Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([OH:28])=[O:27])=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH:34]1([CH2:37]N)[CH2:36][CH2:35]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.CO>[F:33][C:2]([F:1])([F:32])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([O:28][CH2:37][CH:34]4[CH2:36][CH2:35]4)=[O:27])=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:6]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cccc(C(=O)O)c4)ccc32)c1
Reactant: NCC1CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cccc(C(=O)OCC5CC5)c4)ccc32)c1
Temperature: 25 °C

Procedure:
To a solution of 3-{1-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]-1H-benzimidazol-5-yl}benzoic acid (20.0 mg, 0.0440 mmol) and cyclopropylmethylamine (6.3 mg, 0.088 mmol Aldrich, Cat. No. 359521) in N,N-dimethylformamide (DMF) (1 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (23 mg, 0.053 mmol, Adv. ChemTech. Cat. No. RC8105) and N,N-diisopropylethylamine (23 μL, 0.13 mmol). The reaction mixture was stirred at r.t. 2 h., then diluted with MeOH, and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=508.2.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[N:4][CH:3]=1.[S:16]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17]1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:5]2[S:6][C:2]([C:18]3[CH:19]=[CH:20][S:16][CH:17]=3)=[CH:3][N:4]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(Nc2ncc(Br)s2)cc1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Temperature: 120 °C

Procedure:
A mixture of (5-bromo-thiazol-2-yl)-(4-methoxy-phenyl)-amine (203 mg, 0.710 mmol), 3-thiophene-boronic acid (268 mg, 2.10 mmol, 6.0 equiv), Pd(PPh3)4 (12 mg, 0.0105 mmol, 0.03 equiv), Na2CO3 (326 mg, 3.08 mmol, 8.8 equiv), and water (305 μL, 16.7 mmol, 24 equiv) in toluene (10 mL) is heated in a sealed tube to 120° C. for 1 h, under an argon atmosphere. The resulting suspension is allowed to cool to RT and filtered through a pad of celite, washing the filter cake with CH2Cl2 and water. The layers are separated. The organic phase is dried (Na2SO4), filtered and concentrated. Purification by MPLC (CH3CN/H2O/TFA) affords the title compound as a light beige solid: ES-MS: 289.0 [M+H]+; single peak at tR=7.43 min (System 1); Rf=0.56 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]/[CH:16]=[CH:17]/[CH2:18][CH2:19][NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:7][C:8]=1[O:9]C.C1CCCCC=1.B(Br)(Br)[Br:36]>ClCCl>[BrH:36].[BrH:36].[C:23]1([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]/[CH:17]=[CH:16]/[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][C:5]2[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: BrB(Br)Br
Reactant: COc1ccc(CCNCC/C=C/CCNCCc2ccccc2)cc1OC
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: Br
Product: Oc1ccc(CCNCC/C=C/CCNCCc2ccccc2)cc1O
Temperature: 25 °C

Procedure:
The product of step (d) (0.85 g) and cyclohexene (2.35 g) in dry dichloromethane (40 ml) were cooled to -80° and boron tribromide (9.3 ml., of a 1M solution in dichloromethane) was added under nitrogen. The mixture was allowed to warm to room temperature overnight then excess reagent was destroyed by the addition of methanol. The solution was evaporated to dryness and the residue triturated with ethyl acetate to give a grey solid. Recrystalisation from 2-propanol gave the title compound as the dihydrobromide salt (0.3 g) mp 208°-9°.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C@@H:15]([NH:18]C(OC(C)(C)C)=O)[CH2:16][OH:17])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[ClH:27]>C(Cl)Cl.CCOCC>[ClH:27].[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:26])[CH:15]([NH2:18])[CH2:16][OH:17])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CO)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCOC(=O)N1CCN(C(=O)C(N)CO)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-((S)-2-tert-butoxycarbonylamino-3-hydroxy-propionyl)-piperazine-1-carboxylic acid butyl ester (1.79 g, as described in WO2008044217) in CH2Cl2 (22 mL) was added HCl (4M in dioxane, 8.3 mL) and the reaction mixture was stirred for 2 h at RT. The suspension was diluted with Et2O (1000 mL) and the white cake was filtered, washed with Et2O and dried at HV overnight. The crude (1.19 g) was used without purification.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27]([O:31][C:32]([NH:34][CH2:35][CH2:36][C:37](O)=O)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([NH:34][CH2:35][CH2:36][C:37]1[O:20][N:19]=[C:17]([C@@H:10]2[CH2:11][C:12](=[N:14][O:15][CH3:16])[CH2:13][N:9]2[C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[N:18]=1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Product: CON=C1C[C@@H](c2noc(CCNC(=O)OC(C)(C)C)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 75 %

