Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([O:15][CH3:16])[CH:9]=2)=[CH:6][C:5](=[N:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:4]([CH3:27])[C:3]1=[O:28].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38]>CC(C)=O>[CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[C:10]([O:15][CH3:16])[CH:9]=2)=[CH:6][C:5](=[N:17][C:18]2[C:19]([CH3:26])=[CH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])[N:4]([CH3:27])[C:3]1=[O:28]
Reactant: COc1cc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)ccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(-c2cc(=Nc3c(C)cc(C)cc3C)n(C)c(=O)n2C)cc1OC

Procedure:
To a solution of 3,4-dihydro-1,3-dimethyl-6-(4-hydroxy-3-methoxyphenyl)-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.40 g) in acetone (20 ml) were added potassium carbonate (0.16 g) and ethyl bromoacetate (0.66 ml), and the mixture was refluxed for 10 hours. After being cooled, the mixture was evaporated and suspended in chloroform. The suspension was washed with water, dried over sodium sulfate, and evaporated to give crude oil of 3,4-dihydro-1,3-dimethyl-6-(4-ethoxycarbonylmethoxy-3-methoxyphenyl)-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (0.67 g). This crude oil was used for the following deesterification without further purification.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])(=[O:9])=[O:8].C[Li].[CH3:26][C:27]([CH3:29])=[O:28].FC(F)(F)C(O)=O>C1COCC1.C(OCC)C>[OH:28][C:27]([CH3:29])([CH3:26])[CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17])[S:7]([NH2:6])(=[O:8])=[O:9]
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccccc2C)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccccc1C(C(C)(C)O)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under inert gas, 0.95 g of N-(2,4-dimethoxybenzyl)-C-o-tolylmethanesulfonamide was initially charged in 20 ml of THF, and then, at a temperature of −78° C., 4.06 ml of a 1.6 N methyllithium solution in diethyl ether were added dropwise and the mixture was stirred at constant temperature for 10 minutes. Subsequently, 1.22 ml of acetone were added. After stirring for 10 minutes, the reaction solution was admixed with 2 ml of trifluoroacetic acid and allowed to warm up to room temperature, and the solvent was removed under reduced pressure. The residue was dissolved in 10 ml of dichloromethane, and 1.5 ml of trifluoroacetic acid were added. After stirring at room temperature for 1.5 hours, the reaction solution was concentrated by rotary evaporation and the residue was taken up in a mixture of water and dichloromethane. The solid which precipitates out was filtered off with suction and discarded. The organic phase was dried over MgSO4 and concentrated by rotary evaporation. Since the product was also present in the aqueous phase of the filtrate, this was extracted twice with 50 ml of ethyl acetate, and the combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. Both residues were purified by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation (516 mg). This gave the product with a molecular weight of 243.3 g/mol (C11H17NO3S).
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]1)=O)(C)(C)C.C(OC([NH:26][CH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([C:34]([OH:36])=[O:35])[CH2:30][CH2:29]1)=O)(C)(C)C.[OH:37][CH:38]([OH:44])[C:39]([N:41]([CH3:43])[CH3:42])=[O:40].Cl>C(OCC)(=O)C>[NH2:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15]1.[NH2:26][CH2:27][C@H:28]1[CH2:29][CH2:30][C@H:31]([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]1.[OH:37][CH:38]([OH:44])[C:39]([N:41]([CH3:43])[CH3:42])=[O:40]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: CN(C)C(=O)C(O)O
Agent: Cl
Solvent: CCOC(C)=O
Product: NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
2,2-Dihydroxy-N,N-dimethylacetamide bis-[trans-4-(tert.-butyloxycarbonylaminomethyl)cyclohexanecarboxylate] (3 g) was dissolved in ethyl acetate (50 ml) and ethyl acetate containing hydrochloric acid (50 ml) was added. After 2 h the solvent was evaporated and the residue dissolved in methanol and ether was added. The precipitate formed (0.9 g) had a m.p. of 220° C.
Reaction SMILES: [BrH:1].[CH:2]1([NH:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:20])[C:15]=3[OH:19])[C:10]2=[O:21])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>[Pd].O>[BrH:1].[CH:2]1([NH:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:20])[C:15]=3[OH:19])[CH:10]2[OH:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C1c2ccc(O)c(O)c2CCC1NC1CCCCC1
Agent: [Pd]
Agent: Br
Solvent: O
Product: Oc1ccc2c(c1O)CCC(NC1CCCCC1)C2O

