Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Cl.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33]Cl)[CH:28]=1>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[CH:17][C:16](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH2:33][C:29]5[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=5)[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1ccn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1ccn2c3ccc(Br)cc3c3cc(OCc4cccnc4)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
10-bromo-2-hydroxy-4H-pyrido[3,2,1-jk]carbazole-4-one (300 mg) obtained in Example 59 was suspended in dimethyl sulfoxide (20 ml), and potassium carbonate (400 mg) was added to the suspension. The mixture was stirred at room temperature for 30 minutes and 3-picolylchloride hydrochloride (180 mg) was added and the mixture was, stirred at room temperature for 12 hours. The reaction mixture was poured into ice water (100 ml), and the precipitated crystals were recovered by filtration. The resulting crude crystals were washed with methanol and ether in succession, and recovered by filtration to obtain the title compound (200 mg, 52%).
Reaction SMILES: [CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:15]=[C:14]3[CH:16]=[CH:17][O:18][C:13]3=[CH:12][C:11]=2[C:19]([O:21][CH3:22])=[O:20])=[N:5]1)([CH3:3])[CH3:2].Cl.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.CN(C1C=CC(N=NC2C=CC(S(O)(=O)=O)=CC=2)=CC=1)C>[CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][CH:6]([C:10]2[N:15]=[C:14]3[CH:16]=[CH:17][O:18][C:13]3=[CH:12][C:11]=2[C:19]([O:21][CH3:22])=[O:20])[NH:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2occc2nc1C1=NC(C)(C(C)C)C(=O)N1
Agent: CN(C)c1ccc(N=Nc2ccc(S(=O)(=O)O)cc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: COC(=O)c1cc2occc2nc1C1NC(=O)C(C)(C(C)C)N1
Temperature: 0 °C

Procedure:
A solution of 22.1 mmol of methyl 5-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)furo[3,2-b]pyridine-6-carboxylate in methanol is cooled to 0° C. and a few drops of methyl orange indicator added. The solution is stirred and treated with 22.1 mmol of concentrated hydrochloric acid. The solution is then treated with 22.1 mmol of sodium cyanoborohydride, and the pH maintained at ~3 by the addition of 2N methanolic HCl, stirred overnight, cooled to 0° C. and the pH of the solution adjusted to about 0 with HCl to decompose residual NaCNBH3. The pH is thereafter adjusted to 5-6 with 5N NaOH. The methanol is removed in vacuo and water added to dissolve inorganic salts. The mixture is extracted with CH2Cl2 and the extracts dried and concentrated to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:36][N:37]([CH3:42])[CH2:38][CH2:39][CH2:40]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[O:15][CH2:40][CH2:39][CH2:38][N:37]([CH3:42])[CH3:36])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(O)c(NC(=O)OC(C)(C)C)c1
Reactant: CN(C)CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(OCCCN(C)C)c(NC(=O)OC(C)(C)C)c1
Reaction time: 12 h

Procedure:
To a stirred, cooled (about 0° C.) solution of (2-hydroxy-5-methyl-phenyl)-carbamic acid tert-butyl ester (447 mg, 2.0 mmol), triphenyl phosphine (525 mg, 2.0 mmol), and 3-(dimethylamino)-1-propanol (237 μL, 2.0 mmol) in dry tetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate (394 μL, 2.0 mmol) in 1 mL of tetrahydrofuran). After stirring for 12 hours, the reaction was diluted with 30 mL of ethyl acetate and washed with 30 mL of 10% aqueous sodium carbonate (2×30 mL), brine (1×30 mL), then dried (MgSO4), and filtered. The filtered solution was concentrated under reduced pressure to provide the desired crude product.
Reaction SMILES: N[CH2:2][C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[OH2:10]>>[OH:10][CH2:2][C:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O
Reactant: NCC1(O)CCCCC1
Product: OCC1(O)CCCCC1

