Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[NH2:9][CH2:10][CH:11]1[CH2:13][CH2:12]1>>[CH:11]1([CH2:10][NH:9][C:2]2[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=2)[CH2:13][CH2:12]1
Reactant: NCC1CC1
Reactant: Clc1ccc(I)cn1
Product: Ic1ccc(NCC2CC2)nc1
Yield: 77 %

Procedure:
A solution of 500 mg (2.09 mmol) of 2-chloro-5-iodo pyridine in 1.64 g (23.1 mmol) of aminomethylcyclopropane was heated to 100° C. in a sealed tube for 48 h. The mixture was then concentrated, dissolved in EtOAc, washes with water and brine, dried with MgSO4, filtered, and concentrated. Recrystallization from hexanes provided 440 mg (1.61 mmol; 77%) of cyclopropylmethyl-(5-iodo-pyridin-2-yl)-amine. ESI MS m/z 275 [C9H11 IN2+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([C:15]#[N:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]#[N:16]
Reactant: Clc1ccccn1
Reactant: N#CCc1ccccc1
Product: N#CC(c1ccccc1)c1ccccn1

Procedure:
The dl-threo-ritalinic acid used in step (i) may be prepared through multi-step process in which 2-chloropyridine and benzyl cyanide initially are coupled to form α-pyrid-2-yl-phenylacetonitrile. The resulting α-pyridyl-2-ylphenylacetonitrile then is hydrated in the presence of acid to yield α-pyrid-2-ylphenylacetamide which in turn is catalytically hydrogenated to yield α-piperid-2-ylphenylacetamide and then is hydrolysed and epimerized to dl-threo-ritalinic acid. The solvent used in the step (i) along with water may be selected from organic solvents. The solvent used to dissolve ester of tartaric acid may be selected from organic solvents. Conventional esters of tartaric acid used, may include dibenzoyltartaric acid and ditoluoyltartaric acid, the preferred one being (+)-dibenzoyltartaric acid of 0.2 to 1.6 eq to that of ritalinic acid, preferably, 1.06 eq in a solvent, preferably methanol adding at a temperature ranging preferably below 50° C., for a period preferably ranging from 5 min to 5 h. Heating the mass in step (ii) at reflux temperature preferably in 1 h to 2 h and filtering the mass through hyflo bed. The filtrate is cooled to a temperature preferably 20° C. to 25° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH2:9][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH2:9][C@H:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:11]([N:13]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)[CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(C=O)c2)NC(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(N(C)C(=O)[C@H](Cc2cccc(CO)c2)NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(S)-tert-Butyl 3-(3-formylphenyl)-1-((4-methoxyphenyl)(methyl)amino)-1-oxopropan-2-ylcarbamate (2.71 g, 6.58 mmole) was dissolved in methanol (66 ml). The solution was cooled to 0° C. in an ice bath. NaBH4 was added to the cooled solution and the resulting reaction mixture was stirred for 30 min. The reaction was confirmed to be complete by tlc and HPLC/MS. The reaction was concentrated under reduced pressure and then partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×). The combined organics were washed with H2O (2×) and brine (2×). The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by flash column using EtOAc/hexanes. Yield=1.3 g. MS (m/z) 415 [M+14]+.
Reaction SMILES: P(=O)(O)(O)O.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2(O)[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1.[OH-].[NH4+]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COc1cccc(C2(O)CCN(C)CC2)c1
Agent: O=P(O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(C2=CCN(C)CC2)c1
Yield: 97.5 %

