Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N:41]2[C:45]([CH2:46][N:47]([CH3:49])[CH3:48])=[CH:44][N:43]=[N:42]2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]([F:21])([F:22])[F:23])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N:41]2[C:45]([CH2:46][N:47]([CH3:49])[CH3:48])=[CH:44][N:43]=[N:42]2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1N
Reactant: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Product: CN(C)Cc1cnnn1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(N3CCOCC3)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-amino-5-morpholin-4-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J1) (181 mg, 0.5 mmol) and 3-[3-(5-dimethylaminomethyl-[1,2,3]triazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example K8) (172 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (179 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.COC(C)(C)C.CC(C)([O-])C.[Na+].[CH:69]1([C:72]([N:74]2[CH2:79][CH2:78][NH:77][CH2:76][CH2:75]2)=[O:73])[CH2:71][CH2:70]1>O1CCOCC1>[CH:69]1([C:72]([N:74]2[CH2:79][CH2:78][N:77]([C:2]3[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:20][CH:21]([CH3:23])[CH3:22])[S:10]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)(=[O:12])=[O:11])=[CH:4][CH:3]=3)[CH2:76][CH2:75]2)=[O:73])[CH2:70][CH2:71]1
Reactant: CC(C)CN(Cc1ccc(Br)cc1)S(=O)(=O)Cc1ccccc1
Reactant: O=C(C1CC1)N1CCNCC1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: CC(C)CN(Cc1ccc(N2CCN(C(=O)C3CC3)CC2)cc1)S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
In a vial, N-[(4-bromophenyl)methyl]-N-isobutyl-1-phenyl-methanesulfonamide (53 mg, 0.13 mmol), 2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl (3.2 mg, 0.0067 mmol), chloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)[2-(2 aminoethylphenyl)]palladium(II), methyl-t-butylether adduct (6 mg, 0.0067 mmol) and sodium tert-butoxide (20 mg, 0.20 mmol) were combined and the vial was purged with nitrogen. 1,4-Dioxane (1 mL) and cyclopropyl(piperazin-1-yl)methanone (31 mg, 0.20 mmol) were then added and the reaction was stirred at ambient temperature for 16 hours. The reaction was then partitioned between water and dichloromethane and the dichloromethane layer was isolated with a phase separator cartridge, concentrated and purified by preparative reverse phase HPLC to yield 27 mg of N-[4-(4-cyclopropanecarbonyl-piperazin-1-yl)-benzyl]-N-isobutyl-C-phenyl-methanesulfonamide. 1H NMR (400 MHz, DMSO) δ 7.38-7.34 (m, 5H), 7.21 (d, J=8.5 Hz, 2H), 6.94 (d, J=6.8 Hz, 2H), 4.40 (s, 2H), 4.16 (s, 2H), 3.82-3.78 (m, 2H), 3.62-3.58 (m, 2H), 3.20-3.05 (m, 4H), 2.80 (d, J=7.5, 2H), 2.12-1.92 (m, 1H), 1.60-1.45 (m, 1H), 0.83-0.69 (m, 4H), 0.67 (d, J=7.1 Hz, 6H); LCMS (m/z) ES+ 470.2 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([S:8](Cl)(=[O:10])=[O:9])=[C:5]([Br:7])[N:6]=1.[NH4+:12].[OH-]>C1COCC1>[Br:1][C:2]1[S:3][C:4]([S:8]([NH2:12])(=[O:10])=[O:9])=[C:5]([Br:7])[N:6]=1
Reactant: O=S(=O)(Cl)c1sc(Br)nc1Br
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1sc(Br)nc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.9 %

