Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.[CH2:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:21][CH3:22]>C(Cl)(Cl)Cl>[CH2:20]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=3[N:7]=2)[CH2:25][CH2:24]1)[CH2:21][CH3:22]
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Reactant: CCCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCCN1CCN(c2ncc3c(=O)c(C(=O)OCC)cn(CC)c3n2)CC1
Yield: 84.6 %

Procedure:
As described in Example XII, the condensation of 2.8 g of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine with 2.2 g of 1-propyl-piperazine, in chloroform (40 cm3) gives, after the treatments described in Example XII. 3.14 g of 2-(4'-propyl-piperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido-(2,3-d)pyrimidine (yield 84%); melting point 149°C, after recrystallisation from ethyl acetate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([O:16][CH2:17][CH3:18])[C:12]=1[O:13][CH2:14][CH3:15])[C:7]([OH:9])=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:25](OCC)(=O)[CH3:26].[OH-].[Na+]>O1CCCC1>[CH2:17]([O:16][C:11]1[CH:10]=[C:6]([C:7](=[O:9])[CH2:25][CH3:26])[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:12]=1[O:13][CH2:14][CH3:15])[CH3:18]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1OCC
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)CC)cc(OCC)c1OCC
Reaction time: 120 h

Procedure:
3,4,5-Triethoxybenzoic acid (2.54 g) was dissolved in tetrahydrofuran (250 ml), and lithium aluminum hydride (1.20 g) was added thereto, followed by heating under reflux for 24 hours. Ethyl acetate and then a 2N aqueous solution of sodium hydroxide were added to the reaction solution, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml), and manganese dioxide (5.10 g) was added thereto, followed by stirring for 120 hours. Insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 ml), and ethylmagnesium bromide (1M tetrahydrofuran solution, 15 ml) was added thereto, followed by stirring at room temperature for 30 minutes. 1N Hydrochloric acid was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in acetone (100 ml), and Jones' reagent (2 ml) was added thereto under ice-cooling, followed by stirring at the same temperature for 30 minutes. 2-Propanol (10 ml) was added to the reaction solution and the mixture was concentrated under reduced pressure. The residue was subjected to partitioning between ethyl acetate and water. The organic layer was washed with a saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3',4',5'-triethoxypropiophenone (0.76 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[C:6]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[N:5]=[C:4]([CH3:26])[N:3]=1>O1CCOCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:26])[N:5]=[C:6]2[C:7]=1[N:8]=[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[N:18]2[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1
Reactant: Cc1nc(Cl)c(NC(=O)c2ccccc2F)c(Nc2ccc(Cl)cc2)n1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1nc(Cl)c2nc(-c3ccccc3F)n(-c3ccc(Cl)cc3)c2n1

Procedure:
A solution of N-[4-chloro-6-(4-chlorophenylamino)-2-methylpyrimidin-5-yl]-2-fluorobenzamide I-(7A-80)b (0.25 g) in dioxane (6 ml) was treated with 50% propanephosphoric acid cyclic anhydride (PPM) in ethyl acetate (0.6 ml) and heated to reflux overnight. It was determined that the product was a mixture of desired product and the hydroxy compound (displacement of the chlorine atom). The reaction was therefore concentrated under reduced pressure and heated overnight in refluxing POCl3 (6 ml). The reaction mixture was concentrated to dryness, diluted with ethyl acetate, and poured onto ice. Saturated NaHCO3 solution was added next and the mixture stirred. The organic layer was separated, washed with brine, dried (Na2SO4), filtered, and concentrated to dryness. The crude product was purified via TLC preparative plate using 5% methanol/methylene chloride as the solvent to obtain the desired compound I-(7A-80)c (88 mg, 42% from 4,6-dichloro-2-isopropyl-pyrimidin-5-ylamine) as a solid: +ESI MS (M+1) 373.2; 1H NMR (400 MHz, CDCl3) δ 7.80–6.90 (m, 8H), 2.76 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:29])=[O:9])[CH:3]=1.C(NC(C)C)(C)C.[CH:37]1([CH2:40][NH:41][CH2:42][CH2:43][CH3:44])[CH2:39][CH2:38]1>C(O)C>[CH:37]1([CH2:40][N:41]([CH2:42][CH2:43][CH3:44])[C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([S:17]([NH:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])(=[O:19])=[O:18])=[CH:13][C:12]=3[CH3:29])=[O:9])[CH:3]=2)[CH2:39][CH2:38]1
Reactant: CCCNCC1CC1
Reactant: CCOC(=O)CCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Solvent: CC(C)NC(C)C
Solvent: CCO
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(S(=O)(=O)NCCCC(=O)OCC)cc2C)ncn1
Temperature: 160 °C

