Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][C:12]([C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][NH:20]3)([OH:15])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H].C>CO>[ClH:1].[NH:20]1[C:21]2[C:17](=[C:16]([C:12]3([OH:15])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)[CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:19]1
Reactant: OC1(c2cccc3[nH]ccc23)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: Cl
Solvent: CO
Product: OC1(c2cccc3[nH]ccc23)CCNCC1
Yield: 78.2 %

Procedure:
A mixture of 13.7 g of the hydrochloride of Example 2 in 600 ml of methanol was subjected to hydrogen at 40° C. in the presence of 4.7 g of palladized charcoal and the mixture was then filtered. The filtrate was evaporated to dryness under reduced pressure at 40° C. and the residue was triturated in ether, filtered and dried at 20° to 25° C. under reduced pressure to obtain 7.9 g of 4-(1H-indol-4-yl)-4-piperidinol hydrochloride melting at 270° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([F:33])([F:32])[F:31])[CH2:11][N:12]2[C:20](=[O:21])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]2=[O:22])=[O:8])[S:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH3:40][N:41]1[C:45](B2OC(C)(C)C(C)(C)O2)=[C:44]([CH3:55])[CH:43]=[N:42]1>O1CCOCC1.O.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>[CH3:40][N:41]1[C:45]([C:2]2[CH:3]=[C:4]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:31])([F:32])[F:33])[CH2:11][N:12]3[C:13](=[O:22])[C:14]4[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:20]3=[O:21])=[O:8])[S:5][CH:6]=2)=[C:44]([CH3:55])[CH:43]=[N:42]1
Reactant: O=C(N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O)c1cc(Br)cs1
Reactant: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cnn(C)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 80 °C
Yield: 93.9 %

Procedure:
To a solution of 4-bromo-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (200 mg, 0.37 mmol) in dioxane/H2O (5:1, 6 mL) was added K2CO3 (0.17 g, 1.23 mmol), tetrakistriphenylphosphine Pd(0) (42 mg, 0.036 mmol) and 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (413 mg, 1.86 mmol) [from Preparation 17]. The reaction mixture was heated to 80° C. in a sealed tube for 2 h. The reaction solution was concentrated under vacuum, and purified on silica gel (10-50% EtOAc/Hex) to give the title compound (192 mg, 94%) as a white solid: LC-MS (ES) m/z 553 (M+H)+.
Reaction SMILES: BrC1C=CC([C:8]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]=3[CH:9]=2)=CC=1.C1C2C=CC3C(=CC=CC=3)C=2C=C(B(O)O)C=1.[Br:39][C:40]1[CH:41]=[C:42](I)[CH:43]=[CH:44][CH:45]=1>>[Br:39][C:40]1[CH:45]=[C:44]([C:10]2[CH:11]=[CH:12][C:21]3[CH:20]=[CH:19][C:18]4[C:17]([C:8]=3[CH:9]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:43]=[CH:42][CH:41]=1
Reactant: Brc1cccc(I)c1
Reactant: Brc1ccc(-c2ccc3c(ccc4ccccc43)c2)cc1
Agent: OB(O)c1ccc2ccc3ccccc3c2c1
Product: Brc1cccc(-c2ccc3ccc4ccccc4c3c2)c1