Procedure:
To a mixture of 2,4-dibromothiazole-5-sulfonyl chloride (3.17 g, 9.28 mmol) in THF (51.4 mL) was added 33% aqueous NH4OH (24.1 mL, 278 mmol) and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated in vacuo and the residue was taken up in ethyl acetate (100 mL) and water (100 mL). The aqueous layer was extracted with ethyl acetate (50 mL) and the combined organic layers were washed with water (50 mL) and brine (50 mL), then dried and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→20/80) to give 1.7 g (57% yield) of the title compound as a white solid. LC/MS (FA) ES+ 321, 323, 325. 1H NMR (400 MHz, DMSO-d6) δ: 8.33 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:21])[N:11]([C:18](Cl)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[N:22]1([CH2:27][CH:28]([OH:31])[CH2:29][OH:30])[CH2:26][CH2:25][CH2:24][CH2:23]1.N1C=CC=CC=1>C1COCC1>[OH:31][CH:28]([CH2:27][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:29][O:30][C:18]([N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:9](=[CH:8]/[C:3]2[NH:4][C:5]([CH3:7])=[CH:6][C:2]=2[CH3:1])/[C:10]1=[O:21])=[O:19]
Reactant: OCC(O)CN1CCCC1
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Cl)c3ccccc32)[nH]1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)OCC(O)CN3CCCC3)c3ccccc32)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a reaction mixture of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carbonyl chloride (150 mg, 0.5 mmol) and 3-pyrrolidin-1-yl-propane-1,2-diol (88 mg, 0.6 mmol) in 3.0 mL of THF was added 80 μl of pyridine dropwise at room temperature. Upon addition, the reaction mixture was stirred at room temperature for 20 min., and filtered. The orange solid was then washed with ethyl acetate and hexane sequentially and dried in a vacuum oven overnight to give 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 2-hydroxy-3-pyrrolidin-1-yl-propyl ester as an orange solid. 1HNMR (400 MHz, CDCl3 and 2 drops of DMSO-d6) δ 12.63 (s, br, 1H, NH-1′), 11.77 (s, br, 1H, OH), 7.86-7.88 (m, 1H), 7.51-7.53 (m, 1H), 7.42 (s, 1H, H-vinyl), 7.18-7.25 (m, 2H), 6.06 (d, J=2.3 Hz, 1H, H-4′), 4.65-4.73 (m, 2H), 4.44-4.56 (m, 2H), 3.91-3.93 (m, 1H), 3.33-3.52 (m, 2H), 2.88-3.15 (m, 2H), 2.40 (s, 3H, CH3), 2.36 (s, 3H, CH3), and 2.01-2.32 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:11]3([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[CH2:10][N:9]2[CH:24]2[CH2:26][CH2:25]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.[N:34]([C@@H:37]([C@@H:42]([CH3:45])[CH2:43][CH3:44])[C:38]([O:40][CH3:41])=[O:39])=[C:35]=[O:36]>>[CH3:41][O:40][C:38](=[O:39])[CH:37]([NH:34][C:35]([N:14]1[CH2:15][CH2:16][C:11]2([CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([CH:24]3[CH2:26][CH2:25]3)[CH2:10]2)[CH2:12][CH2:13]1)=[O:36])[CH:42]([CH3:45])[CH2:43][CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C1CC1)C2c1ccc(Cl)cc1
Reactant: CC[C@H](C)[C@H](N=C=O)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)C(NC(=O)N1CCC2(CC1)CN(C1CC1)C2c1ccc(Cl)cc1)C(=O)OC

Procedure:
Treat the compound from Example 2 with TFA according to the procedure of step D in Example 1 and treat the resultant product from this reaction with (2S,3S)-2-isocyanato-3-methylvaleric acid, methyl ester according to the procedure Example 1 step E to give the title compound which is characterized by LCMS. (MWT 448).
Reaction SMILES: ClC1C=C(N[C@H](C2CC2)C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)=O)C=C(F)C=1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49](OC(C)(C)C)=O)[CH2:44]2)=[O:41])[CH:34]=[C:35]([Cl:37])[CH:36]=1.NC1C(C#N)=C(Cl)N=CN=1.ClC1[C:68]2[CH2:75][C:74](=[O:76])[NH:73][C:69]=2[N:70]=[CH:71][N:72]=1>>[Cl:37][C:35]1[CH:34]=[C:33]([NH:38][CH2:39][C:40]([NH:42][C@@H:43]2[CH2:48][CH2:47][CH2:46][N:45]([C:49]3[C:68]4[CH2:75][C:74](=[O:76])[NH:73][C:69]=4[N:70]=[CH:71][N:72]=3)[CH2:44]2)=[O:41])[CH:32]=[C:31]([Cl:30])[CH:36]=1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)CNc2cc(Cl)cc(Cl)c2)C1
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](NC(=O)[C@H](Nc2cc(F)cc(Cl)c2)C2CC2)C1
Agent: N#Cc1c(N)ncnc1Cl
Product: O=C1Cc2c(ncnc2N2CCC[C@@H](NC(=O)CNc3cc(Cl)cc(Cl)c3)C2)N1

