Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([F:18])[CH:11]=1)(=O)OCC)C.[H-].[Na+].[CH3:21][C:22]1[N:23]=[C:24]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[S:25][C:26]=1[C:27](=O)[CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[F:18][C:12]1[CH:11]=[C:10](/[CH:9]=[C:27](/[C:26]2[S:25][C:24]([C:33]3[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:37][CH:38]=3)=[N:23][C:22]=2[CH3:21])\[CH2:28][CH2:29][CH2:30][CH3:31])[CH:15]=[CH:14][C:13]=1[C:16]#[N:17]
Reactant: CCOP(=O)(Cc1ccc(C#N)c(F)c1)OCC
Reactant: CCCCC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC/C(=C\c1ccc(C#N)c(F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Yield: 98.2 %

Procedure:
1.0 g (4-Cyano-3-fluoro-benzyl)-phosphonic acid diethyl ester was dissolved in 50 ml tetrahydrofuran and cooled in an ice bath. At 0° C. 103 mg sodium hydride were added and the mixture stirred for fifteen minutes. Then 1.2 g 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-pentan-1-one, dissolved in 20 ml tetrahydrofuran, were added dropwise. The cooling bath was removed and the reaction mixture stirred at room temperature for two hours. Then 1.0 g (4-Cyano-3-fluoro-benzyl)-phosphonic acid diethyl ester and 103 mg sodium hydride were added and the reaction mixture stirred for an additional hour. Then 20 ml water were added and the mixture extracted five times with portions of 25 ml ethyl acetate. The combined organic layers were dried over MgSO4, then the solvent was removed in vacuo to obtain 1.6 g 2-Fluoro-4-{(E)-2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-hex-1-enyl}-benzonitrile as a yellow oil.
Reaction SMILES: [NH3:1].[O:2]1[CH:8]2[CH:3]1[C:4]([CH3:27])([CH3:26])[O:5][C:6]1[CH:12]=[CH:11][C:10]([S:13]([C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])(=[O:15])=[O:14])=[CH:9][C:7]=12.O>C(O)C>[NH2:1][C@@H:8]1[C:7]2[CH:9]=[C:10]([S:13]([C:16]([F:25])([F:24])[C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])(=[O:14])=[O:15])[CH:11]=[CH:12][C:6]=2[O:5][C:4]([CH3:26])([CH3:27])[C@H:3]1[OH:2]
Reactant: N
Reactant: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)F)cc2C2OC21
Solvent: O
Solvent: CCO
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)F)cc2[C@@H](N)[C@@H]1O
Reaction time: 72 h

Procedure:
30 ml of 28% v/v aqueous ammonia were added to a solution of 1.086 g of 3,4-epoxy-6-heptafluoropropylsulfonyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (prepared as described in Preparation 3) in 30 ml of ethanol, and the resulting mixture was allowed to stand at room temperature for 3 days. At the end of this time, the reaction mixture was poured into water and extracted with methylene chloride. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and then the resulting residue was purified by column chromatography through silica gel, using a 1:1 by volume mixture of cyclohexane and ethyl acetate as the eluent. The fractions containing the desired compound were then recrystallized from a mixture of ethyl acetate and hexane, to afford 0.796 g of the title compound, melting at 176°-177° C.
Reaction SMILES: [C:1]([C:4]1[CH2:5][O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][C:8]=2[CH:9]=1)(=O)[CH3:2].Cl.[NH2:22][OH:23]>CCO.N1C=CC=CC=1>[C:1](=[N:22][OH:23])([C:4]1[CH2:5][O:6][C:7]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][C:8]=2[CH:9]=1)[CH3:2]
Reactant: CC(=O)C1=Cc2cc(Oc3ccccc3)ccc2OC1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)C1=Cc2cc(Oc3ccccc3)ccc2OC1
Reaction time: 48 h

