Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.C(N(CC)CC)C.O>CN(C)C=O>[O:21]=[C:15]1[CH:14]([N:8]2[CH2:7][C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:27](=[O:28])[C:26]4[CH:30]=[CH:31][C:23]([F:22])=[CH:24][CH:25]=4)[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)c4ccc(F)cc4)ccc3C2=O)C(=O)N1
Reaction time: 18 h
Yield: 53.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.60 mmol) and 4-fluorobenzoyl chloride (0.19 mL, 1.60 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.45 mL, 3.20 mmol) at room temperature under nitrogen. After 18 h, water (200 mL) was added and the solids were isolated by filtration. The crude product was triturated in 1 N aq. HCl (50 mL) for 2 h then in EtOAc (50 mL) for 18 h. The product was isolated by filtration, washed with EtOAc (25 mL) and dried in vacuo to give N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-fluoro-benzamide as a white solid (0.34 g, 53% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.06 min (94.63%); mp: 295-297° C.; 1H NMR (DMSO-d6) δ 1.85-2.12 (m, 1H, CHH), 2.22-2.47 (m, 1H, CHH), 2.54-2.70 (m, 1H, CHH), 2.79-3.03 (m, 1H, CHH), 4.31 (d, J=17.4 Hz, 1H, CHH), 4.45 (d, J=17.4 Hz, 1H, CHH), 4.59 (d, J=5.7 Hz, 2H, CH2), 5.11 (dd, J=5.1, 13.2 Hz, 1H, CH), 7.32 (t, J=8.9 Hz, 2H, Ar), 7.47 (d, J=7.7 Hz, 1H, Ar), 7.54 (s, 1H, Ar), 7.70 (d, J=7.7 Hz, 1H, Ar), 7.99 (dd, J=5.6, 8.8 Hz, 2H, Ar), 9.18 (t, J=5.9 Hz, 1H, NH), 10.98 (br. s., 1H, NH); 13C NMR (DMSO-d6) δ 22.50, 31.21, 42.78, 47.13, 51.59, 115.26 (d, J=22.0 Hz), 122.08, 122.94, 127.08, 129.93 (d, J=8.8 Hz), 130.39, 130.64 (d, J=2.2 Hz), 142.39, 143.85, 163.93 (d, J=248.7 Hz), 165.22, 167.92, 170.98, 172.85; LCMS: MH=396; Anal Calcd for C21H18N3O4+0.1H2O: C, 63.50; H, 4.62; N, 10.58. Found: C, 63.19; H, 4.54; N, 10.55.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[Br:20][CH2:21][C:22](Br)=[O:23].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][OH:13])[CH:7]=1)[C:22](=[O:23])[CH2:21][Br:20])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cccc(CO)c1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCN(C(=O)CBr)c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 3.42 g (19.2 mmol) of the compound of Example 532A in 20 ml toluene, was added 2.42 ml (30 mmol) pyridine. The mixture was cooled to 0° C.; 4.025 gm (20.0 mmol) of bromoacetyl bromide (diluted with 5 ml toluene) was added in a dropwise fashion. The reaction mixture was allowed to stir for 5 hours at 0° C. and then was allowed to warm to room temperature. Saturated potassium carbonate solution was added, and the mixture was stirred vigorously for 2 hours. The mixture was extracted with EtOAc; the organic layer was washed with 1N H3PO4, water, and brine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([O:10][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)ccc1O
Product: CCCCCCCCCCCCCCOc1ccc(O)c(C(=O)OC)c1
Yield: 43 %

