Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[H-].[Na+].F[C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17].O>CS(C)=O.ClCCl.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[C:16]#[N:17])[CH2:6][CH2:5]2
Reactant: Cc1ccc2c(c1)CCN2
Reactant: N#Cc1ccccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1ccc2c(c1)CCN2c1ccccc1C#N
Reaction time: 2 h

Procedure:
A slurry of 5-methylindoline (31 g, 0.23 mole), sodium hydride (11.3 g, 60% in oil) and dimethylsulfoxide (120 ml) was stirred at room temperature for 1 hour. A solution of o-fluorobenzonitrile (31 gm, 0.25 mole) in dimethylsulfoxide (25 ml) was added dropwise at a temperature below 20° C. Upon completion of the addition, the mixture was stirred for 2 hours at room temperture. The reaction mixture was partitioned between methylene chloride (700 ml) and ice-water (700 ml). The dichloromethane solutions were separated. The aqueous phase was extracted with dichloromethane (2 times, 600 ml). The combined dichloromethane solutions were washed with 2N hydrochloric acid (2 times, 500 ml), water (500 ml), brine (2 times, 400 ml), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in ethanol (300 ml) and heptane (100 ml), and chilled in a freezer. The precipitate was collected. The mother liquor was concentrated and purified by flash chromatography on a silica gel column (400 g, 230-400 mesh) eluted with hexane:dichloromethane (3:1, 3 l); hexane:dichloromethane (1:1, 2 l) and dichloromethane (2 l). The fractions containing product were pooled and concentrated to yield 33 g (73% overall yield). The analytical sample was prepared by high-pressure liquid chromatography (Water Associates Prep 500, 10 g, 2 chamber, elution with hexane:dichloromethane, 9:1, 12 l) followed by crystallization from ethanol, mp 59°-60° C.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([OH:11])=O)[N:8]=1)(=[O:3])[NH2:2].[NH2:20][C@@H:21]([CH3:37])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:36])[CH:29]=2)=[N:24]1>>[Cl:36][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][N:23]([CH2:22][C@@H:21]([NH:20][C:9]([C:7]3[N:8]=[C:4]([C:1]([NH2:2])=[O:3])[N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=3)=[O:11])[CH3:37])[N:24]=2)[CH:35]=[CH:34][C:31]=1[C:32]#[N:33]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)nc1C(N)=O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(C(N)=O)n1

