Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:27])=[C:8]2[C:16]([Cl:17])=[C:15]([Cl:18])[N:14]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+].CO>>[Cl:18][C:15]1[N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[F:26])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])[C:7]([OH:27])=[C:8]2[C:16]=1[Cl:17]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2Cc1ccccc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)c(Cl)n(Cc3ccccc3F)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 2,3-dichloro-7-cyano-1-(2-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 437 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]([CH2:37][C:38]2[CH:43]=[C:42]([O:44][CH2:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=3)[CH:41]=[C:40]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[NH2:8][CH2:7][CH:6]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]2[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=2[Cl:35])=[CH:21][CH:22]=1)[C:5]([N:4]([CH:1]1[CH2:2][CH2:3]1)[CH2:37][C:38]1[CH:43]=[C:42]([O:44][CH2:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=2)[CH:41]=[C:40]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[CH:39]=1)=[O:36]
Reactant: COCCCc1cc(CN(C(=O)C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCc2ccccn2)c1
Agent: Cl
Solvent: ClCCl
Product: COCCCc1cc(CN(C(=O)C(CN)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCc2ccccn2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a CH2Cl2 solution (0.03 M) of tert-butyl (3-{cyclopropyl[3-(3-methoxypropyl)-5-(2-pyridin-2-ylethoxy)benzyl]amino}-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 12 h. Following the removal of the volatiles in vacuo, the resulting residue was directly subjected to column chromatography (SiO2, 90:10 (v/v) CH2Cl2: 2.0 M NH3 in MeOH) to afford the title compound as a white froth. MS (ESI+): 720.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH2:21][O:22][CH3:23].O>CN(C=O)C>[CH3:23][O:22][CH2:21][CH2:20][N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1ccc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-nitroindole (3.5 g; 21.6 mmol) in DMF (100ml) was added Cs2CO3 (13.9 g; 42.6 mmol). The mixture thus obtained was stirred 1 h hour at room temperature then 1-bromo-2-methoxyethane (5.9 g; 42.6 mmol) was added dropwise. The resulting mixture was heated to 120° C. under stirring for 4 hours. After cooling, the mixture was poured into water (500 ml) and the crude product was filtered, dried under vacuum to give 1-(2-methoxyethyl)-5-nitro-1H-indole which was used in the following reaction without any further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:22]([NH2:24])=[O:23])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][OH:20])=[CH:14][CH:13]=3)[C:6]=2[CH:21]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].O>ClCCl>[CH3:25][S:26]([O:20][CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([N:7]2[C:6]3[CH:21]=[C:2]([Cl:1])[C:3]([C:22]([NH2:24])=[O:23])=[CH:4][C:5]=3[N:9]=[C:8]2[CH2:10][CH3:11])=[CH:17][CH:16]=1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCO)cc1
Solvent: ClCCl
Solvent: O
Product: CCc1nc2cc(C(N)=O)c(Cl)cc2n1-c1ccc(CCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 49.7 %

Procedure:
A mixture of 6-chloro-2-ethyl-1-[4-(2-hydroxyethyl)phenyl]-1H-benzimidazole-5-carboxamide (Example 111, step 4, 500 mg, 1.45 mmol), triethylamnine (293 mg, 2.90 mmol) and methansulfonyl chloride (322 mg, 2.9 mmol) in dichloromethane (20 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water, and extracted with dichloromethane (50 ml). The organic layer was washed with brine (50 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by TLC with hexane/ethyl acetate (1:1) to afford 304 mg (50%) of the title compound as white solids.
