Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:45])[NH:11][CH:12]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:13]([OH:37])[CH2:14][N:15]([S:20]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[C:26]3=[CH:33][N:34]([CH3:36])C)(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.[CH2:46](N)[C:47](C)([CH3:49])[CH3:48]>C(O)C>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:45])[NH:11][CH:12]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:13]([OH:37])[CH2:14][N:15]([S:20]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[C:26]3=[CH:33][NH:34][CH2:36][C:47]([CH3:49])([CH3:48])[CH3:46])(=[O:22])=[O:21])[CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:2]1
Reactant: CC(C)(C)CN
Reactant: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2c(c1)C(=CN(C)C)C(=O)N2
Solvent: CCO
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc2c(c1)C(=CNCC(C)(C)C)C(=O)N2
Reaction time: 22 h
Yield: 70.1 %

Procedure:
To a solution of {1-benzyl-3-[(3-dimethylaminomethylene-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 21 (32mg, 0.05 mmol) in absolute ethanol (1 ml) was added neopentylamine (29 μl, 0.25 mmol). The resulting solution was stirred 22 h and then concentrated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 500 μm) using 8:2 ethyl acetate:hexane as eluant to provide [1-benzyl-3-({3-[(2,2-dimethyl-propylamino)-methylene]-2-oxo-2,3-dihydro-1H-indole-5-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 22 (24 mg, 70%). TLC: Rf 0.63 (ethyl acetate:hexanes). MS m/z 685 (MH)+. 1H NMR (CDCl3) is consistent with structure.
Reaction SMILES: [C:1](OC(=O)C)(=O)[CH3:2].[NH2:8][C:9](=[N:30][OH:31])[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]2)[CH:11]=1>>[CH3:1][C:2]1[O:31][N:30]=[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:23])[CH2:18][CH2:17]3)[CH:11]=2)[N:8]=1
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(C(N)=NO)ccn2)CC1
Reactant: CC(=O)OC(C)=O
Product: Cc1nc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)no1

Procedure:
Acetic anhydride (3 mL) was added to 2,2-dimethylpropyl 4-{4-[amino(hydroxyimino)methyl]pyridin-2-yl}piperazine-1-carboxylate (215 mg) obtained in Example 26-1), and heated under reflux for 2 hours, then the excess acetic anhydride was evaporated away, the residue was diluted with ethyl acetate, washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away, and the resulting residue was isolated and purified through silica gel column chromatography (hexane/ethyl acetate=7/3) to obtain 36 mg of the entitled compound as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1.CCOCC.C([Li])(C)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>CCCCCCC.O>[CH2:35]([O:34][C:32]([C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[C:5]2=[N:6][CH:7]=1)=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCCCCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)OCc3ccccc3)cnc21
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 50.9 %

Procedure:
Into a Round bottom flask was added compound 20 (425.0 mg, 0.001203 mol) and Ether (8.0 mL, 0.076 mol) under an atmosphere of Nitrogen, −78 Celsius. Into the reaction mixture, was added 1.7 M of tert-Butyllithium in Heptane (1.5 mL) slowly. The reaction mixture was stirred at −78 Celsius for 90 minutes, followed by addition of benzyl chloroformate (0.20 mL, 0.0014 mol). 2 hours later at −78 Celsius, the reaction mixture was poured into water, extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage to give product 21 (250 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1B(O)O)(=[O:3])[CH3:2].Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[NH2:18][C:17]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:1](=[O:3])[CH3:2])[CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(=O)Nc1ccccc1B(O)O
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: CC(=O)Nc1ccccc1-c1cccc(N)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
2-acetylaminophenyl boronic acid (0.124 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) were combined in DME (2 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H20 and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (0-50% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.103 g in 98% yield.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>O1CCCC1>[CH3:1][N:2]([CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:28][C:27]1[CH:30]=[CH:31][C:24]([CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=1
Reactant: CNCc1cccc2ccccc12
Reactant: CC(C)c1ccc(CCl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)c1ccc(CN(C)Cc2cccc3ccccc23)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
1.71 g (0.01 mole) of N-methyl-1-naphthylmethylamine was dissolved in 30 ml of tetrahydrofuran, and 1.2 g (0.012 mole) of triethylamine was added. With stirring at room temperature, 1.85 g (0.011 mole) of p-isopropylbenzyl chloride was added, and the mixture was reacted at room temperature for 6 hours. The reaction mixture was filtered, and the solvent was removed under reduced pressure. The residue was distributed between ether and a saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was collected. The organic layer was washed with water, dried over sodium sulfate and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column and eluted with 4% ethyl acetate/n-hexane. The eluate was concentrated to give 2.82 g (yield 93%) of an oily substance.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[CH:14](OC(=O)C)=[O:15]>O>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][N:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH:14]=[O:15])[CH3:2]
Reactant: CCOC(=O)CNc1ccccc1
Reactant: CC(=O)OC=O
Solvent: O
Product: CCOC(=O)CN(C=O)c1ccccc1
Reaction time: 8 h
Yield: 70 %

