Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[F:30])[NH:26][CH2:25][CH2:24]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[F:30])[N:26]([C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=1)[CH2:25][CH2:24]2
Reactant: Fc1cc2c(cc1F)NCC2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CCc3cc(F)c(F)cc32)nc(N2CCOCC2)cc1=O
Yield: 42.8 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 232 mg of 5,6-difluoroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 167 mg of 2-[2-(5,6-difluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of an off-white powder, the characteristics of which are the following:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=O.O.[NH2:12][NH2:13]>C(O)C>[N:6]1[CH:7]=[CH:8][N:9]=[CH:10][C:5]=1[C:3]([NH:12][NH2:13])=[O:2]
Reactant: COC(=O)c1cnccn1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cnccn1
Temperature: 78 °C
Yield: 67.7 %

Procedure:
To the title compound of Example 19.1 (1.28 mg, 9.3 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.54 mL, 11.1 mmol) and then heated at 78° C. overnight. The reaction mixture was cooled and concentrated in vacuo. The residue was triturated with ethyl acetate, filtered and dried to give the title product as a yellow solid (870 mg, 68%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.[F:15][CH2:16][CH:17](O)[CH2:18][F:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[F:15][CH2:16][CH:17]([N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1)[CH2:18][F:19]
Reactant: OC(CF)CF
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(C(CF)CF)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of Pyrazole-4-boronic acid pinacol ester (6.6 g, 34 mmol, 1 eq.) in dry THF (150 mL) was added 1,3-Difluoro-2-propanol (5.1 g, 51 mmol, 1.5 eq.) followed by triphenylphosphine (13.5 g, 51 mmol, 1.5 eq.) and Diisopropyl azodicarboxylate (10.5 g, 51 mmol, 1.5 eq.) at 0° C. under nitrogen atmosphere. After the addition, the reaction mixture was stirred at RT for 48 h. The reaction mixture was concentrated under vacuum and the residue was solubilized in EtOAc, washed with water (three times), dried over sodium sulfate, filtered and concentrated. The crude product was redissolved in EtOAc and Pet. Ether was added. The precipitate obtained was filtered off and the filtrate concentrated under reduced pressure to give the title compound as a oil (contaminated with triphenyl phosphine oxide).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[CH2:9]([NH2:11])[CH3:10].O=O>[Pd]>[CH2:9]([NH:11][C:7](=[O:8])[C:3]1[CH:4]=[CH:5][CH:6]=[N:1][CH:2]=1)[CH3:10]
Reactant: CCN
Reactant: O=Cc1cccnc1
Agent: [Pd]
Agent: O=O
Product: CCNC(=O)c1cccnc1
Reaction time: 2 h
Yield: 47 %

Procedure:
In a 100 ml three-necked flask were charged 2 g of pyridine-3-aldehyde, 50 g of a 30 weight percent aqueous ethylamine solution and 3 g of the same commercially available palladium catalyst as in Example 1. The reaction was conducted at a reaction temperature of 30° C. for 2 hours by introducing oxygen at a rate of 10 l/hour into the flask from its gas inlet equipped with a filter to give nicotinic acid monoethylamide at a yield of 47%.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([CH2:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[OH:25][C:26]1([CH2:32][CH2:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.Cl>>[OH:25][C:26]1([CH2:32][CH2:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:31][CH2:30][N:29]([CH2:1][C@@H:3]2[C@@H:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:6][N:5]([CH2:14][C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:4]2)[CH2:28][CH2:27]1
Reactant: OC1(CCCc2ccccc2)CCNCC1
Reactant: O=C[C@H]1CN(CC(=O)OCc2ccccc2)C[C@@H]1c1ccccc1
Agent: Cl
Product: O=C(CN1C[C@H](CN2CCC(O)(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1)OCc1ccccc1
Yield: 69.7 %

Procedure:
The title compound was prepared from 30 mg (0.094 mmol) of 2-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)acetic acid, benzyl ester (from EXAMPLE 8, Step C) and 28 mg (0.10 mmol) of 4-hydroxy-4-(3-phenylpropyl)-piperidine.HCl using a procedure analogous to that described in EXAMPLE 1, Step J to provide 34.5 mg (70%) of the title compound: RF: 0.26 (19:1 v/v CH2Cl2/MeOH); 1H NMR (300 MHz) δ 1.24-1.69 (m, 8H), 2.16-3.14 (m, 14H), 3.43 (ABq, J=16.8, 2H), 5.16 (ABq, J=12.2, 2H), 7.15-7.37 (m, 15H).
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=1)[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[OH-].[Na+]>CO>[CH3:1][N:2]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:21][CH:22]=1)[C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10]
Reactant: CCOC(=O)c1ccc(N(C)C(=O)c2ccccc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1C(=O)N(C)c1ccc(C(=O)O)cc1
Yield: 67.5 %

