Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:17][C:18]1[CH:36]=[CH:35][C:21]([O:22][CH2:23][C:24]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:33]O)=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].CS(Cl)(=O)=O.C(N(CC)CC)C.[Br-:49].[Li+]>O1CCCC1.O>[Br:49][CH2:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[NH:26][C:24](=[O:25])[CH2:23][O:22][C:21]1[CH:35]=[CH:36][C:18]([O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:19][CH:20]=1
Reactant: [Br-]
Reactant: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Nc2ccccc2CO)cc1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOc1ccc(OCC(=O)Nc2ccccc2CBr)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 50.7 %

Procedure:
To a solution of 3.5 g of 2-[4-(hexadecyloxy)phenoxy]-N-[2-(hydroxymethyl)phenyl]acetamide and 1.29 g of methanesulfonyl chloride in 60 ml of tetrahydrofuran is added 853.89 mg of triethylamine followed by stirring at room temperature for 2.5 hours. Also added is 6.11 g of lithium bromide followed by stirring at room temperature for 4 hours. The mixture is poured into water and extracted with ether. The organic layer is dried and passed through a pad of magnesium silicate. The solvent is evaporated to a residue which is crystallized from hexane to give 2.0 g of the desired product as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([OH:32])=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=3)=[CH:18][C:17]=2[F:33])=[CH:12][N:11]=1>>[NH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:32][C:23]2[CH:24]=[C:25]([C:28]([F:29])([F:30])[F:31])[CH:26]=[CH:27][C:22]=2[C:19]2[CH:20]=[CH:21][C:16]([C:13]3[CH:12]=[N:11][C:10]([NH2:9])=[N:15][CH:14]=3)=[C:17]([F:33])[CH:18]=2)[N:7]=1
Reactant: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3O)cc2F)cn1
Reactant: Nc1ccnc(Cl)n1
Product: Nc1ccnc(Oc2cc(C(F)(F)F)ccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)n1

Procedure:
The title compound was prepared in a manner similar to that described in Example 555 using 2-chloropyrimidin-4-amine and 4′-(2-aminopyrimidin-5-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-ol. MS (ESI): mass calcd. for C21H14F4N6O, 442.12; m/z found, 443.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.46 (s, 2H), 7.80-7.74 (m, 1H), 7.74-7.67 (m, 1H), 7.67-7.62 (m, 1H), 7.52 (s, 1H), 7.51-7.44 (m, 1H), 7.44-7.31 (dd, J=17.9, 10.0, 2H), 6.20-6.08 (dd, J=6.0, 1.4, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH2:23]I)[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[C:1]([O:4][C@@H:5]1[O:22][C@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1O[C@H](CI)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1O[C@H](C)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Yield: 45.1 %

Procedure:
1,2,3,4-Tetra-O-acetyl-6-deoxy-6-iodo-β-D-glucopyranose (251.6 mg, 0.549 mmol) was dissolved in 20 mL of ethanol. To this solution was added 1 mL of triethylamine and 5% palladium on carbon (50.0 mg). The reaction mixture was exposed to 60 psi of hydrogen in a Parr apparatus at room temperature for 5 hours. The palladium on carbon was filtered off and the ethanol was removed in vacuo to yield a white solid. Purification via column chromatography over silica gel yielded 82.3 mg of the title compound as a white solid. (45%). MS(FAB) calculated for C14H20O9 (M+): 332.1. Found: 331.1.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1>>[Br:1][CH2:2][C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: Cc1ccc(N)nc1
Product: Cc1ccc(NC(=O)CBr)nc1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A16 (Step 5) starting from bromoacetyl bromide and 2-amino-5-picoline.
Reaction SMILES: [N:1]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7][CH2:6][CH2:5][C:4](=O)[C:3](=O)[CH2:2]1.N1(C(OCC)=O)CCC(=O)C(=O)CC1.Br.Br.[NH2:31][CH2:32][C:33]([NH2:35])=[NH:34]>>[NH2:35][C:33]1[CH:32]=[N:31][C:5]2[CH2:6][CH2:7][N:1]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][CH2:3][C:4]=2[N:34]=1
Reactant: CCOC(=O)N1CCCC(=O)C(=O)C1
Reactant: N=C(N)CN
Agent: Br
Agent: CCOC(=O)N1CCC(=O)C(=O)CC1
Product: CCOC(=O)N1CCc2ncc(N)nc2CC1

