Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][OH:24])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH:25]=[O:26])=[CH:11][N:10]=1)=[O:8])[CH3:2].O.P([O-])(O)(O)=[O:32].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][CH:29]=1)[C:7]([C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][OH:24])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:25]([OH:32])=[O:26])=[CH:11][N:10]=1)=[O:8])[CH3:2]
Reactant: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCO)c(OC)cc23)c1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OCCO)c(OC)cc23)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.2 %

Procedure:
To a stirred solution of 1-(3-ethoxy-benzoyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde (70 mg, 0.17 mmol) in t-butanol (1 mL) and water (1 mL) solution was added sodium dihydrogenphosphate monohydrate (97 mg, 0.71 mmol), 2-methyl-2-butene (0.12 mL, 1.06 mmol) and sodium chlorite (98.0 mg, 1.06 mmol) at room temperature. The reaction suspension was then stirred at room temperature for 14 hrs. The resulting two-phase mixture was partitioned between dichloromethane and water and acidified to pH=3 by addition of acetic acid. The aqueous phase was then extracted with dichloromethane (3×20 mL). The combined extracts were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a brown semi-solid oil. The crude product was recrystallized in ethyl acetate to afford 1-(3-ethoxy-benzoyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carboxylic acid (40 mg, 57% yield) as a light yellow solid. HR-MS m/e calcd for C24H25N1O7 (M−H+) 412.1391, found 412.1394; 1H NMR (300 MHz) compatible.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13]3([CH3:25])[CH2:18][CH:17]([CH3:19])[CH2:16][C:15](=[O:20])[CH:14]3[C:21]([O:23][CH3:24])=[O:22])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>CO>[C:1]1([C:7]2[CH:8]=[C:9]([C:13]3([CH3:25])[CH2:18][CH:17]([CH3:19])[CH2:16][CH:15]([OH:20])[CH:14]3[C:21]([O:23][CH3:24])=[O:22])[CH:10]=[CH:11][CH:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1C(=O)CC(C)CC1(C)c1cccc(-c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1C(O)CC(C)CC1(C)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
A solution of methyl (2RS,4RS)-2-(3-phenylphenyl)-2,4-dimethyl-6-oxocyclohexanecarboxylate (131 mg) in methanol (4 mL) at 0° C. was treated with sodium borohydride (44 mg). The resulting mixture was allowed to warm to rt over 30 min. Once at the prescribed temperature, the mixture was stirred for 2 h, and then was concentrated under vacuum. The resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under vacuum to provide methyl (2RS,4RS)-2-(3-phenylphenyl)-6-hydroxy-2,4-dimethylcyclohexanecarboxylate (93 mg) as a mixture of diastereomers. Mass spectrum m/z 361.34 (M+Na+).
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:6]([CH3:14])[C:4]1=[O:5])[CH3:2].Cl[CH:16]([P:20]([O:25][CH2:26][CH3:27])(=[O:24])[O:21][CH2:22][CH3:23])[CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[N:10]([CH2:19][CH2:18][CH2:17][CH2:16][P:20](=[O:24])([O:25][CH2:26][CH3:27])[O:21][CH2:22][CH3:23])[CH:9]=[N:8][C:7]=2[N:6]([CH3:14])[C:4]1=[O:5])[CH3:2]
Reactant: CCn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: CCCC(Cl)P(=O)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOP(=O)(CCCCn1cnc2c1c(=O)n(CC)c(=O)n2C)OCC

