Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N:16]([CH3:26])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:19])=[O:18])[CH:15]=1)[NH:12][C:11]([C:27]1[S:28][CH:29]([CH2:32][N:33]3[CH2:38][CH2:37][S:36][CH2:35][CH2:34]3)[CH2:30][N:31]=1)=[CH:10]2.CO.[OH:41]OS([O-])=O.[K+].S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.O>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[C:14]([N:16]([CH3:26])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)(=[O:19])=[O:18])[CH:15]=1)[NH:12][C:11]([C:27]1[S:28][CH:29]([CH2:32][N:33]3[CH2:34][CH2:35][S:36](=[O:41])[CH2:37][CH2:38]3)[CH2:30][N:31]=1)=[CH:10]2
Reactant: O=S([O-])OO
Reactant: COCCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCSCC4)S3)cc2c1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCS(=O)CC4)S3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a mixture of N-{5-(3-methoxypropoxy)-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylpyridine-2-sulfonamide (110 mg), methanol (3 mL), water (3 mL) and tetrahydrofuran (3 mL) was added OXONE (registered trade mark, 60 mg) at room temperature, and the mixture was stirred at room temperature for 1 hr. Aqueous sodium sulfite solution was added to the reaction mixture, and the mixture was stirred for 30 min, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-methanol (100:0-90:10, volume ratio). The obtained crystals were washed with cliisopropyl ether to give the title compound (35 mg, yield 32%) as colorless crystals. The crystals were recrystallized from acetone-hexane to give colorless prism crystals. melting point 176-177° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:45])([CH3:44])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:11]=[CH:10][C:9]=1[C:23]1[C:24](=[O:43])[O:25][C:26]2[C:31]([C:32]=1[CH3:33])=[CH:30][CH:29]=[C:28]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:27]=2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:56][CH2:57][C:58](Cl)=[O:59]>C1COCC1.C(OCC)C>[CH3:45][Si:2]([CH3:44])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[CH:11]=[CH:10][C:9]=1[C:23]1[C:24](=[O:43])[O:25][C:26]2[C:31]([C:32]=1[CH2:33][C:58](=[O:59])[CH2:57][Cl:56])=[CH:30][CH:29]=[C:28]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[CH:27]=2
Reactant: O=C(Cl)CCl
Reactant: Cc1c(-c2ccc(OCOCC[Si](C)(C)C)cc2OCOCC[Si](C)(C)C)c(=O)oc2cc(OCOCC[Si](C)(C)C)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)CCOCOc1ccc(-c2c(CC(=O)CCl)c3ccc(OCOCC[Si](C)(C)C)cc3oc2=O)c(OCOCC[Si](C)(C)C)c1
Temperature: -20 °C
Reaction time: 0.17 h

Procedure:
At room temperature, 3-[2,4-Bis-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-chromen-2-one (1.6 g, 2.37 mmol) in THF (10 mL) was added LiHMDS (2.9 mL, 2.84 mmol) slowly. The reaction mixture was stirred for 10 min and then added into chloroacetyl chloride (0.28 mL, 1.5 equiv.) in THF (20 mL) at −20° C. The reaction mixture was maintained at −20° C. for 1 hour, then diluted with diethyl ether (200 mL), washed with aqueous NH4Cl (100 ml), brine and organic layer was dried over anhydrous MgSO4. The resulting product was then concentration by vacuum to dryness and purified by silica gel column chromatography to yield the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:16][C:13]2[CH:14]=[CH:15][C:10]([NH2:9])=[CH:11][C:12]=2[Cl:17])=[N:6][CH:7]=1
Reactant: Nc1ccc(O)c(Cl)c1
Reactant: Clc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ccc(Oc2ncc(Br)cn2)c(Cl)c1
Yield: 62.6 %