Procedure:
The title compound of Example 146 was prepared in similar manner as described in Example 134 except the key intermediate (R)-tert-butyl 3-((R)-2-(3-chloro-5-fluorophenylamino)-2-cyclopropylacetamido)piperidine-1-carboxylate was replaced with (R)-tert-butyl 3-(2-(3,5-dichlorophenylamino)acetamido)piperidine-1-carboxylate and the 4-amino-6-chloropyrimidine-5-carbonitrile was substituted for 4-chloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one. 1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.17 (s, 1H), 8.03 (d, J=7.18 Hz, 1H), 6.62 (t, J=1.70 Hz, 1H), 6.54 (d, J=1.89 Hz, 2H), 4.13 (d, J=12.46 Hz, 3H), 3.69 (dd, J=11.33, 15.86 Hz, 10H), 2.84-3.22 (m, 2H), 1.82 (d, J=3.40 Hz, 1H), 1.66-1.76 (m, 1H), 1.43-1.63 (m, 2H). EIMS (m/z): calcd. for C19H20Cl2N6O (M+1H) 435. found 435.
Reaction SMILES: C([O:8][C:9](=[O:28])[CH2:10][S:11](=[O:27])(=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)C1C=CC=CC=1.[NH2:29][CH2:30][C@@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[OH:32]>>[OH:32][C@H:31]([C:33]1[CH:34]=[CH:35][C:36]([OH:44])=[C:37]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])[CH:38]=1)[CH2:30][NH:29][CH:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:15]=[CH:14][C:13]([NH:12][S:11]([CH2:10][C:9]([OH:8])=[O:28])(=[O:26])=[O:27])=[CH:18][CH:17]=2)[CH2:24][CH2:23]1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)CC(=O)OCc3ccccc3)cc2)CC1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNC2CCN(c3ccc(NS(=O)(=O)CC(=O)O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from [4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-acetic acid benzyl ester (which was obtained in Example 236) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.60 (m, 2 H), 1.90–2.05 (m, 2 H), 2.50–2.90 (m, 5 H), 2.94 (s, 3 H), 3.50–3.65 (m, 2 H), 4.65–4.75 (m, 1 H), 6.80–6.90 (m, 3 H), 7.00–7.10 (m, 3 H), 7.23 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 543.3 (MH+); HRMS Calcd. for C29H37N4O8S2(MH+): 543.1578. Found: 543.1572.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[F:15][C:16]([F:43])([F:42])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>COCCOC>[F:15][C:16]([F:42])([F:43])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[O:38])=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1

Procedure:
A solution of 26.6 g. of diethyl malonate and 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 4.5 hours, cooled, poured on ice, acidified, and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. Addition of a small amount of ethanol to the residue gives a solid which is filtered and discarded. The ethanol filtrate is concentrated and the residue is recrystallized from ether to yield the product.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]([NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:3]1=[O:30].[CH2:32](I)[CH3:33]>C1CCCCC1.CCOC(C)=O>[CH3:31][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-:24])=[O:23])=[C:8]([N:11]([CH2:32][CH3:33])[C:12](=[O:21])[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:3]1=[O:30]
Reactant: CCI
Reactant: CCCCCN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: CCCCCN1C(=O)C(C)(C)c2cc(N(CC)C(=O)CCc3ccccc3)c([N+](=O)[O-])cc21

Procedure:
N-(3,3-Dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-N-ethyl-3-phenyl-propionamide is prepared from N-(3,3-dimethyl-6-nitro-2-oxo-1-pentyl-2,3-dihydro-1H-indol-5-yl)-3-phenyl-propionamide (214 mg) and ethyl iodide (46 μl; 0.57 mmol) as described in Example 57b. The compound (55 mg) is obtained by flash chromatography on silica gel eluting with cyclohexane/EtOAc.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C([OH:12])C.C(OO)(=O)C>C(O)(=O)C>[NH2:1][C:2]1[N+:7]([O-:12])=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: CCO
Agent: CC(=O)OO
Solvent: CC(=O)O
Product: Nc1cc(Cl)nc(N)[n+]1[O-]
Temperature: 35 °C
Reaction time: 8 h

