Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:20]([CH3:22])[CH3:21])[C:13]([O:15]C(C)(C)C)=[O:14])[C:8](=[O:23])[C:7]3=[CH:24][N:25](S(C4C=CC(C)=CC=4)(=O)=O)[C:5]([C:6]=23)=[N:4][CH:3]=1.CCO.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:20]([CH3:21])[CH3:22])[C:13]([OH:15])=[O:14])[C:8](=[O:23])[C:7]3=[CH:24][NH:25][C:5]([C:6]=23)=[N:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(Cl)cnc42)CN([C@@H](C(=O)OC(C)(C)C)C(C)C)C3=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)[C@H](C(=O)O)N1Cc2c(Cl)cnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 110.5 %

Procedure:
A mixture of (R)-tert-butyl 2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoate (650 mg, 1.25 mmol), EtOH (4 mL), and aqueous NaOH (1N, 2 mL) was stirred at room temperature for 40 min. The mixture was subsequently diluted with DCM and washed with brine. The organics were dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (5% MeOH/DCM) gave a yellow oil (425 mg), which was dissolved in 50% TFA/DCM. The solution was stirred at room temperature for 1 h, concentrated, and dried under vacuum to give the title compound as a yellow solid (360 mg, 93%). 1H NMR (500 MHz, CD3OD) δ 0.91 (d, J=7.0 Hz, 3H), 1.11 (d, J=7.0 Hz, 3H), 2.36-2.47 (m, 1H), 4.80-5.08 (m, 3H), 7.76 (s, 1H), 8.19 (s, 1H). [M+H] calc'd for C14H14ClN3O3, 308, 310; found, 308, 310.
Reaction SMILES: [Br:1][C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([C:8](=[O:16])[NH:9][C:10]3=[O:15])[C:6]=2[C:5]([O:17][CH3:18])=[CH:4][CH:3]=1.[CH2:19](I)[CH3:20]>>[Br:1][C:2]1[C:14]2[CH2:13][CH2:12][CH:11]3[CH:7]([C:8](=[O:16])[N:9]([CH2:19][CH3:20])[C:10]3=[O:15])[C:6]=2[C:5]([O:17][CH3:18])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)c2c1C1C(=O)NC(=O)C1CC2
Reactant: CCI
Product: CCN1C(=O)C2CCc3c(Br)ccc(OC)c3C2C1=O

Procedure:
Using the procedure of example 64, but starting with 6-bromo-3a,4,5,9b-tetrahydro-9-methoxy-1H-benz[e]isoindole-1,3-(2H)-dione and ethyl iodide instead of methyl iodide afforded the desired compound; M+ 337; mp 170°-4°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([O:32]C)=[O:31])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[C:11]2[C:6]([C:7](=[O:36])[CH2:8][C:9]([CH3:35])([CH3:34])[O:10]2)=[CH:5][CH:4]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:16][CH2:17][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([OH:32])=[O:31])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:19][CH2:20]2)=[C:11]2[C:6]([C:7](=[O:36])[CH2:8][C:9]([CH3:34])([CH3:35])[O:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c4OC(C)(C)CC5=O)CC3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(c1CCN1CCC(n3ccc4ccc(C(=O)O)cc43)CC1)OC(C)(C)CC2=O
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
3.5 g of the above crude product of methyl 1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxylate was dissolved in 28.0 mL of tetrahydrofuran and added with 14 mL of 1 N aqueous sodium hydroxide. 14 mL of methanol was added and the mixture was heated to 40° C. and stirred for 30 minutes. 7 mL of tetrahydrofuran and 3.5 mL of methanol were added and the mixture was stirred for 2 hours and further stirred at the same temperature for about 16 hours. When the reaction mixture was cooled with an ice-water bath and the pH was adjusted to 7 with 12.2 mL of 1 N hydrochloric acid and 0.5 mL of 1 N sodium hydroxide, crystals precipitated. 10 mL of water was further added to this slurry, and crystals were obtained by filtration and the crystals were washed with 21 mL of a mixture of 2-propanol and water (5:1). The crystals were dried in vacuo and 2.45 g of the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:32])=[CH:3][CH2:4][N:5]1[C:9]2[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=2[N:7]=[C:6]1[N:17]1[CH2:21][CH:20]2[CH2:22][N:23]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:24][CH:19]2[CH2:18]1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:6]([N:17]3[CH2:18][CH:19]4[CH2:24][N:23]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:22][CH:20]4[CH2:21]3)[N:5]([CH2:4][CH:3]=[C:2]([CH3:32])[CH3:1])[C:9]=2[CH:10]=1
Reactant: CC(C)=CCn1c(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)=CCn1c(N2CC3CN(C(=O)OC(C)(C)C)CC3C2)nc2ccc(N)cc21
Yield: 85 %

