Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)=[C:11]2[N:12]=[CH:13][N:14]=[C:15]([OH:16])[C:10]2=[N:9]1.C([O-])([O-])=O.[Cs+].[Cs+].CS(C)=O.FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=2)=[C:11]2[N:12]=[CH:13][N:14]([CH2:44][C:45]([F:48])([F:47])[F:46])[C:15](=[O:16])[C:10]2=[N:9]1
Reactant: Oc1ncnc2c(-c3ccc(C(F)(F)F)cc3)n(-c3ccccc3Cl)nc12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: O=c1c2nn(-c3ccccc3Cl)c(-c3ccc(C(F)(F)F)cc3)c2ncn1CC(F)(F)F
Reaction time: 8 h

Procedure:
To a stirred mixture of 2-(2-chlorophenyl)-3-(4-(trifluoromethyl)phenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol (I-2A-2b: 100 mg, 0.26 mmol) and Cs2CO3 (85 mg, 0.26 mmol) in DMF (1.5 ml) was added a DMSO solution (0.1 ml) of 2,2,2-trifluoroethyl trifluoromethanesulfonate (60 mg, 0.26 mmol). After stirring overnight, the reaction mixture was extracted from water with ethyl acetate. The organic solution was washed with half saturated aqueous NaCl and then concentrated in vacuo. The crude residue was purified on a Biotage™ Flash 12S column using 20% ethyl acetate in hexanes as eluant to give the title compound 2A-2 (65 mg, 53%) as a solid: +ES MS (M+1) 473.4; 1H NMR (CD3OD) δ 8.17 (s, 1H), 7.73-7.52 (m, 8H), 4.83 (q, J=9.1 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([CH2:13][CH2:14][OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19](C)([O-])[CH3:20].[K+].C(Br)C=C>CS(C)=O>[CH2:20]([O:15][CH2:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:17][CH:16]=1)[CH:19]=[CH2:18]
Reactant: OCCc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CS(C)=O
Product: C=CCOCCc1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A reaction flask was charged with 4-benzyloxy phenethyl alcohol of formula (6), (12 g, 0.052 mol), potassium tert-butoxide (8.842 g, 0.079 ml) and 50 ml and DMSO. The mixture was stirred under nitrogen at 50° C. for 30 minutes. A solution of allyl bromide (6.8 ml, 0.079 mol) was added drop wise to the reaction mixture with cooling about 20–25° C. The mixture was then stirred at 50° C. for 2 h. and cooled to room temperature. The reaction mixture was subsequently quenched with 150 ml of water. The desired product was extracted from neutralized aqueous mixture with toluene. The toluene extract was then washed with water and concentrated under vacuum to afford the title compound of formula (7), 13.9 g, (98%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Li]CCCC.Cl[P:18]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[C:25]1([P:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: Brc1cccc2cccnc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(P(c2ccccc2)c2cccc3cccnc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
To a stirred solution of 8-bromoquinoline (20.8 g, 100 mmol) in dry THF (200 mL) under nitrogen was added n-BuLi (62.5 mL, 1.6 M in hexanes, 100 mmol) at −78° C. and the mixture was stirred for 30 minutes. Chlorodiphenylphosphine (17.9 mL, 100 mmol) was then added and the solution was allowed to warm up to room temperature and stirred for 2 h. The solution was then cooled to −78° C. and quenched by addition of saturated aqueous NH4Cl solution (100 mL). After warming up to room temperature, the solution was filtered, the precipitated solid collected, taken up in CH2Cl2 (200 mL) and filtered over silica gel eluting with further portions of CH2Cl2 (4×200 mL). The combined filtrates were evaporated to give 1 as a light yellow solid (19 g, 60% yield). 1H NMR (400.13 MHz, CDCl3) δ 8.37 (dd, 1H, J=4.0, 1.6 Hz, C2—H), 8.17 (dd, 1H, J=8.0, 1.6 Hz, C3—H), 7.82 (d, 1H, J=8.4 Hz, C5—H), 7.44 (t, 1H, J=7.6 Hz, C6—H), 7.40 (dd, 1H, J=8.0, 4.0 Hz, C4—H), 7.3-7.2 (m, 10H, Ph-H), 7.14 (ddd, 1H, J=7.2, 3.6, 1.6 Hz, C7—H) ppm; 13C NMR (100.61 MHz, CDCl3) δ 149.8, 149.6 (d, J=17.2 Hz), 138.4 (d, J=12.1 Hz), 137.4 (d, J=11.1 Hz), 136.2, 134.4, 134.2 (d, J=21.2 Hz), 128.8, 128.4 (d, J=19.2), 127.9, 126.57, 121.41 ppm; 31P NMR (161.97 MHz, CDCl3) δ 15.0 ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[CH:11]=[C:10]([CH3:14])[N:9]1[CH3:15].FC1C=CC=CC=1[N:23]1C(=O)C=C(C)N1.IC.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[NH2:23][C:11]1[C:12](=[O:13])[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[N:9]([CH3:15])[C:10]=1[CH3:14]
Reactant: Cc1cc(=O)n(-c2ccccc2F)n1C
Reactant: Cc1cc(=O)n(-c2ccccc2F)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(N)c(=O)n(-c2ccccc2F)n1C
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
2-(2-Fluorophenyl)-1,5-dimethyl-1H-pyrazol-3(2H)-one To a solution of 2-(2-fluorophenyl)-5-methyl-1H-pyrazol-3(2H)-one (500 g, 2602 mmol) in THF (2500 ml) heated to 58° C. was added iodomethane (163 ml) dropwise over 15 mins and the mixture was stirred at 65° C. for 30 mins. K2CO3 (198 g) was added over 20 mins and stirred for 16 hrs. Further iodomethane (16.3 ml) was added and stirring continued for 1 hr. The resulting mixture was cooled to 0° C., filtered and washed with THF (50 ml). The filtrate was evaporated to dryness and purified by column chromatography, eluting with EtOAc/Heptane to give the title compound as a red solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.O>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:32][C:33]1[CH:38]=[CH:37][C:36]([C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)[CH:5]=[C:4]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:3]=2)=[CH:35][CH:34]=1
Reactant: FC(F)(F)Oc1ccc(Nc2cc(N3CCCCC3)cc(Cl)n2)cc1
Reactant: OB(O)c1ccc(F)cc1
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: Fc1ccc(-c2cc(N3CCCCC3)cc(Nc3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 60 %

