Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15](/[CH:21]=[CH:22]/[C@:23]([CH2:28][O:29][CH3:30])([CH3:27])[C:24]([OH:26])=[O:25])=[CH:16][CH:17]=2)[N:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]([Cl:56])([Cl:55])[CH2:33][O:34][C:35]([C@@H:37]1[CH2:42][CH2:41][CH2:40][N:39]([C:43](=[O:54])[C@@H:44]([NH:46][C:47](=[O:53])[C@@H:48](O)[CH:49]([CH3:51])[CH3:50])[CH3:45])[NH:38]1)=[O:36].C(N(CC)C(C)C)(C)C.CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[Cl:55][C:32]([Cl:31])([Cl:56])[CH2:33][O:34][C:35]([C@@H:37]1[CH2:42][CH2:41][CH2:40][N:39]([C:43](=[O:54])[C@@H:44]([NH:46][C:47](=[O:53])[C@@H:48]([O:25][C:24](=[O:26])[C@@:23]([CH2:28][O:29][CH3:30])([CH3:27])/[CH:22]=[CH:21]/[C:15]2[CH:14]=[C:13]3[C:18]([CH:19]=[CH:20][C:11]([C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH3:10])=[N:12]3)=[CH:17][CH:16]=2)[CH:49]([CH3:50])[CH3:51])[CH3:45])[NH:38]1)=[O:36]
Reactant: COC[C@](C)(/C=C/c1ccc2ccc([C@@H](C)NC(=O)OC(C)(C)C)nc2c1)C(=O)O
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC[C@](C)(/C=C/c1ccc2ccc([C@@H](C)NC(=O)OC(C)(C)C)nc2c1)C(=O)O[C@H](C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 78 %

Procedure:
To a solution of (E)-(S)-4-[2-((R)-1-tert-butoxycarbonylamino-ethyl)-quinolin-7-yl]-2-methoxymethyl-2-methyl-but-3-enoic acid (176 mg, 0.34 mmol) in dichloromethane (2 mL), was added (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (205 mg, 0.47 mmol), 4-dimethylaminopyridine (116 mg, 0.95 mmol), N,N-diisopropylethylamine (123 mg, 0.95 mmol) and 2-methyl-6-nitrobenzoic anhydride (164 mg, 0.47 mmol). The reaction mixture was stirred at room temperature for 18 h, was then treated with saturated solution of sodium hydrogen carbonate, extracted with dichloromethane (2×) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated. The crude residue was purified by silica gel chromatography using a Biotage KP-Sil 50 g cartridge eluting with a gradient of iso-hexanes/ethyl acetate 9:1 to 0:1 to give the title product (0.22 g, 78%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 0.85-1.10 (m, 6H), 1.20-1.70 (m, 23H), 2.05-2.20 (m, 1H), 2.30-2.45 (m, 1H), 3.44 (s, 3H), 3.60-3.95 (m, 4H), 4.15-4.32 (m, 1H), 4.68-4.70 (m, 1H), 4.90-5.05 (m, 2H), 5.20-5.45 (m, 1H), 6.10-6.28 (m, 1H), 6.60-6.85 (m, 2H), 7.10-7.20 (m, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.66-7.74 (m, 2H), 8.00 (d, J=4.0 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H). LCMS (m/z) 828.5 [M+H], Tr=3.48 min.
Reaction SMILES: N1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])NC1=O.N1C=CC(=O)NC1=O.C[Si](C)(C)CCO[CH2:26][Cl:27]>>[CH2:4]([O:11][CH2:26][Cl:27])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=c1cc[nH]c(=O)[nH]1
Product: ClCOCc1ccccc1

