Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=[O:4].[CH3:12][N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C(OCC)C>[Br-:1].[CH3:12][NH+:13]1[CH:17]=[CH:16][N:15]([CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH3:11])=[O:4])[CH2:14]1
Reactant: Cc1ccccc1C(=O)CBr
Reactant: Cn1ccnc1
Solvent: CCOCC
Product: Cc1ccccc1C(=O)CN1C=C[NH+](C)C1
Product: [Br-]
Yield: 33.5 %

Procedure:
A solution of 4.22 g (0.02 mol) of 1-bromo-2-(2-methylphenyl)-2-oxoethane, 2.64 g (0.032 mol) of 1-methylimidazole and 60 ml of diethyl ether was stirred at room temperature for approximately 17 hours. The reaction solvent was decanted and the residue was washed with diethyl ether. The residue was dissolved in hot acetonitrile, and the resulting solution was cooled and diluted with diethyl ether. The solid was collected and recrystallized twice from acetonitrile/diethyl ether to afford 1.99 g of 1-methyl-3-[2-(2-methylphenyl)-2-oxoethyl]-1H-imidazolium bromide as white needles. (34% yield) mp=152°-154° C.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].OS([O-])=O.[Na+].Cl.Cl.[NH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:24]([NH2:26])=[NH:25].C(O)C>O>[CH3:2][C:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]2[NH:30][C:29]3[CH:28]=[CH:27][C:23]([C:24](=[NH:25])[NH2:26])=[CH:22][C:21]=3[N:20]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: N=C(N)c1ccc(N)c(N)c1
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2nc3cc(C(=N)N)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-tert-butylbenzaldehyde (0.4000 g, 0.00247 mol) was added 3 mL of 40% NaHSO3 (aq). The mixture was stirred for 2 h at 25° C. 3,4-Diaminobenzamidine dihydrochloride (0.56 g, 0.0025 mol) and ethanol (8 mL) were added. The mixture was refluxed for 3 h. The reaction was then poured into water. The precipitate filtered and recrystallized from 2N HCl to afford 1H-benzimidzole-5-carboximidamide, 2-[4-(1,1-dimethylethyl)phenyl]- (400 mg, 44%) as a white solid: 1H NMR (DMSO-d6) δ9.47 (bs, 2 NH), 9.15 (bs, 2 NH), 8.30 (d, 2 arom-H, J=8 Hz), 8.21 (s, 1 arom-H), 7.88 (d, 1 arom-H, J=8 Hz), 7.73 (d, 1 arom-H, J=9 Hz), 7.68 (d, 2 arom-H, J=8 Hz), 1.35 (s, 9 tert-butyl-H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[S:6].Br[CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]2[C:19]([CH3:24])=[N:20][CH:21]=[C:22]([CH3:23])[C:11]=12>O1CCOCC1>[NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[S:6][CH2:8][CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]2[C:19]([CH3:24])=[N:20][CH:21]=[C:22]([CH3:23])[C:11]=12
Reactant: Cc1cnc(C)n2c1c(CCBr)c1ccccc12
Reactant: S=C1NCCN1
Solvent: C1COCCO1
Product: Cc1cnc(C)n2c1c(CCSC1=NCCN1)c1ccccc12
Yield: 59.2 %

