Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:29]=[C:28]([NH2:30])[C:27]4[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:31][CH3:32])[CH:26]=4)[N:21]=3)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)(C)(C)C>Cl>[NH2:30][C:28]1[C:27]2[C:22](=[CH:23][C:24]([O:33][CH3:34])=[C:25]([O:31][CH3:32])[CH:26]=2)[N:21]=[C:20]([N:17]2[CH2:18][CH2:19][CH:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:35])=[O:5])=[CH:8][CH:9]=3)[CH2:15][CH2:16]2)[N:29]=1
Reactant: COc1cc2nc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)nc(N)c2cc1OC
Agent: Cl
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)O)cc4)CC3)nc(N)c2cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 106.8 %

Procedure:
A solution of 4-[1-(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-piperidin-4-ylamino]-benzoic acid tert-butyl ester (5) (0.55 g, 1.15 mmol) in HCl (10 mL, 1M in 1,4-dioxane) was capped with a drying tube and stirred at 25° C. for 12 h. The reaction mixture was concentrated to give a pale yellow solid residue (0.52 g, 91.3%); 1H NMR (DMSO) δ 12.08 (br s, 2H), 8.85 (br s, 1H), 8.64 (br s, 1H), 7.73 (s, 1H), 7.67 (d, 2H, J=8.7), 7.48 (s, 1H), 6.65 (d, 2H, J=8.8), 6.47 (br s, 1H), 4.51 (d, 2H, J=13.2), 3.88 (s, 3H), 3.84 (s, 3H), 3.71 (m, 1H), 3.35 (t, 2H, J=12.0), 2.06 (d, 2H, J=10.4), 1.47 (m, 2H); 13C NMR (DMSO) δ 167.8, 161.6, 155.7, 151.7, 151.1, 147.1, 136.2, 131.6, 117.1, 111.6, 105.0, 101.7, 99.1, 56.5, 56.4, 48.1, 43.6, 31.2; HRMS (FAB) m/z 424.2003 (M+H)+ (C22H25N5O4 requires 424.1985); Anal. (C22H25N5O4 ·2HCl) C, H, N.
Reaction SMILES: Br[C:2]1[C:3]([Cl:18])=[C:4]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[N:19]1([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:27]2[CH:22]([CH2:23][NH:24][CH2:25][CH2:26]2)[CH2:21][CH2:20]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([O:12][C:11]([NH:10][C:4]1[C:3]([Cl:18])=[C:2]([N:24]2[CH2:25][CH2:26][CH:27]3[N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH2:21][CH:22]3[CH2:23]2)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC2CNCCC21
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(N2CCC3C(CCN3C(=O)OC(C)(C)C)C2)c1Cl
Temperature: 105 °C
Yield: 56.6 %

Procedure:
A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (440 mg, 1.326 mmol), tert-butyl octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (300 mg, 1.326 mmol), Pd2dba3 (121 mg, 0.133 mmol), BINAP (248 mg, 0.398 mmol), and cesium carbonate (1296 mg, 3.98 mmol) in Dioxane (12 mL) was evacuated and back filled with nitrogen 3× and heated at 105° C. overnight. The reaction mixture was filtered through a plug of celite and the filtrate was concentrated. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (80 g column, eluting with 5-35% ethyl acetate/hexanes), tert-butyl 5-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (358 mg) was obtained as a foaming solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]1[C@H:14]([N+:15]([O-])=O)[CH2:13][C:12]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)=[CH:11][CH2:10]1>[Zn].CO.C(O)(=O)C>[NH2:15][C@@H:14]1[CH2:13][C:12]([CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]2)=[CH:11][CH2:10][C@H:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1]
Reactant: O=[N+]([O-])[C@@H]1CC(CN2CCC(O)CC2)=CC[C@H]1c1ccc(Cl)cc1Cl
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: N[C@@H]1CC(CN2CCC(O)CC2)=CC[C@H]1c1ccc(Cl)cc1Cl
Yield: 75.8 %

