Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClCCl>[CH2:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][N:3]1[C:20](=[O:22])[CH3:21]
Reactant: c1ccc2c(c1)CCCNC2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCCc2ccccc2C1
Temperature: 0 °C
Yield: 97.1 %

Procedure:
A suspension of 2,3,4,5-tetrahydro-1H-2-benzazepine hydrochloride (10 g, 54.4 mmol) in dry dichloromethane (450 mL) was stirred at 0° C. Triethylamine (18.21 mL, 130.6 mmol) was added followed by the dropwise addition of acetic anhydride (6.18 mL, 65.3 mmol) in dry dichloromethane (50 mL). The reaction was then stirred for 1 hour whilst allowing the temperature to rise slowly to room temperature. The resulting mixture was washed with 1 N hydrochloric acid (200 mL) and brine (200 mL), dried over sodium sulfate and concentrated in vacuo to give 10 g of product as colorless oil (yield was 97%). It was used in next step without further purification. MS obsd. (ESI+) [(M+H)+] 190.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([Cl:9])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:14](OC(=O)C)(=[O:16])[CH3:15]>Cl>[CH3:15][C:14]([C:7]1[C:2]([Cl:1])=[CH:3][C:4]([Cl:9])=[C:5]([F:8])[CH:6]=1)=[O:16]
Reactant: Fc1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1cc(F)c(Cl)cc1Cl
Temperature: 120 °C

Procedure:
To a warm solution of 1,3-dichloro4-fluorobenzene at 70° C. (175.0 gm), anhydrous aluminum chloride was added in small portion with stirring (260.0 g). Then acetic anhydride was added in small portion with stirring (125 mL) followed by an additional amount of aluminum chloride (159.0 g). The temperature was slowly raised to 120° C. with stirring for 25 hours. The thick reaction mixture was cooled and poured into 400 cc of concentrated hydrochloric acid containing ice. The oil was extracted with methylene chloride, washed with water, dried over anhydrous magnesium sulfate and concentrated to give 165.0 g of oil (2).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4].N12CCCN=C1CCCCC2.[CH:28]([C:30]([CH2:32][CH3:33])=[O:31])=[CH2:29]>O1CCCC1>[CH2:1]([C:5]1([CH2:29][CH2:28][C:30](=[O:31])[CH2:32][CH3:33])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:14][CH3:15])[CH:11]=2)[C:6]1=[O:16])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1Cc2cc(OC)ccc2C1=O
Reactant: C=CC(=O)CC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCC1(CCC(=O)CC)Cc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.8 %

Procedure:
A solution of crude 2-butyl-5-methoxy-1-indanone (218 mg, 1 mmol) in tetrahydrofuran (THF, 2 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.030 mL, 0.2 mmol) and ethyl vinyl ketone (EVK, 0.200 mL, 2 mmol). The resulting solution was stirred under a nitrogen atmosphere at room temperature for 16 hours, followed by heating in an oil bath at 60° C. for 24 hours. Evaporation of the solvent under vacuum left a residue that was shown by NMR to be approximately a 1:1 mixture of starting material and product. The residue was purified by preparative layer chromatography on three 0.1×20×20 cm silica gel GF plates using 5% EtOAc in CH2Cl2 as developing solvent. The product band was eluted with EtOAc to provide 2-butyl-5-methoxy-2-(3-oxo-pentyl)-1-indanone (84 mg) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1COCC1.O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:1][CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH:14]=[CH:15][CH:16]=3)[CH2:7][CH2:6]2)=[O:32])=[CH:26][CH:25]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)Nc3ccc(F)cc3)CC2)c1
Yield: 10.9 %

