Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[C@@H:53]1[O:65][C@H:64]([CH2:66][O:67][C:68](=[O:70])[CH3:69])[C@@H:59]([O:60][C:61](=[O:63])[CH3:62])[C@H:54]1[O:55][C:56](=[O:58])[CH3:57])(=O)C.C(=O)(O)[O-].[Na+]>COCCOC.C(OCC)(=O)C>[C:56]([O:55][C@@H:54]1[C@H:59]([O:60][C:61](=[O:63])[CH3:62])[C@@H:64]([CH2:66][O:67][C:68](=[O:70])[CH3:69])[O:65][C@H:53]1[N:14]1[CH:13]=[N:12][C:11]2[C:15]1=[N:16][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:18][C:10]=2[NH:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:58])[CH3:57]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Temperature: 55 °C

Procedure:
To a suspension of ethyl 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 63) (40.0 g, 0.103 moles) in anhydrous 1,2-dimethoxyethane (240 ml) under an atmosphere of nitrogen was added 4-methylmorpholine (11.5 g, 12.5 ml, 0.114 moles) and the resultant mixture was heated to 45° C. with stirring. To this mixture was then added trimethylsilyl trifluoromethanesulphonate (27.5 g, 22.4 ml, 0.124 moles) over a period of 10 minutes. The resultant orange solution was then heated to 55° C., and a solution of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (36.1 g, 0.113 moles) in 1,2-dimethoxyethane (100 ml plus 20 ml to rinse through) was added over a period of 10 minutes. The reaction was then stirred at 57–60° C. for 2 hours after which time the mixture was cooled to ambient temperature. The reaction mixture was then cautiously added to a mixture of saturated aqueous sodium bicarbonate solution (400 ml) and ethyl acetate (400 ml) with vigorous stirring. The layers were separated and the aqueous phase was extracted with ethyl acetate (400 ml). The combined organic phases were dried over anhydrous magnesium sulphate and were then concentrated in vacuo to give the crude product as an orange foam (74.9 g) that could be used as such for the next step. This crude product can be purified using flash chromatography on silica gel eluting with a gradient system of 10% v/v diethyl ether in dichloromethane changing to 25% v/v diethyl ether in dichloromethane to give the title compound as a colourless foam.
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH:6]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]2=[O:18])[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.CC(C)([O-])C.[K+].Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].O>CN(C)C=O>[CH2:36]([O:35][C:33]([CH2:32][N:8]1[C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[CH2:11][CH2:12][CH2:13][CH:6]([N:5]2[C:4](=[O:19])[C:3]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]3[C:1]2=[O:24])[C:7]1=[O:18])=[O:34])[CH3:37]
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2ccccc2CCCC1N1C(=O)c2ccccc2C1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1C(=O)C(N2C(=O)c3ccccc3C2=O)CCCc2ccccc21
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of 3-phthalimido-3,4,5,6-tetrahydro-1-benzazocin-2(1H)one (1.7 g) in dimethylformamide (10 ml) is stirred at 0° C. under a nitrogen atmosphere. A solution of potassium t-butoxide (0.75 g) in dimethylformamide (6 ml) is added and the reaction mixture is stirred at 0° C. for five minutes. A solution of ethyl bromoacetate (1.0 g) in dimethylformamide (5 ml) is added and the reaction mixture stirred at 0° C. for 11/2 hours. Water (3 ml) is added, and the reaction mixture is evaporated under high vacuum. The residue is distributed between ethyl acetate (100 ml) and water (50 ml) and the aqueous layer is washed with water (50 ml) and dried over sodium sulfate. The residue is recrystallized from methanol/ether to give 1-ethoxycarbonylmethyl-3-phthalimido-3,4,5,6-tetrahydro-1-benzazocin-2(1H)one, mp 79°-81° C. used in the next synthetic step.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=[C:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25].C([O-])([O-])=O.[K+].[K+]>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][N:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=[C:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25]
Reactant: O=S(Cl)Cl
Reactant: O=c1c(Cc2ccccc2)nc2c(n1CCO)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: O=c1c(Cc2ccccc2)nc2c(n1CCCl)CCCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
Thionylchloride (2.96 ml, 1.3 eq.) was added dropwise under ice-cooling to compound 643 (9.09 g, 32 mM) dissolved in chloroform (30 ml), and stirred at room temperature for 2 hours. Dilute aqueous K2CO3 was added to the reaction mixture, which mixture was then extracted twice with chloroform, dried with anhydrous sodium sulfate and concentrated in vacuo. The residue was charged on a column of silica-gel (C-200, 100 g) packed with chloroform and eluted with chloroform to obtain compound 644 (7.55 g, yield: 78.0%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[H][H].Cl[CH2:11][C:12]([C:15]1[CH:27]=[CH:26][C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][C:17]=2[CH:16]=1)([OH:14])[CH3:13]>O.CN(C)C=O>[N:3]1([CH2:13][C:12]([C:15]2[CH:27]=[CH:26][C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][C:17]=3[CH:16]=2)([OH:14])[CH3:11])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CC(O)(CCl)c1ccc2c(c1)Cc1ccccc1-2
