Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)(=O)=O.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.CC(C)(O)[C:24]#[N:25].C(N(CC)CC)C>CO>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:19]2[CH:8]3[CH2:9][CH2:10][C:5]2([C:24]#[N:25])[CH2:6][CH2:7]3)=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)C1CCC(=O)CC1
Reactant: CC(C)(O)C#N
Reactant: COc1ccc(CN)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(CN2C3CCC2(C#N)CC3)cc1
Temperature: 100 °C
Yield: 97 %

Procedure:
This synthesis was performed according to scheme 2, with details as follows. In a dry, pressure resistant vessel of 20 ml, 1.25 g (6.5 mmole) 4-methanesulfonylcyclohexanone 9, 0.89 g (6.5 mmole) 4-methoxybenzylamine, 1.11 g (13 mmole) acetone cyanohydrine and 1.32 g (13 mmole) triethylamine were dissolved in 16 ml dry methanol. The vessel was closed and heated to 100° C. for 50 hours. Methanol was evaporated and the residue was redissolved in dichloromethane. The solution was washed with a saturated NaHCO3 solution and dried over MgSO4. After filtration of the solids, the volatile components were evaporated. 7-(4-methoxybenzyl)-7-azabicyclo[2.2.1]heptane-1-carbonitrile 6a was obtained as a brown oil in a 97% yield and characterised by proton (1H-NMR) and carbon (13C-NMR) nuclear magnetic resonance, and mass spectrum (MSES) as follows:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:17]C)=[CH:9][CH:10]=3)[C@:5]3([N:23]=[C:22]([NH2:24])[CH2:21][O:20][CH2:19]3)[C:4]=2[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:24][C:22]1[CH2:21][O:20][CH2:19][C@:5]2([C:4]3[CH:3]=[C:2]([Br:1])[CH:15]=[C:14]([F:16])[C:13]=3[O:12][C:11]3[C:6]2=[CH:7][C:8]([OH:17])=[CH:9][CH:10]=3)[N:23]=1
Reactant: COc1ccc2c(c1)[C@@]1(COCC(N)=N1)c1cc(Br)cc(F)c1O2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC1=N[C@@]2(COC1)c1cc(O)ccc1Oc1c(F)cc(Br)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
In a 100-mL flask, (S)-2′-bromo-4′-fluoro-7′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (0.233 g, 0.593 mmol) was dissolved in DCM (7.5 mL). The solution was cooled to 0° C., and a DCM solution of boron tribromide (1 M, 1.78 mL, 1.78 mmol) was added. The mixture was stirred at 0° C. for 1 h, then was quenched with saturated aqueous NH4Cl (18 mL) and aqueous NH4OH (2 mL). The aqueous phase was extracted 5% MeOH-DCM (3×40 mL). The organics were combined, washed with dilute brine (15 mL), dried over sodium sulfate and concentrated to afford 187 mg of (S)-5-amino-2′-bromo-4′-fluoro-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][SH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.[SH:13][CH2:14][CH2:15][OH:16].II.C(OCC)(=O)C>C(O)C.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][S:12][S:13][CH2:14][CH2:15][OH:16])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCS
Reactant: SCCc1ccc2c(c1)OCO2
Agent: II
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: OCCSSCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
35 g of 2-(1,3-benzodioxol-5-yl)ethanethiol and 75 g of 2-mercaptoethanol were dissolved in 150 ml of ethanol, followed by the addition of 43 g of iodine. The obtained mixture was stirred at a room temperature for 30 minutes, followed by the addition of 2 l of ethyl acetate and 2 l of water. The mixture was separated into two phases. The ethyl acetate layer was washed with water twice, then with 1 l of a 1% aqueous solution of sodium hydrogensulfite twice and finally with water thrice, dried over anhydrous sodium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (benzen/ethyl acetate=10:1) to obtain 11.5 g of the title compound as a colorless oil.
Reaction SMILES: C(OC([NH:8][CH:9]1[C:39](=[O:40])[N:11]2[C:12]([C:23]([O:25][CH:26]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[NH2:22])[CH2:14][S:15][C@H:10]12)=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCCCCCC>C(#N)C.O>[NH2:8][CH:9]1[C:39](=[O:40])[N:11]2[C:12]([C:23]([O:25][CH:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:24])=[C:13]([C:16]3[C:19](=[O:20])[C:18](=[O:21])[C:17]=3[NH2:22])[CH2:14][S:15][C@H:10]12
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(N)c(=O)c3=O)CS[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCCC
Solvent: CC#N
Solvent: O
Product: Nc1c(C2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)[C@H]3SC2)c(=O)c1=O
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
Diphenylmethyl 7-(t-butoxycarbonylamino)-3-(2-amino-3,4-dioxo-1-cyclobutenyl)-3-cephem-4-carboxylate (400 mg, 0.712 mmol) was added to a stirred solution of p-toluenesulfonic acid monohydrate (272 mg, 1.43 mmols) in acetonitrile (1.6 mL). Stirring was continued for 0.5 hr at 22° C., at which time additional acetonitrile (1mL) and H2O (2 drops) were added. Stirring was continued for an additional 0.5 hr at 22° C. and then for 0.33 hr at a water bath temperature of 3520 -40° C. The solution was applied to a Michel-Miller HPLPLC column (22×300 mm, purchased from Ace Glass) containing Partisil Prep 40 ODS-3 (purchased from Whatman Chemical Separation Inc., Clifton, N.J.). The column was eluted with a mixture of 80% acetonitrile-20% H2O (50%) and 0.05M (pH 6.5) ammonium phosphate (50%). The appropriate fractions were combined and acetonitrile was removed on a rotary evaporator. The resulting mixture was extracted with ethyl acetate (3X). The combined extracts were washed (saturated aqueous NaCl), dried (MgSO4), and partially concentrated. Dilution with n-heptane precipitated the title compound as a yellow powder (93.6 mg, 28% yield). Analytical HPLC indicated a purity of 97 area percent.
Reaction SMILES: C(OC(=O)[NH:7][C@:8]([CH2:26][OH:27])([CH3:25])[CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:13]([Cl:24])[CH:12]=1)(C)(C)C>O1CCOCC1>[ClH:24].[NH2:7][C@:8]([CH3:25])([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([F:17])[C:14]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:13]([Cl:24])[CH:12]=1)[CH2:26][OH:27]
Reactant: CCCCCOc1c(F)cc(CC[C@](C)(CO)NC(=O)OC(C)(C)C)cc1Cl
Solvent: C1COCCO1
Product: CCCCCOc1c(F)cc(CC[C@@](C)(N)CO)cc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
[(R)-3-(3-Chloro-5-fluoro-4-pentyloxy-phenyl)-1-hydroxymethyl-1-methyl-propyl]-carbamic acid tert-butyl ester (10 mg) is dissolved in dioxane containing 4 M HCl (0.5 ml). After stirring at RT for 18 h the product is precipitated by the addition of Et2O to yield the title compound as white solid. MS (ESI+): m/z=319 (MH+).
Reaction SMILES: C(OC(=O)CCCNC(NC1SC(C2C=CC(S(C)(=O)=O)=C(F)C=2)=C(C)N=1)=O)C.[N:30]1([C:35]2[CH:36]=[C:37]([C:45]3[S:49][C:48]([NH2:50])=[N:47][C:46]=3[CH3:51])[CH:38]=[CH:39][C:40]=2[S:41]([CH3:44])(=[O:43])=[O:42])[CH:34]=[CH:33][N:32]=[CH:31]1.[CH2:52]([O:54][C:55](=[O:61])[CH2:56][CH2:57][N:58]=[C:59]=[O:60])[CH3:53]>>[CH2:52]([O:54][C:55](=[O:61])[CH2:56][CH2:57][NH:58][C:59]([NH:50][C:48]1[S:49][C:45]([C:37]2[CH:38]=[CH:39][C:40]([S:41]([CH3:44])(=[O:43])=[O:42])=[C:35]([N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)[CH:36]=2)=[C:46]([CH3:51])[N:47]=1)=[O:60])[CH3:53]
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Reactant: CCOC(=O)CCN=C=O
Agent: CCOC(=O)CCCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(F)c2)s1
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(-n3ccnc3)c2)s1