Procedure:
A solution of 44 mg (0.10 mmol of tert-butyl 5-[1-(3-methylbut-2-enyl)-6-nitro-1H-benzimidazol-2-yl]hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate in 7.5 ml of ethanol was added dropwise to a suspension of 56 mg (1.00 mmol) of iron and 10 mg (0.18 mmol) of ammonium chloride in 0.75 ml of water, and the mixture was boiled at reflux for 3 hours. The catalyst was filtered off and washed with ethanol. The filtrate was concentrated under reduced pressure. The 35 mg of the desired product thus obtained were used in the next stage without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]=[C:8](S(C)(=O)=O)[N:7]=1)=[O:5])C.[CH3:18][CH2:19][O-:20].[Na+]>C(O)C>[CH2:19]([O:20][C:8]1[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:11]=[C:10]([CH2:12][CH3:13])[N:9]=1)[CH3:18]
Reactant: CC[O-]
Reactant: CCOC(=O)c1cc(CC)nc(S(C)(=O)=O)n1
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(CC)cc(C(=O)O)n1
Reaction time: 2 h
Yield: 45.7 %

Procedure:
To a solution of 6-ethyl-2-methanesulfonyl-pyrimidine-4-carboxylic acid ethyl ester (100 mg, 0.39 mmol) in ethanol (4 mL), sodium ethylate (134 mg, 1.94 mmol) is added. The reaction mixture is stirred for 2 h, ethanol is evaporated and the residue is dissolved in EtOAc (25 mL). The org. solution is washed with 1M aq. KHSO4, followed by brine, dried over MgSO4, filtered and evaporated give 2-ethoxy-6-ethyl-pyrimidine-4-carboxylic acid as a yellow oil (35 mg); LC-MS: tR=0.72 min, [M+H]+=197.07.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH:5]([CH2:7][CH2:8][CH3:9])[CH2:4][N:3]1[CH2:10][C:11]1[N:15]([CH2:16][C:17]([OH:19])=O)[CH:14]=[N:13][CH:12]=1.C(N(CC)CC)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH2:27]([NH:34][C:17](=[O:19])[CH2:16][N:15]1[C:11]([CH2:10][N:3]2[CH2:4][CH:5]([CH2:7][CH2:8][CH3:9])[CH2:6][C:2]2=[O:1])=[CH:12][N:13]=[CH:14]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCC1CC(=O)N(Cc2cncn2CC(=O)O)C1
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCC1CC(=O)N(Cc2cncn2CC(=O)NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
In a 10 ml, three necked flask fitted with a magnetic stirrer, under inert atmosphere, {5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetic acid x50 (0.1 g, 0.33 mmol) is dissolved in DMF (1 ml). Triethylamine (0.1 ml, 0.66 mmol), benzylamine (37 μl, 0.33 mmol) and TBTU (0.16 g, 0.33 mmol) are added and the mixture is stirred for 0.5 h at room temperature. An additional amount of benzylamine (0.0165 mmol) is added and stirring is continued overnight. The solvent is evaporated and the residue is purified by chromatography on silicagel (AcOEt/MeOH/NH4OH: 90/9/1 (v/v/v)). The product is treated with a methanolic solution of HCl and the obtained solid is recrystallized from acetonitrile to afford N-benzyl-2-{5-[(2-oxo-4-propylpyrrolidin-1-yl)methyl]-1H-imidazol-1-yl}acetamide 124.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:16]1([S:22]([C:25]2[CH:30]=[CH:29][C:28](F)=[C:27]([F:32])[CH:26]=2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[F:32][C:27]1[CH:26]=[C:25]([S:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:23])=[O:24])[CH:30]=[CH:29][C:28]=1[O:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: O=C(O)Cc1cc(O)cc(C(F)(F)F)c1
Reactant: O=S(=O)(c1ccccc1)c1ccc(F)c(F)c1
Product: O=C(O)Cc1cc(Oc2ccc(S(=O)(=O)c3ccccc3)cc2F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in example 2 step (iii) but instead using the product from example 25 step (iv) and the product from example 24 step (i).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=O.[CH:21]([N:24]1[CH2:29][CH2:28][N:27]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:32]=2[C:38]([F:41])([F:40])[F:39])[CH2:26][CH2:25]1)([CH3:23])[CH3:22]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][N:27]2[CH2:26][CH2:25][N:24]([CH:21]([CH3:23])[CH3:22])[CH2:29][CH2:28]2)=[C:32]([C:38]([F:41])([F:40])[F:39])[CH:33]=1)=[O:20]
Reactant: CC(C)N1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1Cl
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCN(Cc2ccc(NC(=O)Cc3ccc(-n4cnc5cccnc54)cc3Cl)cc2C(F)(F)F)CC1

