Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[C:31]1([NH:30][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]3[CH2:13][CH2:14][O:15][C:16]4[CH:22]=[CH:21][C:20]([C:23]5[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=5)=[CH:19][C:17]=4[CH:18]=3)=[O:11])=[CH:5][CH:4]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CNc4ccccc4)cc2)CCO3)cc1

Procedure:
A solution of N-(4-chloromethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (0.15 g) and aniline (0.1 ml) in dimethylformamide (10 ml) was stirred at room temperature over night. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (ethyl acetate/hexane) to give crude crystals, which were recrystallized from ethanol-hexane to give N-(4-((phenylamino)methyl)-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 115) (0.1 g) as colorless crystals.
Reaction SMILES: CS[C:3]1[N:8]=[N:7][C:6](SC)=[C:5]2[CH:11]=[N:12][C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:4]=12.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[O:24]1[CH2:25][CH2:26][N:21]([C:3]2[N:8]=[N:7][C:6]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[C:5]3[CH:11]=[N:12][C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:14][C:4]=23)[CH2:22][CH2:23]1
Reactant: CSc1nnc(SC)c2cc(-c3ccccc3)ncc12
Reactant: C1COCCN1
Product: c1ccc(-c2cc3c(N4CCOCC4)nnc(N4CCOCC4)c3cn2)cc1
Temperature: 180 °C

Procedure:
1 part by weight of 1,4-dimethylmercapto-7-phenylpyrido[3,4-d]pyridazine and 10 parts by volume of morpholine are placed in a glass tube, and the glass tube is sealed. The reaction system is heated at 180°C for 8 hours. The excess amount of morpholine is removed by evaporating under reduced pressure, and water is added to the residue. Thus precipitated crude crystals are collected by filtration. The crude crystals are adsorbed on a column packed with silica-gel, followed by eluting with a mixture of acetone and benzene (1:4). The eluate is concentrated under reduced pressure and recrystallized from methanol to obtain 1,4-dimorpholino-7-phenylpyrido[3,4-d]pyridazine as pale yellow needles melting at 186° to 188°C.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=2)[N:4]([S:14]([C:17]2[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:3]=1.[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[C:24]([NH:32][NH:33][C:11]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:3]=[C:2]2[I:1])=[O:12])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NNC(=O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)ccc32)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NNC(=O)c4ccccc4)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a stirring suspension of 3-iodo-1-tosyl-1H-indole-5-carboxylic acid (515 mg, 1.17 mmol) and benzohydrazide (159 mg, 1.167 mmol) in THF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.51 mL, 2.92 mmol) followed by HATU (488 mg, 1.28 mmol) in one portion and the solution was stirred at RT for 2 h. The reaction was quenched with 20 mL of ice cold H2O and extracted with EtOAc (2×50 mL). The organic layer was washed with 10 mL of sat. NaHCO3 followed by brine, and dried over Na2SO4. It was concentrated to about 5 mL and the precipitated solid was filtered, rinsed with EtOAc (2×2 mL). The white solid was collected and dried in a vacuum oven for 5 h at 40° C. affording N′-benzoyl-3-iodo-1-tosyl-1H-indole-5-carbohydrazide (305 mg, 47%) as an off-white crystalline solid. MS (ESI, pos. ion) m/z: 560.0 (M+1). 1H NMR (400 MHz, DMSO-D6) δ ppm 10.67 (1H, s), 10.52 (1H, s), 8.19 (1H, s), 8.08 (1H, d, J=8.4 Hz), 78.03-7.88 (6H, m), 7.67-7.49 (3H, m), 7.42 (2H, d, J=8.2 Hz), 2.33 (3H, s).
Reaction SMILES: [NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.CS([O-])(=O)=O.[C:19]([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[C:27](O)[CH:26]=[CH:25]2)(=[NH:21])[NH2:20].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CO.CN(C=O)C.N1C=CC=CC=1>[NH2:1][N:2]=[CH:3][NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:27]2[CH:26]=[CH:25][C:24]3[C:29](=[CH:30][CH:31]=[C:22]([C:19](=[NH:20])[NH2:21])[CH:23]=3)[C:28]=2[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[O:10])=[CH:7][CH:6]=1
Reactant: NN=CNc1ccc(C(=O)O)cc1
Reactant: COC(=O)Cc1c(O)ccc2cc(C(=N)N)ccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)[O-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)Cc1c(OC(=O)c2ccc(NC=NN)cc2)ccc2cc(C(=N)N)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
170 Milliliters of anhydrous pyridine and 72 ml of DMF were added to 8.1 g of 4-aminoiminomethylaminobenzoic acid.methanesulfonate, 10.0 g of 6-amidino-1-methoxycarbonylmethyl-2-naphthol.methanesulfonate, 71.6 g of DCC and 170 mg of DMAP, followed by stirring for 2 hours under cooling with ice and 24 hours at room temperature. The precipitate was filtered and washed with a small amount of DMF. The filtrate and the wash liquid were combined and this was concentrated under reduced pressure. To the residue was added 50 ml of DMF, and the resulting solution was added dropwise to 700 ml of ether, followed by stirring for 24 hours under cooling with ice. The supernatant was decanted, and then to the residue was added 200 ml of acetone, followed by stirring for 1 hour under cooling with ice. The precipitate was collected by filtration to obtain a crude product. To the collected precipitate was added 300 ml of methanol to dissolve the precipitate. To the solution was added 2 g of active carbon, followed by stirring for 30 minutes at room temperature. Insoluble matter was filtered off and the filtrate was concentrated under reduced pressure. To the residue was added 100 ml of methanol to dissolve the residue with heating. The resulting solution was added dropwise to 300 ml of acetone, followed by stirring for 24 hours under cooling with ice. Then, the precipitate was collected by filtration to obtain 4.2 g of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][OH:7].[Li]CCCC.[B:18](OC)([O:21]C)[O:19]C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[CH3:12][O:11][C:9]1[CH:8]=[C:5]([CH2:6][OH:7])[CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[B:18]([OH:21])[OH:19]
Reactant: COB(OC)OC
Reactant: COc1cc(CO)cc(OC)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)cc(OC)c1B(O)O
Temperature: 25 °C

