Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][CH:3]1[CH:11]=[CH:10][CH2:9][CH2:8][CH:4]1[C:5]([OH:7])=O.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[Cl:14][C:15]1[CH:16]=[C:17]([N:18]2[C:1](=[O:13])[CH2:2][C:3]3[CH2:11][CH2:10][CH2:9][CH2:8][C:4]=3[C:5]2=[O:7])[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)CC1C=CCCC1C(=O)O
Product: O=C1CC2=C(CCCC2)C(=O)N1c1cccc(Cl)c1

Procedure:
A mixture of tetrahydrohomophthalic acid (46.0 g., 0.25 mole) and m-chloroaniline (31.8 g., 0.25 mole) is heated by an oil bath until molten for two hours. When removed from the oil bath, the reaction mixture solidifies and is recrystallized twice from ethanol/ethyl acetate, giving 2-(m-chlorophenyl)-5,6,7,8-tetrahydroisoquinoline-1,3(2H,4H)-dione.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:37][CH2:38][N:33]([C:30]3[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:32][CH:31]=3)[CH2:34][CH2:35]2)=[O:48])[C:44]=1[CH3:45]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)cc1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Methoxyphenyl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (CDCl3, 400 MHz) 6.88 (m, 4H), 5.00 (s, 2H), 3.78 (m, 3H), 3.76 (m, 2H), 3.70 (m, 2H), 3.08 (m, 4H), 2.30 (s, 3H) ppm; MS (ES) M+Na expected=439.0, found 439.0.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][OH:17])=[CH:14][CH:13]=1)[CH:9]=[CH2:10].[C:20](O)(=[O:24])[C:21]([CH3:23])=[CH2:22]>COC1C=CC(O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:20]([O:17][CH2:16][C:15]1[CH:18]=[CH:19][C:12]([O:11][CH2:8][CH:9]=[CH2:10])=[CH:13][CH:14]=1)(=[O:24])[C:21]([CH3:23])=[CH2:22]
Reactant: C=CCOc1ccc(CO)cc1
Reactant: C=C(C)C(=O)O
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCOc1ccc(COC(=O)C(=C)C)cc1
Yield: 80.4 %

Procedure:
To a 250 ml reaction flask fitted with a Dean-Stark water trap, condenser and magnetic stirrer was added toluene (100 ml), 4allyloxybenzyl alcohol (30.0 g; 0.18 moles), methacrylic acid (15.7 g; 0.18 moles), 4-methoxyphenol (0.6 g) and p-toluene sulfonic acid (0.23 g). The stirred solution was heated under reflux until all of the water was removed (2 hours). The solution was cooled and washed with an equal volume of sodium bicarbonate solution and then with sodium chloride solution. The organic layer was dried over magnesium sulfate and the solvent removed by distillation under reduced pressure to yield 4-allyloxybenzyl methacrylate (33.6 g; 81% yield) as an orange colored viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:15]#[N:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:17]([O:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27]Br)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[C:17]([O:21][C:22](=[O:23])[NH:24][CH2:25][CH2:26][CH2:27][N:12]1[CH2:13][CH2:14][C:9]([C:15]#[N:16])([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:10][CH2:11]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: N#CC1(c2ccc(Cl)cc2Cl)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NCCCN1CCC(C#N)(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To a stirred solution of 4-(2,4-dichlorophenyl)piperidine-4-carbonitrile (0.736 g, 2.88 mmol) in acetone (20 ml), N-(tert-butoxycarbonyl)-3-bromopropylamine (0.754 g, 3.17 mmol), potassium carbonate (1.594 g, 11.53 mmol) and sodium iodide (0.865 g, 5.7 mmol) were added and the solution refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between chloroform (20 mL) and water (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate) to yield 0.925 g (78%) of the required product as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH3:5])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:46][CH2:47][C:48]1[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=1[CH3:54]>ClCCl.O>[CH2:1]([O:3][CH:4]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:46][CH2:47][C:48]2[C:49]([OH:56])=[N:50][C:51]([CH3:55])=[CH:52][C:53]=2[CH3:54])=[O:12])=[CH:13][CH:14]=1)[CH3:5])[CH3:2]
Reactant: CCOC(C)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(C)c1ccc(C(=O)NCc2c(C)cc(C)nc2O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.7 %

