Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([OH:19])[CH:5]=2.BrC1C(=O)C2C(C=1C1C=CC=CC=1)=CC=C(O)C=2.[O:39]=[S:40]1(=[O:49])[CH2:45][CH2:44][N:43]([CH2:46][CH2:47]O)[CH2:42][CH2:41]1>>[Br:1][C:2]1[C:3](=[O:20])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[CH:8][CH:7]=[C:6]([O:19][CH2:47][CH2:46][N:43]1[CH2:44][CH2:45][S:40](=[O:49])(=[O:39])[CH2:41][CH2:42]1)[CH:5]=2
Reactant: O=S1(=O)CCN(CCO)CC1
Reactant: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(O)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(O)cc21
Product: O=C1C(Br)=C(c2ccc(F)cc2F)c2ccc(OCCN3CCS(=O)(=O)CC3)cc21
Yield: 65 %

Procedure:
The procedure of Step 6 of Example 1 was repeated except for using 2-bromo-3-(2,4-difluorophenyl)-6-hydroxy-1H-inden-1-one obtained in Step 5 of Example 82 as a starting material instead of 2-bromo-6-hydroxy-3-phenyl-1H-inden-1-one, 2-(1,1-dioxothiomorpholin-4-yl)ethanol instead of 4-(2-hydroxyethyl)morpholine to obtain the title compound (65%).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH:13]([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:24]=[C:25]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=2)[NH2:26])[CH2:18][CH2:17]1)([CH3:15])[CH3:14].CCN(CC)CC.[CH3:41][NH:42][C:43]1[N:48]=[CH:47][N:46]=[C:45]([O:49][C:50]2[CH:51]=[C:52]3[C:57](=[CH:58][CH:59]=2)[NH:56][CH2:55][CH2:54][CH2:53]3)[CH:44]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH:13]([N:16]1[CH2:17][CH2:18][N:19]([CH2:22][C:23]2[CH:24]=[C:25]([NH:26][C:2]([N:56]3[C:57]4[C:52](=[CH:51][C:50]([O:49][C:45]5[CH:44]=[C:43]([NH:42][CH3:41])[N:48]=[CH:47][N:46]=5)=[CH:59][CH:58]=4)[CH2:53][CH2:54][CH2:55]3)=[O:4])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=2)[CH2:20][CH2:21]1)([CH3:15])[CH3:14]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CNc1cc(Oc2ccc3c(c2)CCCN3)ncn1
Reactant: CC(C)N1CCN(Cc2cc(N)cc(C(F)(F)F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNc1cc(Oc2ccc3c(c2)CCCN3C(=O)Nc2cc(CN3CCN(C(C)C)CC3)cc(C(F)(F)F)c2)ncn1
Temperature: 2 °C
Reaction time: 0.05 h

