Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[CH:28][N:27]=1>CN1C(=O)CCC1>[N:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:26]([O:18][C:16]2[CH:15]=[CH:14][C:12]3[N:13]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]4[OH:1])[S:10][C:11]=3[CH:17]=2)=[N:27][CH:28]=1
Reactant: Clc1ncnc2ccccc12
Reactant: Oc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Oc3ncnc4ccccc34)cc2s1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 33.1 %

Procedure:
To a reaction mixture of 2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-ol (15.1 mg, 0.057 mmol; see Example 3 above) in 0.4 mL of NMP was added cesium carbonate (47 mg, 0.143 mmol) and stirred for 1-3 min at room temperature. To this mixture was added 4-chloroquinazoline (18.8 mg, 0.114 mmol). The reaction mixture was stirred at room temperature for 5 hours or until done by LC. The crude reaction mixture was filtered, purified by preparative HPLC, freebased, concentrated under reduced pressure and lyophilized to give the title compound (7.4 mg) as a solid. ES/MS m/z 393.2 (MHS, Rt=2.10 min.
Reaction SMILES: [SH:1][CH2:2][C:3]([CH3:10])([CH3:9])[CH2:4][S:5]([NH2:8])(=[O:7])=[O:6].C[O-].[Na+].CO.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[CH:24][N:25]=2)[N:22]=1>CO>[S:5]([CH2:4][C:3]([CH3:10])([CH3:9])[CH2:2][S:1][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[CH:24][N:25]=2)[N:22]=1)(=[O:7])(=[O:6])[NH2:8]
Reactant: CC(C)(CS)CS(N)(=O)=O
Reactant: Clc1ccc2nccn2n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CSc1ccc2nccn2n1)CS(N)(=O)=O
Yield: 66 %

Procedure:
To a solution of 0.37 g of 3-mercapto-2,2-dimethyl-1-propylsulfonamide and 0.37 g of 28% sodium methoxide-methanol solution in 50 ml of methanol was added 0.31 g of 6-chloroimidazo[1,2-b]pyridazine, followed by refluxing at 80°-85° C. for 3 hours. The reaction solution was concentrated under reduced pressure. The residue to which 30 ml of water were added was extracted with tetrahydrofuran and ethyl acetate (1:1). The extract was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was recrystallized from ethanol to obtain 0.4 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[H-].[Na+].[C:14]([C:18]1[CH:19]=[C:20]([C:24](Cl)=[O:25])[N:21]([CH3:23])[N:22]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:24]([C:20]2[N:21]([CH3:23])[N:22]=[C:18]([C:14]([CH3:16])([CH3:15])[CH3:17])[CH:19]=2)=[O:25])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Cl
Reactant: Nc1cc(Br)ncc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)cc1C(=O)Nc1cc(Br)ncc1[N+](=O)[O-]
Reaction time: 0.17 h

Procedure:
A solution of 2-bromo-5-nitro-pyridin-4-ylamine (62 mg, 0.28 mmol) in THF (5 mL), was treated with NaH (34 mg, 0.85 mmol) under Ar. The resulting solution was stirred for 10 min and then treated with 5-tert-butyl-2-methyl-2H-pyrazole-3-carbonyl chloride (62 mg, 0.31 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was purified by direct application to silica preparative TLC plates (2000 micron) and eluted with 3:7 EtOAc-hexanes to yield 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid (2-bromo-5-nitro-pyridin-4-yl)-amide. 1H-NMR (400 MHz, CDCl3) δ: 11.2 (s, 1H), 9.18 (s, 1H), 9.11 (s, 1H), 6.65 (s, 1H). 4.18 (s, 1H), 1.34 (s, 9H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[N:12]=[CH:13][C:14]([C:17]([OH:19])=O)=[N:15][CH:16]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:42][CH2:43][C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:52](=[O:63])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:61])[F:60])[CH2:48][CH2:47]1)=[O:45]>CN(C=O)C>[O:45]=[C:44]([N:46]1[CH2:47][CH2:48][N:49]([C:52](=[O:63])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:61])[F:60])[CH2:50][CH2:51]1)[CH2:43][NH:42][C:17]([C:14]1[CH:13]=[N:12][C:11]([OH:10])=[CH:16][N:15]=1)=[O:19]
Reactant: O=C(O)c1cnc(O)cn1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cnc(O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
DIPEA (553 mg, 0.732 mL, 4.28 mmol) was added to a stirred solution of 5-hydroxy-pyrazine-2-carboxylic acid (200 mg, 1.42 mmol) in DMF (3 mL). HOBT (231 mg, 1.71 mmol) and EDCI (328 mg, 1.71 mmol) were then added at room temperature. After 2 minutes 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (600 mg, 1.71 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, methanol was then added, filtered the solid precipitated. The solid obtained was purified by column chromatography (using silica gel of 60-120 mesh and 10% MeOH in CHCl3 as eluent) to afford 205 mg (32.85%) of 5-hydroxy-pyrazine-2-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 91.22%. 1H NMR (DMSO-d6): δ 8.3 (bt, 1H), δ 8.0 (m, 2H), 7.9-7.76 (m, 2H), 7.7 (m, 1H), 7.6-7.5 (d, 2H), 4.26-4.1 (dd, 2H), 3.8-3.68 (m, 2H), 3.6-3.5 (m, 2H), 3.4 (m, 2H), δ 3.2-3.0 (m, 2H).
