Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:21][CH3:22])[C:5]2[NH:9][C:8](=[O:10])[N:7]([C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=3[F:18])[C:6]=2[C:19]=1[F:20].[N+:23]([O-])([OH:25])=[O:24].C(OCC)(=O)C>CCCCCC>[F:1][C:2]1[C:3]([N+:23]([O-:25])=[O:24])=[C:4]([O:21][CH3:22])[C:5]2[NH:9][C:8](=[O:10])[N:7]([C:11]3[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=3[F:18])[C:6]=2[C:19]=1[F:20]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(F)c(F)c2c1[nH]c(=O)n2-c1ccc(I)cc1F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1c([N+](=O)[O-])c(F)c(F)c2c1[nH]c(=O)n2-c1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 48.2 %

Procedure:
6,7-Difluoro-1-(2-fluoro-4-iodo-phenyl)-4-methoxy-1,3-dihydro-benzoimidazol-2-one (3.0 g, 7.14 mmol) was added portion wise to fuming nitric acid at −78° C. over a period of 1 minute and the resulting mixture was stirred at room temperature for 5 minutes. The reaction was monitored by TLC (50% ethyl acetate in hexane). The reaction mixture was quenched with cold water. The solid formed was collected, washed with water and dried to give the crude product. Purification by column chromatography on silica gel (10-40% ethyl acetate in hexane) afforded 1.6 g of the product (48.2% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]2[N:24]=[C:25]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[C:26]3[CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29][C:27]=3[N:28]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1>ClCCl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]2[N:24]=[C:25]([CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[C:43]([O:47][CH3:48])[CH:42]=3)[C:26]3[CH2:32][NH:31][CH2:30][CH2:29][C:27]=3[N:28]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1
Reactant: COc1cccc(Cc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc3c2CN(C(=O)OC(C)(C)C)CC3)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(Cc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc3c2CNCC3)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL, 26.05 mmol) in dichloromethane (2 mL) was added to tert-butyl 2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenylamino)-4-(3-methoxybenzyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (14 mg, 0.03 mmol) and stirred at rt for 1 hour. The solvents were removed under reduced pressure and the product was used without further purification. MS (ES+) m/z 457.3 (M+H)+
Reaction SMILES: [Cl-].[Ca+2:2].[Cl-].[Na].[CH3:5][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[O:49][C:47](=[O:48])[C@H:46]([CH2:50][CH:51]([CH3:53])[CH3:52])[NH:45][C:43](=[O:44])[C@@H:42]([CH2:54][CH:55]([CH3:57])[CH3:56])[NH:41][C:39](=[O:40])[C@H:38]([CH2:58][C:59]([OH:61])=[O:60])[NH:37][C:35](=[O:36])[C@H:34]([CH:62]([CH3:64])[CH3:63])[NH:33][C:31](=[O:32])[C@@H:30]([CH2:65][CH:66]([CH3:68])[CH3:67])[NH:29][C:27](=[O:28])[C@H:26]([CH2:69][CH:70]([CH3:72])[CH3:71])[NH:25][C:23](=[O:24])[C@H:22]([CH2:73][CH2:74][C:75]([OH:77])=[O:76])[NH:21][C:19](=[O:20])[CH2:18]1)[CH3:7].CC(CCCCCCCCC[C@H]1OC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)C1)C>>[Ca:2].[CH3:7][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C@H:17]1[O:49][C:47](=[O:48])[C@H:46]([CH2:50][CH:51]([CH3:52])[CH3:53])[NH:45][C:43](=[O:44])[C@@H:42]([CH2:54][CH:55]([CH3:56])[CH3:57])[NH:41][C:39](=[O:40])[C@H:38]([CH2:58][C:59]([OH:61])=[O:60])[NH:37][C:35](=[O:36])[C@H:34]([CH:62]([CH3:63])[CH3:64])[NH:33][C:31](=[O:32])[C@@H:30]([CH2:65][CH:66]([CH3:68])[CH3:67])[NH:29][C:27](=[O:28])[C@H:26]([CH2:69][CH:70]([CH3:72])[CH3:71])[NH:25][C:23](=[O:24])[C@H:22]([CH2:73][CH2:74][C:75]([OH:77])=[O:76])[NH:21][C:19](=[O:20])[CH2:18]1)[CH3:5]
Reactant: [Ca+2]
Agent: CC(C)CCCCCCCCC[C@@H]1CC(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O1
Agent: [Cl-]
Agent: [Na]
Product: [Ca]

