Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30](OCC)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36]([NH2:42])[C:37]1[O:41][CH:40]=[CH:39][CH:38]=1>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:35])=[C:13]([C:30]([NH:42][CH2:36][C:37]3[O:41][CH:40]=[CH:39][CH:38]=3)=[O:31])[C:14](=[O:29])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2ccc(S(C)(=O)=O)cc2)c1=O
Reactant: NCc1ccco1
Product: CS(=O)(=O)c1ccc(Cn2c(=O)c(C(=O)NCc3ccco3)c(O)c3ncc(Cc4ccccc4)cc32)cc1

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-1-[4-(methylsulfonyl)benzyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and furfurylamine employing methods similar to those described in Example 2. The product was obtained as a light beige solid: 1H NMR (CDCl3) δ 10.37 (1H, br t, J=5.5 Hz), 8.62 (1H, s), 7.81 (2H, d, J=8 Hz), 7.39 (1H, s), 7.30 (3H, m), 7.17 (2H, d, J=8 Hz), 7.06 (1H, s), 7.03 (2H, m), 6.33 (2H, m), 5.40 (2H, br), 4.66 (2H, br d, J=5.5 Hz), 4.05 (2H, s), 3.01 (3H, s); HRMS calcd for C29H25N3O6S+H+: 544.1542. Found: 544.1534.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][N:9]([CH3:23])[CH2:10][CH2:11][NH:12][C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([N:12]([CH2:11][CH2:10][N:9]([CH3:8])[CH3:23])[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(NCCN(C)C)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(N(CCN(C)C)C(C)=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (0.170 ml, 1.800 mmol) was added to methyl 4-{[2-(dimethylamino)ethyl]amino}benzoate (0.2 g, 0.900 mmol) stirred in triethylamine (0.502 ml, 3.60 mmol) and CH2Cl2 (2 ml). The mixture was stirred at room temperature for 2 h and then concentrated. The product was used without further purification. MS: cal'd 265 (MH+), exp 265 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:9]([OH:12])[CH2:10][CH3:11]>>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:12][CH2:9][CH2:10][CH3:11])[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: CCCO
Product: CCCOc1cncc(Br)c1
Reaction time: 4 h
Yield: 25 %

Procedure:
n-Propanol and 3,5-dibromopyridine were processed as described in Example 7A except that the heating time was extended to 4 hours. The reaction mixture was quenched onto ice/water, extracted with ethyl ether, and concentrated under reduced pressure. The residue was purified on silica gel (hexanes:ethyl acetate, 8:2) to provide the title compound as a colorless oil (25% yield). MS (DCI/NH3) m/z 216/218 (M+H)+.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH:23]5[CH2:26][O:25][CH2:24]5)[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[O:25]1[CH2:26][CH:23]([C:21]2[CH:22]=[C:17]([C:14]3[N:13]=[CH:12][C:11]4[CH:10]=[N:9][N:8]([C:6]5[CH:5]=[CH:4][CH:3]=[C:2]([N:27]6[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]6)[N:7]=5)[C:16]=4[CH:15]=3)[CH:18]=[N:19][CH:20]=2)[CH2:24]1
Reactant: Fc1cccc(-n2ncc3cnc(-c4cncc(C5COC5)c4)cc32)n1
Reactant: C1CNCCN1
Product: c1cc(N2CCNCC2)nc(-n2ncc3cnc(-c4cncc(C5COC5)c4)cc32)c1
Yield: 13 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 1-(6-fluoropyridin-2-yl)-6-(5-(oxetan-3-yl)pyridin-3-yl)-1H-pyrazolo[4,3-c]pyridine and piperazine, 114 was obtained as an off-white solid (14.3 mg, 13%). 1H NMR (400 MHz, DMSO) δ 9.36-9.31 (s, 1H), 9.20-9.14 (d, J=2.1 Hz, 1H), 9.10-9.05 (s, 1H), 8.70-8.62 (m, 2H), 8.57-8.52 (t, J=2.0 Hz, 1H), 7.81-7.74 (t, J=8.1 Hz, 1H), 7.28-7.22 (d, J=7.7 Hz, 1H), 6.85-6.78 (d, J=8.4 Hz, 1H), 5.08-5.00 (dd, J=8.3, 6.1 Hz, 2H), 4.77-4.70 (t, J=6.3 Hz, 2H), 4.47-4.38 (m, 1H), 3.65-3.56 (m, 4H), 2.99-2.75 (m, 4H).; MS (ESI) m/z: 414.2 [M+H]+
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[CH2:21]1>>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH2:21]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: c1ccc(C2CCNC2)nc1
Product: O=C(O)c1cn(C2CC2)c2nc(N3CCC(c4ccccn4)C3)c(F)cc2c1=O
Yield: 88 %

