Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)=[C:6]([CH2:22][CH2:23][CH3:24])[C:5]=1[OH:25])(=[O:3])[CH3:2].O[Li].O.Cl>CO.O1CCCC1.O>[C:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[C:6]([CH2:22][CH2:23][CH3:24])[C:5]=1[OH:25])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(=O)OC)cc2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCc1c(OCc2ccc(C(=O)O)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 63.3 %

Procedure:
A solution of 684 mg (2.0 mmoles) of methyl 4-(4-acetyl-3-hydroxy-2-propylphenoxy)methylbenzoate in 9 ml MeOH, 9 ml tetrahydrofuran and 3 ml water was treated with 420 mg (10 mmoles) LiOH.H2O and stirred at room temperature for 4 hours. The reaction mixture was diluted with water, acidified by addition of concentrated HCl and extracted with dichloromethane. The combined extracts were washed with water, dried with MgSO4 and evaporated to give a white solid. Recrystallization of this material from ether gave 416 mg (63% yield) of the title compound as fine white needles mp 188°-188.5° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2S(=O)(=O)[NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1)=[O:13].[H-].[Na+].CN1CCC[C:33]1=[O:37]>[Cu]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:25]2[CH2:24][CH2:23][N:22]([CH:19]3[CH2:20][CH2:21][CH:16]([CH2:15][CH2:14][C:12]([O:11][CH3:10])=[O:13])[CH2:17][CH2:18]3)[C:33]2=[O:37])=[CH:3][CH:4]=1)#[N:7]
Reactant: COC(=O)CCc1ccc(N2CCNS2(=O)=O)cc1
Reactant: N#Cc1ccc(F)cc1
Reactant: CN1CCCC1=O
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Product: COC(=O)CCC1CCC(N2CCN(c3ccc(C#N)cc3)C2=O)CC1

Procedure:
2-64=cyano-phenyl)-5-[4-(2-methoxycarbonyl-ethyl)-phenyl]-3,4-dihydro-2H,5H-1,2,5-thiadiazole-1,1-dioxide 4-Fluoro-benzonitrile and sodium hydride in N-methyl-pyrrolidone were used without copper salts.
Reaction SMILES: [CH:1]([S:5]([C:7]1[N:11]=[CH:10][NH:9][N:8]=1)=[O:6])([CH2:3][CH3:4])[CH3:2].[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16](Cl)=[O:17])[CH:13]=[CH2:14].O1CCCC1.C(N(CC)CC)C>C(Cl)Cl>[CH2:12]([N:15]([CH2:19][CH:20]=[CH2:21])[C:16]([N:9]1[CH:10]=[N:11][C:7]([S:5]([CH:1]([CH2:3][CH3:4])[CH3:2])=[O:6])=[N:8]1)=[O:17])[CH:13]=[CH2:14]
Reactant: CCC(C)S(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)C(C)CC)n1

Procedure:
A mixture of 5.76 g. 3-sec.butylsulphinyl-1,2,4-triazole, 5.31 g. diallylcarbamoyl chloride, 50 ml. dry tetrahydrofuran and 5 ml. dry triethylamine was kept under anhydrous conditions at room temperature for 72 hours. The reaction mixture was filtered and the filtrate evaporated under reduced pressure at room temperature to give a residual oil which was dissolved in methylene dichloride. The resulting solution was washed with water, dried over anhydrous sodium sulphate and distilled under reduced pressure at room temperature to give 1-diallylcarbamoyl-3-sec.butylsulphinyl-1,2,4-triazole as a residual oil, nD25 1.5268, for which a satisfactory elemental analysis was obtained.
