Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[C:15]([C:24]([NH:26][CH3:27])=[O:25])=[CH:14][C:13]2=[O:28])[CH2:6][CH2:5]1.[CH2:29]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)[CH3:30].C([BH3-])#N.[Na+]>C(O)(=O)C>[CH2:29]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=4)[C:15]([C:24]([NH:26][CH3:27])=[O:25])=[CH:14][C:13]3=[O:28])[CH2:6][CH2:5]2)=[CH:33][CH:32]=1)[CH3:30]
Reactant: CCc1ccc(C=O)cc1
Reactant: CNC(=O)c1cc(=O)n(CCN2CCC(N)CC2)c2cc(OC)ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCc1ccc(CNC2CCN(CCn3c(=O)cc(C(=O)NC)c4ccc(OC)cc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 82.1 %

Procedure:
To 4 mL of a methanol solution containing 0.14 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide, 48 mg of 4-ethylbenzaldehyde and 40 μL of acetic acid were added, and stirred at room temperature for 80 min. To the reaction mixture, 52 mg of sodium cyanoborohydride was added, and stirred at the same temperature for 75 min. After the solvent was removed under reduced pressure, chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; chloroform:methanol=30:1], to give 0.14 g of 1-(2-(4-(4-ethylbenzylamino)piperidin-1-yl)ethyl)-7-methoxy-N-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide as a pale yellow solid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([C:12]2[C:20]3[C:15](=[C:16]([O:26][CH3:27])[N:17]=[C:18]([C:21]#[C:22][CH2:23][CH2:24][OH:25])[CH:19]=3)[N:14]([CH3:28])[CH:13]=2)[CH:11]=1)(=[O:5])=[O:4])[CH3:2].[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[OH:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[O:38][C:9]1[CH:8]=[CH:7][C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:11][C:10]=1[C:12]1[C:20]2[C:15](=[C:16]([O:26][CH3:27])[N:17]=[C:18]([C:21]#[C:22][CH2:23][CH2:24][OH:25])[CH:19]=2)[N:14]([CH3:28])[CH:13]=1
Reactant: CCS(=O)(=O)c1ccc(F)c(-c2cn(C)c3c(OC)nc(C#CCCO)cc23)c1
Reactant: Oc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c3c(OC)nc(C#CCCO)cc23)c1
Yield: 60.1 %

Procedure:
A mixture of Example 126B (50 mg, 0.120 mmol), 2,4-difluorophenol (15.62 mg, 0.120 mmol) and cesium carbonate (58.7 mg, 0.180 mmol) in dimethylsulfoxide (0.5 mL) was heated at 120° C. in a microwave oven (Biotage Smith Synthesizer) for 45 minutes. The reaction mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate (3×). The combined organic phases were washed with water (2×), saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and the residue was absorbed on silica gel and purified by flash chromatography (silica gel, 20-90% ethyl acetate/heptanes) to give the title compound (38 mg, 60% yield)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O>C(OCC)(=O)C.O1CCCC1.[C].[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 40 %

Procedure:
3-Fluoro-4-nitrophenol (5.0 g, 31.83 mmol) was dissolved in ethyl acetate (50 ml) and tetrahydrofuran (75 ml), and then palladium carbon (2.0 g) was added and the mixture was stirred for 8.5 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered off, the filtrate was washed with ethanol, the solvent was distilled off under reduced pressure and the obtained crystals were washed with addition of hexane:ethanol=1:1. The crystals were filtered out, washed with diethyl ether and dried by aspiration to obtain the title compound (1.62 g, 12.74 mmol, 40.61%) as light yellow crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([O:19]C)=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:15]([CH:16]([CH2:21][CH2:22][CH3:23])[C:17]([OH:19])=[O:18])=[C:14]([CH3:24])[N:13]=[C:12]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:11]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)CCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1-c1ccc2c(c1)CCO2
Yield: 92.4 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(2,3-dihydrobenzofuran-5-yl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.100 g; 0.248 mmol), sodium hydroxide 10N solution (0.248 mL; 2.48 mmol) in methanol (2.5 mL) to afford 0.089 g (91%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[C:30]#[N:31])[CH2:5][N:6]1[C:11](=[O:12])[CH2:10][N:9]([CH2:13][C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([Cl:23])=[CH:18][CH:17]=3)[CH2:8][CH:7]1[C:24]([OH:26])=[O:25].[N:32]1C=NC=N[CH:33]=1.CC(O)=O>CCO>[NH2:31][C:30]1[C:29]2[C:2](=[CH:3][C:4]([CH2:5][N:6]3[C:11](=[O:12])[CH2:10][N:9]([CH2:13][C:14]4[NH:15][C:16]5[C:21]([CH:22]=4)=[CH:20][C:19]([Cl:23])=[CH:18][CH:17]=5)[CH2:8][CH:7]3[C:24]([OH:26])=[O:25])=[CH:27][CH:28]=2)[N:1]=[CH:33][N:32]=1
Reactant: c1ncncn1
Reactant: N#Cc1ccc(CN2C(=O)CN(Cc3cc4cc(Cl)ccc4[nH]3)CC2C(=O)O)cc1N
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1ncnc2cc(CN3C(=O)CN(Cc4cc5cc(Cl)ccc5[nH]4)CC3C(=O)O)ccc12
Temperature: 25 °C
Yield: 9.3 %

