Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([OH:33])=O)[C:25]=1[CH3:34])(=[O:12])=[O:11].[F:35][C:36]([F:43])([F:42])[CH2:37][NH:38][CH2:39][CH2:40][NH2:41].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([NH:41][CH2:40][CH2:39][NH:38][CH2:37][C:36]([F:43])([F:42])[F:35])=[O:33])[C:25]=1[CH3:34])(=[O:11])=[O:12]
Reactant: NCCNCC(F)(F)F
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)NCCNCC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 72.2 %

Procedure:
A mixture of {5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (267 mg, 0.51 mmol), N-(2,2,2-trifluoro-ethyl)-ethane-1,2-diamine (123 mg, 0.86 mmol), HOBt (104 mg, 0.77 mmol), EDAC (154 mg, 0.81 mmol) and TEA (0.14 mL, 1 mmol) in DMF (3 mL) was stirred At rt for 48 hours. The reaction was concentrated, diluted with sat. sodium bicarbonate and extracted with DCM. The organic layer was washed with brine, dried and purified on a silica gel column to give 237 mg (72%) of the titled compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[O:6][CH:7]=1.[F:16][C:17]1[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19]([NH2:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:16][C:17]1[C:25]([O:26][CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)[O:6][CH:7]=2)=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19]([NH2:21])=[O:20]
Reactant: COc1ccc(-c2nc(CCl)co2)cc1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)co2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.5 %

Procedure:
To a solution of 4-Chloromethyl-2-(4-methoxy-phenyl)-oxazole (0.100 g, 0.4 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.077 g, 0.40 mmol) and potassium carbonate (0.216 g, 1.50 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.044 g, 27%). 1H NMR (DMSO-d6, 400 MHz): δ 4.01 (s, 3H), 5.12 (s, 2H), 7.10 (m, 3H), 7.40 (m, 1H), 7.85 (br s, 1H), 7.93 (d, J=8.80 Hz, 2H), 8.13 (br s, 1H) and 8.25 (s, 1H). MS ES+(361.16), HPLC (method I) Rt=15.47 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](Br)[CH:13]=2)[N:8]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:7]=1.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:13]=2)[N:8]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH:7]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)CCc1cn(S(=O)(=O)c2ccccc2)c2ccc(Br)cc12
Product: COC(=O)CCc1cn(S(=O)(=O)c2ccccc2)c2ccc(-c3ccccc3)cc12

Procedure:
The ester 93 was prepared from the methyl ester 89 by following the procedure as described in example 70 by substituting 3-Thienyl boronic acid with Phenyl boronic acid, (M+1=420).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:37])[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34](O)=[O:35])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:50]1([S:53]([NH2:56])(=[O:55])=[O:54])[CH2:52][CH2:51]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([O:14][CH:15]2[CH2:32][CH:31]3[N:17]([C:18](=[O:37])[O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:56][S:53]([CH:50]5[CH2:52][CH2:51]5)(=[O:55])=[O:54])=[O:35])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCOC(=O)N4C3)nc(Cl)cc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCOC(=O)N4C3)nc(Cl)cc2c1
Temperature: 25 °C
Yield: 15.8 %

