Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:12]=[C:11](Cl)[C:10]2[C:5](=[C:6]([O:16][CH3:17])[C:7]([O:14][CH3:15])=[CH:8][CH:9]=2)[N:4]=1>O1CCCC1>[Cl:2][C:3]1[N:12]=[C:11]([NH2:1])[C:10]2[C:5](=[C:6]([O:16][CH3:17])[C:7]([O:14][CH3:15])=[CH:8][CH:9]=2)[N:4]=1
Reactant: N
Reactant: COc1ccc2c(Cl)nc(Cl)nc2c1OC
Solvent: C1CCOC1
Product: COc1ccc2c(N)nc(Cl)nc2c1OC

Procedure:
Ammonia was passed into a solution of 2,4-dichloro-7,8-dimethoxyquinazoline (287 g., 1.11 moles) in tetrahydrofuran (6 liters) for five hours at room temperature. After stirring an additional hour the suspension was concentrated in vacuo to 2 liters and filtered. The solid was suspended in 2 liters of water, filtered, washed with water and cold methanol. Recrystallization from dimethylformamide/water yielded 164 g. (62%) of pure product, M.P. 300°. (dec.).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.C(N(CC)CC)C.[CH3:23][C:24]1[N:25]=[C:26]2[N:31]=[C:30]([C:32]3[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=3)[C:29]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:28][N:27]2[CH:46]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1.C(O)(=O)C>[CH3:23][C:24]1[N:25]=[C:26]2[N:31]=[C:30]([C:32]3[CH:33]=[CH:34][C:35]([CH2:36][N:1]4[CH2:4][CH:3]([C:5]5[N:6]=[C:7]([C:10]6[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=6)[NH:8][N:9]=5)[CH2:2]4)=[CH:38][CH:39]=3)[C:29]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:28][N:27]2[CH:46]=1
Reactant: Cc1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: Cc1cn2cc(-c3ccccc3)c(-c3ccc(CN4CC(c5n[nH]c(-c6ccccn6)n5)C4)cc3)nc2n1
Reaction time: 1 h
Yield: 26.5 %

Procedure:
418.6 mg (1.53 mmol) 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 12 mL NMP. After addition of 0.43 mL (3.05 mmol) triethylamine the reaction mixture is stirred for one hour. 435 mg (1.38 mmol) 4-(2-Methyl-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde and 0.19 mL acetic acid are added. The reaction mixture is stirred over night at room temperature. 706.1 mg (3.33 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature over the weekend. The reaction mixture is treated with saturated NaHCO3 and stirred for two hours. The precipitate is filtered off, washed with water, dried and purified by chromatography (silicagel, eluents: dichloromethane/methanol) yielding 182.1 mg (24%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH2:6][Li])[CH3:3].[O:8]1[CH:18]2[CH:9]1[CH2:10][C:11]1[C:16]([CH2:17]2)=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CCOCC>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:5][CH2:6][C@@H:18]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[OH:8]
Reactant: [Li]CCCN(C)C
Reactant: c1ccc2c(c1)CC1OC1C2
Solvent: CCOCC
Solvent: O
Product: CN(C)CCC[C@@H]1Cc2ccccc2C[C@H]1O

Procedure:
to a solution of 0.1 mol of dimethylamino propyllithium in 500 ml of ether cooled to 0°-5° C. is added dropwise a solution of 7.3 g (0.05 mol) of 2,3-epoxy-1,2,3,4-tetrahydronaphthalene in 100 ml of ether. The reaction mixture is then heated under reflux for 2 hours and decomposed with water. The organic layer is separated and dried and the desired 1,2,3,4-tetrahydro-3-(3-dimethylaminopropyl)-2-naphthalenol separated from byproducts by column chromatography on neutral alumina.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]=[O:13].C1N2CCN(CC2)C1.[C:22](#[N:25])[CH:23]=[CH2:24]>C(OCC)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:12]([OH:13])[C:23]([C:22]#[N:25])=[CH2:24]
Reactant: C=CC#N
Reactant: COC(=O)c1ccc(C=O)c(Cl)n1
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: C=C(C#N)C(O)c1ccc(C(=O)OC)nc1Cl

