Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][CH:9]=[CH:8]2)=[O:4].O1CCCC1.[Br:20]N1C(C)(C)C(=O)N(Br)C1=O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([Br:20])=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2ncccc2c1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2ncc(Br)cc2c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 9.6 %

Procedure:
To a mixture of quinoline-6-carboxylic acid methyl ester (0.50 g, 2.7 mmol) and tetrahydrofuran (10 mL) was added 1,3-dibromo-5,5-dimethyl hydantoin (0.76 g, 2.7 mmol) on an ice bath, and the solution was stirred at 50° C. for 4 hours. Water, an aqueous solution of saturated sodium bicarbonate and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was washed with brine, the solvent was then evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1), and the title compound (69 mg, 0.26 mmol, 10%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([CH2:23][CH3:24])[C:10]1=[O:25].[CH2:26]([N:28]([CH2:39][CH3:40])[CH2:29][CH2:30][O:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH3:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([O:31][CH2:30][CH2:29][N:28]([CH2:39][CH3:40])[CH2:26][CH3:27])=[CH:38][CH:37]=3)=[N:15][CH:16]=2)[N:11]([CH2:23][CH3:24])[C:10]1=[O:25]
Reactant: CCN(CC)CCOc1ccc(N)cc1
Reactant: CCN1C(=O)N(c2c(Cl)cccc2Cl)Cc2cnc(S(C)(=O)=O)nc21
Product: CCN(CC)CCOc1ccc(Nc2ncc3c(n2)N(CC)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 180 °C
Yield: 22.7 %

Procedure:
A mixture of 100 mg (0.25 mmol) of 3-(2,6-dichlorophenyl)-1-ethyl-7-methanesulfonyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one and 120 mg (0.5 mmol) of 4-[2-(diethylamino)ethoxy]aniline was heated at 180° C. for 35 minutes and then cooled. The residue was chromatographed on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined and evaporated. The residue was evaporated with toluene and then dissolved in 50 ml of dichloromethane. The solution was washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 30 mg (22%) of 3-(2,6-dichlorophenyl)-1-ethyl-7-[4-[2-(diethylamino)ethoxy]anilino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as an orange colored solid of melting point 85° C.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([NH2:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.O=[C:12]([CH2:16][CH3:17])[C:13]([OH:15])=[O:14]>>[CH:1]1([CH2:6][CH2:7][C:8]([NH:10]/[C:12](=[CH:16]\[CH3:17])/[C:13]([OH:15])=[O:14])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCC(=O)C(=O)O
Reactant: NC(=O)CCC1CCCC1
Product: C/C=C(\NC(=O)CCC1CCCC1)C(=O)O
Reaction time: 8 h

Procedure:
A solution of 1.41 g (10 mmole) of 3-cyclopentylpropionamide and 1.53 g (15 mmole) of 2-ketobutyric acid was stirred and refluxed under a small Dean-Stark trap. After 8 hrs. the solution was cooled, resulting in heavy crystallization. The solid was collected on a filter and washed with toluene and CH2Cl2. Yield of white crystals=1.44 g, mp 180.5°-182° (prelim. softening). The material was recrystallized from methyl ethyl ketone. Yield of white needles=0.63 g (28%), mp 184°-185° (slight prelim. softening). Tlc (4:1 toluene-AcOH) now showed a single spot, and NMR indicated essentially pure Z-isomer.
Reaction SMILES: CC[N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C.[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.N1CCCC1>CN(C=O)C.O>[CH3:10][O:11][C:12](=[O:22])[C:13]1[CH:14]=[CH:15][C:16]([C:17]([N:3]2[CH2:4][CH2:6][CH2:9][CH2:7]2)=[O:19])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNC1
Solvent: O
Product: COC(=O)c1ccc(C(=O)N2CCCC2)cc1
Reaction time: 0.03 h
Yield: 8.2 %

