Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)(=[O:20])=[O:19]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:23]=[CH:22][C:21]([S:18]([CH3:17])(=[O:20])=[O:19])=[CH:26][CH:25]=1)(=[O:29])=[O:28])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Product: CS(=O)(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 127 mg of 4-Methanesulfonyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 2.92 (s, 3H), 7.34 (m, 3H), 7.434 (m, 2H), 7.51 (dd, 1H, J=8.8 Hz, 2.4 Hz), 7.60 (m, 1H), 7.75 (d, 1H, J=8.8 Hz), 7.80-7.86 (m, 4H), 9.86 (b, 1H). MS: m/z 450.9 (M++1).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1.C(N(CC)CC)C.[CH3:14][S:15][C:16]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)=[CH:21][C:17]=1[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[CH3:14][S:15][C:16]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:28][CH:27]=2)=[CH:21][C:17]=1[C:18]([O:1][CH:2]1[CH2:6][CH2:5][O:4][CH2:3]1)=[O:19]
Reactant: OC1CCOC1
Reactant: CSc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1C(=O)OC1CCOC1
Reaction time: 8 h

Procedure:
3-Hydroxytetrahydrofuran (0.04 mole), toluene (50 ml) and triethylamine (0.04 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. A solution of 2-methylthio-5-(4-trifluoromethylphenoxy)benzoyl chloride (0.04 mole) in toluene (20 ml) is slowly added at room temperature with stirring. After the addition is completed, stirring is continued for a period of about eight hours. After this time, the reaction mixture is washed with water and dried over anhydrous magnesium sulfate. The dried solution is then stripped of solvent under reduced pressure leaving a residue. This residue is purified by silica gel chromatography using toluene and ethyl acetate/toluene mixture as the eluant to yield the desired product 3-tetrahydrofuryl 2-methylthio-5-(4-trifluoromethylphenoxy)benzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[CH2:19][NH2:20])=[CH:14][CH:13]=1>>[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[CH2:19][NH:20][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])=[CH:14][CH:13]=1
Reactant: Cc1ccccc1C(=O)O
Reactant: NCC(c1ccc(F)cc1)N1CCOCC1
Product: Cc1ccccc1C(=O)NCC(c1ccc(F)cc1)N1CCOCC1

Procedure:
From 2-methylbenzoic acid and 2-(4-fluoro-phenyl)-2-morpholin-4-yl-ethylamine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](F)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[OH:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1.[H-].[Na+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[O:14][CH:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1[N+](=O)[O-]
Reactant: CN1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)CC1
Reaction time: 1 h

Procedure:
3,4-Dinitrofluorobenzene (1.86 g, 10 mmol) and 4-hydroxy-1-methylpiperidine (1.38 g, 12 mmol) were dissolved in THF (20 ml) and stirred at ambient temperature while sodium hydride (60% dispersion in mineral oil, 0.40 g, 10 mmol) was added in several small portions. The reaction mixture was stirred for one hour and then reduced in vacuo, partitioned between ethyl acetate and water, and the organic phase washed with brine, dried (MgSO4) and reduced in vacuo. The resulting residue was subject to column chromatography, eluting with 5% MeOH/DCM to give a yellow solid (1.76 g, 2:1 ratio of 4-(3,4-dinitro-phenoxy)-1-methyl-piperidine and a 4-(4-fluoro-2-nitro-phenoxy)-1-methyl-piperidine).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[CH2:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:22])/[C:9](/[S:10]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:11])=[O:12])=[CH:28]\[C:27]2[CH:30]=[CH:31][C:24]([Br:23])=[CH:25][CH:26]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COc1ccc(CS(=O)(=O)CC(=O)c2ccc(Br)cc2)cc1
Product: COc1ccc(CS(=O)(=O)/C(=C/c2ccc(Br)cc2)C(=O)c2ccc(Br)cc2)cc1

Procedure:
The title compound is prepared by the methods described in Synthesis Example 10. A solution of 1-(4-bromophenyl)-2-(4-methoxybenzylsulfonyl)ethanone (10 mmol) and 4-bromobenzaldehyde (10 mmol) was subjected to the procedure described as Method A in part C of Synthesis Example 10 and the product obtained was purified by column chromatography. m.p. 146-150° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:4][C:3]=1[N+:14]([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:14][C:3]1[CH:4]=[CH:5][C:6]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:7][C:2]=1[CH3:1]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])c(C)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(N)c(C)n1

