Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[BH4-].[Na+].O.[NH2:6][C:7]1[N:12]=[C:11]([SH:13])[N:10]=[C:9]([OH:14])[CH:8]=1.Cl[C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])[CH3:17]>CN(C=O)C>[NH2:6][C:7]1[N:12]=[C:11]([S:13][C@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[CH3:17])[N:10]=[C:9]([OH:14])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: C[C@@H](Cl)c1ccccc1F
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](Sc1nc(N)cc(O)n1)c1ccccc1F
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
NaH (60% in oil, 1.05 g, 26.3 mmol) was added in portions followed by NaBH4 (0.099 g, 2.7 mmol) to 6-amino-2-mercaptopyrimidin-4-ol monohydrate (4.23 g, 26.3 mmol) in DMF (40 mL). After 30 minutes, 1-[(1R)-1-chloroethyl]-2-fluorobenzene (5.0 g, 31.5 mmol) in DMF (10 mL) was added and the reaction mixture was stirred for 24 h. The reaction mixture was concentrated and partitioned between water and DCM, the organic phase was dried (MgSO4) and evaporated. The residue was purified by flash column chromatography (a stepwise gradient of 5-10% MeOH in CHCl3) to give the title compound (5.20 g, 75% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:10]=[N:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[O:7])=[CH:4][CH:3]=1.C(NC1C=CC([O:33][C:34]([N:36]2[CH2:41][CH2:40][CH:39]([O:42][Si](C(C)(C)C)(C)C)[CH2:38][CH2:37]2)=O)=NC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.CCCCCCC>CN(C)C=O>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:34]([N:36]3[CH2:41][CH2:40][CH:39]([OH:42])[CH2:38][CH2:37]3)=[O:33])=[N:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(C(=O)Oc2ccc(NC(=O)c3ccccc3)cn2)CC1
Reactant: O=C(Nc1ccc(O)nc1)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(OC(=O)N2CCC(O)CC2)nc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
A solution of 4-chloro-N-(6-hydroxy-pyridin-3-yl)-benzamide (0.50 g, 2.00 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-piperidine-1-carboxylic acid 5-benzoylamino-pyridin-2-yl ester (0.90 g, 2.00 mmol) and triethylamine (0.20 g, 2.00 mmol) in dimethylformamide (10 mL) was stirred overnight at room temperature. The solvent was evaporated in vacuo. The residue was dissolved in dichloromethane, filtered over a short pad of silicagel and washed with ethyl acetate:heptane 50:50. The solvent was evaporated in vacuo and the residue was redissolved in acetonitrile and hydrofluoric acid (min. 40% in water, 0.50 mL) was added. After stirring overnight at room temperature the solvent was evaporated in vacuo. Dichloromethane and triethylamine (1 mL) were added and the solution was extracted twice with water, dried over sodium sulphate, filtered and evaporated in vacuo. Crystallisation from ethyl acetate:heptane yielded the title compound (321 mg, 43% yield).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][C:8]([CH2:11][O:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:9][N:10]=1.Cl.C(=O)([O-])O.[Na+]>CC(C)=O>[CH3:16][O:15][CH2:14][CH2:13][O:12][CH2:11][C:8]1[S:7][C:6]([CH:2]=[O:1])=[N:10][CH:9]=1
Reactant: COCCOCc1cnc(C2OCCO2)s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COCCOCc1cnc(C=O)s1
Yield: 79.2 %

