Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:11][C:12](=O)[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[C:7]([Br:10])=[CH:8][CH:9]=1)=O.C([O-])(=O)C.[NH4+:28].O>C(O)(=O)C>[Br:10][C:7]1[N:6]2[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[NH:28][C:3](=[O:2])[C:5]2=[CH:9][CH:8]=1
Reactant: [NH4+]
Reactant: COC(=O)c1ccc(Br)n1CC(=O)c1ccc(C(F)(F)F)cc1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cn2c(Br)ccc12
Temperature: 130 °C
Yield: 97.4 %

Procedure:
A mixture of 5-bromo-1-[2-oxo-2-(4-trifluoromethyl-phenyl)-ethyl]-1H-pyrrole-2-carboxylic acid methyl ester (0.09 g, 0.23 mmol) and ammonium acetate (90 mg, 1.17 mmol) in glacial acetic acid (3 mL) were heated to 130° C. overnight. At this time, the reaction was treated with water. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to afford 6-bromo-3-(4-trifluoromethyl-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one (80 mg, 97%) as light brown solid. 1H NMR (chloroform-d) δ ppm 7.75-7.83 (m, 7H), 7.68-7.74 (m, 2H), 7.27 (d, J=1.5 Hz, 1H), 7.23 (s, 1H), 7.20 (s, 1H). LC-MS calcd. for C14H7BrF3N2O [(M−H)−] 356, obsd. 354.9.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=2[Cl:14])=[N:5][N:6]=1.BrC1S[C:19]([N:21](C)[CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=NN=1>CN1C(=O)CCC1.C(Cl)Cl>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[S:3][C:2]([N:21]([CH3:19])[CH:22]3[CH2:23][C:24]([CH3:30])([CH3:31])[NH:25][C:26]([CH3:29])([CH3:28])[CH2:27]3)=[N:6][N:5]=2)=[C:8]([Cl:14])[CH:9]=1
Reactant: Clc1cc(Br)ccc1-c1nnc(Br)s1
Reactant: CN(c1nnc(Br)s1)C1CC(C)(C)NC(C)(C)C1
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CN(c1nnc(-c2ccc(Br)cc2Cl)s1)C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C

Procedure:
A stirred solution of 2-bromo-5-(4-bromo-2-chlorophenyl)-1,3,4-thiadiazole (700 mg, 1.975 mmol) and 5-bromo-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1,3,4-thiadiazol-2-amine (Intermediate 4) (1009 mg, 5.92 mmol) in NMP (4 mL) was heated to 120° C. for 3 hours. The reaction mixture was allowed to cool to room temperature then diluted with DCM (100 mL) and washed with saturated NaHCO3(aq) (100 mL). The organic phase was separated, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo to a brown liquid. The crude material was purified by silica flash chromatography, running a gradient from 0-10% [2M NH3 in MeOH]/DCM over 30 minutes, collecting at 320 nm to afford the title compound as a light brown glass-like solid (750 mg, 86% yield). LC-MS: Rt 1.10 min; MS m/z 445.1 [M+2H]+ [Method A]. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.96 (d, J=8.59 Hz, 1H), 7.93 (d, J=2.02 Hz, 1H), 7.70 (dd, J=8.59, 2.02 Hz, 1H), 4.36 (tt, J=12.38, 3.28 Hz, 1H) 3.01 (s, 3H), 1.62 (dd, J=12.13, 3.03 Hz, 2H), 1.43 (t, J=12.13 Hz, 2H), 1.28 (br. s., 1H), 1.20 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[F:7][C:8]([F:15])([F:14])[C:9](OCC)=[O:10]>O1CCCC1>[F:7][C:8]([F:15])([F:14])[C:9]([NH:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4])=[O:10]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC(CO)CO
Solvent: C1CCOC1
Product: O=C(NC(CO)CO)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4 g of 2-aminopropan-1,3-diol (43.9 mmol) were supplemented with 20 ml of tetrahydrofuran. The reaction mixture was then cooled to 0° C. on an ice bath and 5.8 ml of ethyl trifluoroacetate (48.3 mmol) were gradually added. This solution was stirred for 2 hours at room temperature.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([NH2:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>>[CH2:14]([NH:19][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1)[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CC(C)(C)CN
