Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11](Cl)=[O:12].[CH2:22]([NH:24][CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:23]>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:10]=1[C:11]([N:24]([CH2:22][CH3:23])[CH:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:12]
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Reactant: CCCCCCC(C)NCC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCC(C)N(CC)C(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.5 %

Procedure:
Triethylamine (2.02 g, 20 mmol) was added to a mixture of the compound of Example b (2.47 g, 10 mmol) and N-ethyl-N-(1-methylhept-1-yl)amine (3.15 g, 20 mmol) in toluene (25 mL). The reaction was stirred 2.5 h at ambient temperature, then was partitioned between ethyl acetate and dilute citric acid. The organic phase was washed twice with sat aq NaHCO31 followed with brine, then was dried (MgSO4), concentrated, and kugelrohr distilled under vacuum. The fraction which distilled at 157° C. was collected to afford 1.16 g of the title compound as an amber oil, a 38% yield.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:7]([O:17][CH3:18])[CH:6]=1)=O.[NH2:19][C:20]1[S:21][CH2:22][CH2:23][N:24]=1>C(O)C>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([C:3]2[N:19]=[C:20]3[N:24]([CH:2]=2)[CH2:23][CH2:22][S:21]3)[CH:10]=[CH:9][C:8]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: COc1cc(C(=O)CBr)ccc1-c1ccccn1
Reactant: NC1=NCCS1
Solvent: CCO
Product: COc1cc(-c2cn3c(n2)SCC3)ccc1-c1ccccn1

Procedure:
A solution of 2-bromo-1-(3-methoxy-4-pyridin-2-ylphenyl)ethanone (200 mg, 0.65 mmol) and 2-amino-2-thiazoline (67 mg, 0.65 mmol) in ethanol (5 mL) was heated to reflux for 2 h, then concentrated. The residue was dissolved in ethyl acetate (25 mL) and washed with a solution of saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), then dried (MgSO4) and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc:hexanes (2:1) to afford 6-(3-methoxy-4-pyridin-2-ylphenyl)-2,3-dihydroimidazo[2,1-b][1,3]thiazole. 1H NMR (CD3OD, 300 MHz) δ 8.86 (d, 1H), 8.67 (t, 1H), 8.35 (d, 1H), 8.17 (s, 1H), 8.04 (m, 1H), 7.84 (m, 1H), 7.62 (s, 1H), 7.54 (m, 1H), 4.60 (m, 2H), 4.26 (m, 2H), 4.07 (s, 3H) ppm. MS (ESI) 310 (M)+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[Br:11]N1C(=O)CCC1=O.O.BrC1C=CC(C(C)C)=CC=1O>C(=S)=S>[Br:11][C:5]1[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=[CH:7][C:6]=1[OH:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1cccc(O)c1
Agent: CC(C)c1ccc(Br)c(O)c1
Solvent: O
Solvent: S=C=S
Product: CC(C)c1cccc(O)c1Br
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a solution of 3-isopropylphenol (10.0 g, 73.4 mmol) in carbon disulfide (200 mL) was slowly added N-bromosuccinimide (13.1 g, 73.4 mmol) with ice-cooling, and the mixture was stirred for 1 hour. The reaction solution was stirred at room temperature for 1 hour, and then water was added thereto, which was extracted with ethyl acetate. The combined organic layer was washed with water and a saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=15:85) to obtain a mixture of 2-bromo-5-isopropylphenol and 2-bromo-3-isopropylphenol (3:1) 11.0 g (yield 70%).
Reaction SMILES: [N:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]3=[O:22])[CH2:9][CH2:8]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:30]1[CH:35]=[C:34]([C:36](Cl)=[O:37])[CH:33]=[N:32][CH:31]=1.N>ClCCl>[N:30]1[CH:35]=[C:34]([C:36]([N:4]2[CH2:3][CH2:2][N:1]([C@H:7]3[CH2:12][CH2:11][C@H:10]([N:13]4[C:17]5[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=5[NH:15][C:14]4=[O:22])[CH2:9][CH2:8]3)[CH2:6][CH2:5]2)=[O:37])[CH:33]=[N:32][CH:31]=1
Reactant: O=c1[nH]c2ccccc2n1[C@H]1CC[C@H](N2CCNCC2)CC1
Reactant: O=C(Cl)c1cncnc1
Agent: N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cncnc1)N1CCN([C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Reaction time: 2 h