Procedure:
A mixture of 2-(1,3-dioxolan-2-yl)-5-[(2-methoxyethoxy)methyl]-1,3-thiazole (0.40 g), 1M hydrochloric acid (2 mL) and acetone (10 mL) was stirred with heating under reflux for 4 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (0.26 g, yield 81%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (3:1, volume ratio).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[O:5][C:6]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:8]=1.Cl>C(O)C>[Cl:3][C:4]1[O:5][C:6]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:8]=1
Reactant: COC(=O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
An aqueous solution of 1N sodium hydroxide (34 ml) was dropwise added to an ethanol (50 ml) solution of methyl 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionate (8.50 g), with cooling with ice. After stirring for 20 minutes with cooling and then for 30 minutes at room temperature, 2N hydrochloric acid was added thereto, and the crystals thus precipitated were collected by filtration to obtain 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (8.00 g, 99%). This was recrystallized from ethyl acetate to give colorless prisms. mp 169-170° C.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].C1COCC1.[F:22][C:23]1[CH:28]=[CH:27]C([Mg]Br)=[CH:25][CH:24]=1.[Cl-].[NH4+]>O>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(c1ccc(F)cc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 4 (19.89 g, 88 mmol) in absol. THF (160 ml) was added dropwise to a 1 M solution of 4-fluorophenylmagnesium bromide in THF (220 ml, 220 mmol) under argon and while cooling with ice and the mixture was stirred at RT for 20 h. The reaction mixture was worked up by adding saturated ammonium chloride solution (100 ml) and water (100 ml) while cooling with ice, and extracting the mixture with diethyl ether (3×100 ml). The organic phase was washed with water and saturated sodium chloride solution, dried (Na2SO4) and concentrated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[C:18]12([CH2:28][NH2:29])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.C(N(CC)C(C)C)(C)C>ClCCl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([NH:29][CH2:28][C:18]12[CH2:27][CH:22]3[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]3)[CH2:25]1)[CH2:19]2)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.8 %

Procedure:
To a suspension of 5-bromo-2-chlorobenzoic acid (5.00 g) in dichloromethane (25 ml) at 0° C. was added oxalyl chloride (3.7 ml) and DMF (5 drops). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 h, then concentrated under reduced pressure to yield a solid. The solid was dissolved in dichloromethane (20 ml) and added dropwise to a solution of 1-adamantanemethylamine (3.36 g) and N,N-diisopropylethylamine (5.55 ml) in dichloromethane (20 ml). The resulting solution was allowed to stir at room temperature under a nitrogen atmosphere for 20 h. The reaction mixture was diluted with dichloromethane and washed in sequence with water, 10% aqueous potassium carbonate solution, 10% aqueous potassium hydrogen sulfate and saturated brine. The organic phase was then dried over soidum sulfate, filtered and concentrated under reduced pressure to afford the subtitled compound as a solid (7.84 g).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].[NH:10]([CH2:12][CH2:13][OH:14])[NH2:11].Cl>C(O)C.O.C(OCC)(=O)C>[NH2:6][C:5]1[N:10]([CH2:12][CH2:13][OH:14])[N:11]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNCCO
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(N)n(CCO)n1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of 4,4-dimethyl-3-oxo-pentanenitrile (5.0 g, 0.04 mol) in absolute ethanol (50 mL), add 2-hydrazino-ethanol (3 mL, 1.1 equiv.) and concentrated HCl (0.5 mL). Reflux the reaction for 4 hours then cool to room temperature and dilute with water and ethyl acetate. Wash the organics with water then saturated aqueous saturated sodium chloride then dry with magnesium sulfate, filter and concentrate in vacuo. Trituration from hexanes and dichloromethane gives a white solid (4.8 g, 66%). MS (ES), m/z 184 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](C(S)C(OCC)=O)=[S:10])=[CH:4][CH:3]=1.[NH:18]([C:20]([O:22][CH3:23])=[O:21])[NH2:19]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:19][NH:18][C:20]([O:22][CH3:23])=[O:21])=[S:10])=[CH:6][CH:7]=1
Reactant: COC(=O)NN
Reactant: CCOC(=O)C(S)C(=S)Cc1ccc(Cl)cc1
Solvent: ClCCl
Product: COC(=O)NNC(=S)Cc1ccc(Cl)cc1

