Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[CH3:16][N:17]([CH3:37])[CH2:18][CH2:19][C:20]1([CH:35]=O)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH2:24][CH2:23][C:22]2[CH:31]=[CH:32][CH:33]=[CH:34][C:21]1=2>C1COCC1.CCCCCC.C(OCC)C>[S:4]1[CH2:5][CH2:6][CH2:7][S:8][C:3]1=[CH:35][C:20]1([CH2:19][CH2:18][N:17]([CH3:37])[CH3:16])[C:21]2[CH:34]=[CH:33][CH:32]=[CH:31][C:22]=2[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]1=2
Reactant: CN(C)CCC1(C=O)c2ccccc2CCc2ccccc21
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C)CCC1(C=C2SCCCS2)c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-trimethylsilyl-1,3-dithiane (2.5 mL, 12.8 mmol) in 10 mL of THF stirred at −78° C. and maintained under a nitrogen atmosphere was added butyllithium (5.1 mL of a 2.5M solution in hexane; 12.8 mmol) dropwise. The mixture was stirred in the cold for 20 minutes and then treated with 5-(2-dimethylamino-ethyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-carbaldehyde (102), 3.1 g in 20 mL of THF; 10.6 mmol) added dropwise. The solution was stirred for 1.5 hours at −78° C., warmed to ambient temperature and stirred an additional 1.5 hours. The solution was diluted with ethyl ether and quenched with saturated aqueous ammonium chloride. The organic layer was washed with saturated aqueous ammonium chloride (1×), saturated aqueous sodium bicarbonate (1×), and brine (1×), dried the over sodium sulfate, filtered, and evaporated to dryness. The resulting oil was purified by chromatography on silica gel (95:5 of methylene chloride:methanol). The product fractions were evaporated to dryness to yield the title product as an oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=2)[N:7]([CH2:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:6]=1.[C:24](O)(C(F)(F)F)=O.C=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl.O1CCOCC1>C(#N)C>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[CH:12]=3)[N:7]([CH2:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C:6]=2[CH2:24]1
Reactant: O=C(O)C(F)(F)F
Reactant: CNCCc1cn(CCc2ccc(C)nc2)c2ccc(C)cc12
Agent: C=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CN(C)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The title compound was prepared by General Method 4. 150 mg of N-methyl-2-(5-methyl-1-(2-(6-methylpyridin-3-yl)ethyl)-1H-indol-3-yl)ethanamine was dissolved in acetonitrile (4 mL) containing 5% TFA and the reaction mixture was heated to reflux. 37% aqueous formaldehyde (0.04 mL) was added and the reflux was continued for additional 1.5 h. The reaction mixture was cooled to 25° C., concentrated under reduced pressure and partitioned between ethyl acetate and satd. Aqueous NaHCO3. The organic layer was dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by silica gel chromatography (eluent Methanol: aqueous NH3, 95:5) to obtain the product. The free base was converted into its dihydrochloride salt by treatment of dioxane-HCl. 1H NMR (DMSO) δ 11.7 (bs, 1H), 8.6 (s, 1H), 8.3 (d, 1H), 7.7 (d, 1H), 7.3 (d, 1H), 7.25 (s, 1H), 6.9 (d, 1H), 4.8 (m, 1H), 4.4 (m, 1H), 4.35 (t, 2H), 3.7 (bs, 1H), 3.55 (s, 3H), 3.5 (m, 1H), 3.4 (bs, 1H), 3.1 (t, 2H), 3.05 (bs, 1H), 2.65 (3, 3H), 2.35 (s, 3H). MS m/z observed 320. HPLC RT 3.63 min.
Reaction SMILES: C([Li])CCC.C([Mg]Br)CCC.[CH:12]1([N:15]([CH2:23][C:24]2[CH:29]=[CH:28][C:27](Br)=[C:26]([Br:31])[CH:25]=2)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]1.CN([CH:35]=[O:36])C>C1(C)C=CC=CC=1>[Br:31][C:26]1[CH:25]=[C:24]([CH:29]=[C:28]([CH:35]=[O:36])[CH:27]=1)[CH2:23][N:15]([CH:12]1[CH2:14][CH2:13]1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(Br)c(Br)c1)C1CC1
Reactant: CN(C)C=O
Agent: CCCC[Mg]Br
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(Cc1cc(Br)cc(C=O)c1)C1CC1
Temperature: 25 °C

