Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([O:14][CH3:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[C:4]=1[S:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)Cl.[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>C(N(CC)CC)C>[CH:26]1([C:29]([N:9]2[CH2:8][CH2:7][C:6]3[CH:12]=[C:13]([O:14][CH3:15])[C:3]([O:2][CH3:1])=[C:4]([S:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:5]=3[CH2:11][CH2:10]2)=[O:30])[CH2:28][CH2:27]1
Reactant: O=C(Cl)C1CC1
Reactant: COc1cc2c(c(Sc3ccccc3)c1OC)CCNCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(c(Sc3ccccc3)c1OC)CCN(C(=O)C1CC1)CC2

Procedure:
To a solution of 1.58 g. (0.005 mole) of 7,8-dimethoxy-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine in 25 ml. of methylene chloride and 1.0 g. of triethylamine is added dropwise 1.05 g. (0.010 mole) of cyclopropanecarboxylic acid chloride at 5° C. and the mixture is stirred at room temperature for 3 hours. The reaction mixture is filtered and the filtrate is washed with water, 5% potassium carbonate solution and then with water, dried and subsequently concentrated to give 3-cyclopropanecarbonyl-7,8-dimethoxy-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:20][C@@H:21]([CH3:31])[CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26](OC)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[Si:13]([O:20][C@@H:21]([CH3:31])[CH2:22][O:23][CH2:24][C@H:25]([OH:30])[C:26]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH3:5])=[CH:11][N:10]=1)=[O:27])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)[C@@H](O)COC[C@H](C)O[Si](C)(C)C(C)(C)C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)[C@@H](O)COC[C@H](C)O[Si](C)(C)C(C)(C)C)nc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.9 %

Procedure:
Trimethylaluminium (1.966 mL, 3.93 mmol) was added slowly to 5-methylpyridin-2-amine (0.407 g, 3.76 mmol) in toluene (20 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 10 minutes. (S)-methyl 3-((S)-2-(tert-butyldimethylsilyloxy)propoxy)-2-hydroxypropanoate (Intermediate AS3) (1 g, 3.42 mmol) in toluene (4 mL) was added and the reaction was allowed to warm to room temperature and then heated at reflux for 4 hours (a further 5ml toluene was added to aid stirring). The reaction mixture was concentrated in vacuo. The residue was neutralised with citric acid (1M, aq) and then diluted with water and extracted with EtOAc. The combined organics were dried (MgSO4) and evaporated to afford the product (0.994 g) which was used without further purification. 1H NMR (400 MHz, CDCl3) δ 0.07 (6H, d), 0.88 (9H, s), 1.15 (3H, d), 2.30 (3H, s), 2.79-3.11 (1H, m), 3.39-3.51 (2H, m), 3.80-3.91 (2H, m), 3.94-4.03 (1H, m), 4.31-4.36 (1H, m), 7.49-7.56 (1H, m), 8.09-8.16 (2H, m), 9.20 (1H, s); m/z (ES+) (M+H)+=369.52; HPLC tR=2.73 min.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C([Li])CCC.[F:24][C:25]([F:39])([F:38])[C:26]([C:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]([CH3:37])[CH:29]=1)=[O:27]>COCCOCCOC.CCOCC>[F:16][C:13]1[CH:14]=[CH:15][C:10]([N:6]2[C:5]3[CH:17]=[CH:18][C:2]([C:26]([OH:27])([C:28]4[C:36]5[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:30]([CH3:37])[CH:29]=4)[C:25]([F:24])([F:39])[F:38])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])=[CH:11][CH:12]=1
Reactant: Cn1cc(C(=O)C(F)(F)F)c2ccccc21
Reactant: O=c1[nH]c2cc(Br)ccc2n1-c1ccc(F)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: COCCOCCOC
Product: Cn1cc(C(O)(c2ccc3c(c2)[nH]c(=O)n3-c2ccc(F)cc2)C(F)(F)F)c2ccccc21
Reaction time: 0.5 h

