Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[NH2:2]>[Pd].O>[O:3]=[C:1]1[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[NH:2]1
Reactant: NC(=O)C1(N2CCCCC2)CCNCC1
Agent: [Pd]
Solvent: O
Product: O=C1NC2CCCCN2C12CCNCC2

Procedure:
A mixture of 5 g of 4-carbamoyl-4-piperidino-piperidine, 0.5 g of 5% palladium-on-charcoal catalyst and 50 ml of water is boiled under reflux for 50 hours. The reaction mixture is then cooled, and the catalyst is removed by filtration. The filtrate is concentrated and allowed to stand. The precipitated crystals are collected by filtration, dried and recrystallized from chloroform to give 1,2,3,5,6,7,8,8a-octahydro-2-oxo-imidazo[1,2-a]pyridine-3-spiro-4'-piperidine as colorless crystals, m.p. 193° C. 2,3,5,6,7,8-Hexahydro-2-oxo-imidazo[1,2-a]pyridine-3-spiro-4'-piperidine is obtained from the mother liquor. Overall yield is 65%.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[CH:10]=1)C1C=CC=CC=1>CCO.[Pd]>[C:29]([O:28][C:26]([N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:11]2[CH:10]=[C:9]([OH:8])[CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])[CH2:21][CH2:22]1)=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1ccc(O)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 89.8 %

Procedure:
The methyl 4-benzyloxy-2-(1-tert-butoxycarbonylpiperidin-4-yloxy)benzoate (12.8 g) was dissolved in EtOH (135 mL). 10% Pd/C catalyst (1.3 g) was added and the reaction was placed under an H2 atmosphere (4.1 bar) for 4 h at room temperature. The catalyst was filtered and the ethanol was removed in vacuo to give 9.15 g (89.7%) of a white foam.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH3:4].O>C(O)C>[CH2:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:16])[C:12]([F:14])([F:15])[F:13])[CH3:4]
Reactant: CCOCCCCCC(=O)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOCCCCCC(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.4 %

Procedure:
2.6 g (0.07 mol) of sodium borohydride was added gradually to a solution of 30 g (0.14 mol) of 7-ethoxy-1,1,1-trifluoro-2-heptanone in 200 ml of ethanol at 0° C. The solution was stirred for 24 hours at room temperature. 200 ml of water was added and extracted with diethyl ether. The organic layer was washed with a small amount of water, dried over anhydrous magnesium sulfate and concentrated. The residue was distilled under the reduced pressure, to obtain 28 g of racemic 7-ethoxy-1,1,1-trifluoro-2-heptanol. Boiling point; 133-137° C. (50 mmHg).
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH:31]([CH3:33])[CH3:32]>>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][NH:17][C:18](=[O:28])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH2:26][CH3:27])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)Br
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(C)C)c(OC(F)F)c2)n1

