Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[OH:29].[Cl-].[NH4+]>CN(C)C=O>[F:19][C:20]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:21]=1[O:29][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]#[C:11][CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(Oc2ccc([N+](=O)[O-])cc2F)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 21.1 %

Procedure:
To 2 ml of N,N-dimethylformamide were added 0.2 g of 4-chloro-6-(2-butynyloxy)pyrimidine, 0.23 g of potassium carbonate, and 0.21 g of 2-fluoro-4-nitrophenol, followed by stirring at 60° C. for 7 hours. The reaction mixture was then left for cooling to room temperature and poured into a saturated aqueous ammonium chloride solution, which was extracted three times with chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and then with water, and dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 0.07 g of 4-(2-fluoro-4-nitrophenoxy)-6-(2-butynyloxy)pyrimidine (the present compound (65)), m.p.: 132.1° C.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:20]3[CH:19]=[N:18][CH2:17][N:16]([NH2:21])[C:15]=3[N:14]=[CH:13][N:12]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].C(O[C:26](=[O:28])[CH3:27])(=O)C>>[C:2]([O:3][C@@H:2]1[C@H:4]([O:5][C:4](=[O:5])[CH3:6])[C@@H:6]([CH2:8][O:9][C:26](=[O:28])[CH3:27])[O:7][C@H:1]1[NH:10][C:11]1[C:20]2[CH:19]=[N:18][CH2:17][N:16]([NH2:21])[C:15]=2[N:14]=[CH:13][N:12]=1)(=[O:3])[CH3:1]
Reactant: NN1CN=Cc2c(N[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)ncnc21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](Nc2ncnc3c2C=NCN3N)[C@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
reacting said N4 -(β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine with acetic anhydride in the presence of an acid scavenger to produce N4 -(2,3,5-tri-O-acetyl β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine or, alternatively reacting said N4 -(β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine with phosphoryl chloride in trimethylphosphate at a temperature below about 10° C. to produce N4 -(5-O-phosphono-β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[C:8]([NH:13][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][S:4][CH:3]=1.[F:16][C:17]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[CH:19][N:18]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN1CCCC1=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:16][C:17]1[C:22]([C:2]2[C:6]([C:7]3[C:8]([NH:13][CH2:14][CH3:15])=[N:9][CH:10]=[CH:11][CH:12]=3)=[CH:5][S:4][CH:3]=2)=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1F
Reactant: CCNc1ncccc1-c1cscc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCNc1ncccc1-c1cscc1-c1cccnc1F
Temperature: 100 °C
Reaction time: 24 h
Yield: 23.5 %

Procedure:
A mixture of 3-bromo-4-(2-ethylaminopyridin-3-yl)thiophene (0.31 g), 2-fluoro-3-tributylstannylpyridine (0.507 g) and Pd(Ph3P)2Cl2 (0.035 g) in N-methylpyrrolidinone (3 mL), in a sealed tube, was heated at 100° C. for 17 hours. The mixture was cooled and tetrabutylammonium fluoride (1M in tetrahydrofuran, 1 mL) was added. After one day, the mixture was diluted with ethyl acetate, washed with water, dried, filtered, and evaporated. The residue was fractionated by chromatography to give 3-(2-fluoropyridin-3-yl)-4-(2-ethylaminopyridin-3-yl)thiophene (0.077 g) mp 127-129° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH:12]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)O)[C:6]3[CH2:20][CH2:21][N:22]([CH3:24])[CH2:23][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[CH:12]/[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]3[CH2:20][CH2:21][N:22]([CH3:24])[CH2:23][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)c2cccnc2)C1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: CN1CCc2c(c3cc(Cl)ccc3n2/C=C/c2cccnc2)C1
Temperature: 5 °C