Procedure:
A solution containing (±)-1-(3-amino-4-cyano-benzyl)-4-(5-chloro-1H-indol-2-ylmethyl)-6-oxo-piperazine-2-carboxylic acid (200 mg, 0.30 mmol), 1,3,5-triazine (244 mg, 3.00 mmol), and glacial HOAc (180 mg, 3.00 mmol) in absolute EtOH (20 mL) is maintained at reflux for 16 hours. The reaction mixture is cooled to ambient temperature and the solid is collected on a Buchner funnel and washed with EtOH followed by diethyl ether. Oven-drying in vacuo provided 13 mg (76%) of the title compound as an off-white solid. 1H NMR (300 MHz, d6-DMSO) δ2.63 (m, 1H), 3.06 (d, J=16.4 Hz, 1H), 3.24-3.42 (m, 4H), 3.68 (ABq, ΔAB=34.5 Hz, JAB=14.1 Hz, 2H), 3.96 (m, 1H), 4.63 (ABq, ΔAB=400 Hz, JAB=15.8 Hz, 2H), 6.27 (s, 1H), 6.99 (dd, J=8.6, 2.0 Hz, 1H), 7.29 (d, J=8.5 Hz, 2H), 7.40 (s, 1H), 7.46 (s, 1H), 7.69 (br s, 2H), 8.10 (d, J=8.5 Hz, 1H), 8.32 (s, 1H), 11.20 (s, 1H) ppm; MS (ion spray): m/z 465 (M+H).
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[SH2:7]>>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[S:7][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccs1
Reactant: S
Product: c1csc(Sc2cccs2)c1
Temperature: 560 °C

Procedure:
Through a 570-mm long silica tube, 26 mm in diameter, heated to a temperature of 560° C, for 90 minutes are passed 40.0 g (0.34 mole) of 2-chlorothiophene and hydrogen sulphide at a rate of 5.2 litres per hour. The molar ratio of 2-chlorothiophene to hydrogen sulphide is 1:1. The condensate is distilled to give 16 g (48.2 percent by weight) of di(2-thienyl) sulphide boiling at 133°-140° C (5 mm Hg), nD20 = 1.6603, and 6.5 g of the starting 2-chlorothiophene (conversion 84 percent by weight).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9](Cl)(=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:9]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])(=[O:25])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O

Procedure:
N-hydroxysuccinimide (69.8 g, 0.598 mol) was added drop by drop to 1 L of chloroform solution of palmitoyl chloride (165 ml, 0.544 mol) with stirring while cooling with ice, and then triethylamine (83.1 ml, 0.598 mol) was added dropwise over 30 minutes. Then, the whole was stirred while cooled with ice for 30 minutes, allowed to gradually reach room temperature, and stirred for 7 hours. The reaction mixture was washed with water (500 ml×3), then dried over magnesium sulfate, and concentrated under reduced pressure to give 260.3 g (quant) of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13](=[CH:21]O)[C:14](=O)[CH2:15]3)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:23][C:24]1[N:28]=[C:27]([NH2:29])[NH:26][N:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]3[CH2:17][CH2:18][CH2:19][CH:12]2[C:13]2[CH:21]=[N:23][C:24]4[N:25]([C:14]=2[CH2:15]3)[N:26]=[C:27]([NH2:29])[N:28]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1CC2CCCC(C1=CO)N2S(=O)(=O)c1ccc(Cl)cc1
Reactant: Nc1n[nH]c(N)n1
Product: Nc1nc2ncc3c(n2n1)CC1CCCC3N1S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Prepared as described in Example 5 using 9-(4-chlorophenylsulfonyl)-2-(hydroxymethylene)-9-azabicyclo[3.3.1]nonan-3-one which was prepared as described in Example 34 and 3,5-diamino-1,2,4-triazole.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17](=[O:33])[NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[N:22]=[CH:21][N:20]=2)[CH2:12]1)=O)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:18][C:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)=[O:33])[CH:24]=1
Reactant: COc1ccccc1-c1cc(NC(=O)[C@@H]2CCCN(C(=O)OCc3ccccc3)C2)ncn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1cc(NC(=O)[C@@H]2CCCNC2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.5 %

