Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]1[CH:25]([N:26]2[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]2)[C:24]2=[CH:33][CH:21]([O:22][C:23]2=[O:34])[CH:20]2[CH:16]([O:17][C:18](=[O:36])[CH:19]2[CH3:35])[CH2:15][C:14]2([CH3:37])[CH:12]1[O:13]2.C(OC1C(N2CCC(C)CC2)C2=CC(OC2=O)C2C(OC(=O)C2C)CC2(C)C1O2)(=O)C>N1C=CC=CC=1>[CH3:35][CH:19]1[C:18](=[O:36])[O:17][CH:16]2[CH:20]1[CH:21]1[CH:33]=[C:24]([CH:25]([N:26]3[CH2:31][CH2:30][CH:29]([CH3:32])[CH2:28][CH2:27]3)[CH:11]([O:10][C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:8])[CH:12]3[C:14]([CH3:37])([CH2:15]2)[O:13]3)[C:23](=[O:34])[O:22]1
Reactant: CC1CCN(C2C3=CC(OC3=O)C3C(CC4(C)OC4C2O)OC(=O)C3C)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: CC(=O)OC1C(N2CCC(C)CC2)C2=CC(OC2=O)C2C(CC3(C)OC13)OC(=O)C2C
Solvent: c1ccncc1
Product: CC1CCN(C2C3=CC(OC3=O)C3C(CC4(C)OC4C2OC(=O)c2ccccc2)OC(=O)C3C)CC1
Reaction time: 2 h
Yield: 50.4 %

Procedure:
Benzoyl chloride (400 μmol; 46 μl) is added to a solution of the compound of Example 9 (100 μmol; 40 mg) in pyridine (0.5 ml). The reaction mass is stirred for 2 hours then treated in the same manner as for the preparation of the compound of Example 17. 25 mg of product is obtained in the form of a white powder. Melting point: 234° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=3[F:30])[CH:17]=[CH:16][N:15]=2)=[O:12])[CH2:7][CH2:6]1)[CH3:3]>O1CCCC1.[OH-].[OH-].[Pd+2]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:11]([N:8]3[CH2:7][CH2:6][CH:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH2:10][CH2:9]3)=[O:12])[CH:19]=2)=[C:22]([F:30])[CH:23]=1
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ccn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 98.3 %

Procedure:
2-{[4-(Dimethylaminomethyl)piperidin-1-yl]carbonylamino}-4-(2-fluoro-4-nitrophenoxy)pyridine (183 mg) was dissolved in tetrahydrofuran (20 ml). 20% palladium hydroxide on carbon (123 mg) was added thereto, followed by stirring under a hydrogen atmosphere overnight. The catalyst was removed by filtration and washed with tetrahydrofuran. The filtrate and the washing were combined and concentrated under reduced pressure, the resultant residue was dried under reduced pressure to provide the titled compound as pale yellow powder (167 mg, 98%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][C:8]1[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:24][C:25]([N:27]([CH:36]([CH3:38])[CH3:37])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1)=[O:26]>CN(C=O)C>[CH:36]([N:27]([C:28]1[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=1)[C:25](=[O:26])[CH2:24][NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH3:37])[CH3:38]
Reactant: Nc1ccccc1Nc1ncccn1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CNc2ccccc2Nc2ncccn2)C(C)C)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of N-pyrimidin-2-yl-benzene-1,2-diamine (82 mg, 0.441 mmol) in DMF (2 mL) was added potassium carbonate (61 mg, 0.441 mmol), potassium iodide (7 mg, 0.044 mmol), and 2-Bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (126 mg, 0.441 mmol). The resultant reaction mixture was stirred overnight at 60° C. The solvent was removed in vacuo and the crude material partitioned between CH2Cl2 (35 mL) and water (15 mL). The organic phase was separated, dried with MgSO4, filtered and concentrated to a yellow oil which upon trituration with EtOH (6 mL) and filtration gave the title compound (96.7 mg, 0.247 mmol) as yellow crystals: 1H NMR (CDCl3, 300 MHz): 8.36 (d, 2H, J=4.9 Hz), 7.38 (dd, 1H, J=1.2, 7.8 Hz), 7.06-6.90 (m, 6H), 6.75 (t, 1H), 6.66 (t, 1H), 6.36 (dd, 1H, J=1.2, 7.8 Hz), 4.97 (m, 1H), 3.87 (s, 3H), 3.43 (s, 2H), 1.04 (d, 6H, J=6.8 Hz); TLC (EtOAc): Rf =0.62; MS (FAB) m/z 392.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[N:5]([CH2:8][C:9]#[CH:10])[C:6]=1[Cl:7].[OH-].[Na+].[I:23]I>CO.O>[Cl:1][C:2]1[C:3]([C:19]#[N:20])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[N:5]([CH2:8][C:9]#[C:10][I:23])[C:6]=1[Cl:7]
Reactant: C#CCn1c(Cl)c(Cl)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1c(Cl)c(Cl)n(CC#CI)c1-c1ccc(Cl)c(Cl)c1
Reaction time: 12 h

