Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:31]([O-])=O)[C:18]([NH:19][CH:20]4[CH2:25][CH2:24][N:23]([CH:26]([CH3:30])[CH2:27][C:28]#[N:29])[CH2:22][CH2:21]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].CCOC(C)=O>[NH2:31][C:17]1[C:18]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([CH:26]([CH3:30])[CH2:27][C:28]#[N:29])[CH2:24][CH2:25]2)=[C:13]2[CH:12]=[CH:11][N:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])[C:14]2=[N:15][CH:16]=1
Reactant: CC(CC#N)N1CCC(Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(CC#N)N1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 50 °C
Reaction time: 14 h
Yield: 61.6 %

Procedure:
A suspension of 3-[4-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-butyronitrile (11.3 g, 24.1 mmol) and palladium on carbon (3.2 g, 10%, wet, Degussa, E101 NE/W) in EtOAc (150 ml) was stirred under a hydrogen atmosphere (2-3 balloons) at 50° C. for 14 h. The reaction mixture was cooled to 25° C. then was filtered through Celite and the Celite was washed with EtOAc (2×20 ml). The filtrate and washings were concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (gradient: 0 to 8% CH3OH in CH2Cl2) afforded 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-butyronitrile (6.51 g, 61%) as a grey foam. TLC: 5% CH3OH in CH2Cl2, Rf=0.40; 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J=7.8 Hz, 2H), 7.81 (s, 1H), 7.56-7.49 (m, 1H), 7.48-7.39 (m, 3H), 6.52 (d, J=4.2 Hz, 1H), 4.74 (d, J=8.5 Hz, 1H), 3.75-3.63 (m, 1H), 3.13-3.00 (m, 1H), 2.90-2.69 (m, 3H), 2.51 (dd, J=16.7, 6.3 Hz, 1H), 2.45-2.32 (m, 3H), 2.06 (d, J=10.9 Hz, 2H), 1.61-1.46 (m, 2H), 1.19 (d, J=6.7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.C(N(CC)CC)C>C1COCC1>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCCN(c2ccc(N)cn2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) in THF (30 mL) was added tert-butyl piperidin-3-ylcarbamate (700 mg, 3.5 mmol) and triethylamine (0.64 mL, 4.6 mmol) and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness, the residue was dissolved in dichloromethane and washed with 1 N HCl aq. and water. The organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness. The residue was dissolved in tetrahydrofuran (30 mL), degassed with nitrogen, charged with catalytic 10 wt. % Pd/C (0.3 g) and the reaction mixture was placed under an atmosphere of hydrogen (40 Psi) until the reduction was complete as indicated by LCMS analysis. The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated to provide the desired product (850 mg, 93%) as a purple solid: ESI MS m/z 293 [C15H24N4O2+H]+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[C:9](=S)([S:15]CC(O)=O)[S:10][CH2:11][C:12](O)=[O:13].C(N(CC)CC)C>CC(O)C>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][N:7]1[C:12](=[O:13])[CH2:11][S:10][C:9]1=[S:15])[CH3:3]
Reactant: CCOC(=O)CN
Reactant: O=C(O)CSC(=S)SCC(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(=O)CN1C(=O)CSC1=S
Yield: 80.8 %

