Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[C:12]3[CH:20]=[C:19]([C:21]#[C:22][CH2:23][OH:24])[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1>[Pd].C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:25])[C:12]3[CH:20]=[C:19]([CH2:21][CH2:22][CH2:23][OH:24])[S:18][C:13]=3[N:14]([CH2:16][CH3:17])[CH:15]=2)=[O:9])=[CH:26][CH:27]=1
Reactant: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)sc21
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCCO)sc21
Yield: 57 %

Procedure:
A solution of N-(4-chlorobenzyl)-7-ethyl-2-(3-hydroxy-1-propynyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Example No. 14) (0.197 g) in 1/1 CH2Cl2/CH3OH (50 mL) is hydrogenated over 10% Pd/C (59 mg) at 35 psi for 2 h. The reaction mixture is filtered through a Celite pad, and the filtrate is concentrated in vacuo. The resulting yellow solid is purified via column chromatography (CH2Cl2, CH2Cl2:CH3OH; 98:2, 95:5). Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.114 g (57%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:23])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[C:19](Br)[CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(Cl)Cl>[CH2:1]([N:8]1[CH2:16][C@H:15]2[C@:10]([CH3:23])([CH2:11][CH2:12][C:13]3[C:20]([Cl:21])=[C:19]([CH3:24])[CH:18]=[CH:17][C:14]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]12CCc3c(ccc(Br)c3Cl)[C@H]1CN(Cc1ccccc1)C2
Reactant: CB1OB(C)OB(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc2c(c1Cl)CC[C@]1(C)CN(Cc3ccccc3)C[C@H]21
Temperature: 130 °C
Yield: 78.5 %

Procedure:
A mixture of cis-2-benzyl-7-bromo-6-chloro-3a-methyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (0.154 mmol, 60 mg), tetrakis(triphenylphosphine)Pd(0) (7.68 μmol, 8.96 mg), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.184 mmol, 52 μl, 46.3 mg) and potassium carbonate (0.230 mmol, 32.2 mg) in 1,4-Dioxane (1 ml) and Water (0.5 ml) was heated in a microwave reactor at 130° C. for 20 min. The reaction mixture was diluted with DCM and water, the phases were separated and the aqueous was extracted with DCM (using a hydrophobic frit). The combined organic extracts were concentrated in vacuo and purified by silica column chromatography (eluting with neat heptane—2:1 heptane:ethyl acetate). The fractions containing the product compound were concentrated in vacuo and then redissolved in MeOH and then passed through Strata SCX column (1 g) and concentrated in vacuo to afford cis-2-benzyl-6-chloro-3a,7-dimethyl-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole (39.4 mg), m/z=326.2 [M+H]+.
Reaction SMILES: [C:1]1(=[O:12])[N:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[CH:3]=[CH:2]1.C(O[C:17](=[O:19])[CH3:18])(=O)C>>[C:4]1(=[O:11])[N:5]([CH2:6][CH2:7][C:8]([O:10][C:8](=[O:9])[CH2:7][CH2:6][N:5]2[C:17](=[O:19])[CH:18]=[CH:3][C:4]2=[O:11])=[O:9])[C:1](=[O:12])[CH:2]=[CH:3]1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CCN1C(=O)C=CC1=O
Product: O=C(CCN1C(=O)C=CC1=O)OC(=O)CCN1C(=O)C=CC1=O
Temperature: 130 °C

