Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[O:13])=[CH:8][CH:7]=1.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[O:13])=[CH:8][CH:7]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1ccc(I)cc1)c1ccc(OCCCBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCOc1ccc(C(=O)c2ccc(I)cc2)cc1
Temperature: 45 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A solution of (4-(3-bromopropoxy)phenyl)(4-Iodophenyl)methanone (50.0 g, 112 mmol), and sodium azide (10.2 g, 157 mmol) was dissolved in DMF (300 ml). The reaction was heated to 45° C. and left to stir overnight. Upon completion, the reaction mixture was filtered to remove sodium salt and concentrated under reduced pressure. The crude was then further extracted with chloroform, the organic layer was washed with brine, and dried over anhydrous sodium sulfate to afford 40.3 g (88.0% yield) of (4-(3-azidopropoxy)phenyl)(4-iodophenyl)methanone as grey solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:13][NH2:14]>>[NH:13]([C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[NH2:14]
Reactant: Cc1cc(Cl)nc2ncccc12
Reactant: NN
Product: Cc1cc(NN)nc2ncccc12
Temperature: 25 °C

Procedure:
A solution of 2-chloro-4-methyl-1,8-naphthyridine (330 mg, 1.8 mmol) in NH2NH2 was refluxed at 130° C. for 2 hours. The reaction mixture was cooled to room temperature, then excess NH2NH2 was removed on the rotary evaporator. The residue was taken up in 20 mL of CH2Cl2. The mixture was washed with saturated NaHCO3 (3×15 mL), brine (lx 20 mL), and then dried over MgSO4 and concentrated. The residue was washed with hexane to give 2-hydrazinyl-4-methyl-1,8-naphthyridine. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.56 (s, 3 H) 6.66 (s, 1 H) 7.22 (dd, J=7.91, 4.40 Hz, 1 H) 8.11 (dd, J=8.06, 1.90 Hz, 1 H) 8.82 (dd, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12](=S)[NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[N:4]=1.CC(C)=[O:26]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])=[O:26])[N:4]=1
Reactant: COc1nc(NC(=S)NS(=O)(=O)c2ccccn2)nc(OC)n1
Reactant: CC(C)=O
Product: COc1nc(NC(=O)NS(=O)(=O)c2ccccn2)nc(OC)n1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture containing 2.7 g of N-[(4,6-dimethoxy-1,3,5-triazin-2-yl)aminothioxomethyl]-2-pyridinesulfonamide, 2.98 g of mercuric oxide and 75 ml of acetone is stirred at ambient temperature for 60 hours and then filtered. Evaporation of the filtrate in vacuo yields the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1OCc1ccccc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)ccc1-c1ccccc1OCc1ccccc1
Temperature: 70 °C

