Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[CH2:3]1.N1(C2C=CC(S(N)(=O)=O)=CC=2)CCNCC1.FC1C=CC(S(N)(=O)=O)=CC=1.Cl[CH2:47][CH2:48][CH:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52](C)[CH2:51][O:50]1.C[C@H]1CNC[C@@H](C)N1.C1(C[C@H]2COC(=O)N2C(=O)C(C2C=CC=CC=2)C)C=CC=CC=1>>[C@H:49]1([CH2:48][CH2:47][N:7]2[C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]3[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:13][CH:14]=3)[CH2:3][C@H:2]2[CH3:1])[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52][CH2:51][O:50]1
Reactant: CC1COC(CCCl)c2ccccc21
Reactant: CC1CN(c2ccc(S(N)(=O)=O)cc2)CC(C)N1
Agent: CC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccccc1
Agent: C[C@@H]1CNC[C@H](C)N1
Agent: NS(=O)(=O)c1ccc(F)cc1
Product: C[C@@H]1CN(c2ccc(S(N)(=O)=O)cc2)C[C@H](C)N1CC[C@@H]1OCCc2ccccc21

Procedure:
Following the general procedure of EXAMPLE 49 and making non-critical variations 2-(isochroman-1-yl)ethanol-O-methanesulfonate (LXXX, 0.412 g) and 4-(3,5-dimethylpiperazin-1-yl)benzenesulfonamide [(IV), 0.433 g; prepared from 4-fluorobenzenesulfonamide, III, and cis-2,6-dimethylpiperazine, II (Aldrich), by the method of EXAMPLE 47] gives the title compound; mp 170-175 (decomp)°; MS (m/z) 429; IR (mineral oil) 1153, 1596, 1325, 1162 and 1096 cm-1.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4])([CH3:27])[CH3:26]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Reactant: CC(C)N
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC(C)C)[nH]n1
Yield: 46 %

Procedure:
As described for example 8b, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using isopropylamine instead of 4-aminomorpholine, to the title compound (50 mg, 46%), which was obtained as a white solid. MS: m/e=359.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:16][CH2:17][C:18]2[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=2)[CH:5]=[C:6]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:7]=1.[Br:32][C:33]1[C:34](Cl)=[N:35][C:36]([Cl:39])=[N:37][CH:38]=1>>[Br:32][C:33]1[C:34]([NH:1][C:2]2[CH:3]=[C:4]([CH2:16][CH2:17][C:18]3[CH:19]=[C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH:21]=[CH:22][CH:23]=3)[CH:5]=[C:6]([S:8]([NH:11][C:12]([CH3:14])([CH3:15])[CH3:13])(=[O:10])=[O:9])[CH:7]=2)=[N:35][C:36]([Cl:39])=[N:37][CH:38]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cc(N)cc(CCc2cccc(NC(=O)OC(C)(C)C)c2)c1
Reactant: Clc1ncc(Br)c(Cl)n1
Product: CC(C)(C)NS(=O)(=O)c1cc(CCc2cccc(NC(=O)OC(C)(C)C)c2)cc(Nc2nc(Cl)ncc2Br)c1
Yield: 44 %

Procedure:
The desired compound was prepared according to the procedure of Example B5, step G using tert-butyl [3-(2-{3-amino-5-[(tert-butylamino)sulfonyl]phenyl}ethyl)phenyl]carbamate and 5-bromo-2,4-dichloropyrimidine as the starting materials in 44% yield. LCMS for C27H33BrClN5O4SNa (M+Na)+: m/z=660.3, 662.3.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH:10]=[CH:11][N+:12]([O-])=O)=[CH:8][CH:7]=[CH:6][C:5]=1[O:15][CH3:16])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-]>>[CH:1]([C:4]1[C:5]([O:15][CH3:16])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][NH2:12])([CH3:3])[CH3:2]
Reactant: COc1cccc(C=C[N+](=O)[O-])c1C(C)C
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Product: COc1cccc(CCN)c1C(C)C
Yield: 99.4 %

