Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][S:12]([OH:15])(=[O:14])=[O:13])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].[C:16]([OH:25])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].[OH-].[CH2:27]([P+:31]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH2:34][CH3:35])[CH2:28][CH2:29][CH3:30]>CC(C)=O>[C:16]([O-:25])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].[CH2:40]([P+:31]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:32][CH2:33][CH2:34][CH3:35])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:41][CH2:42][CH3:43].[C:1]12([CH2:11][S:12]([OH:15])(=[O:13])=[O:14])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3]
Reactant: O=C(O)c1ccccc1O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C([O-])c1ccccc1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Camphorsulphonic acid (5 mmol), salicylic acid (0.6909 g, 5 mmol) and tetrabutylphosphonium hydroxide (˜40% sol. in H2O) (3.414 g, 5 mmol) were dissolved in 20 ml of acetone and stirred for 15 min at room temperature. The solvent was evaporated and the remaining viscous liquid was dried at 0.01 mbar with stirring for 24 hrs. The desired compound is isolated as a colourless liquid; 1H-NMR (300 MHz, d6-DMSO) δ(ppm)=7.79 (dd, J1=7.9 Hz, J2=1.8 Hz), 7.52 (m, 1H), 6.94 (m, 3H), 2.97 (d, J=14.8 Hz, 1H), 2.71 (quin, J=10.8 Hz, 1H), 2.36 (d, J=14.8 Hz, 1H), 2.19 (m, 9H), 1.93 (t, J=4.5 Hz, 1H), 1.84 (m, 2H), 1.42 (m, 16 H), 1.26 (m, 2H), 1.05 (s, 3H), 0.91 (t, J=6.9 Hz, 12H), 0.74 (s, 3H). Tg−33° C., T5% onset 203° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.1 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (14 g, 42.68 mmol) and acetaldehyde (3.75 g, 85.36 mmol) in dichloroethane (150 mL), acetic acid (15.36 g, 256.08 mmol) was added and the reaction stirred at room temperature for 20 minutes. Sodium triacetoxyborohydride (27.01 g, 128.04 mmol) was then added at 0° C. and the reaction mixture stirred at room temperature for 2 h. The solvent was then removed under reduced pressure and water added to the residue. The mixture was extracted with DCM. The combined extracts were dried over sodium sulfate and concentrated under reduced pressure to give the crude product was purified by column chromatography to afford methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (14 g, 93.33%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:20][CH3:21])[CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CC=O
Reactant: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)C1CCOCC1
Reaction time: 6 h
Yield: 96.6 %

Procedure:
To a stirred solution of methyl 5-bromo-2-methyl-3-[(oxan-4-yl)amino]benzoate (2.0 g, 6.1 mmol) in DCE (10 ml) under a nitrogen atmosphere was added acetaldehyde (1.0 ml, 18 mmol) followed by acetic acid (2.1 ml, 37 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (6.6 g, 31 mmol). The reaction was stirred for 16 h at room temperature after which time additional acetaldehyde (1.0 ml, 22 mmol) and sodium triacetoxyborohydride (3.0 g, 14 mmol) were added and the reaction was stirred for a further 6 h whereupon distilled water (100 ml) was added and the phases were separated. The aqueous phase was washed with EtOAc (3×100 ml), the combined organics were then dried using Na2SO4, filtered and evaporated to afford the title compound as a colourless oil (2.10 g, 93%) which was suitable for use without any further purification. LC-MS 96%, 2.38 min (3.5 minute LC-MS method), m/z=356.1/357.9, 1H NMR (500 MHz, Chloroform-d) δ 7.70 (d, J=2.0 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 3.95 (d, J=11.3 Hz, 2H), 3.88 (d, J=9.1 Hz, 3H), 3.32 (td, J=11.5, 2.5 Hz, 2H), 3.04 (q, J=7.1 Hz, 2H), 2.98-2.87 (m, 1H), 2.44 (s, 3H), 1.77-1.55 (m, 4H), 0.86 (t, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.Cl>C(O)C.O=[Pt]=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH2:5]2
Reactant: Clc1ccc2ncccc2c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: Clc1ccc2c(c1)CCCN2
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 6-chloroquinoline (1.5 g, 9.17 mmol) in C2H5OH (50 ml) was added PtO2 (41.5 mg, 0.18 mmol) and concentrated HCl (0.1 ml) under an atmosphere of hydrogen gas. The reaction was stirred overnight at room temperature, then concentrated in vacuo, diluted with water (100 ml), adjusted to pH 8 with aqueous sodium bicarbonate. The resulting solution was extracted with dichloromethane (3×80 ml) and the organic layers were combined, dried over anhydrous magnesium sulfate, concentrated in vacuo to afford 6-chloro-1,2,3,4-tetrahydroquinoline as a colorless oil (1.2 g, 78%).
Reaction SMILES: COC([C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[NH2:10])=O.N1CCNCC1>CN1CCCC1=O>[NH2:10][C:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[S:6][CH:5]=1
Reactant: COC(=O)c1sc2ccccc2c1N
Agent: C1CNCCN1
Solvent: CN1CCCC1=O
Product: Nc1csc2ccccc12
Yield: 83.3 %

