Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:18][C@H:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10].[C:19]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1>CO>[C:41]1([CH3:51])[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:48])=[O:49])=[CH:45][CH:46]=1.[OH:1][C@@H:2]([CH2:18][N:32]1[CH2:33][CH2:34][CH:29]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:30][CH2:31]1)[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10]
Reactant: c1ccc2c(C3CCNCC3)cccc2c1
Reactant: O=C1OCCC1=Cc1ccccc1OC[C@@H]1CO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1OCCC1=Cc1ccccc1OC[C@@H](O)CN1CCC(c2cccc3ccccc23)CC1

Procedure:
The reaction was performed in same manner as in Example 307 using (S)-α-(2′-(2,3-epoxypropan-1-yloxy)benzylidene)-γ-butyrolactone (5.8 g) and 4-(naphthalen-1-yl)piperidine (5.0 g) in methanol (100 ml) and the obtained oil was treated with ethyl acetate/p-toluenesulfonic acid to give the title compound (7.8 g), melting point 119-121° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[C:6]1(=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>C1(C)C=CC=CC=1>[CH2:1]([N:5]=[C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C1CCCCC1
Reactant: CCCCN
Solvent: Cc1ccccc1
Product: CCCCN=C1CCCCC1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
1-Butylamine (9.88 mL, 0.1 mol) and toluene (15 mL) was added to cyclohexanone (10.36 mL, 0.1 mol) and the reaction mixture was heated under reflux for 24 h under dehydration condition by using Dienstark reflux condenser packing molecular sieves 4A. After the reaction mixture was cooled to room temperature, evaporated under reduced pressure. The residue was distilled under reduced pressure (2 mmHg) at 64° C. to give butyl-cyclohexylideneamine (1-015-01) (12.8 g, 84%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:26][C:25](=[O:27])[C:24]4[C:23]5[C:18](=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:17]=[CH:16][C:15]=4[N:14]=3)=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(#N)C.O.[CH:36]([NH2:39])([CH3:38])[CH3:37]>[Cl-].[Na+].O>[CH:36]([NH:39][C:25]([C:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16][C:15]=1[NH:14][C:13]([C:12]1[N:8]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:9]=[C:10]([C:28]([F:31])([F:29])[F:30])[CH:11]=1)=[O:26])=[O:27])([CH3:38])[CH3:37]
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2ccc3ncccc3c12
Reactant: CC(C)N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)ccc2ncccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.3 %

Procedure:
To a suspension of 150 mg (0.30 mmol) of the above 2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-3-oxa-1,8-diaza-phenanthren-4-one in 6 mL of a mixture acetonitrile: H2O 4:1 (v/v) is added 78 μL (0.91 mmol) of isopropylamine. The reaction mixture is stirred for 6 hours at ambient temperature. Brine is then added to the mixture and the product is extracted with ethyl acetate (3 times). The regrouped organic phases are dried on Na2SO4, filtrated and evaporated. The purification of the residue by flash chromatography (SiO2, heptane/ethyl acetate 1:1) affords 100 mg (65%) of a white solid; LC/MS:503/505 (M+H)+, m.p.: 182-183° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:14]\[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)/[C:9]([O:11]CC)=[O:10])=[CH:4][CH:3]=1.Cl>O1CCCC1.CO.[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:14]\[O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:28][C:29]=3[CH3:30])=[CH:19][CH:18]=2)/[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/C(=O)O)c2ccc(Br)cc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
Ethyl E-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetate (600 mg) was dissolved in tetrahydrofuran (6 ml)-methanol (3 ml), and 1N aqueous solution of sodium hydroxide (3 ml) was added and the mixture was stirred for 1 hour at 40° C. 1N HCl (3.3 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residual crystals were recrystallized from ethyl acetate to obtain E-2-(4-bromophenyl)-2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]acetic acid (516 mg, yield 99%) as colorless crystals. m.p. 159-160° C. (decomposition)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[C:7]=2[CH:21]=1)#[N:2].C(O)(=O)C.Cl.[H][H]>C(O)C.[Pd]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[C@@H:9]([OH:14])[C@H:8]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])[C:7]=2[CH:21]=1
Reactant: [H][H]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Agent: [Pd]
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)Oc2ccc(CN)cc2[C@@H](N2CCCC2=O)[C@@H]1O

