Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11]([CH2:14][S:15][C:16](=S)[S:17]CC(O)=O)(O)=[O:12].[OH-].[Na+]>>[O:12]=[C:11]1[CH2:14][S:15][C:16](=[S:17])[N:1]1[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)CSC(=S)SCC(=O)O
Reactant: Nc1cccc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc(N2C(=O)CSC2=S)c1
Temperature: 25 °C
Yield: 82.1 %

Procedure:
3-amino-benzoic acid (6.00 g, 43.77 mmol), bis(carboxymethyl)trithiocarbonate (10.2 g, 45.09 mmol) in 1.029 N aqueous sodium hydroxide (44.5 g, 44.06 mmol) was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature. The precipitated solid was filtered, washed successively with 3N aqueous HCl (3×20 mL), water (3×20 mL), ethanol (2×20 mL) and dried in vacuum oven at 60° C. for 2 h to obtain 3-(4-oxo-2-thioxo-thiazolidin-3-yl)-benzoic acid (9.10 g, 82%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 4.34 (2H, s), 7.52-7.55 (1H, m), 7.67 (1H, t, J=8 Hz), 7.87 (1H, t, J=2 Hz), 8.02-8.05 (1H, dt, J=1.2 & 2.8 Hz); ESI-MS: 253.30.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:17][CH2:18][CH2:19][CH3:20])[CH:3]=[CH:4][C:5]([CH:7]1[CH:14]2[CH:10]([O:11][C:12](=[O:15])[CH2:13]2)[CH2:9][CH:8]1[CH3:16])=[O:6].[BH4-].[Na+].Cl>CO>[OH:6][CH:5]([CH:7]1[CH:14]2[CH:10]([O:11][C:12](=[O:15])[CH2:13]2)[CH2:9][CH:8]1[CH3:16])[CH:4]=[CH:3][C:2]([CH3:1])([CH3:21])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC(C)(C)C=CC(=O)C1C(C)CC2OC(=O)CC21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCC(C)(C)C=CC(O)C1C(C)CC2OC(=O)CC21
Reaction time: 1 h

Procedure:
The crude racemic (3aR,4S,5R,6aS)-[S*,R*-(E)]-rac-4-(4,4-Dimethyl-1-oxo-2-octenyl)hexahydro-5-methyl-2H-cyclopenta[b]furan-2-one (10.0 g, 0.0342 mole) in methanol (150 mL) solution was cooled to 0° and treated with sodium borohydride (1.0 g, 0.0264 mole). After stirring for 1 hour at 0°, 3N HCl (15 mL) was added dropwise. The methanol was stripped off under reduced pressure using a 40° bath and the residue was partitioned between water and ether. The ether layer was washed with NaHCO3 solution and witb brine, dried over sodium sulfate and stripped of solvent. The residue of crude, racemic [3aR-[3a alpha,4alpha-(1S*,2E),5beta, 6a alpha]]-4-[1-(hydroxy)-4,4-dimethyl-2-octenyl]hexahydro-5-methyl-2H-cyclopenta[b]furan-2-one was a viscous amber oil weighing 10.26 g (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][C:8]2[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([OH:14])[C:7]=2[CH2:6]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([O:14][C:13]1[C:7]2[CH2:6][N:5]([CH2:4][C:3]3[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=3[Cl:1])[CH2:10][CH2:9][C:8]=2[S:11][C:12]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:26])[CH3:25]
Reactant: CCOC(=O)c1sc2c(c1O)CN(Cc1ccccc1Cl)CC2
Reactant: CC(=O)OC(C)=O
Product: CCOC(=O)c1sc2c(c1OC(C)=O)CN(Cc1ccccc1Cl)CC2

Procedure:
A solution of 5-o-chlorobenzyl-2-ethoxycarbonyl-3-hydroxy-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (35.3 g; 0.1 mole) in acetic anhydride (200 cc) is refluxed during one hour, under a nitrogen atmosphere. The reaction mixture is then evaporated to dryness and the residue is dissolved in ether. The organic phase is washed with water, dried over anhydrous sodium sulfate, treated with vegetable charcoal, filtered and evaporated in vacuo. The resulting pale yellow crystals are recrystallized from cyclohexane; M.p. = 110° C; Yield: 31.9 g (80%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][NH:7][CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:15]([N:18]=[C:19]=[O:20])[CH2:16][CH3:17]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[C:19]([NH:18][CH2:15][CH2:16][CH3:17])=[O:20])=[CH:13][CH:14]=1
Reactant: CCCN=C=O
Reactant: Clc1ccc(CNC2CCCC2)cc1
Product: CCCNC(=O)N(Cc1ccc(Cl)cc1)C1CCCC1
Yield: 73.4 %