Procedure:
To a stirred mixture of 1.91 g (5.5 mmol) of 4,5-dichloro-2-(3,4-dichlorophenyl)-1-(2-propynyl)pyrrole-3-carbonitrile in 500 mL of methanol is added 69 mL of 10% aqueous sodium hydroxide and then 0.70 g (2.7 mmol) of iodine. The mixture is stirred for 12 hours and then acidified and diluted with 200 mL of water. The precipitated solids are collected and recrystallized from methanol to afford 0.51 g while crystals, m.p. 115°-116° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][C:19](N(C)C)=[O:20].O=P(Cl)(Cl)Cl>>[C:19]([C:12]1[C:11]2[C:15](=[CH:16][CH:17]=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:10]=2)[NH:14][CH:13]=1)(=[O:20])[CH3:18]
Reactant: CC(=O)N(C)C
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1c[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
In a manner similar to that described in Reference example 1, 5-benzyloxyindole was reacted with DMA/POCl3 to give 3-acetyl-5-benzyloxyindole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:32]
Reactant: O=C=Nc1ccccc1Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4Cl)cc3)c2cc1OC
Yield: 81 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was dissolved in toluene (5 ml) with heat, 2-chlorophenyl isocyanate (0.05 ml) was added, and the admixture was refluxed with heat for 30 minutes. The reaction solution was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 64 mg of the title compound (yield: 81%).
Reaction SMILES: C[Si](C)(C)CCOC[N:7](COCC[Si](C)(C)C)[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][N:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)=[C:12]2[N:11]=[C:10]([CH:28]2[CH2:33][CH2:32][C:31]([CH2:39][OH:40])([C:34]([O:36]CC)=[O:35])[CH2:30][CH2:29]2)[C:9]=1[C:41]([O:43]CC)=[CH2:42].Cl.[Li+].[OH-]>O1CCOCC1.C1COCC1.CO.O>[C:41]([C:9]1[C:10]([CH:28]2[CH2:29][CH2:30][C:31]([CH2:39][OH:40])([C:34]([OH:36])=[O:35])[CH2:32][CH2:33]2)=[N:11][C:12]2[N:13]([N:14]=[CH:15][C:16]=2[C:17]2[CH:18]=[N:19][N:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:21]=2)[C:8]=1[NH2:7])(=[O:43])[CH3:42]
Reactant: C=C(OCC)c1c(C2CCC(CO)(C(=O)OCC)CC2)nc2c(-c3cnn(-c4ccccc4)c3)cnn2c1N(COCC[Si](C)(C)C)COCC[Si](C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)c1c(C2CCC(CO)(C(=O)O)CC2)nc2c(-c3cnn(-c4ccccc4)c3)cnn2c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.7 %

Procedure:
To a solution of ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-6-(1-ethoxyvinyl)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate (167 mg, 0.211 mmol) in dioxane (2 mL) was added 2 mL of HCl (4 N, aq) at 0° C. The reaction mixture was stirred at rt for 1 h, then 60° C. for 1 h. The reaction mixture was evaporated to dryness. The residue was treated with LiOH (10 eq) in THF/MeOH/H2O (2/1/1 mL) at 80° C. overnight. The reaction mixture was carefully acidified with HCl (aq) to pH=6-7, and evaporated to dryness. The crude product was purified by a reverse phase HPLC to afford 4-(6-acetyl-7-amino-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylic acid as a pale yellow solid (27.7 mg). HPLC-MS TR=4.39 min (UV 254 nm, 10 min method); mass calculated for formula C25H26N6O4 474.2, observed LCMS m/z 475 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[N:12]=[C:11]([C:13]3[O:21][C:20]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[CH:14]=3)[O:10][N:9]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:28]([O:31][C:32](Cl)=[O:33])[CH2:29][CH3:30]>C(Cl)Cl.CCOCC>[CH2:28]([O:31][C:32]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[N:12]=[C:11]([C:13]3[O:21][C:20]4[CH:19]=[CH:18][N:17]=[CH:16][C:15]=4[CH:14]=3)[O:10][N:9]=2)[CH2:3][CH2:2]1)=[O:33])[CH2:29][CH3:30]
Reactant: CCCOC(=O)Cl
Reactant: c1cc2oc(-c3nc(CC4CCNCC4)no3)cc2cn1
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCOC(=O)N1CCC(Cc2noc(-c3cc4cnccc4o3)n2)CC1
Reaction time: 16 h

