Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[H-].[Na+].[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:9]=2)[N:4]([C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:3]=1
Reactant: CCOC(=O)c1ccc2[nH]nc(Br)c2c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 97.8 %

Procedure:
To a suspension of ethyl 3-bromo-1H-indazole-5-carboxylate (10.72 gm, 0.04 mol) in 160 mL of THF was added NaH (2.8 g, 0.068 mol) portionwise at 5-10 C under ice/water bath. The solution was stirred for 15 minutes further until no more bubbling. Tritylchloride (14 g, 0.05 mol) was added in several portions. After the addition, the cooling bath was removed and the orange suspension was stirred at room temperature for overnight. The reaction mixture was poured slowly into 100 mL of saturated NH4Cl with stirring and 100 mL EtOAc. The layers were separated and the aqueous phase extracted with Ethyl acetate (2 L×2). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over Na2SO4, filter and concentrated. The solid was triturated with hexane (100 mL), filtered and washed with hexane and dried under vacuum to give 20 gram product as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH2:18][OH:19])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1>C(Cl)(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([CH:18]=[O:19])=[CH:11][C:12]2[N:13]([CH:15]=[CH:16][N:17]=2)[CH:14]=1
Reactant: OCc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Product: O=Cc1cc2nccn2cc1-c1ccc(Cl)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A mixture of [6-(2,4-dichloro-phenyl)-imidazo[1,2-a]pyridin-7-yl]-methanol (125 mg, 0.43 mmol) and MnO2 (371 mg, 4.27 mmol) in CHCl3 (2 mL) was stirred at 60° C. for 2 h, then cooled to RT and filtered through a Celite pad. The solid was washed with AcOEt and the filtrate was evaporated to dryness to give the crude title compound (104 mg, 0.36 mmol, 84%) which was used in the next step without further purification. HPLC: AtRet=1.22.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.C(O)(=O)C(O)=O.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]2[CH2:36][CH2:35][NH:34][CH2:33]2)=[CH:28][CH:27]=1>>[CH3:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]2[CH2:36][CH2:35][N:34]([C:14]([C:10]3[CH:11]=[N:12][O:13][C:9]=3[C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=3)=[O:16])[CH2:33]2)=[CH:30][CH:31]=1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(C2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: Cc1ccc(C2CCN(C(=O)c3cnoc3-c3ccc(C(F)(F)F)cc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 3-(4-methylphenyl)pyrrolidine oxalate (15.1 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (6.3 mg). Calcd for C22H19F3N2O2: 400.1399, found 400.1400.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[C:26]1([N:36]=[C:37]=[O:38])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH3:24][CH:22]([CH3:23])[C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:37]([NH:36][C:26]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH:29]=[CH:28][CH:27]=3)=[O:38])[CH2:9][CH2:10]2)[CH:15]=1)=[O:25]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Reactant: O=C=Nc1cccc2ccccc12
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)Nc3cccc4ccccc34)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 1-naphthyl isocyanate: ESMS m/e: 515.3 (M+H)+.
Reaction SMILES: C[Al](C)C.[CH2:5]([NH2:9])[CH2:6][CH2:7][CH3:8].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1/[CH:19]=[CH:20]/[CH:21]=[C:22](\[O:27][CH3:28])/[C:23](OC)=[O:24]>C1(C)C=CC=CC=1.ClCCl>[CH2:5]([NH:9][C:23](=[O:24])/[C:22](/[O:27][CH3:28])=[CH:21]/[CH:20]=[CH:19]/[C:11]1[NH:10][C:18]2[C:13]([CH:12]=1)=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCN
Reactant: COC(=O)/C(=C/C=C/c1cc2ccccc2[nH]1)OC
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCCNC(=O)/C(=C/C=C/c1cc2ccccc2[nH]1)OC
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 47.3 %

Procedure:
A 2M solution of trimethylaluminium in toluene (0.4 ml) was added at room temperature under nitrogen to a solution of butylamine (0.04 ml, 0.39 mmol) in dichloromethane (10 ml). Stirring was continued for 30 minutes and methyl (2Z,4E)-5-(2-indolyl)-2-methoxy-2,4-pentadienoate (0.1 g, 0.39 mmol) was added. The solution was refluxed for 5 hours; after cooling to 10° C., the reaction was quenched with 10% HCl and the separated organic layer was washed with a saturated solution of NaHCO3 and water, dried over Na2SO4 and evaporated under vacuum. The solid residue was triturated with isopropyl ether, to give 55 mg (47.3%) of the title compound as a solid, m.p.=185-186° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([O:14]CC)=O)=[N:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:1]1([C:7]2[C:8]([C:12]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:14])=[N:9][O:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1nocc1-c1ccccc1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1nocc1-c1ccccc1
Yield: 84.1 %

