Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[O:29]1[C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][NH:31][C:30]1=[O:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]1[C:10]([CH2:11][N:36]2[CH2:35][CH2:34][C:33]3([O:29][C:30](=[O:39])[NH:31][CH2:32]3)[CH2:38][CH2:37]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: O=C1NCC2(CCNCC2)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CC3)CNC(=O)O4)n(C)c2n1
Reaction time: 18 h
Yield: 55.1 %

Procedure:
A solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and 1-oxa-3,8-diazaspiro[4.5]decan-2-one (50 mg, 0.32 mmol) in DCE (3 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 95:5 to 90:10 to 85:15) to afford 327 as a white solid (77 mg, 56%). LCMS (Method G): RT=5.35 min, M+H+=518. 1H NMR (CDCl3, 400 MHz) δ 8.9 (m, 1 H); 7.72 (m, 1 H); 7.29 (m, 2 H); 4.99 (bs, 1 H); 4.35 (m, 4H); 3.90-3.83 (m, 7 H); 3.80 (s, 2 H); 3.36 (s, 2 H); 2.95 (s, 3 H); 2.76-2.65 (m, 4 H); 2.03 (m, 2 H) and 1.82 (m, 2 H)
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C=O.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCl>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:25])[C:12]1[CH:13]=[CH:14][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(NCCO[Si](C)(C)C(C)(C)C)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N(C)CCO[Si](C)(C)C(C)(C)C)cc1
Yield: 88.6 %

Procedure:
To a solution of ethyl 4-[(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)amino]benzoate (2.52 g, 7.79 mmol) in dichloromethane (32 ml) were added 37% aqueous formaldehyde solution (2.08 ml, 25.7 mmol) and sodium triacetoxyborohydride (6.93 g, 32.7 mmol) and the mixture was heated under reflux overnight. Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:0-7:3, v/v) to give the title compound (2.33 g, 89%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([O:4][C:5]([N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[CH2:15]([NH2:19])[CH2:16][CH2:17][CH3:18].C([BH3-])#N.[Na+].Cl>CO.C(O)(=O)C>[CH3:1][C:2]([CH3:14])([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([NH:19][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCNC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 1-(1,1-dimethylethoxycarbonyl)-4-piperidone (IX, 1.50 g) in methanol (15 ml) under nitrogen is cooled in an ice bath, treated with butylamine (X, 0.93 ml) and sodium cyanoborohydride (235 mg), adjusted to pH 5 with glacial acetic acid as determined on moistened pH test paper, and stirred at 20°-25° for 24 hrs during which additional sodium cyanoborohydride (115 mg) is added. The mixture is then adjusted to pH 3 using hydrochloric acid (3M) and concentrated under reduced pressure, the residue is diluted with water (20 ml) and extracted with ether (2×20 ml), and the organic phase is discarded. The aqueous phase is adjusted to pH 12 with potassium hydroxide, saturated with sodium chloride, and extracted with methylene chloride (3×25 ml). The combined organic phase is dried over sodium sulfate and concentrated under reduced pressure to give the title compound, Anal. Calcd for C14H28N2O2 : C=65.59, H=11.01, N=10.93, found: C=65.44, H=11.05, N=10.81.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][CH:8]([NH:11][C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:9][OH:10])(C)(C)C.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]O)=[CH:22][CH:21]=1>>[CH2:15]([O:14][C:12](=[O:13])[NH:11][CH:8]1[CH2:7][C:6](=[O:5])[O:18][CH:9]1[O:10][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=1)[CH:16]=[CH2:17]
Reactant: OCc1ccc(Cl)cc1
Reactant: C=CCOC(=O)NC(CO)CC(=O)OC(C)(C)C
Product: C=CCOC(=O)NC1CC(=O)OC1OCc1ccc(Cl)cc1

