Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH2:4][N:3]3[C:2]1=[O:13].CC(C)([O-])C.[K+].C1COCC1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[CH2:25]([N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH2:4][N:3]3[C:2]1=[O:13])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]c2cccc3c2n1CC=C3
Reactant: BrCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccccc2)c2cccc3c2n1CC=C3
Reaction time: 0.17 h

Procedure:
A mixture of 4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (I, J. Heterocyclic Chem., 19, 837-49 (1982), 1.0 g, 5.8mmol) in DMF (10 ml) is cooled to 0° and treated with potassium t-butoxide in THF (1.98 M, 3.2 ml, 6.3 mmol) maintaining the reaction temperature at 0°. The resulting mixture is stirred at 0° for 10 minutes. Benzyl bromide (0.73 ml, 6.1 mmol) is then added while maintaining the reaction temperature at 0°. After 1 hour, the mixture is partitioned with methyl t-butyl ether (MTBE) from water followed by several water washes. The MTBE phase is concentrated under reduced pressure. The concentrate is cooled to 0°, filtered and washed two times with 0° MTBE. The product is dried at 50° under reduced pressure with a nitrogen purge to give the title compound, CMR (CDCl3, 100 MHz) 153.78, 136.44, 128.69, 127.67, 127.60, 126.73, 125.86, 122.90, 122.78, 121.28, 116.92, 116.17, 108.36, 44.95 and 42.37 δ.
Reaction SMILES: [CH3:1][CH2:2][C@H:3]1[O:20][C:18](=[O:19])[CH2:17][C@@H:16]([OH:21])[C@H:15]([CH3:22])[C@@H:14]([O:23][C@@H:24]2[O:29][C@H:28]([CH3:30])[C@@H:27](O[C@@H]3O[C@@H](C)[C@H](O)[C@@](O)(C)C3)[C@H:26]([N:42]([CH3:44])[CH3:43])[C@H:25]2[OH:45])[C@@H:13]([CH2:46][CH:47]=[O:48])[CH2:12][C@@H:11]([CH3:49])[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH3:50])=[CH:5][C@@H:4]1[CH2:51][O:52][C@@H:53]1[O:58][C@H:57]([CH3:59])[C@@H:56]([OH:60])[C@@H:55]([O:61][CH3:62])[C@H:54]1[O:63][CH3:64]>Cl>[CH3:1][CH2:2][CH:3]1[O:20][C:18](=[O:19])[CH2:17][CH:16]([OH:21])[CH:15]([CH3:22])[CH:14]([O:23][CH:24]2[O:29][CH:28]([CH3:30])[CH2:27][CH:26]([N:42]([CH3:44])[CH3:43])[CH:25]2[OH:45])[CH:13]([CH2:46][CH:47]=[O:48])[CH2:12][CH:11]([CH3:49])[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH3:50])=[CH:5][CH:4]1[CH2:51][O:52][CH:53]1[O:58][CH:57]([CH3:59])[CH:56]([OH:60])[CH:55]([O:61][CH3:62])[CH:54]1[O:63][CH3:64]
Reactant: CC[C@H]1OC(=O)C[C@@H](O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](O)[C@H](C)O3)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)C(=O)C=CC(C)=C[C@@H]1CO[C@@H]1O[C@H](C)[C@@H](O)[C@@H](OC)[C@H]1OC
Agent: CCC1OC(=O)CC(O)C(C)C(OC2OC(C)CC(N(C)C)C2O)C(CC=O)CC(C)C(=O)/C=C/C(C)=C\C1COC1OC(C)C(O)C(OC)C1OC
Agent: CC[C@H]1OC(=O)C[C@@H](O)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)[C@@H](O[C@H]3C[C@@](C)(O)[C@@H](O)[C@H](C)O3)[C@H](N(C)C)[C@H]2O)[C@@H](CC=O)C[C@@H](C)C(=O)/C=C/C(C)=C/[C@@H]1CO[C@@H]1O[C@H](C)[C@@H](O)[C@@H](OC)[C@H]1OC
Agent: Cl
Product: CCC1OC(=O)CC(O)C(C)C(OC2OC(C)CC(N(C)C)C2O)C(CC=O)CC(C)C(=O)C=CC(C)=CC1COC1OC(C)C(O)C(OC)C1OC

