Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1(=[CH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15](OC)=[O:16])=[CH:13][CH:12]=2)[CH2:9][CH2:8]1.O>O1CCCC1>[C:7]1(=[CH:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:15][OH:16])=[CH:19][CH:20]=2)[CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc(C=C2CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(C=C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 101.3 %

Procedure:
To a suspension of lithium aluminum hydride (0.16 g) in tetrahydrofuran (30 mL) was added methyl 4-(cyclopropylidenemethyl)benzoate (0.80 g), and the mixture was stirred at room temperature for 5 hours. Water (0.4 mL) was added to the reaction mixture, and the mixture was stirred for 3 days. Insoluble materials were removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give 4-(cyclopropylidenemethyl)benzyl alcohol (0.69 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](N)[S:8][C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4].N(OCCC(C)C)=O>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][S:8][C:9]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:4]
Reactant: COC(=O)c1nc(N)sc1CCc1ccccc1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: COC(=O)c1ncsc1CCc1ccccc1
Yield: 55 %

Procedure:
Reflux one equiv of 2-amino-5-phenethyl-thiazole-4-carboxylic acid methyl ester and 3 equiv of isoamyl nitrite in THF (0.13M) for 3 h. Evaporate volatile components to give 55% yield of title compound. BPLC (GRAD80-100M) t=2.410 (99%). MS (APCI): 248 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].[N:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]=[O:17].C(N(CC)CC)C>C(C(C)=O)C>[N+:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][C:16]([NH:15][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:17])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)c2ncccc12
Reactant: CCOC(=O)CN=C=O
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)Oc1ccc([N+](=O)[O-])c2cccnc12
Reaction time: 0.5 h

Procedure:
5-Nitro-8hydroxyquinoline (19.0 g) was added to a solution containing 13.6 g of ethyl isocyanatoacetate in 250 ml of methyl ethyl ketone. This mixture was then stirred at room temperature while triethylamine (1.0 g) was added. Stirring was continued at ambient temperature for about 30 minutes when a crystalline mass precipitated. This crystalline solid was collected by filtration, washed with carbon tetrachloride and subsequently dried leaving the desired ethyl N-(((5-nitro-8-quinolinyl)oxy)carbonyl)glycinate as cream colored crystals, m.p. 121°-122° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1([CH3:12])[CH2:10][O:9][C:8](=[O:11])[CH2:7][CH2:6]1>CO>[CH3:1][O:2][C:8](=[O:11])[CH2:7][CH2:6][C:5]([CH3:12])([CH3:4])[CH2:10][OH:9]
Reactant: C[O-]
Reactant: CC1(C)CCC(=O)OC1
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC(C)(C)CO
Temperature: 50 °C
Reaction time: 4 h
Yield: 933.6 %

