Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:21]([OH:23])=O)[CH2:16][CH:15]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14]1)[CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]([C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1)[NH2:25].CN1CCOCC1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH2:1]([O:8][N:9]([CH2:12][C:13]1([C:21]([NH:25][NH:24][C:26]2[N:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][N:27]=2)=[O:23])[CH2:14][CH:15]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:16]1)[CH:10]=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NNc1nccc(C(F)(F)F)n1
Reactant: CCCCC1CC(CN(C=O)OCc2ccccc2)(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCCC1CC(CN(C=O)OCc2ccccc2)(C(=O)NNc2nccc(C(F)(F)F)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.1 %

Procedure:
To a mixture of (1-[(benzyloxy-formyl-amino)-methyl)]-3-butyl-cyclobutanecarboxylic acid (0.10 g, 0.31 mmol), 2-hydrazino-4-(trifluoromethyl)pyrimidine (0.067 g, 0.37 mmol), NMM (0.095 g, 0.93 mmol) and HOAt (0.05 g, 0.37 mmol) in DMF (3 mL) at room temperature was added 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide hydrochloride (0.072 g, 0.37 mmol). After stirring at room temperature 18 h, the reaction mixture was then purified by preparative, reverse-phase HPLC to afford the title compound as a white solid (0.07 g, 47%). MH+480.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([OH:16])=O)[CH:8]=2)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([C:14]([NH:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)=[O:16])[CH:8]=2)=[O:4]
Reactant: NCCc1ccccn1
Reactant: COC(=O)c1cc2ccc(C(=O)O)cc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc2ccc(C(=O)NCCc3ccccn3)cc2[nH]1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.3 %

Procedure:
A solution of 2-(methoxycarbonyl)indole-6-carboxylic acid (290 mg, 1.32 mmol) and 1,1'-carbonyldiimidazole (257 mg, 1.59 mmol) in THF (20 mL) was stirred at reflux for 1 h then cooled and evaporated. A solution of 2-(2-aminoethyl)pyridine (0.19 mL, 1.6 mmol) in DMF (5 mL) was added and the mixture stirred at 80° C. for 2 h, then cooled and evaporated. Trituration with hot EtOAc gave 2-(methoxycarbonyl)-N-[2-(2-pyridinyl)ethyl]indole-6-carboxamide as a white solid (360 mg, 84%), mp 191-193° C. 1H NMR [(CD3)2SO] δ12.24 (s, 1H, indole NH), 8.61 (t, J=5.5 Hz, 1H, amide NH), 8.54-8.50 (m, 1H, H-6'), 7.97 (s, 1H, H-3 or H-7), 7.71 (td, J=7.6, 1.8 Hz, 1H, H-4'), 7.70 (d, J=8.6 Hz, 1H, H-4), 7.55 (dd, J=8.6, 1.4 Hz, 1H, H-5), 7.29 (d, J=7.8 Hz, 1H, H-3'), 7.23 (ddd, J=7.4, 4.8, 0.8 Hz, 1H, H-5'), 7.20 (s, 1H, H-3 or H-7), 3.90 (s, 3H, CO2Me), 3.64 (q, J=6.8 Hz, 2H, NHCH2CH2 py), 3.03 (t, J=7.4 Hz, 2H, NHCH2CH2 py); 13C NMR δ166.6 (CONH), 161.5 (CO2Me), 159.2 (C-2'), 136.7, 131.0, 129.1, 128.5 (C-2,6,8,9), 149.0, 136.4, 123.1, 121.6, 121.4, 118.9, 112.2, 107.5 (C-3,4,5,7,3',4',5',6'), 51.9 (OCH3), 39.3, 37.3 (NHCH2CH2 py). Anal. (C18H17N3O3) C,H,N.
Reaction SMILES: ClC1C=C(N(C)CC(O)=O)C=CC=1Cl.[Br:15][C:16]1[C:17]([Br:31])=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][C:27]([OH:29])=O)[C:20]=2[CH:30]=1.C1(C2C=CC=CC=2)C=CC(C(NC)CN2CCCC2)=CC=1.[C:53]1([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:58]=[CH:57][C:56]([CH:59]([NH:67][CH3:68])[CH2:60][N:61]2[CH2:66][CH2:65][O:64][CH2:63][CH2:62]2)=[CH:55][CH:54]=1>>[C:53]1([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH:54]=[CH:55][C:56]([CH:59]([N:67]([CH3:68])[C:27](=[O:29])[CH2:26][N:21]2[C:20]3[CH:30]=[C:16]([Br:15])[C:17]([Br:31])=[CH:18][C:19]=3[O:24][CH2:23][C:22]2=[O:25])[CH2:60][N:61]2[CH2:62][CH2:63][O:64][CH2:65][CH2:66]2)=[CH:57][CH:58]=1
Reactant: O=C(O)CN1C(=O)COc2cc(Br)c(Br)cc21
Reactant: CNC(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Agent: CN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Product: CN(C(=O)CN1C(=O)COc2cc(Br)c(Br)cc21)C(CN1CCOCC1)c1ccc(-c2ccccc2)cc1
Yield: 58 %

