Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[N:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[CH2:3]1.[F:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][C:21]=1[O:22][CH:23]([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[CH2:3][N:2]([C:18]2[CH:19]=[CH:20][C:21]([O:22][CH:23]([CH3:24])[CH3:25])=[C:16]([F:15])[CH:17]=2)[CH:11]=1
Reactant: CC(C)Oc1ccc(B(O)O)cc1F
Reactant: COc1ccc2c(c1)CN(Cl)C=C2Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CN(c1ccc(OC(C)C)c(F)c1)C=C2Cl
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 52.3 %

Procedure:
To a solution of 2,4-dichloro-7-methoxyisoquinolin (0.25 g, 1.1 mmol), 3-Fluoro-4-isopropoxyphenylboronic acid (0.21 g, 1.1 mmol) in 1,4-Dioxane (5 ml) and water (1 ml) was added K2CO3 (0.3 g, 2.2 mmol). The reaction mass was degasified for 20 min. Pd (Ph3P)4 (0.06 g, 0.05 mmol) was added to the above reaction mass and degasified again for 5 min at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 90° C. for 18 h. The reaction mass was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.2 g, 54%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d): δ ppm 8.08 (d, J=9.26 Hz, 1H) 7.93 (dd, J=12.51, 2.25 Hz, 1H) 7.80 (dt, J=8.50, 1.00 Hz, 1H) 7.74 (s, 1H) 7.45 (d, J=2.50 Hz, 1H) 7.09 (t, J=8.50 Hz, 1H), 3.99 (s, 3H), 3.95 (m, 1H), 1.41 (d, J=6.25 Hz, 6H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][S:27]([C:24]2[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=2)(=[O:29])=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCCCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCCCCc2ccccc2)cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A solution of 6-phenyl-1-hexanol (2.9 g, 16.27 mmoles), CH2Cl2 (30 ml), triethylamine (4.76 ml, 34.16 mmoles) and p-toluensulphonyl chloride (3.26 g, 17.08 mmoles) was kept under stirring at room temperature for 1 night, washed with water, 5% HCl and NaHCO3 and evaporated to give 5.4 g of the title compound (yield: 100%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][C@@H:43]1[CH2:48][O:49][CH3:50])=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:25]=[CH:26][C:27]([C:29]([F:30])([F:31])[F:32])=[CH:28][C:3]=3[C:2]([F:33])([F:34])[F:1])[N:7]=[CH:8]4)[C:17](=[O:24])[N:18]=2)[CH2:44][C@@H:43]1[CH2:48][O:49][CH3:50])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: COC[C@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1C(=O)OC(C)(C)C

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(R)-Methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO[CH:19](OC)[CH2:20][C:21](=[O:23])[CH3:22].Cl>C(O)(=O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:19]=[CH:20]/[C:21](=[O:23])[CH3:22])=[C:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(CC(C)=O)OC
Reactant: Cn1c(-c2ccccc2)cc2ccccc21
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)/C=C/c1c(-c2ccccc2)n(C)c2ccccc12
Reaction time: 14 h
Yield: 88.7 %

Procedure:
2.07 g of 1-methyl-2-phenyl-1H-indole, 1.32 g of 1,1-dimethoxy-3-butanone and 12 mL of acetic acid were mixed, then, 313 mg of 35 wt % hydrochloric acid was added into the mixture at room temperature, the added mixture was stirred for about 14 hours at the same temperature to cause a reaction. At a time point about 10 minutes after starting of stirring and reaction, blue solid precipitated to render stirring difficult. Therefore, 8 mL of acetic acid was added. After completion of the reaction, 60 mL of water was added dropwise, and the precipitated crystals were filtrated. The crystals were washed with 10 vol % methanol/water, then, dried to obtain 2.44 g of trans-4-[1-methyl-2-phenyl-1H-indol-3-yl]-3-buten-2-one (blue green solid). Yield: 89%.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:16])[N:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[CH:6][C:7]=1[OH:8].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:3](=[O:16])[N:4]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:5]=[CH:6][C:7]=1[O:8][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=1
Reactant: O=c1c(Cl)c(O)cnn1-c1ccc(Cl)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c(Cl)c(OCc2ccc(Cl)cc2)cnn1-c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 59.1 %