Procedure:
A mixture of 2-imidazolidinethione (3.1 g), 5-(2-bromoethyl)-1,4-dimethylpyrimido[1,6-a]indole (6 g, described in Example 13) and dry dioxane (400 ml) is refluxed for 6 hours. The resulting precipitate is collected by filtration and dissolved in water and the solution is neutralized with aqueous sodium bicarbonate. After adding a few drops of 10% sodium hydroxide, the aqueous mixture is extracted with chloroform. The combined extracts are washed with water, dried over magnesium sulfate, filtered and evaporated. The residue is crystallized from acetonitrile to obtain the title compound (3.8 g): mp 157°-159° C.; ir (CHCl3) 3400, 1610, 1595 and 1570 cm-1 ; uv(MeOH) λmax 250,299,311 and 325 nm; ε=35200, 4840, 8200, and 10870, respectively; and nmr (CDCl3) δ2.52(s), 2.99(s), 3.43(m), 3.60(s), 4.25(s) and 7.1-8.2(m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[CH3:23][Sn](C)(C)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH3:23])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: C[Sn](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(C)c2nc(-c3ccccc3)sc2c1O
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (301 mg, 0.80 mmol), tetramethyltin (442 μL, 3.18 mmol) and bis(triphenylphosphine)palladium(II) dichloride (56 mg, 0.08 mmol) in dimethylformamide (5 mL) was stirred at 130° C. for 30 min before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (218 mg): 1H NMR (CDCl3, 200 MHz): δ=11.39 (s, 1H), 8.09 (m, 2H), 7.50 (m, 3H), 4.57 (q, J=7.0 Hz, 2H), 2.96 (s, 3H), 1.52 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:27][CH2:28][CH2:29][CH2:30][S:31](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:33])=[O:32]>>[Cl:27][CH2:28][CH2:29][CH2:30][S:31]([NH:21][CH2:20][CH:19]([NH:22][C:23]([O:25][CH3:26])=[O:24])[CH2:18][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:33])=[O:32]
Reactant: CCCCCCCCCCCCCCCCSCC(CN)NC(=O)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)NC(=O)OC

Procedure:
3-Hexadecylthio-2-methoxycarbonylaminopropylamine IVe3 is allowed to react and worked up by the same procedure as described in (4). m.p. 67°-69° C. The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][CH:25]=O)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O1CCCC1.[OH-].[NH4+:38].II>O>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C@@H:23]([CH:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:24][C:25]#[N:38])[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: [NH4+]
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC=O)C4CCCC4)c3)ncnc21
Agent: II
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)OCn1ccc2c(-c3cnn([C@H](CC#N)C4CCCC4)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 86.8 %

Procedure:
A solution of (1R)-(4-(1-(1-cyclopentyl-3-oxopropyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-37, 169 mg, 0.399 mmol) in tetrahydrofuran (THF, 1.2 mL, 15 mmol) at room temperature was added a 14.3 M solution of ammonium hydroxide (NH4OH) in water (1.2 mL), followed by iodine (I2, 112 mg, 0.439 mmol, 1.1 equiv). The resulting reaction mixture was stirred at room temperature for 25 min. When LCMS showed that the reaction was deemed complete, the reaction mixture was quenched with 10% aqueous Na2S2O3 (10 mL) before being extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by Combiflash (SiO2) with 0-60% EtOAc/hexane gradient elution to afford (R)-(4-(1-(2-cyano-1-cyclopentylethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate ((R)-12, 145.6 mg, 167.8 mg theoretical, 86.8% yield) as a colorless foam.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:29]2[C:28]3[C:23](=[CH:24][C:25]([OH:30])=[CH:26][CH:27]=3)[NH:22][C:21]=2[C:20]([C:31]([NH2:33])=[O:32])=[CH:19][CH:18]=1>N1C=CC=CC=1.CCOC(C)=O>[N:1]1([C:7]([O:30][C:25]2[CH:26]=[CH:27][C:28]3[C:29]4[C:21](=[C:20]([C:31](=[O:32])[NH2:33])[CH:19]=[CH:18][C:17]=4[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[F:10])[NH:22][C:23]=3[CH:24]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(O)ccc12
Reactant: O=C(Cl)N1CCOCC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(OC(=O)N3CCOCC3)ccc12
Reaction time: 22 h
Yield: 31.4 %

