Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[CH:10]([OH:27])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([NH:46][C@H:47]([C:51](O)=[O:52])[CH:48]([CH3:50])[CH3:49])([O:31][CH2:32][CH:33]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]2[C:34]1=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][C:9](=[O:28])[CH:10]([O:27][C:51](=[O:52])[C@H:47]([CH:48]([CH3:49])[CH3:50])[NH:46][C:29]([O:31][CH2:32][CH:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]2[C:45]1=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:30])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CCCCCCCCCCCCCCCCC(O)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCC(OC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of benzyl-2-hydroxystearate (3.2 g, 8.2 mmole), N-FMOC-L-valine (3.4 g, 10 mmole) and DMAP (0.12 g, 1 mmole) in 80 ml dichloromethane was added a solution of DCC (2.5 g, 12 mmole) and the mixture was stirred overnight at room temperature. The mixture was cooled to 5° C. and the urethane was filtered. The filtrate was evaporated and the product was isolated by silica gel column chromatography. Yield: 4.5 g
Reaction SMILES: [CH:1]12[CH2:9][CH:5]([CH2:6][NH:7][CH2:8]1)[CH2:4][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:2]2.Br[CH2:18][CH2:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>CC#N>[C:13]([O:12][C:10]([N:3]1[CH2:2][CH:1]2[CH2:9][CH:5]([CH2:6][N:7]([CH2:18][CH2:19][O:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:8]2)[CH2:4]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: N#Cc1ccc(OCCBr)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC(C2)C1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC2CC(CN(CCOc3ccc(C#N)cc3)C2)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
tert-Butyl-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate (3.62 g; 16 mmol; see Example F above) was added to added to a stirred solution of 4-(2-bromoethoxy)benzonitrile (3.62g; 16 mmol; see Example 67(a) above) and TEA (3.34 mL; 24 mmol) in MeCN (70 mL) and the reaction mixture was stirred at 60° C. overnight and then stored at room temperature for 48 h. The solids were filtered off, washed with IPA (2×100 mL) and the filtrate concentrated. The residue was partitioned between DCM and NaHCO3 (sat.), the organic layer was separated, dried (MgSO4) and concentrated. The oily residue was subjected to column chromatography (DCM:MeOH; 25:1) to give the title compound in a 72% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13]/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][NH:22][CH3:23].[OH-].[Na+]>O.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([N:22]([CH3:23])[CH3:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CNC
Reactant: CCOC(=O)/C=C/COc1ccc(Cl)c2cccnc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CC(COc1ccc(Cl)c2cccnc12)N(C)C
Reaction time: 48 h
Yield: 15 %

Procedure:
A mixture of 5.8 g (20 mmol) of ethyl (E)-4-(5-chloroquinoline-8-yloxy)-2-butenoate, 20 ml of a 60% solution of dimethylamine in water and 0.34 g (1.0 mmol) of tetrabutylammonium hydrogen sulfate in 50 ml of dichloromethane, 40 ml of water and 10 ml of 2N sodium hydroxide solution was allowed to stand for two days at room temperature. The organic phase was separated off, and the aqueous phase was extracted twice using dichloromethane. After drying over magnesium sulfate, the solvent was stripped off in vacuo and the residue obtained was chromatographed on silica gel (ethyl acetate:heptane 7:3; followed by ethyl acetate). 1.0 g (15%) of the title compound was obtained as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>O>[N+:8]([C:5]1[CH:4]=[CH:3][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:7][N:6]=1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCC2)cn1
Temperature: 120 °C
Yield: 72.4 %

Procedure:
A mixture of 600 mg (2.93 mmol) of 5-bromo-2-nitropyridine and 1.05 g (14.63 mmol) of pyrrolidine is heated in a Biotage microwave machine for 1 hour at 120° C. The reaction medium is diluted with water and then extracted with ethyl acetate. The organic phase is washed twice with water, dried over MgSO4 and then filtered. The filtrate is evaporated under reduced pressure and then chromatographed on silica gel, eluting with a heptane/ethyl acetate mixture from (100/0 v/v) up to (50/50 v/v) to give 410 mg of 2-nitro-5-pyrrolidin-1-ylpyridine.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][CH:10]([S:13]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19]3)(=[O:15])=[O:14])[CH2:9]1.[C:26]1([CH2:32][CH2:33][CH2:34][CH:35]=O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:26]1([CH2:32][CH2:33][CH2:34][CH2:35][N:8]2[CH2:12][CH2:11][CH:10]([S:13]([C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20](=[O:25])[CH2:19]4)(=[O:15])=[O:14])[CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C1Cc2cc(S(=O)(=O)C3CCNC3)ccc2N1
Reactant: O=CCCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1Cc2cc(S(=O)(=O)C3CCN(CCCCc4ccccc4)C3)ccc2N1

