Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(C[O:9][C:10]([C:12]2[N:13]3[CH:16]([S:17][CH:18]=2)[C:15]([CH:20](OC(=O)C)[C:21]2[N:32]=[C:31]4[N:23]([C:24]5[CH2:25][CH2:26][CH2:27][C:28]=5[C:29]([O:33][CH2:34][CH3:35])=[N:30]4)[CH:22]=2)(Br)[C:14]3=[O:40])=[O:11])=CC=1)([O-])=O.[H][H]>C1COCC1.P([O-])([O-])([O-])=O>[CH2:34]([O:33][C:29]1[C:28]2[CH2:27][CH2:26][CH2:25][C:24]=2[N:23]2[C:31](=[N:32][C:21]([CH:20]=[C:15]3[C:14](=[O:40])[N:13]4[CH:16]3[S:17][CH:18]=[C:12]4[C:10]([OH:11])=[O:9])=[CH:22]2)[N:30]=1)[CH3:35]
Reactant: [H][H]
Reactant: CCOc1nc2nc(C(OC(C)=O)C3(Br)C(=O)N4C(C(=O)OCc5ccc([N+](=O)[O-])cc5)=CSC43)cn2c2c1CCC2
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: CCOc1nc2nc(C=C3C(=O)N4C(C(=O)O)=CSC34)cn2c2c1CCC2

Procedure:
6-[acetoxy-(5-ethoxy-7,8-dihydro-6H-3,4,8b-triaza-as-indacen-2-yl)-methyl]-6-bromo-7-oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (1.03 gram, 1.565 mmol) was suspended in 20 ml THF and 20 ml pH=6.5 aqueous phosphate buffer. The mixture was then subjected to 45 psi hydrogen for two hours. Then it was filtered through a pad of celite and concentrated in vacuo to remove most of the THF. The solution was then cooled to zero degree and basified to pH=8 with 1 N sodium hydroxide. Then it was purified via reverse phase HPLC using 1 liter of water followed by 5%˜25% acetonitrile and water. Water was then removed through concentrate in vacuo and 100 mg of product was collected.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O.[Cl-].[NH4+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:26][CH3:27])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCC(OC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 9 h
Yield: 76.3 %

Procedure:
A mixture of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (460 mg, 1.12 mmol), potassium carbonate (201 mg, 1.46 mmol) and methyl iodide (207 mg, 1.46 mmol) in N,N-dimethylformamide (4.5 mL) was stirred at room temperature for 9 hr. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (363 mg, 0.855 mmol, 76%).
Reaction SMILES: C([O:4][C:5]1[CH:35]=[CH:34][CH:33]=[CH:32][C:6]=1[C:7]([O:9][C:10]1[C:11]([CH3:31])=[C:12]([CH3:30])[C:13]2[O:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24]C(=O)C)[S:15][C:14]=2[C:28]=1[CH3:29])=[O:8])(=O)C.[OH-].[K+]>CO>[OH:4][C:5]1[CH:35]=[CH:34][CH:33]=[CH:32][C:6]=1[C:7]([O:9][C:10]1[C:11]([CH3:31])=[C:12]([CH3:30])[C:13]2[O:17][CH:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[OH:24])[S:15][C:14]=2[C:28]=1[CH3:29])=[O:8]
Reactant: CC(=O)Oc1ccccc1C(=O)Oc1c(C)c(C)c2c(c1C)SC(c1ccccc1OC(C)=O)O2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1OC(=O)c1ccccc1O)SC(c1ccccc1O)O2
Yield: 47 %

