Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[C:12](=O)([O-])[O-].[K+].[K+].C(=O)(OC)OC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[CH:6]2
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2[nH]ccc2c1
Agent: [K+]
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2C)c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 183 %

Procedure:
A mixture of 5-methoxyindole (1 g, 6.79 mmol), potassium carbonate (0.5 g), N,N-dimethylformamide (10 mL) and dimethyl carbonate (1.7 mL, 20 mmol) was stirred and heated to reflux (˜130° C.). The progress of the reaction was monitored by HPLC. Within 5 h, the starting indole had been consumed and after the mixture was cooled to ˜3° C., it was treated with ice cold water (30 mL). The formed precipitate was filtered off, then was washed in turn with water (2×30 mL) and hexanes (30 mL). The colorless product was dried under vacuum at 25° C. for 48 h to afford 5-methoxy-1-methylindole (1.067 g, 97.4% yield).
Reaction SMILES: [Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5](O)=[O:6].S(Cl)([Cl:12])=O>CN(C)C=O>[Cl:1][C:2]([F:9])([F:8])[CH2:3][CH2:4][C:5]([Cl:12])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCC(F)(F)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)CCC(F)(F)Cl

Procedure:
15.8 g of 4-chloro-4,4-difluorobutyric acid are mixed with 50 ml of thionyl chloride and 0.2 ml of dimethylformamide and heated to +70° C. over the course of 2 hours and then maintained at +70° C. for a further 30 minutes. The reaction mixture is distilled in vacuo, and the liquid boiling at 35°-37° C./21 mbar is collected. 10.5 g of 4-chloro-4,4-difluorobutyryl chloride are obtained in the form of a clear colourless liquid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:9]2=[O:27])(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH2:36][OH:37]>C(#N)C>[OH:37][CH2:36][CH2:35][N:5]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:9]2=[O:27])[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: OCCBr
Reactant: CS(=O)(=O)Nc1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N(CCO)c1ccc2c(c1)C(=O)N(CC(=O)OCc1ccccc1)C2=O
Temperature: 110 °C
Yield: 95.7 %

Procedure:
To a solution of benzyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (0.700 g, 1.802 mmol) in acetonitrile (20 ml), K2CO3 (0.498 g, 3.605 mmol) and 2-bromoethanol (0.509 ml, 7.21 mmol) were further added. The mixture was heated under MW irradiation at 110° C. for 2 hours. 2-Bromoethanol (0.272 ml, 3.734 mmol) and K2CO3 (0.268 g, 1.931 mmol) were added, and the reaction was heated under MW irradiation at 110° C. for additional 3 hours. The mixture was then diluted with acetonitrile, the insoluble inorganic salts were filtered off and the filtrate was evaporated to dryness. The crude was purified by trituration with Et2O affording benzyl 2-(5-(N-(2-hydroxyethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (0.746 g, 1.725 mmol, 96% yield, MS/ESI+ 432.9 [MH]+).
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][C:6]([CH3:16])([CH3:15])[CH2:7][C:8]1[CH:13]=[CH:12][C:11](F)=[CH:10][CH:9]=1.Cl.[OH:30][CH:31](COC1C=CC=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl>C(OCC)C>[ClH:1].[OH:2][CH:3]([CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)[CH2:4][NH:5][C:6]([CH3:15])([CH3:16])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:30][CH3:31])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccccc2)cc1
Reactant: CC(C)(Cc1ccc(F)cc1)NCC(O)COc1cccc2ccccc12
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(CC(C)(C)NCC(O)COc2ccc3ccccc3c2)cc1

Procedure:
Using the method of Example 4, supra, 2-naphthyl glycidyl ether (400 mg, 2 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (358 mg, 2 mmol) were used to prepare the free base of the title compound: GC/EI-MS, m/z (rel. int.) 364 (M−15, 1), 253 (100), 183 (2), 163 (3), 144 (4), 127 (10), 121 (22), 115 (20), 71 (11). The free base in diethyl ether was treated with excess 1M HCl (diethyl ether). The resulting solid was recrystallized from hot acetonitrile to afford 496 mg of the hydrochloride product as a white solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH2:9][Si:10](C)(C)[O:11]C)(=[O:5])[C:2]([CH3:4])=[CH2:3].CO.[CH3:17][Si:18]([O:28][CH3:29])([O:26][CH3:27])[O:19][Si:20]([CH3:25])(OC)[O:21][CH3:22]>C(O)(=O)C>[C:1]([O:6][CH2:7][CH2:8][CH2:9][SiH2:10][O:11][Si:20]([CH3:25])([O:21][CH3:22])[O:19][Si:18]([CH3:17])([O:28][CH3:29])[O:26][CH3:27])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCC[Si](C)(C)OC
Reactant: CO[Si](C)(OC)O[Si](C)(OC)OC
Solvent: CO
Solvent: CC(=O)O
Product: C=C(C)C(=O)OCCC[SiH2]O[Si](C)(OC)O[Si](C)(OC)OC
Reaction time: 1 h
Yield: 82 %