Procedure:
Compounds of this type may be prepared from isophorone utilizing the methods described in U.S. Pat. Nos. 3,270,044 and 3,352,913 to form an amino methyl cyclohexanol which is then reacted with a carboxylic acid in a fusion cook by heating stoichiometric quantities of the amine and the acid until molten and stirring the molten mixture with a nitrogen sweep to drive off water vapor. The progress of the reaction is stopped when an acid number just below theoretical is obtained. Similarly, the carboxylate derivative can be formed from a hydroxymethyl cyclohexanol.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:28])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:29][C:30]1[CH:35]=[C:34]([S:36]([CH3:38])=[O:37])[CH:33]=[C:32]([F:39])[C:31]=1[C:40]1[N:45]=[C:44]([C:46](O)=[O:47])[CH:43]=[CH:42][C:41]=1[F:49].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:46]([C:44]3[CH:43]=[CH:42][C:41]([F:49])=[C:40]([C:31]4[C:32]([F:39])=[CH:33][C:34]([S:36]([CH3:38])=[O:37])=[CH:35][C:30]=4[F:29])[N:45]=3)=[O:47])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CS(=O)c1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cc(S(C)=O)cc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 14.1 %

Procedure:
A mixture of 3-amino-4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (12.0 mg, 0.031 mmol), 6-[2,6-difluoro-4-(methylsulfinyl)phenyl]-5-fluoropyridine-2-carboxylic acid (11.6 mg, 0.037 mmol), HATU (29.2 mg, 0.077 mmol) in DMF (0.07 mL) and DIPEA (11.9 mg, 0.092 mmol) was stirred at room temperature for 16 h. The reaction mixture was filtered, concentrated under reduced pressure and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a colorless gum (3.0 mg, 14%). LCMS calc. for C33H37F3N5O6S (M+H)+: m/z=688.2. Found: 688.2.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:13](=[O:14])O[C:11](=[O:15])[C:10]2[N:6]1[CH:7]=[CH:8][CH:9]=2.C(OCC)(=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[H-].[Na+]>CN(C)C(=O)C.CO>[CH2:22]([O:21][C:19]([C:18]1[C:13](=[O:14])[N:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH3:16])[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]2[C:11]=1[OH:15])=[O:20])[CH3:23]
Reactant: CC(C)CCn1c(=O)oc(=O)c2cccn21
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CCOC(=O)c1c(O)c2cccn2n(CCC(C)C)c1=O
Temperature: 120 °C
Reaction time: 16 h
Yield: 55.6 %

Procedure:
To a solution of 4-(3-methyl-butyl)-6-oxa-3a,4-diaza-indene-5,7-dione (Example 1e, 0.080 g, 0.36 mmol) and diethyl malonate (0.58 mL, 3.6 mmol) in N,N-dimethylacetamide (1 mL) was added sodium hydride (0.017 g, 0.43 mmol) and 1 drop of methanol. The reaction mixture was heated to 120° C. and stirred for 16 h. The reaction was allowed to cool to 25° C. and quenched with saturated aqueous ammonium chloride solution and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3×3 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (Merck silica gel 60, 40-63 μm, ethyl acetate/dichloromethane, 2-5%) to afford the desired product, 4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (0.058 g, 0.20 mmol, 55% yield) as a light tan solid. 1H NMR (400 MHz, DMSO-d6) δ 0.93 (6H, d, J=6.4 Hz), 1.30 (3H, t, J=6.8 Hz), 1.49 (2H, q, J1=15.2 Hz, J2=7.6 Hz), 1.63 (1H, m), 4.23-4.30 (4H, m), 6.56 (1H, m), 6.87 (1H, m), 7.68 (1H, m); LC-MS (ESI) calcd for C15H20N2O4 292.33, found 293.30 [M+H+].
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([C:23]#[N:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[I:27]I.[OH-].[Na+]>C(O)(=O)C.S([O-])([O-])(=O)=O.[Ag+2]>[I:27][C:22]1[C:12]2[N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]=2[C:19]([O:25][CH3:26])=[CH:20][C:21]=1[C:23]#[N:24]
Reactant: II
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C#N)cc(OC)c21
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(I)c(C#N)cc(OC)c21
Yield: 14.7 %