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-1,3-dihydrobenzimidazol-2-one (152 mg, 0.5 mmol) in anhydrous bis(2-methoxyethyl)ether (10 mL) was added 0.5 mL (1.25 mmol) of a solution of 2.5 M n-butyllithium in hexanes. After 30 minutes, a solution of 2,2,2-trifluoro-1-(1-methyl-1H-indol-3-yl)ethanone (114 mg) in bis(2-methoxyethyl) in 1 mL of ether was added. The mixture stirred for 1 hour and was quenched with ammonium chloride solution. The resulting precipitate was filtered, washed with water, and dried to afford the title compound as an off-white solid. MS m/z 456 (MH+).
Reaction SMILES: C1C2C(=CC=CC=2)[C@@H](N)[C@H]1O.B.CCN(C1C=CC=CC=1)CC.[CH:24]([C:27]1[C:36]2[C:37](=[O:45])[O:38][C:39]3([CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:35]=2[C:34]2[C:33](=[O:46])[CH2:32][C:31]([CH3:48])([CH3:47])[CH2:30][C:29]=2[N:28]=1)([CH3:26])[CH3:25].CO>O1CCCC1>[OH:46][C@H:33]1[CH2:32][C:31]([CH3:48])([CH3:47])[CH2:30][C:29]2[N:28]=[C:27]([CH:24]([CH3:26])[CH3:25])[C:36]3[C:37](=[O:45])[O:38][C:39]4([CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)[C:35]=3[C:34]1=2
Reactant: CC(C)c1nc2c(c3c1C(=O)OC31CCOCC1)C(=O)CC(C)(C)C2
Agent: B
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CCN(CC)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1nc2c(c3c1C(=O)OC31CCOCC1)[C@@H](O)CC(C)(C)C2
Temperature: 0 °C
Reaction time: 24 h

Procedure:
0.700 g (1R,2S)-(+)-cis-1-Amino-2-indanol are dissolved in 150 ml tetrahydrofurane and to this solution are dropwise added 6.12 ml of a borane-diethylaniline-complex. After completion of gas evolution the solution is cooled to 0° C. and 5.54 g 4-Isopropyl-7,7-dimethyl-2′,3′,5′,6′,7,8-hexahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3,9(6H)-dione in 150 ml tetrahydrofurane are added dropwise. The temperature is raised during 2 hours to room temperature and the mixture is stirred for 24 hours. 10 ml Methanol are added dropwise and the solvents are evaporated in vacuo. The residue was dissolved in dichloromethane and is washed with 0.1 M hydrochloric acid and saturated aqueous sodium bicarbonate solution consecutively. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 3:2).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[CH2:13][C:14]([O-:16])=[O:15])([OH:3])=[O:2].[CH3:17]O>>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:4]([C:1]([OH:3])=[O:2])[CH:9]=1
Reactant: CO
Reactant: O=C([O-])Cc1ccc([N+](=O)[O-])cc1C(=O)O
Product: COC(=O)Cc1ccc(N)cc1C(=O)O
Yield: 90 %