Procedure:
A solution of 2-(3-piperidin-4-ylmethyl-[1,2,4]oxadiazol-5-yl)furo[3,2-c]pyridine (Preparation 12, 0.65 g, 2.3 mmol) and pyridine (0.37 mL, 4.6 mmol) in anhydrous CH2Cl2 (25 mL) was added via cannula to a stirred solution of n-PrOCOCl (0.51 mL, 4.6 mmol) in anhydrous CH2Cl2 (35 mL). After 16 h, the reaction mixture was diluted with Et2O (200 mL), before being washed with H2O (100 mL), saturated aqueous Na2CO3 (100 mL), and H2O (100 mL). The organic phase was dried, filtered and concentrated. Flash chromatographic purification (EtOAc) of the residue furnished the title compound: RT=3.11 min; m/z (ES+)=371.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4]([NH:7][C@H:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][O:10][C:11](=[O:13])[CH3:12])=[N:3]1.[NH:20]1[C:24]2=[N:25][CH:26]=[CH:27][CH:28]=[C:23]2[C:22]([CH:29]=O)=[CH:21]1.C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[C:6](=[CH:29][C:22]2[C:23]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:20][CH:21]=2)[S:5][C:4]([NH:7][C@H:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][O:10][C:11](=[O:13])[CH3:12])=[N:3]1
Reactant: CC(=O)OC[C@H](NC1=NC(=O)CS1)c1ccccc1
Reactant: O=Cc1c[nH]c2ncccc12
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CC(=O)OC[C@H](NC1=NC(=O)C(=Cc2c[nH]c3ncccc23)S1)c1ccccc1
Temperature: 150 °C
Yield: 145.3 %

Procedure:
To a suspension of acetic acid 2-[4-oxo-4,5-dihydro-thiazol-2-ylamino]-2-(R)-phenyl-ethyl ester (400 mg, 1.43 mmol) and 1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (77.3 mg, 0.53 mmol) in toluene (5 mL) in a microwave tube was added benzoic acid (17.64 mg, 0.144 mmol) and piperidine (14.5 uL, 0.144 mmol) at room temperature. The microwave tube was sealed and heated to 150° C. in a closed microwave for 1 h. Then, the mixture was cooled to room temperature and diluted with toluene. The solids were collected by filtration and washed with toluene and dichloromethane. After drying in air, 313 mg (53.6% yield) of acetic acid 2-[4-oxo-5-(1H-pyrrolo[2,3,b]pyridine-3-ylmethylene)-4,5-dihydro-thiazol-2-ylamino]-2-(R)-phenyl-ethyl ester was isolated as a white solid: mp 243.7-246.8° C.; HRES(+) m/e calcd for C21H18N4O3S (M+H)+ 407.1173. found 407.1172.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([N+:20]([O-])=O)[CH:5]=1>C(OCC)(=O)C.[Ni]>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([NH2:20])[CH:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c([N+](=O)[O-])c1
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c(Oc2ccccc2)c(N)c1

Procedure:
25 g of 3,5-dinitro-4-phenoxy-benzoic acid methyl ester are dissolved in 250 ml of ethyl acetate, combined with 10 g of Raney nickel and hydrogenated. After absorption of the calculated amount of hydrogen, the catalyst is filtered off, the solvent is removed, whereupon the remaining oil crystallises. The raw product may be further reacted directly or recrystallized from methanol/water, whereby the diamino ester is obtained in form of colorless crystals melting at 140°-142° C. in excellent yield. Alternatively, the hydrogenation may also be carried out in an autoclave at 50° C. and 100 atmospheres guage pressure. The reaction time is then 3 to 5 hours, depending on the reactivity of the Raney nickel.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([O:16]C)=O)[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:19][NH2:20]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([NH:19][NH2:20])=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCCC1
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(C(=O)NN)CCCC1

