Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH:33][C:34](=[O:36])[CH3:35])([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=O)[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=[O:3])[CH3:2].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[C:9]([O:8][CH2:7][C:6]([NH:33][C:34](=[O:36])[CH3:35])([CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)[CH2:5][O:4][C:1](=[O:3])[CH3:2])(=[O:11])[CH3:10]
Reactant: CCCCCC(=O)c1ccc(-c2ccc(CCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCc1ccc(-c2ccc(CCC(COC(C)=O)(COC(C)=O)NC(C)=O)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of acetic acid 2-acetoxymethyl-2-acetylamino-4-(4′-hexanoyl-biphenyl-4-yl)-butyl ester (prepared according to Scheme 1) (1 mmol) in trifluoroacetic acid (10 mL) is added triethylsilane (2.5 mmol). The resulting mixture is stirred at room temperature for 12 h. After concentrating under reduced pressure, the residue is dissolved in DCM and the organic solution is washed with saturated NaHCO3 and brine and dried over Na2SO4. After concentration, the crude product is purified by column chromatography using EtOAc/hexane (1/1) to give the desired compound as a white solid. MS: (ES+): 482.3 (M+1)+.
Reaction SMILES: [CH2:1]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([O:18][CH2:19][CH:20]2[O:22][CH2:21]2)[CH2:12][C:11]1([CH3:24])[CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:25][CH:26]1[CH2:31][C:30]([CH3:33])([CH3:32])[N:29]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:28]([CH3:44])([CH3:43])[CH2:27]1.Cl(O)(=O)(=O)=O>>[CH2:35]([O:34][N:29]1[C:30]([CH3:32])([CH3:33])[CH2:31][CH:26]([O:25][CH:20]([CH2:19][O:18][CH:13]2[CH2:12][C:11]([CH3:24])([CH3:23])[N:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:15]([CH3:16])([CH3:17])[CH2:14]2)[CH2:21][OH:22])[CH2:27][C:28]1([CH3:43])[CH3:44])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCON1C(C)(C)CC(OCC2CO2)CC1(C)C
Reactant: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCCCCCCCON1C(C)(C)CC(OCC(CO)OC2CC(C)(C)N(OCCCCCCCC)C(C)(C)C2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of 1-(1-octyloxy-2,2,6,6-tetramethylpiperidin-4-yloxy)-2,3-epoxypropane (prepared in Example 11) and 4-hydroxy-1-octyloxy-2,2,6,6-tetramethylpiperidine (prepared in Example 5) in the presence of a catalytic amount of perchloric acid.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH:4]([CH2:5][CH:6]=[C:7]2[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.C(C1N(C(C(OCC2C=CC=CC=2)=O)=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C(=O)C1)C=C.[C:57]1([SH:63])[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:1]=[C:2]1[N:8]2[CH:4]([CH2:5][CH:6]([S:63][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH:7]2[C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:3]1
Reactant: Sc1ccccc1
Reactant: O=C(OCc1ccccc1)C1=CCC2CC(=O)N12
Agent: C=CCC1CC(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)C1C(Sc2ccccc2)CC2CC(=O)N21