Procedure:
Using a method similar to Example 659, Step 2, using 2-isopropyl-1-methoxy-3-(2-nitro-vinyl)-benzene (3.92 g, 17.7 mmol), LAH (53.1 mmol) and AlCl3 (53.1 mmol) gave 2-(2-isopropyl-3-methoxy-phenyl)-ethylamine (3.4 g) as a viscous oil. 1HNMR (CDCl3): 7.08 (t, 1H), 6.77-6.73 (m, 2H), 3.80 (s, 3H), 3.22 (m, 1H), 2.89 (m, 2H), 2.80 (m, 2H), 1.32 (d, 6H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:38])[CH:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:26][CH:25]=4)=[O:22])=[CH:16][C:15]=3[CH:39]=2)=[CH:7][CH:6]=1)=[O:4]>CO.C1COCC1.[OH-].[Na+]>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[CH:13][C:14]3[CH2:20][CH2:19][CH2:18][C:17]([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:38])[CH:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:26][CH:25]=4)=[O:22])=[CH:16][C:15]=3[CH:39]=2)=[CH:9][CH:10]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(C(=O)O)cc4)ccc3CCC2)cc1)C1CCOCC1
Yield: 86.3 %

Procedure:
A mixture of 2-(4-methoxycarbonylphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-6,7-dihydro-5H-benzocyclohepten-8-carboxamide (0.25 g) in methanol (25 ml), THF (25 ml) and 1N NaOH (5 ml) was refluxed overnight. The reaction mixture was concentrated, and neutralized using 1N HCl. The precipitate was filtered, washed with water and dried to give 2-(4-carboxyphenyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-6,7-dihydro-5H-benzocyclohepten-8-carboxamide (0.21 g) as colorless amorphous.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[N:15]1([CH2:28][CH2:29][CH2:30][OH:31])[C:27]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[CH:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:52]1[C:56](=[O:57])[C:55]2=[CH:58][CH:59]=[CH:60][CH:61]=[C:54]2[C:53]1=[O:62]>O1CCCC1>[N:15]1([CH2:28][CH2:29][CH2:30][O:31][N:52]2[C:56](=[O:57])[C:55]3[C:54](=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:53]2=[O:62])[C:27]2[C:26]3[N:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:20]=[CH:19][C:18]=2[N:17]=[CH:16]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OCCCn1cnc2cnc3cccnc3c21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCCCn1cnc2cnc3cccnc3c21
Reaction time: 8 h
Yield: 78.1 %

Procedure:
Diisopropyl azodicarboxylate (1.01 mL, 6.05 mmol) was added dropwise to a stirred solution of 3-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propan-1-ol (1.15 g, 5.04 mmol), triphenylphosphine (1.59 g, 6.05 mmol), and N-hydroxyphthalimide (0.986 g, 6.05 mmol) in tetrahydrofuran (25 mL) at 0° C. The reaction was allowed to warrn to room temperature and was stirred overnight. The product was isolated by filtration and washed with a minimal amount of tetrahydrofuran to afford 1.47 g of 2-[3-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)propoxy]-1H-isoindole-1,3(2H)-dione as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([OH:27])=O)=[CH:22][CH:23]=3)[C:18]([CH3:28])=[C:17]2[CH3:29])=[CH:11][CH:10]=1)#[N:2].[C:30]1([CH:36]([NH2:39])[CH2:37][CH3:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([NH:39][CH:36]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:37][CH3:38])=[O:27])=[CH:22][CH:23]=3)[C:18]([CH3:28])=[C:17]2[CH3:29])=[CH:11][CH:10]=1)#[N:2]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C#N)cc2)c2ccc(C(=O)O)cc12
Reactant: CCC(N)c1ccccc1
Product: CCC(NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C#N)cc1)c1ccccc1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using 1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid, and 1-phenylpropan-1-amine instead of the (S)-1-(4-bromophenyl)ethanamine. ESI-MS (m/z): 498 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][CH:23]([CH3:29])[CH2:24][O:25][CH2:26][CH2:27][OH:28]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][CH:23]([CH3:29])[CH2:24][O:25][CH2:26][CH2:27][OH:28])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: CC(N)COCCO
Product: CC(COCCO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
Prepared by the method of example 2 step a), using the product of example 4, step b) and (+/−)-2-[2-aminopropoxy]ethanol,
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[N:8][NH:9]2)=[CH:5][CH:4]=1.I>>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([OH:2])[CH:11]=2)[CH:7]=[N:8]1
Reactant: COc1ccc2cn[nH]c2c1
Agent: I
Product: Oc1ccc2cn[nH]c2c1
Yield: 85.5 %