Procedure:
A mixture of 282 mg of 5-(o-acetoxybenzoyloxy)-2-(o-acetoxyphenyl)-4,6,7-trimethyl-1,3-benzoxathiole, 290 mg of potassium hydroxide and 3 ml of methanol was reacted at 10° C. for 12 hours. Subsequent treatment of the reaction mixture was conducted in the same manner as in Example 40. From the fraction eluted with a 50:1 by volume mixture of benzene and ethyl acetate from a silica gel chromatography column were obtained 110 mg of the title compound.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.CSC.[CH2:12]([O:19][C:20]1[C:25]([CH2:26]O)=[C:24]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:23]=[C:22]([CH3:37])[N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][C:20]1[C:25]([CH2:26][Cl:8])=[C:24]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:23]=[C:22]([CH3:37])[N:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(CO)c(OCc2ccccc2)n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CSC
Solvent: ClCCl
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(CCl)c(OCc2ccccc2)n1
Temperature: -40 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
To a 0° C. solution of NCS (70.2 mg, 0.515 mmol) in DCM (2 mL) was added DMS (34.9 mg, 0.562 mmol). The reaction mixture was cooled to −40° C., then a solution of [2-(benzyloxy)-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-methylpyridin-3-yl]methanol (Cpd J, 175 mg, 0.468 mmol) in DCM (1 mL) was added drop-wise keeping the internal temperature below −30° C. Upon complete addition the reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was washed with brine, dried with MgSO4, filtered, then concentrated under vacuum. The residue was purified by column chromatography (0-30% EtOAc/heptane) to give the title compound (Cpd K, 120 mg, 65%) as an oil. 1H NMR (400 MHz, chloroform-d) δ 7.50 (d, J=7.3 Hz, 2H), 7.44-7.29 (m, 3H), 6.94 (s, 1H), 5.46 (s, 2H), 4.83 (s, 2H), 4.70 (s, 2H), 2.47 (s, 3H), 0.97 (s, 9H), 0.14 (s, 6H); MS 392 [M+H].
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]([CH2:30][CH2:31][CH2:32][O:33]C)[C:16](=[O:29])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:10][CH2:9]1)(C)(C)C.B(Br)(Br)Br>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]([CH2:30][CH2:31][CH2:32][OH:33])[C:16](=[O:29])[CH:17]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[C:22]([F:28])[CH:21]=3)[N:19]=2)[CH2:12][CH2:13]1
Reactant: COCCCn1c(N2CCC(NC(=O)OC(C)(C)C)CC2)nc(-c2ccc(C#N)c(F)c2)cc1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1ccc(-c2cc(=O)n(CCCO)c(N3CCC(N)CC3)n2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a solution of {1-[4-(4-cyano-3-fluoro-phenyl)-1-(3-methoxy-propyl)-6-oxo-1,6-dihydro-pyrimidin-2-yl]-piperidin-4-yl}-carbamic acid tert-butyl ester (200 mg, 0.41 mmol) in DCM was added 1M BBr3 (4 mL) at −78° C. The mixture was stirred at RT for 2 h and quenched at 0° C. with MeOH. The solution was washed with aqueous saturated NaHCO3. The organic layer was dried and concentrated. The residue was purified by preparative HPLC to give 35 mg of the title product as the hydrochloride salt (23%). 1H NMR (400 MHz, CD3OD): 1.65-1.69 (m, 2H), 1.97-2.19 (m, 4H), 3.13-3.22 (m, 2H), 3.48-3.55 (m, 1H), 3.73 (t, J=8.0 Hz, 2H), 4.55 (t, J=8.0 Hz, 2H), 4.94-4.95 (m, 2H), 6.71 (s, 1H), 7.88-8.05 (m, 3H). [M+H] Calc'd for C19H22FN5O2, 371. Found, 371.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[O:21][CH2:22][CH3:23].[OH-].[NH4+:25].Cl>O>[NH2:25][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1[O:21][CH2:22][CH3:23]
Reactant: CCOc1c(Cl)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)O
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: O
Product: CCOc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)O
Temperature: 80 °C
Yield: 66.5 %

Procedure:
6-Chloro-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-ethoxy-pyrimidine-4-carboxylic acid (380 mg, 1.1 mmol) was slurried in water (3.5 mL) and 28% aqueous ammonium hydroxide solution (720 μL, 10.6 mmol) was added. The reaction mixture was sealed and heated at 80° C. for 24 h. The reaction mixture was then acidified to pH 7 via dropwise addition of concentrated hydrochloric acid, and the crude product transferred into a 500 mL separatory funnel containing 100 mL 0.1M hydrochloric acid solution. The product was then extracted with dichloromethane five times. The combined organic layers were then dried, filtered and concentrated to yield the title compound (250 mg, 69% yield) as a tan solid: 1H NMR (DMSO-d6) δ 7.58 (dd, 1H, J=8, 9 Hz), 7.38 (dd, 1H, J=2, 9 Hz), 3.98 (q, 2H, J=7 Hz), 3.90 (d, 3H, J=1 Hz), 1.31 (t, 3H, J=7 Hz).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:36][C:37]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:43]=[CH:42][C:38]=1[C:39](O)=[O:40]>C(Cl)(Cl)Cl>[F:36][C:37]1[C:45]([C:46]([F:47])([F:48])[F:49])=[CH:44][CH:43]=[CH:42][C:38]=1[C:39]([N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1)=[O:40]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cccc(C(F)(F)F)c2F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 3.66 g of 1-Boc-piperazine, 4.53 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 3.61 g of 1-hydroxybenzotriazole, 4.50 g of 2-fluoro-3-(trifluoromethyl)benzoic acid and 40 ml of chloroform was stirred at room temperature for 4 hours. The reaction mixture was diluted with chloroform and then was washed with water and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=4/1 to 2/1) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:22].Cl>CCO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[N:16][C:17]([CH2:20][NH2:21])=[CH:18][CH:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:22]
Reactant: Cc1cc(-c2ncccc2-c2ccc(C#N)nc2)ccc1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1cc(-c2ncccc2-c2ccc(CN)nc2)ccc1F
Reaction time: 0.5 h
Yield: 94.1 %

