Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([CH:8]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[N:6][OH:7])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:31][C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=2)[N:33]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]([CH:8]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=3)[N:33]=2)=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][C:36]([Cl:42])=[CH:37][CH:38]=3)[N:33]=2)=[CH:11][CH:10]=1)=[N:6][OH:7])[CH3:2]
Reactant: Clc1ccc2ccc(CBr)nc2c1
Reactant: CCOC(=O)C(=NO)C(c1ccc(O)cc1)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=NO)C(c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1)c1ccc(OCc2ccc3ccc(Cl)cc3n2)cc1
Reaction time: 18 h
Yield: 82.5 %

Procedure:
To a solution in dry DMF (20 mL) of bis(4-hydroxyphenyl)methyloximinoacetic acid ethyl ester (0.64 g, 2 mmol), prepared as in step 1, was added cesium carbonate (1.6 g, 5 mmol), the mixture was stirred for 10 mutes, and 2-bromomethyl-7-chloroquinoline (1 g, 4 mmol) was added. After stirring for 18 hours, the mixture was poured into water and the precipitated solid was collected by filtration, washed with water, and dried in vacuo. Chromatography on silica gel (hexane/EtOAC 3:1) afforded bis(4-(7-chloro-2-quinolylmethoxy)phenyl)-methyloximinoacetic acid ethyl ester (1.1 g).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:13]([C:15]#[N:16])=[CH:12][N:11]=[C:10]([O:17][CH3:18])[C:9]=3[C:8]([C:19]3[CH:20]=[N:21][NH:22][CH:23]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:27][C:28]([NH2:30])=[O:29].O>C1COCC1>[C:15]([C:13]1[C:14]2[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]=[C:8]([C:19]3[CH:20]=[N:21][N:22]([CH2:27][C:28]([NH2:30])=[O:29])[CH:23]=3)[C:9]=2[C:10]([O:17][CH3:18])=[N:11][CH:12]=1)#[N:16]
Reactant: NC(=O)CBr
Reactant: COc1ncc(C#N)c2c1c(-c1cn[nH]c1)cn2C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ncc(C#N)c2c1c(-c1cnn(CC(N)=O)c1)cn2C1CCCC1
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To a solution of 1-cyclopentyl-4-methoxy-3-(1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-7-carbonitrile (55.3 mg) in THF (2 mL) was added sodium hydride (dispersion in mineral oil, 14.4 mg) at 0° C., and the mixture was stirred for 1 hr. To the reaction mixture was added 2-bromoacetamide (29.8 mg) at 0° C., and the reaction mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted twice with ethyl acetate and THF. The combined organic layers was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane/methanol) to give the title compound (27.5 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[ClH:16]>C(O)C.C(O)(C)C.O=[Pt]=O>[ClH:16].[CH:9]1([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Nc1ccccc1O
Reactant: O=C1CCCCC1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: Oc1ccccc1NC1CCCCC1

