Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]([F:15])([F:14])[CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([NH2:13])[CH2:8]1>C1(C)C(C)=CC=CC=1>[F:5][C:6]([F:14])([F:15])[CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]([N:13]=[C:1]=[O:2])[CH2:8]1
Reactant: NC1CCCC(C(F)(F)F)C1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C=NC1CCCC(C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 130 parts of phosgene in 450 parts of xylene at 0° to 5°C. is added dropwise a solution of 100 parts of 3-trifluoromethylcyclohexylamine (prepared as in Example 1) in 450 parts of xylene. The reaction mixture is stirred at 0°C. for 1 hour, allowed to come to ambient temperature, and then refluxed 4 hours. The excess phosgene is trapped in a gas scrubber. The xylene is stripped on a rotary evaporator and the residue is distilled under reduced pressure to yield 62.4 parts of 3-trifluoromethylcyclohexyl isocyanate, b.p. 68°-69°C/9mm.
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:27])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:27])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CCCCCCNC(=O)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCCCNC(=O)Oc1ccc2c(c1)CCCN2

Procedure:
A mixture of hexyl-carbamic acid 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-yl ester (0.732 g., 2 mmol) and 5% Pd—C (0.08 g.) in absolute ethanol (20 ml) was shaken in a par apparatus at room temperature (38° C.) under 50 psi pressure of hydrogen for 4 hours. Pd—C was then discarded through filtration. The reaction mixture was concentrated under vaccum and the separated solid was washed with chloroform (2×5 ml) to give 2a; yield: 0.60 g. (64.1%), m.p.: 100° C., C16H24N2O2; 1H NMR δ ppm (CDCl3): 0.88 (bs, 3H), 1.25-1.30 (m, 5H), 1.51-1.58 (m, 3H), 1.85-1.97 (m, 3H), 2.74 (t, 2H), 3.16-3.29 (m, 4H), 3.6 (bs, 1H), 4.87 (bs, 1H), 6.39-6.4 (m, 1H), 6.68-6.71 (m, 2H), IR vmax (KBr) (cm−1): 770, 816, 886, 956, 1006, 1101, 1152, 1221, 1243, 1311, 1354, 1505, 1626, 1702, 1848, 2372, 2856, 2929, 3392, 3760, 3809, 7874, MS: m/z: 277 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[S:11][CH:12]=2)=[CH:4][C:3]=1[F:19].Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:13]3[C:14]([CH3:17])([CH3:18])[CH2:15][O:16][C:21]3=[O:23])[S:11][CH:12]=2)=[CH:4][C:3]=1[F:19]
Reactant: CC(C)(CO)Nc1nc(-c2ccc(Cl)c(F)c2)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(Cl)c(F)c2)cs1

Procedure:
In the same manner as described in step 7 of Example 78, using 2-[4-(4-chloro-3-fluoro-phenyl)-thiazol-2-ylamino]-2-methyl-propan-1-ol (810 mg, 2.66 mmol), prepared in the previous step, triphosgene (946 mg, 3.19 mmol) and diisopropylethyl amine (1.1 mL) in 20 mL of methylene chloride, the title compound was isolated (125 mg, 14%) after purification on silica gel using 6:1 hexane:ethyl acetate as the eluent. mp 140-142° C.
Reaction SMILES: [OH:1][C:2]([C@H:5]1[CH2:9][CH2:8][NH:7][C@H:6]1[CH3:10])([CH3:4])[CH3:3].[Cl:11][C:12]1[C:19]([CH3:20])=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+]>CS(C)=O>[Cl:11][C:12]1[C:19]([CH3:20])=[C:18]([N:7]2[CH2:8][CH2:9][C@H:5]([C:2]([OH:1])([CH3:4])[CH3:3])[C@@H:6]2[CH3:10])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CS(C)=O
Product: Cc1c(N2CC[C@H](C(C)(C)O)[C@@H]2C)ccc(C#N)c1Cl
Temperature: 100 °C
Reaction time: 1 h
Yield: 16.3 %

