Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[OH:10])[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19]>CC(C)=O>[CH2:18]([O:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)[CH3:19]
Reactant: Oc1cccc2cc[nH]c12
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1H-indol-7-ol (500 mg, 3.75 mmol) in acetone (10 mL) at r.t. was added potassium carbonate (3.11 g, 22.5 mmol), followed by iodoethane (0.45 mL, 5.63 mol). The mixture was stirred at r.t. for 16 h then solvent removed under reduced pressure. The crude product thus obtained was purified by chromatography over silica gel to afford 7-ethoxy-1H-indole: 1H NMR (400 MHz, MeOD) δ ppm 1.51 (t, J=6.95 Hz, 3H), 4.22 (q, J=6.91 Hz, 2H), 6.42 (d, J=3.03 Hz, 1H), 6.63 (d, J=7.58 Hz, 1H), 6.92 (t, J=7.83 Hz, 1H), 7.04-7.23 (m, 2H); MS (ES+): m/z 162.20 (MH+).
Reaction SMILES: Cl.[C:2]([N:6]([C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[CH3:7])(=[O:5])[CH:3]=[CH2:4].Cl.[C:21]([N:29]1[CH2:34][CH2:33][CH2:32][C:31]([C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([Cl:58])[CH:52]=2)([CH2:35][CH2:36][CH2:37]N2CCC(C(N3CCCC3)=O)CC2)[CH2:30]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.O>[ClH:57].[C:2]([N:6]([C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:10][N:11]([CH2:37][CH2:36][CH2:35][C:31]2([C:51]3[CH:56]=[CH:55][C:54]([Cl:57])=[C:53]([Cl:58])[CH:52]=3)[CH2:32][CH2:33][CH2:34][N:29]([C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:30]2)[CH2:12][CH2:13]1)[CH3:7])(=[O:5])[CH:3]=[CH2:4]
Reactant: O=C(c1ccccc1)N1CCCC(CCCN2CCC(C(=O)N3CCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Reactant: C=CC(=O)N(C)C1(c2ccccc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)N(C)C1(c2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Temperature: 80 °C
Yield: 80.5 %

Procedure:
A mixture of 0.27 g of 4-(acryloyl-N-methylamino)-4-phenylpiperidine hydrochloride, 0.45 g of the compound obtained in step B of EXAMPLE 1 and 0.3 g of K2CO3 in 3 ml of DMF is heated at 80° C. for 2 hours. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a gradient of a DCM/MeOH mixture (99/1; v/v to 95/5; v/v) as the eluent. The product obtained is dissolved in DCM and acidified by the addition of ethereal hydrogen chloride and the precipitate formed is filtered off to give 0.2 g of the expected product, m.p.=128° C.
Reaction SMILES: C(OC([NH:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17](/[CH:21]=[CH:22]/[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=2)[CH2:13]1)=O)C1C=CC=CC=1.NC1C=CC(C2CCC(C(OC)=O)C2)=CC=1>>[NH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=2)[CH2:13]1
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)CC(NC(=O)OCc1ccccc1)C2
Agent: COC(=O)C1CCC(c2ccc(N)cc2)C1
Product: CCOC(=O)CCc1ccc2c(c1)CC(N)C2

Procedure:
Ethyl (2E)-3-(2-{[(benzyloxy)carbonyl]amino}-2,3-dihydro-1H-inden-5-yl)acrylate was reduced by the general procedure of Intermediate 84, step (ii), to give the title compound (Intermediate 88); 1H NMR (CD3OD) δ 1.01-1.18 (m, 3H), 2.44-2.70 (m, 2H), 2.73-2.96 (m, 2H), 3.02-3.35 (m, 4H), 3.92-4.05 (m, 2H), 4.30-4.42 (m, 1H), 6.84-7.23 (m, 3H); MS m/e MH+ 234.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:22](=[O:33])[CH2:23][C:24]([C:26]1[S:27][CH:28]=[CH:29][C:30]=1[C:31]#[N:32])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:11]1[CH:12]=[CH:13][C:8]2[NH:7][C:24]([C:26]3[S:27][CH:28]=[CH:29][C:30]=3[C:31]#[N:32])=[CH:23][C:22](=[O:33])[NH:21][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1sccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccsc1C1=CC(=O)Nc2cc(-c3ccccc3F)ccc2N1

