Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([N+:21]([O-])=O)[CH:5]=1.CC(C)=O>CO.[Ni]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([NH2:21])[CH:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c(S(N)(=O)=O)c1
Agent: [Ni]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)c1cc(N)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
35 g (~0.1 mol) of 3-nitro-4-phenoxy-5-sulphamylbenzoic acid methyl ester are suspended in 150 ml of methanol and are hydrogenated with Raney nickel (5-10%) in an autoclave at 40°-50° and 100 atmospheres gauge. The precipitated amino compound is dissolved by the addition of acetone on a steambath and the Raney nickel is removed by filtration.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:22](=[O:23])[C:21]4[CH:25]=[CH:26][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:19][CH:20]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 660 mg; 0.30 mmol; 1.0 eq.) and 4-(trifluoromethyl)benzoyl chloride (125 mg, 0.60 mmol; 2.0 eq.) as a white powder (31.2 mg, 28%). HPLC, Rt: 4.02 min. (purity 99.4%). LC/MS, M+(ESI): 373.2, M−(ESI): 373.1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][C@@H:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:5]1.C1OCCOCCOCCOCCOCCOC1.[C-:47]#[N:48].[K+]>CS(C)=O.O>[CH3:1][O:2][CH2:3][C@H:4]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:7][C@@H:6]([C:47]#[N:48])[CH2:5]1
Reactant: [C-]#N
Reactant: COC[C@H]1C[C@H](S(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC[C@@H]1C[C@H](C#N)CN1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
5 (13.76 g, 0.034 mol) was dissolved in DMSO (17 mL). 18-Crown-6 (5 eq) and finely ground KCN (5 eq) were added and the reaction mixture was stirred for 6 h at 80° C. The reaction solution was diluted with H2O (17 mL) and then extracted with ethyl acetate. The organic solution was dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluting with hexanes/ethyl acetate (4/1, v/v) to afford 13.76 g (69% yield) of the desired product 6 as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C1COCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(F)cc1)N1CCCCC1

Procedure:
A solution of piperidine (5.64 g, 66 mmol), diisopropylethyl amine (1 3.64 mL, 78 mmol), and p-fluorobenzenesulfonyl chloride (13.64 mL, 78 mmol) in THF at 0° C. was stirred for 2 hours at ambient temperature. The solvent was removed in vacuo and the crude reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with aqueous HCl, and brine. It was dried over sodium sulfate, and filtered. Removal of the solvent gave near quantitative yield of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:9][C:6]([CH3:8])([CH3:7])[CH2:5][C:4](C)=[CH:3]1.[OH2:11].[O:12]=[O+][O-]>C(O)(=O)C>[O:11]=[C:4]([CH3:3])[CH2:5][C:6]([CH3:8])([CH3:7])[CH2:9][C:2]([OH:1])=[O:12]
Reactant: O
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: O=[O+][O-]
Solvent: CC(=O)O
Product: CC(=O)CC(C)(C)CC(=O)O
Temperature: 150 °C
Reaction time: 2 h

Procedure:
In accordance with the usual procedure 41 grams isophorone in 45 grams aqueous acetic acid (50% H2O) was ozonized at ambient temperature and pressure for approximately two hours. Additional acetic acid (60 mls) and water (30 mls) were added and treatment with ozone continued. After 8 hours no further ozone uptake was observed and the reaction was terminated. The resulting reaction product was then slowly added to refluxing acetic acid over a period of about one hour and, when a negative test was obtained using starch iodide, the water and acetic acid were stripped by gradually heating to 150° C. under a vacuum of 50-100 mm Hg. Distillation of the resulting crude product yielded 40.3 grams 5-keto-3,3-dimethylhexanoic acid (B.P. 96° C.-101° C. at 0.2 mm Hg) which was indicated by gas-liquid chromatography to be 99 percent pure.
Reaction SMILES: CN(C)CCNC.[Li]CCCC.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][N:16]=1.[I:23]I>C1COCC1.CCOCC>[I:23][C:21]1[C:18]([CH:19]=[O:20])=[CH:17][N:16]=[C:15]([O:14][CH3:13])[CH:22]=1
Reactant: COc1ccc(C=O)cn1
Reactant: II
Agent: CNCCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(I)c(C=O)cn1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 15.9 %

