Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([O:39][CH3:40])=[C:14]([NH:17][C:18]3[NH:23][C:22]4=[N:24][CH:25]=[CH:26][C:21]4=[C:20]([NH:27][C:28]4[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:29]=4[C:30]([NH:32]C)=[O:31])[N:19]=3)[CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6].ClC1N=C(NC2C=CC=C(F)C=2C(N)=O)C2C=CN(S(C3C=CC(C)=CC=3)(=O)=O)C=2N=1.[OH-].[NH4+].CN(C)CCC(N1C2C(=CC(OC)=C(N)C=2)CCC1)=O>>[CH3:41][N:2]([CH3:1])[CH2:3][CH2:4][C:5]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([O:39][CH3:40])=[C:14]([NH:17][C:18]3[NH:23][C:22]4=[N:24][CH:25]=[CH:26][C:21]4=[C:20]([NH:27][C:28]4[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:29]=4[C:30]([NH2:32])=[O:31])[N:19]=3)[CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCCN3C(=O)CCN(C)C)[nH]c2nccc1-2
Agent: COc1cc2c(cc1N)N(C(=O)CCN(C)C)CCC2
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(F)c4C(N)=O)nc(Cl)nc32)cc1
Agent: [NH4+]
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3ccnc-3[nH]1)N(C(=O)CCN(C)C)CCC2

Procedure:
According to General Protocol III, 2-[(2-{[1-(N,N-dimethyl-β-alanyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (0.043 g) was prepared from 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (0.15 g, 0.33 mmol), 27% aqueous ammonium hydroxide, and 1-[3-(dimethylamino)propanoyl]-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinamine (0.12 g, 0.42 mmol). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80-1.90 (m, 2 H), 1.97-2.08 (bs, 6 H), 2.53-2.59 (m, signal underneath DMSO, 2 H), 2.63-2.71 (m, 2 H), 2.73-2.83 (m, 2 H), 3.68 (m, 2 H), 3.86 (s, 3 H), 6.27 (s, 1 H), 6.83-6.88 (m, 1 H), 6.90-6.98 (m, 1 H), 7.00-7.05 (m, 1 H), 7.39-7.48 (m, 1 H), 7.56 (s, 1 H), 8.00-8.11 (m, 2 H), 8.31 (s, 1 H), 8.45 (d, J=7.7 Hz, 1 H), 10.47 (s, 1 H), 11.82 (bs, 1 H); ESIMS (M+H)+=547.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:15](=[O:16])[C:14]4[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=4[S:12]3(=[O:22])=[O:21])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[CH2:24][C:25]([O:27][CH3:28])=[O:26].[H-].[Na+]>CS(C)=O.Cl>[CH3:28][O:27][C:25]([C:24]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[S:12](=[O:22])(=[O:21])[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[C:15]=1[OH:16])=[O:26]
Reactant: O=C1c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Reactant: COC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Temperature: 40 °C
Yield: 43.5 %

Procedure:
To 2-Benzo[1,3]dioxol-5-ylmethyl-1,1-dioxo-1,2-dihydro-1λ6 -benzo[d]isothiazol-3-one (1.115 g, 3.517 mmol) in DMSO(6 mL) was added methyl 2-chloroacetate (0.61 mL, 6.96 mmol). The mixture was heated to 40° C. and sodium hydride (0.562 g, 60% in oil, 14 mmol) was added slowly over 1 hour. The mixture was maintained at 40° C. for 3 h and then cooled to room temperature and diluted with 1N HCl (100 mL). The mixture was extracted with ethylacetate (2×100 mL) and the organic phase washed with brine and dried over MgSO4. Chromatography, silica gel, eluant CHCl3, and crystallization from methylene chloride/hexane afforded the required product (0.596 g, 44%);
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1.C1COCC1.Cl>C(Cl)Cl.[I-].[Zn+2].[I-]>[NH2:6][CH2:5][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH3:7])=[CH:10][CH:11]=1)([OH:17])[CH3:16]
Reactant: C[Si](C)(C)C#N
Reactant: COc1ccc(C(C)=O)cc1
Agent: Cl
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C(C)(O)CN)cc1
Temperature: 25 °C
Yield: 24 %