Procedure:
Methyl 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylate and hydrazine monohydrate were reacted in methanol under heating to obtain 1-[(tert-butoxycarbonyl)amino]cyclopentanecarbohydrazide.
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Br-:11].[Li+].CC(=O)CCC>>[Br:11]/[CH:2]=[CH:3]/[C:4](=[O:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC(=O)/C=C/Cl
Reactant: [Br-]
Agent: [Li+]
Solvent: CCCC(C)=O
Product: CCCCCC(=O)/C=C/Br

Procedure:
A mixture of 68.0 g. (0.424 mole) of 1-chloro-trans-1-octen-3 one (Example 723) and 444 g. (4.24 moles) of anhydrous lithium bromide in 900 ml. of 2-pentanone is refluxed for 30 minutes, cooled, and partitioned between ice water and ether. The organic phase is washed with water and saturated brine, dried (NaSO4), and evaporated to an oil. This material is used directly without purification.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@H:15]([OH:28])[C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[N:24]=3)[N:19]=[CH:18][CH:17]=2)[C@H:10]([C:29]([F:32])([F:31])[F:30])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[N:24]=3)[N:19]=[CH:18][CH:17]=2)[OH:28])[C@H:10]([C:29]([F:30])([F:32])[F:31])[CH2:9]1
Reactant: COc1ccc2nccc([C@@H](O)CN3CC[C@H](NC(=O)OC(C)(C)C)C[C@H]3C(F)(F)F)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2nccc([C@@H](O)CN3CC[C@H](N)C[C@H]3C(F)(F)F)c2n1
Reaction time: 2 h

Procedure:
{(2S,4S)-[(R)-hydroxy-(6-methoxy-[1,5]naphthyridin-4-yl)ethyl]-2-(trifluoromethyl)piperidin-4-yl}carbamic acid tert-butyl ester (1j) is dissolved in CH2Cl2 and TFA (1:1, v/v). After 2 hrs, the solution is concentrated to dryness under vacuum and the residue is redissolved in 4 M HCl in dioxane. After 30 min, the slurry is triturated with Et2O and filtered. The solid is dissolved in H2O and the solution is made basic with aqueous NaOH. The basic aqueous solution is concentrated to dryness under vacuum and the residue is dried under high vacuum. The resulting solid is extracted with CH2Cl2/MeOH (10:1, v/v), and the combined extracts are concentrated and dried under high vacuum to give the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][N:17]([C:19]2[O:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH3:18])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(O)(=O)C.[N:32](OCCC(C)C)=O>C(Cl)(Cl)Cl>[O:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[N:17]([CH2:16][CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C:2](=[N+:1]=[N-:32])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1)[CH3:18]
Reactant: COC(=O)C(N)Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1
Reactant: CC(C)CCON=O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)=[N+]=[N-]

Procedure:
A mixture of methyl 2-amino-3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino]ethoxy]phenyl]propanoate (5.00 g), acetic acid (4.4 mL) and chloroform (160 mL) was treated dropwise with isoamyl nitrite (3.2 mL). The mixture was heated at reflux for 1.5 hrs, cooled, diluted with chloroform (200 mL) and washed successively with dilute hydrochloric acid (200 mL), water (2×200 mL) and brine (200 mL). The chloroform solution was dried over MgSO4, evaporated and the residue chromatographed on silica gel using 3% ethyl acetate in dichloromethane as eluent to afford the title compound, a gum.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][C:8](=[CH:12][CH2:13][CH:14]1[CH2:19][CH:18]2[C:16]([CH3:20])([CH2:17]2)[C:15]1([CH3:22])[CH3:21])[C:9](=[O:11])[CH3:10].CI.O>O1CCCC1>[CH3:7][C:8]([CH3:1])([CH:12]=[CH:13][CH:14]1[CH2:19][CH:18]2[C:16]([CH3:20])([CH2:17]2)[C:15]1([CH3:22])[CH3:21])[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)C(C)=CCC1CC2CC2(C)C1(C)C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C(C)(C)C=CC1CC2CC2(C)C1(C)C
Temperature: -35 °C
Reaction time: 0.08 h
Yield: 77.9 %