Procedure:
4 g (0.004 mmol) of tylosin base are stirred in 80 ml of 0.2N hydrochloric acid for 4 hours at room temperature. The reaction medium obtained is washed with dichloromethane and the aqueous phase is separated and adjusted to pH 8.0. The latter phase is extracted twice with 120 ml of dichloromethane, and the organic phases are combined, dried over sodium sulfate and evaporated. The residue consists of demycarosyltylosin.
Reaction SMILES: [N:1]1([C:6]2[N:10]=[C:9]([CH:11]=O)[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]2[N:27]=[C:28]([CH2:30][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:29]=[C:22]2[N:21]=1.N1CCCN2CCCCCC=12>O1CCCC1>[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]2[N:27]=[C:28]([CH:30]=[CH:11][C:9]3[N:8]([CH2:13][C:14]([F:17])([F:16])[F:15])[N:7]=[C:6]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:10]=3)[N:29]=[C:22]2[N:21]=1
Reactant: Cc1cc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2n1
Reactant: O=Cc1nc(N2CCCC2)nn1CC(F)(F)F
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(C)n2nc(C=Cc3nc(N4CCCC4)nn3CC(F)(F)F)nc2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.4 %

Procedure:
A mixture of 3-(pyrrolidin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazole-5-carbaldehyde (54 mg, 218 μmol, Eq: 1.00), ((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (99.8 mg, 218 μmol, Eq: 1.00) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (82.8 mg, 544 μmol, Eq: 2.5) in tetrahydrofuran (3.36 ml) was stirred for 18 hours at 25° C. under argon atmosphere. Chromatography afforded 5,7-dimethyl-2-{2-[5-pyrrolidin-1-yl-2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-vinyl}-[1,2,4]triazolo[1,5-a]pyrimidine (20 mg/23.4%) as a light yellow viscous oil. MS: m/z=393.4 (M+H+).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)=[NH:4].[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[F:26])N>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: CS(=O)(=O)NCCNc1nonc1C(=N)NO
Reactant: Nc1ccc(F)c(Cl)c1
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1

Procedure:
The title compound was prepared according to the procedure of Example 17 step E, using N-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-chloro-4-fluoroaniline [Aldrich, product #228583] as the starting materials. LCMS for C12H15ClFN6O4S (M+H)+: m/z=393.0. 1H NMR (400 MHz, DMSO-d6): δ 11.50 (s, 1H), 8.91 (s, 1H), 7.19 (m, 2H), 6.96 (dd, J=6.7, 2.5 Hz, 1H), 6.71 (m, 1H), 6.26 (t, J=6.4 Hz, 1H), 3.32 (m, 2H), 3.13 (q, J=5.8 Hz, 2H), 2.89 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])([OH:3])=[O:2].[CH2:20](O)[CH3:21]>Cl>[Cl:19][C:14]1[CH:13]=[C:12]([N:7]2[C:8]([C:9]([NH2:11])=[O:10])=[C:4]([C:1]([O:3][CH2:20][CH3:21])=[O:2])[CH:5]=[N:6]2)[CH:17]=[C:16]([Cl:18])[CH:15]=1
Reactant: CCO
Reactant: NC(=O)c1c(C(=O)O)cnn1-c1cc(Cl)cc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1cnn(-c2cc(Cl)cc(Cl)c2)c1C(N)=O

