Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:28]([OH:30])=O)=[CH:5][C:6]2[N:10]=[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:15]=4[N:16]=3)[N:8]([CH3:26])[C:7]=2[CH:27]=1.[CH2:31]([O:33][CH2:34][CH2:35][NH2:36])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:31]([O:33][CH2:34][CH2:35][NH:36][C:28]([C:4]1[C:3]([O:2][CH3:1])=[CH:27][C:7]2[N:8]([CH3:26])[C:9]([NH:11][C:12]3[S:13][C:14]4[CH:20]=[C:19]([O:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:15]=4[N:16]=3)=[N:10][C:6]=2[CH:5]=1)=[O:30])[CH3:32]
Reactant: COc1cc2c(cc1C(=O)O)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Reactant: CCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1OC
Yield: 82.6 %

Procedure:
6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-ethoxy-ethyl)-amide (72 mg) was prepared by following General Procedure F starting from 6-methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 2-ethoxyethylamine (17 mg), HBTU (78 mg), and DIEA (45 uL). LC/MS: m/z 510.7. 1H NMR (DMSO-d6, 400 MHz): δ 12.27 (s, 1H), 8.34 (t, 1H), 8.16 (s, 1H), 7.90 (s, 1H), 7.71 (d, 1H), 7.35 (d, 1H), 7.26 (s, 1H), 4.0 (s, 3H), 3.64 (s, 3H), 3.56-3.43 (m, 6H), 1.16 (t, 3H).
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)(O)=[O:2].[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:2])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: Nc1ccccc1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)Nc1ccccc1
Yield: 42 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.20 g) obtained in Example 9 and aniline to give Compound 27 (0.10 g, 42%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][CH:10]1[C:9](=[O:14])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:13][CH2:12][CH2:11]1
Reactant: BrBr
Reactant: O=C1CCCCC1c1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1ccccc1Cl
Temperature: 25 °C
Yield: 112.7 %

Procedure:
2-(2-Chloro-phenyl)-cyclohexanone (51 mg, 0.25 mmol) was dissolved in chloroform (1 mL). To this solution bromine (42.3 mg, 0.27 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (81 mg) which was used directly in the next step without further purification.
Reaction SMILES: [CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH2:13])=[CH:3][C:2]2=1.Br[CH2:15][CH2:16][O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:18][O:17][CH2:16][CH2:15][N:12]1[CH:9]2[CH2:10][CH2:11][CH:1]1[C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[CH2:8]2
Reactant: COCCBr
Reactant: Nc1ccc2c(c1)C1CCC(C2)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCN1C2CCC1c1cc(N)ccc1C2
Yield: 12.5 %

Procedure:
12-Aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine (J. Med. Chem. 1988, 31, 433-444) (150 mg, 0.86 mmol), 1-bromo-2-methoxy-ethane (120 mg, 0.86 mmol) and potassium carbonate (119 mg, 0.86 mmol) were stirred together in acetone (5 mL) at 50° C. for 6 h. The mixture was filtered and concentrated before purifying on silica gel chromatography (0-50% MeOH in CH2Cl2) to obtain 12-(2-Methoxy-ethyl)-12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamine as a clear oil (25 mg, 13%). MS (m/e) 233 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:19][CH2:20]Br>CN(C)C=O>[Br:1][C:2]1[C:9]2[O:10][CH2:19][CH2:20][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: BrCCBr
Reactant: O=Cc1cc(O)c(O)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.6 %

