Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][C:9](=[C:12]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH2:16][CH2:15][C:14]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:13]2=3)[CH2:8][CH2:7]1)=O)C.CS(O)(=O)=O>>[CH:21]1[CH:20]=[N:19][C:18]2[C:12]([C:13]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:14]=3[CH2:15][CH2:16][C:17]=2[CH:22]=1)=[C:9]1[CH2:10][CH2:11][NH:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Agent: CS(=O)(=O)O
Product: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Temperature: 107.5 °C
Yield: 100.2 %

Procedure:
A mixture of 4-(8-chloro-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylic acid ethyl ester (loratadine) (50.0 g, 0.13 mol), and 90% v/v aqueous methanesulfonic acid (165 ml) was heated to 105-110° C. for 9 hrs. The reaction mass was cooled to ambient temperature, quenched into water (300 ml) and the resulting solution heated at 90-100° C. for 1 hour. The reaction mixture was cooled to ambient temperature and extracted once with toluene (100 ml). The pH of the aqueous layer was adjusted between 4.0 to 5.0 with liquor ammonia and charcoalized (2.5 g decolorizing charcoal). The pH of the charcoalized solution was adjusted to >9.5 with liquor ammonia, and the sticky semi-solid mass which separated was extracted into toluene (300 ml). The toluene extract was concentrated under reduced pressure at below 65° C. and degassed to obtain an off-white to white solid of desloratadine (yield 40.5 g, purity >99.0%). HPLC analysis of the sample (as per the procedure described in example 2) did not show any peak due to impurity at relative retention time of 0.85 to 0.99 (relative to desloratadine peak).
Reaction SMILES: ClC1C=CC(C2SC(C3C=CC=CC=3OC(F)F)NN=2)=CC=1.CCN(C(C)C)C(C)C.[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36]>>[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[CH:35]=[O:36]
Reactant: O=C(Cl)c1ccccc1F
Agent: FC(F)Oc1ccccc1C1NN=C(c2ccc(Cl)cc2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=Cc1ccccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To the solution of 5-(4-chloro-phenyl)-2-(2-difluoromethoxy-phenyl)-2,3-dihydro-[1,3,4]thiadiazole is added DIEA (0.16 mmol) and 2-fluorobenzoyl chloride (0.16 mmol) and the reaction mixture is stirred for 12 hours at room temperature. After evaporation of the solvent, the residue is purified by automated chromatography (hexane/EtOAc) to give 5-(4-chloro-phenyl)-2-(2-difluoromethoxy-phenyl)-[1,3,4]thiadiazol-3-yl]-(2-fluoro-phenyl)-methanone: 1H NMR (400 MHz, CDCl3) δ 7.39-7.35 (m, 1H), 7.34-7.29 (m, 4H), 7.25 (dd, J1=7.8 Hz, J2=1.2 Hz, 1H), 7.19-7.13 (m, 3H), 7.04 (m, 1H), 6.97 (m, 2H), 6.50 (dd, J1=71.6 Hz, J2=71.2 Hz, 1H). LC/MS: (ES+) 462.8 (M+1)+.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][C:29](=O)[CH2:28][CH2:27]2>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:29]2[CH2:28][CH2:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([Cl:23])[CH:25]=3)[CH2:30]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Reactant: O=C1CCc2cc(Cl)ccc2C1
Product: CCCC(NC1CCc2cc(Cl)ccc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6-chloro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.6, 19.6, 24.3, 26.6, 27.9, 28.0, 29.2, 30.0, 36.0, 36.5, 36.6, 36.9, 53.1, 53.3, 56.0, 59.1, 60.5, 60.8, 67.3, 104.7, 126.1, 128.5, 128.7, 130.7, 130.8, 131.2, 131.5, 131.6, 133.6, 137.3, 137.7, 138.0, 172.4; MS m/z 472.4 (M+1).
Reaction SMILES: [C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:13][CH:12]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([O:41]CC)=[O:40])[CH:34]=3)=[O:31])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:28])[CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:13][CH:12]([NH:29][C:30](=[O:31])[NH:32][C:33]3[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=3)[C:39]([OH:41])=[O:40])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)CC(C)(C)C)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)CC(C)(C)C
Yield: 76.8 %

