Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[N:15]([CH2:16][C:17]([O:19]C)=[O:18])[C:14]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:13][N:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[Na+]>CO>[C:1]12([C:11]3[N:15]([CH2:16][C:17]([OH:19])=[O:18])[C:14]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[N:13][N:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)Cn1c(-c2ccccc2)nnc1C12CC3CC(CC(C3)C1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1c(-c2ccccc2)nnc1C12CC3CC(CC(C3)C1)C2

Procedure:
Methyl [3-(1-adamantyl)-5-phenyl-4H-1,2,4-triazol-4-yl]acetate (4-55) (15 mg), 0.5 N NaOH (1 mL) and methanol (0.5 mL) were reacted at room temperature for 17 h. The methanol was evaporated in vacuo. The aqueous residue was acidified with acetic acid and extracted ten times with chloroform. The extracts were dried (MgSO4) and evaporated in vacuo to give [3-(1-adamantyl)-5-phenyl-4H-1,2,4-triazol-4-yl]acetic acid (4-54). MS: 338 (M+1).
Reaction SMILES: [C:1]([CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=[C:8]([CH2:22][C:23]([O:25]C)=[O:24])[CH:7]=1)([O:3]C)=[O:2].[OH-].[Na+]>CCO>[C:23]([CH2:22][C:8]1[CH:9]=[C:10]([O:12][CH2:13][CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:6]([CH2:5][C:1]([OH:3])=[O:2])[CH:7]=1)([OH:25])=[O:24]
Reactant: COC(=O)Cc1cc(CC(=O)OC)cc(OCC=Cc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cc(CC(=O)O)cc(OCC=Cc2ccccc2)c1
Reaction time: 12 h

Procedure:
To a solution of 2.98 g (8.82 mmoles) of 1,3-di-(carbomethoxymethyl)-5-cinnamyloxybenzene in 50 ml EtOH is added 26 ml of 1N NaOH. After 12 hours, the reaction mixture is concentrated down in vacuo, taken up in H2O and acidified to pH 4 with 1N HCl. The solid precipitate is collected and recrystallized from MeOH to afford 1,3-di-(carboxymethyl)-5-cinnamyloxybenzene which is used directly in the next step.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH:31]1[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32]1)/[CH:10]=[CH:11]/[C@H:12]1[C@@H:16]([F:17])[CH2:15][C:14](=[O:18])[C@@H:13]1[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([O:27]C(C)C)=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Si:1]([O:8][C@@H:9]([CH:31]1[CH2:32][C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:39]1)/[CH:10]=[CH:11]/[C@H:12]1[C@@H:16]([F:17])[CH2:15][C:14](=[O:18])[C@@H:13]1[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCC/C=C\C[C@H]1C(=O)C[C@H](F)[C@@H]1/C=C/[C@@H](O[Si](C)(C)C(C)(C)C)C1Cc2ccccc2C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H](/C=C/[C@H]1[C@@H](F)CC(=O)[C@@H]1C/C=C\CCCC(=O)O)C1Cc2ccccc2C1
Reaction time: 3 h
Yield: 97.4 %

Procedure:
To a stirring mixture consisting of (Z)-isopropyl 7-((1R,2R,3S)-2-((S,E)-3-(tert-butyldimethylsilyloxy)-3-(2,3-dihydro-1H-inden-2-yl)prop-1-enyl)-3-fluoro-5-oxocyclopentyl)hept-5-enoate (prepared in Step L, 580 mg) in DCM (30 mL) at room temperature was added Dess-Martin reagent (1.5 g) and the reaction mixture was stirred for 3 hours. The mixture was concentrated under reduced pressure and the residue was redissolved in diethyl ether. The insoluble materials were removed by filtration. The crude product in diethyl ether was applied to a silica gel column. Elution with hexanes-ethyl acetate (4:1 with 0.4% acetic acid) afforded the title intermediate (522 mg, 89%).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@H:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:27]1[N:32]=[CH:31][C:30]([CH:33]2[CH2:35][CH2:34]2)=[CH:29][N:28]=1>>[CH:33]1([C:30]2[CH:29]=[N:28][C:27]([N:23]3[CH2:24][CH2:25][CH:20]([C@@H:18]4[O:17][C:14]5=[CH:15][N:16]=[C:11]([C:8]6[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=6)[CH:12]=[C:13]5[CH2:19]4)[CH2:21][CH2:22]3)=[N:32][CH:31]=2)[CH2:35][CH2:34]1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCNCC2)C3)CC1
Reactant: Clc1ncc(C2CC2)cn1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)O[C@@H](C2CCN(c4ncc(C5CC5)cn4)CC2)C3)CC1

