Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:8])=[N:6][CH:7]=1.CN(C)CC(O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:25]1[O:29][C:28]([CH:30]2[CH2:32][CH2:31]2)=[N:27][C:26]=1[CH2:33][O:34][C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1>[Cu]I.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:25]2[O:29][C:28]([CH:30]3[CH2:32][CH2:31]3)=[N:27][C:26]=2[CH2:33][O:34][C:35]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=2)=[N:6][CH:7]=1
Reactant: Sc1ccc(Cl)cn1
Reactant: COC(=O)c1ccc(OCc2nc(C3CC3)oc2Br)cc1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2nc(C3CC3)oc2Sc2ccc(Cl)cn2)cc1
Temperature: 120 °C

Procedure:
An oven-dried flask was charged with CuI (0.004 g, 0.02 mmol), 5-chloropyridine-2-thiol (0.015 g, 0.10 mmol), N,N-dimethylglycine (0.002 g, 0.02 mmol) and K3PO4 (0.048 g, 0.23 mmol), evacuated and backfilled with N2. Methyl 4-[(5-bromo-2-cyclopropyl-1,3-oxazol-4-yl)methoxy]benzoate (0.036 g, 0.10 mmol) and DMF (0.5 ml) was added under N2. The reaction mixture was heated at 120° C. overnight. The reaction was cooled to rt and filtered through a pad of silica gel eluting with EtOAc. The filtrate was concentrated and purified by reverse phase HPLC to give methyl 4-({5-[(5-chloropyridin-2-yl)sulfanyl]-2-cyclopropyl-1,3-oxazol-4-yl}methoxy)benzoate. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=2.5 Hz, 1H), 7.90 (d, J=8.7, 2H), 7.48 (dd, J=8.4, 2.5 Hz, 1H), 6.95 (d, 3=8.7 Hz, 2H), 6.87 (d, J=8.4 Hz, 1H), 5.05 (s, 2H), 3.88 (s, 3H), 2.12 (m, 1H), 1.10 (m, 4H); FIRMS exact mass calc for C20H17ClN2O4S [M+H]+: 417.0670; observed: 417.0671.
Reaction SMILES: C(OC([N:8]1[C:12]2[CH:13]=[C:14]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30])=O)(C)(C)C.CC1C=C(C=CC=1C)N>C1(C)C=CC=CC=1>[CH3:29][C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:30])[C:23]=1[C:9]1[NH:8][C:12]2[CH:13]=[C:14]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:16][C:11]=2[N:10]=1
Reactant: Cc1cccc(C)c1-c1nc2ccc(C(=O)C(F)(F)F)cc2n1C(=O)OC(C)(C)C
Agent: Cc1ccc(N)cc1C
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1-c1nc2ccc(C(=O)C(F)(F)F)cc2[nH]1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(2,6-dimethylphenyl)-6-(2,2,2-trifluoroacetyl)-benzoimidazole-1-carboxylic acid tert-butyl ester (617 mg) and 3,4-dimethylaniline (118 mg) in toluene (10 mL) was added 4 Å molecular sieves and pTos-OH (50 mg) then the mixture was stirred at 120° C. for 18 h. The sieves were filtered and the filtrate evaporated under reduced pressure to give 1-[2-(2,6-dimethylphenyl)-3H-benzoimidazol-5-yl]-2,2,2-trifluoro-ethanone as an oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][OH:8].CC(C)([O-])C.[K+].F[C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29].O>C1COCC1>[F:27][C:25]1[CH:26]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([O:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=2)[CH:24]=1
Reactant: OCCc1cccc(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OCCc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dissolved 3-(trifluoromethyl)phenethyl alcohol (657 mg, 3.46 mmol) in THF (5 mL). After cooling to 0° C., potassium tert-butoxide (1M THF, 4.08 mmol, 4.08 mL) was added and the mixture was warmed to ambient temperature and stirred for 30 min. The reaction mixture was cooled to −78° C., and 2,4-difluoronitrobenzene (500 mg, 3.14 mmol) was added. The reaction mixture was allowed to slowly warm to ambient temperature. The mixture was poured into H2O and extracted with EtOAc (2×). The combined organics were washed with brine and dried over Na2SO4. The title compound was purified by crystallization from a EtOAc:Hexane mixture.
Reaction SMILES: Cl[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([CH3:13])[C:7](=[O:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[CH:17]=[C:18]([C:28]([NH:30][C:31]2[CH:35]=[CH:34][N:33](C(OC(C)(C)C)=O)[N:32]=2)=[O:29])[CH:19]=[C:20]([O:22][C@H:23]2[CH2:27][CH2:26][O:25][CH2:24]2)[CH:21]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:13][N:8]1[C:7](=[O:14])[C:6]2[CH:5]=[CH:4][C:3]([O:15][C:16]3[CH:17]=[C:18]([CH:19]=[C:20]([O:22][C@H:23]4[CH2:27][CH2:26][O:25][CH2:24]4)[CH:21]=3)[C:28]([NH:30][C:31]3[CH:35]=[CH:34][NH:33][N:32]=3)=[O:29])=[CH:2][C:12]=2[O:11][CH2:10][CH2:9]1
Reactant: CN1CCOc2c(ccc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)Nc4ccn(C(=O)OC(C)(C)C)n4)c3)c2Cl)C1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN1CCOc2cc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)Nc4cc[nH]n4)c3)ccc2C1=O
Temperature: 140 °C
Yield: 76 %

