Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]([CH3:11])[CH3:10])=[N:6][CH:7]=1.C([Li])CCC.CCCCCC.CON(C)[C:26](=[O:28])[CH3:27].[NH4+].[Cl-]>C1COCC1>[CH:9]([O:8][C:5]1[N:6]=[CH:7][C:2]([C:26](=[O:28])[CH3:27])=[CH:3][CH:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(Br)cn1
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1ccc(OC(C)C)nc1
Temperature: -66 °C
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
A round-bottomed flask was charged with 5-bromo-2-iso-propoxypyridine (IM1) (5.00 g, 23.1 mmol) in THF (100) under N2 and cooled in an acetone/dry-ice bath to −66° C. (internal temperature). A solution of 2.5 M n-butyllithium in hexane (10.1 mL, 25.3 mmol) was added drop wise over 10 minutes at keeping the internal temperature below −55° C. The mixture was stirred at −65° C. for 15 minutes. N-methoxy-N-methylacetamide (3.07 mL, 28.9 mmol) dissolved in THF (10 mL) was then added drop wise over 10 minutes while keeping the internal temperature below −65° C. After stirring for 1 h the mixture was allowed to reach room temperature. The mixture was poured into saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and evaporated to dryness. Flash chromatography (silica, heptanes/EtOAc 4:1) gave the title compound as a colorless oil (3.20 g, 77%) sufficiently pure for the next step.
Reaction SMILES: [C:1](CCSCCC#N)#[N:2].[C:10]([NH:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[N:25]=[N:26][C:27]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][C:30]([N+:36]([O-:38])=[O:37])=[CH:29][C:28]=1Br)[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])(=[O:12])[CH3:11].[C-]#N.[Na+]>O>[C:10]([NH:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[N:25]=[N:26][C:27]1[C:32]([N+:33]([O-:35])=[O:34])=[CH:31][C:30]([N+:36]([O-:38])=[O:37])=[CH:29][C:28]=1[C:1]#[N:2])[N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])(=[O:12])[CH3:11]
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Reactant: N#CCCSCCC#N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 60 °C
Reaction time: 0.42 h

Procedure:
Into a reactor there are introduced 765 parts of bis (β-cyanoethyl) sulfide, followed by 14.35 parts of cuprous bromide. On heating to 60° C. with continuous stirring, a brownish-yellow solution of the copper complex is obtained. 95.8 parts of 3-acetamido-4-(2'bromo-4',6'-dinitrophenylazo)-N,N-diethylaniline are added, and the temperature is raised to 115° C. Raising the temperature to 115° C. causes the compound to completely dissolve. At ths temperature, a solution of 10.8 parts of sodium cyanide in 40 parts of water is introduced into the reactor during a period of 20 minutes, allowing the steam to escape. Stirring is continued for a further 20 to 30 minutes while verifying by thin layer chromatography that the starting organic bromo-derivative is absent. The reaction mass is cooled to 30°-35° C., which causes crystallization of the dyestuff. The resultant product is filtered off, washed with water to displace the solvent contained in the paste, and dried. 80.2 parts of 3 -acetamido-4-(2'cyano-4',6'-dinitro-phenylazo)-N,N-diethylaniline are obtained. The titre (purity) of this product is 98.5% and it contains a copper concentration of less than 3000 parts per million. The wash water is introduced into a decanter, and the organic solvent part is withdrawn and reunited with the fraction of solvent obtained during filtration. There are thus recovered 720 parts of bis(β-cyanoethyl) sulfide which contain 4.35 parts of the cyanoazo dyestuff (giving an overall balance of the reaction of 98%) and 5.75 parts of copper (which corresponds to a recovery of 91% of the initial copper complex.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[F:8][C:9]([F:16])([F:15])[C:10](OCC)=[O:11]>CCOCC>[F:8][C:9]([F:16])([F:15])[C:10]([NH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7])=[O:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NCCNCCO
Solvent: CCOCC
Product: O=C(NCCNCCO)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.8 %

