Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Al](C)C.[NH2:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1.[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[C:56]([Cl:57])=[CH:55][CH:54]=[CH:53][N:52]=3)[N:49]=[CH:50][C:43]=12)[C:37](OC)=[O:38])([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Si:14]([O:31][CH2:32][CH2:33][O:34][CH2:35][C@H:36]([O:41][C:42]1[N:47]=[CH:46][N:45]=[C:44]2[N:48]([C:51]3[C:56]([Cl:57])=[CH:55][CH:54]=[CH:53][N:52]=3)[N:49]=[CH:50][C:43]=12)[C:37]([NH:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)=[O:38])([C:27]([CH3:28])([CH3:29])[CH3:30])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1ncccc1Cl
Reactant: N#Cc1ccc(N)nc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](OCCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1ccc(C#N)cn1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 17.6 %

Procedure:
Trimethylaluminium (2M in hexane) (0.455 mL, 0.91 mmol) was added to 6-aminonicotinonitrile (104 mg, 0.87 mmol) in toluene (10 mL) cooled to 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 20 minutes. (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AB2) (500 mg, 0.79 mmol) in toluene (2 mL) was added and the reaction was allowed to warm to room temperature. The temperature was increased to 60° C. and stirred for 4 hours, then heated at reflux for 24 hours. The reaction mixture was concentrated in vacuo and neutralised with citric acid (1M, aq) and then diluted with water (10 ml) and DCM (10 mL). The mixture was poured onto a phase separator and the organic layer was evaporated in vacuo. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were neutralised with MP-carbonate and evaporated to dryness to afford the product (100 mg, 17.6%). m/z (ES+) (M+H)+=719.51; HPLC tR=3.58 min.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:10]([C:12]([OH:14])=O)=[CH:9][O:8][C:7]=2[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>>[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:12]([C:10]2[C:11]3[C:2](=[O:1])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]=3[O:8][CH:9]=2)=[O:14])=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1coc2c1C(=O)CCCC2
Product: COc1ccc(NC(=O)c2coc3c2C(=O)CCCC3)cc1

Procedure:
Starting from 4-oxo-5,6,7,8-tetrahydro-4H-cylohepta[b]furan-3-carboxylic acid and 4-methoxyaniline, General Procedure B provided the title compound:
Reaction SMILES: [CH2:1]([N:5]1[C:17]2[CH:16]=[CH:15][C:14]([C:18]#[N:19])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:20]#[N:21])[CH:10]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[F:24][C:25]([F:34])([F:33])[C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29].O>CS(C)=O>[CH2:1]([N:5]1[C:17]2[CH:16]=[CH:15][C:14]([C:18](=[NH:19])[NH:29][C:28]3[CH:30]=[CH:31][CH:32]=[C:26]([C:25]([F:33])([F:34])[F:24])[CH:27]=3)=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:20]#[N:21])[CH:10]=2)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CCCCn1c2ccc(C#N)cc2c2cc(C#N)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCn1c2ccc(C#N)cc2c2cc(C(=N)Nc3cccc(C(F)(F)F)c3)ccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 28.3 %

Procedure:
A slurry of 9-butyl-3,6-dicyanocarbazole (4 g, see Example 1C) and sodium hydride (50% in oil, 1.41 g) in 20 ml of anhydrous dimethylsulfoxide is treated dropwise with m-trifluoromethylaniline (4.72 g). The reaction mixture is stirred at room temperature for four days and then poured into 500 ml of water and stirred vigorously for two hours. The resultant precipitate is collected by filtration and purified by column chromatography using one liter of silica gel. Elution with dichloromethane and 1% ethyl acetate/dichloromethane yields 1.8 g of 9-butyl-6-cyano-N-[3-(trifluoromethyl)-phenyl]-9H-carbazole-3-carboximidamide. Elution with 20% ethyl acetate/dichloromethane and ethyl acetate/dichloromethane/methanol (2:7:1) yields 1.6 g of the desired diamidine, which is recrystallized from two liters of water containing 15 ml of 10% hydrochloric acid to yield 1.5 g of the title compound, melting point 205°-210° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1.O>CN(C=O)C>[Si:15]([O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[C:9]([N+:12]([O-:14])=[O:13])[CH:8]=[CH:7][CH:6]=2)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cccc2ncc(O)cc12
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cnc2cccc([N+](=O)[O-])c2c1
Reaction time: 2 h

