Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH3:25][O:26][CH2:27][CH2:28]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH2:28][CH2:27][O:26][CH3:25])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Reactant: COCCO
Product: COCCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c1
Yield: 70 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and 2-methoxyethanol (7.6 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107. The title compound was obtained in 70% yield (16.9 mg). 1H NMR (500 MHz, CDCl3) δ ppm 2.47 (s, 3 H) 3.40 (s, 3 H) 3.67-3.70 (m, 2 H) 4.42-4.45 (m, 2 H) 6.92 (s, 1 H) 7.37 (dd, J=8.02, 7.74 Hz, 1 H) 7.45 (dd, J=8.73, 1.96 Hz, 1 H) 7.45 (ddd, J=8.02, 2.34, 1.17 Hz, 1 H) 7.72 (dd, J=8.73, 0.60 Hz, 1 H) 7.72 (dd, J=1.96, 0.60 Hz, 1 H) 7.74 (dd, J=2.34, 1.59 Hz, 1 H) 7.87 (ddd, J=7.74, 1.59, 1.17 Hz, 1 H). MS (ESI+) m/z 440 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[O:19][C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[NH:20][C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][C:30]3=[O:35])[CH2:25][CH2:24]2)=[O:22])=[O:10])=[N:6][CH:7]=1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:32]1[CH2:33][CH2:34][N:29]([C@H:26]2[CH2:27][CH2:28][C@H:23]([C:21]([NH:20][C:12]3[C:13]4=[N:14][CH:15]=[CH:16][CH:17]=[C:18]4[O:19][C:11]=3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:10])=[O:22])[CH2:24][CH2:25]2)[C:30](=[O:35])[CH2:31]1)(=[O:38])[CH3:37]
Reactant: O=C(Nc1ccc(Cl)cn1)c1oc2cccnc2c1NC(=O)[C@H]1CC[C@H](N2CCNCC2=O)CC1
Reactant: CC(=O)Cl
Product: CC(=O)N1CCN([C@H]2CC[C@H](C(=O)Nc3c(C(=O)Nc4ccc(Cl)cn4)oc4cccnc34)CC2)C(=O)C1

Procedure:
N-(5-Chloropyridin-2-yl)-3-({[trans-4-(2-oxopiperazin-1-yl)cyclohexyl]carbonyl}amino)furo[3,2-b]pyridine-2-carboxamide (50 mg) obtained in Example 125 and acetyl chloride (9 μl) are treated in a similar manner to Example 122 to give the title compound (41 mg).
Reaction SMILES: [OH:1]/[N:2]=[C:3](\Cl)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[F:10].[C:12]([CH2:15][C:16](=O)[CH3:17])(=[O:14])[CH3:13].[O-]CC.[Na+].Cl>C(O)C>[F:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[C:15]([C:12](=[O:14])[CH3:13])=[C:16]([CH3:17])[O:1][N:2]=1
Reactant: O/N=C(\Cl)c1ccccc1F
Reactant: CC(=O)CC(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)c1c(-c2ccccc2F)noc1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.3 %

Procedure:
A solution of (E)- and/or (Z)-N-hydroxy-2-fluoro-benzenecarboximidoyl chloride (6.5 g, 37 mmol) in ethanol (29 mL) was added dropwise to a solution of acetylacetone (4.6 g, 46 mmol) containing sodium ethoxide (14.8 g, 46 mmol) in ethanol (83 mL) at ice-bath cooling temperature. After complete addition, the resulting mixture was allowed to warm up to room temperature and stirred for 1.5 h. The mixture was then acidified with HCl (6 N) and concentrated and the mixture extracted with ethyl acetate and then washed with water and brine and dried over sodium sulphate. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 75:25) afforded the title compound (7.0 g, 85%) which was obtained as a light yellow liquid. MS: m/e=220.1 [M+H]+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH2:11][O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[O:8][N:7]=1)=O)C.O.[NH2:21][NH2:22]>C(O)C>[Si:13]([O:12][CH2:11][C:9]1[O:8][N:7]=[C:6]([C:4]([NH:21][NH2:22])=[O:3])[CH:10]=1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CCOC(=O)c1cc(CO[Si](C)(C)C(C)(C)C)on1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(C(=O)NN)no1
Temperature: 60 °C