Procedure:
Starting from 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid (1.33 g, 4.7 mmol) and 2-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.64 g, 88%) as an off-white solid, mp 203°-204° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10]CC#N.[C:14]([OH:17])(=[O:16])[CH3:15]>>[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:15][C:14]([OH:17])=[O:16]
Reactant: N#CCCCc1ccccc1Br
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)CCCc1ccccc1Br
Temperature: 60 °C
Reaction time: 16 h

Procedure:
Methanesulfonyl chloride (7.7 mL, 97 mmol) in 100 mL dry THF is added to a solution of 3-(2-bromo-phenyl)-propan-1-ol (17.4 g, 80.9 mmol) and triethyl amine (14.7 g, 146 mmol) in 200 mL dry THF at 0° C. under an argon atmosphere. Water is added and the mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give 23 g (97%) methanesulfonic acid 3-(2-bromo-phenyl)-propyl ester as an oil. Methanesulfonic acid 3-(2-bromo-phenyl)-propyl ester (23g, 78 mmol) in 300 mL dry DMF is added to a suspension of potassium cyanide (15.3 g, 235 mmol) in dry DMF. The reaction mixture is stirred at 60° C. for 16 hours. Water is added and the mixture is extracted with ethyl acetate (3 times). The organic phase is washed with brine (twice), dried with MgSO4 and concentrated in vacuo. The residue is placed on a plug of silica gel and eluted with ethyl acetate/heptane (1:4) and concentrated in vacuo to give 16.0 g 4-(2-bromo-phenyl)-butyronitrile (91%) as an oil. 300 mL concentrated HCl is added to 4-(2-bromo-phenyl)-butyronitrile (16.0 g, 71 mmol) in 150 mL acetic acid. The reaction mixture is stirred at 60° C. for 16 hours. The reaction mixture concentrated in vacuo partly and is poured into water. The mixture is extracted with ethyl acetate (3 times). The organic phase is washed with brine (twice), dried with MgSO4 and concentrated in vacuo to give the title compound as a crystalline material.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Cl.[CH3:25][C@@H:26]1[CH2:30][CH2:29][C@@H:28]([CH3:31])[NH:27]1>>[CH3:25][C@@H:26]1[CH2:30][CH2:29][C@@H:28]([CH3:31])[N:27]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CC(C)NC(=O)c1ccc(-c2ccc(OCCCCl)cc2)cc1
Reactant: C[C@@H]1CC[C@@H](C)N1
Agent: Cl
Product: CC(C)NC(=O)c1ccc(-c2ccc(OCCCN3[C@H](C)CC[C@H]3C)cc2)cc1

Procedure:
The product from Example 1A and (2R,5R)-2,5-dimethylpyrrolidine hydrochloride were processed as described in Example 10F to provide the title compound.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[Cl:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]1[C:21](CO)=[C:20](C)[N:19]=[C:14]12>N1C=CC=CC=1>[C:5]([O:4][CH2:1][C:2]1[N:13]2[CH:12]=[CH:11][C:10]3[C:15]([C:14]2=[N:19][C:20]=1[CH3:21])=[CH:16][CH:17]=[CH:18][C:9]=3[Cl:8])(=[O:7])[CH3:6]
Reactant: Cc1nc2c3cccc(Cl)c3ccn2c1CO
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCc1c(C)nc2c3cccc(Cl)c3ccn12
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.8 %

Procedure:
Acetic anhydride (0.71 g) was added dropwise to a suspension of 7-chloro-3-hydroxymethyl-2-methylimidazo[2,1-a]isoquinoline (1.43 g) in pyridine (14 ml) and the mixture was stirred at room temperature for 24 hours. The mixture was evaporated in vacuo and the residue was extracted with chloroform after an addition of water to it. The extract was washed with water, dried over magnesium sulfate, treated with activated charcoal and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 3-acetoxymethyl-7-chloro-2-methylimidazo[2,1-a]isoquinoline (0.6 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:9]2[C@@H:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:21](O)=O.N>Cl>[NH:1]1[C:2]2[CH:3]=[C:4]([N:9]3[C@@H:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:12][O:11][C:10]3=[O:20])[CH:5]=[CH:6][C:7]=2[N:8]=[CH:21]1
Reactant: O=CO
Reactant: Nc1ccc(N2C(=O)OC[C@@H]2c2ccccc2)cc1N
Agent: Cl
Agent: N
Product: O=C1OC[C@H](c2ccccc2)N1c1ccc2nc[nH]c2c1
Temperature: 0 °C

