Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]2[C:22]([Cl:23])=[C:21]3[C:16]([CH:17]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:18][CH2:19][O:20]3)=[CH:15][C:14]=2[Cl:29])=[CH:10][CH:9]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:29][C:14]1[CH:15]=[C:16]2[C:21](=[C:22]([Cl:23])[C:13]=1[O:12][C:11]1[CH:30]=[CH:31][C:8]([C:6]([OH:7])=[O:5])=[CH:9][CH:10]=1)[O:20][CH2:19][CH2:18][CH:17]2[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)OC(C)(C)C)cc1)c2Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CCOc2c1cc(Cl)c(Oc1ccc(C(=O)O)cc1)c2Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.6 %

Procedure:
Ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6,8-dichlorochroman-4-carboxylate (45.1 g, 96.5 mmol) was dissolved in dichloromethane (500 ml). Trifluoroacetic acid (100 ml) was added slowly to the solution. The mixture was stirred for 2 hours at ambient temperature. The crude mixture was concentrated and the residue was dissolved in EtOAc (500 ml). The EtOAc solution was washed with saturated NaHCO3 (3×100 ml) and brine (250 ml), dried over MgSO4, filtered, and concentrated to provide 40.3 g of the title compound as a light brown solid (102%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][C:13]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])C1C=CC=CC=1>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:20]([C:19]1[C:13]2[CH2:14][CH:15]([CH2:17][OH:18])[O:16][C:12]=2[CH:11]=[CH:10][C:9]=1[OH:8])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1c(O)ccc2c1CC(CO)O2
Reaction time: 48 h
Yield: 87.2 %

Procedure:
5-Benzyloxy-4-tert-butyl-2-formylbenzofuran (5.0 g, 16 mmol) was dissolved in a 25:1 mixed solution (260 ml) of ethyl acetate and acetic acid. After adding 10% Pd on carbon (5.0 g), the solution was stirred under a hydrogen atmosphere for 48 h. After filtering off the Pd on carbon, the filtrate was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and concentrated. The concentrate was subjected to silica gel chromatography and eluted with a solvent system consisting of a 4:1 mixture of hexane and ethyl acetate to afford 4-tert-butyl-5-hydroxy-2-hydroxymethyl-2,3-dihydrobenzofuran [3.1 g (yield, 87%)] as a colorless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[N+:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:11])=[O:10].Cl>C(Cl)Cl>[C:5]([C:21]1[CH:20]=[CH:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N+:9]([O-:11])=[O:10])=[CH:23][CH:22]=1)(=[O:7])[CH3:6]
Reactant: O=[N+]([O-])c1ccccc1-c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1

Procedure:
A suspension of 96.0 g. of aluminum chloride and 135 ml. of methylene chloride is stirred and treated with a mixture of 60 ml. of methylene chloride, 63 ml. of acetyl chloride, and 77.4 g. of 2-nitrobiphenyl. The mixture is heated at reflux for three hours and cautiously poured into 1200 g. of ice and 900 ml. of concentrated hydrochloric acid. The mixture is extracted with methylene chloride. The extract is washed with water and aqueous sodium bicarbonate, dried (Na2SO4), and the solvent removed to give a dark oil. This is stirred with 200 ml. of ether and the resulting solid recovered and washed with 1:1 ether:Skellysolve B; yield 53.50 g., m.p. 106°-109°. For analysis a sample is recrystallized from ether; m.p. 108°-111°.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH2:10][N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[CH:19][C:18]4=[O:27])[CH2:13][CH2:12]3)[C:7]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:6][C:5]=2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([C:4]2[CH:9]=[C:8]([CH2:10][N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][C:18]4=[O:27])[CH2:13][CH2:12]3)[C:7]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:6][C:5]=2[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccn(C2CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)cc3OC(C)C)CC2)c(=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1cc(-c2ccc(F)cc2)c(C2CC2)cc1CN1CCC(n2ccc(C(=O)O)cc2=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
A mixed solution of methyl 1-(1-((2-cyclopropyl-4′-fluoro-5-isopropoxybiphenyl-4-yl)methyl)piperidin-4-yl)-2-oxo-1,2-dihydropyridine-4-carboxylate (103 mg), a 1 M aqueous sodium hydroxide solution (1 mL), and ethanol (2 mL) was stirred at 70 C for 1 hour. The obtained reaction solution was neutralized with 1 M hydrochloric acid and, in this state, stirred at room temperature for 3 hours. The resulting solid was collected by filtration and recrystallized (ethyl acetate) to obtain the title compound (70.3 mg).
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].O[C:6]([C:9]1[CH:14]=[C:13]([CH:15]([C:20]([CH3:23])([CH3:22])[CH3:21])[O:16][SiH:17]([CH3:19])[CH3:18])[CH:12]=[C:11]([CH:24](C(C)(C)C)[O:25][SiH](C)C)[CH:10]=1)([CH3:8])[CH3:7]>ClCCCl.[I-].[Zn+2].[I-]>[C:1]([O:4][C:6]([C:9]1[CH:10]=[C:11]([CH2:24][OH:25])[CH:12]=[C:13]([CH:15]([C:20]([CH3:22])([CH3:21])[CH3:23])[O:16][SiH:17]([CH3:19])[CH3:18])[CH:14]=1)([CH3:8])[CH3:7])(=[S:3])[CH3:2]
Reactant: C[SiH](C)OC(c1cc(C(O[SiH](C)C)C(C)(C)C)cc(C(C)(C)O)c1)C(C)(C)C
Reactant: CC(O)=S
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCCl
Product: CC(=S)OC(C)(C)c1cc(CO)cc(C(O[SiH](C)C)C(C)(C)C)c1
Temperature: 50 °C

