29][C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[C:32]([F:38])[CH:31]=4)=[N:27][N:28]=3)=[O:23])=[C:17]([F:39])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])C.C1COCC1.CO>O>[F:39][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[NH:21][C:22]([C:24]1[O:25][C:26]([NH:29][C:30]2[CH:31]=[C:32]([F:38])[C:33]([F:37])=[C:34]([F:36])[CH:35]=2)=[N:27][N:28]=1)=[O:23])[O:14][C@@H:11]1[CH2:10][CH2:9][C@H:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1CCC(Oc2ccc(NC(=O)c3nnc(Nc4cc(F)c(F)c(F)c4)o3)c(F)c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(O[C@H]2CC[C@@H](C(=O)O)CC2)cc1F)c1nnc(Nc2cc(F)c(F)c(F)c2)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
A solution of lithium hydroxide (1.61 g, 38.3 mmol) in water (10 mL) was added in one portion to a solution of 4-(3-fluoro-4-{[5-(3,4,5-trifluoro-phenylamino)-[1,3,4]oxadiazole-2-carbonyl]-amino}-phenoxy)-cyclohexanecarboxylic acid ethyl ester (Intermediate 2, 2.0 g, 3.83 mmol) in a 1:1 mixture of THF and methanol (60 mL) was added and the mixture stirred at ambient temperature for 4 h. The mixture was concentrated in vacuo, acidified with a 1M aqueous solution of citric acid and then filtered to leave a solid. The solid was washed with water, dried and recrystallised from ethanol (30 mL) to give the title compound as a white solid (1.1 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[C:23]([CH2:25][OH:26])[N:22]([CH3:27])[N:21]=1)=[CH:16][CH:15]=3.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:30](=[O:31])[N:29]([CH3:32])[C:12]2[N:13]([CH3:28])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[C:23]([CH2:25][O:26][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[N:22]([CH3:27])[N:21]=1)=[CH:16][CH:15]=3
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1CO
Product: Cn1nc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)cc1COC(=O)C(C)(C)C

Procedure:
The process is carried out as indicated in Example 70 above, with the compound from Example 82, 3-(2,4-dichlorophenyl)-6-(5-hydroxymethyl-1-methyl-1H-pyrazol-3-yl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, and pivaloyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Br:10])[CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>>[Br:10][C:8]1[CH:7]=[C:4]2[C:3](=[C:2]([Cl:1])[CH:9]=1)[O:11][C:12](=[O:14])[CH:13]=[CH:5]2
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc(Br)cc(Cl)c1O
Solvent: CCN(CC)CC
Product: O=c1ccc2cc(Br)cc(Cl)c2o1
Temperature: 136 °C

Procedure:
To a 5L round bottom flask fitted with a mechanical stirrer and condenser was placed 3-chloro-5-bromosalicylaldehyde (554.1 g, 2.35 mol, 1 equiv.), acetic anhydride (1203 g, 11.8 mol, 5 equiv.) and triethylamine (237.4 g, 2.35 mol, 1 equiv.). The reaction solution was heated at reflux (131-141° C.) overnight. The dark brown reaction mixture was cooled to 50° C. and ice (2 L) added (ice-bath cooling) with stirring. After one hour the mixture was filtered and the filtrate combined with EtOH (1 L). To this mixture was added EtOH (300 mL) and the reaction mixture stirred for one hour. The precipitate that formed was collected by filtration and washed with water: EtOH (3×1.3 L), vacuum and dried then dried on a fluid-bed drier. The total isolated yield is 563 g or 92%.