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-carbamoyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (400 mg, 1.4 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (366 mg, 1.4 mmol). The product was purified with flash-chromatography. Yield 410 mg. LC-MS: [M+1]=528.24.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[C:20]([F:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[C:18]([F:26])=[C:17]([F:27])[C:14]=1[CH2:15]Br>CN(C=O)C>[CH3:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][C:14]2[C:17]([F:27])=[C:18]([F:26])[C:19]([C:22]([F:23])([F:25])[F:24])=[C:20]([F:21])[C:13]=2[F:12])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(N)cc1C(=O)O
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Solvent: CN(C)C=O
Product: Cc1ccc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)cc1C(=O)O
Yield: 26.2 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-methylbenzoic acid (2.06 g, 15.0 mmole), DMF (60 ml), TEA (4 ml), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (5.52 ml, 17.7 mmole), 1.50 g (27.0% yield) of 2-methyl-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid was obtained as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C:17]4([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[CH2:22][CH2:21][N:20]([CH:23]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:24]([OH:26])=[O:25])[CH2:19][CH2:18]4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[N:3]=1.[CH3:43][Si](C=[N+]=[N-])(C)C>CO>[CH3:43][O:25][C:24](=[O:26])[CH:23]([N:20]1[CH2:21][CH2:22][C:17]([CH2:16][CH2:15][N:14]2[CH:12]3[CH2:11][CH2:10][CH:9]2[CH2:8][CH:7]([N:6]2[C:5]4[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=4[N:3]=[C:2]2[CH3:1])[CH2:13]3)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:18][CH2:19]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCN(C(C(=O)O)c2ccccc2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C(c1ccccc1)N1CCC(CCN2C3CCC2CC(n2c(C)nc4ccccc42)C3)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a stirred solution of (4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo-[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)(phenyl)acetic acid (prepared above) (12 mg, 0.02 mmol) in methanol (2 mL) was added (trimethylsilyl)diazomethane (100 μL, 2.0 M in hexans). The reaction mixture was stirred for 30 minutes at room temperature. After evaporation of the solvents, the residue was purified by flash chromatography, eluting with a gradient of 0-10% methanol in ethyl acetate, to afford an oil (10 mg, 81%) as methyl(4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-4-phenylpiperidin-1-yl)(phenyl)acetate. 1H NMR (300 MHz, CDCl3) δ 7.67 (d, J=7.1 Hz, 1H), 7.45-7.42 (m, 2H), 7.37-7.27 (m, 8H), 7.23-7.15 (m, 3H), 4.61 (m, 1H), 3.89 (s, 1H), 3.67 (s, 3H), 3.25-3.24 (m, 2H), 2.72-2.70 (m, 1H), 2.55 (s, 4H), 2.42-2.16 (m, 6H), 2.03-1.85 (m, 7H), 1.81-1.76 (m, 3H), 1.61-1.58 (m, 2H). HRMS m/z (M+H)+ calcd: 577.3543, obsd: 577.3557.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27])[C:20]([OH:22])=O>CCCCCCC.CCOC(C)=O>[Cl:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[C:26]([F:29])([F:28])[F:27])[C:20]([N:2]([CH3:1])[C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:22]
Reactant: CNc1cnccc1-c1ccccc1C
Reactant: O=C(O)c1ccc(C(F)(F)F)c(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(C(F)(F)F)c(Cl)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3-chloro-4-(trifluoromethyl)benzoic acid (CAS RN 115754-20-6) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown solid (37%). MS (ESI): m/z=405.10 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10](OCC)=[O:11])[N:9]=1)[CH3:3].[BH4-].[Na+].C(O)(C)C.[ClH:21]>O>[ClH:21].[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)[CH3:1]
Reactant: CCOC(=O)c1csc(CN(C)C)n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CN(C)Cc1nc(CO)cs1

Procedure:
Alternatively, a mixture of 2.14 g of ethyl 2-dimethylaminomethyl-4-thiazolecarboxylate and 0.38 g of sodium borohydride in 20 ml. of isopropanol was heated with stirring at reflux temperature for about 14 hours. The reaction mixture was cooled, and 2 ml. of water were added carefully followed by 4 ml. of 5 N aqueous hydrochloric acid. The volatile constituents were removed by evaporation. Methanol (10 ml.) was added and the mixture heated to refluxing temperature for about one hour. Methanol was removed by evaporation and the residual solids digested in 10 ml. of isopropanol on the steam bath. The isopropanol solution was separated by decantation and the solids reextracted with 10 ml. of isopropanol. The isopropanol solutions and extracts were combined and the combined solution filtered while hot to remove insoluble material. The filtrate was chilled and a crystalline solid appeared which separated and was recovered by filtration. Recrystallization of the filter cake from isopropanol gave 1.73 g of 2-dimethylaminomethyl-4-thiazolemethanol hydrochloride melting at 153°-154° C.
Reaction SMILES: [C@H]1(C[N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[C:37]([O:41][CH3:42])=[CH:38][CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:53][CH2:54][N:55]2[CH2:60][CH2:59][C@H:58]([OH:61])[C@@H:57]([CH3:62])[CH2:56]2)CC1>>[OH:61][C@H:58]1[CH2:59][CH2:60][N:55]([CH2:54][CH2:53][N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([C:21]3[NH:22][C:23]4[C:28]([CH:29]=3)=[C:27]([O:30][CH2:31][C:32]3[C:36]5[C:37]([O:41][CH3:42])=[CH:38][CH:39]=[CH:40][C:35]=5[O:34][CH:33]=3)[CH:26]=[CH:25][CH:24]=4)=[O:20])[CH2:14][CH2:13]2)[CH2:56][C@@H:57]1[CH3:62]
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Reactant: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(C[C@@H]6CCCN7CCCC[C@H]67)CC5)cc34)c12
Agent: Cl
Product: COc1cccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CC[C@H](O)[C@@H](C)C6)CC5)cc34)c12

