Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH2:7][CH2:6][CH:5]([C:8]2[S:22][C:11]3[N:12]=[C:13]([CH3:21])[N:14]=[C:15]([C:16](OCC)=[O:17])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+].Cl>CCOC(C)=O.O.CCO.C1COCC1>[CH3:1][C:2]1([CH3:23])[CH2:7][CH2:6][CH:5]([C:8]2[S:22][C:11]3[N:12]=[C:13]([CH3:21])[N:14]=[C:15]([CH2:16][OH:17])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: CCOC(=O)c1nc(C)nc2sc(C3CCC(C)(C)CC3)cc12
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nc(CO)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.3 %

Procedure:
To a mixture of ethyl 6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine-4-carboxylate (13.0 g), THF (150 mL), and EtOH (150 mL) was added calcium chloride (6.6 g), followed by stirring at room temperature for 30 minutes and then adding NaBH4 (1.8 g) in small divided portions over 15 minutes under ice-cooling. After stirring at room temperature for 4.5 hours, to the reaction mixture were added water (100 mL) and EtOAc (100 mL) under ice-cooling. 1 M Hydrochloric acid (100 mL) was added thereto until the suspension became a solution, followed by concentration under reduced pressure and extracting with EtOAc. The organic layer was washed sequentially with water, saturated aqueous sodium bicarbonate, and brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column (chloroform/EtOAc) to obtain [6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methanol (9.35 g).
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:31])[CH:11]([NH:23]C(OC(C)(C)C)=O)[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClCCl.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)(Cl)(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH2:15]([NH:14][C:12](=[O:13])[CH:11]([NH2:23])[C:10]([NH:9][CH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:31])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Reaction time: 2.5 h

Procedure:
Combine N,N′-diphenethyl-2-(t-butoxycarbonylamino)malonamide (0.425 g, 1.00 mmol) and dichloromethane (7 mL). Add trifluoroacetic acid (1.5 mL). After 2.5 hours, evaporate in vacuo to give a residue. Repeatedly, add carbon tetrachloride to co-evaporate residual trifluoroacetic acid and evaporate in vacuo to give the title compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[S:11][CH:12]=[CH:13][C:14]=1[CH3:15].Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1>[Cl-].[Cl-].[Zn+2].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.C1COCC1>[Br:9][C:10]1[S:11][C:12]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)=[CH:13][C:14]=1[CH3:15]
Reactant: Cc1ccsc1Br
Reactant: Cc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cccc(-c2cc(C)c(Br)s2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.2 %

Procedure:
Add 2.0 M lithium diisopropylamide (9.76 mL, 19.52 mmol) to a −78° C. solution of 2-bromo-3-methyl-thiophene (2.0 mL, 17.75 mmol) and THF (30 mL). After 45 minutes add ZnCl2 (0.5 M in THF, 39.0 mL, 19.50 mmol) and stir the solution for 30 min. Add 2-bromo-6-methyl-pyridine (2.4 mL, 21.29 mmol) and Pd(PPh3)4 (0.50 g, 0.44 mmol). Warm the solution to ambient temperature and stir for 2 h. Wash the reaction with saturated NH4Cl solution (20 mL). Wash the aqueous layer with CH2Cl2 (30 mL). Combine the organic layers, wash with saturated NH4Cl solution (20 mL), dry over Na2SO4, filter and concentrate. Purify the resulting residue by silica gel column chromatography (10%-20% EtOAc/hexane gradient) to furnish the title compound (2.34 g, 49%). LC-ES/MS m/z (79Br/81Br) 267.7/269.5 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[N:8]=1)=[O:5].[CH:26](=O)[CH2:27][CH3:28].C(O)(=O)C>C1COCC1>[F:25][C:20]1[CH:21]=[C:22]([F:24])[CH:23]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:26][CH2:27][CH3:28])[CH2:18][CH2:19]2)[N:8]=1)=[O:5]
Reactant: O=C(Nc1cccc(OC2CCNCC2)n1)c1c(F)cc(F)cc1F
Reactant: CCC=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCN1CCC(Oc2cccc(NC(=O)c3c(F)cc(F)cc3F)n2)CC1
Yield: 68.7 %