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[C:18]([CH3:25])=[C:17]([CH3:26])[N:16]=1.CN(C)C=O.C(N(CC)CC)C>C(OCC)(=O)C>[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:18]([CH3:25])=[C:17]([CH3:26])[N:16]=1
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(CCCCNC(=O)OC(C)(C)C)c1C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
Tert-butyl 4-aminobutylcarbamate (60 g, 339 mmol) was slowly added to a mixture of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (50 g, 226 mmol), anhydrous N,N-dimethylformamide (500 mL) and triethylamine (50 mL, 339 mmol). The reaction mixture was allowed to stir overnight and then it was concentrated under reduced pressure to provide an oil. The oil was dissolved in ethyl acetate and then washed with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to provide a dark oil. This material was purified by column chromatography (silica gel eluting with 40/60 ethyl acetate/hexanes) to provide 64.5 g of tert-butyl 4-(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)butylcarbamate as a bright orange oil which solidified on standing.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:12]=2)=[C:7]([F:27])[CH:6]=1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:36](=[O:37])[CH2:35][C:33]#[N:34])[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])=[CH:6][C:7]=3[F:27])[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2C[C@@H]1CCCN1
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Yield: 69.1 %

Procedure:
A solution of 3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-((S)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.4 g Crude, 3.65 mmol, 1.00 equiv), 2-cyanoacetic acid (0.47 g, 5.48 mmol, 1.50 equiv), HATU (2.08 g, 5.48 mmol, 1.50 equiv), TEA (2.54 ml, 18.25 mmol, 5.00 equiv) in DCM (40 mL) was stirred overnight at room temperature. The resulting mixture was diluted with water, and extracted with DCM. The DCM layers were combined and washed with brine, dried over Na2SO4 and concentrated. The residue was submitted to flash chromatography (SiO2, PE: EtOAc=2:1 to 1:1) to give 1.28 g (69%) of 3-((S)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile as a yellow solid.