Procedure:
A mixture of 130 g of 2-[2-(4-chlorophenyl)-1-thioxoethyl]thioglycolic acid, ethyl ester, 45 g of methyl hydrazinocarboxylate and 500 ml of dichloromethane was heated at reflux for 4 hours, then concentrated in vacuo. The residue was taken up in 1.2 liters of ether and extracted with three 500 ml portions of 0.5N sodium hydroxide. The alkaline extracts were combined, washed with ether and acidified with 6N hydrochloric acid to pH 4. The solution was extracted three times with a mixture of ether and dichloromethane. The organic phases were combined and concentrated. The residual oil was concentrated at 70°-75° C. for one hour at 0.1 mmHg. The residue was crystallized from acetone-methylcyclohexane and then from toluene, giving the desired product as ivory colored crystals, mp 147.5°-148° C. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90MHz: 3.80 (s, 3H, OCH3); 4.03 (s, 2H, CH2CS); 7.31 (bs, 4H, C6H4); 8.60 (bs, 1H, NH); 9.90 (bs, 1H, NH).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].[NH:16]1[CH2:22][CH2:21][CH2:20][CH:19]([OH:23])[CH2:18][CH2:17]1>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[S:12]([N:16]1[CH2:22][CH2:21][CH2:20][CH:19]([OH:23])[CH2:18][CH2:17]1)(=[O:14])=[O:13]
Reactant: OC1CCCNCC1
Reactant: COC(=O)c1ccc(Br)c(S(=O)(=O)Cl)c1
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)c(S(=O)(=O)N2CCCC(O)CC2)c1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
To a solution of methyl 4-bromo-3-chlorosulfonyl-benzoate (7.22 g, 23.03 mmol, 1.00 Eq) in DCM (100 mL) was added azepan-4-ol (2.65 g, 23.03 mmol, 1.00 Eq) and TEA (2.33 g, 23.03 mmol, 1.00 Eq). The resulting mixture was stirred at 25° C. until the starting material was consumed. The solvent was removed and the residue was purified by silica gel chromatography (PE:EA=1:1) to give desired compound methyl 4-bromo-3-(4-hydroxyazepan-1-yl)sulfonyl-benzoate (7.00 g, 17.85 mmol, 77.49% yield). LCMS: 393/395 [M+1].
Reaction SMILES: [CH2:1]([O:8][N:9]([C:16](=[O:33])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](Cl)=[O:43].C(ON(CCCCC#N)C(=O)CCCCCl)C1C=CC=CC=1>>[Br:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:43])[N:24]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16](=[O:33])[N:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCCCNOCc1ccccc1
Reactant: O=C(Cl)CCCCCCCBr
Agent: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCl
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCCCN(OCc1ccccc1)C(=O)CCCCCCCBr

Procedure:
Compound [III] (1.50 g, 3.32 mmol) was combined with 8-bromooctanoyl chloride (0.963 g, 3.99 mmol) following the conditions used for (3). The crude oil was purified by silica gel column chromatography with 1:1 hexane/EtOAc as the eluant, giving 2.06 g (95%) of [IV] as an oil: NMR δ 1.17-2.00 (m, 24H), 2.23-2.50 (m, 6H), 3.36 (t, 2H, J=6), 3.60 (t, 2H, J=6), 3.63 (t, 2H, J=6), 4.77 (s, 4H), 7.33 (s, 10H). Anal. (C35H50BrN3O4) C, H, N.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[N:12][N:11]=[N:10]2)=[CH:5][CH:4]=1.Cl.O1CCOCC1>CO>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[N:12][N:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2nnnn2-c2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(-n2nnnc2CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl 4-({1-[4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-1-piperazinecarboxylate (613 mg, 1.486 mmol, Intermediate 15) in methanol was added 4M hydrogen chloride in 1,4-dioxane (10 mL, 40 mmol). The reaction mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][CH:4]=[C:3]([C:7](O)=[O:8])[CH:2]=1.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]>>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][C:16]([C:7]([C:3]2[CH:4]=[CH:5][CH:6]=[C:1]([CH3:10])[CH:2]=2)=[O:8])=[CH:17][C:12]=1[CH3:11]
Reactant: COc1ccccc1C
Reactant: Cc1cccc(C(=O)O)c1
Product: COc1ccc(C(=O)c2cccc(C)c2)cc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
m-Toluic acid (13.6 g, 0.10 mole) and o-methylanisole (12.2 g, 0.10 mole) are combined in 50 ml of polyphosphoric acid (PPA) and warmed with stirring to 80°C for 2 hours. The cooled reaction mixture is then poured into ice water and extracted into ethyl acetate (200 ml) and washed with 5% sodium hydroxide to give 14.4 g of product (60%), m.p. 62°-4°C, upon removal of the solvent in vacuo.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH:15]=[C:16](Br)Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]#[CH:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=C(Br)Br)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 79.4 %

