Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:16][CH2:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH2:22][CH2:21]1)=[O:19].O[Li].O>CN(C=O)C>[C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:8][C:3]([CH2:2][NH:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[CH2:22][CH2:21]2)=[O:19])=[CH:4][CH:5]=1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Li]O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNCc1ccc(-c2ccccc2)cc1)N1CCC(Oc2ccccc2Cl)CC1
Reaction time: 8 h
Yield: 11.5 %

Procedure:
A mixture of biphenyl-4-yl-methanol (250 mg, 1.35 mmol) and aqueous HBr (48%) (3 mL) was stirred at 10° C. for 3 hrs. After completion of the reaction, the mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer collected was concentrated under reduced pressure to afford 330 mg (98.5% Yield) 4-bromomethyl-biphenyl. 4-Bromomethyl-biphenyl (120 mg, 0.485 mmol) was added to a stirred mixture of 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (134 mg, 0.44 mmol) (prepared according to Step 1 and 5 of the General Scheme), LiOH.H2O (40 mg, 0.97 mmol) and 4 Å molecular sieves (350 mg) in DMF (4 mL) and stirring was continued overnight. The reaction mixture was filtered and filtrate was diluted with cold water, extracted with ethyl acetate and organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using neutral alumina and 5% MeOH in DCM as eluent) to afford 22 mg (11.4% Yield) of 2-[(biphenyl-4-ylmethyl)-amino]-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone. LC/MS [M+H]+: 435, 90.56%. 1H NMR (CDCl3): δ7.64-7.52 (m, 4H), 7.5-7.3 (m, 6H), 7.24-7.15 (dt, 1H), 7.0-6.86 (m, 2H), 4.6 (q, 1H), 4.0-3.8 (m, 3H), 3.7-3.6 (m, 3H), 3.5 (s, 2H), 3.4-3.3 (m, 1H), 2.0-1.8 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10](N1C=CN=C1)(N1C=CN=C1)=[S:11].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:10](=[S:11])[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1cnc(Cl)cc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: S=c1[nH]c2cnc(Cl)cc2[nH]1
Reaction time: 8 h

Procedure:
A stirred mixture of 6-chloropyridine-3,4-diamine (500 mg, 3.48 mmol), 1,1′-thiocarbonyldiimidazole (1.24 g, 6.97 mmol), and triethylamine (0.49 mL, 3.48 mmol) in anhydrous DMF (15.0 mL) was microwaved in a Biotage Initiator at 100° C. at normal power for 1 h. Then the reaction mixture was evaporated at reduced pressure, and the resulting residue extracted with DCM (200 mL) and allowed to stand at 10° C. overnight. The mixture filtered and the solids washed with cold DCM (2×20 mL), and air dried to afford the title compound as a solid. LC-MS: calculated for C6H4ClN3S 184.98 observed m/e: 186.07 (M+H)+ (Rt 0.62/2.0 min)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](OC)=[O:12])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:15].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH3:15]
Reactant: COC(=O)c1ccc2c(c1)cc(C)n2C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc2cc(CO)ccc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 1,2-Dimethyl-1H-indole-5-carboxylate (crude, 1.14 mg, 5.31 mmol) in THF (54 ml) Lithiumaluminium hydride (1 M in THF, 5.31 ml) was added at 0° C. The reaction mixture was stirred at rt for 2 hours. Sodium sulfate decahydrate was added to the reaction mixture to destroy the excess of Lithiumaluminium hydride. After 1 hour, methanol was added and the fine suspension was filtered off. The filtrate was concentrated under vacuum to afford crude (1,2-Dimethyl-1H-indol-5-yl)methanol. MS (Method V) [M+H]+=176.3.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]([C:13](Cl)=[O:14])[CH:10]=[CH:9][N:8]=2)[CH2:3][CH2:2]1.[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[C:36]([NH2:38])[CH:35]=[CH:34][C:33]=3[CH3:39])[CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:18]1>>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:40])[C:32]3[CH:37]=[C:36]([NH:38][C:13]([C:11]4[CH:10]=[CH:9][N:8]=[C:7]([N:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[CH:12]=4)=[O:14])[CH:35]=[CH:34][C:33]=3[CH3:39])[CH:27]=[CH:28][CH:29]=2)[CH2:19][CH2:18]1
Reactant: Cc1ccc(N)cc1C(=O)Nc1cccc(CN2CCN(C)CC2)c1
Reactant: O=C(Cl)c1ccnc(N2CCOCC2)c1
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1C(=O)Nc1cccc(CN2CCN(C)CC2)c1
Yield: 27 %

