Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8](Cl)=[N:7][C:6]([OH:10])=[N:5]1)([CH3:3])[CH3:2].[F-:11].[K+]>S1(CCCC1)(=O)=O>[CH:1]([N:4]1[C:8]([F:11])=[N:7][C:6]([OH:10])=[N:5]1)([CH3:3])[CH3:2]
Reactant: [F-]
Reactant: CC(C)n1nc(O)nc1Cl
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CC(C)n1nc(O)nc1F

Procedure:
16.2 g of 1-isopropyl-5-chloro-3-hydroxy-1,2,4-triazole, 29 g of dry potassium fluoride and 150 ml of sulpholane are heated together for 16 hours to 160°-200°C. The solvent is evaporated in a high vacuum and the residue then treated with 10 % acetic acid and extracted with ethyl acetate. The ethyl acetate is evaporated off and the residueal solid is recrystallised from water, in the process of which 1-isopropyl-5-fluoro-3-hydroxy-1,2,4-triazole is obtained in the form of white crystals with a melting point of 80°-95°C. The product can be recrystallised from an organic solvent in order to purify it further.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:23][CH2:24]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:31]1([C:37]2([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:23][CH2:24][N:40]3[CH2:39][CH2:38][C:37]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)([C:43]([NH2:45])=[O:44])[CH2:42][CH2:41]3)[CH2:13][CH2:12][N:11]([C:14](=[O:22])[C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: O=C(c1ccc(Cl)cc1)N1CCC(CCCS(=O)(=O)[O-])(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Product: NC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CCN(C(=O)c3ccc(Cl)cc3)C2)CC1

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3,4-dichloro-phenyl)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (0.6 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (0.72 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C[N:34](C)[CH2:35][CH2:36][NH2:37]>>[ClH:1].[NH2:34][CH2:35][CH2:36][NH:37][C:12](=[O:14])[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:31])([F:30])[F:32])[CH2:21][CH2:22]2)=[O:16])=[CH:7]1
Reactant: CN(C)CCN
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21
Product: Cl
Product: NCCNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) N1,N1-dimethyl-ethane-1,2-diamine, gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.C(N(CC)CC)C.[CH2:24]([N:26]([CH2:39][CH3:40])[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=1[O:37][CH3:38])[CH3:25].O>O1CCCC1>[Cl:1][C:2]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([NH:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH2:28][CH2:27][N:26]([CH2:39][CH3:40])[CH2:24][CH3:25])=[C:31]([O:37][CH3:38])[CH:32]=1)=[O:8]
Reactant: CCN(CC)CCOc1ccc(N)cc1OC
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CCOc1ccc(NC(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1OC
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
171 mg (0.82 mmol) of CDl was added to a solution of 185 mg (0.73 mmol) of (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (cf intermediate product Z2b) in 5 mL tetrahydrofuran and the reaction mixture was stirred for 30 minutes at 50° C. Then 0.1 mL (0.73 mmol) of triethylamine and 200 mg (0.73 mmol) of 4-(2-diethylamino-ethoxy)-3-methoxy-phenylamine (see intermediate product Z6b) were added and the solution was stirred for 16 hours at RT. The reaction solution was added to water and stirred for 45 minutes at RT. After filtration the residue was dried in the circulating air dryer.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:28]3[N:29]=[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]4[CH:36]=3)[CH:26]=[CH:27][C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:39][N:38]=[N:37][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:28]3[N:29]=[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]4[CH:36]=3)[CH:26]=[CH:27][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[[2-n-propyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([O:17][CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+].Cl.C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]2[N:19]=[N:20][NH:21][N:14]=2)=[C:11]([O:17][CH3:18])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(OCc2ccccc2)ccc1C#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(OCc2ccccc2)ccc1-c1nn[nH]n1
Reaction time: 0.5 h

