Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2]1.C(O)(=O)C.C(O[C:26]1(O[Si](C)(C)C)[CH2:28][CH2:27]1)C.[BH3-]C#N.[Na+].C1COCC1>CO>[CH:26]1([N:9]2[CH2:10][CH2:11][C:6]3([CH2:1][CH2:2][N:3]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:4][CH2:5]3)[CH2:7][CH2:8]2)[CH2:28][CH2:27]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1CC1)CC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
tert-Butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate (250 mg, 0.98 mmol) were dissolved in 10 ml of absolute methanol. 3 g of molecular sieves (3 Å, which had been dried beforehand under high vacuum) were added to this solution. Under argon, glacial acetic acid (0.55 ml, 10 eq.), [(1-ethoxycyclopropyl)oxy]trimethylsilane (0.69 ml, 3.5 eq.) and 4.4 ml of a 1 M NaCNBH3 solution in THF (4.4 mmol, 4.5 eq.) were then added successively. After stirring at RT for 20 minutes, the mixture was heated to 60° C. and stirred at this temperature for about 15 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was taken up in dichloromethane, washed successively with 1 M NaOH solution and NaCl solution, and dried over MgSO4. After the solvent had been removed under reduced pressure, the product was obtained as a colorless oil.
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.I[C:60]1[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[C:62]([O:68][CH3:69])[CH:61]=1>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:60]2[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[C:62]([O:68][CH3:69])[CH:61]=2)=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: COc1ccc(I)cc1OC
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: COc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1OC
Yield: 17 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 4-iodo-1,2-dimethoxybenzene in 17% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([CH3:28])([CH3:27])[CH2:11][O:12][C:13]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[CH3:31][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.ClCCl>[C:1]([O:5][C:6]([N:8]([CH3:31])[CH2:9][C:10]([CH3:28])([CH3:27])[CH2:11][O:12][C:13]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(C(C)(C)C)cc1OCC(C)(C)CNC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: ClCCl
Product: COC(=O)c1ccc(C(C)(C)C)cc1OCC(C)(C)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 61.8 %

Procedure:
To a solution of methyl 2-(3-tert-butoxycarbonylamino-2,2-dimethylpropoxy)-4-tert-butylbenzoate (2.50 g, 6.35 mmol) in THF at 0° C. under N2 was added methyl iodide (4.51 g, 31.8 mmol, 5 eq), followed by sodium bis(trimethylsilyl)amide (12.7 mL, 12.7 mmol, 1.0 M in THF). The cooling bath was allowed to slowly warm to room temperature. The reaction was stirred at room temerature for 2.5 days, then diluted with dichloromethane, washed with water and brine, dried, and concentrated in vacuo to give 1.60 g (61.8%) of the desired product as a viscous oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](C(OC(C)(C)C)=O)[N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.Cl.[N:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl>O1CCCC1.C(N(CC)CC)C>[F:24][C:20]1[CH:19]=[C:18]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:33](=[O:34])[CH2:32][C:29]4[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=4)[CH:3]=3)[NH:7][N:6]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(N)ccc21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)Nc1ccc2[nH]nc(-c3cccc(F)c3)c2c1
Yield: 21.2 %

Procedure:
A solution of 50 mg of tert-butyl 5-amino-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced in Production Example I-26, 26 mg of 4-pyridylacetic acid hydrochloride and 0.05 ml of triethylamine in 5 ml tetrahydrofuran was added 37 mg of 1,1′-carbonyldiimidazole as a condensing agent at room temperature. After the completion of the reaction, the reaction mixture was treated with 5 N hydrochloric acid by the procedure of Production Example I-25-b, to give 11 mg of the title compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].O[CH2:23][C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][CH2:32][OH:33])[CH:27]=[CH:28][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:23][C:24]2[CH:25]=[C:26]([CH2:30][CH2:31][CH2:32][OH:33])[CH:27]=[CH:28][CH:29]=2)=[CH:12][C:11]=1[CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: COc1ccc(F)c(-c2ccc(O)cc2CC(C)(C)C)c1
Reactant: OCCCc1cccc(CO)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(CCCO)c3)cc2CC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 58.6 %

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-ol (312 mg), 3-(3-(hydroxymethyl)phenyl)propan-1-ol (199 mg) and triphenylphosphine (522 mg) in THF (10 mL) was added a 40% solution of diethyl azodicarboxylate in toluene (790 μL) at 0° C., and the mixture was stirred at 0° C. for 5 min and at room temperature for 16 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (277 mg) as a colorless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2)(=[O:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:6]1[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[N:9][NH:10]2)([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc2[nH]ncc2c1
Product: CC(=O)Nc1ccc2[nH]ncc2c1[N+](=O)[O-]
Yield: 91.6 %

