Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[C:23]2[CH2:22][CH2:21][CH2:20][C:19](=O)[C:18]=2[CH:17]=[CH:16][C:15]1=[O:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:13][N:14]1[C:23]2[CH2:22][CH2:21][CH2:20][CH:19]([NH:12][CH2:11][CH2:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[C:18]=2[CH:17]=[CH:16][C:15]1=[O:25]
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Reactant: Cn1c2c(ccc1=O)C(=O)CCC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cn1c2c(ccc1=O)C(NCCc1ccc([N+](=O)[O-])cc1)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
A mixture of 2-(4-nitrophenyl)ethylamine (3.4 g), 5,6,7,8-tetrahydro-1-methyl-5-oxo-2(1H)-quinolinone (3.0 g), and para-toluenesulfonic acid (256 mg) was heated in refluxing toluene (70 ml), with azeotropic removal of water, for a total of 72 hrs. An additional 1.0 g of the amine was added at 24 and 48 hrs. The resulting solution was cooled and concentrated in vacuo. Sodium borohydride (0.6 g) was added to a solution of the residue in ethyl alcohol (70 ml). The resulting mixture was stirred at room temperature for 1 hr, and the mixture was concentrated in vacuo. The residue was quenched with water, and the mixture was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate concentrated. The residue was purified by high performance liquid chromatography (silica gel, eluted with methanol/ethyl acetate) to provide 3.8 g (69%) of product. Recrystallization from ethyl acetate afforded the analytical sample, mp 138°-139° C.,
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[OH:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:2].CCN(CC)CC.[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:2]
Reactant: CCOC(=O)c1ccc(O)c(C#N)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
Dissolve the ethyl 3-cyano-4-hydroxy-benzoate (22.36 g, 117.1 mmoles) in anhydrous CH2Cl2 (400 mL) at 0° C. Add Et3N (24.3 mL, 175.6 mmoles), DMAP (2.14 g, 17.5 mmol), and dropwise Tf2O (49.5 g, 175.6 mmoles). Stir the mixture at room temperature for 2 hours. Concentrate the mixture under reduced pressure and subject residue to silica gel chromatography eluting hexane/EtOAc 4:1, to obtain 34.99 g of ethyl 3-cyano-4-trifluoromethanesulfonyloxy-benzoate (92% yield). MS(ES): m/z=190.0 [M-H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)([O:26][CH3:27])C3C=CC(C#N)=CC=3)=[C:15]3[C:10]([CH:11]=[C:12]([F:35])[C:13]([F:34])=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N-:36]=[N+:37]=[N-:38].[Na+].Cl.C([N:43]([CH2:46][CH3:47])CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[O:26][CH2:27][C:2]3[CH:7]=[CH:6][C:47]([C:46]4[N:36]=[N:37][NH:38][N:43]=4)=[CH:4][CH:3]=3)=[C:15]3[C:10]([CH:11]=[C:12]([F:35])[C:13]([F:34])=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(c1ccc(C#N)cc1)(c1c2cc(F)c(F)cc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cc2nn(-c3ccc(Cl)cc3)c(C(OCc3ccc(-c4nn[nH]n4)cc3)C3CCCCC3)c2cc1F

