Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:6][O:7][C:8]1[CH:34]=[CH:33][C:11]([C:12]([NH:14][C:15]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][C:16]=2[C:17]([O:19]CC)=[O:18])=[O:13])=[CH:10][C:9]=1[Cl:35]>C1COCC1.CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:6][O:7][C:8]1[CH:34]=[CH:33][C:11]([C:12]([NH:14][C:15]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][C:16]=2[C:17]([OH:19])=[O:18])=[O:13])=[CH:10][C:9]=1[Cl:35]
Reactant: CCOC(=O)c1cc(Oc2ccccc2)ccc1NC(=O)c1ccc(OCc2ccc(OC)c(OC)c2)c(Cl)c1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(COc2ccc(C(=O)Nc3ccc(Oc4ccccc4)cc3C(=O)O)cc2Cl)cc1OC
Reaction time: 16 h

Procedure:
A solution of 1C (160 mg, 0.29 mmol) in THF (30 mL) and MeOH (10 mL) at 0° C. was treated with a solution of LiOH monohydrate (60 mg, 1.42 mmol) in water (10 mL). The resulting solution was stirred for 16 hours, and then concentrated to 10 mL. The resulting suspension was taken up in water (10 mL) and brought to pH 5 with 1 N HCl. The solution was extracted with EtOAc (4×25 mL), dried (Na2SO4), filtered and concentrated to afford the 1D as a white solid. (130 mg, 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:10](=O)([O-])[O-].[K+].[K+].IC.O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CS(C)=O>[CH3:8][C:6]1[CH:5]=[C:4]([S:9][CH3:10])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(C)cc(S)c1
Reactant: O=C([O-])[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CS(C)=O
Product: CSc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.5 %

Procedure:
10.0 g (0.072 mol) of 3,5-dimethylbenzenethiol, 9.95 g (0.072 mol) of potassium carbonate and 0.46 g (1.4 mmol) of tetrabutylammonium bromide are suspended in 20 ml of dimethylsulfoxide under argon. Iodomethane (10.2 g, 0.072 mol) is added dropwise, and the mixture is stirred 16 h at ambient temperature. After pouring the mixture into water, the product is extracted with ether, washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product 9.6 g (0.063 mol; 88%) is obtained as a slightly yellow oil, and is used for the next step without further purification.
Reaction SMILES: [CH2:1]([CH:5]1[C:9]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[O:8][C:7](=[O:15])[NH:6]1)[CH2:2][CH2:3][CH3:4].[CH3:16][C:17]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:18]=1[C:19]([N:21]1[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]1)=[O:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O.N>C(Cl)Cl>[CH2:1]([CH:5]1[C:9]2([CH2:14][CH2:13][N:12]([CH:24]3[CH2:25][CH2:26][N:21]([C:19](=[O:20])[C:18]4[C:28]([CH3:32])=[CH:29][CH:30]=[CH:31][C:17]=4[CH3:16])[CH2:22][CH2:23]3)[CH2:11][CH2:10]2)[O:8][C:7](=[O:15])[NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1NC(=O)OC12CCNCC2
Reactant: Cc1cccc(C)c1C(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCC1NC(=O)OC12CCN(C1CCN(C(=O)c3c(C)cccc3C)CC1)CC2
Reaction time: 24 h
Yield: 73 %

