Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]#[N:31])[CH:20]=1.N1C=CC=CC=1.CCCP(=O)=O>CC1CCCO1>[Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:3]=1[C:4]([NH:18][C:19]1[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:22]=[C:21]([C:30]#[N:31])[CH:20]=1)=[O:6]
Reactant: N#Cc1cc(N)n(-c2ccccc2)n1
Reactant: Cc1cc(Cl)c(C(=O)O)cc1-c1ccccn1
Agent: CCCP(=O)=O
Solvent: CC1CCCO1
Solvent: c1ccncc1
Product: Cc1cc(Cl)c(C(=O)Nc2cc(C#N)nn2-c2ccccc2)cc1-c1ccccn1
Temperature: 25 °C
Yield: 30.6 %

Procedure:
A mixture of 2-chloro-4-methyl-5-(pyridin-2-yl)benzoic acid (Preparation 25, 234 mg, 0.94 mmol), 5-amino-1-phenyl-1H-pyrazole-3-carbonitrile (Preparation 53, 191 mg, 1.04 mmol) and pyridine (0.23 mL, 2.83 mmol) in 2-methyl tetrahydrofuran (20 mL) was heated at reflux for 10 minutes. To this refluxing mixture was added propylphosphonic anhydride solution (2.8 mL, 50% w/w in EtOAc) and the reaction heated at reflux under an atmosphere of argon for 18 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc (100 mL) and 2M aqueous sodium hydroxide solution (50 mL). The organic layer was washed with 2M aqueous sodium hydroxide solution (50 mL), saturated aqueous ammonium chloride solution (50 mL), water (50 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-20% EtOAc in DCM followed by trituration with diethylether to afford the title compound as a white solid (119 mg, 31%).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C(=O)(O)[O-].[Na+]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)[CH2:2][C:3]#[CH:4]
Reactant: C1=COCCC1
Reactant: C#CCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C#CCCOC1CCCCO1
Yield: 81.9 %

Procedure:
A solution of 3-butyn-1-ol (50 g, 1 equiv, 713 mmol), p-toluenesulfonic acid monohydrate (1.36 g, 0.01 equiv, 7.13 mmol), and dihydropyran (71.7 mL, 1.10 equiv, 785 mmol) in dichloromethane (500 mL) is stirred at 25° C. for 24 hours. Saturated sodium bicarbonate solution (500 mL) is then slowly added, and the mixture is extracted with dichloromethane (500 mL). The organic extract is dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude product, which is purified by vacuum distillation to afford the title compound (90 g, 82%): b.p.: 65° C., 1 mm Hg.
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.CN1CCOCC1.[F:23][C:24]([F:31])([F:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>C(#N)C>[F:23][C:24]([F:31])([F:30])[C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1
Reactant: N#Cc1ccc(-n2nnnc2CCl)cc1
Reactant: FC(F)(F)[C@@H]1CCCN1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: N#Cc1ccc(-n2nnnc2CN2CCC[C@H]2C(F)(F)F)cc1
Temperature: 160 °C

Procedure:
To a mixture of 4-[5-(chloromethyl)-1H-tetrazol-1-yl]benzonitrile (100 mg, 0.455 mmol, Intermediate 10) and polymer supported N-methylmorpholine (4 mmol/g, 171 mg, 0.683 mmol) in acetonitrile (3 mL) was added (2S)-2-(trifluoromethyl)pyrrolidine (95 mg, 0.683 mmol). The reaction mixture was heated at 120° C. for 20 min in a microwave reactor and at 140° C. for 20 min and at 150° C. for 30 min and finally at 160° C. for 30 min in the microwave reactor.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].CO>O1CCCC1>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CBr)c1ccccc1
Solvent: CO
Solvent: C1CCOC1
Product: O[C@@H](CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.6 %

