Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH2:25][CH3:26])=[C:17]([O:27][CH3:28])[CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C[Si](C)(C)[N:32]([Si](C)(C)C)[S:33]([CH3:36])(=O)=O>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[N:32][S:33][CH3:36])[C:10]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH2:25][CH3:26])=[C:17]([O:27][CH3:28])[CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Si](C)(C)N([Si](C)(C)C)S(C)(=O)=O
Reactant: CCC#CCOc1ccc(CCNC(=O)C(=O)c2ccc(Cl)c(Cl)c2)cc1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC#CCOc1ccc(CCNC(=O)C(=NSC)c2ccc(Cl)c(Cl)c2)cc1OC
Yield: 70.1 %

Procedure:
To a solution of 1.7 g (3.9 mmol) 2-(3,4-dichloro-phenyl)-N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-2-oxo-acetamide in 32 ml THF, 3.0 g (14.0 mmol) N,N-bis(trimethyl-silyl) methanesulfonamide and 0.1 g (0.32 mmol) tetrabutylammonium bromide (TBAF) are added. The mixture is heated at +70° C. for 7 hours. After cooling, the mixture is diluted with ethyl acetate and washed twice with water. After evaporation of the organic phase the residue is purified by flash-chromatography (ethyl acetate 25, hexanes 75) to give 1.31 g (70%) of the 2-(3,4-dichloro-phenyl)-2-methylthioimino-N-[2-(3-methoxy-4-pent-2-ynyloxy-phenyl)-ethyl]-acetamide. 1H-NMR (300 MHz, CDCl3): 1.15 (t, 3 H, CH2CH3), 2.22 (m, 2 H, CH2CH3), 2.73 (s, 3 H, SCH3), 2.83 (t, 2 H, CH2CH2) 3.59 (t, 2 H, CH2CH2) 3.89 (s, 3 H, OCH3) 4.73 (m, 2 H, OCH2) 6.78 (m, 2 H, CH arom.), 7.02 (m, 1 H, CH arom.), 7.12 (t, 1 H, NH), 7.30 and 7.58 (m, 3 H, CH arom.).
Reaction SMILES: C1[O:18][CH2:17][CH2:16]OCCOCCOCCOCCOC1.FC(F)(F)COP(CC(OC)=O)(=O)OCC(F)(F)F.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[NH2:48][C:49]1[N:53]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:52]=[CH:51][C:50]=1[CH:60]=O>C1(C)C=CC=CC=1.C1COCC1>[C:54]1([N:53]2[C:49]3[NH:48][C:17](=[O:18])[CH:16]=[CH:60][C:50]=3[CH:51]=[N:52]2)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: Nc1c(C=O)cnn1-c1ccccc1
Agent: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=c1ccc2cnn(-c3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.2 %

