Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([OH:20])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19].O>N1C=CC=CC=1>[CH2:12]([O:20][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19]
Reactant: C#CCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: C#CCCCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 7.5 °C
Reaction time: 20 h
Yield: 85.8 %

Procedure:
To an ice-cooled solution of p-toluenesulfonyl chloride (17.4 g, 91.3 mmol) in pyridine (30 ml), 7-octyn-1-ol (9.6 g, 76.1 mmol) was added dropwise, and stirred at 5-10° C. for 20 hours. The reaction mixture was added with water (15 ml), stirred, then poured into water (500 ml), and extracted with ether (500 ml). The ether layer was washed with cold 1N-hydrochloric acid, saturated aqueous sodium hydrogencarbonate and water, dried over magnesium sulfate, and concentrated under reduced pressure to afford 18.3 g of 7-octynyl-p-toluenesulfonate (yield; 85.7%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]=[CH:7][N:6]([CH3:12])[C:5]2=[O:13].[CH2:14]([S:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:18])=[O:17])[CH3:15]>COCCO>[CH2:14]([S:16]([N:19]1[CH2:20][CH2:21][N:22]([C:2]2[N:3]=[C:4]3[C:9](=[N:10][CH:11]=2)[N:8]=[CH:7][N:6]([CH3:12])[C:5]3=[O:13])[CH2:23][CH2:24]1)(=[O:18])=[O:17])[CH3:15]
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: Cn1cnc2ncc(Br)nc2c1=O
Solvent: COCCO
Product: CCS(=O)(=O)N1CCN(c2cnc3ncn(C)c(=O)c3n2)CC1
Temperature: 100 °C
Yield: 64.8 %

Procedure:
A solution of 6-bromo-3-methyl-pteridin-4-one (5.516 g, 22.88 mmol) in 2-methoxyethanol (50.81 mL) was treated with 1-ethylsulfonylpiperazine (6.118 g, 34.32 mmol) and the resulting suspension heated for 2 hours at 100° C. The reaction mixture was cooled in an ice-water bath and resultant precipitate collected and washed with cold methanol to give the product as a yellow solid (5.02 g, 65% Yield). 1H NMR (400.0 MHz, DMSO) d 1.25 (t, 3H), 3.10 (q, 2H), 3.34 (m, 4H), 3.49 (s, 3H), 3.85 (m, 4H), 8.37 (s, 1H), 8.84 (s, 1H) ppm; MS (ES+) 339
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(=[O:31])[C:28](Cl)=[O:29].[CH2:33]([OH:35])[CH3:34]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([C:27](=[O:31])[C:28]([O:35][CH2:33][CH3:34])=[O:29])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(-c2ccc3c(ccn3Cc3ccccc3)c2)cc1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCO
Product: CCOC(=O)C(=O)c1cn(Cc2ccccc2)c2ccc(-c3ccc(C(F)(F)F)cc3)cc12

Procedure:
Ethyl 2-{1-benzyl-5-[4-(trifluoromethyl)phenyl]-1H-indol-3-yl}-2-oxoacetate was prepared from 1-Benzyl-5-[4-(trifluoromethyl)phenyl]-1H-indole (0.307 g, 0.874 mmol), oxalyl chloride (0.29 mL, 3.3 mmol), and ethanol (3 mL) following the procedure described in Step 3 of Example 1. The compound was purified by flash chromatography using 10-20% ethyl acetate in hexane as an eluant and dried for 20 minutes at 60° C. to give a light yellow solid (0.249 g, 63%), mp: 99-100° C. 1HNMR (200 MHz, DMSO-d6): δ 8.8 (s, 1H), 8.5 (s, 1H), 7.6-7.95 (m, 6H), 7.25-7.4 (m, 5H), 5.65 (s, 2H), 4.35 (q, 2H, J=7.7 Hz), and 1.35 ppm (t, 3H, J=7.7 Hz).
Reaction SMILES: [C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8])([O:3][CH3:4])=[O:2].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>ClCCl>[CH2:11]([CH:5]([CH2:6][S:7]([N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1)(=[O:9])=[O:8])[C:1]([O:3][CH3:4])=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCN(C)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81.2 %