Procedure:
3-Maleimidopropionic acid (226 mg) was covered with 5 mL of acetic anhydride and the mixture was heated at 130° C. for 3.75 hour, and then aged over night at room temperature. The solution was concentrated to an oil and the NMR spectrum (CDCl3) indicated a mixture of the homoanhydride and the mixed anhydride of acetic and maleimidopropionic acids. The starting acid shows the methylen adjacent to the carbonyl as a triplet centered at 2.68 ppm whereas in the anhydride these resonances appear at 2.81 ppm. Purification was effected by fractional sublimation, first at 70° C. and 0.2 mm and then at 120° C. and 0.2 mm. The latter fraction was removed from the sublimer by dissolving in CDCl3, affording 34 mg of pure homanhydride on evaporation of the solvent. This was recrystallized from CDCl3 and cyclohexane affording material melting at 143°-147° C.
Reaction SMILES: [CH2:1]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:17]([C:22](O)=[O:23])#[C:18][C:19]([OH:21])=[O:20]>>[CH2:1]([N:7]1[C:22](=[O:23])[C:17](=[CH:18][C:19]([OH:21])=[O:20])[S:9][C:8]1=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=S)Nc1ccccc1
Reactant: O=C(O)C#CC(=O)O
Product: CCCCCCN1C(=O)C(=CC(=O)O)SC1=Nc1ccccc1
Yield: 64.5 %

Procedure:
Prepared by the method described in Example 1 from N-hexyl-N'-phenylthiourea (3.4 g, 14 mmoles) and acetylenedicarboxylic acid (1.7 g, 14 mmoles). Recrystallization from acetonitrile gave the product (3.0 g), mp 145°-146° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:15](=[O:30])[NH:14]2)=[O:12])=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:15](=[O:30])[NH:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=C1NN(C(=O)Nc2ccc([N+](=O)[O-])cc2)C(c2ccccc2)C1c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(NC(=O)N2NC(=O)C(c3ccccc3)C2c2ccccc2)cc1
Yield: 27.1 %

Procedure:
1-[(4--Nitrophenyl)aminocarbonyl]-4,5-diphenyl-3-pyrazolidinone (500 mg, 1.24 mmol) was dissolved in 50 mL EtOH and hydrogenated with 5% Pd/C (500 mg) under 60 p.s.i. H2, overnight at room temperature. The mixture was filtered to remove catalyst, solvent removed in vacuo, and the product isolated by chromatography (0-50% EtOAc:hexane gradient) as 125 mg (27%) solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6](C(O)=O)=[CH:5][N:4]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:19])C=CC=CC=1.C([N:31]([CH2:34]C)CC)C>C1(C)C=CC=CC=1>[N:31]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[N:4][CH:5]=1)=[C:34]=[O:19]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(C(=O)O)cn1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(N=C=O)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-methoxy-nicotinic acid (0.459 g, 3 mmol) (Matrix) in toluene (15 mL) was added diphenylphosphoryl azide (0.958 g, 3.5 mmol) (Aldrich), followed by the addition of triethylamine (0.35 g, 3.6 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes and the mixture became clear. Then the mixture was heated at 80° C. for 2 hours. The mixture was cooling down to room temperature to give crude 5-isocyanato-2-methoxy-pyridine as 0.2 M solution of toluene and used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][CH:11]=[C:12]([C:14]([NH:16][C:17]2[C:18]([N:35]3[CH2:40][CH2:39][CH2:38][C@H:37]([NH:41]C(=O)OC(C)(C)C)[CH2:36]3)=[C:19]3[CH:25]=[CH:24][N:23](S(C4C=CC=CC=4)(=O)=O)[C:20]3=[N:21][CH:22]=2)=[O:15])[N:13]=1.C1COCC1>CO.[OH-].[Na+].CCOC(C)=O>[NH2:41][C@H:37]1[CH2:38][CH2:39][CH2:40][N:35]([C:18]2[C:17]([NH:16][C:14]([C:12]3[N:13]=[C:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[S:10][CH:11]=3)=[O:15])=[CH:22][N:21]=[C:20]3[NH:23][CH:24]=[CH:25][C:19]=23)[CH2:36]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: N[C@H]1CCCN(c2c(NC(=O)c3csc(-c4c(F)cccc4F)n3)cnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.5 %

