Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].CO[CH2:12][CH2:13][C:14](OC)(OC)[CH3:15]>[Cl-].[Zn+2].[Cl-].C(O)C>[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:4]=1[N:5]=[CH:12][CH:13]=[C:14]2[CH3:15]
Reactant: COCCC(C)(OC)OC
Reactant: Nc1ccccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: Cc1ccnc2c(Cl)cccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Commercially available 2-chloroaniline (200 g, 1.56 mol) was dissolved in 600 ml ethanol, and dry HCl gas was bubbled through for 10 minutes to give 2-chloroaniline hydrochloride. A new flask was charged with 2-chloroaniline hydrochloride (130 g, 0.793 mol), ferric chloride hexahydrate (25.7 g, 0.095 mol), anhydrous zinc chloride (10.9 g, 0.0799 mol) and 500 ml 2B ethanol. The mixture was heated to 60° C. for 10 minutes and 1,3,3-trimethoxy butane was added dropwise over a period of one hour. The mixture was then refluxed for two hours and allowed to stand overnight at room temperature. Most of the alcohol was removed by distillation and the residue was made alkaline with 25% sodium hydroxide solution. The reaction was cooled, filtered, and the filter pad washed with toluene. The toluene was concentrated to dryness. The product was recrystallized from dichloromethane/pentane to obtained a spectroscopically pure sample (mp: 110° C., 37.0 g, 25% overall yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:8](C)[C:9](=[O:13])[N:10]([CH3:12])[CH:11]=1)=[O:5])C.Cl>CO.[OH-].[Na+]>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]([CH3:12])[C:9](=[O:13])[NH:8]2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1=CN(C)C(=O)N(C)C1c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C=C(C(=O)O)C(c2ccc(F)cc2)NC1=O
Temperature: 25 °C

Procedure:
4-(4-Fluoro-phenyl)-1,3-dimethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid ethyl ester (700 mg) was dissolved in a mixture of 20 mL methanol and 6 mL 10% aqueous NaOH and heated at 45° for 3 hours. The reaction mixture was cooled to room temperature and acidified with conc. HCl. The resulting precipitate and collected by filtration and air-dried to give 4-(4-Fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid.
Reaction SMILES: CC1C=CSC=1CNC1SCC(=O)N=1.C(O[C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([CH:29]=[C:30]3[S:34][C:33]([NH:35][CH2:36][C:37]4[S:38][CH:39]=[CH:40][C:41]=4[CH3:42])=[N:32][C:31]3=[O:43])[N:27]=2)[N:22]=[CH:21][C:20]=1[C:44]#[N:45])(C)C.O=C1C(=CC2N=C3C(=CC=2)N=CC(C#N)=C3)SC(NCC2SC=CC=2)=N1>CC(O)=O>[CH3:42][C:41]1[CH:40]=[CH:39][S:38][C:37]=1[CH2:36][NH:35][C:33]1[S:34][C:30](=[CH:29][C:26]2[N:27]=[C:28]3[C:23](=[CH:24][CH:25]=2)[N:22]=[CH:21][C:20]([C:44]#[N:45])=[CH:19]3)[C:31](=[O:43])[N:32]=1
Reactant: Cc1ccsc1CNC1=NC(=O)C(=Cc2ccc3ncc(C#N)c(OC(C)C)c3n2)S1
Agent: Cc1ccsc1CNC1=NC(=O)CS1
Agent: N#Cc1cnc2ccc(C=C3SC(NCc4cccs4)=NC3=O)nc2c1
Solvent: CC(=O)O
Product: Cc1ccsc1CNC1=NC(=O)C(=Cc2ccc3ncc(C#N)cc3n2)S1
Temperature: 100 °C
Yield: 1.8 %

