Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C@@:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3](O)=[O:4].[CH3:10][S:11][C:12]#[N:13].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH:6]([C@:2]1([CH3:9])[S:1][C:12]([S:11][CH3:10])=[N:13][C:3]1=[O:4])([CH3:8])[CH3:7]
Reactant: CC(C)[C@](C)(S)C(=O)O
Reactant: CSC#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSC1=NC(=O)[C@](C)(C(C)C)S1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
(S)-2-Mercapto-2,3-dimethylbutanoic acid (1.5 g, 0.01 mol) was dissolved in toluene (15 mL) under an atmosphere of nitrogen. Activated 3A sieves (1.5 g) and MeSCN (1.1 mL, 0.015 mol) were added and the resultant mixture was warmed to 110° C. The mixture was stirred for 2 h and cooled to 23° C. The mixture was treated with saturated aqueous NaHCO3 (20 mL), the phases were separated and the aqueous phase was extracted with EtOAc (3×15 mL). The combined organic phases were washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Chromatographic purification (10 g silica gel, 20-30% EtOAc/Hexanes) of the residual material yielded (S)-5-isopropyl-5-methyl-2-(methylthio)thiazol-4(5H)-one. This material was dissolved in MeOH (15 mL) and (S)-exo-aminonorbornane (1.35 g, 0.015 mol, 99.3% ee) was added under an atmosphere of nitrogen. The solution was stirred for 4 h and concentrated. Chromatographic purification (10 g silica gel, 10-40% EtOAc/Hexanes) of the residual material yielded 1.73 g (64%) of the title compound. 1H NMR (400 MHz, CDCl3, 90.15/9.85 mixture of diastereomers, signals for the major diastereomer) δ 3.33-3.40 (m, 1H), 2.36-2.45 (m, 2H), 2.21 (septaplet, 1H, J=8 Hz), 1.84-1.91 (m, 1H), 1.60-1.83 (m, 1H), 1.42-1.68 (m, 3H), 1.62 (s, 3H), 1.13-1.30 (m, 4H), 1.05 (d, 3H, J=8 Hz), 0.90 (d, 3H, J=8 Hz); 13C NMR (100 MHz, CDCl3, 90.15/9.85 mixture of diastereomers, signals for the major diastereomer) δ 191.1, 180.9, 70.9, 59.5, 43.0, 38.5, 35.9, 35.7, 35.6, 28.2, 26.6, 25.6, 19.0, 18.4; IR (neat): 3168, 2959, 2869, 1696, 1585, 1440, 1327, 1256, 1090, 1017, 829 cm−1; Exact Mass (C14H22N2OS+H): calculated=267.1526, measured=267.1525. Chiral LC: 90.15/9.85 dr.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[H-].[Na+].[CH2:9](Br)[C:10]#[CH:11].O>CN(C)C=O>[CH2:11]([S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])[C:10]#[CH:9]
Reactant: O=C(O)CCS
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCSCCC(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 3-mercaptopropionic acid (15 ml) in dry dimethylformamide (250 ml) was stirred at 0° , under nitrogen. Sodium hydride (10.2 g; 80% dispersion in oil) was added carefully and the mixture was stirred at 40° for 1 hour. The mixture was cooled to 0° C. and propargyl bromide (60 g; 80% in toluene) was added dropwise. The mixture was stirred at 20° for 3 hours and then at 80° for 1 hour. The mixture was cooled and poured into water. The aqueous mixture was extracted with diethyl ether, and the extracts washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. The resulting oil (30 g) (mainly prop-2-ynyl 3-(prop-2-ynylthio)propionate) was added to a solution of sodium hydroxide (8.0 g) in water (100 ml) and methanol (100 ml) and the mixture was stirred at 20° for 24 hours. The mixture was extracted with diethyl ether and the aqueous solution was acidified with hydrochloric acid. The acidic mixture was extracted with diethyl ether and the ethereal extracts were dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. 3-(Prop-2-ynylthio) propionic acid was obtained as a red oil (12.0 g) and was used without further purification.
