Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][NH:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[OH:8].[CH2:23]=O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]([CH3:23])[CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[OH:8]
Reactant: C=O
Reactant: COc1ccc(C(O)CNCc2ccccc2Cl)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(O)CN(C)Cc2ccccc2Cl)cc1OC
Yield: 93 %

Procedure:
A reaction mixture of 0.96 g (0.003 m) of N-(2-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-2-aminoethanol from Example 5, 3 ml (0.037 m) of formaldehyde and 0.4 g of sodium borohydride in methanol was reacted to give 0.94 g (93%) of N-(2-chlorobenzyl)-1-(3,4-dimethoxyphenyl)-2-methylaminoethanol as an oil. This material (0.6 g., 0.0018 m) and 0.95 g (0.007 m) of aluminum chloride were reacted as described to give 0.42 g (66%) of 8-chloro-4-(3,4-dimethoxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride, m.p. 212°-217°. This material (0.68 g., 0.002 m) and 1.2 ml (0.013 m) of boron tribromide were reacted to give 0.70 g. (94%) of 8-chloro-4-(3,4-dihydroxyphenyl)-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide, m.p. 266°-269°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[Sn](CCCC)(CCCC)CCCC)CCC.Cl[C:47]1[N:48]=[CH:49][C:50]2[CH:55]=[CH:54][NH:53][C:51]=2[N:52]=1>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:47]3[N:48]=[CH:49][C:50]4[CH:55]=[CH:54][NH:53][C:51]=4[N:52]=3)=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:5]2=[N:6][CH:7]=1
Reactant: Clc1ncc2cc[nH]c2n1
Reactant: Fc1cnc2c(c1)c(I)nn2Cc1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)[Sn](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Product: Fc1cnc2c(c1)c(-c1ncc3cc[nH]c3n1)nn2Cc1ccccc1F

Procedure:
Under an argon atmosphere, 2.000 g (5.389 mmol) of the compound from example 24A were dissolved in 200 ml of 1,4-dioxane, and 9.378 g (16.167 mmol) of hexabutyldistannane were added. Added to the mixture were 2.000 g (1.731 mmol) of tetrakis(triphenylphosphine)palladium(0) and 0.910 g (5.928 mmol) of 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (described in Bioorg. Med. Chem. 17(19), 6926-6936; 2009). The mixture was heated to reflux for 60 h. After cooling, the reaction mixture was filtered through Celite and the filtrate was concentrated on a rotary evaporator. The residue was stirred successively with ethyl acetate, acetonitrile and dimethyl sulfoxide. Subsequently, the residue was dissolved in trifluoroacetic acid, and acetonitrile and water were added until slight turbidity. The mixture was filtered and the filtrate was concentrated on a rotary evaporator and the residue was dried under high vacuum. 161 mg (8% of theory) of the title compound were obtained.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][C:9]([OH:22])=[C:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][C:12]=3[OH:21])[C:4]2=[CH:3][CH:2]=1.C([Li])CCC.CC(C)[O-].[La+3:32].CC(C)[O-].CC(C)[O-]>C1COCC1.CCCCCC>[La:32].[CH:17]1[CH:16]=[C:15]2[CH:14]=[CH:13][C:12]([OH:21])=[C:11]([C:10]3[C:4]4[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=4)[CH:7]=[CH:8][C:9]=3[OH:22])[C:20]2=[CH:19][CH:18]=1
Reactant: [La+3]
