Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[CH:16]=[C:17]([CH2:19][OH:20])[O:18][C:14]=3[C:13]([O:21][CH3:22])=[C:12]([O:23][CH3:24])[CH:11]=2)=[CH:4][N:3]=1>C(Cl)(Cl)Cl.[O-2].[Mn+2]>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[CH:16]=[C:17]([CH:19]=[O:20])[O:18][C:14]=3[C:13]([O:21][CH3:22])=[C:12]([O:23][CH3:24])[CH:11]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)c2cc(CO)oc2c1OC
Agent: [Mn+2]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1cc(Cc2cnc(N)nc2N)c2cc(C=O)oc2c1OC
Temperature: 45 °C
Yield: 59.8 %

Procedure:
To a solution of [4-(2,4-Diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-yl]-methanol (1 eq, 2.74 g, 8.3 mmol) in chloroform, Manganese oxide (10 eq, 7.22 g, 83 mmol) was added at room temperature under Argon. The reaction mixture was heated at 45° C. After completion of the reaction, the hot mixture is filtered and the manganese oxide residue is washed with hot acetonitrile. The filtrate is evaporated to give 4-(2,4-diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-carbaldehyde as a yellow solid (1.63 g, 60%). To a suspension of 4-(2,4-diamino-pyrimidin-5-ylmethyl)-6,7-dimethoxy-benzofuran-2-carbaldehyde (1 eq, 190 mg, 0.58 mmol) and 5-fluoro-1H-indole-2-carboxylic acid methoxy-methyl-amide (2 eq, 886 mg, 1.74 mmol) in Acetic acid (C=0.20 M), a 30% solution of HBr in acetic acid (10 eq, 1.2 mL) was added slowly at 5° C. under Argon. The purple mixture was stirred 20 minutes under Argon until completion. The resulting mixture was poured onto ice water, basified to pH 8 by adding a solution saturated of NaHCO3. After centrifugation of the resulting suspension was filtered and the resulting precipitate was lyophilized overnight. The residue was then digested in methanol to precipitate the amide in excess. After filtration, the filtrate was evaporated to give the compound of formula XII. This compound was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:8]([F:18])=[CH:9][C:10]([CH3:17])=[C:11]([S:13](Cl)(=O)=O)[CH:12]=2)[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1.C(O)C.Cl.O>[Zn].C(OCC)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([F:18])=[CH:9][C:10]([CH3:17])=[C:11]([SH:13])[CH:12]=2)[N:5]=[C:4]([C:19]([F:22])([F:21])[F:20])[N:3]=1
Reactant: Cc1cc(F)c(-n2nc(C(F)(F)F)nc2N)cc1S(=O)(=O)Cl
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1cc(F)c(-n2nc(C(F)(F)F)nc2N)cc1S
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.6 %

Procedure:
In a 25-ml eggplant flask provided with a magnetic stirrer was placed 1.83 g (5 mmol) of 5-(5-amino-3-trifluoromethyl-1H-1,2,4-triazol-1-yl)-4-fluoro-2-methylbenzenesulfonyl chloride, followed by addition of 1.6 g (25 mmol) of zinc, 10 ml of ethanol and 10 ml of (100 mmol) of 18% hydrochloric acid. The mixture was stirred at room temperature for 15 minutes. Then, the mixture was refluxed with heating until the zinc powder was dissolved completely. The mixture was cooled to room temperature. Thereto were added 30 ml of water and 30 ml of ethyl acetate to give rise to phase separation. The aqueous phase was extracted with 30 ml of ethyl acetate. The ethyl acetate phase was washed with water and then with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Vacuum distillation was conducted to distill off ethyl acetate to obtain 1.5 g of a crystal. Yield: 100%
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].[C:7](#N)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(=S)=S>[CH3:4][C:3]1([CH3:5])[CH2:2][NH:1][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:6]1
Reactant: CC(C)(N)CN
Reactant: CCCCCC#N
Solvent: S=C=S
Product: CCCCCC1=NC(C)(C)CN1
Yield: 73.3 %

