Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[NH2:4][CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[OH:7].C([O:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])C.Cl.[Cl-].[Na+]>CO>[F:16][C:15]([F:18])([F:17])[C:14]([NH:4][CH2:5][C@@H:6]([C:8]([OH:10])=[O:9])[OH:7])=[O:13]
Reactant: CCOC(=O)C(F)(F)F
Reactant: NC[C@H](O)C(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CO
Product: O=C(O)[C@@H](O)CNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
To a stirred solution of sodium methoxide in methanol, 11 ml (1 eq., 24.8% w/w solution) was added 5 g of (S)-isoserine. The mixture was stirred at room temperature for 15 minutes until a homogeneous solution was obtained. Ethyltrifluoroacetate, 7 ml (1.25 eq.) was added. The mixture was stirred for 30 minutes after the addition. The completeness of the reaction was monitored by 1H-NMR. The mixture was concentrated under reduced pressure to as low a volume as possible. To the residue 50 ml ethylacetate was added The mixture was cooled to 0°-5° C. 25 ml of 2N HCl (1 eq.) was added, followed by 5 g of solid sodium chloride. The organic layer was separated. The aqueous layer was reextracted with 50 ml of ethylacetate. The combined organic extracts were dried (over 5 g of anhydrous magnesium sulfate), filtered and concentrated under reduced pressure to 20 ml. To it 50 ml heptane was added with stirring in an ice-bath for 30 minutes. The product was filtered and dried to yield 8.86 g (93%) of N-trifluoroacetyl-(S)-isoserine; m.p. 142°-143° C.; [a]D20 : +12.4 (1%, H2O); 1H-NMR (D2O) w 3.78 (d, 2H, J=5.48 Hz), 4.53 (t, 1H, J=5.48 Hz).
Reaction SMILES: [N+:1]([C:4]1[C:16]2[C:17](=[O:23])[C:18]([C:20]([OH:22])=[O:21])=[CH:19][N:14]3[C:15]=2[C:7]([CH:8]2[CH:13]3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=1)([O-])=O>[OH-].[K+].[Ni]>[NH2:1][C:4]1[C:16]2[C:17](=[O:23])[C:18]([C:20]([OH:22])=[O:21])=[CH:19][N:14]3[C:15]=2[C:7]([CH:8]2[CH:13]3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1cn2c3c(ccc([N+](=O)[O-])c3c1=O)C1CCCCC12
Agent: [Ni]
Agent: [K+]
Agent: [OH-]
Product: Nc1ccc2c3c1c(=O)c(C(=O)O)cn3C1CCCCC21
Yield: 68.2 %