Procedure:
To a solution of (6′-chloro-3,4,5,6-tetrahydro-2H[1,4′]bipyridinyl-2′-yl)-(4-trifluoromethoxyphenyl)-amine (200 mg, 0.53 mmol) in 1,4-dioxane (8 mL) were added potassium carbonate (148 mg, 1.06 mmol), and tetrakis(triphenylphosphine)palladium(0) (62 mg, 0.053 mmol), followed by 4-fluorophenyl boronic acid (150 mg, 1.6 mmol). This reaction mixture was refluxed for 8 hours, after which time water was added (10 mL) to the reaction mixture, and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulphate, filtered, and the filtrate was concentrated under vacuum. The resulting product was purified through column chromatography using 230-400 mesh silica gel (15% ethyl acetate in petroleum ether) to afford the desired compound as colorless gummy mass (130 mg, yield 60% ).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]#[C:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1.Cl[CH2:34][C:35]1[CH:44]=[C:43]([O:45][CH3:46])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]=1[O:47][CH3:48]>>[CH3:48][O:47][C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:43]([O:45][CH3:46])=[CH:44][C:35]=1[CH2:34][O:1][CH:2]1[CH:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]#[C:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][N:4]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCC#CCOc3ccccc3)cc2)C(O)C1
Reactant: COc1cc(CCl)c(OC)c2ccccc12
Product: COc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCC#CCOc3ccccc3)cc2)c(OC)c2ccccc12

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-(4-phenoxy-but-2-ynyloxy)-phenyl]-piperidine-1-carboxylate with 2-chloromethyl-1,4-dimethoxy-naphthalene there was obtained tert-butyl (3RS,4RS)-3-(1,4-dimethoxy-naphthalen-2-ylmethoxy)-4-[4-(4-phenoxy-but-2-ynyloxy)-phenyl]-piperidine-1-carboxylate as a pale yellow solid; MS: 638 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:11])=[N:5][C:6]([Cl:10])=[CH:7][C:8]=1[CH3:9])#[N:2].S(=O)(=O)(O)[OH:13].[OH-].[Na+]>O>[Cl:11][C:4]1[C:3]([C:1]([NH2:2])=[O:13])=[C:8]([CH3:9])[CH:7]=[C:6]([Cl:10])[N:5]=1
Reactant: Cc1cc(Cl)nc(Cl)c1C#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(Cl)nc(Cl)c1C(N)=O
Temperature: 105 °C
Reaction time: 3 h