Procedure:
A solution of ethyl 4-(4-(6-chloropyrimidine-4-carboxamido)-3-methylphenylsulfonamido)butanoate (Intermediate 35, 123 mg; 0.31 mmol) and diisopropylamine (105.5 mL; 0.61 mmol) in ethanol (4 ml) was treated with N-(cyclopropylmethyl)propan-1-amine (45.3 mg; 0.4 mmol). The mixture was heated to 160° C. in a microwave for 1 hour and the solvent removed in vacuo. The residue purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give ethyl 4-(4-(6-((cyclopropylmethyl)(propyl)amino)pyrimidine-4-carboxamido)-3-methylphenylsulfonamido)butanoate which was used directly without any further purification. The residue was dissolved in methanol (10 ml) and THF (10 ml) and treated with 5 N NaOH solution (1 ml). After stirring at RT for 5 hours the solvent was removed in vacuo. The residue was redissolved in water (10 ml) and acidified with conc. HCl. The aqueous phase was extracted with EtOAc and the organic extracts passed through a hydrophobic frit and the solvent removed in vacuo. The residue was triturated with petroleum ether to yield the title compound as a white solid.
Reaction SMILES: [NH4+:1].[Cl-].C[Al](C)C.[C:7]1([C:17]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.CO>C1(C)C=CC=CC=1.ClCCl>[C:7]1([C:17]2([CH2:22][C:23]([NH2:1])=[NH:24])[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: N#CCC1(c2cccc3ccccc23)CCCC1
Agent: C[Al](C)C
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: N=C(N)CC1(c2cccc3ccccc23)CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of NH4Cl (2.659 g, 49.72 mmol) in dry toluene (80 mL) was added tri-methyl aluminum (2M in toluene, 25.0 mL, 49.72 mmol) slowly at 5° C. then warm to room temperature and stirred for 2 h. A solution of (1-naphthalen-1-yl-cyclopentyl)-acetonitrile (342) (3.9 g, 16.57 mmol) in toluene (5 mL) was added to the above reaction mixture and stirred for 18 h at 85° C. (reaction was monitored by LC-MS). The reaction mixture was cooled to 0° C. and quenched with a suspension of silica gel in chloroform and then stirred for 0.5 h at room temperature. After being filtered through a sintered funnel, the residue was washed well with methanol and the combined filtrate was concentrated under reduced pressure to get a crude mass. 10% methanol in dichloromethane was added to the residue, from which the insoluble material was again filtered off and the filtrate was concentrated in vacuum to get semi pure 2-(1-naphthalen-1-yl-cyclopentyl)-acetamidine; hydrochloride (343) (4.5 g) as a brown sticky mass. This raw product was used in the next step without purification.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[N:17]=[CH:18][N:19]2[C:24](=[O:25])[N:23]([CH2:26][S:27][CH3:28])[N:22]=[N:21][C:20]=12>CN(C=O)C>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]1[N:17]=[CH:18][N:19]2[C:24](=[O:25])[N:23]([CH2:26][S:27]([CH3:28])=[O:1])[N:22]=[N:21][C:20]=12
Reactant: CSCn1nnc2c(-c3nc4ccccc4o3)ncn2c1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)Cn1nnc2c(-c3nc4ccccc4o3)ncn2c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
An aqueous solution (250 μL) of Oxone™ (54 mg, 0.195 mmol) was added to a stirred solution of 8-(benzo[d]oxazol-2-yl)-3-(methylthiomethyl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (25 mg, 0.0795 mmol) in DMF (1 mL) and the resulting suspension was stirred overnight. The mixture was poured into ice (10 g) and the precipitate was filtered and washed successively with water, ethyl acetate and diethyl ether to give 19 mg of the title compound as a bright yellow solid (73% yield). δH (DMSO d6): 9.12 (1H, s), 7.89-7.94 (2H, m), 7.47-7.55 (2H, m), 5.66 (1H, d, J=13.2), 5.53 (1H, d, J=13.2), 2.80 (3H, s). LCMS: 97% pure at 4.63 min., m/z (ES+): 331.1 (MH+).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[O:6][C:7]1[C:24](=[O:25])[N:23]([CH3:26])[C:10]2[N:11]=[C:12]([NH:15][CH:16]3[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]3)[N:13]=[CH:14][C:9]=2[CH:8]=1.[CH3:31]I>O1CCCC1.[Ag]=O.[N+]([O-])([O-])=O.[Ag+]>[F:3][C:4]1[CH:30]=[CH:29][CH:28]=[CH:27][C:5]=1[O:6][C:7]1[C:24](=[O:25])[N:23]([CH3:26])[C:10]2[N:11]=[C:12]([NH:15][CH:16]3[CH2:21][CH2:20][CH:19]([O:22][CH3:31])[CH2:18][CH2:17]3)[N:13]=[CH:14][C:9]=2[CH:8]=1
Reactant: CI
Reactant: Cn1c(=O)c(Oc2ccccc2F)cc2cnc(NC3CCC(O)CC3)nc21
Agent: O=[Ag]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Product: COC1CCC(Nc2ncc3cc(Oc4ccccc4F)c(=O)n(C)c3n2)CC1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
To a slurry of freshly prepared silver oxide (filtered/dried from an aqueous mixture of silver nitrate, 0.44 g, 2.70 mmol) and sodium hydroxide (0.21 g, 5.20 mmol)) in 2 mL tetrahydrofuran was added pyrimidin-7(8H)-one (Step A, 0.20 g, 0.52 mmol) and methyl iodide (0.065 mL, 1.04 mmol). After stirring at 50° C. for three days, additional silver oxide and methyl iodide (0.98 mL, 15.7 mmol) were added; the temperature was increased to reflux and the reaction continued for 2 weeks. Following this time period, the mixture was cooled to room temperature, evaporated and purified by column chromatography (SiO2, CH2Cl2/MeOH/NH4OH—90/9/1). Fractions containing product were combined and evaporated under reduced pressure to provide the free amine. This was dissolved in methanol (1-2 mL) and hydrochloric acid in ether (1M, 1.0 eq) was added. Isolation of the solid via filtration, rinsing with ether and drying provided 0.030 g of the hydrochloride salt (Mass spec. M+1=399, MP=135.0-145.0° C.).
Reaction SMILES: P(Br)(Br)[Br:2].[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH2:11][CH2:12]O)([O-:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].O>C(OCC)C>[Br:2][CH2:12][CH2:11][C:10]1[CH:9]=[C:8]([N+:5]([O-:7])=[O:6])[CH:16]=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccc(CCO)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: O=[N+]([O-])c1cccc(CCBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Phosphorus tribromide (0.94 ml) was added dropwise to a solution of 3-nitrophenethyl alcohol (5 g) in anhydrous diethyl ether (30 ml) at 0°. The mixture was stirred at room temperature for 2 hours and then treated with a solution of potassium carbonate and then water. The organic layer was dried and concentrated in vacuo to give the title compound as an oil (4.51 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)Nc1cccc(Br)c1
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: NC(=O)Nc1cccc(-c2cccs2)c1
Temperature: 90 °C
Yield: 85.3 %

