Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.[O:32]1CCCC1>>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[O:32]
Reactant: C1CCOC1
Reactant: N#Cc1ccc(N2CCOCC2)cc1F
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: O=Cc1ccc(N2CCOCC2)cc1F
Temperature: 25 °C
Reaction time: 23.5 h
Yield: 68 %

Procedure:
To a solution of 2-fluoro-4-(morpholino)-benzonitrile (2.82 g, 13.7 mmol) in tetrahydrofuran (27 ml) under a nitrogen atmosphere was added dropwise a 1.5 M solution of DIBAL-H in toluene (18.3 ml, 27.3 mmol) during 13 minutes and the resulting mixture stirred for 23.5 hr at room temperature. The mixture was cooled to −50° C. and the excess DIBAL-H destroyed by careful addition of methanol (27 ml). The mixture was then stirred at room temperature for 10 mins, saturated ammonium chloride (27 ml) added and the resulting mixture stirred at room temperature for 40 mins., and then evaporated under reduced pressure to a yellow solid. This solid was partitioned between dichloromethane (120 ml) and water (120 ml) and solid potassium carbonate added until the aqueous phase was pH 10. The phases were separate via a hydrophobic frit and the organic phase evaporated and the residue purified by a Biotage™ column (40 g, silica) eluting with cyclohexane:ethyl acetate: (7:3) to give 2-fluoro-4-(morpholino)-benzaldehyde (1.96 g, 68%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[CH3:15][O:16][C:17]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:18]=1[CH2:19][NH:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[N:28]([S:45]([C:48]3[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[C:29]([C:31]3[C:39]4[C:34](=[CH:35][C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[CH:38]=4)[N:33]([CH3:44])[CH:32]=3)=[CH:30][C:23]=12.O>ClCCl>[CH3:15][O:16][C:17]1[CH:58]=[C:57]([O:59][CH3:60])[CH:56]=[CH:55][C:18]=1[CH2:19][N:20]([CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[N:28]([S:45]([C:48]3[CH:49]=[CH:50][C:51]([CH3:54])=[CH:52][CH:53]=3)(=[O:47])=[O:46])[C:29]([C:31]3[C:39]4[C:34](=[CH:35][C:36]([O:42][CH3:43])=[C:37]([O:40][CH3:41])[CH:38]=4)[N:33]([CH3:44])[CH:32]=3)=[CH:30][C:23]=12)[C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)=[O:12]
Reactant: COc1ccc(CNCc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)c(OC)c1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CN(Cc2ccnc3c2cc(-c2cn(C)c4cc(OC)c(OC)cc24)n3S(=O)(=O)c2ccc(C)cc2)C(=O)Nc2ccc(OC(F)(F)F)cc2)c(OC)c1
Reaction time: 24 h

Procedure:
0.094 cm3 of 4-(trifluoromethoxy)phenyl isocyanate is added to a solution of 0.080 g of (2,4-dimethoxybenzyl)[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]amine in 6 cm3 of dichloromethane, under an argon atmosphere, at a temperature in the region of 20° C. The reaction medium is stirred at this same temperature for 24 hours. 2 cm3 of water are added. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 98/02 by volume as eluent), 0.150 g of 1-(2,4-dimethoxybenzyl)-1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]-3-(4-trifluoromethoxyphenyl)urea is obtained, the characteristics of which are as follows:
Reaction SMILES: CO[C:3](=[O:17])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([F:15])[CH:13]=2)[NH:8][CH:7]=1)=O.[C:18]1([CH2:30][C:31]([NH2:33])=[O:32])[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[CH:19]=1>>[C:18]1([C:30]2[C:31](=[O:32])[NH:33][C:3](=[O:17])[C:4]=2[C:6]2[C:14]3[C:9](=[CH:10][C:11]([Cl:16])=[C:12]([F:15])[CH:13]=3)[NH:8][CH:7]=2)[C:28]2=[C:29]3[C:24](=[CH:25][CH:26]=[CH:27]2)[CH2:23][CH2:22][CH2:21][N:20]3[CH:19]=1
Reactant: COC(=O)C(=O)c1c[nH]c2cc(Cl)c(F)cc12
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Product: O=C1NC(=O)C(c2cn3c4c(cccc24)CCC3)=C1c1c[nH]c2cc(Cl)c(F)cc12