Procedure:
1-[1-(2-toluoylmethyl)-2-oxo-5-(3,3-dimethylbutanoyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (442 mg) was dissolved in methanol (20 ml), aqueous lithium hydroxide monohydrate (151 mg) solution (10 ml) and tetrahydrofuran (10 ml) were added, and the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, extracted with methylene chloride. The solvent was evaporated under reduced pressure, diisopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 324 mg of the titled compound as colorless powder (Yield: 77.1%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](=[O:26])=[N:21]S(Cl)(=O)=O.C(#N)C.ClS(NC=O)(=O)=O>CS(C)=O>[C:1]1([CH2:7][C:8]([CH:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[N:12]([C:20]([NH2:21])=[O:26])[C:11]2=[O:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)C1C(=O)Nc2cnccc21
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=CNS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: CC#N
Product: NC(=O)N1C(=O)C(C(=O)Cc2ccccc2)c2ccncc21

Procedure:
The title compound was prepared from 3-phenylacetyl-6-azaoxindole according to the procedure of Example 2C, using 3-phenylacetyl-6-azaoxindole (1.0 g, 3.9 mmol), N-chlorosulfonyl isocyanate (0.41 mL, 4.7 mmol) and acetonitrile (40 mL). Reaction time: 4 hours. The crude N-chlorosulfonyl carboxamide was hydrolysed by stirring in DMSO (6 mL) for 1 hour in a flask open to the air. After dilution with water, the product was collected by filtration, dried, and recrystallized from acetic acid. Yield: 172 mg (15%). M.p. 131°-133° C. (dec.).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[O:7][C:8]2[C:14]([Cl:15])=[CH:13][C:12]([Br:16])=[CH:11][C:9]=2[CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[Br:16][C:12]1[CH:13]=[C:14]([Cl:15])[C:8]2[O:7][C:6]([CH2:5][CH2:4][NH2:1])=[CH:10][C:9]=2[CH:11]=1
Reactant: [N-]=[N+]=NCCc1cc2cc(Br)cc(Cl)c2o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCCc1cc2cc(Br)cc(Cl)c2o1
Temperature: 65 °C
Yield: 85.1 %

Procedure:
To a solution of the product of step D (500 mg, 1.66 mmol) in THF (8 mL) was added triphenylphosphine (72 mg, 3.32 mmol) followed by water (3 mL). The reaction mixture was heated to 65° C. for 4 h and concentrated in vacuo. Purification by column chromatography (SiO2, 95:5 dichloromethane/methanol) provided 2-(5-bromo-7-chlorobenzofuran-2-yl)ethanamine (388 mg, 85%) as a colorless liquid: 1H NMR (CDCl3, 400 MHz) δ 7.51 (t, J=2.4 Hz, 1H), 7.36 (t, J=2.4 Hz, 1H), 6.45 (s, 1H), 3.12 (t, J=8.4 Hz, 2H), 2.94 (t, J=8.8 Hz, 2H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:17][O:18][CH2:19][CH2:20]Br)[C:14]([OH:16])=[O:15])[N:12]=1)=[O:6].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[CH:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:17][O:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])[C:14]([OH:16])=[O:15])[N:12]=1)=[O:6]
Reactant: O=CNc1nc(C(=NOCCBr)C(=O)O)cs1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 35.7 %