Procedure:
404 μl of thioacetic acid and 376 mg of zinc iodide are added to 1 g of 1-(1-hydroxy-1-methylethyl)-3,5-bis[(tert-butyl)dimethylsilanyloxymethyl]benzene in solution in 4.7 ml of 1,2-dichloroethane. The mixture is heated at 50° C. for 40 min. After returning to AT, the salts are removed by filtration, the organic phase is concentrated under RP and the residue is purified by flash chromatography on silica (Biotage 40+M) using a gradient from 0 to 30% AcOEt in heptane. 248 mg of 1-[3-[(tert-butyl)dimethylsilanyloxymethyl]-5-(hydroxymethyl)phenyl]-1-methylethyl thioacetate are thus obtained.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][C:5]=1[O:15][CH2:16][CH3:17])=[N+:2]=[N-:3].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[C:19]#[CH:20]>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:5]1[CH:6]=[C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])[CH:13]=[CH:14][C:4]=1[N:1]1[CH:20]=[C:19]([C:18]([O:22][CH2:23][CH3:24])=[O:21])[N:3]=[N:2]1)[CH3:17]
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])c(OCC)c1
Reactant: C#CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCNC(=O)c1ccc(-n2cc(C(=O)OCC)nn2)c(OCC)c1
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 4-azido-3-ethoxy-N-ethylbenzamide (0.70 g) obtained in Example 131d) in toluene (30 ml) was added ethyl propiolate (0.61 ml), and the mixture was heated under reflux overnight under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1 to ethyl acetate) to give the title compound as a white powder (0.59 g, 60%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:19]=[N:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:28]([NH:32][S:33]([C:36]1[S:37][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:39][CH:40]=1)(=[O:35])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([NH:32][S:33]([C:36]1[S:37][C:38]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[C:10]([C:18]4[CH:19]=[N:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=4)[N:9]=3)[CH:3]=2)=[CH:39][CH:40]=1)(=[O:34])=[O:35])([CH3:31])([CH3:29])[CH3:30]
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)cn1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)s1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)nc4)cc(C(F)(F)F)n3)c2)s1

Procedure:
N-tert-Butyl-5-{3-[4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide was prepared from 2-(3-bromo-phenyl)-4-trifluoromethyl-6-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example B.2) (0.448 g, 1.0 mmol) and N-tert-butyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-sulfonamide (example C.1) (0.414 g, 1.2 mmol) according to the general procedure III. Obtained as an off-white solid (0.45 g), which was subsequently deprotected.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=2)[CH:26]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=3)[CH:26]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN(c3ccc(SC)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[[4-(methylthio)phenyl]amino]piperidine (644 mg) and 4-chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (588 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C@@H:21]([N:23](C(OC(C)(C)C)=O)[CH2:24][CH2:25][C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([NH:34][C:35]([NH:37][C:38]4[CH:43]=[N:42][C:41]([C:44]#[N:45])=[CH:40][N:39]=4)=[O:36])=[CH:28][C:27]=3[Cl:46])[CH3:22])=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(OCC)C>CCOC(C)=O>[ClH:46].[ClH:1].[Cl:46][C:27]1[C:26]([CH2:25][CH2:24][NH:23][C@H:21]([C:18]2[CH:19]=[CH:20][C:15]([N:12]3[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]3)=[CH:16][CH:17]=2)[CH3:22])=[CH:31][C:30]([O:32][CH3:33])=[C:29]([NH:34][C:35]([NH:37][C:38]2[CH:43]=[N:42][C:41]([C:44]#[N:45])=[CH:40][N:39]=2)=[O:36])[CH:28]=1
Reactant: COc1cc(CCN(C(=O)OC(C)(C)C)[C@@H](C)c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1cc(CCN[C@@H](C)c2ccc(N3CCNCC3)cc2)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
A 4N HCl solution in EtOAc (18 mL) was added slowly to a stirred solution of 4-(4-{(S)-1-[tert-butoxycarbonyl-(2-{2-chloro-4-[3-(5-cyano-pyrazin-2-yl)-ureido]-5-methoxy-phenyl}-ethyl)-amino]ethyl}-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.1 g) in EtOAc (100 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred for 8 hours. Diethyl ether (50 mL) was added and stirring continued for 15 minutes. The supernatant was decanted and the isolated solid triturated again with diethyl ether (50 mL). The solid was dried under reduced pressure then dissolved in methanol and precipitated back out of solution using diethyl ether. The isolated solid was further triturated with diethyl ether then dried under reduced pressure. The obtained solid was triturated with ethyl acetate, acetone, ethanol followed by diethyl ether and dried at reduced pressure to give the title compound (0.025 g, 34%) as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:15]1N=CN(C(N2C=NC=C2)=O)C=1.CO>C1COCC1>[CH3:15][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:9]=[CH:10][C:2]=1[I:1]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1I
Temperature: 70 °C
Yield: 86 %