Reactant: c1c[nH]cn1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(O)(Cn1ccnc1)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a slurry of 743 mg. of a 60% sodium hydride dispersion in oil in 50 ml. of dry dimethylformamide were added, in portions, 2.53 g. of imidazole. After hydrogen evolution had ceased, 3.2 g. of 1-chloro-2-(9H-fluoren-2-yl)-2-propanol in 50 ml. of dry dimethylformamide were added. The mixture was heated to 60° C. for one hour and then stirred overnight at room temperature. After heating an additional 2.5 hours at 85° C., the reaction mixture was poured into 700 ml. of water. The aqueous solution was extracted three times with ethyl acetate. The combined organic extracts were washed first with water followed by a saturated sodium chloride solution wash, dried over sodium sulfate, and evaporated to dryness. The residue was purified by chromatography over silica gel followed by crystallization from tetrahydrofuran/hexanes to provide 1.27 g. of the desired title product, m.p. 183°-184° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:2]1.Cl[S:18]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[S:18]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=2)(=[O:20])=[O:19])=[CH:2]1
Reactant: COc1ccc(CNCc2ccoc2)cc1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC)cc2)Cc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
110 mg of 1-(furan-3-yl)-N-(4-methoxybenzyl)methanamine (example 5-27a) was mixed with methyl 4-(chlorosulfonyl)benzoate (example 5-10c) (117 mg, 0.5 mmol) and triethyl amine (100 uL) in DCM (5 mL). The mixture was stirred overnight at ambient temperature and concentrated. The residue was re-dissolved in ethyl acetate (20 mL), washed with 1N HCl (aq., 2 mL), followed by water (5 mL) and brine (5 mL) then dried over magnesium sulfate. The crude product was purified by preparative TLC (40% Ethyl Acetate/hexanes) to give methyl 4-(N-(furan-3-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoate as a white solid. Saponification as in example 5-10 gave 4-(N-(furan-3-ylmethyl)-N-(4-methoxybenzyl)sulfamoyl)benzoic acid as a white crystalline solid (68 mg, 64% yield). MS (M−H, 400.1); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 3.72 (s, 3H), 4.13 (s, 2H), 4.26 (s, 2H), 5.99 (s, 1H), 6.87 (m, 4H), 6.87 (d, 2H, J=8.8 Hz), 7.13 (d, 2H, J=8.8 Hz), 7.39 (s, 1H), 7.49 (s, 1H), 7.95 (d, 2H, J=8.4 Hz), 8.09 (d, 2H, J=8.8 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=S)[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2].[C:23]1(=[O:38])[N:27]([CH2:28][C:29](=[O:32])[CH2:30][NH2:31])[C:26](=[O:33])[C:25]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:24]12>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]=[C:12]([NH:31][CH2:30][C:29]([CH2:28][N:27]3[C:23](=[O:38])[C:24]4=[CH:37][CH:36]=[CH:35][CH:34]=[C:25]4[C:26]3=[O:33])=[O:32])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:8]=2[CH:22]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Reactant: NCC(=O)CN1C(=O)c2ccccc2C1=O
Solvent: CCO
Product: O=C(CNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1)CN1C(=O)c2ccccc2C1=O

Procedure:
In the manner given in example 12, 7-nitro-1,3-dihydro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione is heated with (3-phthalimidoacetonyl)amine, ethylene ketal in ethanol to give 7-nitro-5-(o-chlorophenyl)-2-[ (3-phthalimidoacetonyl)amino]-3H-1,4-benzodiazepine, ethylene ketal.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([O:18]C)=[O:17])=[CH:10]2)=[CH:5][CH:4]=1.[OH-].[Li+]>CO.O>[CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[CH:13]=[CH:12][C:11]([C:16]([OH:18])=[O:17])=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(=O)n(-c2ccc(N(C)C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)c1ccc(-n2cc(C(=O)O)ccc2=O)cc1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
After 357 mg (1.31 mmol) of methyl 1-(4-dimethylaminophenyl)-1,6-dihydro-6-oxo-3-pyridinecarboxylate was dissolved in 12 mL of methanol and 4 mL of water, 94 mg (3.93 mmol) of lithium hydroxide was added to the solution. Afterward, the resulting reaction solution was stirred at about 50° C. for about 5 hours. After termination of the reaction was determined by liquid chromatography, the solvent was removed in vacuo, and aqueous HCl was then added to the reaction solution to titrate until a neutral solution was obtained. The resulting solid compound was filtrated and used in Example 113-3 without an additional purification process.