Procedure:
This compound was prepared analogous to Example 13 by reacting a mixture of ethyl hexahydroazepine-3,4-dione-1-carboxylate and ethyl hexahydroazepine-4,5-dione-1-carboxylate (prepared from ethyl hexahydroazepine-4-one-1-carboxylate by selenium dioxide oxidation) with 2-amino-acetamidine dihydrobromide.
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([NH:18][C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1.[CH2:22](C(C)=O)C(C)C.[OH-].[K+].COS(=O)(=O)OC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Br:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([N:18]([CH3:22])[C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(=O)CC(C)C
Reactant: CC(=O)Nc1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CC(=O)N(C)c1ccc(Br)c2c1C(=O)c1ccccc1C2=O
Temperature: 30 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
A mixture of 4-bromo-1-acetylaminoanthraquinone (purity 98%, 35.1 g), methyl isobutyl ketone (500 g), tetra-n-butyl ammonium bromide (0.3 g) and 96% potassium hydroxide (12.0 g) was stirred for 1 hour while being maintained at 30° C. Dimethylsulfuric acid (25.2 g) was dropped at 30° C. over 2 hours. The mixture was stirred at 30° C. for 1 hour, 40° C. for 2 hours and 50° C. for 4 hours, successively. After water (250 g) was added, the solution was stirred for 1 hour, while being maintained at 50° C. Then, the same procedure as in Example 3 was applied to obtain, after methyl isobutyl ketone was recovered, 4-bromo-N-acetyl-1-methylaminoanthraquinone (34.8 g, purity 93.6%, yield 91.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C([O:13][CH2:14][CH:15]1[N:25]2[C:26]3[C:21]([C:22](=[O:32])[C:23]([C:27](OCC)=[O:28])=[CH:24]2)=[CH:20][C:19]([I:33])=[CH:18][C:17]=3[CH2:16]1)(=O)C>C(Cl)Cl.CCOC(C)=O.CO>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:27]([C:23]2[C:22](=[O:32])[C:21]3[C:26]4=[C:17]([CH2:16][CH:15]([CH2:14][OH:13])[N:25]4[CH:24]=2)[CH:18]=[C:19]([I:33])[CH:20]=3)=[O:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn2c3c(cc(I)cc3c1=O)CC2COC(C)=O
Reactant: NCc1ccc(Cl)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(I)cc3c1=O)CC2CO
Temperature: 100 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of 4-chlorobenzylamine (2 mL) and ethyl 2-((acetyloxy)methyl)-8-iodo-6-oxo-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinoline-5-carboxylate (Preparation 9, 0.70 g) is heated to 120° C. under a stream of nitrogen for 7 h, to 100° C. for 18 h, and then to 130° C. for 8 hours. Upon cooling, the mixture is diluted with a mixture of CH2Cl2, EtOAc, and methanol (2/2/1) and absorbed onto silica gel. This material is chromatographed eluting with 0-4% methanol in CH2Cl2 to give a wet brown solid. The crude product is recrystallized by dissolving in hot acetic acid and slowly adding water until cloudiness persisted. Upon standing, crystals form which are collected to provide 340 mg (43%) of the title compound as a tan solid. Physical characteristics: M.p. 222-223° C.; MS (ESI+) m/z 495 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C[N:9]([CH3:39])[C:10]1[CH:15]=[C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=2)[NH:21][CH:20]=[C:19]3[CH:28]2[CH2:33][CH2:32][N:31]([S:34]([CH2:37][CH3:38])(=[O:36])=[O:35])[CH2:30][CH2:29]2)[CH:13]=[CH:12][N:11]=1.CNC>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:37]([S:34]([N:31]1[CH2:32][CH2:33][CH:28]([C:19]2[C:18]3[C:22](=[C:23]([C:25]([NH2:27])=[O:26])[CH:24]=[C:16]([C:14]4[CH:13]=[CH:12][N:11]=[C:10]([NH:9][CH2:39][CH2:2][CH3:3])[CH:15]=4)[CH:17]=3)[NH:21][CH:20]=2)[CH2:29][CH2:30]1)(=[O:36])=[O:35])[CH3:38]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccnc(N(C)C)c4)cc23)CC1
Agent: CNC
Solvent: O=C(O)C(F)(F)F
Product: CCCNc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)ccn1
Yield: 33.5 %

