Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:3]=1.[B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.C(N(CC)C(C)C)(C)C.[Cl:41][C:42]1[CH:43]=[C:44]([N:62]2[C:67](=[O:68])[NH:66][C:65](=[O:69])[C:64]([C:70]#[N:71])=[N:63]2)[CH:45]=[C:46]([Cl:61])[C:47]=1[O:48][C:49]1[CH:54]=[C:53]([CH:55]([CH3:57])[CH3:56])[C:52](=[O:58])[N:51]([CH2:59]O)[N:50]=1>C(Cl)Cl>[Cl:61][C:46]1[CH:45]=[C:44]([N:62]2[C:67](=[O:68])[NH:66][C:65](=[O:69])[C:64]([C:70]#[N:71])=[N:63]2)[CH:43]=[C:42]([Cl:41])[C:47]=1[O:48][C:49]1[CH:54]=[C:53]([CH:55]([CH3:56])[CH3:57])[C:52](=[O:58])[N:51]([CH2:59][O:10][C:9](=[O:11])[CH2:8][C:4]2[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=2)[N:50]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(CO)c1=O
Reactant: O=C(O)Cc1cccnc1
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(Oc2c(Cl)cc(-n3nc(C#N)c(=O)[nH]c3=O)cc2Cl)nn(COC(=O)Cc2cccnc2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 22.4 %

Procedure:
A solution of pyridin-3-yl-acetic acid hydrochloride salt (57.3 mg, 0.33 mmol) in methylene chloride (1.84 mL) was treated with N,N,N′,N′-tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate (119 mg, 0.39 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.99 mmol). The resulting solution was stirred at 25° C. for 2.5 h. At this time, 2-[3,5-dichloro-4-(1-hydroxymethyl-5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile (200 mg, 0.42 mmol) was added to the reaction. The reaction mixture was stirred at 25° C. for 18 h. At this time, the reaction mixture was diluted with methylene chloride (50 mL) and washed with water (3×150 mL). The organics were dried over sodium sulfate, filtered, rinsing with methylene chloride and concentrated in vacuo. Biotage flash chromatography (40S, 1-4% methanol/methylene chloride) followed by supercritical fluid chromatography (Daicel OD column, 60% methanol) afforded pyridin-3-yl-acetic acid 3-[2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-5-isopropyl-6-oxo-6H-pyridazin-1-ylmethyl ester (43.2 mg, 22%) as a yellow solid. ES+-HRMS m/e calcd for C25H19N7O6Cl2 (M+H+) 584.0847, found 584.0848.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>C(OCC)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CCOC(=O)CCc1ncc[nH]1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCc1nccn1-c1ccc(C)cc1[N+](=O)[O-]
Reaction time: 6 h
Yield: 92.9 %

Procedure:
1-Fluoro-4-methyl-2-nitrobenzene 239 mg, ethyl 3-(1H-imidazol-2-yl)propanoate 252 mg, potassium carbonate 415 mg and N,N-dimethylacetamide 10 mL were stirred at 100° C. for 11.5 hours, and then at 130° C., for 6 hours. The reaction liquid was diluted with diethyl ether, washed with water and saturated brine by the order stated, and dried over magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was subjected to silica gel chromatography (ethyl acetate) to provide 422 mg of the title compound.
Reaction SMILES: C([NH:4][CH:5]=[CH:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[C:9]([O:18][CH3:19])[CH:8]=1)(=O)C.[CH:20]([NH2:23])([CH3:22])[CH3:21].[CH:24]([OH:27])(C)[CH3:25]>>[C:24]([C:5]([NH2:4])=[CH:6][C:7]1[CH:17]=[CH:16][C:10]([O:11][CH2:12][CH:13]([OH:15])[CH2:14][NH:23][CH:20]([CH3:22])[CH3:21])=[C:9]([O:18][CH3:19])[CH:8]=1)(=[O:27])[CH3:25]
Reactant: CC(C)N
Reactant: COc1cc(C=CNC(C)=O)ccc1OCC1CO1
Reactant: CC(C)O
Product: COc1cc(C=C(N)C(C)=O)ccc1OCC(O)CNC(C)C

