Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]2[CH:12]=[N:13][NH:14][C:8]=2[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:17]=1[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]2=[CH:12][N:13]([CH2:24][C:23]3[CH:22]=[CH:21][C:20]([C:18](=[O:19])[C:17]4[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:16]=4[Cl:15])=[CH:27][CH:26]=3)[N:14]=[C:8]2[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)n1ncc2[nH]ncc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc2nn(Cc3ccc(C(=O)c4ccc(Cl)cc4Cl)cc3)cc2c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In DMF (5 ml) was dissolved 5-t-butyl-1H-pyrazolo [3,4-d]pyridazin-4(5H)-one (288 mg) followed by addition of 4-(2,4-dichlorobenzoyl)benzyl bromide (791 mg) and potassium carbonate (318 mg), and the mixture was stirred at room temperature for 15 hours. This reaction mixture was extracted with ethyl acetate and the organic layer was serially washed with water and saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (n-hexaneethyl acetate=1:1). Then, 5-t-butyl-2-[4-(2,4-dichlorobenzoyl)benzyl]-2H-pyrazolo [3,4-d]pyridazin-4(5H)-one was washed with n-hexane-diethyl ether and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:28][CH:29]([S:31](Cl)(=[O:33])=[O:32])[CH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([S:31]([CH:29]([CH3:30])[CH3:28])(=[O:33])=[O:32])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 39 %

Procedure:
According to the procedure for compound 398 using 2-propanesulfonyl chloride (82 mg, 0.57 mmol) afforded 17.9 mg (39% yield) of 400, as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCOCC1>[CH2:23]([NH:30][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:4][N:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: Nc1nc(Cl)ncc1-c1nnn[nH]1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCc2ccccc2)ncc1-c1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 10.1 %

Procedure:
In a microwave tube, 2-chloro-5-(1H-tetrazol-5-yl)pyrimidin-4-amine (200 mg, 1.0 mmol) was dissolved into 3 mL of dioxane and DIPEA (1.5 mmol, 1.5 eq.). After the addition of benzylamine (5.0 mmol, 5.0 eq.), the tube was capped and irradiated in a CEM Discover microwave reactor to 120° C. for a total of 60 minutes in three 20 minutes intervals. LC/MS was taken every 20 minutes to follow the disappearance of starting material. After the complete consumption of the starting material, the reaction was cooled to room temperature and a precipitate formed. This solid was collected by filtration, washed several times with water, then with hot EtOAc. It was dried under vacuum to afford 27 mg of desired product. This material was carried forward without further purification. MS (EI) for C12H12N8: 269 (M+H).
Reaction SMILES: N[C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH3:12])[N:8]=[CH:7][CH:6]=2.[OH-:14].[Na+]>>[OH:14][C:2]1[C:3](=[O:13])[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([CH3:12])[N:8]=[CH:7][CH:6]=2
Reactant: Cc1nccc2[nH]c(=O)c(N)cc12
Reactant: [OH-]
Agent: [Na+]
Product: Cc1nccc2[nH]c(=O)c(O)cc12
Reaction time: 8 h