Procedure:
To a stirred solution of 0.044 g of 1,3-dihydro-1-{trans-4-[1-piperazinyl]-1-cyclohexyl}-2H-benzimidazol-2-one and 0.2 mL of triethylamine in 3 mL of dichloromethane was added 0.030 g of pyrimidine-5-carboxylic acid chloride. After 2 h, 5 mL of dilute aqueous ammonia was added and the mixture stirred for an additional 30 min. The organic layer was separated, the aqueous layer extracted with two additional 20 mL portions of chloroform and the combined organic extracts dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel eluting with 10% methanol in ethyl acetate gave 0.030 g of 1,3-dihydro-1-{trans-4-[4-(5-pyrimidinecarbonyl)piperazin-1-yl]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 9.76 (s, 1H), 9.29 (s, 1H), 8.83 (s, 2H), 7.16-7.04 (m, 4H), 4.27 (m, 1H), 3.84 (s, 2H), 3.48 (s, 2H), 2.72 (s, 2H), 2.61 (s, 2H), 2.56 (m, 1H), 2.30 (q, 2H), 2.05 (m, 4H), 1.86 (br s, 1H), 1.5 (q, 2H). The dihydrochloride salt was precipitated from chloroform/ethyl acetate: Analysis calculated for C22H26N6O2.2HCl.0.65 CHCl3C: 48.84, H: 5.18, N: 15.09 found C: 48.85, H: 5.36, N: 14.72.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[O-:12][C:13]#[N:14].[K+].[OH-].[Na+]>O.C(O)(=O)C>[CH3:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:5])[NH:14][C:13](=[O:12])[NH:1]2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(C(=O)O)c(N)c1
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(=O)[nH]c(=O)[nH]c2c1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a suspension of 2-amino-4-methylbenzoic acid (58.9 g, 390 mmol) in water (1.5 L) and glacial acetic acid (50 ml) was added dropwise a solution of potassium cyanate (80.5 g, 993 mmol) in water (300 ml). After completion of the addition and stirring at room temperature for half an hour, sodium hydroxide pellets (500 g) were added at such a rate that the temperature was kept below 50° C. (with ice cooling). During the addition the mixture became a clear solution for a short period, and upon continuation of the sodium hydroxide addition a cream precipitate started forming. The suspension was cooled to 0-5° C. and the precipitate was collected by filtration and washed twice with water (150 ml). The solid was poured in water (1 L) and was acidified with concentrated aqueous HCl (30%, 150 ml). The solid was collected by filtration and washed with water (150 ml) to yield 7-methylquinazoline-2,4(1H,3H)-dione (57.0 g, 83%) after drying at 45° C. under vacuum.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][C:23]([O:25][CH3:26])=[O:24].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:37]1[CH2:41]OC[CH2:38]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:38][CH2:37][CH3:41])[C:23]([O:25][CH3:26])=[O:24]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3ccccc3c2c1-c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3ccccc3c2c1-c1ccc(C)cc1
Yield: 75.2 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.150 g; 0.415 mmol), LHMDS 1N in THF (0.462 mL; 0.462 mmol), 1-iodopropane (0.066 mL; 0.677 mmol) in DMF (6 mL) for 3 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-30%) in heptane furnished 0.126 g (75%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)#[CH:25]>>[C:26]1([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: C#Cc1cccc2ccccc12
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1cc(-c3cccc4ccccc34)nn1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 1-ethynylnaphthalene. MS (+ESI) m/z: 423.2.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14]Br)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)N1C(=O)C(NCCCBr)=C(c2ccccc2)S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccc(F)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 31 %

Procedure:
The title compound was prepared as described for Example 5 from 2-tert-butyl-4-[(3-bromopropyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-fluorophenol using 3 equivalents of K2CO3 and with heating at 80° C. for 15 mins, 100° C. for 1 h and 120° C. for 1 h. The reaction mixture was evaporated to dryness and the residue was purified by silica gel column chromatography (Horizons Biotage) using 12-20% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.007 g, 31%). 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.45-7.40 (m, 3H), 7.00-6.96 (m, 2H), 6.82-6.78 (m, 2H), 5.76 (t, 1H), 3.86 (t, 2H), 3.11-3.02 (m, 2H), 1.88-1.80 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 158, 154.7, 156.7, 135.3, 131.8, 129.7, 128.8, 125.3, 116.2, 160.0, 115.6, 115.5, 107.2, 66.7, 61.7, 42.5, 28.9, 27.8; Mass Spectrum: M+H+ 433.
Reaction SMILES: N1CCCCC1.[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[CH:11]=O.C([CH2:20][C:21]([NH:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27])=[O:22])(O)=O.Cl>C1(C)C=CC=CC=1>[OH:7][C:8]1[CH:9]=[C:10](/[CH:11]=[CH:20]/[C:21]([NH:23][C:24]2[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[O:22])[CH:13]=[CH:14][C:15]=1[OH:16]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: O=Cc1ccc(O)c(O)c1
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C(/C=C/c1ccc(O)c(O)c1)Nc1ccccc1C(=O)O
Yield: 83 %