Procedure:
In a similar manner to the procedures described in Reference Example 3, reactions were carried out using quinazoline-2,4-dione, instead of pyrimidine-2,4-dione, and using 2-(trimethylsilyl)ethoxymethyl chloride, instead of benzyloxymethyl chloride, to give the title compound (yield 87%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([OH:33])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=3[CH:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:33])[CH2:15][NH:16][C:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:25]([CH3:30])([CH3:29])[CH2:24][CH2:23][C:22]([CH3:32])([CH3:31])[C:21]=3[CH:20]=2)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)CNC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CNC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.15 g (2.51 mmol) of 4-{1-hydroxy-2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carbonyl)amino]ethyl}piperidine-1-carboxylic acid tert-butyl ester from step a was dissolved in 20 ml of DCM, and 15.61 ml (7.52 mmol) of Dess-Martin periodinane were added. The reaction mixture was stirred at room temperature for 30 min, 20 ml of a saturated sodium hydrogencarbonate solution and 5 ml of a saturated sodium sulfate solution were added, and the mixture was stirred vigorously for 30 min. The organic phase was separated off, and the water phase was extracted again with DCM. The organic phases were combined, dried, stripped off to dryness and purified by means of flash chromatography on silica gel.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][NH:17][CH2:18]2.[F:23][C:24]1[S:28][C:27]([NH:29][S:30](N2C=CN=C2)(=[O:32])=[O:31])=[N:26][CH:25]=1.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[Br:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH2:15][CH2:16][N:17]([S:30]([NH:29][C:27]1[S:28][C:24]([F:23])=[CH:25][N:26]=1)(=[O:32])=[O:31])[CH2:18]2
Reactant: FC(F)(F)c1ccc(-c2cccc3c2CCNC3)c(Br)c1
Reactant: O=S(=O)(Nc1ncc(F)s1)n1ccnc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(Nc1ncc(F)s1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2Br)C1
Yield: 27.5 %

Procedure:
A solution of 5-(2-bromo-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (Intermediate D, 0.400 g, 1.019 mmol), N-(5-fluorothiazol-2-yl)-1H-imidazole-1-sulfonamide (Intermediate N, 1.012 g, 4.07 mmol), and triethylamine (2.84 ml, 20.37 mmol) in 3 mL THF was heated to 80° C. for 30 minutes. LC/MS showed product so the reaction mixture was diluted with EtOAc and washed with 1 N citric acid. The organics were dried over MgSO4 and concentrated. Purification of the resulting residue by silica gel column chromatography (0 to 100% EtOAc/heptane) gave 5-(2-bromo-4-(trifluoromethyl)phenyl)-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.150 g, 0.280 mmol). 1H NMR (400 MHz, Acetone-d6) δ ppm: 8.06 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.51-7.57 (m, 1H), 7.24-7.35 (m, 2H), 7.08 (s, 1H), 7.05 (d, J=5.7 Hz, 1H), 4.37 (s, 2H), 3.30-3.39 (m, 2H), 2.47-2.60 (m, 2H)
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1ccc(F)c2cccnc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(F)c2cccnc12
Yield: 67.7 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-fluoro-quinolin-8-ylamine (Intermediate 50) (350 mg, 2.0 mmol), 2-nitro-benzenesulfonyl chloride (575 mg, 2.59 mmol), pyridine (0.35 ml, 4.3 mmol) and DCM (12 ml) gave the title compound (470 mg, 63%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: [CH:1]([C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1)=[CH2:2].[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13].[C:14]([OH:17])(=[S:16])[CH3:15]>C1C=CC=CC=1>[C-:3]1([CH2:1][CH2:2][O:17][C:14](=[S:16])[CH3:15])[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:13]
Reactant: C=C[c-]1cccc1
Reactant: CC(O)=S
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: c1ccccc1
Product: CC(=S)OCC[c-]1cccc1