Procedure:
To the solution of 4-(1-ethoxyethyl)benzoic acid (167 mg, 0.86 mmol) in dichloromethane (80 mL) was added o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (490 mg, 1.3 mmol) and triethylamine (260 mg, 2.6 mmol). then the 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (131 mg, 0.86 mmol) was added, the solution was stirred at room temperature for 12 hours, water was added and washed 3 times, the organic layer was evaporated and purified by column chromatography (silica gel, dichloromethane/meth anol=20:1) to give 4-(1-ethoxyethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (67 mg, 24%). LRMS (M+H+) m/z: calcd: 390.19. found 390. 1H-NMR (300 MHz, CD3OD) δ 7.73 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 5.96 (s, 1H), 4.58 (d, 2H), 4.43-4.41 (m, 1H), 3.35-3.31 (m, 1H), 2.39 (s, 3H), 2.28 (s, 3H), 1.42-1.40 (d, J=6.6 Hz, 3H), 1.176 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[N:15]=[C:14]([NH:16][C:28]([C:24]2[N:25]=[CH:26][O:27][C:23]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:29])[CH:13]=[N:12]1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CC1(CCCCn2ncc(N)n2)OCCO1
Product: CC(=O)CCCCn1ncc(NC(=O)c2ncoc2-c2ccccc2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[C:13]([CH:14]=[CH2:15])=[CH:12][C:9]([CH2:10][NH2:11])=[C:8]([O:16][CH3:17])[CH:7]=1)(=[O:4])=[O:3].Cl.FC(F)(F)C(O)=O.[C:26]([C:30]1[CH:35]=[CH:34][C:33]([CH:36]=[CH:37][C:38](O)=[O:39])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>C(Cl)Cl.C(N(CC)CC)C>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([CH:36]=[CH:37][C:38]([NH:11][CH2:10][C:9]2[CH:12]=[C:13]([CH:14]=[CH2:15])[C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][C:8]=2[O:16][CH3:17])=[O:39])=[CH:34][CH:35]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: C=Cc1cc(CN)c(OC)cc1NS(C)(=O)=O
Reactant: CC(C)(C)c1ccc(C=CC(=O)O)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1cc(CNC(=O)C=Cc2ccc(C(C)(C)C)cc2)c(OC)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 19 %

Procedure:
To a ice-cooled solution of 4-methanesulfonylamino-2-methoxy-5-vinyl-benzylamine and HCl salt (220 mg, 0.73 mmol) prepared in the synthesis of Example 48 in methylene chloride was treated with trifluoroacetic acid (100 mg, 0.88 mmol)) for 1 hr, and then concentrated under reduced pressure. The part of the crude residue (50 mg, 0.13 mmol) was suspended in methylene chloride and treated with triethylamine followed by 3-(4-tert-butyl-phenyl)-acrylic acid (30 mg) and DMTMM (40 mg). The resulting mixture was stirred for 2 days at ambient temperature and concentrated under reduced pressure. The crude residue was column-chromatographed (hexane/ethylacetate=3/2) to yield a white solid (11 mg, 19%).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:29])[CH2:6][CH2:7][CH2:8][N:9]([C:11]1[CH:16]=[C:15]([C:17]2[N:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][C:26]=3[Cl:27])[O:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[Cl:28])[CH3:10]>O.C1COCC1>[Cl:28][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[N:21]=[C:20]([C:22]3[S:23][CH:24]=[CH:25][C:26]=3[Cl:27])[O:19][N:18]=2)=[CH:16][C:11]=1[N:9]([CH3:10])[CH2:8][CH2:7][CH2:6][C:5]([OH:29])=[O:4]
Reactant: COC(=O)CCCN(C)c1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CCCC(=O)O)c1cc(-c2noc(-c3sccc3Cl)n2)ccc1Cl
Reaction time: 21 h
Yield: 84.1 %