Procedure:
Crude benzyl 7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate prepared from an ethyl acetate solution of 4-allyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidin-2-one (1.00 g) by ozonolysis and cyclisation was dissolved in dry dimethylformamide (5 ml) treated successively with thiophenol (0.20 ml) and potassium carbonate (0.133 q) with stirring. After a period of 1 hour the solution was concentrated under reduced pressure and the residue treated with ethyl acetate. It was then washed with brine, dried over sodium sulphate and concentrated. Chromatography on silica gel 60 (<230 mesh) eluting with 60°-80° petroleum ether/ethyl acetate 7:3 grading to 6:4 gave two fractions containing diastereoisomers of the title compound. The least polar fraction (0.183 g) was an approximately 4:1 mixture of isomers A (5) and B (6); νmax (CHCl3) 3000, 1760 and 1740 (sh); τ(CDCl3) for major isomer A (5), 2.6-2.9 (10H, m, phenyls), 4.88 (2H, s, benzyl CH2), 5.26 (1H, d, J 7 Hz, C2-H), ca 5.90 (1H, br m, C5-H), 6.10 (1H, td, J9 and 7 Hz, C3-H), 6.69 (1H, dd, J16 and 5 Hz, C6-H), 7.32 (1H, dd, J16 and 21/2 Hz, C6-H), 7.73 (1H, dd, J9 and 7 Hz, C4-H) and 7.77 (1H, dd, J9 and 4 Hz, C4-H); minor isomer B (6) had 5.62 (d, J 5 Hz, C2-H); (M+ for mixture at m/e 353.1102. C20H19NO3S requires 353.1085). The more polar fraction (0.102 g) was isomer C (8) which could be crystallized from diethyl ether; m.p. 84°-85°; νmax (CHCl3) 3000, 1765 and d 1740 cm-1 ; τ(CDCl3) 2.6-2.9 (10H, m, phenyls), 4.81 (2H, s, benzyl CH2), 5.84 (1H, d, J 7 Hz, C2-H), 6.04 (1H, ddd, J12, 7 and 5 Hz, C3-H), 6.2-6.5 (1H, m, C5-H), 6.90 (1H, dd, J16 and 4 Hz, C6-H), 7.19 (1H, dd, J16 and 21/2 Hz, C6-H), 7.64 (1H, dt, J12 and 5 Hz, C4-H) and 7.95 (1H, td, J12 and 10 Hz, C4-H); (Found; C, 68.1; H, 5.6; N, 3.9% C20H19NO3S requires C, 68.0; H, 5.4 and N, 4.0%).
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:26][O:27][C:28](=[O:39])[CH2:29][C:30]1[CH:35]=[CH:34][C:33](O)=[C:32]([O:37][CH3:38])[CH:31]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:26][O:27][C:28](=[O:39])[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:32]([O:37][CH3:38])[CH:31]=1
Reactant: COC(=O)Cc1ccc(O)c(OC)c1
Reactant: OC1CCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(OC2CCCC2)c(OC)c1
Temperature: 25 °C
Reaction time: 44 h
Yield: 66.1 %

Procedure:
Cyclopentanol (7.7 ml, 85 mmol) and triphenylphosphine (28 g, 107 mmol) were added to a solution of (4-hydroxy-3-methyoxy-phenyl)-acetic acid methyl ester (14 g, 71 mmol) in tetrahydrofuran (280 ml) under nitrogen at 0° C. Diethylazodicarboxylate (15.7 ml, 100 mmol) was then added dropwise and the reaction was allowed to warm to room temperature and stirred for 44 hours. The solvent was removed under reduced pressure, pentane (200 ml) was added and the suspension was filtered. The filtrate was concentrated under reduced pressure and purified by flash column chromatography on silica gel eluting with a solvent gradient of cyclohexane:ethyl acetate (90:10 changing to 85:15, by volume) to give (4-cyclopentyloxy-3-methoxy-phenyl)-acetic acid methyl ester (12.4 g) as a colourless oil. 1H NMR (400 MHz, CD3OD): δ=6.79-6.85 (2H, m), 6.73-6.79 (1H, d), 4.73-4.79 (1H, brs), 3.79 (3H, s), 3.64 (3H, s), 3.53 (2H, s), 1.74-1.89 (6H, m), 1.56-1.67 (2H, m) ppm. LRMS (electrospray): m/z [M+Na]+ 287. Anal. Found C, 68.01; H, 7.74. C15H20O4 requires C, 68.16; H, 7.63%.
Reaction SMILES: [C:1]([Si:5]([CH3:30])([CH3:29])[O:6][C@H:7]([CH3:28])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[O:21][CH2:20][C@H:19]([O:22][CH2:23][C:24]([O:26]C)=O)[CH2:18][C:16]3=2)[CH:11]=[N:10]1)([CH3:4])([CH3:3])[CH3:2].[NH3:31]>>[Si:5]([O:6][C@H:7]([CH3:28])[CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]3[O:21][CH2:20][C@H:19]([O:22][CH2:23][C:24]([NH2:31])=[O:26])[CH2:18][C:16]3=2)[CH:11]=[N:10]1)([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:29])[CH3:30]
Reactant: COC(=O)CO[C@H]1COc2ccc3cnn(C[C@@H](C)O[Si](C)(C)C(C)(C)C)c3c2C1
Reactant: N
Product: C[C@H](Cn1ncc2ccc3c(c21)C[C@@H](OCC(N)=O)CO3)O[Si](C)(C)C(C)(C)C

Procedure:
A solution of the product from Step A (0.49 g, 1.13 mmol) in methanolic ammonia (7 N, 20 mL, 0.14 mol) was stirred for 18 h at room temperature. The reaction mixture was evaporated to a colorless residue (0.44 g, 93%) which was used in the next reaction: LC/MS (+APCI) m/z 420.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1Cl.[CH3:12][CH:13]([CH3:16])[CH2:14][SH:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]([OH:11])=[O:10])=[N:6][C:7]=1[S:15][CH2:14][CH:13]([CH3:16])[CH3:12]
Reactant: O=C(O)c1ccc(Br)c(Cl)n1
Reactant: CC(C)CS
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)CSc1nc(C(=O)O)ccc1Br
Temperature: 150 °C
Reaction time: 24 h
Yield: 101.4 %

