Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:19]#[C:20][CH2:21][NH:22][C:23]([CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:24]>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1/[CH:19]=[CH:20]\[CH2:21][NH:22][C:23]([CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29]1)=[O:24]
Reactant: O=C(NCC#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)C1CCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(NC/C=C\c1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)C1CCCC1
Yield: 99.1 %

Procedure:
Dissolve 7-chloro-6-[3-(cyclopentanecarbonyl-amino)-prop-1-ynyl]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (170 mg, 0.4 mmol) in EtOAc (50 mL) and submit the mixture to hydrogenation over 10% Pd/C (85 mg) at 15 psi for 10 mins. Filter the mixture through Celite® and concentrate the filtrate to give 7-chloro-6-[(Z)-3-(cyclopentanecarbonyl-amino)-propenyl]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a pale yellow solid (170 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.ClCCl.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:17][C:13]1[CH:12]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1nnc2ccc(-c3cccc([N+](=O)[O-])c3)nn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Temperature: 20 °C

Procedure:
An 11.0 g portion of 3-methyl-6-(3-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine and 41.0 g portion of anhydrous stannous chloride were dissolved in 500 ml of anhydrous ethanol and heated to reflux for 3 hours. The solution was cooled to 20° C. and poured onto 200 g of crushed ice and 500 ml of dichloromethane. A saturated aqueous solution of sodium bicarbonate was added until pH=7. The mixture was filtered and the salts washed with five 100 ml portions of hot ethyl acetate. The organic layers were combined, dried over magnesium sulfate and the volatiles removed in vacuo. The residue was passed through a short column (50 g) of anhydrous magnesium silicate with dichloromethane-methanol (95:5) as eluent. The fractions containing product were collected, evaporated and recrystallized from dichloromethane-hexane to afford 8 g of the desired compound as yellow needles, mp 206°-208° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][O:24][CH2:23][O:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]>C1COCC1.CO.O.[Li+].[OH-]>[C:26]1([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([CH:20]3[CH2:21][O:22][CH2:23][O:24][CH2:25]3)[C:11]([C@H:13]3[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]3)=[O:12])[CH:8]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1COCOC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)C2COCOC2)CC1

Procedure:
Crude 5-cyclohex-1-enyl-3-[[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (24 mg) was dissolved in a mixture of THF, MeOH and H2O (3:2:1) (1.8 mL) and 1N LiOH (0.15 mL) was added. Rest of the procedure has been described earlier (example 3, step VIII). Pure 5-cyclohex-1-enyl-3-[[1,3]dioxan-5-yl-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid was obtained by preparative HPLC.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:8][CH:7]=1)=[O:4].[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>CN(C=O)C>[F:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH:20][CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:8][CH:7]=1)=[O:4]
Reactant: Nc1ccccc1F
Reactant: CCCCOc1ccc(NC(=O)CBr)cc1
Solvent: CN(C)C=O
Product: CCCCOc1ccc(NC(=O)CNc2ccccc2F)cc1
Temperature: 0 °C
Yield: 45.2 %

