Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:24])[CH2:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][C:12]=1[C:21](=O)[CH3:22])=[O:9])[CH3:4].CC(O)=O>CCO.[Cl-].[Na+].O>[CH2:3]([O:5][C:6]([C:7]1[C:8]([OH:9])=[N:10][C:11]2[C:12]([C:21]=1[CH3:22])=[CH:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)=[O:24])[CH3:4]
Reactant: CCOC(=O)CC(=O)Nc1cc(C(F)(F)F)ccc1C(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)ccc2c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.3 %

Procedure:
235 mg (60% in mineral oil, 5.89 mmol) sodium hydride were added to a solution of 1.7 g (5.36 mmol) 3-(2-acetyl-5-(trifluoromethyl)phenylamino)-3-oxopropanoic acid ethyl ester in EtOH (16 ml) and the mixture was refluxed for 3 h and stirred for a further 16 h at RT. Then 1.34 ml (6.70 mmol) AcOH were added and the mixture was diluted with EE (30 ml) and brine (10 ml). The phases were separated and the organic phase was dried over MgSO4, filtered and concentrated to small volume under vacuum. Crystallisation (EE) of the residue yielded 920 mg (3.07 mmol, 57%) 2-hydroxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester.
Reaction SMILES: [O:1]=[O+][O-].[Cl:4][C:5]([Cl:26])([Cl:25])[CH2:6][O:7][C:8](=[O:24])[C:9]([N:13]1[C@H:16]([S:17][C:18](=[O:20])[CH3:19])[C@@H:15]([O:21][CH3:22])[C:14]1=[O:23])=C(C)C>C(OC)(=O)C>[Cl:4][C:5]([Cl:26])([Cl:25])[CH2:6][O:7][C:8](=[O:24])[C:9]([N:13]1[C@H:16]([S:17][C:18](=[O:20])[CH3:19])[C@@H:15]([O:21][CH3:22])[C:14]1=[O:23])=[O:1]
Reactant: CO[C@H]1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(C)C)[C@@H]1SC(C)=O
Reactant: O=[O+][O-]
Solvent: COC(C)=O
Product: CO[C@H]1C(=O)N(C(=O)C(=O)OCC(Cl)(Cl)Cl)[C@@H]1SC(C)=O
Reaction time: 0.25 h

Procedure:
3 equivalents of ozone are conveyed through a solution, cooled to -30°, of 8.4 g of 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-3-methylcrotonic acid 2,2,2-trichloroethyl ester in 765 ml of methyl acetate. After treating with ozone, the reaction mixture is left to stand at the same temperature for 15 minutes and then the excess ozone is removed by a nitrogen current. The reaction mixture is washed at 0° with a 10% aqueous sodium bisulphite solution and then with sodium chloride solution. After separating off, the combined aqueous phases are extracted a further 4 times with methyl acetate. The combined methyl ester solutions are dried over sodium sulphate and concentrated by evaporation in vacuo.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:19])[CH3:1])=[C:7]([C:13]2[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=2)[CH:8]=1)=[O:30]
Reactant: CN(C)CCOc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccc(F)cc1F
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1ccnn1C
Yield: 73.3 %

