Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:9](=[O:10])[O:8][C:6](=[O:7])[CH2:5]1)=[O:2].C([O-])(=O)C.[Na+].Cl.[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:21]>C(Cl)Cl>[CH3:17][O:18][C:19](=[O:29])[C@H:20]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:21][C:6](=[O:7])[CH2:5][C@@H:4]([C:9]([OH:8])=[O:10])[NH:3][CH:1]=[O:2]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=CN[C@H]1CC(=O)OC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)C[C@H](NC=O)C(=O)O

Procedure:
In 179.4 g of methylenechloride, 14.3 g (0.1 mole) of N-formyl-L-aspartic anhydride was suspended, and 9.2 g (0.11 mole) of sodium acetate was added at 20°-25° C. with stirring, and 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride was added at the same temperature during 30 minutes. The mixture was reacted for 5 hours with stirring at the same temperature. Precipitated crystals were filtered, washed and dried. Crystals of a mixture of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester, and N-formyl-β-L-aspartyl-L-phenylalanine methyl ester were obtained in a yield of 30.0 g. The crystals obtained were analyzed by high performance liquid chromatography to give a ratio of α-isomer:β-isomer of 75.0:25.0. The crystals were purified by a conventional method to obtain pure crystals of N-formyl-α-L-aspartyl-L-phenylalanine methyl ester. The yield was 16.1 g (50% yield on L-phenylalanine methyl ester hydrochloride).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([C:6](=O)[CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:6]1[C:5]2[C:10](=[C:11]([F:12])[C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][C:7]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)C1C=Nc2c(ccc(F)c2F)C1=O
Product: CCOC(=O)c1cnc2c(F)c(F)ccc2c1Cl
Temperature: 95 °C
Yield: 97.9 %

Procedure:
A suspension of 26 g of ethyl 7,8-difluoro-4-oxoquinoline-3-carboxylate in 212 g of phosphorus oxychloride was heated at 95° C. for 4 hours, with stirring. After treatment, 27.3 g of ethyl 4-chloro-7,8-difluoroquinoline-3-carboxylate was obtained in the form of a white solid, which melted at 114° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:13]=[CH:12][C:6]([C:7](=[NH:11])[NH:8][NH:9][CH3:10])=[CH:5][CH:4]=1.C(O[C:18](=O)[CH3:19])(=O)C>>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[N:11]=[C:18]([CH3:19])[N:9]([CH3:10])[N:8]=2)=[CH:12][CH:13]=1
Reactant: CNNC(=N)c1ccc(Br)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Product: Cc1nc(-c2ccc(Br)cc2)nn1C
Temperature: 100 °C

Procedure:
A mixture of 4-bromo-N′-methylbenzimidohydrazide hydrochloride 1 (1.7 g) (prepared according to a procedure in synthesis of Sch-1499895) in acetic anhydride (10 ml) was heated at 100° C. for 0.5 hour. After cooling and concentration under reduced pressure, the residue was dissolved in EtOAc, washed with saturated NaHCO3 twice, brine and dried (MgSO4). After evaporation of solvent, the residue was purified on silica gel. Elution with EtOAc gave 3-(4-bromophenyl)-1,5-dimethyl-1H-[1,2,4]-triazole 2BK (1.04 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)=[O:4].[Li+].[OH-].O>O1CCOCC1>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]1[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1
Reactant: COC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 5-(2-oxopyrrolidin-1-yl)-biphenyl-3-carboxylic acid methyl ester (D10) (23 mg, 0.078 mmol) in dioxane (2 ml) was added LiOH (5 mg, 0.117 mmol) and water (1 ml) and stirred at room temperature for 2 hours. The solvent was then evaporated to dryness and the residue was partitioned between ethyl acetate and water. The aqueous layer was separated and acidified to pH=1. The product precipitated in the aqueous layer and was removed by filtration and dried in vacuo to afford D11 (10 mg) as white solid.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[O:6]1[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]1>C(#N)C>[CH2:8]([C:7]12[O:6][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][N:1]1[CH2:2][CH:3]([CH3:4])[O:5]2)[CH2:9][CH2:10][CH3:11]
Reactant: CC(O)CN
Reactant: CCCCCCC1CO1
Solvent: CC#N
Product: CCCCCCC1CN2CC(C)OC2(CCCC)O1
Temperature: 180 °C
Yield: 20 %