Procedure:
6 g of 3-nitro-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid was dissolved in 100 ml of a 2% aqueous potassium hydroxide solution and the solution was catalytically reduced by the Parr method (3 kg/cm2) in the presence of 5 g of Raney nickel. After completion of the reduction, the mixture was filtered and the filter cake on the filter paper was washed with water and the combined filtrate and the washing was rendered neutral with glacial acetic acid to precipitate brown crystals. The resulting crystals were filtered, washed with water, dried and recrystallized from DMF-H2O to obtain 3.7 g of 3-amino-7a,8,9,10,11,11a-hexahydro-4-oxo-4H-pyrido[3,2,1-jk]carbazol-5-carboxylic acid having a melting point of 253°-356° C. (with decomposition).
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([N+:11]([O-])=O)=[C:6]([CH3:14])[N:5]=1.C(O)C>C(Cl)Cl.[Pd]>[F:15][CH:2]([F:1])[O:3][C:4]1[N:5]=[C:6]([CH3:14])[C:7]([NH2:11])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc([N+](=O)[O-])c(C)nc1OC(F)F
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(N)c(C)nc1OC(F)F
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of 2-(difluoromethoxy)-3,6-dimethyl-5-nitropyridine (33.4 g, 153 mmol) from Part F in methylene chloride (100 mL) and ethanol (600 mL) was added 10% palladium on charcoal (3.3 g). The resulting suspension was hydrogenated on a Parr device at 40 psi H2 for 1 h. TLC was used to monitor the reaction. Additional 3.3 g of palladium on charcoal were added hourly until no starting material remained. A total of 13.2 g of Pd/C was added. The reaction mixture was kept under an H2 atmosphere for 2 h after the last addition of catalyst. The reaction mixture was filtered through Celite and sand and the collected solids were washed with ethyl acetate (2×100 mL). The filtrate was concentrated in vacuo to give a grey oil, which was purified by column chromatography on silica gel (35%→50% ethyl acetate in hexanes) to furnish 6-(difluoromethoxy)-2,5-dimethylpyridin-3-amine (25.7 g, 89% yield) as a pale yellow oil which solidified upon cooling in a refrigerator. The product was recrystallized from hexanes below 0° C. to afford white needles: mp 40-42° C.; 1H NMR (400 MHz, CDCl3) δ 7.35 (t, J=74.0 Hz, 1H), 6.84 (s, 1H), 2.27 (s, 3H), 2.15 (s, 3H); LRMS (ESI) m/e 189.2 [(M+H)+, calcd for C8H11N2OF2 189.1].
Reaction SMILES: FC1C=C(O)C=C(C2(C(OCC)=O)CCCC2)C=1.[F:19][C:20]1[CH:21]=[C:22]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:49]=[CH:48][N:47]=[C:46]3[CH3:50])=[CH:41][CH:40]=2)[CH:23]=[C:24]([C:26]2([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31][CH2:30]O[CH2:28][CH2:27]2)[CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N:45]3[CH:49]=[CH:48][N:47]=[C:46]3[CH3:50])=[CH:41][CH:40]=2)[CH:23]=[C:24]([C:26]2([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:31][CH2:30][CH2:28][CH2:27]2)[CH:25]=1
Reactant: CCOC(=O)C1(c2cc(F)cc(OCc3ccc(-n4ccnc4C)cc3)c2)CCOCC1
Agent: CCOC(=O)C1(c2cc(O)cc(F)c2)CCCC1
Product: CCOC(=O)C1(c2cc(F)cc(OCc3ccc(-n4ccnc4C)cc3)c2)CCCC1

Procedure:
The titled compound was prepared from ethyl 1-(5-fluoro-3-hydroxyphenyl)-cyclopentane-1-carboxylate according to the preparation of ethyl 4-[5-fluoro-3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (Example 2).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:20]2[S:42][C:23]3=[N:24][C:25]([N:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]4)=[CH:26][C:27](=[O:28])[N:22]3[N:21]=2)[CH:5]=[C:6]([NH:8][C:9](=[O:19])[CH2:10][NH:11]C(OC(C)(C)C)=O)[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][CH2:10][C:9]([NH:8][C:6]1[CH:5]=[C:4]([C:20]2[S:42][C:23]3=[N:24][C:25]([N:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:26][C:27](=[O:28])[N:22]3[N:21]=2)[CH:3]=[C:2]([Br:1])[CH:7]=1)=[O:19]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cc(Br)cc(-c2nn3c(=O)cc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3s2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC(=O)Nc1cc(Br)cc(-c2nn3c(=O)cc(N4CCNCC4)nc3s2)c1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(2-(3-bromo-5-(2-(tert-butoxycarbonylamino)-acetamido)phenyl)-5-oxo-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-7-yl)piperazine-1-carboxylate (30 mg, 0.045 mmol) in DCM (2 ml) is added TFA (0.5 ml) and the mixture is stirred for 1 h. After the removal of DCM in vacuo, the crude residue is directly purified by preparative HPLC to give the desired product, 2-amino-N-(3-bromo-5-(5-oxo-7-(piperazin-1-yl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-2-yl)phenyl)acetamide: 1H NMR (400 MHz, DMSO-d6) δ 8.70-8.20 (br.s., 3H), 8.19 (t, J=1.8 Hz, 1H), 8.11 (t, J=1.8 Hz, 1H), 7.83 (t, J=1.8 Hz, 1H), 5.61 (s, 1H), 3.84 (s, 2H), 3.79 (t, J=5.2 Hz, 4H), 3.18 (t, J=5.2 Hz, 4H); LC/MS: tR=2.743 min; HRMS: m/z (M+H+)=464.0495 and 466.0479 (Calculated for C17H19BrN7O2S=464.0499 and 466.0479).
Reaction SMILES: [C:1](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:4])[CH:2]=[CH2:3].[CH3:17][O:18][C:19]1[CH:24]=[C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[C:22]([NH2:32])=[CH:21][C:20]=1[NH:33][C:34]1[N:39]=[C:38]([C:40]2[CH:41]=[N:42][N:43]3[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=23)[CH:37]=[CH:36][N:35]=1>CN(C=O)C.C(Cl)Cl>[CH3:17][O:18][C:19]1[C:20]([NH:33][C:34]2[N:39]=[C:38]([C:40]3[CH:41]=[N:42][N:43]4[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=34)[CH:37]=[CH:36][N:35]=2)=[CH:21][C:22]([NH:32][C:1](=[O:4])[CH:2]=[CH2:3])=[C:23]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)[CH:24]=1
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 29.7 %

