Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12](=[O:17])[C:13](=[O:16])[C:14]=2[NH2:15])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[S:18]1[C:22]([C:23]2[C:24]([O:33][CH3:34])=[CH:25][C:26]([O:31][CH3:32])=[C:27]([CH:30]=2)[CH:28]=O)=[CH:21][C:20]2[CH:35]=[CH:36][CH:37]=[CH:38][C:19]1=2.O(C)[Li].Cl>CN(C=O)C>[NH2:15][C:14]1[C:13](=[O:16])[C:12](=[O:17])[C:11]=1[NH:10][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])/[CH:2]=[CH:28]/[C:27]2[CH:30]=[C:23]([C:22]3[S:18][C:19]4[CH:38]=[CH:37][CH:36]=[CH:35][C:20]=4[CH:21]=3)[C:24]([O:33][CH3:34])=[CH:25][C:26]=2[O:31][CH3:32])=[CH:9][CH:8]=1
Reactant: COc1cc(OC)c(-c2cc3ccccc3s2)cc1C=O
Reactant: CC(=O)c1ccc(Nc2c(N)c(=O)c2=O)cc1
Agent: Cl
Agent: [Li]OC
Solvent: CN(C)C=O
Product: COc1cc(OC)c(-c2cc3ccccc3s2)cc1/C=C/C(=O)c1ccc(Nc2c(N)c(=O)c2=O)cc1
Temperature: 25 °C
Yield: 5.6 %

Procedure:
3-(4-Acetyl-phenylamino)-4-amino-cyclobut-3-ene-1,2-dione (Ex-102A, 0.46 g, 2 mmol), and 5-(benzo[b]thien-2-yl)-2,4-dimethoxybenzaldehyde (Ex-3A, 0.596 g, 2 mmol) were dissolved in DMF (10 mL) under nitrogen, and 4.0 ml (4 mmol) of LiOMe (1.0 M in MeOH) was added. The mixture was stirred under nitrogen at room temperature over night. The reaction mixture was poured into ice-water, acidified to pH1 with 3N HCl, extracted with dichloromethane. The combined organic phase was then washed with brine and water, dried over MgSO4, column chromatography (5% MeOH in CH2Cl2) to give 57 mg (5.4%) title compound as a yellow solid, mp>260° C. 1H-NMR (DMSO-d6) δ 10.08 (s, 1H), 8.36 (s, 1H), 8.18 (d, J=8 Hz, 2H), 8.03 (d, J=15 Hz, 1H), 7.82–7.95 (m, 4H), 7.57 (d, J=8 Hz, 2H), 7.27–7.37 (m, 2H), 6.85 (s, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.26 (s, 2H). MS m/z=511[M+H]+, (20%), 416 (100%). HRMS (ES+) Calcd. for C29H22N2O5S: 511.1327. Found: 511.1326.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:16]([NH2:18])=O)=[N:5][N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([C:16]#[N:18])=[N:5][N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:14])([CH3:13])[CH3:15])[CH:7]=1
Reactant: COc1cn(COCC[Si](C)(C)C)nc1C(N)=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cn(COCC[Si](C)(C)C)nc1C#N
Temperature: 50 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
To a solution of 4-methoxy-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-3-carboxamide (compound 280.5, 1.08 g, 4.0 mmol) in toluene (25 mL) was added POCl3 (1.86 mL, 20.0 mmol) dropwise at 0° C. The mixture was stirred for 2 h at 50° C., then quenched with 30 mL of sodium bicarbonate (sat.). The aqueous phase was extracted with 2×100 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1:6) as the eluent to yield 500 mg (49%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][CH:27]1[O:31][C:30](=[O:32])[N:29]([CH3:33])[CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44]>C(O)CCC>[C:42]([OH:47])(=[O:46])[C:43]([OH:45])=[O:44].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:24][CH2:25][CH2:26][CH:27]3[O:31][C:30](=[O:32])[N:29]([CH3:33])[CH2:28]3)[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Reactant: CN1CC(CCCCl)OC1=O
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCCCO
Product: CN1CC(CCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)OC1=O
Yield: 54 %