Procedure:
1,1-Dimethylethyl 3-[({3-[(9-chloro-4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]-5-[(3S)-tetrahydrofuran-3-yloxy]phenyl}carbonyl)amino]-1H-pyrazole-1-carboxylate (107 mg, 0.17 mmol) was dissolved in ethanol (4 mL) and ammonium formate (125 mg, 1.7 mmol) was added in one portion. The reaction was blanketed with argon and 10% palladium on charcoal (30 mg) was added. The mixture was heated to 140° C. for 15 minutes in a microwave reactor then the mixture filtered through diatomaceous earth, washed well with ethanol and evaporated in vacuo. The crude product was chromatographed on silica, eluting with a gradient of 0-10% methanol in DCM, to give the desired compound as a white foam (60 mg). 1H NMR δ (CDCl3): 2.12-2.29 (2H, m), 3.21 (3H, s), 3.57-3.60 (2H, m), 3.88-4.02 (5H, m), 4.41 (2H, t), 4.99 (1H, m), 6.58 (1H, d), 6.70-6.75 (1H, m), 6.76-6.79 (1H, m), 6.81 (1H, d), 7.19 (1H, s), 7.27 (1H, s), 7.51 (1H, d), 7.85 (1H, d), 9.23 (1H, s); m/z 465 (M+H)+, 463 (M−H)−
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][C:7]([C:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=O)[CH3:2].Cl.NC(C(OCC)=O)C(OCC)=[O:26].C([O-])(=O)C.[Na+].C(O)(=O)C>C(OCC)(=O)C.O>[CH2:19]([O:18][C:17]([C:16]1[NH:15][C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=2[C:7]=1[CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:21])=[O:26])[CH3:20]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: CCOC(=O)CCC(=O)C1=C(N2CCOCC2)CCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2c1CCCC2
Temperature: 50 °C
Reaction time: 2 h
Yield: 109.6 %

Procedure:
Crude 4-(2-morpholin-4-ylcyclohex-1-enyl)-4-oxo-butyric acid ethyl ester (454 g), 398 g of diethyl aminomalonate hydrochloride, 162 g of sodium acetate and 350 mL of glacial acetic acid were heated to 108° C. over 30 minutes. The mixture was held at 100-108° C. for 2 hours and then cooled to about 50° C. in a water bath. Water (2500 mL) and 700 mL of ethyl acetate were added. The ethyl acetate layer was separated and washed three times with brine, twice with saturated sodium bicarbonate solutiona and once with brine. The solution was dried over anhydrous sodium sulfate, and the ethyl acetate was removed using a rotary evaporator to give 494 g (105% yield) of crude 3-(2-ethoxycarbonylethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid ethyl ester as an oil. The crude mixture was chromatographed on a silica gel column using a 1:10 mixture of ethyl acetate:hexane as the eluent to give 122.1 g of pure 3-(2-ethoxycarbonylethyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylic acid ethyl ester as a low melting solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C@H:12]([CH3:31])[C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[CH2:17][CH2:16]1)=[O:14])[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.Cl[C:40]([O:42][CH3:43])=[O:41].C(#N)C>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C@H:12]([CH3:31])[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:40](=[O:41])[O:42][CH3:43])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH2:19][CH2:20]1)=[O:14])[CH2:7][CH2:6][CH2:5]2
Reactant: COC(=O)Cl
Reactant: C[C@H](C(=O)N1CCN(c2ccc(S(N)(=O)=O)cc2)CC1)N1CCCc2cc(F)ccc21
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)NS(=O)(=O)c1ccc(N2CCN(C(=O)[C@@H](C)N3CCCc4cc(F)ccc43)CC2)cc1

