Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:5].[Mg+2].[CH3:15][N:16]1[C:21](=[O:22])[C:20]2[CH2:23][N:24]([CH2:27][CH2:28][S:29][CH3:30])[CH2:25][CH2:26][C:19]=2[NH:18][C:17]1=[O:31]>C(O)C>[CH3:15][N:16]1[C:21](=[O:22])[C:20]2[CH2:23][N:24]([CH2:27][CH2:28][S:29]([CH3:30])=[O:5])[CH2:25][CH2:26][C:19]=2[NH:18][C:17]1=[O:31]
Reactant: CSCCN1CCc2[nH]c(=O)n(C)c(=O)c2C1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: CCO
Product: Cn1c(=O)[nH]c2c(c1=O)CN(CCS(C)=O)CC2
Temperature: 55 °C
Reaction time: 2 h

Procedure:
21.8 g of magnesium monoperoxyphthalate (85% pure) were added at 55° C. over a period of 15 min to a solution of 19.5 g of 3-methyl-6-(2-methylsulfanylethyl)-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione in 200 ml of ethanol and the mixture was stirred for 2 h at 55° C. After the pH had been adjusted to 7.5, the mixture was concentrated under reduced pressure. The residue was boiled up several times with methanol, the combined methanol phases were concentrated and the residue was purified by chromatography in a medium-pressure column with silica gel using dichloromethane/methanol (volume ratio 95:5) as the eluent and by recrystallization from isopropanol.
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[N:87]1[CH:92]=[CH:91][N:90]=[CH:89][C:88]=1[CH2:93][C:94](O)=[O:95]>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:94](=[O:95])[CH2:93][C:88]1[CH:89]=[N:90][CH:91]=[CH:92][N:87]=1)[CH2:19][CH2:18]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)Cc1cnccn1
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cc3cnccn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 14 %

Procedure:
The title compound was prepared in 14% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-pyrazine acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 650.6 (M+H)+, 2.12 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=8.68-8.50 (m, 3H), 7.92 (d, J=8.2 Hz, 2H), 7.20 (d, J=8.2 Hz, 3H), 5.29 (dd, J=1.7, 6.0 Hz, 1H), 4.76 (s, 1H), 3.79 (q, J=14.3 Hz, 2H), 2.66-2.53 (m, 2H), 2.42-2.31 (m, 1H), 2.12 (dd, J=6.4, 17.1 Hz, 1H), 1.91-1.74 (m, 3H), 1.72 (br. s., 1H), 1.71 (s, 2H), 1.67 (d, J=11.9 Hz, 2H), 1.57-1.18 (m, 13H), 1.17-1.02 (m, 3H), 1.00 (br. s., 3H), 1.00 (br. s., 3H), 0.94 (s, 3H), 0.92 (br. s., 3H), 0.92 (br. s., 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][NH:14][C:15]=2[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:7][CH:6]=1.[CH3:24]I>CN(C)C=O.C(OCC)(=O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[N:14]=[CH:13][N:12]([CH3:24])[C:11]=2[C:8]2[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=2)=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2nc[nH]c2-c2ccc(OC)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ncn(C)c2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
1.8 g of sodium hydride (50% in white oil) is added in incremental portions to a solution of 10.5 g of 4,5-bis(4-methoxyphenyl)imidazole in 50 ml of absolute dimethylformamide. The mixture is agitated for another 30 minutes and then 5.35 g of methyl iodide in 50 ml of dimethylformamide is dropped thereto. After 60 minutes, the mixture is poured into ice water, the product taken up in ethyl acetate, the organic solution dried over sodium sulfate and concentrated under vacuum. The residue is recrystallized from benzene, thus obtaining 9.59 g of 4,5-bis(4-methoxyphenyl)-1-methylimidazole, mp 122°-123°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.CO[CH:14](OC)[N:15]([CH3:17])[CH3:16].C(OCC)C.O>CN(C=O)C>[CH3:14][N:15]([CH:17]=[CH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10])[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: Cc1ccc(F)cc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)C=Cc1ccc(F)cc1[N+](=O)[O-]
Temperature: 140 °C

