Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:38]1[C:43](O)=[CH:42][CH:41]=[C:40]([CH3:45])[CH:39]=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@H:9]([O:12][C:43]2[CH:42]=[CH:41][C:40]([CH3:45])=[CH:39][CH:38]=2)[C@H:8]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Reactant: Cc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@H](Oc2ccc(C)cc2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 6.23 g of trans-1-ethoxycarbonyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 2.97 g of p-cresol and 250 ml of benzene is added dropwise, at 50° C. under nitrogen, a solution of 4.79 g of diethyl azodicarboxylate in 250 ml of benzene. After the addition is complete, the mixture is stirred overnight at room temperature. The reaction mixture is processed according to the procedure of Example 75 to give the product as a gum.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(O)C.[O:8]1[CH2:30][CH:9]1[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24]>O>[OH:8][CH:9]([CH2:30][NH:4][CH2:3][CH2:1][OH:2])[CH2:10][O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24]
Reactant: NCCO
Reactant: CCCCOC(=O)CCCCCCCCCCCOCC1CO1
Solvent: CCO
Solvent: O
Product: CCCCOC(=O)CCCCCCCCCCCOCC(O)CNCCO
Temperature: 80 °C
Yield: 55.4 %

Procedure:
A 100-ml flask equipped with a stirrer and dropping funnel was charged with 23.7 g (250 mmol) of ethanolamine and 23.7 g of ethanol. While stirring the mixture at 80° C., an ethanol solution of 8.20 g (25 mmol) of butyl 12-(2,3-epoxypropoxy)-dodecanate was added dropwise over 1 hour. After completion of the reaction, water was added to the reaction mixture, followed by extraction with chloroform. The resultant chloroform solution was concentrated under reduced pressure, and the resultant residue was purified by column chromatography on silica gel, thereby obtaining 5.40 g (yield: 55.4%) of the title compound (Ia-15).
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([CH:33]([O:36][CH3:37])[O:34][CH3:35])=[N:9][C:10]2[N:11]([C:17](=[O:32])[NH:18][C:19]3[CH:24]=[C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]([C:30]#[N:31])=[CH:21][N:20]=3)[CH2:12][CH2:13][CH2:14][C:15]=2[CH:16]=1)(=O)=O.CCN(CC)CC.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][C:47]1=[O:52]>C(Cl)Cl>[C:30]([C:22]1[C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:24][C:19]([NH:18][C:17]([N:11]2[C:10]3[C:15](=[CH:16][C:7]([CH2:6][N:49]4[CH2:50][CH2:51][N:46]([CH3:45])[C:47](=[O:52])[CH2:48]4)=[C:8]([CH:33]([O:36][CH3:37])[O:34][CH3:35])[N:9]=3)[CH2:14][CH2:13][CH2:12]2)=[O:32])=[N:20][CH:21]=1)#[N:31]
Reactant: CN1CCNCC1=O
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(COS(C)(=O)=O)c(C(OC)OC)nc32)ncc1C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)C(=O)C4)c(C(OC)OC)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (8-((5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl methanesulfonate (intermediate 170, 368 mg, 0.657 mmol) in DCM (2.7 ml) at room temperature was added NEt3 (0.319 ml, 2.301 mmol) followed by 1-methylpiperazin-2-one (120 mg, 1.052 mmol). The reaction mixture was stirred at room temperature for 2 h and partitioned between DCM and water. The water layer was extracted multiple times with DCM, the combined organic layers were dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography using a gradient of MeOH (0-3%) in DCM to yield the title compound as a white solid. (UPLC-MS 3) tR 0.87 min; ESI-MS 553.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 13.75 (s, 1H), 8.20 (s, 1H), 7.64 (br s, 1H), 7.58 (s, 1H), 5.56 (s, 1H), 5.23 (d, 1H), 4.06-4.01 (m, 2H), 3.70 (br s, 2H), 3.63 (t, 2H), 3.50-3.42 (m, 8H), 3.40 (s, 3H), 3.31 (br s, 2H), 3.14 (br s, 2H), 2.96 (br s, 3H), 2.87-2.80 (m, 2H), 2.71 (br s, 2H), 2.03-1.96 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][N+:6]#[C-:7])[CH3:2].CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>C(O)C>[CH2:1]([O:3][C:4](=[O:8])/[C:5](/[N+:6]#[C-:7])=[CH:11]/[N:12]([CH3:14])[CH3:13])[CH3:2]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: COC(OC)N(C)C
Solvent: CCO
Product: [C-]#[N+]/C(=C\N(C)C)C(=O)OCC
Reaction time: 24 h
Yield: 71.1 %