Procedure:
A flask was charged with 216 g of γ-methacryloxypropyldimethylmethoxysilane and 500 g of methanol. Under a nitrogen stream, the flask was cooled to 5° C., to which 18.0 g of 0.2N acetic acid was added dropwise over 15 minutes while the liquid temperature was maintained below 10° C. After the completion of dropwise addition, stirring continued for one hour at room temperature. Then, 2260 g of 1,3-dimethyl-1,1,3,3-tetramethoxydisiloxane was added. Stirring continued for 2 hours at room temperature and for a further 8 hours at 60° C. The methanol and volatile matter were removed from the reaction solution by heating in vacuum, obtaining 1-(γ-methacryloxypropyl)-3,5-dimethyl-3,5,5-trimethoxytrisiloxane (M-2) in a yield of 82%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]=O)(C)(C)C.[C:16](#[N:20])[CH2:17][C:18]#[N:19]>C(O)C.N1CCCCC1>[NH2:19][C:18]1[N:7]=[C:8]2[CH:12]=[CH:11][S:10][C:9]2=[CH:13][C:17]=1[C:16]#[N:20]
Reactant: N#CCC#N
Reactant: CC(C)(C)OC(=O)Nc1ccsc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: N#Cc1cc2sccc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
(2-Formyl-thiophen-3-yl)-carbamic acid tert-butyl ester described in Preparation Example U-2 (500 mg, 2.20 mmol) and malononitrile (153 mg, 2.31 mmol) were dissolved in a solution of ethanol (10 mL) to which piperidine (catalytic amount) had been added, and the mixture was stirred for 1 hour under reflux. The reaction mixture was cooled to room temperature, the precipitated solid was filtered, and title compound (215 mg, 1.23 mmol, 56%) was obtained as a white solid.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([C@@H:12]([NH2:14])[CH3:13])[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]=2[C:21]=1[CH3:22].[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28](Cl)[N:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:23][C:24]1[C:29]([C:30]#[N:31])=[C:28]([NH:14][C@H:12]([C:10]2[N:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:8]3[C:21]([CH3:22])=[C:4]([F:3])[CH:5]=[CH:6][C:7]=3[N:11]=2)[CH3:13])[N:27]=[CH:26][N:25]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: Cc1c(F)ccc2nc([C@H](C)N)n(-c3ccccn3)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c(F)ccc2nc([C@H](C)Nc3ncnc(N)c3C#N)n(-c3ccccn3)c12
Temperature: 90 °C
Yield: 48.5 %

Procedure:
To a solution of (S)-1-(6-fluoro-7-methyl-1-pyridin-2-yl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride (300 mg, 0.87 mmol) in IPA (10 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (135 mg, 0.87 mmol) and DIPEA (448 μL, 2.62 mmol) and the reaction mixture heated at 90° C. for 16 h. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, eluting with 0-10% methanol in EtOAc). The product was triturated with diethyl ether then subjected to HPLC purification (C18, 10-90% MeCN in H2O, 0.1% formic acid, 20 min gradient) to give 289 as a white solid (164 mg, 48%). 1H NMR 400 MHz 6 (DMSO-d6): 8.55 (1H, br s), 8.00-7.91 (1H, m), 7.81-7.73 (1H, m), 7.70-7.60 (1H, m), 7.53 (1H, dd, J=8.7, 4.6 Hz), 7.55-7.45 (1H, m), 7.21-7.09 (1H, m), 7.06 (1H, dd, J=10.3, 8.7 Hz), 5.65-5.13 (1H, m), 1.63 (3H, s), 1.46 (3H, d, J=6.7 Hz). LCMS (Method K): RT=3.40 min, [M+H]+=389
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1.[Cl:11][CH2:12][CH2:13][C@@H:14]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)O>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C@@H:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][Cl:11])[CH:3]=1
Reactant: O[C@@H](CCCl)c1cccs1
Reactant: N#Cc1ccc(Cl)cc1O
Product: N#Cc1ccc(Cl)cc1O[C@H](CCCl)c1cccs1