Procedure:
To a solution of sodium methoxide (6.32 mg, 0.117 mmol) in anhydrous MeOH (346 mL), 5,5-dimethyl-tetrahydro-pyran-2-one (150 mg, 1.17 mmol) is added dropwise at room temperature under nitrogen. The mixture is stirred at 50° C. for 4 hours and filtered through a silica gel short column (eluent: diethyl ether). The filtrate is concentrated under reduced pressure to give 5-hydroxy-4,4-dimethyl-pentanoic acid methyl ester (175 mg, 93%); TLC (hexane/AcOEt, 2:1) Rf 0.27, 1H NMR (400 MHz, chloroform-d) δ ppm 0.89 (s, 6H), 1.63 (m, 2H), 2.32 (m, 2H), 3.28 (d, 2H), 3.68 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Br:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[O:20])=[CH:17][CH:16]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CCCCc1cc2ccccc2o1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
A solution of 2-n-butylbenzofurane (19.8 g, 114 mmol) and 4-bromobenzoyl chloride (25.0 g, 114 mmol) in dry dichloromethane (300 mL, 0.4 M) was cooled to 0° C. and treated with AlCl3 (16.6 g, 1.1 equiv., 125.4 mmol) in 3 portions. After the additions were complete, the solution was stirred for 3 h and carefully added to ice water. After separation, the aqueous layer was extracted with dichloromethane (2×200 mL) and the combined organic layers were washed with water, sat'd aq NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by flash column chromatography (1-2% ethyl acetate in heptane) afforded (4-bromo-phenyl)-(2-butyl-benzofuran-3-yl)-methanone (14.6 g, 36%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:14]I>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[CH:7][N:8]2[CH3:14])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1c[nH]c2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(C)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6-bromo-3-methyl-1H-indole (200 mg, 0.95 mmol) in DMF (8 mL) was added NaH (114 mg, 2.85 mmol, m %/60%). The mixture was stirred at room temperature for 1 h before the addition of MeI (162 mg, 1.14 mmol). The system was stirred at room temperature for 4 h then the mixture was quenched with water and extracted with EtOAc. The organic layer was concentrated to give crude product which was used in next step without further purification. LCMS (m/z): 224.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[C:10]([O:17][CH2:18][C@@H:19]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH3:20])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[OH:38]>>[CH2:1]([N:8]1[C:12]([C:13](=[O:15])[NH:30][C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=2[OH:38])=[C:11]([CH3:16])[C:10]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:23])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH3:20])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(O)cc1O
Reactant: Cc1c(OC[C@H](C)NC(=O)OC(C)(C)C)nn(Cc2ccccc2)c1C(=O)O
Agent: Cl
Product: Cc1c(OC[C@H](C)NC(=O)OC(C)(C)C)nn(Cc2ccccc2)c1C(=O)Nc1ccc(O)cc1O

Procedure:
Using 1-benzyl-3-({(2S)-2-[(tert-butoxycarbonyl)amino]propyl}oxy)-4-methyl-1H-pyrazole-5-carboxylic acid and 4-aminobenzene-1,3-diol hydrochloride, and in the same manner as in Example 2, step C, the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([S:17][CH2:18][C:19]#[N:20])[N:11]=2)=[CH:5][CH:4]=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]([S:17][CH2:18][C:19](=[N:22][OH:23])[NH2:20])[N:11]=2)=[CH:7][CH:8]=1
Reactant: NO
Reactant: COc1ccc(Nc2cc(C)nc(SCC#N)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2cc(C)nc(SCC(N)=NO)n2)cc1
Yield: 29 %

Procedure:
A mixture of 11.20 g (0.04 mole) of [4-(p-anisidino)-6-methyl-2-pyrimidinylthio]acetonitrile, 5.52 g (0.08 mole) of hydroxylamine hydrochloride and 16.90 g (0.16 mole) of sodium carbonate in 150 ml of N,N-dimethylformamide was heated on a steam bath for three and one-half hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was dissolved in ethyl acetate, diluted with petroleum ether and was cooled in ice. The precipitate which formed was collected and recrystallized from a mixture of ethanol-petroleum ether to afford 3.7 g of product, m.p. 189°-191° d.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1Oc1ccc(O)cc1
Yield: 98.2 %

Procedure:
To a solution of 4-(2-nitrophenoxy)phenol (1.00 g, 4.3 mmol) in ethanol (50 ml) were added an iron powder (1.21 g, 0.022 g-atom) and a solution of ammonium chloride (0.14 g, 2.6 mmol) in water (10 ml), followed by reflux for 2 hours. The insoluble matter was filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and after drying, the solvent was evaporated under reduced pressure to give 4-(2-aminophenoxy)phenol (0.85 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH2:27])[CH:24]=[CH:23][C:22]=2[F:28])[N:13]=1)(C)(C)C.[F:30][C:31]([F:42])([F:41])[C:32]1[N:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=1>>[NH2:7][C:8]1[S:9][CH2:10][C@@H:11]2[C@@H:16]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:14][C@:12]2([C:21]2[CH:26]=[C:25]([NH:27][C:38]([C:35]3[CH:34]=[N:33][C:32]([C:31]([F:41])([F:30])[F:42])=[CH:37][N:36]=3)=[O:39])[CH:24]=[CH:23][C:22]=2[F:28])[N:13]=1
Reactant: O=C(O)c1cnc(C(F)(F)F)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(C(F)(F)F)cn4)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1

