Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:22]>C(Cl)Cl.O1CCOCC1>[ClH:22].[NH:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)SCc1ccccc12
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: c1ccc2c(c1)CSC21CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
150 mg (0.49 mmole) of 1′-t-butoxycarbonylspiro[benzo[c]thiophene-1(3H),4′-piperidine] [prepared as described in step (b) above] were dissolved in 3 ml of anhydrous methylene chloride, and 1 ml of a 4 N solution of hydrogen chloride in dioxane was added. The mixture was then stirred at room temperature for 1 hour. At the end of this time, the crystals which deposited were collected by filtration, to give 108 mg (yield 91%) of the title compound as white crystals.
Reaction SMILES: Cl[C@H:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH3:7][N:8]1[C:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:11][N:10]=[C:9]1[SH:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[CH3:7][N:8]1[C:12]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:11][N:10]=[C:9]1[S:18][CH:2]([CH3:6])[C:3]([OH:5])=[O:4]
Reactant: Cn1c(S)nnc1-c1cccs1
Reactant: C[C@@H](Cl)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(Sc1nnc(-c2cccs2)n1C)C(=O)O
Reaction time: 2.5 h
Yield: 12.2 %

Procedure:
(R)-2-chloro-propionic acid (500 mg, 4.6 mmol), 4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (1.09 g, 5.58 mmol) and potassium carbonate (1.94 g, 14.03 mmol) were dissolved in acetonitrile (15 ml) at room temperature. Reaction proceeded for 2.5 h and was partitioned between ethyl acetate (350 ml) and water 3 times, washed with 1 M HCl, once with saturated brine, dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. Reaction was not completed at this stage and the crude was stirred in DMF (10 ml) overnight. Extraction was repeated and purification was performed by SPE (solid phase extraction) chromatography on silica gel using 300 ml ethyl acetate, 100 ml 1%, and 100 ml 3% formic acid in ethyl acetate, yielding title compound (150.7 mg, 12%) 1H-NMR (CDCl3), d (ppm): 7.52 (dd, 2H), 7.19 (m, 1H), 4.21 (q, 1H), 3.78 (s, 3H), 1.64 (d, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15]1([NH:21][NH2:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[NH:21]([N:22]1[C:5](=[O:13])[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:2]([Cl:1])[C:3]1=[O:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NNc1ccccc1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Solvent: ClC(Cl)Cl
Product: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.14 g (20 mmol) of 3-chloro-4-phenylfuran-2,5-dione were initially charged in 50 ml of chloroform and, at room temperature, admixed dropwise with stirring with 2.16 g (20 mmol) of phenyl hydrazine, and the mixture was stirred at room temperature overnight. The mixture was filtered, washed three times with sodium bicarbonate solution and once with water, dried over sodium sulfate and concentrated under reduced pressure. Yield: 5.4 g of a crystalline solid, m.p. 144-146° C.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:43]3[CH:44]=[CH:45][C:46]([F:48])=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CN(C=O)C>[F:48][C:46]1[CH:45]=[CH:44][C:43]2[N:39]([CH:36]3[CH2:35][CH2:34][N:33]([CH2:1][C@@H:3]4[C@@H:7]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)[CH2:6][N:5]([C@H:14]([CH:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)[C:15]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=5)=[O:16])[CH2:4]4)[CH2:38][CH2:37]3)[CH:40]=[N:41][C:42]=2[CH:47]=1
Reactant: Fc1ccc2c(c1)ncn2C1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4cnc5cc(F)ccc54)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 73.3 %