Procedure:
To a solution of 4-fluoro-2-nitrotoluene (5 g, 32 mmol) in DMF (32 ml) was added dimethylformamide dimethyl acetal (5.56 ml, 42 mmol) and the mixture warmed at 140° C. for 18 hours in Argon atmosphere. Then the solution was allowed to reach room temperature and diethyl ether (100 ml) and water (100 ml) was added. The organic layer was washed with water (2×100 ml) and brine (1×100 ml), dried (MgSO4) and solvent concentrated at reduced pressure, affording N,N-dimethyl-2-(4-fluoro-2-nitrophenyl)ethenylamine as a red solid. No further purification was necessary.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH2:13][N:14]([CH3:39])[C:15]([N:17]2[CH2:30][CH2:29][C@:20]3([NH:24][C@H:23]([C:25]([O:27]C)=O)[CH2:22][CH2:21]3)[CH2:19][C@@H:18]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH3:42]>>[F:1][C:2]([F:40])([F:41])[C:3]1[CH:4]=[C:5]([CH2:13][N:14]([CH3:39])[C:15]([N:17]2[CH2:30][CH2:29][C@:20]3([NH:24][C@H:23]([C:25]([NH2:42])=[O:27])[CH2:22][CH2:21]3)[CH2:19][C@@H:18]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)[C@@H]1CC[C@@]2(CCN(C(=O)N(C)Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H](c3ccc(F)cc3C)C2)N1
Reactant: N
Product: Cc1cc(F)ccc1[C@H]1C[C@]2(CC[C@@H](C(N)=O)N2)CCN1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 94.9 %

Procedure:
In a sealed tube a solution of methyl(2S,5S,7R)-8-{[{[3,5-bis(trifluoromethyl)phenyl]methyl}(methyl)amino]carbonyl}-7-(4-fluoro-2-methylphenyl)-1,8-diazaspiro[4.5]decane-2-carboxylate (Intermediate 23, 80 mg, 0.136 mmol) in 7 M methanolic ammonia (5 ml, 35.0 mmol) was shaken overnight. The solvent was evaporated to dryness and the crude was purified by flash-chromatography (Si cartridge 5 g; from 1:0 to 95:5 DCM/MeOH) to give the title compound (74.4 mg, 0.129 mmol, 95% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.95 (s, 1H) 7.61 (s, 2H) 7.15-7.28 (m, 2H) 6.84-6.97 (m, 2H) 6.78 (t, 1H) 4.63 (d, 1H) 4.34 (d, 1H) 4.08-4.22 (m, 1H) 3.48-3.55 (m, 1H) 3.33-3.42 (m, 1H) 2.93 (s, 3H) 2.76 (t, 1H) 2.65 (br. s., 1H) 2.31 (s, 3H) 2.01-2.16 (m, 1H) 1.38-1.85 (m, 7H); HPLC: Rt=4.91 mins; MS: m/z=575 [M+H]+ and 597 [M+Na]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[Si:1]([O:8][CH2:9][CH:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 29 %

Procedure:
To a solution of 2-(tert-butyldimethylsilanyloxy)-1-phenylethanone (2.5 g, 10 mmol, Example 4) in methanol (30 ml) added with sodium borohydride (378 mg, 10 mmol) at room temperature. The mixture was stirred at room temperature for 5.5 hours and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=3/1) to give 2-(tert-butyldimethylsilanyloxy)-1-phenylethanol (0.73 g, 2.9 mmol, 29%) as a colorless oil.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1.N>>[CH3:10][O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([N+:6]([O-:9])=[O:7])=[CH:14][N:13]=1
Reactant: COc1ncccc1C
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: COc1ncc([N+](=O)[O-])cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
Concentrated sulfuric acid (5 ml) and fuming nitric acid (5 ml) were added to 2-methoxy-3-methylpyridine (1.61 g, 13.1 mmol) under ice cooling, and stirred at 0° C. for 1 hour and further stirred at room temperature overnight. The reaction mixture was poured onto ice, neutralized with ammonia solution, extracted with ethyl acetate, dried over magnesium sulfate, the solvent was evaporated, thereby yielding the title compound (1.63 g, 9.71 mmol, and 74%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]1[CH:24]=[N:23][C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[NH:18][C:13]=2[N:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27][O:28][CH2:29]Cl>O1CCCC1>[O:8]([CH2:9][CH2:10][C:11]1[CH:24]=[N:23][C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]([CH2:27][O:28][CH3:29])[C:13]=2[N:12]=1)[Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COCCl
Reactant: CC(C)(C)[Si](C)(C)OCCc1cnc2c(n1)Nc1ccccc1S2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN1c2ccccc2Sc2ncc(CCO[Si](C)(C)C(C)(C)C)nc21