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 39, the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-cyclopropyl-pyrimidine following a procedure analogous to that described for Example 79. LC (method 10): tR=1.61 min; Mass spectrum (ESI+): m/z=482 [M+H]+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([CH2:23][C:24](O)=[O:25])[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[N:40]1([C:45]([NH2:47])=[NH:46])[CH:44]=[CH:43][CH:42]=[N:41]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([NH:3][C:4](=[O:5])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([CH2:23][C:24](=[O:25])[NH:47][C:45](=[NH:46])[N:40]3[CH:44]=[CH:43][CH:42]=[N:41]3)[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(-c2ccc(-c3ccccc3)n2CC(=O)O)cc1
Reactant: N=C(N)n1cccn1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)c1ccc(-c2ccc(-c3ccccc3)n2CC(=O)NC(=N)n2cccn2)cc1
Yield: 38.9 %

Procedure:
To 120 mg pyrrolyl acetic acid from Step 4 was added 97 mg (0.6 mmol, 5 equiv.) of carbonyldiimidazole and 2 mL CH2Cl2. The reaction was mixed at room temperature for one hour, upon which time was added 88 mg (5 equiv.) 1H-pyrazole-1-carboxamidine hydrochloride, 0.16 mL (10 equiv.) triethylamine, and a catalytic amount of 4-dimethylaminopyridine. The reaction was mixed at room temperature for one hour, filtered to remove any precipitates formed, and washed with water. The organic phase was separated from the aqueous phase and concentrated to afford 59 mg crude N-ethyl-4-(1-{[(imino-pyrazol-1-yl-methyl)-carbamoyl]-methyl}-5-phenyl-1H-pyrrol-2-yl)-benzamide, which was used in the next step without purification.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[N:4]([CH2:12][CH3:13])[N:3]=1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15].C(N(CC)CC)C>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:12]([N:4]1[C:5]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:6][C:2]([C:15]#[C:14][Si:16]([CH3:19])([CH3:18])[CH3:17])=[N:3]1)[CH3:13]
Reactant: CCn1nc(Br)nc1N1CCCC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCn1nc(C#C[Si](C)(C)C)nc1N1CCCC1
Temperature: 120 °C
Yield: 47.5 %

Procedure:
A mixture of 3-bromo-1-ethyl-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole (240 mg, 979 μmol, Eq: 1.00), ethynyltrimethylsilane (192 mg, 275 μl, 1.96 mmol, Eq: 2) and triethylamine (149 mg, 205 μl, 1.47 mmol, Eq: 1.5) in tetrahydrofuran (3.65 ml) was purged for 5 minutes with nitrogen. Then copper (I) iodide (1.86 mg, 9.79 μmol, Eq: 0.01), bis(triphenylphosphine)palladium(II) chloride (6.87 mg, 9.79 μmol, Eq: 0.01) and triphenylphosphine (2.57 mg, 9.79 μmol, Eq: 0.01) were added, the vessel was capped and heated to 120° C. for 1 day. Once more copper (I) iodide (1.86 mg, 9.79 μmol, Eq: 0.01), triphenylphosphine (2.57 mg, 9.79 μmol, Eq: 0.01), bis(triphenylphosphine)palladium(II) chloride (6.87 mg, 9.79 μmol, Eq: 0.01) and ethynyltrimethylsilane (192 mg, 275 μl, 1.96 mmol, Eq: 2) were added, the vial was purged with argon, capped again and stirred for one more day at 120° C. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using heptane/ethyl acetate 10-30% as eluent affording 1-ethyl-5-pyrrolidin-1-yl-3-trimethylsilanylethynyl-1H-[1,2,4]triazole (122 mg, 47.5%) as an orange oil. MS: m/z=263.4 (M+H+)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]([NH2:15])=[S:14]>CCO>[C:8]1([CH3:11])[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]([NH2:15])[S:14][CH:2]=2)=[CH:6][CH:7]=1
Reactant: NC(N)=S
Reactant: Cc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: Cc1ccc(-c2csc(N)n2)cc1
Yield: 98.4 %

