Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[NH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][N:8]=1.[N+:17]([O-])([O-:19])=[O:18].[K+]>O>[NH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([N+:17]([O-:19])=[O:18])=[CH:9][N:8]=1.[OH:4][S:1]([OH:5])(=[O:3])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1nccc2ccccc12
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Nc1ncc([N+](=O)[O-])c2ccccc12
Temperature: 0 °C
Yield: 62 %

Procedure:
Cool sulfuric acid (900 mL) to 5° C. using an ice/acetone bath, then add 1-aminoisoquinoline (208.8 g, 1448 mmol) over 45 min keeping the internal temperature of the mixture <20° C. Cool the dark mixture to 0° C. under nitrogen with mechanical stirring then treat with KNO3 (149.4 g, 1477 mmol) in portions over 45 min keeping the reaction mixture's temperature <10° C. Stir the mixture for 2 hours while warming to 15° C. Pour the mixture into water/ice (3 kg) then dilute with additional water (6 L). Stir the slurry for 45 min then filter. Wash the cake with water (6×1.5 L). Partially dry the golden material by air overnight then place in a vacuum oven (50-55° C., ca. 10 torr, nitrogen bleed, 24 h) to afford 1-amino-4-nitroisoquinoline H2SO4 (256.8 g, 62% yield). (ES+): m/z 190 (M++H).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[CH2:14].ClCCC1C=CC=CC=1.P(=O)(O)(O)O>>[CH3:14][CH:13]1[C:12]2[C:11](=[CH:10][CH:17]=[CH:16][CH:15]=2)[CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:1]1
Reactant: C=Cc1ccccc1
Reactant: C=Cc1cccc(Cl)c1
Agent: ClCCc1ccccc1
Agent: O=P(O)(O)O
Product: CC1CC(c2ccccc2)c2ccccc21
Reaction time: 2 h

Procedure:
A solution containing 90 parts of styrene, 174 parts of m-chlorostyrene and 126 parts of m-chloroethylbenzene is added to 722 parts of 93 per cent strength by weight phosphoric acid at 35° to 40° C over 5 hours. After completion of the addition, the emulsion is stirred for 2 hours at 35° to 40° C. The organic phase is separated off and washed with 200 parts of 3 per cent strength by weight sodium hydroxide solution. Fractional distillation gives 27 parts of 1-methyl-3-phenylindan, 71 parts of 1-methyl-3-(m-chloro)-phenylindan (b.p. 168° to 172° C (10 mm), nD25 : 1.5872) and 23 parts of 1-methyl-3-(m-chloro)-phenyl-6-chloroindan (b.p. 197° to 204° C (10 mm)).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]2[CH3:17])=[N:9][CH:10]=1)=[O:4].[CH2:18]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](Cl)=[N:27][N:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>CN1C(=O)CCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:28]3[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:25]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:26][N:27]=3)[CH2:13][C@H:12]2[CH3:17])=[N:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cnc(N2CCNC[C@H]2C)cn1
Reactant: Clc1nnc(Cc2ccccc2)c2ccccc12
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cc4ccccc4)c4ccccc34)C[C@H]2C)cn1
Yield: 18.2 %