Procedure:
To a solution of 2-(benzyloxy)phenol (4.2736 g, 21.34 mmol) and 2,5-dichloronitrobenzene (4.302 g, 22.41 mmol) in 40 mL of DMSO was added cesium carbonate (13.8 g, 42.7 mmol). The reaction was heated to 70° C. under argon for one hour, then cooled to room temperature. The solution was poured into EtOAc, washed with water, sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The titled product was obtained as a brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].O.O.O.COC(=O)CC(C)=O.C(=O)(O)[O-].[Na+].[C:41](=[O:49])([O:46][CH2:47][CH3:48])[O:42][CH:43](Br)[CH3:44]>C(OCC)(=O)C.O.CC(C)=O.C(N(CC)CC)C>[CH3:44][CH2:43][O:42][C:41]([O:46][CH:47]([O:22][C:21]([C@@H:3]1[N:4]2[C:8]([C@@H:7]([NH:10][C:11]([C@H:13]([NH2:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:12])[C@H:5]2[S:6][C:2]1([CH3:24])[CH3:1])=[O:9])=[O:23])[CH3:48])=[O:49]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Reactant: CCOC(=O)OC(C)Br
Agent: COC(=O)CC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)OC(C)OC(=O)[C@@H]1N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1(C)C
Temperature: 40 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
A mixture of ampicillin trihydrate (15 g), methylaceto acetate (5.65 g), triethylamine (4.05 g) and acetone (7.5 ml) was stirred at 40° C. for 3 hours. Acetone (30 ml) and sodium bicarbonate (12.4 g) were added. 1-Bromoethyl ethyl carbonate (14.6 g) was added dropwise during 1 hour. Stirring was continued at 40° C. for 1 hour. Water (37.5 ml) was added and the reaction was stirred at 20° C. for 1 hour. Ethyl acetate (37.5 ml) was added and the phases separated. The organic phase was washed with 20% sodium chloride solution. Acetone (7.5 ml) was added and a solution of ca. 16% hydrochloric acid was added slowly until a stable pH of 2.2 was obtained. The addition takes 11/2-2 hours. The solution was dried over anhydrous sodium sulfate and filtered. Butyl acetate (45 ml) was added and the solution was evaporated in vacuo to remove most of the solvents (bath temperature 35° C.). More butyl acetate (50 ml) was added and partially distilled. The resulting slurry was cooled for several hours and filtered to give 11.6 g bacampicillin.
Reaction SMILES: C(O)(=O)C(O)=[O:3].[C:7]1([C:13]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C(C2C=CC=CC=2)(C2CCNCC2)O)C=CC=CC=1.BrCCCOC1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC>[O:23]([CH2:22][CH2:21][CH2:20][N:17]1[CH2:16][CH2:15][CH:14]([C:13]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[OH:3])[CH2:19][CH2:18]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(O)C(=O)O
Reactant: c1ccc(OCCCN2CCC(=C(c3ccccc3)c3ccccc3)CC2)cc1
Agent: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Solvent: CCCCO
Product: OC(c1ccccc1)(c1ccccc1)C1CCN(CCCOc2ccccc2)CC1
Yield: 53 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 4.0 g (0.015 mole) of α, α-diphenyl-4-piperidinemethanol, 3.2 g (0.015 mole) of 1-bromo-3-phenoxypropane, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave 3.2 g (53%) of title compound as a white solid, mp 87°-88° C.
Reaction SMILES: [CH2:1]([N:8]([CH3:27])[C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCOCC1>[CH2:1]([N:8]([CH3:27])[C:9]1[C:14]2[N:15]=[C:16]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: CN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(Cl)nc12
Solvent: C1COCCO1
Product: CN(Cc1ccccc1)c1ncnc2c(N3CCS(=O)CC3)nc(N3CCNCC3)nc12

Procedure:
8.1 gm (0.002 mol) of 8-(N-benzyl-methylamino)-2-chloro-4-(1-oxido-thiomorpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 158°-160° C.) were refluxed for 30 minutes with 6.9 gm (0.08 mol) of anhydrous piperazine in 150 ml of dioxane. The solvent was then distilled off, and the residue was taken up in about 600 ml of water. After standing for a short time, the reaction product was suction-filtered off, washed with water and dried at about 60° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10](Cl)(Cl)[C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1.Cl>>[C:14]1([C:15]2[O:16][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:18]=[CH:19][C:11]([C:10]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccc(C(Cl)(Cl)Cl)cc1
Reactant: Nc1ccccc1O
Agent: Cl
Product: c1ccc2oc(-c3ccc(-c4nc5ccccc5o4)cc3)nc2c1
Yield: 71.4 %

Procedure:
In the apparatus described under Example 1, 21.8 g of reactant A (0.2 mol), 25.8 g of p-trichloromethyl-benzoyl chloride (0.1 mol) and 3.5 g of B2O3 (0.05 mol) were mixed and slowly heated. Between 190° and 200° C, a vigorous evolution of HCl began. After 2 hours the mixture was cooled and ground in a mortar. After extraction twice with 100 ml of CHCl3 and twice with 100 ml of water, 22.3 g of raw product (71% of the theory) was obtained, melting at 318° to 328° C. Compound XIX can be recrystallized from dimethylformamide, o-dichlorobenzene, nitrobenzene, dimethylsulfoxide or 1,2-dibromoethane. A small specimen recrystallized from o-dichlorobenzene melted at 325° to 329° C. The product can be further purified by chromatography on Al2O3 with 1,2-dibromoethane as the elutant at 120° C, whereupon the melting point becomes 340° to 342° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH2:15][C:16]([NH2:18])=[S:17]>>[CH3:1][O:2][C:3]([C:4]1[N:15]=[C:16]([NH2:18])[S:17][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14]
Reactant: COC(=O)C(=O)C(Cl)c1ccccc1
Reactant: NC(N)=S
Product: COC(=O)c1nc(N)sc1-c1ccccc1

