Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=[O:24])=[CH:18][CH:17]=1.[NH2:26][C:27]1[N:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)[N:30]=[C:29]([N:43]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH3:44])[CH:28]=1>>[C:48]([O:47][C:45]([N:43]([C:29]1[CH:28]=[C:27]([NH:26][C:23](=[O:24])[CH2:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)[N:31]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=2)[N:30]=1)[CH3:44])=[O:46])([CH3:51])([CH3:50])[CH3:49]
Reactant: COc1ccc(Cn2nc(N(C)C(=O)OC(C)(C)C)cc2N)cc1OC
Reactant: COc1cc2nccc(Oc3ccc(CC(=O)O)cc3)c2cc1OC
Product: COc1ccc(Cn2nc(N(C)C(=O)OC(C)(C)C)cc2NC(=O)Cc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1OC
Yield: 66 %

Procedure:
Using an analogous procedure to that described in Example 22, 2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]acetic acid was reacted with 5-amino-3-(N-tert-butoxycarbonyl-N-methylamino)-1-(3,4-dimethoxybenzyl)pyrazole to give N-[3-(N-tert-butoxycarbonyl-N-methylamino)-1-(3,4-dimethoxybenzyl)pyrazol-5-yl]-2-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]acetamide as a solid in 66% yield; 1H NMR: (DMSOd6) 1.45 (s, 9H), 3.18 (s, 3H), 3.65 (s, 3H), 3.66 (s, 3H), 3.73 (s, 2H), 3.92 (s, 3H), 3.95 (s, 3H), 5.08 (s, 2H), 6.4 (d, 1H), 6.42 (m, 1H), 6.58 (d, 1H), 6.76 (d, 1H), 6.84 (d, 1H), 7.2 (d, 2H), 7.4 (s, 1H), 7.41 (d, 2H), 7.49 (d, 1H), 10.26 (br s, 1H); Mass Spectrum: M+H+ 684.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:35]=[C:36]=[S:37])[CH2:29][CH2:28]2)=[CH:12][CH:11]=1>O1CCCC1>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[N:19]=[C:18]2[NH:26][CH:27]2[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][NH:35][C:36]([NH:8][CH2:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[S:37])[CH2:31][CH2:32]2)=[CH:12][CH:11]=1
Reactant: NCc1cccnc1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Solvent: C1CCOC1
Product: Fc1ccc(Cn2c(NC3CCN(CCNC(=S)NCc4cccnc4)CC3)nc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 65.7 %