Procedure:
4.3 g (0.016 mol) of 1-[4-(2-acetylaminovinyl)-2-methoxy-phenoxy]-2,3-epoxy-propane are heated to 80° C. with a solution of 1.4 ml (0.016 mol) of isopropylamine in 100 ml of isopropanol for 3 hours under reflux. The mixture is then evaporated in vacuo and the curde base obtained is crystallised from isopropanol-ethyl acetate. 1-[4-(2-Acetyl-aminovinyl)-2-methoxy-phenoxy]-2-hydroxy-3-isopropylamino-propane of melting point 139°-140° C. is obtained.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][Br:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:13][N:14]([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][CH2:30][CH2:31][CH2:32][CH3:33])[CH3:15]>C(#N)C>[Br-:12].[C:1]([O:9][CH2:10][CH2:11][N+:14]([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][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:13])[CH3:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCCBr)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN(C)C
Solvent: CC#N
Product: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCOC(=O)c1ccccc1
Product: [Br-]

Procedure:
A mixture of 45.0 g (0.1964 mol) of 2-bromoethyl benzoate and an equimolar amount of N,N-dimethyl-n-octadecylamine in 207 ml of acetonitrile was heated at reflux for 4.5 hours. The reaction mixture was then cooled. The solid was then collected, washed with ether, and dried to yield 76.7 g of the title compound; mp=87°-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13](O)[N:12]2[N:16]=[CH:17][N:18]=[C:11]2[CH:10]=1.P(Cl)(Cl)([Cl:21])=O>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:21][C:13]1[N:12]2[N:16]=[CH:17][N:18]=[C:11]2[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:14]=1
Reactant: Oc1nc(-c2ccc(Cl)cc2Cl)cc2ncnn12
Reactant: O=P(Cl)(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: Clc1ccc(-c2cc3ncnn3c(Cl)n2)c(Cl)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
2.07 g (7.4 mmol) of 7-[2,4-dichlorophenyl][1,2,4]triazolo[1,5-c]pyrimidin-5-ol (Example 137A) are introduced into phosphoryl chloride (20 ml), 5.0 g (22 mmol) of benzyltriethylammonium chloride are added, and the reaction mixture is stirred at 120° C. for 16 h. The reaction mixture is concentrated and cautiously poured onto ice, while stirring vigorously, and the mixture is stirred for 10 min. The solid is filtered off with suction. 1100 mg (50% of theory) of the product are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:22])[CH:3]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[F:22][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:24]([F:23])([F:35])[F:36])[CH:27]=2)[CH:7]=[C:6]([F:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Reactant: O=C(c1c(F)cc(Br)cc1F)N1CCC(N2CCCC2)CC1
Product: O=C(c1c(F)cc(-c2cccc(OC(F)(F)F)c2)cc1F)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2,6-difluoro-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 39) was reacted with 3-trifluoromethoxy-phenyl boronic acid to give the title compound as colorless oil. MS: 455.5 (MH+).
Reaction SMILES: [C:1]1([C:13]23[CH2:20][CH2:19][C:16]([NH2:21])([CH2:17][CH2:18]2)[CH2:15][CH2:14]3)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][N:2]=1.[CH:22]1([S:25](Cl)(=[O:27])=[O:26])[CH2:24][CH2:23]1>CN(C=O)C.O>[C:1]1([C:13]23[CH2:20][CH2:19][C:16]([NH:21][S:25]([CH:22]4[CH2:24][CH2:23]4)(=[O:27])=[O:26])([CH2:17][CH2:18]2)[CH2:15][CH2:14]3)[C:5]2=[C:6]3[CH:12]=[CH:11][NH:10][C:7]3=[N:8][CH:9]=[C:4]2[NH:3][N:2]=1
Reactant: NC12CCC(c3n[nH]c4cnc5[nH]ccc5c34)(CC1)CC2
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=S(=O)(NC12CCC(c3n[nH]c4cnc5[nH]ccc5c34)(CC1)CC2)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.6 %