Procedure:
In a typical experiment 2.12g (0.01 mol) of purified vinyl ferrocene and 0.76 (0.01 mol) of thioacetic acid were dissolved in 30 ml of GC spectrophotometric quality benzene and placed in a pyrex photoreactor fitted with a fritted purging tube and reflux condenser. The solution was purged 45 minutes with helium prior and during irradiation of 1.75×1019 photon/min. from a Hanovia 100 watt type SOL high pressure quartz mercury vapor lamp. No change in the infrared bands of the mercaptans (3.9μ) and vinyl groups (6.18μ) nor any product formation could be observed by thin layer chromatography during a photolysis time of up to eight hours. It was observed that photo-decomposition of vinyl ferrocene occurred (formation of dark brown precipitate) along with protection of thioacetic acid from the ultraviolet light.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][CH2:25]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:32]1([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:24][CH2:25][N:41]3[CH2:40][CH2:39][C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]3)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1ccc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc1
Agent: Cl
Product: COc1ccc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc1

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.63 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.3 g). Purify by chromatographed on silica gel eluting sequentially with 50% ethyl acetate/hexane, 4% methanol/dichloromethane, and then 6% methanol/dichloromethane to give the title compound: Rf =0.58 (silica gel, 10% methanol in dichloromethane).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([OH:17])=O)[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:45][CH:44]=1>CN(C=O)C.CS(C)=O>[CH3:2][N:1]1[C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15]([NH:42][C:43]3[CH:44]=[CH:45][C:46]([C:49]([OH:52])([CH3:50])[CH3:51])=[CH:47][CH:48]=3)=[O:17])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: CC(C)(O)c1ccc(N)cc1
Reactant: Cn1c(=O)c2c(ncn2CC(=O)O)n(C)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2CC(=O)Nc2ccc(C(C)(C)O)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 0° C. solution of acid 101 (0.32 g, 1.34 mmol) in DMF/DMSO (1:1, 20 mL) was added HATU (0.0.76 g, 2.01 mmol). The reaction was then stirred an additional 15 min at room temperature. The solution was cooled to 0° C. and amine 135 (0.30 g, 2.01 mmol) was added. The reaction was then stirred at rt overnight. The DMF was concentrated in vacuo and water was added to the reaction. The aqueous layer was extracted with EtOAc The ethyl acetate layer was then washed again with water and the organic layer was concentrated in vacuo. The product was purified by flash chromatography on silica gel eluting with EtOAc/hexanes and EtOAc/MeOH to yield 402 as a pure light brown semi solid (0.086 g, 17.5%). MS (APCI): m/z 372.2 [M−H]+ Anal. Calcd. For C18H21N5O4. 0.35 EtOAc: C, 57.93; H, 5.96; N, 17.41. Found C, 58.36; H, 6.14; N, 16.96.
Reaction SMILES: C(N(CC)C(C1C=C(C2C=NN(CCCO)C=2)C=CC=1NC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(O)OCC)=CC=2OC)N=1)=O)C.[Cl:50][C:51]1[C:55]([C:56]2[N:61]=[C:60]([C:62](=[O:65])[NH:63][CH3:64])[C:59]([NH:66][C:67]3[C:72]([C:73]([F:76])([F:75])[F:74])=[CH:71][N:70]=[C:69]([NH:77][C:78]4[CH:92]=[CH:91][C:81]([CH2:82][P:83](=[O:90])([O:87]CC)[O:84][CH2:85][CH3:86])=[CH:80][C:79]=4[O:93][CH3:94])[N:68]=3)=[CH:58][CH:57]=2)=[CH:54][N:53]([CH2:95][CH2:96][CH2:97][OH:98])[N:52]=1>>[Cl:50][C:51]1[C:55]([C:56]2[N:61]=[C:60]([C:62](=[O:65])[NH:63][CH3:64])[C:59]([NH:66][C:67]3[C:72]([C:73]([F:75])([F:74])[F:76])=[CH:71][N:70]=[C:69]([NH:77][C:78]4[CH:92]=[CH:91][C:81]([CH2:82][P:83](=[O:87])([OH:90])[O:84][CH2:85][CH3:86])=[CH:80][C:79]=4[O:93][CH3:94])[N:68]=3)=[CH:58][CH:57]=2)=[CH:54][N:53]([CH2:95][CH2:96][CH2:97][OH:98])[N:52]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cn(CCCO)nc4Cl)nc3C(=O)NC)n2)c(OC)c1)OCC
Agent: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cn(CCCO)nc4Cl)nc3C(=O)NC)n2)c(OC)c1
Yield: 96.3 %

