Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](Cl)(=O)C>CO>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)CN1C(=O)OC[C@@H]1c1ccccc1
Solvent: CO
Product: COC(=O)CN1C(=O)OC[C@@H]1c1ccccc1
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of (4(S)-phenyloxazolidin-2-on-3-yl)acetic acid (1 g, 4.52 mmol) (Evans in U.S. Pat. No. 4,665,171) in 20 mL of anhydrous methanol was treated hourly with 5 equivalents of acetyl chloride, for a total of 20 equivalents. The resulting solution was stirred overnight. The residue obtained after evaporation of the MeOH was redissolved in 30 mL of CH2Cl2 and treated with 50 mL of saturated aqueous Na2CO3. The organic layer was evaporated and dried (MgSO4) to yield the title compound as a colorless oil (1.001 g, 94%); 1H NMR (CDCl3) δ 3.37 (d, J=18.0 Hz, 1H), 3.69 (s, 3H), 4.13 (t, J=8.3 Hz, 1H), 4.28 (d, J=18.0 Hz, 1H), 4.69 (t, J=8.8 Hz, 1H), 5.04 (t, J=8.4 Hz, 1H), 7.26-7.29 (m, 2H), 7.36-7.42 (m, 3H).
Reaction SMILES: [ClH:1].[CH:2]1([CH2:5][N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[N:20]=[C:19]4[N:14]([C:15](=O)[NH:16][C:17]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=5[Cl:28])=[CH:18]4)[N:13]=3)[CH2:8][CH2:7]2)[CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+]>P(Cl)(Cl)(Cl)=O.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:15]1[N:14]2[N:13]=[C:12]([CH:9]3[CH2:10][CH2:11][N:6]([CH2:5][CH:2]4[CH2:4][CH2:3]4)[CH2:7][CH2:8]3)[N:20]=[C:19]2[CH:18]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:16]=1
Reactant: Cl
Reactant: O=c1[nH]c(-c2ccc(Cl)cc2Cl)cc2nc(C3CCN(CC4CC4)CC3)nn12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2cc3nc(C4CCN(CC5CC5)CC4)nn3c(Cl)n2)c(Cl)c1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
356 mg (0.85 mmol) of 2-[1-(cyclopropylmethyl)piperidin-4-yl]-7-(2,4-dichlorophenyl)[1,2,4]-triazolo[1,5-c]pyrimidin-5(6H)-one hydrochloride (Example 46A) were initially charged in phosphorus oxychloride (6 ml), 775 mg (3.40 mmol) of benzyltriethylammonium chloride were added and the mixture was stirred at 120° C. for 2.5 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (150 ml), and solid sodium bicarbonate was added until a pH of 7 had been reached. The mixture was extracted with dichloromethane (3×50 ml), and the combined organic phases were washed with water (50 ml), dried over magnesium sulfate and concentrated. This gave 307 mg (83% of theory) of the product as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][C:23]([OH:26])([CH3:25])[CH3:24])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.C([O:32][C:33]1[CH:38]=[N:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[OH:26][C:23]([CH3:25])([CH3:24])[CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:36]3[N:37]=[CH:38][C:33](=[O:32])[NH:34][CH:35]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: CC(C)(C)Oc1cnc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H](c1ccc(-c2c[nH]c(=O)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 110 °C
Yield: 55.2 %

