Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:9][CH:10]=[O:11].[CH3:13][C:14](C)([O-])[CH3:15].[K+].C(Cl)C=C>CN(C=O)C>[CH3:1][C:2]1([CH3:12])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH2:5][CH:6]2[CH:9]([CH2:15][CH:14]=[CH2:13])[CH:10]=[O:11]
Reactant: CC(C)(C)[O-]
Reactant: CC1(C)C2CCC(CC=O)C1C2
Agent: [K+]
Solvent: C=CCCl
Solvent: CN(C)C=O
Product: C=CCC(C=O)C1CCC2CC1C2(C)C
Yield: 17.2 %

Procedure:
In a procedure similar to Example 6, 100 g of 6,6-dimethylbicyclo[3.1.1]hept-2-yl acetaldehyde at a purity of 98.3% (0.59 mole) in 50 ml of DMF, 82 g of potassium t-butoxide (0.69 mole) in 300 ml of DMF, and 55 g of allyl chloride in 50 ml of DMF (0.78 mole) were reacted in the usual way to afford 110.5 g of crude product composed of 36% starting material, 31% O-alkylate and 21% C-alkylate. The product was heated at 165°-185° C. for 6 hours. The crude aldehyde, 105.6 g, was distilled to afford 21.4 g of purified product (17% yield). A major impurity in the crude was the dialkylation product. BP product 114° C./1.2 mmHg; 1H-NMR (300 MHz), δ 1.05 (3H, s), 1.21 (3H, s), 1.3-2.6 (12H, m), 5.01 (2H, m), 5.7 (1H, m), 9.47 (1H, m); 13C-NMR (75 MHz), spectra consistent with assigned structures; IR (Neat), 2970, 2700, 1730, 1640, 1450, 1370, 910 cm-1 ; MS (m/e), 205 (M+ -1), 191, 175, 163, 122, 107, 93, 41 (Base);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([O:23][CH3:24])=[O:22])[C:9]=2[CH3:25])=[CH:4][CH:3]=1.C1C(=O)N([Br:33])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:33][CH2:25][C:9]1[C:10]([C:21]([O:23][CH3:24])=[O:22])=[N:11][N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: COC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1CBr
Yield: 85.2 %

Procedure:
19 g of methyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate is placed in 200 ml of CCl4 and 8.54 g of NBS and then 1 g of benzoyl peroxide are added, heating under reflux overnight. On returning to RT, the precipitate that forms is filtered and washed with CCl4. All of the filtrate is evaporated, then taken up in AcOEt and washed with saturated NaCl solution (twice). It is dried over MgSO4 and evaporated. The expected compound crystallizes in iso ether, it is filtered and dried to obtain 19.4 g of the expected compound.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][C:5]=12.CC(O[CH:16](N(C)C)[N:17]([CH3:19])[CH3:18])(C)C>C1COCC1>[CH3:16][N:17]([CH:19]=[C:8]1[C:9](=[O:10])[C:4]2=[N:3][O:2][N:1]=[C:5]2[CH2:6][CH2:7]1)[CH3:18]
Reactant: O=C1CCCc2nonc21
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: C1CCOC1
Product: CN(C)C=C1CCc2nonc2C1=O
Yield: 57.1 %

Procedure:
A THF solution of 4,5,6,7-tetrahydro-2,1,3-benzoxadiazole-4-one 1 g (0.00725 mol) and Bredereck's reagent 1.89 g (0.0109 mol) was stirred at room temperature for 2 days. The crystalline precipitate was filtered, washed with THF and dried, 0.8 g desired product was obtained, the yield is 57%.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.[OH:23][C:24]1[CH:32]=[N:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27]>>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:26]([C:25]3[CH:29]=[CH:30][N:31]=[CH:32][C:24]=3[OH:23])=[O:27])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: O=C(O)c1ccncc1O
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Agent: Cl
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3C(=O)c3ccncc3O)c21