Procedure:
A mixture of 10.9 g (0.1 mol) of 2-aminophenol and 10.4 g (0.1 mol) of cyclohexanone in 200 ml of ethanol is hydrogenated over 0.2 g of PtO2 under standard conditions, 0.1 mol of HCl in isopropanol is added to the reaction mixture, the catalyst is filtered off and the filtrate is evaporated in vacuo and the residue is precipitated with ether.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:38]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:9][C:10]1[C:11]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][C:13]([CH2:16][Br:38])=[CH:14][CH:15]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(OC(=O)c2ccccc2)c(OC(=O)c2ccccc2)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(Oc1ccc(CBr)cc1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
To a solution of 19.94 g (0.06 mol) of 4-methyl-benzene-1,2-diol dibenzoate in 350 mL of carbon tetrachloride was added a catalytic amount of 2,2'-azobisisobutyronitrile, followed by 10.68 g (0.06 mol) of N-bromosuccinimide. The reaction mixture was stirred at room temperature for several days and was then filtered. The filtrate was dried over MgSO4, filtered and evaporated to dryness in a rotary evaporator. Purification of the crude material (24.76 g) by HPLC gave 7.05 g of product which was used directly in the next step.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=O)=[CH:3][CH:2]=1.[NH2:12][C:13]1[S:14][C:15]([CH3:18])=[CH:16][N:17]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:18][C:15]1[S:14][C:13]([NH:12][C:8](=[O:10])[CH2:7][C:4]2[CH:3]=[CH:2][C:1]([CH3:11])=[CH:6][CH:5]=2)=[N:17][CH:16]=1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: Cc1cnc(N)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CC(=O)Nc2ncc(C)s2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
To a suspension of p-tolylacetic acid (1.00 g, 6.66 mmol) and 2-amino-5-methylthiazole (0.760 g, 6.66 mmol) in dichloromethane (10 mL) was added at 0° C. under a nitrogen atmosphere 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.40 g, 7.32 mmol), 1-hydroxybenzotriazole (90 mg, 0.67 mmol) and N,N-diisopropyl ethyl amine (1.8 mL, 10 mmol). The ice bath was removed and the resulting solution was stirred for 3 h at ambient temperature. The reaction mixture was diluted with dichloromethane (20 mL) and washed with aqueous sodium carbonate (half-concentrated, 20 mL) and water (20 mL). The aqueous layers were extracted with dichloromethane (20 mL) and the combined organic layers were dried over sodium sulfate. The filtrate was concentrated and the residue was suspended in TBME (20 mL) and filtered. Washing with TBME (10 mL) afforded the title compound (1.48 g, 90%) as a white solid. MS m/e: 247.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2([C:20]([OH:22])=[O:21])[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)=[O:9])=[C:6]([CH:23]=[C:24]([CH3:26])[CH3:25])[C:5]([CH3:27])=[CH:4][CH:3]=1.[C:28](O)(=[O:30])[CH3:29]>[Pd]>[C:28]([NH:1][C:2]1[C:7]([C:8]([NH:10][C:11]2([C:20]([OH:22])=[O:21])[CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:19]2)=[O:9])=[C:6]([CH:23]=[C:24]([CH3:25])[CH3:26])[C:5]([CH3:27])=[CH:4][CH:3]=1)(=[O:30])[CH3:29]
Reactant: CC(C)=Cc1c(C)ccc(N)c1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reactant: CC(=O)O
Agent: [Pd]
Product: CC(=O)Nc1ccc(C)c(C=C(C)C)c1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Yield: 86 %

Procedure:
To a solution of (225) (48 mg, 0.1 mmol) in acetic acid (10 mL) is added the catalyst, Pd—C (5 wt. % Pd, 21 mg, 1% mmol) under argon. The resulting reaction mixture is moved to the Paar apparatus to run hydrogenation: 55 psi, 90° C., overnight. The catalyst is removed by filtration through a pre-column (10 g silica gel) and washed with EtOH. The combined organic solution is concentrated in vacuo. The residue is purified by HPLC to give a pure product (226) as white solid (35 mg, 86%).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[Cl:11][C:12]1[CH:30]=[CH:29][C:15]([C:16]([CH:18]([OH:28])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17])=[CH:14][CH:13]=1.N1C=CC=CC=1.Cl>O1CCCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]([CH:18]([O:28][C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17])=[CH:29][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOC(=O)CCCCC(O)C(=O)c1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)CCCCC(OC(=O)Oc1ccccc1)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Phenyl chloroformate (14.1 g) was added dropwise to a mixture of ethyl 6-(4-chlorobenzoyl)-6-hydroxyhexanoate (24.5 g), pyridine(7.14 g) and tetrahydrofuran(200 ml) with cooling with ice. After stirring for 3 hours at room temperature, the reaction mixture was poured into ice water, and neutrized by 2N-hydrochloric acid. This was extracted with ethyl acetate. The ethyl acetate layer was washed with water, and dried(MgSO4). The solvent was evaporated to give ethyl 6-(4-chlorobenzoyl)-6-phenoxycarbonyloxyhexanate(32.3 g, 94%) as an oily substance.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>CO.O>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([NH:20][NH2:21])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccccc1Oc1ccccc1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)Cc1ccccc1Oc1ccccc1
Reaction time: 2 h
Yield: 96 %