Procedure:
A mixture of 2-bromo-1-(p-tolyl)ethanone (5.00 g, 23.5 mmol) and thiourea (1.97 g, 25.9 mmol) in 95% EtOH (33.5 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (50 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-(p-tolyl)thiazol-2-amine (4.40 g) as white solids in 99% yield: 1H NMR (500 MHz, CDCl3) δ 7.66 (d, J=8.0 Hz, 2H), 7.18 (d, J=7.5 Hz, 2H), 6.66 (s, 1H), 5.25 (bs, 2H), 2.36 (s, 6H).
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[C:18]1([CH:16]2[CH2:17][NH:14][CH2:15]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(C2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: c1ccc(C2CNC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.2 %

Procedure:
Add 20% palladium hydroxide on activated carbon (0.130 g) and ethanol (25 mL) to a Parr pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 kPa), seal the vessel and agitate the mixture at RT for 15 min. Vent the hydrogen from the reaction vessel and purge the reaction vessel with nitrogen. Add 1-benzhydryl-3-phenylazetidine (0.515 g, 0.00172 mol) and ethanol (75 mL) to the pressure vessel. Purge the reaction vessel with nitrogen, pressurize the reaction mixture with hydrogen (400 kPa), seal the vessel and agitate the reaction at RT for 20 h. Turn off the agitation, vent the excess hydrogen from the vessel, purge the vessel with nitrogen and filter the reaction mixture to remove the palladium on carbon catalyst. Concentrate and purify (silica gel chromatography, eluting with 5:95 to 10:90 2 M ammonia in methanol:DCM) to give the title compound (76 mg, 34%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C@H:13]([NH2:15])[CH3:14].C([O:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][N:38]2[C:46]3[C:41](=[CH:42][C:43]([C:47](O)=[O:48])=[CH:44][CH:45]=3)[C:40]([CH3:50])=[C:39]2[CH3:51])=[CH:33][CH:32]=1)=[O:24])(C)(C)C>>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:11])[F:12])=[CH:5][C:4]=1[C@H:13]([NH:15][C:47]([C:43]1[CH:42]=[C:41]2[C:46](=[CH:45][CH:44]=1)[N:38]([CH2:37][C:34]1[CH:33]=[CH:32][C:31]([C:26]3[C:25]([C:23]([OH:24])=[O:22])=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:36][CH:35]=1)[C:39]([CH3:51])=[C:40]2[CH3:50])=[O:48])[CH3:14]
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@@H](N)c1cc(C(F)(F)F)ccc1C(F)(F)F
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@H](C)c3cc(C(F)(F)F)ccc3C(F)(F)F)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(2,5-bis(trifluoromethyl)phenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 639 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:16][N:15]([C:25]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[O:26])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1.Cl[C:35]1[N:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][N:36]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:33])[N:10]([C@@H:13]2[C@@H:17]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH2:16][N:15]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([C:35]4[N:40]=[CH:39][C:38]([C:41]#[N:42])=[CH:37][N:36]=4)[CH2:29][CH2:28]3)=[O:26])[CH2:14]2)[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)cc1
Reactant: N#Cc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(c3ncc(C#N)cn3)CC2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 65 °C
Reaction time: 22 h

