Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OCC)(=O)C.Cl.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][C:24]3[CH:44]=[CH:43][C:27]([C:28]([CH:30]4[CH2:35][CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]4)=[O:29])=[CH:26][CH:25]=3)=[O:22])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1>>[ClH:8].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][C:24]3[CH:44]=[CH:43][C:27]([C:28]([CH:30]4[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]4)=[O:29])=[CH:26][CH:25]=3)=[O:22])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)c2ccc(NC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)cc2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(C(=O)C2CCCNC2)cc1)c1ccc(-c2ccc(Cl)cc2)cc1
Yield: 166.8 %

Procedure:
4N Hydrogen chloride-ethyl acetate (1 ml) was added to tert-butyl 3-[4-[[(4′-chloro[1,1′-biphenyl]-4-yl)carbonyl]amino]benzoyl]-1-piperidinecarboxylate (100 mg, 0.193 mmol) obtained in 1). One hour later, the solvent was distilled out under reduced pressure. Diisopropyl ether was added to the residue, to give the titled compound (73.3 mg) as a colorless powder.
Reaction SMILES: ClC1C=CC2N(C(CC3C(F)=C4C(=CC=3F)N(C)N=C4)=CN=2)N=1.C([Sn](CCCC)(CCCC)C(OCC)=C)CCC.[F:42][C:43]1[C:51]([CH:52]([C:54]2[N:58]3[N:59]=[C:60]([C:63](=[O:65])[CH3:64])[CH:61]=[CH:62][C:57]3=[N:56][CH:55]=2)C)=[C:50]([F:66])[CH:49]=[C:48]2[C:44]=1[CH:45]=[N:46][N:47]2[CH3:67]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:42][C:43]1[C:51]([CH2:52][C:54]2[N:58]3[N:59]=[C:60]([C:63](=[O:65])[CH3:64])[CH:61]=[CH:62][C:57]3=[N:56][CH:55]=2)=[C:50]([F:66])[CH:49]=[C:48]2[C:44]=1[CH:45]=[N:46][N:47]2[CH3:67]
Reactant: CC(=O)c1ccc2ncc(C(C)c3c(F)cc4c(cnn4C)c3F)n2n1
Agent: [Pd]
Agent: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cn1ncc2c(F)c(Cc3cnc4ccc(Cl)nn34)c(F)cc21
Product: CC(=O)c1ccc2ncc(Cc3c(F)cc4c(cnn4C)c3F)n2n1
Yield: 71.3 %

Procedure:
The title compound as a light yellow solid (350 mg, 0.769 mmol, 71.3%) was synthesized from 6-chloro-3-((4,6-difluoro-1-methyl-1H-indazol-5-yl)methyl)imidazo[1,2-b]pyridazine (360 mg, 1.079 mmol), tributyl(1-ethoxyvinyl)stannane (1.095 ml, 3.24 mmol) and tetrakis-(triphenylphosphine)-palladium (374 mg, 0.324 mmol) using the same procedure as described in the synthesis of compound 31.4. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.09 (s, 1H), 8.07 (s, 1H), 7.78 (d, 1H), 7.71 (s, 1H), 7.26 (d, 1H), 4.59 (s, 2H), 4.02 (s, 3H), 2.74 (s, 3H). LCMS (method B): [MH]+=342.0, tR=2.39 min.
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][CH2:7][C:8]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([C:38]3[S:39][CH:40]=[CH:41][N:42]=3)[CH2:31][C:32]3[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=3)=[CH:25][C:9]=2[C:10]([NH:12][C@@H:13]([CH2:21][CH2:22][S:23][CH3:24])[C:14]([O:16]C(C)(C)C)=[O:15])=[O:11])=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][CH2:7][C:8]2[CH:28]=[CH:27][C:26]([O:29][CH:30]([C:38]3[S:39][CH:40]=[CH:41][N:42]=3)[CH2:31][C:32]3[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=3)=[CH:25][C:9]=2[C:10]([NH:12][C@@H:13]([CH2:21][CH2:22][S:23][CH3:24])[C:14]([OH:16])=[O:15])=[O:11])=[CH:4][CH:3]=1
Reactant: CSCC[C@H](NC(=O)c1cc(OC(Cc2cncn2C)c2nccs2)ccc1CCc1ccc(F)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)c1cc(OC(Cc2cncn2C)c2nccs2)ccc1CCc1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
A mixture of tert-butyl (2S)-2-{2-(4-fluorophenethyl)-5-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxy]benzoylamino}-4-methylsulfanylbutyrate (0.050 g, 0.078 mmol) in TFA was stirred at ambient temperature under a nitrogen atmosphere for 4 hours. The TFA was evaporated away and the residues basified with saturated sodium bicarbonate solution, reacidified with 2NHCl to pH6 and extracted with dichloromethane. The extracts were dried and evaporated to dryness. The residue was dried under high vacuum to give the title compound as a white solid (0.040 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@@H:12]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH2:26][CH3:27])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:28]1([C:31](Cl)=[O:32])[CH2:30][CH2:29]1>C1COCC1>[CH2:26]([O:25][C:20]1[CH:19]=[C:18]([C@H:12]([N:8]2[C:9](=[O:11])[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][C:31]([CH:28]3[CH2:30][CH2:29]3)=[O:32])[CH2:7]2)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:23]=[CH:22][C:21]=1[OH:24])[CH3:27]
Reactant: O=C(Cl)C1CC1
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1O
Solvent: C1CCOC1
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1O
Temperature: 60 °C
Yield: 18.7 %

