Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[C:2]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C1(C)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[F:52][C:53]([F:64])([C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=1)[CH:54](OC)O>C1COCC1>[C:2]([O:6][C:7]([N:9]1[CH2:10][CH2:11][CH:12]([CH:15]=[CH:54][C:53]([F:64])([F:52])[C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[CH2:13][CH2:14]1)=[O:8])([CH3:3])([CH3:4])[CH3:5]
Reactant: COC(O)C(F)(F)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C=CC(F)(F)c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 0.1 %

Procedure:
A suspension of ((1-(t-butoxycarbonyl)piperidin-4-yl)methyl)triphenylphosphonium iodide (5.29 g, 9.00 mmol, from Procedure 17, Step C) in THF (70 mL) was stirred at rt for 40 min. A toluene solution of potassium bis(trimethylsilyl)amide (18 mL, 0.5 M, 9.0 mmol) was added, giving an orange suspension. After 40 min., crude 2,2-difluoro-2-(2-pyridyl)-1-methoxyethanol (940 mg, 4.97 mmol) was added in THF (20 mL). After an additional 50 min., the mixture was quenched by the addition of saturated aq. NH4Cl (10 mL). The mixture was partitioned between ethyl acetate (100 mL) and water (100 mL), and the aqueous layer was extracted with ethyl acetate (3×100 mL). The organic layers were washed in succession with saturated aq. brine (100 mL), dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 90:10 v/v to 80:20 v/v hexanes/ethyl acetate, gave 1.18 mg of the title compound (approximately 95:5 cis/trans mixture) as an oil which solidified upon standing. For the title compound:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]([NH2:24])(=[O:23])[CH2:19]C(O)=O.N1CCCCC1.Cl>O.N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:16])([CH3:17])[CH3:15])[C:12]=1[OH:13])[CH:8]=[CH:19][C:18]([NH2:24])=[O:23])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: NC(=O)CC(=O)O
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(C=CC(N)=O)cc(C(C)(C)C)c1O

Procedure:
3.5-di tert.butyl-4-hydroxycinnamamide was prepared by heating a mixture of 23.4 grams of 3,5-di tert.butyl-4-hydroxybenzaldehyde, 31 grams of malonic acid monoamide, 75 milliliters of pyridine, and 3 milliliters of piperidine at 90° to 100° C. for 101/2 hours. The reaction mixture was poured into a solution of 75 milliliters of concentrated hydrochloric acid and 100 milliliters of water. The solid which precipitated was filtered off, dried, and recrystallized from benzene. Ten grams of product was obtained which melted at 217° to 219° C.
Reaction SMILES: [NH2:1][C:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[C:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].N1C=CC=CC=1.[C:22](Cl)(=[O:24])[CH3:23].Cl>O1CCCC1.O>[C:22]([NH:1][C:2]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[C:3]([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:24])[CH3:23]
Reactant: CCOC(=O)C(C)=C(N)c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)=C(NC(C)=O)c1ccccc1

Procedure:
76 g of ethyl 3-amino-2-methyl-3-phenyl-2-propenoate were maintained at 15° C. in 600 ml of tetrahydrofuran and 32.3 ml of pyridine while adding 28.44 ml of acetyl chloride in 100 ml of tetrahydrofuran. The mixture was refluxed for 1 hour, then cooled and poured into a liter of water acidified to pH 1 with 2N hydrochloric acid. After extracting with ether, washing with water, with a saturated solution of sodium bicarbonate and then with water, drying and concentrating to dryness under reduced pressure, 80 g of the expected product were obtained.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([O:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([Br:22])[CH:21]=1)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.CCOCC>[Br:22][C:20]1[CH:21]=[C:16]([O:15][CH:4]([CH2:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[NH:8][CH:7]=2)[CH2:3][OH:2])[CH:17]=[N:18][CH:19]=1
Reactant: COC(=O)C(Cc1c[nH]c2ccccc12)Oc1cncc(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC(Cc1c[nH]c2ccccc12)Oc1cncc(Br)c1
Yield: 42 %