Procedure:
To a solution of 118 mg (0.31 mmol) of 1-(t-butoxycarbonyl)-4-(3,3-dibromoprop-2-enyl)piperidine (from EXAMPLE 74, Step A) in 4 mL of THF at −78° C. was added 0.370 mL (0.92 mmol) of a 2.5 M solution of butyllithium. After stirring at −78° C. for 45 min, the reaction mixture was quenched with 4 mL of sat'd NH4Cl and diluted with 25 mL of ether. After separating the phases, the aqueous layer was extracted with 25 mL of ether. The combined organic phases were washed with 50 mL of sat'd NaCl, dried over MgSO4 and concentrated. The residue was purified by flash chromatography eluting with 4:1 v/v hexanes/ether to give 55 mg (80%) of the title compound: 1H NMR (500 MHz) δ 1.18-1.26 (2H), 1.47 (s, 9H), 1.60-1.67 (m, 11), 1.77 (br d, J=13.2, 2H), 1.99 (t, J=2.6, 11H), 2.16 (dd, J=6.6, 2.5, 2H), 2.68-2.74 (2H), 4.12 (br d, J=13.0,22H).
Reaction SMILES: [NH2:1][C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:3]=1.[CH:18](=O)[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[OH:21]>CO.C(O)(=O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:5][CH2:6][C:2]([N:1]=[CH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[OH:21])=[N:3]2)=[CH:8][C:9]=1[C:14]([F:17])([F:15])[F:16]
Reactant: O=Cc1ccccc1O
Reactant: NC1=NN(c2ccc(Br)c(C(F)(F)F)c2)CC1
Solvent: CO
Solvent: CC(=O)O
Product: Oc1ccccc1C=NC1=NN(c2ccc(Br)c(C(F)(F)F)c2)CC1
Reaction time: 3 h
Yield: 80.1 %

Procedure:
3-Amino-1-(4-bromo-3-trifluoromethylphenyl)-2-pyrazoline (prepared in Example 39 of our European patent specification No. 22-578) (140 mg) and salicylaldehyde (100 mg) were dissolved together in methanol (2 ml) and 1 drop of glacial acetic acid. The mixture was heated to reflux for 1 hour. During this time a deep orange-red colour developed and the mixture crystallised. It was kept at 0° for 3 hours, then the solid was collected, washed with methanol and dried in vacuo to yield 150 mg 1-(4-bromo-3-trifluoromethylphenyl)-3-(2-hydroxybenzylideneamino)-2-pyrazoline, m.p. 170° (decomp).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[O:11][C:12]([CH3:29])=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=O)=[CH:20][CH:19]=2)[N:14]=1.S(Cl)(Cl)=O.[NH2:34][C:35]([NH2:37])=[O:36]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[O:11][C:12]([CH3:29])=[C:13]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([NH:34][C:35]([NH2:37])=[O:36])=[O:28])=[CH:20][CH:19]=2)[N:14]=1
Reactant: NC(N)=O
Reactant: Cc1oc(-c2cc3ccccc3s2)nc1CCOc1ccc(CCC(=O)O)cc1
Solvent: O=S(Cl)Cl
Product: Cc1oc(-c2cc3ccccc3s2)nc1CCOc1ccc(CCC(=O)NC(N)=O)cc1
Temperature: 60 °C
Yield: 11.7 %

