Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)O1.Br[C:22]1[CH:23]=[C:24]([CH2:28][N:29]([CH3:39])[C:30](=[O:38])[C:31]2[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:25]=[N:26][CH:27]=1>>[CH3:39][N:29]([CH2:28][C:24]1[CH:25]=[N:26][CH:27]=[C:22]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[CH:23]=1)[C:30]([C:31]1[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][N:32]=1)=[O:38]
Reactant: CC1(C)OB(c2ccc3c(c2)CCC(=O)N3)OC1(C)C
Reactant: CN(Cc1cncc(Br)c1)C(=O)c1ncccc1Cl
Product: CN(Cc1cncc(-c2ccc3c(c2)CCC(=O)N3)c1)C(=O)c1ncccc1Cl

Procedure:
In analogy to the procedure described for the preparation of example 45, 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one (intermediate A-34) has been coupled to N-((5-bromopyridin-3-yl)methyl)-3-chloro-N-methylpicolinamide (intermediate A-57) to give the title compound as a light brown amorphous solid. MS: 407.5 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([OH:14])=O)[CH:3]=1.[CH2:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:31])[CH2:29][NH2:30])[CH2:24][CH2:23]1)=[O:21])[CH2:16][CH2:17][CH3:18].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.O>[CH2:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28](=[O:31])[CH2:29][NH:30][C:12]([C:4]2[CH:3]=[C:2]([OH:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[O:14])[CH2:26][CH2:27]1)=[O:21])[CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)c1cc(O)c2ccccc2n1
Reactant: CCCCOC(=O)N1CCN(C(=O)CN)CC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CCCCOC(=O)N1CCN(C(=O)CNC(=O)c2cc(O)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 9.5 g of 4-Hydroxy-quinoline-2-carboxylic acid and 12.2 g of 4-(2-Amino-acetyl)-piperazine-1-carboxylic acid butyl ester in 110 ml of DMF, 7.7 g of HOBT and 9.6 g of EDC was added and the reaction mixture was stirred for 16 h at RT. Then, the reaction mixture was diluted with water and extracted with DCM. The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was used in the next reaction step. Yield: 23 g.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH:25]3[CH3:30])[C:16]3[CH2:17][CH2:18][NH:19][CH2:20][CH2:21][C:22]=3[N:23]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[CH2:31]1[CH2:35][O:34][CH2:33][CH2:32]1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]3[CH3:30])[C:16]3[CH2:17][CH2:18][N:19]([CH2:35][CH2:31][CH2:32][CH2:33][OH:34])[CH2:20][CH2:21][C:22]=3[N:23]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: C1CCOC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4C)n2)CCNCC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CCN(CCCCO)CC3)cc1

Procedure:
During the synthesis of S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-6,7,8,9-tetrahydro-5H-pyrimido[5,4-d]azepin-2-yl)phenyl)urea (Step 3 of Example 286), the title compound sl (a white powder) was obtained as a by-product due to the oxidation of THF during long-term storage: 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.7 Hz, 2H), 6.33 (s, 1H), 4.62 (m, 1H), 3.89-3.55 (m, 6H), 3.39-3.15 (m, 5H), 2.98-2.52 (m, 7H), 1.74 (m, 8H), 1.33-1.02 (m, 6H); LC-MS m/z=483 (M+H).
Reaction SMILES: C([NH:8]C1C=C(C=C(S(Cl)(=O)=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.Cl[S:29]([C:32]1[C:33]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[C:34]([S:41][CH2:42][CH:43]=[CH:44][CH3:45])[CH:35]=[C:36]([CH:40]=1)[C:37]([OH:39])=[O:38])(=[O:31])=[O:30]>>[CH2:42]([S:41][C:34]1[CH:35]=[C:36]([CH:40]=[C:32]([S:29](=[O:31])(=[O:30])[NH2:8])[C:33]=1[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:37]([OH:39])=[O:38])[CH:43]=[CH:44][CH3:45]
Reactant: O=C(O)c1cc(NCc2ccccc2)c(-c2ccccc2)c(S(=O)(=O)Cl)c1
Reactant: CC=CCSc1cc(C(=O)O)cc(S(=O)(=O)Cl)c1-c1ccccc1
Product: CC=CCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1-c1ccccc1