Procedure:
The title compound, MS: m/e=399.4 (M+H+) was prepared from (RS)-5-(pyrrolidine-3-sulfonyl)-1,3-dihydro-indol-2-one trifluoroacetic acid and 4-phenyl-butyraldehyde.
Reaction SMILES: [Na].Cl[C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1.[CH2:14]([OH:18])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][S:6][N:7]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC(C)CO
Agent: [Na]
Product: CC(C)COc1nsnc1-c1cccnc1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
To a solution of sodium (230 mg, 10 mmol) in isobutanol (20 ml) was added 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine (490 mg, 2.5 mmol). The mixture was stirred at 50° C. for 3 h and evaporated. The residue was dissolved in water and extracted with methylene chloride. The combined organic phases were dried and evaporated to give the wanted compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:13][N:12]3[CH:21]=[C:22](C(OCC)=O)[N:23]=[C:11]3[N:10]=2)=[CH:5][CH:4]=1)=[O:2].Br[CH2:30][C:31](=O)CC>>[CH2:30]([C:22]1[N:23]=[C:11]2[N:10]=[C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=3)[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][N:12]2[CH:21]=1)[CH3:31]
Reactant: CCC(=O)CBr
Reactant: CCOC(=O)c1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Product: CCc1cn2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1

Procedure:
This compound was prepared in a manner according to ethyl 7-(4-formylphenyl)-6-phenylimidazo[1,2-a]pyrimidine-2-carboxylate by using 1-bromobutan-2-one instead of ethyl 3-bromo-2-oxopropanoate in step 5.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[H-].[Na+].Cl[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1>CN(C=O)C.CCOC(C)=O>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:15]3[N:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: Clc1ncccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1cnc(OC2CCC3(CC2)OCCO3)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
As shown in step 7-i of Scheme 7, to a solution of 1,4-dioxaspiro[4.5]decan-8-ol (compound 1021, 1.0 g, 6.32 mmol) in DMF (10 mL) was added NaH (370 mg, 9.25 mmol). The reaction mixture was stirred for 20 minutes before the addition of 2-chloropyrimidine (869 mg, 7.59 mmol). The mixture was stirred for 30 minute at RT and then heated to 100° C. for 9 hours. After cooling, the mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, concentrated under reduced pressure, and purified by medium pressure silica gel chromatography (0-40% EtOAc/hexanes) to produce 2-(1,4-dioxaspiro[4.5]decan-8-yloxy)pyrimidine (compound 1022) as a colorless oil: 1H NMR (300 MHz, Chloroform-d) δ 8.52 (d, J=4.8 Hz, 2H), 6.92 (t, J=4.8 Hz, 1H), 5.15 (ddd, J=10.7, 6.5, 4.2 Hz, 1H), 4.05-3.87 (m, 4H), 2.14-1.85 (m, 6H), 1.79-1.65 (m, 2H); ESMS (M+H+)=237.12.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH2:12](B1OC(C)(C)C(C)(C)O1)[CH:13]=[CH2:14]>[Pd]>[CH2:14]([C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[CH:13]=[CH2:12]
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(Br)cc(OC)c1
Agent: [Pd]
Product: C=CCc1cc(OC)cc(OC)c1