Procedure:
DIPEA (1.26 g, 9.7 mmol) was added to a stirred solution of terephthalic acid monomethyl ester (500 mg, 2.77 mmol) in DMF (3 mL) followed by HOBt (410 mg, 3.0 mmol) and EDCI (1.32 g, 7.0 mmol). After 2 minutes of stirring, pyrrolidine (215 mg, 3.0 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with cold water, the precipitate was collected to afford 53 mg (81.9% Yield) of 4-(pyrrolidine-1-carbonyl)-benzoic acid methyl ester. LiOH.H2O (285 mg, 6.8 mmol) was added to a solution of 4-(pyrrolidine-1-carbonyl)-benzoic acid methyl ester (530 mg, 2.27 mmol) in a mixture of methanol (2 mL), THF (6 mL) and H2O (2 mL). The reaction mixture was stirred at ambient temperature for 3 hrs. The reaction mixture was concentrated, the residue was diluted with water, and acidified with conc. HCl. The solid was filtered and dried to afford 41 mg (82.32% Yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1NC.[S:8]1[CH2:14][C:12](=[O:13])[NH:11][C:9]1=S.[CH:15]([N:18](CC)C(C)C)(C)C>C(#N)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:15][NH:18][C:9]1[S:8][CH2:14][C:12](=[O:13])[N:11]=1
Reactant: O=C1CSC(=S)N1
Reactant: CNc1cccs1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CSC(NCc2cccs2)=N1
Temperature: 0 °C
Reaction time: 48 h
Yield: 129 %

Procedure:
To a suspension of thiophen-2-yl-methylamine (22.63 g, 200 mmol) and rhodanine (2-thio-4-thiazolin-4-one) (13.32 g, 100 mmol) in acetonitrile (200 mL) was added DIEA (N,N-diisopropylethylamine) (34.8 mL, 45.0 mmol) at room temperature. Then, it gave a clear solution within 2 min and this solution was cooled to 0° C. To this, mercuric chloride (27.15 g, 100 mmol) was added in three portions within a period of 15 min. After addition, the suspension was allowed to warm to room temperature and stirred for 2 days. The resulting black solids were filtered through a plug of celite and washed with dichloromethane (500 mL) and methanol (1.0 L). The combined solvents were removed under the vacuum and the crude residue was diluted with water (250 mL) and ethyl acetate (250 mL). The two layers were separated and the aqueous layer was extracted with dichloromethane (2×250 mL). The two organic extracts were washed separately with brine solution and dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent under the vacuum gave the crude solid. This solid was dissolved in acetonitrile (˜100 mL) at hot condition and then stored in the refrigerator overnight. The solids were collected by filtration and washed with cold acetonitrile (20 mL). After drying in air, 12.32 g (58% yield) of 2-[(thiophen-2-ylmethyl)-amino]-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C8H8N2OS2 (M+) 212.0078, found 212.0083.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7]([CH3:12])=[CH:8][N:9]=[C:10](Cl)[C:5]2=[N:4][CH:3]=1.Cl.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C(O)C(C)C>[Br:1][C:2]1[N:6]2[C:7]([CH3:12])=[CH:8][N:9]=[C:10]([NH:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:20][CH:21]=3)[C:5]2=[N:4][CH:3]=1
Reactant: NCc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1cnc(Cl)c2ncc(Br)n12
Agent: Cl
Solvent: CC(C)CO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc(NCc2ccc(S(N)(=O)=O)cc2)c2ncc(Br)n12
Temperature: 108 °C
Reaction time: 16 h
Yield: 66.6 %

Procedure:
To a solution of 3-bromo-8-chloro-5-methyl-imidazo[1,2-a]pyrazine (308 mg, 1.25 mmol) in iBuOH (5 mL) is added 4-aminomethyl-benzenesulfonamide hydrochloride (298 mg, 1.38 mmol) and DIPEA (0.43 mL, 3.12 mmol). The reaction is stirred at 108° C. for 16 h. After this time the solution is allowed to cool, resulting in a thick precipitate that is filtered and washed with diethyl ether to give 330 mg of pure product as a beige solid (67%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:29]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][C:6]=2[CH:29]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4o3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.1 %

