Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[OH:24])=[C:4]([CH3:25])[N:3]=1.[N:26]1([CH2:31][CH2:32][CH2:33][CH2:34]O)[CH2:30][CH2:29][CH2:28][CH2:27]1>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:34][CH2:33][CH2:32][CH2:31][N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:22])=[CH:16][C:15]=2[OH:24])=[C:4]([CH3:25])[N:3]=1
Reactant: OCCCCN1CCCC1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1O
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCCCCN2CCCC2)cc1O

Procedure:
The title compound was prepared using the product of step (i) (50 mg), 4-(pyrrolidin-1-yl) butan-1-ol (64.2 mg) and the method of example 74 step (iii) to give a tan solid, 9 mg.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:20]=[C:21]([CH:28]=[CH:29][CH:30]=4)[C:22](N(OC)C)=[O:23])[CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:31]([Mg]Br)[CH3:32]>O1CCCC1.C(=O)([O-])O.[Na+]>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:20]=[C:21]([C:22](=[O:23])[CH2:31][CH3:32])[CH:28]=[CH:29][CH:30]=4)[CH2:17][CH2:18]3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: CON(C)C(=O)c1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Reactant: CC[Mg]Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(=O)c1cccc(N2CCN(CCC3CCC4(CC3)OCCO4)CC2)c1
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a solution of 1.6 g (3.8 mmol) of 3-{4-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]piperazin-1-yl}-N-methoxy-N-methylbenzamide in 25 mL of dry tetrahydrofuran cooled to 0° C. are added 8 mL of 1M ethylmagnesium bromide solution in tetrahydrofuran. The mixture is stirred for 90 minutes then poured in 100 mL of an aqueous saturated sodium hydrogen carbonate solution. The product is extracted twice with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue (1.4 g) is purified over 50 g of silica gel (eluant heptane/ethyl acetate 1/1) to give 1.06 g (72%) of 1-(3-{4-[2-(1,4-dioxaspiro[4.5]dec-8-yl)ethyl]piperazin-1-yl}phenyl)propan-1-one as an oil.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH:11]([CH3:13])[CH3:12])[C:5]([CH3:14])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH:18]([NH2:21])([CH3:20])[CH3:19]>C1(C)C=CC=CC=1>[CH:18]([NH:21][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH:11]([CH3:13])[CH3:12])[C:5]([CH3:14])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])([CH3:20])[CH3:19]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C(C)C
Reactant: CC(C)N
Solvent: Cc1ccccc1
Product: Cc1cc([N+](=O)[O-])c(NC(C)C)c([N+](=O)[O-])c1C(C)C
Temperature: 100 °C
Yield: 73.4 %