Procedure:
The title compound was prepared according to the procedure described in example 11 replacing N-(3,4-dichlorophenyl)-N-methylglycine with (6,7-dibromo-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)acetic acid, and [1-(4-biphenylyl)-2-(1-pyrrolidinyl)ethyl]methylamine with the product from step b) above to give the title compound (52 mg, 58%). MS (ES) m/e 643 [M+H]+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[NH:14][N:13]=NN=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl[C:16](=[O:24])[CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>N1C=CC=CC=1.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:24][C:16]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:13][N:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: c1cc2c(cc1-c1nnn[nH]1)CCO2
Reactant: CCOC(=O)CCC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1nnc(-c2ccc3c(c2)CCO3)o1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 78.2 %

Procedure:
To a solution of 5-(2,3-dihydro-1-benzofuran-5-yl)-1H-tetrazole (4.40 g, 23.38 mmol) in pyridine (50 mL) was added ethyl 4-chloro-4-oxobutyrate (4.62 g, 28.06 mmol), and the resulting mixture was stirred at room temperature for 30 min and at 100° C. for 3.5 hr. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, 1M hydrochloric acid, 1M aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=95/5-0/100) and recrystallized from hexane/ethyl acetate to give the title compound (5.27 g, yield 78%) as pale-yellow crystals.
Reaction SMILES: [CH3:1][Si:2]([CH3:42])([CH2:21][CH2:22][C:23]([F:41])([F:40])[C:24]([F:39])([F:38])[C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]=2)=[CH:10][CH:9]=1.[F:43][CH:44]([CH:57]([F:63])[CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH2:45]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:43][C@H:44]([C@@H:57]([F:63])[CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH2:45][O:20][C:17]1[CH:18]=[N:19][C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:42])[CH2:21][CH2:22][C:23]([F:41])([F:40])[C:24]([F:38])([F:39])[C:25]([F:36])([F:37])[C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:29])([F:30])[F:31])=[CH:9][CH:10]=2)=[N:15][CH:16]=1
Reactant: CCCCCC(F)C(F)COS(=O)(=O)c1ccc(C)cc1
Reactant: C[Si](C)(CCCCOc1ccc(-c2ncc(O)cn2)cc1)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCC[C@H](F)[C@@H](F)COc1cnc(-c2ccc(OCCCC[Si](C)(C)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of compound 47 (0.162 g, 0.250 mmol), toluene-4-sulfonic acid 2,3-difluoro-octyl ester (0.080 g, 0.250 mmol) and cesium carbonate (0.098 g, 0.300 mmol) in DMF 5.0 ml) was stirred at room temperature for 24 h. The reaction mixture was washed with water and the organic layer extracted into ethyl acetate/hexane (3×20 ml, 1:1). The combine extracts were washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residues were purified by column chromatography [silica gel, hexane/ethyl acetate (9:1)] to yield a colorless solid, which was recrystallized from acetonitrile.
Reaction SMILES: OC1C=C(C=CC=1OC)C(OC)=O.ClC1C=C(CCO)C=CC=1.[CH3:24][O:25][C:26](=[O:45])[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)[CH:28]=1.[N+:46]([O-])([OH:48])=[O:47]>>[CH3:24][O:25][C:26](=[O:45])[C:27]1[CH:28]=[C:29]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=2)[C:30]([O:33][CH3:34])=[CH:31][C:32]=1[N+:46]([O-:48])=[O:47]
Reactant: COC(=O)c1ccc(OC)c(OCCc2cccc(Cl)c2)c1
Reactant: O=[N+]([O-])O
Agent: COC(=O)c1ccc(OC)c(O)c1
Agent: OCCc1cccc(Cl)c1
Product: COC(=O)c1cc(OCCc2cccc(Cl)c2)c(OC)cc1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
Methyl 3-hydroxy-4-methoxybenzoate and 2-(3-chlorophenyl)-ethanol were reacted in analogy to step 1 of example 1. The obtained 3-[2-(3-chloro-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester (0.750 g, 2.34 mmol) was added slowly to ice-cooled 100% nitric acid (10 ml). The ice bath was removed and stirring was continued overnight. The mixture was cautiously transferred into a stirred mixture of EA, water and an excess of sodium hydrogencarbonate and extracted with EA. The combined organic extracts were washed with a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. The solid residue was extracted with diethyl ether, and the ethereal solution was evaporated. The residue was stirred with HEP, and the solid was filtered and dried in vacuo to give 0.680 g of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]CC)=O.[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH2:18]>>[CH3:13][N:14]([CH3:19])[CH2:15][CH2:16][CH2:17][NH:18][C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: CN(C)CCCN
Reactant: CCOC(=O)CN1CCCC1=O
Product: CN(C)CCCNC(=O)CN1CCCC1=O