Procedure:
To a solution of methyl 2-(5-fluorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (160 mg, 0.41 mmol) in methanol (30 mL) and water (1 mL) was added sodium hydroxide (48.85 mg, 1.22 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3N). The solids were collected by filtration to afford 2-(5-fluorobenzofuran-2-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a light yellow solid (120.0 mg, 74%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:12](=[O:33])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16](/[CH:26]=[CH:27]/[C:28]([O:30]CC)=[O:29])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O.Cl>O1CCCC1.C(O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:11]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:12](=[O:33])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:15][CH:14]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc2c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccccc3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(/C=C/C(=O)O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a solution of ethyl (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenate (0.70 g, 1.4 mmol) in tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N sodium hydroxide (3 mL). The obtained mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give (E)-3-[3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-2-propenic acid (0.56 g, 84.8%) as crystals.
Reaction SMILES: [F:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3].[C:7]([C@@H:10]1[CH2:14][C@H:13]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12][N:11]1[CH2:25][CH2:26][OH:27])(=[O:9])[NH2:8]>C(Cl)Cl>[F:1][S:2]([O-:5])(=[O:4])=[O:3].[C:7]([C@@H:10]1[CH2:14][C@H:13]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH2:12][N+:11]1([CH2:25][CH2:26][OH:27])[CH3:6])(=[O:9])[NH2:8]
Reactant: COS(=O)(=O)F
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(CCO)C2)cc1
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)[N+](C)(CCO)C2)cc1
Product: O=S(=O)([O-])F
Reaction time: 2 h

Procedure:
0.108 ml of methyl fluorosulfonate was added dropwise at room temperature to a solution of 0.38 of (2S, 4S)-2-carbamoyl-1-(2-hydroxyethyl)-4-(4-methoxybenzylthio)pyrrolidine dissolved in 7.5 ml of dry methylene chloride, and the mixture was stirred at the same temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was washed by decantation with diethyl ether and dried under reduced pressure, to afford 0.396 g of the title compound as an oil.
Reaction SMILES: [Zn:1].BrCCBr.C[Si]([Cl:10])(C)C.[Cl:11][C:12]1[C:13]([F:20])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Cl>O1CCCC1>[Cl-:10].[Cl:11][C:12]1[C:13]([F:20])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][Zn+:1]
Reactant: C[Si](C)(C)Cl
Reactant: [Zn]
Reactant: Fc1c(Cl)cccc1CCl
Solvent: C1CCOC1
Solvent: BrCCBr
Product: Fc1c(Cl)cccc1C[Zn+]
Product: [Cl-]
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, a zinc powder (1.44 g) was suspended in tetrahydrofuran (3.6 ml), 1,2-dibromoethane (38 mg) and trimethylsilyl chloride (43 mg) were successively added at 60° C., and the mixture was stirred for 30 min. A solution of 3-chloro-2-fluorobenzyl chloride (3.58 g) in tetrahydrofuran (9 ml) was added dropwise at 60° C. to the solution prepared above. The mixture was further stirred under heating for 1 hr to give a solution of 3-chloro-2-fluorobenzylzinc chloride in tetrahydrofuran.
Reaction SMILES: [CH3:1][Mg]Br.[O:4]=[C:5]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1>C1COCC1>[OH:4][C:5]1([CH3:1])[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
Methyl magnesium bromide (3.0M in Diethyl ether) (1.5 mL, 4.5 mmol) was added to cold (−10° C.) solution of tert-butyl 3-oxoazetidine-1-carboxylate (650 mg, 3.8 mmol) in THF (10 mL) and stirring was continued at 20-35° C. for 1 h. After which the reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with ethylacetate. The organic layer separated was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the residue. The residue was purified by column chromatography (using 60-120 silica gel and 50% EtOAc in Hexane as eluent) to afford 430 mg of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]=[C:17]1[O:21][C:19](=[O:20])[CH2:18]1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:19](=[O:20])[CH2:18][C:17]([CH3:16])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCCN(Cc2ccccc2)C1
Reactant: C=C1CC(=O)O1
Product: CC(=O)CC(=O)OCC1CCCN(Cc2ccccc2)C1
Yield: 82.7 %

