Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[N:15]=[C:14]([NH:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:18])[C:13]([F:26])=[CH:12][N:11]=1>>[F:26][C:13]1[C:14]([NH:16][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH3:18])=[N:15][C:10]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=2)=[N:11][CH:12]=1
Reactant: CC(Nc1nc(Cl)ncc1F)c1ccc(F)cc1
Reactant: Nc1cccc(O)c1
Product: CC(Nc1nc(Nc2cccc(O)c2)ncc1F)c1ccc(F)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-4-pyrimidinediamine, 3-aminophenol and (±)-N-(2-chloro-5-fluoropyrimidinyl)-1-(4-fluorophenyl)ethylamine were reacted to produce the desired (±)-5-fluoro-N4-[1-(4-fluorophenyl)ethyl]-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.79 (d, 1H, J=3.3 Hz), 7.38–7.34 (dd, 2H, J=5.2 and 8.5 Hz), 7.14 (t, 1H, J=4.5 Hz), 7.09 (d, 1H, J=8.5 Hz), 7.03 (d, 1H, J=8.5 Hz), 6.84 (br s, 1H), 6.84–6.78 (ddd, 1H, J=0.8, 2.0, and 8.2 Hz), 6.46–6.42 (ddd, 1H, J=0.8, 2.0 and 8.2 Hz), 5.26 (overlapped dq, 1H, J=7.1 and 7.9 Hz), 5.18 (d, 1H, J=7.1 Hz), 1.59 (d, 3H, J=7.1 Hz); LCMS: ret. time: 21.52 min.; purity: 92%; MS (m/e): 343 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[O:8][CH2:9][C:10]3([CH2:12][CH2:11]3)[C:6]=2[C:5]([O:13][C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C@H:23]([NH:26]C(=O)OC(C)(C)C)[CH2:24][CH3:25])=[O:22])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:26][C@H:23]([CH2:24][CH3:25])[C:21]([NH:20][C:17]1[CH:18]=[N:19][C:14]([O:13][C:5]2[C:6]3[C:10]4([CH2:9][O:8][C:7]=3[C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:12][CH2:11]4)=[CH:15][CH:16]=1)=[O:22]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2ccc(C)c3c2C2(CC2)CO3)nc1
Reaction time: 3 h
Yield: 95.7 %

Procedure:
To a solution of tert-butyl N-[(1R)-1-[[6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxy-3-pyridyl]carbamoyl]propyl]carbamate (Intermediate 16, 55 mg) in dry DCM (3 ml) at 0° C. TFA (1 ml) was slowly added and the reaction mixture was stirred for 3 hours at the same temperature. The solvent and the excess of TFA were removed under reduced pressure and the residue was diluted with DCM (10 ml) and an aqueous saturated solution NaHCO3 was added while the pH was allowed to reach ˜8. Two phases were separated and the organic layer was dried (Na2SO4), filtered and evaporated affording the title compound (41 mg) as white solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[C:21](=[O:28])[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[C:21](=[O:28])[CH:22]=[C:23]([CH3:27])[CH:24]=[CH:25][CH:26]=1)=[O:17]
Reactant: Cc1cccc(N)c(=O)c1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: Cc1cccc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)c(=O)c1
Reaction time: 48 h
Yield: 48.2 %

