Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([N:10]=[N+]=[N-])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[CH:26]=[CH:27][C:28]([O:33][CH3:34])=[C:29]([CH:32]=1)[CH:30]=O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([NH:10][CH2:30][C:29]2[CH:32]=[C:25]([C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)[CH:26]=[CH:27][C:28]=2[O:33][CH3:34])[CH:6]1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:4]
Reactant: COc1ccc(-c2ccco2)cc1C=O
Reactant: COC(=O)C1CCC(N=[N+]=[N-])C1c1ccc(F)cc1
Product: COC(=O)C1CCC(NCc2cc(-c3ccco3)ccc2OC)C1c1ccc(F)cc1

Procedure:
The title compound was prepared by employing the method described in Example 91, Step D with (1RS,2RS,3RS)-2-(4-fluorophenyl)-3-azidocyclopentanecarboxylic acid methyl ester (from Example 89, Step A) and the known 5-(furan-2-yl)-2-methoxybenzaldehyde (P. J. Ward, et al., J. Med. Chem. 1995, 38, 4985-92).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:11]2[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]3[C:16]([Cl:17])=[C:15]([CH3:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1sc2nc(Cl)nc(NCc3ccccc3)c2c1Cl
Reactant: Cc1ncc[nH]1
Product: Cc1sc2nc(-n3ccnc3C)nc(NCc3ccccc3)c2c1Cl

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2,5-dichloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-5-chloro-6-methyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:20][CH2:21][C:22]([OH:24])=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:27]=[N+:28]([O-:51])[CH:29]=[C:30]([Cl:50])[C:31]=1[CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)O.C(Cl)CCl.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:25][C:26]1[CH:27]=[N+:28]([O-:51])[CH:29]=[C:30]([Cl:50])[C:31]=1[CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:23][C:22](=[O:24])[CH2:21][O:20][C:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: O=C(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(COC(c1ccccc1)(c1ccccc1)c1ccccc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of 2-(trityloxy)acetic acid (7.2 g, 22.62 mmol) in DCM (250 ml), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (7.92 g, 18.85 mmol), EDC (4.34 g, 22.62 mmol), and DMAP (4.60 g, 37.7 mmol) were added at RT. The solution was stirred at the same temperature overnight. A sat. sol. of K2CO3 was added, and the organic phase was separated, washed with HCl 2N and brine, dried over Na2SO4 and evaporated under vacuum. The resulting brown crude was purified by flash chromatography on silica gel (DCM 100% as eluent). (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(trityloxy)acetoxy)ethyl)pyridine 1-oxide was obtained (8.53 g, 11.84 mmol, 62.8% yield, MS/ESI+ 720.1 [MH]+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:27][OH:28].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH3:25])[CH2:9]/[C:10](/[C:12]2[CH:13]=[N:14][CH:15]=[C:16]([Br:18])[CH:17]=2)=[N:27]\[OH:28])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C(CC(=O)c1cncc(Br)c1)c1cccc(Br)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1cncc(Br)c1)c1cccc(Br)c1

Procedure:
In analogy to example 74, step 7, from 3-(3-bromo-phenyl)-1-(5-bromo-pyridin-3-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white solid, MS (ESI+): m/z=472.9850 ([M+H]+, 1Br).
Reaction SMILES: C(C1C=C(C=O)C(O)=C(C2C=CC(OC(F)(F)F)=CC=2)C=1)(C)(C)C.Br[C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[OH:36].[Cl:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][C:43]=1[Cl:44]>>[Cl:37][C:38]1[CH:39]=[C:40]([C:26]2[C:27]([OH:36])=[CH:28][CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=2)[CH:41]=[CH:42][C:43]=1[Cl:44]
Reactant: Oc1ccc(C(F)(F)F)cc1Br
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(OC(F)(F)F)cc2)c1
Product: Oc1ccc(C(F)(F)F)cc1-c1ccc(Cl)c(Cl)c1

Procedure:
3′,4′-Dichloro-5-(trifluoromethyl)-[1,1′-biphenyl]-2-ol was prepared as a yellow oil using the procedure described in Intermediate 5 from 2-bromo-4-(trifluoromethyl)phenol (Tetrahedron 2003, 59, 6545) and 3,4-dichlorophenylboronic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]([CH3:45])[C@@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>>[CH3:38][N:39]([CH3:45])[C@@H:40]1[CH2:44][CH2:43][N:42]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:41]1
Reactant: CN(C)[C@@H]1CCNC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CN(C)[C@@H]1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)C1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and (R)—N,N-dimethylpyrrolidin-3-amine according to conditions described in general procedure C.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].Br[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.[ClH:26]>>[ClH:26].[C:22]([C:21]1[CH:24]=[CH:25][C:18]([CH2:3][CH2:2][CH2:1][CH:4]2[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]2)=[CH:19][CH:20]=1)#[N:23]
Reactant: C=CCC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Product: N#Cc1ccc(CCCC2CCNCC2)cc1

