Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH2:61])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:64](Cl)(=[O:68])[CH:65]([CH3:67])[CH3:66]>>[CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:64](=[O:68])[CH:65]([CH3:67])[CH3:66])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(=O)C(C)C)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (30 mg) was reacted with isobutyryl chloride according to General Procedure F to give (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-7-[2-(isobutyryl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester. This ester, upon hydrolysis according to General Procedure B, gave the title compound. LCMS (m/z): 980.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][OH:15])[NH:11][CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:17][C:18]([C:23]1[CH:24]=[C:25]2[NH:31][CH2:30][C:29]([CH3:33])([CH3:32])[C:26]2=[N:27][CH:28]=1)([F:22])[CH2:19][CH2:20][CH3:21].Cl[CH2:35][C:36](Cl)=[O:37].CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][OH:15])[N:11]([CH2:35][C:36]([N:31]2[C:25]3[C:26](=[N:27][CH:28]=[C:23]([C:18]([F:22])([F:17])[CH2:19][CH2:20][CH3:21])[CH:24]=3)[C:29]([CH3:32])([CH3:33])[CH2:30]2)=[O:37])[CH2:10][C@H:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC(F)(F)c1cnc2c(c1)NCC2(C)C
Reactant: O=C(Cl)CCl
Reactant: C[C@@H]1CN[C@@H](CO)CN1C(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(F)(F)c1cnc2c(c1)N(C(=O)CN1C[C@@H](C)N(C(=O)OC(C)(C)C)C[C@@H]1CO)CC2(C)C
Yield: 60 %

Procedure:
Following methods similar to those described in Preparation 203 or General Procedure 5, starting from (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (0.69 g, 3.0 mmol), 6-(1,1-difluoro-butyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine, chloroacetyl chloride (185 μL, 2.3 mmol) and DIPEA (1.42 mL, 8.4 mmol), gave the title compound (0.61 g, 60%). MS: [M+H]+=511.
Reaction SMILES: C([O:4][C@@H:5]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@H:12]([CH3:31])[O:11][C@H:6]1[O:7]CC=C)(=[O:3])C.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:31][C@@H:12]1[O:11][CH:6]([OH:7])[C@H:5]([OH:4])[C@H:14]([OH:15])[C@H:13]1[OH:23].[OH2:3]
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H]1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O
Product: O
Temperature: 70 °C

Procedure:
The raw product from 76 (65.2 g, 200.0 mmol) is taken up in EtOAc (300 mL). The organic phase is washed with 10% HCl solution (3×50 mL), NaClsat solution (3×50 mL), and a solution of H2O (3×50 mL) and then dried over Na2SO4 and concentrated in a rotary evaporator. Acetyl chloride is added (35.5 mL, 500.0 mmol, 2.5 eq.) in portions to allyl alcohol (300 mL) at 0° C. for 15 min, then the previous raw product is added to the reaction mixture. The reaction mixture is then heated at 70° C. for 2.5 h and then at 40° C. overnight. Monitoring of the reaction by TLC (Chex/EtOAc, 7/3) shows the disappearance of 76 (Rf=0.25) and the presence of a less polar main product (Rf=0.35). The reaction mixture is cooled to 0° C., neutralized by adding NaHCO3 and then filtered on Celite and finally concentrated in a rotary evaporator. The volatile substances are coevaporated with Tol (2×100 mL) to give a yellow oil. The yellow oil is purified by silica gel chromatography (Chex/EtOAc, 8/2→1/1) to give the alcohol 58 in the form of a colorless oil (55 g, 72% starting from commercial L-rhamnose 27).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([NH2:14])[CH3:13]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([NH:14][CH2:12][CH3:13])=[O:6]
Reactant: O=C(O)c1cc(O)ccc1Cl
Reactant: CCN
Product: CCNC(=O)c1cc(O)ccc1Cl