Procedure:
A solution of 4-((bromoacetyl)amino)-1-butoxybenzene (1.0 g, 3.5 mmol) and 2-fluoroaniline (1.0 g, 0.87 mL, 8.8 mmol) in anhydrous DMF (30 mL) was heated to 90°-100° C. overnight with stirring under N2. The solution was cooled, poured into 500 mL of ice-water, and then extracted with CH2Cl2 (3×50 mL). The layers were separated and the organic layer was dried (MgSO4), filtered and then concentrated to an oily residue. Purification by chromatography, eluting with hexane-ethyl acetate (2:1), afforded 0.50 g (45%) of the title compound, mp 92°-94° C.: 1H NMR (DMSO-d6) δ9.86 (s, 1H), 7.47 (d, J=8.8, 2H), 7.04 (ddd, J=9.6, J=8.0, J=1.2, 1H), 6.94 (dt, J=8.0, J=0.8, 1H), 6.86 (d, J=9.6, 2H), 6.63-6.58 (m, 2H), 5.73 (bt, J=2.0, 1H), 3.90 (q, J=6.0, 2H), 3.46 (s, 2H), 1.68-1.64 (m, 2H), 1.44-1.40 (m, 2H), 0.91 (t, J=5.6, 3H); 13C NMR (DMSO-d6) δ168.24, 154.69, 150.90 (d, J=236), 136.46, 131.79, 124.73 (d, J=3.5), 120.79, 116.22 (d, J=6.3), 114.48 (d, J=5.6), 114.33 (d, J=126), 112.11 (d, J=3.6), 67.21, 46.57, 30.75, 18.70, 13.66; MS (El, m/z) 316 (M+).
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27])=[CH:20]2>CC(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([S:26]([N:29]1[CH2:34][CH2:33][N:32]([C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([N:2]4[CH:6]=[CH:5][N:4]=[CH:3]4)=[CH:15][CH:14]=3)[CH2:31][CH2:30]1)(=[O:28])=[O:27])=[CH:20]2
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Reactant: O=S(=O)(c1cc2cc(Cl)ccc2[nH]1)N1CCNCC1
Agent: Cl
Solvent: CC(C)=O
Product: O=C(c1ccc(-n2ccnc2)cc1)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Yield: 60 %

Procedure:
By an analogous method, starting from 4-(1-imidazolyl)benzoic acid hydrochloride and 1-(5-chloroindol-2-ylsulphonyl)piperazine, was prepared 1-(5-chloroindol-2-ylsulphonyl)-4-[4-(1-imidazolyl)benzoyl]piperazine (375 mg, 60% yield) as colourless crystals from acetone; m.p. 155-165° C., 1H NMR (d6DMSO) 3.0-3.2 ppm (broad s, 4H), 3.4-3.8 ppm (broad s, 4H), 7.0 ppm (s, 1H), 7.1 ppm (s, 1H), 7.3 ppm (dd, 1H), 7.5 ppm (m, 3H), 7.7 ppm (d, 2H), 7.8 ppm (m, 2M), 8.3 ppm (s, 1H), 12.4 ppm (broad s, 1H), the spectrum also contained a signal due to acetone, ca 0.05 mol. eq.; MS (M+H)+ 470/472.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C1CCCCC=1>CO>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: C1=CCCCC1
Solvent: CO
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
Dov-Leu-Dil-OBut (5) was prepared as follows: A solution of Z-Leu-Dil-OBut (3, 2.22 mM) was dissolved in anhydrous methanol (10 mL) and cyclohexene (10 mL) was added in a nitrogen atmosphere. To the solution was added 5% Pd--C (1.15 g) and the mixture was heated at reflux for 6 minutes. The catalyst was removed by filtering through a layer of celite, the solvent removed under reduced pressure, and the residue dried in high vacuum for 2 hours.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.Br[C:40]1[CH:41]=[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:43]=[N:44][CH:45]=1.CCCCCCC>C1(C)C=CC=CC=1.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>[F:20][C:17]([F:18])([F:19])[C:15]1[CH:14]=[C:13]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=2)[N:12]=[C:11]([N:9]2[CH:10]=[C:6]([C:40]3[CH:41]=[C:42]([S:46]([NH2:49])(=[O:48])=[O:47])[CH:43]=[N:44][CH:45]=3)[N:7]=[CH:8]2)[CH:16]=1
Reactant: NS(=O)(=O)c1cncc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: NS(=O)(=O)c1cncc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)c1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.503 g, 0.7 mmol), commercially available 5-bromo-pyridine-3-sulfonic acid amide (0.183 g, 0.77 mmol), tetrakis(triphenylphosphine)palladium (0.040 g, 0.030 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (258 mg, 72%). MS (ISP) 514.2 [(M+H)+]; mp>250° C.
Reaction SMILES: [OH-:1].[K+].Br[CH:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][C:7]([CH3:13])([CH3:12])[CH:6](Br)[C:5]1=[O:15]>O>[OH:15][C:5]1[C:6](=[O:1])[C:7]([CH3:13])([CH3:12])[CH2:8][C:9]([CH3:11])([CH3:10])[CH:4]=1
Reactant: [OH-]
Reactant: CC1(C)CC(C)(C)C(Br)C(=O)C1Br
Agent: [K+]
Solvent: O
Product: CC1(C)C=C(O)C(=O)C(C)(C)C1
Reaction time: 24 h

