Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH:22]4[CH2:27][CH2:26][C:25](=[CH:28][O:29]C)[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[C:12]([F:31])[CH:11]=2)[CH2:6][CH2:5]1)[CH3:2].CC(C)=O.Cl.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][CH:19]([CH:22]4[CH2:27][CH2:26][CH:25]([CH:28]=[O:29])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[C:12]([F:31])[CH:11]=2)[CH2:8][CH2:9]1)[CH3:2]
Reactant: CCOC1CCC(c2ccc(C3CCC(C4CCC(=COC)CC4)CC3)c(F)c2)CC1
Agent: Cl
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC1CCC(c2ccc(C3CCC(C4CCC(C=O)CC4)CC3)c(F)c2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
The compound (27) (7.64 g) and acetone (25 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated to 50° C. 6N-Hydrochloric acid (8 ml) was added dropwise thereto in the temperature range of 40° C. to 50° C., and the mixture was stirred for 3 hours, and cooled slowly to room temperature. Water (100 ml) and toluene (100 ml) were added and mixed thereto. The mixture was allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure, and the residue was purified by means of recrystallization from a mixed solvent of heptane and Solmix (heptane: Solmix=1:1 by volume), and dried, giving 2.29 g of 4′-(4-(4-ethoxycyclohexyl)-2-fluorophenyl)bi(cyclohexane)-4-carbaldehyde (28). The yield based on the compound (27) was 31.0%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH:18](=O)[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21].[BH4-].[Na+].[C:29]([OH:32])(=[O:31])[CH3:30]>C(O)C>[C:29]([OH:32])(=[O:31])[CH3:30].[C:29]([OH:32])(=[O:31])[CH3:30].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[OH:21])[CH3:15])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(N)CNc1ccnc2cc(Cl)ccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(CNc1ccnc2cc(Cl)ccc12)NCc1ccccc1O
Yield: 40 %

Procedure:
1.25 g of N1 -(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine and 0.54 g of salicylaldehyde were stirred under reflux overnight in the presence of 1.25 g of molecular sieve (E. Merck, 3 Å). Thereafter, the mixture was filtered and the solvent was evaporated. From a small amount of diethyl ether and ethyl acetate there was obtained a crystalline product which was again taken up in 20 ml of ethanol. After the addition of 0.19 g of sodium borohydride the mixture was left to react overnight, thereafter 5 ml of glacial acetic acid were added thereto and the mixture was evaporated to dryness. After the addition of 10 ml of methanol the mixture was again evaporated. Addition of methanol and evaporation were repeated twice. The residue was then crystallized from 10 ml of ethanol. 0.9 g (40%) of colourless crystalline product of m.p. 150° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[CH3:47][N:48]([CH3:53])[CH2:49][C:50](O)=[O:51]>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=2[F:27])[C:12]2[N:17]=[CH:16][C:15]([CH2:18][NH:19][C:50](=[O:51])[CH2:49][N:48]([CH3:53])[CH3:47])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)NCc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 57.9 %

Procedure:
To a dichloromethane (5 ml) solution of the [6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-3-yl]methylamine (30 mg, 0.0734 mmol) obtained in Example 63 were added triethylamine (12 μl, 0.0881 mmol), 4-dimethylaminopyridine (5 mg, 0.0367 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (17 mg, 0.0881 mmol) and N,N-dimethylglycine (9 mg, 0.0881 mmol). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with dichloromethane. The diluted mixture was washed sequentially with water, a saturated aqueous solution of sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and then, concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate=1:4 eluate was concentrated under reduced pressure to give the title compound (21 mg, 0.0425 mmol, 58%) as a white powder.
Reaction SMILES: [C:1](=[O:26])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]1[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:15])[NH2:14])=[CH:9][N:8]=2)[CH2:4]1.[CH:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([CH3:29])[CH3:28]>C(Cl)Cl>[CH:27]([N:30]1[CH2:35][CH2:34][N:33]([C:1]([O:2][CH:3]2[CH2:4][N:5]([C:7]3[CH:12]=[CH:11][C:10]([C:13](=[O:15])[NH2:14])=[CH:9][N:8]=3)[CH2:6]2)=[O:26])[CH2:32][CH2:31]1)([CH3:29])[CH3:28]
Reactant: NC(=O)c1ccc(N2CC(OC(=O)Oc3ccc([N+](=O)[O-])cc3)C2)nc1
Reactant: CC(C)N1CCNCC1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)OC2CN(c3ccc(C(N)=O)cn3)C2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 10.1 %

