Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C@H:7]1[CH2:24][C@@:23]2([CH3:25])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH2:16][C:17]2=[O:26])[CH2:9][CH2:8]1>C(OC(C)=C)(=O)C>[C:7]([O:6][C@H:7]1[CH2:24][C@@:23]2([CH3:25])[C@@H:10]([CH2:11][CH2:12][C@@H:13]3[C@@H:22]2[CH2:21][CH2:20][C@@:18]2([CH3:19])[C@H:14]3[CH2:15][CH:16]=[C:17]2[O:26][C:17](=[O:26])[CH3:16])[CH2:9][CH2:8]1)(=[O:6])[CH3:8]
Reactant: C[C@]12C[C@H](O)CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C=C(C)OC(C)=O
Agent: O=S(=O)(O)O
Product: CC(=O)OC1=CC[C@H]2[C@@H]3CC[C@H]4CC[C@@H](OC(C)=O)C[C@]4(C)[C@H]3CC[C@]12C
Yield: 137.2 %

Procedure:
A portion (17.23 ml) of a solution of concentrated sulphuric acid (0.4 ml) in isopropenyl acetate (20 ml) was added dropwise to a solution of 2β-hydroxy-5α-androstan-17-one (27.57 g) in isopropenyl acetate (140 ml). The solvent was removed slowly by distillation through a Vigreux column at such a rate that the solution was concentrated to approx. 60 ml after 6 h. The reaction mixture was cooled in an ice-bath to give a crystalline product, which was filtered off and washed with hexane (300 ml). The crop (33.21 g) in toluene was filtered through a column of silica gel (660 g; 0.2-0.5 mm); the eluate was evaporated to dryness and the residue was crystallised from acetone to afford 5α-androst-16-ene-2β,17-diol diacetate (24.38 g), m.p. 133°-134° C.; [α]D +34.4° (c 0.61 in CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Cl:34][C:35]1[CH:36]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[CH:39][C:40]=1[CH3:41]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:42]([C:37]2[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([Cl:34])[CH:36]=2)(=[O:43])=[O:44])[C:6]=1[CH3:14]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(C)c(Cl)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.06 g, 0.294 mmol) in DMF (0.5 mL) is added a solution of BEMP (0.136 mL, 0.47 mmol) in DMF (0.5 mL). After 1 hour, a solution of 3-chloro-4-methyl-benzenesulfonyl chloride (0.105 g, 0.47 mmol) in DMF (0.5 mL) is added. The reaction mixture is stirred at room temperature overnight, then concentrated under reduced pressure to a minimum volume. The residue is loaded on a pre-packed Isolute™ silica column and eluted using a gradient eluent from 100% iso-hexane to 30% ethyl acetate in iso-hexane to afford [1-(3-chloro-4-methyl-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester; MH+=393.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][C:10]([NH2:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1>C(O)C.Cl[Cu]>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: NC1=NN(c2cccc(Cl)c2)CC1
Agent: Cl[Cu]
Solvent: CCO
Product: Nc1ccn(-c2cccc(Cl)c2)n1
Reaction time: 3 h
Yield: 72.9 %

Procedure:
In the same apparatus and following the same modalities as in Example 1, 5 g (0.0255 mole) of 1-(m-chlorophenyl)-3-amino-2-pyrazoline were suspended in 25 ml of ethanol with addition of 0.2 g of CuCl, under an oxygen head. Oxidation was concluded after about 3 hours. The oxidized product was recovered as in Example 1, obtaining 3.6 g of 1-(m-chlorophenyl)-3-aminopyrazole, melting at 106°-107° C.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][O:5][C:4](=[O:7])[N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.Cl.[CH3:18][C:19]1[C:20]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:21][CH:22]=[C:23]([CH3:25])[N:24]=1>>[CH3:18][C:19]1[C:20]([N:26]2[CH2:27][CH2:28][N:29]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:3]4[C@H:2]([CH3:1])[CH2:6][O:5][C:4]4=[O:7])=[CH:16][CH:15]=3)=[O:14])[CH2:30][CH2:31]2)=[N:21][CH:22]=[C:23]([CH3:25])[N:24]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)n1
Reactant: C[C@@H]1COC(=O)N1c1ccc(C(=O)O)cc1
Agent: Cl
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3)CC2)c(C)n1
Yield: 64.2 %

