Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=[O:3].[N:11](OCCC(C)C)=[O:12].C[O-].[Na+]>CO>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH:1]=[N:11][OH:12])=[CH:5][CH:6]=1
Reactant: CC(C)CCON=O
Reactant: CC(=O)c1ccc(Br)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(C=NO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
19.9 g of 4-bromoacetophenone are placed in 150 ml of methanol under nitrogen, and 14.7 ml of isopentyl nitrite are added. To the resulting solution there are then added dropwise, at 17-23° C., 22.2 ml of a 5.4M solution of sodium methanolate in methanol. After 70 hours' stirring at room temperature the orange suspension is concentrated using a rotary evaporator. 300 ml of water are added to the residue, and the mixture is rendered acidic with 60 ml of 2N hydrochloric acid. The resulting yellow suspension is filtered and washed with water; the filter cake is taken up in ethyl acetate and washed with water. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The crude product is recrystallised from ethyl acetate/toluene. In this way (4-bromophenyl)-oxoacetaldehyde oxime is obtained in the form of a colourless powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][C@H:11]3[CH2:14][N:15](C(OC(C)(C)C)=O)[CH2:16][C@@H:10]23)[CH:6]=[N:7][CH:8]=1)#[N:2].FC(F)(F)C(O)=O>>[N:9]1([C:5]2[CH:6]=[N:7][CH:8]=[C:3]([CH:4]=2)[C:1]#[N:2])[CH2:13][CH2:12][C@H:11]2[CH2:14][NH:15][CH2:16][C@@H:10]12
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCN(c3cncc(C#N)c3)[C@@H]2C1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cncc(N2CC[C@H]3CNC[C@H]32)c1
Yield: 100 %

Procedure:
The product of Example 83A (1.35 g, 4.29 mmol) and trifluoroacetic acid were processed according to the procedure described in Example 64C to provide the crude title compound (>100%) which was carried directly to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:28])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:19][CH2:18]3)[CH3:16])[CH:8]=2)=[CH:4][CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:46]1([CH2:52][C:53]([N:55]=[C:56]=[S:57])=[O:54])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(=O)([O-])O.[Na+]>C(O)C.C1(C)C=CC=CC=1.CCCCCC.C(OCC)C.C(OCC)(=O)C>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][CH:17]([N:15]([CH3:16])[C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:56]([NH:55][C:53](=[O:54])[CH2:52][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)=[S:57])=[CH:30][CH:29]=3)[CH:12]=[CH:11][N:10]=2)=[O:28])[CH2:18][CH2:19]1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
To a solution of 3-[4-(4-aminophenoxy)pyridin-2-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (96 mg) in ethanol (5.0 ml) was added (1S)-(+)-10-camphorsulfonic acid (103 mg), followed by stirring at room temperature for 15 min. A solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 2.80 ml) was added to the reaction mixture, followed by stirring at room temperature for 4 hrs. Ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml) were added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing a target compound were concentrated to give a residue, to which diethyl ether (5 ml) and hexane (25 ml) were added to give a precipitate. The precipitate was suspended in the solvent. Then the precipitate was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (57.4 mg, 42%) as white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:26])[CH:3]=1.[NH2:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:10]=3[N:11]=[C:12]([NH:27][CH:28]([CH2:31][OH:32])[CH2:29][OH:30])[N:13]=2)=[C:4]([CH3:26])[CH:3]=1
Reactant: NC(CO)CO
