Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C@H:5]([CH3:11])[CH2:6][C:7]([F:10])([F:9])[F:8])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:19][C:20]1[S:24][C:23]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[S:24][C:23]([S:25]([NH:1][C@H:2]([CH2:3][OH:4])[C@H:5]([CH3:11])[CH2:6][C:7]([F:8])([F:9])[F:10])(=[O:27])=[O:26])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: C[C@H](CC(F)(F)F)[C@H](N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](CC(F)(F)F)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Reaction time: 0.25 h
Yield: 96.4 %

Procedure:
To a stirred solution of (2S,3R)-2-amino-5,5,5-trifluoro-3-methylpentan-1-ol (2.6 g, 15.18 mmol), triethylamine (4.2 mL, 30.38 mmol) and methylene chloride (50 mL) cooled to 0° C., was added 5-chlorothiophene-2-sulfonyl chloride (4.8 g, 18.22 mmol) as a solution in methylene chloride (5 mL), dropwise. After 15 min, the ice bath was removed and the reaction allowed to attain 25° C. overnight. The reaction was quenched by pouring it into saturated sodium bicarbonate solution (25 mL) and additional methylene chloride (150 mL). The organic phase was separated and washed sequentially with 1N HCl solution, H2O, brine and dried over MgSO4. The organic phase was filtered and evaporated to produce a crude oil (6.1 g) that was purified by flash chromatography using ethyl acetate-hexane, 1-6 as eluent. This produced the title compound 5-chloro-N-[(1S, 2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide as a white amorphous solid (5.15 g, 96.4%). The product contained impurities. The white amorphous solid was further purified by recrystallization from 1:4 EtOAc-heptane. The mixture of solvents was added to 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide, heated to obtain a solution, allowed to cool to 25° C. for 3 h and then stored at 0° C. for 19 hours. A crystalline white solid precipitated, was filtered and washed with ice-cold heptane to obtain a white crystalline solid (2.7 g, 40.9%). The recrystallized material still contained impurities. The white solid (2.7 g) was further purified by prep-chiral HPLC [SFC; AD, 25×0.46 cm; mobile phase, 8:2 hexane-I-PrOH (1 mL/min)] to obtain 5-chloro-N-[(1S,2R)-4,4,4-trifluoro-1-(hydroxymethyl)-2-methylbutyl]thiophene-2-sulfonamide as a white crystalline solid, mp 132-133° C. (0.93 g, 14.1%, chiral purity 100%, analytical purity 100%). Mass Spectrum (−ESI): 350 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([Cl:13])[CH:3]=1.Cl.CN.[CH:17]([N:20](C(C)C)CC)(C)C>C(#N)C>[Cl:13][C:4]1[CH:3]=[C:2]([NH:20][CH3:17])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)c1cnc(Cl)cc1NC
Temperature: 70 °C
Yield: 96.5 %

Procedure:
To a solution of ethyl 4,6-dichloronicotinate (5.0 g, 22.7 mmol) in acetonitrile (50 mL) was added methylamine hydrochloride salt (1.84 g, 27.2 mmol) and diisopropylethylamine (14.6 g, 113.6 mmol), and the reaction mixture was heated at 70° C. overnight. LCMS showed the reaction was completed. The reaction was cooled to RT, quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic layers were separated, combined, washed with water (50 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated to afford the title compound (4.7 g, crude), which was directly used in the next step without further purification. MS (ES+) C9H11ClN2O2 requires: 214, 216. found: 215, 217 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH2:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>O>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)Nc1cc(C)c([N+](=O)[O-])cn1
Temperature: 130 °C
Reaction time: 1.5 h

Procedure:
4-Methyl-5-nitro-2-pyridinamine (3.69 g, 2.41 mmol) was added with acetic anhydride (10 ml) and stirred at 130° C. for 1.5 hours. The reaction mixture was left stand for cooling, and then added with distilled water (5.4 ml) at 0° C., heated to 130° C., and stirred for 45 minutes. The reaction mixture was left stand for cooling and concentrated, and the deposited crystals were collected by filtration and washed with distilled water to obtain the title compound (4.71 g, quantitative).
Reaction SMILES: [N+:1](/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10])([O-])=O.[N:14]([Si](C)(C)C)=[N+:15]=[N-].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C=O)C.C1COCC1>[NH:1]1[CH:4]=[C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])[N:15]=[N:14]1
Reactant: N#Cc1cccc(/C=C/[N+](=O)[O-])c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2c[nH]nn2)c1

