Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:6]([CH2:14]Cl)[C:5]=1[OH:16])(=[O:3])[CH3:2].[OH-:17].[K+].Cl>C(O)C.O>[C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)=[C:6]([CH2:14][OH:17])[C:5]=1[OH:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(c(CCl)c1O)CCCC2
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(=O)c1cc2c(c(CO)c1O)CCCC2

Procedure:
To a solution of the product of step (a) (23.8 g) in ethanol (500 ml) was added a solution of potassium hydroxide (11.2 g) in ethanol (250 ml) and water (100 ml). The resulting mixture was heated on a steam bath for 30 minutes, poured into water (2 l) and the mixture was made acid with concentrated hydrochloric acid. It was then extracted with ethyl acetate and the extracts were dried (MgSO4), filtered and the filtrate was evaporated to dryness leaving 7-acetyl-1,2,3,4-tetrahydro-6-hydroxy-5-hydroxymethylnaphthalene as an oil, 21 g (95%).
Reaction SMILES: B.C1COCC1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@H]2N1CCC2.Br.[Br:29][CH2:30][C:31]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:32]>O1CCCC1>[Br:29][CH2:30][C@@H:31]([C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[OH:32]
Reactant: O=C(CBr)c1cccnc1
Agent: B
Agent: Br
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@@H]2CCCN12
Solvent: C1CCOC1
Product: O[C@@H](CBr)c1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
A solution of borane-THF (1.0 M solution, 22.8 mL) was added dropwise into a cold (0° C.) solution of (S)-2-methyl-CBS-oxazaborolidine monohydrate (1.12 g, 3.8 mmol) in tetrahydrofuran (20 mL), over a period of 10 minutes. After stirring at 0° C. for 10 minutes, the mixture was added dropwise to a cold (0° C.) suspension of 3-(2-bromoacetyl)pyridine hydrobromide (10.6 g, 38.0 mmol) in tetrahydrofuran (70 mL) over a period of 10 minutes. After the addition the mixture was stirred at room temperature, under a nitrogen atmosphere, overnight. The reaction was cooled to 0° C. and quenched with hydrogen chloride (0.5 M in methanol, 9 mL). The mixture was further diluted with water and extracted with ethyl acetate. The extracts were washed with water and dried with MgSO4. Evaporation and purification by flash column chromatography (dichloromethane/methyl alcohol 95/5) gave (1R)-2-bromo-1-(3-pyridinyl)-1-ethanol as a brown oil (2.01 g, 27% yield). This oil was dissolved in tetrahydrofuran (18 mL) and then sodium hydroxide (5N, 35 mL) was added. The solution was stirred at room temperature for 10 minutes. The mixture was diluted with water and extracted with dichloromethane. The extracts were washed with water, dried with magnesium sulfate. The extracts were concentrated to give the title compound as a white solid (1.01 g, 84% yield); 1H NMR (300 MHz, DMSO-d6) δ 2.93–2.97 (m, 2 H), 3.14–3.17 (m, 2 H), 3.99–4.01 (m, 2 H), 7.36–7.40 (m, 1 H), 7.63–7.66 (m, 1 H), 8.51–8.55 (m, 3 H); MS (ES) m/z: 122 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][C:11]([NH2:20])=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.N1C=CC=CC=1.[C:27](Cl)(=[O:30])[CH2:28][CH3:29]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:9]=[CH:10][C:11]([NH:20][C:27](=[O:30])[CH2:28][CH3:29])=[N:12][C:13]=1[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCC(=O)Cl
Reactant: Nc1cnc(-c2ccncc2F)c(-c2cccnc2)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Nc1cnc(-c2ccncc2F)c(-c2cccnc2)n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
To a solution of 5-(3-fluoropyridin-4-yl)-6-pyridin-3-ylpyrazin-2-amine (Example 115) (150 mg, 0.56 mmol) in CH2Cl2 (5 mL) was added pyridine (1 mL), cooled at 0° C., propionyl chloride (57 mg, 0.62 mmol) was added dropwise. Upon complete addition, the ice bath was removed and the reaction continued at room temperature overnight. Then CH2Cl2 (10 mL) and aqueous NaOH 10% (10 mL) were added, the organic layer was separated, and washed with H2O and saturated NaCl. The combined organic layers were dried over Na2SO4, filtered and concentrated in vaccuo. The crude product was purified by column chromatography on silica gel, eluting with an EtOAc/hexane gradient (80-100%), yielding the target product (100 mg, 55%)
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:9]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([C:29]#[CH:30])[CH:26]=[CH:27][CH:28]=1.Cl>O>[CH3:16][O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:2]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[CH:30])[CH:24]=3)=[N:3][CH:4]=[N:5][C:6]2=[CH:7][C:8]=1[O:17][CH2:18][CH2:19][O:20][CH3:21].[ClH:1]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Reactant: C#Cc1cccc(N)c1
Agent: Cl
Solvent: O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Yield: 84.4 %

