Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.C([O:9][C:10]1([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[N:23]=[C:22]([NH:24][C:25]([C:27]4[N:28]=[C:29]([CH3:39])[O:30][C:31]=4[C:32]4[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=4)=[O:26])[CH:21]=[N:20]3)[O:16][CH:17]=2)[CH2:12][CH2:11]1)(=O)C(C)(C)C.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C1COCC1>[OH:9][C:10]1([C:13]2[N:14]=[C:15]([CH2:18][N:19]3[N:23]=[C:22]([NH:24][C:25]([C:27]4[N:28]=[C:29]([CH3:39])[O:30][C:31]=4[C:32]4[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=4)=[O:26])[CH:21]=[N:20]3)[O:16][CH:17]=2)[CH2:11][CH2:12]1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3nc(C4(OC(=O)C(C)(C)C)CC4)co3)n2)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: N#N
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Solvent: C1CCOC1
Product: Cc1cccc(-c2oc(C)nc2C(=O)Nc2cnn(Cc3nc(C4(O)CC4)co3)n2)c1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(2-((4-(2-methyl-5-(m-tolyl)oxazole-4-carboxamido)-2H-1,2,3-triazol-2-yl)methyl)oxazol-4-yl)cyclopropyl pivalate (70 mg, 0.14 mmol) in THF (1.4 mL) was treated at 0° C. with DiBAL-H (0.7 mL of a 1M solution in THF, 0.70 mmol) and the resulting solution was stirred for 3.5 h at 0° C. The reaction mixture was poured onto a Rochelle's salt aq. solution (14 mL) and the mixture was vigorously stirred for 2 h at rt. The two layers were separated and the aq. phase was extracted with EA (14 mL). The combined org. layers were dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a yellow oil: TLC: rf (4:6 hept-EA)=0.30. LC-MS-conditions 06: tR=0.86 min, [M+H]+=421.22
Reaction SMILES: [Na].C(O[C:5](=[O:9])[CH2:6][O:7][CH3:8])C.[CH3:10][C:11]([CH3:13])=[O:12].COC(C)(C)C>C1(C)C=CC=CC=1>[CH3:8][O:7][CH2:6][C:5](=[O:9])[CH2:10][C:11](=[O:12])[CH3:13]
Reactant: CCOC(=O)COC
Reactant: CC(C)=O
Agent: [Na]
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: COCC(=O)CC(C)=O
Reaction time: 3 h
Yield: 36.9 %

Procedure:
To a solution of sodium (5.83 g, 243.3 mmol) in dry toluene (62.5 mL) was added ethyl(methyloxy)acetate (24 g, 203.4 mmol) at −5° C. After stirring for 3 h, acetone (14 g, 231.4 mmol) was slowly added, upon which the mixture became brown and viscous. Next added 72 mL of tert-butyl methyl ether, and the reaction mixture was stirred at room temperature for 12 h, after which time the sodium salt precipitated. After collection and washing with additional tert-butyl methyl ether, the sodium salt was dissolved in 46 mL of 20% H2SO4. The contents were extracted with tert-butyl methyl ether and the organic layers concentrated to afford 1-(methyloxy)-2,4-pentanedione (9.76 g, 36.9%). 1H NMR (400 MHz, CDCl3-d3) δ 5.76 (s, 1H), 3.96 (s, 2H), 3.38 (s, 3H), 2.07 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[NH2:6].Br[CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].N1C(C)=CC=CC=1C>C(#N)C>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([C:10]([F:11])([F:12])[F:13])=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:4]=1)[CH3:23])[CH3:22]
Reactant: Nc1ccc(C(F)(F)F)c(C(F)(F)F)c1
Reactant: CCOC(=O)C(C)Br
Solvent: Cc1cccc(C)n1
Solvent: CC#N
Product: CCOC(=O)C(C)Nc1ccc(C(F)(F)F)c(C(F)(F)F)c1
Yield: 49 %

Procedure:
In analogy to intermediate 40B, 3,4-bis(trifluoromethyl)aniline and ethyl 2-bromopropionate with 2,6-lutidine were heated for 20 h at 82° C., diluted with acetonitrile and treated with 1 equivalent of ethyl 2-bromopropionate and 2,6-lutidine and refluxed for 2 days, treated again with 1 equivalent of ethyl 2-bromopropionate and 2,6-lutidine and continued to reflux for 2 days. Workup and purification by flash silica gel column (n-heptane/ethyl acetate 9:1 to 2:1) yielded 49% of the titled compound as yellow oil. MS: 328.08 (M−H−).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[CH2:7][CH:8]([CH3:19])[N:9]3[C:14]=2[C:13]=1[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]3.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:20])[CH2:7][CH:8]([CH3:19])[N:9]3[C:14]=2[C:13]=1[C:12](=[O:15])[C:11]([C:16]([OH:18])=[O:17])=[CH:10]3)(=[O:23])[CH3:22]
Reactant: CC1CC(=O)c2ccc(N)c3c(=O)c(C(=O)O)cn1c23
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2c3c1c(=O)c(C(=O)O)cn3C(C)CC2=O

