Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8]2>C(O)C(C)C>[CH2:6]([O:13][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1])=[O:14])[CH:7]([CH3:11])[CH3:8]
Reactant: COc1cccc2cc(C(=O)O)[nH]c12
Solvent: CC(C)CO
Product: COc1cccc2cc(C(=O)OCC(C)C)[nH]c12
Yield: 119.8 %

Procedure:
Under the conditions of Example 8(A), 8 g of 7-methoxyindole-2-carboxylic acid is converted into the acid chloride and the latter is reacted with isobutanol. After working up of the reaction product and recrystallization from petroleum ether, 6.2 g of 7-methoxyindole-2-carboxylic acid isobutyl ester is obtained, mp 100°-101° C.
Reaction SMILES: [Na].C[Si](C)(C)N[Si](C)(C)C.[NH2:11][C:12]1[C:20]2[O:19][CH:18]=[CH:17][C:16]=2[CH:15]=[CH:14][C:13]=1[Cl:21].Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1.Cl>CN(C=O)C.C(Cl)Cl.C(O)(C)C.C(OCC)C>[Cl:21][C:13]1[CH:14]=[CH:15][C:16]2[CH:17]=[CH:18][O:19][C:20]=2[C:12]=1[NH:11][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][CH2:38][N:39]3[CH2:40][CH2:41][O:42][CH2:43][CH2:44]3)=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Reactant: Nc1c(Cl)ccc2ccoc12
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(C)O
Solvent: CCOCC
Product: COc1cc2c(Nc3c(Cl)ccc4ccoc34)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
The sodium salt of 1,1,1,3,3,3-hexamethyldisilazane (1M solution in THF; 0.592 ml) was added to a solution of 7-amino-6-chlorobenzofuran (0.099 g) in DMF (5 ml) and the reaction mixture was stirred at ambient temperature for 30 minutes. 4-Chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (0.1 g) was added and the resultant mixture was stirred at ambient temperature for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed in turn with water and brine, dried over magnesium sulphate and evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride and methanol as eluent. The material so obtained was dissolved in methylene chloride and a 5M solution of hydrogen chloride gas in isopropanol (0.088 ml) was added. Diethyl ether was added and the precipitate was isolated and dried under vacuum. There was thus obtained the title compound (0.118 g) as a dihydrochloride salt; NMR Spectrum: (DMSOd6 and CF3CO2D) 2.35 (m, 2H), 3.15 (m, 2H), 3.35 (m, 2H), 3.55 (d, 2H), 3.75 (t, 2H), 4.0 (m, 2H), 4.05 (s, 3H), 4.35 (t, 2H), 7.15 (d, 1H), 7.45 (s, 1H), 7.55 (d, 1H), 7.8 (d, 1H), 8.1 (d, 1H), 8.25 (s, 1H), 8.8 (s, 1H); Mass Spectrum: M+H+ 469.
Reaction SMILES: C(O)C.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:11]([O:18][NH2:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O>[CH2:11]([O:18][N:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NOCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: C(=NOCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 112.9 %