Procedure:
Combine 2,4,6-trifluoro-N-[6-(piperidin-4-yloxy)pyridin-2-yl]-benzamide (example 84, 250 mg, 0.71 mmol), propionaldehyde (124 mg, 2.14 mmol), acetic acid (85 mg, 1.42 mmol), molecular sieve 4 Å (0.4 g) and THF (6 mL), stir for 15 min. Then add NaBH(tri-acetate) portionwise and stir for 3 hr. Quench the reaction with 0.1N NaOH, extract with methylene dichloride three times. Combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Chromatography (silica gel) eluting with 5% 2M NH3-methanol in methylene dichloride provides 192 mg (69%) of the title compound: mass spectrum (ion spray): m/z=394.1 (M+1); 1H NMR (CDCl3, ppm): 8.00 (s, br, 1H), 7.84 (d, br, 1H), 7.64 (t, 1H), 6.78 (m, 2H), 6.52 (d, 1H), 4.94 (m, 1H), 2.75 (m, 2H), 2.32 (m, 4H), 2.04 (m, 2H), 1.85 (m, 2H), 1.55 (m, 2H), 0.92 (t, 3H). Mono-hydrochloride salt: Anal calcd for C20H22F3N3O2.HCl.0.25H2O: C, 55.30; H, 5.45; N, 9.67. Found: C, 55.13; H, 5.36; N, 9.61.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[N+:43]([C:46]1[CH:51]=[CH:50][N:49]=[CH:48][C:47]=1[NH2:52])([O-:45])=[O:44]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH:52][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][C:46]=1[N+:43]([O-:45])=[O:44])=[O:9]
Reactant: Nc1cnccc1[N+](=O)[O-]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1cnccc1[N+](=O)[O-])c1cc(Br)ccc1Cl
Temperature: 40 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
Method C—Step a To a mixture of 5-Bromo-2-chlorobenzoic acid (5.00 g, 21.23 mmol) in DMF (40 mL), HATU (8.48 g, 22.29 mmol) and triethylamine (2.97 mL, 21.44 mmol) were added. After 30 min stirring at room temperature 4-nitro-pyridin-3ylamine (2.36 g, 16.99 mmol) was added, the reaction mixture stirred at 40° C. overnight and solvent removed. The crude was then diluted with EtOAc (40 mL) and washed first with saturated Na2CO3 solution (6×30 mL) then 1N HCl (3×30 mL). The organic layer was dried over Na2SO4, filtered and left standing. The precipitate obtained was filtered to get 4.75 g of the title compound (63%).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([F:9])[C:6]([O:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)=[C:5]([F:22])[CH:4]=1)=[CH2:2].B1C2CCCC1CCC2.[OH-:32].[Na+].OO>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:6]2[C:5]([F:22])=[CH:4][C:3]([CH2:1][CH2:2][OH:32])=[CH:8][C:7]=2[F:9])=[CH:12][C:13]=1[C:18]([F:19])([F:21])[F:20]
Reactant: [OH-]
Reactant: C=Cc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1cc(F)c(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of 4-chloro-3-(trifluoromethyl)phenyl 4-ethenyl-2,6-difluorophenyl ether (3.2 g, 9.56 mmol) in THF (10 mL) was added dropwise 9-BBN (38.2 mL, 19.12 mmol) at 0° C. The reaction mixture was stirred at room temperature for overnight. It was mixed with NaOH (19.12 mL, 57.4 mmol) and H2O2 (5.86 mL, 57.4 mmol), the mixture was stirred at 55° C. for 4 h. It was quenched by Na2SO3 and extracted with EA (100 ml×3). Organic phases were collected, combined, dried with anhydrous Na2SO4, and concentrated to afford the title compound (3.10 g, 92% yield). LCMS: rt=4.72 min, [M+H+]=352
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:23][CH2:24][N:25]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: OC1(c2ccc(F)cc2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OC1(c2ccc(F)cc2)CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 80 °C
Yield: 74.3 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (obtained as described in Monatsh. Chem. 1972, 103, 1591) (251 mg, 1.13 mmol), 4-(4-fluorophenyl)piperidin-4-ol (215 mg, 1.13 mmol) and DIPEA (0.20 mL, 1.13 mmol) in DMF (3 mL) were stirred and heated at 80° C. for 1 hour. The resulting solution was cooled to ambient temperature, and quenched with water (10 mL). The precipitated solid was collected by filtration, washed sequentially with water, acetonitrile and ether and dried under vacuum to give 4-(4-fluorophenyl)-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-ol (320 mg, 74%).
Reaction SMILES: [F:1][C:2]([F:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.CC(O)=O.COC1C=CC(C[O:29][C:30](=[O:50])[C@H:31]([N:36]2[CH2:40][C@H:39]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=3)[C@@H:38]([CH:48]=O)[CH2:37]2)[CH2:32][CH:33]2[CH2:35][CH2:34]2)=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CCOC(C)=O>[F:17][C:2]([F:1])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:48][C@@H:38]2[C@@H:39]([C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=3)[CH2:40][N:36]([C@H:31]([CH2:32][CH:33]3[CH2:35][CH2:34]3)[C:30]([OH:50])=[O:29])[CH2:37]2)[CH2:7][CH2:6]1
Reactant: COc1ccc(COC(=O)[C@@H](CC2CC2)N2C[C@H](c3cccc(F)c3)[C@@H](C=O)C2)cc1
Reactant: FC(F)(CCC1CCNCC1)c1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(O)[C@@H](CC1CC1)N1C[C@H](CN2CCC(CCC(F)(F)c3ccccn3)CC2)[C@@H](c2cccc(F)c2)C1
Reaction time: 3 h
Yield: 89.4 %