Procedure:
The title compound was prepared from 2-chloro-5-hydroxybenzoic acid and ethylamine, using a method similar to that used for preparation 52, as a colourless solid. 1HNMR (400 MHz, CDCl3) δ: 1.22 (3H, t), 3.42–3.49 (2H, m), 6.48–6.52 (1H, m), 6.80 (1H, dd), 7.13 (1H, d), 7.38 (1H, d); LRMS ESI m/z 200 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[O:7][CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:12][CH:11]=1)=[O:4].[F:25][C:26]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:27]=1[CH2:28][NH:29][CH2:30][CH2:31][CH3:32].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>CN(C=O)C.CCOC(C)=O>[F:25][C:26]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:27]=1[CH2:28][N:29]([CH2:30][CH2:31][CH3:32])[C:16](=[O:18])[CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][O:7][C:6]2[CH:21]=[CH:22][CH:23]=[CH:24][C:5]=2[C:3]([O:2][CH3:1])=[O:4])=[CH:20][CH:19]=1
Reactant: COC(=O)c1ccccc1OCCc1ccc(OCC(=O)O)cc1
Reactant: CCCNCc1ccc(F)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(CCOc2ccccc2C(=O)OC)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
(4-{2-[2-(Methoxycarbonyl)phenoxy]ethyl}phenoxy)acetic acid (0.150 g, 0.454 mmol) was dissolved in DMF (10 ml), N-(2,4-difluorobenzyl)-N-propylamine (0.084 g, 0.454 mmol) was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.160 g, 0.499 mmol) and N-ethyl-N,N-diisopropylamine (0.123 g, 0.954 mmol) was added. The solution was stirred for two hours at room temperature. EtOAc (20 ml) was added and the organic phase was washed with Na2CO3 (3×20 ml, aq) and HCl (0.5 M, 2×10 ml). The organic layer was dried (MgSO4) and the solvent was removed by evaporation to give 0.220 g of methyl 2-[2-(4-{2-[(2,4-difluorobenzyl)(propyl)amino]-2-oxoethoxy}phenyl)-ethoxy]benzoate (yield 97.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[C:16]([NH2:18])[NH:15][N:14]=1)(=[O:12])=[O:11].C(O)(=O)C.[C:23](OCC)(=[O:28])[CH2:24][C:25]([CH3:27])=O>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][S:10]([C:13]1[N:17]=[C:16]2[N:18]=[C:25]([CH3:27])[CH:24]=[C:23]([OH:28])[N:15]2[N:14]=1)(=[O:12])=[O:11]
Reactant: Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1
Reactant: CCOC(=O)CC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(O)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Reaction time: 24 h
Yield: 74.8 %

Procedure:
A solution of 5.0 g (14.3 mmol) of N-(2,6-dichlorophenyl)-5-amino-1,2,4-triazol-3-sulfonamide, 0.5 ml of acetic acid, and 2.0 ml (15.6 mmol) of ethyl acetoacetate in 100 ml of absolute methanol was heated at reflux for 48 hr. After 24 hr a solid began to form. The solution was cooled and the solid collected. After drying, 4.0 g (75 percent) of the desired product was obtained as a white powder; mp 302° C. decomposes.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[N:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C1COCC1>[Br:1][CH2:2][C:3]([N:15]1[CH2:16][CH2:17][N:12]([C:7]2[N:6]=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:13][CH2:14]1)=[O:4]
Reactant: O=C(Br)CBr
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CBr)N1CCN(c2ncccn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
20.2 g bromacetylbromide was dropped to 16.5 g 1-pyrimidin-2-yl-piperazin and 10.2 g triethylamine in 250 mL THF. The reaction mixture was stirred overnight at RT and evaporated. The residue was extracted with DCM and water. The organic layer was evaporated and the residue was crystallized with petrolether and then purified by chromatography on silica gel (DCM/MeOH:95/5) to yield 8.9 g of the desired compound.
Reaction SMILES: O.O.[OH:3][C:4]([C:7]1[N:8]=[C:9]([CH2:52][CH2:53][CH3:54])[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:11]=1[C:12]([OH:14])=[O:13])([CH3:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:64][C:65]1[O:66][C:67](=[O:71])[O:68][C:69]=1[CH3:70]>CC(C)=O>[CH3:54][CH2:53][CH2:52][C:9]1[N:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:32][N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:11]([C:12]([O:14][CH2:70][C:69]2[O:68][C:67](=[O:71])[O:66][C:65]=2[CH3:64])=[O:13])=[C:7]([C:4]([OH:3])([CH3:6])[CH3:5])[N:8]=1
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1oc(=O)oc1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: -12.5 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
4-(1-hydroxy-1-Methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methyl imidazole-5-carboxylic acid dihydrate (250 g) in acetone (4000 ml) was added to suspension of potassium carbonate (50 g), potassium iodide (15 g) & 4-chloromethyl-5-methyl-1,3-dioxol-2-one (75 g) in acetone (1500 ml) at reflux temperature. Reaction mass was refluxed for 2-6 hrs. Progress of reaction was monitor by HPLC. After completion of reaction mass was filtered, distilled the acetone from filtrate & dissolved the residue obtained in toluene (2500 ml). Toluene layer was washed with brine & dried (Na2SO4). Toluene layer was filtered & cooled to −5 to −20° C. Conc hydrochloric acid (600 ml) was added slowly to above reaction mass at −5 to −20° C. & Stir for 1 hr at −5 to −20° C. Separated the two layers. Ethyl acetate (3000 ml) was added to aqueous layer. The pH of combined layers was adjusted to 5.0-6.5 by slowly adding potassium carbonate solution. Both the layers were separated (Store the ethyl acetate layer containing compound). Aqueous layer was extracted with ethyl acetate (3×2000 ml). The combined organic layer was washed with brine. Ethyl acetate was partially distilled (about 85% of original volume) from organic layer containing compound under reduced pressure. Reaction mass was cooled, filtered, washed with ethyl acetate (3×200 ml) & dried to get Olmesartan Medoxomil (150 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])=O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]3[CH3:18])=[N:9][N:8]=2)[CH:7]=1
Reactant: C[C@H]1COCCN1C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1COCCN1c1nnc2ccc(F)cn12
Temperature: 55 °C
Yield: 28.8 %