Procedure:
3-Bromopheylurea (10.40 g), 2-thiopheneboronic acid (8.20 g) and palladium tetrakistriphenylphosphine (2.63 g) were added to a flask containing 300 mL of dimethoxyethane and 100 mL of 2.0 M aqueous potassium carbonate under an atmosphere of dry N2. The reaction mixture was heated at 90° C. overnight. The reaction mixture was then cooled to room temperature and partitioned between EtOAc and water. The EtOAc layer was dried over MgSO4, filtered and concentrated under vacuum. The resulting residue was tritutrated with ethyl ether to give 9.00 g of 1-(3-(thiophen-2-yl)phenyl)urea.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:29])OC4C=CC=CC=4)=[CH:16][C:15]=3[F:30])[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:3][CH2:2]1.[NH2:31][C:32]1[CH:33]=[C:34]([CH:42]([N:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:45]2)[CH3:43])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1.CCN(C(C)C)C(C)C>C1COCC1>[CH:1]1([C:4]([NH:6][C:7]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:31][C:32]4[CH:33]=[C:34]([CH:42]([N:44]5[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:54])([CH3:56])[CH3:55])=[O:51])[CH2:46][CH2:45]5)[CH3:43])[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=4)=[O:29])=[CH:16][C:15]=3[F:30])[CH:10]=[CH:9][N:8]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: CC(c1cc(N)cc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)c(F)c1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(c1cc(NC(=O)Nc2ccc(Oc3ccnc(NC(=O)C4CC4)c3)c(F)c2)cc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 75.8 %