Procedure:
A mixture of 3-cyano-2,6-dichloro-4-methylpyridine (270g, 1.44 mole) and concentrated sulfuric acid (530ml) was heated and stirred at 100-110° C. for 3 hours. The resultant mixture was cooled, and poured, with stirring, into 21 of water, to produce a precipitate. The precipitate was neutralized with a sodium hydroxide solution and stirred overnight. The precipitate was then filtered, washed with 31 of water, and dried at 80° C. under vacuum.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[CH3:9][S:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[CH3:21][C:22]1([CH3:30])[O:29][C:27](=[O:28])[CH2:26][C:24](=[O:25])[O:23]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>CCO>[CH3:9][S:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][CH:26]2[C:27](=[O:28])[O:29][C:22]([CH3:30])([CH3:21])[O:23][C:24]2=[O:25])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(C=O)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2ccc(S(C)(=O)=O)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Proline (0.126 g, 1.086 mmol) was added to a solution of 4-(methylsulfonyl)benzaldehyde (1.00 g, 5.43 mmol) and Meldrum's acid (1.38 g, 5.43 mmol) in EtOH (10 mL). The mixture was stirred at room temperature for 1 hour and then diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (1.38 g, 5.43 mmol) was added. Stirring was continued for 3 hours and then EtOH was removed under reduced pressure. The residue was diluted with i-PrOH and filtered to provide the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.C[C@@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:10]1
Reactant: C[C@@H]1CNCCN1
Reactant: Clc1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: c1ccc(N2CCNCC2)nc1
Temperature: 25 °C

Procedure:
Dissolve 2,3-dichloropyridine (8.5 g, 0.057 moles) and (R)-(−)-2-methylpiperazine (5.75 g, 0.057 moles) in DMA(125.0 mL) under nitrogen atmosphere. Add anhydrous powdered K2CO3 (23.75 g, 0.172 moles) to this mixture and stir at 135-140° C. for 48 hours. Cool the reaction mixture to room temperature, dilute with water (400 mL), extract with EtOAc (3×200 mL) and wash the combined organic extract with brine (2×150 mL). Dry over MgSO4, concentrate under vacuum to afford crude product as orange yellow liquid. Distil the crude under high vacuum to afford pyridylpiperazine derivative as yellow viscous oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[CH:13]=[O:14])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:15][C:11]1[CH:10]=[C:9]([CH:13]=[O:14])[N:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=1
Reactant: O=Cc1cccn1-c1cccnc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)cn1-c1cccnc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
To a solution of 6.05 g of 1-(2-chloro-3-pyridinyl)-1H-pyrrole-2-carbaldehyde in 20 ml of N,N-dimethylformamide was added 5.72 g of N-bromosuccinimide. The resulting mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture, and a deposited precipitate was collected by filtration to obtain 4.22 g of 4-bromo-1-(2-chloro-3-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([Br:9])[C:6]([C:10]#[N:11])=[N:5]1)[CH:2]=[CH2:3].C([N-]C(C)C)(C)C.[Li+].[F:20][C:21]([F:41])([F:40])[C:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[N:28]=[CH:27]2)=[O:23]>C1COCC1>[CH2:1]([N:4]1[C:8]([C:22]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:28]=[CH:27]3)([OH:23])[C:21]([F:40])([F:20])[F:41])=[C:7]([Br:9])[C:6]([C:10]#[N:11])=[N:5]1)[CH:2]=[CH2:3]
Reactant: C=CCn1cc(Br)c(C#N)n1
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCn1nc(C#N)c(Br)c1C(O)(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.9 %

Procedure:
To a chilled (−78° C.) solution of 1-allyl-4-bromo-1H-pyrazole-3-carbonitrile (116 mg, 0.550 mmol) in dry THF (2 mL) was added lithium diisopropylamide (367 μL, 1.5 M solution in hexanes, 0.55 mmol). After 5 minutes, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (154 mg, 0.500 mmol) in 2 mL of THF was added. After 15 minutes, the mixture was warmed to room temperature, quenched with 10 mL of saturated aqueous sodium bicarbonate and extracted with three 10 mL portions of ethyl ether. The combined organic layers were washed with 10 mL of brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on SiO2 (0-50% ethyl acetate in hexanes, gradient) to afford 213 mg (82%) of the title product. MS m/z 520.19/522.20 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:45]=[C:46]([N+:48]([O-])=O)[CH:47]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:44])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:43])([F:42])[O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8])([O-])=O>CN(C)C=O.O.[Zn]>[NH2:48][C:46]1[CH:45]=[C:6]([CH:5]=[C:4]([NH2:1])[CH:47]=1)[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17](=[O:44])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:42])([F:43])[O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:39])([F:40])[F:41])=[CH:30][CH:29]=2)=[CH:22][CH:21]=1)=[O:8]
Reactant: O=C(/C=C/c1ccc(C(F)(F)Oc2ccc(OCCCC(F)(F)F)cc2)cc1)OCCCCCCOC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(N)cc(C(=O)OCCCCCCOC(=O)/C=C/c2ccc(C(F)(F)Oc3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 83.1 %

