Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1N=C(OC)N=C(OC)N=1.C1COCC1.Cl.[CH2:34]([O:36][C:37](=[O:41])[CH2:38][CH2:39][NH2:40])[CH3:35]>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[O:16])[NH:40][CH2:39][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:41])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: CCOC(=O)CCN
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCNC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.9 %

Procedure:
4.59 g of (RS)-piperidine-1,3-dicarboxylic acid 1-tert.-butyl ester, 3.51 g of 2-chloro4,6-dimethoxy-[1,3,5]-triazine (CDMT), 60 ml of THF and 2.25 ml of N-MM are stirred under argon at 0° C. for 3 hrs. After the addition of 3.07 g of β-alanine ethyl ester hydrochloride and 2.25 ml of N-MM the mixture is stirred at RT for 18 hrs. The reaction mixture is diluted with ethyl acetate and washed in sequence with ice-cold dilute hydrochloric acid, water, dilute sodium carbonate solution, water and saturated sodium chloride solution. After drying over sodium sulphate and evaporation of the solvent there are obtained 6.16 g of (RS)-3-(2-ethoxycarbonyl-ethylcarbamoyl)-piperidine-1-carboxylic acid tert.-butyl ester as a pale yellow oil. MS: 329 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][NH2:28])[CH:21]=1>>[F:1][C:2]1[CH:17]=[C:16]([CH2:18][NH:28][CH2:27][CH2:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH2:13])=[O:12])=[N:9][CH:10]=1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2F)cn1
Reactant: NCCc1cccnc1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3cccnc3)cc2F)cn1
Yield: 82.1 %

Procedure:
Using a method similar to Example 405, a reaction of 5-(2-fluoro-4-formylphenoxy)pyridine-2-carboxamide (Example 403, Part B) (0.040 g, 0.154 mmol) and 2-(pyridin-3-yl)ethylamine (0.019 g, 0.154 mmol) gives the title compound (0.0463 g, 82.2%): TOF MS ES+ 367.2 (M+H)+, HRMS calcd for C20H20N4O2F 367.1570 (M+H)+, found 367.1553, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=6.9 min, 100% purity.
Reaction SMILES: ClC1C=C(C=C(Cl)C=1N1C=C2C=NC=C(Cl)C2=N1)C#N.[N:21]([C:24]1[C:29]([Br:30])=[CH:28][N:27]=[CH:26][C:25]=1/[CH:31]=[N:32]/[C:33]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=1[Cl:40])=[N+]=[N-]>C1(C)C=CC=CC=1>[Br:30][C:29]1[C:24]2[C:25](=[CH:31][N:32]([C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])[N:21]=2)[CH:26]=[N:27][CH:28]=1
Reactant: [N-]=[N+]=Nc1c(Br)cncc1/C=N/c1c(Cl)cccc1Cl
Agent: N#Cc1cc(Cl)c(-n2cc3cncc(Cl)c3n2)c(Cl)c1
Solvent: Cc1ccccc1
Product: Clc1cccc(Cl)c1-n1cc2cncc(Br)c2n1
Yield: 81 %

Procedure:
Following the procedure described for 3,5-dichloro-4-(7-chloropyrazolo[4,3-c]pyridin-2-yl)benzonitrile, [1-(4-azido-5-bromopyridin-3-yl)-meth-(E)-ylidene]-(2,6-dichlorophenyl)-amine was heated under reflux in toluene to afford the title compound as a brown solid (7.5 g, 81% yield). LCMS (Method D): RT=2.90 min, m/z: 344 [M+H+].
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][NH:5]1.Br[CH2:15][C:16]1[S:17][C:18]([C:21]2[CH:22]=[C:23]([NH:28][C:29]3[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=3)[CH:24]=[C:25]([CH3:27])[CH:26]=2)=[CH:19][N:20]=1>O1CCCC1.C(OCC)(=O)C>[CH3:27][C:25]1[CH:26]=[C:21]([C:18]2[S:17][C:16]([CH2:15][C:8]3([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:6][NH:5][C:4]3=[O:3])=[N:20][CH:19]=2)[CH:22]=[C:23]([NH:28][C:29]2[N:34]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:32]=[CH:31][N:30]=2)[CH:24]=1
Reactant: CCOC(=O)C1CCNC1=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CBr)s2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cc2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CCNC1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.8 %

