Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.CCCCCC.C([Li])CCC.[B:28](OC)([O:31]C)[O:29]C.S(=O)(=O)(O)O>C1COCC1>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:4]2[CH:3]=[C:2]([B:28]([OH:31])[OH:29])[CH:7]=[CH:6][CH:5]=2)=[CH:10][CH:11]=1)[CH3:16]
Reactant: COB(OC)OC
Reactant: CCc1ccc(Cc2cccc(Br)c2)cc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCc1ccc(Cc2cccc(B(O)O)c2)cc1
Reaction time: 0.33 h
Yield: 31.6 %

Procedure:
In a nitrogen stream, a solution of 1-bromo-3-(4-ethylbenzyl)benzene (2.19 g, 7.96 mmol) in THF (20 mL) was cooled to −78° C., and an n-butyllithium hexane solution (2.44 M, 3.42 mL) was added dropwise thereto and the mixture solution was stirred at the same temperature for 20 minutes. After addition of trimethyl borate (2.68 mL, 23.87 mmol), the reaction mixture was stirred at the temperature for five minutes and at room temperature for 12.5 hours. After cooling the reaction mixture in an ice bath, concentrated sulfuric acid (10 mL) was added dropwise thereto and the mixture solution was stirred at the same temperature for one hour. The mixture was extracted with ether and the organic layer was washed with water and then dried over sodium sulfate. To a white solid obtained by distilling the solvent under reduced pressure was added hexane-ethyl acetate (10:1)(5 mL), the mixture was filterated and then the obtained solid was washed with hexane-ethyl acetate (10:1). The obtained white powder was dried under reduced pressure to obtain the title compound (604.2 mg, 32%).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:10](=[O:21])[NH:11][CH2:12][CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-].N1C=CC=CC=1NCCNC(C1SC(C(O)=O)=CC=1)=O.C(OC(NC[CH2:53][O:54][C:55](=[O:72])[CH:56]([NH:59][S:60]([C:63]1[C:68]([CH3:69])=[CH:67][C:66]([CH3:70])=[CH:65][C:64]=1[CH3:71])(=[O:62])=[O:61])[CH2:57][NH2:58])=O)(C)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=N)C>CN(C=O)C>[CH3:53][O:54][C:55](=[O:72])[CH:56]([NH:59][S:60]([C:63]1[C:68]([CH3:69])=[CH:67][C:66]([CH3:70])=[CH:65][C:64]=1[CH3:71])(=[O:62])=[O:61])[CH2:57][NH:58][C:3]([C:5]1[S:6][C:7]([C:10](=[O:21])[NH:11][CH2:12][CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)NCCNc2ccccn2)s1
Reactant: Cc1cc(C)c(S(=O)(=O)NC(CN)C(=O)OCCNC(=O)OC(C)(C)C)c(C)c1
Agent: CCN=C=N
Agent: Cl
Agent: O=C(O)c1ccc(C(=O)NCCNc2ccccn2)s1
Solvent: CN(C)C=O
Product: COC(=O)C(CNC(=O)c1ccc(C(=O)NCCNc2ccccn2)s1)NS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carboxylic acid methyl ester was hydrolyzed with LiOH as described before. To a mixture of 5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carboxylic acid (38 mg, 0.12 mmol), salt of 3-amino-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acid 2-tert-butoxycarbonylamino-ethyl ester (47 mg, 0.14 mmol), hydroxybenzotriazole (21 mg, 0.15 mmol) in DMF (20 mL), was added 1-(3-dimethylamino) propyl)-3-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol). The reaction was stirred overnight at room temperature. Insolubles were removed by filtration and the solvent was evaporated. Purification of the residue on silica gel (10% MeOH/EtOAc) gave 60 mg (87%) of pure 3-({5-[2-(Pyridin-2-ylamino)-ethylcarbamoyl]-thiophene-2-carbonyl}-amino)-2-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acid methyl ester. 1HNMR (300 MHz, CDCl3) δ: 2.22 (s, 3H), 2.61 (s, 6H), 3.55 (m, 4H), 3.82 (m, 1H), 4.09 (m, 1H), 6.50(d, 1H), 6.69(t, 1H), 6.90(s, 2H), 7.05(t, 1H), 7.40(m, 3H), 8.10 (s, 1H), 8.43(m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[C:30]=4[C:31]=3[CH3:32])=[O:26])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[Li+].[OH-]>C1COCC1>[CH3:38][O:37][C:33]1[C:30]2[C:31]([CH3:32])=[C:27]([C:25]([NH:24][C:21]3[CH:20]=[CH:19][C:18]([C:15]4[CH:16]=[CH:17][C:12]([S:9]([NH:8][C@@H:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:39])=[O:2])(=[O:10])=[O:11])=[CH:13][CH:14]=4)=[CH:23][CH:22]=3)=[O:26])[O:28][C:29]=2[CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2ccc(NC(=O)c3oc4cccc(OC)c4c3C)cc2)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 80.8 %

