Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:13])[NH:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[N:4][C:3]=1[O:14][CH:15]([CH3:17])[CH3:16].[H-].[Na+].[CH2:20]([O:27][C:28]1[C:33]([CH2:34]Cl)=[C:32]([CH3:36])[CH:31]=[C:30]([CH3:37])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCOC(C)=O>CN(C=O)C>[CH2:20]([O:27][C:28]1[C:33]([CH2:34][N:9]2[C:8](=[O:13])[C:7]3[C:2]([CH3:1])=[C:3]([O:14][CH:15]([CH3:17])[CH3:16])[N:4]=[CH:5][C:6]=3[O:12][CH2:11][CH2:10]2)=[C:32]([CH3:36])[CH:31]=[C:30]([CH3:37])[N:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c(OC(C)C)ncc2c1C(=O)NCCO2
Reactant: Cc1cc(C)c(CCl)c(OCc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(CN2CCOc3cnc(OC(C)C)c(C)c3C2=O)c(OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94608.2 %

Procedure:
To a solution of 6-methyl-7-(propan-2-yloxy)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (131f, 70 mg, 0.30 mmol) in dry DMF (6 mL) was added NaH (36 mg, 0.90 mmol, 60% in oil) at 0° C. The mixture was stirred at 0° C. for 10 minutes. To the mixture was added 2-(benzyloxy)-3-(chloromethyl)-4,6-dimethylpyridine (Cpd Z, 155 mg, 0.6 mmol). The reaction mixture was stirred at room temperature for 14 hours. To the reaction mixture was added EtOAc (20 mL). The solution was washed with brine (5×15 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by column chromatography (petroleum ether/EtOAc, 10/1) to give 4-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-6-methyl-7-(propan-2-yloxy)-3,4-dihydropyrido[4,3-f][1,4]oxazepin-5(2H)-one (131 g, 0.14 g, 100%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([OH:8])[CH:7]=1.Cl[CH2:11][CH2:12][S:13][CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH:7]=1)[O:8][CH2:11][CH2:12][S:13][CH3:14]
Reactant: CSCCCl
Reactant: Oc1cc(Br)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CSCCOc1cc(Br)ccc1Cl
Temperature: 100 °C

Procedure:
5-Bromo-2-chlorophenol (500 mg, 2410 μmol) and (2-chloroethyl)(methyl)sulfane (262 μl, 2651 μmol) were combined with cesium carbonate (942 mg, 2892 μmol) in DMF and heated to 100° C. for 2 h. The mixture was then filtered and purified using reverse phase chromatography. This purified material was carried forward to the next step.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([CH3:17])=[C:12]([CH:18]=[CH2:19])[C:11]=1[O:20][CH3:21])[CH3:9])(C)(C)C>Cl>[ClH:16].[Cl:16][C:14]1[C:13]([CH3:17])=[C:12]([CH:18]=[CH2:19])[C:11]([O:20][CH3:21])=[C:10]([CH:8]([NH2:7])[CH3:9])[CH:15]=1
Reactant: C=Cc1c(C)c(Cl)cc(C(C)NC(=O)OC(C)(C)C)c1OC
Agent: Cl
Product: C=Cc1c(C)c(Cl)cc(C(C)N)c1OC

