Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:8][C:9]1[C:10]([N:16]=[C:17](SC)[S:18][CH3:19])=[N:11][CH:12]=[C:13]([CH3:15])[CH:14]=1.C(N(CC)CC)C>O>[CH2:6]([O:5][C:3]([C:2]1[N:11]2[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([Br:8])[C:10]2=[N:16][C:17]=1[S:18][CH3:19])=[O:4])[CH3:7]
Reactant: CSC(=Nc1ncc(C)cc1Br)SC
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1c(SC)nc2c(Br)cc(C)cn12
Temperature: 60 °C
Reaction time: 4 h

Procedure:
Ethyl bromoacetate (5.4 g) was added to methyl N-(3-bromo-5-methyl-2-pyridyl)(methylsulfanyl)methaneimidothioate, and the mixture was stirred at 60° C. for 4 hours. After cooled to room temperature, triethylamine was added to treat the material, and water was further added thereto. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by column chromatography (ethyl acetate:n-hexane=1:9) to give 8-bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-carboxylic acid ethyl ester (2.4 g) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]([O:20][Si](C(C)(C)C)(C)C)[CH3:19])=[CH:12][CH:11]=2)[C:5]([C:28]#[N:29])=[C:4]([S:30][CH2:31][C:32]2[N:33]=[C:34]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[O:35][C:36]=2[CH3:37])[N:3]=1.Cl>CO>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C@@H:18]([OH:20])[CH3:19])=[CH:14][CH:15]=2)[C:5]([C:28]#[N:29])=[C:4]([S:30][CH2:31][C:32]2[N:33]=[C:34]([C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[O:35][C:36]=2[CH3:37])[N:3]=1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CSc1nc(N)c(C#N)c(-c2ccc(OC[C@H](C)O[Si](C)(C)C(C)(C)C)cc2)c1C#N
Agent: Cl
Solvent: CO
Product: Cc1oc(-c2ccc(F)cc2)nc1CSc1nc(N)c(C#N)c(-c2ccc(OC[C@H](C)O)cc2)c1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
65 mg (0.10 mmol) of the compound from Example 95A are dissolved in 4 ml of methanol, and 1.5 ml of 1 N hydrochloric acid are added. The mixture is stirred at RT for 12 h. The solvent is then removed on a rotary evaporator, and the residue is purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5). After removal of the solvent on a rotary evaporator, the product is obtained as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2].B1([C:39]2[CH:44]=[CH:43][CH:42]=[N:41][CH:40]=2)OCCCO1.[F-].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(COC)OC.C(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][C:19]([C:39]4[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=4)=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([CH3:24])[CH2:6][C:5]1([CH3:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(NC(=O)c3ccc(I)cc3)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: c1cncc(B2OCCCO2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: CCO
Solvent: COCCOC
Product: CC(=O)N1c2ccc(NC(=O)c3ccc(-c4cccnc4)cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Suzuki cross-coupling of 1-acetyl-6-(4-iodobenzoyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (25 mg), pyridine-3-boronic acid-1,3-propanediol cyclic ester (23 mg), cesium fluoride (14 mg), triphenylphosphine (5.0 mg) and tris(dibenzylideneacetone)dipalladium(0) (4.3 mg) in dimethoxyethane/ethanol 4:1 (v/v) (5 ml) was performed according to the method described in example 13.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH:22]([O:44][C:45]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])=[O:46])[CH2:23][O:24][C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:26])=[O:19]>CC(C)=O>[CH3:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]/[CH:35]=[CH:34]\[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][C:25]([O:24][CH2:23][CH:22]([CH2:21][O:20][C:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[O:19])[O:44][C:45]([CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]/[CH:54]=[CH:55]\[CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])=[O:46])=[O:26]
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)CCCCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCCCC
Solvent: CC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCC(COC(=O)CCCCCCC/C=C\CCCCCCCC)OC(=O)CCCCCCC/C=C\CCCCCCCC
Yield: 73 %

Procedure:
The saturated product A was fractionated in acetone, during which a stearin fraction was removed and an olein fraction (B) was obtained in a yield of 73%.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)(=O)[CH3:2].[N:14]1[NH:15][C:16](=[O:20])[CH:17]=CC=1>>[O:20]=[C:16]1[NH:15][N:14]=[C:1]([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:5]=2)[CH:2]=[CH:17]1
Reactant: CC(=O)c1ccc(CC(=O)O)cc1
Reactant: O=c1cccn[nH]1
Product: O=C(O)Cc1ccc(-c2ccc(=O)[nH]n2)cc1

