Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]2[C:19]3=[N:20][C:21]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:22][CH:23]=[C:18]3[CH2:17][N:16]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[C:15]2=[O:39])[CH2:9]1)=O)(C)(C)C.O>FC(F)(F)C(O)=O.ClCCl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([N:16]2[CH2:17][C:18]3[C:19](=[N:20][C:21]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:22][CH:23]=3)[N:14]([CH:10]3[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]3)[C:15]2=[O:39])=[CH:36][CH:35]=1
Reactant: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C3CCCN(C(=O)OC(C)(C)C)C3)C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COc1ccc(N2Cc3cnc(Nc4ccccc4)nc3N(C3CCCNC3)C2=O)cc1
Reaction time: 1.5 h

Procedure:
3-[3-(4-Methoxy-phenyl)-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (70 mg, 0.13 mmols) (from Example 4a supra) was dissolved at 0° C. in a 50% trifluoroacetic acid in dichloromethane solution (5 mL) that contained water (300 μL). After stirring for 1.5 hours the reaction mixture was partitioned between ethyl acetate and 1 N aqueous sodium hydroxide and the pH of the aqueous layer was adjusted to 12 by adding solid sodium hydroxide. The organic layer was then washed with water, dried over sodium sulfate, filtered and concentrated to the crude product. This material was dissolved in tetrahydrofuran and precipitated with an excess of pentane to give 3-(4-methoxy-phenyl)-7-phenylamino-1-piperidin-3-yl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as an off-white solid. (Yield 47 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:6][C:7]([O:9]C)=[O:8].[OH-].[Na+]>CO.O1CCCC1>[NH2:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[CH2:6][C:7]([OH:9])=[O:8]
Reactant: COC(=O)CN(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(CC(=O)O)Cc2ccccc2N)cc1
Yield: 90.1 %

Procedure:
To a solution of 5.14 g (14.1 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]acetate in 50 ml of methanol-tetrahydrofuran (1:1) was added 2.86 ml of 10 N NaOH and the mixture refluxed for 2 hours. The solvent was removed under vacuum and the residue partitioned between water and ether. The water layer was separated and acidified with 2 N citric acid. The solid was filtered, washed with H2O and dried in a vacuum oven at room temperature to give 4.45 g (91%) of crystals, m.p. 145°-147° C. Anal. for C16H18N2O5S: Calc'd: C,54.9; H,5.2; N,8.0; Found: C,55.1; H,5.2; N,7.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([Cl:9])[CH:3]=1.[CH2:10]1[O:20][C:13]2([CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)[O:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:16]2[CH2:17][CH2:18][C:13]3([O:20][CH2:10][CH2:11][O:12]3)[CH2:14][CH2:15]2)=[C:4]([Cl:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1Cl
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Clc1cc(Br)ccc1NC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-bromo-2-chloro-phenylamine (6 g, 29.06 mmol), [CAS 38762-41-3], 1,4-cyclohexanedione monoethyleneketal [CAS 4746-97-8], (6.908 g, 43.59 mmol), and sodium triacetoxy-borohydride (9.239 g, 43.59 mmol) in DCE (100 ml) and acetic acid (0.2 ml) was stirred at r.t. for 2 days. The mixture was then filtered through a pad of diatomaceous earth and washed with DCM. The filtrate was washed with NaHCO3 (aqueous sat. solution), sodium chloride (aqueous sat. solution), dried (MgSO4) and concentrated in vacuo. The crude product thus obtained was purified by column chromatography (silica gel; DCM/AcOEt 4:1 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D38 (8.57 g, 85%).
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(OCCCC)(OCCCC)OCCCC>O>[C:13]1([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1cccc2ccccc12
Reactant: Nc1ccccc1
Agent: CCCCOP(OCCCC)OCCCC
Solvent: O
Product: c1ccc(Nc2cccc3ccccc23)cc1
Temperature: 196 °C
Yield: 91 %

