Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[C:5]([O:17][CH2:18][CH3:19])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](B(CC)CC)[CH3:27]>CN(C=O)C.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:12]1([C:10](=[O:11])[CH2:9][CH2:8][C:6]2[C:5]([O:17][CH2:18][CH3:19])=[CH:4][N:3]=[C:2]([CH2:26][CH3:27])[CH:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCB(CC)CC
Reactant: CCOc1cnc(Cl)cc1CCC(=O)C1CCCC1
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: [K+]
Solvent: CN(C)C=O
Product: CCOc1cnc(CC)cc1CCC(=O)C1CCCC1
Temperature: 150 °C
Yield: 67.6 %

Procedure:
A solution of 3-(2-chloro-5-ethoxy-pyridin-4-yl)-1-cyclopentyl-propan-1-one (1.2 g, 4.3 mmol) dissolved in DMF (10 mL) was treated with potassium carbonate (0.88 g, 6.4 mmol), tetrakis(triphenylphosphine)palladium (0.12 g, 0.11 mmol), and triethylborane (4.5 mL, 4.5 mmol). The reaction was heated to 150° C. for 2 hours. The reaction was quenched with 1 N HCl and then made basic with 2 N NaOH. The mixture was extracted with ether and the organic layers were dried over MgSO4 and concentrated. Purification by silica gel chromatography (0% to 60% EtOAc in hexanes) gave the product (0.8 g, 68%). 1H NMR (300 MHz, CDCl3): δ 1.26 (t, J=7.6 Hz, 3 H), 1.42 (t, J=6.9 Hz, 3 H), 1.55-1.87 (m, 8 H), 2.73 (m, 4 H), 2.86 (m, 3 H), 4.11 (q, J=6.9 Hz, 2 H), 6.93 (s, 1 H), 8.06 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[CH3:14][N:15]1[CH2:20][CH2:19][N:18]([S:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:12])=[O:11])[CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN1CCN(S(=O)(=O)c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of 500 mg (2.26 mmol) of 3-nitrobenzenesulfonyl chloride in 30 mL of dichloromethane were added 275 μL (2.48 mmol) of N-methylpiperazine and 786 μL (5.64 mmol) of triethylamine, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was extracted with dichloromethane and the organic layer was washed with water and saturated saline solution, and then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with diethyl ether to give 510 mg (79%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[CH:11][NH:10][N:9]=2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:36])[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[N:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[N:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[C:3]=12.[H-].[Na+].Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[CH:11][N:10]([CH2:40][CH2:41][N:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)[N:9]=2)=[C:4]2[NH:13][CH:14]=[C:15]([C:16](=[O:36])[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[N:29]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=5)[N:28]=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])[C:3]=12
Reactant: ClCCN1CCOCC1
Reactant: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(-c3cc[nH]n3)ncc(F)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(C(=O)N1CCN(c2nnnn2-c2ccccc2)CC1)c1c[nH]c2c(-c3ccn(CCN4CCOCC4)n3)ncc(F)c12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 41.7 %

Procedure:
1-(4-fluoro-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (40 mg, 0.08 mmol) in DMF (1 mL) was treated with sodium hydride (60% in oil, 33 mg, 0.8 mmol) and stirred at room temperature for 5 min. 4-(2-chloroethyl)morpholine (149 mg, 0.8 mmol) was added and the mixture was stirred at rt for 1 h. Reaction was quenched with H2O and concentrated under reduced pressure. The residue was dissolved in DMF and purified using reverse phase prep HPLC to afford the title compound as a white solid (20 mg, 67%). 1H NMR (500 MHz, MeOD) δ ppm 3.43 (s, 1 H) 3.77 (s, 5 H) 3.81 (s, 5 H) 4.08 (s, 2 H) 4.28 (s, 3 H) 4.37 (s, 4 H) 5.27 (s, 6 H) 7.56 (s, 1 H) 8.06-8.12 (m, 2 H) 8.13 (s, 2 H) 8.38 (s, 1 H) 8.70 (s, 1 H) 8.85 (s, 1 H). LCMS: m/e 600 (M+H)+, ret time 1.22 min (method 3).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][NH:21][CH2:20][CH2:19]2.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[CH2:22][N:21]([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)[CH2:20][CH2:19]2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: COc1cc2c(cc1OC)CN(CCc1ccc([N+](=O)[O-])cc1)CC2
Yield: 71.6 %

