Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[S:8][C:7]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:6][CH:5]=1.Cl[C:14]1[C:18]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[N:17][S:16][N:15]=1>C1COCC1>[CH3:3][C:4]1[S:8][C:7]([CH2:9][CH2:10][CH2:11][O:12][C:14]2[C:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[N:17][S:16][N:15]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(CCCO)s1
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CCCOc2nsnc2-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium hydride (10.2 mmol) was added to a solution of 3-(5-methyl-2thienyl)-1-propanol (4.0 g, 25.5 mmol) in THF (40 ml). The mixture was stirred for 1 h at room temperature, whereupon a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (1.0 g, 5.1 mmol) in THF (10 ml) was added dropwise to the reaction mixture. After stirring overnight at room temperature, the reaction was quenched with water then extracted with diethyl ether. The organic phase was dried over NaCl/Na2SO4 then evaporated to yield crude 3-(3-(5-methyl-2-thienyl)propoxy-1,2,5-thiadiazol-4-yl)pyridine. A solution of 3-(3-(5-methyl-2-thienyl)propoxy-1,2,5-thiadiazol-4-yl)pyridine (1.0 g, 3.2 mmol) and iodomethane (2.3 g, 16.0 mmol) in 60 ml of acetone was refluxed overnight. The solution was evaporated to yield 1.5 g of the quaternized product. Sodium borohydride (0.6 g, 16.0 mmol) was carefully added to a solution of the quaternized product (1.5 g) in ethanol (30 ml). The reaction was evaporated and the resulting residue was taken up in water and extracted with methylene chloride (3×100 ml). The organic phase was dried over NaCl/Na2SO4 then evaporated. The residue was purified by radial chromatography eluting with 0.5% NH4OH/5.0% EtOH in CHCl3. The oxalate salt was made to yield 337 mg of the title compound. M.p. 134°-137° C. (Compound 129).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].[Br:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18]([OH:20])=O)[CH:14]=[CH:15][CH:16]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:27]N(C=O)C>>[Br:10][C:11]1[CH:12]=[C:13]([C:17]2[C:18](=[O:20])[C:7]3[C:5](=[CH:4][C:3]([OH:9])=[C:2]([Cl:1])[CH:8]=3)[O:6][CH:27]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Oc1ccc(Cl)c(O)c1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CN(C)C=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: O=c1c(-c2cccc(Br)c2)coc2cc(O)c(Cl)cc12

Procedure:
This compounds was synthesised in the same manner as described above. 4-Chlororesorcinol (0.34 g, 2.4 mmol), 3-bromophenyl acetic acid (0.51 g, 2.4 mmol), BF3Et2O (5 ml), PCl5 (0.74 g, 3.6 mmol), DMF (5 ml and 10 ml). The precipitate formed was filtered and re-crystallized from methanol to give 3-(3-Bromo-phenyl)-6-chloro-7-hydroxy-chromen-4-one a flakey white solid (0.64 g, 76%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([OH:17])=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1)(=[O:3])[CH3:2].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([O:17][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1c(-c2ccccc2)cc(OC(C)=O)cc1-c1ccccc1
Yield: 92 %

Procedure:
A mixture of 4acetoxy-2,6diphenylphenol (6.1 g, 20 mmol; prepared as described in Ber. 101, 2519 (1968)), ethyl bromoacetate )4.0 g, 24 mmol), potassium carbonate (3.3 g, 24 mmol) and 2-butanone (150 ml) was refluxed for 24 h, then filtered and the solvent evaporated. The residue was purified by chromatography on silica gel) 120 g, eluent benzene) to give 7.2 g (92%) of oily ethyl 4-acetoxy-2,6-diphenylphenoxyacetate.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([OH:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N:49]1([C:55](Cl)=[O:56])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1>N1C=CC=CC=1>[N:49]1([C:55]([O:39][C@H:36]2[CH2:37][CH2:38][C@H:33]([C:30]3[CH:31]=[CH:32][C:27]([C:23]4[N:22]=[C:21]5[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:18]([O:17][C@@H:16]6[CH2:15][O:14][C@@H:13]7[C@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[CH2:10][O:11][C@H:12]67)=[N:19][C:20]5=[CH:25][C:24]=4[Cl:26])=[CH:28][CH:29]=3)[CH2:34][CH2:35]2)=[O:56])[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](O)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: O=C(Cl)N1CCOCC1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](OC(=O)N5CCOCC5)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 50 °C
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]-furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanol (50 mg) is dissolved in pyridine (1 mL), treated with morpholine-4-carbonyl chloride (25 μL) and stirred for 12 hours at 50° C. Morpholine-4-carbonyl chloride (25 μL) is added and the mixture is stirred for 2 hours at 50° C. Then morpholine-4-carbonyl chloride (75 μL) is added and the mixture is stirred for 48 hours at 70° C. The mixture is partitioned between ethylacetate and hydrochloric acid (1 M). The organic phase is dried (MgSO4) and concentrated. The crude product is used directly in the next step.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([C:23]1[CH:24]=[N:25][C:26]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[N:27][CH:28]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:36][Si:37]([CH3:53])([CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:13]([C:23]1[CH:24]=[N:25][C:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][Si:37]([CH3:53])([CH3:36])[CH2:47][CH2:48][Si:49]([CH3:50])([CH3:51])[CH3:52])=[CH:33][CH:34]=2)=[N:27][CH:28]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCCCCCCO
Reactant: CCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCc1cnc(-c2ccc(OCCCCCCCC[Si](C)(C)CC[Si](C)(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethylazodicarboxylate (0.065 g, 0.375 mmol) in THF (5.0 ml) was added dropwise to a stirred solution of 4-(5-decylpyrimidin-2-yl)-phenol (0.094 g, 0.300 mmol), compound 17 (0.083 g, 0.300 mmol) and triphenylphosphine (0.098 g, 0.375 mmol) in THF (10 ml). The treaction mixture was stirred at room temperature for 24 h, the solvent removed in vacuo and the residues purified by column chromatography [silica gel eluted with hexane/ethyl acetate (9:1)] to yield a colorless solid that was recrystallized from acetonitrile.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.COCC([Cl:12])=O.[CH3:13][N+:14]([CH2:17][CH:18]([OH:23])[CH2:19][C:20]([O-:22])=[O:21])([CH3:16])[CH3:15]>C(#N)C>[CH3:1][O:2][CH2:3][C:4]([C:18]([CH2:19][C:20](=[O:21])[O-:22])([CH2:17][N+:14]([CH3:13])([CH3:15])[CH3:16])[OH:23])=[O:6].[Cl-:12]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Reactant: COCC(=O)Cl
Reactant: COCC(=O)O
Solvent: CC#N
Product: COCC(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Product: [Cl-]
Temperature: 30 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
A mixture of methoxyacetic acid (3 ml; 0.04 moles) and methoxyacetyl chloride (3 ml; 0.03 moles) was kept under stirring at 30° C. for 2 hours. To this mixture carnitine chloride (4 g; 0.02 moles) which had been previously dried was added. The resulting mixture was brought to 40° C. and kept under stirring for seven days. The mixture was then taken up with acetonitrile and the unreacted carnitine chloride was filtered off. Upon addition of tert-butyl methyl ether an oil precipitated. The oil precipitation was repeated four times with acetonitrile/tert butyl methyl ether. The oil which finally separated was lyophilized. Four grams of methoxy acetyl carnitine chloride were thus obtained. Yield: 75%