Procedure:
A solution of methyl-3-aminobenzothiophene-2-carboxylate (1 g, 4.83 mmol, 1 eq) in 1-methyl-2-pyrrolidinone (8 mL) and piperazine (2.08 g, 24.13 mmol, 5 eq) was stirred at 130° C. overnight. Ice was added, and the mixture was extracted with EtOAc. The organic extracts were washed twice with water, dried, and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel eluting with 33% ethyl acetate in hexanes to provide 600 mg (83%) of compound 39A as a yellow oil. HPLC: 98% at 1.043 min (retention time) (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, monitoring at 220 nm).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:21]2[S:20][CH2:19][C:18]=1N1CCOCC1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CN(C)C=O.C(O)(=O)C.O>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:36])[C@@H:24]([NH:25][C:26](=[O:35])[CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C@H:21]2[S:20][CH2:19][CH:18]=1)=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3CCOCC3)CS[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 0 °C
Reaction time: 5 h

Procedure:
5.86 g (10 mmols) of 7β-phenoxyacetylamino-3-morpholino-3-cephem-4-carboxylic acid benzhydryl ester are dissolved in 25 ml of dimethyl formamide and 25 ml of glacial acetic acid. The solution is cooled to 0° C. and then 2.04 g of sodium borohydride are added in 100 mg portions over 1 hour, with vigorous evolution of gas occurring after each addition. The reaction mixture is stirred for further 5 hours at room temperature, then diluted with 300 ml of water and extracted with four 100 ml portions of methylene chloride. After neutralisation with aqueous sodium bicarbonate solution, the organic phase is concentrated in vacuo and the dimethyl formamide is distilled off in a high vacuum. The oily, orange residue is chromatographed on silica gel with toluene/ethyl acetate (96:5), affording pure 7β-phenoxyacetylamino-3-cephem-4-carboxylic acid benzhydryl ester as a white foam.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[CH:14]([O:27][C:28]([C:30]1[N:35]2[C:36](=[O:49])[C@@H:37]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@H:34]2[S:33][CH2:32][C:31]=1N1CCOCC1)=[O:29])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(C)C=CC=CC=1>C(O)(=O)C>[CH:14]([O:27][C:28]([C:30]1[N:35]2[C:36](=[O:49])[C@@H:37]([NH:38][C:39](=[O:48])[CH2:40][O:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@H:34]2[S:33][CH2:32][CH:31]=1)=[O:29])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(N3CCOCC3)CS[C@H]12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=CCS[C@H]12
Temperature: 40 °C
Reaction time: 24 h

