Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].Cl.Cl[CH2:11][CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(CCN2CCCC2)c1
Temperature: 80 °C

Procedure:
A mixture of 4-nitro-1H-pyrazole (5.00 g, 44.22 mmol), 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (8.86 g, 52.42 mmol), acetonitrile (50 mL) and potassium carbonate (19.00 g, 137.50 mmol) was heated at 80° C. under an argon atmosphere for 16 hours. The reaction mixture was evaporated in vacuo and partitioned between water and dichloromethane. The aqueous phase was extracted twice with dichloromethane and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. 4-Nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazole was isolated as an orange solid (8.50 g, 91%). MP=39-41° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.29 (s, 1H), 8.06 (s, 1H), 4.27 (t, J=6.22 Hz, 2H), 2.95 (t, J=6.17 Hz, 2H), 2.55 (s, 4H), 1.80 (s, 4H). MS=211 (MH)+. 219b) A mixture of 4-nitro-1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazole (4.40 g, 20.9 mmol), ethanol (100 mL) and 10% palladium on carbon (0.41 g, 30.7 mmol) was hydrogenated in a Paar shaker at 30 psi under hydrogen for 2 h. The reaction mixture was filtered over diatomaceous earth and the filtrate was evaporated in vacuo. 1-(2-Pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-ylamine was isolated as an orange oil, which became a dark gummy material upon standing at room temperature (3.10 g, 82%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.15 (s, 1H), 7.08 (s, 1H), 4.14 (t, J=7.00 Hz, 2H), 2.88 (t, J=6.97 Hz, 4H), 2.52 (s, 4H), 1.765 (s, 4H). MS=181 (MH)+. 219 c) [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-amine was synthesized from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.150 g, 0.487 mmol) and 1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-ylamine (0.105 g, 0.585 mmol) with 2,2-bis-dicyclohexylphosphanyl-biphenyl (0.048 g, 0.088 mmol) as the ligand in a manner analogous to Example 2d. The isolated pure product was treated with 2N hydrogen chloride in dioxane. [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(1-(2-pyrrolidin-1-yl-ethyl)-1H-pyrazol-4-yl]-amine hydrochloride was isolated as a light green solid (70 mg, 30%). MP=Softened at 155-161° C. then melted at 234-236° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 10.47 (s, 1H), 9.57 (s, 1H), 8.80 (d, J=6.44 Hz, 1H), 8.45 (d, J=8.20 Hz, 2H), 8.105 (d, J=8.20 Hz, 2H), 7.99 (d, J=7.09 Hz, 1H), 7.98 (s, 1H), 7.63 (s, 1H), 7.17 (t, J=6.88 Hz, 1H), 4.55 (t, J=5.88 Hz, 2H), 3.655 (d, J=5.44 Hz, 2H), 3.48 (brs, 2H), 3.32 (s, 3H), 2.99 (brs, 2H), 2.00 (brs, 2H), 1.86 (brs, 2H). MS=452 (MH)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:16]([CH3:17])=[CH:15][C:13]([NH2:14])=[C:12]([O:18][CH3:19])[CH:11]=1>C(#N)C>[Br:1][C:15]1[C:16]([CH3:17])=[C:10]([Cl:9])[CH:11]=[C:12]([O:18][CH3:19])[C:13]=1[NH2:14]
Reactant: COc1cc(Cl)c(C)cc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1cc(Cl)c(C)c(Br)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
N-Bromosuccinimid (3.9 g, 22 mmol) was added to 4-chloro-2-methoxy-5-methylanilin (4.04 g, 20 mmol) dissolved in acetonitril (200 ml). The reaction was stirred at r.t. overnight, and the solvent was evaporated. The residue was purified by column chromatography (silica gel, methylene chloride) to yield the title compound (3.1 g, 62%) as an orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Cl:18])=[C:12]([F:17])[CH:13]=2)[N:8]([CH2:19][CH2:20]Cl)[CH:7]=1)=[O:5])[CH3:2].C1CCN2C(=NCCC2)CC1>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][C:11]([Cl:18])=[C:12]([F:17])[CH:13]=2)[N:8]([CH:19]=[CH2:20])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(CCCl)c2cc(Cl)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: C=Cn1cc(C(=O)OCC)c(=O)c2cc(F)c(Cl)cc21
Yield: 65.1 %

