Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH3:19])=[CH:15][CH:16]=1)([CH3:22])[CH3:23]
Reactant: CCOc1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CCOc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 53.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl](4-ethoxyphenyl)amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (0.89 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(4-ethoxyphenyl)urea (0.93 g) was obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.[CH2:25]([S:28](Cl)(=[O:30])=[O:29])[CH2:26][CH3:27]>N1C=CC=CC=1.ClCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][S:28]([CH2:25][CH2:26][CH3:27])(=[O:30])=[O:29])=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[N:2]1
Reactant: CCCS(=O)(=O)Cl
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
4-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-phenylamine was diluted to 0.3 M with anhydrous pyridine, then delivered to an 8 mL vial via pipette (0.225 mmol). Propane-1-sulfonyl chloride was diluted to 1.0 M with anhydrous dichloromethane, and added to the amine solution at rt (0.40 mmol). The solution was stirred overnight at 45° C. To the reaction mixture was added polyamine scavenging resin (0.30 mmol). The solution was stirred overnight at 45° C., then filtered into an 8 mL vial. The filtrate was evaluated by MS and concentrated via HT-12 GeneVac. Crude was purified by HPLC (30×100 mm ODS-A C(18) 5u column). Propane-1-sulfonic acid {4-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-phenyl}-amide was isolated in 100% purity @ 254 nm; LCMS (APCI): 445 [M+H]+
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:21](=[O:22])[C:11]3=[N:10]2)=[CH:4][CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[C:21](=[O:22])[C:11]2=[N:10][N:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:3][CH:4]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]2=[N:19]1
Reactant: C1COCCN1
Reactant: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(Br)nc3)nc-2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(N4CCOCC4)nc3)nc-2c1=O
Temperature: 25 °C
Reaction time: 9 h

Procedure:
5-[(6-Bromopyridin-3-yl)methyl]-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 22), 60 mg, 0.13 mmol] was dissolved in dimethyl sulfoxide (1 mL) and treated with morpholine (35 mg, 0.40 mmol, 3 equiv) and potassium carbonate (19 mg, 0.13 mmol, 1 equiv). The vessel was sealed and placed into an oil bath preheated at 100° C. for 9 hours. The mixture was cooled to ambient temperature, poured into water (5 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were washed three times with water and once with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 94:6; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.29 (1H, br s), 7.69-7.59 (3H, m), 7.57-7.51 (2H, m), 7.44 (1H, m), 7.38-7.29 (3H, m), 6.59 (1H, d, J=9.1 Hz), 5.73 (2H, s), 3.79 (4H, m), 3.50 (4H, m), 2.35 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 453.2038 [(M+H)+; calculated for C26H25N6O2: 453.2034].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(N)cn3)cc2)CC1
Reactant: OB(O)c1cccc(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4cccc(F)c4)cn3)cc2)CC1
Reaction time: 18 h

