Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:9]1[C:17]2[O:16][CH:15]=[CH:14][C:13]=2[CH:12]=[C:11]([F:18])[CH:10]=1)([CH3:8])[C:3](OCC)=[O:4].C([NH2:21])=O.C[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]([C:9]1[C:17]2[O:16][CH:15]=[CH:14][C:13]=2[CH:12]=[C:11]([F:18])[CH:10]=1)([CH3:8])[C:3]([NH2:21])=[O:4]
Reactant: NC=O
Reactant: CCOC(=O)C(C)(C)c1cc(F)cc2ccoc12
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C(N)=O)c1cc(F)cc2ccoc12
Temperature: 100 °C
Yield: 43.7 %

Procedure:
A mixture of 0.156 gm (0.62 mMol) ethyl 2-methyl-2-(5-fluorobenzofur-7-yl)propionate, 0.095 gm (2.12 mMol) formamide, and 0.44 mL (0.44 mMol) sodium methoxide (1.0 M in methanol) in 3 mL dimethylformamide was heated at 100° C. for 45 minutes. The reaction mixture was diluted with ethyl acetate and the organics washed sequentially with water and saturated aqueous sodium chloride. The organics were then concentrated under reduced pressure and the residue subjected to silica gel chromatography, eluting with 2:1 hexane:ethyl acetate. Fractions containing product were combined and concentrated under reduced pressure to provide 0.060 gm (25%) of the desired compound.
Reaction SMILES: [NH2:1][C:2]1[S:12][C:5]2[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:13]([NH2:15])=[O:14].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][C:18]=1[CH3:26]>O1CCCC1.C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:25])[NH:1][C:2]2[S:12][C:5]3[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH2:9][C:4]=3[C:3]=2[C:13]([NH2:15])=[O:14])=[CH:19][C:18]=1[CH3:26]
Reactant: CCN1CCc2c(sc(N)c2C(N)=O)C1
Reactant: Cc1cc(N=C=O)ccc1Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCN1CCc2c(sc(NC(=O)Nc3ccc(Cl)c(C)c3)c2C(N)=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To a stirred solution of compound F4 (450 mg, 2.00 mmol) in anhydrous tetrahydrofuran (10 mL) at room temperature under nitrogen was added a solution of compound F2 (402 mg, 2.40 mmol) in anhydrous methylene chloride (6 mL) dropwise over 3 min. Then the reaction mixture was stirred overnight at room temperature. The reaction mixture was filtered. The filter cake was washed with methylene chloride (5 mL) and then dried under reduced pressure to provide compound F5 as a white solid (301 mg, 38%): 1H NMR (300 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.12 (s, 1H), 7.48-6.75 (m, 5H), 3.45 (s, 2H), 2.77 (d, J=4.8 Hz, 2H), 2.65 (d, J=4.8 Hz, 2H), 2.55-2.45 (m, 2H), 2.30 (s, 3H), 1.07 (t, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1>CO>[CH3:1][S:2][C:5]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]=1
Reactant: C[S-]
Reactant: COC(=O)c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cnc(SC)c([N+](=O)[O-])c1
Reaction time: 4 h
Yield: 63.5 %

Procedure:
Sodium thiomethoxide (9.1 g) in dry methanol (50 mL) is added dropwise to a stirred solution of methyl 6-chloro-5-nitronicotinoate (25.1 g) in dry methanol (400 mL) and the mixture stirred for 4 hours. The pasty mixture is evaporated to low volume, diluted with water and the product extracted into ethyl acetate. The extracts are washed with water and brine, and finally dried (MgSO4). Evaporation gave methyl 6-methylthio-5-nitronicotinoate (16.8 g) as a yellow solid. The solid can be recrystallised from cyclohexane to give a yellow solid m.p. 115-6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([OH:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC(C)=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(CC(C)O)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 99.8 %