Procedure:
To a solution of 80 mg of (S)-2-{4′-[(4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid methyl ester dissolved in 1 mL of THF was added 3 mL of LiOH solution (3.6 g LiOH/50 mL MeOH/50 mL H2O). The mixture was stirred at room temperature for 4 days. The solvents were removed under vacuum and the residue was dissolved in 5 mL of water. The solution was acidified and the resulting suspension was filtered. The solid product was dried under vacuum and triturated with acetonitrile to give 63 mg (81% yield) of (S)-2-{4′-[(4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid, obtained as white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.8 (dd, J=12.5, 6.7 Hz, 6 H) 2.0 (m, 1 H) 2.7 (s, 3 H) 3.6 (dd, J=9.3, 5.8 Hz, 1 H) 3.9 (s, 3 H) 6.9 (d, J=8.1 Hz, 1 H) 7.2 (d, J=7.8 Hz, 1 H) 7.4 (t, J=8.2 Hz, 1 H) 7.8 (d, J=8.8 Hz, 2 H) 7.9 (m, 4 H) 8.0 (d, J=8.8 Hz, 2 H) 8.1 (d, J=9.3 Hz, 1 H) 10.5 (s, 1 H) 12.6 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16]Br)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:18])[NH:7]2.[C:19]1([SH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[Br:1][C:2]1[C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:18])[NH:7]2
Reactant: O=c1ccc2c(Br)c(OCCCCBr)ccc2[nH]1
Reactant: Sc1ccccc1
Product: O=c1ccc2c(Br)c(OCCCCSc3ccccc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 5-bromo-6-(4-bromo-butoxy)-carbostyril [prepared by bromination of 6-(4-bromo-butoxy)-carbostyril] and thiophenol.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C([Li])CCC.Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.CCCCCC>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN([Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 20 g of 1-ethoxycarbonylpiperazine in 400 ml dry tetrahydrofuran was cooled to -65° and 61.5 ml of 2.1M solution of n-butyllithium in hexane was added dropwise over a period of 15 minutes. The mixture was stirred for 15 minutes and a solution of 16.44 ml of chlorotrimethylsilane in 68 ml of tetrahydrofuran was added dropwise over a period of 15 minutes. The mixture was then allowed to warm up to room temperature overnight and evaporated to dryness. Ethyl ether was added, the solids were filtered off, the filtrate was evaporated to dryness and the residue was distilled to give 1-ethoxycarbonyl-4-trimethylsilylpiperazine, b.p. 102°-107°/0.1 mm/Hg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]([C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]([C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH2:9][CH2:10][O:11][S:24]([CH3:23])(=[O:26])=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)CN(CCO)C(=O)OCc1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CN(CCOS(C)(=O)=O)C(=O)OCc1ccccc1

