Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH2:3][OH:4].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH2:15]([NH:1][C@@H:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH2:3][OH:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N[C@H](CO)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=Cc1ccccc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(C[C@@H](CO)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.3 %

Procedure:
A suspension of (2S)-2-amino-3-(4-nitrophenyl)-1-propanol (5.89 g) and benzaldehyde (3.39 g) in dichloromethane (59 ml) was stirred at room temperature for 2.5 hours. The mixture was evaporated, and the residual solid was suspended in ethanol (47 ml)-dichloromethane (11.8 ml). Sodium borohydride (1.25 g) was slowly added to the suspension, and the mixture was stirred at room temperature for 5 hours. The mixture was poured onto water (47 ml) and stirred at room temperature for 15 minutes. The precipitate formed was collected by filtration, washed with water, and dried in vacuo. The crude product was recrystallized from ethanol to give (2S)-2-(benzylamino)-3-(4-nitrophenyl)-1-propanol (5.18 g) as a pale yellow powder. The filtrates obtained above were combined, concentrated, and partitioned between chloroform and water. The organic layer was separated, washed successively with water and brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, chloroform/methanol) to give the additional amount of product (2.78 g) as a white powder.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:39]=[C:40]([CH:42]=[CH:43][CH:44]=2)[NH2:41])[CH:36]=[N:35][CH:34]=[N:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:41][C:40]3[CH:42]=[CH:43][CH:44]=[C:38]([CH2:37][N:32]4[CH:36]=[N:35][CH:34]=[N:33]4)[CH:39]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Nc1cccc(Cn2cncn2)c1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2cccc(Cn3cncn3)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-(1H-1,2,4-triazol-1-ylmethyl)aniline (Maybridge, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: C([O:3][C:4](=[O:15])/[C:5](/[CH3:14])=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])C.[OH-].[K+]>C(O)C.O.CCOCC>[OH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1/[CH:6]=[C:5](\[CH3:14])/[C:4]([OH:15])=[O:3]
Reactant: CCOC(=O)/C(C)=C/c1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: C/C(=C\c1ccccc1O)C(=O)O

Procedure:
To a solution of 35.5 g of (E)-3-(2-hydroxy-phenyl)-2-methyl-acrylic acid ethyl ester in 600 ml of ethanol, a solution of 10.66 g of potassium hydroxide in 500 ml of water was dropped in. After refluxing for 5 hours, another 5.0 g of potassium hydroxide was put in and the mixture was refluxed for another 19 hours. Then the reaction mixture was cooled down, diluted with ether and washed to pH 4 with HCl 2N and water. The organic phase was dried, filtered and evaporated to dryness. The resulting colourless crystals were not further purified.
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[N:18]=[N:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=3)=[N:15]2)=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[I:25][C:21]1[CH:20]=[C:19]([C:16]2[N:17]=[N:18][N:14]([CH2:13][C:10]3[CH:9]=[CH:8][C:7]([C:6]([OH:26])=[O:5])=[CH:12][CH:11]=3)[N:15]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2nnc(-c3cccc(I)c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccc(Cn2nnc(-c3cccc(I)c3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The ester (2.5 g, 5.41 mmol) prepared in Step (b) was suspended in dichloromethane (20 mL) followed by the addition of trifluoroacetic acid (5 mL). The solution was stirred for 16 hours at 25° C., then concentrated in vacuo. The resulting white solid was triturated with hexane/diethyl ether and the carboxylic acid (2.1 g, 100%) was collected by filtration. Mp 241–242° C.
Reaction SMILES: C([C:3]1[N:4]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[C:5]2[C:10]([C:11](=[O:16])[C:12]=1[C:13]([OH:15])=[O:14])=[C:9]([CH3:17])[C:8]([F:18])=[C:7](F)[C:6]=2[F:20])C.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[F:18][C:8]1[C:9]([CH3:17])=[C:10]2[C:5](=[C:6]([F:20])[C:7]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[N:4]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])[CH:3]=[C:12]([C:13]([OH:15])=[O:14])[C:11]2=[O:16]
Reactant: C1CNCCN1
Reactant: CCc1c(C(=O)O)c(=O)c2c(C)c(F)c(F)c(F)c2n1-c1ccc(F)cc1F
Solvent: CC#N
Product: Cc1c(F)c(N2CCNCC2)c(F)c2c1c(=O)c(C(=O)O)cn2-c1ccc(F)cc1F
Temperature: 25 °C
Yield: 78.7 %