Procedure:
To a 120 ml of anhydrous dimethyl sulfoxide (DMSO), 6.32 g of 1-(2-chloroethyl)-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester and 2.89 g of 1,8-diazabicyclo[5,4,0]-7-undecene were added and the mixture was heated at 84°-89° C. for 2 hrs. The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform. The chloroform layer was washed with water and dried. The residue obtained through evaporation of chloroform was recrystallized from ethyl ether to give 3.66 g (65.1% yield) of 1-vinyl-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester. mp: 146°-149° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:9]=[C:8]([CH:10]=O)[CH:7]=[CH:6][N:5]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1.C(O)(=O)C>>[CH3:1][O:2][CH:3]([O:12][CH3:13])[C:4]1[CH:9]=[C:8]([CH2:10][NH:17][CH:14]2[CH2:16][CH2:15]2)[CH:7]=[CH:6][N:5]=1
Reactant: COC(OC)c1cc(C=O)ccn1
Reactant: NC1CC1
Solvent: CC(=O)O
Product: COC(OC)c1cc(CNC2CC2)ccn1

Procedure:
By General Procedure A from 2-(dimethoxymethyl)pyridine-4-carbaldehyde, cyclopropylamine, and acetic acid (1 equiv.). Purification by column chromatography (CH2Cl2/MeOH, 97:3) gave the title compound as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 8.55 (d, 1H), 7.50 (S, 1H), 7.22 (m, 1H), 5.40 (s, 1H), 3.90 (s, 2H), 3.40 (s, 6H), 2.18 (m, 1H), 0.5 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(OCC)C>[N:28]1([CH2:33][C:34]2[CH:41]=[CH:40][C:37]([C:38]3[NH:8][C:5]4=[N:6][CH:7]=[C:2]([Cl:1])[C:3]([N:12]5[CH2:17][CH2:16][N:15]([CH2:18][C:19]6[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=6)[CH2:14][CH2:13]5)=[C:4]4[N:9]=3)=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[N:29]1
Reactant: Nc1ncc(Cl)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCO
Product: Clc1cnc2[nH]c(-c3ccc(Cn4cccn4)cc3)nc2c1N1CCN(Cc2ccncc2)CC1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a mixture of 5-chloro-3-nitro-4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.022 g, 0.06 mmol) and EtOH (2.5 ml) was added 4-pyrazol-1-ylmethyl-benzaldehyde (0.015 g, 0.08 mmol) followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.24 ml, 0.24 mmol). The reaction mixture was stirred at 80° C. for 20 h, then allowed to cool to room temperature and concentrated in vacuo. The resulting residue was absorbed on silica, and the free-running powder was placed on a 10 g isolute silica column. Elution with a gradient of methanol (0 to 8%) in ethyl acetate/dichloromethane (v:v; 1:1) afforded a yellow solid. The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.008 g, 27%); 1H-NMR (500 MHz, DMSO-d6) 2.62 (br s, 4H, piperazine N(CH2)2), 3.61 (s, 2H, NCH2pyridyl), 3.72 (br s, 4H, piperazine N(CH2)2), 5.42 (s, 2H, C6H4CH2N), 6.30 (t, J=2.0 Hz, 1H, pyrazole 4-H), 7.35 (d, J=8.3 Hz, 2H) and 8.13 (d, J=8.3 Hz, 2H) (3,5-C6H4— and 2,6-C6H4—), 7.40 (d, J=5.8 Hz, 2H, pyridine 3-H, 5-H), 7.49 (d, J=1.5 Hz, 1H, pyrazole-H), 7.86 (d, J=1.8 Hz, 1H, pyrazole-H), 8.11 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.54 (d, J=5.9 Hz, 2H, pyridine 2-H, 6-H), 13.45 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[OH-].[Na+]>>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]2([C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(C2(c3ccc(N)cc3)CCCCC2)cc1

Procedure:
240 Parts of aniline is mixed with 240 parts of hydrochloric acid with stirring, and then 75 parts of cyclohexanone is added to the mixture, which is subjected to the condensation reaction with stirring at 102° to 108° C. for about 24 hours. Then, 700 parts of a 45% aqueous sodium hydroxide solution is added and the non-reacted aniline is collected by steam distillation. Thereafter, 1,1-bis(4-aminophenyl)cyclohexane can be obtained as a crude solid by cooling. In the preferred embodiment of the present invention, this intermediate was purified from solvent to afford a high-purity product, which was used.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.N[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[Cu](Cl)Cl.C(#N)C>[O:1]([N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(C)CCCC(C)(C)N1O
Reactant: Nc1ccccc1
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CC1(C)CCCC(C)(C)N1Oc1ccccc1
Yield: 72 %