Procedure:
Synthesis was performed in the same manner as in the synthesis of 2-(4-bromophenyl)phenanthrene except that: phenanthrene-3-boronic acid was used instead of phenanthrene-2-boronic acid; and 3-bromoiodobenzene was used instead of 4-bromoiodobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=O)[C:7](=[CH:18]N(C)C)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.Cl.[C:26]([NH2:29])(=[NH:28])[CH3:27].C[O-].[Na+]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:29]=[C:26]([CH3:27])[N:28]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: CC(=N)N
Reactant: CN(C)C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2C1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5.1 g (0.015 mol) of 8-chloro-1-(2-fluorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepin-5-one and 2.1 g (0.0225 mol) of acetamidine hydrochloride in 150 ml of methanol was stirred at room temperature under argon, and treated with 2.4 g (0.045 mol) of sodium methylate in one portion. After stirring for 10 min, 90 ml of methylene chloride was added and stirring was continued. Another 2.4 g (0.045 mol) of sodium methylate and 2.1 g (0.0225 mol) of acetamidine hydrochloride were added after 2 hrs. The addition of 0.045 mol of sodium methylate and 0.0225 mol of acetamidine hydrochloride was repeated after another 2 hr interval and stirring at room temperature was continued overnight. After diluting with 150 ml of methylene chloride, the mixture was washed with water, dried over sodium sulfate and evaporated at reduced pressure. Recrystallization of the residue from hexane (charcoal) gave white crystals: mp 104°- 107° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([C:15]2[CH:25]=[CH:24][C:18]3[N:19]([CH3:23])[C:20](=[O:22])[O:21][C:17]=3[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:27])[CH:3]=1.[CH3:28][O:29][C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)=[O:31]>>[CH3:28][O:29][C:30]([C:32]1[CH:37]=[C:36]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:26])[C:9]([OH:14])([C:15]3[CH:25]=[CH:24][C:18]4[N:19]([CH3:23])[C:20](=[O:22])[O:21][C:17]=4[CH:16]=3)[C:10]([F:12])([F:13])[F:11])=[C:4]([Cl:27])[CH:3]=2)[CH:35]=[CH:34][CH:33]=1)=[O:31]
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)oc(=O)n2C)C(F)(F)F
Reactant: COC(=O)c1cccc(B(O)O)c1
Product: COC(=O)c1cccc(-c2ccc(C(C)C(O)(c3ccc4c(c3)oc(=O)n4C)C(F)(F)F)c(Cl)c2)c1

Procedure:
The title compound was prepared in analogy to Example 117 from 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (obtained in Example 133, step 3) by Suzuki coupling with 3-methoxycarbonylphenyl-boronic acid [CAS Reg. No. 99769-19-4]. 1H-NMR (, CDCl3): 8.13 (m, 1H), 8.00 (m, 1H), 7.63 (m, 1H), 7.60 (d, 1H), 7.48 (t, 1H), 7.41 (d, 1H), 7.36 (s(br), 1H), 7.31-7.25 (m, 2H), 6.77 (d, 1H), 4.42 (q, 1H), 3.93 (s, 3H), 3.31 (s, 3H), 3.08 (s, 1H), 1.52 (d, 3H).
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.Cl[CH2:14][C:15]1[CH:19]=[C:18]([CH3:20])[O:17][N:16]=1>>[CH3:20][C:18]1[O:17][N:16]=[C:15]([CH2:14][O:1][NH2:2])[CH:19]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cc(CCl)no1
Product: Cc1cc(CON)no1

