Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[CH2:8])([O-:3])=[O:2].CC1(C)O[C@H]2[C@@H]3OC(C)(C)O[C@]3(C(O)=O)O[C@H]2C[O:14]1.O.OO.NC(N)=O>ClCCl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]2[CH2:8][O:14]2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: C=Cc1cccc([N+](=O)[O-])c1
Reactant: CC1(C)OC[C@@H]2O[C@@]3(C(=O)O)OC(C)(C)O[C@H]3[C@@H]2O1
Agent: NC(N)=O
Agent: OO
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(C2CO2)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
3-Nitrostyrene (1 g, 6.71 mmol) was taken with 100 mg Immobilized lipase and 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate (0.3 g, 1.03 mmol) in dry dichloromethane (15 mL) and stirred at 25° C. and added urea hydrogen peroxide (3 g, 32 mmol) portion-wise at a pH 5 for 20 hours. The reaction was monitored occasionally on TLC. The mixture was filtered and washed the residue with dichloromethane and the filtrate was reduced its volume under reduced pressure using vacuum flash evaporator. The product was purified by preparative TLC with 25% EtOAc/hexane. 75% Yield; Yellow oil (Found: C, 58.22; H, 4.28; N, 8.50. C8H7NO3 requires C, 58.18; H, 4.27; N, 8.48%); Rf (25% EtOAc/hexane) 0.50; [α]D20−1.51 (c 2.0, CHCl3); {lit., [α]D18+2.5 (c 2.8, CHCl3, S}; HPLC analysis using a Chiralpak AD column showed it to be 60% ee [hexane: 2-propanol=9:1, flow rate 0.8 cm3 min−1]; νmax (neat/cm−1) 3113, 2995, 1517, 1343, 1301, 1042, 983, 888, 788, 740; δH (300 MHz; CDCl3) 2.80 (1H, dd, J 2.5 and 4.8, HCOCHH), 3.21 (1H, dd, J 3.9 and 4.8, HCOCHH), 3.97 (1H, dd, J 2.5 and 3.9, PhCHOCH2), 7.40-7.75 (2H, m, 2×CH, arom.) and 8.01-8.24 (2H, m, 2×CH, arom.); δC (300 MHz; CDCl3) 51.7 (CH2), 51.9 (CH), 126.0, 126.4, 145.4 and 148.6 (6×C-Ph); MS m/z (rel. intensity %): 165 (M+, 18), 150(32), 136(68), 120(25), 105(17), 90(100), 77(22), 74(12), 65(52), 63 (59).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:17]([F:19])[F:18])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][NH:11][C:12](=[O:14])[CH:13]=2)[CH:7]=1.Br[CH:21]([CH3:25])[C:22]([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:17]([F:19])[F:18])=[C:6]([C:8]2[C:9]([C:15]#[N:16])=[CH:10][N:11]([CH:21]([CH3:25])[C:22]([OH:24])=[O:23])[C:12](=[O:14])[CH:13]=2)[CH:7]=1
Reactant: CC(Br)C(=O)O
Reactant: N#Cc1c[nH]c(=O)cc1-c1cc(Cl)ccc1C(F)F
Product: CC(C(=O)O)n1cc(C#N)c(-c2cc(Cl)ccc2C(F)F)cc1=O

Procedure:
88 mg (0.31 mmol) of 4-[5-chloro-2-(difluoromethyl)phenyl]-6-oxo-1,6-dihydropyridin-3-carbonitrile and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 45° C. Yield: 88 mg (purity 92%, 73% of theory)
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=O)[CH3:12])[CH:7]=[CH:8][CH:9]=1)#[N:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C[Si]([N:33]=[N+:34]=[N-:35])(C)C.[Cl-].N>C(#N)C>[CH3:12][C:11]1[N:10]([C:6]2[CH:5]=[C:4]([CH2:3][C:1]#[N:2])[CH:9]=[CH:8][CH:7]=2)[N:35]=[N:34][N:33]=1
Reactant: CC(=O)Nc1cccc(CC#N)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: N
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Solvent: CC#N
Product: Cc1nnnn1-c1cccc(CC#N)c1
Reaction time: 0.08 h
Yield: 45.6 %

