Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[Li+].CC([N-]C(C)C)C.I[CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>C1COCC1.COC1SC(=O)N(CSP(OC)(OC)=S)N=1>[CH2:1]([O:3][C:4](=[O:22])[CH:5]([C:6]1[CH:7]=[CH:8][C:9]([S:12]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)(=[O:13])=[O:14])=[CH:10][CH:11]=1)[CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Reactant: ICC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: COc1nn(CSP(=S)(OC)OC)c(=O)s1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CC1CCCC1)c1ccc(S(=O)(=O)N2CCN(C)CC2)cc1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of the title C compound, [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (15 g, 0.046 mol) in a mixture of THF (60 mL) and DMTP (10 mL) is cooled to −78° C. under nitrogen. The resulting solution is stirred at −78° C. for 45 min and to this is added LDA (25.6 mL, 6.40 g, 0.059 mol, 25% solution in THF/Hexane). A solution of iodomethylcyclopentane (11.60 g, 0.055 mol) in a mixture of DMTP (12 mL) and THF (20 mL) is added over a period of 15 min at −78° C. and reaction mixture stirred at −78° C. for 3 h further, followed by stirring at 25° C. for 12 h. The reaction mixture is then quenched by the dropwise addition of saturated aqueous ammonium chloride solution (50 mL) and is concentrated in vacuo. The residue is diluted with water (50 mL) and extracted with ethyl acetate (3×100 mL). The organic solution is washed with a saturated aqueous sodium chloride (2×150 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Column chromatography over silica gel (60-120 mesh), using 50% ethyl acetate in hexane as an eluent to afford 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid ethyl ester as a white solid: 1H NMR (400 MHz, CDCl3) δ 0.9-2.1 (m, 11H), 1.2 (t, J=7.1, 3H), 2.3 (s, 3H), 2.5 (br s, 4H), 3.0 (br s, 4H), 3.6 (m, 1H), 4.1 (q, J=7.1, 2H), 7.5 (d, J=8.3, 2H), 7.7 (d, J=8.3, 2H); MS 409 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].Cl.[CH2:15](O)[CH3:16]>>[CH2:15]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([OH:1])[CH:3]=1)[CH3:16]
Reactant: CCO
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Agent: Cl
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(O)c1
Yield: 1492.2 %

Procedure:
3-Hydroxy-4-nitrobenzoic acid (20.0 g, 199 mmol) in ethanol (250 mg) was refluxed for 6 hr in the presence of dry hydrogen chloride (5 g). The solvent was evaporated and the residue was dissolved in methylene chloride. The solution was washed with sodium bicarbonate until the unreacted material was removed as a precipitate. The organic fraction was finally washed with brine, dried over magnesium sulfate to give a brown solid of 3-hydroxy-4-nitrobenzoic acid ethyl ester (17.1 g): mp 80°-81° C. (crystallized from diethyl ether-hexane); Anal. Calcd for C9H9NO5 : C, 51.19% H, 4.30% N, 6.6% and Found: C, 51.23% H, 4.30% N, 6.79%; ir(CHCl3) 3,260, 1,720, 1,535 and 1,320 cm-1 ; and nmr(CDCl3) δ1.35 (3H, t), 4.3 (2H, q), 7.7 (3H, m) and 10.4 (1H, s).
Reaction SMILES: [CH3:1][C:2]([C:4]1[C:5]([OH:11])=[CH:6][CH:7]=[CH:8][C:9]=1[OH:10])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>CC(C)=O>[C:23]([O:22][C:20](=[O:21])[CH2:19][O:11][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=1[C:2](=[O:3])[CH3:1])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(=O)c1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)c1c(O)cccc1OCC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
A solution of 2,6-dihydroxyacetophenone (35.37 g, 0.23 moles), potassium carbonate (51.4 g, 0.37 moles), and t-butyl bromoacetate (28.4 mL, 0.23 moles) in 440 mL of acetone was heated at reflux for 1.5 hours. It was then cooled to room temperature and filtered. The filter cake was washed with acetone and the combined mother liquors were concentrated in vacuo. (2-Acetyl-3-hydroxy-phenoxy)-acetic acid tert-butyl ester was isolated as thick yellow oil, which was used directly used for the next step.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[OH2:9]>>[C:1]([NH2:2])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: N#Cc1cccnc1
Reactant: O
Product: NC(=O)c1cccnc1
Reaction time: 1 h

