Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[ClH:29]>C(O)(C)C>[ClH:29].[OH:1][CH:2]([CH2:16][N:26]1[CH2:27][CH2:28][N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:24][CH2:25]1)[CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2
Reactant: O=C1CCc2cc(OCC3CO3)ccc2N1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CC(C)O
Product: O=C1CCc2cc(OCC(O)CN3CCN(c4ccccc4)CC3)ccc2N1

Procedure:
4.4 Grams of 6-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril and 3.4 g of 4-phenylpiperazine are dispersed in 80 ml of isopropanol and reacted at 50°-60° C. for 3 hours under stirring conditions, then 5 ml of concentrated hydrochloric acid are added thereto and concentrated under reduced pressure to dryness. The thus obtained residue is recrystallized from hot water to obtain 6.1 g of 6-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril monohydrochloride.1/2hydrate in the form of colorless needle-like crystals with a melting point of 223°-224° C.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:14]=3[CH:15]=[N:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:36])[CH2:31][CH2:32][S:33]([O-:35])=[O:34].[Na+].CCOC(C)=O.[Br-]>CS(C)=O.[Cl-].[Na+].O.[Cu]I>[CH3:28][O:29][C:30](=[O:36])[CH2:31][CH2:32][S:33]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:20]=[N:19][N:18]([C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:14]=3[CH:15]=[N:16][CH:17]=2)=[O:11])=[CH:6][N:7]=1)(=[O:35])=[O:34]
Reactant: COC(=O)CCS(=O)[O-]
Reactant: O=C(NCc1ccc(Br)nc1)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: [Cu]I
Agent: [Br-]
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)CCS(=O)(=O)c1ccc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)cn1
Temperature: 110 °C

Procedure:
To a solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (6-bromopyridin-3-ylmethyl)-amide (150 mg, 0.35 mmol) in DMSO (2 mL) was added sodium 3-methoxy-3-oxopropane-1-sulfinate (125 mg, 0.717 mmol) followed by copper (I) iodide (135 mg, 0.708 mmol). The mixture was then warmed in a microwave at 110° C. for 35 minutes. The reaction was monitored by TLC (EtOAc) indicating a new slightly more polar product than starting bromide. The reaction was then diluted with brine (10 mL) and extracted with EtOAc (4×10 mL). The combined organic layers were washed with brine (5×10 mL), dried over magnesium sulfate, filtered and concentrated. The solid was dissolved in dichloromethane and purified by silica gel chromatography eluting with EtOAc-dichloromethane (25:75, then 1:1, then 75:25). The material from the column was triturated with ether to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.BrBr>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C2C=NNC(=O)C2c2ccc(F)cc2)cc1
Agent: BrBr
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(F)cc2)cc1
Temperature: 95 °C
Reaction time: 0.33 h

Procedure:
The dihydropyridazinone product from Example 18 (47 mg, 0.136 mmol) was dissolved in acetic acid (25 mL). Bromine (0.025 mL, 0.16 mmol) was added to the solution and the reaction mixture was stirred at 95° C. for 20 minutes. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure to provide a solid which was eluted through a short pad of silica gel with ethyl acetate. The title compound was crystallized from ethyl acetate/hexanes (yield: 35 mg, 75%). mp 255-256° C. 1H NMR (300 MHz, CDCl3) δ 3.07 (s, 3H), 6.98 (t, J=9 Hz, 2H), 7.16-7.23 (m, 2H), 7.35 (d, J=9 Hz, 2H), 7.86 (s, 1H), 7.91 (d, J=9 Hz, 2H). MS (DCI/NH3) m/z 345 (M+H)+ and m/z 362 (M+NH4)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[C:9]1([CH3:24])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[NH2:16].O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1/[CH:7]=[N:16]/[CH:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH3:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: Cc1ccccc1C(N)c1ccccc1C
Reactant: O=Cc1ccccn1
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1C(/N=C/c1ccccn1)c1ccccc1C