Procedure:
8.41 g (95.4 mmoles) of 1,2-diamino-2-methylpropane, 7.4 g (76.16 mmoles) of hexanenitrile and 0.4 ml of carbon disulfide were heated at 125° C. for 24 hours and then worked up as under Example 23. Distillation at 105°-107° C./0.5 mm gave 9.4 g (73.4%) of product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](=[S:17])[NH2:16])=[CH:11]2.[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C:33]#[C:34][CH3:35].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][N:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:17][CH:34]([CH2:33][C:32]([O:37][CH2:38][CH3:39])=[O:36])[CH2:35][N:16]=1)=[CH:11]2
Reactant: CC#CC(=O)OCC
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=S)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)cn4)cc(OC(COC)COC)c3[nH]2)S1
Temperature: 50 °C
Reaction time: 13 h
Yield: 55 %

Procedure:
A mixture of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carbothioamide (1.69 g), ethyl 2-butynoate (0.84 mL), tributylphosphine (0.9 mL), tetrahydrofuran (20 mL) and toluene (30 mL) was stirred at 50° C. for 13 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate/hexane=0/20/80 to 5/95/0, volume ratio), followed by basic silica gel column chromatography (ethyl acetate/hexane=20/80 to 90/10, volume ratio) to give the title compound (1.14 g, 55%) as a brownish amorphous solid. MS 578 (MH+).
Reaction SMILES: C[Mg]Br.[NH2:4][C:5]1[N:10]=[C:9]([NH2:11])[C:8]([O:12][C:13]2[C:14]([CH:24]([CH3:26])[CH3:25])=[CH:15][C:16]([O:22][CH3:23])=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=2)=[CH:7][N:6]=1.[C:27]([O-])([O-])=O.[K+].[K+].IC>C1COCC1>[NH2:4][C:5]1[N:10]=[C:9]([NH2:11])[C:8]([O:12][C:13]2[C:14]([CH:24]([CH3:26])[CH3:25])=[CH:15][C:16]([O:22][CH3:23])=[C:17]([C:19]([OH:21])([CH3:27])[CH3:20])[CH:18]=2)=[CH:7][N:6]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(C)=O
Agent: C[Mg]Br
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1C(C)(C)O
Temperature: 0 °C
Yield: 45.5 %

Procedure:
To a solution of methylmagnesium bromide (83.4 mmol, 27.8 ml, 3.0 M in Et2O) in 83 mL THF at 0° C. was added 1-[5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-ethanone (2.523 g, 8.3 mmol, from Example 16) in portions. After 16 h the mixture was cooled to 0° C. and was quenched by the addition 10% NH4Cl. H2O was added and the mixture was extracted with ethyl acetate. The combined organics were washed with H2O, washed with brine, dried over NaHCO3, filtered and concentrated in vacuo. The crude solid was taken up in 31 ml DMF. K2CO3 (0.65 g, 4.7 mmol) and iodomethane (0.098 ml, 1.6 mmol) were added and the mixture was warmed to 50° C. Additional portions of iodomethane (0.019 mL, 0.6 mmol) was added at 1, 2 and 3 hr. After 16 h the mixture was cooled and 10% NH4Cl and extracted with ethyl acetate. The combined organics were washed with H2O, washed with brine, dried with Na2SO4, filtered and concentrated in vacuo to give 2-[5-(2,4-diaminopyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-propan-2-ol (0.711 g, yiled) as a white solid. [MH]+=333.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[CH:16][C:15]=1[CH3:20]
Reactant: O=C1CCC(=O)O1
Reactant: Cc1ccccc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)CCC(=O)O)ccc1F
Temperature: 80 °C

Procedure:
200 gm of succinic anhydride and 800 gm of aluminum chloride were added to 250 ml of 2-fluorotoluene, and the mixture was heated at 80° C. for 1 hour. Upon the addition of 5 l of 1% cold hydrochloric acid aqueous solution, the reaction mixture was extracted with ethyl acetate, washed with 1N hydrochloric acid and water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 345 gm of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][N:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[N:21]=[CH:20][CH:19]=[N:18]2)=[O:10])[C@H:6]([CH3:22])[CH2:5][CH2:4]1.C(OC1C(OC(=O)C)=C(I)C=CC=1)(=O)C>ClCCl>[CH3:22][C@H:6]1[N:7]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:17]2[N:21]=[CH:20][CH:19]=[N:18]2)=[O:10])[CH2:8][C@H:3]([CH:2]=[O:1])[CH2:4][CH2:5]1
Reactant: C[C@@H]1CC[C@@H](CO)CN1C(=O)c1ccccc1-n1nccn1
Agent: CC(=O)Oc1cccc(I)c1OC(C)=O
Solvent: ClCCl
Product: C[C@@H]1CC[C@@H](C=O)CN1C(=O)c1ccccc1-n1nccn1
Reaction time: 18 h