Procedure:
Starting with 4-(prop-2-en-1-yl)-1-t-butoxycarbonylpiperidine from Procedure 5, Step B (475 mg, 2.1 mmol) and using essentially the same methods as in Procedure 5, Step D, but substituting 4-bromobenzonitrile (382 mg, 2.1 mmol), the title compound (337 mg) was obtained as the hydrochloride.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:34]([CH2:36][CH2:37][N:38]([CH3:40])[CH3:39])[CH3:35])=[CH:9][C:10]([O:32][CH3:33])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[C:17]([C:30]#[N:31])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:30]([C:17]1[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH:21]=2)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:32][CH3:33])=[CH:9][C:8]([N:34]([CH2:36][CH2:37][N:38]([CH3:39])[CH3:40])[CH3:35])=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:31]
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(C#N)c(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
A solution of acryloyl chloride (0.035 mL, 0.44 mmol) in CH2Cl2 (1 mL) was added to a mixture of 2-{[5-amino-4-(2-dimethylaminoethyl-methylamino)-2-methoxyphenyl]-amino}-4-(1-methylindol-3-yl)pyrimidine-5-carbonitrile (Intermediate 102, 171 mg, 0.36 mmol) and DIPEA (0.120 mL, 0.73 mmol) in CH2Cl2 (3 mL) at 0° C., then the mixture was stirred at 0° C. for 1 h. The mixture was then diluted with CH2Cl2, washed twice with sat. NaHCO3, and then water, then dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (68 mg, 36%) as a yellow solid; 1H NMR: (100° C.) 2.22 (6H, s), 2.40 (2H, t), 2.76 (3H, s), 2.98 (2H, t), 3.77 (3H, s), 3.90 (3H, s), 5.69 (1H, dd), 6.17 (1H, dd), 6.40 (1H, dd), 7.02-7.06 (2H, m), 7.21-7.25 (1H, m), 7.49 (1H, d), 8.23 (1H, d), 8.45 (1H, s), 8.47 (1H, s), 8.63 (1H, s), 8.86 (1H, s), 9.59 (1H, s); m/z: ES+ MH+ 525.32.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>>[CH2:16]([N:18]([CH2:19][CH3:20])[C:13]([C:9]1[CH:10]=[N:11][O:12][C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:15])[CH3:17]
Reactant: O=C(O)c1cnoc1-c1ccc(F)cc1
Reactant: CCNCC
Product: CCN(CC)C(=O)c1cnoc1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 5-(4-fluorophenyl)isoxazole-4-carboxylic acid (10.4 mg, 0.050 mmol) and diethylamine (4.4 mg, 0.060 mmol) as described in synthetic method A and thereafter purified by preparative HPLC method A to give a solid (11.4 mg). MS (pos) m/z 263.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]5([C:29]#[N:30])[CH2:28][CH2:27]5)[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl.[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CO>[C:29]([C:26]1([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:9]3[CH:8]=[CH:7][C:5]4[N:6]=[C:2]([NH:1][C:42](=[O:43])[CH2:41][N:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)[S:3][C:4]=4[CH:10]=3)[CH:13]=2)=[O:31])[CH2:27][CH2:28]1)#[N:30]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)sc5c4)c3)c2)CC1
Reactant: CN1CCN(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CO
Product: CN1CCN(CC(=O)Nc2nc3ccc(Oc4cccc(NC(=O)c5cccc(C6(C#N)CC6)c5)c4)cc3s2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 23.5 %

Procedure:
To a solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (436 mg, 1.02 mmol) produced in Example A15(iii) in pyridine (10 mL) were added (4-methylpiperazin-1-yl)acetic acid dihydrochloride (278 mg, 1.20 mmol), N,N-dimethylpyridine-4-amine (79.3 mg, 649 μmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (470 mg, 2.45 mmol) at room temperature, and the mixture was stirred at room temperature for 14 hr. To the reaction mixture were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (454 mg, 2.37 mmol), (4-methylpiperazin-1-yl)acetic acid dihydrochloride (281 mg, 1.22 mmol), and triethylamine (10 mL) and the mixture was further stirred for 4 hr. To the reaction mixture was added methanol (10 mL) and the mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with saturated aqueous ammonium chloride solution (80 mL×2) and saturated aqueous sodium hydrogencarbonate solution (50 mL), successively, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→90/10) and crystallized from ethyl acetate and hexane to give the title compound (136 mg, 24%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1[N:3]([S:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:22])=[O:21])[CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccn(S(=O)(=O)c2ccccc2)c1C