Procedure:
The reaction of 2,5-dihydroxybenzoic acid methyl ester with 1-bromotetradecane under conditions described in Example 58 gave 2-(hydroxy-5-(tetradecyloxy)benzoic acid methyl ester (43% yield, mp 49°-53°). The nmr and mass spectra were compatible with the structure.
Reaction SMILES: [Cl:1][C:2]1[S:32][C:5]2[C:6]3([CH2:16][CH2:15][N:14]([CH2:17][C:18]4[C:19]([CH3:31])=[N:20][N:21]([C:23]5[N:30]=[CH:29][CH:28]=[CH:27][C:24]=5[CH:25]=[O:26])[CH:22]=4)[CH2:13][CH2:12]3)[O:7][CH2:8][C:9]([F:11])([F:10])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:48][N+:49]#[C-:50])(=O)=O)=CC=1>CO>[Cl:1][C:2]1[S:32][C:5]2[C:6]3([CH2:12][CH2:13][N:14]([CH2:17][C:18]4[C:19]([CH3:31])=[N:20][N:21]([C:23]5[C:24]([C:25]6[O:26][CH:50]=[N:49][CH:48]=6)=[CH:27][CH:28]=[CH:29][N:30]=5)[CH:22]=4)[CH2:15][CH2:16]3)[O:7][CH2:8][C:9]([F:11])([F:10])[C:4]=2[CH:3]=1
Reactant: Cc1nn(-c2ncccc2C=O)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1nn(-c2ncccc2-c2cnco2)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 65 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
To a screw-cap test tube containing 2-(4-((2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-yl)methyl)-3-methyl-1H-pyrazol-1-yl)nicotinaldehyde (0.120 g, 0.25 mmol) in methanol (2.5 mL) are added potassium carbonate (0.104 g, 0.75 mmol) and p-toluenesulfonylmethyl isocyanide (0.054 g, 0.28 mmol) under nitrogen. The reaction tube is quickly sealed (caution: build-up of pressure possible; use a safety shield) and is stirred in a preheated oil bath at 65° C. for 3 hr. with the aid of a magnetic stirrer. The mixture is diluted with methanol and purified using a 2 g SCX cartridge. The solvent is evaporated in vacuo. The resulting residue is purified by normal phase Isco chromatography eluting with hexane/ethanol (5-30%) to give 0.093 g of the title compound. MS (m/z): 518 (M+1)
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/[C:4]1[CH:15]=[C:12]([O:13][CH3:14])[C:9]([O:10][CH3:11])=[CH:8][C:5]=1[O:6][CH3:7].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=1[CH2:28][CH2:29][CH3:30].C(C1C(=O)C(Cl)=C(Cl)C(=[O:36])C=1C#N)#N>>[CH3:1]/[CH:2]=[CH:3]/[C:4]1[CH:15]=[C:12]([O:13][CH3:14])[C:9]([O:10][CH3:11])=[CH:8][C:5]=1[O:6][CH3:7].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=1/[CH:28]=[CH:29]/[CH:30]=[O:36]
Reactant: CCCc1cc(OC)c(OC)cc1OC
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: C/C=C/c1cc(OC)c(OC)cc1OC
Product: COc1cc(OC)c(OC)cc1/C=C/C=O

Procedure:
Preparation of α-asarone via dehydrogenation of 2,4,5-trimethoxyphenylpropane with DDQ containing little amount of silica gel: Addition of a catalytic amount of silica gel (0.2-0.6 g) drastically accelerated the rate of reaction as well as improved the yield of α-asarone when above dehydrogenation process (Example II-a) was conducted under the same condition resulting α-asarone in 72% yield and trans-2,4,5-trimethoxycinnamaldehyde in 18% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:11][CH2:10]1)=[O:5].[C:30](Cl)(Cl)=[O:31].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[O:15][CH:12]1[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:27][CH:26]=[C:25]([O:28][CH3:29])[CH:24]=3)[NH:1][C:30]2=[O:31])[CH2:10][CH2:11]1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(N)c(C(=O)NCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc2[nH]c(=O)n(CCN3CCC(Oc4ccc(Cl)c(Cl)c4)CC3)c(=O)c2c1

