Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[C:8]([OH:9])=[C:7]([CH3:10])[CH:6]=[C:5]([CH3:11])[CH:4]=1.[C:12]([C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[OH:23])([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+].Cl>O>[OH:23][C:17]1[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:21][C:20]([CH3:22])=[CH:19][C:18]=1[CH2:10][C:7]1[CH:6]=[C:5]([CH3:11])[CH:4]=[C:3]([CH3:2])[C:8]=1[OH:9]
Reactant: Cc1ccc(O)c(C(C)(C)C)c1
Reactant: Cc1cc(C)c(O)c(CO)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C)c(O)c(Cc2cc(C)cc(C(C)(C)C)c2O)c1
Temperature: 100 °C
Yield: 51.9 %

Procedure:
In a 300 ml eggplant-type flask equipped with a Dimroth condenser, 10.4 g (0.068 mol) of intermediate 6-(hydroxymethyl)-2,4-dimethylphenol and 11.6 g (0.071 mol) of 2-t-butyl-4-methylphenol were suspended in 50 ml of water. To this suspension, an aqueous solution having 10.3 g (0.26 mol) of sodium hydroxide dissolved in 50 ml of water, was added, and the mixture was stirred by a magnetic stirrer. This mixture was heated to 100° C. and stirred at that temperature for 12 hours. The reaction mixture was cooled to room temperature, then acidified by concentrated hydrochloric acid and extracted with toluene. The obtained toluene solution was washed with water and then dried over anhydrous magnesium sulfate. From the solution having the anhydrous magnesium sulfate removed, toluene was distilled off, and the obtained residue was separated by silica gel chromatography to obtain 10.6 g (0.036 mol, yield: 51.9%) of (2-hydroxy-3-t-butyl-5-methylphenyl)-(2-hydroxy-3,5-dimethylphenyl)methane as a brown highly viscous liquid. By 1HNMR, the liquid was confirmed to be the desired product.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]1[C:10]([OH:12])=O)([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:37][O:38][C:39]([C@@H:41]1[CH2:52][C@:44]2([C:49]([CH3:51])([CH3:50])[C:45]32[CH2:48][CH2:47][CH2:46]3)[CH2:43][N:42]1[C:53](=[O:70])[C@@H:54]([NH:59][C:60](=[O:69])[C@@H:61]([NH2:68])[CH:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1)[C:55]([CH3:58])([CH3:57])[CH3:56])=[O:40].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:37][O:38][C:39]([C@@H:41]1[CH2:52][C@:44]2([C:49]([CH3:50])([CH3:51])[C:45]32[CH2:48][CH2:47][CH2:46]3)[CH2:43][N:42]1[C:53](=[O:70])[C@@H:54]([NH:59][C:60](=[O:69])[C@H:61]([CH:62]1[CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]1)[NH:68][C:10]([C@@H:5]1[CH2:6][CH2:7][CH2:8][CH2:9][N:4]1[CH:1]([CH3:2])[CH3:3])=[O:12])[C:55]([CH3:58])([CH3:57])[CH3:56])=[O:40]
Reactant: CC(C)N1CCCC[C@H]1C(=O)O
Reactant: COC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](N)C1CCCCC1)C(C)(C)C)C(C)(C)C21CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]1CCCCN1C(C)C)C1CCCCC1)C(C)(C)C)C(C)(C)C21CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (S)-1-isopropyl-piperidine-2-carboxylic acid (0.497 g; 2.90 mmol) and HATU (1.65 g; 4.35 mmol) in DCM (100 mL) was cooled to 0° C. and (5R,8S)-7-[(S)-2-((S)-2-Amino-2-cyclohexyl-acetylamino)-3,3-dimethyl-butyryl]-10,10-dimethyl-7-aza-dispiro[3.0.4.1]decane-8-carboxylic acid methyl ester (1.65 g; 2.90 mmol) and DIPEA (2.98 mL; 17.4 mmol) were added. The reaction mixture was stirred for 3 h at room temperature quenched with saturated aqueous bicarbonate. The aq. phase was extracted twice with DCM, the combined organic phases dried with Na2SO4, filtered and the solvent was removed in vacuo. The product was purified by preparative HPLC (method L) to yield the title compound. LC-MS (method E): Rt=1.62 min; M/z=629 [M+]; HPLC (method A3): Rt=5.01 min
