Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=1[O:5][CH2:6][CH:7]1[NH:11][CH2:10][CH2:9][S:8]1.C(N(CC)CC)C.[Cl:23][CH2:24][C:25](Cl)=[O:26]>ClCCCl>[Cl:23][CH2:24][C:25]([N:11]1[CH2:10][CH2:9][S:8][CH:7]1[CH2:6][O:5][C:4]1[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=1[O:2][CH3:1])=[O:26]
Reactant: COc1ccccc1OCC1NCCS1
Reactant: O=C(Cl)CCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1OCC1SCCN1C(=O)CCl
Reaction time: 1 h

Procedure:
A solution of 2-(o-methoxyphenoxymethyl)thiazolidine (100 g) in 1,2-dichloroethane (250 ml) cooled at 10° is heated, under stirring, with triethylamine (68 ml) and a solution of α-chloroacetylchloride (36.2 ml) in 1,2-dichloroethane (50 ml) is added dropwise. After 1 hour, the mixture is washed with water, dried on Na2SO4 and evaporated to dryness. Subsequent crystallization from propan-2-ol gives 3-α-chloroacetyl-2-(o-methoxyphenoxymethyl)thiazolidine m.p. 87°-88° C. (100 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[OH:10])[CH:5]=O.[CH:14]1([C:17](=[O:24])[CH2:18][C:19]([CH:21]2[CH2:23][CH2:22]2)=[O:20])[CH2:16][CH2:15]1.N1CCCCC1>C(O)(=O)C>[CH:21]1([C:19](=[O:20])[C:18](=[CH:5][C:4]2[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]([OH:10])=[C:2]([OH:1])[CH:3]=2)[C:17]([CH:14]2[CH2:15][CH2:16]2)=[O:24])[CH2:22][CH2:23]1
Reactant: O=C(CC(=O)C1CC1)C1CC1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: O=C(C(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)C(=O)C1CC1)C1CC1

Procedure:
A mixture containing 2.75 g of 3,4-dihydroxy-5-nitrobenzaldehyde, 3.8 g of 1,3-dicyclopropyl-l,3-propanedione, 0.2 ml of piperidine and 0.4 ml of acetic acid was refluxed for 1 h with a Dean-Stark separator. After cooling the product was filtered and recrystallized from acetic acid. Yield 2.85 g, mp 159°-162° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH:5][C:6]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Br:1][CH2:2][CH2:3][O:5][C:6]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[O:20][CH3:21]
Reactant: BrCCBr
Reactant: COc1cc(C=O)cc(-c2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=O)cc(-c2ccccc2)c1OCCBr
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.7 %

Procedure:
Under N2, tetrakis-triphenylphosphinepalladium(0) was added to a mixture of the above dioxolane (10 g, 31 mmoles), benzeneboronic acid (4.5 g, 37 mmoles), toluene (67 mL), 2 M aqueous sodium carbonate (33 mL) and methanol (20 mL). The resulting mixture was heated at reflux under N2 for 16 hours. After cooling the mixture was diluted with water (150 mL) and washed with heptane (400 mL). The aqueous phase was made acidic with 3N hydrochloric acid and extracted with ethyl acetate (3×300 mL). The combined organic extracts were dried over MgSO4 and evaporated in vacuo. The residue was purified by column chromatography over silica gel (800 mL) eluting with a mixture of ethyl acetate and heptane (1:2) to afford 5.49 g (77%) of 4-hydroxy-3-methoxy-5-phenylbenzaldehyde. M.p. 107-108° C. 1,2-Dibromoethane (41 mL, 0.48 moles) was added to a mixture of the above 4-hydroxy-3-methoxy-5-phenylbenzaldehyde (5.49 g, 24 mmoles) and potassium carbonate (17 g, 123 mmoles) in DMF (80 ml) and the resulting mixture was stirred vigorously at room temperature for 16 hours. The mixture was poured into water (1 L) and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with saturated sodium chloride (200 mL), dried over MgSO4 and evaporated in vacuo to afford 8.1 g (100%) of 4-(2-bromoethoxy)-3-methoxy-5-phenylbenzaldehyde as an oil.
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][C:6]1[S:7][C:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15](N)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)[N:10]=1.C(O)C>O.Cl>[CH3:5][C:6]1[S:7][C:8]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[CH:13]=2)[N:10]=1
Reactant: CCOC(=O)c1sc(C)nc1Oc1ccc(N)c(C(F)(F)F)c1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1sc(C)nc1Oc1cccc(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 84.5 %