Procedure:
To a solution of 4-butyl-1-oxa-3,8-diaza-spiro[4.5]decane-2-one (12: R=H; R′=n-Bu; 1.09 g; 5.1 mmol)) in 30 mL DCM was added 1.24 g (5.4 mmol) of 1-(2,6-dimethyl-benzoyl)-piperidin-4-one followed by 2.1 mL (7.1 mmol) of Ti(IV)(O-i-Pr)4 The reaction mixture stirred under nitrogen for 18 h. of Sodium triacetoxyborohydride (1.6 g: 7.7 mmol) was added to the reaction mixture followed by glacial HOAc (0.365 mL; 6.4 mmol). The reaction mixture stirred for 24 h. Aqueous ammonia (20 mL; 10% aqueous solution) was added and the solution stirred for an additional 10 min. The mixture was filtered by gravity through a cartridge of ChemElute™. The organics were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with gradient elution (2% to 10% methanol in ethyl acetate with 0.4% ammonia) to provide 1.6 g (73%) of 4-butyl-8-[1-(2,6-dimethyl-benzoyl)-piperidin-4-yl]-1-oxa-3,8-diaza-spiro[4.5]decane-2-one: ms [M]+=428.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][N:39]([CH3:46])[CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:44][CH2:45][CH:40]([N:39]([CH3:46])[CH3:38])[CH2:41][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N(C)C)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 4-dimethylamino-piperidine (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C36H46Cl2N5O2 [(M+H)+] 650.3023, observed 650.3027.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([C:22]#[N:23])=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH:24]S(O)(=O)=O>>[CH3:1][C:2]1[C:7]([O:8][C:9]2[C:10]([C:22]([NH2:23])=[O:24])=[N:11][CH:12]=[C:13]([S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:14]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1C#N
Product: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1C(N)=O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
To concentrated H2SO4 (90 mL) cooled with an ice bath was added 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinonitrile (43 g, 130 mmol) in portions such that the internal temperature did not exceed 50° C. but did not go above 25° C. After complete addition, the mixture was stirred in the ice bath until the reaction started to cool, at which point the reaction was removed from the ice bath and the mixture was heated to 50° C. The reaction was cooled to ambient temperature and then added to ice water slowly over 3 minutes (about 1400 mL of 30% ice in water). The mixture was further cooled in an ice bath to 5° C. and neutralized to about pH 10 with 4M NaOH (5×150 mL) while maintaining the internal temperature below 20° C., at which point a solid formed. The mixture was stirred for 20 minutes, then filtered and washed with MTBE (5×150 mL) and hexanes (5×100 mL), and dried at under vacuum to afford 3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (43 g, 96%).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[O:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:36])([F:19])[F:37])[CH:23]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(OC(F)(F)F)c1
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(OC(F)(F)F)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1O.[OH-:10].[K+].[CH2:12](Cl)[CH:13]=[C:14]([CH3:16])[CH3:15]>C1C=CC=CC=1>[CH3:1][C:2]1[C:3](=[O:10])[C:4]([CH3:8])([CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=CCCl
Reactant: Cc1cccc(C)c1O
Reactant: [OH-]
Agent: [K+]
Solvent: c1ccccc1
Product: CC(C)=CCC1(C)C=CC=C(C)C1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 2,6-dimethylphenol (5.00 g, 41.0 mmol), powdered KOH (85%, 1.5 eq., 4.05 g, 61.5 mmol), prenyl chloride (85%, 1.2 eq., 6.05 g, 49.2 mmol) and (NBu4)HSO4 (50 mg) in benzene (50 ml) was stirred at 0° C. for 3 h. The green suspension was then poured on ice and extracted with pentane. The organic phase was washed with aqueous NaOH (32%), water and brine, dried (MgSO4) and concentrated in vacuo at room temperature. The yellow crude dienone was ca. 85% pure and was converted without further purification. 1H-NMR (400 MHz, CDCl3): 6.81-6.79 (m, 1H), 6.20-10 (m, 2H), 4.92-4.88 (m, 1H, 2′-H), 2.51 (dd, J=13.9, 7.7 Hz, 1H, 1′-Ha), 2.17 (dd, J=13.9, 7.2 Hz, 1H, 1′-Hb), 1.86 (s, 3H), 1.62 (s, 3H), 1.57 (s, 3H), 1.17 (s, 3H, 6-CH3) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH2:10]([N:13]1[C:22](=[O:23])[C:21]2[NH:20][C:19]([C:24]3[N:28]([CH3:29])[N:27]=[C:26]([O:30][CH2:31][C:32](O)=[O:33])[CH:25]=3)=[N:18][C:17]=2[N:16]([CH2:35][CH2:36][CH3:37])[C:14]1=[O:15])[CH2:11][CH3:12]>>[CH3:37][CH2:36][CH2:35][N:16]1[C:14](=[O:15])[N:13]([CH2:10][CH2:11][CH3:12])[C:22](=[O:23])[C:21]2[C:17]1=[N:18][C:19]([N:20]=2)=[C:24]1[N:28]([CH3:29])[NH:27][C:26]([O:30][CH2:31][C:32]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[O:33])=[CH:25]1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=NC(=C1C=C(OCC(=O)Nc3ccc(Cl)c(Cl)c3)NN1C)N=2