Procedure:
Separately, glycine ethyl ester hydrochloride (140 mg, 1 mmol) and bis(carboxymethyl) trithiocarbonate (224 mg, 1 mmol) were dissolved in 2-propanol (6 mL), triethylamine (0.6 mL) was added thereto, and the mixture was heated to reflux for 1 hour while stirring. After the reaction was completed the solvent was removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (1/1 (volume ratio)) as an eluent, to give ethyl-2-(4-oxo-2-thioxothiazolidin-3-yl)acetate in a yield of 177 mg (yield 80.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6](S(C3C=CC(C)=CC=3)(=O)=O)[S:7](=[O:10])(=[O:9])[O:8][C:4]=2[CH:3]=1.[N-]=[N+]=[N-].[Na+]>C(#N)C>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][S:7](=[O:10])(=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2c3ccc(C)cc3OS2(=O)=O)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc2c(c1)OS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Methyl-3-(toluene-4-sulfonyl)-3H-benzo[1,2,3]oxathiazole 2,2-dioxide (100 mg, 0.295 mmol) is dissolved in acetonitrile (5 ml). A solution of sodium azide (of 20 mg, 0.29 mmol of sodium azide in 1 ml of H2O) is added to this solution, and the mixture is stirred at RT overnight. The mixture is then stirred at 60° C. for 1 h, the solvent is distilled off under reduced pressure and the residue is purified by RP chromatography.
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH:21]=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([N:25](CC)[CH2:26]C)C.[ClH:30].CNC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(OCC)(=O)C>[ClH:30].[ClH:30].[CH3:23][N:25]([CH3:26])[CH2:21][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]([S:12]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH:10]=1
Reactant: CCN(CC)CC
Reactant: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccnc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CNC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Phenyl-1-(3-pyridinesulfonyl)-1H-pyrrole-3-carbaldehyde (230 mg) was dissolved in dichloromethane (20 mL), triethylamine (0.52 mL), dimethylamine hydrochloride (302 mg), sodium triacetoxyborohydride (1.06 g) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-methanol=1:0→1:1) to give a free base of the title compound. The obtained free base was dissolved in ethyl acetate (3 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 ml) and ethanol (2 mL) were added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethanol to give the title compound (yield 138 mg, 45%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[NH:30]1[CH2:33][CH:32]([N:34]2[CH2:39][CH2:38][NH:37][C:36](=[O:40])[CH2:35]2)[CH2:31]1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][CH:33]4[NH:30][CH2:31][CH:32]4[N:34]4[CH2:39][CH2:38][NH:37][C:36](=[O:40])[CH2:35]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C1CN(C2CNC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3NCC3N3CCNC(=O)C3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.26 mmol), 4-azetidin-3-ylpiperazin-2-one (44 mg, 0.28 mmol) and 4 Å powdered molecular sieves (250 mg) in MeOH (2 mL) and DCE (5 mL) was stirred at room temperature for 2 h before the addition of sodium triacetoxyborohydride (108 mg, 0.51 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-7%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 514 as a yellow foam (42 mg, 31%). LCMS (Method I): RT 2.28 min [M+H]+ 531.2. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.97 (m, 1 H); 7.79-7.74 (m, 1 H); 7.31-7.24 (m, 2 H); 5.93 (bs, 1 H); 4.35 (m, 4 H); 3.94 (s, 2 H); 3.94-3.80 (m, 7 H); 3.66 (bs, 2 H); 3.43-3.33 (m, 4 H); 3.21 (s, 3 H); 3.06 (s, 2 H); 2.58 (t, J=5.37 Hz, 2 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[C:9]([O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][CH:17]=3)[C:10](Br)=[CH:11][CH:12]=2)[CH2:7][CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].[CH:26]1([N:29]2[CH:33]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:31]=[N:30]2)[CH2:28][CH2:27]1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1>[C:1]([N:4]1[C:13]2[C:8](=[C:9]([O:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][CH:17]=3)[C:10]([C:32]3[CH:31]=[N:30][N:29]([CH:26]4[CH2:28][CH2:27]4)[CH:33]=3)=[CH:11][CH:12]=2)[CH2:7][CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(Br)c(Oc3ccc(C(N)=O)cc3)c2CC[C@@H]1C
Reactant: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)c(Oc3ccc(C(N)=O)cc3)c2CC[C@@H]1C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A 50-mL, round-bottom flask was charged with (S)-4-(1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzamide (0.068 g, 0.17 mmol), 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.059 g, 0.25 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.014 g, 0.02 mmol), potassium carbonate (0.070 g, 0.50 mmol), 1,4-dioxane (20 mL) and water (2 mL). The resulting mixture stirred overnight at 100° C. After cooling to room temperature, the reaction mixture was passed through a short pad of celite, and the filtrate was concentrated under vacuum. The residue was purified by preparative thin layer chromatography (eluting with 1:1, ethyl acetate/petroleum ether). The product was further purified by preparative-HPLC with the following conditions (Waters I): Column, XBridge Prep C18 OBD Column, 19×150 mm 5 um 13 nm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (15.0% to 95% acetonitrile in 12 min; flow rate: 20 mL/min); Detector, UV 254/220 nm. This afforded (S)-4-(1-acetyl-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-1,2,3,4-tetrahydroquinolin-5-yloxy)benzamide (0.029 g, 40%) as an off-white solid. 1H NMR (300 MHz, CD3OD) δ ppm 0.93-1.03 (m, 4H), 1.15 (d, J=6.60 Hz, 3H, 1.19-1.42 (m, 1H), 2.18-2.27 (m, 5H), 2.67-2.75 (m, 1H), 3.56-3.63 (m, 1H), 4.77-4.79 (m, 1H), 6.85-6.88 (m, 2H), 7.37 (m, 1H), 7.63 (d, J=8.40 Hz, 1H), 7.77 (s, 1H), 7.81-7.85 (m, 2H), 7.94 (s, 1H). MS (ESI, pos. ion) m/z 431 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl.C(OCC)C>[C:1]1([CH:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[O:32][CH2:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCCCCCCCCC(c1ccccc1)c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOCC
Product: c1ccc(C(CCCCCCCCC2CO2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1.53 g of 11,11-diphenylundec-1-ene in 25 mL of dichloromethane was added 1.5 g of 50-60% by wt of m-chloroperbenzoic acid and the mixture was stirred at room temperature for 16 hrs. The solution was diluted with diethyl ether and washed with 10% by wt aqueous solution of sodium hydrogen sulfite, saturated aqueous sodium hydrogen carbonate solution, and brine. The organic layer was dried over sodium sulfate and concentration in vacuo gave 1.5 g of 11,11-diphenylundec-1-ene oxide which is characterized by:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:37]1[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reactant: COc1ccc(B(O)O)cc1
Product: COC(=O)c1c(-c2ccc(OC)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 2-benzyl-6-chloro-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (100 mg) and 4-methoxyphenylboronic acid. beige powder (61 mg).
Reaction SMILES: O.[SH2:2].[Na].Br[CH:5]([C:12](=[O:14])[CH3:13])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].CCOCC>O>[SH:2][CH:5]([C:12](=[O:14])[CH3:13])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: S
Reactant: CCOC(=O)CC(Br)C(C)=O
Agent: [Na]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)CC(S)C(C)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
A round bottom flask was charged with sodium hydrogensulfide hydrate (1.23 g, 16.9 mmol) in water (14.2 mL). The solution was cooled to about 0° C. followed by the addition of ethyl 3-bromo-4-oxopentanoate (3.79 g, 16.9 mmol) dropwise over about 30 min. The mixture was stirred at about 0° C. for about 3 h. To the reaction mixture was added Et2O (40 mL) and the reaction was warmed to ambient temperature. The crude product was partitioned between Et2O (15 mL) and water (15 mL). The layers were separated and the aqueous layer was back extracted with Et2O (10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford ethyl 3-mercapto-4-oxopentanoate (1.74 g, 9.87 mmol, 58%, which was used without further purification). LC-MS (Table 1, Method g) Rt=2.24 min, m/z 177 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[N:3]=1.[OH-:23].[K+]>C(O)(C)(C)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[N:10]=[C:9]([CH3:22])[N:8]([C:4]3[N:3]=[C:2]([OH:23])[CH:7]=[CH:6][CH:5]=3)[CH:12]=2)[CH:20]=[CH:19][N:18]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(F)n1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(O)n1