Procedure:
To a toluene (0.1 M) solution of n-butyl lithium (2.5 M in hexanes, 1.2 eq.) was added at −10° C. n-butyl magnesium bromide (2.0 M in THF, 0.4 eq.). The resulting suspension was stirred at −10° C. for 20 min before tert-butyl cyclopropyl(3,4-dibromobenzyl)carbamate (1 eq., Amine 77, Step 2) was added. The now yellow-red suspension was stirred at 0° C. for 30 min before DMF (30 eq.) was added dropwise neat at −78° C. The reaction mixture was allowed to warm slowly to RT over 3 h. The now black suspension was quenched with 10% aq. HCl and then extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, Hex→1:1 (v/v) Hex:EtOAc) afforded the title compound as a golden yellow oil.
Reaction SMILES: OO.[C:3]([O:8][CH2:9][CH3:10])(=[O:7])[C:4]([CH3:6])=O.[CH2:11]([C:13]1[NH:22][C:16]2=[N:17]C=[CH:19][C:20](C)=[C:15]2[N:14]=1)[CH3:12].O.O.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+].C(=O)(O)[O-].[Na+]>O.S(=O)(=O)(O)O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[CH2:11]([C:13]1[NH:22][C:16]2=[N:17][C:4]([C:3]([O:8][CH2:9][CH3:10])=[O:7])=[CH:6][C:20]([CH3:19])=[C:15]2[N:14]=1)[CH3:12]
Reactant: CCc1nc2c(C)ccnc2[nH]1
Reactant: CCOC(=O)C(C)=O
Agent: [Fe+2]
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=C([O-])O
Solvent: O
Product: CCOC(=O)c1cc(C)c2nc(CC)[nH]c2n1

Procedure:
Hydrogen peroxide (30% w/w in water; 14 ml) was added dropwise to stirred and cooled (-10° C.) ethyl pyruvate (22 ml). This mixture and a solution of iron (II) sulphate heptahydrate (37.5 g) in water (45 ml) were added simultaneously, dropwise into a stirred and cooled (-10° C.) solution of 2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine (7.1 g) in water (23 ml) and concentrated sulphuric acid (7.5 ml). The mixture was then poured onto ice and trisodium citrate dihydrate (40 g) was added. The mixture was neutralised with solid sodium bicarbonate and partitioned between chloroform (×3) and water. The organic phases were combined, dried and evaporated. Column chromatography eluting with 10% methanol in ether gave a brown solid which was triturated with ether to give the title compound as a pale yellow solid (1.9 g), m.p. 151°-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].Br[C:13]1[CH:21]=[CH:20][C:19]2[N:18]([CH3:22])[C:17]3[CH2:23][CH:24]4[NH:28][CH:27]([C:16]=3[C:15]=2[C:14]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]4>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc(Cl)cc4)ccc31)C1CCC(C2)N1
Yield: 40 %