Procedure:
The title compound is prepared as described in Example 1 but using (2-chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid and 4-(4-isopropyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (see WO 03/099771). Title compound: ES-MS: 570.9 [M+H]+; single peak at tR=3.46 min (System 1); Rf=0.26 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[O:5][N:4]=1.[N-:16]=[N+]=[N-].[Na+].O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][NH2:16])[N:7]=2)=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2nc(CCl)no2)cc1
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(CN)no2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-chloromethyl-5-(4-methoxy-phenyl)-[1,2,4]oxadiazole (8.90 mmol) in N,N-dimethylformamide (10 mL) was added sodium azide (17.8 mmol). This mixture was stirred at room temperature for 20 hours. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (3×). The combined organic extracts were combined and washed with water (2×), dried over anhydrous sodium sulfate, and evaporated. Then clear oily residue was placed under high vacuum and gently warmed for 18 hours. Upon cooling the material solidified. This solid was dissolved in tetrahydrofuran (15 mL) and treated with triphenylphosphine (9.0 mmol). Bubbling was immediately evident. This mixture was stirred for 16 hours and then treated with water (3.0 mL). This was heated in a 45° C. oil bath for 3 hours. The product was purified by flash chromatography (silica gel; 2:1 ether/dichloromethane), m.p. 66-68° C.
Reaction SMILES: ClCC([NH:5][CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[OH:16])=O.Cl.O.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:5][CH2:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[OH:16]
Reactant: O=C(CCl)NCc1cc([N+](=O)[O-])ccc1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NCc1cc([N+](=O)[O-])ccc1O

Procedure:
12.2 g (0.056 mole) of chloroacetamido compound of step 1 is heated in 100 ml ethanol and 30 ml concentrated hydrochloric acid for 4 hours accompanied by refluxing. After dilution with water, it is neutralized with sodium bicarbonate and the precipitate is separated by suction, accompanied by rewashing with water. The residue is purified by means of reprecipitation. 3 g of the substance is dissolved hot in 25 ml water/5 ml glacial acetic acid. After cooling, it is filtrated and the filtrate is neutralized with ammonia. The pure amimomethyl compound separates out, it is isolated by means of suction and washed with water and isopropanol.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:8]=2[NH:7][CH:6]=1)C.[OH-].[Na+].[N+:24]([CH:27]([CH3:29])[CH3:28])([O-:26])=[O:25]>CCOCC>[CH3:28][C:27]([N+:24]([O-:26])=[O:25])([CH3:29])[CH2:4][C:5]1[C:9]2[C:8](=[C:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:12]=[CH:11][CH:10]=2)[NH:7][CH:6]=1
Reactant: CN(C)Cc1c[nH]c2c(OCc3ccccc3)cccc12
Reactant: CC(C)[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)(Cc1c[nH]c2c(OCc3ccccc3)cccc12)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 29 h
Yield: 92.1 %