Procedure:
Beginning with (5-fluoro-6-chloroindol-3-yl)oxoacetic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH2:24]([NH2:27])[CH:25]=[CH2:26]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:10][CH2:11][C:4]([C:1]([NH:27][CH2:24][CH:25]=[CH2:26])=[O:2])([CH2:9][CH2:8]2)[CH2:5][CH2:6]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: C=CCN
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: C=CCNC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2

Procedure:
In a similar manner to Example 51, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) and allylamine (14.0 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(2-propenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (15.7 mg).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]([OH:22])=[O:21])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na].O.O.[Cl-].[Ca+2:27].[Cl-]>O.[OH-].[Na+]>[Ca+2:27].[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]([O-:22])=[O:21])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][C:20]([O-:22])=[O:21])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C([O-])CCc1nc(-c2ccccc2)c(-c2ccccc2)o1

Procedure:
β-(4,5-Diphenyloxazol-2-yl)propionic acid (oxaprozin) was converted to the sodium salt by stirring the acid (6 kg) in distilled water (60 kg) and 46-48% sodium hydroxide liquor (1.85 kg). A filtered solution of calcium chloride dihydrate B.P, (2.44 kg) in distilled water was added and the title compound precipitated as a white solid. This was collected on a vacuum filter and washed with distilled water until the filtrate was free from chloride. The product was dried in an air oven to give a yield of 6.7 kg (98% of theory) of the title compound as a tetrahydrate.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[CH2:15][C@H:14]([NH:17][C:18](=[O:20])[CH3:19])[CH2:13][CH2:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:29](Br)[CH3:30]>CC(C)=O.C(OCC)(=O)C.CCCCCC>[CH2:29]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:16]=2[CH2:15][C@H:14]([NH:17][C:18](=[O:20])[CH3:19])[CH2:13][CH2:12]3)[CH2:2][CH2:3]1)[CH3:30]
Reactant: CCBr
Reactant: CC(=O)N[C@@H]1CCc2cccc(N3CCNCC3)c2C1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCN1CCN(c2cccc3c2C[C@H](NC(C)=O)CC3)CC1
Yield: 78 %

Procedure:
To a mixture of (R)-N-[8-(piperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]acetamide (100 mg, 0.37 mmol), potassium carbonate (76 mg, 0.54 mmol) and potassium iodide (15 mg, 0.10 mmol) in acetone (20 mL) was added ethyl bromide (56 μL, 0.74 mmol) added and the reaction mixture was vigorously stirred over night. The reaction was filtered and the solvent was evaporated in vacuo. The residue was purified on a silica gel column using chloroform/methanol/concentrated ammonium hydroxide (95:5:0.5) as the eluent. This gave 87 mg (78% yield) of the title compound as an oil which was crystallized from ethyl acetate/hexane. Yield: 55 mg (50%) as white crystals: mp 142-143° C.; [α]21D +27° (c 0.50, chloroform); EIMS (70 eV) m/z (relative intensity) 301 (100, M+).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.[F:40]C1C=CC=CC=1N1CCNCC1.[ClH:53]>O1CCCC1>[ClH:53].[ClH:53].[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:40])[CH2:10][CH2:9]1)=[O:7]
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CN(C)CCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccccc2F)CC1