Procedure:
15 g of 4-acetylphenylacetic acid (preparation described in Can. J. Chem.; 82; 12; 2004; 1760-1768) are converted into the pyridazinone in accordance with GWP 1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:21]2=[N:20][CH:19]=1)CCC>>[C:9]([NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([C:18]2[N:22]3[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[N:26][C:21]3=[N:20][CH:19]=2)[N:7]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)Nc1cccc(Br)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: CC(C)(C)Nc1cccc(-c2cnc3nc(C(F)(F)F)ccn23)n1
Yield: 22 %

Procedure:
6-Bromo-N-(tert-butyl)pyridin-2-ylamine (0.36 g, 1.56 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.6 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (20-80%) and trituration with isohexane gave N-(tert-butyl)-6-(7-trifluoromethylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-ylamine (115 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 1.56 (9H, s), 7.42 (1H, d, J 7), 7.45 (1H, d, J 8), 7.68 (1H, dd, J 8 and 8), 7.78 (1H, d, J 8), 8.53 (1H, s), 10.33 (1H, d, J 7).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[O:13][CH2:12][CH2:11][O:10][C:8]3=[CH:9][C:4]=2[N:3]=[C:2]1[SH:14].[OH-].[Na+].Cl.Cl[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>O>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][S:14][C:2]1[NH:3][C:4]2[CH:9]=[C:8]3[O:10][CH2:11][CH2:12][O:13][C:7]3=[CH:6][C:5]=2[N:1]=1
Reactant: ClCc1ccccn1
Reactant: Sc1nc2cc3c(cc2[nH]1)OCCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CSc2nc3cc4c(cc3[nH]2)OCCO4)nc1
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
4.6 g of 6,7-dihydro-1H-p-dioxino(2,3-f)benzimidazole-2-thiol, suspended in 50 ml of alcohol, were added dropwise while stirring 1.8 g of sodium hydroxide in 25 ml of water and, after 30 minutes, there were added 3.7 g of 2-chloromethyl-pyridine hydrochloride. The mixture was left to boil at reflux overnight, it was then evaporated, and the residue was taken up in methylene chloride. This mixture was washed first with 3N sodium hydroxide, then neutral with water, dried over sodium sulfate and evaporated in vacuo. The crude product was recrystallized from ethyl acetate/petroleum ether. 3.5 g (53% of theory) of 6,7-dihydro-2-[(2-pyridylmethyl)thio]-1H-p-dioxino(2,3-f)benzimidazole of melting point 155°-156° C. were prepared.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=1.[C:13]([C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)[NH2:20])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>O>[C:24]([C:22]1[CH:21]=[C:19]([NH:20][C:2]2[N:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][N:3]=2)[CH:18]=[C:17]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:23]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CCOC(=O)c1cnc(Cl)nc1
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnc(Nc2cc(C(C)(C)C)cc(C(C)(C)C)c2)nc1
Temperature: 110 °C
Yield: 89.9 %

Procedure:
A mixture of ethyl 2-chloropyrimidine-5-carboxylate (335 mg), 3,5-di-tert-butylaniline (370 mg), and K2CO3 (600 mg) was heated at 110° C. After the disappearance of the materials was observed with TLC, the reaction mixture was poured into water, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and the solvent was evaporated. The residue was purified by silica gel flash column chromatography (n-hexane: AcOEt=10:1) to give white crystals of ethyl 2-[N-(3,5-di-tert-butylphenyl)amino]pyrimidine-5-carboxylate (574 mg, 90%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:19]([CH3:22])([CH3:21])O)[CH:12]=[C:13]([C:15]([CH3:18])([CH3:17])O)[CH:14]=1)C1C=CC=CC=1>C(O)C.Cl.[C].[Pd]>[CH:15]([C:13]1[CH:14]=[C:9]([OH:8])[CH:10]=[C:11]([CH:19]([CH3:22])[CH3:21])[CH:12]=1)([CH3:18])[CH3:17]
Reactant: CC(C)(O)c1cc(OCc2ccccc2)cc(C(C)(C)O)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC(C)c1cc(O)cc(C(C)C)c1
Temperature: 60 °C
Reaction time: 23 h
Yield: 100.4 %