Procedure:
To a mixture of (S)-7-amino-2-(1-(3-ethoxy-4-hydroxyphenyl)-2-(methylsulfonyl)ethyl)isoindolin-1-one (5.86 g, 15.0 mol) in THF (60 mL) was added cyclopropanecarbonyl chloride (1.5 mL, 16.1 mmol). The mixture was heated to 60° C. for 1 hour then cooled to room temperature. The solvent was removed and the crude residue purified using column chromatography (MeOH/CH2Cl2; 0-5% over 60 minutes) to give 4.7 g of crude, 68% yield. Further purification was then carried out by prep-HPLC to give (S)—N-(2-(1-(3-ethoxy-4-hydroxyphenyl)-2-(methylsulfonyl)ethyl)-3-oxoisoindolin-4-yl)cyclopropanecarboxamide as a white solid (1.38 g, 20% yield). HPLC: HPLC: Hypersil DBS C8 column, 250×4.6 mm, 5 μm; 99/1 to 85/15 over 15 min Gradient CH3CN/10 mM aq. KH2PO4, 1.0 mL/min, 35° C., run time 20 minutes: tR 12.45 minutes. 1H-NMR (DMSO-d6): 10.51 (1H, s), 9.07 (1H, s), 8.22-8.25 (1H, d), 7.47-7.53 (1H, t), 7.18-7.20 (1H, d), 7.01 (1H, d), 6.78-6.86 (2H, m), 5.82-5.87 (1H, m), 4.61-4.67 (1H, d), 3.91-4.33 (5H, m), 3.02 (3H, s), 1.76-1.82 (1H, m), 1.31-1.36 (3H, t), 0.82-0.96 (4H, m); LC-MS ES+ (M+1) 459.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]([CH3:15])=O>>[CH2:18]([O:17][C:12](=[O:16])[C@H:13]([CH3:15])[NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1)[CH3:19]
Reactant: Nc1ccc2ccccc2c1
Reactant: CCOC(=O)C(C)=O
Product: CCOC(=O)[C@H](C)Nc1ccc2ccccc2c1

