Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:7]2[CH:8]=[C:9]([C:12]3[CH:13]=[C:14]([C:17]#[N:18])[S:15][CH:16]=3)[CH:10]=[CH:11][C:6]=2[NH:5][CH:4]([C:19]([F:22])([F:21])[F:20])[O:3]1.[H-].[Na+].[C:26](Cl)(=[O:28])[CH3:27]>CN(C=O)C.[Cl-].[Na+].O>[C:26]([N:5]1[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[C:14]([C:17]#[N:18])[S:15][CH:16]=3)=[CH:8][C:7]=2[C:2]([CH3:23])([CH3:1])[O:3][CH:4]1[C:19]([F:22])([F:20])[F:21])(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC1(C)OC(C(F)(F)F)Nc2ccc(-c3csc(C#N)c3)cc21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1c2ccc(-c3csc(C#N)c3)cc2C(C)(C)OC1C(F)(F)F
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
4-[4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-6-yl]thiophene-2-carbonitrile (0.25 g, 0.74 mmol) was dissolved in DMF (10 mL), NaH (0.09 g, 2.22 mmol) was added and the mixture was stirred for 30 minutes prior to the addition of acetyl chloride (0.079 mL, 1.11 mmol). Upon disappearance of the starting material the reaction mixture was poured into brine (100 mL) and the product extracted with ether (150 mL), dried over sodium sulfate and concentrated. The residue was purified by a flash column chromatography (silica gel, 25% ethyl acetate/hexane) to yield 4-[1-acetyl-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-6-yl]thiophene-2-carbonitrile (0.1 g, 36%) as an amorphous solid: 1H-NMR (DMSO-d6) δ 8.58 (s, 1H), 8.5 (s, 1H), 7.83-7.80 (m, 2H), 7.64 (d, 1H, J=8.74 Hz), 6.42 (q, 1H, J=10 Hz), 2.24 (s, 3H), 1.73 (s, 3H), 1.42 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[N:14]=2)[N:9]=[CH:8][C:7]=1[F:18])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:31][N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42]>C1COCC1>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[N:14]=2)[N:9]=[CH:8][C:7]=1[F:18])[CH2:31][N:32]1[C:36](=[O:37])[C:35]2[C:34](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]1=[O:42])[CH3:2]
Reactant: CCOC(=O)Cc1c(F)cnc2ccc(OC)nc12
Reactant: O=C1c2ccccc2C(=O)N1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CN1C(=O)c2ccccc2C1=O)c1c(F)cnc2ccc(OC)nc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of (3-fluoro-6-methoxy-[1,5]naphthyridin-4-yl)-acetic acid ethyl ester (6.78 g; prepared in analogy to the corresponding methyl ester described in WO 2007/122258) in THF (30 mL) was added dropwise at −78° C. to a solution of LiHMDS (31 mL; 1M in THF) diluted in THF (20 mL). After stirring for 1 h at −78° C. a solution of N-(bromomethyl)phthalimide (7.40 g) in THF (30 mL) was added dropwise and the mixture was stirred for an additional 1 h at −78° C. and then overnight at rt. The yellow solution was quenched with 1N HCl (280 mL) and extracted with DCM. The combined org. layers were washed with H2O, dried over MgSO4, concentrated and purified by CC (Hept/EA 1:1), affording a light yellow foam (5.49 g; 51% yield).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([C:8]2[N:16]([CH2:17][C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[C:15]3[C:14](=[O:26])[N:13]([CH3:27])[C:12](=[O:28])[N:11]([CH3:29])[C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.N([O-])=[O:32].[Na+]>O>[Cl:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[CH2:17][N:16]1[C:15]2[C:14](=[O:26])[N:13]([CH3:27])[C:12](=[O:28])[N:11]([CH3:29])[C:10]=2[N:9]=[C:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:32])[CH:3]=1
Reactant: Cn1c(=O)c2c(nc(-c3cccc(N)c3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cn1c(=O)c2c(nc(-c3cccc(O)c3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
A solution of 8-(3-aminophenyl)-7-(2-chloro-6-fluorobenzyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione (88 mg, 0.21 mmol) in 310 μL water was treated with concentrated HCl and then sodium nitrite (19 mg, 0.23 mmol) dissolved in ˜300 μL water. The reaction mixture was stirred at 0° C. for 30 min and then heated to 100° C. for 15 min. The reaction mixture was cooled, dried under reduced pressure, and purified by preparative thin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cm silica gel 60 F264) eluting with EtOAc:hexane (2:1) to give 37 mg (43% yield) of the title compound as a pale orange solid: 1H NMR (CDCl3, 400 MHz) 7.22-7.16 (m, 1H), 7.12-7.01 (m, 2H), 6.96-6.91 (m, 2H), 6.86-6.81 (m, 1H), 6.80-6.74 (m, 1H), 5.82 (s, 2H), 3.60 (s, 3H), 3.37 (s, 3H); MS (ESP+) m/e 415 (MH+); TLC (EtOAc:hexanes/2:1) Rf=0.41.
Reaction SMILES: Cl([O-])=O.[Na+].[F:5][C:6]([F:34])([F:33])[CH2:7][CH2:8][CH2:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:13]12[CH3:14])[C@:26]1([CH3:27])[C:21]([CH:22]=[C:23]([CH:31]=[O:32])[CH2:24][CH2:25]1)=[CH:20][CH2:19]3)=[O:11].P([O-])([O-])([O-])=[O:36].[Na+].[Na+].[Na+].O>CC(=CC)C.C1COCC1.C(O)(=O)C.C(O)(C)(C)C>[F:5][C:6]([F:33])([F:34])[CH2:7][CH2:8][CH2:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:13]12[CH3:14])[C@:26]1([CH3:27])[C:21]([CH:22]=[C:23]([C:31]([OH:36])=[O:32])[CH2:24][CH2:25]1)=[CH:20][CH2:19]3)=[O:11]
Reactant: O=P([O-])([O-])[O-]
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CCCC(F)(F)F
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C(=O)O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)CCCC(F)(F)F

