Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:22]2[C@H:9]3[CH2:10][CH2:11][C@@:12]4([CH3:21])[C@H:16]([C@@H:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH2:15][CH2:14][C:13]14[O:20][CH2:19][CH2:18][O:17]1.CC1C=CC=C(C)N=1>Cl([O-])(=O)(=O)=O.C([N+](CC)(CC)CC)C.CN(C)C=O.CO>[CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:22]2[C:9]3=[CH:10][CH2:11][C@@:12]4([CH3:21])[C@H:16]([C@@H:8]3[CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH2:15][CH2:14][C:13]14[O:17][CH2:18][CH2:19][O:20]1
Reactant: COc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Agent: CC[N+](CC)(CC)CC
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: COc1ccc2c(c1)CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CCC21OCCO1
Reaction time: 0.92 h
Yield: 78.7 %

Procedure:
A solution of 2.3 grams of 3-methoxy-13β-methyl-17,17-(ethylenedioxy)gona-1,3,5(10)-triene, 1.1 milliliters of 2,6-dimethylpyridine, and 1.4 grams of tetraethylammonium perchlorate in 45 milliliters of N,N-dimethylformamide and 50 milliliters of methanol was electrolyzed between the same pair of electrodes that were described in Example 1, spaced from each other at a distance of 1.5 centimeters, with a current of 600 milliamperes for a period of 55 minutes. At the end of the electrolysis all traces of methanol were distilled from the solution at a subatmospheric pressure and the solution was then acidified with anhydrous p-toluenesulfonic acid, allowed to stand at room temperature for a period between 20 and 30 minutes and then made alkaline with a saturated solution of sodium bicarbonate. A portion of the product precipitated during the addition of the bicarbonate solution and water was then added to complete its precipitation. In this manner, 1.8 grams of 3-methoxy-13β-methyl-17,17-(ethylenedioxy)gona-1,3,5-(10),9(11)-tetraene having a melting point of 146°-149° C. was obtained.
Reaction SMILES: Cl.C([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])C.[CH2:10]([C:12]1[CH:21]=[C:20]([C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[C:31]([CH3:33])[C:30]([CH2:34][CH:35]([CH3:37])[CH3:36])=[CH:29][N:28]=3)[O:24][N:23]=2)[CH:19]=[C:18]([CH3:38])[C:13]=1[O:14][CH2:15][CH2:16]N)[CH3:11].C(N(CC)CC)C>C(O)C>[CH2:10]([C:12]1[CH:21]=[C:20]([C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[C:31]([CH3:33])[C:30]([CH2:34][CH:35]([CH3:36])[CH3:37])=[CH:29][N:28]=3)[O:24][N:23]=2)[CH:19]=[C:18]([CH3:38])[C:13]=1[O:14][CH2:15][CH2:16][NH:8][CH2:7][CH2:6][C:5]([OH:4])=[O:9])[CH3:11]
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCN
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1OCCNCCC(=O)O
Temperature: 80 °C
Reaction time: 18 h
Yield: 27.1 %

