Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:9].[CH3:17][I:18]>CO>[IH:18].[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[NH:7][C:8]([S:9][CH3:17])=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CI
Reactant: Cn1ccnc1NC(=S)Nc1ccccc1
Solvent: CO
Product: CSC(=Nc1ccccc1)Nc1nccn1C
Product: I

Procedure:
A solution of 3.0 g (0.013 mole) of N-(1-methylimidazol-2-yl)-N'-phenylthiourea in 50 ml of methanol is added 2.13 g (0.015 mole) of methyl iodide. The solution is heated under reflux for 2 hr, the solvent is evaporated and the residue is recrystallized from acetone-ether to give methyl N-(1-methylimidazol-2-yl)-N'-phenylcarbamimidothioate hydroiodide; m.p. 115°-118° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[C:18]([C:23]1([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:25][CH2:24]1)[N:17]=2)[C:7](OC)=[O:8])([O-:3])=[O:2].CO.[BH4-].[Li+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=[CH:12][C:13]=1[C:14]1[S:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[C:18]([C:23]1([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:24][CH2:25]1)[N:17]=2)([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=[N+]([O-])c1cc(CO)ccc1-c1nc2ccc(C3(c4ccccc4)CC3)nc2s1
Temperature: 25 °C

Procedure:
To a 0° C. solution of methyl 3-nitro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)benzoate (1.10 g, 2.5 mmol) in THF and methanol (0.31 mL, 7.6 mmol) was added lithium borohydride, 2.0 M solution in tetrahydrofuran (1.9 mL, 3.8 mmol). The reaction mixture was stirred at ambient temp, and upon completion the reaction mixture was cooled to 0° C. was quenched with ice and sat'd aq. NH4Cl carefully. The reaction mixture was partitioned between DCM and sat'd aq. NH4Cl and extracted with DCM. The combined organics were purified by silica gel chromatography, EA/hexanes gradient, to give (3-nitro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridine-2-yl)phenyl)methanol as an orage solid. MS (ESI) m/z: Calculated: 403.1; Observed: 403.8 (M++1).
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[C:9]([CH:17]3[CH2:19][CH2:18]3)[C:10]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:11][C:6]=2[O:5][C:4]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].I[CH2:34][CH2:35][CH2:36][CH2:37][O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40].CS(C)=O>C(#N)C>[Si:39]([O:38][CH2:37][CH2:36][CH2:35][CH2:34][N:12]([C:10]1[C:9]([CH:17]2[CH2:18][CH2:19]2)=[CH:8][C:7]2[C:3]([C:1]#[N:2])=[C:4]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[O:5][C:6]=2[CH:11]=1)[S:13]([CH3:16])(=[O:15])=[O:14])([C:42]([CH3:43])([CH3:44])[CH3:45])([CH3:40])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)OCCCCI
Reactant: CS(=O)(=O)Nc1cc2oc(-c3ccc(F)cc3)c(C#N)c2cc1C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCCN(c1cc2oc(-c3ccc(F)cc3)c(C#N)c2cc1C1CC1)S(C)(=O)=O
Yield: 68.9 %

Procedure:
A mixture of Example 11A (0.1302 g, 0.352 mmol) and potassium carbonate (0.058 g, 0.422 mmol) in acetonitrile (2 mL) was heated at reflux for 30 minutes, then (4-iodobutoxy)-tert-butyldimethylsilane (0.122 g, 0.387 mmol) was added and the resultant mixture was stirred at reflux for 0.5 hour. The reaction mixture became thick so additional acetonitrile (2 mL) and dimethyl sulfoxide (2 mL) were added, and the resultant mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to a yellow oil that was taken up in ethyl acetate (100 mL) and washed with 1 N aqueous H3PO4, 10% aqueous NaHCO3, and 10% aqueous NaCl. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo leaving a yellow oil. Purification on a silica gel column (12 g) eluting with a gradient of 10/90 ethyl acetate/hexane to 50/50 ethyl acetate/hexane over 20 minutes afforded the title compound (0.135 g, 69%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[CH2:8]([O:10][P:11]([O:15]CC)[O:12][CH2:13][CH3:14])[CH3:9]>>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P:11](=[O:15])([O:12][CH2:13][CH3:14])[O:10][CH2:8][CH3:9]
Reactant: BrCCCCCBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CCCCCBr)OCC
Temperature: 160 °C
Reaction time: 0.67 h
Yield: 104.2 %