Procedure:
By replacing in Example 1, step G, 3-benzylamino-5-chlorosulfonyl-4-phenylbenzoic acid with 5-chlorosulfonyl-3-crotylthio-4-phenylbenzoic acid, and following the procedure described, 3-crotylthio-4-phenyl-5-sulfamylbenzoic acid is obtained crystallizing with 0.5 mole of ethanol with a melting point of 89°-91° C.
Reaction SMILES: [BH4-].[Na+].CO[N:5]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([F:17])([F:16])[F:15])[CH3:7].O.[OH-].[NH4+]>O1CCCC1.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[F:15][C:14]([F:16])([F:17])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[CH:6]([NH2:5])[CH3:7]
Reactant: CON=C(C)c1ccccc1C(F)(F)F
Agent: [Zr+4]
Agent: [BH4-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.1 %

Procedure:
Sodium borohydride (1.17 g) is added slowly to a flask containing zirconium tetrachloride (1.8 g) in tetrahydrofuran (27 mL). A solution of 1-(2-trifluoromethyl-phenyl)-ethanone O-methyl-oxime (1.34 g) in tetrahydrofuran (7.7 mL) is added and the resulting solution is stirred at 25° C. for 12 hours. The reaction mixture is then cooled to 0° C. and water (16 mL) is slowly added. Excess ammonium hydroxide is added and the solution is extracted twice with ethyl acetate. The organic portion is washed twice with 1N hydrochloric acid. The aqueous (acid) layer is basified with sodium hydroxide and extracted twice with ethyl acetate. The organic layer is then washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is removed under reduced pressure to provide the desired product as a yellow oil (0.20 g).
Reaction SMILES: [N:1]1([C:10]2[CH:11]=[C:12]([CH2:16][NH:17][C:18](=O)[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=[CH:14][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[ClH:33]>C1COCC1>[ClH:33].[N:1]1([C:10]2[CH:11]=[C:12]([CH2:16][NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:13]=[CH:14][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cc1ccccc1)NCc1cccc(N2CCc3ccccc32)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: c1ccc(CCNCc2cccc(N3CCc4ccccc43)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
A solution of 15.53 g (45.35 mmole) of 3-(1-indolinyl)-N-phenylacetylbenzenemethanamine of Example 12 in 65 ml distilled THF was added dropwise over 30 minutes to an ice-salt cooled, rapidly stirred slurry of 10.44 g (275.1 mmole, 6.07 equivalents) LiAlH4 in 275 ml distilled THF under nitrogen. After warming to room temperature and stirring for 2 hours, the reaction mixture was heated under reflux for 19 hours and then quenched at 0° C. with 20 ml ice water-THF (1:1), 10 ml 10% NaOH, and 30 ml water. The salts were filtered, washed with CHCl3 and the filtrate was concentrated. The residue was dissolved in CHCl3, washed with brine, dried over Na2SO4, and concentrated to give 11.70 g (78.6%) of crude free base. Conversion to the HCl salt (ether/ethereal HCl) using the procedure of Example 1 gave 11.43 g (69.1%). Recrystallization from hot absolute ethanol gave 2.88 g (17.4% overall) of 3-(1-indolinyl)-N-(2-phenylethyl)benzenemethanamine hydrochloride, m.p. 188°-190° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:25]=[C:26]([NH:40][C:41](OC2C=CC=CC=2)=[O:42])[C:27](=[CH:38][CH:39]=1)[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[C:1]([O:5][C:6]([C:8]1[CH:9]=[C:10]([S:19]([NH:22][C:41]([NH:40][C:26]2[CH:25]=[C:24]([Cl:23])[CH:39]=[CH:38][C:27]=2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[O:42])(=[O:20])=[O:21])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]=1[OH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1cc(S(N)(=O)=O)c2ccccc2c1O
Product: CC(C)(C)OC(=O)c1cc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)c2ccccc2c1O
Yield: 73.2 %

Procedure:
323 mg (1.00 mmol) of 3-t-butoxycarbonyl-4-hydroxy-1-naphthalenesulfonamide and 381 mg (1.00 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Example 17 to obtain 447 mg (yield 73%) of 4-({[(2-benzyloxycarbonyl-5-chloroanilino)carbonyl]amino}sulfonyl)-1-hydroxy-2-naphthalenecarboxylic acid t-butyl ester. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 1.66 (9H, s), 5.34 (3H8 s), 6.98 (1H, d), 7.35–7.48 (5H, m), 7.66 (1H, m), 7.81 (1H, m), 7.89 (1H, d), 8.37 (2H, m), 8.44 (1H, s), 8.71 (1H, d), 10.02 (1H, br), 12.52 (1H, br).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[SH:33][CH2:34][CH2:35][NH:36][C:37](=[O:39])[CH3:38].CC(C)([O-])C.[K+]>O1CCOCC1>[C:37]([NH:36][CH2:35][CH2:34][S:33][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH2:31][CH3:32])=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1)(=[O:39])[CH3:38]
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(F)ccn34)c12
Reactant: CC(=O)NCCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(SCCNC(C)=O)ccn34)c12
Temperature: 95 °C
Yield: 58.3 %