Procedure:
A solution of β-alanine ethyl ester hydrochloride (88 mg, 570 μmol) in ethanol (2 mL) is filtered over PL-HCO3 MP SPE ion exchange. The methanesulfonic acid ester intermediate of Example 48 (90 mg, 190 μmol) and triethylamine (77 mg, 760 μmol) is added to the filtrate and the mixture is stirred in a sealed vial at 80° C. for 18 h. The mixture is cooled to rt and the solvent is evaporated. The crude 3-(2-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-ethylamino)-propionic acid ethyl ester is dissolved in ethanol (2 mL) and 1 N aq. NaOH (2 mL) and the mixture is stirred at rt for 3 h. The mixture is neutralised by adding 1 N aq. HCl, the solvent is removed in vacuo and the residue is separated by prep. HPLC to give the title compound (24 mg) as a white solid; LC-MS: tR=0.90 min, [M+H]+=466.79; 1H NMR (CDCl3): δ1.00 (d, J=6.5 Hz, 6H), 1.30 (t, J=7.3 Hz, 3H), 1.90-1.99 (m, 1H), 2.38 (s, 3H), 2.46 (s, 3H), 2.60-2.68 (m, 4H), 2.73 (q, J=7.5 Hz, 2H), 3.20-3.27 (m, 2H), 3.27-3.33 (m, 2H), 4.07-4.15 (m, 2H), 7.92 (s, 1H), 7.94 (s, 1H), 8.08 (s, 1H), 8.54 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH3:15])[CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1.[C:22]([NH:24][C:25](=[N:33][CH2:34][CH2:35][CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)[CH:39]=1)OC1C=CC=CC=1)#[N:23]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][NH:14][C:25]([NH:24][C:22]#[N:23])=[N:33][CH2:34][CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)[CH:39]=2)[CH3:15])=[CH:4][CH:3]=1
Reactant: N#CNC(=NCCCOc1cccc(CN2CCCCC2)c1)Oc1ccccc1
Reactant: CN(CCN)CCC(c1ccc(Cl)cc1)c1ccccn1
Solvent: CCOC(C)=O
Product: CN(CCNC(=NCCCOc1cccc(CN2CCCCC2)c1)NC#N)CCC(c1ccc(Cl)cc1)c1ccccn1

Procedure:
Preparation is effected analogously to Example 1, using 0.7 g (2.3 mmol) of N-[3-(4-chlorophenyl)-3-(2-pyridyl)propyl]-N-methyl-1,2-ethanediamine and 0.85 g (2.2 mmol) of N-cyano-O-phenyl-N'-[3-[3-(piperidinomethyl)phenoxy]propyl]isourea as starting materials. Working up by chromatography (eluant: ethyl acetate) analogously to Example 1 yields the purified title compound in the form of a viscous oil; MS (+FAB-method): m/z (rel. int.[%])=602 ([M+H]+, 5), 230 (100); IR (KBr): 2165 cm-1 (C≡N). For analytical purposes a sample is converted into the O,O'-ditoluoyltartaric acid salt and recrystallised from ether/isopropanol; m.p.: from 85° C. with decomposition.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.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>[CH3:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][N:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:13][CH2:14]3)=[C:4]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:3]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Br)cc2Oc2ccccc2)CC1
Reactant: Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccccc3)c2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A 100 mL round-bottom flask was purged with and maintained an inert atmosphere of nitrogen then charged with tert-butyl 4-[(4-bromo-2-phenoxyphenyl)methyl]piperazine-1-carboxylate (1.20 g, 2.68 mmol, 1.00 equiv), (3-methylphenyl)boronic acid (0.730 g, 5.37 mmol, 2.00 equiv), Pd(PPh3)4 (0.310 g, 0.270 mmol, 0.10 equiv), potassium carbonate (1.10 g, 7.96 mmol, 2.97 equiv), dioxane (12 mL), and water (2 mL). The resulting solution was stirred overnight at 80° C. and then diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1/9) to provide 1.00 g (81% yield) of tert-butyl 4-[[4-(3-methylphenyl)-2-phenoxyphenyl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 459 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.Cl[S:13]([OH:16])(=[O:15])=[O:14]>ClCCl>[CH3:1][C:2]1([CH3:11])[C:6]2[CH:7]=[C:8]([S:13]([OH:16])(=[O:15])=[O:14])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=S(=O)(O)Cl
Reactant: CC1(C)COc2ccccc21
Solvent: ClCCl
Product: CC1(C)COc2ccc(S(=O)(=O)O)cc21
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3,3-dimethyl-2,3-dihydro-benzofuran (160 mg, 1.08 mmol) in dichloromethane (2 mL) at −10° C. was added chlorosulfonic acid (72 μL, 1.08 mmol). The mixture was stirred at −10° C. for 15 minutes, then the solvent was evaporated to give 3,3-dimethyl-2,3-dihydro-benzofuran-5-sulfonic acid [1H-NMR (300 MHz, CDCl3): 1.37 (s, 6H), 4.35 (s, 2H), 6.85 (d, J=8.2 Hz, 1H), 7.67 (d, J=2.1 Hz, 1H), 7.73 (dd, J1=8.5 Hz, J2=2.1 Hz, 1H), 10.12 (br s, 1H)]. The residue was diluted with thionyl chloride (1 mL, 13.71 mmol) and one drop of dimethylformamide was added. After 45 minutes reflux and evaporation of the solvent, the solid compound was washed in a mixture of dichloromethane/hexane to give 3,3-dimethyl-2,3-dihydro-benzofuran-5-sulfonyl chloride [1H-NMR (300 MHz, CDCl3): 1.41 (s, 6H), 4.41 (s, 2H), 6.92 (d, J=8.8 Hz, 1H), 7.74 (d, J=2.3 Hz, 1H), 7.87 (dd, J1=8.5 Hz, J2=2.1 Hz, 1H)]. A solution of methylamine 2.0 M in tetrahydrofuran (0.81 mL, 1.62 mmol) was then slowly added and the mixture was stirred at room temperature for 15 minutes. The solvent was evaporated to afford 215 mg of 3,3-dimethyl-2,3-dihydro-benzofuran-5-sulfonic acid methylamide. 83% yield. 1H-NMR (300 MHz, CDCl3): 1.38 (s, 6H), 2.66 (d, J=5.3 Hz, 3H), 4.21 (m, 1H), 4.34 (s, 2H), 6.86 (d, J=8.5 Hz, 1H), 7.60 (d, J=2.1 Hz, 1H), 7.66 (dd, J1=8.5 Hz, J2=1.8 Hz, 1H).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:30])[CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=4)[CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)=[CH:6][CH:5]=1.O>CO>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:30])[CH2:11][N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([O:28][CH3:29])[CH:26]=4)[CH2:21][CH2:20][CH2:19]3)[CH2:16][CH2:17]2)=[CH:6][CH:5]=1
Reactant: COc1ccc2c(c1)N(C1CCN(CC(=O)c3ccc(F)cc3)CC1)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)N(C1CCN(CC(O)c3ccc(F)cc3)CC1)CCC2
Reaction time: 1 h

