Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1([CH2:43][CH3:44])[CH2:11][S:10](=[O:13])(=[O:12])[C:9]2[CH:14]=[CH:15][C:16]([N:18]([CH3:20])[CH3:19])=[CH:17][C:8]=2[CH:7]([C:21]2[CH:22]=[C:23]([NH:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[CH:24]=[CH:25][CH:26]=2)[CH:6]1[OH:42])[CH2:2][CH2:3][CH3:4].[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>C(Cl)Cl>[F:45][C:46]([F:51])([F:50])[C:47]([O-:49])=[O:48].[CH2:1]([C:5]1([CH2:43][CH3:44])[CH2:11][S:10](=[O:13])(=[O:12])[C:9]2[CH:14]=[CH:15][C:16]([NH+:18]([CH3:20])[CH3:19])=[CH:17][C:8]=2[CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][C:35]([OH:37])=[O:36])[CH:22]=2)[CH:6]1[OH:42])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCC1(CC)CS(=O)(=O)c2ccc(N(C)C)cc2C(c2cccc(NCCOCCOCC(=O)OC(C)(C)C)c2)C1O
Solvent: ClCCl
Product: CCCCC1(CC)CS(=O)(=O)c2ccc([NH+](C)C)cc2C(c2cccc(NCCOCCOCC(=O)O)c2)C1O
Product: O=C([O-])C(F)(F)F

Procedure:
A solution of 90 mg of tert-butyl (2-{2-[3-(3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)phenylamino]ethoxy}ethoxy)acetate in 1 ml of methylene chloride and 1 ml of trifluoroacetic acid is stirred for 2 h and then concentrated. The product is purified by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:5][N:4]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].N1C=CC=CC=1.O>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([NH:9][S:26]([CH3:25])(=[O:28])=[O:27])=[CH:7][C:6]([C:10]#[C:11][C:12]2[C:13]([CH3:24])=[N:14][CH:15]=[N:16][C:17]=2[N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[CH:5][N:4]=1
Reactant: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncc(C#Cc2c(C)ncnc2N2CCOCC2)cc1NS(C)(=O)=O
Temperature: 25 °C

Procedure:
To 100 mg (0.31 mmol) 2-Methoxy-5-(4-methyl-6-morpholin-4-yl-pyrimidin-5-ylethynyl)-pyridin-3-ylamine (E-9) in 5 mL DCM is added 70 mg (0.61 mmol) methanesulfonyl chloride and 72 μL (0.91 mmol) pyridine and the reaction mixture is stirred over night at RT. Water (2 mL) is added and the reaction mixture is extracted three times with 4 mL ethylacetate. The combined organic phases are dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by RP chromatography (C18, 20-80% ACN in water containing 1% formic acid). Yield: 32 mg (18%). HPLC-MS: M+H=404; tR=0.65 min.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:27](O)=[O:28])=[N:22][N:23]([CH2:25][CH3:26])[CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:21]3[C:20]([Cl:19])=[CH:24][N:23]([CH2:25][CH3:26])[N:22]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: CCn1cc(Cl)c(C(=O)O)n1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: CCn1cc(Cl)c(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)n1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-chloro-1-ethyl-1H-pyrazole-3-carboxylic acid (CAS512810-20-7) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=416.3 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1)([O-:15])=[O:14].O>C(Cl)Cl>[OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:23](=[O:24])[CH2:22][C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][CH:20]=1
Reactant: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reactant: NCCCO
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)NCCCO
Temperature: 25 °C
Yield: 11.4 %