Procedure:
5.95 g (8.38 mmol) of 6-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)-prop-2-enoyl]oxy}hexyl 3,5-dinitrobenzoate are dissolved in a mixture of 54 mL of N,N-di-methylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 200 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 4.53 g of 6-{[(2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)-phenoxy]-methyl}phenyl)prop-2-enoyl]oxy}hexyl 3,5-diaminobenzoate as yellow crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:43])[C@H:3]([NH:38][C:39](=[O:42])[O:40][CH3:41])[C:4](=[O:37])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][NH:33]5)=[N:29][CH:28]=4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1.CCN(C(C)C)C(C)C.[CH3:53][CH:54]([CH3:66])[C@H:55]([NH:59][C:60]1[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=1)[C:56](O)=[O:57].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][CH:2]([CH3:43])[C@H:3]([NH:38][C:39](=[O:42])[O:40][CH3:41])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([C:27]4[NH:31][C:30]([C@@H:32]5[CH2:36][CH2:35][CH2:34][N:33]5[C:56](=[O:57])[C@H:55]([CH:54]([CH3:53])[CH3:66])[NH:59][C:60]5[CH:61]=[N:62][CH:63]=[CH:64][CH:65]=5)=[N:29][CH:28]=4)=[CH:25][CH:26]=3)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:37]
Reactant: CC(C)[C@H](Nc1cccnc1)C(=O)O
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)cc2)[nH]1)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)[C@@H](Nc5cccnc5)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.4 %

Procedure:
To a solution of methyl (S)-3-methyl-1-oxo-1-((S)-2-(5-(4′-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (cj-13) (0.060 g, 0.103 mmol) in DMF (2 mL) was added iPr2NEt (0.18 mL, 1.02 mmol), (S)-3-methyl-2-(pyridin-3-ylamino)butanoic acid (Cap-88) (0.040 g, 0.206 mmol) and HATU (0.078 g, 0.205 mmol). The reaction mixture was stirred for 1.5 h at room temperature and then it was directly purified by prep HPLC (Luna 5u C18/MeCN—H2O—NH4OAc). The resulting solid was repurified by flash chromatography (SiO2/0-10% MeOH—CH2Cl2) and the obtained product was lyophilized from CH3CN—H2O to give the title compound (0.044 g, 56%) as a solid.
Reaction SMILES: [Br:1][C:2]1[C:10]([N+:11]([O-])=O)=[C:9]2[C:5]([C:6]([NH:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[N:7][NH:8]2)=[CH:4][CH:3]=1.N>O.C(O)C>[Br:1][C:2]1[C:10]([NH2:11])=[C:9]2[C:5]([C:6]([NH:14][C:15](=[O:19])[CH2:16][CH2:17][CH3:18])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CCCC(=O)Nc1n[nH]c2c([N+](=O)[O-])c(Br)ccc12
Agent: N
Solvent: CCO
Solvent: O
Product: CCCC(=O)Nc1n[nH]c2c(N)c(Br)ccc12
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
4.25 g of ferrous sulphate heptahydrate dissolved in 25 cm3 of water are added dropwise to 510 mg of N-[6-bromo-7-nitro-1H-indazol-3-yl]butanamide, described in Example 29, in 20 cm3 of ethanol cooled to about 5° C. The temperature rises to about 28° C., the mixture is left stirring for 30 minutes, 5.2 cm3 of 28% aqueous ammonia are then added, the mixture is refluxed for 2 hours, a further 2×1.5 cm3 of 28% aqueous ammonia are then added and the mixture is left stirring for a further 10 minutes and filtered while hot through a sinter funnel packed with Celite. The precipitate is rinsed with 20 cm3 of methanol and the filtrate is concentrated to dryness under reduced pressure (2 kPa; 40° C.). The residue is taken up in 50 cm3 of ethyl acetate and washed with 25 cm3 of saturated sodium hydrogen carbonate solution and then with 25 cm3 of saturated sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate and concentrated under reduced pressure (2 kPa; 40° C.). After drying (90 Pa; 50° C.), 55 mg of N-[6-bromo-7-amino-1H-indazol-3-yl]butanamide are thus obtained in the form of a mauve-coloured solid.
Reaction SMILES: CC(S[C@@H]1[O:10][C@H](CO)[C@H](O)[C@H](O)[C@H]1O)C.[NH:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19].CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.CC1[N+](CC2C=NC(C)=NC=2N)=CSC=1CCO>>[NH:16]1[CH2:23][C@H:22]([OH:10])[CH2:21][C@H:17]1[C:18]([OH:20])=[O:19]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Agent: Cc1ncc(C[n+]2csc(CCO)c2C)c(N)n1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Temperature: 37 °C
Reaction time: 13 h