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[C:7]([CH3:18])=[C:8]([N:12]2[C:16](=[O:17])[CH2:15][NH:14][CH2:13]2)[CH:9]=[CH:10][CH:11]=1.C([O-])([O-])=O.[K+].[K+].[Cl:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl.O>[Cl:25][CH2:26][C:27]([N:14]1[CH2:15][C:16](=[O:17])[N:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=2[CH3:18])[CH2:13]1)=[O:28]
Reactant: Cc1c(Cl)cccc1N1CNCC1=O
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Cl)cccc1N1CN(C(=O)CCl)CC1=O

Procedure:
To a mixture of 3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one acetic acid salt (75) (422 mg, 1 equiv) and K2CO3 (552 mg) in 5 mL of DCM/water (1:1 v/v) was added chloroacetyl chloride (240 μL, 1.5 equiv). One hour later, the organic layer was separated and dried over sodium sulfate to give 1-(2-chloro-acetyl)-3-(3-chloro-2-methyl-phenyl)-imidazolidin-4-one (76).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.[Cl:32][C:33]1[N:34]=[N:35][C:36](Cl)=[CH:37][CH:38]=1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH3:31][C:2]([CH3:30])([CH3:1])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[C@H:23]2[CH2:28][CH2:27][C@H:26]([O:29][C:36]3[N:35]=[N:34][C:33]([Cl:32])=[CH:38][CH:37]=3)[CH2:25][CH2:24]2)[CH:6]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](O)CC2)c(C(=O)O)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](Oc3ccc(Cl)nn3)CC2)c(C(=O)O)s1
Reaction time: 0.5 h

Procedure:
A mixture of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (53 mg, 0.12 mmol) and 3,6-dichloropyridazine (86 mg, 0.58 mmol) in DMF (0.5 mL) was treated with sodium hydride (58 mg, 1.4 mmol, 60% oil dispersion) in two portions. The mixture was stirred until the bubbling slowed, and was sealed and heated by microwave at 100 deg C. for 30 min. After cooling, ethyl acetate (2-3 mL) was added and the mixture was carefully quenched with citric acid (10% aqueous solution, 2-3 mL). Water was added and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was passed through a plug of silica (10% MeOH:DCM eluent) and concentrated to yield 69 mg of 5-(3,3-Dimethyl-but-1-ynyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(6-chloro-pyridazin-3-yloxy)-cyclohexyl]-amino}-thiophene-2-carboxylic acid as a black oil which was carried on without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[N:17]([CH3:18])[N:16]=[CH:15][N:14]=3)/[O:7][C:8]2=O)=[C:4]([N+:19]([O-])=O)[CH:3]=1.O.[NH2:23][NH2:24].C(O)(=O)C>C1COCC1.O>[NH2:19][C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[C:9]2[C:5]=1[C:6]([CH2:12][C:13]1[N:17]([CH3:18])[N:16]=[CH:15][N:14]=1)=[N:23][NH:24][C:8]2=[O:7]
Reactant: NN
Reactant: Cn1ncnc1/C=C1\OC(=O)c2cc(F)cc([N+](=O)[O-])c21
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cn1ncnc1Cc1n[nH]c(=O)c2cc(F)cc(N)c12
Reaction time: 2 h
Yield: 42 %

Procedure:
To a solution of 6-fluoro-3-((1-methyl-1H-1,2,4-triazol-3-yl)methylene)-4-nitroiso-benzofuran-1(3H)-one (3) (4.0 g, 135 mmol) in THF (100 mL) was added hydrazine monohydrate (85%) (6 mL) at room temperature under nitrogen atmosphere. The mixture was stirred for 2 hours, then acetic acid (6 mL) was added and the mixture was heated to and kept at 60° C. for 18 hours. The resulting mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×3). The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness to afford the title compound as a yellow solid (1.6 g, yield 42%). LC-MS (ESI) m/z: 275 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@@H:7]([NH:10][C:11]([C:13]1[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:12])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22].N12CCCN=C1CCCCC2.O>O1CCCC1>[C:1]([O:5][C:6](=[O:20])[C@@H:7]([N:10]1[C:11](=[O:12])[C:13]2[N:14]=[CH:15][CH:16]=[CH:17][C:18]=2[NH:19][C:21]1=[O:22])[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC[C@H](NC(=O)c1ncccc1N)C(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H](C(=O)OC(C)(C)C)n1c(=O)[nH]c2cccnc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
A solution of 217 mg of (S)-2-[(3-amino-pyridine-2-carbonyl)-amino]-butyric acid tert-butyl ester in tetrahydrofuran (10 mL) is treated with 259 mg of 1,1′-carbonyldiimidazole and 0.018 mL of 1,8-diazabicyclo[5.4.0]undec-7-ene. The mixture is stirred at room temperature for 16 h. Then the reaction mixture is added water (1 mL) and the resulting mixture is concentrated and purified by flash chromatography on silica gel to give 130 mg (55%) of (S)-2-(2,4-dioxo-1,4-dihydro-2H-pyrido[3,2-d]pyrimidin-3-yl)-butyric acid tert-butyl ester.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6](=[O:13])[C:7]([C:11]#[N:12])=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:17]>>[OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6](=[O:13])[C:7]([C:11]([NH2:12])=[O:17])=[C:8]([CH3:10])[O:9][C:4]=2[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1oc2cc(O)ccc2c(=O)c1C#N
Product: Cc1oc2cc(O)ccc2c(=O)c1C(N)=O

Procedure:
A slurry of 1 g of 7-hydroxy-4-oxo-2-methyl-4H-1-benzopyran-3-carbonitrile in 6 ml of conc. sulfuric acid was heated for 3 hours on the steam bath. The mixture was poured onto ice. The solid was filtered and recrystallized from ethanol, mp 289°-290°C.
Reaction SMILES: [H-].[Na+].[F:3][S:4]([F:38])([F:37])([F:36])([F:35])[C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13]2[O:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]4[N:31]=[N:32][NH:33][N:34]=4)=[CH:22][CH:21]=3)[N:17]=2)=[CH:7][CH:6]=1.Br[CH2:40][CH2:41][OH:42]>CN(C=O)C>[F:38][S:4]([F:35])([F:3])([F:36])([F:37])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH:12][C:13]2[O:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]4[N:34]([CH2:40][CH2:41][OH:42])[N:33]=[N:32][N:31]=4)=[CH:24][CH:25]=3)[N:17]=2)=[CH:9][CH:10]=1.[F:38][S:4]([F:35])([F:3])([F:36])([F:37])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[CH:12][C:13]2[O:14][CH:15]=[C:16]([CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]4[N:31]=[N:32][N:33]([CH2:40][CH2:41][OH:42])[N:34]=4)=[CH:24][CH:25]=3)[N:17]=2)=[CH:9][CH:10]=1
Reactant: FS(F)(F)(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCc4nn[nH]n4)cc3)co2)cc1
Reactant: OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCCn1nnc(CCCCc2ccc(OCc3coc(C=Cc4ccc(S(F)(F)(F)(F)F)cc4)n3)cc2)n1
Product: OCCn1nnnc1CCCCc1ccc(OCc2coc(C=Cc3ccc(S(F)(F)(F)(F)F)cc3)n2)cc1
Reaction time: 0.25 h

Procedure:
6.4 mg (0.16 mmol) 95% sodium hydride were added to a solution of 82.0 mg (0.156 mmol) 5-[4-(4-{2-[(E)-2-(-4-pentafluorosulfanyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-2H-tetrazole in 2.0 ml DMF and stirred for 15 min. 19.8 mg (0.159 mmol) 2-bromoethanol were added, the mixture stirred overnight and evaporated. Separation by LC-MS (methanol/water 3:1, pH=2.3) on a C4 reversed phase column (YMC-PACK® C4 (Butyl) reversed phase column from YMC Europe GmbH, Schermbeck, Germany) gave 32 mg of the title compound and 6 mg of 2-{5-[4-(4-{2-[2-(4-Pentafluorosulfanyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-phenyl)-butyl]-tetrazol-2-yl}-ethanol (example 8).