Procedure:
2-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-(pyridin-3-yl)ethanol (1 equiv.) is refluxed with 25% sulfuric acid for 2 h. The reaction mixture is cooled to 5° C. with an ice-water bath. KOH (15% aq. solution) is added dropwise to the reaction mixture until pH 9-10 is achieved. The reaction mixture is extracted with EtOAc. The combined organic layers are washed with water followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product is purified by column chromatography over silica gel (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%).
Reaction SMILES: N1C2C3C=CC=CC=3N=CC=2C(=O)N1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:38](=[O:39])[C:26]3=[CH:27][NH:28][C:29]4[CH:30]=[C:31]([N+:35]([O-])=O)[CH:32]=[CH:33][C:34]=4[C:25]3=[N:24]2)=[CH:19][CH:18]=1>>[NH2:35][C:31]1[CH:32]=[CH:33][C:34]2[C:25]3[C:26]([C:38](=[O:39])[N:23]([C:20]4[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=4)[N:24]=3)=[CH:27][NH:28][C:29]=2[CH:30]=1
Reactant: COc1ccc(-n2nc3c4ccc([N+](=O)[O-])cc4[nH]cc-3c2=O)cc1
Agent: O=c1[nH][nH]c2c1cnc1ccccc12
Product: COc1ccc(-n2nc3c4ccc(N)cc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure described for 13a using 12c. 1H-NMR (DMSO-d6) δ (ppm): 6.74 (1H, d, J=2.20 Hz) 6.79 (1H, dd, J=8.79, 2.19 Hz), 7.42 (1H, d, J=8.79 Hz), 7.43 (1H, q, J=5.22 Hz), 7.86 (1H, d, J=8.51 Hz), 8.20 (1H, d, J=9.06 Hz), 8.21 (1H, q, J=5.21 Hz), 8.47 (1H, d, J=6.32 Hz). m/z 307.3 (MH+).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37]C)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[C:26]([O:32]C)[CH:25]=1.[BrH:39]>>[BrH:39].[BrH:39].[OH:32][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[OH:30])[CH2:23][CH:19]1[CH2:20][CH2:21][CH2:22][N:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][CH:7]1[CH2:6][C:5]1[CH:34]=[CH:35][C:36]([OH:37])=[C:3]([OH:2])[CH:4]=1
Reactant: COc1ccc(CC2CCCN2CCCCCCN2CCCC2Cc2ccc(OC)c(OC)c2)cc1OC
Agent: Br
Product: Oc1ccc(CC2CCCN2CCCCCCN2CCCC2Cc2ccc(O)c(O)c2)cc1O
Temperature: 25 °C

Procedure:
A solution of 1,6-bis[2-(3,4-dimethoxybenzyl)pyrrolidin-1-yl]hexane (2.2 g, 4.4 mmol), from Step 2, was heated in 48% hydrobromic acid (11 mL) at reflux temperature for 3 hours (the reaction was followed by TLC on silica gel). The solution was cooled to room temperature; and the aqueous phase was decanted from the oil, which separated from solution. Toluene was added to this oil and then removed in vacuo. This addition and removal of toluene was repeated several times to remove water and hydrogen bromide. The residual solid, 1,6-bis[2-(3,4-dihydroxybenzyl)pyrrolidin-1-yl]hexane dihydrobromide, a mixture of the R,R-; S,S-; and R,S-stereoisomers, was obtained as a foam.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(=O)/C=C\C(O)=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[N:28]([C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[N:27]=[CH:26]2>>[CH3:34][C:33]([CH3:36])([CH3:35])[C:32]([N:28]1[C:29]2[C:25](=[CH:24][C:23]([NH:22][CH:2]3[CH2:6][CH2:5][NH:4][CH2:3]3)=[CH:31][CH:30]=2)[CH:26]=[N:27]1)=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CC(C)(C)C(=O)n1ncc2cc(N)ccc21
Agent: O=C(O)/C=C\C(=O)O
Product: CC(C)(C)C(=O)n1ncc2cc(NC3CCNC3)ccc21

Procedure:
Reaction of tert-butyl 3-oxopyrrolidine-1-carboxylate and 1-(5-amino-1H-indazol-1-yl)-2,2-dimethylpropan-1-one maleate salt using the method of Example 3 followed by deprotection using the method of Example 4 afforded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]([OH:13])=O)[N:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:20]([CH2:22][NH2:23])[OH:21]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([S:9][CH2:10][C:11]([NH:23][CH2:22][CH2:20][OH:21])=[O:13])[N:5]=1
Reactant: NCCO
Reactant: O=C(O)CSc1nc(Cl)cc(Cl)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(CSc1nc(Cl)cc(Cl)n1)NCCO
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
To a suspension of (4,6-dichloro-2-pyrimidinyl-thio)-acetic acid (2.390 g.) in anhydrous benzene (24 ml.), 1.27 ml. of oxalyl chloride in anhydrous benzene (6 ml.) was added at room temperature. The reaction mixture was heated, with agitation, to 40° C., for 30 minutes and held for another 10 minutes at 60° C. The solvent was evaporated under vacuum to give an oily residue, which was taken up again in anhydrous chloroform (50 ml.). The chloroform solution was added drop by drop to a solution of ethanolamine (1.1 ml.) in anhydrous chloroform (40 ml.) while the temperature was kept at about 15° C. The mixture was held at ambient temperature for 60 minutes and the separated solid was then filtered off. The filtrate was evaporated under vacuum to obtain a residue which was crystallised from ethyl acetate/hexane (1.5 g.), m.p. 95°-96° C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][CH:6]=1)([O:3][CH3:4])=[O:2].Br[CH:15]([CH3:28])[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1)=O.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:4][O:3][C:1](=[O:2])[C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:10][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=3)=[C:15]([CH3:28])[N:11]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1
Reactant: COC(=O)c1ccc(C(=O)C(C)Br)cc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(-c2nc(C)c(-c3ccc(C(=O)OC)cc3)o2)cc1

