Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH2:10]O)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:43]N1C(=O)CCC1=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[C:9]([N:12]2[CH:16]=[N:15][N:14]=[N:13]2)[CH2:10][Br:43])=[CH:4][CH:3]=1
Reactant: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1cnnn1
Reactant: O=C1CCC(=O)N1Br
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(C(=C(CBr)n2cnnn2)c2ccc(F)cc2)cc1

Procedure:
A solution of 3,3-bis(4-fluorophenyl)-2-(tetrazol-1-yl)2-propenol (108 mg, 0.34 mmol), triphenylphosphine (118 mg, 0.45 mmol) and N-bromosuccinimide (74 mg, 0.42 mmol) in tetrahydrofuran (5 mL) was stirred in an inert atmosphere for a period of 1.5 hours. The suspension (triphenylphosphine oxide precipitate) was diluted with hexanes (25 mL) and the suspension was filtered. The filtrate was concentrated under reduced pressure and the semi-crystalline solid was filtered through a short silica gel column eluted with 5-10% ethyl acetate in hexanes. The title compound, 108 mg.(84%), was obtained after removal of solvents under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[CH:5][C:6](C)=[C:7]([CH:10]=1)C#N.C(Cl)Cl.[CH3:18][C:19]([OH:21])=[O:20]>O.S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:4]([N+:12]([O-:14])=[O:13])=[CH:5][C:6]([CH3:7])=[C:18]([CH:10]=1)[C:19]([OH:21])=[O:20]
Reactant: CC(=O)O
Reactant: COc1cc(C#N)c(C)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)O)c(C)cc1[N+](=O)[O-]
Temperature: 120 °C
Yield: 58 %

Procedure:
A mixture of 5-methoxy-2-methyl-4-nitrobenzonitrile (2 g, 10.4 mmol) in AcOH (20 mL), water (20 mL) and conc. sulphuric acid (20 mL) was heated to 120° C. for 5 h. Water (100 mL) and DCM (100 mL) were added and the mixture was passed through a hydrophobic frit. The solvent was removed in vacuo to give 5-methoxy-2-methyl-4-nitrobenzoic acid (1.27 g, 58%) as an off-white solid. LCMS (10 cm_ESCI_Formic_MeCN): [M−H]−=210 at 3.37 min. 1H NMR (400 MHz, CDCl3): δ 7.75 (s, 1H), 7.70 (s, 1H), 3.99 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.[S:12](Cl)([Cl:15])(=[O:14])=[O:13].C(N(C(C)C)C(C)C)C.COC1C=C2C(CCN(S(Cl)(=O)=O)C2)=CC=1>>[O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([S:12]([Cl:15])(=[O:14])=[O:13])[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CNCCO2
Reactant: O=S(=O)(Cl)Cl
Agent: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Cl)N1CCOc2ccccc2C1

Procedure:
This compound was prepared from 1.5 g of 2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine, 0.81 mL of sulfuryl chloride and 1.8 mL of ethyl diisopropyl amine using the procedure described for 63f Yield: 0.3 g (oil), EI-MS: 247 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16][CH:17]=[O:18])[CH:6](O)[C:7](=[CH2:14])[CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH3:2].S(Br)([Br:22])=O.O>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([NH:16][CH:17]=[O:18])[CH:6]=[C:7]([CH2:14][Br:22])[CH2:8][CH2:9][O:10][C:11](=[O:13])[CH3:12])[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(CCOC(C)=O)C(O)C(NC=O)C(=O)OCC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C=C(CBr)CCOC(C)=O)NC=O
Reaction time: 1 h

Procedure:
9.19 g (35.9 mmol) of 6-acetoxy-2-formylamino-3-hydroxy-4-methylene-hexanoic acid ethyl ester are dissolved in 100 ml of dichloromethane, and 3.34 ml (43.1 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 10 ml of water are added and the mixture is stirred vigorously for 10 minutes. The organic phase is separated off, washed in succession with water, saturated potassium hydrogen carbonate solution and again with water, dried over magnesium sulfate, filtered and concentrated by evaporation. 6-acetoxy-4-bromomethyl-2-formylamino-hex-3-enoic acid ethyl ester is obtained in the form of a brownish oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.[NH2:13][CH:14]1[CH2:20][N:19]([CH2:21][C:22]2[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:23]=2[CH3:29])[CH2:18][CH2:17][N:16]([CH3:30])[CH2:15]1>CN(C)C=O>[CH3:29][C:23]1[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=1[CH2:21][N:19]1[CH2:20][CH:14]([NH:13][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH2:15][N:16]([CH3:30])[CH2:17][CH2:18]1
Reactant: Cc1ccc(C)c(CN2CCN(C)CC(N)C2)c1
Reactant: O=C(O)c1n[nH]c2ccccc12
Solvent: CN(C)C=O
Product: Cc1ccc(C)c(CN2CCN(C)CC(NC(=O)c3n[nH]c4ccccc34)C2)c1
Temperature: 60 °C
Yield: 67.4 %