Procedure:
A solution of 0.43 g (1.08 mmol) of ethyl 6,7,8-trifluoro-1-(2,4-difluorophenyl)-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.37 g (4.30 mmol) of anhydrous piperazine, and 20 mL of acetonitrile was refluxed overnight, cooled to room temperature, and concentrated in vacuo. The residue was taken up in 10 mL of 6N hydrochloric acid and refluxed for 2 hours. The mixture was cooled and the solids were collected by filtration. The crude product was suspended in water which was made basic (pH 12), and the resulting solution was filtered through a fiberglass pad, and neutralized (pH 6.5). The solids were collected by filtration, washed with water, ether, and dried to give 0.37 g of the title compound, mp 283°-284° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)[CH3:12])=[CH:8][C:6]=2[N:7]=1.[NH2:29][C:30]1[N:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1>>[O:26]1[CH2:27][CH2:28][N:23]([C:4]2[C:5]3[S:10][C:9]([CH:11]([N:13]4[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]4)[CH3:12])=[CH:8][C:6]=3[N:7]=[C:2]([C:33]3[CH:32]=[N:31][C:30]([NH2:29])=[N:35][CH:34]=3)[N:3]=2)[CH2:24][CH2:25]1
Reactant: CC(c1cc2nc(Cl)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Product: CC(c1cc2nc(-c3cnc(N)nc3)nc(N3CCOCC3)c2s1)N1CCN(S(C)(=O)=O)CC1

Procedure:
2-Chloro-6-[1-(4-methanesulfonyl-piperazin-1-yl)-ethyl]-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester in General Procedure A. Purification on silica yielded 300. NMR: (CDCl3): 1.44 (3 H, d, J 7.1, Me), 2.52-2.64 (4 H, m, CH2), 2.73 (3 H, s, Me), 3.21-3.23 (4 H, m, CH2), 3.80-3.83 (4 H, m, CH2), 3.94-4.06 (5 H, m), 5.16 (2 H, s, NH2) and 9.20 (2 H, s, Ar). MS: (ESI+): MH+=505.20
Reaction SMILES: [N:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[O:6][CH2:5][CH2:4][N:3]3[C:2]=1[NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:32][C:31]([F:33])([F:34])[C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:1]2[C:11]3=[C:12]4[C:7](=[CH:8][CH:9]=[CH:10]3)[O:6][CH2:5][CH2:4][N:3]4[C:2]2=[N:13][S:14]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:16])=[O:15])=[CH:26][CH:27]=1
Reactant: O=S(=O)(Nc1nc2cccc3c2n1CCO3)c1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=S(=O)(N=c1n(Cc2ccc(C(F)(F)F)cc2)c2cccc3c2n1CCO3)c1ccccc1
Temperature: 120 °C