Procedure:
288 parts of α-naphthol, 205 parts of aniline and 10 parts of tributyl phosphite are mixed and first heated to 196° C. The reaction commences, with elimination of water. The water is removed by means of a water separator and the aniline which has escaped is returned. The internal temperature is raised to 235° C in the course of 8 hours. At this point, the elimination of water has ended (33 parts of water). The reaction mixture is cooled to 150° C and the excess aniline and α-naphthol are distilled off under reduced pressure. Thereafter, 400 parts of phenyl-α-naphthylamine are obtained at a boiling point of 202° - 203° C/5 mm Hg; the product has a melting point of 55° - 58° C and corresponds to a yield of 91% of theory.
Reaction SMILES: [NH3:1].[CH2:2]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[C:8](Cl)[N:7]=1)[CH:3]=[CH2:4].O>C(O)C.C1COCC1>[CH2:2]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)[N:9]=[C:8]([NH2:1])[N:7]=1)[CH:3]=[CH2:4]
Reactant: N
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: C=CCNc1nc(N)nc2ccc([N+](=O)[O-])cc12
Temperature: 70 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
After 10 ml of ammonia gas was dissolved in 50 ml of ethanol at −78° C., 15 ml of a solution of 2.40 g (9.07 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline in THF was added thereto, followed by stirring overnight in a sealed tube at 70° C. 150 ml of water was added to the reaction solution, and then crystals thus precipitated were filtered out, followed by recrystallization from ethyl acetate-hexane to give 1.88 g (84.6%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:18][C:19]1[NH:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.O>CN(C=O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:20]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=[C:19]2[NH2:18])[N:7]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: Clc1ncnc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Nc1nc2ccccc2n1-c1ncnc(Cl)n1
Temperature: 0 °C
Reaction time: 1.9 h
Yield: 82.7 %

Procedure:
To 1.0 g (6.67 mmol) of 2,4-dichloro-1,3,5-triazine in 3 mL of DMF at 0° C. is added 1.16 mL (6.67 mmol) of DIEA. The resulting yellow solution is stirred at 0° C. for 10 min when-888 mg (6.67 mmol) of 2-aminobenzimidazole is added portionwise over 5 min, followed by an additional 1 mL of DMF. The resulting mixture is stirred at 0° C. for 1.9 h, then at RT for 3.25 h. At this point, the mixture is poured into 40 mL of stirring cold water with additional cold water rinses to a total volume of 100 mL. The light yellow solid is isolated by filtration, rinsed with cold water, and dried in vacuo, giving 1.36 g (83%) of 1-(4-chloro-[1,3,5]triazin-2-yl)-1H-benzoimidazol-2-ylamine (Compound 1174) as a light yellow solid: MS m/z=246 [M+H]+; HPLC Rt=5.79 min.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:33][C:19]3=[N:20][CH:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([OH:29])=[O:28])[CH:23]=[C:18]3[CH:17]=2)=[CH:12][CH:11]=1.CN(C=O)C>C1COCC1>[Br:8][C:17]1[C:18]2[C:19](=[N:20][CH:21]=[C:22]([C:24]3[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=3)[C:27]([OH:29])=[O:28])[CH:23]=2)[O:33][C:16]=1[C:13]1[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cnc3oc(-c4ccc(F)cc4)c(Br)c3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.7 %

Procedure:
NBS (125 mg, 0.702 mmol) was added to a stirred suspension of 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (215 mg, 0.645 mmol) in THF (5 mL)/DMF (1 mL). The solids dissolved and the reaction was stirred at room temperature for 30 min, then quenched with 10% Na2S2O3, and acidified with 1 N HCl. The solvent was evaporated and the material was diluted with water, filtered and dried to afford a mixture of starting material and product. The material was resubjected to the reaction conditions (80 mg of NBS in 3 mL THF/0.5 mL DMF). After 3 h, the reaction was quenched by the addition of 10% Na2S2O3, and the solution was acidified with 0.1 N HCl. The volatiles were removed and the resulting off-white precipitate was collected by filtration, rinsed with water and Et2O, and air-dried to afford the expected product 3-(3-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)benzoic acid (140 mg, 53% yield) as an off-white powder consistent by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (1H, d, J=2.26 Hz), 8.27-8.33 (2H, m), 8.19-8.26 (2H, m), 8.05-8.12 (1H, m), 8.03 (1H, d, J=7.78 Hz), 7.68 (1H, t, J=7.78 Hz), 7.45-7.55 (2H, m). LC-MS retention time: 1.20 min; m/z (MH+): 412, 414. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[F:33])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:35]([CH3:49])[CH2:36][CH2:37][N:38]1C(=O)C2C(=CC=CC=2)C1=O>>[CH3:24][O:23][C:21](=[O:22])[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH:35]([CH3:49])[CH2:36][CH2:37][NH2:38])[CH2:9][CH2:10]2)[CH2:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2[F:33])[CH:16]=1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)c1cccc(N(Cc2cc(Cl)ccc2F)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Product: COC(=O)c1cccc(N(Cc2cc(Cl)ccc2F)C2CCN(C(C)CCN)CC2)c1

