Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[C:11]([NH:16][C:17]([C:19]3([C:22]4[CH:30]=[CH:29][C:25]5[O:26][CH2:27][O:28][C:24]=5[CH:23]=4)[CH2:21][CH2:20]3)=[O:18])[CH:10]=2)=[CH:5][CH:4]=1.[C:31](Cl)(=[O:34])[CH2:32][CH3:33].CCN(CC)CC>ClCCl>[O:26]1[C:25]2[CH:29]=[CH:30][C:22]([C:19]3([C:17]([NH:16][C:11]4[CH:10]=[C:9]([C:6]5[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:31](=[O:34])[CH2:32][CH3:33])=[CH:8][CH:7]=5)[C:14]([CH3:15])=[CH:13][CH:12]=4)=[O:18])[CH2:20][CH2:21]3)=[CH:23][C:24]=2[O:28][CH2:27]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(CN)cc1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCc1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.5 %

Procedure:
N-(4′-(Aminomethyl)-6-methylbiphenyl-3-yl)-1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (40 mg, 0.10 mmol), propionyl chloride (8.7 μL, 0.10 mmol) and Et3N (28 μL, 0.20 mmol) were dissolved in dichloromethane (1.0 mL) and allowed to stir at 25° C. for 3 hours. Volatiles were removed in vacuo and crude product was purified by reverse phase HPLC to afford 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-methyl-4′-(propionamidomethyl)biphenyl-3-yl)cyclopropanecarboxamide (13 mg, 28%). ESI-MS m/z calc. 456.5, found 457.5 (M+1)+; retention time 3.22 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:18]=[C:19]=[S:20])=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:24])[CH2:22][NH2:23].CCOCC>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:23][CH2:22][CH2:21][NH2:24])=[S:20])=[C:16]([CH3:17])[C:11]=2[N:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(N=C=S)ccc2c1ncn2C(=O)OC(C)(C)C
Reactant: NCCN
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1c(NC(=S)NCCN)ccc2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-tert-butoxycarbonyl-4-methyl-5-benzimidazolylisothiocyanate (7.0 g) in CH2Cl2 (600 mL) is added dropwise over 45 minutes to ethylenediamine (8 mL) in solution in CH2Cl2 (200 mL). The mixture is stirred for 3 hours at room temperature. Ether (150 mL) is added to the suspension and the mixture is stirred for 10 minutes at room temperature. The solid is filtered. The filtrate is rotary evaporated, the residue diluted with CH2Cl2 and reprecipitated with ether to afford a second crop. The combined solids are dried overnight in vacuo to afford N-(1-tert-butoxycarbonyl-4-methyl-5-benzimidazolyl)-N'-2-aminoethylthiourea as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](O)=[O:15])=[CH:10][C:9]=2[OH:17])[N:3]=1.Cl.[CH3:19][N:20](C)[CH2:21]CCN=C=NCC.ON1C2C=CC=CC=2N=N1.CNC>CN(C=O)C.O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:20]([CH3:21])[CH3:19])=[O:15])=[CH:10][C:9]=2[OH:17])[N:3]=1
Reactant: Cc1cc(C)n(-c2ccc(C(=O)O)cc2O)n1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)n(-c2ccc(C(=O)N(C)C)cc2O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.4 %