Procedure:
A mixture of 6-methoxy-1H-indazole (560 mg, 3.8 mmol) and HI (2.4 mL 48%) was heated to reflux for 4 h. The mixture was extracted with CH2Cl2. The combined organic layers were washed with water, brine, concentrated in vacuo, and purified by column chromatography (CH2Cl2/MeOH=60/1) to give 1H-indazol-6-ol (intermediate 43) (436 mg, 86%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:37])[C:14]1[CH:19]=[C:18]([CH:20]=[N:21][O:22][CH2:23][CH:24]=[O:25])[C:17]([F:26])=[C:16]([F:27])[C:15]=1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=1[F:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:38][Mg]Br>O1CCCC1>[Si:1]([O:8][CH2:9][CH2:10][O:11][NH:12][C:13](=[O:37])[C:14]1[CH:19]=[C:18](/[CH:20]=[N:21]/[O:22][CH2:23][CH:24]([OH:25])[CH3:38])[C:17]([F:26])=[C:16]([F:27])[C:15]=1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([I:35])=[CH:31][C:30]=1[F:36])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCONC(=O)c1cc(C=NOCC=O)c(F)c(F)c1Nc1ccc(I)cc1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)CO/N=C/c1cc(C(=O)NOCCO[Si](C)(C)C(C)(C)C)c(Nc2ccc(I)cc2F)c(F)c1F
Temperature: -78 °C
Reaction time: 8 h

Procedure:
N-[2-(t-butyldimethylsilanyloxy)-ethoxy]-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-[(2-oxo-ethoxyimino)-methyl]-benzamide (60 mg, 0.092 mmol) prepared in Process A was dissolved in anhydrous tetrahydrofuran (2.0 mL) under an argon atmosphere. This reaction solution was cooled to −78° C., and then 0.93 M methyl magnesium bromide (0.25 mL) was added thereto. The reaction solution was allowed to gradually warm to room temperature, and stirred for eight hours. The reaction was quenched with saturated aqueous solution of ammonium chloride, and the solution was extracted with ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:13]([NH2:16])(=[O:15])=[O:14])[C:9]([OH:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19](OC)(OC)OC>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:9]([CH3:11])([CH3:10])[O:12][C:17]([O:18][CH3:19])=[N:16][S:13]2(=[O:14])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(O)C(c1ccc(Br)cc1)S(N)(=O)=O
Reactant: COC(OC)(OC)OC
Solvent: CC(=O)O
Product: COC1=NS(=O)(=O)C(c2ccc(Br)cc2)C(C)(C)O1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 500 mg of 1-(4-bromophenyl)-2-hydroxy-2-methylpropane-1-sulfonamide in 2 ml of tetramethoxymethane and 0.5 ml of acetic acid was stirred at 100° C. for 3 hours. After the removal of the solvent under reduced pressure, the residue (565 mg) was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:19][C:14](=[O:16])[CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: O=C1C[C@H](NC(=O)OCc2ccccc2)C(=O)O1
Reaction time: 6 h
Yield: 75 %

Procedure:
To a suspension of 16.0 g N-benzyloxycarbonyl-L-aspartic acid (Z-Asp) in 24 ml toluene, was added 7.7 g of acetic anhydride, and the reaction was continued at room temperature for six hours to form N-benzyloxycarbonyl-L-aspartic anhydride (Z-Asp O).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17](Br)=[C:16]([CH3:21])[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:1][S:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[C:16]([CH3:21])[N:15]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: OB(O)c1ccccc1
Reactant: Cc1c(Br)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(-c2ccccc2)c(=O)c(C(=O)NCc2ccc(S(C)(=O)=O)cc2)cn1Cc1ccc(C#N)cc1
Temperature: 75 °C
Reaction time: 72 h

Procedure:
To a solution of 5-bromo-1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (preparation 8, 80 mg, 0.156 mmol), phenylboronic acid (27 mg, 0.22 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.016 mmol) in acetonitrile (2 mL) is added 2 M aqueous K2CO3 solution (0.16 mL, 0.32 mmol). After stirring for 72 h at 75° C., the reaction mixture is filtered, basified with aqueous NH4OH solution and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 59 mg (74% of theory); ESI mass spectrum: [M+H]+=512; Retention time HPLC: 0.98 min (Z003—001).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[Cl-].[NH4+].[O:34]1CCCC1>CO>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:34]
Reactant: C1CCOC1
Reactant: N#Cc1ccc(N2CCOCC2)cc1F
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=Cc1ccc(N2CCOCC2)cc1F
Temperature: 25 °C
Reaction time: 23.5 h
Yield: 68 %