Procedure:
5.0 g of 4-chloro-6,7-bis(2-methoxyethoxy) quinazoline was suspended in 75 ml of water and 2.55 g of 3-aminophenyl acetylene was added at 25-30° C. followed by 1.0 ml of 50% hydrochloric acid. The reaction mass was heated at 35- 40° C. for 1 hour. The solid obtained was filtered and washed with water. The product was dried at 40-45° C. to obtain 5.8 g of erlotinib hydrochloride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:16][C:10]2[N:11]=[CH:12][N:13]=[C:14](O)[C:9]=2[CH:8]=1.P(Cl)(Cl)(Cl)=O.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH:26][C:14]1[C:9]2[CH:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[NH:16][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Oc1ncnc2[nH]c(-c3ccccn3)cc12
Solvent: O=P(Cl)(Cl)Cl
Product: Fc1ccc(Nc2ncnc3[nH]c(-c4ccccn4)cc23)cc1Cl

Procedure:
Under a protective gas, 20 mg (0.09 mmol) of 6-(pyrid-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-ol (see Step 1.2) are heated at boiling with 1 ml of phosphorus oxychloride for 30 min. The reaction mixture is concentrated to dryness by evaporation and made into a suspension in 1 ml of n-butanol. 16.4 mg (0.108 mmol) of 3-chloro-4-fluoro-aniline are added and the suspension is boiled under reflux for 2 hours. The dark-brown suspension is then concentrated by evaporation and the residue is dissolved in methanol. Silica gel is added and drying is carried out. The powder is applied to a silica gel column and elution is carried out with ethyl acetate, yielding the title compound; 1H-NMR (400 MHz, DMSO-d6): 12.5 (sb, HN), 9.64 (s, HN), 8.64 (d, J=5, 1H), 8.38 (s, 1H), 8.35 (dd, J1 =7, J2 =3, 1H), 7.92 (m, 2H), 7.83 (m, 1H), 7.53 (s, 1H), 7.41 (t, J=9, 1H), 7.33 (m, 1H); HPLC: tRet (Grad20)=10.4 min; MS: (M)+ =339.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:19]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[C:18]3[C:13]([N:14]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:15](=[O:27])[NH:16][C:17]3=[O:26])=[N:12]2)=[CH:2]1.N12C[CH2:41][CH2:40][N:39]=[C:38]1[CH2:37][CH2:36][CH2:35]CC2.Cl.N1C=CC=CC=1CCl>CS(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][N:11]2[C:19]([C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][CH:24]=3)=[C:18]3[C:13]([N:14]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:15](=[O:27])[N:16]([CH2:41][C:40]4[CH:35]=[CH:36][CH:37]=[CH:38][N:39]=4)[C:17]3=[O:26])=[N:12]2)=[CH:2]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)Cn1c(=O)[nH]c(=O)c2c(-c3cccn3C)n(Cc3csc4ccccc34)nc21
Agent: Cl
Agent: ClCc1ccccn1
Solvent: CS(C)=O
Product: CC(C)Cn1c(=O)n(Cc2ccccn2)c(=O)c2c(-c3cccn3C)n(Cc3csc4ccccc34)nc21
Temperature: 80 °C

