Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: NC1N=C(N)C2C(=NC=C(CN(C3C=CC=CC=3)C3C=CC=CC=3)N=2)N=1.[CH:27]1[C:37]2[C:31](=[N:32][C:33]3[CH:41]=[CH:40][CH2:39][CH2:38][C:34]=3[CH2:35][CH:36]=2)[CH:30]=[CH:29][CH:28]=1.[H-].[Na+].Br.[NH2:45][C:46]1[N:51]=[C:50]([NH2:52])[C:49]([CH2:53]Br)=[CH:48][N:47]=1>>[NH2:45][C:46]1[N:51]=[C:50]([NH2:52])[C:49]([CH2:53][CH:38]2[C:34]3[CH2:35][CH:36]=[C:37]4[CH:27]=[CH:28][CH:29]=[CH:30][C:31]4=[N:32][C:33]=3[CH:41]=[CH:40][CH2:39]2)=[CH:48][N:47]=1
Reactant: C1=CC2=C(CC=c3ccccc3=N2)CC1
Reactant: Nc1ncc(CBr)c(N)n1
Agent: Br
Agent: Nc1nc(N)c2nc(CN(c3ccccc3)c3ccccc3)cnc2n1
Agent: [H-]
Product: Nc1ncc(CC2CC=CC3=C2CC=c2ccccc2=N3)c(N)n1

Procedure:
9-[(2,4-Diaminopyrimidin-5-yl)methyl]-9,10-dihydrodibenz[b,f]azepine (Formula I: Ar=2,4-diaminopyrimidin-5-yl; W=CH2; X=N; Z=CH═CH; m=n=0) is prepared similarly to N-[(2,4-diaminopteridin-6-yl)methyl]-N,N-diphenylamine as disclosed above by using 9,10-dihydrodibenz[b,f]azepine (158 mg, 0.8 mmol), NaH (50 mg, 2.1 mmol), and 2,4-diamino-5-bromomethylpyrimidine hydrobromide (86 mg, 0.3 mmol). The product can be purified by chromatography.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>C1COCC1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:13](=[O:14])[NH:10][C:5]=2[CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-trifluoromethyl-1,2-phenylenediamine (8.8 g, 50 mmol, Lancaster) and 1,1′-carbonyldiimidazole (9.0 g, 55 mmol, Aldrich) in THF (50 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with EtOAc to give the title compound. MS (ESI, pos. ion) m/z: 203 (M+1).
Reaction SMILES: [C:1]1([C:7]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:15]3[CH:11]([CH2:12][N:13](C(OC=C)=O)[CH2:14]3)[C:10](=[O:21])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:28]>O1CCOCC1>[ClH:28].[C:22]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[C:10](=[O:21])[CH2:9][CH2:8]2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: C=COC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
(3aRS,7aRS)-7,7-Diphenyl-2-vinyloxycarbonylperhydro-4-isoindolone (177 g) is treated with a 5.7N solution (1000 cc) of hydrochloric acid in dry dioxane for 30 minutes at 20° C. The solution is concentrated to dryness under reduced pressure (2.7 kPa) and the residue taken up in ethanol (500 cc), and the reaction mixture is stirred at 60° C. for 30 minutes and then cooled to +5° C. The crystals obtained are drained, washed with ethanol (50 cc) and dried. (3aRS,7aRS)-7,7-Diphenylperhydro-4-isoindolone hydrochloride (130 g), m.p. 270° C. with decomposition, is obtained.
Reaction SMILES: [Br:1]CC1C2C(C=CC=1)=CC1C3C=CC=CC=3OC=1C=2.[CH3:20][C:21]1[CH:37]=[CH:36][C:24]2[S:25][C:26]3[CH:35]=[CH:34][C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:27]=3[C:23]=2[CH:22]=1>C(Cl)Cl>[Br:1][CH2:20][C:21]1[CH:37]=[CH:36][C:24]2[S:25][C:26]3[CH:35]=[CH:34][C:33]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:27]=3[C:23]=2[CH:22]=1
Reactant: BrCc1cccc2cc3c(cc12)oc1ccccc13
Reactant: Cc1ccc2sc3ccc4ccccc4c3c2c1
Solvent: ClCCl
Product: BrCc1ccc2sc3ccc4ccccc4c3c2c1
Yield: 39 %

