Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]4[CH2:20][C@H:19]4[C:21]([OH:23])=O)[CH2:13][CH2:12]3)=[CH:9][S:8][C:7]=2[CH:24]=1.C(OC(C(=NOC(N(C)C)=[N+](C)C)C#N)=O)C.F[B-](F)(F)F.CN1CCOCC1.[CH3:56][C@H:57]1[CH2:62][CH2:61][C@H:60]([NH2:63])[CH2:59][CH2:58]1>CN(C=O)C>[CH3:56][C@H:57]1[CH2:62][CH2:61][C@H:60]([NH:63][C:21]([C@@H:19]2[CH2:20][C@H:18]2[CH2:17][N:14]2[CH2:15][CH2:16][N:11]([C:10]3[C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:25])[F:26])=[CH:24][C:7]=4[S:8][CH:9]=3)[CH2:12][CH2:13]2)=[O:23])[CH2:59][CH2:58]1
Reactant: O=C(O)[C@@H]1C[C@H]1CN1CCN(c2csc3cc(C(F)(F)F)ccc23)CC1
Reactant: C[C@H]1CC[C@H](N)CC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CN2CCN(c3csc4cc(C(F)(F)F)ccc34)CC2)CC1

Procedure:
Stir a solution of trans-2-[4-(6-trifluoromethyl-benzo[b]thiophen-3-yl)-piperazin-1-ylmethyl]-cyclopropanecarboxylic acid (Example 7a) (1.99 g, 5.0 mmol), and O-[(ethoxycarbonyl)-cyanomethylenamino]-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TOTU, 2.05 g, 6.3 mmol) in DMF (50 mL) at 20° C. for 0.5 h. Add N-methylmorpholine (0.58 mL, 5.3 mmol), after which add trans-4-methylcyclohexylamine (1.13 g, 10 mmol), and stir the reaction for 5 h. Concentrate the reaction under reduced pressure to obtain an oil. Purify by column chromatography over silica gel (EtOAc(heptane/methanol/triethylamine, 20:20:1:1) to obtain 1.86, (76%) of colorless crystals LC/MS, m/z=480 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:16]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][Br:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1ccc(-c2ccc(Br)cc2)cc1
Solvent: O
Solvent: ClCCl
Product: BrCc1ccc(-c2ccc(Br)cc2)cc1

Procedure:
A solution of (4′-bromo-biphenyl-4-yl)-methanol, 7.01 g (27.9 mmol) and dibromo-triphenylphosphorane 11.8 g (27.9 mmol) in 150 mL of methylene chloride stirred at room temperature for 2 h. The solution was diluted with 100 mL of water and extracted with 2×200 mL portions of diethyl ether. The organic layers were combined, washed with sat. aq. NaCl, and dried (MgSO4). After the solution was concentrated, the residue was purified through a short plug of silica gel (eluted with 50% EtOAc-Heptane) to afford the desired product in 9.1 g (100%) as a white solid. The material was taken to the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)([OH:4])[CH3:3].[H][H]>[C].[Pd].C(O)C>[CH3:3][C:2]([CH:5]1[CH2:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6]1)([OH:4])[CH3:1]
Reactant: [H][H]
Reactant: CC(C)(O)c1cc2ccccc2o1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(O)C1Cc2ccccc2O1
Yield: 65.8 %

Procedure:
Into 200 ml of ethanol, was dissolved 10.3 g of 2-(1-methyl-1-hydroxyethyl)benzofuran. To the solution, was added 1.1 g of 10% palladium carbon. Hydrogen was introduced into the mixture with shaking at atmospheric pressure and at room temperature until no more hydrogen had been absorbed (it took 6 hours). The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was distilled under reduced pressure to obtain 6.86 g of the intended product boiling at 78°-95° C./0.4 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH:18]1([C:21]2[CH:22]=[CH:23][C:24]([C:27](O)=[O:28])=[N:25][CH:26]=2)[CH2:20][CH2:19]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:24]3[CH:23]=[CH:22][C:21]([CH:18]4[CH2:19][CH2:20]4)=[CH:26][N:25]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Reactant: O=C(O)c1ccc(C2CC2)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(C4CC4)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-cyclopropyl-pyridine-2-carboxylic acid (CAS 1174322-66-7; WO2009091016) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=387.3 [M+H]+.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:20]=[C:19]([C:21]([NH:23][C:24]([NH2:26])=[NH:25])=[O:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1.[ClH:27]>C(O)(C)C>[ClH:27].[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:20]=[C:19]([C:21]([NH:23][C:24]([NH2:26])=[NH:25])=[O:22])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: COCOc1ccccc1-c1cc(C(=O)NC(=N)N)c2ccccc2n1
Agent: Cl
Solvent: CC(C)O
Product: N=C(N)NC(=O)c1cc(-c2ccccc2O)nc2ccccc12