Procedure:
A solution of ethyl-2-isocyanoacetate (10.3 g, 91 mmol) in ethanol (100 ml) was cooled down to 0° C. 1,1-dimethoxy-N,N-dimethyl methanamine (26.6 ml, 200 mmol) was added and the reaction mixture was then allowed to reach RT and stirred for 24 h. The mixture was concentrated and the crude material was purified by flash chromatography (heptane/EtOAc, 100:0 to 40:60) to afford 11 g (64.7 mmol, 71.1% yield) of the title compound. LCMS: (M+H)=169; tR=0.74 min (LC-MS 2); 1H-NMR (CDCl3, 400 MHz) δ (ppm) 7.15 (s, 1H), 4.18 (q, 2H), 3.20 (bs, 6H), 1.26 (t, 3H).
Reaction SMILES: C1(O[C:8](=[O:28])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[F:24])[C:11]=2[C:25](=[O:27])[NH2:26])C=CC=CC=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:32][CH2:31]1>>[F:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:25]([NH2:26])=[O:27])=[C:10]([NH:9][C:8]([NH:39][CH2:38][CH2:37][CH2:36][N:33]2[CH2:32][CH2:31][N:30]([CH3:29])[CH2:35][CH2:34]2)=[O:28])[S:14][N:13]=1
Reactant: Cc1ccc(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Reactant: CN1CCN(CCCN)CC1
Product: Cc1ccc(COc2nsc(NC(=O)NCCCN3CCN(C)CC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2-fluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by the procedure analogous to Example 1. MS (APCl, m/z): 465 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:10](Cl)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[NH:12]1[CH2:15][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH2:13]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][NH:2][C:3]([C:5]1[C:10]([N:12]2[CH2:15][CH:14]([C:16]3[NH:20][C:19]4[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=4[N:17]=3)[CH2:13]2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Reactant: CNC(=O)c1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1nccnc1N1CC(c2nc3cc(Cl)ccc3[nH]2)C1
Temperature: 100 °C
Yield: 49.8 %

Procedure:
A mixture of 3-chloro-pyrazine-2-carboxylic acid methylamide (100 mg, 0.41 mmol) and 2-azetidin-3-yl-5-chloro-1H-benzoimidazole (as prepared by Preparation 5) (71 mg, 0.41 mmol) and K2CO3 (113 mg, 0.82 mmol) was dissolved in DMF (20 mL) and heated for 2 h at 100° C. The mixture was diluted with water (10 mL), and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, and filtered. The filtrate was evaporated in vacuo and the residue was purified by column chromatography to give the pure product (70 mg, yield 44%). [M+1] 343. IC50 (uM) 3.882.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.[NH2:18][OH:19]>CCO.O>[O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][O:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[N:18][OH:19]
Reactant: NO
Reactant: O=Cc1ccccc1OCCN1CCNC1=O
Solvent: O
Solvent: CCO
Product: O=C1NCCN1CCOc1ccccc1C=NO
Temperature: 5 °C
Reaction time: 6 h

Procedure:
A solution of 2-[2-(2-oxoimidazolidin-1-yl)ethoxy]benzaldehyde (10.0 g, 0.043 mol) in EtOH (100 mL) is heated to 50° C. At this temperature, a hydroxylamine solution (4.5 g, 0.068 mol, 50% in water, Aldrich) in EtOH (10 mL) is added. The reaction medium is then stirred for 6 hours at a temperature between 50° C. and 70° C. The reaction medium is evaporated under reduced pressure (Tbath 45° C., 65-70 mbar) until a suspension is obtained. The crude reaction product is then taken up in water (5 mL). The solution obtained is cooled to 5° C. and maintained at this temperature for 15 hours. The precipitate obtained is filtered and washed on the filter with an EtOH/water mixture (2 mL/2 mL) and then with an EtOH/petroleum ether mixture (1 mL/4 mL) and then with petroleum ether (2*10 mL). The solid is then dried under atmospheric pressure at room temperature.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH:7]([CH3:14])[CH2:6]2)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl.O>[CH3:14][CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH:1]3[CH2:2][O:23]3)[CH:4]=2)[C:9](=[O:13])[O:8]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1)CC(C)OC2=O
Solvent: ClCCl
Solvent: O
Product: CC1Cc2cc(C3CO3)ccc2C(=O)O1