Reaction SMILES: [ClH:1].C(=N)(OCC)C.C(N(CC)CC)C.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[N:23]1C(=O)N[C:25]([CH3:29])=[N:24]1>C(Cl)Cl.Cl.C(=N)(OCC)C>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][N:24]=[C:25]([Cl:1])[CH3:29]
Reactant: Cl
Reactant: Cc1nn(-c2ccc(Cl)cc2Cl)c(=O)[nH]1
Agent: CCOC(C)=N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cl)=NNc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
A stirred solution of 13.6 grams (0.1100 mole) of ethyl acetimidate hydrochloride and 13.2 grams (0.1300 mole) of triethylamine in 100 grams of methylene chloride was cooled to about 0° C. for five minutes, and 17.7 grams (0.1000 mole) of 2,4-dichlorophenylhydrazine (1) was added. Upon completion of addition the reaction mixture stirred at 0° C. for about one hour, then it was allowed to warm to ambient temperature where it stirred for about two hours. GC analysis of the reaction mixture indicated the presence of a small amount of unreacted (1). An additional 0.6 gram of ethyl acetimidate hydrochloride was added (total 14.2 gram-0.1150 mole), and the reaction mixture was stirred for an additional one hour. After this time the reaction mixture was washed with about 20 mL of water and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a semi-solid residue. The residue was triturated with 20 mL of hexane, and the resultant solid was collected by filtration. The solid was washed with 50 mL of hexane and dried, yielding 20.4 grams (93.4% yield) of 2-(2,4-dichlorophenyl)hydrazidethaneimidic acid (A).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH:7]2[O:12][C:10](=[O:11])[CH:9]3[O:13][C:14]([CH3:17])([CH3:16])[O:15][CH:8]23)[CH2:4][O:3]1.C(OCC)(=O)C.CCCCCC.C1C=CC=CC=1.C(OCC)(=O)C.CC(C)=O>C(O)(=O)C.O>[CH3:16][C:14]1([CH3:17])[O:13][CH:9]2[C:10]([O:12][CH:7]([CH:5]([OH:6])[CH2:4][OH:3])[CH:8]2[O:15]1)=[O:11]
Reactant: CC1(C)OCC(C2OC(=O)C3OC(C)(C)OC32)O1
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC1(C)OC2C(=O)OC(C(O)CO)C2O1
Temperature: 30 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
2,3:5,6-Di-O-isopropylidene-L-gulonolactone (22.89 g, 88.7 mmol) was dissolved in acetic acid/water (7:1, 200 ml) and stirred at 30° C. for 16 h when t.l.c. (ethyl acetate/hexane 1:1) revealed no starting material (Rf 0.5) and one major product (Rf 0.1). The solvent was removed under reduced pressure to give a yellow oil. Trituration with benzene (50 ml) gave a solid which was shaken with ethyl acetate/acetone (1:1, 250 ml). The resulting suspension was filtered and solvents removed under reduced pressure to yield an amorphous yellow solid, which was recrystallized from ethyl acetate to yield 2,3-O-isopropylidene-L-gulonolactone, (14.31 g, 79%) as a white crystalline solid, m.p. 139°-141° C., [α]D20 +76.2° (C, 1 in acetone).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:23])[N:10](COC(=O)C(C)(C)C)[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25].N>CO>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:23])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:24][CH3:25]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCl
Agent: N
Solvent: CO
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCl
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
Mass Spectrum: M+H+369 and 371 7-(2-Chloroethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (65 g) was suspended in methanol saturated with ammonia gas (1.6 L) and stirred at ambient temperature for 2 days. The solvent was concentrated to about one-fourth and the precipitate collected by filtration and washed with ether to give 7-(2-chloroethoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (44g, 100%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:76])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[N:17](COCC[Si](C)(C)C)[C:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]5[N:40](COCC[Si](C)(C)C)[C:41]([CH:44]6[CH2:48][CH2:47][CH2:46][N:45]6[C:49](=[O:59])[CH:50]([NH:54][C:55]([O:57][CH3:58])=[O:56])[CH:51]([CH3:53])[CH3:52])=[N:42][CH:43]=5)=[CH:35][CH:34]=4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:76])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[CH:38]=[CH:37][C:36]([C:39]5[NH:40][C:41]([CH:44]6[CH2:48][CH2:47][CH2:46][N:45]6[C:49](=[O:59])[CH:50]([NH:54][C:55]([O:57][CH3:58])=[O:56])[CH:51]([CH3:53])[CH3:52])=[N:42][CH:43]=5)=[CH:35][CH:34]=4)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(N3CCN(c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)n5COCC[Si](C)(C)C)cc4)CC3)cc2)n1COCC[Si](C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(N3CCN(c4ccc(-c5cnc(C6CCCN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)CC3)cc2)[nH]1)C(C)C
Yield: 33 %

Procedure:
{1-[2-(5-{4-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl}-phenyl)-piperazin-1-yl]-phenyl}-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (8 mg, 0.007 mmol) in trifluoroacetic acid (1.0 mL) was stirred in a screw-cap vial at 40° C. for 1 hours. The solution was concentrated and subjected to a reverse phase HPLC column (5-95% MeCN—H2O; 0.1% TFA modifier) to afford {1-[2-(5-{4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-piperazin-1-yl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (1.9 mg, 32%) as a white solid (TFA salt): 1H NMR (CD3OD, 300 MHz) 7.66 (s, 2H), 7.60 (d, J=8.7 Hz, 4H), 7.13 (d, J=8.7 Hz, 4H), 5.21 (app t, J=8.1 Hz, 2H), 4.22 (d, J=7.2 Hz, 2H), 4.09 (m, 2H), 3.85 (m, 2H), 3.66 (s, 6H), 3.31 (m, 5H), 2.52 (m, 2H), 2.16 (m, 8H), 0.91 (m, 12H); MS (ESI) m/z 824 [M+H]+.