Procedure:
Sodium borohydride (73 mg) was added at 0° C. to a solution of 1-{1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline (400 mg) in methanol (10 ml). The resultant mixture was stirred at the same temperature for 1 hr and then at room temperature for 1 hr. After the completion of the reaction, water was added to the reaction solution followed by extraction with ethyl acetate. The resulting residue was purified by column chromatography (hexane/ethyl acetate system) to give 1-{1-[2-(4-fluorophenyl)-2-hydroxyethyl]piperidin-4-yl}-7-methoxy-1,2,3,4-tetrahydroquinoline as an oil. This product was dissolved in ethanol and oxalic acid was added thereto. The resulting precipitate of salt was recrystallized form ethanol/ether to give the title compound (280 mg) (yield: 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N:10]2[CH:14]=[C:13](I)[CH:12]=[N:11]2)[CH:9]=1)[C:5]#[N:6].[NH:16]1[CH:20]=[CH:19][CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+]>[Cu]I>[N:16]1([C:13]2[CH:12]=[N:11][N:10]([C:8]3[CH:7]=[C:4]([CH:3]=[C:2]([F:1])[CH:9]=3)[C:5]#[N:6])[CH:14]=2)[CH:20]=[CH:19][CH:18]=[N:17]1
Reactant: N#Cc1cc(F)cc(-n2cc(I)cn2)c1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N#Cc1cc(F)cc(-n2cc(-n3cccn3)cn2)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
To a sealed tube containing dry, deoxygenated dioxane (1 mL) was added 3-fluoro-5-(4-iodo-1H-pyrazol-1-yl)benzonitrile (313 mg, 1.0 mmol), pyrazole (88 mg, 1.3 mmol), trans-diaminocyclohexane (24 μL, 0.2 mmol), potassium carbonate (304 mg, 2.2 mmol), and CuI (4 mg, 0.02 mmol). The reaction was capped and heated with stirring for 48 hr at 100° C. The resulting mixture was partitioned with EtOAc (10 mL) and H2O (10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo on to a plug of silica gel, which was loaded on to a prepacked column and purified via automated flash chromatography utilizing a 5-35% EtOAc/Hexanes gradient to afford 3-(1′H-1,4′-bipyrazol-1′-yl)-5-fluorobenzonitrile as a white solid. 1H NMR (CDCl3, 500 MHz) δ 8.48 (s, 1H), 8.04 (s, 1H), 7.96 (m, 1H), 7.85-7.88 (m, 2H), 7.71 (d, 1H), 7.36 (m, 1H), 6.50 (m, 1H). MS (ESI) 254.15 (M++H).
Reaction SMILES: C[O:2][C:3]1[CH2:4][C:5]2[CH2:6][C@@H:7]([CH3:24])[C@@H:8]3[C@@H:17]([C:18]=2[CH2:19][CH:20]=1)[CH2:16][CH2:15][C@@:13]1([CH3:14])[C@@H:9]3[C@@H:10]2[CH2:23][C@@H:11]2[C@H:12]1[CH2:21][OH:22].OC[C@@H]1CC[C@@H]2[C@H]3[C@H](CC[C@]12C)[C@@H]1C(=CC(=O)CC1)CC3>O1CCOCC1>[OH:22][CH2:21][C@@H:12]1[C@H:11]2[CH2:23][C@H:10]2[C@@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@@H:18]1[C:5](=[CH:4][C:3](=[O:2])[CH2:20][CH2:19]1)[CH2:6][C@H:7]3[CH3:24]
Reactant: COC1=CCC2=C(C1)C[C@@H](C)[C@H]1[C@H]3[C@@H]4C[C@@H]4[C@@H](CO)[C@@]3(C)CC[C@H]21
Agent: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@H]1CC[C@H]2CO
Solvent: C1COCCO1
Product: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@@]3(C)[C@H]([C@@H]4C[C@@H]4[C@H]3CO)[C@@H]21