Procedure:
In a manner analogous to that described in Example 1, 31 g of N-4-chlorobenzyl-N-cyclopentylamine were reacted with 13 g of propyl isocyanate. 32 g of N-4-chlorobenzyl-N-cyclopentyl-N'-propylurea were obtained. Melting point: 103°-105° C.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:18]3[C:9](=[C:10]([C:27]4[CH:36]=[CH:35][C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[CH:28]=4)[C:11]4[C:16]([CH:17]=3)=[CH:15][C:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:13][CH:12]=4)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:37]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:37][C:17]1[C:18]2[C:9]([C:10]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[C:11]3[C:16]=1[CH:15]=[C:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:13]=[CH:12]3)=[CH:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:20][CH:19]=2
Reactant: c1ccc(-c2ccc3c(-c4ccc5ccccc5c4)c4cc(-c5ccccc5)ccc4cc3c2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1c2cc(-c3ccccc3)ccc2c(-c2ccc3ccccc3c2)c2cc(-c3ccccc3)ccc12
Temperature: 60 °C
Reaction time: 6 h
Yield: 80.2 %

Procedure:
First, 9.09 g of 2,6-diphenyl-9-(2-naphthyl)anthracene were dissolved in 100 mL of N,N-dimethylformamide under heat, and then a solution of 3.91 g of N-bromosuccinimide in 10 mL of N,N-dimethylformamide was added to the solution. The mixture was stirred at 60° C. for 6 hours under heat. After having been cooled to room temperature, the reaction solution was poured into 500 mL of water. The resultant solid was sequentially washed with methanol, water, and methanol. After that, the solid was repeatedly recrystallized with toluene and hexane and washed. Thus, 8.55 g of 9-bromo-2,6-diphenyl-10-(2-naphthyl)anthracene were obtained (in 80% yield).
Reaction SMILES: NC(N)=[O:3].[N+]([C:8]1[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=1)[CH2:11][N:12]1[C:16](=O)[C:15](=[O:18])[N:14]([CH2:19][C:20]([OH:22])=[O:21])[C:13]1=C)([O-])=O.Cl>C(O)(=O)C>[CH2:11]([N:12]1[CH2:16][C:15](=[O:18])[N:14]([CH2:19][C:20]([OH:22])=[O:21])[C:13]1=[O:3])[C:10]1[CH:24]=[CH:25][CH:26]=[CH:8][CH:9]=1
Reactant: C=C1N(CC(=O)O)C(=O)C(=O)N1Cc1cccc([N+](=O)[O-])c1
Reactant: NC(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CN1C(=O)CN(Cc2ccccc2)C1=O
Reaction time: 2 h

Procedure:
A mixture of 1.7 g of the above-prepared urea product of paragraph (1) dissolved in 3 mL of acetic acid and 1 mL of concentrated hydrochloric acid was heated to reflux for four hours. After evaporating the solvent therefrom, 3 mL of acetic acid and 1 mL of concentrated hydrochloric acid were added to the residue followed by stirring for two hours. The resulting component was concentrated, washed well with water and recrystallized from ethanol to give 1.2 g of 1-benzyl-2,4-dioxoimidazolidine-3-acetic acid [Compound 3]. The melting point, MS, IR, NMR, and elementary analysis for the compound were:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][O:7][C:8]1[C:16]([CH3:17])=[N:15][C:14]([CH:18]2[CH2:20][CH2:19]2)=[CH:13][C:9]=1[C:10](O)=[O:11])#[N:2].[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][O:7][C:8]1[C:16]([CH3:17])=[N:15][C:14]([CH:18]2[CH2:19][CH2:20]2)=[CH:13][C:9]=1[C:10]([NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1)=[O:11])#[N:2]
Reactant: Cc1nc(C2CC2)cc(C(=O)O)c1OCc1cccc(C#N)c1
Reactant: N#Cc1ccc(N)cc1
Product: Cc1nc(C2CC2)cc(C(=O)Nc2ccc(C#N)cc2)c1OCc1cccc(C#N)c1
Yield: 55.1 %