Procedure:
Ethyl 2-(6-methyl-5-nitropyridin-2-yl)acetate (1.10 g, 4.91 mmol) was dissolved in ethyl acetate and added Pd/C (0.5 g) then stirred under a balloon of hydrogen for 2 hrs. Filtered over catalyst and concentrated to yield ethyl 2-(5-amino-6-methylpyridin-2-yl)acetate: LC-MS: M+1=195;
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:14])[F:13])[C:3]=1[C:18]([N:20]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19]>C(O)=O.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:16][CH3:17])[C:8]=2[C:12]([F:15])([F:13])[F:14])[C:3]=1[C:18]([N:20]([C:29]([O:31][CH3:32])=[O:30])[CH2:21][C:22]([OH:24])=[O:23])=[O:19]
Reactant: COC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(Cl)ccc2c(C(F)(F)F)c(OC)ccc12
Solvent: O
Solvent: O=CO
Product: COC(=O)N(CC(=O)O)C(=O)c1c(Cl)ccc2c(C(F)(F)F)c(OC)ccc12
Reaction time: 2 h
Yield: 64.4 %

Procedure:
N-[[2-Chloro-6-methoxy-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]-N-(methoxycarbonyl)glycine, 1,1-dimethylethyl ester (3.10 g, 6.51 mmol) was suspended in formic acid (122 mL) under nitrogen at room temperature and stirred for 11/2 hours. The reaction mixture was diluted with water (11/2 L) and extracted with ether (2×200 mL). The extracts were combined, dried over magnesium sulfate and concentrated. The residue was recrystallized from benzene to afford the title compound as a white solid (1.76 g, 64%), m.p. 162°-165° C.
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([NH2:16])=[O:15])[NH:9]2.[CH3:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1>>[CH3:18][O:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:30]2[CH2:31][CH2:32][N:33]([CH2:17][CH:2]([OH:1])[CH2:3][O:4][C:5]3[CH:13]=[CH:12][CH:11]=[C:10]4[C:6]=3[CH:7]=[C:8]([C:14]([NH2:16])=[O:15])[NH:9]4)[CH2:34][CH2:35]2)=[CH:27][CH:28]=1
Reactant: COCCOc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: NC(=O)c1cc2c(OCC3CO3)cccc2[nH]1
Product: COCCOc1ccc(C(c2ccccc2)N2CCN(CC(O)COc3cccc4[nH]c(C(N)=O)cc34)CC2)cc1

Procedure:
4-(2,3-Epoxypropoxy)-1H-indole-2-carboxamide is reacted with 1-((4-(2-methoxyethoxy)phenyl)phenylmethyl)piperazine to give 4-(3-(4-((4-(2-methoxyethoxy)phenyl)phenylmethyl)piperazin-1-yl)-2-hydroxypropoxy)-1H-indole-2-carboxamide. The compound obtained is reacted with trifluoroacetic anhydride in a mixture of dioxane and pyridine to give 4-(3-(4-((4-(2-methoxyethoxy)phenyl)phenylmethyl)piperazin-1-yl)-2-hydroxypropoxy)-1H-indole-2-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:11][CH:12]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][CH:18]=2)[C:23]2[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=2)[CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)Oc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1ccc(C(NC(C)c2cc(F)cc(F)c2)c2cccc(N)c2)cc1
Yield: 91.9 %

Procedure:
Following a similar procedure to that described in Example (1b), 1.17 g of N-[1-(3,5-difluorophenyl)ethyl]-N-[(3-nitrophenyl)-(4-isopropoxyphenyl)methyl]amine [prepared as described in step (a) above], 1.50 g of nickel chloride hexahydrate and 437 mg of sodium borohydride were reacted, to obtain 1.0 g of the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([S:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:27][S:28]([NH2:31])(=[O:30])=[O:29].C1CCN2C(=NCCC2)CC1.Cl>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:31][S:28]([CH3:27])(=[O:30])=[O:29])=[O:7])=[C:4]([S:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1
Reactant: CC(C)Sc1cc(Br)ccc1C(=O)O
Reactant: CS(N)(=O)=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)Sc1cc(Br)ccc1C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of 4-bromo-2-(isopropylthio)benzoic acid (47.90 g) in N,N-dimethylformamide (480 ml) was added 1,1′-carbonyldiimidazole (31.00 g) and stirred for 30 minutes at room temperature under nitrogen atmosphere. To the mixture were added methanesulfonamide (18.17 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (39.10 ml) and then stirred at room temperature overnight. The reaction mixture was poured into hydrochloric acid aqueous solution (1N, 2 l) and extracted with ethyl acetate (2 l). The separated organic layer was washed with water (2 l) and brine (2 l), dried over magnesium sulfate and concentrated in vacuo. Then the residue was dried to give 4-bromo-2-(isopropylthio)-N-(methylsulfonyl)benzamide (60.00 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([C:16](OC)=[O:17])[C:3]=1[CH:20]([CH3:22])[CH3:21].[H-].C([Al+]CC(C)C)C(C)C.C[N+]1([O-])CCOCC1>C1(C)C=CC=CC=1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[N:6]([S:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH:16]=[O:17])[C:3]=1[CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)c1cn(S(=O)(=O)c2ccccc2)c(Br)c1C(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: Cc1ccccc1
Product: CC(C)c1c(C=O)cn(S(=O)(=O)c2ccccc2)c1Br
Yield: 86.5 %