Procedure:
A suspension is prepared from 142 g (3.75 mmols) of sodium borohydride and 2.4 liters of abs. toluene and then 2.2 liters of glacial acetic acid are added over 4 hours at 20° C. The hydrogen formed during the exothermic reaction is drawn off. To the triacetoxy borohydride so formed are then added, at 20° C., 400 g (0.683 mmol) of 7β-phenoxyacetylamino-3-morpholino-3-cephem-4-carboxylic acid benzhydryl ester in 1.2 liters of glacial acetic acid and 600 ml of abs. toluene. The reaction mixture is warmed to 40° C. and then stirred for 24 hours at this temperature. The solvent is then removed completely by vacuum distillation and the oily residue is partitioned between 1.4 liters of water and 1.4 liters of toluene. The phases are separated and the aqueous phase is extracted with 600 ml of toluene. The combined organic phases are neutralised with saturated sodium bicarbonate solution and washed with two 50 ml portions of water. The organic phase is concentrated under reduced pressure and the oily residue is dissolved in 1.5 liters of ethanol at 55° C. Inoculation of the slowly cooling solution results in the crystallisation of 7β-phenoxyacetylamino-3-cephem-4-carboxylic acid benzhydryl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[CH3:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=1.CC(=O)OCC>>[CH3:12][C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:2][C:3]3[S:4][C:5]4[C:10]([N:11]=3)=[CH:9][CH:8]=[CH:7][N:6]=4)[CH2:21][CH2:20]2)[CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1nc2cccnc2s1
Reactant: Cc1cccc(N2CCNCC2)n1
Solvent: CCOC(C)=O
Product: Cc1cccc(N2CCN(Cc3nc4cccnc4s3)CC2)n1

Procedure:
The product from Example 38A (50 mg, 0.81 mmol), 1-(6-methyl-2-pyridinyl)piperazine (160 mg, 0.98 mmol), and D1 EA (280 μL, 1.6 mmol) were processed as described in Example 38B to provide the title compound. 1H NMR 1H NMR (300 MHz, DMSO-d6) δ 2.68 (m, 4H) 3.32 (s, 3H) 3.53 (m, 4H) 4.04 (s, 2H) 6.54 (m, 1H) 6.61 (d, J=8.48 Hz, 1H) 7.40 (m, 1H) 7.56 (dd, J=8.31, 4.58 Hz, 1H) 8.33 (dd, J=8.31, 1.53 Hz, 1H); (ESI) m/z 326 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=2[F:32])[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)C1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.4 %

Procedure:
To a solution of (RS)-tert-butyl 4-[(4-chlorobenzenesulfonyl)-(2,5-difluorophenyl)-methyl]-piperidine-1-carboxylate (0.75 g, 1.5 mmol) in dichloromethane (5 ml) was added trifluoroacetic acid (5 ml) and the mixture was stirred at room temperature for 30 minutes. The mixture was washed with sodium hydroxide solution (1N, 5 ml), water (5 ml), dried (MgSO4) and evaporated under reduced pressure to yield (RS)-4-[(4-chlorobenzenesulfonyl)-(2,5-difluorophenyl)methyl]-piperidine as a white solid (0.5 g, 83%).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.[ClH:17].CCOC(C)=O>CCOC(C)=O>[ClH:17].[ClH:17].[F:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: FCCN1CCNCC1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
tert-Butyl 4-(2-fluoroethyl)piperazine-1-carboxylate (460 mg) was dissolved in EtOAc (5 ml), and 4 M hydrogen chloride/EtOAc (2.5 ml) was added thereto. After stirring at room temperature for 7 hours, the precipitated solid was collected by filtration to obtain 1-(2-fluoroethyl)piperazine dihydrochloride (406 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:9][C:10]1([CH3:18])[CH2:17][C:15](=O)[CH2:14][C:12](=[O:13])[CH2:11]1>C(O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:15]1[CH2:17][C:10]([CH3:18])([CH3:9])[CH2:11][C:12](=[O:13])[CH:14]=1
Reactant: Nc1ccccc1Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C=C(Nc2ccccc2Cl)C1

