Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:21]([N:23]([CH2:39][CH3:40])[CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=O)[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:22]>C(O)C.N1CCCCC1>[CH2:39]([N:23]([CH2:21][CH3:22])[CH2:24][CH2:25][CH2:26][NH:27][C:28]([C:30]1[C:34]([CH3:35])=[C:33]([CH:36]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:32][C:31]=1[CH3:38])=[O:29])[CH3:40]
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Reactant: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(C(F)(F)F)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2,4-dimethyl-5-[2-oxo-4-(3-trifluoromethyl-phenyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide as a yellow solid (72.6 mg, 54%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][N:18]=1.[Cl:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](OC)=[O:29])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:33]=[CH:32][C:27]([C:28](=[O:29])[CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][N:18]=2)=[CH:26][CH:25]=1
Reactant: Cc1ccncn1
Reactant: COC(=O)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Cc1ccncn1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
Lithium bis(trimethylsilyl)amide 1.0 M in THF (4.25 L, 4.25 mol) was cooled to −70° C. with stirring under nitrogen. 4-methylpyrimidine (250 g, 2.66 mol) was added followed by Methyl 4-chlorobenzoate (453.2 g, 2.66 mol). The cooling bath was removed and the mixture was allowed to warm to room temperature and stir for 16 h. Water (3 L) and ethyl acetate (3 L) were added followed by acetic acid (200 mL). The layers were separated and the organic layer was washed with brine and dried over magnesium sulfate. The mixture was then concentrated to 800 mL and hexanes (250 mL) were added. The product was filtered, washed with hexanes, and air dried to provide a yellow solid. (388.1 g, 64%): mp 110.4-110.5° C. 1H NMR (acetone-d6/300 MHz) 14.9 (bs, 1H), 8.8 (s, 1H), 8.4 (m, 1H), 7.7 (d, 2H, J=8.7 Hz), 7.3 (d, 2H, J=8.7 Hz), 6.9 (m, 1H), 5.9 (s, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.[F:24][C:25]([F:37])([F:36])[C:26]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([OH:29])[CH:27]=[CH2:28]>>[OH:8][C:9]1[CH:14]=[C:13]([CH2:28][CH2:27][C:26]([OH:29])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:25]([F:24])([F:36])[F:37])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:21])(=[O:22])[NH:19][C:18](=[O:23])[CH2:17]1
Reactant: C=CC(O)(c1ccccc1)C(F)(F)F
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Product: O=C1CN(c2ccc(CCC(O)(c3ccccc3)C(F)(F)F)cc2O)S(=O)(=O)N1

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one and 1,1,1-trifluoro-2-phenyl-but-3-en-2-ol analogous to Example 44: (M−1)−=429; HPLC retention time=1.29 min (method A).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([NH:22][CH2:23][C:24]([OH:26])=O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH:29]1[CH2:33][CH2:32][CH:31]([OH:34])[CH2:30]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:34][CH:31]1[CH2:32][CH2:33][N:29]([C:24](=[O:26])[CH2:23][NH:22][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:28]=[CH:27][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:30]1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)O)ccc21
Reactant: OC1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)N3CCC(O)C3)ccc21
Yield: 87.5 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]amide (102 mg) was prepared by following General Procedure F starting from {[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetic acid (100 mg), 3-pyrrolidinol (23 mg), HBTU (109 mg), and DIEA (63 uL). LC/MS: m/z 485.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 8.54 (q, 1H), 8.11 (s, 1H), 7.93 (s, 1H), 7.82 (d, 1H), 7.67 (d, 1H), 7.51 (d, 1H), 7.39 (d, 1H), 5.04 (d, 1H), 4.32 (d, 1H), 4.15-3.97 (m, 2H), 3.63 (s, 3H), 3.62-3.51 (m, 2H), 3.50-3.33 (m, 2H), 2.05-1.70 (m, 2H).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9](Cl)[N:8]=[CH:7][N:6]=1>CO>[Cl:4][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:2][CH3:1])[N:8]=[CH:7][N:6]=1
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncnc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