Procedure:
This compound is synthesized analogously to example 1 from 4-(4-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 122 (see example 94) and amine 14.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][N:6]=1.[Cl-].[NH4+]>CO>[CH3:1][O:2][C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([N+:14]([O-:16])=[O:15])=[CH:7][N:6]=1
Reactant: C[O-]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A 14% methanol solution of sodium methoxide was added to 25.0 g (120 mmol) of 2-chloro-3,5-dinitropyridine, and the mixture was stirred for 15 minutes at room temperature. The mixture was added to 200 ml of a saturated aqueous ammonium chloride solution, and extracted with 200 ml of ethyl acetate. Washing with saturated saline, drying over anhydrous sodium sulfate, filtering and distilling under reduced pressure (bath temp. 40°-60° C., 40-20 mmHg) yielded yellow crystals, which were recrystallized from methanol to obtain 19.5 g (91.8 mmol) of 2-methoxy-3,5-dinitropyridine as pale yellow crystals (yield: 80%).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([C:16]([OH:18])=O)[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1)#[N:2].[K+].C(C1N=C(C([O-])=O)N(COCC[Si](C)(C)C)C=1)#N.N1C=CC=CC=1.O=S(Cl)Cl.[C:48]([NH:52][S:53]([CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][C:61]([NH2:64])=[C:60]([C:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH:66]=2)[CH:59]=1)(=[O:55])=[O:54])([CH3:51])([CH3:50])[CH3:49]>C(Cl)Cl.O>[C:48]([NH:52][S:53]([CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][C:61]([NH:64][C:16]([C:5]2[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[CH:7]=[C:3]([C:1]#[N:2])[N:4]=2)=[O:18])=[C:60]([C:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH:66]=2)[CH:59]=1)(=[O:54])=[O:55])([CH3:51])([CH3:49])[CH3:50]
Reactant: CC(C)(C)NS(=O)(=O)CCc1ccc(N)c(C2=CCCCC2)c1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Agent: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: O=S(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a suspension of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 11, step (d), 228 mg, 0.746 mmol) and pyridine (66 μL, 0.81 mmol) in DCM (5 mL), SOCl2 (60 μL, 0.81 mmol) was added at 0° C. The resulting mixture was stirred at RT for 1 h and transferred to a mixture of 2-(4-amino-3-cyclohex-1-enyl-phenyl)-ethanesulfonic acid tert-butylamide (as prepared in the previous step, 228 mg, 0.670 mg) and pyridine (66 μL, 0.81 mmol) in DCM (5 mL) at 0° C. The resulting mixture was stirred at RT over night. Water (20 mL) was then added and organic layer was separated, dried (Na2SO4) and concentrated. The residue obtained was purified on silica (20-50% EtOAc/hexane) to obtain the title compound (271 mg, 68%). Mass spectrum (ESI, m/z): Calcd. for C29H43N5O4SSi, 586.2 (M+H), found 586.0.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[O:13])[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O:14]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(C)([O-])C.[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCCC1>[O:14]([C:21]1[CH:26]=[C:25]([CH2:12][C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)=[O:13])[CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Brc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)c1ccc2ncccc2c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Product: O=C(Cc1cccc(Oc2ccccc2)c1)c1ccc2ncccc2c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 19 %