Procedure:
3-Hydroxy-5-nitroquinoline, as described above in Step D, (2.86 g, 15.04 mmol), tert-butyldimethylsilyl chloride (2.95 g, 19.55 mmol) and imidazole (3.07 g, 45.12 mmol) were dissolved in DMF (20 mL) and stirred for 2 hours. The reaction mixture was poured into H2O and extracted with Et2O (2×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: O.[SH2:2].[Na].Br[CH:5]([C:12](=[O:14])[CH3:13])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].CCOCC>O>[SH:2][CH:5]([C:12](=[O:14])[CH3:13])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: S
Reactant: CCOC(=O)CC(Br)C(C)=O
Agent: [Na]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CC(S)C(C)=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 58.4 %

Procedure:
A round bottom flask was charged with sodium hydrogensulfide hydrate (1.23 g, 16.9 mmol) in water (14.2 mL). The solution was cooled to about 0° C. followed by the addition of ethyl 3-bromo-4-oxopentanoate (3.79 g, 16.9 mmol) dropwise over about 30 min. The mixture was stirred at about 0° C. for about 3 h. To the reaction mixture was added Et2O (40 mL) and the reaction was warmed to ambient temperature. The crude product was partitioned between Et2O (15 mL) and water (15 mL). The layers were separated and the aqueous layer was back extracted with Et2O (10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to afford ethyl 3-mercapto-4-oxopentanoate (1.74 g, 9.87 mmol, 58%, which was used without further purification). LC-MS (Table 1, Method g) Rt=2.24 min, m/z 177 (M+H)+.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C@@H:11]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]1)[C:12]([O:14][CH3:15])=[O:13])=O)(C)(C)C>C(O)(C)C.CO>[ClH:1].[NH2:9][CH2:10][C@@H:11]([N:16]1[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)[C@@H](CNC(=O)OC(C)(C)C)N1CCN(S(C)(=O)=O)CC1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: COC(=O)[C@@H](CN)N1CCN(S(C)(=O)=O)CC1
Temperature: 40 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
15 ml of a solution of hydrochloric acid in isopropanol having a concentration of 5-6N are added dropwise to a solution of 3.8 g (10.4 mmol) of methyl (R)-3-tert-butoxycarbonylamino-2-(4-methanesulphonylpiperazin-1-yl)propanoate in 50 ml of methanol. The reaction medium is stirred at 40° C. for 3 h, concentrated under vacuum then taken up in diethyl ether. The product precipitates, is filtered, rinsed with diethyl ether then dried under vacuum. 3 g (97%) of methyl (R)-3-amino-2-(4-methanesulphonylpiperazin-1-yl)propanoate hydrochloride are obtained in the form of a beige solid.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:10][O:11][C:12]1[CH:44]=[CH:43][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[N:19](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:18]2=[O:42])=[CH:14][CH:13]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C@H:9]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH2:10][O:11][C:12]1[CH:44]=[CH:43][C:15]([CH2:16][CH:17]2[S:21][C:20](=[O:22])[NH:19][C:18]2=[O:42])=[CH:14][CH:13]=1
Reactant: CC(C)C[C@H](COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C[C@@H](N)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 128.1 %

Procedure:
A procedure similar to that described in Preparation 2, above, was followed, but using 1.03 g of 5-{4-[2(R)-t-butoxycarbonylamino-4-methylpentyloxy]benzyl}-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in Preparation 16], 10 ml of methylene chloride and 10 ml of trifluoroacetic acid. After completion of the reaction, the methylene chloride and trifluoroacetic acid were removed by distillation under reduced pressure, and the residue was washed with toluene to give 640 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]([NH:10]C(=O)OC(C)(C)C)([CH3:9])[CH3:8])[S:4][N:3]=1.O>Cl.C(OCC)(=O)C>[CH3:8][C:7]([NH2:10])([C:5]1[S:4][N:3]=[C:2]([CH3:1])[N:6]=1)[CH3:9]
Reactant: Cc1nsc(C(C)(C)NC(=O)OC(C)(C)C)n1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nsc(C(C)(C)N)n1
Yield: 87.7 %