Procedure:
A solution of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (1.2 g) and 2-amino-6-methyl-2,4,6-cycloheptatrien-1-one (0.7 g) in xylene (21 ml) is refluxed for 8 hours. The reaction mixture is then allowed to stand at room temperature for 2 days. The crystals that have separated out are collected by filtration, washed with toluene and recrystallized from dimethylformamide to give 4-hydroxy-2-methyl-N-(6-methyl-1-oxo-2,4,6-cycloheptatrien-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.8 g), m.p. 276°-280° C.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28](O)(=[O:32])[C:29]#[C:30][CH3:31]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[C:29]#[C:30][CH3:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CC#CC(=O)O
Agent: Cl
Product: CC#CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (80 mg, 81%), MS (ISP) m/z=397.3 [(M+H)+], mp 176° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and but-2-ynoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][O:26][CH2:27][CH3:28].O>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:24][CH2:25][O:26][CH2:27][CH3:28])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Reactant: CCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1cc(C2CCN(C(=O)OCC)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
Under inert atmosphere, a solution of 12.5 g (0.045 mol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester in 50 ml of anhydrous DMF was added dropwise to a suspension containing 2.75 g (0.068 mol) of sodium hydride (60% in mineral oil) in 200 ml of anhydrous DMF. After stirring at room temperature for 1 hour, 6.6 ml (0.06 mol) of 1-bromo-2-ethoxyethane were added. The reaction mixture was heated at 60° C. for 3 hours. The crude mixture was poured into water and extracted with ethyl acetate. After drying, the solvent was removed under reduced pressure and 16 g of a crude oil were obtained and used in the next step without purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:10][CH2:11][CH2:12][OH:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:26](OC)([CH3:28])[CH3:27].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.O>C1COCC1>[CH3:27][C:26]1([CH3:28])[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@@H:9]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:10][CH2:11][CH2:12][O:13]1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCO)C(=O)OCc1ccccc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](C(=O)OCc2ccccc2)CCCOC1(C)C
Temperature: 60 °C
Reaction time: 5 h
Yield: 74.1 %

Procedure:
To the solution of benzyl N-(tert-butoxycarbonyl)-5-hydroxy-D-norvalinate (Preparation 50, 3 g, 9.28 mmol) in THF (20 mL) was added 2,2-dimethoxypropane (12.07 mL, 92.8 mmol) and PPTS (catalytic amount), and the reaction was stirred for 5 hours at 60° C. The reaction mixture was poured into cold water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (2.5 g, 74%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[F:9][CH:10]([F:13])[CH:11]=[O:12]>O>[F:9][CH:10]([F:13])[CH:11]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)[OH:12]
Reactant: O=CC(F)F
Reactant: Oc1ccccc1
Solvent: O
Product: Oc1ccc(C(O)C(F)F)cc1
Temperature: 100 °C

Procedure:
9.3 g (100 mmol) of phenol and 4.9 g (25 mmol) of 50% w/w difluoroacetaldehyde hydrate in water are introduced into a 100 ml reactor. 50 g of MgO are added. The mixture is stirred and is heated at 100° C. for 7 hours. The catalyst is filtered off.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[CH3:49][C@H:50]1[CH2:55][O:54][CH2:53][CH2:52][NH:51]1>>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:51]2[CH2:52][CH2:53][O:54][CH2:55][C@@H:50]2[CH3:49])=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1
Reactant: C[C@H]1COCCN1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C[C@H]1COCCN1C(=O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and (S)-3-methylmorpholine (EXAMPLE 23, Step A) and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C20H19BrN4O4S, 490.0; m/z found, 489/491 [M−H]−. HPLC (reverse phase): RT=8.36 min. 1H NMR (400 MHz, CDCl3, rotameric broadening): 9.05 (d, J=1.8 Hz, 1H), 9.01 (br s, 1H), 9.00 (d, J=1.8 Hz, 1H), 8.56 (dd, J=7.0, 1.5 Hz, 1H), 8.37 (dd, J=8.4, 1.4 Hz, 1H), 7.91 (dd, J=8.4, 7.4 Hz, 1H), 7.72 (d, J=1.4 Hz, 1H), 7.16 (dd, J=8.0, 1.6 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 4.30 (br m, 1H), 3.91-3.82 (m, 1H), 3.68-3.63 (m, 1H), 3.50 (dd, J=11.5, 2.7 Hz, 1H), 3.38-3.22 (m, 2H), 1.35-1.15 (br m, 3H), 1.0-0.9 (m, 1H).
Reaction SMILES: [N:1]([CH:4]1[CH2:7][N:6]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5]1)=[N+]=[N-].[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:1][CH:4]1[CH2:7][N:6]([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:5]1
Reactant: [N-]=[N+]=NC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NC1CN(C(c2ccccc2)c2ccccc2)C1
Yield: 72.2 %