Procedure:
To a mixture of 2-[(3-methyl-thiophen-2-ylmethyl)-amino]-thiazol-4-one (21.7 mg, 0.10 mmol), AcONa (160 mg, 1.95 mmol) (see Example 5), and 6-formyl-[1,5]naphthyridine-3-carbonitrile (22.0 mg, 0.12 mmol) (see Example 11) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 100° C. (oil bath) for 1.5 hrs. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water, AcOEt and ether to give 6-{2-[(3-methyl-thiophen-2-ylmethyl)-amino]-4-oxo-4H-thiazol-5-ylidenemethyl}-[1,5]naphthyridine-3-carbonitrile as a light brown solid (14.0 mg, 35.8%). HR-ES (+) m/e calcd for C19H13N5OS2 (M+H)+ 414.0454. found 414.0452.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12]3=[CH:14][S:15][CH:16]=[C:11]3[C:10](=[O:17])[NH:9][C:8]=2[CH:18]=1)([O-])=O.N1C=CC=CC=1>[Pd].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12]3=[CH:14][S:15][CH:16]=[C:11]3[C:10](=[O:17])[NH:9][C:8]=2[CH:18]=1
Reactant: O=C1Nc2cc([N+](=O)[O-])ccc2Nc2cscc21
Agent: [Pd]
Solvent: CO
Solvent: c1ccncc1
Product: Nc1ccc2c(c1)NC(=O)c1cscc1N2

Procedure:
A 7.8 g. portion of 4,9-dihydro-7-nitro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in a mixture of 200 ml. of pyridine and 50 ml. of methanol with 200 mg. of 10% palladium on carbon catalyst was shaken for 2 hours in a Parr hydrogenator. The catalyst was filtered and the solvents were removed under vacuum on the steam bath. The residue was dissolved in dilute hydrochloric acid, filtered, and the filtrate was made alkaline with sodium hydroxide. The crystals which form are recovered by filtration and air dried given the desired product as a brown powder, m.p. 212°-215° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:13][C@H:12]([OH:14])[C@@H:11]([C:15]2[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>ClCCl>[C:28]([O:14][C@H:12]1[CH2:13][C@@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][C@@H:11]1[C:15]1[N:19]([CH3:20])[N:18]=[CH:17][CH:16]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1nccc1[C@H]1C[C@H](OCc2ccccc2)C[C@@H]1O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: Cn1nccc1[C@H]1C[C@H](OCc2ccccc2)C[C@@H]1OC(=O)c1ccccc1
Reaction time: 5 h
Yield: 91.8 %

Procedure:
To a solution of the (1S*,2R*,4S*)-4-(benzyloxy)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol (234 mg, 0.859 mmol) prepared in Example 98a and triethylamine (0.40 mL, 2.87 mmol) in dichloromethane (4.0 mL), benzoyl chloride (0.260 mL, 2.24 mmol) was added, and the reaction solution was stirred for 5 hours. To the reaction solution, water (50 mL) was added, and an organic layer was extracted. The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with column chromatography (hexane/ethyl acetate=3:2) to yield the title compound (297 mg, 92%) as a colorless oil.
Reaction SMILES: Cl.C1([C@H]([NH:10][C@H:11]([CH3:21])[CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[CH:17][CH:18]=2)C)C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[OH-].[OH-].[Pd+2]>[NH2:10][C@H:11]([CH3:21])[CH2:12][C:13]1[CH:14]=[C:15]([CH2:19][OH:20])[CH:16]=[CH:17][CH:18]=1
Reactant: C[C@H](Cc1cccc(CO)c1)N[C@H](C)c1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: O=C[O-]
Solvent: CCO
Product: C[C@@H](N)Cc1cccc(CO)c1
Temperature: 75 °C
Reaction time: 1.5 h

