Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([CH:8]([NH2:10])[CH3:9])=[N:6][CH:7]=1.Cl[C:12]1[N:17]=[C:16]([NH:18][C:19]2[CH:23]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[NH:21][N:20]=2)[C:15]([Cl:28])=[CH:14][N:13]=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:28][C:15]1[C:16]([NH:18][C:19]2[CH:23]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[NH:21][N:20]=2)=[N:17][C:12]([NH:10][CH:8]([C:5]2[N:6]=[CH:7][C:2]([F:1])=[CH:3][N:4]=2)[CH3:9])=[N:13][CH:14]=1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: CC(N)c1ncc(F)cn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Nc2nc(NC(C)c3ncc(F)cn3)ncc2Cl)n[nH]1
Temperature: 160 °C
Yield: 27.3 %

Procedure:
A microwave reaction vessel was charged with 1-(5-fluoropyrimidin-2-yl)ethanamine (Method 1, 0.25 g, 1.77 mmol), 2,5-dichloro-N-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 2, 0.50 g, 1.77 mmol), and DIPEA (0.30 g, 2.34 mmol). Anhydrous n-BuOH (2 ml) was added, and the tube was sealed and heated in a microwave reactor at 160° C. for 10 hours. The reaction mixture was purified by silica gel chromatography twice (by ISCO Combiflash with gradient EtOAc and DCM) to afford the title compound as a white solid (0.19 g, 27%). LC-MS, 393 (M+1). 1H NMR (CDCl3) δ 8.50 (s, 2H), 7.75 (s, 1H), 5.50 (s, 1H), 5.20 (m, 1H), 4.68 (m, 1H), 1.55 (d, 3H), 1.20 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:27])=[C:4]2[C:8](=[C:9]([NH:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]=1[CH3:11])[N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:6][CH2:5]2.[Cl:28]S([N:32]=[C:33]=[O:34])(=O)=O.Cl.O>C(Cl)Cl>[ClH:28].[CH3:27][C:3]1[C:2]([NH:1][C:33]([NH2:32])=[O:34])=[C:10]([CH3:11])[C:9]([NH:12][C:13](=[O:18])[C:14]([CH3:16])([CH3:17])[CH3:15])=[C:8]2[C:4]=1[CH2:5][CH2:6][N:7]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCCCCCCCN1CCc2c(C)c(N)c(C)c(NC(=O)C(C)(C)C)c21
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCN1CCc2c(C)c(NC(N)=O)c(C)c(NC(=O)C(C)(C)C)c21
Reaction time: 3 h

Procedure:
N-(5-Amino-4,6-dimethyl-1-octylindolin-7-yl)-2,2-dimethylpropanamide (500 mg) was dissolved in methylene chloride (5.0 mL), and chlorosulfonyl isocyanate (0.14 mL) was added dropwise at −60° C. The mixture was stirred at the same temperature for 3 hr and 6M hydrochloric acid (0.45 mL) was added. The mixture was stirred at room temperature for 30 min. Water (50 mL) was added to the reaction solution and the mixture was extracted with chloroform (100 mL). The chloroform layer was washed with saturated brine and dried over sodium sulfate. Chloroform was evaporated under reduced pressure and the obtained crystalline residue was recrystallized from a mixture of chloroform-diisopropyl ether to give the title compound as crystals (407 mg).
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])=[O:16])[CH:6]=[CH:5][CH:4]=1)#[N:2].[C:24](OC)(=[O:32])[C:25]1[C:26](=[CH:28][CH:29]=[CH:30][CH:31]=1)[SH:27].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:32]=[C:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[S:27][C:1]([C:3]2[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH2:19][Si:20]([CH3:22])([CH3:23])[CH3:21])=[O:16])[CH:6]=[CH:5][CH:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: C[Si](C)(C)CCOC(=O)CCCCCCc1cccc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOC(=O)CCCCCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 50.7 %