Procedure:
3.9 g (17.95 mmol) of ethyl 4-phenyl-3-isoxazolecarboxylate and 5.8 g (36.2 mmol) of t-butyl (2-aminoethyl)carbamate were heated together to 110° for 2 hours under reduced pressure. Chromatography on silica gel and elution with methylene chloride which contained 5% and, respectively, 10% of ethyl acetate yielded an oil which crystallized from ethyl acetate/hexane. In this manner there were obtained 5.0 g (84%) of t-butyl [2-(4-phenyl-3-isoxazolecarboxamido)ethyl]carbamate as white crystals. melting point 170°-171°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:28]1([NH:31][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[NH:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:10][NH:11]3)=[CH:16][CH:15]=2)[CH2:30][CH2:29]1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 35.2 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), cyclopropyl amin (11.6 μL, 0.17 mmol), triethylamine (58 μl, 0.25 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 11.7 mg (35%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.81 (1H, s), 8.68 (1H, d, J=1.7), 8.51 (1H, s), 8.01 (4H, m), 7.50 (5H, m), 7.24 (1H, s), 7.03 (1H, d, J=5.3), 6.89 (1H, t, J=4.2), 2.84 (1H, m), 0.72 (2H, m), 0.56 (2H, m). ESIMS (M+H+): 396.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH2:9][O:10][CH3:11])[CH:8]=1)[NH2:5].Cl[C:13]1[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=1.CS(O)(=O)=O>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:13]2[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([CH2:9][O:10][CH3:11])[CH:8]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: COCc1cc(N)cc(Br)c1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COCc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of the product of Step 2 (258 mg, 1.194 mmol) in dioxane (3.8 mL) were added 2-chloro-4-(trifluoromethyl)pyrimidine (251 mg, 1.373 mmol) and methanesulfonic acid (0.07 mL, 1.015 mmol). The reaction was then stirred overnight at 100° C. The reaction was then cooled, diluted with ethyl acetate and then washed with brine solution. The organic layer was collected, dried over magnesium sulfate and then filtered. Ethyl acetate was then removed in vacuo. Flash chromatography (hexane/ethyl acetate: 70/30) was used for purification to afford N-[3-bromo-5-(methoxymethyl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine as an off-white solid (314 mg, 0.867 mmol, 72.6% yield). MS ESI: [M+H]+ m/z=362.0.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH2:56][C@H:57]1[CH2:62][CH2:61][N:60]([C:63]([O:65][CH2:66][CH3:67])=[O:64])[CH2:59][C@H:58]1[O:68][CH3:69]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:56][C@H:57]1[CH2:62][CH2:61][N:60]([C:63]([O:65][CH2:66][CH3:67])=[O:64])[CH2:59][C@H:58]1[O:68][CH3:69])=[O:11]
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Reactant: CCOC(=O)N1CC[C@H](N)[C@H](OC)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CC[C@H](NC(=O)c2[nH]c(C)c(Cl)c2Cl)[C@H](OC)C1
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
3,4-Dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 1; 304 mg) was dissolved in anhydrous DMF. HATU (596 mg), HOAT (213 mg) and DIEA (274 μl) were added and stirred at ambient for 15 min. Cis(±)ethyl 4-amino-3-methoxypiperidine-1-carboxylate (Intermediate 21; 317 mg) was added and the mixture was stirred at ambient for 18 h. The mixture was diluted with EtOAc and washed with water, 1N HCl, bicarbonate buffer, water, brine and dried over Na2SO4. The solution was concentrated in vacuo to give the title compound as a brown solid (503 mg). MS (ES) MH+: 378, 380 for C15H21Cl2N3O4; NMR: 1.29 (t, 3H), 1.79 (m, 2H), 2.27 (s, 3H), 3.12 (m, 2H), 3.30 (s, 3H), 3.37 (m, 1H), 3.83-4.16 (m, 5H), 7.25 (d, 1H), 12.23 (s, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10](O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].O>C(Cl)Cl>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([S:27]([CH3:26])(=[O:29])=[O:28])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.1 %

