Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:24])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][N:19]=[C:18]([C:21](O)=[O:22])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].CC[N:27](C(C)C)C(C)C.N.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:7]([CH3:24])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:20][N:19]=[C:18]([C:21]([NH2:27])=[O:22])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)n[nH]3)c2nc1NC(C)(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nc2cccc(-c3cc(C(N)=O)n[nH]3)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a 10-mL reaction vial was added ethyl 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylate (467a) (94 mg, 0.27 mmol), LiOH hydrated (56 mg, 1.33 mmol), dioxane (4 mL), and water (1 mL). The reaction mixture was heated at 50° C. for 1 h and at 100° C. for 2 h and then cooled to RT. The solvent was removed under vacuum and HCl (1N, 3 mL) was added, the yellow precipitate obtained was filtered off, washed with water, and dried. 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylic acid (467b) was obtained as a yellow solid and used without further purification. To a 50-mL round-bottomed flask was added 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylic acid (467b) (77 mg, 0.24 mmol), DCM (3 mL), DMF (1 mL), DIPEA (82 μL, 0.47 mmol), ammonia (0.95 mL, 0.47 mmol, 0.5 M in dioxane), and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (123 mg, 0.24 mmol) (Sigma-Aldrich). The reaction mixture was stirred at RT for 30 min, concentrated to half of its volume, and diluted with EtOAc (20 mL). The organic extract was washed with sat NaHCO3 (10 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 30% to 40% EtOAc in hexanes to give 5-(3-(tert-butylamino)-2-methyl-quinoxalin-5-yl)-1H-pyrazole-3-carboxamide (467) (65 mg, 85% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 13.38 (br. s, 1H), 7.85 (dd, J=1.08, 7.34 Hz, 1H), 7.76 (d, J=7.63 Hz, 1H), 7.53 (br. s., 1H), 7.41 (t, J=7.73 Hz, 1H), 7.30 (s, 1H), 7.18 (br. s, 1H), 6.06 (br. s., 1H), 2.58 (s, 3H), 1.52 (s, 9H). m/z (ESI, +ve) 325.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][OH:27])[C:20]([O:28][CH3:29])=[CH:19][C:18]=3[N+:30]([O-])=O)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[H][H].[CH:35](O)=O>[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:17]4[CH:22]=[C:21]([O:23][CH2:24][CH2:25][CH2:26][OH:27])[C:20]([O:28][CH3:29])=[CH:19][C:18]=4[N:30]=[CH:35]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)cc1OCCCO
Reactant: O=CO
Reactant: [H][H]
Agent: [Pd]
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1OCCCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.200 g (0.42 mmole) of 4-(3-chloro-phenyl)-2-[5-(3-hydroxy-propoxy)-4-methoxy-2-nitro-phenylamino]-thiazole-5-carboxylic acid amide (VI.42), 0.150 g of 10% palladium on carbon catalyst, and 4 mL of 96% formic acid was stirred under 1 atmosphere of hydrogen at room temperature for 16 hours. The mixture was filtered through Diatomaceous earth, and the Diatomaceous earth pad was washed with formic acid. The filtrate was heated at reflux for 1 hour, cooled and concentrated under reduced pressure. The residue was dissolved in 4 mL of dimethylsulfoxide and 0.30 g of potassium hydroxide in 1 mL of water was added dropwise. The mixture was stirred at room temperature for 1 hour and then diluted with 10 mL of water. The resulting precipitate was collected by filtration and washed with water to give 0.105 g of 4-(3-chloro-phenyl)-2-[6-(3-hydroxy-propoxy)-5-methoxy-benzoimidazol-1-yl]-thiazole-5-carboxylic acid amide (I.42a) as a purple solid.