Procedure:
A mixture of 94.7 mg (0.2 mmol)[(3R,4S)-4-(4-Chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester, 83.7 mg (0.3 mmol) 2-chloropyrimidine-5-carbonitrile and 129 mg (1 mmol) DIPEA in 2.5 mL DMF was shaken a for 22 h at 65° C. The mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fraction were evaporated to access 58 mg (51%) of the title compound as off-white solid. MS m/e: 577.3 [M+H]+.
Reaction SMILES: [C:1]([CH2:6][CH:7]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:27]([O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CCOC(C)=O>C1COCC1>[CH2:27]([O:34][C:35]1[CH:36]=[C:37](/[CH:38]=[C:6](\[CH3:7])/[C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:40]=[CH:41][CH:42]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(C)=C/c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (carbethoxyethylidene)triphenylphosphorane (available from Aldrich) (5.50 g, 15.2 mmol) in THF (25 mL) was added 3-(benzyloxy)benzaldehyde (available from Aldrich) (2.93 g, 13.8 mmol) in THF (10 mL) under nitrogen at −78° C. The reaction was allowed to slowly warm to room temperature and stirred for 2 hours. EtOAc (100 mL) was added, and the mixture was washed with brine (30×2 mL). The organic layer was dried over MgSO4. The solvent was removed by evaporation. The crude product was purified by passing through a short silica gel column, eluting with hexane/EtOAc (85/15) to give (E)-ethyl 3-(3-(benzyloxy)phenyl)-2-methylacrylate 62.B.
Reaction SMILES: FC1C([O:8][C:9]([C:11]2[C:29]([F:30])=[C:28]([F:31])[C:14]3[N:15]([C:20]4[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=4[CH3:27])[CH2:16][O:17][C:18](=[O:19])[C:13]=3[CH:12]=2)=O)=C(F)C(F)=C(F)C=1F.C1COCC1.Cl.CN.[CH:44]([N:47](CC)C(C)C)(C)C>C(OCC)(=O)C>[CH3:44][NH:47][C:9]([C:11]1[C:29]([F:30])=[C:28]([F:31])[C:14]2[N:15]([C:20]3[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=3[CH3:27])[CH2:16][O:17][C:18](=[O:19])[C:13]=2[CH:12]=1)=[O:8]
Reactant: Cc1cc(I)ccc1N1COC(=O)c2cc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)c(F)c(F)c21
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1cc2c(c(F)c1F)N(c1ccc(I)cc1C)COC2=O
Reaction time: 17 h
Yield: 76.8 %