Procedure:
To a solution of 3-bromo-4,5-dihydroxybenzaldehyde (11.5 g, 0.52 mol) in dimethylformamide (220 ml) was added cesium carbonate (50.7 g, 1.56 mol). The mixture was stirred at ambient temperature for 30 min, then 1,2-dibromoethane (12.76 g, 0.68 mol) were added. After heating at 80° for 4 h, the dimethylformamide was removed under reduced pressure. The residue was partitioned between water and ethyl acetate, and the organic layer was washed with brine and dried. The crude product was purified by flash column chromatography (silica gel, 4:1 hexane:ethyl acetate) to give the desired compound as an off-white solid (9.57 g, 75%).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O-:10])=[O:9])[N:5]2[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[C:15](=[N:22][O:23][CH3:24])[C:16]3[NH:17][C:18](=[NH:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1.[Na+].[C:28]([O:34][CH2:35]I)(=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30].C(OCC)(=O)C>CN(C)C=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:35][O:34][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[O:9])[N:5]2[C:11](=[O:26])[CH:12]([NH:13][C:14](=[O:25])[C:15](=[N:22][O:23][CH3:24])[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C@H:4]2[S:3]1
Reactant: CC(C)(C)C(=O)OCI
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=CC(C)S[C@H]12)c1csc(=N)[nH]1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=CC(C)S[C@H]12)c1csc(N)n1
Temperature: 0 °C

Procedure:
To a suspension of 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (4.8 g.) in water (48 ml.) was added dropwise 1 N aqueous sodium hydroxide solution at the rate that the pH value of the mixture was not more than 7. The mixture was filtered and then lyophilized to give sodium 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as sodium 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (4.8 g.), mp>250° C. This compound is suspended in dried dimethylformamide (20 ml.), and to the suspension was added iodomethyl pivalate (2.30 g.) with vigorous stirring under cooling to 3° to 5° C., and then the mixture was stirred for 20 minutes at the same temperature. The reaction mixture was poured into a mixture of ethyl acetate (60 ml.) and ice-water (10 ml.), and the mixture was well shaken. The ethyl acetate layer was separated, washed with a saturated aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution in turn. After the ethyl acetate layer was dried over magnesium sulfate, ethyl acetate was distilled off under reduced pressure. The residual oil was pulverized in diethyl ether (25 ml.), collected by filtration and then dried to give pivaloyloxymethyl 2-methyl-7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), which can be represented as pivaloyloxymethyl 2-methyl-7-[2-methoxyimino-2-(2-imino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (syn isomer), (1.44 g.), mp 165° to 170° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C@@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[C:10]([C:17](OC)=[O:18])=[CH:9][O:8]1)[CH3:5])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.CC(C)=O>[CH2:1]([O:3][CH:4]([O:6][C@H:7]1[C@@H:12]2[C@@H:13]([CH3:16])[CH2:14][CH2:15][C@@H:11]2[C:10]([CH2:17][OH:18])=[CH:9][O:8]1)[CH3:5])[CH3:2]
Reactant: CCOC(C)O[C@@H]1OC=C(C(=O)OC)[C@H]2CC[C@H](C)[C@@H]12
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CCOC(C)O[C@@H]1OC=C(CO)[C@H]2CC[C@H](C)[C@@H]12
Temperature: -50 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
Methyl (1S, 4aS, 7S, 7aR)-1-[1-(ethoxy)ethoxy]-7-methyl-1, 4a, 5, 6, 7, 7a-hexahydrocyclopenta[c]pyran-4-carboxylate (15.0 g, 0.053 mol) obtained in Example 4 was dissolved in 250 ml of anhydrous tetrahydrofuran, and the reaction mixture was cooled to -50° C., 88 ml of diisobutylaluminum hydride (1.5 mol toluene solution) was added dropwise to this solution. After the reaction mixture was stirred at the same temperature for 3 hours, 10 ml of acetone was added and the solution was further stirred for 20 minutes. Furthermore, a 3% aqueous sodium hydroxide solution was added dropwise and the solution was stirred for 1 hour. After magnesium sulfate was added, the reaction solution was stirred further for 20 minutes, and after insoluble matters were removed by celite filtration, the solution was concentrated under a reduced pressure. The resulting colorless oily substance, i.e., (1S, 4aS, 7S, 7aR)-1-[ 1-(ethoxy)ethoxy]-1, 4a, 5, 6, 7, 7a-hexahydro-4-(hydroxymethyl)-7-methylcyclopenta[c]pyran (12.1 g, yield=90.2%) had the following physicochemical properties:
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:13]([C:15]([O:17]C)=O)=[CH:12][CH:11]=[CH:10][C:9]=2[NH:8][CH:7]=1)([O-])=O.N1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23](C(OC)=O)[C:22]=2C=C1.[N+](C=CC1C=CC=CC=1)([O-])=O>>[C:22]1([CH:5]2[C:6]3=[CH:7][NH:8][C:9]4[CH:10]=[CH:11][CH:12]=[C:13]([C:14]=43)[C:15](=[O:17])[NH:1][CH2:4]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: COC(=O)c1cccc2[nH]cc(CC[N+](=O)[O-])c12
Agent: O=[N+]([O-])C=Cc1ccccc1
Product: O=C1NCC(c2ccccc2)c2c[nH]c3cccc1c23
Temperature: 160 °C