Procedure:
The procedure of Example 1 is repeated using 3.9 g (25 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, and 7.84 g (76 mmol) of tert-butyl nitrite, 24 mg (0.25 mmol) of copper(II) chloride, 120 mL of acetonitrile and 4.65 g (50 mmol) of aniline at 65° C. The crude product is purified by vacuum flash chromatography (heptane) to give 4.2 g of the title compound as a colorless oil in a 72.4% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][C:17]([OH:19])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>CN(C=O)C.ClCCl>[Cl:23][C:17](=[O:19])[CH2:16][C@@H:12]1[CH2:13][CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an argon purged round bottom flask fitted with a magnetic stirbar was added (S)-2-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)acetic acid (235 mg, 0.893 mmol) followed by anhydrous dichloromethane (5 mL). The reaction was treated with anhydrous DMF (2 drops ˜5 μL). The flow of argon was stopped, and the reaction vessel fitted with a balloon. Oxalyl chloride (0.12 mL, 1.38 mmol) was added in two portions, resulting in effervescence. The reaction was stirred at room temperature for 3 hours, before being concentrated to dryness under reduced pressure and dried overnight under high vacuum.
Reaction SMILES: C(N(CC)CC)C.O.OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([OH:38])=O)=[CH:34][N:33]=1.[NH2:41][C:42]1([CH2:48][OH:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>ClCCl>[Cl:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH:41][C:42]2([CH2:48][OH:49])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:38])=[CH:34][N:33]=1
Reactant: NC1(CO)CCCCC1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(NC1(CO)CCCCC1)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.6 %

Procedure:
Triethylamine (2.2 ml, 16.12 mmol, 2 eq), hydroxybenzotriazole hydrate (0.217 g, 1.61 mmol, 0.2 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.7 g, 8.87 mmol, 1.1 eq) are added to a cold (ice bath) solution of 6-chloronicotinic acid (1.27 g, 8.06 mmol, 1 eq) and (1-aminocyclohexyl)methanol (1.04 g, 8.06 mmol, 1 eq) in dichloromethane (80 ml), stirred 30 min at 0° C. and then at room temperature for 1 h. The organic layer is then washed with water, with a saturated solution of aqueous sodium hydrogenocarbonate and dried over magnesium sulfate. The solvent is finally removed to give 2.46 g of a yellow oil.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:50][C:45]2[CH:46]=[CH:47][CH:48]=[N:49][C:44]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N1CCC[C@@H](N)C1)(OC(C)(C)C)=O>>[CH:1]1([N:7]2[CH2:13][C@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:50][C@@H:45]5[CH2:46][CH2:47][CH2:48][NH:49][CH2:44]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)N[C@@H]4CCCNC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (R)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (R)-1-Boc-3-aminopiperidine. Further, after washing with water (10 ml), t-butoxycarbonyl (Boc) protection group was removed using 40% TFA in dichloromethane (6 ml) and purified the product using preparative HPLC and basified using sodium bicarbonate solution to give free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20-1.33 (m, 2H) 1.30-1.80 (m, 7H) 1.81-2.02 (m, 4H) 2.31-2.45 (m, 2H) 2.81 (d, J=12.63 Hz, 1H) 2.97 (d, J=8.08 Hz, 1H) 3.29 (s, 3H) 3.71-3.90 (m, 3H) 3.94 (s, 3H) 4.89 (d, J=8.59 Hz, 1H) 5.32-5.45 (m, 2H) 6.01 (ddd, J=17.56, 12.76, 10.86 Hz, 1H) 7.41-7.53 (m, 2H) 7.82 (s, 1H) 8.00 (d, J=7.83 Hz, 1H) 8.12 (s, 1H) 8.31 (d, J=8.08 Hz, 1H). [M+H] calc'd for C28H36FN7O3, 538. found 538.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([OH:17])=O)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1.[Si]([O:26][CH2:27][CH2:28][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36])(C(C)(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:29]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])[CH2:28][CH2:27][OH:26])=[O:17])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:18]=1
Reactant: O=C(O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Reactant: CC(C)(C)[Si](C)(C)OCCNc1ccccc1Cl
Product: O=C(c1cc2c(s1)-c1ccc(Br)cc1OCC2)N(CCO)c1ccccc1Cl
Yield: 25 %

Procedure:
Following Example 16, 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylic acid was converted to the acid chloride and reacted with N-(2-(tert-butyldimethylsilyloxy)ethyl)-2-chloroaniline. Desilylation gave 233 (yield 25%). MS: (ESI+) 480
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([NH2:7])=[O:6].[NH:14]1[CH2:16][CH2:15]1>CC#N>[N:14]1([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[N+:11]([O-:13])=[O:12])[C:5]([NH2:7])=[O:6])[CH2:16][CH2:15]1
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: C1CN1
Solvent: CC#N
Product: NC(=O)c1ccc([N+](=O)[O-])c(N2CC2)c1
Yield: 41.1 %