Reaction SMILES: [Br:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH:14]1[CH:19]=[CH:18][C:17]([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1>O1CCOCC1>[Br-:1].[O:13]=[C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:3]([CH2:2][P+:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:17]2[CH:16]=[CH:15][CH:14]=[CH:19][CH:18]=2)[NH:4]1
Reactant: O=c1[nH]c(CBr)cc2ccccc12
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: O=c1[nH]c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc2ccccc12
Product: [Br-]
Temperature: 25 °C

Procedure:
A solution of 3-(bromomethyl)isoquinolin-1(2H)-one and PPh3 (1.8 g, 6.87 mmol) in 1,4-dioxane (50 mL) was refluxed for 2 h. After cooling to room temperature, the reaction mixture was filtered to give the desired product (317 mg). LC-MS: m/z 420 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@@H:7]([CH3:18])[CH2:6][NH:5]2.N1C=CC=CC=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:28]([CH:25]1[CH2:27][CH2:26]1)=[O:29]
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@H]1CN(C(=O)C2CC2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
A 250-mL, three-necked, round bottomed flask fitted with a nitrogen inlet, magnetic stir bar, and thermocouple was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxalin-1(2H)-yl)-2,2,2-trifluoroethanone (7.0 g, 21.66 mmol), dichloromethane (140 mL), and pyridine (2.63 mL, 32.5 mmol). The mixture was cooled to 0° C. and cyclopropanecarbonyl chloride (2.36 mL, 26.0 mmol) was slowly added while maintaining the internal temperature below 7° C. The reaction mixture was stirred cold for 30 min. and then warmed to rt. The reaction mixture was washed with 1 M aqueous HCl solution (25 mL) and water (25 mL), and the combined organic layers were concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 4:1 hexanes-ethyl acetate) to afford (S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (8.26 g, 97%) as an off-white solid. MS (ESI, pos. ion) m/z 392 [M+1]+.
Reaction SMILES: [CH3:1][O:2][N:3]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=2)[CH:5]=[CH:4]1.Cl.[NH:18]1[C:22]([C:23]2[CH:24]=[C:25]3[C:35](=[CH:36][CH:37]=2)[O:34][C:28]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][C:26]3=[O:38])=[N:21][N:20]=[N:19]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(N(CC)CC)C>[CH3:1][O:2][N:3]1[C:11]2[C:6](=[C:7]([O:15][CH3:16])[CH:8]=[C:9]([C:12]([N:31]3[CH2:32][CH2:33][C:28]4([CH2:27][C:26](=[O:38])[C:25]5[C:35](=[CH:36][CH:37]=[C:23]([C:22]6[NH:21][N:20]=[N:19][N:18]=6)[CH:24]=5)[O:34]4)[CH2:29][CH2:30]3)=[O:14])[CH:10]=2)[CH:5]=[CH:4]1
Reactant: O=C1CC2(CCNCC2)Oc2ccc(-c3nnn[nH]3)cc21
Reactant: COc1cc(C(=O)O)cc2c1ccn2OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4nnn[nH]4)ccc2O3)cc2c1ccn2OC