Reaction SMILES: O.NN.C([NH:7][C:8]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])(=O)C.C(O)(=O)C.[Cl-].[Na+]>C(OCC)(=O)C>[NH2:7][C:8]1[CH:16]=[C:15]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: CC(=O)Nc1cc(Oc2ccccc2)ccc1C(=O)O
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc(Oc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A suspension of hydrazine monohydrate 5.0 mL of 2-(acetamido)-4-phenoxybenzoic acid 1.5 g was heated and refluxed for 4 hours. After the reaction mixture was cooled to room temperature, acetic acid 10 mL, ethyl acetate and saturated sodium chloride aqueous solution were added to it. The organic layer was separated and collected,dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. Diisopropyl ether and hexane were added to the obtained residue, solid matter was filtrated to give 2-amino-4-phenoxybenzoic acid 1.2 g of white solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:27])=[CH:17][CH:16]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[C:28]1([NH:34][C:35]([N:13]2[CH2:12][CH2:11][N:10]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[Cl:27])=[CH:17][CH:16]=3)[CH2:9][C@@H:8]2[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Clc1ccccc1-c1ccc(CN2CCN[C@@H](Cc3ccccc3)C2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)N1CCN(Cc2ccc(-c3ccccc3Cl)cc2)C[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg of 3-(S)-benzyl-1-(2′-chloro-biphenyl-4-ylmethyl)-piperazine were dissolved in dichloromethane, 2 equiv. phenylisocyanate was be added. The reaction was shaken at room temperature overnight. The reaction was concentrated in vacuo and the crude purified by column chromatography to afford 50 mg of the title compound as the free base. Treatment with 1 equiv. 2 M HCl in dioxane afforded 44 mg of its hydrochloride salt. Yield: 62%, ES MS (+) m/z 496.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][NH:30][CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Reactant: CCOC(=O)CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)CCNCCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 20 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (25 mg), ethyl β-alaninate (14 mg) and acetic acid (0.1 mL) in DCM (5 mL) was added sodium triacetoxyborohydride (26 mg). The reaction was stirred at 20° C. for 2 h. The reaction mixture was partitioned between DCM (25 mL) and water (25 mL). The organic phase was washed with brine (25 mL), and evaporated to afford the crude product ethyl N-{2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}-β-alaninate (D90) (30 mg), which was used directly in the next step. MS (ES): C27H31ClN4O4 requires 510; found 511.2 (M+H+).
Reaction SMILES: C1C([O:7]C2C(I)=CC(C[C@H](N)C([O-])=O)=CC=2I)=CC(I)=C(O)C=1.[Na+:24].[CH:25]1[C:26]([CH2:43][C@@H:44]([NH2:48])[C:45]([OH:47])=[O:46])=[CH:27][C:28]([I:42])=[C:29]([O:32][C:33]2[CH:34]=[C:35]([I:41])[C:36]([OH:40])=[C:37]([I:39])[CH:38]=2)[C:30]=1[I:31]>>[CH:27]1[C:26]([CH2:43][C@H:44]([NH2:48])[C:45]([O-:47])=[O:46])=[CH:25][C:30]([I:31])=[C:29]([O:32][C:33]2[CH:38]=[C:37]([I:39])[C:36]([OH:40])=[C:35]([I:41])[CH:34]=2)[C:28]=1[I:42].[OH2:7].[Na+:24]
Reactant: N[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Reactant: N[C@@H](Cc1cc(I)c(Oc2ccc(O)c(I)c2)c(I)c1)C(=O)[O-]
Agent: [Na+]
Product: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)[O-]
Product: O