Procedure:
The title compound was prepared according to the general procedure of 5-[2-(dimethylamino)-4-pyridinyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting propylamine (1 mL) for dimethylamine to afford 18.2 mg of the title compound (33.5%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[F:29][C:30]1[CH:35]=[C:34](F)[CH:33]=[C:32]([F:37])[C:31]=1[N+:38]([O-:40])=[O:39].C([O-])([O-])=O.[K+].[K+]>CN(P(N(C)C)(N(C)C)=O)C.CCOC(C)=O.O>[CH:1]1([C:4]2[C:5]([N:24]([C:34]3[CH:33]=[C:32]([F:37])[C:31]([N+:38]([O-:40])=[O:39])=[C:30]([F:29])[CH:35]=3)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1F
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(F)c([N+](=O)[O-])c(F)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 50 °C
Reaction time: 15 h
Yield: 66 %

Procedure:
A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (1.00 g, 2.49 mmol), 1,3,5-trifluoro-2-nitrobenzene (0.91 g, 5.11 mmol), K2CO3 (1.06 g, 7.67 mmol) in HMPA (7 mL) was stirred at 50° C. for 8 h. An additional portion of 1,3,5-trifluoro-2-nitrobenzene (0.91 g, 5.11 mmol) was added and the reaction mixture was stirred at 50° C. for another 15 h. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, and evaporated. The residue was taken up in 1:1 CH2Cl2:acetone. The desired isomer precipitated out and was collected by vacuum filtration and dried to afford the title compound (0.92 g, 65%) as a white solid. LCMS (m/z, ES+)=560.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:8]=2[CH3:13])[N:3]=1.CO>[Pt]=O.CCO>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:8]=2[CH3:13])[N:3]=1
Reactant: CCCCCCC=Cc1ccc2nc(N)nc(N)c2c1C
Agent: O=[Pt]
Solvent: CCO
Solvent: CO
Product: CCCCCCCCc1ccc2nc(N)nc(N)c2c1C
Reaction time: 60 h

Procedure:
A mixture of 12.6 g of the olefin mixture of Example 5, 2.0 g of platinum oxide, and 500 ml of methanol was stirred under an atmosphere of hydrogen for 60 h. The catalyst was removed by filtration through a celite pad and the filtrate was evaporated in vacuo. The solid residue was recrystallized from ethanol to afford 10.6 g (83%), m.p. 262°-264° C.; UV (95% EtOH; pH 12). 238 (43,600), 272 (10,900), 347 (5,930); NMR (CDCl3 --CD3OD) 0.89 (3H, t, CH3CH2 --), 1.32 (12H, m, CH2), 2.72 (3H, s, 5--CH3), 2.72 (2H, t, Ar--CH2), 7.20 (1H, d, C7 --H), 7.47 (1H, d, C8 --H). Anal. calc'd for C17H26N4.HCl: C, 63.2; H, 8.43; N, 17.3; Cl, 11.0. Found: C, 63.3; H, 8.46; N, 17.3; Cl, 10.9.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C:11]=3[C:12](=[O:40])[CH2:13][C@@H:14]2[C@H:15]([CH3:30])[CH2:16][CH:17](I)[CH2:18][C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH2:6]1)(=[O:3])[CH3:2].N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC.O>O1CCCC1>[C:1]([O:4][C@H:5]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@@H:7]([CH2:8][CH2:9][C:10]3[C@@H:34]2[CH2:33][CH2:32][C@@:31]2([CH3:39])[C:11]=3[C:12](=[O:40])[CH2:13][C@@H:14]2[C@H:15]([CH3:30])[CH2:16][CH2:17][CH2:18][C:19]([F:28])([C:24]([F:25])([F:26])[F:27])[C:20]([F:22])([F:23])[F:21])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CCC3=C4C(=O)C[C@H]([C@H](C)CC(I)CC(F)(C(F)(F)F)C(F)(F)F)[C@@]4(C)CC[C@@H]32)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CCC3=C4C(=O)C[C@H]([C@H](C)CCCC(F)(C(F)(F)F)C(F)(F)F)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 5 h
Yield: 83.2 %

