Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[N:8]([C:9]([C:11]3[S:12][C:13](Br)=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[N:15]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.C(O)C.[NH2:27][S:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])=[O:29].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]12[N:8]([C:9]([C:11]3[S:12][C:13]([C:34]4[CH:35]=[CH:36][C:31]([S:28]([NH2:27])(=[O:30])=[O:29])=[CH:32][CH:33]=4)=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=4)[N:15]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1nc(-c2ccc(Cl)cc2)c(Br)s1)N1C2CCC1COC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1ccc(-c2sc(C(=O)N3C4CCC3COC4)nc2-c2ccc(Cl)cc2)cc1
Temperature: 92.5 °C
Yield: 56.3 %

Procedure:
To a solution of 3-oxa-8-azabicyclo[13.2.1]octan-8-yl(5-bromo-4-(4-chlorophenyl) thiazol-2-yl)methanone (Step 3 of compound 68, 0.12 g, 0.29 mmol) in a mixture of toluene:ethanol (2 ml: 6 ml) were added 4-aminosulfonylbenzene boronic acid (0.07 g, 0.35 mmol) and potassium carbonate (0.12 g, 0.87 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.015 mmol) under nitrogen and tube was sealed. The reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with ethanol (2×20 ml). The filtrate was concentrated under reduced pressure to obtain a crude product; which was purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.08 g, 56.3%). MS: m/z 490 (M+1).
Reaction SMILES: I[CH3:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[N:14][CH:15]=2)=[CH:6][CH:5]=1>C(Cl)(Cl)Cl.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH2:21][CH2:20][N:19]([CH3:2])[CH2:18][CH:17]=3)=[N:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(-c2cnc(-c3ccncc3)nc2)cc1
Reactant: CI
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CN1CC=C(c2ncc(-c3ccc(Cl)cc3)cn2)CC1
Temperature: 25 °C
Reaction time: 312 h
Yield: 94 %

Procedure:
Iodomethane (0.65 ml) was added to a solution of 5-(4-chlorophenyl)-2-pyridin-4-ylpyrimidine (0.311 g) in a mixture of chloroform (18 ml) and methanol (2 ml), and the reaction stirred at room temperature, in a stoppered flask, for 13 days. The solvents were then removed under reduced pressure, and the residue was re-suspended in a mixture of methanol (10 ml) and water (2 ml), cooled in an ice-bath and treated portionwise with sodium borohydride (0.088 g) (CAUTION-vigorous effervescence). The reaction was stirred in the ice-bath for 1.5 h, at room temperature for a further 1.5 h, then treated with saturated ammonium chloride (30 ml) followed by water (20 ml), and the resultant suspension was extracted with ethyl acetate (50 ml, then 2×25 ml). The combined organic extracts were washed with water (3×25 ml), saturated brine (20 ml), dried (Na2SO4) and evaporated under reduced pressure to furnish the title compound as a cream solid (0.310 g, 94%).
Reaction SMILES: [Li+].[BH4-].[C:3]([CH:7]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[CH2:8]1)(OC)=[O:4].S(=O)(=O)(O)O>C(OCC)C>[OH:4][CH2:3][CH:7]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[CH2:8]1
Reactant: COC(=O)C1CC(=O)N(C)C1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CN1CC(CO)CC1=O
Reaction time: 2 h