Reaction SMILES: ClC(Cl)C.[Br:5][C:6]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([O:14][CH3:15])=[CH:8][C:7]=1[F:16].[CH:17]1([CH2:23][C:24](Cl)=[O:25])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.Cl>[Cl-].[Cl-].[Zn+2]>[Br:5][C:6]1[C:7]([F:16])=[C:8]([C:24](=[O:25])[CH2:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]([O:14][CH3:15])=[CH:10][C:11]=1[O:12][CH3:13]
Reactant: O=C(Cl)CC1CCCCC1
Reactant: COc1cc(F)c(Br)c(OC)c1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(Cl)Cl
Product: COc1cc(OC)c(C(=O)CC2CCCCC2)c(F)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.2 %

Procedure:
Under nitrogen atmosphere, 6 ml of dichloroethane solution with 2.3 g of 2-bromo-3,5-dimethoxy-1-fluorobenzene and 6 ml of dichloroethane solution with 2.3 g of cyclohexylacetylchloride were dropped sequentially to 15 ml of dichloroethane solution with 1.8 g of alminium trichloride, 180 mg of zinc dichloride at −10° C., and then the mixture was stirred at room temperature for 2 hours. 20% of hydrochloric acid solution was added to the reaction solution, extracted with chloroform. Chloroform layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After distilling out the solvents under reduced pressure, residues were separated and purified with silicagel chromatography (hexane/ethyl acetate=5/1) to obtain 780 mg of the above compound as a white solid.
Reaction SMILES: [OH-].[Na+].C([NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][C:13]([CH3:23])([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C:11]=2[C:24]=1[CH3:25])(=O)C>CO.O>[NH2:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][C:13]([CH3:23])([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C:11]=2[C:24]=1[CH3:25]
Reactant: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(CCc1ccccc1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CCc1ccccc1)O2
Temperature: 200 °C
Yield: 51.6 %

Procedure:
Aqueous 6N sodium hydroxide solution (3 ml) was added to a solution of 5-acetylamino-2,4,6,7-tetramethyl-2-(2-phenylethyl)-2,3-dihydrobenzofuran (0.7 g, 2.1 mmol) in methanol (3 ml) and the mixture was heated at 200° C. in an autoclave for 18 hours. The reaction mixture was diluted with water and the product was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (isopropyl ether-ethyl acetate, 2:1). The crude crystals were recrystallized from hexane to obtain the desired compound (0.32 g, yield: 54.5%), m.p. 45°- 46° C. (dec.).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[N:10]=[C:11]([CH2:14][OH:15])[O:12][CH:13]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:26][S:23]([O:15][CH2:14][C:11]1[O:12][CH:13]=[C:9]([C:4]2([CH3:3])[O:8][CH2:7][CH2:6][O:5]2)[N:10]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2coc(CO)n2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2coc(COS(C)(=O)=O)n2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of (4-(2-methyl-[1,3]dioxolan-2-yl)-oxazol-2-yl)-methanol (230 mg, 1.24 mmol) in dry CH2Cl2 (10 mL) was treated at 0° C. with Et3N (0.23 mL, 1.64 mmol) followed by DMAP (15 mg, 0.12 mmol) and Ms-Cl (0.13 mL, 1.61 mmol). After stirring at 0° C. for 1 h, the reaction was quenched with water (10 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude (4-(2-methyl-[1,3]dioxolan-2-yl)oxazol-2-yl)methyl methanesulfonate as a colorless oil. The crude material was dissolved in dry DMF (6 mL) and treated with NaN3 (93 mg, 1.41 mmol) at 80° C. until completion of the reaction. The reaction mixture was then cooled down to rt and partitioned between EA and water. The layers were separated and the org. layer dried over MgSO4, filtered and concentrated under reduced pressure to give crude 2-(azidomethyl)-4-(2-methyl-[1,3]dioxolan-2-yl)oxazole as a colorless oil. To a solution of the crude azide in THF (9 mL) were added polymer-supported Ph3P (1.4 eq.) and water (3 mL). The reaction mixture was stirred at 55° C. until completion of the reaction, cooled down to rt and filtered. The filtrate was partitioned between EA and aq. sat. NaHCO3 and the layers separated. The aq. layer was concentrated under reduced pressure, the residue triturated in EtOH and the solid filtered off. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 01: tR=0.22 min; [M+H]+=185.00.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:13][CH3:14])[CH:8]=[C:9]([F:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F-:15].[Cs+]>CS(C)=O.CCOC(C)=O>[F:15][C:2]1[C:11]2[C:6](=[C:7]([O:13][CH3:14])[CH:8]=[C:9]([F:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [F-]
Reactant: COc1cc(F)cc2c(Cl)nccc12
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc(F)cc2c(F)nccc12
Temperature: 140 °C
Yield: 105.3 %

Procedure:
To a solution of 1-chloro-7-fluoro-5-methoxyisoquinoline (350 mg, 1.654 mmol) in DMSO (3 mL), was added CsF (502 mg, 3.31 mmol) and the mixture was heated to 140° C. for 4 h. The reaction was diluted with EtOAc and washed with water, and brine. The organic phase was collected, dried over sodium sulfate, and concentrated under vacuum to give 1,7-difluoro-5-methoxyisoquinoline (340 mg, 105% yield) which was not purified further. MS m/z 196.1 (M++1).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7]/[CH:8]=[CH:9]/[C:10]1[C:15]([F:16])=[CH:14][C:13]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:12][C:11]=1[F:28])=[O:5])=[N-]>ClCCCl.C1(C)C=CC=CC=1>[F:28][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:19])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:14]=[C:15]([F:16])[C:10]=1[C@H:9]1[C@H:3]2[C@@H:8]1[CH2:7][O:6][C:4]2=[O:5]
Reactant: [N-]=[N+]=CC(=O)OC/C=C/c1c(F)cc(NC(=O)OCc2ccccc2)cc1F
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(F)c([C@@H]2[C@H]3COC(=O)[C@H]32)c(F)c1)OCc1ccccc1

Procedure:
A solution of (2E)-3-{2,6-difluoro-4-[(benzyloxycarbonyl)amino]phenyl}prop-2-enyl diazoacetate (9.7 g, 25.04 mmol) in 100 mL of 1,2-dichloroethane was added dropwise over 14 h to a refluxing solution of bis-(N-t-butylsalicylaldiminato)copper(II) (0.52 g, 1.25 mmol, prepared as described by R. G. Charles, J. Org. Chem. 1957, 22, 677) in toluene (1000 mL). After the addition was complete, the reaction mixture was heated for another hour at reflux, then cooled, filtered and concentrated. The crude oil was purified by column chromatography (0-1% methanol-dichoromethane) to provide the title compound as a racemate.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][S:5][CH2:4]1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>C(Cl)Cl>[C:17]([O:1][CH2:2][CH:3]1[C:8](=[O:9])[CH2:7][CH2:6][S:5][CH2:4]1)(=[O:19])[CH3:18]
Reactant: O=C1CCSCC1CO
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC1CSCCC1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
To an ice-cooled solution of 1.26 g (0.0086 mol) of product from Step C and 1.44 g (0.0142 mol) of triethylamine in 25 ml of methylene chloride was added dropwise 0.75 g (0.0095 mol) of acetyl chloride. The solution was stirred for four hours at 0° C., after which time it was washed with water, a saturated solution of sodium bicarbonate, and water. The organic phase was dried (MgSO4), filtered, and evaporated to give 1.52 g (94%) of product.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][N:6]2[CH:14]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C1COCC1>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1[CH2:24][CH2:25][N:26]([CH2:2][C:3]2[N:4]=[C:5]3[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[CH:7][N:6]3[CH:14]=2)[CH2:27][CH2:28]1