Procedure:
1.4 g of NaNO2 in 30 ml of water are added dropwise with ice cooling in the course of about 20 minutes to 7 g (0.02 mol) of 2-methyl-5-ethoxycarbonyl-4-(4-amino-3-trifluoromethyl-phenoxy)-thiazole (cf. Example (IV-4) in 40 ml of concentrated hydrochloric acid. After the mixture has been stirred for 5 minutes, 300 ml of ethanol are added, and the mixture is then heated slowly to reflux temperature and refluxed for 30 minutes. The volatile constituents are subsequently removed in vacuo, the oil which remains is then taken up in 50 ml of water, a pH of 8 is established by adding dilute sodium hydroxide solution, the mixture is extracted twice with dichloromethane, the extract is dried (over MgSO4) and evaporated in vacuo, and the crude product which remains is filtered chromatographically through silica gel (eluent: toluene). 5.6 g (83.6 % of theory) of 2-methyl-5-ethoxycarbonyl-4-(3-trifluoromethyl-phenyloxy)-thiazole are obtained; melting point: 56° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]12[CH2:15][CH:11]3[CH2:12][CH:13]([CH2:14]1)[C:9](C(O)=O)([CH2:10]3)[CH2:8]2.OS(O)(=O)=O.[N-:25]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl.O>[O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]12[CH2:15][CH:11]3[CH2:12][CH:13]([CH2:14]1)[C:9]([NH2:25])([CH2:10]3)[CH2:8]2
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)C12CC3CC1CC(N1CCCS1(=O)=O)(C3)C2
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: NC12CC3CC1CC(N1CCCS1(=O)=O)(C3)C2
Temperature: 45 °C
Reaction time: 2 h
Yield: 66.3 %

Procedure:
To a stirred solution of the acid obtained in step II (0.29 g, 1.0 mmol) in CHCl3 (5 mL) at room temperature was added conc. H2SO4 (0.53 mL, 10 mmol) followed by the addition NaN3 (0.2 g, 3.0 mmol) in portions over a period of 30 min; while maintaining the temperature below 40° C. The reaction mixture was warmed to 45° C. and stirred for 2 h. The reaction mixture was cooled to ice bath temperature, diluted with water and extracted with EtOAc. The aqueous layer was basified by adding a 50% NaOH solution and extracted with CHCl3. The combined organic layer was washed with brine, dried over Na2SO4 and the solvent was removed under reduced pressure to obtain 1-(1,1-dioxidoisothiazolidin-2-yl)tricyclo[3.3.1.03,7]nonan-3-amine as a viscous liquid (0.17 g) in 66% yield. m/z (M+1) 257; 1H NMR (CDCl3) 300 MHz δ 3.36 (t, J=6.6 Hz, 2H), 3.15 (t, J=7.5 Hz, 2H), 2.40-2.24 (m, 4H), 2.18 (dd, J=3.0, 10.4 Hz, 1H), 2.13-1.83 (m, 6H), 1.76 (dd, (J=2.4, 10.8 Hz, 1H), 1.65-1.58 (m, 1H), 1.48 (dd, J=2.4, 10.8 Hz, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cccnc1CCl
Solvent: ClCCl
Product: COC(=O)c1ccc[n+]([O-])c1CCl

Procedure:
Methyl 2-(chloromethyl)pyridine-3-carboxylate (4.45 g, 23.98 mmol) was taken up in DCM (50 mL) and mCPBA (5.91 g, 26.4 mmol) was added. The resulting solution was allowed to react at room temperature overnight and then purified directly by silica gel chromatography (0-20% MeOH-EtOAc) to afford the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Cl:12])=[N:4][N:3]=1.[CH3:13][C@H:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1>ClCCl>[Cl:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([N:19]2[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][C@H:14]2[CH3:13])=[N:3][N:4]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: Clc1nnc(Cl)c2ccccc12
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(Cl)c2ccccc12
Temperature: 120 °C

Procedure:
1,4-dichlorophthalazine (5.00 g, 25.1 mmol) and (R)-tert-butyl 3-methylpiperazine-1-carboxylate (11.06 g, 55.2 mmol) were mixed intimately and placed in a flask under an Argon atmosphere. The flask was heated at 120° C. for approximately 16 hours, after which time LC/MS showed disappearance of the starting material. The reaction was cooled, taken up in dichloromethane (150 mL), and washed once with aqueous sodium bicarbonate (50% of saturated) and once with saturated sodium chloride solution. The organic phase was dried (MgSO4) and evaporated to give an orange oil. Chromatography over silica gel with a gradient of hexanes/0-10% acetone gave a pale yellow solid JK-1. MS (M+H)+=363.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[O:27]1CCC[CH2:28]1>>[Cl:8][C:6]1[C:5]([O:9][CH:10]([CH3:12])[CH3:11])=[CH:4][C:3]2[N:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH2:15]3)[C:28](=[O:27])[NH:1][C:2]=2[CH:7]=1
Reactant: C1CCOC1
Reactant: CC(C)Oc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)c(N)cc1Cl
Product: CC(C)Oc1cc2c(cc1Cl)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 65 %