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 2.2 g (0.01 mole) of 1,1'-carbonyldiimidazole, 2.2 g (0.01 mole) of unsym-dimethylethylenediamine and 2.5 g (0.01 mole of 1-(2-fluorophenyl)piperazine in a total volume of 100 ml of tetrahydrofuran gave an oil as residue. The hydrochloride was formed in ethereal hydrogen chloride and the solid recrystallized from methanol-diethyl ether to give 2.3 g (46%) of title compound as a white solid, m.p. 153°-155° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.Cl[CH2:24][C:25]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:26].CC(C)([O-])C.[K+].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][C:15]3[CH2:21][CH2:20][CH:19]([O:22][CH2:24][C:25]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[O:26])[CH2:18][C:16]=3[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:11][CH2:12]1
Reactant: OC1CCc2oc(-c3ccc(OCC4CC4)c(Cl)c3)nc2C1
Reactant: O=C(CCl)N1CCOCC1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(COC1CCc2oc(-c3ccc(OCC4CC4)c(Cl)c3)nc2C1)N1CCOCC1
Reaction time: 1 h

Procedure:
To a solution of 2-(3-chloro-4-(cyclopropylmethoxy)phenyl)-4,5,6,7-tetrahydro-1,3-benzoxazol-5-ol (5.63 g) and 4-(chloroacetyl)morpholine (4.58 mL) in THF (50 mL) was added potassium tert-butoxide (3.95 g), and the mixture was stirred for 1 hr under a nitrogen stream. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) to give the title compound (6.22 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[C:30]1([S:36](Cl)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:38])=[O:37])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3ccccc3)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.2 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of benzenesulfonyl chloride (66 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide (113 mg, 79.3%) as a white solid. MS (ESI+APCI) M+1=461.1.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([F:73])([F:72])[CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:71])[C@@H:20]([NH:53]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:21][S:22][CH2:23][C@H:24]([NH:39][C:40](=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1CCCCC1>C(#N)C>[NH2:53][C@@H:20]([CH2:21][S:22][CH2:23][C@H:24]([NH:39][C:40](=[O:52])[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:19](=[O:71])[NH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:9]([P:4](=[O:8])([O:5][CH2:6][CH3:7])[O:3][CH2:1][CH3:2])([F:72])[F:73]
Reactant: CCCCCCCCCCCCOC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)NC(=O)CCCCCCCCCCC
Solvent: CC#N
Solvent: C1CCNCC1
Product: CCCCCCCCCCCCOC[C@H](CSC[C@H](N)C(=O)NCCOCCOCCC(F)(F)P(=O)(OCC)OCC)NC(=O)CCCCCCCCCCC
Reaction time: 0.5 h

Procedure:
A solution of (12R,16R)-12-(((9H-fluoren-9-yl)methoxy)carbonylamino)-16-dodecanamido-1,1-difluoro-11-oxo-4,7,18-trioxa-14-thia-10-azatriacontylphosphonic acid diethyl ester in acetonitrile (0.1M) was stirred at room temperature. Piperidine (final conc. 20%) was then added and the reaction stirred for 30 minutes. After concentration, the crude material was by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-100% EtOAc/Hex, then 0-10% MeOH/DCM to give the title compound as an off-white solid.
Reaction SMILES: C(C1C2C(=CC=CC=2)C(C([O:16][C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([C:29](=[O:31])[CH3:30])=[CH:21][CH:20]=2)=O)=O)=CC=1)(=O)C.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(O)(=O)C>[C:33]1([N:32]=[C:17]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([C:29](=[O:31])[CH3:30])=[CH:21][CH:20]=2)[OH:16])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)c1ccc(C(=O)OC(=O)c2ccc(C(C)=O)c3ccccc23)c2ccccc12
Solvent: CC(=O)O
Product: CC(=O)c1ccc(C(O)=Nc2ccccc2)c2ccccc12