Procedure:
To a semi-solid mixture of 18-crown-6 (4.31 g, 16 mmol) and THF (30 ml) at −40° C. under nitrogen was added bis(2,2,2-trifluoroethyl)-(methoxycarbonylmethyl)phosphonate (0.69 ml, 3.26 mmol) followed by a solution of potassium bis(trimethylsilyl)amide in toluene (6.52 ml of a 0.5M solution, 3.26 mmol). A solution of 5-amino-1-phenyl-1H-pyrazole-4-carboxaldehyde (0.61 g, 3.26 mmol) in THF (10 ml+5 ml washings) was then added via cannula and the resulting mixture was stirred for 20 h, allowing to warm to room temperature. The reaction mixture was partitioned between saturated aqueous ammonium chloride solution and diethyl ether. The aqueous phase was extracted a second time with diethyl ether, and the combined organic extracts were washed with brine, dried (MgSO4) and concentrated. The crude material was dissolved in THF (20 ml), under nitrogen, and the resulting solution cooled to 0° C. A solution of potassium bis(trimethylsilyl)amide in toluene (13.0 ml of a 0.5M solution, 6.5 mmol) was added dropwise and the reaction mixture was stirred for 17 h during which time it was allowed to warm to room temperature. The reaction mixture was partitioned between saturated aqueous ammonium chloride solution and ethyl acetate. The aqueous phase was extracted a second time with ethyl acetate, and the combined organic extracts were washed sequentially with 0.5M aqueous hydrochloric acid and brine before being dried (MgSO4) and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 30% ethyl acetate-hexane to give 1,7-dihydro-1-phenylpyrazolo[3,4-b]pyridin-6-one (0.49 g, 71%). δH (400 MHz; CDCl3) 6.50 (1H, d, J=9), 7.29-7.33 (1H, m), 7.42-7.45 (2H, m), 7.71-7.73 (2H, m), 7.85 (1H, d, J=9), 7.91 (1H, s).
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N+:35]([O-])[CH:36]=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:40]([NH2:49])([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:42])[CH3:41].C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>FC(F)(F)C1C=CC=CC=1.CCOC(C)=O>[Si:1]([O:8][C@H:9]([C:33]1[CH:34]=[N:35][C:36]([NH:49][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([CH3:42])[CH3:41])=[CH:37][CH:38]=1)[C@H:10]1[CH2:14][CH2:13][C@@H:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=2)[N:11]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccc[n+]([O-])c3)N2C(=O)OC(C)(C)C)cc1
Reactant: CC(C)(N)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: CCOC(C)=O
Solvent: FC(F)(F)c1ccccc1
Product: COC(=O)c1ccc(C[C@@H]2CC[C@H]([C@H](O[Si](C)(C)C(C)(C)C)c3ccc(NC(C)(C)c4ccccc4)nc3)N2C(=O)OC(C)(C)C)cc1
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A solution of tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}(1-oxidopyridin-3-yl)methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate (0.465 g, 0.835 mmol) in trifluorotoluene (15 ml) was cooled to 0° C. Cumylamine (0.282 mL, 2.09 mmol) was added, followed by p-toluenesulfonic anhydride (0.273 g, 0.835 mmol) in 2 portions, 5 minutes apart. After 10 minutes, additional cumylamine (0.282 mL, 2.09 mmol) was added, followed by p-toluenesulfonic anhydride (0.273 g, 0.835 mmol) in 2 portions, 5 minutes apart. After 10 minutes, a third addition of cumylamine (0.282 mL, 2.088 mmol) was carried out, followed by p-toluenesulfonic anhydride (273 mg, 0.835 mmol) in 2 portions, 5 minutes apart. After 10 hours, the reaction was diluted with EtOAc (250 mL) and washed with water (2×50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography with 0-100% EtOAc/hexanes to afford tert-butyl (2R,5S)-2-[(R)-{[tert-butyl(dimethyl)silyl]oxy}{6-[(2-phenylpropan-2-yl)amino]pyridin-3-yl}methyl]-5-[4-(methoxycarbonyl)benzyl]pyrrolidine-1-carboxylate (349.1 mg, 62%). LC-MS=674.4 (M+1)+. 1H NMR (600 MHz, CD3OD) δ −0.07 (s, 3H), 0.07 (s, 3H), 0.88 (s, 9H), 1.15-1.92 (m, 20H), 2.75 & 2.46 (2 multiplets, 1H), 3.87 (m, 4H), 4.06 (bs, 1H), 5.31 & 5.12 (2 singlets, 1H), 6.00-6.10 (m, 1H), 7.07 (m, 5H), 7.23 (bs, 1H), 7.36 (bs, 2H), 7.81 (bs, 1H), 7.90 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][CH:14]2[CH2:18][O:17]C(C)(C)[O:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:21])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[S:29]1(=[O:41])(=[O:40])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH2:33][NH:32][CH2:31][CH2:30]1.Cl>CN(C)C=O.CO>[O:41]=[S:29]1(=[O:40])[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH2:33][N:32]([C:2]2[N:11]=[C:10]([NH:12][CH2:13][CH:14]([OH:15])[CH2:18][OH:17])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:21])[CH:8]=3)[N:3]=2)[CH2:31][CH2:30]1
Reactant: O=S1(=O)CCNCc2ccccc21
Reactant: Cc1ccc2nc(Cl)nc(NCC3COC(C)(C)O3)c2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(NCC(O)CO)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.9 %