Procedure:
Prepared from 3-allyloxycarbonylamino-4-hydroxy-butyric acid tert-butyl ester as described for 40 using 4-chlorobenzylalcohol to afford the title compound as a white solid. Anti-diastereomer: HPLC (C18 column) 10.924 min; 1H-NMR (500 MHz, CDCl3) δ 2.41 (d, J=8.0 Hz, 1H), 3.02 (dd, J=18.1, 7.8 Hz, 1H), 4.25 (br, 1H), 4.56 (m, 2H), 4.58 (d, J=11.7 Hz, 1H), 4.79 (d, J=11.7 Hz, 1H), 4.99 (br, 1H), 5.22 (dd, J=10.4, 1.1 Hz, 1H), 5.28 (dd, J=17.2, 1.3 Hz, 1H), 5.44 (s, 1H), 5.86 (m, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H) ppm; LC-MS (ES+) m/e=326 (M+H); Syn-diastereomer: HPLC (C18 column) 10.780 min; 1H-NMR (500 MHz, CDCl3) δ 2.47 (dd, J=17.3, 10.5 Hz, 1H), 2.85 (dd, J=17.3, 8.4 Hz, 1H), 4.55 (m, 3H), 4.58 (d, J=11.7 Hz, 1H), 4.84 (d, J=11.7 Hz, 1H), 5.23 (dd, H=10.4, 1.1 Hz, 1H), 5.30 (d, J=16.6 Hz, 1H), 5.49 (d, J=5.0 Hz, 1H), 5.89 (ddt, J=17.1, 11.0, 5.4 Hz, 1H), 7.23 (d, J=8.3 Hz, 2H), 7.31 (d, J=8.3 Hz, 2H) ppm; LC-MS (ES+) m/e=326 (M+H).
Reaction SMILES: [CH3:1][PH:2](=[O:6])[O:3][CH2:4][CH3:5].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH3:19][C:20]1[NH:21][CH2:22][CH2:23][CH:24]=1>C(Cl)Cl>[CH3:19][C:20]1([CH2:1][PH:2](=[O:6])[O:3][CH2:4][CH3:5])[CH2:24][CH2:23][CH2:22][NH:21]1
Reactant: CC1=CCCN1
Reactant: CCO[PH](C)=O
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCO[PH](=O)CC1(C)CCCN1
Temperature: 0 °C

Procedure:
0.8 g (7.4 mmol) of ethyl methylphosphinate of formula (CH3)(H)P(O)OC2H5 and 488 mg (8 mmol) of triethylamine are dissolved in 20 ml of anhydrous methylene chloride and cooled to 0° C. 0.87 g (8 mmol) of trimethylsilyl chloride is then added. The formation of the intermediate P(OSiMe3)(OEt)(Me) is virtually instantaneous. 0.63 g (7.6 mmol) of 2-methylpyrroline of formula:
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:10][N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[C:20](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH2:1]([O:5][C:6]([C:8]1[N:12]=[C:11]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:10]([CH3:20])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CCCCOC(=O)c1n[nH]c(Cc2ccccc2)n1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCCCOC(=O)c1nc(Cc2ccccc2)n(C)n1
Temperature: 23 °C
Reaction time: 72 h

Procedure:
5-Benzyl-1H-[1,2,4]triazole-3-carboxylic acid butyl ester (100 mg, 0.386 mmol) was dissolved in acetone (3 ml), to which were added potassium carbonate (80 mg, 0.578 mmol) and iodomethane (27 μl, 0.432 mmol) as a solution in acetone (2 ml) at 23° C. The reaction mixture was stirred at 23° C. for 72 h, then filtered and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate; 25 g column; flow 40 ml/min; 0% ethyl acetate to 100% ethyl acetate in 20 min) to give the title compound. UPLC-MS (method F) Rt=0.96 min, [M+H]+=274.3.
Reaction SMILES: C(N(CC)CC)C.F[C:9]([N:11]([CH3:40])[S:12][N:13]([C:15]([O:17][N:18]=[C:19]([CH3:39])[C:20](=[N:22][O:23][C:24]([N:26]([CH3:38])[S:27][N:28]([C:30]([O:32][N:33]=[C:34]([S:36][CH3:37])[CH3:35])=[O:31])[CH3:29])=[O:25])[CH3:21])=[O:16])[CH3:14])=[O:10].[CH3:41][N:42]([CH3:50])[C:43](=[O:49])[C:44]([S:47][CH3:48])=[N:45][OH:46]>C(Cl)Cl>[CH3:39][C:19](=[N:18][O:17][C:15]([N:13]([CH3:14])[S:12][N:11]([C:9]([O:46][N:45]=[C:44]([S:47][CH3:48])[C:43]([N:42]([CH3:50])[CH3:41])=[O:49])=[O:10])[CH3:40])=[O:16])[C:20]([CH3:21])=[N:22][O:23][C:24]([N:26]([CH3:38])[S:27][N:28]([CH3:29])[C:30]([O:32][N:33]=[C:34]([S:36][CH3:37])[CH3:35])=[O:31])=[O:25]
Reactant: CSC(C)=NOC(=O)N(C)SN(C)C(=O)ON=C(C)C(C)=NOC(=O)N(C)SN(C)C(=O)F
Reactant: CSC(=NO)C(=O)N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSC(C)=NOC(=O)N(C)SN(C)C(=O)ON=C(C)C(C)=NOC(=O)N(C)SN(C)C(=O)ON=C(SC)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 13.1 %