Procedure:
2-(2'-Methoxymethyloxyphenyl)quinoline-4-carbonylguanidine (0.51 g) formed in Example 51 was stirred in 24 ml (5M) of an isopropyl alcohol solution of hydrochloric acid at 70° C. for 3 hours. The reaction mixture was cooled with ice, and the precipitate was collected by filtration, and dried to obtain 0.50 g of the above-mentioned compound. m.p. 270° C. or higher
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])[C:3]=1[C:21]#[N:22].[C:23](OC(=O)C)(=[O:25])[CH3:24].C(OC)(=O)C>CO>[C:23]([NH:1][C:2]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[Cl:20])[C:3]=1[C:21]#[N:22])(=[O:25])[CH3:24]
Reactant: COC(=O)C1=C(C)NC(N)=C(C#N)C1c1cccc(Cl)c1Cl
Reactant: CC(=O)OC(C)=O
Solvent: COC(C)=O
Solvent: CO
Product: COC(=O)C1=C(C)NC(NC(C)=O)=C(C#N)C1c1cccc(Cl)c1Cl

Procedure:
6.7 g (20 mmol) of methyl 6-amino-5-cyano-4-(2,3-dichlorophenyl)-2-methyl-1,4-dihydropyridine-3-carboxylate and 33.5 ml (350 mmol) of acetic anhydride are heated under reflux for 30 minutes. Excess acetic anhydride is then converted into methyl acetate by addition of methanol at 25° C., while stirring. The reaction solution is evaporated in vacuo and toluene is then shipped off from the residue twice in vacuo. The residue is then boiled up with 50 ml of toluene. The crystals which have separated out are filtered off and washed with toluene.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[C:31]([F:32])=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:34]([NH2:42])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[F:32][C:31]1[C:26]([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[CH2:19][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[S:15]([CH3:18])(=[O:17])=[O:16])=[N:27][C:28]([NH:42][CH2:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3nc(Cl)ncc3F)c2)S(C)(=O)=O)CC1
Reactant: NCCc1ccccc1
Product: CS(=O)(=O)N(Cc1cccc(-c2nc(NCCc3ccccc3)ncc2F)c1)C1CCNCC1

Procedure:
Intermediate 77 was coupled with phenethylamine following procedure Q. The resulting product was deprotected following procedure R. LC-MS showed the product had the expected M+H+ of 484. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.25 (d, 1H), 8.17 (s, 1H), 7.98 (d, 1H), 7.49 (m, 2H), 7.26 (m, 5H), 4.55 (s, 2H), 3.89 (m, 1H), 3.62 (t, 2H), 333 (m, 2H), 3.03 (s, 3H), 2.98 (m, 2H), 2.90 (t, 2H), 1.89 (m, 4H).
Reaction SMILES: CS([O-])(=O)=O.[C:6]1(=[O:13])[O:12][C:10](=[O:11])[CH2:9][O:8][CH2:7]1.[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][C:10](=[O:11])[CH2:9][O:8][CH2:7][C:6]([OH:12])=[O:13]
Reactant: NCCCCO
Reactant: O=C1COCC(=O)O1
Agent: CS(=O)(=O)[O-]
Product: O=C(O)COCC(=O)NCCCCO

