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+].Cl.[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Fc1ccc2c(c1F)CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CCc3c2ccc(F)c3F)nc(N2CCOCC2)cc1=O
Yield: 39.7 %

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, 287 mg of 4,5-difluoroindoline hydrochloride and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 241 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 155 mg of 2-[2-(4,5-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 a brick-red coloured powder, the characteristics of which are the following:
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C@H:14]([OH:24])[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)C1C=CC=CC=1>C(O)C.[Pd]>[F:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][C@@H:14]([OH:24])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])=[CH:22][CH:21]=1
Reactant: O[C@@H](CCCCCOCc1ccccc1)COc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Product: OCCCCC[C@H](O)COc1ccc(F)cc1
Reaction time: 3 h
Yield: 92.5 %

Procedure:
To a solution of (2S)-7-Benzyloxy-1-(4-fluorophenoxy)-heptane-2-ol (5.8 g, 17.5 mmol) in ethanol (30 ml), 10% of Pd/C (100 mg) was added and stirred under H2 atmosphere at normal temperature and pressure for 3 hours. The reaction mixture was filtered through celite, washed with ethanol and concentrated. The residue was purified by silicia gel chromatography using EtOAc-hexane (1:1) to give (6S)-7-(4-fluorophenoxy)-heptane-1,6-diol (3.92 g, 93%); [α]D+12 (c 3.1, CHCl3), 1H-NMR (CDCl3, 200 Hz): δ 1.29-1.69 (m, 8H), 3.65 (t, J=6.8 Hz, 2H), 3.82-4.02 (m, 2H), 6.75-7.0 (m, 4H); HRMS (EI): calcd. for C13H19O3F(M+) 242.131823 found 242.131900.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][C:11]([F:14])([F:13])[F:12])[CH:3]=1.O.[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([C:16]#[N:17])=[CH:3][C:4]=1[O:10][C:11]([F:14])([F:13])[F:12])=[O:7]
Reactant: CN(C)C=O
Reactant: O=Cc1ccc(Br)cc1OC(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc(C=O)c(OC(F)(F)F)c1

Procedure:
10.63 g (39.51 mmol) of 4-bromo-2-(trifluoromethoxy)benzaldehyde, 3.43 g (29.24 mmol) of zinc cyanide and 1.37 g (1.19 mmol) of tetrakis(triphenylphosphine)palladium(0) are dissolved in 80 ml of DMF. The reaction mixture is then reacted in several portions in a single mode microwave (Emrys Optimizer, 5 min at 220° C.). The combined mixtures are mixed with water and extracted twice with toluene. The combined organic phases are washed with saturated sodium chloride solution and dried with sodium sulfate, and then the solvent is removed in a rotary evaporator. The residue is purified by column chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 10:1). 3.32 g (78% of theory) of the title compound are obtained with a purity of 80% (according to LC-MS).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[N:19]4)(=O)=O)=CC=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1>CS(C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:12][CH:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[N:19]4)[CH2:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nccnc4c3O2)cc1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6nccnc6c5O4)CC3)c2c1
Temperature: 80 °C

Procedure:
To a solution of (2R)-2,3-dihydro[1,4]dioxino[2,3-f]quinoxalin-2-ylmethyl 4-methylbenzenesulfonate (0.462 g, 1.241 mmole) in methyl sulfoxide (25 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.073 g, 4.962 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (250 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.382 g (74%) of the (S)-enantiomer of the title compound as a tan solid. Rf=0.37 (silica, methanol:ethyl acetate 1:9); mp>200° C. dec.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)=[C:4]([O:26][CH3:27])[CH:3]=1.[CH2:28]([NH2:34])[CH:29]1[O:33][CH2:32][CH2:31][CH2:30]1>>[F:8][C:7]1[CH:6]=[C:5]([C:9]2[O:10][C:11]([C:14]3[C:15]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[N:12][N:13]=2)[C:4]([O:26][CH3:27])=[CH:3][C:2]=1[NH:34][CH2:28][CH:29]1[CH2:30][CH2:31][CH2:32][O:33]1
Reactant: NCC1CCCO1
Reactant: COc1cc(F)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Product: COc1cc(NCC2CCCO2)c(F)cc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 53 %

