Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:3]1[CH2:23][C@@H:22]2[C@:9]([CH3:27])([CH2:10][C@H:11]([OH:26])[C@H:12]3[C@H:21]2[CH2:20][CH2:19][C:18]2[C@:13]3([CH3:25])[CH:14]=[CH:15][C:16](=[O:24])[CH:17]=2)[C@H:4]1[C:5](=[O:8])[CH2:6]O)#[N:2].[O:28]1[CH:33]=[CH:32][CH2:31][CH2:30][CH2:29]1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[O:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1[CH2:6][C:5](=[O:8])[C@@H:4]1[C@:9]2([CH3:27])[C@H:22]([C@H:21]3[C@H:12]([C@@H:11]([OH:26])[CH2:10]2)[C@:13]2([CH3:25])[C:18](=[CH:17][C:16](=[O:24])[CH:15]=[CH:14]2)[CH2:19][CH2:20]3)[CH2:23][C@H:3]1[C:1]#[N:2]
Reactant: C[C@]12C[C@H](O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1C[C@@H](C#N)[C@@H]2C(=O)CO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: C[C@]12C[C@H](O)[C@H]3[C@@H](CCC4=CC(=O)C=C[C@@]43C)[C@@H]1C[C@@H](C#N)[C@@H]2C(=O)CC1CCCCO1

Procedure:
The process of claim 9 which additionally comprises reacting (VI) with 2,3-dihydropyran and pyridinium tosylate to produce (VII) 21-tetrahydropyranyl-16α-cyano-11β-hydroxy-3,20-dioxo-1,4-pregnadiene.
Reaction SMILES: [Br:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.O.O.[C:13](O)(=[O:17])[C:14](O)=[O:15]>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[Br:8])[NH:9][C:14](=[O:15])[C:13](=[O:17])[NH:10]2
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(Br)c(Br)cc1N
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cc(Br)c(Br)cc2[nH]c1=O
Temperature: 125 °C
Yield: 91.7 %

Procedure:
A mixture of 4,5-dibromo-1,2-phenylenediamine (1.862 g, 7.0 mmol) and oxalic acid dihydrate (1.06 g, 8.4 mmol) in 2N HCl (100 mL) was heated at 125° C. for 2 h then allowed to cool to 25° C. The solid was collected by vacuum filtration, washed with water and dried at 40° C. under 1 mmHg for 10 h affording 2.053 g (92%) of the title compound as a light brown powder. 1H NMR (DMSO-d6) 11.995 (s, 2H), 7.361 (s, 2H).
Reaction SMILES: [Cl:1]C(OC(Cl)=O)C.[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]2[C:11]=1[CH2:12][CH2:13][N:14]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([N:33]3[CH2:38][CH2:37][N:36](C)[CH2:35][CH2:34]3)[CH:26]=1)(=[O:24])=[O:23])[CH2:15]2.C(N(C(C)C)CC)(C)C.Cl>ClCCCl.CC(C)=O.ClCCl>[ClH:1].[CH3:8][O:9][C:10]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]2[C:11]=1[CH2:12][CH2:13][N:14]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[CH:26]=1)(=[O:24])=[O:23])[CH2:15]2
Reactant: COc1ccc(S(=O)(=O)N2CCc3c(OC)ccc(OC)c3C2)cc1N1CCN(C)CC1
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)=O
Solvent: ClCCCl
Product: COc1ccc(S(=O)(=O)N2CCc3c(OC)ccc(OC)c3C2)cc1N1CCNCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 1-chloroethylchloroformate (0.12 ml;1.11 mmol) and 5,8-dimethoxy-2-[4-methoxy-3-(4-methyl-1-piperazinyl)benzenesulfonyl]-1,2,3,4-tetrahydroisoquinoline (E21) (111 mg;0.223 mmol) in 1,2-dichloroethane (3 ml) was refluxed for 0.75 h, cooled, diluted with diisopropylethylamine (0.19 ml;1.11 mmol) and refluxed for a further 2.5 hrs. The solution was concentrated to a residue which was re-dissolved in methanol, refluxed for 1 hr and then stirred at room temperature for 24 h. The mixture was concentrated, and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried, concentrated to a residue and purified by column chromatography on silica gel using a methanol/dichloromethane solvent gradient. The title compound was prepared by dissolving the pure free base material from chromatography in acetone/dichloromethane and acidifying with 1M ethereal HCl (53 mg, 49%). MH+456/458.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: COc1ccc([N+](=O)[O-])cc1NS(C)(=O)=O
Agent: [Pd]
Solvent: CO
Product: COc1ccc(N)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-Methoxy-5-nitro-methanesulfonylaminobenzene (1 g) in methanol (20 ml) containing palladium on carbon (10%, 100 mg) was stirred at RT under hydrogen for 48 h. The mixture was filtered through celite then evaporated to give 2-methoxy-5-amino-methanesulfonylaminobenzene as a brown gum. This was used without purification in the following reaction.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].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.[Pd]>[CH2:10]([NH:16][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: CCCCCCN
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCCNc1ccc(C#N)cc1
Yield: 78.1 %