Procedure:
Sodium chlorite (53 mg, 0.6 mmol) was added to a mixture of 17β-(5,5,5-trifluoro-1-oxopentyl)-androsta-3,5-diene-3-carboxaldehyde (50 mg, 0.12 mmol), sodium phosphate, monobasic monohydrate (140 mg, 1.18 mmol) in 2-methyl-2-butene in THF (2.0M, 3.0 ml), H2O (0.5 mL), and t-butanol (0.5 ml) at RT. After 6 h acetic acid (3.0 mL) was added, then the aqueous layer was extracted with EtOAc (10 mL), the combined organic extracts were dried (MgSO4), filtered, concentrated, and flash chromatographed (silica gel, 1% AcOH/19% EtOAc/80% hexanes) to yield the title compound as a white waxy solid. ESMS m/e 439 [M+H]+
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:13]3C(=O)C4=CC=CC=C4C3=O)=[CH:8][C:7]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[CH:25]=3)=[N:6]2)[CH2:3][CH2:2]1.O.NN>CO>[NH2:13][CH2:12][C:9]1[C:10](=[O:11])[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:6]=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([F:32])[CH:25]=2)[CH:8]=1
Reactant: COc1ccc(-c2cc(CN3C(=O)c4ccccc4C3=O)c(=O)n(CC3CC3)n2)cc1F
Agent: NN
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cc(CN)c(=O)n(CC3CC3)n2)cc1F
Yield: 99.7 %

Procedure:
To a solution of 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-phthalimidomethyl-2H-pyridazin-3-one (190 mg, 0.43 mmol) in methanol (5 mL) was added hydrazine monohydrate (110 mg, 2.20 mmol), and the mixture was heated under reflux for 2 hours. Methanol was distilled off under reduced pressure, and chloroform (20 mL) was added to the residue. The mixture was successively washed with water (10 mL) and brine (10 mL) in this order, and was then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by preparative thin-layer chromatography on silica gel [developing solvent: chloroform/10% w/v solution of methanol in ammonia (20/1)] to yield the title compound as pale yellow crystals (130 mg, 97.8%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])([OH:15])[CH2:6][CH2:5]2.C(O)=O>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([CH:12]([CH3:14])[CH3:13])[C@:7]([CH2:16][C:17]([OH:19])=[O:18])([OH:15])[CH2:6][CH2:5]2
Reactant: CC(C)[C@H]1c2ccc(F)cc2CC[C@]1(O)CC(=O)OC(C)(C)C
Solvent: O=CO
Solvent: O
Product: CC(C)[C@H]1c2ccc(F)cc2CC[C@]1(O)CC(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.7 %

