Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14]/[N:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([C:25]([CH2:52][CH2:53][CH2:54][CH3:55])=[CH:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][C:28]=1[C:40]([N:42]1[CH2:51][CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)=[O:41])([O-])=O>>[C:34]([O:33][C:31]([C:30]1[CH:38]=[CH:39][C:27]([C:26]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:15][N:14]([C:11]3[CH:12]=[CH:13][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:9][CH:10]=3)[C:25]=2[CH2:52][CH2:53][CH2:54][CH3:55])=[C:28]([C:40]([N:42]2[CH2:51][CH2:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43]2)=[O:41])[CH:29]=1)=[O:32])([CH3:35])([CH3:36])[CH3:37]
Reactant: CCOC(=O)/C=N/Nc1ccc(Oc2ccccc2)cc1
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccc(Oc2ccccc2)cc1
Yield: 51.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(4-phenoxyphenyl)hydrazono)acetate (55 mg, 0.19 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (90 mg, 0.19 mmol) were converted to the title compound (68 mg, 50%) as a pale yellow oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.09 (dd, J=8, 2 Hz, 1H), 8.05-8.03 (m, 1H), 7.44-6.82 (m, 14H), 5.02-4.98 (m, 1H), 4.48-4.39 (m, 1H), 4.34-4.27 (m, 2H), 4.14-3.98 (m, 1H), 3.58-3.35 (m, 1H), 2.83-2.50 (m, 4H), 1.61 (s, 9H), 1.27 (t, J=8 Hz, 1.5H), 1.23 (t, J=8 Hz, 1.5H), 1.16-0.89 (m, 4H), 0.65-0.60 (m, 3H); MS(ESI+) m/z 700.3 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Cl[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:46]=1[N:45]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[C:44](=[O:55])[CH2:43][C:42]2([CH3:57])[CH3:56]>>[CH3:56][C:42]1([CH3:57])[C:41]2[C:46](=[C:37]([CH2:36][O:1][CH:2]3[CH:7]([C:8]4[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH3:27])=[CH:10][CH:9]=4)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]3)[CH:38]=[CH:39][CH:40]=2)[N:45]([CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:52])([CH3:54])[CH3:53])[C:44](=[O:55])[CH2:43]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Reactant: CC1(C)CC(=O)N(COCC[Si](C)(C)C)c2c(CCl)cccc21
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc3c2N(COCC[Si](C)(C)C)C(=O)CC3(C)C)cc1

Procedure:
Analogously to Method D, 0.28 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.21 g of 8-chloromethyl-4,4-dimethyl-1-(2-trimethylsilanylethoxymethyl)-3,4-dihydro-1H-quinolin-2-one are reacted. The title compound is obtained as a yellowish oil. Rf=0.33 (1:2 EtOAc-heptane); Rt=6.81.
Reaction SMILES: [CH2:1]([CH:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH:16]=[CH:17][CH3:18])=[CH:15][C:9]=2[CH2:8][O:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C(O)C.[Pd]>[CH2:1]([CH:6]1[O:11][C:10]2[CH:12]=[CH:13][C:14]([CH2:16][CH2:17][CH3:18])=[CH:15][C:9]=2[CH2:8][O:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CC=Cc1ccc2c(c1)COC(CCCCC)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCC1OCc2cc(CCC)ccc2O1

Procedure:
2.5 g of crude 2-pentyl-6-propenyl-1,3-benzodioxan are dissolved in 75 ml of ethanol and hydrogenated with 0.25 g of palladium/carbon (5% by weight) at room temperature until the hydrogen uptake comes to a standstill. The mixture is filtered and concentrated. The crude product is purified by chromatography on a column of 32 g of basic aluminium oxide with hexane/ether (9:1). Pure 2-pentyl-6-propyl-1,3-benzodioxan is obtained as a colorless oil.
Reaction SMILES: I[C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][C:2]3[CH:17]=[CH:16][C:5]([O:6][CH2:7][CH2:8][NH:9][C:10]4[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=4)=[CH:4][CH:3]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: Ic1ccc(OCCNc2ccncc2)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCNc4ccncc4)cc3)nc2)cc1