Procedure:
A solution of 16 (120 mg, 0.23 mmol) and carbonyldiimidazole (44 mg, 0.27 mmol) in dry THF (25 mL) was refluxed for 3 h under nitrogen. Optionally, the azalactone derivative, if desired, can be isolated. Then, the reaction mixture was cooled to room temperature and cyclopropylsulfonamide (33 mg, 0.27 mmol) and DBU (52 mg, 0.34 mmol) were added. The reaction mixture was heated at 50° C. for 24 h, then cooled down at room temperature and partitioned between water and CH2Cl2. The organic layers were dried (MgSO4), filtered, and the solvent was evaporated. The crude material was purified by column chromatography on silica gel (CH2Cl2/EtOAc, 95:05) to give a solid which was successively triturated in water, filtered, dried, triturated in ether and dried again under high vacuum to give 23 mg (16%) of the title product 17 as a white powder: m/z=530 (M+H)+; 1H NMR (CDCl3): 8.10 (d, J=9.3 Hz, 1H), 7.50 (s, 1H); 7.39 (s, 1H); 7.25 (dd, J=9.3 Hz, 2.5 Hz, 1H); 7.39-7.30 (bs, 1H); 5.90-5.83 (bs, 1H); 5.71 (dd, J=8.0 Hz, 17.9 Hz, 1H); 5.18 (t, J=10.1 Hz, 1H), 4.79 (dd, J=7.3 Hz, 9.0 Hz, 1H), 4.1 (s, 3H), 4.09-3.97 (m, 1H), 3.81-3.66 (m, 2H), 3.62 (d, J=11.6 Hz, 1H), 3.19-3.05 (m, 1H); 2.59-2.22 (m, 4H); 2.01-1.90 (m, 1H), 1.89 (dd, J=5.8 Hz, 8.6 Hz, 1H), 1.70 (dd, J=6.1 Hz, 9.8 Hz, 1H), 1.67-1.58 (m, 2H), 1.75-0.76 (m, 7H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[C:10]([C:18]([F:21])([F:20])[F:19])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[C:10]([C:18]([F:20])([F:19])[F:21])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)nc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn(-c2ccc(F)cc2)nc1C(F)(F)F
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (140 mg, 0.463 mmol) in ethanol (4 mL) was added a solution of NaOH (4 mL, 4.00 mmol) in water (2 mL). The reaction mixture was stirred overnight. The next day, LCMS showed complete reaction so the reaction was concentrated in vacuo and then extracted using dilute HCl and EtOAc. Obtained 1-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (93 mg, 0.339 mmol, 73.2% yield) as a white powder. MS (M+1)=275; HPLC RT=0.82 minutes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[OH:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1>>[OH:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: OB(O)c1cccc(O)c1
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2cccc(O)c2)cc1
Yield: 70 %

Procedure:
Prepared in a similar manner to example 8 from 2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) and 3-hydroxyphenylboronic acid. Yield: 70%. MS (M+H, 312).
Reaction SMILES: Cl[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.CS(C)=O.[CH2:15]([SH:17])[CH3:16].CC([O-])(C)C.[K+]>C1COCC1>[Cl:8][C:5]1[N:4]=[C:3]([C:9]#[N:10])[C:2]([S:17][CH2:15][CH3:16])=[CH:7][CH:6]=1
Reactant: CCS
Reactant: N#Cc1nc(Cl)ccc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCSc1ccc(Cl)nc1C#N
Temperature: 20 °C
Reaction time: 40 h
Yield: 31 %

Procedure:
In a reaction flask with condenser, mechanical stirrer, thermometer and dropping funnel were placed 53.4 g of 3,6-dichloro-2-pyridinecarbonitrile and 300 ml of DMSO. The mixture was chilled to about 10°-15° C. and then 19.8 g of ethanethiol was added. While maintaining the temperature at <20° C., 34.8 g of t-BuOK in 300 ml of THF was added in small portions. After the addition was complete, the reaction mixture was warmed to 20° C. and stirred for about 40 hrs. The reaction mixture was then poured onto about 2 kilograms (kg) of ice, stirred and filtered leaving a solid residue. The residue was washed with water, dissolved in CH2Cl2, dried over MgSO4, concentrated and diluted with hexane to give 19.0 g of 6-chloro-3-ethylthio-2-pyridinecarbonitrile. The filtrate was concentrated and separated on a Water's Prep LC 500 instrument using 15% ethyl acetate in hexane to give another 10.1 g of the same isomer. Total yield of 6-chloro-3-ethylthio-2-pyridinecarbonitrile was 29.1 g (46.5%), m.p. 79°-81° C. Further separation on the Prep LC 500 instrument gave a small amount of 3-chloro-6-ethylthio-2-pyridinecarbonitrile (m.p. 46°-48° C.) and 3,6-bis-ethylthio-2-pyridinecarbonitrile (m.p. 63°-64° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=[O:6].[C:18](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([O:7][CH3:18])=[O:6]
Reactant: O=C(O)c1ccc(C(=O)N2CCCC2)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)N2CCCC2)c(Br)c1