Reaction SMILES: C[Mg+].[Br-].CCOCC.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[C:15]([C:17]1[C:18]2[C:23]([CH:24]=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)=[CH:22][CH:21]=[CH:20][CH:19]=2)#[N:16]>C1(C)C=CC=CC=1>[CH:29]1[C:30]2[C:25](=[CH:24][C:23]3[C:18]([C:17]=2[C:15](=[NH:16])[N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:26]=[CH:27][CH:28]=1
Reactant: C1CCNCC1
Reactant: N#Cc1c2ccccc2cc2ccccc12
Agent: C[Mg+]
Agent: [Br-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: N=C(c1c2ccccc2cc2ccccc12)N1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.6 %

Procedure:
A solution of MeMgBr in ether (3.3 mL, 3.0 M, 9.9 mmol) was added to a solution of piperidine (1.11 g, 13.1 mmol) in toluene (50 mL) at 50° C. The mixture was stirred for 1 h and a white precipitate formed. Next, the mixture was cooled to 0° C. and 9-cyanoantracene (2.00 g, 9.9 mmol) was added. The mixture was allowed to warm to room temperature and the mixture was stirred for 16 h subsequently. The conversion, determined by GC, appeared to be 98%. The mixture was quenched with an aqueous NH4Cl solution (1%, 150 mL). The organic phase was separated from the aqueous phase and the latter was extracted with CH2Cl2 (250 mL) twice. The combined organic phases were dried over Na2SO4, filtered and the solvents were removed under reduced pressure resulting in a sticky residue. Pure product 1.76 g (62%) was obtained by rinsing the residue with ligroin. The ligand was characterized by 1H NMR (300 MHz) (CDCl3) δ (ppm): 8.4 (s, 1H), 7.9 (m, 4H), 7.4 (m, 4H), 5.8 (bs, 1H), 4.0 (bt, 2H), 2.7 (bt, 2H), 1.8 (bm, 2H), 1.5 (p, 2H), 1.2 (bm, 2H) and by 13C-NMR (75.5 MHz) (CDCl3) δ (ppm): 163.3, 130.7, 129.4, 126.6, 125.8, 125.3, 124.6, 123.8, 123.5, 46.5, 41.8, 25.0, 23.8, 22.8.
Reaction SMILES: [OH:1][C@H:2]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([O:20]C)=[O:19])[CH:12]=2)[O:7]1.[Li+].[OH-]>C1COCC1.CO.O>[OH:1][C@H:2]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([OH:20])=[O:19])[CH:12]=2)[O:7]1
Reactant: COC(=O)c1ccccc1-c1ccc2c(c1)CC[C@H](CNC[C@H](O)c1cccnc1)O2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccccc1-c1ccc2c(c1)CC[C@H](CNC[C@H](O)c1cccnc1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To a solution of methyl 2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}-methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 83, 60 mg, 0.143 mmol) in THF (0.50 mL) and MeOH (0.50 mL) was added LiOH (1.0 mL of a 2.0 M aq solution), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with 1.0 mL H2O and purified via preparative HPLC (gradient of 100:0 0.1% TFA/H2O:acetonitrile to 30:70 0.1% TFA/H2O:acetonitrile). The peak of interest was collected and concentrated in vacuo to provide 41 mg of desired final product as a bis-trifluoroacetic acid (TFA) salt; 1H NMR (DMSO-d6, δ): 1.68-1.80 (m, 1H), 2.04-2.18 (m, 1H), 2.72-2.90 (m, 2H), 3.22-3.50 (m, 4H), 4.58 (dd, 1H), 5.41 (d, 1H), 6.82 (d, 1H), 7.02 (d, 1H), 7.04 (s, 1H), 7.30-7.40 (m, 2H), 7.50 (t, 1H), 7.62 (d, 1H), 8.01 (t, 1H), 8.58 (d, 1H), 8.82 (d, 1H), 8.90 (s, 1H), 9.44 (bs, 1H), 9.64 (bs, 1H) MS: m/z=415.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[N:13]=[CH:14][C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:27](O)=[O:28])[CH:25]=[CH:26][C:17]=4[C:16]=3[N:30]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(OC(=O)NCCNC(C1C=C[C:46]2[C:52]3[N:53]=C(NC4C=CC(OC)=C(OC)C=4)N=CC=3CC(=O)[NH:48][C:47]=2C=1)=O)(C)(C)C>>[NH2:48][CH2:47][CH2:46][CH2:52][NH:53][C:27]([C:24]1[CH:25]=[CH:26][C:17]2[C:16]3[N:30]=[C:12]([NH:11][C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:13]=[CH:14][C:15]=3[CH2:21][C:20](=[O:22])[NH:19][C:18]=2[CH:23]=1)=[O:28]