Procedure:
tert-Butyl[1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethyl]carbamate was stirred in 4 N HCl (1.0 mL) for 30 min and evaporated to give 1-(5-chloro-2-methoxy-4-methyl-3-vinylphenyl)ethanamine hydrochloride (480 mg, 1.8 mmol) which was stirred in 1-butanol (86 mL), with DIPEA (1.6 mL, 9.1 mmol) and 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (650 mg, 2.7 mmol, from Example 176, Step 4). The reaction mixture was heated at 120° C. for 2 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc. The extracts were washed with brine and evaporated. Purification on silica gel using 0-50% EtOAc in hexane gave the desired compound (780 mg, 100%). LCMS calculated for C22H27ClN5O2 (M+H)+: m/z=428.2. found: 428.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@@H:12](O)[CH2:13][NH:14][C:15](=[O:21])[O:16]C(C)(C)C)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Cl>CN(C=O)C.O>[CH3:23][C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:21])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: CC(C)(C)OC(=O)NC[C@H](O)c1ccc2c(c1)COC(C)(C)O2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Temperature: 21 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
tert-Butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate, (86.37 g) in DMF (600 ml) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 11.9 g) in DMF (160 ml) with cooling such that the internal temperature remained at 0° C. under nitrogen. The mixture was stirred at 21° C. for 2 h. The mixture was recooled to 0° C. and 2M HCl (134 ml) was added. The mixture was diluted with water and the product was extracted with ethyl acetate twice. The solution was washed with brine twice, dried (MgSO4) and evaporated to give the title compound (63.55 g) LCMS RT=2.66 min.
Reaction SMILES: [H-].[Na+].[CH:3]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[CH:8]=[N:7]1)([CH3:5])[CH3:4].[Cl:16][C:17]1[C:18](F)=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:23]>C1COCC1>[Cl:16][C:17]1[C:18]([O:15][C:11]2[CH:10]=[C:9]3[C:14](=[CH:13][CH:12]=2)[N:6]([CH:3]([CH3:5])[CH3:4])[N:7]=[CH:8]3)=[CH:19][C:20]([F:30])=[C:21]([CH:29]=1)[C:22]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])=[O:23]
Reactant: CC(C)n1ncc2cc(O)ccc21
Reactant: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)n1ncc2cc(Oc3cc(F)c(C(=O)NS(C)(=O)=O)cc3Cl)ccc21
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 8.7 %

Procedure:
Sodium hydride (60% in mineral oil, 0.012 g, 0.306 mmol) was added to a solution of 1-isopropyl-1H-indazol-5-ol (Preparation 39, 0.045 g, 0.225 mmol) in THF (3.0 mL) while cooling the reaction in an ice bath and stirred for 40 minutes. 5-Chloro-2,4-difluoro-N(methylsulfonyl)benzamide (Preparation 28, 0.076 g, 0.28 mmol) was then added and the reaction was heated at 60° C. for 16 hours. The reaction mixture was concentrated in vacuo and the residue treated with EtOAc (25.0 mL) and washed with water (30.0 mL), followed by brine (30.0 mL). The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and the residue purified by silica gel chromatography eluting with 2% Methanol in DCM to yield the title compound as a white solid (8.3 mg):
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[Br:11][C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1.[BH4-].[Na+]>CCO.CO>[Br:11][C:12]1[S:16][C:15]([CH2:17][NH:10][C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: Nc1cc(F)c(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Fc1cc(F)c(NCc2ccc(Br)s2)cc1F
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of 2 g (13.6 mmol) of 2,4,5-trifluorophenylamine and 2.66 g (13.9 mmol) of 5-bromothiophene-2-carbaldehyde in 30 ml of EtOH, 9.4 g of molecular sieves (0.3 nm) were added and the mixture was refluxed for 20 hours. After this time the reaction mixture was cooled to room temperature, filtered and the solvent was evaporated in vacuo. The oil obtained was dissolved in 30 ml of MeOH and 0.51 g (13.6 mmol) of NaBH4 were added in small portions, maintaining the temperature of the reaction at room temperature. The mixture was stirred at this temperature for 20 more hours. After this time the solvent was evaporated in vacuo and the residue was treated with 100 ml of water and extracted twice with ether. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered and evaporated to dryness to give 3.2 g of an oil. This 3.2 g were combined with 3.5 g obtained in a subsequent preparation and the total product obtained (6.7 g) was purified by chromatography on silica gel using mixtures of hexane/AcOEt 5:1→1:1 as eluent Appropriate fractions were combined to give 0.95 g of the title product as an oil. (global yield 8.2%).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1)=[N+]=[N-]>CCOC(C)=O.[Pd]>[NH2:1][CH2:4][CH:5]1[CH2:10][CH:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CC(CN=[N+]=[N-])CC(O[Si](C)(C)C(C)(C)C)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(CN)CC(O[Si](C)(C)C(C)(C)C)C1