Procedure:
By reaction and treatment in the same manner as in Example 49 and using (R)-4-(4-methyl-2-oxooxazolidin-3-yl)benzoic acid (422 mg) described in Preparation Example 37 and 1-(3,5-dimethylpyrazin-2-yl)piperazine hydrochloride (457 mg) described in Preparation Example 59, the title compound (484 mg) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][CH:14]1[CH2:19][NH:18][CH2:17][CH:16]([CH3:20])[NH:15]1.C(Cl)Cl.CO>C(O)CCC>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:18]3[CH2:17][CH:16]([CH3:20])[NH:15][CH:14]([CH3:13])[CH2:19]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CC1CNCC(C)N1
Solvent: CO
Solvent: CCCCO
Solvent: ClCCl
Product: CC1CN(c2ccnc3cc(Cl)ccc23)CC(C)N1

Procedure:
4,7-Dichloroquinoline (0.40 g, 2.0 mmol) and. 2,6-dimethylpiperazine (0.57 g, 5.0 mmol) in n-butanol (20 mL) are reacted according to method B yielding the title product after column chromatography with CH2Cl2-MeOH.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9](O)[CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[ClH:14]>>[Cl:14][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: COc1cccc(C(O)C(C)C)c1
Reactant: Cl
Product: COc1cccc(C(Cl)C(C)C)c1

Procedure:
The preparation was effected in analogy to example 1(b) from 1-(3'-methoxyphenyl)-2-methyl-propan-1-ol and HCl-gas.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.COC(OC)OC.[CH2:21](O)[CH2:22][OH:23]>>[CH:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]32[O:23][CH2:22][CH2:21][O:13]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCCCC1C1CCCCC1
Reactant: OCCO
Solvent: COC(OC)OC
Product: C1CCC(C2CCCCC23OCCO3)CC1

Procedure:
1,260 g (7 mols) of 2-cyclohexyl-cyclohexanone are reacted with 816.2 g (7.7 mols) of trimethylorthoformate and 477.4 g (7.7 mols) of anhydrous 1,2-ethanediol in a manner analogous to that in Example 1.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1B(O)O)[CH3:2].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCCCCC.[C:43]([O:46][CH2:47][CH3:48])(=[O:45])[CH3:44]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[CH2:44][C:43]([O:46][CH2:47][CH3:48])=[O:45])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1B(O)O
Reactant: CCOC(C)=O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)Cc1c(CC)cc(C)cc1CC

Procedure:
Ethyl 2,6-diethyl-4-methylphenylacetate was prepared by the general experimental method from 2,6-diethyl-4-methylphenylboronic acid (186 mg, 1.00 mmol). This involved using 5.75 mg [0.01 mmol] of Pd(dba)2 and 9.1 mg [0.03 mmol] of P(o-tolyl)3. After workup by column chromatography (hexane/ethyl acetate, 5:1), ethyl 2,6-diethyl-4-methylphenylacetate is obtained as a colourless liquid in a yield of 54% of theory. 1H NMR (400 MHz, CDCl3): δ=6.91 (s, 2H), 4.16 (q, J=7.2 Hz, 2H), 3.71 (s, 2H), 2.61-2.69 (m, 4H), 2.32 (s, 3H), 1.19-1.28 (m, 9H) ppm; 13C NMR (101 MHz, CDCl3): δ=171.9, 143.0, 136.7, 127.2, 127.1, 60.6, 34.0, 26.4, 21.1, 15.1, 14.2 ppm; MS (70 eV), m/z (%): 234 (37) [M+], 161 (100), 147 (33), 133 (40), 119 (13); IR (NaCl): ν=2966 (s), 1739 (s), 1458 (w), 1156 (m), 1032 (m) cm−1; elemental analysis: (theor): C=76.88, H=9.46, (exp): C=75.85, H=9.38.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C@H:13]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=3[CH3:34])[C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH3:15])=[N:10][N:9]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:39])[CH2:36][CH2:37][CH3:38]>C(Cl)Cl.N1C=CC=CC=1>[Si:17]([O:16][C@H:14]([CH3:15])[C@H:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:35](=[O:39])[CH2:36][CH2:37][CH3:38])=[CH:7][CH:6]=2)=[N:9][N:10]=1)[NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([Cl:33])[C:26]=1[CH3:34])([C:20]([CH3:22])([CH3:23])[CH3:21])([CH3:19])[CH3:18]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(N)cc3)o2)[C@@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Nc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@@H](C)O[Si](C)(C)C(C)(C)C)o2)cc1
Yield: 99.9 %