Procedure:
Prepared analogously to Compound 3A using diethyl (4-{[4-({6-[3-chloro-1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)pyridin-3-yl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 49B, 480 mg, 0.661 mmol) to afford 445 mg of the desired product (96%). 1H NMR (400 MHz, CD3OD) δ 8.93-9.09 (m, 1H), 8.59 (s, 1H), 8.32 (s, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.62 (d, J=6.6 Hz, 1H), 7.12 (s, 1H), 6.93 (d, J=8.1 Hz, 1H), 4.27 (t, J=6.8 Hz, 2H), 3.82-3.92 (m, 5H), 3.60 (t, J=6.1 Hz, 2H), 3.05 (s, 1H), 2.97-3.02 (m, 4H), 2.11 (quin, J=6.4 Hz, 2H), 1.16 (t, J=6.9 Hz, 3H). MS (ESI): m/z=699.54/701.48 [M+H]+. UPLC: tR=1.21 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:5]1.NN>CCO>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([NH2:10])[CH2:5]1
Reactant: COC[C@H]1CCC[C@H](N2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: CCO
Product: COC[C@H]1CCC[C@H](N)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 218.8 %

Procedure:
Racemic trans-2-(3-methoxymethyl-cyclohexyl)-isoindole-1,3-dione (0.205 g, 0.75 mmol) was suspended in EtOH (5 mL) and hydrazine (0.07 mL, 2.25 mmol) was added. The resulting colorless mixture was stirred at 50° C. for 3 hours before cooled to RT. The solid that precipitated was filtered off and washed with EtOH. The filtrate was evaporated to give 0.235 g of racemic trans-3-methoxymethyl-cyclohexylamine as a white solid (50% pure by NMR).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:12]([NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=O)=[CH:20][CH:19]=1)=[O:13].[NH2:29][OH:30].[OH-].[Na+].Cl>CO.C1COCC1>[OH:30][NH:29][C:22](=[O:24])[C:21]1[CH:26]=[CH:27][C:18]([O:17][CH2:16][CH2:15][NH:14][C:12]([C:4]2[O:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:3]=2[N:2]([CH3:1])[CH3:28])=[O:13])=[CH:19][CH:20]=1
Reactant: NO
Reactant: COC(=O)c1ccc(OCCNC(=O)c2oc3ccccc3c2N(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1c(C(=O)NCCOc2ccc(C(=O)NO)cc2)oc2ccccc12
Reaction time: 8 h

Procedure:
To a solution of crude methyl 4-[2-(3-dimethylaminobenzofuran-2-yl-carbonylamino)-ethoxy]-benzoate in MeOH and THF was added excess aqueous hydroxylamine solution and NaOH(aq.) to give pH 10-11. The reaction mixture was stirred overnight and then neutralized to pH 7-8 with aqueous hydrochloric acid and concentrated in vacuo. The residue was dissolved in acetonitrile and water and purified with prep HPLC to give the title compound (107 mg). 1H NMR (400 MHz, DMSO-d6) δ 9.88 (m, 1H), 9.31 (t, J=6.0 Hz,1H), 8.04 (d, J=7.6 Hz, 1H), 7.70 (m, 3H), 7.57 (t, J=7.6 Hz, 1H), 7.45 (t, J=7.6 Hz, 1H), 6.99 (d, J=9.2 Hz, 2H), 4.76 (d, J=4.8 Hz, 2H), 4.23 (t, J=6.0 Hz, 2H), 3.71 (m, 2H), 2.84 (s, 3H), 2.83 (s, 3H). EM (calc.): 397.2; MS (ESI) m/e (M+1H)+: 398.1, (M−1H)−: 396.2.
Reaction SMILES: [F:1][C:2]1[C:21]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:20][C:5]([O:6][C:7]2[C:8]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:9][C:10]([CH3:13])=[N:11][CH:12]=2)=[C:4]([N+:35]([O-])=O)[CH:3]=1.C(O)C>[Pt]=O.C(OCC)(=O)C>[NH2:35][C:4]1[CH:3]=[C:2]([F:1])[C:21]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:20][C:5]=1[O:6][C:7]1[C:8]([O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N:9][C:10]([CH3:13])=[N:11][CH:12]=1
Reactant: COC(=O)COc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)COc1nc(C)ncc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.8 %