Procedure:
5.0 g (43 mmol) of potassium tert-butoxide dissolved in 50 ml of tetrahydrofuran was added to the solution of 8.7 g (40 mmol) of 3-methyl-5-(1,2,2-trimethylbicyclo-[3.1.0]hex-3-yl)pent-3-en-2-one in 50 ml of the same solvent at −40° C. After 5 minutes of stirring at −35° C. 7.0 g (45 mmol) of methyl iodide was added rapidly and stirring continued at −20° C. for 10 minutes. The reaction mixture was poured on 200 ml of water and worked up as usual. Flash chromatography of the crude product (silica gel; eluent: hexane/MTBE 9:1) followed by Kugelrohr distillation at 150° C./0.1 Torr gave 7.3 g (78% yield) of 3,3-dimethyl-5-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)pent-4-en-2-one.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:22]([O:23]C(=O)C)[C@H:21]([O:27]C(=O)C)[C@@H:20]([CH2:31][O:32]C(=O)C)[O:19][C@H:6]1[S:7][C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=1[CH3:18])(=O)C.C[O-].[Na+]>CO>[S:7]([C:8]1[CH:13]=[C:12]([C:14]([CH3:16])([CH3:15])[CH3:17])[CH:11]=[CH:10][C:9]=1[CH3:18])[C@@H:6]1[O:19][C@H:20]([CH2:31][OH:32])[C@@H:21]([OH:27])[C@H:22]([OH:23])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2cc(C(C)(C)C)ccc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(C)(C)C)cc1S[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
Thioglycoside 9 (1.5 g, 2.94 mmol) was dissolved in of methanol (12 mL). Sodium methoxide (58 mg, 1.07 mmol, 0.37 eq) was added and the reaction was stirred over night. After completion, the solution was neutralized with Amberlite IR 120 (H+) ion exchange resin, filtered and concentrated in vacuo. The remainder was dried in high vacuum to give (2-Methyl-5-tert-butylphenyl) 1-thio-β-D-glucopyranoside S1 (1.0 g) which was used for the next reaction step without further purification. Tetrol S1 (1.0 g) was dissolved in anhydrous acetonitrile (11.3 mL) at RT under argon atmosphere and benzaldehyde dimethylacetal (880 μL, 5.84 mmol, 2 eq) and camphorsulfonic acid (7 mg, 0.029 mmol, 0.01 eq) were added. After 2.5 h (TLC: cyclohexane/ethyl acetate, 1:2), the reaction was quenched with triethylamine, and the solvents were evaporated in vacuo to give 1.5 g of colorless oil. The crude product was purified by column chromatography on silica gel (cyclohexane/ethyl acetate) to afford 10 (1.09 g, 2.53 mmol, 87%). [α]D20=−49.4° (c=1.0, CH2Cl2); IR (CH2Cl2): 3410, 2963, 2870, 1384, 1264, 1082, 1072, 1029, 1003, 972 cm−1; 1H-NMR (400 MHz, CDCl3) δ 7.61 (1H, d, J 2.0 Hz, Ar—H), 7.51-7.46 (2H, m, Ar—H), 7.39-7.35 (m, 3H, Ar—H), 7.29-7.23 (m, 2H, Ar—H), 7.16 (1H, d, J=8.0, Ar—H), 5.54 (1H, s, benzylidene-H), 4.64 (1H, d, J 10.0, 1-H), 4.36 (1H, dd, J1 10.3, J2 4.5, 6-Ha), 3.90-3.73 (2H, m, 3-H, 6-Hb), 3.59-3.47 (3H, m, 2-H, 4-H, 5-H), 2.86 (1H, d, J 2.2, OH), 2.69 (1H, d, J 2.4, OH), 2.42 (3H, s, CH3), 1.32 (9H, s, t-Bu); 13C-NMR (100 MHz, CDCl3) δ 149.7, 137.1, 137.0, 131.0, 130.3, 130.2, 129.4, 128.5, 126.4, 125.5 (C-aromatic), 102.0 (C-benzylidene), 88.8 (C-1), 80.4 (C-2), 74.8 (C-3), 73.0 (C-4), 70.5 (C-5), 68.7 (C-6), 31.4 (tBu), 20.6 (CH3); HRMS (ESI): Calcd for C24H30O5S [M+Na]+ 453.1706. found 453.1714.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]([CH:14]2[CH2:16][CH2:15]2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=1[F:25])=[O:4].[OH-].[Na+]>C1COCC1.CO.O>[CH:14]1([N:13]2[C:12]3[CH:11]=[CH:10][N:9]=[CH:8][C:7]=3[C:6]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[C:5]2[C:3]([OH:4])=[O:2])[CH2:15][CH2:16]1
Reactant: COC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C1CC1
Temperature: 65 °C
Reaction time: 1 h
Yield: 168.8 %