Procedure:
A vigorously stirred suspension of 4-benzyloxy-2-methoxybenzonitrile (1-B) (1.20 g, 5.0 mmol), sodium azide (732 mg, 11.3 mmol), and triethylamine hydrochloride (1.54 g, 11.3 mmol) in toluene (6 mL) was heated at 110° for 48 h. The brown suspension was cooled, water (15 mL) was added, and the mixture stirred for 30 min. The organic layer was separated and extracted with water (5 mL). The combined aqueous extracts were acidified to about pH 1 with concentrated HCl. The gum that initially precipitated solidified upon stirring for 30 min. The solid was filtered, washed with water, and dried to give 5-[4-(benzyloxy)2-methoxyphenyl]-2H-tetrazole (1-C). 1H NMR (500 MHz, CDCl3): δ 12.9 (vbs, 1H), 7.37 (d, 1H, J=8.7 Hz), 7.34-7.48 (m, 5H), 6.78 (dd, 1H, J=2.3, 8.7 Hz), 6.70 (d, 1H, J=2.3 Hz), 5.15 (s, 2H), 4.05 (s, 3H) ppm.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[Cl:31])[C:25](O)=O>>[Br:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: O=C(O)c1ccc(Cl)c(Br)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3ccc(Cl)c(Br)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-bromo-4-chlorobenzoic acid: MS (ESI): m/z 481 (M+1).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.[C:9](C1C=CC(O)=CC=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>C1(C)C=CC=CC=1>[C:9]([C:1]1[CH:2]=[C:3]([CH3:8])[CH:4]=[CH:5][C:6]=1[OH:7])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH3:10]
Reactant: Cc1ccc(O)cc1
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(O)c(C(C)(C)c2ccccc2)c1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
Paracresol 34.15 g (316.0 mmol), Amberlyst 15E 2.50 g, and toluene 20 ml were charged in a sufficiently dried 200 ml reactor purged with argon, 30 ml of a toluene solution containing 4-cumylphenol 14.40 g (105.5 mmol) was added dropwise to the reactor at 80° C. and then the resultant mixture was stirred for 17 hours. After cooling to a room temperature, the resultant mixture was filtered while being washed with hexane. The obtained liquid was purified by silica gel column chromatography to obtain 2-cumyl-4-methylphenol 10.52 g (44%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1.[CH3:20][O:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:23]>CC(N(C)C)=O.C(OCC)(=O)C.O>[CH3:20][O:21][C:22]([C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[N:11]=[CH:10][CH:9]=2)[CH:25]=1)=[O:23]
Reactant: COc1ccc2nccc(Cl)c2c1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(-c2ccnc3ccc(OC)cc23)c2ccccc12
Temperature: 140 °C
Reaction time: 20 h

Procedure:
1.73 g (12.5 mmol) of potassium carbonate and 0.968 g (5 mmol) of 4-chloro-6-methoxyquinoline are added to 0.876 g (5 mmol) of 3-methoxycarbonyl-1H-indole in 20 cm3 of dimethylacetamide under an argon atmosphere. After stirring at a temperature in the region of 140° C. for 20 hours, the reaction mixture is cooled and diluted with 200 cm3 of ethyl acetate and 200 cm3 of water. The organic phase is separated off by settling and washed with three times 200 cm3 of water and 200 cm3 of saturated aqueous sodium chloride solution and then it is dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 and then 7/3 by volume)]. Concentrating these fractions to dryness under reduced pressure (2.7 kPa) results in 0.7 g of 3-methoxycarbonyl-1-(6-methoxyquinol-4-yl)-1H-indole in the form of a white powder. Mass spectrum (EI): m/e 332 (M+•), m/e 301.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:5]([CH3:29])[CH:4]=1)#[N:2].C1C=C(Cl)C=C(C(OO)=[O:38])C=1>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:21])=[O:38])=[CH:16][CH:15]=3)=[CH:12][CH:11]=[C:10]2[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:5]([CH3:29])[CH:4]=1)#[N:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(SC)cc2)n1-c1ccc(C#N)cc1C
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(-c2ccc(S(C)=O)cc2)n1-c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
To a solution of ethyl 3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylthio)phenyl)-1H-pyrrol-2-yl)propanoate (23A) (98 mg, 0.23 mmol) in DCM (1 mL) was added m-CPBA below 0° C. by five portions. Then the reaction mixture was stirred at room temperature for 3 h. TLC showed that the reaction was complete. The mixture was diluted with DCM (10 mL) and washed with sat. NaHCO3 (15 mL), dried over Na2SO4, filtered and concentrated to afford a yellow oil, which was purified by silica gel column chromatography to afford ethyl 3-(1-(4-cyano-2-methylphenyl)-5-(4-(methylsulfinyl)phenyl)-1H-pyrrol-2-yl)propanoate (23B) as a light yellow solid (65 mg, 65%).
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:36]1([CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([N:45]3[CH2:46][CH2:47][CH:42]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[CH2:43][CH2:44]3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)=[CH:22][CH:21]=2)[CH:9]=1
Reactant: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)cc2)S(=O)(=O)N1
Reactant: c1ccc(C2CCNCC2)cc1
Product: O=C1CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(N4CCC(c5ccccc5)CC4)cc3)cc2)S(=O)(=O)N1