Sodium methoxide (2.70 g, 50.0 mmol) was added portionwise over 10 min to a 0° C. suspension of 4,6-dichloro-5-nitropyrimidine (4.85 g, 25.0 mmol) in methanol (90 ml). On complete addition the mixture was stirred at 0° C for 2 h. The precipitate was filtered and the filtrate evaporated. The residue was suspended in isohexane and filtered. The filtrate was evaporated and the residue purified by flash column chromatography on silica, eluting with 5% ethyl acetate in isohexane. Collecting appropriate fractions gave 4-chloro-6-methoxy-5-nitropyrimidine (3.50 g, 74%) as a white solid: δH (400 MHz, CDCl3) 4.15 (3H, s), 8.65 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:19]=1.OO.C(=O)([O-])[OH:23].[Na+]>C(O)(=O)C.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[O:23])=[N:7][C:6]=2[CH:19]=1
Reactant: Clc1ccc2sc(SCCN3CCOCC3)nc2c1
Reactant: O=C([O-])O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=S(CCN1CCOCC1)c1nc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolved in 4 ml of acetic acid were 0.80 g (2.5 mmol) of the compound obtained in Example 31, and 0.37 ml (3.3 mmol) of a 30% aqueous solution of hydrogen peroxide and a catalytic quantity of sodium tungstate were successively added to the solution, which was stirred at room temperature for 1 hour. The solution was poured in 80 ml of water, neutralized with sodium hydrogencarbonate and extracted with 80 ml of chloroform. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residues were purified by silica gel chromatography to obtain 0.52 g of the title compound in the form of white crystalline powders (62% yield).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]([C:13]23[CH2:20][CH2:19][C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([CH2:17][CH2:18]2)[CH2:15][O:14]3)[CH:10]=[CH:11][CH:12]=1)(=O)=O.[C:34]1([SH:40])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:34]1([S:40][C:7]2[CH:8]=[C:9]([C:13]34[CH2:20][CH2:19][C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])([CH2:17][CH2:18]3)[CH2:15][O:14]4)[CH:10]=[CH:11][CH:12]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Sc1ccccc1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(OS(=O)(=O)C(F)(F)F)c3)(CC1)OC2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(Sc4ccccc4)c3)(CC1)OC2
Temperature: 25 °C
Yield: 95.1 %

Procedure:
A solution of tert-butyl 2-(2-(1-(3-(((trifluoromethyl)sulfonyl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate (80 mg, 0.162 mmol), thiophenol (0.025 mL, 0.243 mmol), XantPhos (18.72 mg, 0.032 mmol), and Pd2(dba)3 (14.8 mg, 0.016 mmol) in 1,4-dioxane (1 mL) was degassed with low vacuum under Ar five times using a sonicator. DIPEA (0.085 mL, 0.485 mmol) pre-degassed in the same way was added under an atmosphere of Ar. The mixture was heated to reflux for 2 h, then was cooled to rt, filtered, and the filtrate was concentrated in vacuo. The crude oil was chromatographed (SiO2) using a gradient from 0% to 50% EtOAc/hexane (10 min) to give the title compound (70 mg, 0.154 mmol, 95% yield) as a clear oil. LCMS: [M+Na]+=477.1. 1H NMR (CDCl3) δ: 7.48 (t, J=1.8 Hz, 1H), 7.35-7.27 (m, 6H), 7.26-7.18 (m, 2H), 3.96 (s, 2H), 3.88 (s, 2H), 3.58 (t, J=6.9 Hz, 2H), 2.06-1.97 (m, 4H), 1.73 (dd, J=9.1, 6.8 Hz, 4H), 1.51 (s, 11H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[N:3]=1.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.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>[Cl:1][C:2]1[N:3]=[C:4]([C:11]2[N:10]([CH3:9])[C:18]3[C:13]([CH:12]=2)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(I)n1
Reactant: Cn1c(B(O)O)cc2ccccc21
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: O
Solvent: C1COCCO1
Product: Cn1c(-c2cccc(Cl)n2)cc2ccccc21
Yield: 100.2 %

Procedure:
2-Chloro-6-iodopyridine (400 mg, 1.67 mmol), N-methylindole-2-boronic acid (292 mg, 1.67 mmol), tetrakis(triphenylphosphine)palladium (0) (154 mg, 0.13 mmol) and Na2CO3 (442 mg, 4.18 mmol) were dissolved in water (10 mL) and dioxane (10 mL) and heated using a microwave (110° C., absorption high) for 1 h. The solvents were removed in vacuo and the residue was partitioned between DCM (50 mL) and water (30 mL). The aq fraction was extracted with DCM (30 mL) and the combined organic fractions were dried (MgSO4) and concentrated in vacuo to give the crude title compound (406 mg) as a brown gum. LCMS (ES+): 243.2 [MH]+.
