Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CS(O[CH2:12][CH2:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)(=O)=O.[CH:24]12[CH2:30][CH:27]([CH2:28][CH2:29]1)[CH2:26][CH:25]2[CH2:31][NH:32][C:33](=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][C:35]=1[SH:40].CCCCCC.CC(=O)OCC>CN(C=O)C>[CH:27]12[CH2:30][CH:24]([CH:25]([CH2:31][NH:32][C:33]([C:34]3[C:35]([S:40][CH2:12][CH2:13][C:14]([F:22])([F:23])[C:15]4[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=4)=[N:36][CH:37]=[CH:38][CH:39]=3)=[O:41])[CH2:26]1)[CH2:29][CH2:28]2
Reactant: CS(=O)(=O)OCCC(F)(F)c1ccc(F)cc1
Reactant: O=C(NCC1CC2CCC1C2)c1cccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(NCC1CC2CCC1C2)c1cccnc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 60 °C
Yield: 50 %

Procedure:
553 mg (4 mmol) of K2CO3 and 268 mg (1.0 mmol) of 3,3-difluoro-3-(4-fluorophenyl)-propyl methanesulfonate were added in succession to a solution of 262 mg (1.0 mmol) of N-(bicyclo[2.2.1]heptan-2-ylmethyl)-2-mercapto-nicotinamide in DMF (3 ml), and the mixture was heated for 3 h at 60° C. Dilution with water and extraction with EA were then carried out. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 229 mg (0.5 mmol, 53%) of N-(5-bicyclo[2.2.1]heptanyl-methyl)-2-[[3,3-difluoro-3-(4-fluoro-phenyl)-propyl]sulfanyl]-pyridine-3-carboxylic acid amide. MS: m/z 435.2 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][N:15]2[C:38](=[O:52])[CH:39]([NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:40]([CH3:43])([CH3:42])[CH3:41])=[O:13])[C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[C:48]([O:47][C:45]([NH:44][CH:39]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:38]([N:15]1[CH2:16][CH:17]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=3)[N:23]=[C:22]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:21]=2)[CH2:18][CH:14]1[C:12]([NH:11][C:5]1([C:3]([OH:4])=[O:2])[C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:13])=[O:52])=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: COC(=O)C1(NC(=O)C2CC(Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)CN2C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)CC12CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc2c(OC3CC(C(=O)NC4(C(=O)O)CC45CCC5)N(C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C3)cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.4 %

Procedure:
To a mixture of 1-{[1-(2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-spiro[2.3]-hexane-1-carboxylic acid methyl ester (60 mg, 0.084 mmol) in 3 mL of THF, 1.5 mL of MeOH and 0.4 mL of H2O was added LiOH (30 mg, 1.5 mmol). The mixture was stirred at rt for 3 days. It was then concentrated and partitioned between sat. aq. NaHCO3 and ether. The aqueous layer was acidified to pH=4 with dilute HCl, and extracted three times with EtOAc. The combined EtOAc extracts were dried over magnesium sulfate, filtered and concentrated to provide 55 mg of 1-{[1-(2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(7-methoxy-2-phenyl-quinolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-spiro[2.3]hexane-1-carboxylic acid as a white solid (93%). LC-MS: (retention time 1.71 min), MS m/z 701 (M++1) (Method D).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]#[C:11][CH3:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[H-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[C:1]1([N:7]=[C:8]([S:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[C:11]([S:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC#CC(=O)Nc1ccccc1
Reactant: Sc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=CC(=Nc1ccccc1)Sc1ccccc1)Sc1ccccc1
Reaction time: 4 h
Yield: 22.5 %

