Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.[NH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]1[C:35]2[C:34](=[O:36])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:37])[C:26]=2[C:25]([NH:38][CH2:39][CH2:40][CH2:41][NH2:42])=[CH:24][CH:23]=1.C(OC([NH:50][C@H:51]([C:53](O)=[O:54])[CH3:52])=O)(C)(C)C.C(OC(NCC(O)=O)=O)(C)(C)C>>[NH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:25]1[C:26]2[C:27](=[O:37])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34](=[O:36])[C:35]=2[C:22]([NH:21][CH2:20][CH2:19][CH2:18][NH:17][C:53](=[O:54])[C@H:51]([CH3:52])[NH2:50])=[CH:23][CH:24]=1
Reactant: NCCCNc1ccc(NCCCN)c2c1C(=O)c1ccccc1C2=O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Product: C[C@H](N)C(=O)NCCCNc1ccc(NCCCN)c2c1C(=O)c1ccccc1C2=O

Procedure:
Example 28 was prepared by an equivalent procedure to that described for Example 24 except that the starting anthraquinone was 1,4-bis[(3-aminopropyl)amino]-anthracene-9,10-dione and N-tertiarybutoxycarbonyl-L-alanine replaced N-tertiarybutoxycarbonylglycine.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.Cl>C(O)C>[F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:23][NH:24][CH3:25])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)cc2-c2cccnc2F)cn1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2ccc(C)nc2)c1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl ({5-(2-fluoropyridin-3-yl)-1-[(6-methylpyridin-3-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (86 mg) in ethanol (2 mL) was added a 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) at room temperature. The mixture was stirred for 2 hr, and concentrated under reduced pressure. The residue was basified with a saturated aqueous sodium hydrogencarbonate solution, and, the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (2 mL) and added to a solution (2 mL) of fumaric acid (11.3 mg) in ethanol, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as colorless crystals (yield 14 mg, 18%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:30]=[CH:31][CH:32]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([N:13]2[CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=[O:29])[CH2:9][CH2:8]1.[H-].[Na+].Br[CH2:36][CH2:37][CH3:38].O>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:36]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:13]([CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:30]=[CH:31][CH:32]=[C:3]([CH2:2][OH:1])[CH:4]=3)[CH2:8][CH2:9]2)[C:14]1=[O:29])[CH2:37][CH3:38]
Reactant: CCCBr
Reactant: O=C1Nc2ccccc2C(c2ccccc2)N1C1CCN(Cc2cccc(CO)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1C(=O)N(C2CCN(Cc3cccc(CO)c3)CC2)C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.7 %

Procedure:
To a solution of 100 mg (0.234 mmol) of 3-[1-(3-hydroxymethylbenzyl) piperidin-4-yl]-4-phenyl-3,4-dihydro-2(1H)-quinazolinone in 2 ml of DMF, 11.2 mg (0.28 mmol) of sodium hydride (60%) were added under ice-cooling and stirred at the same temperature for 5 minutes and at room temperature for 5 minutes. After ice-cooling again, 0.032 ml (0.35 mmol) of 1-bromopropane was added thereto and stirred under ice-cooling for 3 hours and at room temperature for 6 hours. To the reaction mixture, 2 mg of tetrabutylammonium iodide were added and further stirred at room temperature for 5 hours. It was poured into water, extracted with ethyl acetate, washed with water, aqueous saturated sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform—2% methanol/chloroform) to give 47 mg (0.10 mmol) of the title compound as colorless oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:26]=[C:27]([N+:31]([O-:33])=[O:32])[CH:28]=[CH:29][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc([N+](=O)[O-])c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 90.1 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.2 g, 0.64 mmol) and 3-iodonitrobenzene (Aldrich, 0.16 g, 0.64 mmol) in triethylamine (4 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. Purification by flash chromatography, elutirg with 3:1 hexanes/ethyl acetate, provided the title compound as yellow solid (0.25 g, 90%), m.p. 46-48° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][CH:14]([CH2:19][CH3:20])[CH2:15][N:16]=[C:17]=[S:18]>>[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH:12][C:17]([NH:16][CH2:15][CH:14]([CH3:13])[CH2:19][CH3:20])=[S:18])(=[O:10])=[O:11]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CCC(C)CN=C=S
Agent: Cl
Product: CCC(C)CNC(=S)NS(=O)(=O)c1sc(Cl)cc1N