Procedure:
A stirred solution of the above benzamide (100 mg, 0.54 mmol) in dry MeCN (4 mL) was treated with aziridine (168 μL, 3.24 mmol) at room temperature for 4 h. The resulting precipitate was collected, washed with cold water, and crystallized twice from EtOAc to give 9 (46 mg, 41%). mp 223-224° C.;; 1H NMR [(CD3)2SO] δ8.21 (br s, 1H, NHH), 7 99 (d, J=8.5 Hz, 1H, H-5), 7.69 (d, J=1.8 Hz, 1H, H-2), 7.67 (br s, 1H, NHH), 7.56 (dd, J=8 5, 1.8 Hz, 1H, H-6), 2.30 (s, 4H, (CH2)2). Anal. Calcd for C9H9N3O3: C, 52.17;H, 4.38, N, 20.28. Found C, 52 10;H, 4.30, N, 20.07%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[H-].[Na+].I[CH3:21].O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][N:10]([CH3:21])[C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCc1ccccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCc1ccccc1Br)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
A solution of tert-butyl [2-(2-bromophenyl)ethyl]carbamate (810 mg, 2.7 mmol) in dry THF (2.0 mL) was transferred to a flask with a suspension of sodium hydride (65 mg, 2.7 mmol) in dry THF (2.0 mL) under an atmosphere of argon. The mixture was stirred for 15 min at room temperature and 10 min at 60° C. Iodomethane (0.19 mL, 2.97 mmol) was added with a syringe. After 4 h the reaction mixture was poured into water and extracted with EtOAc (×3). The organic phases were combined and washed with brine and dried with MgSO4. The crude product was purified by chromatography eluting with petroleum ether/EtOAc 10:1 to afford the title compound as a colourless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([CH2:12][C:13]3[C:14](=[O:21])[NH:15][C:16]([CH3:20])=[CH:17][C:18]=3[CH3:19])[C:7](=[O:22])[C:6]=2[C:23]=1[CH3:24].[CH3:25][N:26]1[C:30](B2OC(C)(C)C(C)(C)O2)=[C:29]([CH3:40])[CH:28]=[N:27]1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>O1CCOCC1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe].C(Cl)Cl>[CH3:19][C:18]1[CH:17]=[C:16]([CH3:20])[NH:15][C:14](=[O:21])[C:13]=1[CH2:12][N:8]1[C:7](=[O:22])[C:6]2[C:23]([CH3:24])=[C:2]([C:30]3[N:26]([CH3:25])[N:27]=[CH:28][C:29]=3[CH3:40])[CH:3]=[CH:4][C:5]=2[O:11][CH2:10][CH2:9]1
Reactant: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(C)c(CN2CCOc3ccc(Br)c(C)c3C2=O)c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CN2CCOc3ccc(-c4c(C)cnn4C)c(C)c3C2=O)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 18.7 %

Procedure:
A suspension of 7-bromo-4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6-methyl-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (126d, 36 mg), 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (34 mg, 0.092 mmol), and sodium carbonate (2M aq, 32 mg, 0.30 mmol) in 1,4-dioxane (3 mL) was degassed with N2 for 10 minutes. The reaction mixture was treated with PdCl2(DPPF)-DCM (8.2 mg, 0.010 mmol) and heated at 100° C. in the microwave for 1 hour, then at 120° C. in the microwave for an additional 1 hour. The reaction mixture was poured into DCM (25 mL) and washed with water (3×25 mL). The organic layer was concentrated under vacuum and the residue was purified by preparative HPLC to give the title compound (Example 126, 7 mg, 19% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.33 (s, 1H), 7.23 (d, J=8.07 Hz, 1H), 6.99 (d, J=8.19 Hz, 1H), 5.93 (s, 1H), 4.66 (s, 2H), 4.09 (t, J=5.44 Hz, 2H), 3.48 (s, 3H), 3.42-3.46 (m, 2H), 2.23 (s, 3H), 2.14 (s, 3H), 2.03 (s, 3H), 1.79 (s, 3H); MS 407.1 [M+1].
Reaction SMILES: CN(CC1C=CC=C(O)C=1)C/C=C/C#CC(C)(C)C.[S:20]1[CH:24]=[CH:23][C:22](/[CH:25]=[CH:26]/[CH2:27][CH2:28][OH:29])=[CH:21]1.[CH2:30]([N:32]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45](O)[CH:44]=1)[CH2:33]/[CH:34]=[CH:35]/[C:36]#[C:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:31]>>[CH2:30]([N:32]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[C:47]([O:29][CH2:28][CH2:27]/[CH:26]=[CH:25]/[C:22]2[CH:23]=[CH:24][S:20][CH:21]=2)[CH:48]=1)[CH2:33]/[CH:34]=[CH:35]/[C:36]#[C:37][C:38]([CH3:39])([CH3:40])[CH3:41])[CH3:31]
Reactant: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1
Reactant: OCC/C=C/c1ccsc1
Agent: CN(C/C=C/C#CC(C)(C)C)Cc1cccc(O)c1
Product: CCN(C/C=C/C#CC(C)(C)C)Cc1cccc(OCC/C=C/c2ccsc2)c1

