Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:11]=1[C:12]#[C:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[OH:20][C:21]1[CH:22]=[C:23]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Na+].[Cl-]>CN(C)C=O>[C:14]1([C:13]#[C:12][C:11]2[N:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[CH2:2][O:20][C:21]2[CH:22]=[C:23]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1nc2ccccn2c1C#Cc1ccccc1
Reactant: CS(=O)(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(OCc2nc3ccccn3c2C#Cc2ccccc2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 19.1 %

Procedure:
0.094 g (0.352 mmol) of 2-(chloromethyl)-3-(phenylethynyl)imidazo[1,2-a]pyridine were dissolved in 2 ml of dimethylformamide with magnetic stirring, 121 mg (0.529 mmol) of N-(3-hydroxyphenyl)methanesulfonamide and 0.172 g (0.529 mmol) of cesium carbonate were added. The mixture was stirred at 60° C. for 3 h before being poured onto 15 ml of a saturated NaCl aqueous solution. The aqueous phase was extracted with 2×20 ml of ethyl acetate. The combined organic phases were dried on Na2SO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo. The crude residue was purified by preparative HPLC and 0.028 g (yield=18%) of N-(3-((3-(phenylethynyl)imidazo[1,2-a]pyridin-2-yl)-methoxy)phenyl)methane sulfonamide were obtained as a white solid. LC-MS: m/z=418 (MH+); UV purity at 254 nm=95%. 1H NMR (300 MHz, DMSO) δ 9.53 (s, 1H), 8.55 (d, J=6.8 Hz, 1H), 7.76-7.57 (m, 3H), 7.54-7.33 (m, 4H), 7.17-7.02 (m, 2H), 6.89 (dd, J=8.0, 1.1 Hz, 1H), 6.79 (t, J=2.1 Hz, 1H), 6.69-6.54 (m, 1H), 5.07 (s, 2H), 3.14 (s, 3H).
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[OH-].[Na+].[P:22]([OH:26])([OH:25])([O-:24])=[O:23].[K+]>>[C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[CH:17]1[NH:18][C:19]2[N:10]([C@@H:1]3[O:9][C@H:6]([CH2:7][O:23][P:22]([OH:26])([OH:25])=[O:24])[C@@H:4]([OH:5])[C@H:2]3[OH:3])[CH:11]=[N:12][C:13]=2[C:14](=[O:15])[N:16]=1
Reactant: O=P([O-])(O)O
Agent: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: [K+]
Agent: [Na+]
Product: O=c1nc[nH]c2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
After completion of fermentation, about 30 g/l of inosine was accumulated in the medium obained in (8) above. As indicated in Table 9, 20 ml of a reaction mixture containing this medium was prepared. In a manner similar to (9), while keeping at 32° C. with vigorously stirring and also keeping pH at 7.2 with 4N NaOH, a reaction was carried out for 13 hours. During the course of reaction, monopotassium phosphate was added as in (9). From 23.5 g/l of initial inosine, 46 g/l of 5'-IMP was produced and accumulated. Also in this case, its molar conversion rate was 90% or more, as in (9).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:12][C:13]([OH:15])=[O:14])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:17]1([S:23]([NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:12][C:13]([OH:15])=[O:14])[C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1cc2ccccc2n(CC(=O)O)c1=O
Solvent: c1ccncc1
Product: O=C(O)Cn1c(=O)c(NS(=O)(=O)c2ccccc2)cc2ccccc21

Procedure:
EX-4A) 2-[3-Amino-2-oxo-2H-quinolin-1-yl]acetic acid, (0.206 g, 0.81 mmol) was treated with benzenesulfonyl chloride (0.172 g, 0.97 mmol) in pyridine for one hour. After removing the pyridine, the residue was recrystallized in acetone to yield a white crystal solid as the product, 2-[3-benzenesulfonylamino-2-oxo-2H-quinolin-1-yl]acetic acid, (EX-4A)(0.1 17 g, y=41% ). HPLC-MS (0 to 95% AcCN/6 min @ 1.0 mL/Min @ 254 nm @ 50° C.): retention time 2.85 min, M+H+=359.2 for formula C17H15N2O2S. 1H NMR (400 MHz, Acetone-d6): d 5.12 (s, 2H), 7.28 (t, J=7.2 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.48-7.63 (m, 4H), 7.75 (dd, J=8, 1.6 Hz, 1H), 7.74 (s, 1H), 8.00-8.03 (m, 2H). 13C NMR (101 MHz, Acetone-d6): d (ppm) 44.8, 115.0, 120.8, 120.9, 123.9, 127.8, 128.1, 129.4, 129.9, 130.1, 134.2, 136.7, 140.4, 158.2, 169.1.
Reaction SMILES: Br[C:2]([CH3:31])([CH3:30])[C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1)=[O:4].[N-:32]=[N+:33]=[N-:34].[Na+]>C(#N)C>[N:32]([C:2]([CH3:31])([CH3:30])[C:3]([NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1)=[O:4])=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C(C)(C)Br)c2c1
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C(C)(C)N=[N+]=[N-])c2c1
Yield: 108 %