Procedure:
To a solution of Example 16A (50 mg, 0.13 mmol) in mixture of methanol/acetic acid (0.5 mL/0.5 mL), Zn powder (85 mg, 1.3 mmol) was added at room temperature. The reaction mixture was stirred for thirty minutes, filtered, concentrated under reduced pressure and purified by high pressure liquid chromotography (eluting with 0-70% acetonitrile/water and 0.1% trifluoroacetic acid) to provide the title compound (35 mg, 76%). 1H NMR (300 MHz, methanol-d4) δ ppm 7.54-7.61 (m, 1H), 7.39-7.49 (m, 2H), 6.14-6.34 (m, 1H), 3.89-4.02 (m, 1H), 3.73-3.84 (m, 1H), 3.51-3.69 (m, 1H), 2.36-3.13 (m, 3H), 1.91-2.19 (m, 1H). MS (ESI) m/z 356 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]2[CH2:26][CH2:25]2)=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)[CH:42]=[O:43]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]2[CH2:26][CH2:25]2)=[C:14]([CH:42]=[O:43])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CN(C(=O)OC(C)(C)C)C4CC4)nc3N21
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(C=O)c(CN(C(=O)OC(C)(C)C)C4CC4)nc3N21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.847 g (4R,9aR)-7-bromo-6-[(tert-butoxycarbonyl-cyclopropyl-amino)-methyl]-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 30 ml toluene was added at −78° C. 1.5 ml of a 1.5M solution of tert-butyllithium and the mixture was stirred at this temperature for 10 min. To the resulting mixture was added 2.00 ml dimethylformamide and the mixture was stirred at −78° C. for 1 h and at 0° C. for 30 min. The reaction was quenched by addition of 10% aqueous citric acid. The phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=1:1 to yield 0.200 g of the title compound as orange yellow solid. (MS: 487.3 (M+H+)).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][C:22](=[O:31])[C:23](=[O:30])[N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:47][N:48]([CH3:53])[S:49](Cl)(=[O:51])=[O:50]>ClCCl>[CH3:47][N:48]([CH3:53])[S:49]([N:27]1[CH2:26][CH2:25][N:24]([C:23](=[O:30])[C:22]([NH:21][C:18]23[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]2)[CH2:14][N:13]2[C:32](=[O:35])[C:33]([OH:34])=[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:37][CH:36]=4)=[O:9])[N:11]=[C:12]32)=[O:31])[CH2:29][CH2:28]1)(=[O:51])=[O:50]
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)C(=O)N1CCNCC1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)S(=O)(=O)N1CCN(C(=O)C(=O)NC23CCC(CC2)Cn2c3nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49.2 %

Procedure:
To a suspension of N-(4-fluorobenzyl)-3-hydroxy-4-oxo-10-((oxo(1-piperazinyl)acetyl)amino)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (0.025 g, 0.040 mmol) in dichloromethane (1 mL) was added diisopropyl ethylamine (0.028 mL, 0.160 mmol) and the solution was stirred at room temperature for 5 min. Added to this was dimethylsulfamoyl chloride (4.26 μL, 0.040 mmol) and the solution was stirred at room temperature for 16 h. The reaction solution was concentrated and purified by preparative HPLC: Solvent A=10% methanol/90% H2O/0-1% trifluoroacetic acid; Solvent B=90% methanol/10% H2O/0.1% trifluoroacetic acid; Start % B=20; Final % B=100; Gradient time=20 min; Stop time=30 min; Column=XTERRA® 19×50 mm, C18, 5 μm to give the title compound as a white solid (12.2 mg, 45% yield). LCMS (M+H) calcd for C27H35FN7O7S: 620.23; found: 620.74. 1H NMR (500 MHz, CDCl3) δ: 12.00 (1 H, s), 8.45 (1 H, s), 8.39 (1 H, t, J=5.95 Hz), 7.36 (2H, dd, J=8.55, 5.49 Hz), 7.01 (2 H, t, J=8.55 Hz), 4.55 (2 H, d, J=6.10 Hz), 4.16 (2 H, d, J=3.66 Hz), 4.02-4.09 (2 H, m), 3.52-3.61 (2 H, m), 3.26-3.36 (2 H, m), 3.18-3.26 (2 H, m), 2.84 (6 H, s), 2.58 (2 H, ddd, J=14.19, 9.16, 5.65 Hz), 2.50 (1H, brs), 1.86-2.11 (4 H, m), 1.66-1.80 (2 H, m).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH:6]=[O:7])=[C:8]([CH3:10])[CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1cc(O)cc(C)c1C=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(OCc2ccccc2)cc(C)c1C=O