Procedure:
Using an analogous procedure to that described in Example 1, 2-morpholinopyridine-4-carbonyl chloride was reacted with N-[3-(4-methylpiperazin-1-ylmethyl)phenyl]-5-amino-2-methylbenzamide. The residue was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and a saturated aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound in 27% yield; Mass Spectrum: M+H+ 529.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[OH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([O:12][CH:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)[C:5]=2[S:4][CH:3]=1
Reactant: Clc1ncnc2c(Br)csc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c(Br)csc23)CC1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
To 7-bromo-4-chlorothieno[3,2-d]pyrimidine obtained in Step 1-3) of Preparation Example 1, t-butyl 4-hydroxypiperidine-1-carboxylate, K2CO3 and N,N-dimethylformamide were added, and stirred at 100° C. for 12 hours in a hermetically sealed reactor. The reaction mixture was cooled to room temperature, extracted with ethyl acetate and distilled water, and the organic layer thus obtained was washed with water and a saline solution. Subsequently, the washed organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:13]=[CH:12][C:7]2[O:8][CH:9]=[CH:10][O:11][C:6]=2[CH:5]=1)=[O:3].O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C(N(CC)CC)C.[CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[S:42][CH:43]([C:47](O)=[O:48])[C:44](O)=[O:45])([CH3:35])[CH3:34]>C(Cl)Cl>[O:8]1[C:7]2[CH:12]=[CH:13][C:4]([C:2]3[O:3][C:44](=[O:45])[C:43]([S:42][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=4[CH:33]([CH3:34])[CH3:35])=[C:47]([OH:48])[CH:1]=3)=[CH:5][C:6]=2[O:11][CH2:10][CH2:9]1
Reactant: CC(C)c1ccccc1SC(C(=O)O)C(=O)O
Reactant: CC(=O)c1ccc2c(c1)OC=CO2
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccccc1Sc1c(O)cc(-c2ccc3c(c2)OCCO3)oc1=O

Procedure:
The title compound was prepared by Method A using 1,4-benzodioxin-6-yl methyl ketone (2 g, 11.22 mmol), trimethylsilyl triflate (2.5 g, 11.22 mmol), triethylamine (2.27 g, 22.44 mmol), methylene chloride (20 mL), and diethyl ester of [(2-isopropylphenyl)thio)propanedioic acid (1.73 g, 5.61 mmol). m.p. 246°-248° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.25 (d, 6H), 3.4 (m, 1H), 4.32 (m, 4H), 6.72 (s, 1H), 6.89 (d, 1H), 7.01 (d, 1H), 7.06 (t, 1H), 7.11 (t, 1H), 7.26 (d, 1H), 7.31 (d, 1H), 7.35 (dd, 1H).
Reaction SMILES: [NH2:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=[CH:3][C:4]([O:6][CH3:7])=[O:5].[C:17]1([C:23](=O)[CH:24]=[CH:25][CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(O)CCC>[CH3:26][C:25]1[CH:24]=[C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:1]=[C:2]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC=CC(=O)c1ccccc1
Reactant: COC(=O)C=C(N)c1cccc([N+](=O)[O-])c1
Solvent: CCCCO
Product: COC(=O)c1c(C)cc(-c2ccccc2)nc1-c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 5.8 %

Procedure:
A mixture of methyl 3-amino-3-(3-nitrophenyl)-acrylate (45 g) and 1-phenyl-2-buten-1-one (44 g) in n-butanol (450 ml) was refluxed for 4 hours. After allowing to cool at ambient temperature, the reaction mixture was evaporated in vacuo. The residue was subjected to a column chromatography on silica gel (500 g) eluting with benzene. The fractions containing the object compound were combined and concentrated under reduced pressure to give methyl 4-methyl-2-(3-nitrophenyl)-6-phenyl-3-pyridinecarboxylate (4.10 g).
Reaction SMILES: ClC1N=C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)C(Cl)=CN=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])[C:24]([Cl:38])=[CH:23][N:22]=1.COC1C(N)=CC2CCC(N3CCOCC3)CCC=2C=1.[CH3:59][O:60][C:61]1[CH:62]=[CH:63][C:64]2[CH2:70][CH2:69][CH:68]([N:71]3[CH2:76][CH2:75][O:74][CH2:73][CH2:72]3)[CH2:67][CH2:66][C:65]=2[C:77]=1[NH2:78]>>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([NH:32][CH3:33])=[O:31])=[N:26][C:21]([NH:78][C:77]2[C:65]3[CH2:66][CH2:67][CH:68]([N:71]4[CH2:72][CH2:73][O:74][CH2:75][CH2:76]4)[CH2:69][CH2:70][C:64]=3[CH:63]=[CH:62][C:61]=2[O:60][CH3:59])=[N:22][CH:23]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1ccc2c(c1N)CCC(N1CCOCC1)CC2
Agent: COc1cc2c(cc1N)CCC(N1CCOCC1)CC2
Agent: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Product: CNC(=O)c1ccccc1Nc1nc(Nc2c(OC)ccc3c2CCC(N2CCOCC2)CC3)ncc1Cl