Procedure:
Synthesized from tert-butyl[(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-trifluoromethylpyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.80 (dd, J=13 0.6, 3.8 Hz, 1 H), 3.11 (dd, J=13.8, 2.9 Hz, 1 H), 3.30-3.44 (m, 1 H), 3.87 (d, J=8.3 Hz, 1 H), 4.25-5.14 (m, 4 H), 7.07 (dd, J=11.9, 8.8 Hz, 1 H), 7.57 (dd, J=6.8, 2.8 Hz, 1 H), 7.86 (dt, J=8.4, 3.6 Hz, 1 H), 8.89 (s, 1 H), 9.53 (s, 2 H)
Reaction SMILES: [CH2:1]([Sn:9](I)(I)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH2:20]>>[CH2:1]([Sn:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O
Reactant: CCCCCCCC[Sn](I)(I)CCCCCCCC
Product: CCCCCCCC[Sn](=O)CCCCCCCC

Procedure:
Similarly, di-n-octyltin diiodide reacts with water to produce di-n-octyltin oxide according to the reaction:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][OH:17])=[CH:9][CH:8]=1)[CH3:2].[C:21]([Si:25]([CH3:41])([CH3:40])[O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)([CH3:24])([CH3:23])[CH3:22].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:17][C:36]2[CH:35]=[CH:34][C:33]([C:30]3[CH:31]=[CH:32][C:27]([O:26][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:40])[CH3:41])=[CH:28][CH:29]=3)=[CH:38][CH:37]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCO)cc1)OC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCCOc2ccc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2)cc1)OC

Procedure:
(2S)-3-[4-(3-Hydroxy-propoxy)-phenyl)-2-methoxy-propionic acid ethyl ester and 4′-(tert-butyl-dimethyl-silanyloxy)-biphenyl-4-ol (Example 196, Step A) were treated under Mitsunobu procedure B (DIAD, toluene), to afford the title compound.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)=O>>[CH3:24][C:20]1[CH:19]=[C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cccc(C(=O)/C=C/N(C)C)c1
Reactant: N#Cc1ccnc(NN)c1
Agent: Cl
Product: Cc1cccc(-c2ccnn2-c2cc(C#N)ccn2)c1

Procedure:
The title compound was prepared in quantitative yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-3-(dimethylamino)-1-(3-methylphenyl)prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 2.35 (3H, s), 6.51 (1H, d, J=1.6 Hz), 7.00 (1H, d, J=3.2 Hz), 7.22 (3H,m), 7.38 (1H, dd, J=5.2, 1.2 Hz), 7.77 (1H, d, J=1.6 Hz), 7.92 (1H, s), 8.42 (1H, d, J=4.8 Hz).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH2:9]([O:11][C:12](=[O:16])[C@H:13]([CH3:15])[NH2:14])[CH3:10].Cl[CH2:18][C:19]1[C:20]([N+:26]([O-:28])=[O:27])=[C:21]([CH3:25])[CH:22]=[CH:23][CH:24]=1>C(O)C>[CH2:9]([O:11][C:12](=[O:16])[C@H:13]([CH3:15])[NH:14][CH2:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH3:18])[C:20]=1[N+:26]([O-:28])=[O:27])[CH3:10]
Reactant: CCOC(=O)[C@H](C)N
Reactant: Cc1cccc(CCl)c1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NCc1cccc(C)c1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 120 ml of triethylamine in 200 ml of absolute ethanol was added dropwise over a period of 30 minutes to a solution of 91.8 g of L-alanine ethyl ester hydrochloride in 300 ml of absolute ethanol. The mixture was warmed to 60° C., a clear solution resulting. To this solution was added dropwise within 1 hour a solution of 55.5 g of 3-(chloromethyl)-2-nitrotoluene in 300 ml of absolute ethanol. Thereafter, the temperature was increased to 80° C. and the mixture was stirred at this temperature overnight. Thereafter, the mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 600 ml of water. The solution was extracted three times with methylene chloride and the extracts were washed successively with water and with saturated sodium chloride solution, dried and evaporated. The thus-obtained crude product was purified by chromatography on silica gel using methylene chloride/5% methanol for the elution. There was obtained N-(3-methyl-2-nitrobenzyl)-L-alanine ethyl ester in the form of a yellow oil; [α]D =-36° (c=1% in methanol).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:10][OH:11].C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH:1](=[N:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: ON=Cc1ccccc1
Reaction time: 5 h
Yield: 99.2 %