Reactant: Clc1ccc(N2CCNCC2)c(Cl)c1
Reactant: CCOc1ccc2nc(CCl)cn2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOc1ccc2nc(CN3CCN(c4ccc(Cl)cc4Cl)CC3)cn2c1
Temperature: 75 °C
Yield: 23.8 %

Procedure:
A mixture of 2-(chloromethyl)-6-ethoxyimidazo[1,2-α]pyridine (0.204 g), 1-(2,4-dichlorophenyl) piperazine (Example 31, Step 1; 0.2283 g), triethylamine (Aldrich; 0.15 mL), and THF (1.3 mL) is stirred at 75° C. until the reaction is judged complete by thin layer chromatography. The cooled mixture is concentrated under reduced pressure and partitioned between dichloromethane and saturated aq. sodium bicarbonate. The combined organic layers are dried with MgSO4 and concentrated under reduced pressure. The residue is chromatographed on silica gel using methanol/dichloromethane (2/98) and crystallized from ethyl acetate/ether to give 0.0936 g of the title compound; mp 171-172° C.; MS m/z 404, 406; IR (mineral oil) 1478, 1189, 797, 1508, 1273 cm-1 ; 1H NMR (CDCl3) δ1.45, 2.77, 3.08, 3.77, 3.98, 6.94, 7.17, 7.34, 7.45, 7.47, 7.60.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][C:32](=[O:36])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].CC(C)([O-])C.[K+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH:17]([N:33]2[CH2:34][CH2:35][N:30]([C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[CH2:31][C:32]2=[O:36])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CC(C1CCN(C(=O)OCc2ccccc2)CC1)N1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.9 %

Procedure:
To a solution of methyl 3-(1-benzyloxycarbonylpiperidin-4-yl)acrylate (5.55 g) and 4-(tert-butoxycarbonyl)-2-piperazinone (3.66 g) in tetrahydrofuran (50 ml) was added potassium tert-butoxide (0.56 g), and the mixture was stirred under nitrogen atmosphere at room temperature for 3 days. The reaction solution was diluted with ethyl acetate (50 ml), washed with 0.5N hydrochloric acid and saturated brine, dried and concentrated, and the residue was purified with silica gel column chromatography (eluent:acetone/hexane=1/2) to give colorless amorphous of methyl 3-(1-benzyloxycarbonylpiperidin-4-yl)-3-[4-(tert-butoxycarbonyl)-2-oxopiperazine-1-yl]propionate (5.51 g).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].C([Li])CCC.C1(O[C:27]#[N:28])C=CC=CC=1>O1CCCC1.CCCCCC.C(OCC)(=O)C.[OH-].[Na+]>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]([CH3:6])([CH3:5])[C:3]#[C:2][C:27]#[N:28])=[CH:8][CH:9]=1
Reactant: N#COc1ccccc1
Reactant: CC(C)(C=C(Br)Br)c1ccc(Cl)cc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C#CC#N)c1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A solution of 1,1-dibromo-3-(p-chlorophenyl)-3-methyl-1-butene (38.5 g, 0.113 mol) in tetrahydrofuran is treated with n-butyllithium (0.25 mol, 100 mL of a 2.5M solution in hexane) under nitrogen over 45 minutes while maintaining the temperature below -65° C., stirred overnight at dry ice/acetone bath temperature, treated dropwise with a solution of phenyl cyanate (14.89 g, 0.125 mol) in tetrahydrofuran over 30 minutes at -65° C. to -70° C., allowed to warm to 10° C., and diluted with ethyl acetate and 5% sodium hydroxide solution. The resultant mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with 5% sodium hydroxide solution and water, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. The residue is distilled to give the title product as an oil (18.7 g, bp 110°-113° C./0.9 mm Hg, 80.7% yield)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[NH:14][C:13]1=[O:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]OC(OC)N(C)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:26]=[CH:27][CH:28]=[CH:29][C:15]=2[N:14]([CH3:31])[C:13]1=[O:30])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=C(NC1N=C(C2CCCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCCC2)c2ccccc21