Procedure:
To a mixture of 4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-amine (0.075 g, 0.267 mmol) in DMF (2.5 mL) was added TEA (0.06 mL, 0.40 mmol) and cyclopropanesulfonyl chloride (0.027 mL, 0.27 mmol, Matrix). The reaction mixture was stirred at ambient temperature for about 16 h. Cyclopropanesulfonyl chloride (0.014 mL, 0.133 mmol, Matrix) was added to the reaction mixture and the reaction continued to stir at ambient temperature for about 4 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concd under reduced pressure. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to give N-(4-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.015 g, 15%) as a white solid: LC/MS (Table 1, Method b) Rt=1.72 min; MS m/z: 386 (M+H)+.
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].Cl[C:7]([O:9][CH:10]([Cl:12])[CH3:11])=[O:8].CN1CCOCC1>C(Cl)Cl>[C:7](=[O:8])([S:5][C:1]([CH3:4])([CH3:3])[CH3:2])[O:9][CH:10]([Cl:12])[CH3:11]
Reactant: CC(Cl)OC(=O)Cl
Reactant: CC(C)(C)S
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(Cl)OC(=O)SC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A solution of tert-butyl thiol (180 g, 2 mol) and 1-chloroethyl chloroformate (284 g, 2 mol) in CH2Cl2 (1 L) was cooled to 0° C. in an ice-water bath. N-Methylmorpholine (212.1 g, 2.1 mol) was added dropwise over a period of 1 h and the reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was diluted with excess CH2Cl2 (2 L), washed with water (2×1 L), saturated bicarbonate solution (1 L) and brine (1 L), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by vacuum distillation (135° C./20 Torr) to provide the title compound (3) as a colorless liquid (350 g, 89%). 1H NMR (CDCl3, 400 MHz): δ 1.50 (s, 9H), 1.79 (d, J=6 Hz, 3H), 6.57 (q, J=5.6 Hz, 1H).
Reaction SMILES: C([O:5]C([NH:8][C@@H:9]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=O)(C)(C)C.[ClH:41].O1CCOCC1>O1CCOCC1>[OH2:5].[ClH:41].[NH2:8][C@@H:9]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])=[O:15])[CH2:10][CH2:11][S:12][CH3:13].[NH2:8][C@@H:9]([C:14]([NH:16][CH2:17][C:18]([NH:20][C@H:21]([C:29]([NH:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37](=[O:38])[O:39][CH3:40])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19])=[O:15])[CH2:10][CH2:11][S:12][CH3:13].[ClH:41]
Reactant: COC(=O)CCCCCNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CCCCCNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](N)CCSC
Product: O
Reaction time: 1 h

Procedure:
The title compound of Example 10 (12.0 g) was dissolved in 50 ml of dioxane to which was added 50 ml of 6 M hydrogen chloride/dioxane. After about one hour, the volatiles were removed in vacuo and the residue triturated thoroughly with diethyl ether. The title compound (10.9 g) was collected as an analytically pure hydrochloride hemihydrate.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:16]3[C@H:12]([CH2:13][NH:14][CH2:15]3)[C:11](=[O:17])[CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:31][C@@H:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33](Cl)=[O:34].FF>ClCCl.N1C=CC=CC=1>[F:31][C@@H:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33]([N:14]1[CH2:13][C@H:12]2[C@H:16]([C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9][CH2:10][C:11]2=[O:17])[CH2:15]1)=[O:34]
Reactant: O=C(Cl)[C@@H](F)c1ccccc1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CNC[C@H]12
Agent: Cl
Agent: FF
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C1CCC(c2ccccc2)(c2ccccc2)[C@@H]2CN(C(=O)[C@@H](F)c3ccccc3)C[C@H]12
Reaction time: 2 h

