Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:37])[C:22]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)([OH:27])[C:23]([F:26])([F:25])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.Cl([O-])=[O:39].[Na+].Cl>C(O)(C)(C)C.CC(=CC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]([CH3:37])[C:22]([C:28]1[CH:33]=[C:32]([CH3:34])[C:31](=[O:35])[N:30]([CH3:36])[CH:29]=1)([OH:27])[C:23]([F:25])([F:26])[F:24])[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]([OH:39])=[O:11])=[C:8]([C:14]([F:17])([F:15])[F:16])[CH:7]=1
Reactant: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C=O)c(C(F)(F)F)c3)cc2Cl)C(F)(F)F)cn(C)c1=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(C(O)(C(C)c2ccc(Oc3ccc(C(=O)O)c(C(F)(F)F)c3)cc2Cl)C(F)(F)F)cn(C)c1=O
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 96.2 %

Procedure:
To a solution of 4-{3-chloro-4-[2-(1,5-dimethyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-2-trifluoromethyl-benzaldehyde (105 mg) in tert.-butanol (1 ml) and 2-methyl-2-butene (0.12 ml) was added a solution of sodium chlorite (28 mg) and sodiumdihydrogenphosphate-dihydrate (34 mg) in water (0.8 ml) at 0° C. The mixture was stirred for 10 minutes at 0° C. and for 4.5 h at room temperature. The mixture was acidified with 1 M aqueous HCl and extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to give the title compound (104 mg) as a colorless solid. MS (m/e, ISP neg. ion)=562.1 [M−H+].
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[Cl:20][CH2:21][CH2:22][O:23][CH:24]([C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1)[C:25]([OH:27])=O.[C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])(=[O:40])[NH:38][NH2:39]>CN(C=O)C.O.C(OCC)(=O)C.C(Cl)CCl>[Cl:20][CH2:21][CH2:22][O:23][CH:24]([C:28]1[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=1)[C:25]([NH:39][NH:38][C:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:27]
Reactant: O=C(O)C(OCCCl)c1cc(F)c(F)c(F)c1
Reactant: CC(C)(C)OC(=O)NN
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)C(OCCCl)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.6 %

Procedure:
HOBT (1.91 g), IPEA (4.31 mL) and EDC (2.71 g) were sequentially added to a solution of (2-chloroethoxy)-(3,4,5-trifluorophenyl)acetic acid (1.9 g) and tert-butyl carbazate (1.03 g) in DMF (30 mL), and the reaction solution was stirred at room temperature for five hours. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.75 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[C:10]([Br:11])=[CH:9][C:8]([Br:12])=[CH:7][N:6]=1>O>[Br:11][C:10]1[C:5]([O:2][CH3:1])=[N:6][CH:7]=[C:8]([Br:12])[CH:9]=1
Reactant: Brc1cnc(Br)c(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ncc(Br)cc1Br
Temperature: 50 °C
Reaction time: 2 h

Procedure:
80 ml of a 28% sodium methoxide solution was incorporated with 30.0 g of 2,3,5-tribromopyridine under ice-cooling, followed by stirring at 50° C. for 2 hours. The reaction solution was diluted with water and extracted with diethyl ether. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (ethyl acetate/hexane=1:20), to give 18.5 g of the title compound.
Reaction SMILES: [O:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N+:14]([O-])=[CH:13][CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].C[Si]([C:22]#[N:23])(C)C.CN(C)C(Cl)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[O:1]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:22]#[N:23])[CH:12]=1)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)(C)[Si](C)(C)OCCc1cc[n+]([O-])cc1
Agent: CN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1ccnc(C#N)c1
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
4-[2-(tert-Butyldimethylsiloxy)ethyl]pyridine-N-oxide (12.5 g, 49.3 mmol) was dissolved in dichloromethane (100 mL), then trimethylsilyl cyanide (5.31 g, 53.5 mmol) was added thereto at room temperature, and dimethylcarbamoyl chloride (5.76 g, 53.5 mmol) was added thereto over 30 minutes. Then, the mixture was stirred for 24 hours. After completion of the reaction was confirmed by thin-layer chromatography, a 10% aqueous potassium carbonate solution (150 mL) was added to the mixture, and the mixture was further stirred for 10 minutes. The reaction mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to give 4-[2-(tert-butyldimethylsiloxy)ethyl]pyridine-2-carbonitrile (12.5 g, yield 97%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.O.[C:13]1(C)C=CC=C[CH:14]=1>>[CH2:13]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH:11]=[CH:14]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1ccccc1
Solvent: O
Product: C1=Cc2ccccc2C1
Yield: 72 %

