Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br.[OH-].[Na+].C(=O)([O-])O.[Na+].[ClH:42]>C(Cl)Cl.C(O)C.O>[ClH:42].[OH:2][C:3]1[C:15]2[CH2:14][CH2:13][C@H:12]3[C@H:8]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:21](=[O:30])[C:22]4=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]4[C:24]3=[O:25])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCCN1C(=O)c2ccccc2C1=O
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCO
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCCCN1CC[C@@H]2c3cccc(O)c3CC[C@@H]21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 14 %

Procedure:
A solution of 2.00 g (0.005 mol) of rac-cis-N-[4-(1,2,3a,4,5,9b-hexahydro-6-methoxy-3H-benzo[e]indol-3-yl)butyl]phthalimide in 100 ml of methylene chloride was treated dropwise with a solution of 2.4 ml (0.025 mol) of boron tribromide in 100 ml of methylene chloride, whereupon the mixture was stirred at room temperature for 1.5 hours. 32 ml (0.065 mol) of 2N sodium hydroxide solution were added dropwise while cooling with an ice bath. The mixture was poured into water, whereupon an aqueous sodium hydrogen carbonate solution was added until a pH of 8 had been reached. The mixture was extracted with methylene chloride, the extracts were dried over sodium sulphate and the solvent was distilled off in a vacuum. Chromatography over silica gel with methylene chloride/methanol 20:1 yielded an oil which was dissolved in ethanol and treated with ethanolic HCl. Distillation of the solvent and recrystallization from methanol gave 0.3 g (14%) of rac-N-[4-(cis-1,2,3a,4,5,9b-hexahydro-6-hydroxy-3H-benzo[e]indol-3-yl)butyl]phthalimide hydrochloride as white crystals with m.p. 258°-260° (dec.).
Reaction SMILES: [C:1]1([C:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]([F:34])([F:33])[C:23]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][NH:25][N:24]=1.C(N(CC)CC)C>CN(C)C=O>[CH2:31]([O:30][C:28]([C:27]1[C:23]([C:22]([F:33])([F:34])[F:21])=[N:24][N:25]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:26]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
Triphenylmethyl chloride (1.1 g, 3.6 mmol) was added to a solution of ethyl 3-(trifluoromethyl)-pyrazole-4-carboxylate (0.75 g, 3.6 mmol) and triethylamine (1 mL, 7.2 mmol) in N,N-dimethylformamide (12 mL). This mixture was stirred at room temperature overnight, then the solvent was evaporated and the residue was diluted with water (30 mL) and extracted with ethyl acetate. The organic extract was washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and chromatographed (10% ethyl acetate/petroleum ether) to give 3-trifluoromethyl-1-trityl-1H-pyrazole-4-carboxylic acid ethyl ester (1.28 g, 79%).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][C:6]#[N:7])[CH3:2].[NH2:10][OH:11]>CCO>[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][C:6](=[N:10][OH:11])[NH2:7])[CH3:2]
Reactant: NO
Reactant: CCN(CC)CCC#N
Solvent: CCO
Product: CCN(CC)CCC(N)=NO
Yield: 92.6 %

Procedure:
A solution of 3-(diethylamino)propanenitrile (1 g, 8 mmol) and NH2OH (50% in water, 0.73 cm3, 11.9 mmol) in EtOH (10 cm3) were heated to reflux for 24 hours, after which the solvent and excess hydroxylamine were removed by rotary evaporator. The residue was freeze-dried and kept in high vacuum line until it slowly solidified to give 3-(diethylamino)-N′-hydroxypropanimidamide (1.18 g, 92.6%) as a white solid, mp 52-54° C.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[O:5])[CH3:2].[CH3:7][N:8]([CH2:10][C:11]1[S:15][C:14]([CH2:16][S:17][CH2:18][CH2:19][NH:20][C:21]2[N:25]([CH3:26])[N:24]=[C:23]([NH2:27])[N:22]=2)=[CH:13][CH:12]=1)[CH3:9].C(=O)([O-])[O-].[Na+].[Na+].O>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:5])[NH:27][C:23]1[N:22]=[C:21]([NH:20][CH2:19][CH2:18][S:17][CH2:16][C:14]2[S:15][C:11]([CH2:10][N:8]([CH3:7])[CH3:9])=[CH:12][CH:13]=2)[N:25]([CH3:26])[N:24]=1)[CH3:2]
Reactant: CN(C)Cc1ccc(CSCCNc2nc(N)nn2C)s1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc(NCCSCc2ccc(CN(C)C)s2)n(C)n1
Yield: 56.2 %