Procedure:
5-Bromo-6-chloropicolinic acid (2 g, 8.46 mmol; CAN 959958-25-9), 2-methylpropane-1-thiol (915 mg, 1.1 mL, 10.2 mmol) and cesium carbonate (6.89 g, 21.1 mmol) were suspended in DMSO (100 mL). The reaction mixture was heated to 150° C. and stirred for 1 d and was poured onto ice-water/1N HCl (100 mL). The aqueous layer was extracted with EtOAc (2×250 mL). The combined extracts were washed with ice-water/brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (2.49 g, 51%) as an orange solid which was used in the next step without further purification. MS (EI): m/e=288.4 [M−H]−.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([N:16](CCO)[C:17]3([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:30][C:31]([NH2:33])=[NH:32])=[N:5][CH:4]=1.Cl.ClC1C2C(=CC(S(NC3(C(O)=O)CCCC3)(=O)=O)=CC=2)C(NC(N)=N)=NC=1.CNC>C(Cl)Cl.CN(C=O)C>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]3)(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:30][C:31]([NH2:33])=[NH:32])=[N:5][CH:4]=1
Reactant: CN(C)C(=O)C1(N(CCO)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Agent: CNC
Agent: Cl
Agent: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)O)CCCC3)cc12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN(C)C(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
1-[({4-Chloro-1-guanidino-7-isoquinolinyl}sulphonyl)(2-hydroxyethyl)amino]-N,N-dimethylcyclopentanecarboxamide hydrochloride ##STR97## Oxalyl chloride (3.5 ml, 4.0 mmol) was added to a suspension of N-({4-chloro-1-guanidino-7-isoquinolinyl}sulphonyl)cycloleucine hydrochloride (870 mg, 1.94 mmol) in CH2Cl2 (100 ml), followed by DMF (5 drops), and the reaction stirred at room temperature for 2 h. The solution was concentrated in vacuo and azeotroped with toluene to give a yellow gum. This was dissolved in CH2Cl2 (100 ml), the solution cooled to -20° C., and cooled N,N-dimethylamine (10 ml) added. The reaction was allowed to warm to room temperature with stirring, over 30 min, then concentrated in vacuo, and the residue azeotroped with toluene. The crude product was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880 NH3 (95:5:0.5) as eluant, and crystallised from MeOH to afford to afford 1-[({4-chloro-1-guanidino-7-isoquinolinyl}sulphonyl)amino]-N,N-dimethylcyclopentanecarboxamide (302 mg, 0.69 mmol) as a yellow solid. mp. 264-268° C.
Reaction SMILES: [CH2:1]([C:3]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([CH3:32])[CH:24]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([OH:21])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])=[C:8]([CH3:22])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].Cl.[CH3:34][O:35][C:36](=[O:39])[CH2:37][NH2:38]>>[CH3:34][O:35][C:36](=[O:39])[CH2:37][NH:38][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([C:3]([CH2:4][CH3:5])([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]([OH:21])([CH:18]([CH3:19])[CH3:20])[CH:15]([CH3:16])[CH3:17])=[C:8]([CH3:22])[CH:7]=2)[CH2:1][CH3:2])=[CH:24][C:25]=1[CH3:32]
Reactant: COC(=O)CN
Reactant: CCC(CC)(c1ccc(OCC(O)(C(C)C)C(C)C)c(C)c1)c1ccc(C(=O)O)c(C)c1
Agent: Cl
Product: CCC(CC)(c1ccc(OCC(O)(C(C)C)C(C)C)c(C)c1)c1ccc(C(=O)NCC(=O)OC)c(C)c1
Yield: 86.8 %

Procedure:
Using a procedure analogous to Example 1J, 4-{1-ethyl-1-[4-(2-hydroxy-2-isopropyl-3-methyl-butoxy)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid (0.30 g, 0.68 mmol) and glycine methyl ester hydrochloride (0.094 g, 0.75 mmol) gives the titled compound (0.30 g, 0.59 mmol, 86%).
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Cl:8][C:9]1[CH:10]=[C:11]([CH2:16][CH2:17][C:18](=O)[CH3:19])[CH:12]=[CH:13][C:14]=1[Cl:15].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].CO>C1COCC1.C(=O)=O.C(O[Ti](OCC)(OCC)OCC)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH2:16][CH2:17][C@H:18]([NH:7][S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH3:19])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CC(=O)CCc1ccc(Cl)c(Cl)c1
Agent: CCO[Ti](OCC)(OCC)OCC
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](CCc1ccc(Cl)c(Cl)c1)N[S@@](=O)C(C)(C)C
Temperature: 75 °C
Reaction time: 72 h
Yield: 62.3 %