Procedure:
Prepared according to general working method I from [2-(4-iodo-phenoxy)-ethyl]-pyridin-4-yl-amine (95 mg, 0.28 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (70 mg, 0.33 mmol).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.Cl[C:11]1[CH:12]=[CH:13][C:14]([N+:18]([O-:20])=[O:19])=[C:15]([CH:17]=1)[NH2:16]>C(O)C>[NH2:16][C:15]1[CH:17]=[C:11]([S:9][C:6]2[CH:7]=[CH:8][C:3]([Br:2])=[CH:4][CH:5]=2)[CH:12]=[CH:13][C:14]=1[N+:18]([O-:20])=[O:19]
Reactant: Sc1ccc(Br)cc1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Na]
Solvent: CCO
Product: Nc1cc(Sc2ccc(Br)cc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 6262.1 %

Procedure:
Sodium (0.269 g) was added to ethanol (20 ml) and the resultant solution was allowed to cool to ambient temperature then 4-bromothiophenol (2.21 g) was added. The mixture was stirred for 5 minutes then 5-chloro-2-nitroaniline (2 g) was added. The mixture was then heated under reflux under argon for 3 hours then allowed to cool down. The resultant solid was collected by filtration , washed with ethanol then dried to give the title compound (236 g) as a solid. NMR: 6.3 8 (dd, 1H), 6.65 (m, 1H), 7.42 (m, 4H), 7.7 (m, 2H), 7.9 (d, 1H); MS: 327 (M+H)+.
Reaction SMILES: C[N:2]([C@@H:10]([CH3:26])[C:11](=[O:25])[NH:12][C@H:13]1[CH2:19][O:18][C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[NH:15][C:14]1=[O:24])[C:3](=O)OC(C)(C)C.O[CH2:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH:31]=[CH:32][N:33]2[C:38]1[CH:45]=[CH:44][CH:43]=[CH:42][C:39]=1[C:40]#[N:41]>>[C:40]([C:39]1[CH:42]=[CH:43][CH:44]=[CH:45][C:38]=1[N:33]1[C:34]2[C:30](=[C:29]([CH2:28][N:15]3[C:14](=[O:24])[C@@H:13]([NH:12][C:11](=[O:25])[C@@H:10]([NH:2][CH3:3])[CH3:26])[CH2:19][O:18][C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]3=4)[CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32]1)#[N:41]
Reactant: N#Cc1ccccc1-n1ccc2c(CO)cccc21
Reactant: C[C@@H](C(=O)N[C@H]1COc2ccccc2NC1=O)N(C)C(=O)OC(C)(C)C
Product: CN[C@@H](C)C(=O)N[C@H]1COc2ccccc2N(Cc2cccc3c2ccn3-c2ccccc2C#N)C1=O
Temperature: 60 °C
Yield: 10.3 %