Procedure:
To a solution of N-(3-cyanomethyl-phenyl)-acetamide (500 mg, 2.87 mmol) in anhydrous acetonitrile (5 mL) was added trifluoromethanesulfonic anhydride (1.62 g, 5.74 mmol) slowly at −5° C. The resulting mixture was stirred for 5 min, trimethylsilylazide (1.32 g, 11.48 mmol) was added slowly keeping the temperature below −5° C. The resulting mixture was stirred at −5° C. for 1 h. The reaction was poured into cooled aqueous ammonia chloride and extracted with ethyl acetate three times. The combined organic layers were dried over sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (1-2% MeOH in DCM) to afford the title compound (260 mg, 1.31 mmol, 45% yield) as a yellow solid. MS (ESI) m/z 199.9 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6].[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:16]=1[C:17](Cl)=[O:18]>ClCCl>[Cl:14][C:15]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:16]=1[C:17]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:5][CH3:6])=[CH:9][CH:10]=1)=[O:18]
Reactant: CCOc1ccccc1
Reactant: O=C(Cl)c1cc(I)ccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2cc(I)ccc2Cl)cc1
Temperature: 6 °C
Reaction time: 2 h

Procedure:
A jacketed 2 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and pressure-equalized addition funnel with gas bubbler was charged with aluminum chloride (97.68 g, 0.733 mol, 1.04 equiv), dichloromethane (0.65 L, KF=0.003 wt % water) and the suspension was set stirring under nitrogen and was cooled to about 6° C. Then ethoxybenzene (90 mL, 0.712 mol, 1.01 equiv) was added over 7 minutes keeping internal temperature below 9° C. The resulting orange solution was diluted with dichloromethane (75 mL) and was cooled to −7° C. Then a solution of 2-chloro-5-iodobenzoyl chloride (≦0.706 mol) in 350 mL dichloromethane was added over 13 minutes keeping the internal temperature below +3° C. The reaction mixture was warmed slightly and held at +5° C. for 2 hours. HPLC analysis suggested the reaction was complete and the reaction was quenched into 450 mL pre-cooled (˜5° C.) 2N aq. HCl with stirring in a jacketed round bottom flask. This quench was done in portions over 10 min with internal temperature remaining below 28° C. The quenched biphasic mixture was stirred at 20° C. for 45 min and the lower organic phase was washed with 1N aq. HCl (200 mL), twice with saturated aq. sodium bicarbonate (200 mL per wash), and with saturated aq. sodium chloride (200 mL). The washed extract was concentrated on a rotary evaporator to afford crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone as an off-white solid (268.93 g, 99.0 area % by HPLC at 220 nm, 1.0 area % regioisomer at 200 nm, 98.5% “as-is” yield).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([Cl:11])[N:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.[NH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1>>[Cl:11][C:6]1[C:7]2[CH2:8][CH2:9][N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:2]=2[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:5]=1
Reactant: ClCCc1c(Cl)nc(N2CCOCC2)nc1Cl
Reactant: Nc1cccnc1
Product: Clc1nc(N2CCOCC2)nc2c1CCN2c1cccnc1
Yield: 0.1 %