Procedure:
To a stirred solution of 3-hydroxypropylamine (507 mg, 6.76 mmol) and triethylamine (1.88 mL, 0.013 mol) in DCM (10 mL) at 0° C. was added (4-nitro-phenyl)-acetyl chloride (1.35 g, 6.76 mmol) in DCM (10 mL) dropwise. The dark red solution was allowed to warm to room temperature and then poured into water (50 mL). The layers were separated and the organic layer was dried (Na2SO4) and concentrated in vacuo. The crude material was purified by preparative thin layer chromatography (TLC) (5%-MeOH—CHCl3) to afford 183 mg (11%) of the title compound as a solid. 1H-NMR (CDCl3; 400 MHz): δ 8.12 (d, 2H, J=8.7 Hz), 7.39 (d, 1H, J=8.7 Hz), 6.09 (br s, 1H), 3.58 (s, 2H), 3.57-3.54 (m, 2H), 3.40 (br s, 1H), 3.36-3.31 (m, 2H), 1.63-1.57 (m, 2H).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:25][CH2:26][C:27]([NH:29][C:30]1[N:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1)=[O:28]>C(#N)C>[Br-:25].[C:19]1([C:12]2([C:10]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N+:1]([CH2:26][C:27](=[O:28])[NH:29][C:30]5[N:31]=[N:32][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:34][CH:35]=5)([CH2:6][CH2:5]4)[CH2:2]3)=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CBr)Nc1ccc(C(F)(F)F)nn1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1ccc(C(F)(F)F)nn1
Product: [Br-]
Reaction time: 8 h
Yield: 93.8 %

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 1e) (61.1 mg) and 2-bromo-N-(6-trifluoromethyl-pyridazin-3-yl)-acetamide (Example 3a) (53.0 mg) were dissolved in acetonitrile (2 mL) and left overnight. The solvent was evaporated and the product was purified by column chromatography on silica eluting with 10% methanol in dichloromethane to afford the titled compound (107 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Li]CCCC.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C>C1COCC1.CCCCCC>[F:13][C:2]([F:1])([F:12])[C:3]1[C:8]2[S:9][C:10]([B:19]([OH:24])[OH:20])=[CH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1cccc2ccsc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2cccc(C(F)(F)F)c2s1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
To a solution of 7-trifluoromethyl-benzo[b]thiophene (0.52 g, 0.0026 mol) in THF (30 mL) at −78° C. was added 2.5 M of n-BuLi in hexane (1.4 mL). The reaction was then slowly warmed up to −30° C. over 30 min. and stirred at this temperature for 10 min prior to recooling to −78° C. and treatment with triisopropyl borate (0.7255 g, 0.0038 mol). The reaction was then slowly warmed up to 0° C. then was quenched with saturated ammonium chloride and the solvent removed in vacuo. To the residue was added aqueous sodium hydroxide (10 mL, 2N solution) followed by water (30 mL) then this mixture was extracted with DCM. The aqueous solution was acidified using dilute sulfuric acid (2N solution), filtered and the residue dried in vacuo to yield 7-trifluoromethylbenzo[b]thiophen-2-boronic acid. 1H NMR (400 MHz, MeOD) δ ppm 7.55 (1H, t, J=7.45 Hz), 7.75 (1H, d, J=7.07 Hz), 8.02 (1H, s) and 8.17 (1H, d, J=#7.83 Hz).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14](Cl)=[O:15].[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26][OH:27])[CH3:23]>CCOCC>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]([CH3:21])([C:17]([F:20])([F:19])[F:18])[C:14]([O:27][CH2:26][CH2:25][N:24]([CH2:28][CH3:29])[CH2:22][CH3:23])=[O:15]
Reactant: CCN(CC)CCO
Reactant: CC(OCc1ccc2ccccc2c1)(C(=O)Cl)C(F)(F)F
Solvent: CCOCC
Product: CCN(CC)CCOC(=O)C(C)(OCc1ccc2ccccc2c1)C(F)(F)F
Reaction time: 18 h