Procedure:
The title compound was prepared from 40 mg of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid, 4-methoxy-benzyl ester (prepared above as Aldehyde 5), 40 mg 1-piperidin-4-yl-5-fluoro-1-H-benzoimidazole (from Step C ) and 60 mg of sodium triacetoxyborohydride in 4 mL of THF and 1 mL of DMF, using a procedure analogous to that described in Example 95, Step D to provide 43 mg of the title compound as an oil.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]3[C:10](=[CH:11][C:12]([S:16][C:17]4[CH:22]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:20]=[C:19]([F:29])[CH:18]=4)=[CH:13][CH:14]=3)[O:9][C:8](=[O:30])[CH:7]=2)=[CH:2]1.C1C=C(Cl)C=C(C(OO)=[O:39])C=1.C(Cl)Cl>C(Cl)(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([C:17]4[CH:22]=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:20]=[C:19]([F:29])[CH:18]=4)=[O:39])=[CH:13][CH:14]=3)[O:9][C:8](=[O:30])[CH:7]=2)=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=c1cc(-c2ccoc2)c2ccc(Sc3cc(F)cc(-c4ccccc4)c3)cc2o1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=c1cc(-c2ccoc2)c2ccc(S(=O)c3cc(F)cc(-c4ccccc4)c3)cc2o1
Reaction time: 2 h

Procedure:
To a solution of 4-(3-furyl)-7-(5-phenyl-3-fluorophenylthio)coumarin (Example 17) (106 mg) in CHCl3 (3 mL) was added m-CPBA (88 mg; 50%). After 2 h, CH2Cl2 was added and the resulting solution was washed with 10% aq. NaHSO3, saturated aq. NaHCO3, dried (MgSO4) and concentrated. Chromatography of the residue (silica gel; hexane/EtOAc (7:3)) provided the title compound as a solid.
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]1[C:13](C(O)=O)=[CH:12][C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[NH:5]1>N1C=CC=CC=1>[Br:1][C:13]1[C:4](=[O:3])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[N:8][CH:7]=2
Reactant: O=C(O)c1cc2ccncc2[nH]c1=O
Reactant: BrBr
Solvent: c1ccncc1
Product: O=c1[nH]c2cnccc2cc1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 47.5 %

Procedure:
Bromine (0.539 mL, 10.52 mmol) was added dropwise to a 0° C. mixture of 2-oxo-1,2-dihydro-1,7-naphthyridine-3-carboxylic acid (1.00 g, 5.26 mmol) in pyridine (25.0 mL). The mixture stirred at 0° C. for 20 minutes and then at room temperature for 18 hours. The reaction was then heated at 50° C. for 18 hours. The reaction mixture was then concentrated to afford a brown solid. This material was partitioned between DCM and saturated aqueous sodium thiosulfate solution. The aqueous phase was separated and extracted with DCM. The combined organic phases were washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford a brown solid. The resulting material was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-10% MeOH in DCM to afford 3-bromo-1,7-naphthyridin-2(1H)-one (0.562 g, 2.497 mmol, 47.5% yield) as a tan solid. m/z (ESI) 225.0, 227.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[C:7]([CH:9]=[O:10])[CH:8]=1)([O-:3])=[O:2].[P:11]([O-:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14]>CO>[N+:1]([C:4]1[S:5][CH:6]=[C:7]([CH:9]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[OH:10])[CH:8]=1)([O-:3])=[O:2]
Reactant: O=Cc1csc([N+](=O)[O-])c1
Reactant: CCOP([O-])OCC
Solvent: CO
Product: CCOP(=O)(OCC)C(O)c1csc([N+](=O)[O-])c1
Yield: 72.4 %