Procedure:
A solution of N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide (26.4 mg, 0.0870 mol), 1-fluoro-4-isocyanatobenzene (11.9 mg, 0.0870 mmol), in THF (1.00 mL) was stirred for 12 h at 25° C. The resulting crude mixture was diluted with water (10 mL), the aqueous layer was extracted with CH2Cl2 (3×20 mL). The combined organic layers were concentrated in vacuo and the residue was purified by preparative TLC using 2.5% of NH3 (2.0 M in methanol) in CH2Cl2 to give the desired product N-{3-[1-(3-{[(4-fluoroanilino)carbonyl]amino}propyl)-4-piperidinyl]phenyl}-2-methylpropanamide (4.18 mg, 10.9%): 1H NMR (400 MHz, CDCl3) 7.45 (q, 2H, J=4.7 Hz), 7.23–7.21 (m, 4H), 7.05 (t, 4H, J=7.8 Hz), 6.75 (m, 1H), 4.05 (m, 1H), 3.19 (s, 1H), 2.71 (m, 1H), 2.53 (m, 1H), 2.26–2.21 (m, 3H), 1.80–1.60 (m, 9H), 1.25 (d, 6H, J=6.4 Hz); ESMS m/e: 439.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][CH:16]=O)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([NH:15][CH3:16])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(NC=O)c(OC)cc1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(C(=O)OC)c(OC)cc1OC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A 1.60 g portion of methyl 2,4-dimethoxy-5-formylaminobenzoate was dissolved in 20 ml of tetrahydrofuran, and 1.7 ml of borane dimethylsulfide complex was added under ice-cooling, followed by 2 hours of stirring at 60° C. Then, 3 ml of methanol and 4 ml of concentrated hydrochloric acid were added, followed by stirring at 75° C. for a while and then spontaneously cooled. The thus precipitated product of interest was collected by filtration, washed with tetrahydrofuran and then dried under a reduced pressure to give 1.08 g of methyl 2,4-dimethoxy-5-methylaminobenzoate.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23](F)=[N:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:14]2[CH2:15][CH2:16][CH2:17][C@@:10]3([C:9](=[O:18])[N:8]([CH:5]4[CH2:6][CH2:7][O:2][CH2:3][CH2:4]4)[CH2:12][CH2:11]3)[CH2:13]2)=[N:24][CH:25]=1
Reactant: Fc1ccc(Cl)cn1
Reactant: O=C1N(C2CCOCC2)CC[C@]12CCCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N(C2CCOCC2)CC[C@]12CCCN(c1ccc(Cl)cn1)C2
Temperature: 120 °C

Procedure:
A mixture of (5S)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (29.4 mg, 0.000107 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 92, steps 1-3), 5-chloro-2-fluoropyridine (17 mg, 0.00013 mol) and potassium carbonate (0.029 mL, 0.00032 mol) in N,N-dimethylformamide (0.6 mL, 0.008 mol) was heated at 120° C. for 5 h. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 350.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21]C)=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[C:1]([C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[CH:12][C:11]([OH:21])=[CH:10][CH:9]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2c(=O)n(C)c(C(C)(C)C)c(-c3ccccc3)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cn1c(C(C)(C)C)c(-c2ccccc2)c2cc(O)ccc2c1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a methylene chloride (5 mL) solution of 3-tert-butyl-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one (100 mg, 0.311 mmol) under argon at −70° C. was added boron tribromide (1.0M, 0.934 mL, 0.934 mmol). The contents of the reaction flask were warmed to room temperature and stirred 24 h. Extracted with methylene chloride (3×), then the combined organic extracts were washed with brine and dried with anhydrous sodium sulfate. Filtration followed by evaporation of solvent in vacuo gave a solid which was triturated with ethanol. Recrystallization from ethyl acetate/ethanol afforded the title compound.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:51])[C@H:7]([CH2:47][CH:48]=[CH:49][CH3:50])[CH2:8][C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@H:10]1[CH2:23][C:24]([CH3:46])([CH3:45])[CH2:25][CH2:26][O:27][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:2][CH2:3][CH3:4].[F-]>O1CCCC1.C(OCC)C>[CH2:1]([NH:5][C:6](=[O:51])[C@H:7]([CH2:47][CH:48]=[CH:49][CH3:50])[CH2:8][C@@H:9]1[O:13][C:12]([CH3:15])([CH3:14])[N:11]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@H:10]1[CH2:23][C:24]([CH3:46])([CH3:45])[CH2:25][CH2:26][OH:27])[CH2:2][CH2:3][CH3:4]
Reactant: CC=CC[C@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)NCCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC=CC[C@H](C[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC(C)(C)CCO)C(=O)NCCCC
Reaction time: 4 h

