Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])(C)(C)C.[O:23]1[C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:24]1=[O:30].O>CCOCC>[CH2:12]([C:3]1[C:2]([C:28](=[O:29])[CH2:27][CH2:26][CH2:25][C:24]([OH:30])=[O:23])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: O=C1CCCC(=O)O1
Reactant: CCCCCCc1nc2ccccc2cc1Br
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: CCCCCCc1nc2ccccc2cc1C(=O)CCCC(=O)O
Temperature: -100 °C
Reaction time: 2 h

Procedure:
To the solution of 3-bromo-2-hexyl-quinoline in ether was added tert-butyl lithium at −100° C. The reaction mixture was stirred for 2 hours at −100° C. To the reaction mixture a solution of dihydro-pyran-2,6-dione in ether was added at −100° C. and stirred for 30 minutes and was allowed to warm up to RT. The stirring was continued for 3 hours. The water was added to the reaction mixture and was stirred for 20 minutes. Solvent was evaporated under vacuum and water was added to the crude mixture. It was then acidified by using dilute HCl and was extracted with ether. The product was purified by column chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1)=[N:9][C:8]([C:25]1[NH:29][C:28](=[O:30])[NH:27][N:26]=1)=[CH:7]2>Cl.CCOC(C)=O>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([NH:12][C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)=[N:9][C:8]([C:25]1[NH:29][C:28](=[O:30])[NH:27][N:26]=1)=[CH:7]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3cccc(Cl)c23)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(-c2cc3cccc(Cl)c3c(N[C@H]3CCNC3)n2)[nH]1
Yield: 251.4 %

Procedure:
A solution of (S)-tert-butyl 3-((8-chloro-3-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)isoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (170 mg, 0.52 mmol) in HCl/EtOAc (10 mL) was stirred at RT for 2 hours. The reaction mixture was subsequently concentrated in vacuo to give an HCl salt of the title compound (160 mg, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.90 (s, 1H), 11.85 (s, 1H), 9.134 (s, 2H), 7.86-7.84 (dd, J1=2.8 Hz, J2=6.8 Hz, 1H), 7.64-7.62 (m, 3H), 7.57-7.56 (d, J=6.4 Hz, 1H), 5.0 (s, 1H), 3.65-3.60 (m, 1H), 3.24-3.21 (m, 2H), 2.40-2.36 (m, 1H), 2.11-2.07 (m, 1H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][NH:6][S:7]([C:10]1[S:14][C:13]([NH:15][C:16]([N:18]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[C@H:19]2[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]2)=[O:17])=[N:12][CH:11]=1)(=[O:9])=[O:8])C.[OH-].[Na+]>CO>[CH3:29][CH:28]([CH3:30])[CH2:27][CH2:26][N:18]([CH:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)[C:16](=[O:17])[NH:15][C:13]1[S:14][C:10]([S:7]([NH:6][CH2:5][C:4]([OH:31])=[O:3])(=[O:8])=[O:9])=[CH:11][N:12]=1
Reactant: CCOC(=O)CNS(=O)(=O)c1cnc(NC(=O)N(CCC(C)C)[C@H]2CC[C@H](C)CC2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCN(C(=O)Nc1ncc(S(=O)(=O)NCC(=O)O)s1)C1CCC(C)CC1

Procedure:
{2-[3-(3-methyl-butyl)-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-acetic acid ethyl ester was dissolved in MeOH and treated with 15 equivalents of 1N NaOH for 2 days at room temperature. MeOH was removed by evaporation. Addition of 1N HCl to pH<1 caused precipitation. The precipitate was isolated by filtration, washed with water and dried to give {2-[3-(3-methyl-butyl)-3-(4-methyl-cyclohexyl)-ureido]-thiazole-5-sulfonylamino}-acetic acid as crystals.
Reaction SMILES: [CH2:1]([P:3]([OH:5])[OH:4])[CH3:2].[CH2:6]([O:8][CH:9]=[CH2:10])[CH3:7].[O-]S(OOS([O-])(=O)=O)(=O)=O.[Na+].[Na+]>O>[CH2:1]([P:3]([CH2:7][CH2:6][O:8][CH2:9][CH3:10])(=[O:5])[OH:4])[CH3:2]
Reactant: C=COCC
Reactant: CCP(O)O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CCOCCP(=O)(O)CC
Temperature: 100 °C
Yield: 95.6 %

