Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:15]2[CH:16]=[C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1)[CH3:10].C(OC([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][C@@H:34]1[C:39](O)=[O:40])=O)(C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:15]2[CH:16]=[C:17]([C:20]3[CH2:21][CH2:22][N:23]([C:39]([C@H:34]4[CH2:35][CH2:36][CH2:37][CH2:38][NH:33]4)=[O:40])[CH2:24][CH:25]=3)[CH:18]=[CH:19][C:14]=2[N:13]=[CH:12]1)[CH3:10]
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCNCC3)cc21
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C(=O)O
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: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H](c1ccc(Cl)cc1Cl)n1cnc2ccc(C3=CCN(C(=O)[C@H]4CCCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a stirred solution of the crude (R)-1-(1-(2,4-dichlorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-benzo[d]imidazole (1.2 g, 3.1 mmol) and (R)-1-(t-butoxycarbonyl)piperadine-2-carboxylic acid (0.71 g, 3.1 mmol) in N,N-dimethylformamide (DMF, 10 mL) at 0° C. under nitrogen was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 1.4 g, 3.7 mmol) and diisoproylethylamine (iPr2NEt, 0.80 g, 6.2 mmol). The reaction mixture was stirred at room temperature for 1 h, and diluted with ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 10-100% ethyl acetate in hexanes) to afford the desired product (1.5 g, 2.6 mmol, 85%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:18]1[C:23]([CH3:24])=[C:22]([C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])[C:21]([CH3:31])=[C:20]([CH3:32])[C:19]=1[O:33]C)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16]C)=[O:15].N1C(C)=CC(C)=CC=1C.[I-].[Li+].Cl>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:18]1[C:23]([CH3:24])=[C:22]([C:25](=[O:30])[CH2:26][CH2:27][CH2:28][CH3:29])[C:21]([CH3:31])=[C:20]([CH3:32])[C:19]=1[OH:33])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: CCCCC(=O)c1c(C)c(C)c(OC)c(C(CCCCCC(=O)OC)c2ccccc2F)c1C
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: Cc1cc(C)nc(C)c1
Product: CCCCC(=O)c1c(C)c(C)c(O)c(C(CCCCCC(=O)O)c2ccccc2F)c1C
Yield: 46.2 %

Procedure:
A mixture of methyl 7-(fluorophenyl)-7-(2-methoxy-3,4,6-trimethyl-5-valerylphenyl)heptanoate (0.23 g), collidine (0.38 ml) and lithium iodide (0.2 g) was refluxed for 18 hours. After allowing to cool, the mixture was acidified with addition of lN hydrochloric acid and extracted with ethyl acetate. The organic layer was washed in turn with lN hydrochloric acid, water and saturated saline and dried with anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7-(fluorophenyl)-7-(2-hydroxy-3,4,6-trimethyl-5-valerylphenyl)heptanoic acid (0.1 g) (Compound 36). The physical properties and spectrum data thereof are shown in Tables 3 and 4.
Reaction SMILES: [CH3:1][C:2]([OH:20])([CH3:19])[CH2:3][NH:4][C:5]1[N:6]=[N:7][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:10]=1.C(N(CC)CC)C.Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[CH3:19][C:2]1([CH3:1])[O:20][C:29](=[O:31])[N:4]([C:5]2[N:6]=[N:7][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][CH:10]=2)[CH2:3]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(O)CNc1ccc(C#Cc2ccccc2)nn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CN(c2ccc(C#Cc3ccccc3)nn2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
A solution of 2-methyl-1-(6-(phenylethynyl)pyridazin-3-ylamino)propan-2-ol (Example 152, step 1) (90 mg, 337 μmol) and triethylamine (102 mg, 141 μl, 1.01 mmol, 3 equiv.) in 4 ml of THF was cooled to 0-5° C. and then triphosgene (99.9 mg, 337 μmol, 1 equiv.) was added and the reaction was stirred for 1 hour at 0-5° C. The mixture was quenched with 5 ml of 5% sodium bicarbonate solution and worked up with ethyl acetate/water. The crude material was adsorbed onto silicagel and purified by flash chromatography over a heptane to 50% ethyl acetate in heptane gradient to yield the title compound (51 mg, 52% yield) as a crystalline light yellow solid, MS: m/e=294.2 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:11]=2)[C:6](=[O:19])[C:5]([C:20]([OH:22])=O)=[CH:4]1)[CH3:2].FC1C=CC([N:30]2C3C(=CC=C(C4C=CN=CC=4)C=3)C(=O)C(C(N)=O)=C2)=CC=1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[CH:11]=2)[C:6](=[O:19])[C:5]([C:20]([NH2:30])=[O:22])=[CH:4]1)[CH3:2]
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2cc(-c3ccncc3)ccc2c1=O
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(-c3ccccn3)cc21
Product: CCn1cc(C(N)=O)c(=O)c2ccc(-c3ccccn3)cc21