Procedure:
To a solution of (R)-3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (XXX) (7.0 g) in 50 mL of methanol was added 10% palladium hydroxide (1.5 g) under an atmosphere of nitrogen and the mixture was stirred at room temperature under an atmosphere of hydrogen for 8 hours. The reaction mixture was filtered through celite and the solvent was evaporated. The obtained product was taken in diethyl ether, stirred, filtered, the residue was washed with diethyl ether and dried under vacuum to yield (R)-piperidine-3-carboxylic acid [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amide (compound #18A) as a white solid (3.5 g, 72%), melting point 210-213° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(OC(=O)C)(=O)C.C(NC1C=CC=CC=1)(=O)C.[N+:27]([O-])([OH:29])=[O:28].OS(O)(=O)=O>>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([N+:27]([O-:29])=[O:28])[C:3]=1[NH2:4]
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(F)cc1F
Agent: CC(=O)Nc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: Nc1c(F)cc(F)cc1[N+](=O)[O-]

Procedure:
Thus WO 96/02493, starting from 2,4-difluoroaniline, discloses a synthesis proceeding via five stages. 2,4-Difluoroaniline is first reacted with acetic anhydride, the resulting acetanilide is nitrated by means of HNO3 /H2SO4, the acetyl radical is removed and 2,4-difluoro-6-nitroaniline is obtained. By reaction of the 2,4-difluoro-6-nitroaniline with sodium nitrite, the amino group can be removed and 3,5-difluoronitrobenzene is obtained, which can be converted into 3,5-difluoroaniline by reduction.
Reaction SMILES: NC1C=CC(C2C(C)=CC(=O)NN=2)=CC=1.[NH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:20][CH:19]=1)[NH2:17]>>[NH:16]([C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:25]([CH3:31])=[CH:26][C:27](=[O:30])[NH:28][N:29]=2)=[CH:22][CH:23]=1)[NH2:17]
Reactant: CC1CC(=O)NN=C1c1ccc(NN)cc1
Agent: Cc1cc(=O)[nH]nc1-c1ccc(N)cc1
Product: Cc1cc(=O)[nH]nc1-c1ccc(NN)cc1

Procedure:
The title compound was prepared from 6-(4-aminophenyl)-5-methyl-2H-pyridazin-3-one similarly as 6-(4-hydrazinophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][F:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[CH2:45]([O:47][C:48]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])[CH3:46]>C(OCC)(=O)C>[CH2:45]([O:47][C:48]([N:50]1[CH2:51][CH2:52][N:53]([C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][F:14])[CH2:54][CH2:55]1)=[O:49])[CH3:46]
Reactant: CC(C)(C)OC(=O)N[C@@H](CF)C(=O)O
Reactant: CCOC(=O)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CF)NC(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
To a solution of 150 mg (R)-2-tert-Butoxycarbonylamino-3-fluoro-propionic acid were added 0.18 ml N-ethylmorpholine, 237 mg TOTU and 115 mg 1-ethoxycarbonylpiperazine. After stirring for 12 h the reaction mixture was diluted with ethyl acetate and washed with aqueous LiCl (4%), 0.1 M HCl, saturated aqueous NaHCO3 and brine. The crude product obtained was used without further purification. Yield: 160 mg.
Reaction SMILES: [C:1]1(=O)[O:5][CH2:4][CH2:3][O:2]1.O[C:8]1[CH:21]=[CH:20][C:11]([C:12]([C:14]2[CH:19]=[CH:18]C=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.[I-].[Na+].[OH-].[Na+]>O.C1(C)C=CC=CC=1.CO>[OH:2][CH2:3][CH2:4][O:5][C:1]1[CH:18]=[CH:19][C:14]([C:12]([C:11]2[CH:20]=[CH:21][CH:8]=[CH:9][CH:10]=2)=[O:13])=[CH:15][CH:16]=1
Reactant: O=C1OCCO1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1)c1ccc(OCCO)cc1
Temperature: 88 °C