Procedure:
A solution containing 2-nitro-4-thiophenecarboxaldehyde (2.61 g, 16.6 mmol), diethyl phosphite (2.14 mL, 16.6 mmol), and methanol (5 mis) was adsorbed onto excess basic alumina. After 16 hours the product was extracted with methylene chloride, concentrated and purified by column chromatography (silica gel). Elution with methylene chloride-methanol 19:1 gave the product (3.55 g) as an oil. 1H NMR (CDC13): d, 5.05 (dd,1H,PCH), 4.15 (m,4H,CH2), 1.33 (dt,6H,CH3). MS (DCl): 296 (MH+). C9H14NO6PS.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 4-bromo-2-nitrophenol (5.2 g, 23.8 mmol) in acetone (100 ml) was added potassium carbonate (9.0 g, 65.1 mmol) followed by benzyl bromide (2.6 ml, 21.8 mmol). The resulting mixture was stirred at room temperature for 30 minutes and then heated to reflux overnight. The solids were then removed by filtration, washing with acetone, and the filtrate reduced in vacuo. The residue was dissolved in ethyl acetate and washed with 2M aqueous sodium hydroxide solution (×3) and then brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and reduced in vacuo to afford 4-bromo-2-nitro-1-[phenylmethyl)oxy]benzene (6 g), 92% yield. 1H NMR (500 MHz, CDCl3): δ 5.26 (s, 2H), 7.05 (d, J=8.9 Hz, 1H), 7.42 (m, 5H), 7.63 (dd, J=2.5 Hz, 1H), 8.01 (d, J=2.45 Hz, 1H). 13C NMR (500 MHz, CDCl3): δ 71.6, 112.4, 116.9, 127.1, 128.5, 128.6, 128.9, 135.2, 136.9, 140.7, 151.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11](=O)[CH2:12][C:13]([C:15]1[C:16]([OH:36])=[C:17]([CH:25]2[CH2:29][CH2:28][N:27]([CH3:30])[CH:26]2[CH2:31][O:32]C(=O)C)[C:18]([O:23][CH3:24])=[CH:19][C:20]=1[O:21][CH3:22])=[O:14].C([O-])(O)=O.[Na+]>Cl>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]1[O:36][C:16]2[C:15]([C:13](=[O:14])[CH:12]=1)=[C:20]([O:21][CH3:22])[CH:19]=[C:18]([O:23][CH3:24])[C:17]=2[C@@H:25]1[CH2:29][CH2:28][N:27]([CH3:30])[C@H:26]1[CH2:31][OH:32]
Reactant: COc1cc(OC)c(C2CCN(C)C2COC(C)=O)c(O)c1C(=O)CC(=O)c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(OC)c2c(=O)cc(-c3ccc([N+](=O)[O-])cc3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of n-BuLi (15% in hexane, 2.54 mL, 5.8 mmol) in THF (25 mL), maintained at 0° C. under nitrogen atmosphere, hexamethyldisilazane (1.25 mL, 5.8 mmol) was added dropwise and stirred for 15 min. To this, a solution of (−)-trans-2-chloro-4-nitro-benzoic acid 2-(2-acetoxymethyl-1-methyl-pyrrolidin-3-yl)-6-acetyl-3,5-dimethoxy-phenyl ester (1.6 g, 3 mmol) in THF (25 mL) was added dropwise, maintaining the temperature at 0° C. After the addition, the reaction was allowed to warm to room temperature and stirred for 2.5 hrs. The reaction mixture was acidified with dilute HCl, basified with 10% NaHCO3 solution to pH 8 to 9. The aqueous layer was extracted with chloroform (3×50 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous Na2SO4. The organic layer was concentrated under reduced pressure and under vacuum to yield acetic acid 3-{3-[3-(2-chloro-4-nitro phenyl)-3-oxopropionyl]-2-hydroxy-4,6-dimethoxyphenyl}-1-methylpyrrolidin-2-ylmethyl ester as a yellow solid (1.6 g). This ester was dissolved in conc. HCl (16 mL) and stirred at room temperature for 3 hrs to effect cyclisation. At the end of 3 hrs, the reaction mixture was basified with solid NaHCO3 to pH 8 to 9. The aqueous layer was extracted with chloroform (3×50 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure and dried over vacuum. The residue was purified by column chromatography with 3% methanol in chloroform and 0.1% ammonia as eluent to yield the title compound as a yellow solid.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].OS(O)(=O)=O.CCN(CC)CC.[CH3:30][C:31]([CH3:33])=O>>[CH3:30][C:31]1([CH3:33])[O:3][C@@H:2]2[C@@H:4]([C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]2[N:10]2[C:11](=[O:12])[NH:13][C:14](=[O:15])[CH:16]=[CH:17]2)[O:5]1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1ccc(=O)[nH]c1=O

