Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:13])[NH:9][C:8](=[O:10])[CH:7]2[CH2:11][CH2:12][C:2]1([C:4]2([CH3:6])[CH3:5])[CH3:3].[Br-].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:30][CH2:29][N+:24]2([CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]1[CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][N:9]2[C:8](=[O:10])[CH:7]3[C:4]([CH3:6])([CH3:5])[C:2]([CH3:3])([CH2:12][CH2:11]3)[C:1]2=[O:13])[CH2:29][CH2:30]1
Reactant: CC12CCC(C(=O)NC1=O)C2(C)C
Reactant: c1ccc(N2CC[N+]3(CCCC3)CC2)nc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC12CCC(C(=O)N(CCCCN3CCN(c4ccccn4)CC3)C1=O)C2(C)C

Procedure:
A mixture of 4.07 g (0.0225 mol) of DL-camphorimide (II), 6.71 g (0.0225 mol) of 8-(2-pyridyl)-8-aza-5-azoniaspiro[4,5]-decane bromide (III) and 3.73 g (0.027 mol) of potassium carbonate was refluxed in 80 ml of absolute dimethylformamide for 24 hours, then the resulting mixture was cooled, filtered, and dimethylformamide was distilled off under reduced pressure. The residue was dissolved in 100 ml of 5% HCl, the resulting solution was extracted twice with 50 ml of ether to remove impurities of non-basic nature, and saturated with soda. The precipitated base was extracted with ethyl acetate, the extract was dried with potassium carbonate and purified by passing through a column packed with a neutral aluminum oxide 5 cm thick (with ethyl acetate as eluent). After the solvent was distilled off, there was obtained a free base in the form of an oil which was then crystallized. Mp. 96°-97° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[NH:25][C:24](=[O:26])[C:23]3[C:18](=[CH:19][C:20]([O:29][CH3:30])=[CH:21][C:22]=3[O:27]C)[N:17]=2)=[CH:11][C:10]=1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[Mg+2].[Br-]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[NH:25][C:24](=[O:26])[C:23]3[C:18](=[CH:19][C:20]([O:29][CH3:30])=[CH:21][C:22]=3[OH:27])[N:17]=2)=[CH:11][C:10]=1[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCc4ccccc4)c(C)c3)nc2c1
Agent: [Br-]
Agent: [Mg+2]
Solvent: c1ccncc1
Product: COc1cc(O)c2c(=O)[nH]c(-c3cc(C)c(OCc4ccccc4)c(C)c3)nc2c1
Yield: 64.7 %

Procedure:
A mixture of 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5,7-dimethoxy-3H-quinazolin-4-one (1.2 g, 2.92 mmol) and magnesium bromide (0.644 g, 3.5 mmol) in pyridine (50 mL) was stirred at reflux for 12 h. The mixture was concentrated and the solid residue was made into slurry with HCl (2 N, 100 mL). The solid was collected by filtration, washed with water and hexanes to yield 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5-hydroxy-7-methoxy-3H-quinazolin-4-one as a white solid (0.76 g, 65%). A solution of ammonium formate (0.945 g, 15 mmol) and 2-(4-benzyloxy-3,5-dimethyl-phenyl)-5-hydroxy-7-methoxy-3H-quinazolin-4-one (0.1 g, 0.25 mmol) in DMF (50 mL) was mixed with palladium carbon (0.1 g) and stirred at 85° C. for 14 h. The resulting suspension was cooled to room temperature, passed through a Celite pad, and washed with DCM. The filtrate was concentrated and the residue was diluted with water (20 mL). The resulting solid was collected by filtration and washed with hexanes to afford 5-hydroxy-2-(4-hydroxy-3,5-dimethylphenyl)-7-methoxyquinazolin-4(3H)-one (57 mg, 74%) as light yellow solid. Selected data: MS (ES) m/z: 312.94; MP 291.3-293° C.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]([NH2:32])[NH:30][N:31]=1>O1CCCC1>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:28]=[C:29]([NH:32][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[NH:30][N:31]=1
Reactant: O=C1Nc2ccccc2/C1=C/O
Reactant: COc1ccccc1-c1cc(N)[nH]n1
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(NC=C2C(=O)Nc3ccccc32)[nH]n1