Procedure:
From 12.8 g. of ethyl 2-oxo-1-pyrrolidineacetate and 15.3 g. of 3-(dimethylamino)propylamine (U.S. Pat. No. 2,459,080), following the procedure of Example 1, there is obtained N-[3-(dimethylamino)propyl]-2-oxo-1-pyrrolidineacetamide; b.p. 157°-159° C./0.15 mm.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.Br[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([N:14]2[C:18]([CH2:19][CH3:20])=[C:17]([CH2:21][N:22]3[C@@H:31]([CH2:32][O:33][CH2:34][CH3:35])[CH2:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)[C:16]([CH2:36][CH3:37])=[N:15]2)=[C:9]([CH3:38])[CH:8]=1.C(I)C>O1CCCC1>[CH2:36]([C:16]1[C:17]([CH2:21][N:22]2[C@@H:31]([CH2:32][O:33][CH2:34][CH3:35])[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23]2)=[C:18]([CH2:19][CH3:20])[N:14]([C:10]2[C:11]([CH3:13])=[CH:12][C:7]([CH2:1][CH3:2])=[CH:8][C:9]=2[CH3:38])[N:15]=1)[CH3:37]
Reactant: [Li]CCCC
Reactant: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cc(Br)cc2C)c1CC
Solvent: CCI
Solvent: C1CCOC1
Product: CCOC[C@H]1Cc2ccccc2CN1Cc1c(CC)nn(-c2c(C)cc(CC)cc2C)c1CC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
To a solution of n-butyl lithium (2.5 M hexane solution; 0.062 ml, 0.16 mmol) chilled to -78° C., a solution of (R)-2-[1-(4-bromo-2,6-dimethylphenyl)-3,5-diethyl-1H-pyrazol-4-ylmethyl]-3-ethoxymethyl-1,2,3,4-tetrahydro-isoquinoline (72 mg, 0.14 mmol) in anhydrous tetrahydrofuran (0.2 ml) was added dropwise. After stirring at -78° C. for 10 minutes, anhydrous ethyl iodide (0.056 ml, 0.70 mmol) was added. The resulting mixture was warmed to ambient temperature and stirred for 1 hour. The reaction was quenched by addition of aqueous ammonium chloride (1 ml), then extracted with ethyl acetate/water (5 ml of each). The separated organic extract was washed with an equal volume solution of aqueous ammonium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford a yellow oil (46 mg). Flash chromatography (silica gel, 40 micron mesh; elution with ethyl actate/hexane=1:5 in volume) afforded the title compound (10 mg) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1OS(C(F)(F)F)(=O)=O)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4].[CH:36]([C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1)=[O:37]>>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:28][CH:27]=2)[C:7](=[O:24])[C:8]2[C:13]([C:14]=1[C:42]1[CH:41]=[CH:40][CH:39]=[C:38]([CH:36]=[O:37])[CH:43]=1)=[CH:12][C:11]([Cl:23])=[CH:10][CH:9]=2)=[O:4]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Product: COC(=O)c1c(-c2cccc(C=O)c2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 272 and using 6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-4-trifluoromethanesulfonyloxy-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester and 3-formylphenylboronic acid.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH:8]2[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]2)=[CH:19][CH:18]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccc(Cl)cc2)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The title compound was prepared as described in General Method 1 using 10 mL of methyl acetoacetate, 3.9 g of NaH 60% dispersion in oil, 58 mL of 1.6M n-butyl lithium in hexane, 13.5 g of 4-chlorobenzaldehyde and 250 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 15 minutes at 0°0 C. then allowed to warm to room temperature overnight. The crude product was triturated from diethyl ether to afford a solid (m.p. 149°-150° C.). 1H NMR (CDCl3) δ 2.83 (dd, 1 H), 2.95 (dd, 1 H), 3.60 (dd, 2 H), 5.67 (dd, 1 H), 7.33-7.44 (m, 4 H).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:34]=[CH:33][C:15]3[N:16]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]4)[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].O1CCOCC1>Cl>[CH3:1][NH:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:34]=[CH:33][C:15]3[N:16]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]4)[S:18][C:14]=3[CH:13]=2)[CH:8]=[CH:7][N:6]=1
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)sc3c2)ccn1
Agent: Cl
Solvent: C1COCCO1
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCNC4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(S)-tert-butyl 3-(6-(2-(methylcarbamoyl)pyridin-4-yloxy)benzo[d]thiazol-2-ylamino)piperidine-1-carboxylate (56 mg, 0.12 mmol) was dissolved in 4 ml of 4M HCl in dioxane (16 mmol). The reaction solution was stirred at room temperature for 1 hour. The crude reaction solution was evaporated in vacuo to give (S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide (46 mg, 0.12 mmol) as white solid. ES/MS m/z 384.0 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].[C:22]([Cu])#[N:23].[OH-].[NH4+].Cl>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:22]#[N:23])[C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]=1[OH:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c1ccccc1n2C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c1ccccc1n2C
Temperature: 120 °C
Yield: 38.8 %