Procedure:
To a solution of 4-((1R,2R)-1-(5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl)-2-(tert-butyldimethylsilyloxy)propylamino)-2-chloro-3-methylbenzonitrile (intermediate 69d) (308 mg, 0.62 mmol) in CH2Cl2 (10 mL) and pyridine (1.5 mL) was added butyrylchloride (90 μL, 0.87 mmol) at room temperature. The resultant solution stirred for 90 hours and quenched with 2N aq. HCl (15 mL). The mixture was further partitioned between H2O (40 mL) and CH2Cl2 (35 mL). The aqueous layer was extracted with CH2Cl2 (35 mL). The combined organic extracts were washed with sat. aq. NaHCO3 (2×45 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a colourless oil (352 mg, 100%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.42 (s 1H), 7.93 (dm, J=8.8 Hz, 2H), 7.85 (dm, J=8.8 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 6.94 (d, J=8.6 Hz, 1H), 5.74 (d, J=9.2 Hz, 1H), 5.03 (dd, J=6.5, 9.0 Hz, 1H), 4.66 (pentet, J=6.3 Hz, 1H), 2.38 (t, J=7.2 Hz, 2H), 2.35 (s, 3H), 1.70 (sextet, J=7.4 Hz, 2H), 1.44 (d, J=6.1 Hz, 3H), 0.95 (t, J=7.4 Hz, 3H), 0.81 (s, 9H), 0.09 (s, 3H), −0.01 (s, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](O)([C:14]([F:17])([F:16])[Cl:15])[C:10]([F:13])([F:12])[Cl:11])=[CH:5][CH:4]=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].Cl>N1C=CC=CC=1>[CH3:1][N:2]([S:20]([CH3:19])(=[O:22])=[O:21])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:14]([F:17])([F:16])[Cl:15])[C:10]([F:13])([F:12])[Cl:11])=[CH:5][CH:4]=1
Reactant: CNc1ccc(C(O)(C(F)(F)Cl)C(F)(F)Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CN(c1ccc(C(C(F)(F)Cl)C(F)(F)Cl)cc1)S(C)(=O)=O
Reaction time: 1.5 h

Procedure:
To 6.1 g (20 mmole) N-methyl-4-(1,3-dichlorotetrafluoro-2-hydroxy-2-propyl)aniline in 30 ml pyridine add 3.4 g (30 mmole) methanesulfonyl chloride. Stir 1.5 hours, pour onto water, acidify with concentrated HCl and filter. Dissolve the solid in 1N NaOH, wash with Et2O, acidify and filter. Recrystallize the solid from Et2O-hexane to give the product; m.p. 140°-142° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:13]=[C:14]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[C:10]=3[CH2:9][S:8](=[O:30])(=[O:29])[C:6]=2[CH:7]=1.CC([O-])(C)C.[Na+].[CH3:37][NH:38][CH3:39]>C1(C)C=CC=CC=1.C1COCC1>[CH3:37][N:38]([CH3:39])[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:13]=[C:14]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[C:10]=3[CH2:9][S:8](=[O:30])(=[O:29])[C:6]=2[CH:7]=1
Reactant: O=C(c1nn(-c2ccccc2)c2c1CS(=O)(=O)c1cc(Br)ccc1-2)N1CCOCC1
Reactant: CNC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CN(C)c1ccc2c(c1)S(=O)(=O)Cc1c(C(=O)N3CCOCC3)nn(-c3ccccc3)c1-2
Temperature: 90 °C

Procedure:
7-bromo-3-(morpholin-4-ylcarbonyl)-1-phenyl-1,4-dihydrothiochromeno[4,3-c]pyrazole 5,5-dioxide (100 mg, 0.20 mmol, 1 eq.), NaOtBu (280 mg, 0.29 mmol, 1.4 eq.) are taken in degassed toluene in a sealed tube. Tris(dibenylidene acetone)dipalladium(0) (5 mg, 0.005 mmol, 0.025 eq.), 2-ditertiary butyl phosphino-2′,4′,6′-triisopropyl biphenyl (3.5 mg, 0.008 mmol, 0.04 eq.) are then added followed by dimethylamine in THF (3 mL, 2 M) and the reaction mixture is heated at 90° C. for 16 h. After this time, reaction mixture is filtered through a celite pad, evaporated and purified by silica gel flash chromatography to afford the title compound as a pale brown solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.61-7.59 (m, 3H), 7.51-7.49 (m, 2H), 7.10 (s, 1H), 6.81-6.79 (dd, J=2.6, 9.0 Hz, 1H), 6.61-6.59 (d, J=9.0 Hz, 1H), 4.76 (s, 2H), 3.96 (m, 2H), 3.65 (m, 4H), 3.59 (m, 2H), 2.97 (s, 6H). MS (ESI+): 453.0. HPLC (max plot) 91.39%; Rt 4.20 min.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[I-:18].[Na+].CNC1CCCCC1NC>O1CCOCC1.[Cu]I>[I:18][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1
Reactant: Fc1ccc(-n2ncc3c(Br)cccc32)cc1
Reactant: [I-]
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: Fc1ccc(-n2ncc3c(I)cccc32)cc1
Temperature: 110 °C
Yield: 95.2 %