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)NCCNC(=O)OC(C)(C)C)cc2NC(=O)C3)cc1OC
Reactant: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)O)cc2NC(=O)C3)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C(=O)NCCCN)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to that described for Method N, 2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carboxylic acid (I-53) and tert-butyl 4-aminopropylcarbamate were converted to (2-{[2-(3,4-dimethoxy-phenylamino)-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepine-9-carbonyl]-amino}-ethyl)-carbamic acid tert-butyl ester, which was subsequently deprotected (Method K) to give I-72 (30%): HRMS Calcd. for C14H26N6O4: 463.2093, Found 463.2078.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:32][O:33][CH:34]([O:51][CH3:52])[C:35]1[C:40]([O:41][CH2:42][O:43][CH3:44])=[C:39]([C:45]([F:48])([F:47])[F:46])[CH:38]=[CH:37][C:36]=1[CH2:49][OH:50].O[C:54]1[CH:59]=[CH:58][C:57]([C:60]2[CH:65]=[CH:64][C:63]([CH2:66][C:67]([O:69][CH3:70])=[O:68])=[CH:62][CH:61]=2)=[CH:56][CH:55]=1>O1CCCC1>[CH3:52][O:51][CH:34]([O:33][CH3:32])[C:35]1[C:40]([O:41][CH2:42][O:43][CH3:44])=[C:39]([C:45]([F:46])([F:47])[F:48])[CH:38]=[CH:37][C:36]=1[CH2:49][O:50][C:54]1[CH:55]=[CH:56][C:57]([C:60]2[CH:65]=[CH:64][C:63]([CH2:66][C:67]([O:69][CH3:70])=[O:68])=[CH:62][CH:61]=2)=[CH:58][CH:59]=1
Reactant: COCOc1c(C(F)(F)F)ccc(CO)c1C(OC)OC
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCOc1c(C(F)(F)F)ccc(COc2ccc(-c3ccc(CC(=O)OC)cc3)cc2)c1C(OC)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.4 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (3.10 g, 12.3 mmol) and tri-n-butylphosphine (3.10 ml, 12.4 mmol) were successively added to a solution of [2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)phenyl]methanol (3.20 g, 10.3 mmol) obtained in Example (6-6) and methyl (4′-hydroxy-1,1′-biphenyl-4-yl)acetate (2.50 g, 10.3 mmol) obtained in Example (6-2) in tetrahydrofuran (40 ml) and the mixture was stirred at room temperature for 5 hours. After the formed white precipitate was removed by filtration, the precipitate was washed with ethyl acetate. After the filtrate was poured into water and the mixture was extracted with ethyl acetate (three times), the organic layer was successively washed with a 3N aqueous sodium hydroxide solution, water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=4/1) to give methyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-4-yl)acetate (3.16 g, yield: 58%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]>N1C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(CCNS(C)(=O)=O)CC1
Reaction time: 12 h
Yield: 39.3 %

Procedure:
Methanesulfonyl chloride (0.7 mL, 9.0 mmol) was added to a cooled solution of 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.33 g, 5.8 mmol) in pyridine (25.0 mL). The reaction was stirred for 12 h and partitioned between partitioned between aqueous sodium bicarbonate and methylene chloride. The organic phase was washed with 1M hydrochloric acid, aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate and concentrated. Purification of the crude residue by flash chromatography over silica gel using 0-5% methanol in methylene chloride gave 4-(2-methanesulfonylamino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (0.70 g, 70%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([NH2:10])[C:6]([O:8][CH3:9])=[O:7])[CH3:3].Cl.C(N(CC)CC)C.[NH:19]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:20]([C:24](O)=[O:25])[CH:21]([CH3:23])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:19]([C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C@H:20]([C:24]([NH:10][C@H:5]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][CH:2]([CH3:3])[CH3:1])=[O:25])[CH:21]([CH3:23])[CH3:22]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