Procedure:
Prepared as in Example 15 from (R)-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 15a) and 3-hydroxyisonicotinic acid. 1H NMR (400 MHz, DMSO-d6) δ 1.45 (m, 1H), 1.52-1.74 (m, 4H), 1.84 (m, 1H), 3.19 (m, 2H), 4.18 (dd, 1H, J=10.2, 4.0 Hz), 4.64 (t, 1H, J=10.0 Hz), 5.25 (m, 1H), 6.61 (d, 1H, J=8.2 Hz), 6.87 (d, 1H, J=8.2 Hz), 7.08 (d, 1H, J=5.5 Hz), 7.46 (t, 1H, J=8.2 Hz), 7.84 (br s, 1H), 8.07 (d, 1H, J=5.5 Hz), 8.19 (s, 1H), 8.29 (br s, 1H), 10.28 (s, 1H), 10.9 (br s, 1H). MS 432 (MH+).
Reaction SMILES: Br[C:2]1[C:3]([C@H:8]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[NH:9][C:10]([C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][CH:18]=[N:19]3)=[CH:14][CH:13]=2)=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1>CO.CCOC(C)=O.[OH-].[Pd+2].[OH-].[Pd]>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[C@H:8]([C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)[NH:9][C:10]([C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH2:18][NH:19]2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br)c1ccc2cccnc2c1
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(N[C@@H](c1ccc(C(F)(F)F)cc1)c1ccccn1)c1ccc2c(c1)NCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)—N-((3-bromopyridin-2-yl)(4-(trifluoromethyl)phenyl)-methyl)quinoline-7-carboxamide (Example 195) (0.130 g, 0.267 mmol) in MeOH (0.8 mL) and EtOAc (0.800 mL) was added palladium hydroxide, (20 wt % Pd (dry basis) on carbon, wet) (0.019 g, 0.134 mmol). The resulting mixture was then stirred at rt under H2 (balloon) overnight. The mixture was then filtered through Celite® brand filter agent and the Celite® filter agent was washed with MeOH (2×3 mL). The combined filtrates were concentrated, and the residue was dissolved in MeOH (1 mL). The solution was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was dissolved in MeOH (1 mL). The solution was washed through PL_HCO3 MP-SPE and the resin was washed with MeOH (2×1 mL). The combined filtrates were concentrated and dried in vacuo to give the title compound as a yellow solid. 1H NMR (400 MHz, MeOH) δ ppm 8.59 (d, J=4.7 Hz, 1H), 7.84 (td, J=7.7, 1.6 Hz, 1H), 7.61-7.68 (m, 2H), 7.54-7.60 (m, 2H), 7.49 (d, J=7.8 Hz, 1H), 7.36 (dd, J=7.5, 5.0 Hz, 1H), 6.93-7.07 (m, 3H), 6.44 (s, 1H), 3.25-3.30 (m, 2H), 2.78 (t, J=6.4 Hz, 2H), 1.91 (dt, J=11.6, 6.0 Hz, 2H). MS (ESI pos. ion) m/z: 412.1 (M+H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][N:11]3[C:20]([C:21](O)=[O:22])=[C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([Br:30])[CH:17]=4)[C:12]3=[O:31])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:32][NH:33][CH3:34].C1COCC1>>[CH3:32][N:33]([CH3:34])[C:21]([C:20]1[N:11]([CH2:10][C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][O:3][C:4]=3[CH:9]=2)[C:12](=[O:31])[C:13]2[C:18]([C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:17][C:16]([Br:30])=[CH:15][CH:14]=2)=[O:22]
Reactant: CNC
Reactant: O=C(O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Product: CN(C)C(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)OCO2