Procedure:
To a solution of 5-benzyloxy-α,α,α′,α′-tetramethyl-1,3-benzenedimethanol (22.9 g, 76 mmol) in ethanol (500 mL), concentrated hydrochloric acid (2.6 mL) and a 10% palladium-carbon catalyst (8.0 g) were added. Under hydrogen atmosphere, the mixture was stirred for 23 hours at 60° C. The reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure, to thereby yield 13.6 g of 3,5-diisopropylphenol as a solid (yield 100%). The solid was crystallized from hexane, to thereby yield colorless needles.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[CH2:12]C(OCC)=O.O.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11](=[O:18])[CH3:12]
Reactant: CCOC(=O)CC(=O)c1cccc([N+](=O)[O-])c1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)c1cccc([N+](=O)[O-])c1Cl
Yield: 87.6 %

Procedure:
According to the procedure of Example 2, ethyl 2-chloro-3-nitro-β-oxobenzenepropanoate (14.0 g, 51.5 mmol) is reacted with 30% water/trifluoroacetic acid to give 1-(2-chloro-3-nitrophenyl)ethanone (9.0 g, 87%), mp=41-43° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)[CH:24]=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][C:29]=2[N:31]2[CH2:36][CH2:35][CH:34]([N:16]3[CH2:15][CH2:14][N:13]([C:10]4[CH:11]=[CH:12][C:3]([C:2]([F:1])([F:19])[F:20])=[C:4]5[C:9]=4[N:8]=[CH:7][CH:6]=[CH:5]5)[CH2:18][CH2:17]3)[CH2:33][CH2:32]2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)c2ncccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: FC(F)(F)c1ccc(N2CCN(C3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc12

Procedure:
Using the synthetic methods described in previous examples, 5-(trifluoromethyl)-8-(piperazin-1-yl)quinoline (Step 3) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to give the desired product as a white solid; MP. 202-204° C.; MS (ES) m/z (relative intensity) 492 (M+H)+ (100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:18])[CH2:16]Cl)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:18])[CH2:16][N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)CCl)CC1
Solvent: ClCCl
Product: CN1CCN(CC(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)CC1
Reaction time: 8 h

Procedure:
A solution of trans-[4-(2-chloro-acetylamino)-cyclohexyl]-carbamic acid tert-butyl ester (330 mg, 1.14 mmol) in DCM (12 mL) was added to a solution of methylpiperazine (0.1 mL, 0.95 mmol) in DCM (1 mL) at RT. The resulting mixture was allowed to stir overnight, then diluted with DCM, and washed with a saturated aqueous solution of NaHCO3. The aqueous phase was extracted with DCM and then EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure to yield 199 mg of trans-{4-[2-(4-methyl-piperazin-1-yl)-acetylamino]-cyclohexyl}-carbamic acid tert-butyl ester without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:27][CH:26]=2)[CH:5]=[C:6]([F:24])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=2)[CH2:12][CH2:11]1.CI.[C:38]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[F:24][C:6]1[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[N:35]([CH3:38])[N:34]=[N:33][N:32]=3)=[CH:27][CH:26]=2)[CH:3]=[C:2]([F:1])[C:7]=1[O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:17]=[CH:18][C:19]([CH2:22][CH3:23])=[CH:20][N:21]=2)[CH2:12][CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: CCc1cnc(N2CCC(COc3c(F)cc(-c4ccc(-c5nnn[nH]5)cc4)cc3F)CC2)nc1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cnc(N2CCC(COc3c(F)cc(-c4ccc(-c5nnnn5C)cc4)cc3F)CC2)nc1
Temperature: 80 °C