Procedure:
Into a flask, 7.00 g of 5-bromo-2-chloropyrimidine, 5.19 g of 4-amino-2-chlorophenol, 9.98 g of potassium carbonate and 70 ml of dimethylsulfoxide were introduced, and reacted in a nitrogen atmosphere at 120° C. for 1.5 hours under stirring. After the completion of the reaction, the product was poured into water, and extracted with ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then purified by silica gel column chromatography, whereby 6.80 g of oily 4-(5-bromo-2-pyrimidinyloxy)-3-chloroaniline was obtained.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[C:26]#[N:27])[CH2:19][CH2:18]3)=[O:16])[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:31]>C(OCC)(=O)C>[ClH:31].[ClH:31].[C:1]1([C:7]#[C:8][C:9]2[CH:10]=[C:11]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([C:23]4[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=4)[CH2:26][NH2:27])[CH2:21][CH2:22]3)=[O:16])[CH:12]=[N:13][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1cccc(C2CCN(C(=O)c3cncc(C#Cc4ccccc4)c3)CC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: NCc1cccc(C2CCN(C(=O)c3cncc(C#Cc4ccccc4)c3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 3-[1-(5-phenylethynyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzonitrile (0.15 g, 0.25 mmol) in ethyl acetate (20 ml) was cooled to 0° C. and then saturated with hydrogen chloride gas. The reaction mixture was stirred at ambient temperature for 4 hours and then concentrated to dryness under vacuum. The residue was treated with ethyl acetate (10 ml) and the solvent removed under vacuum. This process was repeated twice to give 3-[1-(5-phenylethynyl-pyridine-3-carbonyl)-piperidin-4-yl]-benzylamine di-hydrochloride as a white solid (0.11 g). 1H NMR [(CD3)2SO, 500 MHz]: δ 8.83 (s, 1H), 8.63 (s, 1H), 8.08 (s, 1H), 7.61 (m, 2H), 7.45 (m, 3H), 7.44 (s, 1H), 7.37 (m, 3H), 4.64 (br m, 1H), 4.00 (m, 2H), 3.62 (br m, 1H), 3.25 (br m, 1H), 2.90 (br m, 2H), 1.88 (br m, 1H), 1.70 (m, 3H). MS(EI): 396(M++H).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:10][C:6]=2[CH:5]=[C:4](Br)[N:3]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C.O.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>[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:2]2[C:7]3[S:8][C:9]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:10][C:6]=3[CH:5]=[C:4]([C:7]3[CH:2]=[N:3][CH:4]=[CH:5][CH:6]=3)[N:3]=2)[CH:19]=1
Reactant: CCNC(=O)Nc1nc2cc(Br)nc(Br)c2s1
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)nc(-c3cccnc3)c2s1
Temperature: 90 °C
Yield: 46.9 %

Procedure:
To a solution of 1-(4,6-dibromo-thiazolo[5,4-c]pyridin-2-yl)-3-ethyl-urea (0.07 g, 0.17 mmol) in DMF:H2O (3:1, 4 mL) was added pyridine-3-boronic acid (0.08 g, 0.68 mmol) and potassium phosphate tribasic (0.09 g, 0.43 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was degassed by bubbling nitrogen for 15-20 min followed by addition of Pd(PPh3)4 (0.04 g, 0.07 mmol). The resulting solution was again degassed for 15-20 min followed by heating up to 90° C. overnight. After completion of reaction (TLC monitoring), the reaction mixture was cooled, water was added and extracted with ethyl acetate, dried over Na2SO4 and evaporated to dryness under high vacuum. The crude residue was purified by Prep HPLC to get the desired product (0.015 g, 23%).
Reaction SMILES: [P:1]([Cl:4])(Cl)[Cl:2].[CH3:5][CH:6]1[CH2:10][CH2:9][CH:8]([CH3:11])[N:7]1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH3:5][CH:6]1[CH2:10][CH2:9][CH:8]([CH3:11])[N:7]1[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][C:17]=1[P:1]([Cl:4])[Cl:2]
Reactant: ClP(Cl)Cl
Reactant: Cc1ccc(N2C(C)CCC2C)cc1
Solvent: c1ccncc1
Product: Cc1ccc(N2C(C)CCC2C)c(P(Cl)Cl)c1

Procedure:
A solution of PCl3 (36.3 g, 264.3 mm) in 200 mL of pyridine was treated with (+/−)-2,5-dimethyl-1-N(4′-methylphenyl)pyrrolidine (10.0 g, 52.8 mm) over a period of 5 min. The resulting mixture was then refluxed for 2 days to give the crude (+/−)-2,5-dimethyl-1-N(2′-dichlorophosphino-4′-methylphenyl)pyrrolidine (31P NMR: δ164.7 (s), 159.9 (s) ppm). After precipitates (Py.HCl) were filtered off, the excess PCl3 and pyridine solvent were removed from filtrates, a mixture of 100 mL of pyridine and 300 mL of THF was added to the resulting residue. Next, polymer-supported secondary amines (15.0 g, 1.1 mmol/g, 16.5 mmol) was slowly added into the mixture above while stirring at room temperature for a period of 10 min. The resulting suspension was refluxed overnight before the solution was filtered off. The resin was washed with THF (2×50 mL), hexane (3×50 mL), CH2Cl2 (4×50 mL), and hexane (2×50 mL). The resulting resin was dried in vacuum overnight to yield the polymer-supported (+/−)-2,5-dimethyl-1-N(1-N(2′-chlorophosphino-4′-methylphenyl)pyrrolidine. 31P NMR (122 MHz, CDCl3): δ145.1, 136.0 ppm.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8](=O)([O:12]CC)[O:9][CH2:10][CH3:11].[H-].[Na+]>C1COCC1>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:8]([O:9][CH2:10][CH3:11])=[O:12]
Reactant: O=C1CCCCC1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCCC1=O

