Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][C@@H:4]([CH3:8])[CH2:3]1.CCN(C(C)C)C(C)C.[F:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1>>[OH:1][C:2]1([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:37]4[CH2:38][CH2:39][C@H:35]([F:34])[CH2:36]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:8])[CH2:3]1
Reactant: F[C@H]1CCNC1
Reactant: C[C@@H]1CCC[C@](O)(CNC(=O)c2c(Cl)ccc3nc(Cl)ccc23)C1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(O)(CNC(=O)c2c(Cl)ccc3nc(N4CC[C@H](F)C4)ccc23)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid ((1R,3R)-1-hydroxy-3methyl-cyclohexylmethyl)-amide, DIPEA and (S)-3-fluoropyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.16 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 1H), 0.83 (d, 3H). m/z: 420 [M+H]
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]#[N:11])=[N:5]2.Cl>[Pd].CO>[N:1]1[N:2]=[N:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([CH2:10][NH2:11])=[N:5]2
Reactant: N#Cc1ccc2nnnn2n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ccc2nnnn2n1
Reaction time: 5 h
Yield: 81.6 %

Procedure:
Tetrazolo[1,5-b]pyridazine-6-carbonitrile (228 mg, 1.58 mmol), as prepared in the previous step, was added to a mixture of 10% Pd/C (118 mg), MeOH (8.5 mL), and 12 N HCl (0.54 mL), and was then shaken in a Parr hydrogenation apparatus at 40 psig for 5 h. The mixture was then filtered through Celite, the filter cake was washed with MeOH (2×5 mL), and concentrated to afford 255 mg of the hydrochloride salt of the title compound as an off-white solid (1.29 mmol, 82% yield, assuming dihydrochloride salt). A portion of the salt was neutralized with saturated Na2CO3 and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated to afford the title compound (free base). 1H-NMR (300 MHz, CDCl3) δ 8.36 (d, 9.3 Hz, 1H), 7.65 (d, 9.3 Hz, 1H), 4.27 (s, 2H), 1.62 (br s, overlapped with water peak). LC/MS (m/z) [M+1]+ 151.0 (calculated for C5H6N6, 150.1).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].CI.[O:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[O:13]1[C@H:17]2[CH2:16][C@@H:15]([CH2:14][O:13][CH3:17])[CH2:14][CH2:15][C@@H:16]12
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Product: COC[C@H]1CC[C@H]2O[C@H]2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The product (4.63 g) obtained by the reaction in 2) was dissolved in tetrahydrofuran (50 ml), potassium bis(trimethylsilyl)amide (0.5N toluene solution, 80 ml) was added, and methyl iodide (2.93 ml) was then added. After heating the mixture to 0° C., it was stirred for 1 hour, quenched with a saturated aqueous solution of ammonium chloride and then diluted with diethyl ether. An organic layer was separated, washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the title compound (3.7 g) as a colorless oil.
Reaction SMILES: [CH2:1]([N:7]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:20]([OH:22])=[O:21].[CH3:23]O>O>[CH2:14]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH:20]([O:22][CH3:23])=[O:21]
Reactant: O=CO
Reactant: CO
Agent: CCCCCCN(CCCCCC)CCCCCC
Solvent: O
Product: COC=O