Procedure:
The crude product was taken up in 500 cm3 of toluene, 1.5 g of p-toluene sulfonic acid was added, the reaction mixture was refluxed for 2 hours on a water separator and washed 3 times with 50 cm3 of saturated aqueous NaHCO3 solution, and the solvent was removed in vacuo. Filtration through 200 g of silica gel (hexane/methylene chloride) gave 18.4 g (72%) of 29 as a colorless oil.
Reaction SMILES: [F:1]/[CH:2]=[C:3]1\[CH:4]=[C:5]2[C@:18]([CH3:21])([CH2:19][CH2:20]\1)[C@@H:17]1[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:22])[CH2:11][CH2:10]3)[CH2:7][CH2:6]2.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[F:1]/[CH:2]=[C:3]1\[CH:4]=[C:5]2[C@:18]([CH3:21])([CH2:19][CH2:20]\1)[C@@H:17]1[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C:12](=[O:22])[CH2:11][CH2:10]3)[CH2:7][CH2:6]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=C/C(=C\F)CC[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: C[C@]12CC/C(=C/F)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 70.6 %

Procedure:
1200 mg of (Z)-3-fluoromethylene-4-androsten-17-beta-ol is dissolved in 30 ml of acetone and mixed at 0° C. with 1.5 ml of Jones reagent. Then it is added to water, extracted three times with dichloromethane, washed neutral, dried on sodium sulfate and concentrated. After chromatography on silica gel with hexane/ethyl acetate, 842 mg of (Z)-3-fluoromethylene-4-androsten-17-one is obtained with a melting point of 101°-102° C.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].[N:9]1([CH2:14][CH:15]([N:17]2[C:30]3[CH:29]=[C:28]([C:31](=S)N)[CH:27]=[CH:26][C:25]=3[S:24][C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10]1>C(OCC)(=O)C>[NH:1]1[CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]2[N:8]=[C:31]1[C:28]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH:15]([CH3:16])[CH2:14][N:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[C:30]=2[CH:29]=1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: NC1CCCCC1N
Solvent: CCOC(C)=O
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C3=NC4CCCCC4N3)cc21
Temperature: 150 °C
Yield: 30.9 %

Procedure:
1,2-Diaminocyclohexane (9.12 g) is added to an ethanolic solution (32 cc) of 10-[(2RS)-1-(pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2.96 g). The mixture is heated in an autoclave to 150° C. for 10 hours. The reaction mixture is diluted with ethyl acetate (150 cc) and washed with distilled water (4×100 cc). The organic phase is separated after settling has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is purified by chromatography on a column (height: 23 cm; diameter: 2.5 cm) of FLUKA type 507 C neutral alumina, eluting with 50:50 (by volume) mixtures (1 liter) of cyclohexane and ethyl acetate and collecting 50-cc fractions. Fractions 2 to 15 containing the pure product are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 2-(3a,4,5,6,7,7a-hexahydro-1H-benzimidazol-2-yl)-10-[(2RS)-1-(pyrrolidinyl)-2-propyl]phenothiazine (1.07 g) in the form of a brown product of meringue-like consistency.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3=[O:19])[S:11][CH:12]=2)=[CH:4][CH:3]=1.Br[C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3=[O:19])[S:11][C:12]=2[C:21]2[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCCN1c1nc(-c2ccc(Cl)cc2)cs1
Reactant: NS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: NS(=O)(=O)c1ccc(-c2sc(N3CCCCC3=O)nc2-c2ccc(Cl)cc2)cc1
Temperature: 150 °C
Yield: 32.6 %