Procedure:
Under atmospheric nitrogen, 30.79 g of 1-amino-2-propanol was added drop-wise to a solution of 52.59 g of 1,2-epoxyoctane (in a ratio of 1:1 mol) in acetonitrile (100 g). The mixture was stirred and eventually solidified followed by the removal of acetonitrile in vacuum. Under atmospheric nitrogen, 30.00 g of valeric acid and the product of the first step, 83.33 g of 2-(2-hydroxypropylamino)octan-1-ol (in a ratio of 1:1.5 mol) were added to a flask with a Dean Stark trap and a condenser. The reaction mixture was heated to 180° C. and stirred. Water was collected in the trap. The reaction flask was connected to a distillation apparatus. At 180° C. and under a vacuum of 1.33 Pa, approximately 30 g were distilled over to a flask containing molecular sieves to absorb the final equivalent of water. The product was distilled from the reaction mixture and further purified by extraction with petroleum ether followed by distillation. The product, 7a-butyl-2-hexyl-6-methyl-tetrahydro-2H-oxazolo[2,3-b]oxazole, was isolated with 20% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][N:25]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[CH:16]=[C:17]([CH:23]=[CH:24][N:25]=2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)c1ccnc(Cl)c1
Reactant: COc1ccc(B(O)O)cc1OC
Product: CCOC(=O)c1ccnc(-c2ccc(OC)c(OC)c2)c1

Procedure:
3,4-Dimethoxyphenylboronic acid (215 mg) and ethyl 2-chioroisonicotinate (200 mg) were treated in the same manner as in Preparation Example 1 to obtain the title compound.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[OH:11][NH:12][CH:13]([CH2:22][S:23]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:34][N:33]=2)[CH2:28][CH2:27]1)(=[O:25])=[O:24])[CH2:14][CH2:15][C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>C(Cl)Cl>[OH:11][N:12]([C@H:13]([CH2:22][S:23]([N:26]1[CH2:27][CH2:28][N:29]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]([F:43])([F:42])[F:41])=[CH:34][N:33]=2)[CH2:30][CH2:31]1)(=[O:25])=[O:24])[CH2:14][CH2:15][C:16]1[N:17]=[CH:18][CH:19]=[CH:20][N:21]=1)[CH:1]=[O:2]
Reactant: O=CO
Reactant: O=S(=O)(CC(CCc1ncccn1)NO)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CN(O)[C@@H](CCc1ncccn1)CS(=O)(=O)N1CCN(c2ccc(OCC(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 906.9 %

