Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1(Br)[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[N:4]=[C:3]1[CH3:18].[NH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[NH2:21].Cl>O>[CH3:18][C:3]1[CH:2]([N:21]=[N:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[C:6](=[O:7])[N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[N:4]=1
Reactant: NNc1ccccn1
Reactant: CC1=NN(c2ccc(S(=O)(=O)O)cc2)C(=O)C1(Br)Br
Agent: Cl
Solvent: O
Product: CC1=NN(c2ccc(S(=O)(=O)O)cc2)C(=O)C1N=Nc1ccccn1

Procedure:
41.0 g (0.10 mole) of 4,4-dibromo-3-methyl-1-(4-sulfophenyl)-2-pyrazolin-5-one, which can be prepared according to the method of Machiele, U.S. Pat. No. 3,952,009 (Example 1), and 16.0 g (0.15 mole) of 2-hydrazinopyridine were combined in 180 ml of water. The mixture was heated on the steam bath a total of six hours. After a few minutes of heating, the solution goes to a very thick slurry. The mixture was cooled somewhat, 10 ml of concentrated HCl were added, and the orange solid was isolated by suction filtration. After washing once with tetrahydrofuran, twice with ether, and drying, the yield of dye was 17.8 g (50 percent).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:25])[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]O.C(Br)(Br)(Br)[Br:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:27][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10]([NH:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])=[O:25]
Reactant: CCCCCCCN(CCCCCO)C(=O)Nc1ccc(F)cc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCN(CCCCCBr)C(=O)Nc1ccc(F)cc1F
Reaction time: 3 h
Yield: 100 %

Procedure:
Part D. To a solution of N'-(2,4-difluorophenyl)-N-heptyl-N-5-hydroxypentylurea (15.0 g, 0.042 mol) and carbon tetrabromide (16.75 g, 0.051 mol) in methylene chloride (350 mL) under a nitrogen atmosphere at ambient temperature, a solution of triphenylphosphine (13.24 g, 0.051 mol) in methylene chloride (100 mL) was added slowly. The reaction mixture was stirred for 3 hours and was concentrated in vacuo to give crude viscous oil. The product was purified by flash chromatography on silica gel (400 mL) eluting with hexane:ethyl acetate (90:10 v:v) to give N-(5-bromopentyl)-N'-(2,4-difluorophenyl)-N-heptylurea as a viscous colorless oil (17.5 g, 0.042 mol). 1H NMR (CDCl3) δ 8.14-8.00(m, 1H), 6.92-6.79(m, 2H), 6.35(bs, 1H), 3.49-3.25(m, 6H), 1.99-1.26 (m, 16H), 0. 915 (t, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([Sn](C)(C)C)=[CH:6][C:5]=2[N:4]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:3]=1.Br[C:26]1[CH:34]=[C:33]([F:35])[CH:32]=[C:31]2[C:27]=1[CH:28]=[CH:29][N:30]2[S:36]([C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)(=[O:38])=[O:37]>CN(C=O)C.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>[F:1][C:2]1[C:10]2[C:9]([NH2:11])=[CH:8][C:7]([C:26]3[CH:34]=[C:33]([F:35])[CH:32]=[C:31]4[C:27]=3[CH:28]=[CH:29][N:30]4[S:36]([C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)(=[O:37])=[O:38])=[CH:6][C:5]=2[N:4]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:3]=1
Reactant: C[Sn](C)(C)c1cc(N)c2c(F)nn(S(=O)(=O)c3ccccc3)c2c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)n2ccc3c(Br)cc(F)cc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1cc(-c2cc(F)cc3c2ccn3S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc2c1c(F)nn2S(=O)(=O)c1ccccc1

Procedure:
A solution of 3-fluoro-1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (0.65 g), 4-bromo-6-fluoro-1-[(4-nitrophenyl)sulfonyl]-1H-indole (0.69 g) and Pd(PPh3)4 (0.17 g) in DMF (5 ml) was heated to 120° C. for 18 h. The mixture was concentrated in vacuo and purified by silica cartridge (100 g) by Flashmaster II using a gradient of cyclohexane and ethyl acetate to give the title compound, 0.48 g as an orange solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.[C:11]([NH:13][C:14](=[N:17][CH3:18])SC)#[N:12]>>[C:11]([NH:13][C:14]([NH:17][CH3:18])=[N:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1)#[N:12]
Reactant: NCCSCc1nccs1
Reactant: CN=C(NC#N)SC
Product: CNC(=NCCSCc1nccs1)NC#N