Procedure:
To a solution of N-(3,4-dihydro-5-oxa-1,2a-diaza-acenaphthylen-2-yl)-benzenesulfonamide (125 mg, 0.40 mmol) in DMF (2.5 mL) was added 1-bromomethyl-4-trifluoromethyl-benzene (190 mg, 0.80 mmol) and potassium carbonate (55 mg). The resulting mixture was heated to 120° C. in a microwave reactor for 1 h and then diluted with EtOAc, washed with H2O and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield N-[1-(4-trifluoromethyl-benzyl)-3,4-dihydro-1H-5-oxa-1,2a-diaza-acenaphthylen-2-ylidene]-benzenesulfonamide (2nd compound to elute off the column); which was further purified by HPLC (reverse phase C-18 column, 45-100% acetonitrile/water containing 0.05% trifluoroacetic acid) to yield N-[1-(4-trifluoromethyl-benzyl)-3,4-dihydro-1H-5-oxa-1,2a-diaza-acenaphthylen-2-ylidene]-benzenesulfonamide trifluoroacetic acid salt. MS 474 (M+1)+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][C:26]=4Cl)[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:30][C:31]1[CH:32]=[C:33]([NH2:38])[CH:34]=[CH:35][C:36]=1[F:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>COCCOCCOC>[N:1]1([CH2:7][CH2:8][NH:9][C:10]([C:12]2[NH:13][C:14]([CH:18]=[C:19]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][C:26]=4[NH:38][C:33]4[CH:34]=[CH:35][C:36]([F:37])=[C:31]([Cl:30])[CH:32]=4)[NH:21][C:20]3=[O:29])=[C:15]([CH3:17])[CH:16]=2)=[O:11])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2nccc(Cl)c21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COCCOCCOC
Product: Cc1cc(C(=O)NCCN2CCOCC2)[nH]c1C=C1C(=O)Nc2nccc(Nc3ccc(F)c(Cl)c3)c21
Temperature: 185 °C
Yield: 28 %

Procedure:
A mixture of 5-(4-chloro-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl)-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide (10 mg, 0.024 mmol), 3-chloro-4-fluoro-phenylamine (50 mg, 0.34 mmol), p-toluene sulfonic acid monohydrate (5 mg, 0.026 mmol) and 1 mL of 2-methoxyethyl ether was heated to 180-190° C. in a sealed tube for 6 hours, cooled to room temperature and concentrated. The residue was then purified using preparative TLC plates eluting with 10% methanol in dichloromethane to give 5-[4-(3-chloro-4-fluoro-phenylamino)-2-oxo-1,2-dihydro-pyrrolo[2,3-b]pyridin-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide as an orange solid (yield is about 28%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]([NH2:25])=O)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:25])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2ncc(C(N)=O)c(Nc3cccc(Br)c3)c2cc1OC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3cccc(Br)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 3.02 g of 4-[(3-bromophenyl)amino]-6,7-dimethoxy-3-quinolinecarboxamide, 2.43 ml of pyridine, and 22.5 ml of dichloromethane at 0° C. was added 3.18 ml of trifluoroacetic anhydride during 3 min. The reaction mixture was warmed to 25° C., stirred for 60 min, and concentrated. The residue was dissolved in 38 ml of methanol. The resulting solution was treated with 15 ml of 5 N NaOH at 25° C. After 5 m the solution was acidified with carbon dioxide and evaporated free of methanol. The residue was partitioned with dichloromethane-water. The organic layer was washed with water, dried, and evaporated to give a white solid. Recrystallization from ethyl acetate-hexane gave mp 224-228° C.
Reaction SMILES: C[C:2](C)([O-:4])C.[Na+].[C:7]([O:11][CH3:12])(=[O:10])[CH2:8][SH:9].COC([C:17]1[C:18]2[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=2[S:20][C:21]=1Cl)=O.O>CN(C=O)C>[CH3:12][O:11][C:7]([C:8]1[S:9][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[S:20][C:21]=2[C:2]=1[OH:4])=[O:10]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1c(Cl)sc2ccccc12
Reactant: COC(=O)CS
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc2c(sc3ccccc32)c1O
Yield: 54.7 %