Procedure:
A solution of tert-butyl 3-(tert-butyldimethylsilyloxy)-5-((methylsulfonyloxy)methyl) piperidine-1-carboxylate from step C in EtOAc was hydrogenated under hydrogen atmosphere with 10% Pd/C (500 mg) overnight. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound. MS (m/z): 345 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)=O.Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[Cl:1][C:2]1[C:16]([Cl:17])=[C:15]([OH:18])[CH:14]=[CH:13][C:3]=1[C:4](=[N:20][OH:21])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1
Reactant: NO
Reactant: O=C(c1cccc(F)c1)c1ccc(O)c(Cl)c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: ON=C(c1cccc(F)c1)c1ccc(O)c(Cl)c1Cl

Procedure:
To a solution of 5 g of 2,3-dichloro-4-hydroxy-3'-fluorobenzophenone in 50 ml of pyridine, 1.58 g of hydroxylamine hydrochloride is added. The mixture is refluxed for 18 hours. The pyridine is evaporated in vacuo and the residue is partitioned between 5% HCl and ethylacetate. The ethylacetate is washed with water, dried over Na2SO4 and evaporated to give 2,3-dichloro-4-hydroxy-3'-fluorobenzophenone oxime as a mixture of isomers, mp 178°-185° C.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].N1C[CH2:15][CH2:14][CH2:13]1.CC(C)=O>C(#N)C>[CH3:13][C:14]1([CH3:15])[CH2:1][C:2](=[O:3])[C:4]2[C:5](=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=2)[O:11]1
Reactant: CC(=O)c1cc(O)ccc1O
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CC(C)=O
Product: CC1(C)CC(=O)c2cc(O)ccc2O1
Temperature: 45 °C
Yield: 81.6 %

Procedure:
A reaction mixture of 100 g (0.65 mol) of 2,5-dihydroxyacetophenone in 1 l of acetonitrile, 130 ml (1.55 mol) of pyrrolidine and 290 ml (3.95 mol) of acetone was heated at 45° C. for 8 h. The sol. were then removed i. vac. and the residue was dissolved in 1 l of EA. The organic phase was washed twice with dilute hydrochloric acid, stirred with activated carbon and dried over magnesium sulfate and substantially concentrated. The residue was stirred with petroleum ether and the precipitate was filtered off with suction giving 102 g of 2,2-dimethyl-6-hydroxychroman-4-one, m.p. 161° C.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].O1CCCC1.[CH2:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([C:26](OCC)=[O:27])[CH2:22][CH2:21]1)[CH3:19]>CCCCCC.C(O)(=O)C>[O:27]=[C:26]([C@H:23]1[CH2:24][CH2:25][C@H:20]([CH2:18][CH3:19])[CH2:21][CH2:22]1)[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: COP(C)(=O)OC
Reactant: CCOC(=O)[C@H]1CC[C@H](CC)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CC[C@H]1CC[C@H](C(=O)CP(=O)(OC)OC)CC1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of nitrogen, 47 ml. of a 1.25 M solution of n-butyllithium in n-hexane were added dropwise to a solution of 7.64 g. of dimethyl methylphosphonate in 120 ml. of tetrahydrofuran at -70° C. After one hour of stirring at -70° C., a solution of 5.63 g. of ethyl trans-4-ethylcyclohexanecarboxylate [c.f. N. L. Allinger and L. A. Freiberg, J. Org. Chem., 31, 894, (1966)] in 30 ml. of tetrahydrofuran was added dropwise at -70° C., and the mixture was stirred at the same temperature for one hour and further stirred at -5° C., for one hour. The reaction mixture was then acidified with acetic acid and concentrated under reduced pressure. The residue was diluted with diethyl ether, washed with water and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by distillation to give 5.0 g. of the title compound having the following physical characteristics:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:30])([C@@H:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][CH:27]=2)[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH3:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:31]Br.CO.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C@H:12]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[Br:31])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:29])[C:19](=[O:28])[NH:20][N:21]=2)[CH3:13])([CH3:30])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: BrBr
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc([C@@H](C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1C(=O)NN=C2COc3cc(Br)c([C@H](C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a solution of 3-methyl-3-[(R)-1-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester (diastereomer 1, 0.283 g, 0.683 mmol) in AcOH (1 mL) was added a solution of bromine (0.070 mL, 1.366 mmol) in AcOH (1 mL) drop-wise and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was quenched by the addition of saturated aqueous NaS2O3 solution and aqueous NaHCO3 solution to pH 7-8. MeOH (5 mL), TEA (0.146 g, 1.439 mmol) and di-tert-butyl dicarbonate (0.188 g, 0.864 mmol) were added in sequence to the above mixture and the reaction mixture was stirred at ambient temperature for 1.5 h. The aqueous solution was extracted with EtOAc (3×10 mL) and the combined organic phase was washed with saturated brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by prep-TLC (eluting with 50% EtOAc in petroleum ether) to give 3-[(R)-1-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.128 g, 36%) as a solid. LC/MS (Table 1, Method 25) Rt=0.913 min.; MS m/z: 437 [M+H−56]+ and 439 [M+H−56]+. 1H NMR (CDCl3, 400 MHz): δ 8.26 (brs, 1H), 7.25 (s, 1H), 6.70 (s, 1H), 4.75-4.70 (m, 1H), 4.60 (d, J=12.8 Hz, 2H), 3.98-3.91 (m, 2H), 3.55 (m, 2H), 3.44 (d, J=8.4 Hz, 1H), 1.52 (d, J=6.8 Hz, 3H), 1.46 (s, 9H), 1.32-1.27 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Br:16][C:17](Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[CH:4]=[C:17]([Br:18])[Br:16]
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccc(CN2CCCC2)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(CN2CCCC2)ccc1C=C(Br)Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde (prepared according to the teachings in WO2008/148868) (10.0 g, 44.70 mmol) and tetrabromomethane (22.2 g, 67.05 mmol) in DCM (300 ml) was stirred at 0° C. A solution of triphenylphosphine (35.2 g, 134.10 mmol) in DCM (500 ml) was added. The mixture was stiffed for 30 min at 0° C. The mixture was concentrated in vacuo. The residue was taken up into CHCl3, and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue (crude 1-[[3-chloro-4-(2,2-dibromoethenyl)phenyl]methyl]-pyrrolidine) was used as such in the next reaction step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9](=[O:16])[NH:10]2.Br[CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]2[C:6]=1[C:7]([CH3:25])=[C:8]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9]([O:16][CH2:28][CH3:29])=[N:10]2
Reactant: CCBr
Reactant: COC(=O)Cc1cc(C)cc2[nH]c(=O)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1nc2cc(C)cc(CC(=O)OC)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 40 °C