Procedure:
10-amino-6,7-dihydro-5-methyl-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (0.02 mole) and acetic anhydride (50 ml.) are stirred and heated on a steam bath for 3 hours. After cooling, the solid precipitate is separated by filtration to give 10-acetamido-6,7-dihydro-5-methyl-1,7-dioxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. This product is reduced using sodium borohydride to provide 10-acetamido-6,7-dihydro-7-hydroxy-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]#[C:21][C:22]3[CH:23]=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=3)=[C:18]([CH3:29])[N:17]=[C:16]([NH2:30])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:28][C:25]1[N:24]=[CH:23][C:22]([C:21]#[C:20][C:19]2[C:18]([CH3:29])=[N:17][C:16]([NH2:30])=[N:15][C:14]=2[N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:27][CH:26]=1
Reactant: Cc1nc(N)nc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(N2CCNCC2)c1C#Cc1ccc(N)nc1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
7.1 g (17.3 mmol) of 4-[2-amino-5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester are dissolved in DCM (400 mL) and 40 mL TFA are added. The reaction mixture is stirred over night at RT. The reaction mixture is adjusted to neutral pH using concentrated aqueous Na2CO3 solution and the DCM is evaporated at reduced pressure. The residue is washed with water, taken up in acetonitrile and freeze dried yielding 4.0 g (13.0 mmol) of the desired product which is used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:26]=[CH:25][C:14]([O:15][C:16]3[C:22]([Cl:23])=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=3[Cl:24])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:27][C:28]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:29]=1[C:30]([N:32]=[C:33]=[O:34])=[O:31]>C1(C)C=CC=CC=1>[F:27][C:28]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:29]=1[C:30]([NH:32][C:33]([NH:20][C:19]1[CH:21]=[C:22]([Cl:23])[C:16]([O:15][C:14]2[CH:25]=[CH:26][C:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])=[CH:12][CH:13]=2)=[C:17]([Cl:24])[CH:18]=1)=[O:34])=[O:31]
Reactant: Nc1cc(Cl)c(Oc2ccc(S(=O)(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cc(Cl)c(Oc2ccc(S(=O)(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
To a 250 mL flask equipped with stirrer, condenser, under nitrogen atmosphere was added 10 g (0.023 mol) of 4-(4-[4-chlorophenylsulfonyl]phenoxy)-3,5-dichloroaniline and 130 mL of toluene. The mixture was heated up to 80° to obtain a clear solution. A solution of 6.82 g of 2,6-difluorobenzoylisocyanate and 4 mL of toluene was added. The resulting mixture was stirred at 80° for 1.5 hours. The reaction mixture was cooled and filtered to give 14.2 g (0.023 mol) of a white solid; mp 207.2°-209.2° C.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[C:18]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[CH:17]=[N:16]3)[CH:10]=[N:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[Cl:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[CH2:24][NH:23][C:18]1[CH:17]=[N:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:11]3[CH:10]=[N:9][NH:8][CH:12]=3)[CH:14]=2)[N:19]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2ccc3nc(NCc4cccc(Cl)c4)cnc3c2)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Clc1cccc(CNc2cnc3cc(-c4cn[nH]c4)ccc3n2)c1
Yield: 22.3 %

Procedure:
To a solution of 4-[2-(3-Chloro-benzylamino)-quinoxalin-6-yl]-pyrazole-1-carboxylic acid tert-butyl ester (0.35 g, 0.80 mmol) in DCM (4 mL), was added HCl in dioxane (0.4 mL) at room temperature. After completion of the reaction, the reaction mixture was concentrated and washed with DCM (4 mL) to obtain the title compound (0.06 g, 22%).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH:18]=[CH:17][CH2:16][CH:15]2[CH:11]1[C:12](=O)[NH:13][C:14]2=O)=O)(C)(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:6][NH:8][CH2:9][CH:10]1[CH:18]=[CH:17][CH2:16][CH:15]2[CH:11]1[CH2:12][NH:13][CH2:14]2
Reactant: CC(C)(C)OC(=O)NCC1C=CCC2C(=O)NC(=O)C12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CNCC1C=CCC2CNCC12