Procedure:
9.7 g (0.05 mol) of 1-ethyl-3-methylxanthine were stirred at 70° C. for 6 hours with 12.7 g (0.06 mol) of diethyl chlorobutanephosphonate and 8.3 g of potassium carbonate. The solution was filtered, the solvent was evaporated, and the residue which remained was chromatographed (eluent: ethyl acetate/methanol 10: 1) and crystallized from ethyl acetate/diisopropyl ether.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:3]1=[O:15].[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[CH2:29][CH2:28][NH:27][CH2:26][C@H:25]2[OH:30])=[CH:20][CH:19]=1.C(N(CC)CC)C>>[OH:30][C@@H:25]1[C@@H:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH2:29][CH2:28][N:27]([CH:2]2[CH2:6][CH2:5][N:4]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=3)[C:3]2=[O:15])[CH2:26]1
Reactant: Cc1ccc(CN2CCC(Br)C2=O)cc1
Reactant: COc1ccc([C@@H]2CCNC[C@H]2O)cc1
Solvent: CCN(CC)CC
Product: COc1ccc([C@H]2CCN(C3CCN(Cc4ccc(C)cc4)C3=O)C[C@@H]2O)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (Intermediate 2, 450 mg, 1.68 mmol), (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (313 mg, 1.5 mmol) and triethylamine (23 mL, 16.8 mmol) was stirred at 60° C. for 1 h, followed by heating at 85° C. for 1 h, 120° C. for 1 h and at 140° C. for 1 h. The mixture was cooled and then quenched with 40 mL of water and extracted with 3×50 mL of chloroform. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified via silica gel chromatography (24 g column, gradient of 0-80% ethyl acetate/petroleum ether) to yield 375 mg of (±)-rel-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one as a mixture of four diastereomers. LCMS (method F) RT 1.84 min (74% AP), m/z 395.2 (M+H+); 1H NMR (300 MHz, DMSO-d6) δ ppm 7.31-7.41 (m, 8H) 6.86 (d, J=9.07 Hz, 2H) 4.66 (s, 1H) 3.73 (s, 3H) 3.49 (s, 2H) 2.59 (d, J=10.58 Hz, 2H) 2.32-2.47 (m, 3H) 1.89 (td, J=12.65, 4.53 Hz, 2H) 1.56 (d, J=11.71 Hz, 2H).
Reaction SMILES: [ClH:1].[CH2:2]([C:9]1[N:10]=[C:11]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:12]2[CH2:18][CH2:17][N:16](CC3C=CC=CC=3)[CH2:15][C:13]=2[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1CC=CCC=1>CCO.[Pd]>[ClH:1].[CH2:2]([C:9]1[N:10]=[C:11]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[C:12]2[CH2:18][CH2:17][NH:16][CH2:15][C:13]=2[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1ccc(-c2nc(Cc3ccccc3)nc3c2CCN(Cc2ccccc2)C3)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1=CCC=CC1
Solvent: CCO
Product: Fc1ccc(-c2nc(Cc3ccccc3)nc3c2CCNC3)cc1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
To a solution of 2,7-dibenzyl-4-(4-fluoro-phenyl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride in EtOH was added 10% Pd/C (1 equiv) followed by 1,4-cyclohexadiene (5 equiv). The mixture was heated at 85° C. for 5 h, filtered and concentrated. The residue was dissolved in CH2Cl2 and treated with Dowex 550A resin. After 1 h, the resin was removed by filtration and the filtrate was concentrated. Chromatography on SiO2 (2 M NH3 in MeOH/CH2Cl2) afforded the title compound. MS (ESI): exact mass calcd. for C20H18FN3, 319.15; m/z found, 320.4 [M+H]+. 1H NMR (MeOH-d4): 7.70-7.67 (m, 2H), 7.36-7.35 (m, 2H), 7.31-7.25 (m, 4H), 7.20-7.17 (m, 1H), 4.42 (s, 2H), 4.26 (s, 2H), 3.48 (t, J=6.1, 2H), 3.09 (t, J=6.1, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[NH:5][CH3:6].Br.Br[CH:13]([C:15]1[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]2[C:24]=1[O:23][C:22]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[CH:21][C:20]2=[O:31])[CH3:14]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]([CH3:6])[CH:13]([C:15]2[CH:16]=[C:17]([C:32]([N:34]([CH3:36])[CH3:35])=[O:33])[CH:18]=[C:19]3[C:24]=2[O:23][C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:21][C:20]3=[O:31])[CH3:14])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CNc1ccc(F)c(Cl)c1
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: CC(c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1ccc(F)c(Cl)c1
Yield: 53.5 %

Procedure:
3-chloro-4-fluoro-N-methylaniline (260 mg, 1.63 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (200 mg, 0.41 mmol, as described in Example 3.03), using an analgous procedure to that described in Example 3.00, to afford 8-(1-((3-chloro-4-fluorophenyl)(methyl)amino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (107 mg, 53.7%) as a white solid. Mass Spectrum: M+H+ 488. NMR Spectrum: (DMSOd6) 1.55 (d, 3H), 2.63 (s, 3H), 2.91 (s, 3H), 3.01 (s, 3H), 3.20-3.29 (m, 2H), 3.30-3.37 (m partially hidden by H2O, 2H), 3.42-3.49 (ms, 2H), 3.49-3.57 (m, 2H), 5.54 (s, 1H), 5.55 (q, 1H), 6.79 (dd, 1H), 6.98 (dd, 1H), 7.23 (dd, 1H), 7.68 (d, 1H), 7.87 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27]C)=O)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.[NH3:29].O1CCCC1>CO>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([NH2:29])=[O:27])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: N
Reactant: COC(=O)c1cccc(Cc2c(-c3ccccc3)[nH]c3cc(OC)ccc23)n1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(Cc3cccc(C(N)=O)n3)c(-c3ccccc3)[nH]c2c1

