Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:15]1[CH2:25][CH2:24][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:16]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:1]1([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([N:15]2[CH2:25][CH2:24][CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:16]2)=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)c2ncoc2-c2ccccc2)CC1
Temperature: 25 °C

Procedure:
5-Phenyl-1,3-oxazole-4-carboxylic acid (40 mg, 0.211 mmol), ethyl isonipecotate (36.2 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.0 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C18H20N2O4: 328.1423, found 328.1430.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[C:16]([O:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH:15]=[CH:14][C:13]=1[CH3:29].C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][O:18][C:16]2[CH:15]=[CH:14][C:13]([CH3:29])=[C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:17]=2)=[CH:22][CH:23]=1)#[N:28]
Reactant: Cc1ccc(OCCc2ccc(C#N)cc2)cc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cc1ccc(OCCc2ccc(C#N)cc2)cc1NS(=O)(=O)c1ccccc1
Reaction time: 8 h
Yield: 98.7 %

Procedure:
Benzenesulfonyl chloride (22 μL; 0.17 mmol) was added to a cold solution (ice :water temperature) of amino-5-[2-(4-cyanophenyl)ethoxy]-2-methyl-benzene (0.041 g; 0.16 mmol; from step (ii) above) in pyridine (4 mL) The reaction flask was left overnight in a refrigerator. NaHCO3/aq (sat.) was added and the solution extracted twice with EtOAc. The combined organic phases were washed with water, HCl/aq (2M) and water. Drying (MgSO4) and evaporation of the solvent in vacuo afforded 0.062 g (100%) of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].I([Cl:19])(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>C1COCC1>[Cl:19][CH2:14][C:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[N:10][C:9]([Cl:12])=[CH:8][CH:7]=2)=[O:15]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: O=I(=O)Cl
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(CCl)c1cnc2ccc(Cl)nc2c1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 33.3 %

Procedure:
To a solution of 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (3.0 g, 12 mmol) in THF (120 mL) was added benzyltrimethylammonium dichloroiodate (4.3 g, 12 mmol) and the reaction mixture was stirred at 70° C. for 5 h. The reaction mixture was cooled, diluted with satd. aq. sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/ethyl acetate) to afford the desired product (1.1 g, 32%) as an off-white solid. ESI MS m/z 275 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]2=[CH:15][S:16][CH:17]=[C:6]2[C:5]1=O)[CH:2]=[CH2:3].O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>CCCCCC.O>[CH2:1]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]2=[CH:15][S:16][CH:17]=[C:6]2[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C(=O)c2cscc2Nc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: C=CCN1Cc2cscc2Nc2ccccc21

Procedure:
A solution of 4.6 g. of 9-allyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one in 100 ml. of dried tetrahydrofuran is added dropwise with stirring, under nitrogen, to a suspension of 2.9 g. of lithium aluminum hydride in 100 ml. of dried tetrahydrofuran. The reaction mixture is heated under reflux with stirring overnight, then cooled in an ice bath and treated, with stirring under nitrogen, with 3 ml. of water, 3 ml. of 15% sodium hydroxide and finally with 9 ml. of water. The complex is filtered and washed several times with ether. The combined filtrate and washings are dried over sodium sulfate, filtered and the filtrate is concentrated to a dark blue oil. This oil is dissolved in 20 ml. of 30% methylene chloride in hexane and chromatographed on an alumina column as described in the previous example. Concentration of the solvent mixture yields a dark green oil which is heated to boiling in 80 ml. of hexane. The boiling hexane is decanted from a dark brown insoluble oil and then cooled giving crystals of the desired product, mp. 67°-69° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)=[N:16][C:12]=2[CH:11]=1.[H][H]>CO.C(OCC)(=O)C.[C].[Pd]>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[C:15]([CH:17]3[CH2:21][CH2:20][CH2:19][O:18]3)=[N:16][C:12]=2[CH:11]=1
Reactant: [H][H]
Reactant: c1coc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc2oc(-c3ccc4c(c3)nc(C3CCCO3)n4C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 34.5 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(furan-2-yl)-1-(tetrahydropyran-4-yl)benzimidazole (see Working Example 63) (90 mg, 0.234 mmol) in methanol/ethyl acetate (1:1, 6 mL) was added 10% palladium-carbon (20 mg), a hydrogen atmosphere was substituted in the flask, and this was stirred at room temperature for 20 hours. After the reaction was complete, this was filtered through Celite and the filtrate was concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (31.4 mg, 34% yield) as a colorless amorphous mass.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:27])[CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([CH3:24])[N:21]=[C:20]([Cl:25])[CH:19]=3)[O:15][N:14]=2)=[CH:8][C:7]=1[CH3:26].[C:28](O)(=[O:31])[CH2:29][OH:30].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl.CC(=O)OCC>[Cl:25][C:20]1[CH:19]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:9]3[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][CH:3]([OH:27])[CH2:2][NH:1][C:29](=[O:30])[CH2:28][OH:31])=[C:7]([CH3:26])[CH:8]=3)[N:17]=2)[CH:23]=[C:22]([CH3:24])[N:21]=1
Reactant: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CN)c(C)c3)no2)cc(Cl)n1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(-c2nc(-c3cc(C)c(OCC(O)CNC(=O)CO)c(C)c3)no2)cc(Cl)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.9 %