Procedure:
To a solution of 1-(5-carbamoylpyridin-2-yl)-azetidin-3-yl 4-nitrophenyl carbonate (0.36 g, 1 mmol) in DCM (5 mL) under nitrogen was added 1-isopropylpiperazine (0.13 g, 1 mmol). The resulting solution was stirred under N2 at room temperature for 24 h. The reaction mixture was then filtered and the filter cake was washed with DCM. The combined filtrates were concentrated to afford the crude product. After further purified by preparative HPLC, the title compound (35 mg, 10%) was obtained as a yellow solid. [1HNMR (500 MHz, CDCl3) δ8.58 (d, 1H), 7.96 (dd, 1H), 7.76 (s, 1H), 7.77 (s, 1H), 7.15 (s, 1H), 6.41 (d, 1H), 5.21 (m, 1H), 4.32 (m, 2H), 3.92 (m, 2H), 3.41 (m, 4H), 2.65 (m, 1H), 2.40 (m, 4H), 0.95 (d, 6H); LCMS RtA=1.59 min, [M+H]+=348.2].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@H:18](O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C@@H:18]([O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Oc1cncc(Br)c1
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cncc(Br)c2)C1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-7, 5-bromopyridin-3-ol was reacted with (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a white solid. MS: 343.1 and 345.1 (M+H+).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[N:12]=[CH:11][C:10]([C@H:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH3:14])=[CH:9][CH:8]=1.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C>C1COCC1>[C:24]([O:23][C:21]([N:18]1[CH2:17][CH2:16][N:15]([C@@H:13]([C:10]2[CH:9]=[C:8]([B:28]([OH:33])[OH:29])[C:7]([F:6])=[N:12][CH:11]=2)[CH3:14])[CH2:20][CH2:19]1)=[O:22])([CH3:26])([CH3:25])[CH3:27]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: C[C@H](c1ccc(F)nc1)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, Aldrich; 20.0 mL, 50.0 mmol) was added (dropwise over 20 min) to a solution of (R)-tert-butyl 4-(1-(6-fluoropyridin-3-yl)ethyl)piperazine-1-carboxylate (10.0 g, 32.3 mmol) in THF (150 mL) at −78° C., and the resulting mixture was stirred at −78° C. for 20 min. Triisopropyl borate (15.0 mL, 65.2 mmol) was then added (dropwise over 10 min), followed by additional THF (20 mL) to rinse solidified triisopropyl borate from the side of the flask. The resulting mixture was stirred at −78° C. for min, and the cooling bath was then removed. The reaction mixture was stirred for 1 h, and 1 N aq. NaOH (100 mL) and water (40 mL) were then sequentially added. The resulting mixture was stirred for 10 min, and the organic layer was separated. The organic layer was extracted with 1 N aq. NaOH (40 mL), and the aqueous layers were then combined and pH-adjusted with N aqueous HCl to a final pH of about 5. The resulting mixture was extracted with EtOAc (3×200 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide (R)-5-(1-(4-(tert-butoxycarbonyl)piperazin-1-yl)ethyl)-2-fluoropyridin-3-ylboronic acid (9.27 g, 81% yield) as a white solid. 1H NMR (400 MHz, d4-MeOH) δ 8.39 (br. s., 1H), 8.26 (d, J=6.5 Hz, 1H), 4.54-4.63 (m, 1H), 3.31 (br. s., 4H; masked by MeOH), 3.13 (br. s., 4H), 1.80 (d, J=6.8 Hz, 3H), 1.45 (s, 9H). 19F NMR (377 MHz, d4-MeOH) δ −60.93 (br. s., 1F). m/z (ESI, +ve) 354.2 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:13]=[CH:14][C:15]=1[CH3:16])[CH2:7][C@H:8]([C:10]([OH:12])=[O:11])[NH2:9].S(Cl)([Cl:19])=O.[CH3:21]O>>[ClH:19].[CH3:21][O:11][C:10](=[O:12])[C@@H:8]([CH2:7][C:6]1[CH:13]=[CH:14][C:15]([CH3:16])=[C:4]([O:3][CH3:2])[CH:5]=1)[NH2:9]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: COc1cc(C[C@@H](N)C(=O)O)ccc1C
Agent: Cl
Product: COC(=O)[C@H](N)Cc1ccc(C)c(OC)c1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methoxy-4-methyl-D-phenylalanine hydrochloride (1.75 g) in methanol (8 ml) was added dropwise thionyl chloride (0.7 ml) at room temperature over 10 minutes. The total mixture was stirred at 40 to 50° C. for 2 hours and thionyl chloride (0.7 ml) was added further to the mixture. The total mixture was stirred for further 1 hour and the solvent was evaporated under reduced pressure. The produced solid substance was triturated with diisopropyl ether and collected by filtration to give 3-methoxy-4-methyl-D-phenylalanine methyl ester hydrochloride (1.70 g) in the form of colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([N:20]([CH3:40])[C:21]3[C:22]4[CH:29]=[CH:28][N:27](S(C5C=CC(C)=CC=5)(=O)=O)[C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].CO>CO.O.C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]([N:20]([CH3:40])[C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)C4CCCCN(C(=O)CNc5cc(Cl)cc(Cl)c5)C4)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CN(c1ncnc2[nH]ccc12)C1CCCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 90 °C
Yield: 46.2 %