Procedure:
4-(2-Dimethylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (26.0 mg, 0.1 mmol) was treated with 2,4-difluorophenyl isocyanate (12.4 μL, 0.1 05 mmol) in a similar manner as described in Example 1.2 to afford Compound 141 as a white solid in 73.3% yield. LCMS m/z (%)=416 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 8.95 (s, 1H), 8.46 (s, 1H), 8.08-8.02 (m, 1H), 7.45-7.42 (m, 2H), 7.37 (d, J=2.7 Hz, 1H), 7.33-7.27 (m, 1H), 7.12 (d, J=8.95 Hz, 1H), 7.05-6.98 (m, 1H), 6.24 (d, J=2.7 Hz, 1H), 4.03 (t, J=5.80 Hz, 2H), 3.67 (s, 3H), 2.54 (t, J=5.73 Hz, 2H), 2.12 (s, 6H).
Reaction SMILES: N[C:2]1[C:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:4]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=[C:6]([CH:11]=1)[CH2:7][N:8]([CH3:10])[CH3:9].Cl.[N:25]([O-])=O.[Na+].[S:29](=[O:31])=[O:30]>O.C(O)(=O)C>[CH2:17]([C:3]1[C:2]([S:29](=[O:31])(=[O:30])[NH2:25])=[CH:11][C:6]([CH2:7][N:8]([CH3:10])[CH3:9])=[CH:5][C:4]=1[O:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=N[O-]
Reactant: O=S=O
Reactant: CCCCOc1cc(CN(C)C)cc(N)c1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCOc1cc(CN(C)C)cc(S(N)(=O)=O)c1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of (5-amino-4-benzyl-3-n-butoxybenzyl)dimethylamine (6.25 g) in a mixture of concentrated hydrochloric acid (10 ml) and acetic acid (10 ml) a solution of sodium nitrite (1.4 g) in water (5 ml) is dropwise added during 30 minutes, keeping the temperature at 0°-3° C. by external cooling. After additional stirring at 0° C. for 10 minutes, the resulting diazonium-solution is slowly added to a solution or cupric chloride dihydrate (1.5 g) in water (4 ml) and acetic acid (25 ml) saturated with dry sulphur dioxide while stirring at 22°-25° C. After stirring for a further 1 hour, the mixture is cooled to precipitate crude (4-benzyl-3-n-butoxy-5-chlorosulfonylbenzyl)dimethylamine hydrochloride. The hydrochloride is collected by filtration and washed with a minor amount of ice-cold acetic acid. It is then added in portions to a stirred, saturated solution of dry ammonia in methanol (30 ml) keeping the temperature at 10°-12° C. by external cooling. The resulting solution is stirred for 16 hours at 22°-25° C. and is then diluted with water (100 ml) to precipitate crude (4-benzyl-3-n-butoxy-5-sulfamylbenzyl)dimethylamine. After filtration and recrystallization twice from aqueous ethanol it is obtained with a melting point of 109°-111° C. The material (IR, analysis) is identical with the material prepared as in Example 180.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[OH-].[Na+].S(OCC)(O[CH2:19][CH3:20])(=O)=O>O>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)[CH3:20]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(CCC(=O)O)cc1
Temperature: 100 °C

