Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([Cl:12])[CH2:4][C:5](Cl)([Cl:10])[C:6]([F:9])([F:8])[F:7].C(CN)O>CN(C)C=O>[Cl:10][C:5](=[CH:4][CH:3]([Cl:12])[CH:2]([CH3:1])[CH3:13])[C:6]([F:7])([F:8])[F:9]
Reactant: CC(C)C(Cl)CC(Cl)(Cl)C(F)(F)F
Solvent: NCCO
Solvent: CN(C)C=O
Product: CC(C)C(Cl)C=C(Cl)C(F)(F)F
Temperature: 96 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
A mixture comprising 5-methyl-2,2,4-trichoro-1,1,1-trifluorohexane (51.5 g), monoethanolamine (6.1 g), cuprous chloride (0.1 g) and dimethylformamide (100 ml) is stirred and heated at 96° C. (internal temperature) under a nitrogen atmosphere. When the initial green colour of the mixture is discharged further aliquots of monoethanolamine are added until a geen colour persists and GLC analysis shows that the starting material has been consumed. The reaction is complete after 5 hours. The crude product is isolated by precipitation with water, extraction with dichloromethane and removal of the solvent under reduced pressure. Distillation affords 2,4-dichloro-5-methyl-1,1,1,trifluorohex-2-ene (71%), b.p. 79°-82° C./100 mm Hg; 'Hnmr (CDCl3)τ9.2-8.8 (q, 6H); 8.2-7.8 (m, H); 5.6-5.3 (m, H); 3.9-3.4 (pair of doublets, H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9](=O)[CH3:10])=[C:4]([F:12])[CH:3]=1.[NH3:13].[BH4-].[Na+].[OH-].[NH4+]>C(O)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH:9]([NH2:13])[CH3:10])=[C:4]([F:12])[CH:3]=1
Reactant: CC(=O)c1c(F)cc(Br)cc1F
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CC(N)c1c(F)cc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 62 %

Procedure:
To a mixture of 1-(4-bromo-2,6-difluorophenyl)ethanone (450 mg, 0.91 mmol), titanium isopropoxide (1.14 mL, 4.61 mmol) in ethanol (10 mL) was added a solution of 2M ammonia in ethanol (4.8 mL, 9.6 mmol), and the resulting mixture was stirred at room temperature. After 18 hours, sodium borohydride (115 mg, 3.48 mmol) was added and stirring was continued at room temperature for three hours. The reaction mixture was poured into a 2M aqueous ammonium hydroxide solution (100 mL) then filtered. The filtrate was extracted with ethyl acetate (3×50 mL), and the combined extract was washed with water (100 mL), then brine (100 mL), dried over sodium sulfate, filtered and concentrated to give 1-(4-bromo-2,6-difluorophenyl)ethanamine (236 mg, 62% yield), MS (EI) for C8H8BrF2N: 237 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[C:4]([CH3:12])[N:3]=1.C(N(CC)CC)C.[CH3:20][CH:21]([CH3:24])[CH2:22][NH2:23]>CN(C)C=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:23][CH2:22][CH:21]([CH3:24])[CH3:20])[CH:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Reactant: CC(C)CN
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(NCC(C)C)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 2,4-dichloro-6-methyl-3-nitropyridine (125 g, 0.604 mol) in anhydrous N,N-dimethylformamide (625 mL) was cooled to 0° C. Triethylamine (84.2 mL, 0.604 mol) was added. 2-Methylpropylamine (66 mL, 0.664 mol) was added dropwise to the resulting solution over a period of one hour; the reaction reached a temperature of 17° C. and became yellow. The reaction was allowed to warm to room temperature and stir overnight. The reaction mixture was filtered to remove salts, and then the N,N-dimethylformamide was removed under reduced pressure. The crude product was dissolved in ethyl acetate (750 mL), and the solution was washed with water (3×1 L), dried over magnesium sulfate, and then concentrated under reduced pressure. Hexane (300 mL) was added to the resulting yellow oil; the mixture was heated until the oil dissolved and then placed in a freezer. After ten minutes, the recrystallization mixture was seeded with crystals made in a previous run and then left undisturbed for four hours. The resulting precipitate was filtered, washed with cold hexane, and dried in a vacuum oven at room temperature to provide 98 g of 2-chloro-N-(2-methylpropyl)-6-methyl-3-nitropyridin-4-amine.