Procedure:
A mixture of ethyl-5-({[tert-butyl(dimethylsilyl)]oxy}methyl)isoxazole-3-carboxylate (1.68 g, 5.9 mmol) and hydrazine hydrate (44 g, 8.8 mmol) in ethanol (30 mL) is heated to 60° C. for 4 hours. The mixture is cooled to room temperature and the solvents are removed in vacuo to yield 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)isoxazole-3-carbohydrazide as orange crystals.
Reaction SMILES: O1CCCC1.[C:6]1([CH3:22])[CH:11]=[CH:10][C:9]([NH:12][C:13](=[S:21])[CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[CH:17]=[CH2:18])=[CH:8][CH:7]=1.II.C1CCN2C(=NCCC2)CC1>O>[CH3:20][C:16]1([CH3:19])[C:17](=[CH2:18])[S:21][C:13](=[N:12][C:9]2[CH:8]=[CH:7][C:6]([CH3:22])=[CH:11][CH:10]=2)[CH2:14][CH2:15]1
Reactant: C=CC(C)(C)CCC(=S)Nc1ccc(C)cc1
Agent: II
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: C=C1SC(=Nc2ccc(C)cc2)CCC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
In a tetrahydrofuran (25 ml) solution of 4,4-dimethyl-5-hexenethioic acid p-tolylamide (1.2 g), a tetrahydrofuran (10 ml) solution of iodine (1.5 g) was added dropwise at 0° C., followed by raising the temperature to room temperature and further stirring overnight. After cooling to 0° C., a tetrahydrofuran (3 ml) solution of DBU (1.8 g) was added dropwise. After raising the temperature to room temperature and further stirring overnight, water was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 0.53 g of the target compound.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:15])[NH:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:16]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:11]([C:8]1[NH:7][C:6](=[O:15])[C:5]([CH:2]([NH:1][C:21]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:22])[CH2:3][CH3:4])=[N:10][N:9]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CCC(N)c1nnc(C(C)(C)C)[nH]c1=O
Reactant: O=C(Cl)C1CCCC1
Product: CCC(NC(=O)C1CCCC1)c1nnc(C(C)(C)C)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 110 mg (0.50 mmol) 6-(1-aminopropyl)-3-tert-butyl-1,2,4-triazin-5(4H)-one, 70 mg (0.50 mmol) cyclopentanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]([F:24])([F:23])[F:22])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12]/[C:13](=[N:16]/[H])/[NH:14][OH:15])[C:7]([CH2:18][CH2:19][CH3:20])=[CH:6]2)#[N:2].[C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=O)#[N:26].C(N(CC)C(C)C)(C)C>C(#N)C>[C:25]([C:27]1[CH:28]=[C:29]([C:30]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:21]([F:24])([F:23])[F:22])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:18][CH2:19][CH3:20])[N:16]=2)[CH:33]=[CH:34][CH:35]=1)#[N:26]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(C(F)(F)F)c(C#N)ccc21)NO
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C#N)c2)n1
Temperature: 150 °C
Yield: 58.9 %

Procedure:
To a solution of (1Z)-2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 3-cyanobenzoyl chloride (0.204 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.079 g (59% yield) of pure product: MS (ES) m/z 435 (M+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH2:8][C:9]2([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=1.[C:27]([N:31]1[C:35]([NH2:36])=[CH:34][CH:33]=[N:32]1)([CH3:30])([CH3:29])[CH3:28].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[C:27]([N:31]1[C:35]([NH:36][C:2]2[N:7]=[C:6]([CH2:8][C:9]3([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[CH:5]=[CH:4][CH:3]=2)=[CH:34][CH:33]=[N:32]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)C1(Cc2cccc(Br)n2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)n1nccc1N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 1.33 g of 1-tert-butyl 4-ethyl 4-((6-bromopyridin-2-yl)methyl)piperidine-1,4-dicarboxylate, 650 mg of 1-tert-butyl-1H-pyrazol-5-amine (WO2007/126126, page 72, Reference 1), 360 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, 322 mg of tris(dibenzylideneacetone)dipalladium(0)-chloroform complex, 1.98 g of potassium phosphate and 30 ml of 1,4-dioxane was stirred at 100° C. for 4 hours, followed by cooling down to room temperature. An insoluble matter was filtered off using Celite and washed with ethyl acetate. The resulting ethyl acetate solution was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate=20/1−3/2) to give the title compound as a pale brown oil.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][N:10](C(OC)=O)[C@H:9]([CH2:17][C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=3)[CH2:8]2)[O:4][NH:3]1.Br>>[F:26][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([F:24])[C:21]=1[F:25])[CH2:17][C@@H:9]1[CH2:8][C@H:7]([C:5]2[O:4][NH:3][C:2](=[O:1])[CH:6]=2)[CH2:12][CH2:11][NH:10]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@H]1Cc1cc(F)c(F)c(F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@H](Cc3cc(F)c(F)c(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71 %