Procedure:
Prepared from {3-[3-(3-cyano-thiophen-2-yl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K55) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (258 mg).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)=[O:16])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>[C].[Pd].CC(O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]2)=[O:16])[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: O=C(CC1CCN(Cc2ccccc2)CC1)N1CCC(O)CC1
Agent: [Pd]
Solvent: CC(C)O
Product: O=C(CC1CCNCC1)N1CCC(O)CC1
Temperature: 80 °C
Yield: 89.4 %

Procedure:
14.2 g (0.05 mol) of 1-(1-benzyl-4-piperidylacetyl)-4-hydroxypiperidine [1] and 127.9 g of 2-propanol were mixed with each other. To this mixture, 1.42 g of 5% palladium-carbon (containing water at 50% content) was added. The reaction was allowed to proceed for 14 hours at 50° C. under the flow of hydrogen. The catalyst was removed by filtration therefrom, and the filtrate was concentrated under a reduced pressure. 23.6 g of acetonitrile was added to the concentrated residue, and the temperature of the mixture was increased to a reflux temperature of 80° C. The crystals which precipitated at room temperature were collected by filtration and the resultant wet crystals were dried under a reduced pressure, whereby 9.08 g of the title compound in the state of white powder was obtained (the yield was 89.4%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]=1[O:14][CH3:15].[OH:16][C:17]1[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=1[C:27](=[O:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[OH:16][C:17]1[C:22]([CH2:23][CH2:24][CH3:25])=[C:21]([O:26][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:7]=2[O:14][CH3:15])[CH:20]=[CH:19][C:18]=1[C:27](=[O:29])[CH3:28]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COc1cccc(CCCCBr)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCCCCc2cccc(OC)c2OC)ccc(C(C)=O)c1O
Yield: 82.5 %

Procedure:
A mixture of 4.36 g (15.9 mmol) of 1-(4-bromobutyl)-2,3-dimethoxybenzene, 3.10 g (15.9 mmol) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 4.4 g (32 mmol) of potassium carbonate and 2.4 g (16 mmol) of sodium iodide in 100 mL of acetone was stirred at reflux for 30 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification by high pressure liquid chromatography using 20% ethyl acetate-hexane gave 5.07 g (88% yield) of 1-[2-Hydroxy-4-[4-(2,3-dimethoxyphenyl)butoxy]-3-propylphenyl]-ethanone as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[CH2:9]([O:8][C:6]([C:5]1[CH:16]=[CH:17][C:2]([O:1][C:18](=[O:25])[CH2:19][CH2:20][CH2:21][C:22]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[O:7])=[CH:16][CH:17]=2)=[O:23])=[CH:3][CH:4]=1)=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: O=C(Cl)CCCC(=O)Cl
Product: O=C(CCCC(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1)Oc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
A similar procedure to Example 1 is carried out by using 22.8 g of benzyl p-hydroxybenzoate and 8.45 g of glutaric acid dichloride to yield di(p-benzyloxycarbonylphenyl)glutarate, m.p. 93°-94° C., as white crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[I:13].[CH3:14][O-:15].[Na+]>CO>[I:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[CH2:2][O:15][CH3:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(CBr)c(I)c1
Agent: [Na+]
Solvent: CO
Product: COCc1ccc(C(=O)OC)cc1I
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
Into a 250-mL round-bottom flask, was placed a mixture of methyl 4-(bromomethyl)-3-iodobenzoate (compound 20.1, 3.0 g, 8.5 mmol) and sodium methoxide (1.8 g, 33 mmol) in methanol (100 mL). The resulting solution was stirred for 2 h at 50° C., then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate (50 mL) and the solids were filtered off. The filtrate was concentrated under reduced pressure to yield 2.0 g (77%) of the title compound as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[N:22]([CH3:23])[CH2:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[OH:30])[C:12]3=[O:31])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:38][N:39]1[CH:43]=[C:42](B2OC(C)(C)C(C)(C)O2)[CH:41]=[N:40]1>C1COCC1.C(OCC)(=O)C.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:30][C@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[N:13]1[C:12](=[O:31])[C:11]2[C:16](=[C:17]3[N:22]([CH3:23])[CH2:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:42]4[CH:41]=[N:40][N:39]([CH3:38])[CH:43]=4)=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN1CC=Cc2c(Cc3ccc(Cl)nc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CC=Cc2c(Cc3ccc(-c4cnn(C)c4)nc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Temperature: 100 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one (Example 1, 0.040 g, 0.092 mmol) in 2 mL of THF under an atmosphere of nitrogen was added aqueous cesium carbonate (1 M, 0.18 mL, 0.18 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.057 g, 0.28 mmol), and bis(tri-tert-butylphosphine)palladium(0) (4.0 mg, 0.0078 mmol). The reaction was heated at 100° C. for 16 h, cooled to rt, diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate and brine. The solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 483.1 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H), 8.52 (d, J=8.6 Hz, 1H), 8.40 (s, 1H), 8.08 (s, 1H), 7.95 (br s, 2H), 7.61-7.39 (m, 3H), 4.78 (s, 2H), 4.49 (s, 2H), 4.23 (br s, 1H), 3.92 (s, 3H), 3.74 (br s, 1H), 3.20 (s, 3H), 2.11 (br s, 1H), 1.83-1.63 (m, 5H), 1.29-1.23 (m, 2H).
Reaction SMILES: C(OC([NH:8]OS(C1C(C)=CC(C)=CC=1C)(=O)=O)=O)(C)(C)C.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=O)[CH2:30][C:31]2[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][N:32]=2)=[CH:25][CH:24]=1>C(O)(C(F)(F)F)=O>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:30]=[C:31]3[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][N:32]3[N:8]=2)=[CH:25][CH:24]=1
Reactant: N#Cc1ccc(CC(=O)c2ccc(F)cc2)nc1
Reactant: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2cc(-c3ccc(F)cc3)nn2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18.3 %