Procedure:
A mixture of 0.19 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-4-(methoxycarbonyl)methoxy-2-methylpyrimidine, 5 mg of platinum oxide, 2 ml of ethanol and 2 ml of ethyl acetate was stirred for 1.5 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, and the filtrate was concentrated to obtain 0.17 g of 5-{2-amino-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-4-(methoxycarbonyl)methoxy-2-methylpyrimidine.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[CH:23][C:24]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[N:25][CH:26]=2)O1>C1COCC1.C(OCC)(=O)C.O>[N:27]1([C:24]2[N:25]=[CH:26][C:21]([C:2]3[S:6][C:5]([N+:7]([O-:9])=[O:8])=[C:4]([C:10]([NH2:12])=[O:11])[CH:3]=3)=[CH:22][CH:23]=2)[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: NC(=O)c1cc(Br)sc1[N+](=O)[O-]
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2ccc(N3CCOCC3)nc2)sc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
5-Bromo-2-nitrothiophene-3-carboxamide (2.50 g, 9.96 mmol) and 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl]morpholine (2.89 g, 9.96 mmol) were combined in THF (40 ml). Tetrakis(triphenylphoshine)palladium(0) (0.58 g, 0.50 mmol) was added and the reaction mixture was heated to reflux overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate (500 ml) and water (500 ml). A red solid crashed out. The mixture was filtered and the solid was washed with ethyl acetate to yield the title compound as a red solid.
Reaction SMILES: [C:1](/[CH:3]=[CH:4]/[C@H:5]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1](/[CH:3]=[CH:4]/[C@H:5]([N:13]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:24]([F:25])([F:26])[F:27])(=[O:15])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CBr
Reactant: N#C/C=C/[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN([C@@H](/C=C/C#N)Cc1ccccc1)S(=O)(=O)c1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
To a solution of compound 31g (4.2 g, 10.6 mmol) in DMF (100 mL) was added ethyl bromoacetate (2.1 g, 12.7 mmol) and K2CO3 (3.5 g, 25.4 mmol). The mixture was stirred at rt for 12 h, then water (100 mL) was added to the mixture. The mixture was extracted with EA three times and the combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated and the residue was purified by CC (hexane/EA=5:1) to give compound 31h (3.7 g, 73% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[CH2:4][NH:5][C:6]1[C:7](=O)[C:8](=[O:13])[C:9]=1[O:10]CC.ClCCl.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][C:7]1[C:8](=[O:13])[C:9](=[O:10])[C:6]=1[NH:5][CH2:4][C:3]1[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:2]=1[Cl:1])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOc1c(NCc2c(C)cccc2Cl)c(=O)c1=O
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: Cc1cccc(Cl)c1CNc1c(NC(C)(C)C)c(=O)c1=O
Reaction time: 144 h