Procedure:
16.62 g (100 mmol) of 3-(4-hydroxyphenyl)-propionic acid is dissolved with stirring and covering with argon in 45 ml (225.0 mmol) of 5 N sodium hydroxide solution, and 15.73 g (100 mmol), (98%) of diethyl sulfate is instilled quickly so that the temperature does not exceed 40° C. (water cooling). After completion of the addition, it is heated for 30 more minutes to 100° C. After the cooling, it is extracted with diethyl ether, then acidified with sulfuric acid to pH 4 and the precipitated compound is taken up in ether. After drying on sodium sulfate, it is evaporated to dryness in a vacuum. The title compound is obtained as solid.
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:12]([I:13])=[CH:11][C:10]([NH2:14])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22]>C(Cl)Cl>[CH:1]1([C:4]2[O:5][C:6]3[C:12]([I:13])=[CH:11][C:10]([NH:14][S:23]([CH2:21][CH3:22])(=[O:25])=[O:24])=[CH:9][C:7]=3[CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cc(I)c2oc(C3CC3)cc2c1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(I)c2oc(C3CC3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of the title compound from Step 2 (1.0 g, 3.3 mmol) in 20 mL of dry DCM was added a solution of pyridine (793 mg, 10 mmol) in DCM (10 mL), followed by addition of EtSO2Cl (473 mg, 3.7 mmol). The reaction mixture was stirred at room temperature for 1 h. It was diluted with DCM (20 mL) and washed with water (20 mL×2) and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude title compound (1.3 g, 100% yield) that was used directly in the next step. 1H NMR (CDCl3, 400 MHz): δ 7.42 (d, J=2.0 Hz, 1H), 7.38 (d, J=2.0 Hz, 1H), 6.88 (br, 1H), 6.40 (s, 1H), 3.09 (q, J=7.2 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H), 2.04-2.08 (m, 1H), 1.06-0.97 (m, 4H). LCMS: 409 (M+18)+.
Reaction SMILES: CC(C)(C)[C@@H](C(O)=O)N[C:5](OCCCC=C)=[O:6].Cl.[NH2:19][C@@H:20]([C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:21]([OH:23])=[O:22].[CH3:31][C:32]([CH3:39])([CH2:35][CH2:36][CH:37]=[CH2:38])[CH2:33][OH:34]>>[CH3:31][C:32]([CH3:39])([CH2:35][CH2:36][CH:37]=[CH2:38])[CH2:33][O:34][C:5]([NH:19][C@@H:20]([C:24]1([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:21]([OH:23])=[O:22])=[O:6]
Reactant: C=CCCC(C)(C)CO
Reactant: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: CC1([C@H](N)C(=O)O)CCCCC1
Agent: Cl
Product: C=CCCC(C)(C)COC(=O)N[C@H](C(=O)O)C1(C)CCCCC1

Procedure:
(2S)-({[(2,2-Dimethylhex-5-en-1-yl)oxy]carbonyl}amino)(1-methylcyclohexyl)acetic acid was prepared according to the procedure for 3-methyl-N-[(pent-4-enyloxy)carbonyl]-L-valine using (2S)-amino(1-methylcyclohexyl)acetic acid-HCl and 2,2-dimethylhex-5-en-1-ol. LRMS (ESI) m/z 326.3 [(M+H)+; calcd for C18H32NO4: 326.2].
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:9](=[O:10])C1.FC(F)(F)C([O-])=O.[C:32]([C:35]1[C:36]([NH:49][C:50]2[CH:55]=[CH:54][N:53]=[C:52]([F:56])[CH:51]=2)=[N:37][N:38]([C:40]2([CH2:46][C:47]#[N:48])[CH2:45][CH2:44][NH2+:43][CH2:42][CH2:41]2)[CH:39]=1)(=[O:34])[NH2:33]>C(#N)C.CS(C)=O>[C:32]([C:35]1[C:36]([NH:49][C:50]2[CH:55]=[CH:54][N:53]=[C:52]([F:56])[CH:51]=2)=[N:37][N:38]([C:40]2([CH2:46][C:47]#[N:48])[CH2:41][CH2:42][N:43]([C:9]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[O:10])[CH2:44][CH2:45]2)[CH:39]=1)(=[O:34])[NH2:33]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccnc(F)c3)n2)CC[NH2+]CC1
Reactant: OCC(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CS(C)=O
Solvent: CC#N
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccnc(F)c3)n2)CCN(C(=O)OCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,2,2-trifluoroethanol (15 mg, 0.15 mmol) in acetonitrile (1.0 mL) was added TEA (0.043 mL, 0.31 mmol) followed by N,N′-disuccinimidyl carbonate (59 mg, 0.23 mmol). The resulting mixture was allowed to stir at ambient temperature for 4 hours. A solution of 4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-4) (70 mg, 0.15 mmol) and TEA (0.043 mL, 0.31 mmol) in DMSO (1.0 mL) was then added to the reaction mixture dropwise. The resulting mixture was heated to 50° C. and allowed to stir for 16 hours. The crude reaction mixture was cooled to ambient temperature and purified directly by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #30-1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14]OS(C)(=O)=O)=[CH:10][CH:9]=1>O1CCCC1>[CH3:7][C:8]1[N:13]=[CH:12][C:11]([CH2:14][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:10][CH:9]=1
Reactant: Cc1ccc(COS(C)(=O)=O)cn1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: Cc1ccc(CN2CCOCC2)cn1
Temperature: 20 °C
Reaction time: 19 h
Yield: 66.8 %