Procedure:
To a solution of 3-methoxyphenylacetone (1, 1.0 g) in methanol (30 ml) was added NaBH4 (360 mg) in portions in the period of 20 min at 0° C. The resulting solution was stirred at such temperature for another 40 min. No more starting materials were detected from TLC. Ice water was added to the reaction slowly. It was extracted with CHCl3 three times. The combined organic phase was washed with brine, and dried over Na2SO4. Removal of the solvent afforded the crude product. Purification of the crude product by using a silica gel column gave the desired product 2 (1.01 g, 100%).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][CH2:13][CH2:14][C:15]2([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:20][CH2:19][N:18]([C:21]3[S:22][C:23]([Br:26])=[CH:24][N:25]=3)[CH2:17][CH2:16]2)[CH:6]=1.[OH-].[Na+].O1CCCC1.CO>O>[Br:26][C:23]1[S:22][C:21]([N:18]2[CH2:19][CH2:20][C:15]([CH2:14][CH2:13][O:12][C:7]3[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:10]=[C:9]([Cl:11])[CH:8]=3)([N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)[CH2:16][CH2:17]2)=[N:25][CH:24]=1
Reactant: COC(=O)Cc1cc(Cl)cc(OCCC2(N3CCCC3)CCN(c3ncc(Br)s3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(Cl)cc(OCCC2(N3CCCC3)CCN(c3ncc(Br)s3)CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.8 %

Procedure:
A mixture of [3-[2-[1-(5-bromothiazole-2-yl)-4-pyrrolidine-1-ylpiperidine-4-yl]ethoxy]-5-chlorophenyl]acetic acid methyl ester (1.45 g), 2N sodium hydroxide (3.3 mL), tetrahydrofuran (15 mL) and methanol (15 mL) was stirred at room temperature for 3 hours. To the reaction solution was added water and washed with chloroform. The water layer was neutralized with 2N hydrochloric acid and extracted with chloroform. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (916 mg). Yield: 65%.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@H:4]([O:7][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@:3]1([CH3:26])[OH:25].[Cl:27][C:28]1[C:35]([CH3:36])=[C:34](F)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:27][C:28]1[C:35]([CH3:36])=[C:34]([NH:1][C@@H:2]2[CH2:6][CH2:5][C@H:4]([OH:7])[C@:3]2([OH:25])[CH3:26])[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: CC(C)(C)[Si](O[C@H]1CC[C@@H](N)[C@]1(C)O)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(N[C@@H]2CC[C@H](O)[C@@]2(C)O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 6.4 %

Procedure:
The title compound is prepared by essentially following the procedure described in Example 1, using rel-(1S,2R,5 S)-2-amino-5-(tert-butyl(diphenyl)silyl)oxy-1-methyl-cyclopentanol (409 mg, 1.1 mmol, Preparation 43) and 2-chloro-4-fluoro-3-methyl-benzonitrile (142 mg, 0.84 mmol). A 0.2 M solution of the crude product in THF is treated with tetrabutylammonium fluoride (1.3 mL, 1.3 mmol, 1.0 M in THF) and stirred at room temperature for 16 h. The mixture is treated with water, concentrated in vacuo and extracted with EtOAc. The organic extracts are dried over magnesium sulfate, filtered, and concentrated. The resulting material is purified on silica gel (25-100% EtOAc/hexanes) to give the title compound as a pale yellow oil (15 mg, 6%). The relative stereochemistry is determined by NMR studies. 1H-NMR (400 MHz, DMSO-d6) δ 7.47 (d, J=8.8 Hz, 1H), 6.78 (d, J=8.8 Hz, 1H), 5.60-5.57 (m, 1H), 4.98 (d, J=4.2 Hz, 1H), 4.68 (s, 1H), 3.73-3.70 (m, 2H), 2.12 (s, 3H), 2.09-2.09 (m, 2H), 1.69-1.67 (m, 1H), 1.52-1.49 (m, 1H), 1.07 (s, 3H). LC-ES/MS m/z 281 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH:15]([F:17])[F:16])[N:12]3[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:24]1([S:30]([C:33]2[CH:34]=[C:35]([NH2:39])[CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[N:24]1([S:30]([C:33]2[CH:34]=[C:35]([NH:39][C:21]([C:20]3[CH:19]=[N:18][N:12]4[C:13]([CH:15]([F:16])[F:17])=[CH:14][C:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)=[N:10][C:11]=34)=[O:23])[CH:36]=[CH:37][CH:38]=2)(=[O:32])=[O:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Product: O=C(Nc1cccc(S(=O)(=O)N2CCOCC2)c1)c1cnn2c(C(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.7) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 582.1 [(M+H)+]; mp 231° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.[C:34]([O:38][C:39]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])=[O:40])([CH3:37])([CH3:36])[CH3:35]>CN(C=O)C.ClCCl>[C:34]([O:38][C:39](=[O:40])[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC(=O)NCCCCCN
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NCCCCCNC(=O)OC(C)(C)C)c23)cc1
Temperature: 80 °C
Yield: 71 %