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][CH2:12][N:13]([CH3:31])[CH2:14][CH2:15][C:16]1([OH:30])[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:26])[CH:22]=2)[CH:17]1[CH:27]([CH3:29])[CH3:28].[CH3:32][O:33][CH2:34][C:35]([OH:37])=[O:36]>>[CH3:32][O:33][CH2:34][C:35]([OH:37])=[O:36].[CH3:32][O:33][CH2:34][C:35]([O:30][C:16]1([CH2:15][CH2:14][N:13]([CH2:12][CH2:11][CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH3:31])[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:26])[CH:22]=2)[CH:17]1[CH:27]([CH3:28])[CH3:29])=[O:36]
Reactant: CC(C)C1c2ccc(F)cc2CCC1(O)CCN(C)CCCc1nc2ccccc2[nH]1
Agent: COCC(=O)O
Product: COCC(=O)OC1(CCN(C)CCCc2nc3ccccc3[nH]2)CCc2cc(F)ccc2C1C(C)C

Procedure:
The method of claim 9 further including the step of contacting the thus-formed 2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-ol with methoxyacetic acid or an activated derivative of methoxyacetic acid to form 2-[2-{[3-(1H-benzimidazol-2-yl)propyl]methylamino}ethyl]-6-fluoro-1-isopropyl-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:42][O:43][CH2:44][CH2:45][NH2:46]>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([NH:46][CH2:45][CH2:44][O:43][CH3:42])[N:4]=1
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Reactant: COCCN
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCCNc1ncc(-c2ccc(Oc3ccnc(-c4cnn(C)c4)c3)c(C)n2)c(OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A solution of Example C2 (0.15 g, 0.36 mmol) in DCM (5 mL) was treated portion-wise with mCPBA (0.11 g, 0.43 mmol), stirred at RT overnight, treated with 2-methoxyethanamine (0.5 mL) and stirred at RT for 4 h. The mixture was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to obtain 4-methoxy-N-(2-methoxyethyl)-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-2-amine (100 mg, 63%). MS (ESI) m/z: 448.2 (M+H+).
Reaction SMILES: C1C=C(SSC2N=CC=CC=2)N=CC=1.C(N(CC)CC)C.[SH:22][CH2:23][C:24]([OH:26])=[O:25].[C:27]([SH:31])([CH3:30])([CH3:29])[CH3:28]>O1CCCC1.CCOCC>[C:27]([S:31][S:22][CH2:23][C:24]([OH:26])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)S
Reactant: O=C(O)CS
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)SSCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 11 g (50 mmol) of 2-,2′-dipyridyl disulfide and 8.4 mL (60 mmol) of triethyl amine in 100 mL of tetrahydrofuran at 0° C. as added 2.8 mL (40 mmol) of mercaptoacetic acid in 5 mL of tetrahydrofuran. The ice bath was removed and after one hour 6.8 mL (65 mmol) tert-butyl thiol was added. The reaction was allowed to stir overnight at ambient temperature before diluting with ether and washing three times with 1N aqueous HCl. The product was then extracted into 10% aqueous NaOH. The aqueous phase was washed twice with ether and then acidified with HCl to pH ˜3.5. The product was extracted with ether, dried with Na2SO4, filtered and evaporated under reduced pressure to give a crude product. This material was distilled by Kugelrohr distillation to give 6.6 g (37 mmol, 92%) of partially purified product. This material was used in the next step without further purification.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([NH:26][CH:27]([B:30]3[O:34][C:33]([CH2:36][CH2:37][CH:38]([CH3:47])[CH2:39][C:40]([O:42]C(C)(C)C)=[O:41])([CH3:35])[C:32]([CH3:49])([CH3:48])[O:31]3)[CH2:28][CH3:29])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O.ClCCl>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:24]([NH:26][CH:27]([B:30]3[O:34][C:33]([CH2:36][CH2:37][CH:38]([CH3:47])[CH2:39][C:40]([OH:42])=[O:41])([CH3:35])[C:32]([CH3:48])([CH3:49])[O:31]3)[CH2:28][CH3:29])=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCC(NC(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)B1OC(C)(C)C(C)(CCC(C)CC(=O)OC(C)(C)C)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(NC(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)B1OC(C)(C)C(C)(CCC(C)CC(=O)O)O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.2 %