Procedure:
The strain M33 was grown as in Example 1. A biomass containing M33 cells up to a concentration of 0.5 mg/ml and 3-cyanopyridine up to a concentration of 8% was added into a I00-ml flask containing 40 ml of distilled water (pH 7.6). The flask was incubated at 30° C. under stirring conditions. After 60 minutes, a I0%-nicotinamide solution was obtained. Nicotinic acid and 3-cyanopyridine were not present in the reaction mixture.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:22][CH2:23][CH2:24][C:25]2[NH:26][CH:27]=[N:28][CH:29]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15]C(=O)C(F)(F)F)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.CO.O.[Li+].[OH-]>C1COCC1>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:22][CH2:23][CH2:24][C:25]3[NH:26][CH:27]=[N:28][CH:29]=3)[C:2]([Br:1])=[CH:7][N:6]=2)=[CH:14][CH:13]=1
Reactant: O=C(Nc1ccc(Nc2ncc(Br)c(NCCc3cnc[nH]3)n2)cc1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Nc2ncc(Br)c(NCCc3cnc[nH]3)n2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.2 %

Procedure:
N-(4-{5-Bromo-4-[2-(3H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-phenyl)-trifluoro acetamide (1 g, 1.9 mmole) was dissolved in THF (10 ml), MeOH (10 ml) and water (5 ml) and LiOH (455 mg) was added in one portion at room temperature. The reaction mixture was stirred at room temperature for two days, the solvent removed under reduced pressure. The residue was dissolved in ethyl acetate and water and extracted with ethyl acetate (3×). The combined organic layers were combined and dried over magnesium sulfate. After evaporation of the solvent one obtains 350 mg of N2-(4-Amino-phenyl)-5-bromo-N4-[2-(3H-imidazol-4-yl)ethyl]pyrimidine-2,4-diamine. ESI-MS: 375.
Reaction SMILES: [F:1][C:2]([F:23])([CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10](=[O:13])[CH2:11]2)[CH2:7][C@H:6]1[OH:14].[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.[Cl-].[Na+].O>[F:23][C:2]([F:1])([CH2:15][O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9][C:10](=[O:13])[CH2:11]2)[CH2:7][C@H:6]1[O:14][CH:25]1[CH2:26][CH2:27][CH2:28][CH2:29][O:24]1
Reactant: C1=COCCC1
Reactant: O=C1C[C@@H]2[C@@H](CCC(F)(F)COc3ccccc3)[C@H](O)C[C@@H]2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C1C[C@@H]2[C@@H](CCC(F)(F)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2O1
Temperature: 25 °C

Procedure:
(3aR,4R,5R,6aS)-4-(3,3-Difluoro-4-phenoxybutyl)-5-hydroxyhexahydro-2H-cyclopenta[b]furan-2-one, prepared in Step D, is dissolved in DCM (0.1 M) under a nitrogen atmosphere. Dihydropyran (1.1 molar equivalents) is added, followed by a catalytic amount of p-toluenesulfonic acid. The reaction is stirred at room temperature under a nitrogen atmosphere and the reaction progress is monitored by TLC. Upon completion, brine is added to the reaction mixture and the layers are separated. The organic phase is dried over sodium sulfate, filtered, and the solvent is evaporated. The crude product is purified by flash chromatography on regular silica gel eluted with ethyl acetate-hexanes to afford the title intermediate.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[C:19]([O:23][C:24]([NH:26][C@H:27]([C:43]([NH:45][C:46]1[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[C:47]=1[O:48][CH2:49][C@H:50]1[O:55][CH2:54][C@@H:53]([CH2:56][O:57][Si](C(C)(C)C)(C)C)[N:52]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:51]1)=[O:44])[CH:28]([C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=1)[C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([NH:26][C@H:27]([C:43]([NH:45][C:46]1[CH:75]=[CH:74][CH:73]=[C:72]([F:76])[C:47]=1[O:48][CH2:49][C@H:50]1[O:55][CH2:54][C@@H:53]([CH2:56][OH:57])[N:52]([C:65]([O:67][C:68]([CH3:69])([CH3:70])[CH3:71])=[O:66])[CH2:51]1)=[O:44])[CH:28]([C:29]1[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=1)[C:36]1[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=1)=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cccc(F)c1OC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Nc1cccc(F)c1OC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1)C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 50 %