Procedure:
In air, 2-pyridinecarboxaldehyde (36.0 mg, 32.0 μL, 0.336 mmol, 1.00 equiv) was added to a solution of di-o-tolylmethanamine (73.1 mg, 0.346 mmol, 1.03 equiv) in CH2Cl2 (5 mL). After heating at reflux for 30 min with azeotropic removal of water using a Dean-Stark trap, the reaction mixture was concentrated under reduced pressure and dried under high vacuum to give ligand (L-3), (E)-N-(Pyridin-2-ylmethylene)-1,1-dio-tolylmethanamine, as a yellow oil (0.102 g, 98% yield).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]([O:9][C:10]([C:12]2([C:18]3[CH:30]=[CH:29][C:21]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:20][CH:19]=3)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:7][CH:6]=1)=[O:4].ClCCl.FC(F)(F)C(O)=O>C(OCC)(=O)C>[OH:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]([C:12]2([C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:29][CH:30]=3)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:11])=[CH:31][CH:32]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)c1ccc(C2(C(=O)Oc3ccc(C(=O)NO)cc3)CCCCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(C2(C(=O)Oc3ccc(C(=O)NO)cc3)CCCCC2)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of tert-butyl 4-[1-({4-[(hydroxyamino)carbonyl]phenoxy}-carbonyl)cyclohexyl]-benzoate (PX118926) (0.12 g, 0.27 mmol), dichloromethane (4 ml), and trifluoroacetic acid (1 ml) was stirred under argon atmosphere at room temperature until the starting material disappeared (ca. 2 hours). The mixture was supplemented with ethyl acetate (150 ml), the obtained solution was washed successively with water (2×100 ml), brine (50 ml), and dried (Na2SO4). The solvents were evaporated and the residue was chromatographed on silica gel with chloroform-isopropanol (9:1) as eluent to give the title compound in 48% yield as crystals, m.p. 169-170° C. 1H NMR (DMSO-d6, HMDSO) δ: 1.18-2.05 (8H, m); 2.34-2.69 (2H, m, overlapped with a signal of DMSO); 7.05 (2H, d, J=8.5 Hz); 7.62 (2H, d, J=8.4 Hz); 7.78 (2H, d, J=8.5 Hz); 7.99 (2H, d, J=8.4 Hz); 9.09 (1H, br s); 11.26 (1H, br s). HPLC analysis on Chromasil 100 C18 column: impurities 5% (column size 4.6×150 mm; mobile phase acetonitrile−0.1M phosphate buffer (pH 2.5), 60:40; detector UV 254 nm; sample concentration 1.0 mg/ml; flow rate 1.5 ml/min). Anal. Calcd for C21H21NO6*0.25H2O, %: C, 65.02; H, 5.59; N, 3.61. Found, %: C, 64.88; H, 5.49; N, 3.45.
Reaction SMILES: F[P-](F)(F)(F)(F)F.CN(C(=[N+](C)C)ON1C2=NC=CC=C2N=N1)C.C(N(C(C)C)CC)(C)C.[CH:34]1([C:37]([OH:39])=O)[CH2:36][CH2:35]1.[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([Cl:47])[C:42]=1[S:48]([O:51][C:52]1[CH:61]=[CH:60][C:55]2[NH:56][C:57]([NH2:59])=[N:58][C:54]=2[CH:53]=1)(=[O:50])=[O:49]>CN(C)C=O.O.C(#N)C.C(OCC)C>[Cl:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([Cl:40])[C:42]=1[S:48]([O:51][C:52]1[CH:61]=[CH:60][C:55]2[NH:56][C:57]([NH:59][C:37]([CH:34]3[CH2:36][CH2:35]3)=[O:39])=[N:58][C:54]=2[CH:53]=1)(=[O:50])=[O:49]
Reactant: Nc1nc2cc(OS(=O)(=O)c3c(Cl)cccc3Cl)ccc2[nH]1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: O=C(Nc1nc2cc(OS(=O)(=O)c3c(Cl)cccc3Cl)ccc2[nH]1)C1CC1
Temperature: 20 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
To a solution of 468 mg of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate in 5 cm3 of dimethylformamide are added 159 mg of diisopropylethylamine and 106 mg of cyclopropanecarboxylic acid. After stirring the reaction medium for one hour at a temperature in the region of 20° C., 220 mg of 2-amino-1H-benzimidazol-5-yl 2,6-dichlorobenzenesulfonate are obtained. The mixture is stirred overnight at a temperature in the region of 20° C. The reaction medium is diluted with 50 cm3 of water and the insoluble material is filtered off, washed with three times 5 cm3 of water, filtered off by suction and dried under a stream of air. The solid obtained is solidified in 10 cm3 of a mixture of diethyl ether and acetonitrile (7/3 by volume) and then filtered off by suction, washed with three times 2 cm3 of diethyl ether and dried under reduced pressure over phosphorus pentoxide. 98 mg of 2-[(cyclopropylcarbonyl)amino]-1H-benzimidazol-5-yl 2,6-dichlorobenzenesulfonate are obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:13]2[N:14]=[C:15]([CH3:19])[CH:16]=[C:17](O)[C:12]2=[CH:11][C:10]=1[CH3:20].P(Br)(Br)[Br:22].C([O-])(O)=O.[Na+]>BrC1C=CC=CC=1.C(Cl)(Cl)Cl>[Br:22][C:17]1[C:12]2[N:13]([C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:10]([CH3:20])[CH:11]=2)[N:14]=[C:15]([CH3:19])[CH:16]=1