Procedure:
A solution of 4-(3,3-difluoro-3-(2-pyridyl)propyl) piperidine (20 mg. 0.083 mmol, from EXAMPLE 202, Step E) and AcOH (0.0050 mL, 5.2 mg, 0.087 mmol) in 1,2-dichloroethane (1.1 mL) was transferred to a vial containing 2-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclopropyl)propanoic acid (4-methoxy)benzyl ester (30 mg, 0.076 mmol, from EXAMPLE 21, Step E). Molecular sieve pellets (100 mg, 3 Å) were added and the mixture was stirred for 10 min. at RT before the addition of sodium triacetoxyborohydride (19 mg, 0.090 mmol). After 3 h, the mixture was diluted with EtOAc (40 mL) and washed with saturated aq. NaHCO3 (20 mL) followed by saturated aq. NaCl (20 mL). The aq. layers were extracted with EtOAc (40 mL) and the combined organic layers were dried (Na2SO4), decanted, and evaporated. The crude product was purified by flash column chromatography on silica gel, eluting with 50:50 v/v CH2Cl2/EtOAc, to give 36 mg of the title compound. Further purification by preparative HPLC on a 20×250 mm Chiralcel OD column, eluting with 98:2 v/v hexanes/i-PrOH, gave 23 mg of the title compound: 1H NMR (500 MHz, CD3OD) δ 8.60 (d, J=5, 1H), 7.94 (td, J=8, 2, 1H), 7.66 (d, J=8, 1H), 7.48 (dd, J=8, 5, 1H), 7.35 (d, J=8, 2H), 7.25 (td, J=8, 6, 1H), 7.01-6.95 (m, 2H), 6.92-6.87 (m, 2H), 5.13 (s, 2H), 3.77 (s, 3H), 3.33 (dd, J=9, 6, 1H), 3.10 (q, J=9, 2H), 2.84-2.74 (m, 2H), 2.66-2.59 (m, 2H), 2.52 (dd, J=9,7, 1H), 2.36-2.21 (m, 5H), 1.81 (bt, J=12, 1H), 1.73 (bt, J=12, 1H), 1.71-1.51 (m, 4H), 1.30-1.24 (m, 2H), 1.21-0.99 (m, 3H), 0.72-0.64 (m, 1H), 0.45-0.55 (m, 2H), 0.07-0.00 (m, 2H); ESI-MS 650 (M+H); HPLC A: 3.33 min.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:28]=1[Mg]Br>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:28]3[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[C:27]=3[CH3:26])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Reactant: Cc1cccc([Mg]Br)c1C
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)c1C