Procedure:
According to an analogous method to Example W-3, 1-quinolin-6-yl-ethanone described in Preparation Example 131 (171 mg, 1 mmol), 1-phenoxy-3-bromobenzene (274 mg, 1.1 mmol), bis(dibenzylideneacetone)palladium (10 mg, 0.0187 mmol), 1,1′-bis(diphenylphosphino)ferrocene (12.5 mg, 0.0225 mmol), potassium tert-butoxide (236 mg, 2.1 mmol) and tetrahydrofuran (15 mL) were stirred at 70° C. for 6 hours under nitrogen atmosphere, and the title compound (64 mg, 0.189 mmol, 19%) was obtained as a pale yellow oily substance.
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:14]([N:16]2[CH:20]([C:21]([OH:23])=O)[CH2:19][CH:18]=[N:17]2)=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.CS(Cl)(=O)=O.[N:37]1[CH:42]=[CH:41][CH:40]=[N:39][C:38]=1[NH2:43]>ClCCl>[CH:7]1([CH2:12][C@@H:13]([C:14](=[O:15])[N:16]2[CH:20]([C:21]([NH:43][C:38]3[N:39]=[CH:40][CH:41]=[CH:42][N:37]=3)=[O:23])[CH2:19][CH:18]=[N:17]2)[CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Reactant: Nc1ncccn1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)Nc1ncccn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
1-Methyl-1H-imidazole (0.24 mL, 3.0 mmol) was added into a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (352 mg, 1.0 mmol) in dichloromethane (DCM) (5.0 mL). The resulting solution was cooled to 0° C., and then methanesulfonyl chloride (0.08 mL, 1.05 mmol) was added dropwise at 0° C. To the reaction mixture was then added 2-pyrimidinamine (105 mg, 1.1 mmol), and stirring continued for 30 min at room temperature. After this time, the solvent was removed under reduced pressure to provide a residue which was purified by Combiflash automated silica gel chromatography (80-100% EtOAc in Hex) to afford 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-oxo-4-{5-[(2-pyrimidinylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}butanoate (270 mg, 0.63 mmol, 63% yield). MS: 430 ([M+H]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([CH2:12][OH:13])=[CH:9][CH:8]=2)[CH:2]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[S:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=2)[CH:2]=1
Reactant: OCc1ccc(-c2cccnc2)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: O=Cc1ccc(-c2cccnc2)s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
To a solution of (5-pyridin-3-yl-thiophen-2-yl)-methanol (144 mg in 7.5 mL dry methylene chloride) was added 327 mg of the 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one and the mixture stirred at room temperature. After 4 hours, the reaction was quenched by addition of a mixture of saturated sodium bicarbonate and saturated sodium thiosulfite (1:1) and extracted with diethyl ether. The aqueous portion was extracted further with methylene chloride and the combined organics then washed with water and brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane, 75:25; then 80:20) gave the title compound (80 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:27](=[N:29][OH:30])[NH2:28])[CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[C:18]2[CH:19]=[CH:20][N:21]=[C:22]([O:23][CH2:24][CH3:25])[C:17]=2[C:16]2[C:11](=[CH:12][CH:13]=[N:14][CH:15]=2)[N:10]=1.N1C=CC=CC=1.[C:37]([O:40][C:41]([CH3:46])([CH3:45])[C:42](Cl)=O)(=[O:39])[CH3:38]>O1CCOCC1>[C:37]([O:40][C:41]([C:46]1[O:30][N:29]=[C:27]([C:4]2[CH:5]=[C:6]([Cl:26])[C:7]([NH:8][C:9]3[C:18]4[CH:19]=[CH:20][N:21]=[C:22]([O:23][CH2:24][CH3:25])[C:17]=4[C:16]4[C:11](=[CH:12][CH:13]=[N:14][CH:15]=4)[N:10]=3)=[C:2]([Cl:1])[CH:3]=2)[N:28]=1)([CH3:45])[CH3:42])(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CCOc1nccc2c(Nc3c(Cl)cc(C(N)=NO)cc3Cl)nc3ccncc3c12
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCOc1nccc2c(Nc3c(Cl)cc(-c4noc(C(C)(C)OC(C)=O)n4)cc3Cl)nc3ccncc3c12
Temperature: 110 °C

Procedure:
To a solution of 3,5-dichloro-4-[(10-ethoxypyrido[4,3-c]-1,6-naphthyridin-6-yl)amino]-N′-hydroxybenzenecarboximidamide (50 mg, 0.11 mmol) in 1,4-dioxane (1 mL) was added pyridine (0.1 mL) and 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.016 mL, 0.11 mmol). The reaction was heated to 110° C. for 4 h in a sealed tube. After cooling to room temperature, the solvents were evaporated and the residue was dissolved in THF/MeOH, filtered and purified by reverse phase HPLC to afford the title compound.
Reaction SMILES: [CH2:1]([C:13]([O:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([O:22]CC2C=CC=CC=2)=[O:21])=[CH:18][CH:17]=1)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>[Pd].C(OCC)(=O)C>[CH2:1]([C:13]([O:15][C:16]1[CH:31]=[CH:30][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCC(=O)Oc1ccc(C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCC(=O)Oc1ccc(C(=O)O)cc1
Reaction time: 6 h
Yield: 87 %