Procedure:
A mixture of (3-((R)-2-((R)-1-phenylethylamino)propyl)phenyl)methanol hydrochloride (Example 276, step b) (1.92 g), 20% palladium hydroxide on carbon (0.757 g) and ammonium formate (2.28 g) in ethanol (30 mL) was stirred at 75° C. for 1.5 hours, then allowed to cool. The suspension was filtered through diatomaceous earth, washing the residue well with ethanol. The combined filtrate and washings were concentrated in vacuo to afford a pale yellow gum as a mixture of desired product and des-hydroxy analogue. Yield 1.54 g. Used directly
Reaction SMILES: [CH3:1][NH:2][CH3:3].[NH:4]1[C:12]2[C:7](=[C:8]([C:13]3[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=O)[CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[NH:4]1[C:12]2[C:7](=[C:8]([C:13]3[CH:14]=[C:15]([CH2:19][C:20]([N:2]([CH3:3])[CH3:1])=[O:22])[CH:16]=[CH:17][CH:18]=3)[CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: O=C(O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCCl
Product: CN(C)C(=O)Cc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Dimethylamine (2M in THF, 5 mL) was added to a mixture of [3-(1H-indol-4-yl)-phenyl]-acetic acid (1.26 g, 5 mmol), EDC (1.19 g, 1.25 eq.) and HOBt (675 mg, 1 eq.) in THF (10 mL) was stirred at rt for 5 hours. The reaction was concentrated, diluted with ethyl acetate, washed with 10% Na2CO3 (3×), brine, dried and concentrated. The residue was purified on a silica gel column to give 658 mg of 2-[3-(1H-indol-4-yl)-phenyl]-N,N-dimethyl-acetamide as a solid.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([Br:26])=[C:8]([F:25])[CH:9]=[C:10]2[C:15]=1[N:14]([CH:16]1[CH2:18][CH2:17]1)[CH:13]=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]2=[O:24])(=O)C.C[O-].[Na+].O.Cl>C(O)C>[Br:26][C:7]1[C:6]([CH2:5][OH:4])=[C:15]2[C:10]([C:11](=[O:24])[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][N:14]2[CH:16]2[CH2:18][CH2:17]2)=[CH:9][C:8]=1[F:25]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(COC(C)=O)c(Br)c(F)cc2c1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2c(CO)c(Br)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
In 58 ml of ethanol was suspended 1.46 g of ethyl 8-acetoxymethyl-7-bromo-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, and 19 mg of sodium methoxide was added to the suspension, after which the resulting mixture was stirred at room temperature for seven hours. To the reaction mixture was added 60 ml of water and the pH was adjusted to 7 with 1N hydrochloric acid, after which the crystals formed were collected by filtration, to obtain 1.28 g of colorless, crystalline ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=S)=[CH:4][CH:3]=1.CI.[CH3:17][NH2:18]>CC#N.CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10]/[C:9]/2=[N:18]\[CH3:17])=[CH:4][CH:3]=1
Reactant: CN
Reactant: S=c1ccccn1-c1ccc(I)cc1
Solvent: CO
Solvent: CI
Solvent: CC#N
Product: C/N=c1\ccccn1-c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of 1-(4-iodophenyl)pyridine-2(1H)-thione (98 mg, 0.31 mmol) in CH3CN (5 mL), CH3I (0.25 mL, 4.0 mmol) was added. After being stirred at room temperature overnight, the mixture was concentrated in vacuo to give a solid. The solid was dissolved in MeOH (7 mL). To the solution, CH3NH2 (2M in THF, 0.80 mL, 1.6 mmol) was added. After being stirred at room temperature overnight, the mixture was purified by HPLC to give (E)-N-(1-(4-iodophenyl)pyridin-2(1H)-ylidene)methanamine (59 mg).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[O:12][CH3:13])=[O:2].[C:14]1([N:20]=[C:21]=[S:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:21]([NH:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[S:22])=[CH:7][C:6]=1[O:12][CH3:13])=[O:2]
Reactant: COc1cc(N)ccc1NNC=O
Reactant: S=C=Nc1ccccc1
Product: COc1cc(NC(=S)Nc2ccccc2)ccc1NNC=O

Procedure:
Procedure (18.) was employed with 1-formyl-2-(4-amino-2-methoxyphenyl)hydrazine (1.0 g, 0.0056 mole) and phenyl isothiocyanate (0.75 g, 0.0056 mole). Yield 0.90 g (51%), m.p. 183°-184° C.
Reaction SMILES: CC1[C@H]2C(C)(C)[C@H](C2)CC=1.S([O-])([O-])=O.[Na+].[Na+].[CH3:17][C:18]1[CH:23]2[C:24]([CH3:26])([CH3:25])[CH:21]([CH2:22]2)[CH:20]([OH:27])[CH:19]=1.CC1[C@@H]2C(C)(C)[C@@H](C2)C(=O)C=1.[BH4-].[Na+]>C(O)C.C(O)(=O)C.CO>[CH3:17][C:18]1[C@@H:23]2[CH2:22][C@@H:21]([C:24]2([CH3:26])[CH3:25])[C:20](=[O:27])[CH:19]=1
Reactant: CC1=CC(O)C2CC1C2(C)C
Agent: CC1=CC(=O)[C@@H]2C[C@H]1C2(C)C
Agent: CC1=CC[C@H]2C[C@@H]1C2(C)C
Agent: O=S([O-])[O-]
Solvent: CCO
Solvent: CO
Solvent: CC(=O)O
Product: CC1=CC(=O)[C@H]2C[C@@H]1C2(C)C
Temperature: 30 °C
Yield: 16.6 %

