Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:26][C:27]1([CH3:46])[C:31](=[CH2:32])[S:30][C:29]([S:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[CH2:41][C:42]([O:44][CH3:45])=[O:43])=[N:28]1>>[CH3:6][N:4]([CH3:5])[CH:3]=[C:41]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][S:33][C:29]1[S:30][C:31](=[CH2:32])[C:27]([CH3:26])([CH3:46])[N:28]=1)[C:42]([O:44][CH3:45])=[O:43]
Reactant: COC(OC)N(C)C
Reactant: C=C1SC(SCc2ccccc2CC(=O)OC)=NC1(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: C=C1SC(SCc2ccccc2C(=CN(C)C)C(=O)OC)=NC1(C)C

Procedure:
This product (5.21 g), dimethylformamide dimethyl acetal (4.8 g) and pyridinium tosylate were heated together in a flask equipped with a Vigreaux column topped by a distillation head. The mixture was heated by an oil bath at 95° for 6 hours, causing the methanol produced by reaction to slowly distil off. The reaction mixture was then cooled, diluted with an aqueous solution of sodium hydrogen carbonate and extracted into ethyl acetate. The extract was washed with water, dried over magnesium sulphate and evaporated to give an oil which was purified by column chromatography (stationary phase: silica, eluent: 4:1 hexane:ethyl acetate) to give methyl 3-dimethylamino-2-[α-(4,4-dimethyl-5-methylene-2-thiazolin-2-ylthio)-o-tolyl]prop-2-enoate. (Compound 13A)
Reaction SMILES: [H-].[Na+].CN1CCC([OH:9])C1.ClC1C=NC=C(Cl)C=1C(O)=O.[C:21]1([P:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>[C:34]1([P:27](=[O:9])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CN1CCC(O)C1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)c1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a suspension of 2.1 g (60% in oil, 0.052 mole) of sodium hydride in 125 ml of dimethylformamide heated to 60° C. under a nitrogen gas blanket was added a solution of 2.65 g (0.026 mole) of N-methyl-3-pyrrolidinol and 5.0 g (0.026 mole) of 3,5-dichloropyridine-4-carboxylic acid in 40 ml of dimethylformamide dropwise at such a rate as to maintain 60° C. Subsequent to this addition, the mixture was heated to 75° C. for 3 hr. The solvent was then removed by rotary evaporation (60° C., 5 mm). The entire solid residue was suspended in 150 ml methylene chloride and hydrogen chloride added until a pH of 3 was reached. To the resulting mixture was added 15 g (0.057 mole) of triphenylphosphine and 15 g carbon tetrachloride and the entire mixture heated to reflux. After 1 hr, 7.5 g (0.029 mole) of triphenylphosphine and 7.5 g carbon tetrachloride were added, followed by the same increments 1 hr later. The reaction was driven to completion by adding 20 ml of triethylamine. The reaction mixture was washed with 6×50 ml of 3N hydrochloric acid, dried over sodium sulfate, filtered and concentrated by rotary evaporation. To the residue was added ethyl acetate, which caused much tarry material to fall out of solution, leaving the desired product and triphenylphosphine oxide in solution. The mixture was chromatographed by column chromatography using silica gel as the stationary phase and ethyl acetate as eluent. Similar fractions were combined and ethyl acetate removed by rotary evaporation, yielding 0.6 g (7%), of white crystals, m.p. 134°-38° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][C:20]([NH:22][NH2:23])=O)[CH:15]=3)[N:10]=[CH:9]2)=[CH:5][CH:4]=1.Cl[C:27]1[N:28]=[N:29][C:30]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:31][CH:32]=1>C(O)CCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:19][C:20]4[N:22]5[N:23]=[C:30]([C:33]6[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=6)[CH:31]=[CH:32][C:27]5=[N:28][N:29]=4)[CH:15]=3)[N:10]=[CH:9]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(Cn2cnc3ccc(CC(=O)NN)cc3c2=O)cc1
Reactant: Clc1ccc(-c2cccnc2)nn1
Solvent: CCCCO
Product: COc1ccc(Cn2cnc3ccc(Cc4nnc5ccc(-c6cccnc6)nn45)cc3c2=O)cc1
Yield: 53.4 %