Procedure:
To a stirred solution of (S)-2-methylpropane-2-sulfinamide (373 mg, 3.08 mmol) and Intermediate 4A (700 mg, 3.22 mmol) in THF (2 mL) at rt was added tetraethoxytitanium (1.22 mL, 5.86 mmol). The reaction mixture was heated at 75° C. for 16 h, and allowed to cool and stay at rt for 72 h. Another equivalent of Ti(OEt)4 (1.22 mL, 5.86 mmol) and (S)-2-methylpropane-2-sulfinamide (373 mg, 3.08 mmol) were added. The reaction mixture was heated at 75° C. for 16 h before cooled down. This THF solution was stirred in a round-bottomed flask under argon at −40 to −50° C. L-Selectride (2016 μL, 2.016 mmol) was added dropwise. The resulting mixture was then warmed up to 0° C. during a 1.5 h period. It was cooled in dry ice and MeOH was added dropwise until gas evolution stopped. The mixture was stirred at rt for 20 min. It was filtered through Celite and rinsed with CH2Cl2 and the filtrate was washed with brine (2×) and dried over Na2SO4, filtered and concentrated. The residue was purified on flash chromatography (0-100% hexanes/EtOAc) to give Intermediate 4B (620 mg, 1.92 mmol, 59.6% yield) as slightly tan oil (slow eluent) and an impure (S)—N—((S)-4-(3,4-dichlorophenyl)butan-2-yl)-2-methylpropane-2-sulfinamide. LC-MS (ESI) m/z 322.0 (M+H), RT=2.34 min (Method B).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].C(Cl)(Cl)Cl.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(OCC)(=O)C>[Br:1][CH2:2][C:3]([N:20]1[CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:16])[CH2:22][CH2:21]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Reaction time: 0.5 h

Procedure:
With cooling with ice, bromoacetyl bromide (680 μL) was added to a chloroform (10 ml) solution of 1-tert-butyloxycarbonylpiperazine (1 g) and triethylamine (2.2 mL). At that temperature, this was stirred for 0.5 hours, and then at room temperature for further 0.5 hours. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=7/3) to obtain 340 mg of the entitled compound.
Reaction SMILES: [N:1]([CH2:4][C:5]1[S:9][C:8]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)=[N:7][CH:6]=1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1>[CH3:15][C:10]1([C:8]2[S:9][C:5]([CH2:4][NH2:1])=[CH:6][N:7]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: CC1(c2ncc(CN=[N+]=[N-])s2)OCCO1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1(c2ncc(CN)s2)OCCO1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of the crude azide (113 mg, 0.50 mmol) in THF (6 mL) were added polymer supported Ph3P (262 mg, 1.00 mmol) and water (2 mL). The reaction mixture was stirred at 60° C. for 1 h, cooled down to rt, filtered and concentrated under reduced pressure. The residue was redissolved in CH2Cl2/MeOH 9:1, dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as an orange oil. LC-MS-conditions 02: tR=0.48 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[O:32]1[C:40]2[CH:39]=[CH:38][N:37]=[C:36]([N:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[C:35]=2[CH:34]=[CH:33]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:30])([F:31])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:44]4[CH2:45][CH2:46][N:41]([C:36]5[C:35]6[CH:34]=[CH:33][O:32][C:40]=6[CH:39]=[CH:38][N:37]=5)[CH2:42][CH2:43]4)=[O:24])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: c1cc2occc2c(N2CCNCC2)n1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCN(c2nccc3occc23)CC1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-(4-furo[3,2-c]pyridinyl)piperazine as in General Procedure 10 to give the title compound. LCMS: m/z=633.03 (M+H+); retention time=0.63 minutes.
Reaction SMILES: Br[C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:10]([O:14][C:15](=[O:20])[NH:16][CH2:17][CH2:18][NH2:19])([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:10]([O:14][C:15]([NH:16][CH2:17][CH2:18][NH:19][C:2]([CH3:9])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:20])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)NCCNC(=O)OC(C)(C)C

