Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:21])=[N:8][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:18])[CH:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(C)nn(-c2cccc([N+](=O)[O-])c2)c1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2cccc(N)c2)c1C

Procedure:
The compound of Example 2 (1.8 g,) was dissolved in ethanol then 0.2 g 5% Pd/C was added to the solution. The mixture was treated with hydrogen gas at 45 psi. Upon completion of the reaction, the solution was filtered through Celite, and the filtrate concentrated under vacuum. The named product slowly crystallized upon standing (m.p. 93° C.-95° C.).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20]C)=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.I[Si](C)(C)C.C(=O)(O)O.[CH2:31]([O:35][C:36]([NH:38][CH:39]1[CH2:43][CH2:42][NH:41][CH2:40]1)=[O:37])[CH2:32][CH2:33][CH3:34]>ClCCl.C(#N)C>[CH2:31]([O:35][C:36]([NH:38][CH:39]1[CH2:43][CH2:42][N:41]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:40]1)=[O:37])[CH2:32][CH2:33][CH3:34]
Reactant: COC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCCCOC(=O)NC1CCNC1
Agent: C[Si](C)(C)I
Agent: O=C(O)O
Solvent: CC#N
Solvent: ClCCl
Product: CCCCOC(=O)NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
To a solution of 1.0 g (3.4 mmole) of methyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 25 ml dichloromethane was added 0.6 ml (0.8 g, 4.2 mmole) of iodotrimethylsilane while stirring at room temperature under a nitrogen atmosphere. The mixture was warmed to reflux and stirred overnight. The reaction was cooled to room temperature, concentrated, and the residue taken up in 25 ml acetonitrile. To the resulting suspension was added a solution of 1.6 g (8.5 mmole) of 3-butoxycarbonylaminopyrrolidine bicarbonate in 10 ml acetonitrile while under nitrogen. The reaction was warmed to reflux for four hours, then cooled to room temperature. The formed precipitate was filtered, washed with acetonitrile and ether, yielding 1.26 g (82%) of 7-[3-(butoxycarbonyl)amino-1-pyrrolidinyl]-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 228°-230° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[NH:7][CH:8]=[CH:9][C:2]=12.[N+:10]([O-])([OH:12])=[O:11].C(=O)(O)[O-].[Na+]>O>[N+:10]([C:9]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][N:1]=2)[NH:7][CH:8]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: c1cnc2[nH]ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2nccnc12
Temperature: 0 °C

Procedure:
7-Nitro-5H-pyrrolo[2,3-b]pyrazine (5) is prepared by adding 5H-pyrrolo[2,3-b]pyrazine (3) to fuming nitric acid while cooling (e.g. 0° C.). After stirring for one to several hours, water is carefully added and the mixture neutralized with saturated sodium bicarbonate. The solids are collected by filtration and dried to provide 7-nitro-5H-pyrrolo[2,3-b]pyrazine 5.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1)=[CH2:2].[OH-].[Na+].Cl.CCCCCC>CO>[CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)=[CH2:2]
Reactant: C=CC1CCC(C(=O)OC)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Product: C=C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
55.3 g of methyl 4-vinylcyclohexane carboxylate was dissolved in 60 mL of methanol, and was cooled to 15° C. Then, 100 g of 20% sodium hydroxide aqueous solution was added thereto. The solution was further stirred at room temperature for 2 hours, and then concentrated hydrochloric acid was added to make the system acidic. Extraction was performed with hexane, and then the organic layer was washed with saturated saline. The resultant product was dried over anhydrous sodium sulfate, and concentrated, to obtain 52.4 g of reaction mixture. 23.0 g of trans-4-vinylcyclohexane carboxylic acid was obtained by recrystallization from hexane.
Reaction SMILES: CO[CH:3]([CH3:8])[CH2:4][C:5]([NH2:7])=[O:6].[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13]N.[OH-].[Na+]>>[CH3:9][N:10]([CH3:15])[CH2:11][CH2:12][CH2:13][NH:7][C:5](=[O:6])/[CH:4]=[CH:3]/[CH3:8]
Reactant: COC(C)CC(N)=O
Reactant: CN(C)CCCN
Agent: [Na+]
Agent: [OH-]
Product: C/C=C/C(=O)NCCCN(C)C