Procedure:
A solution of LiOH (0.280 g, 6.66 mmol) in H2O (6.0 mL) was added over 1 minute to a solution of 4-({2-chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-methyl-amino)-butyric acid methyl ester (2.03 g, 4.76 mmol) in THF (55.0 mL) at 0° C. The ice bath was removed and the solution was allowed to equilibrate to room temperature at which point THF (20.0 mL) was added. The resulting suspension was stirred for 21 h and then EtOH (10 mL) was added and the solution was stirred for 10.5 h. The reaction solution was then diluted with 3M NaOH (1.05 mL) and EtOH (3.0 mL) and stirred for 30 min. The solution was diluted with dichloromethane (100 mL), washed with aqueous NaHCO3 (50 mL), and the solvent was removed by rotary evaporation. The residue was purified by flash column chromatography (silica gel, gradient elution using dichloromethane then EtOAc) to give 1.65 g (84%) of the title compound as a white solid. 1H NMR (CDCl3): 7.86 (d, 1H, J=1.9 Hz), 7.76 (dd, 1H, J=8.2 and 1.9 Hz), 7.60 (d, 1H, J=5.2 Hz), 7.49 (d, 1H, J=8.2 Hz), 7.14 (d, 1H, J=5.5 Hz), 3.16 (t, 2H, J=7.0 Hz), 2.85 (s, 3H), 2.48 (t, 3H, J=7.3 Hz), 2.02-1.92 (m, 2H).
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>C(O)C>[C:1]([N:6]1[CH2:11][CH2:10][N:9]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([Cl:12])=[CH:14][CH:15]=2)[CH2:8][CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1

Procedure:
A mixture of 1-carboethoxypiperazine (25 g; 0.157 mole), 4-chlorobenzyl chloride (26 g; 0.162 mole) and ethanol (250 ml) was gently refluxed for 5 hours and the solvent removed in vacuo. The resulting oil crystallised on cooling to give the hydrochloride of the title compound. Recrystallisation from ethanol gave 29 g (58%) of material of m.p. 208°-210°. (Found; C, 52.70; H, 6.41; N, 8.62; Cl, 21.51; C14H19ClN2O2HCl requires; C, 52.67; H, 6.31; N, 8.78; Cl, 22.20%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:19]#[CH:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].CI.[CH3:25]COC(C)=O>C1COCC1>[C:1]([N:8]([C@H:9]([C:19]#[CH:20])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:25])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: C#C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: C#C[C@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C

Procedure:
(R)-2-(N-Boc-N-methylamino)-1-(tert-butyldimethylsilyloxy)-but-3-yne was synthesized according to Method Y above by the treatment of (R)-N-Boc-2-amino-1-(-tert-butyldimethylsilyloxy)-but-3-yne (200 mg, 0.67 mmol) (Example 104B) with NaH (21 mg, 0.87 mmol) and MeI (189 mg, 1.34 mmol) in THF (12 mL). The product was obtained after silica gel column chromatography with a 0-10% EtOAc in hexanes gradient. (Yield 200 mg, 95%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][P:12]([CH2:21][C@H:22]([OH:32])[CH2:23][NH:24]C(OC(C)(C)C)=O)([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:13])[O:3]1.[ClH:33].O1CCOCC1>O1CCOCC1>[ClH:33].[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][P:12]([CH2:21][C@H:22]([OH:32])[CH2:23][NH2:24])([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:13])[O:3]1
Reactant: CC(C)(C)OC(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OC1OC(=O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: NC[C@@H](O)CP(=O)(CC1CCCCC1)OC1OC(=O)c2ccccc21
Yield: 100 %

Procedure:
To a solution of ((R)-3-tert-butoxycarbonylamino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid 3-oxo-1,3-dihydro-isobenzofuran-1-yl ester (140 mg, 0.3 mmol) in 2 mL dioxane was added a 4N HCl/dioxane solution (5.0 mL, 20 mmol). After 2 h the reaction mixture was concentrated in vacuo and the resulting residue taken up in ethyl acetate and was concentrated in vacuo to yield ((R)-3-amino-2-hydroxy-propyl)-cyclohexylmethyl-phosphinic acid 3-oxo-1,3-dihydro-isobenzofuran-1-yl ester hydrochloride (120 mg, 0.3 mmol). 1H NMR (CD3OD, 300 MHz): δ 7.92 (m, 1H), 7.73 (m, 2H), 7.15 (m, 1H), 4.40 (m, 1H), 3.4-3.22 (m, 1H), 3.20-3.04 (m, 1H), 2.01-1.8 (m, 6H), 1.75-1.60 (m, 4H), 1.50-1.0 (m, 7H). 31P NMR (CD3OD, 300 MHz): δ 61.4, 60.6. LC/MS m/z: [M+H]+=368
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]([CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[C:16]#[N:17].[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:13]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=2)[C:2]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:3]([C:16]#[N:17])[C:4]1=[O:15])[CH3:14]
Reactant: C1CCNC1
Reactant: CCn1c(=O)c(C#N)c(Cl)c2ccc(C)nc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCn1c(=O)c(C#N)c(N2CCCC2)c2ccc(C)nc21