Procedure:
A solution of 2-chloro-N-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-6-methylquinazolin-4-amine (431.2 mg, 1.4 mmol) and triethylamine (0.8 mL), 2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (296.1 mg, 1.5 mmol) in N,N-dimethyl-formamide (1.0 mL) was stirred at 160° C. for 4 hours. After being cooled to room temperature, the reaction mixture was dissolved in methanol (2.0 mL). To the above mixture, concentrated hydrochloric acid (0.5 mL) was added, and the resulting mixture was stirred at room temperature for 1 hour, and then extracted with ethyl acetate (100 mL). The organic layer was washed with brine (50 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to afford 59.2 mg of the product as a white solid (yield was 10%). MS obsd. (ESI+) [(M+H)+] 429, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.83, 1.01 Hz, 1 H), 7.90 (d, J=7.58 Hz, 1 H), 7.66-7.55 (m, 2 H), 7.50-7.35 (m, 2 H), 7.35-7.28 (m, 1 H), 5.21 (brs, 2 H), 4.56 (brs, 2 H), 4.05-3.95 (m, 1 H), 3.86 (dd, J=13.26, 4.42 Hz, 1 H), 3.73-3.56 (m, 3 H), 3.53 (t, J=5.05 Hz, 2 H), 2.39 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[S:8][C:4]=2[CH:3]=1.Cl.[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][NH2:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>>[F:1][C:2]1[C:19]([CH3:20])=[CH:18][C:5]2[N:6]=[C:7]([C:9]3[N:32]([C:29]4[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:31][CH:30]=4)[N:33]=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2nc(C(=O)CC(=O)C(F)(F)F)sc2cc1F
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Product: Cc1cc2nc(-c3cc(C(F)(F)F)nn3-c3ccc(S(C)(=O)=O)cc3)sc2cc1F
Yield: 41 %

Procedure:
The procedure of Example 9 was repeated using 1-(6-fluoro-5-methylbenzothiazol-2-yl)-4,4,4-trifluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-fluoro-5-methyl-2-[1-(4-methylsulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]-benzothiazole (yield, 41%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[N+:19]#[C-:20].[OH:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>Cl(O)(=O)(=O)=O>[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:13]=1[NH:19][C:20]1[N:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]2=[N:1][C:25]=1[C:24]1[CH:23]=[C:22]([OH:21])[CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1cccc(O)c1
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: [C-]#[N+]c1c(C)cccc1C
Agent: [O-][Cl+3]([O-])([O-])O
Product: Cc1cccc(C)c1Nc1c(-c2cccc(O)c2)nc2ccc([N+](=O)[O-])cn12

Procedure:
Compound (12) was prepared according to the general synthesis instructions from 1.0 ml of 2-amino-5-nitropyridine solution (0.1 M, DCM), 0.575 ml of 2,6-dimethylphenyl isocyanide solution (0.2 M, DCM), 0.500 ml of 3-hydroxybenzaldehyde solution (0.3 M, DCM), and 10 μl of perchloric acid (w=20%).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[NH:10][C:8]=2[N:9]=1)[CH3:2].I[CH3:29].[H-].[Na+].Cl>CN(C)C=O>[CH2:1]([S:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH3:29])[C:8]=2[N:9]=1)[CH3:2]
Reactant: CCSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1nc2c(ccc(=O)n2C)c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reaction time: 0.75 h