Procedure:
Following reductive amination General Procedure AA above and using 2-aminonaphthalene (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared as a solid having a melting point of 52-56° C. The reaction was monitored by silica gel tlc (Rf=0.50 in 25% EtOAc/hexanes). Purification was by flash chromatography with silica gel using 25% EtOAc/hexanes as the eluant.
Reaction SMILES: [Br:1][C:2]([CH3:24])([CH3:23])[C:3]([O:5][CH2:6][CH2:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[C:12]([N+:19]([O-])=O)[CH:11]=1)=[O:4].Cl.[Sn](Cl)Cl.[OH-].[K+]>C(O)C.O1CCCC1>[Br:1][C:2]([CH3:24])([CH3:23])[C:3]([O:5][CH2:6][CH2:7][O:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([NH2:16])[CH:13]=[C:12]([NH2:19])[CH:11]=1)=[O:4]
Reactant: CC(C)(Br)C(=O)OCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(Br)C(=O)OCCOC(=O)c1cc(N)cc(N)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3,5-Dinitro-benzoic acid 2-(2-bromo-2-methyl-propionyloxy)-ethyl ester (9 g, 0.022 mol) was dissolved in 100 ml ethanol/tetrahydrofuran (1:1). In succession, 10N HCl (27 ml, 0.27 mol) and tin(II)chloride (50.1 g, 0.22 mol) were added. The solution was stirred at room temperature 18 h. The reaction mixture was poured into a separatory funnel containing 100 ml ice-cold water followed by the addition of 20% KOH (ice-cold, 444 g). The mixture was extracted with ether (3×100 ml). The combined organic phases were washed with water (3×100 ml) and brine, dried with solid MgSO4 and concentrated to 5.6 g.
Reaction SMILES: [BH4-].[Na+].[OH-].[Na+].O.[CH3:6][CH:7]([C:11](=[O:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:8](=[O:10])[CH3:9]>CO>[CH3:6][CH:7]([CH:11]([OH:16])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH:8]([OH:10])[CH3:9]
Reactant: CC(=O)C(C)C(=O)CC(C)C
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CC(O)C(C)C(C)O
Yield: 90 %

Procedure:
To the mixture of 2.5 g sodium borohydride, 0.05 g sodium hydroxide, and 25 ml water was added dropwise the mixture of 14.2 g 3,6-dimethyl-2,4-heptandione and 30 ml methanol at 0-10° C. Upon completing the addition, the solvent was removed by reduced pressure distillation. The reaction mixture was continuously extracted with 40 ml ethyl acetate for 15 hours. The solvent was removed. Distillation under reduced pressure gave colorless liquid 3,6-dimethyl-2,4-heptanediol, and the yield was 90%. IR spectrum had a strong absorption peak at 3400 cm−1, and had no absorption peak at about 1700 cm−1. This demonstrated that the reduction reaction was carried out completely.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH2:17][C:18]#[N:19]>>[S:1]1[CH:5]=[C:4](/[CH:6]=[C:17](/[C:16]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([O:13][CH3:12])[CH:15]=2)\[C:18]#[N:19])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1csc2ccccc12
Product: COc1ccc(/C(C#N)=C/c2csc3ccccc23)cc1OC
Yield: 92.3 %

Procedure:
Benzo[b]thiophene-3-carboxaldehyde (200 mg) was condensed with 3,4-dimethoxybenzyl cyanide (218 mg) through Method A (production step 2), to thereby yield the target product (yield: 365 mg, 92%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=O)[CH3:17])[C:11]=3[OH:19])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:20]([C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]1)=[S:23])[NH2:21].Cl.C(OCC)(=O)C>CN(C)C=O>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=[N:21][NH:20][C:22]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]4)=[S:23])[CH3:17])[C:11]=3[OH:19])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)c1nn(C)c(-c2ccc3c(c2)CCC3)c1O
Reactant: COC(=O)C1CCN(C(=S)NN)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCN(C(=S)NN=C(C)c2nn(C)c(-c3ccc4c(c3)CCC4)c2O)CC1
Yield: 76.5 %