Procedure:
The product from Example 5 (14.4 g; 47 mmol) is reacted in anhydrous pyridine (270 ml) with methanesulphonyl chloride (4.47 ml; 58 mmol) and then worked up as described in Example 2. Yield: 14.7 g (82%), brown oil.
Reaction SMILES: [CH3:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.C(Cl)(=O)C(Cl)=O.Br.[NH2:15][C:16]1[C:24](O)=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl.O>[CH3:1][C:2]1([C:5]2[O:7][C:24]3[C:16](=[C:17]([C:18]([OH:20])=[O:19])[CH:21]=[CH:22][CH:23]=3)[N:15]=2)[CH2:4][CH2:3]1
Reactant: CC1(C(=O)O)CC1
Reactant: Nc1c(O)cccc1C(=O)O
Agent: Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC1(c2nc3c(C(=O)O)cccc3o2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To an ice-cold solution of 1-methylcyclopropanecarboxylic acid (214 mg, 2.14 mmol) in dichloromethane (10 mL) was added oxalyl chloride (0.19 mL, 2.14 mmol) dropwise. The ice bath was removed and stirring was continued for 1 h. 2-Amino-3-hydroxybenzoic acid hydrobromide (500 mg, 2.14 mmol) was added followed by triethylamine (0.90 mL, 6.42 mmol). The resulting reaction mixture was stirred at room temperature overnight. The reaction was quenched with aqueous 1 N HCl (25 mL) until the solution reached pH 1. The reaction mixture was extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered and concentrated to a brown solid. The crude was dissolved in toluene (10 mL) and the solution was treated with p-toluenesulfonic acid monohydrate (477 mg, 2.50 mmol). The reaction mixture was then heated to reflux for 1 h. The reaction was cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer was separated, then washed with water (5×50 mL), brine, dried (Na2SO4), filtered and concentrated to afford 2-(1-methylcyclopropyl)benzoxazole-4-carboxylic acid (306 mg, 65%) as a light yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 12.89 (br s, 1H), 7.85 (dd, J=8.0, 0.9 Hz, 1H), 7.81 (dd, J=7.7, 0.9 Hz, 1H), 7.39 (t, J=7.9 Hz, 1H), 2.91 (s, 3H), 1.42-1.37 (m, 2H), 1.10-1.05 (m, 2H); MS (ESI+) m/z 218 (M+H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[C:8]([NH:10][C:11](=[O:17])[NH:12][CH2:13][C:14]([OH:16])=[O:15])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26]O>S(=O)(=O)(O)O.O>[CH3:26][O:15][C:14](=[O:16])[CH2:13][NH:12][C:11]([NH:10][C:8](=[O:9])[CH:7]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:17]
Reactant: CO
Reactant: O=C(O)CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 80 °C
Yield: 68 %

Procedure:
A solution of {3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-acetic acid (30 mg, 0.08 mmol) in methanol (5 mL) was treated with concentrated sulfuric acid (4 drops). The reaction was heated to 80° C. for 8 h. At this time, the reaction was cooled to 25° C. and diluted with water (10 mL). This solution was extracted with ethyl acetate (3×20 mL). The organics were washed with a saturated aqueous sodium bicarbonate solution (1×20 mL), a saturated aqueous sodium chloride solution (1×20 mL) and water (1×10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded {3-[3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionyl]-ureido}-acetic acid methyl ester (21 mg, 68%) as a white solid:mp 134.5-136.6° C.; EI-HRMS m/e calcd for C18H22Cl2N2O4 (M+) 400.0957, found 400.0970.
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](OCCN2CCOCC2)[CH:6]=1)C.[NH2:21][C:22]1[N:26]([C:27]2[CH:28]=[C:29]([CH:36]=[CH:37][C:38]=2[CH3:39])[C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])[N:25]=[CH:24][C:23]=1[C:40](=[O:49])C1C=CC=C(CO)C=1.C(N(C(C)C)CC)(C)C>C(O)C>[NH2:21][C:22]1[N:26]([C:27]2[CH:28]=[C:29]([CH:36]=[CH:37][C:38]=2[CH3:39])[C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])[N:25]=[CH:24][C:23]=1[C:40](=[O:49])[C:8]1[CH:9]=[CH:10][C:5]([CH3:4])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(CO)c2)c1N
Reactant: CCOC(=O)c1cccc(OCCN2CCOCC2)c1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)c2cnn(-c3cc(C(=O)NC4CC4)ccc3C)c2N)cc1
Temperature: 65 °C
Yield: 21.9 %