Procedure:
36 mg of 4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzene carboxylic acid was dissolved in 0.4 ml of DMF, and 36 mg of 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride, 25 mg of 1-hydroxybenzotriazole, and 93 μl of dimethylamine (2.0M THF solution) were added and stirred at room temperature for 4 hours. To the reaction mixture was added 10 ml of water, and extracted with 15 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using a preparative thin-layer silica gel column chromatography (ethyl acetate) to yield 11.4 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH:23]3[NH:27][CH2:26][CH2:25][S:24]3)[CH2:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[C:28]([N:31]=[C:32]=[S:33])(=[O:30])[CH3:29]>CC(C)=O>[C:28]([NH:31][C:32]([N:27]1[CH2:26][CH2:25][S:24][CH:23]1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][N:11]1[CH2:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:13][CH2:12]1)=[S:33])(=[O:30])[CH3:29]
Reactant: CC(=O)N=C=S
Reactant: Fc1cccc(C2=CCN(CCOc3ccccc3C3NCCS3)CC2)c1
Solvent: CC(C)=O
Product: CC(=O)NC(=S)N1CCSC1c1ccccc1OCCN1CC=C(c2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
A mixture of 2.69 g of 2-{2-[2-(4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)ethyloxy]phenyl}thiazolidine, 0.78 g of acetyl isothiocyanate and 20 ml of acetone is stirred at room temperature for 2 hours. The reaction mixture is treated in the same manner as described in Example 73. 2.2 g of N-acetyl-2-{2-[2-(4-(3-fluorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)ethyloxy]phenyl}thiazolidine-3-carbothioamide are obtained. Yield: 65%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=1.[CH3:25][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([F:36])[CH:30]=1)([CH3:28])=[O:27]>>[CH3:28][P:26]([C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:2]2[CH:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([C:21]([F:24])([F:23])[F:22])=[CH:4][N:3]=2)=[C:31]([F:36])[CH:30]=1)([CH3:25])=[O:27]
Reactant: CP(C)(=O)c1ccc(N)c(F)c1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Cl)ncc1C(F)(F)F
Product: CC(C)S(=O)(=O)c1ccccc1Nc1cc(Nc2ccc(P(C)(C)=O)cc2F)ncc1C(F)(F)F

Procedure:
This compound can be prepared as described in Example 80 by reacting 2-chloro-N-[2-(propan-2-ylsulfonyl)phenyl]-5-(trifluoromethyl)pyridin-4-amine with 4-(dimethylphosphoryl)-2-fluoroaniline.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:24])[CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:25]([NH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:24])[CH:3]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc(-n2ccc(N)cc2=O)sc1C(=O)NCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1nc(-n2ccc(NC(=O)c3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of 2-(4-amino-2-oxopyridin-1(2H)-yl)-N-benzyl-4-methylthiazole-5-carboxamide (0.17 g, 0.50 mmol) and 4-dimethylaminopyridine (0.01 g) in pyridine (10 mL) was added benzoyl chloride (0.07 mL, 0.60 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 6 hours, and water (100 mL) was added. The title compound was precipitated as a solid which was collected by filtration and washed with water and t-butylmethyl ether (0.17 g, 76%): mp 246-248° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.78 (t, J=5.7 Hz, 1H), 8.67 (d, J=7.8 Hz, 1H), 7.95-7.90 (m, 2H), 7.66-7.47 (m, 3H), 7.35-7.18 (m, 6H), 6.94 (dd, J=7.8, 2.1 Hz, 1H), 4.39 (d, J=5.7 Hz, 2H), 2.55 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.4, 161.9, 161.0, 153.8, 150.3, 149.4, 139.8, 134.1, 132.9, 131.6, 129.0, 128.7, 128.4, 127.7, 127.2, 123.9, 104.2, 103.9, 43.1, 17.5; MS (ES+) m/z 445.3 (M+1).
Reaction SMILES: [C:1]([CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=O)([O:3][CH2:4][CH3:5])=[O:2].[C:14]1([CH:21]=CC=[C:17](O)[CH:16]=1)[OH:15]>CS(O)(=O)=O>[OH:15][C:14]1[CH:21]=[C:4]2[C:5]([C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:6]=3[C:1](=[O:2])[O:3]2)=[CH:17][CH:16]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)C1CCCCCC1=O
Agent: CS(=O)(=O)O
Product: O=c1oc2cc(O)ccc2c2c1CCCCC2
Reaction time: 4 h
Yield: 78 %