Procedure:
Example 1 was carried out in laboratory plant 1. 1760 g/h of methyl formate via stream (1a) and 849 g/h of water via stream (1c) were metered by means of metering pumps into the stirred vessel A1. Stream (1c) was taken from the mixing vessel X and was composed of fresh water via stream (1b) and recycled water from the distillation apparatus B2 via stream (3c). Stream (1b) was selected so that the sum of stream (1b) and stream (3c) gave the desired stream (1c). The stirred vessel A1 was operated at 110° C. and 1.3 MPa abs. The output was introduced into tube reactor A2 which was likewise operated at 110° C. and 1.3 MPa abs. The output from tube reactor A2 was introduced into tube reactor A3. 1964 g/h of tri-n-hexylamine were fed via stream (8a) into this tube reactor A3. The output from tube reactor A3 was introduced into tube reactor A4. A further 1661 g/h of tri-n-hexylamine were fed via stream (8b) into this tube reactor A4. The streams (8a) and (8b) were taken from the vessel Y which served to distribute the tri-n-hexylamine recirculated via stream (8) to the two tube reactors A3 and A4. Tube reactor A3 was operated at 115° C. and 1.3 MPa abs, and tube reactor A4 was operated at 110° C. and 1.3 MPa abs. A product mixture comprising 58.4% by weight of tri-n-hexylamine, 16.4% by weight of formic acid, 12.3% by weight of methanol, 7.8% by weight of water and 6.9% by weight of methyl formate was obtained as stream (2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[Br:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[NH2:32].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:32][C:23]2[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:30])[F:31])=[CH:27][C:22]=2[Br:21])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccc(C(F)(F)F)cc2Br)CC1

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (4.90 g, 21.00 mmol) was dissolved in dry methylene chloride (30 mL) and dry pyridine (4.30 mL). To the reaction mixture was then added thionyl chloride (3.00 g, 25.20 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was then added successively, under nitrogen atmosphere, 2-bromo-4-trifluoromethyl-phenylamine (5.60 g, 23.50 mmol), dry triethylamine (7.43 g, 73.5 mmol), dry methylene chloride (38 mL), 4-(dimethylamino)pyridine (0.26 g, 2.18 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then partitioned with aqueous 2N HCl and tert-butyl methyl ether. The organic layer was washed with aqueous 2N HCl, aqueous NaHCO3, brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (30% ethyl acetate/hexanes) to yield the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:22])=[C:14]([C:18]([F:21])=[CH:19][CH:20]=3)[C:15]([NH2:17])=[O:16])=[N:7][C:6]=2[CH:23]=1.[CH2:24]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH2:26]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:26]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][O:11][C:12]3[C:13]([F:22])=[C:14]([C:18]([F:21])=[CH:19][CH:20]=3)[C:15]([NH2:17])=[O:16])=[N:7][C:6]=2[CH:23]=1)[CH:25]=[CH2:24]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: NC(=O)c1c(F)ccc(OCc2nc3cc(Br)ccc3s2)c1F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1ccc2sc(COc3ccc(F)c(C(N)=O)c3F)nc2c1
Temperature: 120 °C
Yield: 0.6 %

Procedure:
To a solution of 3-(5-bromo-benzothiazol-2-ylmethoxy)-2,6-difluoro-benzamide (0.1 g, 0.025 mol) in 5 ml of anhydrous DMF was added Allyl tributyltin (0.083 g, 0.025 mol) and degassed the reaction mixture for the 10 minutes. Tetrakis (triphenylphosphine) Palladium (0) (0.029 g, 0.0025 mol) was added and again degassed for 10 min. The reaction mixture was heated at 120° C. for 1 h under the nitrogen atmosphere, then cooled to r.t. Water was added to the reaction mixture and extracted with ethyl acetate, The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The compound was crystallized with ethyl acetate/hexane to give the title compound as brown solid (0.050 g, 55%). 1H NMR (DMSO-d6, 400 MHz): δ 3.52 (d, 2H, J=6.4 Hz), 5.07-5.13 (m, 1H) 5.68 (s, 2H) 5.98-6.05 (m, 1H), 7.10 (dt, 1H, J=8.4 Hz (o-coupling), 7.31 (d, 1H, J=8.4 Hz (o-coupling), 7.38 (dt, 1H, J=9.2 Hz (o-coupling), J=5.2 Hz), 7.83 (s, 1H), 7.89 (broad s, 1H), 8.05 (d, 1H, J=8.4 Hz (o-coupling), 8.17 (broad s, 1H) MS ES+ (361.05), HPLC (method 5) Rt=16.74 min.
Reaction SMILES: C(N1CCCC(C(OCC)=O)C1)(=O)C1C=CC=CC=1.[CH3:20][CH:21]1[NH:26][CH2:25][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]1.[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38](Cl)=[O:39]>>[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37][C:38]([N:26]1[CH:21]([CH3:20])[CH2:22][CH2:23][CH:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:25]1)=[O:39]
Reactant: O=C(Cl)Cc1cccs1
Reactant: CCOC(=O)C1CCC(C)NC1
Agent: CCOC(=O)C1CCCN(C(=O)c2ccccc2)C1
Product: CCOC(=O)C1CCC(C)N(C(=O)Cc2cccs2)C1
Yield: 59.8 %