Procedure:
117.2 g (1.0 mole) of 3-methoxybutyric acid amide are heated with 103.7 g (1.05 mole) of 3-dimethylaminopropylamine for 10 hours in a temperature range of 145°-175° C. The mixture is allowed to cool, 1.5 g of sodium hydroxide are added and the mixture is heated in a high vacuum at 120°-130° C. The methanol is split off within about 30 minutes, vigorous foaming occurring. The temperature is increased and 130 g (0.76 mole=76% of the theoretical yield) of light yellow oil having a Bp0.1 of 132°-134° C. are distilled off.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][SH:9].[OH-].[K+].Cl[CH2:13][CH2:14][OH:15].Cl>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][S:9][CH2:13][CH2:14][OH:15]
Reactant: SCCc1ccccn1
Reactant: OCCCl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OCCSCCc1ccccn1
Reaction time: 6 h
Yield: 22.4 %

Procedure:
2-Pyridineethanethiol (1.9 g) and potassium hydroxide (0.77 g) in methanol (15 ml) were stirred under nitrogen for 15 min. 2-Chloroethanol (1.10 g) was added and the solution stirred under nitrogen for 6 h. The mixture was acidified to pH5 with 2N hydrochloric acid and then left overnight. The methanol was evaporated in vacuo and the residue partitioned between water (150 ml) and diethyl ether (150 ml), separated and the aqueous phase re-extracted with diethyl ether (100 ml). The combined ethereal layers were dried and evaporated in vacuo to give an oil. Purification by FCC eluting with System G (98:2:1) gave the title compound (0.56 g) as a colourless oil. T.l.c. (diethyl ether) Rf 0.21
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.C1(=O)[O:14][C:12](=[O:13])CCC1.C1C2C(CO)C3C(=CC=CC=3)C=2C=CC=1>>[C:12]([OH:14])(=[O:13])[CH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C1CCC(=O)O1
Reactant: O=C1CCCC(=O)O1
Agent: OCC1c2ccccc2-c2ccccc21
Product: O=C(O)CCCC(=O)O

Procedure:
The mixed diesters (E) are readily prepared in two stages from succinic anhydride (r=2) or glutaric anhydride (r=3). In the first stage, the appropriate cyclic anhydride is reacted with 0.5 equivalents of 9-fluorenyl methanol to form the fluorenylmethyl mono-ester of succinic or glutaric acid. In the second stage, reaction of the mono-ester with pentafluorophenol under standard esterification conditions affords the mixed diester.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:10]=[C:9]3O)[CH2:3][CH2:2]1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:39][C:40]1[NH:44][N:43]=[C:42]([NH2:45])[CH:41]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:10]=[C:9]3[NH:45][C:42]2[CH:41]=[C:40]([CH3:39])[NH:44][N:43]=2)[CH2:3][CH2:2]1
Reactant: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C3CC3)cccc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(C4CC4)cccc23)n[nH]1
Temperature: 95 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To 8-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol (50 mg, 0.15 mmol) were added phosphoryl tribromide (0.86 g) and toluene (2 mL) followed by DIEA (0.053 mL, 0.3 mmol). The mixture was heated at 95° C. for 0.5 h. The mixture was cooled and partitioned between EtOAc and a saturated aq sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (100 mg, 1 mmol) in DMF (3 mL) and the mixture was stirred at rt overnight. The mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 8-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (30 mg, 48%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79-0.90 (m, 2H) 1.04-1.16 (m, 2H) 2.17 (s, 3H) 2.95-3.10 (m, 1H) 5.97 (s, 1H) 7.32 (d, J=7.35 Hz, 1H) 7.52 (t, J=7.91 Hz, 1H) 7.96-8.06 (m, 2H) 8.43 (d, J=8.10 Hz, 1H) 8.67 (s, 1H) 10.57 (br s, 1H) 12.15 (br s, 1H); LC-MS (ESI) m/z 411 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:50][CH3:51])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:29]=[CH:28][CH:27]=[C:14]([C:15]([N:17]([CH3:26])CCN3CCOCC3)=[O:16])[CH:13]=2)=[C:6]([C:31]2[CH:36]=[C:35]([C:37](=[O:49])[NH:38][C@@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][CH2:41][CH2:40]3)[CH:34]=[CH:33][N:32]=2)[CH:5]=1)[CH3:2].CN[CH2:54][CH2:55][OH:56]>>[CH2:1]([N:3]([CH2:50][CH3:51])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:29]=[CH:28][CH:27]=[C:14]([C:15]([N:17]([CH2:54][CH2:55][OH:56])[CH3:26])=[O:16])[CH:13]=2)=[C:6]([C:31]2[CH:36]=[C:35]([C:37](=[O:49])[NH:38][C@@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42][CH2:41][CH2:40]3)[CH:34]=[CH:33][N:32]=2)[CH:5]=1)[CH3:2]
Reactant: CNCCO
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCOCC3)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCO)c2)c(-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1