Procedure:
2-(Trimethylsilyl)ethyl 7-(6-cyano-2-pyridyl)heptanoate (0.52 g, 1.6 mmol) and methyl thiosalicylate (0.43 g, 2.5 mmol) were dissolved in toluene (2 ml), and triethylamine (0.44 ml, 2.3 mmol) was added thereto. The reaction mixture was refluxed for 16 hrs and subjected to a silica gel (35 g) column chromatography. The fractions eluted with hexane-ethyl acetate (4:1, v/v) were collected and concentrated to give the titled compound (0.38 g, 27%) as a yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.C(N(CC)CC)C.[C:19]1([C:25](Br)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[CH:8][N:9]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:10]=1
Reactant: COC(=O)Cc1c[nH]cn1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 72 h

Procedure:
To a suspension of the product from Step A (7.49 g, 42.4 mmol) in methylene chloride (200 ml) was added triethylamine (17.7 ml, 127 mmol) and triphenylmethyl bromide(16.4 g, 50.8 mmol) and stirred for 72 h. After this time, the reaction mixture was washed with sat. aq. NaHCO3 (100 ml) and water (100 ml). The organic layer was evaporated in vacuo and the residue was purified by flash chromatography(30-100% ethyl acetate in hexanes gradient elution) to provide the title compound as a white solid. 1H NMR(CDCl3, 400 MHz) δ 7.35(1H, s), 7.31(9H, m), 7.22(6H, m), 6.76(1H, s), 3.68(3H, s) and 3.60(2H, s) ppm.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]([CH2:21][C:22](O)=[O:23])[CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33].O>C(Cl)Cl.C(Cl)(=O)C(Cl)=O>[CH3:31][S:32]([NH:35][C:22](=[O:23])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:20]=2[CH:19]=1)(=[O:34])=[O:33]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)Cc1ccc2c3ccccc3n(Cc3ccccc3)c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC(=O)Cc1ccc2c3ccccc3n(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
0.055 ml (0.63 nmol) of oxalyl chloride was added, with ice-cooling, to a mixture of 100 mg (0.32 mmol) of (9-benzylcarbazol-2-yl)acetic acid (prepared as described in Example 42) in 3 ml of methylene chloride, and the whole was stirred for 30 minutes at room temperature. After this time, the solvent was removed by evaporation under reduced pressure. 5 ml of methylene chloride, 0.08 ml (0.99 mmol) of pyridine and 60 mg (0.63 mmol) of methanesulfonamide were added to the residue thus obtained, with ice-cooling. The reaction mixture was then stirred for 12 hours at room temperature. After the reaction had been allowed to go to completion, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic fraction was then washed with water and dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography, using 30 g of silica gel with a 50% v/v solution of methanol in ethyl acetate as eluent, to yield 46 mg of the title compound as an amorphous solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([C:10](OC)=[O:11])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1.C(Cl)Cl.O=[Mn]=O>[O:1]1[C:5]2[CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2ccoc2c1
Agent: O=[Mn]=O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc2ccoc2c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a solution of methyl benzofuran-6-carboxylate (1 eq.) in dry THF was added a solution of LiAlH4 (1M in THF, 1.5 eq.) at 0° C. under argon. The reaction mixture was stirred at 0° C. for 2.5 h. Water, aqueous NaOH (2N) and water were then added and the mixture was stirred at 20° C. for 30 min. The crude was passed through a pad of celite and solvent removed under reduced pressure. To a solution of the residue (1 eq.) in DCM was added MnO2 (10 eq.). The dark suspension was stirred at 20° C. for 15 h, filtered through a pad of celite and the solvent removed under reduced pressure to afford benzofuran-6-carboxaldehyde which was used as such without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[CH:4]=[C:3]1[CH2:12][NH:13][CH3:14].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:31].[NH2:32][C:33]1[N:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([OH:43])=O)=[CH:35][C:34]=1[CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:31].[NH2:32][C:33]1[N:38]=[CH:37][C:36](/[CH:39]=[CH:40]/[C:41]([N:13]([CH2:12][C:3]2[N:2]([CH3:1])[C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][C:9]=3[CH3:11])[CH3:14])=[O:43])=[CH:35][C:34]=1[CH2:44][N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1
Reactant: CNCc1cc2cccc(C)c2n1C
Reactant: Nc1ncc(/C=C/C(=O)O)cc1CN1CCOCC1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1cccc2cc(CN(C)C(=O)/C=C/c3cnc(N)c(CN4CCOCC4)c3)n(C)c12
Yield: 80 %