Procedure:
A mixture of 5-chloro-4,6-dinitro-o-cymene (4.0 g, 0.0155 mole) and isopropylamine (3.2g, 0.054 mole) in toluene is heated in a bomb at 100° C. for 4 hours. The cooled mixture is washed with aqueous bicarbonate solution, dried over magnesium sulfate, and concentrated to leave the crude product which is purified by dry column chromatography to yield 3.2 g of product with mp 54°-55° C. By using one of the aforementioned procedures for the dinitration of the appropirate N-alkyl-4-alkyl-m-toluidines or by reacting the appropriate amine with the desired 3-chloro-2,4-dinitro-6-alkyltoluene the following compounds are prepared.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=O.II.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)C>[CH2:1]([N:8]1[C:9]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:10]=2[N:11]=[C:18]1[C:17]([O:21][CH2:22][CH3:23])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Cl)cc1NCc1ccccc1
Reactant: CCOC(=O)C=O
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nc2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 500 ml of ethanol solution containing 26 g of 2-benzylamino-4-chloroaniline was added 45.7 g of polymer form (45-50% toluene solution) of ethyl glyoxylate, further 28.4 g of iodine was added and the reaction mixture was stirred at room temperature for 20 minutes. Then 27.8 g of sodium thiosulfate aqueous solution was added thereto, the crystals being separated were collected by filtration, and washed with water and ethanol, then dried. There was obtained 26.1 g of ethyl 1-benzyl-6-chlorobenzimidazol-2-carboxylate as in the form of pale brown powdery product.
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.[F:18][CH:19]([F:29])[C:20]1[N:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=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:26]([C:23]3[CH:22]=[N:21][C:20]([CH:19]([F:29])[F:18])=[CH:25][N:24]=3)=[O:27])[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)c1cnc(C(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3cnc(C(F)F)cn3)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-difluoromethyl-pyrazine-2-carboxylic acid (CAS 1174321-06-2, US2009209757) following procedure I yielded the title compound as a light yellow solid. MS (ISP): m/z=398.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>O1CCOCC1>[CH2:20]([O:19][C:17](=[O:18])[C:16](=[CH:15][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:11])[F:10])[N:3]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:21]
Reactant: Nc1cccc(C(F)(F)F)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: C1COCCO1
Product: CCOC(=O)C(=CNc1cccc(C(F)(F)F)n1)C(=O)OCC
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of 2-amino-6-trifluoromethylpyridine (15.0 g, 92.5 mmol) and diethyl ethoxymethylenemalonate (18.5 mL, 20.0 g, 92.5 mmol) in 1,4-dioxane (30 mL) was stirred at 100° C. for 48 h. Upon cooling to room temperature, 2-[(6-trifluoromethylpyridin-2-ylamino)methylene]malonic acid diethyl ester precipitated from solution, which was separated by filtration, washed with diethyl ether and air-dried (27.2 g, 89%): δH (400 MHz, CDCl3) 1.35 (3H, t, J 7.2), 1.39 (3H, t, J 7.0), 4.28 (2H, q, J 7.2), 4.33 (2H, q, J 7.2), 7.03 (1H, d, J 8.2), 7.38 (1H, d, J 7.4), 7.82 (1H, t, J 8.1), 9.12 (1H, d, J 12.9), 11.20 (1H, d, J 12.5). m/z (ES+) 333 [MH]+, 287 [M-EtO]+
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([O:11]C)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.Cl>C(Cl)Cl>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](=[O:19])[C:8]2[CH:7]=[CH:6][C:5]([OH:11])=[CH:10][CH:9]=2)=[CH:16][CH:15]=1
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
510 g of aluminium chloride (3.82 M), then 3.5 l of dry methylene chloride, and, slowly, 430 g (4 M) of anisole are added to a 5-liter flask; the flask is cooled to maintain the temperature at about 25° C, and 600 g (3.44 M) of 4-chlorobenzoyl chloride is then added dropwise; the reaction mixture is next heated 6 hours under reflux, is left to cool to about 25° C, and the reaction mixture is poured onto 5 kg of ice and 0.5 l of concentrated HCl; the mixture is stirred well during this hydrolysis; the methylene chloride phase is decanted, washed once with water, and transferred to another 5-liter vessel. The methylene chloride is removed by evaporation and replaced in the flask by 2 l of chlorobenzene; a Dean-Stark apparatus is connected and the reaction mixture is refluxed to dehydrate the medium; when this operation is complete the mixture is cooled to approximately 50° C and 800 g (6 M) of aluminium chloride is added; the reaction mixture is heated 1 hour 30 minutes under reflux (very gentle reflux), and demethylation proceeds rapidly; the reaction mixture is cooled and poured onto 6 kg of ice and 0.5 l of concentrated HCl; the mixture is stirred for 1 hour 30 minutes and the precipitate is dried; the latter is washed with water, with methylene chloride, and then dried:
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(Cl)=[O:4].[CH2:16]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C@@H:31]([NH:34][C:35](=[O:48])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:32][OH:33])=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(CC)CC>C1COCC1>[CH3:1][O:2][P@@:3]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:4])[O:33][CH2:32][CH:31]([NH:34][C:35](=[O:48])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[CH2:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:25][CH:26]=1
Reactant: COP(=O)(Cl)CCCOc1ccccc1
Reactant: O=C(CCCCCCc1ccccc1)N[C@@H](CO)Cc1ccc(OCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CO[P@](=O)(CCCOc1ccccc1)OCC(Cc1ccc(OCc2ccccc2)cc1)NC(=O)CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
With ice-bath cooling, phosphonochloridate 53 (123 mg, 0.50 mmol) in dry THF (1.0 mL) was added dropwise to a solution of 55 (100 mg, 0.22 mmol) and Et3N (94 μL, 0.67 mmol) in dry THF (0.5 mL). After 10 min, the mixture was warmed to rt and stirred overnight. The Et3N.HCl precipitate was removed by filtration and the solvent evaporated under reduced pressure. The residue was dissolved in EtOAc, washed successively with KHSO4 (5% w/v), saturated NaHCO3, water, brine and dried (MgSO4). The solvent was removed in vacuo and the residue (209 mg) was purified on a C-18 reverse phase column to provide a diastereomeric mixture of 56a,b (82 mg, 56%) as an oil.
Reaction SMILES: [CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=O)=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:17](N1C=CN=C1)(N1C=CN=C1)=[S:18]>C(OCC)(=O)C.C(Cl)Cl.[Pd]>[CH3:1][N:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:17]=[S:18])=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CN(C)c1ccc(N=O)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CN(C)c1ccc(N=C=S)cc1