Procedure:
The reaction was run in the same manner as ethyl 1-benzoyl-3-piperidinecarboxylate, starting with ethyl 6-methyl-3-piperidinecarboxylate (263.1 mg; 1.54 mmol) and 2-thiopheneacetyl chloride (190 μl; 1.54 mmol). The crude product was distilled at 210° C./0.1 torr, giving ethyl 1-(2-thiopheneacetyl)-6-methyl-3-piperidinecarboxylate (272.2 mg) as a light yellow oil. MS m/z (positive ion) 591(dimer+; 25) 296 (MH+; 100).
Reaction SMILES: [CH2:1]([O:3]C1C=CC2C(=CC=CC=2)N1C(OCC)=O)[CH3:2].C(O)(=O)C.[NH:23]([C:25]([C:27]1[C:28]([N:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[C:29]2[CH:35]=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1)=[O:26])[NH2:24]>C1COCC1.C(#N)C>[C:1]([NH:24][NH:23][C:25]([C:27]1[C:28]([N:36]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)=[C:29]2[CH:35]=[CH:34][NH:33][C:30]2=[N:31][CH:32]=1)=[O:26])(=[O:3])[CH3:2]
Reactant: CCOC(=O)N1c2ccccc2C=CC1OCC
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C(=O)NN)cnc3[nH]ccc23)CC1
Solvent: CC(=O)O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)NNC(=O)c1cnc2[nH]ccc2c1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Ethyl 2-ethoxyquinoline-1(2H)-carboxylate (226 mg, 0.916 mmol) was added to acetic acid (50.0 mg, 0.832 mmol) in THF/ACN (5 mL), and the reaction was stirred at room temperature for 1 hour. tert-Butyl 4-(5-(hydrazinecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (300 mg, 0.832 mmol, Example 18) was added, and the reaction was heated to 70° C. for 1 hour. The reaction was then concentrated to dryness. The resulting residue was crystallized from DCM to yield tert-butyl 4-(5-(2-acetylhydrazinecarbonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazine-1-carboxylate (241 mg, 71.9% yield) as a solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:15][CH:16]([CH2:18][O-:19])[CH3:17].[Na+]>>[CH2:18]([O:19][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[N:10]=1)[C:5]([OH:7])=[O:6])[CH:16]([CH3:17])[CH3:15]
Reactant: CC(C)C[O-]
Reactant: CC(C)Oc1cc(C(=O)O)cc(Cl)n1
Agent: [Na+]
Product: CC(C)COc1cc(C(=O)O)cc(OC(C)C)n1
Temperature: 210 °C
Yield: 25 %