Agent: CC(C)[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: [La]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 258 mg (0.90 mmol) of (R)-1,1'-bi-2-naphthol in 4.5 ml of THF Was added dropwise 0.56 ml (0.90 mmol) of a 1.6N n-butyllithium solution in hexane, at 0° C. in an argon atmosphere. After completion of the dropping, the temperature was raised to room temperature, 95 mg (0.30 mmol) of powdery lanthanum isopropoxide was added, and the mixture was stirred at room temperature for 15 hours. The insoluble matter was allowed to precipitate and the supernatant was submitted, as a lanthanum/(R)-1,1'-bi-2-naphthol complex solution (0.05 mol/l), to the reaction proper.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21]OS(C)(=O)=O)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCOCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]3)[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: Cc1[nH]c2ccc(CCN3CCN(C)CC3)cc2c1C(=O)OCc1ccccc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a solution of 5-(2-methanesulfonyloxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (424 mg, 1.1 mmol, Example 56, Step D) in dioxane (10 mL) was added 1-methylpiperazine (0.6 mL, 5.5 mmol). The mixture was stirred at 70° C. overnight and then partitioned between methylene chloride and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give a solid residue, which was recrystallized from ethyl acetate to give 191 mg (45%) of the desired product as a white solid: mp 167-168° C.; MS(APCI+): m/z 392.3 (MH+); Anal. Calcd for C24H29N3O2.0.5H2O: C, 71.97; H, 7.55; N, 10.49. Found: C, 72.35; H, 7.54; N, 10.12.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:14]([NH:16][C:17]3[N:22]=[C:21]([CH2:23][C:24]([O:26]CC)=[O:25])[CH:20]=[CH:19][CH:18]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Li+].[OH-]>C1COCC1.CCO>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:29][CH:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[C:14]([NH:16][C:17]3[N:22]=[C:21]([CH2:23][C:24]([OH:26])=[O:25])[CH:20]=[CH:19][CH:18]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)Cc1cccc(NC(=O)C(OC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(NC(=O)C(OC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
Ethyl 2-[6-[[2-(4-cyclopropylsulfonylphenyl)-2-tetrahydropyran-4-yloxy-acetyl]amino]-2-pyridyl]acetate (Example A9; 0.4 g, 0.796 mmol) was taken in THF(12 mL) and EtOH (4 mL), to it was added aqueous solution of LiOH (0.033 g, 0.796 mmol in 4 mL water) and stirred for 1 h at room temperature. Completion of reaction was confirmed by TLC. Organic solvent was removed under reduced pressure. The obtained residue was diluted with water (50 mL) and washed with ethyl acetate (2×20 mL). The aqueous layer was acidified with 1N HCl to pH 1-2 and extracted with Ethyl acetate (3×50 mL). The combined organic layer was washed with brine (50 mL) dried over anhydrous sodium sulphate and the solvent was removed under vacuum to get the pure product (0.320 g).
Reaction SMILES: Cl[C:2]1([S:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])[CH2:8][CH:7]2[N:4]([C:5](=[O:16])[CH:6]2[CH2:9][CH:10]=[CH:11][C:12]([O:14][CH3:15])=[O:13])[CH:3]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].N12CCCCC1C=NCCC2>C(OCC)(=O)C>[CH3:15][O:14][C:12]([CH:11]=[CH:10][CH2:9][CH:6]1[C:5](=[O:16])[N:4]2[CH:7]1[CH2:8][C:2]([S:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:28])=[C:3]2[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[O:13]
Reactant: COC(=O)C=CCC1C(=O)N2C1CC(Cl)(S(=O)c1ccccc1)C2C(=O)OCc1ccccc1
Agent: C1=NCCCN2CCCCC12
Solvent: CCOC(C)=O
Product: COC(=O)C=CCC1C(=O)N2C(C(=O)OCc3ccccc3)=C(S(=O)c3ccccc3)CC12
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