Procedure:
N-Phenylglycine ethyl ester (100 g; 0-56 mol) was added in small portions to acetic formic anhydride (100 g; 1.14 mol) with vigorous stirring. The mixture was allowed to stir overnight, then it was poured into water, and extracted with ether. The ether solution was washed with sodium bicarbonate solution and then with water. The ether was evaporated in vacuo to give an oil which was distilled to give N-phenyl-N-formylglycine ethyl ester (81 g; 70%) having a bp 115°-117° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:32]#[C:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]>C(OCC)(=O)C.[Pd]>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:46])([CH3:48])[CH3:47])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:32][CH2:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1C#CCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of Example 15C (1.2 g) in ethyl acetate (120 mL) was added Pd/C (500 mg, 5%). The mixture was stirred under an atmosphere of hydrogen (balloon) overnight. The insoluble material was filtered off and washed with ethyl acetate. The filtrate was concentrated to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH2:55]([CH2:57][NH2:58])[OH:56]>C(OCC)(=O)C.CN(C=O)C>[OH:56][CH2:55][CH2:57][NH:58][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([NH:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: NCCO
Reactant: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1CNc1ccc(C(=O)NCCO)cn1
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a mixture of 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid (200 mg, 0.65 mmol) and 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (228 mg, 0.71 mmol) was added DMF (2 mL). After stirring for 2 min at ambient temperature N,N-diisopropyl ethyl amine (553 μL, 3.23 mmol) and ethanolamine (47 μl, 0.78 mmol) were added and the resulting solution was stirred for 2 h at this temperature. It was diluted with ethyl acetate (15 mL) and washed with water (20 mL) and brine (15 mL). The aqueous layers were extracted with ethyl acetate and the combined organic layers were dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate: methanol=30:70:0 to 0:95:5) afforded the title compound (200 mg, 88%) as a white solid. MS: m/e=353.2 [M+H]+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:11]=[C:12]([O:33][CH3:34])[C:13]2[CH:18]=[CH:17][N:16]([C@@H:19]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[CH2:20]3)[C:14]=2[N:15]=1>ClCCl>[NH2:9][C:10]1[N:11]=[C:12]([O:33][CH3:34])[C:13]2[CH:18]=[C:17]([Cl:1])[N:16]([C@@H:19]3[O:27][C@H:26]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[C@@H:21]([O:22][C:23](=[O:25])[CH3:24])[CH2:20]3)[C:14]=2[N:15]=1
Reactant: COc1nc(N)nc2c1ccn2[C@H]1C[C@H](OC(C)=O)[C@@H](COC(C)=O)O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: COc1nc(N)nc2c1cc(Cl)n2[C@H]1C[C@H](OC(C)=O)[C@@H](COC(C)=O)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 53.7 %

Procedure:
36.6 mg (0.27 mmol) of N-chlorosuccinimide are added to a solution of 50 mg (0.14 mmol) of 2-amino-7-(2-deoxy-3,5-di-O-acetyl-β-D-erythropentofuranosyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine in 3 ml of dichloromethane, and the mixture is stirred at room temperature for 12 h. The solvent is stripped off and the residue is chromatographed on silica gel in CH2Cl2/acetone (9:1). 30 mg (54%) of a colorless foam are obtained from the slowly migrating main zone.
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)=[N:5][C:4]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:2]>[Pd].CO>[NH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[O:7][C:3]([CH2:1][CH3:2])=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:5]=2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)oc1CC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1nc(-c2ccc(N)cc2)oc1CC
Yield: 86.4 %

Procedure:
The same operation as in Example (95b) was performed using ethyl 5-ethyl-2-(4-nitrophenyl)-1,3-oxazole-4-carboxylate obtained in Example (99a) (0.57 g, 2 mmol), 10% Pd/C (0.2 g) and methanol (10 mL), to obtain 0.45 g of the title compound as a yellow solid (88%).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][SiH2]C1C=CC=CN=1.[F-].[K+].C(=O)([O-])[OH:20].[K+].OO>CO.O.O1CCCC1>[C:11]1([CH:2]([OH:1])[CH2:3][OH:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C([O-])O
Reactant: OC(C[SiH2]c1ccccn1)c1ccccc1
Agent: OO
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: OCC(O)c1ccccc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 95.5 %