Procedure:
The ketone (2.53 g, 9.5 mmol) is dissolved in 90 ml of an EtOH/pyridine mixture (1:1), and treated with hydroxylamine hydrochloride (0.99 g, 14.3 mmol). The mixture is stirred for 2 days. The reaction mixture is partitioned between ether and water, and the aqueous layer is extracted twice with ether. The combined organic layer is then washed twice with 2N HCl and water, dried (MgSO4), and evaporated. The residue is purified by flash chromatography (10% EtOAc/hexane) to give 3-acetyl-6-phenoxy-2H-1-benzopyran oxime as a crystalline solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([O:13][C:14]3[C:15]4[O:23][CH:22]=[CH:21][C:16]=4[CH:17]=[N:18][C:19]=3[NH2:20])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].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.O>[C:24]1([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([O:13][C:14]4[C:15]5[O:23][CH:22]=[CH:21][C:16]=5[CH:17]=[N:18][C:19]=4[NH2:20])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(Cl)nn12
Reactant: OB(O)c1ccccc1
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
Solvent: O
Product: C[C@H](Oc1c(N)ncc2ccoc12)c1nnc2ccc(-c3ccccc3)nn12

Procedure:
A mixture of 7-[(S)-1-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethoxy]furo[3,2-c]pyridine-6-ylamine (15.0 mg, 0.045 mmol), phenylboronic acid (11.1 mg, 0.091 mmol), Pd(PPh3)4 (5 mg, 0.004 mmol), potassium carbonate (18.8 mg, 0.136 mmol) and 4:1 dioxane:water (2 mL) was heated in a microwave reactor at 100° C. for 30 min. The solution was loaded into a SCX cartridge, washed with MeOH and ejected with 2M NH3 in MeOH. The filtrate was concentrated in vacuo, redissolved in MeOH (0.5 mL) and purified via HPLC. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=2.10 (d, J=6.8 Hz, 3H), 6.55 (q, J=6.6 Hz, 1H), 6.77 (d, J=2.5 Hz, 1H), 7.48-7.56 (m, 3H), 7.59 (d, J=2.3 Hz, 1H), 7.76 (d, J=9.6 Hz, 1H), 7.80-7.85 (m, 2H), 8.05 (s, 1H), 8.21 (d, J=9.6 Hz, 1H). MS (ES+): m/z 373.09 (100) [MH+]. HPLC: tR=2.28 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1]C1N=C(C)C=C(C)N=1.[Br:10][CH:11]([C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17](SC)[N:16]=1)[C:12](=[O:14])[CH3:13].CC1C=C(C)N=C(SC)N=1>>[Br:10][CH:11]([C:15]1[CH:20]=[C:19]([CH3:21])[N:18]=[C:17]([CH3:1])[N:16]=1)[C:12](=[O:14])[CH3:13]
Reactant: Cc1cc(C)nc(C)n1
Reactant: CSc1nc(C)cc(C(Br)C(C)=O)n1
Agent: CSc1nc(C)cc(C)n1
Product: CC(=O)C(Br)c1cc(C)nc(C)n1

Procedure:
This material is prepared from 2,4,6-trimethyl-pyrimidine following the 2-step protocol used to prepare 1-bromo-1-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-propan-2-one (AC3) from 4,6-dimethyl-2-methylsulfanyl-pyrimidine (AC1).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.C([O:17][B:18]([CH:24]=[CH2:25])OCCCC)CCC.Cl>C1COCC1.O>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([CH:25]=[CH:24][BH:18][OH:17])[CH:8]=1
Reactant: C=CB(OCCCC)OCCCC
Reactant: Brc1cccnc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: OBC=Cc1cccnc1
Reaction time: 1 h
Yield: 78 %