Procedure:
To 4.075 liters of 85% phosphoric acid at 60° C. in a 22 liter flask equipped with a condenser, thermometer, and stirrer was added portionwise 1.015 kg (4.35 mol) of 4-(3-methoxyphenyl)-1-methyl-4-piperidinol via a powder funnel. The reaction mixture was stirred for 3 hours at a temperature between 70° C. and 80° C. whereupon 4 liters of water was added and the temperature of the reaction mixture adjusted to approximately 50° C. The mixture was neutralized to pH 8.5 by the addition of 8.5 liters of 28% ammonium hydroxide while maintaining the temperature of the reaction mixture above 50° C. The resulting aqueous solution was extracted at 60° C. with 1.25 liters of hexane three times. The organic extracts were combined and washed twice with 1 liter of water, once with 0.5 liters of saturated sodium chloride solution and dried over 250 g of anhydrous sodium sulfate. Evaporation of the volatiles under reduced pressure provided 862.5 g of 97.9% pure 1,2,3,6-tetrahydro-4-(3-methoxyphenyl)-1-methylpyridine.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([CH3:37])=[CH:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:24][CH2:25][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([CH3:37])=[CH:29]2)[CH2:27][CH2:28]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: CC1=CC2(CCN(C(=O)c3cnc4c(C(=O)O)cnn4c3NCc3ccccc3)CC2)c2ccccc21
Product: CC1=CC2(CCN(C(=O)c3cnc4c(C(=O)NS(C)(=O)=O)cnn4c3NCc3ccccc3)CC2)c2ccccc21
Yield: 63.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(3-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.130 g, 0.264 mmol) obtained in step 2 and methanesulfonamide (0.126 g, 1.32 mmol), the title compound (0.096 g, 64%) was obtained.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]([CH3:62])[CH2:21][N:22]([S:53]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1)(=[O:55])=[O:54])[C:23]1[CH:40]=[C:39]([C:41]2C=CC=CC=2)[C:38]([C:47]2C=CC=CC=2)=[CH:37][C:24]=1[O:25][CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(=O)([O-])O.[Na+]>C1COCC1>[OH:18][CH2:19][C@H:20]([CH3:62])[CH2:21][N:22]([S:53]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=1)(=[O:55])=[O:54])[C:23]1[CH:40]=[C:39]([CH3:41])[C:38]([CH3:47])=[CH:37][C:24]=1[O:25][CH2:26][C:27]1[CH:28]=[CH:29][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:35][CH:36]=1
Reactant: COC(=O)c1ccc(COc2cc(-c3ccccc3)c(-c3ccccc3)cc2N(C[C@@H](C)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S(=O)(=O)c2ccccn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(COc2cc(C)c(C)cc2N(C[C@@H](C)CO)S(=O)(=O)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
840 mg of methyl 4-[(2-{[(2R)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropyl](pyridin-2-ylsulfonyl)amino}-4,5-diphenylphenoxy)methyl]benzoate was dissolved in 8.40 mL of THF, and 0.554 mL of a 1 M tetrabutyl ammonium fluoride/THF solution was added thereto at room temperature, followed by stirring at room temperature for 2 hours. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40 to 0:100) to obtain 468 mg of methyl 4-[(2-{[(2R)-3-hydroxy-2-methylpropyl](pyridin-2-ylsulfonyl)amino}-4,5-dimethylphenoxy)methyl]benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[C:8](=[O:27])[NH:7][C:6]=2[CH:28]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>N1C=CC=CC=1>[C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH2:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[C:8](=[O:27])[NH:7][C:6]=2[CH:28]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)NC(=O)C(CCCN1CCN(c3ccc(F)cc3)CC1)O2
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)NC(=O)C(CCCN1CCN(c3ccc(F)cc3)CC1)O2
Temperature: 0 °C
Yield: 71.5 %

Procedure:
To a solution of 6-amino-2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-2H-1,4-benzoxazin-3(4H)-one (500 mg) in pyridine (5 ml) was added acetic anhydride (0.18 ml) while stirring. The mixture was stirred at room temperature for further 4 hours, which was then poured into ice-water. Precipitated crystals were collected by filtration, followed by recrystallization from dichloromethane-ethyl acetate to give 397 mg (71.5%) of 6-acetamido-2-{3-[4-(4-fluorophenyl)-1-piperazinyl]propyl}-2H-1,4-benzoxazin-3(4H)-one, m.p. 111°-112° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[NH:8][C:7]2[CH2:9][CH2:10][C:11](=[O:12])[C:6]=2[N:5]=1)[CH3:3].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1.C1(C)C=CC=CC=1.[NH4+].[Cl-]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH-].[Na+]>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:5]2[C:6]3[C:11](=[O:12])[CH2:10][CH2:9][C:7]=3[N:8]=[C:4]2[CH:2]([CH3:1])[CH3:3])=[CH:16][CH:15]=1
Reactant: CC(C)c1nc2c([nH]1)CCC2=O
Reactant: Clc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(=O)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 33.2 %

