Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:17][N:18]([CH3:31])[CH2:19][CH2:20][CH2:21][C:22]1[C:23]([CH3:30])=[C:24]([CH:28]=O)[NH:25][C:26]=1[CH3:27]>N1CCCCC1.C(O)C>[CH3:31][N:18]([CH3:17])[CH2:19][CH2:20][CH2:21][C:22]1[C:23]([CH3:30])=[C:24]([CH:28]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:25][C:26]=1[CH3:27]
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN(C)C
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)c(C)c1CCCN(C)C

Procedure:
A mixture of 6-pyridin-3-yl-1,3-dihydroindol-2-one (100 mg, 0.48 mmol), 4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (100 mg, 0.48 mmol), and piperidine (1 drop) in ethanol (2 mL) was stirred at reflux overnight. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 3-[4-(3-dimethylaminopropyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]-6-pyridin-3-yl-1,3-dihydroindol-2-one.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[NH:21]1[CH2:24][CH:23]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:22]1.C(OC)(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:21]3[CH2:24][CH:23]([C:25]([OH:28])([CH3:27])[CH3:26])[CH2:22]3)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: CC(C)(O)C1CNC1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cn1c(CCN2CC(C(C)(C)O)C2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 22.6 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (300 mg, 1.01 mmol) in DCE (20 mL) was added 2-azetidin-3-ylpropan-2-ol (118 mg, 1.02 mmol), trimethyl orthoformate (1.11 mL, 10.14 mmol) and acetic acid (0.06 mL, 1.01 mmol). The reaction mixture was stirred at room temperature for 6 h, sodium triacetoxyborohydride (323 mg, 1.52 mmol) was added and the resulting mixture stirred for a further 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-10% MeOH in DCM) to give the title compound as a pale yellow oil (90 mg, 23%). LCMS (Method A): RT=2.37 min, [M+H]+ 395.2
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].C(=O)(O)[O-].[Na+].O1CCOCC1.[Cl:27][CH2:28][C:29](Cl)=[O:30]>CCOCC.O>[Cl:27][CH2:28][C:29]([N:7]([CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)[C:8]1[C:9]([CH3:15])=[CH:10][CH:11]=[CH:12][C:13]=1[CH3:14])=[O:30]
Reactant: Cc1cccc(C)c1NCC1OCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(C)c1N(CC1OCCO1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
N-(1,3-Dioxolan-2-ylmethyl)-2,6-dimethylaniline (7.8 grams), sodium bicarbonate (7.0 grams), dioxane (20 ml) and water (4 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture was cooled to a temperature of about 0°C and chloroacetyl chloride (5.0 grams) was added, with stirring, over a period of about 15 minutes. After the addition was completed stirring was continued for a period of about 1 hour. After this time ether (100 ml) was added to the mixture and the resulting solution was washed with water. The washed solution was then dried over anhydrous magnesium sulfate and stripped of solvents leaving a solid residue. The residue was recrystallized from an ether-pentane mixture to yield the desired product N-α-chloroacetyl-N-(1,3-dioxolan-2-ylmethyl)-2,6-dimethylaniline having a melting point of 58° to 60°C.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[CH3:13]I>>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:13]
Reactant: CI
Reactant: Oc1ccccc1OC(F)(F)F
Product: COc1ccccc1OC(F)(F)F
Reaction time: 17 h
Yield: 78 %