Procedure:
3-[(E)-2-Nitroethenyl]benzonitrile (2.79 g, 16.0 mmol) and azidotrimethylsilane (2.76 g, 24.0 mmol) was stirred in anhydrous DMF (100 mL) at 50° C. To this was added tetrabutylammonium fluoride (17.6 mL of a 1.0M solution in THF, 17.6 mmol) via syringe pump over 20 min. The resulting reaction was quenched with MeOH (25 mL) and concentrated in vacuo to a volume of ca. 30 mL. The resulting crude mixture was dissolved in EtOAc (300 mL) and washed with H2O (2×100 mL). The product was then extracted from the EtOAc layer with 1M aqueous NaOH (4×75 mL). The combined basic aqueous portions were treated with 4M HCl to obtain an endpoint of pH=4, and the product was extracted into EtOAc (4×100 mL). The combined EtOAc extracts were dried (MgSO4), filtered and concentrated in vacuo to obtain 3-(1H-1,2,3-triazol-4-yl)benzonitrile as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1.[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][Cl:23])=[CH:18][CH:17]=1.[ClH:24].[OH-].[Na+]>C1(C)C=CC=CC=1>[ClH:23].[ClH:24].[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:6]2([CH2:22][C:19]3[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=3)[C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:15]=[CH:14][C:13]=3[C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)=[CH:18][CH:17]=1
Reactant: ClCc1ccncc1
Reactant: COc1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2

Procedure:
The title compound was prepared following the procedure of Example 5 from 1.8 g (9.2 mmole) of 2-methoxyfluorene, 3.0 g of 4-picolylchloride.HCl, 20 ml of 50% NaOH, 100 mg of cetyl Bu3PBr, and 30 ml of toluene by reaction at 50° for 6 hrs. The material was chromato-graphed to yield 1.6 g of product. δ: 3.37(s,4H), 3.89(s,3H), 6.52(broad,4H), 6.80(m,1H), 7.01(d,J=2.1Hz,1H), 7.26(m,5H), 7.45(d,J=7.5Hz,1H), 8.11(broad,4H).
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[C:13](=O)[NH:12][C:11]4[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=4[S:9][C:8]=3[S:19][C:5]=2[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:13]2[C:7]3[C:6]4[CH2:1][CH2:2][CH2:3][CH2:4][C:5]=4[S:19][C:8]=3[S:9][C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[N:12]=2)[CH2:37][CH2:36]1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccccc2Sc2sc3c(c21)CCCC3
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCN(C2=Nc3ccccc3Sc3sc4c(c32)CCCC4)CC1

Procedure:
In the same manner as in Example 80 and using 1,2,3,4-tetrahydro-[1]benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 1,2,3,4-tetrahydro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[NH2:32][S:33]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39]([NH2:41])=[O:40])(=[O:35])=[O:34]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:32][S:33]([C:36]3[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=3)[C:39]([NH2:41])=[O:40])(=[O:34])=[O:35])=[O:31])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: NC(=O)c1cccc(S(N)(=O)=O)c1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccc(C(N)=O)c3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-(aminosulfonyl)benzamide: 1H-NMR (CDCl3) δ 8.47 (1H, s), 8.01 (2H, d, J=8.9 Hz), 7.60-7.11 (10H, m), 6.70 (1H, br.s), 6.30 (1H, br.s), 3.38-3.35 (2H, m), 2.77-2.71 (2H, m), 2.29 (3H, s), 2.17 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[CH2:11][CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1.[C:17]([NH:21][NH2:22])([CH3:20])([CH3:19])[CH3:18].Cl.C(N(CC)CC)C>CO>[C:17]([N:21]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][C:10]([CH2:11][CH2:12][CH2:13][OH:14])=[N:22]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(CCCO)CC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)n1nc(CCCO)cc1-c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 14 h