Procedure:
Using 3,4-dichloroaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methyl-pyrazol-3-yl)oxyacetic acid (Example 36), according to the method described in Example 36.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]C(C)(C)C)=[O:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[ClH:24]>C(Cl)Cl.O1CCOCC1>[ClH:24].[NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(N)nc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(/C=C/C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of tert-butyl(2E)-3-(6-aminopyridin-3-yl)acrylate (380 mg, 1.73 mmol; which may be prepared as described in Step 1) in DCM (3.45 mL) under Argon was added trifluoroacetic acid (3.45 mL). The mixture was stirred at room temperature for 1 h, then HCl 4N in dioxane (6.9 mL) was added. A beige solid started precipitating at the half of the addition. After concentration, the solid was triturated in Et2O, filtered, rinsed with Et2O and dried under vacuum to give the title compound as a beige solid (265 mg, 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[O:23])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:31][CH2:32][N:33]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)=[O:23])[CH2:17][CH2:16]1
Reactant: O=C(NCCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: O=C(Cl)c1cc(F)ccc1C(F)(F)F
Product: O=C(NCCCC1CC1)c1ccc(N2CCN(C(=O)c3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-Fluoro-2-trifluoromethylbenzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-cyclopropylpropyl)amide, the title compound was obtained as a white powder (28% yield). 1H NMR (400 MHz, CDCl3) δ 8.07, 7.89, 7.76, 7.28-7.24, 7.10-7.08, 7.02, 4.06-4.03, 3.90-3.86, 3.82-3.72, 3.51, 3.37, 1.76-1.70, 1.30, 0.70-0.67, 0.44-0.40, 0.03-0.003.
Reaction SMILES: [O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(=O)(O)[O-].[Na+]>ClCCl>[O:1]([CH2:19][CH2:20][C:21]1([CH2:27][CH2:28][NH:29][S:38]([CH3:37])(=[O:40])=[O:39])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[Si:2]([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](OCCC1(CCN)CCCCC1)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCC1(CCNS(C)(=O)=O)CCCCC1)(c1ccccc1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of 2-[1-[2-(tert-butyldiphenylsiloxy)ethyl]cyclohexyl]ethylamine (409 mg) dissolved in dichloromethane (10 mL) was added triethylamine (0.28 mL). Methanesulfonyl chloride (0.12 mL) was added to the solution under ice cooling, and it was stirred at that temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the solution, and it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (silica gel, hexane:ethyl acetate=6:1) to give the title compound (327 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:22]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)[N:24]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([NH:16][CH:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:42](Cl)(=[O:44])[CH3:43].O>CN(C)C=O>[CH:17]1([NH:16][C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:42](=[O:44])[CH3:43])[CH:7]=[CH:6][CH:5]=4)[C:22]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([NH:29][CH:30]5[CH2:31][CH2:32][CH2:33][CH2:34]5)[N:24]=4)=[C:11]3[CH:12]=[CH:13][CH:14]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(=O)Cl
Reactant: Nc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
To a suspension of 2-(3-aminophenyl)-N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-7-amine (150 mg, 0.33 mmol) in dimethylformamide (10 mL) was added triethylamine (51 δL, 0.36 mmol). The reaction mixture was cooled to 0° C. and flushed with nitrogen, then acetyl chloride (26 μL, 0.36 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. Water was added and the resulting mixture was extracted with ethyl acetate. The ethyl acetate phase was dried (magnesium sulfate), filtered and concentrated to a solid. This solid was purified by flash chromatography (95:5 chloroform:methanol) to give N-(3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)acetamide (151 mg, 92%) as a tan solid. 1H NMR (CDCl3): δ 8.19 (s, 1H), 7.95 (d, 1H), 7.82 (d, 1H), 7.75 (d, 1H), 7.63 (s, 1H), 7.36–7.25 (m, 3H), 6.28 (d, 1H), 6.00 (m, 2H), 5.17 (d, 1H), 4.32 (m, 1H), 3.96 (m, 1H), 2.11 (s, 3H), 2.11–2.02 (m, 4H), 1.76–1.48 (m, 12H); MS m/z 496 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([C:24]([OH:26])=O)[CH:21]=[C:20]([S:27][CH2:28][CH3:29])[N:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:31]([NH2:33])[CH3:32]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]([C:24]([NH:33][O:31][CH3:32])=[O:26])[CH:21]=[C:20]([S:27][CH2:28][CH3:29])[N:19]=2)[CH2:14][CH2:13]1)=[O:10]
Reactant: CCSc1cc(C(=O)O)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1
Reactant: CON
Agent: Cl
Product: CCSc1cc(C(=O)NOC)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)n1