Procedure:
A solution of 2.3g (106 m moles) of LiBH4 in 150 ml of diethyl ether was slowly added dropwise at +5° C to 17.0g (107 m mols) of 4-carbomethoxy-1-methyl-pyrrolidone in 20 ml of absolute diethyl ether. Stirring was continued for 2 hours at room temperature, then the mixture was acidified with 2N sulfuric acid (pH 2), the solvent and water were distilled off to a large extent in vacuo and the remaining residue was extracted with methylene chloride. The dried methylene chloride phase was concentrated and the residue was distilled in vacuo. 5 g of the compounds desired were obtained in a 98 % purity: nD20 : 1.4950.
Reaction SMILES: NC1[S:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(O)CO.[OH-].[K+].C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([SH:3])[CH:10]=1
Reactant: Cc1ccc2nc(N)sc2c1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc(N)c(S)c1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
A mixture of 2-amino-6-methylbenzothiazole (15 g, 91.3 mmol), ethylene glycol (22.26 g, 0.36 mol) and 50% w/v KOH (180 ml) was heated under reflux for 62 h. On cooling to room temperature, toluene (60 ml) was added and the reaction mixture was cooled in an ice-bath and acidified with acetic acid (final pH 5-6). The reaction mixture was extracted with toluene (5×300 ml) and the combined organic extracts were washed with brine (2×200 ml), dried (MgSO4) and the solvent removed under reduced pressure to give the title compound (11.1 g, 86%) as a yellow solid which was used without further purification.
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH2:7][CH2:8][CH3:9])[NH:5][CH:6]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[C:10]1([C:2]2[N:3]=[C:4]([CH2:7][CH2:8][CH3:9])[NH:5][CH:6]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: CCCc1nc(I)c[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCc1nc(-c2ccccc2)c[nH]1
Yield: 77 %

Procedure:
[step 1] 4-Iodo-2-propylimidazole obtained in Reference Example A16 was dissolved in dioxane/water (2 mL/1 mL), phenylboronic acid (0.108 g, 0.889 mmol), 1,1-bisdiphenylphosphinoferrocene dichloropalladium (0.052 g, 0.064 mmol) and sodium carbonate (0.202 g, 1.91 mmol) were added, and the mixture was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give 4-phenyl-2-propylimidazole (0.091 g, 77%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH2:7].[H-].[Na+].[CH3:11][N:12]([CH3:33])[C:13]1[CH:32]=[CH:31][C:16]([CH2:17][C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[S:27](Cl)(=[O:29])=[O:28])=[CH:15][CH:14]=1.C1COCC1>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH3:8])=[N:4][O:5][C:6]=1[NH:7][S:27]([C:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[S:22][C:18]=1[CH2:17][C:16]1[CH:15]=[CH:14][C:13]([N:12]([CH3:11])[CH3:33])=[CH:32][CH:31]=1)(=[O:28])=[O:29]
Reactant: Cc1noc(N)c1Cl
Reactant: CN(C)c1ccc(Cc2sc3ccccc3c2S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccc(N(C)C)cc3)sc3ccccc23)c1Cl

Procedure:
N-(4-chloro-3-methyl-5-isoxazolyl)-2-(4-dimethylaminobenzyl)benzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 4-chloro-3-methyl-5-aminoisoxazole (0.52 mmoles, 69 mg), NaH (1.3 mmoles, 31 mg), 2-(4-dimethylaminobenzyl)-benzo[b]thiophene-3-sulfonylchloride (0.58 mmoles, 0.21g) and THF (4 ml). Flash chromatography (5% methanol/chloroform) provided 0.16 g (66%) of a yellow gummy solid, m.p. 105°-110° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[C:4]([NH:17][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[N:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:4]2[N:5]=[C:6]([CH2:8][C:9]3[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:16])[N:7]=[C:2]([NH:1][C:26](=[O:28])[CH3:27])[N:3]=2)=[CH:25][CH:24]=1)#[N:23]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(Nc2nc(N)nc(Cc3c(Cl)cccc3Cl)n2)cc1
Product: CC(=O)Nc1nc(Cc2c(Cl)cccc2Cl)nc(Nc2ccc(C#N)cc2)n1
Temperature: 25 °C
Yield: 45 %

Procedure:
Compound (1) (0.00135 mol) and acetic acid anhydride (20 ml) were combined and heated to reflux for 10 minutes. The reaction mixture was then removed from the oil bath and cooled to RT. The precipitate was filtered off, yielding 0.25 g (45%) of N-[4-[(4-cyanophenyl)amino]-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]-acetamide (compound 22).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].C1(C)C(C)=CC=CC=1.[Cl:19][CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[O:10][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([CH2:20][Cl:19])=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: Cc1cc(Cl)cc(Cl)c1O
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: Cc1cc(Cl)cc(Cl)c1OC(=O)c1ccc(CCl)cc1

