Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f28) and commercially available methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C([SiH](CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH2:12]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=3)[NH:8][CH:7]=2)[CH2:24][CH2:23]1)=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc2[nH]cc(C3CCN(C(=O)OCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59 %

Procedure:
A solution of 5-cyanoindole (10.00 g, 70.34 mmol) in acetonitrile (120 ml) was added to a solution of 1-benzyloxycarbonyl-4-piperidone (8.20 g, 35.17 mmol) and trimethylsilyl trifluoromethanesulfonate (6.80 ml, 35.17 mmol) in acetonitrile (230 ml) via addition funnel at 0° C. over 1.5 h. Triethylsilane (4.2 ml, 26.28 mmol) was added at 0° C. and reaction mixture was allowed to gradually warm to RT over 2 h. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate, brine, dried over MgSO4, and concentrated in vacuo. The residue was diluted with acetonitrile (300 ml) and hexanes (200 ml) and stirred for 20 min. The organics were removed in vacuo and the residue was chromatographed (SiO2, 20-40% ethyl acetate/hexanes) to give 1-benzyloxycarbonyl-4-(5-cyanoindol-3-yl)piperidine as a white crystalline solid (59%).
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([F:11])[CH:5]=1)[CH3:3].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[F:11][C:6]1[CH:5]=[C:4]([C:2](=[O:1])[CH3:3])[CH:9]=[CH:8][C:7]=1[CH3:10]
Reactant: Cc1ccc(C(C)O)cc1F
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1ccc(C)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of 4-(1-hydroxyethyl)-2-fluorotoluene (55.8 mg, 0.36 mmol) in methylene chloride (1 mL) were added molecular sieve 4A (56.0 mg) and PCC 94.0 mg (0.43 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield the title compound as a pale yellow oil (47.5 mg, 86.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[H-].[Na+].Br.Br[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.C(OCC)C>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Reactant: BrCc1ccncc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cc2cc(F)ccc2n1Cc1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
A solution of 1 g (4.73 mmol) of ethyl 5-fluoro-1H-indole-2-carboxylate is added dropwise to a suspension of 0.38 g (9.45 mmol) of 60% sodium hydride in 10 ml of dimethylformamide, stirred at 0° C. under argon. The mixture is stirred for 30 minutes at 0° C. and then for 30 min at 20° C. The reaction mixture is cooled and 1.24 g (4.2 mmol) of 4-bromomethylpyridine hydrobromide are added portionwise. The mixture is stirred for 30 minutes at 0° C. and then for 30 minutes at 20° C. The reaction mixture is cooled again to 0° C. and a further 0.38 g (9.45 mmol) of 60% sodium hydride in 10 ml of dimethylformamide is added. After 30 minutes at 0° C., 1.24 g (4.2 mmol) of 4-bromomethylpyridine hydrobromide are added portionwise. The reaction mixture is then stirred for 20 hours at 20° C. After this time, the mixture is poured into a solution of 100 ml of ice-water and 100 ml of ethyl ether. The organic phase is separated out and the aqueous phase is re-extracted with 100 ml of ethyl ether. The organic phases are combined, washed with 50 ml of water and then dried over sodium sulfate, filtered and then concentrated under reduced pressure. The residue is purified by preparative chromatography (eluent: dichloromethane/acetone). 0.65 g of expected product is obtained in the form of an oil, which is used without further purification in the subsequent synthesis.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.C[O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH:40][C:41]2[CH:49]=[C:48](B3OC(C)(C)C(C)(C)O3)[CH:47]=[C:46]3[C:42]=2[CH:43]=[CH:44][NH:45]3)(=[O:39])=[O:38])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:48]2[CH:47]=[C:46]3[C:42]([CH:43]=[CH:44][NH:45]3)=[C:41]([NH:40][S:37]([C:34]3[CH:35]=[CH:36][C:31]([OH:30])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH:49]=2)=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(S(=O)(=O)Nc2cc(B3OC(C)(C)C(C)(C)O3)cc3[nH]ccc23)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3Br)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(NS(=O)(=O)c4ccc(O)cc4)c4cc[nH]c4c3)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 21 %