Procedure:
To sodium hydride in mineral oil (60%, 0.007 g, 0.33 mmol) was added tetrahydrofuran (1.8 mL) and the suspension was cooled to 0° C. Ethyl 2-oxopyrrolidine-3-carboxylate (0.044 g, 0.28 mmol) was added and the solution was stirred for 15 minutes. N-{3-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (0.100 g, 0.23 mmol) was dissolved in tetrahydrofuran (1.8 mL) and then added to the flask. The reaction was allowed to warm to room temperature overnight. The reaction was diluted with ethyl acetate, washed carefully with water, dried over magnesium sulfate, filtered and concentrated. The solid was purified by silica gel chromatography to yield ethyl 3-{[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methyl}-2-oxopyrrolidine-3-carboxylate (0.03 g, 27% yield). MS ESI: [M+H]+ m/z 505.7. 1H NMR (500 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.83 (d, J=5.2, 1H), 8.11 (s, 1H), 8.02-7.84 (m, 2H), 7.47 (s, 1H), 7.28 (d, J=5.2, 1H), 7.14 (s, 1H), 4.11 (q, J=7.4, 2H), 3.58 (in 1H), 3.28-3.21 (m, 2H), 3.15-3.03 (m, 1H), 2.66-2.54 (m, 1H), 2.31 (s, 3H), 2.27-2.16 (m, 1H), 1.15 (t, J=7.3, 3H). rhSYK activity=+++
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][CH2:18][CH2:19][S:20][CH2:21][CH2:22][CH3:23])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>>[OH:1][CH2:2][CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=1)[CH2:17][CH2:18][CH2:19][S:20]([CH2:21][CH2:22][CH3:23])=[O:32]
Reactant: CCCSCCCN(CCO)CCCCc1ccc(C#N)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCCS(=O)CCCN(CCO)CCCCc1ccc(C#N)cc1
Yield: 24.6 %

Procedure:
3.1 g of 4-[4- [(2-hydroxyethyl)[3-(propylthio)propyl]amino]butyl]benzonitrile was oxidized with 2.2 g of m-chloroperbenzoic acid in analogy with example 2. The yield was 0.8 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH:14](OC)OC)[CH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])/[CH:9]=[CH:11]/[N:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1ccc(Br)cc1
Product: CN(C)/C=C/C(=O)c1ccc(Br)cc1
Yield: 61 %

Procedure:
A solution of 1-(4-bromophenyl)ethanone (2.0 g, 10 mmol) in DMF-DMA (25 mL) was stirred at 100° C. for 16 h. The solution was concentrated and purified by flash column chromatography (hexanes:EtOAc=4:1˜2:1) to give the title compound (1.57 g, 61%) as an orange-brown solid.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH3:22])[OH:19])[CH3:9].CN(C1C=CC=CN=1)C.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>ClCCl.C(OCC)(=O)C>[O:35]([C:33]([O:18][CH:14]1[CH2:13][CH2:12][C:11]([CH2:20][S:21][CH3:22])([OH:19])[CH:10]([C:2]2([CH3:9])[O:1][CH:3]2[CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[CH:15]1[O:16][CH3:17])=[O:34])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COC1C(O)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC1C(OC(=O)Oc2ccccc2)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Yield: 81 %

Procedure:
In dichloromethane (2 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (200 mg) and dimethylaminopyridine (115 mg). To the solution was added, under ice-cooling, phenyl chloroformate (95 μl ), and the mixture was stirred for 16 hours. The reaction mixture was diluted with ethyl acetate (70 ml), washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: ethyl acetate - hexane=1:4) to afford 4-O-phenoxycarbonyl-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (222mg: yield 81%) as a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:13][OH:14])=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:13][O:14][CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][O:16]3)=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1
Reactant: C1=COCCC1
Reactant: Cc1cc(Cl)c2cc(C)c(CO)cc2n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)c2cc(C)c(COC3CCCCO3)cc2n1
Yield: 58.9 %

Procedure:
A solution of (4-chloro-2,6-dimethyl-quinolin-7-yl)-methanol (example 59c, 300 mg, 1.35 mmol), 3,4-dihydro-2H-pyran (342 mg, 4.06 mmol), and pyridinium toluene-4-sulfonate (374 mg, 1.49 mg) in dichloromethane (3 mL) and toluene (3 mL) was stirred at r.t. for 3 d, then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), and evaporated. Flash chromatography (SiO2, hexane/ethyl acetate gradient) afforded the title compound (243 mg, 59%). White solid, ISP-MS: m/e=306.3 ([M+H]+).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([CH2:21][C:22](OCC)=[O:23])#[N:20]>>[NH2:20][C:19]1[CH:21]=[C:22]([OH:23])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: CCOC(=O)CC#N
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Nc1cc(O)c2ccccc2n1
Reaction time: 1 h