Procedure:
To a solution of 3,5-dimethoxybenzyl alcohol (80 g) in THF (1900 ml) was added n-BuLi (1.6 M in n-hexane, 750 ml) portionwise at −50° C. for 0.5 hour under argon. The mixture was warmed up to room temperature for 2 hours and cooled again to −60° C. To the mixture was added (MeO)3B (200 ml). The resulting mixture was warmed to room temperature and stirred over night. To the reaction mixture was added a solution of citric acid (300 g) in H2O (1200 ml) portionwise at 0° C. The aqueous layer was separated, saturated with NaCl and extracted with AcOEt. The combined AcOEt extract was dried (Na2SO4) and evaporated. The crystalline residue was triturated with AcOEt and collected by filtration to yield the title compound (75.1 g). mp. 92-98° C.; IR (Nujol) 3460, 3408, 3218, 1613, 1578, 1288, 1231, 1123, 1055, 960, 779 cm−1; MS (APCI) m/z 230 (M+NH4).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[S:14]([N:17]2[C@H:22]([CH3:23])[CH2:21][N:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[CH2:19][C@@H:18]2[CH3:35])(=[O:16])=[O:15])[CH2:6]1)=[O:4].[OH-:36].[Li+].[CH2:38]1COCC1>O>[S:14]([C:11]1[CH:12]=[CH:7][C:8]([CH3:38])=[CH:9][CH:10]=1)([OH:15])(=[O:16])=[O:36].[CH3:35][C@H:18]1[CH2:19][N:20]([C:24]2[CH:25]=[CH:26][C:27]([O:30][C:31]([F:33])([F:32])[F:34])=[CH:28][CH:29]=2)[CH2:21][C@@H:22]([CH3:23])[N:17]1[S:14]([C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[CH2:13][C@@H:5]([C:3]([OH:4])=[O:2])[CH2:6]2)(=[O:15])=[O:16]
Reactant: [OH-]
Reactant: COC(=O)[C@H]1Cc2cccc(S(=O)(=O)N3[C@H](C)CN(c4ccc(OC(F)(F)F)cc4)C[C@@H]3C)c2C1
Reactant: C1CCOC1
Agent: [Li+]
Solvent: O
Product: C[C@@H]1CN(c2ccc(OC(F)(F)F)cc2)C[C@H](C)N1S(=O)(=O)c1cccc2c1C[C@@H](C(=O)O)C2
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 20 °C

