Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>C(NCC)C.[Pd](Cl)Cl.[Cu]I>[OH:35][CH2:31][CH2:32][CH2:33][CH2:34][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)c1ccc(CCCCO)cc1
Yield: 75.8 %

Procedure:
To a mixture of 0.082 g (0.005 eq) of palladium chloride, and 0.244 g (0.01 eq) of triphenylphosphine, and 20.00 g (1.0 eq) of methyl 4-bromobenzoate in diethylamine which is stirred under nitrogen is added 0.178 g (0.01 eq) of copper (I) iodide and 6.52 g (1.0 eq) of 3-butyn-1-ol. The reaction mixture is stirred under nitrogen at room temperature (about 25° C.) for eighteen hours. Diethylamine is then removed under reduced pressure, water is added, and the mixture extracted with benzene. The benzene extracts are filtered through silica to remove the metal residue and the filtrate concentrated under reduced pressure to yield methyl 4-(4-hydroxybut-1-yl)benzoate. Recrystallization from a mixture of benzene and hexane yields pure material in 75.8% yield, m.p. 95.5°-96.0° C.; IR (KBr) νmax 3310, 2955, 1718, 1604, 1433, 1275, 1177, 1108, 1040, 955, 852, and 769 cm-1 ; 1H NMR (CDCl3) delta 7.98 (d, J=8.3 Hz, 2H, Ar), 7.49 (d, J=8.3 Hz, 2H, Ar), 3.93 (s, 3H, --CH3), 3.87 (m, 2H, --CH2OH), 2.74 (t, J=6.2 Hz, 2H, --yl--CH2 --), 1.88 (m, 1H, --OH).
Reaction SMILES: [OH-].[K+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].[C:17](=[S:19])=[S:18].[CH3:20]I>C(O)C.O>[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][NH:3][C:17](=[S:19])[S:18][CH3:20])([OH:16])=[O:15]
Reactant: NCCCCCCCCCCC(=O)O
Reactant: S=C=S
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSC(=S)NCCCCCCCCCCC(=O)O
Reaction time: 12 h

Procedure:
A suspension of 56 g. (1.0 mol.) of potassium hydroxide and 100 g. (0.5 mol.) of 11-aminoundecanoic acid in 170 ml. of water was stirred for 30 minutes at 25° then 40 g. (0.52 mol.) of carbon disulfide and 80 ml. of ethanol were added and the reaction mixture was stirred at 25° for 12 hours. The mixture was refluxed gently for two hours and cooled. Methyl iodide (71 g., 0.3 mol.) and 130 ml. of ethanol were added to the mixture and it was stirred at 25° for 12 hours. The mixture was evaporated to remove the ethanol and the solid residue was collected by filtration to give methyl 10-carboxydecyldithiocarbamate.
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]([N+:30]([O-:32])=[O:31])([N+:27]([O-:29])=[O:28])[CH2:8][N:9]([N+:24]([O-:26])=[O:25])[CH2:10][C:11]([N+:21]([O-:23])=[O:22])([N+:18]([O-:20])=[O:19])[CH2:12][CH2:13][O:14]C(=O)C)(=O)C.CO.Cl>O>[N+:30]([C:7]([N+:27]([O-:29])=[O:28])([CH2:8][N:9]([N+:24]([O-:26])=[O:25])[CH2:10][C:11]([N+:18]([O-:20])=[O:19])([N+:21]([O-:23])=[O:22])[CH2:12][CH2:13][OH:14])[CH2:6][CH2:5][OH:4])([O-:32])=[O:31]
Reactant: CC(=O)OCCC(CN(CC(CCOC(C)=O)([N+](=O)[O-])[N+](=O)[O-])[N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: O=[N+]([O-])N(CC(CCO)([N+](=O)[O-])[N+](=O)[O-])CC(CCO)([N+](=O)[O-])[N+](=O)[O-]