Reaction SMILES: COC(=O)C(O)=CC(=O)N(CC1C=CC(Cl)=C(Cl)C=1)C.C=O.[CH3:23][N:24]1[C:28]([CH2:29][C@H:30]([NH:34][C:35]([CH2:37][CH2:38]N)=[O:36])[C:31]([OH:33])=[O:32])=[CH:27][N:26]=[CH:25]1.[N+]([O-])(O)=O.[Cl:44][C:45]1[CH:46]=[C:47]([CH:61]=[CH:62][C:63]=1[Cl:64])[CH2:48][N:49]([CH3:60])[C:50]([C:52]1[CH2:53][N:54](C)[C:55](=[O:58])[C:56]=1[OH:57])=[O:51]>>[Cl:44][C:45]1[CH:46]=[C:47]([CH:61]=[CH:62][C:63]=1[Cl:64])[CH2:48][N:49]([CH3:60])[C:50]([C:52]1[CH2:53][N:54]([CH:29]([C:28]2[N:24]([CH3:23])[CH:25]=[N:26][CH:27]=2)[CH:30]([NH:34][C:35](=[O:36])[CH2:37][CH3:38])[C:31]([OH:33])=[O:32])[C:55](=[O:58])[C:56]=1[OH:57])=[O:51]
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: Cn1cncc1C[C@H](NC(=O)CCN)C(=O)O
Agent: C=O
Agent: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Solvent: O=[N+]([O-])O
Product: CCC(=O)NC(C(=O)O)C(c1cncn1C)N1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Yield: 1 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and L-anserine nitrate as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as a white solid (3.3 mg, 1% yield). 1H NMR (500 MHz, CDCl3) δ: 8.56 (s, 1H), 7.36 (d, 1H, J=8.24) 7.29 (m, 1H), 7.20 (s, 1H), 7.04 (m, 1H), 4.69 (m, 1H), 4.52 (s, 2H), 4.05 (s, 2H), 3.76 (s, 3H), 3.65 (t, 2H, J=5.80), 3.14 (m, 2H), 2.94 (s, 2H), 2.51 (m, 2H). HRMS (M+H) calcd for C23H26N5Cl2O6: 538.1260. found: 538.1280.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17]([NH2:24])[C:16]=2[N:15]=[C:14]1[CH2:25][CH2:26][CH2:27][CH3:28].[CH3:29][N:30]([CH3:35])[S:31](Cl)(=[O:33])=[O:32]>ClCCl>[NH2:24][C:17]1[C:16]2[N:15]=[C:14]([CH2:25][CH2:26][CH2:27][CH3:28])[N:13]([CH2:12][CH2:11][CH2:10][CH2:9][NH:8][S:31]([N:30]([CH3:35])[CH3:29])(=[O:33])=[O:32])[C:21]=2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=1
Reactant: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCN
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc(C)c(C)c2n1CCCCNS(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 113 h
Yield: 11 %

Procedure:
Triethylamine (0.031 mL, 0.23 mmol) was added to a solution of 1-(4-aminobutyl)-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine (67 mg, 0.23 mmol) in dichloromethane (45 mL). The reaction mixture was cooled in an ice bath. Dimethylsulfamoyl chloride (0.025 mL, 0.23 mmol) was added. The reaction mixture was removed from the ice bath. The reaction mixture was allowed to stir at ambient temperature for ˜113 hours. Analysis by HPLC indicated that the reaction was not complete. The dichloromethane was removed under reduced pressure. 1,2-Dichloroethane (50 mL) was added and the reaction mixture was heated to 60° C. After 3 hours, more dimethylsulfamoyl chloride (2.5 μL) was added and heating was continued. After 22 hours the reaction temperature was raised to reflux and the reaction mixture was refluxed for 100 hours. The reaction mixture was extracted twice with water. The aqueous fractions were combined and concentrated under reduced pressure. The resulting residue was recrystallized from methyl acetate to provide 10 mg of N′-[4-(4-amino-2-butyl-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)butyl]-N,N-dimethylsulfamide as an off-white crystalline solid, m.p. 129.5-131° C. M/Z 397.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[C:30]2[CH3:34])[N:25]=[N:26][CH:27]=1>>[ClH:21].[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[C:30]2[CH3:34])[N:25]=[N:26][CH:27]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: CC1(C)OB(c2cccc(C(F)(F)F)c2F)OC1(C)C