Procedure:
To a solution of (RS)-1-amino-3-{4-[5-(2-chloro-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propan-2-ol (134 mg, 0.345 mmol) in DCM (10 mL), glycolic acid (54 mg, 0.707 mmol) and DIPEA (132 mg, 1.02 mmol) is added. The mixture is cooled to 0° C. and TBTU (134 mg, 0.416 mmol) is added. The mixture is stirred at 0° C. for 1 h, then at rt for 16 h before it is diluted with EA (250 mL), washed with 1 N aq. NaOH solution (3×25 mL), 1 N aq. KHSO4 (25 mL) and brine (25 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by prep. HPLC to give N-((RS)-3-{4-[5-(2-chloro-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide (23 mg) as a colourless resin; LC-MS: tR=0.91 min, [M+1]+=447.44.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1.[K+].[Br-]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:33]3[CH2:32][CH2:31][N:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH3:22])[CH:25]=4)[CH2:35][CH2:34]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: COc1cccc(N2CCNCC2)c1
Agent: [Br-]
Agent: [K+]
Product: COc1cccc(N2CCN(C(=O)Oc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)CC2)c1
Yield: 96 %

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3-methoxy-phenyl)-piperazine, yield 96%. White solid, m.p. 109-111° C.; IR (KBr): ν 1721 (C═O) cm−1.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH:8][CH2:9][C@H:10]1[CH2:15][CH:14]=[CH:13][CH2:12][C@H:11]1[OH:16]>N1C=CC=CC=1.CO.CCOCC>[C:1]([O:8][CH2:9][CH:10]1[CH2:15][CH:14]=[CH:13][CH2:12][CH:11]1[OH:16])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OC[C@H]1CC=CC[C@H]1O
Solvent: CO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)OCC1CC=CCC1O
Reaction time: 20 h
Yield: 92.9 %