Procedure:
Crude 3,3,5,7,7-pentanitro-5-azanonane-1,9-diol-1,9-diacetate (66.5 g) was stirred in 615 ml of warm (50° C.) MeOH in a 2000 ml round-bottom flask. Distilled water (265 ml) was added followed by 19 ml of concentrated hydrochloric acid. The mixture was heated at 67°-69° C. (mild reflux) overnight before nearly all the solvent was removed under reduced pressure on a rotary evaporator (water bath at 35° C.). The white solid (mp 118°-120° C.) was removed by filtration and washed with cold water. Crystallization from methanol-water gave 50.0 g, mp 121.5°-123° C. The second crop (2.9 g, mp 118°-120° C.) raised the yield to 52.9 g (97 percent). 1H NMR (acetone-d6 +1 dr. D2O): δ3.00 (t, 2H), 2.90 (t, 2H), 5.57 (s, 2H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[I:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>N1C=CC=CC=1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([I:24])=[CH:26][CH:27]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(NC(=O)c3ccc(I)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
A mixture of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (300 mg), 4-iodobenzoyl chloride (520 mg) and a catalytic amount of N,N-dimethylaminopyridine in pyridine (4 ml) was stirred for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with saturated aq. NaHCO3, water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].C(N(CC)CC)C.Cl[CH2:20][CH2:21][N:22]([CH2:33][CH2:34]Cl)[S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CN(C)C=O>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([S:23]([N:22]2[CH2:21][CH2:20][N:1]([C@H:2]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][C@H:3]3[OH:11])[CH2:34][CH2:33]2)(=[O:25])=[O:24])=[CH:27][CH:28]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCN([C@H]3c4ccccc4C[C@H]3O)CC2)cc1
Temperature: 80 °C

Procedure:
To 8 g of (1S,2R)-1-aminoindan-2-ol (53.6 mmol) dissolved in 80 ml of dimethylformamide there are added 15 ml of triethylamine (107.2 mmol) and 15.8 g of N,N-bis(2-chloroethyl)-p-toluenesulphonamide (53.6 mmol). The mixture is heated at 80° C. for 24 hours and then the dimethylformamide is evaporated off. The residue is taken up in dichloromethane, washed, dried, filtered and evaporated. The oil obtained is purified by flash chromatography on silica (eluant: dichloromethane/ethyl acetate 95/5) to yield the expected product in the form of a meringue.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[C:3]([OH:5])=[O:4].O=S(Cl)Cl.[CH3:15]O>>[CH3:15][O:4][C:3](=[O:5])[C@@H:2]([NH2:1])[CH2:6][CH2:7][CH2:8][CH2:9][OH:10]
Reactant: N[C@@H](CCCCO)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)CCCCO
Temperature: 0 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
(S)-2-Amino-6-hydroxy-hexanoic acid (Chemstep) (5.54 mmol, 1.37 g) was dissolved in 100 mL of MeOH and cooled at 0° C. SOCl2 (13.8 mmol, 1 mL, 2.5 eq) was added dropwise. The reaction mixture was stirred overnight at room temperature after which time the solvent was removed in vacuo. The crude solid was recrystallised from MeOH (3×100) to give the methyl ester 82 as an oil (5.52 mmol, 0.89 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:11][C:12]1([F:30])[CH2:17][CH2:16][C:15]([CH2:28][NH2:29])([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:29][CH2:28][C:15]1([C:18]2[CH:19]=[N:20][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:22][CH:23]=2)[CH2:16][CH2:17][C:12]([F:11])([F:30])[CH2:13][CH2:14]1)=[O:6]
Reactant: O=C(O)c1ccccc1Cl
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1)c1ccccc1Cl

Procedure:
From 2-chlorobenzoic acid and (4,4-difluoro-1-(6-(trifluoromethyl)pyridin-3-yl)cyclohexyl)methanamine. LCMS (MH+): m/z=433.2, tR (minutes, Method D)=0.78
Reaction SMILES: N[C@@H](CC1C=CC=CC=1)C(N[C@H:6]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=2[N:8]([CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)[C:7]1=[O:29])=O.C(N(CC)CC)C.C1(N=C=S)C=CC=CC=1>O1CCCC1>[C:13]1([C:11]2[C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]=3[N:8]([CH2:23][C:24]3[NH:28][N:27]=[N:26][N:25]=3)[C:7](=[O:29])[CH2:6][N:12]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(Cc2nnn[nH]2)C1=O
Solvent: C1CCOC1
Solvent: S=C=Nc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1CN=C(c2ccccc2)c2ccccc2N1Cc1nnn[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 179.4 %

Procedure:
To a mixture of (3S)-3-[((2S)-2-amino-3phenylpropanoyl)amino]-1,3-dihydro-5-phenyl-1 -[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (12 g) and triethylamine (3.83 ml) in tetrahydrofuran (240 ml) was added phenyl isothiocyanate (2.99 ml) at room temperature. After stirring for 4 hours at room temperature, the solvent of the reaction mixture was evaporated under reduced pressure. Hydrochloric acid was added to the residue, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from ether to give (3S)-3-[[(2S)-2-[N'-phenyl)thioureido]-3-phenylpropanoyl]amino ]1,3-dihydro-5-phenyl-1-[(1H-tetrazol-5-yl)methyl]-2H-1,4-benzodiazepin-2-one (14.26 g).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([CH3:29])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[C:15]3[O:14][CH:13]([CH2:12][NH:31][CH3:30])[CH2:17][C:16]=3[CH:18]=[C:19]([CH3:29])[CH:20]=2)=[CH:23][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)cc(-c4ccc(Cl)cc4)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C)cc(-c3ccc(Cl)cc3)c2O1