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2C(C)C
Product: Cc1cc(F)ccc1-c1nc(NC(CO)CO)nc2c1ccc(=O)n2C(C)C

Procedure:
The product of Example 56, and serinol were reacted by the procedure of Example 60 to afford the title compound 4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-isopropyl-8H-pyrido[2,3-d]pyrimidin-7-one 1H-NMR: δ 1.61 (m, 6H), 2.15 (m, 3H), 3.45 (br s, 2H), 3.85 (m, 5H), 5.74 (m, 1H), 6.21 (d, 1H, J=9.8 Hz), 6.36 (br s, 1H), 6.91-7.20 (m, 4H). LC MS (m/e)=387 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([N:13]([C:15]2[CH:16]=[C:17]3[C:26](=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])[O:25][CH2:24][C:23]2[N:18]3[C@H:19]([CH3:37])[C:20](=[O:36])[NH:21][N:22]=2)[CH3:14])([CH3:12])[CH2:9]1)=O)(C)(C)C.[ClH:38]>CCOC(C)=O>[ClH:38].[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]1[CH:27]=[C:26]2[C:17]([N:18]3[C:23]([CH2:24][O:25]2)=[N:22][NH:21][C:20](=[O:36])[C@H:19]3[CH3:37])=[CH:16][C:15]=1[N:13]([CH3:14])[C:10]1([CH3:12])[CH2:9][NH:8][CH2:11]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(N(C)C4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(N(C)C4(C)CNC4)cc3N21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-{[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-methyl-amino}-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.250 g, 0.491 mmol) in EtOAc (2 mL) was added HCl (4M in EtOAc, 3 mL). The reaction mixture was stirred at ambient temperature for 30 min and then concentrated in vacuo to give (R)-7-(2-fluoro-phenyl)-4-methyl-6-[methyl-(3-methyl-azetidin-3-yl)-amino]-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid which was used directly in the next step without further purification. LC/MS (Table 1, Method 25), Rt=0.722 min., MS m/z: 410 [M+H]+
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:18]=2[N+]([O-])=O)[C:15]([C:29]([O:31][CH2:32][CH2:33][C:34]#[N:35])=[O:30])=[C:14]([CH3:36])[NH:13][C:12]=1[CH3:37])=[O:10])C1C=CC=CC=1.C(O)=O.CO>C(Cl)(Cl)Cl.[Pd]>[C:34]([CH2:33][CH2:32][O:31][C:29]([C:15]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:11]([C:9]([OH:10])=[O:8])=[C:12]([CH3:37])[NH:13][C:14]=1[CH3:36])=[O:30])#[N:35]
Reactant: CC1=C(C(=O)OCCC#N)C(c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])C(C(=O)OCc2ccccc2)=C(C)N1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CC1=C(C(=O)O)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
The solution of 3-benzyloxycarbonyl-5-(2-cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4-(4-nitronitrophenyl)pyridine (3.24 g, 7.02 mmol) in 160ml of 4.4% (w/w) formic acid/MeOH mixture was stirred with Pd/C (10%, 3.24 g) for 30 min., the reaction was quenched by addition of 10 ml of CHCl3. The mixture was filtered and concentration of filtrate give a yellow powder, which was dissolved in CHCl3, washed with water and 1N HCL. After drying and removal of solvent, 3-(2-cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine-5-carboxylic acid was obtained as a yellow powder (1.94 g, 75%)
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH3:10][O:11][C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[NH:23]C(=O)C>>[CH3:10][O:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17]([N+:1]([O-:4])=[O:2])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[NH2:23]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1NC(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1N
Temperature: -20 °C
Yield: 5 %

Procedure:
A mixture of concentrated nitric acid (0.49 mL) and concentrated sulfuric acid (3.9 mL) was cooled to −20° C. and 2-acetylamino-4-trifluoromethyl-benzoic acid methyl ester (2.10 g, 8.04 mmol) was added portionwise. The mixture was allowed to warm slowly to r.t. and was then heated to 45° C. for 30 min. The mixture was poured onto ice and the white precipitate was filtered off. The white solid was then dissolved in MeOH (8 mL) and this solution was treated with sulfuric acid (0.8 mL) and heated to reflux for 45 min. The mixture was concentrated in vacuo and was then taken up in EtOAc, washed twice with aqueous potassium hydrogencarbonate, once with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica gel 60, toluene/EtOAc 96:4) affording pale yellow crystals that were recrystallized in EtOAc to provide 2-amino-5-nitro-4-trifluoromethyl-benzoic acid methyl ester (116 mg, 0.44 mmol, 5%) as a white solid, m.p. 175-177° C., 1H-NMR (DMSO-d6, 400 MHz) 8.59 (s, 1H), 8.04 (br s, 2H), 7.40 (s, 1H), 3.88 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10])#[N:2].[N+:11]([O-])([OH:13])=[O:12].O>C(O)(=O)C>[C:1]([C:3]1[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10])#[N:2]
Reactant: Cc1cccc(C#N)c1O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])cc(C#N)c1O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a heated (45° C.), stirred solution of 2-cyano-6-methylphenol (5 g) in glacial acetic acid (32 mL) was added a solution of fuming nitric acid (3.2 mL) in acetic acid (12 mL). After 1 h at elevated temperature (45° C.), the reaction mixture was cooled (to 0° C.), water added and partitioned between DEE/water. The organic phase was washed with water, brine, dried over sodium sulfate and concentrated in vacuo to afford a solid. Recrystallization from DEE afforded the title compound as yellow crystals (3.6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.CC(C)([O-])C.[K+].F[C:16]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:17]=1[C:18]([O:20][CH3:21])=[O:19].CN(C)C=O>CC1CCCO1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:8][C:16]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])[CH:5]=[N:6][CH:7]=1
Reactant: Oc1cncc(Br)c1
Reactant: COC(=O)c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: COC(=O)c1ccc(F)cc1Oc1cncc(Br)c1
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-bromopyridin-3-ol (1.060 g) in 2-methyltetrahydrofuran (15 mL) was added potassium tert-butoxide (6.09 mL, 1.0M in tetrahydrofuran) dropwise. After stirring for 5 minutes, methyl 2,4-difluorobenzoate (1.049 g) was added as a solution in 2-methyltetrahydrofuran (2 mL) and the reaction was heated to 75° C. N,N-Dimethylformamide (2 mL) was added to the reaction and the reaction was stirred overnight. The reaction was cooled, diluted with ethyl acetate (100 mL) and washed with water (50 mL), brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (SF40-80) eluting with a gradient of 5% to 35% ethyl acetate/hexanes gave the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2C(N)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].IC.[CH3:22][N:23]([CH:25]=O)[CH3:24]>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:25]([N:23]([CH3:22])[CH3:24])=[CH:5][CH:4]=1
Reactant: COc1ccc(N)c2sc(N)nc12
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: COc1ccc(N(C)C)c2sc(N)nc12