Procedure:
To a solution of {4-[4-(5-amino-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (0.10 g, 0.3 mmol, 1.0 equiv) and 3-fluorophenyl boronic acid (0.086 g, 0.61 mmol, 2.0 equiv) in 5 Ml dichloromethane was added pyridine (0.05 Ml, 0.61 mmol, 2.0 equiv), copper (II) acetate (0.084 g, 0.46 mmol, 1.5 equiv) and 4 Å molecular sieves. The heterogeneous mixture was allowed to stir open to atmosphere for 18 h. Purification by silica gel chromatography (20-45% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.27 (m, 2 H) 1.47 (br. S., 1 H) 1.53 (dd, J=12.51, 2.65 Hz, 1 H) 1.67 (br. S., 1 H) 1.85 (d, J=12.38 Hz, 4 H) 2.29 (d, J=6.57 Hz, 2 H) 3.34 (s, 2 H) 3.64 (s, 3 H) 6.69 (td, J=8.46, 2.53 Hz, 1 H) 6.89 (dt, J=11.62, 2.15 Hz, 1 H) 6.96 (dd, J=7.83, 1.77 Hz, 1 H) 7.33 (d, J=8.34 Hz, 2H) 7.63 (dd, J=8.59, 2.78 Hz, 1 H) 7.84 (d, J=8.59 Hz, 1 H) 7.95 (d, J=8.34 Hz, 2 H) 8.47 (s, 1 H) 8.71 (s, 1H); (M+H)+ 419.3.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)=[O:7].[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(CC1C=C(CN(C)C)C(O)=C(CN(C)C)C=1)C>[Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:14])=[O:7]
Reactant: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)O)c1
Reactant: NCc1cccnc1
Agent: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccc(Cl)cc1Cl)Nc1cccc(C(=O)NCc2cccnc2)c1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To solution of 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid (102 mg, 0.3 mmol), 3-aminomethyl pyridine (0.036 ml, 0.36 mmol) in DMF 3.0 mL was added EDC (86.3 mg, 0.45 mmol), HOBt (60.8 mg, 0.45 mmol) and DIPEA (0.078 ml, 0.45 mmol). Reaction mixture was stirred at room temperature, and separated by EtoAC and brine. The organic phase was dried (MgSO4 anh) and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=30:1) to give 3-[2-(2,4-dichloro-phenoxy)-acetylamino]-N-pyridine-3-ylmethyl-benzamide as a white-solid (71.4 mg, 55% yield).
Reaction SMILES: C([O:4][CH:5](OC(C)C)[C:6]([CH3:27])([CH3:26])[C:7](=[O:25])[C@H:8]([CH3:24])[C@@H:9]([O:15][C:16]([O:18][CH2:19][C:20]([Cl:23])([Cl:22])[Cl:21])=[O:17])[C@@H:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1.O>[O:25]=[C:7]([C@H:8]([CH3:24])[C@@H:9]([O:15][C:16]([O:18][CH2:19][C:20]([Cl:21])([Cl:22])[Cl:23])=[O:17])[C@@H:10]([CH3:14])[CH2:11][CH:12]=[CH2:13])[C:6]([CH3:27])([CH3:26])[CH:5]=[O:4]
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)C(OC(C)C)OC(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)C=O

Procedure:
A mixture of (4R,5S,6S)-1,1-diisopropoxy-5-(2,2,2-trichloroethoxycarbonyloxy)-2,2,4,6-tetramethyl-8-nonen-3-one (4.58 g) and p-toluenesulfonic acid monohydrate (0.45 g) in 100 mL of 3:1 THF/water is heated at reflux for 7 hours. The mixture is cooled and poured into sat. aq. NaHCO3, then extracted with ethyl acetate. The extract is dried over Na2SO4, filtered, and evaporated. The product is purified by chromatography on Sio2 (3% ethyl acetate/hexanes).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:21]N(C)C=O.[H-].[Na+].CI>O>[CH3:21][N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18](=[O:20])[CH3:19]
Reactant: CN(C)C=O
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CC(=O)N(C)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
A 12.5 g portion of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide was added to 500 ml of dimethylformamide under argon. A 2.47 g portion of sodium hydride (50% in oil) was added, this mixture was stirred one hour, then 3.2 ml of methyl iodide was added. This mixture was stirred for 2.5 days, then poured into 1.5 liters of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and concentrated in vacuo. The residue was chromatographed as described in Example 1. Fractions 8-15 were combined, concentrated and the solid recrystallized from dichloromethane-hexane, giving 8.5 g of the desired product, mp 200°-203° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:15]N(C)C)[C:10](OCC)=[O:11])=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2].[NH:21]([C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[O:28])=[CH:25][N:24]=1)[NH2:22]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:15]=[N:22][N:21]([C:23]3[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH2:30][CH:31]4[CH2:36][CH2:35][O:34][CH2:33][CH2:32]4)=[O:28])=[CH:25][N:24]=3)[C:10]=2[OH:11])=[C:5]([O:19][CH3:20])[CH:4]=1)#[N:2]
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1OC
Product: COc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCOCC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 188 using ethyl 2-(4-cyano-2-methoxyphenyl)-3-(dimethylamino)acrylate and 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.1 Hz, 11 H) 1.22 (d, J=9.6 Hz, 3 H) 1.62 (d, J=12.1 Hz, 2 H) 3.19 (dd, J=11.6, 5.6 Hz, 4 H) 3.86 (d, J=9.6 Hz, 2 H) 3.97 (s, 3 H) 7.38-7.57 (m, 2 H) 8.43 (br. s., 2H) 8.72 (br. s., 1 H) 8.92 (s, 1 H). MS m/z [M+H]+ 434.4.
Reaction SMILES: [CH2:1]=[C:2]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][C:7]2[S:6][CH:5]=[CH:4][C:3]1=2.C(Br)=C.[NH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[S:6]1[C:7]2[CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:2](=[CH:1][C:24]3[CH:25]=[C:20]([NH2:19])[CH:21]=[CH:22][CH:23]=3)[C:3]=2[CH:4]=[CH:5]1
Reactant: C=C1c2ccccc2CCc2sccc21
Reactant: Nc1cccc(B(O)O)c1
Agent: C=CBr
Product: Nc1cccc(C=C2c3ccccc3CCc3sccc32)c1