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and 2-methylbutyl isothiocyanate by a procedure analogous to the procedure described in example 3-a (yield 28%); mp 116.5-118° C., 1H-NMR (DMSO-d6): δ0.8 (2 d, 6H, 2×CH3), 1.10 (m, 1H), 1.30 (m, 1H), 1.65 (m, 1H), 3.40 (m, 2H+HDO, CH2), 6.45 (br, 2H, NH2), 6.65 (s, 1H, H-4), 8.25 (br t, 1H, NH), 11.3 (br s, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=S)[CH2:10][CH2:11][NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>C(O)CCC>[F:1][C:2]1[C:7]2[N:8]3[C:14]([CH3:15])=[N:17][N:18]=[C:9]3[CH2:10][CH2:11][NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc2c1NC(=S)CCN2
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1c(F)cccc1NCC2
Temperature: 130 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
A disposable tube was charged with 9-fluoro-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (40 mg, 0.204 mmol) and a stirbar. nBuOH (5 mL) was added, followed by acetohydrazide (30.2 mg, 0.408 mmol), and the solution was stirred at 130° C. overnight. The solution was concentrated with celite and purified by silica gel chromatography (eluting with methylene chloride/methanol/1% ammonium hydroxide) to yield 10-fluoro-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as an off-white amorphous solid (0.022 g, 0.101 mmol, 50%).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:14]=3[CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3].[H-].[Na+].CC1C=CC(S(O[CH2:34][C@@H:35]([NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH3:36])(=O)=O)=CC=1.O>CN(C=O)C>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([O:20][CH2:36][C@@H:35]([NH:37][C:38](=[O:39])[O:40][C:41]([CH3:42])([CH3:44])[CH3:43])[CH3:34])[CH:17]=[CH:16][C:14]=3[CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCCOc1ccc(-c2cc3ccc(O)cc3o2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1ccc(-c2cc3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 31.6 %

Procedure:
To a solution of 2-(4-propoxyphenyl)-1-benzofuran-6-ol (918 mg) in DMF (10 mL) was added sodium hydride (60% oil, 137 mg), and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added (2S)-2-[(tert-butoxycarbonyl)amino]propyl 4-methylbenzenesulfonate (1.13 g), and the mixture was stirred at 60° C. for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (460 mg).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[NH:8][CH2:9][CH2:10][S:11][C:12](OC2C=CC([N+]([O-])=O)=CC=2)=[O:13])C=CC=CC=1.[NH2:36][CH:37]([CH:47]([CH3:49])[CH3:48])[CH2:38][O:39][Si](C(C)(C)C)(C)C>>[OH:39][CH2:38][CH:37]([NH:36][C:12]([S:11][CH2:10][CH2:9][NH2:8])=[O:13])[CH:47]([CH3:48])[CH3:49]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)SCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(N)CO[Si](C)(C)C(C)(C)C
Product: CC(C)C(CO)NC(=O)SCCN
Yield: 417.1 %

Procedure:
N-triphenylmethyl-2-paranitrophenoxycarbonylthioethylamine (0.58 g) and 2-amino-1-tert-butyldimethylsilyloxy-3-methylbutane (acetate: 0.52 g) were subjected to the reactions described in References 2 and 4 to give 2-(1-hydroxymethyl-2-methylpropyl)aminocarbonylthioethylamine (formate: 1.03 g). The product (0.83 g) was dissolved in anhydrous methanol (10 ml), to which were then added triethylamine (0.91 ml) and mitomycin A (372 mg: 0.82 molar equivalent). The reaction solution was treated in a similar manner to that described in Example 1 to obtain Compound 48 (290 mg) in the form of grayish blue powders with a yield of 52%.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[CH3:22])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][C@@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[CH3:22])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: C[C@H]1CCCC[C@H]1Oc1cc(Cl)ncn1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(O[C@@H]2CCCC[C@@H]2C)ncn1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
In 1 ml of tetrahydrofuran was suspended 0.03 g of sodium hydride (60% in oil), to which 0.2 ml of a tetrahydrofuran solution containing 0.04 g of 2-butyn-1-ol was slowly added dropwise under stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, and 0.2 ml of a tetrahydrofuran solution containing 0.12 g of 4-chloro-6-(cis-2-methylcyclohexyloxy)pyrimidine was slowly added dropwise, followed by stirring at room temperature for 5 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with t-butyl methyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.10 g of 4-(2-butynyloxy)-6-(cis-2-methylcyclohexyloxy)pyrimidine (the present compound (172)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[C:4]([CH3:24])[N:3]=1.Cl.[NH2:26][OH:27].C([O-])(O)=O.[Na+]>>[CH3:1][C:2]1[CH:7]=[C:6](/[C:8](=[N:26]/[OH:27])/[CH2:9][CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:5]=[C:4]([CH3:24])[N:3]=1
Reactant: Cc1cc(C(=O)CC(c2ccccc2)c2ccccn2)cc(C)n1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2ccccc2)c2ccccn2)=N/O)cc(C)n1