Reaction SMILES: [Cl:1][C:2]1[S:13][C:5]2=[N:6][C:7]([CH2:11][Cl:12])=[CH:8][C:9](=[O:10])[N:4]2[CH:3]=1.S(Cl)([Cl:17])(=O)=O.C([O-])(O)=O.[Na+]>ClC(Cl)C>[Cl:1][C:2]1[S:13][C:5]2=[N:6][C:7]([CH2:11][Cl:12])=[C:8]([Cl:17])[C:9](=[O:10])[N:4]2[CH:3]=1
Reactant: O=c1cc(CCl)nc2sc(Cl)cn12
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=c1c(Cl)c(CCl)nc2sc(Cl)cn12
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
2-chloro-7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, (6.07 g), prepared according to Example 5, was reacted with sulfuryl chloride (3.8 g) in dichloroethane (150 ml) under stirring at room temperature for 4 hours. The reaction mixture was treated with 5% aqueous NaHCO3 solution then the organic phase was separated and evaporated in vacuo to dryness. Crystallization from methanol gave 5.6 g of 2,6-dichloro-7-chloromethyl-5H-thiazolo[3,2-a]pyrimidine-5-one, m.p. 117°-119° C. dec., which was reacted with triphenylphosphine (5.95 g) in acetonitrile (115 ml) at the reflux temperature for 20 hours. The solution was evaporated in vacuo to dryness and the residue was purified with isopropyl ether to give 10.4 g of [2,6-dichloro-5H-thiazolo[3,2-a]pyrimidine-5-one-7-yl]-methyl-triphenylphosphonium chloride, which was suspended in dimethylsulfoxide (50 ml) and treated with potassium tert-butoxide (2.41 g) dissolved in dimethylsulfoxide (45 ml) at room temperature.
Reaction SMILES: [H-].[Na+].COP([CH:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=1)[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)(=O)OC.[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=1.O>C1COCC1>[N:25]1[CH:30]=[CH:29][C:28](/[CH:31]=[C:9](\[C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:23]#[N:24])/[O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)=[CH:27][CH:26]=1
Reactant: O=Cc1ccncc1
Reactant: COP(=O)(OC)C(OC1CCCCO1)c1cccc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cccc(/C(=C\c2ccncc2)OC2CCCCO2)c1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
Sodium hydride (2.28 g, 94.98 mmol) was added to a solution of [(3-cyano-phenyl)-(tetrahydro-pyran-2-yloxy)-methyl]phosphonic acid dimethyl ester (20.58 g, 63.3 mmol) in dry THF and the mixture was stirred at room temperature for 15′. Pyridine-4-carbaldehyde (6.78 g, 63.3 mmol) was then added and the reaction mixture was stirred at 50° C. for 3 h under nitrogen atmosphere. In order to affect completion a further addition of pyridine-4-carbaldehyde (0.68 g, 6.33 mmol) was required. Distilled water (40 ml) was slowly poured into the reaction mixture and the solvent (THF) was removed under reduced pressure. The water layer was extracted with EtOAc (3×100 ml), DCM (1×100 ml) and the organic layers were dried over Na2SO4. The filtrate was evaporated to dryness to give the crude product 3-[(E)-2-Pyridin-4-yl-1-(tetrahydro-pyran-2-yloxy)-vinyl]-benzonitrile as a brown oil (19.0 g, 62.10 mmol, 98%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([C:15]#[C:16][C:17]3[CH:22]=[C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:19][N:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:31])=[CH:4][N:3]=1>CO.O1CCCC1.[Pd]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]3[CH:22]=[C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:20]=[CH:19][N:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:31])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(C#Cc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccnc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Yield: 88.2 %

Procedure:
To a mixture of tert-butyl [2-({3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethynyl)pyridin-4-yl]carbamate (740 mg, 1.6 mmol) in methanol (15 mL) and tetrahydrofuran (15 mL) was added 10% palladium on carbon (148 mg, 0.139 mmol). The resultant mixture was hydrogenated at 55 psi for 20 hours. The crude mixture was filtered and concentrated to give the desired product as a light yellow solid (0.65 g, 87%). LCMS for C22H24Cl2N5O2 (M+H)+: m/z=460.0, 462.0.