Procedure:
The present compound was synthesized by a method similar to that in Example 249 and using 2-(benzo[1,3]dioxol-5-ylmethyl)-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (200 mg) and dimethylamine THF solution. Colorless crystals (160 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[C:5]([O:10][CH3:11])=[C:4]([CH2:12][CH3:13])[CH:3]=1.C([Li])CCC.[C:19](=[O:21])=[O:20]>C1COCC1.CCOC(C)=O>[CH2:12]([C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([CH2:8][CH3:9])[C:5]=1[O:10][CH3:11])[C:19]([OH:21])=[O:20])[CH3:13]
Reactant: CCc1cc(Br)cc(CC)c1OC
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc(C(=O)O)cc(CC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
At -78° C., to a stirred solution of 4-bromo-2,6-diethylanisole (12.0 g, 49.4 mmol) in THF (329 mL) was added dropwise n-butyllithium (27.2 mL, 43.5 mmol). After 3 h, the reaction was poured into crushed dry ice and allowed to warm to ambient temperature. The reaction mixture was diluted with EtOAc, concentrated, suspended in H2O, acidified (pH 1), filtered and the collected solids washed with H2O. The crude product was slurried in hexane (15 mL), collected by filtration and dried to give 6.76 g (66%) of the title compound. 1H NMR: consistent. IR (KBr) consistent. mass spectrum (EI), m/z 208 (M+). Anal. Calcd. for C12H16O3 : C, 69.21; H, 7.74; N, 0.00. Found: C, 69.28; H, 7.49; N, 0.07.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](S)=[CH:9][C:8]=1[CH3:14])[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[C:23](C)(C)[C:24](OCC)=[O:25]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:24](=[O:25])[CH3:23])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C(C)=O)cc1C
Temperature: 80 °C
Reaction time: 18 h
Yield: 159 %

Procedure:
To intermediate 4 (710 mg, 1.81 mmol) in DMF (50 mL) was added the K2CO3 (275 mg, 1.99 mmol) followed by the ethyl 2-bromo-2-methylpropanate (280 μL, 1.91 mmol; Aldrich) and the reaction heated to 80° C. After 18 h, the reaction cooled to rt and the solvent removed in vacuo. The residue treated with water (200 mL), extracted 3×50 mL CH2Cl2, dried over Na2SO4, filtered and the solvent removed under vaccum. The residue was chromatographed (CH2Cl2/MeOH: 99/1). To afford 680 mg (77%) of Intermediate 5 as a clear oil. 1H NMR(CDCl3): δ 7.95 (d, 2H), 7.60 (d, 2H), 7.15 (d, 2H), 6.75 (d, 2H), 6.05 (t, 1H), 4.45 (d, 2H), 4.15 (q, 2H), 2.65 (s, 3H), 1.50 (s, 6H), 1.20 (t, 3H).
Reaction SMILES: [NH2:1][C@H:2]([C:15](=[O:28])[N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].[CH3:29][C:30]1[CH:31]=[C:32]([CH2:39][C@@H:40]([NH:44][C:45]([N:47]2[CH2:52][CH2:51][CH:50]([N:53]3[CH2:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[NH:55][C:54]3=[O:63])[CH2:49][CH2:48]2)=[O:46])[C:41](O)=[O:42])[CH:33]=[C:34]2[C:38]=1[NH:37][N:36]=[CH:35]2.CC1C=C(C[C@@H](NC(N2CCC(C3C(=O)NC4C(C=3)=CC=CC=4)CC2)=O)C(N[C@H](C(=O)N2CCN(C3C=CN=CC=3)CC2)CCCCNC(=O)OC(C)(C)C)=O)C=C2C=1NN=C2>>[CH3:29][C:30]1[CH:31]=[C:32]([CH2:39][C@@H:40]([NH:44][C:45]([N:47]2[CH2:48][CH2:49][CH:50]([N:53]3[CH2:62][C:61]4[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=4)[NH:55][C:54]3=[O:63])[CH2:51][CH2:52]2)=[O:46])[C:41]([NH:1][C@H:2]([C:15](=[O:28])[N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:42])[CH:33]=[C:34]2[C:38]=1[NH:37][N:36]=[CH:35]2
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)N1CCN(c2ccncc2)CC1
Reactant: Cc1cc(C[C@@H](NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc2cn[nH]c12
Agent: Cc1cc(C[C@@H](NC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12
Product: Cc1cc(C[C@@H](NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)N2CCN(c3ccncc3)CC2)cc2cn[nH]c12