Procedure:
564 g (6 mol) of ethylphosphonous acid are dissolved in 860 g of water and initially charged to a 5 l five-neck flask equipped with thermometer, reflux condenser, high-performance stirrer and dropping funnel. After heating the reaction mixture to 100° C., 504 g (7 mol) of vinyl ethyl ether and 500 g of a 5% strength sodium peroxodisulfate solution (1.5 mol % based on vinyl ethyl ether) are added dropwise at atmospheric pressure over 1 h. The water is then distilled off in vacuo. The residue is taken up in tetrahydrofuran and the insoluble salts are filtered off. The solvent of the filtrate is removed in vacuo. Chromatographic purification leaves 953 g (82% of theory) of ethyl(2-ethoxyethyl)phosphinic acid being obtained as oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]([C:18]([NH:20][NH2:21])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[CH3:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]2[O:19][C:1](=[O:2])[NH:21][N:20]=2)=[CH:10][CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(-c2ccccc2C(=O)NN)cc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2ccccc2-c2n[nH]c(=O)o2)cc1
Yield: 91.6 %

Procedure:
6.5 g of phosgene are dissolved in 60 ml of chloroform. 1.45 g of the hydrazide prepared in step A in 40 ml of chloroform are added dropwise and the mixture is refluxed for 4 hours. It is evaporated and the residue is taken up with DCM, washed with water, dried over sodium sulfate, filtered and evaporated to give 1.48 g of the expected product.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH-].[Li+].[Si](=O)=[O:15].S(=O)(=O)(O)O>O>[N+:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[OH:15])([O-:11])=[O:10]
Reactant: O=[Si]=O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=S(=O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1O
Yield: 73.5 %

Procedure:
59.1 g (1 mol) of 2,4-difluoronitrobenzene and 300 g of water are initially introduced and 52.7 g (2.2 mol) of 50% strength lithium hydroxide solution are added dropwise at 45° C. The temperature is allowed to rise to 55° C. as a result of the exothermic reaction. After the end of this addition (5 hours) 60.1 g of silicon dioxide (Aerosil) are added and the pH is adjusted to 1.5 with sulfuric acid. The product is distilled over by the introduction of steam and isolated as described in example 1. 115.5 g (0.735 mol, 74% of theory) of 2-nitro-5-fluorophenol are obtained, which do not differ from the material prepared by example 1 with respect to purity.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([NH:19][C:20](=[O:22])[CH3:21])([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])[C:6](OCC)=[O:7])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO>[CH2:1]([O:3][C:4]([C:5]1([NH:19][C:20](=[O:22])[CH3:21])[CH2:11][C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:18][C:6]1=[O:7])=[O:23])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccccc1N)(NC(C)=O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(NC(C)=O)Cc2ccccc2NC1=O
Temperature: 25 °C

Procedure:
A solution of 1.0 eq. of 80 and 0.3 eq of p-toluenesulfonic acid hydrate in EtOH was refluxed for 2 hrs. The mixture was then stirred at rt for a time sufficient for reaction completion. After rotary evaporation, 100 mL of saturated aqueous NaHCO3 was added and the mixture was extracted with EtOAc. The combined organic extracts were dried over MgSO4 and vacuum filtered. The filtrate was rotary evaporated and dried under vacuum to yield 81.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=O)C1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.C1C=CC=CC=1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>C(Cl)Cl.CCOCC>[OH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)=[O:25]
Reactant: CCOC(=O)CCCCc1ccc2ccccc2c1OCc1ccccc1
Reactant: C1CCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccccc1
Product: O=C(CCCCc1ccc2ccccc2c1O)N1CCCC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 76 %

Procedure:
A mixture of the compound of Example 131 Part B (1.00 g, 3.0 mmole), oxalyl chloride (1.3 mL, 15.0 mmole) and benzene (10 mL) was stirred at room temperature for 21 hours and concentrated under vacuum. The residue was dissolved in methylene chloride (10 mL) and added dropwise to a stirred solution of pyrrolidine (0.53 mL, 6.3 mmole) in methylene chloride (10 mL) at 0°. After 6.5 hours, the mixture was diluted with ether, washed with water and 1.0N hydrochloric acid, then dried over magnesium sulfate and concentrated under vacuum. The crude material was hydrogenated using the procedure of Example 86. Recrystallization of the crude product (ethyl acetate/ethanol) provided the title compound (0.63 g, 76%) as an off-white solid, mp 166°-160°.
Reaction SMILES: [C:1]1([C:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([CH2:22][NH:23][S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-])=O)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>C(O)C.[Pd]>[NH2:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][NH:11][CH2:10][CH2:9][CH2:8][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:22][NH:23][S:24]([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25]
Reactant: Cc1ccc(S(=O)(=O)NCC(CCCNCc2cccc([N+](=O)[O-])c2)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NCC(CCCNCc2cccc(N)c2)(c2ccccc2)c2ccccc2)cc1
Yield: 74.7 %