Temperature: 50 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a stirred solution of 2.00 g (1.02 mmol) 4-methoxy-benzothiazole-2,7-diamine in 30 ml DMF at room temperature was added 4.25 g (3.07 mmol) potassium carbonate and the mixture heated to 50° C. A solution of 0.64 ml (1.02 mmol) iodomethane in 10 ml DMF was then added dropwise over 3 h and stirring continued for a further 1 h at 50° C. The mixture was then filtered and the filtrate concentrated in vacuo. Flash chromatography (20/1 dichloromethane/methanol) afforded 600 mg (26%) 4-methoxy-N7,N7-dimethyl-benzothiazole-2,7-diamine as a yellow solid, ES-MS m/e (%): 224 (M+H+, 100); 540 mg (25%) 4-methoxy-N7-methyl-benzothiazole-2,7-diamine as a yellow solid, ES-MS m/e (%): 210 (M+H+, 100) and 340 mg (17%) recovered starting material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:29]4[C:28]([NH2:30])=[N:27][CH:26]=[N:25][C:24]=4[N:23]([CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11].[C:37](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[C:29]4[C:28]([NH2:30])=[N:27][CH:26]=[N:25][C:24]=4[N:23]([CH:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)[CH:22]=3)=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:11]
Reactant: Nc1ncnc2c1c(-c1ccc3c(c1)CCN3C(=O)Cc1cc(F)ccc1F)cn2C1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCC(n2cc(-c3ccc4c(c3)CCN4C(=O)Cc3cc(F)ccc3F)c3c(N)ncnc32)CC1
Yield: 18.4 %

Procedure:
To 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(4-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (85 mg, 0.174 mmol) was added N,N-Dimethylformamide (DMF) (2 mL) and cesium carbonate (170 mg, 0.522 mmol). The mixture was then added iodomethane (0.014 mL, 0.226 mmol) and the reaction was let stir at room temp overnight. The reaction was then filtered using the syringe filter and the filtrate was then diluted with water (20 ml) then extracted with EtOAc (3×15 ml). The organics were combined, washed with brine, dried over MgSO4, filtered, concentrated and then loaded on to a 10 g Biotage SNAP column. Elution with 0 to 10% MeOH in DCM over 30 min gradient afforded 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-(1-methyl-4-piperidinyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (16 mg, 0.032 mmol, 18.30% yield) as a white solid. LC/MS (ES) m/z=503.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 1H), 8.08 (d, J=8.08 Hz, 1H), 7.40 (s, 1H), 7.36 (s, 1H), 7.15-7.30 (m, 4H), 4.56 (d, J=3.54 Hz, 1H), 4.29 (t, J=8.46 Hz, 2H), 3.95 (s, 2H), 3.27 (t, J=8.46 Hz, 2H), 2.93 (br. s., 2H), 2.27 (s, 3H), 2.04-2.18 (m, 4H), 1.85-1.93 (m, 2H). NHs not observed.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:7])([CH2:5][OH:6])[CH3:4].[C:8](O)(=[O:36])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].[Sn]>>[C:8]([O:1][CH2:2][C:3]([CH3:7])([CH2:5][OH:6])[CH3:4])(=[O:36])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CC(C)(CO)CO
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: [Sn]
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCC(C)(C)CO
Temperature: 100 °C

Procedure:
64.2 g neopentyl glycol (0.617 mole), 246.9 g montanic acid (0.617 mole) and 0.4 g tin powder were heated to 210° C. as in Example 1 with application of a gentle vacuum. The vacuum was increased to 150 mbar over a period of 5 h. The product had an acid number of approximately 2. A brown-yellow hard wax having a dropping point of 72° C. was obtained after cooling to 100° C., bleaching and filtering.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[O:18][CH:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH:20]([NH2:22])[CH3:21].[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[CH:4][C:3]=1[O:18][CH:19]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[CH:20]([NH:22][S:33]([CH:30]1[CH2:32][CH2:31]1)(=[O:35])=[O:34])[CH3:21]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CC(N)C(Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl)c1ccc(F)cc1
Product: CC(NS(=O)(=O)C1CC1)C(Oc1cc2cnn(-c3ccc(F)cc3)c2cc1Cl)c1ccc(F)cc1

Procedure:
Prepared according to the procedure described for Example 1 starting with (1RS,2SR)-1-[6-chloro-1-(4-fluorophenyl)indazol-5-yl]oxy-1-(4-fluorophenyl)propan-2-amine (35a-rac-1, 35 mg, 0.08 mmol) and cyclopropylsulphonyl chloride (27 μl, 0.25 mmol). Yield: 2 mg (5%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][C:6]([O:22][CH3:23])=[C:7]([O:20][CH3:21])[CH:8]=2)[N:3]=1.[C:24]([O:28][C:29](=[O:43])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[CH:32][CH:31]=1)([CH3:27])([CH3:26])[CH3:25]>C(O)CCCC>[C:24]([O:28][C:29](=[O:43])[C:30]1[CH:35]=[CH:34][C:33]([NH:36][CH:37]2[CH2:42][CH2:41][N:40]([C:2]3[N:11]=[C:10]([NH:12][C:13]4[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=4)[C:9]4[C:4](=[CH:5][C:6]([O:22][CH3:23])=[C:7]([O:20][CH3:21])[CH:8]=4)[N:3]=3)[CH2:39][CH2:38]2)=[CH:32][CH:31]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: COc1cc2nc(Cl)nc(Nc3ccc(C)cc3)c2cc1OC
Reactant: CC(C)(C)OC(=O)c1ccc(NC2CCNCC2)cc1
Solvent: CCCCCO
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)nc(Nc3ccc(C)cc3)c2cc1OC
Temperature: 120 °C
Yield: 85.4 %

Procedure:
2-chloro-6,7-dimethoxy-N-(4-methylphenyl)-4-quinazolinamine (0.099 g, 0.3 mmol) prepared according to the procedures described in Gazit et al (Bioorg Med Chem, 1996, 4:1203) was added to a solution of (49) (0.10 g, 0.37 mmol) in n-pentanol (5 mL) at 25° C. The mixture was heated to 120° C. and maintained at that temperature for 12 h. The reaction mixture was then cooled to room temperature and the desired product was filtered and rinsed with acetone to give 0.146 g (85.3%) of the title compound: TLC (Rf =0.40; 5% MeOH/CH2Cl2); 1H NMR (DMSO) δ 12.41 (br s, 1H), 10.71 (br s, 1H), 8.08 (s, 1H), 7.63 (d, 2H, J=8.7), 7.57 (s, 1H), 7.55 (d, 2H, J=8.3), 7.24 (d, 2H, J=8.3), 6.63 (d, 2H, J=8.8), 6.44 (d, 1H, J=6.9), 4.41 (d, 2H, J=12.9), 3.91 (s, 3H), 3.89 (s, 3H), 3.73 (m, 1H), 3.42 (m, 2H), 2.31 (s, 3H), 2.03 (d, 2H, J=10.8), 1.49 (s, 9H), 1.41 (m, 2H); 13C NMR (DMSO) δ 165.2, 157.2, 155.2, 151.3, 150.7, 146.9, 136.6, 134.7, 130.9, 129.0, 124.0, 117.7, 111.2, 104.6, 102.3, 99.3, 79.0, 56.5, 56.1, 47.9, 43.7, 30.8, 28.0, 20.6; HRMS (FAB) m/z 570.3070 (M+H)+ (C33H39N5O4 requires 570.3080); Anal. (C33H39N5O4 ·1HCl) C, H, N.
Reaction SMILES: [C:1]([N:8](C#N)[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:16]([N:18](CC)CC)C.ClC(OCC(C)C)=O.[BH4-:31].[Na+:32]>C1COCC1.O>[BH4-:31].[Na+:32].[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([CH2:11][OH:13])[CH2:10][C:16]#[N:18])([CH3:5])([CH3:6])[CH3:7]
Reactant: CCN(CC)CC
Reactant: C[C@@H](C(=O)O)N(C#N)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CC#N
Temperature: -10 °C
Reaction time: 0.07 h
Yield: 64 %

Procedure:
A solution of N-Boc cyanoalanine (2 g, 9.3 mmol) in THF (30 mL) was cooled in an ice/NaCl bath to −10° C. and treated with triethylamine (0.94 g, 9.3 mmol) followed by dropwise addition of isobutyl chloroformate (1.35 g, 9.9 mmol). The reaction mixture was stirred for 4 minutes at −10° C. and filtered through a coarse scintered glass funnel. Meanwhile, in another flask, a solution of NaBH4 (0.71 g, 19 mmol) in water (10 mL) was prepared and cooled in an ice/water bath. The filtered solution of the mixed anhydride was added dropwise to the cold NaBH4 solution and the resulting mixture was stirred for 2 hours. The THF was removed on the rotary evaporator and the reaction was acidified with 5% NaHSO4 solution to pH 3 and diluted with ethyl acetate and water. The organics were extracted twice with aqueous NaHCO3 and dried over MgSO4. The solvent was removed to afford 1.2 g (64%) of (S)-(2-Cyano-1-hydroxymethyl-ethyl)-carbamic acid tert-butyl ester; 1H NMR (CDCl3, 400 MHz) δ 1.45 (s, 9H), 2.09-2.17 (m, 1H), 2.73 (d, 1H, J=6.0), 3.76 (dd, 1H, J1=4.7, J2=10.8), 3.80-3.86 (m, 1H), 3.91-3.99 (m, 1H), 4.98-5.07 (m, 1H).