Procedure:
Prepared in an analogous fashion to Example 1047 replacing (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 3-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine was replaced with 2-Methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamine to afford 2-[5-Chloro-2-(2-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide. LC/MS (ESI): 537.20. 1H NMR (400 MHz, DMSO, d6) δ 8.71 (m, 2H), 8.14 (m, 1H), 7.79 (m, 1H), 7.70 (m, 1H), 6.89 (m, 2H), 3.69 (s, 3H), 3.51 (m, 4H), 3.11 (m, 6H), 2.79 (m, 1H), 2.71 (s, 3H), 2.33 (m, 4H), 1.44 (m, 2H).
Reaction SMILES: C([N:8]1[C:20]2[C:19]([O:21][CH2:22][CH2:23][CH2:24]Br)=[C:18]3[N:26](C(OC(C)(C)C)=O)[C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][C:32]=4[C:17]3=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:41])[CH:13]=2)(OC(C)(C)C)=O.C([CH:49]([NH2:56])[CH:50]1[CH2:55][CH2:54][CH2:53][NH:52][CH2:51]1)(OC(C)(C)C)=O>>[Cl:41][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:20]1[C:19]([O:21][CH2:22][CH2:23][CH2:24][N:52]3[CH2:53][CH2:54][CH2:55][CH:50]([CH2:49][NH2:56])[CH2:51]3)=[C:18]3[NH:26][C:27]4[CH:28]=[CH:29][C:30]([Cl:33])=[CH:31][C:32]=4[C:17]3=[CH:16][C:15]2=1
Reactant: CC(C)(C)OC(=O)C(N)C1CCCNC1
Reactant: CC(C)(C)OC(=O)n1c2ccc(Cl)cc2c2cc3c4cc(Cl)ccc4n(C(=O)OC(C)(C)C)c3c(OCCCBr)c21
Product: NCC1CCCN(CCCOc2c3[nH]c4ccc(Cl)cc4c3cc3c2[nH]c2ccc(Cl)cc23)C1
Reaction time: 8 h
Yield: 99 %

Procedure:
The title compound was prepared in a manner analogous to Example 70 except the staring material is 5,7-diBOC-2,10-dichloro-6-(3-bromopropoxy)indolo[2,3-b]carbazole and the reagent is 3-(Boc-aminomethyl)piperidine. The reaction can be completed at room temperature overnight 1H-NMR (400 MHz, CDCl3) δ ppm 9.76 (s, 2 H), 8.34 (s, 1 H), 8.08 (s, 2 H), 7.40-7.31 (m, 4 H), 4.35 (t, J=5.6 Hz, 2 H), 3.35-3.20 (m, 2 H), 2.89-2.75 (m, 2 H), 2.70-2.53 (m, 2 H), 2.18-1.71 (m, 9 H), 1.17-1.03 (m, 2 H); MS (ESI) m/z 493.2 (M−H)−; MS (ESI) m/z 495.1 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[S:32](Cl)(=[O:34])=[O:33].CCN(CC)CC.Cl>O1CCOCC1>[Cl:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[S:32]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2nccc(Oc3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)c2c2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
Compound 137 (50 mg, 0.16 mmol), 2,3-dichloro-benzenesulfonyl chloride (45 mg, 0.18 mmol), and Et3N (0.07 mL, 0.49 mmol) were suspended in dioxane (2 mL), and stirred overnight at 80° C. The reaction mixture was acidified with 1M HCl, and filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude product was purified via Biotage eluting with a gradient of 25 to 100% EtOAc in hexanes to provide 173 (14 mg, 17% yield) as a white solid. LC-MS (M+H=512, obsd.=512).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[C:4]([F:16])[C:3]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][CH3:27])[C:23]([C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=1.C(O)(C(F)(F)F)=O>COCCO>[F:16][C:4]1[C:3]([O:17][CH3:18])=[C:2]([NH:1][C:20]2[N:25]=[C:24]([NH:26][CH3:27])[C:23]([C:28]([F:31])([F:29])[F:30])=[CH:22][N:21]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:11][CH2:12][O:13][CH2:14][CH2:15]1)=[O:9]
Reactant: CNc1nc(Cl)ncc1C(F)(F)F
Reactant: COc1c(N)ccc(C(=O)N2CCOCC2)c1F
Solvent: COCCO
Solvent: O=C(O)C(F)(F)F
Product: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)c(F)c2OC)ncc1C(F)(F)F
Temperature: 95 °C
Reaction time: 2 h