Procedure:
To 30.7 mmol 2-Iodo-5-methanesulfonyl-benzoic acid in 250 ml THF was added 33.7 mmol CDI and the mixture was heated at 70° C. for 1 h. Methanol (12.4 ml) was then added and the mixture was heated at 70° C. for a further 1 h. The mixture was then cooled to room temperature and concentrated in vacuo. The residue was chromatographed over SiO2 (ethyl acetate/dichloromethane 4:1) to afford the title compound (86%) as a white crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@@H:26]([OH:28])[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH2:16][C:15]([F:37])([F:36])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:39]1[CH:48]=[N:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>ClCCl.O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:39]3[CH:48]=[N:47][C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=3)[CH2:27][C@H:21]2[C:20](=[O:29])[NH:19][C@:18]2([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:30][C@H:17]2[CH2:16][C:15]([F:36])([F:37])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@@H](O)C[C@H]1C(=O)N2
Reactant: Oc1cnc2ccccc2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)[C@@]12C[C@H]1CC(F)(F)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3cnc4ccccc4n3)C[C@H]1C(=O)N2
Temperature: 0 °C
Reaction time: 20 h
Yield: 61.5 %

Procedure:
To (2S,6S,13aS,14aR,16aS)-ethyl 6-(tert-butoxycarbonylamino)-12,12-difluoro-2-hydroxy-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 1e, 19 mg, 0.036 mmol) was added 2-hydroxyquinoxaline (8.06 mg, 0.055 mmol) followed by tetrahydrofuran (357 μl). Triphenylphosphine (15.23 mg, 0.058 mmol) was added and the solution was cooled to 0° C. DIAD (10.5 μl, 0.054 mmol) was added dropwise and the mixture was stirred at 0° C. for 15 min and at room temperature for 20 hr. The reaction mixture was diluted with dichloromethane and filtered through Celite. The solvent was evaporated under reduced pressure and the residue was purified by prep-TLC (dichloromethane/ethyl acetate=3/2, 2×) to provide the title compound (2R,6S,13aS,14aR,16aS)-ethyl 6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxo-2-(quinoxalin-2-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (14.6 mg, 61.8% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([C:13]2[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=O)=[C:3]1[CH3:25].[CH3:26][N:27]([CH3:37])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]([CH3:36])[CH3:35])[CH:29]=1>C(OC(=O)C)(=O)C>[CH3:35][N:34]([CH3:36])[C:30]1[CH:29]=[C:28]([N:27]([CH3:37])[CH3:26])[CH:33]=[CH:32][C:31]=1[C:11]1([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]=2[CH3:25])[C:13]2[C:14](=[CH:18][C:19]([N:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[C:15](=[O:16])[O:17]1
Reactant: CN(C)c1cccc(N(C)C)c1
Reactant: Cc1c(C(=O)c2ccc(N(C)C)cc2C(=O)O)c2ccccc2n1C
Solvent: CC(=O)OC(C)=O
Product: Cc1c(C2(c3ccc(N(C)C)cc3N(C)C)OC(=O)c3cc(N(C)C)ccc32)c2ccccc2n1C