Procedure:
A solution of 14.7 g (66 mmol) of ethyl N-methyl-N-(4-nitrosophenyl)glycinate in 200 mL of ethyl acetate was reduced (10% Pd/C, 50 psi H2) until uptake was complete, dried 1 hr (Na2SO4), filtered, concentrated, and dissolved in a solution of 12.5 g (70 mmol) of thiocarbonyldimidazole in 100 mL CH2Cl2 /300 ml toluene. When tlc showed only product (2 hr,Rf 0.6, CH2Cl2), the solution was washed with 2×100 mL of water, passed throug a silica plug to remove color, and recrystallized from hexane (300 mL) to give 13.6g (54 mmol, 82%) mp 90-91°. Anal. C12H14N2O2S (250): Calcd.: C,57.58; H,5.64; N,11.19; S,12.81. Found: C,57.63; H,5.59; N,11.17; S,12.49. MS(FD) m/z250. 1H NMR(CDCl3)δ: 7.10,d,2H,ArH; 6.58,d,2H,ArH; 4.18,q,2H,CH2 --O; 4.05,s,2H,CH2 --N; 3.07,s,3H,CH3 --N; 1.25,s,3H,CH3 --C.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1.N([O-])=O.[Na+].[BrH:21]>O1CCOCC1.O.[Cu]Br>[Br:21][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:7]=1
Reactant: N#Cc1ccccc1-c1cc(N)ccc1F
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1ccccc1-c1cc(Br)ccc1F
Temperature: 2 °C