Procedure:
To an ice cold solution of Intermediate 139a (574 mg, 2.26 mmol) in THF (23.0 mL) was added sequentially triphenylphosphine (1.18 g, 4.52 mmol), triethylamine (1.26 mL, 9.04 mmol) and hexachloroethane (1.07 g, 4.52 mmol). The cooling bath was removed and the reaction was heated to 55° C. overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was taken up in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH. The residue was concentrated in vacuo and then re-submitted to the above reaction conditions overnight. The reaction was cooled and partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (154 mg, 29%). 1H NMR (300 MHz, CDCl3): 0.94 (3H, d, J=6.3 Hz), 3.13 (1H, dt, J=12.2, 3.1 Hz), 3.32 (1H, ddd, J=12.4, 9.5, 3.2 Hz), 3.49 (1H, dd, J=11.1, 8.6 Hz), 3.56-3.68 (1H, m), 3.84 (1H, ddd, J=12.1, 9.4, 2.7 Hz), 3.92-4.01 (2H, m), 7.16 (1H, ddd, J=9.9, 7.5, 2.3 Hz), 7.68 (1H, ddd, J=10.0, 4.8, 0.8 Hz), 7.85 (1H, m).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)=[O:3].C=CC1C=C[NH+]=CC=1.[Br-:26].[Br-].[Br-]>CO>[F:17][C:14]([F:15])([F:16])[C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH2:1][Br:26])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1
Reactant: CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [Br-]
Agent: C=Cc1cc[nH+]cc1
Solvent: CO
Product: O=C(CBr)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 91.8 %

Procedure:
A stirred suspension of 1 g (3.9 mmol) of 3,5-bis(trifluoromethyl)acetophenone (Lancaster, Windham, N.H., USA) in dry methanol (20 mL) and 1 g (15 mmol, 2.6 eq) of poly(4-vinyl pyridinium tribromide)(Aldrich, Milwaukee, Wis. , USA) was protected from moisture with dry nitrogen, and heated at reflux for 70 min. The polymer was filtered from the cooled solution and washed with methanol and twice with dichloromethane. The solvents were removed in vacuo to give 1-[3,5-bis(trifluoromethyl)phenyl]-2-bromoethan-1-one (1.2 g, 92%). 1H-NMR (DMSO-d6; 300 MHz) δ8.43 (m, 2H), 8.12 (m, 1H), 4.46 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-])=O)=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH2:31][CH3:32])([CH3:30])[CH3:29])=[CH:24][C:23]=1[C:33]([CH2:36][CH3:37])([CH3:35])[CH3:34])=[O:16].C(O)(=O)C>O>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH2:12])=[CH:4][C:3]=1[C:15]([NH:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([CH2:31][CH3:32])([CH3:29])[CH3:30])=[CH:24][C:23]=1[C:33]([CH2:36][CH3:37])([CH3:35])[CH3:34])=[O:16]
Reactant: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc([N+](=O)[O-])c3ccccc3c2O)c(C(C)(C)CC)c1
Solvent: O
Solvent: CC(=O)O
Product: CCC(C)(C)c1ccc(OCCCNC(=O)c2cc(N)c3ccccc3c2O)c(C(C)(C)CC)c1
Yield: 85 %

