Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:19])[CH:7]=[CH:8][CH2:9][CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]([CH3:4])[CH3:3].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:1]([NH:5][C:6](=[O:19])/[CH:7]=[CH:8]/[CH2:9][CH2:10]/[CH:11]=[CH:12]\[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CNC(=O)C=CCCC#Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CC(C)CNC(=O)/C=C/CC/C=C\c1ccccc1
Yield: 60.5 %

Procedure:
N-Isobutyl-7-phenylhept-2-en-6-ynamide (100 mg) and 5% Pd/BaSO4 (17 ml) in dry methanol (3 ml) at 20° C. was treated with hydrogen until hydrogen uptake was 85% of theoretical. The mixture was diluted with methanol, filtered and the solvent was removed from the filtrate. The residue was treated with ether and the solvent removed in a stream of nitrogen. The product was purified by chromatography on silica (15 g), eluting with 1:1 ether:hexane grading to 100% ether to give N-isobutyl-7-phenylhepta-2E,6Z-dienamide (61 mg) as a yellow oil which crystallised on standing mp 42°-5° C.
Reaction SMILES: [NH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:22])=[C:8]([NH:10][C:11]([C:13]2[N:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[O:12])[CH:9]=1)[C:2]#[N:3].[NH2:23][OH:24]>CCO>[OH:24]/[N:23]=[C:2](\[NH2:3])/[NH:1][C:4]1[CH:5]=[CH:6][C:7]([CH3:22])=[C:8]([NH:10][C:11]([C:13]2[N:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]3=[N:15][CH:14]=2)=[O:12])[CH:9]=1
Reactant: Cc1ccc(NC#N)cc1NC(=O)c1cnc2ccccn12
Reactant: NO
Solvent: CCO
Product: Cc1ccc(N/C(N)=N/O)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of N-(5-cyanamido-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (68) 3.52 g (12.1 mmol) in 200 mL of EtOH was added 0.75 mL NH2OH (50 wt % in water, 12.1 mmol). The resulting mixture was stirred at room temperature overnight. The precipitate was filtered, washed with EtOH (10 mL) and air dried to give N-(5-(2-hydroxyguanidino)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (69) as a white solid, which was used directly in the next step without further purification. 1H NMR (400 MHz, d6-DMSO) δ 9.44 (s, 1 H), 9.46 (dd, J=6.8, 0.8 Hz, 1 H), 8.54 (s, 1 H), 8.34 (s, 1 H), 7.76 (dd, J=7.2, 2.2 Hz, 1 H), 7.59 (s, 1 H), 7.52-7.43 (m, 2 H), 7.18-7.06 (m, 2 H), 2.13 (s, 3 H). MS m/z 325.1 (M+1)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)[CH3:2].C(N(CC)CC)C.[C:19](Cl)([O:21][CH2:22][CH3:23])=[O:20].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:19]([N:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1)[CH2:1][CH3:2])([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)Cl
Reactant: CCNCCc1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N(CC)CCc1ccncc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 3.0 g. of 4-[2-(ethylamino)ethyl]-pyridine and 2.0 g. of triethylamine in 60 ml. of dry chloroform is treated at 0°C. with a solution of 2.1 g. of carboethoxy chloride in 10 ml. of dry chloroform. After stirring for two hours, the mixture is poured into ice water and 5 percent aqueous sodium hydroxide added. The chloroform layer is separated, washed with water and dried over potassium carbonate. The solvent is evaporated and the residue distilled in vacuo to give 4-[2-(N-carboethoxy-N-ethylamino)ethyl]pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[CH3:13][C:14](OC(C)=O)=[O:15].CCN(CC)CC>CN(C1C=CN=CC=1)C.O>[C:14]([O:12][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:15])[CH3:13]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1cc(Br)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
In a 50 mL round-bottomed flask fitted with condenser and magnetic stirrer were placed methyl 5-bromosalicylate (5.0 g, 21.64 mmol), Ac2O (2.65 g, 25.97 mmol), Et3N (2.63 g, 25.97 mmol) and catalytic amount of DMAP. The reaction mixture was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to give methyl 2-acetoxy-5-bromobenzoate (5.9 g, 98%). To a stirred solution of methyl 2-acetoxy-5-bromobenzoate (5.9 g, 21.61 mmol) in acetonitrile (80 mL) were added 4-acetoxystyrene (3.68 g, 22.69 mmol), N,N-diisopropylethylamine (8.38 g, 64.82 mmol), biphenyl-2-yl-di-t-butyl phosphine (368 mg, 1.29 mmol) and palladium acetate (291 mg, 1.29 mmol) under N2. The reaction mixture was heated to 80° C. for 48 h and then cooled to room temperature. Water was added and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water, brine, dried and concentrated to give crude product, which was purified by column chromatography, using 20% ethyl acetate in hexane to give (3.19 g, 42%) of the di-acetoxy stilibene. To a solution of the di-acetoxy stillbene (500 mg, 1.41 mmol) in acetonitrile: THF (10 mL: 10 mL), NaOH (388 mg, 8.47 mmol) was added and stirred for 24 h at room temperature. The reaction mixture was neutralized by dilute HCl and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried and concentrated to give a crude product, which was purified by crystallization in ethyl acetate and hexane to give 2-hydroxy-5-[(E)-2-(4-hydroxyphenyl)vinyl]benzoic acid (250 mg, 69%). MS (ES) m/z: 256.06 (M), 255.05 (M−1); 13C-NMR (CD3OD): δ 172.3, 161.1, 157.1, 132.7, 129.6, 129.3, 128.0, 127.5, 127.1, 124.3, 117.4, 115.3, 112.7. Mp. 241-243° C.
Reaction SMILES: [F:1]F.[F:3][C:4]1[N:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[N:5]=1.[F-].[Na+]>ClC(Cl)(Cl)F>[F:10][C:8]1[N:9]=[C:4]([F:3])[N:5]=[C:6]([F:11])[C:7]=1[F:1]
Reactant: FF
Reactant: Fc1cc(F)nc(F)n1
Agent: [F-]
Agent: [Na+]
Solvent: FC(Cl)(Cl)Cl
Product: Fc1nc(F)c(F)c(F)n1
Yield: 63.9 %