Procedure:
88.5 g (0.5 mole) of 2,4-dichloro-6-methylphenol, 180 ml of dry xylene, 95 g (0.5 mole) of p-chloromethylbenzoyl chloride and 0.5 ml of pyridine were refluxed for 24 hours in a weak current of nitrogen with the exclusion of moisture. After cooling, the slightly turbid (pyridine hydrochloride), orange-colored solution was filtered free of a small amount of a blackish brown resin, and the filtrate was freed of xylene at diminished pressure. The residue (165 g=100%) crystallized after two days of standing to a light brown crystal mass, which was triturated in 200 ml of ice-cold petroleum ether and suction filtered. After drying, nearly colorless crystals were obtained with a melting point of 71°-73° C. Recrystallization from petroleum ether (1:10) yielded white needles melting at 74°-75° C.; no change in the melting point was brought about by repeated recrystallization.
Reaction SMILES: [NH2:1][C:2](=[N:8][NH:9][C:10](=O)[C:11]1[C:16]([NH:17][CH:18]([CH3:20])[CH3:19])=[CH:15][C:14]([NH:21][C:22]2[CH:30]=[CH:29][C:25]3[N:26]=[CH:27][S:28][C:24]=3[CH:23]=2)=[N:13][CH:12]=1)C(OCC)=O>CO>[S:28]1[C:24]2[CH:23]=[C:22]([NH:21][C:14]3[CH:15]=[C:16]([NH:17][CH:18]([CH3:20])[CH3:19])[C:11]([C:10]4[NH:1][CH:2]=[N:8][N:9]=4)=[CH:12][N:13]=3)[CH:30]=[CH:29][C:25]=2[N:26]=[CH:27]1
Reactant: CCOC(=O)C(N)=NNC(=O)c1cnc(Nc2ccc3ncsc3c2)cc1NC(C)C
Solvent: CO
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc[nH]1
Temperature: 180 °C