Procedure:
The title compound was prepared from (S)-tert-butyl 5-amino-6-oxo-6-(4-(pyridin-4-yl)piperazin-1-yl)hexylcarbamate and (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinazolin-3 (4H)-yl)piperidine-1-carboxamido)propanoic acid using the same procedure as described for tert-butyl (S)-5-((R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carboxamido)propanamido)-6-oxo-6-(4-(pyridin-4-yl)piperazin-1-yl)hexylcarbamate. The title compound was obtained in 66% yield. MS (ESI) 850 (M+H) ; Rf=2.07.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[OH:11].I[CH3:24]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][CH2:7][N:8]([CH2:9][CH:10]([C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[OH:11])[CH3:24]
Reactant: CI
Reactant: COc1ccc(CCNCC(O)c2ccc(C)s2)cc1OC
Solvent: c1ccccc1
Product: COc1ccc(CCN(C)CC(O)c2ccc(C)s2)cc1OC

Procedure:
solution of α-{[(3,4-dimethoxyphenethyl)amino]methyl}-5-methyl-2-thiophenemethanol (2.29 g, 0.007 mole, described in Example 16, and the lower alkyl halide, iodomethane (9.94 g, 0.07 mole), in 70 ml benzene is stirred at 25° C for 3 days. The mixture is concentrated under reduced pressure. The residual oil is taken up in methanol and made alkaline with 10% NaOH. The mixture is extracted with chloroform. The extract is washed with water, dried (K2CO3) and concentrated to give a yellow oil, which is purified by chromatography to give the title compound; nmr (CDCl3) δ 2.41 (s, 3H), 2.46 (s, 3H), 2.6 - 2.8 (m, 6H), 3.68 (s, 1H), 3.83 (s, 3H), 3.88 (s, 3H), 4.88 (t, 1H), 6.6 - 6.9 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:19])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:21].[CH3:23][S:24]([CH:27]=[CH2:28])(=[O:26])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[F:19])=[CH:8][CH:9]=2)[N:4]([CH2:28][CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])[C:3]1=[O:21]
Reactant: C=CS(C)(=O)=O
Reactant: CC1(C)C(=O)Nc2cc(NC(=O)c3ccncc3F)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C(=O)N(CCS(C)(=O)=O)c2cc(NC(=O)c3ccncc3F)ccc21

Procedure:
To a solution of N-(3,3-dimethyl-2-oxoindolin-6-yl)-3-fluoroisonicotinamide (example 72, 100 mg, 334 μmol) in DMF (1.67 ml) under an argon atmosphere was added methylsulfonylethene (35.5 mg, 31.6 μl, 334 μmol) and cesium carbonate (109 mg, 334 μmol). After 3 hours at room temperature the reaction mixture was poured into water and the aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane/methanol (with 10% ammonia) as eluent followed by preparative HPLC. The title compound was obtained as off-white solid (60 mg).
Reaction SMILES: Cl.I[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[N:9][C:10]=2[NH2:12])[N:5]([CH:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[N:4]=1.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[NH:35][C:36]([C:38]1[N:39]([CH3:47])[C:40]2[C:45]([CH:46]=1)=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:12][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[N:5]([CH:13]3[CH2:17][CH2:16][NH:15][CH2:14]3)[N:4]=[C:3]([C:24]3[CH:23]=[CH:22][C:21]([NH:35][C:36]([C:38]4[N:39]([CH3:47])[C:40]5[C:45]([CH:46]=4)=[CH:44][CH:43]=[CH:42][CH:41]=5)=[O:37])=[C:20]([O:19][CH3:18])[CH:25]=3)[C:11]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Nc1ncnc2c1c(I)nn2C1CCNC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(C3CCNC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 80 °C
Reaction time: 24 h
Yield: 77.1 %