Procedure:
To a solution of 1-(4-(4-chlorophenyl)thiazol-2-yl)piperidin-2-one (Step 2 of compound 10, 0.5 g. 1.71 mmol) in dimethyl acetamide (5 ml) were added 4-bromobenzenesulfonamide (0.48 g, 2.05 mmol) and potassium acetate (0.42 g, 4.27 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To this was added palladium(II) acetate (0.02 g, 0.08 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 150° C. for 15 hr under stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 ml), reaction mixture was washed with water (2×10 ml), dried over sodium sulphate and concentrated under reduced pressure to obtain a crude product; which was purified by preparative HPLC to obtain the title compound (0.25 g, 32.7%). MS: m/z 450 (M+1).
Reaction SMILES: COCCOC.CC1(C)C(C)(C)OB([C:15]2[S:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[C:16]=2[CH3:24])O1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH:43]=[C:42]([C:44]3[CH:45]=[N:46][C:47]([NH2:51])=[C:48](Br)[CH:49]=3)[CH:41]=[N:40]2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl.C(Cl)Cl.O>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH:43]=[C:42]([C:44]3[CH:45]=[N:46][C:47]([NH2:51])=[C:48]([C:15]4[S:19][C:18]5[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=5[C:16]=4[CH3:24])[CH:49]=3)[CH:41]=[N:40]2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(Br)c3)cn2)CC1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)sc2ccccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: Cc1c(-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)sc2ccccc12
Temperature: 100 °C

Procedure:
To the DME solution of 4,4,5,5-tetramethyl-2-(3-methylbenzo[b]thiophen-2-yl)-[1,3,2]dioxaborolane (2.3 mL, 0.50 mmol, 2 eq.) from the previous step were added 4-[4-(6-amino-5-bromopyridin-3-yl)-pyrazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (BB3) (120 mg, 0.29 mmol, 1 eq.), potassium carbonate (104 mg, 0.75 mmol, 3 eq.), water (0.5 mL), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium DCM (10 mg, 0.01 mmol, 0.05 eq.). The mixture was evacuated and filled with nitrogen (3×) and heated in a microwave reactor to 100° C. for 30 min. The crude was passed through Thiol-SPE to remove Pd. The clear solution was purified with the MDPS. 1H NMR (400 MHz, CD3OD): δ=1.47 (s, 9H), 1.87-2.00 (m, 2H), 2.09 (d, J=10.4 Hz, 2H). 2.31 (s, 3H), 2.95 (br. s., 2H), 3.35 (s, 2H), 4.22 (d, J=13.4 Hz, 2H), 4.37 (tt, J=11.6, 4.1 Hz, 1H), 7.36-7.47 (m, 2H), 7.75-7.82 (m, 3H), 7.87 (d, J=7.6 Hz, 1H), 8.05 (s, 1H), 8.25 (d, J=1.8 Hz, 1H). MS (ES+): m/z=490.37 (100) [MH+]. HPLC: tR=0.93 min (UPLC-ACQUITY, Analytical).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[N:31]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN=C=NCCCN(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([N:34]1[CH2:33][CH2:32][N:31]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:36][CH2:35]1)=[O:6]
Reactant: O=C(O)c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3.0 g (19 mmol) of 2,4-difluorobenzoic acid and 4 mL of DIEA (1.2 equiv.) in 40 mL of dry DCM is added 3.08 g (1.2 equiv) of HOBt and 4.2 g (22.55 mmol) of t-butyl piperazine-1-carboxylate, and the mixture was stirred at RT for 30 min. 4.4 g (11 equiv.) of EDCI are added and the reaction mixture is stirred overnight at RT. Water is added and the resulting mixture is extracted with DCM. The organic layer is dried over anhydrous MgSO4, filtered and concentrated in vacuo to obtain t-butyl 4-(2,4-difluorobenzoyl)piperazine-1-carboxylate as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 1.47 (s, 9H), 3.30 (m, 2H), 3.41 (m, 2H), 3.53 (m, 2H), 3.76 (m, 2H), 6.86 (dt, 1H, J=8.8 Hz and 0.8 Hz), 6.97 (dt, 1H, J=8.8 Hz and 0.8 Hz), 7.41 (dd, 1H, J=14.4 Hz and 7.2 Hz).
Reaction SMILES: [OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[C:5](I)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(NC(C)C)(C)C.[C:30]1([C:36]#[CH:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[OH:1][C:2]1[C:3]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:4]=2[C:5]([C:37]#[C:36][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[N:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1nc(I)c2c(-c3ccccc3)noc2c1O
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C#Cc2ccccc2)c2c(-c3ccccc3)noc2c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.5 %

