Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4](I)[CH:3]=1.[Li]C(CC)C.CCCCCC.C(=O)=O.[CH3:24][C:25]([CH3:27])=[O:26].B(F)(F)F>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([CH2:24][C@H:25]([OH:26])[CH3:27])[CH:3]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(F)cc1I
Agent: FB(F)F
Agent: O=C=O
Agent: [Li]C(C)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C[C@@H](C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An oven dried 3-necked round bottom flask (rbf), which contained a magnetic stirring bar, was sealed with rubber septum having a thermometer. While cooling to rt, the flask was evacuated and backfilled with argon. This sequence was repeated 3 times. In the flask, a solution of 4-fluoro-2-iodo-1-methylbenzene (25 g, 105.9 mmol) in anhydrous THF (800 mL) was stirred at −78° C. in a dry ice/acetone bath under argon gas. After 30 min, 1.4 M sec-BuLi in hexane (83.2 mL, 116.5 mmol) was added dropwise at that temperature for 20 min. After adding, the mixture was stirred at −78° C. in the dry ice/acetone bath for 30 min, and stirred more for 30 min without the bath. And then, the solution was cooled again in the dry ice/acetone to −78° C. and a solution of R-(+)-propylene (8 g, 137.7 mmol) in 50 mL anhydrous THF was added dropwise at the temperature for 10 min. And then, the mixture was cooled to −105° C. and 46.5% solution of BF3 in diethyletherate (19.6 mL) was added dropwise. And the mixture was stirred at −78° C. for 2 h, and then quenched slowly by sat. NH4Cl at −78° C. and stirred at ambient temperature for overnight. Water (20 mL) was added and extracted with EtOAc, dried over anhydrous MgSO4, evaporated and purified by column chromatography (DCM/hexane 9/1) to give (R)-1-(5-fluoro-2-methylphenyl)propan-2-ol (F-1) as pale yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:19][O:20][CH2:21][CH2:22][N:23]=[C:24]=S>>[Cl:18][C:3]1[C:2]2[N:1]=[C:24]([NH:23][CH2:22][CH2:21][O:20][CH3:19])[N:12]([CH2:13][C:14]([CH3:15])([OH:16])[CH3:17])[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1
Reactant: COCCN=C=S
Reactant: CC(C)(O)CNc1c(N)c(Cl)nc2ccccc12
Product: COCCNc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Yield: 65.7 %

Procedure:
The method described in Part A of Example 7 was used to treat 1-[(3-amino-2-chloro-4-quinolinyl)amino]-2-methyl-2-propanol (3.00 g, 11.3 mmol) with 2-methoxyethyl isothiocyanate (1.59 g, 13.6 mmol) to provide 2.59 g of 1-{4-chloro-2-[(2-methoxyethyl)amino]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol after chromatographic purification.
Reaction SMILES: CON(C)[C:4]([C@@H:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][C@@H:7]1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:5].[CH3:27][Mg]Br.C[O-].[Na+]>CO>[CH2:12]([N:9]1[CH2:10][CH2:11][C@H:6]([C:4](=[O:5])[CH3:27])[C@@H:7]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)[C@@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of 1-[(3SR,4SR)-1-benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanone (example 5 (c)) the title compound was prepared from (3S,4R)-1-benzyl-3-(4-chloro-phenyl)-piperidine-4-carboxylic acid methoxy-methyl-amide and methylmagnesium bromide with subsequent epimerisation with NaOMe in methanol. The title compound was obtained as off-white solid. MS (m/e): 328.2 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]12[CH2:9][CH:8]3[CH2:10][C:4]([N:11]4[CH2:15][CH2:14][CH2:13][C:12]4=[O:16])([CH2:5][CH:6]1[CH2:7]3)[CH2:3]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]([N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[C:32]#[N:33])=[O:26]>CS(C)=O.CCOC(C)=O>[O:16]=[C:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:4]12[CH2:10][CH:8]3[CH2:9][C:2]([NH:1][CH2:24][C:25]([N:27]4[CH2:31][CH2:30][CH2:29][C@H:28]4[C:32]#[N:33])=[O:26])([CH2:3]1)[CH:6]([CH2:7]3)[CH2:5]2
Reactant: NC12CC3CC1CC(N1CCCC1=O)(C3)C2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC1CC(N1CCCC1=O)(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a stirred mixture of 1-(3-aminotricyclo[3.3.1.03,7]non-1-yl)pyrrolidin-2-one prepared as in preparation 9 (0.25 g, 1.1 mmol) and K2CO3 (0.46 g, 3.3 mmol) in DMSO (5 mL) at an ice bath temperature was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.2 g, 1.1 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-{N-[2-(2-oxopyrrolidin-1-yl)hexahydro-2,5-methanopentalen-3a(1H)-yl]glycyl}pyrrolidine-2-carbonitrile as a viscous liquid (0.16 g) in 40% yield. m/z (M+1) 357; 1H NMR (CDCl3) 300 MHz δ 4.78 (d, J=7.4 Hz, 1H), 3.70-3.38 (m, 2H), 3.46 (s, 2H), 3.41 (t, J=7.0 Hz, 2H), 2.60 (dd, J=4.0, 10.2 Hz, 1H), 2.40-1.75 (m, 17H), 1.72-1.62 (m, 1H), 1.58-1.50 (m, 1H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@@H:4]1[F:36].[C:37](Cl)(=[O:39])[CH3:38]>>[C:37]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@@H:4]1[F:36])(=[O:39])[CH3:38]
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@@H](F)C1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@@H]1F