Procedure:
To a suspension of 0.76 g (4.8 mmol) of N-phenyl-1-propynecarboxamide in toluene (15 mL) was added 1.0 g (4.8 mmol) of phosphorus pentachloride at room temperature and stirred for 4 hours. After removal of the solvent, the residue was dissolved in DMF (15 mL). To a solution of 1.2 mL (12 mmol) of thiophenol in DMF (15 mL) was added 0.31 g (7.1 mmol) of sodium hydride (60% in oil) under ice cooling and stirred for 0.5 hours. The mixture was added to the above-described DMF solution of the residue and stirred under ice cooling for 3 hours. After dilution with tert-butyl methyl ether (150 mL), the mixture was washed sequentially with water and a saturated NaCl solution, dried over anhydrous MgSO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain 0.39 g of phenyl N-phenyl-3-(phenylthio)-2-butenimidothioate (hereinafter referred to as the present compound 44).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2F)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]#[C:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[CH:21][C:20]=1[CH3:31])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2)C=CC=1C(C1C=C(I)C=CC=1C)=O.C([Si](C)(C)C)#C>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]#[C:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[CH:22]=[CH:21][C:20]=1[CH3:31])=[O:18]
Reactant: Cc1ccc(C#C[Si](C)(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Agent: C#C[Si](C)(C)C
Agent: Cc1ccc(I)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl
Product: Cc1ccc(C#C[Si](C)(C)C)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 406, using compound 430 (7.17 mmol) and ethynyltrimethylsilane (7.17 mmol). The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:8 as the eluent to afford the title compound as yellow solid.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C@H:16]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=2[F:31])=[O:21])[CH2:17][OH:18])[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.COCCOC>[NH2:8][C:3]1[C:2]([C:25]2[CH:26]=[CH:27][C:22]([C:20]([NH:19][C@@H:16]([C:12]3[CH:13]=[CH:14][CH:15]=[C:10]([Cl:9])[CH:11]=3)[CH2:17][OH:18])=[O:21])=[C:23]([F:31])[CH:24]=2)=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(N[C@H](CO)c1cccc(Cl)c1)c1ccc(B(O)O)cc1F
Reactant: Nc1nccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Nc1nccnc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Temperature: 120 °C
Yield: 68 %

Procedure:
To the reaction mixture of 3-chloropyrazin-2-amine (288 mg, 2.22 mmol), (S)-4-(1-(3-chlorophenyl)-2-hydroxyethylcarbamoyl)-3-fluorophenylboronic acid (500 mg, 1.48 mmol), PdCl2(dppf)-DCM (108 mg, 0.148 mmol), DME (1.1 mL), 2M Na2CO3 (3.703 mL) was added. The reaction mixture was heated at microwave synthesizer (120° C., 12 min). To the reaction mixture, anhydrous sodium sulfate was added, filtered, and concentrated. The crude product was pre-purified by flash chromatography eluting with EtOAc (containing 10% MeOH) in heptane. The pure fractions were combined and concentrated to provide 389 mg of the desired product in 68% yield. LCMS (m/z): 387 (MH+), 0.69 min.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46](O)=[O:47])[C:41]2=[O:49])=[CH:36][CH:35]=1>>[F:32][C:4]1[CH:3]=[C:2]([NH:1][C:46]([C:42]2[C:41](=[O:49])[N:40]([C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)[CH:45]=[CH:44][N:43]=2)=[O:47])[CH:31]=[CH:30][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[O:23])=[CH:20][CH:21]=3)[S:15][C:8]=12
Reactant: O=C(O)c1nccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1)c1nccn(-c2ccc(F)cc2)c1=O
Yield: 72 %

Procedure:
Prepared from (4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)(morpholino)methanone (Example 129, Step A) and 4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carboxylic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (3 to 5% MeOH in CH2Cl2) to afford 47 mg (72%) of the desired product. LRMS (APCI pos) m/e 666.2 (M+1). 1H-NMR (400 MHz, CDCl3/CD3OD) δ 8.47 (d, 1H), 8.06 (dd, 1H), 7.93 (d, 2H), 7.90 (d, 1H), 7.87 (s, 1H), 7.82 (d, 1H), 7.59 (m, 4H), 7.52 (d, 1H), 7.40 (t, 1H), 7.34 (m, 3H), 6.67 (d, 1H), 3.69-3.79 (m, 8H); 19F NMR (376 MHz, CDCl3/CD3OD) δ −112.7, −128.7.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[C:22]=S.N=C=N>O1CCCC1>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:22]([NH:21][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: S=C=Nc1ccccc1
Agent: N=C=N
Solvent: C1CCOC1
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(Nc4ccccc4)nc23)[C@H]2C=C[C@@H]1C2