Procedure:
Tetrabutylammonium bromide (785 mg) was added to a stirred mixture of Intermediate 17 (800 mg), 4-chlorobenzyl bromide (1101 mg) in sodium hydroxide 20% aq. (9 mL) and toluene (20 mL). The RM was stirred at room temp under nitrogen atm. for 1.5 hours. Sat. NH4Cl aq solution (50 mL) was added and the mixture was extracted with EtOAc (2×50 ml). The organics were combined, dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (467 mg). LC/MS MH+ 289, Rt 0.92 min (2 minute run).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[C@@H](O)[C@@H]1NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC2C=CC=CC=2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC([C@@H](N)CCN)=O)CCNC1=O.OS(O)(=O)=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[CH3:113][C:114]([CH3:134])=[CH:115][CH2:116][CH2:117]/[C:118](/[CH3:133])=[CH:119]/[CH2:120][CH2:121]/[C:122](/[CH3:132])=[CH:123]/[CH2:124][S:125][CH2:126][C@H:127]([NH2:131])[C:128]([OH:130])=[O:129]>C(Cl)Cl>[CH3:7][C:4]([CH3:5])([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH3:10])[C:11](=[O:13])[NH:131][C@H:127]([C:128]([OH:130])=[O:129])[CH2:126][S:125][CH2:124]/[CH:123]=[C:122](\[CH3:132])/[CH2:121][CH2:120]/[CH:119]=[C:118](\[CH3:133])/[CH2:117][CH2:116][CH:115]=[C:114]([CH3:134])[CH3:113])[CH3:6]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: CC(C)C[C@@H]1NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CCN)NC(=O)[C@@H](NC(=O)[C@@H](N)CCN)CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a 100 mL round bottom flask, N-Boc-L-alanine (1.0 mmol), coupling reagent (520 mg of PBOP or 380 mg of HATU, 1 mmol) and N,N-diisopropyl-ethyl-amine (650 mg, 5 mmol) were mixed in CH2Cl2 (10 mL). The reaction mixture was stirred at room temperature for 30 minutes. S-trans, trans-farnesyl-L-cysteine (325 mg, 1 mmol) was added to the reaction mixture and stirred at room temperature overnight. CH2Cl2 was removed by rotary evaporation. The resulting residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with an NH4Cl saturated solution (50 mL), dried over Na2SO4, and concentrated to afford a crude mixture. The crude mixture was purified by preparative HPLC (170 mg, 35%) to yield Compound N-3. 1H-NMR (500 MHz, CDCl3): δ 1.37 (bt, 3H), 1.44 (s, 9H), 1.60 (bs, 6H), 1.68 (bs, 6H), 1.99 (t, J=8.2 Hz, 2H), 2.04-2.10 (m, 6H), 2.89 (dd, J=6.3, 13.9 Hz, 1H), 3.01 (dd, J=7.5, 14.1 Hz, 1H), 3.14-3.24 (m, 2H), 4.31-4.39 (m, 1H), 4.74-4.77 (m, 1H), 5.08-5.10 (m, 2H), 5.23 (t, J=7.5 Hz, 1H). 13C-NMR (125 MHz, CDCl3): δ 16.1, 16.2, 17.8, 18.6, 19.1, 25.7, 26.5, 26.7, 28.5, 30.0, 33.0, 33.1, 39.7, 49.7, 49.8, 51.7, 51.8, 51.9, 76.8, 77.0, 77.3, 80.5, 80.7, 119.6, 123.8, 124.3, 131.3, 135.3, 140.1, 155.7, 155.9, 173.0, 173.1; ES-MS: mass calcd for Chemical Formula: C26H44N2O5S 496.7. Found (M+Na) m/z 519.4.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2N=CN=[C:11]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:24])=[CH:18][C:17]=3[F:36])[CH:10]=2)=CC=1.NC1C=CC(OC2C=CN=[C:47]([C:51]([NH2:53])=[O:52])[CH:46]=2)=C(F)C=1>C(Cl)Cl.CN(C=O)C>[C:51]([C:47]1[CH:46]=[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:24])=[CH:18][C:17]=2[F:36])[CH:10]=[CH:9][N:8]=1)(=[O:52])[NH2:53]
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Reactant: NC(=O)c1cc(Oc2ccc(N)cc2F)ccn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Oc2ccc(NC(=O)NC(=O)Cc3ccc(F)cc3)cc2F)ccn1
Reaction time: 17 h
Yield: 68.5 %

