Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:9][O:10]2)=[CH:5][CH:4]=1.B(Br)(Br)[Br:18].CO>ClCCl>[BrH:18].[CH2:14]([NH:13][CH:8]1[CH2:7][C:6]2[C:11](=[CH:12][C:3]([OH:2])=[CH:4][CH:5]=2)[O:10][CH2:9]1)[CH2:15][CH3:16]
Reactant: CCCNC1COc2cc(OC)ccc2C1
Reactant: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: Br
Product: CCCNC1COc2cc(O)ccc2C1
Temperature: -78 °C
Yield: 99.8 %

Procedure:
(7-Methoxy-chroman-3-yl)-propyl-amine (1.3 g, 5.87 mmol) was dissolved in dichloromethane (100 ml) and cooled to −78° C. Boron tribromide (11.7 ml, 122.52 mmol) was added and the reaction mixture was allowed to reach room temperature over night. The reaction mixture was cooled to −78° C. and a mixture of methanol and dichloromethane (2:3) was slowly added. The reaction mixture was allowed to reach room temperature and was then evaporated to dryness to yield the crude product (1.69 g, 5.86 mmol)
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(O)(=O)C.[C:8]1([C:14]([CH:16]=O)=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH3:1][NH:2][N:3]=[CH:16][C:14](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CC(=O)c1ccccc1
Reactant: CNN
Solvent: O
Solvent: CC(=O)O
Product: CNN=CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.8 %

Procedure:
A mixed solution of methylhydrazine (0.554 mL, 10.5 mmol)/acetic acid (1 mL)/water (7.6 mL) was added to phenylglyoxal (1.34 g, 10 mmol) in water (130 mL), and the mixture was stirred at room temperature for 20 hours. The reaction solution was extracted with chloroform, and the extract was dried, filtered, evaporated and dried by means of a vacuum pump to give oxo(phenyl)acetaldehyde methylhydrazone (1.44 g (crude), yield 89%) as a yellow solid.
Reaction SMILES: [I-].[CH:2]1([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][N+:14]([CH3:17])([CH3:16])C)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH:18]1C=CN=[CH:19]1.[ClH:23]>C(O)C.CCOCC>[ClH:23].[CH:2]1([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH2:13][N:14]2[CH:16]=[CH:19][N:18]=[CH:17]2)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: C[N+](C)(C)Cc1cccn1C1CCCCC1
Reactant: c1c[nH]cn1
Agent: Cl
Agent: [I-]
Solvent: CCOCC
Solvent: CCO
Product: c1cc(Cn2ccnc2)n(C2CCCCC2)c1

Procedure:
A solution of (1-cyclohexyl-pyrrol-2-yl)methyl trimethylammonium iodide (3.48 g) and imidazole (0.68 g) in ethanol (70 ml) was heated under reflux for 3 hours. The solution was evaporated and the residue was chromatographed on silica gel. Elution with chloroform gave an oil which was dissolved in ether. An excess of ethereal hydrogen chloride was added and the resulting solid was filtered off and crystallised from methanol/ethyl acetate to give 1-cyclohexyl-2-(imidazol-1-ylmethyl) pyrrole hydrochloride as a hygroscopic solid (0.80 g), m.p. 147°-149°.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][N:4]=1.[Si]([C:17]#[N:18])(C)(C)C.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CC([O-])=O.[Na+]>CC(O)=O>[N:19]1([CH:9]([C:6]2[CH:5]=[N:4][C:3]([C:2]([F:12])([F:11])[F:1])=[N:8][CH:7]=2)[C:17]#[N:18])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: C1COCCN1
Reactant: O=Cc1cnc(C(F)(F)F)nc1
Reactant: C[Si](C)(C)C#N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#CC(c1cnc(C(F)(F)F)nc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.8 %

Procedure:
To a mixture of 2-trifluoromethyl-pyrimidine-5-carbaldehyde (572 mg, 3.25 mmol) and TMSCN (645 mg, 6.49 mmol) in HOAc (10 ml) was added dropwise morpholine (311 mg, 3.57 mmol), followed by NaOAc (320 mg, 3.90 mmol). The mixture was stirred at room temperature overnight. The solvent was removed in vacuum. The residue was basified by addition of sat. aq. NaHCO3 solution to pH 8; then extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to yield the title compound (591 mg, yield: 67%). 1H NMR (CDCl3 400 MHz): δ ppm 9.10 (s, 2H), 4.96 (s, 1H), 3.88-3.71 (m, 4H), 2.79-2.55 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]([C:10]([O:12][CH3:13])=[O:11])[NH2:9])=[C:6]([NH2:14])[N:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:16]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42]>CN(C)C=O>[NH2:1][C:2]1[C:7]2[N:8]([C:10]([O:12][CH3:13])=[O:11])[NH:9][C:41](=[O:42])[NH:14][C:6]=2[N:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[N:16]=2)[N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)N(N)c1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1NC(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Temperature: 60 °C
Reaction time: 5 h
Yield: 42.1 %