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and N-(tert-butoxycarbonyl)-β-alanine, this compound was obtained in 75% yield (91.9% purity by HPLC).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH3:11])[C:6](=[O:12])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:4](=[O:21])[C:3]=1[NH:22][C:23]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[N:36]=[CH:37][N:38]([C:40]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:39]=2)=[O:34])=[CH:28][CH:27]=1)=O.[OH-].[Na+].Cl>CO>[CH2:8]([N:7]1[C:2]2[N:1]=[C:23]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([NH:32][C:33]([C:35]4[N:36]=[CH:37][N:38]([C:40]([C:47]5[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=5)([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[C:53]5[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=5)[CH:39]=4)=[O:34])=[CH:30][CH:31]=3)[NH:22][C:3]=2[C:4](=[O:21])[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:6]1=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCCn1c(N)c(NC(=O)Cc2ccc(NC(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)cc2)c(=O)n(Cc2ccccc2F)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(=O)c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)cc3)nc21
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 68.3 %

Procedure:
A solution of 1-trityl-1H-imidazole-4-carboxylic acid (4-{[6-amino-1-butyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-amide (68.5 mg, 0.09 mmol) in methanol (2.0 mL) at 25° C. was treated with a 10% aqueous sodium hydroxide solution (1.06 mL, 0.26 mmol). The reaction was then warmed to 50° C. for 1 h. At this time, additional methanol (1.0 mL) was added. The reaction was continued at 50° C. for 2.5 h. At this time, the reaction was treated with a 3N aqueous hydrochloric acid solution (0.88 mL) and was stirred for 10 min. The resulting solid was collected by filtration, washed with water, and was dried in vacuo to afford 1-trityl-1H-imidazole-4-carboxylic acid {4-[3-butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (46.6 mg, 69.6%): EI-HRMS m/e calcd for C46H40N7O3F (M+) 757.3177, found 757.3160.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[I-].C[N+]1C=CN([C:28](=[O:37])[N:29]([CH3:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)C=1>>[C:17]([C@H:14]1[CH2:15][CH2:16][C@H:11]([C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([O:1][C:28](=[O:37])[N:29]([CH3:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:7][CH:6]=2)=[O:10])[CH2:12][CH2:13]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[C@H]1CC[C@H](C(=O)Nc2ccc(O)cc2)CC1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Agent: [I-]
Product: CN(C(=O)Oc1ccc(NC(=O)[C@H]2CC[C@H](C(C)(C)C)CC2)cc1)c1ccccc1

Procedure:
The title compound (353 mg, 86% yield, white crystals) was prepared from cis/trans-4-tert-butyl-cyclohexanecarboxylic acid (4-hydroxy-phenyl)-amide (275 mg, 1.00 mmol) and 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (343 mg, 1.00 mmol). HPLC-MS m/z=409 (M+1); Rt=5.28 and 5.42 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C@H:17]([OH:22])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25](OC(=O)C)([CH3:28])([CH3:27])[CH3:26].Cl(O)(=O)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([CH3:23])[C:14]([C@H:17]([O:22][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([O:20][CH3:21])=[O:19])=[C:15]([Cl:16])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1Cl
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Br)c3)nn2c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.3 %