Procedure:
Isopropylmagnesium chloride (2.0 M in THF) (5.0 mL, 10 mmol) was added to a solution of 3-bromopyridine (1.60 g, 10.0 mmol) in THF (15 mL) under nitrogen atmosphere at room temperature and the mixture was stirred for 1 h. Vinylboronic acid dibutyl ester (3.4 mL) was added to the reaction dropwise and the mixture was stirred at room temperature for 18 h. Water was added and the pH was adjusted to 7 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (1.04 g, 78%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:19](=[O:20])[NH:18][N:17]=[C:7]3[CH2:8][C:9]([CH3:16])([CH3:15])[CH2:10][C:11]4[NH:12][C:13]([CH:14]=1)=[C:5]2[C:6]=43.[CH3:21][N:22]([CH2:24][CH2:25]Cl)[CH3:23].CN(C)CCN1C2CC(C)(C)CC3=NNC(=O)C4C(C=23)=C1C=CC=4>>[CH3:21][N:22]([CH3:23])[CH2:24][CH2:25][N:12]1[C:11]2[CH2:10][C:9]([CH3:16])([CH3:15])[CH2:8][C:7]3=[N:17][NH:18][C:19](=[O:20])[C:4]4[C:5]([C:6]=23)=[C:13]1[CH:14]=[C:2]([F:1])[CH:3]=4
Reactant: CN(C)CCCl
Reactant: CC1(C)CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1
Agent: CN(C)CCn1c2c3c4c(cccc41)C(=O)NN=C3CC(C)(C)C2
Product: CN(C)CCn1c2c3c4c(cc(F)cc41)C(=O)NN=C3CC(C)(C)C2

Procedure:
Compound 40 was prepared from 8-fluoro-2,2-dimethyl-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one and N,N-dimethylamino-2-chloroethane according to the procedures similar to those for Compound 28. 1H NMR (DMSO-d6) δ 10.1 (s, 1H), 7.56 (dd, 1H, J=9.6, 1.8 Hz), 7.21 (dd, 1H, J=10.2, 1.8 Hz), 4.22 (m, 2H), 2.74 (s, 2H), 2.51 (m, 2H), 2.26 (s, 2H), 2.17 (s, 6H), and 1.06 (s, 6H). MS (ESI) m/e [M+1]+ 343.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([C:7]1[S:8][CH:9]=[C:10]([C:12]([O:14]CC)=[O:13])[N:11]=1)[CH2:5][CH3:6].Cl>C1COCC1.O>[CH2:4]([C:7]1[S:8][CH:9]=[C:10]([C:12]([OH:14])=[O:13])[N:11]=1)[CH2:5][CH3:6]
Reactant: CCCc1nc(C(=O)OCC)cs1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (0.2 g) was added to a solution of ethyl 2-propylthiazole-4-carboxylate (example 56, step b) (0.24 g) in a mixture of THF (4 mL) and water (1 mL). The resulting suspension was stirred overnight at RT. The reaction was acidified with aqueous HCl solution (2M, 3 mL) and evaporated. The residue was partitioned between brine (5 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2×20 mL). The combined organic solutions were dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a white solid. Yield 0.17 g.
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[C:11]([SH:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])([CH3:5])[CH3:4].Br[CH:20]([CH2:24][CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22].Cl>O.C(O)C>[C:3]([C:7]1[CH:12]=[C:11]([S:13][CH:20]([CH2:24][CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCC(Br)C(=O)O
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCC(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A base solution (22 grams of NaOH in 41 milliliters (ml) of water) was added to a solution of 2,6-di-t-butyl-4-mercaptophenol (64.3 grams; 0.27 mole) in 540 ml. of absolute ethanol with stirring while cooling the reaction mixture under nitrogen. Following the base addition, a solution of 2-bromohexanoic acid (52.8 grams; 0.27 mole) in 27 ml. of ethanol was added and the resulting reaction mixture was stirred at room temperature for about 6 hours and left standing overnight. The reaction mixture was then diluted with about 400 ml. of water and acidified with cold 6N HCl. The yellow brown precipitate resulting from the acidification was obtained by filtration, washed with water and recrystallized from a methylenechloride-hexane mixture. As a result of these operations, the desired 2-((3,5-di-tert-butyl-4-hydroxyphenyl)thio)hexanoic acid compound was obtained as a white crystalline solid having a melting point of 140°-142° C. Analysis calculated for C20H32O3S: C, 68.15; H, 9.14; S, 9.10. Found: C, 68.14; H, 9.34; S, 8.86.
Reaction SMILES: C1(C)C(C)=CC=CC=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]([N:24]=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)C2C=CC=CC=2)[CH:14]=[CH:15][CH:16]=1.[C:32]1(=[O:38])[O:37][C:35](=[O:36])[CH2:34][CH2:33]1>CCOCC>[CH2:25]([N:24]1[C:35](=[O:36])[CH2:34][CH:33]([C:32]([OH:37])=[O:38])[CH:17]1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH3:9])[CH:12]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1cccc(C(N=Cc2ccccc2)c2ccccc2)c1
Reactant: O=C1CCC(=O)O1
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: COc1cccc(C2C(C(=O)O)CC(=O)N2Cc2ccccc2)c1