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.CS(O[CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)=[CH:21][C:20]=1[CH3:40])(=O)=O.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C:30]2[CH:31]=[CH:32][C:27]([C:26]#[C:25][C:22]3[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][N:7]4[CH2:8][CH2:9][CH:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[C:20]([CH3:40])[CH:21]=3)=[N:28][CH:29]=2)=[CH:34][CH:35]=1
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCOS(C)(=O)=O
Reactant: CC(C)C1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCC(C(C)C)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
164 mg (1.0 mmol) 4-isopropyl-piperidine (used as the hydrochloride) are added to a solution of 88 mg (0.2 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl methanesulphonate and 0.34 mL (2 mmol) ethyldiisopropylamine in 1.8 mL DMF and the reaction mixture is stirred for 24 h at RT. It is filtered using an injection filter and the reaction mixture is purified by HPLC.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])=[N:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].[C:29]([C:31]1[CH:32]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[CH:34]=[CH:35][C:36]=1[F:37])#[N:30].[Cl-].[NH4+]>O1CCCC1.O>[Cl:1][C:2]1[S:6][C:5]([N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[O:17][CH3:18])[S:38]([C:33]2[CH:34]=[CH:35][C:36]([F:37])=[C:31]([C:29]#[N:30])[CH:32]=2)(=[O:39])=[O:40])=[N:4][CH:3]=1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: COc1ccc(CNc2ncc(Cl)s2)c(OC)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncc(Cl)s2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
Under an atmosphere of nitrogen, 5-chloro-N-(2,4-dimethoxybenzyl)-1,3-thiazol-2-amine (Preparation 208, 3.0 g 10.5 mmol) was dissolved in tetrahydrofuran (20 ml) and cooled to −70° C. Lithium hexamethyldisilazane (1 M in tetrahydrofuran, 12.6 ml, 12.6 mmol) was added dropwise, keeping the temperature below −60° C. After 5 minutes, the cooling bath was removed and the reaction warmed to room temperature, stirred for a further 5 minutes then cooled back to −70° C. 3-Cyano-4-fluorobenzenesulfonyl chloride (2.54 g, 11.6 mmol) in tetrahydrofuran (10 ml) was added dropwise keeping the temperature below −60° C. and the reaction mixture was warmed to room temperature. Saturated aqueous ammonium chloride solution (50 ml) was added followed by water to dissolve the solid which had precipitated out. The aqueous layer was extracted with ethyl acetate (50 ml) and the organic extracts dried over magnesium sulphate and decolourising charcoal, filtered through Celite™ and the filtrate evaporated in vacuo. The resulting gum was purified using a short column (silica gel, 150 g) eluting with ethyl acetate:heptane (1:1, by volume) affording a gum which was triturated with tert-butyl ether, filtered, washed with heptane and dried in vacuo to give the title compound as a buff solid, 2.84 g, 57% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Na].[C:27]1([C:33]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:34](O)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:41][C:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:37]([F:38])([F:39])[F:40])[C:34]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:14]([NH:13][CH2:12][C:11]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:10]=1[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:20])=[O:35]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Reactant: O=C(O)C(O)(c1ccccc1)C(F)(F)F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)C(O)(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (200 mg, 0.544 mmol) and the sodium salt of 