Procedure:
By a similar operation as in Reference Example 41 and using ethyl 2-methyl-1H-pyrrole-3-carboxylate (8.81 g), sodium hydride (60% in oil, 2.58 g) and benzenesulfonyl chloride (7.8 mL), the title compound was obtained as white crystals (yield 14.3 g, 85%).
Reaction SMILES: [F:1][C:2]1[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][O:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[C:13]([CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:9]=2[C:8](=[O:33])[N:7]([C:34]2[N:35]=[N:36][C:37]([O:40]C)=[CH:38][CH:39]=2)[C:6]1=[O:42].Cl.C(O)(=O)C.C(=O)(O)[O-].[Na+]>C1COCC1.C(OCC)(=O)C>[F:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:2]([F:1])[C:3]=1[CH2:4][N:5]1[C:10]2[S:11][C:12]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:30][O:31][CH3:32])=[O:29])=[CH:23][CH:22]=3)=[C:13]([CH2:14][N:15]([CH2:16][CH2:17][O:18][CH3:19])[CH3:20])[C:9]=2[C:8](=[O:33])[N:7]([C:34]2[N:35]=[N:36][C:37]([OH:40])=[CH:38][CH:39]=2)[C:6]1=[O:42]
Reactant: CONC(=O)Nc1ccc(-c2sc3c(c2CN2CCOCC2)c(=O)n(-c2ccc(OC)nn2)c(=O)n3Cc2c(F)cccc2F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCCN(C)Cc1c(-c2ccc(NC(=O)NOC)cc2)sc2c1c(=O)n(-c1ccc(O)nn1)c(=O)n2Cc1c(F)cccc1F
Temperature: 60 °C
Reaction time: 3 h
Yield: 41.2 %

Procedure:
To a solution of the compound (1.34 g, 2 mmol) obtained in Example 57 in THF (30 ml) was added a solution of 4N HCl in acetic acid (2 ml, 8 mmol), and the mixture was stirred at room temperature for 20 hours, at 50° C. for 10 hours and further at 60° C. for 3 hours. The reaction liquid was distributed between aqueous solution of sodium bicarbonate and ethyl acetate, and the organic layer was extracted. The aqueous layer was subjected to salting-out, and extracted with ethyl acetate. The organic layers were collected and combined and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by NH-silica gel (Produced by Fuji Silysia Chemical Ltd.) column chromatography (eluent; ethyl acetate/methanol=8/1). To the eluate was added diisopropylether to give powders. The powders were collected by filtration, washed with diisopropylether to obtain the title compound (539 mg, 41%) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1O.CCN=C=NCCCN(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([C:4]2[O:6][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]=2)=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[C:9]([F:11])[CH:10]=1
Reactant: Nc1ccccc1O
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(-c2nc3ccccc3o2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.3 %

Procedure:
2-Chloro-4-fluoro-5-nitrobenzoic acid (4.00 g, 18.2 mmol), 2-aminophenol (2.09 g, 20.1 mmol), CHCl3 (80 mL), and WSC (3.84 g, 20.0 mmol) were added together and stirred at room temperature for 2 hours. Water was added, and this was extracted with chloroform/acetone (3:1). After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. To a toluene (80 mL) solution of the solid obtained was added p-toluenesulfonic acid monohydrate (0.18 g, 1.8 mmol), and this was heated to reflux for 40 hours. After the reaction solution was concentrated, water was added, and the precipitated crystals were filtered, and after being washed with water were dried to yield the title compound (1.40 g, 26% yield) as yellowish-brown crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])[C:3]=1[C:4]#[N:5].[S:19](Cl)(=[O:22])(=[O:21])[NH2:20]>>[S:19]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH3:18])[C:3]=1[C:4]#[N:5])(=[O:22])(=[O:21])[NH2:20]
Reactant: CCOCCOCCOc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Product: CCOCCOCCOc1cccc(NS(N)(=O)=O)c1C#N
Yield: 69 %

Procedure:
Prepared as in Example 215a from 2-amino-6-(2-(2-ethoxyethoxy)ethoxy)benzonitrile (Example 250b) and sulfamoyl chloride in 69% yield. MS 330 (MH+).
Reaction SMILES: FC1C=CC(C2CCNCC2OCC2C(O)=CC3C(=CC=CC=3)C=2)=CC=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]2[O:48][CH2:49][C:50]2[CH:59]=[CH:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]=2)=[CH:31][CH:30]=1)#[N:28]>O1CCCC1>[NH2:28][CH2:27][C:29]1[CH:34]=[CH:33][C:32]([CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:45])[CH3:46])=[O:42])[CH2:37][CH:36]2[O:48][CH2:49][C:50]2[CH:59]=[CH:58][C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]=2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: Oc1cc2ccccc2cc1COC1CNCCC1c1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CN)cc2)C(OCc2ccc3ccccc3c2)C1
Yield: 79 %