Procedure:
2-(2-aminoethylamino)ethanol (10 g, 96.01 mmol) was added via syringe to a stirred solution of ethyl trifluoroacetate (13.64 g, 96.01 mmol) in dry Et2O (30 mL) at 0° C. The resulting solution was stirred at room temperature for 2 hours by which time a white precipitate had formed. The precipitate was removed by filtration, washed with Et2O (100 mL), and dried in vacuo for 3 hours to afford the title compound (13.6 g, 100%). 1H NMR (300 MHz, CDCl3) δ (t, J=5.1 Hz, 2H), 3.45 (t, J=5.6 Hz, 2H), 2.86 (t, J=5.6 Hz, 2H), 2.78 (t, J=4.9 Hz, 2H), 2.22 (br s, 2H); mass spectrum (API-TIS) m/z 201 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][N:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2Cl)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:42])=[C:39]([OH:41])[CH:40]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[CH:20][N:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:17]=2[O:41][C:39]2[CH:40]=[C:35]([F:34])[CH:36]=[CH:37][C:38]=2[CH3:42])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(F)cc1O
Reactant: COc1cc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cl)n(-c3ccccc3)c2cn1
Product: COc1cc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3cc(F)ccc3C)n(-c3ccccc3)c2cn1

Procedure:
The title compound was prepared from the compound of step 5 (100 mg, 212 μmol) and 5-fluoro-2-methylphenol analogously as described in example 1, step 6. Yield: 98.0 mg.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=[C:10]([N:19]2[CH2:24][CH2:23][CH:22]([NH2:25])[CH2:21][CH2:20]2)[N:9]=1.C(=O)(O)[O-].[Na+].Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33]>O1CCOCC1>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[C:12]([CH2:14][S:15]([CH3:18])(=[O:16])=[O:17])[N:11]=[C:10]([N:19]2[CH2:20][CH2:21][CH:22]([NH:25][C:32](=[O:33])[O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:23][CH2:24]2)[N:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(N2CCC(N)CC2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1cc(CS(C)(=O)=O)nc(N2CCC(NC(=O)Oc3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.1 %

Procedure:
1-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonylmethyl)pyrimidin-2-yl]piperidin-4-amine (500 mg, 1.35 mmol) was dissolved in dioxane (10 mL). Sodium bicarbonate (171 mg, 1.50 mmol) was added. Then phenyl chloroformate (0.171 mL, 1.35 mmol) was added dropwise over 2 minutes. The slurry was stirred at RT for 3 hours. Phenyl chloroformate (0.021 mL, 0.27 mmol) and sodium bicarbonate (21 mg, 0.12 mmol) were added. Stirring at room temp was continued for 1 hour and the reaction mixture evaporated to dryness and partitioned between water (10 mL) and ethyl acetate (10 mL). The water was extracted with a second portion of ethyl acetate (10 mL). The combined organics were dried over magnesium sulfate and evaporated to give the desired material as a foam (701 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:20]=[C:21]=[O:22])(=[O:19])=[O:18]>C(#N)C>[CH3:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:21]([NH:20][S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])(=[O:18])=[O:19])=[O:22])[N:3]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: Cc1nc(C)nc(N)n1
Solvent: CC#N
Product: Cc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2Cl)n1

Procedure:
To 12.3 g of 2-amino-4,6-dimethyl-1,3,5-triazine in 200 ml of acetonitrile was added with stirring 21.7 g of 2-chlorobenzenesulfonyl isocyanate. All of the solid dissolved after the reagents were added and the mixture was then evaporated to dryness. The solid residue was triturated with ethyl ether and isolated by filtration to give impure N-[(4,6-dimethyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-chlorobenzenesulfonamide melting at 115°-118° C. The nuclear magnetic resonance absorption spectrum of this product, in trifluoroacetic acid, showed singlet peaks at 2.69 and 2.9 parts per million.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[N+:29]([O-])=O)[CH:3]=1.[CH3:32]CO.CCOC(C)=O>[Pd]>[CH2:1]([C:2]1[N:7]=[C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[NH2:29])[CH:3]=1)[CH3:32]
Reactant: CCO
Reactant: Cc1cc(-c2ccncc2[N+](=O)[O-])cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(-c2ccncc2N)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Reaction time: 18 h
Yield: 95 %