Procedure:
A mixture of 1-(2-bromoethyl)-4-nitrobenzene (9.64 g), 1,2,3,4-tetrahydro-6,7-dimethoxyisoquinoline hydrochloride (10.59 g) and potassium carbonate (17.38 g) in isopropanol (150 ml) was refluxed for 48 h. The mixture was then filtered and the filtrate evaporated to dryness. The resulting residue was taken up in water and extracted with dichloromethane. The organic layer was washed with water, dried and evaporated to give an oil which crystallised in a mixture of 2-propanol and diethyl ether to give the title compound (10.27 g). M.p.: 118°-119°.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:10][C@@:9]([CH3:14])([C:11]([OH:13])=[O:12])[CH2:8][CH2:7][C:6]=2[C:15]=1[CH3:16].[CH2:19](O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>CO.O>[CH3:19][O:12][C:11]([C@@:9]1([CH3:14])[CH2:8][CH2:7][C:6]2[C:15]([CH3:16])=[C:2]([OH:1])[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]=2[O:10]1)=[O:13]
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@](C)(C(=O)O)O2
Reactant: CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: CO
Solvent: O
Product: COC(=O)[C@@]1(C)CCc2c(C)c(O)c(C)c(C)c2O1

Procedure:
A solution of 2g(8 mmoles) of optically pure (R)-(+)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid; [α]D25 + 65.84° (c 1.18, C2H5OH) and 0.1g of p-toluenesulfonic acid monohydrate in 40 ml of methanol was stirred and refluxed for 3.75 hr. After cooling, the solution was diluted with water and worked-up with ether in the usual manner (the ether extracts were additionally washed with saturated aqueous sodium bicarbonate solution) giving 2g (94.7%) of (R)-(+)-3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxylic acid methyl ester as a colorless solid, mp 132°-134.5°; [α]D25 + 61.4° (c 4.91, CH3OH). The analytical specimen was obtained by recrystallization of a sample from aqueous methanol as a colorless solid, mp 133.5°-135°; [α]D25 + 61.85° (c 5.07, CH3OH).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]([C:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[N:9][C:10]1([N:16]=[C:17]=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CCCCC>[N:8]([C:19]1([NH:25][C:26]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)=[N:9][C:10]1([NH:16][C:17]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C=NC1(N=NC2(N=C=O)CCCCC2)CCCCC1
Reactant: NC1CCCCC1
Solvent: CCCCC
Product: O=C(NC1CCCCC1)NC1(N=NC2(NC(=O)NC3CCCCC3)CCCCC2)CCCCC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4.22 grams (.0426 moles) of cyclohexylamine in 20 ml pentane in a 125 ml erlenmeyer flask, cooled to 5° C. in an ice bath, was slowly added a solution of 5.78 grams (.0213 moles) of 1,1'-azobis (1-isocyanatocyclohexane) in 20 ml of pentane. During the addition, a solid product formed. After the addition was complete, the reaction was stirred an additional 30 minutes at 0°-5° C. The reaction mixture was filtered and the filter cake washed with pentane and dried. The dry white solid weighed 5.4 grams (54% crude yield) and melted at 105°-109° C. with decomposition. The infrared spectrum of the product contained a strong carbonyl band at 1655 cm-1 and NH bands at 3200 cm-1 to 3440 cm-1.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=[O:18])[O:16]1.C(OCC)(=O)C>CN(C)C=O>[C:1]([O:6][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=[O:18])[O:16]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1OC(Cl)c2ccccc21
Reactant: CCCC(=O)O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC(=O)OC1OC(=O)c2ccccc21
Reaction time: 192 h