Procedure:
In analogy to example 1, step 2, from 1-(2,6-dimethyl-pyridin-4-yl)-3-phenyl-3-pyridin-2-yl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a light yellow foam, MS (ESI+): m/z=332.3 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([NH2:24])[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:2].[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([NH:24][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:2]
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)C(N)CCOc1ccc(OC(C)(C)C(=O)OCC)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C(CCOc1ccc(OC(C)(C)C(=O)OCC)cc1)NCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.1 %

Procedure:
A sample of 2-amino-4-[4-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenoxy]-butyric acid ethyl ester (612 mg, 1.73 mmol) and benzaldehyde (220 mg, 2.08 mmol) was dissolved in 10 mL of methylene chloride followed by addition of sodium triacetoxyborohydride (550 mg, 2.60 mmol). After 4 hours of stirring at room temperature the reaction mixture was partitioned between additional methylene chloride (50 mL) and 0.1 N HCl (50 mL). The pH of the mixture was then adjusted to ˜13 with 1.0 N NaOH and the layers separated. The aqueous later was extracted with additional methylene chloride (25 mL). The combined organic phases were dried over sodium chloride, then concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate/hexanes) to yield 492 mg of product (64%) as an oil. HPLC RT1=2.78 min; 1H NMR (400 MHz, CDCl3) δ7.28-7.18 (m, 5H), 6.79-6.76 (m, 2H), 6.70-6.68 (m, 2 H), 4.22-4.12 (m, 4H), 4.08-4.02 (m, 1H), 3.99-3.91 (m, 1H), 3.83-3.80 (d, J=12.7 Hz, 1H), 3.65-3.62 (d, J=12.7 Hz, 1H), 3.49-3.47 (m, 1H), 2.17-2.09 (m, 1 H), 2.00-1.92 (m, 1H), 1.49 (s, 6H), 1.26-1.20 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3([CH3:17])[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.[N+](C1C=CC(S(O[CH2:31][C:32]([F:35])([F:34])[CH3:33])(=O)=O)=CC=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CC(N(C)C)=O.C(O)(C)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:31][C:32]([F:35])([F:34])[CH3:33])[C:7](=[O:12])[C:6]3([CH3:17])[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: CC12COCCN1c1nc(Cl)ncc1NC2=O
Reactant: CC(F)(F)COS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(F)(F)CN1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Temperature: 60 °C
Reaction time: 22 h

Procedure:
2-Chloro-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (384 mg, 1.508 mmol), 2,2-difluoropropyl 4-nitrobenzenesulfonate (767 mg, 2.73 mmol), cesium carbonate (1240 mg, 3.81 mmol) were combined in DMA (2 mL) at ambient temperature for about 1 hour and then heated in an oil bath at 60° C. After about 22 hours, the reaction mixture was allowed to cool to ambient temperature, diluted reaction mixture with 25 mL EtOAc, transferred to a separatory funnel, and the reaction vessel rinsed twice with 10 mL 1:1 EtOAc/water. An additional 10 mL of water was then added, the layers were mixed and then separated. The organic layer was extracted with water (10 mL) and the combined aqueous layers were extracted with 10 mL of EtOAc, which was then extracted with 5 mL brine. The combined organic layers were dried over sodium sulfate, filtered, and concentrated on a rotovap to give a residue. The residue was combined with isopropanol (5 mL) and heated in an oil bath at 50° C. oil bath. An addition 1.5 mL was added and the solution was allowed to cool to ambient temperature with stirring to give a solid. Collected the solid by filtration, rinse the filter cake with 1 mL isopropanol and air dry for 2 hours, then dry under vacuum to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=S)=[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:4]=1.O.O.O.C([O-])(=O)C.[Pb+2].C([O-])(=O)C.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]#[N:12])=[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:4]=1
Reactant: COc1ccc(NC(N)=S)c(N2CCOCC2)c1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(NC#N)c(N2CCOCC2)c1

Procedure:
A mixture of 1-(4-methoxy-2-morpholinophenyl)thiourea (3.8 g) suspended in water (26 ml), lead acetate trihydrate (5.7 g) in water (26 ml) and potassium hydroxide (8.4 g) in water (24 ml) was heated at 90°-95° C. for 30 minutes to give N-(4-methoxy-2-morpholinophenyl)cyanamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[C:37]([N:11]([CH2:12][C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=2)=[CH:16][CH:17]=1)[S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:9])=[O:10])(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3ccccc3Cl)s2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)c1cccc(-c2ccc(CN(C(=O)c3ccccc3)S(=O)(=O)c3ccccc3Cl)s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.5 %