Procedure:
56 mg (0.132 mmol) of the compound obtained in example 56A were initially charged in 3 ml of dimethylformamide, and 27.6 μl (0.159 mmol) of N,N-diisopropylethylamine and 25.7 mg (0.159 mmol) of carbonyldiimidazole were added. After 5 h at RT, another 27.6 μl (0.159 mmol) of N,N-diisopropylethylamine and 25.7 mg (0.159 mmol) of carbonyldiimidazole were added and the mixture was heated to 60° C. The next day, another 27.6 μl (0.159 mmol) of N,N-diisopropylethylamine and 25.7 mg (0.159 mmol) of carbonyldiimidazole were added and the mixture was heated to 60° C. for 2 further days. The reaction mixture was purified by means of preparative HPLC (acetonitrile:water (+0.05% formic acid) gradient). 25 mg of the title compound were obtained (42% of theory).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[C:4]=2[N:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH:12]=O)[N:7]=1.FC(F)(F)C(O)=O.[F:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][CH:34]=[C:35]2[N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:30][CH:29]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[F:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][CH:34]=[C:35]2[N:38]2[CH2:43][CH2:42][N:41]([CH2:12][CH2:11][CH2:10][CH2:9][O:8][C:6]3[N:7]=[C:2]([CH3:1])[C:3]4[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[C:4]=4[N:5]=3)[CH2:40][CH2:39]2)=[CH:30][CH:29]=1
Reactant: Fc1ccc2cccc(N3CCNCC3)c2c1
Reactant: Cc1nc(OCCCC=O)nc2c1ccc(=O)n2C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(OCCCCN2CCN(c3cccc4ccc(F)cc34)CC2)nc2c1ccc(=O)n2C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
4-(4,8-dimethyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yloxy)-butyraldehyde (78.4 mg, 0.30 mmol) and 1-(7-fluoro-naphthalen-1-yl)-piperazine trifluoroacetic acid (105 mg, 0.306 mmol) were combined in methylene chloride and triethylamine (63 mg, 0.63 mmol) was added. The mixture was stirred in a vial over sieves for 10 min. Sodium triacetoxyborohydride (89 mg, 0.420 mmol) was added and the reaction was stirred overnight. The reaction was quenched slowly with water and the mixture was filtered. The residue was partitioned between CH2Cl2 and water. The organic layer was washed with water and concentrated. Purification by liquid chromatography (MPLC, gradient of 100% CH2Cl2 to 100% of a 10% MeOH in CH2Cl2 solution) gave the title compound as a white foam (89 mg, 0.187 mmol, 62.4%). MS: APCI: M+1: 476.2 (Exact Mass: 475.24).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH3:14]
Reactant: CC/C=C\CCCCCCCCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC/C=C\CCCCCCCCCCBr
Reaction time: 3 h
Yield: 17.7 %

Procedure:
Cis-11-tetradecen-1-ol (1 g, 4.72 mmol) and carbon tetrabromide (1.56 g 4.72 mmol) were dissolved in dichloromethane (3 ml) and the solution was cooled in ice bath. A solution of triphenylphosphine (1.24 g, 4.72 mmol) in 2 mL of dichloromethane was added dropwise. After siring at 0° C. for 15 minutes and at room temperature for 3 h the solvent was evaporated and the residue was diluted with ether. The ether solution was filtered and concentrated and purified using column chromatography on silica gel eluting with hexane:ethyl acetate (3:1) to give 0.23 g of (Z)-14-bromo-3-tetradecene.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18]([O:20]C)=[O:19])=[N:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-]>CO.C1COCC1.O>[C:1]1([C:7]2[C:8]([C:18]([OH:20])=[O:19])=[N:9][O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1noc(-c2ccccc2)c1-c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1noc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a thick suspension of methyl 4,5-diphenylisoxazole-3-carboxylate (306 mg, 1.09 mmol) in MeOH (8 mL), THF (2 mL) and water (2 mL) at rt was added LiOH, hydrate (46.0 mg, 1.09 mmol) and the reaction mixture was allowed to stir at rt for 1 hr. During this time, the reaction became homogeneous. The MeOH and THF were removed in vacuo and the remaining aqueous mixture was acidified to pH ˜1 with 1N HCl. The mixture was then extracted with EtOAc (30 mL). The organic layer was washed with brine (20 mL), dried (MgSO4) and concentrated to afford 4,5-diphenylisoxazole-3-carboxylic acid (290 mg, 1.09 mmol, 100% yield) as a yellow solid. HPLC retention time=1.72 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient.
Reaction SMILES: N[C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH3:20])=[O:18].C=O.[C:23](#N)C.[C:26]([BH3-])#[N:27].[Na+]>CCOCC.C(O)(=O)C>[CH3:23][N:27]([CH3:26])[C:2]1[C:7]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1N
Reactant: [BH3-]C#N
Reactant: CC#N
Agent: C=O
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)Cc1cccc(C(=O)c2ccccc2)c1N(C)C
Reaction time: 2 h

