Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)=[CH:9][C:8]([N:18]2[C:22]([CH:23]([CH3:25])[CH3:24])=[N:21][N:20]=[N:19]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:26][C:27]1[N:28]=[CH:29][C:30]([CH2:33][NH2:34])=[N:31][CH:32]=1>>[F:1][C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)=[CH:9][C:8]([N:18]2[C:22]([CH:23]([CH3:25])[CH3:24])=[N:21][N:20]=[N:19]2)=[CH:7][C:3]=1[C:4]([NH:34][CH2:33][C:30]1[CH:29]=[N:28][C:27]([CH3:26])=[CH:32][N:31]=1)=[O:6]
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1ccc(-c2cc(-n3nnnc3C(C)C)cc(C(=O)O)c2F)nc1
Product: Cc1ccc(-c2cc(-n3nnnc3C(C)C)cc(C(=O)NCc3cnc(C)cn3)c2F)nc1

Procedure:
2-Fluoro-5-(5-isopropyl-tetrazol-1-yl)-3-(5-methyl-pyridin-2-yl)-benzoic acid was reacted with C-(5-methyl-pyrazin-2-yl)-methylamine using the procedure of step 4 of Example 7 to provide 2-fluoro-5-(5-isopropyl-tetrazol-1-yl)-N-(5-methyl-pyrazin-2-ylmethyl)-3-(5-methyl-pyridin-2-yl)-benzamide, MS (M+H)=447.
Reaction SMILES: N1(O[C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)C2C=CC=CC=2N=N1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH3:28])[CH2:23][CH2:22]1.C(N(CC)CC)C>O1CCCC1>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH3:28])[CH2:23][CH2:22]2)=[O:19])=[CH:17][CH:16]=1
Reactant: CCN1CCC(N)CC1
Reactant: Nc1ccc(C(=O)On2nnc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN1CCC(NC(=O)c2ccc(N)cc2)CC1
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 84 %

Procedure:
To a mixture of 1.0424 g (4.1 mmole) of 4-amino-benzoic acid benzotriazol-1-yl ester and 8 mL of dry tetrahydrofuran at 0 degrees was added 0.5257 g (4.1 mmole) of 4-amino-1-ethylpiperidine followed by 1.0372 g (10.3 mmole) of triethylamine. The cooling bath was removed and the mixture stirred at room temperature for 65 minutes. Volatiles were removed under reduced pressure and the residue taken up in ethyl acetate, and the organic layer washed twice with 50 mL of 0.5 M sodium carbonate, 50 mL water, and then 50 mL brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.8522 g 4-amino-N-(1-ethyl-piperidin-4-yl)-benzamide, as a white solid which was used without further purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:27])[N:14]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[NH:15][CH:16]([CH:19]([CH3:21])[CH3:20])[C:17]=2[OH:18])=[N:3]1.[N+:29]([O-])([OH:31])=[O:30]>OS(O)(=O)=O>[OH:18][C:17]1[C:16]([CH:19]([CH3:21])[CH3:20])=[N:15][N:14]([CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C:13](=[O:27])[C:12]=1[C:4]1[NH:5][C:6]2[CH:11]=[CH:10][C:9]([N+:29]([O-:31])=[O:30])=[CH:8][C:7]=2[S:2](=[O:1])(=[O:28])[N:3]=1
Reactant: CC(C)CCN1NC(C(C)C)C(O)=C(C2=NS(=O)(=O)c3ccccc3N2)C1=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(C)CCn1nc(C(C)C)c(O)c(C2=NS(=O)(=O)c3cc([N+](=O)[O-])ccc3N2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of 5h (0.097 g, 0.025 mmol) in conc H2SO4 (0.65 mL) cooled on ice bath was added conc HNO3 (0.10 mL). After stirring 30 min at 0° C., the reaction mixture was poured onto crushed ice (1.5 g). The resulting precipitate was collected by filtration to give 5i (0.091 g, 85%) as a yellow solid. 1H NMR (400 MHz, D6-DMSO) δ 13.90 (s, 1 H), 8.57 (d, J=2.8 Hz, 1 H), 8.49 (dd, J=9.2, 2.8 Hz, 1 H), 7.82 (d, J=8.8 Hz, 1 H), 4.11 (t, J=6.8 Hz, 2 H), 3.23 (m, 2 H), 1.61 (m, 2 H), 1.21 (d, J=8 Hz, 6 H), 0.93 (d, J=8 Hz, 6 H). MS (ESI+) m/e 450 [M+H]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]([C:19]1[CH:24]=[C:23]([CH3:25])[C:22](=C)[N:21]([CH3:27])[CH:20]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:30])C>>[CH2:1]([N:8]1[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[N:16]=[C:17]1[C:19]1[CH:24]=[C:23]([CH3:25])[C:22](=[O:30])[N:21]([CH3:27])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: C=C1C(C)=CC(C(=O)Nc2ccc(F)cc2NCc2ccccc2)=CN1C
