Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[C:17](Cl)(=[O:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:17](=[O:26])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CC(Cl)Cl
Product: O=C(CCc1ccccc1)Nc1ccc2oc3c(c2c1)CCCCCC3
Yield: 70.9 %

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.69 mmol), hydrocinnamoyl chloride (0.10 mL, 0.69 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (8 mL) provided N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)-3-phenylpropanamide (0.17 g). MS (ESI) m/z 348 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][N:8](CC3C=CC=CC=3)[CH2:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[Cl:21]C(OC(Cl)C)=O>ClCCl>[ClH:21].[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH2:7][NH:8][CH2:9][C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: CC(Cl)OC(=O)Cl
Reactant: COC(=O)c1cccc2c1CN(Cc1ccccc1)C2
Solvent: ClCCl
Product: COC(=O)c1cccc2c1CNC2
Product: Cl
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-benzyl-2,3-dihydro-1H-isoindole-4-carboxylic acid methyl ester (0.3 g, 1.12 mmol) in dichloromethane (4 ml) at −10° C., was added dropwise α-chloroethyl chloroformate (0.16 ml, 1.46 mmol) and stirred at −10° C. for 30 mins. The solvent was removed by evaporation under reduced pressure and the residue dissolved in methanol (5 ml) and heated to 90° C. for 40 mins. The solution was cooled to room temperature and the solvent removed by evaporation under reduced pressure. The residue was diluted with ethyl acetate (30 ml), extracted into sat. NaOH solution to give a hygroscopic solid, used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].CO.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccc(C=O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c(-c2ccc(CO)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Yield: 45.2 %

Procedure:
To a mixture of 2-benzyl-6-chloro-4-(4-formylphenyl)-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (66 mg), methanol (1.0 ml) and THF (1.0 ml) was added sodium borohydride (6 mg) at 0° C. with stirring, and the mixture was stirred for 1 hr. The reaction mixture was concentrated, and the residue was partitioned between 1N hydrochloric acid and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC to give the title compound (30 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[CH2:10][N:11]([CH3:13])[CH3:12].[CH2:15]([O:17][C:18]([N:20]=[C:21]=[S:22])=[O:19])[CH3:16]>C(#N)C>[CH2:15]([O:17][C:18]([NH:20][C:21]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[CH2:10][N:11]([CH3:12])[CH3:13])=[S:22])=[O:19])[CH3:16]
Reactant: CN(C)CC(=O)Nc1ccccc1N
Reactant: CCOC(=O)N=C=S
Solvent: CC#N
Product: CCOC(=O)NC(=S)Nc1ccccc1NC(=O)CN(C)C
Reaction time: 0.08 h
Yield: 62.9 %

Procedure:
A suspension of N-(2-aminophenyl)-2-dimethylaminoacetamide (8.9 g) (prepared as described in Example 6) in acetonitrile (50 ml) was treated with ethoxycarbonyl isothiocyanate (6.4 g), dropwise with stirring, maintaining the temperature at 15°-20° C. by external cooling. When the addition was complete, the solid had dissolved but after being left to stand for a further 5 minutes, another solid precipitated. This was filtered off and washed with ice-cold acetonitrile to give 1-ethoxycarbonyl-3-(2-dimethylaminoacetamidophenyl)thiourea (9.4 g), m.p. 159°-160° C. (with decomposition).