Benzyl 3-chloro-6-(3-methoxycarbonylprop-2-en-1-yl)-7-oxo-3-phenylsulphinyl-1-azabicyclo[3.2.0]heptane-2-carboxylate (68) (0.015 g) was stirred in ethyl acetate (2 ml) at room temperature under argon and treated with 1,5-diazabicyclo[5.4.0]undec-5-ene (0.005 g). After a period of 15 mins. the reaction mixture was washed with brine and dried over sodium sulphate. Removal of the solvent gave a single diastereoisomer of benzyl 6-(3-methoxycarbonylprop-2-ene-1-yl)-7-oxo-3-phenylsulphinyl-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (69) (0.013 g) as a gum; νmax (CHCl3) 2980, 1795, 1730, 1720, 1660 and 1045 cm-1 ; τ(d6 -acetone) 2.3-2.8 (10H, m, phenyls), 3.12 (1H, dt J 16 and 6 Hz, CH2 -CH=), 4.12 (1H, dt J 16 and 1 Hz, =CH-CO), 4.68 (2H, s, benzyl CH2), 5.72 (1H, ddd J 10, 9 and 6 Hz, C5-H), 5.9-6.3 (1H, m, C6-H), 6.39 (3H, s, OCH3), 6.81 (1H, dd J 18 and 9 Hz, C4-H), 7.25 (1H, dd J 18 and 10 Hz, C4-H) and 6.9-7.4 (2H, m, CH2 -CH=).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:11]([O:15][C:16](=[O:35])[N:17]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[O:34])=[CH:29][N:28]=1)[CH2:18][C:19]1[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)([CH3:14])([CH3:13])[CH3:12].COC1N=CC(C=O)=CC=1.[OH-].[K+]>CO.O>[C:11]([O:15][C:16](=[O:35])[N:17]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[NH:8][CH:9]=2)[OH:34])=[CH:29][N:28]=1)[CH2:18][C:19]1[CH:20]=[N:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)cn1
Reactant: Clc1cnc2[nH]ccc2c1
Agent: COc1ccc(C=O)cn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C(O)c3c[nH]c4ncc(Cl)cc34)cn2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
To 5-chloro-1H-pyrrolo[2,3-b]pyridine (532, 0.092 g, 0.60 mmol) in methanol (15.0 mL) were added (5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (585, 0.240 g, 0.70 mmol, prepared according to the protocol of Example 17, Scheme 19, Steps 1-3, replacing 4-chlorobenzaldehyde 40 with 6-methoxy-pyridine-3-carbaldehyde in Step 1) and potassium hydroxide (1.2 g, 0.021 mol). The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (586, 0.110 g, 37%).
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][OH:6].Cl.Cl[C:9]1[CH:18]=[C:17]2[C:12]([C:13](NC3C=CC(Cl)=CC=3F)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29]>C(O)(=O)C.O>[CH3:2][O:3][CH2:4][CH2:5][O:6][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[N+:28]([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1Cl
Reactant: COCCO
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: O
Product: COCCOc1cc2ncncc2cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Sodium (148 mg, 6.4 mmol) was added to 2-methoxyethanol (10 ml), the mixture stirred for 15 minutes to give a complete solution and the volatiles removed by evaporation. The residue was dissolved in DMSO (5 ml) and 7-chloro-4-(4-chloro-2-fluoroanilino)-6-nitroquinazoline hydrochloride (500 mg, 1.3 mmol) was added. The mixture was stirred at ambient temperature for 18 hours then diluted with a solution of acetic acid (1 ml) in water (20 ml). The resulting precipitate was collected by filtration, washed with water, dried and purified by column chromatography eluting with methylene chloride/methanol (96/4). The purified product was recrystallised from methylene chloride/isohexane to give 4-chloro-2-fluoroanilino)-7-(2-methoxyethoxy)-6-nitroquinazoline (304 mg, 60%) as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]1[C:6]2[CH:7]=[C:8]([C:11](=[O:13])[CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.[Br:14]Br>O1CCOCC1>[Br:14][CH2:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH2:3][CH:2]([CH3:1])[C:6]=2[CH:7]=1)=[O:13]