Procedure:
To a stirred solution of 1-cyclopropyl-3-(2-fluoro-4-iodo-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (150.0 mg, 0.33 mmol) in anhydrous THF (3.5 mL) and anhydrous methanol (1.0 mL) under N2 was added freshly prepared 1N aqueous sodium hydroxide (0.66 ml, 2.0 eq). The reaction mixture was stirred at 65° C. for 1 h. The resultant reaction mixture was evaporated in vacuo and azeotroped with toluene (3×5 ml) to give a yellow solid. The yellow solid was redissolved in water (5 mL), and concentrated. Acetic acid (2 drops) was added. A yellow solid precipitated out, and the solid was filtered, rinsed well with water, and dried on high-vacuum pump to give 243.6 mg (77.4%) of the product. 1H-NMR (500 MHz, DMSO-d6) δ ppm 8.54 (s, 1H), 8.32 (d, J=6.0 Hz, 1H), 7.95 (br s, 1H), 7.65-7.52 (m, 2H), 7.33 (d, J=8.4 Hz, 1H), 6.67 (t, J=9.6 Hz, 1H), 3.53-3.28 (m, 1H), 1.20-1.07 (m, 2H), 0.85 (m, 2H); LC-MS (method C): [M+H]+=438.0, RT=0.67 min.
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.N[C:15]1[CH:19]=C[NH:17][N:16]=1>C(O)(=O)C>[C:7]1([C:5]2[N:17]3[N:16]=[CH:15][CH:19]=[C:13]3[N:2]=[CH:3][CH:4]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cc[nH]n1
Reactant: CN(C)C=CC(=O)c1ccccc1
Solvent: CC(=O)O
Product: c1ccc(-c2ccnc3ccnn23)cc1

Procedure:
A reaction mixture of 5.25 g. of 3-dimethylaminoacrylophenone [von H. Meerwein et al., Annalen der Chemie, Band 641, 1-39, (1961)] and 2.50 g. of 3-aminopyrazole in 25 ml. of glacial acetic acid is refluxed for 3.5 hours, cooled overnight and evaporated to a thick yellow oil. This oil is dissolved in methylene chloride, washed with a saturated aqueous solution of sodium bicarbonate, dried over sodium sulfate and then passed through a sintered glass funnel or a chromatographic column packed in vacuo with hydrous magnesium silicate. Additional methylene chloride is passed through the funnel (column). The effluent is refluxed on a steam bath. The gradual addition of hexane produces crystals. The crystallization from methylene chloride with hexane is repeated giving the desired product, m.p. 72°-73° C.
Reaction SMILES: [CH2:1]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[C:6]([C:8]1[C:12](Cl)=[C:11]([CH3:14])[NH:10][N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[Br:19]C1C(C(OCC)=O)=NNC=1C>>[Br:19][C:12]1[C:8]([C:6]([N:5]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])=[N:9][NH:10][C:11]=1[CH3:14]
Reactant: CCOC(=O)c1n[nH]c(C)c1Br
Reactant: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Cl
Product: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Br
Yield: 75 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1B, ethyl 4-bromo-5-methyl-1H-pyrazole-3-carboxylate (Tabrizi, M. A. et al., Bioorg. Med. Chem., 16:2419-2430 (2008)) (5.68 g, 24.4 mmol) was converted to the title compound (5.79 g, 75%). 1H NMR (CDCl3) δ 3.51 (t, J=7.4 Hz, 2H), 3.38-3.26 (m, 2H), 2.34 (s, 3H), 1.73-1.34 (m, 6H), 1.22-1.13 (m, 2H), 1.03-0.75 (m, 6H); MS(ESI+) m/z 316.2 (M+H)+.