Procedure:
A mixture of 3.02 g crude tert-butyl (1S,2S)-(6-fluoro-2-hydroxy-1-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)acetate and 8 mL 96% formic acid was stirred at 25° C. for four hours. The solution was diluted with 6 mL water; then heated to 75° C and filtered. The filtrate was slowly cooled to 25° C. with stirring. The resulting suspension was cooled to 0° C., stirred for one hour, and suction filtered. The precipitate was washed with 15 mL water, air dried at 25° C. for one hour, then oven dried at 50° C. for 22 hours to give 1.59 g (1S,2S)-(6-fluoro-2-hydroxy-l-isopropyl-1, 2,3,4-tetrahydronaphthalen-2-yl)acetic acid as a colorless solid, m.p. 102-103.5° C., [α]D27 = 78.80° (CHCl3).
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:22])[C:8]=1[O:23][CH3:24])(=O)=O.[C-:25]#[N:26].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([CH3:21])[C:15]=1[CH2:14][O:13][C:9]1[C:8]([O:23][CH3:24])=[C:7]([CH2:6][C:25]#[N:26])[CH:12]=[CH:11][CH:10]=1
Reactant: [C-]#N
Reactant: COc1c(COS(C)(=O)=O)cccc1OCc1c(C)cccc1C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1c(CC#N)cccc1OCc1c(C)cccc1C

Procedure:
The solution of 3-(2,6-dimethylbenzyloxy)-2-methoxybenzyl methanesulfonate (Step C, 8.8 g, 30.26 mmol) and NaCN (1.60 g, 32.6 mmol) in dry DMF (40 ml) was heated at 85° C. for 18 hours then cooled and diluted with EtOAc (50 ml). The organic layer was washed with water (30 ml), concentrated, and passed through short silica gel column using methylene chloride to give the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7].[C:33]([NH2:37])(=[O:36])[CH:34]=[CH2:35]>C1(C)C=CC=CC=1>[F:30][C:27]([F:28])([F:29])[C:25]1[CH:24]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:31])[F:32])[CH:26]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:35][CH2:34][C:33](=[O:36])[NH2:37])[CH2:10][C@H:9]1[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1)=[O:7]
Reactant: C=CC(N)=O
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1c[nH]c2ccccc12
Solvent: Cc1ccccc1
Product: NC(=O)CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-(1H-indol-3-yl-methyl)piperazine (150 mg), acrylamide (24 mg) in toluene (1.5 ml) was stirred at room temperature for 1 hour and then was refluxed for 5 hours. After additional acrylamide (24 mg) was added, the whole mixture was refluxed for 3 hours and evaporated under reduced pressure. The obtained residue was purified by column chromatography on a silica gel eluting with a mixture of ethyl acetate and methanol (10:1) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(2-carbamoylethyl)-2-(1H-indol-3-yl-methyl)piperazine (89 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[Cl:37][C:38]1[CH:39]=[CH:40][C:41]([O:47][CH3:48])=[C:42](B(O)O)[CH:43]=1>>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([O:47][CH3:48])=[C:40]([C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[C:7]([C:9]3[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=3[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=2)[CH:39]=1
Reactant: COc1ccc(Cl)cc1B(O)O
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Product: COc1ccc(Cl)cc1-c1cccc(CN(C(=O)c2cc(C(=O)O)c(C(=O)O)cc2C(=O)O)[C@H]2CCCc3ccccc32)c1

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 5-chloro-2-methoxyphenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16]O[CH2:14][CH2:13]2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH2:32])[CH:23]=[CH:24][C:25]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:32][C:2]2[N:7]=[C:6]([C:8]([OH:11])([CH3:9])[CH3:10])[CH:5]=[C:4]([N:12]3[CH2:13][CH2:14][CH2:16][CH2:17]3)[N:3]=2)[CH:23]=[CH:24][C:25]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: CC(C)(O)c1cc(N2CCOCC2)nc(Cl)n1
Product: COc1cc(Nc2nc(N3CCCC3)cc(C(C)(C)O)n2)ccc1-n1cnc(C)c1

Procedure:
Using in analogous manner the procedure described in example 1e), 2-(2-chloro-6-morpholin-4-yl-pyrimidin-4-yl)-propan-2-ol (77 mg, 0.3 mmol) was reacted with 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol) to give the title compound was obtained as off-white foam (70 mg, 52%). MS ISP (m/e): 453.3 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.73 (d, 1H), 7.62 (s, 1H), 7.14 (d, 1H), 6.97 (s, 1), 6.92 (dd, 1H), 6.87 (s, 1H), 6.14 (s, 1H), 4.28 (br s, 1H), 4.10 (m, 3H), 3.85 (s, 3H), 3.47 (m, 2H), 2.30 (s, 3H), 1.55-1.70 (m, 4H), 1.51 (s, 6H), 1.32 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][CH2:7][N:8]1[CH:16]=[C:15]2[C:10]([N:11]=[C:12]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:13]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[C:14]2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[N:9]1>>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]2[C:15]3[C:10](=[N:9][N:8]([CH2:7][CH2:6][NH:5][C:1](=[O:3])[CH3:2])[CH:16]=3)[N:11]=[C:12]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:13]=2[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:18][CH:19]=1
Reactant: NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Reactant: CC(=O)Cl
Product: CC(=O)NCCn1cc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc2n1
Yield: 48 %