Procedure:
Two g of the compound of Example 2 was suspended in 80 ml of absolute ethanol and hydrogen chloride 9as was bubbled through for 5 minutes. The mixture was then heated under reflux for 2 hours and cooled, and was then filtered. The solids were collected and dried to obtain 1.25 g of the desired product, m.p. 164°-166°.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.C(Cl)(=O)C(Cl)=O.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.CN1CCOCC1>ClCCl.CN(C)C=O>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([NH:31][C:15](=[O:17])[CH2:14][N:3]2[CH2:4][CH2:5][CH2:6][CH:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]2=[O:1])=[N:29][CH:30]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reactant: Nc1ccc(Cl)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(CN1CCCC(c2ccccc2)C1=O)Nc1ccc(Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (0.100 g, 0.429 mmol; Example 91D) in dichloromethane (0.5 mL) was added oxalyl chloride (2.0 Min dichloromethane) (0.322 mL, 0.643 mmol) and a catalytic amount of N,N-dimethylformamide. After stirring for 30 minutes at 0° C., a reddish solution resulted. The reaction was concentrated, the residue was dissolved in dichloromethane (1 mL) and 5-chloropyridin-2-amine (0.047 g, 0.364 mmol) was added followed by N-methylmorpholine (0.071 mL, 0.643 mmol). After stirring for 1 hour, the reaction was loaded onto a silica gel column (SF15-24, Analogix®) and the product was eluted using a gradient of 25% ethyl acetate/hexanes to 70% ethyl acetate/hexanes over 30 minutes (Flow=30 mL/minute). Some color streaked through the column, so a second column was run under identical conditions to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.84 (s, 1H), 8.23 (d, J=2.7, 1H), 8.14 (d, J=8.8, 1H), 7.65 (dd, J=2.6, 8.9, 1H), 7.42-7.13 (m, 5H), 4.34-4.15 (m, 2H), 3.78 (dd, J=6.0, 7.9, 1H), 3.71-3.47 (m, 2H), 2.33-2.14 (m, 1H), 1.99 (m, 3H); MS (ESI+) m/z 344.0 (M+H)+.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:25]1([CH2:31][O:32][CH2:33][CH2:34][Br:35])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CC#N>[Br-:35].[F:17][C:13]1[CH:12]=[C:11]([C:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)([OH:10])[C:4]23[CH2:5][CH2:6][N+:1]([CH2:34][CH2:33][O:32][CH2:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)([CH2:2][CH2:3]2)[CH2:8][CH2:7]3)[CH:16]=[CH:15][CH:14]=1
Reactant: BrCCOCc1ccccc1
Reactant: OC(c1cccc(F)c1)(c1cccc(F)c1)C12CCN(CC1)CC2
Solvent: CC#N
Product: OC(c1cccc(F)c1)(c1cccc(F)c1)C12CC[N+](CCOCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 43.2 %