Procedure:
2-(Ethylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (120 mg) and iodomethane (37.8 μl) were dissolved in N,N-dimethylformamide (2 ml), sodium hydride (60% in oil, 86 mg) was added thereto under ice-cooling, and the mixture was stirred for 45 min. 0.5M Hydrochloric acid (6 ml) was added thereto under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained white solid residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (123 mg) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[S:21][CH:20]=[N:19][CH:18]=1)CCC.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.[Cu](I)I.CN(C=O)C>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:17]1[S:21][CH:20]=[N:19][CH:18]=1)([O-:9])=[O:8]
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N#Cc1csc([N+](=O)[O-])c1-c1cncs1
Temperature: 110 °C
Yield: 61.4 %

Procedure:
A microwave vial equipped with a stir bar was added 4-bromo-5-nitrothiophene-3-carbonitrile (0.24 g, 1.05 mmole) and tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12 mmol), copper iodide (0.028 g, 0.15 mmol) and then purged with N2 (g) inlet prior to addition of 5-(tributylstannyl)thiazole (0.63 g, 1.67 mmol), dioxane (2.3 mL) and few drops of DMF. The reaction mixture was heated at 110° C. for 30 min and then concentrated under reduced pressure. Purification by flash chromatography (silica, 40:60 ethyl acetate/hexane) gave 5-nitro-4-(thiazol-5-yl)thiophene-3-carbonitrile (153 mgs, 61%) Retention time (min)=1.715, method [4], MS (ESI) 238.0 (M+H).
Reaction SMILES: C(N(CC)CC)C.NCCN[C@H]1C[CH2:28][C@@:27]2([CH3:30])[C@@H:14]([CH2:15][CH2:16][C@@H:17]3[C@@H:26]2[CH2:25][CH2:24][C@@:22]2([CH3:23])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[OH:31])[CH2:13]1.FC(F)(F)C([O:36][CH2:37][CH3:38])=O>CO>[OH:31][C@H:21]1[CH2:20][CH2:19][C@H:18]2[C@H:17]3[C@H:26]([CH2:25][CH2:24][C@:22]12[CH3:23])[C@:27]1([CH3:28])[C@H:14]([CH2:13][C:37](=[O:36])[CH2:38][CH2:30]1)[CH2:15][CH2:16]3
Reactant: C[C@]12CC[C@H](NCCN)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Reactant: CCOC(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CO
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 22 h
Yield: 21.2 %

Procedure:
Triethylamine (TEA) (3.0 mL, 21.5 mmol, 15.5 equiv.) was added to 1.39 mmol of crude 3β-[N-(2-aminoethyl)-amino]-17β-hydroxy-5α-androstane in 8.0 mL dry methanol, followed by 3.21 mL (27.0 mmol, 19.4 equiv.) of ethyl trifluoroacetate (Aldrich). After stirring for 22 h at room temperature, the reaction was concentrated on a rotary evaporator. The residue was partitioned between methylene chloride and aqueous 1N hydrogen chloride (HCl), shaken, and separated. The organic layer was washed with water, saturated aqueous sodium bicarbonate, water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography on a 20 mm column using one column volume of methylene chloride, one column volume of 5% methanol in methylene chloride, and then one column volume of 10% methanol in methylene chloride, as eluants. Isolation and concentration of the product afforded 155 mg (21.2% yield over two steps from 17β-hydroxy-5α-androstan-3-one) of pure product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([I:8])=[CH:6][N:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4](=[O:16])[N:3]=1.[Cl:17][CH2:18][C:19]([CH2:21]Cl)=O.ClCC1N=C2C=CN(C3C=CC(F)=CC=3)C(=O)N2C=1>>[Cl:17][CH2:18][C:19]1[N:1]=[C:2]2[C:7]([I:8])=[CH:6][N:5]([C:9]3[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=3)[C:4](=[O:16])[N:3]2[CH:21]=1
Reactant: Nc1nc(=O)n(-c2ccc(F)cc2)cc1I
Reactant: O=C(CCl)CCl
Agent: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Product: O=c1n(-c2ccc(F)cc2)cc(I)c2nc(CCl)cn12