Procedure:
Using the procedure outlined in 6A, 10-methyl-benzo[b]naphtho[1,2-d]thiophene (H. G. Pars Pharmaceutical Laboratories, Inc.) gave a 39.0% yield of 10-(bromomethyl)-benzo[b]naphtho[1,2-d]thiophene, mp 202°-203°, (CH2Cl2), (C,H,Br,S).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5]([C:7]1[CH:12]=[C:11]([NH:13][CH:14]2[CH2:17][CH2:16][CH2:15]2)[N:10]=[C:9]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:8]=1)=[O:6]>C1COCC1>[CH3:22][CH2:21][O:20][C:18]([C:9]1[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:12]=[C:11]([NH:13][CH:14]2[CH2:15][CH2:16][CH2:17]2)[N:10]=1)=[O:19]
Reactant: CCOC(=O)c1cc(C(=O)OC)cc(NC2CCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(=O)O)cc(NC2CCC2)n1
Reaction time: 1 h

Procedure:
Add 1 N lithium hydroxide (0.80 mL, 0.802 mmol) to a solution of 6-cyclobutylaminopyridine-2,4-dicarboxylic acid 2-ethyl ester 4-methyl ester (0.223 g, 0.802 mmol) in THF (2 mL) at 0° C. Stir for 1 h, acidify the solution to about pH =2, concentrate the solvent to one half volume. Partition the residue between ethyl acetate and water, and extract the aqueous layer with ethyl acetate (2×15 mL). Wash the combined organic extracts with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:13]2OC(=O)[S:15][N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:21]([C:27]([O:29][CH3:30])=[O:28])#[C:22][C:23]([O:25][CH3:26])=[O:24]>ClC1C=CC=CC=1Cl>[F:19][C:2]([F:20])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]([C:27]([O:29][CH3:30])=[O:28])[S:15][N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COC(=O)C#CC(=O)OC
Reactant: O=c1oc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ns1
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1snc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1C(=O)OC
Yield: 65.9 %

Procedure:
A solution of 20.7 g (0.0657 mol) of 5-(α,α,α,α',α',α'-hexafluoro-3,5-xylyl)-1,3,4-oxathiazol-2-one and 18.7 g (0.131 mol) of dimethyl acetylenedicarboxylate in 52 g of o-dichlorobenzene was held at reflux for 10 hours (gas chromatography assay revealed the product had formed in 77% yield) and was concentrated under vacuum to 90° at 0.5 torr. The residue was crystallized from methanol to give 17.9 g of solid, m.p. 71°-74°. The solid was recrystallized to give 14.3 g (53% yield) of white solid, m.p. 73°-75°.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH3:30].[OH-].[Na+]>C(O)C>[Br:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[CH:14][CH2:13][O:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]([CH3:30])[CH:8]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)COc1ccc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(OCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)ccc1OCC(=O)O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
{4-[3,3-Bis-(4-bromo-phenyl)-allyloxy]-2-methyl-phenoxy}-acetic acid methyl ester (1.9 g, 3.5 mmol) was dissolved in warm ethanol (100 ml). 1N NaOH (7 ml, 7 mmol) was added and the reaction mixture was stirred for 2 h at 60° C. after which it was evaporated. The residue was treated with water (50 ml) and 1N HCl (8 ml) and extracted with dichloromethane (2×250 ml). The combined organic phases were dried and evaporated to give the title compound in 1.8 g (99%) yield.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([OH:21])=O)[N:13]2[CH3:18])C1C=CC=CC=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:22][C:19]([C:12]2[N:13]([CH3:18])[C:14]3[C:10]([CH:11]=2)=[C:9]([OH:8])[CH:17]=[CH:16][CH:15]=3)=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cn1c(C(=O)O)cc2c(OCc3ccccc3)cccc21
Reactant: Nc1ccccc1
Product: Cn1c(C(=O)Nc2ccccc2)cc2c(O)cccc21