Procedure:
The title compound was prepared (0.026 g, 21%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[7-(4-chlorophenyl) 5-methyl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.16 g, 0.37 mmol) and methylamine (0.115 g, 3.7 mmol). mp 210-213° C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([CH3:35])[CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:20][CH:19]=1.B(Br)(Br)[Br:37]>>[BrH:37].[OH:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[NH:9][C:8](=[O:14])[C:7]3[S:15][CH:16]=[CH:17][C:6]=3[C:5]=2[C:4]=1[C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]([CH3:35])[CH2:25][NH:26][CH3:27])=[CH:20][CH:19]=1
Reactant: BrB(Br)Br
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CN(C)C(=O)OC(C)(C)C)cc1
Product: Br
Product: CNC[C@H](C)c1ccc(-c2c(O)cc(C)c3[nH]c(=O)c4sccc4c23)cc1
Yield: 54 %

Procedure:
Following General Procedure F, (R)-tert-butyl 2-(4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propyl(methyl)carbamate (2.08 g, 4.23 mmol) was treated with BBr3 (1.0 M in CH2Cl2, 40 mL, 40 mmol) to afford the desired product as a yellow solid (1.05 g, 65%); 1H NMR (500 MHz, CD3OD) δ 7.60-7.54 (m, 2H), 7.46 (dd, J=7.8, 1.9 Hz, 1H), 7.37 (dd, J=7.9, 1.8 Hz, 1H), 7.31 (dd, J=7.7, 1.7 Hz, 1H), 7.08 (d, J=0.8 Hz, 1H), 6.16 (d, J=5.4 Hz, 1H), 3.37-3.24 (m, 3H), 2.74 (s, 3H), 2.57 (s, 3H), 1.50 (d, J=6.8 Hz, 3H); ESI MS m/z 379 [C22H22N2O2S+H]+; HPLC >99% (AUC), tR=8.74 min.
Reaction SMILES: [F:1][C:2]1C(F)=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]1([NH:37][C:38]([NH:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[S:39])[C@H:13]([CH2:14]O)[C@@H:12]([CH2:16][O:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:11][CH2:10]1.N1C=CC=CC=1.F[C:56]([F:69])(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[NH4+].[Cl-]>C(Cl)Cl.O>[F:1][C:2]1[C:56]([F:69])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:10][O:11][C@H:12]([CH2:16][O:17][C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C@H:13]1[CH2:14][S:39][C:38]([NH:40][C:41](=[O:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[N:37]2
Reactant: O=C(NC(=S)N[C@@]1(c2cccc(F)c2F)CO[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CO)c1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC1=N[C@@]2(c3cccc(F)c3F)CO[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H]2CS1)c1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 101.7 %

Procedure:
To a solution of N-(((3S,4R,5S)-3-(2,3-difluorophenyl)-4-(hydroxymethyl)-5-((trityloxy)methyl)tetrahydrofuran-3-yl)carbamothioyl)benzamide (34.0 g, 0.0511 mol, 1.0 equiv.) in CH2Cl2 (204 mL) at −20° C., pyridine (10.3 ml, 0.128 mol, 2.50 equiv.) was added. A solution of trifluoromethanesulfonic anhydride (9.46 mL, 0.0563 mol, 1.10 equiv.) in CH2Cl2 (34 mL) was then added over 12 min while maintaining temperature below −17° C. The reaction was stirred for 30 min at −20° C. then allowed to warm up slowly to 5° C. Sat aq. NH4Cl (85 mL) and water (32 mL) were added. The aqueous layer was then extracted with CH2Cl2 (68 mL). The organic phase was concentrated under reduced pressure providing title compound (33.6 g) as an orange foam.
Reaction SMILES: [C:1]1([C:7]([C:9]2[CH:25]=[CH:24][C:12]([C:13]([N:15]3[CH2:20][CH2:19][C:18]4[CH:21]=[CH:22][O:23][C:17]=4[CH2:16]3)=[O:14])=[CH:11][CH:10]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.[CH2:31]=O>C(O)(=O)C>[C:1]1([C:7]([C:9]2[CH:25]=[CH:24][C:12]([C:13]([N:15]3[CH2:20][CH2:19][C:18]4[CH:21]=[C:22]([CH2:31][N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)[O:23][C:17]=4[CH2:16]3)=[O:14])=[CH:11][CH:10]=2)=[CH2:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=O
Reactant: C=C(c1ccccc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Reactant: C1CCNC1
Solvent: CC(=O)O
Product: C=C(c1ccccc1)c1ccc(C(=O)N2CCc3cc(CN4CCCC4)oc3C2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 0.724 g (2.198 mmol) of the above 6-[4-(1-phenylethenyl)benzoyl]-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 10 ml of acetic acid, 0.28 ml (3.30 mmol) of pyrrolidine and 0.27 g (3.30 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with ethyl acetate 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3]1.S(Cl)([Cl:21])=O.CCOC(C)=O>C1(C)C=CC=CC=1>[Cl:21][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3]1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C1CCC(O)C=C1c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(Cl)C=C1c1ccccc1
Reaction time: 3 h
Yield: 102.1 %