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (100 mg, 0.5 mmol), isothiocyanatobenzene (60 L, 0.5 mmol), and PS-carbodiimide (769 mg, 1.01 mmol) were heated overnight at 70° C. in a sealed tube with tetrahydrofuran (10 mL). The solids were removed by filtration and the filtrate was concentrated. The organics were purified by reverse phase chromatography (Gilson) to afford, following neutralization and concentration, the title compound as a yellow solid (21%). 1H NMR (d-4 methanol): 7.73 (m, 3H), 7.29 (m, 2H), 6.98 (m, 1H), 6.44 (m, 1H), 6.40 (m, 1H), 5.31 (m, 1H), 4.88 (m, 3H), 2.98 (s, 1H), 2.89 (s, 1H), 2.73 (m, 1H), 2.37 (m, 1H), 1.57 (m, 1H), 1.30 (m, 2H). MS: 394.9 (M+H). HPLC retention time: 2.33 minutes (G Method).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[CH:24]=[N:25][NH:26][CH:27]=1>>[Br:22][C:23]1[CH:24]=[N:25][N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: Brc1cn[nH]c1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-n3cc(Br)cn3)n2)cc1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.2) (0.98 g, 3.0 mmol) and commercially available 4-bromo-pyrazole (0.66 g, 4.50 mmol) according to the general procedure IVa. Obtained as a white solid (0.83 g, 59%). MS (ISP) 437.0 [(M+H)+]; mp 175.5° C.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.BrC1C(C)=CC=CN=1>>[CH3:33][C:32]1[C:27]([C:24]2[O:23][C:22]([C:9](=[O:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:26][CH:25]=2)=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccnc1-c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: Cc1cccnc1Br
Product: Cc1cccnc1-c1cnc(C(=O)CCCCCCc2ccccc2)o1
Yield: 40 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)-5-(3-methylpyridin-2-yl)oxazole. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (130 mg, 0.196 mmol) and 2-bromo-3-methylpyridine following General Procedure A. Flash chromatography (10% EtOAc/hexanes) yielded the title compound as a thick oil (28 mg, 40%): 1H NMR (CDCl3, 400 MHz) δ 8.52 (dd, 1H, J=4.7, 1.5 Hz), 7.57 (ddd, 1H, J=7.6, 1.4, 0.6 Hz), 7.55 (s, 1H), 7.29-7.24 (m, 2H), 7.18-7.15 (m, 4H), 4.89 (dd, 1H, J=7.6, 5.9 Hz), 2.59 (t, 2H, J=7.8 Hz), 2.55 (s, 3H), 1.93 (m, 2H), 1.61 (m, 2H), 1.36 (m, 4H), 0.89 (s, 9H), 0.10 (s, 3H), −0.02 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 165.6, 150.9, 147.1, 146.0, 142.8, 139.3, 130.3, 128.3, 128.2, 127.1, 125.5, 122.6, 68.6, 36.5, 35.9, 31.4, 29.1, 25.7, 25.7, 25.1, 20.4, 18.2, −5.0, −5.2.
Reaction SMILES: [Si]([O:8][C@H:9]1[C@:16]2([CH3:17])[N:12]([C:13](=[O:28])[N:14]([C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([Cl:26])[C:19]=3[CH3:27])[CH2:15]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:26][C:20]1[C:19]([CH3:27])=[C:18]([N:14]2[CH2:15][C@:16]3([CH3:17])[C@H:9]([OH:8])[CH2:10][CH2:11][N:12]3[C:13]2=[O:28])[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: Cc1c(N2C[C@]3(C)[C@H](O[Si](C)(C)C(C)(C)C)CCN3C2=O)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1c(N2C[C@]3(C)[C@H](O)CCN3C2=O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 11 h
Yield: 89.9 %