Procedure:
To a mixture of ethanol (100 mL), potassium carbonate (8.98 g, 65 mmol), and O-benzylhydroxylamine hydrochloride (10.0 g, 62.7 mmol) was added benzaldehvde (6.65 g, 62.7 mmol). The mixture was refluxed for 5 hours, allowed to cool to room temperature, and diluted with water (500 mL). The aqueous solution was extracted with ethyl acetate (500 mL). The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated by rotary evaporation to give the title compound as a yellow oil (14.96 g, 119%).
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH2:15][OH:16])[CH:12]=[CH:13][CH:14]=2)[O:8][CH2:7][CH2:6][O:5]1.CCN(CC)CC.[S:24](Cl)([CH3:27])(=[O:26])=[O:25]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:3][C:4]1([C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[CH2:15][O:16][S:24]([CH3:27])(=[O:26])=[O:25])[O:5][CH2:6][CH2:7][O:8]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(c2cccc(CO)c2)OCCO1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(c2cccc(COS(C)(=O)=O)c2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [3-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-methanol (786 mg, 4.05 mmol) in dry CH2Cl2 (10.0 mL) was treated at 0° C. with Et3N (0.75 mL, 5.33 mmol) followed by DMAP (49 mg, 0.41 mmol) and Ms-Cl (0.40 mL, 5.15 mmol). After stirring at 0° C. for 1 h, the reaction mixture was quenched with water (10 mL), extracted with CH2Cl2 (10 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (80:20 to 20:10 hept-EA) gave the title compound as a white solid. LC-MS-conditions 02: tR=0.91 min.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:13])/[CH:9]=[C:10](\Cl)/[CH3:11])(=[O:3])[CH3:2].[CH3:17][O-:18].[Na+]>CO>[C:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:13])/[CH:9]=[C:10](\[O:18][CH3:17])/[CH3:11])(=[O:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(=O)c1cccc(NC(=O)/C=C(/C)Cl)c1
Agent: [Na+]
Solvent: CO
Product: CO/C(C)=C\C(=O)Nc1cccc(C(C)=O)c1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A mixture of 400 ml of methanol, 41 g of m-acetyl-3-chlorocrotonanilide and 9.4 g of sodium methylate was stirred at 20° C for 72 hours and the mixture was vacuum filtered to recover the sodium chloride formed and the desired product. The solid was dissolved in refluxing acetone and the mixture was filtered. The filtrate was evaporated to dryness under reduced pressure. The waste waters were evaporated to dryness and the residue was taken up in 200 ml of a 7-3 benzene-ethyl acetate mixture. The mixture was vacuum filtered and the solid was dissolved in refluxing acetone. The solution was filtered and the filtrate was evaporated to dryness for a total yield of 19.5 g of m-acetyl-3-methoxy-crotonanilide melting at 168° C.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][C:44]([OH:46])=O>>[NH:42]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:43][C:44]([NH:1][C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:21]([NH:23][CH2:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:46]
Reactant: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: CC(C)[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Yield: 98.6 %

Procedure:
III (8.0 g, 14 mmol) was deblocked as described for II and coupled with Boc-Gly-OH by the excess mixed anhydride method and worked up as described under III to obtain the title compound in 98.6% yield, Rf2 0.75. Anal. Calcd. for C32H43N5O8 : C 61.42, H 6.92, N 11.19%. Found: C 61.12, H 7.21, N 11.19%.
Reaction SMILES: COC1C=C(C=C(OC)C=1OC)[CH2:6][O:7][C:8](=[O:13])/[CH:9]=C(\N)/C.COC1C=C(C=C(OC)C=1OC)COC(C1[CH:31]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[N+:48]([O-:50])=[O:49])[C:32]([C:38]([O:40]C)=O)=C(C)NC=1C)=O>C(O)C>[CH3:6][O:7][C:8]([CH2:9][C:38](/[CH:32]=[CH:31]/[C:42]1[C:43]([N+:48]([O-:50])=[O:49])=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:40])=[O:13]
Reactant: COc1cc(COC(=O)/C=C(/C)N)cc(OC)c1OC
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2cc(OC)c(OC)c(OC)c2)C1c1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: COC(=O)CC(=O)/C=C/c1ccccc1[N+](=O)[O-]
Yield: 78 %

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-nitrobenzylideneacetoacetic acid methyl ester and 75 ml of β-aminocrotonic acid 3,4,5-trimethoxybenzyl ester in 120 ml of ethanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3,4,5-trimethoxybenzyl ester of melting point 125° C (from ethanol).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:26]([CH3:28])[CH3:27])=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)=[CH:12][C:11]([Cl:25])=[CH:10][CH:9]=2)=[O:4].[I-].[Li+]>N1C=CC=CC=1>[Cl:25][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6]([CH:26]([CH3:28])[CH3:27])[C:5]([C:3]([OH:4])=[O:2])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:22])[F:24])[CH:16]=1
Reactant: COC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1-c1cccc(C(F)(F)F)c1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CC(C)c1nc2ccc(Cl)cc2c(-c2cccc(C(F)(F)F)c2)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 20 step D from 6-chloro-2-isopropyl-4-(3-trifluoromethyl-phenyl)-quinoline-3-carboxylic acid methyl ester (50 mg, 0.12 mmol) and lithium iodide in pyridine. Off-white solid (19 mg, 39.35%). LC-MS: 392 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[N:15]([CH2:16][CH3:17])[CH:14]=[N:13][CH:12]=3)[S:10][C:3]=12.[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1[OH:28].C(=O)([O-])[O-].[K+].[K+].CO.C(Cl)Cl>O(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([N:15]1[C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:28][C:20]3[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=3[F:18])[CH:8]=2)=[CH:12][N:13]=[CH:14]1)[CH3:17]
Reactant: CCn1cncc1-c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCn1cncc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Temperature: 195 °C
Yield: 52.3 %