Procedure:
Piperidine (0.39 mL, 4.0 mmol) was added to a suspension of 3,4-dihydroxybenzaldehyde (0.55 g, 4.0 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (0.74 g, 3.3 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 1 M HCl. (E)-2-[[3-(3,4-Dihydroxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (0.82 g, 83%) was obtained as a brown crystalline solid; mp 204-206° C.; lit. [24] 204-206° C.; δH (500 MHz, DMSO-d6) 6.50 (d, J=15.5 Hz, 1H, CH═CHCO), 6.77 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.00 (dd, J5′,6′=8.0, =2.0 Hz, 1H, H6′), 7.08 (d, J2′,6′=2.0 Hz, 1H, H2′), 7.14 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.44 (d, J=15.5 Hz, 1H, CH═CHCO), 7.61 (td, J4,5=J5,6=8.0, J3,5=1.5 Hz, 1H, H5), 8.00 (dd, J3,4=8.0, J3,5=1.5 Hz, 1H, H3), 8.58 (d, J5,6=8.0 Hz, 1H, H6), 9.11 (s, 1H, OH), 9.52 (s, 1H, OH), 11.25 (s, 1H, NH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[O:28]1[CH2:30][C@H:29]1[CH2:31][O:32][C:33]1[CH:34]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:36]=[CH:37][CH:38]=1>C(Cl)(Cl)Cl.CO>[CH2:18]([NH:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:30][C@H:29]([OH:28])[CH2:31][O:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:40](=[O:42])[CH3:41])[CH:34]=3)=[CH:27][CH:26]=2)[CH2:10][CH2:11]1)=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CC(=O)Nc1cccc(OC[C@@H]2CO2)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3cccc(NC(C)=O)c3)cc2)CC1
Yield: 28.9 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide 0.421 g, 1.0 mmol) was reacted with N-{3-[(2S)oxiranylmethoxy]phenyl}acetamide (0.207 g, 1.0 mmol) according to Procedure G (eluant. 20:1 chloroform-methanol) to give the title compound (0.168 g, 0.289 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[NH2:32][C@H:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:34][OH:35]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH:32][C@H:33]([C:36]([O:38][CH3:39])=[O:37])[CH2:34][OH:35])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H](N)CO
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -70 °C