Procedure:
{circle around (2)}: A mixture comprising 3.5 g of benzyl 4-n-dodecylcarbonyloxybenzoate, 0.4 g of palladium/carbon and 20 g of ethyl acetate was stirred for 6 hours under hydrogen atmosphere. Then, palladium/carbon was filtered off, and ethyl acetate was distilled off from the filtrate. The resultant residue was recrystallized from toluene, whereby 2.40 g of 4-n-dodecylcarbonyloxybenzoic acid was obtained in the form of a colorless crystal.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].[Se](=O)=[O:58]>C(O)(=O)C.O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH:27]([OH:58])[CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Solvent: O
Solvent: CC(=O)O
Product: CCC1C=C(C)C(O)C(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 22 °C
Reaction time: 21 h
Yield: 27.4 %

Procedure:
A solution of 6 g (7.59 mmole) of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclo-hexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]-octacos-18-ene-2,3,10,16-tetraone (containing approximately 10% of the 17-methyl analog) and 0.87 g (7.8 mmole) selenium dioxide in 60 ml glacial acetic acid and 10 ml water was stirred at 22° C. for 21 hours. The solution was lyophilyzed and the residue was chromatographed on 300 g silica gel using methylene chloride and methanol/methylene chloride as eluent. The new product was rechromatographed on silica gel with 4% methanol/methylene chloride as eluent to yield 1.68 g (27% yield) 17-ethyl-1,14,20-trihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos -18-ene-2,3,10,16-tetraone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13]O)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[N-:19]=[N+:20]=[N-:21].[Na+]>>[N:19]([CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)=[N+:20]=[N-:21]
Reactant: OCc1ccccc1-c1ccncc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=NCc1ccccc1-c1ccncc1

Procedure:
The product of Example 120A, thionyl chloride and sodium azide were processed according to the method of Example 115A to provide the product. MS (ESI+) m/z 211 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1I.O1CCCC1.C(N(CC)CC)C.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu](I)I.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.CN1CCCC1=O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33]
Reactant: C#C[Si](C)(C)C
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(I)c(F)c1
Agent: I[Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: C[Si](C)(C)C#Cc1ccc(N2C[C@H](Cn3ccnn3)OC2=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 257.5 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Intermediate 6, 0.50 g, 1.3 mmol), tris(dibenzylideneacetone)dipalladium (0) (24 mg, 0.026 mmol), tri-2-furylphosphine (12 mg, 0.05 mmol), and copper iodide (5.0 mg, 0.013 mmol) were combined in a flask and degassed. Tetrahydrofuran (7.5 ml), triethylamine (0.54 g, 5.4 mmol) and a minimal amount of 1-methyl-2-pyrrolidinone (1.5 ml) were added to obtain a brown solution. (Trimethylsilyl)acetylene (0.18 g, 1.8 mmol) was added and the reaction was stirred at room temperature overnight. The solution was adsorbed onto silica gel and chromatographed eluting with ethyl acetate to give the title compound as a brown oil (1.2 g) (contains 1-methyl-2-pyrrolidinone).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][N:16]1[N:25]=[C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([Cl:36])[CH:29]=2)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:37]#[N:38])[CH:22]=2)[C:17]1=[O:39])=[O:14])(C)(C)C>>[C:13]([CH2:15][N:16]1[N:25]=[C:24]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([Cl:36])[CH:29]=2)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:37]#[N:38])[CH:22]=2)[C:17]1=[O:39])([OH:14])=[O:12]
Reactant: COc1ccc(CNc2nn(CC(=O)OC(C)(C)C)c(=O)c3ccc(C#N)cc23)cc1Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNc2nn(CC(=O)O)c(=O)c3ccc(C#N)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
Trifluoroacetic acid (5 ml) was added to 0.41 g of the t-butyl ester prepared in Example 22. The obtained mixture was stirred at room temperature for one hour and freed from the trifluoroacetic acid by vacuum distillation. The obtained residue was recrystallized from ethanol/water to give 0.06 g of the title compound as a yellow crystal.