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (310 μl) and water (1.5 mL) were added to a solution of 1,4-dimethoxy-1H-indole-6-carboxylic acid (300 mg), 6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one hydrochloride (478 mg), WSC (311 mg) and HOBT (249 mg) in DMF (6 mL), and stirred at 90° C. for 30 minutes. Water was added thereto at room temperature, and a white precipitate was thus obtained. This was dried under reduced pressure, washed with a mixed solvent of methanol and diethyl ether, and dried again under reduced pressure to obtain the above-described compound as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ: 8.41 (1H, d, J=2.2 Hz), 8.23 (1H, dd, J=8.5, 2.2 Hz), 7.63 (1H, d, J=3.4 Hz), 7.33 (1H, d, J=8.5 Hz), 7.11 (1H, s), 6.58 (1H, s), 6.37 (1H, d, J=3.4 Hz), 4.34-4.18 (1H, br m), 4.05 (3H, s), 3.89 (3H, s), 3.73-3.14 (3H, br m), 2.98 (2H, s), 2.15-1.76 (4H, br m); MS [M+H]+=489.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N-]>ClCCl.CCCCCCC.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][O:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:14]
Reactant: OC1CCCC1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CCCCCCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)COC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
To a solution of cyclopentanol (0.91 mL, 9.5 mmol) in dichloromethane (20 mL) is added rhodium (II) acetate dimer (10 mg) followed by ethyl diazoacetate (0.95 mL, 9.0 mmol). The reaction mixture is stirred at rt overnight. The reaction mixture is diluted with heptane, and filtered. The filtrate is evaporated, and the residue vacuum distilled at 150° C. to give 1.04 g of the product 444. 1H NMR (CDCl3) δ 4.21 (q, 2H), 4.04 (s, 2H), 1.85-1.45 (m, 8H), 1.29 (t, 3H)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.Br[CH:20]([CH2:28][CH3:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:3][C:2]([F:17])([F:18])[F:1])[CH:20]([CH2:28][CH3:29])[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:6][C:7]=1[C:13]([F:16])([F:14])[F:15])#[N:10]
Reactant: CCC(Br)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(NCC(F)(F)F)cc1C(F)(F)F
Product: CCC(C(=O)OC(C)(C)C)N(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in step B of example 1 using 4-[(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile and tert-butyl 2-bromobutanoate: 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J=8.8 Hz, 1H), 7.14 (d, J=2.7 Hz, 1H), 7.00 (dd, J=8.8, 2.8 Hz, 1H), 4.05 (m, 3H), 2.12 (m, 1H), 1.93 (m, 1H), 1.41 (s, 9H), 1.02 (t, J=7.5 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10].N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C1COCC1.[OH-].[Na+]>[CH2:21]([O:20][C:18](=[O:19])[NH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(CO)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(CO)cc1F)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-amino-3-fluorobenzylalcohol (20.7 g, 147 mmol) and pyridine (35.5 ml, 79 mmol) in THF (320 ml) and 2N NaOH (80 mL) was added benzyl chloroformate (24.8 mL, 170.6 mmol) at 0° C. over a period of 15 min. The reaction mixture was stirred for 20 min at 0° C. and for 2 h at room temperature. The reaction was quenched with water and diluted with EtOAc. The phases were separated and the organic phase was washed with 5% NaHSO4, saturated aq. NaHCO3 and brine, dried over Na2SO4, filtered and evaporated. The title compound was crystallized from EtOAc and cyclohexane: TLC (cyclohexane-EtOAc 3:1) Rf=0.45; HPLC RtE=1.02 min; ESIMS [M+NH4]+=293; ESIMS [M−H]−=274; 1H NMR (360 MHz, CDCl3): δ 8.00 (t, 1H), 7.40-7.25 (m, 5H), 7.10-7.00 (m, 2H), 6.82 (s broad, 1H), 5.15 (s, 2H), 4.55 (d, 2H).