Procedure:
5% Palladium-carbon (200 mg) was added to 3-azido-1-benzhydrylazetidine (630 mg) obtained from Referential Example 104 in ethyl acetate (12 mL). The resultant mixture was subjected to catalytic reduction in a hydrogen atmosphere for 15 hours. The catalyst was filtered off. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as a solid (410 mg, 65%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH2:16]([O:18][NH2:19])[CH3:17].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:13][CH:12]([NH:19][O:18][CH2:16][CH3:17])[CH2:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(CC(C)=O)cc1OC
Reactant: CCON
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCONC(C)Cc1ccc(OC)c(OC)c1
Temperature: 10 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
1-(3,4-Dimethoxyphenyl)-2-propanone (1.35 g, 7.5 mmol) was dissolved in H2O (15 ml) and a solution of O-ethylhydroxylamine hydrochloride (1 g, 10 mmol) and Na2CO3 (0.53 g, 5 mmol) in water (10 ml) was added dropwise under stirring at 10° C. The reaction was left at room temperature overnight and then extracted with diethyl ether. After evaporation of the solvent, the residue was dissolved in EtOH (20 ml) and concentrated hydrochloric acid (1 ml), then hydrogenated over PtO2 at 3,6×106 Pa (50 psi). The solvent was removed under vacuum. The residue was dissolved in 30 ml of water, the aqueous phase was made basic with NaHCO3 and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated to dryness. The crude residue was purified by flash chromatography, to afford 0.75 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CC(C)=O>[CH2:26]([O:1][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([O:8][CH2:14][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[CH:7]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1cc(O)cc(O)c1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1-c1ccccc1
Yield: 168.1 %

Procedure:
Compound 1 (1.81 g, 7.00 mmol) obtained in Example 1 was dissolved in acetone (50 mL), and potassium carbonate (5.88 g, 42.6 mmol) and benzyl bromide (3.33 mL, 28.0 mmol) were added thereto and stirred with heating under reflux for 1.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane/ethyl acetate=20/1 to 9/1) to obtain methyl 3,5-bis(benzyloxy)-2-phenylphenylacetate (2.58 g, 84%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[N:25]=[CH:24]4)([OH:20])[C:16]([F:19])([F:18])[F:17])=[CH:7][N:8]2[CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.[CH2:37]([N:39](CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CN>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[N:25]=[CH:24]4)([OH:20])[C:16]([F:17])([F:19])[F:18])=[CH:7][N:8]2[CH2:11][C:12]([NH:39][CH3:37])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccc(Br)cc21
Reactant: CCN(CC)CC
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: CNC(=O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccc(Br)cc21
Reaction time: 0.08 h
Yield: 14.5 %

Procedure:
To a room temperature solution of 135 mg (0.24 mmol) of (6-bromo-3-{2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]-1-hydroxyethyl}indol-1-yl)acetic acid in 1 mL of DMF was added 121 mg (1.2 mmol) of triethylamine followed by 210 mg (0.40 mmol) of benzotriazole-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP). After 5 minutes, 162 mg (2.4 mmol) of methyl amine was added. The mixture stirred overnight and was filtered and purified by HPLC using CH3CN-water buffered with 0.1% TFA (5-90% gradient). The material from the column was concentrated to remove CH3CN. The resulting aqueous portion was extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 20.0 mg (15%) of the title compound. LCMS [M+H]=576.35.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:17]([NH2:19])=[O:18])=[C:9]([NH:12][C:13](=O)[CH2:14][CH3:15])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.C[O-].[Na+].Cl>O>[CH2:14]([C:13]1[NH:19][C:17](=[O:18])[C:8]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][S:10][C:9]=2[N:12]=1)[CH3:15]
Reactant: CCC(=O)Nc1scc(-c2ccccc2)c1C(N)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCc1nc2scc(-c3ccccc3)c2c(=O)[nH]1
Reaction time: 18 h