Procedure:
In the same manner as Example 1-B-01, from 4-[4,6-dichloro-5-(2-chloroethyl)-pyrimidin-2-yl]-morpholine (1.25 g) and 3-aminopyridine (1.97 g), the desired compound (pale yellow powder, 1.07 mg, 88%) was obtained.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:17]([CH2:18]/[CH:19]=C(\C)/CCC(OC)=O)=[C:16]([CH2:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:32]OS([O-])=O.[K+]>C(Cl)Cl.CO.N1C=CC=CC=1>[Si:1]([O:8][C:9]1[C:17]([CH2:18][CH:19]=[O:32])=[C:16]([CH2:28][CH3:29])[C:15]([CH3:30])=[C:14]2[C:10]=1[C:11](=[O:31])[O:12][CH2:13]2)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=S([O-])OO
Reactant: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1C/C=C(\C)CCC(=O)OC)C(=O)OC2
Agent: [K+]
Solvent: c1ccncc1
Solvent: CO
Solvent: ClCCl
Product: CCc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC=O)C(=O)OC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of methyl (E)-6-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate (10.6 g) in methylene chloride (150 ml), methanol (150 ml) and pyridine (5 ml) was treated with an excess of Oxone® -70° C. The reaction was quenched with dimethylsulfide (20 ml) and stirred for 5 hours at 25° C. The reaction mixture was poured into 1N aqueous sodium hydrogen sulfate. Extraction with 1:1 ethyl acetate:hexane gave an oil which on purification by silica gel chromatography gave 2-(4-t-butyldimethylsilyloxy-1,3-dihydro-6-ethyl-7-methyl-3-oxoisobenzofuran-5-yl)-acetaldehyde, m.p. 90.9°-91.6° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[Cl-].[OH:11][NH3+:12].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.C(O)C>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[N:12][OH:11]
Reactant: [NH3+]O
Reactant: Cc1ccccc1C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C=NO
Yield: 70.7 %

Procedure:
A mixture of 2-methylbenzaldehyde (10.8 g, 90 mmol), hydroxylammonium chloride (9.4 g, 135 mmol), sodium hydroxide (18.0,0.45 mol), ethanol (80 ml) and water (20 ml) was heated at reflux for 1 h. A solution of citric acid (20 g) in water (700 ml) was added and the mixture was left for crystallisation. The precipitate was collected and recrystallised from water to give 8.6 g of 2-methylbenzaldehyde oxime. M.p. 49.0-49.4° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.Cl[C:10]1[N:15]=[C:14]([C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[CH:17]=2)[CH:13]=[CH:12][N:11]=1>CN1C(=O)CCC1>[CH3:25][N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:1][C@H:2]3[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]3)[N:15]=2)=[CH:17]1
Reactant: Cn1cc(-c2ccnc(Cl)n2)c2ccccc21
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CN1CCCC1=O
Product: Cn1cc(-c2ccnc(N[C@H]3CC[C@H](O)CC3)n2)c2ccccc21
Temperature: 120 °C

Procedure:
trans-4-Aminocyclohexanol (0.45 g, 4 mmol) was added to 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole (0.23 g, 1 mmol) in NMP (8 mL), and the resulting mixture heated to 120° C. for 3 h. A second aliquot of trans-4-aminocyclohexanol (0.16 g, 1 mmol) was added, and the resulting mixture was heated to 130° C. The reaction mixture was cooled and partitioned between water and EtOAc, the organic layer separated, washed twice with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was recrystallized from DCM/EtOAc/hexanes to give trans-4-[4-(1-methyl-1H-indol-3-yl)-pyrimidin-2-ylamino]-cyclo-hexanol (148 mg, 46% yield) as a light-yellow solid. MS=323 [M+H]+; MP=194.5-195.3° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([Sn](CCCC)(CCCC)[C:21]1[S:22][CH:23]=[CH:24][N:25]=1)CCC>O1CCOCC1.C(Cl)Cl.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>[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1ccc2nc(Br)sc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc2nc(-c3nccs3)sc2c1
Temperature: 130 °C
Yield: 84.5 %