Procedure:
A mixture of 2-(4-methyl-benzoyl)-3-phenylamino-acrylonitrile 2 (205 mg, 0.78 mmol), N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt 7 (Example 6C, 250 mg, 0.78 mmol) and diisopropylethylamine (0.14 mL, 0.78 mmol) in 8 mL of ethanol was heated at 65° C. in for 18 h. Solvent was removed and the residue was purified by silica gel column chromatography (EtOAc/hexanes, gradient from 1/3 to 3/1). The product can be further purified by trituration with Et2O to give 3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 3 as a white solid (64 mg, 22%). HPLC (4 minute gradient) tR 2.26 min; MS m/z 375.2 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J=4.0, 1H), 7.93 (d, J=8.0, 1H), 8.51 (d, J=4.0, 1H), 7.83 (bs, 1H), 7.82 (s, 1H), 7.70 (d, J=7.9, 2 H), 7.53 (d, J=8.0, 1H), 7.35 (d, J=7.9, 2 H), 6.95 (bs, 2H), 2.86 (m, 1H), 2.40 (s, 3H), 2.14 (s, 3H), 0.68 (m, 2H), 0.56 (m, 2H); 13C NMR (300 MHz, DMSO-d6) δ 187.4, 166.0, 151.9, 141.3, 141.1, 139.2, 136.9, 135.6, 133.0, 131.2, 129.1, 128.3, 128.0, 126.5, 102.6, 23.1, 21.0, 17.2, 5.6 ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[N:14]=2)=[CH:6][CH:5]=1)([O-])=O.CN(C)C=O.Cl.C(=O)([O-])[O-].[Na+].[Na+]>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][C:12]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=3)[N:14]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc(-c3ccc([N+](=O)[O-])cc3)c(-c3ccc([N+](=O)[O-])cc3)o2)cc1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(-c2nc(-c3ccc(N)cc3)c(-c3ccc(N)cc3)o2)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Then, 4.32 g (0.01 mol) of 2,4,5-tris(4-nitrophenyl)oxazole was mixed with 200 ml of N,N-dimethylformamide and 8 g of an iron powder (reduced iron available from Wako Pure Chemical Industries, Ltd.). To the resulting mixture, 4 ml of concentrated hydrochloric acid and 12 ml of water were added, and the mixture was heated to 100° C. while stirring well. After reacting for 1 hour, the reacting solution was neutralized to pH: 8 with a saturated aqueous solution of sodium carbonate, and while maintained at 100° C., it was filtered in a heated state. The filtrate was poured into 1 l of iced water. The white precipitate formed of 2,4,5-tris(4-aminophenyl)oxazole was filtered off and dried. Yield: 3.27 g (96%).
Reaction SMILES: [CH2:1]([C:13]1[N:14]=[N:15][N:16]([C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=O)[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(C1N=NN(CC(O)=O)N=1)CCCCCCCCC.[CH3:43][O:44][C:45]1[CH:51]=[C:50]([O:52][CH3:53])[CH:49]=[C:48]([O:54][CH3:55])[C:46]=1[NH2:47].C(C1C=CC=C(C(C)C)C=1N)(C)C>>[CH2:1]([C:13]1[N:14]=[N:15][N:16]([C:18]([CH3:23])([CH3:22])[C:19]([NH:47][C:46]2[C:48]([O:54][CH3:55])=[CH:49][C:50]([O:52][CH3:53])=[CH:51][C:45]=2[O:44][CH3:43])=[O:21])[N:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COc1cc(OC)c(N)c(OC)c1
Reactant: CCCCCCCCCCCCc1nnn(C(C)(C)C(=O)O)n1
Agent: CC(C)c1cccc(C(C)C)c1N
Agent: CCCCCCCCCCc1nnn(CC(=O)O)n1
Product: CCCCCCCCCCCCc1nnn(C(C)(C)C(=O)Nc2c(OC)cc(OC)cc2OC)n1