Procedure:
To formic acid (54 mL, 1.4 mol) at 8° C. was added acetic anhydride (11 mL, 100 mmol) and the mixture was stirred at RT for 10 minutes. The mixed anhydride was then recooled to 8° C., and added to a solution, pre-cooled to 0° C., 2-[3-(hydroxyamino)-4-({4-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]piperazin-1-yl}sulfonyl)butyl]pyrimidine (16.32 g, 33.3 mmol) in DCM (170 mL) and formic acid (65 mL, 1.7 mol). The reaction was brought to room temperature and stirred for one hour. Volatiles were then removed in vacuo, and the residue azeotroped with toluene (2×50 mL). The residue was then dissolved in MeOH/DCM (1:1, 250 mL) and stirred overnight at room temperature. The solution was then concentrated in vacuo, and partitioned between DCM (250 mL) and sat. NaHCO3 (250 mL). The DCM layer was then filtered through silica gel (20 g) washing with 5% MeOH/DCM and the volatiles removed in vacuo to give the racemic title compound as a pale yellow foam (15.68 g, 302 mmol, 91%).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCCC1>[C:30]([N:26]1[CH2:25][CH2:24][CH:23]([NH:22][C:20](=[O:21])[C:19]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[C:3]([CH3:6])([CH3:4])[CH3:5])[CH2:18][CH2:17]2)=[O:29])[CH2:28][CH2:27]1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.8 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxo-N-piperidin-4-ylacetamide dihydrochloride (Example 182(A), 0.35 g, 0.79 mmol), acetyl chloride (72.5 mg, 1.02 mmol) and triethylamine (439 μL, 3.15 mmol) in tetrahydrofuran (4 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give The title compound (0.34 g, quant.) as a white powder.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH3:25])=[CH:17][C:16]=1[C:26]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)([OH:28])[CH3:27])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].[CH3:46]I.O>C1COCC1>[CH:29]1([C:26]([C:16]2[CH:17]=[C:18]([CH3:25])[C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:15]=2[CH2:14][N:7]([CH2:6][C:5]2[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=[C:3]([C:2]([F:1])([F:42])[F:43])[CH:4]=2)[C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)([O:28][CH3:46])[CH3:27])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CI
Reactant: Cc1cc(C(C)(O)C2CCCCC2)c(CN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)cc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(C)(c1cc(C)c(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a solution of 1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-5-methyl-4-(trifluoromethyl)phenyl)-1-cyclohexylethanol (18 mg, 0.028 mmol) in THF (3 mL) was added sodium hydride (60% dispersion in mineral oil, 8 mg, 0.202 mmol) at room temperature. After stirring for 5 minutes methyl iodide (12.2 mg, 0.086 mmol) was added and the solution was stirred at room temperature for 18 hours. Water (5 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The organics were combined, dried with anhydrous sodium sulfate, filtered and concentrated to give an oil (17 mg). This material was purified by flash chromatography on a 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 10% ethyl acetate in heptane) to yield the title compound (11 mg, 59%). 1H NMR (400 MHz, CDCl3) δ7.75 (s, 1H) 7.70 (s, 2H) 7.39 (s, 1H) 7.01 (s, 1H) 5.19 (d, J=17.42 Hz, 1H) 5.0 (d, J=17.42 Hz, 1H) 4.74 (q, J=16.72 Hz, J=16.18 Hz, 2H) 4.17 (s, 3H) 3.0 (s, 3H) 2.42 (s, 3H) 1.99 (d, J=12.40 Hz, 1H) 1.72 (m, 2H) 1.58 (s, 3H) 0.99 (m, 8H). MS calc. 637.5, found 638.5 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].Br[C:13]1[CH:14]=[N:15][CH:16]=[N:17][CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:13]2[CH:14]=[N:15][CH:16]=[N:17][CH:18]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: Brc1cncnc1
Reactant: COC(=O)c1nccnc1N
Product: COC(=O)c1nccnc1Nc1cncnc1

Procedure:
The title compound, MS: m/e=232.1 (M+H+), was prepared in accordance with the general method of example 4, step 2 from 3-aminopyrazine-2-carboxylic acid methyl ester and 5-bromopyrimidine.
Reaction SMILES: O.[NH2:2][NH2:3].N[O:5][C:6](=O)[CH2:7][N:8]1[CH2:12][CH:11]([CH2:13][CH2:14][CH3:15])[CH2:10][C:9]1=[O:16]>CCO.[Cl-].[Na+].O>[O:16]=[C:9]1[CH2:10][CH:11]([CH2:13][CH2:14][CH3:15])[CH2:12][N:8]1[CH2:7][C:6]([NH:2][NH2:3])=[O:5]
Reactant: CCCC1CC(=O)N(CC(=O)ON)C1
Reactant: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCC1CC(=O)N(CC(=O)NN)C1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
In a 250 ml three necked flask fitted with a magnetic stirrer, hydrazine hydrate (5.78 g, 0.18 mol, 3 eq) is added to a solution of 1-[2-(aminooxy)-2-oxoethyl]-4-propylpyrrolidin-2-one x40 (11.99 g, 60.29 mmol) in EtOH (125 ml). The mixture is heated 4 h at reflux, cooled down to room temperature, diluted with brine and extracted with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and evaporated to afford 11.0 g of 2-(2-oxo-4-propylpyrrolidin-1-yl)acetohydrazide x41.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Br:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3].[F:31][C:32]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br>>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:27]=[CH:28][C:29]=1[Br:30])[O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH2:34][C:33]2[CH:36]=[CH:37][C:38]([F:40])=[CH:39][C:32]=2[F:31])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[C:16]=2[CH3:24])=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: C=CCOc1cc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)ccc1Br
Product: C=CCOc1cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1Br