Procedure:
A solution of 6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one (1.69 g, 8.98 mmol) in DCM (60 mL) was treated with m-CPBA (3.10 g, 17.96 mmol) overnight at room temperature. The reaction was then diluted with water (50 mL) and DCM (50 mL). The organic layer was further washed successively with saturated aqueous sodium bicarbonate (30 mL), water (30 mL), and brine (30 mL). The organic layer was then dried over magnesium sulfate, filtered and concentrated. The residue was purified via MPLC (15-40% EtOAc/Hex) to give 3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][C:31]4[CH:36]=[C:35](Cl)[N:34]=[CH:33][N:32]=4)=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:38][CH2:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]1>CCO>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][C:31]4[CH:36]=[C:35]([NH:38][CH2:39][CH2:40][CH2:41][N:42]5[CH2:43][CH2:44][N:45]([CH3:48])[CH2:46][CH2:47]5)[N:34]=[CH:33][N:32]=4)=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCN(CCCN)CC1
Reactant: CC(C)(C)c1cc(NC(=O)c2cccc3cc(Oc4cc(Cl)ncn4)ccc23)n(-c2ccc(F)cc2)n1
Solvent: CCO
Product: CN1CCN(CCCNc2cc(Oc3ccc4c(C(=O)Nc5cc(C(C)(C)C)nn5-c5ccc(F)cc5)cccc4c3)ncn2)CC1

Procedure:
100 mg (0.19 mMol) 6-(6-Chloro-pyrimidin-4-yloxy)-naphthalene-1-carboxylic acid [5-tert-butyl-2-(4-fluoro-phenyl)-2H-pyrazol-3-yl]-amide (Step 20.1) and 73 μl (0.42 mMol) 1-(3-aminopropyl)-4-methylpiperazine are dissolved in 5 ml EtOH. The reaction mixture is stirred at reflux for 30 h. It is worked up by removal of all volatiles under reduced pressure. The remaining crude product is purified by flash chromatography (combi-flash: 14 g column, CH2Cl2/MeOH; gradient 0-20% MeOH) to give the title compound as a yellow solid: m.p.: 131-133° C.
Reaction SMILES: [C:1]([CH2:3][C:4](N)=O)#[N:2].F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>C1COCC1.C(O)C>[C:1]([CH2:3][C:4]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:43])[CH3:42])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:19]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Reactant: N#CCC(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](n2c(CC#N)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-Cyanoacetamide (120 mg, 1.5 mmol) and triethyloxonium tetrafluoroborate (270 mg, 1.4 mmol) in THF (1.1 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (0.5 mL) and added to a suspension of tert-butyl ({trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methyl)carbamate (150 mg, 0.40 mmol) in ethanol (1.7 mL). The mixture was stirred at 85° C. for 2 h. The solid was filtered and the filtrate was concentrated and purified on flash chromatography (0-10% methanol/dichloromethane) to give the desired product (0.12 g, 71%). LCMS calculated for C22H28N5O2S (M+H)+: m/z=426.2. Found: 426.0.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:12][CH2:11][O:10][C:9]=2[CH:13]=1)(=[O:4])[CH2:2][CH3:3].[Br:14]Br>C1COCC1>[Br:14][CH:2]([CH3:3])[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:12][CH2:11][O:10][C:9]=2[CH:13]=1)=[O:4]
Reactant: BrBr
Reactant: CCC(=O)c1ccc2c(c1)OCC2
Solvent: C1CCOC1
Product: CC(Br)C(=O)c1ccc2c(c1)OCC2
Yield: 40 %

Procedure:
8.8 gr of 2,3-dihydro-6-propionylbenzo[b]furane in 50 ml of anhydrous THF are treated with 2.6 ml of bromine according with already described process. The product so obtained is recrystallized from methanol: 8 gr of 6-(α-bromopropionyl)-2,3-dihydrobenzo[b]furane are obtained.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[H-].[Na+].[CH2:31](Br)[CH:32]=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.C(OCC)C>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:31][CH:32]=[CH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: BrCC=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1c(N(Cc2ccc(OCC=Cc3ccccc3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
The product from Example 33A (0.1 g, 26 mmoles) in DMF (0.65 mL) was treated with sodium hydride (0.011 g, 0.26 mmoles). After 10 minutes, the reaction mixture was treated with cinnamyl bromide (0.10 g, 0.52 mmoles) and shaken overnight. The mixture was diluted with diethyl ether (50 mL), washed with saturated ammonium chloride (50 mL) and water (2×50 mL), brine (50 mL), dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1cc(Cl)cc(Sc2ccc(Br)cc2)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: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3cc(Cl)cc(Cl)c3)cc2)c1C
Yield: 31.1 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-3,5-dichlorobenzene (0.2 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(3,5-dichloro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.083 g, 31%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([O:18][CH3:19])[C:12]([O:20][CH3:21])=[CH:11]2.[N:22]([O-])=O.[Na+].C(OCC)(=O)C>Br.O.[Cu]>[CH3:19][O:18][C:13]1[C:12]([O:20][CH3:21])=[CH:11][C:10]2[C:15]([CH:14]=1)=[CH:16][CH:17]=[C:8]1[C:9]=2[N:22]=[N:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: COc1cc2ccc(-c3ccccc3N)cc2cc1OC
Reactant: O=N[O-]
Agent: [Cu]
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2ccc3c4ccccc4nnc3c2cc1OC
Reaction time: 0.5 h
Yield: 17.9 %