Procedure:
Photographs taken before and after adding calcium ion to a 0.05 mass % aqueous sodium surfactin solution are demonstrated as FIG. 1 for reference. As shown in FIG. 1(1), sodium surfactin was dissolved completely before addition of calcium ion. The white part in the upper part of FIG. 1(1) was composed of bubbles formed by sodium surfactin as a surfactant. On the one hand, as shown in FIG. 1(2), when 1 mL of a saturated aqueous calcium chloride solution was added to about 150 mL of a 0.05 mass % aqueous sodium surfactin solution, it was observed that the bubbles disappeared, and surfactin became insolubilized by calcium ion to form calcium surfactin and deposited in the lower part.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].F[C:9](F)(F)[C:10](O)=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1)=[O:39].C(Cl)(=O)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:10]([N:42]1[CH2:43][CH2:44][CH2:45][CH:40]([C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:39])[CH2:41]1)(=[O:11])[CH3:9]
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCCNC1
Solvent: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCCC(C(=O)Nc2ccc3cc2CCc2cccc(c2)Nc2ncc(Cl)c(n2)N3)C1
Yield: 34 %

Procedure:
The desired compound was prepared according to the procedure of Example A20, using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-3-carboxamide bis(trifluoroacetate) and acetyl chloride as starting materials in 34% yield. LCMS for C26H28ClN6O2 (M+H)+: m/z=491.2.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:24])[NH:4][C:5](=[O:23])[N:6]([CH:8]2[CH2:13][S:12][CH:11]([CH2:14][O:15]CC3C=CC=CC=3)[CH2:10][O:9]2)[CH:7]=1.B(Cl)(Cl)Cl.CO.C(Cl)Cl.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3](=[O:24])[NH:4][C:5](=[O:23])[N:6]([CH:8]2[CH2:13][S:12][CH:11]([CH2:14][OH:15])[CH2:10][O:9]2)[CH:7]=1
Reactant: O=c1[nH]c(=O)n(C2CSC(COCc3ccccc3)CO2)cc1Cl
Agent: ClB(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c(=O)n(C2CSC(CO)CO2)cc1Cl
Temperature: -78 °C
Reaction time: 4 h
Yield: 18.9 %

Procedure:
5-Chloro-1-(5-benzyloxymethyl-1,4-oxathian-2-yl) uracil (0.42 g) was dissolved in methylene chloride (40 ml), and the solution cooled to -78° C. To the solution, 3M boron trichloride (11.5 ml) was added dropwise, and the mixture stirred at the same temperature for 4 hours. After adding a mixed solution of methanol-methylene chloride (1/1, 14 ml) at room temperature, sodium bicarbonate was added thereto. Upon stirring and filtering the mixture, the filtrate was concentrated under reduced pressure, and the residue was purified on a silica gel column (eluent: chloroform/methanol=10/1) to obtain the desired product (0.06 g) as white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7](Cl)=[O:8])[CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:30]([O:37][C:38](=[O:44])[C@H:39]([CH:41]([CH3:43])[CH3:42])[NH2:40])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.C(OCC)(=O)C>[CH2:30]([O:37][C:38](=[O:44])[C@H:39]([CH:41]([CH3:42])[CH3:43])[NH:40][C:7]([N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:8])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: O=C(Cl)N1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H](NC(=O)N1CCOCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.8 ml (8.1 mmol) of (morpholinocarbonyl)chloride (preparation: J. Med. Chem. 31, 2277 (1988)) and 4.1 ml (24.1 mmol) of N-ethyldiisopropylamine are added to a solution of 4 g (10.5 mmol) of (L)-valine-benzyl ester 4-toluenesulfonate in 56 ml of methylene chloride and the mixture is stirred at RT for 24 h. The reaction mixture is diluted with ethyl acetate and washed in succession with 1N hydrochloric acid, water, saturated sodium hydrogen carbonate solution and brine. The organic phase is dried over sodium sulfate and concentrated by evaporation. Chromatography on silica gel with ethyl acetate yields N-morpholinocarbonyl-(L)-valine-benzyl ester in the form of a colourless oil. The ester is directly further used in a).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH2:21][CH2:22][CH3:23].N1C=CC=CC=1>CN(C1C=CN=CC=1)C>[C:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]=1[CH2:21][CH2:22][CH3:23])(=[O:3])[CH3:2]
Reactant: CCCc1cc(-c2ccccc2)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCc1cc(-c2ccccc2)ccc1OC(C)=O
Temperature: 55 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
6.1 g (60 mmol) of acetic anhydride are added dropwise to a solution of 10.6 g (50 mmol) of 4-hydroxy-3-propyl-biphenyl, 4.3 g (55 mmol) of pyridine and 0.1 g of 4-(N,N-dimethylamino)pyridine, and the mixture is heated at 50 to 60° C. for 2 hours. The reaction solution is left standing overnight at 20° C. and washed with water and dilute hydrochloric acid, and the organic phase is dried and concentrated. 11.4 g (yield: 89.8% of theory) of 4-acetoxy-3-propyl-biphenyl are obtained as a pale oil of log p=4.32 (pH=2.3).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:18])[CH2:9][CH2:10][CH2:11][N:12]([CH2:14][C@@H:15]([OH:17])[CH3:16])[CH3:13])([CH3:6])([CH3:5])[CH3:4].Cl[C:20]1[C:21]2[C:28]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])[O:26][C:22]=2[N:23]=[CH:24][N:25]=1.O>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[C:3]([O:7][C:8](=[O:18])[CH2:9][CH2:10][CH2:11][N:12]([CH2:14][C@@H:15]([O:17][C:20]1[C:21]2[C:28]([C:29]3[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)=[C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])[O:26][C:22]=2[N:23]=[CH:24][N:25]=1)[CH3:16])[CH3:13])([CH3:4])([CH3:6])[CH3:5]
Reactant: C[C@H](O)CN(C)CCCC(=O)OC(C)(C)C
Reactant: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(Cl)c23)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H](C)CN(C)CCCC(=O)OC(C)(C)C)c23)cc1

