Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Li]CCCC.B(OC)(OC)OC.[Br:22]Br>C1COCC1>[Br:22][C:7]1[C:6]([CH3:8])=[CH:5][C:4]([NH2:9])=[CH:3][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: Cc1cc(C)cc(N)c1
Agent: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(N)cc(C)c1Br
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3,5-dimethyl-phenylamine (400 mg) in THF (35 mL) was added n-BuLi (1.45 mL, 2.5 M solution in hexane) at −78° C. The mixture was stirred at −78° C. for 20 min, allowed to warm up to −40° C. for 5 min, and then was cooled down to −78° C. again. After 10 min, B(OMe)3 (0.4 mL) was added dropwise. The mixture was stirred at −78° C. for 2.5 h, warmed up to 10° C. slowly, and then was cooled down to −78° C. again. Bromine (0.185 mL) was added dropwise to the mixture. The mixture was stirred at −78° C. for 1.5 h, and allowed to warm up to 0° C. for 1 h. The reaction was quenched with saturated NaHCO3 aqueous solution and 20% Na2S2O3 aqueous solution. The aqueous layer was extracted with EtOAc, and the organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane=5:95 to 40:60) to give 4-bromo-3,5-dimethyl-phenylamine as a white solid: MS (m/z) 200 (M+1); 1H NMR (CDCl3, 400 MHz) δ 6.43 (s, 2H), 3.52 (s, 2H), 2.31 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](F)=[O:7].[OH-].[Na+].[Cl:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([NH2:26])[C:22]=1[C:23](O)=[O:24]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.C1(C)C=CC=CC=1>[Cl:16][C:17]1[C:22]2[C:23](=[O:24])[O:7][C:6]([C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=3)=[N:26][C:21]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(F)c1cccc(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1oc(-c2cccc(C(F)(F)F)c2)nc2cccc(Cl)c12
Reaction time: 1.5 h
Yield: 92.2 %

Procedure:
48 g of 3-trifluoromethylbenzoyl fluoride and 20 g of 50% strength aqueous sodium hydroxide solution are added simultaneously via 2 feed apparatuses in the course of 25 minutes at from 25° to 36° C. to a stirred mixture of 42.9 g of 6-chloroanthranilic acid and 0.45 g of triethylbenzylammonium chloride and 700 g of toluene. Stirring is continued for 90 minutes at 27° C., after which the water is separated off at from 87° to 104° C. After the addition of 32.7 g of thionyl chloride in the course of 15 minutes at 70° C., stirring is continued for 90 minutes at 82° C. The mixture is extracted once with water and once with 0.4 N sodium hydroxide solution, and is evaporated down to give 75 g (92%) of 5-chloro-2-(m-trifluoromethylphenyl)-4H-3,1-benzoxazin-4-one of melting point 116°-120° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].[CH3:21][N:22]([CH3:25])[CH:23]=O.COC(OC)N(C)C>O>[CH3:21][N:22]([CH:25]=[C:10]([C:11](=[O:13])[CH3:12])[C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:14])[CH3:23]
Reactant: CN(C)C=O
Reactant: CC(=O)CC(=O)Nc1ccccc1C
Agent: COC(OC)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(=O)C(=CN(C)C)C(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of N-(2-methylphenyl)-3-oxobutanamide (10.0 g), potassium carbonate (7.23 g) and N,N-dimethylformamide (130 mL) was added dropwise 1,1-dimethoxy-N,N-dimethylmethanamine (12.5 g) over 30 min at room temperature, and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was slowly poured into water, and the mixture was extracted with dichloromethane. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (10.2 g).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH2:18][CH2:17][CH:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15][CH:14]=3)=[CH:10][CH:11]=2)[N:6]([CH3:27])[C:5]1=[O:28].C(Cl)Cl.Cl.CCOC(C)=O>CO>[NH2:19][CH:16]1[CH2:17][CH2:18][C:13]([C:9]2[N:8]=[C:7]3[N:6]([CH3:27])[C:5](=[O:28])[N:4]([CH2:3][C:2]([CH3:1])([CH3:30])[CH3:29])[C:12]3=[CH:11][CH:10]=2)=[CH:14][CH2:15]1
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CCC(NC(=O)OC(C)(C)C)CC3)nc21
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CCC(N)CC3)nc21
Temperature: 25 °C