Procedure:
6-(2-Aminophenyl)-2,3-dimethoxynaphthalene (5, 70 mg, 0.25 mmol) was dissolved in 48% hydrobromic acid (4.25 mL), cooled in ice-salt bath, and treated dropwise with stirring with sodium nitrite (0.13 g) in water (2.2 mL). Stirring was continued for 0.5 h., and to the cold solution was then added with stirring freshly precipitated copper (0.5 g). The mixture was allowed to rise slowly to room temperature and left overnight. The solid was filtered off and washed with hot chloroform. The chloroform solution was washed with diluted sodium hydroxide solution, then with water, dried (anhydrous Na2SO4) and rotaevaporated to give the crude product. Chromatography on silica gel using 50:50 hexanes:ethyl acetate afforded the title compound (13 mg) in 18% yield; 1H NMR (CDCl3) d 4.11(3H, s), 4.24(3H, s), 7.37(1H, s), 7.89˜7.94 (2H, m), 8.14(1H, d, J=8.9), 8.41(1H, d, J=8.8), 8.61˜8.66(1H, m), 8.75˜8.80(1H, m), 9.24(1H, s); 13C NMR d 56.1, 56.4, 104.0, 107.3, 112.3, 116.5, 118.5, 121.7, 126.7, 128.6, 128.8, 131.1, 131.2, 131.9, 141.5, 146.3, 150.9, 151.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([NH2:12])[NH:9][N:8]=1.[NH:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22](=O)[CH2:23][C:24](OCC)=[O:25])=[CH:21][C:16]=2[N:15]=[N:14]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH:13]1[C:17]2[CH:18]=[CH:19][C:20]([C:22]3[NH:12][C:10]4[N:9]([N:8]=[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[N:11]=4)[C:24](=[O:25])[CH:23]=3)=[CH:21][C:16]=2[N:15]=[N:14]1
Reactant: CCOC(=O)CC(=O)c1ccc2[nH]nnc2c1
Reactant: Nc1nc(-c2ccccn2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: O=c1cc(-c2ccc3[nH]nnc3c2)[nH]c2nc(-c3ccccn3)nn12
Temperature: 170 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a solution of 3-(pyridin-2-yl)-1H-1,2,4-triazol-5-amine (100 mg, 0.57 mmol) in diphenyl ether (3 ml) was added ethyl 3-(1H-1,2,3-benzotriazol-5-yl)-3-oxopropanoate (300 mg, 1.29 mmol) and 4-methylbenzene-1-sulfonic acid (5 mg, 0.02 mmol). After stirring 1 h at 170° C., the solids were collected by filtration, washed with ethyl acetate (2×10 ml), methanol (3×10 ml) and dried to give 5-(1H-benzo[d][1,2,3]triazol-5-yl)-2-(pyridin-2-yl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a off-white solid (36.7 mg, 18%).
Reaction SMILES: [CH2:1]([N:19]=[C:20]=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:22]([CH2:47][CH2:48][SH:49])([C:25]([C:28]([C:31]([C:34]([C:37]([C:40]([C:43]([F:46])([F:45])[F:44])([F:42])[F:41])([F:39])[F:38])([F:36])[F:35])([F:33])[F:32])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23].N1(C2CCCCCCC2)CCCCCCN1>>[CH2:1]([NH:19][C:20]([S:49][CH2:48][CH2:47][C:22]([C:25]([C:28]([C:31]([C:34]([C:37]([C:40]([C:43]([F:44])([F:45])[F:46])([F:41])[F:42])([F:38])[F:39])([F:35])[F:36])([F:33])[F:32])([F:30])[F:29])([F:27])[F:26])([F:24])[F:23])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCS
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Agent: C1CCCC(N2CCCCCCN2)CCC1
Product: CCCCCCCCCCCCCCCCCCNC(=O)SCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 100 °C
Reaction time: 6 h