Procedure:
This compound was prepared according to the procedure of Example 1. A mixture of 4.6 g (0.015 mole) of α,α-bis-(p-fluorophenyl)-4-piperidinemethanol, 2.7 g (0.015 mole) of 5-(3-chloropropyl)-3-methyl-2-oxazolidinone, 5.3 g (0.05 mole) of anhydrous sodium carbonate and 0.4 g of potassium iodide in 100 ml of 1-butanol gave a gum as residue. The gum was converted to the oxalic acid salt and the solid was recrystallized from absolute ethanol to yield 4.5 g (54%) of white solid, m.p. 150°-153° C., with decomposition.
Reaction SMILES: [CH3:1][C:2]([CH3:40])([CH3:39])[C:3](=O)[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][C:28](=[O:30])[O:27][N:26]=3)=[CH:15][CH:14]=2)=[C:8]([CH2:31][CH2:32][CH3:33])[N:7]2[N:34]=[C:35]([CH3:37])[N:36]=[C:6]12.Cl.[NH2:42][O:43][CH2:44][CH3:45].N1C=CC=CC=1.Cl>O.C(OCC)(=O)C>[CH2:44]([O:43]/[N:42]=[C:3](\[C:2]([CH3:39])([CH3:40])[CH3:1])/[CH2:4][N:5]1[C:10](=[O:11])[C:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[NH:29][C:28](=[O:30])[O:27][N:26]=3)=[CH:17][CH:18]=2)=[C:8]([CH2:31][CH2:32][CH3:33])[N:7]2[N:34]=[C:35]([CH3:37])[N:36]=[C:6]12)[CH3:45]
Reactant: CCON
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(CC(=O)C(C)(C)C)c2nc(C)nn12
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C/C(=N/OCC)C(C)(C)C)c2nc(C)nn12
Temperature: 110 °C
Reaction time: 16 h
Yield: 7.4 %

Procedure:
A mixture of 4-(3,3-dimethyl-2-oxobutyl)-2-methyl-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.3 g), (aminooxy)ethane hydrochloride (1.1 g) and pyridine (10 mL) was stirred at 110° C. for 16 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.024 g, 7%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[CH3:37]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[C:29]([CH3:37])[CH:30]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(F)c(C)c2)c1

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 4-fluoro-3-methyl-phenylboronic acid, 5-(4-fluoro-3-methylphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=48%).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C@@H:7]([C:25]([OH:27])=[O:26])[NH:8][C:9]([C:11]2([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:39]1[CH:44]=[CH:43][C:42]2[C:45]([O:47][C:48](=O)[C:41]=2[CH:40]=1)=[O:46].C(C1NC=CN=1)(C1NC=CN=1)=O>ClCCl>[O:46]=[C:45]1[C:42]2[CH:43]=[CH:44][N:39]=[CH:40][C:41]=2[C:48](=[O:47])[N:1]1[C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]([C:25]([OH:27])=[O:26])[NH:8][C:9]([C:11]2([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:28][CH:29]=1
Reactant: O=C1OC(=O)c2cnccc21
Reactant: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(N)cc3)C(=O)O)CCCC2)cc1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CC2(C(=O)N[C@@H](Cc3ccc(N4C(=O)c5ccncc5C4=O)cc3)C(=O)O)CCCC2)cc1
Reaction time: 18 h
Yield: 23.1 %

Procedure:
A solution of 4-amino-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine (98 mg, 0.23 mmol), DIPEA (30 μL, 0.23 mmol) and 3,4-pyridinedicarboxylic acid anhydride (114 mg, 0.77 mmol) in dichloromethane (10 mL) was stirred 18 hr at room temperature. The mixture was concentrated to remove most of the dichloromethane and the residue was taken up in DMF (3 mL). Carbonyl diimidazole (103 mg, 0.64 mmol) was added to the resulting solution and the reaction was allowed to proceed for 18 hr. The resulting mixture was purified directly by RP-HPLC on a 4×30 cm Rainin C-18 column using a gradient of 5 to 95% acetonitrile:water containing 0.75% trifluoroacetic acid at a flow of 49 mL/min over 35 min. The peak eluting at 45.6% acetonitrile was concentrated and lyophilized to give 4-(2,3-dihydro-1,3-dioxo-1H-pyrrolo[3,4-c]pyridin-2-yl)-N-[[1-[(4-methoxyphenyl)methyl]cyclopentyl]carbonyl]-L-phenylalanine (28 mg) HR FABMS: obs. mass 528.2146. Calcd. mass 528.2134 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)=[CH:22][C:4]=1[O:5][CH:6]([C:14]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])[CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])#[N:2].[OH-].[Na+].Cl>CO>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[CH:6]([O:5][C:4]1[CH:22]=[C:23]([O:26][CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[CH:24]=[CH:25][C:3]=1[C:1]#[N:2])[CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CCC(Oc1cc(OCc2ccsc2)ccc1C#N)c1c(F)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#Cc1ccc(OCc2ccsc2)cc1OC(CCC(=O)O)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
A solution of ethyl (RS)-4-(2-cyano-5-(3-thienylmethoxy)phenoxy)-4-(2-chloro-6-fluorophenyl)butanoate (360 mg) in methanol (10 mL) containing 1 N sodium hydroxide (3 mL) is stirred at ambient temperature for 16 hours. The reaction mixture is poured into 0.5 N HCl (20 mL) and extracted twice with ethyl acetate (20 mL). The combined organic phases are washed with brine (20 mL), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a dark yellow oil. Crystallisation from a mixture of cyclohexane and ethyl acetate gives (RS)-4-(2-chloro-6-fluorophenyl)-4-(2-cyano-5-(3-thienylmethoxy)phenoxy)-butanoic acid (210 mg) in the form of a beige solid, m.p. 128-130° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][OH:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH:21](Br)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH:21]([N:4]1[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][OH:9])[CH2:2][CH2:3]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCCN1CCNCC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Yield: 84.4 %