Procedure:
To a solution of 1H-indazole-3-carboxylic acid (1.0 g) in N,N-dimethylformamide (20 ml), N,N'-carbonyldiimidazole (1.1 g) is added, and the mixture is heated at 60° C. for 2 hours. 6-Amino-1-(2,5-dimethylbenzyl)-4-methylhexahydro-1H-1,4-diazepine (1.5 g) is added to the reaction mixture, and the mixture is heated at 60° C. for 2 hours. The solvent is evaporated under reduced pressure, and the residue is diluted with water and extracted with chloroform. The organic layer is washed successively with water and aqueous sodium hydroxide solution, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (1.6 g) as an oil. The free base thus obtained is converted to the fumarate of the title compound in a usual manner, m.p. 168°-170° C. (recrystallized from ethanol).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:8]=[C:7]([Cl:9])[CH:6]=[C:5](OC(F)(F)F)[N:4]=1>C(OC)(C)(C)C>[NH2:1][C:7]1([Cl:9])[CH:6]=[CH:5][N:4]=[C:3]([Cl:2])[NH:8]1
Reactant: N
Reactant: FC(F)(F)Oc1cc(Cl)nc(Cl)n1
Solvent: COC(C)(C)C
Product: NC1(Cl)C=CN=C(Cl)N1
Reaction time: 1 h
Yield: 32.5 %

Procedure:
4.3 g (0.25 mol) of gaseous ammonia were passed into a mixture of 23.3 g (0.1 mol) of 2,4-dichloro-6-trifluoromethoxypyrimidine in 150 ml of methyl tert-butyl ether in the course of 45 minutes while stirring at -50° to -45° C. Stirring was continued for 30 minutes at -50° C., for 1 hour at -30° C. and for 1 hour at 25° C. The precipitate which separated out was filtered off under suction, washed with water and dried, 5.4 g (33.1% of theory) of 4-amino-2,4-dichloropyrimidine of melting point 270°-272° C. being obtained as a byproduct. The filtrate was washed with water, dried, partially evaporated down under reduced pressure and subjected to fractional chromatography using 5:1 petroleum ether/ether, 3 g (12.8% of theory) of starting material being obtained as a colorless oil from the first fractions and 9 g (42% of theory) of the title compound being obtained as colorless crystals of melting point 55°-56° C. from the final fraction. The conversion was 48.3%.
Reaction SMILES: ClC1C=C(C=CC=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=CC2N(C3CCCCC3)C(C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.[Cl:83][C:84]1[CH:85]=[C:86](B(O)O)[CH:87]=[CH:88][C:89]=1[Cl:90]>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:86]4[CH:87]=[CH:88][C:89]([Cl:90])=[C:84]([Cl:83])[CH:85]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Agent: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Product: COc1ccc(-c2ccc(Cl)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 4 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 3,4-dichlorophenylboronic acid (50 mg, 0.2625 mmol) to produce the title compound (5 mg, 4% yield).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([O:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][C@H:27]([OH:31])[CH2:26]4)=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:11][CH:10]=1.[C:38](#[N:41])[CH:39]=[CH2:40]>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:23]3[C:22]([O:24][C@@H:25]4[CH2:30][CH2:29][CH2:28][C@H:27]([O:31][CH2:40][CH2:39][C:38]#[N:41])[CH2:26]4)=[N:21][CH:20]=[N:19][C:18]=3[O:17][C:16]=2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@@H]4CCC[C@H](O)C4)c23)cc1
Reactant: C=CC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@@H]4CCC[C@H](OCCC#N)C4)c23)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add a solution of 10 mg of potassium tert-butoxide in 0.5 ml of THF dropwise to a solution of 150 mg (0.36 mmol) of (+/−)-cis-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}cyclohexanol in 1 ml of acrylonitrile. Stir the reaction mixture with exclusion of light at RT for approx. 2 h. After dilution with dichloromethane, wash successively with 1N hydrochloric acid, satd. sodium hydrogencarbonate solution and satd. sodium chloride solution, and concentrate the organic phase under reduced pressure. After purification of the residue by means of preparative RP-HPLC (eluent: acetonitrile/water gradient), 136.9 mg of the target product are obtained (81% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[S:18])[NH2:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:21].[Cl:22][CH2:23][C:24](=O)[CH2:25]Cl>O1CCOCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:20])[N:9]([CH3:19])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:18][CH:25]=[C:24]([CH2:23][Cl:22])[N:17]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:21]
Reactant: CN1Cc2c(C(N)=S)ncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: O=C(CCl)CCl
Solvent: C1COCCO1
Product: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccc(F)c(Cl)c2C1=O
Yield: 35.1 %