Procedure:
As described for example 26, 2-(4,5-difluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.54 mmol) instead of 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole was converted using rac-tetrahydrofurfurylamine instead of thiomorpholine to the title compound (129 mg, 53%) which was obtained as an off-white solid. MS: m/e=451.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][NH:12][C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)=[CH:5][CH:4]=1.[C:25]([OH:31])([C:27](F)(F)F)=[O:26]>>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([N:12]([CH2:11][CH2:10][O:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:27][C:25]([O:31][C:15]([CH3:21])([CH3:16])[CH3:14])=[O:26])=[CH:14][C:15]=1[C:21]([F:22])([F:23])[F:24])#[N:18]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(OCCNc2ccc(C#N)c(C(F)(F)F)c2)cc1
Product: COc1ccc(OCCN(CC(=O)OC(C)(C)C)c2ccc(C#N)c(C(F)(F)F)c2)cc1

Procedure:
Synthesized as described in Example 70B from 4-[(2-{[4-(methyloxy)phenyl]oxy}ethyl)amino]-2-(trifluoromethyl)benzonitrile, excluding TFA deprotection of tert-butyl ester. Purified by flash chromatography (EtOAc/hexanes), obtained as a colorless gum: MS (APCI) m/z 451 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:30][CH2:29][CH2:28][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH:17]([OH:27])[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:11])=O)(C)(C)C.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([NH:38][C:39]([N:8]1[CH2:30][CH2:29][CH2:28][C@H:9]1[C:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH:17]([OH:27])[CH2:18][O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:11])=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COCc1ccccc1
Product: O=C(NCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)COCc1ccccc1

Procedure:
By the same procedure as in Example 21-C), while using (2S)-1-[N-(tert-butoxycarbonyl)-L-prolyl]-2-(2-benzyloxy-1-hydroxyethyl)pyrrolidine (274 mg) and benzyl isocyanate (89 μl), there was obtained 243 mg of the title compound.
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](O)=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=5[N:14]([CH3:22])[CH:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)cc(F)c2)c2c(N)ncnc21

Procedure:
A solution of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl (150 mg, 0.443 mmol), (3,5-difluorophenyl)acetic acid (76 mg, 0.443 mmol), HATU (169 mg, 0.443 mmol), DIEA (0.310 mL, 1.774 mmol) was stirred at room temperature overnight. LCMS indicated partial conversion, with a mixture of starting material, desired product and bis-acylated material, so the reaction mixture was poured into water (10 mL), and a precipitate formed. The precipitate was collected by filtration, and the residue was washed with water (10 mL), and dried at the pump for an hour. The beige solid was adsorbed onto silica, and purified by flash chromatography (0-10% methanol in DCM, 12-g column) to afford a pale yellow solid which showed presence of bis-acylated material. The product was adsorbed onto silica and purified by flash chromatography (100% EtOAc-10% MeOH in EtOAc, then 10% MeOH in DCM, 24-g column) to afford 5-{1-[(3,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (92 mg, 49.5% yield) as a white solid. LC-MS (ES) m/z=420 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.21-3.28 (m, 2H), 3.74 (s, 3H), 3.95 (s, 2H), 4.24 (t, J=8.34 Hz, 2H), 6.04 (br. s., 2H), 7.06 (d, J=6.57 Hz, 2H), 7.14 (t, J=9.60 Hz, 1H), 7.21-7.29 (m, 2H), 7.33 (s, 1H), 8.07-8.21 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:10]/[S@:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[O:12])/[CH3:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([NH:10][S@:11]([C:13]([CH3:14])([CH3:16])[CH3:15])=[O:12])[CH3:9])=[CH:6][CH:7]=1
Reactant: C/C(=N\[S@@](=O)C(C)(C)C)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](N[S@@](=O)C(C)(C)C)c1ccc(Br)cc1
Temperature: -50 °C

Procedure:
(S,E)-N-(1-(4-bromophenyl)ethylidene)-2-methylpropane-2-sulfinamide (0.5 g, 1.66 mmol) was dissolved in THF/H2O=50:1 (10 mL) and cooled to −50° C. Then NaBH4 (0.19 g, 4.97 mmol) was added. The resulting mixture was warmed to RT over 3 h and then concentrated. The residue was purified by column chromatography to afford the titled compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([Si](C(C)C)(C(C)C)C(C)C)[CH:7]=[CH:6]2)[CH3:2].[F-].[NH4+]>C1COCC1.CO>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)[CH3:2]
Reactant: CCc1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The Indole 9 (2.2 g, 7.29 mmol) was dissolved in THF (20 mL) and a solution of ammonium fluoride (NH4F; 1.4 g, 37.8 mmol) in MeOH (20 mL) was added and stirred for 72 hours at room temperature. The solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with 2N H3PO4, dried over MgSO4, filtered and evaporated to give compound 10 as an off white solid (1.06 g; M+1=146.2).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@:6]([NH:16][C:17](=[O:19])[CH3:18])([CH3:15])[CH2:7][CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2].[CH2:20]([C@@]1(CCC2N(C)C=CC=2)COC(=O)N1)C>>[C:1]([O:4][CH2:5][C@@:6]([NH:16][C:17](=[O:19])[CH3:18])([CH2:15][CH3:20])[CH2:7][CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@](C)(CCc1cccn1C)COC(C)=O
Reactant: CC[C@@]1(CCc2cccn2C)COC(=O)N1
Product: CC[C@@](CCc1cccn1C)(COC(C)=O)NC(C)=O
Yield: 77 %