Procedure:
4-tert.-Butyloxycarbonylaminomethyl-1,3-dioxo-1,3,3a,4,7,7a-hexahydroisoindole is reduced with lithium aluminium hydride by a method analogous to that described in Example A, method IIb: yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccccc4)cc3CC[C@@H]12
Yield: 70 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), phenylboronic acid (95 mg, 0.78 mmol),0.65 mL of 2M sodium carbonate solution and 2 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), followed by recrystallization from ethyl acetate, to give 139 mg (70%) of the title compound as a white solid. mp 155°. FDMS: m/e=305.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]([OH:31])[CH:10]([CH2:18][CH2:19][N:20]2[C:28](=O)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]2[OH:30])[C:11]([O:13]C(C)(C)C)=[O:12])=[CH:3][CH:2]=1.[BH4-].[Na+]>>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH:9]([OH:31])[CH:10]([CH2:18][CH2:19][N:20]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C(CCN1C(=O)c2ccccc2C1O)C(O)CCc1ccc(-c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(O)C(CCN1Cc2ccccc2C1=O)C(O)CCc1ccc(-c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a solution of the compound (160 mg) obtained from Step 2 above in trifluororacetic acid (2 ml) at room temperature was added sodium borohydride (36 mg) and stirred for 1 h. The volatiles were evaporated under reduced pressure and the residue purified by preparative TLC using 10% methanol-DCM as the mobile phase (100 mg).
Reaction SMILES: C[NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[N:31]1([CH2:37][CH2:38][CH2:39][N:40]2[CH2:45][C:44]3[CH:46]=[C:47](/[CH:50]=[CH:51]/[C:52](O)=[O:53])[CH:48]=[N:49][C:43]=3[NH:42][C:41]2=[O:55])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[ClH:30].[CH3:13][C:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[S:8][C:4]=1[CH2:3][NH:2][C:52](=[O:53])/[CH:51]=[CH:50]/[C:47]1[CH:48]=[N:49][C:43]2[NH:42][C:41](=[O:55])[N:40]([CH2:39][CH2:38][CH2:37][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH2:45][C:44]=2[CH:46]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCCN1CCOCC1)C(=O)N2
Reactant: CNCc1sc2ccccc2c1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: Cl
Product: Cc1c(CNC(=O)/C=C/c2cnc3c(c2)CN(CCCN2CCOCC2)C(=O)N3)sc2ccccc12
Yield: 86 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[3-(3-morpholin-4-yl-propyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3,-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.86 g, 86%) was prepared as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.96 (br s, 1H), 10.01 (br s, 1H), 8.39 (s, 1H), 8.01 (d, J=7.0 Hz, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.73 (d, J=7.0 Hz, 1H), 7.58-7.51 (m, 1H), 7.40 (t, J=7.5 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.21-7.12 (m, 1H), 5.16-4.63 (m, 2H), 4.51-4.49 (m, 2H), 3.94-3.92 (m 2H), 3.80-3.75 (m, 2H), 3.43-3.36 (m, 5H), 3.14-2.93 (m, 6H), 2.41 (s, 3H), 1.96-2.09 (m, 2H); MS (ESI) m/e 520 (M+H)+.
Reaction SMILES: [N:1]1[C:6](C)=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH3:9][S:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:24]#[N:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+].ClCCCN1CCCC1>C(#N)C.CN(C)C=O>[N:1]1([CH2:2][CH2:8][CH2:9][S:10][C:12]2[CH:17]=[CH:16][C:15]([C:18]3([C:24]#[N:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)c1ccc(C2(C#N)CCOCC2)cc1
Reactant: Cc1cccc(C)n1
Agent: ClCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#CC1(c2ccc(SCCCN3CCCC3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
2,6-Lutidine (3.33 ml, 28.6 mmol) was added to a solution of 4-[4-(methylsulfinyl)phenyl]tetrahydro-2H-pyran-4-carbonitrile (2.3 g, 9.23 mmol) in acetonitrile (70 ml). The mixture was cooled in an ice-acetone bath and trifluoroacetic anhydride (3.87 ml, 27.69 mmol) added slowly. The solution was stirred at this temperature under nitrogen for 3 hours. The reaction mixture was then concentrated in vacuo and the residue taken up in methanol (7 ml). Triethylamine (7 ml) was added at 0° C. and the mixture stirred at 0° C. for 30 minutes. N,N-Dimethylformamide (10 ml) was added at 0° C., followed by potassium carbonate (2.8 g, 20.31 mmol) and 1-(3-chloro-propyl)-pyrrolidine (2.72 g, 18.46 mmol) in N,N-dimethylformamide (10 ml). The mixture was then warmed to room temperature and stirred for 18 hours. The reaction mixture was concentrated in vacuo. The residue was taken up in water (50 ml) and extracted with ethyl acetate (2×150 ml). The organic layers were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (97:3:0.3 to 95:5:0.5 by volume) to provide the title compound (2.62 g, 86%) as a solid. 1H NMR (400 MHz, CDCl3) δ 1.77-1.80 (m, 4H), 1.84-1.91 (m, 2H), 2.01-2.14 (m, 4H), 2.48-2.52 (m, 4H), 2.58 (t, 2H), 2.99 (t, 2H), 3.89 (t, 2H), 4.06-4.10 (m, 2H), 7.34-7.39 (m, 4H). LRMS APCI+ m/z 331 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1Br.[Li]C(C)(C)C.[CH3:15][CH:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:17](=[O:18])[CH:16]([CH3:15])[CH2:21][CH2:20][OH:19]
Reactant: Clc1ccc(Br)c(Cl)c1
Reactant: CC1CCOC1=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(CCO)C(=O)c1ccc(Cl)cc1Cl
Temperature: -95 °C
Reaction time: 1 h
Yield: 112.6 %