Procedure:
The solid 4-phenyl-2-propionylaminothiophene-3-carboxylic amide was added to a mixture of ethanol (50 ml) and sodium methoxide (2.24 g) and the resultant mixture was heated under reflux with stirring for 18 hours. The cooled mixture was diluted with water (300 ml) and acidified with concentrated hydrochloric acid. The resulting solid was collected by filtration, washed with water followed by acetonitrile and dried in vacuo to give 2-ethyl-5-phenyl-3H-thieno[2,3-d]pyrimidin-4-one (2.38 g), which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[S:10])[NH:8][CH:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].[CH3:14]I.Cl>>[C:1]([C:4]1[C:5](=[O:11])[NH:6][C:7]([S:10][CH3:14])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c[nH]c(=S)[nH]c1=O
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CSc1ncc(C(C)=O)c(=O)[nH]1
Temperature: 40 °C
Yield: 69.1 %

Procedure:
5-Acetyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (Ryan Scientific) (2.3 g, 13.51 mmol) was dissolved in NaOH (20.27 mL, 20.27 mmol), then MeI (0.894 mL, 14.30 mmol) was added to the reaction mixture while stirring. The reaction mixture was heated at 40° C. for 1.5 hours. Additional MeI (0.894 mL, 14.30 mmol) was added and the reaction was allowed to stir at rt for 18 hours. The reaction mixture was cooled with an ice-water bath, acidified to pH 6 with concentrated HCl solution, then the resulting precipitate was filtered to obtain 1.72 g of the desired product (69% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.49 (br. s., 6H) 8.35 (s, 1H) 13.40 (br. s., 1H). MS (ES+): m/z=185.1 (100) [MH+]. HPLC: tR=1.0 minute over 3 minutes. Purity: >90% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].F[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.CC(C)([O-])C.[K+]>CS(C)=O>[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:6][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:22]=12)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: Fc1cccc2ccccc12
Reactant: CNCC[C@H](O)c1cccs1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1
Temperature: 60 °C

Procedure:
(S)-(−)-3-methylamino-1-(2-thienyl)-propan-1-ol (20.0 g) and 1-fluoronaphthalene (68.3 g) were charged into a 4-neck round bottomed flask. Potassium tert-butoxide (13.1 g) and DMSO (36.0 g) were then added, and the resulting mixture was heated to 60° C. for 8 hours. After completion of the reaction, the reaction mixture was cooled down and washed with water. Layers were separated, and the organic layer was further extracted with 32% HCl(aq) (14.7 g) to separate Duloxetine® from 1-floronaphthalene. The acidic aqueous layer was adjusted to pH 12-13 with 45% NaOH(aq) (17.6 g) to obtain Duloxetine® in a free base form as an oily liquid (31.3 g, 90%). Optical purity of the resulting Duloxetine® measured by chiral HPLC was 95% e.e.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH3:16])=[C:6]([CH:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)O)[CH:7]=1.CC(C)=[O:19]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:15][CH3:16])=[C:6]([CH:8]2[C:12](=[O:11])[CH:13]=[CH:14][CH:10]2[OH:19])[CH:7]=1
Reactant: CCc1ccc(Br)cc1C(O)c1ccco1
Reactant: CC(C)=O
Solvent: O
Product: CCc1ccc(Br)cc1C1C(=O)C=CC1O
Temperature: 55 °C
Reaction time: 44 h