Procedure:
To a suspension of 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid (0.3 g, 0.67 mmol) in N,N-dimethylformamide (3 mL) is added trifluoroacetic acid pentafluorophenyl ester (0.127 mL, 0.74 mmol) and pyridine (0.60 mL, 0.74 mmol). After stirring for 4 hours the reaction mixture is diluted with ethyl acetate and washed 3 times with 1.0 M HCl solution, 3 times with 5% aqueous NaHCO3 solution, 2 times with water and once with saturated brine solution. The organic layers were collected and dried over Na2SO4, filtered and concentrated in vacuo affording 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid pentafluorophenylester as a dark orange oil (0.34 g, 83.1%). To a suspension of 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid pentafluorophenylester (0.33 g, 0.54 mmol) in freshly distilled THF (10 mL) is added methylamine hydrochloride (0.037 g, 0.54 mmol) and N,N-diisopropylethylamine (0.019 mL, 1.08 mmol). After stirring for 17 hours, the reaction mixture was diluted with ethyl acetate and washed 2 times with water and 2 times with saturated brine solution. The organic layers were collected and dried over Na2SO4, filtered and concentrated in vacuo affording 7,8-difluoro-1-(4-iodo-2-methyl-phenyl)-4-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carboxylic acid methylamide as a yellow solid (0.19 g, 76.9%); mp 219–223° C.; 1NMR (400 MHz; DMSO-d6) 8.40 (s, 1H), 8.06 (d, 1H, J=6.8), 7.74 (s, 1H), 7.50 (d, 1H, J=8.4), 6.87 (d, 1H, J=8.0), 5.61 (s, 2H), 2.76 (d, 3H, J=4.4), 2.25 (s, 3H); MS(APCI)m+1=459; Anal.calcd/found for C17H13F2IN2O3 C 45.00/45.39, H 3.01/3.16, N 6.05/5.88.
Reaction SMILES: [C@@H:1]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O.[Cl:18][C:19]1[C:20](=[O:35])[NH:21][C:22](=[O:34])[N:23]([CH:33]=1)[C@@H:24]1[O:32][C@H:29]([CH2:30][OH:31])[C@@H:27]([OH:28])[C@H:25]1O>>[CH2:1]=[C:25]1[C@H:27]([OH:28])[C@@H:29]([CH2:30][OH:31])[O:32][C@H:24]1[N:23]1[CH:33]=[C:19]([Cl:18])[C:20](=[O:35])[NH:21][C:22]1=[O:34]
Reactant: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1Cl
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: C=C1[C@H](n2cc(Cl)c(=O)[nH]c2=O)O[C@H](CO)[C@H]1O

Procedure:
Protection, oxidation, methylidenation and deprotection reactions were carried out similarly as in Example 7 except that the uridine was replaced by 5-chlorouridine to obtain 2'-methylidene-2'-deoxy-5-chlorouridine.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]#[N:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.CN(C)[CH:19]=[O:20]>>[CH:19]([C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[CH:10]=2)[NH:6][CH:7]=1)=[O:20]
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2[nH]cc(C=O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Phosphoryl chloride (4.24 ml, 45.48 mmol) was added dropwise to dimethylformamide (3.52 ml, 45.48 mmol) and stirred for 30 mins at room temperature. A solution of 1H-indole-5-carbonitrile (5.39 g, 37.9 mmol) in dimethylformamide (10 ml) was added dropwise. A solid precipitated, further dimethylformamide (10 ml) was added to aid stirring and the reaction mixture was then stirred at room temperature for 3 hr. Water was added to quench the reaction mixture which was then stirred for 18 hr. The stirring was stopped and the reaction mixture was left to stand, after 24 hr a pink solid had precipitated in the organic layer. The layers were separated and organic layer filtered, washed with water and dried to give the desired product (5.44 g, 84%). 1H NMR (DMSO) δ 7.60-7.80 (m, 2H), 8.20-8.30 (m, 2H), 10.00 (s, 1H), 12.20-12.35 (s, br, 1H).
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:18][C:19]1[N:23]=[C:22]([S:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[NH:21][N:20]=1>C(O)(=O)C>[CH2:25]([S:24][C:22]1[N:23]=[C:19]2[N:18]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:20]2[N:21]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Solvent: CC(=O)O
Product: c1ccc(CSc2nc3nc(-c4ccccc4)cc(-c4ccccc4)n3n2)cc1
Temperature: 25 °C
Yield: 34.3 %

Procedure:
A solution of 8.40 g (37.5 mmol) of dibenzoylmethane and 7.73 g (37.5 mmol) of 3-amino-5-benzylthio-1,2,4-triazole in 50 ml of glacial acetic acid was heated at reflux for 24 hours. Upon cooling to room temperature the solid which separated was collected by filtration and dried. The product was chromatographed on silica gel (HPLC) eluting with EtOAc-hexane (3:7, v/v) to afford 5.08 g (34%) of the desired product as a colorless solid, m.p. 122.5°-123.5° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][CH2:8][C:9](O)=O.[C:12]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[C:22]([NH2:27])[CH:21]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N>Cl>[C:12]([C:20]1[CH:25]=[CH:24][C:23]2[N:26]=[C:9]([CH2:8][S:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[NH:27][C:22]=2[CH:21]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1N
Reactant: O=C(O)CSc1ccccn1
Agent: Cl
Agent: N
Product: O=C(c1ccccc1)c1ccc2nc(CSc3ccccn3)[nH]c2c1