Procedure:
Using 4-chloro-2-hydroxybenzonitrile (303 mg, 1.97 mmol) and (S)-α-(2-chloroethyl) thiophenemethanol (349 mg, 1.97 mmol), and the procedure described in Example 5(a), the title compound was prepared as a white crystalline solid (373 mg, 61%).
Reaction SMILES: Br[C:2]1[C:3]([CH:9]=[N:10][C:11]([CH3:14])([CH3:13])C)=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.C(#N)C.[CH:18]1(C#C)[CH2:23][CH2:22]C[CH2:20][CH2:19]1>ClCCl.[Zn]>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[C:3]([CH:4]=1)=[CH:9][N:10]=[C:11]([CH:13]1[CH2:22][CH2:23][CH2:18][CH2:19][CH2:20]1)[CH:14]=2
Reactant: C#CC1CCCCC1
Reactant: CC(C)(C)N=Cc1cc(Cl)ncc1Br
Agent: [Zn]
Solvent: ClCCl
Solvent: CC#N
Product: Clc1cc2cnc(C3CCCCC3)cc2cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
A round-bottom flask containing N-((5-bromo-2-chloropyridin-4-yl)methylene)-2-methylpropan-2-amine (164.5 mg, 0.5969 mmol), DPPPNiCl2 (16.0 mg, 0.0295 mmol) and zinc (84.0 mg, 1.28 mmol) was evacuated and purged with nitrogen 5 times. Acetonitrile (6 mL, 100 mmol) and cyclohexylacetylene (86.0 uL, 0.658 mmol) were added to the flask and the reaction mixture was stirred at 80° C. under a nitrogen balloon for 30 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane, and filtered through celite, rinsing with dichloromethane. The filtrate was evaporated in vacuo and the crude product purified via flash chromatography on silica gel (12 g silica, solvent gradient: 0-40% ethyl acetate in dichloromethane) to yield 80.4 mg (55%) of 3-chloro-7-cyclohexyl-2,6-naphthyridine. LCMS (ESI): M+H=247.2; 1H NMR (500 MHz, DMSO) δ 9.39 (s, 1H), 9.28 (s, 1H), 8.20 (s, 1H), 7.88 (s, 1H), 2.91-2.81 (m, 1H), 1.97 (d, J=11.3 Hz, 2H), 1.84 (d, J=13.0 Hz, 2H), 1.75 (d, J=12.9 Hz, 1H), 1.58 (ddd, J=24.8, 12.5, 2.9 Hz, 2H), 1.49-1.37 (m, 2H), 1.27 (ddd, J=16.3, 12.6, 9.2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1Cl)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[SH:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[S:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[O:5])[CH3:2]
Reactant: COC(=O)CCS
Reactant: CCOC(=O)c1cnccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnccc1SCCC(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.3 %