Procedure:
To a solution of 118 (4 g, 15.16 mmol) in Ph2O (60 ml) was added 2-fluoro-4-nitrophenol (4.76 g, 30.33 mmol) and potassium carbonate (8.38 g, 60.66 mmol). The reaction mixture was heated to 195° C. for 18 hrs the cooled to room temperature. The residue was purified by column chromatography (eluents EtOAc/Hex (9/1 to 5/5) then MeOH/CH2Cl2 (98/2)), to afford title compound 119 (3.05 g, 52% yield) as a yellow solid. MS (m/z): 385.0 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.F[C:11]1([CH:19]=[CH:18][N:17]=[CH:16][CH2:15]1)[C:12]([OH:14])=[O:13]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][C:11]=2[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(O)C1(F)C=CN=CC1
Product: O=C(O)c1ccncc1NCc1ccc(F)cc1
Yield: 55 %

Procedure:
The title compound was prepared in 55% yield from 4-fluorobenzylamine and 4-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. NMR (500 MHz, DMSO-d6): δ 13.45 (br s, 1H), 8.11 (s, 1H), 8.03 (br s, 1H), 7.83 (d, 1H, J=5.0 Hz), 7.58 (d, 1H, J=5.0 Hz), 7.36-7.42 (m, 1H), 7.16-7.23 (m, 2H), 7.05-7.11 (m, 1H), 4.60 (s, 2H). [M+H] calc'd for C13H11FN2O2, 247; found 247.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[F:10][C:11]([F:25])([F:24])[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH:21]([CH3:23])[CH3:22])[C:19]#[N:20])=[CH:14][CH:13]=1.Br[CH2:27][CH2:28][CH2:29][Cl:30]>C1(C)C=CC=CC=1.O1CCCC1>[F:10][C:11]([F:24])([F:25])[C:12]1[CH:13]=[CH:14][C:15]([C:18]([CH:21]([CH3:23])[CH3:22])([CH2:27][CH2:28][CH2:29][Cl:30])[C:19]#[N:20])=[CH:16][CH:17]=1
Reactant: ClCCCBr
Reactant: CC(C)C(C#N)c1ccc(C(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)C(C#N)(CCCCl)c1ccc(C(F)(F)F)cc1
Yield: 89.2 %

Procedure:
To a solution consisting of a 0.5M solution of bis(trimethylsilyl)amide in toluene (2.2 mL, (1.1 mmoles) and tetrahydrofuran (7.8 mL) stirring at -78° under an argon atmosphere was added dropwise a solution of the compound of Example 7, Step (a) (227 g, 1.00 mmole) in tetrahydrofuran (1.0 mL). After stirring for 1.0 hour at -78°, 3-bromo-1-chloropropane (236 mg 1.50 mmoles) was added in one portion, and the resulting mixture was stirred for 30 minutes at -78° and then 2.0 hours at room temperature. The mixture was partitioned between diethyl ether and water, the aqueous layer was extracted with ether, and the combined organic extracts were washed with water and then brine. After drying over sodium sulfate, the solution was filtered and then evaporated. A compound (271 mg) was obtained as a red oil which was characterized by NMR as follows: 1H NMR(CDCl3) d 7.65 (d, 2H), 7.53 (d, 2H), 3.48 (m, 2H), 1.19 (d, 3H), 0.79 (d, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([O:10]C)=O.[CH3:22][NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([N:23]([CH2:2][C:3]2[O:4][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:6][C:7]=2[CH2:8][OH:10])[CH3:22])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CNC1CCCCC1
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CBr
Product: CN(Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1CO)C1CCCCC1