Procedure:
According to the general procedure B, 4-Chlorobenzonitrile (69 mg, 0.50 mmol) reacted with n-hexylamine (80 μl, 0.60 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (58 mg, 0.60 mmol) in toluene at 70° C. for 8 h to give the title compound as a solid (79 mg, 78%). On the other hand, the reaction of 4-chlorobenzonitrile (69 mg, 0.50 mmol) with n-hexylamine (61 mg, 0.60) using K3PO4 and DME also occurred in 92% yield to afford the title compound (93 mg) at 100° C. for 13 h. 1H-NMR (300 MHz, CDCl3): δ 7.39 (d, 2H, J=8.4 Hz), 6.54 (d, 2H, J=8.7 Hz), 4.34 (bs, 1H, —NH—), 3.13 (t, 2H, J=6.9 and 7.2 Hz). 13C{1H}-NMR (100 MHz, CDCl3): δ 151.43, 133.47, 120.60, 111.56, 97.69, 43.03, 31.37, 28.89, 26.55, 22.43, 13.88. GC/MS(EI): m/z 202 (M+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH:8]1[C:20]2[NH:19][C:18](=[O:21])[C:17](=[O:22])[NH:16][C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2>O1CCCC1>[N:1]1([CH:8]2[C:20]3[NH:19][C:18](=[O:21])[C:17](=[O:22])[NH:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Solvent: C1CCOC1
Product: O=c1[nH]c2c([nH]c1=O)C(N1CCNCC1)c1ccccc1-2
Reaction time: 72 h
Yield: 35.2 %

Procedure:
Piperazine (1.1 g, 12.8 mmol) was suspended in 15 ml of dry tetrahydrofuran at -20° C. 9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione (1.5 g, 6.4 mmol) was added over 25 min. and the temperature was slowly rised to room temperature while stirring. After 20 hours another portion of piperazine (0.55 g, 6.4 mmol) was added and stirring was continued for 72 hours. The reaction mixture was evaporated in vacuo to dryness and the remanence was suspended in 10 ml 6M HCl. The product was filtered off and washed with 1M HCl and dried to give 1.7 g of the crude product, which was purified by dissolving in aqueous sodium hydroxide and precipitated by adding to hydrochloric acid. The procedure was repeated and the product was finally washed with ethanol and dried to give 0.64 g (27%) of the title compound as a hydrochloride. M.p. 259°-263° C. 1H-NMR (DMSO-d6, δ): 2.65-3.15 (m, 8H), 4.7 (s, 1H), 7.17 (t, 1H), 7.34 (t, 1H), 7.45 (d, 1H), 7.57 (d, 1H), 8.93 (s, 2H), 11.8 (s, 1H), 12.3 (s, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:34]C(OC(C)(C)C)=O)=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH:31]3[CH2:33][CH2:32]3)[C:14]=2[N:15]2[CH2:21][C:20]([F:23])([F:22])[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1B(O)O>>[NH2:34][C:4]1[S:3][C:2]([C:44]2[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=2[F:42])=[N:6][C:5]=1[C:7]([NH:9][C:10]1[CH:11]=[N:12][N:13]([CH:31]2[CH2:32][CH2:33]2)[C:14]=1[N:15]1[CH2:21][C:20]([F:23])([F:22])[CH2:19][NH:18][CH2:17][CH2:16]1)=[O:8]
Reactant: OB(O)c1cc(F)ccc1F
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnn(C2CC2)c1N1CCN(C(=O)OC(C)(C)C)CC(F)(F)C1
Product: Nc1sc(-c2cc(F)ccc2F)nc1C(=O)Nc1cnn(C2CC2)c1N1CCNCC(F)(F)C1
Yield: 42 %