Procedure:
2-Chloromethyl-6-(4-fluoro-phenyl)-8-iodo-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from 4-amino-1-(4-fluoro-phenyl)-5-iodo-1H-pyrimidin-2-one and 1,3-dichloroacetone using the methods as described above for the preparation of 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[C:10](Cl)=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:8].[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:9]1[C:10]([C:21]2[CH:22]=[CH:23][C:18]([S:17][CH3:16])=[CH:19][CH:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: CSc1ccc(B(O)O)cc1
Reactant: O=C(c1ccccn1)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CSc1ccc(-c2ncccc2C(=O)c2ccccn2)cc1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
2-Chloro(3-pyridyl) 2-pyridyl ketone (Ryan Scientific Inc., South Carolina, U.S.) (810 mg, 3.7 mmol) and 4-(methylthio)benzeneboronic acid (830 mg, 5 mmol) were dissolved in toluene (50 mL) and ethanol (5 mL). To this solution was added 2 M Na2CO3 (6 mL, 12 mmol) followed by tetrakis (triphenylphosphine)palladium (250 mg, 0.2 mmol) and the resulting mixture was refluxed overnight under nitrogen atmosphere. The mixture was then cooled to room temperature and diluted with water (25 mL), stirred and the aqueous layer was separated and extracted with ethyl acetate (1×75 mL). The combined organic layers were washed with water (2×50 mL), brine (1×50 mL), dried over sodium sulfate, filtered and concentrated at reduced pressure to give the crude product. Purification by column chromatography over silica gel using 40% ethyl acetate in hexane gave the title compound (770 mg, 68% yield) as a white solid; mp 122-123° C.; 1H NMR (CDCl3) δ 8.87 (dd, J=4.8 and 1.7 Hz, 1H), 8.45 (d, J=4.7 Hz, 1H), 8.0 (dd, J=7.7 and 1.4 Hz, 2H), 7.75 (m, 1H), 7.45-7.3 (m, 4H), 7.12 (d, J=8.4 Hz, 2H), 2.44 (s, 3H); 13C NMR (CDCl3) δ 196.0, 157.6, 153.5, 150.7, 148.8, 139.3, 137.4, 136.6, 136.5, 133.6, 129.4 (2C), 126.5, 125.7 (2C), 123.5, 121.1, 15.3; LRMS (APIMS) m/z 307 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]2[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[C:25]([CH:27]1[CH2:29][CH2:28]1)=[O:26]>C1COCC1>[CH:27]1([C:25](=[O:26])[C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]3[O:10][CH2:11][C:12]([CH3:15])([CH3:14])[N:13]=3)=[CH:4][CH:3]=2)[CH2:29][CH2:28]1
Reactant: CC1(C)COC(C(C)(C)c2ccc(Br)cc2)=N1
Reactant: CN(C)C(=O)C1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)COC(C(C)(C)c2ccc(C(=O)C3CC3)cc2)=N1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A solution of 4-bromo-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl)toluene, prepared according to Example 2, (10.0 g. 0.0338 mole) in 400 mL THF was cooled to −78° C., n-butyllithium (16 mL, 0.042 mole) was added via syringe, and the mixture was stirred at −78° C. for 30 minutes. While keeping the temperature below −75° C., N,N-dimethyl cyclopropylcarboxylic acid amide (11.5 g, 0.102 mole) in 30 mL THF was added dropwise, and the mixture was stirred at −78° C. for 30 minutes. The mixture was allowed to warm to −15° C., and was quenched with water. The product was extracted with methylene chloride, washed with saturated NaCl solution, dried over Na2SO4, and concentrated. The residue was cooled to 0° C., treated with minimal acetonitrile, and filtered, to afford 6.95 g of 4-(cyclopropyl-oxo-methyl)-α,α-dimethyl-α-(4,4-dimethyloxazolin-2-yl)toluene as a white solid (72%).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.BrC(F)(F)C[OH:17].C(N(CC)CC)C>O1CCCC1>[C:1]12([C:11]([OH:12])=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OCC(F)(F)Br
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(O)C12CC3CC(CC(C3)C1)C2