Procedure:
A solution of 1 g of triethylamine in 10 ml of methylene chloride was added dropwise to a solution of 3 g of the crude carbamic fluoride and 1.1 g of methyl 2-(dimethylamino)-N-hydroxy-2-oxoethanimidothioate in 50 ml of methylene chloride at 10° to 20° C. and stirred at room temperature for 2.5 hours. The solution was washed with three 50 ml portions of water, and the organic layer was dried over anhydrous magnesium sulfate. The mixture was filtered, and the filtrate was evaporated. Ether was added to the crude product followed by dilution with methylene chloride until the mass could flow freely. The solid was separated by filtration to give a mixture. The mother liquor was concentrated and diluted with ethers to give 0.5 g of the title compound, m.p. 87°-110° C. (glass).
Reaction SMILES: [C:1]([O:9][O:10]C(=O)C1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].Cl>C(Cl)(Cl)Cl.CO>[C:2]1([C:1]([O:9][OH:10])=[O:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(OO)c1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
19 g (78 mmol) of dibenzoyl peroxide are dissolved in 125 ml of chloroform at −5° C. 2.2 g (94 mmol) of sodium dissolved in 50 ml of methanol under a stream of nitrogen are added dropwise. After stirring at −5° C. for 30 minutes, ice-cold water is added and the medium is acidified with a 2N aqueous hydrochloric acid solution. Extraction with dichloromethane is carried out and then the organic phase is dried over magnesium sulphate, filtered and concentrated. 9 g of benzenecarboperoxoic acid are obtained in the form of a white solid with a yield of 83%.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:17]([OH:19])=[O:18])[CH:3]=1.[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C([O-])(=O)C.[NH4+:35]>C(O)C>[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[C:3]2[C:2](=[O:1])[N:6]([C:7]3[CH:8]=[CH:9][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:11][CH:12]=3)[N:5]=[C:4]2[C:17]([OH:19])=[O:18])=[CH:24][CH:23]=1.[NH4+:35]
Reactant: O=C(O)c1cc(O)n(-c2ccc(S(=O)(=O)O)cc2)n1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN(C)c1ccc(C=C2C(=O)N(c3ccc(S(=O)(=O)O)cc3)N=C2C(=O)O)cc1
Reaction time: 7 h

Procedure:
2.85 g of 5-hydroxy-1-(4-sulfophenyl)-1H-pyrazole-3-carboxylic acid, 1.65 g of 4-dimethylaminobenzaldehyde and 0.8 g of ammonium acetate in 25 mL of ethanol were heated at 60° C. After 7 hours, the mixture was cooled and filtered.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH:25]=[C:24]([C:26]3[C:27]([O:41][C:42]4[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=4[C:49]#[N:50])=[C:28]4[C:33](=[CH:34][CH:35]=3)[N:32]([C:36]([O:38][CH3:39])=[O:37])[C@@H:31]([CH3:40])[CH2:30][CH2:29]4)[CH:23]=[N:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[Cl:48][C:45]1[CH:46]=[CH:47][C:42]([O:41][C:27]2[C:26]([C:24]3[CH:23]=[N:22][N:21]([CH:18]4[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]4)[CH:25]=3)=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH2:30][C@H:31]([CH3:40])[N:32]3[C:36]([O:38][CH3:39])=[O:37])=[C:43]([C:49]#[N:50])[CH:44]=1
Reactant: COC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(Oc3ccc(Cl)cc3C#N)c2CC[C@@H]1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)N1c2ccc(-c3cnn(C4CCNCC4)c3)c(Oc3ccc(Cl)cc3C#N)c2CC[C@@H]1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.2 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a solution of (S)-methyl 6-(1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)-5-(4-chloro-2-cyanophenoxy)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.057 g, 0.094 mmol) in dichloromethane (2.0 mL) and the reaction mixture stirred at rt for 1.5 h. The reaction mixture was concentrated and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-methyl 5-(4-chloro-2-cyanophenoxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.041 g, 86%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.01-1.09 (m, 4H), 1.49-1.79 (m, 4H), 1.80-2.07 (m, 4H), 2.52-2.63 (m, 2H), 2.99 (br d, J=12.31 Hz, 2H), 3.72 (s, 3H), 4.03-4.23 (m, 1H), 4.45-4.70 (m, 1H), 6.44 (br d, J=9.09 Hz, 1H), 7.47-7.64 (m, 3H), 7.67 (s, 1H), 7.95 (s, 1H), 8.10 (d, J=2.35 Hz, 1H). MS (ESI, pos. ion) m/z 506 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:19])[C:7](=[O:18])[CH2:8][CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.N[C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=1[O:30][CH2:31][CH3:32].O.Cl>C(O)C>[CH:13]1([N:10]2[CH2:9][CH2:8][C:7](=[O:18])[N:6]([CH3:19])[C:5]3[C:11]2=[N:12][C:2]([NH:1][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][C:22]=2[O:30][CH2:31][CH3:32])=[N:3][CH:4]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(N)ncc21
Reactant: CCOc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Yield: 44.7 %