Procedure:
Following the procedure for Example 105, tert-butyl 4-(4-(2-bromo-5-(tert-butoxycarbonylamino)thiazole-4-carboxamido)-1-cyclopropyl-1H-pyrazol-5-yl)-6,6-difluoro-1,4-diazepane-1-carboxylate and 2,5-difluoro-phenylboronic acid was reacted to give 143 as a beige foam (60 mg, 42% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.92-7.84 (m, 2H), 7.17-7.08 (m, 1H), 7.07-6.99 (m, 1H), 6.15 (s, 2H), 3.68 (t, J=13.2 Hz, 2H), 3.52-3.32 (m, 5H), 3.11 (t, J=5.4 Hz, 2H), 1.95 (s, 1H), 1.26-1.20 (m, 2H), 1.08-1.00 (m, 2H). LCMS (ES+) m/z 496 (M+1).
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[CH:23])=[CH:18][CH:17]=1.C(N(CC)CC)C.O>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[O:14][N:13]=[C:2]([C:3]3[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=3)[CH:23]=2)=[CH:18][CH:17]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(C(Cl)=NO)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cc(-c3ccc(Cl)cc3)on2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution (70 ml) of methyl 4-[chloro(hydroxyimino)methyl]benzoate (1.65 g) and 4-chloro-ethynylbenzene (1.06 g) in tetrahydrofuran was added dropwise a solution (10 ml) of triethylamine (2.5 ml) in tetrahydrofuran under an argon atmosphere at 0° C. This mixture was stirred overnight at room temperature and poured into water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from hexane-tetrahydrofuran to give methyl 4-[5-(4-chlorophenyl)-3-isoxazolyl]benzoate (2.20 g, yield 91%) as colorless crystals. melting point: 225–226° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([C:22](=[O:27])NCOC)([CH3:21])[CH3:20])[CH:17]=2)[NH:12][C:11]=1[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([CH3:20])([CH3:21])[CH:22]=[O:27])[CH:17]=2)[NH:12][C:11]=1[C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCNC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNC(=O)OC(C)(C)C)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(C)(C)C=O)cc3c2CCNC(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of (2-{2-(3,5-dimethylphenyl)-5-[1-(methoxymethylcarbamoyl)-1-methyl-ethyl]-1H-indol-3-yl}ethyl)carbamic acid tert--butyl ester (296 mg in 5 mL dry tetrahydrofuran) at 0° C. was added 1.8 mL of a 1M lithium aluminum hydride solution in tetrahydrofuran and the mixture stirred at low temperature. After 1 hour, the reaction was quenched by the careful addition of 0.3M aqueous a sodium bisulfate solution. The resulting mixture was extracted with ethyl acetate and the organic portion washed successively with 0.3M aqueous sodium bisulfate, water and brine. This was then dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography on silica gel (hexane:ethyl acetate, 85:15) to give the title compound (253 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:3]=1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)cc1Oc1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)cc1Oc1cccc(C(F)(F)F)c1