Procedure:
To a stirred solution of 4-chloro-pyridine-3-carboxylic acid ethyl ester (4.30 g, 23.2 mmol) in dry tetrahydrofuran (45 ml) is added potassium tert-butoxide (3.12 g, 27.9 mmol) portion wise at 0° C., followed by the addition of methyl 3-mercaptopropanoate (3.35 g, 27.9 mmol). The reaction mixture is stirred at RT for 2 h. After completion of the reaction, the solvent is distilled off and the residue is diluted with water (30 ml). The aqueous layer is extracted with EtOAc (3×40 ml). The combined organic layers are washed with water (40 ml), brine (40 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product, which is purified by column chromatography (silica gel, 30% EtOAc/hexane) to get 4-(2-methoxycarbonyl-ethylsulfanyl)-pyridine-3-carboxylic acid ethyl ester (3.0 g, 11.2 mmol, 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[NH2:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)=[O:6].[CH2:19]([O:21][C:22](=[O:35])[CH2:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH:32]=O)=[C:27]([CH3:34])[CH:26]=1)[CH3:20]>CO>[CH2:19]([O:21][C:22](=[O:35])[CH2:23][O:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([C:32]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=4)[CH:15]=[CH:16][C:17]=3[N:18]=2)=[C:27]([CH3:34])[CH:26]=1)[CH3:20]
Reactant: CCOC(=O)COc1cc(C)c(C=O)c(C)c1
Reactant: Nc1ccc(C(=O)Nc2cccc(Cl)c2)cc1N
Solvent: CO
Product: CCOC(=O)COc1cc(C)c(-c2nc3ccc(C(=O)Nc4cccc(Cl)c4)cc3[nH]2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3,4-diamino-N-(3-chloro-phenyl)-benzamide (0.1 mL in 0.2 M DMSO solution), (4-formyl-3,5-dimethyl-phenoxy)-acetic acid ethyl ester (0.1 mL in 0.2 M toluene solution) and FeCl3 (0.05 mL in 0.02M THF solution) was stirred in open air at ambient temperature overnight. The mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to give {4-[6-(3-Chloro-phenylcarbamoyl)-1H-benzoimidazol-2-yl]-3,5-dimethyl-phenoxy}-acetic acid ethyl ester: MS (m/z) 478 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[C:6]([F:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH2:9][Br:30])[CH:3]=1
Reactant: OCc1cc(F)cc(Br)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cc(Br)cc(CBr)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(3-Bromo-5-fluorophenyl)methanol (0.78 g, 3.8 mmol) and triphenylphosphine (2.0 g, 7.6 mmol) were combined in tetrahydrofuran (20 mL) and cooled to 0° C. N-Bromosuccinimide (1.4 g, 7.98 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% ethyl acetate/hexanes) gave 0.8 g (79%) as a white powder. 1H-NMR (CDCl3, 300 MHz) 7.30 (s, 1H), 7.14-7.18 (m, 1H), 7.01-7.05 (m, 1H), 4.36 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[C:44]([NH2:56])[CH:43]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([NH2:32])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:63][S:64](Cl)(=[O:66])=[O:65]>O>[CH2:1]([N:8]([CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)=[C:44]([NH:56][S:64]([CH3:63])(=[O:66])=[O:65])[CH:43]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:20]([NH:32][S:64]([CH3:63])(=[O:66])=[O:65])[CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(CCN(CCCCCCN(CCc2ccc(OCc3ccccc3)c(N)c2)Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(CCN(CCCCCCN(CCc2ccc(OCc3ccccc3)c(NS(C)(=O)=O)c2)Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 7.5 g. (0.01 m.) of N,N'-dibenzyl-N,N'-bis[2-(3-amino-4-benzyloxyphenyl)-ethyl]-hexamethylene-diamine in 30 ml. of pyridine is added 2.5 g. of methanesulfonyl chloride. The reaction mixture is allowed to stand at room temperature overnight and is then added to excess water to yield N,N'-dibenzyl-N,N'-bis[2-(4-benzyloxy-3-methanesulfonamidophenyl)-ethyl]-hexamethylenediamine.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][CH:13](C(O)=O)[C:14]([OH:16])=[O:15].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:12][C:13](=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:14]([OH:16])=[O:15]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C(=O)O)C(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CC(=Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 0 °C
Reaction time: 24 h

Procedure:
630 ml of pyridine was added to 76 g of 4-nitrobenzaldehyde (m.p. 105°-106.5° C.), 118 g of methylmalonic acid (prepared by hydrolysis of diethyl methylmalonate) and 85 g of piperidine. The mixture was heated with stirring over a steam bath for 24 hours. After being allowed to cool, the reaction mixture was then added to a mixture of 1,250 ml of concentrated hydrochloric acid and 2.5 kg of ice. The resulting oil content was then extracted with diethyl ether. The oil content was further extracted with a 5% aqueous solution of sodium hydroxide. The aqueous solution was then slightly acidified. The resulting crystal composition was then filtered off and dried. (Yield: 86 g (83%))
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([Cl:17])[CH:13]=[CH:12]2.[C:18](=[O:20])=[O:19]>C1COCC1>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[C:7]([C:18]([OH:20])=[O:19])[CH:8]=[CH:9][CH:10]=2)[N:15]=1
Reactant: Clc1ccc2cccc(Br)c2n1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cccc2ccc(Cl)nc12
Yield: 99 %

Procedure:
nBuLi (2.2M in hexanes; 7.50 ml, 16.49 mmol) was added dropwise over 2 min to a solution of 8-bromo-2-chloroquinoline (4.00 g, 16.49 mmol, Biofine International, Inc., Vancouver, BC) in THF (82 ml) at −78° C. The resulting mixture was stirred at −78° C. for 20 min before CO2 was bubbled into the solution for 5 min at −78° C. The mixture was quenched with 2 N HCl (10 ml). The resulting mixture was partitioned between 100 ml of Et2O and 1 N NaOH. The organic layer was separated, and the aq. layer was acidified to ˜pH 2 with 5 N HCl and extracted 3 times with 150 ml Et2O. The combined organic extracts were dried over Na2SO4 and concentrated to provide 2-chloroquinoline-8-carboxylic acid (181a, >99% yield) as a light brown solid. MS (ESI, pos. ion) m/z: 208.2 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[N:19]C1C=CC=CC=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32]N)[CH:27]=1>>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][N:19]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[C:9]([C:3]4[CH:2]([CH3:1])[S:7][C:6](=[O:8])[NH:5][N:4]=4)[CH:10]=3)[NH:14][C:13]2=[O:18])[CH:27]=1
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=Nc1ccccc1)C(=O)N2
Reactant: NNc1cccnc1
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(=NNc1cccnc1)C(=O)N2
Yield: 64 %