Procedure:
Prepared by a similar procedure as described for preparation 15. Starting materials: N-hydroxyphthalimide and 3-chloromethyl-5-methylisoxazole (Maybridge).
Reaction SMILES: [C:1]1([NH:7][N:8]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH2:23][CH3:24])[C:15]4[C:20]([C:21]=3[CH:22]=2)=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH3:33][C:34]([CH3:36])=[O:35]>C(C1OC1)Cl.CCOCC.CCCCCC>[O:35]1[CH2:36][CH:34]1[CH2:33][N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[N:8]=[CH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]([CH2:23][CH3:24])[C:15]3[C:20]([C:21]=2[CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: CC(C)=O
Reactant: CCn1c2ccccc2c2cc(C=NNc3ccccc3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCC1CO1
Solvent: CCCCCC
Product: CCn1c2ccccc2c2cc(C=NN(CC3CO3)c3ccccc3)ccc21
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A mixture of 9-ethyl-3-carbazolecarboxaldehyde phenylhydrazone (3.1 g, 0.01 mol), 85% powdered potassium hydroxide (2.0g, 0.03 mol) and anhydrous potassium carbonate (˜5 g) in 25 ml of epichlorohydrin was stirred vigorously at 55–60° C. for 1.5–2 h. The course of the reaction was monitored using thin layer chromatography on silica gel 60 F254 plates (commercially obtained from Merck) using a 1:4 volume per volume mixture of acetone and hexane as the eluant. After termination of the reaction, the mixture was cooled to room temperature, diluted with ether and washed with water until the wash water was neutral in pH. The organic layer was dried over anhydrous magnesium sulfate, treated with activated charcoal, and filtered. Ether was removed, and the residue was dissolved in the mixture of toluene and 2-propanol in 1:1 ratio by volume. The crystals formed upon standing were filtered off, and washed with 2-propanol to give 3.0 g (81.2%) of 9-ethyl-3-carbazolecarboxaldehyde N-2,3-epoxypropyl-N-phenylhydrazone. The solid product had a melting point (m.p.) of 136–137° C. after being recrystallized from a mixture of toluene and 2-propanol in 1:1 ratio by volume. A 1H-NMR spectrum of 9-ethyl-3-carbazolecarboxaldehyde N-2,3-epoxypropyl-N-phenylhydrazone was obtained in CDCl3 with a 250 MHz NMR. The peaks were found at (ppm) δ=8.35 (s, 1H, 4-HHt); δ=8.14 (d, J=7.8 Hz, 1H, 1-HHt); δ=7.93 (d, J=7.6 Hz, 1H, 2-HHt); δ=7.90 (s, 1H, CH═N); δ=7.54–7.20 (m, 8H, Ph, Ht); δ=6.96 (t, J=7.2 Hz, 1H, 4-HPh); δ=4.37 (m, 3H, CH2CH3, one of the NCH2 protons); δ=4.04 (dd, J1=4.3 Hz, J2=16.4 Hz, 1H, next of the NCH2 protons); δ=3.32 (m, 1H, CH); δ=2.88 (dd, 1H, part of the ABX system, cis-HA of CH2O, JAX=2.6 Hz, JAB=4.9 Hz); δ=2.69 (dd, 1H, part of the ABX system, trans-HB of CH2O, JBX=4.0 Hz); δ=1.44 (t, J=7.2 Hz, 3H, CH3). An elemental analysis found the following weight percents of the elements: C, 78.32; H, 6.41; N, 11.55, which compares with the following calculated elemental weight percent for a compound with the formula C24H23N3O: C, 78.02; H, 6.28; N, 11.37.
Reaction SMILES: C1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10](=[O:19])[CH:9]([NH:20][C:21]([O:23]C3C=CC([N+]([O-])=O)=CC=3)=O)[N:8]=2)CCCCC1.C(N([CH2:38][CH3:39])CC)C.CN(C)C=O.[CH3:45][C:46]([CH3:61])([C:48]([NH:50][S:51]([C:54]1[CH:59]=[CH:58][CH:57]=[C:56]([NH2:60])[CH:55]=1)(=[O:53])=[O:52])=[O:49])[CH3:47]>CO>[CH2:39]1[CH2:38][CH:7]([C:9]2([NH:20][C:21]([NH:60][C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([S:51]([NH:50][C:48]([C:46]([CH3:61])([CH3:45])[CH3:47])=[O:49])(=[O:53])=[O:52])[CH:55]=3)=[O:23])[N:8]=[CH:7][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:18])[C:10]2=[O:19])[CH2:13][CH2:12][CH2:17]1
Reactant: CC(C)(C)C(=O)NS(=O)(=O)c1cccc(N)c1
Reactant: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCC2)c2ccccc21
Reactant: CCN(CC)CC
Solvent: CO
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)Nc2cccc(S(=O)(=O)NC(=O)C(C)(C)C)c2)(C2CCCCC2)N=Cc2ccccc21
Yield: 78.5 %

Procedure:
The title compound was prepared in the same way as that described in Example 11, Step 4, using 5-cyclohexyl-1,3-dihydro-1-methyl3(R,S)-[(4-nitrophenyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (0.3 g, 0.69 mmol), triethylamine (96 μl, 0.69 mmol), dimethylformamide (6 ml) and 1-(1,1-dimethylethylcarbonylaminosulphonyl)-3-aminobenzene (194 mg, 0.76 mmol). After trituration with hot methanol, the title compound (0.15 g, 39%) was afforded as a colourless solid. mp 235° C. (dec.). 1H NMR (360 MHz, D6-DMSO) δ 3 0.84-0.98 (1H, m), 1.04(9H, s), 1.06-1.40 (4H, m), 1.41-1.68 (3H, m), 1.73-1.82 (1H, m), 1.88-1.96 (1H, m), 2.89-3.00 (1H, m), 3.33 (3H, s), 5.06 (1H, d, J=8.3 Hz), 7.32-7.50 (4H, m), 7.52-7.58 (2H, m), 7.64 (1H, t, J=7.0 Hz), 7.75 (1H, d, J=7.9 Hz), 8.03 (1H, s), 9.39 (1H, s), 11.62 (1H, brs).
Reaction SMILES: [O-][C:2]#[N:3].[K+].C1OCCOCCOCCOCCOCCOC1.[Cl:23][C:24]1[CH:42]=[CH:41][CH:40]=[CH:39][C:25]=1[CH2:26][N:27]1[C:31]2[CH:32]=[C:33]([CH2:36]Cl)[CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[CH3:38]>CS(C)=O>[Cl:23][C:24]1[CH:42]=[CH:41][CH:40]=[CH:39][C:25]=1[CH2:26][N:27]1[C:31]2[CH:32]=[C:33]([CH2:36][C:2]#[N:3])[CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[CH3:38]
Reactant: Cc1nc2ccc(CCl)cc2n1Cc1ccccc1Cl
Reactant: N#C[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1nc2ccc(CC#N)cc2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 43 %