Procedure:
The named compound is prepared by substituting 5-(2-methoxy-phenyl)-2H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.2551 gms. 5-(2-methoxy-phenyl)-2H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.0 mL) overnight.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:14])[CH3:13])=[N:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:5])C.[OH-].[Na+].[Li+].[OH-].Cl>O>[C:12]([NH:11][C:9]1[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]=1)(=[O:14])[CH3:13]
Reactant: CCOC(=O)c1sc(NC(C)=O)nc1-c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1nc(-c2ccccc2)c(C(=O)O)s1
Reaction time: 12 h

Procedure:
To 2.2 g (7.62 mmol) 2-acetylamino-4-phenyl-thiazole-5-carboxylic acid ethyl ester in 10 mL water is added 5 mL 4N NaOH and the mixture is allowed to stand at rt for 12 h. 1 g LiOH is added and the mixture is allowed to stand at rt for 2 h. The mixture is neutralized with aq. 2 N HCl solution and the precipitate is collected and washed with water and ACN to yield the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[N:28]3)[O:23][C:22]2=[O:32])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][C:11]([C:14]2[CH2:18][C@@H:17]([CH2:19][OH:20])[O:16][N:15]=2)=[CH:12][CH:13]=1.[CH3:33][O:34][CH2:35][C:36](O)=[O:37].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C.C(OCC)(=O)C>[CH3:33][O:34][CH2:35][C:36]([O:20][CH2:19][C@H:17]1[O:16][N:15]=[C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:21]4[CH2:25][C@H:24]([CH2:26][N:27]5[CH:31]=[CH:30][N:29]=[N:28]5)[O:23][C:22]4=[O:32])=[CH:3][C:2]=3[F:1])=[CH:9][N:10]=2)[CH2:18]1)=[O:37]
Reactant: COCC(=O)O
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCC(=O)OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
(5R)-3-(3-Fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1, 0.25 g, 0.57 mmol), methoxyacetic acid (0.15 ml, 1.96 mmol), 4-dimethylaminopyridine (0.02 g, 0.16 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.25 g, 1.30 mmol) were combined in DMF (4 ml). The suspension was allowed to stir for one hour at room temperature resulting in a clear solution. The mixture was then diluted with ethyl acetate, washed with water, and dried over magnesium sulfate. The residue obtained upon filtration and evaporation was purified via chromatography (silica gel, 0.5 to 5% methanol in dichloromethane). Evaporation of the product containing fractions and trituration of the resulting solid with diethyl ether yielded the title compound as a white solid (0.25 g), melting point: 170° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[I-].[Na+].O>C(#N)C>[C:20]([O:19][C:17](=[O:18])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][N:12]1[CH2:13][CH2:14][CH:9]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:16][CH:15]=2)[CH2:10][CH2:11]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCCCBr
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
4-(4-fluorobenzoyl)piperidine hydrochloride (0.5 g, 2.01 mmol) was suspended in acetonitrile (5 mL), 4-(Boc-amino) Butyl Bromide was added (0.569 g, 2.01 mmol) and sodium iodide (0.461 g, 3.02 mmol) and the mixture was stirred at 80° C. overnight. Water was added and the aqueous phase was extracted with 30 mL dichloromethane. The combined organic phases were dried with magnesium sulfate, filtrated concentrated and purified with column chromatography on silica using dichloromethane/Methanol (95/0.5) to yield 0.830 g, (2.1 mmol, 100% yield) of the title compound as a brown solid. MS (m/e): 379.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([F:12])[CH:3]=1.C([Li])CCC.[Si:18]([O:25][C@@H:26]([CH3:34])[C:27](N1CCCC1)=[O:28])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C1COCC1>[Si:18]([O:25][C@@H:26]([CH3:34])[C:27]([C:3]1[CH:2]=[CH:7][CH:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[C:4]=1[F:12])=[O:28])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)N1CCCC1
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](O[Si](C)(C)C(C)(C)C)C(=O)c1cccc(C(F)(F)F)c1F