Procedure:
Using 1.91 parts of 5% palladium-on-carbon, 1.89 parts of 2-cyclohexylamino-5,6-dihydroxy-3,4-dihydro-1(2H)-naphthalenone hydrobromide in 50 volume parts of water is subjected to catalytic reduction at ordinary temperature and pressure. When a stoichiometric amount of hydrogen has been absorbed, the reaction mixture is filtered to remove the catalyst and the filtrate is freeze-dried. The residue is recrystallized from a mixture of ethanol and ethyl acetate, whereby 2-cyclohexylamino-1,5,6-trihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide is obtained as colorless crystals. Yield 1.38 parts; melting point: 230°-236° C (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH2:18][CH2:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>O1CCOCC1>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:17](=[O:20])[CH:18]=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH3:16])[CH:10]=3
Reactant: COc1cc2c3c(c1)c1ccc(Br)cc1n3CCC2=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc2c(=O)ccn3c4cc(Br)ccc4c(c1)c23
Yield: 70.4 %

Procedure:
9-bromo-5,6-dihydro-2-methoxy-4H-pyrido[3,2,1-jk]carbazole-4-one (1.0 g) obtained in Example 101, step 6 was dissolved in anhydrous dioxane (40 ml), and DDQ (1.45 g) was added at room temperature. The mixture was heated under reflux in an argon atmosphere for 3 hours and allowed to cool. The reaction mixture was added to 1N aqueous solution of sodium hydroxide (150 ml), and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude crystals were washed with ethanol and recovered by filtration to obtain the title compound (0.7 g, 70%).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][N:24]2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:19][C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][N:24]4[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CC(C)(C)OC(=O)n1ccc2c(N)cccc21
Agent: [Na+]
Product: CC(C)(C)OC(=O)n1ccc2c(NC(=O)Cc3nc(N4CCOCC4)cc(=O)[nH]3)cccc21
Yield: 57.6 %

Procedure:
The product is prepared according to the procedure described in example 5, using 500 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 445 mg of 2-methylpropan-2-yl 4-amino-1 H-indole-1-carboxylate in place of the 2,4-difluoroaniline. 500 mg of 2-methylpropan-2-yl 4-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)-1H-indole-1-carboxylate are obtained in the form of a brown solid, the characteristics of which are the following:
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][OH:25])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=2[Cl:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:33]1[CH:34]=[C:35]([CH:40]=[CH:41][CH:42]=1)[C:36]([O:38][CH3:39])=[O:37].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][N:9]([CH2:22][CH2:23][CH2:24][O:25][C:33]2[CH:42]=[CH:41][CH:40]=[C:35]([C:36]([O:38][CH3:39])=[O:37])[CH:34]=2)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[C:12]=2[Cl:21])[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Reaction time: 18 h
Yield: 26 %

Procedure:
A solution of N-(2,2-Diphenylethyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-hydroxypropylamine (186 mg, 0.42 mmole) and methyl 3-hydroxybenzoate (63 mg, 0.42 mmole) in 15 mL of THF was treated with Ph3P (110 mg, 0.42 mmole) and diisopropylazodicarboxylate (93 mg, 0.46 mmole). The reaction was stirred for 18 hours, diluted with H2O, and extracted with Et2O. The extracts were washed with H2O, dried, and the solvent evaporated. The residue was chromatographed on a silica gel column, and elution with 10% EtOAc in hexane gave the titled product, 64 mg (26% yield). MS (ESI) 583 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.O>[C:26]([Si:23]([O:22][CH2:21][CH2:20][O:12][C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1)([CH3:25])[CH3:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: COc1cc(O)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OCCO[Si](C)(C)C(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 51.8 %