Procedure:
Reaction of [(2-aminoethyl)thiomethyl]thiazole (from the dihydrobromide 20.2 g.) with N-cyano-N',S-dimethylisothiourea (7.75 g.) by a procedure similar to that described in Example 3(a) afforded N-cyano-N'-methyl-N"-[2-(2-thiazolylmethylthio)ethyl]guanidine, m.p. 120°-122.5°, following chromatography on silica gel with acetonitrile as eluant, and recrystallisation from isopropyl alcohol. (Found: C, 42.3; H, 5.1; N, 27.2; S, 25.3. C9H13N5S2 requires: C, 42.3; H, 5.1; N, 27.4; S, 25.1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[C:5]([NH:26][C:27]([O:29][CH2:30][C:31]([Cl:34])([Cl:33])[Cl:32])=[O:28])[O:4][N:3]=1.O[CH:36]([CH2:41][CH:42]([CH3:44])[CH3:43])[C:37]([O:39][CH3:40])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O>[C:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[N:26]([C:27]([O:29][CH2:30][C:31]([Cl:32])([Cl:33])[Cl:34])=[O:28])[C@H:36]([C:37]([O:39][CH3:40])=[O:38])[CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:12][CH:11]=2)[CH2:18][CH2:17]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COC(=O)C(O)CC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1onc(C)c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To tert-butyl 4-[4-(3-methyl-5-{[(2,2,2-trichloroethoxy)carbonyl]amino}isoxazol-4-yl)phenyl]piperazine-1-carboxylate (617 mg, 1.16 mmol), methyl 2-hydroxy-4-methylpentanoate (255 mg, 1.74 mmol) and triphenyl phosphine (460 mg, 1.74 mmol) in dry DMF (15 mL) at 0° C. under dry nitrogen was added diisopropyl azodicarboxylate (0.35 mL, 1.74 mmol) dropwise over ½ hour and the reaction mixture was stirred for 2 days at rt. The reaction was poured into water and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 25/75) to afford methyl N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-3-methylisoxazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate.
Reaction SMILES: [C:1]1([CH2:11][C:12]#[N:13])([CH2:8][C:9]#[N:10])[CH2:4][C:3](=[CH:5][C:6]#[N:7])[CH2:2]1.[NH:14]1[CH:18]=[C:17]([C:19]2[C:20]3[CH:27]=[CH:26][N:25]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:21]=3[N:22]=[CH:23][N:24]=2)[CH:16]=[N:15]1.N12CCCN=C1CCCCC2>C(#N)C>[CH3:33][Si:32]([CH3:35])([CH3:34])[CH2:31][CH2:30][O:29][CH2:28][N:25]1[C:21]2[N:22]=[CH:23][N:24]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([C:3]4([CH2:5][C:6]#[N:7])[CH2:2][C:1]([CH2:8][C:9]#[N:10])([CH2:11][C:12]#[N:13])[CH2:4]4)[CH:18]=3)[C:20]=2[CH:27]=[CH:26]1
Reactant: N#CC=C1CC(CC#N)(CC#N)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CC#N)(CC#N)C4)c3)ncnc21
Temperature: 50 °C

Procedure:
The crude 2,2′,2″-cyclobutane-1,1-diyl-3-ylidenetriacetonitrile (1 g, 0.006 mol) was combined with 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.2 g, 0.0006 mol) in acetonitrile (10 mL) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL, 0.001 mol) was added under nitrogen. The mixture was heated at 50° C. over night. The reaction was concentrated and purified with Combiflash (silica gel, 0-100% EtOAc/Hex) to give the desired product as light brown oil. LCMS calculated for C25H31N8OSi(M+H)+: 487.2; Found: 487.4.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:27]#[N:28])[C:16]([CH3:26])=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]=3F)[N:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:36][N:37]([CH3:43])[C@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>CS(C)=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[O:11][C:12]3[C:13](=[C:15]([C:27]#[N:28])[C:16]([CH3:26])=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]=3[N:40]3[CH2:41][CH2:42][C@H:38]([N:37]([CH3:43])[CH3:36])[CH2:39]3)[N:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CC(=O)N1CCC(c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)CC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)N1CCC(c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)CC1
Temperature: 90 °C
Reaction time: 4 h
Yield: 25.4 %