Procedure:
In a similar manner to that described for Example 57 except in Step 1 the mixture was heated at 60° C. for 2.5 d and in Step 2 the material was purified by silica gel chromatography, tert-butyl methyl((S)-1-oxo-1-((S)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylamino) propan-2-yl)carbamate (250 mg, 688 μmol, Eq: 1.00), 2-(4-(hydroxymethyl)-1H-indol-1-yl)benzonitrile (440 mg, 1.77 mmol, Eq: 2.58) was converted to the title compound (35 mg) as a white solid. MS m/z 494 (MH+)
Reaction SMILES: CC1C(C2CCCC(C3C(C)=CC=CN=3)N2)=NC=CC=1.[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27](CBr)=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N+:32]([O-:34])=[O:33])[CH:25]=1
Reactant: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.829 g, 3.10 mmol), 4-bromomethyl-3-nitrobenzoic acid methyl ester (1.26 g, 4.61 mmol), KI (115 mg, 0.69 mmol), and DIPEA (1.20 mL, 6.89 mmol) in DMF (16 mL) was heated at 60° C. for 18 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 1.40 g (98%) of 4-3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-nitro-benzoic acid methyl ester as a tan solid. To a solution of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-nitro-benzoic acid methyl ester (1.40 g,3.03 mmol) in MeOH (15 mL) and EtOAc (15 mL) was added palladium (50% wet with water), 10 wt. % on activated carbon (0.30 g). The resultant mixture was hydrogenated at 30 psi on a Parr shaker for 3 hours. The mixture was vacuum filtered through celite and the cake was washed with MeOH and EtOAc. The solvent was removed from the filtrate under reduced pressure and the thus obtained oil was purified by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) and provided 0.90 g (69%) of 3-amino-4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzoic acid methyl ester.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]([O:32]CC)=[O:31])[CH:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.O>[OH-].[K+].CO>[OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]([OH:32])=[O:31])[CH:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)c1cnn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
40 mg of the ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carboxylate prepared in Example 3 was dissolved in 2 mL of 1 N KOH in methanol. 200 mL of water was then added and the mixture stirred at at 50° C. for 24 hours. The solvent was then removed and the residue dissolved in 3 mL water and brought to a pH of 3-4 by addition of 37% HCl. The resulting solid was collected by filtration and washed with water and ether then air dried to provide the product, 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carboxylic acid.
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]([CH2:23][OH:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:10])C1C=CC=CC=1.[CH2:25]([O:32][C:33]([NH:35][C@H:36](C(O)=O)[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CO.O1CCCC1.[C].[Pd].C(OCC)(=O)C>[CH2:25]([O:32][C:33]([NH:35][C@H:36]([C:9]([NH:11][C@H:12]([CH2:23][OH:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:10])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C(N[C@H](CO)Cc1c[nH]c2ccccc12)OCc1ccccc1
Agent: [Pd]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12)OCc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 62 %

Procedure:
A mixture of N-benzyloxycarbonyl-(L)-tryptophanol (0.974 g) in methanol (10 ml), palladium-carbon (10%, 0.195 g) was subjected to catalytic hydrogenation at room temperature under 1 atmospheric pressure. After the palladium-carbon was filtered off, the filtrate was concentrated under reduced pressure to yield an oily substance. This oily substance and N-benzyloxycarbonyl-(L)-phenylalanine (0.90 g) were dissolved in tetrahydrofuran (THF) (20 ml), and 1-hydroxybenzotriazole (HOBt) (0.506 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD·HCl) (0.69 g) were added at 0° C. After stirring at room temperature for 21 hours, the reaction mixture was poured over ethyl acetate. The ethyl acetate layer was washed by sequential additions of a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated saline and then dried (MgSO4). After the solvent was distilled off, the oily residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:1) to yield N-benzyloxycarbonyl-(L)-phenylalanyl-(L)-tryptophanol (0.878 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[C:4]([C:3]1[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=1[Cl:1])(=[O:5])[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 16 h
Yield: 156 %

