Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[N:22]=[C:21]([NH2:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>C(OCC)(=O)C>[O:25]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[N:22]=[C:21]([NH:23][C:26](=[O:28])[CH3:27])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(N)c2c1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of 2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine (50 mg, 0.14 mmol, prepared in analogy to Example 59) and acetic anhydride (2 mL) was heated with stirring at 110° C. for 2 hours under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium carbonate and brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give 30 mg of the product as a white powder. MS obsd. (ESI+) [(M+H)+] 397, 1H NMR (400 MHz, CD3OD) δ ppm 7.87 (d, J=7.6 Hz, 1 H), 7.80 (s, 1 H), 7.56 (m, 3 H), 7.28 (m, 1 H), 7.21 (m, 1 H), 5.11 (s, 2 H), 4.48 (s, 2 H), 2.99 (s, 2 H), 2.47 (s, 6 H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[C:29]([O:33][C:34](=[O:36])[CH3:35])([CH3:32])([CH3:31])[CH3:30].C[O:38][C:39](=O)[CH2:40][CH:41]([OH:50])[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[C:29]([O:33][C:34](=[O:36])[CH2:35][C:39](=[O:38])[CH2:40][CH:41]([OH:50])[CH2:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)CC(O)CCc1ccccc1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CC(O)CCc1ccccc1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 95.2 %

Procedure:
A solution of 2.0 M LDA in heptane/THF/ethylbezene (9.4 mL, 18.8 mmol) was added slowly to a stirred solution of tert-butylacetate (2.18 g, 18.8 mmol) in dry THF (20 mL) under N2 at −78° C. After being stirred at −78° C. for 25 min., a solution of the above made 3-hydroxy-5-phenyl-pentanoic acid methyl ester (1.3 g, 6.25 mmol) in dry THF (10 mL) was then added through a cannula. The resultant clear solution was stirred at −78° C. for 1 h and then at −55° C. for another 1 h. The reaction was quenched by the addition of 20% aqueous acetic acid (20 mL). Two layers were separated and the aqueous layer was extracted with EtOAc (3×30 mL). Combined organic layer was washed with H2O (50 mL, brine (50 mL, dried with sodium sulfate, and then concentrated to leave an oil. Flush column chromatography purification on silica gel (4:1 Hexane/EtOAc to 2:1 Hexane/EtOAc) afforded the intermediate 5-Hydroxy-3-oxo-7-phenyl-heptanoic acid tert-butyl ester as a colorless oil (1.74 g, 95%). 1H NMR (300 MHz, CDCl3) δ1.45 (s, 9H), 1.6-1.9 (m, 2H), 2.50-2.85 (m, 4H), 3.35 (s, 3 H), 3.95-4.10 (m, 1H), 7.10-7.30 (m, 5H). ESMS calcd (C17H24O4): 292.2; found: 291.2 (M−H)+.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:19])/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>O.O1CCOCC1.[OH-].[Na+]>[CH:16]1([C:14]([C:11]2[CH:12]=[CH:13][C:8](/[CH:7]=[CH:6]/[C:5]([OH:19])=[O:4])=[CH:9][CH:10]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: COC(=O)/C=C/c1ccc(C(=O)C2CC2)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)/C=C/c1ccc(C(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
A solution of lithium hydroxide (27 mg, 1.1 mmol) in water (2.00 ml) was added to a solution of (E)-3-(4-(cyclopropanecarbonyl)phenyl)acrylic acid methyl ester (217 mg, 0.94 mmol) in 1,4-dioxane (2.00 ml). 1,4-Dioxane was added until a clear solution was obtained. The reaction mixture was stirred for 16 h at room temperature. It was diluted with an 1 N aqueous solution of sodium hydroxide (50 ml) and washed with tert-butyl methyl ether (2×40 ml). The aqueous solution was acidified with a 10% aqueous solution of sodium hydrogensulphate until pH 3 was obtained. It was extracted with ethyl acetate (3×100 ml) The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo to give 170 mg of crude (E)-3-(4-(cyclopropanecarbonyl)phenyl)acrylic acid which was used in the next step without further purification.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:12](=[O:19])[CH2:13][CH:14]([OH:18])[C:15]=1[C:16]#[N:17])([O:3][CH3:4])=[O:2].Cl>[Zn].C(O)(=O)C>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH:15]([C:16]#[N:17])[CH:14]([OH:18])[CH2:13][C:12]1=[O:19])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCCCCCC1=C(C#N)C(O)CC1=O
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)CCCCCCC1C(=O)CC(O)C1C#N
Reaction time: 3 h
Yield: 63.8 %