Procedure:
In analogy to the procedure described in example 8 a], 4-hydroxy-2,6-dimethyl-benzaldehyde was reacted with benzyl bromide in the presence of potassium carbonate to yield 4-benzyloxy-2,6-dimethyl-benzaldehyde as orange liquid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[C:9]([C:16]([O-])=[O:17])=[C:10]([CH2:14][CH3:15])[CH:11]=[N:12][CH:13]=1>C1COCC1>[Cl:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10]([CH2:14][CH3:15])[C:9]=1[CH2:16][OH:17]
Reactant: CCc1cncc(Cl)c1C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1cncc(Cl)c1CO
Reaction time: 1 h
Yield: 88 %

Procedure:
To a suspension of LAH (0.92 g, 24.24 mmol) in anhydrous THF (20 mL) at 0° C. was added dropwise a solution of 5-chloro-3-ethylpyridine-4-carboxylate (2.59 g, 12.12 mmol) in THF (30 mL). After stirring for 1 hour, the reaction mixture was slowly quenched with 15% NaOH and then diluted with water. Ethyl acetate was added, the mixture was stirred for 10 minutes, and the precipitated white solid was filtered off. The solid was washed with ethyl acetate (2×50 mL). The combined organic layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to provide (3-chloro-5-ethylpyridin-4-yl)methanol as a thick oil (1.83 g, 88% yield), which was used for the next step without any further purification; M+ 166.5.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[N:16]=[CH:17][O:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:26][C:27]1[N:28]=[C:29]([N:37]2[CH2:41][CH2:40][NH:39][C:38]2=[O:42])[S:30][C:31]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH3:26][C:27]1[N:28]=[C:29]([N:37]2[CH2:41][CH2:40][N:39]([CH2:14][C:15]3[N:16]=[CH:17][O:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:38]2=[O:42])[S:30][C:31]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCc1ncoc1-c1ccccc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ncoc3-c3ccccc3)C2=O)nc1C
Yield: 81 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 4-(bromomethyl)-5-phenyloxazole to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 81% yield: MS (ES+) m/z 413.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([C:17]#[N:18])=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[C:1]([O:5][C:6]([C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:17]#[N:18])=[CH:10][N:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ncc(C#N)cc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ncc(C#N)cc1N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a mixture of 5-cyano-3-nitro-pyridine-2-carboxylic acid tert-butyl ester (130 mg, 0.522 mmol) in water (3 ml) was added acetic acid (0.149 ml, 2.61 mmol), the mixture was stirred at room temperature for 20 min, sodium dithionite (454 mg, 2.61 mmol) was added and stirring was continued for 23 h. Additional sodium dithionite (182 mg, 1.043 mmol) was added and the reaction mixture stirred for another 48 h. The mixture was extracted with DCM, the combined organic layers were washed with water and saturated aq. NaCl, dried with Na2SO4 and evaporated to provide the title compound as yellow solid. The product was used for the next step without further purification.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:10](OC(=O)C)(=[O:12])[CH3:11]>C(Cl)Cl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10](=[O:12])[CH3:11])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CCC2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.1 %

Procedure:
A mixture of 2,3-dihydro-1H-indene (100.0 g, 0.85 mol) and acetic anhydride (104.2 g, 1.35 mol) was added drop-wise to a slurry of A1C13 (272.0 g, 2.04 mol) in CH2Cl2 (1000 ml) at 0° C. over a period of 3 h. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 15 h. Then the reaction mixture was poured into ice water (500 mL) and extracted with ethyl acetate (500 mL×3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4 and evaporated in vacuo. The residue that was purified by column chromatography (petroleum ether:ethyl acetate=20:1) to give the product (120.0 g, 88%). 1H NMR (400 MHz, CDCl3) δ 2.08-2.15 (m, 2H), 2.58 (s, 3H), 2.95 (t, J=7.2, 4 H), 7.28 (d, J=8.0, 1H), 7.75 (d, J=8.0, 1H) 7.82 (s,1H).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:29]5[CH2:30][CH2:31][N:27]([CH3:26])[C:28]5=[O:32])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CN1CCNC1=O
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)nc2)CC1
Yield: 61 %