Procedure:
A solution of 2-(4-fluorophenyl)acetyl isocyanate (Compound D of Example 11, 0.29 M in toluene, 54.9 mL, 15.9 mmol, 2.1 eq) was added to 4-(4-amino-2-fluorophenoxy)picolinamide (1.86 g, 7.53 mmol, 1.0 eq) in 10/3 DCM/DMF (65 mL) at room temperature and the reaction mixture was stirred for 17 h. The reaction mixture was concentrated in vacuo and the residue redissolved in CHCl3. The organic layer was washed with saturated aqueous NaCl, the organic fraction separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting 1/3 hexane/EtOAc, then to elute product 5% MeOH in CHCl3), and the appropriate fractions concentrated in vacuo to afford the product (2.2 g, 69%) as a solid. 1H NMR (DMSO-d6) δ 11.07 (s, 1H), 10.62 (s, 1H), 8.54 (d, 1H, J=5.60 Hz), 8.16-8.19 (m, 1H), 7.76-7.84 (m, 2H), 7.35-7.49 (m, 5H), 7.16-7.23 (m, 3H), 3.76 (s, 2H); MS (ESI+) m/z 427 (M+H)+. HRMS (ESI+) calcd.: 427.1218. found: 427.1214.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[CH2:17][CH2:16][CH2:15][O:14][C:10]2=[N:11][C:12]=1[CH3:13])(=O)=O.C(N(CC)CC)C.[C:27]([O:30][CH2:31][CH3:32])(=[O:29])C>CN(C)C(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:13][C:12]1[N:11]=[C:10]2[O:14][CH2:15][CH2:16][CH2:17][C:9]2=[N:8][C:7]=1[C:27]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(C)=O
Reactant: Cc1nc2c(nc1OS(=O)(=O)C(F)(F)F)CCCO2
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1nc2c(nc1C)OCCC2
Temperature: 25 °C

Procedure:
A solution of 3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazin-2-yl trifluoromethanesulfonate (298 mg, 1.00 mmol), palladium(II) acetate (11 mg, 0.0490 mmol), bis(diphenylphosphino)ferrocene (55 mg, 0.0992 mmol), and triethylamine (202 mg, 2.00 mmol) in N,N-dimethylacetamide (3.0 mL) was heated at 80° C. for 24 h under carbon monoxide. After being cooled to ambient temperature, the reaction mixture was diluted ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtrated and concentrated in vacuo. The crude was purified by silica gel column chromatography (hexane:ethyl acetate=3:1 to ethyl acetate) to give ethyl 3-methyl-7,8-dihydro-6H-pyrano[2,3-b]pyrazine-2-carboxylate. MS (APCI): m/z 223 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:11][NH:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:23]I>C(O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9](=[O:20])[N:10]([CH3:23])[N:11]=2)=[CH:14][CH:15]=1
Reactant: CI
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2)c1=O
Reaction time: 8 h

Procedure:
To a stirred, room temperature, suspension of 4-benzyl-5-(4-chlorophenyl)-3H-1,2,4-triazol-3-one (10.85 g, 3.797×10-2 mole), 1 molar aqueous NaOH (42 ml, 4.2×10-2 mole), and ethanol (15 ml) was added methyl iodide (3.6 ml, 5.8×10-2 mole). After stirring overnight, the reaction was transferred to a separatory funnel where it was extracted with EtOAc (3x). The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving a yellowish foam. Purification of this foam by a combination of flash chromatography (20% EtOAc/CH2Cl2) and crystallization from cyclohexane afforded colorless crystals 5.92 g (52%), mp 90°-91° C.
Reaction SMILES: [CH2:1]1[N:9]2[CH:4]([NH:5][S:6](=[O:16])(=[O:15])[C:7]3[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:8]=32)[CH2:3][CH2:2]1.[C:17]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)(=[O:19])[CH3:18].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:16]=[S:6]1(=[O:15])[C:7]2[CH:13]=[C:12]([O:14][C:23]3[CH:24]=[CH:25][C:20]([C:17](=[O:19])[CH3:18])=[CH:21][CH:22]=3)[CH:11]=[CH:10][C:8]=2[N:9]2[CH2:1][CH2:2][CH2:3][CH:4]2[NH:5]1
Reactant: O=S1(=O)NC2CCCN2c2ccc(O)cc21
Reactant: CC(=O)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)cc1
Reaction time: 8 h