Procedure:
α-(p-Carbomethylbenzamido)-p-carbomethoxypropiophenone, obtained by reacting p-carbomethoxybenzamide with α-bromo-p-carbomethoxypropiophenone, was refluxed with phosphorus oxychloride in toluene to yield dimethyl-4,4'-(4-methyloxazol-2,5-diyl)dibenzoate, G. The VIII was obtained in a similar manner as in Example 1.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([C:13]([O:15]CC)=[O:14])[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>C(O)C.C1COCC1.O>[C:1]1([NH:7][C:8]([C:10]2([C:13]([OH:15])=[O:14])[CH2:11][CH2:12]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1(C(=O)Nc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.2 %

Procedure:
To a solution of ethyl 1-(phenyl carbamoyl)cyclopropane carboxylate (13 g, 55.79 mmol) in ethanol/THF (1/1, 100 mL) was added KOH (4.69 g, 83.69 mmol) in H2O (8 mL) and the mixture was stirred at room temperature overnight. The ethanol and THF were removed under reduced pressure. The residue was neutralized with HCl (5 mol/L, 20 mL), and extracted with EtOAc (150 mL×3). The combined organic phases were dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to afford the title compound as a white solid (10.1 g, 88.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[CH:16][C:15]([C:21]([CH:23]2[CH2:25][CH2:24]2)=[O:22])=[C:14]3[NH:26][CH:27]2[CH2:32][CH2:31][C:30]([N:34](CC=C)CC=C)([CH3:33])[CH2:29][CH2:28]2)[CH:5]=[C:6]([O:9][CH3:10])[C:7]=1[OH:8]>O1CCOCC1.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>[NH2:34][C:30]1([CH3:33])[CH2:31][CH2:32][CH:27]([NH:26][C:14]2[C:13]3[C:18](=[CH:19][CH:20]=[C:11]([C:4]4[CH:5]=[C:6]([O:9][CH3:10])[C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=4)[CH:12]=3)[N:17]=[CH:16][C:15]=2[C:21]([CH:23]2[CH2:25][CH2:24]2)=[O:22])[CH2:28][CH2:29]1
Reactant: C=CCN(CC=C)C1(C)CCC(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(OC)c4)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COc1cc(-c2ccc3ncc(C(=O)C4CC4)c(NC4CCC(C)(N)CC4)c3c2)cc(Cl)c1O
Temperature: 80 °C