Procedure:
To a solution of 3-methoxy-4-nitrophenol (1 g, 5.9 mmol) in anhydrous DMF (25 mL) were added K2CO3 (2.45 g, 17.7 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (1.7 g, 7.1 mmol) sequentially. The reaction mixture was heated at 70° C. for 20 h. The mixture was cooled to room temperature, and diluted with water. The mixture was extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (0-20% EtOAc in hexanes) to give tert-butyl-[2-(3-methoxy-4-nitro-phenoxy)-ethoxy]-dimethyl-silane as a light yellow oil (1.0 g, 52%).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH:19]=[CH:18][C:16]([NH2:17])=[N:15][C:13]1=[O:14]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:17][C:16]1[CH:18]=[CH:19][NH:12][C:13](=[O:14])[N:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: c1ccncc1
Product: O=C(Nc1cc[nH]c(=O)n1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Over a period of about 1 h, benzyloxycarbonyl chloride (52 mL, 0.36 mol) was added dropwise to a suspension of cytosine (8, 20 g, 0.18 mol) in dry pyridine (1000 mL) at 0° C. under nitrogen in oven-dried equipment. The solution then was stirred overnight, after which the pyridine suspension was evaporated to dryness, in vacuo. Water (200 mL) and 4N hydrochloric acid were added to reach pH ~1. The resulting white precipitate was filtered off, washed with water and partially dried by air suction. The moist precipitate was refluxed with absolute ethanol (500 mL) for 10 minutes, cooled to 0° C., filtered, washed thoroughly with ether, and dried, in vacuo. Yield 24.7 g (54%). M.p.>250° C. Anal. for C12H11N3O3. Found(calc.); C: 58.59(58.77); H: 4.55(4.52); N: 17.17(17.13). No NMR spectra were recorded since it was not possible to get the product dissolved.
Reaction SMILES: O[CH:2]([C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][C@@H:27]([CH3:34])[CH2:26]2)[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6][C:5]1([CH2:21][OH:22])[CH3:20].C(C=P(CCCC)(CCCC)CCCC)#N>C1C=CC=CC=1>[CH3:20][C:5]12[CH2:6][N:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH2:8][CH2:9][N:4]1[CH2:3][CH:2]([C:23]1[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][C@@H:27]([CH3:34])[CH2:26]3)[O:22][CH2:21]2
Reactant: C[C@H]1Cc2cc(C(O)CN3CCN(C(=O)OCc4ccccc4)CC3(C)CO)ccc2C(=O)O1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: c1ccccc1
Product: C[C@H]1Cc2cc(C3CN4CCN(C(=O)OCc5ccccc5)CC4(C)CO3)ccc2C(=O)O1
Temperature: 135 °C

Procedure:
The mixture of benzyl 4-(2-hydroxy-2-((S)-3-methyl-1-oxoisochroman-6-yl)ethyl)-3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate (762 mg, 1.60 mmol) and cyanomethylenetributylphosphorane (471 mg, 1.90 mmol) in dry benzene was degassed and heated to 135° C. in a microwave reactor for 3.5 h. After which point, the reaction mixture was cooled down to rt, concentrated to dryness and purified on silica gel to afford the title compound (cis or trans): MS: m/e 451.2 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.Cl.[F:29][CH:30]1[CH2:33][NH:32][CH2:31]1.C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[N:18]1([C:16]2[N:17]=[C:11]3[CH:10]=[C:9]([NH:8][C:7]([C:6]4[N:2]([CH3:1])[N:3]=[CH:4][C:5]=4[C:25]([N:32]4[CH2:33][CH:30]([F:29])[CH2:31]4)=[O:26])=[O:24])[CH:14]=[CH:13][N:12]3[N:15]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Reactant: FC1CNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CC(F)C2)c1C(=O)Nc1ccn2nc(N3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 39.3 %