Procedure:
4-Methylene-9,10-dihydro-4H-1-thia-benzo[f]azulene is converted to the vinyl bromide as in Preparation 24 and the vinyl bromide coupled with 3-aminophenylboronic acid using the procedures essentially as described in Example 219.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[C:20]([O:21][C:22]4[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][C:18]([C:29]([F:32])([F:31])[F:30])=[CH:17][N:16]=3)[S:11][N:10]=1)[CH2:2]2.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41].[ClH:47]>C(Cl)Cl>[ClH:47].[CH3:28][C:23]1[C:22]([O:21][C:20]2[C:15]([NH:14][C:12]3[S:11][N:10]=[C:9]([CH:3]4[CH2:2][CH:1]5[N:8]([C:40](=[O:42])[CH3:41])[CH:5]([CH2:6][CH2:7]5)[CH2:4]4)[N:13]=3)=[N:16][CH:17]=[C:18]([C:29]([F:30])([F:31])[F:32])[CH:19]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ncccc1Oc1cc(C(F)(F)F)cnc1Nc1nc(C2CC3CCC(C2)N3)ns1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C2CCC1CC(c1nsc(Nc3ncc(C(F)(F)F)cc3Oc3cccnc3C)n1)C2
Yield: 47.5 %

Procedure:
3-(8-azabicyclo[3.2.1]octan-3-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (45 mg, 0.0973 mmol) was dissolved in CH2Cl2 (2 mL) and triethylamine (67.8 μL, 0.486 mmol) and acetic anhydride (13.8 μL, 0.146 mmol) were added. After 10 minutes the reaction was partitioned between saturated aqueous NaHCO3 and CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (10% methanol in EtOAc) to afford 1-(3-(5-(3-(2-methylpyridin-3-yloxy)-5-(trifluoromethyl)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)ethanone hydrochloride (25 mg, 0.0462 mmol, 47.5% yield) as a solid after HCl salt formation. Mass spectrum (apci) m/z=505.2 (M+H—HCl).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([CH:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[CH2:11][N:10]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:9]1)=O)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>>[CH3:2][C:1]1[S:42][C:6]([CH:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:11][N:10]([C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])[CH2:9]2)=[N:5][N:4]=1
Reactant: CC(=O)NNC(=O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cc1nnc(C2CC(c3ccc(OC(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)s1

Procedure:
106 mg (0.231 mmol) of the compound from Example 121A and 187 mg (0.462 mmol) of Lawesson reagent were reacted according to the General Method 9. Yield: 10 mg (10% of theory)
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7]O)[CH:2]=[CH2:3].C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1COCC1>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:6]=1[CH2:7][N:29]=[N+:30]=[N-:31])[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc(OC)cc1CO
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCOc1ccc(OC)cc1CN=[N+]=[N-]
Yield: 86 %