Procedure:
A sample of 1.51 g of sodium hydride (60% in oil) is washed with hexane under argon to remove the oil. To the washed sodium hydride is added 5 ml of N,N-dimethylformamide. To this mixture is added dropwise a solution of 8.69 g of ethyl 4-[(2-methylbenzoyl)amino]benzoate in 20 ml of dimethylformamide. The mixture is stirred at room temperature for 0.5 hour and then 5.23 g of methyl iodide is added. The mixture is stirred at room temperature for 16 hours. The mixture is diluted with water and extracted with dichloromethane. The extract is dried (Na2SO4), concentrated to reduce the volume and the solution filtered through a thin pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give 11 g of an oil (1:1 mixture of product and N,N-dimethylformamide). The preceding product, ethyl 4-[N-methyl-N-(2-methylbenzoyl)amino]benzoate, (11 g) is dissolved in 30 ml of methanol and 25 ml of 2N NaOH added. The mixture is refluxed for 2 hours and the solvent removed. The residue is extracted with ether (discard) and the remaining residue dissolved in 50 ml of water. The basic solution is acidified with 2N citric acid and the solid filtered off and washed with water. The product is air dried to give 6.72 g of crystals, m.p. 187°-190° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:26])=[C:12]([N:16]2[CH2:19][CH:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.C(N(CC)CC)C.[C:34](Cl)(=[O:37])[CH2:35][CH3:36].[OH-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[F:26][C:11]1[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][C:12]=1[N:16]1[CH2:19][CH:18]([CH:20]2[CH2:25][CH2:24][N:23]([C:34](=[O:37])[CH2:35][CH3:36])[CH2:22][CH2:21]2)[CH2:17]1
Reactant: CCC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CC(C3CCNCC3)C2)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCC(C2CN(c3cccc(CO)c3F)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
4-{1-[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (120 mg) and triethylamine (145 mg) were mixed with dichloromethane (3 ml), and propanoyl chloride (48 mg) was added thereto, followed by stirring at room temperature for 1 hour. A 1 M aqueous NaOH solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3 ml), and a 1 M TBAF/THF (0.5 ml) solution was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous ammonium chloride solution and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 1-(4-{1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}piperidin-1-yl)propan-1-one (98 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:22]=[CH:21][C:17]([C:18](F)=O)=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[O:7][C:18]([C:17]3[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:23])[F:24])=[CH:22][CH:21]=3)=[N:11][C:4]=2[CH:3]=1
Reactant: O=C(F)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(F)ccc1C(=O)O
Product: O=c1oc(-c2ccc(C(F)(F)F)cc2)nc2cc(F)ccc12
Yield: 91.3 %