Procedure:
A mixture of 1,5-dibromopentane (500 g.) and triethylphosphite (72.0 g.) was stirred at 160° C. for 40 minutes and then excess 1,5-dibromopentane was distilled off under reduced pressure to give oily diethyl 5-bromopentylphosphonate (129.6 g.).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](=[NH:5])[NH2:4].O/[C:9](/[CH:18]([CH3:20])[CH3:19])=[CH:10]\[C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13].Cl>C(O)C>[CH:18]([C:9]1[N:4]=[C:3]([C:2]([F:7])([F:6])[F:1])[N:5]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=1)([CH3:20])[CH3:19]
Reactant: N=C(N)C(F)(F)F
Reactant: CCOC(=O)C(=O)/C=C(\O)C(C)C
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(C(C)C)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,2,2-trifluoroethanimidamide (7.08 g, 53.7 mmol, Matrix) in ethanol (85 mL, 1400 mmol) was added ethyl (3Z)-4-hydroxy-5-methyl-2-oxohex-3-enoate (10.00 g, 53.70 mmol, Alfa Aesar). The mixture was then cooled in an ice bath, and a solution of hydrogen chloride in ethanol (84 mL, prepared by bubbling HCl gas through the ethanol for 10 minutes) was added. The reaction was allowed to warm to room temperature and stir overnight. The mixture was added dropwise to a saturated solution of sodium bicarbonate. After complete neutralization was achieved, ethanol was removed in vacuo. The product was extracted with three portions of DCM. The combined extracts were dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel, eluting with a gradient from 0-25% EtOAc/Hexanes (9.14 g, 65%). 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 4.52 (q, J=7.1 Hz, 2H), 3.22 (hept, J=6.9 Hz, 1H), 1.45 (t, J=7.1 Hz, 3H), 1.38 (d, J=6.9 Hz, 6H); LCMS (M+H)+: 263.1
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:11][C:12]1[CH:20]=[C:19]2[C:15]([C:16]([CH3:26])([CH3:25])[C:17](=[O:24])[N:18]2[CH:21]2[CH2:23][CH2:22]2)=[CH:14][CH:13]=1>>[CH:21]1([N:18]2[C:19]3[C:15](=[CH:14][CH:13]=[C:12]([NH:11][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][N:9]=[CH:10][C:2]=4[F:1])[CH:20]=3)[C:16]([CH3:25])([CH3:26])[C:17]2=[O:24])[CH2:23][CH2:22]1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N)ccc21
Reactant: O=C(O)c1ccncc1F
Product: CC1(C)C(=O)N(C2CC2)c2cc(NC(=O)c3ccncc3F)ccc21

Procedure:
Prepared in analogy to example 26 from 3-fluoroisonicotinic acid and 6-amino-1-cyclopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one (example 14c). The title compound was obtained as light yellow solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20](S(C)(=O)=O)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]>C(O)(=O)C.CO>[CH2:10]([O:12][C:13]([C:15]1[C:16](=[O:35])[C:17]2[CH:22]=[N:21][C:20]([NH:9][CH2:8][CH2:7][CH2:6][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[N:19][C:18]=2[N:27]([CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH:28]=1)=[O:14])[CH3:11]
Reactant: NCCCn1ccnc1
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(S(C)(=O)=O)ncc2c1=O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCCn3ccnc3)ncc2c1=O
Temperature: 25 °C
Yield: 170.1 %