Procedure:
A solution of methyl (2-phenoxyphenyl)acetate (6.0 g) in methanol (100 ml) was added dropwise with stirring to hydrazine hydrate (12 ml). The resulting mixture was stirred for 2 hours, then diluted with water and extracted with ether. The extracts were washed with water, dried and concentrated to give almost pure (2-phenoxyphenyl)acetohydrazide (5.8 g, 96% yield) as a waxy solid with amp of about 65° C., 1H NMR (CDCl3): delta 3.60 (2H,s) ppm. Concentrated sulphuric acid (4 drops) was added to a mixture of this hydrazide and triethyl orthoformate (20 ml) and the resulting mixture was heated at 90° C. for one hour. After cooling, water was added to the mixture and it was extracted with ether. The extracts were washed, dried, concentrated and chromatographed using increasing proportions (up to 50%) of ethyl acetate in hexane as eluant to give 2-(2-phenoxyphenylmethyl)oxa-1,3,4-diazole (3.14 g, 52% yield) as a yellow oil, IH NMR (CDCl3): delta 4.31 (2H,s) and 8.28 (1H,s) ppm.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14]CC)=O)=[CH:8][C:7]([CH3:17])=[CH:6][CH:5]=2.[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[NH2:20][CH2:19][CH2:18][NH:21][C:12](=[O:14])[CH2:11][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:17])[CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccc(C)cc12
Reactant: NCCN
Product: Cc1ccc2[nH]c(C)c(CC(=O)NCCN)c2c1
Temperature: 115 °C
Yield: 39 %

Procedure:
A mixture of 1.18 g (4.8 mmol) of ethyl (2,5-dimethylindol-3-yl)acetate and 7.5 mL of ethylenediamine was heated at 115° C. overnight. The excess ethylenediamine was removed under reduced pressure and the residue was chromatographed with 1:1 CH2Cl2-(EtOH+10% ethanolic NH3). The pure fraction of N-(2-aminoethyl)-(2,5-dimethylindol-3-yl)acetamide obtained (1.2 g) was treated with 15 mL of hexamethyldisilazine HDS) at gentle reflux (130° C.) overnight. The mixture was concentrated to dryness, dissolved in EtOH and treated with etheric HCl to acidic. Addition of ether in 3 portions induced light brown crystals. Yield: 39%; m.p. 245-7° C.; 1H NMR (DMSO-d6) d 11.02 (br. s, 1H), 9.94 (br. s, 2H), 7.23 (s, 1H ), 7.16 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 3.90 (s, 2H), 3.79 (s, 4H), 2.36 (s, 6H).
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Br[CH2:53][C:54]1[CH:63]=[CH:62][C:57]([C:58]([O:60][CH3:61])=[O:59])=[CH:56][CH:55]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:53][C:54]3[CH:55]=[CH:56][C:57]([C:58]([O:60][CH3:61])=[O:59])=[CH:62][CH:63]=3)[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCc2ccc(C(=O)OC)cc2)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.05 M) was added methyl 4-(bromomethyl)benzoate (1.6 eq.) and cesium carbonate (1.3 eq.). The reaction was heated to 80° C. and stirred for 12 h. After cooling to rt, the reaction was diluted with ether and quenched with water. The aqueous layer was extracted with ether. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 5% EtOAc in Hex→100% EtOAc) to afford the title compound as a foam.
Reaction SMILES: [CH2:1]([S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[NH2:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>>[CH2:1]([S:5]([NH:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14])(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: CCCCS(=O)(=O)Nc1cc(C(=O)Nc2ccccc2)ccc1OC
Yield: 92 %