Procedure:
To a solution of (S)-2-(1-((6-amino-5-bromopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (80 mg, 0.18 mmol) were added 4-methoxy-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-4-yl)benzenesulfonamide (137 mg, 0.27 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane complex (14 mg, 0.02 mmol) and 182 μl of a 2M aqueous solution of cesium carbonate in dioxane (2 ml). The mixture was stirred under argon atmosphere at 100° C. for 18 hours and then diluted with ethyl acetate. The resulting solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The crude product was purified using SP1® Purification System (50% to 100%, hexane-ethyl acetate) to obtain 27 mg (21% yield, 95% purity) and 98 mg (72% yield, 88% purity) of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:15]2[N:7]([N:8]=[C:9]3[C:14]=2[CH:13]=[CH:12][CH:11]=[CH:10]3)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH2:19][CH2:18]1.C(Br)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:23]([N:20]1[CH2:19][CH2:18][CH:17]([CH2:16][N:3]2[CH2:4][CH2:5][CH2:6][N:7]3[N:8]=[C:9]4[C:14]([CH:13]=[CH:12][CH:11]=[CH:10]4)=[C:15]3[C:2]2=[O:1])[CH2:22][CH2:21]1)[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCCn3nc4ccccc4c3C2=O)CC1
Reactant: BrCCc1ccccc1
Product: O=C1c2c3ccccc3nn2CCCN1CC1CCN(CCc2ccccc2)CC1

Procedure:
The product was prepared using the method described in example 2e), using tert-butyl 4-[(1-oxo-4,5-dihydro-1H-[1,4]diazepino[1,2-b]indazol-2(3H)-yl)methyl]piperidine-1-carboxylate (example 16a) and phenethyl bromide as reagents. The product was purified by flash chromatography on silica gel, using the mixture chloroform:methanol in a ratio of 95:5 as eluent. Thus, 223 mg of 2-[(1-phenethylpiperidin-4-yl)methyl]-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-b]indazol-1-one were obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:7]([C:8](O)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[CH3:11][N:5]1[CH:6]=[C:7]([C:8]([Cl:17])=[O:9])[C:3]([C:2]([F:13])([F:12])[F:1])=[N:4]1
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Cl)c(C(F)(F)F)n1
Temperature: 25 °C
Yield: 98.6 %

Procedure:
To 3-(Trifluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid (3.00 g, 15.5 mmol) suspended in dichloromethane was added oxalyl chloride (2.24 g, 17.8 mmol) and dimethylformamide (one drop). The reaction mixture was stirred at room temperature until bubbling stopped at which point the organic solution was evaporated in vacuo to obtain 3.25 g (99%) of the title compound.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[CH:16]=[O:17])[CH:2]=[CH2:3].[CH3:19][Si:20]([CH3:28])([C:22]([CH3:27])([CH3:26])[CH:23]([CH3:25])[CH3:24])Cl.C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([O:15][Si:20]([CH3:28])([CH3:19])[C:22]([CH3:27])([CH3:26])[CH:23]([CH3:25])[CH3:24])[C:7]=1[CH:16]=[O:17])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)c1c(C)c(OC)cc(O)c1C=O
Reactant: CC(C)C(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1c(C)c(OC)cc(O[Si](C)(C)C(C)(C)C(C)C)c1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.4 %