Procedure:
A solution of (3aR,7aR)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.12 g), triethylamine (0.9 cc) and pyridine (0.5 cc) in dichloromethane (30 cc) is added, at 0° C., to a solution of (S)-α-fluorophenylacetyl chloride [prepared from acid (1 g) by the method described by S. Hamman et al., J. Fluorine Chem., 37, 85 (1987)] in dichloromethane (20 cc). The reaction mixture is stirred for 2 hours allowing the temperature to return to 20° C. and is then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in ethyl acetate (100 cc). The solution is washed with water (2×100 cc) and then with saturated sodium bicarbonate solution (50 cc) and with saturated sodium chloride solution (50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.2-0.063 mm, diameter 3 cm, height 40 cm), eluting under a nitrogen pressure of 0.7 bar with ethyl acetate and collecting 100 cc fractions to give (3aR,7aR)-2-[(S)-α-fluorophenylacetyl]-7,7-diphenyl-4-perhydroisoindolone (1 g) in the form of a white meringue.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:18]([O:20][CH3:21])=[O:19])[C:8](=[CH:13][C:14]=1[N+:15]([O-])=O)[C:9]([O:11][CH3:12])=[O:10])(=O)[CH3:2].CO.C1(C)C([S:30]([OH:33])(=[O:32])=[O:31])=CC=CC=1>[Pt].C1(C)C=CC=CC=1>[CH3:18][C:7]1[CH:6]=[CH:5][C:14]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:13][CH:8]=1.[CH3:2][C:1]1[NH:15][C:14]2[CH:13]=[C:8]([C:9]([O:11][CH3:12])=[O:10])[C:7]([C:18]([O:20][CH3:21])=[O:19])=[CH:6][C:5]=2[N:4]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: COC(=O)c1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)OC
Agent: [Pt]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2nc(C)[nH]c2cc1C(=O)OC
Product: Cc1ccc(S(=O)(=O)O)cc1
Reaction time: 2 h

Procedure:
A mixture of dimethyl 4-acetamido-5-nitrophthalate, methanol and 5% platinum on carbon is hydrogenated in a Parr hydrogenator. The reaction mixture is filtered through diatomaceous earth and the filtrate is concentrated in vacuo. The thus-obtained crude diamine intermediate (48.09, 0.180 mol) is mixed with o-toluenesulfonic acid (51.4 g, 0.270 mol) and toluene (400 mL), and stirred for 2 hours at reflux temperatures with azeotropic removal of water, cooled and concentrated in vacuo. The resultant residue is recrystallized from methanol to afford the p-toluene sulfonate salt of the title product. The salt is dissolved in hot water, made basic with sodium bicarbonate and extracted with methylene chloride. The combined extracts are washed with brine, dried (MgSO4) and concentrated in vacuo to give a red solid. Recrystallization of a portion of the red solid affords the title product as white crystals, mp 151°-152° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH3:27])=[S:22])[CH2:17][CH2:18][CH3:19]>>[BrH:1].[CH2:24]([N:23]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=2)([OH:4])[CH2:2][S:22][C:21]1=[N:20][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:25][CH2:26][CH3:27]
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Reactant: CCCCNC(=S)NCCCC
Product: Br
Product: CCCCN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1CCCC

Procedure:
6.2 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone were reacted with 3.8 g of 1,3-di-n-butylthiourea according to the prescription given in Example 12 and the end product was precipitated with diisopropyl ether. Colorless amorphous solid body: decomposition beginning at 100° C., γC=N 1615 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C(N1C2C=C([C:40]3[CH:41]=[C:42]4C=[CH:47][NH:46][C:43]4=[N:44][CH:45]=3)C=C(C(OC)=O)C=2C=N1)(C)C.[C:53](=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:53][N:46]([CH3:47])[C:43]1[N:44]=[CH:45][C:40]([C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[O:16])[C:5]3[C:6]([CH3:14])=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=3[CH:10]=2)=[CH:41][CH:42]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(-c2cnc3[nH]ccc3c2)cc2c1cnn2C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N(C)C)nc3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 110 °C
Reaction time: 4 h
Yield: 30.4 %