Procedure:
20 g (67.1 mmol) of 3-bromo-4-(pyrrolidin-1-ylcarbonyl)benzoic acid is dissolved in 400 mL of N,N-dimethylformamide and combined with 21.9 g (67.1 mmol) cesium carbonate with stirring. Then 4.21 mL (67.1 mmol) of iodomethane is slowly added dropwise at ambient temperature and the mixture is stirred for 16 hours at ambient temperature. After the solid constituents have been removed by filtration with suction, volatile constituents are removed in vacuo. Yield: 20.94 g (75%); Rf value: 0.42 (silica gel; dichloromethane/ethanol=98:2); C13H14BrNO3 (312.17); mass spectrum: (M+H)+=312/314 (bromine isotope).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:26]([C:40]2[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]=2[F:53])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[C:54]([O-:57])([O-])=[O:55].[Na+].[Na+]>COCCOC.O>[CH2:47]([O:46][C:44]1[CH:43]=[C:42]([O:49][CH:50]([CH3:51])[CH3:52])[C:41]([F:53])=[C:40]([CH:26]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[C:4]2[N:5]([C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:6]=[C:2]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[C:54]([OH:57])=[O:55])[N:3]=2)[CH:45]=1)[CH3:48]
Reactant: O=C([O-])[O-]
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(=O)O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 170 °C

Procedure:
A suspension of 66.3 (100 mg, 0.13 mmol), 2-carboxyl phenylboronic acid (30 mg, 0.2 mmol), Na2CO3 (56 mg, 0.52 mmol) in 3:1 DME/H2O (3 mL) was degassed and then added in Pd(PPh3)4 (10 mg). The reaction mixture was heated to 170° C. for 15 mins in microwave. The reaction mixture was adjust to PH ˜4-5, then partitioned between EtOAc and sat. NaCl, the organic layer was collected and dried over (Na2SO4), filtered and concentrated to afford Intermediate 133.1. The crude material was used in the next step without further purification. LCMS (2 min grad.) RT=2.13 min, 814.3 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:18][S:19]([C:22]1[CH:23]=[CH:24][C:25]([C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[C:26]([CH:30]=1)[C:27](O)=[O:28])(=[O:21])=[O:20]>>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([C:27]([C:26]2[CH:30]=[C:22]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:23]=[CH:24][C:25]=2[C:31]2[S:32][CH:33]=[CH:34][N:35]=2)=[O:28])[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)O)c1
Reactant: Fc1cc(C(F)(F)F)ccc1N1CCNCC1
Product: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3F)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 1-(2-Fluoro-4-trifluoromethyl-phenyl)-piperazine (Example F) and 5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid (Example O). MS (ISP): 514.3 MH+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[I:9]N1C(=O)CCC1=O.O.C([O-])(O)=O.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[I:9]
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cncc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1cnc(I)c(Cl)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 6-chloropyrazin-2-amine (10.0 g, 77 mmol) in DMSO (100 ml) was treated with 1-iodopyrrolidine-2,5-dione (20.84 g, 93 mmol). The reaction mixture was stirred at RT for 2 days and then added to water (800 ml). The pH was adjusted to pH 8-9 using a sat. NaHCO3 solution and the resulting suspension was filtered, washing with water (×3) and dried under vacuum to afford the titled compound as an orange solid;
Reaction SMILES: [Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9](Cl)[C:4]=2[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[NH2:16].C(N(C(C)C)CC)(C)C>C(O)CCC>[Br:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:16][C:15]3[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:13]([OH:12])[CH:14]=3)[C:4]=2[CH:3]=1
Reactant: Clc1ncnc2[nH]c(Br)cc12
Reactant: COc1ccc(N)cc1O
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2ncnc3[nH]c(Br)cc23)cc1O
Temperature: 120 °C
Yield: 69.9 %