Procedure:
To 450 ml. of xylene was added 143.3 gm of 3-methoxyphenylbenzylidenebenzylamine and 63.9 gm. of succinic anhydride. The solution was refluxed for 15 hours, cooled and extracted with saturated sodium bicarbonate solution. After washing the basic solution with ether, the aqueous phase was acidified with concentrated hydrochloric acid to provide a white gum. The gum was dissolved in ether, dried (Na2SO4), filtered and concentrated in vacuo to a semi-solid which was titurated with anhydrous ethyl ether and the resultant solid removed by filtration and discarded. Concentration in vacuo provided 18.5 g of the desired product as a gum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[C:16]([CH2:18][CH2:19][CH2:20][NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:24][CH:23]=1)#[N:17]>>[C:16]([CH2:18][CH2:19][CH2:20][N:21]([C:22]1[CH:23]=[CH:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)[C:13]([CH:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=2)[CH2:7][CH2:8][CH2:9]1)=[O:15])#[N:17]
Reactant: CC(C)c1ccc(NCCCC#N)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(CCCC#N)c1ccc(C(C)C)cc1)CCC2
Yield: 52.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.56 g) and (3-cyanopropyl) (4-isopropylphenyl)amine (1.79 g) as starting materials, N-(3-cyanopropyl)-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.56 g) was obtained. melting point: 74-750° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4].CN(C)C=O.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:43](Br)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:4]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirred solution of piperazine-1,2,4-tricarboxylic acid 1-benzyl ester 4-tert-butyl ester 2-methyl ester (20.0 g, 53 mmol), prepared as described by Bigge et al. (Tetrahedron Let. 1989, 30, 5193), in tetrahydrofuran (500 mL) was added N,N-dimethylformamide (50 mL). The reaction was cooled to about −78° C., and a 1M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (80 mL) was added. The reaction was stirred at about −78° C. for about 1 hour, and then benzyl bromide (9.4 mL, 79 mmol) was added. The reaction was stirred for about 30 minutes more at about −78° C., then warmed to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution, and the mixture was extracted three times with ethyl acetate. The combined organic layers were extracted twice with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 31 g of crude product. Purification by silica gel chromatography using 10-20% ethyl acetate/hexanes as eluent afforded the title compound of part 1-A (20.33 g, 82%): +APcl MS (M−55)+ 413, (M−99)+ 369; 1H NMR=400 MHz (CDCl3) δ: 7.37 (arom, m, 5H), 7.22 (arom, m, 3H), 7.00 (arom, m, 2H), 1.41 (BOC, d, 9H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:15]1(B(O)O)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.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>[N+:12]([C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([C:23]2[C:24]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:20]=[CH:21][CH:22]=2)[CH:11]=1)([O-:14])=[O:13]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1Br
Reactant: OB(O)c1cccc2ccccc12
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: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1-c1cccc2ccccc12