Procedure:
A suspension of 3-iodo-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (2.186 g, 5.96 mmol) in ethylene glycol dimethyl ether (50 mL) was treated with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (2.66 g, 6.56 mmol), tetrakis(triphenylphosphine)palladium (0.413 g, 0.358 mmol), and a solution of sodium carbonate (2.65 g, 25.03 mmol) in water (25 mL). The reaction mixture was stirred for 24 h at 80° C. The organic solvent was removed under reduced pressure. Dichloromethane (100 mL) and 1N sodium hydroxide (50 mL) were added. The product precipitated out of the aqueous layer. The aqueous layer was evaporated under reduced pressure. The resulting solid was washed with copious amounts of dichloromethane and ethyl acetate. The organic solvent was removed under reduced pressure to give 2.218 g (77%) of pure N2-[4-(4-amino-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) δ 9.443 (s, 1H), 8.256 (s, 1H), 8.1168-8.0965 (d, 1H, J=8.12 Hz), 7.7181-7.6983 (d, 1H, J=7.92 Hz), 7.598-7.5778 (d, 1H, J=8.08 Hz), 7.349-7.291 (m, 4H), 7.171-7.132 (m, 1H), 5.332-5.313 (m, 1H), 4.041 (s, 3H), 3.96 (s, 3H), 3.224-3.058 (m, 3H), 2.926-2.910 (m, 1H), 2.213-2.158 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.09 min (100%), MH+ 483.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:27][NH:26][CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:28])[CH:9]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.[C:31]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:43].Cl>>[ClH:43].[CH3:31][N:26]1[CH2:25][CH2:24][C:19]2[N:20]([CH3:23])[C:21]3[CH:22]=[C:14]([N:11]4[CH:12]=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=5[O:29][CH3:30])=[CH:9][C:10]4=[O:28])[CH:15]=[CH:16][C:17]=3[C:18]=2[CH2:27]1
Reactant: COc1cc(F)ccc1-c1ccn(-c2ccc3c4c(n(C)c3c2)CCNC4)c(=O)c1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Agent: Cl
Product: COc1cc(F)ccc1-c1ccn(-c2ccc3c4c(n(C)c3c2)CCN(C)C4)c(=O)c1
Yield: 52 %

Procedure:
4-(4-Fluoro-2-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (37 mg, 0.092 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (21 mg, 52%) as a yellow solid: mp 294-298° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.83 (br s, 1H), 7.65 (d, J=7.1 Hz, 1H), 7.61 (d, J=1.4 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.46 (dd, J=8.4, 6.9 Hz, 1H), 7.12-7.10 (m, 1H), 7.08 (d, J=1.4 Hz, 1H), 6.91 (overlapping ddd, J=8.4, 2.4 Hz, 1H), 6.55 (d, J=1.6 Hz, 1H), 6.48 (dd, J=7.1, 1.6 Hz, 1H), 4.62 (d, J=12.2 Hz, 1H), 4.30 (dd, J=14.2, 7.5 Hz, 1H), 3.86 (s, 3H), 3.80-3.76 (m, 1H), 3.75 (s, 3H), 3.52-3.42 (m, 1H), 3.24-3.15 (m, 2H), 2.79 (d, J=4.6 Hz, 3H); ESI MS m/z 418 [M+H]+; HPLC (Method B)>99% (AUC), tR=12.6 min.
Reaction SMILES: [I:1][C:2]1[C:6]2[C:7]([O:11][CH3:12])=[N:8][CH:9]=[CH:10][C:5]=2[NH:4][CH:3]=1.C1OCCOCCOCCOCCOC1.[H-].[Na+].[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[C:33]([F:40])[C:32]=1F>CN(C=O)C>[F:30][C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[C:33]([F:40])[C:32]=1[N:4]1[C:5]2[CH:10]=[CH:9][N:8]=[C:7]([O:11][CH3:12])[C:6]=2[C:2]([I:1])=[CH:3]1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: COc1nccc2[nH]cc(I)c12
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nccc2c1c(I)cn2-c1c(F)cc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (200 mg) in DMF (6 ml) were added 15-crown-5 (0.159 ml) and sodium hydride (60% dispersion in mineral oil, 32.1 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1,2,3-trifluoro-5-nitrobenzene (0.101 ml), and the mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (258 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=O)[CH3:10].CC([O-])=O.[Na+].Cl.[NH2:18][OH:19]>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9](=[N:18][OH:19])[CH3:10]
Reactant: CC(=O)Cc1ccccc1Br
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(Cc1ccccc1Br)=NO
Temperature: 25 °C
Reaction time: 18 h
Yield: 94 %