Procedure:
Intermediate 18 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 3:2 hexanes/ethyl acetate) to give tert-butyl 2-(4-chlorophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (100 mg, 40%) as a yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.16 (s, 1H), 7.86-7.90 (m, 2H), 7.62-7.66 (m, 1H), 7.43-7.45 (m, 1H), 7.32-7.42 (m, 1H), 7.29-7.32 (m, 1H), 5.25 (br s, 1H), 4.68 (br s, 1H), 4.70 (s, 1H), 3.60 (s, 3H), 2.50 (d, J=16.3 Hz, 1H), 2.17-2.33 (m, 2H), 1.89-1.97 (m, 1H), 1.55-1.65 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:53]([CH:56]2[CH2:58][CH2:57]2)(=[O:55])=[O:54])=[C:6]([CH2:8][N:9]([CH3:52])[C:10]([CH:12]([NH:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[C:33]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[N:32][CH:31]=[CH:30]3)[C:13]2[CH:18]=[CH:17][C:16]([C@H:19]([CH2:23][OH:24])[CH:20]([F:22])[F:21])=[C:15]([CH3:25])[CH:14]=2)=[O:11])[CH:7]=1.[C:59](Cl)(Cl)=[O:60]>C(#N)C.ClCCl>[C:40]([O:39][C:38]([N:37]([C:33]1[C:34]2[C:29](=[CH:28][C:27]([NH:26][C@H:12]3[C:10](=[O:11])[N:9]([CH3:52])[CH2:8][C:6]4[CH:7]=[C:2]([CH:3]=[CH:4][C:5]=4[S:53]([CH:56]4[CH2:57][CH2:58]4)(=[O:54])=[O:55])[NH:1][C:59](=[O:60])[O:24][CH2:23][C@H:19]([CH:20]([F:21])[F:22])[C:16]4[CH:17]=[CH:18][C:13]3=[CH:14][C:15]=4[CH3:25])=[CH:36][CH:35]=2)[CH:30]=[CH:31][N:32]=1)[C:45](=[O:46])[O:47][C:48]([CH3:49])([CH3:50])[CH3:51])=[O:44])([CH3:43])([CH3:42])[CH3:41]
Reactant: Cc1cc(C(Nc2ccc3c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc3c2)C(=O)N(C)Cc2cc(N)ccc2S(=O)(=O)C2CC2)ccc1[C@H](CO)C(F)F
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2ccc1[C@@H](C(F)F)COC(=O)Nc1ccc(S(=O)(=O)C3CC3)c(c1)CN(C)C(=O)[C@@H]2Nc1ccc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
To a solution of 16K (0.144 g, 0.175 mmol) in acetonitrile (5 mL) and dichloromethane (2.5 mL) at 0° C. was added phosgene solution (20% in toluene, 0.101 mL, 0.192 mmol) dropwise. The mixture was stirred at 0° C. for 30 min. Extra phosgene was removed by bubbling Ar for 20 min. The resulting solution was added dropwise via syringe pump into a solution of TEA (0.195 mL, 1.398 mmol) in dichloromethane (60 mL) at rt over 3.0 h. The reaction mixture was stirred at rt over night. The solvent was removed and the crude product was purified by flash chromatography (0-80% ethyl acetate/hexanes). The desired fractions were collected, concentrated to give a mixture of diastereoisomers (0.12 g, 0.141 mmol, 81% yield). The diastereoisomers were separated using a prep chiral HPLC equipped with a Whelko-01 column to give 16L (34 mg, 48% yield). MS (ESI) (m/z): 850.0 (M+H)+.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8])([O-])=O.C(=O)([O-])[O-].[Na+].[Na+]>CO.[Fe]>[NH2:2][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: NC(=O)c1ccccc1N
Temperature: 80 °C

Procedure:
Concentrated hydrochloric acid (140μL) was added to a solution of the nitrobenzamide, V.3 (147 mg, 0.30 mmol) in methanol (2 ml). Iron (72 mg) was added and the reaction mixture was heated to 80° C. for 2 hours, before cooling. The reaction mixture was basified (saturated sodium carbonate solution), extracted into ethyl acetate, dried over magnesium sulphate and the solvent removed in vacuo to yield an off-white solid which was purified using flash chromatography(ethyl acetate) to yield the desired 2-aminobenzamide, VI.3 (47 mg, 34%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]1([C@H:17]([N:19]2[CH:27]=[N:26][C:25]3[C:20]2=[N:21][CH:22]=[N:23][C:24]=3[CH3:28])[CH3:18])[CH2:16][O:15]1>>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C@:14]([OH:15])([C@H:17]([N:19]1[CH:27]=[N:26][C:25]2[C:20]1=[N:21][CH:22]=[N:23][C:24]=2[CH3:28])[CH3:18])[CH2:16][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Cc1ncnc2c1ncn2[C@H](C)[C@@]1(c2ccc(F)cc2F)CO1
Product: Cc1ncnc2c1ncn2[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 16.7 %