Procedure:
To a 2 L, 3-neck round bottom flask, equipped with a mechanic stirrer and an internal temperature controller, is added a solution of 2,4-dichlorobromobenzene (65.5 g, 290.7 mmol) in 1.1 L of THF under nitrogen. The solution is cooled to −95° C. with a MeOH/liquid nitrogen bath. To this solution is added t-BuLi (400 mL, 1.6 M in pentane, 639.5 mmol) slowly via syringe pump followed by the addition of a solution of α-methyl-γ-butyrolactone (43.5 g, 434.8 mmol) in THF (100 mL). The internal temperature is controlled <−80° C. After 1 h stirring <−80° C., the reaction mixture is quenched with saturated NH4Cl solution and warmed to room temperature. Water (2 L) and EtOAc (1 L) are added and separated. The aqueous layer is extracted with EtOAc (2×2 L). The combined organic solutions is dried (MgSO4) and filtered. The filtrate is concentrated in vacuo to dryness to give 80.9 g of 1-(2,4-dichlorophenyl)-4-hydroxy-2-methylbutan-1-one as light yellow oil. The residue is used for Swern oxidation. To a 2 L, 3-neck round bottom flask, equipped with a mechanic stirrer and an internal temperature controller, is added DMSO (104.1 mL, 1465.7 mmol) and CH2Cl2 (1.1 L). The solution is cooled to −80° C. with a MeOH/liquid nitrogen bath. To this solution is added oxalyl chloride (63.9 mL, 732.9 mmol) slowly via syringe pump. The mixture is stirred at −80° C. for 15 min followed by the addition of a solution of the above obtained crude 1-(2,4-dichlorophenyl)-4-hydroxy-2-methylbutan-1-one in CH2Cl2 (150 mL) slowly via syringe pump. After stirring <−70° C. for 1 h, to the mixture is added Et3N (456 mL, 3271.7 mmol). The cooling bath is removed after 5 min and the mixture is stirred at room temperature for 1.5 h. The mixture is diluted with hexanes (6 L) and washed with water (6 L). The aqueous layer is extracted with hexanes (6 L). The combined organic solutions is concentrated in vacuo to dryness and the residue is subjected to column chromatography (silica gel, 1/6 EtOAc/heptane) to give 36 g (50% for two steps) of light yellow oil as the title compound: 1H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 7.61 (d, J=8.3 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.37 (dd, J=2.0, 8.3 Hz, 1H), 3.81–3.76 (m, 1H), 3.18 (dd, J=8.2, 18.6 Hz, 1H), 2.65 (dd, J=5.0, 18.6 Hz, 1H), 1.21 (d, J=7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 206.1, 202.4, 139.5, 139.2, 134.4, 132.7, 132.4, 129.6, 48.8, 42.0, 18.6; IR (liq.) 2974, 2936, 1996, 1910, 1708, 1585, 1457, 1374, 1228, 1191, 1106, 1064, 978, 828, 810 cm−1; MS (CI) m/z 247 (M+), 245 (M+).
Reaction SMILES: [CH2:1](I)[CH3:2].[CH3:4][CH2:5][C@H:6]([C@@H:8]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:9]([OH:11])=[O:10])[CH3:7].O>>[C:16]([O:15][C:13]([NH:12][C@@H:8]([C:9]([O:11][CH2:1][CH3:2])=[O:10])[C@@H:6]([CH2:5][CH3:4])[CH3:7])=[O:14])([CH3:17])([CH3:19])[CH3:18]
Reactant: CCI
Reactant: CC[C@@H](C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: O
Product: CCOC(=O)[C@H](NC(=O)OC(C)(C)C)[C@H](C)CC