Procedure:
To a solution of Example 405A (3.2 g, 8.5 mmol) in THF (20 mL) and ether (30 mL) was slowly added LiAlH4 powder (323 mg, 8.5 mmol) in several portion at rt. While LAH was added a lot of solid material precipitated from the solution and the temperature arises to about 40° C. Water (2 mL) and diluted HCl was added slowly and the mixture was neutralized with NaHCO3 and extracted with ethyl acetate. The organic phase was washed with water and concentrated. The residue was separated by flash chromatography (20-80% EtOAc in hexane) to give the desired product (1.24 g, 42%). MS (DCI) m/z 347, 349 (M+1)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CN(C=O)C>[CH3:33][O:32][C:30](=[O:31])[CH2:29][N:21]([C:15]1[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=1[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:22](=[O:27])[C:23]([F:26])([F:24])[F:25]
Reactant: O=C(Nc1ccc(Cl)cc1Cc1ccccc1)C(F)(F)F
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)C(F)(F)F)c1ccc(Cl)cc1Cc1ccccc1
Yield: 89.2 %

Procedure:
Powdered potassium carbonate (1.10 g, 7.97 mmol) is added to a stirred solution of N-(2-benzyl-4-chloro-phenyl)-2,2,2-trifluoro-acetamide (1.25 g, 3.98 mmol) and methyl bromoacetate (1.34 g, 8.76 mmol) in anhydrous DMF (5 mL). The resultant mixture is stirred at ambient temperature under nitrogen for 2 hours. After dilution with EtOAc (60 mL), the mixture is washed with water (25 mL×3), dried over MgSO4, filtered, concentrated and chromatographed on-silica (gradient 0-15% EtOAc in hexane) to give 1.37 g (3.55 mmol, 89% yield) of the title compound as oil. ESIMS: m/z 386 [(M+H)+, 35Cl], 388 [(M+H)+, 37Cl].
Reaction SMILES: C(OC(=O)[N:5]([C:7]1[C:16]2[C:11](=[C:12]([Cl:17])[CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([OH:18])[N:8]=1)[NH2:6])C.CN(C)[CH:22]=[O:23]>>[Cl:17][C:12]1[C:11]2[NH:10][C:9](=[O:18])[N:8]3[C:22](=[O:23])[NH:6][N:5]=[C:7]3[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)N(N)c1nc(O)nc2c(Cl)cccc12
Product: O=c1[nH]nc2c3cccc(Cl)c3[nH]c(=O)n12
Temperature: 25 °C

Procedure:
1.27 g (0.0045 mol) of ethyl-8-chloro-2-hydroxy-quinazoline-4-yl-carbazate in 75 ml of dimethylformamide were boiled under reflux for 2 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off, dried in a vacuum and recrystallized from methanol/tetrahydrofuran. Yield: 0.66 g (62%) of 7-chloro-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as yellowish crystals; m.p. 348°-350° C.
Reaction SMILES: N#N.COC(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:28])[CH2:14][CH2:15][C:16]2[CH:21]=[C:20]([O:22]C)[C:19]([O:24]C)=[C:18]([O:26]C)[CH:17]=2)[C:7]=1NC1C=CC=CC=1.B(Br)(Br)Br.[Cl-].[Na+].O.CC[O:46][C:47]([CH3:49])=[O:48]>C(Cl)Cl>[OH:22][C:20]1[CH:21]=[C:16]([CH2:15][CH2:14][C:13]([NH:12][C:8]2[CH:7]=[C:6]([NH:12][C:8]3[CH:9]=[C:49]([CH:11]=[CH:6][CH:7]=3)[C:47]([OH:46])=[O:48])[CH:11]=[CH:10][CH:9]=2)=[O:28])[CH:17]=[C:18]([OH:26])[C:19]=1[OH:24]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cccc(NC(=O)CCc2cc(OC)c(OC)c(OC)c2)c1Nc1ccccc1
Agent: BrB(Br)Br
Agent: N#N
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(CCc1cc(O)c(O)c(O)c1)Nc1cccc(Nc2cccc(C(=O)O)c2)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve 3-{3-[3-(3,4,5-Trimethoxy-phenyl)-propionylamino]-phenylamino-benzoic acid methyl ester (91) (36 mg, 0.08 mmol) in anhydrous DCM (2.3 mL) at −78° C., add dropwise a 1M solution of BBr3 in DCM (930 μL, 0.93 mmol) and stir for additional 30 min at −78° C. After slowly warming up stir the reaction solution for additional 4 h at rt. Cool reaction mixture to 0° C., add dropwise water/THF (1+1) and remove solvent. Purify the crude product by preparative RP HPLC (gradient, water/CH3CN 95:5 to 5:95) to obtain 3-{3-[3-(3,4,5-Trihydroxy-phenyl)-propionylamino]-phenylamino}-benzoic acid (92) (10 mg, 33%) as a white solid. 1H NMR (400 MHz, CD3OD): 2.60 (t, 2H, J=7.7 Hz); 2.85 (t, 2H, J=7.7 Hz); 6.29 (s, 2H); 6.70 (dd, 1H, J1=8.0 Hz, J2=2.0 Hz); 7.06 (d, 1H, J=8.0 Hz), 7.21 (t, 1H, J=8.0 Hz), 7.33-7.37 (m, 2H), 7.45 (mc, 1H); 7.50-7.54 (m, 1H); 7.77 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Li]>O1CCCC1>[NH2:1][C:2]1[C:3]([C:4]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: [Li]c1ccccc1F
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Solvent: C1CCOC1
Product: Nc1nc(Cl)ccc1C(=O)c1ccccc1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (500 mg, 2.32 mmol, Example 3) was dissolved in anhydrous tetrahydrofuran (14 mL) and cooled to −78° C. A solution of 2-fluorophenyl lithium (4-6 equiv, freshly prepared following the same procedure as in Example 4) was added. The reaction was stirred at −78° C. for 1-3 hrs and quenched with aqueous ammonium chloride solution. The resulting mixture was extracted with ethyl acetate, washed with saturated sodium chloride, dried over sodium sulfate and evaporated in vacuo. The product was then purified on silica gel to give (2-Amino-6-chloro-pyridin-3-yl)-(2-fluoro-phenyl)-methanone as a white solid (445.5 mg, 77% yield). HRMS, observed: 250.0306, Calcd for M+: 250.0309.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([O:15]CC)=[O:14])=[CH:5]2.[OH-].[K+].O>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([OH:15])=[O:14])=[CH:5]2
Reactant: CCOC(=O)c1cnc2cc(F)c(F)cc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc2cc(F)c(F)cc2c1
Temperature: 20 °C
Reaction time: 4 h
Yield: 90.2 %