Procedure:
A solution of 41 mg (0.138 mMol) of triphosgene in 5 ml of CH2Cl2 is cooled to 2° C. Then a solution of 123 mg (0.41 mMol) of 3-(4-isopropylpiperazin-1-ylmethyl)-5-trifluoromethyl-aniline and 82 μl (0.59 mMol) Et3N in 2 ml CH2Cl2 is added during 5 min. The mixture is stirred for 3 min at 2° C. and then warmed up to rt in a water bath. A solution of 100 mg (0.39 mMol) of 6-methylamino-4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-pyrimidine (Step 3.2) and 54 μl (0.39 mMol) Et3N in 2 ml of CH2Cl2 is added during 5 min and stirring continued for 2 h at rt. EtOAc and a sat. solution of Na2CO3 is added to the reaction mixture. The aqueous phase is separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Column chromatography (Combi Flash; EtOAc/EtOH/Et3N 95:5:0→90:10→90:10:1) gives the title compound: MS: [M+1]+=584; TLC(EtOAc/EtOH/NH3conc. 90:10:1): Rf=0.11; HPLC: AtRet=10.1.
Reaction SMILES: S(Cl)(Cl)=O.CC1C=CSC=1C(O)=O.CC1C=CSC=1C(Cl)=O.[CH3:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29]([N:31]=[C:32]=[S:33])=[O:30].[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[N:42]=[CH:41][CH:40]=[C:39]2[O:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[C:51]([F:56])[CH:50]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[N:42]=[CH:41][CH:40]=[C:39]2[O:48][C:49]1[CH:55]=[CH:54][C:52]([NH:53][C:32]([NH:31][C:29]([C:25]2[S:26][CH:27]=[CH:28][C:24]=2[CH3:23])=[O:30])=[S:33])=[C:51]([F:56])[CH:50]=1
Reactant: Cc1ccsc1C(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: Cc1ccsc1C(=O)Cl
Agent: Cc1ccsc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4sccc4C)c(F)c3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-methyl-2-thiophenecarboxylic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-methyl-2-thiophenecarbonyl isothiocyanate was prepared using the resultant 3-methyl-2-thiophenecarbonyl chloride as a starting compound according to the description of the literature. 3-Methyl-2-thiophenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (42 mg, yield 53%).
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[NH2:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[N:21]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[CH3:26][C:24]1[CH:23]=[C:22]([CH3:27])[N:21]=[C:20]([NH:19][C:3]([C:5]2[CH:6]=[CH:7][N:8]3[C:12]=2[CH2:11][S:10][CH:9]3[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:4])[CH:25]=1
Reactant: Cc1cc(C)nc(N)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(NC(=O)c2ccn3c2CSC3c2cccnc2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 60° and 70° C., to a solution of 2-amino-4,6-dimethylpyridine (2.4 g) and triethylamine (4.1 g) in dioxane (100 cc) which is heated to a temperature in the vicinity of 60° C., in the course of 25 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 5 hours and 30 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. The residue is dissolved in methylene chloride (400 cc). The solution obtained is washed with distilled water (100 cc), twice with an aqueous 1N sodium hydroxide solution (200 cc in total) and 3 times with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolorizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 50° C. A crude product (6.3 g) is thereby obtained, which is dissolved in boiling acetonitrile (140 cc). Decolorizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 20° C. for 1 hour. The crystals formed are separated by filtration, washed twice with acetonitrile cooled to a temperature in the vicinity of 4° C. (20 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-(4,6-dimethyl-2-pyridyl) 3-(3-pyridyl)-1H,3H-pyrrolo-[1,2-c]thiazole-7-carboxamide (3.9 g) in the form of white crystals, m.p. 171° C., is thereby obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[C:9]([C:16]#[N:17])[CH:8]=2)[CH:2]=1.[N:18]1C=CC=C(C2N3C(CCCC3)=CC=2C#N)[CH:19]=1.S(Cl)(N=C=O)(=O)=O>>[C:19]([C:8]1[C:9]([C:16]#[N:17])=[C:10]2[N:15]([C:7]=1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:14][CH2:13][CH2:12][CH2:11]2)#[N:18]
Reactant: N#Cc1cc2n(c1-c1cccnc1)CCCC2
Reactant: N#Cc1cc(-c2cccnc2)n2c1CCCC2
Agent: O=C=NS(=O)(=O)Cl
Product: N#Cc1c(C#N)c(-c2cccnc2)n2c1CCCC2

Procedure:
2-Cyano-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile is prepared according to the same method described in Example 15, from 19.3 g of a mixture of approximately 35 mol % of 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile and 65 mol % of 3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-2-carbonitrile and from 36.6 g of sulphonyl isocyanate chloride. 2.8 g of 2-cyano-3-(3-pyridyl)-5,6,7,8-tetrahydroindolizine-1-carbonitrile are thus obtained in the form of a white solid melting at 178° C.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=2[N:6]=1.[CH3:15][N:16]([CH3:25])[C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18].COC(O)C.Cl>C(O)(C)C>[ClH:1].[CH3:15][N:16]([CH3:25])[C:17]([N:19]1[CH2:20][CH2:21][N:22]([C:2]2[NH:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:5]=3[N:6]=2)[CH2:23][CH2:24]1)=[O:18]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: COc1cc2nc(Cl)[nH]c2cc1OC
Agent: COC(C)O
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2nc(N3CCN(C(=O)N(C)C)CC3)[nH]c2cc1OC

Procedure:
3.50 g 2-chloro 5,6-dimethoxybenzimidazole, 7.50 g N,N-dimethyl 1-piperazine carboxamide [J. Org. Chem. 13 144 (1948)], 20 ml methoxyethanol was reacted as described in Example I. The product was converted to the HCl salt with HCl in isopropyl alcohol. Yield: 5.33 g mp 252°-254° C (85%)
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[O:25]([C:32]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:24][N:21]1[CH2:22][CH2:23][N:18]([C@H:15]2[CH2:16][CH2:17][C@H:12]([N:4]3[C:5]4=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]4[C:2]([C:35]4[CH:34]=[N:33][C:32]([O:25][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[N:37][CH:36]=4)=[N:3]3)[CH2:13][CH2:14]2)[CH2:19][CH2:20]1
Reactant: CC1(C)OB(c2cnc(Oc3ccccc3)nc2)OC1(C)C
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@H](n3nc(-c4cnc(Oc5ccccc5)nc4)c4c(N)ncnc43)CC2)CC1