Procedure:
To a solution of 4,4-diphenyl-1-(3-nitrobenzylamino)-5-(tosylamino)pentane (0.17 g) in ethanol (10 ml) was added hydrochloric acid (0.1 ml) as well as 10% palladium-on-carbon (80 mg) and the mixture was subjected to catalytic hydrogenation at atmospheric temperature and pressure. The catalyst was then removed from the reaction mixture and the filtrate was concentrated to dryness. The group was dissolved in water and the solution was made basic with aqueous ammonia. The resulting precipitate was recovered by filtration, rinsed with water, and dried to provide the title compound (0.12 g) as light-tan powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][CH:16]3[CH2:25][CH2:24][C:19]4(OCC[O:20]4)[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(O)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([CH2:14][CH2:15][CH:16]3[CH2:17][CH2:18][C:19](=[O:20])[CH2:24][CH2:25]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc([C@H]2CC[C@H](CCC3CCC4(CC3)OCCO4)CC2)cc1
Solvent: O=CO
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1CCC(CC[C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A mixture of 31.1 g of 4-chloro-1-[trans-4-[2-(1,4-dioxa-8-spiro[4.5]decyl)ethyl]cyclohexyl]benzene, 207 ml of toluene and 103 ml of formic acid is stirred at room temperature for 1.25 hours while gassing with nitrogen. Thereafter, the reaction mixture is poured into 500 ml of water and extracted with methylene chloride. The organic phases are washed with saturated sodium hydrogen carbonate solution and with water, dried over sodium sulphate and filtered. Concentration of the filtrate gives 4-[2-[trans-4(4-chlorophenyl)cyclohexyl]ethyl]cyclohexanone.
Reaction SMILES: C(OC([NH:11][CH:12]([C:21]([O:23][CH2:24][C@@H:25]([C:33]([O:35]CC1C=CC=CC=1)=[O:34])[NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])=[O:22])[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[OH:14])=O)C1C=CC=CC=1>[Pd].C(O)(=O)C>[C:15]1([CH:13]([OH:14])[CH:12]([C:21]([O:23][CH2:24][C@@H:25]([C:33]([OH:35])=[O:34])[NH:26][C:27](=[O:32])[C:28]([F:29])([F:30])[F:31])=[O:22])[NH2:11])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(NC(C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)OCc1ccccc1)C(O)c1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: NC(C(=O)OC[C@H](NC(=O)C(F)(F)F)C(=O)O)C(O)c1ccccc1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
A mixture of benzyl O-(N-benzyloxycarbonyl-3-phenyl-D,L-serinyl)-N-trifluoroacetyl-L-serinate (324 mg) and 10% palladium on activated carbon (400 mg) in acetic acid (5 ml) was hydrogenated at 40 psi under hydrogen at room temperature for 2 hours. The reaction mixture was filtered with Celite (filter aid, trade mark, made by Nakarai Chemicals) and concentrated and lyophilized to give O-(3-phenyl-D,L-serinyl)-N-trifluoroacetyl-L-serine (150 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[CH:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:18])([F:17])[F:19])=[N:14][N:15]=4)[CH:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)cn12
Reactant: O=Cc1ccc(Cl)cc1
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4ccc(Cl)cc4)CC3)cn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine with 4-chlorobenzaldehyde was carried out according to General Synthetic Method 9. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-chlorophenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21](=[O:24])[CH:20]=[C:19]2[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33]>>[CH2:3]([N:2]([CH3:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[C:15]([O:34][CH3:35])=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21](=[O:24])[CH:20]=[C:19]2[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][N:29]=[CH:28][C:27]=1[Cl:33])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNC
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Product: CCCCN(C)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12