Procedure:
0.5 mol of fluorine in the form of a 30% by volume mixture with helium was introduced into a suspension of 29.0 g (0.216 mol) of 2,4,6-trifluoropyrimidine, 21 g of sodium fluoride (0.5 mol) and 250 ml of trichlorofluoromethane at a temperature of -78° C. The rate of introduction was 0.15 mol of fluorine per hour. After the introduction was complete, the reaction mixture was filtered and 21.0 g of tetrafluoropyrimidine (=64% of theory) were obtained from the filtrate by distillation.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:12][CH:13]=[C:14]([CH:16]=O)[N:15]=1)[CH2:2][CH3:3].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[NH:19][NH2:20]>>[CH2:23]([O:22][C:18](=[O:21])[NH:19][N:20]=[CH:16][C:14]1[N:15]=[C:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:1][CH2:2][CH3:3])[NH:12][CH:13]=1)[CH3:24]
Reactant: CCOC(=O)NN
Reactant: CCCOc1ccccc1-c1nc(C=O)c[nH]1
Product: CCCOc1ccccc1-c1nc(C=NNC(=O)OCC)c[nH]1

Procedure:
A 43. gm. portion of 2-o-propoxyphenyl-4-imidazolecarboxaldehyde and 1.98 gm. of ethyl carbazate are reacted as described in Example 32 giving the desired product, m.p. 129°-132° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=O)[C:5]([CH3:8])([CH3:7])[CH3:6].[S-:10][C:11]#[N:12].[K+]>O>[C:5]([C:4]1[N:12]=[C:11]([SH:10])[NH:2][CH:3]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: N#C[S-]
Reactant: CC(C)(C)C(=O)CN
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(C)c1c[nH]c(S)n1