Procedure:
[I; R=H, R1C2H5, R2H, R6H, R7 -pyridinyl] was prepared from 2.94 g 1-ethyl-1,4-dihydro-4-oxo-7-(2-pyridinyl)-3-quinolinecarboxylic acid (U.S. Pat No. 3,753,993) according to the procedure of Example 1, part (h), and was obtained (2.66 g) in the form of a light-tan solid, m.p. 245°-246° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:11][C:12]([CH:14]2[CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:21]=3)[CH2:16][N:15]2[C:38]([N:40]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53]C=C)[NH:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:39])=[O:13])[CH2:8][CH:7]1[CH:9]=[CH2:10])=[O:5])[CH3:2]>ClCCl.C(OC(N1CC(OC2C3C(=CC(OC)=CC=3)N=C(C3C=CC=CC=3)C=2)CC1C(=O)NC1(C(OCC)=O)CC1C=C)=O)(C)(C)C>[CH2:1]([O:3][C:4]([C:6]12[CH2:8][CH:7]1[CH:9]=[CH:10][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][N:40]([NH:41][C:42]([O:44][C:45]([CH3:47])([CH3:48])[CH3:46])=[O:43])[C:38](=[O:39])[N:15]1[CH:14]([CH2:18][CH:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:21]=3)[CH2:16]1)[C:12](=[O:13])[NH:11]2)=[O:5])[CH3:2]
Reactant: C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Agent: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C12CC1C=CCCCCCN(NC(=O)OC(C)(C)C)C(=O)N1CC(Oc3cc(-c4ccccc4)nc4cc(OC)ccc34)CC1C(=O)N2
Yield: 20.6 %

Procedure:
Compound 120 (200 mg, 0.26 mmol) was dissolved in degassed dichloromethane (30 ml). Hoveyda-Grubbs catalyst 11 generation (16 mg, 0.026 mmol) was then added and the mixture was refluxed under argon atmosphere overnight. The solvent was then evaporated and the crude product was purified by silica chromatography (1% methanol in ether) which gave 39 mg (20%) of the title product. MS (M+H+) 728.2
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])[CH:5]=[CH:6][CH:7]=1.[CH2:17](I)[CH3:18]>Cl>[Cl:1][C:2]1[C:3]([CH3:16])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][N:10]=[C:9]2[S:15][CH2:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[ClH:1]
Reactant: Cc1c(Cl)cccc1NC(=S)NCC(N)=O
Reactant: CCI
Agent: Cl
Product: CCSC1=NCC(=O)N1c1cccc(Cl)c1C

Procedure:
The title compound was prepared by the procedure described in Example 6 using 12.0 g of 2-[3-(3-chloro-2-methylphenyl)-thioureido]-acetamide, and 25.0 g of ethyl iodide. The hydrochloride salt was prepared in ethereal hydrogen chloride. Crystallization from ethyl acetate afforded the title compound as a white solid, monohydrochloride (5.1 g), m.p. 161-163° C. (dec.). Anal. Calcd. for. C12H13Cl N2O S . HCl: C, 47.22; H, 4.62; N, 9.18. Found: C, 47.03; H, 4.40; N, 9.09. Mass spectrum (+FAB, [M+H]+) m/z 269/271. 1H-NMR (DMSO-d6 ; 400 MHz) δ9.05-9.85 (broad s, 2H), 7.62 (d, 1H), 7.39 (t, 1H), 7.33 (d, 1H), 4.48 (q, 2H), 3.20 (m, 2H), 2.15 (s, 3H), and 1.29 ppm (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:13])[N:4]=[C:3]1[SH:14].[C:15]([O:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([C:25]2[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1)(=[O:17])[CH3:16].[OH-].[Na+]>CO>[C:15]([O:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([C:25]2[CH:26]=[CH:27][C:28]([CH2:29][S:14][C:3]3[N:2]([CH3:1])[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][C:9]=4[CH3:13])[N:4]=3)=[CH:31][CH:32]=2)=[O:24])=[CH:21][CH:20]=1)(=[O:17])[CH3:16]
Reactant: Cc1cccc2nc(S)n(C)c(=O)c12
Reactant: CC(=O)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)Oc1ccc(C(=O)c2ccc(CSc3nc4cccc(C)c4c(=O)n3C)cc2)cc1
Yield: 0.2 %