Reaction SMILES: [CH3:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[C:3]1=[O:18].[CH3:19][Li].O>C(OCC)C>[OH:18][C:3]1([CH3:19])[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[CH:6]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:2]1[CH3:1]
Reactant: [Li]C
Reactant: CC1C(=O)c2ccccc2C=Cc2ccccc21
Solvent: CCOCC
Solvent: O
Product: CC1c2ccccc2C=Cc2ccccc2C1(C)O

Procedure:
To a stirred solution of 5-methyl-6-oxo-dibenzo[a,e]cyclooctene (0.1 g) in anhydrous diethyl ether (10 ml) under nitrogen at 0° C. was added methyl lithium (0.43 ml of a 1.4 M solution in diethyl ether). After stirring for approximately 30 minutes water (10 ml) was added. The phases were separated and the ethereal layer was washed with water (2×10 ml), dried (Na2SO4) and the solvent removed in vacuo to give the title compound as a colourless solid (0.104 g), mP 86°-87° C. δ1.43 (CDCl3 360 MHz,) (3H, s, C--CH3), 1.44 (3H, d, J=7.0 Hz, --CH--CH3), 2.03 (1H, s, --OH), 4.07 (1H, q, J=7.0 Hz, --CH--CH3), 6.75 (1H, d, J=11.8 Hz, CHA =CHB), 6.96-7.21 (8H, m, ArH and CHA =CHB), 7.41 (1H, d J=7.5 Hz, ArH), 7.85 (1H, d J=7.9 Hz, ArH) m/e 250 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[C:25]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:37][CH2:38][N:33]([C:25]3[C:26]([CH3:32])=[C:27]([CH3:31])[CH:28]=[C:29]([CH3:30])[C:24]=3[CH3:23])[CH2:34][CH2:35]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: Cc1cc(C)c(C)c(N2CCNCC2)c1C
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2c(C)c(C)cc(C)c2C)CC1
Yield: 64 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(2,3,5,6-tetramethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH3:24][NH2:25].O>CS(C)=O>[Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5]([NH:25][CH3:24])=[N:6][CH:7]=1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Reactant: CN
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(-c2cccc(NCc3cccc(F)c3)n2)c(Cl)cn1

Procedure:
A mixture of 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (Intermediate B) (15 mg, 0.045 mmol) was added DMSO (0.4 ml) and methyl amine 40% in water (200 μl, 2.293 mmol) in a microwave tube was microwaved at 145° C. for 900 seconds and the reaction progress was followed by LCMS. Most of the amine was removed under vacuum, 0.5 ml of DMSO was added, filtered and purified by prep LC. After lyapholization 13.9 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 343.0 (MH+), retention time=0.67 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 2.97 (s, 3H) 4.62 (s, 2H) 6.81 (d, J=8.50 Hz, 1H) 6.91-7.02 (m, 3H) 7.09 (d, J=9.96 Hz, 1H) 7.17 (d, J=7.62 Hz, 1H) 7.27-7.39 (m, 1H) 7.69 (dd, J=8.50, 7.33 Hz, 1H) 8.03 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][C:5]([NH:21][C:22](=[O:30])[CH2:23][C:24]([C:26]([F:29])([F:28])[F:27])=O)=[C:4]([F:31])[CH:3]=1.C(O)(=O)C.[O-:36][C:37]#[N:38].[K+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([F:31])[C:5]([N:21]2[C:22](=[O:30])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[NH:38][C:37]2=[O:36])=[CH:6][C:7]=1[O:8][C:9]1[C:10]([O:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#C[O-]
Reactant: COC(=O)COc1ncccc1Oc1cc(NC(=O)CC(=O)C(F)(F)F)c(F)cc1Cl
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Temperature: 50 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