Procedure:
A cooled mixture of ethylchloroformate (0.45 g) in pyridine was treated with a solution of N5 -[2-[[[5-[(dimethylamino)methyl]-2-thienyl]methyl]thio]ethyl]-1-methyl-1H-1,2,4-triazole-3,5-diamine (0.7 g) in pyridine (8 ml). Sodium carbonate (2 g) and water (10 ml) were added and the mixture evaporated in vacuo. The residue was dissolved in water (15 ml) and extracted with hot isopropanol (30 ml). The extract was evaporated and the residue purified by column chromatography (silica:methanol:0.88 ammonia; 79:1) to give the title compound (0.48 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([Cl:22])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:22][CH2:16][C:10]1[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(F)cc1OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(CCl)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from step (iii) (1.06 g), methane sulphonyl chloride (0.351 ml) and triethylamine (0.636 ml) in DCM (20 ml) was stirred at RT for 2 h. The mixture was partitioned between water/DCM, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/DCM 1:1, yield 0.7 g.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10](I)[C:3]=12.[NH:30]1[C:38]2[CH:37]=[CH:36][CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[C:33]=2[CH:32]=[N:31]1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>CN(C=O)C.C(O)C.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:12][C:13]3[O:14][C:15]4[C:20]([C:21](=[O:29])[C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:9]=[C:10]([C:34]3[CH:35]=[CH:36][CH:37]=[C:38]4[C:33]=3[CH:32]=[N:31][NH:30]4)[C:3]=12
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: Nc1ncnc2c1c(I)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: Nc1ncnc2c1c(-c1cccc3[nH]ncc13)nn2Cc1oc2ccccc2c(=O)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 8.2 %