Procedure:
Ethyl 2-amino-2-(2-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinoyl)hydrazono)acetate (7) (300 mg, 0.679 mmol) was taken in a sealed tube and heated at 180° C. for 1 h. The reaction mass was dissolved in methanol then concentrated. The crude material obtained was purified by flash column chromatography through silica gel and MeOH: CHCl3 as eluting agents. The material was further purified by prep HPLC to obtain N2-(benzo[d]thiazol-6-yl)-N4-isopropyl-5-(4H-1,2,4-triazol-3-yl)pyridine-2,4-diamine. 1H NMR: 400 MHz, CD3OD: δ 1.32 (d, J=4.00 Hz, 6H), 1.43 (t, J=6.80 Hz, 3H), 3.72-3.74 (m, 1H), 4.41 (q, J=6.80 Hz, 2H), 6.17 (s, 1H), 7.48 (dd, J=2.40, 8.8 Hz, 1H), 7.93 (d, J=8.80 Hz, 1H), 8.33 (s, 1H), 8.61 (s, 1H), 9.02 (s, 1H). LC/MS: Ascentis Express C18, 5×2.1 mm-2.7 μm; Solvent A=2% ACN: 98% H2O: 10 mM NH4COOH; Solvent B=98% ACN: 2% H2O: 10 mM NH4COOH; gradient 0-100% B over 3 min; retention time: 1.789 min; LCMS (ES-API), m/z 422.0 (M−H). HPLC: XBridge (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 15 min (23 min run time); Flow rate: 1.0 μL/min; Retention time: 7.569 min; Purity: 99%.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[NH2:33])=[CH:28][N:27]=3)=[CH:20][CH:21]=2)[CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:16]1[C:17]2[C:22](=[CH:21][CH:20]=[C:19]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH2:33])=[O:34])=[CH:28][N:27]=3)[CH:18]=2)[CH2:23][CH2:24][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(C(N)=O)cn3)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CNCC3)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Add drop wise via an addition funnel a solution of trifluoroacetic acid (3.3 mL) in dichloromethane (10 mL) to a stirred solution of 7-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.2 g, 3.3 mmol)) in dichloromethane (50 mL) at 0° C. Warm to room temperature and stir for 18 hours. Evaporate on a rotary evaporator, dissolve the residue in methanol, and then apply in equal parts to 2-10 g SCX cartridges. Wash each cartridge with methanol until neutral pH then elute product with 2.0 M ammonia in methanol. Collect the basic eluent and concentrate on a rotary evaporator to yield 6-(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-nicotinamide (0.9 g, 3.3 mmol): 1H NMR (CDCl3, 300.00 MHz): 8.57 (s, 1H); 8.15 (d, 1H); 7.15-7.13 (m, 1H); 6.96-6.89 (m, 2H); 6.80 (s, 1H); 5.87 (br, 2H); 4.01 (s, 2H); 3.17-3.13 (m, 2H); 2.82-2.78 (m, 2H); 1.73 (br, 1H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl-].[CH3:12][O:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:34][C:35]1[C:40]([C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[O:49][CH3:50])=O)=[CH:39][C:38]([Br:51])=[CH:37][N:36]=1>C1COCC1>[Br:51][C:38]1[CH:39]=[C:40]([C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=2[O:49][CH3:50])=[CH:12][O:13][CH3:14])[C:35]([NH2:34])=[N:36][CH:37]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1C(=O)c1cc(Br)cnc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=C(c1ccccc1OC)c1cc(Br)cnc1N
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 84.8 %

Procedure:
Into a 50 ml flame-dried round bottomed flask were added potassium bis(trimethylsilyl)amide (832 mg, 39.2 mmol) and anhydrous THF (10 ml). The slurry was cooled to 0° C. for 5 minutes under nitrogen, then (methoxymethyl)triphenylphosphonium chloride (1.53 g, 4.47 mmol) was added. The resulting red-orange solution was stirred at room temperature for 45 min, then a solution of (2-amino-5-bromo-pyridin-3-yl)-(2-methoxy-phenyl)-methanone (601 mg, 1.95 mmol in 10 ml THF) was added all at once. The reaction was stirred under nitrogen for 4 hours then quenched by addition of a saturated aqueous solution of ammonium chloride (25 ml). Ethyl acetate (100 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated to give a brown, sticky oil. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 554 mg (84%) of 5-bromo-3-[2-methoxy-1-(2-methoxy-phenyl)-vinyl]-pyridin-2-ylamine as a mixture of E- and Z-isomers.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11][Br:12])=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl.C(Cl)(Cl)Cl.CO>[C:35]([O:18][C:5]1[C:6]([CH2:15][CH2:16][CH3:17])=[C:7]([CH:13]=[CH:14][C:4]=1[C:1](=[O:3])[CH3:2])[O:8][CH2:9][CH2:10][CH2:11][Br:12])(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCc1c(OCCCBr)ccc(C(C)=O)c1OC(C)=O
Reaction time: 3 h

Procedure:
In methylene chloride were dissolved 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propyl bromide (2.8 g), triethylamine (6.2 ml) and dimethylaminopyridine (10 mg). To the solution was added dropwise acetic anhydride (4.2 ml) under ice-cooing. The reaction was allowed to proceed for 3 hours, and there was added methanol (5 ml). The mixture was left standing for 10 minutes. The solvent was evaporated off to leave syrup, which was dissolved in chloroform. The solution was washed with water, dried and concentrated. The resulting syrup was purified by means of a silica gel flash chromatography (chloroform) to give 3-(3-acetoxy-4-acetyl 2-propylphenoxy)propyl bromide (2.7 g) as colorless and transparent syrup.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Br:19])=[CH:17][C:5]2[C:6]([C:12]([O:14]CC)=[O:13])=[C:7]([CH:9]3[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.O[Li].O.Cl>O1CCOCC1.O>[NH2:1][C:2]1[C:18]([Br:19])=[CH:17][C:5]2[C:6]([C:12]([OH:14])=[O:13])=[C:7]([CH:9]3[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1c(C2CC2)oc2cc(N)c(Br)cc12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc2oc(C3CC3)c(C(=O)O)c2cc1Br
Yield: 97.6 %