Procedure:
In this reference example, 15.01 g of 1-benzyl-3-piperidine methanol and 6.76 g of diketene were reacted similarly as in Reference Example 1, and the reaction product was purified by silica gel column chromatography (eluent:n-hexane:ethyl acetate=1:1 v/v), to obtain 17.50 g of acetoacetic acid-(N-benzyl-3-piperidinylmethyl) ester (yield: 82.5%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21]>>[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: Cc1ccc(C)c(N)c1
Product: Cc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2,5-dimethylaniline (48 μl, 0.386 mmol) similar to Example 58 and isolated as a light tan solid (14 mg, 21%). 1H NMR (CDCl3): 9.70 (dd, J=0.8, 2.0 Hz, 1H), 8.74–8.70 (m, 1H), 8.67 (dd, J=1.8, 4.8 Hz, 1H), 7.75 (s, 1H), 7.43–7.38 (m, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.19 (s, 1H), 7.10 (d, J=7.8 Hz, 1H), 6.56 (s, 1H), 2.38 (s, 3H), 2.26 (s, 3H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.N1C=CN=C1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40]O)=[CH:30][CH:29]=1>C(Cl)Cl.[Al]>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH2:40][I:20])=[CH:30][CH:29]=1
Reactant: OCc1ccccc1-c1ccc(Cl)cc1
Reactant: II
Agent: [Al]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(-c2ccccc2CI)cc1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Triphenylphosphine (8.47 g, 32.3 mmol), iodine (8.94 g, 35.2 mmol), imidazole (2.40 g, 352 mmol), and CH2Cl2 (110 mL) were combined in a round-bottom flask, and the mixture was stirred for 15 minutes. A solution of (4′-chloro-biphenyl-2-yl)-methanol in CH2Cl2 (40 mL) was then added, and the reaction was stirred at room temperature for 16 hours (flask was wrapped in aluminum foil to shield it from the light). A saturated aqueous Na2S2O2 was added. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×100 mL). The organic layers were combined, dried over MgSO4, and concentrated. The crude residue was purified by flash chromatography on silica gel (0-10% EtOAc/heptanes) to afford the title compound as an off-white solid (5.33 g, 55% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.51-7.53 (m, 1H), 7.38-7.46 (m, 4H), 7.28-7.37 (m, 2H); 7.15-7.17 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:17][C:16](=[S:18])[CH2:15][CH2:14][C@@H:13](OC(=O)C)[O:12][C:11](=[O:23])[C:10]2[C:24]([CH3:31])=[C:25]([O:29][CH3:30])[CH:26]=[C:27]([OH:28])[C:9]=2[CH:8](C)[S:7][CH2:6]1)=[O:4].[C:33](=O)([O-])[O-:34].[K+].[K+]>CO.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[NH:17][C:16](=[S:18])[CH2:15][CH2:14][C@@H:13]([CH2:33][OH:34])[O:12][C:11](=[O:23])[C:10]2[C:24]([CH3:31])=[C:25]([O:29][CH3:30])[CH:26]=[C:27]([OH:28])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CSC(C)c2c(O)cc(OC)c(C)c2C(=O)O[C@H](OC(C)=O)CCC(=S)N1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)O[C@H](CO)CCC(=S)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A mixture of 24 mg of the product of Example 11 and 8.3 mg of potassium carbonate in 0.5 ml of methanol was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and with water. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was crystallized from ethyl acetate/hexane to yield 16 mg of (4R,9S)-15-hydroxy-9-hydroxymethyl-13-methoxy-12-methyl-11-oxo-6-thioxo-3,4,5,6,7,8,9,11-octahydro-1H-10,2,5-benzoxathiaazacyclotridecine-4-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C[N:12](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:35][C:36]1[CH:37]=[CH:38][C:39]([F:54])=[C:40]([C@@:42]2([CH:51]([F:53])[F:52])[NH:47][C:46](=S)[CH2:45][CH2:44][C:43]2([F:50])[F:49])[CH:41]=1.C(N(CC)C(C)C)(C)C.[NH4+].[Cl-]>CN(C=O)C>[NH2:12][C:46]1[CH2:45][CH2:44][C:43]([F:50])([F:49])[C@:42]([C:40]2[CH:41]=[C:36]([NH:35][C:8](=[O:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[CH:37]=[CH:38][C:39]=2[F:54])([CH:51]([F:53])[F:52])[N:47]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1ccc(F)c([C@@]2(C(F)F)NC(=S)CCC2(F)F)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC1=N[C@@](c2cc(NC(=O)c3ccc(Cl)cn3)ccc2F)(C(F)F)C(F)(F)CC1
Reaction time: 0.08 h