Procedure:
50 mg (0.074 mmol) of tert-butyl 5-[2-[1(RS)-[[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]amino]propyl]-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvalerate were dissolved in 1 ml of trifluoroacetic acid and 1 ml of dichloromethane. The solution was stirred at room temperature for 15 minutes and then evaporated under a vacuum. The residue was co-evaporated with toluene to give 46 mg of 5-[2-[1(RS)-[[N-[(9-fluorenyl)methoxycarbonyl]-L-leucyl]amino]propyl]-4(RS),5,5-trimethyl-1,3,2-dioxaborolan-4-yl]-3(RS)-methylvaleric acid as an oil; MS: m/e 621 [M+H]+.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:11]=[CH:10][O:9][CH:8]=1.CON(C)[C:15](=[O:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].C([O-])(O)=O.[Na+]>CCOCC.C1COCC1>[O:9]1[CH:10]=[CH:11][C:7]([C:15](=[O:25])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:8]1
Reactant: Brc1ccoc1
Reactant: CON(C)C(=O)CNC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(=O)c1ccoc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 37.2 %

Procedure:
To a solution of n-BuLi (2.5 M in hexane, 7.68 mL) in anhydrous ether (10 mL) was added dropwise (over a 20-min period) a solution of 3-bromofuran (2.35 g, 16 mmol) in anhydrous THF (15 mL) under nitrogen atmosphere at −78° C. After stirring at −78° C. for 20 min, a solution of the Weinreb amide 45 (1.75 g, 8 mmol) in THF (15 mL) was added slowly to the mixture. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was poured into a saturated NaHCO3 solution and extracted with EtOAc. The organic phase was dried over anhydrous MgSO4, filtered and evaporated under vacuum. The residue was further purified by silica column chromatography to provide the titled compound (671 mg, 37%). MNa+248.
Reaction SMILES: Cl.CS([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:26])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]Br)=[CH:18][CH:17]=3)=[C:13]([C:27]3[CH:32]=[CH:31][C:30]([O:33]S(C)(=O)=O)=[CH:29][CH:28]=3)[S:12][C:11]=2[CH:38]=1)(=O)=O.CN(C)C=O.[NH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1.[I-].[K+]>C(Cl)(Cl)Cl.CO>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:26])[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:44]4[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]4)=[CH:20][CH:21]=3)=[C:13]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[S:12][C:11]=2[CH:38]=1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCBr)cc2)cc1
Reactant: C1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 110 °C
Reaction time: 120 h

Procedure:
A 1.5 g. portion of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-(4-bromoethoxybenzoyl)-benzo[b]thiophene, hydrochloride, was combined with 25 ml. of dimethylformamide, 5 ml. of piperidine and 150 mg. of potassium iodide, and was stirred for two hours at ambient temperature. The reaction was then heated to 110° C. in an oil bath, under a nitrogen atmosphere, and stirred for 5 days. The course of the reaction was followed by thin layer chromatography on silica gel plates, using a 9/1 mixture of chloroform/methanol as the eluting solvent. As the reaction went on, the spot indicating the protected comopund gradually disappeared, and was replaced, first by spots indicating the two possible mono-protected compounds, and then by a spot indicative of the desired product.