Procedure:
N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-fluoroimidazo[1,2-a]pyridine-3-carboxamide (0.028 g, 0.065 mmol) (Example 74, Step A), N-(2-mercaptoethyl)acetamide (0.078 g, 0.65 mmol), and potassium tert-butoxide (0.022 g, 0.20 mmol) were added to a minimal amount of deoxygenated 1,4-dioxane in a sealed tube and heated for 18 hours at 95° C. The reaction mixture was cooled, concentrated under reduced pressure and purified by silica gel chromatography eluting with methanol (containing 6% ammonium hydroxide) and dichloromethane (1:9), to yield the product (20 mg) as a white powder. MS ESI (+) m/z 528 (M+1) detected.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1F.[OH2:20]>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[NH:9][CH2:8][CH2:7][O:20][CH2:5][CH2:6][OH:18]
Reactant: O
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: ClCCl
Product: O=C(O)c1cn(C2CC2)c2cc(Cl)c(NCCOCCO)cc2c1=O
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (10 g, 0.035 mol) in 1-methyl-2-pirolidone (70 mL) 2-(2-amino-ethoxy)-ethanol (18 mL, 0.18 mol, 5 eq.) was added, the reaction mixture was stirred at 110° C. for 24 hours. Then was diluted with water (200 mL) and CH2Cl2 (60 mL) and the pH was adjusted to 10. The aqueous layer was extracted with CH2Cl2 (5×50 mL) and then the pH was adjusted to 6.7. After 10 minutes first product precipitated. Filtrated off yielding 2.7 g of crude 7-chloro-1-cyclopropyl-6-[2-(2-hydroxy-ethoxy)-ethylamino]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid. (according to LC-MS 100% pure Intermediate 6B) Over night second product precipitated. Filtrated off yielding 7.7 g of yellow product (according to LC-MS a mixture of Intermediate 6A and Intermediate 6B in a 1:1 ratio).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][N:14]([CH:21]1[CH2:26][CH2:25][C:24](=[O:27])[NH:23][C:22]1=[O:28])[C:15]2=[O:20].[CH3:29][O:30][CH2:31][C:32](Cl)=[O:33]>C1COCC1>[O:28]=[C:22]1[CH:21]([N:14]2[CH2:13][C:12]3[C:16](=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][NH:9][C:32](=[O:33])[CH2:31][O:30][CH3:29])[C:15]2=[O:20])[CH2:26][CH2:25][C:24](=[O:27])[NH:23]1
Reactant: COCC(=O)Cl
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
Triethylamine (0.5 g, 5.0 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and methoxyacetyl chloride (0.3 g, 2.7 mmol) in THF (30 mL) at room temperature. The mixture was stirred at room temperature overnight. Reaction mixture was quenched with methanol (1 mL) and then concentrated. The residue was stirred with 1N HCl (30 mL) for 30 minutes and filtered. The solid was slurried with ethanol (15 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-methoxy-acetamide (0.4 g, 57%) as a white solid: mp 232-234° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.32-2.64 (m, 2H), 2.85-3.00 (m, 1H), 3.31 (s, 3H, CH3), 3.87 (s, 2H, CH2), 4.35 (d, J=6.2 Hz, 2H, CH2), 4.41 (d, J=17.3 Hz, 1H), 4.49 (d, J=17.3 Hz, 1H), 5.10-5.17 (dd, J=5.0 and 13.2 Hz, 1H, CH), 7.45-7.64 (m, 3H, Ar), 8.46 (t, J=5.8 Hz, 1H, NH), 11.00 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.16, 38.42, 46.18, 51.54, 58.61, 71.46, 121.60, 128.23, 130.69, 131.56, 134.65, 140.01, 168.03, 169.20, 170.97, 172.82, Anal. calcd. for C17H19N3O5: C, 59.12; H, 5.55; N, 12.17. Found: C, 59.10; H, 5.51; N, 12.05.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].[CH:20](OC)(OC)OC.O>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([N:12]2[C:11]3[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=3[N:1]=[CH:20]2)=[CH:14][CH:15]=1
Reactant: COC(OC)OC
Reactant: COC(=O)c1ccc(Nc2ccc(F)cc2)c(N)c1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(c1)ncn2-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 27d (0.18 g, 0.693 mmol) and trimethyl orthoformate (0.7 mL, 6.39 mmol) in DMF (2 mL) was refluxed for 5 h and then cooled to room temperature. Water was added to the mixture. The resulting solid was filtered, washed, with water, and dried. The crude product 27e was used in the next reaction without purification. MS m/z (M+H+) 271.1.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15](Cl)=[CH:14][CH:13]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+]>[Cu].CN(C)C=O>[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([N:7]([C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([N:8]([C:15]3[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=3)[C:15]3[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=3)[CH:2]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N(c2ccc([N+](=O)[O-])cc2)c2cccc(N(c3ccc([N+](=O)[O-])cc3)c3ccc([N+](=O)[O-])cc3)c2)cc1
Reaction time: 96 h