Procedure:
2-Trifluoromethoxyanisole was prepared from 2-trifluoromethoxyphenol by following Method C in 78% yield. Methyl iodide was used in this reaction as an alkylating agent and the reaction was conducted at room temperature for 17 h. The product was used without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:28][CH3:29])=[C:14]([C:16]2(O)[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[NH:18][C:17]2=[O:26])[CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[OH:37][C@H:38]1[CH2:42][NH:41][C@H:40]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[CH2:39]1>>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:28][CH3:29])=[C:14]([C:16]2([N:41]3[CH2:42][C@H:38]([OH:37])[CH2:39][C@H:40]3[C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[NH:18][C:17]2=[O:26])[CH:15]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COc1ccc(CO[Si](C)(C)C(C)(C)C)cc1C1(O)C(=O)Nc2ccc(Cl)cc21
Reactant: CN(C)C(=O)[C@@H]1C[C@@H](O)CN1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CO[Si](C)(C)C(C)(C)C)cc1C1(N2C[C@H](O)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 50.0 g of the compound obtained in Step 204-3 and (4R)-4-hydroxy-N,N-dimethyl-L-prolinamide trifluoroacetate (138 mmol) as starting materials, respectively 5.25 g (Isomer A: colorless amorphous) and 14.9 g (Isomer B: colorless amorphous) of two species of diastereoisomers of the title compound and a mixture of isomers A and B (11.0 g) were obtained by a similar method to Step 28-2.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[C:10]([F:11])=[CH:9][C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[C:7]([CH3:17])[CH:6]=1)[CH3:4].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:32]=[CH:31][C:23]2[O:24][C@H:25]([C:28](O)=[O:29])[CH2:26][O:27][C:22]=2[CH:21]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:11][C:10]1[CH:9]=[C:8]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:7]([CH3:17])=[CH:6][C:5]=1[C@H:3]([NH:2][C:28]([C@H:25]1[O:24][C:23]2[CH:31]=[CH:32][C:20]([C:19]([F:34])([F:18])[F:33])=[CH:21][C:22]=2[O:27][CH2:26]1)=[O:29])[CH3:4]
Reactant: Cc1cc([C@@H](C)N)c(F)cc1NS(C)(=O)=O
Reactant: O=C(O)[C@@H]1COc2cc(C(F)(F)F)ccc2O1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@@H](C)NC(=O)[C@@H]2COc3cc(C(F)(F)F)ccc3O2)c(F)cc1NS(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of (R)—N-(4-(1-aminoethyl)-5-fluoro-2-methylphenyl)methanesulfonamide hydrochloride (48 mg, 0.17 mmol) in N,N-dimethylformamide (3 mL) was stirred for 5 mins. (S)-6-trifluoromethyl-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxylic acid (40 mg, 0.1 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (200 mg, 0.4 mmol) and N,N-diisopropylethylamine (50 μL, 0.3 mmol) was added and the reaction was stirred at 50° C. overnight. Purification by HPLC afforded the final compound. m/z=477.1 (M+H)+. 1H NMR (400 MHz; DMSO-d6) δ 9.16 (s, 1H), 8.66 (t, 1H, J=8.3 Hz), 7.38 (d, 1H, J=2.2 Hz), 7.28-7.21 (m, 2H), 7.05-7.01 (m, 1H), 6.88 (d, 1H, J=8.5 Hz), 5.17-5.08 (m, 1H), 5.04-5.01 (m, 1H), 4.45-4.41 (m, 1H) 4.37-4.31 (m, 1H), 2.99 (s, 3H), 2.09 (s, 3H), 1.37 (d, 3H, J=6.9 Hz).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:28])([C:7]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])[C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-])=O)[CH:19]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:29].O>C(OCC)(=O)C.CO.[Cl-].[Cl-].[Cl-].[Ti+3]>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:28])([C:7]3[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:27])[C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([NH2:24])[CH:19]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:29]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(NC(=O)c4cccc([N+](=O)[O-])c4)cc3CC[C@@H]12
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CN1C(=O)CC[C@]2(C)c3ccc(NC(=O)c4cccc(N)c4)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 200 mg portion of the product of Example 268 was dissolved in ethyl acetate and methanol. Twenty ml of 20% aqueous titanium trichloride was added, the flask was evacuated and the mixture was stirred at ambient temperature for 16 h. The mixture was then made basic with ammonium hydroxide, resulting in an exotherm and the formation of a dark solid. Water was added to break up the solid, and the mixture was extracted with dichloromethane. The remaining reaction mixture was filtered, and the solid filter cake was washed with dichloromethane. The organic layers were collected, dried and concentrated under vacuum. The residue was recrystallized from dichloromethane/hexane to obtain 190 mg of the desired product. It was purified by chromatography over silica gel, eluting with ethyl acetate going to 10% methanol/ethyl acetate, and recrystallized again from dichloromethane/hexane to obtain 80.5 mg of purified product, m.p. 154°-156°. FDMS: m/e=363.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:21]2[CH2:26][CH2:25][CH:24]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)=[C:13]([C:15]#[C:16][CH:17]([OH:20])[CH2:18][CH3:19])[CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[CH3:40]I>>[F:37][C:2]([F:1])([F:36])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:21]2[CH2:22][CH2:23][CH:24]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:28])=[O:29])[CH2:25][CH2:26]2)=[C:13]([C:15]#[C:16][CH:17]([O:20][CH3:40])[CH2:18][CH3:19])[CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CI
Reactant: CCC(O)C#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCC(S(=O)(=O)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Product: CCC(C#Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N1CCC(S(=O)(=O)c2ccccc2)CC1)OC