Procedure:
A mixture of 7-benzyloxy gramine (1.99 g, 7.10 mmol), solid NaOH (298 mg, 7.22 mmol) and 2-nitropropane (4.5 mL, 50 mmol) is heated to reflux. After 10 minutes at reflux, a thick slurry developed which is difficult to stir. Gas evolution is observed, and an additional 1 mL of 2-nitropropane is added to loosen the mixture. After 29 hours, the mixture is allowed to cool to ambient temperature. Ether (30 mL) is added and the mixture is filtered. The filtrate is treated with 10% acetic acid (6 mL), the layers are separated and the organic layer is rinsed with water (2×25 mL). The organic layer is dried (Na2SO4) and concentrated to give 2.12 g of 3-(2-methyl-2-nitropropyl)-7-(benzyloxy)indole (92%). MS (ES+) m/z 325.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2[CH:36]=[CH:37][CH:38]=[N:39][C:34]=2[CH2:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)c(Cl)c3)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h
Yield: 47.6 %

Procedure:
To a solution of 1-(3,4-dichloro-phenyl)-piperazine (0.14 g, 0.601 mmol) in isopropanol (6.0 mL) was added 2,6-lutidine (95 uL, 0.802 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a, d]cyclohepten-7-yl]-propan-2-ol (0.37 g, 1.0 mmol), added in three portions over 2 h. The reaction was then stirred at 80° C. for 18 hours. The reaction was concentrated in vacuum, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% methanol) to yield the title compound as a white solid (0.15 g, 69%). 1H-NMR (MeOD) δ: 1.55 (6H, s), 2.35-2.65 (8H, m), 3.15-3.25 (4H, m), 5.30 (2H, br s), 6.20 (1H, t), 6.82 (1H, dd), 7.23-7.55 (5H, m), 7.59 (1H, d), 8.50 (1H, dd).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[H-].[Na+].[CH:12]1([O:17][C:18]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[N:21][NH:22][CH:23]3Cl)[CH2:16][CH2:15][CH2:14][CH2:13]1>CN(C)C=O>[CH:12]1([O:17][C:18]2[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[N:21][N:22]=[C:23]3[CH2:8][C:7]2[C:6]([Cl:9])=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COc1ccc2c(c1OC1CCCC1)C=NNC2Cl
Reactant: Cc1c(Cl)cncc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Cc3c(Cl)cncc3Cl)nncc2c1OC1CCCC1
Reaction time: 1 h
Yield: 57.1 %

Procedure:
A solution of 3,5-dichloro-4-methyl-pyridine (13.86 g, 85.56 mmoles) in dry dimethylformamide (100 ml) was added, under nitrogen and stirring, with 55% NaH (3.73 g, 85.56 mmoles). The mixture was stirred for 1 hour then added with a solution of 5-cyclopentyloxy-1-chloro-6-methoxy-2H-phthalazine (7.95 g, 28.52 mmoles), obtained as described in example 7, in dry dimethylfomamide (70 ml). The mixture was left to stand for one night, quenched with water, diluted with water and extracted methyl aceate. The extract was washed with water and anhydrified over Na2SO4, then evaporated to dryness. The residue was flash chromatographed (eluent:petrolatum/ethyl acetate 1:1) to give 6.58 g of the title product (yield: 57%).
Reaction SMILES: C[Mg]Br.[CH:4]1([NH:8][C:9]2[C:14]([C:15]#[N:16])=[CH:13][N:12]=[C:11]([S:17][CH3:18])[N:10]=2)[CH2:7][CH2:6][CH2:5]1.[CH3:19][C:20](OC(C)=O)=[O:21]>C1(C)C=CC=CC=1>[C:15]([C:14]1[C:9]([N:8]([CH:4]2[CH2:5][CH2:6][CH2:7]2)[C:20](=[O:21])[CH3:19])=[N:10][C:11]([S:17][CH3:18])=[N:12][CH:13]=1)#[N:16]
Reactant: CSc1ncc(C#N)c(NC2CCC2)n1
Reactant: CC(=O)OC(C)=O
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Product: CSc1ncc(C#N)c(N(C(C)=O)C2CCC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
A solution of methyl magnesium bromide (3.0 M in Et2O, 0.58 mL, 1.75 mmol) was added, at RT, to a solution of 4-cyclobutylamino-2-methylsulfanyl-pyrimidine-5-carbonitrile (350 mg, 1.59 mmol) in toluene (32 mL) and the resulting mixture was stirred for 30 min. Ac2O (3.0 mL, 31.8 mmol) was then added and the reaction mixture was heated at reflux for 5 days. The reaction mixture was then cooled to RT, quenched with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc/hexane, 0/100 to 30/70 in 10 min) to afford 207 mg (50% yield) of N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-N-cyclobutyl-acetamide as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][CH3:15])[CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18](/[CH:22]=[CH:23]/[C:24](O)=[O:25])[CH:17]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([S:14][CH3:15])[CH2:12][NH:13][C:24](=[O:25])/[CH:23]=[CH:22]/[C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(CN)SC)cc1OC
Reactant: O=C(O)/C=C/c1cccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(C(CNC(=O)/C=C/c2cccnc2)SC)cc1OC
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
To a solution of the crude oily 2-(3,4-dimethoxy-phenyl) -2-(methylthio)ethylamine (0.96 g) and trans-3-(3-pyridyl) acrylic acid (0.63 g, 4.2 mmol) in dimethylformamide (10 ml), diethylphosphoric cyanide (0.69 ml) and triethylamine (1.17 ml) were sequentially added under ice-cooling and stirred for 10 minutes under ice-cooling. Aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The organic layers were combined, washed with water and aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled out under reduced pressure and the residue was purified by silica gel column chromatography (hexane: chloroform:ethanol=8:2:1) to yield the titled compound (788 mg, 47%).
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].Br[CH2:15][CH:16]=[CH:17][CH2:18][CH3:19]>>[CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([CH2:15][CH:16]=[CH:17][CH2:18][CH3:19])[C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: CCC=CCBr
Product: CCC=CCn1c(C)c(C)c(C=O)c1C(=O)OC