Procedure:
2-(1-Acetylpiperidin-4-yl)-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-104) (0.23 g, 0.61 mmol) was dissolved in dimethyl sulfoxide (7 ml), triethylamine (0.18 ml, 1.30 mmol) and (3S)-3-(dimethylamino)pyrrolidine (85.0 μl, 0.67 mmol) were added, followed by stirring an external temperature of about 90° C. for 4 hours. After dilution with ethyl acetate, this was washed with water, dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure and the resulting residue was purified by silica gel column chromatography (silica gel 10 g, dichloromethane:methanol=30:1) to obtain a colorless oil (73 mg, 25%). This was dissolved in dioxane and freeze-dried into solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:32][CH2:31][CH2:30][CH:29]1[CH2:33][C:34](O)=[O:35]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34](=[O:35])[CH2:33][CH:29]5[CH2:30][CH2:31][CH2:32][O:28]5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)CC1CCCO1
Agent: Cl
Product: O=C(CC1CCCO1)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (85 mg, 77%), MS (ISP) m/z=443.5 [(M+H)+], mp 181.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and rac-(tetrahydro-furan-2-yl)-acetic acid.
Reaction SMILES: [I-:1].[Zn+2:2].[I-].[C@@H:4]12[O:10][C@@H:7]([CH2:8][CH2:9]1)[CH2:6][C@H:5]2[CH2:11]O>C1COCC1>[I-:1].[C@@H:4]12[O:10][C@@H:7]([CH2:8][CH2:9]1)[CH2:6][C@H:5]2[CH2:11][Zn+:2]
Reactant: OC[C@@H]1C[C@@H]2CC[C@H]1O2
Reactant: [Zn+2]
Agent: [I-]
Solvent: C1CCOC1
Product: [Zn+]C[C@@H]1C[C@@H]2CC[C@H]1O2

Procedure:
The title compound was prepared in an analogous manner to tetrahydro-2H-pyran-4-yl)zinc(II) iodide except that (1R,2S,4S)-7-oxabicyclo[2.2.1]heptan-2-ylmethanol was used instead of tetrahydro-2H-pyran-4-ol in Step 1 to afford a 0.15M solution of ((1R,2R,4S)-7-oxabicyclo[2.2.1]heptan-2-ylmethyl)zinc(II) iodide in THF.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:17][OH:18])(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][CH:35]=[CH:36][N:37]=2)=[C:29]([F:38])[C:28]=1[F:39].O1C=NC(C2C=CC(CN([C@@H]3CCCC[C@H]3CO)S(C3C=CC(Cl)=CC=3)(=O)=O)=CC=2)=N1>>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[O:34][CH:35]=[CH:36][N:37]=3)=[C:29]([F:38])[C:28]=2[F:39])[C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[CH2:17][OH:18])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)s1
Reactant: Fc1c(CBr)ccc(-c2ncco2)c1F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncon2)cc1)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: O=S(=O)(c1ccc(Cl)s1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Yield: 17.4 %

Procedure:
The title compound was synthesized from 5-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)thiophene-2-sulfonamide (100 mg, 0.32 mmol), cesium carbonate (126 mmol, 0.39 mg), and 2-(4-(bromomethyl)-2,3-difluorophenyl)oxazole (93 mg, 0.39 mmol) according to the procedure described for N-(4-(1,2,4-oxadiazol-3-yl)benzyl)-4-chloro-N-(trans-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 11) to give 5-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-(trans-2-(hydroxymethyl)cyclohexyl)thiophene-2-sulfonamide (28 mg, 17%). 1H NMR (400 MHz, CDCl3) δ ppm 7.78-7.84 (m, 1H), 7.79 (s, 1H), 7.50-7.57 (m, 1H), 7.37 (d, J=4.03 Hz, 1H), 7.32 (s, 1H), 6.95 (d, J=3.78 Hz, 1H), 4.58 (d, J=14.00 Hz, 1H), 4.42 (d, J=14.00 Hz, 1H), 3.53-3.73 (m, 2H), 2.98-3.19 (m, 1H), 2.38 (br. s., 1 H), 1.59-1.84 (m, 3H), 1.40-1.57 (m, 2H), 1.29-1.39 (m, 1H), 1.01-1.26 (m, 3H). Analytical HPLC R.T.=22.41 min. MS [M+H]+=503. HRMS [M+H]+ calc'd 503.0678, found 503.0654.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:24])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([C:19]([OH:21])=[O:20])=[CH:14][CH:13]=[C:12]([O:22][CH3:23])[C:11]=2[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[N+:37]([C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1)([O-:39])=[O:38]>ClCCl>[C:1]([O:5][C:6]([N:8]([CH3:24])[C:9]1[CH:18]=[CH:17][C:16]2[C:15]([C:19]([O:21][C:43]3[CH:44]=[CH:45][C:40]([N+:37]([O-:39])=[O:38])=[CH:41][CH:42]=3)=[O:20])=[CH:14][CH:13]=[C:12]([O:22][CH3:23])[C:11]=2[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C(=O)O)c2ccc(N(C)C(=O)OC(C)(C)C)nc12
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(N(C)C(=O)OC(C)(C)C)nc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 90.5 %