Procedure:
The title compound was prepared from N-methylbutan-1-amine and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6): δ 9.40 (br s, 1H), 8.57 (s, 2H), 7.85 (d, 1H), 7.05 (d, 1H), 4.24 (br s, 1H), 3.96 (t, 2H), 3.87 (s, 3H), 2.62 (br, 4H), 2.39 (br s, 3H), 1.70 (m, 2H), 1.60 (m, 2H), 1.47 (m, 4H), 1.26 (m, 2H), 0.85 (t, 3H); MS (ESI): 508.1.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH2:16])[CH3:15].[CH3:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[CH:24]=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][C:14]([CH3:17])([NH:16][CH2:24][C:20]1[N:19]([CH3:18])[CH:23]=[CH:22][CH:21]=1)[CH3:15]
Reactant: CC(C)(N)COc1ccc2ccccc2c1Cl
Reactant: Cn1cccc1C=O
Product: Cn1cccc1CNC(C)(C)COc1ccc2ccccc2c1Cl
Yield: 39 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine and methyl-1H-pyrrole-2-carbaldehyde in 39% yield as a red oil.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[NH:5][C:6](=[O:18])[C:7]([CH3:17])([CH3:16])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].O[Li].O>C1COCC1.O>[C:12]([O:11][C:9]([NH:8][C:7]([CH3:17])([CH3:16])[C:6]([NH:5][C:4]([CH3:20])([CH3:19])[C:3]([OH:21])=[O:2])=[O:18])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)C(C)(C)NC(=O)C(C)(C)NC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)NC(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-tert-butoxycarbonyl α,α-dimethylglycyl α,α-dimethylglycine methyl ester 3 (20.42 g, 67.53 mmol) was dissolved in THF (530 mL) and a solution of LiOH.H2O (8.50 g, 0.203 mol) in de-ionized H2O (270 mL) added in one portion. The reaction mixture was stirred for 4 h 30 min at room temperature. The solvents were evaporated and the residue redissolved in H2O (800 mL). The solution was washed with Et2O (2×500 mL) and acidified to pH 1-2 by addition of concentrated hydrochloric acid. This resulted in the precipitation of a white solid, which was collected by filtration, washed with H2O (4×100 mL) and dried under vacuum overnight (16.18 g, 83%). The compound has been prepared before,4 but as far as we have been able to establish has not been appropriately characterised; 1H NMR (200 MHz, DMSO-d6) δ 12.33 (br s, 1H, COOH), 7.43 (s, 1H, NH(Aib2)), 6.84 (br s, 1H, NH(Aib1)), 1.36 (s, 15H, (CH3)3/CH3), 1.27 (s, 6H, CH3); 13C NMR (75 MHz, DMSO-d6) δ 175.9, 173.7, 154.2, 78.2, 55.8, 55.1, 28.1, 25.0, 24.4; HRMS (m/z): [M+Na]+ calcd. for C13H24N2O5Na, 311.1582. found, 311.1590; Anal. Calcd. for C13H24N2O5: C, 54.15; H, 8.39; N, 9.72. Found: C, 54.5; H, 8.4; N, 9.6.
Reaction SMILES: [CH:1]([C:5]1[C:6]([OH:15])=[C:7]([CH:13]=O)[CH:8]=[C:9]([CH:12]=1)[CH:10]=[O:11])([CH2:3][CH3:4])[CH3:2].[C:16](OCC)(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].N1CCCCC1>C(O)C>[CH:1]([C:5]1[CH:12]=[C:9]([CH:10]=[O:11])[CH:8]=[C:7]2[C:6]=1[O:15][C:16](=[O:23])[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13]2)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cc(C=O)cc(C=O)c1O
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1cc2cc(C=O)cc(C(C)CC)c2oc1=O