Procedure:
136 G. of 4-chloro-2-(3-trifluoromethyl-phenoxy)-benzoic acid are boiled at reflux for 2.5 hours in a mixture of 1000 ml. of methanol and 100 ml. of concentrated sulfuric acid. After concentration of the mixture under vacuum, the residue is poured on to ice and extracted with benzene. The benzene extracts are washed with water, aqueous sodium bicarbonate solution and again with water. After evaporation of the benzene, there is obtained 4-chloro-2-(3-trifluoromethylphenoxy)-benzoic acid methyl ester in the form of an oil.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[N+:18]([O-])([O-:20])=[O:19].[K+]>OS(O)(=O)=O.[OH-].[K+]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[C:4]([C:14]([F:16])([F:17])[F:15])[C:3]=1[N+:18]([O-:20])=[O:19]
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1[nH]c2cc(Br)cc(C(F)(F)F)c2[nH]c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c2cc(Br)c([N+](=O)[O-])c(C(F)(F)F)c2[nH]c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
To a solution of 7-bromo-5-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (31 mg, 0.10 mmol) in concentrated H2SO4 (0.5 mL) at 0° C. was added KNO3 (11 mg, 0.109 mmol, Baker). The mixture was stirred at 0° C. for 0.5 h, then at room temperature for 12 h and it was poured into ice water (2 g). The precipitate was collected by filtration, affording 32 mg (91.4%) of crude title compound. It was dissolved in 1N KOH (1 mL) and filtered. The filtrate was acidified to pH 2 with 4N HCl to give a brown precipitate, which was collected by filtration, and dried at 50° C. for 4 h, affording pure title compound (28 mg, 79.3%) as a yellow powder. Mp: 292°-94° C., IR (KBr, cm-1): 3412, 3068, 3937, 1718, 1556, 1387. 1H NMR (DMSO-d6): δ7.644 (s, 1H), 11.721 (s, 1H), 12.423 (s, 1H). HRMS: calcd for C9H3ClF3N3O4 (M+) m/z: 352.9258, found: 352.9259.
Reaction SMILES: [CH2:1]([N:21]=[N+]=[N-])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.C1COCC1>[CH2:1]([NH2:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCN=[N+]=[N-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCCN
Yield: 51 %

Procedure:
The crude azide was reduced to the title amine as follows: To a magnetically stirred solution of 132 mg (0.43 mmol) of arachidonyl azide in 3 mL of dry diethyl ether was added 4 mL of 1.0 M solution of lithium aluminum hydride (4.0 mmol) in THF dropwise at room temperature. The reaction mixture was refluxed for 3 hours and then quenched with wet diethyl ether. The white suspension was filtered, and the filtrate was evaporated to dryness. Chromatography on silica gel (10–50% MeOH in dichloromethane) gave 65 mg (51%) of arachidonylamine as a white solid: TLC (20% EtOAc—CH2Cl2) Rf 0.33; 1H NMR (200 MHZ, CDCl3) δ5.38 (m, 8H), 2.82 (m, 6H), 2.70 (t, J=6.6 Hz, 2H), 2.08 (m, 4H), 1.40 (m, 4H), 1.26 (m, 6H), 0.89 (t, J=6.4 Hz, 3H). Anal. (C20H35N)C, H, N.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-])=O)[C:5]=2[N:4]=[CH:3]1>CCO.[Pd]>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2c([N+](=O)[O-])cccc21
Agent: [Pd]
Solvent: CCO
Product: Cn1cnc2c(N)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
A suspension of 1-methyl-4-nitro-1H-benzimidazole [2.1 g, 12 mmol, prepared as described in Viktor Milata et. al., Org. Prep. Proced. Int. 25 (6), 703-704 (1993)] and 5% Pd/C (0.21 g) in EtOH (40 mL) was vigorously stirred under an atmosphere of hydrogen at rt overnight. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to afford the title compound (1.65 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[C:24]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=2[S:22](=[O:31])(=[O:30])[N:21]=1.CCOCC.[K+].[Br-]>C(Cl)(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:24]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=3[S:22](=[O:30])(=[O:31])[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Cc1ccc2c(c1)C(Cl)=NS2(=O)=O
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)C(NCCCOc1cccc(CN3CCCCC3)c1)=NS2(=O)=O
Reaction time: 0.25 h