Procedure:
liothyronine sodium; liotrix.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:22])=[C:16]([S:19][CH2:20][CH3:21])[N:17]=2)[C:12](=[O:23])[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10]1.ClC1C=CC=C(C(OO)=[O:37])C=1.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:22])=[C:16]([S:19]([CH2:20][CH3:21])=[O:37])[N:17]=2)[C:12](=[O:23])[C:11]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(SCC)c(F)cc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(S(=O)CC)c(F)cc2c1=O
Yield: 77.9 %

Procedure:
In 10 ml of methylene chloride was dissolved 1.00 g of ethyl 1-(2,4-difluorophenyl)-7-ethylthio-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate, and 580 mg of m-chloroperbenzoic acid (purity: 80%) was added thereto, after which the resulting mixture was subjected to reaction with ice-cooling for 5 hours. The precipitates were removed by filtration, and to the filtrate thus obtained was added 10 ml of water, after which the pH thereof was adjusted to 7.5 with saturated aqueous sodium hydrogencarbonate solution. The organic layer was thereafter separated, washed with 10 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: toluene-ethyl acetate (10:1 by volume)] to obtain 810 mg (yield 77.9%) of ethyl 1-(2,4-difluorophenyl)-7-ethylsulfinyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 150°-151° C. The physical properties of this compound were identical with those of the compound obtained in Example 44.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[N:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=S)[S-:19])=[CH:13][CH:12]=2)=[N:9][CH:10]=1)[CH2:2][CH2:3][CH3:4].C([NH+](CC)CC)C.ClC(OC)=O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([C:5]1[CH:10]=[N:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[S:19])=[CH:13][CH:12]=2)=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cnc(-c2ccc(NC(=S)[S-])cc2)nc1
Agent: CC[NH+](CC)CC
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCc1cnc(-c2ccc(N=C=S)cc2)nc1
Yield: 81 %

Procedure:
6.77 g of triethylammonium p-(5-butyl-2-pyrimidinyl)phenyldithiocarbamate were largely dissolved in 60 ml of chloroform and 2.5 ml of triethylamine. The mixture was subsequently treated dropwise with 2.00 ml of methyl chloroformate within 5 minutes while stirring and cooling with an ice bath. The ice bath was removed after 10 minutes. After a further 60 minutes the yellowish solution was washed once with 20 ml of 0.5N hydrochloric acid and three times with 20 ml of water each time, dried over sodium sulphate and concentrated. Chromatography of the residue on 60 g of silica gel with hexane/ethyl acetate (vol. 95:5) gave 3.65 g of p-(5-butyl-2-pyrimidinyl)phenyl isothiocyanate which was recrystallized twice from hexane for further purification. Yield 3.17 g; m.p. (C--S) 60.8° C., cl.p. (S--I) 77.8° C.
Reaction SMILES: C[C:2]1[C:7]2[C:8](=[O:17])[N:9]([CH2:13][C:14]([O-:16])=[O:15])[S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:18][O-].[Na+].Cl>CN(C=O)C.O>[OH:17][C:8]1[C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[S:10](=[O:12])(=[O:11])[NH:9][C:13]=1[C:14]([O:16][CH3:18])=[O:15]
Reactant: Cc1cccc2c1C(=O)N(CC(=O)[O-])S2(=O)=O
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1
Temperature: 10 °C
Reaction time: 0.5 h

Procedure:
In a nitrogen atmosphere, a solution of 30 grams (0.117 moles) of methyl-2,3-dihydro-3-oxo-1,2-benzisothiazoline-2-acetate 1,1-dioxide in 50 ml DMF is added, with stirring, to a suspension of 18.9 grams (0.351 moles) of sodium methoxide in 100 ml DMF over a period of about 5 minutes and the internal temperature is maintained at 15°-30° C. by means of an ice bath. The stirring is continued for 30 minutes at about 30° C. after the completion of the addition. With external cooling, a solution of 35 ml concentrated HCl in 600 ml of water is added, maintaining the internal temperature below 35° C. After this addition, the mixture is cooled to 10° C. and filtered. The filter cake is washed thoroughly with water and the product is dried. Yield is 23.5 grams (78.2%) m.p. 173°-175° C. The total addition and stirring time prior to acidification should be less than 1 hour. For example, if the addition should take 30 minutes the batch should be stirred only an additional 15-20 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[Cl:28][C:29]1[CH:38]=[C:37]2[C:32]([NH:33][CH2:34][CH2:35][N:36]2[CH:39]2[CH2:41][CH2:40]2)=[CH:31][C:30]=1[F:42]>CCCCCCC.C(OCC)(=O)C>[Cl:28][C:29]1[CH:38]=[C:37]2[C:32](=[CH:31][C:30]=1[F:42])[N:33]([C:11]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[O:4][C:3]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:2]=1[Cl:1])=[O:12])[CH2:34][CH2:35][N:36]2[CH:39]1[CH2:41][CH2:40]1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: Fc1cc2c(cc1Cl)N(C1CC1)CCN2
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CC2)c2cc(Cl)c(F)cc21

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 7-chloro-1-cyclopropyl-6-fluoro-1,2,3,4-tetrahydro-quinoxaline and using a gradient of n-heptane:ethyl acetate (100:0 to 0:100) for the chromatographic purification. Light yellow solid (19%). MS (ESI): m/z=494.041 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(C(=O)O)cc1-c1ccnn1C
Yield: 75 %