Procedure:
Synthesized according to General Procedure 1. The reaction was set-up with 0.07 mmol of (R)-4-(4-(2-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)benzene sulfonamide, 0.18 mmol of triethyl amine, 0.11 mmol of methyl chloroformate and 0.75 mL of acetonitrile. LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=505.3; tR=2.28 min.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=[O:9]>C(O)C.[C].[Pd]>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=[O:9]
Reactant: O=C(O)C1CC2C=CC1C2
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C1CC2CCC1C2
Reaction time: 24 h
Yield: 94 %

Procedure:
15.7 g (110 mmol) of crude 5-norbornene-2-carboxylic acid was dissolved in 300 ml of ethanol, 1.55 g of 5% palladium-carbon powder was added, and the mixture was stirred under an atmosphere of hydrogen for 24 hours. After the catalyst was filtered off, the solvent was distilled off, and 14.5 g of crude 2-norbornanecarboxylic acid was obtained. Crude yield: 94%.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.FC(F)(F)C(O)=O.[NH2:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][C:47]([C:49]([N:51]3[CH2:57][C:56]4([CH3:59])[CH2:58][CH:52]3[CH2:53][C:54]([CH3:61])([CH3:60])[CH2:55]4)=[O:50])=[CH:48][C:43]=2[N:42]=[CH:41]1>C1COCC1>[CH3:59][C:56]12[CH2:58][CH:52]([N:51]([C:49]([C:47]3[CH:46]=[CH:45][C:44]4[N:40]([CH2:39][CH2:38][NH:37][C:6]([C:2]5[O:1][CH:5]=[CH:4][CH:3]=5)=[O:8])[CH:41]=[N:42][C:43]=4[CH:48]=3)=[O:50])[CH2:57]1)[CH2:53][C:54]([CH3:61])([CH3:60])[CH2:55]2
Reactant: O=C(O)c1ccco1
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc3c(c2)ncn3CCN)C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc3c(c2)ncn3CCNC(=O)c2ccco2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.7 %