Procedure:
A solution of (5-bromo-2-ethylphenyl)furan-2-ylmethanol (40.73 g, 0.145 mol) in acetone (1150 ml) and water (170 ml) is heated to 55° C. and 30 drops of polyphosphoric acid are added. The mixture is stirred at 55° C. for 44 hours, then cooled to room temperature. The reaction mixture is concentrated under reduced pressure to remove most of the acetone then ethyl acetate (500 ml) is added, and the reaction mixture is partitioned. The aqueous phase is extracted into ethyl acetate and the organic solutions are combined, washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 5-(5-bromo-2-ethylphenyl)-4-hydroxycyclopent-2-enone.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([CH:13]([CH3:15])[CH3:14])[C:5]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[PH2:22])([CH3:3])[CH3:2].[CH3:23][C:24](=[CH:26][C:27](=[O:32])[CH:28]=[C:29]([CH3:31])[CH3:30])[CH3:25]>>[CH3:30][C:29]1([CH3:31])[CH2:28][C:27](=[O:32])[CH2:26][C:24]([CH3:25])([CH3:23])[P:22]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:5]1[C:6]([CH:13]([CH3:14])[CH3:15])=[CH:7][C:8]([CH:10]([CH3:11])[CH3:12])=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3]
Reactant: CC(C)=CC(=O)C=C(C)C
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P)c(C(C)C)c1
Product: CC(C)c1cc(C(C)C)c(-c2ccccc2P2C(C)(C)CC(=O)CC2(C)C)c(C(C)C)c1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
A flask was charged with 10.8 g of (2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (66% potent, 7.13 g, 22.8 mmol, 1.0 equiv) and 6.6 g of 2,6-dimethyl-2,5-heptadien-4-one (47.7 mmol, 2.1 equiv). The vessel was purged with argon gas and immersed in an oil bath at 170° C. with magnetic stirring. The flask was sealed with a Teflon stopcock and the reaction was allowed to proceed under a static argon atmosphere. The flask was removed from the oil bath after 14 h and the contents allowed to cool to room temperature under argon gas. Anhydrous ethanol (70 mL) was added to the unpurified solids and the solids were broken up manually. The slurry was warmed to 80° C., held for an hour, and cooled to room temperature. The product was isolated by filtration, washes with ethanol and dried in vacuo to give 7.82 g of 2,2,6,6-tetramethyl-1-(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphinan-4-one (98 area % by HPLC, 74% yield).
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:15]([O:17][C:18](=[O:27])[CH:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:27])[CH:19]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:13][CH:12]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:16]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: Oc1ccc(C2=CCCCCC2)cc1
Product: CCCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)OCC

Procedure:
Analogously to the process described in Example 1, 11.5 g of p-(1-cycloheptenyl)-phenol and 26.4 g of 2-bromooctanoic acid ethyl ester give α-[p-(1-cycloheptenyl)-phenoxy]-octanoic acid ethyl ester as a colourless oil of boiling point 155°-160° C/0.04 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:20]([O:22]C)=[O:21])[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[Na+].O.Cl>CO>[C:20]([C:11]1[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:17])[CH3:18])[N:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([F:1])[CH:3]=2)[CH:10]=1)([OH:22])=[O:21]
Reactant: COC(=O)c1cc(-c2ccc(C)c(F)c2)nn(CC(C)C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)c(=O)n(CC(C)C)n2)cc1F
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
To a suspension of 6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one (5.27 g, 16.6 mmol) in methanol (50 mL) was added a 2 mol/L aqueous sodium hydroxide (50 mL), and the mixture was stirred at 60° C. for 15 minutes. The temperature of the reaction mixture was allowed to drop back to room temperature, and then, water was added. After the system was acidified with concentrated hydrochloric acid, the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-hexane to yield the title compound as colorless fine-needles (4.73 g, 93.8%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O-].C[O-].[Mg+2:12].[Mg].CO>CCCCCCC>[C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg+2:12].[C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Agent: C[O-]
Agent: [Mg+2]
Agent: [Mg]
Solvent: CO
Solvent: CCCCCCC
Product: [O-]c1ccccc1
Temperature: 70 °C
Yield: 81.1 %

Procedure:
A mixture of 282 g of phenol and 86 g of magnesium methylate prepared from metallic magnesium and methanol was heated at 70° C. to make a solution, to which 300 ml of n-heptane was added. The mixture was refluxed at 98° C. for 24 hours, then cooled, and evaporated in a rotary evaporator to remove heptane, phenol and methanol, thereby giving 170 g of magnesium phenolate.