Procedure:
The Pd-catalyzed cross-coupling reaction of 5-Bromo-1,3-dimethoxybenzene with allyl boronic acid pinacol ester produced 5-allyl-1,3-dimethoxybenzene 1 in excellent yield. AlI3 will be used for demethylating 5-Allyl-1,3-dimethoxybenzene with CS2 as solvent to produce 5-allylresorcinol 2. The bis(phosphinite) PCP ligands 3 will be obtained by diphosphorylation of 5-allylresorcinol 2 with the respective chlorophosphine and sodium hydride as a base. Iridium complexes 4 will be obtained from reaction of the respective PCP ligands 3 with [Ir(COD)Cl]2 or [Ir(COE)2Cl]2. Hydrosilylation of complexes 4 will produce the hydrosilylated complexes 5. Reaction of complexes 5 with silica gel will afford the Si2O-supported Ir complexes 6. To date, 5-allyl-1,3-dimethoxybenzene 1 has been prepared in 92% yield.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([S:14](Cl)(=[O:16])=[O:15])[CH:13]=1>C(Cl)Cl>[F:7][C:8]1[CH:9]=[CH:10][C:11]([O:18][CH3:19])=[C:12]([S:14]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)(=[O:15])=[O:16])[CH:13]=1
Reactant: COc1ccc(F)cc1S(=O)(=O)Cl
Reactant: C1COCCN1
Solvent: ClCCl
Product: COc1ccc(F)cc1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
To a mixture of morpholine (5.8 g, 66.9 mmol) and TEA (9.3 ml, 66.9 mol) in CH2Cl2 (20 ml) was added dropwise a solution of the product of example 82 (5.0 g, 22 mmol) in CH2Cl2 (10 ml) at 0° C. After stirring at room temperature for one hour, the mixture was diluted with CH2Cl2, washed with water, dried and concentrated under reduced pressure. The resulting residue was purified by column chromatography (PE/EA=10/1) to give the titled compound (5.53 g, yield 90.3%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1.[Cl:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([NH2:33])[CH:30]=[CH:29][C:27]=2[N:28]=1.N1C=CC=CC=1>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[S:25][C:26]2[CH:32]=[C:31]([NH:33][C:20]([C:17]3[CH:16]=[CH:15][C:14]([C:11]4[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=4)=[CH:19][CH:18]=3)=[O:22])[CH:30]=[CH:29][C:27]=2[N:28]=1
Reactant: Nc1ccc2nc(Cl)sc2c1
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc2nc(Cl)sc2c1)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
Add oxalyl chloride (10 mL, 114.6 mmol) and DMF (4 drops) to a stirring suspension of 4′-fluoro-biphenyl-4-carboxylic acid (4.9 g, 22.7 mmol) in CH2Cl2 (150 mL). Stir the reaction mixture at room temperature for 3 h. Concentrate the mixture in vacuo, add n-hexane, re-concentrate, and re-dissolve in CH2Cl2. Add the resultant 4′-fluoro-biphenyl-4-carbonyl chloride solution to a mixture of 2-chloro-benzothiazol-6-ylamine (3.31 g, 17.9 mmol) and pyridine (3.0 mL) in CH2Cl2 (150 mL). Stir the reaction mixture overnight at room temperature. Dilute the reaction mixture with CH2Cl2. Wash the reaction mixture twice with 1.0M HCl and once with 1.0M NaOH. Dry the mixture over Na2SO4, concentrate in vacuo, and triturate with MeOH to yield the desired product (6.34 g, 93%). 1H NMR (400 MHz, DMSO-d6): δ10.59 (s, 1H), 8.69 (d, J=1.6 Hz, 1H), 8.09 (d, J=8.0 Hz, 2H), 7.96 (d, J=8.8 Hz, 1H), 7.87-7.79 (m, 5H), 7.38-7.31 (m, 2H).
Reaction SMILES: [C:1]1([NH:7][C:8]2[N:12]=[CH:11][N:10]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH:29]1([CH2:34][C:35](Cl)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30]1>CN1C(=O)CCC1>[CH:29]1([CH2:34][C:35]([NH:19][C:15]2[CH:14]=[C:13]([N:10]3[CH:11]=[N:12][C:8]([NH:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:9]3)[CH:18]=[CH:17][N:16]=2)=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: Nc1cc(-n2cnc(Nc3ccccc3)n2)ccn1
Reactant: O=C(Cl)CC1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(CC1CCCC1)Nc1cc(-n2cnc(Nc3ccccc3)n2)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(3-Phenylamino-[1,2,4]triazol-1-yl)-pyridin-2-ylamine (50 mg, 0.20 mMol) was dissolved in 2.5 mL of NMP with (50 μL, 67.4 mg, 0.52 mMol) of Hunig's base and (30 μL, 32 mg, 0.2 mMol) of cyclopentylmethyl carbonyl chloride. The reaction was stirred at ambient temperature for 18 hr. LC shows starting material, mono acylated material, and a majority of the bis acylated imide. Another aliquot of the acylating agent was added and the reaction was stirred until all starting material was consumed. Five drops of 2.0N sodium hydroxide was then added and the reaction was stirred for ten hours at ambient temperature, until all of the imide was hydrolyzed. The reaction mixture was acidified with TFA and the crude material was purified via HPLC, C18 silica with a gradient of acetonitrile/water/0.1% TFA as the eluent. Yield ˜13 mg of a pale yellow powder as the TFA salt; (18%). 1H NMR 500 MHz (DMSO-d6) ∂ 1.29m, 2H), 1.5 (m, 2H), 1.77 (m, 2H), 2.25 (m, 1H), 2.4 (d, 2H), 6.88 (t, 1H), 7.28 (t, 2H), 7.53 (d, 1H), 7.63 (d, 2H), 8.35 (d, 1H), 8.55 (d, 1H), 9.2 (s, 1H), 9.57 (s, 1H), 10.6 (s ex, 1H). LC/MS [M+H+] 363
Reaction SMILES: O[C:2]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]2)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+].[H][H]>FC(F)(F)C(O)=O>[C:3]1([CH:2]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH2:13][CH2:12]3)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: O=C1CCc2cc(C(O)(c3ccccc3)c3cccnc3)ccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCc2cc(C(c3ccccc3)c3cccnc3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 240 mg of 6-[1-hydroxy-1-phenyl(3-pyridyl)methyl]-3,4-dihydrocarbostyril in 5 ml of trifluoroacetic acid at 0° C. was added 280 mg of sodium borohydride. When hydrogen evolution ceased the mixture was stirred at 25° C. for 30 minutes, then the solvent was removed under reduced pressure. The residue was added to aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent removed under reduced pressure and the residue chromatographed on silica gel, eluting with 3% methanol in methylene chloride to give 6-[phenyl(3-pyridyl)methyl]-3,4-dihydrocarbostyril, m.p. 95°-96° C.
Reaction SMILES: [NH3:1].[NH2:2][C:3]1[CH:4]=[C:5]([C:11]#[N:12])[C:6](=[CH:9][CH:10]=1)[C:7]#[N:8].C[O-].[Na+]>>[NH2:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:9][CH:10]=1)[C:7](=[NH:8])[NH:12][C:11]2=[NH:1]
Reactant: N
Reactant: N#Cc1ccc(N)cc1C#N
Agent: C[O-]
Agent: [Na+]
Product: N=C1NC(=N)c2cc(N)ccc21