Procedure:
The first stage consists of condensing 2-carbetoxycycloheptanone with resorcinol in methanesulphonic acid, the reaction is taken to 25° C. for 4 hours. The intermediate 3-hydroxy-8,9,10,11-tetrahydrocyclohepta[c]chromen-6(7H)-one thus formed precipitates by adding ethanol then water then it is isolated by filtration, dried under vacuum at 60° C. and a yield of 78% is obtained. In a second stage, sulphonylisocyanate chloride is converted, in toluenic solution, to sulphamoyl chloride by the action of the formic acid, then condensed with the previous intermediate dissolved in N,N-dimethylacetamide (DMA). The reaction medium is treated with water and extracted with 2-methyltetrahydrofurane (2-MeTHF). The crude compound 1 is then obtained by filtration of the precipitate obtained by adding methylcyclohexane to the organic phase. Finally, pure compound 1 is obtained by recrystallization of the crude product by dissolution in acetone while hot and precipitation by adding methylcyclohexane (the addition of the antisolvent methylcyclohexane having the main purpose of increasing the yield).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=2)[N:24]=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=3)[N:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: Cn1cc(-c2cccc(Br)n2)cn1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: Cn1cc(-c2cccc(Nc3sc(-c4c(F)cc(C(C)(C)O)cc4F)cc3C(N)=O)n2)cn1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 2-bromo-6-(1-methyl-1H-pyrazol-4-yl)pyridine (114 mg, 0.48 mmol) as starting materials.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:8]=[C:9]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[CH:11]=2)=O.Cl.[CH3:34][N:35](N)[C:36]([NH2:38])=[NH:37].[O-]CC.[Na+]>C(O)C>[CH3:18][O:17][C:12]1[CH:11]=[C:10]2[C:15]([CH:16]=[C:7]([C:5]3[CH:4]=[CH:3][N:38]=[C:36]([NH:35][CH3:34])[N:37]=3)[CH:8]=[C:9]2[N:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:23][CH2:24]2)=[CH:14][CH:13]=1
Reactant: COc1ccc2cc(C(=O)/C=C/N(C)C)cc(N3CCN(C(=O)OC(C)(C)C)CC3)c2c1
Reactant: CN(N)C(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CNc1nccc(-c2cc(N3CCN(C(=O)OC(C)(C)C)CC3)c3cc(OC)ccc3c2)n1

Procedure:
To a solution of tert-butyl 4-(3-(3-(dimethylamino)acryloyl)-7-methoxynaphthalen-1-yl)piperazine-1-carboxylate 108 (1.5 g) in ethanol (50 ml) was added methyl amino guanidine hydrochloride (0.75 g) and 21% wt sodium ethoxide in ethanol (1 ml). The reaction was stirred at reflux for 2 days, and more sodium ethoxide (0.5 ml) was added to the reaction. The reaction was allowed to reflux overnight. The solvents were concentrated under reduced pressure and the residue was redissolved in ethyl acetate (100 ml) and water (50 ml). The organics were separated, washed with water (1×50 ml), dried over sodium sulfate and concentrated. Column chromatography (pre-packed SiO2, 40% ethyl acetate in hexanes to 75% ethyl acetate in hexanes) gave tert-butyl 4-(7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)piperazine-1-carboxylate 111 as a light yellow solid. LC/MS (m/z): 450 [M+H].
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1.Cl>>[NH:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[S:25][C:24]([C:26]5[CH:33]=[CH:32][C:29]([CH2:30][NH:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4])=[CH:28][CH:27]=5)=[CH:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1
Reactant: NC(CO)CO
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Agent: Cl
Product: OCC(CO)NCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from serinol and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. The product was converted to the mesylate salt analogous to example 17 being converted to the HCl salt. 1H NMR (400 MHz, MeOH) d 8.37 (s, 1H), 7.67 (s, 1H), 7.59 (d, 2H), 7.49 (s, 1H), 7.41 (m, 5H), 7.30 (d, 1H)7.19 (dd, 1H), 6.48 (d, 1H), 3.85s, 2H), 3.59 (m, 4H), 2.72 (m, 1H); LC-MS: 446 (MH+); HPLC RT: 3.2 minutes.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1.[OH-].[K+]>C(O)C.O>[I:1][C:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][N:4]([CH3:12])[N:3]=1
Reactant: CCOC(=O)c1cn(C)nc1I
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(C(=O)O)c(I)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.1 %