Procedure:
To a solution of Example 57a (0.500 g, 1.00 mmoles) in DMF (5 ml), ethanol (2.5 ml) and water (2.5 ml), 4-Indazoleboronic acid pinacol ester (0.491 g, 2.00 mmoles) and sodium carbonate (0.533 g, 5.02 mmoles) were added and the system is degassed for 30 min Tetrakis triphenylphosphine Palladium (0.229 g, 0.197 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol: dichloromethane to afford the title compound as brown solid (0.040 g, 8% yield). MP: 248-252° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.24(s,1H), 8.27(s,1H), 8.07(dd, J=7.9, 1.6Hz, 1H),8.01(s, 1H), 7.78(m,1H), 7.63(d, J=8.4Hz, 1H), 7.51-7.32(m, 10H), 7.14(br s,1H),5.56(s, 1H). Mass: 486.04(M++1).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[NH:46][C:44](=[O:45])[C@H:43]([C@H:47]([OH:54])[C@@H:48]([CH2:50]/[CH:51]=[CH:52]/[CH3:53])[CH3:49])[N:42]([CH3:55])[C:40](=[O:41])[C@H:39]([CH:56]([CH3:58])[CH3:57])[N:38]([CH3:59])[C:36](=[O:37])[C@H:35]([CH2:60][CH:61]([CH3:63])[CH3:62])[N:34]([CH3:64])[C:32](=[O:33])[C@H:31]([CH2:65][CH:66]([CH3:68])[CH3:67])[N:30]([CH3:69])[C:28](=[O:29])[C@@H:27]([CH3:70])[NH:26][C:24](=[O:25])[C@H:23]([CH3:71])[NH:22][C:20](=[O:21])[C@H:19]([CH2:72][CH:73]([CH3:75])[CH3:74])[N:18]([CH3:76])[C:16](=[O:17])[C@H:15]([CH:77]([CH3:79])[CH3:78])[NH:14][C:12](=[O:13])[C@H:11]([CH2:80][CH:81]([CH3:83])[CH3:82])[N:10]([CH3:84])[C:8](=[O:9])[CH2:7][N:6]([CH3:85])[C:4]1=[O:5].[C:86]([O:89]C(=O)C)(=[O:88])[CH3:87]>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][CH2:2][C@@H:3]1[NH:46][C:44](=[O:45])[C@H:43]([C@H:47]([OH:54])[C@@H:48]([CH2:50]/[CH:51]=[CH:52]/[CH3:53])[CH3:49])[N:42]([CH3:55])[C:40](=[O:41])[C@H:39]([CH:56]([CH3:57])[CH3:58])[N:38]([CH3:59])[C:36](=[O:37])[C@H:35]([CH2:60][CH:61]([CH3:62])[CH3:63])[N:34]([CH3:64])[C:32](=[O:33])[C@H:31]([CH2:65][CH:66]([CH3:68])[CH3:67])[N:30]([CH3:69])[C:28](=[O:29])[C@@H:27]([CH3:70])[NH:26][C:24](=[O:25])[C@H:23]([CH3:71])[NH:22][C:20](=[O:21])[C@H:19]([CH2:72][CH:73]([CH3:75])[CH3:74])[N:18]([CH3:76])[C:16](=[O:17])[C@H:15]([CH:77]([CH3:79])[CH3:78])[NH:14][C:12](=[O:13])[C@H:11]([CH2:80][CH:81]([CH3:83])[CH3:82])[N:10]([CH3:84])[C:8](=[O:9])[CH2:7][N:6]([CH3:85])[C:4]1=[O:5].[C:86]([O-:89])(=[O:88])[CH3:87]
Reactant: CC(=O)OC(C)=O
Agent: C/C=C/C[C@@H](C)[C@@H](O)[C@H]1C(=O)N[C@@H](CC)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 12 g (10 mmol) of Cyclosporin A (MW: 1202.61) in 40 ml of acetic anhydride (MW: 102.09, d 1.082), 40 ml of pyridine (MW: 79.01, d 0.978) and 0.4 g of 4-N,N-dimethylaminopyridine (MW: 122.17) was added. This solution was stirred for overnight at room temperature, and then the mixture was diluted with 600 ml of ethyl acetate. The mixture was washed with brine, saturated ammonium chloride water solution and with 15% of sodium bicarbonate. The organic phase was dried with sodium sulphate. filtered and evaporated under the reduced pressure. The toluene was added to the mixture until all of pyridine was evaporated to yield the pale yellow solid residue, which was purified by flash chromatography on a silica gel column (100-200 mesh) with eluent of ethyl acetate in haxene (1/3) to give the 11.8 g (9.48 mmol, 95%) of Cyclosporin A-acetate (MW: 1244.65).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24](O)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C.[CH3:58][NH:59][CH:60]1[CH2:65][CH2:64][CH2:63][CH:62]([N:66]2[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]2)[CH2:61]1>CN(C=O)C>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:59]([CH3:58])[CH:60]3[CH2:65][CH2:64][CH2:63][CH:62]([N:66]4[CH2:67][CH2:68][N:69]([CH3:72])[CH2:70][CH2:71]4)[CH2:61]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CNC1CCCC(N2CCN(C)CC2)C1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N(C)C3CCCC(N4CCN(C)CC4)C3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AH using 2-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid (50 mg, 0.13 mmol), EDCI (50 mg, 0.26 mmol), HOBt monohydrate (40 mg, 0.26 mmol), DIPEA (90 μL, 0.52 mmol), N-methyl-3-(4-methylpiperazin-1-yl)cyclohexanamine (27 mg, 0.13 mmol) and DMF (1 mL). The resulting crude compound was purified by FCC eluting with 99:1 DCM:7N NH3 in MeOH followed by purification using prep method D.
Reaction SMILES: ClCCl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([O:30][CH3:31])[CH:21]=2)[CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13].FC(F)(F)C(O)=O>C(OCC)(=O)C>[CH3:31][O:30][C:22]1[C:21]2[C:7]3[C:6]([O:5][CH3:4])=[C:11]([O:12][CH3:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=3[CH2:16][CH2:17][CH2:18][CH2:19][C:20]=2[CH:25]=[C:24]([O:26][CH3:27])[C:23]=1[O:28][CH3:29]
Reactant: COc1cc(CCCCc2cc(OC)c(OC)c(OC)c2)cc(OC)c1OC
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(c(OC)c1OC)-c1c(cc(OC)c(OC)c1OC)CCCC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 6 %