Procedure:
To a stirred solution of ethyl 4-hydroxy-2-phenylcyclohex-2-enecarboxylate (10 mg, 0.407 mmol) in toluene(2 ml) was added thionyl chloride(0.074 ml, 1.02 mmol) at 5° C. After stirring for 3 hr. at room temperature. AcOEt was added to the reaction mixture and it was washed with water, sat.NaHCO3 aq. and brine, dried over MgSO4. Concentration of the organic layer afford 110 mg of ethyl 4-chloro-2-phenylcyclohex-2-enecarboxylate(y=100%) as a pale yellow oil. 1H-NMR(ppm, 300 MHz, CDCl3) δ 7.25-7.37(5H, m), 6.27 and 6.18(1H, d and t, J=4.6 and 1.7 Hz), 4.87-4.91 and 4.74-4.79(1H, m), 4.03 and 3.96(2H, q, J=6.9 and 7.1 Hz), 3.68-3.76(1H, m), 2.05-2.37(4H, m), 1.09 and 0.97(3H, t, J=6.9 and 7.1 Hz)
Reaction SMILES: CI.[CH3:3][C@@H:4]1[CH2:9][C@H:8]2[C@H:10]3[C:20](=[CH:21][CH2:22][C@:6]2([CH3:7])[C@H:5]1[C:24]([O-:26])=[O:25])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3.[CH:27](N(C(C)C)CC)(C)C.[I-]>C(#N)C>[CH3:27][O:25][C:24]([C@H:5]1[C@H:4]([CH3:3])[CH2:9][C@H:8]2[C@H:10]3[C:20](=[CH:21][CH2:22][C@:6]12[CH3:7])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:23])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3)=[O:26]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)[O-]
Agent: [I-]
Solvent: CC#N
Solvent: CI
Product: COC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)C3=CC[C@@]21C
Reaction time: 2 h

Procedure:
Methyl iodide (7.9 ml) is added to a solution of 16α-methylandrosta-4,9(11)-dien-3-one 17β-carboxylate (7.9 g) and diisopropylethylamine (17.5 ml) in acetonitrile (175 ml). The mixture is allowed to stand at 20°-25° for 2 hr and then a second addition of amine (9 ml) and iodide (4 ml) is made. The mixture is allowed to stand overnight at 20°-25° and then concentrated under reduced pressure. The residue is partitioned (water and methylene chloride) and the extract is concentrated and chromatographed on silica gel (750 g) . Elution is performed with acetone/methylene chloride (2-5%/98-95%). The appropriate fractions are pooled and concentrated to give the title compound, m.p. 127.5° (acetone-hexane)
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]([CH3:15])[NH2:14]>C(N(CC)CC)C.CO>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:14][N:13]([CH3:15])[CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CN(C)N
Solvent: CO
Solvent: CCN(CC)CC
Product: CN(C)Nc1cc(F)ccc1[N+](=O)[O-]
Yield: 48.8 %

Procedure:
10 g (0.0628 mol) of 2,4-difluoronitrobenzene was stirred for 4 days with 4.36 g (0.0728 mol) of N,N-dimethylhydrazine in 7.08 g of triethylamine and 100 ml methanol. The mixture was concentrated and the resulting solid dissolved in methylene chloride, washed with water and brine, dried with MgSO4 and concentrated to yield an orange solid. The solid was triturated in 95% ethanol/water, filtered and dried to give 6.1 g 4-fluoro-2-(2,2-dimethylhydrazino) nitrobenzene, m.p. 67°-71° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:18][O:19][C:20]([O:23][Si](C)(C)C)=[CH:21][CH3:22].C(Cl)Cl>CC#N.Cl[Ti](Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:21]([CH3:22])[C:20]([O:19][CH3:18])=[O:23])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC=C(OC)O[Si](C)(C)C
Reactant: OC(c1ccccc1)c1ccc2[nH]ncc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)C(C)C(c1ccccc1)c1ccc2[nH]ncc2c1
Reaction time: 1 h