Procedure:
6-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 0.41 mmol), prepared as in reference 1, is mixed with 3-hydroxy-4-methoxyaniline (170 mg, 1.22 mmol) and diisopropylethylamine (213 μL, 1.22 mmol) in n-butanol (1.3 mL). The mixture is heated to 120° C. for 18 hours, with stirring. The reaction is then cooled to ambient temperature and the solvent is removed. The resultant crude product is purified by flash column chromatography using a gradient of 3-5% MeOH in DCM to yield 5-(6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-methoxy-phenol (96 mg; 66%); 1H NMR (500 MHz, d-methanol) δ 8.17 (s, 1H), 7.16 (s, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.92 (d, J=8.6 Hz, 1H), 6.61 (s, 1H), 3.87 (s, 3H), 3.75 (s, 3H); LC-ESMS observed [M+H]+ 349.0 (calculated for C14H13BrN4O2, 348.0).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4](=[N:6][OH:7])[NH2:5].[Cl:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]1[NH:5][CH:15]([C:14]2[CH:17]=[CH:18][CH:19]=[CH:20][C:13]=2[Cl:12])[O:7][N:6]=1
Reactant: O=Cc1ccccc1Cl
Reactant: NC(=NO)c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ccccc1C1=NOC(c2ccccc2Cl)N1
Yield: 24 %

Procedure:
2-Chlorobenzamidoxime (3.4 g), 2-chlorobenzaldehyde (2.8 g), p-toluenesulphonic acid (1 g) and toluene (100 ml) were heated to reflux for 16 hours in Dean and Stark apparatus. The solution was then run down, and the residue was recrystallised from methanol to give 1.4 g of desired product, mp 75°-78° C.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[N:17]=[CH:16][C:15]([C:18]2[N:23]3[N:24]=[C:25]([NH:27][C:28]([CH:30]4[CH2:32][CH2:31]4)=[O:29])[N:26]=[C:22]3[CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1>C1COCC1>[CH2:1]([O:8][C:12]1[N:17]=[CH:16][C:15]([C:18]2[N:23]3[N:24]=[C:25]([NH:27][C:28]([CH:30]4[CH2:31][CH2:32]4)=[O:29])[N:26]=[C:22]3[CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(Nc1nc2cccc(-c3ccc(Cl)nc3)n2n1)C1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1nc2cccc(-c3ccc(OCc4ccccc4)nc3)n2n1)C1CC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
At 0° C. and under N2 atmosphere, Benzyl alcohol (2 eq) in a solution of THF was treated with NaH 60% in mineral oil (4 eq) for 30 min. Then cyclopropanecarboxylic acid [5-(6-chloro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-amide prepared by method A was added to the solution and the mixture was stirred at 70° C. for 3 hours. The reaction was completed. The reaction mixture was quenched with water and the compound was extracted with EtOAc. The compound was washed with brine, dried on MgSO4, filtrated and concentrated. Compound was purified on Prep HPLC.
Reaction SMILES: [CH:1]([C:4]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:7]1[C:8]([NH2:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH3:21])[CH3:22]
Reactant: [H][H]
Reactant: CC(C)c1cccc(C(C)C)c1Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cccc(C(C)C)c1Nc1ccccc1N
Yield: 99 %