Procedure:
Morpholine (43.2 kg, 495.9 mol) was then added over 2 hrs to the solution of methanesulfonic acid 6-methyl-pyridin-3-ylmethyl ester (198 mol; Example 1) in tetrahydrofuran (161 kg) under nitrogen at 15-20° C. and the resulting slurry stirred for 19 hrs. The suspension was filtered through a Silica (15.5 kg) column and the cake washed five times with tetrahydrofuran (43.5 kg). 440 L of the solution was then removed under vacuum distillation and heptane (41.52 kg) added. This was repeated two more times followed by the addition of heptane (48.6 kg) and the solution filtered through a Celite® (4.08 kg) bed at 40° C. and the cake washed twice with heptane (7.2 kg). Then the filtrate cooled to 20° C. over 3 hrs then to −12° C. over 5 hrs and held for 12 hrs at −12° C. The suspension was filtered and the cake washed with cold (0° C.) heptane (8.5 kg) and then dryed at 25° C. under vacuum, which gave 25.44 kg, 67% yield of 4-(6-Methyl-pyridin-3-ylmethyl)-morpholine as a beige solid. 1H NMR (400 MHz; CDCl3): δ 8.4 (d, J=1.72 Hz, 1H), 7.54 (dd, J=2.1, 7.91 Hz, 1H), 7.1 (d, J=7.92 Hz, 1H), 3.68 (apparent t, J=4.6, 9.28 Hz, 4H), 3.4 (s, 2H), 2.5 (s, 3H), 2.4 (apparent t, J=4.5, 8.93 Hz, 4H); 13C NMR (100 MHz, CDCl3): δ 157.3, 149.8, 137.2, 129.9, 122.9, 66.9, 60.3, 53.5, 24.1 ppm; MS (ESI) m/z 193 [M+1]+; Melting point: 51-52° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36](OC(C)C)=[CH:35]C=3)=[CH:29][C:28]=2C2C=CC=CC=2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.C(O[C:53]1[CH:58]=[CH:57][C:56](B(O)O)=[CH:55][CH:54]=1)(C)C.[CH3:62][C:63]1C=C(B(O)O)C=C[C:68]=1C>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([CH3:35])=[C:63]([CH3:68])[CH:62]=3)=[CH:29][C:28]=2[C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[C:23]([F:25])([F:26])[F:24])[N:3]=1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: CC(C)Oc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(-c3ccccc3)c2)cc1
Product: Cc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(-c3ccccc3)c2)cc1C

Procedure:
The title compound was prepared as described above for (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-isopropoxy-[1,1′:3′,1″-terphenyl]-4′-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 54b) by replacing the 4-isopropoxyphenyl boronic acid in Step 2 with 3,4-dimethylphenyl boronic acid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1C=O.[C:11]([Si:15]([CH3:28])([CH3:27])[O:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:14])([CH3:13])[CH3:12].[C:29](=[O:32])([O-])[O-].[K+].[K+]>>[F:1][C:2]1[CH:3]=[CH:6][C:7]([O:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][O:16][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:28])[CH3:27])=[CH:21][CH:22]=2)=[C:8]([CH:9]=1)[CH:29]=[O:32]
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(F)cc1F
Agent: [K+]
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Oc2ccc(F)cc2C=O)cc1