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:16]=[C:15]([C:17]([OH:19])=O)[C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:3][CH:2]=1.O>CO>[CH3:27][C:24]1[CH:23]=[CH:22][C:21]2[NH:20][C:14]3[C:15]([C:17](=[O:19])[C:26]=2[CH:25]=1)=[CH:16][C:8]1[NH:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:28])=[CH:6][C:5]=2[C:10](=[O:11])[C:9]=1[CH:13]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Solvent: O
Solvent: CO
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 80 °C
Yield: 83.9 %

Procedure:
To 200.0 g of polyphosphoric acid (118%) was added in portions with stirring at 80° C. 50.0 g (133 mmol) of 2,5-bis(p-toluidino)terephthalic acid. The stirred mixture was irradiated in the microwave oven for 2.0 minutes, during which time the temperature rose to 230° C. The reaction mixture was cooled to 150° C. and drowned in 400 g of methanol with vigorous stirring. The resultant methanol suspension was heated at reflux for one hour, cooled to 60° C., added to 800 g of water, and heated at 60° C. for 30 minutes. The solid component was collected by filtration, washed with 12.0 liters of water, and reslurried with water. [A sample of the crude pigment was collected at this point for X-ray analysis.] After 50.0 g of 50% aqueous sodium hydroxide was added, the alkaline slurry was heated at 90-92° C. for two hours. The solid component was collected by filtration and washed with 12.0 liters of water. The resultant presscake (280 g total, with a pigment content of 40.0 g) was reslurried with water. After adjustment of the pH to 9.0, the slurry was heated for two hours in an autoclave at 140° C., then cooled to room temperature. After adjustment of the pH to 4.5, the slurry was treated with an emulsion of 2.0 g of an anionic surfactant, 25 g of a petroleum distillate, and 40 g of water and stirred for three hours at 45° C. The solid component was collected by filtration and washed with 6.0 liters of water. The presscake was dried overnight in an oven at 60° C. to give 38.0 g of pigmentary quality 2,9-dimethylquinacridone. X-ray diffraction patterns of both the dried acid crude (collected as described above) and the finished pigment were similar to the diffraction pattern of a commercially available 2,9-dimethylquinacridone pigment (i.e., QUINDO Magenta RV-6832 from Bayer Corporation) prepared by a conventional heating method.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[CH:4][CH:3]=1.[C:14]([CH2:16][C:17]([OH:19])=[O:18])#[N:15].N1C=CC=CC=1>C1C=CC=CC=1>[C:14]([C:16](=[CH:8][C:7]1[C:2]([Br:1])=[CH:3][CH:4]=[C:5]([O:12][CH3:13])[C:6]=1[O:10][CH3:11])[C:17]([OH:19])=[O:18])#[N:15]
Reactant: COc1ccc(Br)c(C=O)c1OC
Reactant: N#CCC(=O)O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COc1ccc(Br)c(C=C(C#N)C(=O)O)c1OC
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of 6-bromo-2,3-dimethoxybenzaldehyde (48.4 g, 0.20 mole), NH4OAc (1.93 g, 0.025 mole), cyanoacetic acid (0.186 mole, 15.8 g), pyridine (42 mL), and benzene (193 mL) was stirred at reflux for 2 hours using a Dean-Stark trap for water removal. Upon cooling to room temperature a solid was filtered and washed with hexane. The solid was dissolved in 1N KOH, and was extracted with ether. The aqueous layer was acidified with 10% HCl and was extracted with CH2Cl2. The combined CH2Cl2 layers were washed with water, saturated aqueous NaCl, dried (MgSO4), filtered, and evaporated to yield 41.7 g yellow solid, (67%); mp 130°-2°; M+ 311.
Reaction SMILES: [CH2:1]=O.[Cl:3][CH2:4][CH2:5][CH2:6][NH:7][CH3:8].[P:9]([O-])([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[O:10]>O1CCOCC1>[Cl:3][CH2:4][CH2:5][CH2:6][N:7]([CH2:1][P:9]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[O:10])[CH3:8]
Reactant: C=O
Reactant: CCOP(=O)([O-])OCC
Reactant: CNCCCCl
Solvent: C1COCCO1
Product: CCOP(=O)(CN(C)CCCCl)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