Procedure:
A stirred mixture of 7.41 g. (0.03 mole) of 4-chloro-1-ethyl-1,2-dihydro-7-methyl-2-oxo-1,8-naphthyridine-3-carbonitrile, 2.13 g. (0.03 mole) of pyrrolidine and 3.18 g. (0.03 mole) of sodium carbonate in 100 ml. of ethanol was heated under reflux for 1 hour. The mixture was filtered and the filter cake was triturated with 200 ml. of water. The insoluble material was collected, air dried and was recrystallized from 2-ethoxyethanol to give 7.4 g. of the title product, m.p. 211°-213° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[N:14][C:15]2[N:16]([C:18]([C:21]3([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[CH2:23][CH2:22]3)=[CH:19][N:20]=2)[CH:17]=1)[C:5]([O:7]C)=[O:6].[OH-].[Li+]>C1COCC1.CO.O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[CH:13]=[N:14][C:15]2[N:16]([C:18]([C:21]3([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[CH2:23][CH2:22]3)=[CH:19][N:20]=2)[CH:17]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)c(F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of methyl 3-fluoro-4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoate (100 mg, 0.2 mmol) in 5 ml of THF-MeOH—H2O (3:1:1) was added 2M of lithium hydroxide in water (0.23 mL) at 0° C. under N2. The solution was stirred for 10 min at 0° C., and 1.5 h at RT. The reaction solution was concentrated to dryness to give the desired product which was directly used in next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:15]1[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=1)([CH2:11][CH2:12][CH2:13]I)[CH2:6][CH2:5]2.[CH3:29][NH2:30]>O1CCCC1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([C:15]1[C:23]3[C:18](=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=1)([CH2:11][CH2:12][CH2:13][NH:30][CH3:29])[CH2:6][CH2:5]2
Reactant: CN
Reactant: CS(=O)(=O)Nc1cccc2c(C3(CCCI)CCc4cc(F)ccc43)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNCCCC1(c2c[nH]c3c(NS(C)(=O)=O)cccc23)CCc2cc(F)ccc21
Yield: 49 %

Procedure:
Stir N-{3-[5-fluoro-1-(3-iodo-propyl)-indan-1-yl]-1H-indol-7-yl}-methane sulfonamide (88 mg, 0.17 mmol) and methylamine (40% in water, 2 ml) in tetrahydrofuran (1 ml) at room temperature under nitrogen for 30 minutes. Dilute with dichloromethane and 10% aqueous potassium carbonate. Filter the white solids that crush out and dry under high vacuum to obtain the title compound (35 mg, 49%). LC-MS m/z 416.1 (M++1).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].CC(OC([N:15]([C:23]1[NH:24][C:25]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][C:41]3[CH:46]=[C:45]([C:47]#[N:48])[CH:44]=[C:43]([Cl:49])[CH:42]=3)[C:34]=2[F:50])=[O:30])=[C:26]([Br:28])[N:27]=1)C(OC(C)(C)C)=O)=O)(C)C>ClCCl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:15][C:23]1[NH:24][C:25]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][C:41]3[CH:46]=[C:45]([C:47]#[N:48])[CH:44]=[C:43]([Cl:49])[CH:42]=3)[C:34]=2[F:50])=[O:30])=[C:26]([Br:28])[N:27]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(N)nc3Br)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
TFA (3.30 μl, 0.043 mmol) was added to a solution of bis(1,1-dimethylethyl)(4-bromo-5-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate (0.030 g, 0.043 mmol) in dichloromethane (2 mL). The mixture was stirred at RT overnight. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile:water with 0. % TFA) to give the title compound (11 mg, 41%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02-8.12 (m, 1H), 7.80 (s, 1H), 7.46-7.53 (m, 2H), 7.44 (s, 1H), 7.35 (t, 1H), 6.61 (br. s., 2H), 4.47 (s, 2H). ES MS m/z 499.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@H:4]([CH2:34][OH:35])[N:5]([O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C(OCC1C=CC=CC=1)=O>CO.[Pd]>[CH3:1][O:2][C:3](=[O:36])[C@H:4]([CH2:34][OH:35])[NH:5][O:16][Si:17]([C:30]([CH3:33])([CH3:31])[CH3:32])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)[C@H](CO)N(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CO)NO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Yield: 81 %

