Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[CH2:9][CH2:8][C:7](=O)[C:6](=O)[C:5]=2[C:4]([CH3:14])([CH3:13])[CH:3]1[CH3:15].CC1(C)C2CCCC(=O)C=2C(C)(C)C1C.[C:32]([NH2:35])(=[S:34])[CH3:33]>COCCOCCOC>[CH3:33][C:32]1[S:34][C:7]2[CH2:8][CH2:9][C:10]3[C:2]([CH3:16])([CH3:1])[CH:3]([CH3:15])[C:4]([CH3:14])([CH3:13])[C:5]=3[C:6]=2[N:35]=1
Reactant: CC1C(C)(C)C2=C(C(=O)C(=O)CC2)C1(C)C
Reactant: CC(N)=S
Agent: CC1C(C)(C)C2=C(C(=O)CCC2)C1(C)C
Solvent: COCCOCCOC
Product: Cc1nc2c(s1)CCC1=C2C(C)(C)C(C)C1(C)C
Temperature: 130 °C
Reaction time: 24 h

Procedure:
1,1,2,3,3-Pentamethyl-2,3,6,7-tetrahydro-1H-indene-4,5-dione is first prepared with 1,1,2,3,3-pentamethyl-1,2,3,5,6,7-hexahydro-inden-4-one (Cashmeran®) (commercially available at IFF) via oxidation with (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) (prepared as described by Barton in Tetrahedron Letters, 1984, 25(6), pages: 603-606). A 100 mL reaction flask is charged with 1,1,2,3,3-pentamethyl-2,3,6,7-tetrahydro-1H-indene-4,5-dione (10 g, 0.04 mol), thioacetamide (CH3CSNH2) (3.5 g, 0.04 mol), and diglyme (50 mL). The reaction mixture is heated to 130° C. and stirred for 24 hours. The crude mass is washed once with aqueous sodium carbonate (10%, 100 mL) followed by twice with brine (30 mL). Diglyme is recovered by roto-evaporation. The crude product is further purified with liquid chromatography (Biotage® system) and then crystallized. Product 2,6,6,7,8,8-hexamethyl-5,6,7,8-tetrahydro-4H-3-thia-1-aza-as-indacene (˜10 g) is obtained.
Reaction SMILES: [CH2:1]([C:8]1([OH:14])[CH2:12][CH2:11][O:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C=CC=CN=1.[CH2:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C@H:24]([NH2:31])[C@@H:23]1[OH:32]>ClCCl>[CH2:1]([C@@:8]([OH:14])([CH2:12][CH2:11][OH:10])[C:9]([NH:31][C@H:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][C@H:23]1[OH:32])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1c2ccccc2C[C@H]1O
Reactant: O=C1OCCC1(O)Cc1ccccc1
Agent: Oc1ccccn1
Solvent: ClCCl
Product: O=C(N[C@H]1c2ccccc2C[C@H]1O)[C@](O)(CCO)Cc1ccccc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
3-Benzyl-3-hydroxy-dihydro-furan-2-one (21c) (0.5 g, 2.6 mmol) and 2-hyroxypyridine (0.27 g, 2.8 mmol) in dry dichloromethane (15 mL) was added (1S,2R)-(−)-cis-1-amino-2-indanol (0.43 g, 2.8 mmol). The reaction mixture was stirred at 50° C. for 24 h and then evaporated. The residue was dissolved in ethyl acetate (80 mL) and washed with 1M HCl (20 mL), followed by saturated aqueous NaHCO3 (20 mL), and thereafter dried, filtered, and concentrated. The residue purified by silica gel flash chromatography using petroleum ether:acetone (3:1) gave 0.26 g of first eluted (compound 21d-(S)) and 0.33 g of second eluted (compound 21d-(R)) together in 66% yield of the title compounds.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[CH:18]=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:26].CO>>[ClH:26].[CH:21]1[C:22]2[C:17](=[C:16]([NH:15][C@H:12]3[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]3)[CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2cccc3cnccc23)CC1
Agent: Cl
Solvent: CO
Product: N[C@H]1CC[C@H](Nc2cccc3cnccc23)CC1