Procedure:
(R)-2-amino-2-cyclohexyl-1,1-diphenylethanol (59 mg, 0.2 mmol), dry tetrahydrofuran (2 mL) and borane dimethylsulfide complex (100 μL, 1.0 mmol) were added to a dry flask under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 1.5 hr to form (R)-4-cyclohexyl-5,5-diphenyl-1,3,2-oxazaborolidine. A solution of bromoacetophenone (199 mg, 1.0 mmol) in dry tetrahydrofuran (4 mL) was added to the borane/(R)-4-cyclohexyl-5,5-diphenyl-1,3,2-oxazaborolidine complex at the rate of 9 mL/hr by means of a syringe pump. The resulting mixture was stirred at room temperature for an additional 1.5 hr. Methanol was added to quench the reaction and then the solvent was removed by evaporation. The resulting residue was chromatographed on silica gel (hexane/ethyl acetate, 25:1) and combination of the like fractions, followed by removal of the solvent gave (R)-2-bromo-1-phenylethanol (170 mg, 97.9% ee). The enantiomeric excess was measured by HPLC (Chiralcel OD-H column, mobile phase, hexane/2-propanol 9:1, flow rate=0.7 mL/min).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[CH2:16]([O:18][CH:19]([O:27][CH2:28][CH3:29])[CH2:20][N:21]1[CH:25]=[C:24](I)[N:23]=[CH:22]1)[CH3:17].CC(OC)(C)C>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:24]3[N:23]=[CH:22][N:21]([CH2:20][CH:19]([O:27][CH2:28][CH3:29])[O:18][CH2:16][CH3:17])[CH:25]=3)[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: CCOC(Cn1cnc(I)c1)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(Cn1cnc(-c2cc3nccc(Cl)c3s2)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
To a stirred solution of 7-chlorothieno[3,2-b]pyridine (9.26 g, 54.6 mmol) in THF (88 mL) at −15° C. was added n-BuLi (21.84 mL, 54.6 mmol). After 30 min, a solution of ZnCl2 0.5M in THF (109 mL, 54.6 mmol) was added at −15° C. and the reaction mixture was warmed to RT over 45 min. A solution of palladium tetrakistriphenylphosphine (0.841 g, 0.73 mmol) and iodide 260 (11.29 g, 36.4 mmol) in THF (33 mL) was added and the mixture was heated to reflux for 3 h then concentrated. The residue was diluted with water and ammonium hydroxide and extracted with DCM. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; AcOEt/Hex:0/100 to 100/0 over 20 CV) to produce a material that upon trituration with. MTBE afforded the title compound 261 (1.2 g, 3.41 mmol, 9% yield) as light-brown solid. MS (m/z): 437.45 (M+H).
Reaction SMILES: C(OP([CH:9]([O:15][CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.CC(C)([O-])C.[K+].[F:23][C:24]([F:46])([F:45])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33](=[O:44])[C:34]2[CH:39]=[C:38]([CH:40]=O)[CH:37]=[CH:36][C:35]=2[O:42][CH3:43])=[CH:27][CH:26]=1>O1CCCC1>[CH3:16][O:15][C:9](=[CH:40][C:38]1[CH:37]=[CH:36][C:35]([O:42][CH3:43])=[C:34]([C:33](=[O:44])[NH:32][CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:24]([F:23])([F:45])[F:46])=[CH:26][CH:27]=2)[CH:39]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(OC)P(=O)(OCC)OCC
Reactant: COc1ccc(C=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1ccc(OC)c(C(=O)NCc2ccc(C(F)(F)F)cc2)c1)OC
Temperature: 0 °C
Yield: 75.4 %

Procedure:
Ethyl 2-(diethoxyphosphoryl)-2-methoxyacetate (265 mg, 1.10 mmol) was dissolved in 3 ml of dehydrated tetrahydrofuran and potassium t-butoxide (123 mg, 1.10 mmol) was added under stirring and cooling with ice under an atmosphere of argon, which was stirred for 30 minutes. Next, N-[[4-(trifluoromethyl)phenyl]methyl]-5-formyl-2-methoxybenzamide (338 mg, 1.00 mmol) dissolved in 2 ml of dehydrated tetrahydrofuran was added. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice water, which was extracted with ethyl acetate, washed with water and brine in sequence, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=3:1 v/v) to obtain 330 mg (78%) of the title compound (mixture of geometrical isomers relevant to double bond) as colorless crystals.
Reaction SMILES: [CH:1]1([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:14]([O:16]CC)=O)=[CH:10][C:9]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C(C)=CC=CC=1>[CH2:27]([NH:34][C:14]([C:11]1[C:12](=[O:13])[N:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[N:8]=[C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH:10]=1)=[O:16])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)nn(CC2CCCC2)c1=O
Solvent: Cc1ccccc1C
Product: COc1ccc(-c2cc(C(=O)NCc3ccccc3)c(=O)n(CC3CCCC3)n2)cc1
Yield: 78.5 %

Procedure:
In xylene, 2-cyclopentylmethyl-4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and benzylamine were reacted at 140° C. for 2 hours. Post-treatments were conducted as in Example 68, whereby the title compound was obtained in a yield of 78.5%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]([CH3:17])=[N:15][O:14][N:13]=2)=O)[CH:6]=[CH:7][CH:8]=1)#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:24][OH:25]>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[C:16]([CH3:17])=[N:15][O:14][N:13]=2)=[N:24][OH:25])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: NO
Reactant: Cc1nonc1C(=O)Nc1cccc(C#N)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Cc1nonc1C(=NO)Nc1cccc(C#N)c1
Yield: 10.8 %