Procedure:
To a solution of 75.1 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid allyl ester in 0.6 l of N,N-dimethylformamide were added 81.0 g of dimethyl-(1,1,2-trimethyl-propyl)-chlorosilane and 45.5 g of triethylamine. The mixture was stirred for 4 h at room temperature and then evaporated in vacuo. The residue was taken up in 2 l of ethyl acetate, and the mixture was successively washed with 1N hydrochloric acid and with brine, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was crystallized from hexane to give 108.8 g of 2-formyl-5-methoxy-6-methyl-3-[dimethyl-(1,1,2-trimethyl-propyl)silanyloxy]-benzoic acid allyl ester as white crystals of m.p. 81°-82° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1.Br[CH2:20][CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[NH:9][C:10](=[O:18])[C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:4][CH2:3]1
Reactant: O=c1[nH]c(C2CCNCC2)cc2ccccc12
Reactant: OCCBr
Agent: Cl
Product: O=c1[nH]c(C2CCN(CCO)CC2)cc2ccccc12
Yield: 34.5 %

Procedure:
By the reaction in the same manner as in Example 2a, using 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrochloride (1.1 g) and 2-bromoethanol (1.0 g) as starting materials, 3-[1-(2-hydroxyethyl)piperidin-4-yl]-2H-isoquinolin-1-one (0.39 g) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([CH3:23])([CH3:22])[C:14]4[C:9]3=[C:10]([CH:11]=[C:12](Br)[CH:13]=4)[C:4]=2[CH:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][C:15]1([CH3:22])[C:14]2[C:9]3=[C:10]([C:4]4[CH:3]=[C:2]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:7]=[CH:6][C:5]=4[N:8]3[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=3)[CH:11]=[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:13]=2
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)c2ccccc2-n2c3ccc(Br)cc3c3cc(Br)cc1c32
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)c2ccccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32

Procedure:
19.8 g (45 mmol) of 3,6-dibromo-8,8-dimethyl-8H-indolo[3,2,1-de]acridine, 11.4 g (94 mmol) of phenylboronic acid and 164 ml of saturated NaHCO3 solution are suspended in 1500 ml of toluene and 150 ml of ethanol. 1.9 g (1.6 mmol) of Pd(PPh3)4 are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][N:30]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:35]O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:35][C:31]3[N:30]([CH3:29])[CH:34]=[CH:33][CH:32]=3)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cn1cccc1CO
Product: Cn1cccc1COc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and (1-methyl-1H-pyrrol-2-yl)-methanol according to the procedure of Example 69. MS (ESI) m/z 473.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:36])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH:34]=[CH:33][N:32]=[N:31]2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][O:14][C:12]1[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]2[NH:20][C:21](=[O:36])[CH2:22][C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([N:30]4[CH:34]=[CH:33][N:32]=[N:31]4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-methoxy-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert.-butyl ester (Example M38) (394 mg, 0.758 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (169 mg).
Reaction SMILES: Br[CH2:2][C:3]#[C:4][CH2:5][N:6]1[CH2:10][CH2:9][C@H:8]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[C:7]1=[O:19].[NH:20]1[CH:24]=[CH:23][N:22]=[CH:21]1>O1CCCC1>[CH3:16][C:15]([Si:12]([CH3:14])([CH3:13])[O:11][C@H:8]1[CH2:9][CH2:10][N:6]([CH2:5][C:4]#[C:3][CH2:2][N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[C:7]1=[O:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(CC#CCBr)C1=O
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(CC#CCn2ccnc2)C1=O
Yield: 83.1 %