Procedure:
Add phenyl N-[4-[[2-(cyclopropanecarbonylamino)-4-pyridyl]oxy]-3-fluoro-phenyl]carbamate (220 mg, 0.53 mmol), tert-butyl 4-[1-[3-amino-5-(trifluoromethyl)phenyl]-ethyl]piperazine-1carboxylate (165 mg, 0.442 mmol) and DIEA (120 mg, 0.88 mmol) in THF (10 mL), stir the reaction under N2 at 80° C. for 12 hrs. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:1) affords the title compound (230 mg, 75.6%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.Br.O>C(O)(=O)C>[OH:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cccc2c(N3CCCC3)cccc12
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Oc1cccc2c(N3CCCC3)cccc12

Procedure:
5-Methoxy-1-pyrrolidinyl-naphthalene (90 g) is dissolved in glacial acetic acid (1 liter). 48% hydrobromic acid is added to the solution and the resulting reaction mixture heated to reflux for 3 hours. The reaction mixture is poured into water and crushed ice and the solution made alkaline to pH 8 to 9. The aqueous mixture is extracted with methylene chloride. The methylene chloride extract is back-extracted with 2% KOH solution and the combined basic layers made acidic by the addition of aqueous HCl. The addition is continued until a white precipitate appears. The aqueous solution is extracted with methylene chloride and the organic layer washed with H2O, dried, filtered and evaporated in vacuo, yielding the desired product.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([NH2:14])[C:3]=1[C:4]([OH:6])=[O:5].[C:15](=O)([O-])O.[Na+].C(=O)=O.S(OC)(OC)(=O)=O.[Na]>O.CC(C)=O>[CH3:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([NH2:14])[C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1C(=O)O
Reactant: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1c(N)ccc([N+](=O)[O-])c1C