Procedure:
50 g of 1-hydroxy-4-nitro-N-[γ-(2,4-di-tert-amylphenoxy)propyl]-2-naphthamide obtained in Step (a) above was reduced in 500 ml of a 90% acetic acid aqueous solution using 50 g of reduced iron. The reaction mixture was poured into water and extracted with ethyl acetate. After removal of the ethyl acetate by distillation, the residue was recrystallized from ligroin to obtain 40 g of the object compound. The melting point was 132° - 133° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[C:9](N1C=CN=C1)(N1C=CN=C1)=[S:10].[C:21]1([S:27]([CH2:30][CH2:31][NH:32][CH:33]([CH3:35])[CH3:34])(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH:6][C:9](=[S:10])[N:32]([CH:33]([CH3:35])[CH3:34])[CH2:31][CH2:30][S:27]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:28])=[O:29])[CH3:2]
Reactant: CC(C)NCCS(=O)(=O)c1ccccc1
Reactant: CCN(CC)CCN
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=S)N(CCS(=O)(=O)c1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
A mixture of 2.78 g (0.024 mole) of N,N-diethylethylenediamine and 4.82 g (0.027 mole) of 1,1'-thiocarbonyldiimidazole in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hr. A solution of 5.00 g (0.022 mole) of N-[2-(phenylsulfonyl)ethyl]-2-propanamine in 100 ml of tetrahydrofuran was added, and the solution was refluxed for 48 hrs. The solvent was removed in vacuo and the residue was dissolved in 400 ml of a 50/50 mixture of methylene chloride and ether. The organic solution was extracted with water and was dried over magnesium sulfate. The solvent was removed in vacuo, and the residue was recrystallized from a mixture of methylene chlorideether-hexane to give 5.95 g (72.5%) of pale yellow solid, m.p. 81.5°-82.5° C.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH:10]1(Br)[CH2:14][CH2:13][CH2:12][CH2:11]1.[H-].[Na+].[BH4-].[Na+]>CN(C=O)C.CO.O>[CH:10]1([O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[CH2:1][OH:9])[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: BrC1CCCC1
Reactant: O=Cc1ccccc1O
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccccc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.1 %

Procedure:
Salicylaldehyde (1.0 g, 8.2 mmol) was dissolved in DMF (10 mL), cyclopentyl bromide (1.76 mL, 16.4 mmol) and sodium hydride (394 mg, 9.8 mmol) were added thereto, and then the mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was dried, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 90:10) to give an oily matter. The resulting oily matter was dissolved in methanol (10 mL), sodium borohydride (620 mg, 16.4 mmol) was added thereto, and then the mixture was stirred at room temperature for 2 hours. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=100:0 to 70:30) to give the title compound (349 mg, yield 25%).
Reaction SMILES: C([C:5]1[N:9]2C([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4C4NN=NN=4)=[CH:16][CH:15]=3)CC=C[C:8]2=[CH:7][N:6]=1)CCC.[CH2:31]([OH:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1C(=O)N(Br)C(=O)C1>C(Cl)(Cl)Cl>[C:32]1([CH2:31][O:38][C:5]2[NH:6][CH:7]=[CH:8][N:9]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: OCc1ccccc1
Reactant: CCCCc1ncc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: c1ccc(-c2ccccc2)cc1
Product: c1ccc(COc2ncc[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 203 mg (0.318 mmol) of biphenyl bicyclic imidazole (trityl protected Example 11) and 200 μL (1.9 mmol) of benzyl alcohol in 0.5 mL of anhydrous chloroform was added 57 mg (0.32 mmol) of NBS in one portion. The resulting orange-red solution was stirred at room temperature for 2 hours, and the reaction mixture was washed with aqueous sodium bisulfite, water,and brine. The combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was used directly in the subsequent Step 2 without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[CH:17]([C:19]1[CH:20]=[CH:21][C:22]2[N:26]=[N:25][N:24]([CH3:27])[C:23]=2[CH:28]=1)O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:37])=O>C(Cl)Cl>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][CH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[CH:17]([C:19]1[CH:20]=[CH:21][C:22]2[N:26]=[N:25][N:24]([CH3:27])[C:23]=2[CH:28]=1)[Cl:37])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: Cn1nnc2ccc(C(O)c3ccc(Cl)cc3CO[Si](C)(C)C(C)(C)C)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1nnc2ccc(C(Cl)c3ccc(Cl)cc3CO[Si](C)(C)C(C)(C)C)cc21
Reaction time: 0.5 h

