Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:18][CH:19]1[N:22]([CH2:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21](=[O:34])[CH2:20]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl.CCOCC>[CH2:12]([S:18]([CH:19]1[N:22]([CH2:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21](=[O:34])[CH2:20]1)=[O:9])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCCCSC1CC(=O)N1CC(=O)CCc1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCS(=O)C1CC(=O)N1CC(=O)CCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of m-chloroperbenzoic acid (2.48 g, 0.0144 mol) in dichloromethane (50 ml) was added dropwise to a stirred solution of 4-hexylthio-1-(4-phenyl-2-oxobutyl)azetidin-2-one (4.0 g, 0.012 mol) in dichloromethane (50 ml) at -60° C. Stirring was continued at -60° C. for 30 minutes then the mixture was poured into an aqueous solution of sodium hydrogen carbonate and sodium sulphite. The layers were separated and the aqueous was extracted with dichloromethane. The combined extracts were dried (MgSO4) and evaporated to give a solid which was slurried in ether, filtered, washed with ether and petrol. The solid was recrystallised from ethyl acetate to give the title compound as white crystals, 920 mg, (22%), m.p. 154-5° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]3[C:21]([CH3:27])=[N:22][CH:23]=[N:24][C:25]=3[CH3:26])=[O:19])[CH2:10][CH2:9]2)=[CH:2]1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][C:43](O)=[O:44])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][C:43](=[O:44])[N:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH:14]([CH3:28])[CH2:15][CH2:16][NH:17][C:18]([C:20]3[C:25]([CH3:26])=[N:24][CH:23]=[N:22][C:21]=3[CH3:27])=[O:19])[CH2:12][CH2:13]2)[CH2:6][C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(NCc2ccsc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2ccsc2)C(=O)CC2CCN(C(=O)OC(C)(C)C)CC2)CC1
Yield: 79.8 %

Procedure:
Following general procedure E: a solution of 4,6-dimethyl-pyrimidine-5-carboxylic acid (3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-amide (41 mg, 0.1 mmol), 4-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 0.22 mmol), EDCI (39 mg, 0.20 mmol), HOBT (27 mg, 0.20 mmol), and DIPEA (0.05 ml, 0.3 mmol) in CH2Cl2 (2 ml) was stirred overnight. Purification of the crude product by column chromatography on silica gel (CH2Cl2/MeOH, 9:1) afforded 4-{[(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-thiophen-3-ylmethyl-carbamoyl]-methyl}-piperidine-1-carboxylic acid tert-butyl ester (50 mg, 80%).
Reaction SMILES: C(OC([N:11]([C:20]1[N:49]=[C:23]2[N:24]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:48])([F:47])[F:46])[CH:40]=3)[C:25]([CH3:38])=[C:26]([C:36]#[N:37])[C@@H:27]([C:28]3[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=3)[N:22]2[N:21]=1)[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1>CO.[Pd]>[C:36]([C:26]1[C@@H:27]([C:28]2[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=2)[N:22]2[N:21]=[C:20]([NH:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:49]=[C:23]2[N:24]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([C:45]([F:46])([F:47])[F:48])[CH:40]=2)[C:25]=1[CH3:38])#[N:37]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC(=O)OC(C)(C)C)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NCC(=O)OC(C)(C)C)nc2N1c1cccc(C(F)(F)F)c1