Procedure:
To a round bottom flask was added tert-butyl {-4-[1-(2,2-dimethylpropyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-5-yl]cyclohex-3-en-1-yl}carbamate (17-1) (338 mg, 0.815 mmol), DCM (2 mL), MeOH (2 mL), and a 4N solution of HCl in EtOAc (2.038 ml, 8.15 mmol). The reaction mixture was then capped & stirred at room temperature for several hours. The reaction was then concentrated to yield 5-(4-Aminocyclohex-1-en-1-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (17-2) as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[CH:20]=[C:21]([F:28])[C:22]([C:25](O)=[O:26])=[N:23][CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:22]3[C:21]([F:28])=[CH:20][C:19]([Cl:18])=[CH:24][N:23]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ncc(Cl)cc1F
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cc3F)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-chloro-3-fluoro-pyridine-2-carboxylic acid (CAS 207994-08-9) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=399.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C@H:9]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:8]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:7][CH:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C(Cl)Cl>[CH3:26][C:23]([Si:20]([CH3:22])([CH3:21])[O:19][C@@H:8]1[C@@H:9]([CH2:10][O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:5]([CH2:3][OH:2])=[CH:6][CH2:7]1)([CH3:24])[CH3:25]
Reactant: COC(=O)C1=CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1COCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC=C(CO)[C@@H]1COCc1ccccc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
A 500-mL 3-necked round bottomed flask, equipped with an argon inlet, a temperature probe, and a mechanical stirrer, was charged with (4S,R)-4-[[(1,1-Dimethylethyl)dimethylsilyl]oxy]-5-[(phenylmethoxy)methyl]-1-cyclopentene-1-carboxylic acid methyl ester (7) (10 g, 26.55 mmol, as prepared in Example 9) in DCM (200 mL). The solution was cooled to −78° C. and to this solution diisobutylaluminum hydride (1 M, 66.39 mL, 66.375 mmol in toluene) was added slowly. The reaction mixture was stirred at −78° C. for 2 hours to complete the reaction. The reaction mixture was poured into saturated solution of potassium sodium tartrate (400 mL). The mixture was stirred for 2 hours. The organic layer was separated and the aqueous layer was extracted with n-hexane (200 mL). The combined organic layer was washed with water (50 mL), dried over magnesium sulfate, and concentrated in vacuo to give the title compound (9.3 g) as a yellowish oil.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:11][O:12][C:13]([C:15]1[S:16][C:17]([CH3:29])=[CH:18][C:19]=1B1OC(C)(C)C(C)(C)O1)=[O:14].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[N:4]1[CH:3]=[C:2]([C:18]2[CH:19]=[C:15]([C:13]([O:12][CH3:11])=[O:14])[S:16][C:17]=2[CH3:29])[N:6]2[C:5]=1[CH:10]=[CH:9][CH:8]=[N:7]2
Reactant: Brc1cnc2cccnn12
Reactant: COC(=O)c1sc(C)cc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnc3cccnn23)c(C)s1
Temperature: 100 °C