Procedure:
2-[(t-Butyloxycarbonyl)(methyl)amino]-8-methoxyquinoline-5-carboxylic acid (0.311 g), ethyldimethylaminopropylcarbodiimide hydrochloride (0.269 g), 4-nitrophenol (0.195 g), N,N-dimethylaminopyridine (20 mg) and dichloromethane (20 ml) were combined and then stirred at room temperature for 17 h. The reaction mixture was evaporated in vacuo onto silica and purified by flash chromatography to give the title compound (0.384 g) as a pale yellow solid.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13]>O>[CH2:9]([O:8][C:6]([CH2:5][NH:4][CH2:13][CH2:12][C:11]([O:15][CH2:16][CH3:17])=[O:14])=[O:7])[CH3:10]
Reactant: CCOC(=O)CN
Reactant: C=CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)CCNCC(=O)OCC
Temperature: 25 °C

Procedure:
A 4.7 M aqueous solution of sodium hydroxide (50 mL) is added into a stirred, ice-cooled solution of ethyl glycinate hydrochloride (32.19 g, 0.23 mole) in water (50 mL). Then, ethyl acrylate (23.1 g, 0.23 mole) is added and the mixture is stirred at room temperature until completion of the reaction is ascertained by TLC. After 19 h the solution is partitioned with dichloromethane (3×100 mL). The organic layer is dried with anhydrous sodium sulfate, filtered and evaporated. The residue is distilled to afford AA (28.8 g, 61%).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[S:19][C:10]3=[N:11][C:12]([S:17][CH3:18])=[C:13]([Cl:16])[C:14]([CH3:15])=[C:9]3[C:8]=2[NH2:20])=[O:6])[CH2:3][CH2:2]1.[OH:21]O.O>C(O)(=O)C>[CH:1]1([NH:4][C:5]([C:7]2[S:19][C:10]3=[N:11][C:12]([S:17]([CH3:18])=[O:21])=[C:13]([Cl:16])[C:14]([CH3:15])=[C:9]3[C:8]=2[NH2:20])=[O:6])[CH2:3][CH2:2]1
Reactant: CSc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Temperature: 35 °C
Reaction time: 16 h
Yield: 71 %