Procedure:
(2S,4R)-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluorobenzyl)piperidine-1-carboxylate (598 mg, 1.61 mmol) (from example 143, step 3) was dissolved in hydrogen bromide (33% in AcOH, 7 mL, 99.92 mmol) and stirred at room temperature for 20 h. The solvent was evaporated in vacuo and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2S,4R)-2-(3,4,5-trifluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (357 mg, 70.8%). 1H NMR (600 MHz, dmso) δ 1.05 (q, 1H), 1.32 (dq, 1H), 1.70-1.78 (m, 2H), 2.33-3.58 (m, 6H), 5.68 (s, 1H), 7.12-7.19 (m, 2H). HRMS Calculated for [C15H15F3N2O2+H]+: 313.1164. Found: 313.1158
Reaction SMILES: [CH2:1]([NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:21])=O>>[CH2:1]([N:9]=[C:10]([Cl:21])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCNC(=O)c1ccc(Cl)cc1
Product: CCCCCCCCN=C(Cl)c1ccc(Cl)cc1
Yield: 76.2 %

Procedure:
N-Octyl 4-chlorobenzamide (17.2 g, 64.2 mmole) and thionyl chloride (42.59 g, 358 mmole) were stirred and heated at reflux for one hour. The product was isolated by fractional distillation at reduced pressure (b.p. 70°-90° C. at 15 mm Hg) to yield 14.0 g (77%) of impure title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][NH2:24])([O-:16])=[O:15]>C(O)C>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][N:24]=[CH:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1)([O-:16])=[O:15]
Reactant: NNc1ccccc1[N+](=O)[O-]
Reactant: O=Cc1ncc(C(F)(F)F)cc1Cl
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1NN=Cc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3-chloro-5-(trifluoromethyl)pyridine-2-carboxaldehyde (1.05 g) and 2-nitrophenylhydrazine (0.76 g) in ethanol (75 ml) was heated at reflux for 2.5 hours and then allowed to cool to room temperature overnight. The resulting orange solid was isolated by filtration and recrystallised (petrol) to afford the title compound as admixture of isomers, m.p. 127-35° C.
Reaction SMILES: OS(O)(=O)=O.[CH2:6]([C:8]1([C:11]([C:13]#[N:14])=[O:12])[CH2:10][CH2:9]1)[CH3:7].[OH2:15]>C(O)(C)(C)C.C(Cl)Cl>[C:8]([NH:14][C:13](=[O:15])[C:11]([C:8]1([CH2:6][CH3:7])[CH2:10][CH2:9]1)=[O:12])([CH3:10])([CH3:9])[CH3:6]
Reactant: CCC1(C(=O)C#N)CC1
Reactant: O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CCC1(C(=O)C(=O)NC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of H2SO4 (98%) is added dropwise at 0°-5° C., in the course of 10 minutes, to a solution of 12.3 g of 1-ethylcyclopropanecarboxylic acid cyanide in 13 g of tert-butanol and 13 ml of methylene chloride. The solution is subsequently stirred for 4 hours at room temperature; 2 ml of H2O is then added and stirring is continued for a further 30 minutes. The pH value of the solution is brought to 6 with 80 ml of ZnNaOH, and the organic phase is separated. After removal of the solvent, the residue is crysrallised out from 50 ml of petroleum ether (b.p. 40° to 65° C.) at 50° C. to thus yield 13.1 g of white crystals of pure (1-ethylcyclopropyl)-glyoxylic acid tert-butylamide having a melting point of 37.5°-39° C.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:9][C:10]([CH2:12][O:13][C:14](=[O:33])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22](=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][N+:29]([O-:31])=[O:30])=[O:11])([CH3:8])[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:3][CH2:4][C:5]([NH:9][C:10]([CH2:12][O:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:22](=[O:32])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][N+:29]([O-:31])=[O:30])=[O:11])([CH2:6][OH:7])[CH3:8]
Reactant: CC1(NC(=O)COC(=O)c2ccccc2OC(=O)CCCCCO[N+](=O)[O-])COC(C)(C)OC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: CC(CO)(CO)NC(=O)COC(=O)c1ccccc1OC(=O)CCCCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a solution of 2-(6-nitrooxy-hexanoyloxy)-benzoic acid (2,2,5-trimethyl-[1,3]dioxan-5-yl carbamoyl)-methyl ester (5.5 grams) in a mixture of Methanol (55 ml) and water (2.5 ml), was added p-toluenesulfonic acid (0.2 grams) and stirred at room temperature for 2 hours. The reaction mixture poured onto cold water, extracted with Ethyl acetate, washed the organic layer with water, dried over Sodium sulphate and distilled under vacuum to get crude compound which was purified by column chromatography using Hexane:Ethyl acetate as eluant to get 1 grams of 2-(6-Nitrooxy-hexanoyloxy)-benzoic acid (2-hydroxy-1-hydroxy methyl-1-methyl-ethylcarbamoyl)-methyl ester as light yellow syrup. The product was characterized by 1H NMR (DMSO-d6) δ 1.16 (s, 3H, CH3), 1.45 (m, 2H, CH2), 1.70 (m, 4H, CH2X2), 2.64 (t, 2H, CH2), 3.50 (m, 4H, CH2X2), 4.55 (t, 2H, CH2), 4.70 (s, 2H, CH2), 4.80 (t, 2H, OH X2), 7.25 (d, 1H, Ar), 7.40 (m, 2H, Ar & NH), 7.70 (t, 1H, Ar), 8.00 (d, 1H, Ar).
Reaction SMILES: Cl.CO.[CH3:4][O:5][C:6](=[O:22])[C:7]([N+:19]([O-])=O)=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][CH:10]=1>CCOCC>[ClH:18].[CH3:4][O:5][C:6](=[O:22])[C:7]([NH2:19])=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][CH:10]=1
Reactant: COC(=O)C(=Cc1c[nH]c2cc(Cl)ccc12)[N+](=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C(N)=Cc1c[nH]c2cc(Cl)ccc12
Reaction time: 1.5 h
Yield: 180.1 %