Procedure:
The title compound, white cristalline solid, MS: m/e=311.2, 313.2 (M+H+), was prepared in accordance with the general method of example 1a from 2-fluoro-6-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-pyridine and KOH in tert-butanol.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.Br[CH2:21][C:22]1[C:30]2[O:29][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OC(=O)C)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:21][C:22]2[C:30]3[O:29][C:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:27][C:26]=3[CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1nc2cccc(CBr)c2o1
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc2cccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)c2o1

Procedure:
1.8 g of 4-(2-quinolinylmethyloxy)phenol, 1.98 g of ethyl 7-bromomethylbenzoxazole-2-carboxylate and 1.0 g of potassium carbonate are combined in 100 ml of acetone and refluxed for 18 hours. The mixture is cooled, diluted with ethylacetate and filtered. The filtrate is concentrated and the crude product purified by flash chromatography on silica gel in 5% ethanol in chloroform/hexane (1:1) to give ethyl 7-(4-(quinolin-2-ylmethoxy)phenoxymethyl)benzoxazole-2-carboxylate.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:15])[CH3:14].[F:16][C:17]1[CH:18]=[C:19]([CH:25]=[C:26]([F:28])[CH:27]=1)[C:20](OCC)=[O:21].C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[F:16][C:17]1[CH:18]=[C:19]([C:20](=[O:21])[CH2:14][C:13]#[N:15])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: CC#N
Reactant: CCOC(=O)c1cc(F)cc(F)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CCC(=O)c1cc(F)cc(F)c1
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 43 %

Procedure:
Diisopropylamine (10.6 mL, 76 mmol) was dissolved in dry THF (10 mL) and the solution cooled to −20° C. A solution of n-butyllithium (2.5N in hexanes, 30.5 mL, 76 mmol) was added slowly at such a rate as to keep the internal temperature below 0° C. After stirring for 5 min, the solution was cooled to −20° C. and added to a solution of acetonitrile (2.37 mL, 45.3 mmol) and ethyl 3,5-difluorobenzoate (6.23 g, 36.2 mmol) in dry THF (18 mL) at such a rate as to keep the temperature below −40° C. A further 10 mL of dry THF was used to transfer the remaining lithium diisopropylamide to the reaction. The reaction was allowed to warm to ambient over 2 h before being quenched with saturated aqueous ammonium chloride solution. The reaction was extracted with ethyl acetate (×2) and the extracts discarded. The aqueous was acidified with 2N HCl and extracted with ethyl acetate. The organic extract was washed with 2N HCl and brine before being dried over MgSO4, filtered and evaporated. Purification using chromatography (silica gel, gradient 5 to 100% ethyl acetate/isohexane) gave 3-(3,5-difluorophenyl)-3-oxopropanenitrile as a yellow solid (2.82 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[C:13]([OH:20])=[CH:14][CH:15]=[C:16]([C:17]([OH:19])=[O:18])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:26]O>>[CH3:26][O:18][C:17]([C:16]1[C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]=2[C:13]([OH:20])=[CH:14][CH:15]=1)=[O:19]
Reactant: CO
Reactant: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3)nc12
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 76 %