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 2,3-dimethylphenylmagnesium bromide. Yield: 54 mg of a white solid. LC-MSD, m/z for C24H19BrN2O2 [M+H]+=447.0, 449.0; HPLC retention time: 2.6 min.
Reaction SMILES: [OH-].[K+].F[C:4]1[C:26]([F:27])=[C:25]([F:28])[CH:24]=[CH:23][C:5]=1[N:6]([CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:7]([CH3:10])[CH2:8][OH:9].C(OC=C(C(OCC)=O)C(OCC)=O)C.O>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.CN(C=O)C>[F:28][C:25]1[CH:24]=[CH:23][C:5]2[N:6]([CH:11]=[C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C@@H:7]([CH3:10])[CH2:8][O:9][C:4]=2[C:26]=1[F:27]
Reactant: CCOC(=O)C(=CN(c1ccc(F)c(F)c1F)[C@@H](C)CO)C(=O)OCC
Agent: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=CN1c2ccc(F)c(F)c2OC[C@@H]1C)C(=O)OCC
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Potassium hydroxide (180 mg) and benzyltrimethylammonium chloride (49.5 mg) were dissolved in DMF (15 ml) by heating to 70° C. and a solution of diethyl [2,3,4-trifluoro[(1S)-2-hydroxy-1-methylethyl]anilino]methylenemalonate (1 g, 99.8% ee) and diethyl ethoxymethylenemalonate (120 mg) in DMF (5 ml) was added thereto. The obtained mixture was stirred at the same temperature for 4 hours. After adding water, the liquid reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography. Thus, 871 mg (99.8% ee) of the title compound was obtained as a yellow oily substance. Various spectral data was identical with those described in Japanese Patent No. 2,769,174.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]([C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[S:33]([CH3:36])(=[O:35])=[O:34])[CH2:26][CH2:25]1.N1CCCCC1>CN(C=O)C.CO>[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]([C:37]2[CH:43]=[CH:42][C:40]([NH:41]/[C:13](=[C:6]3\[C:5](=[O:23])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[CH:10][CH:11]=4)/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:39][CH:38]=2)[S:33]([CH3:36])(=[O:35])=[O:34])[CH2:26][CH2:25]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CS(=O)(=O)N(CCN1CCOCC1)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: C1CCNCC1
Product: CS(=O)(=O)N(CCN1CCOCC1)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Examples 1 and 187 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-[N-(2-morpholinoethyl)-N-methylsulphonyl-amino]-aniline in DMF and subsequent treatment with piperidine in methanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([I:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].I[CH3:17].[H-].[Na+].OS([O-])(=O)=O.[K+]>C1COCC1>[C:1]([O:5][C:6](=[O:15])[N:7]([C:8]1[CH:9]=[CH:10][C:11]([I:14])=[CH:12][CH:13]=1)[CH3:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(I)cc1
Temperature: 25 °C
Yield: 106.9 %

Procedure:
A solution of 15.96 g (50 mmol) (4-Iodo-phenyl)-carbamic acid tert-butyl ester and 24.96 ml (400 mmol) iodomethane in 250 ml THF was treated at −18° C. with 4.36 (100 mmol) 55% NaH during 1 h. The reaction was warmed up over night to room temperature, neutralized at 0° C. with aqueous 10% KHSO4, evaporated and extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous 10% NaCl, dried (Na2SO4) and evaporated to yield 17.8 g (quantitative) of (4-Iodo-phenyl)-methyl-carbamic acid tert-butyl ester, MS: 333 (M).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:14](=[O:21])([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[NH2:15]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:17]([O:16][C:14](=[O:21])[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(N)=O
Reactant: Brc1ccccc1C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccccc1C1CCCCC1
Temperature: 80 °C

Procedure:
To a solution of 1-bromo-2-cyclohexyl-benzene (5 mmol) in dioxane (20 mL) was added solid Pd(OAc)2 (0.1 g) and solid CsCO3 (10 mmol). tert-Butyl carbamate (7 mmol) was added to the reaction mixture, and the contents were heated at 80° C. for 2 h. The reaction mixture was cooled to room temperature and filtered through Celite. The solvent was removed in vacuo and the residue obtained was purified by flash column chromatography using DCM as eluant to yield (2-cyclohexylphenyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]([OH:21])[C@@H:7]([O:13]CC1C=CC=CC=1)[C@H:8]([OH:12])[CH2:9][CH:10]=[O:11])(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:4][CH2:5][C@@H:6]([OH:21])[C@@H:7]([OH:13])[C@H:8]([OH:12])[CH2:9][CH:10]=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@@H](O)[C@@H](OCc1ccccc1)[C@H](O)CC=O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OC[C@@H](O)[C@@H](O)[C@H](O)CC=O
Yield: 48 %

Procedure:
Pd/C (10%, contained 50% of water) (40 mg) was added to the solution of 6-O-acetyl-4-O-benzyl-2-deoxy-D-glucose (1.15 mmol) in ethyl alcohol (50 mL). The mixture was hydrogenated using Paar apparatus (at 45 psi of H2) for 24 hr. The reaction mixture was then filtered through Celite, evaporated to dryness, and product was purified by column chromatography (SilicaGel, 60) using chloroform:methanol as eluent. (Yield 48%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]=[O:17]>O1CCCC1>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:16]([NH:15][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:17])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)CN=C=O
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)NC1CCN(Cc2ccccc2)CC1
Yield: 93.8 %