Procedure:
A mixture of ethyl 2-bromo-benzothiazole-6-carboxylate 1w (150 mg, 0.53 mmol), 2-tributylstannylthiazole 9p (0.25 mL, 0.79 mmol), and Pd(PPh3)4 (30 mg, 0.03 mmol) in dioxane (2 mL) was heated at 130° C. for 30 min under microwave. The reaction mixture was diluted with CH2Cl2, washed with aq. NaHCO3, dried over Na2SO4, and concentrated. Purification by flash column chromatography (silica gel, 10% EtOAc/heptane) gave 9q (130 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:5]=[C:4]([NH:16][C:17]([CH3:23])([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>ClC1C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:2]3[N:7]=[C:6]([NH:8][C:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:11])[CH3:12])[N:5]=[C:4]([NH:16][C:17]([CH3:22])([CH3:23])[C:18]([CH3:19])([CH3:21])[CH3:20])[N:3]=3)[CH2:34][CH2:33]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)C(C)(C)Nc1nc(Cl)nc(NC(C)(C)C(C)(C)C)n1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: Clc1ccccc1
Product: COc1ccc(N2CCN(c3nc(NC(C)(C)C(C)(C)C)nc(NC(C)(C)C(C)(C)C)n3)CC2)cc1

Procedure:
A mixture of 6.84 g. of 2-chloro-4,6-bis[(1,1,2,2-tetramethylpropyl)amino]-s-triazine and 7.69 g. of N-(p-methoxyphenyl)piperazine (prepared from the commercially available dihydrochloride salt) in 150 ml. of chlorobenzene is refluxed for 5 hours and then cooled. The reaction mixture is washed with two 25 ml. portions of water. The organic layer is dried over anhydrous potassium carbonate and magnesium sulfate and the solvent is stripped with a water pump. The residual amber oil is crystallized by slurrying in isopropanol. Recrystallization from 150 ml. of propanol (using charcoal for decolorization) gives the desired product as a white solid, m.p. 155°-157° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25](O)=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.CC[N:31]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][C:25]([NH2:31])=[O:26])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)CC1=O
Agent: N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)CC1=O
Reaction time: 8 h

Procedure:
The solution of 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-2-oxopiperidin-4-yl)propanoic acid (28 mg, 0.063 mmol), EDCI (38 mg, 0.189 mmol), HOBt (26 mg, 0.189 mmol), and DIEA (82 mg, 0.63 mmol) in CH2Cl2 was filled with NH3 at 0° C. The mixture was stirred overnight, and washed with water. The organic phase was separated and concentrated to give the crude product, which was purified by preparative HPLC to afford 3-((S)-1-((S)-1-(4-bromophenyl)ethyl)-4-(4-fluorophenyl)-2-oxopiperidin-4-yl)propanamide (6 mg, 21%□. LC-MS Method 2, tR=1.869 min, m/z=447. 1H NMR (CDCl3): δ 1.46 (d, 3H), 1.77 (m, 1H), 1.92 (m, 1H), 1.96 (m, 1H), 2.08 (m, 1H), 2.14 (m, 3H), 2.24 (m, 1H), 2.51 (d, 1H), 3.02 (m, 1H), 3.12 (m, 1H), 5.32 (m, 1H), 5.71 (m, 1H), 5.94 (q, 1H), 6.76 (m, 2H), 6.99 (m, 2H), 7.16 (m, 2H), 7.24 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[CH:16]=O)([CH3:7])[CH3:6])[CH3:2].[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1.N1CCCC1>CO>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1/[CH:16]=[C:24]1\[C:25](=[O:29])[NH:26][C:27]2[C:23]\1=[CH:22][CH:21]=[C:20]([Cl:19])[CH:28]=2)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C=O
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: CO
Solvent: C1CCNC1
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C
Yield: 77.9 %