Procedure:
To a solution of 6-methyl-N,N-di-BOC-3′-nitro-4,4′-bipyridin-2-amine in EtOH/EtOAc (1:1, 0.2M) was added Pd/C (10% by weight) and the reaction was stirred under a H2 balloon for 18 hrs. Filtered through Celite, washed with EtOAc and concentrated the filtrate to afford 6-ethyl-N2,N2-di-BOC-4,4′-bipyridine-2,3′-diamine in >95% yield. LCMS (m/z): 401.0 (MH+); LC Rt=2.81 min.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH:11]=2)[C:6](=[C:20](OCC)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]1=[O:30])(=O)C.[CH3:31][N:32]([CH2:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[CH3:33]>>[CH3:33][N:32]([CH2:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39]/[C:20](=[C:6]2\[C:5](=[O:30])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:11]=3)/[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:37][CH:36]=1)[CH3:31]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(-c3ccccc3C)ccc21)c1ccccc1
Product: Cc1ccccc1-c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-(2-tolyl)-2-indolinone and 4-(dimethylaminomethyl)-aniline
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][CH3:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(N)ccc1Cl
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CNc1ccc(Cl)c(C(=O)OC)c1

Procedure:
55.0 g (296 mmol) of methyl 2-chloro-5-aminobenzoate and 49.1 g (356 mmol) of potassium carbonate are suspended in 500 ml of acetonitrile p.a. 22.1 ml (356 mmol) of methyl iodide are added dropwise to the reaction mixture. The suspension is then boiled under reflux for 3 hours. After cooling, the reaction mixture is filtered. The filtrate is diluted with water. The aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulphate and filtered. The solvent is removed under reduced pressure on a rotary evaporator. The crude product is purified by column chromatography. This gives 30.0 g (51%) of methyl 2-chloro-5-(methylamino)benzoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+].[S:35]1[CH2:39][C:38](=[O:40])[NH:37][C:36]1=[O:41]>C1COCC1>[O:41]=[C:36]1[N:37]([CH2:15][C:13]2[N:14]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=3)=[O:8])[S:11][CH:12]=2)[C:38](=[O:40])[CH2:39][S:35]1
Reactant: O=C1CSC(=O)N1
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CI)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccc(F)c1)Nc1nc(CN2C(=O)CSC2=O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Fluoro-benzyl)-3-(4-iodomethyl-thiazol-2-yl)-urea (Intermediate 7, 0.3 mmol) was taken up in THF (3 ml) and DIPEA (1 eq.) and potassium carbonate (1 eq.) was added, followed by thiazolidine-2,4-dione (1 eq.). The reaction was stirred at room temperature overnight. Solvent is removed in vacuo and the crude material was purified by column chromatography with a gradient of 0-60% of (9:1 EtOAc/MeOH) and hexanes to afford 1-(4-((2,4-dioxothiazolidin-3-yl)methyl)thiazol-2-yl)-3-(3-fluorobenzyl)urea (EX #109) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][C:5]2=[O:16].[CH3:17][CH:18](O)[CH:19]=[CH2:20].O>COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:17]([CH:6]1[C:5](=[O:16])[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([CH3:1])[CH:3]=2)[C:7]21[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:18]=[CH:19][CH3:20]
Reactant: C=CC(C)O
Reactant: Cc1ccc2c(c1)C(=O)CC21CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1C(=O)c2cc(C)ccc2C12CCCCC2
Yield: 587.7 %

Procedure:
A solution of 2.50 g of 5'-methyl-2',3'-dihydro-spiro[cyclo-hexane-1,1'-[1H]indene]-3'-one, 24.1 ml (280 mol) of 3-buten-2-ol and 250 mg of p-toluenesulfonic acid in 250 ml of 2,2-dimethoxy-propane was boiled under reflux for 88 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 6:1). In addition to 8.4 g of educt, there were obtained 18.4 g (59%) of (RS)-2'-(2-buten-1-yl)-5'-methyl-2',3'-dihydro-spiro[cyclohexane-1,1'-[1H]indene]-3'-one as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][OH:18])=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([O:26][C:27]1(OCCCC)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:23][CH2:24][CH3:25]>>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16][CH2:17][O:18][C:27]3([O:26][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[N:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCCCOC1(OCCCC)CCCCCC1
Reactant: CC(C)c1nc(CCO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Product: CCCCOC1(OCCc2nc(C(C)C)c(Sc3cc(Cl)cc(Cl)c3)n2C)CCCCCC1
Yield: 20.8 %