Procedure:
A solution of 1 33 mg (0.301 mmol) of tert-butyl (3RS,4RS)-4-(4-cyano-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 0.5 ml of tetrahydrofuran was treated with 1.5 ml (1.5 mmol) of a 1M borane-tetrahydrofuran complex solution in tetrahydrofuran and the mixture was heated to reflux under argon for 6 hours. The reaction mixture was partitioned between methylene chloride and water, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product (163 mg) was purified by chromatography on silica gel with a 14:1:0.1 mixture of methylene chloride, methanol and a 25% ammonia solution as the eluent. There were obtained 106 mg (79% of theory) of tert-butyl (3RS,4RS)-4-(4-aminomethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless resin; MS: 447 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:14])[C:10]([O:12]C)=[O:11])=[C:5]([F:15])[CH:4]=1.[CH3:16][CH:17]([C:23](=[O:26])[CH2:24][CH3:25])C(OCC)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:15][C:5]1[CH:4]=[C:3]([CH2:2][CH:17]([CH3:16])[C:23](=[O:26])[CH2:24][CH3:25])[CH:8]=[CH:7][C:6]=1[CH:9]([CH3:14])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)C(C)C(=O)CC
Reactant: COC(=O)C(C)c1ccc(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(=O)C(C)Cc1ccc(C(C)C(=O)O)c(F)c1
Yield: 70.6 %

Procedure:
A suspension of compound (20) (0.78 g, 2.82 mmol), ethyl 2-methyl-3-oxopentanoate (0.46 mL, 2.82 mmol) and anhydrous potassium carbonate (0.70 g, 5.1 mmol) in acetone (40 mL) was allowed to react in the same manner as in Example 15. The obtained residue was subjected to silica gel column chromatography and elution with an n-hexane/ethyl acetate (7:2) solution followed by conventional decarboxylation and hydrolysis to give 0.53 g (53%) of compound (24) of interest as clear colorless oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([O:18][C:19]([N:21]([C:29]1[CH:34]=[C:33]([CH3:35])[C:32]([CH2:36]Br)=[CH:31][N:30]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[O:20])([CH3:17])([CH3:16])[CH3:15].C(OCC)(=O)C>CN(C=O)C>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:36][C:32]1[CH:31]=[N:30][C:29]([N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[CH:34][C:33]=1[CH3:35])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: Cc1cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ncc1CBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1C)C(=O)OCC
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
To a suspension of NaH (0.24 g, 6.0 mmol, 60%) in DMF (5 mL) was added diethyl malonate (0.91 mL, 6.0 mmol) and the mixture was stirred for 15 min. A solution 2-[N,N-bis(tert-butoxycarbonyl)amino]-5-bromomethyl-4-methyl-pyridin (2.0 g, 5.0 mmol) in DMF (5 mL) was added and the resulting solution stirred for 120 min at 60 ° C. Ethyl acetate was added and the mixture was washed with water and brine and dried. After evaporation of the solvent, the crude product was purified by flash chromatography (CH3OH/CH2Cl2, 1:100→1:20) to give a pure fraction 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-4-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.15 g, 48%) and an impure fraction 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]4-methyl-pyridin-3-ylmethyl)-malonic acid diethyl ester (1.1 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH3:18][N:19]([CH3:35])[C@@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=O)=[O:26])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:18][N:19]([CH3:35])[C@@H:20]1[CH2:24][CH2:23][N:22]([C:25]([C:27]2[CH:31]=[C:30]([CH3:32])[NH:29][C:28]=2[CH:33]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])=[O:26])[CH2:21]1
Reactant: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one (56.8 mg, 0.25 mmol) and 3-[3-(3R)-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-[3-(3R)-dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-fluoro-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (63.9, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][C:14]([F:17])([F:16])[F:15])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:18](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][C:14]([F:15])([F:16])[F:17])[C:11]=1[O:12][CH3:18])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(O)c(OC(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1cc(Cl)c(OC)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
Methyl 3-chloro-4-hydroxy-5-trifluoromethoxybenzoate (2.64 g) was dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (3.60 g) and dimethylsulfuric acid (1.64 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1) to obtain the title compound (1.70 g) as a colorless oily substance.