Procedure:
A stirred solution of 4.6 gms. (0.0165 mole) of methyl 2-amino-3-benzoylphenylacetate and 13.2 ml. (0.165 mole) of 37% formaldehyde in 66 ml. of acetonitrile was treated with 3.14 gms. (0.0495 mole) of sodium cyanoborohydride. Glacial acetic acid (1.65 ml.) was added over a 10 minute period and stirring contained for 2.0 hrs. at room temperature. An additional 1.65 ml. of glacial acetic acid was added and the mixture stirred over a weekend (co. 65 hours). The mixture was diluted with ether and the ether solution was successively washed with 3N potassium hydroxide solution, water, dried over sodium sulfate and concentrated under vacuum to give approximately 1.0 gms. (18%) of a yellow oil. A portion of the oil was molecularly distilled for an analytical sample.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.Cl.[CH3:17][NH:18][C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:21][C:20]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[CH3:17][NH:18][C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][N:27]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:26][CH2:25]2)=[N:21][C:20]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: CCOC(=O)c1nc(N2CCNCC2)sc1NC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)sc1NC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 11.3 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (25 mg, 0.18 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (16 μl, 0.18 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 10 minutes. This solution was added to a solution of ethyl 5-methylamino-2-piperazin-1-yl-thiazole-4-carboxylate hydrochloride (41 mg, 0.15 mmol) and DIPEA (79 μl, 0.45 mmol) in anhydrous DCM (2 ml) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters Xbridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 7 mg of a solid (0.017 mmol, 11%).
Reaction SMILES: [CH2:1]([O:3]/[N:4]=[C:5](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:6](O)=[O:7])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:40][CH:41]1[C:66](=[O:67])[N:43]2[C:44]([C:50]([O:52][CH:53]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[O:51])=[C:45]([CH2:48][Cl:49])[CH2:46][S:47][C@H:42]12.C([O-])(O)=O.[Na+]>ClCCl>[Cl:49][CH2:48][C:45]1[CH2:46][S:47][C@@H:42]2[CH:41]([NH:40][C:6](=[O:7])/[C:5](/[C:9]3[N:10]=[C:11]([NH:14][C:15]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[S:12][CH:13]=3)=[N:4]\[O:3][CH2:1][CH3:2])[C:66](=[O:67])[N:43]2[C:44]=1[C:50]([O:52][CH:53]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)=[O:51]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IVb) (1.095 g, 2.4 mmoles) in dichloromethane (20 mL) was added phosphorus pentachloride (500 mg). After stirring for 1 hour at room temperature, the mixture was added in one portion to an ice-cooled solution of Compound V (1.083 g, 2.4 mmoles) and BSA (1 mL) in dichloromethane (20 mL). After stirring for 0.5 hour the reaction mixture was poured into 10% aqueous NaHCO3 (200 mL) and extracted with CHCl3 (100 mL). The extract was washed with water, dried over MgSO4, and evaporated under reduced pressure. The residue was chromatographed on a silica gel column. Elution with CHCl3 gave VIb as an amorphous powder, 1.76 g (86%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.[Br-].[Cl:24][C:25]1[CH:26]=[C:27]([CH:48]=[CH:49][CH:50]=1)[CH2:28][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:48]=[CH:49][CH:50]=1)/[CH:28]=[CH:18]/[C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:4]2=[O:11])[CH:22]=[CH:21][CH:20]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:48]=[CH:49][CH:50]=1)/[CH:28]=[CH:18]\[C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][CH2:12][N:3]2[C:2](=[O:1])[C:10]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:4]2=[O:11])[CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: Clc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(/C=C/c2cccc(Cl)c2)c1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(/C=C\c2cccc(Cl)c2)c1
Yield: 30 %
Yield: 30 %