Procedure:
To a stirred solution of N,N,N′-trimethylethylenediamine (1.9 mL, 15 mmol) in anhydrous THF (65 mL) under argon at −70° C. was slowly added 1.6M n-BuLi in hexanes (9.0 mL, 14 mmol). After stirring at −70° C. for 15 minutes, 6-methoxy-nicotinaldehyde (1.3 g, 9.8 mmol) was added dropwise. After the addition was complete, stirring was continued at −70° C. for another 15 minutes. Then 1.6M n-BuLi in hexanes (10 mL, 16 mmol) was added dropwise and stirring continued at −45° C. for 4 h. The solution was cooled to −70° C. and then a solution of iodine (3.0 g, 12 mmol) and anhydrous THF (25 mL) was added dropwise. When the addition was complete, stirring was continued at −70° C. for 30 minutes and then at RT for 3 h. The crude product was taken up in ether (40 mL) and washed successively with saturated ammonium chloride (2×40 mL) and 5% sodium thiosulfate (2×20 mL). The organic phase was dried, filtered and concentrated. Purification by column chromatography with EtOAc-heptanes (1:1) as eluent gave 0.41 g (15% yield) of 4-iodo-6-methoxynicotinaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH:10]([F:16])[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[BH4-].[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:17])[CH:10]([F:16])[N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=C(c1ccc(Cl)cc1Cl)C(F)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC(c1ccc(Cl)cc1Cl)C(F)n1cncn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of 2.4 g of 1-(2,4-dichlorophenyl)-2-fluoro-2-(1H-1,2,4-triazol-1-yl)ethanone in 9.5 ml of methanol and 0.5 ml of water is added at 5°-10° C., with stirring, 0.12 g of sodium borohydride, and the resulting mixture is stirred firstly for 1 hour at 0°-5° C. and then for 2 hours at room temperature, in the course of which a clear solution gradually forms. This solution is then poured into ice-water, and the mixture is extracted twice with dichloromethane. The combined extracts are dried over sodium sulfate, filtered, and concentrated by evaporation. The residue is distilled under high vacuum to obtain the above alcohol as a diastereoisomeric mixture; b.p. of the crude product: 150°-160° C./0.07 mbar. Crystallisation from diethyl ether/diisopropyl ether yields the purified diastereoisomeric mixture in the form of beige crystals; melting range 103°-112° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.[CH3:22]N(C)C=O.[H-].[Na+].CI>C(OCC)(=O)C.O1CCCC1>[CH3:22][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2C)CC1
Reaction time: 1 h

Procedure:
Combine (1H-benzimidazol-2-yl)(1-ethoxycarbonyl-piperidin-4-yl)amine (1.44 g, 5.0 mmol) and dimethylformamide (3 mL) and tetrahydrofuran (25 mL). Add sodium hydride (0.34 g, 60% in oil, 8.5 mmol). After 1 hour, add methyl iodide (1 mL). After 18 hours, evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give (1-methyl-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine: Rf=0.25 (silica gel, ethyl acetate).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:18]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:14][N:15]=2)=[O:9])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(Nc1ncc(CN2CCOCC2)s1)N(C1CCCCC1)C1CCCCC1
Yield: 34.4 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (100 mg, 0.30 mmol), acetic acid (18 μL, 0.30 mmol), morpholine (78 μL, 0.90 mmol) and sodium triacetoxyborohydride (70 mg, 0.33 mmol) to afford 42 mg (34%) of the desired product after purification.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:33]=[C:31]([CH3:32])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[CH2:22][C@@H:21]1[OH:34])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:45][O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.CCOCC>C(Cl)Cl>[CH2:47]([O:46][CH2:45][N:28]1[C:29](=[O:30])[C:31]([CH3:32])=[CH:33][N:25]([C@@H:23]2[O:24][C@H:20]([CH2:19][O:18][Si:1]([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C@@H:21]([OH:34])[CH2:22]2)[C:26]1=[O:27])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: ClCOCc1ccccc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)n(COCc2ccccc2)c1=O
Reaction time: 14 h
Yield: 88 %