Procedure:
A solution of 2.0 g of (S)-1-(4-bromo-2-butynyl)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone, 1.3 g of imidazole and 50 ml of tetrahydrofuran is stirred at room temperature for 72 hours. The solution is concentrated in vacuo. The residue is purified by chromatography (alumina, activity grade 2.5, 2% methyl alcohol/methylene chloride) to give 1.6 g of the desired product as a colorless oil.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]([NH:26][CH2:27][CH:28]2[CH2:30][CH:29]2[C:31](OCC)=O)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C[O:39]CC1>>[C:7]1([C:13]([NH:26][CH2:27][CH:28]2[CH2:30][C:29]2([CH3:31])[OH:39])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)C1CC1CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC1(O)CC1CNC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a mixture of lithium aluminum hydride (0.077 g; 2.04 mmol) in 10 ml THF is added ethyl 2-triphenylmethylaminomethylcyclopropane-1-carboxylate (0.714 g; 1.85 mmol) in 20 ml THF and stirred overnight. The reaction mixture is quenched with water, filtered, concentrated in vacuo and flash chromatographed using hexane:ethylacetate;3:l to obtain 2-triphenylmethylaminomethyl-1-hydroxy-methylcyclopropane as a clear oil which is used directly in the next step.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]([F:21])([F:20])[F:19])[O:17][CH:11]2C(OCC)=O)=[CH:6][CH:5]=1>C(O)C.O>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:18]([F:19])([F:20])[F:21])[CH:11]=[O:17])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C1OC1(c1ccc(C)cc1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(C=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a solution of 4.8 g of potassium hydroxide in 20 ml of ethanol and 5 ml of water, 8.0 g or ethyl 3-(4-methylphenyl)-2,3-epoxy-4,4,4-trifluorobutyrate was added with ice-cooling. The reaction solution was stirred at room temperature for 3 hours. Thereafter, the reaction solution was poured into ice water. The resulting solution was washed with diethyl ether and adjusted to pH 3 with 10% HCl and extracted twice with diethyl ether. The ether layers were combined and washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure and the residue was subjected to distillation under a reduced pressure by heating in an oil bath (140°-160° C.) to obtain 3.0 g of the desired aldehyde (b.p. 110°-120° C./110-120 mmHg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:27]([NH:31][S:32]([C:35]1[S:36][C:37](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:39]=1)(=[O:34])=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][S:32]([C:35]1[S:36][C:37]([C:2]2[CH:7]=[C:6]([C:8]3[N:13]=[C:12]([CH:14]([F:16])[F:15])[CH:11]=[C:10]([C:17]4[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=4)[N:9]=3)[CH:5]=[CH:4][N:3]=2)=[CH:38][CH:39]=1)(=[O:33])=[O:34])([CH3:30])([CH3:28])[CH3:29]
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)nc2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)F)n3)ccn2)s1

Procedure:
5-{4-[4-Difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-pyridin-2-yl}-thiophene-2-sulfonic-acid tert-butylamide was prepared from 2-(2-chloro-pyridin-4-yl)-4-difluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.7) (0.39 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example C.1) (0.414 g, 1.2 mmol) according to the general procedure III. Obtained as an off-white solid (0.36 g), which was subsequently deprotected.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([CH2:13][CH3:14])[N:3]=1.[CH2:15]([O:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH2:23])=[NH:22])[CH2:16][CH3:17].C(N(CC)CC)C>C(#N)C>[CH2:13]([C:4]1[N:3]=[C:2]2[N:22]=[C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[O:18][CH2:15][CH2:16][CH3:17])[NH:23][C:8](=[O:10])[C:7]2=[CH:6][N:5]=1)[CH3:14]
Reactant: CCCOc1ccccc1C(=N)N
Reactant: CCOC(=O)c1cnc(CC)nc1Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCOc1ccccc1-c1nc2nc(CC)ncc2c(=O)[nH]1

Procedure:
In a similar manner to Example 3 reaction of ethyl 4-chloro-2-ethyl-5-pyrimidine carboxylate (0.86 g) with 2-propoxybenzamidine (from sodium, 0.1 g, in ethanol, 10 ml, and 2-propoxybenzamidine methanesulphonate, 1.20 g) and triethylamine (0.4 g) in acetonitrile (25 ml) for 3 days at ambient temperature yielded a crude product, which was recrystallised twice from 2-propanol-ether to yield the title compound, 95 mg, m.p. 118°-119° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:16])[CH2:7][C:8]1[CH:9]=[N:10][C:11]([O:14]C)=[CH:12][CH:13]=1.I[CH3:18]>CC(OC)(C)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11](=[O:14])[N:10]([CH3:18])[CH:9]=1
Reactant: CI
Reactant: COc1ccc(CC(=O)c2ccco2)cn1
Solvent: COC(C)(C)C
Product: Cn1cc(CC(=O)c2ccco2)ccc1=O
Temperature: 100 °C
Reaction time: 3 h
Yield: 287.1 %