Procedure:
To a solution of butyric acid (1.10 g., 12.5 mmol.) in dimethylformamide (13 ml.) is added triethylamine (1.78 g., 17.6 mmol.) and 3-chlorophthalide (2.10 g., 12.5 mmol.). The reaction mixture is stirred for 8 days, ethyl acetate (40 ml.) is added and the mixture is filtered. The filtrate is washed with 4×15 ml. water, dried over magnesium sulfate, filtered and concentrated in vacuo. Yield 2.28 g. (82.8%). 1H-NMR ppm (CDCl3): 7.93 (dd, J=0.7. 7.5 Hz, 1H), 7.76 (dt, J=1.1, 7.5 Hz, 1H), 7.65 (dt, J=1.0, 8.2 Hz, 1H), 7.58 (dd, J=0.7, 8.2 Hz, 1H), 7.46 (s, 1H), 2.42 (t, J=7.4 Hz, 2H), 1.72 (sextet, J=7.4 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][C:10]=1[I:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].B>C1COCC1>[OH:14][CH2:13][C:12]1[CH:16]=[CH:17][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[C:10]([I:18])[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)O)cc1I
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CO)cc1I
Yield: 78.8 %

Procedure:
A mixture of Example 511B (363 mg, 1.0 mmol) in THF (2 mL) at 0° C. was slowly treated with a 1.0M solution of borane in THF (2.0 mL, 2.0 mmol), allowed to reach room temperature, slowly quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel to provide 275 mg (79%) of the desired product. MS (ESI) m/e 350 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 8.44 (s, 1H), 7.77 (d, J=0.7 Hz, 1H), 7.25-7.32 (m, 2H), 5.25 (t, J=5.8 Hz, 1H), 4.44 (d, J=5.4 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21](I)[S:22][C:13]=12.C([Sn](CCCC)(CCCC)[C:29]1[CH:33]=[C:32]([CH:34]2[O:38][CH2:37][CH2:36][O:35]2)[S:31][CH:30]=1)CCC>O1CCOCC1.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>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[NH:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][N:15]=[C:14]2[CH:20]=[C:21]([C:29]3[CH:33]=[C:32]([CH:34]4[O:38][CH2:37][CH2:36][O:35]4)[S:31][CH:30]=3)[S:22][C:13]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(I)sc23)c(Cl)cc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1csc(C2OCCO2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4csc(C5OCCO5)c4)sc23)c(Cl)cc1Cl
Yield: 75.1 %