Procedure:
Prepared according to the procedure described for Example 128 using 1-butanesulfonyl chloride (0.47 g, 3.0 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (0.73 g, 3.0 mmol) to afford the product (1.0 g); m.p. 182-183° C. after recrystallization from ethanol.
Reaction SMILES: [C:1]([C:4]1[C:9]([Br:10])=[CH:8][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][N:5]=1)(=[O:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[Br:10][C:9]1[C:4]([C:1](=[O:3])[CH:2]=[CH:17][N:18]([CH3:20])[CH3:19])=[N:5][CH:6]=[C:7]([C:11]([F:13])([F:14])[F:12])[CH:8]=1
Reactant: CC(=O)c1ncc(C(F)(F)F)cc1Br
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=CC(=O)c1ncc(C(F)(F)F)cc1Br
Yield: 98.7 %

Procedure:
728 mg of 2-acetyl-3-bromo-5-(trifluoromethyl)pyridine and 466 mg of N,N-dimethylformamide dimethyl acetal were reacted in 5 mL of toluene at 100° C. for 16 hours. The reaction liquid was concentrated under reduced pressure to obtain 866 mg of 1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-3-(dimethylamino)-2-propen-1-one (after-mentioned intermediate No. IV-7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22]C)=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(NC(=O)C(C)C)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C(=O)Nc1cc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)ccc1Cl
Yield: 57.6 %

Procedure:
A mixture of methyl 2-(4-chloro-3-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (216 mg, 0.52 mmol) in methanol (8 mL) and 4.2 mL of aqueous solution of sodium hydroxide (1 M, 4.2 mmol) was stirred at reflux for 2 h. Thin layer chromatography indicated that the starting material was consumed completely. Methanol was removed under reduced pressure and the residue was acidified to pH=6 with 1 M hydrochloric acid solution. The precipitated white solid were collected by filtration and dissolved in Ethyl acetate, dried over anhydrous sodium sulfate. The solvent was removed in vacuo to afford 120 mg of 2-(4-chloro-3-isobutyramidophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a white solid. LC-MS (M+1)=383.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH2:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl>CN(C=O)C.O>[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCC(Br)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(C(=O)OCC)C(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
To a solution of diethyl malonate (8.01 g; 50 mmol) in dry DMF (25 mL) under nitrogen atmosphere was added potassium carbonate (7.6 g; 55 mmol), which has been dried at 120° C. for 12 h before using. After stirring for 15 min at room temperature, ethyl 2-bromovalerate (8.53 mL; 50 mmol) was slowly added under nitrogen and the mixture was vigorously stirred at room temperature for 24 h. The reaction mixture was poured in water (240 mL) and neutralized by adding a solution of hydrochloric acid 6N. The product was extracted with diethyl ether (2x240 mL) and the combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by distillation under reduced pressure furnished 12.8 g (99%) of the title compound as a colorless liquid (bp. 117° C., 2 mbar, temperature of the oil bath 165° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH2:10][C:11]([N:13]([C:15]1([C:23]#N)[CH2:20][CH2:19][N:18]([O:21][CH3:22])[CH2:17][CH2:16]1)[CH3:14])=[O:12].S(=O)(=O)(O)[OH:26].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[C:10]1[C:11](=[O:12])[N:13]([CH3:14])[C:15]2([CH2:20][CH2:19][N:18]([O:21][CH3:22])[CH2:17][CH2:16]2)[C:23]=1[OH:26]
Reactant: CON1CCC(C#N)(N(C)C(=O)Cc2cc(C)c(C)cc2Cl)CC1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CON1CCC2(CC1)C(O)=C(c1cc(C)c(C)cc1Cl)C(=O)N2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
To a solution of 2-(2-chloro-4,5-dimethyl-phenyl)-N-(4-cyano-1-methoxy-piperidin-4-yl)-N-methyl-acetamide (compound P4.27) (1.15 g, 3.29 mmol) in methanol (˜3 ml) at 10° C. was added concentrated sulfuric acid (0.876 ml, 16.43 mmol) dropwise and the reaction mixture was stirred at room temperature overnight. After further treatment with concentrated sulfuric acid (0.876 ml, 16.43 mmol) and stirring at 80° C. overnight, additional concentrated sulfuric acid (0.876 ml, 16.43 mmol) was added and stirring continued at 90° C. over another night. The mixture was poured on ice, neutralised carefully with 30% aqueous sodium hydroxide to pH 5-6, the resulting precipitate filtered and dried to afford a first crop of product as a beige solid (225 mg). The mother liquor was concentrated, and the residue purified by chromatography on silica gel (ethyl acetate) to further deliver 462 mg of product as a yellowish solid. Yield: 687 mg of 3-(2-chloro-4,5-dimethyl-phenyl)-4-hydroxy-8-methoxy-1-methyl-1,8-diaza-spiro[4.5]dec-3-en-2-one (title compound P2.26) as a solid, mp 191-192° C.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]([F:49])([F:48])[C:7]1[CH:8]=[C:9]([C@H:17]2[O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]3[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=3[C:34]3[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[C:37]([F:43])=[C:36]([OH:44])[C:35]=3[O:45]C)[C@H:18]2[CH3:47])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1>C(Cl)Cl.O>[F:49][C:6]([F:5])([F:48])[C:7]1[CH:8]=[C:9]([C@H:17]2[O:21][C:20](=[O:22])[N:19]([CH2:23][C:24]3[CH:29]=[C:28]([C:30]([F:31])([F:33])[F:32])[CH:27]=[CH:26][C:25]=3[C:34]3[CH:39]=[C:38]([CH:40]([CH3:41])[CH3:42])[C:37]([F:43])=[C:36]([OH:44])[C:35]=3[OH:45])[C@H:18]2[CH3:47])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1
Reactant: COc1c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)cc(C(C)C)c(F)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c(O)c(O)c1F
Reaction time: 8 h