Procedure:
134 g (0.478 mol) of ethyl 3-iodo-1-methyl-1H-pyrazole-4-carboxylate were initially charged in 850 ml of ethanol, and a solution of 29.5 g (0.526 mol) of KOH in 340 ml of water was added dropwise. After 2 days of stirring at room temperature, the mixture was concentrated, the residue was taken up in water and extracted with ethyl acetate and, after separation, the aqueous phase was adjusted to pH 1 using hydrochloric acid, resulting in the precipitation of a solid. Filtration with suction and 3 hours of drying under reduced pressure at 40° C. gave 88 g (70% of theory) of 3-iodo-1-methyl-1H-pyrazole-4-carboxylic acid [logP (pH 2.3)=0.57]. The aqueous phase was extracted with ethyl acetate and the organic phase was concentrated, which gave another 5.1 g (2.1% of theory) of product.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:11]([OH:13])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:14](N(CC)CC)C.N[C@@H](C(O)=O)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[O-]S([O-])(=O)=O.[Mg+2].C(=O)C1C=CC=CC=1.Cl.C(N(CC)CC)C>>[CH3:14][O:12][C:11](=[O:13])[C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[N:2]=[CH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O=Cc1ccccc1
Product: COC(=O)[C@@H](Cc1ccccc1)N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 1.0 eq D-phenylalanine HCl (1.6 g, 7.4 mmol) was added 1.0 eq triethylamine to dissolve the D-phenylalanine. To this solution was added 1 equiv. of MgSO4 followed by the addition of 1.0 eq benzaldehyde, the reaction was stirred overnight at room temperature under N2 atmosphere. The reaction mixture was sripped of solvent and pumped on the residue contained a good deal of triethylamine hydrochloride which was removed by dissolving the product in THF and filtering out the TEA.HCl. The crude benzylidene looked fine by NMR and was all taken on in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5](=[CH:10][O:11][CH3:12])[C:6]([O:8][CH3:9])=[O:7].[Br:17]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][C:5](=[CH:10][O:11][CH3:12])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC=C(Oc1ccccc1C)C(=O)OC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC=C(Oc1ccccc1CBr)C(=O)OC

Procedure:
A mixture of 2.2 g of methyl 2-(2-methylphenoxy)-3-methoxyacrylate, 1.78 g of N-bromosuccinimide, and a catalytic amount of azobisisobutyronitrile was heated at reflux in carbon tetrachloride for 4 hours. The solid was filtered, and the solvent evaporated to give crude methyl 2-(2-bromomethylphenoxy)-3-methoxyacrylate. A mixture of this crude material, 2.0 g of N-benzyloxy propionamide, and 3.9 g of caesium carbonate was heated at reflux in acetonitrile for 20 hours. The solid was filtered, the solvent evaporated, and the residue purified by silica gel chromatography to give methyl 2-{2-[(1-benzyloxyiminopropyl)oxymethyl]phenoxy}-3-methoxyacrylate (isomer Z) (0.75 g).
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O.[N+](C1C2C(=O)C3C(=C([N+]([O-])=O)C=CC=3)C(=O)C=2C=CC=1)([O-])=O.[N+](C1C2C(=O)C3C(=CC=CC=3[N+]([O-])=O)C(=O)C=2C=CC=1)([O-])=O.C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.[N+](C1C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C=1)([O-])=O.[H][H].C1(C=CC(O)=CC=1)O>>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)c2c1cccc2[N+](=O)[O-]
Reactant: [H][H]
Agent: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2c1cccc2[N+](=O)[O-]
Agent: O=C1c2cccc([N+](=O)[O-])c2C(=O)c2cccc([N+](=O)[O-])c21
Agent: O=C1c2ccccc2C(=O)c2cc([N+](=O)[O-])ccc21
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Reaction time: 2 h
Yield: 72.6 %

Procedure:
5.0 g of crude 1-nitroanthraquinone containing dinitroanthraquinones having a purity of 81% and containing 8% of 1,5-dinitroanthraquinone, 4% of 1,8-dinitroanthraquinone and 7% of other dinitroanthraquinones and being free from anthraquinone and 2-nitroanthraquinone (0.016 mole of 1-nitroanthraquinone and 0.0032 mold of all the dinitroanthraquinones) was hydrogenated in the same way as in Example 5. The reaction was stopped when the amount of hydrogen absorbed reached 0.0816 mole, and the inside of the flask was purged with nitrogen. The amount of hydrogen absorbed corresponded to the sum of the amount of hydrogen required to convert the nitro group to an amino group (0.0672 mole) and 90% of the amount of hydrogen required to convert 1-aminoanthraquinone to its hydroquinone derivative (0.0144 mole). The reaction mixture was filtered in a stream of nitrogen to separate the catalyst and insoluble materials from it. The filtrate was oxidized with air at 20° to 30° C. for 2 hours with stirring to afford 3.2 g of 1-aminoanthraquinone having a purity of 98%. The yield of the product was 88% on a purity basis. The resulting 1-aminoanthraquinone contained about 1% of 1,8-diaminoanthraquinone and only traces of other diamino isomers.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](O)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:18]>CCOCC>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([Cl:18])[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2c(O)ncnc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Temperature: 105 °C
Yield: 83.3 %