Procedure:
Pivaloyl chloride (1.036 g, 1.1 equivalents) was added at -20° C. to a solution of 2-hydroxymethyl-cyclohex-4-eneol (7, 1.00 g, 7.81 mmol) in pyridine (10 ml). The reaction mixture was kept at -20° C. for 20 hours, diluted with methanol and ether (50 ml), and the organic layer extracted with 20 ml portions of 10% HCl containing copper sulfate until the blue color in the organic layer had disappeared. The ethereal layer was dried (magnesium sulfate), the solvent removed under vacuum, and the residue chromatographed on silica gel (hexane:EtOAc 7:3, Rf=0.43) to yield 2-pivaloyloxymethyl-cyclohex-4-eneol (8, 1.54 g, 93%) as a colorless oil. (IR, CCl4 1730 cm-1). 3,4-trans 1-Methoxy-3-pivaloyloxymethyl-4-(2'-hydroxyethyl)-tetrahydrofuran 9 and 1-Methoxy-3-pivaloyloxymethyl-4-(2',2'-dimethoxyethyl)-tetrahydrofuran.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15](=[O:35])[C@H:16]([CH2:25][C:26]1[CH:31]=[C:30]([I:32])[C:29]([OH:33])=[C:28]([I:34])[CH:27]=1)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[Br:36][CH2:37][CH2:38][CH2:39]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:13][O:14][C:15](=[O:35])[C@H:16]([CH2:25][C:26]1[CH:31]=[C:30]([I:32])[C:29]([O:33][CH2:39][CH2:38][CH2:37][Br:36])=[C:28]([I:34])[CH:27]=1)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19]
Reactant: OCCCBr
Reactant: COC(=O)[C@H](Cc1cc(I)c(O)c(I)c1)NC(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1cc(I)c(OCCCBr)c(I)c1)NC(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
Diethylazodicarboxylate (197 μ1, 1.25 mmol) was added dropwise to a solution of N-t-butoxycarbonyl-3,5-diiodo-L-tyrosine methyl ester (274 mg, 0.5 mmol), 3-bromo-1-propanol (76 mg, 0.55 mmol) and triphenylphosphine (328 mg, 1.25 mmol) in tetrahydrofuran (5 ml) under argon atmosphere at −15° C. and the mixture was stirred at the same temperature for 0.5 hrs., at 0-5° C. for 0.5 hrs., and then at room temperature for 23 hrs. The solvent of the reaction mixture was distilled off at room temperature under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=9) to give O-(3-bromopropyl)-N-t-butoxycarbonyl-3,5-diiodo-L-tyrosine methyl ester (145 mg, 43%) as colorless crystals.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[NH:9][C:10]=1[CH2:11][CH2:12][C:13]12[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2)=[O:5])C.[CH3:29][O:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38])=[O:32]>>[CH3:29][O:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[C:37]([NH:38][C:4]([C:6]2[N:7]=[C:8]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[NH:9][C:10]=2[CH2:11][CH2:12][C:13]23[CH2:14][CH:15]4[CH2:21][CH:19]([CH2:18][CH:17]([CH2:16]4)[CH2:22]2)[CH2:20]3)=[O:5])[CH:39]=[CH:40][CH:41]=1)=[O:32]
Reactant: CCOC(=O)c1nc(-c2ccccc2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)OCc1cccc(N)c1
Product: COC(=O)OCc1cccc(NC(=O)c2nc(-c3ccccc3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-phenyl-1H-imidazole4-carboxylic acid ethyl ester (Example 46) was hydrolized according to the procedure of Example 20, step c. The acid was reacted with 3-methoxycarbonyloxymethyl-aniline using the procedure of Example 20, step d to produce 5-(2-adamantan-1-yl-ethyl)-2-phenyl-1H-imidazole-4-carboxylic acid (3-methoxycarbonyloxymethyl-phenyl)-amide, which was deprotected according to the procedure of Example 22, step b to afford the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) 12.69 (1H, br s), 9.56 (1H, s), 8.08 (2H, d), 7.80 (1H, s), 7.65 (1H, d), 7.48 (2H, t), 7.39 (1H, t), 7.26 (1H, t), 7.00 (1H, d), 5.16 (1H, m), 4.49 (2H, d), 2.99 (2H, m), 1.96 (3H, br s), 1.67-1.55 (12H, m), 1.43 (2H, m). Found: C, 76.26; H, 7.38; N, 9.09%; C29H33N3O2 requires: C, 76.45; H, 7.30; N, 9.22%.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[N:4]1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C>[C:24]([O:23][C:21](=[O:22])[CH2:20][N:3]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[N:4]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc(N2C(=O)c3ccccc3C2=O)n1
Reaction time: 18 h