Procedure:
1-[5-(2,3-dihydro-1H-inden-5-yl)-4-hydroxyl-1-methyl-1H-pyrazol-3-yl]ethanone (50 mg, 0.195 mmol) and methyl 1-(hydrazinecarbonothioyl)piperidine-4-carboxylate (51 mg, 0.234 mmol, synthesized in accordance with WO2006062240) in N,N-dimethylformamide was stirred with concentrated hydrochloric acid (24 μL, 0.293 mmol) at room temperature for 1 day. After the reaction, ethyl acetate was added, and the reaction solution was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. The resulting organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by medium pressure silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)→ethyl acetate) to obtain the desired product (68 mg, 77% yield).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([NH:8][C:9]2[C:14]([N+:15]([O-])=O)=[CH:13][N:12]=[C:11]3[N:18]([S:21]([C:24]4[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:19]=[CH:20][C:10]=23)[CH2:6][C@@H:5]([NH:31][S:32]([CH:35]2[CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH2:4]1)[CH3:2].O.O.[Sn](Cl)Cl>CCO>[NH2:15][C:14]1[C:9]([NH:8][C@@H:7]2[C@H:3]([CH2:1][CH3:2])[CH2:4][C@H:5]([NH:31][S:32]([CH:35]3[CH2:37][CH2:36]3)(=[O:33])=[O:34])[CH2:6]2)=[C:10]2[CH:20]=[CH:19][N:18]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([CH3:28])=[CH:29][CH:30]=3)(=[O:22])=[O:23])[C:11]2=[N:12][CH:13]=1
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c([N+](=O)[O-])cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c(N)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Temperature: 75 °C
Yield: 98.4 %

Procedure:
To a suspension of N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)cyclopropanesulfonamide (0.172 g, 0.314 mmol) in EtOH (6 mL) was added tin (II) chloride dihydrate (0.142 g, 0.628 mmol). The reaction mixture was heated at about 75° C. for about 15 h. Tin (II) chloride dihydrate (0.128 g, 0.565 mmol) was added and the reaction mixture was heated at about 70° C. for about 40 min then heated at about 80° C. for about 3 h. The reaction was cooled to ambient temperature and the solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc (20 mL) and washed with 1N aqueous NaOH (10 mL), water (10 mL) and brine (10 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and concd under reduced pressure. EtOH (10 mL) was added and the mixture was concd under reduced pressure to give N-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.160 g, 98%) as a yellow oil: LC/MS (Table 1, Method n) Rt=0.75 min; MS m/z 518 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[N:5]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:6]([C:16]([O:18]C)=[O:17])=[C:7]([N:9]3[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]3[CH3:15])[N:8]=2)[CH2:3][CH2:2]1.C[Si](C)(C)[O-].[K+]>C1COCC1>[CH:1]1([C:4]2[N:5]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[C:33]4[NH:37][N:36]=[N:35][N:34]=4)=[CH:23][CH:22]=3)[C:6]([C:16]([OH:18])=[O:17])=[C:7]([N:9]3[C:10]([CH3:15])=[CH:11][CH:12]=[C:13]3[CH3:14])[N:8]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1c(-n2c(C)ccc2C)nc(C2CC2)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1nc(C2CC2)n(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of methyl 2-cyclopropyl-4-(2,5 dimethyl-1H-pyrrol-1-yl)-1 [(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylate (Example 42, 1.91 g) in anhydrous THF was added potassium trimethylsilanolate (1.57 g) and the mixture stirred at ambient temperature for 20 hours. The solvent was removed under reduced pressure and the residue taken up in water (25 mL). The aqueous solution was filtered and extracted with ethyl acetate. The aqueous layer was acidified to pH 4.5 with 1N HCl and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate and evaporated to give the title compound 2-cyclopropyl-4-(2,5-dimethyl-1H-pyrrol-1-yl)-1-[(2'-(1H-tetrazol-5-yl)biphen-4-yl)methyl]-1H-imidazole-5-carboxylic acid. MS (CI, CH4 +NH3) 480 (M+).
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([C:9]([C:11]2[C:16]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)=O)[CH2:5][CH2:4]1.FC(F)(F)S(O)(=O)=O>>[Cl:25][C:21]1[CH:22]=[CH:23][C:24]2[C:9](=[C:6]3[CH2:7][CH2:8][N:3]([CH3:2])[CH2:4][CH2:5]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:16]3[CH2:17][CH2:18][C:19]=2[CH:20]=1
Reactant: CN1CCC(C(=O)c2ncccc2CCc2cccc(Cl)c2)CC1
Agent: Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: CN1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
A solution of 177 g (0.49 mole) of a product of Step D above in 480 mL (814.1 g, 5.31 mole) of trifluoromethanesulfonic acid at 90°-95° C. for 18 hours under nitrogen. Completeness of the reaction is determined by thin-layer chromatography. The cooled reaction is quenched with ice-water and the pH is adjusted to 6 with barium carbonate. The product is extracted into methylene chloride, which is concentrated under reduced pressure to about 1 liter and washed with water. The product is extracted into 1N hydrochloric acid, which is treated with 30 g of Darco, and filtered through celite. The pH of the filtrate is adjusted to 10 with 50% aqueous sodium hydroxide and the product is extracted into methylene chloride, which is removed under reduced pressure. The residue is dissolved in hot hexane, which is filtered to remove insolubles. The filtrate is concentrated to a residual beige powder. Yield: 126 g (HPLC purity 80%), 65% of theory.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[CH3:14][CH2:15][CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:21][CH:17]([CH2:18][CH2:19][CH3:20])[CH2:16][CH2:15][CH3:14])=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)c1ccc(OC)c(OC)c1