Procedure:
A mixture of (S)-methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (7.81 g, 19.02 mmol), t-butylacetate (160 mL) in DCM (330 mL) was added perchloric acid (3.43 mL, 57.1 mmol) and the mixture was stirred at rt for 3 h. It was then quenched with sat.aq.NaHCO3 (adjusted to pH=7-8 by the addition of solid NaHCO3). This mixture was diluted with EtOAc and the organic phase was washed with water. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo to obtain ˜7 g of crude product as an oil. Filtration through 70 g of silica gel eluting with CH2Cl2 gave (S)-methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (5.71 g, 12.23 mmol, 64.3% yield). 1H NMR (400 MHz, CDCl3) δ 8.20 (t, J=1.6 Hz, 1H), 7.95 (dt, J=7.8, 1.1 Hz, 1H), 7.63-7.53 (m, 1H), 7.37 (t, J=7.9 Hz, 1H), 6.94 (s, 1H), 5.69 (s, 1H), 3.76 (s, 3H), 2.70 (s, 3H), 1.30 (s, 9H). LCMS (M+H)=466 and 468.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>ClCCl.C(O)C>[F:2][C:3]1[CH:4]=[C:5]([N:9]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3cccc(F)c3)ccc21
Yield: 97 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(3-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 97% of theory, C26H25FN6O3 (488.5) Rf value: 0.13 (silica gel; dichloromethane/ethanol=4:1) ##EQU127##
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:19])[O:8][C:7]2[C:9](OCCCCO)=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5]1.[Cl:20][C:21]1[CH:26]=[C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[C:23](Cl)[C:22]=1[Cl:36].[Cl-].[Na+].C1C[O:42]CC1>CN1CCCN(C)C1=O>[Cl:36][C:22]1[C:21]([Cl:20])=[CH:26][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][C:23]=1[O:42][C:12]1[C:6]2[CH2:5][C:4]([CH3:3])([CH3:19])[O:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: CC1(C)Cc2cccc(OCCCCO)c2O1
Reactant: C1CCOC1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Product: CC1(C)Cc2c(Oc3cc(OCc4ccccc4)cc(Cl)c3Cl)cccc2O1
Temperature: 40 °C

Procedure:
Under a nitrogen atmosphere, a solution of 0.32 gram (0.008 mole) of 60% sodium hydride (in mineral oil) in 2 mL of THF was stirred and a solution of 1.65 grams (0.007 mole) of 4-(2,2-dimethyl-2,3-dihydrobenzo[2,3-b]furan-7-yloxy)butan-1-ol (Step B) in 10 mL of THF was added drop-wise. Upon completion of addition the reaction mixture was warmed to 40° C. where it stirred during a 15-minute period. After this time the reaction mixture was allowed to cool to ambient temperature and then it was concentrated under reduced pressure to a residue. To the residue was added a solution of 1.00 gram (0.0035 mole) of 1,2,3-trichloro-5-(phenylmethoxy)benzene (Step C) in 35 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. Upon completion of addition the reaction mixture was heated to 130° C. where it was stirred during an 18-hour period. After this time the reaction mixture was cooled and stirred with 50 mL of an aqueous solution saturated with sodium chloride, then it was extracted with three 25 mL portions of diethyl ether. The combined extracts were washed with one 25 mL portion of water, dried with sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on silica gel using 25% methylene chloride in hexane and 50% methylene chloride in hexane as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.54 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)([OH:3])=[O:2].[H][H].[ClH:21]>C(O)C.[Pd]>[ClH:21].[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[N:15]2[CH:16]=[N:17][CH:18]=[C:14]2[CH2:13][CH2:12][CH2:11]1)([OH:3])=[O:2]
Reactant: O=C(O)CCCCCCc1cccc2cncn12
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(O)CCCCCCC1CCCc2cncn21