Procedure:
2′-(4-Fluoro-3-methylphenyl)-[3,3′-bipyridine]-6-carbonitrile (2.2 g), Pd/C (0.4 g) and conc. HCl (3 mL) in EtOH (100 mL) was hydrogenated in a par shaker at 40 psi overnight. The reaction mixture was filtered through Celite® and concentrated. The concentrate was treated with CH2Cl2 (120 mL) and sat. aq. NaHCO3 (25 mL). Organic layer was separated and the aqueous layer was re-extracted with CH2Cl2 (2×50 ml). Combined organic layers were stirred over anhydrous Na2SO4 for 30 min, filtered, concentrated and dried under high vacuum to obtain thick viscous liquid of (2′-(4-Fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methanamine (2.1 g, purity 97%). 1H NMR (300 MHz, DMSO-d6): δ 8.66 (dd, J=4.7, 1.6 Hz, 1H), 8.26 (s, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.54 (dd, J=8.0, 2.2 Hz, 1H), 7.48 (dd, J=7.7, 4.8 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.97 (dd, J=6.9, 1.5 Hz, 2H), 3.78 (s, 2H), 2.58 (br s, 2H), 2.16 (s, 3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]2=[CH:14][N:15]([C:17]3[C:22]([Cl:23])=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=3[Cl:26])[N:16]=[C:12]2[CH:11]=[CH:10][N:9]=1)(C)(C)C.Cl>>[NH2:7][C:8]1[C:13]2=[CH:14][N:15]([C:17]3[C:22]([Cl:23])=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=3[Cl:26])[N:16]=[C:12]2[CH:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc2nn(-c3c(Cl)cc(C#N)cc3Cl)cc12
Agent: Cl
Product: N#Cc1cc(Cl)c(-n2cc3c(N)nccc3n2)c(Cl)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 31.1 %

Procedure:
A mixture of [2-(2,6-dichloro-4-cyano-phenyl)-2H-pyrazolo[4,3-c]pyridin-4-yl]carbamic acid tert-butyl ester (5.0 g, contaminated with residual tert-butyl carbamate) and HCl (4 N in dioxane, 40 mL, 160 mmol) was stirred at 50° C. for 6 h then concentrated to dryness under reduced pressure. The resultant residue was partitioned between ethyl acetate and sodium bicarbonate (sat. aq.). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to afford the title compound as a yellow solid (1.17 g, 39% yield over 2 steps). 1H NMR (400 MHz, CDCl3): δ 8.95 (s, 1H), 8.48 (s, 2H), 7.58 (d, J=6.9 Hz, 1H), 7.27-7.22 (m, 1H), 7.19-7.14 (m, 1H), 6.91-6.88 (m, 1H). LCMS (Method D): RT=1.95 min, m/z: 304 [M+H+].
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:15]C)(=O)[CH2:9][C:10]([O:12][CH3:13])=[O:11].[Na]>CO>[C:10]([O:12][CH2:13][C:5]1[O:6][CH:2]=[CH:3][CH:4]=1)(=[O:11])[CH2:9][C:8]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)=[O:15]
Reactant: OCc1ccco1
Reactant: COC(=O)CC(=O)OC
Agent: [Na]
Solvent: CO
Product: O=C(CC(=O)OCc1ccco1)OCc1ccco1
Reaction time: 4 h