Procedure:
When in the general procedure of Example 88 an appropriate amount of 5-dodecyl-α,α-dimethyl-2H-tetrazole-2-acetic acid was substituted for 5-decyl-2H-tetrazole-2-acetic acid and 2,4,6-trimethoxyaniline was substituted for 2,6-diisopropylaniline, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:3]=[C:4]([CH:11]=[CH:12][N:13]=2)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])=[CH:18][CH:17]=1
Reactant: CON(C)C(=O)c1ccnc(Br)c1
Reactant: OCc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CON(C)C(=O)c1ccnc(-c2ccc(CO)cc2)c1

Procedure:
By following procedures described in Example 32, starting from 2-bromo-N-methoxy-N-methyl-isonicotinamide and 4-hydroxymethyl phenyl boronic acid [but using Pd2(dba)3 instead of Pd(PtBu3)2], step 1 gave 2-(4-hydroxymethyl-phenyl)-N-methoxy-N-methyl-isonicotinamide.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH2:12][CH2:13][CH2:14][OH:15].Br[CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:19]=1[O:20][CH2:21][C:22]#[N:23]>>[CH3:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:15][CH2:14][CH2:13][CH2:12][NH:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[C:19]=1[O:20][CH2:21][C:22]#[N:23]
Reactant: OCCCNc1ccc2ccccc2n1
Reactant: Cc1cccc(CBr)c1OCC#N
Product: Cc1cccc(COCCCNc2ccc3ccccc3n2)c1OCC#N

Procedure:
MS (ESI) 362 (M+H)+. Prepared from 3-(quinolin-2-ylamino)-propan-1-ol and (2-bromomethyl-6-methyl-phenoxy)-acetonitrile.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([O:6][CH2:7][C@H:8]2[O:12][C@@H:11]([N:13]3[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]3=[O:15])[CH2:10][C@@H:9]2[OH:22])[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.[Si:29](Cl)([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.N1C=CN=C1>CN(C=O)C>[Si:29]([O:22][C@@H:9]1[C@@H:8]([CH2:7][O:6][N:5]2[C:4](=[O:23])[C:3]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]3[C:1]2=[O:28])[O:12][C@@H:11]([N:13]2[CH:21]=[C:19]([CH3:20])[C:17](=[O:18])[NH:16][C:14]2=[O:15])[CH2:10]1)([C:42]([CH3:45])([CH3:44])[CH3:43])([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.9 %

Procedure:
A mixture of 5′-O-phthalimidothymidine (8.54 g, 22 mmol), t-butyldiphenylsilylchloride (6.9 ml, 26.5 mmol), imidazole (3.9 g, 57.3 mmol) and dry DMF (130 ml) was stirred at room temperature for 16 h under argon. The reaction mixture was poured into ice-water (600 ml) and the solution was extracted with CH2Cl2 (2×400 ml). The organic layer was washed with water (2×250 ml) and dried (MgSO4). The CH2Cl2 layer was concentrated to furnish a gummy residue which on purification by silica gel chromatography (eluted with EtOAc:Hexanes; 1:1, v/v) furnished 12.65 g (92%) of 3′-O-(t-butyldiphenylsilyl)-5′-O-phthalimidothymidine as crystalline material (mp 172-173.5° C.). 1H NMR (DMSO-d6) δ 11.31 (s, 1, NH), 7.83 (m, 4, ArH), 7.59 (m, 4, TBDPhH), 7.51 (s, 1, C6H), 7.37-7.45 (m, 6, TBDPhH), 6.30 (dd, 1, H1′, J1′,2′=8.8 Hz, J1′,2″=5.6 Hz), 4.55 (m, 1, H4′), 4.15 (m, 1, H3′), 3.94-4.04 (m, 2, H5′,5″), 2.06-2.13 (m, 2, H2′,2″), 1.97 (s, 3, CH3), 1.03 (s, 9, C(CH3)3). Anal. Calcd. for C34H35O7N3Si: C, 65.26; H, 5.64; N, 6.71. Found: C, 65.00; H, 5.60; N, 6.42.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]3)[C:5]=2[CH:6]=1.[N+:28]([O-:31])([OH:30])=[O:29]>CC(C)=O>[CH:1]1[CH:2]=[CH:3][C:4]2[S:15][C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:18][CH2:17]3)[C:5]=2[CH:6]=1.[N+:28]([O-:31])([O-:30])=[O:29]
Reactant: O=[N+]([O-])O
Agent: OCCOCCN1CCN(C2=Nc3ccccc3Sc3ccccc32)CC1
Solvent: CC(C)=O
Product: O=[N+]([O-])[O-]
Reaction time: 1 h