Procedure:
2-(4-fluoro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid (500 mg, 1.84 mmol) obtained in step 3 was dissolved in methanol, H2SO4 (0.49 ml, 9.20 mmol) was added dropwise thereto and refluxed for 15 hours. The resulting solution was cooled to room temperature, concentrated under a reduced pressure to remove methanol, and the residue was neutralized with NaHCO3. Then, the neutralized residue was extracted with ethyl acetate and concentrated under a reduced pressure to obtain a residue which was purified by silica gel chromatography to obtain the title compound (397 mg, 1.39 mmol) in a yield of 76%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:34])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH:32]=[CH:31][CH:30]=[N:29]2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)[CH:23]=3)[CH2:20][C:19](=[O:34])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cccn3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3cccn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-dimethylamino-2-[3-oxo-3-(3-pyrazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example M46) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (75 mg).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([CH:17]1[CH2:22][O:21][CH2:20][CH2:19][O:18]1)=[O:16].[CH:23](=[O:25])[CH3:24]>O1CCCC1>[CH3:13][O:14][C:15]([C:17]1([CH:23]([OH:25])[CH3:24])[CH2:22][O:21][CH2:20][CH2:19][O:18]1)=[O:16]
Reactant: COC(=O)C1COCCO1
Reactant: CC=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(C(C)O)COCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
A solution of N,N-diisopropylamine (1.67 g, 2.3 mL, 16.5 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at −78° C. under nitrogen. n-Butyllithium (6.6 mL, 16.5 mmol, 2.5 M solution in hexane) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. A solution of [1,4]dioxane-2-carboxylic acid methyl ester (1.61 g, 11 mmol) in tetrahydrofuran (10 mL) was added and the reaction mixture was stirred at −78° C. for 30 minutes. Acetaldehyde (1.45 g, 1.8 mL, 33 mmol) was added in one portion. The cooling bath was removed and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 5° C. and ice-cold 1 M hydrochloric acid was added to acidify the reaction mixture to pH 2. Sodium chloride was added to saturate the solution and the mixture was extracted with diethyl ether (4×). The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 1:1 to 0:1 to afford the title compound (1.49 g, 71%), as an oil, and as a 3:1 mixture of diastereoisomers. LCMS (m/z) 213.2 [M+H], Tr=0.62 min.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[CH3:22][S:23]([OH:26])(=[O:25])=[O:24]>CC(C)=O>[CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[S:23]([O-:26])(=[O:25])(=[O:24])[CH3:22]
Reactant: CS(=O)(=O)O
Agent: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Solvent: CC(C)=O
Product: CS(=O)(=O)[O-]

Procedure:
Clopidogrel base was dissolved in acetone to obtain a clear solution. Methanesulfonic acid was added to the solution at 20° C. The reaction mixture was heated to reflux temperature for 2 to 10 hrs. The solvent was evaporated to dryness under reduced pressure to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:13][CH2:12][CH2:11][NH:10][CH2:9][C:8]=2[CH:14]=1)([O-])=O.O.NN>C(O)C.[Pd]>[CH:14]1[C:8]2[CH2:9][NH:10][CH2:11][CH2:12][S:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:1]
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCCS2
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CNCCS2
Yield: 89.7 %

Procedure:
To a mixture of 2-nitro 6,7,8,9-tetrahydro-5-thia-8-aza-benzocycloheptene (1.0 g, 0.0047 mol), hydrazine hydrate (10 mL) in ethanol (40 mL) was added 10% palladium on carbon (0.2 g) and refluxed 3 days, filtered and concentrated to give 6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamine (0.76 g, 90%) as a yellow solid. MP: 110-111° C.; 1H-NMR (DMSO-d6) δ 7.08-15 (d, 1H), 6.45 (s, 1H), 6.25-33 (d, 1H), 5.15 (s, 2H), 3.78 (s, 2H), 3.10-20 (m, 2H), 2.50-60 (m, 2H), 2.00-22 (br, 1H); LC/MS (ESI+): 181 (M+H).