Procedure:
To a stirred solution of potassium hydroxide (50 g) in 1500 ml of distilled water was added the brominated compound of step 1 (50 g). Stirring was continued for 24 hours. The solution was filtered to remove brominated compound which had not dissolved. The filtrate was cooled in an ice bath and concentrated sulphuric acid added dropwise until a white solid precipitated. The mixture was stirred for 30 minutes, after which the white solid was collected and recrystallized from a hot mixture of 200 ml of methanol and 100 ml of water, giving 2-hydroxy-4,4,6,6-tetramethylcyclohex-2-enone as white crystals, 13.5 g, melting range 85°-86° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:17])(O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Br:15])[CH:2]=1.C[O:19][CH:20](OC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1.C1(C)C=CC=CC=1>[C:21]1([CH:20]2[O:17][CH:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Br:15])[O:19]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(OC)c1ccccc1
Reactant: OC(O)(Cc1ccccc1Br)c1cccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: Brc1ccccc1C1OC(c2ccccc2)OC1c1cccnc1

Procedure:
37 g (0.1258 mol) of 1-(pyrid-3-yl)-2-(2-bromophenyl)-ethanediol and 38.5 g (0.2516 mol) of benzaldehyde dimethyl acetal were refluxed together in 440 ml of 10:1 chlorobenzene/toluene with 1 g of p-toluenesulfonic acid. The resulting methanol was distilled off as an azeotrope with toluene. After the end of the reaction, the chlorobenzene was distilled off under reduced pressure and the product wa purified by chromatography over silica gel.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[CH:11]=[C:12]([C:16]([OH:18])=O)[S:13][C:14]=2[CH3:15])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(OC(=O)[NH:52][C@@H:53]1[CH2:58][CH2:57][CH2:56][C:55]([F:60])([F:59])[C@@H:54]1[NH2:61])(C)(C)C.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>O.ClCCl>[NH2:52][C@H:53]1[C@@H:54]([NH:61][C:16]([C:12]2[S:13][C:14]([CH3:15])=[C:10]([C:3]3[N:4]4[N:5]=[CH:6][CH:7]=[CH:8][C:9]4=[N:1][CH:2]=3)[CH:11]=2)=[O:18])[C:55]([F:60])([F:59])[CH2:56][CH2:57][CH2:58]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N
Reactant: Cc1sc(C(=O)O)cc1-c1cnc2cccnn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1sc(C(=O)N[C@@H]2[C@H](N)CCCC2(F)F)cc1-c1cnc2cccnn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-(imidazo[1,2-b]pyridazin-3-yl)-5-methylthiophene-2-carboxylic acid (0.06 g, 0.24 mmol) and BOP (0.16 g, 0.36 mmol) was added tert-butyl[(1R,2R)-2-amino-3,3-difluorocyclohexyl]carbamate (0.06 g, 0.26 mmol) followed by diisopropylethylamine (0.09 mL, 0.49 mmol). The mixture was allowed stir at room temperature overnight. The resulting solution was diluted with water and extracted three times with dichloromethane. The combined organic layers were dried with magnesium sulfate, filtered, concentrated and to the resulting residue was added dichloromethane and trifluoroacetic acid (1 mL, 53 mmol). The compound was purified by prep HPLC. The compound was neutralized by taking the fractions and adding an aqueous saturated sodium bicarbonate solution and extracting three times with ethyl acetate. The combined organics were dried with magnesium sulfate, filtered, and concentrated to afford the title compound as a yellow solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.62 (d, 1H); 8.28 (s, 1H); 8.21 (d, 1H); 7.99 (s, 1H); 7.90 (d, 1H); 7.29 (dd, 1H); 4.55 (m, 1H); 3.08 (m, 1H); 2.47 (s, 3H); 2.11 (m, 1H); 1.85 (m, 1H); 1.71 (m, TH); 1.59 (m, 2H); 1.45 (m, 1H). LRMS (APCI) calc'd for (C18H19F2N5OS) [M+H]+, 392.1. found 392.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19](=O)[CH3:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].S(O)(O)(=O)=O.[NH2:33][OH:34]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19](=[N:33][OH:34])[CH3:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[CH:12]=[N:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1
Reactant: NO
Reactant: COc1ccc(COc2ccc(C(C)=O)cc2OC)cn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(COc2ccc(C(C)=NO)cc2OC)cn1
Temperature: 25 °C
Reaction time: 64 h
Yield: 96.3 %