Procedure:
The compounds of this invention may be prepared using methods known to those skilled in the art, or the novel methods of this invention. Specifically, the compounds of this invention with Formula I, II or III can be prepared as illustrated by the exemplary reaction in Scheme 1. Reaction of cyclohexanone with diethyl carbonate in THF in the presence of NaH produced ethyl 2-oxocyclohexanecarboxy late. Reaction of ethyl 2-oxocyclohexanecarboxylate with urea at 175-185° C. produced 5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H )-dione. Reaction of 5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H )-dione with hexamethyldisilazane (HMDS) in toluene in the presence of concentrated sulfuric acid, produced the intermediate 2,4-di(trimethylsilyloxy)-5,6,7,8-tetrahydroquinazol. Reaction of 2,4-di(trimethylsilyloxy)-5,6,7,8-tetrahydroquinazoline with methyl 3-(bromomethyl)benzoate in DMF , followed by treatment with 1,4-dioxane and methanol, produced 1-(3-methoxycarbonylbenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H )-dione. Treatment of the ester with NaOH in water-methanol produced 1-(3-carboxybenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione. Coupling of the acid with a substituted amine, such as 1-(pyrimidin-2-yl)piperazine, in the presence of coupling agents, such as 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisopropylethylamine (DIPEA) in DMF, produced the targeted compound 1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H, 3H)-dione.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=4[C:16]=3[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:26].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CC(C)=O>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][O:26][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3[O:13][C:14]4[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=4[C:16]=3[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=2)[C:2]=1[Br:1])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: CCCCCc1c(-c2ccc3c(Br)c(O)ccc3c2)oc2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCCCCc1c(-c2ccc3c(Br)c(OCC(=O)OCC)ccc3c2)oc2ccccc12

Procedure:
Following the procedure described in Method B, Step 5 of Example 1, the title compound was prepared from 1-bromo-6-(3-pentyl-benzofuran-2-yl)-naphthalen-2-ol (1.5 g, 3.66 mmol), cesium carbonate (2.4 g, 7.34 mmol), ethyl bromoacetate (0.48 mL, 4.3 mmol) in acetone (35 mL). The title compound was obtained as an off-white solid (1.6 g), mp 93-95° C. Mass spectrum (+APCl, [M+H]+) m/z 495. 1HNMR (300 MHz, DMSO-d6): δ8.34 (s, 1H), 8.24 (d, 1H, J=9.0 Hz), 8.12 (d, 1H, J=9.1 Hz), 8.06-8.02 (m, 1H), 7.69 (d, 1H, J=7.1 Hz), 7.61 (d, 1H, J=7.7 Hz), 7.48 (d, 1H, J=9.1 Hz), 7.37-7.26 (m, 2H), 5.1 (s, 2H), 4.18 (q, 2H, J=7.1 Hz), 3.01 (t, 2H, J=7.3 Hz), 1.76-1.64 (m, 2H), 1.43-1.26 (m, 4H), 1.22 (t, 3H, J=7.1 Hz), and 0.85-0.79 ppm (m, 3H). Elemental Analysis for C27H27BrO4.1.0H2O: Calculated: C, 63.16; H, 5.69; N, 0.00. Found: C, 62.90; H, 5.19; N, 0.15.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].Cl.[OH-].[Na+].O>O1CCOCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ccc3c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCN3)nc1
Yield: 92.9 %