Procedure:
[3-(4-Methoxy-benzyl)-4-oxo-3,4-dihydro-quinazolin-6-yl]-acetic acid hydrazide (0.024 g, 0.071 mmol) and 3-chloro-6-pyridin-3-yl-pyridazine (0.012 g, 0.063 mmol) were heated to 130° C. in butanol (0.5 mL) for several hours. The compound was purified via reverse phase HPLC on a C18 column eluting with acetonitrile in water (0.1% TFA) to give 0.016 g (53%) of 3-(4-methoxy-benzyl)-6-(6-pyridin-3-yl [1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-3H quinazolin-4-one. 1H NMR (400 MHz, CDCl3) δ 9.08 (m, 1H), 8.71 (dd, 1H, J=4.8, 1.6 Hz), 8.39 (m, 1H), 8.25 (m, 1H, 8.13 (d, 1H, J=9.6 Hz), 7.99 (s, 1H), 7.77 (dd, 1H, J=8.4, 2.0 Hz), 7.58 (d, 1H, J=8.4 Hz), 7.48 (d, 1H, J=9.6 Hz), 7.41 (m, 1H), 7.21 (d, 2H, J=8.4 Hz), 6.77 (d, 2H, J=8.8 Hz), 5.05 (s, 2H), 5.05 (s, 2H), 4.71 (s, 2H), 3.70 (s, 3H). Mass spectrum (LCMS, ESI pos.): Calcd for C27H21N7O2; found: 476.1, 477.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:13])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([Cl:12])[CH:8]=[CH:7][CH:6]=2.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O.C(O)(O)=O>CC#N.O>[Cl:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:2]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]([F:26])([F:25])[F:14])[C:3]([CH3:13])=[N:4]2
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Cc1nc2cccc(Cl)c2nc1Cl
Agent: O=C(O)O
Solvent: O
Solvent: CC#N
Product: Cc1nc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F
Temperature: 100 °C
Reaction time: 13.5 h

Procedure:
A mixture of 3,5-dichloro-2-methylquinoxaline (1.1209 g, 5.261 mmol), 2-(trifluoromethyl)phenylboronic acid (1.099 g, 5.787 mmol), tetrakis(triphenyl-phosphine)palladium (0.3040 g, 0.2630 mmol), and sodium carbonate anhydrous (2.788 g, 26.30 mmol) in 53 mL of CH3CN—H2O (3:1) was stirred at 100° C. After 13.5 h, the mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was washed with brine (50 mL×3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a red syrup. The red syrup was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and then 50% isocratic of EtOAc for 20 min as eluent to give 5-chloro-2-methyl-3-(2-(trifluoromethyl)phenyl)quinoxaline as a red solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (1 H, dd, J=8.4, 1.4 Hz), 8.02 (1 H, dd, J=7.6, 1.2 Hz), 7.98 (1 H, d, J=7.8 Hz), 7.73-7.92 (4 H, m), 2.47 (3 H, s); LC-MS (ESI) m/z 323.0 [M+H]+.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].O.[CH2:6]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:7][CH:8]([CH3:10])[CH3:9].C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[CH2:19]([O:18][C:13]1[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[CH:16]=[CH:17][C:12]=1[O:11][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CCOc1ccccc1OCCC(C)C
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)CCOc1ccc([N+](=O)[O-])cc1OCCC(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 300 ml. of conc. HNO3 and 300 ml. of H2O was added dropwise 90 g. (0.36 m.) of o-diisoamyloxybenzene while maintaining a temperature of 19°-21°C. Stirring was continued for an additional 60 minutes at 19°-21°C, then the solution was poured into 3 liters of ice. The crude product was collected by filtration, washed with cold H2O and airdried to give 90 g. It was recrystallized from 300 ml. of MeOH to give 25.5 g. A chromatographic column, 32 inches long with O.D. 3/4 inch, was packed with 20 inches of neutral alumina. The 25 g. of crude product was dissolved in a 250 ml. mixture of 50/50 CHCl3 and CCl4. After the mixture was placed on the column, it was washed several times with the same solvent mixture. The first fraction, very light yellow in color, was collected and concentrated to dryness in vacuo to yield 15 g. m.p. 44°-47°C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:19]Br.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([F:24])[CH:23]=1)[CH2:19][N:11]1[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]1
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(Cc2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A mixture of piperidin-4-ylcarbamic acid tert-butyl ester (5 g, 24.9 mmol), 3,5-difluorobenzyl bromide (2.9 ml, 22.7 mmol) and diisoproylethylamine (5.9 ml, 34.03 mmol) in dichloromethane (50 ml) was stirred at room temperature for 2 h. After this period, trifluoroacetic acid (32 ml) was added and the reaction mixture was stirred for a further 2 h. The solvent was evaporated in vacuo and a saturated solution of sodium carbonate was added. The mixture was extracted with dichloromethane, and the separated organic layers were dried (Na2SO4), filtered, and the solvent evaporated in vacuo to yield D5 (4.5 g, 90%) as a solid. C12H16F2N2 requires 226. Found 227 (MH+)
Reaction SMILES: [C:1](/[CH:3]=[CH:4]\[S:5][CH2:6][C:7]([NH:9][CH:10]1[C:32](=[O:33])[N:12]2[C:13]([C:19]([O:21]CC3C=CC([N+]([O-])=O)=CC=3)=[S:20])=[C:14]([CH:17]=[CH2:18])[CH2:15][S:16][C@H:11]12)=[O:8])#[N:2].CO.C(O)(=O)C.[H][H]>[Pd].O1CCCC1>[C:1](/[CH:3]=[CH:4]\[S:5][CH2:6][C:7]([NH:9][CH:10]1[C:32](=[O:33])[N:12]2[C:13]([C:19]([OH:21])=[S:20])=[C:14]([CH:17]=[CH2:18])[CH2:15][S:16][C@H:11]12)=[O:8])#[N:2]
Reactant: C=CC1=C(C(=S)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)CS/C=C\C#N)[C@H]2SC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C=CC1=C(C(O)=S)N2C(=O)C(NC(=O)CS/C=C\C#N)[C@H]2SC1