Procedure:
To a solution of 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (4.93 g, 20.3 mmol) in THF (50 mL) cooled to −78° C. was added slowly over 10 min butyl lithium (8.11 mL, 20.3 mmol, 2.5 M in hexanes). The reaction was transferred via cannula to a cooled solution (−78° C.) of 110 (4.35 g, 16.9 mmol) in THF (50 mL). The reaction was stirred for 10 min after all aryl lithium was added. The reaction was quenched with H2O and extracted with DCM. The organic layer was concentrated and the resulting residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (1 to 5% EtOAc) to afford impure (S)-2-(tert-butyldimethylsilyloxy)-1-(2-fluoro-3-(trifluoromethyl)phenyl)propan-1-one (112) which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH:14]1([C:17]2[NH:18][CH:19]=[C:20]([C:22]3[C:23]([O:32][CH3:33])=[CH:24][C:25]([O:30][CH3:31])=[C:26]([CH:29]=3)[CH:27]=O)[N:21]=2)[CH2:16][CH2:15]1.C[O-].[Li+]>CN(C)C=O>[CH:14]1([C:17]2[NH:18][CH:19]=[C:20]([C:22]3[C:23]([O:32][CH3:33])=[CH:24][C:25]([O:30][CH3:31])=[C:26](/[CH:27]=[CH:2]/[C:1]([C:4]4[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:11])=[O:12])=[CH:8][CH:9]=4)=[O:3])[CH:29]=3)[N:21]=2)[CH2:15][CH2:16]1
Reactant: COc1cc(OC)c(-c2c[nH]c(C3CC3)n2)cc1C=O
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: COc1cc(OC)c(-c2c[nH]c(C3CC3)n2)cc1/C=C/C(=O)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-acetyl-benzenesulfonamide (Ex-26A, 0.12 g, 0.59 mmol) and 5-(2-cyclopropyl-1H-imidazol-4-yl)-2,4-dimethoxy-benzaldehyde (Ex-105B, 0.16 g, 0.59 mmol) in N,N-dimethylformamide (16 mL) was added lithium methoxide (1.0M in methanol, 2.4 mL, 2.4 mmol). The reaction mixture was allowed to stir for 18 hours at ambient temperature. The reaction was quenched with water. The aqueous solution was extracted with dichloromethane. The combined dichloromethane was concentrated. The crude product was purified by flash chromatography. Elution with methanol (10%, v/v, in dichloromethane) gave the title compound as red solid: m.p. 156–160° C. 1H NMR (DMSO-d6) δ 11.65 (bs, 1H), 8.32 (s, 1H), 8.19 (d, J=9.0 Hz, 2H), 8.00 (d, J=15.7 Hz, 1H), 7.95 (d, J=9.0 Hz, 2H), 7.62–7.52 (m, 2H), 7.24 (bs, 1H), 6.73 (s, 1H), 3.96 (s, 3H), 3.94 (s, 3H), 1.98–1.94 (m, 1H), 0.88–0.85 (m 4H). MS m/z=454 ([M+H]+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[C:5]([CH2:7][C:8]#[N:9])=[O:6].[C:14](OCC)(OCC)([O:16]CC)[CH3:15].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>O>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[F:13])[C:5](/[C:7](=[C:14](/[OH:16])\[CH3:15])/[C:8]#[N:9])=[O:6]
Reactant: CCOC(C)(OCC)OCC
Reactant: N#CCC(=O)c1ccc(F)c(F)c1
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: O
Product: C/C(O)=C(/C#N)C(=O)c1ccc(F)c(F)c1

Procedure:
A solution of 10.2 g. of 3,4-difluorobenzoylacetonitrile, 9.2 g. of triethyl orthoacetate and 20 ml. of acetic anhyride is heated on a steam bath for 0.5 hour and then poured into 200 ml. of water which is then heated on the steam bath for 2 hours. On cooling, the solid is filtered and then dissolved in methylene chloride. This solution is extracted with two portions of aqueous sodium bicarbonate and the aqueous extracts are combined and acidified with concentrated hydrochloric acid. The precipitate is extracted into methylene chloride, passed through a pad of Magnesol®, heated and diluted with hexane. Upon cooling, colorless crystals result, yielding the title compound, m.p. 51°-54° C.
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:14]([O:17][C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[N:23]([C:27](=[O:39])[NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[CH:22]=[CH:21]4)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:38][C:35]([F:36])([F:37])[C:31]1[CH:30]=[C:29]([NH:28][C:27]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([O:17][C:14]4[C:15]5[CH2:16][NH:8][CH2:9][C:10]=5[N:11]=[CH:12][N:13]=4)=[CH:26][CH:25]=3)[CH:21]=[CH:22]2)=[O:39])[CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ncnc4c3CNC4)ccc21
Reaction time: 1 h