Procedure:
A mixture of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (150 mg, 0.404 mmole), 3-fluoroazetidine hydrochloride (135 mg, 1.21 mmole), N-ethyldiisopropylamine (353 ul, 2.02 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 606 ul, 1.01 mmole) in tetrahydrofurane (7 ml) is stirred for 22 h at room temperature. The solvent is removed under reduced pressure and the residue (994 mg) is triturated for 2 hrs with sat. aqueous sodium bicarbonate solution (30 ml). The solid is collected by filtration, washed with water and dried affording 4-(3-fluoro-azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid (2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-amide (68 mg, 39.3%) as an off-white solid. mp.: 247-250° C. MS: m/z=425.1 (M+H+)
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[CH3:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH3:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[N:5]=[C:4]([CH3:11])[C:3]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH2:23][CH2:22]1
Reactant: CC1CCNCC1
Reactant: Cc1nc2nccn2c(Cl)c1-c1c(F)cccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: Cc1nc2nccn2c(N2CCC(C)CC2)c1-c1c(F)cccc1Cl
Reaction time: 1 h
Yield: 62.5 %

Procedure:
At room temperature, 45 mg (0.16 mmol) of 5-chloro-6-(2-chloro-6-fluorophenyl)-7-methylimidazo[1,2-a]pyrimidine and 63 mg (0.64 mmol) of 4-methylpiperidine were mixed. After one hour, chloroform and aqueous saturated ammonium chloride solution were added to the reaction mixture. The separated organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was subjected to silica gel chromatography to give 35 mg (0.10 mmol, 61%) of 5-(4-methylpiperidin-1-yl)-6-(2-chloro-6-fluorophenyl)-7-methylimidazo[1,2-a]pyrimidine.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH3:19])([CH3:18])[CH2:7][CH:8]([NH:12][C:13](=[O:17])[CH2:14][O:15][CH3:16])[C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:31]=2[C:32]([NH:34][CH2:35][C:36]#[CH:37])=[O:33])[C:26]([Cl:43])=[CH:25][N:24]=1>>[Cl:43][C:26]1[C:27]([NH:29][C:30]2[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:31]=2[C:32]([NH:34][CH2:35][C:36]#[CH:37])=[O:33])=[N:28][C:23]([NH:1][C:2]2[CH:21]=[CH:20][C:5]3[C:6]([CH3:19])([CH3:18])[CH2:7][CH:8]([NH:12][C:13](=[O:17])[CH2:14][O:15][CH3:16])[C:9](=[O:11])[NH:10][C:4]=3[CH:3]=2)=[N:24][CH:25]=1
Reactant: COCC(=O)NC1CC(C)(C)c2ccc(N)cc2NC1=O
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)C(NC(=O)COC)CC3(C)C)ncc1Cl

Procedure:
Title compound was prepared from N-(8-Amino-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-2-methoxy-acetamide and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 1221d. Title compound was isolated as a white solid (60 mg, 54%) HPLC 99% purity, LCMS 596 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.69 (s, 1H), 9.39 (s, 1H), 9.16 (s, 1H), 8.94 (t, 1H), 8.18 (s, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.48-7.44 (m, 2H), 7.34-7.29 (m, 1H), 7.26 (d, J=7.9 Hz, 1H), 7.15 (s, 1H), 7.09 (d, J=8.7 Hz, 1H), 4.22-4.17 (m, 1H), 4.00 (s, 2H), 3.82 (s, 2H), 3.33 (s, 3H), 3.10 (s, 1H), 2.19-2.15 (m, 1H), 1.91 (t, J=12.2 Hz, 1H), 1.33 (s, 3H), 1.24 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][C:29]2[C:30](=[O:37])[N:31]=[C:32](SC)[NH:33][CH:34]=2)=[CH:24][N:23]=1>C(O)C>[CH3:21][C:22]1[N:23]=[CH:24][C:25]([CH2:28][C:29]2[C:30](=[O:37])[N:31]=[C:32]([NH:18][CH2:17][CH2:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=4)=[CH:11][CH:12]=3)[NH:33][CH:34]=2)=[CH:26][N:27]=1
Reactant: CSc1nc(=O)c(Cc2cnc(C)nc2)c[nH]1
Reactant: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: CCO
Product: Cc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)nc2=O)cn1
Temperature: 125 °C
Reaction time: 50 h
Yield: 19.9 %