Procedure:
This compound was prepared by heating 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one following in part the procedure described in Example E-4 without purification of 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one by reacting said unpurified 3-amino compound with aqueous sodium hydroxide solution or by similarly reacting said purified 3-amino compound with aqueous sodium hydroxide solution. These procedures are described as follows. Following the procedure described in Example E-4 using 27 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carboxylic acid hydrazide, 60 ml of concentrated sulfuric acid, 200 ml of water and 9.1 g of sodium nitrite and after concentrating the reaction mixture to dryness on a rotary evaporator, the residue containing the corresponding said 3-amino compound was treated with 75 ml of 35% sodium hydroxide solution and 100 ml of water and the resulting aqueous mixture was heated on a steam bath for 30 hours and then acidified with acetic acid. The acidified mixture was allowed to stand at room temperature overnight and the resulting product that separated was collected, washed with water and air-dried. It was then recrystallized from 400 ml of boiling dimethylformamide, filtering off the insoluble material, concentrating the filtrate to a volume of about 200 ml and then allowing it to stand at room temperature for 3 hours. The yellow crystalline solid was collected, washed with methanol and dried at 100° C. to yield 7.6 g of 3-hydroxy-5-methyl-1,6-naphthyridin-2-(1H)-one, m.p. >320° C. The same compound was also prepared by heating a mixture containing 3-amino-5-methyl-1,6-naphthyridin-2(1H)-one with 25 ml of 10% aqueous sodium hydroxide solution on a steam bath for 7 hours and then cooled to room temperature. The reaction mixture was acidified with acetic acid and the resulting white crystalline precipitate was collected, washed with water and dried at 95° C. to yield 1.2 g of 3-hydroxy-5-methyl-1,6-naphthyridin-2(1H)-one, m.p. >320° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[OH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[O:20]=[C:21]1[CH:26]=[CH:25][N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=2)[CH:23]=[CH:22]1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Reactant: Oc1ccncc1
Product: CN(C(=O)Oc1ccc(Cn2ccc(=O)cc2)cc1)c1ccccc1
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield as colorless crystals using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 4-hydroxypyridine. 1H NMR (400 MHz; CDCl3): δ 3.43 (br s, 3H), 4.92 (s, 2H), 6.43 (d, 2H), 7.17 (br s, 4H), 7.22-7.42 (m, 9H); HPLC-MS: m/z=335.0 (M+1); Rt=2.55 min.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>COCCOC>[C:12]1([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][C:7](=[O:11])[NH:8]3)=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1Cc2ccc(Br)cc2N1
Solvent: COCCOC
Product: O=C1Cc2ccc(-c3ccccc3)cc2N1
Yield: 47.2 %

Procedure:
6-Bromooxindole (800 mg, 3.8 mmol), (prepared as described for the starting material in Example 62), phenylboronic acid (500 mg, 4.1 mmol) sodium hydrogen carbonate (saturated aqueous solution, 50 ml) and 1,2-dimethoxyethane (100 ml) were mixed together and the solution was degassed using alternatively vacuum and argon. Tetrakis(triphenylphosphine)palladium(0) (50 mg) was added and the solution degassed again before heating it to reflux for 8 hours. The reaction mixture was evaporated to dryness using a rotary evaporator and the solid residue partitioned between water (75 ml) and ethyl acetate (100 ml). The aqueous phase was reextracted with more ethyl acetate (100 ml×3), the organic phases were combined, washed with brine and passed directly through a short plug of silica to remove the baseline impurities. The solvent was evaporated and the solid was triturated in ether and filtered to give 6-phenyloxindole as a pink solid (375 mg, 60%).
Reaction SMILES: [Br-:1].[NH2:2][CH2:3][CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=1)=[O:13])([CH3:8])[CH3:7].[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br-:1].[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:37][C:38]([NH:2][CH2:3][CH2:4][CH2:5][N+:6]([CH2:9][CH2:10][NH:11][C:12]([C:14]2[C:19]([NH2:20])=[N:18][C:17]([NH2:21])=[C:16]([Cl:22])[N:15]=2)=[O:13])([CH3:7])[CH3:8])=[O:39])=[CH:35][CH:36]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: C[N+](C)(CCCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[N+](C)(CCCNC(=O)Cc1ccc(OCc2ccccc2)cc1)CCNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (3-amino-propyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate M) (1.0 g, 2.52 mmol), 4-benzyloxyphenylacetic acid (0.61 g, 2.52 mmol), N-methylmorpholine (1.0 mL, 9.10 mmol), N,N′-dicyclohexylcarbodiimide (0.52 g, 2.52 mmol) and 1-hydroxybenzotriazole (0.34 g, 2.52 mmol) in anhydrous DMF (20 mL) is stirred under a nitrogen atmosphere at RT for 16 h. The reaction mixture is concentrated under vacuum and is purified by column chromatography (basic alumina, 0-3% MeOH in DCM) to afford the title compound as a white solid. M+ 540. 1H NMR (400 MHz, DMSO-d6) δ 8.23 (1H, t), 8.07 (1H, t), 7.52 (2H, br), 7.41-7.28 (5H, m), 7.16 (2H, d), 7.09 (2H, br), 6.91 (2H, d), 5.05 (2H, s), 3.58-3.3.51 (2H, m), 3.40-3.25 (6H, m), 3.11-3.03 (2H, m), 3.02 (6H, s), 1.87-1.75 (2H, m).
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]3[S:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.C[O:26][B:27](OC)[O:28]C>O1CCCC1>[C:1]1([C:7]2[CH:19]=[CH:18][C:10]3[S:11][C:12]4[C:17]([B:27]([OH:28])[OH:26])=[CH:16][CH:15]=[CH:14][C:13]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COB(OC)OC
Reactant: c1ccc(-c2ccc3sc4ccccc4c3c2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc2c1sc1ccc(-c3ccccc3)cc12
Temperature: -78 °C