Procedure:
196 parts by wt. of furfuryl alcohol and 132 parts by wt. dimethyl malonate (stoichiometric proportions) are mixed and 0.5-0.75% wt. sodium metal added. The mixture is heated to a temperature in the range from 214°-240° F. under a nitrogen atmosphere. Methanol is evolved and removed as the reaction progressed. After a period of 4 hours, a waxy solid is obtained. The liquid product obtained after washing with water is difurfuryl malonate.
Reaction SMILES: [CH3:1][NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1.Cl[C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([N+:33]([O-:35])=[O:34])=[CH:28][N:27]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[CH3:1][N:2]([C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]3[CH:16]=[CH:15][N:14]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:4]1)[C:26]1[CH:31]=[C:30]([CH3:32])[C:29]([N+:33]([O-:35])=[O:34])=[CH:28][N:27]=1
Reactant: CN[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(N(C)[C@@H]2CCN(c3ncnc4c3ccn4COCC[Si](C)(C)C)C2)ncc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 86.3 %

Procedure:
A solution of (R)—N-methyl-1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-amine (0.287 mmol), 2-chloro-4-methyl-5-nitropyridine (0.347 mmol), and DIPEA (1.435 mmol) in NMP (1.5 mL) was stirred at 200° C. for 30 minutes in a microwave reactor and then cooled to ambient temperature. The solution was poured into water, extracted with EtOAc, concentrated, and purified by column chromatography to give the title compound in 86.3% yield.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:21]Cl>O1CCCC1.CN(C)C=O>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][CH2:21][S:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: ClCOc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccccc1S
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1SCOc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A solution of 28 g (0.25 mol) of potassium tert.-butylate in 120 ml of tetrahydrofuran was slowly added dropwise to a solution of 33.6 g (0.2 mol) of methyl 2-mercapto-benzoate in 50 ml of tetrahydrofuran at 5° C. At the end of the dropwise addition, stirring was continued at 5° C. for a further 30 minutes. The solid product precipitated was filtered off with suction and dissolved in 100 ml of dimethylformamide. A solution of 42.3 g (0.2 mol) of chloromethyl 2,4-dichlorophenyl ether in 60 ml of dimethylformamide was added dropwise to this solution, while stirring at 25° C. The mixture was subsequently stirred at 30° C. for 1 hour and then worked up by stirring into 1.5 liters of ice-water. The suspension thereby formed was filtered off with suction and the solid product precipitated was dried in air. 62 g (90.4% of theory) of 1-(2,4-dichlorophenoxy)-1 -(2-methoxycarbonyl-phenylthio)-methane were obtained in this manner in the form of colourless crystals of melting point 122°-124° C.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH3:13][NH2:14]>C(#N)C>[CH3:13][NH:14][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5]
Reactant: O=S(=O)(CCCl)c1ccccc1
Reactant: CN
Solvent: CC#N
Product: CNCCS(=O)(=O)c1ccccc1

Procedure:
A solution of 2-chloroethylphenyl sulfone and a large excess of methylamine (40% solution in water) in acetonitrile is stirred at room temperature overnight. The solvent is removed in vacuo and the residue is partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution is extracted with dilute sulfuric acid. The acidic extract is made basic with 50% sodium hydroxide and the basic solution is extracted with methylene chloride. The methylene chloride solution is dried over magnesium sulfate and the solvent is removed in vacuo to give the title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6]O.[NH:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][N:8]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: OC[C@H]1CCCO1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C[C@H]1CCCO1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To a mixture of (R)-(tetrahydrofuran-2-yl)methanol (Fluka, 4.0 g, 39.2 mmol) and di-tert-butyl hydrazine-1,2-dicarboxylate (9.1 g, 39.2 mmol) in THF (50 mL) was added triphenylphosphine (14.4 g, 54.8 mmol) followed by (E)-di-tert-butyl diazene-1,2-dicarboxylate (12.6 g, 54.8 mmol) portionwise. This mixture was stirred at ambient temperature for 16 hours then concentrated under reduced pressure and purified by column chromatography (SiO2, 1-25% EtOAc/hexanes gradient) to give the title compound (11.8 g, 37.3 mmol, 95% yield). MS (DCI/NH3) m/z 317 (M+H)+.
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[CH:12][C:11]=2[O:19][CH3:20])[CH:7]=[CH:8][CH:9]=1>CO.O1CCCC1.[Pd]>[ClH:1].[ClH:1].[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[C:14]([CH:13]=[CH:12][C:11]=2[O:19][CH3:20])[NH2:16])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1cccc(CN)c1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(N)cc1-c1cccc(CN)c1
Reaction time: 24 h
Yield: 149.7 %