Procedure:
(R)-2-Methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-carboxylic acid methyl ester (150 mg, 0.63 mmol), 1-benzyl-4-chloro-phthalazine (161.75 mg, 0.635 mmol) are added into a microwave vial followed by NMP (3.3 mL) and triethylamine (0.265 mL, 1.91 mmol). The vial is sealed and irradiated in the microwave at 180° C. for 30 min. The crude material is directly purified via flash chromatography on silica gel (40-100% EtOAc in heptane). Desired product is then washed with water and lyophilized to afford the title compound (52 mg, 18% yield).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][OH:53])[CH:46]([O:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH:6]([O:58][Si:59]([C:62]([CH3:65])([CH3:64])[CH3:63])([CH3:61])[CH3:60])[CH2:5][C:4]1=[O:66])[CH3:2].C(N(CC)CC)C.[CH3:74][S:75](Cl)(=[O:77])=[O:76]>C(Cl)Cl>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:56])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][O:53][S:75]([CH3:74])(=[O:77])=[O:76])[CH:46]([O:54][CH3:55])[CH2:45]2)[CH:7]([CH3:57])[CH:6]([O:58][Si:59]([C:62]([CH3:63])([CH3:64])[CH3:65])([CH3:61])[CH3:60])[CH2:5][C:4]1=[O:66])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCO)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOS(C)(=O)=O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (80.8 mg) in methylene chloride (1.0 mL) was added triethylamine (23 μL) followed by methanesulfonyl chloride (7.2 μL) and the mixture stirred at room temperature. After 10 minutes, the reaction was quenched by the addition of saturated sodium bicarbonate solution, extracted with ethyl acetate, and the organic portion dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (2:1)+1% methanol) gave the title compound (74 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]1([C:21]2[O:25][N:24]=[C:23]([CH2:26][NH2:27])[CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:27][CH2:26][C:23]1[CH:22]=[C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[O:25][N:24]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCc1cc(-c2ccccc2)on1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnc2ccccc2c1NCc1cc(-c2ccccc2)on1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
A suspension of 4-chloro-3-nitroquinoline (2.29 g, 11.0 mmol) and (5-phenylisoxazol-3-yl)methylamine (1.92 g, 11.0 mmol) in dichloromethane (200 mL) was cooled to 0° C., and triethylamine (2.30 mL, 16.5 mmol) was added. The resultant solution was allowed to warm to room temperature slowly and stirred overnight. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography on silica gel (eluting with 3% to 8% methanol in dichloromethane) to provide 2.90 g of 3-nitro-N-[(5-phenylisoxazol-3-yl)methyl]quinolin-4-amine.
Reaction SMILES: Cl.[C:2]([C@@H:5]1[CH2:9][C@H:8]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH2:7][NH:6]1)(=[O:4])N.[OH-:20].[Na+]>Cl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][S:10][C@@H:8]2[CH2:7][NH:6][C@H:5]([C:2]([OH:20])=[O:4])[CH2:9]2)=[CH:13][CH:14]=1
Reactant: [OH-]
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Agent: Cl
Agent: [Na+]
Product: COc1ccc(CS[C@@H]2CN[C@H](C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4.0 g of (2S,4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine hydrochloride were dissolved in 40 ml of 2N aqueous hydrochloric acid, and the resulting solution was stirred for 1.5 hours on an oil bath at 95°-100° C. At the end of this time, the solution was cooled to room temperature, and then about 40 ml of a 2N aqueous solution of sodium hydroxide were added to the solution, whilst stirring, to adjust its pH to a value of between 4 and 6. The crystals which separated were collected by filtration, washed with water and dried in the air, to yield 3.25 g of the title compound as crystals, melting at 198°-200° C.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]2[N:22]=[N:23][C:24]([C:27](=[O:34])[NH:28][CH2:29][CH2:30][CH:31]3[CH2:33][CH2:32]3)=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)=[O:14]>O1CCCC1.O>[CH:31]1([CH2:30][CH2:29][NH:28][C:27]([C:24]2[N:23]=[N:22][C:21]([N:18]3[CH2:17][CH2:16][N:15]([C:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[C:6]([OH:35])=[O:5])=[O:14])[CH2:20][CH2:19]3)=[CH:26][CH:25]=2)=[O:34])[CH2:33][CH2:32]1
Reactant: COC(=O)c1ccccc1C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)c3ccccc3C(=O)O)CC2)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.1 %

Procedure:
Lithium hydroxide monohydrate (0.066 g, 1.57 mmol) was added to a solution of 2-{4-[6-(2-cyclopropylethylcarbamoyl)pyridazin-3-yl]piperazine-1-carbonyl}benzoic acid methyl ester (0.230 g) in tetrahydrofuran (10 mL) and water (5 mL) stirred at ambient temperature overnight. THF was removed in vacuo, the residue was dissolved in ethyl acetate (100 mL), neutralized by addition of 5% HCl solution, washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was recrystallized from dichloromethane and hexanes to yield 0.107 g of the title compound (42% yield).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:15]([CH2:29][CH3:30])[N:14]=2)[CH:12]=1.[CH3:31][C:32]([S:35]([N:37]=[C:38]1[CH2:41][O:40][CH2:39]1)=[O:36])([CH3:34])[CH3:33]>O1CCCC1>[CH2:29]([N:15]1[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:17][C:13]([C:11]2[CH:12]=[C:7]([C:38]3([NH:37][S:35]([C:32]([CH3:34])([CH3:33])[CH3:31])=[O:36])[CH2:41][O:40][CH2:39]3)[CH:8]=[N:9][CH:10]=2)=[N:14]1)[CH3:30]
Reactant: CCn1nc(-c2cncc(Br)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)S(=O)N=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCn1nc(-c2cncc(C3(NS(=O)C(C)(C)C)COC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 66.4 %