Procedure:
Phthalimide 29 was coupled with 3-chlorobenzyltriphenylphosphonium bromide. Purification by flash chromatography (5% EtOAc-hexanes) gave (E)-2-(3-(3-(3-chlorostyryl)phenyl)propyl)isoindoline-1,3-dione (0.100 g, 30%) and (Z)-2-(3-(3-(3-chlorostyryl)phenyl)propyl)isoindoline-1,3-dione (0.180 g, 30%) as colorless oils. Trans-isomer: 1H NMR (400 MHz, CDCl3) δ 7.80-7.84 (m, 2H), 7.68-7.72 (m, 2H), 7.50 (t, J=1.6 Hz, 1H), 7.37 (dt, J=7.6, 1.2 Hz, 1H), 7.35 (s, 1H), 7.29 (d, J=7.6 Hz, 1H), 7.21-7.26 (m, 3H), 7.12 (dt, J=6.4, 2.0 Hz, 1H), 7.03 (d, J=4.4 Hz, 2H), 3.78 (t, J=7.2 Hz, 2H), 2.72 (t, J=7.6 Hz, 2H), 2.05-2.12 (m, 2H).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:15](=[O:17])[CH3:16])[CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]>C(Cl)(Cl)Cl.CO>[Br:1][CH2:16][C:15]([C:11]1([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:14][CH2:13][CH2:12]1)=[O:17]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: BrBr
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(CBr)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of bromine (18 ml) in chloroform (80 ml) was added dropwise at 10°-15° C. over 1.5 hours to a stirred solution of the above 1-[1-(3,4-dichlorophenyl)-cyclobutyl]ethanone (89.6 g) in a mixture of methanol (120 ml) and chloroform (20 ml). When the addition was complete, the mixture was stirred at ambient temperature for 1 hour, then poured onto an excess of ice-water. The aqueous layer was separated and the product extracted into dichloromethane (2×150 ml). The combined organic solutions were washed with saturated aqueous sodium hydrogen carbonate solution (2×200 ml) then with water, dried over calcium chloride and the solvent removed in vacuo to yield an oil. The oil was distilled to give 2-bromo-l-[1-(3,4-dichlorophenyl)-cyclobutyl]ethanone (88.31 g), b.p. 148°-154° C./0.66 mbar.
Reaction SMILES: [H-].[Na+].[C:3]([N:6]1[CH2:11][CH2:10][C:9]([C:13]#[CH:14])([OH:12])[CH2:8][CH2:7]1)(=[O:5])[CH3:4].[H][H].[F:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20]Cl>CN(C=O)C.O>[C:3]([N:6]1[CH2:11][CH2:10][C:9]([C:13]#[CH:14])([O:12][CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=2[F:17])[CH2:8][CH2:7]1)(=[O:5])[CH3:4]
Reactant: C#CC1(O)CCN(C(C)=O)CC1
Reactant: Fc1ccccc1CCl
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CC1(OCc2ccccc2F)CCN(C(C)=O)CC1