0.8 mL of 37% aqueous formaldehyde solution is added to suspension of 3-chloro-N-methylpropan-1-amine (1.4 g or 1.3 mmol) in dioxane (30 mL), the resulting mixture is slightly heated until it becomes a solution. The solution is cooled to room temperature, 1.6 mL of diethyl phosphate is added thereto, stirring at room temperature for 30 min, and then stirring at 90-100° C. for 3 h, the reaction is completed. The solvent is removed under reduced pressure, and the residue is purified by column chromatography (eluent: 1-4% MeOH in DCM) to obtain 2.3 g target compound (yield: 81%). The analytical data of the obtained product are as follows: 1HNMR (400 MHz, CDCl3): δ=4.17-4.10 (m, 4H), 3.74-3.53 (m, 4H), 3.28-3.08 (m, 2H), 2.80 (s, 3H), 2.25-2.09 (m, 2H), 1.29 (t, J=6.8 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]=1[C:13]([NH2:15])=[O:14].N1C=CC=CC=1.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>O1CCCC1>[C:26]1([O:25][C:23](=[O:24])[NH:1][C:2]2[S:6][N:5]=[C:4]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]=2[C:13](=[O:14])[NH2:15])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCCCSc1nsc(N)c1C(N)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCSc1nsc(NC(=O)Oc2ccccc2)c1C(N)=O
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 5-amino-3-pentylsulfanyl-isothiazole-4-carboxylic acid amide (2.2 g, 9.0 mmol) in 36 mL of tetrahydrofuran was added pyridine (0.90 g, 11 mmol) and phenyl chloroformate (1.7 g, 11 mmol). After stirring for 3 hours, additional pyridine (0.15 g, 1.9 mmol) and phenyl chloroformate (0.29 g, 1.9 mmol) was added, and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, diluted with water and extracted 2× with CH2Cl2, 1× with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated for 12 hours with ether-hexane, and the resulting solids were collected and dried in vacuo, affording 2.6 g (79%) of (4-carbamoyl-3-pentylsulfanyl-isothiazol-5-yl)-carbamic acid phenyl ester as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 7.41 (t, 2 H, J=7.3 Hz), 7.29-7.20 (m, 3H), 3.31 (t, 2H, J=7.3 Hz), 1.72 (m, 2H), 1.50-1.30 (m, 4H), 0.90 (t, 3H, J=7.1 Hz) ppm; MS (APCl, m/z): 366 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N:9]1[CH:13]=[C:12]([C:14]2[N:15]=[C:16]3[C:22]([C:23]([OH:25])=O)=[CH:21][N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:17]3=[N:18][CH:19]=2)[N:11]=[CH:10]1.[NH2:34][C@H:35]([CH:44]1[CH2:46][CH2:45]1)[C:36]([N:38]1[CH2:41][CH:40]([C:42]#[N:43])[CH2:39]1)=[O:37].C(Cl)CCl>CN(C1C=CN=CC=1)C.ClCCl>[C:42]([CH:40]1[CH2:41][N:38]([C:36](=[O:37])[C@H:35]([NH:34][C:23]([C:22]2[C:16]3[C:17](=[N:18][CH:19]=[C:14]([C:12]4[N:11]=[CH:10][N:9]([C:3]5[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=5[F:1])[CH:13]=4)[N:15]=3)[N:20]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:33])[CH3:32])[CH:21]=2)=[O:25])[CH:44]2[CH2:45][CH2:46]2)[CH2:39]1)#[N:43]
Reactant: N#CC1CN(C(=O)[C@H](N)C2CC2)C1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(-c3cn(-c4cc(F)ccc4F)cn3)cnc21
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(-c3cn(-c4cc(F)ccc4F)cn3)cnc21
Yield: 49.7 %

Procedure:
A solution of 2-[1-(2,5-difluoro-phenyl)-1H-imidazol-4-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.067 g, 0.14 mmol), (R)-1-(2-amino-2-cyclopropylacetyl)azetidine-3-carbonitrile (0.038 g, 0.21 mmol), DMAP (0.021 g, 0.17 mmol) and EDC (0.036 g, 0.19 mmol) in 2 mL dichloromethane was stirred for 13.5 h. Dichloromethane (10 mL) was added, and the solution was sequentially washed with 10 mL of a 1 M citric acid solution, 10 mL of water, and 10 mL of a sat. aq. NaCl solution then dried over Na2SO4, filtered and concentrated. The residue was purified using column chromatography (80% EtOAc/hexanes) to afford 0.044 g (48%) of 2-[1-(2,5-difluoro-phenyl)-1H-imidazol-4-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide as a foamy pale yellow solid. MS: (M+Na)+=655.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:31])=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)CCl)CC1
Reactant: CCOc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: CCOc1ccccc1N1CCN(C(=O)c2cn(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.OC(C(F)(F)F)=O.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][C:29]#[N:30])[CH2:24][CH2:23]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:21][C@H:22]2[CH2:27][CH2:26][C@H:25]([CH2:28][C:29]#[N:30])[CH2:24][CH2:23]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: N#CC[C@H]1CC[C@H](N)CC1