Procedure:
A microwave vial, equipped with a flea stir bar, was charged with (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (22 mg, 0.051 mmol), 2-tert-butoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine (21 mg, 0.076 mmol), Cs2CO3 (33 mg, 0.10 mmol), water (0.1 mL) and dioxane (1 mL). The mixture was sparged with N2 for 5 min and PdCl2(dppf) (4 mg, 0.005 mmol) was added. The mixture was sparged with N2 for 5 min and heated at 110° C. for 40 min in the microwave. The reaction mixture was filtered and the filtrate was purified by prep HPLC under acidic conditions, which led to loss of the t-butyl group, to afford the title compound (12.6 mg, 55%) as an oil. LC-MS Method 1 tR=1.27 min, m/z=448, 390; 1H NMR (CD3OD) 0.96 (s, 3H), 1.26 (s, 3H), 1.56 (d, 3H), 2.17 (s, 2H), 2.22 (m, 1H), 2.47 (m, 2H), 3.02 (m, 1H), 5.56 (q, 1H), 7.00 (d, 2H), 7.20-7.30 (5H), 7.58 (d, 2H), 7.77 (s, 1H), 8.14 (s, 1H).
Reaction SMILES: N[C:2]1[N:6]([CH2:7][CH:8]=[CH2:9])[N:5]=[C:4]([CH3:10])[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].N([O-])=O.[Na+].[ClH:20]>O.[Cu](Cl)Cl>[Cl:20][C:2]1[N:6]([CH2:7][CH:8]=[CH2:9])[N:5]=[C:4]([CH3:10])[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: C=CCn1nc(C)c(C(=O)OCC)c1N
Reactant: Cl
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: C=CCn1nc(C)c(C(=O)OCC)c1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6.7 g (0.032 mole) of ethyl 5-amino-3-methyl-1-(2-propenyl)-1H-pyrazole-4-carboxylate (XV) in 30 mL of concentrated hydrochloric acid was added 8.6 g (0.064 mole) of copper (II) chloride. The mixture was cooled to 0° C. and 2.65 g (0.038 mole) of sodium nitrite was added portionwise over 20 minutes. The mixture was stirred at room temperature for 1 hour, and then at 40° C. for 2 hours. The mixture was diluted with 50 mL of water and extracted twice with chloroform. The chloroform extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with ethyl acetate-hexane (1:4) to give 5.0 g of ethyl 5-chloro-3-methyl-1-(2-propenyl)-1H-pyrazole-4-carboxylate (XVI) as a light yellow oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].C(N(C(C)C)CC)(C)C.Cl[C:21]1[O:22][C:23]2[C:24](=[C:26]([C:38]#[N:39])[C:27]([CH3:37])=[C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:29]=2[F:30])[N:25]=1>ClCCl>[C:38]([C:26]1[C:24]2[N:25]=[C:21]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[O:22][C:23]=2[C:29]([F:30])=[C:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:27]=1[CH3:37])#[N:39]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CCOC(=O)CCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CCCNc1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
With cooling with ice, ethyl 4-aminobutanoate hydrochloride (149 mg, 0.892 mmol) and diisopropylethylamine (303 μl, 1.78 mmol) were added to a dichloromethane (7 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (213 mg, 0.743 mmol), followed by stirring at room temperature for 15 hours. The reaction liquid was concentrated under reduced pressure, ethyl acetate was added, followed by washing with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1→1:1, v/v) to obtain the entitled compound (279 mg, 99%) as a white solid.
Reaction SMILES: C(OC([NH:8][C:9]1([C:18]([OH:20])=[O:19])[CH2:16][CH:15]2[NH:17][CH:11]([CH2:12][O:13][CH2:14]2)[CH2:10]1)=O)(C)(C)C.[Br:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C@H:29]1[C:34]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:33]([CH2:40]Br)[NH:32][C:31]([C:42]2[S:43][CH:44]=[CH:45][N:46]=2)=[N:30]1>>[NH2:8][C:9]1([C:18]([OH:20])=[O:19])[CH2:10][CH:11]2[N:17]([CH2:40][C:33]3[NH:32][C:31]([C:42]4[S:43][CH:44]=[CH:45][N:46]=4)=[N:30][C@@H:29]([C:23]4[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=4[Br:21])[C:34]=3[C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:15]([CH2:14][O:13][CH2:12]2)[CH2:16]1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC2COCC(C1)N2
Product: CCOC(=O)C1=C(CN2C3COCC2CC(N)(C(=O)O)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Br
Yield: 22.6 %

Procedure:
The title compound was prepared in analogy to Example 133 by using 7-(tert-butoxycarbonylamino)-3-oxa-9-azabicyclo[3.3.1]nonane-7-carboxylic acid 139a (49 mg) and ethyl (4R)-6-(bromomethyl)-4-(2-bromo-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 70a (55 mg). 15 mg of the title compound was isolated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[CH:5]=1.[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][N:14]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:17]([C:16]2[CH:15]=[N:14][C:13]([Cl:12])=[CH:21][CH:20]=2)=[O:18])[CH:5]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: COC(=O)c1cccc(N)c1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: COC(=O)c1cccc(NC(=O)c2ccc(Cl)nc2)c1

Procedure:
3-[(6-Chloro-pyridine-3-carbonyl)-amino]-benzoic acid methyl ester was prepared from 3-amino-benzoic acid methyl ester and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of a small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C14H11N2O3Cl [M+H]+: 291.0531. Found: 291.0531.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@@:5]12[O:12][C@@H:9]([CH:10]=[CH:11]1)[C:8](=[O:13])[CH2:7][C:6]2=[O:14])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][CH2:4][C@@:5]12[O:12][C@@H:9]([CH2:10][CH2:11]1)[C:8](=[O:13])[CH2:7][C:6]2=[O:14])[CH3:2]
Reactant: CCOC[C@]12C=C[C@H](O1)C(=O)CC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC[C@]12CC[C@H](O1)C(=O)CC2=O
Yield: 82.9 %