Procedure:
A suspension of 37.7 g of ethyl 6,7-difluoroquinoline-3-carboxylate in a mixture of 20 cm3 of ethanol and 160 cm3 of a 1 N aqueous potassium hydroxide solution was stirred for 4 hours, at a temperature of 20° C. 600 cm3 of water was added to the solution and the insoluble material was extracted twice with 400 cm3 of diethyl ether. The aqueous solution was neutralized with 161 cm3 of a 1 N aqueous hydrochloric acid solution. The precipitate obtained was dewatered, washed 3 times with 150 cm3 of water, and dried under vacuum at a temperature of 50° C. 30 g of 6,7-difluoroquinoline-3-carboxylic acid was obtained in the form of white crystals, which melted at 290° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[SH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-:3])=[O:2].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[CH2:24](I)[CH3:25]>[OH-].[Na+]>[CH2:24]([S:14][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:25]
Reactant: CCI
Reactant: O=[N+]([O-])c1cnc2ccccc2c1S
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCSc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
20.52 g (0.1 mole) of 3-nitro-4-quinoline-thiol are taken up in 150 ml of a molar sodium hydroxide solution. After addition of some sodium pyrosulfite crystals 23.3 g (0.15 mole) of ethyl iodide are added at 60° C. After the reaction has been completed the product formed is extracted with dichloro methane and the extract is evaporated. The 4-ethylthio-3-nitro-quinoline thus obtained (18.6 g) is dissolved in alcohol, an aqueous sodium sulfide solution is added, the reaction mixture is refluxed and then diluted with water. The product is extracted with dichloro methane, the extract is clarified and evaporated. From the residue (13.6 g, yield 83.5%) the hydrochloride is formed by usual methods. Thus 14.0 g of 3-amino-4-ethylthio-quinoline-hydrochloride are obtained. The product is identical with the compound prepared according to Example 1 or 2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[C:17]([Br:24])[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:15]2[CH:16]=[C:17]([Br:24])[CH:18]=[C:19]([NH2:21])[CH:20]=2)([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cc([N+](=O)[O-])c2)COC1
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)cc(Br)c2)COC1
Reaction time: 1.5 h