Procedure:
35.2 g. 1-Amino-3,3-dimethylbutan-2-one hydrochloride and 30 g. potassium thiocyanate in 50 ml. water was warmed on the steam bath for 2 hours. After cooling, the solid formed was collected, washed with water, dried and recrystallised from industrial methylated spirit to give 4-tert.butylimidazole-2-thiol, melting point 232° - 234° C. A solution/suspension of this in industrial methylated spirit was added to a solution of 4.5 g. sodium hydroxide in 100 ml. water. 17.6 g. Ethyl iodide was added forming a lower layer and the mixture was shaken for two minutes whilst the ethyl iodide reacted and dispersed. After 20 minutes the alkali was neutralised by passing in carbon dioxide and the methylated spirit removed by evaporation. The solid was collected, washed with water, dried and on recrystallisation from toluene gave 2-ethylthio-4-tert.butylimidazole, melting point 116.5° - 120° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][N+:4]([O-:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[F:10][B-:11]([F:14])([F:13])[F:12].[Na+].[F:16]F>C(#N)C>[F:10][B-:11]([F:14])([F:13])[F:12].[F:10][B-:11]([F:14])([F:13])[F:12].[OH:9][N+:4]12[CH2:7][CH2:8][N+:1]([F:16])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2
Reactant: FF
Reactant: [O-][N+]12CCN(CC1)CC2
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: O[N+]12CC[N+](F)(CC1)CC2
Yield: 70 %

Procedure:
A solution of 1,4-diazabicyclo[2.2.2]octane N-oxide (1.26 g, 9.8 mmole) and sodium tetrafluoroborate (1 g, 9.1 mmole) in acetonitrile (250 mL) was cooled to 8° C. and treated with a mixture of fluorine in nitrogen (10% V/V, 30 mmole). The reaction was evaporated, the remaining solid washed with acetone and dried to afford 1.03 grams of 1-hydroxyl-4-fluoro- 1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (70% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.C1([C:30]2[NH:31]C3C=CC=C4C(=O)NCCC=2C=34)C=CC=CC=1.BrC1NC2C=C(F)C=C3C(=O)NCCC=1C=23.C(C1C=CC(B(O)O)=CC=1)=O.CN>>[F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:23])[NH:21][CH2:20][CH2:19][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][C:14]([CH2:15][NH:31][CH3:30])=[CH:17][CH:18]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23
Reactant: O=Cc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: CN
Agent: O=C1NCCc2c(Br)[nH]c3cc(F)cc1c23
Agent: O=Cc1ccc(B(O)O)cc1
Product: CNCc1ccc(-c2[nH]c3cc(F)cc4c3c2CCNC4=O)cc1

Procedure:
4-(8-fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)-benzaldehyde (100 mg, 0.32 mmol; prepared in a manner similar to that described for compound 12 for 2-bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one and 4-formylphenylboronic acid) was reacted with methylamine (1.62 mmol) as described for Compound PPP to yield 8-fluoro-2-(4-methylaminomethyl-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 32 mg (31%) as a yellow solid: m.p. 1543-155° C.; 1H NMR (300 MHz, d6-DMSO) 2.28 (s, 3H), 3.04 (m, 2H), 3.40 (m, 2H), 3.69 (s, 2H), 7.32 (dd, J=9.0, 2.4 Hz, 1H), 7.44 (m, 3H), 7.57 (d, J=8.1 Hz, 2H), 8.25 (br t, 1H), 11.67 (br s, 1H). HRMS (MALDI MH+) Calcd for C19H18N3OF: 324,1512. Found: 325.1524. Anal. (C19H18N3OF.0.3 H2O) C, H, N.
Reaction SMILES: [F:1][CH:2]([F:23])[C:3]1[N:7]2[C:8]3[CH:9]=[C:10]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:11](=O)[NH:12][C:13]=3[CH:14]=[CH:15][C:6]2=[N:5][N:4]=1.O=P(Cl)(Cl)[Cl:26]>C(#N)C>[Cl:26][C:11]1[N:12]=[C:13]2[C:8](=[CH:9][C:10]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:7]1[C:3]([CH:2]([F:23])[F:1])=[N:4][N:5]=[C:6]1[CH:15]=[CH:14]2
Reactant: O=c1[nH]c2ccc3nnc(C(F)F)n3c2cc1-c1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: FC(F)c1nnc2ccc3nc(Cl)c(-c4ccccc4)cc3n12
Temperature: 140 °C