Procedure:
Step AS (3). To a solution of 2-allyloxy-5-methoxybenzyl alcohol (5 g, 26 mmol) in 75 mL of anhydrous THF was added diphenylphosphoryl azide (6 mL, 28.5 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (4.6 mL, 31 mmol) at 0° C. The mixture was refluxed for 1 h. The reaction was concentrated and the residue purified by silica gel chromatography eluting with 25% EtOAc in hexane to yield 2-allyloxy-5-methoxybenzyl azide as a colorless oil (4.9 g, 87%). (M−N3)+=177; 1H NMR (400 MHz, CDCl3) δ ppm 3.76 (s, 3H) 4.36 (s, 2H) 4.47-4.57 (m, 2H) 5.21-5.31 (m, 1H) 5.31-5.46 (m, 1H) 5.95-6.14 (m, 1H) 6.79-6.82 (m, 2H) 6.83-6.85 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16].Cl.[NH2:20][OH:21].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[N:20][OH:21])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16]
Reactant: Cc1ccsc1C(=O)Cc1ccccc1[N+](=O)[O-]
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccsc1C(Cc1ccccc1[N+](=O)[O-])=NO
Yield: 76.7 %

Procedure:
A mixture of 22.0 g of 1-(3-methyl-2-thienyl)-2-(2-nitrophenyl)ethanone in 210 ml of 95% ethanol, 11.7 g of hydroxylamine hydrochloride in 28 ml water, and 25.04 g of sodium acetate trihydrate in 28 ml water was refluxed overnight. The mixture was allowed to cool. The precipitate was collected and crystallized from 95% ethanol to give 17.85 g of product, mp 105°-100° C.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1.CN([CH:28]=[O:29])C.Cl>O1CCCC1.O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[C:18]=1[CH:28]=[O:29]
Reactant: CN(C)C=O
Reactant: Fc1ccc(Br)cc1F
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(Br)ccc(F)c1F
Yield: 56.2 %

Procedure:
A solution of 152 mmol of 2,2,6,6-tetramethylpiperidine and 152 mmol of n-butyllithium (1.6 M solution in n-hexane) in 280 ml of dry tetrahydrofuran is admixed with 145 mmol of 1-bromo-3,4-difluorobenzene at −75° C. This temperature is maintained for 4 hours, and then 174 mmol of DMF are added dropwise. The reaction mixture is then slowly thawed, hydrolyzed with water at −20° C., acidified using hydrochloric acid and extracted with tert-butyl methyl ether. The combined organic extracts are washed with saturated sodium chloride solution and dried using sodium sulfate. The solvent is removed under reduced pressure, and the raw product is purified by chromatography over silica gel (eluent: dichloromethane/n-heptane 1:1) and recrystallization from n-heptane, yielding 18 g (56%) of 2-bromo-5,6-difluorobenzaldehyde in the form of slightly yellow crystals.—M.p.: 40-43.5° C.—1H-NMR (400 MHz, CDCl3/TMS): δ=10.31 (dd, 4J(HF)=2 Hz, 5J(HF)=1.5 Hz, 1 H, CHO), 7.45 (ddd, 3J(HH)=9 Hz, 4J(HF)=4 Hz, 5J(HF)=2 Hz, 1 H, Har), 7.28 (ddd, 3J(HH)=9 Hz, 3J(HF)=9 Hz, 4J(HF)=8 Hz, 1 H, Har).—19F-NMR (376.5 MHz, 1H broad-band decoupled, CDCl3/CFCl3): δ=−136.4 (d, 3J=19.2 Hz), −139.2 (d, 3J=19.2 Hz).
Reaction SMILES: C([O:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][CH:13]=[N:12][C:11]=1[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([O:25][CH3:26])=[O:24])[CH:18]=1)C1C=CC=CC=1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[CH3:26][O:25][C:23]([C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][C:11]1[N:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([OH:27])=[O:8])=[O:24]
Reactant: [H][H]
Reactant: COC(=O)c1cccc(Oc2ncccc2C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Oc2ncccc2C(=O)O)c1
Yield: 76.2 %

Procedure:
To a solution 2-(3-Methoxycarbonyl-phenoxy)-nicotinic acid benzyl ester (1.1 g) in methanol (15 ml) and ethyl acetate (15 ml) was added 10% palladium on carbon (0.2 g). This was shaken under 30 psi hydrogen for 2 hours. The catalyst was removed by filtration, and the solution was concentrated to give a solid which was triturated in methylene chloride/hexane to give a white solid (0.630 g). MW 273.26; MS (m/e) 274 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][N:33]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:36]([C:35]3[CH:34]=[N:33][C:32]([Cl:31])=[CH:40][CH:39]=3)=[O:37])=[CH:19][CH:20]=2)[CH2:11][O:10][C:9]1([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(N)cc2)COC1(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1[C@@H](CCc2ccc(NC(=O)c3ccc(Cl)nc3)cc2)COC1(C)C
Temperature: 50 °C
Yield: 82.2 %