Procedure:
To a solution of (S)-4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid methyl ester, in THF, is added a solution of lithium hydroxide in water, which is stirred at 20° C. and concentrated under reduced pressure. The reaction mixture is cooled to 9° C., neutralized with 32% HCl, and extracted from toluene. Water is removed from the organic solution by azeotropic distillation. Following distillation, the organic solution is cooled to ambient temperature and transferred to a feeding vessel. The reactor is charged with p-toluenesulfonic acid in toluene and water is removed by azeotropic distillation. The solution is cooled to 60° C., followed by the addition of the organic solution from the feeding vessel. The mixture is stirred at 83° C., then cooled to 10° C. to induce crystallization. The product suspension is filtered, the filter cake rinsed with heptane, and dried on a rotovap, at 40° C., to afford (S)-4-[cis-2,6-dimethyl-4-(4-trifluoromethoxy-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid tosylate. 1HNMR δ 1.60 (d), 1.62 (d), 2.33 (s), 3.23 (m), 3.49 (m), 3.39 (m), 4.05 (m), 4.49 (m), 3.40 (dd), 3.23 (dd), 7.14 (d), 7.14 (d), 7.09 (d), 7.09 (d), 7.59 (d), 7.59 (d), 7.71 (d), 7.26, dd, 7.57 (d), 7.57 (d), 7.40 (d).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[N:25]1([CH2:31][C:32]2[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=2)[CH:35]=O)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:35]([C:34]3[CH:37]=[CH:38][CH:39]=[C:32]([CH2:31][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[CH:33]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1cccc(CN2CCOCC2)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: Brc1cnc2[nH]c(-c3cccc(CN4CCOCC4)c3)nc2c1N1CCN(Cc2cccnc2)CC1
Temperature: 70 °C
Reaction time: 9 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-pyridin-3-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.060 g, 0.15 mmol) and EtOH (4.5 ml) was added 3-morpholin-4-ylmethyl-benzaldehyde (0.035 g, 0.17 mmol) followed by a freshly prepared 1M aqueous solution of Na2S2O4 (0.55 ml, 0.55 mmol). The reaction mixture was stirred at 70° C. for 9 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, and the free-running powder was placed on a 10 g isolute silica column. Elution of the column with a gradient of methanol (2 to 10%) in ethyl acetate/dichloromethane (v:v; 4:1) afforded a yellow solid which was triturated with diethyl ether. The pale yellow precipitate was collected by filtration, and was successively washed with diethyl ether, water, and diethyl, then dried in vacuo (0.003 g, 4%). 1H-NMR (500 MHz, DMSO-d6) 2.40 (br s, 4H) and 3.59 (t, J=4.50 Hz, 4H) (morpholine N(CH2)2, and morpholine O(CH2)2), 2.63 (br s, 4H, piperazine N(CH2)2), 3.68 (br s, 4H, piperazine N(CH2)2), 3.56 (s, 2H) and 3.62 (s, 2H) (NCH2-pyridyl and C6H4CH2), 7.40 (dd, J=4.5, 7.7 Hz, 1H, pyridine 5-H), 7.45 (d, J=7.7 Hz, 1H, PhH), 7.49 (t, J=7.7 Hz, 1H, PhH), 7.78 (d, J=7.8 Hz, 1H, pyridine 4-H), 8.07 (d, J=7.6 Hz, 1H, PhH), 8.14 (s, 1H, PhH), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.50 (dd, J=1.5, 4.8 Hz, 1H, pyridine 6-H), 8.56 (d, J=1.4 Hz, 1H, pyridine 2-H), 13.48 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]([OH:16])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=2[NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.OS(O)(=O)=O.CO.[C:34]([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]([O:16][CH3:34])([CH3:15])[CH3:14])[CH:10]=[CH:9][C:8]=2[NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: O=C([O-])O
Reactant: CC(C)(O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(C)(C)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(1-hydroxy-1-methyl-ethyl)-phenyl]-amide (as prepared in example 12, 18.0 mg, 0.0514 mmol) in 1 mL of DCM was added conc H2SO4 (50 μL) followed by 50 μL of MeOH. The resulting mixture was stirred at RT for 0.5 h and then treated with 10 mL of saturated NaHCO3 aqueous solution. The mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with H2O (10 mL), brine (10 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1% MeOH/DCM) gave 8.2 mg (44%) of the title compound as a white solid. 1H-NMR (CDCl3; 400 MHz): δ 12.31 (s, 1H), 9.65 (s, 1H), 8.30 (d, 1H, J=8.6 Hz), 7.76 (s, 1H), 7.35 (dd, 1H, J=8.6, 2.3 Hz), 7.25 (d, 1H, J=2.3 Hz), 5.88 (m, 1H), 3.11 (s, 3H), 2.23-2.37 (m, 4H), 1.75-1.90 (m, 4H), 1.55 (s, 6H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][N:16](C(OCC1C=CC=CC=1)=O)[CH2:15][CH2:14]2)=[O:10].C(O)C.[H][H]>[Pd].C(N(CC)CC)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH2:17][NH:16][CH2:15][CH2:14]2)=[O:10]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(c1)CCN(C(=O)OCc1ccccc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NOC1CCCCO1)c1ccc2c(c1)CCNC2
Yield: 90.6 %