Procedure:
1-adamantanecarbonyl chloride and 2-bromo-2,2-difluoroethanol were mixed in tetrahydrofuran, and ice-cooled. Triethylamine was added into the mixture, and then a typical liquid separating operation and a distillation removal of solvent were conducted, to obtain 1-adamantanecarboxylic acid=2-bromo-2,2-difluoroethyl. Next, conversion into sodium sulfinate by sodium dithionite and oxidation by hydrogen peroxide were conducted for the mixture, to obtain intended sodium 2-(1-adamantanecarbonyloxy)-1,1-difluoroethanesulfonate.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[S:12])SC)(=[O:3])[CH3:2].[N-:13]=[N+:14]=[N-:15].[Na+]>O1CCOCC1.O>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][N:8]1[C:9]([SH:12])=[N:15][N:14]=[N:13]1)(=[O:3])[CH3:2]
Reactant: CSC(=S)NCCCNC(C)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)NCCCn1nnnc1S
Reaction time: 4 h
Yield: 48.7 %

Procedure:
A mixture of a solution of methyl N-(3-acetamidopropyl)dithiocarbamate (193 g) in dioxane (610 ml) and a solution of sodium azide (79.42 g) in water (500 ml) was refluxed under stirring for 4 hours. Dioxane was distilled off and the remaining aqueous layer was washed with diethyl ether (150 ml×2), adjusted to pH 1 with 17.5% hydrochloric acid, and cooled in an ice bath. Precipitates were collected by filtration and washed with ice-water to give white powder of 1-(3-acetamidopropyl)-1H-tetrazol-5-thiol (91.75 g), mp. 152° to 154° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([CH3:27])[CH2:11][CH2:10][N:9]([C:12]2[N:13]=[N:14][C:15]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:16]([CH3:19])[C:17]=2[CH3:18])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CCO.O>[CH2:20]([C:15]1[N:14]=[N:13][C:12]([N:9]2[CH2:10][CH2:11][C:6]([CH3:27])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[C:17]([CH3:18])[C:16]=1[CH3:19])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)C1(C)CCN(c2nnc(Cc3ccccc3)c(C)c2C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(Cc2ccccc2)nnc(N2CCC(C)(C(=O)O)CC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a solution of 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-4-methyl-piperidine-4-carboxylic acid ethyl ester (0.60 g, 1.6 mmol) in EtOH (5 mL) is added sodium hydroxide (0.5 g, 13.2 mmol) in H2O (5 mL). After being stirred at 25° C. for two hr, the mixture is concentrated, and extracted with CH2Cl2 (2×10 mL) to remove impurities. The aqueous layer is acidified by 1N HCl to pH˜5, and extracted with CH2Cl2 (6×20 mL). The combined organic solution is dried over Na2SO4, filtered and concentrated to give 1-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-4-methyl-piperidine-4-carboxylic acid (0.49 g, 89%).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:8][CH2:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6]O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:17].[NH+]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[NH+]1C=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[OH:13][C:11]([CH3:14])([CH3:12])[CH2:10][CH2:9][CH2:8][C:2]([CH3:15])([CH3:1])[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:26]/[CH:27]=[C:28]1/[CH2:32][C@@H:33]([OH:17])[CH2:34][CH2:35][C:29]/1=[CH2:30]
Reactant: CC(C)(O)CCCC(C)(C)CCCCO
Reactant: c1cc[nH+]cc1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: ClCCl
Product: C=C1CC[C@H](O)C/C1=C/C=C/CCCC(C)(C)CCCC(C)(C)O
Yield: 44.3 %

Procedure:
660 mg of 5,5,9-Trimethyl-decane-1,9-diol (3.05 mmol) was oxidized by reaction with 4.36 g of pyridinium-dichromate (3.8 eq.) in 97 ml of CH2Cl2 at room temperature over night. Filtration over a pad of silica gel, removal of the solvent and flash chromatography (SiO2, hexane/ethylacetate=7/3) furnished 452 mg of the title compound as colourless oil.