Procedure:
This compound was prepared according to the procedure described for the synthesis of (S)—N1-(4-(diethylamino)-2-(4-((1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyridin-2-yl)phenyl)-N3-methyl-N3-(2-morpholinoethyl)isophthalamide Example 131, using 2-(methylamino)ethanol in place of N-methyl-2-morpholinoethanamine. MS (ES, m/z): 620.32 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([O:23]C)=[O:22])[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:6])=[O:5])[CH3:3].[Li+].[OH-].CC(O)=O>C1COCC1.O>[CH3:3][C:2]([C:8]1[CH:9]=[C:10]2[C:15](=[C:16]([C:18]3[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=3)[C:21]([OH:23])=[O:22])[CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2)([S:4]([CH3:7])(=[O:5])=[O:6])[CH3:1]
Reactant: COC(=O)c1cccc(-c2cc(C(C)(C)S(C)(=O)=O)cc3cccnc23)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(c1cc(-c2cccc(C(=O)O)c2)c2ncccc2c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ester from step 1 in THF (0.08M) was added LiOH (2N, 5 eq). The reaction mixture was stirred at rt for 5 h, acidified with AcOH, diluted with water and extracted with CH2Cl2. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The title compound was isolated by filtration from Hexane/ether as a solid.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([OH:10])[CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].I[CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[O:18][C:19]=1[CH3:20].C(OC)(C)(C)C>CN(C)C=O>[CH2:1]([C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=3)[O:18][C:19]=2[CH3:20])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H]1CCC[C@H](O)C1
Reactant: COc1cccc(-c2nc(CI)c(C)o2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: C=CC[C@@H]1CCC[C@H](OCc2nc(-c3cccc(OC)c3)oc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.8 g of cis-3-allylcyclohexanol are dissolved in 20 ml of dimethyl-formamide, and 770 mg of sodium hydride (60% strength suspension in paraffin oil) are added. After 30 minutes, 4 g of 4-iodomethyl-5-methyl-2-(3-methoxyphenyl)oxazole, dissolved in 20 ml of dimethylformamide, are added dropwise. The mixture is stirred at room temperature for 1 hour. 200 ml of methyl tert-butyl ether are then added to the reaction mixture, and the mixture is washed three times with water. The organic phase is dried over MgSO4 and the solvent is then removed under reduced pressure. The residue is purified on silica gel using the mobile phase n-heptane:ethyl acetate=10:1. This gives 750 mg of 4-(cis-3-allyl-cyclohexyloxymethyl)-2-(3-meLhoxpheny,”-5-methyloxazole as an Oil. C21H27NO3 (341.45), MS(ESI): 342 (M+H+), Rf(n-heptane:ethyl acetate=2:1)=0.26.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(OC(C)(C)C)(=[O:15])C.[C:21]([O:25][CH2:26][C:27](=[O:30])[CH2:28][F:29])([CH3:24])(C)C.CC(C)=O.C(=O)=O.S(=O)(=O)(O)O.[Cl-].[Na+]>CCCCCC.O1CCCC1>[F:29][CH2:28][C:27]1([OH:30])[CH2:26][O:25][C:21](=[O:15])[CH2:24]1
Reactant: CC(C)(C)OCC(=O)CF
Reactant: CC(=O)OC(C)(C)C
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: O=C1CC(O)(CF)CO1
Temperature: -74 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A 750 mL 4-necked sulfonation flask equipped with magnetic stirring bar, thermometer and an argon in/outlet, was charged with 16.87 g (166.7 mmol) diisopropylamine and 100 mL tetrahydrofuran. The solution was cooled to −74° C. and 100 mL butyllithium 1.6M in hexane were added leading to a raise of the internal temperature to −55° C. The light-yellow solution was stirred at −50° C. to −10° C. for 30 min (ice/ethanol cooling bath), then re-cooled to −74° C. and 19.36 g (166.7 mmol) tert-butyl acetate were added dropwise. The slightly turbid solution was stirred at −20° C. for 30 min, then re-cooled to −74° C. and 22.23 g (150 mmol) crude 1-tert-butoxy-3-fluoro-propan-2-one were added dropwise within 15 min. The acetone/CO2 bath was replaced by an ice/water bath and the reaction mixture was stirred at ca. −10° C. for 45 min. After re-cooling to −75° C. 52.5 g (508.5 mmol) sulfuric acid 95% were added drop by drop within 15 min. The resulting two-phase mixture was allowed to attain RT (45 min) and then heated under reflux for 2 h (oil bath temperature 80° C., internal temperature 54-61° C., strong gas evolution). After cooling to RT the mixture was treated with sodium chloride solution 10% (50 mL), the phases were separated and the aqueous layer was extracted with ethyl acetate (5×150 mL). The combined organic phases were washed with sat. sodium bicarbonate solution (2×50 mL) and brine (2×50 mL), dried over magnesium sulfate, filtered and evaporated (40° C./15 mbar) to provide 15.78 g of crude 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one as yellow-brown oil. This material contained 2% acetic acid by 1H-NMR. From the combined aqueous layers an additional 1.38 g of crude 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one were obtained by further extraction with ethyl acetate (2×150 mL) followed by further work-up as described above; combined yield 17.16 g (85.3%) of crude 4-fluoromethyl-4-hydroxy-dihydro-furan-2-one.
Reaction SMILES: [CH:1]1([C:10]([OH:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>[OH-].[Na+].O1CCOCC1>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:1]2([C:10]([OH:12])=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][NH:2]2)=[O:22])=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: O=C(O)C1NCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)C1(C(=O)Nc2ccc(Cl)cc2)NCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.2 %