Procedure:
3-Bromoimidazo[1,2-b]pyridazine (0.40 g, 2.02 mmol), methyl-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (0.86 g, 3.03 mmol), Pd2(dba)3 (0.19 g, 0.20 mmol), tricyclohexylphosphine (0.14 g, 0.51 mmol), aqueous tribasic potassium phosphate (1.27 M, 1.45 mL, 6.85 mmol), and 1,4-dioxane (10.1 mL) were placed in a flask and purged with nitrogen for five minutes. The solution was heated to 100° C. for four hours. The solution was cooled to room temperature, poured into an aqueous solution of saturated sodium bicarbonate, and extracted with ethyl acetate (×3). The combined organic layers were dried with magnesium sulfate, filtered, and concentrated and the residue purified by flash chromatography to afford the title compound as a yellow solid. 1H NMR (500 MHz, CD3SOCD3) δ 8.62 (d, 1H); 8.24 (s, 1H); 8.21 (d, 1H); 8.06 (s, 1H); 7.30 (dd, 1H); 3.83 (s, 3H); 2.58 (s, 3H). LRMS (APCI) calc'd for (C13H11N3O2S) [M+H]+, 274.0. found 274.0.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:26]([C:40]2[CH:45]=[C:44]([O:46][CH2:47][CH3:48])[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]=2[F:53])[NH:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:30][CH:29]=2)[N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[C:54]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][C:58]=1B(O)O)(=[O:56])[CH3:55]>>[CH2:47]([O:46][C:44]1[CH:43]=[C:42]([O:49][CH:50]([CH3:52])[CH3:51])[C:41]([F:53])=[C:40]([CH:26]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[N:38]=[C:37]([CH3:39])[O:36][N:35]=3)=[CH:32][CH:33]=2)[C:4]2[N:5]([C:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:6]=[C:2]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][C:57]=3[C:54](=[O:56])[CH3:55])[N:3]=2)[CH:45]=1)[CH3:48]
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(Br)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: CCOc1cc(OC(C)C)c(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)c2nc(-c3ccccc3C(C)=O)cn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1

Procedure:
According to the procedure for Intermediate 93.4, Intermediate 66.3 was coupled with 2-acetylphenylboronic acid to afford Intermediate 111.1.
Reaction SMILES: N[C:2]1[CH:13]=[CH:12][C:11](Br)=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[Cl:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>COCCOC.O.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:15][C:16]1[CH:21]=[C:20]([C:11]2[CH:12]=[CH:13][CH:2]=[C:3]([CH:10]=2)[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])[CH:19]=[CH:18][CH:17]=1
Reactant: CON(C)C(=O)c1cc(Br)ccc1N
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cccc(-c2cccc(Cl)c2)c1
Temperature: 85 °C
Yield: 60.4 %

Procedure:
A mixture of 2-amino-5-bromo-N-methoxy-N-methylbenzamide (7.78 g, 30 mmol), 3-chlorophenyl boronic acid (5.63 g, 36 mmol), tetrakis(triphenylphosphine)palladium (0) (1.73 g, 1.5 mmol), and sodium carbonate, (7.63 g, 72 mmol) in a mixture of DME and water (150 mL/30 mL) was degassed to remove the oxygen and heated at 85° C. under nitrogen for 3 hours. The reaction, mixture was cooled to room temperature and treated with brine (30 mL) and ethyl acetate (100 mL). The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with brine and dried with MgSO4. After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethyl acetate/1:1) to give 5-(3-chlorophenyl)-N-methoxy-N-methylbenzamide as a brown oil (5 g, 57%). To a solution of this benzamide (5 g, 17.2 mmol) in anhydrous THF was added in a dropwise fashion a solution of methyllithium in ether (1.4M, 28.6 mL, 40 mL) at −78° C. under nitrogen. After stirring for 30 minutes, the reaction mixture was treated with a saturated aqueous ammonium chloride solution (50 mL) at −78° C. Ethyl acetate (100 mL) was added, organic layer was separated, and aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed (brine) and dried (MgSO4). After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane: ethyl acetate/2:1) to afford 1-(4-amino-3′-chloro-biphenyl-3-yl)-ethanone as a yellow solid (2 g, 47%): mp 89-90° C.; 1H-NMR (CDCl3) δ 7.89 (d, 1H, J=2.0 Hz), 7.51 (m, 2H), 7.25-7.40 (m, 3H), 6.73 (d, 1H, J=8.6 Hz), 6.38 (br, 2H), 2.65 (s, 3H); MS (EI) m/z 268([M+Na]+, 60%); Anal. Calc. For C14H12ClNO: C, 68.44; H, 4.92; N, 5.70. Found: C, 68.40; H, 4.89; N, 5.61.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:10]=[C:11]3[C:16]([N:17]4[CH2:22][CH:21]5[CH2:23][CH:18]4[CH2:19][NH:20]5)=[N:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:10]=[C:11]3[C:16]([N:17]4[CH2:22][CH:21]5[CH2:23][CH:18]4[CH2:19][N:20]5[S:39]([CH3:38])(=[O:41])=[O:40])=[N:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2c3ncnc(N4CC5CC4CN5)c3nn2-c2ccccc2Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC2CC1CN2c1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Yield: 101.9 %