Procedure:
To a 1 L round bottom flask was added the resultant compound from Example 1E (84.5 g, 0.305 mol) and dichloromethane (305 mL). The mixture was cooled to 0° C. in an ice water bath and a solution of N-methyl piperazine (35.5 mL, 32.1 g) dissolved in dichloromethane (305 mL) was added dropwise with vigorous stirring over 90 min. After the addition was completed, the ice-water bath was removed and the mixture was stirred an additional 4 h while warming to ambient temperature. The solution was then poured into a separatory funnel containing 1 L of a 5% aqueous NaOH solution. The layers were partitioned and the organic layer was dried over potassium carbonate. Concentration in vacuo yielded an oil, which was filtered through 200 g of silica gel using 4:1 hexane/ethyl acetate as an eluant. Concentration gave 84.3 g (81%) of the desired product as a yellow oil: IR (film); 1735, 1165, 955 cm-1 ; 1H NMR (CDCl3) δ 2.30 (s, 3H), 2.42 (t, 4H, J=4.8), 2.88 (dd, 1H, J=7.7, 14.0), 2.93 (dd, 1H, J=3.7, 14.0), 3.06 (dd, 1H, J=7.0, 13.6), 3.18-3.27 (m, 5H), 3.43 (dd, 1H, J=8.82, 13.9), 3.67 (s, 3H), 7.14-7.17 (m, 2H), 7.24-7.34 (m, 3H); 13C NMR (75 MHz, CDCl3 ) δ 37.91, 42.22, 45.36, 45.83, 49.61, 52.21, 54.36, 127.06, 128.66, 128.92, 129.06, 136.79, 173.33.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Cl.Cl.[CH2:15]([C:19]1([N:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18].C(B)#N.[Na].CO.C(Cl)(Cl)Cl>CO.C(O)(=O)C>[CH2:15]([C:19]1([N:25]([CH3:27])[CH3:26])[CH2:24][CH2:23][N:22]([CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:21][CH2:20]1)[CH2:16][CH2:17][CH3:18]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: CCCCC1(N(C)C)CCNCC1
Agent: BC#N
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCC1(N(C)C)CCN(CCN(C)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 113 %