Procedure:
Following the procedure described for Example 155, -(5-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-2-(4-(phenylsulfonyl)piperidin-1-yl)phenyl)pent-1-yn-3-ol (Example 162) was reacted with sodium hydride and methyl iodide to afford 1,1,1,3,3,3-hexafluoro-2-(3-(3-methoxypent-1-ynyl)-4-(4-(phenylsulfonyl)piperidin-1-yl)phenyl)-2-propanol as a mixture of enantiomers.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:28][O:29][CH2:30][CH3:31])[N:18]([CH2:19][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])([CH3:22])[CH3:21])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>CN(C)C=O>[CH2:30]([O:29][CH2:28][C:17]1[N:18]([CH2:19][C:20]([CH3:22])([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH3:21])[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH:5][C:1](=[O:3])[CH3:2])[C:15]=2[N:16]=1)[CH3:31]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NS(C)(=O)=O
Reactant: CC(=O)Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOCc1nc2c(NC(C)=O)nc3ccccc3c2n1CC(C)(C)NS(C)(=O)=O
Temperature: 25 °C

Procedure:
Acetyl chloride (150 μL, 1.1 equivalents (eq)) was added to N-{2-[4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}methanesulfonamide (750 mg, 1 eq) in a mixture of triethylamine (401 μL, 1.5 eq) and N,N-dimethylformamide (DMF) (5 mL) and the resulting solution was stirred at ambient temperature. After 2 hours acetic anhydride (1 mL) was added. The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (silica gel eluted with a gradient of 0-10% methanol in dichloromethane containing 1% ammonium hydroxide) to provide 278 mg of N-(2-ethoxymethyl-1-{2-methyl-2-[(methylsulfonyl)amino]propyl}-1H-imidazo[4,5-c]quinolin-4-yl)acetamide as a white powder, mp 75-76° C. Anal. calcd for C20H27N5O4S.0.40H2O: C, 54.50; H, 6.36; N, 15.89. Found: C, 54.70; H, 6.10; N, 15.58.
Reaction SMILES: [F:1][C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9]C(=O)OC(C)(C)C)[CH2:4][CH:3]=1.[ClH:17].CC(O)=O>>[ClH:17].[F:1][C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH2:9])[CH2:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCC1CC=C(F)CC1
Agent: Cl
Solvent: CC(=O)O
Product: NCC1CC=C(F)CC1

Procedure:
tert-Butyl [(4-fluorocyclohex-3-en-1-yl)methyl]carbamate (1.62 g, 7.06 mmol) was stirred in 25 mL of 1M HCl/AcOH at rt for 2 h. The solvent was evaporated and the product was precipitated in ether, filtered and dried under vacuum. Yield: 1.13 g (97%). 1H NMR (400 MHz, METHANOL-D4) δ 1.44-1.53 (m, 1 H), 1.80-1.89 (m, 2 H), 1.90-1.98 (m, 1 H), 2.16-2.23 (m, 2 H), 2.26-2.34 (m, 1 H), 2.88 (d, J=6.25 Hz, 2 H), 5.12-5.19 (m, 1 H).
Reaction SMILES: CO[C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)=[O:4].[CH3:16][NH2:17]>>[CH3:16][NH:17][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)=[O:4]
Reactant: CN
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Product: CNC(=O)c1ccc2c(N)cccc2n1
Temperature: 25 °C

Procedure:
76 mg (0.376 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester is dissolved with 10 ml of a 2.0 M methanolic methylamine solution. After 90 minutes under reflux and another 16 hours at room temperature, the solvent is removed under reduced pressure, and the residue is purified on silica gel with hexane-ethyl acetate (0-80%). 72 mg (95% of theory) of the product is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=1)=[O:14])[CH2:8]2)([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CN(C)C=O.O>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][CH:7]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=1)=[O:14])[CH2:8]2
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)C1Cc2cccc([N+](=O)[O-])c2C1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cccc2c1CC(C(=O)Nc1ccc(N3CCOCC3)cc1)C2
Temperature: 90 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
To a solution of the crude nitro compound (3.5 g) in N,N-dimethylformamide (25 mL) and water (3 mL) was added, in portions, sodium dithionite (7.0 g, 40 mmol). The mixture was stirred at 90° C. for 3 hours. The solvent was evaporated in vacuo and water (200 mL) was added. The mixture was made alkaline with 2 M sodium hydroxide and extracted with chloroform. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give 1.1 g of the crude product (GC purity 89%): EIMS (70 eV) m/z (relative intensity) 337 (100, M+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][O:16][P:17]([O:20]C)[O:18][CH3:19]>C1(C)C=CC=CC=1>[CH3:15][O:16][P:17]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:20])[O:18][CH3:19]
Reactant: COP(OC)OC
Reactant: BrCc1ccccc1-c1ccccc1
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccccc1-c1ccccc1)OC
Yield: 96.9 %