Reaction SMILES: C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O.[Mg+2].[C@H:28]1([NH:37][C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[CH:41][CH:42]=[C:43]([NH2:48])[CH:44]=3)[N:39]=2)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1.[CH3:49][C:50]1[C:54]([N:55]=[C:56]=[O:57])=[C:53]([CH3:58])[O:52][N:51]=1>>[CH3:49][C:50]1[C:54]([NH:55][C:56]([NH:48][C:43]2[CH:44]=[C:45]3[C:40](=[CH:41][CH:42]=2)[N:39]=[C:38]([NH:37][C@H:28]2[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29]2)[CH:47]=[CH:46]3)=[O:57])=[C:53]([CH3:58])[O:52][N:51]=1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: Cc1noc(C)c1N=C=O
Agent: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Mg+2]
Product: Cc1noc(C)c1NC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound, MS: m/e=414.6 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 3,5-dimethylisoxazol-4-yl isocyanate.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1)[CH3:2].Cl[CH2:19][CH2:20][CH2:21][NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([C:3]1[N:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:19][CH2:20][CH2:21][NH:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:12][CH2:13]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[N:4]=1)[CH3:2]
Reactant: Fc1ccc(NCCCCl)cc1
Reactant: CCc1nc2ccccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2ccccc2n1C1CCN(CCCNc2ccc(F)cc2)CC1
Temperature: 100 °C
Yield: 37 %

Procedure:
To a stirred solution of 2-ethyl-1-piperidin-4-yl-1H-benzimidazole (0.6 g) and (3-chloropropyl)-(4-fluorophenyl)amine (0.4 g) in DMF (7 ml) was added K2CO3 (1.1 g) and KI (0.1 g). The mixture was heated at 100° C. for 2 h, and then allowed to cool to rt. Water (50 ml) was added and the mixture extracted with ethyl acetate (80 ml), and the organic layer separated and washed with water. This was further dried and concentrated in vacuo. The oil was purified by flash chromatography (95:5 DCM:MeOH), and the solid recrystallised from ether to yield 0.3 g of the title compound as colourless crystals. Mp. 121-124° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[C:9]([C:11]1[CH:16]=[CH:15][N:14]2[N:17]=[CH:18][C:19]([C:20]3[N:25]=[C:24](N[C@@H]4CCCN(C(OC(C)(C)C)=O)C4)[CH:23]=[CH:22][N:21]=3)=[C:13]2[CH:12]=1)#[N:10]>CN(C=O)C>[OH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][C:22]2[CH:23]=[CH:24][N:25]=[C:20]([C:19]3[CH:18]=[N:17][N:14]4[CH:15]=[CH:16][C:11]([C:9]#[N:10])=[CH:12][C:13]=34)[N:21]=2)[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2ccnc(-c3cnn4ccc(C#N)cc34)n2)C1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: CN(C)C=O
Product: N#Cc1ccn2ncc(-c3nccc(N[C@H]4CC[C@H](O)CC4)n3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-4-aminocyclohexanol (85 mg, 0.74 mmol) was added to a solution of 3-(4-(1H-benzo[d][1,2,3]triazol-1-yloxy)pyrimidin-2-yl)pyrazolo[1,5-a]pyridine-5-carbonitrile (byproduct of Preparation 7a, 105 mg, 0.30 mmol) in N,N′-dimethylformamide (3 mL) and the mixture was stirred at ambient temperature overnight. The solvent was then evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent evaporated. The crude product was purified by flash chromatography (dichloromethane to 9:1 dichloromethane/methanol) to give the title compound (66 mg, 67%) as a yellow solid.
Reaction SMILES: C(SC1C=CC(C=CC2C=CC(S(CCC[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45])(=O)=O)=CC=2)=CC=1)CCCCCCCCCCCCCCCCC.[CH3:46][C:47]1[CH:52]=[CH:51][C:50]([S:53]([CH2:56][CH2:57][CH2:58]OC2CCCCO2)(=[O:55])=[O:54])=[CH:49][CH:48]=1.BrCCC[CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][OH:79]>>[CH3:46][C:47]1[CH:48]=[CH:49][C:50]([S:53]([CH2:56][CH2:57][CH2:58][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][O:79][CH:40]2[CH2:41][CH2:42][CH2:43][CH2:44][O:45]2)(=[O:54])=[O:55])=[CH:51][CH:52]=1
Reactant: CCCCCCCCCCCCCCCCCCSc1ccc(C=Cc2ccc(S(=O)(=O)CCCCCCCCO)cc2)cc1
Reactant: OCCCCCCCCCCCCBr
Reactant: Cc1ccc(S(=O)(=O)CCCOC2CCCCO2)cc1
Product: Cc1ccc(S(=O)(=O)CCCCCCCCCCCCOC2CCCCO2)cc1

Procedure:
4-octadecylthio-4'-[(1-hydroxy)-8-octylsulfonyl]stilbene. 4n) As described in Examples 1a and 2a 12-bromo-1-dodecanol gives 12-(4-methylphenyl)sulfonyl-1-tetrahydropyranyloxydodecane. Using this compound similarly gives:
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH2:10][OH:11])[CH:9]=[C:4]2[CH:3]=[N:2]1.CS(C)=O.CCN(CC)CC>C(Cl)Cl>[NH:1]1[C:5]2=[CH:6][N:7]=[C:8]([CH:10]=[O:11])[CH:9]=[C:4]2[CH:3]=[N:2]1
Reactant: OCc1cc2cn[nH]c2cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cc2cn[nH]c2cn1
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
1H-pyrazolo[3,4-c]pyridine-5-methanol (1.08 g, 7.27 mmol) was dissolved in DCM (120 mL) at rt, and DMSO (30 mL) and NEt3 (3.01 mL, 21.7 mmol) were added. After stirring for 10 min, SO3-pyridine (3.45 g, 13.45 mmol) was added. The mixture stirred at rt for ca. 1.5 hr, and quenched with sat. NH4Cl solution. The reaction mixture was extracted with DCM, washed with water and with brine, and dried with Na2SO4. The crude product was purified by a flash column to afford 1H-pyrazolo[3,4-c]pyridine-5-carboxaldehyde (220 mg, 21%).