Procedure:
The (S)-3-(3,4-diaminophenyl)-4-phenyloxazolidin-2-one was dissolved in 2.5 mL of 5N aqueous hydrochloric acid and 0.25 mL of formic acid was added to the solution. The reaction was stirred at reflux for 1 h before the reaction was cooled down to 0° C. and the reaction mixture was neutralized with buffer (pH7) and conc. ammonia. The aqueous layer was than extracted by means of 25 mL dichloromethane three times. The organic layers were combined, dried, filtered and the solvent was removed under reduced pressure. The final product was purified by means of FPLC using chloroform-methanol gradient (0→10%). The product elutes at about 5% methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[C:17]3[N:16]=2)[C:5]([O:8]C)=[N:6][CH:7]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:28].Cl>CO.O1CCOCC1>[F:1][C:2]1[CH:3]=[C:4]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]([O:26][CH3:28])=[O:25])=[C:17]3[N:16]=2)[C:5]([OH:8])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ncc(F)cc1[C@H]1CCCN1c1ccn2ncc(C(=O)O)c2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3O)nc12
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
To a suspension of (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl) pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation B; 5.01 g, 14.0 mmol) in MeOH (150 mL) was added dropwise TMSCHN2 (8.41 mL, 16.8 mmol). The reaction was stirred for 30 minutes, and then quenched with 1 mL of acetic acid. The solvent was removed under reduced pressure and the residue was dried under high vacuum to give the crude methyl ester. To the crude methyl ester was added 4N HCl in dioxane (100 mL) and the reaction was sealed and heated to 90° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM (100 mL) and washed with saturated NaHCO3 (40 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude desired product (4.67 g, 93.2% yield). MS (apci) m/z=357.9 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][CH:22]3[CH2:26][CH2:25][C:24](=[O:27])[NH:23]3)[C@H:16]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:9]([CH3:34])[C:8](=[O:35])[CH2:7][CH2:6]2.[H-].[Na+].[CH3:38]I.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][NH:14][C@H:15]1[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C@@H:22]3[CH2:26][CH2:25][C:24](=[O:27])[N:23]3[CH3:38])[C@H:16]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:9]([CH3:34])[C:8](=[O:35])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1CN[C@H]1CCCN(CC3CCC(=O)N3)[C@H]1c1ccccc1)N(C)C(=O)CC2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1CN[C@H]1CCCN(C[C@@H]3CCC(=O)N3C)[C@H]1c1ccccc1)N(C)C(=O)CC2
Reaction time: 0.33 h
Yield: 12.5 %

Procedure:
To 6-Methoxy-1-methyl-7-{[1-(5-oxo-pyrrolidin-2-ylmethyl)-(2S,3S)-2-phenyl-piperidin-3-ylamino]-methyl}-3,4-dihydro-1H-quinolin-2-one (194 mg, 0.408 mmol) in 5 mL of THF at room temperature was added 18 mg (0.448 mmol) of 60% sodium hydride suspended in mineral oil and stirred for 20 minutes. Methyl iodide (0.028 mL, 0.448 mmol) was then added and stirred for 1 hour 18 mg (0.448 mmol) of 60% sodium hydride suspended in mineral oil was added and stirred overnight. A small amount of water was added and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate, washed twice with water, dried over MgSO4, filtered, and concentrated. Silica gel chromatography using (95:5 ethyl acetate/methanol) as the eluent gave 25 mg (13%) of the title compound, a pale yellow oil. Rf=0.07 (9:1 ethyl acetate/methanol). MS (M+H)+=491.2; 1H NMR (400 MHz, CDCl3): δ 1.42–1.60 (m, 3H), 1.84–1.88 (dd, J=13.4 Hz, 4.8 Hz, 1H), 2.01–2.14 (m, 5H), 2.17–2.24 (m, 2H), 2.54–2.57 (t, J=7.3 Hz, 3H), 2.67–2.73 (m, 1H), 2.76–2.78 (t, J=7.3 Hz, 2H), 2.88 (s, 3H), 3.13 (s, 3H), 3.21–3.24 (d, J=10.9 Hz, 1H), 3.32–3.33 (d, J=3.0 Hz, 1H), 3.36–3.40 (d, J=14.3 Hz, 1H), 3.56 (s, 3H), 3.61–3.68 (m, 2H), 6.49 (s, 1H), 6.65 (s, 1H), 7.18–7.34 (m, 5H). 13C NMR (100 MHz, CDCl3): δ 20.4, 23.9, 25.5, 27.5, 29.6, 31.8, 45.4, 54.2, 55.5, 56.3, 58.0, 59.9, 72.7, 109.9, 116.0, 127.1, 128.1, 129.0, 133.6, 140.9, 152.8, 170.0, 175.0. The dihydrochloride salt was prepared by the addition of 2 M HCl In ether to a solution of the product in ethyl acetate. Concentration gave a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Cu][C:13]#[N:14].CN(C)C=O.C(OCC)(=O)C>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]#[N:14])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: N#C[Cu]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h
Yield: 63 %