Procedure:
To a stirred solution of 2 (117.0 g, 243.8 mmol) and Hunig's base (diisopropylethylamine, 63.0 g, 487.5 mmol) in CH2Cl2 (400 mL) at 23° C. was added a solution of benzyl chloromethyl ether (40.7 g, 260.0 mmol) over a 15 min. period. The resultant mixture was maintained at 23° C. and stirred for 14 h. Ether (1 L) was added to the mixture and the ethereal solution was washed with 10% aqueous HCl (1×100 mL) and H2O (200 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/AcOEt 40:1 then 10:1) to yield 128.9 g (88%) of 3 as a white solid. Rf(CH2Cl2/AcOEt 10:1) 0.31. 1H-NMR (CDCl3): 1.10 (s, 9H, C-Me3), 1.65 (s, 3H, 5-Me), 2.16 (m, 1H, 2′-Hβ), 2.41 (m, 1H, 2′-Hβ), 2.53 (br s, 1H 3′-OH), 3.84 (d, 1H, J=8.8 Hz, 5′-CHH), 3.98 (d, 1H, J=8.8 Hz, 5′-CHH), 4.01 (s, 1H, 4′-H), 6.64 (br s, 1H, 3′-H), 4.70 (s, 2H, OCH2Ph), 5.50 (s, 2H, NCH2O), 6.41 (dd, 1H, J=8.0, 5.8 Hz, 1′-H), 7.20-7.50 (m, 13H, aromatic-H), 7.65-7.69 (m, 3H, 6-H and aromatic-H). 13C-NMR (CDCl3): 12.86 (−5-CH3), 19.45 (+, C-Me3), 27.09 (−, C-Me3), 41.16 (+, 2′-C), 64.25 (+, 5′-C), 70.70 (+, O—C—Ph), 71.97 (−, 4′-C), 72.29 (+, N—C—C), 85.51 (−, 3′-C), 87.20 (−, 1′-C), 110.47 (+, 5-C), 127.72, 128.08, 128.36 (−, aromatic-C), 130.25 (−, 6-C), 132.42, 133.00 (+, aromatic-C) 134.39, 135.37, 135.62 (−, aromatic-C), 137.95 (+, aromatic-C), 151.01 (+, 2-C), 163.68 (+, 4-C).
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[CH:12]=O.[CH:14](=[O:18])[CH2:15][CH2:16][CH3:17].C(OC(C)C)(C)C>O.CCO>[CH2:16](/[C:15](=[CH:12]\[C:4]1[NH:3][C:11]2[C:6]([CH:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2)/[CH:14]=[O:18])[CH3:17]
Reactant: O=Cc1cc2ccccc2[nH]1
Reactant: CCCC=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(C)OC(C)C
Product: CC/C(C=O)=C\c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.8 %

Procedure:
To a solution of KOH pellets (0.4 g, 7.1 mmol) in H2O (5 ml), indole-2-carboxaldehyde (0.5 g, 3.44 mmol) in EtOH (45 ml) was added. After cooling to 0° C. butyraldehyde (0.31 ml, 3.44 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The ethanol was removed under vacuum and the aqueous solution was adjusted to pH 5 and extracted with EtOAc (3×10 ml). The combined organic layers were washed with brine (10 ml), dried over Na2SO4 and evaporated under vacuum. The residue was purified by flash-chromatography (hexane/EtOAc 7:3) to afford, after trituration with isopropyl ether, 0.3 g (44%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH2:39][CH2:40][O:41][CH3:42]>>[CH3:34][O:35][CH2:36][CH2:37][N:38]([CH2:39][CH2:40][O:41][CH3:42])[C:1](=[NH:2])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[O:33])[CH:4]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: COCCNCCOC
Product: COCCN(CCOC)C(=N)c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Yield: 11 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.1 equivalents of bis(2-methoxyethyl)amine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:8](=[O:19])[C:7]2([CH3:21])[CH3:20].C([Li])CCC.Br[CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>O1CCCC1>[Si:31]([O:30][CH2:29][CH2:28][CH:11]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[F:1])[C:7]([CH3:21])([CH3:20])[C:8]1=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC1(C)C(=O)N(Cc2cccc(F)c2)c2c(F)cccc21
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(C(CCO[Si](C)(C)C(C)(C)C)c2cccc(F)c2)c2c(F)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.3 %

Procedure:
7-fluoro-1-(3-fluorobenzyl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.01 g, 3.5 mmol) was dissolved in tetrahydrofuran and cooled to −78° C. n-Butyl lithium (2.5 M in hexane, 1.55 mL, 3.97 mmol) was added dropwise and the mixture was warmed to 0° C. (2-Bromoethoxy)-tert-butyldimethylsilane (1.14 mL, 5.25 mmol) was added and the mixture was allowed to warm to 25° C. The mixture was stirred for 16 hours then quenched with saturated aqueous ammonium chloride, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-10% ethyl acetate in hexane) to afford 0.8 g (55%) 1-[3-{[tert-butyl(dimethyl)silyl]oxy}-1-(3-fluorophenyl)propyl]-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH2:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>S(Cl)(Cl)=O>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:14]=1)=[O:7]
Reactant: Nc1cccc(-c2ccccn2)c1
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Nc2cccc(-c3ccccn3)c2)cc1I
Temperature: 25 °C
Reaction time: 264 h