Procedure:
1M TBAF (1766 μl, 1.766 mmol) in THF was added to a solution of tert-butyl (2S,5S)-2-[(2-{[N-(tert-butoxycarbonyl)-4-fluoro-β-(4-fluorophenyl)-L-phenylalanyl]amino}-6-fluorophenoxy)methyl]-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)morpholine-4-carboxylate (977 mg, 1.177 mmol) in THF (5.89 mL) at room temperature and the reaction stirred at room temperature until completion (6 hours). The reaction was quenched with a saturated aqueous solution of KH2PO4 and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic fractions were dried over MgSO4, filtered and the solvent was evaporated under reduced pressure. The crude material was then purified on silica gel (120 g), eluting with a gradient of 0-100% a 7:2:1 CHCl3/EtOAc/MeOH blend in CHCl3 to afford the title compound (439 mg, 0.589 mmol, 50% yield) as a white foam, MS (ESI): m/z=616.4 (M+H-boc); 96% pure by LC/MS.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[O:8][CH2:9][CH2:10][O:11][C:4]=2[CH:3]=1.[CH2:12]([CH2:15]OC)OC>>[CH:12]([C:2]1[N:7]=[N:6][C:5]2[O:8][CH2:9][CH2:10][O:11][C:4]=2[CH:3]=1)=[CH2:15]
Reactant: Clc1cc2c(nn1)OCCO2
Reactant: COCCOC
Product: C=Cc1cc2c(nn1)OCCO2
Temperature: 95 °C
Yield: 50 %

Procedure:
A solution of 3-chloro-6,7-dihydro[1,4]dioxino[2,3-c]pyridazine (13.6 g, 0.079 mol) containing ca. 15% of a bromo species in dimethoxyethane (400 ml) was degassed under argon for 10 min then tetrakis(triphenylphosphine)palladium (0) (2 g), potassium carbonate (10.33 g), triethenylboroxin pyridine complex (11.32 g) and water (55 ml) were added. The mixture was heated at 95° C. for 48 h and cooled and evaporated to dryness. The mixture was treated with aqueous sodium bicarbonate solution and extracted (5×) with DCM. Extracts were dried (sodium sulphate), evaporated and the residue chromatographed on silica gel (500 g), eluting with 0-100% ethyl acetate-hexane, affording the product (6.43 g, 50%); [also some impure fractions (1.8 g)]
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:21][CH2:20][CH2:19]S[CH2:17]1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.O[O:43][S:44]([O-:46])=O.[K+].C(=O)(O)[O-].[Na+]>COCCOC.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:21][CH2:20][CH2:19][S:44](=[O:46])(=[O:43])[CH2:17]1
Reactant: CCOC(=O)c1cc(Br)cc2c(C3CCCSC3)c[nH]c12
Reactant: O=S([O-])OO
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(Br)cc2c(C3CCCS(=O)(=O)C3)c[nH]c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
Ethyl 5-bromo-3-(tetrahydro-2H-thiopyran-3-yl)-1H-indole-7-carboxylate (0.375 g, 1.02 mmol) was dissolved in 1,2-Dimethoxyethane (DME) (25 mL). A solution of 0.0004M EDTA (7 mL) was added followed by the portion-wise addition of a suspension of oxone (1.88 g, 3.05 mmol) and sodium bicarbonate (0.855 g, 10.18 mmol) in 7 mL water. The reaction was stirred for 3 hours at room temperature. The reaction was diluted with water and extracted with dichloromethane. The combined organics were washed with water 2×. The combined aqueous layers were backwashed with dichloromethane. The combined organics were washed with water, brine, dried with MgSO4 and concentrated. The crude compound was purified by Combiflash silica column chromatography using 0-10% ethylacetate/dichloromethane on silica to give 0.290 g (71%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[CH:12]=[CH:13][C:14](OCC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][CH2:13][CH2:14][OH:15])[CH:19]=[CH:20][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=Cc1cccc(OCc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1cccc(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of ethyl 3-benzyloxycinnamate in tetrahydrofuran (300 ml) was added dropwise to a suspension of lithium aluminum hydride in tetrahydrofuran (300 ml) at 0° C. and then stirred for 2 hours. To the reaction mixture was added carefully water and the insoluble material was filtered off. The filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with 1N-hydrochloric acid and water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:4, v/v), 3-(3-benzyloxyphenyl)propanol (52.7 g, 62%) was obtained. Oily substance.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH3:8][C:9]([CH3:12])([O-])[CH3:10].[K+].C(O)C(N)(CO)CO>C(Cl)Cl>[CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([O:5][C:9]([CH3:12])([CH3:10])[CH3:8])=[O:4]
Reactant: CCC(C)C(=O)O
Reactant: CC(C)(C)[O-]
Agent: NC(CO)(CO)CO
Agent: [K+]
Solvent: ClCCl
Product: CCC(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 2-methylbutanoic acid (1.029 Ml, 8.29 mmol) in DCM (10 Ml) was added potassium tert-butoxide (20 wt % in THF) (4.66 Ml, 8.29 mmol) dropwise at 0° C. The resulting suspension was allowed to warm to room temperature, and stirred for 1.5 hr. The reaction mixture was diluted with DCM (10 Ml), MP-®Trisamine Resin (3.86 g, 3.22 mMol/g; Argonaut Technologies, Inc.) was added, and the resulting suspension was stirred at room temperature for 1.5 hours. The resin was removed by vacuum filtration, and the resulting filtrate was washed with 1 N NaOH (1×20 Ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated to afford tert-butyl 2-methylbutanoate. 1H NMR (500 MHz, CDCl3) δ 2.24 (sextet, 1H), 1.61 (m, 1H), 1.44-1.39 (overlapping s, m, 10H), 1.09 (d, 3H), 0.90 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]([NH:23][CH:24](P(OC)(OC)=O)[C:25]([O:27][CH3:28])=[O:26])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([O:20][C:21]([NH:23]/[C:24](=[CH:9]\[C:6]1[CH:7]=[N:8][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=1)/[C:25]([O:27][CH3:28])=[O:26])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1ccc(C(F)(F)F)nc1)NC(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 12 h