Procedure:
trans-6-Cyano-3,4-dihydro-2,2-dimethyl-4-(2-oxopyrrolidinyl)-2H-1-benzopyran-3-ol (5 g, prepared as described in J.Med.Chem. 29, 2194 (1986)), in ethanol (375 ml) and glacial acetic acid (75 ml) containing concentrated HCl (5 ml) was shaken in the presence of 10% Pd/C (1 g) in an atmosphere of hydrogen for 4 h. The catalyst was filtered off and the solution neutralised with 10% aqueous NaOH solution, and the solution evaporated to dryness. Acid-base extraction, and drying of a dichloromethane solution of the residue, furnished, after recrystallisation from ethyl acetate-pentane, 2.03 g of the required aminomethyl compound of example 4 of mp 191°-193° C. as the hemihydrate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[F:18][C:19]([F:32])([O:23][C:24]1[CH:25]=[C:26]([CH2:30]Br)[CH:27]=[CH:28][CH:29]=1)[CH:20]([F:22])[F:21].O>COCCOC>[F:1][C:2]1[CH:7]=[C:6]([C:8](=[O:15])[CH:9]([CH2:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:19]([F:18])([F:32])[CH:20]([F:21])[F:22])[CH:25]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Reactant: CCOC(=O)CC(=O)c1ccnc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (3.80 g, 18.2 mmol) in carbon tetrachloride (50 ml) were added N-bromosuccinimide (3.54 g, 19.9 mmol) and 2,2′-azobis(isobutyronitrile) (136 mg, 0.83 mmol), and the mixture was heated under reflux for 4 hrs. After cooling, the reaction solution was filtered, and the filtrate was concentrated to give ethyl 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-(2-fluoropyridin-4-yl)-3-oxopropionate (3.5 g, 16.6 mmol) in 1,2-dimethoxyethane (35 ml) was added sodium hydride (60% in oil, 0.66 g, 16.6 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (5 ml), and the mixture was stirred at room temperature for 1 hr. The reaction solution was poured into water (100 ml), and the mixture was extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:hexane=1:1) to give ethyl 3-(2-fluoropyridin-4-yl)-3-oxo-2-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)propionate (4.78 g, 69%) as a colorless oil.
Reaction SMILES: C(=O)(OCC)[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[N:15]3[C:23]([C:26]#[N:27])=[CH:24][CH:25]=[C:14]3[CH:13]2[CH2:28][CH3:29])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-:34].[Na+]>C(O)C>[CH2:28]([CH:13]1[N:12]([S:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=2)(=[O:11])=[O:10])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=2)[N:15]2[C:23]([C:26]([NH2:27])=[O:34])=[CH:24][CH:25]=[C:14]12)[CH3:29]
Reactant: [OH-]
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)N2c3cc(F)ccc3-n3c(C#N)ccc3C2CC)cc1
Agent: [Na+]
Solvent: CCO
Product: CCC1c2ccc(C(N)=O)n2-c2ccc(F)cc2N1S(=O)(=O)c1ccc(O)cc1
Yield: 14 %