Procedure:
To a cold solution of 34 g (0.142 mol) of 1-(diphenylmethyl)-3-hydroxyazetidine in 200 mL of CH2Cl2 was added 30 mL (212 mol) of triethylamine. To the cold mixture a solution of 19.5 g (0.171 mol) of methanesulfonyl chloride in 50 mL of CH2Cl2 was added dropwise. The reaction was stirred at room temperature for 2 h. Water was added and the methylene chloride was removed under vacuo. The product was extracted with ether, the combined extracts were dried over anhydrous sodium sulfate, and filtered to yield 36 g of product. 1H NMR (300 MHz, CDCl3) δ 2.98 (s, 3H), 3.21 (m, 2H), 3.66 (m, 2H), 4.39 (s, 3H), 5.10 (m, 1H), 7.22 (m, 2H), 7.27 (m, 4H), 7.38 (m, 4H).
Reaction SMILES: [Br:1]Br.C([NH:7][S:8]([C:11]1[C:20]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=2[C:14]([C:21]2[C:25]([CH3:26])=[CH:24][S:23][C:22]=2[C:27]([O:29][CH3:30])=[O:28])=[CH:13][CH:12]=1)(=[O:10])=[O:9])(C)(C)C>ClCCl>[Br:1][C:24]1[S:23][C:22]([C:27]([O:29][CH3:30])=[O:28])=[C:21]([C:14]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=3[C:11]([S:8](=[O:10])(=[O:9])[NH2:7])=[CH:12][CH:13]=2)[C:25]=1[CH3:26]
Reactant: COC(=O)c1scc(C)c1-c1ccc(S(=O)(=O)NC(C)(C)C)c2c1CCCC2
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1sc(Br)c(C)c1-c1ccc(S(N)(=O)=O)c2c1CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Bromine (0.045 g, 0.015 ml, 0.28 mmol) was added dropwise to a stirred suspension of methyl 3-(4-(N-(tert-butyl)sulfamoyl)-5,6,7,8-tetrahydronaphthalen-1-yl)-4-methylthiophene-2-carboxylate (59c, 0.10 g, 0.24 mmol) in 15 ml dichloromethane at a temperature of about 0° C. The reaction mixture was then stirred at about 25° C. for 2 hours. the progress of the reaction was monitored by TLC. The reaction mixture was then concentrated. 20 ml of dichloromethane was added to the residue so obtained. The mixture so formed was washed with water (2×10 ml), brine (1×10 ml) and the organic layer so obtained was dried over sodium sulfate. The dried organic layer was then concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 20% ethyl acetate in hexanes as an eluent to obtain the title compound (0.08 g, 67.4%).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:15])=[C:9]([CH2:13][CH3:14])[C:10]=2[CH3:12])[S:5][C:4]=1[C:16]([O:18]C)=[O:17])#[N:2].[OH-].[Na+]>C(O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:15])=[C:9]([CH2:13][CH3:14])[C:10]=2[CH3:12])[S:5][C:4]=1[C:16]([OH:18])=[O:17])#[N:2]
Reactant: CCc1c(C)nc2sc(C(=O)OC)c(C#N)c2c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1c(C)nc2sc(C(=O)O)c(C#N)c2c1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of methyl 3-cyano-5-ethyl-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylate (2.70 g, 9.9 mmol), prepared above, in ethanol (100 mL), was added aqueous NaOH (1.25 N, 15.7 mL, 19.6 mmol), and the mixture was stirred for 2 h at 60° C. The volatiles were removed under reduced pressure and the residue was dissolved in water (150 mL) and then acidified using concentrated HCl until the pH was adjusted to 5-6. The precipitate was collected via filtration and washed thoroughly with water, dried in air to give 3-cyano-5-ethyl-4,6-dimethylthieno[2,3-b]pyridine-2-carboxylic acid (2.38 g, 93%). MS (ES−) m/z: 259.
Reaction SMILES: [C:1]([Si:5]([CH3:27])([CH3:26])[O:6][C@@H:7]([C@H:9]1[C:15](=[O:16])[N:14]2[C@@H:10]1[C@@H:11]([CH3:25])[C:12]([S:23][CH3:24])=[C:13]2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH:28]O>CC(C)=O.C(O)C.C(OCC)(=O)C>[Si:5]([O:6][C@@H:7]([C@H:9]1[C:15](=[O:16])[N:14]2[C@@H:10]1[C@@H:11]([CH3:25])[C:12]([S:23]([CH3:24])=[O:28])=[C:13]2[C:17]([O:19][CH2:20][CH:21]=[CH2:22])=[O:18])[CH3:8])([C:1]([CH3:3])([CH3:2])[CH3:4])([CH3:27])[CH3:26]
Reactant: OO
Reactant: C=CCOC(=O)C1=C(SC)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Solvent: CCO
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C1=C(S(C)=O)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Reaction time: 96 h