Procedure:
Starting from 1,3-dihydro-5-(3,6-dihydro-6-methyl-2-oxo -2H-1,3,4-thiadiazin-5-yl)-3-phenylimino-2H-indol-2-one, and 3-pyridylhydrazine and following the method described in Example 21, the desired compound was obtained.
Reaction SMILES: [O-:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl[C:10]1[CH:15]=[C:14]([NH:16][CH2:17][CH3:18])[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][N:11]=1.O>C1COCC1>[CH2:17]([NH:16][C:14]1[C:13]([N+:19]([O-:21])=[O:20])=[CH:12][N:11]=[C:10]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:15]=1)[CH3:18]
Reactant: CCNc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: [O-]c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]

Procedure:
A solution of sodium phenoxide (prepared from phenol and NaH) (6 mmol) in THF (3 mL) was added to a solution of the product from Step 1 (600 mg, 3.0 mmol) in THF (2 mL) and the resulting solution was heated to reflux overnight. The solution was cooled, poured into H2O and extracted with EtOAc. The organic layers were washed with H2O and brine, dried, filtered and concentrated to give a residue which was purified by column chromatography (5-80% EtOAc in hex) to give the title compound which was used directly in the next step. MS (ES+) m/e 260. [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=2)[C:10]1=[O:31].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[NH:32]([C:14]1[N:13]=[C:12]2[N:11]([C:23]3[CH:28]=[CH:27][C:26]([CH2:29][OH:30])=[CH:25][CH:24]=3)[C:10](=[O:31])[N:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:18][C:17]2=[CH:16][N:15]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccccc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccc(CO)cc1)C(=O)N(c1ccc(Cl)cc1Cl)C2
Product: O=C1N(c2ccc(Cl)cc2Cl)Cc2cnc(Nc3ccccc3)nc2N1c1ccc(CO)cc1
Temperature: 120 °C
Yield: 57 %

Procedure:
A mixture of 350 mg (0.7 mmol) of 3-(2,4-dichlorophenyl)-3,4-dihydro-1-[4-(hydroxymethyl)phenyl]-7-methanesulfonyl-pyrimido[4,5-d]pyrimidin-2(1H)-one and 2 ml of aniline was heated at 120° C. for 3 hours. The reaction was cooled to room temperature then partitioned between 2M hydrochloric acid (20 ml) and dichloromethane (20 ml). The organic layer was separated, washed with saturated aqueous sodium bicarbonate (20 ml), dried over magnesium sulfate, filtered and evaporated to give 200 mg (57%) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[4-(hydroxymethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one as a yellow solid of melting point 121-125° C. [Mass spectrum (ESI) MH+ =492].
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][C:11]#[N:12].O=[C:14]1[CH2:19][CH2:18][S:17][CH2:16][CH:15]1[C:20](OC)=[O:21].C([O-])(=O)C.[NH4+].O>C(#N)C>[O:21]=[C:20]1[N:3]2[C:2]([NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=32)=[C:10]([C:11]#[N:12])[C:14]2[CH2:19][CH2:18][S:17][CH2:16][C:15]1=2
Reactant: COC(=O)C1CSCCC1=O
Reactant: N#CCc1nc2ccccc2[nH]1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: N#Cc1c2c(c(=O)n3c1[nH]c1ccccc13)CSCC2
Temperature: 140 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A mixture of 1H-benzimidazol-2-ylacetonitrile (13 g), methyl 4-oxotetrahydro-2H-thiopyran-3-carboxylate (15.3 g), and ammonium acetate (33 g) was heated and stirred at 140° C. for 1 hour. The reaction mixture was cooled to room temperature, water and acetonitrile were added, and the resulting precipitate was collected by filtration and dried under reduced pressure to obtain 12-oxo-3,4,6,12-tetrahydro-1H-thiopyrano[4′,3′:4,5]pyrido[1,2-a]benzimidazole-5-carbonitrile (16 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:24][CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][C:14]=2[CH2:23][N:24]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)(=[O:37])=[O:36])[CH2:25][CH3:26])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To (2′-ethylaminomethyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.096 g, 0.25 mmol) and 4-chlorobenzenesulfonyl chloride (0.070 g, 0.33 mmol) in CH2Cl2 (1 mL) was added triethylamine (0.06 mL, 0.45 mmol), and the mixture was stirred for 15 minutes at room temperature. Once no starting material was seen by analytical LCMS, the solution was concentrated and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.