Procedure:
A mixture of methyl 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxylate (500 mg), a solution (about 7 mol/L, 20.1 mL) of ammonia in methanol, and tetrahydrofuran (6.7 mL) was stirred at room temperature for 61 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (490 mg). 1H-NMR (CDCl3) δ ppm: 3.86 (3H, s), 4.42 (2H, s), 5.37-5.60 (1H, br), 6.77 (1H, dd, J=2.3, 8.8 Hz), 6.92 (1H, d, J=2.3 Hz), 7.24-7.29 (1H, m), 7.31-7.39 (2H, m), 7.40-7.49 (2H, m), 7.50-7.58 (2H, m), 7.69 (1H, t, J=7.8 Hz), 7.75-7.95 (1H, br), 7.97-8.03 (1H, m), 8.09 (1H, br s).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([C:14](=[O:21])[CH2:15][NH:16][CH:17]2[CH2:20][CH2:19][CH2:18]2)=[CH:6][C:5]=1[Br:22].[BH4-].[Na+]>>[NH2:3][C:4]1[C:9]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:7]([CH:14]([OH:21])[CH2:15][NH:16][CH:17]2[CH2:18][CH2:19][CH2:20]2)=[CH:6][C:5]=1[Br:22]
Reactant: Nc1c(Br)cc(C(=O)CNC2CCC2)cc1C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: Nc1c(Br)cc(C(O)CNC2CCC2)cc1C(F)(F)F

Procedure:
m.p. of the hydrochloride: 189°-191° C. (decomp.), was prepared from 4'-amino-3'-bromo-2-cyclobutylamino-5'-trifluoromethyl-acetophenone hydrochloride and sodium borohydride analogous to Example 1.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[Cl:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([Cl:20])[C:18]=1[OH:19])[C:12](OC)=[O:13]>C([O-])(=O)C.[Ca+2].C([O-])(=O)C.[Sb]=O>[CH3:1][C:2]([CH3:7])([CH2:5][O:6][C:12]([C:11]1[CH:16]=[C:17]([Cl:20])[C:18]([OH:19])=[C:9]([Cl:8])[CH:10]=1)=[O:13])[CH2:3][O:4][C:12]([C:11]1[CH:16]=[C:17]([Cl:20])[C:18]([OH:19])=[C:9]([Cl:8])[CH:10]=1)=[O:13]
Reactant: COC(=O)c1cc(Cl)c(O)c(Cl)c1
Reactant: CC(C)(CO)CO
Agent: CC(=O)[O-]
Agent: O=[Sb]
Agent: [Ca+2]
Product: CC(C)(COC(=O)c1cc(Cl)c(O)c(Cl)c1)COC(=O)c1cc(Cl)c(O)c(Cl)c1
Temperature: 200 °C
Yield: 69.5 %

Procedure:
A mechanically stirred mixture of 0.6 g of calcium acetate, 0.6 g of antimony oxide, 15.7 g (0.15 M) of 2,2-dimethyl-1,3-propanediol, and 132 g (0.6 mole) of methyl 3,5-dichloro-4-hydroxybenzoate was heated under a nitrogen atmosphere at 200° C. for 18 hours. The reaction mixture was washed three times with benzene in a Waring Blendor and extracted for five days with 2 liters of hot benzene. The extract, on cooling, yielded 50.5 g of 4,4'-[2,2-dimethyl-1,3-propanediylbis(oxycarbonyl)]bis(2,6-dichlorophenol) melting at 180°-181° C. The infrared spectrum was consistent with the indicated structure. The compound contained 4.115 meq. of OH/g, indicating a molecular weight of 486 for the bisphenol.
Reaction SMILES: I[C:2]1[C:3]([CH:13]([CH3:15])[CH3:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:16][N:17](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[C:16]([C:2]1[C:3]([CH:13]([CH3:15])[CH3:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:17]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(I)c(C(C)C)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(C#N)c(C(C)C)cc1C
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 83 %