Procedure:
Dissolved in 1.2 ml (0.128 mmol) of dichloromethane were 50 mg (0.128 mmol) of 1,4-bis(3,4,5-trimethoxyphenyl)butane, followed by the addition of 0.12 ml of trifluoroacetic acid and 178 mg (0.39 mmol) of ferric perchlorate. After stirred at room temperature for 40 minutes, the reaction mixture was dissolved in 20 ml of ethyl acetate. The resulting solution was washed with 2N-HCl and then with saturated NaCl. The organic layer was thereafter dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby brown oil was obtained. The oil thus obtained was purified by TLC (silica gel: "MERCK #5744", eluent: 1:1 mixed solvent of ethyl acetate and hexane), whereby 3 mg of the title compound were obtained as colorless oil (yield: 6%).
Reaction SMILES: N(C([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[N:10][N:9]2[CH:15]=1)=O)=[N+]=[N-].C[N:17](C=O)C>O>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:9]([CH:15]=[C:6]([NH2:17])[N:7]=2)[N:10]=1
Reactant: [N-]=[N+]=NC(=O)c1cn2nc(Cl)ccc2n1
Reactant: CN(C)C=O
Solvent: O
Product: Nc1cn2nc(Cl)ccc2n1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 42 %

Procedure:
To a 100-mL, round-bottomed flask was added azido(6-chloroimidazo[1,2-b]pyridazin-2-yl)methanone from Step 2 (2.3 g, 10 mmol) and DMF (40 mL). The solution was heated to 100° C. and H2O (1.8 mL, 100 mmol) was added. The mixture was stirred for 45 min and then allowed to cool to room temperature. The mixture was poured into water (150 mL) and then concentrated in vacuo. The solid residue was dissolved in 1:2 MeOH/CH2Cl2 (900 mL) and concentrated onto silica. Purification by silica gel chromatography (1 to 5% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as a yellow-green solid (0.71 g, 42% yield). MS (ESI positive ion) m/z: 169 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 7.69 (d, J=9.2 Hz, 1H), 7.37 (s, 1H), 7.05 (d, J=9.2 Hz, 1H), 5.74 (broad s, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CCCC2)c(OCC2CC2)n1
Reactant: C1CSCCN1
Product: O=C(c1ccc(N2CCCC2)c(OCC2CC2)n1)N1CCSCC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-pyrrolidin-1-yl-pyridine-2-carboxylic acid (Example 14 a) and thiomorpholine (CAN 123-90-0) as starting materials, MS (LC/MS): 348.1 [M+H]+.
Reaction SMILES: [C:1]([SiH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])([CH2:4][CH3:5])([CH3:3])[CH3:2].[Mg].Cl[C:13](C)(CCC)C.Cl[SiH](Cl)Cl>>[CH2:7]([SiH:6]([CH2:9][CH3:10])[C:1]([CH3:3])([CH2:4][CH2:5][CH3:13])[CH3:2])[CH3:8]
Reactant: CC[SiH](CC)C(C)(C)CC
Reactant: CCCC(C)(C)Cl
Agent: Cl[SiH](Cl)Cl
Agent: [Mg]
Product: CCCC(C)(C)[SiH](CC)CC