Procedure:
A plasmid (pHuCol-Fl, FIG. 6) encoding the gene sequence of the first 80 amino acids of human Type 1 (α1) collagen (FIG. 5 (Seq. ID No. 2) placed behind the isopropyl-β-D-thiogalactopyranoside (IPTG)-inducible tac promotor and also encoding β-lactamase is transformed into Escherichia coli proline auxotrophic strain NM519 (pro-) by standard heat shock transformation. Transformation cultures are plated on Luria Broth (LB) containing 100 μg/ml ampicillin and after overnight growth a single ampicillin-resistant colony is used to inoculate 5 ml of LB containing 100 μg/ml ampicillin. After growth for 10-16 hours with shaking (225 rpm) at 37° C., this culture is used to inoculate 1 L of M9 minimal medium (M9 salts, 2% glucose, 0.01 mg/mL thiamine, 100 μg/ml ampicillin, supplemented with all amino acids at 20 μg/mL except proline which is supplemented at 12.5 mg/L) in a 1.5 L shaker flask. After growth at 37° C., 225 rpm, for 15-20 hours post-inoculation, the optical density at 600 nm is constant at approximately 0.5 OD/ml. The cells are harvested by centrifugation (5000 rpm, 5 minutes), the media decanted, and the cells resuspended in 1 L of M9 minimal media containing 100 μg/ml ampicillin, 0.08M L-hydroxyproline, and 0.5M NaC1. Following growth for 1 hour at 37° C., 225 rpm, IPTG is added to 1 mM and the cultures allowed to grow for an additional 5-15 hours. Cells are harvested by centrifugation (5000 rpm, 10 minutes) and lysed by mechanical disruption. The hydroxyproline-containing collagen fragment is purified by ammonium sulfate fractionation and column chromatography.
Reaction SMILES: Cl[CH2:2]Cl.C[Li].[Cl:6][C:7]1[CH:8]=[C:9]([C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=1)[CH:10]=[O:11].O>C(OCC)C.[Ti](Cl)(Cl)(Cl)Cl>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]([OH:11])[CH3:2])[C:12]([N+:15]([O-:17])=[O:16])=[CH:13][N:14]=1
Reactant: O=Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: ClCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Li]C
Solvent: CCOCC
Solvent: O
Product: CC(O)c1cc(Cl)ncc1[N+](=O)[O-]
Temperature: -50 °C
Yield: 99.7 %

Procedure:
An oven dried 250 mL 3 neck r.b.f. equipped with an internal thermometer was charged with diethyl ether (180 mL) and titanium tetrachloride, 1.0 M in dichloromethane (20.5 mL, 20.5 mmoles) under an Argon atmosphere. The solution was cooled in a CO2(a)/acetone −78° C. bath and methyl lithium, 1.6 M in diethyl ether (12.8 mL, 20.5 mmoles) was added via a syringe at a rate such that the internal temperature was </=−50° C. The resultant anion solution was stirred at −50° C. for 1 hour, at which time 2-chloro-5-nitroisonicotinaldehyde (2.54 g, 13.66 mmoles) in diethyl ether (16+4 mL) was added via syringe with the internal temp </=−50° C. After stirring for an additional hour at −50° C., the reaction was poured into H2O (500 mL), and after mixing two light yellow layers formed. Diethyl ether was added (500 mL), the layers were separated, and the organic was washed with H2O (250 mL), with NaCl(sat.) (250 mL), dried over MgSO4, filtered and concentrated yielding 1-(2-chloro-5-nitropyridin-4-yl)ethanol (2.76 g, 100% yield). LCMS (m/z): 203.0 (MH+); LC Rt=2.42 min. 1H NMR (CDCl3): δ 8.99 (s, 1H), 7.88 (s, 1H), 5.52 (m, 1H), 1.56 (d, J=9.0, 3H).