Procedure:
Morpholine-4-carbonyl chloride (11.29 mg, 0.075 mmol) was added to a solution of 4-(2-fluorophenyl)-7-hydroxy-9H-carbazole-1-carboxamide (Example 40-1, 18.6 mg, 0.058 mmol) in pyridine (1 mL). After 22 h at rt, additional morpholine-4-carbonyl chloride (11.29 mg, 0.075 mmol) was added. After 15 h, the mixture was diluted with EtOAc (30 mL), washed with water (10 mL) and brine (5 mL), and dried and concentrated. The residue was purified by preparative HPLC to provide 8-carbamoyl-5-(2-fluorophenyl)-9H-carbazol-2-yl morpholine-4-carboxylate as a white solid (7.9 mg, 27%). 1H NMR (400 MHz, chloroform-d) δ 9.94 (1H, br. s.), 7.41-7.65 (3H, m), 7.33 (2H, t, J=8.14 Hz), 7.20 (1H, d, J=8.58 Hz), 6.92-7.15 (4H, m), 6.73 (1H, dd, J=8.58, 1.98 Hz), 3.80 (4H, t, J=4.62 Hz), 3.67-3.76 (2H, m), 3.62 (2H, br. s.). Mass spectrum m/z 434.0 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:8][S:9]([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At r.t. to a solution of tetrahydro-4H-pyran-4-ol (90 uL, 1 mmol; Aldrich, Cat. No. 198234) in methylene chloride (3 mL) was added methanesulfonyl chloride (91 uL, 1.2 mmol), followed by triethylamine (0.20 mL, 1.5 mmol) and 4-dimethylaminopyridine (12 mg, 0.098 mmol). The mixture was stirred at r.t. for 3 h. It was diluted with methylene chloride. The solution was washed with water and brine, dried over Na2SO4. After filtration, the filtrate was concentrated to yield 0.21 g of the product (crude) which was directly used in the next step reaction without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:15]2[C:14]3[CH:13]=[C:12]([CH3:18])[CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6][CH2:5]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH3:29])[CH2:28][O:27]2)=[CH:22][CH:21]=1.C(O)(=O)C(O)=O>CN(C=O)C.C1COCC1.O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([OH:27])([CH3:28])[CH2:29][N:8]2[C:9]3[CH:10]=[CH:11][C:12]([CH3:18])=[CH:13][C:14]=3[C:15]3[CH2:16][CH2:17][N:4]([CH3:3])[CH2:5][CH2:6][C:7]2=3)=[CH:24][CH:25]=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: CC1(c2ccc(Cl)cc2)CO1
Agent: O=C(O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccc(Cl)cc2)CCN(C)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (67 mg, 0.28 mmol) in 5 mL of DMF, 3,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.934 mmol) was added and stirred at RT for 5 min. 2-(4-Chlorophenyl)-2-methyloxirane (235 mg, 1.4 mmol) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by column chromatography using 10% methanol-DCM. The freebase (30 mg, 0.078 mmol) was dissolved in THF (1.0 mL) and oxalic acid (9.8 mg, 0.078 mmol) in THF (1.0 mL) was added slowly, the mixture was stirred at RT for 20 min. and the formed solid was filtered, washed with ether and dried to afford product as oxalate salt.
Reaction SMILES: [C:1](=[O:6])=[N:2][C:3](Cl)=[O:4].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][NH:36][OH:37])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.O1CCCC1.Cl>O>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[C:3](=[O:4])[NH:2][C:1](=[O:6])[O:37]3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1
Reactant: O=C=NC(=O)Cl
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(CNO)cc2)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(Cn3oc(=O)[nH]c3=O)cc2)cc1
Reaction time: 0.5 h
Yield: 53 %

Procedure:
N-(Chlorocarbonyl)isocyanate (0.2 mL, 2.6 mmol) was added dropwise into a cold (−5° C.) mixture of N-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ylmethyl}-hydroxylamine (1.1, 2.6 mmol), and tetrahydrofuran (20.0 mL). The reaction mixture was stirred for 30 minutes, poured into water, acidified with HCl (2 N), and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acidic silica gel (hexanes/EtOAc 2:1) gave a white solid (0.68 g, 53% yield): mp 196–198; MS m/e 493 (M+);
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[S:26]1(=[O:33])(=[O:32])[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]1>>[CH3:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:5]3[C:6]([F:8])=[CH:7][C:2]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31][S:26]4(=[O:33])=[O:32])=[CH:3][C:4]=3[F:25])=[O:10])[CH2:12][CH2:13]2)=[N:18][CH:19]=[C:20]([CH3:24])[CH:21]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Reactant: O=S1(=O)CCCCN1
Product: Cc1cnc(N2CCN(C(=O)c3c(F)cc(N4CCCCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 87.5 %