Procedure:
From 4-benzyloxy-1-methyl-1H-indole-2-carboxylic acid and aniline the title compound was prepared by a method analogous to that described in Example 11. MS ES (M++H)=267.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)([O-])=O.O.Cl>CCO>[CH3:20][N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:5]2[C:4]([NH2:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: CN1CCC(Nc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CN1CCC(Nc2ccc([N+](=O)[O-])cc2N)CC1
Temperature: 65 °C
Yield: 25.5 %

Procedure:
(2,4-Dinitro-phenyl)-(1-methyl-piperidin-4-yl)-amine 51 (1.50 g, 5.352 mmol) was dissolved in anhydrous EtOH (20 mL) in a 2 neck 250 mL argon purged flask. The reaction vessel was fitted with a condenser and dropping funnel and heated in an oil bath to 65° C. H2O (20 mL), EtOH (40 mL) and aqueous (NH4)2S (50 wt %, 2.55 g, 18.73 mmol) were charged to the dropping funnel and added to the hot reaction mixture dropwise over 30 minutes. The reaction was heated at 75° C. for 2 hours then cooled to room temperature overnight. Mixture was acidified by the addition of aqueous 4M HCl to adjust pH to 2. The reaction mixture was filtered to remove any insoluble material and the filtrate was concentrated under reduced pressure to remove EtOH. The resulting aqueous solution was basified by the addition of aqueous 2M ammonium hydroxide solution to adjust pH to 10. The aqueous solution was diluted with dichloromethane and transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with dichloromethane and the combined organic layers were washed with H2O, brine, and dried over magnesium sulphate, filtered and concentrated to afford a dark red oil. The product was purified using silica gel dry column chromatography with a solvent system of 5% 2M NH3 in methanol/95% dichloromethane to afford an orange solid 52 N1-(1-Methyl-piperidin-4-yl)-4-nitro-benzene-1,2-diamine Yield: 0.342 grams (25.5%). 1H NMR (DMSO) δ: 1.42-1.55 (m, 2H), 1.89-1.93 (m, 2H), 1.97-2.05 (m, 2H), 2.17 (s, 3H), 2.70-2.81 (m, 2H), 3.30-3.42 (m, 1H), 5.20 (br s, 2H), 5.63 (br d, 1H, J=7.4), 6.53 (d, 1H, J=9.0), 7.39 (d, 1H, J=2.9), 7.49 (dd, 1H, J=8.9, 2.7); MS (ESI): 251 (MH+, 100%).
Reaction SMILES: Br[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([NH:21]C(=O)OCC)[NH:6]2.[NH2:27][C@H:28]([CH2:31][CH3:32])[CH2:29][OH:30]>>[NH2:21][C:5]1[NH:6][C:7]2[C:3]([N:4]=1)=[C:2]([NH:27][C@H:28]([CH2:31][CH3:32])[CH2:29][OH:30])[N:10]=[C:9]([S:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1[F:20])[N:8]=2
Reactant: CCOC(=O)Nc1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]1
Reactant: CC[C@@H](N)CO
Product: CC[C@H](CO)Nc1nc(SCc2cccc(F)c2F)nc2[nH]c(N)nc12

Procedure:
The titled compound was prepared from the product of Example 5, step (e) (50 mg) and (2R)-2-amino-1-butanol (66 μl) using the method of example 5, step (f) and purified by preparative HPLC to yield a white solid.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][Si](C)(C)C)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH3:19][SiH:20]([CH3:26])[O:21][Si:22]([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.C1([Pt](Cl)Cl)C=CC=C1>[CH3:19][Si:20]([CH3:26])([CH:1]([O:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[O:21][Si:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: C[SiH](C)O[Si](C)(C)C
Reactant: C=CCCCCOc1ccc(O[Si](C)(C)C)cc1
Agent: Cl[Pt](Cl)C1C=CC=C1
Solvent: Cc1ccccc1
Product: CCCCCC(Oc1ccc(O)cc1)[Si](C)(C)O[Si](C)(C)C
Yield: 94 %