To a mixture of 0.71 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]trifluoroacetoacetamide and 2 ml of acetic acid, 0.33 g of potassium cyanate was added, and the mixture was stirred at 50° C. for 1 hour, then, at 110° C. for 1.5 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.30 g of 3-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].C([O-])([O-])=O.[Na+].[Na+].[CH2:21]([O:23][CH:24]([O:28][CH2:29][CH3:30])[C:25]([NH2:27])=O)[CH3:22]>C1COCC1.CC(=O)OCC>[CH2:21]([O:23][CH:24]([O:28][CH2:29][CH3:30])[C:25]([NH2:27])=[S:2])[CH3:22]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(OCC)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(OCC)C(N)=S
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
To a suspension of phosphorus pentasulfide (27 g) in dry THF (100 ml) at 0° C. under vigorous stirring, Na2CO3 (13 g) was added. The reaction mixture was stirred for 30 min at 0° C. and for 30 min at r.t., then diethoxyacetamide (6 g) was added and stirring was continued at r.t. for 70 h. The reaction was then diluted with EA, washed with 10% Na3PO4, brine, dried over Na2SO4 and the solvent removed in vacuo. The crude residue was purified by flash-chromatography (EE/PE 1/1) to give the title compound as a white solid (4.4 g).
Reaction SMILES: [CH3:1][C:2]1([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:15]2=[O:29])[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.C(N(CC)CC)C.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>C(Cl)Cl>[CH3:1][C:2]1([CH2:13][N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH:23]3[CH2:28][CH2:27][N:26]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:25][CH2:24]3)[C:15]2=[O:29])[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC1(Cn2c(=O)n(C3CCNCC3)c3ccccc32)Cn2cc([N+](=O)[O-])nc2O1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(Cn2c(=O)n(C3CCN(C(=O)OCc4ccccc4)CC3)c3ccccc32)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.4 %

Procedure:
To a mixture of 1-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-(3-piperidin-4-yl)-1,3-dihydrobenzimidazol-2-one prepared in Example 579 (90 mg, 0.23 mmol) and methylene chloride (5 ml), triethylamine (75 mg, 0.74 mmol) and benzyl chloroformate (126 mg, 0.74 mmol) were added in this order with cooling on ice-bath followed by stirring at room temperature for 3 hours. The reaction mixture was washed with water, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/acetone=1/1) to afford benzyl 4-[3-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)-2-oxo-2,3-dihydrobenzimidazol-1-yl]piperidine-1-carboxylate (25 mg, yield 21%) as a white powder.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10](O)[CH2:11][CH2:12][CH:13]=[CH2:14].O>N1C=CC=CC=1>[CH2:1]([O:8][CH2:14][CH2:13][CH2:12][CH:11]=[CH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCCCO
Solvent: O
Solvent: c1ccncc1
Product: C=CCCCOCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Benzoyl chloride (0.2 mol, 23 ml) was added dropwise to a solution of 4penten-1-ol (0.2 mol, 20 ml) in pyridine and stirred overnight at room temperature. The reaction mixture was poured into 100 mlof water and the organic layer separated. The product mixture was washed, sequentially, with dilute HCl, saturated aqueous Na2CO3, and water. The organic layer was dried over anhydrous Na2CO3 and the product distilled: bp 90°-98° (1.0 mmHg); yield 26.9g, (71%); NMR (neat) δ 1.5 (broad m, 4, alkyl), 3.8 (t, 2, --OCH2 --), 4.6 (m, 2, =CH2), 5.2 (m, 1, =CH--), 7.3 (m, 5, ArH).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:20][N:21]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:5][O:6][C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.Br[C:34]([CH3:39])([CH3:38])[C:35]([NH2:37])=[O:36]>O1CCOCC1>[OH:3][C@@H:4]([CH2:20][N:21]([C:26]1[CH:31]=[CH:30][C:29]([O:32][C:34]([CH3:39])([C:35](=[O:36])[NH2:37])[CH3:38])=[CH:28][CH:27]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:5][O:6][C:7]1[C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(O)cc1