Procedure:
A 3-l. three-necked flask, equipped with a thermometer and a mechanical stirrer was charged with 316 g (1.4 moles) of stannous chloride dihydrate and a solution of 111 g (3 moles) of dry hydrogen chloride gas in 1 l. of methyl alcohol. The colorless solution was stirred and cooled to -30° in a dry ice-acetone bath. 112.3 g (0.40 moles) of alphanitro-6-chloro-3-indoleacrylic acid methylester was added in 4 equal portions over 1 hour, maintaining the temperature between -25 and -20°. After the addition was complete, the temperature was allowed to rise to -10° and stirring at this temperature was continued for 90 minutes. Then 500 ml. of ether was added to the yellow suspension, followed by addition of 500 ml of 12N hydrochloric acid (concentrated), the temperature was kept below 5°. The mixture was then filtered through a Buchner funnel. The filter cake was washed with 1000 ml of methyl alcohol-9N aqueous hydrochloric acid 1:1, precooled to -20°, and 400 ml of ether. The tan product was dried at 40°/0.1 mmHg for 8 hours and then at 20°/0.1 mmHg to constant weight to yield 103.4 g (90%) of crude product, m.p. 191° (dec.).
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=O)[CH:6]=1.[CH2:16]([SH:19])[CH2:17][SH:18].B(F)(F)F.CCOCC>C1C=CC=CC=1>[CH2:16]1[S:19][C:5]2([NH:4][C:3]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14](=[O:15])[C:2]=3[N:1]=[CH:6]2)[S:18][CH2:17]1
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Reactant: SCCS
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: CCOCC
Product: O=C1C2=C(NC3(C=N2)SCCS3)c2ccccc21
Temperature: 25 °C
Yield: 63.6 %

Procedure:
A suspension of 9H-indeno[1,2-b]pyrazine-3,9(4H)-dione (0.50 g, 2.52 mmol) in benzene (10 ml), 1,2-ethanedithiol (0.63 ml, 7.56 mmol) and boron trifluoride etherate (0.31 ml, 2.52 mmol) was refluxed for 23 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered off and washed with benzene and water and dried. The crude material (0.64 g) was recrystallized twice from ethanol to give 0.44 g (64%) of the title compound. M.p. 284°-290° C. 1 -NMR (DMSO-d6, δ): 3.75-3.94 (m, 4H), 7.46-7.57 (m, 2H), 7.8 (m, 2H), 7.95 (s, 1H), 12.6 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:8]2[CH2:12][CH:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[O:10]C2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)N2CC(CCl)OC2)C=CC=CC=1.ClC1C=C([O-])C=CC=1Cl.[Na+].Cl>>[ClH:21].[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[Cl:21])[O:14][CH2:13][CH:11]([OH:10])[CH2:12][NH:8][CH:7]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1ccc(OCC2CN(C(c3ccccc3)c3ccccc3)CO2)cc1Cl
Agent: Cl
Agent: ClCC1CN(C(c2ccccc2)c2ccccc2)CO1
Agent: [Na+]
Product: OC(CNC(c1ccccc1)c1ccccc1)COc1ccc(Cl)c(Cl)c1