Procedure:
(2,3,4,5,6-Pentafluorophenyl) prop-2-enoate (0.030 mL, 0.19 mmol) was added dropwise to a solution of 4-methoxy-6-(4-methylpiperazin-1-yl)-N′(4-pyrazolo[1,5-a]-pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 69, 67 mg, 0.16 mmol) in DMF (0.6 mL) at r.t. under N2. The resulting solution was stirred at r.t. for 1.5 h and then diluted with CH2Cl2 (9 mL). This solution was added to 1.5 g flash silica which was wet with CH2Cl2 in a dry-loaded cartridge, and the crude product was eluted from the silica using CH2Cl2. Further purification by FCC, eluting with 2-7% of 2N methanolic ammonia in CH2Cl2 provided material which was further purified by FCC, eluting with 5-20% CH3OH in CH2Cl2. Appropriate fractions were concentrated in vacuo and trituration provided a crystalline solid that was washed with THF (0.1 mL) to give the title compound (23 mg, 28%) as a beige crystalline solid; 1H NMR: 2.33-2.43 (3H, m), 2.62-2.81 (4H, m), 2.94 (4H, s), 3.85 (3H, s), 5.72 (1H, d), 6.18 (1H, m), 6.55-6.69 (1H, m), 6.89 (1H, s), 7.05 (1H, m), 7.26 (1H, d), 7.35-7.43 (1H, m), 8.15 (1H, s), 8.34 (1H, d), 8.44 (1H, d), 8.49 (1H, s), 8.79 (1H, d), 8.80 (1H, s), 9.03 (1H, s); m/z: ES+ MH+ 485.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[CH2:31]([O:33][C:34]([C:36]1([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]([OH:62])=[O:61])[CH2:44][C:43]2[C:38](=[C:39]([O:51]C)[C:40]([O:49][CH3:50])=[C:41]([O:47][CH3:48])[C:42]=2[O:45]C)[CH2:37]1)=[O:35])[CH3:32]>O>[CH2:31]([O:33][C:34]([C:36]1([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][C:60]([OH:62])=[O:61])[CH2:44][C:43]2[C:42](=[O:45])[C:41]([O:47][CH3:48])=[C:40]([O:49][CH3:50])[C:39](=[O:51])[C:38]=2[CH2:37]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)C1(CCCCCCCC(=O)O)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C1(CCCCCCCC(=O)O)CC2=C(C1)C(=O)C(OC)=C(OC)C2=O
Reaction time: 0.25 h
Yield: 68 %

Procedure:
A water (1 ml) solution of CAN (238 mg, 0.435 mmols) was dropwise added to an acetonitrile (2 ml) solution of 8-(2-ethoxycarbonyl-4,5,6,7-tetramethoxyindan-2-yl)octanoic acid (78.6 mg, 0.174 mmols) with cooling with ice and then stirring was continued for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried. The solvent was evaporated in vacuo and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to ethyl acetate only) to obtain the entitled compound (50 mg) as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]3([C:18]#N)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:8][CH2:7]2)[N:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:4][NH:3]1.[CH2:26]([Mg]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([C:12]1([N:9]2[CH2:8][CH2:7][C:6]3([N:5]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:4][NH:3][C:2]3=[O:1])[CH2:11][CH2:10]2)[CH2:18][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: N#CC1(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CCCCC1
Reactant: Br[Mg]Cc1ccccc1
Product: O=C1NCN(c2ccccc2)C12CCN(C1(Cc3ccccc3)CCCCCC1)CC2
Yield: 54 %