Procedure:
To a stirred solution of 6-bromo-N-((1,2-dihydro-4,6-dimethyl-2-oxopyridin-3-yl)methyl)-1-isopropyl-3-methyl-1H-indazole-4-carboxamide (300 mg, 0.696 mmol) in DMF (30 mL) was added 6-(dimethylamino)pyridin-3-yl-3-boronic acid, 1 (127 mg, 0.765 mmol) followed by sodium carbonate (184.4 mg, 1.74 mmol) dissolved in water (3 mL) and degassed with argon for 1 h. Then PdCl2(PPh3)2 (48.8 mg, 0.069 mmol) was added and again degassed with argon for 15 min and stirred at 110° C. for 4 h. The reaction mixture was filtered through Celite pad and washed with ethyl acetate (50 mL). The filtrate was diluted with water and extracted with ethyl acetate (4×90 mL). The combined organic layers were separated and washed with cold water (2×50 mL), brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford the crude product (450 mg). The crude compound was purified by silica gel chromatography (eluent: 5% MeOH: DCM) to afford 100 mg of desired product which was triturated with hexane and the solid was filtered and dried to afford the title compound as an off white solid (100 mg, 30%). 1H NMR (DMSO-d6, 400 MHz): δ 1.559 (d, J=6.8 Hz, 6H), 2.102 (s, 3H), 2.403 (s, 3H), 2.539 (s, 3H), 3.125 (s, 6H), 4.616 (s, 2H), 4.754-4.820 (m, 1H), 5.893 (s, 1H), 6.557 (d, J=8.8 Hz, 1H), 7.313 (s, 1H), 7.401 (d, J=5.2 Hz, 1H), 7.448 (s, 1H), 7.707 (d, J=8.8 Hz, 1H), 8.438 (s, 1H), 11.502 (brs, 1H). 1H NMR (D2O Ex in DMSO, 400 MHz): δ 1.559 (d, J=6.8 Hz, 6H), 2.115 (s, 3H), 2.408 (s, 3H), 2.538 (s, 3H), 3.124 (s, 6H), 4.616 (s, 2H), 4.754-4.820 (m, 1H), 5.899 (s, 1H), 6.557 (d, J=8.8 Hz, 1H), 7.318 (s, 1H), 7.450 (s, 1H), 7.718 (d, J=8.8 Hz, 1H), 8.438 (s, 1H). LCMS (ES+): 473.19.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.S(Cl)([Cl:12])=O>C(Cl)Cl.O>[ClH:12].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][Cl:12])=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Br)cn1
Solvent: ClCCl
Solvent: O
Product: Cl
Product: ClCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.8 %

Procedure:
A mixture of (5-bromo-pyridin-2-yl)-methanol (104 g, 0.66 mol) in methylene chloride (833 mL) in two neck flask was placed in water bath. Thionyl chloride (80.5 mL, 1.33 mol) was dropwise added to the reaction mixture using dropping funnel and stirred at room temperature for 1.5 hr. Then, thionyl chloride (20 mL, 0.33 mol) was additionally added to the reaction mixture and stirred for 2.5 hr. After completion of the reaction, the reaction mixture was transferred to a round bottom flask. Methylene chloride and thionyl chloride were evaporated off. Toluene (2×100 mL) was added to the residue and azeotropically removed all the residual thionyl chloride. The residue was dried on vacuum for overnight to give the title compound (129.6 g, 96%) as a pink solid. MS-ESI m/z 207.91 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[C:5]([C:6]#[N:7])=[C:4]([F:11])[CH:3]=1.[CH:12](C1C=CC(C#N)=C(OC)C=1C)=[CH2:13]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:10][C:8]1[CH:9]=[C:2]([CH:12]=[CH2:13])[CH:3]=[C:4]([F:11])[C:5]=1[C:6]#[N:7]
Reactant: C=Cc1ccc(C#N)c(OC)c1C
Reactant: N#Cc1c(F)cc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: C=Cc1cc(F)c(C#N)c(F)c1