Procedure:
Using the compound obtained in Example 373 and 2-bromopropane, white powdery N-[2-(3-difluoromethoxy-4-isopropoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 98.
Reaction SMILES: [CH2:1]([N:3]([CH:7](C)C)[CH:4](C)C)C.BrC1[S:12][C:13]([Br:16])=[CH:14][N:15]=1.CNC>C(O)C>[Br:16][C:13]1[S:12][C:7]([N:3]([CH3:1])[CH3:4])=[N:15][CH:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Brc1cnc(Br)s1
Agent: CNC
Solvent: CCO
Product: CN(C)c1ncc(Br)s1
Temperature: 140 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a microwave vial was added N-ethyl-N-isopropylpropan-2-amine (0.72 mL, 4.1 mmol), 2,5-dibromothiazole (1.00 g, 4.1 mmol) and dimethylamine (40% in water, 0.52 mL, 4.1 mmol) in ethanol (10 mL). The vial was sealed and stirred at 140° C. under microwave irradiation for one hour, then was concentrated and purified by MPLC (eluted with a gradient of 0-50% ethyl acetate in hexanes) to yield the product as a white, crystalline solid (0.25 g, 29%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:14][O:15][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[C:21]([O:25][CH3:26])[NH:22]3)=[C:18]([NH2:27])[N:17]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>CN(C=O)C>[CH:8]1([CH2:14][O:15][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[C:21]([O:25][CH3:26])[N:22]3[CH2:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:18]([NH2:27])[N:17]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COc1nc2c(N)nc(OCC3CCCCC3)nc2[nH]1
Reactant: BrCC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(OCC3CCCCC3)nc2n1CC1CCOCC1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
2-[(Cyclohexylmethyl)oxy]-8-(methoxy)-9H-purin-6-amine trifluoroacetate salt (0.28 g) was heated with anhydrous potassium carbonate (0.3957 g) in anhydrous DMF (5 mL) under nitrogen for 1 hour at 60° C. (external). The reaction mixture was cooled to room temperature before adding 4-(bromomethyl) tetrahydro-2H-pyran (0.14 g) in anhydrous DMF (1 mL). The reaction mixture was heated to 50° C., overnight. The reaction mixture was quenched into water (20 mL) and extracted into ethyl acetate (20 mL, 3 times). The organic layers was separated, combined and then washed with brine (20 mL). The organic layer was separated and then dried by passing through a hydrophobic frit. Evaporation under reduced pressure gave pale yellow oil that solidified on standing. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (30-80%) to give the title compound as a white solid (0.1677 g).
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.[OH-].[Na+].[Cl-].[Na+].O.Cl[CH2:23][CH2:24][C:25]1[N:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[C:30]([C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1)[CH:29]=2>C1(C)C=CC=CC=1>[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH2:23][CH2:24][C:25]1[N:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[C:30]([C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][CH:36]=1)[CH:29]=2
Reactant: C[C@@H]1CCCN1
Reactant: N#Cc1ccc(-c2ccc3cc(CCCl)nnc3c2)cc1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H]1CCCN1CCc1cc2ccc(-c3ccc(C#N)cc3)cc2nn1
Temperature: 85 °C
Yield: 27 %

Procedure:
(2R)-2-methylpyrrolidine (L)-tartrate (0.100 g, 0.425 mmol) was partitioned between toluene (0.5 mL) and 5 M NaOH/brine (1:1, 1 mL total). The organic phase was then added to the product from Example 169D (0.01 g, 0.034 mmol) and heated to 85° C. in a sealed tube for 48 hours. After cooling, the reaction mixture was concentrated under reduced pressure and purified by column chromatography (100% dichloromethane to 95:5 dichloromethane/methanol) to afford the product in 27% yield as a yellow solid. 1H NMR (CD3OD, 300 MHz) δ 8.73 (m, 1H), 8.21 (dd, J=3, 9 Hz, 1H), 8.14 (s, 1H), 8.12 (d, J=9 Hz, 1H), 8.06 (d, J=9 Hz, 2H), 7.92 (d, J=9 Hz, 2H), 3.72-3.48 (m, 4H), 3.15-2.90 (m, 2H), 2.86-2.75 (m, 1H), 2.21-2.10 (m, 1H), 1.98-1.91 (m, 2H), 1.67-1.60 (m, 1H), 1.31 (d, J=6 Hz, 3H). MS (ESI) [M+H]+ at 343.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[NH:19][C:18](=[O:31])[N:17]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:43]1[CH:48]=[CH:47][C:46]([CH2:49][CH2:50]Br)=[CH:45][CH:44]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH2:50][CH2:49][C:46]4[CH:47]=[CH:48][CH:43]=[CH:44][CH:45]=4)[C:18](=[O:31])[N:17]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCCc1ccccc1
Reactant: COC(=O)Cn1c(=O)[nH]c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)n(CCc2ccccc2)c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-[7-(2-Chlorophenyl)-3-methoxycarbonylmethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (49 mg) was dissolved in N,N-dimethylformamide (1 ml), and potassium carbonate (20 mg) and 2-phenethyl bromide (0.03 ml) were added to the solution. Then, the mixture was stirred at 50° C. overnight. The reaction mixture was diluted with ethyl acetate, and washed with water and 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed by distillation to give 52 mg of the title compound.
Reaction SMILES: [C:1]123[CH2:13][CH:8]4[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]4)[CH:5]1[NH:4]C(=O)[O:2]2)[CH2:11]3.[OH-].[K+]>O1CCOCC1>[NH2:4][CH:5]1[CH:6]2[CH2:7][CH:8]3[CH2:9][CH:10]([CH2:11][C:1]1([OH:2])[CH2:13]3)[CH2:12]2
Reactant: O=C1NC2C3CC4CC(C3)CC2(C4)O1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NC1C2CC3CC(C2)CC1(O)C3
Yield: 70 %