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 1 hour) by using Intermediate 41 (69 mg) and 10% hydrogen chloride/methanol solution (4 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (0.5 ml) and diethyl ether (2 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (58.7 mg) as light yellow powdery solid.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][C@H:2]1[C:3]([O:5][CH3:6])=[O:4].C(N[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15])CC>>[CH3:6][O:5][C:3]([C@@H:2]1[CH2:7][CH2:8][CH2:9][N:1]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:15])=[O:16])=[O:4]
Reactant: CCCNS(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2
Reactant: COC(=O)[C@@H]1CCCN1
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C(=O)C(=O)N2

Procedure:
The title compound was prepared from L-Pro-OMe following the procedure for 2,3-Dioxo-2,3-dihydro-1H-indole-5-sulfonic acid propylamide.
Reaction SMILES: C(O[CH:6]=[CH:7][C:8](=O)[C:9]([F:12])([F:11])[F:10])CCC.C[CH2:15][O:16][C:17]([CH2:19][C:20]([NH2:22])=[O:21])=[O:18].C[O-].[Na+].Cl>CO.O>[O:21]=[C:20]1[C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:6][CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[NH:22]1
Reactant: CCCCOC=CC(=O)C(F)(F)F
Reactant: CCOC(=O)CC(N)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(F)(F)F)[nH]c1=O
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a stirred solution of 2.0 g (0.0102 mol) of 4-butoxy-1,1,1-trifluoro-3-buten-2-one (VIIIa) and 1.3 g (0.0102 mol) of ethyl malonate monoamide in 10 mL methyl alcohol was added 2.2 mL (0.0102 mol) of a 25% solution of sodium methoxide in methanol. The solution turned into a thick yellow suspension which was refluxed overnight. The suspension was cooled to room temperature, poured into water, acidified with one normal hydrochloric acid and extracted with methylene chloride. The combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to afford 1.7 g (74%) of a yellow solid. m.p. 63°-64° C.; 1H NMR (CDCl3) δ4.0 (3H, s), 7.33 (1H, d, J=8 Hz), 8.4 (1H, d, J=8 Hz); IR (mineral oil) 3080, 1675 (br), 1605, 1450, 1375 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][NH2:19])[CH2:11][CH2:10]1.ClC/C=C/CN1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].COC1C=CC=CC=1N1CCNCC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][N:19]2[C:29](=[O:30])[C:28]3=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]3[C:26]2=[O:35])[CH2:13][CH2:14]1
Reactant: O=C1c2ccccc2C(=O)N1C/C=C/CCl
Reactant: COc1ccccc1N1CCN(C/C=C/CN)CC1
Agent: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(C/C=C/CN2C(=O)c3ccccc3C2=O)CC1
Yield: 85.6 %