Procedure:
p-Nitrobenzyl 7-[2-((Z)-2-cyanovinylthio)acetamido]-3-vinylthio-3-cephem-4-carboxylate (300 mg) was hydrogenated in the presence of 10% palladium on carbon (270 mg) in a mixture of tetrahydrofuran (9 ml), methanol (1.5 ml) and acetic acid (0.033 ml) at ambient temperature for 3 hours under 1 atmospheric pressure of hydrogen. The catalyst was filtered off and washed with methanol. The filtrate and washings were combined and concentrated in vacuo. The residue was dissolved in a mixture of ethyl acetate and water at pH 7. The aqueous layer was separated, adjusted to pH 7 with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated in vacuo and triturated with diisopropyl ether to give 7-[2-((Z)-2-cyanovinylthio)acetamido]-3-vinylthio-3-cephem-4-carboxylic acid
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)C>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Nc1ncccc1OCc1ccccc1Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: S=C(Nc1ccc(Cl)cc1)Nc1ncccc1OCc1ccccc1Cl

Procedure:
A mixture of 2-amino-3-(2-chlorobenzyloxy)pyridine (1.81 g, 0.0077 mol), 4chlorophenyl isothiocyanate (1.59 g, 0.0094 mol) and toluene (10 ml) was refluxed for 2.5 hours, cooled and treated with diethyl ether to induce crystallisation of the product. Yield 2.54 g (90%), m.p. 177° 179 ° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:24][O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>O.CCO.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>[CH3:24][O:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([NH2:7])=[O:6])[CH:3]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: NC(=O)c1cccc(Br)c1
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: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cccc(-c2cccc(C(N)=O)c2)c1
Yield: 74.1 %

Procedure:
To a stirred mixture 3-bromobenzoic acid amide (0.76 g; 3.8 mmol) and toluene (25 mL), Pd(PPh3)4 (0.180 g; 0.16 mmol), a solution of Na2CO3 (2.543 g; 24 mmol) in H2O (10 mL), and one of 3-methoxyphenylboronic acid (1.132 g; 7.45 mmol) in EtOH (10 mL) were added. The mixture was refluxed for 1 h under vigorous stirring, cooled, and the acqueous phase extracted with AcOEt. The combined organic layers were dried over Na2SO4 and concentrated. Purification of the residue by column chromatography (cyclohexane/EtOAc 1:1 then 4:6) and recrystallization gave the desired product (0.64 g) as white solid. Yield 74%. Mp: 138–40° C. (EtOH). MS (EI): m/z 227 (M+, 100%). 1H NMR (CDCl3): δ 3.88 (s, 3H); 5.71 (br s, 1H); 6.11 (br s, 1H); 6.94 (m, 1H); 7.18 (m, 2H); 7.39 (t, 1H); 7.53 (t, 1H); 7.77 (m, 2H); 8.05 (t, 1H) ppm. IR (Nujol): 3327, 3148, 1676, 1640, 1613, 1584 cm−1.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]=[CH:7]2.[Br:20][C:21]1[N:22]=[C:23]([C:42]#[CH:43])[C:24]([N:27]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[N:25][CH:26]=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.FC(F)(F)C(O)=O>CO>[C:38]([O:37][C:35]([N:27]([C:28]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:34])[C:24]1[C:23]([C:42]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:8]=[CH:7]4)[CH:43]=2)=[N:22][C:21]([Br:20])=[CH:26][N:25]=1)=[O:36])([CH3:41])([CH3:40])[CH3:39]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(C=NO)ccc21
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)no1
Reaction time: 17 h
Yield: 16.5 %