Procedure:
To a solution of 3β-acetoxy-23ξ-iodo-25,26,26,26,27,27,27-heptafluoro-5α-cholest-8(14)-en-15-one (310 mg; 0.446 mmol) and 2,2'-azobisisobutyronitrile (10 mg) in tetrahydrofuran (4 ml) was added tributyltin hydride (0.15 ml; 0.603 mmol) under argon. After 5 h, water (20 ml) was added and the resulting mixture was extracted twice with ether (10 ml portions). The ether solution was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness. The residue (300 mg) was subjected to chromatography on a silica gel (6 g) column. Using 4% ethyl acetate in hexane as the eluting solvent, fractions 8 ml in volume were collected. The contents of fractions 20-56 were pooled (227 mg) and recrystallized from methanol to give 3β-acetoxy-25,26,26,26,27,27,27-heptafluoro-5α-cholest-8(14)-en-15-one (211 mg; 83% yield); MP 187°-188° C. The product showed a single component on TLC in one solvent system (35% ether in hexane, Rf 0.45) and one major (~ 98%) component (Rf 0.45) and a minor component (Rf 0.485) in another solvent system (15% ethyl acetate in hexane). The structure was confirmed by I.R., N.M.R., and M.S. analyses.
Reaction SMILES: [C:1](Cl)(=O)C.[C:5]1([C:11]2[S:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][N:15]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[C:5]1([C:11]2[S:12][C:13]([C:16]([O:18][CH3:1])=[O:17])=[CH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1cnc(-c2ccccc2)s1
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cnc(-c2ccccc2)s1