Procedure:
In a similar manner to the method described in Example 140a, 2,4-difluoro-benzaldehyde (Aldrich) reacted with 4-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-phenol and potassium carbonate to give a light brown oil which solidifies on standing.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH3:18][C:19]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].COC(=O)C1C=CC(C2C=CC(C(F)(F)F)=CC=2)=NC=1C>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][C:21]([C:20]2[C:19]([CH3:18])=[N:27][C:26]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=3)=[CH:25][CH:24]=2)=[O:22])[CH:10]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CN)c1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(=O)O
Agent: COC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Product: CCOC(=O)C(C)(C)Oc1cccc(CNC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c1

Procedure:
In analogy to the procedures described in example 26B] and 26C], 2-(3-aminomethyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 52B]) was reacted with 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid (prepared from 2-methyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester (example 1L]) in analogy to the procedure described in example 53B]) to give 2-methyl-2-[3-({[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-methyl)-phenoxy]-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as amorphous colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:15](=[O:21])[CH2:16][CH2:17][C:18]=3[O:19][CH3:20])[C:11]([CH3:22])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[CH:31]([CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:32]>O1CCCC1.CCCCCC.O1CCCC1.C(C1C=CC=CC=1)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:15](=[O:21])[CH:16]([CH:31]([OH:32])[CH:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)[CH2:17][C:18]=3[O:19][CH3:20])[C:11]([CH3:22])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: COC1=C(c2nc(-c3ccc(Cl)cc3)ncc2C)C(=O)CC1
Reactant: O=CC1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1=C(c2nc(-c3ccc(Cl)cc3)ncc2C)C(=O)C(C(O)C2CCOCC2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.5 %

Procedure:
A solution of 2-[2-(4-Chloro-phenyl)-5-methyl-pyrimidin-4-yl]-3-methoxy-cyclopent-2-enone (69.5 mg, 0.22 mmol) in anhydrous tetrahydrofuran (3 ml), under nitrogen, was cooled to −78° C. and stirred for 10 minutes before the drop wise addition of lithium diisopropylamide (as a 2.0M solution in hexane/tetrahydrofuran/ethylbenzene) (0.14 ml, 0.28 mmol). The resulting brown solution was stirred at −78° C. for a further 45 minutes before the drop wise addition of 4-formyltetrahydropyran (34 mg, 0.30 mmol). The orange solution was then warmed to room temperature. After 2.5 h the reaction was shown to have reached a steady state and was therefore quenched with saturated ammonium chloride (5 ml), ethyl acetate (5 ml) and water (1 ml). The biphasic mixture was separated and the aqueous layer further extracted with ethyl acetate (2×5 ml). Combined organics were dried over magnesium sulphate, filtered and stripped to dryness to yield a yellow oil. This was purified by normal phase chromatography (100% dichloromethane−5% methanol:dichloromethane) to give 2-[2(4-Chloro-phenyl)-5-methyl-pyrimidin-4-yl]-5-[hydroxy-(tetrahydro-pyran-4-yl)-methyl]-3-methoxy-cyclopent-2-enone as a dark yellow oil (50.3 mg, 0.12 mmol, 53% yield).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:21]([C:25]1[N:34]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33](=[O:42])[C:32]2[C:27](=[CH:28][C:29]([Cl:43])=[CH:30][CH:31]=2)[N:26]=1)[CH:22]([CH3:24])[CH3:23])[C:12](=[O:20])[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([C@@H:21]([C:25]1[N:34]([CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:33](=[O:42])[C:32]2[C:27](=[CH:28][C:29]([Cl:43])=[CH:30][CH:31]=2)[N:26]=1)[CH:22]([CH3:23])[CH3:24])[C:12](=[O:20])[C:13]1[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=1
Reactant: Cc1ccc(C(=O)N(CCCNC(=O)OC(C)(C)C)C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CCCN)[C@@H](c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97 %