Procedure:
A solution of 3,5-dimethyl-2-mercapto-4(3H)-quinazolinone (917 mg), 4-(4-acetoxybenzoyl)benzyl bromide (1.785 g) and 1N-aqueous sodium hydroxide solution (4.5 ml) in methanol (20 ml) was stirred at room temperature for 4 hours. This reaction mixture was concentrated and extracted with chloroform and the extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=6:1) to provide the title compound as colorless solid (4.26 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]2[C:27]3[C:22](=[CH:23][C:24]([CH:28]=O)=[CH:25][CH:26]=3)[NH:21][N:20]=2)[CH:12]=1>>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[C:19]2[C:27]3[C:22](=[CH:23][C:24](/[CH:28]=[C:3]4/[C:2](=[O:10])[NH:1][C:9]5[C:4]/4=[CH:5][CH:6]=[CH:7][CH:8]=5)=[CH:25][CH:26]=3)[NH:21][N:20]=2)[CH:12]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Yield: 83.7 %

Procedure:
The title compound (61 mg, 84%) was synthesized as a yellow solid according to the method described for (E/Z)-3-((3-iodo-1H-indazol-6-yl)methylene)-5-methoxyindolin-2-one (oil temp 75° C., reflux 90 min) using oxindole (26.6 mg, 0.2 mmol) and (E)-3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H, NH), 10.64 (s, 1H, NH), 8.91 (s, 1H), 8.48 (d, J=4.4 Hz, 1H), 8.36 (d, J=8.4 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.90 (s, 1H), 7.80 (s, 1H), 7.73 (d, J=16.8 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H, partially overlapping with the peak at 7.60 ppm), 7.60 (d, J=17.2 Hz, 1H, partially overlapping with the peak at 7.61 ppm), 7.54 (d, J=8.4 Hz, 1H), 7.43 (dd, J=7.8 Hz, 4.8 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 6.85 (t, J=7.8 Hz, 1H); MS ESI 365.1 [M+H]+, calcd for [C23H16N4O+H]+ 365.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].CCCCCC.CCOC(C)=O>C(Cl)Cl>[CH3:17][S:18]([O:1][CH2:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)CC1
Temperature: 0 °C
Yield: 89.5 %