Procedure:
Potassium cyanate (0.450 g) and 0.450 g of 18-crown-6 were added to a solution of 1.20 g of 1-(2-chlorobenzyl)-6-chloromethyl-2-methylbenzimidazole in 10 ml of dimethylsulfoxide, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was extracted with the addition of chloroform, water and a small amount of aqueous ammonia. The organic layer was concentrated, and the residue was purified through silica-gel column chromatography (eluent: a mixture of chloroform and methanol at a ratio of 20:1) to give 0.500 g of 1-(2-chlorobenzyl)-2-methylbenzimidazole-6-acetonitrile.
Reaction SMILES: [C:1]1([C:7]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:15][C:14]3[N:13](S(C4C=CC(C)=CC=4)(=O)=O)[N:12]=[C:11]([NH:26][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1>[C:35]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([NH:26][C:27](=[O:34])[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:10]=3[CH:9]=[CH:8]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(NC(=O)c3ccccc3)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2)c1ccccc1
Yield: 268.8 %

Procedure:
But starting with 0.14 g of N-[6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazol-3-yl)benzamide and 0.78 cm3 of aqueous 1N sodium hydroxide solution in 10 cm3 of tetrahydrofuran. 0.27 g of N-(6,6-diphenyl-6,7-dihydro-1H-indazol-3-yl)benzamide is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[C:13]([O:21]C)=[N:14][C:15]([CH3:20])=[C:16]([CH2:18][CH3:19])[CH:17]=1.[B].C([O-])(O)=O.[Na+]>C(Cl)Cl.CCCCCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[C:13](=[O:21])[NH:14][C:15]([CH3:20])=[C:16]([CH2:18][CH3:19])[CH:17]=1
Reactant: CCc1cc(OCc2nc3ccccc3o2)c(OC)nc1C
Agent: O=C([O-])O
Agent: [B]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: CCc1cc(OCc2nc3ccccc3o2)c(=O)[nH]c1C
Temperature: 25 °C
Yield: 51.6 %

Procedure:
3[(Benzoxazol-2-yl)methoxy]-2-methoxy-5-ethyl-6-methylpyridine (140 mg, 0.47 mmol) was dissolved in methylene chloride (5 ml) and cooled in an ice bath under an atmosphere of nitrogen. 1M Boron tribomide (2.3 mL, 2.3 mmol) in hexane was added to this solution and the reaction mixture was allowed to warm to room temperature over a 0.75 hour period. This mixture was re-cooled in an ice bath and saturated aqueous NaHCO3 (5 mL) was added to quench the reaction. The methylene chloride layer was dried (Na2SO4), filtered and evaporated. The residue was triturated with diethyl ether to give 69 mg of crude product. Recrystallization from methanol yielded 60 mg (45%), m.p. 198°-200° C.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]([CH3:36])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[C:34]([CH3:35])=[CH:33][CH:32]=[C:31]([CH3:36])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Cc1ccc(C)c2sc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(C)c2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 69.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4,7-dimethylbenzothiazole (91 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 111 mg (69%) of the title compound as an amorphous foam. FDMS: m/e=422. α[D]589 =+63.27 (c=0.95, chloroform).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(O)[CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]([CH2:14][O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:11][CH2:12][Cl:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(O)(COCc1ccccc1)COCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: ClCC=C(COCc1ccccc1)COCc1ccccc1
Reaction time: 0.5 h

Procedure:
Crude 1-benzyloxy-2-benzyloxymethylbut-3-en-2-ol (1.42 g, 3.16 mmol) in 10 ml of CH2Cl2 was added to 0.71 g thionyl chloride (6 mmol) and 2 drops of DMF in 10 ml of CH2Cl2, and the solution was stirred for 0.5 h and evaporated in vacuum. Toluene was added and the mixture was evaporated in vacuum to yield crude 1-benzyloxy-2-benzyloxymethyl-4-chlorobut-2-ene.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:15][CH2:14]1>C(OCC)(=O)C.CO>[CH3:1][C:2]1[C:3]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][S:21]([CH3:24])(=[O:22])=[O:23])[CH2:17][CH2:18]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reaction time: 8 h
Yield: 81.9 %