Procedure:
A mixture of compound 1 (1.56 g), 2-chloro-4-fluoro-3-methylbenzonitrile (1.27 g), lithium carbonate (1.16 g) and DMSO (37.5 ml) was stirred at 100° C. for 1 hr. The reaction mixture was cooled and partitioned between water and ethyl acetate. The organic layer was washed with water, dried (sodium sulfate), and concentrated. The obtained residue was purified by silica gel column chromatography (ethyl acetate-hexane), and crystallized from ethyl acetate-hexane to give the title compound (357 mg) as crystals.
Reaction SMILES: CC([O-])(C)C.[K+].[Cl:7][C:8]1[C:9]([NH2:14])=[N:10][CH:11]=[N:12][CH:13]=1.[CH2:15]([O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>C(O)(C)(C)C>[CH2:15]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:14][C:9]2[C:8]([Cl:7])=[CH:13][N:12]=[CH:11][N:10]=2)=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1ncncc1Cl
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: Clc1cncnc1NCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
2.1 g (19 mmol) of potassium tert-butylate are added to a suspension of 2.2 g (17.2 mmol) of 5-chloro-pyrimidin-4-ylamine in tert-butanol (50 ml) and the temperature is kept at 60° C. After stirring for 1 h, a solution of 4.1 g (17.2 mmol) of 4-benzyloxy-benzyl chloride in tert-butanol (40 ml) is added dropwise and the reaction mixture is stirred at this temperature for 1 h. The reaction mixture is cooled to room temperature and poured into water (300 ml). The precipitate is filtered off and the filtrate is extracted with ethyl acetate (2×200 ml). The combined organic layers are dried with magnesium sulphate and concentrated in vacuo. The residue is purified by chromatography on silica gel (toluene/dioxane=6:1) to yield 2.0 g (37%) of the title compound as a beige powder of m.p. 95°-100° C.
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][NH:2]1.Br[C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:28]([CH:29]4[CH2:31][CH2:30]4)=[CH:27][C:26]([CH:32]4[CH2:34][CH2:33]4)=[CH:25][N:24]=3)[CH2:19][CH2:18]2)=[O:16])=[N:13][CH:14]=1>>[CH:29]1([C:28]2[C:23]([N:20]3[CH2:21][CH2:22][N:17]([C:15]([C:12]4[CH:11]=[CH:10][C:9]([N:2]5[CH2:3][CH2:4][CH2:5][S:1]5(=[O:7])=[O:6])=[CH:14][N:13]=4)=[O:16])[CH2:18][CH2:19]3)=[N:24][CH:25]=[C:26]([CH:32]3[CH2:34][CH2:33]3)[CH:27]=2)[CH2:30][CH2:31]1
Reactant: O=C(c1ccc(Br)cn1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=S1(=O)CCCN1
Product: O=C(c1ccc(N2CCCS2(=O)=O)cn1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 39.2 %

Procedure:
Using isothiazolidine 1,1-dioxide (105 mg) and (5-bromopyridin-2-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (338 mg) described in Preparation Example 142 and by the reaction and treatment in the same manner as in Example 1, the title compound (145 mg) was obtained.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:12])=[CH:8][C:9]=2[CH3:11])[S:4][C:3]=1[C:13]#[N:14].[NH2:15][NH2:16]>CS(C)=O>[CH3:12][C:7]1[N:6]=[C:5]2[S:4][C:3]3[C:13]([NH2:14])=[N:16][NH:15][C:2]=3[C:10]2=[C:9]([CH3:11])[CH:8]=1
Reactant: NN
Reactant: Cc1cc(C)c2c(Br)c(C#N)sc2n1
Solvent: CS(C)=O
Product: Cc1cc(C)c2c(n1)sc1c(N)n[nH]c12
Temperature: 25 °C
Yield: 99.8 %