Procedure:
The title compound is prepared by the same procedure as 4-{3-[5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-ureido}-butyric acid ethyl ester (Example 164) by replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72) with 5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148) and replacing ethyl-4-isocyanatobutyrate with 3-isocyanato-propionic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:17])[CH2:10][CH2:11][C:12]([CH3:16])=[C:13]([CH3:15])[CH3:14])=[CH:3][CH2:4][OH:5].ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)Cl>[O:26]1[C:13]([CH3:15])([CH3:14])[C:12]1([CH3:16])[CH2:11][CH2:10][C:9]([CH3:17])=[CH:8][CH2:7][CH2:6][C:2]([CH3:1])=[CH:3][CH2:4][OH:5]
Reactant: CC(=CCO)CCC=C(C)CCC(C)=C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=CCO)CCC=C(C)CCC1(C)OC1(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 23.6 g. of 3,7,10,11-tetramethyl-2,6,10-dodecatrien-1-ol in 500 ml. of methylene chloride, there was added under ice cooling 22.6 g. of m-chloroperbenzoic acid (79% by weight water solution). This addition was carried out portionwise. After this addition, the mixture was agitated for 2 hours at 0°C. After this period, the reaction mixture was diluted with 1,000 ml. of diethyl ether and washed with ice cold 1N aqueous sodium hydroxide and a saturated sodium chloride solution. After washing, the reaction mixture was dried over sodium sulfate and evaporated. By chromatography on Kieselgel, there was obtained 10,11-epoxy-3,7,10,11-tetramethyl-2,6-dodecadien-1-ol, b.p. 104°- 107°C./0.02 mmHg; nD20 = 1.4867.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[C:28]([C:30]1[CH:37]=[CH:36][C:33]([CH2:34][Zn+])=[CH:32][CH:31]=1)#[N:29]>C(C1C=CC=C(C(C)C)C=1N1C=CN(C2C(C(C)C)=CC=CC=2C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:34][C:33]5[CH:36]=[CH:37][C:30]([C:28]#[N:29])=[CH:31][CH:32]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Reactant: N#Cc1ccc(C[Zn+])cc1
Agent: CC(C)c1cccc(C(C)C)c1-n1ccn(-c2c(C(C)C)cccc2C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5ccc(C#N)cc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-cyano-benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1; [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]-(3-chloropyridyl)-palladium(II) dichloride (Pd-PEPPSI-IPr) is used as catalyst. LC (method 9): tR=0.74 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][C:15]1[CH:20]=[C:19]([C:21]2[N:22]=[C:23]([N:26]=[C:27]([NH2:29])[NH2:28])[S:24][CH:25]=2)[CH:18]=[CH:17][N:16]=1.CN(C)C=[O:33]>>[CH:15]([O:33][CH:9]([CH3:8])[CH3:10])([CH3:20])[CH3:14].[NH2:28][C:27](=[N:26][C:23]1[S:24][CH:25]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([CH2:14][N:5]3[C:1](=[O:11])[C:2]4=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]4[C:4]3=[O:6])[CH:20]=2)[N:22]=1)[NH2:29]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CN(C)C=O
Reactant: NC(N)=Nc1nc(-c2ccnc(CCl)c2)cs1
Agent: [K]
Product: CC(C)OC(C)C
Product: NC(N)=Nc1nc(-c2ccnc(CN3C(=O)c4ccccc4C3=O)c2)cs1
Reaction time: 14 h