Procedure:
To a mixture of 1-(2-bromophenyl)propan-2-one (1.5 g, 7.04 mmol) and NaOAc (693 mg, 8.45 mmol) in MeOH (50 mL) at RT was added hydroxylamine hydrochloride (539 mg, 7.8 mmol). After the reaction mixture was stirred at RT for 18 h, it was concentrated in vacuo. Water was added (100 mL), and the mixture was extracted with EtOAc (50 mL×3), dried (MgSO4) and concentrated in vacuo to afford 1-(2-bromophenyl)propan-2-one oxime as a yellow solid (1.51 g, 94%). MS (ESI): m/z=228.1 [M+1]+.
Reaction SMILES: [CH3:1][C:2]([CH3:23])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=O)[CH2:8][CH:7]=1.[OH-].[K+].O.NN>C(O)COCCO>[CH3:1][C:2]([CH3:23])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH2:8][CH:7]=1
Reactant: COc1ccc(C(=O)CC2CC=C(CCC=C(C)C)CC2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: COc1ccc(CCC2CC=C(CCC=C(C)C)CC2)cc1
Temperature: 125 °C

Procedure:
To a solution of ketone 2E (R=4-Methyl-3-pentenyl) (10 g) in diethylene glycol (30 mL) is added potassium hydroxide (4.3 g) and hydrazine hydrate (4.5 mL). The solution is sequentially heated to 100° C., 125° C., and 150° C., all for 30 minutes each, then cooled to room temperature. The reaction mixture is extracted between ethyl ether and water, and the combined organic layers are washed with brine and dried over magnesium sulfate. The solution is concentrated in vacuo, and the product is purified by silica gel filtration using 20:1 hexanes:ethyl acetate as an eluent.
Reaction SMILES: Br[C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][CH2:7][C:8]([F:20])([F:19])[C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:24]([C@:26]1([OH:33])[CH2:30][CH2:29][N:28]([CH3:31])[C:27]1=[O:32])#[CH:25]>>[F:19][C:8]1([F:20])[C:9]2[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=2[C:4]2[CH:3]=[C:2]([C:25]#[C:24][C@:26]3([OH:33])[CH2:30][CH2:29][N:28]([CH3:31])[C:27]3=[O:32])[C:22]([F:23])=[CH:21][C:5]=2[O:6][CH2:7]1
Reactant: CCOC(=O)c1nc2c(s1)C(F)(F)COc1cc(F)c(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CCOC(=O)c1nc2c(s1)C(F)(F)COc1cc(F)c(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Ethyl 9-bromo-8-fluoro-4-oxo-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate was subjected to General Procedure P to afford 400 mg (95%) of ethyl 9-bromo-4,4,8-trifluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate. Ethyl 9-bromo-4,4,8-trifluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford (R)-ethyl 4,4,8-trifluoro-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[2,3]oxepin o[4,5-d]thiazole-2-carboxylate. Crude (R)-ethyl 4,4,8-trifluoro-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[2,3]oxepin o[4,5-d]thiazole-2-carboxylate was subjected to General Procedure P to afford 190 mg (44.4%) of 4,4,8-trifluoro-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxamide. M+1=438.0.