Procedure:
2-bromo-dibenzo[b,d]thiophene (10 g), phenylboronic acid (5.1 g) tetrakis(triphenylphosphine)palladium (2.2 g) and potassium carbonate (18.38 g) were refluxed in a mixture of toluene (110 mL), ethanol (20 mL) and water (90 mL) overnight. The reaction was quenched with water and the toluene layer was removed and passed through a celite column and the toluene layer was evaporated in a rotary evaporator to yield 5.2 g 2-phenyl-dibenzo[b,d]thiophene. 2-phenyldibenzo[b,d]thiophene (5.2 g) was dissolved in anhydrous tetrahydrofuran (50 mL) under nitrogen atmosphere, and the solution was then cooled to −78° C. 20.0 mL of n-butyl lithium (1.6 M solution) was added dropwise into the reaction mixture, and continuously stirred to equilibriate to room temperature. The reaction mixture was then cool to −60° C., and trimethyborate (5.67 mL) was added and the reaction was allowed to stir overnight. The reaction was then quenched with 20% aqueous hydrochloric acid, and extracted the organic layer with ethyl acetate; ethyl acetate layer was then washed thoroughly with water and dried over anhydrous sodium sulfate, and was evaporated to dryness to yield 4.2 g of 8-phenyldibenzo[b,d]thiophene-4-boronic acid.
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:12][PH3+].[Si:21]([O:28][C:29]1[C:36]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[C:35]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:34]=[CH:33][C:30]=1[CH:31]=O)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>C1COCC1>[Si:21]([O:28][C:29]1[C:30](/[CH:31]=[CH:12]\[C:11]2[CH:10]=[C:9]([O:8][CH3:7])[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:33][CH:34]=[C:35]([O:45][Si:46]([C:49]([CH3:50])([CH3:52])[CH3:51])([CH3:48])[CH3:47])[C:36]=1[O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(C[PH3+])cc(OC)c1OC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(/C=C\c2ccc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (0.89 mL, 2.23 mmol, 2.5 M in hexanes) was added dropwise over 10 min to a solution of 3,4,5-trimethoxybenzylphosphonium bromide (0.96 g, 1.83 mmol) in THF (10 mL) at −10° C. The reaction mixture was stirred at this temperature for 15 min then cooled to −70° C. and a solution of 31 (0.93 g, 1.88 mmol) in THF (4 mL) was added and the reaction mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was cooled to 0° C. and water was added. The reaction mixture was extracted with TBME (3×) and the organic phase was washed successively with water and brine, dried (Na2SO4) and concentrated in vacuo to give crude product (1.5 g). Purification by column chromatography (SiO2; 5:95 TBME:cyclohexane+1% Et3N) gave 32 compound (0.6 g, 50%) as a 86:14 mixture of Z:E isomers:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15]([Br:19])=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH3:22]I.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:17]([F:18])=[CH:16][C:15]([Br:19])=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc(Br)c2[nH]ccc2c1OCc1ccccc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc2c(OCc3ccccc3)c(F)cc(Br)c21
Yield: 85.5 %