Procedure:
A mixture of 0.34 g (0.001 mole) of 2-[(1,2-dimethyl-3-indolyl)carbonyl]-5-dimethylaminobenzoic acid prepared as described in Example 1 of U.S. Pat. No. 3,540,910 was interacted with 0.16 g (0.001 mole) of N,N,N',N'-tetramethyl-m-phenylenediamine in 5 ml of acetic anhydride in a similar manner to the procedure described in Example 1, part C hereinabove to obtain 3-[2,4-bis(dimethylamino)phenyl]-3-(1,2-dimethyl-3-indolyl)-6-dimethylaminophthalide (Formula III: R0 =R1 =R3 =Y1 =H; R2 =N(CH3)2 ; R=R5 =R6 =CH3 ; R4 =N(CH3)2) which melts over the range of 146°-152° C. A significant infrared absorption maximum appeared at 1760 cm-1 (C=O; s). A toluene solution of this product spotted on silica gel developed an intense grape-red-colored image.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C@@H:13]2[CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:12]2[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:24]([F:27])([F:26])[F:25])[C:6]=2[NH:5]1.Cl.F[C:30](F)(F)C1C2NC(=O)[C@@H]3CNC[C@@H]3C=2C=CC=1.IC>C1COCC1>[CH3:30][N:5]1[C:6]2[C:7]([C:24]([F:27])([F:25])[F:26])=[CH:8][CH:9]=[CH:10][C:11]=2[CH:12]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:14][CH:13]2[C:4]1=[O:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2c3cccc(C(F)(F)F)c3NC(=O)[C@@H]2C1
Reactant: O=C1Nc2c(cccc2C(F)(F)F)[C@H]2CNC[C@@H]12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)C2CN(C(=O)OC(C)(C)C)CC2c2cccc(C(F)(F)F)c21
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (40 mg of 60% dispersion in mineral oil, 1.0 mmol) in 5 mL of THF was added (±)-cis-tert-butyl 4-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate, the intermediate from Example 3 (80 mg, 0.22 mmol) in 3 mL of THF. The mixture was stirred for 30 min and then there was added iodomethane (0.10 mL, 1.6 mmol) and the resulting mixture was allowed to stir at ambient temperature for 18 h. The reaction was filtered through a pad of silica gel and concentrated. The residue was purified by chromatography (ISCO, elution with 1-10% EtOAc in hexane) to afford tert-butyl 5-methyl-4-oxo-6-(trifluoromethyl)-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate. To this material in 4 mL of hexane was added HCl (4 mL of a 4N solution in 1,4-dioxane, 16 mmol) and the resulting solution was allowed to stir at ambient temperature overnight. The solvents were removed in vacuo and the residue was purified by HPLC (C18 reverse phase, elution with gradient H2O/CH3CN+0.5% TFA). Pure fractions were combined and concentrated. The residue was partitioned between aq NH4OH and CHCl3, the organics were washed with brine, dried (K2CO3) and concentrated to afford 12 mg (60%) of the title compound of Example 4. 1H NMR (CDCl3): δ 7.60 (d, 1H), 7.42 (d, 1H), 7.18 (t, 1H), 3.81 (dd, 1H), 3.39 (s, 3H), 3.37-30 (m, 2H), 3.22-3.18 (m, 1H), 3.05-2.98 (m, 1H), 2.81 (t, 1H). LRMS (ESI): 271.16 (M+H)+.
Reaction SMILES: [C@H:1]12[CH2:24][C@H:4]([N:5]([C:7]3[N:12]=[C:11](S(C)(=O)=O)[N:10]=[C:9]([C:17]4[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=4)[CH:8]=3)[CH2:6]1)[CH2:3][O:2]2.C(=O)([O-])[O-].[K+].[K+].Cl.[CH:32]12[CH2:37][CH:35]([CH2:36]1)[CH2:34][NH:33]2>CS(C)=O>[CH:32]12[CH2:37][CH:35]([CH2:36]1)[CH2:34][N:33]2[C:11]1[N:10]=[C:9]([C:17]2[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=2)[CH:8]=[C:7]([N:5]2[CH2:6][C@@H:1]3[CH2:24][C@H:4]2[CH2:3][O:2]3)[N:12]=1
Reactant: C1NC2CC1C2
Reactant: CS(=O)(=O)c1nc(-c2cnc(N)nc2)cc(N2C[C@@H]3C[C@H]2CO3)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Nc1ncc(-c2cc(N3C[C@@H]4C[C@H]3CO4)nc(N3CC4CC3C4)n2)cn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 57.4 %