Procedure:
A solution of 5-sec-butyl-4-hydroxyisophthalaldehyde of formula I (0.5 g, 2.42 mmol), diethyl malonate (0.38 g, 2.42 mmol) in ethanol (20 mL) was treated with piperidine (0.3 mL) and refluxed. Most of the excess solvent was evaporated under reduced pressure, and the residue was neutralized with acetic acid. To this residue water (20 mL) was added and extracted 3-fold with 20 mL of CHCl3. The combined organic layers were dried on Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was chromatographed over silica gel (SiO2, 230-400 flash), eluting with a gradient of 20% ethyl acetate in hexane to 40% ethyl acetate in hexane, which upon concentration provides ethyl 8-sec-butyl-6-formyl-2-oxo-2H-chromene-3-carboxylate (General Formula II). (0.47 g, 65% yield). White solid, m. p. 89-90° C.; 1H NMR (CDCl3, 300 MHz): δ 10.05 (s, 1H), 8.60 (s, 1H), 8.05 (brs, 1H), 8.01 (brs, 1H) 4.44 (q, 2H, J=7.1 Hz), 3.51-3.40 (m, 1H), 1.78-1.69 (m, 2H), 1.43 (t, 3H, J=7.1 Hz), 1.33 (d, 3H, J=7 Hz), 0.88 (t, 3H, J=7.4 Hz); 13C NMR (CDCl3, 75 MHz): δ 190.2, 162.7, 156.5, 155.8, 148.5, 137.3, 132.9, 131.7, 129.9, 119.2, 118.0, 62.2, 33.4, 29.6, 20.4, 14.2, 12.0; ESI-MS (m/z): 303 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=2)=[CH:11][CH:12]=1)=[O:5].C(OCC)(=O)C.O.[CH3:32][N:33](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[S:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:32]#[N:33])[CH:15]=2)=[CH:11][CH:12]=1)=[O:5]
Reactant: CN(C)C=O
Reactant: Nc1ncccc1C(=O)NCc1ccc(Oc2cccc(Br)c2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cccc(Oc2ccc(CNC(=O)c3cccnc3N)s2)c1
Temperature: 140 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
Next, to a solution of a mixture of 2-amino-N-(5-(3-bromophenoxy)-thiophen-2-ylmethyl)-nicotinamide and debrominated compound (100 mg, 0.247 mmol) in N,N-dimethylformamide (3.0 mL) were added zinc cyanide (58 mg, 0.495 mmol) and tetrakis(triphenylphosphine)palladium(0) (285 mg, 0.247 mmol) under nitrogen atmosphere, and the solution was stirred at 140° C. from 3 hours and a half. The reaction solution was allowed to room temperature, ethyl acetate and water were added to the reaction solution, which was then partitioned, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and the title compound (9 mg, 10%) was obtained as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12]C(C)(C)O[C:9]2=[O:15])=[CH:4][CH:3]=1.Cl.[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=1.C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)C(c2ccc(Br)cc2)O1
Reactant: COc1cc(CCN)ccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc(CCNC(=O)C(O)c2ccc(Br)cc2)ccc1O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-(4-Bromo-phenyl)-2,2-dimethyl-[1,3]dioxolan-4-one (15 g, 55 mmol) is dissolved in 50 ml of ethanol. 4-(2-Amino-ethyl)-2-methoxy-phenol hydrochloride (14 g, 69 mmol) and triethylamine (7.0 g, 69 mmol) are added and the mixture is stirred for 72 hours at room temperature. The solvent is removed in vacuum and the residue is extracted with ethyl acetate and 1N hydrochloric acid. The aqueous layer is extracted twice with ethyl acetate and the combined organic phases are washed with brine, dried over sodium sulfate and evaporated. The remaining 2-(4-bromo-phenyl)-2-hydroxy-N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-acetamide is purified by chromatography on silica gel. 1H-NMR (300 MHz, CDCl3): 2.71 (t, 2H, CH2CH2), 3.54 (t, 2H, CH2CH2), 3.80 (s, 3H, OCH3), 5.59 (s, 1H, CHOH), 6.16 (bs, 1H, NH), 6.52-7.35 (m, 7H, CH arom.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[O:22][C:23]([F:26])=[CH:24][CH:25]=4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1.Cl[C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29].ClC([O-])=O>N1C=CC=CC=1>[CH:31]([O:30][C:28](=[O:29])[NH:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([NH:18][C:19]([C:21]4[O:22][C:23]([F:26])=[CH:24][CH:25]=4)=[O:20])[CH:14]=[CH:15][C:16]=3[Cl:17])=[N:8][C:5]2=[N:6][CH:7]=1)([CH3:33])[CH3:32]
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1cnc2nc(-c3cc(NC(=O)c4ccc(F)o4)ccc3Cl)[nH]c2c1
Agent: O=C([O-])Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1cnc2nc(-c3cc(NC(=O)c4ccc(F)o4)ccc3Cl)[nH]c2c1

Procedure:
The 6-amino imidazopyridine 1-9 (900 mg) was placed in pyridine at 0° C. and isopropyl chloroformate (1M in toluene, 1 eq) was added dropwise. Batches of 100 μl of chloroformate were added until no starting material was detected by LC-MS. The pyridine was evaporated and the residue was purified by ISCO (gradient AcOEt/Hexane) to yield the desired product as an off white powder (360 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]([O:12]C)=[O:11])=[CH:6][N:5]2[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O.[OH-].[Li+].C1COCC1>O>[NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][N:5]2[C:14]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc2nc(N)c(-c3ccccc3)n2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc2ccc(C(=O)O)cn2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 101.2 %

Procedure:
The 2-amino-3-phenyl-6-(carbomethoxy)imidazo-[1,2-a]-pyridine (83.9 g, 0.314 mol), lithium hyroxide monohydrate (65.9 g, 1.57 mol), 1113 ml of THF, and 371 ml of H2O were combined and stirred for 18 hours at RT. The reaction was concentrated in vacuo and the residue taken up in 5 L of H2O. The pH was adjusted to 5 with 5N HCl. The resulting precipitate was filtered and air dried for 72 hours to give 80.5 g of product. (quant. yeild). NMR, MS(FD).