Procedure:
474 mg of 3-[N-tert-butoxycarbonyl-4(S)-(4-tert-butyl-diphenylsilyloxy-2,2-dimethylbutyl)-2,2-dimethyl-1,3-oxazolidin-5(S)-yl]-2(R)-but-2-enyl-propionic acid (N-butyl)amide are dissolved in 5 ml of tetrahydrofuran, and 1.2 ml of a 1M tetraburylammonium fluoride solution in tetrahydrofuran are added at room temperature under argon. After 4 h, the reaction mixture is diluted with diethyl ether, washed with water and brine, dried (Na2SO4) and concentrated. Purification over silica gel (mobile phase A) gives the title compound: Rf (A)=0.40; FAB-MS: (M+H)+ =483.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:27])=[C:6]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:28]([O:27][C:5]1[C:4]([C:1](=[O:3])[CH3:2])=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[C:6]=1[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)c1cc2c(c(CN3CCN(C(=O)OC(C)(C)C)CC3)c1O)OCO2
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C(C)=O)cc2c(c1CN1CCN(C(=O)OC(C)(C)C)CC1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
A solution of tert-butyl 4-[(6-acetyl-5-hydroxybenzo[d][1,3]dioxol-4-yl)methyl]piperazine-1-carboxylate (0.18 g, 0.48 mmol) in pyridine (1.0 mL) was added with acetic anhydride (1.0 mL) and 4-dimethylaminopyridine (0.010 g), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with ice water, the mixture was extracted with ethyl acetate, and the organic layer was washed successively with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (7:3→3:7)) to obtain tert-butyl 4-[(5-acetoxy-6-acetylbenzo[d][1,3]dioxol-4-yl)methyl]piperazine-1-carboxylate (0.18 g, 87%).
Reaction SMILES: [NH2:1][CH:2]([CH3:12])[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C>[OH:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][CH:2]([NH:1][C:20](=[O:22])[CH3:21])[CH3:12])=[CH:10][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)CCc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)CCc1ccc(O)cc1

Procedure:
4-(3-Aminobutyl)phenol (510 mg, 3.087 mmol) and triethylamine (1.3 ml, 9.26 mmol) were dissolved in 30 ml of ethyl acetate. At 0° C., acetic anhydride (029 ml, 3.087 mmol) was added. The cooling bath was removed after 1 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 472 mg (74%) of N-[3-(4-hydroxyphenyl)-1-methylpropyl]acetamide, M+H+: 208.14 and 54 mg (7%) of 4-(3-acetylaminobutyl)phenyl acetate, M+H+: 250.13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([CH2:48][C:49]([N:51]2[CH2:56][CH2:55][N:54]([CH3:57])[CH2:53][CH2:52]2)=[O:50])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([CH2:48][C:49]([N:51]6[CH2:52][CH2:53][N:54]([CH3:57])[CH2:55][CH2:56]6)=[O:50])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CN1CCN(C(=O)Cc2cccc(Br)c2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CC(=O)N4CCN(C)CC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 2-(3-bromo-phenyl)-1-(4-methyl-piperazin-1-yl)-ethanone (126 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 2-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-methyl-piperazin-1-yl)-ethanone was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-182) as a yellow powder (36 mg, 19%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C([N:18]1[C:26]2[C:21](=[CH:22][C:23]([S:27](Cl)(=[O:29])=[O:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1)=O.[OH-].[Na+]>ClCCl>[NH:18]1[C:26]2[C:21](=[CH:22][C:23]([S:27]([N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)(=[O:29])=[O:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1
Reactant: O=C(N1CCc2cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3c(c2)CCN3)CC1
Reaction time: 0.75 h