Procedure:
A mixture of 5 g benzyl 6-[(tetrahydro-2H-pyran-2-yloxy)carbamoyl]-3,4-dihydroisoquinoline-2(1H)-carboxylate, 250 mg Pd/C (5%), 250 ml ethanol and 5 ml triethylamine is hydrogenated at ambient hydrogen pressure. The reaction mixture is filtered, evaporated and 3.05 g of yellowish foam are obtained.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]([N:18]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[C:31]([O-])(=[O:33])C.[Na+]>O>[CH2:11]([N:18]1[C:30]2[CH:29]=[CH:28][C:27]([CH:31]=[O:33])=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[C:22]([CH:4]=[O:5])[CH:23]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCn1c2ccccc2c2ccccc21
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCn1c2ccc(C=O)cc2c2cc(C=O)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
As a specific example, in one embodiment, a 271 ml quantity of DMF (3.5 mol) can be added to a 1-liter, 3-neck round bottom flask equipped with mechanical stirrer, thermometer, and addition funnel. The contents can be cooled in a salt/ice bath. When the temperature inside the flask reached 0° C., 326 ml of POCl3 (3.5 mol) can be slowly added. During the addition of POCl3, the temperature inside the flask is not allowed to rise above 5° C. After the addition of POCl3 is completed, the reaction mixture can be allowed to warm to room temperature. A 126 g quantity of N-heptylcarbazole can be then added, and the flask can be heated to 90° C. for 24 hr. using a heating mantle. The reaction mixture can be cooled to room temperature, and the solution can be added slowly to a 4.5 liter beaker containing a solution of 820 g sodium acetate dissolved in 2 liters of water. The beaker can be cooled in an ice bath and stirred for 3 hr. The brownish solid obtained can be filtered and washed repeatedly with water, followed by a small amount of ethanol (50 ml). For a N-heptyl carbozole starting material, the resulting product was recrystallized once from toluene using activated charcoal and dried under vacuum in an oven heated at 70° C. for 6 hr to obtain 80 g (51% yield) of N-heptyl-3,6-diformyl-carbazole.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]1([CH3:14])[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C.C(OCC)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:14])[CH3:22])[CH3:21]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccccc1C
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 102.3 %

Procedure:
Cesium carbonate (53.86 g, 165.3 mmol) was added to a solution of 2-cresol (10.0 g, 92.5 mmol) in anhydrous DMF (500 mL) at room temperature under an atmosphere of nitrogen. After five minutes, ethyl 2-bromopropionate (16.7 mL, 92.5 mmol, d=1.394) was added rapidly dropwise and the resultant mixture was allowed to stir at 90° C. for 18 h. The reaction mixture was diluted with diethyl ether, then extracted twice with 1N HCl and twice with water. The organic layer was dried over MgSO4 and concentrated in vacuo to provide the title compound (19.7 g, 100%). 1H NMR (400 MHz, CDCl3): δ7.16 (d, 1H, J=7.43 Hz), 7.11 (t, 1H, J=7.43 Hz), 6.89 (t, 1H, J=7.48 Hz), 6.70 (d, 1H, J=7.43 Hz), 4.75 (q, 1H, J=6.65 Hz), 4.23 (q, 2H, J=6.65 Hz), 2.30 (s, 3H), 1.64 (dd, 3H, J=7.04 Hz, 0.78 Hz,), 1.26 (td, 3H, J=7.04 Hz, 0.78 Hz). Rf=0.37 in 25% ether in hexanes.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[CH:16]=1)O>P(=O)(O)(O)O>[OH:18][C:17]1[CH:19]=[CH:20][CH:21]=[CH:14][C:16]=1[N:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1cccc(O)c1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: O=P(O)(O)O
Product: Oc1ccccc1N(c1ccccc1)c1ccccc1