Procedure:
6-Trifluormethylpyridine-3-carbaldehyde (4.85 g, 27.70 mmol) and methyl {[(benzyloxy)carbonyl]amino}(dimethoxyphosphoryl)acetate (9.17 g, 27.70 mmol, 1.0 equivalent) are dissolved in THF (70 ml) and cooled to −70° C. At −70° C., N,N,N,N-tetramethylguanidine (6.38 g, 55.39 mmol, 6.95 ml, 2.0 equivalents) is slowly added dropwise and then stirred at −70° C. for 4 h and subsequently at RT for 12 h. The reaction mixture is concentrated and then extracted from water with ethyl acetate (2×100 ml), and the combined organic phases are washed with saturated brine and dried over sodium sulphate. The crude product after concentration in vacuo is chromatographed (silica gel, eluent: toluene then toluene/ethyl acetate 10:1). 6.93 g (66% of theory) of the title compound are obtained.
Reaction SMILES: [Br-].C([O:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH2:18][N:17](CC2C=CC=CC=2)[C:16]2[C:15](=[O:26])[NH2+:14][C:13]([NH:27]C(=O)C)=[N:12][C:11]1=2)(=O)C>[Pd].CO>[OH:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:18]=[N:17][C:16]2[C:15](=[O:26])[NH:14][C:13]([NH2:27])=[N:12][C:11]1=2
Reactant: CC(=O)NC1=NC2=C(C(=O)[NH2+]1)N(Cc1ccccc1)CN2CCCCOC(C)=O
Agent: [Pd]
Agent: [Br-]
Solvent: CO
Product: Nc1nc2c(ncn2CCCCO)c(=O)[nH]1
Temperature: 40 °C
Reaction time: 4 h
Yield: 96.1 %

Procedure:
9-(4-Acetoxybutyl)-N2-acetyl-7-benzylguaninium bromide (39.7 g; content 97.5%; 80.8 mmol) was added to a mixed solution of methanol (404 ml) and 7.48 g (1.62 mmol) of 5% Pd/C (water content 54%). The reaction was carried out at 50° C. for 4 h under hydrogen atmosphere (1 atm). After completion of the reaction (confirmed by HPLC), the reaction mixture was filtered through Celite, and the solvent was removed by distillation under reduced pressure. Then, water (130 ml) and 25% NaOH (45.2 g) were added to the residue and stirred overnight at 40° C. The mixture was neutralized by 2N HCl stirred at room temperature for 2 h. The precipitated crystals were filtered and dried at 50° C. under reduced pressure for a yield of 17.33 g of 9-hydroxybutylguanine (97.2% purity, 93.4% yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:37])([CH2:34][CH2:35][CH3:36])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:33])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])=[CH:20][C:19](C)=[CH:18][C:17]=12)=[O:12])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:37])([CH2:34][CH2:35][CH3:36])[CH2:9][NH:10][C:11]([C:13]1[C:14]([CH3:33])=[N:15][N:16]2[C:21]([O:22][CH2:23][C:24]3[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:31])=[CH:20][CH:19]=[CH:18][C:17]=12)=[O:12]
Reactant: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3Cl)cc(C)cc12)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(C)(N)CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.8 %