Procedure:
Dissolve 1.00 g (3.0 mmol) 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine in 5 ml DMF and add 1.15 g (8.9 mmol) DIEA. Add 1.20 g (5.9 mmol) 5-[(tert.-butyloxycarbonyl)amino]-1-pentylamine [obtainable from 1,5-diaminopentane according to J. Med. Chem. 47 (20), 4933-4940 (2004)] and then heat the mixture to 80° C. for 3 h. After cooling, dilute the mixture with dichloromethane and wash successively with water and saturated sodium chloride solution. Dry the organic phase over magnesium sulphate and concentrate by evaporation. Purify the residue by RP-HPLC (column: Gromsil 250 mm×30 mm, 10 μm; acetonitrile/water gradient: 0-3 min 5% acetonitrile, 3-50 min 5%→98% acetonitrile, 50-55 min 98% acetonitrile). A total of 1.07 g (67% of theor.) of tert.-butyl-(5-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}pentyl)carbamate is obtained in two fractions, in the form of beige crystals.
Reaction SMILES: [CH3:1][Mg]Br.[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=1[F:15]>C1COCC1>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([CH3:1])([OH:14])[CH3:13])=[CH:7][C:6]=1[F:15]
Reactant: CC(=O)Cc1ccc(Cl)c(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)Cc1ccc(Cl)c(F)c1
Temperature: 76 °C
Yield: 88.1 %

Procedure:
To a solution of methylmagnesium bromide (100 mL, 100.0 mmol, 1.0 M in THF) was added a solution of 1-(4-chloro-3-fluorophenyl)propan-2-one (9.00 g, 48.20 mmol) in THF (20 mL) dropwise at 0° C. under N2 and the reaction mixture was heated at 76° C. for 12 h. It was then cooled to rt and quenched with saturated NH4Cl aqueous solution (50 mL) and the mixture was poured into water (200 mL). The resulting mixture was extracted with EtOAc (100 mL×4) and the combined organic phases were washed with brine (100 mL×2), dried over anhydrous Na2SO4 (50 g) and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=8:1) to give the title compound as yellow liquid (8.61 g, 88.2%).
Reaction SMILES: Cl.[NH2:2][OH:3].S([O-])([O-])(=O)=O.[Na+].[Na+].Cl.[C:12]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[NH2:24])[CH2:17][CH2:16]1)(=[O:14])[CH3:13].Cl[C:26](Cl)(Cl)[CH:27]([OH:29])O>O>[C:12]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][C:22]=2[NH:24][C:27](=[O:29])[CH:26]=[N:2][OH:3])[CH2:17][CH2:16]1)(=[O:14])[CH3:13]
Reactant: NO
Reactant: CC(=O)N1CCc2cccc(N)c21
Reactant: OC(O)C(Cl)(Cl)Cl
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCc2cccc(NC(=O)C=NO)c21
Temperature: 55 °C
Yield: 82 %

Procedure:
Intermediate 6 was synthesized according to the procedure described by Yang et al. (J. Am. Chem. Soc., 1996, 118, 9557). Hydroxylamine hydrochloride (7.10 g, 0.102 mol) and sodium sulfate (40 g, 0.28 mol) were taken up in 200 mL water and 10 mL 2 M aqueous hydrochloric acid in a 1 L round-bottomed flask, and 1-acetyl-7-amino-2,3-dihydro-(1H)-indole (5.0 g, 28 mmol) was added. Chloral hydrate (5.63 g, 34.0 mmol) was then added, and the flask covered with a rubber septum and nitrogen balloon and heated at 55° C. overnight. After cooling to room temperature, the isonitrosoacetanilide 6 was collected by filtration and dried under vacuum to give product of sufficient purity that it could be used in the next step (5.74 g, 82% yield): 1H NMR (400 MHz, DMSO-D6) δ 2.30 (s, 3H) 3.07 (t, J=8.0 Hz, 2H) 4.13 (t, J=7.8 Hz, 2H) 7.09 (dd, J=7.3, 1.3 Hz, 1H) 7.14 (t, 1H) 7.48 (s, 1H) 7.73 (d, J=7.8 Hz, 1H) 10.76 (s, 1H) 12.33 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH2:15])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.[C:16]1([CH:22]([CH2:26][CH3:27])[C:23](O)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:1][O:2][C:3]1[C:8]([CH2:9][C:10]2[S:14][C:13]([NH:15][C:23](=[O:24])[CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:26][CH3:27])=[N:12][CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: COc1ncccc1Cc1cnc(N)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCC(C(=O)Nc1ncc(Cc2cccnc2OC)s1)c1ccccc1
Reaction time: 16 h