Procedure:
Using (4-bromo-2,6-difluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (429 mg) described in Preparation Example 111 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (425 mg) was obtained.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32](=[O:33])[NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:29][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A161) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16](C)[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[Si]([O:32][C:33]([O:35][CH3:36])=[CH2:34])(C(C)(C)C)(C)C.C([Sn](F)(CCCC)CCCC)CCC>O1CCCC1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([CH2:34][C:33]([O:35][CH3:36])=[O:32])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][CH:16]=[N:17]1)([CH3:21])[CH3:20]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Reactant: C=C(OC)O[Si](C)(C)C(C)(C)C
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: CCCC[Sn](F)(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Temperature: 80 °C
Yield: 53.3 %

Procedure:
A mixture of 194 mg (0.500 mmol) of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411, 0.436 mL (2.00 mmol) of 1-(tert-butyldimethylsilyloxy)-1-methoxyethene, 19.6 mg (0.025 mmol) of dichlorobis(tri-o-tolylphosphine)palladium(II) (19.6 mg, 0.0250 mmol) and 309 mg (1.00 mmol) of tributyltin fluoride (309 mg, 1.00 mmol) in 3.0 ml of tetrahydrofuran was degassed and then heated for 18 hours at 80° C. The mixture was filtered through Celite, the filtrate mixed with 10 ml of water, the mixture was acidified to pH2 and extracted with ethyl acetate. The organic phases were combined, dried with MgSO4 and concentrated. The residue was purified by flash chromatography (0-5% gradient of methanol in dichloromethane) to afford 98 mg of Methyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate (51%). M/z 382.2. calc. 381. 18
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[C:21]1[CH:25]=[CH:24][N:23]([C:26]2([CH2:30][C:31]#[N:32])[CH2:29][NH:28][CH2:27]2)[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](Cl)(=[O:35])[CH3:34].C(N(CC)CC)C>C(Cl)Cl>[C:33]([N:28]1[CH2:29][C:26]([CH2:30][C:31]#[N:32])([N:23]2[CH:24]=[CH:25][C:21]([C:9]3[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:12]4[CH:13]=[CH:14][C:15]5[N:16]([C:17]([CH3:20])=[N:18][N:19]=5)[C:11]=4[CH:10]=3)=[N:22]2)[CH2:27]1)(=[O:35])[CH3:34]
Reactant: Cc1nnc2ccc3c(cc(-c4ccn(C5(CC#N)CNC5)n4)n3Cc3ccccc3)n12
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CC(CC#N)(n2ccc(-c3cc4c(ccc5nnc(C)n54)n3Cc3ccccc3)n2)C1
Reaction time: 0.08 h
Yield: 92.9 %