Procedure:
Prepared using intermediate 44 and N-methylcyclohexylamine.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.Cl.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1)[CH:10]=3
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: ClCc1ccncc1
Agent: Cl
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCc4ccncc4)cc13)Sc1ccc(Br)cc1-2
Yield: 54.1 %

Procedure:
According to Example 34, the compound (150 mg) produced in Example 37 was reacted with 4-chloromethylpyridine hydrochloride (84 mg) to obtain the title compound (98 mg; 54%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][CH2:8][CH2:9]Br.[CH:11]12[NH:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][CH:13]([NH:19][C:20]1[C:21]([CH3:29])=[C:22]3[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]3)[CH2:12]2>CN(C)C=O>[CH2:9]([N:18]1[CH:15]2[CH2:16][CH2:17][CH:11]1[CH2:12][CH:13]([NH:19][C:20]1[C:21]([CH3:29])=[C:22]3[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]3)[CH2:14]2)[CH2:8][CH3:7]
Reactant: Cc1c(NC2CC3CCC(C2)N3)ccc2[nH]ncc12
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN1C2CCC1CC(Nc1ccc3[nH]ncc3c1C)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 41.7 %

Procedure:
Potassium carbonate (122 mg, 0.883 mmol) and then n-propyl bromide (40 μl, 0.440 mmol) were added to a solution of the N-(8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine (74 mg, 0.289 mmol) obtained in Example 501 in N,N-dimethylformamide (2 ml), and the resulting mixture was stirred at room temperature for 15 hours. After the solid was removed by filtration, the solvent was distilled off under reduced pressure as an azeotrope with toluene. The residue was purified by a silica gel column chromatography (chloroform/methanol/triethylamine=100/1/5) and then a preparative thin-layer chromatography (200×200×0.5 mm, 2 plates, eluent: chloroform/methanol/triethylamine=100/5/5) to obtain N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-4-methyl-1H-indazol-5-amine (36 mg, 42%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[N+:19]([CH3:22])([O-:21])=[O:20].Cl>CS(C)=O.O>[N+:19]([CH2:22][C:7]1([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([O-:21])=[O:20]
Reactant: C[N+](=O)[O-]
Reactant: CCOC(=O)C=C1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CC1(C[N+](=O)[O-])CCCCC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 88.4 %

Procedure:
To a mixture of 64.72 g (0.469 mole) potassium carbonate suspended in 469.5 mL dimethyl sulphoxide is measured in, during the course of 1 to 2 hours at 95° C., a solution of 158 g, (0.939 mole) ethyl cyclohexylideneacetate and 85.94 g (1.408 mole) nitromethane. After completion of the addition, stirring is continued at 95° C. for 2 to 3 hours. Subsequently, with ice-water cooling, the reaction solution is acidified with about 150 mL concentrated hydrochloric acid and diluted with 1.5 L of water. The resultant phases are separated and the aqueous phase is extracted several times with petroleum ether. The combined organic phases are washed neutral with water and dried over anhydrous sodium sulphate. The solvent is subsequently distilled off in a vacuum. 190.3 g Ethyl 1-nitromethyl-cyclohexaneacetate in the form of an oil are obtained; yield 88.4% of theory. Composition according to HPLC: 90% of the desired product of Step 2 and 6% ethyl cyclohexylideneacetate (Step 1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][NH:39][CH:40]=O)[CH2:33][CH2:32]2)=[CH:16][CH:15]=1>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[N:23]=[C:22]2[NH:30][CH:31]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][N:39]3[C:4](=[O:6])[C:3]4[C:2](=[CH:10][CH:9]=[C:8]([S:11][CH3:12])[CH:7]=4)[N:1]=[CH:40]3)[CH2:33][CH2:32]2)=[CH:16][CH:15]=1
Reactant: CSc1ccc(N)c(C(=O)O)c1
Reactant: O=CNCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Product: CSc1ccc2ncn(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)c(=O)c2c1
Reaction time: 5 h
Yield: 41.5 %