Procedure:
A solution of 1,1-dimethylethyl 4-({2-amino-4-chloro-5-[(1-methylethyl)oxy]phenyl}amino)-1-piperidinecarboxylate (D85, 200 mg, 0.52 mmol) in tetrahydrofuran (2 ml) was treated with N,N′-carbonyldiimidazole (125 mg, 0.78 mmol) and heated at 50° C. for 17 hrs. The mixture was concentrated under vacuum and the residue treated with Na2CO3 solution (5 ml) and extracted with ethyl acetate (2×10 ml). The combined extract was dried (MgSO4), concentrated under vacuum to leave the title compound as an oil (140 mg, 65%). M+−H=408.2.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1)#N.N1[C:19]2[C:14](=C[CH:16]=[CH:17][CH:18]=2)C=C1>>[CH2:16]1[C:17]2[CH:18]([N:9]=[C:6]3[C:5]=2[CH:4]=[CH:3][CH:8]=[CH:7]3)[CH2:19][CH2:14]1
Reactant: N#Cc1ccc(NN)cc1
Reactant: c1ccc2[nH]ccc2c1
Product: c1ccc2c(c1)=NC1CCCC=21

Procedure:
In Step B, (R,S)-2-(3-oxo-cyclopentyl)-isoindole-1,3-dione (1) is reacted with 4-cyano-phenylhydrazine in a typical Fischer indole synthesis to give a tetrahydrocyclopenta[b]indole of formula (2). The skilled artisan will recognize that there are a variety of acidic conditions to effect a Fischer indole synthesis, including both proton and Lewis acids. The preferred conditions use a mixture of glacial acetic acid with 4 N HCl in dioxane, at a temperature of about 50° C. to the reflux temperature of the solvent, for about 4 to 24 hours. The product is isolated by addition of water followed by filtration of the resulting solid. The solid is sonicated in methanol to give material of sufficient purity. Alternatively, the reaction is effected using a Lewis acid, such as zinc chloride, in an amount of about 2 to 4 equivalents. Other preferred conditions for Step B use ethanol at reflux temperature for about 4 to 24 hours. The product is isolated and may be purified by filtration of the reaction mixture, followed by silica gel chromatography of the filtrate.
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][OH:11])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].S(O[C@@H:23]1[CH2:28][CH2:27][O:26][C:24]1=[O:25])(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl>[C:3]([NH:10][O:11][C@H:23]1[CH2:28][CH2:27][O:26][C:24]1=[O:25])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: CC(C)(C)OC(=O)NO
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NO[C@H]1CCOC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A suspension of 60% NaH (350 mg, 8.8 mmol) in dry CH2Cl2 under N2 at 0° C. was added a solution of BocNHOH in CH2Cl2 (5 mL). The reaction mixture was stirred at 0° C. for 30 minutes, where after a solution of (R)-α-tosyloxy-γ-butyrolactone (2 g, 7.8 mmol) in CH2Cl2 (5 mL) was added. The reaction mixture was allowed to warm up to room temperature, and left with stirring overnight. The reaction mixture was quenched with 1M phosphate buffer pH=6.3 (20 mL) and the organic phase separated. The aqueous phase was extracted with CH2Cl2 (2×20 mL), and the combined organic fractions extracted with NaCl (aq., sat.) (15 mL). The organic fraction was dried with Na2SO4, filtered and evaporated to dryness. Column chromatography (150 g SiO2, eluent: EtOAc:PE60/80=1:2) gave 1.5 g (89%) of (S)-α-N-Boc-aminoxy-γ-butyrolactone. [α]D25=−42°; [α]36525=−127°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=O)[CH2:10]2)(=[O:3])[CH3:2].[ClH:16].[CH3:17][NH:18][CH3:19]>>[ClH:16].[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH:9]([N:18]([CH3:19])[CH3:17])[CH2:10]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CCC(=O)C2
Reactant: CNC
Agent: Cl
Product: CC(=O)Nc1cccc2c1CCC(N(C)C)C2