Procedure:
A mixture of [3-(4-chlorobenzyl)-4,7-dimethyl-2-oxo-1,2-dihydroquinolin-5-yl]acetic acid methyl ester (1.0 g), bromoethane (0.24 mL), potassium carbonate (1.1 g) and N,N-dimethylformamide (10 mL) was heated at 40° C. for 17 hours. The mixture was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0:1 to 1:5 by volume) gave title compound as a gum, 0.28 g.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12](=[O:39])[NH:13][CH:14]([C:33](=[O:38])N(OC)C)[CH2:15][CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:17]1C)([CH3:10])([CH3:9])[CH3:8].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1COCC1>[C:7]([O:11][C:12](=[O:39])[NH:13][CH:14]([CH:33]=[O:38])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:17]=1)([CH3:8])([CH3:10])[CH3:9]
Reactant: CON(C)C(=O)C(CC1c2ccccc2N(Cc2ccccc2)C1C)NC(=O)OC(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C=O)Cc1cn(Cc2ccccc2)c2ccccc12
Reaction time: 0.25 h
Yield: 73.6 %

Procedure:
A suspension of LiAlH4 (143 mg, 3.76 mmol) in THF (5 mL) was added over 10 min to a solution of [2-(1-benzyl-2-methyl-2,3-dihydro-1H-indol-3-yl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (2 g, 4.32 mmol) in THF (35 mL) at −20° C. The reduction was complete in 15 min (silica gel, 50% EtOAc/petroleum ether, Rf 0.76). Saturated sodium potassium tartrate (10 mL) was added, and the solvent removed. Water was added and the residue extracted with Et2O. The Et2O was washed with brine, dried and filtered. Removal of the solvent gave the title compound (1.204 g, 93%). 1H NMR (CDCl3) δ 13C NMR (CDCl3) δ 200.3, 155.5, 137.3, 136.6, 128.7, 128.1, 127.6, 127.0, 126.7, 122.1, 119.5, 119.0, 109.8, 109.1, 79.9, 60.2, 49.9, 28.3, 25.2,
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][C:5](=O)[CH2:6]2.[ClH:12].[NH2:13][OH:14]>CO>[ClH:12].[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4][C:5](=[N:13][OH:14])[CH2:6]2
Reactant: CN1C2CCCC1CC(=O)C2
Reactant: NO
Agent: Cl
Solvent: CO
Product: CN1C2CCCC1CC(=NO)C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.5 %