Procedure:
v)—Following a procedure analogous to that described under v of Example 4, the product obtained in the previous step (0.38 g) was converted to (7α,14β,15β,16β,17α)-3-methoxy-7-methyl-15,16-methyleneestra-2,5(10)-diene-17-methanol (0.36 g). vi)—Following a procedure analogous to that described under iv of Example 1, the product obtained in the previous step (0.36 g) was converted to (7α,14β,15β,16β,17α-17-(hydroxymethyl)-7-methyl-15,16-methyleneestr-4-en-3-one (0.21 g), [α]D20=+67.6 (c=0.58, dioxane).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[C@@H:20]2[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][OH:28])[C@@H:22]([OH:30])[C@H:21]2[OH:31])=[C:13]([NH:32][C@H:33]([CH2:41][OH:42])[CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:12]=1)(C)(C)C>Cl.CO>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[N:19]=[C:18]2[C:14]([N:15]=[CH:16][N:17]2[C@@H:20]2[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][OH:28])[C@@H:22]([OH:30])[C@H:21]2[OH:31])=[C:13]([NH:32][C@H:33]([CH2:41][OH:42])[CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[N:12]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1nc(N[C@H](CO)Cc2ccccc2)c2ncn([C@@H]3C[C@H](NC(=O)CO)[C@@H](O)[C@H]3O)c2n1
Agent: Cl
Solvent: CO
Product: NCC#Cc1nc(N[C@H](CO)Cc2ccccc2)c2ncn([C@@H]3C[C@H](NC(=O)CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
{3-[9-[(1R,2S,3R,4S)-2,3-Dihydroxy-4-(2-hydroxy-acetylamino)-cyclopentyl]-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-9H-purin-2-yl]-prop-2-ynyl}-carbamic acid tert-butyl ester (Intermediate XA) is dissolved in 1.25 M HCl in MeOH. After stirring at RT for 3 days, the solvent is removed in vacuo to yield the title compound. This is used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.CS(O[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[C:30]([O:38]COC)[C:29]=1[CH:42](OC)[O:43]C)(=O)=O>>[CH:42]([C:29]1[C:30]([OH:38])=[C:31]([C:34]([F:35])([F:37])[F:36])[CH:32]=[CH:33][C:28]=1[CH2:27][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[CH:19]([CH3:21])[CH3:20])=[CH:6][CH:7]=1)=[O:43]
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(C(C)C)c1
Reactant: COCOc1c(C(F)(F)F)ccc(COS(C)(=O)=O)c1C(OC)OC
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C=O)cc2)c(C(C)C)c1