Procedure:
Under an atmosphere of argon protective gas, tert-butyl N-[(benzyloxy)carbonyl]-N-{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}glycinate (23.0 mg, 34 μmol) was dissolved in degassed methanol (2.3 ml). After addition of palladium on activated carbon (10%-ig; 15.2 mg), the mixture was hydrogenated under a hydrogen atmosphere (˜1 atm) at RT for 0.5 h. The reaction mixture was then filtered, the filtrate was concentrated under reduced pressure and the residue was purified by preparative HPLC (Kromasil C18 column, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (21.2 mg, quant.).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:7])=[CH:3]\[C:4](=O)[CH3:5].CO[C:10]1(OC)[CH2:14][CH2:13][CH2:12][N:11]1[CH3:15].C(O[Na])(C)(C)C.CC(O)(C)C>C1(C)C=CC=CC=1>[CH3:15][N:11]1[C:10]2=[N:1][C:2]([CH3:7])=[CH:3][C:4]([CH3:5])=[C:14]2[CH2:13][CH2:12]1
Reactant: CC(=O)/C=C(/C)N
Reactant: COC1(OC)CCCN1C
Agent: CC(C)(C)O[Na]
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: Cc1cc(C)c2c(n1)N(C)CC2
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 2.36 g (23.8 mmol) of (Z)-4-aminopent-3-en-2-one in 8 mL of toluene was added 5.88 g (40.5 mmol) of 2,2-dimethoxy-1-methylpyrrolidine. The reaction mixture was heated at reflux and stirred for 2 h, cooled to 90° C., and then treated with 4.65 g (48.4 mmol) of t-BuONa and 4 mL of t-BuOH. The reaction mixture was stirred at 90° C. for another 16 h. The cooled reaction mixture was quenched by the addition of 20 mL of sat aq NH4Cl. The mixture was extracted with EtOAc. The combined organic layer was washed with brine, dried (MgSO4) and concentrated under diminished pressure. The residue was purified by flash chromatography on a silica gel column (25 2.6 cm). Elution with 10:1 hexanes/ethyl acetate gave the product as a yellow oil: yield 1.60 g (42%); silica gel TLC Rf 0.15 (4:1 hexanes/ethyl acetate); 1H NMR (CDCl3) δ 2.05 (s, 3H), 2.32 (s, 3H), 2.76 (t, 2H, J=8.4 Hz), 2.86 (s, 3H), 3.34 (t, 2H, J=8.4 Hz) and 6.10 (s, 1H); 13C NMR (CDCl3) δ 17.8, 24.0, 24.3, 33.1, 52.4, 113.1, 118.1, 141.2, 154.5 and 163.7; mass spectrum, m/z 162.1 (M+) (theoretical 162.1).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:5]=[C:6]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:7]=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:3]>O=[Mn]=O>[C:2]([C:4]1[CH:14]=[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:7]=[C:6]([CH:5]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:1])[CH3:3]
Reactant: CCOC(=O)c1cc(C(=O)OCC)cc(C(C)O)c1
Agent: O=[Mn]=O
Product: CCOC(=O)c1cc(C(C)=O)cc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.6 %

Procedure:
A stirred solution of diethyl 5-(1-hydroxyethyl)isophthalate (587 mg, 2.2 mmol) and MnO2 (960 mg, 11 mmol) was heated to reflux. After 5 h, the reaction was cooled to room temperature and additional MnO2 (0.6 g) was added and heated to reflux for another 16 h. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to provide diethyl 5-acetylisophthalate (521 mg, 90%) as a white solid. 1H NMR (CDCl3): d 8.62 (s, 1H), 8.56 (s, 2H), 4.32 (q, J=7.2 Hz, 2H), 2.58 (s, 3H), 1.32 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C([O-])(=O)C.[Na+].O>CO>[CH3:16][O:15][C:13](=[O:14])[CH2:12][NH:8][C:7]1[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(C)c1ccc(N)cc1
Reactant: COC(=O)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CNc1ccc(C(C)C)cc1