Procedure:
tert-butyl-1-piperazinecarboxylate (5.94 g, 31.9 mmol, 2.00 equiv) was added to a solution of 1-(trifluoroacetyl)indoline-5-sulfonyl chloride (1-6, 5.00 g, 15.9 mmol, 1 equiv) in dichloromethane (50 mL) at 23° C., and the resulting mixture was stirred for 45 minutes. The brown-colored reaction mixture was concentrated and the resulting tan-colored solid dried in vacuo. A solution of the solid in a mixture of 1,4-dioxane (100 mL) and methanol (30 mL) was treated with aqueous 1N NaOH solution (47.9 mL, 47.9 mmol, 3.00 equiv), and the resulting mixture was stirred for 1 hour. The mixture was concentrated, and the resulting solid suspended in diethyl ether (130 mL) and filtered. The filtered solid was then partitioned between aqueous saturated sodium chloride solution (150 mL) and ethyl acetate (4×85 mL). The organic layer was dried over sodium sulfate and concentrated to provide the tert-butyl 4-(2,3-dihydro-1H-indol-5-ylsulfonyl)piperazine-1-carboxylate (2-1) as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 7.41 (m, 2H), 6.57 (d, 1H, J=8.9 Hz), 3.69 (t, 2H, J=8.6 Hz), 3.50 (t, 2H, J=4.9 Hz), 3.09 (t, 2H, J=8.6 Hz), 2.93 (t, 2H, J=4.9 Hz) 1.42 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]5[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:40])=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]5[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:40])=[N:7]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(C4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(C4CCNCC4)cc3)cc12
Yield: 12.9 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperidine-1-carboxylate (113 mg, 0.194 mmol) was deprotected in TFA/DCM (5/5 ml). This afforded 12 mg (12.9% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.55 (s, 1H), 8.09-8.08 (d, 1H), 7.65-7.62 (m, 2H), 7.51 (s, 1H), 7.41-7.34 (m, 3H), 7.06-7.00 (m, 2H), 6.90-6.87 (s, 1H), 5.38 (s, 2H), 3.54-3.47 (m, 2H), 3.20-3.13 (m, 2H), 3.01-2.93 (m, 1H), 2.22 (s, 3H), 2.20 (s, 3H), 2.14-1.88 (m, 4H). MS: m/z=480.2 (M+1), HPLC: 98.73% in method B.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:18]([O:20][P:21]([O:25]CC)[O:22][CH2:23][CH3:24])[CH3:19]>>[CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH2:14][P:21](=[O:25])([O:22][CH2:23][CH3:24])[O:20][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCOP(OCC)OCC
Reactant: CC1(COc2ccc(CBr)cc2)CCCCC1
Product: CCOP(=O)(Cc1ccc(OCC2(C)CCCCC2)cc1)OCC
Temperature: 145 °C

Procedure:
A mixture of the 4-[((1-methyl)cyclohexyl)methoxy]benzyl bromide and 1.7 g (10 mmol) of triethylphosphite was heated at 145° C. for 0.2 hour. The reaction was cooled to room temperature and flash chromatographed to give 1.3 g of product as an oil.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[Cl:5][C:6]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:26])[NH:21][C:20]2=[O:27])=[CH:14][C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:5][C:6]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([CH3:26])[N:21]([CH:2]([F:4])[F:3])[C:20]2=[O:27])=[CH:14][C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9]
Reactant: FC(F)Cl
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C(F)F
Temperature: 80 °C