Procedure:
A solution of n-butyllithium in hexanes (1.6 M, 0.35 mL, 0.56 mmol, 1.5 equiv) was added to a solution of 3-bromo-5-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}pyridine (152 mg, 0.37 mmol, 1.0 equiv) in tetrahydrofuran (1.5 mL) and hexanes (1.5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 10 minutes, and then 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (Example 95, Step 4, 75 mg, 0.43 mmol, 1.15 equiv) was added neat via syringe. The reaction mixture was stirred at −78° C. for 5 minutes, then the cooling bath was removed. After 5 minutes, the mixture was quenched with water (2 mL) and extracted with EtOAc (3×5 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (50-100% EtOAc/hexane, then 0-5% MeOH/EtOAc) to give N-[3-(5-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}pyridine-3-yl)oxetan-3-yl]-2-methylpropane-2-sulfinamide (125 mg, 57%). Calc'd (M+1)+: 508.6. Found: 509.5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:8][NH:9][NH2:10]>>[CH3:8][N:9]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:10]
Reactant: CNN
Reactant: Brc1ccccn1
Product: CN(N)c1ccccn1
Reaction time: 16 h
Yield: 74.4 %

Procedure:
2-Bromopyridine (5 mL, 52.4 mmol) and methylhydrazine (20 mL, 360 mmol) were mixed together in a flask fitted with a water-condenser. After a few minutes a vigorous exothermic reaction occurred with refluxing of the methylhydrazine. When the reaction had subsided, the mixture was left for 16 hours, and the excess methylhydrazine was removed under reduced pressure. The cooled residue was stirred with aqueous sodium hydroxide solution (30 ml of 20%), and the resulting solution was extracted with ether (3×100 ml). The combined extracts were dried (K2CO3) and purified by silica gel chromatography 0-3% EtOH/CH2Cl2 to give 4.8 g of N-Methyl-N-pyridin-2-yl-hydrazine.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([NH2:39])=[O:38])[C:32](=[O:40])[CH2:31]2>CN(C)C=O.CN(C1C=CN=CC=1)C>[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([C:37]([NH2:39])=[O:38])[C:32](=[O:40])[CH:31]2[C:7](=[O:9])[C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1
Reactant: O=C(O)c1csc(Br)c1
Reactant: NC(=O)N1C(=O)Cc2cc(Cl)ccc21
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: CN(C)C=O
Product: NC(=O)N1C(=O)C(C(=O)c2csc(Br)c2)c2cc(Cl)ccc21

Procedure:
The title compound was prepared according to the procedure of Example 55. A 1.00 g (4.83 mmole) portion of 5-bromo-3-thiophenecarboxylic acid (prepared as described in J. Am. Chem. Soc., 76, 2445 (1954)) was combined with 848 mg (5.23 mmole) of 1,1′-carbonyldiimidazole in 5 ml of N,N-dimethylformamide and the intermediate imidazolide coupled directly with 848 mg (4.02 mmole) of 5-chloro-2-oxindole-1-carboxamide in the presence of 1.33 g (10.89 mmole) of 4-(N,N-dimethylamino)pyridine. The resulting crude green product (1.22 g, 76% yield) was recrystallized to furnish 540 mg (1.35 mmole, 34% yield) of yellow solid, m.p. 238-40° C. (acetic acid).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:16]=[C:17]([CH3:19])[CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C@H:3]1[O:20][CH3:21].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:16]=[C:17]([CH3:19])[CH:18]=3)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4][C@H:3]2[O:20][CH3:21])=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCOC(=O)c1cc(C)cc(N2CC[C@H](N)[C@H](OC)C2)c1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)cc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)c1
Yield: 76.4 %