Product: Cc1nccn1Cc1cc(-c2cccc(C(F)(F)F)c2F)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=337.4 (M+H+), was prepared from 2-(2-fluoro-3-trifluoromethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([CH:13]=[O:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].O.O.P([O-])(O)(O)=[O:26].[Na+].Cl([O-])=O.[Na+].CC(=CC)C>O1CCCC1.O>[CH2:15]([C:11]1([C:13]([OH:26])=[O:14])[CH2:12][CH:7]2[CH2:6][N:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:22])[CH2:9][CH:8]2[CH2:10]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=P([O-])(O)O
Reactant: CN(C)C(=O)N1CC2CC(C=O)(Cc3ccccc3)CC2C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC2CC(Cc3ccccc3)(C(=O)O)CC2C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
5-Benzyl-5-formyl-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14b (0.729 g, 2.43 mmol) was dissolved in the solvent mixture of 28 mL of tetrahydrofuran and 14 mL of water under nitrogen atmosphere, followed by addition of sodium dihydrogenphosphate dihydrate (1.14 g, 7.29 mmol), sodium chlorite (0.66 g, 7.29 mmol) and 2-methyl-2-butene (0.513 g, 7.32 mmol) upon cooling to 0° C. The reaction mixture was stirred at 0° C. for 2 hours. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-benzyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 14c (0.76 g, yield 98%) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:20][CH:19]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[C:31](F)([F:33])F)#[N:2].S(Cl)(Cl)=O.C[N:40](C=O)C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:17])[C:12]3([CH2:15][CH2:14][CH2:13]3)[N:11]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][C:27]([NH2:40])=[O:29])=[CH:22][CH:23]=3)[C:10]2=[S:30])=[CH:5][C:4]=1[CH2:31][F:33])#[N:2]
Reactant: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(=O)O)cc3)C2=S)cc1C(F)(F)F
Reactant: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#Cc1ccc(N2C(=O)C3(CCC3)N(c3ccc(CCCC(N)=O)cc3)C2=S)cc1CF
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-(7-(4-Cyano-3-(trifluoromethyl)phenyl)-8-oxo-6-thioxo-5,7 -diazaspiro[3.4]octan-5-yl)phenyl)butanoic acid, RD141 (Formula 51) (60 mg, 0.12 mmol) in DMF (3 mL) was added thionyl chloride (0.01 mL, 0.15 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. Then ammonia was bubbled into the mixture. The mixture was partitioned with ethyl acetate (25 mL) and water (25 mL). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane:acetone, 70:30) to yield 4-(4-(7-(4-Cyano-3 -(fluoromethyl)phenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl)phenyl)butanamide, RD130 (Formula 52) (37 mg, 61%) as a white powder. 1H NMR δ 7.97 (d, 1H, J=1.8 Hz), 7.95 (d, 1H, J=8.3 Hz), 7.85 (dd, 1H, J=8.3 Hz), 7.39 (d, 2H, J=8.3 Hz), 7.22 (d, 2H, J=8.3 Hz), 5.59 (br s, 2H), 2.77 (t, 2H, J=7.5 Hz), 2.62-2.68 (m, 2H), 2.51-2.59 (m, 2H), 2.31 (t, 2H, J=7.5 Hz), 2.16-2.25 (m, 1H), 2.05 (p, 2H, J=7.5 Hz), 1.57-1.70 (m, 1H).