Procedure:
To a solution of allyl (4R,5S,6S)-6-[(1R)-1-(tertbutyldimethylsilyloxy)ethyl] -4-methyl-3-methylthio-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (31.4 mg) in a mixture of acetone (1.0 ml) and ethanol (0.1 ml) was added a 30% aqueous solution of hydrogen peroxide (0.2 ml). The reaction was allowed to stand at ambient temperature for 4 days. The mixture was diluted with ethyl acetate, washed with water, 5% aqueous sodium thiosulfate solution, brine, and dried. The solvent was removed off under reduced pressure and the residue was purified by silica gel column chromatography [ethyl acetate-n-hexane (1:3, V/V)] to afford allyl (4R,5S,6S)-6-[(1R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-methyl-3-methylsulfinyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (10.1 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:18]3[CH2:17][N:16]4[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]4)[CH2:10][C:9]=3[NH:8][C:5]2=[CH:6][CH:7]=1.N1CCC[C@H]1C(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[CH:36]=[C:37]([C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1)[CH3:38]>CN(C=O)C.[Cu]I>[F:45][C:42]1[CH:43]=[CH:44][C:39](/[C:37](/[CH3:38])=[CH:36]/[N:8]2[C:9]3[CH2:10][CH:11]4[N:16]([CH2:17][C:18]=3[C:4]3[C:5]2=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH2:15][CH2:14][CH2:13][CH2:12]4)=[CH:40][CH:41]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCCCC1C3
Reactant: CC(=CBr)c1ccc(F)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN1CCCCC1C2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-Methyl-5,6,6a,7,8,9,10,12-octahydroindolo[2,3-b]quinolizine (100 mg, 0.416 mmol) was dissolved in DMF (5 mL). Copper (I) iodide (7.9 mg, 0.0416 mmol), L-proline (9.6 mg, 0.08 mmol) and K3PO4 (176 mg, 0.00832 mmol) were added and the reaction mixture was stirred for 10 min at RT. 1-(1-Bromoprop-1-en-2-yl)-4-fluorobenzene (107 mg, 0.005 mmol) was added dropwise and the reaction mixture was purged with nitrogen. The reaction mixture was heated at 85° C. overnight (prolonged heating in some cases was required). The DMF was evaporated under reduced pressure, the residue was diluted with water and the solid was filtered. The solid material was purified by silica gel chromatography (100-200 mesh). The product was further purified by reverse phase HPLC. Yield: 80 mg as TFA salt;
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[C:17]([NH2:22])[N:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([O:13][C:19]2[CH:20]=[C:15]([Cl:14])[N:16]=[C:17]([NH2:22])[N:18]=2)[C:9]([F:11])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: O[C@H](c1ccc(Br)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1nc(Cl)cc(O[C@H](c2ccc(Br)cc2)C(F)(F)F)n1
Temperature: 80 °C

Procedure:
To a solution of (R)-1-(4-bromophenyl)-2,2,2-trifluoroethanol (150 mg, 0.60 mmol) in dioxane (10 mL) was added 4,6-dichloropyrimidin-2-amine (120 mg g, 0.71 mmol) and Cs2CO3 (290 mg, 0.88 mmol), and the reaction mixture was heated to 80° C. for 30 h. Then the reaction was cooled to RT. EtOAc was added and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (R)-4-(1-(4-bromophenyl)-2,2,2-trifluoroethoxy)-6-chloropyrimidin-2-amine as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:12]([CH3:15])=[N:13][CH:14]=[C:7]1[CH:6]=[CH:5]2.[F:16][C:17]1[CH:18]=[C:19]([C:24]2([C:30]#[N:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:20]=[C:21]([SH:23])[CH:22]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:16][C:17]1[CH:18]=[C:19]([C:24]2([C:30]#[N:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[CH:20]=[C:21]([S:23][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]2[C:12]([CH3:15])=[N:13][CH:14]=[C:7]2[CH:6]=[CH:5]3)[CH:22]=1
Reactant: Cc1ncc2ccc3cc(Br)ccc3n12
Reactant: N#CC1(c2cc(F)cc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ncc2ccc3cc(Sc4cc(F)cc(C5(C#N)CCOCC5)c4)ccc3n12
Temperature: 80 °C