Procedure:
A solution of (±)-2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionyl chloride (3.0 g.) in ether (20 ml.) is added dropwise at ambient temperature to a stirred solution of 2-diethylaminoethanol (3.0 ml.) in ether (100 ml.). The mixture is stored for 18 hours, filtered, and the solid is washed with ether. The filtrate and washings are evaporated to an oil (3.5 g.), which is dissolved in ether and run through a column of silica gel made up in ether. The column is eluted with 200 ml. of ether, and the eluate evaporated to give 2.4 g. of an oil which is similarly passed through a column of alumina (Neutral, Grade I, 30 g.). Elution with ether yields (±)-2-diethylaminoethyl 2-(2-naphthylmethoxy)-3,3,3-trifluoro-2-methylpropionate (1.05 g.) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:35]([O:37]CC)=[O:36])=[C:21]([CH2:23][N:24]3[C:32](=[O:33])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]3=[O:34])[N:22]=2)[CH2:14][CH2:13]1)=[O:10].[Li+].[OH-:41]>C1COCC1.O>[C:32]([C:31]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:25]([NH:24][CH2:23][C:21]1[N:22]=[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:13][CH2:14]2)[S:19][C:20]=1[C:35]([OH:37])=[O:36])=[O:34])([OH:41])=[O:33]
Reactant: [OH-]
Reactant: CCOC(=O)c1sc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)nc1CN1C(=O)c2ccccc2C1=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc(CNC(=O)c4ccccc4C(=O)O)c(C(=O)O)s3)CC2)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-1,3-thiazole-5-carboxylate (Example 277; 194 mg, 0.32 mmol) in anhydrous THF (2 ml) was added 2 N LiOH (0.82 ml). The mixture was stirred at room temperature for 4 h. The mixture was acidified to pH 3 and the precipitate that formed was diluted with water and extracted with EtOAc, dried over Na2SO4 and concentrated in vacuo to give the title compound (160 mg).
Reaction SMILES: CO[C:3]1[CH:7]=[CH:6][S:5][C:4]=1OC.[Cl:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:10][CH2:11][CH:12]1[O:15][C:3]2=[CH:4][S:5][CH:6]=[C:7]2[O:14][CH2:13]1
Reactant: OCC(O)CCl
Reactant: COc1ccsc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: ClCC1COc2cscc2O1

Procedure:
Under a nitrogen atmosphere in a 500 mL round bottom flask equipped with a reflux condenser, 20.0 g (0.139 mol) dimethoxythiophene, 17.8 g (0.161 mol) 3-chloro-1,2-propanediol, and 5 g p-toluenesulfonic acid was dissolved in 350 mL toluene. The reaction was then heated to ˜90 C overnight. At this time TLC indicated consumption of starting material. After cooling the reaction mixture was concentrated to ˜100 mL and poured into saturated potassium carbonate solution. The mixture was extracted with DCM and the combined extracts were dried with magnesium sulfate. Solvent removal gave a dark oil that was purified by column chromatography using 3:1 hexanes/DCM. Solvent removal gave the product as a white solid. Structure and purity were confirmed by 1H/13C NMR and LC-MS.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH:7]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:39]=[N:38][C:20]5[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:22]6[CH:27]=[N:26][C:25]([C:28]#[N:29])=[CH:24][C:23]=6[C:19]=5[CH:18]=4)=[CH:13][CH:12]=3)[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[CH:40]1[N:44]=[CH:43][N:42]([C:45](N2C=NC=C2)=[S:46])[CH:41]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:28]([C:25]1[N:26]=[CH:27][C:22]2[N:21]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:36])[CH3:37])[C:20]3[N:38]=[CH:39][C:17]([C:14]4[CH:15]=[CH:16][C:11]([CH2:10][N:9]5[CH:7]6[CH2:6][CH2:5][CH:4]5[CH2:3][CH:2]([O:1][C:45]([N:42]5[CH:41]=[CH:40][N:44]=[CH:43]5)=[S:46])[CH2:8]6)=[CH:12][CH:13]=4)=[CH:18][C:19]=3[C:23]=2[CH:24]=1)#[N:29]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(-c3ccc(CN4C5CCC4CC(O)C5)cc3)cnc21
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2cc(-c3ccc(CN4C5CCC4CC(OC(=S)n4ccnc4)C5)cc3)cnc21
Yield: 96.6 %