Procedure:
A mixture of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-iodothieno[3,2-b]pyridine-6-carbonitrile (564 mg, 1.18 mmol), tributyl-(5-[1,3]dioxolan-2-yl-thiophen-3-yl)-stannane (680 mg, 1.52 mmol) and a pinch of bis(triphenylphosphine)palladium(II) chloride in 15 mL of dioxane is heated at reflux for 5 hours. Additional bis(triphenylphosphine)palladium(II) chloride is added and the reaction is heated at reflux overnight. Additional bis(triphenylphosphine)palladium(II) chloride and 10 mL of dioxane are added and the reaction is heated at reflux for 5 hours. The reaction mixture is concentrated in vacuo and partitioned between water and chloroform. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 1:1 hexane:ethyl acetate. The fractions containing product are combined and concentrated in vacuo to provide 447 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-[5-(1,3-dioxolan-2-yl)thien-3-yl]thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 219-221° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 3.92-4.10 (m, 4H), 6.08 (s, 1H), 7.36 (s, 1H), 7.63 (s, 1H), 7.75 (s, 1H), 7.80 (s, 1H), 7.97 (s, 1H), 8.60 (s, 1H), 9.69 (s, 1H); MS 502.1 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:7]=1.[C:19](OC(=O)CC)(=O)[CH2:20][CH3:21].Cl>C(N(CC)CC)C>[CH2:20]([C:21]1[O:18][C:5]2[C:6]([C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:19]
Reactant: O=C(Cc1cccc(F)c1)c1cc(F)ccc1O
Reactant: CCC(=O)OC(=O)CC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
Intermediate 73 (3.00 g, 12.08 mmoles) was taken in a RB flask and to this triethylamine (25 ml) and propionic anhydride (4.92 g, 37.82 mmoles) were added and the mixture was refluxed for 24 h. After cooling to RT, the reaction mixture was acidified by the addition of 1N HCl solution, extracted with ethyl acetate, washed with sodium bicarbonate solution, dried with sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-yellow solid (1.80 g, 52% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 7.80(m, 1H), 7.76(m,2H), 7.51(dd, J=8.0,6.4Hz), 7.22(m,1H), 7.18(m, 2H), 2.56(q, J=7.6Hz, 2H), 1.20(t, J=7.6Hz, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@H:5]([OH:12])[CH2:4][CH2:3]1.[Na].F[C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]3[CH3:30])=[N:22][N:23]=2)[CH:20]=1.N>CN(C=O)C.CO.C(Cl)Cl>[CH3:30][C@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][N:24]1[C:21]1[N:19]2[CH:20]=[C:15]([O:12][C@@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:16]=[CH:17][C:18]2=[N:23][N:22]=1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@H](O)c2ccccc21
Agent: N
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 47.5 %

Procedure:
To a solution of Intermediate B (232 mg, 1.6 mmol) in dry DMF (10 mL) under N2 was added sodium (60% dispersion in oil, 320 mg, 8.0 mmol) and the resulting opaque brown solution was stirred at RT for 45 min (CARE: gas evolution). A solution of Intermediate 81c (342 mg, 1.46 mmol) in dry DMF (7 mL) was added and the dark brown solution stirred at 60° C. under N2 for 90 min. The cooled solution was concentrated in vacuo, redissolved in MeOH (3 mL) and then applied to an SCX-2 cartridge (20 g), washing with MeOH (50 mL). The product was eluted with 2M NH3 in MeOH (50 mL); concentration in vacuo gave a dark brown solid. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as a pale brown foam (262 mg, 45%). LCMS (Method 3): Rt 2.30 min, m/z 378 [MH+].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH2:8])=[O:7].[CH3:9][NH:10][CH3:11]>C(O)C>[CH3:9][N:10]([CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH2:8])=[O:7]
Reactant: NC(=O)CCCCBr
Reactant: CNC
Solvent: CCO
Product: CN(C)CCCCC(N)=O
Reaction time: 3 h
Yield: 70 %

Procedure:
5-Bromopentanamide (10.11 g) was dissolved in ethanol (50 ml) and a 33% solution of dimethylamine in ethanol (20 ml) added. The solution was allowed to stand at room temperature for 3 hours, more dimethyl amine added (20 ml) and the solution allowed to stand at room temperature for 18 hours. The solution was evaporated to an oil which was dissolved in dilute HCl and the solution of pH 2 was washed twice with dichloromethane, basified with NaOH, saturated with NaCl and extracted 10 times with dichloromethane. The combined latter extracts were dried over K2CO3 and evaporated to give 5-dimethylaminopentanamide as acolourless solid (5.72 g, 70%) (mp 86°-7°).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:18])[CH2:14][O:13][CH2:12][C:11]3=[CH:15][N:16]=[CH:17][N:10]23)=[CH:5][CH:4]=1.C[Si](I)(C)C.CO>C(#N)C>[CH3:18][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH2:14][O:13][CH2:12][C:11]2=[CH:15][N:16]=[CH:17][N:10]12
Reactant: COc1ccc(C2(C)COCc3cncn32)cc1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: CC#N
Product: CC1(c2ccc(O)cc2)COCc2cncn21
Reaction time: 0.5 h