Procedure:
5-(5-Nitropyridin-2-yloxy)-1H-indole (3.00 g, 11.8 mmol) was dissolved in 1,4-dioxane (30 mL). To the solution were added boran-trimethylamine complex (3.43 g, 47.0 mmol) and hydrochloric acid (1.96 mL, 23.5 mmol) and the resulting solution was refluxed for 1 hour. After cooling for 30 minutes, 6 M hydrochloric acid (9.40 mL, 56.4 mmol) was added to the solution, and the mixture was refluxed again. Thirty minutes later, the reaction mixture was cooled with ice and the pH of the solution was adjusted to 8 by dropwise addition of concentrated aqueous sodium hydroxide. Water (150 mL) was added to the solution, and the mixture was extracted with ethyl acetate (150 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated to yield 2.82 g of the title compound as reddish orange oil.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:16]=2[C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].FC(F)(C1C=CC(N)=CC=1OCCN1CCCC1)C(F)(F)F>>[NH2:21][C:19]1[CH:18]=[CH:17][C:16]([C:24]([F:29])([F:30])[C:25]([F:26])([F:27])[F:28])=[C:15]([CH:20]=1)[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc([N+](=O)[O-])ccc2C(F)(F)C(F)(F)F)CC1
Agent: Nc1ccc(C(F)(F)C(F)(F)F)c(OCCN2CCCC2)c1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cc(N)ccc2C(F)(F)C(F)(F)F)CC1

Procedure:
tert-Butyl 4-(5-amino-2-(perfluoroethyl)benzyl)piperazine-1-carboxylate was prepared from 1-Boc-4-(5-nitro-2-pentafluoroethyl-benzyl)-piperazine similar to that described in the preparation of 4-pentafluoroethyl-3-(2-pyrrolidin-1-yl-ethoxy)-phenylamine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][CH:4]=[N:3]1.C(N(CC)CC)C.O1CCOCC1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][C:24]=1[CH2:33]Br>C(OCC)(=O)C>[CH3:1][N:2]1[C:6]([N:7]2[CH2:33][C:24]3[C:23](=[CH:28][CH:27]=[C:26]([C:29]([F:30])([F:32])[F:31])[CH:25]=3)[CH2:22]2)=[CH:5][CH:4]=[N:3]1
Reactant: FC(F)(F)c1ccc(CBr)c(CBr)c1
Reactant: Cn1nccc1N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cn1nccc1N1Cc2ccc(C(F)(F)F)cc2C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
1-Methyl-1H-pyrazol-5-amine (1.53 g) and triethylamine (4.60 mL) were added to a 1,4-dioxane (53 mL) solution of 1,2-bis(bromomethyl)-4-(trifluoromethyl)benzene (5.25 g) at a room temperature, and the obtained solution was then stirred at 100° C. for 1 hour. Thereafter, the reaction solution was diluted with ethyl acetate, and was then washed with water and a saturated saline. The resultant was dried over anhydrous sodium sulfate, and was then concentrated under a reduced pressure. The residue was purified by column chromatography (silica gel 60N, hexane:ethyl acetate=2:1 to 40:60), so as to obtain the title compound (785 mg) in the form of a colorless solid.
Reaction SMILES: N.O.O[N:4]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([C:35]=1[CH2:36][CH2:37][CH2:38][C:39]1([C:56]([OH:58])=O)[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][O:47][C:48]3[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[CH:49]=3)[CH2:41][CH2:40]1)=[CH:33][C:32]([O:59][CH3:60])=[CH:31][CH:30]=2>O1CCOCC1.ClCCl.O.C(N(CC)CC)C>[Cl:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([C:35]=1[CH2:36][CH2:37][CH2:38][C:39]1([C:56]([NH2:4])=[O:58])[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][O:47][C:48]3[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[CH:49]=3)[CH2:41][CH2:40]1)=[CH:33][C:32]([O:59][CH3:60])=[CH:31][CH:30]=2
Reactant: On1nnc2ccccc21
Reactant: COc1ccc2ncc(Cl)c(CCCC3(C(=O)O)CCN(CCOc4cc(F)cc(F)c4)CC3)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COc1ccc2ncc(Cl)c(CCCC3(C(N)=O)CCN(CCOc4cc(F)cc(F)c4)CC3)c2c1
Temperature: 20 °C
Reaction time: 17 h
Yield: 75.5 %