Procedure:
4d (80 mg, 0.3 mmol) and 4-(3-Fluoro-5-mercapto-phenyl)-tetrahydro-pyran-4-carbonitrile (4e, 88 mg, 0.37 mmol) were dissolved in 1,4-dioxane (3 mL) and degassed for 10 minutes with N2. iPr2NEt (0.10 mL, 0.6 mmol), Pd2dba3 (14 mg, 0.02 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17 mg, 0.03 mmol) were added, and the reaction was degassed for another 10 minutes with N2. The reaction was then sealed and heated to 80° C. overnight. After cooling to room temperature, the reaction was concentrated and purified by silica gel chromatography (0-20% MeOH in EtOAc) to give the desired product, 4f.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:12]([N:16]=[C:17]([NH2:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C(N(CC)CC)C.CP(C)C.[CH3:39][C@H:40]1[C:45](=O)[C@@H:44]([CH3:47])[CH2:43][N:42]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:41]1.[B][B][B][B][B][B][B][B][B][B]>C1COCC1.CO.O>[C:51]([O:50][C:48]([N:42]1[CH2:43][CH:44]([CH3:47])[CH:45]([NH:19][C:17]2[N:18]=[C:11]3[C:10]([C:3]4[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=4[F:1])=[CH:15][CH:14]=[CH:13][N:12]3[N:16]=2)[CH:40]([CH3:39])[CH2:41]1)=[O:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)C1=O
Reactant: Nc1nc2c(-c3ccc(F)c(F)c3F)cccn2n1
Agent: CP(C)C
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CC1CN(C(=O)OC(C)(C)C)CC(C)C1Nc1nc2c(-c3ccc(F)c(F)c3F)cccn2n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 38.4 %

Procedure:
To a solution of 8-(2,3,4-trifluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine (prepared in analogy to example 66a-c) (300 mg, 1.14 mmol) and hexachloroethane (296 mg, 1.25 mmol) in dry THF (8 mL) was added triethylamine (287 mg, 396 μL, 2.84 mmol) under an argon atmosphere followed by trimethylphosphine (1 M in THF, 1.25 mL, 1.25 mmol). The reaction mixture was stirred at room temperature for 45 minutes, then (3R,5S)-tert-butyl 3,5-dimethyl-4-oxopiperidine-1-carboxylate (315 mg, 1.25 mmol) added and the mixture heated to 150° C. in the microwave for 3 hours. A solution of decaborane (139 mg, 148 μL, 1.14 mmol) in MeOH (3 mL) was added to the reaction mixture and stirred at 50° C. for 2 hours. Further decaborane (139 mg, 148 μl, 1.14 mmol) in MeOH (3 mL) was added and stirred at 50° C. for another 2 hours. The reaction mixture was poured in water and extracted with dichloromethane. The organic layers were combined, dried over Na2SO4 and evaporated. The residue was purified by flash-chromatography over 70 g SiO2-flash pack using gradient 0-100% EtOAc in heptane over 35 minutes to give the title compound as off-white foam (208 mg, 39%) as a mixture of cis- and trans-isomers. MS ISP (m/e): 476.2/420.2/376.3 (13/40/62) [(M+H)+/(M−tBu)+/(M−Boc)+].
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([CH2:11][CH3:12])[CH2:9][C@H:8]2[C@H:13]3[C:22]([CH:23]=[CH:24][C@:6]12[CH3:7])=[C:21]1[C:16](=[CH:17][C:18](=[O:25])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH2:11]([C@@H:10]1[CH2:9][C@H:8]2[C@H:13]3[C:22]([CH:23]=[CH:24][C@:6]2([CH3:7])[C@H:5]1[OH:4])=[C:21]1[C:16](=[CH:17][C:18](=[O:25])[CH2:19][CH2:20]1)[CH2:15][CH2:14]3)[CH3:12]
Reactant: CC[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3C=C[C@]2(C)[C@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CCC4=C3C=C[C@]2(C)[C@H]1O
Reaction time: 4 h
Yield: 86.7 %

Procedure:
A solution of 2.5 g of 17β-acetoxy-16α-ethyl-4,9,11-estratrien-3-one in 120 ml of methanol and 5 ml of water is stirred, after adding 6.0 g of potassium carbonate, for 4 hours at room temperature. The mixture is then poured into water and extracted with ethyl acetate. Crystallization of the crude product from ethyl acetate yields 1.9 g of 16α-ethyl-17β-hydroxy-4,9,11-estratrien-3-one, m.p. 139°-141° C.