Procedure:
A solution of 3-imidazol-1-yl-propylamine (6 μL, 0.036 mmol) and 8-cyclohexyl-2-methanesulfonyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (30 mg, 0.08 mmol) in 0.5 mL of acetic acid was heated to 110° C. for 0.5 hour. After cooling to room temperature, the mixture was dissolved in 2 mL of methanol and loaded to HPLC for purification (32 mL/min 5-100% MeCN/H2O gradient over 10 min). 26 mg of 8-Cyclohexyl-2-(3-imidazol-1-yl-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a white solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 9.23 (s, 1H), 8.49 (s, 1H), 7.57 (br, 1H), 7.09 (br, 1H), 6.96 (br, 1H), 6.10 (br, 1H), 5.02 (m, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.11 (t, J=6.6 Hz, 2H), 3.51 (br, 2H), 2.20-1.50 (m, 8H), 1.40 (t, J=7.2 Hz, 3H), 1.26 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H28N6O3: 425.22 (M+H). Found: 425.2.
Reaction SMILES: C([O:5][C:6](=[O:28])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17][C:18]2[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=2[C:20]([O:22][CH3:23])=[O:21])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:23][O:22][C:20]([C:19]1[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=1[S:17][CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:28])=[O:5])=[CH:14][CH:13]=1)=[O:21]
Reactant: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccccc1SCCc1ccc(OCC(=O)O)cc1
Yield: 96 %

Procedure:
Methyl 2-({2-[4-(2-tert-butoxy-2-oxoethoxy)phenyl]ethyl}thio)benzoate (4.630 g, 11.502 mmol) was take up in DCM (50 ml) and treated with trifluoroacetic acid (44.40 g, 389.405 mmol) at r.t for 4 h. The mixture was evaporated and azeotroped with toluene. The crude was purified by preparative HPLC (started with isocratic acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions was pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two potions of brine and dried (MgSO4). The solvent was removed by evaporation to give 3.825 g of [4-(2-{[2-(methoxycarbonyl)phenyl]thio}ethyl)phenoxy]-acetic acid (yield for two steps 63.9% overall).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10](OS(C(F)(F)F)(=O)=O)[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH:26][CH2:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[OH:26][CH2:27][C:28]1[CH:33]=[C:32]([C:10]2[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]3[CH:6]=[N:5][N:4]([CH:1]([CH3:3])[CH3:2])[C:8]=3[N:9]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)nc2c1cnn2C(C)C
Reactant: OCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2cccc(CO)c2)nc2c1cnn2C(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of ethyl 1-isopropyl-6-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (1 g, 2.62 mmol), 3-(hydroxymethyl)phenyl boronic acid (0.438 g, 2.88 mmol) and Pd(PPh3)4 (0.303 g, 0.262 mmol) in 1,4-dioxane (15 mL) was purged with argon for 10 min. Then 2M Na2CO3 solution (4.5 mL, 9.4 mmol) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h and after completion of the reaction water was added to it. Extraction was carried out using EtOAc the combined organic layers were washed with water dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 0.81 g of target compound.
Reaction SMILES: C([O:3][C:4](=[O:57])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]1[CH:19]=[C:18]([NH:20][C:21]([O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[CH:17]=[C:16]([CH3:30])[C:15]=1[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([S:37]([C:40]2[CH:44]=[C:43]([C:45]([NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[NH:46])[S:42][C:41]=2[S:55][CH3:56])(=[O:39])=[O:38])[CH:32]=1)=[O:12])C.[Li+].[OH-]>C1COCC1.O>[C:51]([O:50][C:48]([NH:47][C:45](=[NH:46])[C:43]1[S:42][C:41]([S:55][CH3:56])=[C:40]([S:37]([C:33]2[CH:32]=[C:31]([C:15]3[C:16]([CH3:30])=[CH:17][C:18]([NH:20][C:21]([O:23][CH2:24][CH2:25][Si:26]([CH3:27])([CH3:29])[CH3:28])=[O:22])=[CH:19][C:14]=3[NH:13][C:11](=[O:12])[NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:57])=[O:3])[CH:36]=[CH:35][CH:34]=2)(=[O:39])=[O:38])[CH:44]=1)=[O:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CCOC(=O)CCCCCNC(=O)Nc1cc(NC(=O)OCC[Si](C)(C)C)cc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc(NC(=O)OCC[Si](C)(C)C)cc2NC(=O)NCCCCCC(=O)O)c1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 99 %