Procedure:
The compound 22 (345 mg, 1 mmol) was converted to the acetal with 1,1-di-n-butoxycycloheptane (2.42 g, 10 mmol) in the same manner as the example 20 to give the compound 29 (107 mg, 20.8%). PMR (CDCl3 -0.1% d5 -Py): δH 0.90 (3 H, t, J 7.4 Hz, CH3) 1.24 (6H, d, J 7Hz, (CH3)2C), 3.00 (2H, t, J 6Hz, CH2 -Im), 3.11 (3 H, m, OCH2CH3, (CH3)2CH), 3.52(3 H, s, NCH3), 3.71 (2 H, t, J 6 Hz, OCH2), 6.83 (2 H, d, J 1.6 Hz, arom-H), 7.12 (t-like, arom-H). Elementary analysis (for C26H38N2O2Cl2S) Calcd. : C, 60.80% H, 7.46% N, 5.46% Found: C, 60.99% H, 6.56% N, 5.41%
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2Cl)[CH2:6]1)(=[O:3])[CH3:2].[NH:27]1[CH:31]=[CH:30][CH:29]=[N:28]1.C([O-])([O-])=O.[K+].[K+].C(O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@@]2(C)[C@H]3CCC2N2C=CC=N2)C1)(=O)C>>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2[N:27]2[CH:31]=[CH:30][CH:29]=[N:28]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: c1cn[nH]c1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(Cl)=C(C=O)C[C@@H]32)C1
Agent: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4cccn4)CC[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4cccn4)=C(C=O)C[C@@H]32)C1
Yield: 62.8 %

Procedure:
Reaction of 3β-acetoxy-17-chloro-16-formylandrosta-5,16-diene (Compound 3) (0.5 g, 1.329 mmol), pyrazole (136 mg, 1.994 mmol) and K2CO3 (551 mg, 3.99 mmol) as described for Synthesis Example 7 after FCC (silica gel, pet. ether/EtOAc, (4:1)) gave a mixture (341 mg, approx. 3:1) of 3β-acetoxy-17-(1H-pyrazol-1-yl)-16-formylandrosta-5,16-diene and 3β-acetoxy-17-(1H-pyrazol-1-yl)androsta-5-ene. This mixture resisted separation by chromatography.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C([O-])(=O)C.[Na+].[I:15]Cl>C(O)(=O)C>[CH2:1]([C:3]1[CH:9]=[C:8]([I:15])[CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2]
Reactant: CCc1ccccc1N
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cc(I)ccc1N
Temperature: 20 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-ethylaniline (1.88 g, available from Aldrich) and sodium acetate (1.27 g) in acetic acid (20 ml) was added iodine monochloride (1 ml, available from Aldrich). The mixture was stirred at 20° C. for 90 min and then the solvent was removed in vacuo. The residue was partitioned between ethyl acetate (25 ml) and saturated aqueous sodium carbonate solution (25 ml). The organic layer was dried using a hydrophobic frit and the solvent was removed in vacuo. Purification by C18 SPE eluting with 20% acetonitrile in water gave the title compound as a purple solid (0.402 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[N:9]([O-])=O.[Na+].O.O.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:9])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(F)c1
Reaction time: 0.17 h

Procedure:
A 10 g portion of 3-fluoroaniline was suspended in 100 ml of concentrated hydrochloric acid, 50 ml of 13% sodium nitrite aqueous solution was gradually added thereto under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes. Next, a suspension consisting of 75 g of tin chloride dihydrate and 50 ml of concentrated hydrochloric acid was added thereto, and the mixture was stirred for 1 hour while gradually returning to room temperature. Under ice-cooling, the reaction solution was adjusted to a pH value of about 9 by adding sodium hydroxide and extracted with chloroform, and then the thus obtained organic layer was dried with anhydrous sodium sulfate and the solvent was evaporate d under a reduced pressure. The residue was made into hydrochloride with 1 N hydrochloric acid/ethanol and then recrystallized from an ether-ethanol mixed solvent to obtain 11 g of the title compound as a white powder.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=2[CH:30]=[O:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:33]1C=CC(F)=CC=1C(=O)C>>[C:30]([C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[C:8]1[NH:9][C:10]2[C:15]([C:7]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[CH:14][CH:13]=[C:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH:11]=2)(=[O:31])[CH3:33]
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(-c3ccc(F)cc3C=O)[nH]c2c1
Reactant: CC(=O)c1cc(F)ccc1Br
Product: CC(=O)c1cc(F)ccc1-c1[nH]c2cc(C(=O)OC(C)(C)C)ccc2c1C1CCCCC1
Yield: 65 %