Procedure:
To a flask containing 2-chloro-6-isopropoxyisonicotinic acid (1.05 g, 4.83 mmol) was added 28 mL (9.66 mmol) of freshly prepared sodium isobutoxide (0.35 M in isobutanol). This mixture was split evenly into two 20 mL microwave vials and each vial was heated under microwave irradiation at 210° C. for 20 min. The reaction mixture was purified by C18 medium pressure chromatography using a gradient of acetonitrile in water to afford 310 mg (25%) of 2-isobutoxy-6-isopropoxyisonicotinic acid. 1H NMR (300 MHz, DMSO-d6) δ 0.95 (d, 6H, J=7 Hz), 1.27 (d, 61-1, J=6 Hz), 1.96-2.05 (m, 1H), 3.96 (d, 2H, J=7 Hz), 5.05-5.13 (m, 1H), 6.59 (s, 1H), 6.63 (s, 1H).
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:10]=[C:9]([N:11]([CH3:17])[CH2:12][C@@H:13]2[CH2:15][C@H:14]2[CH3:16])[N:8]=[C:7]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=1)=[O:4])[NH2:2].[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:32]1[C:43](O)=[O:44])=[O:30])([CH3:27])([CH3:26])[CH3:25].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(=O)([O-])[O-]>ClCCCl>[CH3:17][N:11]([CH2:12][C@@H:13]1[CH2:15][C@H:14]1[CH3:16])[C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[N:8]=1)[C:3]([NH:1][NH:2][C:43]([C@H:32]1[C@@H:33]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:34][CH2:35][CH2:36][N:31]1[C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:30])=[O:44])=[O:4]
Reactant: C[C@@H]1C[C@H]1CN(C)c1cc(C(=O)NN)cc(N(C)S(C)(=O)=O)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](c2ccccc2)[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@@H]1C[C@H]1CN(C)c1cc(C(=O)NNC(=O)[C@H]2[C@@H](c3ccccc3)CCCN2C(=O)OC(C)(C)C)cc(N(C)S(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-[4-(hydrazinocarbonyl)-6-(methyl[(trans-2-methylcyclopropyl)methyl]amino)pyridin-2-yl]-N-methylmethanesulfonamide (3A.3b-1, 59.0 mg, 0.17 mmol) in 1,2-dichloroethane (2 ml) were added cis-1-(tert-butoxycarbonyl)-3-phenylpiperidine-2-carboxylic acid (Intermediate 1A.5, 45.9 mg, 0.15 mmol), 1-hydroxybenzotriazole (23.2 mg, 0.16 mmol), diisopropylethylamine (0.090 ml, 0.52 mmol), and polystyrene bound carbodiimide (246 mg, 0.34 mmol, 1.31 mmol/g). The reaction mixture was allowed to stir gently at room temperature for 18 h. Macroporous carbonate resin (360 mg, 0.68 mmol, 2.74 mmol/g) was added to the reaction, and the mixture was again allowed to stir gently for 18 h. The reaction mixture was filtered and concentrated in vacuo to yield tert-butyl cis-2-[(2-{2-(methyl[(trans-2-methylcyclopropyl)methyl]amino)-6-[methyl(methylsulfonyl)amino]isonicotinoyl}hydrazino)carbonyl]-3-phenylpiperidine-1-carboxylate.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:14]1)=O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@@H](c2ccc(F)cc2)C1
Solvent: C1CCOC1
Product: Fc1ccc([C@@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)cc1

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(4-fluorophenyl)piperidin-1-yl]methanone (20 mg, 0.058 mmol) was treated with BH3 THF according to the above general procedure. Flash chromatography gave the title compound.
Reaction SMILES: Cl.C([O:4][C:5](=[O:29])[CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:14](=[C:15]([Cl:18])[C:16]=1[Cl:17])[C:13](=[O:19])[C:12]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1)([CH3:20])[CH2:11]2)C.C(=O)(O)[O-].[Na+:34].C(O)C.Cl>O>[Na+:34].[O:19]=[C:13]1[C:14]2[C:10](=[CH:9][C:8]([O:7][CH2:6][C:5]([O-:29])=[O:4])=[C:16]([Cl:17])[C:15]=2[Cl:18])[CH2:11][C:12]1([C:21]1[CH:22]=[CH:23][C:24]([CH2:27][NH2:28])=[CH:25][CH:26]=1)[CH3:20]
Reactant: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccc(CN)cc1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(c2ccc(CN)cc2)Cc2cc(OCC(=O)[O-])c(Cl)c(Cl)c2C1=O