Procedure:
To a solution of (1S*,5S*)-1-ethoxymethyl-8-oxabicyclo[3.2.1]oct-6-ene-2,4-dione (2.8 g, 0.014 mol) in ethyl acetate (10 ml) is added 10% palladium on carbon (0.056 g), followed by stirring under a 1 bar hydrogen atmosphere for 24 hours. The reaction mixture is then filtered through diatomaceous earth and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silical gel to afford (1S*,5S*)-1-ethoxymethyl-8-oxabicyclo[3.2.1]octane-2,4-dione (2.3 g) as a pale yellow solid.
Reaction SMILES: C([Li])CCC.[CH:6]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[CH2:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.Cl[CH2:22][CH:23]1[O:28][CH2:27][CH2:26][N:25]([CH:29]([CH3:31])[CH3:30])[CH2:24]1.O>CCCCCC.O1CCCC1.C1C=CC=CC=1>[CH:29]([N:25]1[CH2:26][CH2:27][O:28][CH:23]([CH2:22][CH:11]2[C:12]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[CH2:14][CH2:15][C:16]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]2=3)[CH2:24]1)([CH3:31])[CH3:30]
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Reactant: CC(C)N1CCOC(CCl)C1
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: O
Solvent: CCCCCC
Product: CC(C)N1CCOC(CC2c3ccccc3CCc3ccccc32)C1

Procedure:
A solution of n-butyl lithium in n-hexane (1.6 N, 1.6 ml) was added to 10,11-dihydro-5H-dibenzo[a,d]cycloheptene (390 mg) in anhydrous tetrahydrofuran at room temperature, and the resulting mixture was stirred under reflux for 40 minutes. A solution of 2-chloromethyl-4-isopropylmorpholine (362 mg) in benzene was added thereto while stirring under heating, and the resulting mixture was stirred under reflux for 4 hours, followed by addition of excess water. The reaction mixture was extracted with ethyl acetate. The ethyl acetate extract was dried, evaporated and chromatographed to afford 5-(4-isopropylmorpholin-2-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as oily material. M.P., 219°-221° C. (hydrochloride).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16]([NH:17][C@H:18]([CH3:23])[C:19]([F:22])([CH3:21])[CH3:20])=[C:15]([C:24]([NH2:26])=[O:25])[CH:14]=[N:13][N:12]3[CH:27]=2)[CH:6]=[CH:7][CH:8]=1.[CH:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH:28]1([C:31]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[C:11]4[C:16]([NH:17][C@H:18]([CH3:23])[C:19]([F:22])([CH3:21])[CH3:20])=[C:15]([C:24]([NH2:26])=[O:25])[CH:14]=[N:13][N:12]4[CH:27]=3)[CH:6]=[CH:7][CH:8]=2)=[O:32])[CH2:30][CH2:29]1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(CN)c3)cc12)C(C)(C)F
Reactant: O=C(O)C1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3cccc(CNC(=O)C4CC4)c3)cc12)C(C)(C)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To a solution of 6-(3-(aminomethyl)phenyl)-4-(((1R)-2-fluoro-1,2-dimethylpropyl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (Example 68, 15 mg, 0.041 mmol), cyclopropanecarboxylic acid (3.40 μl, 0.041 mmol) and triethylamine (8.49 μl, 0.061 mmol) in DMF (0.5 mL) was added BOP (17.96 mg, 0.041 mmol) and the resulting mixture was stirred at rt for 30 minutes. The reaction mixture was purified by reverse-phase preparative HPLC (condition C) to yield the title compound (9.6 mg, 53%). HPLC (condition J): retention time=2.140 minute. LC/MS (M+H)+=438.2. 1H NMR (500 MHz, MeOD) δ ppm 8.08 (1 H, s), 7.86 (1 H, d, J=1.7 Hz), 7.50-7.57 (2 H, m), 7.35 (1 H, t, J=7.6 Hz), 7.19 (1 H, d, J=7.5 Hz), 7.09 (1 H, d, J=1.7 Hz), 4.39-4.49 (3 H, m), 1.54-1.61 (1 H, m), 1.51 (3 H, d, J=3.6 Hz), 1.44-1.48 (6 H, m), 0.89-0.95 (2 H, m), 0.72-0.78 (2 H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>>[NH:2]=[C:1]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1CNC(CN2CCCC2)C1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCCC1CN1CCCC1
Yield: 12 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of 1-(pyrrolidin-2-ylmethyl)pyrrolidine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]O.N1C=CC=CC=1.S(Cl)([Cl:22])=O>O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][Cl:22]
Reactant: OCCCCCCCCCCCBr
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: ClCCCCCCCCCCCBr
Temperature: 25 °C