Procedure:
N-(3-Cyanophenyl)-4-methyl-1,2,5-oxadiazole-3-carboxamide (25 mg, 0.11 mmol) was suspended in benzene (2 mL) under an atmosphere of nitrogen. Phosphorus pentachloride (25 mg, 0.12 mmol) was added and the solution was heated at reflux for 2.5 hrs. The reaction was then evaporated to dryness. The crude was dissolved in EtOH (1.6 mL) and hydroxylamine (200 μL, 3 mmol, 50% solution in water) was added to the reaction. The crude was purified by preparative LCMS to afford the desired product (2.9 mg). MF=C11H9N5O2; LCMS calculated for C11H10N5O2 (M+H)+: m/z=244.1.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[C:21]([O:25][C@@H:26]([C:31]1[C:32](I)=[C:33]2[CH:40]=[CH:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([F:48])=[C:44]([F:49])[CH:43]=3)[C:34]2=[N:35][C:36]=1[CH3:37])[C:27]([O:29]C)=[O:28])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C@@H:26]([C:31]1[C:32]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:2]=2[F:1])[O:9][CH2:8][CH2:7][CH2:6]3)=[C:33]2[CH:40]=[CH:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([F:48])=[C:44]([F:49])[CH:43]=3)[C:34]2=[N:35][C:36]=1[CH3:37])[C:27]([OH:29])=[O:28])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2c(ccn2Cc2ccc(F)c(F)c2)c1I
Reactant: CC1(C)OB(c2cc3c(cc2F)OCCC3)OC1(C)C
Product: Cc1nc2c(ccn2Cc2ccc(F)c(F)c2)c(-c2cc3c(cc2F)OCCC3)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
The title compound was prepared from 2-(7-fluorochroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and (S)-methyl 2-(tert-butoxy)-2-(1-(3,4-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate in a manner similar to that described in Example 87. The crude acid was recrystallized from an isopropanol/water mixture to give the title compound as a single isomer. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.36 (d, J=8.2 Hz, 1 H), 7.16-6.96 (m, 4 H), 6.68 (d, J=11.1 Hz, 1 H), 6.16 (s., 1 H), 5.57-5.45 (m, 2 H), 5.30 (d, J=15.2 Hz, 1 H), 4.26 (t, J=5.1 Hz, 2 H), 2.87-2.75 (m, 2 H), 2.71 (s, 3 H), 2.05 (d, J=4.9 Hz, 2 H), 1.02 (s, 9 H); LCMS (m/z) ES+=539 (M+1).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:27]=[CH:26][C:12]([CH2:13][N:14]([CH3:25])[S:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:37][C:34]([F:35])([F:36])[C:30]1[CH:29]=[C:28]([C:10]2[CH:11]=[C:12]([CH:26]=[CH:27][C:9]=2[OH:8])[CH2:13][N:14]([CH3:25])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccc(COc2ccc(CN(C)S(=O)(=O)c3ccc(F)cc3)cc2-c2cccc(C(F)(F)F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(Cc1ccc(O)c(-c2cccc(C(F)(F)F)c2)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
Intermediate 35 (700 mg, 1.25 mmol) was dissolved in TFA/DCM (1/1) and stirred at room temperature for 1 h. Solvent was removed in vacuo and the residue was purified via silica gel chromatography (0-40% EtOAc/hexane) to afford 350 mg (64%) of N-(3-(3-trifluoromethylphenyl)-4-hydroxybenzyl)-4-fluoro-N-methylbenzenesulfonamide (36). 1HNMR (CD3OD, 400 MHz): δ 7.91 (m, 2H), 7.80 (s, 1H), 7.65 (m, 2H), 7.59 (d, 1H), 7.15-7.25 (m, 4H), 6.94 (d, 1H), 4.97 (s, 1H), 4.13 (s, 2H), 2.64 (s, 3H). MS (ESI): MH+=440.1. HPLC (Method B) tR=3.45 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[N:6]=[C:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[N:13][N:14]=[C:7]1[NH:6][CH:5]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ccc2c(c1)c(-c1ccccc1)nc1nncn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc2c(c1)C(c1ccccc1)Nc1nncn1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.8 %