Product: Cc1cc(-c2nc3ccc(F)cc3n2Cc2ccccc2)cn(C)c1=O
Temperature: 150 °C
Reaction time: 1 h

Procedure:
1,5-Dimethyl-6-methylene-1,6-dihydro-pyridine-3-carboxylic acid (2-benzylamino-4-fluoro-phenyl)-amide I-12′ (186.000 mg; 0.509 mmol) is dissolved in acetic acid and stirred at 150° C. for 1 h in the microwave. The reaction mixture is then concentrated under reduced pressure and purified on silica chromatography Combiflash (Column: Redisep Rf, 12 g; gradient: DCM/MeOH=100%/0% to 90%/10%; flow rate=30 ml/min; 28 column volumes; detection wavelength: 254 nm). The product containing fractions are combined and concentrated under reduce pressure. The product is then dissolved in acetonitrile:water 1:1 and freeze dried.
Reaction SMILES: Cl.[OH:2][CH:3]1[CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:15][CH2:16][N:17]=[C:18]=[S:19]>ClCCl>[OH:2][CH:3]1[CH2:6][N:5]([C:18]2[S:19][CH2:15][CH2:16][N:17]=2)[CH2:4]1
Reactant: OC1CNC1
Reactant: S=C=NCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OC1CN(C2=NCCS2)C1
Reaction time: 2 h
Yield: 95 %

Procedure:
A 1.5 ml solution of acetonitrile anhydride containing 219 mg of 3-hydroxyazetidine hydrochloride (5) was cooled to 0° C. in the stream of nitrogen, and, to this solution, there were added 0.31 ml of triethylamine and subsequently a 0.3 ml solution of acetonitrile anhydride containing 250 mg of chloroethylisothiocyanate dissolved therein, and the resultant solution was stirred for 30 minutes at the same temperature, and, after left still until it had a room temperature, the solution was further stirred for two hours. Next, dichloromethane was added to the reaction liquid, and the resultant solution was washed with a saturated aqueous solution of potassium carbonate, and, thereafter, the dichloromethane layer was dried with magnesium sulfate, and then was condensed under reduced pressure, and, thus, there was obtained 300 mg (yield: 95%) of 3-hydroxy-1-(1,3-thiazolin-2-yl)azetidine (6) in the form of colorless needle crystal.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[F:31])=[O:19])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[S:32]1[CH:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33]1.O>N1C=CC=CC=1>[F:31][C:22]1[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:30])[F:29])=[CH:26][C:21]=1[NH:20][C:18](=[O:19])[NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:7]2[N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:37]([C:34]4[CH:35]=[CH:36][S:32][CH:33]=4)=[O:38])[C:10]3=[CH:9][CH:8]=2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccsc1
Reactant: Nc1n[nH]c2nc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)ccc12
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc3c(NC(=O)c4ccsc4)n[nH]c3n2)cc1)Nc1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
A solution of 1-[4-(3-amino-1H-pyrazolo[3,4-b]pyridin-6-yl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea (80.0 mg, 0.186 mmol) in pyridine (2 ml) is cooled to 5° C. under argon and thiophene-3-carboxylic acid chloride (27 mg, 0.186 mmol, 1.0 eq.) is added. The mixture is stirred at ambient temperature for 5.5 h. Another equivalent of thiophene-3-carboxylic acid chloride (27 mg, 0.186 mmol) is added and the mixture is stirred at ambient temperature overnight. The reaction is taken up with water, and then extracted with ethyl acetate. The organic phase is washed twice with a salt solution, dried with magnesium sulphate, and concentrated. An orange yellow solid is then obtained. The crude is purified on a silica column, with an eluent gradient of 0% to 5% of methanol in dichloromethane. A beige solid is obtained:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[C:30]([CH3:37])[CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>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:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]4[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=4[F:26])(=[O:13])=[O:14])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:30]([CH3:37])[CH:29]=1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Reactant: Cc1cc(Cl)ccc1B(O)O