Procedure:
A solution of tert-butyl 5-((hydroxyimino)methyl)-1H-indole-1-carboxylate (260.3 mg, 1 mmol) in methanol (1 mL) was added slowly to a stirred solution of tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (438.1 mg, 1.100 mmol) and (diacetoxyiodo)benzene (354.3 mg, 1.100 mmol) in methanol (2 mL) containing trifluoroacetic acid (15 μL, 0.1947 mmol) at ambient temperature. The reaction was stirred at this temperature for 17 hours then concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 40 g column) loaded with dichloromethane and eluted with 0 to 50% ethyl acetate/petroleum ether. Product fractions were combined and concentrate in vacuo to give the sub-title product as a white solid (108 mg, 16% Yield). 1H NMR (400.0 MHz, DMSO-d6) δ 1.22 (s, 18H), 1.57 (s, 9H), 6.73 (d, 1H), 7.69 (d, 1H), 7.80 (s, 1H), 7.89 (dd, 1H), 8.11 (d, 1H), 8.23 (d, 1H) and 8.94 (s, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:17][C:18]1[CH:19]=[C:20](OS(C(F)(F)F)(=O)=O)[CH:21]=[N:22][CH:23]=1.C(OCC)(=O)C>[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:17][C:18]1[CH:23]=[N:22][CH:21]=[C:20]([C:9]#[C:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:19]=1
Reactant: O=S(=O)(Oc1cncc(Cl)c1)C(F)(F)F
Reactant: C#Cc1ccc(F)cc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1ccc(C#Cc2cncc(Cl)c2)cc1
Temperature: 60 °C
Yield: 65 %

Procedure:
Add 4-fluorophenylacetylene (1.0 g, 8.35 mmol), triethylamine (4 mL, 30 mmol), copper (I) iodide (76 mg, 0.40 mmol), and bis(triphenylphosphine)palladium (II) dichloride (140 mg, 0.20 mmol) to a solution of trifluoromethanesulfonic acid 5-chloropyridin-3-yl ester, (prepared as described in PREPARATION 25) in ethyl acetate (1.95 g, 7.5 mmol), (7 mL) under nitrogen and heat at 60° C. for 12 h. Concentrate and purify the residue by silica gel chromatography, eluting with dichloromethane to give the title compound as a white solid (1.12 g, 65%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[Na].[CH3:21][C:22]1[C:23]([OH:28])=[N:24][CH:25]=[CH:26][N:27]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][O:28][C:23]2[C:22]([CH3:21])=[N:27][CH:26]=[CH:25][N:24]=2)[N:14]=1)=[O:8]
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CI)cs1
Reactant: Cc1nccnc1O
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccnc1OCc1csc(NC(=O)NCc2cccc(F)c2)n1
Reaction time: 8 h

Procedure:
1-(3-fluorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (1.0 mmol) and excess of 3-methylpyrazin-2-ol sodium salt were dissolved in N,N-dimethylformamide (3 ml). The mixture was stirred overnight. Water (20 ml) was added and the product was extracted three times with dichloromethane. The organic was dried over Na2SO4, filtered, and concentrated. The crude was purified by column chromatography using 0-70% gradient of saturated ammonia/MeOH and dichloromethane. 1H NMR (400 MHz, DMSO-d6): 10.73 (s, 1H), 7.48 (d, 1H), 7.36 (m, 1H), 7.15 (d, 1H), 7.06-7.12 (m, 3H), 6.96)m, 1H), 6.89 (s, 1H), 4.99 (s, 2H), 4.33 (d, 2H), 2.28 (s, 3H). MS (ES+): M/Z 374 (M+1).
Reaction SMILES: [NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@@H:2]([C:9]([OH:11])=O)[CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:34][CH2:35][C:36]([OH:38])=[O:37].C([O-])(O)=O.[Na+]>COCCOC.O>[NH:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@@H:2]([C:9]([NH:34][CH2:35][C:36]([OH:38])=[O:37])=[O:11])[CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CCCCC1
Reactant: NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)NCC(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.1 %