Procedure:
5-chloropicolinic acid (19 mg, 0.12 mmol) and HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (67.4 mg, 0.177 mmol) was dissolved DMF (1 mL). The reaction mixture was stirred for 5 minutes. Then (S)-6-(5-amino-2-fluorophenyl)-6-(difluoromethyl)-5,5-difluoropiperidine-2-thione (25 mg, 0.081 mmol) and DIPEA (N,N-di-isopropyl ethylamine) (52 mg, 0.07 ml, 0.4 mmol) were added. The reaction mixture was stirred for 1 hour at room temperature. Satureted aqueous NH4Cl was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure Ammonia in methanol (7M, 2 mL) was added and the reaction mixture was stirred at 55° C. in a sealed vial overnight. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica (heptane:ethyl acetate). The product was dissolved in ethyl acetate and washed 5 times with satureted aqueous NaHCO3/water to remove thiourea byproducts. The combined organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to give (S)—N-(3-(6-amino-2-(difluoromethyl)-3,3-difluoro-2,3,4,5-tetrahydropyridin-2-yl)-4-fluorophenyl)-5-chloropicolinamide. 1H NMR (DMSO-d6, 600 MHz): δ 10.78 (s, 1H), 8.79 (dt, J=2.4, 1.1 Hz, 1H), 8.20 (dd, J=8.4, 2.4 Hz, 1H), 8.16 (dd, J=8.4, 0.7 Hz, 1H), 7.96-7.90 (m, 1H), 7.88 (dd, J=6.8, 2.7 Hz, 1H), 7.20 (dd, J=11.6, 8.8 Hz, 1H), 6.74 (t, J=55.2 Hz, 1H), 6.38 (s, 2H), 2.51 (dt, J=3.7, 1.8 Hz, 2H), 2.19-1.98 (m, 2H).
Reaction SMILES: C([O-])=O.[K+].C(O)=O.O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=1>[Pd].O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:25]=[CH:26][C:27]([NH2:30])=[CH:28][CH:29]=1
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3)c2cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [K+]
Solvent: O=CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Temperature: 60 °C
Yield: 82.6 %

Procedure:
A solution containing potassium formate (5.0 kg), formic acid (3.0 kg), and water (16.0 kg) was added to a mixture of 6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10% palladium on carbon (50% water wet, 0.4 kg) in tetrahydrofuran (40.0 kg) that had been heated to approximately 60° C. The addition was carried out such that the temperature of the reaction mixture remained approximately 60° C. When the reaction was deemed complete as determined using in-process HPLC analysis (<2% starting material remaining, typically 1 5 hours), the reactor contents were filtered. The filtrate was concentrated by vacuum distillation at approximately 35° C. to half of its original volume, which resulted in the precipitation of the product. The product was recovered by filtration, washed with water (12.0 kg), and dried under vacuum at approximately 50° C. to afford the title compound (3.0 kg; 97% AUC).