Procedure:
Methyl 2-carboxy-4-nitrophenyl acetate was prepared from 2-carboxy-4-nitrophenylacetate and methanol by the procedure described above. Hydrogenation of this nitro compound gives methyl 4-amino-2-carboxy-phenylacetate (yield 90%). The guanidination of the amino compound with 3,5-dimethylpyrazole-1-carboxamidine nitrate (ADMP) was performed by a standard method described previously (Tsunematsu & Makismi, J. Biochem. 88, pp 1773-1783, (1980)). 2.2 g of amino compound (10 mmole), 1.9 g of triethylamine (19 mmole) and 3.0 g of ADMP (15 mmole) was heated in 20 ml of THF and refluxed for 18 hrs. The white precipitate was filtered and washed with cold methanol to give 1.5 g of methyl 2-carboxy-4-guanidinophenylacetate, (yield 46%). One spot on TLC, Rf=0.6 (Butanol:acetic acid:pyridine:water=4:1:1:2), it shows an orange color when sprayed with Sakaguchi reagent. NMR spectrum (CF3COOH), δ 8.4, 7.7 (b, 4H), 6.6 (b, 4H) 4.4 (s, 2H), 4.1 (s, 3H). Anal. Calc. for C11H13N3O4. 1/2 H2O: C, 50.77; H, 5.42; N, 16.15. Found: C, 51.03; H, 5.38; N, 16.19. 0.9 g of methyl 2-carboxy-4-guanidinophenylacetate (3 mmole) was heated with 1.5 g of PCl5 (7.2 mmole) at 70°-80° C. for 2 hrs, white solid precipitated out during the heating. The solid was filtered off and purified by silica gel column chromatography with methylene chloride and methanol (5:1) as an eluent to give 0.5 g of 7-guanidino-3-methoxyisocoumarin (yield 59%). One spot on TLC, Rf=0.7 (Butanol:acetic acid:pyridine:water=4:1:1:2); m.p. 185°-186° C. (dec);, NMR spectrum (d6 -DMSO): δ 7.9, 7.6 (b, 3H), 7.7 (b, 4H), 6.1 (s, 1H), 3.9 (s, 3H); mass spectrum (FAB+), m/e=234 (M+ -Cl). Anal. Calc. for C11H12N3O3Cl1. 1/2 H2O: C, 47.40; H, 4.67; N, 15.08; Cl, 12.75. Found: C, 47.42; H, 4.74; N, 15.05; Cl, 12.68.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:40]=[CH:39][C:11]([CH2:12][C:13]2[CH:38]=[CH:37][CH:36]=[CH:35][C:14]=2[O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[C:25]3[CH2:33][OH:34])[CH2:20][CH2:19]2)=[CH:10][CH:9]=1)=[O:7])C(C)C.[OH-].[Na+].Cl>CO>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([CH2:12][C:13]2[CH:38]=[CH:37][CH:36]=[CH:35][C:14]=2[O:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([N:24]3[C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[N:26]=[C:25]3[CH2:33][OH:34])[CH2:20][CH2:19]2)=[CH:39][CH:40]=1)([OH:7])=[O:5]
Reactant: CC(C)COC(=O)c1ccc(Cc2ccccc2OCCN2CCC(n3c(CO)nc4ccccc43)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(Cc2ccccc2OCCN2CCC(n3c(CO)nc4ccccc43)CC2)cc1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 110 %

Procedure:
The 1-[2-[2-(4-isobutyloxycarbonylbenzyl)phenoxy]ethyl]-4-(2-hydroxymethyl-1H-benzimidazol-1-yl)piperidine (49 mg) obtained in Example 103 was dissolved in methanol (0.5 ml), added with 1 N aqueous sodium hydroxide (0.18 ml) and stirred at 50° C. for 2.5 hours. After the reaction mixture was added with 1 N aqueous hydrochloric acid (0.72 ml), the solvent was evaporated under reduced pressure. The residue was purified by LH-20 column chromatography (elution solvent: dichloromethane:methanol=1:1) to obtain 48.3 mg of the title compound as hydrochloride. Yield: 100%.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C@@H:10]2[CH2:15][O:14][C:13]3=[N:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][N:12]3[CH2:11]2)=[CH:4][CH:3]=1.[C:22]([Si](C)(C)C)#[CH:23].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[C:22]([C:2]1[N:7]=[CH:6][C:5]([CH2:8][O:9][C@@H:10]2[CH2:15][O:14][C:13]3=[N:16][C:17]([N+:19]([O-:21])=[O:20])=[CH:18][N:12]3[CH2:11]2)=[CH:4][CH:3]=1)#[CH:23]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1ccc(Br)nc1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C#Cc1ccc(CO[C@@H]2COc3nc([N+](=O)[O-])cn3C2)cn1
Yield: 57.2 %