Procedure:
Starting from 2.03 g (0.01 mol) of 5-acetylamino-2-tetralone and 2.45 g (0.03 mol) of dimethylaminehydrochloride the title compound is obtained analogously to Example 4.1.11 in a yield of 1.35 g (50.2% of theory) and with a melting point of 199° C. which does not change after recrystallisation from methanol/ether.
Reaction SMILES: CS[C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[NH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1>C(#N)C>[N+:5]([NH:4][C:3]([N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)=[NH:8])([O-:7])=[O:6]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: CC#N
Product: N=C(N[N+](=O)[O-])N1CCCC1
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a mixture of 1.0g of S-methyl-N-nitroisothiourea and 15ml of acetonitrile was dropwise added 0.61g of pyrrolidine within 2 minutes, followed by stirring for 30 minutes. The reaction mixture was concentrated. The resulting precipitate was washed with ethyl ether to afford 1.09g of 1-(N-nitroamidino)pyrrolidine as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]1([CH2:47][CH2:48][CH2:49][CH2:50][NH2:51])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:51][CH2:50][CH2:49][CH2:48][CH2:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCCCCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCCCc1ccccc1

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 4-phenylbutylamine (46 uL) according to Method A to give the title compound (34 mg). 1H-NMR (400 MHz, CD3OD) d 7.76 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.26-7.11 (m, 10H), 6.98 (d, J=8.5 Hz, 1H), 4.76 (s, 2H), 4.50 (t, J=6.9 Hz, 1H), 4.23 (dd, J=5.2 Hz, J=9.3 Hz, 1H), 3.17 (m, 1H), 3.09-2.91 (m, 4H), 2.75 (dd, J=9.4 Hz, J=13.6 Hz, 1H), 2.58 (t, J=7.5 Hz, 2H), 1.54 (m, 2H), 1.42 (m, 2H), 1.34 (s, 9H); IR (KBr) 3296, 2925, 1738, 1687, 1643 cm−1; HRMS m/z 661.2987 (calc. of monoisotopic mass for C36H43N3O9 gives 661.2999).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][CH2:24][C@H:25]([OH:27])[CH3:26]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:23][CH2:24][C@H:25]([OH:27])[CH3:26])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Reactant: C[C@@H](O)CN
Solvent: C1CCOC1
Product: C[C@@H](O)CNc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cn1
Temperature: 140 °C
Yield: 17.4 %

Procedure:
Following the procedure described above in Example 51, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile (0.10 g, 0.32 mmol) was reacted with (R)-1-amino-2-propanol (0.47 g, 6.32 mmol) in 2 mL of THF. The reaction mixture was heated up in a sealed vial in a microwave reactor at 140° C. for 40 min. The crude product was purified by preparative HPLC and lyophilized to give a yellow solid (20.7 mg, 17.6% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 1.08 (d, J=6.32 Hz, 3 H) 3.08-3.20 (m, 2 H) 3.76-3.90 (m, 1 H) 4.73 (d, J=4.55 Hz, 1 H) 6.55-6.68 (m, 1 H) 6.95 (s, 1 H) 7.25-7.34 (m, 1 H) 7.36-7.47 (m, 1 H) 7.50-7.60 (m, 1 H) 8.21 (s, 1 H) 8.78 (s, 1 H) 9.60 (s, 1 H); HRMS (ESI+) calcd for C18H15ClFN5O 372.10219, found (MH+) 372.1019.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[C:9]1([CH3:19])[C:10]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:15]([C:10]1[C:9]([CH3:19])=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:17])=[O:16]
Reactant: Cc1noc(N)c1Br
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)Nc1onc(C)c1Br
Yield: 88 %

Procedure:
N-(4-Bromo-3-methyl-5-isoxazolyl)-2-toluenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2-toluenesulfonyl chloride according to the procedures described. in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give white crystalline solid, m.p. 93-96° C., yield 88%.
Reaction SMILES: [C:1]([CH:3]1[CH2:7][S:6][CH2:5][C:4]1=[O:8])#[N:2].[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=1>CN(C)C=O>[C:1]([C:3]1([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=2)[C:4](=[O:8])[CH2:5][S:6][CH2:7]1)#[N:2]
Reactant: N#CC1CSCC1=O
Reactant: COC(=O)C(C)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)c1ccc(CC2(C#N)CSCC2=O)cc1
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
4-Cyano-3-tetrahydrothiophenone (5.0 g) was dissolved in N,N-dimethylformamide (30 ml), then, sodium hydride (oil, about 60%, 950 mg) was added under ice cooling, and stirred at the same temperature for 30 minutes. Then, to the mixture was added a solution of methyl 2-(4-bromomethylphenyl)propionate (10.1 g) in N,N-dimethylformamide (10.0 ml) under ice cooling, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give the title compound (5.5 g, 46%).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9](Br)([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Br:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1I.O>CN(C)C(=O)C.[Zn].[Cu]Br>[CH2:1]([O:3][P:4]([C:9]([C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[Br:13])([F:11])[F:10])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: Cc1ccc(I)c(Br)c1
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Agent: [Cu]Br
Agent: [Zn]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C)cc1Br
Reaction time: 3 h
Yield: 82.3 %