Procedure:
Add 22 mg (0.54 mmol) sodium hydride (60% dispersion in mineral oil) to a solution of 100 mg (0.43 mmol) 4-{[(2S)-2-hydroxypropyl](methyl)amino}butyric acid tert.-butyl ester in 1 ml THF, with ice cooling. After stirring for ten minutes with ice cooling, add a solution of 161 mg (0.45 mmol) 4-chloro-6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidine in 2 ml THF and 8 mg (0.02 mmol) tetra-n-butylammonium iodide. Stir the reaction mixture for 16 hours at room temperature. After adding water and ethyl acetate, wash the separated organic phase with 1 N hydrochloric acid and concentrate by vacuum evaporation. Take up the residue in acetonitrile/DMSO and purify by preparative RP-HPLC (gradient: water/acetonitrile). 114 mg (93% purity, 45% of theor.) of the desired product is obtained.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[C:21]1([CH:31]([NH2:33])[CH3:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[NH:33][CH:31]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[CH3:32])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: CC(N)c1cccc2ccccc12
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NC(C)c2cccc3ccccc23)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and 1-naphthalen-1-yl-ethylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H25NO5 [M+H]+: 408.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([OH:16])=O.[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[NH:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([Li])CCC.[Cl-].[NH4+]>C1(C)C=CC=CC=1.O1CCCC1.CN(C)C=O>[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:14](=[O:16])[CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH3:5])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: COc1ccccc1CC(=O)O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccccc1CC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
Thionyl chloride (6.91 mL) was added slowly to a warmed (50° C.) solution of 2-methoxyphenylacetic acid (13.77 g, 0.083 mol) and dimethylformamide (0.1 mL) in toluene (50 mL) and the mixture was stirred at 50° C. for 2 h. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (50 mL). To a cooled solution (-20° C.) of (4S)-4-benzyl oxazolidine-2-one (14.7 g, 83 mmol) in tetrahydrofuran (80 mL) was slowly added n-butyl lithium (1.6 M, 52 mL, 83 mmol) and the mixture was warmed to 0° C. To this solution was slowly added the solution of the acid chloride (above) in tetrahydrofuran over 20 min. The mixture was warmed to room temperature and was stirred for 72 h. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The combined organic fractions was washed with water and brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with hexane/EtOAc (90:10 increasing to 50:50) to give the title compound (12.8 g) 1H NMR (360 MHz, CDCl3) δ7.37-7.15 (7 H, m), 6.92 (2 H, m), 4.71 (1 H, m), 4.30 (1 H, d, J 17.6 Hz), 4.26-4.17 (4 H, m), 3.82 (3 H, s), 3.29 (1 H, dd, J 13.4, 3.1 Hz), and 2.81 (1 H, dd, J 13.3 9.4 Hz).
Reaction SMILES: C1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:36]([O:38][CH3:39])=[O:37])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]3[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=3)[CH2:24][C:25]([OH:27])=[O:26])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=CC=3)C=2C=CC=1.ClC(OCC1C=CC=CC=1)=O>>[CH3:39][O:38][C:36]([C@@H:19]([NH:18][C:16]([O:15][CH2:14][C:12]1[CH:11]=[CH:6][CH:7]=[CH:8][CH:13]=1)=[O:17])[CH2:20][S:21][CH2:22][CH:23]([C:28](=[O:35])[C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)[CH2:24][C:25]([OH:27])=[O:26])=[O:37]
Reactant: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C(Cl)OCc1ccccc1
Product: COC(=O)[C@H](CSCC(CC(=O)O)C(=O)c1cccnc1)NC(=O)OCc1ccccc1
Yield: 12 %