Procedure:
The amide coupling of 3-(3-cyano-benzyloxy)-6-cyclopropyl-2-methyl-isonicotinic acid (189) (112 mg, 0.4 mmol) and 4-amino-benzonitrile (51 mg, 0.4 mmol), as described in Example 67, gave 3-(3-cyano-benzyloxy)-N-(4-cyano-phenyl)-6-cyclopropyl-2-methyl-isonicotinamide (190) (90.0 mg, 61% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[C:20]([C:24]2[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=2)[CH:19]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CNCC3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-aminomethylpiperidine (200 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (183 mg) were condensed in the same manner as described in Example 2 to give the title compound as yellow syrup.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=1.BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]>>[CH3:8][N:7]1[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[N:4]=[C:3]1[CH2:2][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: Cn1c(CBr)nc2ccccc21
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: BrCC1CCCCO1
Product: Cn1c(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)nc2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)-1-methyl-1H-benzoimidazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (20%) as a colorless solid: mp>240° C.; 1H NMR (300 MHz, CDCl3) δ7.58-7.53 (m, 2H), 7.30-7.14 (m, 5H), 7.06-6.99 (m, 1H), 6.60 (s, 1H), 6.51 (s, 1H), 5.28 (ABq, 2H), 4.81 (d, J=9.3 Hz, 1H), 4.71 (d, J=9.3 Hz, 1H), 4.22-4.10 (m, 4H), 3.85 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.6, 154.5, 149.1, 144.1, 142.3, 141.7, 137.8, 136.1, 131.9, 128.5, 123.3, 123.0, 122.1, 121.5, 121.4, 118.6, 112.0, 110.1, 109.7, 98.5, 79.3, 64.1, 63.6, 57.3, 37.1, 29.8; MS (ES+) m/z 440.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@@H:13]2[O:18][C:17]3[C:19]([CH:28]=CC)=[C:20]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:32].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[O:18][C:17]3[C:19]([CH:28]=[O:32])=[C:20]([NH:23][C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC=Cc1c(NC(=O)OC)ccc2c1O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)Nc1ccc2c(c1C=O)OC(COS(=O)(=O)c1ccc(C)cc1)CO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of {(2R)-7-[(methoxycarbonyl)amino]-8-[1-propenyl]-2,3-dihydro-1,4-benzodioxin-2-yl}methyl 4-methylbenzenesulfonate (5.12 g, 11.8 mmole) in tetrahydrofuran (400 mL) was added 2.42 mL of 4% aqueous osmium tetroxide (0.39 mmole). After 0.5 hour, sodium periodate (12.6 g, 59.1 mmole) in water (100 mL) was added dropwise over a period of 1 hour. The heterogeneous solution was stirred under nitrogen at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuum to yield the (R)-enantiomer of the title compound as a light beige solid (4.80 g, 97%).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:15])[C:4]=2[CH:3]=1.[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[C@@H:18](O)[CH2:17]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[C@H:18]([O:1][C:2]1[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5](=[O:15])[C:4]=3[CH:3]=1)[CH2:17]2
Reactant: O=C1c2ccccc2-c2ccc(O)cc21
Reactant: O[C@H]1CN2CCC1CC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2-c2ccc(O[C@@H]3CN4CCC3CC4)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
To a 0° C. mixture of 2-hydroxyfluoren-9-one (196 mg, 1.00 mmol; Aldrich), (3R)-quinuclidin-3-ol (151 mg, 1.20 mmol; Acros), and polymer-bound triphenylphosphine (500 mg, 3 mmol/g; Aldrich) in THF (5 mL) was added diethylazodicarboxylate (200 μL, 1.27 mmol; Aldrich). After 1 h, the reaction mixture was allowed to warm to room temperature and was stirred overnight (16 h). The mixture was filtered through diatomaceous earth, the filter pad rinsed with dichloromethane, and the organic extracts purified twice by flash chromatography (80 g silica gel, eluting with 1-5% of 10% NH4OH/MeOH in CH2Cl2) to afford the title compound (104 mg, 0.340 mmol, 34% yield). MS (DCl/NH3): m/z 306 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]=[O:5].[C-:11]#[N:12].[K+].OS([O-])=O.[Na+]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH:4]([OH:5])[C:11]#[N:12]
Reactant: [C-]#N
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#CC(O)c1cc(Cl)ccc1F
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To 2-fluoro-5-chloro-benzaldehyde (12.7 g, 17 mmol) in ethyl acetate (50 mL) was added a solution of KCN (3.3 g) and NaHSO3 (5.3 g) dissolved in H2O (25 mL). It was left stirring overnight before extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried and concentrated. The crude product was purified by silica gel chromatography to give 121A (3.1 g, 99% yield) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.C(=O)([O-])[O-:11].[Na+].[Na+]>C(O)(=O)C.OO>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:11]
Reactant: Cc1cccnc1C
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc[n+]([O-])c1C
Temperature: 95 °C