Procedure:
2-(1-benzothien-3-ylmethyl)-7-isobutyl-3-(1-methyl-1H-pyrrol-2-yl)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione was dissolved in anhydrous dimethylsulfoxide and 1,8-diazabicyclo[5.4.0]undec-7-ene was added. 2-picolyl chloride hydrochloride was added and the mixture was heated at 80° C. for 18 h. The crude reaction product was purified by semi-prep RPHPLC eluting with water/acetonitrile/trifluoroacetic acid mixtures. 525 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([CH3:9])[N:3]=1.[Cu][C:11]#[N:12]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:11]#[N:12])=[C:4]([CH3:9])[N:3]=1
Reactant: N#C[Cu]
Reactant: Cc1nc(N)ccc1Br
Solvent: CN(C)C=O
Product: Cc1nc(N)ccc1C#N

Procedure:
A mixture of 2-amino-5-bromo-6-methylpyridine (20.0 g, 0.107 mol) (Maybridge) and copper (I) cyanide 11.0 g, 0.123 mol) in DMF (25 ml) was heated to reflux for 4 h. The DMF was evaporated in vacuo and the residue was partitioned between ethyl acetate and 10% sodium cyanide solution. The organic layer was washed with 10% sodium cyanide solution and brine, dried (Na2SO4) and evaporated in vacuo to a brown solid. This was dissolved in a minimum amount of ethyl acetate and the product was precipitated by adding hexanes. The mixture was filtered to give the title compound as a brown powder:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17]>P(Cl)(Cl)(Cl)=O>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:17][C:16]([NH2:18])=[N:15][N:14]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: NNC(N)=S
Reactant: O=C(O)c1ccc2cnccc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nnc(-c2ccc3cnccc3c2)s1
Temperature: 80 °C

Procedure:
Commercially available isoquinoline-6-carboxylic acid (15.4 g, 89 mmol) and thiosemicarbazide (12.2 g, 133 mmol) were mixed in 150 ml phosphorus oxychloride. The mixture was heated at 80° C. for 60 hours. After removing the excess phosphorus oxychloride via rotatory evaporation at a reduced pressure, the remaining residue was mixed with ice water and the pH increased to pH 12 with KOH. After filtration and washing with water, a yellow amorphous solid 1a was obtained as the crude product (17 g, y (yield)=85%). It was used directly for next step. A pure sample of the product was obtained by subjecting the crude product to a silica gel column chromatography with a gradient of 1-5% 2M NH3 methanol solution in dichloromethane as the eluent. 1H NMR (400 MHz, DMSO-d6): δ 7.73 (s, 2H), 8.02 (d, J=6 Hz, 1H), 8.27 (m, 2H), 8.38 (s, 1H), 8.66 (d, J=6 Hz, 1H), 9.45 (s, 1H). MS (API-ES) m/z (%): 229 (100%, M++1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CC([O-])(C)C.[K+].[F:18][C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[C:21](F)[CH:20]=1>CS(C)=O.O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:21]2[CH:22]=[C:23]([N+:25]([O-:27])=[O:26])[CH:24]=[C:19]([F:18])[CH:20]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1ccc(Oc2cc(F)cc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-hydroxybenzoic acid methyl ester (3.00 g, 19.5 mmol) in DMSO (30 ml) was added t-BuOK (2.56 g, 21.5 mmol) at room temperature and the mixture was stirred at room temperature for 30 minutes under N2 flow. 1,3-Difluoro-5-nitrobenzene (2.34 ml, 20.5 mmol) was added dropwise at room temperature. The mixture was heated at 90° C. for 2 hours under N2 flow. The reaction mixture was cooled to room temperature, diluted with H2O, and then extracted with EtOAc. The extract washed with H2O and brine, dried over MgSO4, filtered and concentrated under vacuum giving the title compound as a dark brown oil, which was crystallized with i-Pr2O. The crystals were collected by filtration to give the desired product as pale yellow crystal (1.92 g, 40%). The filtrate gave additional product (1.46 g, 30%) as pale yellow crystal by silica gel column chromatography eluting with 4:1 EtOAc/hexane.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:24]>CO.CCOCC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:16][C:17]=1[O:22][CH3:23].[ClH:24]
Reactant: COc1cc(C2(O)CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1cc(C2(O)CCNCC2)ccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-Chloro-3-methoxy-phenyl)-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (502 mg) in MeOH (5 mL) was added a solution of HCl in ether (2 M, 9.5 mL). The resultant mixture was stirred at room temperature for 1 h followed by the addition of ether (50 mL). The reaction mixture was stirred at 0° C. for an additional 30 min, then filtered and concentrated to provide 4-(4-Chloro-3-methoxy-phenyl)-piperidin-4-ol in the form of HCl salt as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:13])[C:8](OCC)=[O:9])=[CH:3][CH:2]=1.[NH3:14]>>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([CH3:13])[C:8]([NH2:14])=[O:9])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)c1ccncc1
Reactant: N
Product: CC(C(N)=O)c1ccncc1
Temperature: 70 °C
Yield: 38.8 %