Procedure:
8.45 g of 2-(2-pyridylthio)acetic acid (0.05 mole) and 10.6 g of 4-benzoyl-1,2-phenylenediamine (0.05 mole) in 100 ml of 4N hydrochloric acid are heated under reflux for 2 days. The mixture is allowed to cool and is neutralized with ammonia solution. It is extracted with ethyl acetate (3×100 ml), and the extract dried (Na2SO4), filtered and concentrated to a volume of 125 ml. From this solution, 11.7 g (68%) of 5-benzoyl-2-(2-pyridylthiomethyl)benzimidazole crystallize. The product thereby obtained is identical to that obtained by Method A, and the data for the identification appeat in Tables 1 and 2.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][O:5][CH:4]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[NH:3]1.C([Li])CCC.[CH3:20][S:21]C>O1CCCC1.CCCCCC>[CH3:1][C:2]1([CH3:14])[CH2:6][O:5][CH:4]([C:7]2[S:8][C:9]([S:21][CH3:20])=[CH:10][C:11]=2[O:12][CH3:13])[NH:3]1
Reactant: COc1ccsc1C1NC(C)(C)CO1
Reactant: CSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(SC)sc1C1NC(C)(C)CO1
Temperature: -45 °C
Reaction time: 1.5 h

Procedure:
27 g (0.128 moles) of 3,4-dihydro-4,4-dimethyl-2-(3-methoxy-2-thienyl)-oxazole are dissolved in 400 ml of absolute tetrahydrofuran, the solution is cooled to -45° C. and 88 ml (0.141 moles) of a 1.6 molar solution of butyllithium in n-hexane is added dropwise such that the temperature in the reaction mixture does not exceed -45° C. After completion of the addition it is stirred further for 1.5 hours at -45° C., a solution of 13.9 g (0.147 moles) of dimethylsulfide in 70 ml of absolute tetrahydrofuran is added and stirring continues for an additional 30 minutes at this temperature. Then it is heated to -20° C., poured onto water and extracted several times with ether. The combined ether phases are dried with sodium sulfate, decolored with activated charcoal, evaporated in vacuo and the crystalline residue is recrystallized from petroleum ether. Yield: 24.7 g (75%), m.p. 56°-58° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:11])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].N1C=CN=C1.[CH3:17][Si:18]([CH3:21])([CH3:20])Cl.C(=O)(O)[O-].[Na+]>CCCCCC.CN(C)C=O>[Cl:1][CH2:2][C:3]([O:11][Si:18]([CH3:21])([CH3:20])[CH3:17])([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:4][C:5]#[CH:6]
Reactant: C[Si](C)(C)Cl
Reactant: C#CCC(O)(CCl)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: C#CCC(CCl)(CCCC)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, ice-cold solution of 7.22 g. of 4-chloromethyl-4-hydroxy-1-octyne and 7.16 g. of imidazole in 28 ml. of dimethylformamide is added 6.5 ml. of trimethylchlorosilane via a syringe during 15 minutes. The resulting mixture is stirred at room temperature overnight, diluted with hexane and poured into a mixture of ice and saturated sodium bicarbonate solution. The hexane solution is separated, washed with saturated sodium bicarbonate, water and brine, dried over ahydrous sodium sulfate and concentrated in vacuo to give 11.8 g. of a colorless liquid which is vacuum distilled at b.p. 50°-57° C./3.5-4 mm. to give 9.7 g. of product as a colorless liquid; PMR δ 3.58 (s), 2.50 (d), 1.99 (t), 0.87 (s,OTMS).