Procedure:
By referring to the Step 4 of Example 1, 5-acetylaminoindazole (6 g, 34.2 mmol), HNO3 (2.0 mL, 48 mmol), were used to obtain a product (6.9 g, 91.7%).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C@@H:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:11][C@H:10]([CH2:25][CH2:26][C:27](O)=[O:28])[C:9]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[Li+].Cl>O1CCCC1.C(OCC)(=O)C.C(O)C>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C@@H:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:11][C@H:10]([CH2:25][CH2:26][CH2:27][OH:28])[C:9]1=[O:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC[C@H]1O[C@H](c2ccccc2)c2ccccc2N(Cc2ccccc2)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1[C@@H](CCCO)O[C@H](c2ccccc2)c2ccccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The mixture of 0.4 g of methyl ester of trans-1-benzyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-propionic acid obtained in Example 12, 0.16 g of sodium borohydride and 0.16 g of lithium chloride in 15 ml of tetrahydrofuran were stirred for 10 minutes at room temperature. To the resultant was added 30 ml of ethanol, which was stirred for 2 hours at 60° C. To the reaction mixture were added 100 ml of 1N hydrochloric acid and 150 ml of ethyl acetate. The ethyl acetate layer was washed with an aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent, hexane:ethyl acetate=2:1) to give 0.19 g of trans-1-benzyl-3-(3-hydroxypropyl)-5-phenyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one as needles, m.p. 59°-62° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][C:7]1=[S:12])(=[O:4])=[O:3].[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH:17]=O.CC([O-])=O.[Na+]>CO>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:9]2[S:8][C:7](=[S:12])[N:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[C:10]2=[O:11])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: CS(=O)(=O)NN1C(=O)CSC1=S
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)NN1C(=O)C(=Cc2ccc(Cl)c(Cl)c2)SC1=S
Reaction time: 24 h
Yield: 54.5 %

Procedure:
3-(Methanesulfonylamino)-4-oxo-2-thionothiazolidine 269 mg (1.19 mmol, 1.0 equiv) was dissolved in 3 mL MeOH followed by the addition of 208 mg 3,4-dichlorobenzaldehyde (1.19 mmol, 1.0 equiv) and 10 mg NaOAc (0.119 mmol, 0.1 equiv). The solution was allowed to stir for 24 hours, at which time the yellow solid was removed by filtration. The solid was washed (4×MeOH) and dried under vacuum to give the 248 mg of the product as a yellow solid (0.649 mmol, 55%). 1H NMR (DMSO, 400 MHz) δ 8.01 (d, J=1.0 Hz, 1 H), 7.95 (s, 1 H), 7.84 (d, J=8.4 Hz, 1 H), 7.63 (dd, J=2.1, 8.4 Hz, 1 H), 3.28 (s, 3 H).
Reaction SMILES: [O:1]1[CH2:19][CH:2]1[CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:18])[C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH2:20]1[NH:22][CH2:21]1>>[N:22]1([CH2:19][CH:2]([OH:1])[CH2:3][O:4][C:5]2[C:17]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:10](=[O:18])[C:9]=3[CH:8]=[CH:7][CH:6]=2)[CH2:20][CH2:21]1
Reactant: O=C1c2ccccc2-c2c(OCC3CO3)cccc21
Reactant: C1CN1
Product: O=C1c2ccccc2-c2c(OCC(O)CN3CC3)cccc21

Procedure:
4 g of 4-(2,3-epoxypropoxy)-9-fluorenone are allowed to stand at room temperature over night together with 15 cc of ethylene imine. The excess ethylene imine is removed by evaporation, the residue is taken up in ether and the solution is concentrated by evaporation until crystallization commences. The title compound has an M.P. of 113°-116°.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:3]([C:5]2[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:28][CH2:29]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)nn1C
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccc(F)cn2)c1COc1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 37 %

Procedure:
As described for example 81c, 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (73 mg, 0.21 mmol) was converted, using 4-aminotetrahydropyran instead of morpholine, to the title compound (32 mg, 37%) which was obtained as a white solid. MS: m/e=416.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C([Li])CCC.C1C[O:19][CH2:18]C1>>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([CH:18]=[O:19])[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: C1CCOC1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Li]CCCC
Product: O=Cc1cnc2[nH]ccc2c1
Reaction time: 1 h
Yield: 61 %