Procedure:
Starting from N-[(1S*,3S*,4S*)-4-amino-3-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f62) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1NC(C1C(N2N=CC=N2)=CC=CN=1)=O.[CH3:32][C@:33]1([NH:39][C:40]2[CH:45]=[N:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=2)[CH2:37][CH2:36][CH2:35][C@@H:34]1[NH2:38].[F:50][C:51]1[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:52]=1[C:53](O)=[O:54]>>[F:50][C:51]1[CH:59]=[CH:58][CH:57]=[C:56]([F:60])[C:52]=1[C:53]([NH:38][C@H:34]1[CH2:35][CH2:36][CH2:37][C@:33]1([CH3:32])[NH:39][C:40]1[CH:45]=[N:44][C:43]([C:46]([F:49])([F:47])[F:48])=[CH:42][N:41]=1)=[O:54]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1c(F)cccc1F

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 63 mg, 0.24 mmol) and 2,6-difluorobenzoic acid (CAS number 385-00-2; 46 mg, 0.29 mmol) except this was purified by column chromatography (silica, 0-20% ethyl acetate/petrol) followed by reverse phase chromatography (C18 silica, 0-100% water (with 0.05% ammonia)/acetonitrile) to afford the title compound.
Reaction SMILES: [S:1]([Cl:5])(=[O:4])(=[O:3])[OH:2].[F:6][C:7]([F:13])=[CH:8][C:9]([F:12])([F:11])[F:10]>>[C:9]([CH2:8][C:7]([O:3][S:1]([Cl:5])(=[O:2])=[O:4])([F:13])[F:6])([F:12])([F:11])[F:10]
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)=CC(F)(F)F
Product: O=S(=O)(Cl)OC(F)(F)CC(F)(F)F
Reaction time: 24 h
Yield: 72.7 %

Procedure:
A 250 mL Hastelloy shaker tube was loaded with 60 g (0.51 mole) chlorosulfuric acid (HOSO2Cl), cooled in liquid nitrogen, evacuated and loaded with 60 g (0.45 mole) of 1,1,3,3,3-pentafluoropropene. The reaction vessel was allowed to warm and kept on a shaker at 20° C. at autogenous pressure for 24 hours. After 24 hours, the pressure tube was unloaded, and the reaction mixture quenched by ice and the organic layer washed with 5% sodium bicarbonate, water and dried under MgSO4. After distillation, 81.3 g of CF3CH2CF2OSO2Cl was obtained containing 6% of CF3CH2CF2OSO2F.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)O[C:2]2=[O:3].[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>CN(C=O)C>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:13][NH:14][C:15]([NH2:17])=[S:16])=[O:3]
Reactant: NNC(N)=S
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: CN(C)C=O
Product: NC(=S)NNC(=O)c1ccccc1N
Temperature: 70 °C
Reaction time: 20 h
Yield: 46.6 %