Procedure:
In a manner similar to that described for the preparation of methyl 3-(nitroethyl)-indole-4-carboxylate D above, methyl indole4-carboxylate (85 mg, 0.49 mmol) and nitrostyrene (80 mg, 0.54 mmol) were heated at 160° C. in a sealed tube for 12 h. The product was isolated by silica gel chromatography as a brown oil, 132 mg (83%). The intermediate nitro alkane was reduced/cyclized as described to give (rac)-3-phenyl-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one as a white solid, 51.4 mg (48%, after chromatography and recrystallization). mp 201-203° C.; 1H NMR (300 MHz, d6-DMSO) δ3.73 (m, 2H), 4.42 (m, 1H), 7.28 (br m, 8H), 7.64 (d, 1H, J=7.9 Hz), 7.77 (d, 1H, J=7.9 Hz), 11.32 (br s, 1H); HRMS (FAB, MH+) Calcd for C17H15N2O: 263.1184, Found: 263.1180; Anal. (C17H14N2O.0.25 H2O) C, H, N.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[C:20]3=[O:34])[CH:13]=[C:14]([Cl:17])[CH:15]=2)[CH:10]=[CH:9]1)=O)(C)(C)C.[OH-].[Li+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][NH:8]2)=[C:12]([CH2:18][N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:20]2=[O:34])[CH:13]=1
Reactant: COC(=O)CCn1c(=O)n(Cc2cc(Cl)cc3c2ccn3C(=O)OC(C)(C)C)c2ccccc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)CCn1c(=O)n(Cc2cc(Cl)cc3[nH]ccc23)c2ccccc21
Reaction time: 2 h
Yield: 75 %

Procedure:
6-Chloro-4-[3-(2-methoxycarbonyl-ethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl]-indole-1-carboxylic acid tert-butyl ester 270 mg (0.56 mmol) is taken up in dioxane 4 mL and then the lithium hydroxide 53 mg 2.23 mmol in water is added to the solution. The reaction is stirred for 2 hours and then made acidic by the addition of 1N HCl. The compound is then extracted into ethyl acetate and then the ethyl acetate is dried (MgSO4) filtered and evaporated in vacuo. The oil is taken up in dichloromethane and TFA is added. The reaction is stirred for 1 hour and then evaporated in vacuo to give a solid that is taken up in ethyl acetate and precipitated with hexanes. The solid is collected and washed with hexanes to give the title compound (156 mg, 0.42 mmol, 76%). LCMS (ESMS): m/z 370.8 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH:6][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.5 %

Procedure:
A mixture of 2-nitro-5-chloroaniline (Tokyo Kasei Kogyo Co., Ltd., 3 g, 17.4 mmol), pivaloyl chloride (2.1 mL, 17.4 mmol) and N,N-diisopropylethylamine (3.1 mL, 17.4 mmol) in dichloromethane (80 mL) was stirred at room temperature for 20 h. 4-Dimethylaminopyridine (531 mg, 4.4 mmol) was added and the stirring was continued for 3 days. The mixture was poured into water (30 mL) and the mixture was extracted with dichloromethane (30 mL). After removal of solvent, the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:20 as eluent) to afford the title compound (1.54 g, 34%) as a pale yellow solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[H-].[Na+].Cl[C:21]1[N:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1.O>CS(C)=O>[C:1]([NH:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][C:21]2[N:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: Clc1cnc(Cl)nc1
Reactant: CC(=O)Nc1ccc(OCCOCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1ccc(OCCOCCOc2ncc(Cl)cn2)cc1
Yield: 63.5 %