Procedure:
A mixture of (4-amino-2-fluoro-3-methoxyphenyl)(morpholino)methanone (0.18 g, 0.72 mmol) and 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (0.10 g, 0.47 mmol) in a solution of 2-methoxyethanol (2 mL) and TFA (0.055 mL) was stirred at 95° C. for 2 hours. The reaction was concentrated and purified by reverse phase HPLC to give the title compound. Additional compounds made using the above procedure are shown in Table 6 below.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:13])[C:7](=O)[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:14]1([C@@H:20]([NH2:22])[CH3:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1(C)C=CC=CC=1>[C:1]([NH:5][C:6](=[O:13])[C:7](=[N:22][C@H:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:21])[C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)C(=O)C(C)(C)C
Reactant: C[C@H](N)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](N=C(C(=O)NC(C)(C)C)C(C)(C)C)c1ccccc1
Yield: 79.6 %

Procedure:
A solution of 30.0 g (162 mmol) of N-tert-butyl-3,3-dimethyl-2-oxo-butyramide (D. Seyferth, R. C. Hui, Tetrahedron Lett. 1984, 25, 5251) and 50 g (413 mmol) of (S)-1-phenylethylamine in 150 ml of toluene was boiled under reflux on a water separator for 20 hours. Subsequently, the solvent and excess amine were removed in a vacuum. The residue was treated with 200 ml of hexane at 0° C. and stirred. After filtration of the suspension and concentration in a vacuum the residual oil was distilled. There were obtained 37.2 g (80%) of (S)-N-tert-butyl-3,3-dimethyl-2-(1-phenylethylimino)-butyramide of boiling point 140° C. at 0.3 mbar. [α]=-40.7 (c=1.0, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][C:16]1[N:17]=[CH:18][N:19]([CH2:21][CH2:22][S:23]([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:20]=1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([S:23]([CH2:22][CH2:21][N:19]3[CH:20]=[C:16]([CH3:15])[N:17]=[CH:18]3)(=[O:25])=[O:24])=[CH:27][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1cn(CCS(=O)(=O)c2ccc(C(=O)O)cc2)cn1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: Cc1cn(CCS(=O)(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)cc2)cn1

Procedure:
70 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(4-methyl-1H-imidazole-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-(4-methyl-1H-imidazol-1-yl)ethylsulfonyl)benzamide. MS (Q1) 481.0 (M)+.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:16])([F:15])[C:5]1[CH:6]=[N:7][C:8]2[CH2:9][CH2:10][NH:11][CH2:12][C:13]=2[CH:14]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:33]([C@:27]1([C:30]([N:11]2[CH2:10][CH2:9][C:8]3[N:7]=[CH:6][C:5]([C:4]([F:15])([F:3])[F:16])=[CH:14][C:13]=3[CH2:12]2)=[O:31])[CH2:28][CH2:29][C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH2:26]1)([CH3:35])[CH3:34]
Reactant: FC(F)(F)c1cnc2c(c1)CNCC2
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.7 %

Procedure:
To a solution of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine dihydrochloride (159 mg, 0.574 mmol) of Step A-1, (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (0.21 g, 0.79 mmol) of Step A-4 in Example 1 in dichloromethane (10 mL) were added 4-dimethylaminopyridine (38 mg, 0.32 mmol) and diisopropylethylamine (180 mg, 1.4 mmol) followed by bromotris(pyrrolydino)phophonium hexafluorophosphate (270 mg, 0.57 mmol). After being stirred overnight at room temperature, the solution was diluted with dichloromethane, washed with saturated NaHCO3, water and brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography on silica eluting with 30% ethyl acetate in hexanes to give 300 mg of desired product. MS calculated for C23H32F3N3O3: (M+H)+456; found 356.2 (M−Boc+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][C:20]=2[N+:21]([O-])=O)[N:17]([CH3:24])[C:16](=[O:25])[C:15]3([CH3:27])[CH3:26])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28](O)(=O)C>[Pd]>[CH3:24][N:17]1[C:18]2[CH:19]=[C:20]3[N:21]=[C:9]([CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][C:4]([CH3:28])=[CH:3][CH:2]=4)[NH:11][C:12]3=[CH:13][C:14]=2[C:15]([CH3:27])([CH3:26])[C:16]1=[O:25]
Reactant: CC(=O)O
Reactant: CN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Agent: [Pd]
Product: Cc1ccc(CCc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)N4C)cc1