Procedure:
Sodium hydride (39.98 g as a 50% mineral oil suspension, 883 mmole) was suspended in dry DMF (500 ml). 1-Acetyl-4-ethynyl-4-hydroxypiperidine (126.5 g; 758 mmole), dissolved in 500 ml of DMF, was added dropwise to the sodium hydride suspension at such a rate as to maintain the solvent temperature below 30° C. After evolution of hydrogen had ceased, 2-fluorobenzylchloride (120.8 g; 99 ml; 833 mmole), dissolved in 200 ml of DMF, was added dropwise, maintaining the temperature below 25° C. After allowing the mixture to react for 3 hours, 2 l. of water was added to quench the reaction. The mixture was extracted with ether and the combined ether extracts were back extracted with 5% hydrochloric acid. The organic phase was finally extracted with saturated aqueous sodium chloride and dried over anhydrous potassium carbonate. The mixture was filtered and the volatile components removed in vacuo. A residue of material, slightly impure by TLC, remained (193 g; 700 mmole; 84.3%). A 10 g sample was purified by preparative high performance liquid chromatography (HPLC) using hexane:ethylacetate (2:1) and finally ethylacetate as the effluents on silica gel. The residue was an oil which crystallized upon standing. Recovery was 7 g of material which appeared pure by TLC on silica gel in hexane:ethylacetate (2:1), Rf =0.1 and in chloroform:methanol (9:1), Rf =0.6, MS (ci MH+ =276), NMR-CDCl3 and IR-CHCl3 are consistent with the structure, m.p.=59°-62° C.
Reaction SMILES: [N+](C1C=C(N[C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2C=O)C=CC=1)([O-])=O.C[C:20]1[N:29]=[C:28]2[C:23]([CH:24]=[C:25]([CH2:40][CH2:41][CH2:42]C3C=CN=CC=3)[C:26](=[O:39])[N:27]2[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N+:36]([O-:38])=[O:37])[CH:31]=2)=[CH:22][CH:21]=1.[Li+].[CH3:50]C([N-]C(C)C)C>CN(C=O)C>[N+:36]([C:32]1[CH:31]=[C:30]([N:27]2[C:28]3[C:23](=[CH:22][CH:21]=[CH:20][N:29]=3)[CH:24]=[C:25]([CH2:40][CH2:41][CH2:42][CH2:50][C:11]3[CH:12]=[CH:15][CH:16]=[CH:17][N:18]=3)[C:26]2=[O:39])[CH:35]=[CH:34][CH:33]=1)([O-:38])=[O:37]
Reactant: CC(C)[N-]C(C)C
Reactant: Cc1ccc2cc(CCCc3ccncc3)c(=O)n(-c3cccc([N+](=O)[O-])c3)c2n1
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCCc2ccccn2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), ethyl 6-(pyridin-2-yl)hexanoate (2.0 eq., prepared in Synthetic Example 11) and LDA (2.0 eq.) to obtain 1-(3-nitrophenyl)-3-[4-(pyridin-2-yl)butyl]-1,8-naphthyridin-2(1H)-one, mp 163 to 165° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:8]=2)[NH:3]1.[CH:22]([C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29](B(O)O)[CH:30]=1)([CH3:24])[CH3:23].[CH2:36]([SH:39])[CH:37]=[CH2:38]>>[CH2:36]([S:39][CH2:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:27]3[CH:26]=[C:25]([CH:22]([CH3:24])[CH3:23])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])[CH:8]=2)[NH:3][C:2]([CH3:1])([CH3:21])[CH:11]=1)[CH:37]=[CH2:38]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: C=CCS
Reactant: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Product: C=CCSCC1=CC(C)(C)Nc2ccc(-c3cc(C(C)C)ccc3OC)cc21

Procedure:
Trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester was coupled with 5-isopropyl-2-methoxyphenylboronic acid. Bromination and coupling reaction with allyl mercaptan gave 25 mg of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[N:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:9].[I:17][CH3:18]>CC(C)=O>[IH:17].[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=[N:7][C:8]([S:9][CH3:18])=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CI
Reactant: CN1CCCC1=NC(=S)Nc1ccccc1
Solvent: CC(C)=O
Product: CSC(=Nc1ccccc1)N=C1CCCN1C
Product: I

Procedure:
To a solution of 34.86 g (0.15 mole) of N-(1-methyl-2-pyrrolidinylidene)-N'-phenylthiourea in 500 ml of acetone is added 21.3 g (0.15 mole) of iodomethane in acetone. The solution is refluxed for 1/2 hour and allowed to stand at room temperature for an additional hour. A solid, crystallizes upon cooling (ice bath). Following recrystallization from methanol-isopropanol, pure methyl N-(1-methyl-2-pyrrolidinylidene)-N'-phenylcarbamimidothioate hydroiodide is obtained; m.p. 145°-147° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:5]=[CH:4][C:3]=1[C:12]([NH2:14])=[O:13].[CH:15]1([CH2:21][C:22](OC)=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(O)C.[H-].[Na+]>O>[CH:15]1([CH2:21][C:22]2[NH:14][C:12](=[O:13])[C:3]3[CH:4]=[N:5][N:6]([CH:7]4[CH2:11][CH2:10][CH2:9][CH2:8]4)[C:2]=3[N:1]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)CC1CCCCC1
Reactant: NC(=O)c1cnn(C2CCCC2)c1N
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c(CC2CCCCC2)nc2c1cnn2C1CCCC1

Procedure:
Under argon, 75 mg (0.39 mmol) of 5-amino-1-cyclopentyl-1H-pyrazole-4-carbox-amide and 183 mg (1.16 mmol, 3 equiv.) of methyl cyclohexylacetate are introduced into 1.5 ml of absolute ethanol. At 0° C., 54 mg of sodium hydride (60% dispersion in mineral oil; 1.35 mmol, 3.5 equiv.) are slowly added in a countercurrent of argon. The resulting mixture is slowly heated and stirred under reflux for 18 h. For workup, 20 ml of water are added, and the mixture is extracted several times with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated in vacuo. The crude product is purified by preparative HPLC.