Procedure:
was prepared as follows. To a 2-liter flask equipped with a mechanical stirrer, argon inlet, Dean Stark trap, condenser, stopper and situated in an oil bath was added benzene (200 grams). The oil bath temperature was raised to 100° C. and 19 grams of benzene were removed. There was no indication of water. The flask was removed from the oil bath and allowed to cool to 25° C. 2,4-Dichlorobenzoyl chloride (0.683 mol, 143 grams) was added to form a solution. Thereafter, anhydrous aluminum chloride (0.8175 mol, 109 grams) was added portion-wise over 15 minutes with vigorous gas evolution. Large volumes of hydrochloric acid were evolved as determined by odor. The solution turned orange-yellow and then red. The reaction was stirred for 16 hours under argon and was then added to 1 liter of ice water in a 2-liter beaker. The mixture was stirred until it became white and was then extracted with methylene chloride (1 liter). The methylene chloride layer was dried over sodium bicarbonate and filtered. The filtrate was concentrated using a rotary evaporator and a vacuum pump to yield an oil which, upon cooling, became a solid crystalline mass (154.8 grams). Recrystallization from methanol gave 133.8 grams of benzoyl-2,4-dichlorobenzene as white needles (melting point 41-43° C.) in the first crop.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[NH2:20][C:21]1[C:26]([Br:27])=[CH:25][C:24]([SH:28])=[CH:23][C:22]=1[Br:29]>>[NH2:20][C:21]1[C:26]([Br:27])=[CH:25][C:24]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)=[CH:23][C:22]=1[Br:29]
Reactant: Nc1c(Br)cc(S)cc1Br
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3cc(Br)c(N)c(Br)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-amino-3,5-dibromo-thiophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:27])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][C:12]=2[C:24]([CH3:26])=[CH2:25])=[CH:4][CH:3]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:27])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:13][C:12]=2[CH:24]([CH3:25])[CH3:26])=[CH:4][CH:3]=1
Reactant: C=C(C)c1cc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(Cl)cc1
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCOCC2)cc(C(C)C)c1C(=O)NCc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 57.1 %

Procedure:
A solution of N-[(4-chlorophenyl)-methyl]-2-isopropenyl-6-methyl-4-morpholin-4-yl-benzamide (0.19 g, 0.49 mmol) in ethyl acetate is degassed and flushed with argon for 10 min followed by the addition of Pearlman's catalyst (20% Pd(OH)2/C, 0.08 g). The resulting mixture is stirred under an atmosphere of hydrogen for 2 h. After completion of reaction (monitored by NMR), the reaction mixture is filtered through a pad of celite. The filtrate is concentrated and the residue is purified by preparative HPLC affording N-[(4-chlorophenyl)-methyl]-2-isopropyl-6-methyl-4-morpholin-4-yl-benzamide (example 14) (0.075 g, 0.28 mmol, 57%). [M+H]+ 387.2.
Reaction SMILES: C(OC([O:6][C:7]1[CH:8]=[CH:9][C:10]([N+:16]([O-:18])=[O:17])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13])=O)C>[OH-].[K+].O>[C:12]([C:11]1[CH:15]=[C:7]([OH:6])[CH:8]=[CH:9][C:10]=1[N+:16]([O-:18])=[O:17])([OH:14])=[O:13]
Reactant: CCOC(=O)Oc1ccc([N+](=O)[O-])c(C(=O)O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(O)ccc1[N+](=O)[O-]

Procedure:
5-Ethoxycarbonyloxy-2-nitrobenzoic acid (6.12 g) was dissolved in a solution of potassium hydroxide (3.2 g of 85% pure material) in water (10 ml) and heated under reflux for 2 hours, to cleave off the ethoxy-carbonyl residue and form the di-potassium salt of 3-carboxy-4-nitrophenol. The solution so prepared was mixed with toluene and distilled until the water had been removed. Dimethyl sulphoxide (50 ml) was added and the mixture distilled until the vapour temperature reached 190°. A further quantity (50 ml) of dimethyl sulphoxide (50 ml) was then added, together with 3-chloro-4,5-difluorobenzotrifluoride (5.43 g), and the mixture heated at 100° for 4 hours. The mixture was diluted with water (200 ml) and acidified with dilute hydrochloric acid. The mixture was extracted twice with ether and the extracts washed with water, dried and evaporated. The brown oil remaining was crystallised from carbon tetrachloride to give the required compound (2 g) with a melting point of 145°-148°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:27]2[CH:28]=[CH:29][C:24]([OH:23])=[CH:25][CH:26]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
Reactant: OB(O)c1ccc(O)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: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccc(O)cc2)c1
Yield: 14.5 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 4-hydroxyphenylboronic acid (0.024 g; 0.177 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 18 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.010 g (14%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-hydroxybiphenyl-3-carboxamide as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1B1OC(C)(C)C(C)(C)O1)[O:6][CH2:7][C:8]([CH3:20])([CH3:19])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)=[CH:36][N:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[N:44]=2)=[CH:36][N:35]=1)[O:6][CH2:7][C:8]([CH3:19])([CH3:20])[C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: COc1cc(OCC(C)(C)C(=O)OCc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)nc1
Product: COc1cc(OCC(C)(C)C(=O)OCc2ccccc2)ccc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)cn1
Yield: 83.3 %