Procedure:
When the reaction conditions of Example 1 are employed but 11.6 g of 4-fluoroanthranilic acid and 14.4 g of p-trifluoromethylbenzoyl fluoride are used, 21.1 g (91%) of 7-fluoro-2-(p-trifluoromethylphenyl)-4H-3,1-benzoxazin-4-one of melting point 137°-139° C. are obtained.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)CCC.I[C:24]1[C:25]([NH:38][C@@H:39]2[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]2)=[N:26][C:27]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[N:28][C:29]=1[O:30][CH3:31].CCN(CC)CC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.O1CCOCC1>[S:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[C:24]1[C:25]([NH:38][C@@H:39]2[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]2)=[N:26][C:27]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[N:28][C:29]=1[O:30][CH3:31]
Reactant: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1I
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1nc(N2CCOCC2)nc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1-c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Tributylstannylbenzothiazole (221 mg, 0.520 mmol), Compound 21 (150 mg, 0.289 mmol), Tetrakis(triphenylphosphine)palladium (67 mg, 0.0578 mmol), and CuI (11 mg, 0.0578 mmol) were combined. Dioxane (4 mL) was added followed by Et3N (161 μL, 1.16 mmol) and the mixture was degassed and heated to reflux for 2 h. The solution was cooled to room temperature and an aqueous 10% KF solution was added and the mixture was stirred for 30 min. The mixture was diluted with EtOAc and washed with water, brine, dried (MgSO4), filtered and evaporated to dryness. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane to give the title compound as a yellow solid. 1H NMR (CDCl3) δ 10.74 (br s, 1H), 7.86-7.82 (m, 2H), 7.41 (t, J=7.2 Hz, 1H), 7.27 (t, J=7.2 Hz, 1H), 4.25 (br s, 1H), 4.09 (s, 3H), 3.87 (br s, 4H), 3.78-3.76 (m, 4H), 3.52 (br s, 4H), 2.03 (br s, 1H), 1.90 (br s, 1H), 1.76-1.73 (m, 1H), 1.66-1.64 (m, 1H), 1.33 (s, 9H); LCMS 3.28 min, 527 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:16]4[N:17]=[CH:18][N:19]=[C:15]4[C:14]([NH:20][CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)=[N:13][CH:12]=3)=[CH:8][CH:9]=2)[CH2:4][NH:3]1.FC(F)(F)C(O)=O>ClCCl.O>[NH:24]1[CH2:23][CH2:22][CH:21]([NH:20][C:14]2[C:15]3[N:16]([N:17]=[CH:18][N:19]=3)[C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[C:2](=[O:1])[NH:3][CH2:4]4)=[CH:12][N:13]=2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc(-c3ccc4c(c3)CNC4=O)n3ncnc23)CC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCc2cc(-c3cnc(NC4CCNCC4)c4ncnn34)ccc21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 20.4 %

Procedure:
The product of Step 2 (64 mg, 0.14 mmol) is suspended in dichloromethane (0.5 mL), trifluoroacetic acid (0.25 mL) and H2O (3 drops). The reaction mixture is stirred and room temperature for 40 min. The mixture is purged with nitrogen and then basified to pH 9 with 2M NaOH (aq.). The aqueous layer is extracted with dichoromethane and ethyl acetate. The combined organics are dried (MgSO4) and solvent is removed in vacuo to yield the title compound as an off-white solid (10 mg, 20%). 1H-NMR (400 MHz, d6-DMSO) =1.13 (t, 2H, J=6.8), 1.57-1.70 (m, 2H), 2.58-2.72 (m, 2H), 3.02-3.08 (m, 2H), 4.13-4.30 (m, 1H), 4.50 (s, 2H), 7.81 (d, 1H, J=8), 7.92 (s, 1H), 8.03-8.11 (m, 2H), 8.18 (s, 1H), 8.63 (s, 1H), 8.69 (s, 1H). LCMS: Rt 6.55 min (86.9%), m/z (APCI) 350 (M+H)+.
Reaction SMILES: [Cl-].[NH4+:2].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1.CO>C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:9]=[C:8]([C:10](=[NH:2])[NH2:11])[CH:7]=[CH:6][N:5]=1
Reactant: [NH4+]
Reactant: N#Cc1ccnc(Cl)c1
Agent: [Cl-]
Solvent: CO
Solvent: Cc1ccccc1
Product: N=C(N)c1ccnc(Cl)c1
Temperature: 25 °C