Procedure:
A solution of 17-1 (9 g, 28 mmol), potassium hydroxide (2.36 g, 42 mmol) and methyl iodide (6 g, 42 mmol) in DMF (30 mL) was stirred at room temperature for 2 h. The mixture was poured into water (50 mL), extracted with ethyl acetate (3×50 mL). The extracts were washed with water (3×50 mL) and brine (2×50 mL), dried over MgSO4, filtered, and evaporated to afford 33-3 (8 g, 90%) which was used directly in next step. LRMS: calc 333.0 and found: 334.0 [M+1].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[CH:4][CH:3]=1.[ClH:12].N([C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]3[N:32]=[CH:31][NH:30][C:28]3=2)[N:23]=[C:22]([CH3:33])[CH:21]=1)C1C=CC=CC=1>C(O)C>[ClH:12].[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]4[N:32]=[CH:31][NH:30][C:28]4=3)[N:23]=[C:22]([CH3:33])[CH:21]=2)=[CH:7][CH:6]=1)(=[O:11])[CH2:9][CH3:10]
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: CCC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: CCO
Product: CCC(=O)c1ccc(Nc2cc(C)nc3ccc4nc[nH]c4c23)cc1
Reaction time: 8 h

Procedure:
A mixture containing 14.9 g. (0.1 m) of p-aminopropiophenone 21.7 g. (0.1 m.) of the compound of Example I, C. and 500 ml. of ethanol was refluxed with stirring overnight. It was then concentrated in vacuo to give 34 g. m.p. 287°-289°, complete 320°C. The crude product was recrystallized from 1000 ml. of MeOH to yield 27 g.m.p. softens 318°, melts 328°-330°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:14]=[CH:13][C:12]3[NH:11][C:10](=[O:15])[C:9](=[O:16])[NH:8][C:7]=3[C:6]=2[CH:17]=1.[CH3:18][C:19]1(OC)[CH2:23][CH2:22][C:21]([CH3:26])(OC)O1>>[CH3:18][C:19]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]3[CH:14]=[CH:13][C:12]4[NH:11][C:10](=[O:15])[C:9](=[O:16])[NH:8][C:7]=4[C:6]=3[CH:17]=2)[C:21]([CH3:26])=[CH:22][CH:23]=1
Reactant: COC1(C)CCC(C)(OC)O1
Reactant: Nc1ccc2ccc3[nH]c(=O)c(=O)[nH]c3c2c1
Product: Cc1ccc(C)n1-c1ccc2ccc3[nH]c(=O)c(=O)[nH]c3c2c1

Procedure:
8.8 mmol of 9-aminobenzo[f]quinoxaline-2,3(1H,4H)-dione were reacted with 8.8 mmol of 2,5-dimethyl-2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:41])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example J26) (219 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-2-yl-phenyl)-propionic acid tert-butyl ester (Example K3) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a yellow solid (271 mg, 69%).
Reaction SMILES: Cl.[N:2]1[C:12]2[C:11]3[S:13][C:14]([C:16]4[CH:30]=[CH:29][C:19]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:18][CH:17]=4)=[CH:15][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1>O1CCOCC1.C(Cl)Cl>[N:2]1[C:12]2[C:11]3[S:13][C:14]([C:16]4[CH:30]=[CH:29][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=4)=[CH:15][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCc1ccc(-c2cc3c(s2)-c2ncccc2OCC3)cc1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
Following Scheme 5,2-bromo-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepine and 4-(N-Boc-aminomethyl)-phenylboronic acid were reacted to give tert-butyl 4-(6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)benzylcarbamate. MS: (ESI+)=409.1. Hydrogen chloride in dioxane (4 ml, 4 N) was added to a solution of 67 mg (0.16 mmol) of tert-butyl 4-(6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)benzylcarbamate in 6 ml of methylene chloride and the mixture was stirred for 2 hours. The precipitate was collected, washed with methylene chloride and ethyl ether and dried in vacuum to give 335 (34 mg, 55%). MS: (ESI+) 309.1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+].[C:16](=S)=[S:17].II>C(O)C.O1CCOCC1>[N:1]([C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[C:16]=[S:17]
Reactant: S=C=S
Reactant: Nc1ccc(C(=O)O)cc1
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: O=C(O)c1ccc(N=C=S)cc1
Temperature: 25 °C
Reaction time: 0.13 h