Procedure:
To a solution of 2-fluoro-4-(morpholino)-benzonitrile (2.82 g, 13.7 mmol) in tetrahydrofuran (27 ml) under a nitrogen atmosphere was added dropwise a 1.5 M solution of DIBAL-H in toluene (18.3 ml, 27.3 mmol) during 13 minutes and the resulting mixture stirred for 23.5 hr at room temperature. The mixture was cooled to −50° C. and the excess DIBAL-H deastoyed by careful addition of methanol (27 ml). The mixture was then stirred at room temperature for 10 mins, saturated ammonium chloride (27 ml) added and the resulting mixture stirred at room temperature for 40 mins., and then evaporated under reduced pressure to a yellow solid. This solid was partitioned between dichloromethane (120 ml) and water (120 ml) and solid potassium carbonate added until the aqueous phase was pH10. The phases were separate via a hyrophobic frit and the organic phase evaporated and the residue purified by a Biotage™ column (40 g, silica) eluting with cyclohexane:ethyl acetate: (7:3) to give 2-fluoro-4-(morpholino)-benzaldehyde (1.96 g, 68%) as a white solid.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][C:70]([N:73]3[CH2:78][CH2:77][CH:76]([CH3:79])[CH2:75][CH2:74]3)=[CH:71][CH:72]=2)[C:56]=1[CH3:80].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[N:69][C:70]([N:73]5[CH2:74][CH2:75][CH:76]([CH3:79])[CH2:77][CH2:78]5)=[CH:71][CH:72]=4)[C:56]=3[CH3:80])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccc(N3CCC(C)CC3)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCC(C)CC3)nc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.024 g, 0.050 mmol), 2,5-dimorpholinopyridin-3-amine (0.098 g, 0.37 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(6-(4-methylpiperidin-1-yl)pyridin-3-yl)quinoline (0.12 g, 0.31 mmol), Pd2dba3 (0.011 g, 0.012 mmol) and sodium tert-butoxide (0.074 g, 0.77 mmol) in toluene (3.1 mL) at 100° C. for 5 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/methanol/ammonium hydroxide (90/9/1)) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(6-(4-methylpiperidin-1-yl)pyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.43 (1H, d, J=2.3 Hz), 7.84 (1H, dd, J=8.9, 2.4 Hz), 7.74 (1H, d, J=5.3 Hz), 7.59 (1H, dd, J=9.8, 1.8 Hz), 7.55 (1H, d, J=2.5 Hz), 7.35-7.45 (1H, m), 6.95 (1H, d, J=9.0 Hz), 6.40 (1H, d, J=2.5 Hz), 4.39 (2H, d, J=13.5 Hz), 3.59-3.80 (8H, m), 3.17 (4H, m), 2.94-3.04 (4H, m), 2.87 (4H, m), 2.13 (3H, s), 1.69 (3H, m), 1.14 (2H, m), 0.94 (3H, d, J=6.3 Hz). Mass Spectrum (ESI) m/e=616.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1=[C:3]([CH3:9])[C:4]([O:6][C:7]1=[O:8])=O.[NH2:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>CC(C)=O>[C:15]([C:14]1[CH:18]=[CH:19][C:11]([N:10]2[C:4](=[O:6])[C:3]([CH3:9])=[C:2]([CH3:1])[C:7]2=[O:8])=[CH:12][CH:13]=1)([OH:17])=[O:16]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: CC1=C(C)C(=O)N(c2ccc(C(=O)O)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
37.8 g (0.3 mol) of dimethylmaleic anhydride was slowly added to a solution of 41.1 g (0.3 mol) of p-aminobenzoic acid and 300 ml of acetone in a 250 ml flask at 10° C. The mixture was stirred for 2 hours to obtain a yellow precipitate. Thereafter, the precipitate was collected by filtration under reduced pressure and recrystallized from a solution of DMF/water (50:50 (w/w)) to give an intermediate. The intermediate was treated with sodium acetate and acetic anhydride at 85° C. for 4 hours, cooled to room temperature, and placed in an ice bath to obtain a precipitate. The precipitate was collected by filtration under reduced pressure and recrystallized from a solution of ethanol/water (50:50 (w/w)) to give N-(p-carboxyphenyl)dimethylmaleimide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[CH2:11]([N:29]=[C:30]=[O:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:11]([NH:29][C:30]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH2:10])=[O:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: NCCCCCCCCN
Product: CCCCCCCCCCCCCCCCCCNC(=O)NCCCCCCCCN