Procedure:
To a solution of Example B1 (20 mg, 0.04 mmol) and methyl iodide (10 μL, 0.16 mmol) in DMF (3 mL) is added Cs2CO3 (40 mg, 0.12 mmol). The resulting suspension is heated to 80° C. for 1 h, cooled to rt, and diluted with H2O (20 mL). The mixture is extracted with EtOAc (2×20 mL), and the combined organics are washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by flash chromatography (EtOAc/hexanes gradient) afford the title compounds (Example C1) and (Example C2) as white solids.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]3[O:44][C:43]([C:45]([O:47][CH2:48]C)=[O:46])=[CH:42][C:41]=3[CH:50]=2)O1>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:37]3[CH:38]=[CH:39][C:40]4[O:44][C:43]([C:45]([O:47][CH3:48])=[O:46])=[CH:42][C:41]=4[CH:50]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CCOC(=O)c1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2o1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COC(=O)c1cc2cc(-c3n[nH]c4cc(-c5c(F)c(OC)cc(OC)c5F)ncc34)ccc2o1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (9 mg, 0.02 mmol; from step 6) and ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-benzofuran-2-carboxylate. LCMS (M+H)+: m/z=466.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:36]1[CH:41]=[CH:40][N:39]=[C:38]([NH2:42])[N:37]=1>CCO>[C:1]([O:5][C:6](=[O:34])[NH:7][C@@H:8]([CH2:24][C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27][CH:26]=1)[CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:36]3[CH:41]=[CH:40][N:39]=[C:38]([NH2:42])[N:37]=3)[CH:18]=2)[CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1nccc(Cl)n1
Reactant: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2cccc(N)c2)c1)Cc1c[nH]c2ccccc12
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H](COc1cncc(-c2cccc(Nc3ccnc(N)n3)c2)c1)Cc1c[nH]c2ccccc12
Temperature: 80 °C

Procedure:
A mixture of Example 121A (0.07 g, 0.153 mmol) and 4-chloro-2-pyrimidinylamine (0.021 g, 0.163 mmol) was dissolved in EtOH (1 mL). The mixture was heated to 80° C. overnight then cooled and evaporated. The product was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.Cl.N1C=CC=CC=1.[O:17]1[CH:21]=[CH:20][CH2:19][CH2:18]1>N1C=CC=CC=1>[O:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: C1=COCC1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Agent: Cl
Solvent: c1ccncc1
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F

Procedure:
In 50 ml of pyridine were dissolved 2.5 g of 5-fluorouracil and 2.4 g of pyridine hydrochloride. To this solution were added 4.5 ml of 2,3-dihydrofuran in 4 portions and the mixture was reacted for 20 hours at 120° C. in an oil bath. After the reaction, a small amount of the reaction liquid was extracted and subjected to thin layer chromatography to check the state of preceeding of the reaction whereby the composition of the product was 90% of the end product, 5% of unreacted 5-fluorouracil and 5% of by-products. The reaction liquid was treated in the same manner as described in Example 7 to obtain 2.6 g of 1-(2-tetrahydrofuryl)-5-fluorouracil. The yield of the end product was 70% based on the initially used 5-fluorouracil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:30]([O:32]C)=[O:31])[C:26]([O:28]C)=[O:27])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>O.CO>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:26]([OH:28])=[O:27])[C:30]([OH:32])=[O:31])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C(CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C(CCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.1 %

Procedure:
A mixture of dimethyl 2-[7-(4,5-diphenyl-2-oxazolyl)heptyl]propanedioate (6.00 g, 13 mmol), 5N sodium hydroxide solution (13.4 mL), water (120 mL) and methanol (20 mL) was stirred at room temperature. After 10 minutes, the mixture was heated to reflux for 1 hour before adding water (80 mL,) and 5N NAOH solution (13 mL). After a further 3 hours at reflux, the mixture was cooled, acidified with 2N HCl solution and extracted with diethyl ether. The combined extracts were dried over sodium sulphate and the solvent evaporated to leave a white solid, 2-[7-(4,5-diphenyl-2-oxazolyl)heptyl]propanedioic acid (5.65 g, 100%). An analytical sample was prepared by recrystallizing 1.15 g from a mixture of CH2Cl2, diethyl ether and hexane to give pure product (1.05 g), m.p. 115°-117° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1.[C:19]([O:22][CH2:23][C:24](Cl)=[O:25])(=[O:21])[CH3:20]>C(Cl)Cl>[C:19]([O:22][CH2:23][C:24](=[O:25])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][N:10]=1)(=[O:21])[CH3:20]
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.9 %