Procedure:
1-(4-chlorophenyl)-6-hydroxyhexane-1,3-dione (2.0 g, 8.310 mmol) was dissolved in 15 mL of methanol. t-BuNHNH2.HCl (2.1 g, 16.620 mmol) was dissolved in 15 mL of methanol and then added with triethylamine (TEA; 2.3 mL, 16.620 mmol). After they were all dissolved, the mixture was added into a solution of 1-(4-chlorophenyl)-6-hydroxyhexane-1,3-dione, and then stirred for 14 hours at 40° C. The reaction progress and completion were confirmed by TLC. Upon completion of the reaction, while the temperature was kept at room temperature, the solvent was removed under reduced pressure. The reaction residue was diluted with EtOAc, and added with water. The aqueous layer was extracted with EtOAc and the organic layer was dried with anhydrous MgSO4 and filtered and concentrated under reduced pressure. The concentrate was separated by column chromatography (EtOAc:Hexane=2:3, v/v) to obtain 1.57 g (64%) of target compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]2(=[O:23])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][N:9]2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.C(Cl)Cl.[Br:27]Br>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([P:8]2(=[O:23])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][N:9]2[C:17]2[CH:18]=[CH:19][C:20]([Br:27])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: O=P1(c2ccc(F)cc2)c2ccccc2CN1c1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=P1(c2ccc(F)cc2)c2ccccc2CN1c1ccc(Br)cc1
Reaction time: 1 h
Yield: 58 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.0 g, 0.003 mol) in 25 ml. of methylene chloride was added dropwise a solution of bromine (0.8 g, 0.1 mol) in 25 ml. of methylene chloride with constant stirring. The reaction mixture was stirred for one hour and washed with water, then sodium bisulfite, again with water, dried over magnesium sulfate and concentrated in vacuo to yield a yellow solid. The yellow solid was slurried in anhydrous diethyl ether to yield 1-(4-fluorophenyl)-2-(4-bromophenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.7 g, 56.4% yield) as a white solid having a melting point of 201°-205° C. and the following analysis:
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C@H:16]3[CH2:20][C@@H:19]([OH:21])[CH2:18][NH:17]3)=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[N:24]1([CH2:29][C:30](O)=[O:31])[CH:28]=[N:27][CH:26]=[N:25]1>>[N:24]1([CH2:29][C:30]([N:17]2[CH2:18][C@H:19]([OH:21])[CH2:20][C@@H:16]2[C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)=[O:15])=[O:31])[CH:28]=[N:27][CH:26]=[N:25]1
Reactant: O=C(O)Cn1cncn1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@H]1C[C@@H](O)CN1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@H]1C[C@@H](O)CN1C(=O)Cn1cncn1
Yield: 70 %