Procedure:
A solution of 3-phenyl-N-(1,3,3-trimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-propionamide (532 mg) in acetic acid (8 ml) is hydrogenated at 2-4 bar at RT using Pd/C (10%, 80 mg), where upon ring closure occurs. After evaporation of the solvent the residue is taken-up in NaOH solution (2 N) and extracted with EtOAc (2×20 ml). The combined organic layer is washed with brine, dried over Na2SO4 and evaporated. The residual material is triturated with acetone to give the desired compound (466 mg).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH2:14])[CH2:10][C@H:9]1[C:15]([N:17]1[CH2:21][CH2:20][S:19][CH2:18]1)=[O:16])=O)(C)(C)C.C(N(CC)C(C)C)(C)C.Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33]>C1COCC1>[C:35]1([O:34][C:32](=[O:33])[NH:14][CH2:13][C@H:11]2[CH2:10][C@@H:9]([C:15]([N:17]3[CH2:21][CH2:20][S:19][CH2:18]3)=[O:16])[NH:8][CH2:12]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CN)C[C@H]1C(=O)N1CCSC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(NC[C@@H]1CN[C@H](C(=O)N2CCSC2)C1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 17D (32 mg, 0.1 mmol) in anhydrous THF (5 mL) was added N,N-diisopropylethylamine (0.035 mL, 0.2 mmol), followed by phenyl chloroformate (17.22 mg, 0.11 mmol). The mixture was stirred for 8 hours at room temperature and concentrated under reduced pressure. The residue was taken up in anhydrous dichloromethane (3 mL) and trifluoracetic acid (0.075 mL) in dichloromethane (0.075 mL) were added. The mixture was stirred for 5 hours at room temperature, concentrated under reduced pressure and purified using RP-HPLC to provide the titled compound. MS (ESI) m/e 336 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 1.77 (m, 1 H) 2.69 (m, 2 H) 3.07 (m, 1 H) 3.17 (m, 2 H) 3.25 (m, 1 H) 3.52 (m, 2 H) 3.75 (m, 1 H) 3.88 (m, 1 H) 4.52 (m, 1 H) 4.66 (m, 2 H) 7.10 (d, 2 H) 7.21 (t, 1 H) 7.37 (t, 2 H).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:17]2[C:16]([NH2:18])=[N:15][S:14](=[O:20])(=[O:19])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1.C1C=C(Cl)C=C(C(OO)=[O:29])C=1>C(Cl)Cl.CC(O)=O>[CH3:1][S:2]([CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:17]2[C:16]([NH2:18])=[N:15][S:14](=[O:19])(=[O:20])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Solvent: ClCCl
Solvent: CC(=O)O
Product: CS(=O)CCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 5-(4-(methylthio)butoxy)-1H-benzo[c][1,2,6]thiadiazin-4-amine-2,2-dioxide (Example 244) (79 mg, 0.25 mmol) in DCM/CH3CO2H (20:1, 20 mL) was added MCPBA (1.0 equiv.) at room temperature. The reaction mixture was then stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by chromatography on silica gel eluting with 15% MeOH in dichloromethane to give the title compound (74 mg, 90%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.74-1.77 (m, 2H), 1.88-1.95 (m, 2H), 2.50 (s, 3H), 2.68-2.73 (m, 1H), 2.77-2.83 (m, 1H), 4.19 (t, 2H), 6.58-6.60 (d, J=8.4 Hz, 1H), 6.73-6.75 (d, J=8.0 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.79 (s, 1H), 8.33 (s, 1H), 10.92 (s, 1H). MS 332 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC(C)=O.O>[CH2:18]([O:11][C:4]1[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=[C:2]([Br:1])[CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cc(Br)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To an ice-cold solution of 3-bromo-5-nitro-phenol (21.0 g, 96.33 mmol) in acetone (420.0 mL) was added K2CO3 (40.0 g, 289.41 mmol) followed by addition of benzyl bromide (17.20 mL, 144.40 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with water and extracted with EtOAc (3×250.0 mL). The combined organics was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified over silica gel (100-200 M, 5% EtOAc-Hexane) to get the desired product (27.0 g, 91%).