Procedure:
A mixture of trans 3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AD) (0.300 g, 0.00068 mol), 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (int AV) (0.304 g, 0.00102 mol), sodium carbonate (0.180 g, 0.00170 mol) in 1,2-dimethoxyethane (10 mL) and water (20 mL) was stirred rapidly and tetrakis(triphenylphosphine)palladium(0) (0.047 g, 0.000040 mol) added. The reaction mixture was stirred 18 hours at 80° C. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL). The phases were separated and the aqueous phase was extracted with ethyl acetate (3×25 mL). The combined organic phases were dried over magnesium sulfate, and the solvent was removed in vacuo. The product was purified by flash column chromatography on silica using dichloromethane/methanol/ammonium hydroxide (95:5:0.5). The solvent was removed in vacuo to give trans-1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (0.155 g, 0.00032 mol): 1H NMR (DMSO-d6, 400 MHz) 8.78 (s, 2H), 8.25 (s, 1H), 7.48 (t, 2H), 7.28 (t, 1H), 7.27 (d, 2H), 4.65 (m, 1H), 1.44-2.36 (m, 20H); TLC (dichloromethane/methanol/ammonium hydroxide=90:10:0.5) Rf 0.33.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH2:16])[CH3:15])=[N:9]2.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][CH2:6][N:7]3[C:8]([CH:14]([NH:16][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][N:22]3[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[CH3:15])=[N:9]2
Reactant: CC(N)c1nc2ccc(F)c3c2n1CCO3
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c3c2n1CCO3
Temperature: 100 °C
Yield: 82 %

Procedure:
A mixture of 1-(6-fluoro-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethylamine (85 mg, 0.38 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (92 mg, 0.38 mmol) and DIPEA (132 μL, 0.76 mmol) in IPA (1 mL) was heated for 18 h at 100° C. After cooling to RT, the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (Si—PPC, gradient 0-5% MeOH in DCM) to afford the title compound as a pale yellow oil (132 mg, 82%). LCMS (Method J): RT=2.22 min, [M+H]+=424
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]=[C:9]([N:11]([CH3:20])[N:12]=CC1C=CC=CC=1)[S-])=O)(=O)C.[OH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:30]=[C:31]([CH:37]=[CH:38][CH:39]=2)[O:32][CH2:33][CH2:34][CH2:35][NH2:36])[CH2:24][CH2:23]1>>[CH3:20][N:11]1[C:9]([NH:36][CH2:35][CH2:34][CH2:33][O:32][C:31]2[CH:37]=[CH:38][CH:39]=[C:29]([CH2:28][N:25]3[CH2:24][CH2:23][CH:22]([OH:21])[CH2:27][CH2:26]3)[CH:30]=2)=[N:8][C:6]([CH2:5][OH:4])=[N:12]1
Reactant: CC(=O)OCC(=O)N=C([S-])N(C)N=Cc1ccccc1
Reactant: NCCCOc1cccc(CN2CCC(O)CC2)c1
Product: Cn1nc(CO)nc1NCCCOc1cccc(CN2CCC(O)CC2)c1
Yield: 32.5 %