Procedure:
A mixture comprising 4-aminobenzoic acid (0.20 g, 1.5 mmol), dioxane (5 mL), a saturated sodium hydrogencarbonate aqueous solution (5 mL) and carbon disulfide (0.37 mL, 6.1 mmol) was stirred in a nitrogen atmosphere at room temperature for 19 hours and then concentrated under reduced pressure to dryness. The obtained residue was dissolved in water (8.0 mL), and 1M sodium hydroxide aqueous solution (1.5 mL) was added. With stirring at room temperature, an ethanol (8.0 mL) solution of iodine (0.38 g, 1.5 mmol) was dropwise added thereto over a period of 8 minutes, followed by stirring at room temperature for further 12 minutes. Then, the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to remove ethanol and dioxane as far as possible. Then, 1M hydrochloric acid (4.5 mL) was added, and the precipitated solid was collected by filtration to obtain 4-isothiocyanatobenzoic acid as a ocher solid (0.20 g, yield: 78%). The HPLC purity was 62%.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:32]=[CH:31][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[C:15]4=[CH:14][C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:33]([F:36])([F:35])[F:34])([CH3:3])[CH3:2].[Li+].[OH-].Cl>>[CH:1]([O:4][C:5]1[CH:32]=[CH:31][C:8]([CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][CH:22]([CH2:23][C:24]([OH:26])=[O:25])[C:15]4=[CH:14][C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:33]([F:36])([F:34])[F:35])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)O)cc1C(F)(F)F
Temperature: 70 °C
Reaction time: 4 h
Yield: 36.9 %

Procedure:
To a solution of tert-butyl 2-(7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.418 g, 0.830 mmol) in dioxanes (10 mL) was added 1.0 M solution of LiOH (aq, 2.5 mL). The reaction was stirred at 70° C. for 4 h and acidified with 1 M HCl (aq) to pH 3.0. The mixture was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a yellow solid (137 mg). LCMS m/z=448.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, J=5.94 Hz, 6H), 2.15-2.26 (m, 1H), 2.51-2.59 (m, 1H), 2.64-2.72 (m, 1H), 2.72-2.82 (m, 1H), 3.53-3.63 (m, 1H), 3.91-4.00 (m, 1H), 4.05-4.14 (m, 1H), 4.74-4.82 (m, 1H), 5.05 (s, 2H), 6.01 (s, 1H), 6.75 (dd, J=8.72, 2.40 Hz, 1H), 7.06 (d, J=2.27 Hz, 1H), 7.18 (d, J=8.84 Hz, 1H), 7.26-7.32 (m, 1H), 7.63-7.69 (m, 2H), 12.28 (bs, 1H).
Reaction SMILES: O.[NH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+:11]>C1(C)C=CC=CC=1>[NH2:2][C:3]1[CH:4]=[C:5]([O-:9])[CH:6]=[CH:7][CH:8]=1.[Na+:11]
Reactant: Nc1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1cccc([O-])c1

Procedure:
Another three-necked flask equipped with a Dean-Stark water separator, condenser, nitrogen inlet and outlet, thermometer and a mechanical stirrer is charged with 261.91 grams (2.4 moles) of meta-aminophenol, 192 grams (2.4 moles) of 50% aqueous sodium hydroxide and 720 milliliters of toluene. The mixture is heated at 100°-140° C. for three hours to remove all of the water and toluene and provide sodium meta-aminophenolate.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][OH:15].O1CCCC1>CN(C)C=O>[CH2:18]([O:17][C:13]([CH2:14][O:15][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)CO
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
11 g of sodium hydride was added to a mixture of 39.63 g of 2-chloro-3-nitropyridine, 31.23 g of ethyl glycolate, 250 ml of tetrahydrofuran and 20 ml of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 5 hours, then, the reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 48.3 g of 2-(ethoxycarbonyl)methoxy-3-nitropyridine.