Procedure:
To a solution of 2-(3,5-dichloro-phenylamino)-1-(3-{methyl-[7-(tosyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amino}-azepan-1-yl)-ethanone (235 mg. 0.39 mmol) in MeOH:H2O (4:1, 5 mL) was added K2CO3 (216 mg, 1.56 mmol) and heated at 90° C. for 1 h. The reaction mixture was cooled to rt and concentrated in vacuo to give a residue which was subjected to column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled compound (80.6 mg, 46%). 1H NMR (DMSO-d6, 400 MHz): 11.60 (1s, 1H), 8.08 (s, 1H), 7.12 (d, J=4 Hz, 1H), 6.72 (s, 1H), 6.69 (s, 1H), 6.63 (s, 1H), 6.62 (s, 1H), 6.38-6.35 (m, 1H), 4.98-4.85 (m, 1H), 4.29 and 1.28 (2d, J=2.1 Hz, 1H), 4.10-3.88 (m, 3H), 3.65-2.32 (m, 2H), 3.17 (s, 3H), 1.93-1.76 (m, 6H). LC-MS: m/z [M+1]=447.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]([OH:5])[CH3:4].[H-].[Na+].F[C:11]1[CH:12]=[CH:13][C:14]2[S:15](=[O:26])(=[O:25])[C:16]3[C:21]([O:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3.O>CN(C)C(=O)C>[F:1][C:2]([F:7])([F:6])[CH:3]([CH3:4])[O:5][C:11]1[CH:12]=[CH:13][C:14]2[S:15](=[O:25])(=[O:26])[C:16]3[C:21]([O:22][C:23]=2[CH:24]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: CC(O)C(F)(F)F
Reactant: O=S1(=O)c2ccccc2Oc2cc(F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(Oc1ccc2c(c1)Oc1ccccc1S2(=O)=O)C(F)(F)F
Temperature: 12.5 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
(rac)-1,1,1-Trifluoro-2-propanol (Oakwood) (189.30 g, 1.66 mole) in N,N-dimethylacetamide (200 mL) was added to a stirred, ice-bath cooled mixture of hexanes washed sodium hydride (60% dispersion in mineral oil) (Aldrich) (66.40 g, 1.66 mole) and N,N-dimethylacetamide (1900 mL) under nitrogen. The reaction was stirred at ambient temperature (5-20° C.) for 0.5 hour. 3-Fluorophenoxathiin 10,10-dioxide (Example 47) (277.78 g, 1.11 mole) in N,N-dimethylacetamide (1800 mL) was added at a bath temperature of 5-15° C. and stirred at ambient temperature for 1 hour. The reaction mixture was poured into water (8 L) and extracted with ethyl acetate (3 L, 2 L). The combined extracts were washed with water (4 L, 2 L), brine (0.5 L), dried over magnesium sulfate and filter. The volatiles were removed by spin evaporation in vacuo. The residue was stirred with hexanes (1 L) and collected by suction filtration to give 399.51 g of crude product. Recrystallization from 2-propanol (1.5 L) gave 304.62 g (79% yield) of (rac)-3-(2,2,2-trifluoro-1-methylethoxy)phenoxathiin 10,10-dioxide, m.p. 98-100 C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([C:24]2[CH2:33][CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)[O:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33][C:24]=1[C:21]1[O:22][CH:23]=[C:19]([CH2:18][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)=[CH:4][CH:3]=2)[N:20]=1
Reactant: Oc1ccc(CCCCn2cncn2)cc1
Reactant: ClCc1coc(C2=Cc3ccccc3CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C1=C(c2nc(COc3ccc(CCCCn4cncn4)cc3)co2)CCc2ccccc21
Temperature: 80 °C
Reaction time: 6 h
Yield: 49 %