Reactant: CC(C)(Br)C(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)CN(C[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(OC(C)(C)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Sodium hydride (10.8 mg of a 60% dispersion in oil, 0.27 mmol) was added to a solution of the phenol prepared in example 91 (100 mg, 0.25 mmol) in dry dioxane (1 ml) and the mixture stirred for 1 h at room temperature. 2-Bromo-2-methylpropanamide(Coutts, I.G.C., Southcott, M. R. J. Chem. Soc. Perkin Trans. 1, 1990, 767) was then added and the mixture heated at 100° C. for 8 h. The reaction mixture was filtered, concentrated in vacuo, and purified by flash chromatography (1:1 ethyl acetate: hexanes) to afford a light yellow solid (94.4 mg, 94%). MS (FD+) 489.6, Mp 84-86° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][C@H:8]([CH2:12][C@H:13]([CH3:18])[CH2:14][CH2:15][CH2:16][CH3:17])[C:9](O)=[O:10])([CH3:4])([CH3:3])[CH3:2].CSC.B>C1COCC1>[C:1]([O:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:9][OH:10])[CH2:12][C@H:13]([CH3:18])[CH2:14][CH2:15][CH2:16][CH3:17])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCC[C@@H](C)C[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCCC[C@@H](C)C[C@H](CO)CC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of the crude acid 139 (6.14 mmol) in 30 mL THF at 0° C. was added borane-dimethyl sulfide complex (2.0 M solution in THF, 4.6 mL, 9.2 mmol), and the mixture was allowed to warm slowly to ambient temperature overnight. Additional BH3DMS was added until the acid was completely consumed (ca. 5 mL). The reaction was quenched by addition of MeOH, then partitioned between Et2O and sat. NaHCO3 (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated to provide alcohol 140. LRMS: m/z 226.1; 1H NMR (CDCl3): δ 3.63 (dd, J=11.0, 4.2 Hz, 1H), 3.42 (dd, J=11.0, 6.8 Hz, 1H), 2.30 (dd, J=14.9, 7.6 Hz, 1H), 2.20 (dd, J=14.9, 5.6 Hz, 1H), 2.03 (m, 2H), 1.42 (s, 9H), 1.24 (m, 6H), 1.02 (m, 2H), 0.85 (m, 6H). The crude product was used without purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:22][N:23](/[CH:25]=[N:1]/[C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1)[CH3:24]
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2nc1N
Reactant: COC(OC)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(OC)c(OC)cc2nc1/N=C/N(C)C
Temperature: 25 °C
Yield: 17.8 %

Procedure:
A mixture of methyl 2-amino-6,7-dimethoxy-3-quinolinecarboxylate (3.60 g, 13.04 mmol) and 4.10 g of dimethylformamide dimethylacetal in 60 mL of toluene containing 40 mg of p-toluenesulfonic acid is heated at reflux for 2 hours. Upon cooling to room temperature a solid formed and is collected by filtration to provide 736 mg of methyl 2-{[(E)-(dimethylamino)methylidene]amino}-6,7-dimethoxy-3-quinolinecarboxylate as an off-white solid, mp 166–168° C. MS 318.1, 319.0 (M+H)+ Analysis for C16H19N3O4 Calcd: C, 60.56; H, 6.03; N, 13.24. Found: C, 60.63; H, 6.08; N, 13.32.