Procedure:
Sodium hydride (60% in oil, 0.538 g, 13.4 mmol) is added to a stirred solution of 2-(1H-pyrazol-3-yl)-isoindole-1,3-dione (2.39 g, 11.2 mmol) in dry DMF (25 ml) at room temperature. After 10 minutes tert-butyl bromoacetate (1.81 ml, 11.2 mmol) is added and the reaction is stirred for 18 hours. The reaction is quenched with water (1 ml), ethyl acetate (150 ml) is added and the organic phase is washed with water (3×100 ml) followed by brine (1×100 ml). The solvent is removed and the product is purified by chromatography on silica (gradient elution: ethyl acetate—hexane) to give the titled compound.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH2:10]([N:12]1[C:16]([O:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=2)=[CH:15][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([NH:36][S:37]([CH2:40][C:41]([F:44])([F:43])[F:42])(=[O:39])=[O:38])([CH3:35])[CH3:34])[CH:28]=2)=[N:13]1)[CH3:11].[C:45]([NH:48][NH2:49])(=[O:47])[CH3:46]>CN(C=O)C>[C:45]([NH:48][NH:49][C:22]([C:21]1[CH:25]=[CH:26][C:18]([O:17][C:16]2[N:12]([CH2:10][CH3:11])[N:13]=[C:14]([C:27]3[CH:28]=[C:29]([C:33]([NH:36][S:37]([CH2:40][C:41]([F:42])([F:44])[F:43])(=[O:39])=[O:38])([CH3:34])[CH3:35])[CH:30]=[CH:31][CH:32]=3)[CH:15]=2)=[CH:19][CH:20]=1)=[O:24])(=[O:47])[CH3:46]
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(=O)O)cc1
Reactant: CC(=O)NN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(=O)NNC(C)=O)cc1
Temperature: 22 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
(1-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (161 mg, 0.36 mmol, 1.2 equiv) and diisopropylethylamine (117 mg, 0.91 mmol, 3 equiv) were added to a stirring solution of 4-({1-ethyl-3-[3-(2-{[(2,2,2-trifluoroethyl)sulfonyl]amino}propan-2-yl)phenyl]-1H-pyrazol-5-yl}oxy)benzoic acid (155 mg, 0.30 mmol, 1 equiv) in DMF (3 mL). Acetohydrazide (45 mg, 0.61 mmol, 2 equiv) was then added and the mixture was stirred at 22° C. for 16 hours. The mixture was purified directly by reversed phase HPLC (0-95% acetonitrile:water with 0.025% TFA). Pure fractions were identified, combined, and lyophilized to give N-{2-[3-(5-{4-[(2-acetylhydrazinyl)carbonyl]phenoxy}-1-ethyl-1H-pyrazol-3-yl)phenyl]propan-2-yl}-2,2,2-trifluoroethanesulfonamide (35% yield). This material was stirred in THF (1 mL) at 22° C. and 3,3,3-triethyl-1-(methoxycarbonyl)diazathian-3-ium-1-ide 2,2-dioxide (38 mg, 0.16 mmol, 1.5 equiv) was added. The resulting mixture was stirred at 22° C. for 16 hours then purified directly by reversed phase HPLC (0-95% acetonitrile:water with 0.025% TFA). Pure fractions were identified, combined, and lyophilized to give the title compound (21% yield). Calc'd (M+1)+: 550.2. Found: 550.1.
Reaction SMILES: [Cl:1][CH2:2][Si:3]([Cl:6])(Cl)[Cl:4].[F:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1>C1COCC1>[Cl:1][CH2:2][Si:3]([Cl:6])([Cl:4])[C:11]1[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: ClC[Si](Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Fc1ccc([Si](Cl)(Cl)CCl)cc1

Procedure:
In the same apparatus as Example 1, was added 5.6 g of chloromethyltrichlorosilane (0.03 mol) and 50 ml of THF. Through the dropping funnel was firstly added 22 ml of 4-fluorophenylmagnesiumbromide (2.0 M in diethylether) to give chloromethyldichloro(4-fluorophenyl)silane.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18]([OH:20])=O)[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[Cl:44][C:45]1[CH:46]=[C:47]([C@H:53]([NH2:56])[CH2:54][CH3:55])[CH:48]=[N:49][C:50]=1[O:51][CH3:52].C(N(CC)CC)C>CN(C)C=O>[Cl:44][C:45]1[CH:46]=[C:47]([C@H:53]([NH:56][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:20])[CH2:54][CH3:55])[CH:48]=[N:49][C:50]=1[O:51][CH3:52]
Reactant: CC[C@@H](N)c1cnc(OC)c(Cl)c1
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1cnc(OC)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (75 mg, 0.270 mmol) in dimethylformamide (2 ml) was added 1-hydroxybenzotriazole (41 mg, 0.30 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (58 mg, 0.30 mmol). The mixture was stirred for 2 h at 50° C., then (R)-1-(5-chloro-6-methoxy-pyridin-3-yl)-propylamine hydrochloride (70 mg, 0.3 mmol) and triethylamine (82 mg, 0.81 mmol) were added and the mixture was stirred at 25° C. overnight. The mixture was filtered through a small filter cartridge and the solution was purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 103 mg (83%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(5-chloro-6-methoxy-pyridin-3-yl)-propyl]-amide as white solid. LC/MS (method 2): Rt=1.24 min; m/z=461.12 (M+H+). 1H-NMR: δ (ppm)=8.08 (2H, m), 7.86 (1H, s), 7.19 (1H, s), 4.97 (1H, d), 4.83-4.89 (2H, m), 3.80-4.30 (8H, m), 3.68 (2H, bs), 2.03-2.10 (1H, m), 1.99-1.92 (1H, m), 1.72-1.84 (3H, m), 1.52-1.59 (1H, m), 1.18-1.19 (3H, d), 0.87 (3H, t).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:11]C1C2C(=CC=CC=2)NC=1>>[CH3:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[CH:7]=[CH:8]1
Reactant: Cc1c[nH]c2ccccc12
Reactant: Cc1cccc2cc[nH]c12
Product: Cc1cccc2ccn(C)c12
Yield: 90 %