Reactant: CC(=O)c1ccc2c(c1)C(C)CO2
Reactant: BrBr
Solvent: C1COCCO1
Product: CC1COc2ccc(C(=O)CBr)cc21
Reaction time: 0.25 h
Yield: 18.5 %

Procedure:
To a stirred solution of 1-[3-methyl-2,3-dihydro-benzofuran-5-yl]ethanone (1.4 g, 7.94 mmol) (Maybridge Chemical) in dioxane (10 mL) was added dropwise a solution of bromine (1.52 g, 9.5 mmol) in dioxane (30 mL). After stirring 15 minutes the mixture was concentrated in vacuo and the residue chromatographed on silica gel (2:1 hexane-dichloromethane) to provide 375 mg (19%) of 2-bromo-1-(3-methyl-2,3-dihydro-benzo-furan-5-yl)ethanone.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].CCN=C=NCCCN(C)C.Cl.[CH2:24]([NH2:29])[CH2:25][CH:26]([CH3:28])[CH3:27].O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:29][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: CC(C)CCN
Reactant: O=C(O)c1ccc(Br)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)CCNC(=O)c1ccc(Br)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-3-fluorobenzoic acid (2.00 g, 9.13 mmol) was dissolved in dichloromethane (20 mL) and cooled in an ice/water bath as EDCl (2.10 g, 10.9 mmol) was added. After addition, the reaction mixture was allowed to warm to ambient temperature and stirred for 30 minutes before adding isoamylamine (1.59 g, 18.3 mmol). After 12 hours, water was added and the reaction mixture was extracted with ethyl ether. The combined organic layers were washed sequentially with 1N HCl, 1N NaOH and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by chromatography on silica gel eluting with 5% ethyl acetate in heptane to afford the title compound (I-5a).
Reaction SMILES: [ClH:1].Br[C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[F:12]C1C=C(C=CC=1C)N>>[ClH:1].[F:12][C:8]1[CH:3]=[C:4]([NH:10][NH2:11])[CH:5]=[CH:6][C:7]=1[CH3:9]
Reactant: Cc1ccc(NN)c(Br)c1
Reactant: Cc1ccc(N)cc1F
Agent: Cl
Product: Cc1ccc(NN)cc1F

Procedure:
3-Fluoro-4-methylphenylhydrazine hydrochloride (21.4 g) was prepared as described for 2-bromo-4 methylphenylhydrazine hydrochloride in Example 4, except using 3-fluoro-4-methylaniline as starting material. ##STR39##
Reaction SMILES: CO[C@H](C1C=CC=CC=1)C(O)=O.[F:13][C:14]1[C:19]([O:20][CH2:21][CH2:22][OH:23])=[CH:18][C:17]([O:24][CH3:25])=[CH:16][C:15]=1[C@@H:26]([NH:39][C:40]1[CH:48]=[CH:47][C:43]([C:44]([NH2:46])=[NH:45])=[CH:42][CH:41]=1)[C:27]1[NH:31][C:30](=[O:32])[N:29]([C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[N:28]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O.C1([O:65][C:66](=O)[O:67][CH2:68][C:69]([CH3:71])=[CH2:70])C=CC=CC=1>C(O)(=O)C.O.C(OCC)(=O)C>[CH3:71][C:69](=[CH2:70])[CH2:68][O:67][C:66](=[O:65])[N:45]=[C:44]([C:43]1[CH:42]=[CH:41][C:40]([NH:39][C@H:26]([C:15]2[CH:16]=[C:17]([O:24][CH3:25])[CH:18]=[C:19]([O:20][CH2:21][CH2:22][OH:23])[C:14]=2[F:13])[C:27]2[NH:31][C:30](=[O:32])[N:29]([C:33]3[N:34]=[CH:35][CH:36]=[CH:37][N:38]=3)[N:28]=2)=[CH:48][CH:47]=1)[NH2:46]
Reactant: C=C(C)COC(=O)Oc1ccccc1