Procedure:
The procedure of synthesizing Compound 34a was repeated, except that 2-methylpentan-2-ylmagnesium chloride THF solution (100 mL), which had been prepared from magnesium (2.43 g, 100 mmol) and 2-chloro-2-methylpentane (12.0 g, 99.0 mmol); trichlorosilane (9.70 mL, 96.1 mmol); and ethylmagnesium chloride THF solution (0.93M, 200 mL, 1.86 mmol) were employed, whereby the Compound 42a was obtained as a colorless liquid (boiling point; 40 mmHg, 100 to 103° C. fraction, 6.62 g, 40%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@:8]12[CH:15]=[CH:14][CH2:13][C@@H:12]1[C:11](=O)[N:10]([C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C@@:8]12[CH:15]=[CH:14][CH2:13][C@@H:12]1[C:11](=[S:34])[N:10]([C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:18])[CH2:9]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)C=CC[C@@H]2C1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: C[C@H](c1ccccc1)N1C[C@]2(C(=O)OC(C)(C)C)C=CC[C@@H]2C1=S
Temperature: 80 °C
Reaction time: 4 h
Yield: 133.3 %

Procedure:
[(1S,5S)-4-Oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]oct-7-en-1-yl]carboxylic acid tert-butyl ester (88.0 mg, 0.27 mmol) was dissolved in toluene (8 mL). Lawesson's reagent (81.5 mg, 0.20 mmol) was added, and the mixture was stirred at 80° C. for four hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (10% ethyl acetate/hexane) to give 91.6 mg of the title compound as a yellow oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=1)[C:8]([NH:10][C:11]1[S:12][C:13](Br)=[CH:14][N:15]=1)=[O:9])([CH3:3])[CH3:2].[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][SH:32]>>[CH3:27][O:28][C:29](=[O:33])[CH2:30][CH2:31][S:32][C:13]1[S:12][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:17]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:19]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:6]=2)=[N:15][CH:14]=1
Reactant: COC(=O)CCS
Reactant: CC(C)Oc1cc(Oc2ccccc2)cc(C(=O)Nc2ncc(Br)s2)c1
Product: COC(=O)CCSc1cnc(NC(=O)c2cc(Oc3ccccc3)cc(OC(C)C)c2)s1
Yield: 7.5 %

Procedure:
3-[2-(3-Isopropoxy-5-phenoxy-benzoylamino)-thiazol-5-yl-sulfanyl]-propionic acid methyl ester (30 mg) was prepared from 3-isopropyloxy-5-phenoxy-N-(5-bromothiazol-2-yl)benzamide (example 1, step 2) (370 mg, 0.85 mmol) and 3-mercaptopropionic acid methyl ester (0.5 mL, 4.0 mmol) in 7% yield following general procedure F.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.S(=O)(=O)(O)[OH:23].O.[Mn]([O-])(=O)(=O)=O.[K+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])(=[O:23])=[O:17])[CH3:15])=[CH:10][CH:9]=1
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Reactant: O=S(=O)(O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(c1ccc(-c2ccccc2F)cc1)S(=O)(=O)CC(=O)O

Procedure:
170 gm (0.556 mol) of a diastereoisomeric mixture of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid were dissolved in 1.7 liters of acetone, and a solution of 19.9 gm (0.195 mol) of concentrated sulfuric acid inf 70 ml of water was added. While stirring, 67.2 gm (0.425 mol) of potassium permanganate were added in small portions, and the temperature was maintained at 20°-25° C. The mixture was stirred for 1 hour, the manganese dioxide was suction-filtered off, the filter cake was washed with acetone, and the filtrate was evaporated in vacuo. The residue was diluted with 4 liters of glacial acetic acid, and the precipitated crystalline reaction product was suction-filtered off, washed, dried and recrystallized from toluene. Yield: 158.2 gm (88.5% of theory); m.p. 144°-146° C.
Reaction SMILES: [C:1]([NH:10][C:11](=[N:18][S:19](=[O:26])(=[O:25])[NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(OC1C=CC=CC=1)=[O:2].[H-].[Na+].O>C1COCC1>[CH2:21]([N:20]1[C:1](=[O:2])[NH:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:18][S:19]1(=[O:26])=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCNS(=O)(=O)N=C(NC(=O)Oc1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCN1C(=O)NC(c2ccccc2)=NS1(=O)=O