Procedure:
603 mg of 8-[(2-(tert-butyldimethylsilyloxy)ethyl]-10H-pyrazino[2,3-b][1,4]benzothiazine was dissolved in 6 ml of tetrahydrofuran. After adding 63 mg of 70% sodium hydride, the resulting mixture was stirred under ice-cooling for 15 minutes. Then 0.14 ml of chloromethyl methyl ether was added thereto and the resulting mixture was stirred for 1 hour and for additional 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 463 mg of the title compound as a brown oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[S:28]([CH3:31])(=[O:30])=[O:29].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18]([C:24]4[CH:25]=[CH:26][C:27]([S:28]([CH3:31])(=[O:29])=[O:30])=[C:22]([F:21])[CH:23]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2nn3c(I)c(C)nc3s2)cc1OC
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2nn3c(-c4ccc(S(C)(=O)=O)c(F)c4)c(C)nc3s2)cc1OC
Temperature: 25 °C
Yield: 25.7 %

Procedure:
To a suspension of 2-(3,4-dimethoxy-phenyl)-5-iodo-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole (0.035 g, 0.087 mmol, 1 eq) in dioxane (1.8 mL), 3-fluoro-4-(methylsulfonyl)phenylboronic acid (0.047 g, 0.217 mmol, 2.5 eq), Pd(Ph3P)2Cl2 (0.006 g, 0.0087 mmol, 0.1 eq), potassium carbonate (0.06 g, 0.435 mmol, 5 eq) and water (0.8 mL) were added. The reaction mixture was subjected to MW irradiation (120° C., 35 min, 200 W), cooled to RT and concentrated. The residue was purified by silica gel chromatography (0-0.5% MeOH in DCM). Product fractions afforded an oily residue that was further purified by trituration with Et2O providing a pale yellow solid (0.02 g) and by preparative HPLC to give the pure product (0.010 g, 25%). HPLC-MS: (50-100% B in 8 min, 0.6 mL/min): tR=2.41 min, [M+H]+ m/z 448.1. 1H NMR (300 MHz, CDCl3) δ/ppm 8.03 (dd, J=8.3, 7.7, 1H), 7.81-7.70 (m, 2H), 7.39 (dt, J=3.4, 2.0, 2H), 6.94 (d, J=8.2, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 3.26 (s, 3H), 2.59 (s, 3H).
Reaction SMILES: [NH:1]([C:20]([O:22]C(C)(C)C)=O)[C@H:2]([C:13]([NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10].Cl.CCOC(C)=O.[N:34]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][CH2:46][C@H:35]1C(ON1C(=O)CCC1=O)=O>CCN(CC)CC>[N:34]1([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:48][CH2:47][CH2:46][C@H:35]1[C:20]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]([NH2:19])=[O:18])=[O:14])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:12])[NH:8][N+:9]([O-:11])=[O:10])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)NCC(N)=O