Reaction SMILES: [C:1]([N:4]([C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH3:5])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>O.CN(C=O)C.COCCOC>[C:1]([N:4]([C:6]1[CH:14]=[CH:13][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=1)[CH3:5])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C)c1ccc(C(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CC(=O)N(C)c1ccc(CO)cc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
An oven dried flask, under nitrogen flow, was charged with a stir bar, 4-(N-acetyl-N-methyl-amino)benzoic acid (1.0 g, 5.18 mmol), prepared as in step7, anhydrous DME (10.3 mL), and anhydrous DMF (3.0 mL). The resulting solution was cooled to -20° C., and 4-methylmorpholine (0.60 mL, 5.4 mmol) and isobutyl chloroformate (0.70 mL, 5.4 mmol) were added sequentially via syringe. The reaction mixture was stirred under N2 at -20° C. for 1 hour. The resultant yellow mixture was filtered and the precipitate washed with DME (2×, ~1 mL). The combined filtrate and washings were cooled to 0° C. and sodium borohydride (800 mg, 21.1 mmol) dissolved in water (2.0 mL) was added dropwise. The reaction was stirred at 0° C. for 15 min. and quenched with saturated aqueous ammonium chloride. The resulting mixture was partitionedbetween ethyl acetate and brine. The combined organic layers were dried (MgSO 4), filtered and concentrated in vacuo to give an oil. Purification by flash chromatography on silica gel (90% ethyl acetate/hexane) provided 4-(N-acetyl-N-methyl-amino)benzyl alcohol as a colorless oil which solidified on standing. Recrystallization from hexane provided the alcohol as a colorless solid (543.0 mg, 58.5%). 1H NMR (300 MHz, CDCl3) d 7.45 (2H, d, J=8.5 Hz), 7.18 (2H, d, J=8.5 Hz), 4.75 (2H, s), 3.27 (3H, s), 1.90 (3H, br s). MS m/e 180 (M+H)+, 197 (M+NH4)+.
Reaction SMILES: [Li][CH3:2].[CH3:3][C:4](=[CH:8][CH:9]([CH3:11])[CH3:10])[C:5]([OH:7])=O.Cl>CCOCC>[CH3:3][C:4](=[CH:8][CH:9]([CH3:11])[CH3:10])[C:5](=[O:7])[CH3:2]
Reactant: [Li]C
Reactant: CC(=CC(C)C)C(=O)O
Agent: Cl
Solvent: CCOCC
Product: CC(=O)C(C)=CC(C)C

Procedure:
Under an atmosphere of N2, a 1.6 M solution of MeLi in Et2O (500 ml, 800 mmol) was added during 105 min. dropwise with stirring between 0-10° C. to a solution of 2,4-dimethylpent-2-enoic acid (41.0 g, 320 mmol) in Et2O (1.6 L). The reaction mixture was heated to reflux for 1 h, and then between 5-15° C. 5 N HCl (200 ml) was added dropwise. The organic layer was separated, the aqueous one extracted with Et2O (200 ml). The combined organic solutions were washed with water (200 ml) and brine (100 ml), dried (Na2SO4) and concentrated in a rotary evaporator to afford crude 3,5-dimethylhex-3-en-2-one, which was taken up in Et2O (160 ml). Under N2 at room temp., this solution was added dropwise with stirring to a suspension of LAH (3.34 g, 880 mmol) in Et2O (320 ml) during 1 h. The reaction mixture was refluxed for 2 h, and then quenched between 0-5° C. by addition of water (10 ml) and brine (20 ml). The organic layer was separated and the aqueous one extracted with Et2O (100 ml). The combined ethereal extracts were washed with water (100 ml) and brine (50 ml), dried (Na2SO4), and concentrated under reduced pressure. Silica-gel FC (pentane/Et2O, 4:1, Rf=0.40) of the resulting residue provided 34.7 g (85% over 2 steps) of 3,5-dimethylhex-3-en-2-ol.