Procedure:
A mixture of 1 part of 3-pyridinemethanamine, 3.9 parts of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-1H-benzimidazol-2-amine and 45 parts of tetrahydrofuran was stirred for 4 hours at room temperature. The reaction mixture was evaporated in vacuo. The residue was purified by column-chroratography over silica gel using a mixture of trichloromethane and methanol (94:6 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 3.4 parts (65.7%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-N'-(3-pyridinylmethyl)thiourea; mp. 147.2° C. (compound 102).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:30])[N:14]([CH3:29])[C:15]([C:25]([O:27][CH3:28])=[O:26])=[C:16](OS(C(F)(F)F)(=O)=O)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH2:1]([N:8]1[C:12]2[C:13](=[O:30])[N:14]([CH3:29])[C:15]([C:25]([O:27][CH3:28])=[O:26])=[C:16]([C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2ccn(Cc3ccccc3)c2c(=O)n1C
Reactant: OB(O)c1ccc(Cl)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: C1COCCO1
Solvent: O
Product: COC(=O)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A mixture of methyl 1-benzyl-6-methyl-7-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (7.5 g, 16.9 mmol), 4-chlorophenylboronic acid (3.89 g, 23.64 mmol) and Na2CO3 (7.52 g, 70.9 mmol) in 1,4-Dioxane (100 mL) and Water (20 mL) degassed with N2 for 15 minutes. The mixture was treated with palladium tetrakis (1.024 g, 0.887 mmol) and then stirred at 90° C. under N2 atmosphere overnight. The mixture was diluted with water and then extracted with Ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-40% ethyl acetate/hexanes) to afford methyl 1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (6.4 g, 15.7 mmol, 93% yield) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.40 (s, 2H) 7.31-7.37 (m, 4H) 7.23-7.27 (m, 2H) 7.05 (d, J=2.93 Hz, 1H) 6.12 (d, J=2.93 Hz, 1H) 5.87 (s, 2H) 3.62 (s, 3H) 3.61 (s, 3H); LCMS (m/z) ES+=407 (M+1).
Reaction SMILES: CN(C)[C:3](=[O:5])[CH3:4].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=[CH2:30])[CH:24]=1.N1C(C)=CC(C)=CC=1C>ClCCCl>[Br:22][C:23]1[CH:24]=[C:25]([CH:29]2[CH2:30][C:3](=[O:5])[CH2:4]2)[CH:26]=[CH:27][CH:28]=1
Reactant: C=Cc1cccc(Br)c1
Reactant: CC(=O)N(C)C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCCl
Product: O=C1CC(c2cccc(Br)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
N,N-Dimethylacetamide (9.0 g, 103 mmol) was dissolved in 1,2-dichloroethane (200 mL). The solution was cooled to 0° C. before trifluoromethanesulfonic anhydride (63 g, 223 mmol) was added. The reaction was stirred for an additional 60 min at 0° C. Then 1-bromo-3-vinylbenzene (15 g, 81.9 mmol) and 2,4,6-collidine (10.5 g, 86.6 mmol) were added. The reaction was heated to reflux overnight, quenched by addition of water (300 mL) and stirred for 2 hr at rt. The mixture was extracted with DCM (300 mL×3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. Purification by CC (EA/PE=1:20) gave the title compound 2a (5.0 g, 27%) as a pale yellow solid.
Reaction SMILES: [BH4-].[Li+].C[O:4][C:5](=O)[C@@H:6]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9].CO.C(OC(C)(C)C)=O>O1CCCC1>[C:21]([O:20][C:18](=[O:19])[NH:17][C@H:6]([CH2:5][OH:4])[CH2:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)[C@H](CS(=O)(=O)c1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC=O
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CS(=O)(=O)c1ccccc1

Procedure:
To a solution of lithium borohydride in tetrahydrofuran (2M, 1.14 ml, 2.28 mmol) was added slowly at 0° C. a solution of (R)-3-benzenesulfonyl-2-tert-butoxycarbonylamino-propionic acid methyl ester (0.52 g, 1.51 mmol) in tetrahydrofuran (3 ml). After stirring at room temperature for 2.5 hours methanol was added (0.5 ml). The mixture was partitioned between ethyl acetate and saturated ammoniumchloride solution. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (SiO2, heptane/EtOAc=1:1 to yield a white solid, (0.292 g, 61%); MS (ISP): 316.0 ((M+H)+/); 216.1 ((M+H—BOC)+.).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=12.BrC1C=C(O)C=CC=1.[C:19]1([CH:25]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[C:27]2=[O:36])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[C:37]1([CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28]([OH:35])([C:9]3[C:4]4[C:5](=[N:1][O:2][N:3]=4)[CH:6]=[CH:7][C:8]=3[OH:10])[C:27]2=[O:36])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Oc1ccc2nonc2c1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1c(O)ccc2nonc12