Procedure:
To a solution of [(2R,5R)-5-(hydroxymethyl)-2-methylpiperidin-1-yl][2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (0.76 g, 2.5 mmol) in dichloromethane (25 mL) was added (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (0.06 g, 0.38 mmol) and diacetoxyiodobenzene (0.81 g, 2.5 mmol). The mixture was stirred at ambient temperatures for 18 hours, then washed with aqueous sodium thiosulfite (1×30 mL) and aqueous sodium bicarbonate (2×50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 0-2% methanol in dichloromethane to provide (3R,6R)-6-methyl-1-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidine-3-carbaldehyde as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=O)[CH:3]=1.CCN(CC)CC.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:10])[CH:3]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: N#Cc1cc(Cl)ccn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 4-chloropyridine-2-carboxamide (150 mg, 0.96 mmol) in THF (5 ml) at −15° C. was added NEt3 (331 μl, 2.40 mmol) followed by TFAA (150 μl, 1.08 mmol). After stirring for 2 hours at 0° C. the reaction was concentrated then diluted with EtOAc (30 ml) and washed with water (2×15 ml), dried (Na2SO4), filtered and concentrated at reduced pressure. The title compound was obtained as white solid (105 mg, 79%) after purification by FCC.
Reaction SMILES: CO[C:3]1[C:6](=[O:7])[C:5](=[O:8])[C:4]=1[NH:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]([C:20]2[S:21][CH:22]=[CH:23][C:24]=2[NH:25][CH2:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=[CH:29][CH:28]=2)=[O:19])[CH:13]=[CH:14][C:15]=1[Cl:16].ClC1C=CC(N)=CC=1N.[CH3:46][O:47][CH2:48][CH2:49][NH2:50]>>[N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27]([CH2:26][NH:25][C:24]2[CH:23]=[CH:22][S:21][C:20]=2[C:18]([NH:17][C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([NH:9][C:4]3[C:5](=[O:8])[C:6](=[O:7])[C:3]=3[NH:50][CH2:49][CH2:48][O:47][CH3:46])[CH:11]=2)=[O:19])=[CH:28][CH:29]=1
Reactant: COc1c(Nc2cc(NC(=O)c3sccc3NCc3ccnc4ccccc34)ccc2Cl)c(=O)c1=O
Reactant: COCCN
Agent: Nc1ccc(Cl)c(N)c1
Product: COCCNc1c(Nc2cc(NC(=O)c3sccc3NCc3ccnc4ccccc34)ccc2Cl)c(=O)c1=O

Procedure:
EXAMPLE 47 was prepared according to the procedure described in EXAMPLE 3 using N-{3-[(2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino]-4-chlorophenyl}-3-[(quinolin-4-ylmethyl)amino]thiophene-2-carboxamide (prepared according to the procedure described in EXAMPLE 1 using 4-chloro-1,3-phenylenediamine instead of 1,3-phenylenediamine) and 2-methoxyethylamine instead of dimethylamine. MS (ES+): m/z 561.9 [M+1]
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:40]CC2C=CC=CC=2)[C@@H:15]([N:25](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:48][CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:40])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:18]=[C:19]([F:24])[CH:20]=[C:21]([F:23])[CH:22]=2)[CH2:12][O:11][C@@H:10]([O:48][CH2:49][C:50]([CH3:53])([CH3:52])[CH3:51])[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)CO1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Yield: 93.5 %