Procedure:
2-[2-(4-Acetamidophenoxy)ethoxy]ethanol (9 g) was dissolved in dry dimethylsulfoxide (60 ml) and granular sodium hydride (0.9 g) was added portionwise to the solution. 2,5-Dichloropyrimidine (5.6 g) was slowly added to the cooled stirred solution and on completion of the addition the mixture was stirred at room temperature for 1 hour. The mixture was poured into water (200 ml) and the solid was collected by filtration. The product was recrystallised from ethanol/water to give 2-{2-[2(4-acetamidophenoxy)ethoxy]ethoxy}-5-chloropyrimidine (8.4 g), m.p. 110° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1.[NH4+:15].[OH-]>O>[NH2:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:3]=1
Reactant: [NH4+]
Reactant: Brc1cccc(CN2CCCCC2)n1
Agent: [OH-]
Solvent: O
Product: Nc1cccc(CN2CCCCC2)n1
Temperature: 95 °C

Procedure:
To a solution of 2-bromo-6-(piperidylmethyl)pyridine (5.21 g, 20 mmol) in IpOH (30 mL) in a sealed tube at RT, a catalytic amount of Cu (100 mg) and 28–30% NH4OH (35 mL) were added. The stirred suspension was heated to 95° C. for 40 h. After cooling to RT, the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (4×80 mL). The organic layers were combined, then washed with H2O (50 mL) followed by brine (50 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound as a dark yellow oil. This was used as crude. MS m/z: 193 (M+H)+.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:38]=[CH:39][C:40]2[N:41]([N:43]=[CH:44][N:45]=2)[CH:42]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[N:45]1[CH:44]=[N:43][N:41]2[CH:42]=[C:37]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)[CH:38]=[CH:39][C:40]=12
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Brc1ccc2ncnn2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccc3ncnn3c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 63.4 %

Procedure:
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (300 mg, 0.63 mmol) and 6-bromo-[1,2,4]triazolo[1,5-a]pyridine (149 mg, 0.75 mmol) in dry 1,4-dioxane (15 mL) were added 2M aq Cs2CO3 (2 mL) and Pd(PPh3)Cl2 (40 mg, 0.056 mmol). After addition, the mixture was heated to reflux for 2 h under N2 atmosphere. The solid was filtered off and diluted with water (50 mL) and EtOAc (100 mL), the mixture was extracted with EA (3×50 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by prep TLC to afford (S)-3-((S)-1-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (188 mg, yield: 63.5%). LC-MS Method tR=1.18 min, m/z=471, 418; 1H NMR (CDCl3): δ 1.05 (s, 3H), 1.12 (s, 3H), 1.49-1.51 (m, 3H), 2.15-2.18 (m, 2H), 2.21-2.23 (m, 1H), 2.32-2.37 (m, 1H), 2.82-2.87 (m, 1H), 3.01-3.06 (m, 1H), 5.63-5.68 (m, 1H), 7.01-7.06 (m, 2H), 7.19-7.22 (m, 3H), 7.29-7.32 (m, 3H), 7.33-7.36 (m, 2H), 7.36-7.38 (m, 1H), 7.75-7.78 (m, 1H), 7.11-7.13 (m, 1H), 8.79 (s, 1H).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[C:24]1(B(O)O)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:32]1([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)[C:33]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][CH:31]=1
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1Nc2cccc(-c3cccc4ccccc34)c2/C1=C/c1ccc[nH]1
Temperature: 100 °C

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (40 mg, 0.119 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (119 μL , 0.238 mmol), (Ph3P)4Pd (3 mg, 0.003 mmol) (Aldrich), and 1-naphthaleneboronic acid (22.5 mg, 0.131 mmol) (Lancaster) in 3 mL of a 3:1 mixture of 1,2-dimethoxyethane:distilled water was heated at 100° C. under a nitrogen atmosphere for 20 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 20% ethyl acetate-hexanes then 30% ethyl acetate-hexanes elution) to yield a crude solid. Recrystallization from chloroform-pentane provided pure (Z)-1,3-dihydro-4-(1-naphthalenyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (yield 31 mg, 78%) as yellow crystals (mp 210-212° C.).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7][C:6]2([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[NH:5]1.[CH2:27](Br)[C:28]#[CH:29]>CN(C=O)C>[O:3]=[C:4]1[C:9]2([CH2:10][CH2:11][CH2:12][CH2:13]2)[N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:7][C:6]2([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[N:5]1[CH2:29][C:28]#[CH:27]
Reactant: C#CCBr
Reactant: CC(C)(C)OC(=O)N1CC2(CCCCCC2)NC(=O)C12CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCN1C(=O)C2(CCCC2)N(C(=O)OC(C)(C)C)CC12CCCCCC2
Reaction time: 1 h