Product: CC(C)(C)CN[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
from 4-phenylcyclohexanone and neopentylamine. Colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Cl)=[CH:4][CH:3]=1.[C:10]([NH:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1)([CH3:13])([CH3:12])[CH3:11].CO.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1COCC1>[C:10]([NH:14][C:15](=[O:23])[C:16]1[C:21]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: Fc1ccc([Mg]Cl)cc1
Reactant: CC(C)(C)NC(=O)c1ccc(Cl)nc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)NC(=O)c1cnc(Cl)cc1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 47.9 %

Procedure:
14.1 ml (14.1 mMol) 4-Fluoro-phenylmagnesium chloride solution (1M in THF) were added over 10 minutes to a solution of 1.0 g (4.7 mMol) N-tert.-butyl-6-chloro-nicotinamide in 5.0 ml THF cooled to 0° C. and the reaction mixture was stirred 18 hours at 35° C. After cooling to 0° C., 1.14 ml (28.2 mMol) methanol were added over 20 minutes, followed, after 15 minutes, by 1.17 g (5.2 mMol) 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. After 30 minutes at room temperature, the brown solution was concentrated under reduced pressure to about 10 g, heated to 50° C. and 20 ml tert.-butyl-methylether were added. The resulting suspension was stirred 1 hour at 55° C., then 1 hour at room temperature and filtered. The filtrate was concentrated under reduced pressure and digested in 5 ml n-hexane/ethyl acetate 4:1 to yield 0.69 g (48%) N-tert.-butyl-6-chloro-4-p-fluoro-phenyl-nicotinamide as a light brown powder of m.p.=168-173° C.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[CH2:16][NH:15][CH2:14][CH2:13][C:12]=3[CH2:11]2)(=O)=O)=CC=1.O.[BrH:21]>C1(O)C=CC=CC=1>[BrH:21].[BrH:21].[C:17]12[CH2:18][NH:10][CH2:11][C:12]=1[CH2:13][CH2:14][NH:15][CH2:16]2
Reactant: Cc1ccc(S(=O)(=O)N2CC3=C(CNCC3)C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: O
Product: C1CC2=C(CN1)CNC2
Yield: 98 %

Procedure:
1.5 g of N8 -(p-toluenesulfonyl)-3,8-diazabicyclo[4.3.0]non-1(6)-ene, prepared in Preparation 8, was suspended in 15 ml of 48% hydrobromic acid and 2 g of phenol, and the reaction mixture was refluxed for 4 hours. After cooling the reaction mixture, 20 ml of water was added. The mixture was washed with chloroform (40 ml×3). The aqueous phase was taken and decolorized by active carbon. The aqueous phase was concentrated under reduced pressure and thus resulting solid was washed with 1:1 methanol-ethylether solvent. 0.9 g of the title compound was obtained (yield 98%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[S:21]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]#[N:10])=[CH:11][CH:12]=1)([CH3:20])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(CCCO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
A 16.1 g (0.1 mol) quantity of 4-(3hydroxypropyl)benzonitrile was admixed with 27.8 ml (0.2 mol) of triethylamine and 300 ml of methylene chloride. To the mixture was added 15.5 ml (0.2 mol) of methanesulfonyl chloride at 0° C. The reaction mixture was stirred at room temperature for 12 hours and then concentrated. The concentrate was diluted with 500 ml of benzene, and washed with saturated aqueous solution of sodium chloride. The washed dilution was dried over Na2SO4 and concentrated, giving 24.0 g (yield 100%) of crude 4-(3-mesyloxypropyl)benzonitrile in the form of an oil.