Procedure:
The title product tert-butyl 2-(2-acetyl-4-fluorophenyl)-3-cyclohexyl-1H-indole-6-carboxylate 33c was synthesized following the procedure reported for the synthesis of tert-butyl 3-cyclohexyl-2-(4-fluoro-2-formylphenyl)-1H-indole-6-carboxylate 32d, using 1-(2-bromo-5-fluorophenyl)ethanone 33b instead of 2-bromo-5-fluorobenzaldehyde 32c, and was obtained in 65% yield as a white solid; m/z 436 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[CH2:10]([N:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu]I>[CH2:10]([N:17]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=2[CH3:9])[C:18]1=[O:22])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1c(Br)cccc1Br
Reactant: O=C1NCCN1Cc1ccccc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c(Br)cccc1N1CCN(Cc2ccccc2)C1=O
Temperature: 120 °C
Reaction time: 18.25 h
Yield: 24.5 %

Procedure:
Step 2 A mixture of 1,3-dibromo-2-methylbenzene (0.147 mL, 1.064 mmol), 1-benzylimidazolidin-2-one (75 mg, 0.426 mmol), copper (I) iodide (8.11 mg, 0.043 mmol), (+/−)-trans-1,2-diaminocyclohexane (5.1 mL, 0.043 mmol) and tripotassium phosphate (181 mg, 0.851 mmol) in dioxane (2 mL) was sonicated while bubbling with argon for 1 min. The mixture was heated in a sealed tube at 120° C. After 18.25 h, the mixture was cooled to rt, diluted with EtOAc and filtered through Celite. The filtrate was concentrated and the residue was purified by column chromatography (eluting with a gradient from 20:80 EtOAc-hexane to EtOAc) to provide 1-benzyl-3-(3-bromo-2-methylphenyl)imidazolidin-2-one as a waxy white solid (36 mg, 25%). 1H NMR (400 MHz, chloroform-d) δ 7.49 (1 H, dd, J=7.9, 0.9 Hz), 7.28-7.40 (5 H, m), 7.19 (1 H, dd, J=7.8, 1.0 Hz), 7.08 (1 H, t, J=7.9 Hz), 4.46 (2 H, s), 3.64 (2 H, dd, J=8.8, 6.8 Hz), 3.37 (2 H, dd, J=8.8, 7.0 Hz), 2.36 (3 H, s). Mass spectrum m/z 346.8 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:40])[CH:9]([C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[C:23]([O:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:22]([O:35]S(C)(=O)=O)[N:21]=1)[CH2:10][CH2:11][CH2:12][CH:13](OS(C)(=O)=O)[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CS(Cl)(=O)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH3:40])[C@@H:9]1[CH2:10][CH2:11][CH2:12][C@@H:13]([CH3:14])[N:21]2[C:22](=[O:35])[C:23]([O:30][S:31]([CH3:34])(=[O:32])=[O:33])=[C:24]([C:26]([O:28][CH3:29])=[O:27])[N:25]=[C:20]12)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1nc(C(CCCC(C)OS(C)(=O)=O)N(C)C(=O)OC(C)(C)C)nc(OS(C)(=O)=O)c1OS(C)(=O)=O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc2n(c(=O)c1OS(C)(=O)=O)[C@H](C)CCC[C@H]2N(C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of the methyl 2-{1-[(tert-butoxycarbonyl)(methyl)amino]-5-[(methylsulfonyl)oxy]hexyl}-5,6-bis[(methylsulfonyl)oxy]pyrimidine-4-carboxylate (62 g, 98 mmol) and cesium carbonate (64 g, 196 mmol) in DMF (400 mL) was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and then cooled further to 0° C. More cesium carbonate (60 g) was added followed by MsCl (10 mL) and stirring continued for 1 hour. The reaction mixture was filtered to remove solids and the solids were then washed with methylene chloride until the filtrate ran clear. The filtrate was then stripped and finally under high vacuum at 35° C. to remove the DMF. The thick dark red residual sludge was diluted with ether and filtered. The filter cake was washed with ether. The resulting cream colored solid was dissolved in methylene chloride and washed once with cold half-saturated brine and the solution dried over sodium sulfate. Filtration and concentration gave the racemic trans diastereomer as determined by NMR and LC-MS: 1H NMR (400 MHz, CDCl3) δ 5.74 (m, 1H), 5.41 (dd, J=1.6, 13.5 Hz, 1H), 3.92 (s, 3H), 3.50 (s, 3H), 2.95 (s, 3H), 1.60-2.94 (m, 6H), 1.57 (d, J=7.3 Hz, 3H), 1.44 (s, 9H). ES MS M+1=460.12.