Procedure:
Using methyl 5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (4.8 g), and a 1.5 mol/L solution (50 mL) of diisobutylaluminum hydride in toluene, tetra-n-propylammonium perruthenate (218 mg), N-methylmorpholine N-oxide (1.6 g) and molecular sieves 4A powder (2.5 g), a procedure as in Reference Example 6 was performed to give crude 5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.83 g) as an oil. Furthermore, using 40% methylamine methanol solution (877 mg), sodium borohydride (474 mg) and crude 5-bromo-4-isopropyl-1-(phenylsulfonyl)-1H-pyrrole-3-carbaldehyde (3.83 g), a procedure as in Reference Example 66 was performed to give the title compound as a colorless oil (yield 502 mg, 11%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[C:8]([CH3:14])=[N+:9]([O-:13])[CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>C(O)(=O)C>[CH3:5][O:6][C:7]1[C:8]([CH3:14])=[N+:9]([O-:13])[CH:10]=[CH:11][C:12]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc[n+]([O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reaction time: 8 h

Procedure:
8 ml of concentrated nitric acid are added in four portions of 2 ml each to 5.4 g of 3-methoxy-2-methylpyridine 1-oxide in 12 ml of glacial acetic acid at 80° C. in the course of 6 hours, the mixture is stirred at the same temperature overnight, a further 8 ml of nitric acid are added in three portions in the course of 6 hours and the mixture is stirred for a further 15 hours. After cooling, the mixture is poured onto ice (40 g) and brought to pH 6 with 10N sodium hydroxide solution, the byproduct (3-methoxy-2-methyl-4-nitropyridine) which has precipitated out is filtered off and the filtrate is extracted four times with 50 ml of methylene chloride. After drying, the combined organic phases are concentrated completely and the residue is recrystallized from a little methylene chloride/petroleum ether. 4.2 g (57% of theory) of the title compound are obtained in the form of yellow crystals of m.p. 103°-104° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].BrN1C(=[O:16])CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[O:16]
Reactant: Cc1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(F)cc1Br
Temperature: 80 °C
Yield: 41 %

Procedure:
2-Bromo-4-fluorotoluene (10.215 g) was dissolved in ethyl acetate (100 ml), N-bromosuccinimide (11.3 g) and 70% benzoyl peroxide (200 mg) were added thereto, and the resulting mixture was stirred under heating at 80° C. for 1 hr. After the reaction solution was cooled, the resulting insoluble matters were filtered off. The resulting filtrate was washed with an aqueous solution of saturated sodium bicarbonate, dried (over MgSO4) and evaporated. The resulting residue was dissolved in acetic acid (30 ml), water (30 ml) and hexamethylene tetramine (15.14 g) were added thereto, and the resulting mixture was heated under stirring at 100° C. for 1 hr. To the mixture was added 38% hydrochloric acid (20 ml), which was then stirred for 1 hr, and then it was cooled as it was, and extracted with ethyl acetate. The resulting organic phase was washed with an aqueous solution of saturated sodium bicarbonate, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a colorless solid (4.376 g, yield; 41%.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[S:15][C:14]4[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[K+].[K+].[CH3:69][O:70][C:71]1[CH:72]=[C:73]([CH:75]=[CH:76][C:77]=1[O:78][CH3:79])[NH2:74]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:20][C:18]1[CH:17]=[CH:16][C:14]2[S:15][C:11]([C:8]3[N:6]4[N:7]=[C:2]([NH:74][C:73]5[CH:75]=[CH:76][C:77]([O:78][CH3:79])=[C:71]([O:70][CH3:69])[CH:72]=5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)=[CH:12][C:13]=2[CH:19]=1
Reactant: Cc1ccc2sc(-c3cnc4ccc(Cl)nn34)cc2c1
Reactant: COc1ccc(N)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccc3ncc(-c4cc5cc(C)ccc5s4)n3n2)cc1OC
Temperature: 110 °C
Yield: 91 %