Reactant: BrP(Br)Br
Reactant: Cc1cc(O)c2cc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Brc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)c2cc(C)c(-c3ccc(Cl)cc3Cl)n2n1
Temperature: 25 °C

Procedure:
A solution of 7-(2,4-dichlorophenyl)-2,6-dimethylpyrrolo[1,2-b]pyridazin-4-ol (34.2 g, 111.5 mmol) and phosphorus tribromide (50 mL, 142.5 g, 526.4 mmol) in bromobenzene (500 mL) is refluxed for 1 h. After cooling to room temperature, the mixture is diluted with CHCl3. Saturated NaHCO3 solution is added at 0° C. to neutralize and the mixture is separated immediately. The aqueous layer is extracted with CHCl3 (2×). The combined CHCl3 solution is dried over MgSO4 and filtered. The filtrate is concentrated in vacuo to dryness. The residue is subjected to column chromatography (silica gel, 1/10 EtOAc/heptane) to afford 38.8 g (93%) of light yellow solid as the title compound: 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J=1.5 Hz, 1H), 7.29 (m, 2H), 6.64 (s, 1H), 6.49 (s, 1H), 2.28 (s, 3H), 2.15 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.9, 136.8, 135.2, 134.3, 130.1, 129.3, 127.1, 125.6, 125.1, 124.2, 123.2, 114.8, 102.3, 22.0, 12.8; MS (EI) m/z 369 (M+), 371 (M+), 373 (M+); HRMS (FAB) calcd for C15H11BrCl2N2+H 368.9561, found 368.9572.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[C:25]1([CH:31]=[CH:32][S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1CCN2C(=NCCC2)CC1>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:36][S:33]([CH:32]=[CH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:34])=[O:35])=[O:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: NS(=O)(=O)C=Cc1ccccc1
Reactant: COc1cc(Cl)ccc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(Cl)ccc1C(=O)NS(=O)(=O)C=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of 4-chloro-2-methoxybenzoic acid (509 mg, 2.7 mmol) and CDI (443 mg, 2.7 mmol) in dichloromethane (25 ml) was heated to reflux for 30 minutes. After cooling down to room temperature 2-phenyl-ethenesulfonic acid amide (for preparation see example 1-1, steps i) and ii)) (500 mg, 2.7 mmol) and DBU (416 mg, 2.7 mmol) were added and the mixture was stirred at room temperature overnight. After washing twice with 1N HCl (50 ml each) and water (50 ml) the mixture was dried over Na2SO4 and concentrated in vacuo. Preparative HPLC (RP18, methanol-water-gradient) returned the title compound (570 mg, 60% yield) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:21])[CH:7]([O:18][CH2:19][CH3:20])[CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][NH:13]2)[CH3:4].Cl[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=2)[O:27][C:28]=1[CH3:29]>CN(C)C=O.O>[CH2:3]([O:5][C:6](=[O:21])[CH:7]([O:18][CH2:19][CH3:20])[CH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:23][C:24]1[N:25]=[C:26]([C:30]2[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=2)[O:27][C:28]=1[CH3:29])[CH3:4]
Reactant: CCOC(=O)C(Cc1cccc2[nH]ccc12)OCC
Reactant: COc1cc(OC)cc(-c2nc(CCl)c(C)o2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cccc2c1ccn2Cc1nc(-c2cc(OC)cc(OC)c2)oc1C)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.8 %

Procedure:
0.048 g (1.10 mmol) Sodium hydride (55% in mineral oil) was added in one portion below 5° C. and under argon to a stirred solution of 0.261 g (1.00 mmol) rac-2-ethoxy-3-(1H-indol-4-yl)-propionic acid ethyl ester and 0.321 g (1.20 mmol) 4-chloromethyl-2-(3,5-dimethoxy-phenyl)-5-methyl-oxazole in 15.0 ml N,N-dimethylformamide. The reaction mixture was warmed up to room temperature and then stirred for 16 hours at ambient temperature. It was then diluted with cold water and extracted two times with ethyl acetate. The combined organic phases were dried over MgSO4, filtered and evaporated. The residue formed was purified by flash-chromatography (silica gel; eluent: gradient of hexane and ethyl acetate) to give 0.413 g (84%) rac-3-{1-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethyl]-1H-indol-4-yl}-2-ethoxy-propionic acid ethyl ester as light yellow solid.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:27])[NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([C:24](=[O:26])[CH3:25])[CH2:20][CH2:19]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:28]Br>CO>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:27])[NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([C:24](=[O:26])[CH2:25][Br:28])[CH2:20][CH2:19]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C1CCC(NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Reactant: BrBr
Solvent: CO
Product: O=C(NC1CCC(C(=O)CBr)CC1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7.77 g (21 mmol) of 9H-fluoren-9-ylmethyl(4-acetylcyclohexyl)carbamate (cis compound) is dissolved in 100 mL of methanol at ambient temperature and combined with 1.09 mL (21 mmol) of bromine. The mixture is stirred for 16 hours at ambient temperature, cooled, and the crystals precipitated are suction filtered. Yield: 6.35 g (50%); NMR: LG201641.
Reaction SMILES: [C:1](=[S:8])([S:3][CH2:4][C:5]([OH:7])=[O:6])[NH2:2].[Na:9].[Na].[OH-].[Na+].N[CH2:14]C(O)=O.C[C@H](N)C(O)=O>C(=S)=S.O>[C:1](=[S:8])([S:3][CH:4]([C:5]([OH:7])=[O:6])[CH3:14])[NH2:2].[Na:9].[Na:9]
Reactant: NCC(=O)O
Reactant: NC(=S)SCC(=O)O
Agent: C[C@H](N)C(=O)O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: S=C=S
Product: CC(SC(N)=S)C(=O)O

Procedure:
This example describes the preparation of disodium carboxymethyl dithiocarbamate useful as a suspressant in ore flotation processes. To a 1-Liter round bottom flask fitted with a stirrer, thermometer, reflux condenser and a dropping funnel was added 253 milliliters of water and 84.0 grams (2.1 moles) of sodium hydroxide. After the NaOH had completely dissolved and the temperature had cooled below about 30° C., 75.0 grams (1.0 mole) of glycine was added and the mixture stirred until it was dissolved. Over the next 6 hours 76.14 grams (1.0 mole) of CS2 was slowly added while the temperature was maintained below about 40° C. The reaction product mixture was considered to be a 40 percent aqueous solution of disodium carboxymethyl dithiocarbamate and was used as prepared in the subsequent ore flotation processes. Similarly, disodium 1-carboxyethyl dithiocarbamate was prepared from α-alanine, CS2 and NaOH.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][C:11]2=[O:24])[S:5][C:6]=1[C:7]([OH:9])=O.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:40]([NH2:47])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl.C(OCC)(=O)C>[CH2:40]([NH:47][C:7]([C:6]1[S:5][C:4]([N:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][C:11]2=[O:24])=[N:3][C:2]=1[CH3:1])=[O:9])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of 4-methyl-2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)thiazole-5-carboxylic acid (0.10 g, 0.29 mmol) and 4-methylmorpholine (0.032 mL, 0.29 mmol) in anhydrous dichloromethane (6 mL) was added isobutylchloroformate (0.044 mL, 0.34 mmol) dropwise at 0° C. After stirring at ambient temperature for 2 hours, the reaction mixture was cooled to 0° C. and benzylamine (0.032 mL, 0.29 mmol) was added dropwise. Stirring at ambient temperature was continued for 18 hours, then the reaction mixture was diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixture of ethyl acetate/dichloromethane 