Procedure:
[(R)-5-(3-Bromo-5-nitro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (930 mg, 2.13 mmol) was dissolved in 5 ml methanol. Raney-Nickel was added and the reaction was hydrogenated for 1.5 hrs at r.t. The reaction was filtered over Celite, washed with dichloromethane/methanol (9/1). Volatiles were removed under reduced pressure yielding the title compound as white solid.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([O:10]C(=O)C)[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([C:40]#[N:41])=[N:18][C:19]=3[NH:23][CH2:24][CH:25]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)[O:7][C@@H:6]1[CH2:42][O:43]C(=O)C)(=O)C>N.C(O)C.[Pd]>[NH2:41][CH2:40][C:17]1[N:16]=[C:15]2[C:20]([N:21]=[CH:22][N:14]2[C@H:8]2[C@H:9]([OH:10])[C@H:5]([OH:4])[C@@H:6]([CH2:42][OH:43])[O:7]2)=[C:19]([NH:23][CH2:24][CH:25]([C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[CH:27]=2)[N:18]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4cccc(C)c4)c4cccc(C)c4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Agent: N
Solvent: CCO
Product: Cc1cccc(C(CNc2nc(CN)nc3c2ncn3[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cccc(C)c2)c1
Yield: 50.1 %

Procedure:
(2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-(6-{[2,2-bis(3-methylphenyl)ethyl]amino}-2-cyano-9H-purin-9-yl)tetrahydro-3-furanyl acetate (620 mg, 1 mmol) (Preparation 66) was dissolved in a saturated solution of 0.88 concentrated aqueous ammonia in ethanol (20 ml). The solution was then stirred under an atmosphere of hydrogen gas (414 kPa, 60 psi) at room temperature for 64 hours in the presence of 10% Palladium on carbon (120 mg). The reaction mixture was then filtered through Arbocel (Trade Mark) and the filtrate was evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:(90:10 by volume) increasing in polarity to dichloromethane:methanol:0.88 concentrated aqueous ammonia (80:20:2 by volume). The solvent was removed under reduced pressure to give the title compound (253 mg) as a foam.
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH2:19])[CH2:8][CH2:7]1)=O)C.C(N(CC)CC)C.[C:27](Cl)(Cl)=[S:28]>C(Cl)Cl>[NH:6]1[CH2:7][CH2:8][CH:9]([N:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[NH:19][C:27]2=[S:28])[CH2:10][CH2:11]1
Reactant: CCOC(=O)N1CCC(Nc2ccccc2N)CC1
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: S=c1[nH]c2ccccc2n1C1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To a solution of 4-(2-amino-phenylamino)-piperidine-1-carboxylic acid ethyl ester (0.76 g, 2.9 mmol) and triethylamine (0.81 ml, 5.8 mmol) in methylene chloride (10 mL) at 0° C. was added a solution of thiophosgene (0.22 mL, 2.9 mmol) in methylene chloride (10 mL) at room temperature. The reaction mixture was stirred for 2 h then quenched with 1N sodium hydroxide. The organic phase was separated and dried over sodium sulfate, filtered and concentrated. The crude product (i.e.; 4-(2-thioxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid ethyl ester) was treated with 10% sodium hydroxide (10 mL) and refluxed for 4 h. The reaction was allowed to cool to room temperature and the aqueous layer was washed with ethyl ether (50 mL), acidified to pH<2 with 6N hydrochloric acid, washed with ethyl ether (50 ml) and filtered (to remove a small amount of precipitated solid). The aqueous layer was adjusted to pH 10 by slowly adding sodium carbonate and then cooled to 0° C. The solid that formed was collected by filtration to give 1-piperidin-4-yl-1,3-dihydro-benzoimidazole-2-thione (0.2 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[C:19]([F:21])[C:18]([NH:22][C:23]([N:25]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[C:26]3=[O:36])=[O:24])=[CH:17][C:16]=2[Cl:37])[CH:11]=[CH:10][N:9]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[C:16]([Cl:37])=[CH:17][C:18]([NH:22][C:23]([N:25]3[CH2:29][CH2:28][N:27]([CH:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)[C:26]3=[O:36])=[O:24])=[C:19]([F:21])[CH:20]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2cc(F)c(NC(=O)N3CCN(C4CCOCC4)C3=O)cc2Cl)ccn1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Oc2cc(F)c(NC(=O)N3CCN(C4CCOCC4)C3=O)cc2Cl)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
tert-Butyl(4-(2-chloro-5-fluoro-4-(2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamido)phenoxy)pyridin-2-yl)carbamate (1.32 g, 2.400 mmol) was combined with TFA (20 mL), stirred at RT overnight and concentrated to dryness. The residue was treated with DCM, sonicated, the solid removed via filtration and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford N-(4-((2-aminopyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (382 mg, 35%). MS (ESI) m/z: (M+H+): 450.1.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:27][C:28]1([F:34])[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CS(C)=O.CCOC(C)=O>[F:27][C:28]1([F:34])[CH2:33][CH2:32][N:31]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=2)[CH2:30][CH2:29]1
Reactant: FC1(F)CCNCC1
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCC(F)(F)CC3)n2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of triazine A1 (270 mg, 0.9 mmol) in DMSO (0.9 mL) were added K2CO3 (370 mg, 2.7 mmol) and 4,4-difluoropiperidine hydrochloride (140 mg, 0.9 mmol). The mixture was stirred for 2 hours at 80° C. After cooling to room temperature it was diluted with EtOAc and extracted with water. The organic layer was washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was stirred with DCM to give the solid title compound B2 which was isolated by filtration and dried in vacuo (white powder, 110 mg, 32%). 1H NMR (300 MHz, d6-DMSO, 300K) δ 1.90-2.15 (m, 4H), 3.81-3.98 (m, 4H), 4.21 (s, 2H), 6.88 (s, 2H), 6.98-7.04 (m, 1H), 7.21-7.34 (m, 1H), 7.44-7.60 (m, 1H), 7.78-7.90 (m, 1H), 8.25 (s, 1H), 9.77 (s, 1H). MS (ES) C15H18F2N6O2S requires: 384. found: 385 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[O:6][CH:7]=1.[OH-:15].[Na+]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:6][CH:7]=[C:3]([CH2:2][OH:15])[N:4]=2)=[CH:9][CH:10]=1
Reactant: [OH-]
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Agent: [Na+]
Product: OCc1coc(-c2ccc(Cl)cc2)n1
Temperature: 25 °C