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:12])([CH3:11])[CH3:10])=[N:7][CH:8]=1.Br[C:16]1[N:21]=[C:20]2[N:22]([C@H:27]3[CH2:32][CH2:31][C@H:30]([O:33][CH3:34])[CH2:29][CH2:28]3)[C:23](=[O:26])[CH2:24][NH:25][C:19]2=[N:18][CH:17]=1>CN(C)C=O>[OH:12][C:9]([C:6]1[N:7]=[CH:8][C:3]([C:16]2[N:21]=[C:20]3[N:22]([C@H:27]4[CH2:32][CH2:31][C@H:30]([O:33][CH3:34])[CH2:29][CH2:28]4)[C:23](=[O:26])[CH2:24][NH:25][C:19]3=[N:18][CH:17]=2)=[CH:4][CH:5]=1)([CH3:11])[CH3:10]
Reactant: CO[C@H]1CC[C@H](N2C(=O)CNc3ncc(Br)nc32)CC1
Reactant: CC(C)(O)c1ccc([Sn](C)(C)C)cn1
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H](N2C(=O)CNc3ncc(-c4ccc(C(C)(C)O)nc4)nc32)CC1
Temperature: 120 °C

Procedure:
2-(5-(Trimethylstannyl)pyridin-2-yl)propan-2-ol (See Example 5.E) (9.43 g, 31.4 mmol), 7-bromo-1-(trans-4-methoxycyclohexyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (10.02 g, 29.4 mmol), [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloropalladium(II) dichloromethane adduct (2.398 g, 2.94 mmol) and N,N-dimethylformamide (25 mL) were combined in a round-bottom flask with a stirbar. The atmosphere in the vessel was removed under vacuum and replaced with nitrogen gas three times. The resulting mixture was stirred vigorously and heated at 120° C. under nitrogen for 35 min. The resulting mixture was purified using flash chromatography, split into 4 separate columns, (2-15% methanol in dichloromethane). Fractions containing the desired product were combined and most of the solvent removed under reduced pressure. The resulting mixture was purified using reverse-phase preparatory HPLC (20-40% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min), split into 6 runs. Fractions containing the desired product were combined and all of the acetonitrile and some of the water were removed under reduced pressure at 25° C. The remaining yellow solution was loaded onto 50 g of Strata X-C ion exchange resin from Phenomenex. The column was washed successively with water, acetonitrile, methanol and then 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol wash and was concentrated under reduced pressure and dried under high vacuum to give the desired product (4.85 g, 12.20 mmol, 42% yield) as a pink foam-solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.03 (d, J=1.56 Hz, 1H), 8.28 (s, 1H), 8.24 (dd, J=2.34, 8.20 Hz, 1H), 7.74 (d, J=7.81 Hz, 1H), 7.61 (s, 1H), 5.26 (s, 1H), 4.90 (tt, J=3.71, 12.10 Hz, 1H), 4.13 (s, 2H), 3.28 (s, 3H), 3.20 (tt, J=4.00, 10.84 Hz, 1H), 2.58 (qd, J=2.93, 12.82 Hz, 2H), 2.14 (d, J=10.15 Hz, 2H), 1.68 (d, J=10.93 Hz, 2H), 1.47 (s, 6H), 1.17-1.35 (m, 2H); MS (ESI) m/z 398.3 [M+1]+; mp 196-198° C. (uncorrected).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=1[F:16].Cl[C:22]1[CH:23]=[C:24]2[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>>[Cl:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:22]2[CH:23]=[C:24]3[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][N:25]3[C:26](=[O:28])[N:27]=2)=[CH:10][C:9]=1[F:16]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(Oc2ccc(Cl)c(Cl)c2)c(F)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(Cl)c(Cl)c3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, (4-(3,4-dichlorophenoxy)-3-fluorophenyl)methanol and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:14])[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[C:39](Cl)(=[O:55])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>>[C:39]([NH:8][C@H:9]([C:13]([NH:15][C@H:16]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:17][CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:14])[CH:10]([CH3:11])[CH3:12])(=[O:55])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCCCC(=O)N[C@H](C(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(C)C