Procedure:
Following a similar procedure to that described in reference example 1 section a, but using acetyl chloride instead of 4-fluorobenzoyl chloride and 2-(2-aminoethyl)-4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridine (obtained in example 90) instead of N,O-dimethylhydroxylamine, the desired compound was obtained (yield: 48%).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([O:40]CC)=[O:39])=[O:34])=[CH:29][CH:28]=1>>[CH:1]1([CH:7]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([C:33]([N:35]([CH3:43])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:34])=[CH:31][CH:32]=2)[C:9]2[C:10]([CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(O)C1CCCCC1
Product: Cc1nn(-c2ccc(OC(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 92.5 %

Procedure:
Using cyclohexyl{3-methyl-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazol-4-yl}methanol (0.97 g) synthesized in Example 25(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.63 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (1.3 g, 63%) was obtained as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12](=[O:19])OCC(Cl)(Cl)Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[N:28]=[C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[S:30][CH:31]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:1]([NH:4][C:5]1[N:10]=[CH:9][C:8]([NH:11][C:12]([N:35]2[CH2:36][CH2:37][N:32]([C:29]3[S:30][CH:31]=[C:27]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[F:20])[N:28]=3)[CH2:33][CH2:34]2)=[O:19])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Reactant: Fc1ccccc1-c1csc(N2CCNCC2)n1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4F)cs3)CC2)cn1
Temperature: 70 °C
Reaction time: 12 h
Yield: 45.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl [6-(acetylamino)pyridin-3-yl]carbamate (273 mg, 0.835 mmol), 1-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.760 mmol) and diisopropylethylamine (0.265 ml, 1.52 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 12 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to give the desired product (153 mg, 45.8%) as a solid.
Reaction SMILES: [CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[CH:1]1([N:9]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]2[C:19]([C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[CH3:16])=[O:20])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)NN(C2CCCCCCC2)C1=O
Reactant: Cc1ccccc1C(=O)Cl
Product: Cc1ccccc1C(=O)N1N(C2CCCCCCC2)C(=O)C1(C)C

Procedure:
2-Cyclooctyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-methylbenzoyl chloride were used for a similar reaction and treatment as Example 96, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([OH:22])=[O:21]>C(O)C>[CH3:1][N:2]([CH2:4][CH:5]([C:13]1([OH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][C:9]([OH:12])=[CH:10][CH:11]=1)[CH3:3].[CH:20]([O-:22])=[O:21]
Reactant: O=CO
Agent: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Solvent: CCO
Product: O=C[O-]

Procedure:
A mixture of O-desmethylvenlafaxine (23.9 g), 96 wt % formic acid (4.79 g) and 2B ethanol (100 mL) was evaporated to give a syrupy residue. This material was redissolved in 2 B ethanol (100 mL) and evaporated to give a solid, which upon trituration in ether (200 mL) followed by filtration and vacuum drying (18 h; 50° C.; 50 mmHg) gave 27 g of product. This material was recrystallized from a hot solution of methanol (30 mL) and acetone (400 mL), which upon cooling to room temperature followed by filtering and vacuum drying (18 h; 50° C.; 50 mmHg) gave 20 g (71.2% yield) of product. m.p. 151° C.
Reaction SMILES: I(O)(=O)(=O)=O.CC1(C)[O:11][C@H:10]([C@H:12]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:14](=[O:24])[C@H:13]2[N:25]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])CO1>C1COCC1>[CH:10]([C@H:12]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:14](=[O:24])[C@H:13]1[N:25]1[C:26](=[O:35])[C:27]2=[CH:34][CH:33]=[CH:32][CH:31]=[C:28]2[C:29]1=[O:30])=[O:11]
Reactant: COc1ccc(N2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2[C@@H]2COC(C)(C)O2)cc1
Agent: [O-][I+3]([O-])([O-])O
Solvent: C1CCOC1
Product: COc1ccc(N2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2C=O)cc1