Procedure:
A solution of 4.73 g (1 eq) tert-butyl methyl(2-oxoethyl)carbamate in 20 ml methanol was added to a solution of 7 g (1 eq) 4-butyl-N,N-dimethylpiperidin-4-amine bis hydrochloride in 50 ml methanol at room temperature and the reaction mixture obtained was stirred for 50 min at room temperature. 3.43 g (2 eq) sodium cyanoboron hydride were added in portions to this reaction mixture and it was then stirred for 12 h at room temperature. The reaction course was monitored by thin-layer chromatography (20% MeOH/CHCl3). Once the conversion was complete, the reaction mixture was cooled to 0° C. and adjusted to a pH of ˜5 with acetic acid. 2 g tert-butyl formylmethyl methylcarbamate and 1.7 g sodium cyanoboron hydride were again added and the reaction mixture was stirred for a further 60 min at room temperature. The methanol was then distilled off, 100 ml saturated NaHCO3 solution were added and the mixture obtained was extracted with ethyl acetate (2×200 ml) and the combined organic phases were dried over Na2SO4. Following removal of the solvent under reduced pressure, 10.5 g of crude product were obtained in the form of a pale yellow oil.
Reaction SMILES: C([NH:18][C@H:19]([C:25]([C@@:27]1([N:36]2[C:46]3[N:45]=[C:43]([NH2:44])[NH:42][C:40](=[O:41])[C:39]=3[N:38]=[CH:37]2)[O:35][C@H:32]([CH2:33][OH:34])[C@@H:30]([OH:31])[C@H:28]1[OH:29])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>N1C=CC=CC=1>[NH2:18][C@H:19]([C:25]([C@@:27]1([N:36]2[C:46]3[N:45]=[C:43]([NH2:44])[NH:42][C:40](=[O:41])[C:39]=3[N:38]=[CH:37]2)[O:35][C@H:32]([CH2:33][OH:34])[C@@H:30]([OH:31])[C@H:28]1[OH:29])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)[C@@]1(n2cnc3c(=O)[nH]c(N)nc32)O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: NCCCC[C@H](N)C(=O)[C@@]1(n2cnc3c(=O)[nH]c(N)nc32)O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 800 mg of (Nα-FMOC-lysyl)guanosine in anhydrous pyridine was added anhydrous piperidine (4 mol eq.). The mixture was allowed to stir for 5 hr at 0° C. and then was evaporated to dryness. The residue was dissolved in DMF and purified by slow addition of the DMF solution to a rapidly stirred solution of EtOH—Et2O, yielding a precipitate.
Reaction SMILES: C(OC(=O)C([C@H](CC1C=CC=CC=1)COC)(N)[C@@H](C(OC(C)(C)C)=O)C(N)=O)C1C=CC=CC=1.[C:35]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH:40]=[CH:39][C:38]([C:41]2[O:42][C:43]([CH2:46][C:47]([OH:49])=O)=[CH:44][CH:45]=2)=[CH:37][CH:36]=1.FC(F)(F)C(O)=O.[CH3:63][NH:64][C:65](=[O:72])[C@H:66]([C:68]([CH3:71])([CH3:70])[CH3:69])[NH2:67].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CO.C(Cl)Cl>[CH3:69][C:68]([CH3:71])([CH3:70])[C@H:66]([NH:67][C:47](=[O:49])[CH2:46][C:43]1[O:42][C:41]([C:38]2[CH:37]=[CH:36][C:35]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[CH:40][CH:39]=2)=[CH:45][CH:44]=1)[C:65](=[O:72])[NH:64][CH3:63]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COC[C@@H](Cc1ccccc1)C(N)(C(=O)OCc1ccccc1)[C@H](C(N)=O)C(=O)OC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CNC(=O)[C@@H](NC(=O)Cc1ccc(-c2ccc(-c3ccccc3)cc2)o1)C(C)(C)C
Yield: 58 %

Procedure:
According to the procedure described in Example 1(f) for the preparation of N-(1(S)-benzyl-2-methoxy-ethyl-3(R)-t-butoxycarbonyl-amino-succinamic acid benzyl ester, 2-(2-biphenyl-4-yl-furan-5-yl)-acetic acid was coupled to L-t-leucine N-methylamide trifluoroacetic acid salt with BOP. Flash column chromatography with 0-5% MeOH/CH2Cl2 gradient eluant provided in 58% yield N-[2,2-dimethyl-1(S)-(N-methyl-carbamoyl)-propyl)-2-(2-biphenyl-4-yl-furan-5-yl)-acetamide as an orange foam, which decomposed >75° C. and was used without further purification. 1H NMR (acetone-d6): δ 7.72 (d, 2H, J=8.5 Hz), 7.61 (d, 4H, J=7.7 Hz), 7.45 (t, 2H, J=7.5 Hz), 7.35 (t, 1H, J=7.4 Hz), 6.65 (d, 1H, J=3.3 Hz), 6.56 (d, 1H, J=9.2 Hz), 6.36 (d, 1H, J=3.3 Hz), 5.9 (bs, 1H), 4.22 (d, 1H, J=9.2 Hz), 3.71 (s, 2H), 2.79 (d, 3H, J=4.5 Hz), 0.94 (s, 9H). Anal. Calculated for C25H28N2O3.0.6 H2O.0.1 MTBE: C, 72.21; H, 7.23; N, 6.61. Found: C, 72.10; H, 6.97; N, 6.39.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5](C)=[C:6]([CH:10]=1)C(O)=O.[C:15](=O)([O-])[O-].[Na+].[Na+].CI.[C:23]([O:26][CH2:27]C)(=[O:25])[CH3:24]>CN(C=O)C.O>[CH3:15][O:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:6])=[C:24]([CH:10]=1)[C:23]([O:26][CH3:27])=[O:25]
Reactant: CCOC(C)=O
Reactant: Cc1c(C(=O)O)cc(O)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1C
Temperature: 60 °C