19.9 g (110 mmols) of H-Leu-OMe. HCl are dissolved in 120 ml of dimethylformamide and 14.6 ml (105 mmols) of triethylamine are added at 0°C. The precipitated triethylamine hydrochloride is filtered off, the filtrate is added to a solution of 25.1 g (100 mmols) of Z-Val-OH in 200 ml of dimethylformamide (0°C), and 22.6 g (110 mmols) of dry dicyclohexylcarbodiimide are then added. After 1 hour's stirring at 0°C and standing overnight in the refrigerator the mixture is filtered and the solution evaporated in a high vacuum at 40°C. The oily residue is taken up in 30 ml of ethyl acetate, and the solution is cooled to 0°C and freed of precipitated dicyclohexylurea. After adding n-hexane the product crystallises out from the filtrate overnight. Melting point 102°-105°C; [α]D : -41° (c = 2.88 in methanol).
Reaction SMILES: C(O[O:5][C:6]1[C:11]([CH3:12])=[N:10][C:9]([CH3:13])=[C:8]([CH3:14])[N:7]=1)(=O)C.[C:15](Cl)(=[O:20])[C:16](C)(C)C.Cl.[Cl:23][CH2:24][CH2:25][NH2:26]>O1CCCC1.C(N(CC)CC)C.C(Cl)(Cl)Cl>[Cl:23][CH2:24][CH2:25][NH:26][C:15](=[O:20])[CH2:16][O:5][C:6]1[C:11]([CH3:12])=[N:10][C:9]([CH3:13])=[C:8]([CH3:14])[N:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(=O)OOc1nc(C)c(C)nc1C
Reactant: NCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc(C)c(OCC(=O)NCCCl)nc1C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
Triethylamine (3.50 ml, 25 mM) was added to compound 037 (4.90 g, 25 mM) dissolved in tetrahydrofuran (50 ml) and pivaloyl chloride (3.05 g, 25 mM) was added dropwise at -5° C., then the mixture was stirred for 30 minutes. Chloroform (50 ml) in solution with 2-chloroethylamine hydrochloride (2.90 g, 25 mM) and triethylamine (3.9 ml, 28 mM) was added dropwise thereto, then the mixture was stirred for 4 hours while slowly reaching room temperature. The reaction mixture was concentrated in vacuo, the residue was dissolved in chloroform and washed with dilute aqueous potassium carbonate. The aqueous layer was extracted with chloroform. The organic layer was combined, dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was charged on a column of silica gel (C-200, 40 g), and eluted successively with chloroform and chloroformmethanol (20:1) to obtain the product (5.66 g, yield: 7.5%).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7](#[N:10])[CH2:8][CH3:9].CO[C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1>O1CCCC1>[C:7]([CH:8]([CH3:9])[C:13]([C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[CH:18][CH:19]=1)=[O:22])#[N:10]
Reactant: CCC#N
Reactant: COC(=O)c1ccc(C#N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C#N)C(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.9 %

Procedure:
Potassium-tert-butoxide (7.76 g, 69.2 mmol) and propionitrile (4.84 mL, 69.2 mmol) was added to a solution of 4-cyano-benzoic acid methyl ester (11.15 g, 69.2 mmol) in tetrahydrofuran (100 mL). This mixture was stirred at room temperature for 16 hours, and then quenched onto an aqueous 10% solution (weight/volume) citric acid (100 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were dried over magnesium sulphate, filtered, and evaporated under reduced pressure. This crude residue was triturated with tert-butyl methyl ether to give the title compound as a solid (7.00 g, 55%). 1H NMR (400 MHz, CDCl3): δ 1.65 (d, 3H), 4.35 (m, 1H), 7.85 (d, 2H), 8.10 (d, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([F:36])([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:19]=[C:20]([C:26]5[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=5)[S:21][C:22]=4[CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[I-].Cl[CH2:53][C:54]([N:56]([CH3:58])[CH3:57])=[O:55]>C(Cl)Cl>[F:36][C:11]1([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:19]=[C:20]([C:26]5[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=5)[S:21][C:22]=4[CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH2:12][CH2:13][N:8]([CH2:53][C:54]([N:56]([CH3:58])[CH3:57])=[O:55])[CH2:9][CH2:10]1
Reactant: CN(C)C(=O)CCl
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3(F)CCN(C(=O)OC(C)(C)C)CC3)ccc1-2
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3(F)CCN(CC(=O)N(C)C)CC3)ccc1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-fluoro-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (45 mg, 88 μmol) in DCM (2.5 mL) was added TFA (0.8 mL) and the reaction mixture stirred at RT for 1 h before being concentrated in vacuo. The residue was dissolved in DCM (2 mL) and triethylamine (88 μL, 0.61 mmol), tetrabutylammonimum iodide (8 mg, 21 μmol) and 2-chloro-N,N-dimethyl-acetamide (14 μL, 0.1 mmol) added. The reaction mixture was stirred at RT for 16 h then diluted with DCM (20 mL) and washed with saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with DCM (3×5 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2 20% ethyl acetate in DCM then 2% MeOH in DCM) producing impure material. The material was subjected to flash chromatography (Si—NH2 eluting with DCM) to yield 523. LCMS: RT=3.43 min, [M+H]+=499 [ad823805] 1H NMR 400 MHz (d6-DMSO) δ: 8.37 (1H, d, J=8.4 Hz), 7.96 (1H, s), 7.18 (1H, dd, J=1.8, 8.4 Hz), 7.09 (1H, d, J=1.8 Hz), 5.93 (1H, sept, J=6.6 Hz), 4.37 (2H, t, J=5.1 Hz), 3.42 (2H, t, J=5.1 Hz), 3.30 (2H, s), 3.09 (3H, s), 2.93 (3H, s), 2.92-2.85 (2H, m), 2.55-2.46 (2H, m), 2.31-2.11 (2H, m), 1.97-1.87 (2H, m), 1.59 (6H, d, J=6.6 Hz)
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][P:9](=[O:16])([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][P:9](=[O:16])([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1
Reactant: CCCP(=O)(CCC)Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCCP(=O)(CCC)Cc1ccc(N)cc1
Reaction time: 16 h
Yield: 66.8 %

Procedure:
A mixture of 4-nitrobenzyldipropylphosphine oxide (3.0 g) and 5% Pd-C (0.3 g) in ethanol (50 ml) was vigorously stirred under hydrogen atmosphere for 16 hours, and the Pd-C was filtered off. The filtrate was concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:5→1:4) and recrystallized from ethanol-ethyl acetate to give 4-aminobenzyldipropylphosphine oxide (1.78 g) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.[CH2:17]([NH2:20])[CH:18]=[CH2:19]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([NH:20][CH2:17][CH:18]=[CH2:19])=[O:12])[CH2:8]1
Reactant: C=CCN
Reactant: COc1cccc(OC2CN(C(=O)Cl)C2)c1
Solvent: C1CCOC1
Solvent: O
Product: C=CCNC(=O)N1CC(Oc2cccc(OC)c2)C1
Reaction time: 17 h
Yield: 76.8 %

Procedure:
A solution of 4.85 g (0.02 mole) of 3-(3-methoxyphenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.5 g (0.06 mole) of 2-propenylamine and stirred for 17 hr, diluted with 200 ml of water and extracted with 3×50 ml of methylene chloride. The combined extracts were dried then concentrated in vacuo to yield 4.03 g of oil residue. The residue was chromatographed on a spinning TLC plate (chromatotron) in 3 portions (3 runs) using a ethyl acetate/methylene chloride gradient. The 4th fraction of each run was combined and concentrated in vacuo to yield a white solid (1.2 g), which was recrystallized from benzene-ligroin yielding 0.94 g (18%) of fine white crystals, m.p. 121°-123° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([S:11][CH3:12])=[N:8][CH:7]=[N:6]2.C1C(=O)N(Br)C(=O)C1.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(Cl)(Cl)(Cl)Cl>[CH3:12][S:11][C:9]1[C:10]2=[C:2]([CH2:1][N:25]3[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]3)[CH:3]=[CH:4][N:5]2[N:6]=[CH:7][N:8]=1
Reactant: OC1CCNCC1
Reactant: CSc1ncnn2ccc(C)c12
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CSc1ncnn2ccc(CN3CCC(O)CC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of 5-methyl-4-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (200 mg, 1.12 mmol), NBS (218 mg, 1.23 mmol), and AKIN (spatula tip) in carbon tetrachloride (4 mL) was heated at 80° C. for 1 h. After cooling to rt, the solution was filtered to remove succinimide. To the filtrate was added 4-hydroxypiperidine (126 mg, 1.34 mmol, Aldrich) and DIPEA (214 μL, 1.23 mmol). The reaction was stirred at rt overnight and was then concentrated in vacuo. The residue was suspended in methanol and filtered. The filtrate was concentrated and the crude product was purified by flash chromatography on silica gel (20% MeOH/EtOAc) to give the title compound (229 mg, 74%) as a colorless solid. 1 H NMR (DMSO-d6) δ 8.25 (s, 1H), 7.88 (d, 1H, J=2 Hz), 6.81 (d, 1H, J=2 Hz), 4.54 (br s, 1H), 3.76 (s, 2H), 3.48-3.44 (m, 1H), 2.75-2.71 (m, 2H), 2.62 (s, 3H), 2.10-2.08 (m, 2H), 1.70-1.68 (m, 2H), 1.38-1.36 (m, 2H); MS(ESI+) m/z 279.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[C:17]3[N:33]=[CH:32][S:31][C:18]=3[N:19]=[C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=3)[N:21]=2)[CH:6]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH3:14])[CH:8]=1.CC[N:36]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[C:17]3[N:33]=[CH:32][S:31][C:18]=3[N:19]=[C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH2:36])=[O:27])=[CH:24][CH:23]=3)[N:21]=2)[CH:6]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C@@H:10]2[CH3:14])[CH:8]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc(Nc2nc(-c3ccc(C(=O)O)cc3)nc3scnc23)cc(N2CCC[C@@H]2C)c1
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2nc(-c3ccc(C(N)=O)cc3)nc3scnc23)cc(N2CCC[C@@H]2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
The mixture of (S)-4-(7-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzoic acid, EDCI (56 mg, 0.29 mmol), HOBt (39 mg, 0.29 mmol) and Et3N (39 mg, 0.39 mmol) in DCM (20 mL) was stirred at room temperature for 3 hrs, then ammonia was bubbled into this mixture for 3 h. The mixture was filtered and the filtrate was concentrated to give a residue which was purified by column chromatography (DCM:MeOH=50:1) to afford (S)-4-(7-(3-methoxy-5-(2-methylpyrrolidin-1-yl)phenylamino)thiazolo[5,4-d]pyrimidin-5-yl)benzamide (12 mg, 10%) as yellow solid. 1H NMR (300 MHz, DMSO): δ 9.99 (s, 1H), 9.40 (s, 1H), 8.49 (s, 1H), 8.46 (s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 7.49 (s, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 5.88 (s, 1H), 3.93-3.90 (m, 1H), 3.79 (s, 3H), 3.43-3.40 (m, 1H), 3.18-3.15 (m, 1H), 2.06-1.98 (m, 3H), 1.69 (s, 1H), 1.15 (d, 3H, J=6.0 Hz). LC-MS: 461 [M+H]+, tR=1.6 min. HPLC: 95.06% at 214 nm, 95.01% at 254 nm, tR=5.55 min.