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 2,1,3-benzoxadiazol-5-ol to replace 3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 1-(diphenylmethyl)-3-hydroxy-3-(5-hydroxy-2,1,3-benzoxadiazol-4-yl)-1,3-dihydro-2H-indol-2-one was obtained (71%) as a colorless solid: MS (ES+) m/z 472.0 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])[CH:18]=[C:17]([Cl:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.Cl.[NH2:29][OH:30].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])[CH:18]=[C:17]([Cl:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:29][OH:30])=[NH:14])=[CH:15][CH:16]=1
Reactant: NO
Reactant: N#Cc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
1.1 g of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-benzonitrile, 247 mg of hydroxylamine hydrochloride and 430 mg of triethylamine are stirred for 48 hours at 80° C. in 25 ml of ethanol. The reaction mixture is poured onto water and extracted with ethyl acetate. Concentration of the organic phase and crystallisation from diethyl ether yield 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxy-benzamidine having a melting point of 144-146° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[N:6][CH:7]=1.[CH2:24]([C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[CH3:25]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[N:6]=[CH:7][C:2]([N:27]4[C@H:26]([CH2:24][CH3:25])[CH2:30][O:29][C:28]4=[O:31])=[N:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(Br)cn3)CC2)c(C)c1
Reactant: CC[C@@H]1COC(=O)N1
Product: CC[C@@H]1COC(=O)N1c1cnc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cn1
Yield: 85.2 %

Procedure:
Using (5-bromopyrazin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (113 mg) described in Preparation Example 232 and (R)-4-ethyloxazolidin-2-one (52 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (105 mg) was obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C=O.O.[C:17](=O)(O)[O-:18].[Na+]>C1COCC1>[C:1]1([CH2:17][OH:18])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc2c1Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Fluorene 60 g (0.36 mol) was dissolved in dehydrated THF 1500 ml. Subsequently, butyl lithium-hexane solution 225 ml (1.6 M) was slowly dropped in at 0° C. under argon gas atmosphere. Next, paraformaldehyde 12 g was added and the mixture was agitated at a room temperature for 5 hours. After agitation, saturated sodium bicarbonate water 600 ml was added, and extracted with diethyl ether. An organic layer was washed twice with an aqueous saturated NaCl solution, and then the solvent was evaporated off after drying using anhydrous magnesium sulfate. The obtained pasty solid matter was refined by recrystallization with a mixed solvent of hexane and ethanol to obtain a white needle crystal 50 g of fluorenyl methanol. It was determined by measurement of 1H-NMR that the obtained compound had a structure illustrated in the above-described formula (6). The melting point and the measurement result of 1H-NMR will be shown in the following paragraph.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[N:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:18].[Cl:25][C:23]1[N:22]=[CH:21][N:20]=[C:19]([N:10]2[C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=[C:9]2/[CH:1]=[CH:2]/[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:24]=1
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Clc1cc(-n2c(/C=C/c3ccccc3)nc3ccccc32)ncn1

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 4,6-dichloropyrimidine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate/n-hexane to give the titled compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[O:17][CH:18]=[C:19]([CH2:21][CH2:22][O:23]S(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:34]([O:36][C:37](=[O:49])[C:38]([O:41][C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)([CH3:40])[CH3:39])[CH3:35]>>[CH2:34]([O:36][C:37](=[O:49])[C:38]([O:41][C:42]1[CH:47]=[CH:46][C:45]([O:23][CH2:22][CH2:21][C:19]2[N:20]=[C:16]([C:7]3[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[CH:8]=3)[O:17][CH:18]=2)=[CH:44][CH:43]=1)([CH3:40])[CH3:39])[CH3:35]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2coc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2coc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)n2)cc1
Yield: 70 %