Procedure:
A solution of (bromo-difluoro-methyl)-phosphonic acid diethyl ester (25.00 g, 93.6 mmol) in N,N-dimethylacetamide (50 mL) was added drop wise into a suspension of activated zinc (6.12 g, 93.6 mmol) under Argon. The reaction was initiated by heating and kept under 50° C. After the mixture was stirred for 3 h, copper (I) bromide (13.43 g, 93.6 mmol) was added and stirred for 1 h. A solution of 2-bromo-1-iodo-4-methyl-benzene (11.88 g, 40.0 mmol) in N,N-dimethylacetamide (25 mL) was added slowly to the reaction mixture. The resulting suspension was then stirred at room temp for 18 h. Water (100 mL) was added to the reaction mixture and the solution filtered through celite. The filtrate was diluted with EtOAc (250 mL) and organic layer was washed with H2O (50 mL), NaHCO3 (5%, 50 mL) and H2O (50 mL). The solvent was removed and the residue was purified by column chromatography on silica gel, eluting with hexanes/EtOAc (4:1) to provide a colorless oil (11.75 g, 82%): 1H NMR (300 MHz, CDCl3) δ 7.51 (d, 1H), 7.49 (s, 1H), 7.19 (d, 1H), 4.26 (m, 4H), 2.36 (s, 3H), 1.48 (s, 9H), 137 (m, 6 H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.[CH3:9][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH3:9][C:4]1([CH2:7][NH2:8])[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#CC1CCOCC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1(CN)CCOCC1
Reaction time: 1.5 h

Procedure:
A mixture of tetrahydropyran-4-carbonitrile (5.00 g) and THF (50 ml) was admixed at 0° C. with lithium hexamethyldisilazide (1 M, 63 ml), and, after 90 minutes, methyl iodide (4.26 ml) was added dropwise with good cooling. After 12 hours, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was dissolved in THF (200 ml), and lithium aluminum hydride (3.79 g) was added. The mixture was boiled at reflux for 6 hours, Water (3.8 ml) and then sodium hydroxide solution (40%; 3.8 ml) were cautiously added dropwise to the cooled suspension. The precipitate was filtered off and the filtrate was concentrated. This afforded the product with the molecular weight of 129.20 (C7H15NO); MS (ESI): 130 (M+H+).
Reaction SMILES: C([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]([O:27][CH3:28])=[O:26])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C>CO>[C:25]([C:21]1[NH:20][CH:24]=[CH:23][N:22]=1)([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ncc[nH]1

Procedure:
After a solution of 3.2 g (8.7 mmol.) of 1-trityl-2-carbomethoxyimidazole in 40 mL of a 5% solution of acetic acid in methanol was refluxed for 30 minutes, it was concentrated in vacuo. Recrystallization from ethanol afforded colorless needles, mp 187°-188° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:17][CH2:16][C@@H:15](O)[CH2:14][C@H:13]1[CH2:12][S:11][C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:9]2.[F:27]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C(N(CC)CC)C>C1COCC1>[F:27][C@H:15]1[CH2:16][CH2:17][C@:8]2([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:9]=[C:10]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[S:11][CH2:12][C@@H:13]2[CH2:14]1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CC[C@@H](O)C[C@H]2CS1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3ccccc3F)CC[C@H](F)C[C@H]2CS1
Reaction time: 15 h

Procedure:
tert-Butyl(±)-[(4aR*,6R*,8aS*)-8a-(2-fluorophenyl)-6-hydroxy-4a,5,6,7,8,8a-hexahydro-4H-benzo[d][1,3]thiazin-2-yl]carbamate obtained in Preparation Example 64-(4) (500 mg) was dissolved in THF. Then, perfluorobutanesulfonyl fluoride (0.43 mL, specific gravity: 1.682 g/cm3), a triethylamine-trihydrofluoric acid complex (0.39 mL, specific gravity: 0.989 g/cm3) and triethylamine (0.99 mL, specific gravity: 0.73 g/cm3) were sequentially added at room temperature. After completion of the addition, the mixture was stirred for 15 hours. The reaction solution was concentrated under reduced pressure and then the residue was purified by silica gel column chromatography to obtain the title compound (351 mg).