Procedure:
About 6.21 g (23.5 mMol) of 4-(5-hexenyloxy)-1-trimethylsilyloxy benzene, 3.48 g (23.5 mMol) of pentamethyldisiloxane and 694 mg (17.7 μMol of Pt) of 0.5 percent cyclopentadienylplatinum dichloride solution (dichloromethane) were refluxed for 7 hours in 25 ml of toluene. After the hydrosilylation was complete, the toluene was removed by vacuum distillation on a rotary evaporator. The crude product was purified by chromatography on silica gel. Further chromatography on silica gel using petroleum ether/ethyl acetate mixtures on a Harrison Research chromatotron gave 94 percent pure 4-(1-pentamethyldisiloxanylhexyloxy)phenol as a pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[CH2:19][O:20][CH2:21][C:22](O)=[O:23])=[C:13]([C:26]([O:28]C)=[O:27])[CH:12]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][C:13]=2[C:26]([OH:28])=[O:27])=[O:25])[CH:8]=1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Cc1ccc(Br)cc1N
Product: Cc1ccc(Br)cc1NC(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O

Procedure:
Using the same method as in Example 15-(i), 5-bromo-2-methylaniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 2-[((2-[(5-bromo-2-methylphenyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester (yield: 92%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:21]=[C:20]([C:22](O)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Cl.[CH3:26][O:27][C:28]1[C:37]([O:38][CH3:39])=[CH:36][CH:35]=[C:34]2[C:29]=1[CH2:30][CH2:31][NH:32][CH2:33]2>>[C:1]([NH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:21]=[C:20]([C:22]([N:32]3[CH2:31][CH2:30][C:29]4[C:34](=[CH:35][CH:36]=[C:37]([O:38][CH3:39])[C:28]=4[O:27][CH3:26])[CH2:33]3)=[O:23])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1OC)CCNC2
Reactant: CC(=O)NCc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(CNC(C)=O)cc3)nc3ccccc13)C2
Yield: 5 %

Procedure:
Reaction of 2-(4-(acetamidomethyl)phenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 67 (5% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 1.91 (s, 3H), 2.73 and 2.98 (2t, 2H), 3.48 and 4.03 (2t, 2H), 3.69-3.82 (4s, 6H), 4.34-4.36 (m, 2H), 4.41 and 4.93 (2s, 2H), 6.62 and 7.01 (2d, 1H), 6.80 and 7.08 (2d, 1H), 7.42-7.47 (m, 2H), 7.75-8.17 (m, 4H), 8.44-8.51 (m, 3H); MS (ESI) m/z 497 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:12]2[CH2:17][CH2:16][N:15]([C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(O)(=O)C>[C:30]1([N:11]([CH:12]2[CH2:13][CH2:14][N:15]([C@@H:18]3[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]3[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:16][CH2:17]2)[S:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:36](=[O:38])[CH3:37])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Nc1ccc(S(=O)(=O)N(c2ccccc2)C2CCN([C@@H]3CCCC[C@@H]3c3ccccc3)CC2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(S(=O)(=O)N(c2ccccc2)C2CCN([C@@H]3CCCC[C@@H]3c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of (+/−)-4-amino-N-phenyl-N-[cis-1-(2-phenyl-cyclohexyl)-piperidin-4-yl]-benzenesulfonamide (0.1 g, 0.2 mmol) in acetic acid (5 ml) was treated with acetic anhydride (1 ml) and stirred at room temperature for 1 h. The volatiles were evaporated and the residue was purified by flash chromatography on silica gel, eluting with dichloromethane/methanol/ammonia 110:10:1. The product was crystallised from hexane/ether, yielding the title compound (0.06 g, 59%) as a white solid, MS (ISP): m/e 532.5 (M+H+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=[CH2:21])[CH:15]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].[N+](=[C:24]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)=[N-]>C1C=CC=CC=1>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH2:21][CH:20]2[C:16]2[CH:15]=[C:14]([C:12]3[CH:13]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=[C:6]4[C:11]=3[N:10]=[CH:9][CH:8]=[CH:7]4)[CH:19]=[CH:18][CH:17]=2)=[CH:26][CH:27]=1
Reactant: C=Cc1cccc(-c2cc(C(C)C)cc3cccnc23)c1
Reactant: [N-]=[N+]=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Solvent: c1ccccc1
Product: CC(C)c1cc(-c2cccc(C3CC3(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c2)c2ncccc2c1
Temperature: 21 °C