Procedure:
2-[4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]-ethylamine (0.354 mmol, 1 eq) and 5-(2-methyl-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.322 mmol, 0.9 eq) were dissolved in dry ethanol (300 μL) and stirred at 125° C. for 50 hours. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 10; 15 ml/min in the gradient of MeOH in DCM: 0-10% in 25CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 5-(2-methyl-pyrimidin-5-ylmethyl)-2-{2-[4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl]ethylamino}-1H-pyrimidin-4-one (0.064 mmol, yield: 18%, HPLC-MS/UV:[M+H]+=483.37; rt: 0.89 mins; purity: 93%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.66 (s, 3H), 2.93 (t, J=7.39, 2H), 3.54 (s, 2H), 3.60-3.70 (m, 2H), 5.39 (br.s., 1H), 7.01 (d, J=8.69, 1H), 7.08 (d, J=8.50 2H), 7.27-7.31 (m, 2H), 7.66 (s, 1H), 7.89 (dd, J=9.58, J=2.73, 1H), 8.36-8.42 (m, 1H), 8.51 (s, 2H), 11.21 (br.s., 1H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]C(C)(C)C.[NH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16].Cl.O>C1COCC1>[NH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:16]
Reactant: NCC(=O)c1ccccc1
Reactant: Brc1ccccn1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: NCC(O)(c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (−78° C.), stirred solution of 2-bromopyridine (0.38 mL, 4.0 mmol) in THF (40 mL) under Ar was added dropwise t-BuLi (5.2 mL, 8.8 mmol). After 30 min, 2-aminoacetophenone•HCl (687 mg, 4.00 mmol) was added as a solid in one portion. The reaction was allowed to slowly warm to RT as the bath warmed. Water was added and the reaction mixture was extracted with EtOAc, dried (MgSO4), filtered and concentrated to afford a solid. Purification by flash chromatography afforded 68 mg as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 8.50 (d, J=4.80 Hz, 1H), 7.70-7.19 (m, 8H), 3.72 (d, J=13.14 Hz, 1H), 3.38 (d, J=13.14 Hz, 1H).
Reaction SMILES: C([O:5][CH2:6][CH:7]([CH3:20])[CH2:8][C:9](=[O:19])[CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])(C)(C)C.FC(F)(F)C(O)=O>>[OH:5][CH2:6][CH:7]([CH3:20])[CH2:8][C:9](=[O:19])[CH2:10][CH:11]([CH3:18])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)CCCC(C)CC(=O)CC(C)COC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCCC(C)CC(=O)CC(C)CO

Procedure:
Treatment of rac.-1-tert. butoxy-2,6,10-trimethylundecan-4-one with trifluoroacetic acid followed by alkali using the procedure described in Example 6 gave rac.-1-hydroxy-2,6,10-trimethylundecan-4-one as a pale-yellow oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].B([C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([OH:19])=[O:18])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: O=C(O)c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(O)c1cccc(-c2ccncc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a degassed mixture containing 4-chloro-3-nitropyridine (3.0 g, 18.9 mmol), 3-boronobenzoic acid (3.7 g, 22.7 mmol), potassium carbonate (5.2 g, 37.8 mmol) and dioxane (189 mL) was added tetrakis(tiphenylphosphine)palladium(0) (0.30 g, 0.28 mmol) in one portion under a nitrogen atmosphere. The mixture was heated with fast stirring at 100° C. for 15 h, cooled to room temperature, filtered and concentrated to afford 3-(3-nitropyridin-4-yl)benzoic acid as a tan residue which was used without further purification. LCMS: retention time: 1.375 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 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 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 245 (MH+).