Procedure:
To a solution of 5′-amino-2′-fluorobiphenyl-2-carbonitrile (11.17 g, 52.6 mmol) in 1,4-dioxane (60 ml) was added 48% hydrobromic acid (250 ml) and the resulting suspension was cooled to 2° C., whilst stirring with an air stirrer. To this was added, dropwise over 20 min, a solution of sodium nitrite (4.18 g, 60.6 mmol) in water (11 ml), keeping the temperature below 5° C. The mixture was then stirred at 2±2° C. for 2 h before adding a cooled (5° C.) solution of freshly purified copper(I) bromide (25.40 g, 177.1 mmol) in 48% hydrobromic acid (75 ml). The mixture was stirred at 1±1° C. for 10 min before heating to 47° C. over 1 h. The mixture was diluted with ice-cold water (1.25 l) and extracted with ethyl acetate (2×500 ml). The combined organic extracts were washed with 1 M aqueous Na2SO3 (100 ml), then saturated aqueous NaCl (100 ml), dried (MgSO4) and evaporated in vacuo to leave 16.08 g of 5′-bromo-2′-fluorobiphenyl-2-carbonitrile as a light brown solid: 1H NMR (360 MHz, CDCl3) δ 7.12 (1H, t, J 9.1 Hz), 7.47-7.57 (4H, m), 7.68 (1H, td, J 7.7, 1.3 Hz), 7.79 (1H, d, J 7.8 Hz).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[C:25]([O:26][CH3:27])=[CH:24][C:16]3[CH2:17][CH2:18][O:19][C:20](=[O:23])[N:21]([CH3:22])[C:15]=3[CH:14]=2)[N:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH:33]=[CH:32][C:31]=1[NH2:42]>>[CH3:27][O:26][C:25]1[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:42][C:31]3[CH:32]=[CH:33][C:34]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:35][C:30]=3[O:29][CH3:28])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][C:15]2[N:21]([CH3:22])[C:20](=[O:23])[O:19][CH2:18][CH2:17][C:16]=2[CH:24]=1
Reactant: COc1cc(N2CCOCC2)ccc1N
Reactant: COc1cc2c(cc1Nc1ncc(C(F)(F)F)c(Cl)n1)N(C)C(=O)OCC2
Product: COc1cc2c(cc1Nc1ncc(C(F)(F)F)c(Nc3ccc(N4CCOCC4)cc3OC)n1)N(C)C(=O)OCC2
Yield: 43 %

Procedure:
In an analogous manner to Example 1513, the product was prepared from 3-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-2-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 2-Methoxy-4-morpholin-4-yl-phenylamine. Product was isolated as a white solid (55 mg, 43%). mp: 221-223° C., MS (ESI+): 575 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.38 (s, 1H), 8.30 (s, 1H), 7.83 (s, 1H), 7.68 (s, 1H), 7.60 (br d, 1H), 7.03 (s, 1H), 6.63 (s, 1H), 6.32 (br d, 1H), 4.36 (t, J=6 Hz, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 3.75 (m, 4H), 3.11 (m, 4H), 3.01 (s, 3H), 2.93 (t, J=6 Hz, 2H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([C:27](=[O:29])[CH3:28])[C@@H:10]([CH3:30])[CH2:9]1)=[O:7].[N:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.[F-].[Cs+]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:36]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:37])[CH:16]=2)[N:11]([C:27](=[O:29])[CH3:28])[C@@H:10]([CH3:30])[CH2:9]1)=[O:7]
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2N(C(=O)c2ccco2)C[C@@H]1C
Reactant: O=C(Cl)N1CCCC1
Agent: [Cs+]
Agent: [F-]
Product: CC(=O)N1c2ccc(C(=O)N3CCCC3)cc2N(C(=O)c2ccco2)C[C@@H]1C
Temperature: 80 °C
Yield: 7.9 %

Procedure:
A 1.5 mL reaction vial was charged with (S)-1-(4-(furan-2-carbonyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoxalin-1 (2H)-yl)ethanone (0.2 M in 1,4-dioxane, 150 μL, 0.03 mmol), and pyrrolidine-1-carbonyl chloride (4 mg, 0.030 mmol). Cesium fluoride was then added (5 mg, 0.030 mmol) and the reaction mixture was purged with nitrogen. Bis(triphenylphosphine)palladium(II) dichloride (1 mg, 0.0015) was then added, and the reaction was purged with nitrogen and heated overnight at 80° C. on a heater shaker. The reaction was diluted with ethyl acetate (0.5 mL) washed with brine (0.5 mL). The aqueous layer was separated and washed with ethyl acetate (1 mL) and the combined organic layers were concentrated under a stream of nitrogen. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford (S)-1-(4-(furan-2-carbonyl)-2-methyl-6-(pyrrolidine-1-carbonyl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.0009 g, 8%). MS (ESI, pos. ion) m/z 382.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[O:18])=[CH:12][CH:11]=2)[CH:4]=1.[CH2:27](C1C=CC(N=C=O)=CC=1)C>>[CH2:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][C:5]3[CH:4]=[C:3]([NH:2][CH3:1])[N:8]=[CH:7][N:6]=3)=[CH:15][CH:14]=2)=[O:18])=[CH:25][CH:24]=1)[CH3:27]
Reactant: CCc1ccc(N=C=O)cc1
Reactant: CNc1cc(Cc2ccc(NC(=O)Nc3ccc(C)cc3)cc2)ncn1
Product: CCc1ccc(NC(=O)Nc2ccc(Cc3cc(NC)ncn3)cc2)cc1
Reaction time: 6 h