Procedure:
(−)-α-pinene (136.2 g, 1 mole) was oxidised by bubbling in O2 in the presence of cobalt stearate (0.5 g), which is added portionwise, maintaining the temperature at approximately 5-55° C., for at least 50-60 hours. When the reaction was complete, the peroxide index was approximately 27-29%. After cooling to room temperature, the excess of peroxides was decomposed by adding to the reaction mixture an equal quantity of a hot aqueous solution (˜50° C.) of 5% ferrous sulphate and 1% sulphuric acid; the peroxide index was approximately 0 within approximately 2 hours. The organic phase was then separated and washed 2-3 times with water until a pH of 5-6 is obtained. The non-reacted (−)-α-pinene was removed by column distillation at a temperature of approximately 100° C. and at a pressure of 20-25 mmHg (2.6×10−2−3.3×10−2 bar). The distillation residue was constituted by a mixture of terpenes which was characterized by oxygenated functions (alcohol, ketone and aldehyde functions). A Bertagnini reaction was then carried out by adding to the reaction mixture a solution containing sodium sulphite (120 g, 0.954 mole), while maintaining the temperature at 55-60° C. Because the pH of the mixture gradually moved to basic values, a 50% acetic acid solution was added until the pH is neutral. When the pH remained stable at ˜7, the reaction, might be regarded as complete. The organic phase (containing the alcohols PINOCARVEOL, MIRTENOL, VERBENOL) was separated and the aqueous phase was counter-extracted 2-3 times with hexane. The aqueous solution was alkalinised to pH ˜14 and then extracted with hexane, thus obtaining the fraction containing carbonyl products (MIRTENAL AND VERBENONE). The hexane extract, washed 2-3 times with water, was concentrated to obtain a high-boiling oily residue constituted to the extent of more than 80% by VERBENONE. The residue was dissolved with methanol; the methanol solution was cooled to −5 to −1° C. and, while maintaining this temperature, sodium borohydride was added until the MIRTENAL was undetectable (monitoring by TLC). The reduction was then stopped by the addition of a small amount of acetic acid, until the solution was neutral. The methanol solution was concentrated to ⅔ the volume, then diluted with water and extracted with hexane. The hexane solution was evaporated under vacuum and the residue is distilled at 80° C./1.5 mm Hg (1.9×10−3 bar) to give VRBENONE (25 g, yield 16.6%) with [α]D2b=−217° (c=10 in ethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([CH:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.CS[C:20]1[NH:26][C:24](=[O:25])[CH:23]=[CH:22][N:21]=1>N1C=CC=CC=1>[O:25]=[C:24]1[CH:23]=[CH:22][NH:21][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([CH:8]([CH3:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])=[CH:16][CH:17]=2)=[N:26]1
Reactant: CSc1nccc(=O)[nH]1
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Product: CCOC(=O)CC(C)C(=O)c1ccc(Nc2nc(=O)cc[nH]2)cc1

Procedure:
A stirred mixture of ethyl 3-(4-aminobenzoyl)butyrate and 2-methylthiouracil in dry pyridine are heated together to afford the title compound.
Reaction SMILES: Cl.C([N:5]1[C:17]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][N:13]([C:19]4[CH:20]=[N:21][CH:22]=[CH:23][C:24]=4[CH3:25])[C:14]3=[O:18])=[CH:9][C:8]=2[CH:7]=[N:6]1)(=O)C.C(OCC)(=O)C>CO>[CH3:25][C:24]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N:13]1[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][C:17]3[NH:5][N:6]=[CH:7][C:8]=3[CH:9]=2)[C:14]1=[O:18]
Reactant: CC(=O)n1ncc2cc3c(cc21)C(=O)N(c1cnccc1C)CC3
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccncc1N1CCc2cc3cn[nH]c3cc2C1=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 11.5 %