Procedure:
To a stirred suspension of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one (5.48 g, 19.07 mmol) and potassium carbonate (10.54 g, 76.29 mmol) in methanol (100 mL) and water (10 mL) was added hydroxylamine sulfate (4.70 g, 28.61 mmol). The resulting mixture was heated to reflux. After 64 h, the mixture was allowed to cool to room temperature and was diluted with water (250 mL). The resulting suspension was filtered, and the filtercake was washed with water (50 mL) and dried to provide 5.55 g (96%) of 1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)phenyl)ethan-1-one oxime as a white solid.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:32]=[CH:31][N:14]3[C:15](=[O:30])[C:16](/[CH:25]=[CH:26]/[C:27](O)=[O:28])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].[CH3:33][S:34]([NH2:37])(=[O:36])=[O:35].CN(C1C=CC=CN=1)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:32]=[CH:31][N:14]3[C:15](=[O:30])[C:16](/[CH:25]=[CH:26]/[C:27]([NH:37][S:34]([CH3:33])(=[O:36])=[O:35])=[O:28])=[C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCOCC4)nc3c2)n1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)NS(C)(=O)=O)c(N4CCOCC4)nc3c2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
(E)-3-{8-[2-(4-Isopropyl-1,3-thiazol-2-yl)ethyl]-2-morpholino-4-oxo-4-H-pyrido -[1,2-a]pyrimidin-3-yl}-2-propenoic acid (24 mg) was dissolved in dimethylformamide (2 ml), added with methanesulfonamide (15 mg), dimethylaminopyridine (20 mg) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (31 mg), and then the mixture was stirred at room temperature for 24 hours. The reaction solution was added with ethyl acetate and hexane, washed with 0.2 M hydrochloric acid, and dried over sodium over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (14 mg) as yellow powder.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[CH:26][C:27]=1[CH3:28].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:24]3[CH:25]=[CH:26][C:27]([CH3:28])=[C:22]([CH3:21])[CH:23]=3)[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(Cl)cc1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(C(C)(C)C)n3)CC2)cc1C

Procedure:
199 mg (87%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-chlorophenyl)-1H-pyrazol-3-yl)propanal (80 mg, 0.275 mmol), 1-(3,4-dimethylphenyl)piperazine (52 mg, 0.275 mmol), DIPEA (0.072 mL, 0.413 mmol) and NaBH(OAc)3 (175 mg, 0.825 mmol).
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][CH:6]2[CH:5]([O:13]C(OCC)C)[CH2:4][C:3]1=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(=O)([O-])O.[Na+].C(OCC)C>C(O)C>[CH2:1]=[C:2]1[CH:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][CH:6]2[CH:5]([OH:13])[CH2:4][C:3]1=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: C=C1C(=CC(=O)OCC)CC(OC(C)OCC)C2OC(C)(C)OC12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: C=C1C(=CC(=O)OCC)CC(O)C2OC(C)(C)OC12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Ethyl (2-methylene-3,4-(dimethylmethylenedioxy)-5-(1-ethoxyethoxy)cyclohexylidene)acetate was dissolved in 5 ml of ethanol, and a catalytic amount of pyridinium p-toluenesulfonate was added, followed by stirring at room temperature for 15 minutes. A sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and extraction was conducted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford 0.202 g of ethyl (2-methylene-3,4-(dimethylmethylenedioxy)-5-hydroxycyclohexylidene)acetate having the following property.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH:11]([CH2:16][N+:17]([O-])=O)[CH2:12][N+:13]([O-])=O>[Pt].[Pd].[Ni].CO>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH:11]([CH2:16][NH2:17])[CH2:12][NH2:13])=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(C[N+](=O)[O-])C[N+](=O)[O-]
Agent: [Ni]
Agent: [Pd]
Agent: [Pt]
Solvent: CO
Product: Cc1cc(N)ccc1C(CN)CN
Yield: 101.4 %