Procedure:
To a mixture of 1-piperazineethanol (11.4 g), potassium carbonate powder (24.3 g) and N,N-dimethylformamide (100 ml) was added dropwise benzhydryl bromide (21.7 g) under stirring. The mixture was stirred at room temperature for 2 hours, diluted with water and extracted with ethyl ether. The ethyl ether layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was purified by silica gel chromatography [eluent: hexane-ethyl acetate (2:1)] to give 21.9 g (84.2%) of 4-benzhydryl-1-piperazineethanol as an oil. IR(Neat): 3380 cm-1. NMR(CDCl3)δ: 2.46(10H, broad s), 3.57(2H, t, J=6.5), 4.20(1H, s), 7.03-7.45(12H, m).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[N+:22]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1N

Procedure:
Prepared from (2′,5′-difluoro-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example B17) by catalytic hydrogenation with Pd/C according to the general procedure G (method a). Obtained as a light yellow gum (2.18 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:13]3([CH2:15][CH2:14]3)[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[O:10][CH:9]([C:20]([O:22]C)=[O:21])[O:8][C:7]=2[C:24]=1[O:25][CH3:26].[OH-].[Na+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:13]3([CH2:15][CH2:14]3)[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[O:10][CH:9]([C:20]([OH:22])=[O:21])[O:8][C:7]=2[C:24]=1[O:25][CH3:26]
Reactant: COC(=O)C1Oc2ccccc2C2(CC2)c2ccc(OC)c(OC)c2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c1OC)OC(C(=O)O)Oc1ccccc1C21CC1
Reaction time: 1.3 h