Procedure:
Prepared in a similar manner to example 4 using 3,4-dimethoxy benzoic acid and heptan-4-amine. MS (M+H, 279.37).
Reaction SMILES: [CH3:1][Mg]I.[OH:4][CH2:5][C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][C:12]2[CH:13]=[C:14]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH2:26][C:27]([CH3:29])=[O:28])=[CH:20][C:19]=3[CH3:30])[CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1>C1COCC1>[OH:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]2[CH:13]=[C:14]([C:18]3[C:19]([CH3:30])=[CH:20][C:21]([O:25][CH2:26][C:27]([CH3:1])([OH:28])[CH3:29])=[CH:22][C:23]=3[CH3:24])[CH:15]=[CH:16][CH:17]=2)=[CH:31][CH:32]=1
Reactant: CC(=O)COc1cc(C)c(-c2cccc(COc3ccc(CO)cc3)c2)c(C)c1
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: Cc1cc(OCC(C)(C)O)cc(C)c1-c1cccc(COc2ccc(CO)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In an atmosphere of nitrogen, a THF solution of methylmagnesium iodide was dropwise added under ice-cooling to a THF solution of 1-[(3′-{[4-(hydroxymethyl)phenoxy]methyl}-2,6-dimethylbiphenyl-4-yl)oxy]acetone, followed by stirring at room temperature for 30 minute to obtain 1-[(3′-{[4-(hydroxymethyl)phenoxy]methyl}-2,6-dimethylbiphenyl-4-yl)oxy]-2-methylpropan-2-ol.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:20])[C:16]#[C:17][CH2:18][OH:19].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:19][CH2:18][C:17]#[C:16][CH2:15][OH:20])[N:3]=[CH:4][N:5]=1
Reactant: OCC#CCO
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCC#CCOc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 9 h
Yield: 61.8 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 608 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 527 mg of 2-butyn-1,4-diol, to which 245 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 465 mg of 4-(2-fluorophenyl)-6-(4-hydroxy-2-butynyloxy)pyrimidine.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[O-]CC.[Mg+2:12].[O-]CC>C1(C)C=CC=CC=1>[C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O-:4])[O-:2].[Mg+2:12]
Reactant: Oc1ccccc1O
Agent: CC[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: [O-]c1ccccc1[O-]
Temperature: 100 °C