Procedure:
Sodium tert-butoxide (360 mg, 3.7 mmol, 3.3 equiv) was added to a solution of methyl thioglycolate (0.110 ml, 1.23 mmol, 1.1 equiv) in DMF (10 ml). 2-chloro-benzo[b]thiophene-3-carboxylic acid methyl ester (235 mg, 1.12 mmol, 1 equiv, available from Maybridge) was then added and the mixture became orange. When no starting material was observed by TLC, water was added followed by extraction with EtOAc. Purification by column chromatography yielded 162 mg (61%) of 1-hydroxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester as an orange solid.
Reaction SMILES: [CH3:1]COCC.[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([CH3:19])([CH3:18])C)N=1)([CH3:9])(C)C>C1(C)C=CC=CC=1.C([Pd]Cl)C=C>[CH2:15]([C:14]12[CH2:18][CH:16]([CH2:12][CH2:13]1)[CH:19]=[CH:1]2)[CH2:10][CH2:6][CH3:9]
Reactant: CCOCC
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: C=CC[Pd]Cl
Solvent: Cc1ccccc1
Product: CCCCC12C=CC(CC1)C2

Procedure:
A 50 weight percent solution of butylnorbornene (5.0 g, 0.033 mol) was prepared in toluene. Lithium tetrakis(pentafluorophenyl)borate·2.5 Et2O (0.0012 g, 0.0014 mmol) was combined with (allyl)palladiumchloride dimer (100 μl of a 1.4 mmol solution in toluene) and 2,6-di-t-butylpyridine (100 μl of a 2.9 mmol solution in toluene) in toluene and added to the monomer mixture. A polymeric puck formed within 5-10 min at room temperature.
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]=[C:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:25][N:24]=1
Reactant: Cc1ccc(C=C2CCN(C(=O)OC(C)(C)C)CC2)cc1Oc1ccc(C(F)(F)F)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(C=C2CCNCC2)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 114.8 %

Procedure:
To a solution of tert-butyl 4-(4-methyl-3-(5-(trifluoromethyl)pyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.50 g, 0.0011 mol) in CH2Cl2 (5 mL) cooled to 0° C. under a N2 atmosphere was added TFA (0.85 mL, 0.011 mol) slowly. The resulting mixture was stirred for 2 h at RT. The reaction was concentrated under reduced pressure to give the title compound (440 mg).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11].C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[Cl:8][C:7]1[C:2]([NH:10][NH2:11])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: NNc1ncccc1Cl
Yield: 89.4 %

Procedure:
To 30 ml of an n-butanol solution containing 7.0 g of 2,3-dichloropyridine were added 7.1 g of hydrazine monohydrate and 6.54 g of anhydrous potassium carbonate, and the mixture was heated under reflux for 17.5 hours. After cooling, the precipitate was collected by filtration to yield 6.07 g of the title compound.
Reaction SMILES: [N:1]1[N:2]=[C:3]([CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[N:20]=[C:19]([NH2:21])[C:18]([N+:22]([O-])=O)=[CH:17][CH:16]=3)[CH2:10]2)[N:4]2[CH2:8][CH2:7][CH2:6][C:5]=12.[CH:25]1([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]=O)[N:29]=2)[CH2:27][CH2:26]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(O)C>O>[CH:25]1([C:28]2[N:29]=[C:30]([C:34]3[NH:21][C:19]4=[N:20][C:15]([N:11]5[CH2:12][CH2:13][CH2:14][CH:9]([C:3]6[N:4]7[CH2:8][CH2:7][CH2:6][C:5]7=[N:1][N:2]=6)[CH2:10]5)=[CH:16][CH:17]=[C:18]4[N:22]=3)[CH:31]=[CH:32][CH:33]=2)[CH2:27][CH2:26]1
Reactant: O=Cc1cccc(C2CC2)n1
Reactant: Nc1nc(N2CCCC(c3nnc4n3CCC4)C2)ccc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1cc(-c2nc3ccc(N4CCCC(c5nnc6n5CCC6)C4)nc3[nH]2)nc(C2CC2)c1
Temperature: 110 °C
Yield: 20.6 %