Procedure:
Toluene-4-sulfonic acid 2-[2-(3,5-di-tert-butyl-4-hydroxyphenyl)oxazol-4-yl]ethyl ester (Eli Lilly and Co, Eur. Pat. Appl. 98-308063) (490 mg, 1.04 mmol) was coupled to 2-(4-hydroxyphenoxy)-2-methylpropanoic acid ethyl ester (American Home Products U.S. Pat. No. 3,795,691) (203 mg, 0.90 mmol) following the procedure described in Example 1 to provide the product (330 mg, 70%) as a clear, colorless oil:
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>CS(C)=O>[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: COC[C@H]1CCCN1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H]1CCCN1c1nc2cc(C(=O)OC)ccc2[nH]c1=O
Temperature: 75 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (600 mg, 2.51 mmol) in DMSO (8 mL) was added DIEA (650 mg, 5.03 mmol), and (2R)-2-(methoxymethyl)pyrrolidine (318 mg, 2.76 mmol). The solution was stirred for 4 h at 75° C. Then the reaction was quenched by the addition of water (50 mL) to give the precipitate, which was collected by filtration to afford methyl 3-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a gray solid (650 mg, 81%).
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])[C:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)=[CH:8][O:9][C:4]=2[C:3]=1[CH3:23].C([O-])([O-])=O.[K+].[K+].[CH2:30]([CH:32]1[O:34][CH2:33]1)Br.O>CN(C)C=O>[O:34]1[CH2:33][CH:32]1[CH2:30][O:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6](=[O:20])[C:7]([C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=3)=[CH:8][O:9][C:4]=2[C:3]=1[CH3:23]
Reactant: BrCC1CO1
Reactant: COc1ccc(-c2coc3c(C)c(O)ccc3c2=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2coc3c(C)c(OCC4CO4)ccc3c2=O)cc1OC

Procedure:
7-Hydroxy-8-methyl-3-(3,4-dimethoxyphenyl)-4H-1-benzoyran-4-one [see example 12] (3.12 g) is dissolved in dimethylformamide (15 ml) and K2CO3 (3.5 g) is added to the solution. While stirring, epibromhydrine (2.47 g) is dropped into the mixture. After heating for 5 h at 60°, the content of the reaction flask is poured into water (500 ml) and the precipitated product is filtered off and recrystallized from ethanol. The product is dried in vacuo to constant weight to yield 7-(2,3-epoxypropoxy)-8-methyl-3-(3,4-dimethoxyphenyl)-4H-1-benzopyran-4-one, m.p. 214°.
Reaction SMILES: [C:1](=[O:20])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[NH2:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(#N)C>C(#N)C.O.[OH-].[Na+].O>[N:7]1[CH:6]=[CH:5][C:4]([CH2:3][O:2][C:1]([NH:21][C@H:22]([C:30]([OH:32])=[O:31])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:20])=[CH:9][CH:8]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccncc1)Oc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccncc1
Reaction time: 8 h

Procedure:
8 g of 4-pyridylmethyl 4-nitrophenyl carbonate and 4.82 g of L-phenylalanine were dissolved in 350 ml of acetonitrile/water 1:1, and about 45 ml of 2N NaOH were added to pH 10. The mixture was stirred overnight and was freed from the acetonitrile in vacuo. The aqueous solution was brought to pH 6, washed three times with diethyl ether, subsequently brought to pH 1 and concentrated to give a solid residue. This was dissolved in water and the solution was extracted intensively with ethyl acetate and then brought to pH 2 and the precipitate which had separated out was filtered off with suction. After drying, the precipitate weighed 7.3 g.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[Br:13]Br>C(OCC)(=O)C>[Br:13][CH:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[C:8]1=[O:12]
Reactant: BrBr
Reactant: O=C1CCCc2cc(Cl)ccc21
Solvent: CCOC(C)=O
Product: O=C1c2ccc(Cl)cc2CCC1Br

Procedure:
5 g of 6-chloro-1-tetralone are reacted with 4.4 g of bromine in ethyl acetate analogously to the instructions indicated in Example 29 (a). After distilling off the solvent under reduced pressure, 2-bromo-6-chloro-1-tetralone is obtained as an amorphous residue, which is used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:22][CH2:21][C:20]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([OH:23])[CH2:19][CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: OC1(c2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 1.5 h
Yield: 89 %