Procedure:
A solution of catechol (2.20 g, 20 mmol) and toluene (45 ml) was dehydrated by distilling 5 mL of the solution. Thereafter, 2.29 g (20 mmol) of magnesium(II) ethoxide was added to the solution while stirring. The mixed solution was refluxed for 1 hour, and then, while the distillation temperature was 100° C. or higher, distilled until the amount of the solution became half. After the distillation, solid content of the product was isolated by suction filtering using a membrane suction filter. The residual solid content was heated to 100° C. under vacuum using a vacuum dryer so that remaining volatile components were completely removed. The solid content (catechol-magnesium complex) was black in color. The yield amount was 2.57 g (19.5 mmol), and the yield percentage was 97%. Catechol-magnesium complex was dissolved into acetylacetone until saturated, and then filtered to be used as a coating liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][N:21]2C(=O)C3=CC=CC=C3C2=O)=[N:18][N:17]=[C:16]1[CH2:32][CH2:33][N:34]([CH3:36])[CH3:35].O.NN>C(O)C>[CH3:35][N:34]([CH3:36])[CH2:33][CH2:32][C:16]1[N:15]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:21][CH2:20][C:19]2=[N:18][N:17]=1
Reactant: CN(C)CCc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccccc1C(=O)c1ccccc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CN(C)CCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1C, 2'-chloro-2-[3-[2-(dimethylamino)ethyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is refluxed with hydrazine hydrate to give 1-[2-(dimethylamino)ethyl]-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine. Its methanesulfamate is obtained by treatment with methanesulfamic acid in ether.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:18][CH:17]=1>CC(C)=O>[C:27]([O:26][C:25](=[O:31])[NH:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:21][CH:20]=1)([CH3:28])([CH3:30])[CH3:29]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCc1ccc(OCc2ccccc2)cc1
Yield: 87.3 %

Procedure:
To a suspension of potassium carbonate (K2CO3; 1.4 grams (g), 10.11 millimole (mmol)) in acetone (40 milliliters (mL)) was added bromomethylbenzene (1.73 g, 10.11 mmol) and tert-butyl 2-(4-hydroxyphenyl)ethylcarbamate (2 g, 8.4 mmol). The reaction mixture was heated at reflux for 15 hours (h) and then concentrated in vacuo. The residue was partitioned between diethyl ether (Et2O) and water (H2O), and the organic fraction was washed with brine, dried over sodium sulfate (Na2SO4), suction filtered, and concentrated in vacuo. The residue was purified by silica gel (SiO2) flash chromatography with 25% Et2O in hexane to afford [2-(4-benzyloxyphenyl)-ethyl]-carbamic acid tert-butyl ester as a white solid (2.4 g). This was dissolved in CH2Cl2 (50 mL) and trifluoroacetic acid (5 mL) was added. After stirring 16 h, the solvent was removed in vacuo, and the residue was redissolved in CH2Cl2, washed with 1 M sodium hydroxide (NaOH), dried (Na2SO4) and filtered. The solvent was removed in vacuo to yield 2-(4-benzyloxyphenyl)-ethylamine (1.5 g). This was used without purification in the next step.
Reaction SMILES: CS[CH:3]([C:14]1[CH:19]=[C:18]([C:20]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH2:22][CH3:23])[CH:17]=[CH:16][C:15]=1[O:29][CH3:30])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]>[Zn].C(O)(=O)C>[CH3:28][CH2:27][O:26][C:24]([C:20]([C:18]1[CH:17]=[CH:16][C:15]([O:29][CH3:30])=[C:14]([CH2:3][C:4]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:5])[CH:19]=1)=[CH:21][CH2:22][CH3:23])=[O:25]
Reactant: CCC=C(C(=O)OCC)c1ccc(OC)c(C(SC)C(=O)OCc2ccccc2)c1
Agent: [Zn]
Solvent: CC(=O)O
Product: CCC=C(C(=O)OCC)c1ccc(OC)c(CC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Benzyl 2-methylthio-2-[5-[1-(2-ethoxycarbonyl)butenyl]-2-methoxyphenyl]acetate (2.14 g, 4.99 mmol) and glacial acetic acid (100 mL) were mixed and zinc powder (13.0 g, 199 mmol) was added under stirring at room temperature. After stirring for 6 hours at room temperature, the insolubles were remove by filtration and the filtrate was concentrated. The residue was dissolved into ethyl acetate (50 mL), washed with water and brine, then dried over anhydrous sodium sulfate and concentrated to afford 1.86 g (97%) of the title compound as a pale yellow oil.