Procedure:
methanesulfonate by (a) reacting diglycolic anhydride and 4-aminobutanol to produce [2-(4-hydroxybutyl]amino-2-oxoethoxy]acetic acid, (b) heating to cyclize the latter to obtain 4-(4-hydroxybutyl)-3,5-dioxomorpholine, (c) esterifying the latter with methanesulfonyl chloride to produce 4-(3,5-dioxomorpholino)butyl methanesulfonate and (d) reacting the mesylate with 3-[bis(4-butoxy-o-tolyl)methyl]piperidine.
Reaction SMILES: [F:1][C:2]1([F:45])[CH2:3][CH2:4][N:5]([C:31]([C:33]2[S:37][C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[N:35][C:34]=2[CH3:44])=[O:32])[C:6]2[CH:30]=[CH:29][CH:28]=[CH:27][C:7]=2/[C:8]/1=[CH:9]/[C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)=[O:11].[ClH:46].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[ClH:46].[ClH:46].[F:45][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:31]([C:33]2[S:37][C:36]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)=[N:35][C:34]=2[CH3:44])=[O:32])[C:6]2[CH:30]=[CH:29][CH:28]=[CH:27][C:7]=2/[C:8]/1=[CH:9]/[C:10]([NH:12][CH2:13][CH:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1)=[O:11]
Reactant: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccccc2)sc1C(=O)N1CCC(F)(F)/C(=C\C(=O)NCC2CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 36 h

Procedure:
To a solution of 420 mg of tert-butyl (Z)-{4-[({[4,4-difluoro-1-(4-methyl-2-phenylthiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]acetyl}amino)methyl]-piperidino}carboxylate in 6 ml of ethyl acetate was added 660 μl of a 4N HCl/ethyl acetate solution, followed by stirring at room temperature for 1.5 days. To the reaction solution was added a saturated aqueous solution of sodium bicarbonate, followed by extracting with ethyl acetate. The organic layer was washed with a saturated aqueous solution of NaCl and dried over anhydrous magnesium sulfate, followed by evaporating the solvent. The residue was purified by silica gel column chromatography (eluting with methanol) and, after making into a hydrochloride using a 4N HCl/ethyl acetate solution, the salt was collected by filtration and washed with ethyl acetate to give 97 mg of (Z)-[4,4-difluoro-1-(4-methyl-2phenyl -thiazole-5-carbonyl)-2,3,4,5-tetrahydro-1H-1-benzoazepin-5-ylidene]-N-[(4-piperidyl)methyl]acetamide dihydrochloride as a colorless powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[CH2:14][N:15]1[C:23]2[CH:22]=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=2[C:17]2[CH2:26][C@H:27]([NH:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][C:16]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:36][CH2:37][C:38](O)=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:38](=[O:39])[CH2:37][Cl:36])[C@H:9]1[CH2:14][N:15]1[C:23]2[CH:22]=[CH:21][C:20]([C:24]#[N:25])=[CH:19][C:18]=2[C:17]2[CH2:26][C@H:27]([NH:29][C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][C:16]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CCl
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@@H]3[C@@H](O)CCN3C(=O)OC(C)(C)C)c3ccc(C#N)cc23)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(C[C@@H]3[C@H](OC(=O)CCl)CCN3C(=O)OC(C)(C)C)c3ccc(C#N)cc23)C1
Reaction time: 8 h
Yield: 53.6 %