Procedure:
To a solution of {6-(3-chloro-4-hydroxy-5-methoxyphenyl)-4-[4-(diallylamino)-4-methylcyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (49 mg, 0.088 mmol) in dioxane (3 mL) was added Pd(PPh3)4 (10 mg, 0.008 mmol) and N,N-dimethylbartituric acid (68 mg, 0.438 mmol). The resultant mixture purged with N2 and heated to 80° C. for 16 h. The solution was allowed to cool to rt, diluted with ethyl acetate, filtered and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The purified product was concentrated, diluted with a saturated NaHCO3 solution, extracted with a mixture of CHCl3/isopropanol (3:1), and dried with Na2SO4 to obtain the desired product as the free base (5 mg, 4%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.14 (s, 1H), 8.34 (s, 1H), 8.00 (dd, J=8.7, 2.0 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.26 (d, J=2.2 Hz, 1H), 7.20 (d, J=2.2 Hz, 1H), 4.29-4.21 (m, 1H), 3.97 (s, 3H), 2.89-2.80 (m, 1H), 2.14-2.07 (m, 2H), 1.92-1.71 (m, 4H), 1.70-1.61 (m, 2H), 1.28 (s, 3H), 1.25-1.06 (m, 4H); ESI MS m/z 480 [C27H30ClN3O3+H]+; HPLC>99% (AUC), tR=10.46 min.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:27]=[C:26]([F:28])[C:7]([CH2:8][N:9]2[C:13]([O:14][CH3:15])=[C:12]([CH3:16])[C:11]([C:17]3[N:22]=[C:21]([NH2:23])[C:20]([O:24][CH3:25])=[CH:19][N:18]=3)=[N:10]2)=[C:6]([F:29])[CH:5]=1)[CH3:2].Cl.Br[C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:29])[C:7]([CH2:8][N:9]2[C:13]([O:14][CH3:15])=[C:12]([CH3:16])[C:11]([C:17]3[N:22]=[C:21]([NH:23][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[C:20]([O:24][CH3:25])=[CH:19][N:18]=3)=[N:10]2)=[C:26]([F:28])[CH:27]=1)[CH3:2]
Reactant: Brc1ccncc1
Reactant: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(N)n3)c(C)c2OC)c(F)c1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CCOc1cc(F)c(Cn2nc(-c3ncc(OC)c(Nc4ccncc4)n3)c(C)c2OC)c(F)c1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
619 mg of 2-[1-(4-ethoxy-2,6-difluorobenzyl)-5-methoxy-4-methyl-1H-pyrazol-3-yl]-5-methoxypyrimidin-4-amine 1-5-1 (1.53 mmol, 1.0 eq.), 445-38 mg of 4-bromopyridine hydrochloride (1:1) (2.29 mmol, 1.5 eq.), 190.15 mg of (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (305 mmol, 0.2 eq.), 587 mg of sodium-tert-buylat (6.12 mmol, 4.0 eq.) and 419 mg of tris-(dibenzylideneacetone)dipalladium(0) (0.458 mmol, 0.3 eq.) were suspended in 10 mL of dry DMF and stirred under nitrogen atmosphere at 110° C. bath temperature for 24 hours. The reaction mixture was partitioned between half saturated aqueous ammonium chloride solution and DCM. The separated aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (hexane (0-100%)/ethyl acetate). The column was washed with methanol to receive a 50% pure target compound. This was stirred with acetone and the suspension was filtered off.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2[N:22]=[C:5]([CH:6]=[C:7]3[C:40]([CH:41]=[CH2:42])=[C:39]([CH3:43])[C:9](=[CH:10][C:11]4[C@@H:32]([CH3:33])[C@H:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:13](=[C:14]([CH2:27][C:28]([OH:30])=[O:29])[C:15]5[NH:19][C:18]([CH:20]=2)=[C:17]([CH3:23])[C:16]=5[C:24]([OH:26])=O)[N:12]=4)[NH:8]3)[C:4]=1[CH3:44].[CH3:45]CC1C(C)=C2NC=1C=C1N=C(C(CC(OC)=O)=C3N=C(C=C4NC(=C2)C(C=C)=C4C)[C@@H](C)[C@@H]3CCC(O)=O)C(C(NCCN)=O)=C1C.CCC1C(C)=C2NC=1C=C1N=C(C(CC(N[C@H](C([O-])=O)CC([O-])=O)=O)=C3N=C(C=C4NC(=C2)C(C=C)=C4C)[C@@H](C)[C@@H]3CCC([O-])=O)C(C([O-])=O)=C1C.[Na+].[Na+].[Na+].[Na+]>>[CH3:1][CH2:2][C:3]1[C:21]2[N:22]=[C:5]([CH:6]=[C:7]3[C:40]([CH:41]=[CH2:42])=[C:39]([CH3:43])[C:9](=[CH:10][C:11]4[C@@H:32]([CH3:33])[C@H:31]([CH2:34][CH2:35][C:36]([OH:38])=[O:37])[C:13](=[C:14]5[C@@H:27]([C:28]([O:30][CH3:45])=[O:29])[C:24](=[O:26])[C:16]6[C:17]([CH3:23])=[C:18]([CH:20]=2)[NH:19][C:15]5=6)[N:12]=4)[NH:8]3)[C:4]=1[CH3:44]
Reactant: C=Cc1c(C)c2cc3nc(c(CC(=O)O)c4[nH]c(cc5nc(cc1[nH]2)C(C)=C5CC)c(C)c4C(=O)O)[C@@H](CCC(=O)O)[C@@H]3C
Reactant: C=Cc1c(C)c2cc3nc(c(CC(=O)OC)c4nc(cc5[nH]c(cc1[nH]2)c(C)c5CC)C(C)=C4C(=O)NCCN)[C@@H](CCC(=O)O)[C@@H]3C
Agent: C=Cc1c(C)c2cc3nc(c(CC(=O)N[C@@H](CC(=O)[O-])C(=O)[O-])c4nc(cc5[nH]c(cc1[nH]2)c(C)c5CC)C(C)=C4C(=O)[O-])[C@@H](CCC(=O)[O-])[C@@H]3C
Agent: [Na+]
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)[C@@H]4C(=O)OC)[C@@H](CCC(=O)O)[C@@H]3C

