Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)[C:14](C)(OC3C=CC(C4NN=NN=4)=CC=3)C)[C:11]3[CH:35]=[C:36]([F:40])[C:37]([F:39])=[CH:38][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:41][O:42][C:43](=[O:53])[C:44]1[CH:49]=[C:48]([F:50])[C:47]([OH:51])=[C:46]([F:52])[CH:45]=1.[C:54]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:41][O:42][C:43](=[O:53])[C:44]1[CH:45]=[C:46]([F:52])[C:47]([O:51][CH2:14][CH:13]([N:12]2[C:11]3[CH:35]=[C:36]([F:40])[C:37]([F:39])=[CH:38][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:54])[CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:48]([F:50])[CH:49]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(Oc1ccc(-c2nnn[nH]2)cc1)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: COC(=O)c1cc(F)c(O)c(F)c1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1cc(F)c(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3C)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-2-methyl-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (example 123, intermediate b), 3,5-difluoro-4-hydroxy-benzoic acid methyl ester (commercially available), triphenylphosphine and di-tert-butyl azodicarboxylate. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 70:30). Light yellow foam (37%). MS (Turbo Spray): m/z=575.4 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[Cl:19][C:20]1[N:24]=[C:23](Cl)[S:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:23]3[S:22][N:21]=[C:20]([Cl:19])[N:24]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Reactant: Clc1nsc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nc(Cl)ns3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (1.0 g, 4.0 mmol) and 3,5-dichloro-1,2,4 thiadiazole (0.45 mL, 4.8 mmol) in DMF (24 mL) was added cesium carbonate (2.61 g, 8 mmol). The mixture was stirred at room temperature overnight. The reaction was diluted with H2O, acidified to pH 3 with aqueous HCl (1N). The mixture was extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (silica, Ethyl acetate) affording the title compound (1.25 g, 85%) as a white solid: 1H NMR (CDCl3) δ7.48 (d, 1H), 7.19 (d, 1H), 5.68 (dd, 1H), 5.18 (s, 1H), 4.18 (q, 2H), 3.10 (dd, 1H), 2.45 (dd, 1H), 2.39 (s, 3H), 1.25 (t, 3H). MS found: (M+H)+=369.
Reaction SMILES: [H][H].[CH3:3][N:4]([CH2:11][CH:12]([OH:17])[CH2:13][N:14]=[N+]=[N-])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Pd].C(O)C>[CH3:3][N:4]([CH2:11][CH:12]([OH:17])[CH2:13][NH2:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN(CC(O)CN=[N+]=[N-])c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(CC(O)CN)c1ccccc1
Yield: 99 %