Procedure:
To a solution of (7R,7aR)-4-[7-(tert-Butyldimethylsilanyloxy)-7a-methyl-3-oxotetrahydropyrrolo[1,2-c]imidazol-2-yl]-2-chloro-3-methylbenzonitrile (58E) (17 mg, 0.04 mmol) in THF (2 mL) was added acetic acid (100 □L) and a 1 M solution of TBAF in THF (122 □L, 0.12 mmol). After stirring at rt for 11 h, additional TBAF solution was added (100 □L), and after stirring for another 6 h, 200 □L TBAF solution was added. The reaction was stirred overnight, then 100 □L TBAF was added and the reaction stirred an additional 1.5 h. The reaction was then quenched with saturated aqueous NH4Cl and extracted with EtOAC. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The resulting residue was purified via preparative HPLC (Luna C-18, 100×21.2 mm, eluting with 40-100% solvent B (A=90% H2O—10% MeOH—0.1% TFA and B=10% H2O—90% MeOH—0.1% TFA) over 10 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (11 mg). LC/MS m/z 306 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=[O:13])=[CH:11][C:4]=2[NH:3]1.CI.[C:16](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:16][N:3]1[C:2](=[O:1])[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([CH:12]=[O:13])=[CH:11][C:4]1=2
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)COc2ccc(C=O)cc21
Yield: 85.3 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (0.5 g, 2.82 mmol), methyl iodide (0.6 g, 4.23 mmol) and cesium carbonate (1.37 g, 4.23 mmol) were dissolved in dry dimethylformamide (2 mL). The reaction mixture was irradiated by microwave at 100° C. for 30 minutes. The solvent was removed and the residue was washed with water and extracted with dichloromethane. Purification by silica chromatography (ISCO) produced 4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde (0.46 g, 85%). 1H NMR (400 MHz, DMSO-d6): δ 9.95 (s, 1H), 7.62 (s, 1H), 7.59 (d, 1H), 7.20 (d, 1H), 4.80 (s, 2H), 3.34 (s, 3H); MS (ESI) m/z: Calculated for C10H9NO3: 191.1. found: 192.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=1[F:18].[Zn](CC)[CH2:20][CH3:21].CCCCCCC.C(=O)(O)[O-].[Na+]>O1CCOCC1.O>[CH2:20]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=1[F:18])[CH3:21]
Reactant: CC(C)(C)OC(=O)n1ccc2cc(F)c(Br)cc21
Reactant: CC[Zn]CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCCCCCC
Product: CCc1cc2c(ccn2C(=O)OC(C)(C)C)cc1F
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 6-bromo-5-fluoro-1H-indole-1-carboxylate (1.57 g, 5.0 mmol) in dioxane (10 mL) was added a solution of Et2Zn in heptane (3.5 mL, 1.0M, 3.5 mmol) at room temperature. The mixture was kept stirring for 30 min at 90° C. and then cooled down to 0° C., into which saturated sodium bicarbonate was added dropwise. The mixture was then treated with water and extracted with CH2Cl2. The organic layer was dried over Na2SO4 and evaporated. The resulting oil was passed through a silica plug and eluted with 10% ethyl acetate in hexane. The eluent was evaporated to give tert-butyl 6-ethyl-5-fluoro-1H-indole-1-carboxylate as an oil which was solidified upon standing (1.25 g, 95%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[NH:3]1.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]>CN(C)C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[CH2:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]1[C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)CC(=O)Nc2ccccc2N1
Solvent: CN(C)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)CC(=O)Nc2ccccc2N1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 150 °C
Reaction time: 9 h
Yield: 10.9 %

Procedure:
To a solution of 4,4-dimethyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.0 g) in N,N-dimethylaniline (20 ml) was added 4-nitrobenzoyl chloride (0.98 g) at ambient temperature. The mixture was stirred at 150° C. for 9 hours. The resulting mixture was diluted with chloroform and the organic layer was washed successively with 1N hydrochloric acid and saturated aqueous sodium bicarbonate. Drying, filtering and the removal of solvents afforded a crude product. The crude product was chromatographed on silica gel (1% methanol in chloroform) to give 4,4-dimethyl-5-(4-nitrobenzoyl)-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (195 mg) as a slightly yellow solid.
Reaction SMILES: Br[CH2:2][CH:3]1[C:11]2[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[C:5](=[O:15])[O:4]1.[C:16]([C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].CCOC(C)=O>C1COCC1.O>[C:16]([C:20]1[CH:21]=[CH:22][C:23]([N:24]2[C:3]([OH:4])([CH3:2])[C:11]3[C:6](=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:15])=[CH:25][CH:26]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C1OC(CBr)c2cccc([N+](=O)[O-])c21
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(N2C(=O)c3c([N+](=O)[O-])cccc3C2(C)O)cc1
Temperature: 0 °C