Procedure:
Into a 100 mL single-neck flask, 28.5 mL of trimethylsilyl cyanide was added dropwise to 10 g of 4′-methoxyacetophenone and 2.28 g of zinc iodide while stirring under a nitrogen atmosphere at room temperature. The reaction was allowed to stir at this temperature overnight. In the morning, the mixture was diluted with methylene chloride (100 mL) and the organic layer was backwashed once with sat. Na2HCO3, dried over MgSO4, and concentrated under reduced vacuum to yield 13 g. as a tan oil. Because of possible stability problems, this material was used immediately and placed into 200 mL THF in a 500 mL single-neck flask. While stirring at room temperature under a nitrogen atmosphere, 70 mL of BH3-THF complex was added syringe wise and the reaction was stirred overnight. In the morning, 10 mL of concentrated hydrochloric acid was added dropwise at room temperature and severe foaming was present. The mixture was then concentrated under reduced vacuum. The resulting HCl salt was liberated while being stirred in 1N NaOH and the free amine was extracted into ethyl acetate. This organic layer was washed with H2O, dried over Na2SO4, and concentrated under reduced vacuum to yield 7.31 g. of a 2 spot material. This material was purified via silica gel chromatography employing the Water's prep. 2000 and eluting with a solvent of methylene chloride/methanol 9:1 to yield intermediate title compound (3.01 g, 24%) as an oil as the top spot. (FD) M.S. 180.3 (M*−1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35](Br)=[CH:34][N:33]=3)[N:18]=[C:17]([CH2:39][CH2:40][CH3:41])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:42]1[CH:46]=[CH:45][CH:44]=[C:43]1[Sn](CCCC)(CCCC)CCCC.O1CCOCC1.[F-].[K+]>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:28][CH2:29][CH2:30][O:31][C:32]3[N:37]=[CH:36][C:35]([C:43]4[S:42][CH:46]=[CH:45][CH:44]=4)=[CH:34][N:33]=3)[N:18]=[C:17]([CH2:39][CH2:40][CH3:41])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: CCCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(-c2ccc(C)cc2)c(OCCOc2ncc(Br)cn2)n1
Agent: Cl[Pd]Cl
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(-c2ccc(C)cc2)c(OCCOc2ncc(-c3cccs3)cn2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
A mixture of 4-tert-butyl-N-[6-{2-(5-bromopyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)-2-n-propylpyrimidin-4-yl]benzenesulfonamide (300 mg), 2-thienyltributyltin (670 mg), bis(triphenylphosphine)palladium (II) chloride (16 mg) and dioxane (5 ml) is refluxed for 80 minutes. After cooling, the reaction solution is diluted with ethyl acetate, and thereto is added 10% aqueous potassium fluoride solution. The mixture is stirred at room temperature for one hour, and the reaction solution is washed, dried, and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane/ethyl acetate=30:1~10:1), and crystallized from methylene chloride/n-hexane to give 4-tert-butyl-N-[6-{2-(5-(2-thienyl)pyrimidin-2-yloxy)ethoxy}-5-(4-methylphenyl)-2-n-propylpyrimidin-4-yl]-benzenesulfonamide (209 mg) as crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7](O)[CH3:8].S(Cl)([Cl:12])=O>ClCCl>[Cl:12][CH:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccccn1
Solvent: ClCCl
Product: CC(Cl)c1ccccn1
Temperature: 20 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To an ice-cooled solution of 1-(pyridin-2-yl)ethanol (4.5 g, 36 mmol) in dry dichloromethane (100 mL) was slowly added thionyl dichloride (20 mL). The mixture was then warmed to 20° C. After 2 h, the reaction was concentrated in vacuo, and the resulting residue was diluted with water (40 mL) and dichloromethane (60 mL). The solution was neutralized with saturated aqueous sodium carbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution (3×30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude 2-(1-chloroethyl)pyridine (5.0 g, 97% yield). The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:21][O:22][C:23](=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br.[I-].[Na+]>CN(C)C=O>[CH3:21][O:22][C:23](=[O:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:8]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COC(=O)CCCCCCCCCCBr
Reactant: COc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
As described in example 1(a), the reaction is carried out with 28.7 g (0.11 mol) of 4-chloro-N-(4-methoxyphenyl)-benzamide, 4.5 g (0.18 mol) of sodium hydride, 36.7 g (0.13 mol) of 11-bromoundecanoic acid methyl ester, 100 cc. of dimethylformamide and 3 g (0.02 mol) of sodium iodide. Reaction time: 5 hours, reaction temperature: 80° C. The crude product is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([CH2:14][CH3:15])[CH2:11][C@H:10]1[C:16]([O:18]C)=[O:17].C[Si](C)(C)[O-].[K+].[ClH:26]>C(OCC)C.O1CCOCC1>[ClH:26].[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([CH2:14][CH3:15])[CH2:11][C@H:10]1[C:16]([OH:18])=[O:17]
Reactant: CCN1C[C@@H](C(=O)OC)[C@H](c2ccc(F)cc2F)C1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCN1C[C@@H](C(=O)O)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of methyl (3S,4R)-4-(2,4-difluorophenyl)-1-ethylpyrrolidine-3-carboxylate, from preparation 18 (5.9 g, 22 mmol) in diethyl ether (59 mL) at room temperature under dry nitrogen was added potassium trimethylsilanolate (2.36 g, 26 mmol) in a single portion. The resulting mixture was stirred at room temperature under N2 for 3 hours. A solution of 4M hydrogen chloride in dioxane (20 mL) was then added and the resulting mixture was stirred under dry nitrogen at room temperature for 18 hours, and then concentrated in vacuo to afford the title compound as a white solid containing potassium chloride residues (7.0 g).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C(O[C:12]([C:14]1[O:15][C:16]2[CH:27]=[CH:26][CH:25]=[CH:24][C:17]=2[C:18]=1[N:19]=[CH:20]N(C)C)=[O:13])C.C(O)(=O)C>O1CCCC1>[OH:13][C:12]1[C:2]([C:1]#[N:3])=[CH:20][N:19]=[C:18]2[C:17]3[CH:24]=[CH:25][CH:26]=[CH:27][C:16]=3[O:15][C:14]=12
Reactant: CC#N
Reactant: CCOC(=O)c1oc2ccccc2c1N=CN(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cnc2c(oc3ccccc32)c1O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
A solution of 1.5 mL (30.0 mmol) of acetonitrile in 30 mL of tetrahydrofuran is added to a −78° C. solution of 11.4 mL of 2.5 M n-butyllithium (29.00 mmol) in 35 mL of tetrahydrofuran. After stirring at −78° C. for 15 min a solution of 3.7 g (14.2 mmol) of 3-(dimethylaminomethyleneamino)benzofuran-2-carboxylic acid ethyl ester in 50 mL of tetrahydrofuran is added dropwise. After stirring at −78° C. for 30 minutes, the reaction mixture is allowed to warm to 0° C. The reaction mixture is cooled to −78° C. and 3 mL of acetic acid is added. The solution is warmed to room temperature and the resulting precipitate is collected. This solid is combined with 20 mL of acetic acid and heated at reflux temperature for 1.5 hours. The mixture is cooled to room temperature and the solid is collected by filtration washing with saturated sodium bicarbonate, water, diethyl ether and ethyl acetate to provide 2.45 g of a red solid, mp>310° C.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.CO.[NH4+].[Cl-]>CN(C=O)C.O>[CH3:27][O:26][C:22](=[O:25])[CH2:23][CH2:24][N:14]1[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:12]([CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:13]1=[O:21]
Reactant: C=CC(=O)OC
Reactant: O=c1[nH]c2ccccc2n1Cc1cccc2ccccc12
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.6 %