Procedure:
4-Bromo-1-(4-fluorophenyl)indazole (291 mg, 1 mmol), copper(I)iodide (9.5 mg, 0.05 mmol), sodium iodide (300 mg, 2 mmol) and (1R,2R)—(N,N′-dimethylcyclohexane-1,2-diamine (14.2 mg, 0.1 mmol) in dioxane (1 ml) were mixed and stirred in argon at 110° C. All starting material was consumed after 24 h. The mixture was cooled and ammonia (5 ml, 28% in water) and water (20 ml) were added followed by extraction with DCM (2×15 ml). The organic phase was concentrated and the crude product was purified by flash chromatography (EtOAc/Heptane) to give the title compound (322 mg, 98%).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu](I)I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:17]3[CH:18]=[N:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Brc1cnc2ccccc2c1
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cnc3ccccc3c2)CCN(C)C1
Yield: 42.8 %

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (500 mg, 2.50 mmol), 3-bromoquinoline (1.040 g, 5.0 mmol), potassium phosphate tribasic (1.325 g, 6.25 mmol), L-proline (87 mg, 0.756 mmol) and copper iodide (143 mg, 0.752 mmol) in DMF (4 mL) was stirred at 150° C. for 14 h. The reaction mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was re-crystallized from MeOH-ether (1:99) to afford 2,8-dimethyl-5-quinolin-3-yl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (350 mg). 1H NMR (Freebase, CDCl3) δ (ppm): 9.0 (s, 1H), 8.2 (d, 1H), 8.17 (s, 1H), 7.82 (t, 1H), 7.68 (t, 1H), 7.61 (t, 1H), 7.25 (s, 1H), 7.18 (d, 1H), 7.0 (d, 1H), 3.7 (s, 2H), 2.8 (m, 4H), 2.58 (s, 3H), 2.4 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]2[CH:11]=1.O=P(Cl)(Cl)Cl.CN([CH:20]=[O:21])C>>[Cl:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][N:5]2[C:11]=1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Clc1ccc2nc(Cl)cn2c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c(Cl)nc2ccc(Cl)cn12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
Compound 12 (1.0 g, 5.4 mmol) was dissolved in DMF (5 mL) and the solution cooled to 0° C.in an ice-water bath. To this solution was added POCl3 (0.6 mL, 6.4 mmol) and the mixture stirred for 15 min. The bath was removed and the mixture warmed to room temperature and stirred for 3 hours. This reaction mixture was poured into ice water. The aqueous suspension was made basic by the addition of concentrated NH4OH and the precipitated solid collected by filtration. This solid was dissolved in CHCl3 (50 mL) and the solution extracted with water (3×50 mL), dried (MgSO4) and solvent removed under reduced pressure to give 1.0 g (87%) of compound 50 as a white solid.
Reaction SMILES: [CH3:1][CH:2]([C:8](=[O:11])[CH2:9][CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][CH:9]([CH3:10])[C:8](=[O:11])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: BrBr
Reactant: CCOC(=O)C(C)C(=O)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of ethyl 2-methyl-3-oxopentanoate (5.0 g, 34.7 mmol) in chloroform at 0° C. was added bromine (1.79 mL, 34.7 mmol) in chloroform (10 mL) drop-wise. The resulting solution was stirred at rt for 16 h. The solution was washed with water, dried over sodium sulfate, and concentrated to give the title compound. 1HNMR (500 MHz, CDCl3), δ4.781-4.740 (dd, J=6.6 Hz, 1H), 4.140-4.098 (dd, J=7.0 Hz, 1H), 3.770 (s, 3H), 1.797-1.783 (d, J=6.6 Hz, 3H), 1.455-1.442 (d, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13](O)=[O:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1.S(Cl)([Cl:28])=O>>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([C:13]([Cl:28])=[O:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(C(=O)O)cccc2c1=O
Reactant: O=S(Cl)Cl
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc2c(C(=O)Cl)cccc2c1=O
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of thionyl chloride (10 mL) and 3-methyl-4-oxo-2-(3-(trifluoromethyl)phenyl)-3,4-dihydroquinazoline-8-carboxylic acid 33 (1.00 g, 2.87 mmol) was heated at reflux for 1 h. Upon cooling to room temperature, all volatiles were removed under vacuum, to give 34 (1.05 g, 100% yield) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-:15])=[O:14])=[C:8]2[C:3]=1[C:4](=O)[NH:5][CH:6]=[N:7]2.O=P(Cl)(Cl)[Cl:19]>>[Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-:15])=[O:14])=[C:8]2[C:3]=1[C:4]([Cl:19])=[N:5][CH:6]=[N:7]2
Reactant: Cc1cc(Br)c2c(=O)[nH]cnc2c1[N+](=O)[O-]
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Br)c2c(Cl)ncnc2c1[N+](=O)[O-]