Procedure:
The title compound (trans) was prepared as a yellow-orange oil in 85.1% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1-bromo-2-pentene (trans).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].[CH:24](=O)[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Reactant: COc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (150 mg, 0.485 mmol) in dimethylformamide (3 mL) was added p-anisaldehyde (79.2 mg, 0.582 mmol) and oxone (179 mg, 0.291 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, and after this was filtered and washed with water, drying yielded the title compound (184 mg, 89% yield) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:19]([CH3:21])[CH3:20])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:22]>O1CCOCC1>[NH2:22][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:19]([CH3:21])[CH3:20])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: COc1ccc(-c2cn(C(C)C)c3ncnc(Cl)c23)cc1
Solvent: C1COCCO1
Product: COc1ccc(-c2cn(C(C)C)c3ncnc(N)c23)cc1
Temperature: 120 °C

Procedure:
A mixture of 4-chloro-7-isopropyl-5-(4-methoxyphenyl)pyrrolo-[2,3-d]pyrimidine (1.6 g), concentrated ammonia (80 ml, S.G. 0.880) and 1,4-dioxane (80 ml) was heated in a pressure vessel at 120° C. for 18 hours. The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure to give a solid residue which was partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, dried, filtered and evaporated to give 4-amino-7-isopropyl-5-(4-methoxyphenyl)pyrrolo[2,3-d]-pyrimidine. The structure was confirmed by 1H nmr.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:27][C@H:26]([CH3:28])OS1(=O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:26]([CH3:28])[CH2:27][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:8]2[C:13]([CH:14]=1)=[C:12]([Cl:15])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2c(Cl)cccc2[nH]1
Product: CCOC(=O)c1cc2c(Cl)cccc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound, m.p.: 115–119° C., ISP-MS: m/e=381.3 (M+H+) and αD20=−8.0, was prepared in accordance with the general method of example 12b) from 4-chloro-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[F:24][C:21]([F:22])([F:23])[C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([NH2:1])[C:5]=2[CH:6]=[CH:7][N:8]=1
Reactant: O=[N+]([O-])c1cccc2c(Oc3cccc(C(F)(F)F)c3)nccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)nccc12
Yield: 94.7 %

Procedure:
The title compound was prepared following the procedure described in Step 3 of Intermediate-1 using 5-nitro-1-(3-(trifluoromethyl)phenoxy)isoquinoline (200 mg, 0.59 mmol), iron powder (267 mg, 4.7 mmol), and NH4Cl (312 mg, 5.9 mmol) in EtOH (4 mL) and water (1 mL) to afford 170 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 7.79 (d, J=5.7 Hz, 1H), 7.70-7.50 (m, 6H), 7.40 (t, J=7.8 Hz, 1H), 6.93 (d, J=7.2 Hz, 1H), 6.02 (br s, 2H).