Procedure:
Compounds of Examples 63 and 64 were obtained by performing the same reaction as in Example 62 except that 2-(3-thienymethoxy)ethanol or (E)-N-methyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-hydroxybenzylamine was used instead of the starting compound, (E)-4-(3-thienyl)-3-buten-1-ol or (E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-hydroxybenzylamine, which was used in the above-mentioned reaction.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[N:11]=[C:12](\Cl)/[C:13]1[S:21][C:16]2=[N:17][CH:18]=[CH:19][N:20]=[C:15]2[CH:14]=1.[C-:23]#[N:24].[K+]>C1COCC1.O.C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1/[N:11]=[C:12](\[C:23]#[N:24])/[C:13]1[S:21][C:16]2=[N:17][CH:18]=[CH:19][N:20]=[C:15]2[CH:14]=1
Reactant: [C-]#N
Reactant: Cc1ccc([N+](=O)[O-])cc1/N=C(\Cl)c1cc2nccnc2s1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: Cc1ccc([N+](=O)[O-])cc1/N=C(\C#N)c1cc2nccnc2s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.7 %

Procedure:
To a solution of (Z)—N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carbimidoyl chloride 76 (100 mg, 0.301 mmol) in THF (15 mL), water (0.5 mL) and acetonitrile (15 mL) was added potassium cyanide (98 mg, 1.503 mmol). The reaction was stirred at rt for 6 h. Quenched in NaHCO3 solution and resulting precipitate was collected to give crude (E)-N-(2-methyl-5-nitrophenyl)thieno[2,3-b]pyrazine-6-carbimidoyl cyanide 77 (62 mg, 63.8%) which was used without further purification. (m/z)=324 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]2[CH:7]=[C:8]([NH:14][CH:15]([CH3:17])[CH3:16])[CH:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:5]=2[O:4][CH2:3]1.[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1)[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:19]([O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([N:14]([CH:15]([CH3:17])[CH3:16])[C:8]2[CH:9]=[C:10]([CH:11]([CH3:12])[CH3:13])[C:5]3[O:4][CH2:3][C:2]([CH3:1])([CH3:18])[C:6]=3[CH:7]=2)=[CH:25][CH:24]=1)[CH3:20]
Reactant: CC(C)Nc1cc(C(C)C)c2c(c1)C(C)(C)CO2
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N(c2cc(C(C)C)c3c(c2)C(C)(C)CO3)C(C)C)cc1
Yield: 7.9 %

Procedure:
Following general procedure E and using 3,3-dimethyl-7-isopropyl-5-(isopropyl)amino-2,3-dihydro-benzofuran (Compound 35, 0.21 g, 0.86 mmol), ethyl-4-iodo-benzoate (0.0.29 g, 1.03 mmol), cesium carbonate (0.39 g, 1.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.020 g, 0.020 mmol) and (S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.04 g, 0.064 mmol) in 6 mL of anhydrous toluene, the title compound (0.027 g) was obtained; some of the product was eluted as a mixture with the starting amine. Some 5-(isopropyl)amino-3,3-dimethyl-7-isopropyl-2,3-dihydro-benzofuran (Compound 35) was also recovered. 1H NMR (300 MHz, CDCl3): δ 7.82 (d, 2H, J=9.2 Hz), 6.72 (d, 1H, J=2.0 Hz), 6.64 (d, 1H, J=2.0 Hz), 6.50 (d, 2H, J=9.0 Hz), 4.40-4.26 (m, 5H), 3.10 (heptet, 1H, J=7.0 Hz), 1.34 (t, 3H, J=7.1 Hz), 1.33 (s, 6H), 1.23 (d, 6H, J=7.0 Hz), 1.15 (d, 6H, J=6.5 Hz).