Procedure:
To 5-Bromo-1H-pyrrolo[2,3-b]pyridine (1.5 g, 7.61 mmol) in THF (200 mL) at −78 C, under nitrogen, was added n-butyl lithium (2.5M in hexanes, 15.2 mmol, 6.1 mL), and the reaction solution was stirred with an overhead motor. After 1 hr, the resulting orange gel was quenched with methylormate (4.56 g, 76 mmol) and the reaction solution was allowed to slowly warm to 23C. The solution was poured into water and extracted with ethyl acetate, dried (Na2SO4) to give 1H-Pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.68 g, 61% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.I[CH2:13][CH3:14].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:13][CH3:14])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]
Reactant: CCI
Reactant: NC(=O)c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOc1ccc(Cl)cc1C(N)=O
Yield: 36.6 %

Procedure:
A mixture of 5-chlorosalicylamide (16.0 g., 0.093 mole), iodoethane (31.8 g., 0.204 mole), and potassium carbonate (13.1 g., 0.095 mole) in ethanol (225 ml.) was heated under reflux for 20 hours. The hot mixture was filtered. The filtrate was reduced to dryness. The residue was triturated with water. The mixture was filtered and the collected solid recrystallized from acetonitrile to give 5-chloro-2-ethoxybenzamide (6.8 g., 36.6%) m.p. 136°-139°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10](I)[C:3]=12.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)[CH:33]=[N:32]1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[O:15][C:16]4[C:21]([C:22](=[O:30])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH3:13])[N:9]=[C:10]([C:37]3[CH:38]=[C:39]4[C:34]([CH:33]=[N:32][NH:31]4)=[CH:35][CH:36]=3)[C:3]=12
Reactant: CC1(C)OB(c2ccc3cn[nH]c3c2)OC1(C)C
Reactant: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(I)c2c(N)ncnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1ccccc1)n1nc(-c2ccc3cn[nH]c3c2)c2c(N)ncnc21
Temperature: 80 °C
Reaction time: 12 h
Yield: 10.2 %

Procedure:
To a solution of Example 57b (0.500 g, 0.98 mmoles) in DMF (10 ml), ethanol (4 ml) and water (4 ml), 6-Indazoleboronic acid pinacol ester (0.478 g, 1.96 mmoles) and sodium carbonate (0.519 g, 4.90 mmoles) were added and the system is degassed for 30 min. Tetrakis triphenylphosphine Palladium (0.214 g, 0.185 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.050 g, 10% yield). MP: 176-178° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.18 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 8.05 (dd, J=8.0, 1.6 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 7.83 (m, 1H), 7.73 (s, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.52 (dt, J=7.9, 0.8 Hz, 1H), 7.41 (dd, J=8.3, 1.2 Hz, 1H), 7.31-7.16 (m, 5H), 6.01 (q, J=6.9 Hz, 1H), 1.92 (d, J=7.1 Hz, 3H). Mass: 500.04 (M++1).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.[CH3:35][N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH2:45]Br)=[N:37]1>CN(C=O)C.C1(C)C=CC=CC=1>[CH:21]([N:12]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[CH:3]([CH2:45][C:38]2[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[N:36]([CH3:35])[N:37]=2)[C:4](=[O:34])[N:5]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:6]2[CH:27]=[CH:26][CH:25]=[CH:24][C:7]1=2)([CH3:23])[CH3:22]
Reactant: Cn1nc(CBr)c2ccccc21
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 22.8 %

Procedure:
To a stirring solution of 330 mg (0.73 mmol) of 2-(2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 10 mL DMF at 0° C. is added dropwise over 5 min 1.75 mL (0.87 mmol, 1.1 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 10 min, then a solution of 180 mg (1.18 mmol, 1.1 equiv) of 1-methyl-3-bromomethyl-1H-indazole in 3 mL DMF is added. The resulting solution is stirred 3 h at RT and then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 2/1 as eluent followed by further purification via silica gel MPLC using a Si60 column and hexane/EtOAc 1/1 as eluent followed by lyophilization in acetonitrile/H2O afforded 100 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ7.74 (d, 1H, J=8.3), 7.25-6.76 (m, 16H), 4.85 (m, 1H), 4.11 (s, br, 2H), 3.97 (dd, 1H, J=5.6, 7.8), 3.77 (s, 3H), 3.70 (s, 3H), 3.63 (dd, 1H, J=7.8, 15.9), 3.48 (dd, 1H, J=5.6, 15.9), 0.92 (d, 6H, J=6.8); low resolution MS (FAB)m/e 602 (MH+), 437. Anal. (C36H35N5O4) Calcd. C, 71.86; H, 5.86; N, 11.64; Found C, 71.69; H, 5.91; N, 11.56.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:10](=[O:21])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[CH3:29][C:30]1([CH3:43])[C:34]2([CH2:38][S:39](Cl)(=[O:41])=[O:40])[C:35]([CH2:37][CH:31]1[CH2:32][CH2:33]2)=[O:36].C(N(CC)CC)C>ClCCl.C(Cl)(Cl)Cl>[CH3:29][C:30]1([CH3:43])[CH:31]2[CH2:32][CH2:33][C:34]1([CH2:38][S:39]([N:8]1[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[C:10](=[O:21])[CH2:9]1)(=[O:41])=[O:40])[C:35](=[O:36])[CH2:37]2
Reactant: CC1(C)C2CCC1(CS(=O)(=O)Cl)C(=O)C2
Reactant: Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1N1CCN(S(=O)(=O)CC23CCC(CC2=O)C3(C)C)CC1=O
Reaction time: 12 h