Procedure:
To a solution of tert-butyl {(3S)-1-[5-({[2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (175.3 mg, 0.2523 mmol) in MeOH (2.0 mL), aq. NaOH (1.0 M, 2.0 mL) was added, followed by THF (2.0 mL). After stirring at room temperature for 5 h, the reaction mixture was diluted with EtOAc (50 mL), washed with brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was dissolved in DCM (2.0 mL), and TFA (2.0 mL) was added. The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (59.1 mg, 52%). LCMS calc. for C22H22F2N6OS (M+H)+: m/z=455.1. found 455.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1.[F:20][C:21]([F:31])([F:30])[CH2:22][N:23]1[CH:27]=[C:26]([CH:28]=O)[CH:25]=[N:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)[Cl:47]>ClCCCl>[ClH:47].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([N:14]3[CH2:15][CH2:16][N:17]([CH2:28][C:26]4[CH:25]=[N:24][N:23]([CH2:22][C:21]([F:31])([F:20])[F:30])[CH:27]=4)[CH2:18][CH2:19]3)=[N:10][CH:11]=[CH:12][N:13]=2)=[CH:4][CH:3]=1
Reactant: ClCCl
Reactant: Fc1ccc(-c2nccnc2N2CCNCC2)cc1
Reactant: O=Cc1cnn(CC(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cl
Product: Fc1ccc(-c2nccnc2N2CCN(Cc3cnn(CC(F)(F)F)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42 %

Procedure:
Dissolve 3′-(4-fluoro-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.150 g, 0.581 mmol) in DCE (5 mL). Add 1-(2,2,2-trifluoro-ethyl)-1H-pyrazole-4-carbaldehyde (0.124 g, 0.697 mmol) followed by sodium triacetoxyborohydride (0.185 g, 0.872 mmol) and stir at ambient temperature for 18 hr. Add 1-(2,2,2-trifluoro-ethyl)-1H-pyrazole-4-carbaldehyde (0.062 g, 0.349 mmol) and stir at ambient temperature for 2 hr. Add sodium triacetoxyborohydride (0.092 g, 0.436 mmol) and stir at ambient temperature for 72 hr. Purify via SCX chromatography. Add resin-bound-isocyanate (0.796 g, 1.16 mmol) and DCM (8 mL) and shake at ambient temperature for 4 hr. Filter, concentrate and purify (silica gel chromatography, eluting with 100:0 to 0:100 hexanes:ethyl acetate, then 10:90 methanol:ethyl acetate) to give the free base of the title compound (103 mg, 42%). Dissolve the free base (0.099 g, 0.237 mmol) in methanol and add a solution of ammonium chloride (0.013 g, 0.237 mmol) in a minimal volume of methanol. Shake for 18 hr. at ambient temperature and concentrate to give the title compound (108 mg, 100%). MS (ES): m/z=421[M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)[C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:8][C:7]=1[CH3:30].[OH-].[Na+].O.Cl>C(O)C>[Br:29][C:26]1[CH:25]=[CH:24][C:23]([C:15]([C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=2)=[CH:14][CH2:13][S:12][C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]([CH3:30])[CH:8]=2)=[CH:28][CH:27]=1
Reactant: COC(=O)COc1ccc(SCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(SCC=C(c2ccc(Br)cc2)c2ccc(Br)cc2)ccc1OCC(=O)O
Yield: 93.5 %

Procedure:
A solution of {4-[3,3-bis-(4-bromo-phenyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid methyl ester (530 mg, 0.94 mmol) in ethanol (20 ml) and 1M NaOH (2.0 ml, 2.0 mmol) was stirred at room temp. for 2 h. The reaction mixture added water (20 ml) and 1N HCl (3.0 ml). The water phase was extracted dichloromethane (2×50 ml) and the combined organic phases dried with MgSO4, filtered and evaporated to give 482 mg (93%) of {4-[3,3-bis-(4-bromophenyl)-allylsulfanyl]-2-methyl-phenoxy}-acetic acid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[NH:13]([C:19]([O:21][CH3:22])=[O:20])[NH:14][C:15](OC)=[O:16]>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4]>[NH:13]([C:19]([O:21][CH:22]1[CH2:6][C:7]([CH3:9])([CH3:8])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:20])[NH:14][C:15]([O:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([CH3:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:16]
Reactant: COC(=O)NNC(=O)OC
Reactant: CN1C(C)(C)CC(O)CC1(C)C
Agent: [Ti+4]
Agent: CCCC[O-]
Product: CN1C(C)(C)CC(OC(=O)NNC(=O)OC2CC(C)(C)N(C)C(C)(C)C2)CC1(C)C
Yield: 38.6 %