Procedure:
Solid t-butoxycarbonyl-O-mesitylenesulfonylhydroxylamine (13.0 g 41.8 mmol)1 was added portionwise with stirring to TFA (40 ml) over 10 min then stirred for a further 30 minutes. The solution was poured onto ice (250 ml) and left until the ice melted. The resulting white solid was filtered off, washed with water, and dissolved in DCM (300 ml). The solution was dried over 4 Å mol. sieves for 1.5 hours, filtered and 6-[2-(4-fluorophenyl)-2-oxoethyl]nicotinonitrile (3.32 g 13.8 mmol) was added. The reaction was stirred at room temperature for 4 days, washed with water (100 ml), dried and purified by column chromatography. Elution with cyclohexane/ethyl acetate (3:1) gave the title compound as a yellow solid (0.6 g 18%). NMR: (CDCl3): δ 6.87 (1H, s) 7.15-7.20 (3H, m) 7.57 (1H, dd) 7.95 (2H, m) 8.84 (1H, d). Ref 1 Josef G Krause, Synthesis, 1972, 140.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:26]=[CH:25][C:14]3[N:15]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CC(N(C)C)=O>[C:35]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][C:16]2[S:17][C:13]3[CH:12]=[C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:27])[CH:9]=4)[CH:26]=[CH:25][C:14]=3[N:15]=2)[CH2:20]1)(=[O:37])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCNC4)sc3c2)ccn1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCN(C(C)=O)C4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 36.7 %

Procedure:
To the solution of (S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide (13 mg, 30 μmol) and triethylamine (13 μL, 90 μmol) in 300 μL of DMA was added acetic anhydride (6 μl, 60 μmol). The reaction solution was stirred at room temperature for 1.5 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give (S)-4-(2-(1-acetylpiperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (4.8 mg, 11 μmol) as white powder. ES/MS m/z 426.2 (MH+).
Reaction SMILES: C[O:2][C:3]1[C:18]([O:19]C)=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[C:18]([OH:19])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][Cl:15])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCCl)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1Cc2cc(O)c(O)cc2CCN1CCCCl
Reaction time: 10 h