Procedure:
49.7 g (0.253 mol) of 2-methyl-3-nitro-6-aminobenzoic acid are dissolved in380 ml of acetone and 43 g (0.51 mol) of sodium hydrogen carbonate are added. The mixture is then heated to boiling until evolution of CO2 is complete. 35.3 g (0.28 mol) of dimethyl sulfate are then added in the course of two hours at the boiling point of acetone to the suspension of the sodium salt of 2-methyl-3-nitro-6-aminobenzoic acid thus obtained, andthe mixture is subsequently refluxed for a further 3 hours and then allowedto cool. After pouring the reaction mixture into 1.8 l of water, it is extracted with methylene chloride. After drying, the organic phase is concentrated. The solid obtained is sufficiently pure for the subsequent reaction (NMR). Yield: 50 g (0.238 mol)=94% of theory, m.p.: 92°-94° C.
Reaction SMILES: [S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.Cl>C1COCC1.C(Cl)Cl>[S:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[B:15]([OH:20])[OH:16]
Reactant: c1cc2ccsc2cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: OB(O)c1cc2ccncc2s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cold (−78° C.) solution of thieno[2,3-c]pyridine (2.040 g, 15.09 mmol) in anhydrous THF (50 mL) was added n-butyllithium (6.64 mL, 16.60 mmol) dropwise. The reaction mixture was stirred for 60 minutes at −78° C. A solution of triisopropyl borate (4.16 mL, 18.11 mmol) was added and the reaction mixture was stirred for 30 minutes at −78° C. The solution was allowed to warm to room temperature over a 2 hour period. TLC showed the reaction was complete. Aqueous HCl (1N, 1000 mL) and DCM (500 mL) were added to the reaction mixture. The aqueous and organic layers were separated. The aqueous layer was concentrated to a volume of 500 mL and a solid precipitate was filtered and dried to give the title compound as off-white, needle-shaped crystals (2.4 g, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.24 (s, 1H), 8.41 (d, J=4.80 Hz, 1H), 8.66 (d, J=6.32 Hz, 1H), 9.10 (br s, 2H), 9.72 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH2:15])[CH:6]=[C:7]([O:12][CH3:13])[C:8]=1[CH2:9][CH2:10][CH3:11].Br[C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[F:24]>>[F:23][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([F:24])[C:17]=1[CH:15]=[CH:14][C:5]1[CH:6]=[C:7]([O:12][CH3:13])[C:8]([CH2:9][CH2:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: Fc1cccc(F)c1Br
Reactant: C=Cc1cc(OC)c(CCC)c(OC)c1
Product: CCCc1c(OC)cc(C=Cc2c(F)cccc2F)cc1OC

Procedure:
This compound was synthesized from (3,5-dimethoxy-4-1-propylphenyl)-ethene and 1-bromo-2,6-difluorobenzene quantitatively in the same procedure as described in preparation of 31B. 1HNMR (CDCl3, ppm): δ 1.32 (d, J=7.1 Hz, 6H), 3.62 (qint, J=7.1 Hz, 1H), 3.90 (s, 6H), 6.73 (s, 2H), 6.8-7.2 (m, 4H), 7.41 (d, J=16.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([N+:10]([O-])=O)[CH:3]=1.C(O)C.Cl>[Fe].O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([NH2:10])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cc(Cl)ccc1C=O
Temperature: 85 °C
Yield: 82.8 %