Procedure:
To a stirred solution of 5-hydroxy-2-methyl-3-nitrobenzoic acid (1.50 g, 7.61 mmol) in DMF (15 mL) was added sodium carbonate (3.23 g, 30.5 mmol) and methyl iodide (1.88 mL, 30.5 mmol). The resulting reaction mixture was heated at 60° C. for 8 h. On completion, the reaction mixture was diluted with water and extraction was carried out using ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure to give the crude title compound (1.7 g) which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[OH:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][C:19]=1[C:27]([F:30])([F:29])[F:28]>C1COCC1.O>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[C:19]([C:27]([F:29])([F:28])[F:30])[CH:20]=2)=[O:26])=[C:3]([OH:16])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(OCc2ccccc2)cc1O
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(OCc2ccccc2)cc1O
Reaction time: 1.25 h

Procedure:
To a solution of 1.00 g (4.6 mMol) 2-amino-5-benzyloxy-phenol [preparation see: WO 03/045925; page 146] in 15 ml THF, a solution of 1.1 g (5.0 mMol) 4-chloro-3-trifluoromethyl-phenylisocyanate in 15 ml THF is added dropwise. After 75 min at rt, the reaction mixture is diluted in water and EtOAc, the aq. phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Trituration from hexane gives the crystalline title compound: m.p.: 182-184° C.; HPLC: tRet=17.5.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[O:6][CH2:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.S(Cl)([Cl:23])=O>C(Cl)Cl.CN(C)C=O>[N:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:16]=[CH:17][C:8]=1[CH2:7][O:6][C:5]1[CH:4]=[C:3]([CH:20]=[CH:19][CH:18]=1)[CH2:2][Cl:23]
Reactant: OCc1cccc(OCc2ccc3ccccc3n2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
25.6g (93.5 mmoles) of 2-(3-hydroxymethylphenoxy)methylquinoline is dissolved in 30 ml of methylene chloride and 3 drops of dimethylformamide is added. 60.7 ml of a 2.0M solution of thionyl chloride in methylene chloride is then added dropwise at 0° C. The mixture is allowed to warm to room temperature and stirred for 5 hours. The solution is washed with sodium bicarbonate solution, dried, concentrated in vacuo and the crude product purified by silica gel HPLC to yield 12.1 g 3-(2-quinolinylmethyloxy)benzylchloride as a pale yellow solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[S:10][CH:9]=[C:8]([C:11]([OH:13])=O)[CH:7]=2)[CH:3]=[N:2]1.Cl.[CH3:15][C:16]1([CH3:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:15][C:16]1([CH3:22])[CH2:21][CH2:20][N:19]([C:11]([C:8]2[CH:7]=[C:6]([C:4]3[CH:5]=[N:1][NH:2][CH:3]=3)[S:10][CH:9]=2)=[O:13])[CH2:18][CH2:17]1
Reactant: O=C(O)c1csc(-c2cn[nH]c2)c1
Reactant: CC1(C)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCN(C(=O)c2csc(-c3cn[nH]c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
5-(1H-Pyrazol-4-yl)-thiophene-3-carboxylic acid (0.075 g, 0.39 mmol) and 4,4-dimethylpiperidine hydrochloride (0.087 g, 0.58 mmol) were dissolved in DMF (3 mL) then DIPEA (0.2 g, 1.55 mmol) and HATU (0.175 g, 1.55 mmol) were added and the reaction mixture was stirred at room temperature overnight. The solvent was removed by evaporation then the residue was dissolved in DCM and washed with aqueous sodium hydrogen carbonate solution. The organics were dried by evaporation. The crude material was purified by HPLC, eluting with 5%-98% acetonitrile in water (0.1% formic acid) over 20 minutes. The fractions containing the desired product were freeze-dried to give the title compound (0.063 g). LCMS m/z 290.18 [M+H]+ R.T.=8.74 min (Analytical Method 2).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][S:18]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29](Cl)=[O:30])[CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19].Cl>O1CCCC1.O>[OH:3][NH:2][C:29](=[O:30])[CH:28]=[CH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18](=[O:20])(=[O:19])[NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[CH:22]=1
Reactant: COc1ccccc1NS(=O)(=O)c1cccc(C=CC(=O)Cl)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1NS(=O)(=O)c1cccc(C=CC(=O)NO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.36 g, 5.20 mmol) in tetrahydrofuran (6 ml) a saturated NaHCO3 solution (4.5 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-[3-(2-methoxy-phenylsulfamoyl)-phenyl]-acryloyl chloride (16c) (0.37 g,1.05 mmol) in tetrahydrofuran (5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was poured into water, the obtained solution was acidified with 2N HCl and extracted with ethyl acetate. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate and washed with diethyl ether affording the title compound (0.23 g, 64%). M.p. 181° C. 1H NMR (DMSO-d6, HMDSO) δ: 3.45 (3H, s); 6.49 (1H, d, J=16.0 Hz); 6.76-7.96 (9H, m); 9.09 (1H, br s); 9.54 (1H, s); 10.78 (1H, br s). HPLC analysis on Symmetry C8 column: impurities 1.3% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 35:65; sample concentration 0.15 mg/min; flow rate 1.2 ml/min; detector UV 230 nm). Anal. Calcd for C16H16N2O5S, % N C 55.16, H 4.63, N 8.04. Found, %: C 55.14, H 4.52, N 7.99.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([O:35][CH2:36][CH2:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([O:35][CH2:36][CH2:37][CH3:38])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: CCCOc1ccc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCOc1ccc2c(c1CN1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-3-oxo-6-propoxy-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0210 g, 0.0405 mmol) in methylene chloride (1 mL) was added with trifluoroacetic acid (1 mL) at room temperature, and the mixture was stirred overnight. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate, thereby made basic, and then extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain the objective (Z)-2-[(1H-indazol-3-yl)methylene]-7-(piperazin-1-ylmethyl)-6-propoxybenzofuran-3(2H)-one (0.0160 g, 94%).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1[CH2:17][N:16]([CH2:18][C:19](=[O:30])[NH:20][CH:21]2[CH2:25][C:24](=[O:26])[O:23][CH:22]2[O:27]CC)[C:15](=[O:31])[CH:14]([NH:32][C:33]([C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[O:34])[CH2:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>CC#N.O>[C:1]([NH:9][CH2:10][C:11]1[CH2:17][N:16]([CH2:18][C:19](=[O:30])[NH:20][CH:21]2[CH2:25][C:24](=[O:26])[O:23][CH:22]2[OH:27])[C:15](=[O:31])[CH:14]([NH:32][C:33]([C:35]2[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[CH:38]=[CH:37][N:36]=2)=[O:34])[CH2:13][CH:12]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1OC(=O)CC1NC(=O)CN1CC(CNC(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CC(CNC(=O)c2ccccc2)=CCC(NC(=O)c2nccc3ccccc23)C1=O)NC1CC(=O)OC1O
Yield: 51 %