Procedure:
The method consists of a first synthesis stage, in which a mixture of 4-acetylnaphthalic anhydride, aniline, and glacial acetic acid is heated under reflux, the reaction mixture is cooled, the precipitated gray crystals are separated by filtration, treated with hydrochloric acid solution, then with hot sodium carbonate solution, and recrystallized from acetic acid. Acetyl derivative, the 4-acetylnaphthalic acid phenylimide is obtained.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)(=[O:16])=[O:15])[CH:11]=2)[CH2:6]1.[Li+].[OH-]>C1COCC1>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([N:20]2[CH2:19][CH2:18][N:17]([S:14]([C:10]3[CH:11]=[C:12]4[C:7](=[CH:8][CH:9]=3)[CH2:6][CH:5]([CH2:4][C:3]([OH:33])=[O:2])[CH2:13]4)(=[O:15])=[O:16])[CH2:22][CH2:21]2)=[CH:24][CH:25]=1
Reactant: COC(=O)CC1Cc2ccc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC1Cc2ccc(S(=O)(=O)N3CCN(c4ccc(C(F)(F)F)cc4)CC3)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
{5-[4-(4-Trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-acetic acid methyl ester (118 mg, 0.245 mmol) was dissolved in THF (10 mL). To this solution was added 1M LiOH (5 mL) and was stirred at room temperature for 3 h. TLC indicated that the reaction was complete. The reaction mixture was then quenched with Dowex 50WX4-50 until neutral and then filtered to afford pure {5-[4-(4-trifluoromethyl-phenyl)-piperazine-1-sulfonyl]-indan-2-yl}-acetic acid (112 mg, 98%) as a white solid. The product can be further purified by silica gel flash column chromatography (dichloromethane/MeOH/AcOH 95:5:0.1). 1H NMR (400 MHz, MeOH-d4) δ 7.60 (s, 1H), 7.56 (d, 1H), 7.45 (d, 2H), 7.41 (d, 1H), 7.00 (d, 2H), 3.32 (m, 4H), 3.22 (m, 2H), 3.17 (m, 4H), 2.88 (m, 1H), 2.72 (m, 2H), 2.47 (d, 2H); LCMS: 468.8 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]([CH:14]=[C:15]1[CH:21]=[CH:20][CH:19]=[C:17]([NH2:18])[CH2:16]1)=[O:13]>>[CH3:10][O:11][C:12]([CH:14]=[C:15]1[CH:21]=[CH:20][CH:19]=[C:17]([NH:18][C:2]2[N:7]=[C:6]([NH:18][C:17]3[CH2:16][C:15](=[CH:14][C:12]([O:11][CH3:10])=[O:13])[CH:21]=[CH:20][CH:19]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH2:16]1)=[O:13]
Reactant: COC(=O)C=C1C=CC=C(N)C1
Reactant: Fc1cnc(Cl)nc1Cl
Product: COC(=O)C=C1C=CC=C(Nc2ncc(F)c(NC3=CC=CC(=CC(=O)OC)C3)n2)C1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-(methoxycarbonylmethylene)aniline were reacted to produce the desired N2,N4-bis(3-methoxycarbonylmethylenephenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 10.23 (br s, 1H), 10.05 (br s, 1H), 8.26 (d, 1H, J=4.6 Hz), 7.64 (d, 1H, J=8.2 Hz), 7.51 (br s, 1H), 7.46 (d, 1H, J=8.2 Hz), 7.33 (br s, 1H), 7.29 (t, 1H, J=7.6 Hz), 7.20 (t, 1H, J=7.6 Hz), 7.06 (d, 1H, J=7.6 Hz), 6.93 (d, 1H, J=7.6 Hz), 3.63 (s, 2H), 3.58 (s, 3H), 3.57 (s, 3H), 3.56 (s, 2H); LCMS: ret. time: 21.74 min.; purity: 92%; MS (m/e): 425 (MH+).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:18][CH:19]([F:21])[F:20])[C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([Li])CCC.IC>C1COCC1>[C:1]1([C:7](=[N:14][C:15]([CH3:22])([CH2:18][CH:19]([F:20])[F:21])[C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CCCC
Reactant: N#CC(CC(F)F)N=C(c1ccccc1)c1ccccc1
Solvent: CI
Solvent: C1CCOC1
Product: CC(C#N)(CC(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
13.07 g (38.62 mmol) of rac-2-[(diphenylmethylene)amino]-4,4-difluorobutanonitrile from Example 67A were initially charged in 255 ml of abs. THF, and 15.6 ml (39.0 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for a further 10 min. Subsequently, 22.6 g (154.46 mmol) of iodomethane were added to the reaction solution at −78° C. The reaction mixture was gradually brought to 0° C. over 3.5 h. After complete depletion of the starting material, the reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate=15/1). 11.4 g of the target compound were obtained (91% of theory, 92% purity).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=O)[CH3:2].[CH3:10][C@@H:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)C.O>C1(C)C=CC=CC=1>[CH3:10][C@H:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:18]=[C:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:3]1[CH2:1][CH3:2]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CCC1CCCCC1=O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCC1CCCCC1=N[C@H](C)c1ccccc1