Procedure:
In 70 ml of N,N-dimethylformamide was dissolved 7.1 g (0.028 mol) of 4-chloro-2-(4-chlorophenyl)-5-hydroxy-3(2H)-pyridazinone, and thereto were added 4.5 g of p-chlorobenzyl chloride and 5.4 g of anhydrous potassium carbonate. The resulting reaction mixture was heated under stirring on an oil bath at 120° to 130° C. for 2 hours. After allowing to cool, the reaction mixture was poured into 500 ml of water. The solid thus precipitated was taken out by filtration, washed with water, dried and then recrystallized from an ethyl acetate-benzene mixture to give 6.3 g of the intended compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:13]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:17]([F:20])([F:19])[F:18])=[O:14])[N:8]2[CH2:11][CH3:12])=[CH:4][C:3]=1[C:31]([NH:33][C:34]1([C:37]#[N:38])[CH2:36][CH2:35]1)=[O:32].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:48]2)=CC=1>O1CCCC1.C(OCC)(=O)C>[C:37]([C:34]1([NH:33][C:31]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[Cl:1])[N:8]([CH2:11][CH3:12])[C:7]([C:13]([NH:15][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)[C:17]([F:18])([F:20])[F:19])=[O:14])=[CH:6]3)=[O:32])[CH2:35][CH2:36]1)(=[S:48])[NH2:38]
Reactant: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)NC3(C#N)CC3)c(Cl)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1c(C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc2cc(C(=O)NC3(C(N)=S)CC3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 12.1 %

Procedure:
6-Chloro-N5-(1-cyanocyclopropyl)-1-ethyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide (0.200 g, 0.35 mmol) is initially charged in tetrahydrofuran (5.5 ml) under argon, 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide (0.305 g, 0.75 mmol) is added and the mixture is stirred at room temperature for 48 h. Then 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulphide (0.150 g, 0.38 mmol) is added again and the mixture is stirred at room temperature for a further 12 h. The reaction mixture is then diluted with ethyl acetate and washed with a sodium hydrogencarbonate solution. The organic phase is dried with magnesium sulphate, filtered and concentrated under reduced pressure. The residue is purified by means of preparative HPLC (Kromasil100, C18 250×20; eluent: acetonitrile in water, gradient: 10-100%) to obtain 0.025 g (11% of theory) of N5-(1-carbamothioylcyclopropyl)-6-chloro-1-ethyl-N2-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}-1H-indole-2,5-dicarboxamide.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18]C)=O)[CH2:5]1.[NH2:20][NH2:21].O>CO>[NH:20]([C:16]([C@@H:6]1[CH2:5][C:4](=[N:3][O:2][CH3:1])[CH2:8][N:7]1[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[O:18])[NH2:21]
Reactant: NN
Reactant: CON=C1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Solvent: O
Solvent: CO
Product: CON=C1C[C@@H](C(=O)NN)N(C(=O)OC(C)(C)C)C1
Reaction time: 48 h

Procedure:
1-tert-butyl 2-methyl (2S,4EZ)-4-(methoxyimino)-1,2-pyrrolidinedicarboxylate (1.95 mmoles; 530 mg) was dissolved in 4 mL of MeOH and a solution of 4 mL of MeOH and 1.5 mL (d=1.03; 30.86 mmoles) of 80% hydrazine.hydrate was added (final c(NH2NH2)=13%). The reaction mixture was agitated for 2 days. Solvents were evaporated in vacuo and the residue re-dissolved in MeOH and evaporated (3×). The desired compound, tert-butyl (2S,4EZ)-2-(hydrazinocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate, was isolated as a yellow oil (500 mg; 94%).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.O(C1C=CC(C(C2C=CC(OC#N)=CC=2)(C)C)=CC=1)[C:22]#[N:23].O>C1COCC1.[Cl-].[Na+].O>[Br:3][C:4]1[N:5]([C:22]#[N:23])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC(C)(c1ccc(OC#N)cc1)c1ccc(OC#N)cc1
Reactant: COc1ccc(-c2c(Br)[nH]c3ccccc23)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2c(Br)n(C#N)c3ccccc23)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.7 %