Procedure:
prepared by reaction of 3-chloro-2-oxo-3-phenyl-propionic acid methyl ester with thiourea. LC-MS: tR=0.77 min; [M+H]+=235.1.
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[C:23]=2[F:25])[N:18]=[CH:17][C:16]=1[Cl:28])(=O)OCC)C.[C:29]([O:33][C:34](=[O:45])[NH:35][C@@H:36]1[CH2:41][CH2:40][C@@H:39]([CH2:42][CH:43]=O)[O:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30].CCCCCC>O1CCCC1.C(OCC)(=O)C>[C:29]([O:33][C:34](=[O:45])[NH:35][C@@H:36]1[CH2:41][CH2:40][C@@H:39]([CH2:42][CH:43]=[CH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:26][CH3:27])[C:23]=3[F:25])[N:18]=[CH:17][C:16]=2[Cl:28])[O:38][CH2:37]1)([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOP(=O)(Cc1c(Cl)cnc2ccc(OC)c(F)c12)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CC=O)OC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ncc(Cl)c(C=CC[C@@H]3CC[C@@H](NC(=O)OC(C)(C)C)CO3)c2c1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
A solution of n-butyllithium (1.6 M in n-hexane, 4.72 mL, 7.55 mmol, 1.5 eq) is added dropwise at 0° C. to a stirred solution of (3-chloro-5-fluoro-6-methoxy-quinolin-4-ylmethyl)-phosphonic acid diethyl ester (1.82 g, 5.03 mmol, 1.0 eq) in tetrahydrofuran (130 mL). After 2 hours stirring at 0° C., a solution of (3R,6S)-[6-(2-oxo-ethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester (1.22 g, 5.03 mmol, 1.0 eq) in tetrahydrofuran (30 mL) is added dropwise within 2 minutes. After 10 minutes stirring at 0° C., the reaction mixture is quenched with water (10 mL). Then solvent is evaporated and the residue is extracted with ethyl acetate (3×150 mL) and water (100 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: n-hexane:ethyl acetate, 10:1 to 1:1, v/v) to afford (3R,6S)-{6-[3-(3-chloro-5-fluoro-6-methoxy-quinolin-4-yl)-allyl]-tetrahydro-pyran-3-yl}-carbamic acid tert-butyl ester as a light red solid (1.82 g, 80% yield).
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].[CH3:9][Si:10](Cl)([CH3:12])[CH3:11]>>[CH3:1][C:2](=[C:4]([O:8][Si:10]([CH3:12])([CH3:11])[CH3:9])[CH:5]([CH3:7])[CH3:6])[CH3:3]
Reactant: CC(C)C(=O)C(C)C
Reactant: C[Si](C)(C)Cl
Product: CC(C)=C(O[Si](C)(C)C)C(C)C

Procedure:
Reaction between 2,4-dimethyl-3-pentanone (1.2.4.3), trimethylsilyl chloride, and base gave 2,4-dimethyl-3-trimethysilyloxy-2-pentene (1.2.4.4) which was reacted with 1-fluoropyridinium triflate (1.2.4.5) to form 2,4-dimethyl-2-fluoro-3-pentanone (1.2.4.6). This product was reacted with (CH3)3S(O)+I− to form the title compound (1.2.4.2).
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])(C)(C)C.Cl[C:17]1[CH:26]=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>>[N:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:25]=[CH:26][C:17]=1[NH:15][CH2:14][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][N:8]1[C:6]([OH:5])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: Clc1cnc2ccccc2n1
Product: O=C(O)N1CCCCC1CNc1cnc2ccccc2n1

Procedure:
The title compound (0.73 g) was prepared from (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1 ml) and 2-chloroquinoxaline (0.5 g) according to the procedure of D8.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:8][CH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>C1C=CC=CC=1.N1C=CC=CC=1.C(O)(C)C>[C:1]1([O:7][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[CH2:9][Cl:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccccc1CCl
Reactant: Oc1ccccc1
Solvent: CC(C)O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1ccccc1)c1ccccc1CCl
Temperature: -20 °C
Reaction time: 4 h