Procedure:
The product of step (i) above was dissolved in toluene (10 ml). A solution of phosgene 2.0 M in toluene (10 ml) was added, the solution heated under reflux for 1 hour and cooled. Ethyl acetate and aqueous NaHCO3 solution were added, the organic phase separated, dried and concentrated to leave a residue which was purified by chromatography (dichloromethane:methanol, 95:5). The titled product was obtained as a solid (0.11 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH3:2].C(OO)(=[O:19])C>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][C:8]1[CH:9]=[N+:10]([O-:19])[CH:11]=[CH:12][CH:13]=1)[CH3:2]
Reactant: CC(=O)OO
Reactant: CCOc1cccc(Oc2cccnc2)c1
Solvent: CC(=O)O
Product: CCOc1cccc(Oc2ccc[n+]([O-])c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 85 g of 3-(3-ethoxyphenoxy)pyridine in 500 ml of glacial acetic acid is treated with four 20 g portions of 40% peracetic acid in acetic acid. The mixture is stirred at 25° C. for 24 hours and is refluxed for 16 hours. The mixture is concentrated at reduced pressure, dissolved in 500 ml of dichloromethane and washed with excess 25% sodium hydroxide solution. The organic layer is dried, concentrated and distilled to yield 3-(3-ethoxyphenoxy)pyridine 1-oxide, bp 175°-177° C. at 0.4 mM.
Reaction SMILES: [CH:1]1([CH2:4][S:5][CH:6]2[CH2:15][CH2:14][C:9]3(OCC[O:10]3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.Cl>CC(C)=O>[CH:1]1([CH2:4][S:5][CH:6]2[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]2)[CH2:3][CH2:2]1
Reactant: C1COC2(CCC(SCC3CC3)CC2)O1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(SCC2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
8-[(Cyclopropylmethyl)thio]-1,4-dioxaspiro[4.5]decane (14.1 g, 61.7 mmol) was added to a stirred mixture of 1M hydrochloric acid (120 ml, 120 mmol) and acetone (300 ml) and the mixture was stirred at room temperature overnight. The acetone was removed by evaporation and the residue was extracted with ethyl acetate and washed with water, dried and evaporated to yield an oil used unpurified in the next step. 4-[(cyclopropylmethyl)thio]cyclohexanone (11.5 g, 62.4 mmol, 100% yield)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:18]([CH2:23][CH:24]=[CH2:25])[C:19]([O:21]C)=[O:20])[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:18]([CH2:23][CH:24]=[CH2:25])[C:19]([OH:21])=[O:20])[C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([F:17])[CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](C(=O)OC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H](C(=O)O)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of the product from Step B (1.57 g, 4.358 mmol) in THF (30 mL) and water (20 mL) was added lithium hydroxide (1.2 g, 50.0 mmol). After stirring at room temperature for 12 h, the reaction was quenched with 1N hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:16]([NH2:18])=O>O>[CH3:15][O:14][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12])[N:1]=[CH:16][NH:18][C:4]2=[O:6]
Reactant: NC=O
Reactant: COc1cc(C(=O)O)c(N)cc1[N+](=O)[O-]
Solvent: O
Product: COc1cc2c(=O)[nH]cnc2cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 67 %

Procedure:
A solution of 2-amino-5-methoxy-4-nitrobenzoic acid (1 6.6 g, 78 mmol) in formamide (250 ml) was heated at reflux for 4.5 hours. The reaction mixture was cooled to 0° C., diluted with water and the resulting precipitate collected by filtration, washed with water and dried under vacuum to give 6-methoxy-7-nitro-3,4-dihydroquinazolin-4-one ( 11.56 g, 67%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[NH:4][N:3]=1.[CH:15](OC)=[O:16]>>[CH:15]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([F:12])([F:14])[F:13])[CH:9]=2)[NH:4][N:3]=1)=[O:16]
Reactant: Nc1n[nH]c2ccc(C(F)(F)F)cc12
Reactant: COC=O
Product: O=CNc1n[nH]c2ccc(C(F)(F)F)cc12

Procedure:
A mixture of 5.0 g. of 3-amino-5-trifluoromethylindazole, prepared as in Example 1, and 25 ml. of methyl formate is refluxed for eight hours, then concentrated in vacuo to leave crude 3-formylamino-5-trifluoromethylindazole.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].Cl[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][CH2:6][OH:7]
Reactant: OCCNCCO
Reactant: COc1ccc(CCCl)cc1
Product: COc1ccc(CCN(CCO)CCO)cc1