Procedure:
Hydrogen was introduced into a mixture of 1.85 g of 3-(N-methyl-N-phenylamino)-2-hydroxypropylazide (prepared as described in Preparation 89), 0.9 g of 10% w/w palladium-on-carbon and 30 ml of ethanol for 1.5 hours. At the end of this time, the atmosphere was replaced with nitrogen, the palladium-on-carbon catalyst was removed from the reaction mixture by filtration, and the filtrate was concentrated by evaporation under reduced pressure, to give 1.6 g of the title compound which decomposed at 136° C.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:34]([NH2:36])=[O:35])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][CH2:29][CH:30]([CH3:33])[CH2:31][CH3:32])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].CC(CC)CN>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:34]([NH2:36])=[O:35])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH:28][CH2:29][C@@H:30]([CH3:33])[CH2:31][CH3:32])[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCC(C)CNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Agent: CCC(C)CN
Product: CC[C@H](C)CNCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 58.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylbutyl)amino]methyl}phenyl)-1H-indole-7-carboxamide, substituting (2S)-2-methyl-1-butanamine (52 mg, 0.6 mmol) for 2-methyl-1-butanamine to afford 30 mg of the title compound (58.7%).
Reaction SMILES: CC1CC(C)CN(C2N=CC=CC=2C(O)=[O:12])C1.ON1C2C=CC=CC=2N=N1.Cl.C(OC(=O)C1C=CC(CCN)=CC=1OC)C.[CH:45]1([N:51]=[C:52]=[N:53][CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>CN(C)C=O.C(N(CC)CC)C>[C:52]([NH:51][CH:45]1[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50]1)([NH:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1)=[O:12]
Reactant: CC1CC(C)CN(c2ncccc2C(=O)O)C1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCOC(=O)c1ccc(CCN)cc1OC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
5.85 g of 2-(3,5-dimethylpiperidino)-nicotinic acid (prepared from 2-chloronicotinic acid and 3,5-dimethylpiperidine) were dissolved in 25 ml of dimethylformamide. After the addition of 10.41 g of 1-hydroxybenzotriazole (32.4%), 6.5 g of 4-(2-aminoethyl)-2-methoxybenzoic acid ethyl ester . hydrochloride, 6.92 ml of triethylamine and 6.18 g of dicyclohexylcarbodiimide the mixture was stirred for 30 minutes at 50° C. and left to stand overnight at room temperature. Dicyclohexylurea obtained was suction-filtered and washed with 25 ml of dimethylformamide. The combined filtrates were poured into 250 ml of ice-water. Extraction three times with 100 ml of ethyl acetate each time, washing of the acetic ester phase with sodium dicarbonate solution and water and concentration in vacuo gave the ethyl 4-(2-<2-(3,5-dimethylpiperidino)-pyridine-3-carboxamido>ethyl)-2-methoxybenzoate.
Reaction SMILES: [NH3:1].Cl[S:3]([C:6]1[C:7]([O:26][CH3:27])=[CH:8][C:9]([O:24][CH3:25])=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[N:15]=[CH:14][CH:13]=2)[CH:11]=1)(=[O:5])=[O:4]>CO>[NH2:1][S:3]([C:6]1[C:7]([O:26][CH3:27])=[CH:8][C:9]([O:24][CH3:25])=[C:10]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[N:15]=[CH:14][CH:13]=2)[CH:11]=1)(=[O:5])=[O:4]
Reactant: N
Reactant: COc1cc(OC)c(S(=O)(=O)Cl)cc1-c1ccnn1-c1ccccc1Cl
Solvent: CO
Product: COc1cc(OC)c(S(N)(=O)=O)cc1-c1ccnn1-c1ccccc1Cl
Reaction time: 8 h

Procedure:
8.2 20 ml of a 32% ammonia solution are added at room temperature to a solution of 413.3 mg of “B2” in 5 ml of dry methanol. The mixture is stirred overnight, approximately half of the solvent is removed, the precipitated crystals are separated off and washed with water, giving 230 mg of 5-(5-aminosulfonyl-2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole (“C1”) and, as by-product, 5-(5-hydroxysulfonyl-2,4-dimethoxyphenyl)-1-(2-chlorophenyl)-1H-pyrazole (“C2”).
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:2][C:3]2[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1cccnc1CBr
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccnc1COc1ccc(F)cc1
Reaction time: 3 h
Yield: 62.7 %

Procedure:
2-Bromomethyl-3-nitropyridine (100 mg, 0.456 mmol) prepared in Step 2 was added at room temperature to a solution of 4-fluorophenol (56 mg, 0.502 mmol) and potassium carbonate (189 mg, 1.37 mmol) in N,N-dimethylformamide (3 ml) and then stirred for 3 hours. The reaction mixture was diluted with ethyl acetate (10 ml), washed with a saturated sodium bicarbonate solution, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (dichloromethane/n-hexane=2/1, v/v) to give 71 mg of the titled compound as yellow solid.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>CS(C)=O>[CH2:21]([O:3][C@@H:2]1[C@H:4]([OH:5])[C@@H:6]([CH2:7][OH:8])[O:9][C@H:1]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[O:12])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)n1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O

Procedure:
Cytidine (10 g, 0.041 mol), sodium hydride (2.4 g, 1.5 eq), bromopentane (7.6 ml, 1.5 eq.) in DMSO (90 ml) were reacted as per the procedure of Example 71, Step 1 to yield the 2′ and 3′ isomers as a foam (7.6 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.[CH:21]1([NH:24][C:25]([C:27]2[C:35]3[CH:34]=[C:33]([C:36]4[C:41]([Cl:42])=[CH:40][N:39]=[C:38](Cl)[N:37]=4)[S:32][C:31]=3[C:30]([O:44][CH3:45])=[CH:29][CH:28]=2)=[O:26])[CH2:23][CH2:22]1>O1CCOCC1>[CH:21]1([NH:24][C:25]([C:27]2[C:35]3[CH:34]=[C:33]([C:36]4[C:41]([Cl:42])=[CH:40][N:39]=[C:38]([NH:10][CH2:11][CH2:12][CH2:13][N:14]5[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]5)[N:37]=4)[S:32][C:31]=3[C:30]([O:44][CH3:45])=[CH:29][CH:28]=2)=[O:26])[CH2:22][CH2:23]1
Reactant: CN1CCN(CCCN)CC1
Reactant: COc1ccc(C(=O)NC2CC2)c2cc(-c3nc(Cl)ncc3Cl)sc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(C(=O)NC2CC2)c2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)sc12
Yield: 40.3 %