Procedure:
In analogy to the procedure described in example 31, [rac]-4-{[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-methoxymethyl}-benzonitrile (example 48) was reacted with sodium azide in the presence of triethylamine hydrochloride in DMF to obtain the title compound as brown oil. MS: m/e=535.2 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][CH2:31][CH2:32][C:3]1=2.CO.C(Cl)[Cl:43].Cl>C(OCC)C>[ClH:43].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]([F:24])([F:25])[F:26])=[CH:19][N:18]=4)=[CH:13][C:12]3=[O:27])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:28][NH:29][CH2:30][CH2:31][CH2:32][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)cn5)cc4=O)cc31)CNCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of tert-butyl 6-methyl-8-(2-oxo-4-(5-(trifluoromethyl)pyridin-2-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (80 mg, 0.20 mmol) in 5:1 MeOH/CH2Cl2 (6.0 mL) was treated with anhydrous 1.0 M HCl in diethyl ether (32 mL), and the resulting suspension was stirred at ambient temperature for 1 h. The solids were collected by filtration, washed with Et2O and dried to yield the title compound (58 mg, 85%) as a yellow powder: mp 264-270° C. decomp.; 1H NMR (500 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.89 (s, 2H), 8.39 (dd, J=8.5, 2.0 Hz, 1H), 8.34 (d, J=8.0 Hz, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.28 (d, J=1.5 Hz, 1H), 7.11 (dd, J=8.0, 1.5 Hz, 1H), 7.07 (d, J=7.5, 2.0 Hz, 1H), 4.47 (s, 2H), 3.74 (s, 3H), 3.47-3.45 (m, 2H), 3.11 (t, J=5.0 Hz, 2H), 2.08-2.06 (m, 2H); ESI MS m/z 439 [M+H]+; HPLC (Method A) 95.1% (AUC), tR=14.7 min.
Reaction SMILES: [C:1]([N:4]([CH3:27])[NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:17](=[O:26])[C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[CH3:28]C(C)([O-])C.[K+].CI>CN1CCCC1=O.C(OCC)(=O)C>[C:1]([N:4]([CH3:27])[N:5]([C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:17](=[O:26])[C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][CH:7]=1)[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C)Nc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CC(=O)N(C)N(C)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
To a solution of 4-(2-acetyl-2-methylhydrazino)-8-(2,6-dichlorobenzoylamino)quinoline (140 mg) in N-methylpyrrolidone (1.5 ml) was added potassium tert-butoxide (40.9 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. Methyl iodide (59.1 mg) was added thereto under ice-cooling, and the mixture was stirred for 12 hours at ambient temperature. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (methanol-dichloromethane) and recrystallized from ethanol to give 4-(2-acetyl-1,2-dimethylhydrazino)-8-(2,6-dichlorobenzoylamino)quinoline (62 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:16]([F:19])([F:18])[F:17])[O:13]2)=[CH:8][CH:7]=1)([CH3:5])[CH3:4].[Cl:25]Cl>CCOC(C)=O.C(Cl)Cl>[Cl:25][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[C:3]([CH3:5])([CH3:4])[CH2:2][OH:1])[O:13][CH:12]([C:16]([F:18])([F:19])[F:17])[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10]2
Reactant: ClCl
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)CO)cc2OC1C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)CO)cc2OC1C(F)(F)F

Procedure:
A single treatment of ethyl 7-(2-hydroxy-1,1-dimethylethyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (5.4 g 16 mmoles) with Cl2 was performed as described in Example 115 Step 2. Chromatography of the residue using a gradient of 0-10% EtOAc—DCM as eluent gave the title compound, 3.7 g, as a nearly colorless oil.
Reaction SMILES: C(C1C=C([CH2+]=NC2C=CC(OC3C=CN=C(C(NC)=O)C=3)=CC=2F)N(C2C=CC=C(CO)C=2)N=1)(C)(C)C.[C:38]([C:42]1[CH:46]=[C:45]([NH:47][C:48]([NH:50][C:51]2[CH:67]=[CH:66][C:54]([O:55][C:56]3[CH:61]=[CH:60][N:59]=[C:58]([C:62]([NH:64][CH3:65])=[O:63])[CH:57]=3)=[CH:53][C:52]=2[F:68])=[O:49])[N:44]([C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][OH:76])[CH:70]=2)[N:43]=1)([CH3:41])([CH3:40])[CH3:39].N1C=CC=CC=1.[CH3:83][O:84][CH2:85][C:86](Cl)=[O:87]>ClCCl.CCOC(C)=O>[CH3:83][O:84][CH2:85][C:86]([O:76][CH2:75][C:71]1[CH:72]=[CH:73][CH:74]=[C:69]([N:44]2[C:45]([NH:47][C:48](=[O:49])[NH:50][C:51]3[CH:67]=[CH:66][C:54]([O:55][C:56]4[CH:61]=[CH:60][N:59]=[C:58]([C:62](=[O:63])[NH:64][CH3:65])[CH:57]=4)=[CH:53][C:52]=3[F:68])=[CH:46][C:42]([C:38]([CH3:41])([CH3:39])[CH3:40])=[N:43]2)[CH:70]=1)=[O:87]
Reactant: COCC(=O)Cl
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Agent: CNC(=O)c1cc(Oc2ccc(N=[CH2+]c3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(COC(=O)COC)c3)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.5 %