Procedure:
A solution of 4-isopropylaniline (5.05 g, 37.3 mmol), methyl bromoacetate (5.99 g, 39.2 mmol) and anhydrous sodium acetate (3.21 g) in absolute methanol (30 mL) was heated to reflux for 2 h. The solution was cooled and poured into 300 mL water. The resulting solid was collected by filtration and recrystallized from ethanol/water to afford pure product, methyl-2-(4-isopropylanilino)acetate, m.p. 35-36° C. (4.53 g, 55%). 1H NMR (CDCl3, 300 MHz): δ 7.06 (2H, d, J=8.2 Hz), 6.57 (2H, d, J=8.2 Hz), 4.18 (1H, v br), 3.90 (2H, s), 3.78 (3H, s), 2.81 (1H, m, J=7.0 Hz), 1.20 (6H, d, J=7.0 Hz). Mass spectrum (ES+): m/z 209 (3), 208 (31), 148 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)[CH:7]=1.[CH3:33][N:34]([CH3:43])[CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH:30]([F:32])[F:31])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:40]3[CH2:41][CH2:42][N:37]([CH2:36][CH2:35][N:34]([CH3:43])[CH3:33])[CH2:38][CH2:39]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Reactant: CN(C)CCN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]-pyrimidine-3-amido]-1H-pyrazol-1-yl]acetic acid (100 mg, 0.22 mmol) in DMF (10 mL) was added dimethyl[2-(piperazin-1-yl)ethyl]amine (68 mg, 0.43 mmol), DIEA (125 mg, 0.97 mmol) and HATU (123 mg, 0.32 mmol). The resulting solution was stirred at room temperature overnight and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#-Analyse HPLC-SHIMADZU(HPLC-10)): Column, XBridge BEH130 Prep C18 OBD Column, 19&#65533; 100 mm 5 um 13 nm; mobile phase, Water with 10 mM NH4CO3 and ACN (15% ACN up to 40% in 6 min); Detector, UV 254/220 nm. This resulted in 79.1 mg (61%) of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-(2-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]-2-oxoethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 25) [M+H]+=602.2, RT=0.89 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.7, 7.1 Hz), 8.69-8.67 (m, 2H), 8.30 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.48-3.42 (m, 4H), 2.45-2.32 (m, 8H), 2.13 (s, 6H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18]>CO>[CH2:9]([N:8]([CH2:18][CH2:17][C:16]([O:20][CH3:21])=[O:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C=CC(=O)OC
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CO
Product: COC(=O)CCN(Cc1ccccc1)Cc1ccccc1
Yield: 98.8 %

Procedure:
A! Starting from dibenzylamine (48.7 ml, 0.25 mole) and methyl acrilate (112.5 ml, 1.25 moles) in 259 ml of methanol, and following the procedure of Example 15,A!, there were obtained 70 g (yield: 99%) of methyl 3-(N,N-dibenzylamino)-propanoate which was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2/[C:10](=[CH:18]/[C:19]2[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[C:24](O)=[O:25])/[C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH:42]1([CH2:45][NH:46][CH2:47][C@@H:48]2[CH2:52][CH2:51][CH2:50][NH:49]2)[CH2:44][CH2:43]1>CN(C=O)C.C(Cl)Cl>[CH:42]1([CH2:45][NH:46][CH2:47][C@@H:48]2[CH2:52][CH2:51][CH2:50][N:49]2[C:24]([C:23]2[CH:22]=[C:21]([CH3:27])[NH:20][C:19]=2/[CH:18]=[C:10]2\[C:11](=[O:17])[NH:12][C:13]3[C:9]\2=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:16]=[CH:15][CH:14]=3)=[O:25])[CH2:43][CH2:44]1
Reactant: Cc1cc(C(=O)O)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Reactant: C1CN[C@H](CNCC2CC2)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCC[C@H]2CNCC2CC2)c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 2-[4-(3-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-(3Z) ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (80 mg, 0.22 mmol), EDC (80 mg), HOBt (30 mg) in DMF (4 mL) was added TEA (0.08 mL) and cyclopropylmethyl-(S)-1-pyrrolidin-2-ylmethyl-amine (0.05 mL). The mixture was stirred at rt for 20 hours. The reaction was diluted with DCM, washed with water, NaHCO3, dried and concentrated. The residue was purified on a silica gel column to give the titled compound.
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1([CH2:20][OH:21])[CH:16]([OH:17])[CH:15]([OH:18])[CH:14]([OH:19])[CH2:13][NH:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[C:26](O)(=O)[CH3:27]>CO.O>[CH2:1]([N:12]1[CH2:13][CH:14]([OH:19])[CH:15]([OH:18])[CH:16]([OH:17])[C:11]1([CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:26][CH3:27]
Reactant: CC(=O)O
Reactant: O=C(NCC1(CO)NCC(O)C(O)C1O)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCCCCCN1CC(O)C(O)C(O)C1(CO)CNC(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
2.96 g of 2-benzoylaminomethyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine (Example 3) are dissolved in a mixture of 40 ml of methanol, 2 ml of water and 2.7 ml of acetic acid, and 5.7 ml of nonylaldehyde are added. The solution is cooled to 5° C. in an ice-bath; 1.35 g of sodium cyanoborohydride are then added. The mixture is stirred for 30 minutes, whilst cooling, and then at room temperature for 24 hours. It is concentrated, the residue is dissolved in 30 ml of methanol/water 6:1 and the solution is discharged onto a column 30 cm long and 3 cm wide which is filled with Amberlite IR 120, H+ form. The column is washed thoroughly with methanol/water in the ratio 8:1 and then eluted with 0.2% strength ammonia in methanol/water 6:1. The pure fractions, determined by thin layer chromatography, are combined and concentrated. 2.6 g of an almost colourless oil are obtained.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH3:24][O:25][CH2:26][CH2:27][NH2:28]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:28][CH2:27][CH2:26][O:25][CH3:24])=[O:3])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: COCCN
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: COCCNC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-methoxyethylamine (29.6 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(2-methoxyethyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (31.2 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]([C:22]([NH:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)=[S:23])[NH2:21].Cl>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17](=[N:21][NH:20][C:22]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)=[S:23])[CH3:19])[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Yield: 52.5 %