Procedure:
To a solution of 1-furan-2-yl-2-(6-methoxy-pyridin-3-yl)-ethanone (7) (800.0 g, content 625.6 g, 2.88 mol) obtained in Preparation Example 4 in N-methyl-2-pyrrolidine (NMP) (1.88 L) was added iodomethane (122.6 g, 0.86 mol), and the reaction mixture was stirred at 100° C. for 3 hours and then at room temperature for 17.5 hours. To the reaction mixture was added dropwise MTBE (6.6 L) over a period of 77 minutes, followed by stirring for 1 hour while cooling in an ice bath. The precipitated crystals were collected by filtration and washed with MTBE (2.0 L), and then dried under reduced pressure at 50° C. for 3 hours to give 692.0 g of a crude product of the title compound as a dark brown powder (content 536.4 g, yield 85.7%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1([CH3:16])[O:10][B:9]([OH:11])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]1=2>[N+](C1C=CC=CC=1)([O-])=O>[CH3:5][C:6]1([CH3:16])[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([N+:1]([O-:4])=[O:2])[CH:14]=[CH:15][C:7]1=2
Reactant: O=[N+]([O-])O
Reactant: CC1(C)OB(O)c2ccccc21
Solvent: O=[N+]([O-])c1ccccc1
Product: CC1(C)OB(O)c2cc([N+](=O)[O-])ccc21
Temperature: -42.5 °C
Reaction time: 0.75 h
Yield: 51.8 %

Procedure:
To 106 mL fuming HNO3 at −45° C. was slowly added a solution of 3,3-dimethyl-3H-benzo[c][1,2]oxaborol-1-ol (16.9 g, 104.3 mmol) in 10.5 mL nitrobenzene via a syringe while maintaining the reaction temperature between −40 to −45° C. Once the addition was complete the resulting solution was allowed to stir at −45° C. for an additional 45 min before poured into crushed ice. The ice mixture was allowed to melt and the aqueous solution was extracted with DCM (3×). The combined DCM extracts were dried over Na2SO4 then evaporated. The crude oil remaining was mixed with one liter 1:1 DCM/heptanes. The volume of the solution was reduced under reduced pressure by half and the resulting solution was allowed to stand overnight in a −20° C. freezer. The precipitate formed was filtered out, washed with heptanes and vacuum dried to give the titled compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 7.69 (d, J=8.4 Hz, 1 H) 8.28 (dd, J=8.4, 2.3 Hz, 1 H) 8.48 (d, J=2.2 Hz, 1 H) 9.41 (br. s., 1 H). Amount obtained: 11.2 g (51.8% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([NH:16][CH3:17])[N:14]([CH3:15])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:18]>CO>[CH3:17][NH:16][C:13]1[N:14]([CH3:15])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:18])[C:11]=2[N:12]=1
Reactant: CNc1nc2c(Cl)nc3ccccc3c2n1C
Reactant: N
Solvent: CO
Product: CNc1nc2c(N)nc3ccccc3c2n1C
Temperature: 145 °C

Procedure:
4-Chloro-N,1-dimethyl-1H-imidazo[4,5-c]quinolin-2-amine (0.280 g, 0.88 mmol) and ammonia (15 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated in an oven at 145° C. for two days. An analysis by LC/MS indicated the presence of starting material, and heating at 145° C. was continued for a total of two weeks. The solvent was removed under reduced pressure, and the residue was purified by automated flash chromagraphy (silica cartridge, eluting with 1-20% methanol in dichloromethane with 1% aqueous ammonium hydroxide added) to provide 153 mg of N2,1-dimethyl-1H-imidazo[4,5-c]quinoline-2,4-diamine.