Procedure:
Ethyl[1-oxo-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetate hydrochloride (1.57 g., 0.0034 mole), sodium bicarbonate (1.15 g., 0.0136 mole), absolute ethanol (50 ml.) and water (50 ml.) are combined and heated at reflux for 1.5 hours leaving a solution which is filtered, then neutralized with 1 N hydrochloric acid (10.26 ml., 0.01026 mole) to precipitate 900 mg. of [1-oxo-2-(4-aminomethylphenyl)-2-methyl-6,7-dichloro-5-indanyloxy]acetic acid sodium salt which melts at 270°-271° C. after drying.
Reaction SMILES: [C:1]([O:4][CH2:5][CH3:6])(=[O:3])[CH3:2].CCCCCC.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:23][C:24]([F:45])([F:44])[C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]=[CH:32][CH:31]=[C:30]2[O:35][C:36]1[CH:43]=[CH:42][C:39]([CH:40]=[O:41])=[CH:38][CH:37]=1.[Cl-].[NH4+]>O1CCCC1>[OH:41][CH:40]([C:39]1[CH:42]=[CH:43][C:36]([O:35][C:30]2[C:29]3[C:34](=[C:25]([C:24]([F:45])([F:23])[F:44])[CH:26]=[CH:27][CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[CH:37][CH:38]=1)[CH2:2][C:1]([O:4][CH2:5][CH3:6])=[O:3]
Reactant: CCOC(C)=O
Reactant: O=Cc1ccc(Oc2ccnc3c(C(F)(F)F)cccc23)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)c1ccc(Oc2ccnc3c(C(F)(F)F)cccc23)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Ethyl acetate (0.255 mL, 2.57 mmol) was dissolved in tetrahydrofuran (10 mL), and a 1 M lithium bis(trimethylsilyl)amide hexane solution (2.57 mL, 2.57 mmol) was added thereto at −78° C., and then, the resulting mixture was stirred under a nitrogen atmosphere at −78° C. for 1 hour. Thereafter, a tetrahydrofuran solution of 4-{[8-(trifluoromethyl)quinolin-4-yl]oxy}benzaldehyde (680 mg, 2.14 mmol) synthesized in (22A) was added thereto at −78° C., and the resulting mixture was stirred under a nitrogen atmosphere at −78° C. for 2 hours. To the reaction solution, a saturated aqueous solution of ammonium chloride was added at −78° C., and the organic matter was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 30:70 (v/v)), whereby the objective title compound was obtained as a white solid (730 mg, yield: 84%).
Reaction SMILES: N[C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[BrH:16].N([O-])=O.[Na+]>CC(C)=O.O>[Br:16][C:2]1[C:3]([O:14][CH3:15])=[CH:4][C:5]([O:12][CH3:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)c(OC)cc1OC
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cc(Br)c(OC)cc1OC
Temperature: 25 °C

Procedure:
A 0.65 g portion of methyl 5-amino-2,4-dimethoxybenzoate was dissolved in 10 ml of acetone and 1.5 ml of water, 1.80 ml of 48% hydrobromic acid was added, and then 0.23 g of sodium nitrite dissolved in 1 ml of water was added dropwise under ice-cooling, followed by a short period of stirring. Next, 0.51 g of cuprous bromide was added, and the mixture was warmed to room temperature. After completion of the reaction, insoluble matter was filtered, and the resulting residue was mixed with water, extracted with chloroform and then dried over anhydrous sodium sulfate. By evaporating the solvent under a reduced pressure, methyl 5-bromo-2,4-dimethoxybenzoate was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[S:14](F)(=[O:16])=[O:15])[CH2:10][N:9](C(=O)C(F)(F)F)[CH2:8][CH2:7]2)[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[S:14]([C:28]1[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=1)(=[O:15])=[O:16])[CH2:10][NH:9][CH2:8][CH2:7]2)[CH3:2]
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOc1cc2c(cc1S(=O)(=O)F)CN(C(=O)C(F)(F)F)CC2
Solvent: C1CCOC1
Product: CCOc1cc2c(cc1S(=O)(=O)c1ccc(F)cc1)CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice bath cooled solution of 6-ethoxy-2-(2,2,2-trifluoro-ethanoyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl fluoride (1.30 g, 3.66 mmol) in THF (13 mL) was added dropwise 4-fluorophenylmagnesium bromide (18.3 mL, 18.3 mmol). The mixture was stirred at room temperature overnight before quenching with aqueous sodium potassium tartrate tetrahydrate (13 g). The aqueous was extracted twice with diethyl ether. The organics were combined, dried and evaporated to dryness. The resulting oil was purified by chromatography on silica, eluting with 1 to 10% MeOH/NH3 in dichloromethane to yield the title compound D31 as a solid (700 mg). MH+ 336. 1H NMR δ (CDCl3)1.22-1.37 (3H, t), 2.74-2.91 (2H, m), 3.08-3.19 (2H, t), 4.01 (2H, s), 4.13-4.25 (2H, m), 6.58 (1H, s), 7.06-7.20 (2H, m), 7.83 (1H, s), 7.91-8.01 (2H, m).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:15][C:16]([O-:18])=[O:17].C(O)(=O)CCC(O)=O>C(O)(C)C>[CH2:2]([O:18][C:16](=[O:17])[CH3:15])[CH3:3].[NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C([O-])CCl
Agent: C1CNCCN1
Agent: O=C(O)CCC(=O)O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(C)=O
Temperature: 25 °C