Procedure:
0.25 g (0.53 mmol) of the product from Example 34 was dissolved in 15 ml of ethanol and 5 ml of 2N NaOH was added. The solution was heated to reflux for 3 hours, after which time it was concentrated then neutralized with 2N HCl. The mixture was extracted with ethyl acetate (2×20 ml) and the combined organic layers were dried (MgSO4) and concentrated. The crude solid was subjected to column chromatography on silica gel eluting with chloroform:methanol (95:5). The fractions containing product were combined and concentrated to yield a light tan solid, which was crystallized from ethyl acetate:hexane to yield 32 mg (14%) of product, mp 168-170° C. (d).
Reaction SMILES: [C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2].[N-:24]=[N+:25]=[N-:26].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]3[NH:26][N:25]=[N:24][N:15]=3)=[CH:12][CH:11]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(COc2ccc(C#N)cc2)ccc(C(C)=O)c1O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(COc2ccc(-c3nnn[nH]3)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 19.0 g. of 4-(4-acetyl-3-hydroxy-2-propylbenzyloxy)benzonitrile, 13.0 g. of sodium azide, and 10.9 g. of ammonium chloride in 250 ml. of dimethylformamide was heated to 115° C. for eight hours. An additional 13.0 g. of sodium azide and 10.9 g. of ammonium chloride were added every 2.5 hours during this period. The reaction was stirred overnight at room temperature and then heated an additional six hours with more reagents being added. The reaction mixture was then evaporated under reduced pressure and the residue was dissolved in 800 ml. of water. The solution was made acidic with hydrochloric acid and the resulting precipitate was filtered. The precipitate was dissolved in 1N sodium hydroxide and the solution was washed once with ethyl acetate. The basic solution was made acidic with hydrochloric acid and the precipitate was recovered by filtration. The precipitate was crystallized first from isopropyl alcohol/ethyl acetate/water and then recrystallized from isopropyl alcohol providing 10.3 g. of the desired title product, m.p. 203°-205° C. IR, NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CO.[H][H]>[Ni].C(Cl)Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.76 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H) naphthalenylidene]methanamine (Ketimine) (50 g), methanol (300 ml), Raney Nickel (0.15 g wet basis) and DCM (12.5 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.76%].
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([NH:9][NH2:10])=[O:8].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>C(O)C>[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[N:10][NH:9][C:7]([C:6]2[S:5][C:4]3[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=3[C:2]=2[Cl:1])=[O:8])=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: NNC(=O)c1sc2ccccc2c1Cl
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Product: O=C(NN=Cc1ccc([N+](=O)[O-])cc1)c1sc2ccccc2c1Cl
Yield: 66.7 %

Procedure:
A solution of 3-chlorobenzo[b]thiophene-carboxylic acid hydrazide (34 mg, 0.15 mmol) and p-nitrobenzaldehyde (23 mg, 0.15 mmol) in ethanol (10 mL) was refluxed for 6 h. The precipitate was collected by filtration and washed with ethanol, dried to give 36 mg (67%) of the title compound. 1H NMR (DMSO-d6): 12.40 (bs, 1H), 8.60−7.60 (m, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:24]>C1(C)C=CC=CC=1.[Ag]=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([O:22][CH3:24])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCOC(=O)CC(O)c1ccc(OCc2ccccc2)cc1
Agent: O=[Ag]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(OC)c1ccc(OCc2ccccc2)cc1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
40 g of ethyl 3-(4-benzyloxyphenyl)-3-hydroxypropionate, 75 g of silver oxide and 83 ml of iodomethane were initially charged in 350 ml of toluene and stirred in a closed vessel at bath temperature 70° C. for 24 hours. Then a further 20 ml of iodomethane were added and the mixture was stirred at bath temperature 70° C. for a further 48 hours. The reaction mixture was filtered through a short silica gel layer and washed with toluene, and then the toluene was removed under reduced pressure. The residue was purified on silica gel with the eluent ethyl acetate:n-heptane=1:2. This gave 22.9 g of ethyl 3-(4-benzyloxyphenyl)-3-methoxypropionate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26](O)=[O:27])[N:9]=2)=[CH:4][CH:3]=1.[CH3:29][CH2:30][N:31](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([O:19][CH3:20])[CH:17]=[CH:18][C:13]=3[N:12]3[C:21]([CH3:24])=[N:22][N:23]=[C:11]3[C@H:10]([CH2:25][C:26]([NH:31][CH2:30][CH3:29])=[O:27])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(c1ccc(Cl)cc1)=N[C@@H](CC(=O)O)c1nnc(C)n1-2
Reactant: CCN(C(C)C)C(C)C
Agent: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OC)ccc2-n2c(C)nnc21
Reaction time: 48 h
Yield: 47 %