Procedure:
Triethylamine (9.30 g, 91.9 mmol) was added at 0° C. to a stirred solution of 2-amino-5-trifluoromethylpyridine (5.0 g, 30.8 mmol) in DCM, and stirring was continued for 15 min. 2-Chloro-2-oxoethyl acetate (5.03 g, 36.8 mmol) was added at 0° C., and the temperature was raised to room temperature and the mixture was stirred for 4 hrs. The reaction mixture was diluted with DCM and washed with ice-water, aq. NaHCO3 solution and saturated brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude compound. This was purified by column chromatography (100-200 silica gel), eluting with 0-20% EtOAc/pet ether to give the title compound (3.30 g) as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[OH:23])=[N:12][N:13]([CH3:15])[CH:14]=2)=[CH:4][CH:3]=1.[C:24]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[C:37](O)=[O:38])([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C(N=C=NC(C)C)(C)C.O.[OH-].[Li+].C(O)(=O)C>CN(C)C1C=CN=CC=1.ClCCl.O.C(OCC)(=O)C>[C:27]([O:26][C:24]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH:32]1[C:37](=[O:38])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[C:11]([C:16]3[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=3[OH:23])=[N:12][N:13]([CH3:15])[CH:14]=2)=[CH:6][CH:7]=1)=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: Cc1ccc(O)c(-c2nn(C)cc2C#Cc2ccc(N)cc2)c1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(O)c(-c2nn(C)cc2C#Cc2ccc(NC(=O)C3CCCCN3C(=O)OC(C)(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 2-[4-(4-amino-phenylethynyl)-1-methyl-1H-pyrazol-3-yl]-4-methyl-phenol (1) (15.2 g, 50 mmol) and N-Boc-2-piperidinecarboxylic acid (2) (34.4 g, 150 mmol) and 4-dimethylaminopyridine (DMAP, 0.6 g, 5 mmol) in dry dichloromethane (600 mL) was added N,N′-diisopropylcarbodiimide (DIPC, 23.3 mL, 150 mmol) slowly. The reaction mixture was stirred at rt overnight. Water (˜100 mL) was added, and the mixture was stirred at rt for one hour. The organic layer was collected, filtered and concentrated. To the resultant residua was added THF (200 mL) and methanol (200 mL). A solution of lithium hydroxide monohydrate (21 g, 500 mmol) in water (100 mL) was slowly added above solution. The mixture was stirred at rt for 2 hours. It was then neutralized with acetic acid (29 mL, 500 mmol). The mixture was diluted with ethyl acetate (˜300 mL), and washed with brine, and dried over sodium sulfate. It was filtered, concentrated and purified with silica column chromatography eluting with dichloromethane-ethyl acetate (v/v 9/1). After crystallizing with hexanes/ethyl acetate, the title compound (3, 20.09 g) was obtained as white powder in 78% yield. 1H NMR (CDCl3, 500 MHz) δ 10.48 (s, 1H), 8.41 (s, 1H), 7.60 (s, 1H), 7.54 (d, 2H, J=8.0 Hz), 7.48 (d, 2H, J=8.0 Hz), 7.06 (d, 1H, J=8.0 Hz), 6.94 (d, 1H, J=8.0 Hz), 4.88 (br s, 1H), 4.08 (br s, 1H), 3.94 (s, 3H), 2.87 (t, 1H, J=6.1 Hz), 2.34 (s, 3H), 1.76-1.55 (m, 4H), 1.53 (s, 9H), 1.47 (m, 1H), 1.27 (m, 1H). LCMS (ESI) m/z 515.16 (MH+, 100), 415.15; HPLC: tR=6.88 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[CH3:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[CH3:17])[NH2:13].[K+].[Br-]>>[CH3:9][C:10]1[CH:11]=[C:12]([NH:13][C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[NH:2])[CH:14]=[CH:15][C:16]=1[CH3:17]
Reactant: N#Cc1ccccn1
Reactant: Cc1ccc(N)cc1C
Agent: [Br-]
Agent: [K+]
Product: Cc1ccc(NC(=N)c2ccccn2)cc1C
Yield: 71.2 %

Procedure:
The title compound was prepared from 2-cyanopyridine (8.6 g, 83 mmol) and 3,4-dimethylaniline (10 g, 83 mmol) by following the procedure described in preparation 10 (13.2 g, yield 71.2%, mp 105-107° C., purity 99.9% by HPLC). 1H-NMR (CDCl3): δ 2.24-2.25 (d, 6H), 5.75-6 (bs, 2H, D2O exchangeable), 6.75-6.81 (m, 2H), 7.11-7.13 (d, 1H), 7.36-7.39 (m, 1H), 7.78-7.82 (m, 1H) 8.39-8.41 (d, 1H), 8.55-8.57 (m, 1H). IR (KBr) cm−1: 3445, 3303, 1645, 1625. MS m/z:227 (M+).