Procedure:
4,6-Diazaindole 4 (2.74 g, 13.2 mmol) was slurried in POCl3 (37 mL, 400 mmol) and heated at 105° C. for 3.5 h. The reaction mixture was cooled, diluted with Et2O (150 mL) and the resulting precipitate was collected by filtration, rinsed with EtOAc and Et2O and dried under vacuum to yield 7-chloro-4,6-diazaindole 5 (2.48 g, 11.0 mmol, 83%) as a yellow powder which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:32]([O:31][C:29]([N:23]1[CH2:28][CH2:27][N:26]([C:4](=[O:5])[C:3]2[CH:7]=[C:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)[CH:9]=[CH:10][C:2]=2[F:1])[CH2:25][CH2:24]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (100 mg, 0.33 mmol), tert-butyl piperazine-1-carboxylate (187.3 mg, 1.0 mmol), HATU (255 mg, 0.67 mmol), and DIPEA (0.5 ml, 3.0 mmol) were dissolved in DMF (25 ml) and stirred at room temperature for 24 h. The reaction mixture was partitioned between DCM and water (50 ml each), and the organic phase was washed with aqueous sodium bicarbonate and brine, dried over sodium sulphate, filtered, and concentrated to get the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether:Ethyl Acetate=1:3) to afford target compound (100 mg, 64%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][NH:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].O.C(=O)([O-])O.[Na+].Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>O1CCCC1>[CH2:32]([O:31][C:29]([N:8]([CH2:9][C:10]1[N:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[CH:12][CH:11]=1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1cccc(CNCC(=O)OC(C)(C)C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccc(CN(CC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 6-{[(2-tert-butoxy-2-oxoethyl)amino]methyl}pyridine-2-carboxylate (2.81 g) in tetrahydrofuran (30.0 mL) were added water (30.0 mL) and sodium hydrogen carbonate (962 mg), and then benzyl chloroformate (1.47 mL) was added thereto under ice-cooling. The reaction suspension was stirred at room temperature overnight and extracted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl 6-({[(benzyloxy)carbonyl](2-tert-butoxy-2-oxoethyl)amino}methyl)pyridine-2-carboxylate (3.27 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].C([O-])([O-])=O.[K+].[K+].[C:13](Cl)(=[O:17])[C:14]([CH3:16])=[CH2:15]>CN(C)C=O>[OH:6][CH:3]([CH2:4][OH:5])[CH2:2][NH:1][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: NCC(O)CO
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)C(=O)NCC(O)CO
Temperature: 0 °C

Procedure:
4.65 g of 3-amino-1,2-propanediol (0.05 mol) were dissolved in 30 ml of dimethylformamide (anhydrous). This solution and 13.8 g of K2CO3 were placed in a 100 ml three-necked flask with dropping funnel and gas inlet and gas outlet tubes. The mixture was cooled to 0° C. in an ice bath. While stirring gently and slowly bubbling nitrogen through, 6.18 ml of methacryloyl chloride (0.06 mol) dissolved in 30 ml of dimethylformamide were added dropwise over the course of 30 minutes. The mixture was stirred, while cooling in ice, for a further hour and then allowed to warm to room temperature and was stirred for a further 30 minutes. The reaction mixture was filtered through a fluted filter, and the residue was discarded. The filtrate was concentrated to a viscous oil in a rotary evaporator. This oil was dissolved in 30 ml of methanol, a second filtration was carried out, and the filtrate was again concentrated in a rotary evaporator. The residues of the solvent were removed under high vacuum. The yield was 8.52 g.