Procedure:
Ethyl 2-bromo-2-methylpropanoate (2.0 g, 13.47 mmol) was added to tert-butyl(2-aminoethyl)carbamate (2.0 g, 12.48 mmol) and K2CO3 (4.31 g, 31.2 mmol) in DMF (35 ml) at room temperature. After 18 h at room temperature the reaction mixture was partitioned between aqueous saturated NaHCO3 and EtOAc, extracted 2× with EtOAc, the combined organic layers dried over Na2SO4 and evaporated. The residue was preabsorbed onto isolate and purified by normal phase chromatography: 120 g RediSep® column, eluting with a gradient from DCM to 9:1 DCM containing 0.3% NH3. The product containing fractions were combined and evaporated to give the title compound as a colourless oil. 1H NMR (400 MHz, DMSO-d6) δ 6.74 (t, 1H), 4.07 (q, 2H), 2.95 (q, 2H), 2.45-2.35 (m, 2H), 2.17-2.02 (m, 1H), 1.38 (s, 9H), 1.19 (d, 9H).
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[C:20](\[CH3:29])/[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@:17]1([CH2:18][OH:19])[CH2:29][C@@:20]1([CH3:1])[C@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22]
Reactant: CC[Zn]CC
Reactant: C/C(CO)=C(\C)C(C)c1ccccc1
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccccc1)[C@]1(C)C[C@]1(C)CO
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 10.9 g, 13.2 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −15° C. Chloroiodomethane (4.68 g, 26.5 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between −15 and −20° C. After completion of the dropwise addition, the mixture was stirred at −15° C. for 30 minutes. (Z)-2,3-Dimethyl-4-phenylpent-2-ene-1-ol (1.26 g, 6.63 mmol) was added dropwise at −10 to −15° C. over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at 12° C. for 60 minutes. Next, a 20% aqueous sulfuric acid solution (4.8 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1S*,2S*)-1,2-Dimethyl-2-((S*)-1-phenylethyl)cyclopropyl]methanol (0.47 g, 2.3 mmol, 35% yield) was obtained as the main isomer, and [(1S*,2S*)-1,2-dimethyl-2-((R*)-1-phenylethyl)cyclopropyl]methanol (0.45 g, 2.2 mmol, 33% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])=[CH:16][CH:15]=1>>[CH3:11][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][C@@H:21]([OH:23])[CH3:22])=[CH:18][CH:19]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: C[C@H](O)Cc1ccc(N)cc1
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Cl)n1
Product: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(C[C@H](C)O)cc2)n1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 2-chloro-4,6-dimethyl-3-nitropyridine (step 2 of Example 1) and (2S)-1-(4-aminophenyl)-2-propanol (step 2 of Example 248).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[N:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1>S(=O)(=O)(O)O>[Cl:5][C:6]1[N:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:1]([O-:4])=[O:2])[CH:12]=2)[N:7]=1
Reactant: Oc1nc(Cl)nc2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2nc(Cl)nc(O)c2c1

Procedure:
A cooled mixture of 70 ml of concentrated sulfuric acid and 35 ml of concentrated nitric acid was added dropwise to a cooled, stirred solution of 90 g of 2-chloro-4-hydroxyquinazoline [J. Chem. Soc., 1947, p. 775] in 270 ml of concentrated sulfuric acid at a rate such that the temperature remained at 5°-10° C. Stirring was continued until the reaction mixture reached room temperature, whereupon it was poured into crushed ice. The 2-chloro-4-hydroxy-6-nitro-quinazoline thus precipitated is filtered off, washed well with water and used directly in the next step.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[K+].C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1.[O:68]1[C:70]([CH2:73][CH3:74])([CH2:71][CH3:72])[CH2:69]1>C1(C)C=CC=CC=1>[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([O:24][CH2:69][C:70]([CH2:73][CH3:74])([OH:68])[CH2:71][CH3:72])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:1]([O:8][C@@H:9]1[C@@:29]2([CH3:30])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:31])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21]([OH:24])([CH3:23])[CH3:22])[CH2:12][C@@H:11]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:34])[CH3:35])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCC1(CC)CO1
Agent: CC(C)(O)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCC(O)(CC)COC(C)(C)C1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 10 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene (261.4 mg, 0.456 mmol), potassium hydride (35% in oil, 0.53 ml, 4.625 mmol), dibenzo-18-crown-6 (165 mg, 0.458 mmol), toluene (0.75 ml) and 1,2-epoxy-2-ethylbutane (450 mg, 4.493 mmol) were subjected to reaction using a procedure similar to that of Example 21(1) (at external temperature of 95° C. for 2 hours and 10 min.), worked up and the thus obtained residue was purified by column chromatography (hexane:ethyl acetate=10:1) and preparative thin layer chromatography (1 sheet (0.5 mm thickness), hexane:ethyl acetate=20:1, developed twice) to give the titled compound (32.0 mg, 10%) and 1α,3β-bis(tert-butyldimethylsilyloxy)-20-hydroxy-20-methylpregna-5,7,16-triene (138.5 mg, 53%), each as a colorless oil.