Procedure:
A solution of tert-butyl 2-(3-methyl-1,2,4-thiadiazol-5-yl)propan-2-ylcarbamate (0.15 g, 0.58 mmol) in saturated hydrochloride in ethyl acetate (10 mL) was stirred at room temperature for 1 h. Then water (20 mL) was added. The water phase was washed with ethyl acetate (2×20 mL). Then the water phase was adjusted with sodium hydroxide solution (2 M) to pH=9˜10 and extracted with ethyl acetate (3×20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated to give product (0.08 g, 87%) as yellow oil; MS (EI): m/e 231.1 [M+H]+.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)SC)#[N:2].[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15]>N1C=CC=CC=1>[C:1]([NH:3][C:4]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])=[N:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])#[N:2]
Reactant: NCCCCCO
Reactant: CSC(=NC#N)SC
Solvent: c1ccncc1
Product: N#CNC(=NCCCCCO)NCCCCCO

Procedure:
Heating dimethyl N-cyanodithioimidocarbonate with an excess of 5-aminopentan-1-ol in pyridine gives N-cyano-N',N"-bis(5-hydroxypentyl)guanidine, which may be treated with p-toluenesulphonyl chloride in pyridine and the product heated with thiourea in acetone to give N-cyano-N',N"-bis(5-(S-isothioureido)pentyl)guanidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[CH2:28](O)[CH2:29][OH:30]>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([O:14][CH2:28][CH2:29][OH:30])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: OCCO
Agent: [K+]
Agent: [OH-]
Product: O=C(OCCO)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Temperature: 80 °C

Procedure:
3,4-Bis(benzyloxy)benzoic acid was dispersed in ethylene glycol, and heated to 80° C. A catalytic amount of KOH was added to the solution that was left to react until all solids were dissolved. The solution was precipitated into cold water and left to stir for several hours, yielding a white solid. The solid was obtained by filtration, rinsed with water, and then freeze dried.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[C:6](C2C=CC=CC=2)=[C:7]([C:14]([C:16]2[CH:17]=[CH:18][C:19]3[N:24]=C(C4C=CC=CC=4)[O:22][C:21](=[O:31])[C:20]=3[CH:32]=2)=[O:15])[N:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]2.Cl>O.CN1CCCC1=O>[NH2:24][C:19]1[CH:18]=[CH:17][C:16]([C:14]([C:7]2[N:8]3[C:13]([CH:12]=[CH:11][CH:10]=[CH:9]3)=[C:5]([O:4][CH3:3])[CH:6]=2)=[O:15])=[CH:32][C:20]=1[C:21]([OH:31])=[O:22]
Reactant: COc1c(-c2ccccc2)c(C(=O)c2ccc3nc(-c4ccccc4)oc(=O)c3c2)n2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(C(=O)c2ccc(N)c(C(=O)O)c2)n2ccccc12
Temperature: 80 °C
Yield: 105.6 %