Procedure:
10.6 g of benzaldehyde, 7.0 g of hydroxylamine hydrochloride and 14.0 g of sodium carbonate were added to 200 ml of methanol and then stirred for 5 hours at normal temperature. The reaction mixture was filtered and then methanol was distilled off under reduced pressure from the filtrate to obtain 12.0 g (Yield 99%) of the title compound (III-1) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[Cl:19][CH2:20][C:21](Cl)=[O:22]>CN(C=O)C>[Cl:19][CH2:20][C:21]([NH:12][C:10]1[S:11][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=1)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: Nc1nnc(-c2ccccc2)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CCl)Nc1nnc(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.5 %

Procedure:
To a mixture of 5-phenyl-1,3,4-thiadiazol-2-amine (C1, 1.06 g, 6 mmol) and K2CO3 (0.83 g, 6 mmol) in anhydrous DMF (20 mL), was added chloroacetyl chloride (C2, 0.48 mL, 6 mmol). The mixture was stirred at room temperature for 4 h. The reaction mixture was then poured into ice-water (100 mL), stirred, and then filtered. The resulting solid was washed with water, and then dried in the oven under vacuum to afford compound C3 (1.15 g, 76%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:30])([F:29])[F:28])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:52]1[C:57](=[O:58])[CH2:56][NH:55][CH2:54][C:53]1=[O:59]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:27]([F:28])([F:29])[F:30])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:55]4[CH2:56][C:57](=[O:58])[NH:52][C:53](=[O:59])[CH2:54]4)=[O:22])=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C1CNCC(=O)N1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)ccc1C(=O)N1CC(=O)NC(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 100-mL round-bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (452 mg, 1.00 mmol, 1.00 equiv), dichloromethane (50 mL), TEA (202 mg, 2.00 mmol, 2.00 equiv), EDCI (384 mg, 2.00 mmol, 2.00 equiv), HOBt (270 mg, 2.00 mmol, 2.00 equiv). The mixture was stirred for 0.5 h at room temperature. This was followed by the addition of piperazine-2,6-dione (125 mg, 1.10 mmol, 1.10 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of DCM. The resulting mixture was washed with 3×50 mL of brine. The mixture was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 210 mg (38%) of 4-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]piperazine-2,6-dione as a light yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24](=[O:34])[N:25]([CH3:33])[CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:11][N:10]=1)(C)(C)C.[ClH:36]>CCOC(C)=O>[ClH:36].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24]([N:25]([CH3:33])[CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[O:34])=[CH:11][N:10]=1
Reactant: COc1cc2c(CC(=O)N(C)Cc3cccnc3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2c(CC(=O)N(C)Cc3cccnc3)cnc(CN)c2cc1OC

Procedure:
As described in Example 1, {6,7-dimethoxy-4-[(methyl-pyridin-3-ylmethyl-carbamoyl)-methyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester was treated with HCl in EtOAc to give 2-(1-aminomethyl-6,7-dimethoxy-isoquinolin-4-yl)-N-methyl-N-pyridin-3-ylmethyl-acetamide hydrochloride. MS: APCI (M+H) calc'd for C21H24N4O3+H 381.4; found 381.1.
Reaction SMILES: [CH:1]12[O:6][CH:5]1[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]1[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=1)=[O:8])[CH2:2]2.C1C=CN=CC=1.[FH:27].C(Cl)Cl>>[F:27][C@H:1]1[C@H:5]([OH:6])[CH2:4][N:3]([C:7]([O:9][CH2:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[O:8])[CH2:2]1
Reactant: F
Reactant: O=C(OCc1ccc2ccccc2c1)N1CC2OC2C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1ccc2ccccc2c1)N1C[C@@H](O)[C@H](F)C1
Temperature: 25 °C
Reaction time: 36 h
Yield: 23.3 %