Procedure:
A mixture of 1-[4-(4-hydroxyphenyl)butyl]-1,2,4-triazole (450 mg), 4-chloromethyl-2-(3,4-dihydro-2-naphthyl) oxazole (565 mg), potassium carbonate (290 mg) and N,N-dimethylformamide (10 ml) was stirred for 6 hours at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to a silica gel column chromatography. A crystalline product obtained from the fraction eluted with chloroform-methanol (50:1, v/v) was recrystallized from ethyl acetate-hexane to give 1-[4-[4-[2-(3,4-dihydro-2-naphthyl)-4-oxazolylmethoxy]phenyl]butyl]-1,2,4-triazole as colorless prisms, mp 96-97° C. The yield was 49%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]2[N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:15]=[C:16]([CH2:17][CH3:18])[C:3]=12.Cl.C([OH:28])C>>[CH2:17]([C:16]1[C:3]2[C:2](=[O:28])[C:11]3[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=3)[NH:5][C:4]=2[N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:15]=1)[CH3:18]
Reactant: CCc1nn(-c2ccccn2)c2nc3cc(F)c(F)cc3c(Cl)c12
Reactant: CCO
Agent: Cl
Product: CCc1nn(-c2ccccn2)c2[nH]c3cc(F)c(F)cc3c(=O)c12
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of 4-chloro-3-ethyl-6,7-difluoro-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (2.49 g, 7.22 mmol) in ethanol (120 mL), 6N hydrochloric acid (6 mL, 36.0 mmol) was added and the mixture was heated under reflux for 6 hours. The solution was allowed to cool to room temperature, and the resulting crystals were collected by filtration. The crystals were washed with ethanol, air dried, and recrystallized from ethanol to give the title compound (1.73 g, 73% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH:5]=[C:6]([NH2:10])[CH:7]1[CH2:9][CH2:8]1)[CH3:2].[F:12][C:13]([F:31])([F:30])/[C:14](/O)=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=1)=O>>[CH2:1]([O:3][C:4](=[O:11])[C:5]1[C:14]([C:13]([F:12])([F:31])[F:30])=[CH:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:20][CH:19]=2)=[N:10][C:6]=1[CH:7]1[CH2:8][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)C=C(N)C1CC1
Reactant: O=C(/C=C(\O)C(F)(F)F)c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)c1c(C(F)(F)F)cc(-c2ccc(OC(F)(F)F)cc2)nc1C1CC1

Procedure:
In analogy to the procedure described in example 18 d], 3-amino-3-cyclopropyl-acrylic acid ethyl ester (J. P. Célérier, E. Deloisy, P. Kapron, G. Lhommet, P. Maitte, Synthesis 1981, 130–133) was reacted with (Z)-4,4,4-trifluoro-3-hydroxy-1-(4-trifluoromethoxy-phenyl)-but-2-en-1-one (example 16 a]) to give the title compound as colorless oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[N:7]2.[CH2:22]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH2:13][NH:12][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:7]=1
Reactant: C=Cc1ccccc1
Reactant: COc1ccccc1CNc1ccc2c(Br)cccc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccccc1CNc1ccc2c(/C=C/c3ccccc3)cccc2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
(5-Bromo-quinolin-2-yl)-(2-methoxy-benzyl)-amine (200 mg, 0.583 mmol) was dissolved in 3 mL dimethylformamide. Styrene (79 mg, 0.760 mmol), triethylamine (77 mg, 0.760 mmol), tri-o-tolylphosphine (14 mg, 0.046 mmol) and palladium(II)acetate (5 mg, 0.022 mmol) were added. The reaction mixture was stirred in a sealed tube at 100° C. for 2 h. The reaction mixture was poured into 30 mL water and extracted three times with ethyl acetate (30 mL each). The combined organic extracts were dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->80:20 gradient). The title compound was obtained as a light yellow solid (142 mg, 67%),
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([OH:17])=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([O:17][CH2:19][C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[C:22]#[N:23])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cc(N2CCCC2)c2ccc(O)cc2n1
Reactant: N#Cc1ccccc1CBr
Product: Cc1cc(N2CCCC2)c2ccc(OCc3ccccc3C#N)cc2n1