Procedure:
A mixture of 3.7 parts of 2-amino-5-(methylthio)benzoic acid and 8.9 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]formamide was stirred for 5 hours at 150°-160° C. The whole was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 1,1'-oxybisethane and acetonitrile. The product was filtered off and dried, yielding 4.5 parts (41.5%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-6-(methylthio)-4(3H)-quinazolinone; mp. 101.4° C. (compound 138).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:13]([CH2:14][N:15]([C@@H:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[NH:46][C:47](OC1C=CC([N+]([O-])=O)=CC=1)=[O:48])[C:39]([O:41][CH3:42])=[O:40].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1COCC1>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:13]1[CH2:12][CH2:11][N:10]([C:47]([NH:46][C:45]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=2[Cl:35])=[O:48])[CH2:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3cccc(F)c3)C2)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 231 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate and 210 mg of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate in 4.0 mL of THF was added 0.139 mL of triethylamine at room temperature, followed by stirring overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 394 mg of a pale yellow foamy substance of methyl 4-({[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]carbonyl}amino)-3-chlorobenzoate as a crude product. ESI+: 674
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)CCC.[Cl:20][C:21]1[C:25](Cl)=[N:24][S:23][N:22]=1>C1(C)C=CC=CC=1.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>[Cl:20][C:21]1[C:25]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)=[N:24][S:23][N:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Reactant: Clc1nsnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Clc1nsnc1-c1ccccc1
Reaction time: 8 h
Yield: 48 %

Procedure:
1.9 g (0.00517 mol) of tributylphenyl stannane and 0.29 g (0.00025 mol) of tetrakis (triphenylphosphine)palladium(0) were added to a solution of 0.775 g (0.005 mol) of 3,4-dichloro-1,2,5-thiadiazole in 10 mL of toluene under nitrogen and heated at reflux. After 8 h, 0.145 g (1.25×10−4 mol) of tetrakis(triphenylphosphine)palladium(0) were added. After 24 h of reflux, 48% of product formed by quantitative HPLC (versus a reference prepared as reported by L. Weinstock et al., J. Org. Chem., vol. 32, p 2823 (1967)).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[C:24]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:22][N:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:24]3[CH:23]=[CH:22][N:21]=[C:20]([F:19])[CH:25]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1ccnc(F)c1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccnc(F)c3)cn2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(2-fluoro-pyridin-4-yl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.90 min; [M+H]+=395.98.
Reaction SMILES: [F:1][C:2]1([F:11])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[O:3]1.C([Li])(CC)C.C(O[B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)(C)C>O1CCCC1>[F:11][C:2]1([F:1])[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([B:21]3[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]3)[C:5]=2[O:6]1
Reactant: FC1(F)Oc2ccccc2O1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC1(C)OB(c2cccc3c2OC(F)(F)O3)OC1(C)C
Temperature: -75 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
2,2-Difluorobenzo[d][1,3]dioxole (6 g, 38.0 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled to −75° C. sec-Butyllithium (1.4 M in cyclohexane; 29.8 mL, 41.7 mmol) was added dropwise, keeping the temperature below −65° C. The reaction mixture was then stirred at −75° C. for 1 h to ensure complete deprotonation. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (7.06 g, 38.0 mmol) was then added to the reaction mixture dropwise keeping the temperature below −65° C. The reaction mixture was then allowed to warm to room temperature and sit at room temperature for 2 h and was then partitioned between diethyl ether and water. The aqueous phase was acidified to pH 3 with 12 N HCl. The product was extracted with diethyl ether and the organic phase was dried and concentrated under vacuum to provide the title compound as an off-white solid (7.06 g, 65.5%): 1H NMR (300 MHz, CDCl3) δ 7.43 (dd, J=7.5, 1.5 Hz, 1H), 7.13 (dd, J=7.9, 1.5 Hz, 1H), 7.05 (t, J=7.7 Hz, 1H), 1.37 (s, 12H); EIMS m/z 284.