Procedure:
A solution of Rac-(S,S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine 4A-1 (63 mg, 0.12 mmol) in dichloromethane (2 ml) was charged with triethylamine (0.1 ml). Methanesulfonyl chloride (0.01 ml, 0.14 mmol) was added via syringe, and the resultant mixture was stirred at 23° C. for 3 days. The reaction mixture was then washed with water (2 ml) and the layers were separated. The organic solution was dried over anhydrous magnesium sulfate and concentrated. Purification of the residue by reverse-phase HPLC afforded Rac-(S, S)-3-(4-chlorophenyl)-2-(2-chlorophenyl)-7-(5-methanesulfonyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-2H-pyrazolo[4,3-d]pyrimidine 6A-1 (63 mg, quantitative): MS: 515.0 (M+1)+; 1H NMR (400 MHz, CD3OD) δ 8.3 (s, 0,5H), 8.1 (s, 0.5H), 7.6 (m, 4H), 7.4 (m, 4H), 6.1 (s, 0.5H), 5.2 (s, 0.5H), 4.7 (m, 1H), 4.4 (m, 0.5H), 4.2 (m, 0.5H), 4.0 (m, 1H), 3.8 (m, 1H), 3.5 (m, 3H), 3.0 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21]Cl)=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:18]([CH2:21][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])=[N:19][N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3nnc(CCl)o3)c2[C@@H]2CCCN12
Reactant: CCCNCCC
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nnc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.8 %

Procedure:
A suspension of 1.30 g (3.33 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 10 ml of N,N-dimethylformamide was treated with 1.7 g (0.017 mol) of dipropylamine. After stirring at room temperature for 20 hrs. and at 80° C. for 4 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol 39:1 as the eluent. The product was recrystallized from ether. There were obtained 1.27 g (85%) of (S)-8-chloro-1-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1- c][1,4]benzodiazepin-9-one as white crystals; m.p. 158°-160° and [a]D20 =48.8° (CH2Cl2, c=1%).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[C:8](O)(=O)[CH2:9][CH2:10][CH3:11]>>[CH2:9]([C:8]1[O:4][CH2:3][C:2]([CH3:7])([CH2:5][OH:6])[N:1]=1)[CH2:10][CH3:11]
Reactant: CC(N)(CO)CO
Reactant: CCCC(=O)O
Product: CCCC1=NC(C)(CO)CO1

Procedure:
The procedure described in Example 1 is repeated in all essential details with the exception that 2-amino-2-methyl-1,3-propanediol is reacted with butyric acid in a 1:1 molar ratio according to the method of Purcell to produce 2-propyl-4-methyl-4-hydroxymethyl-2-oxazoline.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: ClCCN1CCCC1
Reactant: COc1cc(Br)ccc1O
Agent: Cl
Product: COc1cc(Br)ccc1OCCN1CCCC1