Procedure:
To a solution of [(4S)-6-(4-Chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetic acid (for a preparation see Intermediate 1) (16.0 g, 40 mmol) in THF at RT was added DIEA (14 mL, 80 mmol) followed by HATU (30.4 g, 80 mmol). The reaction mixture was stirred for 3 h at this temperature and ethylamine (40 mL, 2M in THF, 80 mmol) was added. The mixture was stirred for 48 h before being concentrated under reduced pressure. The crude material was suspended in water and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude solid was purified by chromatography on SiO2 (DCM/MeOH 95/5) and the resulting solid recrystallised in MeCN. The solid was then dissolved in DCM and precipitated with i-Pr2O to give the title compound (8 g, 47% yield) as a white solid.
Reaction SMILES: [C:1]1([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.P(Br)(Br)[Br:28]>C1(C)C=CC=CC=1>[Br:28][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:14][CH:15]=1
Reactant: OCc1ccc(OCc2cccc3ccccc23)cc1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: BrCc1ccc(OCc2cccc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
A suspension of sodium ethoxide (924 mg, 13.6 mmol) in DMF was stirred at 0° C. for 10 min. Ethyl 4-hydroxy benzoate (2.26 g, 13.6 mmol) was slowly added and resulting mixture was stirred at this temp for 0.5 h, then allowed to reach room temp. To this mixture 1-(bromomethyl)naphthalene (2.0 g, 9.0 mmol) was added dropwise [(predissolved in DMF (5 mL)]. Resulting mixture was stirred at room temperature for 16 h. DMF was evaporated off in-vacuo and the residue taken up in EtOAc, and washed with brine, water and 1M NaOH (2×30 mL). The organic layer was dried (MgSO4) and the solvent evaporated off in-vacuo to yield ethyl 4-(naphthalene-1-ylmethoxy)benzoate (1.7 g, 5.55 mmol). This was then dissolved in THF and LiAlH4 (211 mg, 5.55 mmol) was added portionwise, with vigorous stirring. The suspension was stirred at room temperature for 3 h. THF was evaporated off in-vacuo. The crude residue was taken up in EtOAc and washed with water, brine and dried (MgSO4). EtOAc was evaporated off in-vacuo to obtain (4-(naphthalene-1-ylmethoxy)phenyl)methanol (1.3 g, 4.9 mmol) as a crude product. This was used in the next reaction step without further purification. (4-(naphthalen-1-ylmethoxy)phenyl)methanol (1.0 g, 3.8 mmol) was dissolved in toluene (30 mL) and pyridine (305 uL, 3.8 mmol) was added. The solution was cooled to 0° C. PBr3 (359 uL, 3.8 mmol) was added dropwise over 15 min. The mixture was brought up to room temperature and stirred for 1 h. It was washed with K2CO3 solution and extracted with EtOAc (3×30 mL). The EtOAc layer was washed with brine and dried (MgSO4). The solvent was evaporated off in-vacuo to obtain 1-((4-(bromomethyl)phenoxy)methyl)naphthalene (660 mg, 53%). This intermediate was used in the following reaction.
Reaction SMILES: [C:1]([CH2:6][C:7]1[O:8][C:9]([SH:12])=[N:10][N:11]=1)(OCC)=[O:2].[NH3:13]>C(O)C>[C:1]([CH2:6][C:7]1[O:8][C:9]([SH:12])=[N:10][N:11]=1)(=[O:2])[NH2:13]
Reactant: N
Reactant: CCOC(=O)Cc1nnc(S)o1
Solvent: CCO
Product: NC(=O)Cc1nnc(S)o1

Procedure:
A solution of 1.88 g (0.01 mol) of 2-carbethoxymethyl-1,3,4-oxadiazol-5-thiol in 25 ml of absolute ethanol is added dropwise at ambient temperature to 100 ml of a saturated solution of anhydrous ammonia in absolute ethanol. When the reaction is complete, as evidenced by thin layer chromatography, the solution is evaporated to dryness. The residue is dissolved in 100 ml of water and the aqueous solution is acidified to pH 2.5 with dilute hydrochloric acid and extracted with ethyl acetate. The extract is dried (MgSO4) and evaporated to dryness to give 2-carbamoylmethyl-1,3,4-oxadiazole-5-thiol.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6]2.Br>>[C:12]1([CH:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[C:3]([OH:2])[CH:4]=3)[CH2:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COc1ccc2c(c1)CC(c1ccccc1)C2
Agent: Br
Product: Oc1ccc2c(c1)CC(c1ccccc1)C2
Temperature: 25 °C