Procedure:
A dry 3-necked, round bottomed flask, equipped with a magnetic stirrer, nitrogen inlet and cold bath was charged with 400.0 g of {3-[[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-(4-methyl-benzoyl)-amino]-propyl}-carbamic acid tert-butyl ester (the compound of Formula 304 prepared, e.g., as described in Example 1.8 or 3.3) and 1500 g of TFA (20 eq) premixed in DCM (6000 g). The mixture was stirred at room temperature for about 6 hours at which time the reaction was determined to be complete by TLC. The reaction vessel was cooled and slowly charged with 4N sodium hydroxide until basic. The resulting solution was washed with brine, dried over sodium sulfate and concentrated under reduced pressure at 35° C. to give the title compound of Formula I, (R)-N-(3-amino-propyl)-N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinalolin-2-yl)-2-methyl-propyl]-4-methyl-benzamide, 325 g (97% yield) as a white foam solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.C([Li])CCC.[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1.[I:18]I>O1CCCC1.CCCCCC>[I:18][C:6]1[S:5][C:4]([C:12]2([OH:17])[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:3][C:2]=1[CH3:1]
Reactant: Cc1cscn1
Reactant: O=C1CCCC1
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1nc(C2(O)CCCC2)sc1I
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of 4-methylthiazole (2.0 mL, 20.2 mmol) in tetrahydrofuran (130 mL) was added n-butyllithium (8.10 mL, 20.2 mmol, 2.48 M in hexane) dropwise. After 15 minutes, cyclopentanone (1.79 mL, 20.2 mmol) was added in a single portion. After 30 minutes, n-butyllithium (8.10 mL, 20.2 mmol, 2.48 M in hexane) was added dropwise. The reaction was allowed to stir for art additional 20 minutes, after which a solution of iodine (5.13 g, 20.2 mmol) in tetrahydrofuran (15 mL) was added dropwise. The reaction was then quenched by the addition of saturated aqueous Na2S2O3 and ethyl acetate (1.0.0 mL) and allowed to warm to ambient temperature. The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×100 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated to give a dark solid. Trituration of the residue with hexane gave the title compound as a beige solid. MS (ESI) m/z 310 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11](=[S:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[NH:13]1[C:21]2[C:16](=CC=CC=2)C=N1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][N:29](C)C=O>>[NH:13]1[CH:21]=[CH:16][N:29]=[C:28]1[C:3]1[O:4][C:5]2[C:10]([C:11](=[S:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: c1ccc2[nH]ncc2c1
Reactant: CN(C)C=O
Reactant: S=c1c(Br)coc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Product: S=c1cc(-c2ncc[nH]2)oc2ccccc12
Temperature: 0 °C
Yield: 85.5 %

Procedure:
To an eggplant type flask (25 ml), 3-bromothiochromone (121 mg) prepared in Example 8, indazole (236 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added. The mixture was reacted at 80° C. for 20 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography and recrystallized from benzene/hexane to give the titled compound (112.5 mg; yield=85.5%) as crystals. Melting point: 187°-188° C. 1H-NMR(CDCl3, δ ppm): 7.42 (s, H3), 8.54 (d, H5), 7.52-7.70 (m, H6), 7.52-7.70 (m, H7), 7.52-7.70 (m, H8), 8.31 (s, H3'), 7.85 (d, H4'), 7.35-7.62 (m, H5'), 7.35-7.62 (m, H6'), 8.08 (d, H7') .
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][NH2:12])[CH:5]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][NH:12][S:15]([CH3:14])(=[O:17])=[O:16])[CH:5]=1
Reactant: COC(=O)c1cccc(CCN)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cccc(CCNS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
To a solution of 3-(2-amino-ethyl)benzoic acid methyl ester (500 mg) in CH2Cl2 (35 mL) at 0° C. was added methanesulfonyl chloride (292 mg, 2.55 mmol) and triethylamine (1.6 mL, 11.5 mmol). The reaction was stirred at room temperature for 18 h and was washed consecutively with 5.5% HCl, water, saturated NaHCO3, and brine. The organic solution was dried over MgSO4, filtered, and concentrated to yield the title compound (522 mg) as a white solid. MS 275 (M+18).