Procedure:
A solution of 3-[4-(3-hydroxy-8-aza-bicyclo[3.2.1]oct-8-ylmethyl)-phenyl]-9-(2-trimethylsilanylethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (155 mg, 0.29 mmol), DMAP (5 mg, catalytic) and N,N′-thiocarbonyldiimidazole (455 mg, 8.76 mmol) in DCM (10 mL) was heated under reflux for 12 h. The cooled reaction mixture was purified by flash chromatography (silica, 50 g column, Biotage, 0-5% MeOH in DCM) to afford the title compound as a white solid (182 mg, 97%). 1H NMR (CDCl3, 300 MHz): 9.28-9.25 (m, 1H), 9.04 (dd, J=7.0, 2.2 Hz, 1H), 8.69-8.66 (m, 1H), 8.51 (d, J=1.0 Hz, 1H), 8.47-8.39 (m, 1H), 7.81-7.61 (m, 5H), 7.15-7.10 (m, 1H), 6.12 (s, 2H), 4.35 (s, 2H), 3.76-3.61 (m, 4H), 2.32-2.17 (m, 4H), 2.13-1.93 (m, 5H), 1.08-0.96 (m, 2H), 0.00 (s, LCMS (Method B): RT=3.13 min, M+H+=650.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([NH2:12])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])[N:4]=1.[H-].[Na+].[C:25]([C:29]1[CH:33]=[C:32]([C:34](O)=[O:35])[O:31][N:30]=1)([CH3:28])([CH3:27])[CH3:26].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7]([NH:12][C:34]([C:32]2[O:31][N:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:33]=2)=[O:35])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])[N:4]=1
Reactant: COc1nc(-c2ccccc2C(F)(F)F)cc(N)c1[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(C(=O)O)on1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1nc(-c2ccccc2C(F)(F)F)cc(NC(=O)c2cc(C(C)(C)C)no2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine (163 mg, 0.519 mmol, prepared as described in STEP B above) in THF (10 mL) was treated with NaH (62.2 mg, 1.56 mmol, 60% dispersion in oil), and the mixture was allowed to stir at room temperature for 1 h. Simultaneously, a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (114 mg, 0.674 mmol, prepared as described in Example I above) in anhydrous DCM (10 mL) was treated with oxalyl chloride (58.8 μL, 0.674 mmol) and DMF (2 drops), and the mixture was stirred at room temperature for 1 h. Volatile components were removed in vacuo, and the residue was taken up in anhydrous THF (6 mL). The above-prepared acid chloride solution was added to the sodium anilide solution above, and the mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted twice with EtOAc (25 mL). The residue was purified on a 12-g SEPRA Si 50 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:4 over 40 min) to yield 3-tert-butyl-isoxazole-5-carboxylic acid [2-methoxy-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 10.62 (s, 1H), 8.39 (s, 1H), 7.82 (d, J=7.3 Hz, 1H), 7.63-7.69 (m, 1H), 7.58-7.63 (m, 1H), 7.56 (d, J=7.6 Hz, 1H), 6.98 (s, 1H), 4.09 (s, 3H), 1.38 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C21H19N4O5F3: 465.1 (M+H); Measured: 465.1.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[CH2:12][NH:13][C:14](=[O:27])[C@H:15]([CH:24]([CH3:26])[CH3:25])[NH:16]C(OC(C)(C)C)=O)=CC=1)([O-])=O.C(N(CC)CC)C.[NH2:36][C@H:37]1[C@@H:41]([CH3:42])[CH2:40][N:39]([C:43]2[C:52]([F:53])=[CH:51][C:50]3[C:54](=[O:60])[C:55]([C:57]([OH:59])=[O:58])=[CH:56][N:48]4[C:49]=3[C:44]=2[CH2:45][CH2:46][N:47]4[CH3:61])[CH2:38]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(Cl)[Cl:76]>O>[ClH:76].[NH2:16][CH:15]([CH:24]([CH3:26])[CH3:25])[C:14]([NH:13][CH2:12][C:11]([NH:36][C@H:37]1[C@@H:41]([CH3:42])[CH2:40][N:39]([C:43]2[C:52]([F:53])=[CH:51][C:50]3[C:54](=[O:60])[C:55]([C:57]([OH:59])=[O:58])=[CH:56][N:48]4[C:49]=3[C:44]=2[CH2:45][CH2:46][N:47]4[CH3:61])[CH2:38]1)=[O:10])=[O:27]
Reactant: ClCCl
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: C[C@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCN4C)C[C@H]1N
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)C(N)C(=O)NCC(=O)N[C@@H]1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2CCN4C)C[C@@H]1C
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
758 mg (2 mmol) of (N-t-butoxycarbonylvalyl)glycine p-nitrophenyl ester, 202 mg (2 mmol) of triethylamine and 716 mg (2 mmol) of the compound (30) obtained in Example 5 (1) were added to 10 ml of methylene chloride. The mixture solution was stirred overnight at room temperature. 10 ml of water was added to the solution and the solution was acidified with citric acid. The organic layer was separated and was removed by distillation after drying over sodium sulfate. Ethyl acetate--ether was added to the residue, the product came out of the solution, and the solid was filtered off. The solid was added to 10 mi of methanol, and 2.5 ml of 4N hydrochloride solution in dioxane was added to the solution. After the solution was stirred at room temperature for 30 minutes, the solvent was removed by distillation. The powder was filtered off and washed successively with ethanol and ether to obtain 618 mg of the subject compound (96) in a 58% yield. The results of the analysis of this compound were as follows:
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[C:15](=[O:17])=[O:16].O>O1CCCC1>[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[C:15]([OH:17])=[O:16]
Reactant: c1ccc2scnc2c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1nc2ccccc2s1
Yield: 47 %