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[CH3:8][C@H:9]1[CH2:14][N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[C@H:12]([CH3:23])[CH2:11][N:10]1[C@H:24]([C:32]1[CH:44]=[CH:43][C:35]([C:36]([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=1.CI>CCCCC>[CH3:8][C@H:9]1[CH2:14][N:13]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C@H:12]([CH3:23])[CH2:11][N:10]1[C@H:24]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[O:37])=[CH:43][CH:44]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:4])[CH:26]=1
Reactant: CCN(CC)C(=O)c1ccc([C@H](c2cccc(O)c2)N2C[C@@H](C)N(Cc3ccc(F)cc3)C[C@@H]2C)cc1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CI
Product: CCN(CC)C(=O)c1ccc([C@H](c2cccc(OC)c2)N2C[C@@H](C)N(Cc3ccc(F)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Sodium hydride (60% dispersion in oil, 400 mg (240 mg NaH, 10 mmol)) was washed with pentane (2×7 mL), then tetrahydrofuran (10 mL) added as supernatant. 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-hydroxybenzyl)-N,N-diethylbenzamide (Example 1, 1.007 g, 2.0 mmol) was dissolved in the stirred suspension, and when effervescence had subsided, methyl iodide (249 μL, 568 mg, 4 mmol) was added. The reaction mixture was sealed under nitrogen and stirred for 6 h at ambient temperature. The reaction mixture was evaporated to dryness, and the residue partitioned between ethyl acetate (15 mL) and water (5 mL). The organic layer was separated, the aqueous portion extracted with ethyl acetate (2×10 mL) and the combined organic extracts dried over anhydrous sodium sulfate. The organic solution was evaporated to a pale yellow gum, which on trituration and sonication with pentane yielded 4-((alpha-R)-alpha-((2S,5R)-2,5-dimethyl-4-(4-fluorobenzyl)-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide as a flocculent white solid (0.798 g, 77% after drying at room temperature and 5 mm Hg). Calc. for C32H40FN3O2 0.25 H2O: C, 73.60; H, 7.82; N, 8.05; F, 3.64. Found C, 73.58; H, 7.70; N, 8.04; F, 3.84%. 1H NMR (CDCl3, 300 MHz); δ 1.09 (d, J=6.2 Hz, 6H, superimposed on br m, 3H); 1.21 (br m, 3H); 1.99 (m, 2H); 2.57 (br m, 2H); 2.66 (m, 3H); 3.15 (d, J=13.3 Hz, 1H); 3.27 (br m, 2H); 3.54 (br m, 2H); 3.78 (s, 3H); 3.84 (d, J=13 Hz, 1H); 5.10 (s, 1H); 6.76 (s, 1H); 6.70 (d, J=8.1 Hz, 2H); 6.96 (t, J=8.2 Hz, 2H); 7.26 (m, 5H); 7.46 (d, J=7.8 Hz, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[O:34][N:33]=2)=[CH:28][CH:27]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>ClC(Cl)C.CC(O)=O>[NH:2]1[C:1]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:4][CH:3]1[CH2:24][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:36]=[C:35]([C:37]([NH2:39])=[O:38])[O:34][N:33]=2)=[CH:30][CH:31]=1
Reactant: c1ccc2c(c1)CNC2
Reactant: NC(=O)c1cc(-c2ccc(C=O)cc2)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: NC(=O)c1cc(-c2ccc(CC3Cc4ccccc4N3)cc2)no1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
To a solution of isoindoline (11 μL, 0.097 mmol) in dichloroethane (1 mL) was added Na(OAc)3BH (59 mg, 0.278 mmol). The mixture was stirred at room temperature under argon for 20 min. A slurry of 3-(4-formyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 20; 20 mg, 0.093 mmol) in dichloroethane (1 mL) was added, followed by AcOH (20 μL). The reaction mixture was stirred at room temperature overnight. 