Procedure:
A mixture of ethylene carbonate (14.26 g), xylenes (1.19 g) and 4-hydroxybenzophenone (30.41 g) was heated to 88° C. Sodium iodide (1615 mg) was added. Heating was continued until the temperature of the mixture reached 169° C. The melt was cooled to 110° C. and methanol (12.76 g), sodium hydroxide (50% aqueous solution; 4.01 g), toluene (42.51 g) and water (28.88 g) were added. The lower layer was separated (‘cut’) and discarded. Toluene (18.1 g) was added and the solvents were evaporated by heating to the boiling point of 111° C. 4-(2-Hydroxyethoxy)benzophenone was isolated by crystallisation and filtration at 17° C. resulted in 34.1 g (92%) of beige crystals.
Reaction SMILES: S([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:19]=[C:14]2[CH:13]=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>O1CCOCC1.O>[N:19]1[C:18]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][N:16]=[C:15]2[NH:11][CH:12]=[CH:13][C:14]=12
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(CNC(=O)OC(C)(C)C)cnc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1cnc2[nH]ccc2n1
Temperature: 85 °C
Yield: 78.3 %

Procedure:
tert-Butyl (5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamate (5.08 g, 12.6 mmol) in a mixture of 1,4-dioxane (40 mL) and water (10 mL) was treated with NaOH (2.02 g, 50.5 mmol) then heated to about 85° C. for about 75 min. The mixture was cooled to rt then most of the solvent was removed under reduced pressure. The mixture was diluted with water (25 mL) then DCM (25 mL) and EtOAc (50 mL) were added. The layers were separated then the aqueous layer was extracted with EtOAc (2×25 mL). The combined organics were washed with brine (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give tert-butyl (5H-pyrrolo[2,3-b]pyrazin-2-yl)methylcarbamate (2.45 g, 78%): LC/MS (Table 2, Method b) Rt=1.75 min; MS m/z 249 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH3:23])=[C:13]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=2)=[CH:4][CH:3]=1.[N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:25]=[S:26]>CS(C)=O>[C:18]([O:17][C:16]([NH:15][C:13]1[CH:14]=[C:9]([CH:10]=[CH:11][C:12]=1[CH3:23])[O:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:25]([NH:24][C:27](=[O:28])[O:29][CH2:30][CH3:31])=[S:26])=[N:7][CH:6]=1)=[O:22])([CH3:19])([CH3:20])[CH3:21]
Reactant: Cc1ccc(Oc2ccc(N)nc2)cc1NC(=O)OC(C)(C)C
Reactant: CCOC(=O)N=C=S
Solvent: CS(C)=O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2ccc(C)c(NC(=O)OC(C)(C)C)c2)cn1
Yield: 57.9 %