Procedure:
A mixture of 12.75 parts of 2-chloroaniline and 14 parts of dimedone is dissolved in 40 volume parts of ethanol under warming, followed by the addition of 3 drops of glacial acetic acid. The solution is refluxed in a water bath for 2 hours, after which time the ethanol is distilled off and the resulting residue is allowed to cool, whereupon yellow crystals separate. These crystals are collected by filtration, washed with isopropyl ether and recrystallized from acetone. The procedure yields 3-(2-chloroanilino)-5,5-dimethyl-2-cyclohexen-1-one as colorless prisms melting at 150°-152° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+].Cl>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CON=C(C(=O)O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
Ethanol (10 ml.) was added to a suspension of ethyl 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetate (syn isomer) (2.2 g.) in a 1 N aqueous solution of sodium hydroxide (12 ml.) and the mixture was stirred for 15 hours at ambient temperature. The reaction mixture was adjusted to pH 7.0 with 10% hydrochloric acid and ethanol was distilled off under reduced pressure. The residual aqueous solution was washed with ethyl acetate, adjusted to pH 2.8 with 10% hydrochloric acid and stirred under ice-cooling to precipitate crystals. The crystals were collected by filtration, washed with acetone and recrystallized from ethanol to give colorless needles of 2-methoxyimino-2-(2-amino-1,3-thiazol-4-yl)acetic acid (syn isomer) (1.1 g.)
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13]1([CH3:22])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[OH:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:22]
Reactant: COC(=O)c1ccc(Br)c(O)c1
Reactant: Cc1ccccc1B(O)O
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: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2C)c(O)c1
Temperature: 110 °C
Yield: 76.4 %

Procedure:
A mixture of methyl 4-bromo-3-hydroxybenzoate (CombiBlocks, 25 g, 108 mmol), o-tolylboronic acid (22 g, 162 mmol), anhydrous potassium carbonate (44 g, 324 mmol) and Pd(PPh3)4 (6.25 g, 5.4 mmol) was prepared in a mixture of toluene (500 mL) and water (100 mL), and then degassed with N2. The reaction mixture was heated at 110° C. for 12 hours. The reaction mixture was cooled at RT, filtered through a Celite pad and washed with a 10% aqueous solution of NaHCO3, water and brine. The organic layer was dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography (silica, pet ether/EtOAc) affording of the title compound as pale yellow solid (20 g, 77%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.85 (s, 1H), 7.52 (s, 1H), 7.45 (d, 1H), 7.20-7.25, (m, 3H), 7.15 (d, 1H), 7.10 (d, 1H), 3.84 (s, 3H), 2.09 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([N:9]2[N:19]=[C:18]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=3)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:10]2=[O:11])[CH2:5][CH2:4][CH2:3]1.[O:28]=[C:29]([OH:40])[C@@H:30]([C@H:32]([C@@H:34]([C@@H:36]([CH2:38][OH:39])[OH:37])[OH:35])[OH:33])[OH:31]>>[CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([N:9]2[N:19]=[C:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:10]2=[O:11])[CH2:5][CH2:4][CH2:3]1.[O:28]=[C:29]([O-:40])[C@@H:30]([C@H:32]([C@@H:34]([C@@H:36]([CH2:38][OH:39])[OH:37])[OH:35])[OH:33])[OH:31]
Reactant: O=C(O)[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CN1CCCC(n2nc(Cc3ccc(Cl)cc3)c3ccccc3c2=O)CC1
Product: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The molar ratio azelastine : gluconic acid is 1:1.25.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[N:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29]([O:31][CH3:32])=[O:30])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[Si](OC(C1OC([Sn](CCCC)(CCCC)CCCC)=CN=1)CCCCCCC1C=CC=CC=1)(C(C)(C)C)(C)C.ClC1N=CC=CC=1C(OC)=O>>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[N:36]=[CH:35][CH:34]=[CH:33][C:28]=3[C:29]([O:31][CH3:32])=[O:30])=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1cccnc1-c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: CCCC[Sn](CCCC)(CCCC)c1cnc(C(CCCCCCc2ccccc2)O[Si](C)(C)C(C)(C)C)o1
Agent: COC(=O)c1cccnc1Cl
Product: COC(=O)c1cccnc1-c1cnc(C(=O)CCCCCCc2ccccc2)o1
Yield: 94 %