Procedure:
The title compound Is prepared as described in Example 102 but using [6-(4-amino-benzyl)-pyrimidin-4-yl]-methyl-amine (Example 119) and 4-ethyl-phenyl-isocyanate. The reaction mixture is stirred for 6 h. The title compound is obtained as a white solid: ES-MS: 362.0 [M+H]+; single peak at tR=7.14 min (System 2).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:11]1C(CCl)=CC=C(Cl)[N:12]=1>>[Cl:1][C:2]1[C:7]([CH2:8][NH:12][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: ClCc1cccnc1Cl
Reactant: ClCc1ccc(Cl)nc1Cl
Product: CNCc1cccnc1Cl

Procedure:
The reaction according to Reference Example 11 was carried out using (2-chloro-3-pyridyl)methyl chloride in lieu of 2,6-dichloro-3-pyridylmethyl chloride to give the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)c(Cl)nc1Cl

Procedure:
A solution of commercially available (Aldrich) 2,6-dichloro-5-fluoronicotinic acid (5.00 g, 23.8 mmol) in thionyl chloride (15 mL) was heated at reflux for 3 h. After cooling, the solution was concentrated in vacuo to give 2,6-dichloro-5-fluoronicotinoyl chloride as a brown oil which was carried on to the next step without further purification. This transformation can also be accomplished using oxalyl chloride with catalytic DMF in place of thionyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12]O.Cl>>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: CO
Reactant: Nc1c(Cl)cccc1C(=O)O
Agent: Cl
Product: COC(=O)c1cccc(Cl)c1N
Temperature: 65 °C
Reaction time: 10 h
Yield: 75 %

Procedure:
5.13 g (0.03 mol) of 2-amino-3-chlorobenzoic acid and 24 ml (0.59 mol) of methanol were added to a 100 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer, and a dropping funnel, and a hydrogen chloride gas was blown in with stirring at 65° C. After 10 hours, the reaction solution was analyzed by HPLC by the absolute calibration method, and as a result, the yield was 75%.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)[CH3:3].[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=O)[CH3:17]>>[CH2:2]([O:4][C:5]1[CH:10]=[C:9]2[C:8](=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)[NH:11][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[CH:17]2)[CH3:3]
Reactant: CC(=O)c1ccccn1
Reactant: CCOc1ccc(NN)c([N+](=O)[O-])c1
Agent: Cl
Product: CCOc1cc([N+](=O)[O-])c2[nH]c(-c3ccccn3)cc2c1
Yield: 8.4 %

Procedure:
(4-Ethoxy-2-nitrophenyl)hydrazine hydrochloride (5 g, 21 mmol) and 2-acetylpyridine (2.4 ml, 21 mmol) were reacted according to the same procedures as Preparations 4 to 5 to give the title compound (0.5 g, Yield 8%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6](=[N:8][OH:9])[NH2:7])#[N:2].[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:22]=1)[C:19](Cl)=O.N>>[Br:13][C:14]1[CH:22]=[C:18]([C:19]2[O:9][N:8]=[C:6]([C:5]3[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=3)[C:1]#[N:2])[N:7]=2)[CH:17]=[N:16][CH:15]=1
Reactant: O=C(Cl)c1cncc(Br)c1
Reactant: N#Cc1cccc(C(N)=NO)c1
Agent: N
Product: N#Cc1cccc(-c2noc(-c3cncc(Br)c3)n2)c1