Procedure:
Sonogashira coupling of bromide 52 (see Example 2F) (0.310 g, 0.873 mmol) and ethynyltrimethylsilane (0.61 mL, 4.3 mmol) at room temperature for 18 h, followed by desilylation with TBAF, as in Example 2U, gave (6S)-6-[(6-ethynyl-3-pyridinyl)methoxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (130) (0.150 g, 57%) as a white solid: mp 168-170° C.; 1H NMR [(CD3)2SO] δ 8.51 (d, J=1.6 Hz, 1H), 8.02 (s, 1H), 7.74 (dd, J=8.0, 2.2 Hz, 1H), 7.54 (dd, J=8.0, 0.6 Hz, 1H), 4.73 (d, J=12.6 Hz, 1H), 4.70 (d, J=12.6 Hz, 1H), 4.67 (dt, J=12.3, 2.3 Hz, 1H), 4.47 (d, J=11.9 Hz, 1H), 4.29 (s, 1H), 4.20-4.28 (m, 3H). APCI MS m/z 301 [M+H]+.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([C@@H:10]([NH:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Br:27][C:28]1[CH:29]=[CH:30][C:31]([C:34](O)=[O:35])=[N:32][CH:33]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.O>[Br:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([C@@H:10]([NH:15][C:16]([C:18]2[NH:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:35])=[N:32][CH:33]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCCl
Product: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.1 %

Procedure:
A mixture of N-{(1S)-1-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-2,2-dimethylpropyl}-1H-indole-2-carboxamide (5 g, 14.11 mmol), 5-bromo-2-pyridinecarboxylic acid (2.85 g, 14.11 mmol), EDC (2.7 g, 14.11 mmol), HOBt (1.91 g, 14.11 mmol), NMM (2.14 g, 21.14 mmol) in CH2Cl2 (50 mL) was stirred at room temperature for 12 h. The reaction was diluted with water. The two layers were separated and the organic washed with sat. NaHCO3 and 1N HCl. The resulting organic solution was dried over anhydrous Na2SO4 and concentrated to give the title compound (7 g) as a yellow solid. LCMS (m/z): 540.2 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3](=[O:32])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.Cl[C:35]1[C:36]2[C:43]([CH3:44])=[CH:42][NH:41][C:37]=2[N:38]=[CH:39][N:40]=1.C(N(CC)C(C)C)(C)C.C(O)(C)C>C(Cl)Cl>[CH3:1][N:2]([CH3:33])[C:3](=[O:32])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([CH2:20][NH:21][C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])[CH2:19][CH2:18][N:17]([C:35]3[C:36]4[C:43]([CH3:44])=[CH:42][NH:41][C:37]=4[N:38]=[CH:39][N:40]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(CNC(=O)OCc3ccccc3)CCNCC2)c1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c2ncnc(N3CCC(CNC(=O)OCc4ccccc4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 120 °C
Yield: 54 %

Procedure:
3-(4-((Benzyloxycarbonylamino)methyl)piperidine-4-carboxamido)phenyl dimethylcarbamate (0.216 g, 0.441 mmol) from step D, 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.073 g, 0.441 mmol), N,N-diisopropylethylamine (0.230 mL, 1.32 mmol), and isopropanol (5 mL) were combined and heated at 120° C. overnight in a pressure vessel. The crude reaction was diluted with CH2Cl2 and washed with H2O and brine, dried over MgSO4, and concentrated under vacuum. The residue was purified by silica gel chromatography (MeOH:CH2Cl2 gradient) to give the title compound in 54% yield.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:10](=[O:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:17])=[O:18])[CH2:15][C@@:9]1([C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C@H:10]([OH:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC[C@H]2[C@H](S(=O)(=O)c3ccccc3)C[C@]1(c1ccc(F)cc1)N2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccc(F)cc3)[C@H](O)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
(1R*,5S*,6R*)-8-Benzyl-1-(4-fluorophenyl)-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-one (Description 13; 11.65 g, 25.95 mmol) was stirred in methanol (100 ml) then sodium borohydride (981 mg, 25.95 mmol) added and the mixture stirred at room temperature for 2 hours. The reaction mixture was quenched with water then concentrated in vacuo and partitioned between water and ethyl acetate. The organics were collected, dried (MgSO4), and concentrated in vacuo to give a cream solid which was triturated in diethyl ether and filtered to give the title compound as a cream-coloured solid (7.26 g, 62%).
Reaction SMILES: C([C:5]([O:7][CH2:8]CC(O)C)=[O:6])(C)(C)C.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15]C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:8][O:7][CH2:5][O:6][C@@H:16]1[CH2:15][C@@H:13]([OH:19])[CH:18]=[CH:17]1
Reactant: Oc1ccccc1
Reactant: CC(O)CCOC(=O)C(C)(C)C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCO[C@H]1C=C[C@H](O)C1
Reaction time: 0.33 h
Yield: 151.6 %