Procedure:
2.5 ml of acetyl chloride were added to a solution of 4.77 g of the acid of Stage B in 160 ml of methanol, and the mixture was refluxed for 18 hours. After evaporating to dryness under reduced pressure, the residue was taken up in ethyl acetate. The mixture was filtered and concentrated to a reduced volume. The crystals were separated off and the mother liquors were washed with sodium hydroxide. Extraction was carried out with ethyl acetate, followed by washing with water and evaporating to dryness. The 2 crystallized fractions were combined to obtain 4.54 g of the desired product melting at 108° C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([NH:18][CH3:19])=[CH:14][N:13]=3)[CH:9]=2)[CH:4]=[C:3]1[C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)=[O:21].C(N(CC)CC)C.Cl[C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][C:52]=1[O:61][C:62](=[O:64])[CH3:63])=[O:50].O>CCOC(C)=O>[CH3:19][N:18]([C:15]1[CH:14]=[N:13][C:12]([O:11][C:8]2[CH:9]=[C:10]3[C:5]([CH:4]=[C:3]([C:20]([N:22]4[CH2:23][CH2:24][N:25]([CH2:28][C:29]5[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:31][CH:30]=5)[CH2:26][CH2:27]4)=[O:21])[N:2]3[CH3:1])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[C:49]([C:51]1[CH:56]=[CH:55][C:54]([C:57]([F:59])([F:60])[F:58])=[CH:53][C:52]=1[O:61][C:62](=[O:64])[CH3:63])=[O:50]
Reactant: CNc1ccc(Oc2ccc3cc(C(=O)N4CCN(Cc5ccc(OCC(F)(F)F)cc5)CC4)n(C)c3c2)nc1
Reactant: CC(=O)Oc1cc(C(F)(F)F)ccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Oc1cc(C(F)(F)F)ccc1C(=O)N(C)c1ccc(Oc2ccc3cc(C(=O)N4CCN(Cc5ccc(OCC(F)(F)F)cc5)CC4)n(C)c3c2)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
To a stirred solution of 2-acetoxy-4-trifluoromethyl-benzoic acid (180 mg, 0.73 mmol) in CH2Cl2 (6 mL) were added oxalyl chloride (0.08 mL, 0.91 mmol) and DMF (1 drop). The reaction mixture was stirred at room temperature for 1 hour. CH2Cl2 and excess oxalyl chloride were removed in vacuo. Acetic acid 2-chlorocarbonyl-5-trifluoromethylphenyl ester was obtained as a colorless oil (190 mg) and used in the following step without further purification. To a stirred solution of [1-Methyl-6-(5-methylaminopyridin-2-yloxy)-1H-indol-2-yl]{4-[4-(2,2,2-tri-fluoroethoxy)benzyl]piperazin-1-yl}methanone (340 mg, 0.6 mmol) in AcOEt (4 mL) were added triethylamine (0.13 mL, 0.91 mmol) and acetic acid 2-chlorocarbonyl-5-trifluoromethyl-phenyl ester (190 mg, 0.73 mmol) in AcOEt (3 mL) under ice cooling. The reaction mixture was stirred for 10 minutes at 0° C. Water was added to the reaction mixture, and the aqueous layer was extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=50:1) to afford 0.46 g of the title compound as a white powder.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=2)=[N:5][C:6]([S:24][CH3:25])=[N:7][C:8]=1[CH2:9][CH2:10][CH:11](C(OCC)=O)[C:12]([O:14][C:15](C)([CH3:17])C)=[O:13])#[N:2].Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[NH2:2][C:1]1[C:3]2[C:4]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)=[N:5][C:6]([S:24][CH3:25])=[N:7][C:8]=2[CH2:9][CH2:10][C:11]=1[C:12]([O:14][CH2:15][CH3:17])=[O:13]
Reactant: CCOC(=O)C(CCc1nc(SC)nc(-c2cccc([N+](=O)[O-])c2)c1C#N)C(=O)OC(C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C1=C(N)c2c(nc(SC)nc2-c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl ethyl {2-[5-cyano-2-methylthio-4-(3-nitro-phenyl)-pyrimidin-6-yl]-ethyl}-malonate (example 27c, 1.40 g) in CH2Cl2 (15 ml) was cooled to 0° C. A solution of SnCl4 (1 M in CH2Cl2, 11.5 ml) was added dropwise, the ice-bath removed and the solution was stirred for an additional 30 min at room temperature. Water (64 ml) and EtOAc (64 ml) were added and the mixture was vigorously stirred until al solids dissolved. The organic phase was washed with water and brine, dried (MgSO4) and concentrated under reduced pressure, giving the title compound as a crude product.
Reaction SMILES: [C:1]1([O:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(O)C=C(Cl)C=1.[N+](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.ClC1C=C(ON)C=C(Cl)C=1.[CH3:42][C:43]([C:46]([NH:48][C:49]1[N:58]=[C:57]([NH:59][C:60]([C:62]([CH3:65])([CH3:64])[CH3:63])=[O:61])[C:56]2[CH2:55][C:54](=O)[CH2:53][CH2:52][C:51]=2[N:50]=1)=[O:47])([CH3:45])[CH3:44]>C(O)C>[CH3:45][C:43]([C:46]([NH:48][C:49]1[N:58]=[C:57]([NH:59][C:60]([C:62]([CH3:65])([CH3:64])[CH3:63])=[O:61])[C:56]2[CH2:55][C:54](=[N:8][O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:53][CH2:52][C:51]=2[N:50]=1)=[O:47])([CH3:42])[CH3:44]
Reactant: NOc1ccccc1
Reactant: CC(C)(C)C(=O)Nc1nc2c(c(NC(=O)C(C)(C)C)n1)CC(=O)CC2
Agent: NOc1cc(Cl)cc(Cl)c1
Agent: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: Oc1cc(Cl)cc(Cl)c1
Solvent: CCO
Product: CC(C)(C)C(=O)Nc1nc2c(c(NC(=O)C(C)(C)C)n1)CC(=NOc1ccccc1)CC2