Procedure:
Combine tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (4.720 kg, 20.6 mol) with DCM (40 L) and TEA (3020 mL, 21.63 mol) in a 50 L reactor under a nitrogen atmosphere. Cool the solution to about 0° C. and slowly add methane sulfonyl chloride (2.478 kg, 21.63 mol) in DCM (5 L) while keeping the reaction temperature below 10° C. After the addition is complete stir the mixture for 18 h at 15° C. at which time TLC (1:1, hexane:EtOAc) shows no starting material remaining Wash the mixture with water (30 L) and allow the phases to separate. Concentrate the organic phase to a solid. Slurry the solid in MTBE (6 L), collect by filtration, and dry in a vacuum oven at 50° C. to provide the title compound as a white solid (5.67 kg, 91%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][C:20]([C:22]3[N:23](C(OC(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=3)=O)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:34]C(OC(C)(C)C)=O)=O)(C)(C)C.[OH:42][CH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[F:17][C:13]1[C:12]2[C:11]3[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:34])[C:10]=3[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=[CH:19][C:18]=2[N:46]1[CH2:47][CH2:48][CH:43]([OH:42])[CH2:44][CH2:45]1
Reactant: CC(C)(C)OC(=O)Oc1cc2c(C#CC(=O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)OC(C)(C)C
Reactant: OC1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(F)c3c(N4CCC(O)CC4)cc(-c4ccc[nH]4)c1c23
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 4 above) (392 mg, 0.69 mmol) and 4-hydroxy-piperidine (Aldrich, 2.12 g, 20.94 mmol) in DMF(6 mL) was treated with NaH. (Aldrich, 250 mg, 10.42 mmol). The mixture was stirred for 30 minutes at room temperature and overnight at 120° C. The reaction mixture was poured in a mixture of ethyl acetate and water. The aqueous layer was extracted a few more times with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, with 0-50% ethyl acetate in hexanes gradient), and further purified by HPLC (silica gel, 50% ethyl acetate in hexanes) and precipitation out of THF with excess of pentane to give 6-fluoro-5-(4-hydroxy-piperidin-1-yl)-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 85 mg, 38%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[C:11]([CH3:17])[CH:10]=1>CN(C=O)C>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[C:11]([CH3:17])[CH:10]=1
Reactant: c1c[nH]cn1
Reactant: Cc1cc(Br)ccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1Cn1ccnc1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A solution of imidazole (58.0 mg, 0.86 mmol) in 3 mL DMF was treated with NaH (20.0 mg, 0.86 mmol) and heated to 90° C. After 1 h a solution of 4-bromo-1-bromomethyl-2-methyl-benzene (Intermediate 138, 190.0 mg, 0.72 mmol) in 3 mL DMF was added and stirring at 90° C. continued for 1 hour. The solution was cooled to room temperature and concentrated under reduced pressure. The title compound, 160.0 mg (88%) was isolated by column chromatography (5% MeOH-EtOAc) as a colorless solid.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]#[N:13])[CH2:2][CH2:3][CH2:4][CH3:5].O.O.[SH2:16].[Na].[Cl-].[NH4+]>CO>[CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12](=[S:16])[NH2:13])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNc1nc[nH]c1C#N
Reactant: S
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CO
Solvent: O
Product: CCCCCNc1nc[nH]c1C(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
A mixture of 4-(pentylamino)-1H-imidazole-5-carbonitrile (25 g, 0.14 mol), sodium hydrogen sulfide dihydrate (26 g, 0.28 mol) and ammonium chloride (7.5 g, 0.14 mol) in methanol (400 mL) was stirred at room temperature overnight. The conversion was about 60% according to analytical LCMS. The mixture was then stirred at 50° C. for 3 hours. The methanol was removed and the residue was diluted with water and EtOAc. The organic layer was washed with water and brine respectively, dried and concentrated to yield the crude product (30.0 g), which was used for next step without further purification. LCMS calculated for C9H17N4S (M+H): 213.1. found: 213.1.
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:18])=[N:4][C:5](=[O:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[NH2:19][C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.I([O-])(=O)(=O)=O.[Na+].CO>O>[OH:9][CH:8]1[C@H:7]([N:6]2[CH:16]=[C:2]([F:1])[C:3]([NH2:18])=[N:4][C:5]2=[O:17])[O:15][C@H:12]([CH2:13][OH:14])[CH:10]([OH:11])[N:19]1[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: Nc1ncccn1
Reactant: Nc1nc(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1F
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: Nc1nc(=O)n([C@@H]2O[C@H](CO)C(O)N(c3ncccn3)C2O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 5-fluorocytidine (2.42 g) and 2-aminopyrimidine (0.95 g) in water (50 ml) was added sodium metaperiodate (2.13 g) under cooling with an ice-water bath. The solution was stirred at ambient temperature for 8 hours. To the reaction mixture was added methanol (50 ml). The precipitate was filtered off and the filtrate was evaporated in vacuo. The residue was triturated with acetone and air-dried to give 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-pyrimidinyl)morpholin-2-yl]-5-fluorocytosine (2.3 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:6]=1.[CH3:19][O-:20].[Na+]>CN(C)C=O>[C:15]([O:14][C:12]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:5]1[N:6]=[C:2]([O:20][CH3:19])[S:3][CH:4]=1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)NCCSCc1csc(Br)n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(CSCCNC(=O)OC(C)(C)C)cs1
Temperature: 45 °C
Reaction time: 72 h
Yield: 32.7 %