Reaction SMILES: [CH3:1][C:2]1[N:7]2N=N[N:10]=[C:6]2[C:5]2[N:11]=[C:12]([CH2:24][O:25][N:26]=[C:27]([CH3:29])[CH3:28])[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[C:4]=2[C:3]=1[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClC1C=CC=CC=1Cl>[NH2:10][C:6]1[C:5]2[N:11]=[C:12]([CH2:24][O:25][N:26]=[C:27]([CH3:29])[CH3:28])[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[C:4]=2[C:3]([CH3:30])=[C:2]([CH3:1])[N:7]=1
Reactant: CC(C)=NOCc1nc2c(c(C)c(C)n3nnnc23)n1CCCCNC(=O)C(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Product: CC(C)=NOCc1nc2c(N)nc(C)c(C)c2n1CCCCNC(=O)C(C)C
Temperature: 125 °C
Reaction time: 72 h

Procedure:
A mixture of N-{4-[5,6-dimethyl-8-({[(1-methylethylidene)amino]oxy}methyl)-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl]butyl}-2-methylpropanamide (from Part C, approximately 9.71 mmol), triphenylphosphine (5.1 g, 19 mmol), and 1,2-dichlorobenzene (97 mL) was heated at 125° C. for 2 days, then stirred at room temperature for 3 days, then heated at 130° C. for 5 hours. The reaction was allowed to cool to room temperature and was concentrated under reduced pressure. The residue was dissolved in methanol (80 mL) and 1 M aqueous hydrochloric acid (40 mL) and heated at 40° C. for 6 hours. The reaction was allowed to stir at room temperature overnight and a white precipitate formed that was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was partitioned between 1 M aqueous hydrochloric acid (20 mL) and chloroform (10 mL). The aqueous layer was extracted with chloroform (3×10 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The solid was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 5-55% CMA in chloroform). The appropriate fractions were combined and concentrated under reduced pressure. The resulting solid was triturated with acetonitrile and then was recrystallized from acetonitrile to provide N-{4-[4-amino-6,7-dimethyl-2-({[(1-methylethylidene)amino]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]butyl}-2-methylpropanamide as a white powder, mp 180.0-181.0° C.
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[CH3:22][NH:23][CH3:24]>C1COCC1.O>[CH3:22][N:23]([CH3:24])[CH2:2][CH2:1][S:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4]
Reactant: C=CS(=O)(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCS(=O)(=O)N1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.08 h
Yield: 86.9 %

Procedure:
A solution of the above vinylsulfonamide (3.10 g, 10 mmol) in 20 mL of THF was treated with an excess (10 mL, 80 mmol) of 40% aqueous dimethylamine. After 5 min, the mixture was diluted with water to give 3.09 g (87% yield) of benzyl 4-{[2-(dimethyl-amino)ethyl]sulfonyl}-1-piperazinecarboxylate as a white solid: mp (aq. MeOH) 101-103° C.; 1H NMR (CDCl3) δ 7.40-7.30 (m, 5H), 5.15 (s, 2H), 3.59 (m, 4H), 3.26 (m, 4H), 3.07 (dd J=8.1, 6.4 Hz, 2H), 2.74 (dd, J=8.0, 6.4 Hz, 2H), 2.25 (s, 6H); Anal. Calcd. for C16H25N3O4S: C, 54.1; H, 7.1; N, 11.8. Found: C, 53.8; H, 6.9; N, 11.8%.