Procedure:
A mixture of 3,4-diethoxy-3-cyclobutene-1,2-dione (5 g, 29 mmol) and 2-chloro-6-methylbenzylamine (4.57 g, 29 mmol) in absolute ethanol (147 mL) was allowed to stand at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure and suspended in dichloromethane (200 mL). The slurry was stirred at room temperature for 18 hours, filtered, rinsed with dichloromethane, and concentrated under reduced pressure to give 6.42 g (78%) of a solid. A portion of this solid, 3-(2-chloro-6-methyl-benzylamino)-4-ethoxy-cyclobut-3-ene-1,2-dione, (0.4 g, 1.43 mmol) was placed in t-butylamine (4 mL) and dichloromethane (4 mL) and allowed to stand at room temperature for 6 days. The solid was filtered, rinsed several times with ethyl acetate, and dried. This gave 0.31 g (71%) of the title compound as a white solid: mp 254°-257° C.; 1H NMR (DMSO-d6) δ7.46 (br s, 1H), 7.42 (br t, 1H), 7.38-7.22 (m, 3H), 4.93 (d, 2H), 2.40 (s, 3H), 1.34 (s, 9H) ppm. IR (KBr): 3200, 2960, 1790, 1650 cm-1 ; MS (m/z) 306/308 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[N:9]=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:26][S:27]([C:30]1[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=1[F:37])(=[O:29])=[O:28].[NH4+:38].[OH-]>O1CCOCC1>[NH2:38][C:15]1[N:14]=[C:13]([C:12]2[S:11][C:10]([N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[N:9][C:8]=2[C:7]2[C:2]([Cl:1])=[C:3]([NH:26][S:27]([C:30]3[C:31]([F:37])=[CH:32][CH:33]=[CH:34][C:35]=3[F:36])(=[O:28])=[O:29])[CH:4]=[CH:5][CH:6]=2)[CH:18]=[CH:17][N:16]=1
Reactant: O=S(=O)(Nc1cccc(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1Cl)c1c(F)cccc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2Cl)n1
Temperature: 100 °C
Yield: 35 %

Procedure:
In a pressure vessel was placed N-{2-Chloro-3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (300 mg, 0.513 mmol) and NH4OH (2 mL) and 1,4-dioxane (2 mL) were added. The vessel was sealed and heated at 100° C. for 18 h. The reaction mixture was cooled, concentrated onto silica and the residue was column chromatographed to give the title compound (0.10 g, 35% yield). 1H NMR (400 MHz, DMSO-d6) d ppm 10.81 (br. s., 1H), 7.81 (d, J=5.3 Hz, 1H), 7.62-7.73 (m, 1H), 7.39-7.52 (m, 2H), 7.28-7.34 (m, 1H), 7.21 (t, J=9.1 Hz, 2H), 6.55 (s, 2H), 5.44 (d, J=5.3 Hz, 1H), 3.70 (t, J=4.7 Hz, 4H), 3.44 (t, J=4.6 Hz, 4H). MS (ES+): 566 [M+H]+.
Reaction SMILES: [CH:1]([Si:4]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[CH:6]1)([CH3:3])[CH3:2].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1.C(N(CC)CC)C.O>O1CCCC1>[F:28][C:29]([F:39])([F:40])[C:30]1[CH:31]=[C:32]([NH:36][C:37]([NH:21][C:18]2[CH:17]=[CH:16][C:15]([CH2:14][C:7]3[C:8]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]([Si:4]([CH:1]([CH3:2])[CH3:3])([CH:22]([CH3:24])[CH3:23])[CH:25]([CH3:27])[CH3:26])[CH:6]=3)=[CH:20][CH:19]=2)=[O:38])[CH:33]=[CH:34][CH:35]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(N)cc2)c2cccnc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2)c2cccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-phenylamine (113, 70.0 mg, 0.184 mmol) was dissolved in tetrahydrofuran (12 mL) and 3-trifluoromethyl-phenyl isocyanate (41 rag, 0.22 mmol) and triethylamine (28 mg, 0.28 mmol) were added under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated to give crude compound 114 used in the next step.