Procedure:
Trans-4-[4-(2-methyloxyphenyl)piperazinyl]-2-buten-1-yl-amine: according to the method of Example 5, N-(trans-4-chloro-2-buten-1-yl)phthalimide was reacted with 1-(2-methyloxyphenyl)piperazine to obtain N-{4-[4-(2-methyloxy-phenyl)piperazinyl]-trans-2-buten-1-yl}phthalimide, which was then reacted with hydrazine hydrate. Yield: 85.6%, hydrochloride mp: 178-180° C.
Reaction SMILES: [CH2:1]([NH:6][C:7](=O)[CH2:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)[CH:12]=[C:11]2[O:20][CH2:21][O:22][C:10]=12)[CH2:2][CH2:3][CH2:4][CH3:5].C(O)(=O)C.[BH4-].[Na+].Cl>O1CCCC1.O>[CH2:1]([NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)[CH:12]=[C:11]2[O:20][CH2:21][O:22][C:10]=12)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNC(=O)Cc1cc(-c2ncc[nH]2)cc2c1OCO2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCNCCc1cc(-c2ncc[nH]2)cc2c1OCO2
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A solution of N-pentyl-(5-imidazolyl-2,3-methylenedioxyphenyl) acetamide (2.13 g, 6.75 mmol) and acetic acid (3.5 ml, 61.1 mmol) in tetrahydrofuran (80 ml) was added dropwise to a mixture of sodium borohydride (2.34 g, 61.9 mmol) and tetrahydrofuran (25 ml) over 20 minutes under reflux, and then stirring was continued for 2 hours under reflux. The mixture was added dropwise with water (150 ml) and concentrated hydrochloric acid (25 ml) under ice cooling and then stirring was continued at 60° C. for 2 hours. The reaction mixture was separated by adding ethyl acetate (100 ml) and water (150 ml), and the aqueous layer was made alkaline with sodium hydroxide and then extracted with toluene. The organic layer was washed with water and dried over anhydrous sodium sulfate, and then the solvent was evaporated to give N-pentyl-2-(5-imidazolyl-2,3-methylenedioxyphenyl)ethylamine (1.52 g) as an oil.
Reaction SMILES: [CH2:1]([N:5]([CH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1)[C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[OH:30]>>[CH2:1]([N:5]([CH2:21][C:22]1[NH:26][N:25]=[N:24][N:23]=1)[C:6](=[O:20])[C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:14][CH2:15][CH:16]([NH:27][CH2:28][C@H:29]([OH:30])[C:31]3[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=3)[CH2:17][CH2:18]2)=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1nnn[nH]1)C(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCCCN(Cc1nnn[nH]1)C(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from N-butyl-4-(4-oxo-1-piperidineyl)-N-(1H-tetraazol-5-ylmethyl)benzamide (which was obtained in Example 178) (0.14 g, 0.4 mmol) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) (0.12 g, 0.48 mmol) according to the prodedure shown for Example 180 to give 0.22 g of an off-white solid; m.p. 168-170° C.; MS (ES) m/z: 587.5 (MH+); HRMS (ES) Calcd. for C27H39N8O5S(MH+): 587.2759, Found: 587.2751.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].[NH:27]1[CH:31]=[N:30][N:29]=[N:28]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH:7]2[N:6]([S:17]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:5]([CH2:4][CH2:3][CH2:2][N:27]3[CH:31]=[N:30][N:29]=[N:28]3)[CH2:9][CH2:8]2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCCCl)CCC2c2ccc(F)cc2)cc1
Reactant: c1nnn[nH]1
Product: Cc1ccc(S(=O)(=O)N2C(CCCn3cnnn3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=430.5 (M+H+), was prepared in accordance with the general method of example 82b from (2RS,5RS)-2-(3-chloro-propyl)-5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine and 1H-tetrazole.
Reaction SMILES: N1CCCCC1.[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([O:42][CH2:43][CH2:44][C:45]([F:63])([F:62])[C:46]([F:61])([F:60])[C:47]([F:59])([F:58])[C:48]([F:57])([F:56])[C:49]([F:55])([F:54])[C:50]([F:53])([F:52])[F:51])(=[O:41])[CH2:16][C:17]([O:19][CH2:20][CH2:21][C:22]([F:40])([F:39])[C:23]([F:38])([F:37])[C:24]([F:36])([F:35])[C:25]([F:34])([F:33])[C:26]([F:32])([F:31])[C:27]([F:30])([F:29])[F:28])=[O:18]>>[F:39][C:22]([F:40])([C:23]([F:37])([F:38])[C:24]([F:35])([F:36])[C:25]([F:33])([F:34])[C:26]([F:31])([F:32])[C:27]([F:28])([F:29])[F:30])[CH2:21][CH2:20][O:19][C:17](=[O:18])[C:16](=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:15]([O:42][CH2:43][CH2:44][C:45]([F:62])([F:63])[C:46]([F:60])([F:61])[C:47]([F:58])([F:59])[C:48]([F:57])([F:56])[C:49]([F:55])([F:54])[C:50]([F:53])([F:52])[F:51])=[O:41]
Reactant: O=C(CC(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=Cc1ccccc1)C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 2 h

Procedure:
In a 100 mL 3-neck flask, 0.7146 g of piperidine (8.358 mmol) catalyst, 1.4369 g of benzaldehyde (13.543 mmol), and 10.2061 g of bis(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl) malonate (12.818 mmol) were stirred at room temperature. Throughout the reaction, both a solid and liquid were observed. After two hours, some of the liquid was removed mixed with acetone to obtain a GC sample that indicated a deficiency of benzaldehyde. Approximately 1 mL of additional benzaldehyde was added. After 24 hours, the reaction was stopped and solvent was removed on a rotary evaporator. The residue was dissolved in petroleum ether and cooled in dry ice overnight. The sample was then vacuum filtered to yield the desired white solid bis(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)2-benzylidenemalonate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[CH2:44][NH2:45]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:45][CH2:44][C:40]3[S:39][CH:43]=[CH:42][CH:41]=3)=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:37])[CH3:38])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: NCc1cccs1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NCc4cccs4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and 2-thiophenylmethylamine.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][C:26](O)=[O:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[C:16]1([CH2:22][CH2:23][CH2:24][CH2:25][C:26]([N:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH2:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:27])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CNCCCc1ccccc1
Reactant: O=C(O)CCCCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Mg+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)CN(CCCc1ccccc1)C(=O)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.5 %