Procedure:
A suspension composed of 3.0 g (12.48 mmol) of 2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c]-[1,2,4]benzothiadiazin-7-ol 5,5-dioxide, 3.18 g (18.73 mmol) of (4-acetylphenyl)boronic acid, 3.42 g (18.82 mmol) of copper(II) acetate, 3.03 ml (37.15 mmol) of pyridine and about 500 mg of 4 Å molecular sieve in 150 ml of methylene chloride is stirred overnight. The reaction mixture is diluted by adding a further 100 ml of methylene chloride and the suspension is filtered. The filtrate is concentrated and then directly placed on a silica column which is eluted with a CH2Cl2/acetone 99/1 system. The fractions containing the expected product are combined and evaporated, and the residue is taken up in ethyl ether. After filtering off the solid, the title product is recovered in the form of white powder.
Reaction SMILES: C([O:3][C:4](=[O:21])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[NH:16][S:17]([CH3:20])(=[O:19])=[O:18])C>[OH-].[Na+].CCO>[Cl:15][C:10]1[C:11]([O:13][CH3:14])=[CH:12][C:7](/[CH:6]=[CH:5]/[C:4]([OH:21])=[O:3])=[C:8]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:9]=1
Reactant: CCOC(=O)/C=C/c1cc(OC)c(Cl)cc1NS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(/C=C/C(=O)O)c(NS(C)(=O)=O)cc1Cl
Temperature: 0 °C
Yield: 38.8 %

Procedure:
(E)-3-(4Chloro-2-methanesulfonylamino-5-methoxyphenyl)-acrylic acid ethyl ester (320 mg; 0.96 mmol) was refluxed in 2N NaOH/EtOH 1/10 for 10 min. The resulting suspension was cooled to 0° C., filtered, taken up in water and acidified with 2N HCl and extracted with TBME three times. The combined organic phases were dried over Na2SO4 and evaporated to dryness to yield the title compound as yellowish crystals (114 mg; 39%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14](S(C)(=O)=O)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[NH2:31]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:22](=[O:23])[N:21]([CH2:24][CH3:25])[C:12]2[N:13]=[C:14]([NH:31][C:30]3[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:28]([O:27][CH3:26])[CH:29]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(S(C)(=O)=O)nc21
Reactant: COc1ccc(N)cc1OC
Solvent: O
Solvent: CC(=O)O
Product: CCn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(Nc3ccc(OC)c(OC)c3)nc21
Temperature: 160 °C

Procedure:
A mixture of 0.150 g (0.38 mmol) of 6-(2,6-dichlorophenyl)-8-ethyl-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 68 and 0.500 g (3.30 mmol) of 3,4-dimethoxyaniline was heated in a 160° C. oil bath for 5 minutes. The dark blue solution was cooled and dissolved in 2 mL of warm glacial acetic acid. This solution was diluted to 10 mL volume with water to precipitate a solid. The solid was filtered, washed well with water, and dried; wt 0.200 g. Purification was effected by filtration of an ethyl acetate (25 mL) solution through a layer of silica gel and washing the silica gel with ethyl acetate. The filtrate was concentrated to 3 mL volume. The crystals that separated on inducement were filtered and washed with 1 mL of ethyl acetate and then 1 mL of ether; wt 0.116 g; mp 221°-223° C.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH3:44])[C@@H:15]1[CH2:22][N:21]2[C:23]3[CH:24]=[C:25]([C:36]([O:38]C)=[O:37])[CH:26]=[CH:27][C:28]=3[C:29]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:20]2[C:19]2[CH:40]=[CH:41][CH:42]=[CH:43][C:18]=2[O:17][CH2:16]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]>CO.C1COCC1.O>[C:4]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]([CH3:44])[C@@H:15]1[CH2:22][N:21]2[C:23]3[CH:24]=[C:25]([C:36]([OH:38])=[O:37])[CH:26]=[CH:27][C:28]=3[C:29]([CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[C:20]2[C:19]2[CH:40]=[CH:41][CH:42]=[CH:43][C:18]=2[O:17][CH2:16]1)=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCNC(=O)OC(C)(C)C)COc1ccccc1-3
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(CCNC(=O)OC(C)(C)C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 60 °C
Yield: 98 %

Procedure:
Lithium hydroxide monohydrate (4.4 eq) was added to a solution of methyl (7R)-7-[{2-[(tert-butoxycarbonyl)amino]ethyl}(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.02 M) in MeOH/THF/H2O (1/1/1). The reaction was heated at 60° C. for 4 h prior to introducing further lithium hydroxide monohydrate (5 eq) and continuing heating for 2 h. The reaction was allowed to cool to RT, and the solvent volume reduced in vacuo. The residue was partitioned between 1N HCl (aq) and EtOAc, extracting the aqueous fraction a further two times with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the product as an off white foam (98%). (ES+) m/z 548 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>CO>[Cl:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(-c2ccccc2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1-c1ccccc1

Procedure:
Methyl 2-chloro-4-methylsulfonyl-3-phenyl-benzoate was hydrolyzed with sodium hydroxide in aqueous methanol solution and recovered using standard methodology to obtain the title compound, a white solid, which was used as an intermediate without further analysis.