Procedure:
According to the procedure of Example 1, except substituting (1,7-dimethyl-1H-indol-2-ylmethyl)methylamine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(6-amino-5-morpholin-4-ylmethyl-pyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.31 g, 80%) was prepared as pale yellow powder: 1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.38-8.35 (m, 1H), 7.54-7.49 (m, 1H), 7.31-7.14 (m, 2H), 6.85-6.81 (m, 2H), 6.37-6.08 (m, 1H), 5.03-4.81 (m, 2H), 4.31 (br s, 2H), 3.96-3.72 (m, 7H), 3.42-2.99 (m, 10H), 2.72 (s, 3H);
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:13]([CH:15]=2)[NH2:14])[CH2:3]1.[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>ClCCl.N1C=CC=CC=1>[Br:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:14][C:13]2[CH:15]=[C:9]([N:4]3[CH2:3][C@H:2]([CH3:1])[NH:7][C@H:6]([CH3:8])[CH2:5]3)[CH:10]=[CH:11][C:12]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: C[C@@H]1CN(c2ccc(OCc3ccccc3)c(N)c2)C[C@H](C)N1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(OCc3ccccc3)c(NS(=O)(=O)c3ccc(Br)cc3)c2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(cis-3,5-dimethyl-1-piperazinyl)-2-[(phenylmethyl)oxy]aniline (D39) (500 mg, 1.61 mmol) in dichloromethane (8 ml) and pyridine (8 ml) was added 4-bromobenzenesulfonyl chloride (820 mg, 3.21 mmol) and the resulting mixture stirred at room temperature, under an atmosphere of argon for 2 hours. The mixture was then reduced in vacuo, azeotroped with methanol and the residue partitioned between dichloromethane (75 ml) and saturated aqueous sodium hydrogen carbonate (75 ml). The layers were separated, the aqueous re-extracted with dichloromethane (50 ml) and the combined organic layers washed with brine (125 ml), dried over anhydrous magnesium sulphate, filtered and reduced in vacuo. The residue was purified by chromatography on silica gel (gradient: dichloromethane:methanol 25:1 to 10:1) to afford the title compound (D40). MS (ES+) m/e 530/532 [M+H]+.
Reaction SMILES: S1C=C(O)C=NC1.N(C(OCC)=O)=NC([O-])=O.[OH:18][CH:19]([CH2:36]O)[CH:20]([NH:27][C:28](=[S:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:29]1([C:28]2[S:35][CH2:36][CH:19]([OH:18])[CH:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:27]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: OCC(O)C(NC(=S)c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)[O-]
Agent: OC1=CSCN=C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: OC1CSC(c2ccccc2)=NC1c1ccccc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
(4RS, 5RS)-2,4-diphenyl-5,6-dihydro-4H, 1,3-thiazin-5-ol may be prepared in the following manner: a solution of ethyl azodicarboxylate (1.1 g) dissolved in anhydrous tetrahydrofuran (5 cc) is added dropwise at a temperature in the region of 0° C. to a solution, maintained under an argon atmosphere, of N-[(1RS, 2RS)-2,3-dihydroxy-1-phenylpropyl]thiobenzamide (1.7 g) and triphenylphosphine (1.57 g) in anhydrous tetrahydrofuran (17 cc). The solution obtained is stirred at a temperature in the region of 20° C. for 16 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by chromatography on silica (0.063-0.2 mm; 100 g) contained in a column 2.5 cm in diameter [(eluent: cyclohexane/ethyl acetate (3:7 by volume)], collecting 20-cc fractions. Fractions 5 to 11 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in diisopropyl ether, (4RS, 5RS)-2,4-diphenyl-5,6-dihydro-4H-1,3-thiazin-5-ol (0.86 g), m.p. 142° C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[NH:4][C:5]([CH3:9])([CH3:8])[C:6]#[CH:7].[F:11][C:12]1[C:13](I)=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])/[C:15]/2=[CH:22]\[C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28]>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.CN(C=O)C.CCN(CC)CC>[CH3:1][O:2][C:3](=[O:10])[NH:4][C:5]([CH3:9])([CH3:8])[C:6]#[C:7][C:13]1[C:12]([F:11])=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:22]/[C:23]1[NH:27][CH:26]=[N:25][C:24]=1[CH3:28])/[C:16](=[O:21])[NH:17]2
Reactant: C#CC(C)(C)NC(=O)OC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C)(C)C#Cc1c(F)ccc2c1/C(=C/c1[nH]cnc1C)C(=O)N2