Procedure:
Using 1H-1,2,4-triazole (167 mg) and (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-[6-methyl-9(9H)-purinyl]ethyl]oxirane (388 mg), Compound 48 (79 mg) was obtained as colorless prisms by the same way as in Exmaple 1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1)#[N:2].[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[SH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:10][S:9][C:6]1[N:7]=[CH:8][C:3]([C:1]2[S:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[C:11](=[O:19])[N:2]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccccc1S
Reactant: CSc1ccc(C#N)cn1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Yield: 30.3 %

Procedure:
5-Cyano-2-methylthiopyridine (2.26 g, 15.0 mmol) and methyl thiosalicylate (5.05 g, 30.0 mmol) were dissolved in toluene (100 ml), and triethylamine (6.3 ml, 45.0 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs. The solvent was evaporated. The residue was recrystallized from ethanol to give the titled compound (1.30 g, 31%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[C:5]1=[O:14])[CH:2]=[CH2:3].Br[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=1.C1(N(C)C2CCCCC2)CCCCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16](/[CH:3]=[CH:2]/[CH2:1][N:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:13])[C:5]2=[O:14])=[CH:17][C:18]=1[C:23]([F:24])([F:25])[F:26]
Reactant: C=CCN1C(=O)C(=O)c2ccccc21
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: O=C1C(=O)N(C/C=C/c2ccc(Cl)c(C(F)(F)F)c2)c2ccccc21
Temperature: 80 °C

Procedure:
Six separate oven-dried sealed tubes were charged with 1-allyl-1H-indole-2,3-dione (0.100 g, 0.534 mmol), Pd(P(t-Bu)3)2 (0.0082 g, 0.016 mmol), 4-bromo-1-chloro-2-(trifluoro-methyl)benzene (0.139 g, 0.536 mmol), dry toluene (1 mL), and N-cyclohexyl-N-methyl-cyclohexanamine (0.12 mL, 0.57 mmol) under an atmosphere of N2. The tubes were heated for 16 h at 80° C. in an oil bath, and then the reactions were cooled and concentrated in vacuo. The crude material was used in the subsequent step.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[C:28]([O:27][C:26]([NH:25][C@H:22]1[CH2:23][CH2:24][N:20]([C:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)=[O:19])[CH2:21]1)=[O:32])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)C2CCN(C(=O)OCc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
A mixture of 1-[(benzyloxy)carbonyl]piperidine-4-carboxylic acid (5 g, 20 mmol), tert-butyl (3S)-pyrrolidin-3-ylcarbamate (3.9 g, 21 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (9.2 g, 21 mmol), and triethylamine (3.8 g, 38 mmol) in dichloromethane (100 mL) was stirred at room temperature overnight. The reaction solution was washed with water, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel to give 7.5 g of product. MS (M+H) 432.2.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:6]=1)(=O)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:5]2[N:10]=[C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=3)[C:8]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[C:7]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])[N:6]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: C1CCNC1
Reactant: CS(=O)(=O)c1nc(OCc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Fc1ccc(COc2nc(N3CCCC3)nc(-c3ccc(Cl)cc3Cl)c2-c2ccc(Cl)cc2)cc1F