Procedure:
Ethyl 7-hydroxy-4-iodo-3-phenylisoxazolo[4,5-c]pyridine-6-carboxylate (300 mg, 0.73 mmol), copper iodide (56 mg, 0.29 mmol), and PdCl2(PPh3)2 (103 mg, 0.15 mmol) were added to a flask and the flask evacuated. After refilling with nitrogen, THF (5 mL), diisopropylamine (0.6 mL) and phenylacetylene (0.1 mL, 0.95 mmol) were added and the resulting mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was partitioned between 25 mL of 1M hydrochloric acid and 25 mL of EtOAc. The aqueous layer was extracted with additional EtOAc and the combined organic layer was dried over MgSO4 and concentrated. The residue was purified flash chromatography (0-40% EtOAc/hexanes) to afford 195 mg of the title compound. MS: (+) m/z 385.29 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([O:10]CC2C=CC(C(OC)=O)=CC=2)[N:7]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].O1CCCC1>[C:1]([C:5]1[CH:9]=[C:8]([OH:10])[N:7]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(COc2cc(C(C)(C)C)nn2Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cn2nc(C(C)(C)C)cc2O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A mixture of methyl 4-[(3-tert-butyl-5-{[4-(methoxycarbonyl)benzyl]oxy}-1H-pyrazol-1-yl)methyl]benzoate (6.90 g, 15.8 mmol), 10% palladium-carbon (50% water-containing product, 0.35 g) and tetrahydrofuran (50 mL) was stirred overnight at room temperature under a hydrogen atmosphere (balloon pressure). The catalyst was filtered off, and the obtained filtrate was concentrated under reduced pressure to give the title compound (3.70 g, yield 81%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22]C(=O)C)=[O:15])=[CH:9][CH:8]=2)=[C:4]([CH3:28])[CH:3]=1.[OH-].[Li+]>O1CCCC1>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=[O:15])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[OH:22])=[CH:9][CH:8]=2)=[C:4]([CH3:28])[CH:3]=1
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ccc(Oc2ccc(Cl)cc2C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1Oc1ccc(NC(=O)c2ccccc2O)cn1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
Acetic acid 2-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-ylcarbamoyl)-phenyl ester (304 mg, 0.77 mmol) dissolved in tetrahydrofuran (3.8 mL) was treated with an aqueous lithium hydroxide solution (1.0 M, 3.8 mL, 3.8 mmol). The solution was stirred for 30 minutes at 22° C. then quenched with aqueous saturated NH4Cl. The mixture was diluted with ethyl acetate then the organics were washed with water, 2× saturated NaHCO3, saturated NaCl, dried over Na2SO4 and concentrated in vacuo. MS (m/z): 354/356 (M+H)+ ; C19H15N2O3Cl requires 354.8.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[CH:6]([OH:32])[CH:7]([NH:15][C:16]([C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[N:19]2[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[O:17])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3][CH2:2]1.O>ClCCl.Cl.C(OCC)C>[CH:1]1([NH:4][C:5](=[O:33])[C:6](=[O:32])[CH:7]([NH:15][C:16]([C@H:18]2[CH2:22][CH2:21][C:20](=[O:23])[N:19]2[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[O:17])[CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: O=C(NC1CC1)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: O=C(NC1CC1)C(=O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1F
Reaction time: 8 h

Procedure:
(2R)—N-(4-(cyclopropylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-1-(2-fluorobenzyl)-5-oxopyrrolidine-2-carboxamide was oxidized in analogy to reaction step 20.4. The reaction mixture was stirred overnight. Water was added, the precipitate formed was filtered, washed with water and dried in vacuo. The residue obtained was redissolved in dichloromethane, a few drops of HCl (4M in dioxane) and a few drops of diethylether were added. The resulting precipitate was filtered, washed with diethylether and dried in vacuo providing the title compound. ESI-MS [M+H]+=452.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:23](=[O:37])[CH2:24][N:25]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:12]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].CO>C(O)C>[CH2:16]([O:15][C:13]1[CH:12]=[C:11]([CH:23]([OH:37])[CH2:24][N:25]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)N(CC(=O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)N(Cc1ccccc1)CC(O)c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reaction time: 8 h