Procedure:
The title compound was prepared from 3-({(2R)-2-[(fluoren-9-ylmethoxy)carbonylamino]-2-(methoxycarbonyl)ethylthio}methyl)-4-oxo-4-(3-pyridyl)butanoic acid and benzyl chloroformate as described in Example 16 at 12% yield; ESMS, (M+1)+460.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[C:25]([CH:28]([CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1)[CH2:29][CH2:30][CH2:31][Cl:32])([OH:27])=O.[C:46]([O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)(=[O:49])[NH:47][NH2:48]>C(Cl)Cl.O.C(OCC)(=O)C>[CH2:51]([O:50][C:46]([NH:47][NH:48][C:25]([CH:28]([CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1)[CH2:29][CH2:30][CH2:31][Cl:32])=[O:27])=[O:49])[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(CCCCl)C(=O)O)CC1
Reactant: NNC(=O)OCc1ccccc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C(CCCCl)C(=O)NNC(=O)OCc2ccccc2)CC1

Procedure:
IPEA (2.0 ml) and BOPCl (1.55 g) were added to a solution of the crude tert-butyl 4-(1-carboxy-4-chlorobutan-1-yl)piperidine-1-carboxylate (1.25 g) and benzyl carbazate (CAS No. 5331-43-1, 883 mg) in methylene chloride (15 ml), and the reaction solution was stirred at room temperature overnight. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 928 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([N:8]=[C:9]=[O:10])[CH2:3]1.Cl.Cl.[NH2:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([N:21]2[C:25](=[O:26])[C:24]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][NH:22]2)[CH:16]=1.C(N(C(C)C)CC)(C)C>ClCCCl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([NH:8][C:9]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([N:21]3[C:25](=[O:26])[C:24]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:23][NH:22]3)[CH:16]=2)=[O:10])[CH2:3]1
Reactant: CC1CCCC(N=C=O)C1
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCC(NC(=O)NCc2ccnc(-n3[nH]cc(-c4cccnc4)c3=O)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
13.9 mg (100 μmol) of 3-methylcyclohexyl isocyanate are initially charged, 34.0 mg (100 mol) of the compound from Example 4A, dissolved in 0.6 ml of 1,2-dichloroethane, and 25.8 mg (200 μmol) of diisopropylethylamine are added and the mixture is stirred at RT overnight. The mixture is then concentrated, the residue is taken up in DMSO, the precipitate is filtered off and the filtrate is purified by preparative HPLC (Method 3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[C:7]#[C:8][CH2:9][OH:10]>C(OCC)(=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10]
Reactant: OCC#Cc1ncccn1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: OCCCc1ncccn1
Reaction time: 6 h

Procedure:
3-(2-pyrimidyl) prop-2-yn-1-ol (4.45 g, 0.033 M) was dissolved in ethyl acetate (140 mL), 10% Pd/C (890 mg) was added and the mixture stirred under an atmosphere of hydrogen for 6 hours. The reaction mixture was filtered through Celite and the filtrate evaporated to give 3-(2-pyrimidyl) propan-1-ol as a yellow oil, 4.15 g (91%). NMR (CDCl3) 2.1 (2H, m), 3.2 (2H, t), 3.8 (2H, t), 7.2 (1H, t), 8.7 (2H, d) MS found MH+139.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([C:11]2(O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:12]2=[O:29])=[CH:6][C:3]=1[C:4]#[N:5].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[C:12]2=[O:29])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(CN2C(=O)C(O)(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CN2C(=O)C(c3cc(C#N)c(F)cc3O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 91 %