Procedure:
Sodium azide (14.87 g.) was added to a solution of 2-(2-formamidothiazol-4-yl)-2-(2- bromoethoxyimino)acetic acid (syn isomer, 15.7 g.) in N,N-dimethylformamide (100 ml.) and water (75 ml.), and stirred at room temperature for 2 days. To the resultant solution was added water (25 ml.) and adjusted to pH 8.0 with a saturated aqueous solution of sodium bicarbonate. The solution was washed with ethyl acetate (250 ml.). The solution was adjusted to pH 2.5 and extracted with ethyl acetate (350 ml.). The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was recrystalized from a solution of acetone and methylene chloride (3:1) repeatedly. The precipitates were collected by filtration to give 2-(2-formamidothiazol-4-yl)-2-(2-azidoethoxyimino)acetic acid (syn isomer, 4.95 g.).
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[CH:1]1([CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[CH:14][CH:13]=2)[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C(CC1CCCCC1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: OCC(CC1CCCCC1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-cyclohexyl-2-(4-(2-quinolylmethoxy)phenyl)propionic acid, prepared according to the procedure of K. Mohrs et al. U.S. Pat. No. 4,970,215, (1.37 g, 3.5 mmol) in THF (40 mL) at -10° C. was added triethylamine (0.5 mL, 3.6 mmol) and then dropwise a solution of ethyl chloroformate (0.36 mL, 3.6 mmol) in THF (10 mL). The reaction was stirred for 15 minutes at -10° to -5° C. and then was allowed to warm to 0° C. To the mixture was added sodium borohydride (380 mg, 10 mmol) followed by the dropwise addition of methanol (30 mL) for 30 minutes at 0° C. The resulting mixture was stirred for an additional 20 minutes and then was neutralized with 10% citric acid and extracted with ethyl acetate (100 mL). The ethyl acetate extract was washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 2:1 hexane-ethyl acetate to provide 1.14 g of 3-cyclohexyl-2-(4-(2-quinolylmethoxy)phenyl)propan-1-ol as an oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13](=O)[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Product: CCCCc1ccc(-c2cc3ccccc3c(Cl)n2)cc1

Procedure:
The resulting 3-[4-(n-butyl)phenyl]isoquinolin-1-one (2.44 g) was reacted with phosphorus oxychloride (20 ml) according to the method of Example 10-2, to give 1-chloro-3-[4-(n-butyl)phenyl]isoquinoline. The resulting compound was reacted, as it was, with N-ethylpiperazine (11 ml) at 100° C. overnight. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The resulting ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 1.78 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C([O:40][C:41](=[O:62])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([C:51]2[CH:52]=[CH:53][C:54]([F:61])=[C:55]3[C:60]=2[CH2:59][NH:58][CH2:57][CH2:56]3)[CH:44]=1)C.C(N(CC)CC)C>C(Cl)Cl>[F:61][C:54]1[CH:53]=[CH:52][C:51]([C:45]2[CH:44]=[C:43]([CH2:42][C:41]([OH:62])=[O:40])[CH:48]=[CH:47][C:46]=2[O:49][CH3:50])=[C:60]2[C:55]=1[CH2:56][CH2:57][N:58]([C:10](=[O:12])[CH2:9][C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)([CH3:14])[CH3:13])[CH2:59]2
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(F)c3c2CNCC3)c1
Reactant: CC(C)(CC(=O)O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CC(=O)O)cc1-c1ccc(F)c2c1CN(C(=O)CC(C)(C)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of 3-(4-fluoro-phenyl)-3-methyl-butyric acid (20 mg, 0.1 mmol, 1.0 eq.) in DCM (1 mL), 1-hydroxybenzotriazole hydrate (HOBt) (14 mg, 0.1 mmol, 1.0 eq.) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.1 mmol, 1.0 eq.) were added in sequence. The resulting solution was stirred at r.t. for 2 minutes. Then a solution of [3-(5-fluoro-1,2,3,4-tetrahydro-isoquinolin-8-yl)-4-methoxy-phenyl]-acetic acid ethyl ester (34 mg, 0.1 mmol, 1.0 eq.) and triethylamine (42 μL, 0.3 mmol, 3.0 eq.) in DCM (1 mL) was added and the resulting mixture was stirred at r.t. for 18 hours. The mixture was concentrated in vacuo. The residue was dissolved in DMF (0.8 mL). 1M aq. NaOH (1 mL) was added. The mixture was stirred at r.t. for 3 hours. The solution was carefully neutralized with formic acid (0.5 mL), and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:11][CH2:12][N:13]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:20]=[CH:21][C:22]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][NH2:29])=[CH:23][C:15]=2[C:14]1=[O:30])([OH:10])=[O:9].[C:31](S(O)(=O)=O)([NH2:33])=[NH:32]>C(O)(=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([CH2:11][CH2:12][N:13]1[CH2:19][CH2:18][CH2:17][C:16]2[CH:20]=[CH:21][C:22]([C:24]#[C:25][CH2:26][CH2:27][CH2:28][NH:29][C:31]([NH2:33])=[NH:32])=[CH:23][C:15]=2[C:14]1=[O:30])([OH:10])=[O:9]
Reactant: N=C(N)S(=O)(=O)O
Reactant: NCCCC#Cc1ccc2c(c1)C(=O)N(CCC(=O)O)CCC2
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: N=C(N)NCCCC#Cc1ccc2c(c1)C(=O)N(CCC(=O)O)CCC2
Reaction time: 2 h
Yield: 15.2 %