Procedure:
103 g of chlorodifluoromethane are conducted into a suspension of 145.0 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-2,6-dioxo-4-methyl-1(2H)-pyrimidinyl]-benzoate and 59.0 g of anhydrous, finely powdered potassium carbonate in 1 l of dimethylformamide for 6 hours while stirring at 80° C. After cooling the solid constituent is filtered off under suction and rinsed with 100 ml of dimethylformamide. The filtrate is concentrated to a large extent under reduced pressure at 55° C., the residue is poured into 2 l of water and the aqueous mixture is adjusted to pH 3 with concentrated hydrochloric acid. The mixture is extracted with 1.5 l of ethyl acetate and the organic phase is washed twice with 1 l of water each time. dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The resinous residue is purified by chromatography on a silica gel column using ethyl acetate/n-hexane (1:1) as the eluent. The product is dissolved in 1500 ml of hot n-hexane and the solution is treated with charcoal, filtered and concentrated to 700 ml at an elevated temperature. It is subsequently seeded and cooled to 5° C. while stirring. The resulting crystals are filtered off under suction, washed with n-hexane and dried. There is obtained isopropyl 2-chloro-5-[3-difluoromethyl-3,6-dihydro-2,6-dioxo-4-methyl-1(2H)-pyrimidinyl]-4-fluorobenzoate, m.p. 90°-93° C.
Reaction SMILES: [N+:1]1([O-:8])[C:2]([CH3:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.C([O-])(C)(C)C.[K+].[CH:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1>>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH:15]=[CH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N+:1]=2[O-:8])=[CH:17][CH:18]=1
Reactant: Cc1cccc[n+]1[O-]
Reactant: COc1ccc(C=O)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COc1ccc(C=Cc2cccc[n+]2[O-])cc1

Procedure:
Following the general method described in example 2a, 2-picoline-1-oxide was reacted with potassium tert.-butanolate and p-anisaldehyde. After extraction and chromatography the title compound was obtained as a yellow solid material. MS: m/e=227 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH:24]=1
Reactant: COc1ccc(Br)cc1
Reactant: Cc1ccccc1CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccccc1CC(=O)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
2-Methylphenylacetic acid (9.60 g, 64.15 mmoles) was dissolved in 10 ml dichloromethane. To this mixture, oxalylchloride (7 ml, 80.19 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 100 ml dichloromethane. To this mixture, 4-bromoanisole (10 g, 53.47 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (10.6 g, 80.19 mmoles) was added and the reaction mixture was warmed to RT and stirred for 24 h. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as white solid (5.5 g, 33% yield. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 11.52 (s, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.65 (dd, J=8.8, 2.5 Hz, 1H), 7.16 (m, 4H), 6.97 (d, J=8.9 Hz, 1H), 4.47 (s, 2H), 2.14 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]([OH:25])[CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=2F)[C:19]#[N:20])=[CH:9][CH:8]=1.[H-].[Na+]>CN1C(=O)CCC1.COCCOCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[O:25][C:23]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[O:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: N#Cc1ccc(F)c(OC[C@@H](O)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOCCOC
Solvent: CN1CCCC1=O
Product: N#Cc1ccc2c(c1)OC[C@H](c1ccc(OCc3ccc(Cl)c(Cl)c3)cc1)O2
Yield: 54.4 %

Procedure:
3-{(S)-2-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-hydroxy-ethoxy}-4-fluoro-benzonitrile (28.9 g) was dissolved in 30 mL dry NMP and 270 mL dry diglyme under nitrogen and heated to 142° C. internal temperature. A suspension of sodium hydride (2.676 g of 60% NaH in mineral oil) in 6 mL of dry NMP and 54 mL of dry diglyme was added all at once via cannula while stirring. After 15 min the reaction was removed from heating and cooled 5 min, then poured into ice/1 L EtOAc/0.5 L 1 N HCl. The layers were separated and the organic layer washed twice with water, once with brine and dried over Na2SO4. The residue was purified by silica gel flash chromatography (DCM to 1:1 DCM/EtOAc) to provide 31 g of partially purified solid which was then crystallized from refluxing 3:1 MeOH/DCM, to give 15 g of desired product. 1H NMR (400 MHz, CDCl3): 7.54 (d, 1H), 7.46 (d, 1H), 7.33 (m, 2H), 7.28-7.24 (m, 1H), 7.23 (d, 1H) 7.19 (m, 1H), 7.0 (m, 3H), 5.12 (m, 1H), 5.04 (s, 2H), 4.37 (m, 1H), 4.03 (m, 1H).