Procedure:
Following the general procedure outlined in Example 3, 1-azabicyclo[2.2.2]oct-4-yl[bis(3-fluorophenyl)]methanol (0.0507 g, 0.154 mmol) and 2-bromoethyl phenylmethyl ether (0.0365 mL, 0.230 mmol) in 2 CH3CN/3 CHCl3 (4.0 mL) were reacted to give the desired product (0.0362 g, 43.2%). EI-MS m/z 464 (M+) Rt (2.02 min).
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[C:17]1[N:13]([CH:14]=[C:15]([C:21]3[N:25]([CH2:26][CH2:27][OH:28])[N:24]=[CH:23][N:22]=3)[N:16]=1)[CH2:12][CH2:11][O:10]2)=O.[NH:30]([CH:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)[NH2:31]>C(O)(=O)C>[CH3:38][N:35]1[CH2:36][CH2:37][CH:32]([N:30]2[C:5]([C:7]3[CH:20]=[CH:19][C:18]4[C:17]5[N:13]([CH:14]=[C:15]([C:21]6[N:25]([CH2:26][CH2:27][OH:28])[N:24]=[CH:23][N:22]=6)[N:16]=5)[CH2:12][CH2:11][O:10][C:9]=4[CH:8]=3)=[CH:4][CH:3]=[N:31]2)[CH2:33][CH2:34]1
Reactant: CN(C)/C=C/C(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3CCO)nc1-2
Reactant: CN1CCC(NN)CC1
Solvent: CC(=O)O
Product: CN1CCC(n2nccc2-c2ccc3c(c2)OCCn2cc(-c4ncnn4CCO)nc2-3)CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
To a solution of (2E)-3-(dimethylamino)-1-{4-[1-(2-hydroxyethyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-12-yl}prop-2-en-1-one (105 mg, 0.270 mmol) in acetic acid (2.0 mL) was added hydrochloric 4-hydrazinyl-1-methylpiperidine (53 mg, 0.32 mmol). The mixture was stirred at 100° C. for 1 hour under nitrogen atmosphere. After concentration, the residue was purified by preparative HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give 257 (17 mg, 13% yield). LCMS (ESI): RT=4.05 min, m/z: 461.2 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.55 (d, J=8.5 Hz, 1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.23 (d, J=9 Hz, 1H), 7.11 (s, 1H), 6.40 (d, J=1.5 Hz, 1H), 4.98 (t, J=10.5, 1H), 4.84 (t, J=12, 2H), 4.58 (s, 4H), 4.16 (t, J=23 Hz, 1H), 3.88-3.86 (m, 2H), 2.85 (d, J=10 Hz, 2H), 2.15-2.13 (m, 5H), 1.94 (s, 2H), 1.81 (d, J=11.5, 2H)
Reaction SMILES: [O:1]1[C@H:8]([CH2:9][OH:10])[C@@H:6](O)[C@H:4]([OH:5])[CH:3]=[CH:2]1.[OH2:11].[C:12]([O:15][C:16]([CH3:18])=C)(=[O:14])[CH3:13]>>[C:2]([O:1][C@H:8]1[C@H:9]([OH:10])[C@@H:18]([CH2:16][O:15][C:12](=[O:14])[CH3:13])[O:5][CH:4]=[CH:6]1)(=[O:11])[CH3:3]
Reactant: C=C(C)OC(C)=O
Reactant: O
Reactant: OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Product: CC(=O)OC[C@H]1OC=C[C@@H](OC(C)=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 27.5 h
Yield: 60 %

Procedure:
1.02 g (7 mmol) of glucal, 0.5-0.7 ml of H2O and about 2 g of crushed molecular sieves are taken up in 25-50 ml of isopropenyl acetate, and 1 g of lipase from Pseudomonas spec. is added and the mixture is stirred at room temperature for 25-30 h. Filtration and concentration in vacuo are followed by chromatography on silica gel (ethyl acetate/hexane 2:3, v:v). 0.97-1.05 g (60-65%) of 3,6-di-O-acetylglucal are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:13]#N.S(=O)(=O)(O)[OH:22].[OH2:26]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:13]([OH:22])=[O:26]
Reactant: N#Cc1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Reactant: O
Reactant: O=S(=O)(O)O
Product: O=C(O)c1ccc([N+](=O)[O-])c(Sc2ccc(F)cc2F)c1
Temperature: 175 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-(2,4-difluorophenylthio)-4-nitrobenzonitrile (3.6 g), sulfuric acid (3 ml) and water (3 ml) as stirred at 175° C. for 15 minutes. Water as added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated to give crystals of 3-(2,4-difluorophenylthio)-4-nitrobenzoic acid (3.6 g).
Reaction SMILES: S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[C:12]([OH:19])(=O)[CH2:13][CH:14]=[CH:15][CH2:16][CH3:17].[C:20]1([C:26]#[C:27][C:28]2[CH:46]=[CH:45][C:31]([C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[S:41](=[O:44])(=[O:43])[NH2:42])=[O:33])=[CH:30][CH:29]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:20]1([C:26]#[C:27][C:28]2[CH:46]=[CH:45][C:31]([C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[S:41]([NH:42][C:12](=[O:19])[CH2:13]/[CH:14]=[CH:15]/[CH2:16][CH3:17])(=[O:43])=[O:44])=[O:33])=[CH:30][CH:29]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCC=CCC(=O)O
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Product: CC/C=C/CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Reaction time: 1 h
Yield: 66.1 %