Procedure:
The 3-bromo-4,6-dimethylthieno[2,3-b]pyridine-2-carbonitrile (1.11 g, 4.17 mmol) was added to a microwave reaction vial. The DMSO (14 mL) was added, followed by hydrazine (0.392 mL, 12.5 mmol). The vial was sealed and irradiated at 150 degrees for 10 minutes. LCMS showed no remaining starting material. The reaction was cooled to RT, then poured into 150 mL of ice-water. The ice was allowed to melt and resulting slurry was poured through filter paper, washing the solid with cold water (3×). The solid was then dried under vacuum at 60° C. to give 908 mg (98%) of the product as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.07 (s, 1H), 5.35 (bs, 2H), 2.62 (s, 3H), 2.49 (s, 3H). LC/MS: RT=0.38 min., m/z=219.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=O.[C:11]([CH2:13][C:14]([NH:16][NH2:17])=[O:15])#[N:12]>C(O)C.N1CCCCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[C:13]([C:11]#[N:12])[C:14]([NH:16][NH2:17])=[O:15]
Reactant: N#CCC(=O)NN
Reactant: O=Cc1ccc(O)c(O)c1
Solvent: C1CCNCC1
Solvent: CCO
Product: N#CC(=Cc1ccc(O)c(O)c1)C(=O)NN
Yield: 50.2 %

Procedure:
To 0.69 g (5 mmol) 3,4-dihydroxybenzaldehyde and 0.55 g (5.5 mmol) cyanoacethydrazide in 40 ml ethanol was added 2 drops piperidine. After 21/2 hours of reflux, the reaction mixture was cooled, filtered and washed with cold ethanol to give 0.55 g (50% yield) of product, an orange solid, m.p. 220° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1cccc(NC(=O)C(C)(C)C)c1
Temperature: 15 °C
Reaction time: 1 h

Procedure:
To an ice cooled solution of 20 g (162 mmol) 3-methoxy-phenylamine in 400 ml diethylether is added 24.9 ml (178 mmol) triethylamine and slowly within 30 minutes 23.9 ml (195 mmol) pivaloyl chloride. Due to the exothermic reaction the temperature rises despite cooling to 15° C. The temperature is left rising to room temperature, after 1 hour the reaction mixture is poured on ice and extracted with ethyl acetate, washed 2× with water and 1× with brine, dried with Na2SO4 and evaporated to give a crude product which is purified by two crystallizations from CH2Cl2/hexane to yield N-(3-methoxy-phenyl)-2,2-dimethyl-propionamide.
Reaction SMILES: [NH2:1][C:2]([CH2:9][CH3:10])=[C:3]([Cl:8])[C:4](OC)=[O:5].[CH:11]([NH2:13])=O.C[O-].[Na+]>CO>[Cl:8][C:3]1[C:4]([OH:5])=[N:13][CH:11]=[N:1][C:2]=1[CH2:9][CH3:10]
Reactant: NC=O
Reactant: CCC(N)=C(Cl)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ncnc(O)c1Cl
Reaction time: 12 h
Yield: 111.9 %

Procedure:
A mixture of 163.6 g (1.0 mol) of methyl 3-amino-2-chloro-2-pentenoate, 90.8 g (2.0 mol) of formamide and 150 ml of methanol is added dropwise with stirring to 485.8 ml of a 30% strength NaOMe solution in methanol at room temperature. The mixture is subsequently slowly heated to the reflux temperature over the course of 3 h, and is left to stir at this temperature for a further 12 h. Evaporation of the reaction mixture is followed by dissolving in a little H2O, adjustment to a pH of 3.8 with HCl and extraction with ethyl acetate. Drying over MgSO4 and evaporation provide 177.5 g of crude product which is subsequently recrystallized from water. Yield: 130.4 g (82%)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1
Reactant: NCc1ccc(F)cc1Cl
Reactant: O=C1CSC(=S)N1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CSC(NCc2ccc(F)cc2Cl)=N1