Procedure:
To a stirred solution of 1-t-butyloxycarbonyl-4-(2-methyl-phenyl)-3-piperazinone (0.25 g; 0.86 mmol) in dichloromethane (3 mL) was added TFA (1 mL). After 1 hour the solvents were removed under reduced pressure and the residue was taken up into chloroform and evaporated several times to remove excess TFA. The residue was dissolved in chloroform (5 mL) and added to the stirred solution was 10-camphorsulfonyl chloride (376 mg; 1.50 mmol) and triethylamine (0.38 mL; 2.7 mmol). After 12 hours, the mixture was diluted with chloroform (25 mL) and extracted with 5% aqueous HCl (25 mL), water (25 mL), and aqueous NaHCO3 (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 2:1 hexane-ethyl acetate as eluant. The title compound was obtained as a white foam from ether-hexane.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](/OS(C(F)(F)F)(=O)=O)=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:29]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)#[N:30]>O1CCOCC1>[C:29]([C:31]1[CH:36]=[C:35](/[C:6](/[C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:7]\[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:34]=[CH:33][CH:32]=1)#[N:30]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)/C=C(\OS(=O)(=O)C(F)(F)F)c1ccco1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C(\c1cccc(C#N)c1)c1ccco1
Reaction time: 8 h
Yield: 23.5 %

Procedure:
To a solution of ethyl (Z)-3-(2-furyl)-3-{[(trifluoromethyl)sulfonyl]-oxy}-2-propenoate (500 mg, 1.59 mmol) in 7 ml anhydrous dioxane was added potassium phosphate (506 mg, 2.4 mmol), 3-cyanophenyl boronic acid (234 mg, 1.59 mmol), and tetrakis (triphenylphosphine)palladium(0) (46 mg, 0.04 mmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 50 ml ethyl acetate, washed with 2×50 ml water, 2×50 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was chromatographed on silica gel using a gradient from 5% EtOAc in hexane to 10% EtOAc in hexane as the eluent to give ethyl (E) 3-(3-cyanophenyl)-3-(2-furyl)-2-propenoate (100 mg, 24%) as a clear yellow oil after drying. H1NMR (CDCl3) 1.1-1.14 (t, 3H); 4.016-4.035 (m, 2H); 5.293 (s, H); 7.45-7.549 (m, 3H); 7.669 (m, H). ES-MS (M+H+): 268.05
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.C([O:43][C:44]([C@H:46]1[C@@H:51]([NH:52][CH2:53][CH:54]([CH3:56])[CH3:55])[C@H:50]2[CH2:57][C@@H:47]1[CH2:48][CH2:49]2)=O)C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[OH:43][C:44]1[C@H:46]2[C@H:51]([C@H:50]3[CH2:57][C@@H:47]2[CH2:48][CH2:49]3)[N:52]([CH2:53][CH:54]([CH3:56])[CH3:55])[C:17](=[O:19])[C:16]=1[C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:15])(=[O:14])[N:12]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)CN1C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 0.317 g, 0.951 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.192 g, 1.00 mmol) and N-methylmorpholine (0.220 mL, 2.00 mmol) were added sequentially to a solution of crude (1S,2R,3S,4R)-3-isobutylamino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.228 g, 0.952 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in ethanol (15 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (1.23 mL, 3.80 mmol) was added and the reaction mixture was heated at 60° C. for 1.5 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 40 to 100% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)—N-[3-(6-hydroxy-3-isobutyl-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl)-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl]-methanesulfonamide (0.096 g, 0.190 mmol, 20%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 0.83 (3H, d, J=7.2 Hz), 0.93 (3H, d, J=7.1 Hz), 1.19-1.21 (1H, m), 1.28-1.32 (1H, m), 1.43-1.63 (3H, m), 2.09-2.15 (1H, m), 2.54 (1H, bs), 2.61-2.61 (1H, m), 2.74-2.79 (1H, m), 3.05 (3H, s), 3.30 (1H, bs), 3.60 (1H, d, J=9.2 Hz), 3.73-3.79 (1H, m), 7.49-7.52 (1H, m), 7.56-7.58 (2H, m), 10.17 (1H, s). LC-MS (ESI) calcd for C22H28N4O6S2 508.15, found 509.4 [M+H+].