Procedure:
To a suspension of ammonium chloride (10.7 g, 200 mmol) in 250 mL of dry toluene. was added a 2 M solution of Al(CH3) (100 mL, 200 mmol) in toluene dropwise under nitrogen at 0° C. The resulting reaction mixture was stirred at rt until no more evolution of gas was observed and then 2-chloropyridine -4-carbonitrile (13.86 g, 100 mmol) was added. The mixture was stirred at 90° C. overnight. It was then cooled down to 0° C. and 300 mL of methanol were added with subsequent stirring for 1 h at rt. After filtration, the solid was washed with methanol for several times, the solution was evaporated to dryness under vacuum. The residue was washed with methanol to give 2-chloropyridine-4-carboximidamide. (18.3 g, 95%). 1H NMR δ (400 MHz, d6-DMSO): 8.70 (dd, J=4.8, 0.4 Hz, 1H), 8.00 (dd, J=1.6, 0.4 Hz, 1H), 7.84 (dd, J=5.2, 1.6 Hz, 1H), 7.80 (m, 1H), 7.53 (t, J=8.1 Hz, 1H); MS (ESI) m/z (M+H)+ 156.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[C:34]([CH2:38][C:39](Cl)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([C:39](=[O:40])[CH2:38][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
1-{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-3,3-dimethyl-butan-1-one was prepared according to General Procedure I by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with tert-butylacetyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.02 (s, 9H), 1.93-2.06 (m, 4H), 2.30-2.35 (m, 2H), 2.79-2.84 (m, 1H), 3.30 (methyl sulfonyl and water peak), 4.14-4.17 (m, 1H), 4.59-4.62 (m, 1H), 5.05-5.11 (m, 1H), 7.63-7.65 (m, 2H), 8.05-8.07 (m, 2H), 8.38 (s, 1H), 8.57 (s, 1H). Mass spectrum MH+=472, M+Na=493.9.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](O)(=O)[CH2:10][CH2:11][CH2:12][CH3:13]>C(Cl)Cl>[CH2:10]([C:9]1[NH:1][C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[N:8]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(=O)O
Reactant: Nc1cccnc1N
Solvent: ClCCl
Product: CCCCc1nc2cccnc2[nH]1
Yield: 60.4 %

Procedure:
10 g (91.6 mmol) of 2,3-diaminopyridine and 27.4 g of valeric acid are stirred at 170° C. for 18 h. After completion of the reaction, the mixture is diluted with 100 ml of CH2Cl2, washed with saturated NaHCO3 solution, water and saturated NaCl solution, dried over Na2SO4 and concentrated. Chromatography on SiO2 using EA/Hep 20:1 yields 9.7 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[C:17](\[CH3:23])/[C:18](OCC)=[O:19])[CH:5]=[C:6]([F:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4](/[CH:16]=[C:17](\[CH3:23])/[CH2:18][OH:19])[CH:5]=[C:6]([F:15])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)/C(C)=C/c1cc(F)c(Oc2ccccc2)c(F)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: C/C(=C\c1cc(F)c(Oc2ccccc2)c(F)c1)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To a solution of (E)-ethyl 3-(3,5-difluoro-4-phenoxyphenyl)-2-methylacrylate (Intermediate 41.2) (800 mg, 2.51 mmol) in dry DCM (25 mL) under N2 at −78° C. was added a solution of DIBAL-H (8.79 mL, 1M in DCM) dropwise over several minutes. The reaction was allowed to warm to room temperature over 2 hours. The reaction mixture was cooled to 0° C., quenched with 25 mL of Rochelle's Salt solution (10% w/v in water), and stirred vigorously for 1 hour. The resulting suspension was diluted with water (20 mL) and extracted with DCM (3×30 mL). The combined organic layers were dried over Na2SO4 and concentrated. The resulting oil was applied onto a silica gel column (50% EtOAc in hexanes) to yield 566 mg of the title compound (82%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].[CH2:15](Cl)[CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:15]([O:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:12][CH3:13])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCCl
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture of 5-nitrovanillin (2.2 g), butyl chloride (10 ml), potassium carbonate (8 g) and N,N-dimethylformamide (50 ml) is stirred at 100° C. for 24 hours. After cooling, water (300 ml) is added to the reaction mixture, followed by extraction with ethyl acetate (200 ml). The extract solution is washed with water, dried, and concentrated under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane: ethyl acetate=1:1) to afford 4-butoxy-3-methoxy-5-nitrobenzaldehye (2 g) as a pale yellow oily product. This product is dissolved in acetone (100 ml), potassium permanganate (6 g) is added to the mixture, and the mixture is stirred at room temperature overnight. To the reaction mixture are added ethanol (20 ml), water (20 ml) and acetone (200 ml). The whole mixture is left standing for two hours, then insolubles are filtered off. The filtrate is concentrated under reduced pressure. The concentrate is dissolved in water (100 ml) and the mixture is acidified with concentrated hydrochloric acid. Precipitating crystals are collected by filtration to afford 4-butoxy-3-methoxy-5-nitrobenzoic acid (1.6 g) as colorless crystals. This product is recrystallized from a mixture of ethanol and water to give colorless prisms, m.p. 114°-115° C.
Reaction SMILES: [CH:1]([O-:3])=O.C(OC(=O)C)(=O)C.[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>O1CCCC1>[CH:1]([NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[F:11])=[O:3]
Reactant: O=C[O-]
Reactant: Nc1ccccc1F
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: O=CNc1ccccc1F
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Under argon gas, formate (6.1 mL) was added to acetic anhydride (15.5 mL) at 0° C. and the mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with tetrahydrofuran (10 mL). Tetrahydrofuran (20 mL) solution containing 2-fluoroaniline (5.56 g) was added into the diluent at room temperature and stirred at room temperature for 1 hour. A title compound having the following physical properties was obtained by concentrating the reaction mixture. The obtained title compound was used for the following reaction without further purification.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=O)C.C[O-].[Na+].Cl.[NH2:16][C:17]([NH2:19])=[NH:18].Cl>CO.CN(C)C=O>[NH2:19][C:17]1[NH:18][C:7]2=[CH:8][CH:9]=[CH:10][C:6]2=[C:4]([OH:3])[N:16]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C1CCCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1nc(O)c2cccc-2[nH]1
Yield: 18 %