Procedure:
2,6-Difluoro-4-vinylbenzonitrile was prepared from 4-bromo-2,6-difluorobenzonitrile using potassium vinyl trifluoroborate and PdCl2(dppf)2 in an analagous fashion as described for 4-ethenyl-3-methyl-2-(methyloxy)benzonitrile above.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[CH:6][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH3:23])([CH3:22])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:8]=1.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:22][C:13]([NH:12][CH2:11][CH2:10][CH2:9][N:7]1[CH:8]=[C:4]([CH2:3][CH2:2][NH:1][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:5]=[CH:6]1)([CH3:23])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(COc1ccccc1)NCCCn1cnc(CCN)c1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(COc1ccccc1)NCCCn1cnc(CCNC(=O)c2ccccc2)c1

Procedure:
3-[4-(2-Aminoethyl)imidazol-1-yl]-N-(1,1-dimethyl-2-phenoxyethyl)propylamine (2.50 g) and benzoyl chloride (1.10 g) were reacted in a similar manner to Example 55 to give N-(2-{1-[3-(1,1-dimethyl-2-phenoxyethylamino)propyl]imidazol-4-yl}ethyl)benzamide, as an oil. The compound contained 8% of N-(2-{1-[3-(1,1-dimethyl-2-phenoxyethylamino)propyl]imidazol-5-yl}ethyl)benzamide, by 1H nmr and 13C nmr. These compounds may be separated by HPLC.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:13]1([C@@H:19]([NH2:21])[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CCN(C(C)C)C(C)C.C(OCC)(=O)C>CN1C(=O)CCC1>[CH:13]1([C@@H:19]([NH:21][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH3:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C[C@H](N)C1CCCCC1
Reactant: COc1ccc2nc(Cl)sc2c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc2nc(N[C@@H](C)C3CCCCC3)sc2c1
Temperature: 110 °C
Reaction time: 96 h

Procedure:
To the solution of 2-chloro-6-methoxybenzo[d]thiazole (2.0 g, 10 mmol) in 10 ml of NMP was added (S)-1-cyclohexylethanamine (2.3 g, 18 mmol) and DIPEA (3.5 ml, 20 mmol). The reaction solution was stirred at 110° C. for 96 hr. The reaction was worked up by adding 170 ml ethyl acetate and washed with 1×60 ml of saturated NaHCO3, 1×60 ml 5% NaHCO3 solution, 1×60 ml water, 1×60 ml saturated NaCl, dried with sodium sulfate, filtered and concentrated in vaccuo to give (S)—N-(1-cyclohexylethyl)-6-methoxybenzo[d]thiazol-2-amine as crude solid (3.39 grams). ES/MS m/z 291.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])([O-])=O.[CH3:15]O.S(=O)(=O)(O)O>O>[NH2:1][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([O:11][CH3:15])=[O:10]
Reactant: CO
Reactant: O=C(O)C=Cc1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C=Cc1cccc(N)c1

Procedure:
While mixing and stirring 193 g of 3-nitrocinnamic acid, 2 of methanol and 50 g of concentrated sulfuric acid, the mixture was heated under reflux for 2 hours. The reaction solution was poured into water and the crystals obtained were filtered. To a reaction solution under heat-refluxing while mixing and stirring 2 of 2-propanol, 200 ml of water, 20 g of ammonium chloride and 200 g of reduced iron, the crystals obtained above were gradually added, and the solution was further heated under reflux for one hour. The reaction solution still being hot was filtered, the filtrate was poured into 10 of water, and the crystals (methyl 3-aminocinnamate) obtained were collected by filtration. Yield: 108 g.