Procedure:
The reaction was carried out in the similar manner to Reference example 1 (1 g) and (1h) using (4R)-4-ethyl-4-[2-(1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one obtained Reference example 2 (2e) as a starting material to obtain the title compound (yield: 77%).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]([F:39])([F:38])[F:37])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: FC(F)(F)Oc1cccc2sc(Cl)nc12
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(OC(F)(F)F)cccc5s4)cc3CC[C@@H]12
Yield: 77.5 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-trifluoromethoxybenzothiazole (117 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 141 mg (77%) of the title compound as a white solid. mp 168°-173°. FDMS: m/e=478. α[D]589 =+57.89 (c=0.59, chloroform).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]2[C:15]=1[F:26].Cl.[NH:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([N:28]3[CH2:31][CH:30]([OH:32])[CH2:29]3)=[O:25])=[C:16]2[C:15]=1[F:26]
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)c(F)c12
Reactant: OC1CNC1
Agent: Cl
Product: O=C(c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)c(F)c12)N1CC(O)C1

Procedure:
The title compound was prepared by the method substantially similar to that mentioned in Example-12, using (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-4-fluoropyrazolo[1,5-a]pyridine-3-carboxylic acid (prepared by the method mentioned in the Example 248) and 3-azetidinol hydrochloride to afford the crude compound. The crude compound was purified by Preparative TLC (using Silicagel GF254, 1000 u coated 20×20 cm dimension glass plate and 100% EtOAc as eluent) to afford 12 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:26])C(=O)C1.C(=O)(O)[O-].[Na+]>C(#N)C>[NH2:1][C:2]1[C:3]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([F:18])[CH:9]=2)=[N:4][C:5]([Br:26])=[CH:6][N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-c2nccnc2N)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccc(-c2nc(Br)cnc2N)cc1F
Reaction time: 1 h
Yield: 96 %

Procedure:
To a suspension of methyl 4-(3-aminopyrazin-2-yl)-2-fluorobenzoate (31.5 g, 127 mmol) in acetonitrile (430 mL) at 0° C. was added NBS (23.9 g, 134 mmol). The reaction mixture was stirred in ice bath for 1 h, sat. sodium bicarbonate was added, stirred 30 min and product was extracted with ethylacetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was recrystallized in EtOAc and heptane to give methyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate as brown color solid in 96% yield. LCMS (m/z): 326.0/328.0 (MH+), 0.87 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:34]([NH2:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([CH3:36])[CH3:35]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:43][C:34]([CH3:36])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:35])=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1Cl
Reactant: CC(C)(N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C(=O)NC(C)(C)c2ccccc2)cc1Cl
Yield: 97.2 %

Procedure:
In a similar manner to Step 1 of Example 137, 3-chloro-4-methylbenzoic acid (1.00 g, 5.86 mmol) was dissolved in DMF (20 mL), and the solution was treated with EDCI (2.25 g, 11.7 mmol), HOBT monohydrate (792 mg, 5.86 mmol) and cumylamine (1.69 mL, 11.7 mmol). The reaction mixture was added with water. The precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure. The obtained solid was purified by slurry using diisopropylether to obtain 3-chloro-4-methyl-N-(1-methyl-1-phenylethyl)benzamide (1.64 g, yield 97%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15](=O)[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15](=[S:29])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)COc1cc(F)c(C)cc1C(=O)NCc1ccc(Br)cc1F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(F)c(C)cc1C(=S)NCc1ccc(Br)cc1F
Temperature: 115 °C
Yield: 177.9 %