Procedure:
0.1 mole of m-phenylenediamine, 0.5 mole of p-nitrochlorobenzene, 0.24 mole of anhydrous potassium carbonate, and 2 parts by weight of powdery copper in 130 parts of dimethylformamide was refluxed with stirring for 4 days. After the reaction, the reaction mixture was filtered. The filtered matter was washed with dimethyformamide, water, and acetone, and was dried to obtain 26 parts of tetrakis(p-nitrophenyl)-1,3-phenylenediamine of reddish brown color.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:17][C:18]1[CH:23]=[C:22]([S:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1F>>[Cl:17][C:18]1[CH:23]=[C:22]([S:24]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)(=[O:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=S(=O)(Cc1ccc(F)cc1)c1ccc(F)c(Cl)c1
Reactant: CC(C(=O)O)c1cc(O)cc(C(F)(F)F)c1
Product: CC(C(=O)O)c1cc(Oc2ccc(S(=O)(=O)Cc3ccc(F)cc3)cc2Cl)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 50 step (iii) and the product from example 34 step (i).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[CH2:15]([C:18]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=1)([CH2:24][CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH2:17]>>[CH2:15]([C:18]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]3)[CH:27]=1)([CH2:24][CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:16]=[CH2:17]
Reactant: C=CCC(CC)(C(=O)OCC)c1cccc(O)c1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Product: C=CCC(CC)(C(=O)OCC)c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Yield: 25 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-bromomethyl-1-methyl-1,2-dihydroquinolin-2-one was reacted with ethyl 2-allyl-2-(3-hydroxyphenyl)butyrate to give ethyl 2-allyl-2-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]butyrate in 25% yield as a gum.
Reaction SMILES: [OH-].[K+].[C:3]([N:7]1[C:12](=[O:13])[C:11]([CH3:14])=[C:10](Cl)[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4].[CH2:16]([OH:18])[CH3:17]>O>[C:3]([N:7]1[C:12](=[O:13])[C:11]([CH3:14])=[C:10]([O:18][CH2:16][CH3:17])[CH:9]=[N:8]1)([CH3:6])([CH3:5])[CH3:4]
Reactant: CCO
Reactant: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOc1cnn(C(C)(C)C)c(=O)c1C

Procedure:
(Method B): In a mixture of 25 ml of ethanol and 25 ml of water was dissolved 4.7 g of potassium hydroxide and the 5.0 g (0.025 mol) of 2-tert.-butyl-5-chloro-4-methyl-3(2H)-pyridazinone was added thereto. The resulting mixture was stirred under reflux for 26 hours. After ethanol was distilled off, the reaction mixture was added with 100 ml of water and extracted with 100 ml of chloroform. The chloroform layer was washed with 100 ml of water, dried over anhydrous sodium sulfate and free of solvent by distillation to give 5.2 g of a crude product. The crude product was recrystallized from 30 ml of hexane to give 4.5 g of 2-tert.-butyl-5-ethoxy-4-methyl-3(2H)-pyridazinone.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.[Na+].[I-:18].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([CH3:16])[CH:9]=2)=[CH:6][C:7]=1[I:18]
Reactant: [I-]
Reactant: Cc1cc(-c2ccc(O)cc2)ccc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(-c2ccc(O)c(I)c2)ccc1C#N
Temperature: 0 °C
Reaction time: 1.33 h
Yield: 52 %