Procedure:
Isatoic anhydride (4.9 g) and thiosemicarbazide (2.8 g) were dissolved in 30 ml of DMF and the resulting mixture was stirred 20 h at 60 to 80° C. The solvent was removed under reduced pressure and the residue was recrystallized from methanol and ethanol to give 2.94 g of 1-(2-aminobenzoyl)thiosemicarbazide.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:20](=[O:22])[CH3:21])[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:11][CH:12]=2)[O:7][C:6](=[O:23])[CH:5]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([O:36][CH3:37])[C:33]=1[O:34][CH3:35])[CH:29]=O>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:20](=[O:22])[CH:21]=[CH:29][C:28]3[CH:31]=[C:32]([O:36][CH3:37])[C:33]([O:34][CH3:35])=[C:26]([O:25][CH3:24])[CH:27]=3)[C:10]([O:14][CH2:15][CH:16]=[C:17]([CH3:18])[CH3:19])=[CH:11][CH:12]=2)[O:7][C:6](=[O:23])[CH:5]=1
Reactant: CC(=O)c1c(OCC=C(C)C)ccc2c(C)cc(=O)oc12
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C=CC(=O)c2c(OCC=C(C)C)ccc3c(C)cc(=O)oc23)cc(OC)c1OC
Temperature: 25 °C
Yield: 37.3 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-(3-methylbut-2-enyloxy)-8-acetylcoumarin (2.14 g, 0.0075 mol) and 3,4,5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.3 g of product m.p. 148-150° C., 1H-NMR (CDCl3) δ: 1.69 (s, 3H,); 1.72 (s, 3H); 2.44 (d, 3H, J=1.2 Hz); 3.74-3.88 (m, 9H); 4.65 (d, 2H, J=6.5 Hz); 5.34-5.38 (m, 1H); 6.16 (s, 1H); 6.93 (d, 1H, J=16 Hz); 6.95 (d, 1H, J=8.9 Hz); 7.25 (d, 1H, J=16 Hz); 7.63 (d, 1H, J=8.9 Hz).
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[CH:5][S:4][C:3]=1[CH:8]=[O:9].[CH3:10][C:11]1[CH:12]=[C:13]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:14]=[CH:15][C:16]=1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[Br:7][C:6]1[C:2]([C:16]2[CH:15]=[CH:14][C:13]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])=[CH:12][C:11]=2[CH3:10])=[C:3]([CH:8]=[O:9])[S:4][CH:5]=1
Reactant: O=Cc1scc(Br)c1Br
Reactant: Cc1cc(NS(C)(=O)=O)ccc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(NS(C)(=O)=O)ccc1-c1c(Br)csc1C=O
Temperature: 100 °C
Yield: 323.9 %

Procedure:
To the solution of Intermediate 1 (4 g, 15 mmol) in a mixture of DME and H2O (150 mL/50 mL) were added N-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (3.6 g, 1.65 mmol) and Na2CO3 (2.8 g, 3.1 mmol), the mixture was degassed with N2, and Pd(PPh3)4 (500 mg) was added, then the mixture was heated to 100° C. under N2 overnight. The reaction solution was concentrated to remove the organic solution, then the aqueous layer was extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated under reduced pressure, the residue was purified by column chromatography to give N-(4-(4-bromo-2-formylthiophen-3-yl)-3-methylphenyl)methanesulfonamide (2.0 g, yield 35.7%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][C@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[CH:6]=1.[C:34](Cl)(=[O:36])[CH3:35]>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:14][C:13]=2[CH2:22][N:23]([C:34](=[O:36])[CH3:35])[C@H:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26][CH2:25]2)[CH:6]=1
Reactant: CC(=O)Cl
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN[C@@H]2CCc3ccccc32)c1
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN(C(C)=O)[C@@H]2CCc3ccccc32)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: {3-[2-((R)-indan-1-ylaminomethyl)-4-trifluoromethyl-phenoxy]-phenyl}-acetic acid methyl ester and acetyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]=[CH:10][N+:11]([O-:13])=[O:12])[C:4]=1[OH:14].[C:15]([O-])(=[O:17])[CH3:16].[Na+]>C(OC(=O)C)(=O)C.C(O)C>[C:15]([O:14][C:4]1[C:5]([CH:9]=[CH:10][N+:11]([O-:13])=[O:12])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])(=[O:17])[CH3:16]
Reactant: COc1cccc(C=C[N+](=O)[O-])c1O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: COc1cccc(C=C[N+](=O)[O-])c1OC(C)=O
Temperature: 0 °C

