Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]([CH2:26][C:27]#[N:28])[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[O:9])=[CH:4][CH:3]=1.[Sn]([N:44]=[N+:45]=[N-:46])(CCCC)(CCCC)CCCC.Cl>C1(C)C=CC=CC=1.CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:26][C:27]2[NH:46][N:45]=[N:44][N:28]=2)[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CC#N)Cc2ccc(Cl)cc2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(Cc2ccc(Cl)cc2)Cc2nnn[nH]2)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-cyanomethyl-amide, Compound 68 (1 eq.) in toluene was added Bu3SnN3 (10 eq.). The reaction was refluxed for 6 h and cooled to 20° C. then HCl 2N in Et2O was added. After 15 h of stirring, the solid was filtered, dissolved in DCM and precipitated with iPr2O. The solid was purified by chromatography on silica gel (elution with DCM/MeOH: 1/0 to 95/5) to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-(1H-tetrazol-5-ylmethyl)-amide.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)(=[O:22])[CH3:21].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][C:20](=[O:22])[CH3:21])=[N:3][C:4]=1[C:9]1[O:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:13]=1
Reactant: Nc1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Reactant: CC(=O)Nc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)Nc1ccccc1-c1cnc(N)c(-c2nnc(-c3ccccc3)o2)n1
Temperature: 150 °C
Yield: 26.9 %

Procedure:
A solution of 5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (100 mg, 0.31 mmol), 2-ethanamidophenylboronic acid (56.25 mg, 0.31 mmol), tetrakis(triphenylphosphine)palladium (18.17 mg, 0.015 mmol) and Na2CO3 (471 μL, 2M aqueous solution) were added to a 10 mL microwave vial. Dioxane (3 mL) was then added and the vial sealed. The reaction mixture was heated in the microwave at 150° C. for 30 min. After this time methanol was added and the reaction mixture filtered. The solid was then washed with water (5 mL) and MeOH (5 mL) and dried under vacuum to give the product (31.0 mg, 28% yield); 1H NMR (400.0 MHz, DMSO) d 2.04 (s, 3H), 7.26 (t, 1H), 7.44-7.40 (m, 1H), 7.69-7.67 (m, 4H), 7.80 (d, 2H), 8.15-8.13 (m, 3H), 8.73 (s, 1H) and 10.76 (s, 1H) ppm; MS (ES+) 373.0
Reaction SMILES: [S:1]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[O:17])[C:12]([O:14]CC)=[O:13])[N:10]=1)([CH3:4])(=[O:3])=[O:2].[OH-].[Na+].Cl>O>[S:1]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[O:17])[C:12]([OH:14])=[O:13])[N:10]=1)([CH3:4])(=[O:2])=[O:3]
Reactant: CCOC(=O)C(=O)c1csc(NS(C)(=O)=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Nc1nc(C(=O)C(=O)O)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.3 %

Procedure:
Ethyl 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylate (13.9 g.) was added with stirring at ambient temperature to a solution of sodium hydroxide (5.0 g.) in water (150 ml.). The mixture was stirred for 1 hour at ambient temperature, adjusted to pH 7 with conc. hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 0.5 with conc. hydrochloric acid to precipitate yellow crystals. The crystals were collected by filtration, washed with water and dried to give 2-(2-mesylamino-1,3-thiazol-4-yl)glyoxylic acid (10.16 g.).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:10]1(B(O)O)[CH2:12][CH2:11]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C1(C)C=CC=CC=1.O>C(OCC)(=O)C.[Cl-].[Na+].O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:10]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:12][CH2:11]1
Reactant: O=Cc1ccccc1Br
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccccc1C1CC1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A 60 mL reaction vial is charged with 2-bromo-benzaldehyde (10.810 mmoles, 1.264 mL), cyclopropylboronic acid (14.053 mmoles, 1.207 g), potassium phosphate tribasic N-hydrate (37.834 mmoles, 8.031 g), tricyclohexylphosphine (1.081 mmoles, 303.139 mg), toluene (283.654 mmoles, 30.000 mL), and water (83.263 mmoles, 1.500 mL). The mixture is then thoroughly degassed. Next, Pd(OAc)2 (540.482 μmoles, 121.343 mg) is added and the mixture is placed under nitrogen and heated to 100° C. After 2 hours, cool to room temperature and dilute with ethyl acetate (50 mL) and brine (50 mL). Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. Purify by silica gel chromatography eluting with hexanes: dichloromethane 20-50% to afford the title compound. 1H NMR (400.31 MHz, cdcl3): 10.57 (s, 1H), 7.78 (dd, J=1.3, 7.9 Hz, 1H), 7.45 (td, J=7.5, 1.3 Hz, 1H), 7.28 (t, J=7.5 Hz, 1H), 7.09 (d, J=7.9 Hz, 1H), 2.63-2.56 (m, 1H), 1.07-1.02 (m, 2H), 0.77-0.73 (m, 2H).