Procedure:
To a solution of ethyl 6-amino-5-bromo-2-cyclopropylbenzofuran-3-carboxylate (7 g, 22.5 mmol) in 1,4-dioxane and H2O (50 mL and 50 mL) was added LiOH.H2O (4.6 g, 112 mmol). The reaction mixture was refluxed for 2 hours, and then 400 mL H2O was added to the reaction mixture. After acidifying to pH 4˜5 with HCl, the resulting solid were filtered to give the product of 6-amino-5-bromo-2-cyclopropylbenzofuran-3-carboxylic acid (6.5 g, yield: 97%). 1H-NMR (400 MHz, MeOD) δ 7.86 (s, 1H), 6.85 (s, 1H), 4.31 (s, 2H), 2.93˜3.00 (m, 1H), 1.19˜1.22 (m, 2H), 1.13˜1.16 (m, 2H). MS (M+H)+: 296/298.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:14]([C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)([CH3:16])[CH3:15]>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:23][C:21]2[CH:20]=[C:19]([CH3:24])[CH:18]=[C:17]([CH:14]([CH3:16])[CH3:15])[N:22]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: Cc1cc(N)nc(C(C)C)c1
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cc(C)cc(C(C)C)n1
Temperature: 140 °C
Yield: 29.6 %

Procedure:
To a solution of ethyl 4,6-dichloropyridazine-3-carboxylate (260 mg, 1.18 mmol) in acetonitrile (3.9 mL) was added 6-isopropyl-4-methylpyridin-2-amine (265 mg, 1.76 mmol) and then the mixture heated at 140° C. for 48 h. The mixture was cooled, concentrated in vacuo, and then purified by chromatography (silica, 5 to 30% ethyl acetate in hexanes) to give ethyl 6-chloro-4-(6-isopropyl-4-methylpyridin-2-ylamino)pyridazine-3-carboxylate (117 mg, 349 μmol, 30%) as an off white solid. 1H NMR (400 MHz, CHLOROFORM-d6) δ ppm 10.60 (s, 1H), 9.39 (s, 1H), 6.76 (s, 1H), 6.59 (s, 1H), 4.58 (q, J=7.0 Hz, 2H), 3.04 (m, 1H), 2.35 (s, 3H), 1.53 (t, J=7.1 Hz, 3H), 1.35 (d, J=7.0 Hz, 6H), MS (EI/CI) m/z: 335.0 [M+H].
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][NH2:9])=[O:7].[O:15]([C:22]1[C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[O:15]([C:22]1[C:27]([C:28]([NH:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][CH:12]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1cccnc1Oc1ccccc1
Reactant: NNC(=O)c1cccc(C(F)(F)F)c1
Solvent: c1ccncc1
Product: O=C(NNC(=O)c1cccnc1Oc1ccccc1)c1cccc(C(F)(F)F)c1
Yield: 53.3 %