Procedure:
A solution of isoquinoline-1-carboxylic acid {6-(benzoylamino-methyl)-1-[(2-ethoxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-2-oxo-2,3,4,7,-tetrahydro-1H-azepin-3-yl}-amide, 32, as prepared in the above example, in CH3CN/H2O is treated with excess trifluoroacetic acid. The solution is stirred several hours then purified by preparative reverse phase HPLC to afford 51 mg (51% yield) of the desired product. 1H NMR (CD3OD) δ 9.15–9.12 (d, J=8.4 Hz, 1H), 8.56–8.54 (d, J=5.7 Hz, 1H), 8.08–8.04 (m, 2H), 7.92–7.76 (m, 4H), 7.57–7.50 (m, 3H), 5.83 (bs, 1H), 5.61–5.56 (d, d, J=12.6, 3.9 Hz, 1H), 4.90–4.85 (d, J=17.4 Hz, 1H), 4.63–4.60 (m, 1H), 4.41–4.01 (m, 3H), 3.65–3.58 (d, d, J=17.4, 2.7 Hz, 1H), 2.91–2.85 (bd, J=18.9 Hz, 1H), 2.75–2.65 (m, 1H), 2.55–2.46 (m, 2H); MS 572 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:6]([O:8][CH3:9])=[O:7]>CO.O1CCCC1.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[NH2:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
Methyl 3-methoxy-4-nitrobenzoate (4.8 g; 23 mmol) was dissolved in 150 ml of a 2:1 mixed solvent of methanol and tetrahydrofuran, followed by addition of 480 mg of 5% Pd/C. The resulting mixture was stirred for 2 hours under a hydrogen gas atmosphere at room temperature. After completion of the reaction, the Pd/C was filtered off and the solvent was distilled out under reduced pressure, whereby 3.9 g of white crystals were obtained (yield: 54%).
Reaction SMILES: CC1(C)O[C@@H](COS([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=O)=O)CO1.[C:20]1([S:26]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[C:31]([Br:36])[CH:30]=2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-:38].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:20]1([S:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:13][C@@H:12]3[CH2:17][CH2:16][C:15]([CH3:18])([CH3:14])[O:38]3)=[C:31]([Br:36])[CH:30]=2)(=[O:27])=[O:28])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(c1ccccc1)c1ccc(O)c(Br)c1
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)CC[C@@H](COc2ccc(S(=O)(=O)c3ccccc3)cc2Br)O1
Temperature: 25 °C