Procedure:
A stirring solution of [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester (0.816 g, 1.83 mmol) in pyridine (3.7 mL, 0.5 M) was treated with phosphorus pentasulfide (0.41 g, 0.92 mmol) and heated to 115° C. for 3 h. The reaction was allowed to cool to room temperature, diluted with ethyl acetate and successively washed with 1 M HCl and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting brown oil was dissolved in a minimal amount of methylene chloride and flushed through a plug of silica using 40% ethyl acetate in heptane as the eluant. The filtrate was concentrated to afford [2-(4-bromo-2-fluoro-benzylthiocarbamoyl)-5-fluoro-4-methyl-phenoxy]-acetic acid ethyl ester (0.75 g, 89%) as a yellow solid: mp 98–100° C.; Rf 0.45 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 mHz) δ 10.15 (bs, 1H), 8.26 (d, J=8.4 Hz, 1 H), 7.38 (t, J=8.4 Hz, 1 H), 7.26–7.23 (m, 2 H), 6.53 (d, J=10.8 Hz, 1 H), 5.08 (d, J=5.4 Hz, 2 H), 4.67 (s, 3 H), 4.20 (q, J=7.2 Hz, 2 H), 2.23 (s, 2 H), 1.27 (dt, J1=6.8 Hz, J2=0.6 Hz, 3 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:24][C:25]([CH3:29])([CH3:28])[C:26]#[CH:27]>>[CH3:24][C:25]([CH3:29])([CH3:28])[C:26]#[C:27][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(Br)cc1
Reactant: C#CC(C)(C)C
Product: CC(C)(C)C#Cc1ccc(CCS(=O)(=O)Nc2ccccc2S(N)(=O)=O)cc1
Yield: 16 %

Procedure:
The title compound was synthesized as described for Example 179a) in 16% yield, starting from 2-(2-(4-bromophenyl)ethylsulfonamido)benzenesulfonamide and 3,3-dimethyl-1-butyne.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]#[N:21])=[C:7]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:18]=O)[CH:17]=3)[N:8]2[CH3:11])=[CH:4][CH:3]=1.[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C@H:31]([NH2:34])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C@H:31]([NH:34][CH2:18][C:16]2[CH:15]=[N:14][CH:13]=[C:12]([C:7]3[N:8]([CH3:11])[C:9]4[C:5]([C:6]=3[C:20]#[N:21])=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=4)[CH:17]=2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccc(Cl)cc21
Product: Cn1c(-c2cncc(CN[C@H]3CCN(C(=O)OC(C)(C)C)C3)c2)c(C#N)c2ccc(Cl)cc21

Procedure:
6-Chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 126) and (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester are processed according to the method described in Example 170 to give (S)-3-{[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester. MS (ESI) m/z 466.1 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][C:9]([CH:10]=O)=[CH:8][C:7]=1[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:22]([NH:26][OH:27])([CH3:25])([CH3:24])[CH3:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[C:1]([C:6]1[C:13]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:12][C:9]([CH:10]=[N+:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[O-:27])=[CH:8][C:7]=1[C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1c(C(C)(C)C)cc(C=O)cc1C(C)(C)C
Reactant: CC(C)(C)NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCC(=O)c1c(C(C)(C)C)cc(C=[N+]([O-])C(C)(C)C)cc1C(C)(C)C
Yield: 50.2 %

Procedure:
To a solution of 4-n-butanoyl-3,5-di-tert-butylbenzaldehyde (9.63 g, 0.032 mol) in benzene (200 mL) was added tert-butylhydroxylamine (3.52 g, 0.040 mol) and p-toluenesulfonic acid (0.100 g). Using a Dean-Stark trap, the resulting solution was refluxed until no more aldehyde was detected by TLC (Rf=0.30 for product and 0.91 for starting material using 3:1 hexanes/EtOAc). The solvent was removed in vacuo and the residue was crystallized from EtOAc and hexanes to afford the titled compound (50.2% yield) as a white solid, m.p. 216.9–236.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O>[F:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: NS(=O)(=O)c1ccc(F)c(F)c1
Reactant: C1CNCCN1
Solvent: O
Product: NS(=O)(=O)c1ccc(N2CCNCC2)c(F)c1
Temperature: 110 °C
Yield: 74.3 %

Procedure:
A mixture of 0.5 g (3 mmol) 3,4-Difluoro-benzenesulfonamide and 1.15 g (13 mmol) piperazine in 2.3 ml water was heated to 110° C. for 3 h and subsequently the precipitate was filtered off and washed with water and toluene. The residue was dried under high vacuum to yield 0.578 g (86%) of the title compound as white crystals.