Procedure:
Diisopropylethylamine (1.10 mL, 5.78 mmol) and 1-(3-aminopropyl)-4-methylpiperazine (545 mg, 3.47 mmol) are added to a stirred suspension of 2-(2,5-dichloropyrimidin-4-yl)-7-methoxybenzo[b]thiophene-4-carboxylic acid cyclopropylamide (1.14 g, 2.89 mmol) in dry 1,4-dioxane (25 mL) at room temperature. The resultant mixture is heated in an oil bath at 97° C. for 2 days. At room temperature the mixture is filtered off and the solid is washed with MeOH to give the title compound as a solid (600 mg, 33% yield). The filtrate is concentrated and the residue is purified by HLB cartridge eluting with NH4HCO3 (pH=8) in CH3CN 1:0 to 0:1, and then by Stratta® column, eluting with dichloromethane in MeOH 12:1 to 4:1, to give an additional 339 mg of the title compound as a yellow solid. ES+(m/z) 515 (35Cl) and 517 (37Cl) [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[CH:13][CH:12]=1.[Cl:33][C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][C:43]=1[O:44][CH2:45][C@@H:46]([NH2:48])[CH3:47])[C:37]([O:39][CH3:40])=[O:38].CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Cl:33][C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][C:43]=1[O:44][CH2:45][C@@H:46]([NH:48][C:18](=[O:20])[CH2:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][C:9]([NH:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[O:32])=[CH:16][CH:15]=1)[CH3:47])[C:37]([O:39][CH3:40])=[O:38]
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Reactant: COC(=O)c1ccc(OC[C@H](C)N)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC[C@H](C)NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.6 %

Procedure:
A mixture of pentafluorophenyl 4-[N′-(2-methylphenyl)ureido]phenylacetate (508 mg, 1.13 mmol), methyl (S)-3-chloro-4-(2-amino-1-propoxy)benzoate (275 mg, 1.13 mmol) and Et3N (0.240 mL, 1.72 mmol) in DMF (10 mL) was stirred at room temp overnight. The mixture was diluted with EtOAc, and the solution was washed with 0.5 N HCl, sat. NaHCO3, brine, dried over Na2SO4, and evaporated. The residue was recrystallized from MeOH—CHCl3-n-hexane to give 240 mg (42%) methyl (S)-3-chloro-4-[2-[4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoate as a white crystalline powder. 1H-NMR (DMSO-d6) δ1.21 (d, 3H, J=6.4 Hz), 2.25 (s, 3 H), 3.33 (s, 2 H), 3.82 (s, 3 H), 4.04-4.14 (m, 3H), 6.90-6.94 (m, 1H), 7.11-7.16 (m, 4H), 7.29-7.38 (m, 3H), 7.83-7.94 (m, 3H), 8.13-8.17 (m, 2H), 9.34 (s, 1 H); MS(FAB) m/z 510 (M30).
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:20](OCC)(=O)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].CC[O-:33].[Na+]>C(O)C>[C:15]([O:14][C:13]([NH:12][C@H:4]([C@@H:2]1[O:1][C:3](=[O:33])[CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20]1)[CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:19])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1C[C@H]([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)OC1=O
Temperature: 70 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of tert-Butyl(1S)-1-[(2S)-oxiran-2-yl]-2-phenylethylcarbamate (10.0 g, 38.0 mmol) and diethyl malonate (9.0 ml, 59.3 mmol) in ethanol (27 mL) at 0° C. was treated with a solution of NaOEt (16 mL, 21% in ethanol) over 10 minutes, stirred at 70° C. for 2 hours, cooled to 0° C. and quenched with 10% citric acid solution, and partitioned between ethyl acetate and water. The organic phase was washed with saturated NaHCO3and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-35% ethyl acetate in hexanes to give the title compound (13.3 g, 93% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][CH:5]=1.C1(C)C=CC(S(O[CH2:24][CH2:25][Cl:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH2:24][CH2:25][Cl:26])=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OCCCl)c(OC)c1