Procedure:
Using general procedure C with the carbamate (910 mg, 1.91 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (565 mg, 2.60 mmol) and then using general procedure D gave 3-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(5-chloro-2-fluoro-benzyl)-amino]-benzoic acid methyl ester as a white foam (473 mg, 56% over 3 steps).
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=3)=[C:10]([F:22])[CH:9]=2)[CH2:4][CH2:3]1.[Mg].P(OCC)(OCC)(OCC)=O.Br[CH2:36][CH2:37][C@H:38]1[CH2:43][CH2:42][Si@H:41]([CH2:44][CH2:45][CH2:46][CH3:47])[CH2:40][CH2:39]1>[Cu]I.C1COCC1>[CH2:44]([Si@H:41]1[CH2:42][CH2:43][C@H:38]([CH2:37][CH2:36][C@H:2]2[CH2:7][CH2:6][C@H:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]4[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=4)=[C:10]([F:22])[CH:9]=3)[CH2:4][CH2:3]2)[CH2:39][CH2:40]1)[CH2:45][CH2:46][CH3:47]
Reactant: CCCC[Si@H]1CC[C@H](CCBr)CC1
Reactant: Fc1ccc(-c2ccc(C3CCC(Br)CC3)cc2F)cc1F
Agent: [Cu]I
Agent: [Mg]
Solvent: CCOP(=O)(OCC)OCC
Solvent: C1CCOC1
Product: CCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(F)c(F)c4)c(F)c3)CC2)CC1

Procedure:
36.9 g (0.1 mol) of 4-(4-bromocyclohexyl)-2,3',4'-trifluorobiphenyl was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 300 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 500 ml THF solution of 0.5 g of triethyl phosphate, 0.1 g of copper (I) iodide and 26.3 g (0.1 mol) of trans-1-(2-bromoethyl)-4-n-butyl-4-silacyclohexane. After a conventional after treatment, 4-(trans-4-(2-(trans-4-n-butyl-4-silacyclohexyl)ethyl)cyclohexyl)-2,3',4'-trifluorobiphenyl was obtained. The silacyclohexane rings of the product were a mixture of trans isomers and cis isomers. They were separated by means of chromatography to obtain 34.3 g (yield 72.6%) of the trans isomer.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1)[N:16]=[CH:15][CH:14]=[C:13]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)=[O:44])=[C:38]([F:49])[CH:37]=1)#[N:9].[Na].O>C(OCC)(=O)C>[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:19]=1[O:20][CH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[N:16]=[CH:15][CH:14]=[C:13]2[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([NH:45][CH:46]2[CH2:48][CH2:47]2)=[O:44])=[C:38]([F:49])[CH:37]=1)#[N:9]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(F)c4)c3cc2C#N)CC1
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(F)c3)ccnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 113.9 %

Procedure:
After adding 5 ml of trifluoroacetic acid to 340 mg of tert-butyl 4-(((6-cyano-4-(4-(((cyclopropylamino)carbonyl)amino)-3-fluorophenoxy)-7-quinolyl)oxy)methyl)-1-piperidinecarboxylate, the mixture was stirred at room temperature for 7 minutes. Saturated sodium bicarnobate water and ethyl acetate were added to the reaction solution for extraction. The ethyl acetate layer was washed with brine and dried over sodium sulfate. The drying agent was filtered off and the solvent was distilled off under reduced pressure to obtain 320 mg of a light yellow solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1.[CH2:14](I)[CH3:15].C(OC(=O)C)C>CN(C=O)C.CCCCCC>[CH2:14]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1)[CH3:15]
Reactant: CCI
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCn1cc(C=O)c2ccccc21
Reaction time: 0.08 h
Yield: 87.2 %