Procedure:
To a solution of 2-bromo-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-2-methylpropanamide (160 mg, 0.319 mmol) in actonitrile (15 mL) was added sodium azide (62 mg, 0.958 mmol). After being refluxed overnight, the resulting mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (40 mL), washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford 160 mg of the crude product.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:26]=[C:25]([CH3:27])[C:18]([O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[C:17]([CH3:28])[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2].[CH3:30]C1N=C(NCCC)N=C(C(O)=O)C=1>>[CH3:27][C:25]1[CH:26]=[C:15]([C:12]2[N:11]=[C:10]([C:8]3[CH:7]=[C:6]([CH3:29])[N:5]=[C:4]([NH:3][CH2:1][CH2:2][CH3:30])[N:9]=3)[O:14][N:13]=2)[CH:16]=[C:17]([CH3:28])[C:18]=1[O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23]
Reactant: CCCNc1nc(C)cc(C(=O)O)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1
Product: CCCNc1nc(C)cc(-c2nc(-c3cc(C)c(OCC(O)CO)c(C)c3)no2)n1

Procedure:
rac-3-{2,6-Dimethyl-4-[5-(6-methyl-2-propylamino-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-phenoxy}-propane-1,2-diol is prepared in analogy to rac-3-{4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethyl-phenoxy}-propane-1,2-diol using 6-methyl-2-propylamino-pyrimidine-4-carboxylic acid; LC-MS: tR=0.85 min*; [M+H]+=414.15.
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:38])[C:19]([C:35]([OH:37])=[O:36])=[CH:20][N:21]3CC3C=CC(OC)=CC=3OC)=[C:16]([CH3:39])[C:15]=2[F:40])[CH2:10]1)=O)(C)(C)C>FC(F)(F)C(O)=O>[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[C:22]3[C:17]([C:18](=[O:38])[C:19]([C:35]([OH:37])=[O:36])=[CH:20][NH:21]3)=[C:16]([CH3:39])[C:15]=2[F:40])[CH2:10]1
Reactant: COc1ccc(Cn2cc(C(=O)O)c(=O)c3c(C)c(F)c(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(F)c(N2CC[C@@H](N)C2)nc2[nH]cc(C(=O)O)c(=O)c12

Procedure:
A solution of Example 1F (334 mg) in trifluoroacetic acid (25 mL) was refluxed for 3 hours then cooled and concentrated. The concentrate was azeotroped with toluene and dissolved in water (250 mL); and this solution was washed with diethyl ether, filtered through a 0.45 μm syringe membrane filter, and lyophilized. NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 4.01-3.75 (m, 5H), 2.71 (m, 3H), 2.30 (m, 1H), 2.10 (m, 1H).
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[CH2:21]([OH:24])[C:22]#[CH:23].[Cl-].[NH4+]>N1CCCC1.[Cu]I>[OH:24][CH2:21][C:22]#[C:23][C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1
Reactant: C#CCO
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCNC1
Product: OCC#Cc1cc(C(F)(F)F)cc2ncn(-c3ccccc3)c12
Temperature: 75 °C
Reaction time: 5 h
Yield: 183.4 %