Procedure:
5-Amino-1,3-diiminoisoindoline was synthesized by passing gaseous ammonia through methanolic solution of 4-aminophthalonitrile in the presence of sodium methoxide.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[Cl:22])=[C:12]([F:23])[C:8]2[N:9]=[CH:10][NH:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CCO.C(OCC)(=O)C.O.Cl>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]3[NH:11][CH:10]=[N:9][C:8]=3[C:12]=2[F:23])=[C:16]([Cl:22])[CH:17]=1
Reactant: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 16 h
Yield: 39.2 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8b (58 mg, 0.146 mmol) is suspended in EtOH (2 mL) and 1 mL 2 N NaOH is added. After 16 hours, the reaction mixture is diluted with ethyl acetate, water, and 10% HCl solution. The layers are separated and the organic layer is washed with brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure. Trituration with MeOH provides 22 mg (39%) pure desired product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[C:9]2[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:44]=[C:43]3[C:38]([CH:39]=[CH:40][CH:41]=[N:42]3)=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[O:13]=[C:12]1[NH:11][N:10]=[C:9]([CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16]2)[N:8]1[C:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:44]=[C:43]3[C:38]([CH:39]=[CH:40][CH:41]=[N:42]3)=[CH:37][CH:36]=2)=[CH:3][CH:4]=1
Reactant: CC1(C)OB(c2ccc3cccnc3c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2)C1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of 1,1-dimethylethyl (3S)-3-{[4-(4-bromophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl]methyl}-1-pyrrolidinecarboxylate (1.181 mmol) in dioxane (6 mL) was treated with 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (1.215 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (50 mg), and 2M aq potassium carbonate (3 mL). The reaction mixture was purged with nitrogen, sealed, and stirred at 110° C. for 1 h. The solution was cooled to room temperature and the dioxane layer separated from the aqueous layer. The dioxane layer was removed via pipette and was passed through a plug of celite and sodium sulfate. The plug was washed with dioxane (6 mL). All dioxane filtrates were combined and concentrated in vacuo. Silica gel chromatography (0-20% methanol:ethyl acetate) was utilized in purifying the title compound (386 mg, 69%). MS(ES)+ m/e 472.2 [M+H]+.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([OH:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>CN(C)C1C=CN=CC=1.ClCCl.O>[CH3:12][S:13]([O:11][CH:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6][CH2:7][CH2:8]1)(=[O:15])=[O:14]
Reactant: OC1CCCc2cccnc21
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCCc2cccnc21
Reaction time: 8 h