Procedure:
The procedure of Example 1 is repeated using 33.9 g of 1,2,2,6,6-pentamethylpiperidin-4-ol, 13.3 g of dimethyl hydrazine-1,2-dicarboxylate and 0.31 g of tetrabutyl titanate to afford 14.8 g of the title compound as a white solid; mp 189°-191° C.
Reaction SMILES: CS[C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=3[CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3Cl)[O:11][CH2:12][C:6]2=[N:5][N:4]=1.[CH3:25][O-:26].[Na+]>CO>[O:26]1[CH2:12][CH2:6][N:7]([C:3]2[N:7]3[C:8]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=4[CH:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[O:11][CH2:12][C:6]3=[N:5][N:4]=2)[CH2:3][CH2:25]1
Reactant: CSc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)OC2
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccc2c(c1)C(c1ccccc1)OCc1nnc(N3CCOCC3)n1-2
Reaction time: 4 h
Yield: 130 %

Procedure:
To a suspension of Compound 15 (0.76 g) prepared in Example 8-(1) in methanol (20 ml) is added sodium methoxide (0.119 g), and the mixture is stirred for 4 hours, allowed to stand overnight, and concentrated. The residue is extracted with chloroform and the extract is washed with water, dried, and concentrated. The residue is washed with ethyl acetate to give Compound 19 (0.5 g) in 66.5% yield.
Reaction SMILES: O/[C:2](/[CH3:12])=[CH:3]\[C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.[C:13]([CH2:15][C:16]([NH2:18])=[O:17])#[N:14].N1CCCCC1>CCO>[CH3:12][C:2]1[CH:3]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)[NH:18][C:16](=[O:17])[C:15]=1[C:13]#[N:14]
Reactant: C/C(O)=C/C(=O)c1ccncc1
Reactant: N#CCC(N)=O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(-c2ccncc2)[nH]c(=O)c1C#N
Temperature: 25 °C
Yield: 11.6 %

Procedure:
To a solution of (2Z)-3-hydroxy-1-(4-pyridinyl)-2-buten-1-one (8 g, crude, 49 mmol) and cyanoacetamide (4.12 g, 49 mmol) in anhydrous EtOH (100 mL) was added piperidine (4.17 g, 49 mmol) under N2 at 75° C. The mixture was heated at reflux for 1 h, and then cooled to room temperature. After filtration, the solid was collected and washed with H2O to give the crude product (4 g) as two isomers. After separation by HPLC, 1.8 g of 6-methyl-2-oxo-1,2-dihydro-4,4′-bipyridine-3-carbonitrile and 1.2 g of 4-methyl-6-oxo-1,6-dihydro-2,4′-bipyridine-5-carbonitrile were obtained. The identity of 6-methyl-2-oxo-1,2-dihydro-4,4′-bipyridine-3-carbonitrile was established by nOE analysis. 1H NMR (400 MHz, DMSO-d6) δ 12.79 (br. s., 1H), 8.75 (d, 2H), 7.58 (d, 2H), 6.37 (s, 1H), 2.31 (s, 3H).
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([C:13]([O:15]C)=[O:14])=[C:11]([CH3:17])[N:10]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[C:8]=2[N:9]=1>O.O1CCCC1.CO>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[C:12]([C:13]([OH:15])=[O:14])=[C:11]([CH3:17])[N:10]([C@@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[C:8]=2[N:9]=1
Reactant: COC(=O)c1c(C)n([C@H](C)c2ccccc2)c2nc(Cl)ncc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)c2cnc(Cl)nc2n1[C@H](C)c1ccccc1
Yield: 75.4 %