Procedure:
Stir (2R,5R)-5-[(1S,2S)-1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-(2,2-dimethylpropoxy)-morpholine-4-carboxylic acid tert-butyl ester (0.1 g, 0.14 mmol) and 20% palladium hydroxide on carbon (0.1 g, 0.06 mmol, 60% moisture) in ethyl acetate (5 mL) under 1 atmosphere of hydrogen gas at room temperature overnight. Filter the suspension through a pad of filtering agent, wash with ethyl acetate and concentrate to give the title compound (0.06 g, 90%).
Reaction SMILES: Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.[OH:32][C:33]([C:36]1[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[N:39]=[C:38]([O:46][CH:47]2[CH2:52][CH2:51][C:50](=O)[CH2:49][CH2:48]2)[CH:37]=1)([CH3:35])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[OH:32][C:33]([C:36]1[CH:41]=[C:40]([C:42]([F:43])([F:44])[F:45])[N:39]=[C:38]([O:46][C@@H:47]2[CH2:52][CH2:51][C@H:50]([N:25]3[CH2:24][C:23]([CH2:27][C:28]#[N:29])([N:21]4[CH:22]=[C:18]([C:17]5[C:12]6[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=6[N:14]=[CH:15][N:16]=5)[CH:19]=[N:20]4)[CH2:26]3)[CH2:49][CH2:48]2)[CH:37]=1)([CH3:34])[CH3:35]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CNC4)c3)ncnc21
Reactant: CC(C)(O)c1cc(OC2CCC(=O)CC2)nc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(O)c1cc(O[C@H]2CC[C@@H](N3CC(CC#N)(n4cc(-c5ncnc6c5ccn6COCC[Si](C)(C)C)cn4)C3)CC2)nc(C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
{3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (55.3 mg, 0.115 mmol) and 4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexanone were dissolved in dry 1,2-dichloroethane (1.38 mL) and were stirred for 5 min and sodium triacetoxyborohydride (86.1 mg, 0.406 mmol) was added. The reaction mixture was stirred at 25° C. for 16 h, at which time LCMS analysis showed mainly the two diastereomeric products. The reaction was quenched with water, neutralized with NaHCO3 and extracted with ethyl acetate and the solvent was evaporated. The residue was purified by LCMS (pH 10) and the fractions containing the second peak were combined and evaporated to give {1-(cis-4-{[4-(1-hydroxy-1-methylethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo [2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. The first peak was also isolated to give {1-(trans-4-{[4-(1-hydroxy-1-methyl ethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}cyclohexyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. MS (ES): 712(M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]Br.[NH2:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1.O>[OH-].[Na+].ClCCl.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[NH2:11][C:12]1[C:17]([O:18][CH2:4][C:3]2[CH:6]=[C:7]([Cl:10])[CH:8]=[CH:9][C:2]=2[Cl:1])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: Nc1ncccc1O
Reactant: Clc1ccc(Cl)c(CBr)c1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Nc1ncccc1OCc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2,5-dichlorobenzyl bromide (14.8 g, 75.9 mmol) and 2-amino-3hydroxypyridine (7.7 g, 69.7 mmol) in 40% aqueous sodium hydroxide solution (52 ml) and dichloromethane (52 ml) was treated with Adogen 464 (5 ml) and stirred vigorously at room temperature for 16 hours. More water was added and the product extracted into dichloromethane, dried, and the solvent evaporated to obtain the product after trituration with ether (8.6 g, 46%), m.p. 103°-104 ° C.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].C(OCC)(=O)CC(OCC)=O.[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](=[O:23])[CH3:22].[OH-].[Na+].S(=O)(=O)(O)O>C(O)C.C(OCC)(=O)C>[Cl:16][C:17]1[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=1[CH:19]1[CH2:3][C:2](=[O:1])[CH2:22][C:21](=[O:23])[CH2:20]1
Reactant: CC(=O)C=Cc1ccccc1Cl
Reactant: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOC(=O)CC(=O)OCC
Solvent: CCO
Product: O=C1CC(=O)CC(c2ccccc2Cl)C1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 20% sodium ethoxide in ethanol (170.1 g) was added diethyl malonate (80.1 g) at room temperature (immediately precipitated material was observed), and then a solution of crude 2-chlorobenzalacetone (94.6 g) in ethanol (40 ml). The mixture was stirred at 90° C. for 2 hours, cooled at room temperature and under-ice-cooling (for 1 hour). Precipitated materials were filtered and washed with ethyl acetate and isopropylether to give crude ethyl 6-(2-chlorophenyl)-2-hydroxy-4-oxo-2-cyclohexene-1-carboxylate monosodium salt (151.0 g) as pale yellow powder. To said powder was added 2 M sodium hydroxide (350 ml), and the mixture was stirred at 100° C. for 2 hours and cooled. To the mixture was added 2.5 M sulfuric acid (350 ml) for 15 minutes, and the mixture was stirred at 100° C. for 2 hours and cooled. To the mixture was added ethyl acetate (1.4 l), and the mixture was subjected to extraction. The ethyl acetate layer was washed with brine, dried (anhydrous magnesium sulfate), and ethyl acetate was evaporated under reduced pressure. Precipitated crystals were washed with ethyl acetate-isopropylether (1:4) and isopropylether to give 5-(2-chlorophenyl)cyclohexane-1,3-dione (82.1 g) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:13][C:14](=O)[CH3:15]>CN(C=O)C>[CH3:15][C:14]1[N:11]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=2)[S:10][CH:13]=1
Reactant: CC(=O)CBr
Reactant: NC(=S)Nc1cccc(O)c1
Solvent: CN(C)C=O
Product: Cc1csc(Nc2cccc(O)c2)n1
Yield: 61 %