Procedure:
To a solution of 10-Chloro-2-cyclopentyl-6-methyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 1; 280 mg, 1 mmol) and 4-amino-3-ethoxybenzoic acid (WO 2001077101; 205 mg, 1.13 mmol) in ethanol (5 mL) was added water (15 mL) and conc hydrochloric acid (0.17 mL, 2 mmol). The mixture was heated under reflux for 36 hours. The reaction was cooled and a brown solid precipitated. This was filtered and dried, triturated under cold acetonitrile and then dried in vacuo. To yield the title compound as a brown solid (190 mg; 45%)
Reaction SMILES: [CH:1]1([NH:4][CH:5]2[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[O:16]1[CH2:19][C:18](=O)[CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([N:4]([CH:18]2[CH2:19][O:16][CH2:17]2)[CH:5]2[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)C1CCC(NC2CC2)CC1
Reactant: O=C1COC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1CCC(N(C2CC2)C2COC2)CC1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 329A (1.05 g) in dichloromethane (10 mL) was added oxetan-3-one (0.358 g) followed by sodium triacetoxyborohydride (1.05 g). The mixture was stirred overnight. The mixture was diluted with dichloromethane (300 mL) and washed with 2N aqueous NaOH, water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound.
Reaction SMILES: [SH:1][C:2]([CH3:17])([CH3:16])[CH2:3][S:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:14][OH:15])[CH:9]=[C:10]([CH2:12][OH:13])[CH:11]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:26][S:27](=O)(SC)=O>C(O)C.ClCCl>[CH3:16][C:2]([S:1][S:27][CH3:26])([CH3:17])[CH2:3][S:4][CH2:5][C:6]1[CH:11]=[C:10]([CH2:12][OH:13])[CH:9]=[C:8]([CH2:14][OH:15])[CH:7]=1
Reactant: CSS(C)(=O)=O
Reactant: CC(C)(S)CSCc1cc(CO)cc(CO)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCO
Product: CSSC(C)(C)CSCc1cc(CO)cc(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
(5-((2-mercapto-2-methylpropylthio)methyl)-1,3-phenylene)dimethanol (0.120 g, 0.440 mmol) was dissolved in ethanol (5 mL) and 1.0 M potassium phosphate buffer (pH 7) (5.00 mL) and cooled in an ice bath (a ppt formed but it was ignored). S-methyl methanesulfonothioate (0.083 mL, 0.881 mmol) was added and the mixture stirred overnight with gradual (over 30 minutes) warming to room temperature. The reaction was diluted with dichloromethane and the organic layer was removed, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was dissolved in dichloromethane and loaded onto a 500 micron ptlc plate and developed with 66% ethyl acetate in hexane. The band corresponding to the product was scraped, filtered using ethyl acetate, and concentrated to give (5-((2-methyl-2-(methyldisulfanyl)propylthio)methyl)-1,3-phenylene)dimethanol (0.091 g, 0.286 mmol, 64.9% yield). 1H NMR (400 Hz, CDCl3): δ 7.27 (s, 3H), 4.71 (s, 4H), 3.78 (s, 2H), 2.77 (s, 2H), 2.41 (s, 3H), 1.94 (br s, 2H), 1.38 (s, 6H); 13C NMR (400 Hz, CDCl3): δ 141.6, 139.0, 126.7, 124.2, 65.0, 51.8, 44.0, 38.2, 26.7, 25.3; MS (m/z), expected: 341.5. found 341.1 (M+Na). See FIG. 30.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[H][H]>[Pd].CO>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: [H][H]
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: CC(=O)c1cccc(N)c1N

Procedure:
A slurry of 1-(2-amino-3-nitro-phenyl)-ethanone (0.2 g, 1.11 mmol) and 10% palladium on carbon (0.020 g) in methanol (10 mL) was hydrogenated with a hydrogen balloon for 2 h. After completion of the reaction, the reaction mixture was filtered and evaporated under vacuum to obtain the title compound as off white solid (0.120 g, 72.28%)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:12]CCl.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+]>CO>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][CH:3]=1
Reactant: ClCCCl
Reactant: O=C(O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(F)cc1
Yield: 84 %