Procedure:
A mixture of 3.6 mmol of 5-(4-methoxyphenyl)-5-methyl-5,6-dihydro-8H-imidazo[5,1-c][1,4]-oxazine and 10 ml of trimethylsilyl iodide in 40 ml of acetonitrile is heated to reflux for 24 hours. 10 ml of methanol are cautiously added and heating to reflux is continued for 30 minutes. The reaction mixture is evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH3:22])[C:5]([N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:10]=2[CH2:9][CH2:8]1)=[O:6].[CH:23]1([N:29]=[C:30]=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.Cl>O.CC(C)=O>[CH:23]1([NH:29][C:30]([NH:21][S:18]([C:16]2[CH:15]=[CH:14][C:11]3[CH2:12][CH2:13][N:7]([C:5](=[O:6])[N:4]([CH3:22])[CH3:3])[CH2:8][CH2:9][C:10]=3[CH:17]=2)(=[O:20])=[O:19])=[O:31])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C=NC1CCCCC1
Reactant: CN(C)C(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1
Temperature: 25 °C

Procedure:
8.8 Ml. of 2N sodium hydroxide are added while stirring at 25° C. to a mixture of 5.2 g. of 3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide in 180 ml. of acetone, during which the solid material first dissolves and then a new crystalline precipitate immediately results. 2.26 Ml. of cyclohexylisocyanate are then added thereto while cooling externally with ice and stirring, whereupon the solid material passes completely into solution and then a crystalline precipitate soon reappears. The mixture is subsequently stirred for 16 hours at 25° C., then diluted with 350 ml. of water, acidified to pH 2 with 3N hydrochloric acid and finally extracted twice with 500 ml. of chloroform each time. The chloroform extracts are dried over sodium sulfate and evaporated in vacuo at 60° C. The residue is dissolved in 25 ml. of acetone and crystallized by trituration. There is obtained 1-cyclohexyl-3-[(3-dimethylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea, m.p. 113° C. (with decomposition).
Reaction SMILES: C([NH:4][C:5]([NH2:7])=[NH:6])(=O)C.N1CCCC1.CCO.[Br:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C@@H:24]1[NH:29][C:28](=[O:30])/[C:27](=[C:31](/O)\[CH3:32])/[C:26](=O)[CH2:25]1>CCOC(C)=O>[NH2:7][C:5]1[N:4]=[C:31]([CH3:32])[C:27]2[C:28](=[O:30])[NH:29][C@@H:24]([C:18]3[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=3[Br:16])[CH2:25][C:26]=2[N:6]=1
Reactant: C/C(O)=C1/C(=O)C[C@H](c2ccc(F)cc2Br)NC1=O
Reactant: CC(=O)NC(=N)N
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCNC1
Product: Cc1nc(N)nc2c1C(=O)N[C@@H](c1ccc(F)cc1Br)C2
Temperature: 160 °C
Yield: 72.2 %