Procedure:
Methanolic ammonia (20 ml) was added to ethyl 2-(pyridin-4-yl)propanoate (140 mg, 0.78 mmol) in a steel bomb. The reaction mixture was heated to 70° C. for 18 h, then the temperature of the reaction was brought down to room temperature and the volatiles were evaporated. The reaction mixture was washed with n-pentane to afford 45 mg (38.8%) of 2-(pyridin-4-yl)propanamide as an orange color solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30].O.[NH2:33][NH2:34]>CN(C=O)C>[CH3:30][O:29][C:22]1[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=1[CH2:20][C:19]1[C:3]2[C:4](=[O:18])[N:5]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1
Reactant: COc1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)c(OC)c1
Reactant: NN
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c(OC)c1
Yield: 87.9 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(2,4-dimethoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (100 mg, 0.24 mmol, prepared in Synthetic Example 24) in DMF (2 ml) was added hydrazine monohydrate (80%, 50 μl, 1.25 mmol, 5.2 eq.), and the mixture was treated in the same manner as in Example 24 to give 3-(2,4-dimethoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (87 mg, 87%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[Br:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[N:22]([C:25]1[N:30]=[C:29]([C:31](OC)=[O:32])[CH:28]=[C:27]([CH3:35])[N:26]=1)[CH2:23][CH3:24].C([O-])(O)=O.[Na+]>C1COCC1.C(OCC)(=O)C>[Br:12][C:13]1[CH:18]=[C:17]([CH:19]([CH3:20])[CH3:21])[CH:16]=[CH:15][C:14]=1[N:22]([CH2:23][CH3:24])[C:25]1[N:30]=[C:29]([C:31]([C:7]2[S:8][CH:9]=[CH:10][N:11]=2)=[O:32])[CH:28]=[C:27]([CH3:35])[N:26]=1
Reactant: CCN(c1nc(C)cc(C(=O)OC)n1)c1ccc(C(C)C)cc1Br
Reactant: Brc1nccs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(c1nc(C)cc(C(=O)c2nccs2)n1)c1ccc(C(C)C)cc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a solution of n-butyl lithium in hexanes (2.4 M, 1.34 mL, 3.24 mmol) in anhydrous THF (5 mL) at −78° C. under a nitrogen atmosphere was added 2-bromothiazole (0.49 g, 0.27 mL, 3.0 mmol) dropwise. After the addition was complete, the reaction mixture was stirred at −78° C. for 30 min. A solution of methyl 2-(N-(2-bromo-4-(1-methylethyl)-phenyl)-N-ethylamino)-6-methyl-4-pyrimidinecarboxylate (Example 18) (1.0 g, 2.5 mmol) in anhydrous THF (10 mL) was added dropwise. The reaction mixture was then warmed to −60° C. and stirred for 4 h. A saturated aqueous solution of NaHCO3 was added and the reaction mixture was warmed to ambient temperature. Three extractions with ethyl acetate, followed by