Procedure:
The product was obtained analogously to Example 24.1a starting from 4-bromo-2-methoxyphenol and 1-(2-chloroethyl)pyrrolidine hydrochloride. Yield: 3.96 g (45% of theoretical); C13H19BrNO2 (M=300.192); calc.: molpeak (M+H)+: 300/302 (Br); found: molpeak (M+H)+: 300/302 (Br); HPLC-MS: 4.67 minutes (method A).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:16][CH:17]=O)[CH2:5][C@H:6]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[O:7][CH3:8].[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C@H:6]([O:7][CH3:8])[CH2:5][C@@H:4]([C:3]([O:2][CH3:1])=[O:19])[CH2:16][CH2:17][N:30]2[CH2:29][CH2:28][N:27]([C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:26])[CH2:32][CH2:31]2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](CC=O)C[C@@H](OC)c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)[C@@H](CCN1CCN(C(=O)OC(C)(C)C)CC1)C[C@@H](OC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of 4(R)-(4-Fluoro-phenyl)-4-methoxy-2(S)-(2-oxo-ethyl)-butyric acid methyl ester (200 mg, 0.74 mmol) and piperazine-1-carboxylic acid tert-butyl ester (166 mg, 0.89 mmol) was added NaBH(OAc)3 (218 mg, 1.03 mmol) and AcOH (53.4 mg, 51 μL, 0.89 mmol) at room temperature. The mixture was stirred for 8 h at the room temperature. The reaction was quenched by pouring into 20 mL 5% aqueous NaOH and diluted with ethylacetate. The mixture was extracted with ethyl acetate (3×15 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The mixture was concentrated under reduced pressure and the product isolated by flash column chromatography eluting with 6% to 60% ethyl acetate/hexane to provide 270 mg of the title compound as an colorless oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[N+:14]([C:17]1[CH:18]=[C:19]([C:23](=[O:29])[CH:24]=[CH:25][C:26]([OH:28])=[O:27])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15].Cl>C1COCC1>[N+:14]([C:17]1[CH:18]=[C:19]([C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:20]=[CH:21][CH:22]=1)([O-:16])=[O:15]
Reactant: O=C(O)C=CC(=O)c1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)CCC(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 76.2 %

Procedure:
To a suspension of triacetoxyborohydride (Aldrich) (21 g, 10 mmol) in dry THF (220 mL), a solution in dry THF (40 mL) of 4-(3′-nitrophenyl)-4-oxo-2-butenoic acid (2.2 g, 10 mmol)(prepared as described in example 7,(mp. 178-179° C.)), was added on stirring at room temperature, under dry nitrogen atmosphere. The resulting light yellow solution was stirred at room temperature overnight under nitrogen atmosphere. To the colorless reaction mixture, aqueos 1N HCl (50 mL), was slowly added dropwise, on cooling at 0° C. The most of the solvent was evaporated under reduced pressure and the residue taken up with 2N HCl and extracted with the ethyl acetate. The combined organic extracts were washed with brine, dried and concentrated in vacuo, to led to a solid. Recrystallization from diethyl ether/hexane afforded a cream solid (1.7 g ,77%), mp. 162-164° C.
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH3:16])[CH2:5][CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=1[Cl:15].C(N(CC)CC)C.[F:24][CH:25]([F:35])[C:26]1[C:30]([C:31](Cl)=[O:32])=[CH:29][N:28]([CH3:34])[N:27]=1>ClCCl.O>[CH3:1][O:2][N:3]([CH:4]([CH3:16])[CH2:5][CH2:6][C:7]1[C:8]([Cl:15])=[CH:9][C:10]([Cl:14])=[CH:11][C:12]=1[Cl:13])[C:31]([C:30]1[C:26]([CH:25]([F:35])[F:24])=[N:27][N:28]([CH3:34])[CH:29]=1)=[O:32]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC(C)CCc1c(Cl)cc(Cl)cc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)CCc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
To a solution of O-Methyl-N-[1-methyl-3-(2,4,6-trichloro-phenyl)-propyl]-hydroxylamine (0.6 g, 2.1 mmol) prepared as described in example P23d, in dichloromethane (6 ml), was added triethylamine (0.73 ml, 5.2 mmol) followed by drop wise addition of a solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.415 g, 2.1 mmol) in dichloromethane at 0° C. After complete addition of acid chloride, the reaction mixture was stirred for 18 hours at ambient temperature. When the TLC confirmed completion of the reaction, the reaction mass was diluted with water and extracted with dichloromethane (3×60 ml). The combined dichloromethane layer was washed with 2N HCl, followed by sat NaHCO3 then water and finally brine solution, dried over sodium sulfate and solvent was evaporated off under reduced pressure. The resulting crude mass was purified by column chromatography using 60-120μ mesh silica gel and product collected at 30% ethyl acetate in hexane as eluent to give 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid methoxy-[1-methyl-3-(2,4,6-trichloro-phenyl)-propyl]amide (0.53 g, 57%) as a gum like mass.