Procedure:
The appropriate aniline p-toluenesulfonate and ethyl cyanoacetate are combined in equimolar quantities and heated at 225° to 260° C. until a melt required. (Higher temperatures are used if necessary to achieve a melt). The temperature of the melt is lowered to 240° to 250° C. and heating continued for 1 hour. The hot melt is poured into ice-cold chloroform (about 1 to 1.5 liters per mole of aniline reactant) and the mixture stirred for 1 hour. The solid is filtered off, added to water-ethanol (1 liter of 1:1 per mole of aniline reactant) at 45° to 50° C. and the solution made basic with ammonium hydroxide. The solid is separated by filtration and recrystallized from a suitable solvent such as isopropanol.
Reaction SMILES: II.[NH2:3][C:4]1[CH:21]=[CH:20][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[NH:15][C:16](=[O:19])[N:17]([CH3:18])[C:10]=23)=[CH:6][CH:5]=1.[C:22]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:28]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[N:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[CH3:18][N:17]1[C:10]2[C:11](=[N:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]2[CH:20]=[CH:21][C:4]([NH:3][C:32]([NH:31][C:29]3[N:28]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=4)[N:27]=[C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:30]=3)=[O:33])=[CH:5][CH:6]=2)[NH:15][C:16]1=[O:19]
Reactant: Cn1c(=O)[nH]c2nccc(Oc3ccc(N)cc3)c21
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccc(F)cc2)n1
Agent: II
Product: Cn1c(=O)[nH]c2nccc(Oc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(F)cc4)cc3)c21
Yield: 34.9 %

Procedure:
Method I2 was used with 7-(4-aminophenoxy)-1-methyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (25 mg, 0.1 mmol) and phenyl 3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl-carbamate (42 mg, 0.12 mmol) to afford the title compound (18 mg, 35%). 1H-NMR (δ, ppm, DMSO-d6): 1.29 (s, 9H, t-Bu), 3.46 (s, 3H, CH3N), 6.37 (s, 1H, HPyz,4), 6.41 (d, 1H, HPy,6), 7.13 (d, 2H, Harom,Ph,3+5), 7.38 (t, 2H, Harom,4-F-Ph,3+5), 7.48 (d, 2H, Harom,Ph,2+6), 7.57 (dd, 2H, Harom,4-F-Ph,2+6), 7.80 (d, 1H, HPy,6), 8.38 (s, 1H, NHurea), 9.08 (s, 1H, NHurea), 11.61 (bs, 1H, NHPy3). LC-MS (m/z): 516 (M+H, 100). Acc. mass (C27H26N7O3F): calculated 516.2159, found 516.2086.
Reaction SMILES: C[Al](C)C.[C:5](=[N:18][NH2:19])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:20]1(=[O:26])[O:25][CH:23]([CH3:24])[CH2:22][CH2:21]1.ClCCl.O>CCCCCCC.ClCCl>[C:6]1([C:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:18][NH:19][C:20](=[O:26])[CH2:21][CH2:22][CH:23]([OH:25])[CH3:24])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NN=C(c1ccccc1)c1ccccc1
Reactant: CC1CCC(=O)O1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: O
Product: CC(O)CCC(=O)NN=C(c1ccccc1)c1ccccc1
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
At room temperature, 6.0 ml (12.0 mmol) of a 2.0 M trimethylaluminium solution in heptane are added dropwise to a solution of 0.78 g (4.0 mmol) of benzophenone hydrazone in 10 ml of dichloromethane, and the mixture is stirred for 30 min. A solution of 0.40 g (4.0 mmol) of γ-valerolactone in 5 ml of dichloromethane is then added dropwise to the reaction mixture. The reaction mixture is stirred at reflux for 2 h. A further 0.12 g (1.20 mmol) of γ-valerolactone is added, and the reaction mixture is stirred at reflux for 1 h. After cooling, dichloromethane/water is added to the reaction mixture. The organic phase is separated off and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over Na2SO4 and freed from the solvent under reduced pressure. Purification by column chromatography on silica gel (cyclohexane/ethyl acetate) gives 0.9 g (76%) of the desired product; (log P(HCOOH): 2.25); 1H-NMR (ppm): δ (DMSO-d6)=1.01 (d, 1H), 1.10 (d, 2H), 1.45-1.72 (m, 2H), 2.16-2.26 (m, 1H), 2.75-2.86 (m, 1H), 3.51-3.57 (m, 0.3H), 3.65-3.71 (m, 0.7H), 4.43 (d, 0.3H), 4.52 (d, 0.7H), 7.25-7.62 (m, 10H), 8.99 (s, 1H); LC-MS: m/z=297 [M+H]+
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]2[S:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=2)[C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.N1C=CC=C(C[OH:27])C=1>N1C=CC=CC=1>[S:1]1[CH:5]=[C:4]([CH:6]=[CH:7][C:8]2[S:12][C:11]([C:13]([OH:27])=[O:14])=[CH:10][CH:9]=2)[C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: OCc1cccnc1
Reactant: O=C(Cl)c1ccc(C=Cc2csc3ccccc23)s1
Solvent: c1ccncc1
Product: O=C(O)c1ccc(C=Cc2csc3ccccc23)s1