Procedure:
Lithium hydroxide anhydrate (882 mg, 21 mmol) in water (3 mL) was added to (R)-methyl 2-chloro-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (700 mg, 2.1 mmol) in tetrahydrofuran (5 mL) and methanol (10 mL) and the resultant mixture was stirred at room temperature for 12 hours. The mixture was evaporated, added with water (5 mL), acidified with aqueous hydrochloric acid (1M) to pH=2. The precipitate solid was filtered and dried to obtain (R)-2-chloro-6-methyl-7-(1-phenylethyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid as a white solid (500 mg, 75%). LRMS (M+H+) m/z: calcd 315.08. found 315.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[C:15]([S:17](=[O:20])(=[O:19])[NH2:18])[CH:14]=[CH:13][C:12]=1[O:21][CH3:22])[CH3:2].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(N(CC)CC)C>O>[C:24]([NH:18][S:17]([C:15]1[CH:14]=[CH:13][C:12]([O:21][CH3:22])=[C:11]([CH:16]=1)[C:10]([NH:9][CH2:8][CH:4]1[CH2:5][CH2:6][CH2:7][N:3]1[CH2:1][CH3:2])=[O:23])(=[O:19])=[O:20])(=[O:26])[CH3:25]
Reactant: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)ccc1OC
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)NC(C)=O)ccc1OC

Procedure:
A solution of N-(1-Ethyl-pyrrolidin-2-ylmethyl)-2-methoxy-5-sulfamoyl-benzamide, acetic anhydride and triethylamine are reacted at room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate layer is dried, filtered and concentrated under vacuum, and the residue recrystallized from ethyl acetate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=O.[ClH:8].[NH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:19][C:20]([C:22]3[C:23]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[O:21])[CH:16]=2)[CH2:11]1.C(N(CC)CC)C.[BH4-]>CO>[ClH:8].[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][NH:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:19][C:20]([C:22]3[C:23]([C:29]4[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=4)=[C:24]([CH3:28])[CH:25]=[CH:26][CH:27]=3)=[O:21])[CH:16]=2)[CH2:11]1
Reactant: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(N)C3)c1-c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ncc[nH]1
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)Nc2ccc3c(c2)CC(NCc2ncc[nH]2)C3)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Imidazole-2-carboxaldehyde (2.45 g, 25.5 mmol) is added to a solution of 6-methyl-4′-trifluoromethyl-biphenyl-2-carboxylic acid (2-amino-indan-5-yl)-amide hydrochloride (11.1 g, 24.9 mmol) and triethylamine (5.05 mL, 50.0 mmol) in methanol (500 mL). The mixture is stirred at room temperature for 16 hours. Polymer supported borohydride (Aldrich, borohydride on Ambelite IR-400, 2.5 mmol/g, 10.0 g, 25.0 mmol) is added, the mixture stirred for 2 hours, filtered and concentrated under reduced pressure. The residue is taken up in ethanol (100 mL) and a saturated solution of hydrochloric acid gas in diethyl ether (10 mL) is added. The white precipitate is collected to yield 6-methyl-4′-trifluoromethylbiphenyl-2-carboxylic acid [2-(2-imidazolylmethylamino)-indan-5-yl] amide hydrochloride m.p. 240-242° C. Free base has m.p. 169-170° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([C:14]4[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH3:21])[CH:15]=4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([O:26]CC)=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.C>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([C:14]4[CH:15]=[C:16]([CH3:21])[N:17]=[C:18]([CH3:20])[CH:19]=4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Solvent: O
Product: Cc1cc(-c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)cc(C)n1
Yield: 73.1 %