Procedure:
A mixture of 7.7 g (0.040 mol) of 2,5-dichloronitrobenzene and 4.0 g (0.044 mol) of copper (I) cyanide in 4.0 ml (0.05 mol) of N,N-dimethylformamide was refluxed for 3.5 hours. The reaction mixture was poured slowly into 39 ml (0.40 mol) of ethyl acetate and followed by stirring for 10 hours at room temperature. The precipitate was filtered and washed with 3 ml of ethyl acetate. After concentration of the combined filtrate, the residue gave 4.6 g (63.0%) of 4-chloro-2-nitrobenzonitrile purified by the procedure of Example 1.
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:31][C:32]1[CH:37]=[C:36]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][C:2]([F:1])([F:30])[CH2:3][CH2:4]2)=[O:9])[CH:35]=[CH:34][N:33]=1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 20 %

Procedure:
The title compound was synthesized in analogy to example 66, from (4,4-difluoro-piperidin-1-yl)-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-methanone (example 32), 2-chloropyridine-4-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a light yellow foam (20%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-])=O)=[CH:4][CH:3]=1.[NH4+].[OH-:14]>O>[NH2:10][C:5]1[C:6]([C:8]([NH2:9])=[O:14])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: [OH-]
Agent: [NH4+]
Solvent: O
Product: NC(=O)c1nc(Cl)ccc1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 70.5 %

Procedure:
To a suspension of 6-chloro-3-nitropicolinonitrile (2.54 g, 13.8 mmol) in water (27.0 mL) was added NH4OH (5.61 mL, 36.0 mmol) at room temperature. After stirring for 20 min at room temperature, Na2S204 (13.7 g, 79.0 mmol) was added to the mixture. After stirring for 3 hours at room temperature, the reaction mixture was filtered, and washed with water. The filtercake was dried under vacuum to give 3-amino-6-chloropicolinamide (1.67 g, 70%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 5.36 (1H, brs), 6.00 (2H, brs), 7.00 (1H, d, J=8.8 Hz), 7.18 (1H, d, J=8.8 Hz), 7.63 (1H, brs).
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: CC(C)(C)C([O-])([O-])[O-]
Reactant: Cc1ccc(C(=O)NN)cc1-c1ccc2c(c1)NC(=O)C21CCCC1
Solvent: O
Solvent: CC(=O)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: [CH:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[C:14]([C:19]#[N:20])=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:2].[N-:21]=[N+:22]=[N-:23].[Na+].O>ClC1C=CC=CC=1>[N:20]1[NH:21][N:22]=[N:23][C:19]=1[C:14]1[C:13]([CH2:12][O:11][C:4]2[C:3]([CH:1]=[O:2])=[CH:8][C:7]([O:9][CH3:10])=[N:6][CH:5]=2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C=O)c(OCc2cccnc2C#N)cn1
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: O
Product: COc1cc(C=O)c(OCc2cccnc2-c2nn[nH]n2)cn1
Temperature: 110 °C