Procedure:
To a stirred solution of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (9.7 g, 25 mmol) and tetrakis (triphenylphosphine)palladium(0) (2.9 g, 5 mmol) in pyrrolidine (75 ml) was added a solution of 2-propyn-1-ol (5.6 g, 0.1 mol) in pyrrolidine (75 ml), then copper (I) iodide (475 mg, 2.5 mmol). The resulting solution was heated to 75° C. with stirring under nitrogen. After 5 h the reaction mixture was allowed to cool, treated with saturated aqueous ammonium chloride and extracted with diethyl ether. The combined organic extracts were dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to leave a residue (14.5 g). This residue was flash chromatographed over silica gel (eluted with dichloromethane/diethyl ether 4:1) to give the desired product (2.53 g, 32%) m/z, 316.8 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][S:14]([C:17]2[CH:29]=[CH:28][C:20]([C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:4][CH:3]=1.[OH:32][CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[F:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][S:14]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([NH:23][CH2:24][C:25]([N:36]3[CH2:37][CH2:38][CH:33]([OH:32])[CH2:34][CH2:35]3)=[O:26])=[O:22])=[CH:28][CH:29]=2)(=[O:15])=[O:16])=[CH:4][CH:3]=1
Reactant: OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(F)cc2)cc1
Product: O=C(NCC(=O)N1CCC(O)CC1)c1ccc(S(=O)(=O)Nc2ccccc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared from {4-[2-(4-fluoro-phenoxy)-phenylsulfamoyl]-benzoylamino}-acetic acid and 4-hydroxypiperidine according to the method described in Example 1.1/f. MS (EI) 528.4 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10]3[NH:11][N:12]=[CH:13][C:14]=3[C:5]=2[CH:4]=[N:3]1.[H-].[Na+].[CH3:17]I>CN(C)C=O>[CH3:1][N:2]1[C:6]2[CH2:7][CH2:8][CH2:9][C:10]3[N:11]([CH3:17])[N:12]=[CH:13][C:14]=3[C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1CCCc1[nH]ncc1-2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2c1CCCc1c-2cnn1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 19.4 g of 4,5,6,7-tetrahydro-3-methyl-3H-cyclohepta[1,2-c:4,3-c']dipyrazole in 70 ml of N,N-dimethylformamide was added, dropwise, to a suspension of 2.64 g of sodium hydride in 200 ml of N,N-dimethylformamide and the resulting mixture was stirred at room temperature for 15 minutes. A solution of 12.5 ml of methyl iodide in 20 ml of N,N-dimethylformamide was added dropwise and the reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted several times with dichloromethane and the combined dichloromethane layers were washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give a tan powder which was shown to be a 50:50 mixture of the 2,7-dimethyl and 3,7-dimethyl products as shown by 1H NMR. The tan powder was recrystallized from toluene to give a tan solid which was again recrystallized from toluene to give 4,5,6, 7-tetrahydro-3,7-dimethyl-3H-cyclohepta[1,2-c:4,3-c']dipyrazole as tan needles melting at about 191°-195° C.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[NH2:18])[S:13][C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1([C:29]2[N:30]=[C:31]([C:34](O)=[O:35])[S:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[C:23]1([C:29]2[N:30]=[C:31]([C:34]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:14]3[S:13][C:10]4[C:9]([N:15]=3)=[CH:8][C:7]([CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:12][N:11]=4)=[O:35])[S:32][CH:33]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Reactant: O=C(O)c1nc(-c2ccccc2)cs1
Solvent: O
Product: O=C(Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1)c1nc(-c2ccccc2)cs1

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-(pyrrolidin-1-ylmethyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 4-phenylthiazole-2-carboxylic acid. The product was isolated by precipitation by the addition of water, triturated with hot methanol and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2). MS Calcd for C27H23N5OS2: 497.13. Found (M+H)+ m/z=498.
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([CH3:24])([CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH3:16])=[CH:11][CH:10]=1)=[O:7])([O-])=O.[H][H]>CCO.[Pd]>[NH2:1][C:4]1[CH:28]=[CH:27][CH:26]=[CH:25][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([CH3:24])([CH:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)[CH3:16])=[CH:13][CH:14]=1)=[O:7]
Reactant: CN1CCC(C(C)(C)c2ccc(NC(=O)c3ccccc3[N+](=O)[O-])cc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1CCC(C(C)(C)c2ccc(NC(=O)c3ccccc3N)cc2)CC1