Procedure:
2-Oxa-4-azatetracyclo[6.3.1.16,10.01,5]tridecan-3-one (76 mg, 0.395 mmol) in 1,4-dioxane (1 mL) was stirred with 5 M aqueous potassium hydroxide at 70° C. for 1 day. After completion of the reaction, the reaction solution was extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (70% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][S:8][CH2:7]1.I[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]I.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH2:9][C:13]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[S:8][CH2:7]1
Reactant: O=C1CSCN1CCCCBr
Reactant: ICCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CC2(CCCC2)SCN1CCCCBr
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a solution of 3-(4-bromobutyl)-4-thiazolidinone (25 g) in THF (350 ml) cooled to -60° C. was added 1,5-diiodopentane (100 g), and the resultant slurry was cooled to -65° C. A solution of lithium bis(trimethylsilyl)amide (0.220 mole) in hexanes (220 ml) was added dropwise, during which the internal temperature was maintained at or below -55° C. The addition was complete within 30 minutes. The mixture was stirred for additional 15 minutes at the same temperature and thereafter warmed to 0° C. with the aid of an ice bath. The mixture was stirred for additional 20 minutes and thereafter quenched with 500 ml of 0.5N HCl solution. The resultant mixture was placed under vacuum to remove some of the THF and thereafter extracted with ether (350 ml, 2×250 ml). The combined extracts were washed successively with water (400 ml) and brine (400 ml), dried with Na2SO4 and concentrated to a liquid. The liquid was chromatographed (2 silica gel columns) using 20-60% ethyl acetate/hexane as an eluent to obtain about 20.5 g of solid product.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:22]([O:24][P:25]([C:30]1[C:31](=[O:45])[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([S:40]([NH2:43])(=[O:42])=[O:41])=[C:35]([Cl:44])[CH:34]=2)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23].C1CCN2C(=NCCC2)CC1.Cl>C1COCC1>[CH2:27]([O:26][P:25]([C:30]1[C:31](=[O:45])[NH:32][C:33]2[C:38]([CH:39]=1)=[CH:37][C:36]([S:40]([NH:43][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:41])=[O:42])=[C:35]([Cl:44])[CH:34]=2)(=[O:29])[O:24][CH2:22][CH3:23])[CH3:28]
Reactant: O=C(O)c1ccccc1
Reactant: CCOP(=O)(OCC)c1cc2cc(S(N)(=O)=O)c(Cl)cc2[nH]c1=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOP(=O)(OCC)c1cc2cc(S(=O)(=O)NC(=O)c3ccccc3)c(Cl)cc2[nH]c1=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A solution of benzoic acid (111 mg, 0.912 mmol) in 3 ml of anhydrous THF containing 173 mg (1.06 mmol) of carbonyldiimidazole is stirred for 45 minutes at reflux. In parallel, there is prepared a suspension of 300 mg (0.760 mmol) of the compound obtained in Step A in 3 ml of THF, to which there is added 0.125 ml (0.836 mmol) of DBU. Stirring is carried out for 15 minutes at room temperature, and then the benzoic acid solution prepared above is added thereto. The mixture is heated for 3 hours at 60° C. The reaction mixture is cooled in an ice bath and rendered acidic by the addition of 1N HCl. Extraction is carried out with ethyl acetate. The organic phases are combined and washed with a saturated NaCl solution and then dried over MgSO4. After evaporation, the residue is chromatographed over a silica column whilst eluting with a gradient (95/5-90/10) of CH2Cl2/MeOH. The title product is obtained in the form of a white solid.
Reaction SMILES: Cl.[C:2]1([C:8]2[C:12]3=[C:13]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]=[N:15][CH:16]=[C:11]3[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:36]=[C:35]([CH:37]=O)[O:34][N:33]=2)=[CH:28][CH:27]=1>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[CH:36]=[C:35]([CH2:37][N:22]3[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:13]4[N:14]=[N:15][CH:16]=[C:11]5[O:10][N:9]=[C:8]([C:2]6[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=6)[C:12]=45)[CH2:20][CH2:21]3)[O:34][N:33]=2)=[CH:30][CH:31]=1
Reactant: c1ccc(-c2noc3cnnc(NCC4CCNCC4)c23)cc1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2)no1
Agent: Cl
Product: Clc1ccc(-c2cc(CN3CCC(CNc4nncc5onc(-c6ccccc6)c45)CC3)on2)cc1