Procedure:
A mixture of 1-(difluoromethyl)-8-phenyl[1,2,4]triazolo[4,3-a]-1,5-naphthyridin-7(6H)-one (10-1) (19 g, 61 mmol) and POCl3 (28 mL, 304 mmol) in acetonitrile (95 mL) was heated under microwave irradiation at 140° C. for 2 hours. The solvent was removed under reduced pressure, and to the residue was added water. The resulting solid was collected by filtration to give 7-chloro-1-(difluoromethyl)-8-phenyl[1,2,4]triazolo[4,3-a]-1,5-naphthyridine (10-2) as pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[CH3:14].[C:17](OC(=O)C)(=[O:19])[CH3:18]>N1C=CC=CC=1>[C:17]([O:1][C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH3:12])[S:7][C:6]=2[C:13]=1[CH3:14])(=[O:19])[CH3:18]
Reactant: CCCC1Oc2c(C)c(C)c(O)c(C)c2S1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCC1Oc2c(C)c(C)c(OC(C)=O)c(C)c2S1
Yield: 95.6 %

Procedure:
A mixture of 1.6 g of 5-hydroxy-4,6,7-trimethyl-2-propyl-1,3-benzoxathiole (prepared as described in Example 42), 0.8 g of acetic anhydride and 10 ml of pyridine was reacted at room temperature for 15 hours and the reaction mixture was then treated and purified in the same manner as described in Example 4, to give 1.8 g of the title compound as a pale yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:10]([C:11]([N:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(N(C(C)C)C(C)C)C.Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:13]([C:11]([C:10]2[C:5]([O:4][C:3]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=3[Cl:1])=[N:6][CH:7]=[CH:8][CH:9]=2)=[O:12])[CH2:14][CH2:15]1)[CH3:43]
Reactant: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCNc2ccccc21
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCN(C(=O)c2cccnc2Oc2cc(Cl)ccc2Cl)c2ccccc21
Temperature: 100 °C
Yield: 58.5 %

Procedure:
To a solution of [2-(2,5-dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinoxalin-1-yl)-methanone (60 mg, 0.15 mmol, 1.0 equiv; Example 122) in anhydrous DMF (0.5 mL) was added N-ethyldiisopropylamine (96 mg, 129 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and ethyl bromoacetate (55.1 mg, 37 μL, 0.33 mmol, 2.2 equiv; [CAS RN 105-36-2]) and the reaction mixture heated by microwave irradiation to 100° C. for 2 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μM, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 42.7 mg (62%) of the title compound as a light yellow powder. MS (ISP): 486.1 [M+H]+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:21]1[CH:26]=[CH:25][C:24]([CH:27]2[S:33][CH2:32][CH:31]([CH3:34])[NH:30][C:29]3[N:35]([CH2:44][CH3:45])[N:36]=[C:37]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=4)[C:28]2=3)=[C:23]([CH3:46])[CH:22]=1.[CH3:47][C:48]([OH:52])([C:50]#[CH:51])[CH3:49]>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:44]([N:35]1[C:29]2[NH:30][CH:31]([CH3:34])[CH2:32][S:33][CH:27]([C:24]3[CH:25]=[CH:26][C:21]([C:51]#[C:50][C:48]([CH3:49])([OH:52])[CH3:47])=[CH:22][C:23]=3[CH3:46])[C:28]=2[C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=2)=[N:36]1)[CH3:45]
Reactant: CCn1nc(-c2ccccn2)c2c1NC(C)CSC2c1ccc(Br)cc1C
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CCn1nc(-c2ccccn2)c2c1NC(C)CSC2c1ccc(C#CC(C)(C)O)cc1C
Temperature: 150 °C
Yield: 59.4 %