Procedure:
8.9 gm (0.03 mol) of 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane were dissolved in 100 ml of methylene chloride; the solution was admixed at -60° C. with 2.1 ml of boron tribromide. After removing the cooling bath the reaction temperature rose to 20° C. and at this temperature the reaction mixture was stirred for 10 hours. The resulting resinous precipitate was made to crystallize by addition of 100 ml of water and subsequent stirring for one hour. The crystalline precipitate was suction-filtered off and washed with water and methylene chloride. For purification the crystalline product was stirred with acetone and suction-filtered off.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[N:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH:5]=1.[OH-].[Na+]>CO.C1COCC1.O>[Cl:17][C:14]1[N:13]=[N:12][C:11]([O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:18])=[O:2])=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccc(Oc2ccc(Cl)nn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(Oc2ccc(Cl)nn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
A mixture of 3-(6-chloro-pyridazin-3-yloxy)-benzoic acid methyl ester (950 g, 3.6 mmol) and NaOH (700 mg, 16 mmol) in methanol:THF:water (1:1:1, 6 mL) was stirred at room temperature for 8 h, solvents were evaporated. Crude mass was taken in water (40 mL), acidified to pH 4.0 and extracted with ethyl acetate. Evaporation of ethyl acetate furnished 3-(6-chloro-pyridazin-3-yloxy)-benzoic acid (580 mg).
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[CH3:27][C:28]1[S:29][C:30](B(O)O)=[C:31]([CH3:33])[N:32]=1>>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:30]3[S:29][C:28]([CH3:27])=[N:32][C:31]=3[CH3:33])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: Cc1nc(C)c(B(O)O)s1
Product: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3sc(C)nc3C)cc2)C(=O)O1

Procedure:
The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one and 2,4-dimethylthiazole-5-boronic acid following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.82, min, m/z=451; 1H NMR (CDCl3) 7.26 (t, 2H), 7.13 (d, 2H), 7.03 (t, 2H), 6.91 (d, 2H), 5.76-5.64 (m, 2H), 5.06 (dd, 2H), 2.98 (m, 1H), 2.74 (s, 3H), 2.42 (s, 3H), 1.53 (d, 3H).
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[C:12]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[CH2:10]([O:9][C:2](=[O:8])[C:3](=[O:5])[CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][C:12]1=[O:18])[CH3:11]
Reactant: CCOC(=O)C(=O)OCC
Reactant: O=C1CCCCC1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)C1CCCCC1=O
Temperature: 60 °C