Procedure:
A solution of 2-ethoxycarbonyl cyclopentanone (114 ml, 0.77mol) and N,N-dimethylformamide (40 ml) was added dropwise to a mixture solution of sodium methoxide(83.2 g, 0.44 mol) and N,N-dimethylformamide(80 ml), while maintaining the temperature of the reaction system below 0° C. A solution of guanidine HCl salt(81 g, 0.85 mol) and methanol(127 ml) was added to the above reaction mixture and then was heated to reflux for 14 hours. The reaction mixture was neutralized by conc. HCl and the resulting solid was filtered and dried under reduced pressure to give 20.69 g of titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25](=[O:33])[C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=5)[C:19]=4[CH3:34])=[CH:8][CH:9]=[C:10]([C:15]([NH2:17])=[O:16])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[CH3:35][C:36]([CH3:38])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([NH:24][C:20]2[C:19]([CH3:34])=[C:18]([C:7]3[C:6]4[C:5]5[C:13](=[CH:14][C:2]([NH:1][CH:36]([CH3:38])[CH3:35])=[CH:3][CH:4]=5)[NH:12][C:11]=4[C:10]([C:15]([NH2:17])=[O:16])=[CH:9][CH:8]=3)[CH:23]=[CH:22][CH:21]=2)=[O:33])=[CH:31][CH:30]=1
Reactant: CC(C)=O
Reactant: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(N)ccc3c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1c(NC(=O)c2ccc(F)cc2)cccc1-c1ccc(C(N)=O)c2[nH]c3cc(NC(C)C)ccc3c12
Temperature: 40 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
A suspension of 7-amino-4-(3-(4-fluorobenzamido)-2-methylphenyl)-9H-carbazole-1-carboxamide (Example 54-5, 1 g, 2.210 mmol), acetone (3.4 mL, 20 eq.), and acetic acid (0.443 mL, 7.74 mmol) in 1,2-dichloroethane (220 mL) was treated with sodium triacetoxyborohydride (1.639 g, 7.74 mmol) and stirred at 40° C. for 4 h. Additional sodium triacetoxyborohydride (520 mg, 1.1 eq) and acetic acid (0.19 mL, 1.5 eq) were added and the mixture was stirred overnight. The mixture was treated with NaHCO3 (aq) and the organic phase was separated, washed with brine, dried and concentrated. The residue was purified by preparative HPLC. The appropriate effluent fractions were made basic with NaHCO3 (aq) and extracted with EtOAc. The organic phase was washed with brine, dried and concentrated. The residue was triturated with methanol to provide 4-(3-(4-fluorobenzamido)-2-methylphenyl)-7-(isopropylamino)-9H-carbazole-1-carboxamide as an off-white solid (520 mg, 48%). 1H NMR (400 MHz, DMSO-d6) δ 11.01 (1H, s), 10.09 (1H, s), 8.07 (3H, dd, J=8.8, 5.3 Hz), 7.77 (1H, d, J=7.9 Hz), 7.27-7.51 (5H, m), 7.17 (1H, d, J=6.2 Hz), 6.73-6.88 (2H, m), 6.60 (1H, d, J=8.3 Hz), 6.23 (1H, dd, J=8.8, 2.2 Hz), 5.49 (1H, d, J=7.9 Hz), 3.53 (1H, dd, J=13.8, 6.4 Hz), 1.90 (3H, s), 1.04-1.21 (6H, m). Mass spectrum m/z 495.1 (M+H)+.