Procedure:
The product from Example 106B (4.67 g, 22.3 mmol), NaI (3.343 g, 22.3 mmol), and NaOH (892 mg, 22.3 mmol) were combined in methanol (70 mL) at 0° C. and treated with bleach (5.25%, 31.6 g) dropwise over 30 minutes. After being stirred at 0° C. for 80 minutes, the mixture was quenched with 10% aqueous sodium thiosulfate (10 mL). The mixture was acidified with 1M aqueous HCl (25 mL), neutralized with dipotassium hydrogen phosphate, recooled to 0° C., and filtered. The solids were rinsed with water, then mostly dissolved in 50% EtOAc/hexanes and filtered. When this filtrate was mostly concentrated crystals began to form. The solids were slurried with 20% EtOAc/hexanes, collected by filtration, and washed with 10% EtOAc/hexanes followed by hexanes to provide the impure title compound as a light tan powder (52% yield). MS (ESI APCI negative ion detection) m/z 334 (M−H)−; 1HNMR (300 MHz, d6-DMSO) δ 2.52 (s, 3H), 6.98 (d, 1 H), 7.58-7.63 (m, 2 H), 7.73 (s, 1 H), 7.78 (d, 1 H), 8.06 (d, 1 H), 10.66 (s, 1 H).
Reaction SMILES: Cl[C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][CH2:9][C:10]2([CH2:23][CH:24]3[CH2:26][CH2:25]3)[CH2:15][CH2:14][CH:13]([S:16]([CH2:19][CH:20]3[CH2:22][CH2:21]3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[O:7])=[C:4]([C:29]([F:32])([F:31])[F:30])[N:3]=1.[CH3:33][N:34](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:33]([C:2]1[CH:28]=[CH:27][C:5]([C:6]([NH:8][CH2:9][C:10]2([CH2:23][CH:24]3[CH2:26][CH2:25]3)[CH2:15][CH2:14][CH:13]([S:16]([CH2:19][CH:20]3[CH2:22][CH2:21]3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[O:7])=[C:4]([C:29]([F:32])([F:31])[F:30])[N:3]=1)#[N:34]
Reactant: CN(C)C=O
Reactant: O=C(NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1)c1ccc(Cl)nc1C(F)(F)F
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc(C(=O)NCC2(CC3CC3)CCC(S(=O)(=O)CC3CC3)CC2)c(C(F)(F)F)n1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
A mixture of 6-chloro-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2-(trifluoromethyl)nicotinamide (37 mg, 0.076 m-mol), zinc cyanide (44 mg, 0.38 mmol) and tetrakis triphenylphosphine palladium (0) (8.7 mg, 0.008 mmol) in N,N-dimethylformamide (1.5 mL) was heated at 150° C. for 600 s under microwave irradiation. The mixture was allowed to cool to ambient temperature, the supernatant layer removed and evaporated. The residue was partitioned between dichloromethane (5 ml) and water (5 ml) and stirred vigorously for 5 min. The mixture separated using a 5 micron PTFE frit and the filtrate was evaporated. The yellow oil was purified by preparative plate chromatography eluting with 10% ethyl acetate in dichloromethane. Collecting the appropriate band followed by trituration with ethyl acetate, filtration of the solid and evaporation of the filtrate gave a white solid. The solid was recrystallised from ethyl acetate/isohexane which gave 6-cyano-N-({1-(cyclopropylmethyl)-4-[(cyclopropylmethyl)sulfonyl]cyclohexyl}methyl)-2-(trifluoromethyl)-nicotinamide a white solid (21 mg, 57%): 1H NMR (400 MHz, CDCl3) δ 8.11 (1H, d, J=7.9 Hz), 7.95 (1H, d, J=7.9 Hz), 5.98 (1H, s), 3.61 (2H, d, J=6.3 Hz), 2.98-2.88 (3H, m), 2.04-2.01 (2H, m), 1.96-1.84 (4H, m), 1.43-1.37 (2H, m), 1.24 (2H, d, J=6.7 Hz), 1.18-1.12 (1H, m), 0.76 (2H, q, J=6.4 Hz), 0.68-0.64 (1H, m), 0.53-0.49 (2H, m), 0.41 (2H, q, J=5.3 Hz), 0.06-0.05 (2H, m); m/z=484 (M+H+).
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[C:19](=O)[CH2:20][CH2:21][C:22](O)=[O:23])([CH3:4])([CH3:3])[CH3:2].O.[NH2:28][NH2:29]>O>[C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=1[C:19]1[CH2:20][CH2:21][C:22](=[O:23])[NH:29][N:28]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)NCC(O)COc1ccc(C(=O)O)cc1C(=O)CCC(=O)O
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccc(C(=O)O)cc1C1=NNC(=O)CC1

Procedure:
A solution of equimolar amounts of 4-(3-t-butylamino-2-hydroxypropoxy)-3-(3-carboxypropionyl)benzoic acid and hydrazine hydrate in water was heated under reflux for 16 hours. The volume of the solution was reduced in vacuo to give 4-(3-t-butylamino-2-hydroxypropoxy)-3-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)benzoic acid.