Procedure:
This was prepared according to the procedure described in Example 1 using 1-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)cyclohexanecarbonitrile instead of 1-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-8-yl)cycloheptanecarbonitrile and benzylmagnesium bromide instead of phenylmagnesium bromide. Yield was 54%.
Reaction SMILES: [CH:1]([N:4]([CH:20]([CH3:22])[CH3:21])[CH2:5][CH2:6][CH2:7][N:8]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[C:11](=O)[C:9]1=[O:10])([CH3:3])[CH3:2].Cl.[NH2:24][NH:25][C:26]([NH2:28])=[O:27]>>[CH:1]([N:4]([CH:20]([CH3:22])[CH3:21])[CH2:5][CH2:6][CH2:7][N:8]1[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)/[C:11](=[N:24]\[NH:25][C:26]([NH2:28])=[O:27])/[C:9]1=[O:10])([CH3:3])[CH3:2]
Reactant: NNC(N)=O
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2CCCN(C(C)C)C(C)C
Agent: Cl
Product: Cc1ccc2c(c1)/C(=N\NC(N)=O)C(=O)N2CCCN(C(C)C)C(C)C
Yield: 72.2 %

Procedure:
By using 1-(3-diisopropylaminopropyl)-5-methylisatin and semicarbazide hydrochloride, a method analogous to that described in Example 4 was carried out to obtain (E)-1-(3-diisopropylaminopropyl)-5-methylisatin 3-semicarbazone having a melting point of 145°-148° C. (yield: 72.2%).
Reaction SMILES: C(OC([N:8]1[CH2:24][CH2:23][C@@H:11]2[N:12]([CH3:22])[C:13]3[C:14]([C:20]#[N:21])=[CH:15][C:16](Br)=[CH:17][C:18]=3[C@@H:10]2[CH2:9]1)=O)(C)(C)C.[Br-].[CH2:26]([Zn+])[CH:27]([CH3:29])[CH3:28]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:26]([C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([C:20]#[N:21])[CH:15]=1)[N:12]([CH3:22])[C@H:11]1[CH2:23][CH2:24][NH:8][CH2:9][C@@H:10]21)[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)C[Zn+]
Reactant: CN1c2c(C#N)cc(Br)cc2[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CC(C)Cc1cc(C#N)c2c(c1)[C@@H]1CNCC[C@@H]1N2C

Procedure:
Following the general procedure for Example 127–146, the title compound was prepared (13 mg, 48%) as a light yellow oil using (4aS,9bR)-8-bromo-6-cyano-5-methyl-1,3,4,4a,5,9b-hexahydro-pyrido[4,3-b]indole-2-carboxylic acid tert-butyl ester (Example 158, 40 mg, 0.10 mmol), iso-butylzinc bromide (0.5 M in THF, 2.5 mole equivalent) and Pd(PPh3)4 (0.06 mole equivalent).: MS (ESI): 270 (base, M+H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH2:6])=[O:5].[C:7]([O:11][C:12](=[O:25])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([SH:24])=[CH:20][CH:19]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1.CN1CCOCC1>[C:7]([O:11][C:12](=[O:25])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([S:24][CH2:2][CH2:3][C:4](=[O:5])[NH2:6])=[CH:22][CH:23]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: NC(=O)CCBr
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(S)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCCc1ccc(SCCC(N)=O)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
A solution of 3-Bromopropionic acid amide (0.075 g, 0.5 mmol) in THF (5 ml) was added to a solution of [4-(4-mercaptophenyl)butyl]carbamic acid tert-butyl ester 560 (0.13 g, 0.46 mmol) dissolved in THF (15 mL) and 4-methylmorpholine (NMM) (0.3 mL). The reaction mixture was stirred at 50° C. for 4 h and then cooled to room temperature. Two more equivalents of 3-bromoprionic acid amide (0.15 g, 1 mmol) were added. The mixture was further stirred at room temperature for 2 days. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, chloroform/methanol/ammonium hydroxide, 15:1:0.1, v/v) to afford the desired product {4-[4-(2-carbamoylethylsulfanyl)phenyl]butyl}carbamic acid tert-butyl ester 570 (0.13 g, 80%) as a white powder. 1H NMR (300 MHz, CD3OD) δ 1.42 (s, 9H), 1.48 (m, 2H) 1.60 (m, 2H), 2.46 (m, 2H), 2.58 (t, 2H), 3.09 (t, 2H), 3.13 (m, 2H), 7.14 (d, 2H), 7.29 (d, 2H). m/z (ESI) 353 [C18H28N2O3S+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]([O:21]CC1C=CC=CC=1)=[O:20])=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]1[C:19]([OH:21])=[O:20])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CCCCn1c(C(=O)OCc2ccccc2)cc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCn1c(C(=O)O)cc2ccccc21
Yield: 23.1 %