Procedure:
Boron tribromide (17.4 mg, 6.6 μL, 0.0692 mmol) was added to a stirred solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-3′-hydroxy-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (22.6 mg, 0.0346 mmol) in dry CH2Cl2 (1 mL) at −78° C. at room temperature under N2 and the reaction was stirred for 8 h. The reaction was diluted with water (5 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by chiral HPLC (IA column, 20×250 mm, 15% i-PrOH in heptane) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′,3′-dihydroxy-5′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.24 (20% EtOAc in hexanes). LCMS calc.=640.2; found=640.2 (M+1)+. 1H NMR (600 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.85 (s, 1H), 7.70-7.62 (m, 4H), 7.41 (m, 1H), 6.52 (s, 0.5H), 6.51 (s, 0.5H), 6.20 (br s, 2H), 5.65 (d, J=7.9 Hz, 0.5H), 5.38 (d, J=8.0 Hz, 0.5H), 5.00 (d, J=15.5 Hz, 0.5H), 4.92 (d, J=15.6 Hz, 0.5H), 4.15 (d, J=15.5 Hz, 0.5H), 4.02 (d, J=15.6 Hz, 0.5H), 3.88 (t, J=6.7 Hz, 0.5H), 3.77 (t, J=6.7 Hz, 0.5H), 3.19-3.13 (m, 1H), 1.26-1.17 (m, 6H), 0.59 (d, J=6.1 Hz, 1.5H), 0.48 (d, J=6.2 Hz, 1.5H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].Cl.[CH3:24][C:25]1([OH:30])[CH2:29][CH2:28][NH:27][CH2:26]1>>[Br:1][C:2]1[C:3]([N:27]2[CH2:28][CH2:29][C:25]([OH:30])([CH3:24])[CH2:26]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: CC1(O)CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Agent: Cl
Product: CC1(O)CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 6.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 6.2) and 3-methylpyrrolidin-3-ol hydrochloride to afford a white solid. UPLC-MS (Condition 1) tR=2.79 min, m/z=460.9/461.9 [M+H]+, m/z=458.0/460 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.34 (s, 3H) 1.76-1.93 (m, 2H) 3.63 (d, 1H) 3.68 (d, 1H) 3.70-3.76 (m, 1H) 3.88-3.97 (m, 1H) 4.82 (s, 1H) 7.35 (d, J=8.31 Hz, 2H) 7.85 (d, J=9.05 Hz, 2H) 8.33 (d, J=2.20 Hz, 1H) 8.67 (d, J=2.20 Hz, 1H) 10.22 (s, 1H).