Procedure:
To the mixture of 6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-(methylsulfonyl)-[4,5′-bipyrimidin]-2′-amine (380 mg, 1.09 mmol) and potassium carbonate (754 mg, 5.45 mmol) in DMSO (5 mL) was added 2-azabicyclo[2.1.1]hexane hydrochloride (326 mg, 2.73 mmol). The mixture was stirred at 100° C. for 5 h. After removal of the solvent, the residue was purified by Prep-HPLC (formic acid) to afford 2-(2-azabicyclo[2.1.1]hexan-2-yl)-6-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-[4,5′-bipyrimidin]-2′-amine (220 mg, 57% yield). LCMS (ESI): [MH]+=352.1; 1H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 2H), 7.00 (s, 2H), 6.30-6.10 (m, 1H), 5.10-4.90 (m, 1H), 4.83 (d, J=6.4 Hz, 1H), 4.70-4.64 (m, 1H), 3.78-3.76 (m, 1H), 3.66-3.64 (m, 1H), 3.45-3.38 (m, 4H), 2.89-2.87 (m, 1H), 1.93-1.86 (m, 4H), 1.32-1.31 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)[C:8]([Cl:34])=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[CH2:36]([O:38][C:39](=[O:43])[CH2:40][CH2:41][NH2:42])[CH3:37]>>[CH2:36]([O:38][C:39](=[O:43])[CH2:40][CH2:41][NH:42][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:34])[C:9]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][N:15]=[C:14]([CH3:33])[CH:13]=2)=[CH:10][C:2]=1[Cl:1])[CH3:37]
Reactant: Cc1cc(Oc2cc(Cl)c(C(=O)O)cc2Cl)c(C(=O)N2CCN(C3CC3)c3ccccc32)cn1
Reactant: CCOC(=O)CCN
Agent: Cl
Product: CCOC(=O)CCNC(=O)c1cc(Cl)c(Oc2cc(C)ncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 29, from 2,5-dichloro-4-[5-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-2-methyl-pyridin-4-yloxy]-benzoic acid and beta-alanine ethylester hydrochloride (commercially available, CAS RN 4244-84-2). Colorless foam (73%). MS (ESI): m/z=597.169 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:20]=[C:21]([C:25]([C:27]2[C:35]3[CH:34]=[N:33][CH:32]=[N:31][C:30]=3[N:29]([CH:36]([CH3:38])[CH3:37])[CH:28]=2)=[O:26])[CH:22]=[N:23][CH:24]=1>>[CH:36]([N:29]1[C:30]2[N:31]=[CH:32][N:33]=[CH:34][C:35]=2[C:27]([C:25]([C:21]2[CH:20]=[C:19]([NH:18][C:8](=[O:10])[CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[CH:24]=[N:23][CH:22]=2)=[O:26])=[CH:28]1)([CH3:38])[CH3:37]
Reactant: O=C(O)C(OC1CCCCO1)c1ccccc1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)C(OC3CCCCO3)c3ccccc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 1 using phenyl-[(tetrahydro-pyran-2-yloxy)]-acetic acid (Preparation 236) and (5-Amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 95) to afford the title compound as a yellow solid in 68% yield, 60 mg.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([N:11]1[CH2:15][C:14](=[O:16])[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[C:12]1=[O:25])[C:4]([O:6]C(C)(C)C)=[O:5].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([N:11]1[CH2:15][C:14](=[O:16])[N:13]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)[C:12]1=[O:25])[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(CN2C(=O)CN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(CN2C(=O)CN([C@H](C(=O)O)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 109.6 %

Procedure:
A solution containing the product from Example 46D (0.151 g, 0.403 mmol) in dichloromethane (3 mL) was treated with trifluoracetic acid (3 mL), and the mixture was stirred at 25° C. for 16 hours. The solvent was concentrated and the product was purified by reversed phase chromatography on a C18 column eluting with a gradient starting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.141 g, 81% yield) as the trifluoroacetic acid salt.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH:10]([CH2:16][NH2:17])[O:9][CH2:8][CH2:7]2.[CH2:18]=O.Cl>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH:10]([CH2:16][NH:17][CH3:18])[O:9][CH2:8][CH2:7]2
Reactant: COc1cc2c(cc1OC)C(CN)OCC2
Reactant: C=O
Agent: Cl
Product: CNCC1OCCc2cc(OC)c(OC)cc21
Reaction time: 0.33 h

Procedure:
A mixture of 6,7-dimethoxy-1-isochromanmethylamine hydrochloride (6.0 g), described in Example 1, and 37% formaldehyde solution (12 ml) is heated on the steam bath under a reflux condenser for 20 min. A further 6 ml formaldehyde solution is added and heating is continued for 20 min. The solution is evaporated to dryness and the residue is crystallized from isopropanol to give the hydrochloric acid addition salt of the title compound, m.p. 254°-256° C. (dec.).