Procedure:
To a stirred solution of 2.0 g (13 mmol) of 5,6,7,8-tetrahydroquinolin-8-ol and 3.3 g (27 mmol) of 4-(dimethylamino)pyridine in 30 mL of dichloromethane was added 1.3 mL (16 mmol) of methanesulfonyl chloride under an atmosphere of nitrogen. The reaction mixture was stirred for 8 h and then diluted with 30 mL water. The aqueous phase was then extracted with dichloromethane (3×30 mL) and the combined organics were dried over magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a light orange gum that was used without further purification. LC/MS: m/z (ES) 172.0 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[F-].[K+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.O.C(OCC)C.C(Cl)(Cl)Cl>[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=2)=[CH:12][CH:11]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cc(-c2ccc(F)cc2)ccn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 133.5 %

Procedure:
Argon was bubbled for 15 min through a suspension of 1.11 ml (1.276 g, 10.0 mmol) 4-Chloropicoline, 2.798 g (20.0 mmol, 2.0 equiv.) of 4-Fluorophenylboronic acid, and 1.917 g (33.0 mmol, 3.3 equiv.) of KF in 20 ml of Dioxane. Then 155 mg (0.15 mmol, 1.5 mol %)Pd2(dba)3×CHCl3 and 104 ul (93 mg, 0.45 mmol, 4.5 mol %) Tri-tert-butylphosphine were added. The mixture was then stirred for 1 h under argon at 100° C. The reaction was worked up in the usual manner with diethylether, water, and sodium carbonate solution. The combined organic phases were washed with 30 ml of water, dried and concentrated in vaccuo to yield 2.5 g of a light yellow oil which was purified by flash chromatography (heptane/ethyl acetate 1:1) to yield the title compound (1.81 g, 97%) as a white solid, MS (ISP): m/e=188.3 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][N:16](CC3C=CC=CC=3)[CH2:17][CH2:18][C:11]=2[NH:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[CH2:15][NH:16][CH2:17][CH2:18][C:11]=2[NH:10][C:9]1=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c2c(c(=O)n1Cc1ccccc1)CN(Cc1ccccc1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=c1[nH]c2c(c(=O)n1Cc1ccccc1)CNCC2
Yield: 88.7 %

Procedure:
A solution of 70 g of 3,6-dibenzyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione in 1.5 1 of glacial acetic acid was debenzylated in the 6-position by hydrogenolysis on 10 g of 10% palladium/activated charcoal at 70° C. and a hydrogen pressure of 3.5 bar. After the catalyst had been filtered off, the filtrate was concentrated under reduced pressure, the residual oil was taken up with 500 ml of water and the pH was adjusted to 8 with conc. sodium carbonate solution, with stirring, to give 46 g of a white precipitate of 3-benzyl-5,6,7,8-tetrahydro-1H-pyrido[4,3-d]pyrimidine-2,4-dione.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[NH2:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[CH2:22][OH:23].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:21]=1[CH2:22][OH:23])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc(N)c1CO
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)CNC(=O)OC(C)(C)C)c1CO
Reaction time: 1 h
Yield: 17.7 %

Procedure:
To a solution of t-butoxycarbonylaminoacetic acid (3.5 g) in methylene chloride (50 ml) was added triethylamine (2.0 g) and then ethyl chloroformate (1.9 ml) with ice-cooling. After being stirred for 1 hour, 2-amino-6-methylbenzyl alcohol (2.74 g) was added thereto and the mixture was stirred for 7 days at an ambient temperature. To the mixture was added a saturated aqueous solution of sodium hydrogen carbonate and the organic layer was separated, washed with water and dried over magnesium sulfate. The solvent was distilled off and the residue was triturated with diethyl ether to give 2-(t-butoxycarbonylaminoacetamido)-6-methylbenzyl alcohol (1.04 g).