Procedure:
Methyl 2-((3-phenylpropyl)amino)acetate (20.0 mg, 0.0965 mmol) and 5-phenylvaleric acid (22.0 mg, 0.116 mmol) were dissolved in 1 mL of well-dried DCM under argon condition, and EDC (55.5 mg, 0.289 mmol), HOBt (39.1 mg, 0.289 mmol) and DIPEA (82.7 μL, 0.482 mmol) were added and the reaction mixture was stirred for 20 hours at room temperature. Upon completion of the reaction, the reaction was terminated by adding 3 mL of water, and the reaction mixture was extracted with DCM (3 mL×4). The organic layer thus obtained was treated with anhydrous magnesium sulfate to remove water. The precipitate was filtered out and the resulting solution was concentrated by distillation under reduced pressure, and purified by column chromatography to obtain 34.2 mg (0.0931 mmol, 96%) of the desired compound.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.Cl.[CH3:19][NH:20][O:21][CH3:22]>ClCCl>[CH:1]1([CH2:7][CH2:8][C:9]([N:20]([O:21][CH3:22])[CH3:19])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CNOC
Reactant: O=C(Cl)CCC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)CCC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
3-Cyclohexylpropionic chloride (1.00 g, 5.71 mmol) was dissolved in dichloromethane (10 mL). Under ice-cooled condition, pyridine (0.910 mL, 11.3 mmol) and N,O-dimethylhydroxylamine hydrochloride (840 mg, 8.57 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate after adding a saturated sodium hydrogen carbonate aqueous solution. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→80/20) to give 3-cyclohexyl-N-methoxy-N-methylpropaneamide (1.13 g, yield 99%).
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:30][N:31]([CH3:37])[C@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.C(OCC)(=O)C>CS(C)=O.[Cl-].[Na+].O>[CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:12]=3[N:34]3[CH2:35][CH2:36][C@H:32]([N:31]([CH3:37])[CH3:30])[CH2:33]3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C3CC3)nc2c1C#N
Reactant: CN(C)[C@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Yield: 69 %

Procedure:
2-Cyclopropyl-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-173) (70 mg, 0.24 mmol) was dissolved in dimethyl sulfoxide (2 ml), then at room temperature, triethylamine (50 μl, 0.36 mmol) and (3S)-3-(dimethylamino)pyrrolidine (40 μl, 0.31 mmol) were added. After cooling to room temperature, the reaction liquid was fractionated with ethyl acetate and saturated brine. The aqueous layer was further extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, then the solvent was evaporated away, and the resulting residue was purified by preparative TLC (eluent, chloroform:methanol=97:3) to obtain a roughly-purified product (64 mg, 69%).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:14][C:15]=3[N:16]=[C:17]2[C:20]#[N:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].O>CN1CCCC1=O>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:14][C:15]=3[N:16]=[C:17]2[C:20]2[NH:29][N:28]=[N:27][N:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: c1ccc(C[C@@H]2CN3C(c4nnn[nH]4)=Nc4nc(C5CCCC5)[nH]c4C3=N2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
Compound 75 (69 mg, 0.200 mmol) obtained in Example 75 was dissolved in 1-methyl-2-pyrrolidinone (1 mL), to the solution were added sodium azide (52 mg, 0.800 mmol, 4.0 equivalents) and ammonium chloride (42 mg, 0.800 mmol, 4.0 equivalents), and the mixture was stirred at 120° C. for 2 hours. To the reaction mixture was added water, and the deposited crystals were collected by filtration to obtain the title compound (64 mg, 83%) as a white solid.
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[N:6]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:7]=1[C:16]([O:18]C)=O.[Cl-].[NH4+].[CH2:22](O)C>C1COCC1>[OH:18][CH2:16][C:7]1[CH:8]=[CH:9][C:10]([C:12]([O:14][CH2:15][CH3:22])=[O:13])=[CH:11][N:6]=1
Reactant: COC(=O)c1ccc(C(=O)OC)nc1
Reactant: CCO
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(CO)nc1
Reaction time: 2.5 h