Procedure:
In the same manner as in Reference Example 30 and using tert-butyl {5-[(6-aminopyridin-3-yl)oxy]-2-methylphenyl}carbamate (17.5 g, 44.5 mmol), DMSO (100 mL) and ethyl isothiocyanatoformate (6.50 mL, 55.0 mmol) as starting materials, the title compound (11.5 g, 49%) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[CH:26]([C:28]1[C:36]2[C:31](=[C:32]([CH2:37][N:38]([CH3:46])[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH:33]=[CH:34][CH:35]=2)[NH:30][CH:29]=1)=O>CO.N1CCCCC1>[C:41]([O:40][C:39]([N:38]([CH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:31]=1[NH:30][CH:29]=[C:28]2/[CH:26]=[C:7]1\[O:8][C:4]2[C:3]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=2[C:6]\1=[O:9])[CH3:46])=[O:45])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: CN(Cc1cccc2c(C=O)c[nH]c12)C(=O)OC(C)(C)C
Solvent: C1CCNCC1
Solvent: CO
Product: CN(Cc1cccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c12)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.029 g, 0.10 mmol) obtained in Example A16, Step 1 in methanol (3.0 mL) was added with tert-butyl (3-formyl-1H-indole-7-yl)methyl(methyl)carbamate (0.038 g, 0.11 mmol). Then, the mixture was added with 5 drops of piperidine, and the mixture was stirred at 50° C. for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (99:1→95:5)) to obtain tert-butyl (Z)-4-({2-[(7-{[tert-butoxycarbonyl(methyl)amino]methyl}-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.044 g, 71%).
Reaction SMILES: N#N.I[C:4]1[C:5](=[O:14])[N:6]([CH3:13])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1.[S:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C([O-])(=O)C.[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:13][N:6]1[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=[C:4]([C:19]2[S:15][CH:16]=[N:17][CH:18]=2)[C:5]1=[O:14]
Reactant: Cn1cc([N+](=O)[O-])cc(I)c1=O
Reactant: c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: N#N
Solvent: CN(C)C=O
Product: Cn1cc([N+](=O)[O-])cc(-c2cncs2)c1=O
Temperature: 120 °C
Reaction time: 28 h

Procedure:
N2 was bubbled through a solution of 3-iodo-1-methyl-5-nitro-1H-pyridin-2-one (840 mg, 3.0 mmol), thiazole (1280 mg, 15.0 mmol), potassium acetate (0.883 g, 9.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.243 g, 0.21 mmol) in DMF (8 mL) for 10 min. The mixture was then heated to 120° C. and stirred for 28 h. The solvents were removed in vacuo. The black-colored residue was dissolved in a mixture of methanol (8 mL) and methylene chloride (250 mL). Water (30 mL) and sat. NaHCO3 (aq) (15 mL) were added. Layers were separated and the aqueous phase was extracted with methylene chloride (3×80 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated under reduced pressure to 15 mL. The product precipitated and was collected by filtration to afford the desired product as a black solid. 1H-NMR (DMSO-d6, 400 MHz): δ=3.70 (s, 3H), 8.79 (s, 1H), 8.82 (d, J=2.8 Hz, 1H), 9.13 (s, 1H), 9.29 (d, J=3.2 Hz, 1H). MS (ES+): m/z 238.15 [MH+]. HPLC: tR=2.33 min (ZQ2000, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](C(=O)C)=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.ClC1C=C(C(OO)=[O:27])C=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:27])=[C:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc(F)cc1OCc1ccccc1
Solvent: ClCCl
Product: Oc1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 93 %

Procedure:
A mixture of 11 parts of 1-[4-fluoro-2-(phenylmethoxy)phenyl]ethanone, 8.48 parts of 3-chlorobenzenecarboperoxoic acid and 260 parts of dichloromethane was stirred for 5 days at room temperature. The precipitate was filtered off and the filtrate was stirred in a saturate thiosulfate solution for 15 minutes. The organic layer was separated and stirred in a saturate hydrogen carbonate solution for 15 minutes. The organic layer was separated, washed with water, dried, filtered and evaporated. The solid residue was stirred in 240 parts of methanol. 5.3 Parts of sodium methoxide were added portionwise. After complete addition, the whole was stirred for 1 hour at room temperature. After evaporation in vacuo at 50° C., the residue was stirred in water and acidified with a hydrochloric acid solution 3N. Trichloromethane was added, the organic layer was separated, washed twice with water, dried, filtered and evaporated, yielding 10 parts (93%) of 4-fluoro-2-(phenylmethoxy)phenol as a residue (intermediate 77).
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[C:29]1([CH2:39][N:40]2[CH2:44][CH2:43][N:42]([C:45]3[S:46][C:47]([C:51]([O:53]CC)=[O:52])=[C:48]([CH3:50])[N:49]=3)[C:41]2=[O:56])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1>>[C:29]1([CH2:39][N:40]2[CH2:44][CH2:43][N:42]([C:45]3[S:46][C:47]([C:51]([OH:53])=[O:52])=[C:48]([CH3:50])[N:49]=3)[C:41]2=[O:56])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3nccc4ccccc34)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(Cc3nccc4ccccc34)C2=O)sc1C(=O)O
Yield: 75 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 2-(3-(isoquinolin-1-ylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid in 75% yield: MS (ES+) m/z 369.1 (M+1).