Procedure:
To 129 mg (0.5 mmol) of the (2-hydroxy-2-phenylethyl)(2-pyridyl)silane obtained in Example 6, a solution of 58 mg (1.0 mmol) of potassium fluoride and 100 mg(1.0 mmol) of potassium hydrogencarbonate in methanol(1 ml)/tetrahydrofuran(1 ml) was added, followed by 1.71 g (15 mmol) of 30% aqueous hydrogen peroxide. The mixture was continued to be stirred at an inner temperature of 50° C. for 6 hours, and then cooled to room temperature. After addition of 10 ml of water, the mixture was extracted with four portions of 10 ml of diethyl ether. The separated organic layers were combined together and washed with 10 ml of a 15% aqueous sodium thiosulfate solution. After drying over magnesium sulfate, the residue after the evaporation of the solvent was purified with silica gel chromatograph to give 66 mg of phenyl-1,2-ethanediol. Yield: 96%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=[O:20])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6](=[O:22])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCO
Reaction time: 2 h

Procedure:
1 M Solution of borane-tetrahydrofuran complex in tetrahydrofuran (52 mL, 52.0 mmol) was added dropwise to a solution of tetradecanedioic acid mono-tert-butyl ester (10.0 g, 31.9 mmol) in dry tetrahydrofuran (75 mL) at 0 C under argon. The resulting solution was stirred at 0 C for 2 hrs, then the cooling bath was removed and the mixture stirred at room temperature overnight. Saturated aqueous solution of sodium hydrogencarbonate (150 mL) was added and the resulting mixture was extracted with dichloromethane (3×100 mL). Combined organic extracts were extracted with 5% aqueous solution of sodium carbonate (1×150 mL) and 10% aqueous solution citric acid (1×100 mL). Combined organic extracts were dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was subjected to column chromatography (Silicagel 60A, 0.060-0.200 mm; eluent: dichloromethane/methanol 100:0-99:1) to give 14-hydroxy-tetradecanoic acid tert-butyl ester as yellowish oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[O:46][CH2:47][O:48][CH3:49])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:59])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=5[O:46][CH2:47][O:48][CH3:49])=[O:59])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:50]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ccccc4OCOC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccccc4OCOC)cc2)CCN3CC(C)C)cc1
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
A solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-(methoxymethoxy)benzyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1.02 g) in methylene chloride (20.4 ml), was added dropwise to a solution of m-chloroperbenzoic acid (0.51 g) in methylene chloride (40.8 ml) at −78° C., and the mixture was stirred for 20 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[2-(methoxymethoxy)benzyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 220) (820 mg).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[C:38]([O:51][CH3:52])[C:37]=1[OH:53]>>[NH2:26][CH:23]1[CH2:24][CH2:25][N:21]([C:18]2[N:19]=[CH:20][C:15]([NH:14][C:13]3[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([C:40]5[CH:39]=[C:38]([O:51][CH3:52])[C:37]([OH:53])=[C:36]([Cl:35])[CH:41]=5)[CH:11]=4)[N:6]=[CH:5][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:16][CH:17]=2)[CH2:22]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Product: COc1cc(-c2ccc3ncc(C(C)=O)c(Nc4ccc(N5CCC(N)C5)nc4)c3c2)cc(Cl)c1O
Yield: 14.6 %

Procedure:
Following general procedure D, tert-butyl 1-(5-(3-acetyl-6-bromoquinolin-4-ylamino) pyridin-2-yl)pyrrolidin-3-ylcarbamate (80 mg, 0.15 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (65 mg, 0.23 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (11 mg, 15% over two steps) as a yellow-brown: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.28 (s, 1H), 8.31-8.25 (m, 2H), 8.06-7.99 (m, 2H), 7.83 (dd, J=9.2, 2.7 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 7.98 (d, J=9.2 Hz, 1H), 6.71 (d, J=2.2 Hz, 1H), 4.16-4.07 (m, 1H), 4.07-3.96 (m, 2H), 3.91 (s, 3H), 3.88-3.79 (m, 1H), 3.79-3.69 (m, 211), 2.80 (s, 3H), 2.63-2.53 (m, 1H), 2.34-2.23 (m, 1H); ESI MS m/z 504 [C27H26ClN5O3+H]+; HPLC 95.4% (AUC), tR=9.37 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[CH:8]=[CH:7]2.CO>C(O)(=O)C.C(Cl)Cl.CCOC(C)=O.O=[Pt]=O>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH3:13])[CH2:8][CH2:7]2
Reactant: Cn1ccc2cccc(N)c2c1=O
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCc2cccc(N)c2C1=O
Yield: 26.3 %