Procedure:
A mixture of 50 mg (0.143 mmol) 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonitrile and 36 mg (0.143 mmol) iodine and 22 mg (0.072 mmol) silver sulfate in 1 ml acetic acid is stirred at reflux for 3 h. Then the filtrate is poured on 2N NaOH and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 10 mg of the title compound as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][S:8][C:9]1[NH:13][C:12]2[CH:14]=[C:15]([Cl:19])[C:16](I)=[CH:17][C:11]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)#[CH:22]>CN(C=O)C.CO.CCOC(C)=O.[Cu](I)I.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>[C:1]([O:5][C:6](=[O:20])[CH2:7][S:8][C:9]1[NH:13][C:12]2[CH:14]=[C:15]([Cl:19])[C:16]([C:22]#[C:21][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:25][CH:24]=3)=[CH:17][C:11]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(I)c(Cl)cc2[nH]1
Reactant: C#Cc1ccc(Oc2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CSc1nc2cc(C#Cc3ccc(Oc4ccccc4)cc3)c(Cl)cc2[nH]1
Temperature: 120 °C

Procedure:
A 2 mL Biotage™ microwave vial equipped with a stirring bar was charged with copper iodide (1.1 mg, 10 mol %), and Pd(PPh3)2Cl2 (2.1 mg, 5 mol %). A solution of (6-chloro-5-iodo-1H-benzoimidazol-2-ylsulfanyl)-acetic acid tert-butyl ester (Intermediate 4, 25.0 mg, 0.059 mmol) in DMF (0.5 mL) was added to the vial, followed by a solution of 1-ethynyl-4-phenoxy-benzene (15.0 mg, 0.118 mmol) in DMF (250 uL) and TEA (57 uL, 0.41 mmol). The resulting suspension was heated in a microwave synthesizer (Biotage Initiator™) at 120° C. for 5 min. The solvent was removed in vacuo to give dark brown oil which was re-dissolved in a 1:1 MeOH/EtOAc mixture (3 mL) and passed through a Thiol StratoSphere™ SPE cartridge (Polymer Labs). The resulting solution was evaporated to dryness in vacuo to give the crude product as brown solid. LR-MS (API-ES): calculated for C27H23ClN2O3S 490.1, observed m/e 491.0 (M+H)+ (Rt 3.74 min). The crude product was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[C@H:26]12[CH2:32][C@H:29]([NH:30][CH2:31]1)[CH2:28][O:27]2>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:30]3[CH2:31][C@@H:26]4[CH2:32][C@H:29]3[CH2:28][O:27]4)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Reactant: C1O[C@@H]2CN[C@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(N3C[C@@H]4C[C@H]3CO4)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and (1S,4S)-2-oxa-5-aza-bicyclo[2.2.1]heptane trifluoroacetate. Light yellow solid. MS (m/e): 353.1 ([{37Cl}M+H]+, 36%), 351.1 ([{35Cl}M+H]+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+:24]>CO.O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O-:18])=[O:17])=[CH:19][CH:20]=2)=[O:7])=[CH:4][CH:3]=1.[Na+:24]
Reactant: O=C(O)c1ccc(OCCNC(=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C([O-])c1ccc(OCCNC(=O)c2ccc(Cl)cc2)cc1
Yield: 67.5 %

Procedure:
4-[2-(4-Chlorobenzamido)ethoxy]benzoic acid (3.19 g) was dissolved in 50 ml of methanol. A solution of 0.40 g of sodium hydroxide in 5 ml of water was added to the above methanolic solution, the mixture was concentrated in vacuo, the crystallised residue was recrystallised from methanol, and 2.30 g of crystalline product was obtained. M.p. not lower than 300° C.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH2:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2].[O-:26][C:27]#[N:28].[K+]>C(O)(=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH2:23][NH:24][C:27]([NH2:28])=[O:26])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][C:6]([CH3:25])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(CN)ccc2-3)n(C(C)C)n1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(CNC(N)=O)ccc2-3)n(C(C)C)n1