2-phenyl-2-hydroxy-3,3,3-trifluoropropanoic acid from the previous step (144 mg, 0.652 mmol) in DMF (5 mL) at ambient temperature under nitrogen atmosphere was added BOP reagent (288 mg, 0.652 mmol). The mixture was stirred at ambient temperature for 72 h. The solvent was removed under reduced pressure and the residue was purified by preparative reverse phase HPLC using a gradient of 95:5 to 0:100 (water:CH3CN, 0.1% TFA) over 60 min with a flow rate of 60 mL/min. After concentration of desired fractions in vacuo the two diastereomers of 1-(2-hydroxy-2-phenyl-3,3,3-trifluoropropanoyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide were obtained as amorphous solids (isomer 1 (more polar) 8.5 mg; HPLC RT=3.70 min, method A; LC-MS m/z=570.1; isomer 2 (less polar) 70 mg; HPLC RT=3.57 min, method A; LC-MS m/z=570.1).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[CH:44][CH:43]=1)[C:19]([N:21]([CH2:33][CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20]>>[CH2:1]([NH:8][C:9](=[O:16])[NH:10][O:11][CH2:12][C:13]([NH:17][C@@H:18]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[CH:44][CH:43]=1)[C:19]([N:21]([CH2:33][CH:34]([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1)OCC
Reactant: O=C(O)CONC(=O)NCc1ccccc1
Product: CCOC(CN(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CONC(=O)NCc1ccccc1)OCC
Yield: 54.5 %

Procedure:
According to the procedure described in the synthesis method of Compound II-1, 2-(3-benzylureidooxy)acetic acid (Compound VI-6) (247 mg, 1.0 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N-(2,2-diethoxyethyl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) (502 mg, 1.0 mmol) and the obtained residue was purified by silica gel column chromatography (eluent: chloroform:methanol=98:2 to 97:3) to obtain the title compound (381 mg, 52%).
Reaction SMILES: COC1C=CC(C[CH:8]2[S:15][CH:14]3[N:11]([C:12](=[O:25])[C@H:13]3/[N:16]=C\C3C=CC=CC=3O)[C:10]([C:26]([O-:28])=[O:27])=[C:9]2/[CH:29]=[C:30]2/[C:31](=[O:47])[N:32]([C@@H:35]3[CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36]3)[CH2:33][CH2:34]/2)=CC=1.O.CS([O:55][C:56](=O)/[C:57](/[C:69]1[N:73]=[C:72]([NH2:74])[S:71][N:70]=1)=[N:58]\[O:59]CC1C=CC(OC)=CC=1)(=O)=O.ClCCl>C(OC)(C)(C)C>[NH2:74][C:72]1[S:71][N:70]=[C:69](/[C:57](=[N:58]/[OH:59])/[C:56]([NH:16][C@@H:13]2[C:12](=[O:25])[N:11]3[C@@H:14]2[S:15][CH2:8][C:9](/[CH:29]=[C:30]2/[C:31](=[O:47])[N:32]([C@@H:35]4[CH2:39][CH2:38][NH:37][CH2:36]4)[CH2:33][CH2:34]/2)=[C:10]3[C:26]([OH:28])=[O:27])=[O:55])[N:73]=1
Reactant: COc1ccc(CO/N=C(\C(=O)OS(C)(=O)=O)c2nsc(N)n2)cc1
Reactant: COc1ccc(CC2SC3[C@H](/N=C\c4ccccc4O)C(=O)N3C(C(=O)[O-])=C2/C=C2\CCN([C@@H]3CCN(C(=O)OC(C)(C)C)C3)C2=O)cc1
Solvent: ClCCl
Solvent: COC(C)(C)C
Solvent: O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(/C=C4\CCN([C@@H]5CCNC5)C4=O)CS[C@H]23)ns1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A reactor is charged with (7R)-4-methoxybenzyl-3-((E)-((R)-1′-(tert-butoxycarbonyl)-2-oxo-[1,3′-bipyrrolidin]-3-ylidene)methyl)-7-((Z)-(2-hydroxybenzylidene)amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (1 eq), water (6-9 weight % relative to the Schiff base), (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(((4-methoxybenzyl)oxy)imino)acetic methanesulfonic anhydride (2.5 eq) and dichloromethane (1.75 mL per gram of Schiff base). The mixture is stirred for three hours at room temperature, then added to methyl tertiary butyl ether over the course of 2-3 hours, resulting in the formation of a solid. The solid is filtered and the filter cake was washed with additional methyl tertiary butyl ether. The filtered solid is deprotected using conventional methods and dried under vacuum to yield the title compound.