Procedure:
A mixture of 6-(3-(6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)piperidin-1-yl)-3-nitropyridin-2-amine (Intermediate 45) (300 mg, 0.91 mmol), 2-cyclopropylpyridine-6-aldehyde (187.5 mg, 1.27 mmol), sodium dithionite (602.6 mg, 4.46 mmol), ethanol (15 mL) and water (2.4 mL) in a sealed tube was heated to 110° C. for 16 h. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was and purified via preparative TLC to afford the title compound (80 mg, 21%) as a racemic mixture. MS (ES+) (M+H) 427.3; LCMS retention time 2.687 min (Method J). 1H NMR (400 MHz, CDCl3) δ 1.02-1.15 (m, 4H), 1.73-1.82 (m, 1H), 1.89-2.13 (m, 3H), 2.21 (d, 1H), 2.74-2.85 (m, 2H), 2.94-3.01 (m, 2H), 3.02-3.12 (m, 2H), 3.21-3.32 (m, 1H), 3.91-4.10 (m, 2H), 4.33 (d, 1H), 4.65 (d, 1H), 6.75 (d, 1H), 7.20 (d, 1H), 7.66 (t, 2H), 7.88 (d, 1H), 8.05 (d, 1H), 10.20 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH3:20])[CH2:16][CH:17]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CCOC(C)=O.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[NH2:9]
Reactant: CCCN1CC=C(c2ccc([N+](=O)[O-])c(OC)c2)CC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCN1CCC(c2ccc(N)c(OC)c2)CC1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
4-[3-(methyloxy)-4-nitrophenyl]-1-propyl-1,2,3,6-tetrahydropyridine (3.33 g, 12.05 mmol) was placed in a 250 mL high pressure vessel and dissolved in 60 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/C (4.7 g, 1.2 mmol) was added followed quickly by a rubber septum. The flask was evacuated and filled with N2 six times to remove any oxygen. The vessel was then pressurized with H2 (50 psi). The solution stirred overnight. The next morning the vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to give the title compound of step D (2.4 g, 9.66 mmol, 80%). 1H NMR (400 MHz, CDCl3) δ ppm 6.68 (s, 1H), 6.63 (s, 2H), 3.81 (s, 3H), 3.52 (bs, 2H), 3.07 (d, J=11.90 Hz, 2H), 2.40 (s, 1H), 2.32-2.38 (m, 2H), 1.98-2.07 (m, 2H), 1.80 (ddd, J=12.32, 6.00, 3.30 Hz, 4H), 1.51-1.61 (m, 2H), 0.91 (t, J=7.42 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[N:13][N:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[CH:15]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:30]([OH:33])[C:31]#[CH:32]>N1CCCC1.C(Cl)Cl.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>[N:24]1([C:22]([C:19]2[CH:18]=[CH:17][C:16]([N:14]3[CH:15]=[C:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([C:32]#[C:31][CH2:30][OH:33])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[N:12]=[N:13]3)=[CH:21][CH:20]=2)=[O:23])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: O=C(c1ccc(-n2cc(-c3n[nH]c4cc(Br)ccc34)nn2)cc1)N1CCOCC1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4cc(C#CCO)ccc34)nn2)cc1)N1CCOCC1
Temperature: 80 °C
Yield: 28.3 %