Procedure:
By using an identical method as above 77 g of 4-hydroxy-5-methoxy-benzoic acid methyl ester, 99.2 g of 2-chloroethyl p-toluene sulfonate, 77.7 g of potassium carbonate, and 1.7 g (4.1 mmol) of methyl-tricapryl ammonium chloride was converted to 91.6 g of the tide compound: mass spectrum (electrospray, m/e,): M+H 245.0
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18](Cl)=[N:19]3)[CH2:11][CH2:10][N:9]1[CH2:27][C:28]([NH2:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O-:32].[Na+]>CO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]3[C:15]=2[CH:16]=[CH:17][C:18]([O:32][CH3:31])=[N:19]3)[CH2:11][CH2:10][N:9]1[CH2:27][C:28]([NH2:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN(CC(N)=O)[C@@H](Cc3ccccc3)C2)c2ccc(Cl)nc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(N3CCN(CC(N)=O)[C@@H](Cc4ccccc4)C3)ccc(OC)c2n1
Reaction time: 18 h
Yield: 54.7 %

Procedure:
A stirred solution of (S)-2-(2-benzyl-4-(2-chloro-8-methoxyquinolin-5-yl)piperazin-1-yl)acetamide (40 mg, 0.1 mmol) in MeOH (1.2 mL) was treated with sodium methoxide (1.0 mL, 4.4 mmol) as a 25% solution in MeOH. The reaction mixture was allowed to stir for 18 h, then evaporated and purified by silica gel chromatography eluting with EtOAc to afford product as a yellow solid (23 mg, 55%). 1H NMR (MeOH-d4) 8.24-8.40 (br s, 1H), 7.10-7.24 (m, 5H), 7.03 (d, J=8.2, 1H), 6.94 (d, J=8.4, 1H), 6.82-6.88 (m, 1H), 4.03 (s, 3H), 3.97 (s, 3H), 3.42-3.56 (m, 1H), 2.94-3.27 (m, 8H), 2.64-2.85 (m, 2H). LC/MS 2.34 min, [M+1]+ 421.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[C:19](O)(=O)C.C=O.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)[C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1
Reactant: CC(=O)O
Reactant: Cc1nnc2c(NC3CCNCC3)cc(Cl)nn12
Agent: C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1nnc2c(NC3CCN(C)CC3)cc(Cl)nn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(6-Chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazin-8-yl)-piperidin-4-yl-amine (0.26 g; 0.97 mmol) was dissolved in 5.0 ml THF. Acetic acid (0.11 ml; 1.94 mmol), formaldehyde 37% in water (0.29 ml; 3.89 mmol) and STAB (0.27 g; 1.27 mmol) were added and stirred at ambient temperature for 1 hour. The crude material was purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].O=S(Cl)[Cl:15].C(Cl)Cl>N1C=CC=CC=1.O>[CH2:1]([Cl:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCCCCCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: C=CCCCCCCCCCCl
Temperature: 65 °C
Yield: 84.7 %