Procedure:
A solution of 8-amino-2-methylisoquinolin-1(2H)-one (Compound 131A, 100 mg, 0.54 mmol) in acetic acid (10 mL) was hydrogenated over PtO2 (24 mg) at room temperature for 16 h. TLC (5% MeOH in CH2Cl2) showed the reaction was complete. The catalyst was filtered off through Celite and the filtrate was evaporated to dryness to give a residue, which was dissolved in EtOAc (20 mL), washed with aq. sat. NaHCO3 (20 mL), water (10 mL), dried and evaporated, residue was purified by column chromatography on silica gel (5% MeOH in CH2Cl2) to give the desired product (25 mg, 25%). 1H NMR (CDCl3, 300 MHz): δ=2.96 (t, J=6.6 Hz, 2H), 2.98 (s, 3H), 3.55 (t, J=6.9 Hz, 2H), 6.18 (br, 2H), 6.45 (d, J=6.9 Hz, 1H), 6.58 (d, J=7.5 Hz, 1H), 7.15 (t, J=7.5 Hz, 1H).
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([CH:11]([NH:13][CH:14]=[O:15])[CH3:12])[CH2:7][CH2:6]1.[Cl:16][C:17]1[N:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1.C(N(C(C)C)C(C)C)C>C(O)C>[Cl:16][C:17]1[N:22]=[C:21]([N:5]2[CH2:10][CH2:9][CH:8]([CH:11]([NH:13][CH:14]=[O:15])[CH3:12])[CH2:7][CH2:6]2)[CH:20]=[CH:19][N:18]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CC(NC=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CC(NC=O)C1CCN(c2ccnc(Cl)n2)CC1

Procedure:
N-(1-Piperidin-4-yl-ethyl)-formamide; compound with acetic acid (350 mg, 1.61 mmol), 2,4-dichloro-pyrimidine (265 mg, 1.78 mmol) and ethyl-diisopropyl-amine (848 mg, 6.56 mmol) in 20 ml of ethanol were heated under reflux for 5 hours. The mixture was evaporated and the residue dissolved in water and extracted with ethyl acetate. The organic layer was dried with MgSO4 and evaporated.
Reaction SMILES: [C:1]1([Li])[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH:3]=[C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]12.[Cl-].[Cl-].[Cl-].C1([Zr+3:26])C=CC=C1>C1(C)C=CC=CC=1.C(OCC)C>[C:1]1([Zr:26])[CH:16]=[CH:15][CH:14]=[C:13]2[C:2]=1[CH:3]=[C:4]1[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:6]=[C:5]12
Reactant: [Zr+3]C1C=CC=C1
Reactant: [Li]c1cccc2c1C=C1C2=Nc2ccccc21
Agent: [Cl-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: [Zr]c1cccc2c1C=C1C2=Nc2ccccc21
Reaction time: 8 h

Procedure:
A sample of the indeno[1,2-b]indolyl lithium salt produced above (10 g, 42 mmol) is dissolved in toluene (95 mL) to produce an orange slurry. Diethyl ether (35 mL) is added slowly to give an orange solution. This solution is added over 15 min. at room temperature with stirring to a slurry of cyclopentadienylzirconium trichloride (11 g, 42 mmol) in toluene (190 mL) and diethyl ether (190 mL). The mixture turns deep red and is kept at room temperature overnight. The slurry is filtered to recover a red solid, which is washed with toluene (200 mL) and dried under vacuum. Yield of complex 10: 16.5 g. The 1H NMR spectrum is consistent with the proposed structure:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([I:12])=[C:10]([CH3:13])[NH:9][N:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH:17]([CH3:19])[CH3:18].[Cl-].[NH4+]>CN(C)C=O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([I:12])=[C:10]([CH3:13])[N:9]([CH:17]([CH3:19])[CH3:18])[N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1[nH]nc(-c2ccc(Cl)s2)c1I
Reactant: CC(C)I
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1c(I)c(-c2ccc(Cl)s2)nn1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
3-(5-Chloro-2-thienyl)-4-iodo-5-methyl-1H-pyrazole (31.9 mmol) was dissolved in 30 mL dry N,N-dimethylformamide and cooled to 0° C. under nitrogen atmosphere. Sodium hydride (33.5 mmol, 60% dispersion in mineral oil) was added in portions at 0° C. After stirring for 30 min, 2-iodopropane (38.5 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The solution was poured into saturated aqueous ammonium chloride solution and extracted with diethyl ether, dried over MgSO4, filtered and evaporated. The crude product was purified by chromatography on silica gel (cyclohexane:dichloromethane 90:10) to afford 7.5 g 3-(5-chloro-2-thienyl)-4-iodo-1-isopropyl-5-methyl-1H-pyrazole (67% yield)