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: N#CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.88 g, 4.1 mmol) in isopropyl alcohol (14 mL), (trans-4-aminocyclohexyl)acetonitrile TFA salt (0.68 g, 4.9 mmol) and N,N-diisopropylethylamine (3.0 mL, 17 mmol) were added. The reaction was stirred at 90° C. for 2 h. The mixture was concentrated and purified on silica gel (eluting with 0 to 60% EtOAc in dichloromethane) to give the desired product (1 g, 77%). LCMS calculated for C15H17N4O2S (M+H)+: m/z=317.1. Found: 317.0.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=3)[C:17]2=[O:31])[CH2:10][CH2:9]1)=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:54][C:55]1[C:70]([OH:71])=[CH:69][CH:68]=[CH:67][C:56]=1[C:57]([NH:59][C:60]1[CH:65]=[CH:64][C:63]([Cl:66])=[CH:62][N:61]=1)=[O:58]>CN(C)C=O.O.C(N(CC)CC)C>[Cl:66][C:63]1[CH:64]=[CH:65][C:60]([NH:59][C:57](=[O:58])[C:56]2[CH:67]=[CH:68][CH:69]=[C:70]([OH:71])[C:55]=2[NH:54][C:26](=[O:28])[C:25]2[CH:24]=[CH:23][C:22]([C:18]3[C:17](=[O:31])[N:16]([CH2:15][CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:21]=[CH:20][CH:19]=3)=[CH:30][CH:29]=2)=[N:61][CH:62]=1
Reactant: Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(CCn2cccc(-c3ccc(C(=O)O)cc3)c2=O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1)c1ccc(-c2cccn(CCN3CCNCC3)c2=O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 96.8 %

Procedure:
4-(1-{2-[4-(tert-butoxycarbonyl)piperazin-1-yl]ethyl}-2-oxo-1,2-dihydropyridin-3-yl)benzoic acid (731 mg) was dissolved in N,N-dimethylformamide (15 mL), 1-hydroxybenzotriazole (253 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (359 mg) and triethylamine (261 μL) were added, and 2-amino-N-(5-chloro-2-pyridinyl)-3-hydroxybenzamide (412 mg) was added, followed by stirring at room temperature for 7 hours. Water was added to the reaction mixture, and the precipitate formed was collected by filtration and washed with water. The resulting solid was dried under reduced pressure and dissolved in tetrahydrofuran (15 mL), and acetic acid (448 μL) was added, followed by stirring at 60° C. for 5 hours. The reaction mixture was concentrated under reduced pressure, and then azeotroped twice with toluene. The residue was purified by NH-silica gel column chromatography (methanol/chloroform=0% to 5%). The resulting compound was dissolved in ethyl acetate (10 mL), and 4 N hydrochloric acid/ethyl acetate (3.88 mL) was added, followed by stirring at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and aqueous saturated sodium hydrogencarbonate solution was added to the residue, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (methanol/chloroform=0% to 5%) to obtain N-(5-chloropyridin-2-yl)-3-hydroxy-2-({4-[2-oxo-1-(2-piperazin-1-ylethyl)-1,2-dihydropyridin-3-yl]benzoyl}amino)benzamide (867 mg) as a yellow white solid.
Reaction SMILES: [F:1][C:2]([F:13])([C:9]([F:12])([F:11])[F:10])[C:3]([F:8])([F:7])[C:4](Cl)=[O:5].N1C=CC=CC=1.[CH:20]([O:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH2:21].O>ClCCl>[CH2:23]([O:22][CH:20]=[CH:21][C:4](=[O:5])[C:3]([F:8])([F:7])[C:2]([F:13])([F:1])[C:9]([F:12])([F:11])[F:10])[CH2:24][CH2:25][CH3:26]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Reactant: C=COCCCC
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCOC=CC(=O)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -10 °C
Reaction time: 15 h

Procedure:
With stirring and at −10° C., 21.7 g (93.2 mmol) of heptafluorobutyryl chloride—dissolved in 50 ml of dichloromethane—were added to a mixture of 8.11 g (102 mmol) of pyridine and 9.33 g (93.2 mmol) of butyl vinyl ether in 200 ml of dichloromethane. After the addition, stirring was continued at room temperature for another 15 h. 300 ml of water were then added to the mixture, and the organic phase was separated off, dried and concentrated.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[C@H:24]1([NH2:31])[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1.C(#N)C.O>CS(C)=O>[NH2:30][C@H:27]1[CH2:28][CH2:29][C@H:24]([NH:31][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:25][CH2:26]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cccc(CNc2cccc(-c3cc(F)ncc3Cl)n2)c1
Solvent: CC#N
Solvent: O
Solvent: CS(C)=O