two washings of the combined organic layers with water, drying over MgSO4, filtration and concentration in vacuo gave a dark brown oil. Column chromatography (ethyl acetate: hexanes::1:1) afforded the title product, a brown solid (950 mg, 85% yield, Rf 0.43): mp 97-98.5° C.; NMR (CDCl3, 300 MHz):8.0 (s, 1H), 7.60 (s, 1H), 7.4-7.2 (m, 4H, J=6), 3.05-2.9 (m, 1H), 2.8-2.7 (m, 1H), 2.6 (br s, 3H), 1.4-1.2 (m, 9H); CI-HRMS Calcd: 445.0698 (M+H), Found: 445.0699; Anal.(C20H21BrN4S): C, 54.05; H, 4.73; N, 12.61; Br, 18.02; S, 7.21; Found: C, 53.86; H, 4.66; N, 12.53; Br, 18.20; S, 7.46.
Reaction SMILES: [CH:1]([S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][NH:19][C:16]3=[N:17][CH:18]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])([CH3:3])[CH3:2].[I:22]Cl.C(Cl)Cl>N1C=CC=CC=1>[I:22][C:21]1[C:15]2[C:16](=[N:17][CH:18]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([S:4]([CH:1]([CH3:3])[CH3:2])(=[O:6])=[O:5])=[CH:12][CH:11]=3)[N:14]=2)[NH:19][CH:20]=1
Reactant: ClI
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]ccc3n2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2cnc3[nH]cc(I)c3n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
2-(4-Isopropylsulfonylphenyl)-5H-pyrrolo[2,3-b]pyrazine (1 g, 3.318 mmol) was dissolved in anhydrous pyridine (20 mL) and cooled to 0° C. in an ice-bath. 1M ICl in DCM (3.484 mL, 3.484 mmol) was added slowly and the resultant solution stirred at 0° C. After 5 hours a further portion of 1M ICl in DCM (3.484 mL, 3.484 mmol) was added and the reaction allowed to warm to ambient temperature over 16 hours. A further portion of 1M ICl in DCM (3.484 mL, 3.484 mmol) was added and the reaction stirred at ambient temperature for a further 30 minutes. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and saturated aqueous Na2CO3/saturated aqueous Na2S2O3 (1:1). The aqueous layer was extracted with EtOAc (100 mL) and the combined organic extracts washed with saturated aqueous Na2CO3/saturated aqueous Na2S2O3 (1:1) (5×50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was triturated from MeCN to give the sub-title compound as a pale orange solid (1.23 g, 87% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.21 (d, 6H), 3.49 (s, 1H), 8.01 (d, 2H), 8.22 (s, 1H), 8.46 (d, 2H), 9.03 (s, 1H) and 12.71 (s, 1H) ppm; MS (ES+) 428.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[OH-].[NH4+:24].[Cl-].[NH4+]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH2:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: [NH4+]
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(N)=O
Reaction time: 0.58 h