Procedure:
5-{4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (119 mg, 0.2 mmol) was treated as described in general procedure R using 4-phenylpiperidine (162 mg, 1 mmol) to give 5-(4-{4-(2,4-dichloro-phenyl)-2-[4-(4-phenyl-piperidin-1-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:18][CH:17]=1
Reactant: NCc1ccc(Br)cc1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(NCc2ccc(Br)cc2)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
The mixture of methyl 4-fluoro-3-nitrobenzoate (2 g, 10.1 mmol), (4-bromophenyl)methanamine (1.87 g, 10.1 mmol) and K2CO3 (2.77 g, 10.1 mmol) in TI-IF (40 mL) was stirred at 40° C. for 2 hrs, then the mixture was filtered and the filtrate was concentrated to get a yellow solid which was washed by MTBE and EtOAc (10/1,100 mL) to give the titled compound.
Reaction SMILES: Cl.N#[C:3]N.C(C1C(C2N(CC)C(C)=NC=2)=[N:9][C:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20](=O)(=O)NCCOC)=[CH:16][CH:15]=2)=[N:11]C=1)#N.[CH2:36]([OH:38])[CH3:37]>>[OH:38][CH2:36][CH2:37][CH2:3][S:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:10]([NH2:9])=[NH:11])=[CH:19][CH:18]=1
Reactant: CCO
Reactant: CCn1c(-c2nc(Nc3ccc(S(=O)(=O)NCCOC)cc3)ncc2C#N)cnc1C
Reactant: N#CN
Agent: Cl
Product: N=C(N)Nc1ccc(SCCCO)cc1
Reaction time: 6 h

Procedure:
2M Hydrochloric acid (10 ml) and cyanamide (500 mg) were added to a solution of 4-(3-hydroxypropylthio)aniline (Method 83; 900 mg) in ethanol (1 ml). The mixture was stirred under reflux for 19 hours and further 2M hydrochloric acid (0.5 ml) and cyanamide (400 mg) were added and heating continued for a further 6 hours. The volatiles were removed by evaporation, water (5 ml) was added to the residue and the mixture basified with concentrated sodium hydroxide solution to greater than pH11. The aqueous mixture was extracted with EtOAc (2×30 ml) washed with water (5 ml) and brine (10 ml). The organic extracts were combined, evaporated, and azeotroped with methanol to give crude 4-(3-hydroxypropylthio) phenylguanidine (880 mg) as a purple oil (m/z 226). This crude product was treated with 5-(3-dimethylaminoprop-2-en-1-oyl)-1-isopropyl-2-methylimidazole (Method 24; 400 mg, 1.81 mmol) as described in Method 30 to give the title compound (400 mg, 58%). NMR: 1.44 (d, 6H), 1.68 (m, 2H), 2.92 (t, 2H), 3.34 (s, 3H), 3.49 (m, 2H), 4.52 (t, 1H), 5.70 (sept, 1H), 7.05 (d, 1H), 7.30 (d, 2H), 7.42 (s, 1H), 7.64 (d, 2H), 8.39 (d, 1H), 9.51 (s, 1H); m/z 384.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([CH3:26])=[C:7]([CH3:25])[C:8]2[O:12][C:11]([CH3:22])([CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:10][C:9]=2[C:23]=1[CH3:24])(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:4][C:5]1[C:6]([CH3:26])=[C:7]([CH3:25])[C:8]2[O:12][C:11]([CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)([CH3:22])[CH2:10][C:9]=2[C:23]=1[CH3:24])[CH3:2]
Reactant: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(CCc1ccc(F)cc1)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1c(C)c(C)c2c(c1C)CC(C)(CCc1ccc(F)cc1)O2
Temperature: 0 °C
Yield: 71.2 %