Procedure:
The acid chloride of 5-[2-(benzo[b]thiophen-3-yl)ethenyl]thiophene-2-carboxylic acid was prepared as described in Example 9. To a suspension of 5-[2-(benzo[b]thiophen-3-yl)ethenyl]thiophene2-carboxylic acid chloride (5.00 g) and pyridine (50 ml) was added 3-pyridylcarbinol (1.79 g). After refluxing overnight, the mixture was evaporated, and the residue was dissolved in ether, filtered, and concentrated. The residue was purified by high performance liquid chromatography (silica gel, eluted with 2:1 ethyl acetate:hexane). The appropriate fractions were combined and evaporated. The residue was recrystallized from toluene/hexane to afford 1.4 g (23%) of the product, mp 97°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:20]3[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)cc1

Procedure:
The title compound, MS: m/e=308.8 (M+H+), was prepared in accordance with the general method of example 7 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 4-methyl-benzene boronic acid.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[S:14](=[O:16])(=[O:15])[NH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:6])[CH3:3].[CH3:17][NH:18][CH3:19]>ClCCCl>[CH3:3][CH:2]([N:4]1[S:14](=[O:16])(=[O:15])[NH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:6])[CH3:1].[CH3:17][NH2+:18][CH3:19]
Reactant: CNC
Agent: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Solvent: ClCCCl
Product: C[NH2+]C

Procedure:
A solution of 24 g of bentazone (IIa) in 216 g of 1,2-dichloroethane was treated with 22.5 g of a 20% strength aqueous solution of dimethylamine with stirring at 30°-50° C. After addition was complete, the aqueous phase was separated off at 50°-60° C. and evaporated to dryness under reduced pressure and at 50°-60° C. 28 g of bentazone-dimethylammonium (m.p. 145°-147° C.; purity >99% according to HPLC analysis for bentazone and titration for dimethylammonium) were obtained.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH:10]([CH3:13])[CH2:11][CH3:12])[N:9]=1.[Cl-:14].[NH4+:15]>CO>[ClH:14].[CH3:13][CH:10]([CH:8]1[NH:9][C:3](=[NH:15])[CH2:4][CH2:5][CH2:6][CH2:7]1)[CH2:11][CH3:12]
Reactant: CCC(C)C1CCCCC(OC)=N1
Reactant: [NH4+]
Reactant: [Cl-]
Solvent: CO
Product: CCC(C)C1CCCCC(=N)N1
Product: Cl