Procedure:
To a solution of 4-fluorophenylmagnesium bromide (110.0 mmol, 55.0 mL of 2.0 M solution) in 150.0 mL THF at 0° C. was added 1-benzyl-4-piperidone (55.0 mmol, 10.2 mL) dropwise. The resulting solution was stirred under argon atmosphere for 1.5 h and then quenched with 100.0 mL of saturated NH4Cl solution. The organic layer was separated and the aqueous layer was extracted with 100.0 mL of Et2O. The combined organic extracts were washed with brine, separated and dried over Na2SO4. The solution was filtered and the solvent was removed in vacuo to obtain a yellow oil which was purified by passing through a silica gel column with 4:1 hexane/EtOAc followed by 1:1 hexane/EtOAc as the eluting system. 1-Benzyl-4-(4-fluoro-phenyl)-piperidin-4-ol was obtained as a pale yellow oil in 89% yield (13.9 g). It was dissolved in 150.0 mL of toluene and p-toluenesulfonic acid monohydrate (50.0 mmol, 9.5 g) was added. The resulting suspension was heated to reflux for 8 h. After the suspension was cooled, it was basified with 3 N NaOH solution and was extracted with Et2O (2×50 mL). The organic extracts were combined, washed with brine and the oraganic layer was dried over Na2SO4. The solvent was removed in vacuo to obtain 1-benzyl-4-(4-fluoro-phenyl)-1,2,3,6-tetrahydro-pyridine as a yellow viscous oil (12.0 g, 92% yield) which was used in the next step without further purification.
Reaction SMILES: C(N(CC)CC)C.[N-:8]=[N+:9]=[N-:10].[Na+].[N+]([C:15]1[CH:34]=[CH:33][CH:32]=[C:17]2[C:18]([N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[C:21](=[O:22])[C:16]=12)=[O:19])([O-])=O>CS(C)=O>[N:8]([C:32]1[CH:33]=[CH:34][CH:15]=[C:16]2[C:21]([N:20]([C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=3)[C:18](=[O:19])[C:17]=12)=[O:22])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1ccc(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)cc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1cccc2c1C(=O)N(c1ccc(C(=O)O)cc1)C2=O
Temperature: 50 °C
Yield: 80.1 %

Procedure:
1.4 ml (0.01 mol) of triethylamine, followed by 0.72 g (0.011 mol) of sodium azide, are added to a mixture of 3.12 g (0.01 mol) of 4-(3-nitrophthalimidyl)-benzoic acid and 20 ml of dimethylsulphoxide. The reaction mixture is heated for 6 hours at 50° C. and is then evaporated in vacuo at 80° C.; the residue is stirred with 70 ml of water and the resulting solution is then brought to pH 1 with hydrochloric acid. The product which has precipitated is filtered off with suction, washed with 5 ml of methanol and dried for 24 hours in a drying cabinet at 80° C./100 mm Hg. 2.47 g (80% of theory) of 4-(3-azidophthalimidyl)-benzoic acid are obtained; melting point 300° C. (with decomposition). IR spectrum (KBr): 1790 and 1740 cm-1 (CO--N--CO); 2150 cm-1 (N3).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[CH:10][C:9]=2[O:18][CH:19]([CH3:21])[CH3:20])=[O:7])[CH2:3]1.F[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH:19]([O:18][C:9]1[CH:10]=[CH:11][C:12]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:13][C:8]=1[C:6]([N:4]1[CH2:5][CH:2]([O:1][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:3]1)=[O:7])([CH3:21])[CH3:20]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(O)C1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1

Procedure:
A mixture of 0.32 mmol (3-hydroxy-azetidin-1-yl)-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone, 0.32 mmol 4-fluoro-benzotrifluoride and 0.96 mmol cesium carbonate in 10 ml acetonitrile was refluxed overnight. The reaction mixture was concentrated to yield the crude compound, purified by chromatography (methanol/dichloromethane). MS (m/e): 458.4 (M+H+, 100%).