Procedure:
2-Nitro-N-{4-[1-methyl-1-(1-methylpiperidin-4-yl)ethyl]phenyl}benzamide (Step A, 750 mg) was mixed with Pd/C (10%, 200 mg) in EtOH (80 mL) and hydrogenated under a hydrogen atmosphere for 1 h. The solution was filtered through Celite® and evaporated to give the amine used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.Cl.[N:21]1[C:26]2[CH2:27][CH2:28][NH:29][CH2:30][C:25]=2[CH:24]=[N:23][CH:22]=1>>[N:21]1[C:26]2[CH2:27][CH2:28][N:29]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:30][C:25]=2[CH:24]=[N:23][CH:22]=1
Reactant: c1ncc2c(n1)CCNC2
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: Cl
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCc4ncncc4C3)n2)c1

Procedure:
B39 was prepared following the general procedure reported for B10 using A1 and 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine hydrochloride; yield: 29.7 mg (7%), pale yellow solid. MS (ES) C17H18N8O2S requires: 398. found: 399 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH:9]([P:20](=[O:27])([O:24]CC)[O:21]CC)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1>C(O)C.Cl>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:4]=[C:5]([CH:9]([P:20](=[O:21])([OH:27])[OH:24])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOP(=O)(OCC)C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCO
Product: O=P(O)(O)C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Temperature: 95 °C

Procedure:
O,O-Diethyl bis(3-trifluoromethylphenyl)methylphosphonate (6.12 g, 13.9 mmol) was dissolved in ethanol (220 mL) and 118 mL of concentrated hydrochloric acid. The resulting solution was heated at 95° C. for 66 hours. The mixture was concentrated in volume and a precipitate formed. The solid was filtered, washed with H2O (3×20 mL), and dried to give 3.60 g (67.4%)of analytically pure product as a white solid, mp 191°-193° C. 300 MHz 1H NMR (DMSO-d6): δ,4.78 (d,1H, J=23.4 Hz, PCH). MS: 385 (M+1).
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=[C:2]1[C:9]([OH:11])=[O:10]>C(O)(=O)C>[O:1]1[CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3][CH:2]1[C:9]([OH:11])=[O:10]
Reactant: O=C(O)c1ccc(C(=O)O)o1
Solvent: CC(=O)O
Product: O=C(O)C1CCC(C(=O)O)O1
Temperature: 140 °C
Yield: 87.6 %

Procedure:
A 100 mL pressure vessel with a glass liner and an impeller was charged with 1.87 g of furan-2,5-dicarboxylic acid, 0.5 g of 4% Pd/Silica and 40 mL of acetic acid. The pressure vessel was purged 3 times with nitrogen, and 2 times with hydrogen. The vessel was then pressurized to 750 psig hydrogen and heated to 140° C. for 3 hours. After cooling the vessel was vented and the solids were separated by filtration. The acetic acid solution was evaporated under vacuum to provide 1.68 g (88% yield) of tetrahydrofuran-2,5-dicarboxylic acid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:38]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]=[CH:17][N:18]([C:19]3[S:23][C:22]([C:24]([NH2:38])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH3:37])[CH3:30])[CH:20]=3)[C:12]=2[CH:11]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1OC(C)c1ccccc1C
Solvent: CO
Product: Cc1ccccc1C(C)Oc1cc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)sc1C(N)=O

Procedure:
In a similar manner as described for example A9, 1.25 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-[1-(2-methylphenyl)ethoxy]thiophene-2-carboxylate and 60 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: C1(=O)[N:5]([CH:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:12][NH:13]3)[CH2:7][CH3:8])C(=O)C2=CC=CC=C12.O.NN>>[NH2:5][CH:6]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[C:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:12][NH:13]2)[CH2:7][CH3:8]
Reactant: CCC(c1cccc2[nH]nc(-c3ccccc3)c12)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Product: CCC(N)c1cccc2[nH]nc(-c3ccccc3)c12
Yield: 96.1 %

Procedure:
By the procedure similar to that described in Example 33, 1-phthalimidopropyl-3-phenylindazole (6.0 g) and hydrazine hydrate (2.0 g) were treated to obtain 3.8 g of 1-aminopropyl-3-phenylindazole as an oily product.
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13](Br)[CH:12]=[CH:11]2.[CH:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1)=[O:20].[Cl-].[NH4+]>C1COCC1.C(=O)=O.CC(C)=O.CCOC(C)=O>[OH:20][CH:19]([C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH3:6])[CH:9]=2)[CH:14]=1)[C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: COc1ccc2cc(Br)ccc2c1
Agent: O=C=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)c2ccc3cc(OC)ccc3c2)cc1
Reaction time: 0.25 h