Reaction SMILES: [CH:1]1([C:7]2([CH2:11][OH:12])[CH2:10][O:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl>[CH:1]1([C:7]2([CH:11]=[O:12])[CH2:8][O:9][CH2:10]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCC1(C2CCCCC2)COC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=CC1(C2CCCCC2)COC1
Temperature: 25 °C

Procedure:
3-Cyclohexyl-3-hydroxymethyloxetane (7.0 g) was dissolved in dry dichloromethane (20 ml) and added dropwise to a mixture of oxalyl chloride (1.1 eq, 4 ml) in dry dichloromethane (15 ml). At -70° C. a solution of dimethyl sulphoxide (7.15 ml) in dichloromethane (10 ml) was added. After stirring at -70° C. for 30 minutes triethylamine (29 ml) was added over 30 minutes. The reaction mixture was allowed to warm up to room temperature over a period of 3 hours and then quenched in water. Extraction with dichloromethane, followed by washing with dilute hydrochloric acid, saturated sodium bicarbonate solution and brine and drying over magnesium sulphate gave a solution which was evaporated to give 3-cyclohexyl-3-formyloxetane as a colourless oil.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][N:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:15][C:16](=[O:29])[NH:17][C:18]2[CH:23]=[C:22]([Cl:24])[C:21]([O:25][CH3:26])=[CH:20][C:19]=2[O:27][CH3:28])[C:6]1=[O:30].[OH-].[K+].Cl>CO>[Cl:24][C:22]1[C:21]([O:25][CH3:26])=[CH:20][C:19]([O:27][CH3:28])=[C:18]([NH:17][C:16]([CH2:15][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:14][N:5]([CH2:4][C:3]([OH:31])=[O:2])[C:6]2=[O:30])=[O:29])[CH:23]=1
Reactant: COC(=O)CN1Cc2ccccc2N(CC(=O)Nc2cc(Cl)c(OC)cc2OC)C1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(OC)c(NC(=O)CN2C(=O)N(CC(=O)O)Cc3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An off-white suspension of {1-[(5-chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2-oxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid methyl ester (Intermediate I) (400 mg, 0.893 mmol) in MeOH (10 ml) is treated with 5 M KOH (5 ml). The resulting white suspension is left to stir at RT overnight to give clear solution. The aqueous reaction mixture is acidified with dilute HCl (1 M) to pH 4 to give a thick white precipitate which is filtered, washed with water and vacuum dried to afford the title compound as pale yellow solid; [M+H]+ 434.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38]([NH:40][CH2:41][C:42](O)=[O:43])=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.CN(C)C1C=CN=CC=1>[CH:32]1[C:33]2[CH:34]([CH2:36][O:37][C:38]([NH:40][CH2:41][C:42]([O:1][C@H:2]3[CH2:19][CH2:18][C@@:17]4([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]5[C@@H:16]4[CH2:15][CH2:14][C@@:12]4([CH3:13])[C@H:8]5[CH2:9][CH2:10][C:11]4=[O:21])[CH2:3]3)=[O:43])=[O:39])[C:35]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]=2[CH:29]=[CH:30][CH:31]=1
Reactant: C[C@]12CC[C@H](O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: C[C@]12CC[C@H](OC(=O)CNC(=O)OCC3c4ccccc4-c4ccccc43)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of 3β-hydroxyandrostane-6,17-dione (0.40 g) in THF (8 mL), N-(9-fluorenylmethoxycarbonyl)glycine (0.43 g), N,N′-dicyclohexylcarbodiimide (0.32 g) and 4-dimethylaminopyridine (16 mg) were added and the reaction mixture was stirred at room temperature for 1 h. After evaporation to dryness, the residue was purified by flash chromatography (SiO2; EtOAc:n-hexane 6:4) to give 3β-{2-[N-(9-fluorenylmethoxycarbonyl)]aminoacetoxy}androstane-6,17-dione (0.73 mg, 95%). 1H-NMR (300 MHz, acetone, ppm from TMS): δ 7.93-7.30 (8H, m), 6.86 (1H, t), 4.71 (1H, m), 4.40-4.20 (3H, m), 3.91 (2H, d), 2.55-1.25 (20H, m), 0.87 (3H, s), 0.78 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:22]([O:26][C:27]([NH:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]1[NH2:36])=[O:28])([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27]([NH:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C@@H:31]1[NH:36][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=[C:2]([Cl:1])[N:11]=1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2nc(Cl)nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