Procedure:
To the solution of α-[2-(t-butyldimethylsilyloxy)methyl-4-chlorophenyl]-1-methyl-1H-benzotriazole-6-methanol (0.5 g) from Example 75 and pyridine (0.11 ml) in methylene chloride (5 ml) was added thionyl chloride (0.1 ml) at 0° C. the mixture was stirred for 30 minutes. The reaction solution was diluted with methylene chloride (5 ml),and sequentially washed with water and saturated sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, to give the crude 6-[2-(t-butyldimethyl-silyloxy)methyl-α,4-dichlorobenzyl]-1-methyl-1H-benzotriazole.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23]O)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][O:1][C:2]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)c1ccc(SC)cc1O
Reactant: CC(C)(C)OC(=O)NCCO
Product: COC(=O)c1ccc(SC)cc1OCCNC(=O)OC(C)(C)C

Procedure:
Methyl 2-[2-(tert-butoxycarbonylamino)ethoxy]-4-(methylthio)benzoate was prepared (12.6 g, 76%) as described in Example 21-C from methyl 2-hyroxy-4-(methylthio)benzoate and 2-(tert-butoxycarbonylamino)ethanol.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:10](Br)([CH3:13])([CH3:12])[CH3:11]>[OH-].[K+]>[C:10]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)Br
Reactant: C1=Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C)C1C=Cc2ccccc21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
42.0 g of indene (technical grade, 94 % by GC, 39.5 g, 340 mmol), 50 % w aqueous KOH (308 g in 308 nL) and 15.8 g of Adogen (Aldrich, 34 mnuol) dissolved in 139.7 g of tert-butylbromide (1019.6 mmol) were introduced in this order, at room temperature, in a 1 L, jacketed glass reactor with mechanical stirrer (Buïchi). The organic phase turns green. The mixture is heated to 60° C. and vigorously stirred for two hours (a pressure build-up to 2.5 bar-g is observed) and then cooled to room temperature. Total reaction time is 3 h. The organic phase is extracted with technical hexane (3×200mL) and analyzed by GC. Conversion: 74.5% w of 3-tert-butyl-indene and 1.8% of 1-tert-butyl-indene, unreacted indene 13.7% w. The solution was evaporated under reduced pressure (rotovac) and the resulting dark brown viscous liquid was distilled at 1 mmHg, collecting the fraction boiling between 70 and 80° C. (40 g, 76.8% of 3-tert-butyl-indene and 19.5% of 1-tert-butyl-indene, no indene).
Reaction SMILES: [F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:13](O[BH3-])(=O)[CH3:14].[Na+].CO.[CH:21](=O)[CH3:22]>C(=O)([O-])O.[Na+].[OH-].[Na+].C(O)(=O)C>[CH2:21]([N:8]([CH2:13][CH3:14])[C:5]1[C:4]([NH2:9])=[C:3]([N+:10]([O-:12])=[O:11])[C:2]([F:1])=[CH:7][CH:6]=1)[CH3:22]
Reactant: [BH3-]OC(C)=O
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1N
Reactant: CC=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC)c1ccc(F)c([N+](=O)[O-])c1N
Yield: 88.9 %

Procedure:
To a mixture of 4-fluoro-3-nitrobenzene-1,2-diamine (800 mg, 4.67 mmol), sodium acetoxyborohydride (5.94 g, 28.0 mmol), methanol (9 mL) and acetic acid (2.3 mL) was added acetoaldehyde (90%, 1.75 mL, 28.1 mmol) at 0° C. After the resultant mixture was stirred at 0° C. for 30 min, the mixture was diluted with aqueous sodium hydrogen carbonate and aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10 ethyl acetate/n-hexane mixture to give the title compound as a red oil (942 mg, 4.15 mmol, 89%).