Procedure:
13.4 cm3 of a 0.5N solution of aqueous ammonia in dioxane, 0.229 g of 1-hydroxybenzotriazole hydrate, 0.64 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 0.46 cm3 of triethylamine were added, with stirring and under an inert atmosphere, to a mixture of 0.69 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenoxy)ethyl]piperidine-4-carboxylic acid in 30 cm3 of dichloromethane. The suspension obtained was stirred for 17 hours at a temperature in the region of 20° C. The reaction mixture was diluted with 50 cm3 of water, stirred and the phases were separated by settling. The aqueous phase was extracted with twice 25 cm3 of dichloromethane and the organic extracts were combined, washed with 25 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The solid was taken up in 20 cm3 of diisopropyl ether, stirred and then filtered. 0.52 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenoxy)ethyl]piperidine-4-carboxamide was obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]([CH3:19])([CH2:14][C:15]#[C:16][CH2:17][CH3:18])[C:9](OCC)=[O:10].[OH-].[Na+]>CCOCC>[CH3:7][C:8]([CH3:19])([CH2:14][C:15]#[C:16][CH2:17][CH3:18])[CH2:9][OH:10]
Reactant: CCC#CCC(C)(C)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCC#CCC(C)(C)CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a slurry of LiAlH4 (7.4 g, 194 mmol) in anhydrous Et2O (200 ml) at 0° C. was added a solution of ethyl 2,2-dimethylhept-4-ynoate (29 g, 159 mmol) in anhydrous Et2O (100 ml) slowly over a period of 30 min. The reaction mixture was stirred at 0° C. for 3 hours. A 10% aqueous solution of NaOH (35 ml) was added slowly. The solid was filtered off. The filtrate was washed with brine, dried (MgSO4) and the solvent was removed under reduced pressure to afford the titled compound as a colorless liquid (20 g, 89%). TLC: Pet. ether/EtOAc (8/2): Rf=0.3. 1H NMR (CDCl3, 300 MHz) δ 0.95 (6H, s), 1.03 (3H, t), 1.81 (1H, br. s), 2.10 (2H, s), 2.17 (2H, m), 3.14 (2H, s).
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:5]=2[NH:4][C:3]1=[O:36].[C:37](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[C:31]([O:30][C:29](=[O:35])[NH:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:9]3[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:11][C:5]4[N:4]([CH3:37])[C:3](=[O:36])[CH:2]([CH3:1])[O:7][C:6]=4[N:8]=3)=[CH:19][CH:20]=2)[CH2:25][CH2:26][CH2:27]1)([CH3:32])([CH3:34])[CH3:33]
Reactant: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2NC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CC1Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2N(C)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.6 %

Procedure:
A solution of tert-butyl 1-(4-(3-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (50 mg, 0.103 mmol) in DMF (2 ml) was added potassium carbonate (42.7 mg) and iodomethane (7.69 μl, 0.124 mmol). The reaction mixture was stirred at room temperature for 48 h then was diluted with ethyl acetate (20 ml). Washed with water, brine, and dried with Na2SO4, filtered and concentrated to give product 43 mg. 1H NMR (500 MHz, CDCl3): 7.19-7.32 (m, 10H), 4.96 (q, 1H), 3.39 (s, 3H), 2.43-2.48 (m, 4H), 2.04 (m, 1H), 1.79 (m, 1H), 1.70 (d, 3H), 1.24-1.36 (m, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([O:16][CH:15]([C:17](O)=[O:18])[CH2:14][N:13]([CH2:20][CH:21]([F:23])[F:22])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH2:29])[CH:27]=[CH2:28].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(N(CC)CC)C>CC1CCCO1>[CH2:26]([NH:29][C:17]([CH:15]1[CH2:14][N:13]([CH2:20][CH:21]([F:23])[F:22])[CH2:12][C:11]2([CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:25][CH2:24]2)[O:16]1)=[O:18])[CH:27]=[CH2:28]
Reactant: C=CCN
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(CC(F)F)CC(C(=O)O)O2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Product: C=CCNC(=O)C1CN(CC(F)F)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To 9-(tert-butoxycarbonyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-2-carboxylic acid (520 mg, 1.43 mmol), prop-2-en-1-amine (118 μL, 1.57 mmol) and T3P (2.12 mL of 50% w/w, 3.59 mmol) in 2-methyltetrahydrofuran (4 mL) was added triethylamine (597 μL, 4.28 mmol) at room temperature and the reaction mixture was stirred for 2 hours. The reaction mixture was then quenched with saturated NaHCO3 solution (3 mL) and stirred for an additional 10 minutes, then diluted with EtOAc and the layers were separated. The aqueous layer was extracted once more with EtOAc, and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo to an oil. The residue was purified by silica gel column chromatography using 0-50% EtOAc in hexanes to yield tert-butyl 2-(allylcarbamoyl)-4-(2,2-difluoroethyl)-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (480 mg, 83%). ESI-MS m/z calc. 403.2. Found 404.5 (M+1)+; Retention time: 1.78 minutes (3 min run).