Reaction SMILES: O[C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C(N(S(F)(F)[F:24])CC)C.C([O-])(O)=O.[Na+]>ClCCCl>[F:24][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)[C@@H]1C[C@H](F)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a stirred solution of compound obtained in step II (24.5 g, 0.1 mol) in 1,2-dichloroethane (300 mL) cooled to −10° C. was added diethylaminosulfur trifluoride (19.7 mL, 0.15 mol) over a period of 30 minutes. The reaction mixture was stirred at this temperature for 1 h then at room temperature for 16 h. The reaction mixture was quenched by adding mixture of crushed ice (300 g) and solid NaHCO3 (25.2 g, 0.3 mol). The two layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure to obtain 1-tert-butyl 2-methyl (2S,4S)-4-fluoropyrrolidine-1,2-dicarboxylate as a viscous liquid (24.7 g) in 100% yield. [α]D −53.3, (c, 1.0, CHCl3). m/z (M+1) 248; 1H NMR (CDCl3) 300 MHz δ 5.20 (ddd, J=3.8, 3.8, 49.1 Hz, 1H), 4.55 (d, J=9.5 Hz, ½H), 4.42 (d, J=8.9 Hz, ½H), 3.90-3.55 (m, 2H), 3.75 (s, 3H), 2.55-2.20 (m, 2H), 1.46 (s, 3H), 1.41 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl.[NH2:29][OH:30]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20](=[N:29][OH:30])[CH3:21])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: CC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NO)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Yield: 14 %

Procedure:
To a solution of 1-{4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-phenyl}-ethanone (i.e the product of Step 1, 250 mg) in methanol (10 mL) was added acetic acid (1 drop) and hydroxylamine hydrochloride (44 mg) and the mixture was stirred at room temperature over night. After concentration in vacuum, the residue was taken up in ethyl acetate and washed with water. The organic layer was separated, dried (Na2SO4) and concentrated in vacuum. The residue was purified by flash chromatography on silica gel to yield the title compound (37 mg, 14%).
Reaction SMILES: C([O:3][C:4]([CH:6]([NH:15][CH:16]1[C:22](=[O:23])[N:21]2[CH:24]([C:28]([OH:30])=[O:29])[CH2:25][S:26](=[O:27])[CH:20]2[CH2:19][CH2:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])C>CO.O.[OH-].[Na+]>[C:4]([CH:6]([NH:15][CH:16]1[C:22](=[O:23])[N:21]2[CH:24]([C:28]([OH:30])=[O:29])[CH2:25][S:26](=[O:27])[CH:20]2[CH2:19][CH2:18][CH2:17]1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:5])=[O:3]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CCCC2N(C1=O)C(C(=O)O)CS2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(CCc1ccccc1)NC1CCCC2N(C1=O)C(C(=O)O)CS2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3R-[3α,6α(S*R*),9aα]]-6[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-1-oxo-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid (0.5 mmole) in 4 ml of a methanol-water mixture (1:1), 1.5 ml of 1N NaOH can be added. The reaction mixture can be stirred overnight at room temperature and then absorbed onto a strong acid ion-exchange resin such as Dowex 50 X-2, 50-100 mesh. The column can then be first eluted with water and then with 4% pyridine-water. The appropriate fraction can be freeze-dried to give the product as a diastereomeric mixture which can be separated by reverse-phase chromatography.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH:9]1(O)[CH2:13][CH2:12][CH2:11][CH2:10]1.OP(O)(O)=O>O.C1(C)C=CC=CC=1>[OH2:2].[CH:9]1([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OC1CCCC1
Reactant: Oc1cccc(O)c1
Agent: O=P(O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: Oc1ccc(C2CCCC2)c(O)c1
Temperature: 107.5 °C
Reaction time: 1.5 h
Yield: 104.5 %

Procedure:
To a N2 purged pressure reactor is charged resorcinol (44.0 g, 0.40 mol), cyclopentanol (44 mL, 0.49 mol) and 85% aqueous H3PO4 (55 mL, 0.80 mol). The slurry is heated to 95-120° C. for 6-18 hours. The pink reaction mixture is cooled to ˜70° C. and diluted with water (50 mL) and toluene (200 mL). The layers are allowed to separate at 60±5° C. The bottom orange aqueous layer is cut away. The remaining pink organic layer is extracted with 2×50 mL water at 60±5° C. and then stirred with carbon (5 g) at 60±5° C. for 1-2 hours. The slurry is filtered hot through Supercel, rinsing the cake with hot toluene (50 mL). The orange filtrate is diluted with 5 mL water and allowed to cool to ˜30° C. at which time the product crystallizes. The slurry is cooled to 0-5° C. and the product collected, washed with cold toluene (40 mL) and pulled dry on the funnel to afford 41 g of 4-cyclopentyl resorcinol monohydrate as a white to pale pink solid (≧98% area by HPLC). The material can be recrystallized if desired from hot toluene (5 mL/g) and carbon (10% by weight) filtering through Supercel and/or silica gel to the Form I polymorph of 4-cyclopentyl resorcinol afford as a white solid (≧99.7% by HPLC).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[CH2:47]1[C:51]2([CH2:56][CH2:55][CH:54]([OH:57])[CH2:53][CH2:52]2)[CH2:50][CH2:49][CH2:48]1>>[Cl:17][C:18]1[C:19]([O:57][CH:54]2[CH2:53][CH2:52][C:51]3([CH2:47][CH2:48][CH2:49][CH2:50]3)[CH2:56][CH2:55]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OC1CCC2(CCCC2)CC1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OC2CCC3(CCCC3)CC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with spiro[4.5]decan-8-ol, the title compound was obtained as a colorless solid (0.06 g, 14%). 1H NMR (300 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.31 (d, J=12.6 Hz, 1H), 4.68-4.61 (m, 1H), 2.87 (s, 6H), 1.88-1.77 (m, 2H), 1.65-1.51 (m, 8H), 1.44-1.32 (m, 6H); MS (ES−) m/z 431.2, 433.2 (M−1).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([CH2:16]O)=[CH:11][C:10]=2[Cl:18])[C:5](=[O:19])[CH:4]=1.C(N(S(F)(F)[F:28])CC)C.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([CH2:16][F:28])=[CH:11][C:10]=2[Cl:18])[C:5](=[O:19])[CH:4]=1
Reactant: O=c1cc(C(F)(F)F)ccn1-c1c(Cl)cc(CO)cc1Cl
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(C(F)(F)F)ccn1-c1c(Cl)cc(CF)cc1Cl
Temperature: -78 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
A dry flask was flushed with nitrogen and charged with 4-trifluoromethyl-1-(2,6-dichloro-4-hydroxymethylphenyl)-2-pyridone (Compound D) [0.73 g (2.2 mmol)] and dry dichloro-methane (15 ml). The flask was cooled to -78° C. and diethylaminosulphurtrifluoride (0.31 ml, 2.4 mmol) was added slowly dropwise. The reaction was stirred at -78° C. for 2 hours and then slowly allowed to warm up to room temperature. The reaction was slowly added to a saturated solution of sodium hydrogen carbonate (20 ml) and extracted with ethyl acetate (2×30 ml). The combined organic layers were washed well with water, dried over magnesium sulphate, and evaporated in vacuo to give a yellow solid which was chromatographed on silica with 50% petrol/diethyl ether as eluent. Recrystallisation from a mixture of pentane and diethylether gave 4-trifluoromethyl-1-(2,6-dichloro-4-fluoromethylphenyl)-2-pyridone (Compound 40) (0.18 g)
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:9][CH2:8]2)[O:4][N:3]=1.[CH2:10]([NH2:13])[CH2:11][NH2:12]>>[CH:7]1([C:5]2[O:4][N:3]=[C:2]([NH:12][CH2:11][CH2:10][NH2:13])[N:6]=2)[CH2:9][CH2:8]1
Reactant: NCCN
Reactant: Clc1noc(C2CC2)n1
Product: NCCNc1noc(C2CC2)n1
Temperature: 125 °C

Procedure:
3-Chloro-5-cyclopropyl-1,2,4-oxadiazol (72 mg, 0.5 mmol) and TEA (139 μl, 1 mmol) were dissolved in ethane-1,2-diamine (3 ml), placed in a sealed tube and heated at 125° C. for 2 hours. The mixture was cooled to room temperature and evaporated to dryness under reduced pressure and used directly in the next step MS(ESI) m/z=169.1 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]=[CH:5][CH2:6][O:7][C:8]1[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([CH:17]2[C:26]3[C:25](=[O:27])[CH2:24][CH:23]([CH2:28][CH2:29][CH3:30])[CH2:22][C:21]=3[NH:20][C:19]([CH3:31])=[C:18]2[C:32]#[N:33])=[CH:10][C:9]=1[Br:34].O.Cl>O1CCOCC1.[OH-].[Na+]>[Br:34][C:9]1[CH:10]=[C:11]([CH:17]2[C:26]3[C:25](=[O:27])[CH2:24][CH:23]([CH2:28][CH2:29][CH3:30])[CH2:22][C:21]=3[NH:20][C:19]([CH3:31])=[C:18]2[C:32]#[N:33])[CH:12]=[C:13]([O:14][CH2:15][CH3:16])[C:8]=1[O:7][CH2:6][CH:5]=[CH:4][C:3]([OH:35])=[O:2]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCC=CC(=O)OC)c(OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCC=CC(=O)O)c(OCC)c1

Procedure:
A solution of 4-[2-bromo-4-(3-cyano-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydroquinolin-4-yl)-6-ethoxy-phenoxy]-but-2-enoic acid methyl ester (1.2 g) in dioxane (100 ml) and 2N sodium hydroxide (2.2 ml) was stirred for 5 days. The mixture was poured into water and the pH was adjusted to 2 using 4N aqueous HCl. The resulting mixture was extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Yield: 1.5 g. MS-ESI: [M+H]+=529.2/531.2
Reaction SMILES: Cl.O1CCOCC1.Cl[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[O:22][CH3:23])[C:12]([F:24])=[CH:11][N:10]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([CH2:33][S:34][CH3:35])[CH:32]=1)[NH2:29]>C(O)CCC.C(OCC)(=O)C>[Br:25][C:26]1[CH:27]=[C:28]([NH:29][C:9]2[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[O:22][CH3:23])[C:12]([F:24])=[CH:11][N:10]=2)[CH:30]=[C:31]([CH2:33][S:34][CH3:35])[CH:32]=1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Reactant: CSCc1cc(N)cc(Br)c1
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1nc(Nc2cc(Br)cc(CSC)c2)ncc1F
Temperature: 140 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A 4N solution of hydrogen chloride in dioxane (0.54 mL; 2.15 mmol) was added to a stirred solution of 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine (553 mg; 2.15 mmol) and 3-bromo-5-[(methylsulfanyl)methyl]aniline (500 mg; 2.15 mmol) in 1-butanol (4.8 mL). The batch was stirred at 140° C. for 8 hours. After cooling the batch was diluted with ethyl acetate and washed with sodium bicarbonate and saturated aqueous sodium chloride solution. The organic phase was filtered using a Whatman filter and concentrated. The residue was purified by chromatography (hexane/ethyl acetate 4:1) to give the desired product (450 mg; 0.99 mmol).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[N+:28]([C:31]1[CH:32]=[C:33]([C:37](=[O:41])[C:38]#[C:39][CH3:40])[CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]>>[CH3:40]/[C:39](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[CH:38]/[C:37]([C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([N+:28]([O-:30])=[O:29])[CH:32]=1)=[O:41]
Reactant: CC#CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: C/C(=C/C(=O)c1cccc([N+](=O)[O-])c1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 12) from 120 mg (0.25 mmol) of Intermediate 45 and 48 mg (0.25 mmol) of Intermediate 42 to yield 67 mg of Example 25: TLC (DCM/MeOH (4:1): Rf=0.52; 1H NMR (DMSO-d6, 400 MHz) δ11.52 (d, 1H, J=9.1), 8.52 (s, 1H), 8.24 (d, 1H, J=8.2), 8.21 (d, 2H, J=7.7), 7.87 (d, 2H, J=7.7), 7.66 (t, 1H, J=7.9), 7.45 (m, 3H), 7.10 (d, 2H, J=8.2), 6.79 (d, 2H, J=8.3), 5.74 (s, 1H), 4.13 (t, 2H, J=6.6), 4.07 (br s, 1H), 3.15 (m, 1H), 2.87 (t, 2H, J=6.4), 2.75 (m, 1H), 2.31 (s, 3H), 1.68 (s, 3H).; low resolution MS (ES+)m/e 556.3 (MH+).