Procedure:
To a solution of 1-naphthalen-1-ylmethyl-1,3-dihydro-benzimidazol-2-one (200 mg, 0.73 mmol) in DMF (3.0 mL) are added methyl acrylate (0.07 mL, 0.8 mmol) and 40% benzyltrimethyl ammonium hydroxide in MeOH (0.03 mL, 0.073 mmol). The resulting mixture is stirred at room temperature for 1.5 h and then Sat. NH4Cl (5 mL) and water (20 mL) are added. The mixture is extracted with EtOAc (3×50 mL) and the organic layers are combined, washed with water (3×75 dried over MgSO4 and concentrated to give crude product. Purification by flash column chromatography using 30% EtOAc in Hexanes affords 220 mg (84%) of 3-(3-naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]=[C:12](SC)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:20]([C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3([C:37]([NH:39][NH2:40])=O)[CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[N:26][CH:27]=1)#[N:21]>C(O)CCC>[Si:1]([O:8][CH2:9][C:10]1([CH3:19])[S:16][CH2:15][CH2:14][N:13]2[C:37]([C:34]3([C:31]4[CH:32]=[CH:33][C:28]([C:25]5[CH:24]=[CH:23][C:22]([C:20]#[N:21])=[CH:27][N:26]=5)=[CH:29][CH:30]=4)[CH2:36][CH2:35]3)=[N:39][N:40]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(-c2ccc(C3(C(=O)NN)CC3)cc2)nc1
Reactant: CSC1=NCCSC(C)(CO[Si](C)(C)C(C)(C)C)C1
Solvent: CCCCO
Product: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(C#N)cn5)cc4)CC3)n2CCS1
Temperature: 25 °C
Yield: 88.8 %