Procedure:
To a mixture of Methyl 6-chloro-5-formyl-2-pyridincarboxylate (10 mmol, 1.99 g) and DABCO (10 mmol. 1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (˜4-5 min.) was diluted with diethyl ether (300 ml.) and washed with water 3×50 ml. The organic layer was dried over Na2SO4 and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8, v/v) to give the desired product in almost quantitative (2.50 g.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:6]=[C:5]2[N:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=[CH:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:34]([O:38][C:39](=[O:42])[NH:40][CH3:41])([CH3:37])([CH3:36])[CH3:35].O>O1CCCC1>[C:34]([O:38][C:39](=[O:42])[N:40]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:6]=[C:5]2[N:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=[CH:20]1)[CH3:41])([CH3:37])([CH3:36])[CH3:35]
Reactant: CNC(=O)OC(C)(C)C
Reactant: Fc1ccccc1-c1nc(-n2ccc3cnccc32)c2cc(Br)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc2nc(-c3ccccc3F)nc(-n3ccc4cnccc43)c2c1
Temperature: 80 °C
Yield: 61.1 %

Procedure:
6-Bromo-2-(2-fluoro-phenyl)-4-pyrrolo[3,2-c]pyridin-1-yl-quinazoline from step E (0.1 g, 0.23 mmol) was dissolved in tetrahydrofuran (5 ml) in a 50 ml round bottomed flask. Cesium carbonate (0.11 g, 0.35 mmol), Xanphos (0.007 g, 0.002 mmol) and methyl-carbamic acid tert-butyl ester (0.045 g, 0.35 mmol) was then added. The mixture was degassed for 5 mins and tris (dibenzylidineacetone)dipalladium(0) (0.005 g, 0.005 mmol) was added. The resulting solution was then magnetically stirred and the heated to 80° C. for 3 hrs. Water was added and compound extracted into ethyl acetate, dried over sodium sulfate and concentrated in rotary evaporator to yield desired title compound (0.066 g, 58%). MS (ES) 470.1 (M+H)+
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:27]([O:29][CH2:30][CH3:31])=[O:28].[H-].[Na+].[CH3:34]N(C)C=O.CI>O1CCCC1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:22][C:23]([F:25])([F:26])[F:24])=[CH:10][C:11]=2[N:13]([CH3:34])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2n1COC
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylate (1.07 g), 60% sodium hydride (0.10 g) and N,N-dimethylformamide (14 mL) was stirred at room temperature for 40 min. A solution of methyl iodide (0.20 mL) in tetrahydrofuran (3 mL) was added dropwise, and the mixture was stirred at room temperature for 18 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=5:95-15:85) to give the title compound (0.75 g, yield 68%) as pale-yellow needle crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]2[N:16]=[C:17]([CH2:22][CH3:23])[C:18]([N+:19]([O-])=O)=[C:14]2[CH:13]=[CH:12][CH:11]=1.O.C(O)(=O)C>C(O)C.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]2[N:16]=[C:17]([CH2:22][CH3:23])[C:18]([NH2:19])=[C:14]2[CH:13]=[CH:12][CH:11]=1
Reactant: CCc1nn2c(-c3ccc(OC)cc3Cl)cccc2c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CCc1nn2c(-c3ccc(OC)cc3Cl)cccc2c1N
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
7-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (5 mg) was suspended in ethanol (2 mL), and then water (1 mL), acetic acid (0.5 mL) and zinc powder (10 mg) were added and the mixture was heated and stirred at 80° C. for 30 minutes. The reaction mixture was filtered, water was added to the filtrate, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure to obtain [7-(2-chloro-4-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine as crude crystals. These were dissolved in tetrahydrofuran (1 mL) without further purification, and after adding propionaldehyde (0.015 mL) and 3 M aqueous sulfuric acid (0.071 mL), sodium borohydride (5.4 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Water was added to the reaction mixture, extraction was performed with diethyl ether and the extract was washed with saturated sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure and the residue was purified by preparative TLC [n-hexane:ethyl acetate (5:1), Rf=0.5] to obtain the title compound (6 mg) as a light yellow oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH:21]=[N:20][N:19]=[N:18]1>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:18]2[N:19]=[N:20][CH:21]=[N:17]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2ncnn2)cc1
Yield: 24 %