Procedure:
A yellow suspension of 2.45 g (0.00754 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepine-3-thiocarboxamide in 130 ml of dioxan was treated with 1.05 g (0.00829 mol) of 1,3-dichloro-2-propanone. The suspension was boiled at reflux for 20 hrs. and cooled. A further 1.05 g (0.00829 mol) of 1,3-dichloro-2-propanone and 60 ml of dioxan were added and the solution was boiled at reflux for a further 16 hrs. The solution was cooled and completely freed from the solvents. The residue was chromatographed over silica gel with cyclohexane/ethyl acetate 1:2 as the eluent and recrystallized from hot acetonitrile. There were obtained 1.05 g (35%) of 7-chloro-3-(4-chloromethyl-thiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 234°-235°.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Li]CCCC.[CH2:17]([N:19]([CH2:34][CH3:35])[CH2:20][CH2:21][N:22]1[C:32]2[C:27](=[C:28]([Br:33])[CH:29]=[CH:30][CH:31]=2)[C:25](=[O:26])[C:23]1=[O:24])[CH3:18].[NH4+].[Cl-]>CCOCC>[CH2:34]([N:19]([CH2:17][CH3:18])[CH2:20][CH2:21][N:22]1[C:32]2[C:27](=[C:28]([Br:33])[CH:29]=[CH:30][CH:31]=2)[C:25]([OH:26])([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:23]1=[O:24])[CH3:35]
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Reactant: Brc1cnc2ccccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CCN(CC)CCN1C(=O)C(O)(c2cnc3ccccc3c2)c2c(Br)cccc21
Temperature: 25 °C
Yield: 4.7 %

Procedure:
To 3-bromoquinoline (56.3 mg, 1.1 eq) in anhydrous Et2O (1.0 mL) at −50° C. (internal temperature) and under a nitrogen atmosphere was added n-BuLi (0.18 mL, 1.1 eq, 1.53 M in hexanes). Stirring was continued for minutes and then to the resulting red/brown coloured precipitate was added 1-(2-diethylaminoethyl)-4-bromoisatin (80.0 mg, 2.46×10−4 mol) in anhydrous Et2O (2.0 mL) and the resulting dark blue coloured mixture was stirred for a further 8.5 hours at −50° C. Saturated aqueous NH4Cl (1.5 mL) was added and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration, the solvent was removed in vacuo. Purification was carried out by flash chromatography (silica gel, eluting 2% MeOH in CHCl3) to yield the title compound as a yellow oil (5.3 mg, 5%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=2[CH:10]=[N:9]1.N1C2C=CC=C(N)C=2C=N1.IC1C=C[C:32]([O:35]C)=CC=1>>[CH3:32][O:35][C:6]1[CH:5]=[CH:4][C:3]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH2:17])[C:11]=3[CH:10]=[N:9]2)=[CH:2][CH:7]=1
Reactant: Nc1cccc2c1cnn2-c1ccccc1F
Reactant: COc1ccc(I)cc1
Agent: Nc1cccc2[nH]ncc12
Product: COc1ccc(-n2ncc3c(N)cccc32)cc1

Procedure:
Similarly prepared to Intermediate 1 from 1H-indazol-4-amine and 1-iodo-4-(methyloxy)benzene.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[C:13]([O-])(=[O:15])[CH3:14].[Na+].BrCCO.O>CS(C)=O>[OH:15][CH2:13][CH2:14][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: CC(=O)[O-]
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: OCCBr
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCCO
Temperature: 70 °C
Reaction time: 5 h
Yield: 66.5 %