Procedure:
To a suspension of 2.6 g of 7-chloro-5-phenyl-s-triazolo[4,3-a]quinazoline in 100 ml of dimethylformamide was added 1 g of sodium borohydride. The mixture was stirred at room temperature overnight and then poured into ice-water. The resulting precipitate was collected by filtration, washed with water and dried. The so obtained solid was suspended in a mixture of 30 ml of methanol and 30 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 40 minutes. After cooling, the resulting mixture was neutralized with ammonia water. The precipitate formed was collected by filtration, washed with water, and recrystallized from methanol to give 1.2 g of 7-chloro-4,5-dihydro-5-phenyl-s-triazolo[4,3-a]quinazoline as colorless prisms, m.p. 241.5°-243.5° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH2:25])[O:22][N:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH:1]([NH:4][C:5]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[N:24]=[C:23]([NH2:25])[O:22][N:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC(C)C)n3)c3cc(-c4noc(N)n4)ccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)Nc1cncc(-c2c[nH]c3ccc(-c4noc(N)n4)cc23)n1
Temperature: 100 °C
Yield: 29.1 %

Procedure:
To a solution of 3-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-amine (200 mg, 0.41 mmol) in 1,4-dioxane (2.0 mL) was added 10% aq NaOH (1.0 mL) and the reaction was heated at 100° C. for 2 h. The mixture was cooled to RT and treated with ice cold H2O (2.0 mL). The precipitate was collected through filtration and the crude product was purified with preparative HPLC (eluent: 10-60% AcCN in H2O with 0.01% TFA) to give 3-(3-(6-(isopropylamino)pyrazin-2-yl)-1H-indol-5-yl)-1,2,4-oxadiazol-5-amine (40 mg, 24.5%). MS (ESI, pos. ion) m/z: 336.1 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 11.96 (s, 1H), 9.07 (s, 1H), 8.25-8.22 (m, 2H), 7.76 (s, 2H), 7.72 (dd, J=6.8, 1.6 Hz, 1H), 7.64 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 4.30-4.27 (m, 1H), 1.32 (d, J=6.4 Hz, 6H).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:9]2[C@@H:5]([CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]2)[CH2:4][CH2:3]1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](O)=[CH:20][CH:19]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.C1CCCCC1>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([O:1][C@@H:2]2[C@@H:9]3[C@@H:5]([CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8]3)[CH2:4][CH2:3]2)=[CH:20][CH:19]=1
Reactant: Oc1ccc(Cl)c2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CC[C@@H](O)[C@H]2C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H]2CC[C@H](Oc3ccc(Cl)c4ccccc34)[C@H]2C1
Yield: 30.1 %

Procedure:
The process is performed according to the procedure described in Example 11, step 11.1. Starting with 0.15 g (0.66 mmol) of tert-butyl (3aR,4R,6aS)-4-hydroxyhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate, obtained in step 13.1., 0.130 g (0.73 mmol) of 4-chloro-1-naphthol, 0.160 g (0.79 mmol) of diisopropyl azodicarboxylate and 0.206 g (0.659 mmol) of resin-supported triphenylphosphine (triphenylphosphine, polymer-supported, 3.2 mmol/g on polystyrene), and after chromatography on silica gel, eluting with a 95/5 and then a 90/10 mixture of cyclohexane and ethyl acetate, 0.077 g (30%) of expected product is obtained.
Reaction SMILES: Br[C:2]1[C:3]([CH2:9]Br)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[C:11]([N:14]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[CH:18]C2N=C(Cl)C(F)=CC=2C1)(=[O:13])[CH3:12]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[CH:18]=[CH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:14]([C:11](=[O:13])[CH3:12])[CH2:9][C:3]=2[N:4]=1
Reactant: CC(=O)N1Cc2cc(F)c(Cl)nc2C=Cc2ccccc21
Reactant: Clc1ccc(Br)c(CBr)n1
Product: CC(=O)N1Cc2nc(Cl)ccc2C=Cc2ccccc21
Yield: 28 %

Procedure:
Compound 55C (27.7 mg, 28%) was prepared from bb (56.4 mg, 0.35 mmol) and 55B (100 mg, 0.35 mmol) in two steps by a route analogous to that used for the preparation of 1D.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:9]([CH2:11][C:12](OC)=[O:13])[NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH3:18][N:19]=[C:20]=[O:21].C[O-].[Na+]>CO>[CH3:18][N:19]1[C:12](=[O:13])[CH2:11][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)[NH:10][C:20]1=[O:21]
Reactant: COC(=O)CN(N)c1cccc(C(F)(F)F)c1
Reactant: CN=C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CN1C(=O)CN(c2cccc(C(F)(F)F)c2)NC1=O