Procedure:
To a solution of 2-furoic acid (37 mg, 0.33 mmol) in dry THF (2 mL) at room temperature under an inert atmosphere of nitrogen were added HOBt (49 mg, 0.36 mmol) and EDAC (82 mg, 0.43 mmol), and the resulting solution was stirred for 30 min. [1-(2-Aminoethyl)-1H-benzoimidazol-5-yl]-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methanone trifluoroacetate (150 mg, 0.33 mmol) was added to the solution followed by TEA (0.184 mL, 1.32 mmol), and the reaction mixture was stirred for 16 h at room temperature. The volatiles were evaporated in vacuo and the resulting solid was purified by preparative HPLC, dried in vacuo at 50° C. affording 100 mg (70%) of the title compound as a solid. MS-ESI m/z 435; 1H NMR (400 MHz, DMSO-d6) δ 0.88-0.99 (m, 6H), 1.07 (d, 3H), 1.29-1.41 (m, 4H), 1.50-1.52 (m) and 2.10-2.11 (m, 1H), 1.76-1.79 (m, 1H), 3.02 (d), 3.13 (d), 3.32 (d) and 3.47 (d, 2H), 3.69 (t, 2H), 3.87-3.89 (m) and 4.39-4.41 (m, 1H), 4.56 (t, 2H), 6.58 (s, 1H), 6.98 (d, 1H), 7.48 (dd, 1H), 7.77-7.82 (m, 2H), 7.89 (t, 1H), 8.54-8.58 (m, 1H), 9.07 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH:19]([C:22]1[O:26][CH:25]=[N:24][C:23]=1[C:27](O)=[O:28])([CH3:21])[CH3:20]>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:23]3[N:24]=[CH:25][O:26][C:22]=3[CH:19]([CH3:21])[CH3:20])=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: CC(C)c1ocnc1C(=O)O
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: CC(C)c1ocnc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)OCC2(F)F)c1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-isopropyl-oxazole-4-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=397.2 [M+H]+.
Reaction SMILES: C1(C)C=CC=CC=1.[N:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10][CH:9]=1.[N:29]12CC[CH:32]([CH2:33][CH2:34]1)[CH:31](O)[CH2:30]2.[H-].[Na+]>C(O)C>[N:8]1[CH:9]=[CH:10][C:11]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][N:15]2[C:24]([O:26][CH:27]2[CH:32]3[CH2:33][CH2:34][N:29]([CH2:30][CH2:31]3)[CH2:28]2)=[O:25])=[CH:12][CH:13]=1
Reactant: CCOC(=O)N1CCc2ccccc2C1c1ccncc1
Reactant: OC1CN2CCC1CC2
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(OC1CN2CCC1CC2)N1CCc2ccccc2C1c1ccncc1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
To a 50 ml toluene suspension containing 720 mg of ethyl 1-(4-pyridyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate and 973 mg of 3-quinuclidinol, 102 mg of sodium hydride (60%) was added at room temperature. The resulting mixture was heated under reflux for 5 hours and 40 minutes while the resulting ethanol was removed together with toluene. The reaction mixture was cooled to room temperature, followed by addition of 20 ml of water. The resulting mixture was extracted with chloroform. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=100:2:1), thereby 827 mg of 3-quinuclidinyl 1-(4-pyridyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate were obtained as yellow oil. The resulting oil was dissolved in 5 ml of ethyl acetate, 2 ml of a 4N hydrogen chloride in ethyl acetate solution was added. The solvent was then removed under reduced pressure. Ethanol and ether were added to the residue, and the crude crystals thus obtained was recrystallized from ethanol and ether, thereby 402 mg of 3-quinuclidinyl 1-(4-pyridyl)-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate dihydrochloride was obtained as pale yellow crystals.
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)C(C)C)(C)C.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:27][CH:28]=[C:29]([C:31](Cl)=[O:32])[N:30]=2)[CH:21]=1>ClCCl.O>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[S:27][CH:28]=[C:29]([C:31]([C:2]3[S:1][C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=4[CH:3]=3)=[O:32])[N:30]=2)[CH:21]=1
Reactant: O=C(Cl)c1csc(-c2cccnc2)n1
Reactant: c1cc2c(s1)CCCCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(c1csc(-c2cccnc2)n1)c1cc2c(s1)CCCCN2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) solution of 2 mmol of 5,6,7,8-tetrahydro-4H-thieno [3,2-b]azepine, 6 mmol of N,N-diisopropylethylamine in 8 ml of dichloromethane is added 2.2 mmol of 2-(3-pyridinyl)thiazole-4-carbonyl chloride. The mixture is stirred at room temperature for 16 hours and diluted with 50 ml of dichloromethane and 25 ml of water. The organic layer is separated, washed with H2O, 1N NaHCO3, brine and dried (Na2SO4). The solvent is removed under vacuum and the residue chromatographed on silica gel with ethyl acetate-hexane as solvent to give the product as a solid.
Reaction SMILES: Cl.Cl.[C:3](=[NH:9])([NH2:8])[CH2:4][C:5](=[NH:7])[NH2:6].C[O-].[Na+].[F:13][C:14]1[CH:34]=[CH:33][CH:32]=[CH:31][C:15]=1[CH2:16][C:17]1[N:18]=[C:19]([C:26](OCC)=O)[N:20]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]=12>CO>[F:13][C:14]1[CH:34]=[CH:33][CH:32]=[CH:31][C:15]=1[CH2:16][C:17]1[N:18]=[C:19]([C:26]2[N:9]=[C:3]([NH2:8])[CH:4]=[C:5]([NH2:6])[N:7]=2)[N:20]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]=12
Reactant: CCOC(=O)c1nc(Cc2ccccc2F)c2ncccn12
Reactant: N=C(N)CC(=N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Nc1cc(N)nc(-c2nc(Cc3ccccc3F)c3ncccn23)n1
Temperature: 50 °C