Procedure:
To a 0° C. solution of example 1, (4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide, (0.15 g, 0.28 mmol) in dichloromethane (1.5 mL)/pyridine (0.5 mL) was added dropwise methoxyacetyl chloride (0.03 mL, 0.34 mmol). The reaction mixture was allowed to warm to room temperature and stir for 72 h. The reaction mixture was diluted with EtOAc and washed with sat. aqueous.NaHCO3. The combined organic layer was washed with brine, dried and concentrated. The crude material was purified via column chromatography (CH2Cl2: MeOH, 100% CH2Cl2 to 98.5:1.5) to afford 0.16 g (96%) of the desired product as a white solid. MS m/z 605.1 (M+H)+; Retention time (LC-MS): 3.44 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:15][CH2:16][NH2:17])[CH3:2].[C:19](Cl)(=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][CH:16]=[CH:15][C:7]=12)[CH3:2]
Reactant: CCOC(=O)Cc1c(CCN)[nH]c2ccccc12
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)Cc1c2ccccc2n2c(-c3ccccc3)nccc12

Procedure:
12,2 g of 1-phenyl-pyrimido[1,6-a]indole-5-acetic acid ethyl ester (m.p. 59°-62°), obtained from 2-aminoethyl-indole-3-acetic acid ethyl ester and benzoylchloride and the resulting 1-phenyl-3,4-dihydro-pyrimido[1,6-a]indole-5-acetic acid ethyl ester (m.p. 83°-84°), are stirred with 30 ml of ethanol and 40 ml of 2n sodium hydroxide in the course of 3 hours at room temperature. The mixture is acidified with concentrated hydrochloric acid to pH=3 and 30 ml of propyleneoxide, while stirring, are added. After short time 1-phenyl-pyrimido[1,6-a]indole-5-acetic acid crystallises out and is filtered off. The acid is recrystallised from ethanol, m.p. 198-204 (decomposition).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[CH2:30][CH3:31])=[CH:11][CH:10]=1)#[N:2].[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH2:30]([C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:34][N:33]=[N:32][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH3:31]
Reactant: CCOC(=O)c1cccc2nc(CC)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc2nc(CC)n(Cc3ccc(-c4ccccc4-c4nnn[nH]4)cc3)c12
Reaction time: 120 h

Procedure:
A mixture of ethyl 1-[(2'-cyanobiphenyl-4yl)methyl]-2-ethylbenzimidazole-7-carboxylate (1.55 g), sodium azide (2.6 g) and ammonium chloride (2.14 g) in DMF (15 ml) was stirred for 5 days at 110°-120 C. The reaction mixture was worked up according to the procedure described in Working Example 23 to give crystals. Recrystallization from ethanol afforded colorless prisms (0.68 g, 40%), m.p. 188°-189° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])=[CH:20][N:19]=2)[C:3]1=[O:32].Br[C:34]1[C:35]([CH3:54])=[C:36]([N:40]2[CH:49]=[CH:48][C:47]3[C:42](=[CH:43][CH:44]=[C:45]([N:50]([CH3:52])[CH3:51])[CH:46]=3)[C:41]2=[O:53])[CH:37]=[CH:38][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[CH3:51][N:50]([CH3:52])[C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[C:41](=[O:53])[N:40]([C:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:6]3[CH:5]=[C:4]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([C:24]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[O:25])=[CH:20][N:19]=4)[C:3](=[O:32])[N:2]([CH3:1])[CH:7]=3)[C:35]=1[CH3:54])[CH:49]=[CH:48]2
Reactant: Cc1c(Br)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1-n1ccc2cc(N(C)C)ccc2c1=O
Temperature: 100 °C
Yield: 78 %