Procedure:
21.5 g of t-butoxycarbonylproline are dissolved in 500 ml of methylene chloride. The solution is cooled to -70° C. 20.2 g of N-methylmorpholine are added, followed by the addition of 13.7 g of isobutylchloroformate. The reaction mixture is warmed up to -15° C. and again cooled to -70° C. 15.6 g of methyl serinate hydrochloride are added to the reaction mixture which is stirred for sixteen hours at room temperature. The reaction mixture is extracted three times with 1 M potassium bisulfate, three times with a saturated solution of potassium bicarbonate and two times with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of solvent. The product is purified by chromatography on silica gel to give methyl t-butoxycarbonylprolylserinate.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[N:12][C:11]2[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9](=[O:23])[N:8]3[N:24]=[CH:25][N:26]=[C:7]3[C:6]=2[CH:5]=1)(=O)[CH3:2].[CH3:27][C@@H:28]1[O:33][C@H:32]([CH3:34])[CH2:31][NH:30][CH2:29]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(#N)C>[CH3:27][C@H:28]1[CH2:29][N:30]([CH:1]([C:4]2[CH:13]=[N:12][C:11]3[N:10]([CH2:14][C:15]4[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[C:9](=[O:23])[N:8]4[N:24]=[CH:25][N:26]=[C:7]4[C:6]=3[CH:5]=2)[CH3:2])[CH2:31][C@@H:32]([CH3:34])[O:33]1
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(C)=O)cnc32)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(C(C)N4C[C@@H](C)O[C@@H](C)C4)cnc32)cc1
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
9-Acetyl-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 81, 67 mg, 0.19 mmol), (2S,6R)-2,6-dimethylmorpholine (0.060 mL, 0.49 mmol), ACN (1 mL) and acetic acid (0.020 mL, 0.35 mmol) were combined and stirred for 10 minutes. Sodium cyanoborohydride (18 mg, 0.29 mmol) was added and the mixture was stirred for 3 days at 50° C. The mixture was filtered. Purification (HPLC, 10-65% ACN in water) afforded the title compound (26 mg, 23%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.19 (d, J=6.27 Hz, 3H), 1.23 (d, J=6.27 Hz, 3H), 1.92 (d, J=7.03 Hz, 3H), 2.34 (td, J=11.01, 2.32 Hz, 2H), 3.32 (d, J=11.42 Hz, 1H), 3.57 (d, J=11.42 Hz, 1H), 3.77 (s, 3H), 4.12 (d, J=7.03 Hz, 2H), 4.54 (q, J=6.86 Hz, 1H), 5.75 (s, 2H), 6.85 (d, J=8.66 Hz, 2H), 7.62 (d, J=8.66 Hz, 2H), 8.40 (s, 1H), 8.74 (s, 1H), 8.95 (s, 1H). [M+H]=449.3.
Reaction SMILES: Cl[CH2:2][C:3]([NH2:5])=[O:4].[CH:6]1([NH2:11])[CH2:10][CH2:9][CH2:8][CH2:7]1>CC(CC(C)=O)C>[CH:6]1([NH:11][CH2:2][C:3]([NH2:5])=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: NC1CCCC1
Reactant: NC(=O)CCl
Solvent: CC(=O)CC(C)C
Product: NC(=O)CNC1CCCC1

Procedure:
To a solution of spiro[isobenzofuran-1(3H),4'-piperidine] (14 g) in dichloromethane (160 ml) triethylamine (11 ml) was added. After cooling to 10° C. a solution of chloroacetylchloride (8 ml) in dichloromethane (10 ml) was added dropwise during 20 minutes. The reaction mixture was finally allowed to reach room temperature. The mixture was subsequently filtered through silica gel (eluted with ethyl acetate/n-heptane 60:40) affording 12 g of the α-chloroacetamide derivative. A mixture of the thus obtained α-chloroacetamide derivative (1.4 g) and cyclopentylamine in MIBK (25 ml) was refluxed for 2 h. The solvent was evaporated in vacuo and the cyclopentylamino derivative was extracted from an alkaline (pH>9) aqueous solution with ethyl acetate. The organic phase was worked up as above yielding 2.0 g of the α-(cyclopentylamino)acetamide derivative as a visceous oil. To a solution of the α-(cyclopentylamino)acetamide derivative (2 g) in MIBK 1-chloracetylspiro[isobenzofuran-1(3H),4'-piperidine] (1.4 g) and potassium carbonate (1 g) were added. The mixture was refluxed for 3 h. After cooling to room-temperature the mixture was filtered through silica gel (eluted with 4% triethylamine in ethyl acetate. Evaporation of the solvents afforded 2.4 g of the diamide which was reduced with LiAlH4 as described in example 1. The title compound 3a crystallized from a mixture of ethanol and acetone (1:4). Yield 1.3 g, mp 258°-260° C. 1H NMR (DMSO-d6) δ 1.50-2.45 (m, 16 H), 3.25-3.80 (m, 17 H), 5.05 (s, 4 H), 7.10-7.40 (m, 8 H).
Reaction SMILES: P(Br)(Br)([Br:3])=O.[CH2:6]([O:10][C:11]([C:13]1[N:14]=[C:15](O)[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[C:18]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:17]=2)=[O:12])[CH2:7][CH2:8][CH3:9].C(=O)(O)[O-].[Na+].O>C(#N)C>[CH2:6]([O:10][C:11]([C:13]1[N:14]=[C:15]([Br:3])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[C:18]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:17]=2)=[O:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOC(=O)c1nc(O)c2cc(Sc3ccccc3)ccc2c1O
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCCCOC(=O)c1nc(Br)c2cc(Sc3ccccc3)ccc2c1O
Reaction time: 1 h
Yield: 68.2 %