1 M Na2CO3 solution was added and the mixture was extracted with CHCl3 (3×25 mL). The organic layer was washed with brine, dried (Na2SO4), evaporated, and purified by chromatography (20-25% acetone/CH2Cl2) to give 3-[4-(1,3-dihydro-indol-2-ylmethyl)-phenyl]-isoxazole-5-carboxylic acid amide (10 mg, 32%) as an off-white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.36 (br. s., 1H), 7.99 (br. s., 1H), 7.88 (d, J=8.2 Hz, 2H), 7.48-7.61 (m, 3H), 7.09-7.26 (m, 4H), 5.74 (s, 2H), 4.07 (br. s., 1H), 3.92 (s, 1H), 3.30 (d, J=3.0 Hz, 2H), 3.15 (d, J=4.8 Hz, 2H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH3:3].[NH2:27][C:28]1[N:33]=[C:32](Cl)[C:31]([C:35]#[N:36])=[C:30]([CH3:37])[N:29]=1.C(N(CC)CC)C>CS(C)=O>[NH2:27][C:28]1[N:33]=[C:32]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH3:3])[C:31]([C:35]#[N:36])=[C:30]([CH3:37])[N:29]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 85 °C
Yield: 83.3 %

Procedure:
To a 50 mL pear flask were added tert-butyl (S)-4-(5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)piperazine-1-carboxylate (0.85 g, 2.37 mmol) and 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.638 g, 3.78 mmol) in DMSO (12 mL). Triethylamine (1.65 mL, 11.8 mmol) was added to the mixture which was then heated to 85° C. for three hours. The reaction mixture was partitioned between saturated NaHCO3 and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated. The crude product was purified by column chromatography (SiO2, 25-100% EtOAc/heptane gradient) to give the title compound as an off-white solid (0.97 g, 83%). ESI-MS m/z [M+H]+ calc'd for C25H33N9O2, 492. found 492.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:25]([O:27][CH3:28])=[O:26])[CH:2]=[CH2:3]>C(Cl)Cl.C(#N)C.[Pd](Cl)Cl>[CH3:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([O:14][C:13]2[C:4]([CH:1]=[CH:2][CH3:3])=[C:5]([C:25]([O:27][CH3:28])=[O:26])[CH:6]=[C:7]([CH:12]=2)[C:8]([O:10][CH3:11])=[O:9])=[CH:20][CH:19]=1)(=[O:22])=[O:23]
Reactant: C=CCc1c(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)cc1C(=O)OC
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: ClCCl
Product: CC=Cc1c(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)cc1C(=O)OC
Yield: 74.3 %

Procedure:
To a solution of dimethyl 4-allyl-5-(4-(methylsulfonyl)phenoxy)isophthalate (3.0 g, 8.814 mmol) in CH2Cl2 (25 mL) was added bis(acetonitrile-palladium(II) chloride (229 mg, 0.881 mmol). The mixture was refluxed under N2 for 14 hours. After removal of the solvent, the crude material was introduced into a silica gel column and eluted with EtOAc in hexanes (10/90 to 30/70) to afford the title compound (2.65 g, 88%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82 (dd, J=6.69, 1.79 Hz, 3 H) 3.04-3.18 (m, 3 H) 3.93 (d, 6 H) 6.00 (none, 1 H) 6.22 (dd, J=16.01, 6.78 Hz, 1 H) 6.62 (dd, J=16.01, 1.70 Hz, 1 H) 6.94-7.09 (m, 2 H) 7.77 (d, J=1.70 Hz, 1 H) 7.85-8.00 (m, 2 H) 8.28 (d, J=1.70 Hz, 1 H); LC-MS (ESI)+m/z 405.00 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[O:9][CH:10]=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([C:17]1[CH2:18][O:19][CH2:20][CH:21]=1)(=O)=O>>[CH2:1]([C:8]1[C:17]2[CH2:18][O:19][CH2:20][C:21]=2[C:10]([OH:9])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)C1=CCOC1
Reactant: c1ccc(Cc2ncco2)cc1
Product: Oc1cnc(Cc2ccccc2)c2c1COC2

Procedure:
11.2 g (70 millimoles) of 2-benzyloxazole and 10.5 g (70 millimoles) of 3-methylsulfonyl-2,5-dihydrofuran are heated for 7 hours at 160°. The unconverted starting compounds are distilled off in a high vacuum and the distillation residue is extracted with methylene chloride. The 4-benzyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol contained in the extract is separated off by chromatography over silica gel (using methylene chloride and ethyl acetate). 4.3 g are obtained. Recrystallization from benzene/methylene chloride gives a pure product.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][NH2:26].[BH4-].[Na+].O>C(O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][NH:26][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Reactant: COc1ccccc1CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCCC2NCCc1ccccc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
15.2 g (74.5 mmol) of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate [U. Gerlach and T. Wollmann, Tetrahedron Lett. 1992, 33 (38), 5499-5502] and 11.5 g (74.5 mmol) of 2-(2-methoxyphenyl)ethylamine in 50 ml of ethanol were heated under reflux for 2 h. The mixture was then concentrated to dryness under reduced pressure, the residue was taken up in 300 ml of methanol and 5.6 g (149 mmol) of sodium borohydride were, over 20 min, added a little at a time at RT with slight external cooling to the suspension. The brownish solution was stirred at RT for 24 h and then poured into 900 ml of water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate and concentrated. The residue (24.5 g) was purified by flash chromatography on silica gel using the mobile phase cyclohexane/ethyl acetate 2:1.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH2:9][C:8]([OH:10])=[C:7]([C:11]([O:13][CH3:14])=[O:12])[C:6]1=[O:15].[NH3:17]>>[OH:10][C:8]1[CH2:9][N:5]([CH2:4][C:3]([NH2:17])=[O:2])[C:6](=[O:15])[C:7]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CN1CC(O)=C(C(=O)OC)C1=O
Reactant: N
Product: COC(=O)C1=C(O)CN(CC(N)=O)C1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
23 g (0.1 mol) of the 2,5-dihydro-4-hydroxy-3-methoxycarbonyl-2-oxo-1H-pyrrole-1-acetic acid methyl ester described in Example 1 are dissolved in 200 ml of a concentrated aqueous ammonia solution and stirred at room temperature for 12 hours. The yellowish solution is then concentrated to dryness by evaporation under a water-jet vacuum. The resulting solid residue is dissolved in 200 ml of water, and a concentrated aqueous solution of hydrochloric acid is added until a strongly acidic reaction takes place. The resulting colourless precipitate is filtered off, washed with water and acetone and dried at 50° under reduced pressure. 2,5-dihydro-4-hydroxy-3-methoxycarbonyl-2-oxo-1H-pyrrole-1-acetamide is obtained in the form of white crystals having a melting point of 202° (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[N:24]([C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1)=[C:25]=[O:26]>CN(C)C=O.C(OCC)(=O)C>[C:19]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH:17]=[CH:18][C:6]=1[O:5][C:4]1[CH:21]=[CH:22][CH:23]=[C:2]([NH:1][C:25](=[O:26])[NH:24][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:35])([F:37])[F:36])=[CH:29][CH:28]=2)[CH:3]=1)#[N:20]
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Nc4ccc(OC(F)(F)F)cc4)c3)c(C#N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.3 %

Procedure:
N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (150 mg, 0.462 mmol) produced in Example 12(ii) was dissolved in N,N-dimethylformamide (2 mL), 1-isocyanato-4-(trifluoromethoxy)benzene (91 μL, 0.60 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=80/20→100/0), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from diisopropyl ether to give the title compound (147 mg, 60%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:23][O:24][C:25]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:26]=1[CH:27]=O.CCOC(C)=O>ClCCCl>[CH3:23][O:24][C:25]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:26]=1[CH2:27][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=1