1/1 (10 mL) to afford the title compound as a white solid (0.055 g, 44%): mp 219-220° C. (ethyl acetate/dichloromethane); 1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=8.1 Hz, 1H), 7.47-7.15 (m, 10H), 6.22 (dd, J=8.1, 2.6 Hz, 1H), 6.14 (t, J=5.6 Hz, 1H), 6.05 (d, J=2.6 Hz, 1H), 5.03 (s, 2H), 4.58 (d, J=5.6 Hz, 2H), 2.68 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.4, 162.3, 162.0, 153.5, 152.2, 137.8, 134.6, 131.6, 128.9, 128.8, 127.9, 127.8, 127.7, 122.4, 104.1, 97.4, 70.8, 44.1, 17.3; (ES+) m/z 432.2 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:17][CH3:18])=[N:13][CH:14]=[C:15]([Cl:16])[C:10]=2[N:9]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([CH2:42][C:43]#[N:44])[S:40][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.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:16][C:15]1[C:10]2[N:9]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[N:8]=[C:7]([C:37]3[CH:38]=[C:39]([CH2:42][C:43]#[N:44])[S:40][CH:41]=3)[C:11]=2[C:12]([O:17][CH3:18])=[N:13][CH:14]=1
Reactant: CC1(C)OB(c2csc(CC#N)c2)OC1(C)C
Reactant: COc1ncc(Cl)c2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(Cl)c2c1c(-c1csc(CC#N)c1)nn2-c1c(F)cccc1F
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
A mixture of 7-chloro-1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (100 mg), (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thienyl)acetonitrile (84.0 mg) obtained in Step A of Example 93, tetrakis(triphenylphosphine)palladium(0) (13.0 mg) and 2M aqueous sodium carbonate solution (0.200 mL) in DMF (2 mL) was stirred under microwave irradiation at 130° C. for 1.5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (70.2 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]#[N:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(N(CC)CC)C>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][CH3:17])[CH2:13][C@H:12]1[C:18]([NH2:19])=[N:21][OH:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CO[C@@H]1C[C@@H](C#N)N(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CO[C@@H]1C[C@@H](C(N)=NO)N(C(=O)OCc2ccccc2)C1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To benzyl-(2S,4R)-2-cyano-4-methoxypyrrolidine-1-carboxylate, dissolved in ethanol (0.4 M), hydroxylamine hydrochloride (1.3 eq.) and triethylamine (1.5 eq.) were added. The mixture was stirred at 40° C. for 4 hours then at room temperature overnight. The mixture was concentrated in vacuo and the residue dissolved in ethyl acetate washed with brine, dried over Na2SO4, filtered and concentrated to give title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].CN1C(=O)N(C)CCC1.Cl[CH2:19][CH2:20][CH2:21][C:22]1([C:32]([O:34][CH3:35])=[O:33])[CH2:27][CH2:26][CH2:25][CH:24]([C:28]([O:30][CH3:31])=[O:29])[CH2:23]1>C1COCC1>[C:24]12([C:28]([O:30][CH3:31])=[O:29])[CH2:23][C:22]([C:32]([O:34][CH3:35])=[O:33])([CH2:27][CH2:26][CH2:25]1)[CH2:21][CH2:20][CH2:19]2
Reactant: COC(=O)C1CCCC(CCCCl)(C(=O)OC)C1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C12CCCC(C(=O)OC)(CCC1)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a pre-cooled (−78° C.) solution of lithium diisopropylamide (27 mL, 54 mmol) in THF (80 mL) was added DMPU (30.2 g, 236 mol) dropwise, followed by an addition of dimethyl 1-(3-chloropropyl)cyclohexane-1,3-dicarboxylate (11.7 g, 44.7 mmol) in THF (50 mL) within 20 min. The reaction mixture was stirred for 30 min at −78° C. and then allowed to warm up to room temperature over a period of 1.5 h. After quenched with saturated ammonium chloride (100 mL), the mixture was concentrated under reduced pressure. The residue was diluted with water (300 mL) and extracted with dichloromethane (4×100 mL). The combined organic layer was washed with water (100 mL) and brine (100 mL), dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate: 20/1) to afford 8.32 g (82%) of dimethyl bicyclo[3.3.1]nonane-1,5-dicarboxylate as a light yellow oil. ESI-MS m/z: 227 (M+H)+.