Procedure:
To a dried round bottom flask was added methyl 5-iodo-4-isopropyl-2-methylbenzoate (compound 198.2, 2.00 g, 6.29 mmol, 1.0 equiv), zinc cyanide (1.48 g, 12.6 mmol, 2.0 equiv), DMF (20 mL) and Pd(PPh3)4 (364 mg, 0.315 mmol, 0.05 equiv). The system was purged with nitrogen followed by argon and the mixture was heated at 100° C. for 15 hours. The reaction was allowed to cool to room temperature then diluted with ethyl acetate (50 mL) and quenched with 1 M FeSO4 (25 mL). The mixture was stirred vigorously for 40 minutes then filtered through celite and washed with 1 M FeSO4 (15 mL), water (50 mL) and ethyl acetate (150 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (50 mL). The combined organic layers were washed with brine (4×100 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by silica column chromatography (hexanes to 8% ethyl acetate) to obtain the title compound (1.14 g, 83%). 1H NMR (400 MHz, CDCl3): δ 8.19 (s, 1H), 7.25 (s, 1H), 3.91 (s, 3H), 3.37 (septet, J=6.8 Hz, 1H), 2.67 (s, 3H), 1.32 (d, J=6.8 Hz, 6H).
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].C1(C)C=CC=CC=1.Cl[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC([B-](C2C=CC(C)=CC=2)(C2C=CC(C)=CC=2)C2C=CC(C)=CC=2)=CC=1.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.O>[CH2:29]([O:28][C:26](=[O:27])[CH:25]([C:23]#[N:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:30]
Reactant: Clc1ccccc1
Reactant: CCOC(=O)CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(C#N)c1ccccc1
Yield: 53.1 %

Procedure:
A 30-ml four-necked flask was equipped with a stirrer, a thermometer and a reflux condenser. 0.022 g (0.1 mmol) of palladium (II) acetate, 2.459 g (15 mmol) of sodium phosphate and 15 ml of toluene were weighed in the flask, followed by stirring. Further, 0.116 g (0.2 mmol) of tri-tert-butylphosphonium tetra-para-tolylborate obtained in Example B-3 was weighed in air and added into the flask. The flask was purged with argon, followed by stirring at 25° C. for 30 minutes. 0.563 g (5 mmol) of chlorobenzene was added, followed by stirring at 25° C. for 30 minutes. 0.622 g (5.5 mmol) of ethyl cyanoacetate was added, followed by stirring at 100° C. for 12 hours. After the completion of the reaction, 5 ml of water was added, followed by separation. The organic phase was purified by column chromatography to afford 0.502 g of ethyl-2-phenylcyanoacetate (yield: 53 mol % based on chlorobenzene). The identification of the product was made by mass spectroscopy, 1H-NMR and 13C-NMR.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][CH:6]([C:11]([O:13]C)=O)[C:7](OC)=[O:8].C(O)(=O)C.[CH:19]([NH2:21])=[NH:20].Cl>CO>[OH:13][C:11]1[C:6]([O:5][CH3:4])=[C:7]([OH:8])[N:21]=[CH:19][N:20]=1
Reactant: COC(=O)C(OC)C(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1c(O)ncnc1O
Temperature: 0 °C

Procedure:
A modified procedure of Bretschneider, Richter, and Klotzer, Monatsh. Chem. 96(6), 1661-76 (1965), was used. Absolute methanol (1.0 l) was added with ice bath cooling to sodium methoxide (175 g, 3.24 mole) in a 3 L round bottom flask. When the mixture had cooled to less than 20° C., dimethyl methoxymalonate (162.14 g, 1.00 mole) was added, and then solid formamidine acetate (104.11 g, 1.00 mole) was added. The mixture was stirred in the ice bath for 30 minutes, and then refluxed for 1 hour. The mixture was cooled in a cold water bath and then concentrated HCl (about 350 mL) was added until the mixture was strongly acidic on pH test paper. The precipitate was filtered, suspended in cold water (about 400 ml), and then filtered again. The white powder was dried in vacuo (125.84 g, 88.7%), and carried on without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.[CH2:24](Cl)[O:25][CH3:26].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:14][CH2:24][O:25][CH3:26])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COCCl
Reactant: Cc1ccc(C2(O)CCCC2)c(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOC1(c2ccc(C)cc2Br)CCCC1
Temperature: 25 °C
Reaction time: 11 h
Yield: 81 %