Procedure:
A microwave vial charged with acetylguanidine (800 mg, 7.9 mmol) was added pyrrolidine (3.25 mL, 39 mmol), 5 mL of EtOH and 31G (1.3 g, 3.9 mmol). The mixture was heated in a microwave at 160° C. for 10 min. The reaction mixture was diluted with EtOAc (50 mL) and washed with 1M NaHSO4 (40 mL×2), brine, dried over Na2SO4, concentrated in vacuo. The resulting solid was purified by column chromatography (2-5% MeOH in DCM gradient) to give the product 31H as a light yellow crystalline solid (989 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.61 (s, 3H) 2.83 (dd, J=16.29, 5.94 Hz, 1H) 3.22 (dd, J=16.42, 6.06 Hz, 1H) 4.84-5.06 (m, 1H) 7.11 (br. s., 2H) 7.19-7.40 (m, 2H) 7.61 (dd, J=8.59, 2.53 Hz, 1H) 7.98 (d, J=3.28 Hz, 4H). ESI-MS: m/z 351.0 (MH+).
Reaction SMILES: [ClH:1].Cl.[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.C1C=CC2N(O)N=NC=2C=1.[C:54]([C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][C:65]([C:68](O)=[O:69])=[CH:64][CH:63]=2)=[CH:58][CH:57]=1)#[N:55]>C(Cl)Cl.C(Cl)CCl>[ClH:1].[CH:3]1([N:7]2[CH2:13][CH2:12][CH2:11][N:10]([C:68]([C:65]3[CH:64]=[CH:63][C:62]([C:59]4[CH:60]=[CH:61][C:56]([C:54]#[N:55])=[CH:57][CH:58]=4)=[CH:67][CH:66]=3)=[O:69])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4]1
Reactant: N#Cc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: C1CC(N2CCCNCC2)C1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Agent: Cl
Solvent: C=Cc1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(C(=O)N3CCCN(C4CCC4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(Cyclobutyl)-hexahydro-1H-1,4-diazepine dihydrochloride (D4) (0.15 g) was stirred with diethylaminomethyl polystyrene (1.0 g), HOBT (0.045 g), 4′-cyano-4-biphenylcarboxylic acid (0.16 g) in DCM (5 ml). EDC (0.16 g) was then added and the reaction was stirred at rt for 16 h. The polymer supported base was filtered off and the filtrate was diluted with DCM (10 ml) and washed with saturated sodium hydrogen carbonate (2×15 ml). The organic layer was then loaded directly onto a silica column eluting with 0-10% MeOH (containing 10% 0.880 ammonia solution)/DCM. The isolated free base product was dissolved in DCM (5 ml) and treated with excess 1N HCl/diethyl ether solution (1 ml) and stirred for 10 min.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].[C:5]12([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[N:22]=[CH:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=5)[N:19]=4)=[CH:14][CH:13]=3)[O:11][CH:10]1[CH2:9][CH2:8][CH2:7][CH2:6]2>C1COCC1.C(OCC)C>[F:33][C:30]([F:31])([F:32])[O:29][C:26]1[CH:25]=[CH:24][C:23]([N:20]2[CH:21]=[N:22][C:18]([C:15]3[CH:16]=[CH:17][C:12]([CH:5]4[CH2:6][CH2:7][CH2:8][CH2:9][C:10]4=[O:11])=[CH:13][CH:14]=3)=[N:19]2)=[CH:28][CH:27]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(C45CCCCC4O5)cc3)n2)cc1
Agent: [Cl-]
Agent: [In+3]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1CCCCC1c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reaction time: 24 h
Yield: 49.5 %

Procedure:
To a stirred solution of indium chloride (1.259 g, 5.69 mmol) in 15 mL of dry THF in a 100 mL flask was added a solution of 3-(4-(7-oxabicyclo[4.1.0]heptan-1-yl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB54) (1.14 g, 2.85 mmol) in dry tetrahydrofuran (10 mL). Stirring was continued under nitrogen for 24 hours, then the solution was diluted with diethyl ether (50 mL) and washed with water, dried, and concentrated in vacuo. Purification by flash column chromatography using 0-60% ethyl acetate/hexanes as eluent provided the title compound as a white solid (0.566 g, 35%): 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.16 (dd, J=8.6, 2.1 Hz, 2H), 7.83-7.72 (m, 2H), 7.43-7.33 (m, 2H), 7.30-7.21 (m, 2H), 3.68 (dd, J=12.2, 5.4 Hz, 1H), 2.61-2.41 (m, 2H), 2.37-2.24 (m, 1H), 2.23-1.92 (m, 3H), 1.85-1.60 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −58.03; ESIMS m/z 402 ([M+H]+).