Procedure:
Methyl 2-bromo-4-nitrobenzoate (3.86 g, 14.85 mmol) was coupled with 1-naphthylboronic acid (3.06 g, 17.79 mmol) in DMF in the presence of K2CO3 (3.0 eq) and Pd(PPh3)4 (0.03 eq) at 110° C. for 15 hrs. After flash column chromotography purification, the desired compound was obtained as a pale yellow oil (3.86 g, yield 85%). 1H NMR (CDCl3) δ 8.34 (d, J=8.5 Hz, 1H), 8.28 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.92 (m, 2H), 7.47-7.56 (m, 2H), 7.41 (d, J=3.8 Hz, 2H), 7.34 (d, J=6.8 Hz, 1H), 3.40 (s, 3H); 13C NMR (CDCl3) δ 166.4, 149.2, 142.7, 137.2, 136.8, 133.2, 131.3, 131.0, 128.6, 128.4, 126.6, 126.2, 126.0, 125.0, 124.7, 122.3, 52.3.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>N1C=CC=CC=1>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][N:15]2[S:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])[CH:22]=1
Reactant: c1cncc(C2CCCCN2)c1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCCCC2c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 842 mg portion of 4-(acetylamino)benzene sulfonyl chloride was added under ice-cooling to a pyridine solution (10 ml) of 3-(piperidin-2-yl)pyridine and stirred at room temperature for 2 hours. The solvent was concentrated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate and then washed with water, 1 M hydrochloric acid and saturated brine. This was dried with anhydrous sodium sulfate and then concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel column chromatography using chloroform:methanol (98:2) as the elution solvent, thereby obtaining 1.00 g of N-(4-{[2-(pyridin-3-yl)piperidin-1-yl]sulfonyl}phenyl)acetamide as a yellow foamy substance. FAB-MS (Pos): 360 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[Cl:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:38]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:38])=[O:26])=[C:21]([O:28][C@@H:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[Cl:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O[C@H](C)c1ccccc1Cl
Solvent: CO
Product: C[C@@H](Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O)c1ccccc1Cl

Procedure:
In a similar manner as described for example A5, 2.60 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[(1R)-1-(2-chlorophenyl)ethoxy]thiophene-2-carboxylate and 92 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: N[C@@H](CCC(N[C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=O)[CH2:12]S)=O)C(O)=O.CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=[O:29])N2[C@H]1C(O)=O.N1CCC[C@H]1C(O)=O>>[NH:16]1[CH2:14][C@H:11]([OH:29])[CH2:12][C@H:17]1[C:18]([OH:20])=[O:19]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Reaction time: 8 h

Procedure:
A plasmid (pD4-α1, FIG. 67) encoding the gene for the carboxy terminal 219 amino acids of human Type I (α1) collagen with optimized E. coli codon usage fused to the 3′-end of the gene for glutathione S-transferase and under control of the tac promoter and containing the gene for ampicillin resistance was used to transform by electroporation proline auxotrophic E. coli strain JM109 (F-). Transformation cultures were plated on LB agar containing 100 μg/ml ampicillin. After overnight incubation at 37° C., a single colony from a fresh transformation plate was used to inoculate 100 ml of LB media containing 100 μg/ml ampicillin. This culture was grown to an OD600nm of 0.5 and 100 μl aliquots transferred to 1.5 ml tubes. The tubes were stored at −80° C. For expression, a tube was thawed on ice and used to inoculate 25 ml of LB media containing 400 μg/ml ampicillin. After overnight growth at 37° C., a four ml aliquot was withdrawn, centrifuged, the cell pellet washed once with 1 ml of 2×YT media containing 400 μg/ml ampicillin, and the washed cells used to inoculate 1 L of 2×YT medium containing 400 μg/ml ampicillin. This culture was grown at 37° C. to an OD600nm of 0.8. The culture was centrifuged and the cell pellet washed once with 100 ml of M9 medium (1× M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 400 μμg/ml ampicillin). The cells were resuspended in 910 ml of M9 medium (1× M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 400 μg/ml ampicillin) and allowed to grow at 37° C. for 30 minutes. NaCl (80 ml of 5 M), hydroxyproline (7.5 ml of 2M), and IPTG (500 μl of 1 M) were added and growth continued for 3 hours. Cells were harvested by centrifugation and stored at ˜20° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.Br[CH2:18][C:19](=[O:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:21]=[C:19]([CH3:20])[CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(=O)CBr
Reactant: COC(=O)C(C(=O)OC)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc(OCC(C)=O)cc1

Procedure:
Following a procedure similar to that described in Preparation 3, but using 0.5 g of dimethyl 4-hydroxyphenylmalonate, 0.612 g of bromoacetone, 0.616 g of potassium carbonate and 90 ml of dimethylformamide, and then purifying the reaction product by column chromatography through silica gel, using a 2:3 by volume mixture of ethyl acetate and hexane as the eluent, the title compound was obtained having an Rf=0.37 (thin layer chromatography over silica gel, using a 2:3 by volume mixture of ethyl acetate and hexane as the developing solvent).