Procedure:
Toluene-4-(R)-sulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-yl-methyl ester (0.99 g; 0.003 mol) was added to a suspension of 4-benzenesulfonyl-2-bromo-phenol (0.91 g; 0.003 mol, prepared by the procedure of Sung-Eun et al. as described in Example 1) and potassium carbonate (0.88 g; 0.0006 mol) in acetonitrile (4 mL). The mixture was heated under reflux for 72 hours. After cooling to ambient temperature the mixture was diluted with ethyl acetate, filtered, washed with water and saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by crystallization from diethyl ether-hexane to give 4-(S)-(4-benzenesulfonyl-2-bromo-phenoxymethyl)-2,2-dimethy-[3,3]dioxolan as a white crystalline (1.41 g; 84%). Mp. 115.8-118.5° C., [α]=+20.2° (methanol; c=1).
Reaction SMILES: C(I)I.[Zn]([CH2:7][CH3:8])CC.[Br:9][C:10]1[CH:15]=[C:14]2[NH:16][C:17](=[O:36])[C:18]3([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:22][C:21](=[O:31])[NH:20][CH:19]3[C:32](=C)[CH2:33][CH3:34])[C:13]2=[CH:12][CH:11]=1.[CH3:37][O:38][CH:39]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH3:40]>C1(C)C=CC=CC=1>[Br:9][C:10]1[CH:15]=[C:14]2[NH:16][C:17](=[O:36])[C:18]3([CH:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=4)[CH2:22][C:21](=[O:31])[NH:20][CH:19]3[C:32]3([CH2:7][CH3:8])[CH2:34][CH2:33]3)[C:13]2=[CH:12][CH:11]=1.[CH3:37][O:38][CH:39]([Si:41]([CH3:44])([CH3:43])[CH3:42])[CH3:40]
Reactant: C=C(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Reactant: CC[Zn]CC
Agent: COC(C)[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: ICI
Product: CCC1(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Br)ccc23)CC1
Reaction time: 0.17 h

Procedure:
CH2I2 (1.2 g, 4.6 mmol) was dissolved in dry toluene (5 mL) at 0° C. After stirred for 10 min under Argon, Et2Zn (1 M in THF, 3.3 mL, 3.67 mmol) was added. After stirred for 15 min, a solution of racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(1-methylene-propyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (270 mg, 0.46 mmol) prepared in example 161b in dry toluene (10 mL) was added. After stirred at room temperature for 3 h, the reaction was quenched with saturated NH4Cl (20 mL). The aqueous layer was extracted with EtOAc. The combined organic layer was dried over Na2SO4, concentrated, the residue, was used for next step without further purification.