Procedure:
A solution of 76 mg (0.23 mmol) of methyl 3',4'-dimethoxyspiro(cyclopropane-1,12'(12'H)-dibenzo-[d,g][1,3]dioxocin)-6'-carboxylate in 0.46 ml of tetrahydrofuran was combined with 0.172 ml (0.35 mmol) of 2 N aqueous sodium hydroxide and the mixture stirred for 1.3 hour. The resulting mixture was diluted with 0.5 ml of water, extracted with ether, and then acidified with 1 N aqueous hydrochloric acid. The resulting mixture was extracted 3 times with 1 ml portions of ether and the combined ethereal extracts were dried over magnesium sulfate and concentrated by evaporation under reduced pressure to obtain the title compound in quantitative yield as a white solid. The proton and carbon NMR and infrared spectra were consistent with the assigned structure.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]3=[N:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH:24]([C:26]1[N:30]=[C:29]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[O:28][N:27]=1)[CH3:25].[NH4+].[Cl-]>CN(C=O)C>[Cl:37][C:33]1[CH:32]=[C:31]([C:29]2[O:28][N:27]=[C:26]([CH:24]([C:15]3([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13][CH2:12][N:11]4[C:7]([C:4]5[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=5)=[N:8][N:9]=[C:10]34)[CH3:25])[N:30]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)C1CCCn2c(-c3ccncc3)nnc21
Reactant: CC(Cl)c1noc(-c2cccc(Cl)c2)n1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(C)c2noc(-c3cccc(Cl)c3)n2)CCCn2c(-c3ccncc3)nnc21
Temperature: 65 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
A solution of ethyl 3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate (182 mg, 0.67 mmol) in DMF (2 ml) was added to a stirred mixture of NaH (20 mg, 0.81 mmol) in DMF (2 ml). After 45 min a solution of 3-(1-chloroethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (180 mg, 0.74 mmol) in DMF (1 ml) was added and the resulting solution was stirred at 65° C. for 3 h and then cooled to r.t. Aq. sat. NH4Cl solution was added and the mixture was extracted with EA. The organic phase was washed with water and brine, dried and concentrated. Column chromatography (DCM/MeOH 20:1) gave 207 mg (65%) of the title compound as a diastereomeric mixture. 1H NMR: 1.27 (t, 3 H), 1.34 (t, 3 H), 1.48 (d, 3 H), 1.55 (d, 3 H), 2.15 (m, 2 H), 2.18 (m, 4 H), 2.61 (m, 2 H), 4.00 (m, 2 H), 4.18-4.29 (m, 4 H), 4.30-4.40 (m, 2 H), 4.55 (q, 1 H), 4.65 (q, 1 H), 7.37 (t, 1 H), 7.44 (t, 1 H), 7.50 (m, 1 H), 7.55 (m, 1 H), 7.63 (d, 2 H), 7.69 (d, 2 H), 7.83 (m, 1 H), 7.92 (m, 1 H), 7.95 (m, 1 H), 8.05 (m, 1 H), 8.75 (d, 2H), 8.76 (d, 2 H)
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][CH3:38])=[O:36].[N:42]12[CH2:49]C[CH:45]([CH2:46][CH2:47]1)[C@H:44](O)[CH2:43]2>C1(C)C=CC=CC=1.CO.ClCCl.CC(O)C.CC(O)C.CC(O)C.CC(O)C.[Ti]>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][N:15]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[NH:17][C:16]3=[O:24])[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[CH2:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35]([O:37][C@H:38]1[CH:45]2[CH2:46][CH2:47][N:42]([CH2:43][CH2:44]2)[CH2:49]1)=[O:36]
Reactant: O[C@@H]1CN2CCC1CC2
Reactant: COC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1
Agent: [Ti]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: O=C(O[C@@H]1CN2CCC1CC2)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)c1

Procedure:
To a refluxing solution of methyl 3-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2 g, 0.36 mmol) and (S)-3-quinuclidinol (0.184 g, 1.44 mmol) in toluene (2 mL), was added titanium(IV)-i-propoxide (0.105 mL, 0.36 mmol, d=0.97). After refluxing for 18 h, the reaction mixture was diluted with 5% methanol/dichloromethane, washed with water and brine. The organic phase was dried over MgSO4, filtered, concentrated and isolated by reverse phase HPLC to obtain the title compound as an acetate salt (0.08 g, 34%); 1H NMR (DMSO-d6): δ 1.32-1.36 (m, 1H), 1.51-1.54 (m, 4H), 1.79-1.84 (m, 3H), 1.99-2.01 (m, 1H), 2.35 (t, 2H, J=6.8 Hz), 2.52-2.72 (m, 11H), 3.15-3.21 (m, 1H), 3.85 (t, 2H, J=6.8 Hz), 4.61 (d, 4H, J=13.2 Hz), 4.90-4.92 (m, 1H), 6.76 (t, 1H, J=6.8 Hz), 6.84 (d, 2H, J=8 Hz), 6.96 (d, 3H, J=2.4 Hz), 7.17-7.24 (m, 3H), 7.52-7.59 (m, 2H), 7.87-7.92 (m, 2H), 10.80 (br, 1H); MS for C38H44N6O4 m/z 649.11(M+H)+.
Reaction SMILES: C([Li])(C)(C)C.CCCCC.I[C:12]1[C:17]([CH3:18])=[N:16][CH:15]=[CH:14][N:13]=1.[C:19]([O:23][C:24]([N:26]1[CH:31]2[CH2:32][CH2:33][CH:27]1[CH2:28][C:29](=[O:34])[CH2:30]2)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(OCC)C.C(OCC)(=O)C.O>[C:19]([O:23][C:24]([N:26]1[CH:31]2[CH2:32][CH2:33][CH:27]1[CH2:28][C:29]([OH:34])([C:12]1[C:17]([CH3:18])=[N:16][CH:15]=[CH:14][N:13]=1)[CH2:30]2)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Cc1nccnc1I
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Solvent: O
Product: Cc1nccnc1C1(O)CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.6 %