Procedure:
The mixture of 3-bromomethyl-7-nitro-3H-isobenzofuran-1-one (0.50 g, 1.84 mmol, Step E) and 4-tert-butylaniline (1.20 mL, 7.36 mmol) in 20 mL of THF was slowly warmed to RT from 0° C., then heated to reflux for 24 h. After cooling to RT, the mixture was diluted with H2O, and extracted with EtOAc. The combined organic portions were washed with brine, dried over MgSO4, filtered, condensed, and the titled compound was obtained as a light yellowish solid after column chromatography (10 to 35% of EtOAc in hexanes).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1.[C:11]1([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:18]2[CH2:23][C:20]3([O:22][CH2:21]3)[CH2:19]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>C1COCC1>[C:24]1([CH:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:18]2[CH2:23][C:20]([CH2:21][S:10][C:7]3[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=3)([OH:22])[CH2:19]2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(C(c2ccccc2)N2CC3(CO3)C2)cc1
Reactant: Fc1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OC1(CSc2ccc(F)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
Sodium hydride (0.128 g of a 60% dispersion in mineral oil, 3.2 mmol) was added to a solution of 4-fluorobenzenethiol (0.29 mL, 2.7 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature for 10 min and then cooled to 0° C. A solution of 5-(diphenylmethyl)-1-oxa-5-azaspiro[2.3]hexane [prepared by the method of J. L. Castro Pineiro et al. WO 97/42189] (0.68 g, 2.71 mmol) in THF (8 mL) was added and the resulting mixture stirred at −1° C. for 40 min then at room temperature overnight. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (100 mL then 50 mL). The organic extracts were washed with saturated brine (100 mL), combined, dried (MgSO4) and concentrated. The residue was purified by flash silica chromatography, eluting with 25% EtOAc/isohexane, to give the title product as an oil (0.82 g, 80%). 1H NMR (400 MHz, CDCl3) δ 2.67 (1H, s), 2.94–2.96 (2H, m), 3.18–3.20 (2H, m), 3.43 (2H, s), 4.34 (1H, s), 6.96–7.02 (2H, m), 7.15–7.19 (2H, m), 7.23–7.26 (4H, m), 7.34–7.36 (4H, m), 7.41–7.46 (2H, m). (376 MHz, CDCl3) δF −115.2. m/z (ES+) 380 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:20][NH:21][C:22]1[C:27]([CH3:28])=[C:26]([N:29]2[CH2:34][CH2:33][CH:32]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([N:41]4C(C)=CC=C4C)[N:36]=3)[CH2:31][CH2:30]2)[N:25]=[CH:24][N:23]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO>C(O)C.O>[NH2:41][C:37]1[N:36]=[C:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:26]3[N:25]=[CH:24][N:23]=[C:22]([NH:21][CH2:20][CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[O:10])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:27]=3[CH3:28])[CH2:34][CH2:33]2)[CH:40]=[CH:39][CH:38]=1
Reactant: Cc1c(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2cccc(-n3c(C)ccc3C)n2)CC1
Agent: Cl
Agent: NO
Solvent: O
Solvent: CCO
Product: Cc1c(NCC(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)ncnc1N1CCC(c2cccc(N)n2)CC1
Temperature: 90 °C
Yield: 12.2 %

Procedure:
100 mg (0.15 mmol) of tert-butyl 2-benzyloxycarbonylamino-3-{6-[6-(2,5-dimethyl-pyrrol-1-yl)-3′,4′,5′,6′-tetrahydro-2′H-[2.4′]bipyridinyl-1′-yl]-5-methyl-pyrimidin-4-ylamino}-propionate is dissolved in 3 ml of ethanol and 0.3 ml of water. 50 mg (0.75 mmol) of hydroxylamine hydrochloride is added and the reaction medium is heated for 18 hours at 90° C. The solvents are evaporated off under reduced pressure (2 kPa) and the crude residue is purified by chromatography on silica gel eluting with a CH2Cl2/MeOH mixture 90:10.30 mg of expected product is obtained in the form of a resin.
Reaction SMILES: [NH2:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]4[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=4[F:32])=[O:20])=[CH:14][CH:13]=3)=[CH:10][C:4]=2[N:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O.CO>N1C=CC=CC=1>[F:32][C:23]1[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:29])[F:30])=[CH:27][C:22]=1[NH:21][C:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[NH:6][C:2]([NH:1][S:34]([CH3:33])(=[O:36])=[O:35])=[N:3][C:4]=3[CH:10]=2)=[CH:17][CH:16]=1)=[O:20]
Reactant: Nc1nc2cc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)ccc2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1nc2cc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)ccc2[nH]1
Reaction time: 168 h
Yield: 40 %

Procedure:
2-amino-5-(4-((2-fluoro-5-(trifluoromethyl)phenyl)aminocarbonylamino)phenoxy)-1H-benzimidazole (the product of Example 22–600 mg) and methanesulfonyl chloride (5 equiv.) in pyridine was stirred at room temperature for 2 days. The resulting mixture was treated with K2C03 (10 equiv.) and H2O (10 mL) and MeOH (10 mL), and heated at 60 C. for 7 days. The crude solid was collected by filtration. Recrystallization from hot MeOH afforded the title compound (280 mg, 40%);