Procedure:
To a microwave vial was added CuI (2.7 mg, 0.014 mmol), PdCl2(PPh3)2 (0.040 g, 0.056 mmol), PPh3 (0.059 g, 0.23 mmol), 4-(4-bromo-2-methylphenyl)-1-ethyl-7-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepine (0.500 g, 1.13 mmol, prepared using B from Example #2, step A with ethyl hydrazine oxalate, J with 4-bromobenzaldehyde and 1-sulfanylpropan-2-one [Enamine] and K with Na(OAc)3BH) as a solution in DMF (3.76 ml), 2-methylbut-3-yn-2-ol (0.197 ml, 2.26 mmol) and TEA (2.36 ml, 16.9 mmol). The vial was sealed and the solution was sparged with N2 for about 15 min. The mixture was heated in a microwave (300 W, pressure limit 250 atm) at 150° C. for 6 h. The mixture was diluted with water (25 mL) and extracted with EtOAc (2×25 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel; heptane/EtOAc 1:0 to 0:1) to give 4-(4-(1-ethyl-7-methyl-3-(pyridin-2-yl)-4,6,7,8-tetrahydro-1H-pyrazolo[3,4-e][1,4]thiazepin-4-yl)-3-methylphenyl)-2-methylbut-3-yn-2-ol (0.3 g, 59% yield); LC-MS (Table 1, Method g) Rt=2.52 and 2.55 min.; MS m/z: 447.17 and 447.17 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1([C:15]([O-:17])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:18](N(C(C)C)CC)(C)C.C[Si](C=[N+]=[N-])(C)C>C(#N)C.CO>[NH2:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(=O)[O-])CC1
Reactant: CCN(C(C)C)C(C)C
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC#N
Product: COC(=O)C1(N)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 76 %

Procedure:
4-Amino-1-tert-butoxycarbonylpiperidine-4-carboxylate (5 g) in acetonitrile (22 ml) and methanol (2 ml) was treated with diisopropylethylamine (3.65 ml) and trimethylsilyldiazomethane (2M in hexane, 13.9 ml). After overnight stirring and evaporation of solvent, the crude product was chromatographed on silica gel (0–50% ethyl acetate/petrol) to give a yellow oil (4 g, 76%).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([NH:14][NH2:15])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:17](N)(=[NH:19])[CH3:18].[OH-].[Na+].O>C1COCC1>[CH3:18][C:17]1[NH:15][N:14]=[C:12]([C:10]2[O:11][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)[N:19]=1
Reactant: CC(=N)N
Reactant: NNC(=O)c1ccc(-c2ccccc2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(-c3ccccc3)o2)n[nH]1
Yield: 13.3 %