Procedure:
To tetrahydrofuran (20 ml) were added 5-acetylamino-2,4,6,7-tetramethyl-2-[2-(4-fluorophenyl) ethyl]-2,3-dihydrobenzofuran (1.2 g, 3.4 mmol) and lithium aluminum hydride. The mixture was heated under reflux for 3 hours. The reaction mixture was poured into ice water and the product was extracted with ethyl acetate. The extract was washed with water and dried and then the solvent was distilled off. The residue was purified by column chromatography on silica gel (isopropyl ether-ethyl acetate, 2:1) to obtain the desired compound (0.82 g, yield: 71.2%}as oil.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][Cl:37])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].C(=O)(O)[O-].[K+].[I-].[K+]>C1(C)C=CC=CC=1.O>[ClH:37].[C:21]([C:25]1[CH:26]=[CH:27][C:28]([C:31](=[O:38])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][N:12]2[CH2:13][CH2:14][CH:9]([C:7]([OH:8])([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[CH:29][CH:30]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)c1ccc(C(=O)CCCCCCl)cc1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(C(=O)CCCCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Product: Cl
Reaction time: 96 h

Procedure:
A mixture of 22.4 g (0.08 mole) of α,α-diphenyl-4-piperidinemethanol, 23.8 g (0.09 mole) of 4'-tert-butyl-6-chlorocaprophenone, 20 g (0.2 mole) of potassium bicarbonate, 0.1 g of potassium iodide in 300 ml of toluene and 45 ml of water is stirred on a steam bath for about 96 hours after which the organic layer is separated and combined with toluene extracts of the aqueous layer. The combined organic material is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and filtered. The filtrate is diluted with ether and made acidic with ethereal HCl. The resulting precipitate is recrystallized from methanol-butanone to give 4'-tert-butyl-6-[4-(α-hydroxy-α-phenylbenzyl)piperidino]caprophenone hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)\[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[N+]([O-])(O)=O.O>ClCCCl.P(=O)(O)(O)O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[N:17]1[CH:21]=[N:20][CH:19]=[N:18]1)\[CH:11]([OH:16])[C:12]([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)C(=O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Agent: O=P(O)(O)O
Solvent: O=[N+]([O-])O
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Reaction time: 20 h
Yield: 96.2 %

Procedure:
Thereafter, 0.35 g of phosphoric acid and then a solution of 16.12 g (0.0497 mole) of (E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-one (E/Z=97.6/2.4) in 49.37 g of 1,2-dichloroethane were added at 20° to 25° C., and stirring was carried out at the same temperature for 20 hours. The reaction solution was decomposed with addition of 24.17 g of 20% nitric acid and 4.6 g of water, and the organic layer was separated, washed with water and concentrated under reduced pressure to obtain 15.60 g of (-)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol as a crystal. The conversion was 99.8%, and the composition of the product obtained was: E-form alcohol, 95.6%; saturated alcohol, 0.4%; Z-form alcohol, 3.2%; and others, 0.8%. The enantiomer ratio of the E-form alcohol was: (-)-isomer, 85.8% and (+)-isomer, 14.2%. The optical yield was 71.6%.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[C:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])=[CH:4][C:3]=1[O:15][CH3:16].[Cl-:17].[CH3:18][N+:19](=[CH2:21])[CH3:20]>C(#N)C>[ClH:17].[OH:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[C:7]2[CH2:11][CH2:10][CH:9]([CH2:18][N:19]([CH3:21])[CH3:20])[C:8]2=[O:12])=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: [Cl-]
Reactant: C=[N+](C)C
Reactant: COc1cc(C=C2CCCC2=O)ccc1O
Solvent: CC#N
Product: COc1cc(C=C2CCC(CN(C)C)C2=O)ccc1O
Product: Cl
Yield: 91.1 %