Procedure:
A solution of 2-ethylcyclohexanone (6.92 mol, 873 g), (R)-α-methylbenzylamine (6.92 mol, 839 g), and 19.6 mL of acetic acid were refluxed for 12 hours under nitrogen in 2 L of toluene with azeotropic removal of water. The toluene was removed on a rotary evaporator and the product was divided into two portions. The unreacted 2-ethylcyclohexanone was distilled through a short path (bp 30° C., <10 mm), and the remainder of the product was then distilled through a 5" vacuum jacketed Vigreux column affording first a low melting solid (bp 80°-90° C. 23 mm), and then the product (bp 128°-133° C. 21.0 mm, 1.303 kg from both distillations combined, 5.68 mol, 82%).
Reaction SMILES: CN(C)CC(C)C([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)=O.O.NN.[OH-].[Na+].ClC1C=CC([C:28]2[CH:32]([CH3:33])[CH2:31][NH:30][N:29]=2)=CC=1>C(O)CC>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([N:30]2[CH2:31][CH:32]([CH3:33])[CH:28]=[N:29]2)=[CH:12][CH:11]=1
Reactant: CC1CNN=C1c1ccc(Cl)cc1
Reactant: CC(CN(C)C)C(=O)c1ccc(Cl)cc1
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: O
Product: CC1C=NN(c2ccc(Cl)cc2)C1

Procedure:
In a 500 ml round bottomed flask equipped with a reflux condensor was placed 100 g of 3-dimethylamino-2-methyl-4'-chloropropiophenone (0.47 mole), 200 ml of n-propanol, 48 g of hydrazine monohydrate (0.96 mole), and 5 g of 50% aqueous sodium hydroxide. The mixture was refluxed for 2 hours. The solvent was removed in vacuo and the product was partitioned between methylene chloride and water. The organic layer was washed 3 times with water and dried over anyhdrous magnesium sulfate. The organic layer contains 82 g (0.42 mole) of 3-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole an air sensitive solid. NMR data was consistent with the structure.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30]O)=[CH:29][C:24]=2[O:23][CH2:22]1>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][N:15]3[CH2:16][C:17](=[O:18])[N:13]([C:11]4[CH:10]=[N:9][N:8]([CH2:7][C:6]5[C:2]([CH3:1])=[N:3][O:4][C:5]=5[CH3:20])[CH:12]=4)[C:14]3=[O:19])=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: OCc1ccc2c(c1)OCO2
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(Cc3ccc4c(c3)OCO4)C2=O)cn1
Yield: 19 %

Procedure:
Prepared as in example 10-35 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and benzo[d][1,3]dioxol-5-ylmethanol. Yield: 19%. 1H NMR (DMSO, 400 MHz): δ2.143 (s, 3H), 2.408 (s, 3H), 3.977 (s, 2H), 4.440 (s, 2H), 5.202 (s, 2H), 6.003 (s, 2H), 6.897 (m, 3H), 7.788 (s, 1H), 8.181 (s, 1H). MS M+H calculated 410.1; found 410.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.07 uM.
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH2:17][CH2:18][C:19](Cl)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[C:11]1([CH2:17][CH2:18][C:19]([N:8]2[CH2:9][CH2:10][CH:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: c1ccc(C2CCN2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N1CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.8 %

Procedure:
A solution of 2-phenylazetidine (266 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-phenylpropionyl chloride (421.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:4). The fractions containing 3-phenyl-1-(2-phenylazetidin-1-yl)propan-1-one are collected and the solvent is removed in vacuo to give 397 mg of colorless oil.