Procedure:
To 1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (69 mg, 0.16 mmol), 2-(3-Bromo-2-methyl-phenyl)-6-dimethylamino-2H-isoquinolin-1-one (36 mg, 0.10 mmol), potassium phosphate (43 mg, 0.20 mmol), 2-(dicyclohexylphoshphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (2.9 mg, 0.0061 mmol), and bis(dibenzylidineacetone)palladium(0) (1.7 mg, 0.0030 mmol) was added 4 mL of degassed 1:3 water/n-butanol. The headspace of the vessel was evacuated and backfilled with argon 4 times. This was heated at 100° C. for 110 minutes. This was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 2 to 10% methanol/dichloromethane) to yield 6-Dimethylamino-2-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-2H-isoquinolin-1-one (46 mg, 0.078 mmol). MS (ESI) 591.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5](OCC)=[O:6].[CH3:14][NH:15][NH2:16]>>[CH3:14][N:15]([C:5](=[O:6])[C:4]1[CH:10]=[CH:11][C:12]([OH:13])=[C:2]([OH:1])[CH:3]=1)[NH2:16]
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Reactant: CNN
Product: CN(N)C(=O)c1ccc(O)c(O)c1

Procedure:
0.11 g (0.05 mol) of 3,4-dihydroxybenzoic acid, ethyl ester and 106 ml of methylhydrazine (2 mol) were refluxed for 3 days. The reaction mixture was evaporated in vacuo and the oily residue treated with ethanol and evaporated again. This was repeated once more. After retreatment with ethanol, 3,4-dihydroxybenzoic acid, 1-methylhydrazide began to crystallize. The crude product was removed by filtration and recrystallized from ethanol; yield: 3.8 g, melting point 202°-205° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1.[ClH:23].O1CCOCC1.C(OC(C)C)(C)C>ClCCl>[ClH:23].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2OCO3)CC1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1cc2c(c(N3CCNCC3)c1)OCO2
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
In a 50 mL flask, Tert-butyl 4-(benzo[d][1,3]dioxol-4-yl)piperazine-1-carboxylate (1.145 g, 3.74 mmol) was combined with dichloromethane M (20 ml) to give a colorless solution. Hydrochloric acid solution, 4M in dioxane (9.34 ml, 37.4 mmol) was added and the reaction mixture was stirred for 4 hours at room temperature. 15 ml of Diisoproylether were added and the mixture was stirred for 5 min at 0° C. The precipitate was collected by filtration, washed with 2 ml of diisopropylether and dried to yield the title compound as a white solid (0.955 grs, 100%). MS (ISP) m/z=207.4 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C@H:11]([OH:18])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19][C:20]([C:30]([F:33])([F:32])[F:31])=[CH:21][C@@H:22]1[C@H:24]([C:25](Cl)=[O:26])[C:23]1([CH3:29])[CH3:28].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:19][C:20]([C:30]([F:31])([F:32])[F:33])=[CH:21][C@@H:22]1[C@H:24]([C:25]([O:18][C@H:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C@H:9]([CH2:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH2:10]2)=[O:26])[C:23]1([CH3:29])[CH3:28]
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: O[C@@H]1C[C@@H](Cc2cccc(F)c2)c2ccccc21
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O[C@@H]1C[C@@H](Cc2cccc(F)c2)c2ccccc21
Yield: 81.4 %

Procedure:
In the manner of Example 4, the reaction of 1.00 g (0.004 mole) of trans-3-[(3-fluorophenyl)methyl]-1-indanol (98% trans, 2% cis) and 1.07 g (0.004 mole) of cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride in the presence of 0.32 g (0.004 mole) of pyridine and 50 mL of toluene gave 1.52 g of trans-3-[(3-fluorophenyl)-methyl]-1-indanyl cis-3-(2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate. The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][N:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].C(N(CC)CC)C.[Cl:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[Cl:41])[C:35](Cl)=[O:36].O>C1COCC1>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:40]([Cl:41])=[C:32]([Cl:31])[CH:33]=4)=[CH:18][N:17]=3)[CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:2]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cn1ccc2c(Oc3ccc(N)cn3)cccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2c(Oc3ccc(NC(=O)c4ccc(Cl)c(Cl)c4)cn3)cccc21
Yield: 87.3 %