Procedure:
A mixture of 1-fluoro-4-nitrobenzene (20 g), potassium carbonate (23.5 g) and 1H-tetrazole (12 g) in dimethylformamide (60 ml) was heated to 100° under nitrogen for 24 h. On cooling, the solvent was evaporated and the residue taken up in water, extracted with dichloromethane (4×100 ml), dried (Na2SO4) and evaporated to give an orange solid. This was purified by FCC (cyclohexane/ethyl acetate (3:1)) to give the title compound as a solid (6.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[NH:19][C:20]1[N:24]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:23]2[CH:31]=[CH:32][C:33]([CH2:35][OH:36])=[CH:34][C:22]=2[N:21]=1.[CH3:37][O:38][CH2:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.ClCCl>>[CH:25]1([N:24]2[C:23]3[CH:31]=[CH:32][C:33]([CH2:35][OH:36])=[CH:34][C:22]=3[N:21]=[C:20]2[NH:19][C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([C:44]4[CH:43]=[CH:42][CH:41]=[C:40]([CH2:39][O:38][CH3:37])[CH:45]=4)[CH:3]=3)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:6]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COCc1cccc(B(O)O)c1
Reactant: C[Si](C)(C)CCOCn1nc(Nc2nc3cc(CO)ccc3n2C2CCCCC2)c2cc(Br)ccc21
Solvent: ClCCl
Product: COCc1cccc(-c2ccc3c(c2)c(Nc2nc4cc(CO)ccc4n2C2CCCCC2)nn3COCC[Si](C)(C)C)c1
Yield: 103.3 %

Procedure:
In a small microwave tube added (2-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-3-ylamino)-1-cyclohexyl-1H-benzo[d]imidazol-5-yl)methanol (52.4 mg, 0.0000918 mol), 3-(methoxymethyl)phenylboronic acid (25.1 mg, 0.000151 mol) and (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) complexed with dichloromethane (1:1) (16.2 mg, 0.0000198 mol). The tube was flushed with argon and the contents were dissolved in 1,4-dioxane (1.5 mL) and 2 M sodium carbonate (150 uL). The reaction was microwaved for 10 minutes at 120° C. The cooled reaction mixture was filtered through a syringe filter and the filter washed 3× with methanol. The combined eluents were concentrated to yield 58 mg of crude product used directly in the next step.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:17]=[C:18]1[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][N:19]1[CH2:36][C:37](O)=[O:38].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:17]=[C:18]1[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:22][CH2:21][CH2:20][N:19]1[CH2:36][C:37]([N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1)=[O:38]
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
A solution of benzyl piperazine-1-carboxylate (0.196 g, 0.889 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.250 g, 0.808 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.186 g, 0.970 mmol) were stirred together overnight in dichloromethane (5 mL). The reaction was concentrated, loaded directly onto a SF15-silica gel column (Analogix®). The product was eluted using a gradient of 5% to 100% ethyl acetate over 30 minutes to provide the title compound. 1H NMR (300 MHz, CDCl3) δ 7.46-7.07 (m, 15H), 5.15 (s, 2H), 4.22 (s, 2H), 3.75-3.30 (m, 10H), 2.73-2.53 (m, 2H), 1.85 (d, J=5.9, 2H); MS (ESI+) m/z 512.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].Br[CH2:20][C:21]([O:23]C)=[O:22].[OH-:25].[Na+].Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[N:10]([CH2:20][C:21]([OH:23])=[O:22])[C:11](=[O:25])[C:12]([CH3:16])([CH3:15])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: [OH-]
Reactant: CC1(C)CCC(c2ccc(F)c(F)c2)NC1
Reactant: COC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CCC(c2ccc(F)c(F)c2)N(CC(=O)O)C1=O
Reaction time: 0.25 h