Procedure:
To a suspension of 5-phenylfuran-2-carbohydrazide (100 mg, 0.5 mmol) and acetamidine hydrochloride (141 mg, 1.49 mmol) in THF (20 mL), NaOH (59 mg, 1.49 mmol) was added. The mixture was refluxed overnight, cooled, then treated with H2O (30 ml) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with H2O (1×10 mL) and brine (1×10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc:Petroleum ether=1:1) to afford 5-methyl-3-(5-phenylfuran-2-yl)-1H-1,2,4-triazole as a white solid (15 mg, 13%). MS (ES+) C13H11N3O requires: 225. found: 226 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7]Cl)[N:6]=1.[C:9]([O:13][C:14]([NH:16][CH2:17][CH2:18][SH:19])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:19][CH2:18][CH2:17][NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[N:6]=1
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: Nc1nc(CCl)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCSCc1csc(N)n1
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 2-amino-4-chloromethyl-1,3-thiazole (16.2 g, 0.108 mol) in dimethylformamide (80 mL) was added 2-t-butyloxycarbonylaminoethanethiol (28.9 g, 0.163 mol) followed by potassium carbonate (45 g, 0.326 mol). After 1 hour of vigorous stirring reaction mixture was partitioned between ethyl acetate and water. Organic layer was thoroughly washed with water, dried over sodium sulfate and concentrated under reduced pressure. Flash column chromatography of the oily residue (2% methanol in methylene chloride) afforded oily product (20.0 g). 1H NMR (CDCl3) δ 1.42 (s, 9H), 2.65 (m, 2H), 3.35 (m, 2H), 3.80 (s, 2H), 2.65 (m, 2H), 5.00 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH2:42][C:43]1[CH:44]=[C:45]([C:48]([O:50][CH3:51])=[O:49])[S:46][CH:47]=1>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:42][C:43]2[CH:44]=[C:45]([C:48]([O:50][CH3:51])=[O:49])[S:46][CH:47]=2)=[O:10])[CH:3]=1
Reactant: COC(=O)c1cc(N)cs1
Reactant: O=C(O)c1cc(F)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)c1cc(NC(=O)c2cc(F)ccn2)cs1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
A solution of 4-fluoropicolinic acid (1.0 g, 6.4 mmol), HATU (2.9 g, 7.6 mmol), and N-methylmorpholine (0.84 mL, 7.6 mmol) in N,N-dimethylformamide (12 mL) was stirred at 0° C. for 30 minutes. Methyl 4-aminothiophene-2-carboxylate (990 mg, 7.0 mmol) was added, the reaction was stirred for 30 minutes at 0° C., then warmed to room temperature, and stirred for an additional 2 hours. The solvent was removed under reduced pressure, the residue was suspended in acetonitrile/H2O (1:1) and the solids were isolated by filtration, washed with water, acetonitrile, then dried to afford methyl 4-(4-fluoropicolinamido)thiophene-2-carboxylate as a white powder (1.0 g, 56% yield). M+1=281.1.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]=[C:11]1[C:16](=[O:17])[N:15]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=2[S:12]1.C[Si](C)(C)Cl.[OH:32]O.O>C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[CH:10]1[C:11](=[O:32])[C:16](=[O:17])[N:15]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[C:14]2[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=2[S:12]1
Reactant: OO
Reactant: CN(C)CCN1C(=O)C(=Cc2ccc(Cl)cc2Cl)Sc2ccccc21
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)CCN1C(=O)C(=O)C(c2ccc(Cl)cc2Cl)Sc2ccccc21
Reaction time: 0.5 h
Yield: 105 %

Procedure:
The solution of 2-(2,4-dichlorophenylmethylidene)-4-(2-dimethylaminoethyl)-2H-1,4-benzothiazine-3(4H)-one hydrochloride (1 g) in 10 ml of chloroform was cooled below 0° C. and added with trimethylchlorosilane (2 ml), and then added with 30% hydrogen peroxide (0.29 g) for 30 minutes. The solution was stirred for 30 minutes below 0° C., and added with 1 ml of water. After further stirring for 1 hour at room temperature, 10 ml of water was added to the reaction mixture. The aqueous phase of the mixture was adjusted to a pH within 8-9 and the chloroform layer was separated from the mixture. The remaining aqueous phase was extracted with 10 ml of chloroform. The chloroform solutions wee combined, dried and evaporated under reduced pressure. The oily residue was purified by silicagel chromatography to give 2-(2,4-dichlorophenyl)-5-(2-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepine-3,4(5H)-dione (1.0 g) as oil.
Reaction SMILES: [C:1]([O:5][CH:6]([CH2:21][S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:4])[CH:2]=[CH2:3].[CH2:35]([SH:47])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].Cl>C(O)C.O>[CH2:35]([S:47][CH2:3][CH2:2][C:1]([O:5][CH:6]([CH2:7][S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:21][S:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:4])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCCCS
Reactant: C=CC(=O)OC(CSCCCCCCCCCCCC)CSCCCCCCCCCCCC
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCSCCC(=O)OC(CSCCCCCCCCCCCC)CSCCCCCCCCCCCC

Procedure:
A solution of 23.0 grams of 1,3-bis(dodecylthio)-2-propyl acrylate, 9.05 grams of dodecanethiol and 1 milliliter of "Triton B" in 75 milliliters of ethanol was heated under reflux for 6 hours. The reaction mixture was allowed to cool and was then poured into a solution of 5 milliliters of concentrated hydrochloric acid in 300 milliliters of water. The light colored oil which precipitated crystallized on stirring and the crystalline solid was filtered off and allowed to dry. The product, 1,3-bis(dodecylthio)-2-propyl 3-(dodecylthio)propionate, weighed 31.5 grams and melted at 31°-32° C.