Procedure:
A mixture of 1-bromo-4-hydroxy-9-methyl-9H-beta-carboline-3-carboxylic acid ethyl ester (256 mg), CuCN (132 mg) in NMP (N-methyl 2-pyrrolidinone, 2 mL) was heated at 120° C. for 67 min. The mixture was poured into a stirring mixture of EtOAc and diluted ammonium hydroxide solution, then acidified with conc. HCl; then the organic phase was separated from aqueous and washed with sat. NaCl solution, dried over anhydrous sodium sulfate, filtered, concentrated; the residue was purified with column to give the desired product (84 mg). The title compound, ESI MS (m/z): 296 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:22])=[O:21])[C:3]1[CH:4]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.[N:28]1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>O.CN(C)C=O>[CH3:1][N:2]([S:20]([C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)(=[O:21])=[O:22])[C:3]1[CH:4]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([NH2:28])=[O:13])=[CH:8]2
Reactant: On1nnc2ccccc21
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cc(OC(F)(F)F)cc2cc(C(N)=O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.3 %

Procedure:
A mixture of 7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylic acid (1.60 g), 1H-1,2,3-benzotriazol-1-ol (0.77 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.09 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hr. 28% Aqueous ammonia (320 mg) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The residue was washed with hexane to give the title compound (1.25 g, yield 79%) as pale-brown crystals. The crystals were recrystallized from ethyl acetate-hexane to give pale-yellow prism crystals. melting point 228-229° C.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=O)[CH2:2]1)[CH2:8]2.Cl.[NH2:13][OH:14].N1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C:4]3=[N:13][OH:14])[CH2:2]1)[CH2:8]2
Reactant: O=C1C2CC3CC1CN(C3)C2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C1C2CC3CC1CN(C3)C2

Procedure:
A solution of 1-aza-adamantan-4-one (1.1 g), hydroxylamine hydrochloride (0.7 g) and pyridine (0.5 ml) in ethanol (30 ml) was heated under reflux for 1 h. The solution was then treated with saturated K2CO3 solution (30 ml), evaporated to half its volume and extracted with CH2Cl2 (4×50 ml). The combined extracts were dried (K2CO3) and evaporated in vacuo to give D.1 (1.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[I:15]I.OS([O-])(=O)=O.[K+]>O>[OH:1][C:2]1[C:7]([I:15])=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1
Reactant: II
Reactant: Oc1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Product: Oc1ccnc(O)c1I
Temperature: 100 °C

Procedure:
A mixture of 2,4-dihydroxypyridine (1.0 eq), K2CO3 (1.0 eq), and water was stirred at 100° C. so that it became homogeneous. With continued stirring and heating, I2 (1.0 eq) was added in portions, causing the evolution of gas. When the solid I2 was consumed, the mixture was cooled and acidified with aqueous KHSO4 (1.0 eq), generating a precipitate. The precipitate was collected by filtration, rinsed with water, and stored under high vacuum, to give 2,4-dihydroxy-3-iodopyridine.
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([CH:9]3[CH2:13][CH2:12][CH2:11][N:10]3[C:14]3[N:19]=[C:18](O)[CH:17]=[C:16]([CH2:21][O:22][CH3:23])[N:15]=3)[O:6][N:5]=2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:18]1[CH:17]=[C:16]([CH2:21][O:22][CH3:23])[N:15]=[C:14]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:7]2[O:6][N:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:8]=2)[N:19]=1
Reactant: COCc1cc(O)nc(N2CCCC2c2cc(C3CC3)no2)n1
Reactant: O=P(Cl)(Cl)Cl
Product: COCc1cc(Cl)nc(N2CCCC2c2cc(C3CC3)no2)n1
Yield: 85.7 %