Procedure:
In analogy to example 6 there was prepared: on reaction of 2-methyl-4-pyrrolidin-1-yl-quinolin-7-ol with 2-bromomethyl benzonitrile, whereby the product was isolated as free base, 2-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-yloxymethyl)-benzonitrile as a brown solid. ISP mass spectrum, m/e: 344.4 (M+1 calculated for C22H21N3O: 344).
Reaction SMILES: [Cl:1]OC(C)(C)C.[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:15]([NH2:17])=[O:16])=[CH:10][CH:9]=1>CO>[F:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[C:15]([NH:17][Cl:1])=[O:16])=[CH:10][CH:9]=1
Reactant: NC(=O)N(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CC(C)(C)OCl
Solvent: CO
Product: O=C(NCl)N(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
t-Butyl hypochlorite (22.8 g, 0.21 mole) was added to 1,1-di(p-fluorophenyl)urea (49.4 g, 0.2 mole) in 750 ml methanol at 0°-5° and the mixture stirred for 0.5 hour to produce a thin slurry containing step (a) title product.
Reaction SMILES: [ClH:1].[N:2]1([CH:6]2[CH2:23][CH2:22][C:9]3([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3]1>CO>[ClH:1].[ClH:1].[N:2]1([CH:6]2[CH2:7][CH2:8][C:9]3([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[CH2:22][CH2:23]2)[CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(N3CCC3)CC2)CC1
Agent: Cl
Solvent: CO
Product: C1CN(C2CCC3(CCNCC3)CC2)C1

Procedure:
Hydrogen chloride in methanol (1.25 mol/l, 15.5 ml) was added to tert-butyl 9-(azetidin-1-yl)-3-azaspiro[5.5]undecane-3-carboxylate (1 g, 3.24 mmol) and the mixture was refluxed for 45 min. The solvent was removed in vacuo and the residue was dissolved in a small amount of ethanol. A solid was then precipitated out by addition of acetone, and finally diethyl ether was added and the precipitate formed was filtered off with suction. Yield: 0.87 g (95%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:26]([C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[CH2:27].C(N(CC)CC)C.ClCCl>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:21][CH2:22][S:23][CH3:24])[NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([CH:27]=[CH:26][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(I)cc1-c1ccccc1
Reactant: C=Cc1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=Cc2cccnc2)cc1-c1ccccc1
Temperature: 100 °C
Yield: 58.5 %

Procedure:
A mixture of the (4-iodo-2-phenylbenzoyl)methionine methyl ester prepared in Example 210D (655 mg, 1.40 mmol), the vinylpyridine prepared in Example 210E (221 mg, 1.5 mmol), triethylamine (0.29 mL, 2.10 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride, complexed to dichloromethane (1:1) (114 mg, 0.14 mmol) in DMF (2 mL) was degassed with nitrogen, and heated at 100° C. for 14 hours. The reaction mixture was diluted with ether (100 mL), washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate) to give {4-[2-(pyrid-3-yl)ethenyl]-2-phenylbenzoyl}methionine methyl ester (366 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 8.75 (d, 1H), 8.51 (dd, 1H), 7.85 (dt, 1H), 7.76 (d, 1H), 7.59 (dd, 1H), 7.48 (dd, 1H), 7.44 (m, 5H), 7.31 (dd, 1H), 7.22 (d, 1H), 7.16 (d, 1H), 5.94 (br d, 1H), 4.69 (m, 1H), 3.68 (s, 3H), 2.08 (m, 2H), 2.02 (s, 3H), 1.93 (m, 1H), 1.76 (m, 1H). MS (APCI+) m/e 447 (M+H)+.
Reaction SMILES: [C:1]([O-:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].C(Cl)(=O)C1C=CC=CC=1.[C-:20]#[N:21].[Na+]>C1S(=O)(=O)CCC1>[C:1]([C:20]#[N:21])(=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: O=C(Cl)c1ccccc1
Solvent: O=S1(=O)CCCC1
Product: N#CC(=O)c1ccccc1
Reaction time: 2.5 h
Yield: 99.1 %

Procedure:
72 g (0.5 mol) of sodium benzoate were mixed with 140.6 g (1 mol) of benzoyl chloride and 80 ml of tetramethylene-sulphone and 25 g (0.5 mol) of 98% pure sodium cyanide. After a stirring time of 20 minutes, an exothermic rise in the temperature to 85° C. was observed. It was now easier to stir the mixture. The subsequent reaction time was 2.5 hours at 150°-160° C. Working up gave the following yield: 65 g (99.3% of theory) of benzoyl cyanide; melting point 34° C.