Procedure:
71.79 g of 2,3-dimethylpyridine (II) was dissolved in 240 ml of acetic acid, to which 40 ml of 30% hydrogen peroxide solution was added and the resulting mixture was heated at 95° C. for 3 hours. Furthermore, 18 ml of a 30% hydrogen peroxide solution was added to the mixture and heated at 95° C. for 13 hours, and thereafter, 700 ml of water was added thereto and the resulting mixture was neutralized with sodium carbonate and extracted with chloroform. The resulting organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting precipitation was recrystallized from diisopropylether to obtain 71.34 g of 2,3-dimethylpyridine N-oxide (III).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[NH:19][CH:20]=[CH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1.[C:23](O)(=[O:25])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4[N:19]([C:23](=[O:25])[CH3:24])[CH:20]=[CH:21][C:15]=4[CH:14]3[CH3:22])=[O:12])[CH:10]=2)[CH:7]=1
Reactant: CC(=O)O
Reactant: CC1c2cc[nH]c2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Product: CC(=O)n1ccc2c1CCN(C(=O)c1cc3ncc(Cl)cn3n1)C2C

Procedure:
(6-Chloro-pyrazolo[1,5-a]pyrimidin-2-yl)-(4-methyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-5-yl)-methanone is reacted with acetic acid to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([C:9]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[O:10])[O:8][C:4]=2[CH:3]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:41][C:42]([F:57])([F:56])[C:43]1[CH:48]=[CH:47][C:46]([N:49]2[CH2:54][CH2:53][CH:52](O)[CH2:51][CH2:50]2)=[CH:45][CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:57][C:42]([F:41])([F:56])[C:43]1[CH:44]=[CH:45][C:46]([N:49]2[CH2:54][CH2:53][CH:52]([O:1][C:2]3[CH:26]=[CH:25][C:5]4[N:6]=[C:7]([C:9]([NH:11][CH:12]5[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17]5)=[O:10])[O:8][C:4]=4[CH:3]=3)[CH2:51][CH2:50]2)=[CH:47][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(O)cc3o2)CC1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2nc3ccc(OC4CCN(c5ccc(C(F)(F)F)cc5)CC4)cc3o2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a stirred solution of tert-butyl 4-(6-hydroxybenzo[d]oxazole-2-carboxamido)piperidine-1-carboxylate (0.15 g, 0.41 mmol) in toluene (4 mL) at room temperature was added diisopropyl azodicarboxylate (0.1 g, 0.49 mmol), 1-(4-(trifluoromethyl)phenyl)piperidin-4-ol (0.1 g, 0.41 mmol), and triphenylphosphine (0.13 g, 0.49 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=2/3) to afford tert-butyl 4-(6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)benzo[d]oxazole-2-carboxamido)piperidine-1-carboxylate (compound 1) as a off-white solid (0.16 g, 66%). 1H-NMR (CDCl3, 300 MHz): δ 7.65 (m, 1H), 7.48 (m, 2H), 7.15 (m, 1H), 7.05 (m, 2H), 6.96 (m, 2H), 4.56 (m, 1H), 4.12 (m, 3H), 3.60 (m, 2H), 3.28 (m, 2H), 2.93 (m, 2H), 2.04 (m, 8H), 1.47 (s, 9H) ppm; MS (ESI): 589.6 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.Br[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.[Pd](Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc([Mg]Cl)cc1
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(C#N)cc2)cc1
Yield: 91 %