Procedure:
58 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid [prepared as described in step (1) aboveπ were dissolved in 850 ml of dry tetrahydrofuran, and then 38.2 ml of triethylamine were added to the mixture at -15° to -20° C. A solution of 26.3 ml of ethyl chloroformate in 240 ml of dry tetrahydrofuran was then added dropwise to the mixture at -15° to -20° C., and the mixture was stirred at the same temperature for 35 minutes. At the end of this time, 258 ml of 28% w/v aqueous ammonium hydroxide were added to the mixture at -15° to -20° C., and the mixture was allowed to stand overnight at room temperature. Ammonium chloride was then added to the reaction mixture, which was then extracted with tetrahydrofuran. The extract was dried and freed from the solvent by distillation under reduced pressure. The resulting residue was triturated with diethyl ether to cause crystallization. The crystals were collected by filtration and washed with diethyl ether to afford 49.7 g of the title compound as colorless crystals, melting at 146°-148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].C1C(O)=CC=CC=1C.Cl.[N:19]#[C:20][NH2:21].[OH-].[Na+]>CCOCC>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH:4][C:20]([NH2:21])=[NH:19]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: N#CN
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccc(O)c1
Solvent: CCOCC
Product: N=C(N)Nc1c(Cl)cccc1Cl

Procedure:
To 51 g. (0.315 mole) of 2,6-dichloroaniline is added 0.4 moles of etherial HCl and 200 ml of m-cresol. The mixture is then stirred and heated on a steam bath to drive off the ether and excess hydrogen chloride. To the resultant mixture is then added 13.3 g. (0.315 mole) of cyanamide then heated for 2 hours on a steam bath. The reaction mixture is then cooled, added to 150 ml of conc. sodium hydroxide solution, cooled and extracted with 2 liters of ether. The ether layer is washed with 2 × 1 liter of water, dried over sodium sulfate, charcoaled and evaporated. The residue is triturated with hexane and the precipitate is filtered off and washed with ether and dried to obtain 2,6-dichlorophenylguanidine.
Reaction SMILES: [CH2:1]([NH:13][CH2:14][CH2:15][NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:17](OCC)(=[O:22])[CH2:18][C:19]([CH3:21])=O>>[CH2:1]([N:13]1[C:17](=[O:22])[CH2:18][C:19]([CH3:21])=[N:16][CH2:15][CH2:14]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCCCCCCCCCCCNCCN
Product: CCCCCCCCCCCCN1CCN=C(C)CC1=O

Procedure:
Into a four-necked flask provided with a stirrer, thermometer, gas inlet tube, and water measuring tube connected with a reflux condenser, were charged 228.1 g (1 mole) of N-dodecylethylenediamine and 130.1 g (1 mole) of ethyl acetoacetate. While bubbling nitrogen gas, the flask was heated at 150° to 160° C. to distill off 18 g of water and 46 g of ethanol, and then 4-dodecyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one in slight yellow liquid was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[Cl:19][CH2:20][C:21]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=1[O:2][CH3:1])=[O:22]
Reactant: COc1ccc(N)c(OC)c1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)CCl)c(OC)c1
Temperature: 0 °C
Yield: 72 %

Procedure:
A solution was prepared from 15.3 g of 2,4-dimethoxyaniline and 10.1 g of triethylamine in 300 ml of methylenedichloride. The solution was cooled to about 0° C. Eleven and three tenths grams of chloroacetylchloride were added in dropwise fashion with stirring under a nitrogen blanket. After the addition had been completed, the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was then extracted successively with equal volumes of 1N hydrochloric acid and of water. The organic solution was next extracted with cold saturated aqueous sodium bicarbonate followed by a second extraction with water. All these aqueous extracts were discarded. The organic solution was dried, and the solvent removed in vacuo. A residue consisting of 23 g of a purple colored solid was obtained. Twenty-one grams of this residue were chromatographed over silica gel using ethyl acetate as the eluant in order to remove a colored impurity. Fractions containing the desired product, N-chloroacetyl-2,4-dimethoxyaniline were combined and the solvent removed therefrom to yield a tan solid residue. Recrystallization of the residue from an ethyl acetate/hexane solvent mixture gave 16.5 g of N-chloroacetyl-2,4-dimethoxyaniline melting at 90°-91° C. (yield=72%).