Procedure:
To a solution of 3.47 g (19.9 mmol) of alcohol 25 (prepared in 30-(1)), 2.81 g (29.9 mmol) of phenol, and 7.88 g (29.9 mmol) of triphenylphosphine in 100 ml of dry THF is added a solution of 4.65 ml of diethyl azodicarboxylate in 40 ml of dry THF dropwise under ice cooling. After additional stirring at the same temperature for 20 minutes, the mixture is stirred for further 2 and half hours. The reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel (200 g of silica gel, ethyl acetate:n-hexane=1:49 to 1:19) to give 4.35 g of the desired phenyl ether 3 as an oil in 87.4% yield.
Reaction SMILES: [CH:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH:12]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:14]=[CH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[CH3:20][O:19][C:17]([C:15]1[N:14]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH:13]=[N:12][CH:16]=1)=[O:18]
Reactant: OC1CCCc2ccccc21
Reactant: COC(=O)c1c[nH]cn1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cncn1C1CCCc2ccccc21
Reaction time: 16 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-1-naphthol (CAS#529-33-9, 1.00 g, 6.74 mmol), which can be prepared as described in Ollivier, R.; et al. Journal of Medicinal Chemistry, 1997, 40, 952-960, in THF (60 mL), at 0° C. is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 0.85 g, 6.74 mmol) and triphenylphosphine, followed by diisopropyl azodicarboxylate (1.36 g, 6.74 mmol). The cooling bath is then removed. After 16 hours, the solvent is evaporated in vacuo and the residue is purified by silica gel flash chromatography (elution with ethyl acetate) to give a partially purified product, which is dissolved in ethyl acetate and extracted with 1M aqueous HCl. The aqueous layer is basified to a pH of ca. 9 with 2M aqueous NaOH, and then extracted three times with dichloromethane. The organic layers are combined, dried with MgSO4, filtered, and concentrated to furnish 3-(1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 257.2 (M+H)+. The HNO3 salt of the title compound is prepared by dissolving the free base in methanol, followed by treatment with an excess of a 1:1 solution of HNO3—H2O. Concentration and trituration with diethyl ether and methanol, provides the nitric acid salt of 3-(1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.87 (m, 2 H), 2.11-2.33 (m, 2 H), 2.81 (dt, J=17.2, 6.5 Hz, 1 H), 2.93 (dt, J=17.2, 6.0 Hz, 1 H), 3.87 (s, 3 H), 6.33 (t, J=5.9 Hz, 1 H), 6.99 (d, J=7.6 Hz, 1 H), 7.10-7.21 (m, 1 H), 7.21-7.35 (m, 2 H), 8.34 (s, 1 H), 8.58 (s, 1 H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[N:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)=[CH:12][C:11]=1[C:28]([F:31])([F:30])[F:29].C(N(C(C)C)CC)(C)C.CO>O>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[C:20]([C:22]#[N:23])[C:19]3[N:24]=[N:25][N:26]([CH3:27])[C:18]=3[CH:17]=2)=[CH:12][C:11]=1[C:28]([F:30])([F:29])[F:31])(=[O:4])=[O:3]
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCO)c(C(F)(F)F)c3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCOS(C)(=O)=O)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Methanesulfonyl chloride (3.95 ml, 4.53 g) was added dropwise at 0° C. to a solution of 6-(4-(2-hydroxyethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile (5.7 g) and diisopropylethylamine (17.28 ml, 12.79 g). The mixture was stirred at room temperature for 1 hour. 10 ml methanol added and stirred for 5 minutes, followed by cold water (20 ml). Product precipitated, collected by filtration and washed with diethyl ether. Sample dried in the oven to give 2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)-phenoxy)ethyl methanesulfonate (6.3 g). 