Procedure:
A precooled (-78° C.) solution of 7.7 ml (19.2 mmol) of n-butyllithium in 50 ml of dry tetrahydrofuran was treated dropwise with 2.0 ml (18.3 mmol) of benzothiazole. After the addition was complete, the solution was poured into a mixture of excess dry ice in 100 ml of tetrahydrofuran. After being allowed to warm, the resulting solution was treated with water, washed with ether, acidified with HCl, and filtered to give a yellow solid. Digestion with boiling ether followed by filtration gave 1.55 g (47%) of the desired compound as a nearly white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:47]([CH3:46])(=[O:49])=[O:48])[CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:30]=[N:31][C:32]3[C:37]([CH:38]=2)=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C1C(c2cnc3ccccc3c2)=C(c2cc(F)cc(F)c2)c2ccc(OCCCN3CCNCC3)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(CCCOc2ccc3c(c2)C(=O)C(c2cnc4ccccc4c2)=C3c2cc(F)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-6-(3-(piperazin-1-yl)propoxy)-2-(quinolin-3-yl)-1H-inden-1-one (40 mg, 1.2 eq, 0.1 mmol) obtained in Step 3 in CH2Cl2 at 0° C. was added triethylamine (1.5 eq) and methylsulfonyl chloride (1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (53%).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH2:34])[CH2:23][CH3:24])[CH3:21]>C(#N)C>[ClH:1].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: CCN(CC)CC1CCCCN1CCN
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccccc2C(=O)Nc2cccnc21
Product: Cl
Temperature: 45 °C
Reaction time: 3 h

Procedure:
A mixture of 33.4 g (0.122 mol) of 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 28.0 g (0.131 mol) of 2-[2-[(diethylamino)methyl]piperidin-1-yl]ethanamine and 730 ml of anhydrous acetonitrile was stirred for 3 hours at a reaction temperature of 45° C. After standing for 1 hour in an ice bath, the precipitate formed was suction filtered and washed with ice cold acetonitrile. It was dissolved in 400 ml of hot ethanol, 4.6 g of activated charcoal were added, the mixture was filtered whilst hot and the filtrate was evaporated down in vacuo. The residue remaining was dissolved in 150 ml of hot propan-2-ol and stirred at a temperature of 75° C. for 2 hours after the careful addition of 800 ml of ethyl acetate. The mixture was then left to stand for 2 hours at ice bath temperature, the crystals produced were suction filtered and thoroughly washed three times with 20 ml aliquots of ethyl acetate. 37.0 g (62% of theory) of colourless crystals were obtained, m.p. 200°-202° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.[C:27]([CH2:29][C:30](O)=[O:31])#[N:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][N:22]([C:30](=[O:31])[CH2:29][C:27]#[N:28])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: N#CCC(=O)O
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CCNCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CCC2(CC1)CCN(C(=O)CC#N)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
To a solution of 5-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (100 mg, 0.28 mmol), 2-cyanoacetic acid (43.3 mg, 0.51 mmol) in a mixture of DCM and DMF (20 mL/5 mL) were added HATU (241.9 mg, 0.64 mmol) and Et3N (85.8 mg, 0.85 mmol). After addition, the reaction mixture was stirred at rt overnight, then quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the title compound as a beige solid (66.8 mg, 56%).