Procedure:
2,6-diisopropyl-N-(2-nitrophenyl)aniline (9.5 g, 32 mmol) and 10% palladium on carbon (0.4 g) were mixed with 150 ml of ethanol under nitrogen in a plastic coated hydrogenation vessel. The mixture was put on a par hydrogenator and reacted under 40 psi of hydrogen until there is no pressure drop. The catalyst was filtered off through a Celite bed. The solvent was evaporated. The product was used for the next step without further purification. 8.5 g of desired product was obtained.
Reaction SMILES: [OH:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:41][N:42]1[C:51]2[C:46](=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=2)[CH:45]=[C:44]([C:53]2[CH:54]=[C:55]([NH:60]/[C:61](/[NH2:64])=[N:62]/O)[CH:56]=[CH:57][C:58]=2[CH3:59])[C:43]1=[O:65]>CN(C=O)C>[OH:1][C:2]1([C:5]2[O:7][N:62]=[C:61]([NH:60][C:55]3[CH:56]=[CH:57][C:58]([CH3:59])=[C:53]([C:44]4[C:43](=[O:65])[N:42]([CH3:41])[C:51]5[C:46]([CH:45]=4)=[CH:47][N:48]=[C:49]([CH3:52])[CH:50]=5)[CH:54]=3)[N:64]=2)[CH2:4][CH2:3]1
Reactant: O=C(O)C1(O)CC1
Reactant: Cc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C4(O)CC4)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1-hydroxycyclopropanecarboxylic acid (6 mg, 0.06 mmol) in DMF (1 mL) were added DIPEA (31 μL, 0.18 mmol) and HATU (23 mg, 0.06 mmol). After stirring at rt for 15 min, 17 (20 mg, 0.06 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17 was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 3-(5-(5-(1-hydroxycyclopropyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-dimethyl-1,6-naphthyridin-2(1H)-one (A57). MS m/z 404.4 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([O:19]CC)=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1.[OH-].[Li+]>C1COCC1.CO>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=[O:18])=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([CH3:12])[CH:11]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(C)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
220 mg of ethyl 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate (Example 20A; 0.524 mmol, 1 equivalent) were dissolved in 7 ml of THF/methanol 1:1, 2.6 ml of 1 N aqueous lithium hydroxide solution (2.6 mmol, 5 equivalents) were added and the mixture was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was acidified with 1N aqueous hydrochloric acid. The solid obtained was stirred, filtered off, washed with water and dried under reduced pressure. This gave 120 mg of the title compound (60% of theory).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:2]1.[H][H]>C(O)C>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:2]1
Reactant: [H][H]
Reactant: O=C(O)CCC=Cc1ccsc1
Solvent: CCO
Product: O=C(O)CCCCc1ccsc1
Yield: 80 %

Procedure:
3.3 g of the cis and trans mixture of 5-(thiophen-3-yl)-pent-4-enoic acid prepared in example 9a are solubilized in absolute ethanol (50 mL). The compound is then submitted to an hydrogenation reaction with hydrogen (3 atm of H2) on Pd/C 10% (180 mg) carried out at room temperature for a time of 18 hours. The reaction mixture is then filtered on celite and washed with methanol (3×10 mL). The solvent is removed under vacuum, obtaining 2.6 g of the 5-(thiophen-3-yl)-pentanoic acid (yield 80%). Rf=0.35 (ligroin/ethyl acetate 6/4 volume/volume); 1H NMR (CDCl3) δ (ppm): 8.35 (s, 1H, OH broad), 7.24 (m, 1H, ArH), 6.93 (m, 2H, ArH), 2.66 (m, 2H, CH2), 2.38 (m, 2H, CH2), 1.69 (m, 4H, CH2); 13C NMR (CDCl3) δ (ppm): 179.8, 142.3, 128.2, 125.3, 120.1, 33.9, 29.9, 24.4; FT-IR (film) νmax: 2944.3, 2865.4, 1692.9, 1462.7, 1425.3, 1307.6, 1258.2, 1212.9, 1190.2, 930.2, 750.8, 592.0 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([N:15]2[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]2)=[O:9])[CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Product: CN1CCN(C(=O)c2cc(Cl)ccn2)CC1

Procedure:
Using 4-chloropicolinic acid chloride and N-methylpiperazine instead of N-Boc-piperazine, amidation was carried out in the same manner as Step A in Example 1-D-199, to obtain (4-chloro-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (215 mg, 0.398 mmol), and the obtained (4-chloro-pyridin-2-yl)-(4-methyl-piperazin-1-yl)-methanone (105 mg, 0.438 mmol) instead of 4-chloropicolinic acid t-butylamide, amination was carried out in the same manner as Example 1-D-07, to obtain a crude product of [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-(4-methyl-piperazin-1-yl)-methanone as a yellow solid (285 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-200) as a yellow powder (69 mg, 38%).