Yield: 63.4 %

Procedure:
Starting from dibenzyl N-(N-tert-butoxycarbonyl-L-valyl)-L-glutamate (1 g) and hexadecanoyl chloride (620 mg), dibenzyl N-(N-hexadecanoyl-L-valyl)-L-glutamate (800 mg) was obtained as crystals according to a similar manner to that of Example 24.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][NH2:30]>>[NH2:30][CH2:29][CH2:28][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])[CH2:15][CH2:14]2)=[O:12])=[CH:7]1
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: NCCCl
Product: COc1ccccc1C1CCN(C(=O)c2cn(CCN)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-ethylamine gave the title compound.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:33]([O:40][C:41]1[CH:48]=[CH:47][C:44]([CH2:45]I)=[CH:43][CH:42]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:45][C:44]2[CH:47]=[CH:48][C:41]([O:40][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:42][CH:43]=2)[CH2:18]1)[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1
Reactant: ICc1ccc(OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1C[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O1

Procedure:
Analogously to Example 21 D) 1) c), 30.9 g (99.26 mmol) of 5(S)-[1(S)-(Boc-amino)-2-cyclohexylethyl]-dihydrofuran-2-(3H)-one are reacted with 200 ml (200 mmol) of lithium bis(trimethylsilyl)amide 1M in THF and 34 g (104.8 mmol) of 4-benzyloxybenzyl iodide to yield the title compound. The title compound is purified by column chromatography (SiO2, hexane/ethyl acetate: 4/1 to 1/1) and crystallisation (hexane/ethyl acetate); TLC Rf (C)=0.33; tRet (IV)=20.41 min; FAB-MS (M+H+)=508.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[C:8]2[CH2:17][CH:16]([CH3:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=O)=[CH:3][CH:2]=1.O.[NH2:21][NH2:22]>C(O)(C)C>[CH3:18][CH:16]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]2=[N:21][NH:22][C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[C:8]2[CH2:17]1
Reactant: NN
Reactant: CC1CC(=Cc2ccncc2)C(=O)c2ccccc21
Solvent: O
Solvent: CC(C)O
Product: CC1Cc2c(n[nH]c2-c2ccncc2)-c2ccccc21

Procedure:
To 24.0 grams (0.1 oles) of the compound of Step A of this exampel in a flask equipped with stirrer and condenser are added 4.8 grams (0.15 Mole) of hydrazine hydrate (95%) and 150 ml. of isopropanol. The mixture is stirred and refluxed for about 24 hours and the solvent is then crystallized from methanol to given 4,5-dihydro-5-methyl-3-(4-pyridyl)-2h-naphtho[1,2-c]pyrazole.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].Cl.C(N(CC)CC)C.[N-:20]=[N+:21]=[N-:22].[Na+]>COCCOC>[NH:20]1[C:1]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[NH:8][CH:7]=[CH:6]3)=[N:2][N:22]=[N:21]1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: c1cc2cc(-c3nnn[nH]3)ccc2[nH]1

Procedure:
A mixture of 5-cyano-1H-indole (88 g), triethylamine hydrochloride (225 g), and sodium azide (150 g) was heated in 1,2-dimethoxyethane (DME) at reflux temperature for 48 hours. The solvent was evaporated in vaciio and the residue was dissolved in ethyl acetate (500 mL) and water (500 mL). pH was adjusted to 10 by addition of concentrated aqueous NaOH solution. The aqueous phase was separated and pH was adjusted to 4 by addition of acetic acid. The precipitated crystalline title compound 1a was filtered off and subsequently dried in vacuo. Yield 82 g, mp 205° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1Cc2ccc(OC(=O)c3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