Procedure:
Into a mixture of 7 g of 2-(6'-carbomethoxyhexyl)-3-cyano-4-hydroxy-2-cyclopenten-1-one, 52.5 ml of acetic acid and 55 ml of 0.5 N hydrochloric acid was added 15 g of zinc powder. After the addition the reaction mixture was stirred for 3 hours under cooling. Thereafter, the zinc powder was removed by filtration, and the filtrate was diluted with water and extracted with ether. The ether extract was washed with a diluted aqueous sodium bicarbonate solution and with water and then dried. The solvent was distilled off to afford 4.5 g of 2-(6'-carbomethoxyhexyl)-3-cyano-4-hydroxy-cyclopentanone.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:6]=[C:5]([Cl:7])[N:4]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Clc1cc(Cl)[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
A suspension of 3,5-dichloro-1H-pyrazole (690 mg, 5.0 mmol) (i.e. the product of Example 12, Step D), potassium carbonate (3 g, 21 mmol) in N,N-dimethylformamide (10 mL) was treated with ethyl bromoacetate (1.0 mL, 9.0 mmol) and stirred at ambient temperature for 12 h. The suspension was diluted with ethyl acetate, washed with water, and dried over MgSO4. The reaction mixture was then concentrated under reduced pressure giving 1.05 g of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:18][C:19]#[CH:20])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=O.[Cl-].[CH3:22][O:23][CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:18][C:19]#[CH:20])[C:10]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:22][O:23][CH3:24]
Reactant: C#CCC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Product: C#CCC(C(=COC)c1cccnc1)c1ccc(Cl)cc1Cl

Procedure:
starting from 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-4-pentyn-1-one and methoxymethyltriphenylphosphonium chloride there is obtained 3-[2,4-dichloro-α-methoxymethylene-β-(2-propynyl)-phenethyl]-pyridine
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)[S:5][C:6]=1[C:7]([O-:9])=[O:8].[Sn](Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].O1CC[CH2:31][CH2:30]1>>[NH2:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:4]1[S:5][C:6]([C:7]([O:9][CH2:30][CH3:31])=[O:8])=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1nc(Nc2ccccc2[N+](=O)[O-])sc1C(=O)[O-]
Reactant: C1CCOC1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)c1sc(Nc2ccccc2N)nc1C
Temperature: 80 °C
Yield: 77 %

Procedure:
4-Methyl-2-(2-nitrophenylamino)thiazole-5-carboxylate (0.45 g, 1.46 mmol), tin(II) chloride dehydrate (1.66 g, 7.34 mmol) and tetrahydrofuran (25 mL) was added to a 100-mL round bottom flask. The mixture was refluxed at 75-85° C. for 3 h, cooled down to 0° C. and followed by the addition of saturated aqueous sodium carbonate solution (16 mL). The mixture was filtered through a celite cake and the filtrate was washed with saturated aqueous sodium carbonate solution (18 mL), water (2×15 mL) and brine (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo to a small volume and triturated with diethyl ether. The solid was collected by filtration, washed with hexanes and dried in vacuo to afford ethyl 2-(2-aminophenylamino)-4-methylthiazole-5-carboxylate as a white solid (0.31 g, 77% yield): 1H NMR (300 MHz, CDCl3) δ 7.31-7.24 (m, 1H), 7.17-7.12 (m, 1H), 6.84-6.77 (m, 2H), 4.45-4.06 (m, 5H), 2.48 (s, 3H), 1.25 (t, J=7.05 Hz, 3H); MS (ES+) m/z 278.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1)[CH3:33]>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:43][S:40]([C:37]3[CH:36]=[CH:35][C:34]([CH2:32][CH3:33])=[CH:39][CH:38]=3)(=[O:41])=[O:42])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: CCc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: CCc1ccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-ethylbenzenesulfonamide: 1H-NMR (CDCl3) δ 7.77 (2H, d, J=8.4 Hz), 7.47-7.23 (11H, m), 6.39 (1H, br.s), 3.52-3.45 (2H, m), 2.86 (2H, t, J=6.7 Hz), 2.71 (2H, q, J=7.7 Hz), 2.33 (3H, s), 2.25 (3H, s), 1.25 (3H, t, J=7.7 Hz).
Reaction SMILES: [F:1][C:2](=[CH2:11])[C:3]([CH3:10])([CH3:9])[C:4]([O:6]CC)=[O:5].[OH-].[K+]>C(O)C.O>[F:1][C:2](=[CH2:11])[C:3]([CH3:10])([CH3:9])[C:4]([OH:6])=[O:5]
Reactant: C=C(F)C(C)(C)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=C(F)C(C)(C)C(=O)O
Yield: 78.8 %