Procedure:
A solution of 7-({[tert-butyl(dimethyl)silyl]oxy}methyl)-7-methyl-5-(methylthio)-2,3,6,7-tetrahydro-1,4-thiazepine (39.7 g, 124 mmol) and the compound (19.5 g, 70.1 mmol) obtained in Example 60-3) in 1-butanol (750 mL) was stirred at 140° C. for 13 h. The reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:methanol=9:1) to obtain the title compound (33.1 g, 89%) as a white solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14](=O)/[C:15](/[F:29])=[CH:16]/[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:19][CH:18]=1)C>C(Cl)Cl>[F:29]/[C:15](=[CH:16]\[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:24]=[CH:25][CH:26]=[CH:27][N:28]=2)=[CH:21][CH:22]=1)/[CH2:14][OH:13]
Reactant: CCOC(=O)/C(F)=C/c1ccc(-c2ncccn2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OC/C(F)=C/c1ccc(-c2ncccn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
Diisobutylaluminum hydride (1.0 M solution in THF, 5.5 mL, 5.50 mmol) was added dropwise to a 0° C. solution of the product from step A (500 mg, 1.84 mmol) in methylene chloride (15 mL). The resulting solution was stirred for 10 min at 0° C., quenched with methanol (0.25 mL) followed by 15% aq. Rochelle salt (20 mL), and allowed to stir at room temperature for 4 h. The layers were separated and the aqueous layer was extracted with methylene chloride (20 mL). The combined organic layers were dried (MgSO4) and concentrated to provide 415 mg (98%) of the title compound as a colorless solid. MS 231 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:21])[C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[F:20])=[C:4](F)[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=3[F:20])[S:21][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(C(=S)Nc2ccc(Br)cc2F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2nc3ccc(Br)cc3s2)c(F)c1
Temperature: 110 °C
Reaction time: 17 h
Yield: 63.4 %

Procedure:
Intermediate 33 (600 mg, 1.47 mmol) dissolved in DMF (7 ml) and added Na2CO3 (156 mg, 1.47 mmol). This mixture stirred at 110° C. for 17 h. Work up (EtOAc/H2O) afforded the crude. Crude was triturated with Petether and dried to obtain the titled compound (360 mg) as a white solid. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.71-8.65 (m, 1H), 8.13 (d, J 1.9, 1H), 8.01 (d, J 8.7, 1H), 7.91-7.83 (m, 2H), 7.66 (dd, J 1.9, 8.7, 1H), 3.12 (s, 3H).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8])([O-])=O>C(O)C>[NH2:2][C:5]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(N)cc1N
Reaction time: 1.5 h
Yield: 70 %