Procedure:
A mixture of 2-methoxy-6-(2-nitrovinyl)phenol (29.0 grams, 0.15 mole) and sodium acetate (12.4 grams, 0.15 mole) in acetic anhydride (100 ml.) was refluxed for four hours and then poured into ice water. The resulting semi-solid precipitate was dissolved in hot 95% ethanol. Cooling the solution precipitated the crude product which was purified for analysis by chromatography on silica gel with methylene chloride as elutant. The purified 2-methoxy-6-(2-nitrovinyl)phenyl acetate melted at 128° C.-129° C.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([C:4](=[O:15])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:3].[I-].[CH3:18][S+](C)C>O1CCCC1>[CH3:3][C:2]([C:4]1([CH2:5][CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:18][O:15]1)([CH3:16])[CH3:1]
Reactant: C[S+](C)C
Reactant: CC(C)(C)C(=O)CCCOc1ccccc1
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)(C)C1(CCCOc2ccccc2)CO1
Yield: 81.2 %

Procedure:
9 g (41 mMol) of 2,2-dimethyl-6-phenoxy-hexan-3-one are added dropwise to a mixture of 5.5 g (49 mMol) of potassium tert.-butylate in 40 ml of tetrahydrofuran at room temperature, with stirring, whereupon a clear yellowish solution forms. 12.5 g (61.5 mMol) of trimethylsulphonium iodide are then added and the mixture is stirred at 20° to 25° C. for 12 hours. Thereafter, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue which remains is taken up in methylene chloride and the resulting solution is washed three times with water. After the organic phase has been dried, the solvent is stripped off. 7.8 g (81% of theory) of 2-(1,1-dimethyl-ethyl)-2-(3-phenoxypropyl)-oxirane are obtained in this manner in the form of a liquid of refractive index nD20 =1.503. ##STR13##
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)=O.[CH3:12][NH:13][CH3:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:12][N:13]([CH2:1][C:3]1[N:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=1)[CH3:14]
Reactant: CNC
Reactant: O=Cc1cccc(C(=O)O)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)Cc1cccc(C(=O)O)n1
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of 6-formyl-2-pyridinecarboxylic acid (available from Chemstep Product List, 250 mg, 1.65 mmol) in dichloromethane (4.6 ml) was added dimethylamine (2M solution in THF, 2.17 ml, 4.34 mmol) and acetic acid (0.083 ml). The mixture was stirred at room temperature for 15 mins when sodium triacetoxyborohydride (459 mg, 2.17 mmol) was added and the mixture stirred overnight. The reaction mixture was quenched by the addition of a few drops of methanol. The mixture was loaded onto an aminopropyl-SPE cartridge (5 g) pre-eluted with dichloromethane, which was eluted with dichloromethane followed by methanol. Fractions containing product were combined and dried under vacuum. The crude product was taken up in sodium hydroxide solution (2M, 25 ml) and washed with dichloromethane (2×25 ml). The aqueous layer was acidified to pH7 using hydrochloric acid (5M) and concentrated under vacuum to approximately 25 ml. The solution was loaded onto an Oasis cartridge (6 g), which had been pre-eluted with methanol (1 volume) followed by water (1 volume). The cartridge was eluted with water (1 volume) followed by methanol. Fractions containing product were combined and dried to give the title compound (85 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][C:3]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1.[CH3:26][C:27](C)(C)C([O-])([O-])[O-].O>C(O)(=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[O:7][C:26]([CH3:27])=[N:9][N:8]=2)=[CH:4][C:3]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[C:17](=[O:21])[NH:18]2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(C(=O)NN)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc4c(c3)NC(=O)C43CCCC3)c2)o1
Temperature: 150 °C
Reaction time: 3 h
Yield: 34.8 %