Procedure:
Hydrolysis of the ester (1 g) with 1 g of potassium hydroxide in ethanol/water overnight furnished 0.65 g of the title acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[CH:16]1([C:19](Cl)=[O:20])[CH2:18][CH2:17]1>C1(C)C=CC=CC=1>[CH:16]1([C:19]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)=[O:20])[CH2:18][CH2:17]1
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: O=C(Cl)C1CC1
Solvent: Cc1ccccc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C2CC2)cc1
Yield: 85 %

Procedure:
6.0 g (29.5 millimoles) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone, 3.4 g (32.5 millimoles) of cyclopropanecarboxylic acid chloride and 100 ml of absolute toluene are kept for 6 hours at 80° C. The product is filtered off at 10° C., washed first with toluene and then with water, and recrystallized from dimethylformamide/water. 6.8 g (85% of theory) of 6-(p-cyclopropylcarbonylaminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone are obtained as beige crystals, of melting point 267°-268° C.
Reaction SMILES: [N+:1](=[C:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]1=[O:10])=[N-].[C:11]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)N)#[N:12]>C1C=CC=CC=1.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[OH:10][C:4]1[CH2:5][CH2:6][CH2:7][C:8](=[O:9])[C:3]=1[N:1]([C:3]1[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][C:4]=1[OH:10])[C:18]1[CH:19]=[C:13]([CH:14]=[CH:15][CH:17]=1)[C:11]#[N:12]
Reactant: N#Cc1cccc(N)c1
Reactant: [N-]=[N+]=C1C(=O)CCCC1=O
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: N#Cc1cccc(N(C2=C(O)CCCC2=O)C2=C(O)CCCC2=O)c1
Temperature: 80 °C

Procedure:
2-Diazo-cyclohexane-1,3-dione (2 mmoL), prepared by the literature known procedure, 3-cyano-aniline (1 mmoL) and rhodium acetate dimmer (0.01 mmoL) in benzene (10 mL) were heated at 80° C. for 4˜6 hrs. The solid was filtered off and the filtrate was concentrated to give a yellow oil, which was purified by silica gel chromatography to afford the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32](Cl)[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([NH:8][C:9]([C:11]2[C:12](=[O:27])[N:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH2:18][CH3:19])=[O:10])[CH:7]=1.[CH:37]1([C:40]([NH2:42])=[O:41])[CH2:39][CH2:38]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:1][C:2]1[C:3]([O:29][C:30]2[CH:35]=[CH:34][N:33]=[C:32]([NH:42][C:40]([CH:37]3[CH2:39][CH2:38]3)=[O:41])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([NH:8][C:9]([C:11]2[C:12](=[O:27])[N:13]([C:20]3[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=3)[CH:14]=[CH:15][C:16]=2[O:17][CH2:18][CH3:19])=[O:10])[CH:7]=1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F
Reactant: NC(=O)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(Cl)c(Oc2ccnc(NC(=O)C3CC3)c2)cc1F
Yield: 49.4 %

Procedure:
Using the procedure of Example 12, N-(5-chloro-4-((2-chloropyridin-4-yl)oxy)-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.05 g, 0.094 mmol), cyclopropancarboxamide (12 mg, 0.14 mmol), Cs2CO3 (0.05 g, 0.14 mmol), Xantphos (6 mg, 0.010 mmol), Pd2(dba)3 (5 mg, 0.005 mmol) and dioxane (2 mL) were combined to obtain N-(5-chloro-4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (27 mg, 48.4% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.20 (s, 1 H), 10.88 (s, 1 H), 8.50 (d, J=7.8 Hz, 1 H), 8.19 (d, J=5.7 Hz, 1 H), 7.92 (d, J=7.8 Hz, 1 H), 7.59 (d, J=2.4 Hz, 1 H), 7.50 (m, 3 H), 7.36 (t, J=8.7 Hz, 2 H), 6.68 (dd, J=5.7, 2.4 Hz, 1 H), 6.55 (d, J=7.9 Hz, 1 H), 4.28 (q, J=7.0 Hz, 2 H), 1.95 (m, 1 H), 1.33 (t, J=7.0 Hz, 3 H), 0.76 (t, J=5.9 Hz, 4 H); MS (ESI) m/z: 581.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.[O:8]([CH2:15][C:16]1[CH:24]=[C:19]2C=[N:21][CH2:22][CH2:23][N:18]2[N:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.F.[K].C[Si](C(F)(F)F)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CC#N.CN(C=O)C.O>[O:8]([CH2:15][C:16]1[CH:24]=[C:19]2[CH:3]([C:2]([F:7])([F:6])[F:1])[NH:21][CH2:22][CH2:23][N:18]2[N:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(O)C(F)(F)F
Reactant: C1=NCCn2nc(COc3ccccc3)cc21
Agent: C[Si](C)(C)C(F)(F)F
Agent: F
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)C1NCCn2nc(COc3ccccc3)cc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 63 %