Procedure:
Following the procedures for 542, C-[2-(2-Isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-methylamine 532 was reacted with potassium cyanate in acetic acid and water to give 524. MS (ESI+) 399.1. 1H NMR (400 MHz, DMSO) δ 8.27 (d, J=8.2 Hz, 1H), 7.07 (dd, J=8.2, 1.3 Hz, 1H), 6.95 (br, 1H), 6.44 (t, J=6.1 Hz, 1H), 5.83-5.68 (m, 1H), 5.54 (s, 2H), 4.35 (t, J=5.0 Hz, 2H), 4.18 (d, J=6.1 Hz, 2H), 3.42 (t, J=5.0 Hz, 2H), 2.32 (s, 3H), 1.52 (d, J=6.6 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]([CH3:56])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:53])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:52])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42](=[O:51])[NH:43][C:44]4[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][CH:45]=4)[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:55])[CH3:54])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[CH:37]([C:33]1[C:34](=[O:36])[CH2:35][C@:23]2(/[CH:40]=[CH:41]/[C:42](=[O:51])[NH:43][C:44]3[CH:45]=[CH:46][C:47]([CH3:50])=[CH:48][CH:49]=3)[CH2:22][CH2:21][C@:20]3([CH3:52])[C@H:25]([CH2:26][CH2:27][C@H:28]4[C@@:19]3([CH3:53])[CH2:18][CH2:17][C@@H:16]3[C@:29]4([CH3:32])[CH2:30][CH2:31][C@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:56])([CH3:1])[C:3]([OH:5])=[O:4])[C:15]3([CH3:54])[CH3:55])[C:24]=12)([CH3:39])[CH3:38]
Reactant: Cc1ccc(NC(=O)/C=C/[C@@]23CC[C@]4(C)[C@H](CC[C@@H]5[C@@]6(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]6CC[C@]54C)C2=C(C(C)C)C(=O)C3)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)/C=C/[C@@]23CC[C@]4(C)[C@H](CC[C@@H]5[C@@]6(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]6CC[C@]54C)C2=C(C(C)C)C(=O)C3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3a-((E)-3-oxo-3-(p-tolylamino)prop-1-en-1-yl)-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (250 mg, 0.325 mmol) in dichloromethane (5 mL) stirred at rt was added TFA (0.025 mL, 0.325 mmol). The reaction mixture was stirred at rt for 1 h. Upon completion and work-up and purification the title compound was obtained as a trifluoroacetic acid salt (150 mg, 0.181 mmol, 55.8%) as a light white solid. 1H NMR (300 MHz, DMSO-d6) δ=9.70 (s, 1H), 7.51 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 6.83 (d, J=15.8 Hz, 1H), 6.08 (d, J=15.7 Hz, 1H), 4.53-4.32 (m, 1H), 3.30-3.11 (m, 1H), 2.90-2.73 (m, 1H), 2.55-2.51 (m, 1H), 2.35-0.75 (m, 51H); LC/MS: m/z calculated 713.5. Found 714.3 (M+1)+.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([CH3:15])[O:3][CH2:4][CH2:5][C-:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[Li+].[Cl-:18].[Cl-].[Cl-].[CH3:21][Zr:22]([CH3:31])([CH3:30])([CH3:29])([CH3:28])[CH:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1>CCOCC>[Cl-:18].[Cl-:18].[CH3:16][Si:2]([CH3:15])([CH3:1])[O:3][CH2:4][CH2:5][CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[Zr:22]([CH3:31])([CH3:30])([CH3:29])([CH3:28])([CH3:21])[CH:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1
Reactant: C[Zr](C)(C)(C)(C)C1C=CC=C1
Reactant: C[Si](C)(C)OCC[c-]1ccc2ccccc21
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOCC
Product: C[Si](C)(C)OCCC1C([Zr](C)(C)(C)(C)(C)C2C=CC=C2)=Cc2ccccc21
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
A suspension of 1.5 g (6.5 mmol) of lithium [1-(2-trimethylsiloxyethyl)indenide] in ether was added to a suspension of 2.2 g (6.5 mmol) of pentamethylcyclopentadienyl zirconium trichloride in 100 ml of ether at 0° C. After 30 minutes, the formation of a white solid was the volatiles were removed under vacuum to give a yellow oily-solid. This solid was recrystallized in hexane to give a mycrocristalline yellow solid, which was characterized as [1-(2-trimethylsiloxyethyl)indenyl]pentamethylcyclopentadienyl zirconium dichloride (1.7 g, 3.2 mmol, yield: 49%). 1H-NMR (CDCl3): 7.65 (m, 1H); 7.33 (m, 1H); 7.25 (m, 2H); 6.08 (m, 1H); 5.92 (m, 1H); 3.72 (dm, 2H); 3.28 (m, 1H); 2.72 (m, 1H); 2.04 (s, 15H); 0.03 (s, 9H). 13C-NMR (CDCl3): 131.4; 127.1; 126.7; 125.2; 125.1; 124.2; 123.5; 122.6; 116.1; 97.0; 62.6; 32.1; 12.5; −0.6.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:24])=[C:4]([C:20](F)=[CH:21][CH:22]=1)[C:5]([N:7]([CH2:17][CH2:18][OH:19])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:22]=[CH:21][C:20]2[O:19][CH2:18][CH2:17][N:7]([CH2:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:5](=[O:6])[C:4]=2[C:3]=1[CH3:24]
Reactant: COc1ccc(CN(CCO)C(=O)c2c(F)ccc(Br)c2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2CCOc3ccc(Br)c(C)c3C2=O)cc1
Temperature: 65 °C
Reaction time: 14 h
Yield: 59.1 %