Procedure:
A mixture of (2R,3S)-2-((S)-7-cyano-2-isopropoxycarbonylamino-2,3-dihydro-1H-cyclopenta[b]indol-4-ylmethyl)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (950 mg, 1.97 mmol), chloroacetic acid (227 mg, 2.36 mmol), and triphenylphosphine (626 mg, 2.36 mmol) in tetrahydrofuran (20 mL) is treated with diethyl azodicarboxylate (374 μL, 2.36 mmol) dropwise at room temperature. The reaction mixture is stirred overnight. The reaction is diluted with ethyl acetate (50 mL) and then washed with water and brine. The organic portion is dried over sodium sulfate and concentrated. The resulting residue is purified by medium pressure liquid chromatography, eluting with ethyl acetate:hexane (1:1). Fractions containing pure product are combined and concentrated to afford 0.59 g (54%) of the title compound. LC-ES/MS m/z 581.0 [M+Na]+, TR=4.46 min.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@:10]1([CH:50]([OH:57])[C:51]#[C:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH2:11][O:12]2)C1C=CC=CC=1.B(Cl)(Cl)Cl>ClCCl>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@:10]([CH:50]([OH:57])[C:51]#[C:52][Si:53]([CH3:56])([CH3:54])[CH3:55])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@@](C(O)C#C[Si](C)(C)C)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@@](C(O)C#C[Si](C)(C)C)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of 1-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]-3-trimethylsilyl-prop-2-yn-1-ol 4a (0.65 g, 0.81 mmol) in dichloromethane (30 mL) was added dropwise boron trichloride (8.89 mL, 8.89 mmol, 1 M in dichloromethane) at −78° C. The mixture was stirred at −78° C. for 2 hours. After the addition, the reaction mixture was quenched with 5 mL of water and adjusted to pH 6-7 with saturated aqueous sodium hydrogen carbonate. The resulting mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with water (20 mL×2) and then saturated aqueous sodium chloride (20 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound 4b as red oil (0.43 g, 100%). The crude product was used in next step without further purification. The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ(ppm): 7.40 (m, 1H), 7.29 (m, 1H), 7.10 (d, 2H), 6.82 (d, 2H), 4.69 (t, 1H), 4.23 (m, 1H), 4.12 (m, 1H), 4.10 (m, 1H), 4.02 (m, 2H), 3.99 (m, 1H), 3.75 (d, 1H), 3.71 (d, 1H), 2.71 (d, 1H), 2.65 (d, 1H), 1.42 (t, 3H), 0.21 (s, 9H).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](C3C4C(=C(C)C=CC=4)NC=3)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].[CH3:27][N:28]([CH:30]=O)[CH3:29].[H-].[Na+].CI>CCOC(C)=O>[CH3:27][N:28]1[C:29]2[C:1](=[CH:3][CH:6]=[CH:11][C:10]=2[CH3:12])[CH:2]=[C:30]1[C:13]1[N:8]2[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]2=[N:15][C:14]=1[CH3:16]
Reactant: CCC(CC)c1cc(C)nn2c(-c3c[nH]c4c(C)cccc34)c(C)nc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CCC(CC)c1cc(C)nn2c(-c3cc4cccc(C)c4n3C)c(C)nc12
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 8-(1-ethyl-propyl)-2,6-dimethyl-3-(7-methyl-1H-indol-3-yl)-imidazo[1,2-b]pyridazine (0.037 g, 0.11 mmol) and DMF (2 mL) is added 60% NaH (0.005 g, 0.13 mmol). The solution is stirred for 30 minutes and MeI (0.008 mL, 0.13 mmol) is added. The solution is stirred for 1 h, diluted with EtOAc (20 mL), washed with water (2×10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (30%-50% EtOAc gradient) to furnish the title compound (0.025 g, 0.069 mmol, 66%). 1H NMR (CDCl3), δ 0.91 (t, J=7.5 Hz, 6H), 1.77-1.95 (m, 4H), 2.48 (s, 3H), 2.53 (s, 3H), 2.83 (s, 3H), 3.35-3.44 (m, 1H), 4.17 (s, 3H), 6.62 (s, 1H), 6.94-7.01 (m, 2H), 7.25 (s, 1H), 7.30 (dd, J=7.6, 1.3 Hz, 1H). LC/MS (m/z): calcd. for C23H28N4 (M+H)+: 361.6. found: 361.2.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][N:14]=[C:13]([N:18]3[CH:22]=[C:21]([CH:23]4[CH2:25][CH2:24]4)[N:20]=[CH:19]3)[CH:12]=[C:7]12.[F:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.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>[CH:23]1([C:21]2[N:20]=[CH:19][N:18]([C:13]3[CH:12]=[C:7]4[C:8]5[C:3]([CH2:4][CH2:5][N:6]4[C:16](=[O:17])[CH2:15][N:14]=3)=[C:2]([C:30]3[CH:31]=[N:32][C:27]([F:26])=[CH:28][CH:29]=3)[CH:11]=[CH:10][CH:9]=5)[CH:22]=2)[CH2:24][CH2:25]1
Reactant: OB(O)c1ccc(F)nc1
Reactant: O=C1CN=C(n2cnc(C3CC3)c2)C=C2c3cccc(Br)c3CCN12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C1CN=C(n2cnc(C3CC3)c2)C=C2c3cccc(-c4ccc(F)nc4)c3CCN12
Temperature: 85 °C
Reaction time: 0.05 h
Yield: 67.4 %