1H NMR (DMSO) δ: 8.99 (s, 8.99), 8.48 (m, 2H), 7.53 (d, 1H), 4.60 (m, 4H), 4.46 (s, 3H), 3.24 (s, 3H). MS m/z 442 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18]([OH:20])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15].C(N(CC)CC)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][CH:49]([C:52]2[C:60]3[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=3)[NH:54][CH:53]=2)[CH2:48][CH2:47]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:16]=[CH:17]/[C:18]([NH:43][CH2:44][CH2:45][N:46]2[CH2:47][CH2:48][CH:49]([C:52]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[NH:54][CH:53]=3)[CH2:50][CH2:51]2)=[O:20])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: NCCN1CCC(c2c[nH]c3ccccc23)CC1
Reactant: COCCOCOc1ccc(/C=C/C(=O)O)cc1OC
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOCOc1ccc(/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
To a stirred mixture of 3-[3-methoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(E)-propenoic acid (1.75 g) and triethylamine (1.81 ml) in dry N,N-dimethylformamide (10 ml) was added slowly diphenyl phosphinic chloride (1.47 g) at -10° to -15° C. under an inert atmosphere. After being stirred for 30 minutes, a solution of 1-(2-aminoethyl)-4-(3-indolyl)piperidine (1.5 g) in dry N,N-dimethylformamide (10 ml) was added slowly to the reaction mixture at -10° C. After being stirred for 1 hour at ambient temperature, the reaction mixture was poured into ice-water (200 ml) and extracted with chloroform (100 ml). The extract was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silicagel (47 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the object compound were combined and concentrated under reduced pressure to give syrup of 1-[2-[3-[3-methoxy-4-{(2-methoxyethoxy)methoxy}phenyl]-(E)-propenoylamino]ethyl]-4-(3-indolyl)piperidine (2.8 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[O:5][C:6]1[S:7][C:8]([C:11]2[CH:15]=[C:14]([CH:16]([N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])[CH3:17])[O:13][N:12]=2)=[CH:9][N:10]=1.[CH:32](O)([CH3:34])[CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH:32]([O:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[O:5][C:6]1[S:7][C:8]([C:11]2[CH:15]=[C:14]([CH:16]([N:18]3[C:26](=[O:27])[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]3=[O:28])[CH3:17])[O:13][N:12]=2)=[CH:9][N:10]=1)([CH3:34])[CH3:33]
Reactant: CC(c1cc(-c2cnc(Oc3cccc(O)c3)s2)no1)N1C(=O)c2ccccc2C1=O
Reactant: CC(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(Oc2ncc(-c3cc(C(C)N4C(=O)c5ccccc5C4=O)on3)s2)c1
Reaction time: 16 h
Yield: 84.1 %

Procedure:
To a solution of Example 86F (250 mg, 0.68 mmol), isopropanol (78 μL, 1.02 mmol) and triphenylphosphine (267 mg, 1.02 mmol) in tetrahydrofuran (5 mL) was added diethyl azodicarboxylate (175 μL, 1.02 mmol) at 25° C. The reaction was stirred for 16 hours and concentrated. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 10% to 30% ethyl acetate in hexanes to provide 272 mg of the title compound (84%) as a off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.26 (d, J=5.88 Hz, 6H) 1.82 (d, J=6.99 Hz, 3H) 4.55-4.74 (m, 1H) 5.64 (q, J=6.99 Hz, 1H) 6.83-7.05 (m, 3H) 7.18 (s, 1H) 7.38 (t, J=8.27 Hz, 1H) 7.83-7.95 (m, 4H) 7.96 (s, 1H); MS (ESI) m/z 476.1 (M+H)+.