Procedure:
2-{(2-Hydroxy-ethyl)-[2-(4-methoxy-phenyl)-ethyl]-amino}-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (10.0 g, excess). and 1-(2-chloroethyl)4-methoxybenzene (8.5 g, 50 mmol). Yield 1 -1 g, (92%); yellow oil; MS: 240 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]1[CH2:8][N:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6][C@H:5]1[NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)C.CBr.BrCC>>[CH3:1][O:3][C@@H:4]1[CH2:8][N:7]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:6][C@H:5]1[NH:15][C:16](=[O:31])[CH2:17][NH:18][C:19](=[O:30])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[CH:21]=1
Reactant: CCO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CBr
Solvent: CCBr
Product: CO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was synthesized in similar fashion to rel-N-(2-{[(3R,4R)-4-ethoxy-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide, whereby methyl bromide was substituted for bromoethane, and was isolated as a white solid. 1H-NMR (CDCl3) δ: 1.42-1.60 (m, 2H), 1.67-1.82 (m, 2H), 2.22-2.41 (m, 2H), 2.61-2.80 (m, 2H), 3.19-3.28 (m, 1H), 3.30-3.40 (m, 2H), 3.39 (s, 3H), 3.64-3.70 (m, 1H), 3.90-4.00 (m, 2H), 4.10-4.18 (m, 2H), 4.26-4.36 (m, 1H), 6.56-6.64 (m, 1H), 7.20-7.30 (m, 1H), 7.56 (t, J=7.5 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.99 (d, J=7.5 Hz, 1H); 8.08 (s, 1H). MS m/z: 430 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9]Cl)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][N:14](P(N(C)C)(N(C)C)=O)C.[C-]#N.[K+]>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][C:13]#[N:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(CC#N)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 4-methanesulfonylbenzyl chloride (10 g, 49 mmol) in DMF (100 mL) was added HMPA (9.35 mL, 54 mmol) and KCN (3.5 g, 54 mmol). The resulting reaction mixture was stirred 18 h at 80° C., then diluted with water and ethyl acetate. The organic extracts were washed (NaHCO3, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 1:1 to 25:75) provided the (4-methanesulfonyl-phenyl)-acetonitrile compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:12]([OH:15])(=O)=[O:13])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.S(Cl)([Cl:18])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([S:12]([Cl:18])(=[O:15])=[O:13])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Cl)c(S(=O)(=O)O)cc2o1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=c1[nH]c2cc(Cl)c(S(=O)(=O)Cl)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.9 %

Procedure:
To a stirred mixture of 5-Chloro-2-oxo-2,3-dihydro-benzooxazole-6-sulfonic acid (˜10 g, 40 mmol) and CH2Cl2 was added thionyl chloride (5.8 cm3, 80 mmol) at room temperature, causing gas to be evolved. This was stirred at room temperature for two hours but the solid didn't dissolve and FIA only showed starting material. Therefore a few drops of DMF were added and the reaction heated to 50° C. overnight but no reaction occurred. The starting material was filtered off and then treated with neat thionyl chloride (15 cm3) and heated to 70° C. overnight, FIA now detected starting material and product, so the reaction was treated with DMF (2×1 cm3) to aid solvation, FIA showed completion of the reaction. The reaction was diluted with CH2Cl2 (100 cm3) then poured onto ice. The solid formed was filtered off and dried in vacuo yielding 5-Chloro-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl chloride (4.6 g, 43%) as a fine white solid; δH (300 MHz; D6 DMSO) 7.09 (1H, s, Ar—H), 7.69 (1H, s, Ar—H) and 11.81 (1H, s, N—H); m/z (FIANEG) 266.0 [(M−H)−, 100%] and 268.0 [(M−H)−, 67%].
Reaction SMILES: N([O-])=O.[Na+].S(=O)(=O)(O)O.N[C:11]1[C:12]([Br:24])=[C:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:14]([Br:18])=[CH:15][C:16]=1[Br:17].[Cu][C:26]#[N:27].[C-]#N.[K+].[Cl-].[Na+]>N.C(O)(=O)C>[C:26]([C:11]1[C:12]([Br:24])=[C:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:14]([Br:18])=[CH:15][C:16]=1[Br:17])#[N:27]
Reactant: Nc1c(Br)cc(Br)c(CCC(=O)O)c1Br
Reactant: N#C[Cu]
Agent: N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: N#Cc1c(Br)cc(Br)c(CCC(=O)O)c1Br
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
3.5 g of sodium nitrite is introduced at 5° C. under agitation into 42 ml of concentrated sulfuric acid, stirred for 10 minutes,and then heated to 70° C. until a clear solution is obtained. After cooling to 5° C., 21 ml of glacial acetic acid is added under cooling in an ice bath. Then 16 g of 3-(3-amino-2,4,6-tribromophenyl)propionic acid is introduced in incremental portions between 0° C. and 5° C., and the mixture is agitated for 2 hours at 5° C. The mixture is poured on 200 g of ice and then under agitation is introduced into a solution of 18 g of copper(I) cyanide and 33.5 g of potassium cyanide in 450 ml of semiconcentrated ammonia, thus liberating nitrogen. The solution is saturated with sodium chloride and stirred overnight under water cooling. The thus-separated ammonium salt is vacuum-filtered and dissolved in the moist state in 200 ml of water. The solution is brought to pH 1 after treatment with activated carbon, by the addition of concentrated hydrochloric acid. After stirring for several hours in an ice bath, the precipitate is vacuum-filtered, washed with water, and dried at 50° C., thus producing 13 g (83% of theory) of 3-(3-cyano-2,4,6-tribromophenyl)propionic acid as a white powder, mp 164°-166° C.
Reaction SMILES: [CH2:1]([C@@:3]12[CH2:16][C@:15]([OH:18])([CH3:17])[C@:14]([OH:25])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13][C@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([O:26][CH2:27][C:28](O)=[O:29])[CH:6]=[CH:5][C:4]2=1)[CH3:2].OC1C2N=NNC=2C=CC=1.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([C@@:3]12[CH2:16][C@:15]([OH:18])([CH3:17])[C@:14]([OH:25])([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][C@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([O:26][CH2:27][C:28]([N:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)=[O:29])[CH:6]=[CH:5][C:4]2=1)[CH3:2]
Reactant: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(OCC(=O)O)ccc12
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccc3)C[C@H]1CCc1cc(OCC(=O)N3CCN(C)CC3)ccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of the compound of Example 70 (25 mg, 0.07 mmol) in dichloromethane (3 mL) was added hydroxybenztriazole (10 mg, 0.073 mmol), 1-methylpiperazine (0.008 mL, 0.073 mmol), diisopropylethylamine (0.017 mL, 0.1 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (14 mg, 0.073 mmol). The mixture was stirred at room temperature for 4 days and then quenched with saturated aqueous ammonium chloride solution. After the mixture was diluted with water, it was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated. The title compound was isolated by flash chromatography eluting with a gradient of 30% ethyl acetate in hexane to 100% ethyl acetate. Mass spectrum (m/e) 493 (M++1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=2)=[CH:5][CH:4]=1.Br[C:21]1[CH:29]=[C:28]2[C:24]([C:25]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][C:26]=3[N:27]2[CH3:30])=[CH:23][CH:22]=1>>[CH3:30][N:27]1[C:28]2[C:24](=[CH:23][CH:22]=[C:21]([N:14]3[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:1])([F:18])[F:19])=[CH:4][CH:5]=4)=[CH:12][C:13]3=[O:17])[CH:29]=2)[C:25]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][C:26]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Reactant: O=c1cc(OCc2ccc(C(F)(F)F)nc2)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)nc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 21.4 %