Procedure:
A solution of 2-(bromomethyl)biphenyl (4.94 g, 0.020M) and trimethylphosphite (5.0 mL, 5.26 g, 0.042M) in toluene (25 mL) is heated at reflux temperature for 24 hours Toluene and excess trimethylphosphite are removed under reduced pressure and the oily residue is chromatographed over silica gel (195 g, 40-63 μm, EtOAc, 50 mL fractions) using EtOAc to elute the column. The title compound (5.35 g, 0.0194M, 97%) is obtained in fractions 10-19 and is a colorless viscous oil.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C@@H:9]1[CH2:13][NH:12][CH2:11][C@H:10]1[CH2:14][NH:15][C:16]([C:18]1[S:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:17].[N+](C1C=CC([O:33][C:34](=O)[NH:35][C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]3=[O:48])=[CH:38][C:37]=2[F:49])=CC=1)([O-])=O>>[F:49][C:37]1[CH:38]=[C:39]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])[CH:40]=[CH:41][C:36]=1[NH:35][C:34]([N:12]1[CH2:13][C@@H:9]([OH:8])[C@H:10]([CH2:14][NH:15][C:16]([C:18]2[S:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[O:17])[CH2:11]1)=[O:33]
Reactant: O=C(NC[C@@H]1CNC[C@H]1O)c1ccc(Cl)s1
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@H]1O)c1ccc(Cl)s1

Procedure:
79.7 Using general method H, to (3S,4S)-5-chloro-thiophene-2-carboxylic acid (4-hydroxy-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (3R,4S)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-hydroxy-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. Colorless solid. MS 491.0 ([M+H]+)
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18](O)[C:13]=3[C:12]3[CH:22]=[C:23]([F:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:28]>ClC1C=CC=CC=1.ClCCl>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([Cl:28])[C:13]=3[C:12]3[CH:22]=[C:23]([F:26])[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: N#Cc1ncc2c(c1O)c1cc(F)cnc1n2S(=O)(=O)c1ccccc1
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: N#Cc1ncc2c(c1Cl)c1cc(F)cnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 60.8 %

Procedure:
A solution of 9-benzenesulfonyl-3-fluoro-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (500 mg, 1.36 mmol) and phosphorus pentachloride (708 mg, 3.4 mmol) in chlorobenzene (1.5 mL) was heated at 110° C. for 1 hour. The reaction mixture was cooled to ambient temperature and then the solvent removed in-vacuo to afford a residue. The resultant residue was dissolved in dichloromethane (50 mL) and then the solution was diluted with ice/water (50 mL). The layers were separated and the aqueous layer further extracted with dichloromethane (50 mL). The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The resultant residue was triturated with diethyl ether and dried to afford the title compound as a tan solid (320 mg, 65%). 1H NMR (400 MHz, CDCl3): 9.81 (s, 1H), 8.69 (d, J=2.8 Hz, 1H), 8.50 (dd, J=7.6, 2.8 Hz, 1H), 8.24 (d, J=8.0 Hz, 2H), 7.65 (t, J=7.5 Hz, 1H), 7.53 (t, J=7.8 Hz, 2H).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([C:23]([O:25]CC)=O)[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4].C([NH2:31])=O.C[O-].[Na+].CO>O.CN(C)C=O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:7]([C:23](=[O:25])[NH2:31])[C:6]1=[O:28])[CH2:2][CH2:3][CH3:4]
Reactant: NC=O
Reactant: CCCCn1c(=O)c(C(=O)OCC)c(-c2cccc(OC)c2)c2cccnc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)c(C(N)=O)c(-c2cccc(OC)c2)c2cccnc21
Temperature: 60 °C
Reaction time: 9 h
Yield: 89.6 %