Procedure:
The desired compound was prepared from 6.0 g of Boc-Arg(NO2)-Gly-NH2, 40 ml of 4N HCl-AcOEt, 3.4 ml of Et3N and 5.1 g of Boc-Pro-OSu in the same manner as in Example 26-(4).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2([C:12]([O:14]C)=[O:13])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)[NH2:2].[CH:16](=O)[CH3:17].C(O)(=O)C.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C>[CH3:16][C:17]1[N:8]2[CH:7]=[C:6]([C:9]3([C:12]([OH:14])=[O:13])[CH2:11][CH2:10]3)[CH:5]=[CH:4][C:3]2=[N:1][N:2]=1
Reactant: COC(=O)C1(c2ccc(NN)nc2)CC1
Reactant: CC=O
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1nnc2ccc(C3(C(=O)O)CC3)cn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
To a solution of methyl 1-(6-hydrazinopyridin-3-yl)cyclopropanecarboxylate (150 mg, 0.72 mol) in ethanol (3 mL) was added acetaldehyde (33.5 mg, 0.760 mmol) and acetic acid (41 μL, 0.72 mmol). The mixture was stirred at RT for 2 h, and then concentrated to dryness. The residue was dissolved in methylene chloride (3 mL), and iodobenzene diacetate (256 mg, 0.796 mmol) was added dropwise. The reaction mixture was stirred at RT overnight. The reaction solution was concentrated to dryness. The residue was purified through silica gel chromatograph using 10% MeOH in CH2Cl2 to afford the desired compound (50 mg, 30%). Analytical LCMS: (M+H)+=218.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:26]N(C)C)=[CH:5][N:6]2[Si](C(C)(C)C)(C(C)(C)C)C(C)(C)C.CI.C[Si]([C:36]#[N:37])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:26][C:36]#[N:37])=[CH:5][NH:6]2
Reactant: COc1cc(Cl)c2c(CN(C)C)cn([Si](C(C)(C)C)(C(C)(C)C)C(C)(C)C)c2c1
Reactant: C[Si](C)(C)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CI
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(Cl)c2c(CC#N)c[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (4-Chloro-6-methoxy-1-tri-tert-butylsilanyl-1H-indol-3-ylmethyl)-dimethyl-amine (0.73 g, 1.85 mmol) in benzene (20 ml) was added methyl iodide (0.52 g, 3.71 mmol). After stirring at ambient temperature for 16 hours, the solvent was removed under reduced pressure. The residue was suspended in anhydrous tetrahydrofuran (10 ml). To this solution was added, sequentially, trimethylsilyl cyanide (0.27 g, 2.78 mmol) and tetrabutylammonium fluoride (1.45 g, 5.56 mmol, 1M in tetrahydrofuran, after which the solution was stirred for an hour. After solvent was removed under reduced pressure, the residue was partitioned between water and ether. The ether extract was dried (anhydrous sodium sulfate) and concentrated under reduced pressure to give (4-Chloro-6-methoxy-1H-indol-3-yl)-acetonitrile as solid (0.41 g, quantitative). 1H NMR (CDCl3) δ: 3.82 (s, 3H), 4.10 (d, 2H, J+1.17 Hz), 6.79 (d, 1H, J=2.07 Hz), 6.79 (d, 1H, J=2.07), 7.16 (m, 1H), 8.11 (b, 1H).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13](C(OC(C)(C)C)=O)[CH2:14][C:9]=2[CH2:8]1)=[O:6].[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[CH2:8]1[C:9]2[CH2:14][NH:13][CH2:12][C:10]=2[CH2:11][N:7]1[C:5]([C:4]1[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=1[C:2]([F:27])([F:1])[F:26])=[O:6]
Reactant: CC(C)(C)OC(=O)N1CC2=C(C1)CN(C(=O)c1ccccc1C(F)(F)F)C2
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(CNC2)C1