Reactant: Nc1cccc(O)c1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cccc(O)c2)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of 3-hydroxyaniline (1 equiv) in 1,2-dichloroethane is added 4Å powdered molecular sieves, followed by sodium triacetoxyborohydride (1.5 equiv). 2,4-dimethoxybenzaldehyde (1.1 equiv) is added, and the reaction is stirred at room temperature. After completion, the reaction is poured into EtOAc, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:24]=[CH:23][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:2][S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH2:19][CH2:18]3)[S:15][CH:16]=2)=[CH:23][CH:24]=1)(=[O:4])=[O:5]
Reactant: Clc1ncccn1
Reactant: CS(=O)(=O)c1ccc(OCc2csc(C3CCNCC3)n2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(OCc2csc(C3CCN(c4ncccn4)CC3)n2)cc1
Temperature: 90 °C

Procedure:
A mixture of 4-[4-(4-methylsulfonyl-phenoxymethyl)-thiazole-2-yl]-piperidine hydrochloride (100 mg, 0.24 mmol), 2-chloropyrimidine (30 mg, 1.1 eq.) and diisopropylethylamine (122 mg, 4 eq.) in i-PrOH (5 mL) was heated at 90° C. for 1.5 hours. The solvent was removed in vacuo. The residue was purified on silica gel (60% EtOAc in hexanes) to afford the desired product. 1H NMR (CDCl3): δ 8.32 (2H, d, J=4.8 Hz), 7.88 (2H, d, J=8.8 Hz), 7.23 (1H, s), 7.12 (2H, d, J=8.8 Hz), 6.49 (1H, t, J=4.8 Hz), 5.24 (2H, s), 4.89 (2H, m), 3.32 (1H, m), 3.06 (2H, m), 3.04 (3H, s), 2.22 (2H, m), 1.81 (2H, m).
Reaction SMILES: [CH3:1][CH2:2][N:3](C(C)C)C(C)C.[Br:10][C:11]1[C:12]([F:19])=[CH:13][C:14]([CH3:18])=[C:15]([CH:17]=1)[NH2:16].BrCC#N>C1COCC1>[Br:10][C:11]1[C:12]([F:19])=[CH:13][C:14]([CH3:18])=[C:15]([NH:16][CH2:1][C:2]#[N:3])[CH:17]=1
Reactant: Cc1cc(F)c(Br)cc1N
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: C1CCOC1
Product: Cc1cc(F)c(Br)cc1NCC#N
Temperature: 25 °C

Procedure:
Hunig's Base (6.15 mL) was added to 5-bromo-4-fluoro-2-methylaniline (Example 318a, 3.59 g) in THF (50 mL) at room temperature followed by bromoacetonitrile (2.451 mL). The reaction was heated to reflux overnight. The reaction was cooled to room temperature and concentrated. 2N HCl and DCM were added. The organic layer was separated and dried (MgSO4) and concentrated to give the subtitle compound as a solid (6.61 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.S(Cl)(Cl)=O.[OH-].[NH4+:16]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:16])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)cn1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
A 500-mL round-bottomed flask was charged with 5-chloro-2-pyridinecarboxylic acid (Ark Pharm, 10.00 g, 63.5 mmol) and thionyl chloride (Aldrich, 100 ml, 1371 mmol). A catalytic amount of DMF (0.2 ml) was added and the reaction mixture was heated to 80° C. under Argon atmosphere for 4 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with DCM (100 ml) and added slowly to a stirred solution of ammonium hydroxide (131 ml, 3364 mmol) at 0° C. After completed addition, the reaction mixture was allowed to stir an additional 10 min. The reaction mixture was concentrated under reduced pressure and the precipitate was filtered off. The solid was washed with water and dried to give the title compound (8.686 g, 55.5 mmol, 87% yield) as an off-white solid. MS m/z=157 [M+H]+. Calculated for C6H5ClN2O: 156