Procedure:
4-methylphenylmagnesium chloride (98 g, 20% solution in tetrahydrofuran) is added dropwise over five hours to a refluxing solution of 4-bromobenzonitrile (20 g), palladium (II) chloride (0.78 g) and triphenylphosphine (2.3 g) in tetrahydrofuran (100 ml). [HPLC: yield 91-93%]. After cooling to room temperature tetrahydrofuran is removed under vacuum. The residue is taken up in toluene/water (1:1) (200 ml) and filtered. The aqueous phase is separated off. Solvent is removed by distillation and the crude product recrystallised from ethanol to give 4'-methylbiphenyl-4-carbonitrile as a solid, m.pt. 107-109° C. 1H NMR (CDCl3): 2.41(s,3H), 7.29(d,2H), 7.49(d,2H), 7.66 (d,2H), 7.71 (d,2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1.[CH3:17]I.[H-].[Na+].O>CN(C)C=O>[CH3:17][O:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15][CH3:16])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CO)c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc(C(=O)OC)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84 %

Procedure:
To a solution of methyl 4-(hydroxymethyl)-1-naphthalenecarboxylate (1.0 g, 4.62 mmol) in N,N-dimethylformamide (10 ml) was added methyl iodide (1 ml), and sodium hydride (222 mg, 5.55 mmol, 60% in oil) was further added at 0° C., and the mixture was stirred at room temperature for 10 min. To the reaction solution was added water (30 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1-10:1) to give methyl 4-((methyloxy)methyl)-1-naphthalenecarboxylate (898 mg, 84%).
Reaction SMILES: [C:1]1([CH:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]1([CH:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][N:9]([CH2:19][CH2:20][CH2:21][CH2:22][N:23]3[C:27](=[O:28])[C:26]4[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]3=[O:33])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: c1ccc(C2CNCCc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCc2ccccc2C(c2ccccc2)C1

Procedure:
20.0 g (89.5 mmol) 1-phenyl-1,2,4,5-tetrahydrobenzo[d]azepine, 25.2 g (89.5 mmol) N-(4-bromobutyl)-phthalimide and 18.5 g (134.3 mmol) potassium carbonate are stirred in 200 ml DMF for 6 hours at 60° C. The mixture is concentrated under vacuum and the residue is distributed between 300 ml acetic acid ethyl ester and 100 ml water. The watery phase is extracted with 50 ml acetic acid ethyl ester and the combined organic phases are washed with water. The organic phase is dried over sodium sulfate and evaporated under vacuum until dried: Yield 39.5 g.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.[CH3:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH2:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:23](O)=[O:24])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>>[CH3:12][S:13]([C:16]1[CH:17]=[CH:18][C:19]([CH:22]([CH2:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:23]([NH:1][C:2]2[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=2)=[O:24])=[CH:20][CH:21]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1
Reactant: CCOC(=O)c1cnc(N)s1
Product: CCOC(=O)c1cnc(NC(=O)C(CC2CCOCC2)c2ccc(S(C)(=O)=O)cc2)s1

Procedure:
Ethyl 2-aminothiazole-5-carboxylate (2.21 g, 12.8 mmol) was condensed with 2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionic acid (Preparation 41, 1.00 g, 3.2 mmol) using the procedure described for EXAMPLE 65, to give ethyl 2-[2-(4-methanesulfonylphenyl)-3-(tetrahydropyran-4-yl)propionylamino]thiazole-5-carboxylate: m/z (ES+)=508.3 [M+MeCN+H]+. LiOH.H2O (410 mg, 9.8 mmol) was added to a solution of this ester (1.44 g, 3.1 mmol) in THF-H2O (3:1, 30 mL). The mixture was stirred at 20° C. for 16 h and then at 55° C. for 24 h. The solvents were removed in vacuo, then the residue was dissolved in H2O (50 mL). The aqueous solution was washed with EtOAc (20 mL), before being acidified to pH 1 with 2M HCl and extracted with EtOAc (2×100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to give a solid that was recrystallised (EtOAc-MeOH) to give the title compound: RTA=29.5 min; m/z (ES+)=480.2 [M+MeCH+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]([C:11](OCC)=[O:12])=[CH:9][N:10]=1.[BH4-].[Na+]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][C:8]([CH2:11][OH:12])=[CH:9][N:10]=1
Reactant: CCOC(=O)c1cnc(-c2cccs2)s1
Agent: [BH4-]
Agent: [Na+]
Product: OCc1cnc(-c2cccs2)s1
Yield: 94 %

Procedure:
In substantially the same manner as in Reference Example 111, ethyl 2-(2-thienyl)-5-thiazolecarboxylate was subjected to reduction with sodium borohydride to obtain 2-(2-thienyl)-5-thiazolylmethanol. The yield was 94%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 89-90° C.