Procedure:
0.03 mol of 2-(4-hydroxy-3-methoxybenzylidene)cyclopentanone was dissolved in mL anhydrous acetonitrile, treated with 8.4 g (0.09 mol) of N,N-dimethyl-methylene ammonium chloride under refluxing, refluxed for 12 h to yield a solid product which was suction filtered, dried and recrystallized in acetonitrile/chloroform to yield 2-(4-hydroxy-3-methoxybenzylidene)-5-dimethylaminomethyl-cyclopentanone hydrochloride with a yield of 91.1%.
Reaction SMILES: [S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].C(OC(=O)[N:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:33]=[CH:32][C:31](N)=[CH:30][CH:29]=1)[CH:20]=[CH:19]2)C)(C)(C)C.[F:36][CH:37]([F:47])[C:38]1[CH:39]=[C:40](S(N)(=O)=O)[S:41][CH:42]=1>>[NH2:14][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:29]=[CH:30][C:31]([NH:7][C:5]([NH:4][S:1]([C:40]3[S:41][CH:42]=[C:38]([CH:37]([F:47])[F:36])[CH:39]=3)(=[O:3])=[O:2])=[O:6])=[CH:32][CH:33]=1)[CH:20]=[CH:19]2
Reactant: NC(=O)N=S(=O)=O
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc(N)cc3)c(=O)c2cc1F
Reactant: NS(=O)(=O)c1cc(C(F)F)cs1
Product: Nc1cc2ccn(-c3ccc(NC(=O)NS(=O)(=O)c4cc(C(F)F)cs4)cc3)c(=O)c2cc1F

Procedure:
An analogous sulfonylurea coupling and de-protection procedure to that described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and 4-difluoromethylthiophene-2-sulfonamide to give N-({[4-(6-amino-7-fluoro-1-oxoisoquinolin-2(1H)-yl)phenyl]amino}carbonyl)-4-difluoromethylthiophene-2-sulfonamide. ES-MS (M+H)+=523.1; 1H-NMR (DMSO-d6) δ (ppm): 9.24-9.16 (bs, 1H), 8.34-8.28 (m, 1H), 7.88-7.84 (m, 1H), 7.66-7.60 (d, J=12.4 Hz, 1H), 7.48-7.42 (d, J=8.8 Hz, 2H), 7.34-7.26 (d, J=8.8 Hz, 2H), 7.25-7.20 (d, J=7.3 Hz, 1H), 7.19-6.91 (t, J=55.3 Hz, 1H), 6.72-6.66 (d, 8.4 Hz, 1H), 6.58-6.48 (bs, 1H), 6.50-6.46 (d, J=7.3 Hz, 1H), 2.82-2.77 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:19]1[N:27]=[CH:26][N:25]=[C:24]2[C:20]=1[N:21]=[CH:22][NH:23]2.CCN(C(C)C)C(C)C>C(O)CCC>[C:1]1([C:7]2[C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[S:10][C:11]=2[CH2:12][NH:13][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: NCc1sc2ccccc2c1-c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: c1ccc(-c2c(CNc3ncnc4[nH]cnc34)sc3ccccc23)cc1
Temperature: 100 °C
Yield: 38.4 %

Procedure:
A mixture of C-(3-phenylbenzo[b]thiophen-2-yl)methylamine from Example 26 (230 mg, 0.961 mmol), 6-chloro-9H-purine (278 mg, 1.80 mmol) and DIPEA (0.34 mL, 1.92 mmol) in n-butanol (10 mL) was heated at 100° C. for 20 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) and then sonicated in diethyl ether. Further purification by column chromatography (Si—PCC, gradient 0-5% MeOH in DCM) afforded 165 as a white solid (132 mg, 38%). LCMS: RT 4.22 min [M+H]+ 358.1. 1H NMR (DMSO, 400 MHz): δ 12.96 (1H, s), 8.40 (1H, s), 8.23 (1H, s), 8.14 (1H, s), 7.94-7.85 (1H, m), 7.63-7.54 (4H, m), 7.51-7.43 (2H, m), 7.38-7.29 (2H, m), 4.94 (2H, s)