Procedure:
Example 95-1. 9-bromo-2-(4-cyclopropyl-1H-imidazol-1-yl)-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (1.48 g, 3.73 mmol), (6-fluoropyridin-3-yl)boronic acid (1.05 g, 7.45 mmol) and a solution of Na2CO3 (1.97 g, 18.63 mmol) in water (14.5 mL) was treated with DME (58 mL). The suspension was degassed, Pd(PPh3)4 (646 mg, 0.56 mmol) was added and the mixture was heated at 85° C. for 2 h. The mixture was allowed to warm to RT and the solvent was removed under reduced pressure. The residue was dissolved in DCM and extracted with water, saturated aqueous NaHCO3 solution and brine. The combined organic layers were dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 1% MeOH in DCM for 3 min, then from 1% MeOH in DCM to 4% MeOH in DCM in 25 min, 4% MeOH in DCM for 5 min) to yield a beige foam (1.04 g). The residue was crystallized from AcOEt to afford the title compound as white crystals (720 mg). UPLC-MS: MS 414.2 (M+H+); UPLC rt 0.95 min. 1H NMR (600 MHz, DMSO-d6) δ ppm 0.66 (d, J=3.4 Hz, 2 H), 0.72-0.84 (m, 2 H), 1.70-1.88 (m, 1 H), 2.84 (br. s., 2 H), 3.72 (br. s., 2 H), 4.24 (br. s., 2 H), 7.18 (s, 1 H), 7.31 (d, J=8.5 Hz, 1 H), 7.43 (s, 1 H), 7.47-7.57 (m, 2 H), 7.97-8.14 (m, 3 H), 8.27 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N-:9]([C:12]#[N:13])[C:10]#[N:11].[Na+]>>[C:10]([N:9]=[C:12]([NH2:13])[NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[F:1])#[N:11]
Reactant: N#C[N-]C#N
Reactant: Nc1ccccc1F
Agent: [Na+]
Product: N#CN=C(N)Nc1ccccc1F

Procedure:
A solution of 2-fluoroaniline and sodium dicyanamide was processed as described in Example 71A to provide the desired product.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1COCC1>[C:1]1([S:7]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of benzenesulfonyl chloride (1 g, 5.66 mmol) in THF (20 mL) were sequentially added triethylamine (1.97 mL, 14.15 mmol) and piperazine (2.92 g, 33.9 mmol). The reaction was stirred at room temperature for 1 hour before it was extracted with ethyl acetate and washed with water and brine. The ethyl acetate extracts were dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on silica gel (1:1 hexanes/ethyl acetate to 10/1 dichloromethane/methanol) to give 22 as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:7][CH:8]2[C:20](=[O:21])[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][C:11]=3[CH2:10][CH2:9]2)[CH:4]=[CH:5][N:6]=1.[H-].[Na+].[CH3:24]OS(OC)(=O)=O>CN(C)C=O>[CH3:24][N:12]1[C:11]2[CH2:10][CH2:9][CH:8]([CH2:7][N:3]3[CH:4]=[CH:5][N:6]=[C:2]3[CH3:1])[C:20](=[O:21])[C:19]=2[C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2
Reactant: COS(=O)(=O)OC
Reactant: Cc1nccn1CC1CCc2[nH]c3ccccc3c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1,2,3,9-tetrahydro-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one (1.0 g) in dry dimethylformamide (10 ml) was added dropwise under nitrogen to a stirred, ice-cooled suspension of sodium hydride (80% in oil; 0.11 g) in dry dimethylformamide (5 ml). After 0.5 h dimethylsulphate (0.34 ml) was added, and the solution stirred at room temperature for 4 h. The resultant solid was filtered off, washed with ice-cold dry dimethylformamide (2×5 ml) and dry ether (3×15 ml) and dried to give the title compound as a solid (0.25 g) m.p. 223°-224° (dec).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]2[CH:7]=[C:8]([C:10]#[C:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:25][O:24][C:23]([CH3:27])([CH3:26])[O:22][CH2:21]4)=[CH:14][CH:13]=3)[O:9][C:5]=2[CH:4]=1.C(OC(=O)NC1(C#CC2C=CC(C#CCN3C4C(=CC=C(OC)C=4)C(C(=O)C4C=C(OC)C(OC)=C(OC)C=4)=C3)=CC=2)COC(C)(C)OC1)(C)(C)C>>[C:31]([O:30][C:29](=[O:35])[NH:28][C:20]1([CH2:19][CH2:18][C:15]2[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][C:8]3[O:9][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[CH:37]=[CH:36][C:6]=4[CH:7]=3)=[CH:13][CH:14]=2)[CH2:21][O:22][C:23]([CH3:26])([CH3:27])[O:24][CH2:25]1)([CH3:32])([CH3:33])[CH3:34]
Reactant: COc1ccc2cc(C#Cc3ccc(C#CC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)oc2c1
Agent: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)cn(CC#Cc3ccc(C#CC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)c2c1
Product: COc1ccc2cc(CCc3ccc(CCC4(NC(=O)OC(C)(C)C)COC(C)(C)OC4)cc3)oc2c1