Procedure:
A mixture of 2-[2-(3-cyclopropylisoxazol-5-yl]pyrrolidin-1-yl]-4-hydroxy-6-methoxymethylpyrimidine (Method 18) (563 mg, 1.78 mmol) and phosphoryl chloride (1 ml, 10.7 mmol) was heated at reflux for 45 minutes. The volatiles were removed by evaporation, the residue dissolved in DCM, washed with saturated aqueous sodium hydrogen carbonate solution, dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica gel eluting with DCM/diethyl ether (100:0 and then 80:20) to give the title compound (511 mg, 81%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24]Cl)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].C(N(CC)C(C)C)(C)C.[I-].[Na+].[NH2:37][CH2:38][CH2:39][CH2:40][OH:41]>C(O)CCC>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:37][CH2:38][CH2:39][CH2:40][OH:41])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:13][CH:12]([CH2:11][CH:10]([CH2:16]3)[CH2:9]1)[CH2:17]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCCl)ccc1Cl
Reactant: NCCCO
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(OCCNCCCO)ccc1Cl
Temperature: 110 °C

Procedure:
To a solution of 2-chloro-5-[2-chloroethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 11a, 0.15 g) and N,N-diisopropylethylamine (0.50 ml) in 1-butanol (4 ml) was added sodium iodide (0.06 g) and 3-aminopropan-1-ol (0.09 ml). The reaction vessel was sealed and the mixture heated at 110° C. for 24 h. The reaction mixture was partitioned between ethyl acetate and sodium hydrogencarbonate solution, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by RPHPLC (eluting with 25-95% MeCN/0.1% AcONH4 aqueous) to give 2-chloro-5-[2-[(3-hydroxypropyl)amino]ethoxy]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide as the acetate salt. This was converted to the hydrochloride salt by stirring with 4M HCl in dioxane and concentration under reduced pressure. Recrystalisation from isohexane/isopropanol gave the title compound as a white solid (0.1 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]#[N:10])[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[CH3:19].[N-:20]=[N+:21]=[N-:22].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]2[NH:22][N:21]=[N:20][N:10]=2)[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[CH3:19]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(I)ccc1Nc1c(C#N)ccc(F)c1F
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(I)ccc1Nc1c(-c2nnn[nH]2)ccc(F)c1F
Temperature: 100 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
[2,3-Difluoro-6-cyano-phenyl]-(4-iodo-2-methyl-phenyl)-amine (1.11 g, 3 mmol) and Sodium azide(0.255 g, 3.9 mmol) and triethylamine hydrochloride (0. 537 g, 3.9 mmol) were all suspended in 10 ml toluene and stirred at 100° C. for 12 hours. The mixture was concentrated and the residue purified by column chromatography with ethyl acetate/methanol (10/1) to give the product as a foam-like solid. The yield: ˜50% m.p: 83.4-88.7° C. 1H NMR(CDCl3, 400 Hz): δ/ppm 7.69(1H, m, Phenyl-H); 7.42(1H, s, Phenyl-H); 7.27(1H, m, Phenyl-H); 6.91(1H, dd, J=16.2 Hz, 8.3 Hz, Phenyl-H); 6.40(1H, dd, Phenyl-H); 2.28(3H, s, CH3)
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25])=[C:18]([CH:21]=1)[C:19]#[N:20]>>[OH:25][CH2:24][CH2:23][N:22]([C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:6]([C:5]2[S:1][C:2]3[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=3[CH:4]=2)=[O:8])=[CH:21][C:18]=1[C:19]#[N:20])[CH2:26][CH2:27][OH:28]
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: N#Cc1cc(N)ccc1N(CCO)CCO
Product: N#Cc1cc(NC(=O)c2cc3ccccc3s2)ccc1N(CCO)CCO
Yield: 19.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]thiophene-2-carboxylic acid (1.0 g) and 5-amino-2-[N,N-bis(2-hydroxyethyl)amino]benzonitrile (0.9 g), the title compound (0.3 g) was obtained. melting point: 163-168° C.