Procedure:
To a stirred suspension of 2-fluoro-4-hydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (12.0 g, 29.7 mmol) in triethylsilane (14.2 mL, 88.9 mmol) was added trifluoroacetic acid (10.0 mL, 129 mmol). The reaction mixture was stirred at ambient temperature for 168 h and concentrated in vacuo. The residue was recrystallized from ethyl acetate/hexanes to afford 2-fluoro-4-hydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (10.5 g, 90%): 1H NMR (300 MHz, CDCl3) δ 7.37-7.12 (m, 7H), 6.94 (d, J=6.0 Hz, 1H), 6.85-6.79 (m, 3H), 5.07 (s, 1H), 4.88 (ABq, 2H), 3.75 (s, 3H); MS (ES+) m/z 388.9 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([CH:17]4[CH2:19][CH2:18]4)=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH2:27])[C:24]([O:28][CH3:29])=[CH:23][N:22]=3)[C:5]=2[CH3:30])[CH2:3][CH2:2]1.Cl.F[C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1.[H-].[Na+]>CN(C=O)C>[CH:1]1([C:4]2[N:8]([CH2:9][C:10]3[C:15]([F:16])=[CH:14][C:13]([CH:17]4[CH2:19][CH2:18]4)=[CH:12][C:11]=3[F:20])[N:7]=[C:6]([C:21]3[N:26]=[C:25]([NH:27][C:33]4[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=4)[C:24]([O:28][CH3:29])=[CH:23][N:22]=3)[C:5]=2[CH3:30])[CH2:2][CH2:3]1
Reactant: COc1cnc(-c2nn(Cc3c(F)cc(C4CC4)cc3F)c(C3CC3)c2C)nc1N
Reactant: Fc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnc(-c2nn(Cc3c(F)cc(C4CC4)cc3F)c(C3CC3)c2C)nc1Nc1ccncc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
16.5 mg of 2-[5-cyclopropyl-1-(4-cyclopropyl-2,6-difluorobenzyl)-4-methyl-1H-pyrazol-3-yl]-5-methoxypyrimidin-4-amine 1-17-3 (0.040 mmol, 1.0 eq.) and 16.1 mg 4-Fluoropyridine hydrochlorid (0.120 mmol, 3.0 eq.) were suspended in 0.19 mL dry DMF under a nitrogen atmosphere. 19.2 mg of sodium hydride (60% purity) were added and stirred at 90° C. for 2 h. Then the mixture was partitioned between half water and ethyl acetate. The aqueous layer was washed with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to obtain 5.7 mg (0.01 mmol, 20%) of the analytical pure target compound.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:9]([C:10](=[O:12])[N:11]=1)=[CH:8][C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=2.Cl.Cl.[CH2:19]([N:26]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[N:28]=[CH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(C(C)C)CC)(C)C>COCCO.O>[CH2:19]([N:26]1[C:34]2[CH2:33][CH2:32][N:31]([C:2]3[NH:11][C:10](=[O:12])[C:9]4[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=4)[N:3]=3)[CH2:30][C:29]=2[N:28]=[CH:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cc2[nH]c(Cl)nc(=O)c2cc1OC
Reactant: c1ccc(Cn2cnc3c2CCNC3)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Solvent: O
Product: COc1cc2nc(N3CCc4c(ncn4Cc4ccccc4)C3)[nH]c(=O)c2cc1OC
Temperature: 120 °C
Reaction time: 6 h
Yield: 29.9 %

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1 (wherein R is methyl and Z is —C(O)—, 296 mg, 1.24 mmol), 1-benzyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine dihydrochloride 15a (440 mg, 1.54 mmol)) and diisopropylethylamine (1.2 g, 9.26 mmol) in 2-methoxyethanol (10 mL) was stirred at 120° C. for 6 hours. The reaction mixture was concentrated in vacuo to give an oil residue, which was diluted with water. The white precipitate that formed was collected by filtration to give 155 mg of 2-(1-benzyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridin-5-yl)-6,7-dimethoxy-3H-quinazolin-4-one 501, [M+H]+=418.