Procedure:
To 18.3 g of 3',5'-dibenzyloxy-ω-(benzyl-t-butylamino)-acetophenone in ethanol were added 2 g of sodium borohydride. The reaction mixture was allowed to stand overnight. Some methanol was added and the solution was evaporated. To the residue was added water and 2-N sodium hydroxide solution and the water phase was extracted with ether. The ether phase was dried with magnesium sulphate. The ether was evaporated and an oil was collected, which crystallized on standing. M.p. 78°-79°C. The resulting 1-(3',5'-dibenzyloxyphenyl)-2-(benzyl-t-butylamino)-ethanol can be converted to the corresponding 1-(3',5'-dihydroxyphenyl)-2-(t-butylamino)-ethanol by replacing benzyl groups with hydrogen in a known manner.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:16][C:3]1=2.[OH-:22].[K+].[OH-].[Na+]>C(OCC)C.O.C(O)C>[O:1]=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[N:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([OH:22])=[O:19])=[CH:16][C:3]1=2
Reactant: [OH-]
Reactant: CC(C(N)=O)c1ccc2c(c1)C(=O)Cc1cccnc1S2
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CC(C(=O)O)c1ccc2c(c1)C(=O)Cc1cccnc1S2
Reaction time: 5 h
Yield: 81.9 %

Procedure:
To 101 mg of 2-(5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]-thiepin-8-yl)-propionamide were added 0.4 g of potassium hydroxide, 1 ml of water and 4 ml of ethanol and the mixture was refluxed with stirring for 5 hours. After cooling, to this were added water and 3% sodium hydroxide solution, then a small amount of diethyl ether, and the mixture was shaked. The aqueous layer was collected and acidified with acetic acid, and to this was added sodium chloride, and the resulting mixture was extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 115 mg of brown glutinous substance, which was chromatographed over silica gel, eluted with chloroform/methanol(100/1-20/1), and there was obtained 83 mg of 2-(5,6-dihydro-6-oxo benzo[b]pyrido[3,2-f]thiepin-8-yl)-propionic acid as colorless glutinous substance. This was solidified by washing with n-hexane and there was obtained colorless crystals having a melting point of 141°-143° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[C:12]([C:14]1[CH:22]=[C:21]2[C:17](/[C:18](=[CH:24]/O)/[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=2)[CH2:37][CH2:36]1>CCOC(C)=O>[CH2:1]([NH:8][C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=1)[C:12]([C:14]1[CH:22]=[C:21]2[C:17](/[C:18](=[CH:24]/[NH:47][C:44]3[CH:45]=[CH:46][C:41]([N:38]4[CH2:37][CH2:36][N:35]([CH3:34])[CH2:40][CH2:39]4)=[CH:42][CH:43]=3)/[C:19](=[O:23])[NH:20]2)=[CH:16][CH:15]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2cc(C(=O)c3cccc(NCc4ccccc4)c3)ccc2/C1=C/O
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(N/C=C3\C(=O)Nc4cc(C(=O)c5cccc(NCc6ccccc6)c5)ccc43)cc2)CC1
Temperature: 65 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
A small screw cap test tube was charged with 6-(3-Benzylamino-benzoyl)-3-[1-hydroxy-meth-(Z)-ylidene]-1,3-dihydro-indol-2-one (prepared below, 0.021 g, 0.056 mmol) and THF (1 mL). To the resulting solution was added 4-(4-Methyl-piperazin-1-yl)-phenylamine (10.7 mg, 0.056 mmol), and the mixture was stirred for 24 h at 65° C. The reaction mixture was cooled to room temperature. The yellow solid was dissolved in 5 mL of a solvent mixture containing 98% EtOAc/2% i-prOH and washed with water (2×5 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was chromatographed over silica (95/5 chloroform/Hexanes w/0.5% NEt3) to afford the title compound in 51% yield (15.5 mg, 0.028 mmol).