Procedure:
A solution of methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (94 mg, 0.4 mmol) in 6N sodium hydroxide (0.67 ml, 4 mmol) and tetrahydrofuran (4 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜3 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording the desired product (67 mg, 0.3 mmol, 75% yield) as a yellow oil: LC-MS (ES) m/e 223 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH2:16]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS([Cl:22])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:22][CH2:16][C:10]1[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1ccc(F)cc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(CCl)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of the product from step (iii) (1.06 g), methane sulphonyl chloride (0.351 ml) and triethylamine (0.636 ml) in DCM (20 ml) was stirred at RT for 2 h. The mixture was partitioned between water/DCM, the organics separated, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with isohexane/DCM 1:1, yield 0.7 g.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([O:26]CC)=O)=[CH:19][CH:18]=3)[CH:8]=2)=[CH:4][CH:3]=1.[NH3:29]>CO>[ClH:1].[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([NH2:29])=[O:26])=[CH:21][CH:22]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: N
Reactant: CCOC(=O)Cc1ccc(Nc2cc(-c3ccc(Cl)s3)nc3c2CCC3)cc1
Solvent: CO
Product: Cl
Product: NC(=O)Cc1ccc(Nc2cc(-c3ccc(Cl)s3)nc3c2CCC3)cc1
Yield: 24 %

Procedure:
Following general procedure C, ethyl 2-(4-((2-(5-chlorothiophen-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate (0.11 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL), followed by formation of the hydrochloride salt to afford the title compound (0.011 g, 24% over two steps) as a light yellow solid. MW=420.36. 1H NMR (DMSO-d6, 500 MHz) δ 14.09 (s, 1H), 9.64 (s, 1H), 7.74 (s, 1H), 7.51 (s, 1H), 7.36 (d, J=8.5 Hz, 2H), 7.30-7.27 (m, 3H), 6.96-6.86 (m, 2H), 3.42 (s, 2H), 3.14-3.05 (m, 2H), 2.89-2.82 (m, 2H), 2.23-2.13 (m, 2H); APCI MS m/z 384 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH2:11])=[N:3]1.[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].[OH-].[Na+].[ClH:21].[CH2:22]([OH:24])[CH3:23]>C1(C)C=CC=CC=1.ClCCl>[ClH:21].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][C:22]([CH:23]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:12][CH2:13]2)=[O:24])=[N:3]1
Reactant: Cn1nc(N)c2ccccc21
Reactant: CCO
Reactant: CCN(CC)CC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cn1nc(NC(=O)C2CCN(CCc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product of Example 5b) (1.68 g; 0.006 mol) was added to a solution of 1-methyl-1H-3-indazoleamine (0.86 g; 0.006 mol), prepared as described in the Journal of Heterocyclic Chemistry 1979 (16), 783-784, and of triethylamine (2.4 ml; 0.018 mol) in toluene (20 ml). The reaction mixture was stirred at room temperature for 18 h and then the solvent was removed by evaporation at reduced pressure. The residue thus obtained was taken up with 1N NaOH and dichloromethane and transferred to a separatory funnel. The organic phase was separated, dried over Na2SO4 and the solvent was removed by evaporation at reduced pressure. The product thus obtained was transformed into the corresponding hydrochloride by dissolution in ethanol, addition of hydrogen chloride in ethanol and recrystallization from ethanol, to give the desired salt (1.6 g).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:6]2[N:5]=1)=O.[CH2:21]1[N:26]([C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22]1.C(N(CC)C(C)C)(C)C.COCC(O)C>>[N:26]1([C:27]2[CH:28]=[CH:29][C:30]([NH:33][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([CH2:13][NH:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[N:6]4[N:5]=3)=[CH:31][CH:32]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)c1ncc2ccc(CNc3ccccc3)n2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: c1ccc(NCc2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Yield: 30.5 %