Procedure:
Trifluoroacetic acid (0.36 mL) was added to a stirred mixture of 2-phenoxymethyl-6,7-dihydro-pyrazolo[1,5-a]pyrazine (0.43 g, 1.87 mmol) and potassium hydrogen fluoride (0.18 g, 2.34 mmol) in CH3CN (3.7 mL) and DMF (0.4 mL) at 0° C. The mixture was stirred at 0° C. for 5 minutes. Then Ruppert's reagent (0.83 mL, 5.61 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was treated with a saturated solution of Na2CO3, diluted with water and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; 7N solution of ammonia in methanol in DCM 0/100 to 30/70). The desired fractions were collected and the solvents evaporated in vacuo to yield rac-2-phenoxymethyl-4-trifluoromethyl-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine (350 mg, 63% yield) as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=O.P(Cl)(Cl)(Cl)(Cl)Cl.[NH:18]=[N+:19]=[N-:20]>C1C=CC=CC=1>[CH:6]1([N:5]2[C:3]([CH2:2][Cl:1])=[N:20][N:19]=[N:18]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=C(CCl)NC1CCCCC1
Reactant: [N-]=[N+]=N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: ClCc1nnnn1C1CCCCC1
Reaction time: 2 h

Procedure:
Into 150 ml of dried benzene, 17.6 g of N-chloroacetylcyclohexylamine was added. While the inside temperature is kept below 15° C. by ice-cooling the outside of the reaction vessel, 24 g of phosphorus pentachloride (PCl5) was added under stirring condition. After completion of the addition, the stirring is continued for 2 hours at a room temperature, then the reaction mixture is concentrated to a half volume thereof by using an evaporator with a bath temperature of below 50° C. To the concentrated reaction mixture was added dropwise 100 ml of benzene containing 10% of HN3 under stirring condition for 90 minutes while keeping the inside temperature below 15° C. After the addition operation, the reaction mixture is allowed to stand overnight. Then the reaction mixture is refluxed for 3 hours with stirring. The thus obtained concentrate is extracted with 200 ml of chloroform. The chloroform layer is washed with water, 5% NaHCO3 aqueous solution, 5% hydrochloric acid and water in this order and dried with Na2SO4. After removal of the drying agent by filtration, the mother liquour is concentrated and the residue thus obtained is recrystallized from chloroform-petroleum ether to obtain 16.1 g of 1-cyclohexyl-5-chloromethyltetrazol in the form of colorless needle like crystals. Melting point: 101° to 103.5° C.
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]([Cl:25])(=O)C.[ClH:26].[OH-].[Na+]>C(O)(C)C.CC(C)=O>[ClH:25].[ClH:26].[CH3:1][NH:2][CH2:3][CH2:4][C@:5]([CH3:22])([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: CC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CNCC[C@](C)(Oc1cccc2ccccc12)c1cccs1
Temperature: 50 °C

Procedure:
The crude wet duloxetine free base (205.0 g) and an acetone (anti-solvent)(600.0 g) were charged in a 4-neck round flask and heated to a temperature of 50° C. while stirring. To another 4-neck round flask, isopropyl alcohol (IPA) (200.0 g) was charged, and the temperature was set to about 0 to about 5° C. while stirring. Fresh hydrochloride was prepared by dropping acetyl chloride (48.0 g) slowly to the isopropyl alcohol solution and stirring the reaction for one hour at a temperature of about 15° C. to 20° C. Then, the fresh hydrochloric acid in isopropyl alcohol was added to the duloxetine free base solution slowly, and the pH value was controlled in a range from 5.5 to 7.5 with NaOH(aq). The temperature was set at 50° C., and the reaction was gradually cooled to 0° C.˜5° C. The reaction was stirred for another one hour at about 0° C.˜5° C., and after filtration, the purified duloxetine hydrochloride was produced. (190 g, 99% ee; purity; 98% by HPLC assay).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8](C2C=CC(C(N3C4C(=CC=CC=4)[C@H](N(C(=O)C)C4C=CC(Cl)=CC=4)C[C@@H]3C)=O)=CC=2)[CH2:7]1)=[O:5])C.C(O)C.[OH-].[Li+]>O1CCCC1>[NH:8]1[CH2:9][CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1
Reactant: CCOC(=O)C1CCCN(c2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C1CCCNC1
Temperature: 50 °C