Procedure:
Potassium phthalimide (1.65 g) was added to a solution of 4-(2-chloromethylpyridin-4-yl)-2-(diaminomethyleneamino)thiazole (2.39 g) in N,N-dimethylformamide (25 ml). After stirring for 14 hours, the solvent was evaporated in vacuo and the residue was mixed with water. The resulting precipitate was collected by filtration and washed with ethanol and then diisopropyl ether to give 2-(diaminomethyleneamino)-4-(2-phthalimidomethylpyridin-4-yl)thiazole (2.68 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CC(C)=O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:1][C:2]2[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:16][CH:17]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1cc(I)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)c1cc(I)ccc1OCc1ccc(F)cc1

Procedure:
To a solution of methyl 2-hydroxy-5-iodobenzoate (15 g, 53.9 mmol) in acetone (200 ml) was added 1-(bromomethyl)-4-fluorobenzene (9.95 ml, 81 mmol), potassium carbonate (14.91 g, 108 mmol) and the mixture was refluxed overnight. The mixture was allowed to cool and then filtered to remove the potassium carbonate. The solid potassium carbonate was washed with acetone (100 ml). The organics were combined and evaporated under reduced pressure on a buchi to give a solid. The solid was taken up into ethyl acetate (500 ml) and the organic phase was washed with water (2×200 ml), dried (MgSO4) and evaporated under reduced pressure on a buchi. The solid obtained was recrystallised from cyclohexane to yield the title compound as a white solid. 18.2 g.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([OH:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1>>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([O:32][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:2]([CH3:3])[CH3:1])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: CNC
Reactant: BrCCCCCCBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCCN(C)C