Procedure:
2-(4-chloro-2-formyl-phenoxy)-2-methyl-propionic acid ethyl ester (7 g, 26 mmol) and 6-chlorooxindole (3.6 g, 22 mmol) were mixed in anhydrous methanol (30 mL) at room temperature. Then pyrrolidine (1.85 g, 26 mmol) was added slowly. The reaction mixture was heated at 70° C. for 3 h. Then the mixture was cooled to room temperature and filtered. The precipitate was dried and collected to give E/Z-2-[4-chloro-2-(6-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-phenoxy]-2-methyl-propionic acid ethyl ester as a yellow solid (7.2 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6]([C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1)=[O:7].[S:17]1[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23].C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[N:16]1[CH:15]=[CH:14][N:13]2[C:8]([S:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:19]3[C:20](=[O:22])[CH2:21][S:17][C:18]3=[O:23])=[O:7])=[CH:9][CH:10]=[CH:11][C:12]=12
Reactant: O=S(CCCCCl)c1cccc2nccn12
Reactant: O=C1CSC(=O)N1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=C1CSC(=O)N1CCCCS(=O)c1cccc2nccn12
Temperature: 80 °C

Procedure:
To a solution of 0.51 g (2.0 mmol) of 5-(4-chlorobutylsulfinyl)imidazo[1,2-a]pyridine and 0.355 g (2.0 mmol) of thiazolidine-2,4-dione in 10 ml of N,N-dimethylformamide, 0.30 ml (2.0 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by heating at 80° C. for 16 hours. After cooling, the reaction mixture was poured into water, extracted with ethyl acetate, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, chloroform→chloroform/methanol=50/1) to yield 0.33 g (49.0%, light yellow oily substance) of the desired product.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([OH:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[N:5]1.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=1>CN(C)C(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:9][C:8]2[N:4]([CH3:3])[N:5]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:7]=2)[N:16]=1
Reactant: Cn1nc(C(F)(F)F)cc1O
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cn1nc(C(F)(F)F)cc1Oc1cccc(Cl)n1
Temperature: 135 °C

Procedure:
1.8 g (71 mmol) of sodium hydride (95 percent) was suspended in 25 ml of N,N-dimethylacetamide. A solution of 12.46 g (67 mmol) of 1-methyl-5-hydroxy-3-(trifluoromethyl)pyrazole (J. Heterocycl. Chem. 1990, 27, 243) in 40 ml of N,N-dimethylacetamide was added dropwise over 1 hour at 22° C. The resulting solution was added dropwise over 3 hours, under nitrogen, to a solution of 18.5 g (125 mmol) of 2,6-dichloropyridine in 37.5 ml of N,N-dimethylacetamide, heated to 135° C. After a further 5 hours of reaction time, the mixture was cooled to room temperature, the sodium chloride which had precipitated out was filtered off and the filtrate was concentrated. The residue was taken up with toluene and water and the organic phase was washed with saturated sodium chloride solution and concentrated. The solid residue was distilled under vacuum. The title compound distills at 175° C. under 25 mbar. This gave 12.5 g of crude product in the form of a yellow solid (96 percent pure, GC). This was purified by recrystallization from diisopropyl ether. The yield was 11.55 g (62 percent) of colorless crystals, content (GC): 99.9 percent. Other data concerning the product was:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10])#[N:2].C(N(CC)CC)C.Cl.[F:21][C:22]([F:30])([F:29])[CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1COCC1>[F:21][C:22]([F:30])([F:29])[CH:23]1[CH2:28][CH2:27][N:26]([S:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])(=[O:11])=[O:10])[CH2:25][CH2:24]1
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1ccccc1S(=O)(=O)N1CCC(C(F)(F)F)CC1
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To 2-cyanobenzene-1-sulfonyl chloride (201 mg, 1.00 mmol) in THF (5 mL), triethylamine (0.84 mL, 6.00 mmol) and 4-trifluoromethylpiperidine hydrochloride (284 mg, 1.50 mmol) were added. After stirring for 2 h, the reaction was concentrated and diluted with ethyl acetate and washed with water. After drying (Na2SO4), filtering, and concentrating, the residue was purified via silica gel chromatography eluting with 45% ethyl acetate/hexanes to provide 2-(4-(trifluoromethyl)piperidin-1-ylsulfonyl)benzonitrile [95 mg, LC-MS: 319.19 (M+H)+]. The product (52 mg) was dissolved in MeOH (5 mL), conc. HCl (25.0 mg) was added, and the whole was hydrogenated at 50 psi overnight. The reaction was concentrated and purified via preparative HPLC(CH3CN/water/TFA) to provide 210A. LC-MS: 323.21 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([C:11]#[C:12][CH2:13]OS(C)(=O)=O)=[CH:8][C:6]=2[N:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(#N)C>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([C:11]#[C:12][CH2:13][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)OCC#Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CN1CCN(CC#Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of methanesulfonic acid 3-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-prop-2-ynyl ester (150 mg), potassium carbonate (64 mg), N-methylpiperazine (45 μL) and acetonitrile (5 ml) were stirred at 50° C. for 3 hours. The reaction mixture was then cooled, diluted with dichloromethane, washed with brine, dried (MgSO4) and the solvents reduced in vacuo to yield 2-chloro-6-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (101 mg).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[C:7](Cl)=[N:8][CH:9]=[N:10][C:11]=2[Cl:12])=O)[CH2:3][CH2:2]1.[NH2:14][NH2:15]>C1COCC1>[Cl:12][C:11]1[N:10]=[CH:9][N:8]=[C:7]2[NH:14][N:15]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:6]=12
Reactant: O=C(c1c(Cl)ncnc1Cl)C1CC1
Reactant: NN
Solvent: C1CCOC1
Product: Clc1ncnc2[nH]nc(C3CC3)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.4 %