Procedure:
A solution of the benzamidine compound from Step 2. above (0.5 g) in THF (20 ml) is added to a suspension of NaH (110 mg of 60% mineral oil suspension, washed) in THF (10 ml), and the reaction mixture refluxed for about four hours. The mixture is poured into H2O, extracted with diethyl ether, the etheral layer washed, dried and evaporated affording the desired product.
Reaction SMILES: C[O:2][C:3]([C@@:5]12[CH2:23][C@H:22]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:24])[C:14](=[O:25])[N:13]1[C@@H:8]([CH2:9][C@@H:10]([O:26][C:27]3[CH:32]=[C:31]([C:33]4[S:34][CH:35]=[C:36]([CH3:38])[N:37]=4)[N:30]=[C:29]([C:39]4[S:40][CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[N:43]=4)[N:28]=3)[CH2:11][CH2:12]1)[C:7](=[O:48])[NH:6]2)=[O:4].C(C1N=C(C2C=C(O[C@H]3C[C@@H]4N(C(=O)N(C)CCCCC=C[C@H]5[C@](C(O)=O)(NC4=O)C5)CC3)C3C(=C(C)C(OC)=CC=3)N=2)SC=1)#C>>[CH3:38][C:36]1[N:37]=[C:33]([C:31]2[N:30]=[C:29]([C:39]3[S:40][CH:41]=[C:42]([C:44]([F:45])([F:46])[F:47])[N:43]=3)[N:28]=[C:27]([O:26][C@@H:10]3[CH2:9][C@@H:8]4[N:13]([C:14](=[O:25])[N:15]([CH3:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH:21][C@H:22]5[C@:5]([C:3]([OH:4])=[O:2])([NH:6][C:7]4=[O:48])[CH2:23]5)[CH2:12][CH2:11]3)[CH:32]=2)[S:34][CH:35]=1
Reactant: COC(=O)[C@@]12C[C@H]1C=CCCCCN(C)C(=O)N1CC[C@H](Oc3cc(-c4nc(C)cs4)nc(-c4nc(C(F)(F)F)cs4)n3)C[C@H]1C(=O)N2
Agent: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCC/C=C\[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Agent: C#Cc1csc(-c2cc(O[C@@H]3CCN4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@H]4C3)c3ccc(OC)c(C)c3n2)n1
Product: Cc1csc(-c2cc(O[C@H]3CCN4C(=O)N(C)CCCCC=C[C@@H]5C[C@@]5(C(=O)O)NC(=O)[C@@H]4C3)nc(-c3nc(C(F)(F)F)cs3)n2)n1
Yield: 82 %

Procedure:
(1S,4R,6S,18S)-18[6-(4-Methylthiazol-2-yl)-2-(4-trifluoromethylthiazol-2-yl)-pyrimidin-4-yloxy]-13-N-methyl-2,14-dioxo-3,13,15-triazatricyclo[13.4.0.0*4,6*]nonadec-7-ene-4-carboxylic acid 42b was synthesized from compound 41b (250 mg, 1.0 eq.), according to the procedure as described for compound 38, as a green foam in 82% yield. MS (ESI, EI−) m/z=690 (MH−).
Reaction SMILES: [O:1]([C:8]([CH2:10][CH:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12])=O)C1C=CC=CC=1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.CN(C1C=CC=CN=1)C>>[CH2:17]([O:24][C:8]([CH2:10][CH:11]([NH:13][C:14]([NH2:16])=[O:15])[CH3:12])=[O:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: CC(CC(=O)Oc1ccccc1)NC(N)=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: CN(C)c1ccccn1
Product: CC(CC(=O)OCc1ccccc1)NC(N)=O
Temperature: 100 °C

Procedure:
A mixture of phenoxycarbonylpropyleneurea of 1.0 g (4.5 mmol), benzyl alcohol of 2.4 g (22.2 mmol), dibutyltin dilaurate of 20 mg (0.6 wt %) and dimethylaminopyridine of 20 mg (0.6 wt %) was heated for 3 hours at 100° C. with stirring. After confirming the completion of the reaction by the thin layer chromatograpy, the reaction product was concentrated and the resulting crude substance was separated by the chromatography to obtain the aimed substance of 600 mg (56.4%).