Procedure:
The title compound was prepared from dimethylamine, 1,6-dibromohexane, and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedures outlined in Examples 25 & 27. 1H NMR (400 MHz, DMSO-d6): δ 9.38 (br s, 1H), 8.57 (s, 2H), 7.85 (d, 1H), 7.05 (d, 1H), 4.24 (br s, 1H), 3.96 (t, 2H), 3.87 (s, 3H), 2.55 (br, 2H), 2.37 (s, 6H), 1.67 (m, 2H), 1.49 (m, 4H), 1.34 (m, 2H); MS (ESI): 479.9.
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[CH:17](=O)/[CH:18]=[CH:19]/CC.[CH3:23][CH2:24][OH:25]>>[CH2:10]([O:9][C:7]([C:6]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:17]([CH2:18][CH3:19])[CH2:3][CH:2]([OH:4])[N:5]1[C:24](=[O:25])[CH3:23])=[O:8])[CH3:11]
Reactant: CCO
Reactant: CC/C=C/C=O
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Product: CCOC(=O)C1(C(=O)OCC)C(CC)CC(O)N1C(C)=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Sodium (4.02 g, 0.175 mol) was dissolved in a stirred solution of diethyl acetamidomalonate (235.4 g, 1.19 mol) in abs EtOH (1.4 L) at ambient temperature under argon. The reaction mixture was cooled to 0° C., and trans-2-pentenal (100 g, 1.08 mol) was added dropwise maintaining the reaction temperature at <5° C. After the addition, the reaction was allowed to warm to room temperature, stirred for 4 h, then quenched with acetic acid (28 mL). The solution was concentrated in vacuo, and the residue dissolved in EtOAc (1.5 L), washed with 10% NaHCO3solution (2×300 mL), brine, and dried (MgSO4). The solution was filtered and concentrated to 700 mL, then heated to reflux and treated with hexane (1 L). On cooling, the title compound precipitated and was collected, mp 106°-109° C. 1H NMR (CD3OD) δ5.65 (d, 1H, J=5 Hz), 4.1-4.25 (m, 4H), 2.7-2.8 (m, 1H), 2.21(s, 3H), 2.10 (dd, 1H, J=6, 13, Hz),1.86-1.97 (m, 2H), 1.27 (t, 3H, J=7 Hz), 1.23 (t, 3H, J=7 Hz), 1.1-1.25 (m, 1H), 0.97 (t, 3H, J=7 Hz).
Reaction SMILES: [SH:1][C:2](=[C:4]([C:7]#[N:8])[C:5]#[N:6])[SH:3].[Na].[Na].Cl[C:12]1[C:17](Cl)=[N:16][C:15]([C:19]#[N:20])=[C:14]([C:21]#[N:22])[N:13]=1.O>CN(C)C=O>[C:5]([C:4]([C:7]#[N:8])=[C:2]1[S:3][C:12]2=[N:13][C:14]([C:21]#[N:22])=[C:15]([C:19]#[N:20])[N:16]=[C:17]2[S:1]1)#[N:6]
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Reactant: N#CC(C#N)=C(S)S
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)=C1Sc2nc(C#N)c(C#N)nc2S1
Temperature: 40 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
To a stirred solution of 9.3 g (0.05 mol) of disodium dimercaptomethylenemalononitrile in 100 ml of dimethylformamide was gradually added 10 g (0.05 mol) of 2,3-dichloro-5,6-dicyanopyrazine in 70 ml of dimethylformamide. The reaction mixture was stirred at 40° C for 8 hours and poured into 700 ml of water. The resulting solid was collected by suction filtration, washed with water, and dried. The crude product was dissolved in acetone-CHCl3, decolorized with charcoal and dried over MgSO4. Recrystallization from CHCl3 yields 5.0 g (37%) of yellow crystals. M.p. ~280° C (dec.). νCN (cm31 1): 2220.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>ClCCl>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:14]2[CH2:18][CH2:17][CH2:16][C@H:15]2[CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:11])=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCO)cc1
Reactant: C1CN[C@H](CN2CCCC2)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(OCCO)cc1)N1CCC[C@H]1CN1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.2 %