Procedure:
To a 3-neck flask fitted with a reflux condenser and a mechanical stirrer, were added 4-chloro-2-nitrobenzaldehyde (25 g, 135 mmol, 1 equiv), ethanol (375 mL), and water (100 mL). 4-Chloro-2-nitrobenzaldehyde can be obtained from P.H.T. International, Inc., Charlotte, N.C. Iron dust (225 mesh, Aldrich, Milwaukee, Wis.) (22.6 g, 405 mmol, 3 equiv) and concentrated hydrochloric acid (5.7 mL, 67.5 mmol, 0.5 equiv) was added. The slurry was heated to 85° C. for two hours, cooled to room temperature, filtered through diatomaceous earth and rinsed with ethanol (100 mL) and toluene (100 mL). The solution was transferred to a separatory funnel and toluene (300 mL) were added. The organic layer was washed with saturated sodium bicarbonate solution (300 mL) and brine (300 mL), then dried over sodium sulfate and then concentrated to provide 4-chloro-2-aminobenzaldehyde (17.4 g, 83%) as a yellow solid.
Reaction SMILES: [F:1][CH:2]([N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[I-].[CH3:15][S+](C)(C)=O.O1CCCC1>CS(C)=O>[C:4]([C:3]1([CH:2]([N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)[F:1])[CH2:15][O:8]1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)C(=O)C(F)n1cncn1
Reactant: C[S+](C)(C)=O
Agent: [I-]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)C1(C(F)n2cncn2)CO1
Temperature: 60 °C
Reaction time: 6 h
Yield: 32.1 %

Procedure:
A mixture of 20 g of 1-fluoro-1-(1H-1,2,4-triazol-1-yl)-3,3-dimethyl-2-butanone, 13.5 g of potassium tertiary butylate, 24.0 g of trimethylsulfoxonium iodide, 80 ml of tetrahydrofuran and 20 ml of dimethyl sulfoxide is stirred at 60° C. for 6 hours. The reaction mixture is then taken up in ice water and extracted with ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulfate and evaporated. Crystallisation from petroleum ether gives 6.9 g of 2-tert.-butyl-2-[(1H-1,2,4-triazol-1-yl)-fluoromethyl]-oxirane, melting point 72°-74° C.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3S[C:8]=2[C:17]#[N:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.[Mn]([O-])(=O)(=O)=O.[K+].[S:29]([O-:33])(O)(=O)=[O:30].[Na+]>O>[C:1]1([C:7]2[NH:12][C:11]3[CH:10]=[CH:16][CH:15]=[CH:14][C:13]=3[S:29](=[O:33])(=[O:30])[C:8]=2[C:17]#[N:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)([O-])O
Reactant: N#CC1=C(c2ccccc2)Nc2ccccc2S1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: N#CC1=C(c2ccccc2)Nc2ccccc2S1(=O)=O
Reaction time: 2 h

Procedure:
A mixture of 3-phenyl-4H-1,4-benzothiazine-2-carbonitrile (0.10 g, prepared according to Liso et al., J. Heterocycl. Chem. 18, 279 (1981), Liso et al., Synthesis 1983, 755) and acetic acid (6 ml) was added to a stirred solution of potassium permanganate (88 mg) in water (10 ml) at ambient temperature. After 2 h, 3 h and 18 h additional amounts (25 mg, 40 mg and 40 mg) of potassium permanganate were added. Then a 40% solution of sodium hydrogensulfate (200 μl) was added. After stirring for ½ h the mixture was filtered through celite. The filtrate was extracted with ethyl acetate (2×25 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give a solid. Trituration with ethyl acetate (2 ml), filtration and drying gave the title compound as light yellow crystals. Yield 34 mg (38%); mp 286-289° C.; 1H-nmr(DMSO) δ (ppm): 12.21 (br, 1H), 8.07-7.97 (m, 1H), 7.84-7.5 (m, 8H); IR(KBr) ν (cm−1): 3298 (NH), 2198 (C≡N), 1598, 1554, 1514, 1476, 1433, 1301, 1171, 1154, 1136; MS m/e (rel. intensity): 282 (25 %, M+), 250 (4%), 218 (100%), 190 (15%), 115 (10%), 77 (10%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)=[O:24])[NH:20][C:19]=1[CH:32]=O>>[CH3:17][C:18]1[CH:22]=[C:21]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)=[O:24])[NH:20][C:19]=1[CH:32]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Product: Cc1cc(C(=O)N2CCN(C)CC2)[nH]c1C=C1C(=O)Nc2cccc(-c3ccncc3)c21

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3-methyl-5-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde to give the title compound.