Procedure:
The ester was prepared by Method C only, by dissolving 47 g (0.5 mole) of phenol in 60 ml of benzene in the apparatus used in the preparation of the para compound, adding 0.5 ml of absolute pyridine as catalyst, and then adding 95 g (0.5 mole) of undiluted o-chloromethylbenzoyl chloride drop by drop at 55° to 60° C. over a period of about 1 hour, the mixture being stirred for another 4 hours at the refluxing temperature to complete the reaction. The benzene was then distilled out of the clear, light red solution thus obtained. The viscous oily, clear, red residue obtained in a quantitative yield crystallized after standing for a while at -15° C. The crystal mass thus obtained was ground in a chilled mortar with about 100 ml of intensely cooled isopropanol; the undissolved portion was removed by suction filtering and washed with 100 ml of isopropanol chilled to -20° C. After drying, 87 g (70%) was obtained of a colorless crystallizate with a melting point of 39°-41° C. For the analysis, 15 g was dissolved at 35° C. in 125 ml of isopropanol and set aside to crystallize at -20° C. 12.7 g of colorless needles was obtained with a melting point of 39°-41° C.
Reaction SMILES: OCC(N1[CH2:10][CH2:9][N:8]([C:11]2[CH:33]=[CH:32][C:14]([NH:15]C3N=C(C4N(C(C)C)C(C)=NC=4)C(Cl)=CN=3)=[CH:13][CH:12]=2)[CH2:7]C1)=O.CC[OH:36]>[Pd]>[NH2:15][C:14]1[CH:32]=[CH:33][C:11]([N:8]2[CH2:7][CH:10]([OH:36])[CH2:9]2)=[CH:12][CH:13]=1
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CCN(C(=O)CO)CC4)cc3)ncc2Cl)n1C(C)C
Reactant: CCO
Agent: [Pd]
Product: Nc1ccc(N2CC(O)C2)cc1
Reaction time: 0.25 h

Procedure:
A stirred solution of 1-(4-nitrophenyl)-azetidin-3-ol (Method 36; 15.15 g, 87 mM) in EtOH (250 ml) was hydrogenated over 10% Pd/C (1.5 g) for 18 hrs at atmospheric pressure. The reaction mixture was filtered and the filtrate was evaporated and triturated with ether giving the title compound as a grey crystalline solid. Much of the product had precipitated from the reaction mixture and been filtered off with catalyst. This was stirred with DMF (100 ml) for 15 mins and the catalyst filtered off. The filtrate was evaporated (Hi-Vac) and triturated with a little EtOH. The second crop of product was filtered off, washed with ether and dried. NMR: 3.35 (m+water, 2H), 3.90 (t, 2H), 4.32 (s, 2H), 4.45 (m, 1H), 5.41 (d, 1H), 6.20 (d, 2H), 6.45 (d, 2H); m/z 165.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1>>[F:15][C:16]1[CH:21]=[C:20]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Reactant: OB(O)c1cccc(F)c1
Product: Nc1nnc(-c2cccc(F)c2)c(-c2ccccc2)n1
Yield: 61.5 %

Procedure:
6-(3-Fluorophenyl)-5-phenyl-1,2,4-triazin-3-amine (49 mg, 62%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (75 mg, 0.299 mmol) and 3-fluorophenylboronic acid (48.1 mg, 0.344 mmol) according to the general procedure of Example 1.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)#[CH:15].C(#N)C>COCCOC.[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>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]#[C:15][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:17][CH:18]=1
Reactant: Brc1nccs1
Reactant: C#Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Fc1ccc(C#Cc2nccs2)cc1
Yield: 3.9 %

Procedure:
2-Bromo-1,3-thiazole (1.0 g, 6.2 mmol) and CuI (152.4 mg, 0.8 mmol) were combined in DME (17 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (3 mL, 21 mmol) and PdCl2(PPh3)2 (280 mg, 0.40 mmol) were added and 1-ethynyl-4-fluorobenzene (500 mg, 4.2 mmol) was added dropwise. The reaction was heated under reflux for 4 h at which time GC/MS showed the reaction was complete. The mixture was filtered through Celite™, and the filter pad was washed thoroughly with Ethyl acetate. The combined filtrates were then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL), washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane then 98:2 hexane:ethyl acetate to 2-[(4-fluorophenyl)ethynyl]-1,3-thiazole as a white solid which was impure by 1H NMR analysis. The compound (280 mg) was dissolved in DMSO and purified by preparative HPLC with a 30 min gradient from 60:40 water:acetonitrile to 100% acetonitrile to afford 2-[(4-fluorophenyl)ethynyl]-1,3-thiazole (33 mg, 3% yield) as a white solid. M.p. 78–79° C. 1H NMR (CDCl3, 300 MHz) δ 7.83 (d, J=3.0 Hz, 1H), 7.60–7.55(m, 2H), 7.39 (d, J=3.0 Hz, 1H), 7.14–7.00 (m, 2H). MS (ESI) 204 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:4]=1.Cl>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH:4]=1
Reactant: CCCCCCCC=Cc1cccc(OC)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCc1cccc(OC)c1
Yield: 100 %