Procedure:
Quetiapine free base (5.0 g) was dissolved in acetone (50 ml) at room temperature. This was followed by the addition of 68 to 72% nitric acid (0.7 g) at 20 to 25° C. The resulting precipitated solid was stirred for 1 hour. The precipitated product was collected by filtration, washed with acetone (15 ml) and dried to give the title compound as white powder (4.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]([F:26])([F:25])[F:24])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][CH:19](O)[CH3:20])=[CH:14][CH:13]=3)[C:6]=2[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[N:60]([CH:19]([CH3:20])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:7]2[C:6]3[CH:22]=[C:2]([Cl:1])[C:3]([C:23]([F:26])([F:25])[F:24])=[CH:4][C:5]=3[N:9]=[C:8]2[CH2:10][CH3:11])=[CH:13][CH:14]=1)=[N+:61]=[N-:62]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CC(C)O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CC(C)N=[N+]=[N-])cc1
Reaction time: 3 h
Yield: 36.8 %

Procedure:
To a stirred solution of 1-{4-[6-chloro-2-ethyl-5-(trifluoromethyl)-1H-benzimidazol-1-yl]phenyl}-2-propanol (step 8 of Example 247, 1.96 g, 5.12 mmol), triphenylphosphine (1.75 g, 6.66 mmol) and diphenylphosphoryl azide (1.83 mg, 6.66 mmol) in tetrahydrofuran (15 ml) was added diethyl azodicarboxylate (1.16 mg, 6.66 mmol) at room temperature. The resulting mixture was stirred at temperature for 3 h, then under reflux temperature. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (Na2SO4), and concentrated. Purification by flash column chromatography eluting with hexane/ethyl acetate (2:1) and TLC developing with hexane/ethyl acetate (1:1) afforded 769 mg (37%) of the title compound as a slight yellow syrup.
Reaction SMILES: [CH2:1]([C@H:8]([NH:23]C(=O)C1C=CC(F)=C(Br)C=1)[C@@H:9]([OH:22])[CH2:10][C@H:11]([C:13](=[O:21])NCCC(C)(C)C)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:34]([O:37][C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])[CH:46]=1)[C:41]([OH:43])=O)([CH3:36])[CH3:35].N[C@H]([C@H]1OC(=O)[C@H](C)C1)CC1C=CC=CC=1>>[CH:34]([O:37][C:38]1[CH:39]=[C:40]([CH:44]=[C:45]([N:47]2[CH2:51][CH2:50][CH2:49][C:48]2=[O:52])[CH:46]=1)[C:41]([NH:23][C@H:8]([C@@H:9]1[CH2:10][C@@H:11]([CH3:12])[C:13](=[O:21])[O:22]1)[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:43])([CH3:35])[CH3:36]
Reactant: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1ccc(F)c(Br)c1)C(=O)NCCC(C)(C)C
Reactant: CC(C)Oc1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: C[C@@H]1C[C@@H]([C@@H](N)Cc2ccccc2)OC1=O
Product: CC(C)Oc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@@H]2C[C@@H](C)C(=O)O2)cc(N2CCCC2=O)c1

Procedure:
Prepared in an analogous manner to D3 from 3-isopropoxy-5-(2-oxopyrrolidin-1-yl)benzoic acid (D16) and (3R,5S)-5-((S)-1-amino-2-phenylethyl)-3-methyldihydrofuran-2-one (D48).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([F:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:13]([F:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(F)c(I)cc2C1
Product: CC(C)(C)OC(=O)N1Cc2cc(F)c(N3CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-fluoro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and morpholine. Yellow solid. MS (m/e): 323.4 ([M+H]+, 100%).