Procedure:
[4-(5-Aminopyridin-2-yloxy)indole-1-yl]acetic acid ethyl ester (0.715 g, 2.30 mmol) was dissolved in THF (10 mL). To the solution were added triethylamine (0.320 mL, 2.30 mmol), then 3,4-Dichlorobenzoyl chloride (0.481 g, 2.30 mmol), and the resulting solution was stirred for 30 minutes at room temperature. Water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL). After the organic layer was washed with brine, then dried over anhydrous sodium sulfate, the solvent was evaporated. The obtained residue was recrystallized from ethyl acetate and n-hexane to yield 0.972 g of the title compound as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:19][C@H:18]([CH2:20][O:21]C(=O)C)[C@@H:13]([O:14]C(=O)C)[C@H:8]2[O:9]C(=O)C)[C:5]2[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=2[N:3]=1.[N:29]1([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH:33]=[CH:32][N:31]=[CH:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.O>[N:29]1([C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH:1][C:2]3[N:6]([C@@H:7]4[O:19][C@H:18]([CH2:20][OH:21])[C@@H:13]([OH:14])[C@H:8]4[OH:9])[C:5]4[CH:25]=[CH:26][CH:27]=[CH:28][C:4]=4[N:3]=3)=[CH:36][CH:35]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: O=Cc1ccc(-n2ccnc2)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3ccccc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC[C@H]1O[C@@H](n2c(NCc3ccc(-n4ccnc4)cc3)nc3ccccc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
2-Amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-1H-benzimidazole (94 mg) and 4-(1H-imidazol-1-yl)benzaldehyde (41 mg) were suspended in tetrahydrofuran (3 mL), and the mixture stirred at room temperature for 2 hours. To the reaction mixture was added acetic acid (200 μL), and then was added sodium triacetoxyborohydride (56 mg). The mixture was stirred at room temperature for 24 hours. After adding water to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was dissolved in ethanol (2 mL). To the mixture was added 5 mol/L aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added acetic acid (1 mL), and the mixture was concentrated under reduced pressure. The obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (67 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[CH:15]([NH:16][CH3:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(OC[CH2:24][CH2:25][CH:26]([C:38]1[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=1)[O:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1)(=O)=O.[C:46](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[CH2:14][CH:13]2[CH:15]([N:16]([CH3:46])[CH2:17][CH2:24][CH2:25][CH:26]([C:38]3[CH:39]=[CH:40][C:41]([C:44]#[N:45])=[CH:42][CH:43]=3)[O:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=3)[CH:10]([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(OC(CCCOS(C)(=O)=O)c2ccc(C#N)cc2)cc1OC
Reactant: CNC1C2CCC1CN(Cc1ccccc1)C2
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OC(CCCN(C)C2C3CCC2CN(Cc2ccccc2)C3)c2ccc(C#N)cc2)cc1OC
Temperature: 90 °C
Yield: 26.8 %

Procedure:
A mixture of 3-benzyl-N-methyl-3-azabicyclo[3.2.1]octan-8-amine (Preparation B; 1.3 g, 5.95 mmol), 4-(4-cyanophenyl)-4-(3,4-dimethoxyphenoxy)butyl methanesulfonate (Preparation I(iii); 2.41 g, 5.95 mmol), and potassium carbonate (822 mg, 5.95 mmol) in DMF (25 mL) was heated at 90° C. under nitrogen overnight. The mixture was partitioned with water (50 mL) and diethyl ether (40 mL). The aqueous layer was extracted with diethyl ether (2×40 mL). The combined organic extracts were washed with brine (2×30 mL), dried (Na2SO4), filtered and then concentrated in vacuo. The residue was chromatographed on silica gel, eluting with dichloromethane:methanol (98:2), to afford 860 mg (27%) of the sub-title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[K+].Cl>O.C(O)C>[CH2:13]([O:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([Cl:1])[CH:10]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)c1ccc(O)cc1Cl
Reactant: CCCCCCCBr
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCOc1ccc(C(=O)O)c(Cl)c1
Reaction time: 1.5 h
Yield: 75 %

Procedure:
A mixture of 4.0 parts of 2-chloro-4-hydroxybenzoic acid, 8.3 parts of 1-bromoheptane, 2.6 parts of potassium hydroxide, 10 parts of water and 90 parts by volume of ethanol was refluxed for 20 hours. A solution of 2.5 parts of potassium hydroxide in 50 parts of water was then added and refluxing continued for an additional 1.5 hours. The reaction mixture was diluted with 100 parts of water, acidified with concentrated hydrochloric acid and extracted with methylene chloride. The combined extracts were dried over sodium sulfate, the solvent evaporated and the resultant residue recrystallized from hexane. 4.5 Parts of 4-heptyloxy-2-chlorobenzoic acid (75% yield) was obtained having a melting point of 76°-78° C.