Procedure:
To a solution of 100 g (0.588 mole) of 10-undecenyl alcohol and 2 g of pyridine was added 75 g (0.63 mole) of SOCl2 dropwise over a period of 45 minutes at 25° C. The solution was heated at 65° C. for 5 hours. CH2Cl2 (100 mL) was added and the solution was water washed twice, dried with MgSO4, filtered, and the CH2Cl2 evaporated. The residue (103 g) by GC analysis showed a purity of 99.3% VIII with 0.7% alcohol; IR showed no OH band and absorbence at 1641-1. Distillation (15.24 centimeter jacketed Vigreaux column) gave 94 g VIII (bp 104°-105° C. at 6 mm) (GC showed no alcohol; 100% VIII).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([NH:14][CH3:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH3:17])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:41])[CH2:37][CH:38]([CH3:40])[CH3:39]>CC#N.CN(C1C=CN=CC=1)C>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([N:14]([CH3:15])[C:36](=[O:41])[CH2:37][CH:38]([CH3:40])[CH3:39])=[CH:13][C:8]=3[N:7]=[C:6]2[CH:16]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=2)[CH3:17])[CH2:3][CH2:2]1
Reactant: CC(C)CC(=O)Cl
Reactant: CCOc1ccc(C(C)c2nc3cc(NC)ccc3n2CC2CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOc1ccc(C(C)c2nc3cc(N(C)C(=O)CC(C)C)ccc3n2CC2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
To a solution of 1-(cyclopropylmethyl)-2-[1-(4-ethoxyphenyl)ethyl]-N-methyl-1H-benzimidazol-5-amine (349.5 mg, 1.0 mmol) in MeCN (25 mL) was added DIPEA (258.5 mg, 2.0 mmol), DMAP (10 mg) and isovaleryl chloride (180.9 mg, 1.5 mmol) at 0° C. The reaction mixture was stirred overnight at room temperature which was quenched with H2O (150 mL) and extracted with EtOAc (4×50 mL). The combined organic phases were washed with brine and dried with Na2SO4. Upon filtration and evaporation of the solvent, the residue was purified by MPLC using EtOAc on silica gel to give 431.9 mg (99%) of the desired product as a colorless syrup, which was converted to a TFA salt as a white solid. 1HNMR (400 MHz, CD3OD): δ 0.22 (m, 1H), 0.45 (m, 2H), 0.57 (m, 1H), 0.86 (d, J=5.9 Hz, 6H), 1.02 (m, 1H), 1.38 (t, J=7.0 Hz, 3H), 1.83 (d, J=7.0 Hz, 3H), 2.06 (m, 2H), 2.10 (m, 1H), 3.34 (s, 3H), 4.02 (m, 3H), 4.21 (dd, J=15.0, 6.6 Hz, 1H), 4.65 (q, J=7.0 Hz, 1H), 6.90 (d, J=8.6 Hz, 2H), 7.21 (d, J=8.6 Hz, 2H), 7.28 (d, J=8.4 Hz, 1H), 7.62 (s, 1H), 7.72 (d, J=8.6 Hz, 1H). MS (ESI) (M+H)+=434.42 (M+1)+. Anal: Calcd for C27H35N3O2+0.80TFA+0.90MeOH: C, 64.00; H, 7.17; N, 7.54. Found: C, 63.98; H, 7.02; N, 7.34.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1([O:38][C:39](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C(OC(=O)[CH2:57][CH:58]([NH:62][CH2:63][C:64]1[CH:69]=[CH:68][C:67]([F:70])=[CH:66][CH:65]=1)[CH2:59][CH2:60][CH3:61])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[F:70][C:67]1[CH:66]=[CH:65][C:64]([CH2:63][N:62]2[CH:58]([CH2:59][CH2:60][CH3:61])[CH2:57][C:19]([OH:21])=[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)[C:39]2=[O:38])=[CH:69][CH:68]=1
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCCC(CC(=O)OCC)NCc1ccc(F)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCC1CC(O)=C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)C(=O)N1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 16.8 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.103 g, 0.291 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.122 g, 0.321 mmol) and 4-methylmorpholine (0.064 mL, 0.582 mmol) were added sequentially to a solution of rac-3-(4-fluoro-benzylamino)-hexanoic acid ethyl ester (0.078 g, 0.292 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 17 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (25 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.378 mL, 1.17 mmol) was added and the reaction mixture was heated to 60° C. for 4 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 40-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-6-propyl-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.027 g, 0.049 mmol, 17%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:21].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[O:21])[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)c2ccc(Cl)cc2)C1
Reaction time: 8 h

Procedure:
8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (220 mg, 1 mmol) was dissolved in 2 mL NMP and to this was added KOH (560 mg, 10 mmol) followed by 2-bromo-1-(4-chloro-phenyl)-ethanone (233 mg, 1 mmol) The reaction was kept overnight at RT. Water was added and the compound extracted with EtOAc. The organic layer was washed with water, concentrated and purified by column chromatography using silica gel (#100-200 mesh) using 0-3% MeOH:DCM as eluent. The compound was further purified by reverse phase chromatography. 1HNMR (CD3OD, TFA salt) d (ppm): 8.10 (m, 2H), 7.60 (d, 2H), 7.50 (s, 1H), 7.30 (d, 1H), 7.10 (m, 1H), 5.80 (m, 2H), 4.70 (m, 1H), 4.40 (m, 1H), 3.80 (m, 1H), 3.60 (m, 1H), 3.05 (s, 5H).