Procedure:
2-(Methylsulfonyl)-4-(3,4-difluorobenzyloxy)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Reference Example 6, 55 mg, 0.10 mmol) was reacted in excess neat pyrrolidine at 80° C. overnight by the general procedure described in Example 31, Step A. Workup (solvent removal under reduced pressure) and flash column chromatography on silica gel (eluted with 92/8 hexanes/ethyl acetate) afforded the title compound. HPLC/MS: m/e=548 (M++1); Rt=4.76 min. 1H-NMR 500 MHz (CDCl3): δ 2.02 (bs, J=4H), 3.63 (bs, 4H), 5.40 (s, 2H), 7.04 (d, J=8 Hz, 2H), 7.08-7.20 (m, 7H), 7.34 (d, J=2 Hz, 1H).
Reaction SMILES: [OH:1][C@H:2]([CH3:37])[C@H:3]([NH:6][C:7]([C:9]1[NH:10][C:11]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH:17]=[C:16]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:15]=2)=[CH:12][CH:13]=1)=[O:8])[CH2:4][OH:5].C(N(CC)CC)C.[CH:45]([Si:48](Cl)([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])([CH3:47])[CH3:46]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[OH:1][C@H:2]([CH3:37])[C@H:3]([NH:6][C:7]([C:9]1[NH:10][C:11]([C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[N:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=3)[CH:17]=[C:16]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:15]=2)=[CH:12][CH:13]=1)=[O:8])[CH2:4][O:5][Si:48]([CH:52]([CH3:54])[CH3:53])([CH:49]([CH3:51])[CH3:50])[CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](CO)[C@@H](C)O)[nH]2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)[C@@H](C)O)[nH]2)c1
Reaction time: 20 h
Yield: 90.5 %

Procedure:
N-[(1R,2R)-2-Hydroxy-1-(hydroxymethyl)propyl]-5-(3-[(1S)-2-methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxamide (883 mg, 1.65 mmol) synthesized in Example (91a), triethylamine (1.15 mL, 8.27 mmol) and 4-dimethylaminopyridine (404 mg, 3.31 mmol) were dissolved in methylene chloride (20 mL), and triisopropylsilyl chloride (0.60 mL, 2.81 mmol) was added at room temperature, followed by stirring for 20 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=30%-60%) to afford the desired compound (1.03 g, 90%) as a white solid.
Reaction SMILES: C(O)=O.[Cl:4][C:5]1[C:13]([CH3:14])=[N:12][C:11]2[N:7]([N:8]=[C:9]3[CH2:17][N:16]([C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][C@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:19])[CH2:15][C:10]3=2)[C:6]=1[CH3:33].[O:34]1[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl>[Cl:4][C:5]1[C:13]([CH3:14])=[N:12][C:11]2[N:7]([N:8]=[C:9]3[CH2:17][N:16]([C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][C@H:28]4[CH2:32][CH2:31][N:30]([CH:37]5[CH2:38][CH2:39][O:34][CH2:35][CH2:36]5)[CH2:29]4)=[O:19])[CH2:15][C:10]3=2)[C:6]=1[CH3:33]
Reactant: O=C1CCOCC1
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@H]1CCNC1)C3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=CO
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1O[C@H]1CCN(C2CCOCC2)C1)C3
Yield: 55.6 %