Procedure:
t-Butyldiphenylsilyloxy-N-benzyloxycarbonyl-L-serine methyl ester (32.0 g, 65.1 mmol) (obtained as described in Reference Example 39(1)) in methanol (960 ml) was subjected to catalytic hydrogenation in the presence of 10% palladium on charcoal at room temperature for 2 hours. At the end of this time, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using methylene chloride:methanol (95:5) as the eluant to afford t-butyldiphenylsilyloxy-L-serine methyl ester (19.7 g, yield 85%) as a colorless oil. To a solution of the product (t-butyldiphenylsilyloxy-L-serine methyl ester) (19.7 g, 55.0 mmol) in methylene chloride (590 ml) were added carbon disulfide (6.62 ml, 110 mmol) and triethylamine (19.3 ml, 138 mmol) at room temperature and the mixture was stirred overnight. To the resulting mixture were added ethyl chloroformate (13.2 ml, 138 mmol) and triethylamine (19.3 ml, 138 mmol) and the mixture was stirred for 1 hour. After checking the completion of the reaction, methanol was added to the reaction mixture and the resulting mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene as the eluant to afford (2S)-3-(t-butyldiphenylsilyloxy)-2-isothiocyanatopropionic acid methyl ester (14.8 g, yield 67%) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH3:25][CH:26]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:35])[C:29]=2[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:30]3[CH:31]=[CH:32][CH:33]=[C:34]4[C:29]=3[CH2:28][CH2:27][CH:26]4[CH3:25])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC1CCc2c(O)cccc21
Product: CC1CCc2c(Oc3nc(C(=O)NC(C)c4cc(F)c(NS(C)(=O)=O)c(F)c4)co3)cccc21
Yield: 62.6 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 1-methyl-indan-4-ol (39 mg, 0.26 mmol) to give the title compound (40 mg, 63%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH2:1]1[C:5]2=[C:6]3[C:7]([CH2:10][CH2:11]/[C:12]/3=[CH:13]\[CH2:14][NH2:15])=[N:8][CH:9]=[C:4]2[O:3][CH2:2]1.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>ClCCl.C(=O)([O-])O.[Na+]>[CH2:1]1[C:5]2=[C:6]3[C:7]([CH2:10][CH2:11]/[C:12]/3=[CH:13]\[CH2:14][NH:15][C:23](=[O:26])[CH2:24][CH3:25])=[N:8][CH:9]=[C:4]2[O:3][CH2:2]1
Reactant: NC/C=C1\CCc2ncc3c(c21)CCO3
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NC/C=C1\CCc2ncc3c(c21)CCO3
Reaction time: 0.17 h
Yield: 75.6 %

Procedure:
To a mixture of (2E)-2-(1,2,6,7-tetrahydro-8H-cyclopenta[b]furo[3,2-d]pyridin-8-ylidene)ethanamine (220 mg, 0.999 mmol) and triethylamine (167 μL, 1.20 mmol) in dichloromethane (10 mL) was added propionyl chloride (104 μL, 1.20 mmol) under ice-cooling, and the mixture was stirred for 10 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate=0/100→10/90) and recrystallization (chloroform/hexane) to give the title compound (195 mg, yield 75%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(Cl)=[O:14]>O1CCCC1.C1(C)C=CC=CC=1>[F:11][C:10]1[C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[C:8]([I:12])[CH:9]=1
Reactant: Nc1c(F)cc(I)cc1C(=O)O
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2c(F)cc(I)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg (1.78 mmol) of 2-amino-3-fluoro-5-iodo-benzoic acid in 5.0 mL tetrahydrofuran was added 1.4 mL (2.67 mmol) of 20% w/v solution of phosgene in toluene. The reaction was stirred for 16 hours at room temperature. The solution was concentrated to dryness to afford 550 mg (1.79 mmol, quantitative yield) of 8-fluoro-6-iodo-1H-benzo[d][1,3]oxazine-2,4-dione as a brown powder. 1H NMR (500 MHz, DMSO-d6) δ 12.05 (s, 1H), 8.09 (dd, 1H), 7.98 (s, 1H).