Procedure:
3-Diphenylmethyl-5-(3,4-dichloro-phenoxymethyl)-oxazolidine from 3-diphenylmethyl-5-chloromethyl-oxazolidine and sodium 3,4-dichlorophenolate; this product is hydrolysed with alcoholic-aqueous hydrochloric acid to give 1-(3,4-dichlorophenoxy)-2-hydroxy-3-diphenylmethylaminopropane hydrochloride with a melting point of 180°-184°.
Reaction SMILES: [N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7](Cl)=[O:8])([O-:3])=[O:2].[F:16][C:17]([F:29])([C:25]([F:28])([F:27])[F:26])[C:18]([F:24])([F:23])[C:19]([NH:21][NH2:22])=[O:20].N1C=CC=CC=1.Cl>C(OCC)C.O>[N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7]([NH:22][NH:21][C:19](=[O:20])[C:18]([F:23])([F:24])[C:17]([F:16])([F:29])[C:25]([F:27])([F:26])[F:28])=[O:8])([O-:3])=[O:2]
Reactant: NNC(=O)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(Cl)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])NNC(=O)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
To a solution of 1.0 g (0.0041 mole) of 4,4,4-trinitrobutyryl chloride in anhydrous diethyl ether (10 mL) stirred at 20° C. (water bath) was added 0.9 g (0.0039 mole) of N-(heptafluorobutyryl)hydrazine. The mixture became thick with precipitate and sufficient ether (10 mL) was added to allow efficient stirring. Pyridine (0.35 ml, 0.0044 mole) was added dropwise and the mixture was stirred for 5 minutes before 5% hydrochloric acid (10 mL) was added. The ether layer was dried (Na2SO4), the volatiles were removed, and the residue was stirred with water to give 1.5 g, mp 146°-150° C. Crystallization from 1,2-dichloroethane gave the product, N-(4,4,4-trinitrobutyryl)-N'-(perfluorobutyryl)hydrazine, 1.2 g (70%) mp 154°-156° C.; 1H NMR (acetone-d6 +D2O): 2.98 (t, 2H), 3.87 (t, 2H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15]>O.C(#N)C>[N:1]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])=[N+:2]=[N-:3]
Reactant: O=[N+]([O-])c1ccccc1CCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: [N-]=[N+]=NCCc1ccccc1[N+](=O)[O-]

Procedure:
Sodium azide (22.8, 0.351 mol) in water (60 mL) was added to a solution of 2-(2-bromoethyl)-nitrobenzene (27.9 g, 0.121 mol) in acetonitrile (120 mL). The reaction was refluxed for 4 h, cooled, and partitioned between methylene chloride and water. The organic phase was washed with saturated brine, and dried over magnesium sulfate. The title compound was obtained as an oil (22.8 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21]O)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-7, 5-bromopyridin-3-ol was reacted with (S)-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a colorless oil. MS: 357.0 and 359.0 (M+H+).
Reaction SMILES: [Na].[CH3:2][O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][N:23]=3)(=[O:21])=[O:20])[C:15]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:14]([O:40][CH3:41])[N:13]=2)[CH:9]=[CH:8][N:7]=1)=N.Cl.CC[O:45]C(C)=O.O>CO>[CH3:2][O:3][C:4]([C:6]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][N:23]=3)(=[O:20])=[O:21])[C:15]([O:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[O:38][CH3:39])=[C:14]([O:40][CH3:41])[N:13]=2)[CH:9]=[CH:8][N:7]=1)=[O:45]
Reactant: CCOC(C)=O
Reactant: COC(=N)c1cc(-c2nc(NS(=O)(=O)c3ccc(C(C)C)cn3)c(Oc3ccccc3OC)c(OC)n2)ccn1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(-c2nc(NS(=O)(=O)c3ccc(C(C)C)cn3)c(Oc3ccccc3OC)c(OC)n2)ccn1

Procedure:
To 0.586 g of 4-[4-(5-isopropyl-pyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboximidic acid methyl ester sodium salt, product of example 41 c), in methanol (10 ml) were added 6 N HCl (3 ml) and the mixture was refluxed for 1 h until the reaction was complete according to TLC analysis (eluent: CH2CL2/EtOAc: 4/1). The mixture was poured into water and the product extracted into EtOAc. The organic layer was washed with water, dried over Na2SO4 and the solvent removed in vacuo. The residue was purified on a silica gel chromatography column (eluted with Me2Cl2/EtOAc: 4/1). Combination of the purified fractions and evacuation in vacuo afforded 4-[4-(5-isopropyl-pyridine-2-sulfonylamino)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carboxylic acid methyl ester as an off-white solid. ISN mass spectrum, m/e 564.2 (M−1 calculated for C27H27N5O7S: 564).