Procedure:
According to a method similar to Example (40-2) and Example (8-3), from crudely purified methyl (4′-hydroxy-2-isopropyl-1,1-biphenyl-4-yl)acetate (147 mg) obtained in Example (42-3) and 2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl methanesulfonate (252 mg, 0.65 mmol) obtained in Example (26-5), crude methyl (4′-{[2-formyl-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-2-isopropyl-1,1′-biphenyl-4-yl)acetate was obtained (169 mg).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCCC)=[N:18][C:17]3=[O:25])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:36][O:37][C:38](=[O:49])[CH2:39][NH:40][C:41]([CH:43]1[O:48][CH2:47][CH2:46][NH:45][CH2:44]1)=[O:42]>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:29]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:45]4[CH2:46][CH2:47][O:48][C@H:43]([C:41]([NH:40][CH2:39][C:38]([O:37][CH3:36])=[O:49])=[O:42])[CH2:44]4)=[N:18][C:17]3=[O:25])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: COC(=O)CNC(=O)C1CNCCO1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: COC(=O)CNC(=O)[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCO1

Procedure:
Methyl N—({(2S)-4-[5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]morpholin-2-yl}carbonyl)glycinate was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and [(Morpholine-2-carbonyl)-amino]-acetic acid methyl ester following General Procedure B.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O.[O-]CC.[K+].[Cl-].[NH4+]>C(O)C>[N:1]([C:4](=[CH:15][C:11]1[S:10][CH:14]=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1cccs1
Agent: CC[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccs1)N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 2 h
Yield: 24.6 %

Procedure:
A solution of ethyl azidoacetate (1.38 g) and thiophene-2-carboxaldehyde (1 g) in ethanol (20 ml) was added dropwise to a solution of potassium ethoxide (0.9 g) in ethanol (20 ml) at 0° C. The reaction was stirred for 2 hours at 0° C. and 2 hours at ambient temperature then poured into saturated aqueous ammonium chloride solution (150 ml) and extracted with ether. Combined organic extracts were dried (MgSO4), concentrated in vacuo and the residue purified by column chromatography using isohexane as eluent to give the product as a pale yellow crystalline solid (0.49 g, 25%), NMR d(CDCl3) 1.40 (3H, t), 4.37 (2H, q), 7.08 (2H, m), 7.18 (1H, s), 7.38 (1H, m), 7.52 (1H, d).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])(C)(C)C.CCCCC.[CH2:20]([C:27]1([N:34]([CH3:36])[CH3:35])[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[O:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[C:5]1[C:30]1([OH:33])[CH2:31][CH2:32][C:27]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([N:34]([CH3:36])[CH3:35])[CH2:28][CH2:29]1
Reactant: c1ccc2occc2c1
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CN(C)C1(Cc2ccccc2)CCC(O)(c2cc3ccccc3o2)CC1
Temperature: -5 °C
Reaction time: 2 h
Yield: 21.2 %