Procedure:
A pressure flask was charged with 2-methyl-4-nitro-1-(2-nitro-1-nitromethyl-ethyl)-benzene (29.6 g, 0.11 mol), 10 wt % platinum on carbon (3.0 g), 10 wt % palladium on carbon (9.0 g, 50 wt % water), Raney nickel (9.0 g, wet), and methanol (740 mL) under a nitrogen blanket. After attaching the flask to the hydrogenation apparatus, it was subjected to three vacuum degas-nitrogen purge cycles, followed by three nitrogen outgas-hydrogen purge cycles. The vigorously stirred suspension was held under 60 psi hydrogen pressure at 55-60° C. for at least 72 h. The reaction mixture was filtered through a celite pad (15 g) rinsing with methanol (600 mL). The filtrate was concentrated to dryness under reduced pressure to give the crude title compound as a red-brown gum (20 g, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[NH:20][CH2:19][C:18]2[CH:21]=[CH:22][S:23][C:17]=2[CH2:16]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH:15]([CH3:14])[CH2:16][C:17]4[S:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1Cc2sccc2CN1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1Cc2sccc2CN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 51 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)(=[O:35])=[O:34])[C:27]=2[F:41])[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:43]>>[NH2:43][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][S:33]([C:36]3[CH:40]=[CH:39][O:38][CH:37]=3)(=[O:35])=[O:34])[C:27]=2[F:41])[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(N)n3)s2)CC1
Temperature: 90 °C
Yield: 96 %

Procedure:
A suspension of 1,1-dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-1-piperidinecarboxylate (53 mg, 0.085 mmol) in ammonium hydroxide solution (28%, 2 mL, 51.4 mmol) sealed in a 5-mL microwave tube was heated at 90° C. for 3 h under the microwave conditions. The mixture was concentrated and dried under high vacuum to give 49 mg of the title compound. MS (ESI): 501.1 [M+1]+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH3:6][O:5][C:3](=[O:4])[CH2:2][NH:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CBr
Reactant: NCc1ccccc1
Solvent: ClCCl
Product: COC(=O)CNCc1ccccc1
Yield: 86 %

Procedure:
In scheme 6b), methyl bromoacetate 22 is treated with benzylamine in CH2Cl2 at room temperature for 16 h. The N-benzylglycine methyl ester derivative 23 was obtained in 86% yield. This intermediate can be either acylated with a carboxylic acid derivative and DCC in THF or sulfonated with an appropriate sulfonyl chloride and triethylamine in CH2Cl2 to give derivative 24 or 25 as desired in good to excellent yields.
Reaction SMILES: [BH4-].[Na+].[Br-].[CH2:4]([N+:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([NH:18][C:19]([O:21][CH3:22])=[O:20])[CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>CO>[CH2:4]([N:11]1[CH2:16][CH2:15][C:14]([CH3:17])=[C:13]([NH:18][C:19](=[O:20])[O:21][CH3:22])[CH2:12]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)Nc1c[n+](Cc2ccccc2)ccc1C
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)NC1=C(C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.5 %

Procedure:
Sodium borohydride (4.4 g, 116 mmol, 1.20 equiv.) was added in several batches to a solution of 1-benzyl-3-methoxycarbonylamino-4-methyl-pyridinium bromide (35 g, 104 mmol, 1.00 equiv.) in methanol (300 mL). The resulting solution was stirred at ambient temperature for about 16 hours, and then water (200 mL) was added. After concentrating the mixture in vacuo, standard extractive workup with ether (3×200 mL) gave a crude residue that was then purified by silica gel column chromatography (dichloromethane/methanol (20:1)) to afford the title product as a yellow solid (18 g; yield=66%). LC-MS: m/z=261 (M+H)+.