Procedure:
Diphenylamine and 5 times the molar amount of resorcin were reacted at 200° C. for 20 hours in the presence of a phosphoric acid catalyst to obtain a hydroxytriphenylamine derivative. In the product was dissolved double the molar amount of phthalic anhydride by heating at 150° C. for 4 hours in the presence of a zinc chloride catalyst. After completion of the reaction, the reaction mixture was worked up in the same manner as in Synthesis Example 1 to obtain 3'-diphenylamino-6'-(N-p-isopropylphenylanilino)spiro[isobenzofuran-1(3H),9'-(9H)-xanthen]-3-one and 3-diphenylamino-7,12-dihydro-12,12-dimethyl-7-phenyl-spiro[14H-[1]benzopyrano[3,2-b]acridine-14,1'[13'H]-isobenzofuran]-3'-one.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([Cl:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17](Br)=[CH:16][C:15]=4[CH3:23])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=CC(CC3C(OC)=NC4C(C=3Cl)=CC(Br)=CC=4C)=CC=2)C=CC=N1.[Cl:54][C:55]1[CH:60]=[CH:59][C:58]([C:61]([C:63]2[N:67]([CH3:68])[CH:66]=[N:65][CH:64]=2)=[O:62])=[CH:57][CH:56]=1.[Li]CCCC>>[N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([Cl:24])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:61]([C:58]3[CH:59]=[CH:60][C:55]([Cl:54])=[CH:56][CH:57]=3)([C:63]3[N:67]([CH3:68])[CH:66]=[N:65][CH:64]=3)[OH:62])=[CH:16][C:15]=4[CH3:23])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)cc1
Reactant: Cc1cc(Br)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Agent: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: [Li]CCCC
Product: Cc1cc(C(O)(c2ccc(Cl)cc2)c2cncn2C)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloro-8-methylquinoline (393 mg, 0.880 mmol, Intermediate 19: step a) and (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (194 mg, 0.880 mmol, Intermediate 1: step b) in dry degassed THF (16 mL) was cooled to −78° C. and n-BuLi (1.6 M in hexane, 0.5 mL, 0.8 mmol) was added over 1.5 minutes. Stirring was continued at −78° C. for 10 minutes and the dry ice acetone bath was replaced with an ice water bath. Stirring was continued for 1 hour and the reaction mixture was quenched with saturated aqueous NH4Cl solution. EtOAc was added and the layers were separated and the aqueous mixture again extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification using flash column chromatography (5% MeOH in dichloromethane) yielded the substantially pure title compound. MS (ESI) 588.2.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([N:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH2:6]1)=[O:4].[Na+].[Br-:21].O.OOS([O-])=O.[K+]>CC(C)=O>[Br:21][C:14]1[CH:13]=[CH:12][C:11]([O:16][CH3:17])=[C:10]([CH:7]2[CH2:8][CH2:9][N:5]([C:3](=[O:4])[C:2]([F:1])([F:18])[F:19])[CH2:6]2)[CH:15]=1
Reactant: COc1ccccc1C1CCN(C(=O)C(F)(F)F)C1
Reactant: [Br-]
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(Br)cc1C1CCN(C(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 111.1 %

Procedure:
To the title compound of Step A (2.75 g, 10.1 mmol) and NaBr (4.2 g, 41 mmol) in acetone (50 mL)/H2O (50 mL) at 0° C. was added Oxone (6.2 g, 10.1 mmol) portionwise over 1 h. After 3 h, the ice bath was removed and the reaction allowed to warm to rt. Then 5 wt % Na2S2O5 (aq.) was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine and dried to give 3.95 g (>98%) of the title compound. 1H NMR (CDCl3): 7.35 (dd, J=8.7, 3.8, 2.5 Hz, 1H), 7.25 (dd, J=5.5, 2.7 Hz, 1H), 6.77 (dd, J=8.7, 4.5 Hz, 1H), 4.13-4.06 (m, 1H), 3.94-3.82 (m, 4H), 3.75-3.57 (m, 2H), 3.51-3.41 (m, 1H), 2.37-2.05 (m, 2H).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](OC)=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:26][N:27]([CH3:31])[CH2:28][CH2:29][NH2:30].N1C=NC=N1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:30][CH2:29][CH2:28][N:27]([CH3:31])[CH3:26])=[O:17])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reactant: CN(C)CCN
Agent: c1nc[nH]n1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CN(C)CCNC(=O)Cc1ccc(OCc2ccc(-c3ccccc3)cc2)cc1
Reaction time: 2 h
Yield: 102.2 %

Procedure:
A solution of methyl 4-(4-biphenylylmethoxy)phenylacetate (60.0 g), N,N-dimethylethylenediamine (47.7 g), and 1H-1,2,4-triazole (12.6 g) in toluene (120 ml) was stirred under nitrogen at 100° C. for 8 hr and cooled until the temperature of the reaction mixture was reached to 60±2° C., to which ethyl acetate (240 ml) was added for 20 min. The reaction mixture was further heated under reflux for additional 30 min, left to stand at room temperature over night and stirred in an ice bath for 2 hr. The precipitate was collected by filtration and washed with ethyl acetate (120 ml) to obtain the titled compound (71.7 g).