Procedure:
A solution of 2-(2-carboxyethyl)-8-(5-aminopentynyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one trifluoroacetate (20 mg, 0.063 mmol) in saturated aqueous KHCO3 (1 mL) was treated with formamidine sulfonic acid (80 mg, 1.0 mmol), and the resulting mixture stirred for 2 hours. The mixture was then treated with acetic acid, and the volatiles were removed. The residue was purified by HPLC (1/2' C-18 reverse-phase column) eluting with a gradient of 3:7 methanol (0.1% trifluoroacetate)/water (0.1% trifluoroaceate), time 0 to 10 min, to 7:3 methanol(0.1% trifluoroaceate)/water(0.1% trifluoroaceate), time 10 to 40 min, to yield 4.5 mg (15%) of 2-(2-carboxyethyl)-8-(5-guanidinopentynyl)-2,3,4,5-tetrahydro-1H-2-benzazepin-1-one trifluoroacetate as a light brown solid; 1H NMR(D2O) d7.40(s, 1H), 7.25(dd, J=3, 6 Hz, 1H), 7.15(d, J=6 Hz, 1H), 3.80(t, J=6 Hz, 2H), 3.30(m, 4H), 3.15(t, J=6 Hz, 2H), 2.00(t, J=6 Hz, 2H), 1.80(m, 2H); MS(FAB) m/z=357.1(MH+).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:12][C:13](O)=[O:14])=[CH:4][C:3]=1[C:16]([CH3:19])([CH3:18])[CH3:17].[OH:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23].C(N1C=CN=C1)(N1C=CN=C1)=O>>[OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:12][C:13]([NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[OH:20])=[O:14])=[CH:4][C:3]=1[C:16]([CH3:17])([CH3:19])[CH3:18]
Reactant: Nc1ccccc1O
Reactant: CC(C)(C)c1cc(CC(=O)O)cc(C(C)(C)C)c1O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)(C)c1cc(CC(=O)Nc2ccccc2O)cc(C(C)(C)C)c1O
Yield: 86.2 %

Procedure:
Using previously described procedures with 4-hydroxy-3,5-di-t-butyl-phenylacetic acid (45 g, 0.17 mol), 2-hydroxyaniline (20.7 g, 0.19 mol) and 1,1′-carbonyl diimidazole (29 g, 0.18 mol) the title compound (52.1 g, 86%) was obtained as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33](O)=[O:34])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.COC1C=CC(CN(CC2C=CC(OC)=CC=2)C2N=CC(C3C4CCN(C5C=CC(C(O)=O)=CC=5)C=4N=C(N4CCOCC4)N=3)=CN=2)=CC=1.[CH3:99][N:100]([CH3:104])[CH2:101][CH2:102][NH2:103]>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=5)[C:33]([NH:103][CH2:102][CH2:101][N:100]([CH3:104])[CH3:99])=[O:34])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:41][CH:42]=1
Reactant: CN(C)CCN
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)O)c3)cn2)cc1
Agent: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(C(=O)NCCN(C)C)c3)cn2)cc1
Yield: 68.6 %