Procedure:
By using benzyl 3-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-2,2-dimethylpropanoate (1.03 g) and 2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (494 mg), the procedure was carried out in the same manner as in Reference example 1-3) to obtain benzyl 3-[3-methoxy-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]-2,2-dimethylpropanoate (639 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14](=[O:24])[NH:15][CH2:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)[CH:11]=[C:10]([C:25](O)=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[F:51][C:52]1([F:56])[CH2:55][NH:54][CH2:53]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:51][C:52]1([F:56])[CH2:55][N:54]([C:25]([C:10]2[CH:11]=[C:12]([C:14]([NH:15][CH2:16][C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[N:19][CH:18]=3)=[O:24])[CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:26])[CH2:53]1
Reactant: FC1(F)CNC1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)NCc3cnc(C)nc3)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3cnc(C)nc3)cc(C(=O)N3CC(F)(F)C3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4′-methyl-5-((2-methylpyrimidin-5-yl)methylcarbamoyl)biphenyl-3-carboxylic acid (11 mg, 0.030 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (12 mg, 0.061 mmol), 1-hydroxybenzotriazole hydrate (4.7 mg, 0.030 mmol), CH2Cl2 (2 mL) were added 3,3-difluoroazetidine (4.2 mg, 0.046 mmol) and N,N-diisopropylethylamine (11 μL, 0.061 mmol). The mixture was stirred at room temperature overnight, and then concentrated in vacuo. The residue was purified by preparative HPLC (100×21.2 mm C18 column, 30-70% MeCN/water[10 mM Et2NH]) to afford a white foam.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:21])[C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:17]([C:15]1[CH:16]=[C:11]([C:10]2[O:21][C:2]3[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=3[N:9]=2)[C:12]([F:20])=[CH:13][CH:14]=1)([O-:19])=[O:18]
Reactant: Cc1ccc(NC(=O)c2cc([N+](=O)[O-])ccc2F)c(O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: Cc1ccc2nc(-c3cc([N+](=O)[O-])ccc3F)oc2c1

Procedure:
Prepared by the method of Example 15b), from N-(2-hydroxy-4-methylphenyl)-2-fluoro-5-nitrobenzamide (300 mg, 2.8 mmol) and p-toluenesulfonic acid monohydrate (1.17 g, 6.16 mmol) the subtitle compound was obtained (403 mg, 53%). MS m/z 273.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[CH3:12][C:13]1[CH:14]=[C:15]([OH:20])[C:16]([OH:19])=[CH:17][CH:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:18]2[CH:17]=[C:16]([OH:19])[C:15]([OH:20])=[CH:14][C:13]=2[CH3:12])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: COc1ccc(S(=O)O)cc1
Reactant: Cc1ccc(O)c(O)c1
Product: COc1ccc(S(=O)(=O)c2cc(O)c(O)cc2C)cc1

Procedure:
37.5 g of 4-methoxybenzenesulphinic acid (obtained, for example, by reduction of 4-methoxybenzenesulphonyl chloride with sodium sulphite) are condensed oxidatively with 30.7 g of 4-methyl-1,2-benzenediol in a manner analogous to that described in Example 5a) and, after crystallisation from 1,2-dichloroethane, 4-(4-methoxyphenylsulphonyl)-5-methyl-1,2-benzenediol is obtained in the form of colourless crystals having a melting point of 145°-147.5°.