Procedure:
To a stirred solution of 2-(3,4-difluorophenyl)-5,5-dimethylpiperidine from Step A (47.0 mg, 0.209 mmol) in THF (2 mL) at 0° C. was added NaH (12.0 mg of a 60% dispersion in oil, 0.292 mmol). After 15 min, methyl bromoacetate (0.022 mL, 0.229 mmol) was added and the mixture was stirred at ambient temperature for 4 d, with additional methyl bromoacetate (0.022 mL, 0.229 mmol) added on the 2nd and 3rd days. Added NaOH (0.627 mL of a 1M solution) and the mixture was stirred at 50° C. for 16 h. The reaction mixture was acidified with 1 M HCl (5 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound. MS: m/z=284 (M+1).
Reaction SMILES: C(OC(=O)[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([O:20][C:21]2[CH:22]=[N:23][C:24]([CH2:27][O:28][CH3:29])=[CH:25][CH:26]=2)=[CH:15][C:14]=3[O:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[N:8][CH2:7]1)C.[O:38]1[CH2:42][CH2:41]CC1.[CH3:43][Mg]Br.[Cl-].[NH4+]>O1CCCC1.CCCCCC.C(OCC)(=O)C.CO>[CH3:29][O:28][CH2:27][C:24]1[N:23]=[CH:22][C:21]([O:20][C:16]2[CH:17]=[C:18]3[C:13](=[C:14]([O:30][CH:31]4[CH2:32][CH2:33][O:34][CH2:35][CH2:36]4)[CH:15]=2)[NH:12][C:11]([C:9]2[S:10][CH:6]([CH2:5][C:42]([CH3:41])([OH:38])[CH3:43])[CH2:7][N:8]=2)=[CH:19]3)=[CH:26][CH:25]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(COC)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: COCc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C4=NCC(CC(C)(C)O)S4)cc3c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
To a solution of ethyl{2-[5-{[6-(methoxymethyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indol-2-yl]-4,5-dihydro-1,3-thiazol-5-yl}acetate (500 mg) in tetrahydrofuran (10 mL) was added 1M methylmagnesium bromide tetrahydrofuran solution (5 mL) twice at 30 min intervals at room temperature, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was subjected to basic silica gel column chromatography (ethyl acetate:hexane=0:100 to 100:0, volume ratio) and further to silica gel column chromatography (methanol:ethyl acetate:hexane=0:0:100 to 10:90:0, volume ratio). The obtained crude product was purified by preparative HPLC to give the title compound (75 mg, yield 15%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[CH:11][N:12](C)C)[C:7](=[O:15])[C:6]=2[CH:16]=1.[C:17]([O:21][C:22]([N:24]([CH3:26])N)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C>CO.O1CCCC1>[C:17]([O:21][C:22]([N:24]([CH3:26])[NH:12][CH:11]=[C:8]1[C:7](=[O:15])[C:6]2[CH:16]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:10][CH2:9]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CN(N)C(=O)OC(C)(C)C
Reactant: CN(C)C=C1CSc2ccc(Cl)cc2C1=O
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: CN(NC=C1CSc2ccc(Cl)cc2C1=O)C(=O)OC(C)(C)C
Yield: 129.2 %