Procedure:
A solution of 2.7 g of 5-(6-carboxyhexyl)-imidazo[1,5-a]pyridine in a mixture of 120 ml of ethanol and 30 ml of concentrated hydrochloric acid is hydrogenated at 3 atmospheres in the presence of 1 g of 10% palladium on charcoal catalyst until 2 moles of hydrogen are consumed. The mixture is filtered free of catalyst and evaporated to dryness. The residue is recrystallized from isopropanol-ether to yield the 5-(6-carboxyhexyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine hydrochloride melting at 150°-4°.
Reaction SMILES: CC[CH2:3][CH2:4][O-:5].CC[CH2:8][CH2:9][O-:10].CC[CH2:13][CH2:14][O-:15].CC[CH2:18][CH2:19][O-:20].[Ti+4:21].C(O)CCC>C(O)C>[CH2:4]([O-:5])[CH3:3].[CH2:9]([O-:10])[CH3:8].[CH2:14]([O-:15])[CH3:13].[CH2:19]([O-:20])[CH3:18].[Ti+4:21]
Reactant: CCCC[O-]
Agent: [Ti+4]
Solvent: CCO
Solvent: CCCCO
Product: CC[O-]

Procedure:
Organic butyl titanate solution is mixed with a solvent (denatured ethanol) and graphite. The butyl titanate and solvent undergo a metathetical ligand exchange (room temperature decomposition) to form titanium tetraethanolate, butanol, and ethanol. The alcohols are then decanted, and the resulting slurry is then heated at 350° C. to completely decompose the remaining organic components, resulting in TiO2 being deposited on the basal plane surface of the graphite.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([F:37])[CH:10]=[C:11]2[C:15]=1[N:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=1)[N:13]=[C:12]2[S:24]([C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25])=[N+]=[N-].CO>C1COCC1.[Pd]>[Cl:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:14]1[C:15]2[C:11](=[CH:10][C:9]([F:37])=[CH:8][C:7]=2[O:6][CH2:5][CH2:4][NH2:1])[C:12]([S:24]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][CH:28]=2)(=[O:25])=[O:26])=[N:13]1
Reactant: [N-]=[N+]=NCCOc1cc(F)cc2c(S(=O)(=O)c3cccc4ccccc34)nn(Cc3cccc(Cl)c3)c12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: NCCOc1cc(F)cc2c(S(=O)(=O)c3cccc4ccccc34)nn(Cc3cccc(Cl)c3)c12
Reaction time: 2 h
Yield: 82.4 %

Procedure:
A mixture of 7-(2-azido-ethoxy)-1-(3-chloro-benzyl)-5-fluoro-3-(naphthalene-1-sulfonyl)-1H-indazole (0.09 g, 0.17 mmoles) and 10% Pd/C in THF (5 mL), and methanol (15 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 52 Ib/in2 for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The crude product was purified by flash chromatography using as eluent 5% CH3OH/CH2Cl2 to afford the title compound as an off-white solid (0.08 g, 0.14 mmoles), MS: (ES+) 511 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].C([C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:17]2[CH2:22][C:21]([CH3:24])([CH3:23])[CH2:20][C:19]([CH3:26])([CH3:25])[CH2:18]2)=[CH:12][C:11]=1[OH:33])C.[C:34]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:34][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[C:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([CH3:23])([CH3:24])[CH2:22]2)=[CH:12][C:11]=1[O:33][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7]
Reactant: OCCOCCCl
Reactant: CCc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1OCCOCCO
Temperature: 100 °C
Yield: 40 %

Procedure:
2-(2-chloroethoxy)ethanol (139 mg, 1.12 mmol), compound 41 (150 mg, 0.45 mmol), and K2CO3 (185 mg, 1.34 mmol) were combined with dry acetone (5 mL) in a sealed microwave vessel. The mixture was heated at 100° C. for 20 minutes in a Personal Chemistry Emrys Optimizer microwave. The reaction was allowed to cool to room temperature and the solids were removed via filtration. The solids were rinsed twice with acetone and the solvent was removed in vacuuo. The reaction was purified using the Agilent semi prep HPLC (LUNA C18 column, 23 mL/min, 30-70% CH3CN-Water (TFA) to give 76 mg (40%) of the desired compound 50 as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.91 (s, 6H), 0.93 (s, 6H), 1.23 (s, 2H), 1.95 (s, 2H), 1.96 (s, 2H), 2.13 (s, 3H), 3.7-3.78 (m, 2H), 3.87 (t, J=4.6 Hz, 2H), 4.1 (t, J=4.8 Hz, 2H), 6.72 (d, J=8.8 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H), 7.10-7.20 (m, 3H), 7.20-7.30 (m, 2H).
Reaction SMILES: [OH-].[K+].C([O:6][C@H:7]([CH3:24])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH3:23])[CH:18]=[N:17][C:16]=2[NH:15][C:13]1=[O:14])(=O)C.Cl>CO.O>[OH:6][C@H:7]([CH3:24])[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH3:23])[CH:18]=[N:17][C:16]=2[NH:15][C:13]1=[O:14]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)[nH]c2ncn(C)c2c1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@@H](O)CCCCn1c(=O)[nH]c2ncn(C)c2c1=O
Reaction time: 3 h
Yield: 76.3 %