Procedure:
2-(4-t-Butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (31 mg, 0.11 mmol) synthesized in Reference Synthetic Example 33 and 4-hydrazinocarbonothioylaminobenzoic acid (23 mg, 0.11 mmol) were stirred with dimethylformamide (1.1 mL) and concentrated hydrochloric acid (0.05 mL) at room temperature for 30 hours. The reaction solution was partitioned between ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The resulting organic layer was concentrated and purified by silica gel column chromatography (chloroform) to give the desired product as a light brown solid (27 mg, yield 52%).
Reaction SMILES: I[C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C>O1CCCC1>[CH3:7][C:5]1[N:6]=[C:2]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[S:3][CH:4]=1
Reactant: C1CNCCN1
Reactant: Cc1csc(I)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1csc(N2CCNCC2)n1
Temperature: 160 °C
Yield: 65 %

Procedure:
A mixture of 1.33 mmol 2-iodo-4-methyl-thiazole, 4.00 mmol piperazine and 4.00 mmol triethylamine in 4 ml tetrahydrofuran in a sealed tube was heated at 160° C. for 2 h under microwave irradiation. The reaction mixture was concentrated and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to afford the title compound as a yellow oil (yield 65%). MS (m/e): 184.3 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8]N)[CH:5]=[CH:6][CH:7]=1.[N:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][C:11]=1[OH:17].C1(C)C=CC=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[C:12]3[C:11](=[O:17])[NH:10][CH:15]=[CH:14][C:13]=3[NH:8][C:4]=2[CH:3]=1
Reactant: NNc1cccc(Br)c1
Reactant: Oc1ccnc(O)c1
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1[nH]ccc2[nH]c3cc(Br)ccc3c12
Temperature: 232 °C
Reaction time: 0.75 h

Procedure:
(3-Bromophenyl)hydrazine HCl (20.5730 g, 92.4 mmol) was dissolved in 6.25 N aqueous NaOH (16 mL, 100 mmol), ethanol (80 mL) and water (60 mL), and extracted with EtOAc (200 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo. CH2Cl2 (150 mL) was added, dried over MgSO4, filtered and concentrated in vacuo to give (3-bromophenyl)hydrazine as a light orange oil. To a heterogeneous solution of (3-bromophenyl)hydrazine (17.19 g, 92 mmol) in Phenyl ether (82 mL) was added pyridine-2,4-diol (5.11 g, 46.0 mmol). A Dean-Stark trap was set up, and the reaction was heated at 232° C. for 4 hours. A strong effervescence and gas evolution occurred often for 45 min. The solution turned homogeneous with decrease in frequency of strong effervescence and gas evolution. The reaction mixture was cooled to room temperature; precipitation ensued. HPLC and LCMS showed completion of reaction (86784-071-01). Toluene (100 mL) was added, and the mixture stirred overnight at room temperature. The mixture was filtered and the precipitate was collected. Methanol (40 mL) was added, and the solution was stirred for 20 min. The precipitate was filtered and washed with methanol, dried to give 7-bromo-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one as a tan solid. Methanol (60 mL) was added, and the mixture was stirred for 7 h. The precipitate was collected to give 7-bromo-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (4.4374 g, 16.87 mmol, 36.7% yield) a light tan solid. The precipitate was collected to give 7-bromo-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one (4.4374 g, 16.87 mmol, 36.7% yield) a light tan solid. The product had an HPLC Retention Time=2.585 min[mixture of rotamers] [4 min grad, 10% MeOH/water to 90% MeOH/water, 0.1% TFA, YMC COMBISCREEN® ODS-A, 4.6×50 mm, 220 nM; LC/MS+1 263.04; 265.04
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC[O-].[Na+]>C(O)C>[C:9]1([S:15][C:2]2[N:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccc1
Reactant: Fc1cnc(Cl)nc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Fc1cnc(Sc2ccccc2)nc1
Yield: 69 %