Procedure:
A suspension of 12.4 g ethyl 1-cyclopropyl-7-(2,6-dimethyl-4-pyridinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 320 ml water containing 3.5 g sodium hydroxide was heated at reflux for 2.5 hours. The reaction mixture was then decolorized with charcoal, filtered and brought to pH 5-5.5 with acetic acid. The solid that precipitated was collected, dried in vacuo and recrystallized from dimethylformamide to give 8.4 g 1-cyclopropyl-7-(2,6-dimethyl-4-pyridinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, m.p. 300°-302° C.(decompn.).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][CH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][F:23])=[CH:17][CH:16]=1)[C:10]([O:12]C)=[O:11])[C:3]([O:5]C)=[O:4].O1CCCC1>[OH-].[Na+].O>[NH2:1][C@@H:2]([CH2:7][CH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][F:23])=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(CC[C@H](N)C(=O)OC)Cc1ccc(OCF)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CCC(Cc1ccc(OCF)cc1)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 5.9 %

Procedure:
Dimethyl (2S)-2-amino-5-[4-(fluoromethoxy)benzyl]hexanedioate (37 mg, 113 μmol) was solved in 2 ml of a mixture of tetrahydrofurane and water (2:1), and to the solution, four drops of 1N sodium hydroxide were added. The mixture was stirred at room temperature for 14 h and then concentrated in vacuo. The residue was purified by preparative HPLC and the according fractions were lyophilized to yield 2 mg (4.3%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([CH3:35])[C:21](=[O:34])[CH2:22][N:23]4C(=O)C5=CC=CC=C5C4=O)[C:14]=3[Cl:36])[C:5]2=[N:4][C:3]=1[CH3:37].O.NN>CO>[NH2:23][CH2:22][C:21]([N:20]([C:15]1[C:14]([Cl:36])=[C:13]([C:18]([Cl:19])=[CH:17][CH:16]=1)[CH2:12][O:11][C:10]1[C:5]2[N:6]([C:2]([Br:1])=[C:3]([CH3:37])[N:4]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:35])=[O:34]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)cccn2c1Br
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccn2c1Br
Yield: 95.8 %

Procedure:
A mixture of 3-bromo-8-[2,6-dichloro-3-(N-methyl-N-phthalimidoacetylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (450 mg) and hydrazine hydrate (41 mg) in methanol (5 ml) were refluxed for 30 minutes, and hydrazine hydrate (41 mg) was added thereto, and further, the mixture was refluxed for 1.5 hours. The resulting precipitates were filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in chloroform and the solution was washed with water twice and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was crystallized with diethyl ether to give 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-3-bromo-2-methylimidazo[1,2-a]pyridine (338 mg).
Reaction SMILES: [NH2:1][C:2](=[N:20][OH:21])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:8].[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=O)=[CH:31][C:30]=1[NH:38][S:39]([CH3:42])(=[O:41])=[O:40]>>[CH3:8][N:7]([CH2:6][C:5]1[CH:17]=[CH:18][CH:19]=[C:3]([C:2]2[N:1]=[C:33]([C:32]3[CH:36]=[CH:37][C:29]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]4[CH3:22])=[C:30]([NH:38][S:39]([CH3:42])(=[O:41])=[O:40])[CH:31]=3)[O:21][N:20]=2)[CH:4]=1)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11]
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1NS(C)(=O)=O
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cccc(C(N)=NO)c1
Product: CC1CCCCN1c1ccc(-c2nc(-c3cccc(CN(C)CC(=O)OC(C)(C)C)c3)no2)cc1NS(C)(=O)=O

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 51 (440.05 mg; 1.50 mmol), and Intermediate 25 (562.30 mg; 1.80 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography over Alumina column (c-hex/EtOAc: 9.5/0.5), affording the title compound as an off-white powder. HPLC (Method A) Rt 4.76 min (Purity: 96.7%).