Procedure:
To a solution of N-hydroxyphthalimide (2.20 g, 13.5 mmol) and sodium acetate (3.30 g) in dimethylsulfoxide (40 mL) was added 2-bromoethanol (2.88 mL) under an argon atmosphere at room temperature. The reaction mixture was stirred at 70° C. for 5 hours, followed by cooling to room temperature, adding water (40 mL), and extracting with methylene chloride. The resulting organic layer was washed with water, 2.5M hydrochloric acid, and saturated brine. The washed organic layer was dried over magnesium sulfate, the residue resulting from distilling off the solvent under reduced pressure was recrystallized with ethanol and water to afford 1.86 g of the title compound (yield 66%).
Reaction SMILES: [CH2:1](N(CC)C1C=CC=CC=1)C.[Cl:12][C:13]1[C:18]([O:19][CH2:20][C:21]#C)=[CH:17][C:16]([C:23]2[C:24](=[O:34])[CH:25]=[C:26]([C:30]([F:33])([F:32])[F:31])[N:27]([CH3:29])[CH:28]=2)=[C:15]([F:35])[CH:14]=1.[F-].[Cs+]>O>[Cl:12][C:13]1[C:18]2[O:19][C:20]([CH3:21])=[CH:1][C:17]=2[C:16]([C:23]2[C:24](=[O:34])[CH:25]=[C:26]([C:30]([F:31])([F:33])[F:32])[N:27]([CH3:29])[CH:28]=2)=[C:15]([F:35])[CH:14]=1
Reactant: C#CCOc1cc(-c2cn(C)c(C(F)(F)F)cc2=O)c(F)cc1Cl
Reactant: CCN(CC)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Product: Cc1cc2c(-c3cn(C)c(C(F)(F)F)cc3=O)c(F)cc(Cl)c2o1
Temperature: 190 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
To 50 ml of N,N-diethylaniline, 0.64 g (1.8 mmol) of 5-(4-chloro-2-fluoro-5-propargyloxyphenyl)-1-methyl-2-trifluoromethyl-4(1H)-pyridone and 0.56 g (3.7 mmol) of cesium fluoride were added, and the mixture was stirred at from 180 to 200° C. for 2.5 hours. This reaction solution was poured into water and extracted with ethyl acetate. After washing with concentrated hydrochloric acid, water and an aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and then, the obtained residue was purified by silica gel column chromatography to obtain 0.50 g (yield: 75%) of the desired product. Melting point: 208-211° C.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11].[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:28][S:29]([O:8][CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])(=[O:31])=[O:30]
Reactant: CC(CO)N1c2ccccc2Sc2ccc(C#N)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Reaction time: 0.25 h

Procedure:
Triethylamine (10 cc) is added with stirring to a solution, cooled to a temperature in the region of 5° C., of 10-(1-hydroxy-2-propyl)-2-phenothiazinecarbonitrile, L series (12.6 g), in methylene chloride (126 cc), a solution of methanesulphonyl chloride (5.6 cc) in methylene chloride (56 cc) is then introduced dropwise during 25 minutes and stirring is continued for 1 hour 15 minutes at a temperature in the region of 10°-15° C. The reaction mixture is washed successively with distilled water (2×100 cc) and with saturated aqueous sodium chloride solution (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 2-(2-Cyano-10-phenothiazinyl)-1-propyl methanesulphonate, L series (16.2 g), is thereby obtained in the form of an orange-colored oil
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1I.[C:23]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)#[N:24].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[C:16]([C:28]2[CH:29]=[CH:30][C:25]([C:23]#[N:24])=[CH:26][CH:27]=2)=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
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: N#Cc1ccc(-c2ccccc2C(=O)NCCc2c[nH]c3ccc(Cl)cc23)cc1
Yield: 45.5 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-2-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide (0.075 g; 0.176 mmol), 4-cyanophenylboronic acid (0.027 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 2 to 20% ethyl acetate in dichloromethane) furnished 0.032 g (46%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-cyanobiphenyl-2-carboxamide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](Cl)[N:3]=1.[NH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15]([NH:17][CH3:18])=[O:16].C(N(CC)C(C)C)(C)C>C(OCC)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15]([NH:17][CH3:18])=[O:16])[C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1[N+](=O)[O-]
Yield: 49 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-nitropyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in ethyl ether (no microwave—20° C., 3 hours) to afford 2-(2-chloro-5-nitro-pyrimidin-4-ylamino)-N-methyl-benzamide as a yellow solid in 49% yield. Mp: 201-3° C. (dec); MS: 308.09 (M+H); 1H NMR (d6-dmso): δ 12.43 (s, 1H), δ 9.20 (s, 1H), δ 8.75 (br s, 1H), δ 8.19 (d, J=9 Hz, 1H), δ 7.71 (d, J=8 Hz, 1H), δ 7.58 (t, J=8 Hz, 1H), δ 7.33 (t, J=8 Hz, 1H), δ 2.78 (d, J=5 Hz, 3H).
Reaction SMILES: [H-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:18][CH:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH2:16]3)[CH2:11]2)=[CH:6][CH:5]=1.[Cl-:19].[Cl-].[Cl-].[Cl-].[Zr+4:23]>C(OCC)C>[Cl-:19].[Cl-:19].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:18][CH:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH2:16]3)[CH:11]2[Zr+2:23][CH:11]2[C:12]3[CH:17]([CH2:16][CH:15]=[CH:14][CH:13]=3)[CH2:18][CH:10]2[C:7]2[CH:6]=[CH:5][C:4]([Br:3])=[CH:9][CH:8]=2)=[CH:8][CH:9]=1
Reactant: Brc1ccc(C2CC3=CC=CCC3C2)cc1
Reactant: [Zr+4]
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Product: Brc1ccc(C2CC3CC=CC=C3C2[Zr+2]C2C3=CC=CCC3CC2c2ccc(Br)cc2)cc1