Procedure:
(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-phenyl-amine (40.0 mg, 0.140 mmol), 4-(4-morpholino)aniline (49.8 mg, 0.279 mmol) and N,N-Diisopropylethylamine (0.0730 mL, 0.419 mmol) were dissolved in 1-Methoxy-2-propanol (0.50 mL, 5.1 mmol) and the reaction was irradiated at 300 watts, 200° C. for 20 minutes or longer depending on HPLC monitoring. The reaction was then reduced under nitrogen. The crude reaction mixture was purified via Gilson reverse phase chromatography. Combined fractions were lyophilized to afford 17.12 mg of (4-Morpholin-4-yl-phenyl)-(7-phenylaminomethyl-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-amine as a TFA salt. (M+H)=401.16. 1H NMR (400 MHz, DMSO, d6) δ 9.32 (s, 1H), 8.87 (s, 1H), 7.72 (d, 2H, J=8.29 Hz), 7.09 (t, 2H, J=7.32 Hz), 6.97 (m, 2H), 6.76 (m, 1H), 6.67 (m, 3H), 6.60 (t, 1H, J=7.32 Hz), 4.59 (s, 2H), 3.77 (m, 4H), 3.12 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:10][C:9](O[Si](C)(C)C)=[C:8](O[Si](C)(C)C)[CH2:7][C:6]=1[C:21]([O:23][CH3:24])=[O:22])=[O:4].C(O)(=O)C(C)(C)C.[CH3:32][O:33][C:34]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:35]=1[NH2:36].[NH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C.O.C(O)C>[CH3:1][O:2][C:3](=[O:4])[C:5]1[C:6](=[CH:7][C:8]([NH:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:9]([NH:36][C:35]2[CH:37]=[CH:38][C:39]([O:41][CH3:42])=[CH:40][C:34]=2[O:33][CH3:32])[CH:10]=1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COc1ccc(N)c(OC)c1
Reactant: COC(=O)C1=C(C(=O)OC)CC(O[Si](C)(C)C)=C(O[Si](C)(C)C)C1
Reactant: Nc1ccccc1
Agent: CC(C)(C)C(=O)O
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Nc2ccccc2)c(Nc2ccc(OC)cc2OC)cc1C(=O)OC

Procedure:
A solution of 1.31 g (3 mmol) 4,5-Bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1a), 306 mg (3 mmol) pivalic acid and 1 ml of DMF is heated under argon to 120° and a solution of 460 mg (3 mmol) 2,4-dimethoxy-anilin in 1 ml of DMF is added within 5 minutes. The reaction mixture is heated at 120° for 10 minutes, cooled, diluted with water and extracted with ethyl acetate. The organic phase is washed in succession with 1N HCl water, saturated Na2CO3, water and brine, dried with magnesium sulfate and concentrated by evaporation. The evaporation residue, a brown oil, 402 mg (3.9 mmol) pivalic acid and 2 ml of ethanol are heated to reflux and a solution of 358 μl (3.9 mmol) of aniline in 3 ml of ethanol is added dropwise. The reaction mixture is heated to reflux for 15 hours, cooled, diluted with water and extracted with ethyl acetate. The organic phase is washed in succession with 1N HCl, water, saturated Na2CO3, water and bring, dried with magnesium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with ethyl acetate/hexane 1:2 and the product fractions are concentrated by evaporation. This way, in the first product fractions 4-anilino-5-(2,4-dimethoxy-anilino)-phthalic acid dimethyl ester is obtained in the form of a yellow oil: FAB-MS: 437 [M+ +H]. The evaporation residue of the product fractions following thereafter is recrystallized, and 4,5-bis-(2,4-dimethoxy-anilino)-phthalic acid dimethyl ester is obtained in the form of a yellow foam: FAB-MS: 497 [M+ +H].
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=2[N:3]=1.[CH3:32][C:33]1[N:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)[C:6](=[O:30])[N:5]([CH3:31])[C:4]=3[N:3]=[C:2]2[O:39][C:36]2[CH:37]=[N:38][C:33]([CH3:32])=[CH:34][CH:35]=2)=[CH:13][CH:14]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2nc3c(c(=O)n(CCCOC4CCCCO4)c(=O)n3C)n2Cc2ccc(Cl)cc2)cn1
Temperature: 85 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (100 mg, 0.195 mmol, intermediate 14) in DMF (5 mL) was added 6-methylpyridin-3-ol (24 mg, 0.22 mmol) followed by potassium carbonate (76 mg, 0.55 mmol) and the mixture was stirred at 85° C. for 3 h. The mixture was cooled and partitioned between ethyl acetate and brine. The layers were separated and the organic layer was washed with saturated aqueous ammonium chloride, dried and concentrated to give 7-(4-chlorobenzyl)-3-methyl-8-(6-methylpyridin-3-yloxy)-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-1H-purine-2,6(3H,7H)-dione (79 mg, 75% yield) as yellow solid. LCMS retention time 2.297 min; LCMS MH+-THP 456.