Reaction SMILES: [CH2:1]([C:4]([C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=1)([CH2:8][OH:9])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[C:19]([O-])([O-])=O.[K+].[K+].IC.O>CN(C=O)C>[CH3:19][O:15][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([C:4]([CH2:5][CH:6]=[CH2:7])([CH2:8][OH:9])[CH2:1][CH:2]=[CH2:3])=[CH:11][CH:12]=1
Reactant: C=CCC(CO)(CC=C)c1ccc(C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: C=CCC(CO)(CC=C)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 4-(1-allyl-1-hydroxymethyl-but-3-enyl)-benzoic acid (0.793 g, 3.22 mmol) in DMF (11.0 mL) is treated with K2CO3 (0.685 g, 4.96 mmol), and iodomethane (0.25 mL, 4.02 mmol), and stirred at room temperature overnight. The mixture is poured into water (25 mL) and extracted with EtOAc (3×25 mL). The combined extracts are washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted with hexanes using a gradient of 0% to 75% EtOAc to give 0.774 g, (92%) of the title compound as a clear syrup. 1H NMR (CDCl3): δ 8.03-8.00 (m, 2H), 7.44-7.41 (m, 2H), 5.65-5.54 (m, 2H), 5.11-5.06 (m, 4H), 5.05-5.02 (m, 4H), 3.91 (s, 3H), 3.84 (d, 2H, J=6.2 Hz), 2.59-2.46 (m, 4H), 1.33 (t, 1H, J=6.2 Hz).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]2[CH2:11][O:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:12]=[N+:13]=[N-:14].[Na+].C(OC)=O.CO>O>[C:1]1([S:7][CH2:8][CH:9]([OH:10])[CH2:11][N:12]=[N+:13]=[N-:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(SCC2CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: COC=O
Product: [N-]=[N+]=NCC(O)CSc1ccccc1
Yield: 91.9 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 7.2 g of phenylthiomethyloxirane (prepared as described in Preparation 85), 14 g of sodium azide, 65 ml of methyl formate and 270 ml of an 8:1 by volume mixture of methanol and water were used, to give 8.33 g of the title compound as a colorless oil having an Rf value of 0.23 (on silica gel thin layer chromatography, using a 1:10 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: C([O:3][CH2:4][CH2:5][O:6][NH:7][C:8]([C:10]1[CH:15]=[C:14]([CH3:16])[C:13](=[O:17])[N:12]([CH3:18])[C:11]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27])=[O:9])=C.Cl.[OH-].[Na+].C(OCC)(=O)C>C1COCC1>[F:27][C:21]1[CH:22]=[C:23]([I:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:11]1[N:12]([CH3:18])[C:13](=[O:17])[C:14]([CH3:16])=[CH:15][C:10]=1[C:8]([NH:7][O:6][CH2:5][CH2:4][OH:3])=[O:9]
Reactant: C=COCCONC(=O)c1cc(C)c(=O)n(C)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)n(C)c1=O
Temperature: 22 °C
Reaction time: 0.25 h
Yield: 88.6 %

Procedure:
To a stirred solution of 2-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (2-vinyloxyethoxy)-amide (170 g, 0.35 mol), under nitrogen, in THF (850 mL) was added 2M HCl (318 mL), over 15 minutes at 17-22° C. After 1 hour the reaction was complete (as indicated by HPLC) and a solution of 2M sodium hydroxide (318 mL) was added, over 10 minutes, keeping the temperature at approximately 22° C. The pH of the mixture was approximately 8. The mixture was then partitioned with MIBK (1.02 L) and the lower aqueous layer was separated and discarded. The volume of the organic solution was then reduced by distillation, at ambient pressure and with a jacket temperature of 85-95° C. After the removal of 750 mL solvent the rate of distillation had slowed considerably and the mixture was cooled to approximately 22° C. Crystalline 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide Form 2 (1 g, seed, prepared as described in Example 16C) was added to the mixture followed by ethyl acetate (170 mL). After 5 minutes the mixture began to crystallize and iso-hexane (1.7 L) was added at 23-25° C. over 50 minutes. The slurry was held at 25° C. for 80 minutes and then filtered. The solid was washed with iso-hexane (680 mL) then dried in vacuum oven at 30° C. to provide the title material (147 g, 0.31 mol, 89% yield). 1H NMR (D6-DMSO): δ 7.63 (dd, 1H, J 11, 2 Hz, ArH), 7.55 (s, 1H, ArH), 7.38 (d, 1H, J 8.5 Hz, ArH), 6.52 (˜t, 1H, J 8.5 Hz, ArH), 4.91-4.35 (bs, 1H, OH), 3.74 (t, 2H, J 5 Hz, OCH2), 3.51 (˜t, 2H, J 5 Hz, OCH2), 3.25 (s, 3H, NCH3), 2.02 (s, 3H, ArCH3). MS (ESI) (+) m/z 484 (27%, [M+Na]+), 462 (100%, [M+H]+), 385 (8%), 100 (26%).