Reaction SMILES: O=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[CH2:5][CH:4]([C:17](O)=[O:18])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.C1COCC1>[F:15][C:13]([F:14])([F:16])[C:9]1[CH:8]=[C:7]([N:6]2[CH2:2][CH2:3][CH:4]([CH2:17][OH:18])[CH2:5]2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)C1CC(=O)N(c2cccc(C(F)(F)F)c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCC1CCN(c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-Oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid (0.35 g, 1.28 mmol) in diethyl ether (5 ml) was added to a solution of lithium aluminium hydride (0.097 g, 2.56 mmol) in THF (5 ml) at temperature 0° C. over a period of 10 min. The mixture was refluxed for 2 hours and then stirred at room temperature for 20 hours. The reaction mixture was diluted with diethyl ether (15 ml) and quenched with water (10 ml). The organic layer was separated and aqueous layer was extracted with diethyl ether. The combined organic layer was washed with saturated brine solution, dried over Na2SO4 and evaporated to obtain a residue which was purified by preparative TLC to afford [1-(3-trifluoromethyl-phenyl)-pyrrolidin-3-yl]-methanol as a colorless mass (0.2 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([OH:14])=O)[CH2:11][CH2:10]1.C(N(CC)CC)C.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([Cl:25])=[O:14])[CH2:11][CH2:10]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1(c2ccc(Cl)cc2Cl)CC1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cl)C1(c2ccc(Cl)cc2Cl)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1-(2,4-Dichlorophenyl)-cyclopropanecarboxylic acid (0.086 g, 0.37 mmol) and triethylamine (0.08 mL, 0.56 mmol) were combined in CH2Cl2 (2 mL) and cooled to 0° C. Oxalyl chloride (0.05 mL, 0.56 mmol) was added, followed by DMF (3 drops), and the reaction was stirred for 20 minutes at 0° C. and then warmed to room temperature to give the title compound, which was used directly in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:21]=1[CH:9]1[N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:11](=[O:13])[CH2:12][CH:8]1[CH2:7]2.[C:22]1(C)[CH:27]=CC=C[CH:23]=1>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>[CH2:27]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:21]=1[CH:9]1[N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C:11](=[O:13])[CH2:12][CH:8]1[CH2:7]2)[CH:22]=[CH2:23]
Reactant: CC(C)(C)OC(=O)N1C(=O)CC2Cc3cccc(Br)c3C21
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=CCc1cccc2c1C1C(CC(=O)N1C(=O)OC(C)(C)C)C2

Procedure:
A solution tert-butyl 8-bromo-2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate (Example F10, 700 mg), Pd(PPh3)4 (280 mg, 0.12 equiv.), allyltributylstannate (1.65 g, 2.5 equiv.) in toluene (17 mL) was degassed and stirred at reflux over night. The solvent was removed under vacuum. The residue was taken up in acetonitrile (40 mL) and washed twice with n-hexane. The acetonitrile was removed in vacuo and the residue was purified by flash chromatography eluting with ethyl acetate and cyclohexane (1 to 25%) to give 350 mg of the desired products (mixture of allyl and isomer) F14: LCMS (method E), RT: 1.06 min, [ES+[377, M+CH3CN+Na].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=O)=[CH:7][CH:8]=1.[C:11](#[N:15])[CH2:12][C:13]#[N:14].C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:35][C:34](=[O:36])[N:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:32]=2)=[CH:27][CH:26]=1>C(O)C>[NH2:14][C:13]1[O:36][C:34]2[N:33]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:32]=[C:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[C:35]=2[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:12]=1[C:11]#[N:15]
Reactant: N#CCC#N
Reactant: COc1ccc(C2=NN(c3ccccc3)C(=O)C2)cc1