Procedure:
Methyl 2-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)nicotinate. The title compound was prepared from 2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-5-(tributylstannyl)oxazole (83 mg, 0.125 mmol) and methyl 2-chloronicotinate following General Procedure A. Flash chromatography (2-10% EtOAc/hexanes) yielded the title compound as a white solid (60 mg, 94%): 1H NMR (CDCl3, 500 MHz) δ 8.80 (dd, 1H, J=6.4, 3.0 Hz), 8.02 (dd, 1H, J=10.0, 6.0 Hz), 7.72 (s, 1H), 7.39-7.32 (m, 3H), 7.25-7.23 (m, 3H), 4.91 (t, 1H, J=7.0 Hz), 4.01 (s, 3H), 2.66 (t, 2H, J=7.5 Hz), 2.03-1.91 (m, 2H), 1.74-1.68 (m, 2H), 1.46-1.35 (m, 6H), 0.96 (s, 9H), 0.17 (s, 3H), 0.05 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 168.0, 166.5, 151.5, 149.9, 145.2, 143.2, 137.5, 128.8, 128.6, 128.0, 126.4, 126.0, 122.7, 69.1, 53.3, 37.0, 36.3, 31.8, 29.6, 26.2, 26.2, 25.5, 18.6, −4.5, −4.8.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N+:22]([O-])=O)=[C:13]([CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:22][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]=1[CH2:15][C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]
Reactant: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)OC(=O)Cc1cc(OCc2ccccc2)ccc1N
Temperature: 80 °C
Reaction time: 1.2 h
Yield: 102.2 %

Procedure:
A mixture of isopropyl 5-benzyloxy-2-nitrophenylacetate (4.2 g), ammonium chloride (0.42 g) and iron powder (4.2 g) in a mixed solvent of ethanol (20 ml) and water (10 ml) was stirred at 80° C. for 1.2 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate and the ethyl acetate layer was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to give isopropyl 2-amino-5-benzyloxyphenylacetate (3.9 g).
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:10]1[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=[C:2]1[Br:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: BrCc1ccccc1
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1

Procedure:
8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione and benzyl bromide were reacted and purified as described in the General procedure G, step A, to afford 77A.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH2:16]Br>CS(C)=O.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:11]#[N:12])[CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Br)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 41.1 %

Procedure:
To a stirred suspension of sodium hydride (60% susp. in oil, 12.24 g, 255 mmol) in anhydrous DMSO (240 mL) is added dropwise 2-(4-bromophenyl)acetonitrile (20.0 g, 102 mmol) dissolved in anhydrous DMSO (40 mL). After 45 min, the reaction mixture is cooled to 0° C. and 1,3-dibromopropane (30.9 g, 15.5 mL, 153 mmol) dissolved in anhydrous DMSO (40 mL) is added slowly to maintain the temperature below 45° C. The reaction mixture is stirred overnight at room temperature and poured in cold water (1.2 L). The product is extracted with CH2Cl2 (6×100 mL), dried on MgSO4, filtered and concentrated under reduced pressure. The product is purified by flash chromatography eluting with hexane:EtOAc (100% to 95:5) to provide the expected product 1-(4-bromophenyl)cyclobutanecarbonitrile (9.9 g, 41%) as a yellowish oil. 1H NMR (300 MHz, CHLOROFORM-D): δ 7.57-7.49 (2H, m), 7.33-7.24 (2H, m), 2.89-2.77 (2H, m), 2.66-2.34 (3H, m), 2.15-1.99 (1H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][C:11](NCC(OC)=O)=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.ClC([O:30][CH2:31][CH:32](C)[CH3:33])=O.[BH4-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[CH:12][C:11](/[CH:33]=[CH:32]/[CH2:31][OH:30])=[N:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)COC(=O)Cl
Reactant: COC(=O)CNc1ccn(-c2ccc(OC)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(-n2ccc(/C=C/CO)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112.5 %

Procedure:
To a solution of 1-[(4-methoxy)phenyl]-3-[E-2-(carboxy)ethenyl]-1H-pyrazole-5-[(2′-aminosulfonyl-[1,1′]-biphen-4-yl)carboxyamide (1.0 g, 1.93 mmol) in 20 mL of tetrahydrofuran at −20° C. was added triethylamine (0.27 mL, 1.93 mmol) and iso-butyl chloroformate (0.25 mL, 1.93 mmol). This mixture was stirred for 30 min and then there was added sodium borohydride (0.22 g, 5.78 mmol) in a minimal amount of water. The reaction mixture was stirred with slow warming to room temperature for 1 h and then was quenched with 10% aq HCl. After diluting with ethyl acetate, the organics were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by prep HPLC (C18 reverse phase column, elution with a H2O/CH3CN gradient with 0.5% TFA) and lyophilized to afford 0.5 g (52%) of the title compound as a white powder. LRMS (ES+): 504.9 (M+H)+.