Procedure:
The same operation as in Example (1g) was performed using ethyl cis(±)-3-(4-amino-3-methoxypiperidin-1-yl)-5-methylbenzoate obtained in Example (259g) (about 0.24 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (37 mg, 0.21 mmol), WSC hydrochloride (134 mg, 0.70 mmol), HOBT (47 mg, 0.35 mmol), dichloromethane (1.5 mL) and DMA (1.5 mL), to obtain 72 mg of the title compound as a colorless oily substance (75%).
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[CH3:34])=[CH:17]/[C:18]2[N:19]=[C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:21](S(=O)(=O)N(C)C)[CH:22]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CI.[C:37]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[C:3](/[C:16](/[CH3:34])=[CH:17]/[C:18]2[N:19]=[C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:21]([CH3:37])[CH:22]=2)=[CH:4][C:5]2[C:6]([CH3:14])([CH3:15])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1nc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cn1S(=O)(=O)N(C)C
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1nc(/C=C(\C)c2cc3c(cc2C)C(C)(C)CCC3(C)C)cn1C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
Ethyl (E)-4-[2-(5,6,7,8 -tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl)propen-1-yl]-1-N,N-dimethylsulfamoyl-2-imidazolecarboxylate (Compound 4, 70 mg, 0.18 mmol) was dissolved in acetone (10 mL) at room temperature and treated with methyl iodide (0.5 mL) and K2CO3 (350 mg). The suspension was stirred for 30 min, filtered through Celite and concentrated under reduced pressure. The residue was treated with water (5 mL) and the organic material was extracted with ethyl acetate, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes/ethyl acetate=5:1) to give the title compound as a light yellow solid (35 mg, 50%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]2=[N:23][C:24]3[C:37]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[N:31]([CH3:38])[C:30]4[C:25]=3[C:26]([CH:27]=[C:28](O)[CH:29]=4)=[C:19]2[CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]2=[N:23][C:24]3[C:37]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[N:31]([CH3:38])[C:30]4[C:25]=3[C:26]([CH:27]=[C:28]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:29]=4)=[C:19]2[CH:18]=1
Reactant: CN1c2ccccc2-c2nc3ccc(Cl)cc3c3cc(O)cc1c23
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CN1c2ccccc2-c2nc3ccc(Cl)cc3c3cc(OS(=O)(=O)C(F)(F)F)cc1c23
Temperature: 25 °C
Yield: 67 %

Procedure:
(Method L) Under an atmosphere of nitrogen, trifluoromethanesulphonic acid anhydride (1.14 ml, 6.4 mmol, 1 eq) was added dropwise to a stirred cold (0° C.) suspension of 3-chloro-6-hydroxy-8-methyl-8H-quino[4,3,2-kl]acridine, 36 (2.23 g, 6.4 mmol) in DCM (1 L). On warming to RT a green solution was formed. Aqueous work-up (water, 500 mL), separation of the organic layer, drying (MgSO4), filtering, adsorption onto silica, and column chromatography (85:15 hexane:ethyl acetate) gave the title compound as a yellow solid, (2 g, 4.3 mmol, 67%).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C(=O)N(Cl)C(=O)C1.[Cl:21][C:22]1[N:23]([C:32]2[CH:33]=[N:34][N:35]([CH2:37][CH2:38][CH3:39])[CH:36]=2)[C:24]2[C:29]([CH:30]=1)=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=2>C(Cl)Cl.O>[Cl:21][C:22]1[N:23]([C:32]2[CH:33]=[N:34][N:35]([CH2:37][CH2:38][CH3:39])[CH:36]=2)[C:24]2[C:29]([C:30]=1[S:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:28][CH:27]=[C:26]([Cl:31])[CH:25]=2
Reactant: CCOC(=O)c1cccc(S)c1
Reactant: CCCn1cc(-n2c(Cl)cc3ccc(Cl)cc32)cn1
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: CCCn1cc(-n2c(Cl)c(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)cc32)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4.6 %