Procedure:
Proceeding as in Reference 11, but substituting (2R,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-hydroxypyrrolidine-2-carboxamide and 2-(1H-1,2,4-triazol-1-yl)acetic acid gave (2R,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-hydroxypyrrolidine-2-carboxamide (1.37 g, 3.25 mmol, 70% yield) as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C1C(=O)N([Br:18])C(=O)C1>CC(O)=O.O>[Br:18][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccccc1[N+](=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
To a stirred solution of 2-nitroaniline (10.0 g, 72.462 mmol) in AcOH (50 mL) was added NBS (12.0 g, 72.463 mmol) at 0° C. under a N2 atmosphere. The reaction mixture was stirred at 40° C. for 30 min. After completion of starting material (monitored by TLC), reaction mixture was diluted with water and a white precipitate was formed. After filtration, the crude solid was recrystalised from n-hexanes to afford 4-bromo-2-nitroaniline (12 g, 76%), as a brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH3:26])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1.CC(O)[C:29]#[N:30].N12CCCN=C1CCCCC2>C(#N)C>[C:29]([CH2:2][CH2:3][CH2:4][O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([N:12]([CH3:26])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]1)#[N:30]
Reactant: CN([C@H]1CC[C@H](OCCCBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(O)C#N
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CN([C@H]1CC[C@H](OCCCC#N)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To 1.0 g (2.18 mmol) trans-N-[4-(3-Bromo-propoxy)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide in 10 ml acetonitrile was added 0.29 ml (3.1 mmol) acetocyanhydrine in 5 ml acetonitrile and 0.37 ml (2.5 mmol) 1,8-Diazabicyclo-(5,4,0)-undec-7-ene in 5 ml acetonitrile. The solution was stirred at RT over night. An additonal amount of acetocyanhydrine and 1,8-Diazabicyclo-(5,4,0)-undec-7-ene were added and the solution stirred at 50° C. for 6 h. The mixture was concentrated and dissolved in water/ether. The organic phase was washed with brine, dried over Na2SO4 and was evaporated to give 366 mg (41%) trans-N-[4-(3-Cyano-propoxy)-cyclohexyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide as light yellow oil, MS: 404 (M).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[N:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1>ClCCl>[Cl:3][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[N:12][CH:11]=1
Reactant: COc1ccc(CO)cn1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
Thionyl chloride (9.2 mL, 126 mmol) was added dropwise to a solution of (6-methoxy-pyridin-3-yl)-methanol (1.00 g, 7.2 mmol) in dichloromethane (38 mL). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated and dichloromethane (100 mL) was added. The solution was washed with saturated aqueous sodium hydrogen carbonate (this resulted in bubbling). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic layers were washed with brine (150 mL), dried (sodium sulfate), filtered, and evaporated to give 5-chloromethyl-2-methoxy-pyridine (995 mg, 88%) as a clear oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8](C(OC(C)(C)C)=O)[C@H:9]([C:25]([C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1>C(Cl)Cl>[NH2:8][C@H:9]([C:25]([C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])=[O:28])=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)C(=O)OCC[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)CCOC(=O)C(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
Eighty percent TFA in CH2Cl2 (20 mL, v/v) was added to an ice-cooled solution of Boc-Tyr(OBn)-CO2CH2CH2TMS (14.8 g, 31.4 mmol) in CH2Cl2 (40 mL). The resulting mixture was stirred for 1.0 minute before concentrating in vacuo. The procedure was repeated once more, and the resulting residue was diluted with CH2 Cl2 and saturated aqueous NaHCO3. The resulting mixture was filtered through celite. The organic layer was then separated, washed with saturated aqueous NaCl, and dried (MgSO4). Filtration and concentration in vacuo provided an oil which was further purified by flash chromatography (SiO2, CHCl3 :MeOH eluent) to give the desired product;
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:5]=1.[NH3:18]>CO>[CH:12]1([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([O:10][CH3:11])[N:7]=2)[C:3]([NH2:18])=[O:2])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: N
Reactant: COC(=O)c1cc(OC)nc(C2CCCC2)c1
Solvent: CO
Product: COc1cc(C(N)=O)cc(C2CCCC2)n1

Procedure:
A solution of 2-cyclopentyl-6-methoxy-isonicotinic acid methyl ester (3.19 g, 13.6 mmol) in 7 N NH3 in methanol (50 mL) is stirred at 60° C. for 18 h. The solvent is removed in vacuo and the residue is dried under HV to give crude 2-cyclopentyl-6-methoxy-isonicotinamide (3.35 g) as a pale yellow solid; LC-MS**: tR=0.57 min, [M+1]+=221.38.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:17]=[CH:16][C:8]([CH:9]=[CH:10][C:11]2[N:15]=[CH:14][NH:13][N:12]=2)=[CH:7][CH:6]=1)#[N:4].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26]1([O:34][CH2:33]1)[CH2:27][N:28]1[CH:32]=[N:31][CH:30]=[N:29]1>CN(C)C=O.O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH:9]=[CH:10][C:11]2[N:15]=[CH:14][N:13]([CH2:33][C:26]([C:20]3[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=3[F:18])([CH2:27][N:28]3[CH:32]=[N:31][CH:30]=[N:29]3)[OH:34])[N:12]=2)=[CH:16][CH:17]=1)#[N:4]
Reactant: N#Cc1ccc(C=Cc2nc[nH]n2)cc1
Reactant: Fc1ccc(C2(Cn3cncn3)CO2)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C=Cc2ncn(CC(O)(Cn3cncn3)c3ccc(F)cc3F)n2)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
Sodium hydride (55% oil dispersion) (0.4 g.) was added to a solution of 3-(4-cyanostyryl)-1,2,4-triazole (1.6 g.) in dimethylformamide (20 ml.). After the effervescence had ceased, a solution of 2-(2,4-difluorophenyl)-2,3-epoxy-1-(1,2,4-triazol-1-yl)propane (1.9 g.) in dimethylformamide (10 ml.) was added, and the mixture was heated at 75° C. for 5 hours, then stirred at room temperature for 16 hours. The reaction mixture was diluted with water (150 ml.) and extracted with ethyl acetate (100 ml). The organic layer was washed with water, dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was crystallised from a mixture of ethyl acetate and petroleum ether (b.p. 60°-80° C.) to give 2-[3-(4-cyanostyryl)-1,2,4-triazol-1-yl]-1-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl methyl)ethanol, m.p. 189°-91° C.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@@H:15]([C@@H:16]([OH:30])[C@@H:17]([N+:27]([O-])=O)[CH2:18][C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)[CH2:14][O:13][C@@H:12]([O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].O>CO.[Ni](Cl)Cl>[C:3]([O:7][C:8]([N:10]1[C@@H:15]([C@@H:16]([OH:30])[C@@H:17]([NH2:27])[CH2:18][C:19]2[CH:20]=[C:21]([F:26])[CH:22]=[C:23]([F:25])[CH:24]=2)[CH2:14][O:13][C@@H:12]([O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:11]1)=[O:9])([CH3:4])([CH3:6])[CH3:5]
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)[N+](=O)[O-])CO1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H]([C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)CO1
Reaction time: 0.33 h
Yield: 78.7 %