Procedure:
2 g of 4-amino-1-benzylpiperidine was dissolved in 15 ml of tetrahydrofuran. After adding 1.6 g of ethyl isocyanatoacetate, the resulting mixture was heated under reflux for 1 hour. Then the reaction mixture was concentrated under reduced pressure to thereby give 3.15 g of the title compound as white crystals.
Reaction SMILES: [CH:1]([N:4]1[CH2:13][CH2:12][C:11]2[N:10]=[C:9]([NH:14][C:15]([NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH:8]=[C:7]3[N:26](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:27]=[C:5]1[C:6]=23)([CH3:3])[CH3:2].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH:1]([N:4]1[CH2:13][CH2:12][C:11]2[N:10]=[C:9]([NH:14][C:15]([NH:17][C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])=[O:16])[CH:8]=[C:7]3[NH:26][N:27]=[C:5]1[C:6]=23)([CH3:2])[CH3:3]
Reactant: CC(C)N1CCc2nc(NC(=O)N[C@H](C)c3ccccc3)cc3c2c1nn3C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCc2nc(NC(=O)N[C@H](C)c3ccccc3)cc3[nH]nc1c23
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(R)-1-(3-isopropyl-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-(1-phenylethyl)urea (75 mg, 0.123 mmol) was taken in TFA (0.5 mL) and stirred at room temperature for 30 minutes before triethylsilane (155 uL, 0.97 mmol) was added. The reaction mixture was stirred for 15 minutes at room temperature then heated at 80° C. for 30 minutes before it was concentrated, taken in DCM and washed with aqueous sodium bicarbonate, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-15% MeOH-DCM) gave (R)-1-(3-isopropyl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridin-7-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. for C20H24N6O [M+H]+ 365. found 365. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 7.34-7.23 (m, 4H), 7.18 (m, 1H), 6.40 (s, 1H), 4.90 (m, 1H), 3.40 (m, 2H), 3.22 (m, 2H), 2.90 (m, 1H), 1.38 (d, J=7.0, 3H), 1.07 (d, J=9.4, 6H).
Reaction SMILES: Br[C:2]1[C:3]([CH:13]2[CH2:15][CH2:14]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](B(O)O)[CH:17]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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>[CH:13]1([C:3]2[C:2]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)=[CH:10][CH:9]=[C:8]3[C:4]=2[CH2:5][C:6](=[O:12])[N:7]3[CH3:11])[CH2:15][CH2:14]1
Reactant: CN1C(=O)Cc2c1ccc(Br)c2C1CC1
Reactant: OB(O)c1cccnc1
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: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2c1ccc(-c1cccnc1)c2C1CC1
Temperature: 130 °C

Procedure:
To 5-bromo-4-cyclopropyl-1-methyl-1,3-dihydro-indol-2-one, prepared as described in Example 40c, (320 mg, 1.202 mmol), was added 3-pyridine boronic acid (CAS#1692=25-7, 177 mg, 1.443 mmol), 1,2-dimethoxyethane (7.5 mL), and 2 M aqueous sodium carbonate (1.503 ml, 3.01 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3—Pd(0) (Biotage), 0.11 mmol/g loading, (328 mg, 0.036 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 130° C. for 4 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 10 to 100%) to furnish 4-cyclopropyl-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one, HRMS: (ESI) m/z 265.1342 (M+H)+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.12-0.24 (m, 2H), 0.68-0.78 (m, 2H), 1.86-2.00 (m, 1H), 3.19 (s, 3H), 3.59 (s, 2H), 6.80 (d, J=7.8 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.34 (dd, J=7.7, 4.9 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 8.53 (d, J=4.6 Hz, 1H), 8.63 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4](C)[CH:3]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:18][CH:17]=1.[Na]>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][CH:3]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])=[CH:18][CH:17]=1
Reactant: CN1C(=O)c2ccccc2N(C)C1COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: [Na]
Product: CN1c2ccccc2C(=O)NC1COc1ccc(CC2SC(=O)NC2=O)cc1

Procedure:
5-[4-[[1,3-Dimethyl-4-oxo-1,2,3,4-tetrahydro-2-quinazolinyl]methoxy]phenyl methyl] thiazolidin-2,4-dione, sodium salt;