Procedure:
144.5 g. of 2,4-diamino-6-chloropyrimidine are suspended in 2000 ml. of ethanol. While stirring, the suspension is warmed to 35° C. (about 15 minutes), the greater part of the substance passing into solution. The mixture is then cooled to 6°-8° C. and, at this temperature, there are added dropwise within the course of 40 minutes 175 ml. of 40% peracetic acid in glacial acetic acid. After completion of the addition, the mixture is stirred at 6°-8° C. for a further 30 minutes. The mixture is then left to warm up to room temperature and stirred at this temperature for 3 hours. 2000 Ml. of petroleum ether are then added, the mixture is left to stir for 1 hour and then left to stand overnight. The separated precipitate is filtered off, back-washed with 200 ml. of petroleum ether and dried under reduced pressure, there being obtained 2,4-diamino-6-chloropyrimidine-3-oxide. Recrystallization yields analytically-pure product having a melting point of 193° C.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[C:14]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44](O)=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)(=[O:21])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][N:35]2[C:43]3[C:38](=[CH:39][C:40]([C:44]([NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[O:45])=[CH:41][CH:42]=3)[C:37]([CH3:47])=[C:36]2[CH3:48])=[CH:30][CH:29]=1)(=[O:21])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3S(=O)(=O)NC(C)(C)C)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8, Example 1, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride and 1-((2′-(N-(tert-butyl)sulfamoyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 636 [M+H]+.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:16][NH:15][CH2:14][C:8]3([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[C:23](Cl)(=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CCCCCC>[C:23]([N:15]1[CH2:14][C:8]2([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[NH:7][C:6]2([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5]2)[CH2:16]1)(=[O:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: C1CCC2(CC1)CNCC1(CCCCC1)N2
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CCCCCCCCCCCCCCCCCC(=O)N1CC2(CCCCC2)NC2(CCCCC2)C1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
In a 500 ml. 3-necked flask equipped with stirrer, condenser with drying tube, thermometer, dropping funnel and nitrogen inlet was placed a solution of 15.6 g. (0.07 moles) of 7,15-diazadispiro[5,1,5,3]hexadecane in 150 ml. of dry pyridine. Under a dry nitrogen atmosphere, the solution was cooled to 5° C with an external ice bath and a solution of 21.2 g. (0.07 moles) of stearoyl chloride in 50 ml. of hexane was added dropwise with stirring over a 20 minute period. The reaction mixture was then allowed to warm to room temperature and stir for about 16 hours. The reaction mixture was filtered and the filtrate was taken up in ether, washed well with water, then with 2N NaOH solution. The filtrate was again filtered by suction, and the ether solution dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was recrystallized from acetonitrile, yielding colorless crystals, m.p. 56°-59° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:19])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29]Br>CN(C)C=O.O>[F:26][C:27]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:28]=1[CH2:29][O:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[C:4](=[O:19])[CH:3]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: COC(=O)c1cccc(-n2c(C)cc(O)cc2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 11 %

Procedure:
Methyl 3-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)benzoate from step 1) (24.00 g, 92.57 mmol) and K2CO3 (15.35 g, 111.08 mmol) were dissolved in N,N-dimethylformamide (220 mL). 2,4-Difluorobenzyl bromide (20.12 g, 97.20 mmol) was then added and the reaction mixture stirred for 48 hours at room temperature. The reaction mixture was diluted with H2O (1 L) and the precipitate collected by filtration to afford a white solid (4.08 g, 11%). The resulting oil was purified by chromatography (silica gel, ethyl acetate with 10% methanol/hexanes) to afford an off white solid (11.88 g, 33%). The two solids were combined. 1H NMR (400 MHz, CDl3) δ 8.11 (dt, J=1.41, 7.79 Hz, 1H), 7.87 (app t, J=1.78 Hz, 1H), 7.58 (app t, J=7.69 Hz, 1H) 7.45-7.38 (m, 2H), 6.94-6.84 (m, 2H), 5.97 (d, J=2.68 Hz, 1H), 5.90 (ddd, J=0.94, 1.74, 1.74 Hz, 1H), 5.97 (s, 1H), 3.90 (s, 3H), 1.89 (s, 3H). ES-HRMS m/z 386.1179 (M+H C21H17F2NO4 requires 386.1198).
Reaction SMILES: [O:1]=[C:2]([CH3:11])[C:3](=[N:8][O:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5].[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH2:11][C:2](=[O:1])[C:3](=[N:8][O:9][CH3:10])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CON=C(C(C)=O)C(=O)OC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CON=C(C(=O)CBr)C(=O)OC
Temperature: 40 °C
Yield: 87.4 %

Procedure:
In 150 ml of chloroform is dissolved 40 g of methyl 3-oxo-2-methoxyiminobutyrate and the solution is heated to 40° C. Then, a solution of 40 g bromine in 50 ml chloroform is added dropwise over a period of an hour. Thereafter, the reaction is continued under stirring at room temperature for an hour. The reaction mixture is washed with a 5% aqueous solution of sodium hydrogen carbonate and water in the order mentioned, and the organic layer is dried. The solvent is then distilled off to obtain 52.1 g of methyl 4-bromo-3-oxo-2-methoxyiminobutyrate as an oil.
Reaction SMILES: [F:1][CH2:2][C:3]1[N:12]=[C:11](N(C2C=CC(OC)=CC=2)C)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.FCC1NC(=O)C2C(=CC=CC=2)N=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:47])=O>>[Cl:47][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([CH2:2][F:1])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(N(C)c2nc(CF)nc3ccccc23)cc1
Agent: O=c1[nH]c(CF)nc2ccccc12
Solvent: CN(C)c1ccccc1
Product: FCc1nc(Cl)c2ccccc2n1