Procedure:
A solution of 6-{3-[3′-[5-(tert-butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-4-(2-trimethylsilanyl-ethoxycarbonylamino)-biphenyl-2-yl]-ureido}-hexanoic acid ethyl ester ((Example 259: step a) 0.437 g, 0.507 mmol) in THF:water (2:1, 15 mL) was treated with solid LiOH (0.097 g, 4.06 mmol) and stirred at room temperature 18.5 h. The THF was removed in vacuo, and the remaining aqueous solution was acidified to pH 5 with glacial acetic acid. The solution was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (0.4222 g, 99%) as an off-white solid. ESI-MS (m/z): Calcd. for C37H51N5O9S3Si (M+H): 834.3; 834.2.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3](=O)[CH:4]=[C:5](OCC)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:19][NH:20][NH2:21].Cl.[CH3:23][CH2:24][OH:25].C([OH:28])C>>[CH2:24]([O:25][C:2]([C:3]1[CH:4]=[C:5]([C:6]2[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=2)[N:20]([CH3:19])[N:21]=1)=[O:28])[CH3:23]
Reactant: CCOC(=CC(=O)C(Cl)(Cl)Cl)c1ccc(F)cc1
Reactant: CCO
Reactant: CNN
Agent: Cl
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n(C)n1

Procedure:
A solution of 10.15 g [1,1,1-Trichloro-4-ethoxy-4-(4-fluoro-phenyl)-but-3-en-2-one in 50 ml of Ethanol was added dropwise to a solution of 2.1 ml of Methylhydrazine and 4.7 ml of 9N HCl/EtOH in 250 ml of Ethanol. The reaction mixture was stirred at reflux for 2 hrs. The yellow solution was allowed to cool and concentrated in vaccuo. The residue was taken up in 200 ml of Methylene chloride. The organic phase was washed successively with 1N HCl solution and water. After drying over Magnesium sulfate and concentration, the crude product (8.56 g) was purified by chromatography over silica gel using a 2:1 mixture of Heptane and Ethyl acetate as eluant. The solvents were evaporated, and the desired compound was obtained as a yellow oil (2.79 g, 35%), which solidified on standing, MS: m/e=249.1 ([M+1]+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1.[Cl:25][C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(OCC)(=O)C>[Cl:25][C:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1)=[O:28]
Reactant: COC(=O)c1cccc(-c2cccc(OCCCCCCO)c2)n1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(-c2cccc(OCCCCCCOC(=O)Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of methyl 6-(3-(6-hydroxyhexyloxy)phenyl)picolinate (13), (33 mg, 0.10 mmol, 1 eq.) in ethyl acetate (1 mL) was added triphosgene (14 mg, 0.047 mmol, 1.4 eq) dissolved in a minimum amount of ethyl acetate, followed immediately by DIEA (26 μL, 20 mg, 0.15 mmol, 1.5 eq). The mixture was stirred at room temperature for 30 min, the precipitated DIEA hydrochloride was filtered off, and the filtrate evaporated to dryness in vacuo. The oily residue of crude 14 was used directly for the next step.
Reaction SMILES: [C:1]1([CH2:7][C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:27]1(C(=O)CC=C)[C:31]2C=C[CH:34]=[CH:35][C:30]=2N=[N:28]1.O.NN>C1COCC1.CCO>[CH2:30]([C:31]1[NH:27][N:28]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:35]=[CH2:34]
Reactant: Cc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: C=CCC(=O)n1nnc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: NN
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1[nH]nc(-c2ccc(C)cc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