Procedure:
A mixture of Cyclopropyl-(4,6-dichloro-pyrimidin-5-yl)-methanone (0.75 g, 3.5 mmol), anhydrous hydrazine (0.13 mL, 4.1 mmol) and THF (35 mL) was stirred at room temperature for 4 hours. The reaction was partitioned between water and EtOAc. The organic layer was washed with brine, dried and passed through a short silica gel pad to give 4-Chloro-3-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidine (0.50 g, 74%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 11.87 (s, 1H), 8.80 (s, 1H), 2.55 (m, 1H), 1.15 (m, 2H), 1.14 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH2:6][CH:5]([C:7]([O:9]CC)=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.BrC1C=C(C(OCC)=O)N(C2C(Cl)=CC=CN=2)N=1>>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=[O:8])[N:4]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: CCOC(=O)C1CC(Br)=NN1c1ncccc1Cl
Agent: CCOC(=O)c1cc(Br)nn1-c1ncccc1Cl
Product: O=C(O)c1cc(Br)nn1-c1ncccc1Cl

Procedure:
The following Example 10 illustrates an alternative preparation of ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate, which can be used to prepare, for example, ethyl 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (i.e. product of Example 9, Step B).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.C([Mg]Br)C=C.[C:14]([N:21]1[CH2:26][CH2:25][N:24]([C:27]2[O:32][C:31](=[O:33])[C:30]3[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:29]=3[N:28]=2)[CH2:23][CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>O1CCCC1>[C:14]([N:21]1[CH2:22][CH2:23][N:24]([C:27]([NH:28][C:29]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:30]=2[C:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=2)=[O:33])=[O:32])[CH2:25][CH2:26]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3ccc(Cl)cc3c(=O)o2)CC1
Agent: C=CC[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.3 %

Procedure:
To a stirred solution of 2-amino-5-chloropyridine (0.6 g, 4.64 mmol) in tetrahydrofuran (80 mL) at 0° C. under nitrogen was added allylmagnesium bromide (1.0 M in ether, 4.7 mL, 4.7 mmol) dropwise via a syringe. After stirring at 0° C. for 10 min, 2-(4-Boc-1-piperazinyl)-6-chloro-4H-3,1-benzoxazin-4-one (0.8 g, 2.19 mmol) was added. After stirring 15 h at room temperature, the solvent was removed in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium chloride and the layers separated. The organic phase was washed with water, dried (magnesium sulfate), filtered, and concentrated in vacuo to give 0.88 g (82%) of the title compound as a white solid.