Procedure:
A mixture of 1-butyl-3-ethoxycarbonyl-4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridine (45.0 g, 120 mmol), formamide (15.5 ml, 390 mmol) and dimethylformamide (120 ml) was dissolved at 60° C., and thereto was added a 25% solution of sodium methoxide in methanol (108 ml, 390 mmol), and the mixture was stirred at 60° C. for 9 hours. The mixture was cooled to 0° C., and thereto was added water (1.2 liter), and the mixture was stirred for 15 minutes. The precipitated solid was collected by filtration, washed with ethanol, and to dried to give the title compound (37.8 g, yield; 87 %) as white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([Cl:11])[N:3]=1.C(NC(=NC(C)C)O[C:18]([CH3:21])([CH3:20])[CH3:19])(C)C>C1COCC1>[C:18]([O:9][C:8]([C:6]1[CH:5]=[C:4]([Cl:11])[N:3]=[C:2]([Cl:1])[CH:7]=1)=[O:10])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)c1cc(Cl)nc(Cl)c1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of 2,6-dichloropyridine-4-carboxylic acid (8.28 g, 43.1 mmol, Aldrich) in dry THF (30 ml) was added N,N′-diisopropyl-O-t-butylisourea (17 ml, 3.6 M) dropwise over 1 minute. The resulting mixture was stirred at room temperature overnight. The material was then heated to 65° C. and additional N,N′-diisopropyl-O-t-butylisourea (10 ml) was added dropwise. The mixture was stirred for 1 hour and cooled to room temperature. After removing volatiles, the remainder was purified by flash silica gel column (EtOAc/hexanes 5:95 followed by 7.5:92.5) affording tert-butyl-2,6dichloro-4-pyridine carboxylate (7.83 g, 73%) as a white solid. MS (ES+): 248.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH:11]1[CH2:16][C:15](=[O:17])[O:14][C:12]1=[O:13].[CH2:18]([NH2:30])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OCC)C>[CH2:18]([NH:30][C:12](=[O:13])[CH:11]([S:10][C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[CH2:16][C:15]([OH:14])=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: O=C1CC(Sc2nc3ccccc3s2)C(=O)O1
Reactant: CCCCCCCCCCCCN
Solvent: CCOCC
Product: CCCCCCCCCCCCNC(=O)C(CC(=O)O)Sc1nc2ccccc2s1

Procedure:
A mixture of 7 parts of (benzothiazol-2-ylthio)succinic anhydride, 4.8 parts of dodecylamine and 60 parts of diethyl ether is heated at 35° for 3 hours. Filtration of the resulting mixture gives a mixture of the two isomeric mono(dodecylamides), melting at 117°-121°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[N:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.C(Cl)(Cl)Cl.[OH2:32]>S([O-])([O-])(=O)=S.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:9]2[N:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)(=[O:25])=[O:32])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Reactant: COc1ccc(Sc2cccc(Cl)c2)nn1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(S(=O)(=O)c2cccc(Cl)c2)nn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
A mixture of 3-(3-chloro-phenylsulfanyl)-6-methoxy-pyridazine (529 mg), m-chloroperbenzoic acid (MCPBA) (760 mg) and chloroform (20 mL) was prepared and stirred at room temperature for two hours. The reaction mixture was diluted with 5% sodium thiosulfate (20 mL) followed by water (30 mL). The chloroform layer was collected, dried over anhydrous sodium sulfate, filtered and the dried chloroform portion was evaporated to dryness. The resulting solid residue was purified by silica gel chromatography (3:1 hexane/ethyl acetate as eluent) to obtain 3-(3-chloro-benzenesulfonyl)-6-methoxy-pyridazine (29%, 173 mg); mass spectrum, M+, 285.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1[CH:21]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:14][CH2:21][C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(N)c1C(=O)OC
Reactant: O=Cc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1cccc(NCc2ccco2)c1C(=O)OC
Reaction time: 0.08 h
Yield: 109.2 %

Procedure:
To a stirred solution of 3-amino-phthalic acid dimethyl ester (8.23 g, 39.32 mmol) in methylene chloride (200 ml) under a nitrogen atmosphere, 2-furaldehyde (8.14 ml, 98.30 mmol) and acetic acid (13.57 ml, 235.92 mmol) were added. The mixture was stirred for 5 minutes, followed by addition of sodium triacetoxyborohydride (25 g, 117.96 mmol). The reaction was stirred overnight, washed with water (2×200 ml), saturated aqueous sodium bicarbonate (2×200 ml), and brine (200 ml), and dried over MgSO4. The solvent was evaporated in vacuo to give a brown oil (12.42 g), which was used directly without purification.