Procedure:
4-((6-(Trifluoromethyl)pyridin-3-yl)methoxy)pyridin-2(1H)-one (100 mg, 0.37 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (135 mg, 0.370 mmol) were coupled following the procedure of Example 30 (step g) to provide the title compound (44 mg, 21%) as a yellow/brown solid: 1H NMR (300 MHz, CDCl3) δ 8.81 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.37-7.34 (m, 1H), 7.27 (1H, under solvent peak), 7.02 (dd, J=8.3, 1.7 Hz, 1H), 6.07-6.04 (m, 2H), 5.16 (s, 2H), 4.64 (br m, 2H), 3.75 (br m, 2H), 3.63 (s, 3H), 2.80 (br m, 2H), 1.52 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[BH4-].[Na+]>C(O)(C)C>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH:4]([OH:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OC(c1ccccc1)c1ccccc1Cl
Yield: 76 %

Procedure:
A mixture containing 15.0 g (0.0692 mole) of 2-chlorobenzophenone, 4.1 g (0.1094 mole) of sodium borohydride, and 200 ml of anhydrous isopropanol is heated to reflux and maintained at reflux until the reaction is complete (2.0 hours), as indicated by vpc techniques. The solvent is removed in vacuo, whereupon the residue is diluted with ether, washed with a dilute hydrochloric acid solution and with water until neutral, dried (magnesium sulfate), and concentrated in vacuo. Recrystallization of the resulting residue from petroleum ether affords 11.5 g (0.0526 mole) of 2-chlorobenzhydrol, m.p. 61-63°.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][C:6]([CH3:10])([CH3:9])[N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH:2]([CH:3]1[O:8][CH2:7][C:6]([CH3:10])([CH3:9])[N:5]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CC(CO)OCC1(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(C=O)OCC1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To as solution of tert-butyl 2-(hydroxymethyl)-5,5-dimethylmorpholine-4-carboxylate (2.0 g, 8.15 mmol) in dichloromethane (25 mL) was added Dess-Martin periodinane (4.15 g, 9.78 mmol) slowly over 10 minutes and the mixture was stirred at room temperature 3 hours. Saturated sodium bicarbonate solution was added and the mixture extracted with dichloromethane. The dichloromethane layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound. LCMS: 144.0 (M+H-Boc).