Procedure:
5′-O-(t-Butyldimethylsilyl)-2′,3′-O-isopropylidene uridine. A stirred suspension of uridine (1 g, 4.1 mmol) in anhydrous acetone (50 mL) was treated with H2SO4 (0.5 mL) drop wise at room temperature and the resulting mixture was stirred for an additional hour. The reaction was then neutralized with Et3N and was concentrated. The crude mixture was purified by column chromatography (5-8% MeOH:CHCl3) to afford 2′,3′-O-isopropylidene uridine (1.15 g, quant.) as a white solid. 1H NMR (CDCl3) d ppm 1.36 (s, 3H, —CH3), 1.57 (s, 3H, —CH3), 3.80 (dd, 1H, H-5′), 3.91 (dd, 1H, H-5″), 4.26-4.30 (m, 1H, H-4′), 4.95 (dd, 1H, H-3′), 5.02 (dd, 1H, H-2′) 5.56 (d, 1H, H-1′), 5.72 (d, 1H, H-5), 7.36 (d, 1H, H-6).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:22][C:23]1[N:24]=[C:25]([CH:28]=[CH:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([C:38]([F:41])([F:40])[F:39])=[O:37])=[CH:32][CH:31]=2)[O:26][CH:27]=1.O>CN(C=O)C>[F:41][C:38]([F:39])([F:40])[S:36]([C:33]1[CH:34]=[CH:35][C:30](/[CH:29]=[CH:28]/[C:25]2[O:26][CH:27]=[C:23]([CH2:22][O:20][C:17]3[CH:16]=[CH:15][C:14]([CH2:13][S:10]([CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)(=[O:12])=[O:11])=[CH:19][CH:18]=3)[N:24]=2)=[CH:31][CH:32]=1)=[O:37]
Reactant: O=S(=O)(CCn1ccnn1)Cc1ccc(O)cc1
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CS(=O)(=O)CCn4ccnn4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 3.9 %

Procedure:
13.0 mg (0.50 mmol) 95% sodium hydride were given to a solution of 134 mg (0.50 mmol) 4-(2-[1,2,3]triazol-1-yl-ethanesulfonylmethyl)-phenol in 4.0 ml DMF and stirred for 15 min. 168 mg (0.50 mmol) 4-Chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at r.t. overnight. After addition of 10 ml water the resulting precipitate was purified by chromatography on silica gel (eluent: dichloromethane/acetone 20:1) to give 11 mg product.
Reaction SMILES: S(O)(O)(=O)=O.[N:6]1[C:10]2[CH2:11][CH2:12][CH:13]([C:15]([OH:17])=O)[CH2:14][C:9]=2[NH:8][CH:7]=1.S(Cl)(Cl)=O.Cl[CH2:23][CH2:24]Cl>>[N:6]1([C:15]([CH:13]2[CH2:12][CH2:11][C:10]3[N:6]=[CH:7][NH:8][C:9]=3[CH2:14]2)=[O:17])[C:23]2[C:24](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:10]1
Reactant: ClCCCl
Reactant: O=C(O)C1CCc2nc[nH]c2C1
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Product: O=C(C1CCc2nc[nH]c2C1)N1CCc2ccccc21
Temperature: 30 °C
Yield: 82.7 %