Procedure:
5-(2-Methoxy-pyridin-3-ylmethyl)-thiazol-2-ylamine (44 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (15 mg, 0.041 mmol, 21%). ESI-MS m/z calc. 367.1. found 368.1 (M+1)+ Retention time 3.24 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([NH:15][C:16]2[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=2)[CH:14]=1)[C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6].Cl.[NH2:24][C@H:25]([C:32]1[CH:37]=[C:36]([C:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])[CH:35]=[C:34]([Cl:45])[CH:33]=1)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[Cl:45][C:34]1[CH:33]=[C:32]([C@@H:25]([NH:24][C:9](=[O:11])[CH2:8][NH:7][C:5](=[O:6])[C:4]2[CH:12]=[C:13]([NH:15][C:16]3[NH:17][CH2:18][CH:19]([OH:22])[CH2:20][N:21]=3)[CH:14]=[C:2]([OH:1])[CH:3]=2)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:37]=[C:36]([C:38]([OH:44])([CH3:43])[C:39]([F:42])([F:41])[F:40])[CH:35]=1
Reactant: CCOC(=O)C[C@H](N)c1cc(Cl)cc(C(C)(O)C(F)(F)F)c1
Reactant: O=C(O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)c1cc(O)cc(NC2=NCC(O)CN2)c1)c1cc(Cl)cc(C(C)(O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetic acid (Example B) (328.3 mg, 1.065 mmol), (3S)-ethyl 3-amino-3-(3-chloro-5-(1,1,1-trifluoro-2-hydroxypropan-2-yl)phenyl)propanoate hydrochloride salt (from step 1 above) (364.2 mg, 0.968 mmol) and 1-hydroxybenzotriazole hydrate (31.5 mg, 0.206 mmol) was dissolved in a mixture of DMF/DCM (1:1) and stirred at room temperature under nitrogen atmosphere for 10 min to give a cream suspension. N,N′-diisopropylcarbodiimde (210 μL, 1.356 mmol) was added to the above suspension and the reaction mixture was stirred at room temperature overnight (19 h) under nitrogen atmosphere. The solvent was evaporated in vacuo to give a yellow-cream gummy residue. LC-MS analysis of the crude residue shows the desired product: (3S)-ethyl 3-(3-chloro-5-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)-3-(2-(3-hydroxy-5-((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)benzamido)acetamido)propanoate's mass: m/z 630 (35ClM+H) and m/z 632 (37ClM+H); Calcd for C27H31ClF3N5O7: 630.01. The crude residue is used as such for the saponification with lithium hydroxide monohydrate (Step 3)
Reaction SMILES: C(OC([NH:8][C@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=O)(C)(C)C.[CH:18](C1C=CC=CC=1B(O)O)=O.[BH4-].[Na+].C[Si]([Cl:35])(C)C>CO.C(N(CC)CC)C.CO>[ClH:35].[ClH:35].[NH2:8][C@H:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)O
Reactant: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](N)CCCCN
Product: Cl

Procedure:
Nα-tert-Butyloxycarbonyl-lysine was reacted with 2-formylphenylboronic acid in methanol-triethylamine and subsequently treated with sodium borohydride (Wiskur et al, Org. Letters 2001, 3, 1311). The resulting secondary amine was transformed to the methyl ester by treament with methanol and trimethylsilyl chloride, 10:1, to give Nε-(2-boronobenzyl), methyl lysinate, dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[N:5]=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH2:26])[CH3:22]>C1C=CC=CC=1>[ClH:1].[ClH:1].[CH2:21]([N:23]([CH2:27][CH3:28])[CH2:24][CH2:25][NH:26][C:2]1[C:7]2[O:8][CH2:9][C:10](=[O:12])[NH:11][C:6]=2[N:5]=[C:4]([CH3:13])[N:3]=1)[CH3:22]
Reactant: Cc1nc(Cl)c2c(n1)NC(=O)CO2
Reactant: CCN(CC)CCN
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(CC)CCNc1nc(C)nc2c1OCC(=O)N2
Product: Cl
Reaction time: 20 h
Yield: 16 %