Procedure:
n-BuLi (4.4 mL of a 2.5 M solution in hexanes, 11 mmol) was added dropwise to a solution of 6-methoxy-2-bromonaphthalene (2.4 g, 10 mmol) in 80 mL of THF cooled in dry ice-acetone bath. After aging for 15 min, the cold mixture was quickly cannulated to a stirring mixture of methyl 4-formylbenzoate (1.64 g, 10 mmol) in 20 mL of THF cooled in dry ice-acetone bath. After stirring for an additional 15 min, the reaction mixture was poured into a mixture of aq ammonium chloride, hexanes and EtOAc. The organic phase was separated, concentrated and purified by flash chromatography on silica gel (mobile phase=10% to 30% EtOAc in hexanes) to give the title compound as a racemic mixture.
Reaction SMILES: [C:1]1([CH:7]([CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]12[CH2:26]C[CH:22]([CH2:23][CH2:24]1)[C@@H:21](O)[CH2:20]2>C1(C)C=CC=CC=1>[C:1]1([CH:7]([CH2:12][CH2:13][N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[C:8]([O:10][C@@H:11]2[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:26]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COC(=O)C(CCn1cccn1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O[C@H]1CN2CCC1CC2)C(CCn1cccn1)c1ccccc1
Yield: 60.3 %

Procedure:
A mixture of methyl (RS)-2-phenyl-4-(1H-pyrazol-1-yl)butanoate (see Preparation 17) (0.37 g), (R)-3-quinuclidinol (0.24 g) sodium hydride (15 mg, as an 80% dispersion in oil) in toluene (15 ml) as refluxed with continuous removal of distillate and, when necessary, replacement with fresh toluene, for 11/2 hours. The cooled mixture was successively washed with water then saturated brine and extracted with 2M hydrochloric acid. The aqueous layer was washed with ethyl acetate, basified with potassium carbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulphate and evaporated to give the title compound (0.31 g, 61%) as a yellow oil
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>C1COCC1>[OH:2][CH2:1][C:3]1[N:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)nc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(CO)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(6-formyl-pyridin-3-yl)-piperazine-1-carboxylate (0.39 mmol) in THF (10 mL) is added NaBH4 (2.72 mmol) and the reaction mixture is stirred at room temperature for 1 hour. After it is cooled to 0° C., the reaction mixture is slowly mixed with ice cold water (5 mL) and then partitioned between saturated Na2CO3 solution and 10% MeOH in EtOAc. The aqueous phase is extracted with 10% MeOH in EtOAc. The combined organic extracts are washed with saturated aqueous NaCl and dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (100/10/1 EtOAc/MeOH/Et3N) to give tert-butyl 4-(6-hydroxymethyl-pyridin-3-yl)-piperazine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:25]2[S:29][C:28]([C:30]3([O:34]COC)[CH2:33][CH2:32][CH2:31]3)=[N:27][CH:26]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3N=C(C4CCCN(C(OC(C)(C)C)=O)C4)ON=3)NC2=NC=1>>[Cl:1][C:2]1[C:3]([C:25]2[S:29][C:28]([C:30]3([OH:34])[CH2:33][CH2:32][CH2:31]3)=[N:27][CH:26]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(OC6CCN(C)CC6)cc5)cc34)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5noc(C6CCCN(C(=O)OC(C)(C)C)C6)n5)cc34)s2)CCC1
Product: CN1CCC(Oc2ccc(-c3cc4c(-c5cnc(C6(O)CCC6)s5)c(Cl)cnc4[nH]3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 22E, substituting 5-(5-chloro-2-(4-(1-methylpiperidin-4-yloxy)phenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(1-(methoxymethoxy)cyclobutyl)thiazole (Example 72B) for 1 tert-butyl 3-(3-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Example 22D). 1H NMR (500 MHz, DMSO-d6) ppm 12.46 (s, 1H) 8.28 (s, 1H) 8.24 (s, 1H) 7.92 (d, 2H) 7.04 (d, 2H) 6.93 (d, 1H) 6.68 (s, 1H) 4.47 (m, 1H) 2.63 (m, 4H) 2.41 (m, 2H) 2.23 (m, 2H) 2.20 (s, 3H) 1.96 (m, 4H) 1.66 (m, 2H); MS ESI(+) m/z 495.0 [M+H]+.