Procedure:
4,5,6,7-Tetrahydrobenzimidazole-5-carboxylic acid sulfate (1.32 g) was refluxed in 10 ml of 1,2-dichloroethane together with 1.78 g of thionyl chloride for 30 minutes, and the excess of thionyl chloride and the solvent were removed by distillation under reduced pressure. To the residue was added ml of 1,2-dichloroethane, and 1.6 ml of indoline was added dropwise thereto at 30° C. or lower while stirring followed by stirring at room temperature for 2 hours. The reaction mixture was successively extracted once with 30 ml of water and twice with 20 ml of water. The combined aqueous layer was adjusted to a pH of 9 to 10 with a 10% sodium hydroxide aqueous solution and then extracted with methylene chloride. The combined methylene chloride layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from ethyl acetate to obtain 1.1 g (82.7%) of 5-[(2,3-dihydroindol-1-yl)carbonyl]-4,5,6,7-tetrahydrobenzimidazole.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].[CH2:11]([CH:13]1[NH:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15][S:14]1)[CH3:12]>[OH-].[Na+]>[C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7]([N:17]1[CH:16]([C:18]([OH:20])=[O:19])[CH2:15][S:14][CH:13]1[CH2:11][CH3:12])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CCC1NC(C(=O)O)CS1
Agent: [Na+]
Agent: [OH-]
Product: CCC1SCC(C(=O)O)N1C(=O)C(C)CSC(C)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Acetylthio-2-methylpropanoic acid chloride (5.4 g. prepared from 3-acetylthio-2-methylpropanoic acid and thionyl chloride, b.p. 80°) and 2 N sodium hydroxide (15 ml.) are added to a solution of 2-ethyl-4-thiazolidinecarboxylic acid [Z.Naturforschg, 17b, 765 (1962)] (5.2 g.) in normal sodium hydroxide (30 ml.) chilled in an ice-water bath. After three hours stirring at room temperature, the mixture is extracted with ether, the aqueous phase is acidified and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo to yield 3-(3-acetylthio-2-methylpropanoyl)-2-ethyl-4-thiazolidinecarboxylic acid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[CH:7]=[C:8]([C:12]2[O:13][C:14]([CH3:35])=[C:15]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]4)[N:16]=2)[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([NH:5][C:6]1[CH:7]=[C:8]([C:12]2[O:13][C:14]([CH3:35])=[C:15]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[C@H:25]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH2:24][CH2:23]4)[N:16]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4cccc(N)c4)oc3C)ccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4cccc(NC(C)=O)c4)oc3C)ccc21
Reaction time: 16 h
Yield: 55.1 %

Procedure:
To a solution of DMAP (1.0 mg) and acetyl chloride (9.3 mg, 0.12 mmol) in 1 mL dichloromethane was added a solution of ethyl ((1S)-5-{2-[2-(3-aminophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (25 mg, 0.06 mmol) in dichloromethane (1 mL). Then, triethylamine (0.5 mL) was added and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure and redissolved in acetonitrile/methanol. The solution was filtered through a C8-Silica plug before preparative HPLC purification using 10 to 80% acetonitrile in water gradient to afford 15.3 mg (55.6%) of the desired product. 1H NMR (300 MHz/CDCl3) δ 7.97 (s, 1H), 7.70 (d, 2H), 7.49 (s, 1H), 7.37 (t, 1H), 7.03 (d, 1H), 6.76 (s, 1H), 6.69 (d, 1H), 4.11-4.22 (m, 4H), 3.48 (qr, 1H), 2.92 (t, 2H), 2.72-2.88 (m, 2H), 2.68 (dd, 1H), 2.27-2.40 (m, 5H), 2.16 (s, 3H), 1.64-1.76 (m, 1H), 1.24 (t, 3H). EI-LCMS(rel abundance), m/z 463.4 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[C:20]2[C:5]([CH2:6][C:7]3([C:19]2=O)[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:18])[C:13]=2[F:17])[CH2:8]3)=[CH:4][CH:3]=1.C[Si]([N:27]=[C:28]=[N:29][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:21]=[C:20]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([F:18])[C:13]=3[F:17])[CH2:8]1)/[C:19]/2=[N:29]/[C:28]#[N:27]
Reactant: O=C1c2cc(Br)ccc2CC12CCc1c(ccc(F)c1F)C2
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\c2cc(Br)ccc2CC12CCc1c(ccc(F)c1F)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 113.4 %