Procedure:
A mixture of 3-bromo-6-fluoro-N-(2-hydroxyethyl)-N-(4-methoxybenzyl)-2-methylbenzamide (130b, 5.00 g, 12.6 mmol) and Cs2CO3 (8.20 g, 25.3 mmol) in dry DMF (60 mL) was stirred at 65° C. for 14 hours. To the reaction mixture was added brine (100 mL). The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine (4×60 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 5/1) to give 7-bromo-4-(4-methoxybenzyl)-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (130c, 2.8 g, 59%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([O:7]C)=[S:6].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:5]([OH:7])=[S:6]
Reactant: COC(=S)c1c(C)ccc(Br)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(Br)c(C)c1C(O)=S
Yield: 98.9 %

Procedure:
To 100 ml of an ethanol solution containing 17.0 g of methyl 3-bromo-2-methyl-6-methylthiobenzoate, 16 g of a 50% sodium hydroxide aqueous solution was added, and the mixture was refluxed for 3 hours under heating. The reaction mixture was concentrated under reduced pressure. Then, water was added thereto, and the mixture was washed with chloroform. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 15.9 g of the desired product. Melting point: 98°-103° C.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:20]([O:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21]>N1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:20]([O:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:21])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: O=C(Cl)OCCc1ccccc1
Solvent: c1ccncc1
Product: CN1CCC(OC(=O)OCCc2ccccc2)N(c2nnc(C(C)(C)C)s2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and themometer. The solution is cooled to a temperature of about 10° C. and phenethyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-phenethyloxycarbonyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6].[F:10][C:11]1[CH:12]=[C:13]([CH:41]=[CH:42][CH:43]=1)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[O:37][C:36]([CH:38]=O)=[CH:35][CH:34]=4)[CH:31]=3)[N:26]=[CH:25][N:24]=2)=[CH:18][C:17]=1[Cl:40].CCN(C(C)C)C(C)C.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>ClCCCl>[Cl:40][C:17]1[CH:18]=[C:19]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[O:37][C:36]([CH2:38][NH:1][CH2:2][CH2:3][P:4](=[O:9])([O:7][CH3:8])[O:5][CH3:6])=[CH:35][CH:34]=4)[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH:20]=[CH:21][C:16]=1[O:15][CH2:14][C:13]1[CH:41]=[CH:42][CH:43]=[C:11]([F:10])[CH:12]=1
Reactant: COP(=O)(CCN)OC
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COP(=O)(CCNCc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1)OC
Reaction time: 0.5 h

Procedure:
To a suspension of compound 6.2 (153 mg, 1 mmol) and the compound 1.7 (473 mg, 1 mmol) in DCE (5 mL) was added DIPEA (1.5 mmol) and HOAc (1.5 mmol). After stirring the mixture for 30 minutes, 2.0 mmol of NaBH(OAc)3 was added followed by Stirring the mixture overnight. 1.0 mL of 5M NaOH was added and the mixture was extracted with DCM (2×20 mL). Combined organics was washed with brine and dried over MgSO4. Filtration and concentration followed by purification through flash column chromatography on silica gel (10% methanol in DCM) to get pale brown powder. LCMS ESI(+) m/z: 612 (M+1). 1H NMR (CD3OD, 300 MHz) δ 8.64 (s, 1H), 8.45 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.38 (m, 1H), 7.28 (d, J=8.8 Hz, 1H), 7.23 (d, J=5.4 Hz, 1H), 7.05 (m, 1H), 6.90 (d, J=2.7 Hz, 1H), 6.44 (d, J=2.7 Hz, 1H), 5.20 (s, 2H), 3.73 (s, 3H), 3.70 (s, 3H), 2.90 (m, 2H), 2.10 (m, 2H).