Procedure:
Similar procedure as described in example 15a was used, starting with 2-chloro-4-fluoro-benzylamine, rhodanine, mercuric chloride and DIEA to give 2-(2-chloro-4-fluoro-benzylamino)-thiazol-4-one. LC-MS m/e 259 (MH+).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].[H-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>CN(C=O)C>[CH2:9]([O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C#CCCCO
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCCOCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
15 ml of 4-pentin-1-ol is added in drops at 0° C. to a suspension of 17.4 g of sodium hydride (55%) in 200 ml of DMF, and it is stirred for 1 hour at 0° C. Then, 30 ml of benzyl bromide is added in drops at this temperature, and it is stirred for another 2 hours at 0° C. Then, the reaction is carefully neutralized with 1N hydrochloric acid. The phase separation is carried out between diethyl ether and water, and the aqueous phase is extracted several times with diethyl ether. The combined organic phases are washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried on magnesium sulfate and concentrated by evaporation. The residue is distilled in an oil pump vacuum, and 22.7 g of 5-benzyloxypent-1-ine is obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].Br[CH2:19][CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].[Br-]>CN(C)C=O>[C:25]([O:24][C:22]([NH:21][CH2:20][CH2:19][O:17][C:13]1[CH:12]=[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=2)[CH:16]=[CH:15][CH:14]=1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1cccc(-c2cccc(O)c2)c1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cccc(OCCNC(=O)OC(C)(C)C)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
A mixture of 3′-hydroxy-[1,1′-biphenyl]-3-carboxylic acid methyl ester (667 mg) and 2-bromo-1-[(tert-butoxycarbonyl)amino]ethane (980 mg) in N, N-dimethylformamide (15 mL) was treated with potassium carbonate (2.0 g). The mixture was stirred at room temperature for 30 min, and heated to 50° C. in an oil bath for 14 h. Additional bromide (396 mg) was added and the mixture was heated an additional 36 h. The mixture was cooled to room temperature and partitioned between 1:1 hexane ethyl acetate and water. The organic layer was separated, washed with water, dried over sodium sulfate, filtered and concentrated to give the crude product. Purification by silica gel chromatography (eluting with 5:1 hexane/ethyl acetate) afforded the title compound as a colorless oil (826 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:13][CH2:12]4.[CH3:18][C:19]1[N:20]=[N:21][C:22]([CH:25]=[CH2:26])=[CH:23][CH:24]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:26][CH2:25][C:22]3[N:21]=[N:20][C:19]([CH3:18])=[CH:24][CH:23]=3)[C:6]3[CH:11]4[CH2:12][CH2:13][N:14]([CH2:15][C:5]=3[C:4]=2[CH:3]=1)[CH2:16][CH2:17]4
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: C=Cc1ccc(C)nn1
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nn2)C2CCN(CC2)C1