Procedure:
According to the procedure of Preparation 13 (a), except substituting 7-methylindole for the 3-methylindole, the title compound (1.95 g, 90%) was obtained as a light-colored oil: MS (ES) m/e 146.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH3:10])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:19]([Si:16]([CH3:18])([CH3:17])[O:1][CH:2]([CH3:10])[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)C(=O)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(O[Si](C)(C)C(C)(C)C)C(=O)N1CCCC1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 2-hydroxy-1-pyrrolidin-1-yl-propan-1-one (47.0 mmol, 6.72 g) in DMF (25 mL) was added imidazole (70.5 mmol, 4.8 g), N,N-dimethyl-4-aminopyridine (4.7 mmol, 0.57 g) at room temperature. tert-Butyl-dimethylsilyl chloride (48.5 mmol, 7.31 g) was then added while stirring. Some exotherm was observed. The initial pale yellow solution turned brown-red in color and some precipitate was observed after 30 min. The reaction mixture was stirred overnight and was then filtered through a sintered glass funnel. The solid was washed with Et2O. The filtrate was diluted with water (150 mL) and it was extracted with Et2O (2×100 mL). The organic extracts were combined and washed successively with water (100 mL), saturated NH4Cl solution, and the organic layer was separated. It was dried over Na2SO4, filtered, and the solvent was removed in vacuo to obtain 2-(tert-butyl-dimethyl-silanyloxy)-1-pyrrolidin-1-yl-propan-1-one as a golden yellow oil (10.4 g, 86% yield). The product was judged to be >95% pure by NMR and was used in next step without any purification.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[S:16])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:7]=1[NH2:8].[CH:18](O)=O>>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][N:6]1[C:7]2[N:8]=[CH:18][NH:1][C:2]=2[C:3](=[O:17])[NH:4][C:5]1=[S:16]
Reactant: O=CO
Reactant: Nc1c(N)n(Cc2ccccn2)c(=S)[nH]c1=O
Product: O=c1[nH]c(=S)n(Cc2ccccn2)c2nc[nH]c12
Temperature: 70 °C
Yield: 20 %

Procedure:
5,6-Diamino-1-(pyridin-2-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.33 g, 1.3 mmol, obtained from Example 1(c)) in formic acid was heated at 70° C. for 30 minutes. The excess of formic acid was evaporated in vacuo. Sodium hydroxide (10% aq., 2 mL) was added to the residue and the reaction mixture was heated at 70° C. for 1 h. The mixture was then diluted with water (20 mL) and neutralized using 2M sulfuric acid. The precipitated solid was collected by filtration, washed with water and dried. The crude product was purified by preparative HPLC, giving the title compound (0.068 g, 20%) as a solid.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][CH:12]([N:25]=[N+]=[N-])[C@H:11]1[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>O1CCOCC1.[Pd]>[C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:13][CH:12]([NH2:25])[C@H:11]1[F:28])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1F
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: NC1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1F

Procedure:
3.5-Di-O-benzoyl-2-deoxy-2-fluoro-α,β-D-arabinofuranosyl azide [compound (7)] (see Example 2 of PCT International Laid-Open publication WO 93/10137 specification of PCT/JP 92/01489 application) in the form of a colorless syrup (350 mg) was dissolved in dioxane (7 ml). Into this solution, hydrogen was blown at room temperature in the presence as catalyst of palladium black for 1 hour to conduct the catalytic reduction intended, thereby convert the azido group of compound (7) into amino group. The reaction solution obtained was filtered and the filtrate was concentrated up to about a half volume thereof, and then diluted with dichloroethane (50 ml). The diluted solution was dried over calcium chloride, and then a small amount of triethylamine was added thereto, followed by concentration to afford the titled compound (8) as a colorless syrup (324 mg). Crude yield: 99%.