Procedure:
A solution of 3-(trifluoromethyl)benzhydrazide (102.1 mg, 0.5 mmol), 2-phenoxypyridine-3-carbonyl chloride (117 mg, 0.5 mmol) in pyridine (5 mL) was refluxed for 2 h. It was evaporated in vacuo and the residue was purified by column chromatography (silica gel, EtOAc/CH2Cl2=4:1) to give 107 mg (54%) of the title compound. 1H NMR (CDCl3): 10.88 (d, J=6.3 Hz, 1H), 9.80 (d, J=6.3 Hz, 1H), 8.60 (m, 1H), 8.30 (m, 1H), 8.17 (s, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.61 (t, J=7.2 Hz, 1H), 7.51-7.46 (m, 2H), 7.34-7.17 (m, 4H).
Reaction SMILES: [C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:6][C:5]=1[CH:16]=[O:17])(=[O:3])[CH3:2].[BH4-].[Na+].O>C(Cl)Cl.CO>[C:1]([C:4]1[C:8]([CH3:9])=[C:7]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[NH:6][C:5]=1[CH2:16][OH:17])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C=O)[nH]c(-c2ccncc2)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1c(CO)[nH]c(-c2ccncc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.5 %

Procedure:
To a stirred solution of 3-acetyl-2-formyl-4-methyl-5-(4-pyridyl)-1H-pyrrole (84 mg, 0.37 mmol) in CH2Cl2 (2 mL) and methanol (2 mL) was added sodium borohydride (14 mg, 0.37 mmol) at 0° C. and stirred for 30 minutes at room temperature. The mixture was poured into water (15 mL) and extracted with ethyl acetate-ethanol (10:1, 20 mL×3). The combined organic layers were washed with brine, dried over MgSO4, and evaporated in vactio. Recrystallization from ethyl acetate provided the title compound (20 mg, 24% yield) as a solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].Br.Br[CH:11]1[CH2:20][CH2:19][C:18]2[CH:17]=[N:16][CH:15]=[CH:14][C:13]=2[C:12]1=[O:21].CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:7]([O:6][C:4](=[O:5])[CH:3]([C:1]#[N:2])[CH:11]1[CH2:20][CH2:19][C:18]2[CH:17]=[N:16][CH:15]=[CH:14][C:13]=2[C:12]1=[O:21])[CH3:8]
Reactant: CCOC(=O)CC#N
Reactant: O=C1c2ccncc2CCC1Br
Agent: Br
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C#N)C1CCc2cnccc2C1=O
Reaction time: 4 h
Yield: 95 %

Procedure:
To a stirred, cold (4° C.) solution of ethyl cyanoacetate (52.2 mmol) and 6-bromo-7,8-dihydro-6H-isoquinolin-5-one 8B (6.5 mmol) in DMF (10 mL), DIEA (19.5 mmol) was added. The mixture was brought to rt and stirred for 4 h. Solvent was removed and the residue, dissolved in DCM, was repeatedly washed with water. The organic layer was dried (Na2SO4) and concentrated. Purification by chromatography on silica gel (DCM/MeOH 98:2) provided the title compound in 95% yield. ESI (+) MS: m/z 259 (MH+). 1H NMR: 1.15-1.32 (m, 3H), 1.98-2.44 (m, 2H), 3.59-3.82 (m, 3H), 4.20-4.28 (m, 2H), 4.70 (s, 1H), 7.67-7.73 (m, 1H), 8.64-8.68 (m, 1H), 8.75-8.78 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]2[S:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH2:4]1.[Cl:18][C:19]1[N:20]=[C:21]([C:26](O)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:18][C:19]1[N:20]=[C:21]([C:26]([NH:1][CH2:2][CH:3]2[CH2:6][N:5]([C:7]3[S:8][C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=3)[CH2:4]2)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCOC(=O)c1sc(N2CC(CN)C2)nc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCOC(=O)c1sc(N2CC(CNC(=O)c3nc(Cl)c(CC)[nH]3)C2)nc1C
Yield: 55.8 %

Procedure:
The same operation as in Example (221c) was performed using ethyl 2-[3-(aminomethyl)azetidin-1-yl]-4-methyl-1,3-thiazole-5-carboxylate obtained in Example (233c) (51 mg, 0.20 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (52 mg, 0.30 mmol), WSC hydrochloride (115 mg, 0.60 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol) and N-methylmorpholine (0.04 mL, 0.40 mmol), to obtain 46 mg of the title compound as a white solid (56%).