Procedure:
Following the general procedure for the synthesis of derivatives 6 and 7, a solution of 3-hydroxyphenylthiourea (100 mg, 0.59 mmol) and bromoacetone (98 mg, 0.71 mmol) in dry DMF (2.4 mL) was heated at 60° C. for 6 h. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 6/4) in 61% yield (74 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:16])(=O)=O.[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C1(C)C=CC=CC=1>[CH3:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][CH2:10][C:11]2=[O:16]
Reactant: Cc1cccc(C)c1B(O)O
Reactant: O=C1CCc2c(OS(=O)(=O)C(F)(F)F)cccc21
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1-c1cccc2c1CCC2=O
Temperature: 90 °C
Yield: 85.5 %

Procedure:
A mixture of 1-oxo-2,3-dihydro-1H-inden-4-yl trifluoromethanesulfonate (10.0 g, 35.7 mmol), 2,6-dimethylphenylboronic acid (6.96 g, 46.4 mmol), 2-(dicyclohexylphosphino)biphenyl (750 mg, 2.14 mmol), tris(dibenzylideneacetone)dipalladium(0) (1.31 mg, 1.43 mmol), tripotassium phosphate (15.2 g, 71.4 mmol) and toluene (200 mL) was heated under reflux under an argon atmosphere at 90° C. for 16 hr. After cooling the reaction mixture, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (5%-45% ethyl acetate/hexane) to give the title compound (7.21 g, yield 85%) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.O>[CH3:11][S:12]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(N)cc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
A cooled solution of 4′-aminoacetophenon (10 mmol) in pyridine (10 mL) at 0° C. was treated with methanesulfonyl chloride (15 mmol) and stirred at room temperature for 2 h. The reaction mixture was diluted with H2O and extracted with EtOAc several times. The combined organic layers were washed with H2O and brine, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes to afford 4′-(Methylsulfonylamino)acetophenone (13-5, LJO-298).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Br:27])[CH:23]=3)[CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:30]>C(OCC)(=O)C>[ClH:30].[Br:27][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([S:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:15])=[O:16])[CH:26]=[CH:25]2
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Br)ccc3c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the obtained 1-(tert-butoxycarbonyl)-4-(6-bromonaphthalene-2-sulfonyl)piperazine (2.80 g) were added methanol (10 ml) and 4 N hydrochloric acid in ethyl acetate solution (25 ml), and the solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated and the residue was treated with acetone to give amorphous powders. The powders were dried under reduced pressure to give the title compound (2.358 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[NH:10][CH:11]1[CH2:13][CH2:12]1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[N:17][CH:16]=1.OOS([O-])=O.[K+].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH:11]1([N:10]2[C:3]3[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=3[N:1]=[C:14]2[C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13]1
Reactant: N#Cc1ccc(N)c(NC2CC2)c1
Reactant: O=Cc1cccnc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2nc(-c3cccnc3)n(C3CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-amino-3-(cyclopropylamino) benzonitrile, (0.2 g, 0.0011 mol) and nicotinaldehyde (0.14 g, 0.0012 mol) in DMF (5 ml) and H2O (2 ml) was added OXONE® monopersulphate (0.84 g, 0.0013 mol). Reaction mass was stirred at room temperature for 3 h. The reaction mixture was basified with 10% K2CO3 solution to pH˜8-10 and extracted with EtOAc (3×20 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum to afford the crude compound, which was purified by column chromatography to obtain title compound 1-cyclopropyl-2-(pyridine-3-yl)-1H-benzo[d]imidazole-6-carbonitrile. 1H NMR (400 MHz, DMSO-d6), δ: 9.21 (s, 1H), 8.77-8.76 (d, J=4.4 Hz, 1H), 8.45-8.43 (d, J=8 Hz, 1H), 8.25 (s, 1H), 7.89-7.87 (d, J=8 Hz, 1H), 7.68-7.61 (m, 2H), 3.91-3.87 (m, 1H), 1.17-1.12 (m, 2H), 0.71-0.70 (m, 2H). MS (M+1): 261.12; purity 97.77%.