Procedure:
Under nitrogen, 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (260 mg, 1.15 mmol, Example 2B), was coupled with 3-methyl-6-vinylpyridazine (280 mg, 1.86 mmol, Example 148B) according to the procedure described in Example 1B to give the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.65-1.76 (m, 2H) 1.85-1.95 (m, 2H) 2.43 (s, 3H) 2.67 (s, 3H) 2.96-3.09 (m, 3H) 3.17-3.25 (m, 2H) 3.30 (t, J=7.1 Hz, 2H) 4.23 (s, 2H) 4.55 (t, J=7.1 Hz, 2H) 6.82 (d, J=8.5 Hz, 1H) 6.96 (dd, J=8.3, 1.2 Hz, 1H) 7.11 (dd, J=17.1, 8.4 Hz, 2H) 7.16 (s, 1H); MS (DCI/NH3) m/z 347 (M+H)+.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[N:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:28]([Cl:29])=[C:27]([CH3:30])[S:26][C:16]=3[N:17]=2)=[CH:25][CH:24]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccncc3)nc(NCCc3ccc4c(c3)OCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-methylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.O.CC(C)=[O:49].Cl(O)(=O)(=O)=O>C(OCC)(=O)C>[OH:49][C@@H:43]([CH2:45][OH:44])[CH2:42][O:41][C:2]([CH3:40])([CH3:1])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:37])[CH3:38])[NH:13]2)=[O:11])=[N:5]1
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)=O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H](O)CO)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (51.2 mg, 0.078 mmol), water (2 mL), and acetone (10 mL) was cooled to 0° C., then a solution of 35% perchloric acid (0.1 mL) was added dropwise. The reaction was stirred an additional 0.5 h. Then an additional 1 mL of the 35% perchloric acid solution was added at 0° C., the reaction was allowed to warm to rt for 12 h. The mixture was then diluted with ethyl acetate and washed with sodium bicarbonate (sat'd). The organic phase was separated, dried over Na2SO4 and filtered. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-2,3-dihydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (22.1 mg, 42%) as an white powder. HRMS (ES+) m/z Calcd for C33H39Cl2F2N5O4S+H [(M+H)+]: 678.2420. found: 078.2416; C33H39Cl2F2N5O4+[(Na+H)+]: 700.2239. found: 700.2235.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13]/[C:14](=[N:17]/[H])/[NH:15][OH:16].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:40][N:41]1[CH:45]=[C:44]([C:46](O)=O)[C:43]([C:49]([F:52])([F:51])[F:50])=[N:42]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:19][CH2:20][CH3:21])[N:6]2[CH2:13][C:14]1[N:17]=[C:46]([C:44]2[C:43]([C:49]([F:52])([F:50])[F:51])=[N:42][N:41]([CH3:40])[CH:45]=2)[O:16][N:15]=1
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Reactant: [H]/N=C(/Cn1c(CCC)cc2c(Cl)c(C#N)ccc21)NO
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cn(C)nc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Synthesized as described in Example 32A and Example 33 using (1Z)-2-(4-chloro-5-cyano-2-propyl-1H-indol-1-yl)-N-hydroxyethanimidamide (0.030 g, 0.1 mmol) in anhydrous THF (5 mL) with propanephosphonic acid cyclic anhydride (T3P) (0.034 g, 0.12 mmol), 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.0194 g, 0.1 mmol) and DIEA (0.016 g, 0.12 mmol) and stirred at rt for 1 h and then heated at 120° C. for 2 h in the microwave: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1 H), 7.88 (d, J=1.0 Hz, 1 H), 7.53 (d, J=8.5 Hz, 1 H), 7.45 (d, J=8.4 Hz, 1 H), 5.40 (s, 2 H), 4.01 (s, 3 H), 2.96 (t, 2 H), 1.82-1.67 (m, 2 H), 1.03 (t, 3 H); MS (ES) m/z 449 (M+1).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].CO>C(OCC)(=O)C>[C:29]([OH:34])(=[O:33])[C:30]([OH:32])=[O:31].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:18][CH2:17][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccc(Cl)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(4-chlorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 83% overall yield. FDMS m/e=401 (M+ of free base). α[D]589 =-14.17 (c=0.45, methanol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:18]=2)[C@@H:10]([OH:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:37][C:38]1[CH:47]=[CH:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=1.[H-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([O:14][CH2:15][CH3:16])[C@H:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:19][CH:18]=2)[C@@H:10]([O:35][CH2:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH:39]=2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](O)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](OCc2ccc3ccccc3c2)[C@H]1c1ccc(OCCCOCc2ccccc2)cc1

Procedure:
reacting the product of step f) with 2-bromomethyl-naphthalene and sodium hydride to yield (3R,4S,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butylester;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH2:9])=[CH:3][CH:2]=1.Cl[C:11]1[C:16]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][NH:9][C:11]2[C:16]([C:17]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=3)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:3][CH:2]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1Cl
Reactant: NCCc1ccncc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1NCCc1ccncc1
Temperature: 100 °C

Procedure:
4-Pyridineethanamine (Maybridge Chemical Co, Cornwall, England; 0.31 g, 2.5 mmol) is added to a stirred mixture of 2-chloro-N-[3(trifluoromethyl)phenyl]-3-pyridinecarboxamide (intermediate 1a; 0.90 g, 3 mmol), powdered potassium carbonate (0.35 g, 2.5 mmol) and copper(1)iodide; 0.48 g, 2.5 mmol) in dimethylformamide (10 mL). The resulting mixture is then purged with argon and subsequently heated at 100° C. under an argon atmosphere for 2 hours. The mixture is cooled, treated with water (100 mL) and extracted with ethyl acetate (3×80 mL). The combined extracts are washed with an aqueous solution of ammonia (2×50 mL of 10%), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent ethyl acetate and recrystalised from ethyl acetate—hexane to give the title compound as a colourless crystalline solid, m.p. 128-138° C.