Procedure:
Potassium hydroxide (1.0 g, 17.8 mmol) was added to a solution of (R)-1-(5-acetoxyhexyl)-7-methylxanthine (prepared as described for CT12460) (3.8 g, 12.3 mmol) in methanol-water (1:1, 100 ml). After stirring for 3 hours, the pH of the solution was adjusted to 7 by the slow addition of 1 N hydrochloric acid. The solution was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 15% methanol-ethyl acetate to provide (R)-1-(5-hydroxyhexyl)-7-methylxanthine (2.5 g).
Reaction SMILES: C(OC([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=O)(C)(C)C.[C:19]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.[C:35]1([C:41]2([OH:47])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]([N:44]2[CH2:45][CH2:46][C:41]([OH:47])([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:42][CH2:43]2)=[O:18])[N:8]([S:25]([C:22]2[CH:23]=[CH:24][C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:20][CH:21]=2)(=[O:27])=[O:26])[CH2:12]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)N2CCC(O)(c3ccccc3)CC2)N(S(=O)(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]-4-sulfonyl chloride, and 4phenyl-4-piperidinol, the title compound was obtained in 84% purity by HPLC. MS(ESI+): m/z=534.
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]([CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CO.[Pd]>[NH2:12][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[CH:9][C:10]=1[CH3:15])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(C)c(N)c1C
Reaction time: 144 h
Yield: 64.7 %

Procedure:
To a solution of methyl 2,4-dimethyl-3-nitro-benzoate (37 g, 176.9 mmol) in methanol (370 mL), 10% palladium on carbon 50% wet (5.6 g) is added. The reaction is bubbled with hydrogen and placed under a hydrogen atmosphere for 6 days. The mixture is filtered through diatomaceous earth and the filtrate is evaporated to dryness. The resulting residue is purified by flash chromatography (silica gel), eluting with 20% ethyl acetate in hexanes to afford the title compound as a yellow oil (20.5 g, 65%). Mass spectrum (m/z): 180.1 (M+1). 1H NMR (300.16 MHz, DMSO-d6): δ 6.89 (s, 2H), 4.78 (s, 2H), 3.76 (s, 3H), 2.23 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:20](=[O:21])C2CCCC(=C2)C1=O.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([CH:35]=[CH:36][CH:37]=1)[C:31]([NH2:34])([CH3:33])[CH3:32].CN1[CH2:46][CH2:45][O:44]CC1>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:20](=[O:21])[C:6]1[CH2:7][CH2:2][CH2:3][CH2:4][C:46]=1[C:45]([NH:34][C:31]([C:30]1[CH:35]=[CH:36][CH:37]=[C:28]([C:27]([F:38])([F:39])[F:26])[CH:29]=1)([CH3:33])[CH3:32])=[O:44]
Reactant: CN1CCOCC1
Reactant: O=C1C2=CC(CCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: CC(C)(N)c1cccc(C(F)(F)F)c1
Solvent: c1ccccc1
Product: CC(C)(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.2 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydroisophthalimide (1.00 g, 2.75 mmol), 3-trifluoromethylcumylamine (0.730 g, 3.59 mmol), N-methylmorpholine (0.320 g, 3.16 mmol), and benzene (15 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting crude product was recrystallized from chloroform/acetone to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-(3-trifluoromethylcumyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.360 g, 23.1% yield).