Reactant: COc1ccc(C=O)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-c2nn(-c3ccccc3)c3c2C(c2ccc(OC)cc2)C(C#N)=C(N)O3)cc1
Reaction time: 0.02 h
Yield: 81.9 %

Procedure:
A mixture of anisaldehyde (350 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 3-(4-methoxyphenyl)-1-phenyl-1H-pyrazol-5(4H)-one (764 mg, 2.87 mmol, 1 equ.). The reaction mixture was concentrated after 24 h and the precipitate was washed with ethanol and hexanes, and then re-crystallized from ethanol to give 6-amino-3,4-bis(4-methoxyphenyl)-1-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1.06 g, 2.35 mmol, 82%) as a white solid. 1H-NMR (400 MHz) DMSO: 7.93-7.91 (d, 2H), 7.56-7.52 (m, 4H), 7.38-7.35 (t, 1H), 7.15-7.11 (m, 4H), 6.83-6.78 (m, 4H), 4.98 (s, 1H), 3.70 (s, 3H), 3.66 (s, 3H), 13C-NMR (100 MHz) DMSO: 159.5, 158.9, 158.4, 146.6, 145.5, 137.9, 136.6, 129.8, 129.0, 128.3, 127.0, 125.2, 121.0, 120.4, 114.2, 114.1, 97.7, 60.3, 55.5, 55.3, 37.1; LC/MS-MS: 452.3→89.1 m/z; GS1 and GS2 at 30, DP=36, CE=39, CXP=4, tR=3.47 min.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:7]=1.[Cl:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[O:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Cl:18][C:19]1[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:7]=2)[CH2:24][CH2:23]1.[CH2:20]([OH:21])[CH2:19][CH2:31][CH3:30]
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: Cn1c(=O)c(Br)nn(CCCC(F)(F)F)c1=O
Product: CCCCO
Product: Cn1c(=O)c(N2CCC(Oc3ccccc3Cl)CC2)nn(CCCC(F)(F)F)c1=O
Yield: 77 %

Procedure:
The compound 25 (oil) is prepared from the triazine 4a and the intermediate 8a according to the synthesis method 1 in n-butanol (yield: 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1
Reactant: COc1cc(CO)cc(Cl)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CO[Si](C)(C)C(C)(C)C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of [2-chloro-6-(methyloxy)-4-pyridinyl]methanol (for a synthesis see Adamczyk, M.; Akireddy, S. R.; Reddy, Rajarathnam E. Tetrahedron 2002, 58(34), 6951)(8.02 g, 46.22 mmol) in dry DMF (100 ml) was treated with tert-butyldimethylsilyl chloride (8.36 g, 55.46 mmol) and imidazole (3.77 g, 55.46 mmol) and stirred at rt for 2 h. The reaction mixture was treated with water extracted three times with dichloromethane, dried (magnesium sulphate), evaporated and chromatographed on silica gel (100 g), eluting with 1:4 ethyl acetate-hexane to give the desired product (12.38 g, 93%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:13])=[O:5]
Reactant: Cc1ccccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1ccccc1C(=O)Cl

Procedure:
A solution of 2-methylbenzoic acid (10 g, 1.00 equiv) in thionyl chloride (50 mL) was refluxed overnight at 80° C. in an oil bath. The reaction mixture was concentrated under vacuum to afford 2-methylbenzoyl chloride (crude) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14](Cl)=[O:15])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH2:27])[CH:22]=[CH:21]2.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.O>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH:27][C:14]([C:11]1[CH:10]=[N:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:13][CH:12]=1)=[O:15])[CH:22]=[CH:21]2
Reactant: Nn1ccc2cc(F)ccc21