Procedure:
A mixture of {4-[4-(6-Bromo-1H-indazol-3-yl)-[1,2,3]triazol-1-yl]-phenyl}-morpholin-4-yl-methanone (150 mg; 0.33 mmol; 1.0 eq.), propargyl alcohol (39 μl; 0.66 mmol; 2.0 eq.) and Pd(PPh3)4 (19 mg, 0.02 mmol, 0.05 eq.) in pyrrolidine (1.5 mL) was heated O/N at 80° C. in a sealed tube. The reaction mixture was then diluted with DCM and washed with a saturated solution of NH4Cl (three times) and brine. Organic phase was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC gave the title compound as a beige solid (40 mg, 28%). 1H NMR (300 MHz, DMSO-d6-d6): 13.50 (brs, 1H), 9.42 (s, 1H), 8.34 (dd, J=8.5 Hz, 1.0 Hz, 1H), 8.15 (d, J=8.6 Hz, 2H), 7.70-7.67 (m, 3H), 7.28 (dd, J=8.5 Hz, 1.0 Hz, 1H), 5.40 (t, J=6.0 Hz, 1H), 4.35 (d, J=6.0 Hz, 2H), 3.64 (m, 6H), 3.47 (m, 2H).
Reaction SMILES: I[CH2:2][C:3]([OH:5])=[O:4].CN1CCOCC1.C(OC([Cl:20])=O)C(C)C.O[C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH2:46][CH3:47])[CH2:25][NH:26]/[CH:27]=[C:28]1\[C:29](=[O:40])[NH:30][C:31](=[O:39])[C:32]2[C:37]\1=[CH:36][C:35]([I:38])=[CH:34][CH:33]=2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Cl:20][CH2:2][C:3]([O:5][C:22]1[CH:23]=[C:24]([CH2:25][NH:26]/[CH:27]=[C:28]2\[C:29](=[O:40])[NH:30][C:31](=[O:39])[C:32]3[C:37]\2=[CH:36][C:35]([I:38])=[CH:34][CH:33]=3)[CH:41]=[CH:42][C:43]=1[O:44][CH2:45][CH2:46][CH3:47])=[O:4]
Reactant: CCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1O
Reactant: O=C(O)CI
Reactant: CC(C)COC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCOc1ccc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)cc1OC(=O)CCl
Yield: 122 %

Procedure:
To iodoacetic acid (242 mg, 1.3 mmol) in N,N-dimethylformamide (2 mL) at −20 C is added N-methylmorpholine (142 uL, 1.3 mmol) and isobutylchloroformate (178 uL, 1.3 mmol). After 5 min (4Z)-4-{[(3-hydroxy-4-propoxybenzyl)amino]methylene}-6-iodoisoquinoline-1,3(2H,4H)-dione (250 mg, 0.52 mmol) is added. The reaction mixture is allowed to warm to 25 C. After 24 h 15% aq. Citric acid is added. The resulting precipitate is filtered and washed with water to give a brown solid (352 mg). A portion of this material (50 mg) is chromatographed on silica gel (CH2Cl2/MeOH) to give the title compound as a tan powder (23 mg). MS (ESI) m/z 555 (M+H)+1.
Reaction SMILES: CO.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:12]([N+:23]([O-])=O)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1>[C].[Pd].C(OCC)(=O)C>[NH2:23][C:12]1[CH:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([Cl:3])[CH:5]=2)[CH:22]=[CH:21][C:13]=1[C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2cccc(Cl)c2)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
To a mixed solution of methanol 11 mL and ethyl acetate 11 mL of tert-butyl 4-(3-chlorophenyl)-2-nitrobenzoate 1.1 g was added 10% palladium-carbon 0.33 g, and it was stirred under hydrogen atmosphere at room temperature for 3 hours. The solvent was removed under reduced pressure after insoluble matter was filtrated. To the obtained residue, were added acetic acid 11 mL, methanol 11 mL and 10% palladium-carbon 0.33 g sequentially, and it was stirred under hydrogen atmosphere at room temperature for 2 hours. The solvent was removed under reduced pressure after insoluble matter was filtrated to give tert-butyl 2-amino-4-(3-chlorophenyl)benzoate 0.70 g of white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:20][CH2:21][OH:22])[C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[C:28](Cl)=[O:29]>>[CH3:1][N:2]([CH2:20][CH2:21][O:22][C:28]([C:24]1[O:23][CH:27]=[CH:26][CH:25]=1)=[O:29])[C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCC(=O)N(C)CCO
Reactant: O=C(Cl)c1ccco1
Product: CCCCCCCCCCCCCCCC(=O)N(C)CCOC(=O)c1ccco1

Procedure:
N-methyl-N-(2-furoyloxyethyl)palmitamide was prepared by the procedure of example 1 from 31 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)palmitamide and 13 gms. (0.1 mole) of furoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.