Procedure:
To a solution of 2-bromo-4-[(2-tert-butoxycarbonylaminoethyl)thiomethyl]-1,3-thiazole (650 mg, 1.85 mmol) in N,N-dimethylformamide (5 mL) was added sodium methoxide (300 mg, 5.56 mmol) and stirred at 45° C. for 3 days. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The ethyl acetate extract was washed with aqueous lithium chloride and concentrated. The residue was chromatographed on silica gel (10% ethyl acetate-hexane), affording 184 mg of the title compound. 1H NMR (CDCl3) δ 1.54 (9H), 2.78 (t, 2H), 3.42 (m, 2H), 3.74 (s, 2H), 4.18 (s, 3H), 5.24 (br s, 1H), 6.60 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:31][C:32](=[O:44])[C:33]([NH:36]C(=O)OC(C)(C)C)([CH3:35])[CH3:34])[C:11]([N:13]1[CH2:30][CH2:29][CH2:28][C:15]2([C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:36][C:33]([CH3:35])([CH3:34])[C:32]([NH:31][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:11]([N:13]1[CH2:30][CH2:29][CH2:28][C:15]2([C:19](=[O:20])[N:18]([CH3:21])[CH2:17][CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:14]1)=[O:12])=[O:44]
Reactant: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CC(c2ccccc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)N)C2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 1-((2R)-3-(benzyloxy)-1-(2-methyl-1-oxo-4-phenyl-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (1.18 g, 1.945 mmol) in DCM (15 ml) was treated with TFA (7 ml, 91 mmol) and stirred at RT for 1 hour. The solvent was removed in vacuo and the residue was partitioned between EtOAc (200 ml) and sat. sodium bicarbonate solution (100 ml). The organic portion was dried (MgSO4) and concentrated in vacuo to afford the title compound as a diastereomeric mixture;
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1.O.NN>C(O)COCCO>[CH:10]1[C:11]2[CH2:12][C:13]3[C:5](=[N:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[N:7]=[CH:8][CH:9]=1
Reactant: O=C1c2cccnc2-c2ncccc21
Agent: NN
Solvent: OCCOCCO
Solvent: O
Product: c1cnc2c(c1)Cc1cccnc1-2
Temperature: 170 °C
Yield: 91.6 %

Procedure:
A mixture of 18.2 g (100 mmol) of 4,5-Diazafluoren-9-one, 27 ml (400 mmol) of hydrazine monohydrate, and 500 ml diethylene glycol was degassed and placed under nitrogen, and then heated at 170° C. for 12 h. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed to give product 15.4 g (91.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[SH:27].C[O-].[Na+]>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>[Cl:1][C:2]1[CH:7]=[C:6]([S:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: COc1ccccc1S
Reactant: C[C@@](O)(C(=O)Nc1ccc(I)cc1Cl)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1Sc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Reaction time: 18 h

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (0.03 g) was added to a deoxygenated mixture of (R)-N-[2-chloro-4-iodophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 20) (0.2 g), 2-methoxybenzenethiol (0.064 ml) and sodium methoxide (0.058 g) in ethanol (10 ml). The mixture was further deoxygenated by evacuation and refilling with argon (3 cycles) then heated under reflux with stirring under argon for 18 hours, treated with a further portion of tetrakis(triphenylphosphine)palladium(0) (0.03 g), heated a further 24 hours then cooled and filtered. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-10% ethyl acetate/hexane to give the title compound (0.166 g) as an oil. NMR (CDCl3): 1.75 (s, 3H), 3.7 (br s, 1H), 3.85 (s, 3H), 6.9 (m, 2H), 7.2 (m, 1H), 7.3 (dd, 1H), 7.35 (m, 2H), 8.3 (d, 1H), 9.8 (br s, 1H); MS: 404 (M−H)−.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C=CC(S(O)(=O)=O)=CC=2)=[CH:4][C:3]=1OC1C=CC(S(O)(=O)=O)=C(N)C=1.NC1C=C(S(O)(=O)=O)C=CC=1>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Oc2cc(Sc3ccc(S(=O)(=O)O)cc3)c3c(c2N)C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)O
Agent: Nc1cccc(S(=O)(=O)O)c1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Example 3 was repeated, except that the compounds shown in 1st, 2nd and 3rd columns of the following table were used in place of the 1-amino-2-(3'-amino-4'-sulfophenoxy)-4-(4'-sulfophenylthio)anthraquinone, 1-aminobenzene-4-β-sulfatoethylsulfone and 3-aminobenzenesulfonic acid respectively, thereby obtaining a corresponding anthraquinone. The color shade obtained by dyeing cotton with the anthraquinone compound is as shown in a 4th column of the table. Each compound can exhibit superior dye performances as described hereinabove.