To a solution of 2-phenyl-1-p-tolylethanone (1.0 g, 4.76 mmol) in THF (10 mL) added LiHMDS (1.0 M in THF) (9.51 mL, 9.51 mmol) slowly via syringe at 0° C. After stirring for 10 min, 1-(1H-benzo[d][1,2,3]triazol-1-yl)but-3-en-1-one (1.068 g, 5.71 mmol) was added in one portion. The reaction was stirred at 0° C. for 30 min and then quenched with AcOH (2 mL). EtOH (30 mL) and hydrazine hydrate (0.714 g, 14.27 mmol) were added, and the reaction was heated to reflux for 30 min. The reaction was cooled to room temperature, concentrated and the residue was extracted with EtOAc/H2O, washed with brine, dried over MgSO4, and purified by column chromatography to give the title compound as clear oil (0.47 g). LCMS m/z=275.0 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.31 (s, 3H), 3.38-3.43 (m, 2H), 5.07-5.14 (m, 2H), 5.90-6.01 (m, 1H), 7.03-7.09 (m, 2H), 7.19-7.30 (m, 5H), 7.30-7.36 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[F:15][C:16]1[C:36]([C:37]([F:40])([F:39])[F:38])=[N:35][CH:34]=[CH:33][C:17]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:29][C:28](=[CH:30][C:31]#[N:32])[CH2:27]2)[CH2:22][CH2:21]1)=[O:19].N12CCCNC1CCCC=C2>C(#N)C>[F:15][C:16]1[C:36]([C:37]([F:38])([F:39])[F:40])=[N:35][CH:34]=[CH:33][C:17]=1[C:18]([N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[CH2:29][C:28]([CH2:30][C:31]#[N:32])([N:12]3[CH:13]=[C:9]([B:4]4[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]4)[CH:10]=[N:11]3)[CH2:27]2)[CH2:24][CH2:25]1)=[O:19]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#CC=C1CN(C2CCN(C(=O)c3ccnc(C(F)(F)F)c3F)CC2)C1
Agent: C1=CN2CCCNC2CCC1
Solvent: CC#N
Product: CC1(C)OB(c2cnn(C3(CC#N)CN(C4CCN(C(=O)c5ccnc(C(F)(F)F)c5F)CC4)C3)c2)OC1(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a 25 mL flask equipped with a nitrogen inlet, a thermocouple, and a magnetic stirrer were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1, 210 mg, 1.08 mmol, 1.08 equiv), 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-ylidene)acetonitrile (10, 370 mg, 1.0 mmol) and acetonitrile (3 mL) at ambient temperature. The solution was then treated with 1,8-diazabicyclo[5,4,0]undec-ene (DBU, 173 mg, 0.17 mL, 1.12 mmol, 1.12 equiv) at ambient temperature and the resulting reaction mixture was warmed to 50° C. and stirred at 50° C. for overnight. When the reaction was complete as monitored by HPLC, the reaction mixture was directly load on a solica gel (SiO2) column for chromatographic purification (0-2.5% MeOH in ethyl acetate gradient elution) to afford 2-(1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (11, 263 mg, 562.4 mg theoretical, 46.7%) as a white solid. For 11: 1H NMR (400 MHz, DMSO-d6) δ 8.64 (d, J=4.7 Hz, 1H), 8.22 (d, J=0.6 Hz, 1H), 7.88 (dd, J=4.7 Hz, 1H), 7.69 (s, 1H), 4.10-3.99 (m, 1H), 3.58 (d, J=7.8 Hz, 2H), 3.52-3.42 (m, 2H), 3.44 (s, 2H), 3.41-3.33 (m, 1H), 3.28-3.15 (m, 1H), 3.03 (ddd, J=12.9, 9.2, 3.2 Hz, 1H), 2.51-2.44 (m, 1H), 1.77-1.66 (m, 1H), 1.64-1.54 (m, 1H), 1.28-1.17 (m, 2H), 1.24 (s, 12H) ppm; 13C NMR (101 MHz, DMSO-d6) δ 160.22, 152.13 (d, J=265.8 Hz), 146.23 (d, J=5.7 Hz), 145.12, 135.41, 134.66 (d, J=16.9 Hz), 134.43 (qd, J=35.0, 11.7 Hz), 127.58, 120.61 (qd, J=274.4, 4.6 Hz), 117.35, 106.59 (br), 83.10, 61.40, 60.53 (2C), 56.49, 44.17, 38.99, 28.55, 27.82, 27.02, 24.63 ppm; C26H31BF4N6O3 (MW 562.37), LCMS (EI) m/e 563 (M++H).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)=[CH:7][C:5]=2[N:6]=1>CO.[Pd]>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[CH:7][C:5]=2[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3oc(N)nc3c2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3oc(N)nc3c2)CC1
Yield: 900.2 %