Procedure:
3(R,S)-[(Benzyloxycarbonyl)amino]-5-cycloheptyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (Example 1, Step 3, 500 mg) in anhydrous toluene (40 ml) was heated to reflux. A solution of dimethylformamide dimethyl acetal (786 μl) in anhydrous toluene (10 ml) was added dropwise and the mixture was heated at reflux for a further hour. The solvent was evaporated and the residue triturated with diethyl ether to afford the title compound (441 mg) as a colourless solid. 1H NMR (360 MHz, CDCl3) δ 1.24-1.90 (11H, m), 2.00-2.14 (1H, m), 2.90-3.00 (1H, m), 3.40 (3H, s), 5.04-5.18 (3H, m), 6.52 (1H, d, J=7.5 Hz), 7.24-7.60 (9H, m). TLC (silica, petrol (60/80): ethyl acetate 2:1). Rf=0.30.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[O:5][C:3]1=[O:4].[S:9](=[O:12])(=[O:11])=[O:10].[OH-:13].[Na+:14]>ClCCCl.O>[Na+:14].[CH3:1][CH:2]([C:3]([O-:13])=[O:4])[CH:7]([S:9]([OH:12])(=[O:11])=[O:10])[C:6]([O-:5])=[O:8].[Na+:14]
Reactant: [OH-]
Reactant: O=S(=O)=O
Reactant: CC1CC(=O)OC1=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CC(C(=O)[O-])C(C(=O)[O-])S(=O)(=O)O
Reaction time: 8 h

Procedure:
3-Methyl-2-sulfosuccinic acid sodium salt was prepared as follows. 20 g Methylsuccinic anhydride was dissolved in 40 g 1,2-dichloroethane. 15.4 g solid sulfur trioxide was melted and added in portions to 140 g 1,2-dichloroethane in an addition funnel. The sulfur trioxide solution was added slowly to the anhydride solution and stirred overnight. 50 mL water was then added, followed by 7 g sodium hydroxide dissolved in 50 mL water. The layers were separated and the 1,2-dichloroethane layer was again extracted with 50 mL water. The combined water layers were stripped to give 42.2 g yellowish solid. 1H-NMR (D2O) 2.65-2.80 ppm m, 2.47-2.58 ppm m, 1.04 ppm d J=7.07 Hz.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=1.[Li]CCCC.[Cl:15][C:16]1[CH:17]=[C:18]([CH:25]=[C:26]([CH3:28])[N:27]=1)[C:19](N(OC)C)=[O:20].C(=O)(O)[O-].[Na+]>CCOCC.C1COCC1.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]([C:19]([C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([Br:9])[CH:3]=2)=[O:20])[CH:25]=[C:26]([CH3:28])[N:27]=1
Reactant: CON(C)C(=O)c1cc(C)nc(Cl)c1
Reactant: Brc1cc(Br)cc(Br)c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cc(Br)cc(Br)c2)cc(Cl)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To 0.45 grams (1.4 mmol) of 1,3,5-tribromobenzene in 25.0 mL of anhydrous ether at −78° C. was added 0.57 mL of 2.5 M n-BuLi (1.4 mmol) at a rate that maintained the internal temperature of the reaction at less than −70° C. After the addition was complete, the reaction was stirred 1 hour at −78° C., then 0.220 grams (1.1 mmol) of 2-chloro-N-methoxy-6,N-dimethyl-isonicotinamide in 2 mL of THF was added, again keeping the temperature below −70° C. After the addition was complete, the reaction was allowed to stir at −25° C. for 45 minutes; then 100 mL saturated aqueous sodium bicarbonate was added and the reaction was stirred at room temperature for 30 minutes. The phases were separated and the aqueous phase was extracted with ether. The organic fractions were combined and dried with sodium sulfate. The volatiles were removed under reduced pressure and the crude product was chromatographed on silica gel using 5:1 hexane:ethyl acetate to give 330 mg (77% yield) of (2-chloro-6-methyl-pyridin-4-yl)-(3,5-dibromo-phenyl)-methanone.