Procedure:
A slurry of dry calcium chloride (22.7 g, 0.205 mol) in ethanol (300 mL) and THF (300 mL) at 0° C. was treated portionwise with sodium borohydride (15.5 g, 0.41 mol), stirred for 2.5 hours, treated with dimethyl 2,5-pyridinedicarboxylate (20.0 g, 0.103 mol), stirred for 20 minutes, treated with saturated ammonium chloride solution (100 mL), and concentrated. The concentrate was dissolved in dichloromethane, and the solution was washed sequentially with saturated ammonium chloride solution, water, and brine, dried (MgSO4), filtered,and concentrated to provide the desired product containing approximately 10% methyl 6-hydroxymethylnicotinate. This mixture was used directly in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[O:9][C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1)[CH:21]=[O:22].C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[CH3:27][O:26][C:24]1[CH:23]=[C:20]([CH:21]([C:3]2[C:4]3[O:9][C:8]([F:11])([F:10])[C:7]([F:13])([F:12])[O:6][C:5]=3[CH:14]=[CH:15][CH:2]=2)[OH:22])[CH:19]=[C:18]([O:17][CH3:16])[CH:25]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: FC1(F)Oc2ccc(Br)cc2OC1(F)F
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2cccc3c2OC(F)(F)C(F)(F)O3)c1
Yield: 26.4 %

Procedure:
6-Bromo-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxine (1.50 g, 5.23 mmol), 3,5-dimethoxybenzaldehyde (0.79 g, 4.75 mmol), and n-butyl lithium (2.09 ml, 5.23 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 30% EtOAc in hexane in about 40 min.) to give (3,5-Dimethoxy-phenyl)-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-methanol as an oil (0.47 g, 26%): 1HNMR (CDCl3) 7.37 (dd, J=1, 7 Hz, 1H, Ar), 7.17 (t, J=8 Hz, 1H, Ar), 7.06 (dd, J=1, 8 Hz, 1H, Ar), 6.57 (d, J=2 Hz, 2H, Ar), 6.38 (t, J=2 Hz, 1H, Ar), 6.12 (d, J=3 Hz, 1H, CHOH), 3.77 (s, 6H, 2OCH3),2.36 (d, J=3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:22][CH2:23][CH2:24][CH3:25])[N:18]([CH2:19][CH2:20][NH2:21])[C:14]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1>ClCCl>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:22][CH2:23][CH2:24][CH3:25])[N:18]([CH2:19][CH2:20][NH:21][C:1](=[O:3])[CH3:2])[C:14]=2[C:13]2[N:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CCCCc1nc2c(N)nc3cccnc3c2n1CCN
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3cccnc3c2n1CCNC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
Under a nitrogen atmosphere, acetyl chloride (50 μL, 0.7 mmole) in dichloromethane (25 mL) was added dropwise to a cooled (ice bath) solution of 2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine (0.2 g, 0.7 mmol) in dichloromethane (50 mL). After the addition was complete, the reaction mixture was allowed to warm to ambient temperature. After 30 minutes thin layer chromatography indicated that the reaction was complete. The reaction mixture was washed with 10% sodium hydroxide, water and brine; dried; and concentrated under vacuum to provide 0.25 g of crude product. This material was purified by column chromatography (silica gel eluting with dichloromethane) to provide 0.2 g of a solid. This solid was recrystallized from acetonitrile (30 mL) to provide 0.18 g of N′-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]acetamide as a white powder, m.p.228-230° C. Analysis: Calculated for C17H22N6O: %C, 62.56; %H, 6.79; %N, 25.75; Found: %C, 62.50; %H, 6.59; %N, 26.04. HRMS (EI) calcd for C22H26N6O2 (M+) 326.1855, found 326.1846
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10]C)=[O:9])[O:5][C:6]=1[Br:7].[Li+].[OH-].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][C:6]=1[Br:7]
Reactant: COC(=O)c1cc(Br)c(Br)o1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(Br)o1
Reaction time: 4 h
Yield: 98.8 %

Procedure:
To a suspension of methyl 4,5-dibromo-2-furoate (26.19 g, 92.2 mmol) in THF (60 mL) at rt was added LiOH (3 M in water, 60 mL, 180 mmol). The biphasic mixture was stirred for 4 h. The mixture was poured into 1 N HCl (500 mL) and extracted with DCM (3×). The combined organic layers were dried (Na2SO4) and concentrated to provide 24.59 g (99%) of the acid as an off-white solid. 1H NMR (400 MHz, CD3OD): 7.30 (s, 1H).