Procedure:
A stirred mixture of 4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzohydrazide (preparation 53, 0.05 g, 0.16 mmol) and trimethylorthoacetate (0.04 mL, 0.19 mmol) in acetic acid (1 mL) were heated to 150° C. in a sealed tube. After 3 hours, the mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4) and evaporated in vacuo. Purification of the residue by flash chromatography (1:1 hexanes/ethyl acetate) gave the title compound (0.02 g, 35%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])[N:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]2[C:10](=[O:19])[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]2=[O:18])[N:3]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(CN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
The compound 21-4 (200 mg) prepared in Step 4 was dissolved in dichloromethane (10 ml) and to the solution were added triethylamine (130 μl) and methanesulfonyl chloride (67 g), followed by stirring at room temperature for 24 hours. The resulting mixture was extracted with water and dichloromethane, dried, concentrated under reduced pressure, and then crystallized (dichloromethane/petroleum ether) to yield the compound 21-5 (260 mg, 99%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8](=[O:26])[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[C:10]([CH3:17])[NH:11]2.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[C:40](OC(=O)C)([F:42])[F:41]>O>[CH3:1][O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:26][CH:40]([F:42])[F:41])=[C:9]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:10]([CH3:17])=[N:11]2
Reactant: COC(=O)COc1ccc(F)c2[nH]c(C)c(Cc3ccc(Cl)cc3)c(=O)c12
Reactant: CC(=O)OC(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(F)c2nc(C)c(Cc3ccc(Cl)cc3)c(OC(F)F)c12
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of [3-(4-chlorobenzyl)-8-fluoro-2-methyl-4-oxo-1,4-dihydroquinolin-5-yloxy]acetic acid methyl ester (0.29 g), N,N-dimethylformamide (10 mL), potassium carbonate (0.62 g) and acetic acid chlorodifluoromethyl ester (0.31 mL) was stirred at 70° C. for 17 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent removed under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (4:1 by volume) gave title compound, 0.18 g.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.O.C(N=C=NCCCN(C)C)C.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][NH2:50])[CH:44]=1>CN(C=O)C>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:50][CH2:49][C:45]3[CH:44]=[N:43][CH:48]=[CH:47][CH:46]=3)=[O:18])=[CH:19][CH:20]=2)=[N:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: O=C(O)c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1cccnc1)c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Yield: 82.3 %

Procedure:
A solution of 4-(5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamino)-benzoic acid (0.230 g, 0.69 mmol), 3-hydroxybenzotriazole (0.103 g, 0.76 mmol), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrate (0.146 g, 0.76 mmol) in DMF (5 mL) and 3-picolylamine (0.077 mL, 0.76 mmol) is stirred at room temperature for 21 hours. The solvent is removed in vacuo and the residue is triturated with diethyl ether, ethyl acetate and dichloromethane. A pale yellow solid is obtained, washed with water and dried to afford the title compound (241 mg, 82%).
Reaction SMILES: [Br:1]Br.[CH3:3][Si:4]([C:7]#[C:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:18])[CH2:16][CH3:17])=[CH:11][CH:10]=1)([CH3:6])[CH3:5]>O1CCCC1.O>[Br:1][CH:16]([CH3:17])[C:15]([C:12]1[CH:11]=[CH:10][C:9]([C:8]#[C:7][Si:4]([CH3:5])([CH3:6])[CH3:3])=[CH:14][CH:13]=1)=[O:18]
Reactant: CCC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Reactant: BrBr
Solvent: C1CCOC1
Solvent: O
Product: CC(Br)C(=O)c1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Bromine (8.4 g) is slowly added to 1-(4-trimethylsilanylethynylphenyl)propan-1-one (10.0 g) in 100 ml of tetrahydrofuran at 0° C. and subsequently stirred at room temperature for 2 h. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic layer is washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The remainder is purified by chromatography on silica gel, using a mixture of heptane/ethyl acetate 19:1 as eluent to obtain 2-bromo-1-(4-trimethylsilanylethynylphenyl)propan-1-one as a yellow solid.