Reaction SMILES: [CH2:1]([N:5]([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)[CH2:2][CH2:3]C.[O:31]1CCC(N)[CH2:33][CH2:32]1>CN1CCCC1=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:16]2[C:15]([NH:5][CH:1]3[CH2:33][CH2:32][O:31][CH2:3][CH2:2]3)=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[N:17]2)=[CH:25][CH:26]=1
Reactant: NC1CCOCC1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Solvent: CN1CCCC1=O
Product: Clc1ccc(-n2nc3ccccc3c2NC2CCOCC2)cc1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with tetrahydro-pyran-4-ylamine ([38041-19-9]) in N-methyl 2-pyrrolidone for 48 h at 175° C. in a sealed tube to give the title compound as yellow solid. MS: m/e=328.4 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH2:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.S(Cl)([Cl:19])(=O)=O>ClCCl>[Cl:19][CH:5]([C:6](=[O:14])[C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH2:4][C:3]([O:2][CH3:1])=[O:15]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)CCC(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Product: COC(=O)CC(Cl)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 179 g (0.79 mole) of methyl-3-(4-chlorobenzoyl)propionate in 175 mL of dichloromethane was cooled to 0° and treated dropwise with 69.8 mL (117.3 g; 0.86 mole, d=1.68) of sulfuryl chloride. After the addition was complete, the cold bath was removed, and the reaction mixture was allowed to warm to room temperature while stirring overnight. The mixture was treated with 100 mL of water and basified cautiously with 50% sodium hydroxide. The layers were separated, the dichloromethane layer dried over magnesium sulfate and evaporated under reduced pressure (245.3 g). The residue was purified by vacuum distillation (135° C./0.3 mm) to obtain three fractions for a total of 198.6 g (96%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:32])[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[CH:20]=3)[CH2:17][C:16](=[O:32])[NH:15][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccncc3)c2)=Nc2ccc(F)cc2N1

Procedure:
The title compound was prepared from {4-fluoro-2-[3-oxo-3-(3-pyridin-4-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M5) (245 mg, 0.75 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (145 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:3]=1.C1N2CC[N:20](CC2)[CH2:19]1.C(#N)C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:19]#[N:20])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:3]=1
Reactant: C1CN2CCN1CC2
Reactant: Nc1nc(Cl)nc(Nc2cccc(F)c2F)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1nc(N)nc(Nc2cccc(F)c2F)n1
Reaction time: 1 h
Yield: 44.4 %

Procedure:
To 2-amino-4-chloro-6-(2,3-difluorophenylamino)-[1,3,5]triazine (Intermediate 55, 1.0 g, 3.89 mmol) was added DABCO (540 mg, 4.67 mmol), tetra n-butylammonium cyanide (1.15 g, 4.28 mmol) and anhydrous acetonitrile (15 mL). The reaction mixture was stirred at 50 C for 1 h, diluted with 50 mL ethyl acetate, extracted with 1M aq. citric acid (2×50 mL), water (2×50 mL), saturated brine (50 mL) and dried further over anhydrous sodium sulfate. Evaporation of the solvent gave a red gum which was purified by column chromatography on silica eluting with DCM-2% ethyl acetate to give the desired compound (429 mg, 69%). Method B HPLC-MS: MH+ requires m/z=249. Found: m/z=249, Rt=1.64 min (91%).