Procedure:
To a solution of 2-(3-aminomethylphenyl)-4-nitroanisole hydrochloride (1.26 g, 4.2 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL) under nitrogen was added palladium on carbon (10% by weight, 200 mgs, 15 wt. %). The solution was purged with hydrogen and stirred under hydrogen for 24 hours. The reaction was purged with nitrogen and the catalyst was removed by filtration. Solvent was removed in vacuo and the residue was redissolved in dichloromethane (10 mL) and hydrochloride acid was added (4.0 M solution in dioxane, 1.5 equiv., 1.57 mL). The solution was stirred for 1 hour while a solid precipitated. The solid was collected on a Buchner funnel and dried under vacuum to afford 3-(3-aminomethylphenyl)-4-methoxyaniline dihydrochloride (947 mgs, 73% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)=[O:14])=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[H-].[Na+].[CH3:31]I.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][N:22]=3)[CH2:19][CH2:20]2)=[O:14])=[C:6]([N:8]([CH3:31])[S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3NS(C)(=O)=O)CC2)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3N(C)S(C)(=O)=O)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-{5-bromo-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (634 mg) described in Preparation Example 226 was dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (65.1 mg, 60% in oil) was added under ice-cooling. After stirring at room temperature for 10 min, methyl iodide (93 μL) was added, and the mixture was stirred overnight. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (ethyl acetate:hexane) to give the title compound (670 mg).
Reaction SMILES: [OH-].[K+].[N+:3]([CH:6]=[C:7](SC)[S:8]([CH3:10])=O)([O-:5])=[O:4].Cl.[NH2:14][CH2:15][C:16](=O)[CH3:17]>CO>[CH3:10][S:8][C:7]1[NH:14][CH:15]=[C:16]([CH3:17])[C:6]=1[N+:3]([O-:5])=[O:4]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: CC(=O)CN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CSc1[nH]cc(C)c1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 16.8 %

Procedure:
Crushed potassium hydroxide (5.7 g, 0.1 mol) was added portionwise to a refluxing solution of 1-nitro-2-methylthio-2-methylsulphinylethylene (9.3 g, 0.05 mol) and aminoacetone hydrochloride (5.6 g, 0.05 mol) in methanol (100 ml). Reflux was continued for 5 minutes, and then the mixture was cooled and the solvent removed in vacuo. Water was added to the residue, and the solid was recrystallised from chloroform/methanol/petroleum ether to give 2-methylthio-3-nitro-4-methylpyrrole (1.45 g, 16%) m.p. 216-216-5.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH2:25]([O:32][CH2:33][C@H:34]([CH3:37])[CH:35]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCCCCC>C(Cl)Cl>[CH2:25]([O:32][CH2:33][C@@H:34]([CH3:37])[CH:35]=[C:20]([Br:24])[Br:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: C[C@H](C=O)COCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: C[C@@H](C=C(Br)Br)COCc1ccccc1
Temperature: 2.5 °C

Procedure:
An oven dried three-necked 2 L round bottom flask was equipped with a mechanical stirrer, a thermometer, an N2 inlet, and a septum. The flask was charged with 180.71 g (0.689 mol) of triphenylphosphine and 925 mL of CH2Cl2. The reaction mixture was stirred under an N2 atmosphere and cooled to 0-5° C. with an external ice-water bath. The septum was then removed and 114.25 g (0.344 mol) of carbon tetrabromide was added in portions through the open neck of the flask at a rate that maintained the temperature of the reaction mixture below 20° C. After the addition was complete the reaction was stirred for 1 h and then a solution of the (S)-3-benzyloxy-2-methylpropanal from the previous step dissolved in 150 mL of CH2Cl2 was added via cannula over a 5 min period. The reaction mixture was stirred under N2 for an additional 1 h and allowed to warm to room temperature. A separate 10 L three-necked round bottom flask was equipped with a mechanical stirrer and charged with 4 L of hexane. The stirrer was started and the crude reaction mixture was introduced as a slow stream which resulted in formation of a granular precipitate. After the transfer was complete the reaction mixture was filtered and the solids were carefully washed with hexane. The filtrate was evaporated in vacuo and additional solids were deposited. The residue was resuspended in hexane, filtered and the filtrate reevaporated. The resulting oil was purified by Kugelrohr distillation to afford 46.54 g (81% for two steps) of the title compound as an oil.