Procedure:
Using (6-bromopyridin-3-yl) [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (241 mg) described in Preparation Example 144 and 1-methylimidazolidin-2-one (90 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (154 mg) was obtained.
Reaction SMILES: N#N.[H][H].[H][H].C(OCCO)CC.C(C1C=CC=C(CC)C=1N)C.[CH2:25]([C:27]1[CH:39]=[CH:38][CH:37]=[C:36]([CH2:40]C)[C:28]=1[NH:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35])C>>[CH3:25][C:27]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:28]=1[NH:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][CH3:35]
Reactant: [H][H]
Reactant: CCCOCCNc1c(CC)cccc1CC
Agent: CCc1cccc(CC)c1N
Agent: N#N
Solvent: CCCOCCO
Product: CCCOCCNc1c(C)cccc1C

Procedure:
In a steel tube with a diameter of 2.54 cm, which is arranged vertically and provided with a heating jacket, the catalyst prepared according to Example 5(a) is activated with a nitrogen/hydrogen mixture with a hydrogen content of 3.3% by volume for 16 hours at 250° C. The total throughput is 60 ml of the gas mixture per g of catalyst. Per g of catalyst and per hour, 1.0 g of a mixture of 2-propoxyethanol and 2,6-diethylaniline (molar ratio 2:1), together with 56 N1 (2.5 mols) of hydrogen per mol of 2,6-diethylaniline, are then passed over the catalyst at 270° C. and under a pressure of 2 bars. The reaction mixture which issues from the reactor and consists of 2-propoxyethanol, 2,6-diethylaniline, 2,6-diethyl-N-(2'-propoxyethyl)-aniline and by-products is analysed continuously by gas chromatography. The total conversion of 2,6-diethylaniline and the selectivity are calculated from the analytical data. The results are summarised in the table which follows:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[O:30][CH2:31][C:32]#[N:33])[C:24]([Cl:38])=[CH:23][N:22]=1>>[Cl:38][C:24]1[C:25]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[O:30][CH2:31][C:32]#[N:33])=[N:26][C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH2:16][O:17][CH3:18])[C:6]=3[CH:19]=2)=[N:22][CH:23]=1
Reactant: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Product: COCCN1C(=O)CCC(C)(C)c2ccc(Nc3ncc(Cl)c(Nc4ccccc4OCC#N)n3)cc21

Procedure:
The title compound was prepared with a procedure analogous to that used to prepare example 381 by combining 8-Amino-1-(2-methoxy-ethyl)-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and [2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenoxy]-acetonitrile to yield an off-white solid (43%). mp 255° C.; LCMS: m/z=521.20 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.45 (d, 1H, J=7.8 Hz), 8.13 (s, 1H), 7.75 (d, 1H, J=2.0 Hz), 7.65 (s, 1H), 7.46 (m, 1H), 7.30 (d, 1H, J=8.6 Hz), 7.11 (m, 3H), 7.01 (s, 1H), 4.92 (s, 2H), 3.69 (m, 4H), 3.35 (s, 3H), 2.35 (m, 2H), 2.06 (m, 2H), 1.35 (s, 6H).
Reaction SMILES: [OH-].[Na+].CC(O)(C)[C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:8]=1[F:15]>CC(C)=O>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[C:8]=1[F:15])#[CH:5]
Reactant: CC(C)(O)C#Cc1ccc(F)c(F)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: C#Cc1ccc(F)c(F)c1F
Yield: 65.9 %

Procedure:
23 g of sodium hydroxide was added to 229 g of 1-(3-methyl-3-hydroxy-1-butynyl)-2,3,4-trifluorobenzene, and then stirred for 1 hour at 120° C., while acetone that is produced is distilled off using an atmospheric distillation device. This was purified by distillation under a reduced pressure (101 to 108° C./34 kPa (256 mmHg)) to obtain 110 g of 1-ethynyl-2,3,4-trifluorobenzene as an almost colorless oily material.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:15][CH2:14]2)=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=O.[H][H]>CN(C=O)C.[C].[Pd]>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[C:19]([N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:9]=[C:3]3[C:2](=[CH:12][CH:11]=2)[NH:1][C:6](=[O:8])[CH2:5][CH2:4]3)[CH2:18][CH2:17]1)=[O:30]
Reactant: COc1ccc(C(=O)N2CCN(c3ccc(N)c(C=CC(=O)O)c3)CC2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Yield: 60.3 %