Procedure:
6N HCl (5 mL) was added drop wise to a solution of 1-acetyl-7-(4-methylpyridin-3-yl)-6,7-dihydro-1H-pyrazolo[4,3-g]isoquinolin-8(5H)-one (I-69h: 80 mg, 0.249 mmol) in methanol (5 ml) at 0° C. and the resulting reaction mass was stirred at room temperature for 36 hours. The reaction was monitored by TLC (100% ethyl acetate). The reaction mass was concentrated under reduced pressure, basified using saturated NaHCO3 solution and extracted using ethyl acetate. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification by column chromatography on silica gel (100% ethyl acetate), followed by preparative HPLC afforded 8 mg of the product (11.5% yield).
Reaction SMILES: [Cl:1][CH:2]1[CH:7]2[CH2:8][CH:4]([CH2:5][CH2:6]2)[CH:3]1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[NH2:15][C:16]1[N:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=1>ClCCl>[CH3:23][C:18]1[CH:19]=[C:20]([CH3:22])[N:21]=[C:16]([NH:15][C:13]([NH:12][S:9]([CH:3]2[CH:2]([Cl:1])[CH:7]3[CH2:8][CH:4]2[CH2:5][CH2:6]3)(=[O:10])=[O:11])=[O:14])[N:17]=1
Reactant: O=C=NS(=O)(=O)C1C2CCC(C2)C1Cl
Reactant: Cc1cc(C)nc(N)n1
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)C2C3CCC(C3)C2Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
14.1 g (0.06 mole) of 3-chlorobicyclo[2.2.1]hept-2-ylsulfonyl isocyanate in 100 ml of dichloromethane were initially introduced and 7.4 g (0.06 mole) of 2-amino-4,6-dimethylpyrimidine were added in portions at 0° C. The mixture was initially stirred at 0° C. for 2 hours and then at room temperature for 18 hours and then worked up in analogy to Example 5. 14.1 g (66% of theory) of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-3-chlorobicyclo[2.2.1]hept-2-ylsulfonamide were obtained (viscous oil).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:17][CH3:18])[C:9]3[C:14]([OH:15])=[CH:13][N:12]=[CH:11][C:10]=3[N:16]=2)=[N:4][O:5][N:6]=1.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29](O)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([O:15][C:14]2[C:9]3[N:8]([CH2:17][CH3:18])[C:7]([C:3]4[C:2]([NH2:1])=[N:6][O:5][N:4]=4)=[N:16][C:10]=3[CH:11]=[N:12][CH:13]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCn1c(-c2nonc2N)nc2cncc(O)c21
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCn1c(-c2nonc2N)nc2cncc(OC3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Yield: 18.9 %

Procedure:
A mixture of the product from Example 283 (0.1 g, 0.406 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.074 g, 0.369 mmol) and tributylphosphine (0.074 g, 0.369 mmol) in tetrahydrofuran (5 ml) was treated with 1,1′-(Azodicarbonyl)-dipiperidine (0.093 g, 0.369 mmol) and heated at reflux for 18 hours. The reaction was then cooled to RT and then applied to a SCX ion exchange column and eluted with methanol and then a mixture of methanol/0.880 ammonia (9:1). The basic fractions were then reduced and the solid residue chromatographed on silica gel eluting with ethyl acetate to afford the title compound, (0.03 g, 17%); MS (ES+) m/e 430 [M+H]+.
Reaction SMILES: C(C=O)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:24][C:25]([C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1)=[O:26].N(C(C)C)C(C)C.[CH:41]#[C:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>[Pd].CN(C)C=O>[C:41]([C:30]1[CH:31]=[CH:32][C:27]([C:25](=[O:26])[CH3:24])=[CH:28][CH:29]=1)#[C:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: C#CCCCCCCCC
Reactant: CC(=O)c1ccc(I)cc1
Agent: [Pd]
Agent: O=CC=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CCCCCCCCC#Cc1ccc(C(C)=O)cc1