Procedure:
Octadecyl isocyanate (29.5 g, 0.1 mole), C8F17CH2CH2SH (48 g, 0.1 moles) and 2.2.2 diazabicyclooctane (0.1 g) were mixed under nitrogen and heated to 100° C. with stirring for 6 hours. An infrared spectrum showed no --NCO absorption, indicating completion of the reaction. The product is a white wax, melting at 85°-89° C. NMR showed proton resonances at 4.7 ppm (1 proton NH), 3.2 ppm (2 protons CH2CH2NH), 3.1 ppm (2 protons CH2SCO), 2.5 ppm (2 protons C8F17CH2), 1.3 ppm (32 protons CH3 (CH2)16) and 0.8 ppm (3 protons CH3 (CH2)16).
Reaction SMILES: N[C:2]1[N:7]([C:8]2[C:9]([F:21])=[CH:10][C:11]([Cl:20])=[C:12]([CH:19]=2)[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14])[C:6](=[O:22])[N:5]=[CH:4][C:3]=1[C:23]#[N:24].Cl.C([OH:29])(C)C>>[Cl:20][C:11]1[CH:10]=[C:9]([F:21])[C:8]([N:7]2[C:2](=[O:29])[C:3]([C:23]#[N:24])=[CH:4][NH:5][C:6]2=[O:22])=[CH:19][C:12]=1[C:13]([O:15][CH:16]([CH3:18])[CH3:17])=[O:14]
Reactant: CC(C)O
Reactant: CC(C)OC(=O)c1cc(-n2c(N)c(C#N)cnc2=O)c(F)cc1Cl
Agent: Cl
Product: CC(C)OC(=O)c1cc(-n2c(=O)[nH]cc(C#N)c2=O)c(F)cc1Cl

Procedure:
3.40 g of isopropyl 5-[6-amino-5-cyano-2-oxo-1(2H)-pyrimidinyl]-2-chloro-4-fluorobenzoate in a solution of 100 ml isopropanol and 10 ml of 2N hydrochloric acid are stirred for 1 hour at room temperature. The reaction mixture is substantially concentrated under reduced pressure and extracted with ethyl acetate. The organic phase is washed with aqueous sodium bicarbonate solution, thereafter with water, and dried over anhydrous sodium sulphate. Then the organic phase is evaporated to dryness under reduced pressure and the residue dissolved in diethyl ether and the solution treated with charcoal and evaporated to dryness. The residue is recrystallized from diethyl ether/n-hexane. Isopropyl 2-chloro-4-fluoro-5-[5-cyano-3,6-dihydro-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 143°-145° C., is obtained.
Reaction SMILES: [OH:1][N:2]=[C:3]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[CH2:15][CH2:16]2)=[CH:11][CH:10]=3)[CH2:7][CH2:6]1)[CH3:4].[H-].[Na+].[CH3:33][C:34]1([O:37][CH2:36]1)[CH3:35].C(OCC)C>CN(C)C=O>[OH:37][C:34]([CH3:36])([CH3:35])[CH2:33][O:1][N:2]=[C:3]([C@@H:5]1[C@:22]2([CH3:23])[C@H:8]([C:9]3[C@H:19]([CH2:20][CH2:21]2)[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([O:24][CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][O:26]4)[CH2:15][CH2:16]2)=[CH:11][CH:10]=3)[CH2:7][CH2:6]1)[CH3:4]
Reactant: CC1(C)CO1
Reactant: CC(=NO)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=NOCC(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A portion (606 mg) of the 20-hydroxyimino-3β-(2-tetrahydropyranyloxy)-5,7-pregnadiene obtained in (a) was dissolved in 10 ml of dry dimethylformamide, and after addition of 100 mg of sodium hydride (60% in oil), the solution was vigorously stirred for 30 minutes at room temperature. After addition of 0.5 ml of isobutylene oxide, the mixture was heated on an oil bath (80°-100° C.) for 1 hour. After cooling, diethyl ether was added, and the mixture was washed with water and dried, followed by the distilling off of the solvent under vacuum. The residue was subjected to silica gel column chromatography to obtain 271 mg of 20-(2-hydroxy-2-methylpropyloxyimino)-3β-(2-tetrahydropyranyloxy)-5,7pregnadiene.