Procedure:
In a 250 mL three-necked flask, 11-bromoundecanol (10 g, 39.8 mmol), pyridine (2 mL, 24.7 mmol) and thionyl chloride (10 mL, 137 mmol) were successively introduced. The solution was stirred at room temperature and the reaction was followed by IR. After disappearance of the OH band, the mixture was hydrolysed carefully by addition of water, the aqueous layer was extracted three times with diethyl oxide. The organic layers were washed successively with a 10% HCl aqueous solution, water, a saturated aqueous solution of NaHCO3 and water until neutrality. After drying over MgSO4 and elimination of solvents under reduced pressure, the oil was filtered on silica gel (eluent:pentane). A colourless oil was obtained (10.15 g, 35 mmol).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15]C)=[C:4]2[C:9](=[C:10]([O:12]C)[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[Cl:14].[N+]([O-])([O-])=O.[NH4+].[Ce]>C(#N)C.O>[Br:1][C:2]1[C:3](=[O:15])[C:4]2[C:5]([Cl:14])=[CH:6][CH:7]=[N:8][C:9]=2[C:10](=[O:12])[CH:11]=1
Reactant: COc1cc(Br)c(OC)c2c(Cl)ccnc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1C=C(Br)C(=O)c2c(Cl)ccnc21
Yield: 79.1 %

Procedure:
To a cooled (0° C.) solution of 6-bromo-4-chloro-5,8-dimethoxyquinoline (compound 9) (215 mg, 0.71 mmol) in acetonitrile (10 ml) was added a cooled solution of cerium ammonium nitrate (2 g, 3.67 mmol) in water (10 ml), with stirring. The solution was stirred at room temperature for 90 min, diluted with water (20 ml) and extracted with chloroform (3×60 ml). The chloroform layers were joined, dried over sodium sulphate and evaporated, yielding 153 mg (79%) of compound 10.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:9][C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[N:33])[C:8]2=[O:24])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=c1[nH]c(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: N#CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: N#CCCCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O

Procedure:
1,4,5-Triphenylimidazol-2-one was treated with 7-bromo-heptanonitrile and potassium carbonate in butanone to give after chromatographic work-up 7-(3,4,5-triphenyl-2-oxo-2,3-dihydroimidazol-1-yl)heptanonitrile, m.p. 100°-101° C., Found: C, 79.7; H, 6.6; N, 9.8%; C28H27N3O requires: C, 79.9; H, 6.4; N, 10.0%; and
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:16](=[O:32])[NH:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Li+].I[CH3:36]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)=[C:17]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)[C:16]([O:32][CH3:36])=[N:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(n2[nH]c(=O)c(-c3ccc(Cl)cc3)c2-c2ccncc2)CC1
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)c(-c2ccncc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 13.4 %

Procedure:
A solution of 4-[4-(4-chlorophenyl)-3-oxo-5-pyridin-4-yl-2,3-dihydro-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.135 g, 0.3 mmol) in dry DMF (2 mL) was cooled to 0° C. and added lithium hydride (0.0035 g, 0.45 mmol). After stirring for 5 minutes, iodomethane (0.037 mL, 0.6 mmol) was added and the reaction was allowed to gradually warmed to room temperature and stirred for 20 hours. The reaction was diluted with ethyl acetate and washed with water; the aqueous layer was back-washed with ethyl acetate. The combined organic layer was washed with brine, dried (Na2SO4), and concentrated in vacuo. Flash chromatography with 1%, 3%, and 5% methanol/methylene chloride afforded 18.8 mg (13%) of a monomethylated product. MS (ES+): 469.2 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:29])[C:18](=[CH:24][NH:25][CH:26]3[CH2:28][CH2:27]3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12](F)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[C:1]([N:4]1[CH2:9][CH:8]=[C:7]([C:10]2[CH:11]=[C:12]3[C:13]([C:17](=[O:29])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][N:25]3[CH:26]3[CH2:28][CH2:27]3)=[CH:14][C:15]=2[F:16])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(C2=CCN(C(C)=O)CC2)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(C2CC2)c2cc(C3=CCN(C(C)=O)CC3)c(F)cc2c1=O
Temperature: 65 °C
Reaction time: 5.5 h