Procedure:
The product from Example 63D and 2,4-difluorobenzyl bromide were processed as described in Example 6B to provide the title compound. MS (ESI+) m/z 597 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C[O:11][C:12]1[CH:17]=CC=C[C:13]=1C=CC(=O)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:13][C:12](=[O:11])[CH3:17])[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccccc1C=CC(C)=O
Reactant: O=Cc1cccc(F)c1
Product: CC(=O)C=Cc1cccc(F)c1

Procedure:
The title compound was prepared from 3-fluoro-benzaldehyde (4.8 g, 40.0 mmol), following the procedure describing the synthesis of 4-(2-methoxy-phenyl)-but-3-en-2-one (example 1/a stage 1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([CH3:17])[CH:9]=2)[CH2:4][CH2:3]1.[CH3:18]OC(OC)N(C)C.N1CCCC1.C([O-])=O.[NH4+]>CN(C)C=O.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:11](=[CH:12][CH:13]=2)[NH:14][CH:18]=[CH:17]3)[CH2:4][CH2:3]1
Reactant: Cc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc3[nH]ccc3c2)CC1
Temperature: 50 °C

Procedure:
A solution of 1-methyl-4-(3-methyl-4-nitro-phenyl)-piperazine (10a), (2.63 g, 11.2 mmol), N,N-dimethylformamide dimethyl acetal (4.7 mL, 35.84 mmol) and pyrrolidine (1.5 mL, 17.9 mmol) in anhydrous N,N-dimethylformamide (20 mL) was heated at 120° C. for 18 hours. The reaction mixture was concentrated in vacuo, taken up in ethanol (50 mL) containing 2 mL of water and to this was added ammonium formate (3.67 g, 58.2 mmol). Palladium, 10 wt. % on activated carbon (0.84 g) was added and the suspension was stirred and heated at 50° C. for 30 minutes. The reaction mixture was then filtered through a celite pad and the pad rinsed with hot methanol (20 mL). The combined filtrate and washings were concentrated in vacuo and the residue was taken up in ethyl acetate (100 mL), washed with aqueous saturated sodium bicarbonate solution (2×100 mL), brine, dried (MgSO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting first with hexane and then 15% ethyl acetate/hexane to afford the desired title compound as an off-white solid, 1.44 g, 60%.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:24][CH2:23][C:5]2=[C:6]([C:9]3[O:13][N:12]=[C:11]([C:14]4[CH:19]=[C:18]([CH3:20])[C:17]([OH:21])=[C:16]([CH3:22])[CH:15]=4)[N:10]=3)[S:7][CH:8]=[C:4]2[CH2:3]1.[OH-].[Na+].[CH2:28]([CH:30]1[O:32][CH2:31]1)Cl>C(O)(C)C.O>[CH3:22][C:16]1[CH:15]=[C:14]([C:11]2[N:10]=[C:9]([C:6]3[S:7][CH:8]=[C:4]4[CH2:3][C:2]([CH3:25])([CH3:1])[CH2:24][CH2:23][C:5]=34)[O:13][N:12]=2)[CH:19]=[C:18]([CH3:20])[C:17]=1[O:21][CH2:28][CH:30]1[CH2:31][O:32]1
Reactant: ClCC1CO1
Reactant: Cc1cc(-c2noc(-c3scc4c3CCC(C)(C)C4)n2)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Cc1cc(-c2noc(-c3scc4c3CCC(C)(C)C4)n2)cc(C)c1OCC1CO1
Temperature: 50 °C
Reaction time: 18 h
Yield: 99.1 %

Procedure:
A solution of 4-[5-(5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenol (35 mg, 1.18 mmol) in isopropanol (17 mL) is treated with 2 N aq. NaOH (8.6 mL) followed by epichlorohydrine (660 mg, 7.14 mmol). The mixture is stirred at 50° C. for 18 h before it is diluted with water and extracted twice with EA. The combined organic extracts are dried over Na2SO4, filtered, evaporated and dried to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-5-(5,5-dimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-[1,2,4]oxadiazole (480 mg) as a pale yellow oil; LC-MS: tR=1.24 min, [M+1]+=411.31.
Reaction SMILES: [OH-].[Na+].O.C1(O[C:11](=O)[N:12]([CH2:14][CH2:15][C@H:16]([O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)C)C=CC=CC=1>CS(C)=O>[CH3:11][NH:12][CH2:14][CH2:15][C@H:16]([O:22][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=12)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1
Reactant: CN(CC[C@H](Oc1cccc2ccccc12)c1cccs1)C(=O)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1
Temperature: 115 °C
Yield: 92 %