Procedure:
To a refluxing solution of 3-[3-(1-piperidinylmethyl)phenoxy]propylamine (1.33 g, 5.36 mmoles) in dried chloroform (50 ml) under dry nitrogen is added over 45 minutes a solution of 3-chloro-5-methyl-1,2-benzisothiazole 1,1-dioxide (1.21 g, 5.64 mmoles) in dried chloroform (25 ml) while maintaining reflux. After the addition is complete refluxing is continued for 15 minutes and the clear brown solution is allowed to come to room temperature. Evaporation in vacuo gives a tan solid which cannot be crystallized. Column chromatography on silica gel using methylene chloride/methanol/ammonium hydroxide 95/5/0.5 as eluent gives the free methanol base as a brown foam, 1.22 g. Trituration with ether gives an off-white colored solid, 0.73 g, m.p. 120°-124° C. Recrystallization from ethyl acetate/pentane and finally ethyl acetate gives the pure product, 0.169 tan solid, m.p. 120°-4° C. IR (KBr) 3300, 2938, 1622, 1530 cm-1 ; NMR (in DMSO) 6.8-8.0 (7 H,m), 4.05 (2H,t), 3.76 (2H,t), 1.37 (6H,s), 1.4 (6H,s), 2.0-2.4 (6H,m), 2.5 (3H,s), 3.4 (2H,s), 3.6 (2H,t), 4.1 (2H,t), 6.7-8.0 (7H,m), 9.3 (1H,n).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:18]([CH3:22])[C:19](F)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH3:29].O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:18]([CH3:22])[C:19]([NH2:29])=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: N
Reactant: CC(C(=O)F)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Solvent: C1CCOC1
Solvent: O
Product: CC(C(N)=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanoyl fluoride (0.32 mmol) in anhydrous THF (5 mL) at −78° C. was bubbled NH3 (g) for 10 minutes. The reaction mixture was sealed and stirred at −78° C. for 15 min and at rt for 1 hr. Water (100 mL) was added, the reaction mixture was extracted with ethyl acetate (100 mL), dried (Na2SO4), and concentrated to give 115 mg (100% yield) of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-phenylpropanamide, the NMR spectrum of which was consistent with the desired structure.
Reaction SMILES: [K+].[C:2]([N:5]1[C:14]2[N:13]=[CH:12][C:11]([C:15]3[CH:23]=[N:22][CH:21]=[C:20]([F:24])[C:16]=3[C:17]([O-:19])=[O:18])=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=[O:4])[NH2:3].IC.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:27][O:18][C:17](=[O:19])[C:16]1[C:20]([F:24])=[CH:21][N:22]=[CH:23][C:15]=1[C:11]1[CH:12]=[N:13][C:14]2[N:5]([C:2](=[O:4])[NH2:3])[CH2:6][CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)N1CCCc2cc(-c3cncc(F)c3C(=O)[O-])cnc21
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(F)cncc1-c1cnc2c(c1)CCCN2C(N)=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.3 %

Procedure:
To a vial is added 3-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-5-fluoro-isonicotinic acid potassium salt (100 mg, 0.28 mmol) in 2 ml of DMF, followed by the addition of iodomethane (48 mg, 0.34 mmol) and potassium carbonate (47 mg, 0.34 mmol). The reaction mixture is stirred at room temperature for 18 hours. The reaction mixture is concentrated in vacuo. The residue is diluted with EtOAc, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product. Purification by the flash column chromatography affords 28 mg of the titled product.
Reaction SMILES: [H-].[K+].[CH3:3][C@H:4]1[C@H:9]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:7]2([CH3:8])[C@@H:6]([OH:24])[CH2:5]1)[C@:18]1([CH3:19])[C:13]([NH:14][C:15](=[O:23])[CH2:16][CH2:17]1)=[CH:12][CH2:11]3.[CH2:25](Br)[CH:26]=[CH2:27].Cl>>[CH3:3][C@H:4]1[C@H:9]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:7]2([CH3:8])[CH:6]([O:24][C:26](=[CH2:25])[CH3:27])[CH2:5]1)[C@:18]1([CH3:19])[C:13]([NH:14][C:15](=[O:23])[CH2:16][CH2:17]1)=[CH:12][CH2:11]3
Reactant: C=CCBr
Reactant: C[C@@H]1C[C@H](O)[C@@]2(C)CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@H]12
Agent: Cl
Agent: [H-]
Agent: [K+]
Product: C=C(C)OC1C[C@@H](C)[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 1 h