Procedure:
Using Method C above, (1,1-dimethyl-2-propynyl)-carbamic acid methyl ester (47.7 mg, 0.34 mmol) (see below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give
Reaction SMILES: C(OC([NH:8][C:9]1[C:17]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C:9]1[C:17]([O:18][C:19]([F:20])([F:21])[F:22])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12]
Reactant: CC(C)(C)OC(=O)Nc1c(OC(F)(F)F)cccc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1c(OC(F)(F)F)cccc1C(=O)O
Yield: 70.5 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-3-trifluoromethoxy-benzoic acid (0.8 g, 2.5 mmol) in 30% v/v TFA/methylene chloride (50 mL) was stirred at room temperature for 1 h. Concentration of the mixture gave 2-amino-3-trifluoromethoxy-benzoic acid (0.39 g, 71%): 1H NMR (300 MHz, CDCl3) δ 7.88 (d, 1H), 7.34 (d, 1H), 6.63 (t, 1H), 6.04 (br, 2H).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.C([NH:20][C:21]1[C:26]([NH2:27])=[C:25]([NH:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:24]=[C:23]([C:36]2[O:37][CH:38]=[CH:39][N:40]=2)[N:22]=1)C1C=CC=CC=1>C1COCC1>[NH2:20][C:21]1[C:26]2[NH:27][C:6](=[O:7])[N:28]([CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:25]=2[CH:24]=[C:23]([C:36]2[O:37][CH:38]=[CH:39][N:40]=2)[N:22]=1
Reactant: Nc1c(NCc2ccccc2)cc(-c2ncco2)nc1NCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Nc1nc(-c2ncco2)cc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
CDI (821 mg, 5.06 mmol) was added to a solution of N*2*,N*4*-Dibenzyl-6-oxazol-2-yl-pyridine-2,3,4-triamine (940 mg, 2.53 mmol) in THF (15 ml). The solution was heated at 60° C. for 18 hrs under nitrogen. The reaction mixture was allowed to cool then concentrated in vacuo. The crude mixture was then dissolved in concentrated H2SO4 (15 ml) and left for 30 minutes at room temperature. The dark brown solution was added drop-wise onto crushed ice. The pH was adjusted to ˜9 by addition of a saturated aqueous solution of K2CO3 then the mixture was filtered. The solid was washed with EtOAc (200 ml) then the organic and aqueous filtrates were transferred to a separating funnel. The layers were separated and the aqueous was re-extracted with EtOAc (200 ml). The organics were combined, dried (MgSO4) and evaporated to an orange gummy solid. The crude material was triturated with EtOAc and toluene. The solid obtained was filtered and washed with EtOAc to give an off-white solid. This material was purified by HPLC on a Phenomenex Gemini 5 μm column (150×21.2 mmid), eluted with 0.05% formic acid (aq) and 0.05% formic acid in MeCN at a flow rate of 15 ml/min. The gradient was isocratic at 5% organic for 0.6 minutes, then increased linearly from 5% to 80% organic over 12 minutes.
Reaction SMILES: [CH2:1]([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)[CH2:19][CH2:18]1)=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:20]2[CH2:21][CH2:22][CH:17]([C:15]([C:7]3[S:6][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=3)=[CH2:1])[CH2:18][CH2:19]2)=[CH:26][CH:27]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(CCN2CCC(C(=O)c3nc4ccccc4s3)CC2)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C(c1nc2ccccc2s1)C1CCN(CCc2ccc(OC)cc2)CC1
Reaction time: 2 h

Procedure:
Dissolve methyltriphenylphosphonium bromide (2.50 g, 6.99 mmol) in anhydrous tetrahydrofuran (50 mL). Add n-butyllithium (2.8 mL of a 2.5M solution in hexane, 6.99 mmol) and cool to -10° C. Add, by dropwise addition, a solution of [2-benzothiazolyl][1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methanone (2.66 g, 6.99 mmol) in anhydrous tetrahydrofuran (50 mL). Stir for 2 hours then quench with water. Separate the organic phase and extract the aqueous phase with ethyl ether. Combine the organic phases, dry (MgSO4) and evaporate the solvent in vacuo. Purify by chromatography (50% ethyl ether/hexane) to give the title compound as a white powder; mp 84°-85° C.
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:26])[CH2:20][C:21]([O:23]CC)=[O:22])=[C:8]2[CH3:27])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:26])[CH2:20][C:21]([OH:23])=[O:22])=[C:8]2[CH3:27])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)Cc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC(C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Reaction time: 2 h