Procedure:
(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A suspension of 2-fluoromethyl-quinazolin-4(3H)-one (70 mg, 0.39 mmol) in phosphoryl chloride (2 ml) and N,N-dimethylaniline (0.035 ml, 0.27 mmol) was heated under reflux for 12 hours. The reaction mixture was poured onto ice and the precipitate was collected by filtration, then washed and dried to give 4-chloro-2-fluoromethyl-quinazoline, which was used directly for the next reaction. To a solution of 4-chloro-2-fluoromethyl-quinazoline with (4-methoxy-phenyl)-methylamine (160 mg, 1.2 mmol) in isopropyl alcohol (5 ml) was added concentrated HCl (0.05 ml) and the solution was stirred at room temperature overnight. The solution was neutralized with saturated aqueous NaHCO3, and was extracted by ethyl acetate. The extracts were evaporated, and the residue was purified by column chromatography on silica gel with ethyl acetate and hexane (1:1) as eluent, yielding 11 mg (9.5%) of the title compound. 1H NMR (CDCl3): 7.87-7.84 (m, 1H), 7.60-7.54 (m, 1H), 7.14-7.10 (m, 2H), 7.04-7.01 (m, 2H), 6.95-6.91 (m, 2H), 5.60 (s, 1H), 5.44 (s, 1H), 3.85 (s, 3H), 3.60 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]([NH:20]S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)([CH3:19])[CH2:9][O:10][C@@:11]([C:17]#[N:18])([CH3:16])[C:12]([F:15])([F:14])[F:13])[CH:7]=1.C(N[C@H](C(O)=O)CS)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:33])=[C:6]([C@:8]2([CH3:19])[CH2:9][O:10][C@@:11]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:17]([NH2:18])=[N:20]2)[CH:7]=1
Reactant: C[C@](C#N)(OC[C@](C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F)C(F)(F)F
Agent: CC(=O)N[C@@H](CS)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C[C@@]1(c2cc(Br)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Temperature: 80 °C

Procedure:
To a solution of N—[(R)-1-(5-bromo-2-fluoro-phenyl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-2-nitro-benzenesulfonamide (6.54 g, 11.8 mmol) and N-acetyl-cysteine (2.4 g, 26.0 mmol) in MeOH (80 ml) was added K2CO3 (3.62 g, 26.0 mmol) and the reaction mixture was heated at 80° C. for 16 h. After removal of the solvent the residue was dissolved in water and extracted with EtOAc. Combined extracts were washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and concentrated to provide the title compound after chromatographic purification over silica gel (hexane-EtOAc 10:1 to 1:2 containing 0.03% NEt3) as a yellow oil: TLC (hexane-EtOAc 1:1): Rf=0.58; UPLC RtH5=0.843 min; ESIMS: 369, 371 [(M+H)+]; 1H NMR (360 MHz, CDCl3): δ 7.66 (dd, 1H), 7.35 (m, 1H), 6.91 (dd, 1H), 3.97 (m, 2H), 1.53 (s, 3H), 1.49 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:13]=[CH:12][C:11]=1[OH:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32]>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH2:1]([O:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([S:16]([CH3:19])(=[O:17])=[O:18])[CH:13]=[CH:12][C:11]=1[O:20][C:31](=[O:32])[N:30]([CH3:34])[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(O)c(C(=O)OCc2ccccc2)c1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)Oc1ccc(S(C)(=O)=O)cc1C(=O)OCc1ccccc1
Reaction time: 48 h

Procedure:
A mixture of 1 mmol 2-hydroxy-5-methanesulfonyl-benzoic acid benzyl ester, 1.5 mmol of N-methylmorpholine and 0.2 mmol of 4-dimethylaminopyridine in 4 ml of dimethylformamide was treated with 1.3 mmol of N,N-dimethyl-carbamoylchloride. The reaction mixture was stirred at 60° for 48 hours, concentrated in vacuo and the residue taken up in 5 ml of water. Acidification with diluted hydrochloric acid and extraction with ethyl acetate yielded a crude product which was purified by chromatography (SiO2; ethyl acetate/cyclohexane 1.1). MS (m/e): 378.3 (MH+, 100%)