Procedure:
Following the method of Example 17, N-[2-(acetyloxy)acetyl]-1-methyl-2-(phenylmethylene)hydrazinecarboximidothioate (0.75 g) and 3-[3-[1-(4-hydroxypiperidinyl)methyl]phenoxy]propanamine (0.65 g) gave 1-methyl-5-[[3-[3-[1-(4-hydroxypiperidinyl)methyl]phenoxy]propyl]amino]-1H-1,2,4-triazole-3-methanol (0.3 g), t.l.c. System B Rf 0.4. N.m.r. (CDCl3) 2.80,t,(1H); 3.0-3.3,m,(3H); 4.63,t,(1H); 5.52,s,(2H); 5.8-6.1,m,(5H); 6.3-6.7,m,(7H); 7.1-7.4,m,(2H) 7.7-8.7,m, (8H).
Reaction SMILES: CC[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:11]([OH:15])(C)(C)C.[Se](=O)=O.C1(C(C)=C)C=CC=CC=1>C(Cl)Cl.C(O)(=O)C>[OH:15][CH2:11][C:9]([C:8]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[CH2:10]
Reactant: CCCCCCCCCC
Reactant: CC(C)(C)O
Agent: C=C(C)c1ccccc1
Agent: O=[Se]=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: C=C(CO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A 12.5 ml of decane solution of 5 to 6 mol/L of per-tert-butylalcohol is diluted with 50 ml of methylene chloride, then 111 mg of selenium dioxide and 90.1 mg of an acetic acid were added thereto to react while stirring at room temperature for 30 min. Then, 6.5 ml of 2-phenylpropene was added to the reaction solution to react while stirring for 72 hours, followed by condensation under reduced pressure, and purification by silica gel column chromatography to obtain 3.98 g of 3-hydroxy-2-phenylpropene (yield: 59%). Measurement results by 1H-NMR and 13C-NMR of 3-hydroxy-2-phenylpropene obtained are shown below.
Reaction SMILES: [OH-].[Na+].CO.[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH3:31])[C:25]([C:32]([O:34]C)=[O:33])=[CH:24][C:23]=5[C:22]4=[O:36])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:37][CH2:38][CH3:39])[C:9]=2[C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[CH2:7][CH2:6]1.Cl>C(OCC)(=O)C.C1COCC1>[CH:5]1([C:8]2[CH:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([N:21]4[CH2:30][CH2:29][C:28]5[N:27]=[C:26]([CH3:31])[C:25]([C:32]([OH:34])=[O:33])=[CH:24][C:23]=5[C:22]4=[O:36])[CH2:17][CH2:16]3)[CH:11]=[C:10]([O:37][CH2:38][CH3:39])[C:9]=2[C:40]2[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=2)[CH2:6][CH2:7]1
Reactant: CCOc1cc(CN2CCC(N3CCc4nc(C)c(C(=O)OC)cc4C3=O)CC2)cc(C2CC2)c1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(CN2CCC(N3CCc4nc(C)c(C(=O)O)cc4C3=O)CC2)cc(C2CC2)c1-c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
A 2 M aqueous sodium hydroxide solution (1.50 mL) was added at room temperature to a methanol (2 mL)-THF (2 mL) solution of methyl 6-(1-((2-cyclopropyl-6-ethoxy-4′-fluorobiphenyl-4-yl)methyl)piperidin-4-yl)-2-methyl-5-oxo-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate (770 mg), and the mixture was stirred at 50° C. for 1 hour. The reaction mixture was neutralized with hydrochloric acid at room temperature. Then, ethyl acetate was added thereto, and the solvent was distilled off under reduced pressure. The deposited solid was collected by filtration and washed with diethyl ether. The obtained solid was recrystallized (DMSO/ethanol/hexane) to obtain the title compound (221 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][C:10](=[O:12])[CH2:9]2)=[CH:4][CH:3]=1.O.[Cl-].[NH4+].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:9][C@H:10]([OH:12])[CH2:11]2)=[CH:6][CH:7]=1
Reactant: O=C1CC(c2ccc(Br)cc2)C1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: O[C@H]1C[C@@H](c2ccc(Br)cc2)C1
Reaction time: 1.5 h
Yield: 66.6 %

Procedure:
At −78° C., 1.0 M tri(tert-butoxy)lithiumaluminium hydride (24 mL, 24 mmol) was added to a THF (20 mL) solution of 3-(4-bromophenyl)cyclobutanone (4.53 g, 20.1 mmol), and stirred at the same temperature for 1.5 hours. Saturated ammonium chloride water and 1 N hydrochloric acid were added to the reaction liquid, extracted with ethyl acetate, dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, the obtained residue was purified by silica gel column chromatography (C-200, ethyl acetate:hexane=1:4 to 3:7) to obtain the entitled compound (3.04 g, 66%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[O:20]=[C:21]1[CH2:26][NH:25][CH2:24][CH2:23][NH:22]1.O>CN(C=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:25]2[CH2:24][CH2:23][NH:22][C:21](=[O:20])[CH2:26]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C1CNCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CN(c2ccc([N+](=O)[O-])cn2)CCN1
Temperature: 85 °C
Yield: 67.9 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (623 mg, 3.9 mmol) in DMF (6 mL) was added N,N-diisopropylethylamine (1.4 mL, 8.5 mmol) and 2-oxopiperazine (424 mg, 4.24 mmol). The reaction mixture was heated at 85° C. for 40 min by microwave. Then the reaction mixture was cooled to RT, and poured into water (150 mL). The precipitate was filtered, washed with water and dried under vacuum to yield 4-(5-nitropyridin-2-yl)piperazin-2-one as a solid (588 mg, 68% yield). MS (M+1): 223.3
Reaction SMILES: [CH:1]([N:3]([CH2:5][C:6](O)=O)C)=O.[C:9]([O:13][CH3:14])(=[O:12])[C:10]#[CH:11].C(OC(=O)C)(=O)C>>[CH3:1][N:3]1[CH:5]=[CH:6][C:10]([C:9]([O:13][CH3:14])=[O:12])=[CH:11]1
Reactant: CN(C=O)CC(=O)O
Reactant: C#CC(=O)OC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccn(C)c1
Yield: 79.6 %