Reactant: COc1cc(OCCO)c(F)c([C@@H](Nc2ccc(C(=N)N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: CO[C@@H](C(=O)O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(C)COC(=O)N=C(N)c1ccc(N[C@@H](c2nn(-c3ncccn3)c(=O)[nH]2)c2cc(OC)cc(OCCO)c2F)cc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-{[(R)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl](5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]amino}benzamidine (R)-methoxyphenylacetate (0.5 g, 0.755 mmol), potassium carbonate (104 mg, 0.755 mmol), and dimethyl sulfoxide (1.5 mL), carbonic acid 2-methylallyl ester phenyl ester [CAS No. 138621-73-5] (145 mg, 0.755 mmol) was added, and the resulting mixture was stirred at 60° C. for 2 hours and 30 minutes. After cooling the mixture, the reaction solution was added to a mixture of ethyl acetate (5 mL) and water (15 mL), and an aqueous acetic acid solution (prepared from acetic acid (0.1 mL) and water (5 mL)) was added dropwise to the resulting mixture with stirring. The precipitated solid was filtered and sequentially washed with ethyl acetate (10 mL) and water (10 mL). The solid obtained was dried under air flow to obtain the captioned compound (361 mg) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[CH:12]=[C:11]3[NH:14][C:15]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:16][C:10]3=[CH:9][C:8]=2[C:7]([CH3:27])([CH3:26])[C:6]1=[O:28].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:26][C:7]1([CH3:27])[C:8]2[CH:9]=[C:10]3[N:16]=[C:15]([NH:17][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[NH:14][C:11]3=[CH:12][C:13]=2[N:5]([CH2:4][CH2:3][CH:2]=[O:1])[C:6]1=[O:28]
Reactant: CC1(C)C(=O)N(CCCO)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC1(C)C(=O)N(CCC=O)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.7 %

Procedure:
To a solution of N-[5-(3-hydroxy-propyl)-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl]-benzamide (1.12 g) in CH2Cl2 (10 ml) is added Dess Martin reagent (3.5 g; 8.25 mmol) and the mixture is stirred at RT for 4 h. After evaporation to dryness the crude material is purified by flash chromatography on Alox B eluting with CH2Cl2/MeOH gradient to give N-[7,7-dimethyl-6-oxo-5-(3-oxo-propyl)-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl]-benzamide (0.42 g).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C@@H:15]([NH:23]C(OC(C)(C)C)=O)[CH2:16][CH2:17][C:18]2[N:19]=[N:20][NH:21][N:22]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:31])[C@@H:15]([NH2:23])[CH2:16][CH2:17][C:18]2[N:22]=[N:21][NH:20][N:19]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCc2nn[nH]n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 730 mg 4-[(S)-2-tert-butoxycarbonylamino-4-(2H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid butyl ester in 10 ml dichloromethane were added 1.2 ml TFA. After 12 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 900 mg.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C@H:17]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])/[CH:18]=[CH:19]/I)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1/[CH:19]=[CH:18]/[C@@H:17]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: OB(O)c1ccccc1Br
Reactant: COC(=O)CCC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](/C=C/I)O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)CCC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](/C=C/c1ccccc1Br)O[Si](C)(C)C(C)(C)C
Temperature: 60 °C
Reaction time: 12 h
Yield: 68.9 %

Procedure:
The product from Step 1 (64 mg, 0.127 mmol), was placed in a microwave tube together with commercially available 2-bromo phenyl boronic acid (27 mg, 0.129 mmol), potassium carbonate (51 mg, 0.372 mmol), Pd(PPh3)4 (7 mg, 5 mol %), and dioxane (1.5 mL). The tube was sealed, degassed, purged with argon, and heated to 60° C. The reaction mixture was stirred for 12 h, after which time it was quenched with saturated ammonium chloride, extracted with ether, dried, and concentrated. The product was purified by preparatory TLC (silica plate, 8% ethyl acetate/hexanes) to afford 50 mg (70%) of (5S,6R,E)-methyl 8-(2-bromophenyl)-5,6-bis(tert-butyldimethylsilyloxy)oct-7-enoate. 1H NMR (360 MHz, CDCl3): δ 7.49 (dd, J=20 Hz, 7.7 Hz, 2H), 7.24 (t, J=8.3 Hz, 1H), 7.06 (t, J=7.4 Hz, 1H), 6.84 (d, J=15.4 Hz, 1H), 6.10 (dd, J=15.9 Hz, 7.3 Hz), 4.48 (m, 1H), 3.63 (s, 3H), 2.29 (t, J=7.5 Hz), 1.71 (m, 2H), 1.53 (m, 2H), 0.894 (s, 9H), 0.857 (s, 9H), 0.084 (s, 3H), 0.080 (s, 6H), 0.016 (s, 3H). 13C NMR (500 MHz, CDCl3): δ 136.90, 136.61, 132.903, 129.93, 128.59, 127.42, 126.99, 77.0, 76.0, 50.9, 34.35, 33.04, 29.70, 25.99, 20.67, 10.17, −3.95, −4.76.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23]C2C=CC(F)=CC=2)=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1N=NC(Cl)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[Cl:55][C:56]1[CH:63]=[CH:62][CH:61]=[C:60]([F:64])[C:57]=1C[Zn+]>>[CH2:1]([O:8][C:9]1[N:10]=[N:11][C:12]([CH2:23][C:57]2[C:60]([F:64])=[CH:61][CH:62]=[CH:63][C:56]=2[Cl:55])=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cccc(Cl)c1C[Zn+]
Reactant: Fc1ccc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1
Agent: Clc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: [Cl-]
Product: Fc1cccc(Cl)c1Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Yield: 23 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-[(4-fluorophenyl)methyl]pyridazine (Intermediate 51) from 3,4-bis(benzyloxy)-6-chloropyridazine (Intermediate 1) and (2-chloro-6-fluorobenzyl)zinc(II) chloride in 23% yield.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[ClH:12].Cl.[F:14][C:15]1[C:20]([F:21])=[C:19]([F:22])[CH:18]=[CH:17][C:16]=1[NH:23][C:24]([NH:26][C:27]([NH2:29])=[NH:28])=[NH:25]>C(O)C>[ClH:12].[NH2:25][C:24]1[N:23]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[C:20]([F:21])[C:15]=2[F:14])[CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[N:28]=[C:27]([NH2:29])[N:26]=1
Reactant: CCCCCCCCCC=O
Reactant: N=C(N)NC(=N)Nc1ccc(F)c(F)c1F
Agent: Cl
Solvent: CCO
Product: CCCCCCCCCC1N=C(N)N=C(N)N1c1ccc(F)c(F)c1F

Procedure:
100 ml of ethanol, 5.3 ml (28.1 mmol) of 1-decanal and 0.8 ml of concentrated hydrochloric acid were added to 5.0 g (18.7 mmol) of N1-(2,3,4-trifluorophenyl)-biguanide hydrochloride, and the mixture was refluxed for 4 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:2)), and recrystallized from 80% aqueous acetonitrile to obtain 4.7 g of colorless crystals having a melting point of 210 to 212° C.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[C:9]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[N:6][CH:5]=1.[OH-].[Na+].Cl>O1CCOCC1>[C:14]([O:13][C:11]([NH:10][C:9]1[C:4]([C:3]([OH:18])=[O:2])=[CH:5][N:6]=[CH:7][CH:8]=1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)c1cnccc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Temperature: 60 °C

Procedure:
To a solution of 4-tert-Butoxycarbonylamino-nicotinic acid methyl ester (6.02 g, 23.86 mmol) in dioxane (100 mL) was added aq. sodium hydroxide (0.970N solution, 28.05 mL, 27.20 mmol). The solution was heated to 60° C. for 1 hr then cooled. Aqueous hydrochloric acid (1.031M solution, 26.99 mL, 27.20 mmol) was added and the mixture was extracted with chloroform (5×100 mL). The extracts were dried (MgSO4) and evaporated to give 4-tert-Butoxycarbonylamino-nicotinic acid, a cream solid (4.70 g, 83% yield) without further purification.