Procedure:
A solution of 4-fluorobenzoic acid (25.0 g), 1,2-dichloroethane (120 ml), methanol (21.7 ml) and concentrated sulfuric acid (0.8 ml) was stirred for 16.5 hours with refluxing. After the reaction, the reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, extracted with chloroform, and washed with saturated brine. The mixture was dried over magnesium sulfate, and the solvent was distilled away under reduced pressure to give 23.0 g of a colorless transparent liquid (yield 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH2:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14]>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([NH:12][S:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1ccc2cccc(N)c2n1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: Cc1ccc2cccc(NS(=O)(=O)c3ccccc3[N+](=O)[O-])c2n1
Yield: 46.7 %

Procedure:
In a similar fashion using route 14 general procedure 26, 2-methyl-quinolin-8-ylamine (Intermediate 22) (417 mg, 2.64 mmol) and 2-nitrobenzensulfonyl chloride (643 mg, 2.64 mmol) gave the title compound (423 mg, 47%).
Reaction SMILES: [Na].[C:2]([CH2:4][C:5]([O:7]CC)=O)#[N:3].[O:10]=[C:11]([CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:12]>C(O)C>[C:2]([CH:4]1[C:14]([CH3:16])([CH3:15])[CH2:13][C:11](=[O:10])[CH2:12][C:5]1=[O:7])#[N:3]
Reactant: CC(=O)C=C(C)C
Reactant: CCOC(=O)CC#N
Agent: [Na]
Solvent: CCO
Product: CC1(C)CC(=O)CC(=O)C1C#N
Temperature: 25 °C
Yield: 58.9 %

Procedure:
Sodium metal (11.5 g, 0.5 mol) was dissolved in dry ethanol (225 ml) at ambient temperature (20° C.). Ethyl cyanoacetate (60 g, 0.53 mol) was added dropwise with stirring at ambient temperature. To the resulting solution was added dropwise, with stirring, mesityl oxide, and the mixture was heated under reflux for 4 hours. After cooling, the mixture was extracted with diethyl ether to remove any unreacted starting material and acidified with 2M aqueous hydrochloric acid. The brown oil which separated out was extracted into diethyl ether, dried (Na2SO4) evaporated and triturated with 40°-60° C. petroleum ether to give a pale yellow solid, which on recrystallisation from diethyl ether gave 4-cyano-5,5-dimethyl-1,3-cyclohexanedione as a white crystalline solid (48.6 g, 58.9%) m.p. 130°-132° C.
Reaction SMILES: O.[OH-].[Li+].[C:4]([C:6]1[CH:7]=[C:8]([N:13]2[C:17]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([C:25]#[N:26])[CH:19]=3)=[CH:16][C:15]([C:27]([O:29]CC)=[O:28])=[N:14]2)[CH:9]=[CH:10][C:11]=1[F:12])#[N:5].Cl>C1COCC1>[C:4]([C:6]1[CH:7]=[C:8]([N:13]2[C:17]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([C:25]#[N:26])[CH:19]=3)=[CH:16][C:15]([C:27]([OH:29])=[O:28])=[N:14]2)[CH:9]=[CH:10][C:11]=1[F:12])#[N:5]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(C#N)c2)n(-c2ccc(F)c(C#N)c2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(F)cc(-c2cc(C(=O)O)nn2-c2ccc(F)c(C#N)c2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10.0 ml of water and 570 mg (23.8 mmol) of lithium hydroxide are added to 900 mg (1.78 mmol) of the carboxylic ester of Example 132A with 75% purity in 30.0 ml of THF. The mixture is stirred at RT for 5 h and a 1N aqueous hydrogen chloride solution is subsequently added to the reaction solution. The mixture is extracted with dichloromethane, and the combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 527 mg (86% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([CH3:11])[C:4]=2[N:5]=[CH:6][N:7]=1.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:11][C:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]=2[S:10][CH:9]=1
Reactant: Cc1csc2c(Cl)ncnc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncnc2c(CBr)csc12
Temperature: 100 °C

Procedure:
4-Chloro-7-methylthieno[3,2-d]pyrimidine (6.62 g, 33.0 mmol) and NBS (5.87 g, 33.0 mmol) were dissolved in CCl4 (100 mL) and benzoylperoxide (1.0 g, 80% purity) was added thereto. The reaction mixture was stirred at 100° C. for an hour, cooled to room temperature, filtered with Celite and concentrated to obtain the title compound having a yellow color without further purification.