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: [K+]
Product: Cc1cc(Cl)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Temperature: 50 °C
Yield: 39.3 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see EXAMPLE 73, Step 1, 518.97 mg, 1.267 mmol), (4-chloro-2-methylphenyl)boronic acid (324 mg, 1.900 mmol), potassium carbonate (525 mg, 3.80 mmol), and Pd(PPh3)4 (146 mg, 0.127 mmol). The flask was flushed with Ar (g), then 1,4-dioxane (4750 μl) and water (1583 μl) were added. The flask was sealed and heated in a 50° C. heating bath overnight. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g Redi-Sep Gold column, 0-30% EtOAc/Heptane) to give perfluorophenyl 1-(4-chloro-2-methylphenyl)isoquinoline-6-sulfonate (249 mg, 0.498 mmol, 39.3% yield) as a clear oil. m/z (ESI) 500.0 (M+H)+.
Reaction SMILES: [CH:1](/[N:14]=[CH:15]/[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([N:37](C)C(=O)[C@@H](NC(NC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)=S)C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>>[CH:1]([NH:14][C@@H:15]([C:24]#[N:37])[C:16]1[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(/C=N/C(c2ccccc2)c2ccccc2)cc1
Reactant: CN(C(=O)[C@@H](NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)(C)C)C(c1ccccc1)c1ccccc1
Product: N#Cc1ccc([C@H](C#N)NC(c2ccccc2)c2ccccc2)cc1
Reaction time: 20 h
Yield: 96 %

Procedure:
The reaction was run at 0° C. for 20 h with stirring using (E)-4-((benzhydrylimino)methyl)benzonitrile (296 mg, 1.0 mmol, 1.0 equiv) and 10 mol % of (S)—N-benzhydryl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-N,3,3-trimethyl butanamide (4e). The product was subjected to purification by flash column chromatography (9:1, hexanes:Et2O) to afford (R)-4-((benzhydrylamino) (cyano)methyl)benzonitrile (310 mg, 0.96 mmol, 96% yield) as a white solid. The enantiomeric excess was determined to be 93% by chiral HPLC analysis (OD-H, 5.0% IPA in hexanes, 1.0 mL/min, 230 nm, tR(major)=41.1 min, tR(minor)=56.4 min); [α]D24=+27.3° (c=1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ 7.72 (4H, s), 7.57 (2H, d, J=7.5 Hz), 7.45 (2H, d, J=7.5 Hz), 7.39 (2H, t, J=7.8 Hz), 7.29-7.34 (3H, m), 7.23-7.27 (1H, m), 5.25 (1H, s), 4.67 (1H, br s), 2.25 (1H, br s). 13C {1H} NMR (125 MHz, CDCl3): δ 142.2, 140.5, 139.7, 132.7, 129.1, 128.8, 128.2, 128.0, 127.9, 127.4, 127.0, 118.1, 117.7, 113.1, 65.7, 52.0. IR (cm−1): 3310 (m), 3296 (m), 3025 (w), 2925 (w), 2845 (w), 2232 (m), 1609 (w), 1492 (m), 1453 (m), 1349 (m), 1189 (m), 925 (m), 746 (s), 703 (s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:32][C:33]1[C:34]([CH3:50])=[CH:35][C:36]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:37]([CH:41]=1)[C:38](O)=[O:39]>CN(C)C=O>[Br:32][C:33]1[C:34]([CH3:50])=[CH:35][C:36]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:37]([CH:41]=1)[C:38]([NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:39]
Reactant: Cc1cc(OCc2ccccc2)c(C(=O)O)cc1Br
Reactant: Nc1cccnc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccccc2)c(C(=O)Nc2cccnc2)cc1Br
Reaction time: 8 h

Procedure:
3-Aminopyridine (193 mg, 2.06 mmol), and HATU (852 mg, 2.24 mmol) were added to a solution of 5-bromo-4-methyl-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 9; 600 mg, 1.87 mmol) in N,N-dimethylformamide (10 ml). The reaction was stirred overnight and the solid was filtered. Solvent was removed in vacuo and water was added. The solid was filtered and washed with ethyl acetate (10 ml) to give a white solid. The products were combined to yield the title compound as an off white solid. 508 mg.