Procedure:
In a stream of nitrogen and at 0° C., 249 mg (1.30 mmol) of tosylic chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 149 mg (1.30 mmol) of 3-hexenoic acid and 532 mg (4.35 mmol ) of 4-dimethylaminopyridine, and the mixture was stirred for 1 hour. Next, this was mixed with 300 mg (0.80 mmol) of 4-phenylethynyl-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 10 and stirred at room temperature for 1 hour, and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel chromatography to obtain 250 mg (yield: 65.0%) of the title compound.
Reaction SMILES: [CH2:1]([SiH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].BrCC[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH3:38])=[C:31]([F:39])[C:30]=2[F:40])=[CH:25][CH:24]=1.[CH2:41](OP(OCC)OCC)[CH3:42]>[Cu]I.C1COCC1>[CH2:1]([SiH:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:41][CH2:42][C:25]3[CH:24]=[CH:23][CH:28]=[CH:27][C:26]=3[C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH3:38])=[C:31]([F:39])[C:30]=3[F:40])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCOP(OCC)OCC
Reactant: CCCOc1ccc(-c2ccc(CCBr)cc2)c(F)c1F
Reactant: CCCCC[SiH]1CCC(c2ccc(Br)cc2)CC1
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[SiH]1CCC(c2ccc(CCc3ccccc3-c3ccc(OCCC)c(F)c3F)cc2)CC1

Procedure:
6.5 g (20 mmol) of 4-(4-n-pentyl-4-silacyclohexyl)-1-bromobenzene was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.1 g (20 mmol) of 4-(2-bromoethyl)-2',3'-difluoro-4'-n-propoxybiphenyl and catalytic amounts of copper (I) iodide and triethylphosphite to obtain the crude product, which was a mixture of trans isomers and cis isomers with respect to the silacyclohexane ring. After a conventional after treatment, they were separated by means of chromatography to obtain 8. 3 g (yield 80%) of the target product, i.e. the trans isomer.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5](O)=[O:6].IC.[C:19](=O)([O-])[O-].[K+].[K+].O.CN([CH:29]=[O:30])C>>[CH3:19][O:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([O:30][CH3:29])=[O:6]
Reactant: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Solvent: O
Solvent: CI
Product: COC(=O)c1cc(OC)cc(S(F)(F)(F)(F)F)c1

Procedure:
3-Hydroxy-5-(pentafluorosulfanyl)benzoic acid (O5.007; 3.0 g) was dissolved in absolute DMF (75 ml). Then iodomethane (3.6 ml) was added while stirring, followed by finely powdered potassium carbonate (6.3 g). After stirring at 40° C. for 5 hours, the mixture was cooled and admixed with water (250 ml). The mixture was then extracted four times with ether (100 ml). The combined extracts were each washed once with 1 N sodium hydroxide solution (75 ml) and water (100 ml), dried over magnesium sulfate, filtered and concentrated. 2.9 g of the desired compound were obtained.
Reaction SMILES: [Br:1][C:2]1[C:13]([CH:14]=[O:15])=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[CH3:21][CH2:22]O>>[Br:1][C:2]1[C:13]([CH:14]=[O:15])=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([O:9][CH2:21][CH3:22])=[O:8]
Reactant: O=Cc1cccc(OCCC(=O)O)c1Br
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCOc1cccc(C=O)c1Br