Procedure:
A solution of 74.6 g. of stannous chloride dihydrate, 75 ml. concentrated HCl, and 150 ml. ethanol was cooled in an ice bath and stirred while adding 9.66 g. (0.05 mole) of powdered 2,4-dinitrobenzonitrile at a rate that maintained a temperature of 25°-30° C. The resulting yellow solution was held at 40° C. for 90 minutes while a stream of nitrogen was blown over the surface to evaporate most ot the ethanol. The residue was a yellow slurry, which was cooled in an ice bath and stirred while a solution of 70 g. NaOH in 280 g. of water was added slowly. The mixture was then filtered. The filtrate was extracted four times with ethyl acetate and the extract evaporated to dryness. The residue was combined with the solids from the filtration, and the mixture was extracted with four 150 ml. portions of boiling benzene. The benzene solution was evaporated to dryness to give 4.75 g. of crude product, which was recrystallized from benzene to give 4.67 g. (70% yield) of pure 2,4-diaminobenzonitrile, m.p. 105° C. Anal. Calculated for C7H7N3 : C, 63.19; H, 5.30; N, 31.56. Found: C, 62.54, 62.67; H, 5.24, 5.09; N, 31.32, 31.10.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].C(N(CC)CC)C.[CH:15]1[C:25]2[C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[C:22](=[O:30])[O:21][C:20](=[O:31])[C:19]=2[CH:18]=[CH:17][CH:16]=1.Cl>C(Cl)Cl>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:22]([C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[C:25]1[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=1[C:20]([OH:31])=[O:21])=[O:30]
Reactant: CC(C)(S)CN
Reactant: O=c1oc(=O)c2ccccc2c2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(S)CNC(=O)c1ccccc1-c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To an ice-cooled suspension of 1-amino-2-methyl-2-propanethiol hydrochloride (1.08 g, 7.62 mmol) in methylene chloride (20 mL) was added triethylamine (1.2 mL, 8.61 mmol) followed by dibenzo[c,e]oxepin-5,7-dione (1.68 g, 7.42 mmol). After stirring at room temperature for 1 h, cold 2 N HCl (50 mL) was added. After separation, the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic layers were washed with brine and dried under sodium sulfate. The solvent was removed and the resulting residue was triturated with hexane to give the title compound as white solid (2.44 g, 98.9%). mp 150-153° C.; 1H NMR (CDCl3, 300 MHz): δ1.03 (s, 3H), 1.12 (s, 3H), 1.36 (s, 1H), 3.15 (dd, J=13.7 and 5.7 Hz, 1H), 3.38 (dd, J=13.7 and 6.9 Hz, 1H), 6.92 (t, J=6.1 Hz, 1H), 7.09-7.17 (m 2H), 7.38-7.48 (m, 4H), 7.57-7.61 (m, 1H), 7.80-7.83 (m, 1H); 13C NMR (CDCl3, 75 MHz,): δ29.36, 29.75, 44.66, 53.01, 127.28, 127.96, 128.04, 129.38, 129.93, 130.06, 130.20, 131.19, 132.02, 134.69, 138.90, 140.11, 170.99, 171.24; LCMS (m/e): 330 (M+1).
Reaction SMILES: [CH:1]1([C:7]2([N+:15]([O-])=O)[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Ni]>[NH2:15][C:7]1([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:12][N:11]([CH3:13])[C:10](=[O:14])[CH2:9][CH2:8]1
Reactant: CN1CC(C2CCCCC2)([N+](=O)[O-])CCC1=O
Agent: [Ni]
Solvent: CO
Product: CN1CC(N)(C2CCCCC2)CCC1=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 103.3 %

Procedure:
To a solution of 500 mg (2.08 mmol) rac-5-cyclohexyl-1-methyl-5-nitro-piperidin-2-one in 5 ml methanol were added 500 mg wet Raney Nickel and the mixture stirred under a hydrogen atmosphere at normal pressure and ambient temperature for 22 hours. Then the reaction mixture was filtered through a Dicalite pad, the precipitate washed with methanol and the filtrate evaporated: 452 mg title compound were obtained as colourless oil which was used without purification for the next step.
Reaction SMILES: [CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@@H:12]([CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:24][CH2:23]2)[CH2:11]1)C(OC(C)(C)C)=O.[C:45](Cl)(=[O:52])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>>[CH3:1][N:2]([C@H:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@H:12]([CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([N:28]([C:32]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][C:39]([N+:42]([O-:44])=[O:43])=[CH:40][CH:41]=3)=[O:33])[CH2:29][CH:30]=[CH2:31])[CH2:26][CH2:27]2)[CH2:11]1)[C:45]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:52]
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](N(C)C(=O)c3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-(N-(methyl)-N-(t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 31 in Step A and benzoyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:16]2[S:15][C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=3)[C:8](=[O:19])[C:7]=2[C:6]([NH:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C(Cl)(Cl)Cl>[CH2:26]([N:23]([CH2:24][CH3:25])[CH2:22][CH2:21][NH:20][C:6]1[C:7]2[C:8](=[O:19])[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([O:17][CH3:18])[CH:10]=3)[S:15][C:16]=2[C:3]([CH2:2][NH:1][C:36](=[O:37])[O:38][CH3:39])=[CH:4][CH:5]=1)[CH3:27]
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccc(OC)cc3c(=O)c12
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNc1ccc(CNC(=O)OC)c2sc3ccc(OC)cc3c(=O)c12
Temperature: 25 °C

Procedure:
To a solution of 1.55 g of 4-(aminomethyl) -1-[[2-(diethylamino)ethyl]amino]-7-methoxythioxanthen-9-one in 40 mL of chloroform containing 2 mL of triethylamine chilled to 0° C. was added 0.45 mL of methyl chloroformate and the mixture was stirred at room temperature for several hours. The solvent was removed in vacuo, the residue was purified by flash chromatography (silica gel; eluting with chloroform, then 1% triethylamine in chloroform/hexane (1:1)) affording 1.2 g of methyl N-[[1-[[2-(diethylamino) ethyl]amino]-7-methoxy-9-oxothioxanthen-4-yl]methyl]carbamate which was recrystallized from ethyl acetate to yield 0.79 g of a bright yellow solid, m.p. 131°-132° C.