Procedure:
Methyl [1-[3-(trifluoromethyl)phenyl]hydrazino]acetate (5 g) was treated with methyl isocyanate (3.05 ml) and then with sodium methoxide in methanol (60 ml; from sodium (1.16 g)) according to the method of Example 1. The product was purified by FCC eluting with System A (19:1) to give a solid, which was crystallised from System B to give the title compound (1.3 g), m.p. 163°-165°.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[C:24]([C:29]5[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=5)=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>CO.C1COCC1.[Pd]>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[C:24]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][CH:30]=4)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(Nc1ccc(N2CCNCC2)cc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Yield: 49.5 %

Procedure:
A mixture of intermediate (5) (0.19 mole) in methanol (600 ml) and THF (600 ml) was hydrogenated overnight with Pd/C 10% (3 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in DIPE. The precipitate was filtered off, dried, and dissolved in water. The mixture was alkalinized with Na2CO3 and then extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 40 g of N-[4-(1-piperazinyl)phenyl]-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide (intermediate 6).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH:8]([C:10]1[CH:28]=[CH:27][C:13]([O:14][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=2[C:23]([F:26])([F:25])[F:24])=[C:12]([O:29][CH3:30])[CH:11]=1)=O.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[O:7]=[C:2]1[NH:3][C:4](=[O:6])[C:5](=[CH:8][C:10]2[CH:28]=[CH:27][C:13]([O:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=3[C:23]([F:24])([F:25])[F:26])=[C:12]([O:29][CH3:30])[CH:11]=2)[S:1]1
Reactant: O=C1CSC(=O)N1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: COc1cc(C=C2SC(=O)NC2=O)ccc1Oc1ccc(C#N)cc1C(F)(F)F
Temperature: 130 °C

Procedure:
Thiazolidine-2,4-dione (2.55 g, 21.79 mmol) and 4-(4-Formyl-2-methoxy-phenoxy)-3-trifluoromethyl-benzonitrile (21.79 mmol) were dissolved in toluene (150 mL) and treated with benzoic acid (3.27 mmol) and piperidine (2.83 mmol). The flask was equipped with a Dean-Stark trap, and the reaction was refluxed in a 130° C. oil bath for 12 h. After cooling to RT, the product was collected by filtration and triturated with hexanes to afford the title compound. 1H NMR (400 Hz, DMSO-d6) δ 12.68 (NH), 8.32 (d, 1H), 8.00 (dd, 1H), 7.83 (s, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 7.26 (dd, 1H), 6.90 (d, 1H), 3.77 (s, 3H); LC/MS (m/z) [M+1]+ 421.0 (calculated for C19H12F3N2O4S, 421.04).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:15]=[C:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:20]1([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:33]1([CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:27]2[CH2:28][CH2:29][N:30]([CH2:18][CH2:17][CH2:16][C:14]3[O:13][N:12]=[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:15]=3)[CH2:31][CH2:32]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: COc1ccc(-c2cc(CCC=O)on2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2cc(CCCN3CCN(C(c4ccccc4)c4ccccc4)CC3)on2)cc1OC
Yield: 92.4 %

Procedure:
About 2 min after dissolving 3-[3-(3,4-dimethoxyphenyl)isoxazol-5-yl]propanal (10 mg, 0.04 mmol) and 1-(diphenylmethyl)piperazine (10 mg, 0.04 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (24 mg, 0.12 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 18.2 hr and followed the same processes as in Example 1 to obtain 18.4 mg (96.5%) of the target compound.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[OH-].[Na+]>O>[CH2:5]([O:4][C:2](=[O:3])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH3:6]
Reactant: NCCc1ccc(O)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)NCCc1ccc(O)cc1

Procedure:
According to scheme 1, ethyl chloroformate is added to a solution of tyramine (1), sodium hydroxide, and water to produce the [2-(4-hydroxy-phenyl)-ethyl]-carbamic acid ethyl ester (2). The carbamate is treated with cesium carbonate and 4-fluorobenzonitrile in DMF to yield the corresponding biarylether 3. The nitrile functionality of the biaryl; ether 3 is converted to the N-acyl compound 4 by reaction with mrethyllithium followed by hydrolysis in aqueous sulfuric acid. The N-acyl compound 4 is converted to the acetate 5 by oxidation with m-chloroperbenzoic acid (MCPBA) in a suitable solvent. The acetate 5 is reduced with lithium aluminum hydride to afford the compound 4-[4-(2-methylamino-ethyl)-phenoxy]-phenol (6). The compound 6 is treated with benzaldehyde in the presence of sodium triacetoxyborohydride to produce the reductive amination product 4-{4-[2-(benzyl-methyl-amino)-ethyl]-phenoxy}-phenol 7 of formula I. Compounds of formula I wherein D is acetate and q is 0, may also be prepared according to scheme 2 below.