Procedure:
To a solution of 6-chloro-3-(5-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazine (50 mg, 0.168 mmol, 1.0 equiv), xantphos (19 mg, 0.0334 mmol, 0.2 equiv), palladium acetate (4 mg, 0.0167 mmol, 0.1 equiv), and potassium carbonate (461 mg, 3.34 mmol, 20 equiv) in dioxane (5.0 mL) was added 3,4-dimethoxyaniline (28 mg, 0.167 mmol, 1.1 equiv) and heated to 110° C. for 2 h. Purification by column chromatography using 2% methanol in dichloromethane elution gave 42 mg, 0.152 mmol of the yellow solid, 60%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([N+:15]([O-])=O)[CH:12]=[CH:13][CH:14]=2)=[N:5][CH:6]=[CH:7][CH:8]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[NH2:15])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: COc1cccnc1-c1cccc(N)c1
Yield: 100 %

Procedure:
A suspension of 3-(3-methoxypyridin-2-yl)nitrobenzene (0.391 g) in ethanol (8 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 120 mg) under a hydrogen atmosphere for 3 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 3-(3-methoxypyridin-2-yl)aniline (0.34 g).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[N:13]=[C:12]([NH:14][C:15]2[CH:28]=[CH:27][C:18]3[C:19]([C:23]([NH:25][CH3:26])=[O:24])=[C:20]([CH3:22])[O:21][C:17]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1.CI>CC(C)=O>[Cl:7][C:8]1[N:13]=[C:12]([N:14]([CH3:1])[C:15]2[CH:28]=[CH:27][C:18]3[C:19]([C:23]([NH:25][CH3:26])=[O:24])=[C:20]([CH3:22])[O:21][C:17]=3[CH:16]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CNC(=O)c1c(C)oc2cc(Nc3ccnc(Cl)n3)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CNC(=O)c1c(C)oc2cc(N(C)c3ccnc(Cl)n3)ccc12
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 22 %

Procedure:
Potassium carbonate (0.75 mmol) was added to a solution of 6-(2-chloropyrimidin-4-ylamino)-N,2-dimethylbenzofuran-3-carboxamide (0.5 mmol) in 5 ml acetone. After 15 mins, methyl iodide (0.5 mmol) was added. The reaction mixture was stirred at 60° C. for 2 days before the solvent was removed in vacuo. THF was added and the residue was filtered and subjected to column chromatography to provide the 6-((2-chloropyrimidin-4-yl)(methyl)amino)-N,2-dimethylbenzofuran-3-carboxamide in a yield of 22%.
Reaction SMILES: [O-]CC.[Na+].[Na].Cl.[NH2:7]O.[N+:9]([C:12]1[CH:22]=[CH:21][C:15]([CH:16]=[CH:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)([O-:11])=[O:10]>O.CCO>[NH2:7][CH:16]([C:15]1[CH:14]=[CH:13][C:12]([N+:9]([O-:11])=[O:10])=[CH:22][CH:21]=1)[CH2:17][C:18]([OH:20])=[O:19]
Reactant: NO
Reactant: O=C(O)C=Cc1ccc([N+](=O)[O-])cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Yield: 49.1 %