Procedure:
To a stirred solution of ethyl 3-mercaptobenzoate (124.9 mg, 0.68 mmol) in CH2Cl2 (20 mL) under inert atmosphere was added NCS (109 mg, 0.81 mmol) at 0° C.; warmed to RT and stirred for 1 h. To this, compound 3 (200 mg, 0.68 mmol) was added at 0° C.; warmed to RT and stirred for 12 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by preparative HPLC to afford compound 4 (15 mg, 5%) as colorless oil. 1H NMR (500 MHz, CDCl3): δ 7.90 (s, 1H), 7.79-7.77 (m, 1H), 7.69 (s, 1H), 7.66 (s, 1H), 7.48 (d, J=9.0 Hz, 1H), 7.26-7.22 (m, 3H), 7.16 (d, J=9.0 Hz, 1H), 4.32 (q, J=7.5 Hz, 2H), 4.20 (t, J=7.0 Hz, 2H), 2.02-1.98 (m, 2H), 1.37-1.34 (t, J=7.5 Hz, 3H), 1.01 (t, J=7.0 Hz, 3H); LC-MS (ESI): 92.7%; m/z 475.8 (M+H+); (column: X Select C-18, 50×3.0 mm, 3.5 μm); RT 5.03 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[CH:5]=[C:6]([Cl:12])[C:7]=1[O:8][CH2:9][CH2:10][OH:11].[Cl:14][C:15](Cl)([Cl:19])[CH2:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:14][C:15]([Cl:19])=[CH:16][CH2:17][O:13][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([O:8][CH2:9][CH2:10][OH:11])=[C:6]([Cl:12])[CH:5]=1
Reactant: OCCOc1c(Cl)cc(O)cc1Cl
Reactant: ClCCC(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 50 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
This compound was prepared in a manner analogous to that of Example 1 Step C, by the reaction of 10.0 grams (0.045 mole) of 3,5-dichloro-4-(2-hydroxyethoxy)phenol, 12.0 grams (0.066 mole) of 1,1,1,3-tetrachloropropane and 12.0 grams (0.086 mole) of potassium carbonate in 100 mL of DMF. The reaction mixture was warmed to 50° C. where it stirred during an 18 hour period, then it was warmed to 70° C. where it stirred during an additional five hour period. After this time the reaction mixture was cooled, water was added, and the mixture was extracted with two 150 mL portions of diethyl ether. The combined extracts were washed with an aqueous solution saturated with sodium chloride, dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 1:4 ethyl acetate:hexane as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 10.9 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[CH:5]([OH:7])[CH3:6].[C:13]([Cu])#[N:14].CN(C=O)C.[C-]#N.[Na+]>O>[F:12][C:3]1[C:4]([CH:5]([OH:7])[CH3:6])=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[C:13]#[N:14]
Reactant: N#C[Cu]
Reactant: CC(O)c1cc(F)cc(Br)c1F
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)c1cc(F)cc(C#N)c1F
Yield: 95.4 %

Procedure:
A mixture of 9.39 g of 3-bromo-2,5-difluoro-α-methylbenzyl alcohol, 3.82 g of CuCN and 117 mL of DMF is stirred and heated at reflux for 7 hours under N2. When the mixture has cooled, 100 mL of 5% aqueous NaCN is added followed by 350 mL of H2O 30 minutes later. The black solution is extracted with 4×150 mL of CH2Cl2 and these combined extracts washed with H2O, saturated NaHCO3 and H2O (150 mL each) and stripped in vacuo to furnish 6.92 g (95% yield) of 2,5-difluoro-3-(1-hydroxyethyl)-benzonitrile as a brown oil. The product exhibits an M+1 ion at 184 in the mass spectrum and appropriate infrared and N.M.R. spectral data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[C:35]2[C:30](=[CH:31][C:32]([C:36](O)=[O:37])=[CH:33][CH:34]=2)[NH:29][CH:28]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:25][C:36]([C:32]2[CH:31]=[C:30]3[C:35]([C:27]([Cl:26])=[CH:28][NH:29]3)=[CH:34][CH:33]=2)=[O:37])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccccc2Cl)CC1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2Cl)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(2-chlorophenyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (7.5 g, 20 mmol) and 3-chloroindole-6-carboxylic acid (3.9 g, 20 mmol) afforded, after purification (SiO2: 33% to 50% EtOAc in hexane), 8 g (73%) of the title compound.