Procedure:
To a reaction blend containing 100 g (3 Eq, 0.515 mol, MW=194) of piperazine, 26.3 mL (1.1 Eq, 0.189 mol, MW=101, d=0.726) of triethylamine in 200 mL of isopropanol, add to a solution previously prepared of 18.4 mL (1 Eq., 0.172 mol, MW=122.55, d=1.15) of chloroacetate of ethyl in 140 mL of isopropanol under stirring, at room temperature. Keep the reaction medium under stirring, monitoring the reaction termination by means of a chromatography of the thin layer (about 2–3 hours). Add a solution of 40.6 g (0.344 mol) of succinic acid in 140 mL of isopropanol. Keep the system under stirring for about 30 minutes to assure total precipitation of the succinate salt of piperazine formed. Filter this salt and concentrate the filtrate containing the mono and dialkyled derivatives. We obtain a slightly yellowish oil, which is used in later phases without purification.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:37]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=3[C:31](=[O:38])[NH:30][N:29]=2)=[CH:23][C:3]=1[C:4]([N:6]1[CH2:12][CH2:11][CH2:10][N:9](C(OCC2C=CC=CC=2)=O)[CH2:8][CH2:7]1)=[O:5]>[Pd].ClCCl.CO>[N:6]1([C:4]([C:3]2[CH:23]=[C:24]([CH:25]=[CH:26][C:2]=2[F:1])[CH2:27][C:28]2[C:37]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=3[C:31](=[O:38])[NH:30][N:29]=2)=[O:5])[CH2:12][CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c3CCCC4)ccc2F)CC1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cc(Cc2n[nH]c(=O)c3c2CCCC3)ccc1F)N1CCCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of EXAMPLE 544 (584 mg, 1.13 mmol) in 1:1 dichloromethane/methanol (20 mL) was added 10% Pd/C (150 mg) under nitrogen. The suspension was purged with hydrogen, and stirred under hydrogen at room temperature for 18 hours. Solid material was filtered off, and the filtrate was concentrated to provide the title compound. MS (DCI/NH3) m/z 385 (M+H)+.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.CS(C)=O.C1([O:15][C:16](=O)[NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[C:34]4[C:29](=[CH:30][C:31]([O:38][CH3:39])=[C:32]([C:35](=[O:37])[NH2:36])[CH:33]=4)[N:28]=[CH:27][CH:26]=3)=[CH:20][C:19]=2[F:40])C=CC=CC=1.O>C(OCC)(=O)C>[F:40][C:19]1[CH:20]=[C:21]([O:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:38][CH3:39])=[C:32]([C:35](=[O:37])[NH2:36])[CH:33]=3)[N:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23][C:18]=1[NH:17][C:16]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:15]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(F)c3)c2cc1C(N)=O
Reactant: NC1CC1
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(F)c3)c2cc1C(N)=O
Reaction time: 0.17 h

Procedure:
Cyclopropylamine (0.10 ml) was added to dimethylsulfoxide (0.8 ml), and then [4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-fluorophenyl]carbamic acid phenyl ester (80 mg) was dissolved therein and the mixture was stirred for 10 minutes. Water and ethyl acetate were added to the reaction solution and the precipitated crystals were filtered out to obtain the title compound (33 mg).