Procedure:
A mixture of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one (0.658 g, 4.29 mmol) and hydroxylamine hydrochloride (0.312 g, 4.49 mmol) in methanol (6 mL) was stirred for 20 h at room temperature, during which time a white precipitate formed. This solid was collected by filtration, rinsed with additional methanol (2×10 mL), and dried under vacuum for 1 h to afford 0.672 g (76% yield) of 9-methyl-9-aza-bicyclo[3.3.1]nonan-3-one oxime hydrochloride as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.82 (s, 1H), 3.71-3.52 (m, 2H), 3.34-3.23 (m, 1H), 3.12 (d, J=17.5 Hz, 1H), 2.90-2.79 (m, 3H), 2.73-2.55 (m, 1H), 2.42 (d, J=16.8 Hz, 1H), 2.27-2.05 (m, 2H), 1.87-1.42 (m, 4H); MS (ESI) m/z 169 [M+H]+
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[C:8](Cl)=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1.C(N(CC)CC)C>C(#N)C>[Br:6][C:7]1[C:8]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:9][C:10]([Cl:13])=[N:11][CH:12]=1
Reactant: CC(C)(C)N
Reactant: Clc1ncc(Br)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 52 %

Procedure:
tert-Butylamine (5.28 g, 72 mmol) was added to 5-bromo-2,4-dichloropyrimidine (15 g, 66 mmol) and triethylamine (19.9 g, 197 mmol) in acetonitrile (450 mL) at room temperature and the mixture was stirred at room temperature for 16 hours. Then the mixture was evaporated in vacuo and the crude residue was partitioned between EtOAc (450 mL) and water (400 mL). The organic layer was separated, washed with brine (400 mL) then dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:EtOAc 88:12) to afford the title compound as a yellow oil in 52% yield, 8.8 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.CN.[C:28]([BH3-])#[N:29].[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH:29][CH3:28])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.228 g, 0.65 mmol) and methylamine (2M in THF; 0.5 mL, 0.84 mmol) in CH2Cl2 (3.4 mL) was added sodium cyanoborohydride (0.061 g, 0.97 mmol), followed by acetic acid (1 drop). The reaction was stirred at room temperature overnight, until no starting material was seen by analytical LCMS. The solution was neutralized with saturated aqueous NaHCO3 and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:17])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13]C(=O)C)=[CH:9][CH:8]=1)C.[ClH:18]>>[ClH:18].[NH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]([OH:17])=[O:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)COc1ccc(NC(C)=O)cc1
Agent: Cl
Product: Nc1ccc(OCC(=O)O)cc1
Temperature: 10 °C
Yield: 77.6 %

Procedure:
(4-Acetylamino-phenoxy)-acetic acid ethyl ester 1 (375 grams, 1.582 mmol), in concentrated Hydrochloric acid (9.36 liters) was refluxed for 12 Hours. Excess concentrated Hydrochloric acid was distilled off in vacuum and filtered hot. The mixture was cooled to 10° C., filtered and dried to give pure 2 (250 g, 77.6%) as a wheat colored powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:24][C:25]1[CH:29]=[CH:28][O:27][CH:26]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]([CH2:24][C:25]3[CH:29]=[CH:28][O:27][CH:26]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccoc1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccc(OC)cc23)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccoc3)c3ccc(OC)cc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 8 g (26.4 mmol) of 4-(5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester (example 87, part B) and 30 mL (30 mmol) of a freshly prepared 1M solution in ethyl ether of 3-bromomethyl-furan. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 9.9 g (99% of yield) of 4-(1-furan-3-ylmethyl-5-methoxy-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.