Procedure:
The product of EXAMPLE 118 in MeOH is reacted with ammonium chloride by the method of EXAMPLE 27 to generate the title material.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][C:16]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:17]3)=[CH:12][CH:11]=2)[NH2:9])=[N:4][CH:5]=[CH:6][N:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:49]([N:59]1[CH2:64][CH2:63][CH:62]([CH2:65][C:66](O)=[O:67])[CH2:61][CH2:60]1)([O:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:50]>C(Cl)Cl>[CH2:52]([O:51][C:49]([N:59]1[CH2:64][CH2:63][CH:62]([CH2:65][C:66](=[O:67])[NH:9][CH:8]([C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[CH:5][N:4]=2)[C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][C:16]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:17]3)=[CH:12][CH:11]=2)[CH2:61][CH2:60]1)=[O:50])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: O=C(O)CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(CC1CCN(C(=O)OCc2ccccc2)CC1)NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(3-Chloropyrazin-2-yl)(2-phenylquinolin-7-yl)-methanamine (120.00 mg, 0.35 mmol), EDC (100.64 mg, 0.53 mmol) and HOBt (47.29 mg, 0.35 mmol) were suspended in CH2Cl2 (2 mL) and charge with DIEA (122.00 μL, 0.70 mmol) followed by the addition of 1-N-Cbz-4-piperidineacetic acid (127.56 mg, 0.46 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with CH2Cl2 (10 mL) and washed with saturated NaHCO3 (2×20 mL) and brine (2×20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by a 10 g Jones silica gel (wetted with 50% EtOAc/Hexane, dried loaded onto silica, and run with 60% EtOAc/Hexanes→70% EtOAc/Hexanes) affording the desired product; 1H NMR (400 MHz, CHLOROFORM-d) δ 8.56 (1H, d, J=2.47), 8.39 (1H, d, J=2.50), 8.23 (1H, d, J=4.77), 8.11 (2H, d, J=7.06), 7.85 (3H, dd, J=8.60, J=8.38), 7.74 (1H, s), 7.50 (3H, m), 7.32 (6H, m), 6.78 (1H, d, J=7.76), 5.10 (2H, s), 4.11 (2H, m), 2.75 (2H, m), 2.21 (2H, d, J=7.00), 2.01 (1H, m), 1.67 (2H, m), 1.15 (2H, d, J=8.921); MS (ES+): m/z 605.96/606.98/608.93 (100/40/15) [MH+]; HPLC: tR=3.33 min. (OpenLynx, nonpolar—5 min.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][CH3:15])=[C:9]([CH2:11][CH:12]=C)[CH:10]=1.[O:17]=[O+][O-].CSC>CO.ClCCl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:6]=[N:7][C:8]([CH2:14][CH3:15])=[C:9]([CH2:11][CH:12]=[O:17])[CH:10]=1
Reactant: O=[O+][O-]
Reactant: C=CCc1cc(CC(=O)OC)cnc1CC
Solvent: CO
Solvent: CSC
Solvent: ClCCl
Product: CCc1ncc(CC(=O)OC)cc1CC=O
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of 5-allyl-6-ethyl-pyridin-3-yl-acetic acid methyl ester (1.00 g, 4.56 mmol) in 50% methanol in dichloromethane solution (25 mL, 0.2 M) is cooled to −78° C. and treated with ozone. After the solution became blue (30 min), it is purged with nitrogen and treated with dimethyl sulfide (1.7 mL, 23 mmol). After stirring overnight the solvent is removed in vacuo and the product is purified by flash chromatography (50% ethyl acetate in n-heptane) to provide 6-ethyl-5-(2-oxo-ethyl)-pyridin-3-yl-acetic acid methyl ester as a clear oil (0.78 g, 78%): Rf 0.26 (50% ethyl acetate in n-heptane), 1H NMR (CDCl3, 300 MHz) δ 9.77 (s, 1 H), 8.41 (s, 1 H), 7.43 (s, 1 H), 3.76 (s, 2 H), 3.72 (s, 3 H), 3.62 (s, 2 H), 2.77 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H). ESI-LCMS m/z calcd for C12H15NO3: 221.1; found 222.0 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:13]=[C:14]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[C:10]=3[CH2:9][S:8](=[O:30])(=[O:29])[C:6]=2[CH:7]=1.CC([O-])(C)C.[Na+].[CH3:37][NH:38][CH3:39]>C1(C)C=CC=CC=1.C1COCC1>[CH3:37][N:38]([CH3:39])[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:13]=[C:14]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[C:10]=3[CH2:9][S:8](=[O:30])(=[O:29])[C:6]=2[CH:7]=1
Reactant: CNC
Reactant: O=C(c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1cc(Br)ccc1-2)N1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(C)c1ccc2c(c1)S(=O)(=O)Cc1c(C(=O)N3CCOCC3)nn(-c3ccccc3)c1-2
Temperature: 90 °C

Procedure:
7-bromo-3-(morpholin-4-ylcarbonyl)-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (100 mg, 0.20 mmol, 1 eq.), NaOtBu (280 mg, 0.29 mmol, 1.4 eq.) are taken in degassed toluene in a sealed tube. Tris(dibenylidene acetone)dipalladium(0) (5 mg, 0.005 mmol, 0.025 eq.), 2-ditertiary butyl phosphino-2′,4′,6′-triisopropyl biphenyl (3.5 mg, 0.008 mmol, 0.04 eq.) are then added followed by dimethylamine in THF (3 mL, 2 M) and the reaction mixture is heated at 90° C. for 16 h. After this time, reaction mixture is filtered through a celite pad, evaporated and purified by silica gel flash chromatography to afford the title compound as a pale brown solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.61-7.59 (m, 3H), 7.51-7.49 (m, 2H), 7.10 (s, 1H), 6.81-6.79 (dd, J=2.6, 9.0 Hz, 1H), 6.61-6.59 (d, J=9.0 Hz, 1H), 4.76 (s, 2H), 3.96 (m, 2H), 3.65 (m, 4H), 3.59 (m, 2H), 2.97 (s, 6H). MS (ESI+): 453.0. HPLC (max plot) 91.39%; Rt 4.20 min.