Procedure:
tert-Butyl 5-(2-trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrole-2-carboxylate (56.8 g) was stirred with 15 ml of 90 percent trifluoroacetic acid at RT for 3 h. The reaction mixture was concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 40.81 g (85%), M+H+: 283.14.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[CH:34]=[CH:33][C:22]([CH2:23][NH:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][N:24]([CH2:25][C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:17][CH:16]=2)=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN(Cc1ccc(Br)cc1)C(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Prepared using General Procedure 6: To a stirred solution of 4-((tert-butoxycarbonyl)amino)benzoic acid (2.0 g, 8.43 mmol), tert-butyl 2-((4-bromobenzyl)amino)acetate INT-60 (2.53 g, 8.43 mmol) and TEA (1.76 mL, 12.6 mmol) in DMF (15 mL) was added HATU (3.53 g, 9.27 mmol) at room temperature. After stirring at room temperature for 2 h the reaction mixture was diluted with EA (150 mL) and washed with brine (200 mL). The organics were concentrated in vacuo and the residue was purified by chromatography (EA/hexanes) to afford 3.97 g (91%) of tert-butyl 2-(N-(4-bromobenzyl)-4-((tert-butoxycarbonyl)amino)benzamido)acetate INT-61 as a viscous oil. LCMS-ESI (m/z) calculated for C25H31BrN2O5: 519; found: 517/519 [M−H]−, tR=2.68 min (Method 10).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:11]=[CH:10][NH:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[Br:12][CH2:13][CH2:14]Br.[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>[Br:12][CH2:13][CH2:14][N:9]1[C:4]2[N:5]=[C:6]([NH2:8])[N:7]=[C:2]([Cl:1])[C:3]=2[CH:11]=[CH:10]1
Reactant: BrCCBr
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(Cl)c2ccn(CCBr)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine (170 mg, 1.01 mmol), 1,2-dibromoethane (0.70 mL, 8.08 mmol), and tetra-n-butylammonium bromide (20 mg) are dissolved in THF (4 mL), and 30% aqueous NaOH (1.01 mL, 7.58 mmol) is added. The mixture is stirred for 24 h at RT, then partitioned between water and EtOAc. The aqueous solution is extracted with additional EtOAc, and the combined organic layers are dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated to dryness. The residue is purified by column chromatography on silica gel, eluting with 2:1-DCM:EtOAc. Fractions containing product are combined and evaporated to dryness to provide 7-(2-bromoethyl)-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine as a yellow solid: LC/MS (M+1=276.9). 1H NMR (CDCl3) δ 3.66 (t, 2H, J=8.0 Hz), 4.44 (t, 2H, J=8.0 Hz), 4.92 (br s, 2H), 6.39 (d, 1H, J=4.0 Hz), 6.92 (d, 1H, J=4.0 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].[C:29]([N:36]1[CH2:41][CH2:40][NH:39][CH:38]([CH3:42])[CH2:37]1)([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:39]2[CH2:40][CH2:41][N:36]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:37][CH:38]2[CH3:42])[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: O=Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC1CN(C(=O)OC(C)(C)C)CCN1Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carbaldehyde (Intermediate AAA1, 208 mg, 0.48 mmol) and 1-BOC-3-methylpiperazine (96 mg, 0.48 mmol) in dichloroethane (5 mL) was stirred at rt for 30 min. To this was added sodium triacetoxyborohydride (150 mg, 0.67 mmol) followed by acetic acid (29 mg, 0.48 mmol). The resulting reaction mixture was stirred at rt for 20 h. The reaction was quenched with 2N NaOH solution (6 mL) followed by extraction with ethyl acetate (100 mL×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate. Removal of the solvent and subsequent purification by flash chromatography using 25% acetone/hexane provided tert-butyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}-3-methylpiperazine-1-carboxylate as a white solid. 1H NMR (CDCl3, 500 MHz): δ 0.98 (s, 3H), 1.46 (s, 9H), 2.06 (brs, 1H), 2.39 (brs, 1H), 2.60 (brs, 1H), 2.82 (brs, 1H), 3.05 (brs, 1H), 3.15 (m, 1H), 3.54 (brs, 2H), 3.82 (brs, 1H), 4.34 (abq, 2H, J=14.2 Hz), 5.15 (s, 1H), 6.16 (d, 1H, J=5.2 Hz), 6.88 (s, 1H), 7.20-7.60 (m, 7H). MS (API-ES+): 617 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[NH2:6][C:7]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl.[C:20](Cl)(Cl)=[S:21]>O.ClC(Cl)Cl>[OH:18][C:15]1[CH:16]=[CH:17][C:7]([N:6]=[C:20]=[S:21])=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: S=C(Cl)Cl
Reactant: CCOC(=O)c1cc(O)ccc1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(O)ccc1N=C=S
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
To a stirred mixture of 5 parts of calcium carbonate, 18.75 parts of trichloromethane and 12.5 parts of water were added 3.6 parts of ethyl 2-amino-5-hydroxybenzoate. 3 Parts of concentrate hydrochloric acid and 10 parts of water were added and the whole was stirred for 15 minutes under nitrogen atmosphere. After cooling in an ice bath at 10° C., 2.6 parts of carbonothioic dichloride were added dropwise, during a period of 20 minutes, at 10°-15° C. The whole was allowed to reach room temperature and stirring was continued for 2 hours. 300 Parts of trichloromethane and 200 parts of water were added. The organic layer was separated, washed with a hydrochloric acid solution 1N and with a sodium hydrogen carbonate solution 10%, dried, filtered and evaporated. The residue was crystallized from 45 parts of benzene. The product was filtered off and dried, yielding 3.0 parts (67.1%) of ethyl 5-hydroxy-2-isothiocyanatobenzoate (18).