Procedure:
A solution of 1-methoxy-3-non-1-enyl benzene (7.4 g 32 mmol) in 99% EtOH (50 mL) was added 6 M HCl (aq.; 0.5 mL) and stirred with 10% Pd/C under H2-atmosphere (1 atm) to give 7.5 g (quantitative yield) of the desired product, after filtration through Celite and evaporation to dryness of the eluate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC.CC(O)C>[CH3:23][N:19]1[CH2:18][CH:17]([CH2:16][CH2:15][N:11]2[CH2:12][CH2:13][N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH2:9][CH2:10]2)[O:21][C:20]1=[O:22]
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CN1CC(CCCl)OC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCCCO
Product: Cc1cccc(N2CCN(CCC3CN(C)C(=O)O3)CC2)c1
Yield: 64.3 %

Procedure:
This compound was prepared according to the procedure of Example 2. A mixture of 3.5 g (0.02 mol) of 1-(3-methylphenyl)piperazine (Emka-Chemie), 3.3 g (0.02 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 6.4 g (0.06 mol) of anhydrous sodium carbonate and 0.4 g potassium iodide in 100 mL of 1-butanol gave 3.9 g (65%) of white solid, mp 72°-74° C. (2-propanol).
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[C:15](Cl)[CH:16]=[CH:17][C:12]=3[N:11]3[C:19](C#N)=[N:20]N=[C:10]3[CH2:9][N:8]=2)C=CC=CC=1.Cl.C[OH:26]>[OH-].[Na+]>[N:11]1([C:19]([NH2:20])=[O:26])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:7]=[N:8][CH:9]=[CH:10]1
Reactant: CO
Reactant: N#Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)N1C=CN=Cc2ccccc21
Reaction time: 0.17 h

Procedure:
A solution of 1.60 g (0.005 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carbonitrile in a mixture of 50 ml of methanol and 50 ml of 1N sodium hydroxide solution is allowed to stand for ca. 10 minutes at 25°. The reaction mixture is then neutralised with 2N hydrochloric acid, and concentrated to about half its volume. The concentrate is extracted in methylene chloride, the organic solution washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated by evaporation. The residue is crystallised from methanol/ethyl acetate/petroleum ether to obtain 6-phenyl-8-chloro-4H-s-triazolo [4,3-a][1,4benzodiazepine-1-carboxamide, M.P. 285°-289°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][C:14](=[O:18])[NH:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:33])[CH2:21][CH2:22][CH2:23][C:24]1[C:25]([CH3:32])=[C:26]([CH:30]=O)[NH:27][C:28]=1[CH3:29]>>[CH3:33][N:20]([CH3:19])[CH2:21][CH2:22][CH2:23][C:24]1[C:25]([CH3:32])=[C:26]([CH:30]=[C:13]2[C:12]3[C:16](=[CH:17][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[CH:10][CH:11]=3)[NH:15][C:14]2=[O:18])[NH:27][C:28]=1[CH3:29]
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(CCCN(C)C)c2C)cc1
Yield: 77.5 %

Procedure:
6-(4-Methoxyphenyl)-1,3-dihydroindol-2-one (239 mg, 1.0 mmol) was condensed with 4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (208 mg, 1.0 mmol) using method B to give 333 mg (83%) of 3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-6-(4-methoxyphenyl)-1,3-dihydroindol-2-one as a brown solid.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:38])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]([CH:34]3[CH2:37][CH2:36][CH2:35]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:25][CH2:26][CH:27]2[CH2:31][O:30]C(C)(C)[O:28]2)[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([O:4][C:5](=[O:38])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH:34]3[CH2:35][CH2:36][CH2:37]3)[C:15]3[C:20]([C:21]=2[C:22]#[N:23])=[CH:19][CH:18]=[C:17]([O:24][CH2:25][CH2:26][CH:27]([OH:28])[CH2:31][OH:30])[CH:16]=3)=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCC4COC(C)(C)O4)cc3n2C2CCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCC(O)CO)cc3n2C2CCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-{3-cyano-1-cyclobutyl-6-[2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-ethoxy]-1H-indol-2-yl}-phenyl)-carbamic acid isopropyl ester (70 mg, 0.135 mmole) in DCM (2 mL) is added TFA (10 uL). The resulting mixture is stirred at ambient temperature for 2 h. The solvent is removed under reduced pressure and the residue is diluted with ethyl acetate and triturated with hexane and the precipitate collected by filtration and washed well with 50% ethyl acetate in hexane and dried in vacuo to afford {4-[3-cyano-1-cyclobutyl-6-(3,4-dihydroxy-butoxy)-1H-indol-2-yl]-phenyl}-carbamic acid isopropyl ester, compound 1429, 45 mg, (70%).