Procedure:
A solution of 5-bromo-7-methyl-8-nitroquinazolin-4(3H)-one (200 mg, 0.71 mmol) in POCl3 (4 mL) was heated at reflux for 4 h. Then the reaction mixture was concentrated and the residue was co-evaporated with toluene and dried to afford 5-bromo-4-chloro-7-methyl-8-nitroquinazoline which was dissolved in THF (5 mL). Then the solution was treated with 3-(trifluoromethyl)aniline (457 mg, 2.84 mmol) and DIPEA (458 mg, 3.55 mmol) at 0° C. and the reaction mixture was stirred at rt for 12 h before it was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered, concentrated and purified by column chromatography to afford 215 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.36 (s, 1H), 9.15 (s, 1H), 8.72 (s, 1H), 8.29 (s, 1H), 8.23 (d, J=8.4 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 2.47 (s, 3H); MS (m/z): 427.17 (M)+.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2].Br[CH2:23][CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([C:4]1[C:5]([C:19](=[O:21])[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:23][CH3:24])=[C:12]([Cl:17])[CH:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)c(Cl)c2)c1C
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)cc1Cl
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[4-acetyl-1-(3-chloro-4-hydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (prepared as outline in Example 57; 80 mg, 0.27 mmol) in 3 mL of dry DMF was added bromoethane (54 mg, 0.5 mmol) and K2CO3 powder (50 mg). The resulting reaction mixture was warmed to 50° C. and stirred for 1 h. It was quenched by addition of 20 mL of H2O, extracted with diethyl ether (20 mL×2). The combined organic extracts were washed with brine (50 mL), dried (MgSO4), filtered, and concentrated in vacuo to afford 1-[4-acetyl-1-(3-chloro-4-ethoxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone: MS (ESI) 302 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH3:22])=[CH:17][CH:16]=1.[CH3:24][O:25][C:26]([CH2:28]P(OC)(OC)=O)=[O:27]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18](/[C:21](/[CH3:22])=[CH:28]/[C:26]([O:25][CH3:24])=[O:27])=[CH:19][CH:20]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: CC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Product: COC(=O)/C=C(\C)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1

Procedure:
According to the method described for Reference Example 22, 4'-(5-methyl-2-phenyl-4-oxazolylmethoxy)acetophenone was allowed to react with trimethyl phosphonoacetate gave methyl (E)-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2-butenoate. Recrystallization from ethyl acetate--hexane gave colorless prisms, m.p.125°-126° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])=[CH:5][C:4]=1[F:20])=[CH2:2].FC(F)(F)C(O)=O.[CH2:28]([N:35]([CH2:39][Si](C)(C)C)[CH2:36]OC)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[F:20][C:4]1[CH:5]=[C:6]([N:9]2[CH2:13][C@H:12]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])[O:11][C:10]2=[O:19])[CH:7]=[CH:8][C:3]=1[CH:1]1[CH2:2][CH2:36][N:35]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:39]1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: C=Cc1ccc(N2C[C@H](CNC(C)=O)OC2=O)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(Cc4ccccc4)C3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of (S)-(−)-N-[[3-[4-vinyl-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (EXAMPLE 41, Step 1, 3.50 g) and trifluoroacetic acid (0.23 mL) in dry methylene chloride under N2 is treated with a solution of N-benzyl-N-(methoxymethyl) trimethylsilylmethylamine (6.10 g) in dry methylene chloride (50 mL) dropwise over 4.5 hours, and the resulting solution was stirred at ambient temperature for 17 hours. The reaction mixture is then washed with saturated aqueous sodium bicarbonate (30 mL), water (30 mL) and saline (30 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue which is chromatographed on silica gel (230-400 mesh, 350 g), eluting with a gradient of methanol/methylene chloride (1/99-10/90). Pooling and concentration of those fractions with an Rf=0.19 by TLC (methanol/chloroform, 10/90) and trituration with methanol/diethyl ether gives the title compound, NMR (CDCl3, 400 MHz) 7.35, 7.25, 7.13, 6.08, 4.78, 4.03, 3.76, 3.69, 3.62, 2.97, 2.78, 2.56, 2.33, 2.02, 1.85δ.