Procedure:
To {3-[3-(6-benzyl-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridin-7-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (8.0 mg, 0.019 mmol, from Example 90) was added acetyl chloride (1.6 μL, 0.022 mmol, Aldrich) in DCM (0.50 mL), followed by triethylamine (5.3 μL, 0.038 mmol). The reaction was complete in 5 minutes. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH) afforded desired product (8.2 mg, 93%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([OH:28])=O)[C:18]([C:32]([F:35])([F:34])[F:33])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[OH-]>CN(C=O)C.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([NH:14][C:15]3[N:20]=[C:19]([CH2:21][CH2:22][C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([NH2:37])=[O:28])[C:18]([C:32]([F:35])([F:34])[F:33])=[CH:17][N:16]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(=O)O)c4)n3)c2)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2cccc(Nc3ncc(C(F)(F)F)c(CCc4cccc(C(N)=O)c4)n3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
To a solution of 3-(2-(2-((3-(4-methylpiperazin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)benzoic acid (I30) (0.048 g, 0.10 mmol) and HATU (0.051 g, 0.13 mmol) in DMF (2 mL) was added DIPEA (0.068 mL, 0.39 mmol), the resulting solution was then stirred for 10 minutes before addition of NH4OH (0.2 mL). The resulting mixture was then stirred overnight (16 hours) at room temperature. The mixture was diluted with water and extracted with EtOAc (2×20 mL). The combined organic extracts were dried using a phase separation cartridge before concentrating under reduced pressure. The organic residues were then purified using silica gel column chromatography (0-30% MeOH/EtOAc with 1% NH4OH in the MeOH) to give the title compound (6)(0.028 mg, 58%) as a white solid; 1H NMR (400 MHz, d6-DMSO) δ 10.07 (s, 1H), 8.67 (s, 1H), 7.95 (s, 1H), 7.78 (s, 1H), 7.72 (m, 1H), 7.54 (s, 1H), 7.38 (m, 2H), 7.34 (m, 1H), 7.14 (d, J=5.2 Hz, 2H), 6.64 (m, 1H), 3.10 (m, 8H), 2.42 (m, 4H), 2.19 (s, 3H). LCMS Method C: rt 4.80 min; m/z 485.3 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)=[CH:9][C:8]=1[N+:22]([O-])=O)C.O1C2C=CC=CC=2CC(=O)N1.NC1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[F:21][C:17]1[CH:16]=[C:15]([CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]3[O:6][CH2:5][C:4](=[O:3])[NH:22][C:8]=3[CH:9]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)COc1ccc(C#Cc2cccc(F)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C1Cc2ccccc2ON1
Solvent: CCOC(C)=O
Solvent: Nc1ccccc1
Product: O=C1COc2ccc(CCc3cccc(F)c3)cc2N1
Temperature: 23 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
To a solution of [4-(3-fluoro-phenylethynyl)-2-nitro-phenoxy]-acetic acid ethyl ester (1.72 g, 5.01 mmol, 1 equiv) in ethyl acetate (50 mL) was added palladium on carbon (500 mg, 10 wt. %, wet, Degussa type). The reaction vessel was placed under an atmosphere of hydrogen (balloon) and stirred at 23° C. for 15 h. At this time LCMS analysis indicated the reaction contains a mixture of the desired benzoxazinone product (major) and uncyclized aniline (minor). The mixture was filtered through a pad of Celite, washing with ethyl acetate (100 mL). The solution was concentrated, then re-dissolved in ethyl acetate (100 mL) and refluxed for 2 h. LCMS analysis indicates no improvement in cyclized:uncyclized ratio. Para-toluenesulfonic acid hydrate (111 mg) was added and resulting solution was refluxed for a further 1 h. The solution was cooled to 23° C. then washed successively with water, 1.0 N aqueous hydrochloric acid, saturated aqueous brine (100 mL each), dried (MgSO4), filtered and concentrated. The product was purified using an Isco CombiFlash automated chromatography system. The residue was loaded onto a 80 g silica gel column as a solution in dichloromethane (5 mL) then eluted with methanol in dichloromethane (0-5% methanol linear gradient over 18 column volumes at a flow rate of 60 mL/min) to give 1.15 g (4.24 mmol, 85%) of the title compound as a tan solid.
Reaction SMILES: [Na].[N+:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[C-:3].[C:10]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.C1C[O:20]CC1>>[CH:3]([NH:2][C:4](=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:20]
Reactant: C1CCOC1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C1CCCCC1
Agent: [Na]
Product: CCOC(=O)C(NC=O)=C1CCCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of sodium hydide (4.07 g, 60%, 101 mmol) in THF (100) is cooled to 0° C. Two addition funnels are charged with ethyl isocyanoacetate (10.0 g, 88.4 mmol) in THF (10 mL) and cyclohexanone (9.67 g, 88.4 mmol) in THF (10 mL). The solutions are added dropwise to the reaction mixture over a 30 minute period. The resulting mixture is then allowed to warm to room temperature and stirred overnight. The reaction mixture is quenched by the addition of saturated ammonium chloride solution. The layers are separated, and the aqueous layer is washed with ethyl acetate (3×100 mL). The combined organic extracts are washed with brine (200 mL), dried (MgSO4) and then concentrated to an oil under reduced pressure. Ethyl acetate (40 mL) followed by hexane is added to the mixture until the mixture became turbid. The resulting solution is cooled to 0° C. and the desired product crystallized out of solution.