Procedure:
(2S,4R)-1-(4-{4-[Acetyl-4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-piperidine-3-carboxylic acid was prepared from (2S,4R)-1-(4-{4-[acetyl(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-piperidine-3-carboxylic acid ethyl ester (0.300 g, 0.522 mol) was hydrolyzed to the acid by dissolving in tetrahydrofuran and ethanol and lithium hydroxide (1N) was added and heated 50° C. for 2 h. The mixture was cooled to room temperature, acidified to form a white precipitate. The solid was filtered to give to afford the product after HPLC purification.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[C:7]([Cl:9])[C:6]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][C@@H:2]([CH3:19])[CH2:3][N:4]2[CH:8]=[C:7]([Cl:9])[C:6]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=3)=[N:5]2)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1cc(Cl)c(-c2ccc(C#N)c(Cl)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2cc(Cl)c(-c3ccc(C#N)c(Cl)c3)n2)[nH]n1
Yield: 50.6 %

Procedure:
The title compound was synthesized from (S)-4-(1-(2-aminopropyl)-4-chloro-1H-pyrazol-3-yl)-2-chlorobenzonitrile (518 mg, 1.75 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (270 mg, 1.75 mmol), HOBt (285 mg, 2.1 mmol), DIPEA (0.367 mL, 2.1 mmol) and EDCI (404 mg, 2.1 mmol) using DCM as solvent using the method of Example 34(d) to afford 382 mg of the title compound. 1H NMR (400 MHz; d6-DMSO): δ 1.15 (d, 3H), 2.42 (s, 3H), 4.30 (m, 2H), 4.44 (m, 1H), 6.86 (s, 1H), 8.01 (m, 3H), 8.12 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:11][C:12]#[N:13])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].Cl>N1C=CC=CC=1>[S:11]([C:4]1[S:3][C:2]([NH:1][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[C:16]([C:15]([F:14])([F:25])[F:26])[CH:17]=2)=[N:6][C:5]=1[C:7]([F:10])([F:8])[F:9])[C:12]#[N:13]
Reactant: N#CSc1sc(N)nc1C(F)(F)F
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: N#CSc1sc(NC(=O)c2cccc(C(F)(F)F)c2)nc1C(F)(F)F
Temperature: 0 °C
Yield: 56.7 %

Procedure:
2-Amino-5-thiocyanato-4-trifluoromethylthiazole (0.8 g) was dissolved in pyridine (5 ml) and 3-trifluoromethylbenzoylchloride (0.8 g) was added at room temperature with stirring. The mixture was stirred for one night at room temperature. The mixture was poured into ice water and acidified with aqueous hydrochloric acid then extracted with chloroform. The chloroform layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The solid thus obtained was recrystallized from carbon tetrachloride to give N-(5-thiocyanato-4-trifluoromethylthiazol-2-yl)-3-trifluoromethylbenzamide (0.8 g), m. p. 167-168° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]4[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[Cl:26][C:27]1[C:32]([NH2:33])=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]=1>>[NH2:33][C:32]1[CH:31]=[C:30]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:25])[C:13](=[O:24])[N:14]([C:15]5[C:16]([CH3:23])=[N:17][N:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)[CH:29]=[N:28][C:27]=1[Cl:26]
Reactant: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cnc(Cl)c(N)c2)OC1(C)C
Product: Cc1nn(C(C)C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(Cl)c(N)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1-isopropyl-3-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate G, 0.098 mmol) and 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (stage 152.1.1) to give the title compound as a yellow foam. (HPLC: tR 2.55 min (Method A); M+H=448 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.19 (s, 1H), 8.14-8.09 (m, 1H), 7.78-7.73 (m, 1H), 7.57-7.53 (m, 1H), 7.50-7.47 (m, 1H), 7.28-7.24 (m, 1H), 5.68 (s, br, 2H), 4.55 (hp, 1H), 3.58 (s, 3H), 1.95 (s, 3H), 1.44 (d, 6H))