Procedure:
To a solution of (1H-indazol-5-yl)(phenyl)methanol (180 mg, 0.71 mmol) and (1-methoxyprop-1-enyloxy)trimethylsilane (0.32 mL, 1.78 mmol) in 10 mL of dry MeCN was added TiCl4 (2.5 mL of 1.0 M DCM solution, 2.5 mmol) and then stirred 1 h. The reaction was incomplete so added 10 mL of DCM and additional (1-methoxyprop-1-enyloxy)trimethylsilane (0.3 mL, 1.7 mmol) After 1 h, the reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated. HPLC purification resulted in the resolution of the two diastereomers of methyl 3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoate which were taken independently to the next step. MS found: (M+H)+=295.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]3[CH:20]=[C:19]([Sn](CCCC)(CCCC)CCCC)[N:18]=[CH:17]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:34][C:35]([NH:38][S:39]([C:42]1[S:46][C:45](Br)=[CH:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])[CH3:36].CCCCCC>C1(C)C=CC=CC=1.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>[C:35]([NH:38][S:39]([C:42]1[S:46][C:45]([C:19]2[N:18]=[CH:17][N:16]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([CH3:15])[N:12]=3)[CH:20]=2)=[CH:44][CH:43]=1)(=[O:40])=[O:41])([CH3:37])([CH3:34])[CH3:36]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(Cl)c3)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
A stirred mixture of 4-(3,4-dichloro-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.4) (0.45 g, 0.76 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.25 g, 0.84 mmol), tetrakis(triphenylphosphine)palladium (0.053 g, 0.046 mmol) in toluene (8 mL) was heated under reflux conditions for 15 h, hexane (10 mL) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(3,4-dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.41 g) as a light brown solid.
Reaction SMILES: Cl[CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:5]=2[NH:4][C:3]1=[O:15].[N-:16]=[N+:17]=[N-:18].[Na+]>CS(C)=O>[N:16]([CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:5]=2[NH:4][C:3]1=[O:15])=[N+:17]=[N-:18]
Reactant: COc1ccc2c(c1)NC(=O)C(Cl)CC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)NC(=O)C(N=[N+]=[N-])CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-chloro-8-methoxy-2,3,4,5,-tetrahydro-1H-[1]-benzazepin-2-one (12.5 g) and sodium azide (4.3 g) in dimethylsulfoxide (150 ml) was maintained at 80° under an atmosphere of nitrogen for 3 hours. The reaction mixture was poured into ice/water (300 ml) and the suspension was stirred for 30 minutes. The solid was filtered off, washed with water (50 ml) and dried to give 3-azido-8-methoxy-2,3,4,5-tetrahydro-1H-[1]-benzazepin-2-one, m.p. 136°-138°.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]1=[O:9].[C:11](C#N)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH2:21](N(CC)CC)C.Cl>ClCCl.[Cl-].[Zn+2].[Cl-]>[C:11]([CH:4]1[C:5](=[O:8])[CH:6]([CH3:21])[CH2:7][C:2]([CH3:10])([CH3:1])[C:3]1=[O:9])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: N#CC(=O)c1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1CC(C)(C)C(=O)C(C(=O)c2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 5.5 h

Procedure:
Alternatively, the compounds of formula (V) can be prepared according to a second representative procedure, as follows: 4,4-dimethyl-1,3-cyclohexanedione 7 (1 mole eq) (commercially available) and benzoyl cyanide are dissolved in anhydrous dichloromethane and cooled to 0° C. under an atmosphere of nitrogen. To the cooled solution is added anhydrous finely powdered zinc chloride (1.1 mole eq) followed by slow addition of triethylamine (1.2 mole eq). The reaction mixture is stirred at room temperature for 5-6 h and then poured into 2 M hydrochloric acid. The mixture is partitioned and the dichloromethane layer washed with 5% sodium carbonate. The aqueous carbonate phase is then acidified with hydrochloric acid and extracted with methylene chloride and dried (Na2SO4). The solvent is removed and the residue subjected to SiO2 column chromatography (hexane/ethyl acetate) affording 1-benzoyl-3,3,5-trimethylcyclohexan-2,6-dione 8. (W. J. Michaely and G. W. Kraatz, EP-B-135191).