Procedure:
To a solution of (D,L) 2,3-dihydro-1H-isoindole-1-carboxylic acid (372 mg, 2.28 mmol) in 3N aq. NaOH (10 mL), a solution of 4-chlorophenylisocyanate (530 mg, 3.66 mmol) in dioxane (6 mL) was added. The mixture was stirred at room temperature overnight. It was then washed with Et2O (2×). The aqueous layer was separated, acidified with 4N HCl to pH 1 to 2. The product was extracted with EtOAc. The EtOAc solution was dried over Na2SO4, concentrated in vacuo to give the titled compound as a solid (550 mg), which was sufficiently pure to be used in the next reaction. MS 317.0 and 319.0 (M+H, Cl pattern).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[N:10]([CH3:16])[C:9]3[CH:17]=[N:18][C:19]([N:21]([CH3:33])[C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:67][CH:68]1[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]1>CN(C)C=O>[CH:1]1([N:7]2[CH2:13][CH:12]([CH3:14])[C:11](=[O:15])[N:10]([CH3:16])[C:9]3[CH:17]=[N:18][C:19]([N:21]([CH3:33])[C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:67][CH:68]5[CH2:73][CH2:72][N:71]([CH3:74])[CH2:70][CH2:69]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1N(C)c1ncc2c(n1)N(C1CCCCC1)CC(C)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N(C)c1ncc2c(n1)N(C1CCCCC1)CC(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a mixture of 0.058 g (0.00013 mole) of (rac)-4-[(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)-methyl-amino]-3-methoxy-benzoic acid, 0.054 g (0.00014 mole) of 1-[bis(dimethylamino)-methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 3 mL of N,N-dimethylformamide was added 0.030 mL (0.00019 mole) of ethyldiisopropylamine. The mixture was stirred at room temperature for 30 minutes and then 0.022 g (0.00019 mole) of 4-amino-1-methyl-piperidine was then added. The mixture was stirred at room temperature for 3 hours and was then partitioned between ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed successively with water and brine, dried anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-75-25) to give 0.070 g of (rac)-4-[(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl)-methyl-amino]-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-66) as white powder. HRMS (ES+) m/z Calcd for C30H43N7O3+H [(M+H)+]: 550.3500. Found: 550.3504.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([Br:15])[CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:7]=3[NH:8][C:9]=2[CH:10]=1.Cl.Cl[CH2:22][CH2:23][N:24]([CH2:26][CH2:27]Cl)[CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>CC(O)(C)C>[Br:15][C:13]1[CH:12]=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:7]2[NH:8][C:9]3[CH:10]=[C:2]([N:1]4[CH2:27][CH2:26][N:24]([CH3:25])[CH2:23][CH2:22]4)[CH:3]=[CH:4][C:5]=3[C:6]=2[N:14]=1
Reactant: COC(=O)c1cc(Br)nc2c1[nH]c1cc(N)ccc12
Reactant: CN(CCCl)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COC(=O)c1cc(Br)nc2c1[nH]c1cc(N3CCN(C)CC3)ccc12
Yield: 69 %