Procedure:
3-Iodo-4-methylbenzoic acid (154 mg, 0.59 mmol) was heated at 80° C. in thionyl chloride (2 ml) for 3 hrs. The reaction was allowed to cool to room temperature and the excess thionyl chloride evaporated under vacuum. The residue was dissolved in acetone (3 ml), 2-(3-aminophenyl)pyridine (100 mg, 0.59 mmol) and sodium carbonate (400 mg) were added to the solution. The reaction was stirred at room temperature for 11 days, filtered and the filtrate reduced to dryness under vacuum. The residue was dissolved in ether and filtered through a bond-elut (1 g, silica), washing with ether. The solvent was evaporated from the combined filtrate and washings to give 3-iodo-4-methyl-N-(3-pyridin-2-yl-phenyl)benzamide as a cream foam. NMR: δH CDCl3 8.70, (1H, dt), 8.33, (1H, d), 8.18, (1H, t), 7.93-7.89, (2H, m), 7.79-7.75, (4H, m), 7.50, (1H, t), 7.35, (1H, d), 7.26, (1H, m), 2.51, (3H, s).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([NH2:17])=[C:11]3[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([N:27]=[C:28]=[O:29])[CH:20]=1.[Cl:30]CCl>>[Cl:30][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([NH:27][C:28]([NH:17][C:16]2[CH:15]=[CH:14][N:13]=[C:12]3[N:8]([CH2:7][C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH:9]=[CH:10][C:11]=23)=[O:29])[CH:20]=1
Reactant: Nc1ccnc2c1ccn2Cc1ccncc1
Reactant: ClCCl
Reactant: COc1ccc(Br)cc1N=C=O
Product: COc1ccc(Cl)cc1NC(=O)Nc1ccnc2c1ccn2Cc1ccncc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 1d (52 mg, 0.233 mmol) is dissolved in dichloromethane (5.0 mL) and 4-bromo-2-isocyanato-1-methoxy-benzene (1.0 equiv., 44 mg, 0.233 mmol) is then added and stirred at room temperature for 3 hours under nitrogen atmosphere. All solvent is then removed by rotary evaporation and the crude product is purified via preparative TLC to afford Compound 1f as an off-white solid.
Reaction SMILES: [CH2:1]([C@H:8]([NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.ClC(Cl)C(O)=O>C1(C)C=CC=CC=1.CS(C)=O.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:18][C:19]([C:21]1[NH:22][C:23]2[C:28]([CH:29]=1)=[CH:27][C:26]([Cl:30])=[CH:25][CH:24]=2)=[O:20])[C:9](=[O:10])[N:11]1[CH2:12][CH2:13][C:14](=[O:17])[CH2:15][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)C(Cl)Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1CCN(C(=O)[C@H](Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
5-Chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide (Example 46, 669 mg) was added in one portion at 0° C. to a mixture of 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (DEC, 1.80 g, 9.4 mmol) and dichloroacetic acid (307 mg, 1.5 mmol) in anhydrous toluene (e mL) and anhydrous dimethylsulfoxide (e mL). The mixture was stirred at 0-20° C. for 2 h, diluted with ethyl acetate, the resulting solution washed twice with 1N HCl, twice with saturated aqueous NaHCO3, dried, concentrated and the residue purified by chromatography on silica gel eluted with 25%, 50%, and 75% ethyl acetate-hexanes giving a foam (424 mg, 64%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N+]=[N-])[CH:5]=[CH:6][CH:7]=1.[O:18]=[CH:19][C:20](=[CH2:22])[CH3:21]>ClCCl.CCCCCC.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[CH2:21][C:20]2([CH3:22])[CH:19]=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)C=O
Reactant: [N-]=[N+]=C(c1cccc(F)c1)c1cccc(F)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC1(C=O)CC1(c1cccc(F)c1)c1cccc(F)c1
Temperature: 43 °C

Procedure:
A solution of bis(3-fluorophenyl)diazomethane, prepared as in Example 84 by the action of activated manganese dioxide (33 g) on 3,3'-difluorobenzophenone hydrazone (21.76 g) in dichloro-methane (105 mL), was added to a solution of methacrolein (15 mL) in hexane (100 mL). The mixture was heated at 43° C. for 20 hours then the amber solution was evaporated in vacuo. The crude solid was triturated with hexane to yield 23.1 g of 2,2-bis(3-fluorophenyl)-1-methylcyclopropanecarboxaldehyde, mp 92°-93° C. Recrystallization of a sample from hexane furnished the analytical specimen, mp 92°-93.5° C.
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[CH2:12]Br.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([NH2:24])[CH3:23])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:24]([C@H:22]([C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)[CH3:23])[CH2:12]2
Reactant: COC(=O)c1c(Cl)cc(Cl)cc1CBr
Reactant: C[C@H](N)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(Cl)cc1)N1Cc2cc(Cl)cc(Cl)c2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.5 %

Procedure:
A mixture of 2-Bromomethyl-4,6-dichloro-benzoic acid methyl ester (0.119 g, 0.4 mmol), (S)-1-(4-chloro-phenyl)-ethyl amine (0.067 mL, 0.48 mmol), and K2CO3 (0.104 g, 0.8 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography of the product using 30% ethyl acetate in hexane afforded (S)-5,7-dichloro-2-[1-(4-chloro-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.047 g, 35%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.64 (d, 3H), 3.94 (d, 1H), 4.26 (d, 1H), 5.74 (q, 1H) 7.22-7.42 (m, 6H). GC-MS: m/z 340 (M)+.