Procedure:
4-(2-Hydroxy-ethoxy)-benzoic acid (152 mg, 0.84 mmol), (S)(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (193 mg, 1.25 mmol) and triethylamine (303 mg, 3.0 mmol) are dissolved in dichloromethane (5.0 mL) and benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (786 mg, 1.5 mmol) is added to the mixture. The mixture is stirred at room temperature for 3 days. The reaction mixture is diluted with dichloromethane, washed with brine, dried over Na2SO4, filtered and evaporated. The crude product is purified using silica-gel column chromatography (CH2Cl2:2M NH3 in MeOH=20:1) to give 177 mg (66%) of the title compound. Observed Mass 319.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[N+:17]([O-])=O)=[O:2].[H][H]>CO.[Pd]>[NH2:17][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][C:3]=1[CH:1]=[O:2]
Reactant: COC(=O)CCC#Cc1ccc(C=O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCc1ccc(C=O)c(N)c1

Procedure:
Methyl 5-(4-formyl-3-nitrophenyl)pent-4-ynoate (522 mg) was reduced by 5% Pd/C (53 mg) in MeOH with hydrogen balloon at room temperature. Filtration followed by concentration under reduced pressure afforded methyl 5-(3-amino-4-formylphenyl)pentanoate. MS-ESI m/z 236.28 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2C2CCCCO2)=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncn(C3CCCCO3)c2n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Reaction time: 0.5 h

Procedure:
To 4-(2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)morpholine (100 g) in methanol (500 mL) at 50° C. was added p-toluenesulfonic acid monohydrate (6 g). The reaction was stirred for 30 mins, whereupon white solid has crashed fully out of solution. The solid was filtered and collected through a Buchner funnel, rinsed with methanol and dried under vacuum to get 4-(2-chloro-9H-purin-6-yl)morpholine. Cesium carbonate (200 g) and iodomethane (30 mL) were subsequently added to a stirring solution of 4-(2-chloro-9H-purin-6-yl)morpholine in DMF at 50° C. The reaction was monitored by lc-ms until complete, about 30 minutes, whereupon the solvent was concentrated to dryness. Subsequent suspension of the crude reaction in water crashed out 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine (72 g) as a white solid, which was filtered and dried under vacuum overnight.
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=5)[C:19]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:49][NH2:50]>C1COCC1.C(OCC)(=O)C>[CH3:48][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]=[C:20]([NH:21][C:22]4[C:27]([C:28]([NH:50][CH3:49])=[O:30])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=4)[C:19]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=5)(=[O:37])=[O:38])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CN
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4ccc(F)c(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(Nc2nc(Nc3cc4c(cc3OC)CCN4C(=O)CN(C)C)nc3c2ccn3S(=O)(=O)c2ccc(C)cc2)ccc(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.6 %

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,9-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added methylamine (2 M solution in THF) (2.23 mL, 4.45 mmol). The resulting mixture was let stir at rt for 10 min at which time it was diluted with ethyl acetate and washed with water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure. The residue was purified via chromatography on SiO2 and afforded 6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluoro-N-methylbenzamide (143 mg, 0.203 mmol) as an off white solid. (ESIMS (M+H)+=705)
Reaction SMILES: [C:1]([CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8])([O:3][CH3:4])=[O:2].[CH2:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+]>ClCCl>[CH2:11]([CH:5]([CH2:6][S:7]([N:28]1[CH2:29][CH2:30][N:25]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:26][CH2:27]1)(=[O:9])=[O:8])[C:1]([O:3][CH3:4])=[O:2])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
To a 3L round bottom flask was added the resultant compound from Example 1E (370.5 g, 1.34 mol) and dichloromethane (2L). The mixture was cooled to 0° C. in an ice water bath and a solution of N-benzyl piperazine (295.8 g, 1.68 mol) was added dropwise with vigorous stirring over 2 h. After the addition was completed, the mixture was stirred in additional 4 h while at 0° C. The solution was then poured into a separatory funnel containing 2L of a 5% aqueous NaOH solution. The layers were partitioned and the organic layer was dried over potassium carbonate. Concentration in vacuo yielded an oil, which was filtered through 1 kg of silica gel using 3:2 hexane/ethyl acetate as an eluant. Concentration gave 467 g (84%) of the desired product: 1H NMR (CDCl3) δ 7.37-7.12 (m, 10H), 3.66 (s, 3H), 3.51 (s, 2H), 3.42 (dd, 1H), 3.29-3.13 (m, 5H), 3.06 (dd, 1H), 2.96-2.84 (m, 2H), 2.50-2.42 (m, 4H).