Procedure:
To 3-[4-[2-(2-(benzothiophen-2-yl)-5-methyl-4-oxazolyl)ethoxy]phenyl]propionic acid (850 mg, 2.09 mmol) obtained in Example 14 was added thionyl chloride (2 ml, 27.4 mmol) and the mixture was stirred under heating for 40 min at 60° C. The reaction mixture was concentrated and N,N-dimethylaniline (10 ml) was added to the residue. Urea (250 mg, 4.17 mmol) was added and the mixture was stirred under heating for 5 hr at 150° C. Urea (250 mg, 4.17 mmol) was again added and the mixture was heated for 10 hr at 150° C. The reaction mixture was cooled to room temperature and the precipitated solid (468 mg) was collected by filtration. A part (260 mg) thereof was washed successively with water, ethyl acetate/tetrahydrofuran (9:1), 10% aqueous sodium hydroxide solution, 1N hydrochloric acid, water and tetrahydrofuran, and dried to give the title compound (110 mg, yield 21%) as a gray-white solid.
Reaction SMILES: C(O)(=O)C(O)=O.C1(C(C2C=CC=CC=2)=C2CCN(CCCOC3C=CC=CC=3)CC2)C=CC=CC=1.[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[OH:44])=[CH:39][CH:38]=1.Cl[CH2:59][CH2:60][CH2:61][O:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([O:69][CH3:70])[CH:64]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-]>C(O)CCC.CC(O)C>[F:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([C:51]2[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=2)([CH:45]2[CH2:46][CH2:47][N:48]([CH2:59][CH2:60][CH2:61][O:62][C:63]3[CH:68]=[CH:67][CH:66]=[C:65]([O:69][CH3:70])[CH:64]=3)[CH2:49][CH2:50]2)[OH:44])=[CH:39][CH:38]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: COc1cccc(OCCCCl)c1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Solvent: CC(C)O
Product: COc1cccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1
Yield: 66 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 1. A mixture of 3.0 (0.01 mole) of [α,α-bis(4-fluorophenyl)]-4-piperidinemethanol, 2.0 g (0.01 mole) of 1-chloro-3-(3-methoxyphenyoxy)propane, 3.7 g (0.035 mole) of anhydrous sodium carbonate and 0.4 g of potassuim iodide in 100 ml of 1-butanol gave 3.1 g (66%) of the title compound as a white solid, mp 107°-108° C. (2-propanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([O:22]C)[C:11]([C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[CH:12][C:7]=2[CH:6]=1)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([OH:22])[C:11]([C:13](=[O:21])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)C1=Cc2cc(C(=O)c3ccccc3F)c(OC)cc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1=Cc2cc(C(=O)c3ccccc3F)c(O)cc21
Reaction time: 4 h

Procedure:
5.0 g of 4-(o-fluorobenzoyl)-5-methoxybenzocyclobutene-1-carboxylic acid methyl ester are dissolved in 100 ml of dichloromethane; 6.4 g of aluminium trichloride are added and the whole is heated at boiling for 4 hours while stirring. The mixture is poured onto ice; 20 ml of concentrated hydrochloric acid are added and the whole is extracted by shaking twice with 100 ml of dichloromethane each time. The organic phases are combined, washed with water, dried over magnesium sulphate and concentrated to dryness by evaporation. The residue is chromatographed over silica gel and recrystallised from ether/hexane. 4-(o-fluorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester is obtained having a melting point of 72°-73°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](Cl)(Cl)=[S:10]>C1(C)C=CC=CC=1.CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]=[C:9]=[S:10]
Reactant: Nc1ccncc1Br
Reactant: S=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: S=C=Nc1ccncc1Br
Temperature: 25 °C
Yield: 57 %

Procedure:
3-bromopyridin-4-amine (5 g, 28.90 mmol) was suspended in dry toluene (100 mL) and cooled in an ice-bath. A solution of thiophosgene (6.646 g, 4.407 mL, 57.80 mmol) in dry toluene (100 mL) was added dropwise over 25 mins. The resulting orange/red suspension was stirred at reflux overnight. The red suspension was allowed to cool to RT and concentrated under reduced pressure to give a dark brown/red solid. This material was partitioned between saturated NaHCO3 and DCM. The aqueous layer was extracted with further DCM (3×50 mL) and the combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to give a dark red solid/gum. This material was suspended in MeOH/DCM, adsorbed onto silica under reduced pressure and purified by column chromatography (75% EtOAc in hexanes, ˜300 mL silica) to give 3-bromo-4-isothiocyanatopyridine as a red oil which solidified on standing (3.513 g, 57% Yield). MS (ES+) 216.9.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([F:27])[CH:24]=[C:25]([F:26])[C:20]=3[O:19][CH2:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([F:27])[CH:24]=[C:25]([F:26])[C:20]=3[O:19][CH2:18][C:17]2=[O:28])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3c(F)cc(F)cc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: NC1CCN(CCN2C(=O)COc3c(F)cc(F)cc32)CC1

Procedure:
tert-Butyl{1-[2-(6,8-difluoro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 72) (423 mg, 1 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).