Procedure:
Aqueous 50% w/w periodic acid (6.3 ml, 22 mmol) was added to (3S,4S)-4-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-(4-methoxyphenyl)-3-phthalimido-azetidin-2-one (4.22 g, 10 mmol) in 50% aqueous THF (75 ml) and heated under reflux for 2.5h. The cooled solution was extracted twice with ethyl acetate and the combined extracts washed twice with water then with brine, dried and evaporated to give a colourless solid. The solid was triturated with ether and the title compound filtered off and dried in vacuo (3.151 g, 90%); [α]D -214.3° (c=1.00 CHCl3); νmax (CHCl3) 1785 (sh), 1769, 1727, 1514, 1391, 1250, and 1124 cm-1 ; δH (CDCl3) 3.73 (3H, s), 4.77 (1H, dd, J 6.29, 2.78 Hz), 5.80 (1 H, d, J 5.80 Hz), 6.95 and 7.39 (4H, ABq, J 8.97 Hz), 7.7-8.0 (4H, m) and 9.90 (1H, d, J 2.73 Hz); m/z (EI) 350 (14), 149 (100%).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C@H:12]([NH:14]C(=O)COC)[CH3:13])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N(CCO)(CCO)CCO.[OH-].[Na+]>O>[C:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C@H:12]([NH2:14])[CH3:13])=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COCC(=O)N[C@H](C)c1ccc(OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCN(CCO)CCO
Solvent: O
Product: C[C@@H](N)c1ccc(OC(C)(C)C)cc1
Yield: 73 %

Procedure:
(R)—N-1-(4-tert-Butoxyphenyl)ethylmethoxyacetamide from example 1.3 (180 g with a purity of 94%; corresponds to 0.64 mol of pure substance) was mixed with triethanolamine (20 ml) with stirring and then admixed with 50% NaOH (70.8 g, 0.89 mol). The mixture was then stirred at a bath temperature of 140° C. for another seven hours, after which all of the amide had been converted according to GC. The mixture was diluted with water (100 ml), cooled and extracted with tert-butyl methyl ether (3×100 ml). The combined extracts were washed with saturated sodium chloride solution (50 ml) and dried over Na2SO4. After the solvent had been removed on a rotary evaporator, 123.7 g (73%) of (R)-1-(4-tert-butoxyphenyl)ethylamine were obtained in the form of a pale brownish oil. The chemical purity was 99.4%, the optical purity 98.9% ee.
Reaction SMILES: [CH:1]([Sn](CCCC)(CCCC)CCCC)=[CH2:2].Br[C:17]1[CH:18]=[C:19]([C:23]2[O:24][C:25]([CH3:46])=[C:26]([CH2:28][CH2:29][O:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[C@H:36]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:35][CH2:34]4)[N:27]=2)[CH:20]=[CH:21][CH:22]=1.ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[CH3:46][C:25]1[O:24][C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([CH:1]=[CH2:2])[CH:18]=2)=[N:27][C:26]=1[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C@H:36]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:35][CH2:34]2
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4cccc(Br)c4)oc3C)ccc21
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=Cc1cccc(-c2nc(CCOc3ccc4c(c3)CC[C@H]4CC(=O)OCC)c(C)o2)c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a mixture of vinyltributyltin (Aldrich, 65.0 mg, 0.21 mmol), ethyl ((1S)-5-{2-[2-(3-bromophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (50 mg, 0.10 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (4.2 mg, 0.005 mmol) was added toluene (2 mL). The resulting solution was degassed with argon for 30 minutes, and then stirred at 110° C. for 16 h. The reaction mixture was cooled to rt and diluted with 10 mL ethyl acetate. The organic layer was filtered through a silica plug and the filtrate concentrated under reduced pressure. The crude was then redissolved in methanol and filtered through a silica-octyl plug before preparative HPLC purification using 30 to 100% acetonitrile in water (0.1% TFA) gradient to afford the desired product. 1H NMR (CD2Cl2) δ 8.03 (s, 1H), 7.86 (d, 1H), 7.39-7.51 (m, 2H), 7.04 (d, 1H), 6.68-6.84 (m, 3H), 5.88 ( (d, 1H), 5.31-5.35 (m, 1H), 4.10-4.23 (m, 4H), 3.48 (qr, 1H), 2.97 (t, 2H), 2.64-2.89 (m, 3H), 2.29-2.42 (m, 5H), 1.69-1.76 (m, 1H), 1.26 (t, 3H).