Procedure:
A solution of 4.70 g (11.3 mmol) of ethyl 4-(1-acetyl-1,2,3,6-tetrahydro-4-pyridyl)-α-[(cyclopropylamino) methylene]-2,5-difluoro-β-oxobenzenepropionate in 35 ml of t-butyl alcohol was treated with 1.26 g (11.3 mmol) potassium t-butoxide and stirred in an oil bath at 65° C. for 5.5 hours. The mixture was evaporated under vacuum and the residue was dissolved in chloroform and extracted with 0.5 N hydrochloric acid. The organic layer was dried (MgSO4), evaporated and the title compound purified by chromatograph on silica gel and crystallization from toluene, mp 190°-192° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])=[CH:5][CH:4]=1.C([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)(OC(C)(C)C)=O.C(=O)([O-])N.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O>[CH3:26][O:25][C:15]1[C:13]2[N:14]=[C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([CH2:2][N:36]4[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]4)=[CH:28][CH:27]=3)[S:11][C:12]=2[C:18]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Agent: NC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN4CCNCC4)cc3)nc12
Yield: 72 %

Procedure:
Conversion of 4-cloromethyl-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-benzamide (84 mg, 0.20 mmol) with 1-BOC-piperazine (372 mg, 1.9 mmol) using the general procedure C and afterwards cleavage of the neat carbamate in trifluoroacetic acid (1 ml) followed by saturated aqueous sodium carbonate affords the product as colorless crystals in 72% yield. MS: m/e=468 (M+H+).
Reaction SMILES: [H-].[Na+].CC(S)(C)C.[Cl:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][C:19]([O:23]C)=[C:18]4[S:25][CH:26]([CH3:28])[CH2:27][C:16]([C:17]=34)=[C:15]2[CH2:29][CH2:30][OH:31])=[CH:11][CH:10]=1.Cl>CN(C=O)C.CN1C(=O)N(C)CCC1.O>[Cl:8][C:9]1[CH:33]=[CH:32][C:12]([CH2:13][N:14]2[C:22]3[CH:21]=[CH:20][C:19]([OH:23])=[C:18]4[S:25][CH:26]([CH3:28])[CH2:27][C:16]([C:17]=34)=[C:15]2[CH2:29][CH2:30][OH:31])=[CH:11][CH:10]=1
Reactant: COc1ccc2c3c(c(CCO)n2Cc2ccc(Cl)cc2)CC(C)Sc13
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)(C)S
Product: CC1Cc2c(CCO)n(Cc3ccc(Cl)cc3)c3ccc(O)c(c23)S1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 97% NaH (120 mg, 4.88 mmol) in DMF (10 mL) and DMPU (1 mL) cooled to 0° C., there was added 2-methyl-2-propanethiol (550 mg, 6.10 mmol) and the resulting mixture was stirred at 0° C. for one hour. To this clear solution there was added a solution of product from Step 4 (490 mg, 1.22 mmol) in DMF (4 mL). The mixture was heated at 140° C. for 19 hours, cooled, diluted with H2O, acidified with 1N HCl and extracted 3× with Et2O. These extracts were washed 2× with brine, dried, and evaporated. The residue was chromatographed on silica gel, eluting with a 1:1 mixture of EtOAc and hexane, to afford the title product as a thick oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].Br[CH2:15][CH2:16][O:17][CH3:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][CH2:15][CH2:16][O:17][CH3:18]
Reactant: COCCBr
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc(C(=O)OC)ccc1OC
Temperature: 90 °C
Yield: 85.1 %

Procedure:
According to the procedure described in Example 6A Step 1, a mixture of methyl 3-hydroxy-4-methoxybenzoate (5.00 g, 27.4 mmol), 1-bromo-2-methoxyethane (4.96 g, 35.7 mmol), and K2CO3 (4.6 g, 32.9 mmol) in DMF (20 mL) was heated at 90° C. overnight, to afford methyl 4-methoxy-3-(2-methoxyethoxy)benzoate as a solid (5.6 g, 85%). 1H NMR (300 MHz, DMSO-d6) δ 7.60 (dd, 1H), 7.46 (d, 1H), 7.09 (d, 1H), 4.12 (m, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.67 (m, 2H), 3.33 (s, 3H).