Procedure:
A solution of sodium (1.75 g) in ethanol (100 ml) was treated with a mixture of diethyl oxalate (9.41 ml) and cyclohexanone (7.18 ml). The mixture was heated to 60° C. for 5 hours then cooled and then evaporated to yield oxo-(2-oxo-cyclohexyl)-acetic acid ethyl ester as a brown foam (16.635 g). LC-MS (METHOD B): RT 3.10 minutes; 197 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C@H:10]([NH:12]C(=O)OC(C)(C)C)[CH3:11])[CH:6]=[CH:7][CH:8]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[NH2:12][C@H:10]([CH3:11])[CH2:9][C:5]1[CH:4]=[C:3]([CH2:2][OH:1])[CH:8]=[CH:7][CH:6]=1
Reactant: C[C@H](Cc1cccc(CO)c1)NC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)Cc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of (R)-tert-butyl 1-(3-(hydroxymethyl)phenyl)propan-2-ylcarbamate (Example 276, step d) (0.78 g) in dichloromethane (20 mL) was treated with trifluoroacetic acid (5 mL) and stirred at room temperature for 40 minutes. Toluene was added and the solution was concentrated in vacuo. The residue was partitioned between 1M aqueous NaOH and DCM and the phases separated. The aqueous phase was extracted twice more with DCM, then the combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford (R)-(3-(2-aminopropyl)phenyl)methanol as a colourless oil that slowly crystallised to a white solid on standing (0.442 g). A mixture of (R)-(3-(2-aminopropyl)phenyl)methanol (0.223 g), (R)-8-(benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)quinolin-2(1H)-one (0.72 g), sodium iodide (0.219 g) and Hunig's Base (0.77 mL) in acetonitrile (3 mL) was heated at reflux under nitrogen overnight. More (R)-(3-(2-aminopropyl)phenyl)methanol (0.219 g), Hunig's Base (0.51 mL) and acetonitrile (2 mL) were added and the mixture was heated at reflux over a second night. The cooled reaction mixture was diluted with ethyl acetate, washed twice with water, once with brine, then dried (MgSO4) and concentrated onto flash silica in vacuo. The resulting powder was purified by flash chromatography on silica eluting with 5% triethylamine in ethyl acetate to afford the subtitled compound as a pale yellow foam. Yield 0.525 g.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[C:2]#[CH:3].[Mg+2].[Cl-].[Cl-].[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](I)[CH:15]=1>C1COCC1.[NH4+].[Cl-].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>[F:13][C:14]1[CH:15]=[C:16]([C:3]#[C:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cccc(I)c1
Reactant: C#CC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C#Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
A dry, argon-filled Schlenk tube with a magnetic stirrer bar and septum is initially charged with tert-butyl prop-2-ynoate (70 mg, 0.56 mmol) in anhydrous THF (2 ml). After adding (TMP)2Zn.MgCl2 (2.2 ml, 1.2 mmol) at 25° C., the mixture is stirred for 30 min, then a solution of 1-fluoro-3-iodobenzene (160 mg, 0.72 mmol), tetrakis(triphenylphosphine)palladium(0) (33 mg, 5 mol %) in anhydrous THF (2 ml) is added dropwise and the mixture is stirred at 25° C. overnight. For workup, the mixture is diluted with aqueous sat. NH4Cl solution (30 ml) and extracted with ethyl acetate (3×30 ml). After the combined organic phases have been dried over Na2SO4, the solvent has been distilled off and purification has been effected by column chromatography on silica gel (heptane:ethyl acetate), the desired compound (91 mg, 75% of theory) was obtained as a colourless oil.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])(OCC)OCC.C(O[C@@H:20]1[C@H:26]2[C@H:27]3[C@H:36]([CH2:37][CH2:38][C@:23]2([CH2:24][CH3:25])[C:22](=[O:40])[CH2:21]1)[C@@H:35]1[C:30](=[CH:31]C(=O)[CH2:33][CH2:34]1)[CH2:29][CH2:28]3)(=O)C1C=CC=CC=1.C(N(CC)CC)C.O>CCO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:9]([O:8][C:1]1[CH2:33][CH2:34][C@H:35]2[C:30](=[CH:29][CH2:28][C@@H:27]3[C@@H:36]2[CH2:37][CH2:38][C@@:23]2([CH2:24][CH3:25])[C@H:26]3[CH:20]=[CH:21][C:22]2=[O:40])[CH:31]=1)[CH3:10]
Reactant: CCOC(OCC)OCC
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](OC(=O)c1ccccc1)CC2=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC1=CC2=CC[C@@H]3[C@H](CC[C@]4(CC)C(=O)C=C[C@@H]34)[C@H]2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
Triethyl orthoformate (0.6 ml, 3.6 mmol) and p-Toluenesulfonic acid (6 mg, 0.032 mmol) were added to a suspension of 15α-benzoyloxy-18-methyl-estr-4-en-3,17-dione (0.6 g, 1.5 mmol) in EtOH (5 ml). The mixture was stirred at room temperature for 1 h. Triethylamine (1 ml, 7.2 mmol) was added, and the mixture was heated under reflux for 30 min, cooled to room temperature and water (50 ml) was then added. The precipitate was filtered, washed with water and dried. The crude product was purified by flash chromatography, eluting with heptane and ethyl acetate (7:3), crystallized from heptane, and dried under vacuum to afford 3-ethoxy-18-methyl-estra-3,5,15-trien-17-one (0.23 g, yield: 50%).
Reaction SMILES: C([N:9]1[CH2:13][C@@H:12]([S:14][CH3:15])[C@H:11]([NH:16][CH2:17][CH3:18])[CH2:10]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>>[CH2:17]([NH:16][C@H:11]1[C@H:12]([S:14][CH3:15])[CH2:13][NH:9][CH2:10]1)[CH3:18]
Reactant: CCN[C@@H]1CN(C(=O)c2ccccc2)C[C@H]1SC
Agent: [Na+]
Agent: [OH-]
Product: CCN[C@@H]1CNC[C@H]1SC

Procedure:
6.0 g (22 mmol) of 1-benzoyl-trans-3-ethylamino-4-methylthio-pyrrolidine are stirred vigorously with 22 ml of 5N NaOH at 100° C. for 24 hours, until the conversion is homogeneous. The mixture is then extracted with 3×80 ml of ether and the extract is dried over sodium sulphate and concentrated on a rotary evaporator. The crude product is distilled through a micro-puncture column.