Procedure:
6 g (26.307 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole were heated under reflux in 526 ml (52.613 mmol) of 0.1 N aqueous sodium hydroxide solution for 3 h. The mixture was then cooled to room temperature, and the precipitated solid was filtered off, washed with 0.1N aqueous sodium hydroxide solution and dried under high vacuum. This gave 4.79 g (85% of theory) of the target compound.
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[Cl:24][C:25]1[C:30](Cl)=[N:29][CH:28]=[CH:27][N:26]=1>CC(N(C)C)=O.[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:24][C:25]1[C:30]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:29][CH:28]=[CH:27][N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Reactant: Clc1nccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Si](C)(C)Cl
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
To a suspension of activated zinc dust (84.4 g, 1.29 mol, 1.94 eq.) in anhydrous DMA (270 mL) was added 1,2-dibromoethane (9.1 mL, 0.106 mol, 0.16 eq.), followed by the slow addition of chlorotrimethylsilane (13.5 mL, 0.106 mol, 0.16 eq.) over a period of 5 min. The resulting mixture was stirred for 15 min under nitrogen. Then a solution of tert-butyl 4-iodopiperidine-1-carboxylate (329 g, 1.06 mol, 1.59 eq.) in anhydrous DMA (670 mL) was added to the above suspension over a period of 45 min keeping the internal temperature below 65° C. The resulting mixture was stirred for 1 hour while cooling back to room temperature. The prepared zinc reagent was allowed to stand and the upper clear solution was transferred to a degassed and well stirred solution of 2,3-dichloropyrazine (99 g, 0.664 mol, 1 eq.), PdCl2(dppf) CH2Cl2 (16.3 g, 19.9 mmol, 0.03 eq.) and Cul (7.8 g, 41.2 mmol, 0.062 eq.) in anhydrous DMA (670 mL) using a cannula. DMA (400 mL) was used to rinse the remaining zinc dust and added to the above mixture. The resulting mixture was heated to 80° C. under nitrogen and stirred overnight (19 hours). The mixture was cooled to room temperature and diluted with brine (1 L) and ethyl acetate (6 L). The aqueous phase was extracted with ethyl acetate (4 L) and organic extracts were combined, washed with brine (1 L), dried and concentrated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=9:1 to 6:1) to give 92 g of tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:18][CH2:19][CH:20]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:22]1([N:28]2[CH2:33][CH2:32][N:31]([CH2:20][CH2:19][CH2:18][C:9]3[CH:10]=[C:11]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=CCCc1cc(-c2ccccc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(-c2cc(CCCN3CCN(c4ccccc4)CC3)nn2-c2ccccc2)cc1

Procedure:
100 mg (94%) of target compound was obtained by using a method same as in Example 1 by using 3-(1,5-diphenyl-1H-pyrazol-3-yl)propanal (76 mg, 0.275 mmol), 1-phenylpiperazine (0.038 mL, 0.250 mmol), DIPEA (44 mL, 0.250 mmol) and NaBH(OAc)3 (185 mg, 0.875 mmol).