Procedure:
A solution of 2-chloro-5-fluoropyrimidine (10 mmol) in ethanol (15 ml) was added dropwise over 5 min to a solution prepared from thiophenol (10 mmol) and 0.43 M NaOEt in ethanol (25 ml). Subsequently the mixture was heated to boiling and refluxed for 2 hours, filtered hot, the filtrate evaporated, the residue extracted with chloroform (50 ml), the chloroform solution shaken with 2 M NaOH (2×10 ml), then shaken with water (10 ml) and the solution evaporated; yield 69%. 1H NHR (CDCl3): δ7.4 (Pyr), 8.23 (H-4, H-6).
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[C:11](O)=[O:12].C1COCC1.O.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12]
Reactant: O=C(O)C1CCc2ccccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCC1CCc2ccccc2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
A mixture of 4-oxochromene-2-carboxylic acid (20.0 g, 105 mmol) and Pd/C (3.0 g, w/w=10%) in AcOH (200 mL) was placed in Parr hydrogenation apparatus under H2 (50 psi) and stirred for 25 h at rt. It was then filtered and concentrated. The residue was suspended in water (300 mL), stirred for 10 min, filtered and dried to give 3,4-dihydro-2H-chromene-2-carboxylic acid (13.5 g, 72%) as a white solid. BH3 (57 mL, 114 mmol, 2.0 M in THF) was added slowly to a solution of this carboxylic acid in THF (120 mL) at 0° C. The reaction mixture was then warmed to rt and stirred for 5 h at this temperature. THF/H2O (30 mL, 1:1) was added drop wise while keeping the temperature between 0-5° C. and stirred for 20 min. K2CO3 (26.0 g, 189 mmol) was added and the reaction was vigorously stirred for 30 min. The THF layer was separated and concentrated to give the title compound (11.0 g, 89%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 7.10-7.03 (m, 2H), 6.86-6.81 (m, 2H), 4.14-4.08 (m, 1H), 3.85-3.68 (m, 2H), 2.92-2.84 (m, 1H), 2.80-2.73 (m, 1H), 1.98-1.92 (m, 1H), 1.90-1.79 (m, 1H). LCMS: 165 (M+1)+
Reaction SMILES: C(O[C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:25][CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([C:26]5[N:27]([C:31]6[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=6[F:38])[N:28]=[CH:29][N:30]=5)[S:19][C:18]=4[C:17]=3[N:39]=2)[CH2:9]1)=O)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:38][C:32]1[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:31]=1[N:27]1[C:26]([C:20]2[S:19][C:18]3[C:17]4[N:39]=[C:13]([NH:12][CH:10]5[CH2:9][N:8]([CH3:6])[CH2:11]5)[CH:14]=[CH:15][C:16]=4[O:25][CH2:24][CH2:23][C:22]=3[CH:21]=2)=[N:30][CH:29]=[N:28]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CC(Nc2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
3-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-azetidine-1-carboxylic acid tert-butyl ester (300 mg, 0.54 mmol) was dissolved in THF (20 mL), and LiAlH4 was added in the solution. The reaction mixture was stirred at room temperature for 2 hr, filtered to gather the solution, washed by DCM (10 mL), and separated by TLC (DCM/EtOAc=10:1) to give 433 (128.3 mg, yield: 51%). 1H NMR (DMSO-d6, 400 MHz): δ8.36 (s, 1H), 8.28-7.95 (m, 2H), 7.75-7.56 (m, 1H), 7.54 (s, 1H), 6.98-6.83 (m, 1H), 6.73-6.55 (m, 1H), 4.10 (m, 6H), 3.55 (s, 1H), 3.48 (s, 1H), 3.02 (t, J=8.0 Hz, 2H). LC-MS (ESI): m/z=467 [M+H]+