Procedure:
Benzyl 1-(4-ethoxycarbonylbutyl)indole-2-carboxylate (12.44 g) was dissolved in ethanol (120 ml). The mixture was subjected to catalytic reduction by blowing a hydrogen gas in the presence of 10% palladium/carbon. The reaction mixture was filtered through Celite to remove catalyst. The solvent was evaporated, and the residue was purified by silica gel column chromatography using a mixed solvent of ethyl acetate and hexane as an eluent to give 2.19 g of 1-(4-ethoxycarbonylbutyl)indole-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[K+].Cl>CO.C1COCC1>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2F)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(OCc2ccccc2F)cc1
Reaction time: 36 h

Procedure:
Methyl 4-(2-fluorobenzyloxy)benzoate (P1, 10.0 g, 26.9 mmol) was dissolved in methanol (60 mL) and THF (90 mL). A 45 wt % potassium hydroxide solution (20 mL) was then added and the resulting exotherm was controlled by a water bath. After 1.5 days at 20-25° C. the solution became a thick suspension. Using a water bath to control the exotherm, 20 mL of concentrated HCl was added. The mixture was then concentrated to remove the THF and methanol and 150 mL water was added. The solid was isolated by filtration and washed with 50 mL water. After drying under vacuum, the title compound was isolated as a white crystalline solid (9.4 g, 99% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1nc(-c2ccc(Cl)cc2)cs1
Product: O=C(NCCc1nc(-c2ccc(Cl)cc2)cs1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 16 %

Procedure:
This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (30 mg, yield 16%). 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 8.06 (d, J=7.8 Hz, 1H), 7.81 (d, J=8.6 Hz, 2H), 7.64-7.60 (m, 2H), 7.39 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 4.02-3.97 (q, J=5.8 Hz, 2H), 3.39-3.36 (t, J=5.9 Hz, 2H). MS (ESI) m/z: Calculated for C21H14ClF3N4O2S: 478.05. found: 479.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH2:25][CH3:26])[NH:20][CH2:19][CH2:18]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:20]3[CH2:19][CH2:18][C:17]4[C:22](=[CH:23][CH:24]=[C:15]([F:14])[CH:16]=4)[CH:21]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CCC1NCCc2cc(F)ccc21
Product: CCC1c2ccc(F)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[CH2:4][NH:5][C:6]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]>C(O)C.[Pd]>[NH2:16][C:15]1[C:6]([NH:5][CH2:4][CH:3]([O:19][CH3:20])[O:2][CH3:1])=[C:7]([CH:12]=[CH:13][CH:14]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCC(OC)OC
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cccc(N)c1NCC(OC)OC
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To an argon purged solution of methyl 2-(2,2-dimethoxyethylamino)-3-nitrobenzoate (1.4 g, 4.7 mmol) from Step B above in ethanol (50 mL) at room temperature was added 10% palladium on carbon. The reaction was stirred overnight under an atmosphere of hydrogen (balloon pressure). The reaction mixture was filtered through celite and concentrated under reduced pressure to give methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (1.2 g, quantitative yield) as a dark red oil: 1H NMR (300 MHz, DMSO-d6) δ 7.06 (d, J=5.0 Hz, 1H), 6.85 (dd, J=7.8, 1.2 Hz, 1H), 6.74 (t, J=7.8 Hz, 1H), 6.06 (t, J=7.5 Hz, 1H), 4.84 (s, 2H), 4.38 (t, J=5.4 Hz, 1H), 3.80 (s, 3H), 3.23 (s, 6H), 3.04 (dd, J=7.2, 5.7 Hz, 2H); MS (ESI+) m/z 254 (M+H).
Reaction SMILES: [F:1]/[CH:2]=[C:3](/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)\[CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl.O>C(O)C>[C:16]1(/[C:3](=[CH:2]/[F:1])/[CH2:4][NH2:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1c2ccccc2C(=O)N1C/C(=C\F)c1ccccc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: NC/C(=C\F)c1ccccc1