Procedure:
Again the procedure of Example I was used but in this case 0.677 mmol of potassium hydride was used in place of the n-butyllithium and the starting material was 2-(para-bromophenyl) tetrahydroindene in the amount of 0.615 mmol in 8 ml of diethylether. The procedure employed 0.31 mmol of the zirconium tetrachloride. The resulting product was purified and identified as bis(2-(para-bromophenyl) tetrahydroindenyl) zirconium dichloride.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]3[N:16]=[C:15]([C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[NH2:19])[S:14][C:11]3=[N:12][CH:13]=2)[CH2:3][CH2:2]1.[C:24]1([C:30]2[N:31]=[C:32]([C:35](O)=[O:36])[S:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:10]3[N:16]=[C:15]([C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[NH:19][C:35]([C:32]4[S:33][CH:34]=[C:30]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[N:31]=4)=[O:36])[S:14][C:11]3=[N:12][CH:13]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccccc1-c1nc2cc(CN3CCOCC3)cnc2s1
Reactant: O=C(O)c1nc(-c2ccccc2)cs1
Solvent: O
Product: O=C(Nc1ccccc1-c1nc2cc(CN3CCOCC3)cnc2s1)c1nc(-c2ccccc2)cs1

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-(morpholinomethyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 4-phenylthiazole-2-carboxylic acid. The product was isolated by precipitation during the addition of water, triturated with hot methanol and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2). MS Calcd for C27H23N5O2S2: 513.13. Found (M+H)+ m/z=514.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].Br[CH2:15][C:16]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[CH:19]=1)=O>>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([C:16]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:15]=2)[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: COc1cc(OC)cc(C(=O)CBr)c1
Product: COC(=S)c1cc(-c2nc(-c3cc(OC)cc(OC)c3)cs2)c(C)s1
Yield: 27.8 %

Procedure:
100 mg (0.404 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was reacted with 2-bromo-3′,5′-dimethoxy acetophenone (0.444 mmol) in a manner similar to Example 22, step (a) to afford 44 mg (27% yield) of methyl 4-[4-(3,5-dimethoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1.[CH3:23][C:24](=O)[CH2:25][CH2:26][C:27](=O)[CH3:28].C(O)(=O)C>C(O)C>[CH3:28][C:27]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]3[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=3)[CH:7]=2)[C:24]([CH3:23])=[CH:25][CH:26]=1
Reactant: CCCOc1ccc(N)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reactant: CC(=O)CCC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCCOc1ccc(-n2c(C)ccc2C)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Yield: 43.9 %

Procedure:
The compound (200 mg, 0.66 mmol) of example 42 and 2,5-hexanedione (76 mg, 0.66 mmol) were dissolved in ethanol (10 ml) and added with glacial acetic acid (0.1 ml), followed by refluxing for 12 h. The reaction mixture was concentrated to dryness, dissolved in CH2Cl2 (10 ml), and washed with saturated NaHCO3 (10 ml) and saturated saline (10 ml), dried and concentrated. The residue was passed through a silica gel column to give the title compound (110 mg, yield: 44%). 1H NMR (CDCl3) δ: 11.20 (1H, br), 8.42 (1H, d), 7.30 (1H, dd), 7.10 (1H, d), 5.93 (2H, s), 4.23 (2H, t), 2.63 (2H, q), 2.59 (2H, q), 2.06 (6H, s), 2.04 (2H, m), 1.24 (3H, t), 1.18 (3H, t), 1.15 (3H, t).