Procedure:
147 mg (0.85 mmol) of 1,3-propanediimidamide dihydrochloride are introduced into 2 ml of methanol, and 0.37 ml (2.00 mmol) of a 30% strength methanolic sodium methanolate solution is added. The mixture is heated at 50° C. for 30 min. It is then allowed to cool to RT, a solution of 150 mg (0.50 mmol) of ethyl 8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carboxylate from example 10A in 2.0 ml of methanol is added, and the mixture is heated to reflux for 3 h. Cooling is followed by dilution with water and extraction with ethyl acetate. The organic phase is dried over sodium sulfate, and the solvent is removed in vacuo. The residue is purified by preparative HPLC to result in 36 mg (21% of theory) of the desired product as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[C:27]([F:33])[C:3]=1[C:4]([N:6](C(=O)C1C(F)=CC(C#N)=CC=1Cl)[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14])=[O:5].[OH-].[Na+]>CO.O1CCOCC1>[Cl:1][C:2]1[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[C:27]([F:33])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([Cl:13])[C:8]=1[F:14])=[O:5]
Reactant: N#Cc1cc(F)c(C(=O)N(C(=O)c2c(F)cc(C#N)cc2Cl)c2ccnc(Cl)c2F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1cc(F)c(C(=O)Nc2ccnc(Cl)c2F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.2 %

Procedure:
To a solution of 2-chloro-N-(2-chloro-4-cyano-6-fluorobenzoyl)-N-(2-chloro-3-fluoro-pyridin-4-yl)-4-cyano-6-fluoro-benzamide (0.865 g, 1.7 mmol) in MeOH (8.5 mL) and dioxane (8.5 mL) was added sodium hydroxide (0.102 g, 2.5 mmol). The resulting mixture stirred at room temperature for 2.5 hours and then concentrated under reduced pressure. The residue was partitioned between DCM and saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-100% DCM in pentane to give the desired compound as an off-white solid (0.308 g, 55% yield). 1H NMR (300 MHz, CDCl3): δ 8.49-8.40 (m, 1H), 8.25 (d, J=5.4 Hz, 1H), 7.98 (br s, 1H), 7.64 (t, J=1.3 Hz, 1H), 7.47 (dd, J=7.9, 1.5 Hz, 1H). LCMS (Method D): RT=3.33 min, m/z: 328 [M+H+].
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=12)[C:6]1[S:10][CH:9]=[CH:8][CH:7]=1.[C:22](O)(=O)[C@H](C1C=CC=CC=1)O.CC1(C)O[C@H]2[C@@H]3OC(C)(C)O[C@]3(C(O)=O)O[C@H]2CO1.CN(C)CCC(C1SC=CC=1)O.FC1C2C(=CC=CC=2)C=CC=1>>[CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH:5]([O:11][C:12]1[C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=1)[C:6]1[S:10][CH:9]=[CH:8][CH:7]=1
Reactant: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1
Reactant: O=C(O)[C@@H](O)c1ccccc1
Agent: CC1(C)OC[C@@H]2O[C@@]3(C(=O)O)OC(C)(C)O[C@H]3[C@@H]2O1
Agent: CN(C)CCC(O)c1cccs1
Agent: Fc1cccc2ccccc12
Product: CN(C)CCC(Oc1cccc2ccccc12)c1cccs1

Procedure:
The preparation of the enantiomerically pure duloxetine intermediate (S)-AT-OL by its chiral resolution is exemplified in U.S. Pat. No. 5,362,886 (U.S. '886) and in WO 2004/031168, by the use of (S)-(+)-mandelic acid and (−)-2,3:4,6-Di-O-isopropylidene-2-keto-L-gulonic acid, respectively. The U.S. '886 patent describes the preparation of duloxetine by the chiral resolution of N,N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine (rac-AT-OL) with (S)-mandelic acid (Stage a), its reaction with fluoronaphtalene (Stage b) to give N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine (DNT), demethylation with phenyl chloroformate (Stage c), basic hydrolysis in the presence of (Stage d), and acidification (Stage e) in accordance with the following Scheme 1.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.[S:29](=[O:33])(=[O:32])([OH:31])[OH:30].[CH2:34](O)[CH3:35]>>[S:29]([OH:33])([OH:32])(=[O:31])=[O:30].[CH2:34]([O:13][C:11](=[O:12])[C@H:10]([CH3:14])[CH2:9][C@H:8]([NH2:15])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:2][CH:3]=1)[CH3:35].[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[CH2:9][C@@H:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:5][CH:6]=1
Reactant: CCO
Agent: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
10 g (2R,4S)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpentanoic acid (3-a, R1=BOC, R2=R3=H) are added to ethanol (100 ml). The mixture is heated to 65° C. 2 ml of concentrated sulphuric acid is then added over 0.5 h. The mixture is then stirred overnight. The ethanol is removed and heptane added. Further azeotropic distillations are performed using heptane to remove any residual ethanol. The solvent is removed in vacuo to afford (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrogen sulphate (3-a, R1=R2=H, R3=Et). 1H NMR (DMSO): 1.12 (6H), 1.56 (1H), 1.87 (1H), 2.67 (1H), 2.78 (1H), 2.98 (1H), 3.76 (2H), 7.34 (3H), 7.47 (2H), 7.64 (4H), 8.57 (3H). m/z (ES+) 312 ([MH]+, 100.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(O)(=O)C.[N+:14]([O-])([OH:16])=[O:15]>O>[CH3:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(O)c([N+](=O)[O-])c1C