Procedure:
1.56 g (27.94 mmol) of potassium hydroxide dissolved in 4 ml of water are added, at ambient temperature, to 4.4 g (9.31 mmol) of 6-[(1-methoxy-2-phenylindolizin-3-yl)carbonyl]-2-phenyl-4H-3,1-benzoxazin-4-one in 50 ml of N-methylpyrrolidone. The reaction medium is heated at 80° C. for 24 hours. The reaction medium is poured into a 1N aqueous solution of hydrochloric acid. The precipitate formed is filtered off and rinsed with water. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 3.05 g of a green solid are obtained.
Reaction SMILES: OCC[CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1.N[C:51]1C=CC(C2C=NN(CCCCO)C=2)=C2[C:59]=1[C:58](=[O:60])N(C)C2>>[OH:60][CH2:58][CH2:59][CH2:51][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([NH:21][C:22]3[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:47]=[CH:46][C:36]([CH2:37][P:38](=[O:45])([O:42][CH2:43][CH3:44])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:48][CH3:49])[N:23]=3)=[C:14]3[C:18]=2[CH2:17][N:16]([CH3:19])[C:15]3=[O:20])[CH:7]=[N:6]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: CN1Cc2c(-c3cnn(CCCCO)c3)ccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Yield: 38 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 7-amino-4-[1-(4-hydroxybutyl)-1H-pyrazol-4-yl]-2-methyl-2,3-dihydro-1H-isoindol-1-one (Compound 17C, 80 mg, 265 μmol) and to afford 73 mg of the title compound (38%). 1H NMR (400 MHz, CD3OD) δ 8.51 (d, J=8.3 Hz, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.83 (d, J=4.8 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.06 (s, 1H), 6.97 (d, J=8.1 Hz, 1H), 4.54 (s, 2H), 4.24 (t, J=7.1 Hz, 2H), 4.02-4.12 (m, 4H), 3.90 (s, 3H), 3.59 (t, J=6.4 Hz, 2H), 3.34 (d, J=3.5 Hz, 1H), 3.28 (s, 1H), 3.16 (s, 3H), 1.93-2.03 (m, 2H), 1.49-1.60 (m, 2H), 1.26 (t, J=7.1 Hz, 6H). MS (ESI): m/z 718.78 [M+H]+. UPLC: tR=1.20 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[C:26]1([CH:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:33](Cl)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[C:36]1([CH:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:33]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[O:34])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and diphenylacetyl chloride: ESMS m/e: 540.3 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([CH:5]=[N+]=[N-])([CH3:4])[CH3:3].C(OCC)C.[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH2:35])[CH:31]=[CH:30][C:28]=3[N:29]=2)=[C:21]([F:42])[CH:20]=1>O1CCOCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[C:32]([C:34]4([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[CH2:35][CH:5]4[Si:2]([CH3:1])([CH3:3])[CH3:4])[CH:31]=[CH:30][C:28]=3[N:29]=2)=[C:21]([F:42])[CH:20]=1
Reactant: C=C(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1COCCO1
Solvent: CCOCC
Product: C[Si](C)(C)C1CC1(c1ccccc1)c1ccc2nc(-c3ccc(C4OCCCO4)cc3F)sc2c1
Temperature: 150 °C

Procedure:
In a reactor bottle (trimethylsilyl)diazomethane, 2.0 M in diethyl ether (2.4 mL, 4.8 mmol) was added to a mixture of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenylvinyl)-benzo[d]thiazole (0.650 g, 1.6 mmol), in anhydrous dioxane 15.00 mL. The reaction mixture was heated to 150° C. for 18 h. At which time the crude reaction mixture was concentrate in vacuo and purified by silica gel chromatography to afford as a mixture of isomers 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-6-(1-phenyl-2 (trimethylsilyl)cyclopropyl)benzo[d]thiazole. MS (ESI) m/z: Calculated: 503.2; Observed: 504.0 (M++1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.[Br:15]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(O)(=O)C>[Br:15][C:9]1[C:4]2[N:3]=[N:2][NH:1][C:5]=2[CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=1
Reactant: CCOC(=O)c1ccc2nn[nH]c2c1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)c1cc(Br)c2nn[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.3 %

Procedure:
A solution of ethyl 1H-1,2,3-benzotriazole-6-carboxylate (5.0 g, 26.2 mmol) in dichloromethane (25.2 mL) was purged with nitrogen and a solution of bromine (1.35 mL, 26.2 mmol) in acetic acid (5.17 mL) was added dropwise. The mixture was stirred at ambient temperature. After 18 h, additional bromine (0.67 mL, 13.1 mmol) was added and the mixture was stirred at ambient temperature. After 18 h, saturated aqueous sodium thiosulfate was added and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.025% trifluoroacetic acid) gave the title compound (0.73 g): LC-MS [M]=270.0.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:9][CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CO>[CH2:9]([N:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:10][CH2:11][CH3:12]
Reactant: C1CCCNCC1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCN1CCCCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.3 %