Procedure:
To a solution of 6-bromo-5′,6′-difluoro-3′,4′-dihydro-1′H-spiro[indene-2,2′-naphthalen]-1(3H)-one (150 mg, 0.41 mmol) in dried CH2Cl2 (1 mL) was added TiCl4 (1 M solution in DCM, 0.1.24 mmol) dropwise within 15 minutes, and stirred for 1 h. Then to this mixture was added bis-trimethlysilylcarbodiimide (234 mg, 1.24 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was poured into ice-water, extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give (Z)—N-(5-bromo-5′,6′-difluoro-3′,4′-dihydro-1′H-spiro[indene-2,2′-naphthalene]-3(1H)-ylidene)cyanamide (180 mg, crude), which was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([C:20](OC)=[O:21])[O:17][N:16]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=1
Reactant: COC(=O)c1cc(OCc2nc(-c3ccccc3)oc2C)no1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cc(CO)on1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
To a solution of methyl 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolecarboxylate (7.86 g) in tetrahydrofuran (150 mL) was slowly added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 60 mL) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethanol (5.93 g, yield 86%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 99-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7](O)[C:6]=2[CH:17]=1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([Cl:20])[C:6]=2[CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccccc2C=Cc2ccc(Cl)cc21
Solvent: c1ccccc1
Product: Clc1ccc2c(c1)C(Cl)c1ccccc1C=C2

Procedure:
The thus dried 3-chloro-5H-dibenzo[a,d]cyclohepten-5-ol intermediate was mixed with 10 milliliters of benzene and 10 milliliters of thionyl chloride and the resulting mixture stirred at reflux temperature for 2 hours to obtain 3,5-dichloro-5H-dibenzo[a,d]cycloheptene intermediate in the reaction mixture. The mixture was cooled and evaporated under reduced pressure to recover the chloro intermediate as residue.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:31])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:18]3)[CH:10]=2)=[CH:5][C:4]=1F)#[N:2].O.[NH2:34][NH2:35]>C(O)C>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:9]3[N:14]=[C:13]([NH:15][CH3:16])[N:12]=[C:11]([N:17]4[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][C:24](=[O:31])[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:18]4)[CH:10]=3)=[CH:7][CH:8]=2)[NH:35][N:34]=1
Reactant: NN
Reactant: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)n1
Solvent: CCO
Solvent: O
Product: CNc1nc(-c2ccc3c(N)n[nH]c3c2)cc(N2CCC[C@@H](NC(=O)c3ccccc3)C2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
To N-{(3R)-1-[6-(4-cyano-3-fluorophenyl)-2-(methylamino)-4-pyrimidinyl]-3-piperidinyl}benzamide (83 mg, 0.19 mmol) in ethanol (2 mL) was added hydrazine monohydrate (0.5 mL, 10.2 mmol), and the reaction mixture was stirred overnight at 100° C. into a sealed tube. The solution was poured onto water (˜50 mL) and a precipitate formed. The aqueous mixture was filtered, and the solid was further washed with water. The material was dried under vacuum overnight at 45° C. to afford the title compound (52 mg) as an off-white solid. LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.43-1.60 (m, 1H), 1.61-1.75 (m, 1H), 1.76-1.89 (m, 1H), 1.92-2.05 (m, 1H), 2.83 (d, J=4.0 Hz, 3H), 2.91-3.10 (m, 2H), 3.83-3.98 (m, 1H), 4.24-4.57 (m, 2H), 5.38 (s, 2H), 6.45-6.58 (m, 1H), 6.64 (s, 1H), 7.41-7.49 (m, 2H), 7.50-7.56 (m, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.71 (d, J=8.34 Hz, 1H), 7.82-7.90 (m, 2H), 7.98 (bs, 1H), 8.37 (d, J=7.6 Hz, 1H), 11.50 (s, 1H).