Procedure:
A solution of benzo[b]furan (612 mg, 5.12 mmol) in dry THF (40 ml) was cooled to −8° C. under a stream of argon. Thereafter, tert-Butyllithium (6.22 mmol, 4.14 ml of a 1.5 molar pentane solution) was added dropwise such that a reaction temperature of −5° C. was not exceeded during the addition. When the addition had ended the reaction mixture was stirred for two hours at −5° C. Thereafter, a solution of 4-benzyl-4-dimethylaminocyclohexanone (1.20 g, 5.18 mmol) in dry THF (10 ml) was added dropwise at 0° C. The mixture was stirred for one hour at 0° C. and then for four days at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml), the organic phase was separated and the aqueous phase was extracted four times with 30 ml methylene chloride each time. The combined organic phases were dried over sodium sulfate and filtered and the solvent was removed in vacuo. Purification was carried out by means of flash chromatography over silica gel with cyclohexane/ethyl acetate (v/v=8:2). 380 mg 1-benzofuran-2-yl-4-benzyl-4-dimethylaminocyclohexanol with a melting point of 121-124° C. were obtained.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH:12]([OH:59])[CH2:13][C:14](=O)[C@@H:15]([C@H:17]1[N:20]([C:21](=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[C:19](=[O:47])[C@@H:18]1[C@H:48]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH3:49])[CH3:16])=[O:6])[CH:2]=[CH2:3]>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH:12]([OH:59])[CH2:13][C:14]1[C@H:15]([CH3:16])[C@H:17]2[N:20]([C:19](=[O:47])[C@@H:18]2[C@H:48]([O:50][Si:51]([C:54]([CH3:56])([CH3:55])[CH3:57])([CH3:53])[CH3:52])[CH3:49])[C:21]=1[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=O)CC(O)[C@@H]1CCCN1C(=O)OCC=C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C1=C(CC(O)[C@@H]2CCCN2C(=O)OCC=C)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12

Procedure:
A solution of allyl 2-[(3S,4R)-4-[(1R)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl)-4-hydroxy-1-methyl-2- oxobutyl]-3-{(1R)-1-t-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetate (2.36 g) in degassed toluene (120 ml) was heated to reflux for 8 hours. After cooling, the toluene was evaporated to give a residue of allyl (4S,5R,6S)-3-[2-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl)-2-hydroxyethyl]-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate and the residue was taken up into dichloromethane (90.0 ml). To the mixture were added dropwise triethylamine (1.02 ml) and methane sulfonyl chloride (0.52 ml) at 5° C. with stirring and the stirring was continued for 30 minutes at 5° C. To the resultant mixture was added 1,8-diazabicyclo-[5.4.0]-7-undecene (3.36 ml) and the resultant mixture was allowed to warm to around 40° C. After stirring at 40° C. for 2 hours, the mixture was diluted with ethyl acetate and washed in turn with aqueous ammonium chloride, water and brine, and dried over magnesium sulfate. Removal of the solvent gave a residue, which was chromatographed on silica gel (150 ml) eluting with a mixture of n-hexane and ethyl acetate (9:1-4:1 V/V) to give allyl (4S,5R,6S)-3-[(E)-2-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-ethenyl]-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]-hept-2-ene-2-carboxylate (1.12 g).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.Cl[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][N:33]=1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([CH:24]4[CH2:29][CH2:28][N:27]([C:32]5[CH:37]=[CH:36][N:35]=[CH:34][N:33]=5)[CH2:26][CH2:25]4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:16])([F:17])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccncn1
Reactant: O=C1C(n2cc(C3CCNCC3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1C(n2cc(C3CCN(c4ccncn4)CC3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Temperature: 25 °C
Yield: 77 %

Procedure:
In a sealed tube, 6-fluoro-3-[4-(piperidin-4-yl)-1H-1,2,3-triazol-1-yl]-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (50 mg, 0.122 mmol), 4-chloropyrimidine hydrochloride (27.5 mg, 0.182 mmol) and DIEA (212 uL, 1.215 mmol) in 2-propanol (1.2 mL) was heated at 140° C. for 1 h. After cooling to ambient temperature and solvent removal under reduced pressure, the residue was purified by column chromatography on silica gel to afford 46 mg title compound.