Procedure:
NaH (18.35 mg, 0.76 mmol) was stirred in dry THF (1 ml) at 0° C. and 2-bromo-3-(4-methoxyphenyl)-1H-indole (210 mg, 0.69 mmol) dissolved in dry THF (4.5 ml) was added dropwise. The mixture was stirred at 0° C. for 5 min and then 2,2-bis-(4-cyanatophenyl)propane (251 mg, 0.90 mmol) dissolved in dry THF (4.5 ml) was added dropwise. Water was added and this mixture was stirred for 30 min Brine was added and the aqueous mixture was extracted with DCM. The solvent was concentrated and the crude product was purified on silica (EtOAc/n-Heptane 1:4). 198 mg 2-bromo-3-(4-methoxyphenyl)-1H-indole-1-carbonitrile was obtained.
Reaction SMILES: [F:1][C:2]([F:10])=[CH:3][CH:4]1[CH2:8][NH:7][C:6](=[O:9])[CH2:5]1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[C:16]2[C:22]([CH2:23]Br)=[N:21][N:20](C(OC(C)(C)C)=O)[C:17]2=[N:18][CH:19]=1>CN(C=O)C.O>[Br:13][C:14]1[CH:15]=[C:16]2[C:22]([CH2:23][N:7]3[CH2:8][CH:4]([CH:3]=[C:2]([F:10])[F:1])[CH2:5][C:6]3=[O:9])=[N:21][NH:20][C:17]2=[N:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cc(Br)cnc21
Reactant: O=C1CC(C=C(F)F)CN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CC(C=C(F)F)CN1Cc1n[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 4.9 %

Procedure:
To a solution of 4-(2,2-difluorovinyl)pyrrolidin-2-one x98 (2.86 mmol, 2 eq, 0.42 g) in dry DMF (5 ml) maintained at 0° C. is added natrium hydride (60% dispersion in oil; 2.86 mmol, 2 eq, 0.114 g). The resulting mixture is stirred at room temperature for 0.5 hour and tert-butyl 5-bromo-3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate x155 (1.43 mmol, 1 eq, 0.56 g) dissolved in DMF (2 ml) is added. The resulting mixture is stirred overnight at room temperature. The mixture is poured in water and extracted with AcOEt. The cumulated organic layers are dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture is purified twice by chromatography on silicagel (CH2Cl2/MeOH/NH4OH 98/2/0.2) to afford pure 1-[(5-bromo-1H-pyrazolo[3,4-b]pyridin-3-yl)methyl]-4-(2,2-difluorovinyl)pyrrolidin-2-one 221 (0.025 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH3:12])[N:8]=[CH:7][CH:6]=[C:5]2O.P(Cl)(Cl)([Cl:16])=O>>[Br:1][C:2]1[C:11]([CH3:12])=[N:10][C:9]2[C:4]([CH:3]=1)=[C:5]([Cl:16])[CH:6]=[CH:7][N:8]=2
Reactant: Cc1nc2nccc(O)c2cc1Br
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2nccc(Cl)c2cc1Br
Temperature: 95 °C
Reaction time: 1 h

Procedure:
In a similar manner to Example B1, a mixture of 6-bromo-7-methyl-1,8-naphthyridin-4-ol (3.7 g) and phosphorus oxychloride (25 ml) was stirred at 95° C. for 1 hour to give 3-bromo-5-chloro-2-methyl-1,8-naphthyridine, m.p. 160°-164° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:21])=[C:11]([CH2:13][CH2:14][CH:15]3SCCCS3)[N:12]=2)=[CH:4][CH:3]=1.C1C[O:25]CC1.C(Cl)Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:21])=[C:11]([CH2:13][CH2:14][CH:15]=[O:25])[N:12]=2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCC1SCCCS1
Solvent: O
Solvent: ClCCl
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCC=O
Reaction time: 6 h
Yield: 86 %

Procedure:
Add HgClO4.4H2O (1.49 g, 4.00 mmol) to a solution of 2-(4-bromo-phenyl)-4-(2-[1,3]dithian-2-yl-ethyl)-5-methyl-oxazole (0.672 g, 1.75 mmol) in 1:1 THF:CH2Cl2 (16 mL) and water (1.6 mL). After 6 hours, filter and wash the solids with dichloromethane. Concentrate to give 3-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-propionaldehyde (0.445 g, 86%). MS (m/e): 294 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:26](=[O:41])[N:27]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:28]([CH2:31][C@H:32]([OH:34])[CH3:33])[C:29]=2[CH3:30])=[O:24])=[CH:18][C:17]=1[F:42].[C:43]([NH:53][C@H:54]([C:56](O)=[O:57])[CH3:55])([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:26](=[O:41])[N:27]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:28]([CH2:31][C@H:32]([O:34][C:56](=[O:57])[C@@H:54]([NH:53][C:43]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])[CH3:55])[CH3:33])[C:29]=2[CH3:30])=[O:24])=[CH:18][C:17]=1[F:42]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)O)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)[C@H](C)NC(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)c2cc1OC