Procedure:
1-[2-methyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]piperazine (0.257 g, 0.72 mmol) was placed in a 40 mL high vial and dissolved in 10 mL of 1:1 ethyl acetate/methanol. 5 wt % Platinum(sulfided)/C (0.165 g, 0.043 mmol) was added followed quickly by a screw cap septum. The vial was evacuated and filled with nitrogen six times to remove any oxygen. The vial was then pressurized with hydrogen (balloon) and the solution stirred overnight. The next morning the vessel was evacuated and filled with nitrogen six times to remove any hydrogen. The solution was filtered through celite and evaporated to afford 5-methyl-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (0.194 g, 0.59mmol, 82%). 1 H NMR (400 MHz, CHLOROFORM-δ ppm 6.54 (s, 2 H), 3.80 (s, 3 H), 3.30-3.37 (m, 2H), 3.07 (s, 3 H), 2.91-2.98 (m, 6 H), 2.82-2.90 (m, 4 H), 2.15 (s, 3 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([O:15]CC)=[O:14])[C:10]2([C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[C:10]2([C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CC12CCCc1ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1CN(Cc2ccccc2)CC12CCCc1ccccc12
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Ethyl 1′-benzyl-3,4-dihydro-2H-spiro[naphthalene-1,3′-pyrrolidine]-4′-carboxylate (1.1 g, 3.15 mmol) in THF/MeOH/H2O (41 ml) was added 2N sodium hydroxide (4.72 ml, 9.44 mmol). Stir overnight at 50° C. Cooled to room temperature and acidified to pH1-2 with 0.5N HCl and extracted with EtOAc. The organic layer was dried and concentrated. The crude acid was not purified.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][NH:13][C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3.[CH3:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[C:11]([CH:23]=3)[CH2:12][N:13]([C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([CH3:24])=[CH:26][CH:27]=3)[C:14]3[CH:22]=[C:18]([NH:19][C:20]=1[N:21]=2)[CH:17]=[CH:16][CH:15]=3
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Clc1cnc2nc1Nc1cccc(c1)NCc1cccc(c1)N2
Product: Cc1ccc(C(=O)N2Cc3cccc(c3)Nc3ncc(Cl)c(n3)Nc3cccc2c3)cc1
Yield: 48 %

Procedure:
The desired compound was prepared as a white powder according to the procedure of Example C22, step F, using 6-chloro-2,4,8,14,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene and 4-methylbenzoic acid chloride as the starting materials in 48% yield. LCMS for C25H21ClN5O (M+H)+: m/z=442.0.
Reaction SMILES: [NH2:1][C:2]1[O:15][C:5]2[CH2:6][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:16]#[N:17].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[C:16]([C:3]1[C:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C:5]=2[O:15][C:2]=1/[N:1]=[CH:20]/[N:21]([CH3:23])[CH3:22])#[N:17]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)N1CCc2c(oc(N)c2C#N)C1
Product: CCOC(=O)N1CCc2c(oc(/N=C/N(C)C)c2C#N)C1
Yield: 98.2 %

Procedure:
Ethyl 2-amino-3-cyano-4,7-dihydrofuro[2,3-c]pyridine-6(5H)-carboxylate from Example 36A (7.00 g, 29.8 mmol) was heated in dimethylformamide dimethylacetal (14.7 mL, 110 mmol) for 30 min to 110° C. The mixture was then concentrated in vacuo, and the residue was triturated with petroleum ether, the solvent was decanted, and the trituration was repeated. The remaining solid was then triturated with diethyl ether/petroleum ether (1:1), and the precipitate was collected by suction filtration to yield 8.5 g (98%) of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([OH:28])([CH3:27])[CH3:26])=[CH:6][CH:5]=1.[CH3:29]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([O:28][CH3:29])([CH3:26])[CH3:27])=[CH:6][CH:5]=1
Reactant: CC(C)(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(C)(C)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 0.08 h
Yield: 85.8 %

Procedure:
Sodium hydride (60% in oil, 17.5 mg, 0.438 mmol) was added to a stirred solution of 2-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-2-ol (150 mg, 0.365 mmol) in N,N-dimethylformamide (1.5 mL) at room temperature. After stirring 5 min, methyl iodide (77.7 mg, 0.548 mmol) was added to the mixture, and the mixture was stirred at room temperature for 4 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (133 mg, 0.313 mmol, 86%).