Procedure:
When the product of Step E was substituted for tert-butyl-5-((4-(3-(6-methoxy-3-(3,4,5-trimethoxybenzoyl)-1H-indol-1-yl)prop-1-ynyl)phenyl)ethynyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 14, Step D, the similar process afforded the title compound in 69%, as light creamy crystalline compound. 1H-NMR CDCl3) 1.40 (s, 3H); 1.42 (s, 3H); 1.46 (s, 9H); 1.92-2.03 (m, 2H); 2.49-2.55 (m, 2H); 2.99 (s, 4H); 3.65 (d, 2H, J=11.79 Hz); 3.83 (s, 3H); 3.87 (d, 2H, J=11.76 Hz); 4.94 (s, 1H); 6.25 (s, 1H); 6.80 (dd, 1H, J=2.24, 8.48 Hz); 6.97 (d, 1H), J=1.95 Hz); 7.09 (s, 4H); 7.30 (d, 2H, J=8.48 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>C1COCC1>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][C:4]2[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=2)=[CH:11][CH:10]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: Cc1ccoc1C
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccc(Br)cc2)oc1C
Yield: 41.5 %

Procedure:
The title compound was prepared according to the procedure in Example 5, step 1 using commercial 2,3-dimethylfuran (5.00 g, 52.0 mmol), commercial 4-bromobenzylbromide (13.0 g, 52.0 mmol) and 2.5M n-BuLi/hexanes (20.8 mL, 52.0 mmol) in THF. Purification on Biotage KP-Sil eluting with 1% EtOAc/pet. ether gave 5.72 g (41%) of the title compound. 1H NMR (DMSO-d6) δ 1.84 (s, 3H), 2.09 (s, 3H), 3.83 (s, 2H), 5.87 (s, 1H), 7.17 (d, 2H), 7.49 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[N:11]([CH2:15][CH2:16][CH3:17])[CH:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:20]/[OH:21])/[CH2:9][C:10]2[N:11]([CH2:15][CH2:16][CH3:17])[CH:12]=[CH:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: CCCn1ccnc1CC(=O)c1ccc(N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCn1ccnc1C/C(=N\O)c1ccc(N)cc1
Yield: 65.8 %

Procedure:
A solution of 1-(4-aminophenyl)-2-(1-propylimidazol-2-yl)ethanone (600 mg) and hydroxylamine hydrochloride (223 mg) in ethanol (20 ml) was refluxed for 1 day. After the mixture was allowed to be at room temperature, and saturated sodium bicarbonate solution was added to the mixture, the mixture was extracted with ethyl acetate and washed with water and saturated brine. The mixture was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate-diisopropyl ether to give (1E)-1-(4-aminophenyl)-2-(1-propylimidazol-2-yl)ethanone oxime (419 mg) as yellow crystals.