Procedure:
merocyanine 540[MC 540]; Vitamin D; 5-amino-laevulinic acid [ALA]; photosan; chlorin e6, chlorin e6 ethylenediamide, and mono-L-aspartyl chlorin e6;
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[F:22])[NH:18][C:17]([C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([NH2:29])[CH:28]=1)=[CH:16]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[F:22])[NH:18][C:17]([C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([NH:29][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[CH:28]=1)=[CH:16]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.9 %

Procedure:
3-Nitrobenzaldehyde (0.3 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture is stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 6 days. Saturated aqueous sodium bicarbonate solution (100 mL) was added and the mixture was sired for 2 hours. The mixture was shaken, the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give a yellow solid. Recrystallization from methanol gave the product (220 mg), mp 212-214° C.
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)(C)(C)C.O[C:24]1[N:25]([CH3:37])[C:26](=[O:36])[CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[N:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>O1CCCC1>[OH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([O:20][C:24]3[N:25]([CH3:37])[C:26](=[O:36])[CH:27]=[C:28]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][N:31]=4)[N:29]=3)[CH2:18][CH2:19]2)=[CH:12][CH:13]=1
Reactant: Cn1c(O)nc(-c2ccncn2)cc1=O
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1ccc([C@H]2CC[C@@H](O)CC2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cn1c(O[C@H]2CC[C@H](c3ccc(CO)cc3)CC2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of cis-4-[4-(tert-butyl-dimethyl-silanyloxymethyl)phenyl]cyclohexanol (600 mg, 1.87 mmol), 2-hydroxy-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (382 mg, 1.87 mmol), triphenylphosphine (540 mg, 2.06 mmol) in tetrahydrofuran (6.2 ml) was added diisopropyl azodicarboxylate (40 wt % in toluene, 1.04 g, 2.06 mmol) under nitrogen atmosphere. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=60/40 to 50/50) to afford a colorless solid. This compound was dissolved into tetrahydrofuran (7.5 ml) and cooled to 0° C. Tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 3.0 ml, 3.0 mmol) was added to the solution. The mixture was warmed to room temperature and stirred for one hour. The mixture was poured into saturated aqueous ammonium chloride solution, and extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent; ethyl acetate) to afford 2-[trans-4-(4-hydroxymethyl-phenyl)cyclohexyloxy]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (243 mg, 0.619 mmol, 33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[NH:11][NH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[Cl:17][C:18]([Cl:22])([Cl:21])[S:19]Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9](=[O:14])[N:10]([S:19][C:18]([Cl:22])([Cl:21])[Cl:17])[N:11]([S:19][C:18]([Cl:22])([Cl:21])[Cl:17])[C:12]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH][nH]c(=O)n1-c1cccc(Cl)c1
Reactant: ClSC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1n(-c2cccc(Cl)c2)c(=O)n(SC(Cl)(Cl)Cl)n1SC(Cl)(Cl)Cl

Procedure:
To a solution of 42.2g (0.2 mole) 4-(3-chlorophenyl) urazole in 200 ml water was added a solution of 16g (0.4 mole) sodium hydroxide in 20 ml water. A mixture of 74.4g (0.4 mole) trichloromethylsulfenyl chloride and 3g of an emulsifier solution (as in example 1) in 50 ml water was added dropwise to the above basic solution while keeping the reaction mixture at 0° C. The reactants were mixed so that the reaction mixture was kept at a pH greater than 7. The precipitate that formed was filtered and the filter cake was washed with water. After drying and recrystallizing from cyclohexane there was obtained 70g (69%) 4-(3-chlorophenyl)-1,2-bis-(trichloromethylthio) urazole having a melting point of 153° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:36]=[CH:35][C:17]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]([O:31]CC)=[O:30])[C:20]=2[CH3:34])=[CH:16][CH:15]=1)=[O:12].O.[OH-].[Li+].O1CCCC1.CO>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:18][C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]([CH2:28][C:29]([OH:31])=[O:30])[C:20]=2[CH3:34])=[CH:35][CH:36]=1)=[O:12]
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)c2ccccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
Into a dry reaction vessel, ethyl 2-[3-[4-(2-naphthamido)benzyl]-2-methyl-1H-indol-1-yl]acetate (530 mg, 1.11 mmol), lithium hydroxide monohydrate (140 mg, 3.34 mmol), 5 mL tetrahydrofuran, 5 mL methanol, 10 mL water were added successively, and stirred at room temperature for 1 h. The reaction was monitored to be complete by TLC. The solvent was rotate evaporated. It was adjusted to pH=3-4 with 2 N HCl solution. A solid precipitated, and was washed with ethyl acetate, dichloromethane, acetonitrile to obtain the product 100 mg as a white solid, at a yield of 20.1%.