Procedure:
The title compound was prepared according to the procedure described in Example of 73 Step 6 by using (R)—N-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (4.1 g, 7.2 mmol), (S)—N-Cbz-alanine (3.2 g, 14.4 mmol). The title compound was obtained as a white powder (4.2 g, 75.1%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:15](Cl)(=[O:17])=[O:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[NH2:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1>N1C=CC=CC=1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:7]1[CH:6]=[CH:5][C:4]([S:15](=[O:17])(=[O:16])[NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:3][C:2]=1[F:1])=[O:14]
Reactant: Nc1nccs1
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)cc1F)C(F)(F)F
Solvent: c1ccncc1
Product: O=C(Nc1ccc(S(=O)(=O)Nc2nccs2)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h
Yield: 54.2 %

Procedure:
Synthesized according to general procedure 70. Under an N2 atmosphere, a mixture of the 3-fluoro-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (5.0 g, 16.4 mmol) and 2-aminothiazole (1.64 g, 16.4 mmol), and pyridine (9.6 mL) was stirred at RT for 19 h. Purification via silica gel chromatography using 0-10% MeOH in CH2Cl2 gave 2,2,2-trifluoro-N-(2-fluoro-4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide (3.28 g, 54%). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=370.1; tR=1.07 min.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[C:16]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:15]2)=[CH:9]1.[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]Br)[CH:33]=1>ClCCl>[CH3:29][O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38][N:26]2[CH2:25][CH2:24][CH:23]([C:16]3[C:17]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[N:14]([CH2:13][C:10]4[CH:11]=[CH:12][O:8][CH:9]=4)[CH:15]=3)[CH2:28][CH2:27]2)[CH:33]=1
Reactant: c1cnc2c(c1)c(C1CCNCC1)cn2Cc1ccoc1
Reactant: COC(=O)c1cccc(CBr)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CN2CCC(c3cn(Cc4ccoc4)c4ncccc34)CC2)c1
Yield: 86.9 %

Procedure:
0.3 ml of triethylamine were added over a solution of 0.4 g (1.42 mmol) of 1-furan-3-ylmethyl-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine in 5 ml of dichloromethane. A solution of 0.39 g (1.71 mmol) of 3-bromomethyl-benzoic acid methyl ester in 2 ml of dichloromethane was added and the crude mixture was stirred at room temperature for 18 hours. The mixture was diluted with 25 ml of dichloromethane and it was washed with water and brine. The organic phase was dried over magnesium sulphate and after filtration and evaporation, 0.53 g of the crude residue were obtained. The crude mixture was purified by flash chromatography over silica gel affording 0.3 g (49% of yield) of the expected product.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16]CC)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>O>[C:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[OH:16])[C:10]([OH:12])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOc1ccc(C(=O)O)cc1-c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(O)c(-c2ccccc2)c1
Reaction time: 1 h

Procedure:
A solution of 3-phenyl-4-ethoxybenzoic acid (26.6 g, 0.110 mole) and 550 ml of acetic acid was added to a one-liter, three-necked, round-bottom flask equipped with a 250 ml pressure equalizing dropping funnel, thermometer, cold water condenser, nitrogen inlet adapter and a polytetrafluoroethylene-coated magnetic stir bar. The flask was purged with nitrogen and the solution was brought to reflux. Approximately 125 ml of a 48 weight percent solution of HBr was added dropwise over fifteen minutes to the refluxing solution. The solution was refluxed for 30 hours. Without cooling, the solvent was rotary evaporated off leaving a slurry of a pinkish solid. The slurry was poured into one liter of deionized water and the mixture was stirred for one hour and filtered. The filter cake was dried in an 80° C. vacuum oven for three hours yielding 3-phenyl-4-hydroxybenzoic acid.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>CC#N.CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: COC(=O)CN
Agent: Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: COC(=O)CNC1=C(c2ccccc2)S(=O)(=O)N(C(C)(C)C)C1=O
Temperature: 65 °C