Procedure:
To a slurry of 3-amino-5-chloro-4-methyl-6-methylsulfanyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (7.5 g, 22.87 mmol) in glacial acetic acid (75 ml) is added a solution of 30% hydrogen peroxide in water (2.85 ml, 25.16 mmol). The mixture is stirred at 35° C. for 16 hour, cooled to room temperature, and poured over water (300 ml). A bright yellow precipitate is formed. The mixture is stirred at 0° C. for 1 hour then the solid is collected by filtration and dried under vacuum at 60° C. for 3 hours to afford the title compound as a bright yellow solid (5.58 g, 71%). Mass (m/z): 344.1 (M++1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[CH3:53][N:54]1[CH:58]=[C:57]([C:59](Cl)=[O:60])[CH:56]=[N:55]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:59]([C:57]2[CH:56]=[N:55][N:54]([CH3:53])[CH:58]=2)=[O:60])[CH2:25]1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: Cn1cc(C(=O)Cl)cn1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(C(=O)N2CC(CC(=O)Nc3ccc4cc3CCc3cncc(c3)Nc3ncc(Cl)c(n3)N4)C2)cn1
Yield: 50 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 1-methyl-1H-pyrazole-4-carbonyl chloride as the starting materials in 50% yield. LCMS for C27H27ClN9O2 (M+H)+: m/z=544.0.
Reaction SMILES: [CH2:1]([O:3][C:4](OCC)=[CH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8])[CH3:2].[NH4+:15].[OH-]>CC#N.O>[NH2:15]/[C:4](/[O:3][CH2:1][CH3:2])=[CH:5]\[C:6](=[O:11])[C:7]([F:10])([F:9])[F:8]
Reactant: [NH4+]
Reactant: CCOC(=CC(=O)C(F)(F)F)OCC
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CCO/C(N)=C/C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 4,4-diethoxy-1,1,1-trifluorobut-3-en-2-one (7.94 g, 37.4 mmol) in MeCN (30 mL) at room temperature was dropped 28% solution of NH4OH in water (7 mL). It was stirred at room temperature overnight. After solvent was removed under reduced pressure, to it was added CH2Cl2 and washed with water. The organic layer was dried over MgSO4 and concentrated under reduced pressure to afford (E)-4-amino-4-ethoxy-1,1,1-trifluorobut-3-en-2-one as solid (6.371 g, 93%). 1H NMR (300 MHz, CDCl3) δ 9.79 (br, 1H), 5.66 br, 1H), 5.13 (s, 1H), 4.15 (q, 2H), 1.38 (t, 3H); LC-MS (ESI) m/z 184 (M+H)+.
Reaction SMILES: ClC[C:3](=[O:27])[C@:4]1(OC=O)[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.[C:28](=O)(O)[O-:29].[K+]>CO.O>[OH:29][CH2:28][C:3](=[O:27])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([CH2:19][CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1
Reactant: O=C([O-])O
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC[C@]2(OC=O)C(=O)CCl
Agent: [K+]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CO
Temperature: 0 °C

Procedure:
At room temperature, 1.6 g of 21-chloro-17- formyloxy-4-pregnene-3,20-dione is stirred in a mixture of 60 ml of methanol and 9 ml of water with 500 mg of potassium bicarbonate After one hour, the reaction mixture is stirred into ice water. The thus-precipitated product is suctioned off, washed with water, and dried over sodium sulfate, yielding 1.3 g of 21-chloro-17™hydroxy-4-pregnene-3,20-dione; mp 239.4° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([CH3:13])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:16][CH3:17])=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.C(=O)([O-])[O-:19].[Na+].[Na+].C(O)C>O>[OH:19][CH2:2][C:3]1[C:12]([CH3:13])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:16][CH3:17])=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1
Reactant: COc1cc2nc(C)c(CBr)nc2cc1OC
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc2nc(C)c(CO)nc2cc1OC

Procedure:
8.9 g (30 mmols) of 2-(bromomethyl)-6,7-dimethoxy-3-methyl-quinoxaline are suspended in a mixture of 158 g (1.5 mols) of sodium carbonate, 350 ml of water and 100 ml of ethanol. The suspension is boiled under reflux for four hours. 300 ml of water are then added and the resulting mixture is extracted with three times 120 ml of chloroform. The organic phase is dried over magnesium sulphate. The solvent is evaporated in vacuo. The solid residue is recrystallised from methanol. This gives 3.5 g (50%) of a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH:18][C:19]([C:21]2[O:25][N:24]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=2)=[O:20])[C:3]=1[N+:30]([O-])=O.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:30][C:3]1[C:4]([NH:18][C:19]([C:21]2[O:25][N:24]=[C:23]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=2)=[O:20])=[N:5][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])=[CH:7][C:2]=1[Cl:1]
Reactant: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)cc(Cl)c2[N+](=O)[O-])on1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)cc(Cl)c2N)on1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of 3-tert-butyl-isoxazole-5-carboxylic acid [4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide (40.7 mg, 0.0868 mmol, prepared as described in STEP A above) in EtOH (5 mL) and water (2.5 mL) was treated with ammonium chloride (46.4 mg, 0.868 mmol) and iron powder (24.2 mg, 0.434 mmol), and the mixture was stirred at 50° C. for 3 h. The cooled mixture was concentrated in vacuo and partitioned between EtOAc (25 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:3 over 40 min) to yield 3-tert-butyl-isoxazole-5-carboxylic acid [3-amino-4-chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calculated for C21H18N4O2ClF3: 439.1 (M+H); Measured: 439.1.