Procedure:
When the bridging group n is =NO--, 2,4-diamino-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal is prepared from 1,4-cyclohexanedione mono-ethylene ketal and cyanoguanidine, as previously described. The 2,4-diamino moieties are then protected by the reaction of 2,4-diamino-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal with pivalic anhydride in the presence of 4-dimethylaminopyridine, yielding 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydroquinazoline 6-ethylene ketal. The 6-ethylene ketal functional group is then cleaved from the so-prepared molecule with acetic acid and water, affording the corresponding 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone. A second intermediate, an O-(phenyl)hydroxylamine, is prepared by the reaction of an appropriately substituted or unsubstituted phenol, for example, 3,5-dichlorophenol, with O-(2,4-dinitrophenyl)hydroxylamine [prepared by the method of T. Sheradsky et al (Tetrahedron, 28, 3833 (1972)). The so-prepared O-(phenyl)hydroxylamine, for example, O-(3,5-dichlorophenyl)hydroxylamine, is then reacted with the 2,4-di[(1,1-dimethylethyl)carbonylamino]-5,6,7,8-tetrahydro-6-quinazolinone in ethanol, yielding the corresponding 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline. Treatment of the 2,4-di[(1,1-dimethylethyl)carbonylamino]-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline with methanolic hydrochloric acid yields the targeted 2,4-diamino-6-phenoxyimino-5,6,7,8-tetrahydroquinazoline. Example 12 provides a detailed description of how this reaction is conducted.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[CH3:11][C:12]([CH3:15])([O-:14])[CH3:13].[K+].O>COCCOC>[CH3:11][C:12]([O:14][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5])([CH3:15])[CH3:13]
Reactant: CC(C)(C)[O-]
Reactant: N#Cc1c(F)cccc1Cl
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)Oc1cccc(Cl)c1C#N
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 2-fluoro-6-chlorobenzonitrile (10.35 g, 66.5 mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. was added potassium t-butoxide (9.06 g, 80.7 mmol). The mixture was slowly allowed to warm to room temperature over 3 h. The reaction was poured into water and extracted with ether (3 times). The organic layers were washed with brine, dried (MgSO4) and concentrated to afford 13.52 g (97%) of 2-[(1,1-dimethylethyl)oxy]-6-chlorobenzonitrile as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1.[C:16]([Si:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH3:19])([CH3:18])[CH3:17].N1C=CN=C1.O>CN(C)C=O>[O:1]([CH2:2][C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:5]=2[N:4]=1)[Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cccc2[nH]c(CO)nc12
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2[nH]c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Reaction time: 28 h
Yield: 67.2 %

Procedure:
To a solution of methyl 2-hydroxymethyl-1H-benzimidazole-4-carboxylate (1.0 g) in N,N-dimethylformamide (10 ml) were added tert-butylchlorodiphenylsilane (1.87 g) and imidazole (495 mg) at ambient temperature and the mixture was stirred at the same temperature for 28 hours. The reaction mixture was poured into water and the aqueous solution was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (10:1) to give methyl 2-tert-butyldiphenylsiloxymethyl-1H-benzimidazole-4-carboxylate (1.45 g) as an oil.