Procedure:
A mixture of 9.52 g (0.0813 mole) of N-formylsarcosine prepared in the Reference Example 1, 25.56 g (0.304 mole) of methyl propiolate, and 65 ml of acetic anhydride was stirred using a magnetic stirrer over an oil bath at 130° C. for 24 hours. The reaction mixture was concentrated under vacuum. 30 ml of toluene was added to the residue and the mixture was evaporated under reduced pressure. This procedure was repeated to obtain a brown oily substance. This oily substance was distilled under vacuum to obtain 9.01 g (yield 79.6%) of a colorless or light-yellow oil of the title compound as fractions with a boiling point of 93°-96° C. at 4 mmHg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)CCl.[C:16]1([NH2:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Br)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69 %

Procedure:
A mixture of 4-Bromophenylacetic acid (1.5 g, 7.0 mmol, 1 eq.), EDC (2.67 g, 14.0 mmol, 2 eq.), DMAP (846 mg, 7.0 mmol, 1 eq.), and phenylamine (0.765 mL, 8.4 mmol, 1.2 eq.) in 15 mL of DMF was stirred under nitrogen at room temperature for 3.5 hrs. After aqueous workup and recrystallization, 2-(4-Bromophenyl)-N-phenyl-acetamide was obtained in 69% yield (1.4 g). 1H NMR (400 MHz, DMSO-D6) δ ppm 3.6 (s, 2 H) 7.0 (m, 1 H) 7.3 (m, 4 H) 7.5 (m, 2 H) 7.6 (dd, J=8.7, 1.1 Hz, 2 H) 10.2 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([C:14]([OH:16])=[O:15])[CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=O)C(Cl)=O>ClCCl>[CH3:17][O:15][C:14]([CH:10]1[CH2:9][CH2:8][C:7]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[C:12](=[O:13])[CH2:11]1)=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc2c1CCC(C(=O)O)CC2=O
Solvent: ClCCl
Product: COC(=O)C1CCc2c(C)cccc2C(=O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.8 %

Procedure:
To a solution of 1-methyl-5-oxo-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-carboxylic acid (5 g, 22.91 mmol) in dry dichloromethane (DCM) (15 mL), oxalyl chloride (6 mL, 68.75 mmol) was added dropwise at 0° C. The reaction mixture was stirred overnight at room temperature, concentrated in vacuo and to the residue dissolved in DCM (30 mL), methanol (15 mL) was added at 0° C. After stirring 1.5 h at room temperature, the mixture was diluted with water (60 mL) and extracted with DCM (100 mL), the organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give 6.0 g of a yellow oil. Purification by flash chromatography on silica gel (hexane/diethyl ether: 8/2) afforded the title compound as a pale yellow oil (5.6 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.CN(C=O)C.[C:21]([Si:25](Cl)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH3:24])([CH3:23])[CH3:22]>O.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][O:10][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1cccc(Br)c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCc1cccc(Br)c1)(c1ccccc1)c1ccccc1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a mixture of 1.5 g of 2-(3-bromophenyl)ethanol, 1.0 g of imidazole and 15 mL of DMF was added 2.8 g of tert-butyl(chloro)diphenylsilane under ice cooling, and the followed by stirring for 1 hour at the same temperature then for a day at room temperature. Diethyl ether and water were added to the reaction mixture, followed by extraction with diethyl ether. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3), thereby obtaining 3.27 g of [2-(3-bromophenyl)ethoxy](tert-butyl)diphenylsilane.