Procedure:
A mixture of methyl 7-amino-2-bromo-5H-pyrido[3,2-b]indole-4-carboxylate (1.0 g, 3.1 mmol), 2-chloro-N-(2-chloroethyl)-N-methylethanamine hydrochloride (1.20 g, 6.25 mmol) and sodium carbonate (1.66 g, 15 6 mmol) in t-BuOH (40 mL) was heated at reflux overnight. The reaction was partitioned between EtOAc and water and the organic phase was washed with sat. aq. NaHCO3 solution, water, and brine. After drying with sodium sulfate, the solvents were removed and silica gel chromatography (elution with 5% MeOH in DCM) afforded methyl 2-bromo-7-(4-methylpiperazin-1-yl)-5H-pyrido[3,2-b]indole-4-carboxylate (900 mg, 2.14 mmol, 69% yield). MS (ESI) m/z 405.14 (M+H); LCMS Ret Time: 1.995 min; Xbridge S10 4.6×50 mm column, 3 min gradient, 0-100% B, 4 mL/min. Solvent A: 95% MeOH—5% H2O—0.1% TFA; Solvent B: 5% MeOH—95% H2O—0.1% TFA.
Reaction SMILES: [CH2:1](Br)[CH3:2].[Li].[CH3:5][C:6]1([CH3:16])[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([CH3:14])([CH3:13])[C:7]1=[O:15]>C(OCC)C>[CH2:1]([C:7]1([OH:15])[C:8]([CH3:14])([CH3:13])[CH2:9][CH2:10][CH2:11][CH2:12][C:6]1([CH3:16])[CH3:5])[CH3:2]
Reactant: CCBr
Reactant: CC1(C)CCCCC(C)(C)C1=O
Agent: [Li]
Solvent: CCOCC
Product: CCC1(O)C(C)(C)CCCCC1(C)C
Temperature: -30 °C
Yield: 76.4 %

Procedure:
A mixed solution of ethyl bromide (33.30 g, 0.40 moles)/dried diethyl ether (40 ml) was dropped into a mixture of lithium (4.30 g, 0.62 moles)/dried diethyl ether (25 ml) in 2 hours while stirring at -30° C., followed by further adding dried diethyl ether (40 ml) and raising the temperature to 0° C. The mixture was subjected to separation by filtration. The resulting filtrate was dropped into a mixed solution of 2,2,7,7-tetramethylcycloheptanone (15.00 g, 0.09 moles)/dried diethyl ether (40 ml) in 30 minutes while stirring at 0° C. The mixture was stirred at 0° C. for 2 hours. The resulting reaction mixture was treated in the same manner as in Example 1 to obtain 13.50 g (yield 76.4%) of the captioned compound. This compound was a colorless transparent liquid having a woody, earthy and patchuli oil-like odor.
Reaction SMILES: C[C:2]1[C:3](C)=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]#[C:13]CO.[OH-].[Na+].C1(C)C=CC=CC=1>C(OCC)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]#[CH:13])[CH:11]=[CH:2][CH:3]=1
Reactant: Cc1cc2cccc(C#CCO)c2nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C#Cc1cccc2cccnc12
Temperature: 120 °C
Yield: 80 %

Procedure:
8.5 g (40 mmol) of Dimethylhydroxymethyl-8-quinolylacetylene and 1. g (45 mmol) of sodium hydroxide (manufactured by KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98%) were placed in a 300 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with argon gas. 200 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 0.5 hours. Diethyl ether was added to the reaction mixture, the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure by an evaporator. Hexane (250 ml) was added to the residue and the mixture was heated to 70° C. After filtering out the insolubles, the desired compound precipitated by cooling it to −78° C. was filtered and washed with cold hexane (−78° C., 100 ml) and then dried under reduced pressure to give 4.9 g of the desired compound as a yellowish white solid (yield: 80%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][CH2:15][C@@H:16]1[NH:21][C:20](=O)[CH2:19][NH:18][C:17]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([O:14][CH2:15][C@H:16]1[CH2:17][NH:18][CH2:19][CH2:20][NH:21]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CNC(=O)[C@H](COCc2ccccc2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(COC[C@H]2CNCCN2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
A solution of LAH (1.87 g, 49.3 mmol) in THF (50 mL) was chilled to 0° C. To this mixture was added (3S)-3-((benzyloxy)methyl)-2,5-piperazinedione (3.85 g, 16.44 mmol) slowly portion wise. The mixture was allowed to warm to room temperature and then heated at reflux for 1 h. Afterwards, the mixture was chilled to 0° C. and the reaction was quenched with an excess of solid sodium sulfate decahydrate (approximately 50 g). After stirring at room temperature for 1 h, the mixture was filtered. The filtrate was concentrated to give (R)-2-(benzyloxymethyl)piperazine (2.60 g) as a yellow oil. To this was added excess HCl (4M in dioxane) to deliver (2R)-2-((benzyloxy)methyl)piperazine dihydrochloride.