Procedure:
Sodium hydride (23 mg, 0.575 mmol, 60% dispersion in mineral oil) was added to a stirred solution of tert-butyl 16-oxo-6,15-diazadispiro[4.2.6.2]hexadecane-6-carboxylate from Step A (92 mg, 0.273 mmol) in DMF (1 mL). When the gas evolution had ceased, propargyl bromide (70 mg, 0.471 mmol, 80 wt % in toluene) was added to the solution at ambient temperature. After 1 h, the reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to yield the title compound. MS: m/z=397 (M+Na).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([NH2:23])(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.[O-]S(C(F)(F)F)(=O)=O.[C:32]([O:37][CH3:38])(=[O:36])[C@H:33]([CH3:35])O>O1CCCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([S:20]([NH:23][C@H:33]([CH3:35])[C:32]([O:37][CH3:38])=[O:36])(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Reactant: COC(=O)[C@H](C)O
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](C)NS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Temperature: -30 °C
Reaction time: 0.17 h
Yield: 66 %

Procedure:
A solution of potassium tert-butoxide (0.87 ml, 1M in tetrahydrofuran) was added to a solution of [4-(4-chlorophenyl)piperazine-1-sulfonyl]amine (200 mg, 0.73 mmol), [prepared as described in Step 1 above], in tetrahydrofuran (10 ml) at -60° C. After 10 min., a solution of the triflate derivative of methyl (S)-lactate (604 mg, 2.56 mmol) in tetrahydrofuran (3 ml) was added and the reaction mixture was allowed to warm to -30° C. over 30 min. The reaction mixture was quenched with saturated ammonium chloride and the product was extracted into ethyl acetate. The solvent was removed in vacuo and the residue was chromatographed (SiO2, 30% ethyl acetate/hexane) to give methyl 2-(R)-{[4-(4-chlorophenyl)piperazine-1-sulfonyl]-amino}propionate as a colorless oil (66%).
Reaction SMILES: Cl.[C:2]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)#[N:3].Br[CH2:17][CH2:18][CH2:19][C:20]1[CH:30]=[CH:29][CH:28]=[C:22]2[C:23]([NH:25][C:26](=[O:27])[C:21]=12)=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[C:2]([C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:6][N:7]([CH2:17][CH2:18][CH2:19][C:20]2[CH:30]=[CH:29][CH:28]=[C:22]3[C:23]([NH:25][C:26](=[O:27])[C:21]=23)=[O:24])[CH2:8][CH2:9]1)#[N:3]
Reactant: N#CC1(c2ccccc2)CCNCC1
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: N#CC1(c2ccccc2)CCN(CCCc2cccc3c2C(=O)NC3=O)CC1
Temperature: 105 °C

Procedure:
A mixture of 4-cyano-4-phenylpiperidine hydrochloride (111 g, 0.5 mol), 3-bromopropylphthalimide (135.39 g, 0.505 mol), potassium carbonate (276.42 g, 2 mol), and potassium iodide (5.4 g) in DMF (1 L) was stirred and heated at 100-110° C. for 8 hours. About 80% of the solvent was evaporated at reduced pressure, the residue was diluted with dichloromethane (1 L) and washed with brine (3×300 mL) and dried (Na2SO4). Solvent was evaporated from the dichloromethane solution and the residue was treated with isopropanol (400 mL) and cooled. The pale yellow crystalline product formed was filtered, washed with ice-cold isopropanol and dried (168.6 g, 90%); M.p. 96-98° C.