Procedure:
A mixture containing 2 g of 4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one, 1.52 g of triethylamine 1.16 g of 2-diethylaminoethylamine and 50 ml of abs. benzene is refluxed while stirring for 20 hours, then evaporated. After adding water to the residue, the pH is adjusted to 3 and the mixture is extracted with chloroform. The aqueous phase is alkalized to pH 9, extracted with chloroform, the latter organic phase is washed with water, dried and evaporated. The oily residue is taken up in ethanol and ethanolic hydrogen chloride solution is added. The precipitate is filtered to give 0.56 g (16%) of the product, m.p.: 252°-255° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[C:27]([N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)=[O:28].O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[C:19]([C:27]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[O:28])[CH:20]=2)=[CH:3][C:4]=1[C:9]1[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=1
Reactant: O=C(c1cc(B(O)O)ccc1F)N1CCOCC1
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc(-c3ccc(F)c(C(=O)N4CCOCC4)c3)cnc2N)nn1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.70 mmol) and (4-fluoro-3-(morpholine-4-carbonyl)phenyl)boronic acid (197 mg, 0.77 mmol) in 1,4-dioxane (10.0 mL)/water (5.0 mL) was added Cs2CO3 (690 mg, 2.12 mmol) at room temperature. The reaction mixture was degassed with argon for 30 min. Then Pd(PPh3)4 (40 mg, 0.035 mmol) was added and allowed to stir at 110° C. for 30 min in CEM micro wave. The reaction mixture was cooled to RT, diluted with EtOAc (50 mL) and washed with water (50 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 5% MeOH in DCM to afford 210 mg (yield: 72.41%) of title compound as pale yellow solid.
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[NH:19][N:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[CH2:22](Br)[CH:23]=[CH2:24]>>[CH3:1][S:2]([N:5]1[C:10]2[CH:11]=[C:12]([C:15]3[CH2:16][CH2:17][C:18](=[O:21])[N:19]([CH2:24][CH:23]=[CH2:22])[N:20]=3)[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: C=CCBr
Reactant: CS(=O)(=O)N1CCOc2ccc(C3=NNC(=O)CC3)cc21
Product: C=CCN1N=C(c2ccc3c(c2)N(S(C)(=O)=O)CCO3)CCC1=O

Procedure:
6-(3,4-Dihydro-4-methanesulfonyl-1,4(2H)-benzoxazin-6-yl)-2,3,4,5-tetrahydropyridazin-3-one was reacted with allyl bromide instead of methyl iodide, following the procedure of Example 9. The title compound was recovered, yield 2.03 g, mp 153°-155° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](OC(F)(F)F)[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1.[CH2:30]([Sn](CCCC)(CCCC)C=C)[CH2:31]CC>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:30]=[CH2:31])[CH:10]=2)[N:5]=[C:4]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: O=S1(=O)CCN(c2cc(Cl)c3cc(OC(F)(F)F)ccc3n2)Cc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reaction time: 1 h
Yield: 52 %

Procedure:
To a degassed solution of 4-(6-bromo-4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (880 mg, 2 mmol, prepared in analogy to 4-(4-chloro-6-(trifluoromethoxy)quinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 17-1) in N,N-dimethylformamide (50 mL), tributyl(vinyl)tin (760 mg, 2.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (232 mg, 0.2 mmol) was added under argon. After being refluxed for 2 hours, the reaction mixture was concentrated in vacuo and the residue was portioned in ethyl acetate (100 mL) and a saturated aqueous solution of potassium fluoride (100 mL). After the mixture being stirred vigorously for 1 hour, the separated aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 0.4 g of the crude product.
Reaction SMILES: C([C:4]1[C:8](C)=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:6][C:5]=1[NH:16][C:17]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])(O)=O.[Li+].[I-].C1(C(O)=O)CCCCC1>N1C(C)=CC(C)=CC=1C>[C:10]1([C:7]2[S:6][C:5]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[O:18])=[CH:4][CH:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1c(-c2ccccc2)sc(NC(=O)C2CCCCC2)c1C(=O)O
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Solvent: O=C(O)C1CCCCC1
Product: O=C(Nc1ccc(-c2ccccc2)s1)C1CCCCC1

Procedure:
This compound (m.p. 174° C.) was prepared from N-(3-carboxy-methyl-5-phenyl-2-thienyl)-cyclohexane carboxamide (31.1 g, 0.1 mole) and LiI. 2H2O (48.1 g, 0.32 mole) by refluxing in collidine (125 ml.) according to the procedure of Example 53 (a). This compound was also prepared according to the procedure of Example 53(b), using cyclohexane carboxylic acid as the acylating agent. The products of the two processes were spectrally identical and had a melting point of 175° C.