Product: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 5′-chloro-2′-fluoro-N-(3-fluorobenzyl)-2,4′-bipyridin-6-amine (725 mg, 2.185 mmol) was added DMSO (7 ml), trans-cyclohexane-1,4-diamine (1996 mg, 17.48 mmol) and TEA (0.609 ml, 4.37 mmol) was stirred at about 100° C. for 20 hours. The reaction was monitored by LC/MS. The crude reaction mixture was cooled to room temperature, diluted with 3 ml DMSO, filtered, and purified by prep HPLC. (there is a general HPLC conditions in the general experimental session). The fractions were concentrated, mixed with 500 ml ethyl acetate, and basified with saturated sodium bicarbonate 120 ml. The ethyl acetate layer was separated, and the basic water layer was extracted with 300 ml ethyl acetate. The ethyl acetate layers were combined and washed with water (3×), saturated salt solution (1×), dried with sodium sulfate, filtered and concentrated to yield a solid. The solid was dissolved in (1:1 ACN/water) filtered and lyapholized to yield 755 mg of the title compound as free-base. LCMS (m/z): 426.3 (MH+), retention time=0.59 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.10-1.43 (m, 4H) 1.90 (d, J=12.01 Hz, 2H) 2.01 (d, J=12.01 Hz, 2H) 2.70-2.84 (m, 1H) 3.47-3.60 (m, 1H) 4.48 (s, 2H) 6.44 (d, J=8.50 Hz, 1H) 6.51 (s, 1H) 6.71 (d, J=7.33 Hz, 1H) 6.79-6.91 (m, 1H) 7.00 (d, J=9.96 Hz, 1H) 7.05-7.13 (m, 1H) 7.15-7.27 (m, 1H) 7.40 (t, J=7.77 Hz, 1H) 7.85 (s, 1H)
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:18][CH3:19])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](O)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(Cl)(=O)C([Cl:23])=O>ClCCl.C1(C)C=CC=CC=1>[Cl:23][C:11]1[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH2:18][CH3:19])[N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Ethyl 1,6-diethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (0.10 g, 0.38 mmol, 1 equivalent, e.g. which can be as prepared in Intermediate 2C) was dissolved in dichloromethane (1.5 ml). Oxalyl chloride (0.07 ml, 0.10 g, 0.76 mmol, 2.0 equivalents) was added in one portion to the stirred solution. The reaction mixture, a solution, was stirred at room temperature for 2 hours, then was heated to 39° C. and stirred for 22.5 hours at this temperature, and then allowed to cool. The reaction mixture was diluted with toluene and then the solvent was removed in vacuo to give a brown oil which solidified on standing at room temperature to yield the title compound as a brown solid (0.086 g, about 80% theory yield). HPLC (5 min generic solvent gradient): TRET about 3.43. Mass Spectrum: Found: MH+ 282.1.
Reaction SMILES: [Cl:1][CH:2]([Cl:21])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:20])[CH3:19])=[O:4].C(N(CC)CC)C.CC1(C)C2[C:51](=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)[O:50][C:32]2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[C]=[O:72]>O.CC([O-])=O.CC([O-])=O.[Pd+2].CO>[Cl:1][CH:2]([Cl:21])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:32]([O:50][CH3:51])=[O:72])=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:20])[CH3:19])=[O:4]
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: [C]=O
Reactant: CC1(C)O[C@H](c2ccc(I)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc([C@H]2OC(C)(C)N(C(=O)C(Cl)Cl)[C@@H]2CF)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a flask containing 2,2-dichloro-1-((4S,5R)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyloxazolidin-3-yl)ethanone (2.0 g, 4.48 mmol) is added triethylamine (5 mL) and methanol (5 mL). Carbon monoxide gas is bubbled through the solution while stirring for 30 min. Pd(OAc)2 (51 mg, 0.22 mmol) and Xantphos (132 mg, 0.22 mmol) are next added and a balloon containing carbon monoxide is secured to the flask outlet. The reaction is heated for 2 hours at 60° C. and then cooled to room temperature. Next, the reaction is diluted with water, extracted with ethylacetate, dried over Na2SO4, and concentrated under vacuum. The residue is chromatographed on silica gel eluting from 100% hexanes to 50:50 ethylacetate:hexanes to afford the title compound (1.11 g): 1H NMR (400 MHz, CDCl3) 8.10 (d, 2H, J=8.0 Hz), 7.55 (d, 2H, J=8.0 Hz), 6.34 (m, 1H), 5.30-4.42 (m, 4H), 3.95 (s, 3H), 1.97-1.53 (m, 6H). m/z (Cl) 320 [M-(CH3)2CO].