Procedure:
To a hot solution of sodium ethoxide prepared from sodium (9.33 g, 405 mmol) and EtOH (330 ml) was added a hot solution of hydroxylamine hydrochloride (28.17 g, 405 mmol) in water (18 ml). A white precipitate was formed immediately. The mixture was cooled rapidly and the solid removed by filtration and washed with EtOH (40 ml). The filtrate was then returned to the reaction flask and 4-nitrocinnamic acid (30 g, 155 mmol) was added. The mixture was heated to reflux overnight. The resulting mixture was cooled to 0° and the precipitate filtered off and the solid washed with EtOH (50 ml), water (50 ml) and finally EtOH (50 ml) to give the title compound as a pale yellow solid (16 g, 49%). δH (D2O) 8.31 (2H, d, J 8.7 Hz, ArH), 7.69 (2H, d, J 8.7 Hz, ArH), 4.81 (1H, app. dd. J 7.2, 7.1 CHNH2), 2.94 (1H, dd, J 16.4, 7.7 Hz, CHAHB) and 2.86 (1H, dd, J 16.4 and 6.7 Hz, CHAHB); m/z (ES+, 60V) 211 (MH+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C@H:15]2[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:21])[CH2:16]2)[CH:9]=1)=[O:6].[C:27](O)(=O)C.C([BH3-])#N.[Na+].C=O.C(=O)(O)[O-].[Na+].[Cl-].[NH4+]>CO.ClCCl>[ClH:2].[Cl:2][C:3]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:4]=1[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C@H:15]2[CH2:20][CH2:19][N:18]([CH3:27])[C@@H:17]([CH3:21])[CH2:16]2)[CH:9]=1)=[O:6]
Reactant: CC(=O)O
Reactant: C[C@H]1C[C@@H](Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1
Agent: C=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1C[C@@H](Nc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C
Temperature: 0 °C
Reaction time: 18 h
Yield: 108.7 %

Procedure:
Dissolve 2-chloro-4-fluoro-N-((2S,4S)-3-(2-methyl-piperidin-4-ylamino)-phenyl)-benzamide hydrochloride (Example 39, 50 mg, 0.125 mmol) in methanol (5 mL). Add acetic acid (22 μL, 0.375 mmol) followed by sodium cyanoborohydride (11.8 mg, 0.188 mmol). Cool to 0° C. and add 37% formaldehyde (11.2 μL, 0.138 mmol). Warm to room temperature and stir for 18 hr. Add aqueous saturated sodium bicarbonate and dichloromethane. Separate organic layer and extract aqueous with dichloromethane (2×25 mL). Combine organic extracts, dry (MgSO4), filter, and concentrate in vacuo. Purify by column chromatography (0%-10% 2M NH3 in methanol/CH2Cl2) to yield an oil. Make the hydrochloride salt by sonication with one equivalent of ammonium chloride dissolved in methanol to yield 28 mg (54%) of the title compound: mass spectrum (ion spray): m/z 376.2 (M+1); 1H NMR δ (D2O/DCl, ppm) 7.71 (s, 1H), 7.90 (m, 3H), 7.16 (m, 2H), 7.02 (m, 1H), 3.82 (m, 1H), 3.48 (m, 1H), 3.12 (m, 1H), 2.98 (m, 1H), 2.68 (s, 3H), 2.15 (m, 2H), 1.83 (s, 1H), 1.72 (m, 1H), 1.20 (d, J=6.3 Hz, 3H); mp 91-4° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7](COC(=O)C(C)(C)C)[C:6]2=[O:31]>N.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=[O:31]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCCCC1
Agent: N
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCCCC1
Yield: 95.4 %

Procedure:
A solution of 6-methoxy-7-(3-piperidinopropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (2.35 g, 5.45 mmol) in 7M ammonia in methanol (50 ml) was stirred overnight at ambient temperature. The volatiles were removed under vacuum and the residue was triturated with ether, filtered and washed with ether followed by ether/methylene chloride (1/1) and dried under vacuum to give 6-methoxy-7-(3-piperidinopropoxy)-3,4dihydroquinazolin-4-one (1.65 g, 95%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([F:13])=[C:9]([CH:12]=1)[C:10]#[N:11])=[O:4].[OH:14][CH2:15][C@@H:16]1[NH:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:10]([C:9]1[CH:12]=[C:5]([C:3](=[O:4])[CH2:2][N:21]2[CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:17][C@@H:16]2[CH2:15][OH:14])[CH:6]=[CH:7][C:8]=1[F:13])#[N:11]
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Reactant: N#Cc1cc(C(=O)CBr)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)c2ccc(F)c(C#N)c2)[C@@H](CO)C1
Reaction time: 3 h

Procedure:
To a solution of 5-(bromoacetyl)-2-fluorobenzonitrile (13.1 g, 0.054 mol) in DMF (160 mL) was added tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate (13.1 g, 0.065 mol) and K2CO3 (11.77 g, 0.075 mol), and the mixture was stirred at r.t for 3 h. The mixture was washed with water, and extracted with EtOAc. The organic layer was washed with brine dried over Na2SO4 and concentrated in vacuum to give the desired product, which can be used for next step without further purification.