Procedure:
Procedure 1a—The first N-substitution of azepane was carried out using butyl bromide as an N-alkylating agent to form 1-butylazepane. To a stirring solution of azepane (49.97 g, 503.8 mmol) in methanol (220 cm3) cooled in an ice-water bath was added dropwise 1-bromobutane (57 cm3, 530 mmol), and then potassium carbonate (72.5 g, 524 mmol). The mixture was vigorously stirred at room temperature for 24 h. The resulting suspension was filtered through a sintered glass fret and the solution concentrated under reduced pressure at 45° C. in a rotary evaporator. A yellowish suspension was thus obtained and distilled in vacuo (45-47° C., 5.5 mmHg) to give 1-butylazepane as a colourless liquid (50.30 g, 64.3%). δH (500.13 MHz, CDCl3) 2.62 (4H, t, 3J(H,H)=5.5 Hz), 2.45 (2H, m), 1.64 (4H, br m), 1.59 (4H, br m), 1.45 (2H, m), 1.30 (2H, sextet, 3J(H,H)=7.4 Hz), 0.90 (3H, t, 3J(H,H)=7.4 Hz); δC (125.76 MHz, CDCl3) 58.2, 55.7, 29.8, 28.0, 27.1, 20.9, 14.1. ESI-MS: m/z=156 [M+H]+ (100). Calcd. for C10H22N: 156.1752; found: 156.1755.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22]([O:24]C)=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][C:5]=1[F:27])[CH3:2].[OH-].[Na+].Cl>C1COCC1.C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:19]([CH:20]=[O:21])[CH2:18][CH2:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][C:5]=1[F:27])[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3C=O)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.5 %

Procedure:
In a mixture of THF and ethanol (1:1, v/v, 20.0 ml) was dissolved methyl 7-(4-ethoxy-3-fluorophenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (441 mg). To the solution was added 1N sodium hydroxide solution (12.0 ml), and the mixture was stirred at room temperature for 16 hours. The mixture was a little concentrated, and to the residue was added 1N hydrochloric acid to convert weakly acidic solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give crystals, which were washed with ethyl acetate/hexane to give 7-(4-ethoxy-3-fluorophenyl)-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (435 mg) as white crystals.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:15]([O:17]C)=[O:16])[C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].Cl>C1COCC1.[OH-].[Na+]>[C:1]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCC(=O)N[C@H](C(=O)OC)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCCCCC(=O)N[C@H](C(=O)O)C(C)(C)C
Yield: 84.7 %

Procedure:
A solution of methyl N-hept-6-enoyl-3-methyl-L-valinate (1.40 g, 5.48 mmol) in THF (10 mL) and 1N NaOH (10 mL) was stirred at RT for 2 hours. The reaction mixture was acidified to pH 3 with 1 N HCl and extracted with EtOAc (3×150 mL). The combined organic phases were washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to give the title compound (1.12 g). LRMS (ESI) m/z 242.3 [(M+H)+; calcd for C13H24NO3: 242.2].
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]([C:11](=O)[C:12]#[CH:13])=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[CH:24]1([NH:29][C:30]([NH2:32])=[NH:31])[CH2:28][CH2:27][CH2:26][CH2:25]1.[O-]CC.[Na+]>C(O)C.O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:32]=[C:30]([NH:29][CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[N:31]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(=O)c1c(-c2ccc(OC)cc2)nn2c(Cl)cccc12
Reactant: N=C(N)NC1CCCC1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
To a mixture of 1-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-2-propyn-1-one (1.57 g, 5.0 mmol) and N-cyclopentylguanidine hydrochloride (1.07 g, 6.6 mmol) in ethanol (50 mL) was added sodium ethoxide (2.5 mL, 21 wt % in ethanol, 6.6 mmol). The resulting suspension was stirred overnight at room temperature, then diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine and dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (7:3 to 3:2 hexanes-ethyl acetate) provided 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (1.77 g, 83%) as a pale yellow solid. 1H NMR (CDCl3): δ 8.44 (d, 1 H), 8.05 (d, 1 H), 7.60 (d, 2 H), 7.28 (m, 1 H), 7.06–6.96 (m, 3 H), 6.38 (d, 1 H), 5.31 (broad, 1 H), 4.38 (m, 1 H), 3.88 (s, 3 H), 2.12 (m, 2 H), 1.84–1.53 (m, 6 H); MS m/z 420 (M+1).