Procedure:
36 grams (.25 mole) of 1,8 diaminooctane was reacted with 20 gms (0.068 mole) octadecyl isocyanate as in Example 2. Yield: 26.6 gms, melting point 120°-145°-156°C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[F:27].C(=O)([O-])[O-].[Na+].[Na+].Cl>C1(C)C=CC=CC=1.CN(C=O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:20][C:19]=1[F:27]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(OCC(F)(F)F)c(-c2ccc(Cl)c(F)c2)c1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
5-Bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (4.00 g, 13.3 mmol; CAN 1211586-75-2) was dissolved in toluene (90 mL) and DMF (2.0 mL) to give a colorless solution. Then B-(4-chloro-3-fluorophenyl)-boronic acid (2.56 g, 14.7 mmol; CAN 137504-86-0), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (544 mg, 667 μmol) and aqueous sodium carbonate solution (53.3 ml, 107 mmol, 2 M) were successively added under stirring in an argon atmosphere. The reaction mixture was stirred 2.5 h at 90° C. Subsequently the reaction mixture was cooled to ambient temperature, poured into ice-water (300 mL), acidified with 2 N HCl (120 mL) and extracted with isopropyl acetate (3×200 mL). The organic layers were combined, dried with Na2SO4 and concentrated in vacuo. The residue was digested with a mixture of n-heptane and isopropyl acetate (10 mL/2 mL) at ambient temperature, filtered off and washed with isopropyl acetate/n-heptane 1:5 (2×3 ml). The resulting brown solid was digested with dichloromethane (10 mL) at ambient temperature to give the title compound (2.57 g, 55%) after filtration and drying as off-white solid; MS (EI) 347.9 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].Cl[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][C:26]=1[N+:31]([O-:33])=[O:32]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])[CH2:3]1
Reactant: CC1CC(=O)C=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC1CC(=O)C=C(c2ccncc2[N+](=O)[O-])C1
Temperature: 110 °C
Yield: 48 %

Procedure:
To a solution of 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (1.0 equiv.) in degassed dioxane (0.5 M) and 2M Na2CO3 (2 equiv.) was added 4-chloro-3-nitropyridine (1.3 equiv.) and Pd(dppf)Cl2-DCM (0.05 equiv.). The reaction was placed under a reflux condenser and heated in an oil bath to 110° C. for 1 h. Cooled to room temperature, filtered through a pad of Celite, washed the pad with ethyl acetate and concentrated the filtrate under vacuo. The residue was further pumped at 80° C. on a rotary evaporator for one hour to remove boronate by-products (M+H=101) via sublimation. The residue was partitioned between brine and ethyl acetate, and the layers were separated, the aqueous phase was further extracted with ethyl acetate (4×), the organics were combined, dried over sodium sulfate, filtered, and concentrated. The crude was purified via silica gel chromatography loading in DCM and eluting with 2-50% ethyl acetate and hexanes. The pure fractions were concentrated in vacuo to yield an orange oil. The oil was placed under high vacuum (˜500 mtorr) with seed crystals overnight to yield an orange solid. The solid was further purified via trituration in hexanes to yield 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enone (48% 2 steps). LC/MS=233.2 (M+H); Rt=0.69 min, LC=2.70 min. 1H-NMR (400 MHz, CdCl3) δ ppm: 9.31 (s, 1H), 8.88 (d, J=5.1, 1H), 7.30 (d, J=5.1, 1H), 6.00 (d, J=2.4, 1H), 2.62 (dd, J=16.4, 3.5, 1H), 2.53-2.34 (m, 3H), 2.23 (dd, J=16.1, 11.7, 1H), 1.16 (d, J=6.3, 3H).