Reaction SMILES: Br[CH:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][CH:6]=1)=[O:4].[CH2:17]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH2:25]([N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@H:2]([C:3]([C:5]1[CH:15]=[CH:14][C:8]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[CH:7][CH:6]=1)=[O:4])[CH3:16])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(Br)C(=O)c1ccc(NS(C)(=O)=O)cc1
Reactant: c1ccc(CNCc2ccccc2)cc1
Solvent: CC#N
Product: C[C@@H](C(=O)c1ccc(NS(C)(=O)=O)cc1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
Reaction of 4'-(2-bromopropionyl)methanesulfonanilide with 2 molar equivalents of dibenzylamine in acetonitrile provides 4'-(N,N-DIBENZYLALANYL)METHANESULFONANILIDE purified as the hydrochloride, m.p. 216.0°-218.0°C. (dec.).
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(=CC=3)C(=O)N([C@@H](C(C)C)C(O)=O)C4)=CC=2)=CC=1.[CH3:35][CH:36]([CH3:72])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:70])([F:69])[F:68])[CH:62]=4)=[O:59])=[CH:53][CH:52]=3)[CH:48]=2)[C:43]1=[O:71])[C:38]([O:40]C)=[O:39]>>[CH3:35][CH:36]([CH3:72])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[C:47]([C:51]3[CH:52]=[CH:53][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][CH:64]=[C:63]([C:67]([F:70])([F:68])[F:69])[CH:62]=4)=[O:59])=[CH:55][CH:56]=3)[CH:48]=2)[C:43]1=[O:71])[C:38]([OH:40])=[O:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Yield: 88 %

Procedure:
The compound of example 247 was prepared analogous to compound of example 225 by hydrolysis of compound of example 246.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.N([O-])=O.[Na+].[S:14]([Cl:17])(Cl)=[O:15].[OH2:18]>Cl.O>[C:8]([C:5]1[N:6]=[CH:7][C:2]([S:14]([Cl:17])(=[O:15])=[O:18])=[CH:3][CH:4]=1)#[N:9]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc(N)cn1
Reactant: O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: N#Cc1ccc(S(=O)(=O)Cl)cn1
Temperature: -5 °C
Yield: 73.5 %

Procedure:
In parallel, 5-amino-2-cyano pyridine (10 g, 0.084 mol) is dissolved in concentrated HCl (98 ml) and the mixture is cooled to −5° C. To this mixture is added dropwise over a period of 1 h a solution of NaNO2 (8.2 g, 0.118 mol) in water (50 ml), maintaining the reaction temperature between −5° C. and 0° C. This slurry is then added dropwise over a period of 1 h to the above reaction mixture (thionylchloride/water mixture), maintaining the reaction temperature between −5° C. and 0° C. (Note: The diazotized mixture should be also kept at −5° C. through out the addition). As the addition proceeds, a white solid precipitates. When the addition is over, the reaction mixture is stirred for an additional hour. The precipitate is collected by filtration, washed with cold water and dried under vacuum to afford the title compound as light yellow solid (12.5 g, Yield 73.5%). 1H NMR (DMSO-d6:400 MHz) δ 14.49 (1H, s), 8.87 (1H, s), 8.11-8.14 (1H, d), 8.0-8.03 (1H, d); HPLC (max plot) 97% Rt 1.155 min; LCMS: m/z, M+, 202.8.