Procedure:
The title compound was prepared by the method of Example 8 using ethyl iodide (0.4 mL, 5 mmol) instead of methyl iodide and BOC--D--Ile--OH--0.5 H2O (1.0 g, 4 mmol) instead of the title product of Example 1. Concentration afforded the title compound (1.2 g) as a water white liquid and the structure verified by NMR.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:11]=2[C:10]([CH:27]=[O:28])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].Cl>CO.O>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[C:11]=2[C:10]([CH2:27][OH:28])=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cc(C=O)c2c(C(=O)OCc3ccccc3)cccc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)n1cc(CO)c2c(C(=O)OCc3ccccc3)cccc21
Reaction time: 0.08 h
Yield: 100 %

Procedure:
To a solution of benzyl 1-tert-butoxycarbonyl-3-formylindole-4-carboxylate (363 mg) in methanol (15 ml) was added sodium borohydride (109 mg) at 0° C. and the mixture was stirred for 5 minutes. The resulting mixture was diluted with water and the solution was neutralized with 1N hydrochloric acid. The solution was extracted with ethyl acetate, and then the organic solution was washed successively with saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate and concentrated in vacuo to afford benzyl 1-tert-butoxycarbonyl-3-hydroxymethylindole-4-carboxylate (365 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]([F:30])([F:29])[CH2:26][CH2:27]I>C(#N)C>[F:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:27][CH2:26][C:25]([F:30])([F:29])[F:24])[CH2:14][CH2:13]1
Reactant: FC(F)(F)CCI
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)c1cccc(C2CCN(CCC(F)(F)F)CC2)c1F

Procedure:
Preparation according to Example 1: 4-[2-fluoro-3-(methylsulfonyl)phenyl]piperidine (0.02 g, 0.078 mmol), acetonitrile (2 ml), potassium carbonate (0.02 g, 0.14 mmol), 1,1,1-trifluoro-3-iodopropane (0.010 ml, 0.082 mmol). MS m/z (relative intensity, 70 eV) 353 (M+, 11), 271 (15), 270 (bp), 152 (14) 133 (9).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1.C1(N)CCCCC1>C(OCC)(=O)C.CO>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(F)cc2Cl)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: NC1CCCCC1
Product: O=C(O)CCCc1ccc(-c2ccc(F)cc2Cl)cc1
Yield: 84 %

Procedure:
Prepared analogous to Example 1 from 4-(2'-chloro-4'-fluoro-4-biphenylyl)-4-oxo-butyric acid. Yield: 84% of theory; m.p. 81°-82° C. (petroleum ether-cyclohexane). Melting point of the cyclohexylamine salt: 148°-149° C. (from ethyl acetate/methanol 9:1).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:22][C@@:21]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:20]2[C:19](=O)[CH2:18][C@@:17]2([CH3:25])[C@H:11]3[CH2:12][CH2:13]/[C:14]/2=[CH:15]/[CH3:16])[CH2:6][C@@H:5]1[OH:26])[CH3:2].C(O)C.[Cl-].[OH:31][NH3+:32]>[OH-].[Na+]>[CH2:1]([O:3][C@H:4]1[CH2:22][C@@:21]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:20]2[C:19](=[N:32][OH:31])[CH2:18][C@@:17]2([CH3:25])[C@H:11]3[CH2:12][CH2:13]/[C:14]/2=[CH:15]/[CH3:16])[CH2:6][C@@H:5]1[OH:26])[CH3:2]
Reactant: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C/C=C1/CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3C(=NO)C[C@]12C
Yield: 29.7 %

Procedure:
A solution of (Z)-2β-ethoxy-3α-hydroxy-5α-pregn-17(20)-en-11-one (710 mg) in refluxing ethanol (21 ml) was treated with a slurry of hydroxylammonium chloride (1.43 g) in 50% aqueous sodium hydroxide. After 24 hour refluxing, the cooled reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and evaporated to a froth (710 mg). This material was retreated with hydroxylamine as above to give a froth (800 mg) which was purified by preparative TLC (4% methanol in chloroform 22) and crystallisation from ethyl acetate/petrol to yield the title compound (220 mg), m.p. 176°-193°, [α]D +35.9°.