Procedure:
Potassium hydride (40% oil dispersion, 114 mg, 2 mmol) was added to a 5 mL round bottomed flask fitted with a stirrer bar and a rubber septum. The potassium hydride dispersion was washed with dry hexane (2×5 ml) to remove the mineral oil and 3 mL of dry dimethylformamide was added to the flask. Azasteroid (11) (158 mg, 0.5 mmol) was added to the dispersion and the solution stirred at 0° under nitrogen for 1 h. Then allyl bromide (183 mg, 1.5 mmol) was syringed into the solution and the mixture stirred for 2 h at room temperature. The entire solution was poured into 5 mL of 1N HCl and the mixture extracted with 5×2 mL of dichloromethane. The pooled organic layer was washed with 3×5 mL of saturated brine. The product was flash chromatographed with 3/1 dichloromethane/ethyl acetate. Recovered product (78 mg, 0.2 mmol, 44%) δH (CDCl3) 0.89 (s, 3H), 0.99 (d, J=7 Hz,), 1.06 (s, 3H), 3.60 (m, J=7 Hz, 1H), 3.95 (dd, J=12 Hz, J=5 Hz), 4.64 (dd, J=12 Hz, J=5 Hz), 5.1 (m, 2H), 5.79 (m, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:38]=[CH:37][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=4)[C:21]4[N:22]([CH:24]=[CH:25][N:26]=4)[CH:23]=3)[C:13]=2[CH3:36])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:39].[CH2:40]([OH:42])[CH3:41]>>[ClH:39].[CH2:40]([O:42][C:34](=[NH:35])[C:31]1[CH:30]=[CH:29][C:28]([NH:27][C:20]2[C:21]3[N:22]([CH:24]=[CH:25][N:26]=3)[CH:23]=[C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:37]=[CH:38][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=4)[C:13]=3[CH3:36])[N:19]=2)=[CH:33][CH:32]=1)[CH3:41]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn2ccnc2c(Nc2ccc(C#N)cc2)n1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(Nc2nc(-c3cccc(NC(=O)c4ccc(C(C)(C)C)cc4)c3C)cn3ccnc23)cc1
Temperature: 0 °C

Procedure:
4-tert-Butyl-N-{3-[8-(4-cyano-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-2-methyl-phenyl}-benzamide is slurried in 200 mL ethanol (200 proof) and the reaction cooled to 0° C. in an ice bath. The reaction is then saturated with hydrogen chloride gas and allowed to gradually warm to rt over 16 hrs with stirring. The solvent is removed in vacuo and the resulting tan solid 4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-imidazo[1,2-a]pyrazin-8-ylamino}-benzimidic acid ethyl ester hydrochloride (500 mg) is used without further purification.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH:2]([CH2:6][CH2:7][CH3:8])[CH2:3][CH2:4][CH3:5].Cl.[NH2:12][CH:13]([C:18]([NH2:20])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16]>>[CH2:3]([CH:2]([CH2:6][CH2:7][CH3:8])[C:1]([NH:20][C:18](=[O:19])[C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[NH2:12])=[O:9])[CH2:4][CH3:5]
Reactant: CC(C)CC(N)C(N)=O
Reactant: CCCC(CCC)C(=O)Cl
Agent: Cl
Product: CCCC(CCC)C(=O)NC(=O)[C@@H](N)CC(C)C

Procedure:
The title compound was prepared from valproyl chloride (2.0 g, 12.3 mmole) and DL-leucinamide hydrochloride (2.0 g, 12.05 mmole), according to the procedure described in Ex. 1. 2.36 g (9.2 mmole, 76%) of a white crystalline solid, mp 151°-2° C., was thus obtained.