Procedure:
According to the same procedure described in Example 35, using the compound obtained in Example 84 instead of the compound obtained in Example 11 and 3-(4-chlorophenyl)isoxazole-5-carbaldehyde instead of 4-phenylthiophene-2-carbaldehyde, the title compound having the following physical data was obtained.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([S:29][CH3:30])[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([S:29]([CH3:30])=[O:39])[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1noc2c(F)c3c(cc12)CC1(C(=O)NC(=O)NC1=O)[C@H]1[C@H](C)O[C@H](C)CN31
Solvent: ClCCl
Product: C[C@@H]1CN2c3c(cc4c(S(C)=O)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (2R,4S,4aS)-rel-11-fluoro-2,4-dimethyl-8-(methylsulfanyl)-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione Example 62, 50 mg, 0.11 mmol) in dry DCM (1 mL) was added m-chloroperbenzoic acid (39 mg, 0.23 mmol) and stirred at room temperature for 1 hours. Solvents were evaporated and the residue thus obtained purified over a silica gel column to give product as solid. Yield: 18 mg (35%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([OH:14])[CH:5]=[CH:4][C:3]1=2.[Cl:16][C:17](OC(Cl)(Cl)Cl)=[O:18].C1C=CC=CC=1.C(N(CC)CC)C>O>[Cl:16][C:17]([O:14][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:15])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)=[O:18]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC1(C)CCC(C)(C)c2cc(O)ccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)CCC(C)(C)c2cc(OC(=O)Cl)ccc21
Temperature: 25 °C

Procedure:
4.1 g (20 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthol, 1.2 ml of trichloromethyl chloroformate and 40 ml of benzene are introduced into a round-bottomed flask. 3 ml (21 mmol) of triethylamine are added dropwise and the mixture is stirred at room temperature for twelve hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, then dried over magnesium sulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and hexane (40:60). After evaporation of the solvents, 4 g (75%) of the expected chloroformate are collected in the form of a colorless oil.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:12]([C:13](=[O:30])[NH:14][C:15]2[CH:20]=[CH:19][N:18]3[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:23]=[C:17]3[N:16]=2)=[CH:11][N:10]([CH3:31])[N:9]=1)=[O:7])C.O.Cl>C1COCC1.CO>[CH3:31][N:10]1[CH:11]=[C:12]([C:13](=[O:30])[NH:14][C:15]2[CH:20]=[CH:19][N:18]3[CH:21]=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:23]=[C:17]3[N:16]=2)[C:8]([C:6]([OH:7])=[O:5])=[N:9]1
Reactant: CCOC(=O)c1nn(C)cc1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cn1cc(C(=O)Nc2ccn3cc(-c4ccccc4)nc3n2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
NaOH (3N, 1.5 ml) was added to a solution of 1-methyl-4-(2-phenyl-imidazo[1,2-a]pyrimidin-7-ylcarbamoyl)-1H-pyrazole-3-carboxylic acid ethyl ester (390 mg, 1.5 mmol) in a mixture of THF (5 ml) and methanol (5 ml), and the mixture was stirred for 3 h at RT. Water (10 ml) was added, and the mixture was acidified (pH=3) by addition of HCl. The mixture was stirred for 30 min and filtered. The obtained precipitate was washed with a small amount of water, and was dried under vacuum. The thus obtained title compound (240 mg, 45%) was pure enough to be used in the next step. MS (m/e)=363.3 [M+H+].
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([O:7][C:8]1[CH:17]=[CH:16][C:11]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:9]=1)[CH2:5][CH3:6].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](F)[N:20]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C>[F:18][C:19]1[N:20]=[C:21]([O:15][CH2:14][CH2:13][O:12][C:11]2[CH:16]=[CH:17][C:8]([O:7][CH:4]([CH3:3])[CH2:5][CH3:6])=[CH:9][CH:10]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: Fc1cccc(F)n1
Reactant: CCC(C)Oc1ccc(OCCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCC(C)Oc1ccc(OCCOc2cccc(F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of sodium hydride (0.12 g) in 5 ml of THF and 4 ml of HMPA, cooled in an ice bath, is added, dropwise, a solution of 2-[4-(1-methylpropoxy)phenoxy]ethanol (1.00 g) in 5 ml of THF. The mixture is stirred at RT for 2 hours, after which 2,6-difluoropyridine (0.65 g) is added and the mixture is stirred at RT overnight. The THF is removed by rotoevaporation and the product is isolated by column chromatography on silica gel to give 6-fluoro-2-{2-[4-(1-methylpropoxy)phenoxy]ethoxy}pyridine, MS m/e 306 (M+).
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([C@@H:14]3[CH2:18][C@H:17]([S:19]CC4C=CC(OC)=CC=4)[CH2:16][N:15]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:13])[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])O.[Na+]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C(OCC)(=O)C>[N:1]1([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([C@@H:14]3[CH2:18][C@H:17]([SH:19])[CH2:16][NH:15]3)=[O:13])[CH2:8][CH2:7]2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCC(n4ccnc4)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C([C@@H]1C[C@H](S)CN1)N1CCC(n2ccnc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 165.1 %