Procedure:
2-Amino-5-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]cinnamic acid (5 g) was dissolved in DMF (50 ml), and 5% palladium-carbon (0.5 g) was added to the solution. The mixture was reacted at 80° C. for 4 hours using Parr's apparatus at a hydrogen gas pressure of 3 kg/cm2. After removing hydrogen gas, the content was taken out. After removing the catalyst, the reaction mixture was concentrated to half the original volume and poured into a large volume of water. Crystals which precipitated were collected by filtration and recrystallized from ethanol-chloroform to give 2.9 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 238°-239.5° C., colorless granules.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C@H:8]2[C@H:13]3[O:14][C@H:10]([CH2:11][CH2:12]3)[C@H:9]2[C:15]([O:17]C)=O)=[CH:4][C:3]=1[CH3:21].[CH3:22][S:23]([NH:26][C:27]1[CH:42]=[CH:41][C:30]2[NH:31][C:32]([CH2:37][C:38](O)=[O:39])=[N:33][S:34](=[O:36])(=[O:35])[C:29]=2[CH:28]=1)(=[O:25])=[O:24].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:38](=[O:39])[C:37]([C:32]3[NH:31][C:30]4[CH:41]=[CH:42][C:27]([NH:26][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:28][C:29]=4[S:34](=[O:36])(=[O:35])[N:33]=3)=[C:15]([OH:17])[C@H:9]3[C@@H:8]2[C@H:13]2[O:14][C@@H:10]3[CH2:11][CH2:12]2)=[CH:4][C:3]=1[CH3:21]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@H]1[C@@H](NCc2ccc(F)c(C)c2)[C@@H]2CC[C@H]1O2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cc(CN2C(=O)C(C3=NS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)[C@H]3[C@@H]2[C@@H]2CC[C@H]3O2)ccc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of methyl (1R,2S,3R,4S)-3-[(4-fluoro-3-methylbenzyl)amino]-7-oxabicyclo[2.2.1]heptane-2-carboxylate (100 mg, 0.34 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 114 mg, 0.34 mmol) in anhydrous N,N-dimethylformamide (4 mL) under a nitrogen atmosphere, N-methylmorpholine (0.075 mL, 0.68 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg, 0.37 mmol) were added sequentially. The mixture was stirred at 25° C. for 2.5 h, poured into 1.0 M aqueous hydrochloric acid solution, and then was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the amide intermediate which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH2:9][CH2:10][C:11]([O:13][CH2:21][CH3:22])=[O:12])=[O:8])=[CH:14][CH:15]=1
Reactant: CCO
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCC(=O)c1ccc(OC)cc1

Procedure:
21 g of 3-(4-methoxybenzoyl)propionic acid were heated under reflux for 51/4 hours in 350 ml of ethanol after addition of 7.3 ml of concentrated sulfuric acid The reaction mixture was worked up by concentrating it, taking up the remaining residue in 100 ml of water and extracting the mixture with dichloromethane. The organic phase was separated, washed with 50 ml of saturated aqueous sodium bicarbonate solution, then washed with water until neutral, dried and concentrated. 23.3 g of crude ethyl 3-(4-methoxybenzoyl)-propionate were obtained as a yellowish, crystallizing oil.
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:17]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:19]=[CH:20][CH:21]=2)[CH2:12][CH2:11]1.Cl.[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38]N)=[CH:34][CH:33]=1>>[CH3:25][CH:24]([CH3:26])[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][CH2:7][C:6]3[C:36]4[C:35](=[CH:34][CH:33]=[C:32]([O:31][C:30]([F:41])([F:40])[F:29])[CH:37]=4)[NH:38][CH:2]=3)[CH2:15][CH2:14]2)[CH:17]=1)=[O:27]
Reactant: NNc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC3OCCO3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure H and Scheme S using N-(3-{1-[4-(1,3-dioxolan-2-yl)butyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-[4-(trifluoromethoxy)phenyl]hydrazine hydrochloride: ESMS m/e: 488.2 (M+H)+.