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[C:5]2[N:6]([CH2:10][C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[H-].[Na+].O[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][C:27]3[CH2:44][C@:34]4([C:42]5[C:37](=[N:38][CH:39]=[CH:40][CH:41]=5)[NH:36][C:35]4=[O:43])[CH2:33][C:28]=3[CH:29]=2)[N:24]=1>CN(C=O)C>[CH3:1][C:2]1[CH:17]=[C:16]([CH3:18])[C:5]2[N:6]([CH2:10][C:11]([N:13]([CH3:14])[CH3:15])=[O:12])[C:7](=[O:9])[N:8]([CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][C:27]5[CH2:44][C@:34]6([C:42]7[C:37](=[N:38][CH:39]=[CH:40][CH:41]=7)[NH:36][C:35]6=[O:43])[CH2:33][C:28]=5[CH:29]=4)[N:24]=3)[C:4]=2[CH:3]=1
Reactant: O=C1Nc2ncccc2[C@@]12Cc1cc3ccc(CO)nc3cc1C2
Reactant: Cc1cc(C)c2c(c1)[nH]c(=O)n2CC(=O)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(c1)n(Cc1ccc3cc4c(cc3n1)C[C@]1(C4)C(=O)Nc3ncccc31)c(=O)n2CC(=O)N(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5,7-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-N,N-dimethylacetamide (221 mg, 0.893 mmol, described in Intermediate 17) in DMF (0.5 mL), at ambient temperature, was added sodium hydride (60% dispersion in mineral oil; 37 mg, 0.923 mmol). The resulting mixture was stirred for 30 min, then (S)-2-(chloromethyl)-6,8-dihydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (100 mg, 0.298 mmol, described in Intermediate 11) was added and the resulting mixture was stirred at ambient temperature for 2 h. The reaction mixture was quenched with H2O (0.1 mL) and purified directly by silica gel chromatography, eluting with a gradient of CH2 Cl2:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=547 (M+1). HRMS: m/z=547.2466; calculated m/z=547.2452 for C32H31N6O3.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]([OH:12])[CH:5]=[CH:6][CH2:7][CH2:8][CH2:9]CC.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:12][CH:4]([CH:5]=[CH:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH:2]=[CH2:1])(=[O:15])[CH3:14]
Reactant: C=CCC(O)C=CCCCCC
Reactant: CC(=O)OC(C)=O
Product: C=CCC(C=CCCC)OC(C)=O
Yield: 75 %

Procedure:
36 g of 1,5-undecadien-4-ol is stirred and heated to reflux with 32.6 g of acetic acid anhydride for 1 hour. The excess anhydride and the resulting acetic acid are removed by distillation under reduced pressure. The residue is fractionated. Yield: 33.8 g (76%) 1,5-undecadien-4-yl acetate; b.p. 70°-80° C/2 Torr; n20D = 1.4468. 1,5-Nonadien-4-yl acetate was prepared in a similar way; yield: 75%; b.p. 85° C/10 Torr; n22D = 1.4403.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH2:10])=[O:9].[N:21]([O-])=O.[Na+].[Na]>Cl.O.C(OCC)(=O)C>[F:19][C:17]([F:20])([F:18])[C:13]1[CH:12]=[C:11]([C:3]2[C:2]3[N:1]=[N:21][NH:10][C:8](=[O:9])[C:7]=3[CH:6]=[CH:5][N:4]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: NC(=O)c1ccnc(-c2cccc(C(F)(F)F)c2)c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCOC(C)=O
Product: O=c1[nH]nnc2c(-c3cccc(C(F)(F)F)c3)nccc12
Yield: 68.5 %

Procedure:
562 mg of 3-amino-2-(3-trifluoromethylphenyl)-4-pyridinecarboxamide were stirred at 0° C. in 5 ml of concentrated hydrochloric acid during the addition of 160 mg of sodium nitrite in 1 ml of water. After 0.5 hour the mixture was diluted with water and ethyl acetate and made basic with sodium hicarbonate. The organic phase was separated, dried over sodium sulphate and evaporated, and the residue was purified by chromatography on silica gel using ethyl acetate/petroleum ether (1:1) for the elution. There were obtained 400 mg of 8-(3-trifluoromethylphenyl)pyrido[3,4-d]-1,2,3-triazin-4(3H)-one in the form of a solid of melting point 192°-193° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([OH:12])[C:5]2[N:6]=[C:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.[CH2:13]([N:31]([CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[C:32](=[O:43])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].Cl>N1C=CC=CC=1>[CH2:44]([N:31]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:32](=[O:43])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](=[O:40])(=[O:41])[NH:1][C:2]2[CH:11]=[C:10]([OH:12])[C:5]3[N:6]=[C:7]([CH3:9])[O:8][C:4]=3[CH:3]=2)[CH:34]=1)[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]
Reactant: Cc1nc2c(O)cc(N)cc2o1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)c1cccc(S(=O)(=O)Nc2cc(O)c3nc(C)oc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a stirred solution of the 6-amino-4-hydroxy-2-methylbenzoxazole (4.1 g, 0.025 mole) in pyridine (190 ml) was added N,N-dioctadecyl-3-chlorosulfonylbenzamide (Example 5) (18.8 g, 0.026 mole). The mixture was stirred at ambient temperature overnight, then poured into ice water (2 liters) and acidified with hydrochloric acid (200 ml). The resulting precipitate was collected, washed well with water, and dried to yield a tan solid (17.3 g, 81.2 percent). TLC showed the product to be homogeneous.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=3)[CH:11]=[C:10]([CH3:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][N:25]=1>>[Cl:21][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([CH3:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:27]4[CH:28]=[CH:29][C:24]([NH2:23])=[N:25][CH:26]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)cc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(3,4-dichloro-phenyl)-6-methyl-pyridine (example E.85) (0.20 g, 0.509 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.123 g, 0.56 mmol) according to the general procedure VI. Obtained as an off-white solid (0.050 g, 21%). MS (ISP) 406.0 [(M+H)+], 408.1 [(M+2+H)+] and 410 [(M+4+H)+]; mp 99° C. (dec.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[OH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11].S(=O)(=O)(O)O>>[OH:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[O:11]
Reactant: OCCCCl
Reactant: O=C(O)c1cccc(O)c1
Agent: O=S(=O)(O)O
Product: O=C(OCCCCl)c1cccc(O)c1
Yield: 108.4 %

Procedure:
3-Chloro-1-propanol (161.6 g, 1.71 mol) was refluxed with 3-hydroxy-benzoic acid (40.0 g, 0.29 mol) and a catalytic amount of sulfuric acid for a total of 9 hours. The excess alcohol was removed by vacuum distillation. The resulting orange oil was diluted with 400 mL of water and neutralized to pH 7. The solution was extracted with ethyl acetate (3×250 mL). The organic layer was washed with 100 mL of brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by column chromatography with to give 67.5 g of product which contained a small amount of the starting alcohol: 1H NMR (CDCl3) δ2.24 (quint, 2H), 3.70 (t, 2H), 4.48 (t, 2H, J=6 Hz), 5.55 (s, 1H), 7.05-7.63 (m, 4H). ##STR21##