Procedure:
1.44 g of (2S,4S)-2-[4-(imidazol-1-yl)piperidin-1-ylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (1) above] were dissolved in a mixture of 1.5 ml of anisole and 7.5 ml of trifluoroacetic acid, and 350 μl of trifluoromethanesulfonic acid were added to the resulting solution, whilst ice-cooling. The resulting mixture was then stirred at room temperature for 1 hour and then at 35° C. for 30 minutes, after which it was concentrated by evaporation under reduced pressure. The resulting residue was washed with diethyl ether four times to give a colorless powder. The whole of this powder was suspended in ethyl acetate, and the suspension was made alkaline by the addition of an aqueous solution of sodium hydrogencarbonate. The ethyl acetate phase was separated and washed with an aqueous solution of sodium chloride, after which this phase was dehydrated over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, to give 1150 mg of the title compound, as a colorless powder.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:32])([F:31])[C:8]1[CH:9]=[C:10]([S:14]([O:17][C:18]2[CH:19]=[CH:20][C:21]([NH:27][C:28]([NH2:30])=[O:29])=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=2)(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([NH:30][C:28](=[O:29])[NH:27][C:21]1[CH:20]=[CH:19][C:18]([O:17][S:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:31])([F:6])[F:32])[CH:9]=2)(=[O:16])=[O:15])=[CH:23][C:22]=1[N+:24]([O-:26])=[O:25])(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: CC(=O)NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Reaction time: 4 h

Procedure:
1 ml of concentrated sulfuric acid is added, with stirring, to 60 g of 5-(3-trifluoromethylphenylsulfonyloxy)-2-ureidonitrobenzene in 200 ml of acetic anhydride. A clear solution is initially produced, and the temperature rises to about 40° C. The mixture is stirred for a further four hours, and the precipitate produced is filtered off with suction and washed with diisopropyl ether and petroleum ether, melting point 196° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]([F:21])([F:20])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:3]=1.[I-].[K+].CCN(C(C)C)C(C)C.[CH3:33][C:34]1[NH:38][N:37]=[C:36]([NH2:39])[CH:35]=1>CN(C=O)C>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:4]1[N:3]=[C:2]([NH:39][C:36]2[CH:35]=[C:34]([CH3:33])[NH:38][N:37]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Fc1ccc(C(F)(F)c2nc(Cl)c3ccccc3n2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cc3)nc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-(difluoro(4-fluorophenyl)methyl)quinazoline (0.150 g, 0.487 mmol) in DMF (2 mL) at rt were added potassium iodide (0.081 g, 0.487 mmol), DIEA (0.093 mL, 0.535 mmol) and 5-methyl-1H-pyrazol-3-amine (0.048 g, 0.487 mmol). After stirring the reaction mixture at rt overnight, the reaction was quenched by adding water (15 mL). The precipitate was collected by filtration and washed with H2O. The crude solid was triturated with MeOH. 2-(Difluoro(4-fluorophenyl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine was obtained as an off-white solid (0.125 g, 69%). 1H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 3H), 6.31 (s, 1H), 7.34 (m, 2H), 7.68 (m, 3H), 7.87 (m, 2H), 8.68 (m, 1H), 10.69 (s, 1H), 12.20 (s, 1H); LC-MS (ESI) m/z 370 (M+H)+.