Procedure:
NaH (1.51 g, 37.891 mmol) was added to a solution of 1H-indole-3-carbaldehyde (I-38a: 5 g, 34.447 mmol) in dry DMF (40 mL) at 0° C. and the reaction mixture was stirred for 5 minutes. This was followed by dropwise addition of ethyl iodide (6.45 g, 41.336 mmol) over a period of 5 mins and stirring was continued for a further 1 hr. The reaction was monitored by TLC (40% ethylacetate in hexane). The reaction mixture was quenched with chilled water and filtered. The residue was washed with water and dried to afford 5.2 g of the product (86% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[CH3:17][O:18][C:19](=[O:48])[N:20]=[C:21]([S:46][CH3:47])[C:22]([C:36]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([OH:44])[C:37]=1[F:45])=[N:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:26][CH:25]=1.O>CN(C=O)C.C(OCC)(=O)C>[CH3:17][O:18][C:19](=[O:48])[N:20]=[C:21]([S:46][CH3:47])[C:22]([C:36]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[C:38]([O:44][CH2:8][CH2:9][O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[C:37]=1[F:45])=[N:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:26][CH:25]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(O)c1F
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)cc(OCCOC2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
After adding 200 mg of potassium carbonate and 0.1 ml of 2-(2-bromoethoxy)tetrahydro-2H-pyran to a solution of 80 mg of [2-(2-fluoro-3-hydroxy-5-methoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example 3d) in 1 ml of DMF, the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with water and dried through PRESEP™. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (69 mg) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[I-:17].[K+].II>[OH-].[NH4+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([I:17])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Reactant: [I-]
Agent: II
Agent: [K+]
Agent: [NH4+]
Solvent: O
Product: O=C(c1ccc(F)cc1)c1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.9 %

Procedure:
(4-Fluorophenyl)(4-hydroxyphenyl)methanone (20.0 g, 92.5 mmol) in concentrated ammonium hydroxide (770 mL) was allowed to stir at 25° C. for 15 minutes and then treated with potassium iodide (74.79 g, 450.5 mmol) and iodine (23.48 g, 92.5 mmol) in water (185 mL). The reaction mixture was allowed to stir at 25° C. for 18 hours and then filtered. The precipitate was dissolved in ethyl acetate, washed with water and brine, dried, filtered and the filtrate concentrated under reduced pressure to provide the title compound as a pale green solid (23.4 g, 74% yield). 1HNMR (300 MHZ, CD3OD) δ 6.91 (d, 1H, J=8.9 Hz), 7.26 (t, 2H), 7.64 (d, 1H, J=8.9 Hz), 7.78 (t, 2H), 8.17 (s, 1H); MS (DCI) m/z 342.9 (M+H)+, 360 (M+NH4)+.
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)[C:10](=[O:25])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:26]1(=O)[CH2:29][CH2:28][CH2:27]1>CO.[Cl-].[Zn+2].[Cl-].C([BH3-])#N.[Na+]>[CH:26]1([N:22]2[CH2:23][CH2:24][CH:19]([O:18][C:15]3[CH:14]=[CH:13][C:12]([N:11]4[C:10](=[O:25])[C:9]5[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=5)[N:3]=[C:2]4[CH3:1])=[CH:17][CH:16]=3)[CH2:20][CH2:21]2)[CH2:29][CH2:28][CH2:27]1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCNCC2)cc1
Reactant: O=C1CCC1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(OC2CCN(C3CCC3)CC2)cc1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
2-methyl-3-[4-(4-piperidinyloxy-)phenyl}-4(3H)-quinazolinone (370 mg, 1.10 mmol) and cyclobutanone (155 mg, 2.20 mmol) were dissolved in a 0.5M methanol solution (6 mL) of zinc(II) chloride and sodium cyanoborohydride, and stirred at room temperature for 1 Hour. The solvent was distilled off under reduced pressure, ethyl acetate and distilled water were added, the mixture was extracted with ethyl acetate, and the organic phase washed with distilled water. After drying with anhydrous sodium sulfate, the product was purified by silica gel column chromatography (chloroform/methanol=30/1), and the title compound (165 mg, 39%) was obtained as a colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1B(O)O>>[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[C:12]1[N:13]([CH:18]([CH3:19])[CH3:20])[N:14]=[C:15]2[C:11]=1[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]2
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CC(C)n1nc2c(c1-c1ccc(Cl)cc1Cl)CCNCC2
Yield: 21.2 %