Procedure:
Glyoxal synthesis step 1 is shown in FIG. 12. In a 100 mL Schlenk tube containing 46% Pd—C aerogel (110 mg, 0.47 mmol) were placed Cul (190 mg, 1 mmol), Ph3P (250 mg, 1 mmol), 4-iodoacetophenone (0.79 mmol), i-Pr2NH (0.17 mL, 1.2 mmol), deca-1-yne (8 mmol), and previously degassed dimethylformamide (DMF) (0.5 mL) under argon. This was magnetically stirred at 100° C. for a 16-h period. After cooling, the solution was removed and the catalyst was washed with DMF (3×3 mL) and recovered. The combined organic extracts were diluted in Et2O (100 mL), washed with brine (3×30 mL), dried (annh. MgSO4), and evaporated at reduced pressure. The residue (a yellow oil) was purified by preparative high pressure column chromatography (silica gel, n-hexane-EtOAc, 99.5:0.5) to give the product, 1-(4-(dec-1-ynyl)phenyl)ethanone as a yellow oil; yield: 96% 1H NMR (CDCl3): d=7.87 d,(2 H), 7.53 (d, 2 H), 2.55 (s, 3 H), 2.03 (2 H), 1.46 (2 H), 1.31 (m, 10 H), 0.86 (3 H) 13C NMR (CDCl3): d=CH3,14.0; CH2 22.6; CH2 31.5,; CH2 29.3; CH2 28.7; CH2 28.4; CH2 28.7; CH2 18.7; C (alkyne) 100.1; C (alkyne) 78.5; CH3 29.3; C (carbonyl) 199.8; C 136.4; CH 128.4; CH 132.2; C 127.1; CH 132.2; CH 128.4
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:13])([F:12])[F:11])[NH2:5].C(N(CC)CC)C.[CH3:21][C:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:25]([C:22]2([CH3:21])[CH2:24][CH2:23]2)=[O:26])[CH:6]=[CH:7][C:8]=1[O:9][C:10]([F:11])([F:12])[F:13]
Reactant: CC1(C(=O)Cl)CC1
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2ccc(OC(F)(F)F)c(Cl)c2)CC1
Yield: 89.2 %

Procedure:
To a solution of 3-chloro-4-trifluoromethoxyaniline (2.1 g) in methylene chloride (50 ml), triethylamine (1.1 g) was added, and a solution of 1-methylcyclopropanecarbonyl chloride (1.2 g) in methylene chloride was dropwise added thereto while stirring and ice-cooling. After stirring at room temperature for 1 hour, the reaction mixture was washed with 1 N hydrochloric acid, sodium hydrogen carbonate solution and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The crude crystals (2.9 g) were recrystallized from ethanol to give N-(3-chloro-4-trifluoromethoxyphenyl)-1-methylcyclopropanecarboxamide (2.6 g). M.P., 101°-102° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([NH:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18](O)=[O:19])(=O)[CH3:10].P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:10][C:9]1[N:1]([C:2]2[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=2)[C:18](=[O:19])[C:14]2[S:15][CH:16]=[CH:17][C:13]=2[N:12]=1
Reactant: CC(=O)Nc1ccsc1C(=O)O
Reactant: Nc1cccnc1Cl
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: Cc1nc2ccsc2c(=O)n1-c1cccnc1Cl
Temperature: 105 °C
Yield: 31.5 %

Procedure:
To a mixture of pyridine (4 mL), 3-amino-2-chloropyridine (0.514 g, 4 mmol), and 3-acetamidothiophene-2-carboxylic acid (0.370 g, 4 mmol) was added phosphorus trichloride (0.02 mL, 2.3 mmol). The reaction was heated to 105° C. for 3 hours, cooled to ambient temperature and partitioned between ethyl acetate and water. Phases were separated and the aqueous layer was extracted with ethyl acetate. The combined organic phase was washed with water and brine, dried over sodium sulfate and concentrated to a greenish brown oil. This residue was flash chromatographed on silica gel (20×120 mm) eluting with 20-40% ethyl acetate/hexane to afford 0.350 g (63%) of 2-methyl-3-(2-chloropyrid-3-yl)-3H-thieno[3,2-d]pyrimidin-4-one as a yellow foam.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]\[CH:12]([C:19]2[CH:20]=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C1COCC1>[F:18][C:15]([F:16])([F:17])[CH2:14][CH2:13][CH:12]([C:19]1[CH:20]=[N:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=2)=[CH:23][CH:24]=1)/[CH:11]=[CH:10]\[C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:35])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(/C=C\C(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(/C=C\C(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2)cc1

Procedure:
Cis-4-{6,6,6-Trifluoro-3-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-hex-1-enyl}-benzoic acid methyl ester (1.0 g, 2.0 mmol) is taken into THF (5.0 mL) and treated with NaOH (2.5 mL, 5.0 N), then refluxed under nitrogen. The reaction mixture is neutralized with HCl (2.5 mL, 5.0 N), extracted with ethyl ether, dried over sodium sulfate. Concentration gives the title compound.