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.[C:25]([O:29][C:30](=[O:47])[NH:31][CH2:32][CH2:33][NH:34][S:35]([C:38]1[CH:43]=[C:42](Br)[C:41]([F:45])=[CH:40][C:39]=1[F:46])(=[O:37])=[O:36])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([O:29][C:30](=[O:47])[NH:31][CH2:32][CH2:33][NH:34][S:35]([C:38]1[CH:43]=[C:42]([C:13]#[C:12][C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:1])[F:24])=[CH:4][C:5]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)=[N:6][C:7]=23)[C:41]([F:45])=[CH:40][C:39]=1[F:46])(=[O:36])=[O:37])([CH3:28])([CH3:26])[CH3:27]
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(Br)c(F)cc1F
Product: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 7-difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2) (675 mg, 2 mmol) and [2-(5-bromo-2,4-difluoro-benzenesulfonylamino)-ethyl]-carbamic acid tert-butyl ester (1080 mg, 2.6 mmol) according to general procedure II. Obtained as a yellow solid (670 mg, 50%). MS (ISP) 572.0 [(M+H)+]; mp 203-204° C. (dec.).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH:10]2[S:21][C:13]3=[N:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[N:12]3[CH2:11]2)[C:5]=1[CH3:22])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>C(Cl)Cl>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([CH:10]2[S:21](=[O:28])[C:13]3=[N:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[N:12]3[CH2:11]2)[C:5]=1[CH3:22])[CH3:2]
Reactant: CCSc1ccnc(C2Cn3c(nc4ccccc43)S2)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCSc1ccnc(C2Cn3c(nc4ccccc43)S2=O)c1C

Procedure:
A solution of 2-(4-ethylthio-3-methylpyrid-2-yl)-2,3-dihydrothiazolo[3,2-a]benzimidazole (0.01 mole) is dissolved in CH2Cl2 solution (100 ml) at 0° C. and treated with m-chloroperoxybenzoic acid (0.01 mole) for 0.5 hours. The solution is then washed with sodium carbonate solution and dried (MgSO4). Purification by chromatography on silica gives the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[NH:8][C:9]2[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].[CH3:19][N:20](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:21].F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.CNC>C1COCC1>[CH3:19][N:20]([CH3:21])[C:16]([C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[NH:8][C:9]=2[CH:15]=1)=[O:18]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCOC(=O)Cc1nc2ccc(C(=O)O)cc2[nH]1
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cc1nc2ccc(C(=O)N(C)C)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[(Ethoxycarbonyl)methyl]benzimidazole-5-carboxylic acid (1.0 equivalent) was dissolved in THF. HBTU (1.1 equivalents) and diisopropylethylamine (2.0 equivalents) were added, followed by dimethylamine (2.0 M in THF, 1.1 equivalents). The reaction was stirred at room temperature overnight then concentrated and the resulting residue was purified by silica gel chromatography (5:95 MeOH:CH2Cl2) to afford the desired compound. LC/MS m/z 276.2 (MH+), Rt 1.18 minutes.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:16])[CH2:14][CH3:15].[CH3:17][N:18]([CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]1)[CH3:19]>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:16])[CH2:14][CH3:15])=[C:2]2[NH:27][CH:24]1[CH2:25][CH2:26][CH:21]([CH2:20][N:18]([CH3:19])[CH3:17])[CH2:22][CH2:23]1
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Product: CCC(=O)c1cnc2ccc(Cl)nc2c1NC1CCC(CN(C)C)CC1
Yield: 93.4 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)propan-1-one (255 mg, 1.0 mmol) was reacted with trans-4-((dimethylamino)methyl)cyclohexanamine (310 mg, 2.0 mmol) to afford the product (350 mg, 93%) as a white solid: ESI MS m/z 375 [M+H]+.