Procedure:
Add sodium borohydride (0.86 g, 22.60 mmol) to (2R,5R)-5-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-2-nitropropyl]-2-(2,2-dimethylpropoxy)-morpholine-4-carboxylic acid tert-butyl ester (2.30 g, 4.71 mmol) and nickel (II) chloride (1.34 g, 10.36 mmol) in methanol (47 mL) at room temperature over 2 minutes. Stir for 20 minutes, add water (˜3 mL) and concentrate. Dilute with ethyl acetate (˜75 mL), filter through Celite®, wash with 10% aqueous potassium carbonate, saturated aqueous sodium chloride, Dry (magnesium sulfate), filter and concentrate to give the title compound as an off-white solid (1.7 g, 78.7%).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4]([CH:5]=[C:6](Br)Br)[C@H:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C([Li])CCC.Cl[C:23]([O:25][CH3:26])=[O:24].P(O)(O)([O-])=O.[Na+]>C1CCCCC1.O1CCCC1>[CH3:1][C:2]1([CH3:16])[C@@H:4]([C:5]#[C:6][C:23]([O:25][CH3:26])=[O:24])[C@H:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C=C(Br)Br)C1(C)C
Reactant: COC(=O)Cl
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)C#C[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
55 g of tert-butyl (1R,cis) 2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropane-carboxylate were introduced into 550 cm3 of tetrahydrofuran and the mixture was cooled to -70° C. 132 cm3 of a 20% solution of butyllithium in cyclohexane were added over 40 minutes to the mixture which was stirred for 30 minutes at -65° C. 12.5 cm3 of methyl chloroformate were then added thereto and after 2 hours reaction at -70° C., the temperature was allowed to rise again to -20° C. The mixture was poured into an aqueous solution of monosodium phosphate and the mixture was extracted with ether. The organic phase was washed, dried and evaporated to dryness under reduced pressure. 38.3 g of the residue were chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 17.2 g of tert.-butyl (1R,cis) 2,2-dimethyl-3-[2-(methoxy carbonyl)-ethynyl]-cyclopropane-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13](Cl)=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.O1CCOCC1.[NH3:26]>ClCCl>[Cl:1][C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([NH2:26])=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1
Reactant: N
Reactant: O=C(Cl)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 11-chloro-dibenzo[b,f][1,4]thiazepine-3-carbonyl chloride, prepared as described in the previous step, (ca 1.5 mmol) in dichloromethane (10 mL) was treated with a 1,4-dioxane solution of ammonia (0.5 M, 9 mL) under ice bath. The resulting suspension was stirred at room temperature for 1 hour, and the reaction was quenched with water (10 mL). The resulting precipitate was filtered, washed with water and dichloromethane, and dried. The organic layer of the filtrate was washed with saturated aqueous sodium bicarbonate solution and concentrated to additional off white product, which was used in the next step without additional purification. LC-MS: m/z 289 (M+1). 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.19 (br, 1H), 8.00-7.96 (m, 2H), 7.90 (d, 1H), 7.64 (br, 1H), 7.56 (m, 1H), 7.47 (m, 1H), 7.31 (m, 2H).