Procedure:
The title compound was prepared according to the procedure of Example 4B using 3-cyano-N′-hydroxybenzimidamide and 5-bromonicotinoyl chloride (Alfa). 1H NMR (300 MHz, DMSO-d6) δ 7.67 (m, 1H), 7.74 (m, 1H), 8.41 (m, 1H), 8.49 (m, 1H), 8.64 (s, 1H), 8.93 (s, 1H), 9.4 (s, 1H) ppm; MS (DCl/NH3) m/z 327 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:4][NH:3][O:2][CH3:1])=[CH:6][CH:7]=1
Reactant: CON=Cc1ccc(OC)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CONCc1ccc(OC)cc1
Yield: 96 %

Procedure:
Reduction of 4-methoxybenzaldehyde O-methyloxime with sodium cyanoborohydride as described in the preparation of Compound 44-B gave the title hydroxylamine as a clear oil (96% yield). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.49 (3H, s, OCH3), 3.79 (3H, s, OCH3), 3.98 (2H, s, NCH2), 5.62 (1H, broad s, NH), 6.86 (2H, m, aromatics), 7.25 (2H, m, aromatics). The hydrochloride salt was obtained as a white solid: mp 157–158° C. (dec.). Anal. calcd. for C9H13NO2—HCl: C, 53.03; H, 6.92; N, 6.87. Found: C, 53.14; H, 6.76; N, 6.80.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:43])=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([Cl:43])=[O:10])[C:5]2[C:11]([O:33][CH3:34])=[N:12][N:13]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:4]=2[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)O)c12
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)Cl)c12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carboxylic acid (Intermediate 36B, 440 mg, 0.936 mmol) was taken up in DCM (9.32 ml). DMF (93 n1) was added and the reaction was cooled to 0° C. Oxalyl chloride (164 μl, 1.873 mmol) was added and the mixture was allowed to stir for 1 hr eventually reaching room temperature. The mixture was concentrated in vacuo and then further dried under high vacuum. The residue was carried forward without further purification. MS: [M+H]+ m/z 484 (Methyl ester formed LCMS, sample prepared in MeOH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:26][C@@:24]3([CH3:25])[C@@H:20]([CH2:21][CH2:22][C:23]3=[O:27])[C@H:19]3[C@H:10]2[C@@H:11]2[C:16]([CH2:17][CH2:18]3)=[CH:15][C:14](=[O:28])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[CH2:29](OC(OCC)OCC)[CH3:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl.C(O)C>[CH2:29]([O:28][C:14]1[CH2:13][CH2:12][C@H:11]2[C:16](=[CH:17][CH2:18][C@@H:19]3[C@@H:10]2[C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:26][C@@:24]2([CH3:25])[C@H:20]3[CH2:21][CH2:22][C:23]2=[O:27])[CH:15]=1)[CH3:30]
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc([C@H]2C[C@]3(C)C(=O)CC[C@H]3[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]32)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC1=CC2=CC[C@@H]3[C@H]([C@@H](c4ccc(OC)cc4)C[C@]4(C)C(=O)CC[C@@H]34)[C@H]2CC1
Reaction time: 3.5 h

Procedure:
10 g of 11β-(4-methoxyphenyl)-4-oestrene-3,17-dione are placed in a mixture of 260 ml of absolute methylene chloride, 29 ml of ethanol and 26.4 ml of orthoformic acid triethyl ester and, at 0° C., 100 mg of p-toluenesulphonic acid (monohydrate) are added. The whole is then stirred for 3.5 hours at ice-bath temperature and then an excess of saturated sodium hydrogen carbonate solution is added to the reaction mixture. The aqueous phase is extracted repeatedly with methylene chloride and the combined organic phases are dried over sodium sulphate and concentrated in vacuo. The crude product is used directly in the subsequent reaction step. 10.8 g of crude 3-ethoxy-11β-(4-methoxyphenyl)-3,5-oestradien-17-one are isolated.