Procedure:
8.1 g (31.5 mmol) of Boc-(D)-Chg-OH were dissolved in 100 ml of 1,2-dimethoxyethane and then, at 0° C., NHS (3.7 g, 32.0 mmol) and DCC (7.0 g, 34.0 mmol) were added. After 6 h at RT, DCH was filtered off, and a solution of 2.3 g (31.0 mml) of glycine and 2.6 g (31.0 mmol) of NaHCO3 in 350 ml of water was added to the filtrate. Stirring at RT for 24 h was followed by concentration and extraction with 5% citric acid/ethyl acetate. Concentration of the organic phase resulted in 8.2 g (85.0%) of product.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].Br[CH:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH:14]=O.CCOCC>CCO>[OH:10][C:6]1[CH:7]=[CH:8][N:9]2[C:13]([CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:14][N:1]=[C:2]2[C:3]=1[C:4]#[N:5]
Reactant: O=CC(Br)CC(F)(F)F
Reactant: COc1ccnc(N)c1C#N
Solvent: CCOCC
Solvent: CCO
Product: N#Cc1c(O)ccn2c(CC(F)(F)F)cnc12
Temperature: 150 °C
Yield: 19 %

Procedure:
A mixture of compounds D3 (3.31 g, 22.19 mmol) and D8 (6.2 g, 21.86 mmol, 72% purity, calculated by 1H-NMR) in EtOH (10 ml) was subjected to microwave heating at 150° C. for 40 min. After cooling to room temperature, the solvent was evaporated in vacuo. The residue thus obtained was treated with Et2O and a solid precipitated out. The solid thus obtained was filtered off, washed with EtOAc and dried in vacuo to yield compound D9 (1 g, 18%).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:10]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[N:22]([CH3:37])[C:23]3[C:28]([N:29]=2)=[C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:26]=[C:25](Cl)[N:24]=3)[CH2:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11].[F:38][CH:39]([F:43])[C:40](O)=O>>[C:10]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[N:22]([CH3:37])[C:23]3[C:28]([N:29]=2)=[C:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:26]=[C:25]([N:1]2[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=[C:2]2[C:39]([F:43])([F:38])[CH3:40])[N:24]=3)[CH2:16][CH2:15]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C(O)C(F)F
Reactant: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: c1ccc2[nH]cnc2c1
Product: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(-n3c(C(C)(F)F)nc4ccccc43)nc21

Procedure:
Following General Procedure J for Multi-Step Benzimidazole formation, 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine was converted to 463 with difluoroacetic acid. LCMS: M+H+=554.3
Reaction SMILES: [O:1]=[C:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][CH:5]=1.[CH3:20][O:21]C(OC)OC.[CH3:27]C1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.CCN(CC)CC>CO>[CH3:27][O:1][C:2]([O:21][CH3:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC(=O)c2ccccc2)cc1
Reactant: COC(OC)OC
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(Cc1ccc(C(=O)O)cc1)(OC)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of methyl 4(2-oxo-2-phenylethyl)benzoate (1 g, 3.9 mmole) in MeOH (40 mL) was added trimethylorthoformate 10 mL and CSA (50 mg). The reaction mixture was refluxed for 6 h. The mixture was cooled, then Et3N (0.5 mL) was added, and the mixture concentrated. The residue was dissolved in THF and stirred overnight. The reaction was quenched with ACOH (1 mL) and 40 mL pH 7 phosphate buffer. The organic phase was dried (Na2SO4), filtered, and evaporated to yield the title compound 1.1 g.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]([F:46])([F:45])[C:9]1[CH:10]=[C:11]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:12][NH:13][CH2:14][C:15]1[C:16]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:27][CH2:26]2)=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.Cl[C:48]([O:50][CH2:51][CH3:52])=[O:49].O>C1COCC1>[CH2:51]([O:50][C:48](=[O:49])[N:13]([CH2:12][C:11]1[CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=[C:9]([C:8]([F:7])([F:45])[F:46])[CH:10]=1)[CH2:14][C:15]1[C:16]([N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[CH2:27][CH2:26]2)=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:52]
Reactant: FC(F)(F)c1cc(CNCc2cc3ccccc3nc2N2CCN(CC3CCCCC3)CC2)cc(C(F)(F)F)c1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc2ccccc2nc1N1CCN(CC2CCCCC2)CC1
Reaction time: 0.5 h
Yield: 80.9 %

Procedure:
Anhydrous potassium carbonate (0.17 g, 1.23 mmol) was added to a solution of (3,5-bis-trifluoromethyl-benzyl)-[2-(4-cyclohexylmethyl-piperazin-1-yl)-quinolin-3-ylmethyl]-amine (0.23 g, 0.4 mmol) in anhydrous THF (5 mL). After stirring 0.5 h, ethyl chloroformate (0.06 mL, 0.6 mmol) was added slowly under a nitrogen atmosphere. After stirring at RT for overnight, water (25 mL) was added, and the mixture was extracted with ethyl acetate (3×25 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a colorless liquid. Purification by silica gel chromatography and eluting with 10-30% ethyl acetate/hexane afforded the desired final product as a viscous liquid (0.206 g, yield: 81%).