Procedure:
To a stirring solution of 1-(2-bromo-4-methylphenyl)cyclopentanol (4.2 g, 16.5 mmol) in DCM (40 mL) at rt were successively added DIPEA (11 mL, 66 mmol) and MOMCl (2.5 mL, 33 mmol) over a 10 min period. The solution was stirred for 11 h at rt, and afterwards a NH4Cl-saturated aqueous solution (40 mL) was added. The aqueous phase was segregated, and the organic one was washed with water (30 mL), brine (30 mL), dried with anhydrous Na2SO4, filtered, and concentrated to give pure 2-bromo-1-(1-(methoxymethoxy)cyclopentyl)-4-methylbenzene (4.0 g, yield 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[O:5][C:6]=1[CH3:7].[NH3:17]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([OH:5])[C:8]([C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:17][C:6]=1[CH3:7]
Reactant: N
Reactant: Cc1cccnc1C(=O)c1cc(C)c(C)o1
Solvent: CO
Product: Cc1cc(O)c(-c2ncccc2C)nc1C
Temperature: 160 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
(4,5-Dimethylfuran-2-yl)-(3-methylpyridin-2-yl)-methanone (930 mg), methanol (7.5 ml), and a 28% aqueous ammonia solution (9 ml) were placed in a sealed tube and was stirred at 160° C. overnight. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation under the reduced pressure, and the residue was purified by column chromatography using hexane-ethyl acetate to give 5,6,3′-trimethyl-[2,2′]bipyridin-3-ol (109 mg, yield 86%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[SH:40][C:41]([CH3:46])([CH3:45])[CH2:42][CH2:43][OH:44].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.N>O1CCOCC1.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].O>[CH3:45][C:41]([S:40][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]3[N:10]([CH2:11][CH2:12][C:13]4[CH:29]=[CH:28][CH:27]=[CH:26][C:14]=4[CH:15]3[O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[C:9]=2[CH3:30])=[CH:4][CH:3]=1)([CH3:46])[CH2:42][CH2:43][OH:44]
Reactant: CC(C)(S)CCO
Reactant: Cc1c(-c2ccc(Br)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: N
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccc(SC(C)(C)CCO)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 110 °C

Procedure:
To a solution of compound 2-(4-bromophenyl)-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 122A) (60 mg, 0.129 mmoles) in 1,4-dioxane (1.5 mL) in a screw-capped vial under argon are added diisopropylethylamine (33 μL, 0.142 mmole), 3-mercapto-3-methylbutan-1-ol (20 μL, 0.193 mmole), bis(dibenzilideneacetone)palladium(0) (4 mg, 6.4 μmole), Xantphos (4 mg, 6.4 μmole). The reaction mixture is heated at 110° C. overnight. As the reaction is not complete, bis(dibenzilideneacetone)Palladium(0) (4 mg, 6.4 μmole), Xantphos (4 mg, 6.4 μmole), diisopropylethylamine (33 μL, 0.142 mmole), 3-mercapto-3-methylbutan-1-ol (20 μL, 0.193 mmole) are added to the reaction mixture. After one overnight at 120° C., water is added to the reaction mixture and pH adjusted to 9-10 by adding concentrated ammonia solution. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) as eluent with a gradient from (95:5) to (90:10) to afford 3-methyl-3-{4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylsulfanyl}-butan-1-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:52]=[CH:51][CH:50]=[CH:49][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH:18]2[O:33][CH2:34][CH2:35][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[CH2:43][CH2:44][C:45]([O:47]C)=[O:46])=[CH:13][CH:12]=1.[OH-].[Na+].Cl>O1CCOCC1.[Cl-].[Na+].O>[C:45]([CH2:44][CH2:43][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[O:36][CH2:35][CH2:34][O:33][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:49]=[CH:50][CH:51]=[CH:52][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[CH2:19]1)([OH:47])=[O:46]
Reactant: COC(=O)CCc1ccccc1OCCOC1CN(C(=O)OCc2ccccc2)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCCOc2ccccc2CCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A solution of 0.16 g of benzyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-{2-[2-(2-methoxycarbonylethyl)phenoxy]ethoxy}piperidine-1-carboxylate in 4 ml of dioxane is admixed with 0.4 ml of 2N NaOH and stirred at 80° C. over 3 hours. The reaction mixture is cooled to room temperature and acidified to pH 6 with 1N HCl. The solution is admixed with brine and extracted with ethyl acetate (2×). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The crude title compound is obtained as a yellow foam from the residue. Rt=5.64.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.[S:8]([O-:11])([O-:10])=[O:9].[Na+:12].[Na+]>>[CH:3]1([CH2:2][S:8]([O-:11])(=[O:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Na+:12]
Reactant: O=S([O-])[O-]
Reactant: BrCC1CCCC1
Agent: [Na+]
Product: O=S(=O)([O-])CC1CCCC1

Procedure:
The subtitle compound was prepared by the method of Preparation 61 from 1-(bromomethyl)cyclopentane [Preparation 63] and sodium sulphite. The crude product was purified by recrystallisation from water to afford sodium cyclopentylmethanesulfonate as a white solid.