Procedure:
To a solution of 4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,7-dihydro pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester in DCM (20 mL), TFA (20 mL, 260 mmol) is added at 0° C. The reaction is allowed to reach room temperature and stirred for an additional 1 h. TFA/DCM are evaporated and then the product is taken up in EtOAc (100 mL) and washed with dilute NH4OH in H2O (20 mL). The organic layer is separated and the water layer is extracted further with EtOAc (2×). The combined organics are dried and evaporated. The crude residue is separated via FCC (eluted with DCM/MeOH/NH4OH (100:0:0 to 93:6:1)) to give 5-(6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl phenyl)-amide. MS (ESI) m/z 440.9 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.55 (s, 1H) 8.33 (d, J=8.84 Hz, 1H) 8.06 (br. S., 1H) 7.89 (d, J=8.34 Hz, 1H) 7.94 (d, J=3.54 Hz, 1H) 7.57 (t, J=7.96 Hz, 1H) 7.41-7.46 (m, 2H) 7.13 (dd, J=9.09, 2.27 Hz, 1H) 6.74 (d, J=3.03 Hz, 1H) 4.26 (d, J=12.13 Hz, 4H).
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]([O:11]C)=[O:10])[N:8]=1>O1CCOCC1.O>[Cl:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=[O:10])[N:8]=1
Reactant: COC(=O)c1csc(CCl)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1csc(CCl)n1
Yield: 90 %

Procedure:
An aqueous solution of HCl (36%, 68 mL) was added to a solution of methyl 2-(chloromethyl)-1,3-thiazole-4-carboxylate (34 g, 177 mmol) in dioxane (680 mL), water (65 mL) and refluxed overnight. The dioxane was then removed in vacuo and the product was extracted from the aqueous layer with MTBE (4×473 mL), dried over MgSO4 and evaporated to give the title compound (28.3 g, 97%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:20][C:14]3[N:15]=[CH:16][N:17]=[C:18]([Cl:19])[C:13]=3[CH:12]=2)=[CH:7][CH:6]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(=O)CC>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:20]=[C:14]3[N:15]([CH2:34][C:33]4[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=4)[CH:16]=[N:17][C:18]([Cl:19])=[C:13]3[CH:12]=2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCC(C)=O
Product: CCOC(=O)c1ccc(-c2cc3c(Cl)ncn(Cc4ccc(OC)cc4)c-3n2)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A suspension of 3.0 g (10 mMol) of 4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-benzoic acid ethyl ester (WO 97/02266), 2.4 g (17 mMol) of K2CO3, 0.32 g (1 mMol) of tetrabutyl-ammoniumbromide and 2.0 ml (15 mMol) of 4-methoxy-benzylchloride in 25 ml of 2-butanone is stirred for 18 h at 80° C. Then the suspension is filtered, the residue washed with 2-butanone and discarded. The filtrate is diluted with EtOAc and water, the aqueous layer separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated after adding 13 g of SiO2. The resulting powder is put on top of a chromatography column (SiO2) and then eluted with hexane/EtOAc 2:1. 4-[4-Chloro-7-(4-methoxy-benzyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-benzoic acid ethyl ester [TLC (hexane/EtOAc 2:1) Rf=0.40; MS-ES+: (M+H)+=422] is eluated first, followed by the title compound; TLC (hexane/EtOAc 2:1) Rf=0.23; MS-ES+: (M+H)+=422.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16](=[N:19][OH:20])[C:17]#[N:18].[S:21](Cl)([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22]>C(N(CC)CC)C>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16](=[N:19][O:20][S:21]([C:24]1[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=1)(=[O:23])=[O:22])[C:17]#[N:18]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC(=NO)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)ON=C(C#N)c2ccc(Cl)cc2Cl)cc1
Yield: 77.2 %