Reactant: O=C(Cl)c1cnc(-c2cccc(F)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nn1ccc2cc(F)ccc21)c1cnc(-c2cccc(F)c2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (1 mmol) in EtOAc (20 mL) is added to a stirred solution of 5-fluoro-indol-1-ylamine (1 mmol) and potassium carbonate (1 mmol) in EtOAc (10 mL) and H2O (20 mL) at rt and the reaction mixture is stirred at rt overnight. EtOAc is evaporated in vacuo, and the resulting solid is collected by filtration to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (148 mg, 42%) as a solid. MS: 351 (M+H); 1H NMR (300 MHz, CDCl3): δ 6.56 (m, H) 7.02 (m, H), 7.12-7.34 (m, 3H), 7.51 (m, H), 8.24 (d, H), 8.34 (s, H), 8.92 (br, H), 9.24 (br, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13].[C:15](=[O:18])([O-])[O-].[K+].[K+].[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C>[O:24]1[CH2:25][CH2:26][N:21]([C:9]2[CH:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]([CH:10]=2)[O:4][CH2:3][CH2:2][N:21]2[CH2:26][CH2:15][O:18][CH2:23][CH2:22]2)[CH2:22][CH2:23]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1OCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1OCCN1CCOCC1
Temperature: 70 °C
Yield: 24.7 %

Procedure:
A solution of 2-(2-bromoethoxy)-4-fluoro-1-nitrobenzene (160 mg, 0.6 mmol) in 20 mL acetonitrile under a nitrogen atmosphere was treated with potassium carbonate (360 mg, 2.6 mmol) and morpholine (0.3 mL, 3.4 mmol). The reaction mixture was heated to 70° C. for three hours and then filtered and concentrated. The residue was purified by flash chromatography (SiO2, 100% ethyl acetate/hexane) to give 4-(2-(5-morpholino-2-nitrophenoxy)ethyl)morpholine (50 mg, 25%). 1HNMR (CDCl3) δ 7.99 (m, 1H), 6.45 (m, 1H), 6.35 (s, 1H), 4.21 (t, 2H, J=4.0 Hz), 3.85 (t, 4H, J=4.0 Hz), 3.72 (t, 4H, J=4.0 Hz), 3.33 (t, 4H, J=4.0 Hz), 2.89 (t, 2H, J=4.0 Hz), 2.63 (t, 4H, J=4.0 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([O:25][CH3:26])=[O:24].[Na+].[CH3:28][S:29]([O-:31])=[O:30]>CS(C)=O.[Cu]I>[CH3:22][C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:8][C:9]2[C:4]([C:5]=1[C:23]([O:25][CH3:26])=[O:24])=[CH:3][C:2]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:11][CH:10]=2
Reactant: CS(=O)[O-]
Reactant: COC(=O)c1c(C)c(-c2ccc(C(F)(F)F)cc2)nc2ccc(Br)cc12
Agent: [Cu]I
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1c(C)c(-c2ccc(C(F)(F)F)cc2)nc2ccc(S(C)(=O)=O)cc12
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Methyl 6-bromo-3-methyl-2-[4-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (5.1 g, 12.02 mmol) was dissolved in dimethyl sulfoxide (60 mL) and copper(I) iodide (4.58 g, 24.04 mmol) and methanesulfinic acid sodium salt (2.455 g, 24.04 mmol) were added. The reaction vessel was evacuated and flushed with N2 three times, and heated at 120° C. overnight. The reaction mixture was diluted with CH2Cl2 and H2O, stirred for 30 min, filtered through the Celite, and washed with CH2Cl2. The filtrate was extracted three times with CH2Cl2, and the combined organic extracts were washed twice with brine, and dried over Na2SO4. The residue was purified via silica gel flash chromatography (0%-20% EtOAc/CH2Cl2) to afford the desired product as an off white solid (3.3 g, 65%). MS (m/z) 424.0 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:25](O)([CH3:28])([CH3:27])[CH3:26].N>O1CCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: N
Solvent: C1CCOC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
76.5 g (0.5 mols) of p-hydroxyphenylacetic acid was dissolved in 500 ml of tetrahydrofuran (THF). The resulting reaction solution was then cooled to a temperature of from −20° C. to −15° C. To the reaction solution was then added dropwise 231 g (1.1 mols) of trifluoroacetic anhydride. After the termination of dropwise addition, the reaction mixture was stirred at room temperature for 12 hours. The reaction solution was then again cooled to a temperature of from −20° C. to −15° C. To the reaction solution was then added dropwise 37 g (0.5 mols) of t-butanol. The reaction mixture was then stirred at room temperature for 3 hours. To the reaction solution was then added dropwise 100 ml of aqueous ammonia. The reaction mixture was then extracted with water to obtain t-butyl p-hydroxyphenylacetate.