Procedure:
The reaction was carried out in a manner similar to Reference Example 20 a) except for using 15.7 g (129 mmol) of 3,4-dimethylphenol, 130 ml of acetic acid, 8 ml of water and 12.2 g (135 mmol) of 70% nitric acid. 3,4-Dimethyl-2-nitrophenol was thus obtained in the yield of 7.01 g (26.0%).
Reaction SMILES: COC(=O)C.[CH2:6]([O:8][C:9](=[O:24])[CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([S:19](Cl)(=O)=O)=[CH:14][C:13]=1[CH3:23])[CH3:7].S(=O)(=O)(O)O>C(O)C>[CH2:6]([O:8][C:9](=[O:24])[CH2:10][O:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([SH:19])=[CH:14][C:13]=1[CH3:23])[CH3:7]
Reactant: CCOC(=O)COc1cc(C)c(S(=O)(=O)Cl)cc1C
Agent: O=S(=O)(O)O
Solvent: COC(C)=O
Solvent: CCO
Product: CCOC(=O)COc1cc(C)c(S)cc1C

Procedure:
(4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester was prepared as described for 2,6-difluoro-4-mercapto-phenoxy)acetic acid methyl ester (compound 21) in Eur. J. Med. Chem., 1995, 30, 403 (Kawashima, M. S.) except that (4-chlorosulfonyl-2,5-dimethyl-phenoxy)acetic acid ethyl ester was reduced with 4 eq. of zn (dust) in a mixture of konc. sulfuric acid and ethanol at 80° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:11]([F:12])=[C:10](F)[N:9]=[C:8]([F:14])[C:7]=1[Cl:15])[CH3:2].[F:17][C:18]([F:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:19][NH2:20].C([O-])([O-])=O.[Ca+2]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:11]([F:12])=[C:10]([NH:20][CH2:19][C:18]([F:27])([F:17])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:9]=[C:8]([F:14])[C:7]=1[Cl:15])[CH3:2]
Reactant: CCOC(=O)Cc1c(F)c(F)nc(F)c1Cl
Reactant: NCC(F)(F)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(F)c(NCC(F)(F)c2ccccn2)nc(F)c1Cl
Temperature: 70 °C

Procedure:
To a solution of 5.5 g (22 mmol) ethyl(3-chloro-2,5,6-trifluoro-4-pyridinyl)acetate 1-1 in 75 mL DMF was added 3 g (19 mmol) 2,2-difluoro-2-(2-pyridinyl)ethylamine and 4 g (40 mmol) CaCO3 and the reaction mixture was heated to 70° C. for 18 hours. The reaction mixture was then cooled, diluted w. 400 mL ether, washed 2×300 mL water, and 1×300 mL brine, dried over MgSO4, filtered, and concentrated. Purification by automated flash chromatography (90 g silica cartridge, linear gradient 5-50% EtOAc/hex over 30 min, 70 mL/min flow rate.) afforded ethyl (3-chloro-6-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-2,5-difluoro-4-pyridinyl)acetate 1-2 as a white solid. 1H NMR (400 mHz, CDCl3) δ8.66 (br d, 1H, J=4.94 Hz); 7.84 (ddd, 1H, J=7.7, 7.7, and 1.64 Hz); 7.70 (d, 1H, J=7.88 Hz); 7.41 (dd, 1H, J=4.95, 7.14 Hz); 5.40 (br m, 1H); 4.36 (dt, 2H, J=13.9, 6.22 Hz); 4.19 (q, 2H, J=7.14 Hz); 3.77 (d, 2H, J=1.83 Hz); 1.27 (t, 3H, J=7.14 Hz). Mass Spectrum (electrospray) M+H=392.0.