Procedure:
A mixture of Example 83 (150 mg; 0.35 mmol; 1 eq.), tetrahydropyran-4-one (52 mg; 0.52 mmol; 1.5 eq.) and sodium triacetoxyborohydride (74 mg; 0.35 mmol; 1 eq.) in DCE (4 mL) was stirred at 50° C. for 16 hours. The reaction mixture was diluted with DCM, washed with sat. aq. NaHCO3, dried over magnesium sulfate and concentrated in vacuo. Purification by column chromatography (EA to EA/MeOH/TEA, 90/10/2) afforded the title compound (100 mg, 56%) as white foam. 1H NMR (DMSO-d6) δ 7.41-7.30 (m, 1H), 6.99 (dd, J=11.5, 2.2 Hz, 1H), 6.87 (td, J=8.4, 2.3 Hz, 1H), 5.04-4.94 (m, 1H), 4.84-4.78 (m, 2H), 4.73-4.45 (m, 2H), 3.75-3.58 (m, 2H), 3.21-3.05 (m, 2H), 2.84 (s, 1.5H), 2.81 (s, 1.5H), 2.79-2.63 (m, 3H), 2.62 (s, 1.5H), 2.56 (s, 1.5H), 2.35-2.14 (m, 2H), 2.14-2.00 (m, 1H), 1.80-1.67 (m, 1H), 1.62-1.50 (m, 2H), 1.30-1.02 (m, 2H). HPLC (max plot) 94.2%, Rt 2.83 min. UPLC/MS: (MS+) 514.6 ([M+H]+).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][N:5]=1)[NH2:3].[F:14][C:15]([F:28])([F:27])[C:16](=O)[CH2:17][C:18]([C:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1)=O>C(O)C>[C:20]1([C:18]2[N:2]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:11])=[O:12])=[CH:6][N:5]=3)[N:3]=[C:16]([C:15]([F:14])([F:27])[F:28])[CH:17]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Reactant: O=C(CC(=O)C(F)(F)F)C1=CCCCC1
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2C2=CCCCC2)nc1
Yield: 18.3 %

Procedure:
2-Hydrazino-5-(methylsulfonyl)pyridine hydrochloride (128 mg, 0.54 mmol) and 4,4,4-trifluoro-1-(1-cyclohexenyl)-1,3-butanedione (100 mg, 0.45 mmol) were mixed in ethanol (8 ml). The resulting reaction mixture was heated at reflux temperature for 35 hours. The solvent was then removed in vacuo, and the residue was partitioned between EtOAc and water. The organic layer was washed with brine and concentrated in vacuo. The product was purified by flash chromatography using methylene chloride to give the title compound (30.6 mg, 18%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@H:7]([N:10]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[S:11]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][CH3:22])=[CH:16][C:15]=1[CH3:23])(=[O:13])=[O:12])[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].[C:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N:44]1[CH:48]=[CH:47][CH:46]=[CH:45]1)(O)=[O:36].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=N)CC>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([O:5][C:6](=[O:34])[C@H:7]([N:10]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]2[O:31][CH2:32][O:33][C:27]=2[CH:26]=1)[S:11]([C:14]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][CH3:22])=[CH:16][C:15]=1[CH3:23])(=[O:12])=[O:13])[CH2:8][NH:9][C:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N:44]1[CH:48]=[CH:47][CH:46]=[CH:45]1)=[O:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccccc1-n1cccc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CN)C(=O)OC(C)(C)C)c(C)c1
Agent: CCCN=C=N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNC(=O)c2ccccc2-n2cccc2)C(=O)OC(C)(C)C)c(C)c1
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-amino-propionate (1.02 g, 2.0 mmol), 1-(2-carboxyphenyl)pyrrole (581 mg, 3.1 mmol), 1-hydroxybenzotriazole hydrate (279 mg, 2.0 mmol), N-methylmorpholine (0.8 ml, 7.3 mmol) and 4-dimethylaminopyridine (30 mg; 0.25 mmol) in dry dimethylformamide (25 ml) was added 1-ethyl-3,3-dimethylamino)-propyl carbodiimide hydrochloride salt (600 mg, 3.1 mmol) and the material was stirred overnight. The dimethylformamide was removed on the rotary evaporator and the residue was taken up in ethyl acetate (80 ml) and partitioned with an equal volume of aqueous hydrochloric acid (1.5%, 80 ml). The organic phase was collected and washed with equal volumes of 5% aqueous sodium bicarbonate and then brine. The aqueous phases were back extracted with ethyl acetate (2×80 ml) and the organic phases combined, dried over magnesium sulfate, filtered and condensed to provide a residue. This material was chromatographed using preparative TLC plates (45% ethyl acetate/hexanes) to afford tert-butyl-2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-[(2-pyrrol-1-yl)phenylcarbonylamino]-propionate) as a pale yellow foamy solid (927 mg).