A solution of 710 mg of 2,4-dichloro-6-methoxyquinazoline in 20 mL of methylene chloride was combined with 471 mg of triethylamine and 750 mg of (1S,2R)-2-tert-butoxycarbonylaminocyclohexylamine, and stirred at room temperature for 48 hours. After concentrating, the mixture was combined with water, extracted with methylene chloride, and dried. After solvent was distilled off, the residue was purified by column chromatography on silica gel (chloroform:methanol 20:1) to obtain 1.20 g of the desirable compound.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13](I)[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[C:21]1([CH3:33])[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1OB(O)O.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(COC)OC>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.O>[CH2:1]([CH:3]([N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[C:13]([C:22]4[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:21]=4[CH3:33])[C:12]=3[N:11]=[C:10]([CH3:20])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: Cc1cc(C)c(OB(O)O)c(C)c1
Reactant: CCC(CC)N1CCc2c(C)nc3c(I)cccc3c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)cccc3c21
Temperature: 80 °C
Reaction time: 48 h
Yield: 15.2 %

Procedure:
1-(1-Ethylpropyl)-6-iodo-4-methyl-2,3-dihydro-1H-pyrrolo[3,2-c]quinoline (200 mg, 0.526 mmol), mesitylboric acid (95 mg, 0.579 mmol), barium hydroxide octahydrate (249 mg, 0.782 mmol) and tetrakistriphenylphosphinepalladium (12 mg, 0.01 mmol) were suspended into a mixture of dimethoxyethane (6 mL) and water (1 mL), followed by stirring at 80° C. for two days in nitrogen atmosphere. Water was added to the reaction mixture, followed by extracting with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then evaporated. The residue was purified by silica gel column chromatography (ethyl acetate), to give the title compound (28 mg, 0.08 mmol) as a pale yellow oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[H-].[Na+].[N+:11]([C:14]1[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=1)([O-])=O>C1COCC1>[N:4]1([CH2:3][CH2:2][O:1][C:17]2[CH:18]=[CH:19][C:14]([NH2:11])=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: OCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(OCCN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(2-hydroxyethyl)pyrrolidine in THF was added dropwise to a slurry of NaH in THF under N2 at 25° C. over a 5 min period. The mixture was stirred at 25° C. for 30 min, during which time it turned to a dark amber solution. A solution of 4-nitrofluorobenzene in THF was added dropwise and the resultant mixture was stirred at 25° C. for 48 h. The dark brown solution was carefully quenched by the addition of saturated aqueous NaHCO3 and was diluted with EtOAc. The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were washed with saturated aqueous NaHCO3, brine (2×) and were dried over MgSO4 and concentrated in vacuo to give a pale amber oil that was used without further purification. A solution of 1-[2-(4-nitrophenoxy)ethyl]pyrrolidine in EtOH under N2 was treated with 10% Pd/C and placed under an atmosphere of H2 via Parr apparatus. The mixture was agitated for 3 h at ˜45 psi of hydrogen and was then purged with N2, and filtered through a plug of Celite (EtOAc/EtOH wash) under N2 to give a dark brown oil. Purification of the oil by flash chromatography (12 g pre-packed silica gel ISCO column, 0-15% CH3OH/CH2Cl2) afforded 4-(2-pyrrolidin-1-ylethoxy)aniline as a brown oil. A solution of Methyl 5-(4-chlorophenyl)-3-{[(E)-(dimethylamino)methylidene]amino}2-thiophenecarboxylate (Example J13) and aniline in EtOH under N2 was stirred and heated at reflux for 48 h. The mixture was filtered and the white solid was washed with EtOH and dried in vacuo. Purification by reverse phase chromatography (Gilson, 10-95% acetonitrile/water) and concentration via lyophilization afforded the desired product as a TFA salt. 1H NMR (DMSOd6) δ 9.80 (br s, 1H), 8.37 (s, 1H), 7.96 (s, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.50 (d, J=9 Hz, 2H), 7.16 (d, J=9 Hz, 2H), 4.36 (m, 2H), 3.61 (m, 4H), 3.14 (m, 2H), 2.03 (m, 2H), 1.88 (m, 2H). LCMS m/z=452 (M++H).