Procedure:
A solution of the 6-isopropyl-8-(3-vinyl-phenyl)-quinoline from Step 3 (230 mg, 0.84 mmol) and the diazo bis-(4-chloro-phenyl)-methane from Step 2 (530 mg, 2.0 mmol) in benzene (10 mL) was heated to reflux for 18 h, cooled to 21° C., and purified by flash chromatography (eluting with hexane/ethyl acetate, 90:10) to provide the 8-{3-[2,2-bis-(4-chloro-phenyl)-cyclopropyl]-phenyl}-6-isopropyl-quinoline compound as a yellow foam.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:38]([O:41][CH3:42])[O:39][CH3:40])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2C(OCC1C=CC=CC=1)=O)(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:38]([O:39][CH3:40])[O:41][CH3:42])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[NH:13]2)(=[O:3])[CH3:2]
Reactant: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3C(N3C(=O)OCc3ccccc3)C(OC(C)=O)(O1)C2COC(N)=O
Agent: [Pd]
Solvent: CO
Product: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3NC3C(OC(C)=O)(O1)C2COC(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.2 %

Procedure:
To a solution of 11-benzyloxycarbonyl-8-carbamoyloxymethyl-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (100 mg) in methanol (10 ml) was added 10% palladium on carbon (50 mg). The mixture was stirred for 1 hour under hydrogen atmosphere (20 psi) at ambient temperature. The reaction mixture was filtered through cellulose powder and the filtrate was evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (10:1, v/v) to afford A-isomer of 8-carbamoyloxymethyl-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (31 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6]3=[N:13][C@@H:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[N:5]3[C:4]=2[N:3]=1.[C:19]([O:22][CH2:23]Br)(=[O:21])[CH3:20]>>[CH3:1][C:2]1[N:10]([CH2:23][O:22][C:19](=[O:21])[CH3:20])[C:9]2[C:8](=[O:11])[N:7]([CH3:12])[C:6]3=[N:13][C@@H:14]4[CH2:18][CH2:17][CH2:16][C@@H:15]4[N:5]3[C:4]=2[N:3]=1
Reactant: Cc1nc2c([nH]1)C(=O)N(C)C1=N[C@@H]3CCC[C@@H]3N12
Reactant: CC(=O)OCBr
Product: CC(=O)OCn1c(C)nc2c1C(=O)N(C)C1=N[C@@H]3CCC[C@@H]3N12

Procedure:
Treat 5,6a(R),7,8,9,9a(S)-hexahydro-2,5-dimethylcyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one from Example 19a with bromomethyl acetate in accordance with Example 47 to give the title compound as a powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][C:10](=O)[C:11]1[CH:16]=[C:15]([Br:17])[CH:14]=[CH:13][C:12]=1[F:18]>C(O)(=O)C>[Br:17][C:15]1[CH:14]=[CH:13][C:12]([F:18])=[C:11]([C:10]2[NH:1][C:2]3[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=3[N:9]=2)[CH:16]=1
Reactant: Nc1ccc(Cl)cc1NC(=O)c1cc(Br)ccc1F
Solvent: CC(=O)O
Product: Fc1ccc(Br)cc1-c1nc2cc(Cl)ccc2[nH]1
Temperature: 85 °C
Yield: 92.1 %