Procedure:
Mixture of 5-methoxy-2-phenylindane (200 mg) and concentrated HBr (4 ml) was refluxed for 5.5 h. Reaction mixture was allowed to cool to room temperature and 20 ml of ice water and it was extracted with methylene chloride. The combined organic layers were washed with brine and dried with Na2SO4. The solvents were evaporated to give 2-phenylindan-5-ol. 1H-NMR (400 MHz, d6-DMSO): 9.05 (bs, 1H), 7.3-7.28 (m, 4H), 7.26-7.15 (m, 1H), 7.0 (d, 1H, J 8.1 Hz), 6.64 (d, 1H, J 1.9 Hz), 6.55 (dd, 1H, J 1.9, 8.1 Hz), 3.60 (k, 1H, J 8.6 Hz), 3.18 (m, 2H), 2.86 (dt, 2H, J 8.6, 16 Hz).
Reaction SMILES: CC([S@@]([NH:7][C@H:8]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][N:20]=2)=[CH:15][CH:14]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])=O)(C)C.Cl.C(OCC)C>CO>[CH3:11][CH:10]([CH3:12])[CH2:9][C@@H:8]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][N:20]=2)=[CH:17][CH:18]=1)[NH2:7]
Reactant: CC(C)C[C@H](N[S@@](=O)C(C)(C)C)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(C)C[C@H](N)c1ccc(-c2ccc(C(F)(F)F)cn2)cc1
Reaction time: 1 h

Procedure:
A cooled solution (0° C. by internal thermometer) of (S,S)-2-methyl-N-(3-methyl-1-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}butyl)propane-2-sulfinamide (74.0 g, 179 mmol) in methanol (0.90 L) was treated with 2.0M hydrochloric acid in diethylether (233 ml, 466 mmol) dropwise while maintaining the reaction temperature below 15° C. Following 1 hour, the solvent was removed in vacuo and the resulting oil was treated with diethylether to precipitate the product as a fine white solid. The solid was collected via filtration, and washed with diethylether (3×100 ml). The remaining solid was dried in vacuo. The crude material was used for further transformations.
Reaction SMILES: CN(C)[C:3](=[O:22])[CH2:4][CH2:5][C:6]12[C:21]3[N:10]([C:11]4[C:16]([C:17]=3[CH2:18][CH2:19][O:20]1)=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:9][CH2:8][CH2:7]2.[OH-:24].[K+]>>[CH2:9]1[N:10]2[C:21]3[C:6]([CH2:5][CH2:4][C:3]([OH:22])=[O:24])([O:20][CH2:19][CH2:18][C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:7][CH2:8]1
Reactant: [OH-]
Reactant: CN(C)C(=O)CCC12CCCn3c1c(c1ccccc13)CCO2
Agent: [K+]
Product: O=C(O)CCC12CCCn3c1c(c1ccccc13)CCO2

Procedure:
A solution of 1,2,3,3a,5,6-hexahydro-N,N-dimethyl-4-oxa-10b-azafluoranthene-3a-propionamide (described in Example 8, 25 g, 0.08 mole) in a 10% potassium hydroxide solution (500 ml) is stirred at reflux for 18 hr. The solution is cooled, washed with diethyl ether, acidified and extracted with diethyl ether. The organic phase is dried over sodium sulfate, evaporated and crystallized to give 1,2,3,3a,5,6-hexahydro-4-oxa-10b-azafluoranthene-3a-propionic acid (21.5 g), mp 153°-155° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)=[C:4]([F:21])[CH:3]=1.[CH:22]([O:24][CH2:25][CH2:26][O:27][NH2:28])=[CH2:23].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:22]([O:24][CH2:25][CH2:26][O:27][NH:28][C:18]([C:17]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:21])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2)=[O:20])=[CH2:23]
Reactant: O=C(O)c1ccc2[nH]ncc2c1Nc1ccc(Br)cc1F
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1ccc2[nH]ncc2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
To a solution of 4-(4-bromo-2-fluorophenylamino)-1H-indazole-5-carboxylic acid (115 mg, 0.33 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (51 mg, 0.49 mmol) in DMF (3 mL) was added EDCI (69 mg, 0.36 mmol), HOBt (49 mg, 0.36 mmol) and DIPEA (61 μL, 0.36 mmol). The reaction mixture was stirred at room temperature for 4 hours before being concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic extracts were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-10% methanol in DCM) to yield the title compound as a pale yellow solid (96 mg, 67%). LCMS (Method B): RT=3.43 min, [M−H]−=433/435.