Procedure:
A solution of 40 mg (0.073 mmol) of rac-{1-[({7-[(2-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridin-3-yl}carbonyl)amino]-2-methylpentan-2-yl}carbamic acid tert-butyl ester (Example 138A) in 2 ml of dichloromethane was admixed with 0.113 ml of trifluoroacetic acid. The resulting mixture was stirred at room temperature for 18 hours and then heated to 40° C. Further trifluoroacetic acid (0.169 ml) was added in portions over the course of 3 hours. The reaction mixture was concentrated under reduced pressure and the remaining residue was purified by preparative HPLC chromatography (Method 21), which gave 11.0 mg (33% yield) of the target compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[N:12]=1.S(Cl)(Cl)=O.[CH3:26][NH2:27]>>[CH3:26][NH:27][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[S:9][CH:10]=2)[CH:14]=1
Reactant: Cc1ccncc1-c1nc(-c2cccc(C(=O)O)c2)cs1
Reactant: CN
Solvent: O=S(Cl)Cl
Product: CNC(=O)c1cccc(-c2csc(-c3cnccc3C)n2)c1

Procedure:
By the reaction in the same manner as in Example 60 using 3-[2-(4-methyl-pyridin-3-yl)-1,3-thiazol-4-yl]benzoic acid (256 mg), thionyl chloride (0.09 ml) and aqueous methylamine solution (40%, 5 ml), the title compound (191 mg) was obtained as colorless powder crystals.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:10][O:11]C(Cl)Cl.ClCl.C(=O)(O)[O-].[Na+]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH:3]=1)[CH:10]=[O:11]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(I)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: ClCl
Agent: O=C([O-])O
Solvent: ClCCl
Product: COc1ccc(I)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.04 grams (8.72 mmol) of 4-iodoanisole in 36 mL of CH2Cl2, cooled to 0° C., was added dropwise 2.0 mL (18.7 mmol) of titanium tetrachloride. After stirring for 30 min., 0.93 mL (10.3 mmol) of α,α-dichloromethyl methyl ether was added and the reaction maintained at 0° C. for another 2 hours. The reaction mixture was then poured with stirring into a mixture of 50 mL of CH2 Cl2 and 50 mL of saturated aqueous sodium bicarbonate (NaHCO3). After 30 min., this was filtered through diatomaceous earth, the organic layer was separated, the aqueous layer was twice extracted with CH2 Cl2, and all of the organic layers were combined, dried with MgSO4 and concentrated in vacuo. The crude residue was recrystallized from ethanol (EtOH) to give 5-iodo-2-methoxybenzaldehyde as pale yellow needles, 1.37 grams (60%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:25][C:26]1[CH:27]=[C:28]([S:32]([NH:35][CH:36]2[CH2:38][CH2:37]2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[CH:36]1([NH:35][S:32]([C:28]2[CH:27]=[C:26]([NH:25][C:22]([C:21]3[CH:20]=[N:19][N:12]4[C:13]([C:15]([F:17])([F:16])[F:18])=[CH:14][C:9]([C:4]5[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=5)=[N:10][C:11]=34)=[O:24])[CH:31]=[CH:30][CH:29]=2)(=[O:34])=[O:33])[CH2:38][CH2:37]1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NC2CC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 567.9 [(M−H)−]; mp 248° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([O:13][C:14](=[O:20])[CH2:15][Si](C)(C)C)[CH3:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[NH4+].[Cl-]>C1COCC1.C(#N)C.CCOC(C)=O>[CH2:11]([O:13][C:14](=[O:20])[CH2:15][C:6]1[C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=[C:2]([Br:1])[CH:7]=1)[CH3:12]
Reactant: CCOC(=O)C[Si](C)(C)C
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cc(Br)ncc1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-Bromo-5-nitropyridine (1.84 g, 9.06 mmol) and trimethylsilanyl-acetic acid ethyl ester (1.53 g, 9.52 mmol) are dissolved under an atmosphere of argon in dry THF (10 ml). After cooling to −78° C., a solution of tetrabutylammonium fluoride (TBAF, 2.37 g, vacuum-dried overnight) in a mixture of THF and acetonitrile (10 ml/10 ml) is slowly added, so that the reaction temperature did not rise above −65° C. After complete addition, the mixture is stirred at −40° C. for 30 minutes, and at −20° C. for 10 minutes. The reaction mixture is re-cooled to −78° C., and 2,3-dichloro-5,6-dicyano-p-benzochinone (DDQ, 2.06 g, 9.06 mmol) is added. The suspension is allowed to warm to RT. TLC analysis indicated complete conversion. The reaction mixture is diluted with EtOAc and poured into a saturated solution of NH4Cl solution. The organic layer is separated, washed with brine, dried over Na2SO4, and the solvent is evaporated. The residue is purified by FCC (toluene/EtOAc 100:0 to 97:3) to afford the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.26 (t, J=7 Hz, 3H), 4.01 (s, 2H), 4.19 (q, J=7 Hz, 2H), 7.53 (s, 1H), 9.06 (s, 1H). ES−−MS: 287, 289 [M−H]−.