Procedure:
To a stirred solution of 2-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide (example 4, step 2, 60 mg) in dichloromethane (0.5 mL) were added N,N-diisopropyl ethyl amine (21 mg) and benzoyl chloride (20 mg) at 0° C. The mixture was stirred at r.t. overnight. Ice cold water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The product was purified by chromatography (SiO2, cyclohexane/ethyl acetate 1:0 to 0:1) to give N-benzoyl-2-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide (76 mg) as a colorless solid. MS: 568.2 ([M+Na]+)
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][S:14][C:15]1[N:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][O:29][C:30]1[CH:31]=[C:32]([CH:39]=[CH:40][CH:41]=1)[C:33](N(OC)C)=[O:34]>O1CCCC1.C(OCC)(=O)C.O>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][O:29][C:30]1[CH:31]=[C:32]([C:33](=[O:34])[CH2:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]([S:14][CH3:13])[N:20]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: CON(C)C(=O)c1cccc(OCc2ccccn2)c1
Reactant: CSc1nccc(C)n1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CSc1nccc(CC(=O)c2cccc(OCc3ccccn3)c2)n1
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 61.8 %

Procedure:
2.1 ml (15 mmol) diisopropylamine were dissolved in 70 ml dry tetrahydrofuran and cooled to −75° C. and 9.4 ml of a solution of n-butyllithium (1.6 M, 15 mmol) were added over a period of 10 minutes. After stirring for 15 minutes at −75° C. a solution of 1.69 g (12 mmol) 2-methylthio-4-methylpyrimidine in 5 ml dry tetrahydrofuran was added within 10 minutes at −75° C. and the mixture was stirred for additional 15 minutes. Then a solution of 2.73 g (7 mmol) B3 (70% purity) in 5 ml dry tetrahydrofuran was added within 10 minutes at −75° C. The mixture was stirred for one hour at −75° C. and then allowed to warm up to room temperature and finally poured on 100 ml ethyl acetate/water (1:1). The aqueous layer was extracted with 50 ml ethyl acetate and the combined organic layers were dried over sodium sulphate. Removal of the solvent in vacuo and column chromatography on Silica (n-heptane/ethyl acetate 3:1) yielded 1.52 g (62%) C1. (keto-enole ratio measured by NMR in CDCl3 at 400 MHz is about 30:70).
Reaction SMILES: OCC(C)(C)CCCCC(CCCCC(C)(C)CO)C(O)=O.C[Li].Cl.[OH:26][C:27]([CH:30]([CH2:40][CH2:41][CH2:42][CH2:43][C:44]([CH3:48])([CH3:47])[CH2:45][OH:46])[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])(C)[CH3:28]>C1COCC1.C(OCC)(=O)C>[OH:46][CH2:45][C:44]([CH3:48])([CH3:47])[CH2:43][CH2:42][CH2:41][CH2:40][CH:30]([CH2:31][CH2:32][CH2:33][CH2:34][C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])[C:27](=[O:26])[CH3:28]
Reactant: CC(C)(CO)CCCCC(CCCCC(C)(C)CO)C(C)(C)O
Agent: CC(C)(CO)CCCCC(CCCCC(C)(C)CO)C(=O)O
Agent: Cl
Agent: [Li]C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)C(CCCCC(C)(C)CO)CCCCC(C)(C)CO
Reaction time: 2 h
Yield: 41 %

Procedure:
8-Hydroxy-2-(6-hydroxy-5,5-dimethyl-hexyl)-7,7-dimethyl-octanoic acid (1.0 g, 3.16 mmol) was dissolved in THF (40 mL) and cooled in an ice-water bath. Methyl lithium (27 mL) was then added at once. The reaction was continued for 2 h at 0 C. The reaction mixture was poured into dilute hydrochloric acid (5 mL concentrated hydrochloric acid in 60 mL water). The organic layer was separated and the aqueous layer was extracted with diethyl ether (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the crude product (1.0 g). The crude product was purified by column chromatography (hexanes:ethyl acetate=4:1, then 1:1) to give 9-hydroxy-3-(6-hydroxy-5,5-dimethyl-hexyl)-8,8-dimethyl-nonan-2-one (0.41 g, yield 41%) and 7-(1-hydroxy-1-methylethyl)-2,2,12,12-tetramethyltridecan-1,13-diol (0.4 g, 38%, not shown) as a by-product. 1H NMR (300 MHz, CDCl3/TMS): (ppm) 3.46 (s, 4H), 2.65-2.50 (m, 1H), 2.28 (s, 3H), 2.60 (br., 2H), 1.82-1.50 (m, 4H), 1.50-1.25 (m, 12H), 1.02 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): (ppm) 213.4, 71.7, 53.2, 38.3, 34.9, 31.6, 28.7, 28.3, 23.8. HRMS nba): Calcd. for C19H39O3 (MH+): 315.2899, found: 315.2866.