Procedure:
t-Butyl lithium in pentane (1.7 M, 3.8 mL, 6.46 mmol) was added dropwise to a solution of 2-iodo-3-methylpyrazine (0.7 g, 3.18 mmol) in diethyl ether (20 mL) at −50° C. under nitrogen and stirred for 30 minutes. A solution of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.19 g, 0.88 mmol) in diethyl ether (10 mL) was added dropwise and stirred at −50° C. for 1 hour. The reaction mixture was warmed to room temperature, water and ethyl acetate were added, the organics separated, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.1 g) as a pale yellow oil. LCMS m/z 320.2 [M+H]+. R.T.=3.55 min (Analytical Method 3).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:35]1[S:39][N:38]=[CH:37][N:36]=1)[S:7]([C:10]1[N:15]=[C:14]2[NH:16][CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=3[C:29]3[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=3)[C:13]2=[CH:12][CH:11]=1)(=[O:9])=[O:8].C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[CH3:34][N:33]1[C:29]([C:20]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=2[C:18]2[C:13]3[C:14](=[N:15][C:10]([S:7]([NH:6][C:35]4[S:39][N:38]=[CH:37][N:36]=4)(=[O:8])=[O:9])=[CH:11][CH:12]=3)[NH:16][CH:17]=2)=[CH:30][CH:31]=[N:32]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)c[nH]c3n2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: Cn1nccc1-c1cc(C(F)(F)F)ccc1-c1c[nH]c2nc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
A vial was charged with N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonamide (Intermediate J) (46.47 mg, 0.071 mmol) and DCM (0.5 mL) to give a clear solution. TFA (0.1 mL) was added dropwise, and the resulting mixture was stirred for 30 min. The mixture was diluted with methanol, then filtered through Celite® (diatomaceous earth). The filtrate was concentrated, and the residue was triturated with diethyl ether to give a white solid. The diethyl ether was decanted, and the solid was put under vacuum again for 10 min. Diethyl ether was added, and the suspension was sonicated for 1 min to give a fine white precipitate. The mixture was filtered on a membrane filter, and the collected solid was washed with diethyl ether (3×), then dried under a stream of N2 to give 3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonamide (18.02 mg, 0.036 mmol, 50.3% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=12.49 (d, J=2.4 Hz, 1 H), 8.45 (s, 1 H), 8.01 (s, 1 H), 7.94-7.88 (m, 2 H), 7.79 (s, 1 H), 7.65 (d, J=8.3 Hz, 1 H), 7.40 (s, 1 H), 7.35 (d, J=2.7 Hz, 1 H), 6.37 (d, J=1.9 Hz, 1 H), 3.23 (s, 3 H). m/z (ESI) 506.0 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:21](=[O:24])[CH2:22][CH3:23])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1nc(-c2cc(C)cc(C)c2)c(-c2ccncc2)s1
Temperature: 80 °C
Reaction time: 14 h
Yield: 67.5 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.51 g, 1.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.52 mmol) in N,N-dimethylacetamide (20 mL) was added propionyl chloride (0.18 g, 1.96 mmol) and the mixture was stirred at 80° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.41 g, yield 67%).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([NH:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[N:10]=1.C(N(CC)CC)C.[CH3:39][N:40]=[C:41]=[O:42]>C(Cl)Cl>[CH3:39][NH:40][C:41]([N:29]1[CH2:30][CH2:31][CH:26]([NH:25][C:11]2[N:10]=[C:9]([NH2:8])[C:14]([C:15](=[O:16])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])=[CH:13][N:12]=2)[CH2:27][CH2:28]1)=[O:42]
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CN=C=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCC(Nc2ncc(C(=O)c3ccccc3OC)c(N)n2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone trifluoroacetic acid salt (92.4 mg, Example 11) in methylene chloride (3 mL) were added triethylamine (0.12 mL, 0.861 mmol, Aldrich) and methyl isocyanate (6.2 mg, 0.107 mmol, Fluka) at 0° C . After stirring for 1 hour at 0° C., the reaction mixture was concentrated in vacuo and crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid methylamide (32.8 mg). HRMS, observed: 385.1985; Calcd for (M+H)+: 385.1983.