Procedure:
To a solution of 4.59 g of phosphorous oxybromide (16 mmol) in 25 ml of anhydrous acetonitrile were added 1.108 g of 1,4-dihydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (3 mmol) and the mixture was refluxed gently with stirring for 1 h. Then 5.04 g of sodium bicarbonate (60 mmol) were added, followed by the dropwise addition of 8 ml of water. After stirring at ambient temperature for 90 min the mixture was concentrated in vacuo to about one third of its volume, 40 ml of water were added and the mixture was extracted with 30 ml of ethyl acetate. The mixture was filtered by suction. The organic phase was separated, dried over MgSO4, and filtered through a pad of silica gel. Evaporation in vacuo gave 0.885 g of the title compound; 1H NMR (CDCl3): δ=11.84 (s, 1H), 8.21 (d, 1H), 7.91 (d, 1H), 7.40 to 7.55 (m, 6H), 4.46 (t, 2H), 1.84 (m, 2H), 1.48 (m, 2H), 0.98 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21]O)=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.N1C(C)=CC(C)=CC=1C.CS(Cl)(=O)=O.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)=[CH:15][CH:14]=3)=[O:9])=[CH:23][CH:24]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CO)cc2c1O
Reactant: C1COCCN1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(CN3CCOCC3)cc2c1O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(hydroxymethyl)-3-quinolinecarboxamide from Example No. 166 (1.0 g), collidine (0.45 mL), and DMAP (60.0 mg) in 50 mL anhydrous DMF is cooled to 0° C. Methanesulfonyl chloride (0.25 mL) is added dropwise. The reaction is stirred at room temperature for approx. 2-3 h. Morpholine (0.34 mL) is added. The product is precipitated by addition of H2O. The crude product is adsorbed onto silica and chromatographed eluting with 2% MeOH in CH2Cl2. Fractions homogenous by TLC were combined and condensed to afford 352 mg of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([C:13]([F:16])([F:15])[F:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[S:5](F)(=[O:7])=[O:6].CCN(CC)CC.[CH2:25]([CH:32]1[C:40]2[C:35](=[CH:36][CH:37]=[C:38]([OH:41])[CH:39]=2)[C:34](=[O:42])[NH:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[F:9][C:4]([F:10])([S:5]([O:41][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:42])[NH:33][CH:32]2[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)(=[O:7])=[O:6])[C:3]([F:12])([F:11])[C:2]([F:17])([F:1])[C:13]([F:16])([F:15])[F:14]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C1NC(Cc2ccccc2)c2cc(O)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NC(Cc2ccccc2)c2cc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of nonafluorobutanesulfonyl fluoride (712 mg, 2.36 mmol) and NEt3 (0.49 mL, 3.54 mmol) in 3 mL of dichloromethane was added 3-benzyl-5-hydroxyisoindolin-1-one (example 1.4, 282 mg, 1.18 mmol) in 2 mL of dichloromethane slowly. This reaction mixture was stirred at room temperature for overnight. TLC showed complete conversion, the solvent was evaporated. The residue was purified by flash-chromatography on silica gel with 30-80% ethyl acetate in hexane, 474 mg (77%) of the product was obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:28]2[Br:39])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O.O>[CH2:17]([O:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH2:12][C:11]1[CH:14]=[CH:15][CH:16]=[C:9]([O:8][CH3:7])[CH:10]=1)[C:29]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:28]2[Br:39])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1[nH]c2ccc(OCc3ccccc3)cc2c1Br
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1c(Br)c2cc(OCc3ccccc3)ccc2n1Cc1cccc(OC)c1
Reaction time: 23 h
Yield: 84 %

Procedure:
Powdered potassium carbonate (2.79 g, 20.2 mmol) and 3-methoxybenzyl bromide (2.03 g, 10.1 mmol) were added successively to a stirred solution of ethyl 5-(benzyloxy)-3-bromo-1H-indole-2-carboxylate, Lit. WO96/18393 (3.63 g, 9.70 mmol) in N,N-dimethylformamide (20 mL). The reaction was stirred for 23 h and then diluted with water (250 mL). The product was extracted with ethyl acetate (3×100 mL) and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Recrystalization of the residue using methanol afforded 4.03 g (84%) of the desired product. The product had: 1H NMR (300 MHz, CDCl3) δ 7.05-7.91 (m, 9 H), 6.74 (dd, 1 H), 6.53-6.63 (m, 2 H), 5.37 (s, 2 H), 4.37 (q, 2 H), 3.71 (s, 3 H), 1.39 (t, 3 H); mass spectroscopy gave MH+=494.1 (calc'd exact mass for C26H24BrNO4=493.09).