Procedure:
To a stirred suspension of (S)-4-[2-(4-amino-phenyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (150 mg, example 14 (b)) in THF (4 ml) were added sequentially triethylamine (0.13 ml) and 6-chloronicotinoyl chloride (107 mg, CAS 58757-38-3) and the mixture was heated at 50° C. for 4 h. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2; gradient: heptane/EtOAc) to give (S)-4-(2-{4-[(6-chloro-pyridine-3-carbonyl)-amino]-phenyl}-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (177 mg, 82%) as a white solid. MS (ISP): 484.3 ([{37Cl}M+Na]+), 482.3 ([{35Cl}M+Na]+), 462.4 ([{37Cl}M+H]+), 460.5 ([{35Cl}M+H]+), 406.4 ([{37Cl}M+H—C4H8]+), 404.3 ([{35Cl}M+H—C4H8]+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][OH:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]([Si:32]([CH3:35])([CH3:34])Cl)([CH3:31])([CH3:30])[CH3:29].N1C=CN=C1>CN(C)C=O.O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][O:21][Si:32]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:35])[CH3:34])=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(C(CO)c3ccccc3)ccc21
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(c1ccccc1)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(1-benzenesulfonyl-1H-indol-5-yl)-2-phenyl-ethanol CCLXVII (1.06 g, 2.707 mmol), tert-butyldimethylchlorosilane (0.45 g, 2.978 mmol) and imidazole (200 mg, 2.978 mmol) in N,N-dimethylformamide (20 mL) was stirred at room temperature for 4 hours. The resulting mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, 10/90) to give 1-benzenesulfonyl-5-[2-(tert-butyl-dimethyl-silanyloxy)-1-phenyl-ethyl]-1H-indole CCLXVIII as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[C:5]([O:7]C)=[O:6].O.[OH-].[Li+]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(CN(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)Cc1cc(Br)cc(C(=O)O)c1
Reaction time: 3 h

Procedure:
Methyl 3-bromo-5-[(dimethylamino)methyl]benzoate (0.30 g, 1.1 mmol, from Step A) was dissolved in tetrahydrofuran (20 mL) and lithium hydroxide monohydrate (0.555 g, 13.2 mmol) in water (6 mL) was added. After stirring for 3 hours, the mixture was rotovapped to remove THF and reduce the volume of water. The mixture was diluted with an equivalent volume of acetonitrile and filtered. The product was purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Solvent was removed from fractions containing desired product by rotary evaporation to afford a white solid. Yield: 0.26 g (91%); LC-MS: 258.0, 260.0 (M+H)+. 1H NMR (300 MHz, DMSO-d6): δ 7.86 (dd, 1H), 7.76 (dd, 1H), 7.43 (dd, 1H), 3.38 (s, 2H), 2.14 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].NC1C=CC(Br)=CC=1S(N)(=O)=O.[CH2:24]([N:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([OH:41])=[C:33]([C:42](OCC)=[O:43])[C:32]1=[O:47])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[NH2:11][S:8]([C:3]1[S:4][C:5]([Cl:7])=[CH:6][C:2]=1[NH:1][C:42]([C:33]1[C:32](=[O:47])[N:31]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:40]2[C:35]([C:34]=1[OH:41])=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:43])(=[O:9])=[O:10]
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CCOC(=O)c1c(O)c2ccccc2n(Cc2ccccc2)c1=O
Agent: Nc1ccc(Br)cc1S(N)(=O)=O
Product: NS(=O)(=O)c1sc(Cl)cc1NC(=O)c1c(O)c2ccccc2n(Cc2ccccc2)c1=O

Procedure:
The title compound is prepared according to the procedure of Example 84C substituting the product of Example 174A for the product of Example 84A and substituting the product of Example 99A for the product of example Example 84B.