Procedure:
(Z)-1-Fluoro-2-phenyl-3-phthalimidopropene (0.25 g) is treated with hydrazine hydrate (50 mg) in ethanol (2 ml), and then concentrated hydrochloric acid (2 ml) and water (2 ml). Recrystallization of the resulting product (0.19 g) from ethanol/ether affords pure (Z)-2-phenyl-3-fluoroallylamine, as the hydrochloride: m.p. 145°;
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]([C:15]([OH:17])=O)=[CH:5][N:4]=1)#[N:2].[CH3:18][C:19]1[CH:20]=[C:21]([NH2:30])[N:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:23]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[CH3:18][C:19]1[CH:20]=[C:21]([NH:30][C:15]([C:6]2[C:7]([NH:9][CH2:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[N:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=2)=[O:17])[N:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:23]=1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1C(=O)O
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)c2cnc(C#N)nc2NCC(C)(C)C)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-Cyano-4-(2,2-dimethyl-propylamino)-pyrimidine-5-carboxylic acid (150 mg, 0.640 mmol), 5-Methyl-2-phenyl-2H-pyrazol-3-ylamine (211 mg, 1.28 mmol) and 1-hydroxybenzotriazole (147 mg, 1.28 mmol) in DMF (5 ml) is added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (199 mg, 1.28 mmol) at ambient temperature. After being stirred for 15 hours at ambient temperature, the reaction mixture is diluted with ethyl acetate, washed with saturated NaHCO3, dried over MgSO4 and concentrated. The crude product is purified by reverse-phase HPLC to give the product. Rf=0.44 (n-hexane:AcOEt=1:1). 1H NMR (400 MHz, CDCl3) δ 0.98(s, 9H), 2.33(s, 3H), 3.37(d, 2H), 6.55(s, 1H), 7.41-7.53(m,5H), 8.24(s, 1H), 9.01(br, 1H).
Reaction SMILES: C(NC(C)C)(C)C.[H-].[Na+].[C:10]([OH:15])(=[O:14])[CH:11]([CH3:13])[CH3:12].C([Li])CCC.CCCCCC.Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[CH3:12][C:11]([CH3:13])([CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:10]([OH:15])=[O:14]
Reactant: CC(C)C(=O)O
Reactant: BrCCc1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(CCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 21.5 %

Procedure:
To a stirring mixture of diisopropylamine (2.2 mL, 15 mmol) and sodium hydride [60% in mineral oil] (0.66 g, 16.5 mmol) in dry THF (50 mL), isobutyric acid (1.4 mL, 15 mmol) was dropwise added. The mixture was refluxed for 15 min, cooled to 0° C., and 2.5M n-butyllithium (BuLi) in hexane (5.45 mL, 14 mmol;) was added. After 20 min at 0° C., the mixture was heated to 30-35° C. for 30 min. The solution was then cooled to 0° C. and (2-bromoethyl)-benzene (2.8 mL, 15 mmol) was slowly added over 20 min. After ca. 1 h at 30-35° C. the reaction was quenched by adding water (40 mL), while keeping the temperature below 15° C. The aqueous layer was separated, and the organic layer washed with a mixture of Et2O/H2O (1:1). The aqueous layers were combined, extracted with Et2O (20 mL), acidified with 2M HCl solution, and the product was further extracted with Et2O (2×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum to afford the title compound (0.619 g, 21%) as a colorless oil. 1H NMR (CDCl3): δ 1.31 (s, 6H), 1.86-1.95 (m, 2H), 2.59-2.68 (m, 2H), 7.17-7.33 (m, 5H).