Procedure:
To TEA hydrochloride salt (123 mg, 0.89 mmol, 4 equiv.) and 3-((4-formyl-6-methoxypyridin-3-yloxy)methyl)picolinonitrile (70 mg, 0.26 mmol, 1 equiv.) in chlorobenzene (5.0 mL) was added NaN3 (48 mg, 0.89 mmol, 4 equiv.) at rt. The mixture was heated to 110° C. for 2 h, cooled to rt, and added water (5.0 mL). The precipitate was filtered and washed with EtOAc and water and dried under high vacuo to give 5-((2-(2H-tetrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxyisonicotinaldehyde as a white solid. 1H NMR (400 MHz; DMSO) δ=10.23 (s, 1H), 8.61 (d, 1H), 8.16 (s, 1H), 8.10 (d, 1H), 7.38 (dd, 1H), 6.96 (s, 1H) 5.73 (s, 2H), 3.83 (s, 3H). LRMS (M+H+) m/z 313.0.
Reaction SMILES: [C:1]([C@@:3]1([CH2:31][CH3:32])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[N:17][N:18]([C:20]([CH3:29])([CH3:28])[C:21]([O:23]C(C)(C)C)=[O:22])[CH:19]=3)[N:9]=2)[C:4]1=[O:30])#[N:2].[ClH:33]>C(OCC)(=O)C>[ClH:33].[C:1]([C@@:3]1([CH2:31][CH3:32])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[N:17][N:18]([C:20]([CH3:28])([CH3:29])[C:21]([OH:23])=[O:22])[CH:19]=3)[N:9]=2)[C:4]1=[O:30])#[N:2]
Reactant: CC[C@]1(C#N)CCN(c2ccnc(Nc3cnn(C(C)(C)C(=O)OC(C)(C)C)c3)n2)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@]1(C#N)CCN(c2ccnc(Nc3cnn(C(C)(C)C(=O)O)c3)n2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 2-(4-((4-((3R)-3-cyano-3-ethyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-2-methylpropanoate (1.0 g) obtained in Step A of Example 199 in ethyl acetate (10 mL) was added a solution of 4 M hydrogen chloride in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the residue was recrystallized (ethanol/diisopropyl ether) to give the crude title compound (820 mg). The crude title compound (100 mg) was purified by HPLC (C18, mobile phase: water/acetonitrile (containing 10 mM NH4HCO3)), and the solvent was evaporated under reduced pressure. To a solution of the residue in ethanol (3 mL) was added 1 M hydrochloric acid (0.20 mL), and the mixture was stirred at room temperature for 10 min. The solvent was evaporated under reduced pressure, and the residue was recrystallized (ethanol/diisopropyl ether) to give the title compound (820 mg).
Reaction SMILES: [C:1](#N)C.C1OCCOCCOCCOCCOCCOC1.CI.[OH:24][C:25]1[CH:34]=[C:33]([O:35][CH:36]([CH2:38][CH3:39])[CH3:37])[CH:32]=[C:31]2[C:26]=1[C:27](=[O:42])[CH2:28][C:29]([CH3:41])([CH3:40])[O:30]2>[Na]>[CH3:1][O:24][C:25]1[CH:34]=[C:33]([O:35][CH:36]([CH2:38][CH3:39])[CH3:37])[CH:32]=[C:31]2[C:26]=1[C:27](=[O:42])[CH2:28][C:29]([CH3:40])([CH3:41])[O:30]2
Reactant: CCC(C)Oc1cc(O)c2c(c1)OC(C)(C)CC2=O
Reactant: CC#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na]
Solvent: CI
Product: CCC(C)Oc1cc(OC)c2c(c1)OC(C)(C)CC2=O
Reaction time: 3 h
Yield: 92 %

Procedure:
In 100 ml of acetonitrile 5.6 g (20 millimoles) of the sodium salt of 5-hydroxy-7-sec. butoxy-2,2-dimethyl-4-chromanone are dissolved and stirred in the presence of 0.5 g (2 millimoles) of 18-Crown-6 for 30 minutes. Thereafter 4.25 g (1.9 ml, 30 millimoles) of methyl iodide are added and the reaction mixture is stirred for a further 3 hours. The inorganic salt is filtered off, the solvent removed and the residue suspended in carbon tetrachloride, extracted twice with 30 ml of water each, the organic phase is dried over sodium sulfate and evaporated. Thus 5.1 g of the desired compound are obtained in the form of a light yellow oil, yield 92%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27].[NH4+].[Cl-]>C1COCC1.CCCCCC>[Cl:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2([C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[O:9][CH3:10])[OH:27]
Reactant: COc1cccc(OC)c1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cccc(OC)c1C1(O)C(=O)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
Under nitrogen atmosphere, to a solution of 22.8 g of 1,3-dimethoxy benzene in THF (150 ml) was added dropwise a solution of 1.59 mol/L n-butyl lithium in an n-hexane solution (104 ml) over 30 minutes under ice cooling, and the reaction mixture was stirred at room temperature for one hour. The solution was cooled by ice again, 10.0 g of 5-chloroisatin and was added, and the reaction mixture was stirred at room temperature for two hours. An aqueous solution of saturated NH4Cl was added to the solution and the resulting mixture was extracted with EtOAc; the organic layer was washed with saturated brine and dried over Na2SO4, then, the drying agent was separated by filtration and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (silicagel 60N; mobile phase: CHCl3/MeOH=50/1 to 10/1; v/v) to obtain 14.2 g of the title compound.