2-(tert-butoxycarbonylamino)-5-hydroxyindan (100 mg, 0.40 mmol) synthesized in Reference Production Example 1 was dissolved in dry methylene chloride (2 ml), to which pyridine (0.15 ml, 1.8 mmol) and benzoyl chloride (0.14 ml, 1.1 mmol) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, to which diethylether was added. The organic layer was washed with, in the order of, an aqueous solution of saturated potassium hydrogen sulfate, brine, an aqueous solution of saturated sodium hydrogen carbonate, and brine, and then was dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to obtain 2-(tert-butoxycarbonylamino)-5-benzoyloxyindan (130 mg, 0.37 mmol) having the following physical properties:
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[C:17]#[N:18].[Na].[CH2:20]([OH:23])[CH:21]=[CH2:22]>>[CH2:20]([O:23][C:2]1[C:10]2[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[C:17]#[N:18])[CH:21]=[CH2:22]
Reactant: C=CCO
Reactant: N#Cc1cc([N+](=O)[O-])c2nc(C(F)F)[nH]c2c1Cl
Agent: [Na]
Product: C=CCOc1c(C#N)cc([N+](=O)[O-])c2nc(C(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-5-cyano-2-difluoromethylbenzimidazole is reacted with the sodium salt of allyl alcohol to obtain 4-allyloxy-7-nitro-5-cyano-2-difluoromethylbenzimidazole, m.w., 294.2.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]O)[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2].[F:23][C:24]1[CH:29]=[C:28]([NH:30][S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[N+:40]([O-:42])=[O:41])(=[O:33])=[O:32])[CH:27]=[CH:26][C:25]=1[CH2:43][CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:30]([S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[N+:40]([O-:42])=[O:41])(=[O:32])=[O:33])[C:28]3[CH:27]=[CH:26][C:25]([CH2:43][CH2:44][C:45]([O:47][C:48]([CH3:51])([CH3:49])[CH3:50])=[O:46])=[C:24]([F:23])[CH:29]=3)[CH:15]=2)=[C:9]([CH3:22])[CH:8]=1)[CH3:2]
Reactant: CCOCCSc1cc(C)c(-c2cccc(CO)c2)c(C)c1
Reactant: CC(C)(C)OC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOCCSc1cc(C)c(-c2cccc(CN(c3ccc(CCC(=O)OC(C)(C)C)c(F)c3)S(=O)(=O)c3ccccc3[N+](=O)[O-])c2)c(C)c1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of {4′-[(2-ethoxyethyl)thio]-2′,6′-dimethylbiphenyl-3-yl}methanol (0.94 g, 2.98 mmol), tert-butyl 3-(2-fluoro-4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.13 g, 3.13 mmol) and tributylphosphine (1.03 mL, 3.87 mmol) in tetrahydrofuran (25 mL) was added 1,1′-(azodicarbonyl)dipiperidine (1.01 g, 3.87 mmol) under stirring at room temperature, and the mixture was stirred for 3 days. The resulting precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=5/1-hexane/ethyl acetate=3/1) to give a mixture (1.96 g) of tert-butyl 3-(4-{({4′-[(2-ethoxyethyl)thio]-2′,6′-dimethylbiphenyl-3-yl}methyl)[(2-nitrophenyl)sulfonyl]amino}-2-fluorophenyl)propanoate, {4′-[(2-ethoxyethyl)thio]-2′,6′-dimethylbiphenyl-3-yl}methanol and tert-butyl 3-(2-fluoro-4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate as a yellow oil. In the same manner as in Example 144, the title compound (1.25 g, yield 55%, 2 steps) was obtained as a colorless amorphous powder from the above-mentioned mixture (1.96 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:18]([C@H:14]([NH:13][C:11]([C:9]1[NH:8][C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:10]=1)=[O:12])[C:15]([N:29]1[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]1)=[O:17])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Reactant: OC1CCNCC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1)c1cc2cc(Cl)ncc2[nH]1

Procedure:
The title compound was prepared according to EXAMPLE 229 using 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-phenylpropionic acid (EXAMPLE 42) and 4-hydroxypiperidine. Purification by chromatography using dichloromethane/methanol (9:1) as the eluent gave the title compound as an orange powder. m/z (ES+)=427.35 [M+H]+; RT=2.99 min.