Procedure:
Intermediate 50 (550 mg, 0.14 mmol) dissolved in MeOH (25 ml) and added Pd/C (5%) (700 mg). This mixture was stirred under 80 Psi hydrogen pressure for 12 h in an autoclave. After completion of the reaction, reaction mixture filtered through a bed of celite and celite was washed with MeOH. MeOH was removed on rotavapour to obtain the residue. Residue was triturated with petether to obtain the titled compound (400 mg) as an off-white solid.
Reaction SMILES: [ClH:1].[O:2]1[CH2:6][CH2:5][C:4](=O)[CH2:3]1.[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19](Br)=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.C(=O)C1OC=CC=1>>[O:2]1[CH2:6][CH2:5][CH:4]([NH:8][C@H:9]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[C:18]4[C:19]([Cl:1])=[CH:20][N:21]=[CH:22][C:23]=4[CH:24]=[CH:25][CH:26]=3)(=[O:16])=[O:15])[CH2:10]2)[CH2:3]1
Reactant: O=C1CCOC1
Reactant: Cl
Reactant: N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Solvent: O=Cc1ccco1
Product: O=S(=O)(c1cccc2cncc(Cl)c12)N1CC[C@H](NC2CCOC2)C1

Procedure:
Hydrochloride of the compound obtained in Example 19-1 and tetrahydrofuran-3-one were used in the method of Example 4-1 instead of hydrochloride of (S)-3-amino-1-(4-bromo-5-isoquinolinesulfonyl)pyrrolidine and furfural, respectively, to obtain the title compound.
Reaction SMILES: O.O.O.O.O.O.O.O.O.[S-2:10].[Na+].[Na+].Cl[C:14]1[CH:19]=[N:18][CH:17]=[C:16]([Cl:20])[N+:15]=1[O-:21].Cl[CH2:23][S:24][C:25]#[N:26].Cl>CN(C)C=O>[Cl:20][C:16]1[N+:15]([O-:21])=[C:14]([S:10][CH2:23][S:24][C:25]#[N:26])[CH:19]=[N:18][CH:17]=1
Reactant: N#CSCCl
Reactant: [O-][n+]1c(Cl)cncc1Cl
Reactant: [S-2]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CSCSc1cncc(Cl)[n+]1[O-]
Reaction time: 8 h

Procedure:
To a vigorously stirred solution of 9.6 grams (0.04 mole) of sodium sulfide nonahydrate in 100 milliliters of dimethylformamide was gradually added 6.6 grams (0.04 mole) of 2,6-dichloropyrazine-1-oxide in 50 milliliters of dimethylformamide. The reaction mixture was stirred overnight at ~40° C. Thereafter, 4.3 grams (0.04 mole) of chloromethylthiocyanate were gradually added and the mixture stirred for 4 hours. At the completion of the reaction, the dimethylformamide was removed by evaporation under reduced pressure and the residue was dissolved in a mixture of water and chloroform. Two phases formed and the aqueous phase was acidified with hydrochloric acid and extracted with chloroform. The organic portions were combined and washed with both a saturated sodium bicarbonate solution and a saturated sodium chloride solution and dried over magnesium sulfate. The chloroform was thereafter removed by evaporation leaving the 6-chloro-2-(thiocyanatomethylthio)pyrazine-1-oxide as a residue. The product was recrystallized from methanol and was recovered in a yield of 3.0 grams (32 percent of theoretical). The product melted at 95°-98° C and upon analysis was found to have carbon, hydrogen, chlorine, nitrogen and sulfur contents of 31.00, 1.82, 15.20, 18.04 and 27.20 percent, respectively, as compared with the theoretical contents of 30.84, 1.71, 15.20, 17.99 and 27.41 percent, respectively, as calculated for the above-named compound.