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.09 g, 3.64 mmol), methyl glycinate hydrochloride (0.68 g, 5.46 mmol) and TEA (10.10 g, 10.92 mmol) were dissolved in a mixture of MeCN (10 mL) and DMF (5 mL) and the reaction mixture was stirred at 65° C. over night. The reaction mixture was evaporated and the residue was diluted with saturated aqueous NaHCO3 and the mixture was extracted with DCM. The organic phases were combined, dried over MgSO4, filtered and evaporated to give the title compound.
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]#[C:14][C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1)[S:3]([CH3:6])(=[O:5])=[O:4].C(OCC)(=O)C>[Pd].CO>[CH3:1][N:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1)[S:3]([CH3:6])(=[O:4])=[O:5]
Reactant: CN1CCN(c2ccc(Nc3nc4c(C#Cc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCN(c2ccc(Nc3nc4c(CCc5ccccc5N(C)S(C)(=O)=O)cccn4n3)cc2)CC1
Reaction time: 1 h

Procedure:
To a Paar bottle was added N-methyl-N-(2-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-ylethynyl}-phenyl)-methanesulfonamide (50.0 mg, 0.0970 mmol), 10% palladium on carbon (50% wet) (25.0 mg, 0.0117 mmol) and 2:1 ethyl acetate:methanol (10 mL). The mixture was degassed and charged with hydrogen (38 psi). The mixture was shaken on a Paar apparatus for 1 hour. The mixture was degassed and kept under an atmosphere of Nitrogen. The mixture was filtered through a plug of diatomaceous earth and rinsed with dichloromethane. The filtrate was evaporated. N-Methyl-N-[2-(2-{2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-ethyl)-phenyl]-methanesulfonamide was isolated as a pale yellow foam (0.037 g, 73%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.31 (s, 1H), 8.58 (d, J=6.6 Hz, 1H), 7.55 (d, J=7.8 Hz, 2H), 7.48-7.44 (m, 1H), 7.35-7.26 (m, 3H), 7.23 (d, J=7.0 Hz, 1H), 6.92-6.84 (m, 3H), 3.23-3.00 (m, 14H), 2.48-2.43 (m, 4H), 2.22 (s, 3H). MS=520 (MH)+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:16][C@H:15]([CH2:17][N:18]=[N+:19]=[N-:20])[O:14][C:13]3=[O:21])=[CH:8][C:7]=2[F:22])[CH:5]=[CH:4][N:3]=[CH:2]1.[C:23]12CC(CC1)=C[CH:24]=2>O1CCOCC1>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:16][C@H:15]([CH2:17][N:18]4[CH:24]=[CH:23][N:20]=[N:19]4)[O:14][C:13]3=[O:21])=[CH:8][C:7]=2[F:22])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(-n3ccnc3)c(F)c2)C(=O)O1
Reactant: C1=C2CCC(=C1)C2
Solvent: C1COCCO1
Product: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-n2ccnc2)c(F)c1
Yield: 80.5 %

Procedure:
(5R)-3-(4-Imidazol-1-yl-3-fluorophenyl)-5-azidomethyloxazolidin-2-one (755 mg, 1.35 mM) was dissolved in dioxane (40 ml), treated with norbornadiene (115 g, 12.5 mM) and heated under reflux for 16 hours. After removal of the solvent, the residue was dissolved in the minimum of dichloromethane and purified by chromatography on a 20 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (660 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].[F:12][C:13]1[CH:14]=[C:15]([CH:19]([CH2:23][CH3:24])[C:20](O)=[O:21])[CH:16]=[CH:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[I:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:21])[CH:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=2)[CH2:23][CH3:24])=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cc(N)ccc1I
Reactant: CCC(C(=O)O)c1cccc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CCC(C(=O)Nc1ccc(I)c(C(N)=O)c1)c1cccc(F)c1

Procedure:
2-Iodo-5-[(2-(3-fluorophenyl)butanoyl)amino]benzamide is prepared from 5-amino-2-iodobenzamide and 2-(3-fluorophenyl)butanoic acid under standard amide coupling conditions with HATU.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1.CO[C:16]([N:20]([CH3:22])[CH3:21])(OC)[CH3:17]>C(OCC)C>[CH3:21][N:20]([CH3:22])[C:16]([CH3:17])=[CH:10][C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:12])([F:13])[F:1])=[CH:8][CH:7]=1)=[O:11]
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Solvent: CCOCC
Product: CC(=CC(=O)c1ccc(C(F)(F)F)cc1)N(C)C
Temperature: 112 °C

Procedure:
A mixture of 4′-(trifluoromethyl)acetophenone (9.8 g) and N-(1,1-dimethoxyethyl)-N,N-dimethylamine (8.2 g) was heated at 112° C. overnight, under nitrogen. The reaction mixture was cooled and concentrated giving an orange solid. Trituration with diethyl ether gave the title compound as a yellow solid