Procedure:
To a solution of ester from Step 5 (3.5 g, 7.6 mmol) in MeOH/THF (50 mL/35 mL) was added 1M NaOH (22.9 mL, 22.9 mmol). After heating at reflux for 2 h, the mixture was concentrated under vacuum and the residue was partitioned between EtOAc/H2O containing HOAc (3 mL). The organic layer was washed with H2O, brine, and was then dried (MgSO4), filtered, and evaporated. The resulting solid was stirred vigorously with 1:10 EtOAc/hexane for 2 h to give, after filtration, 2.81 g of white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2].Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:28]>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:20])=[C:10]([N:14]3[CH2:15][CH2:16][N:17]([CH2:26][C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)=[O:28])[CH2:18][CH2:19]3)[C:11]=2[F:13])[C:6](=[O:21])[C:5]([C:22]([OH:24])=[O:23])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Reactant: O=C(CBr)c1ccc(F)cc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(F)cc4)CC3)c(F)c21

Procedure:
1-Ethyl-6,8-difluoro-7-{4-[2-(4-fluorophenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid was prepared from 1-ethyl-6,8-difluoro-4-oxo-7-(1-piperazinyl)-1,4-dihydro-quinoline-3-carboxylic acid (0.50 g, 1.48 mmole) and 2-bromo-4′-fluoroacetophenone (0.40 g, 1.86 mmole) by a method similar to that described for Example 4 (64% yield). Mp: 170° C. (dec). 1H NMR (DMSO-d6) δ 1.44 (t, 3H, J=7.0), 2.70 and 3.3 (two m, 8H), 3.94 (s, 2H), 4.58 (q, 2H, J=7.0), 7.37 (n, 2H), 7.90 (d, 1H, J=11.8), 8.11 (m, 2H), 8.92 (s, 1H), 14.92 (br s, 1H). Anal. Calcd. for C24H22F3N3O4•0.5 H2O: C, 59.75; H, 4.80; N, 8.71. Found: C, 59.39; H, 4.66; N, 8.62.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:15].[C:16]([CH2:20][C:21](Cl)=[O:22])([CH3:19])([CH3:18])[CH3:17]>N1C=CC=CC=1>[CH3:17][C:16]([CH3:19])([CH3:18])[CH2:20][C:21]([NH:15][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:22]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Solvent: c1ccncc1
Product: CC(C)(C)CC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 61.5 %

Procedure:
Following the procedure of Example 1, 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (1.0 g, 5.0 mmol) and t-butylacetyl chloride (0.74 mL, 5.5 mmol) in pyridine (10 mL) provided 3,3-dimethyl-N-[7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-yl]butyramide (0.92 g). Mp 182-183° C.; Anal. Calcd. for C19H25NO2: C, 76.22; H, 8.42; N, 4.68; Found: C, 76.13; H, 8.28; N, 4.71.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3](=O)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl.[S:16]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=1)(=[O:19])(=[O:18])[NH2:17]>>[S:16]([C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH:5]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][C:3]([C:2]([F:14])([F:13])[F:1])=[N:27]2)=[CH:24][CH:25]=1)(=[O:19])(=[O:18])[NH2:17]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(/C=C/c1ccccc1)C(F)(F)F
Agent: Cl
Product: NS(=O)(=O)c1ccc(N2N=C(C(F)(F)F)CC2c2ccccc2)cc1
Yield: 73 %

Procedure:
A solution of trans-1,1,1-trifluoro-4-phenyl-3-buten-2-one (5 mmol) and 4-sulfamylphenyl hydrazine hydrochloride (6 mmol) was subjected to Procedure 3. The title compound was obtained in 73% yield, m.p. 178-180° C.; C, H analysis (C18H15SO2N4F3.H2O):