Procedure:
Method 7—Step b A mixture of N-(2-Amino-5-chloro-phenyl)-5-bromo-2-fluoro-benzamide (1.60 g, 4.67 mmol) in acetic acid (10 mL) was heated at 85° C. overnight. Solvent was removed under reduced pressure and the solid obtained was washed with dichloromethane and dried to obtain 1.40 g of the title compound (93%).
Reaction SMILES: Cl.[NH2:2][OH:3].[Br:4][CH2:5][C:6](=O)[C:7]([CH3:10])([CH3:9])[CH3:8].C(O)C>O>[Br:4][CH2:5][C:6](=[N:2][OH:3])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: NO
Reactant: CC(C)(C)C(=O)CBr
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(C)(C)C(CBr)=NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
A solution of 69.5 g (1.0 m) of hydroxylamine hydrochloride in 100 ml of water is chilled in an ice bath as 90 g (0.5 m) of 1-bromo-3,3-dimethyl-2-butanone is added. After addition of 100 ml of 95% ethanol, the mixture is stirred for 16 hours and allowed to warm to room temperature. The resulting white slurry is filtered, and the solid is washed with water and dried to give 55 g of the desired compound, m. 111°-112° C.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[N+](C1C=CC(O[C:36](=[O:44])[O:37][CH2:38][C:39]2[CH:43]=[CH:42][O:41][CH:40]=2)=CC=1)([O-])=O.C(N(CC)CC)C>C1COCC1>[O:41]1[CH:42]=[CH:43][C:39]([CH2:38][O:37][C:36](=[O:44])[N:2]([CH3:1])[CH:3]2[CH2:16][C:15]3[C:6]([CH3:25])([CH:7]4[CH:12]([CH2:13][CH:14]=3)[CH:11]3[CH2:17][CH2:18][CH:19]5[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]35[CH2:9][CH2:8]4)[CH2:5][CH2:4]2)=[CH:40]1
Reactant: O=C(OCc1ccoc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1C2CCC3C4CC=C5CC(N(C)C(=O)OCc6ccoc6)CCC5(C)C4CCC32CN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
Compound 7B (10 mg, 0.029 mmol), carbonic acid furan-3-ylmethyl ester 4-nitro-phenyl ester (2.4 mg, 0.032 mmol) and triethylamine (12.0 μL, 0.087 mmol) were dissolved in THF (1 mL) and stirred at room temperature overnight. The crude reaction mixture was purified on silica gel column using 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (10.1 mg, 74.2% yield).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30](Cl)[N:29]=[CH:28]2>>[Br:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[N:31]=[C:30]([NH:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11])[N:29]=[CH:28]2
Reactant: Clc1ncc2cc(Br)ccc2n1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc3cc(Br)ccc3n2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 6-bromo-2-chloroquinazoline. ESI-MS (m/z): 520, 522 [M]+[M+2]+.
Reaction SMILES: [N+:1]([C:4]([CH3:9])([CH2:7][OH:8])[CH2:5][OH:6])([O-:3])=[O:2].O1CC[CH2:13]OO1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[CH3:9][C:4]1([N+:1]([O-:3])=[O:2])[CH2:7][O:8][CH2:13][O:6][CH2:5]1
Reactant: C1COOOC1
Reactant: CC(CO)(CO)[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1([N+](=O)[O-])COCOC1

Procedure:
2-Nitro-2-methyl-1,3-propanediol 405.00 grams (3.00 moles), 98% trioxane 92.80 grams (1.00 mole), p-toluenesulfonic acid 3.00 grams (0.016 mole), and benzene 600 ml were placed in a two liter three-necked RB flask. The flask was fitted with a thermometer, a mechanical stirrer and a Dean-Stark trap connected to a condenser. The mixture was stirred and refluxed. The slurry gradually became a homogeneous solution (usually about 30 minutes after heating started) and the benzene-water azeotrope started to distill over. Refluxing was continued until 45 ml of water was collected (i.e., approximately four hours). During this period the solution temperature was between 78° C. and 82° C. After 45 ml of water had been collected, the reaction mixture was cooled and neutralized with 3 ml triethylamine. Benzene was distilled from the clear solution first at atmospheric pressure (approximately 415 ml benzene was recovered at a solution temperature of 82° C.-100° C.) and then at about 125 mm of pressure (approximately 120 ml benzene was recovered at a solution temperature of about 48° C.-110° C.). A clear, pale-yellow, viscous liquid, 450.67 grams, containing a mixture of the reaction products polynitroformal and 5-methyl-5-nitro-1,3-dioxane was obtained as the resulting product.