Procedure:
To toluene (200 ml), (2,4-dichlorophenyl)-hydroxyiminoacetonitrile (8.60 g, 40 mmol) prepared in the Step 27-1-1, tosyl chloride (9.50 g) and triethylamine (5.0 g) were added, and the mixture was heated under reflux for 5 hours. After being allowed to cool, the mixture was washed with water and dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:3) to give the title compound (11.4 g, 77%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[Cl:22])[CH3:14])[CH:9]=[CH:8][N:7]=1.[Li+].[BH4-].O>C1COCC1.Cl>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH:13]([CH3:14])[C:12]([C:10]1[CH:9]=[CH:8][N:7]=[C:6]([O:5][CH2:4][CH2:3][OH:2])[CH:11]=1)([OH:27])[C:23]([F:26])([F:25])[F:24]
Reactant: COC(=O)COc1cc(C(O)(C(C)c2ccc(Cl)cc2Cl)C(F)(F)F)ccn1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc(Cl)cc1Cl)C(O)(c1ccnc(OCCO)c1)C(F)(F)F
Temperature: 45 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
{4-[2-(2,4-Dichloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-pyridin-2-yloxy}-acetic acid methyl ester (Example 120, 70 mg) was dissolved in THF (5 mL) and treated with LiBH4 (10 mg). After 2 h stirring at 45° C. another portion of LiBH4 (5 mg) was added and the reaction mixture further stirred at 45° C. for 2 h. After cooling down to r.t., 3 drops of 1N aqueous HCl were added, followed by water (5 mL). The reaction mixture was then extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (10 g silica gel, ethyl acetate/heptane 30:70) to give the title compound as colorless foam (52 mg). MS (m/e)=410.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]#[N:12])[C:6]([C:13]1[C:17]([CH3:18])=[CH:16][S:15][C:14]=1[CH3:19])=[C:5]2[C:20]1[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=1.B(F)(F)F.S(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]#[N:12])[C:6]([C:13]1[C:17]([CH3:18])=[CH:16][S:15][C:14]=1[CH3:19])=[C:5]2[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1
Reactant: COc1ccc(-c2c(-c3c(C)csc3C)n(C#N)c3ccc(Cl)cc23)cc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: CSC
Solvent: O
Product: Cc1csc(C)c1-c1c(-c2ccc(O)cc2)c2cc(Cl)ccc2n1C#N
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.3 %

Procedure:
5-chloro-2-(2,4-dimethylthiophen-3-yl)-3-(4-methoxyphenyl)-1H-indole-1-carbonitrile (75 mg, 0.19 mmol) was dissolved in 4 ml DCM and the mixture was cooled in an ice bath. BF3.SMe2 (0.20 ml, 1.91 mmol) was added drop wise and the mixture was stirred at room temperature for 24 h. A few drops MeOH were added at 0° C. followed by NaHCO3 (aq, sat) and brine. The layers were separated and the organic layer was concentrated. The crude product was purified on silica (MeOH/DCM 1:99). 42.0 mg 5-chloro-2-(2,4-dimethylthiophen-3-yl)-3-(4-hydroxyphenyl)-1H-indole-1-carbonitrile was obtained.
Reaction SMILES: [OH:1][N:2]=[CH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[Cl:17]N1C(=O)CCC1=O>CN(C=O)C.[Cl-].[Na+].O>[Cl:17][C:3](=[N:2][OH:1])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=NO)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(Cl)=NO)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
tert-Butyl 4-((hydroxyimino)methyl)piperidine-1-carboxylate (2.0 g, 8.8 mmol) in DMF (100 mL) was charged with 1-chloropyrrolidine-2,5-dione (1.2 g, 8.8 mmol). The reaction stirred at ambient temperature overnight. The material was poured into a 1:1 brine:water mixture and the resultant solution was extracted with ethyl acetate. The organic layer was wash twice with water, dried, and concentrated to afford the title compound (2.3 g, 100%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=O)([CH3:3])[CH3:2].[CH:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.[BH4-].[Na+].C(O)(=O)C>CO>[CH:1]([O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][NH:26][C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:19][C:16]1[CH:15]=[CH:14][CH:13]=[CH:18][CH:17]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccccc1C=O
Reactant: Nc1ccccc1Oc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)Oc1ccccc1CNc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.6 %

Procedure:
To a solution of 1.64 g of 2-isopropoxybenzaldehyde in 10 ml of methanol was added 1.85 g of 2-aminodiphenyl ether, and then the mixture was stirred at room temperature for 30 minutes and cooled on ice-water. To the cooled reaction solution was gradually added 1.50 g of sodium borohydride, followed by stirring under ice-cooling for 30 minutes and then at room temperature for 30 minutes. An aqueous acetic acid solution (1.5 ml of acetic acid—30 ml of water) was added dropwise to the reaction solution, followed by stirring at room temperature for 10 minutes. After extraction with ethyl acetate, the extract was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate−hexane=1:25) to give 2.65 g of N-(2-isopropoxybenzyl)-2-phenoxyaniline as an oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:33])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccccc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and benzoyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.