Procedure:
The title compound (37 mg) was prepared according to Example 189 using 230 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 308 mg of 2,4-dichlorophenylboronic acid. MS (ESI): exact mass calculated for C16H19Cl2N3, 323.10. found, m/z 324.4 [M+H]+, 326.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.73-7.72 (m, 1H), 7.54-7.51 (m, 1H), 7.37-7.35 (m, 1H), 4.65 (br s, 1H), 4.11-4.05 (m, 1H), 3.43-3.40 (m, 2H), 3.29-3.16 (m, 3H), 2.70-2.63 (m, 2H), 1.39-1.32 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([O:20]CC)=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH3:25])[C:12]3[CH:16]([CH2:17][C:18]([OH:20])=[O:19])[O:15][B:14]([OH:23])[C:13]=3[CH:24]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(Cl)c3)cc(C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Oc2ccnc(Cl)c2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(2-chloropyridin-4-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (6 mL, 1:1) was added aqueous NaOH solution (100 mg in 1.5 mL of water). After stirring at room temperature for two hours, the reaction mixture was evaporated and then acidified to pH 3 using 1 M HCl. This was then extracted with EtOAc, the organic layers were combined, washed by brine and concentrated. HPLC purification gave desired product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 9.2 (b, 1H), 8.23 (d, J=6 Hz, 1H), 7.22 (s, 1H), 7.09 (s, 1H), 6.95 (s, 1H), 6.88 (dd, J=6, 2 Hz, 1H), 5.49 (dd, J=9.2, 2.4 Hz, 1H), 3.04 (dd, J=15.6, 2.8 Hz, 1H), 2.28 (s, 3H), 2.13 (dd, J=15.2, 9.2 Hz, 1H). 1 proton assumed to be exchanged with solvents. MS (ESI) m/z=332 [M−H]+.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13](=[O:21])[C:14]([C:18]([OH:20])=[O:19])=[CH:15][NH:16][CH:17]=2)=[CH:8][CH:7]=1.[CH3:22]O>>[F:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[C:13](=[O:21])[C:14]([C:18]([O:20][CH3:22])=[O:19])=[CH:15][NH:16][CH:17]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c[nH]cc(-c2ccc(F)cc2)c1=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Thionyl chloride (0.8 ml) was added to a suspension of 5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (400 mg) in methanol (9 ml) at 0° C. The reaction mixture was stirred at 70° C. overnight. The reaction mixture was returned to room temperature and concentrated under reduced pressure. The resulting residue was washed with saturated aqueous sodium bicarbonate and water, and then further washed with diethyl ether to give 304 mg of the title compound as a solid.
Reaction SMILES: N(OS(=O)(=O)O)=[O:2].[CH2:8]([O:15][C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([O:29][CH3:30])[C:17]=1[C:18](N)=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O.ClCCl>[CH2:8]([O:15][C:16]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([O:29][CH3:30])[C:17]=1[C:18]([OH:2])=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=NOS(=O)(=O)O
Reactant: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C(N)=O
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(F)(F)F)cc(OCc2ccccc2)c1C(=O)O
Temperature: 0 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
To a solution of 1.81 g (12.81 mmol) nitrosylsulfuric acid in 1.5 ml water at 0° C. under nitrogene, was added dropwise a suspension of 463 mg (1.423 mmol) 2-benzyloxy-6-methoxy-4-trifluoromethyl-benzamide in 2.9 ml dichloromethane. The reaction mixture was stirred at 0° C. for 4 hours. The reaction mixture was poured over ice and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The crude solid was purified with flash column chromatography on silica (20 g) eluting with a gradient formed from n-heptane and ethyl acetate (0%=>100% in 15 minutes) to provide 431 mg (y: 64.9% yield) of the title compound as a white solid. MS (m/e): 325.1 (M−H)