Procedure:
Using 3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (38.2 mg, 0.0579 mmol) obtained in Step A in Example 1-D-53 instead of 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid, and N,N-dimethyl ethylenediamine (15.1 μl, 0.116 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of 3-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-N-(2-dimethylamino-ethyl)-benzamide as a yellow liquid (29 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-55) as a yellow powder (17.2 mg, 61%).
Reaction SMILES: [OH:1][N:2]([CH:5]([C:26]1[CH:31]=[CH:30][C:29]([O:32]COC)=[CH:28][CH:27]=1)[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH:3]=[O:4].O>ClCCl>[OH:1][N:2]([CH:5]([C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1)[CH2:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)(=[O:9])=[O:8])[CH:3]=[O:4]
Reactant: COCOc1ccc(C(CS(=O)(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)N(O)C=O)cc1
Solvent: ClCCl
Solvent: O
Product: O=CN(O)C(CS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
A suspension of Example 129 (186 mg, 0.366 mmol) in dichloromethane (20 mL) at −78° C. was treated with boranetrifluoride diethyl etherate (55.6 mL, 0.439 mmol), stirred at 0° C. for 3 hours and left at room temperature overnight, treated with water, extracted with ethyl acetate, dried (Na2SO4), filtered, concentrated and purified on silica gel with 80% ethyl acetate/hexanes to provide 45 mg (26%) of the title compound as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=1.C(N(CC)C(C)C)(C)C.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=1)[S:39]([C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)(=[O:41])=[O:40]
Reactant: CCCCc1ccc(CNCCCCCCC(=O)OC)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCc1ccc(CN(CCCCCCC(=O)OC)S(=O)(=O)c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 7-(4-butyl-benzylamino)-heptanoic acid methyl ester prepared of Example 1, Step A (0.10 g, 0.33 mmol), N,N-diisopropylethylamine (0.85 g 0.66 mmol) and pyridine-3-sulfonyl chloride hydrochloride, prepared of Preparation 2, (0.070 g, 0.33 mmol) in 3 mL CH2Cl2 was stirred at room temperature overnight. The mixture was diluted with CH2Cl2 and the organic solution was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (10% EtOAc/hexanes to 30% EtOAc/hexanes) to afford the title compound of Step B. 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 8.75 (d, 1H), 8.04 (d, 1H), 7.41 (dd, 1H), 7.23 (m, 4H), 4.30 (s, 2H), 3.62 (s, 3H), 3.08 (t, 2H), 2.55 (t, 2H), 2.19 (t, 2H), 1.10-1.58 (m, 12H), 0.87 (t, 3H); MS 447 (M+1).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([O:26][C@@H:27]1[C@@:31]2([CH2:51][O:52][C@H:28]1[C@H:29]([N:53]1[C:69]3[N:68]=[CH:67][N:66]=[C:57]([NH:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[C:56]=3[N:55]=[CH:54]1)[O:30]2)[CH2:32][O:33][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O:70]1CCCC1>>[CH2:19]([O:26][C@@H:27]1[C@@:31]2([CH2:51][O:52][C@H:28]1[C@H:29]([N:53]1[C:69]3[N:68]=[CH:67][N:66]=[C:57]([NH:58][C:59](=[O:70])[C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)[C:56]=3[N:55]=[CH:54]1)[O:30]2)[CH2:32][OH:33])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](OC[C@@]12CO[C@@H]([C@H](n3cnc4c(NCc5ccccc5)ncnc43)O1)[C@@H]2OCc1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C1CCOC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Tetrabutylammonium fluoride (1.0 M in THF, 1.0 ml, 1.0 mmol) was added, at room temperature, to a tetrahydrofuran solution (7.0 ml) of Compound 42 (173.6 mg, 0.244 mmol), and the mixture was stirred for 25 minutes at room temperature. The reaction mixture was distilled under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (CHCl3-MeOH, 15:1) to obtain a white powder, Compound 43 (115.4 mg, 0.244 mmol, quant.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][CH2:16][CH2:15][C:8]3([S:12][C:11](=N)[NH:10][C:9]3=[O:14])[C:6]=2[CH:7]=1.Cl.C[OH:20]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][CH2:16][CH2:15][C:8]3([S:12][C:11](=[O:20])[NH:10][C:9]3=[O:14])[C:6]=2[CH:7]=1
Reactant: CO
Reactant: N=C1NC(=O)C2(CCOc3ccc(F)cc32)S1
Agent: Cl
Product: O=C1NC(=O)C2(CCOc3ccc(F)cc32)S1

Procedure:
2.195 g of (±)-6-fluoro-2,3-dihydro-2'-iminospiro-[4H-1-benzopyran-4,5'-thiazolidin]-4'-one were dissolved in 12 ml of methanol and 12 ml of 37% aqueous hydrochloric acid and the solution was boiled overnight. The colorless crystals which separated were removed and washed with water. After drying in vacuo, there was obtained (±)-6-fluoro-2,3-dihydrospiro[4H-1-benzopyran-4,5'-thiazolidine]-2',4'-dione of melting point 147°-149° C. (95% of theory).