Procedure:
A plastic (HDPE) bottle was charged with naphthalen-2-ylmethyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (945 mg, 3.509 mmol) and HF-pyridine (264 μL, 10.527 mmol) in DCM (17.55 ml, 3.509 mmol) and the reaction mixture was stirred for 36 hours at ambient temperature. The reaction was slowly quenched with aqueous saturated NaHCO3 and diluted with water and DCM. The reaction mixture was extracted with DCM, and the combined organics layers were dried over Na2SO4 and concentrated to give the product as an oil (237 mg, 23.3% yield)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]([O:16][C:17]2[C:18]([CH3:24])=[N:19][N:20]([CH3:23])[C:21]=2[CH3:22])[C:11]([C:14]#[N:15])=[N:12][CH:13]=1.S(=O)(=O)(O)[OH:26].[OH-].[Na+]>O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]([O:16][C:17]2[C:18]([CH3:24])=[N:19][N:20]([CH3:23])[C:21]=2[CH3:22])[C:11]([C:14]([NH2:15])=[O:26])=[N:12][CH:13]=1
Reactant: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1C#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.4 %

Procedure:
A flask was charged with 5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinonitrile (35.19 g, 88.1 mmol), and sulfuric acid (227.3 g, 2317 mmol) and stirred at ambient temperature overnight. Water (100 mL) was slowly added to the reaction which was cooled in an ice bath, then ice (150 g) was added. 40% NaOH was slowly added until the pH was about 12. The mixture was extracted ethyl acetate (750 mL×2), and dichloromethane (500 mL). The organic layers were dried over sodium sulfate and concentrated in vacuo to afford 5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)picolinamide (27.69 g, 77.9 mmol, 89% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[N:37]([CH3:38])[N:36]=[C:35]([CH3:39])[C:34]=1[S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1.C(Cl)Cl>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:34]5[C:35]([CH3:39])=[N:36][N:37]([CH3:38])[C:33]=5[Cl:32])(=[O:41])=[O:42])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.7 %

Procedure:
A solution of 8-(4-amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione (2.0 g, 4.77 mmol) in pyridine (30 mL) under argon at 25° C. was treated with 5-chloro-1,3-dimethyl-pyrazole-4-sulfonyl chloride (1.31 g, 5.72 mmol). The reaction mixture was stirred at 25° C. for 24 h. The reaction mixture was then diluted with methylene chloride (500 mL) and washed with a 1.0N aqueous hydrochloric acid solution (3×100 mL). The combined water layers were extracted with methylene chloride (1×250 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was stirred in acetonitrile (25 mL) for 20 min and then placed in the freezer for 1 h. The solids were collected by filtration, washed with cold acetonitrile, and dried in vacuo to afford 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (2.53 g, 87%) as a yellow solid; FAB-HRMS m/e calculated for C28H27ClFN7O4S (M+H)+ 612.1596, found 612.1585.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[N+](C)([O-])=O>[CH3:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([C:4]1[CH:5]=[CH:6][C:1]([O:7][CH3:8])=[CH:2][CH:3]=1)=[O:13]
Reactant: COc1ccccc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C[N+](=O)[O-]
Product: COc1ccc(C(=O)c2ccccc2C)cc1
Temperature: 60 °C
Reaction time: 7 h
Yield: 74.2 %

Procedure:
To commercially available nitromethane (10 ml) were added commercially available anisole (1.081 g), commercially available 2-methylbenzoyl chloride (1.546 g) and commercially available ytterbium(III) trifluoromethanesulfonate (620 mg), and the admixture was stirred at 60° C. for 7 hours. The reaction mixture was treated in the same manner as described in Example 120 to obtain 1.679 g of the title compound (yield: 74%).