Procedure:
To a solution of 3-(2-bromo-3-formylphenoxy)propanoic acid from the previous step (I eq.) in EtOH (0.13 M) was added conc. sulfuric acid (0.8 eq.). The reaction was heated at reflux for 30 min. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic extracts were washed with water and sat. aq. NaHCO3. Drying over Na2SO4, filtration and concentration of the filtrate in vacuo afforded the title compound as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27](=[O:28])[N:26]([CH2:29][C:30]([O:32]C(C)(C)C)=[O:31])[N:25]=[C:24]4[CH2:37][C@@H:38]4[CH2:42][CH2:41][N:40]([C:43]([CH:45]5[CH2:47][CH2:46]5)=[O:44])[CH2:39]4)=[CH:19][CH:18]=3)=[CH:16][C:11]=2[CH:10]=[CH:9]1>ClCCl>[O:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([N:23]4[C:27](=[O:28])[N:26]([CH2:29][C:30]([OH:32])=[O:31])[N:25]=[C:24]4[CH2:37][C@@H:38]4[CH2:42][CH2:41][N:40]([C:43]([CH:45]5[CH2:47][CH2:46]5)=[O:44])[CH2:39]4)=[CH:21][CH:22]=3)=[CH:16][C:11]=2[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)Cn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (50 mg, 0.117 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (80 mg, 0.58 mmol, 5 eq) and tert-butylchloroacetate (21 mg, 0.14 mmol, 1.2 eq). The vial was capped, purged with nitrogen gas, and stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction was complete. The reaction mixture was cooled to room temperature and then poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extractions were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude intermediate ester (MS(ES)+ m/e 487.3 [M+H]+). In a 50 mL round bottom flask, the crude 1,1-dimethylethyl (4-[4-(1-benzofuran-5-yl)phenyl]-3-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)acetate was dissolved in 9 mL dichloromethane. Trifluoroacetic acid (1 mL, 12.98 mmol) was added to the solution, which was allowed to stir at room temperature for 16 h under a nitrogen bubbler. Analysis by LC/MS displayed the reaction complete. The reaction was concentrated to dryness and the residue was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 10-75% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (32 mg, 56%). MS(ES)+ m/e 487.3 [M+H]+.
Reaction SMILES: C(O)C.[Na].[C:5](OCC)(=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH2:15]([O:17][C:18](=[O:23])[CH2:19][NH:20]C=O)[CH3:16].[S-:24][C:25]#[N:26].[K+].Cl>CCOCC.O>[SH:24][C:25]1[NH:20][C:19]([C:18]([O:17][CH2:15][CH3:16])=[O:23])=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:26]=1
Reactant: CCOC(=O)CNC=O
Reactant: N#C[S-]
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [K+]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1nc(S)[nH]c1C(=O)OCC
Reaction time: 8 h
Yield: 44.6 %

Procedure:
Absolute ethanol (58 g; 1.25 mol) was added to a suspension of clean sodium (29 g; 1.25 g atom cut into small pieces) in anhydrous ether (700 mL). Diethyl oxalate (182 g; 1.25 mol) was added slowly to this mixture so that the exothermic reaction did not become too vigorous. The N-formyl-glycine ethyl ester (131 g; 1.0 mol) was added dropwise with stirring to the resulting solution and a red-brown precipitate formed. The mixture was allowed to stand overnight then water (1 L) was added to dissolve the precipitate and the ether layer was separated. Potassium thiocyanate (170 g; 1.75 mol) and concentrated hydrochloric acid (240 mL) were added to the aqueous solution. The yellow aqueous solution was slowly heated to 40°-60° C. for 6 hours and cooled. The yellow granular precipitate was filtered. The filtrate was concentrated to give an additional amount of the same product. The total product yield of 109.0 g (45%) of diethyl 2-mercapto-4,5-imidazoledicarboxylate was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[CH2:9][CH2:10][NH:11][C:20](=[O:21])[O:22][CH2:23][CH3:24]
Reactant: CCOC(=O)Cl
Reactant: COc1cccc(CCN)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)NCCc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
To an ice-cold solution of 2-(3-methoxyphenyl)-1-ethanamine (5.00 g, 33.1 mmol) and Et3N (5.10 mL, 3.70 g, 36.6 mmol) in CH2Cl2 (100 mL) was added ethyl chloroformate (3.50 mL, 3.62 g, 33.4 mmol). The resulting solution was allowed to warm to RT and was stirred for 2 h. Water (100 mL) was added and the mixture was extracted with CH2Cl2 (3×50 mL), dried (MgSO4) and concentrated to yield ethyl 3-methoxyphenethylcarbamate (7.32 g, 99% yield) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.22 (t, J=7.8 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.77 (d, J=8.0 Hz; 1H), 6.74 (s, 1H), 4.65 (brs, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.80 (s, 3H), 3.44 (q, J=6.4 Hz, 2H), 2.79 (t, J=7.0 Hz, 2H), 1.23 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 224.2 (M+H+).