Procedure:
Sodium hydroxide (19 g) and water (25 mL) were added to a solution of (S)-N-Methyl-[3-(naphthalen-1-yloxy)-3-thiophen-2-yl-propyl]-carbamic acid phenyl ester (64.8 g) dissolved in DMSO (250 mL). The mixture was heated at 115° C. for 6 hours, cooled to ambient temperature, and water (200 mL) was added. The mixture was then extracted with toluene (2×200 mL) and the organic layers were combined. The organic layers were then washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated. The resulting residue was then dissolved in methanol (500 mL), combined with activated carbon (2 g), and heated at reflux for 1 hour. After cooling, the mixture was filtered through Celite® (20 g), the filter cake was washed with methanol (50 mL), and the solution was concentrated to yield duloxetine base as an oil (37.07 g, Yield: 92% yield, Chiral HPLC: 90% ee).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:10]=2[CH:9]=1.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26].C(N(C(C)C)C(C)C)C>>[F:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]2[CH2:12][CH2:13][N:14]([C:25](=[O:26])[CH2:24][O:23][CH3:22])[CH2:15][CH2:16][C:10]=2[CH:9]=1
Reactant: COCC(=O)Cl
Reactant: Fc1cccc(COc2ccc3c(c2)CCNCC3)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCc2ccc(OCc3cccc(F)c3)cc2CC1
Yield: 98 %

Procedure:
The title compound was prepared in analogy to Example 1 d) from 7-(3-fluoro-benzyloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride [Example 1c)] and methoxy-acetic acid chloride with N-ethyl-diisopropylamine as the base. Yield: 98% of theory as a colourless oil; MS: m/e=344 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[F:18][C:19]1[C:20]([C:29](O)=[O:30])=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:20]3[C:19]([F:18])=[CH:24][C:23]([C:25]([F:27])([F:26])[F:28])=[CH:22][N:21]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1F
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ncc(C(F)(F)F)cc3F)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 3-fluoro-5-trifluoromethyl-pyridine-2-carboxylic acid (CAS 89402-28-8) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=433.3 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].I[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37].C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][N:17]2[CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CC(C)CCI
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCCN2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCCN2CCC(C)C)c1
Temperature: 78 °C

Procedure:
To a solution of 4-Methyl-2-(5-piperidin-2-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester, compound 10b (30.0 mg, 0.067 mmol) in CH3CN (0.5 mL) was added 1-iodo-3methylbutane (16.0 mg, 0.08 mmol) and cesium carbonate (44.0 mg, 0.134 mmol). The reaction was heated to 78° C. overnight. The reaction was cooled to room temperature, concentrated in vacuo, diluted with EtOAc, washed with NaHCO3, and brine. The solution was filtered, and concentrated, then purified via Gilson HPLC to give the compound as a light yellow oil. (31.8 mg, 92%) Calculated for C31H42F3NO2 (M+H) 517.67, Found 518.4.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:2].N1C=CC=CC=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[S:26]([CH3:25])(=[O:28])=[O:27])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CCNCCCCNC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCN(CCCCNC(=O)OCc1ccccc1)S(C)(=O)=O
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a mixture of benzyl 4-(ethylamino)butylcarbamate (Step 1, 250 mg, 1.00 mmol) in dichloromethane was added pyridine (145 mg, 1.8 mmol) and then methanesulfonyl chloride (137 mg, 1.20 mmol) at 0° C. The reaction was stirred overnight and diluted with dichloromethane. The phases were separated, and the organic phase was washed with hydrochloride solution (1 N), saturated sodium bicarbonate and saline. The separated organic layer was concentrated and purified by Biotage column chromatography to give benzyl 4-(N-ethylmethylsulfonamido)butylcarbamate (231 mg).