Procedure:
A solution of 6-chloro-2,3-dihydro-3-dimethylaminomethylene-4H-1-benzothiopyran-4-one (34.13 g), 1-t-butoxycarbonyl-1-methylhydrazine (59.14 g), and acetic acid (23.14 ml) in methanol (2 l) and tetrahydrofuran (1 l) was stirred at ambient temperature for 6 hours and then evaporated in vacuo. To the residue was added aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo to give 3-(2-t-butoxycarbonyl-2-methylhydrazinomethylene)-6-chloro-2,3-dihydro-4H-1-benzothiopyran-4-one (61.65 g).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]([N:33]=[C:34]=[O:35])[CH:30]=[CH:31][CH:32]=1>O1CCCC1>[C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:34]([NH:33][C:29]4[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:36])[F:37])[CH:28]=4)=[O:35])[CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-trifluoromethylphenyl isocyanate (0.170 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 55.4 mg (15.7%) of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](F)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C.CC(C)([O-:35])C.[Na+]>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)=[CH:19][CH:20]=2)[C:5]([C:8]([NH2:9])=[O:35])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Br)cc1F
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: CN1CCN(c2ccc(Nc3cc(Br)cnc3C(N)=O)cc2)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A solution of EXAMPLE 49A (1.8 g, 8.96 mmol) and 4-(4-methylpiperazin-1-yl)aniline (1.713 g, 8.96 mmol) in t-butanol (10 mL) was treated with triethylamine (1.87 mL, 13.43 mmol) was subjected to microwave irradiation (Biotage, Initiator) at 190° C. for 1.5 hours. The reaction mixture was concentrated and purified on silica gel with 0-10% methanol in dichloromethane. The collected material was taken into t-butanol (5 mL), treated with sodium t-butoxide (1.73 g, 18 mmol), and the reaction mixture was stirred at 90° C. for 2 hours. The mixture was concentrated and purified on silica gel with 3-13% methanol in dichloromethane to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:13]#CN.[CH2:16]([N:23]1[C:27]([C:28](=O)[CH:29]=[CH:30][N:31](C)[CH3:32])=[CH:26][N:25]=[C:24]1[CH3:35])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[O-].[Na+]>CO.Cl.CC(N(C)C)=O>[CH2:16]([N:23]1[C:27]([C:28]2[CH:29]=[CH:30][N:31]=[C:32]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([S:8](=[O:10])(=[O:9])[NH:11][CH3:12])=[CH:4][CH:3]=3)[N:13]=2)=[CH:26][N:25]=[C:24]1[CH3:35])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CNS(=O)(=O)c1ccc(N)cc1
Reactant: N#CN
Reactant: Cc1ncc(C(=O)C=CN(C)C)n1Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CNS(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C)n3Cc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 69.6 %

Procedure:
4-Amino-N-methyl-benzenesulphonamide (250 mg, 1.34 mmol) was dissolved in the minimum amount of MeOH and 1M ethereal hydrogen chloride (1.34 ml) added. The volatiles were removed by evaporation and cyanamide (68 mg, 1.62 mmol) was added followed by dimethylacetamide (0.5 ml) and the mixture heated at 100° C. for 45 minutes. The mixture was allowed to cool and 1-benzyl-5-(3-dimethylaminoprop-2-en-1-oyl)-2-methylimidazole (Method 50; 230 mg, 0.86 mmol) and sodium methoxide (150 mg, 2.78 mmol) were added and the mixture heated to reflux for one hour. The mixture allowed to cool and was partitioned between EtOAc and aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (Na2SO4) and the volatiles removed by evaporation. The residue was purified by chromatography on silica eluting with DCM/7N methanolic ammonia (96:4). The purified product was triturated with minimal hot EtOAc to give the title compound (260 mg, 70%) as a cream solid. NMR: 2.28 (s, 3H), 2.37 (d, 3H), 5.96 (s, 2H), 6.93 (d, 2H), 7.15-7.28 (m, 5H), 7.54 (d, 2H), 7.75-7.81 (m, 3H), 8.40 (d, 1H), 9.86 (s, 1H); m/z 435.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:29][CH:30]([CH2:32][OH:33])[CH3:31]>ClCCl>[OH:33][CH2:32][CH:30]([NH:29][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=1)[CH3:31]
Reactant: CC(N)CO
Reactant: O=C(O)c1cccc(I)c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CO)NC(=O)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.7 %

Procedure:
To a solution of 3-iodobenzoic acid (10.02 g, 40.30 mmol), in dry dichloromethane, at room temperature (180 mL) under a nitrogen atmosphere, EDCI (7.72 g, 40.30 mmol) was added followed by triethylamine (8.0 mL, 60.45 mmol) and the mixture was stirred at room temperature for further 5 minutes. DL Alaninol (3.02 g, 40.3 mmol) was then added and the mixture stirred at room temperature for 16 hrs. The reaction mixture was washed with a mixture of saturated brine and saturated sodium bicarbonate (1:1; 2×150 mL) followed by saturated brine solution (100 mL). The organics were separated and dried over magnesium sulfate and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel (DCM:MeOH, 1% to 8% methanol gradient) to afford compound 1 (4.14 g, 13.6 mmol, 34% yield) as an off white solid.