Procedure:
The title compound was synthesized by an analogous method to Example 8 starting from 2-(4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-6-(ethylthio)pyrimidine-4-carboxylic acid (Example 202) and methoxylamine hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[C:15]([S:19]([NH:22][C@@H:23]1[CH2:28][CH2:27][C@H:26]([C:29](O)=O)[CH2:25][CH2:24]1)(=[O:21])=[O:20])([CH3:18])([CH3:17])[CH3:16]>>[C:15]([S:19]([NH:22][C@@H:23]1[CH2:24][CH2:25][C@H:26]([C:29]2[NH:8][C:7]3[C:2](=[N:3][C:4]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[N:5][CH:6]=3)[N:1]=2)[CH2:27][CH2:28]1)(=[O:21])=[O:20])([CH3:18])([CH3:16])[CH3:17]
Reactant: Nc1cnc(-c2ccccc2)nc1N
Reactant: CC(C)(C)S(=O)(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Product: CC(C)(C)S(=O)(=O)N[C@H]1CC[C@@H](c2nc3nc(-c4ccccc4)ncc3[nH]2)CC1

Procedure:
By following the same procedure as described in Example 1 except that use was made of 4,5-diamino-2-phenylpyrimidine and cis-4-tert-butylsulfonylaminocyclohexanecarboxylic acid in place of 4-trifluoromethyl-1,2-phenylenediamine, the title compound was prepared.
Reaction SMILES: C([O:5][NH:6][C:7](=[O:29])[C@@H:8]([N:26]([CH3:28])[CH3:27])[CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(=[O:12])=[O:11])(C)(C)C.[Cl:30]CCCl>>[ClH:30].[CH3:27][N:26]([CH3:28])[C@@H:8]([CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)(=[O:11])=[O:12])[C:7]([NH:6][OH:5])=[O:29]
Reactant: CN(C)[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NOC(C)(C)C
Reactant: ClCCCl
Product: CN(C)[C@@H](CS(=O)(=O)c1ccc(Oc2ccccc2)cc1)C(=O)NO
Product: Cl
Temperature: -30 °C
Reaction time: 8 h

Procedure:
This compound, (R)-N-tert-butoxy-2-dimethylamino-3-(4-phenoxyphenylsulfonyl)-propionamide, was dissolved in 1,2-dichloroethane (50 ml), cooled to -30° C. and bubbled for 15-20 minutes with hydrochloric acid gas in a pressure tube. The flask was then sealed and the mixture stirred overnight. After cooling the tube was cautiously vented and its contents evaporated, to yield a gum, which upon trituration with 2:1 hexane/ethyl acetate gave a white powder, (R)-2-dimethylamino-N-hydroxy-3-(4-phenoxyphenylsulfonyl)-propionamide hydrochloride (0.43 g), m.p. 65-70° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[C:4](OC)=[O:5].[Cl:10][C:11]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:12]=1[CH2:13][NH2:14]>>[Cl:10][C:11]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:12]=1[CH2:13][NH:14][C:4](=[O:5])[CH:3]([O:8][CH3:9])[O:2][CH3:1]
Reactant: COC(=O)C(OC)OC
Reactant: NCc1cc(Cl)ccc1Cl
Product: COC(OC)C(=O)NCc1cc(Cl)ccc1Cl

Procedure:
A solution of methyl dimethoxyacetate (0.823 g, 6.08 mmol) and 2,5-dichlorobenzylamine (1.0 g, 5.7 mmol) was heated to 90° C. in a sealed tube for 48 h. The crude material was purified by column chromatography on silica gel [eluting with 40% EtOAc in hexanes] to afford the title compound as a clear oil. 1H NMR (400 MHz, CDCl3) δ=3.41 (s, 6H), 4.53 (d, J=6.6 Hz, 2H), 4.75 (s, 1H), 7.19-7.23 (m, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H). MS (ES+): m/z=278/280/282 [MH+]. HPLC: tR=3.03 min (ZQ2, polar—5 min).
Reaction SMILES: C([O:4][CH2:5][CH:6]([NH:12][C:13](=[O:71])[C:14]1[C:19]([I:20])=[C:18]([NH:21][C:22](=[O:28])[CH2:23][O:24]C(=O)C)[C:17]([I:29])=[C:16]([C:30](=[O:69])[NH:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:68])[C:37]2[C:42]([I:43])=[C:41]([NH:44][C:45](=[O:51])[CH2:46][O:47]C(=O)C)[C:40]([I:52])=[C:39]([C:53](=[O:66])[NH:54][CH:55]([CH2:61][O:62]C(=O)C)[CH2:56][O:57]C(=O)C)[C:38]=2[I:67])[C:15]=1[I:70])[CH2:7][O:8]C(=O)C)(=O)C.O.N>CO>[OH:24][CH2:23][C:22]([NH:21][C:18]1[C:17]([I:29])=[C:16]([C:30]([NH:31][CH2:32][CH2:33][CH2:34][NH:35][C:36](=[O:68])[C:37]2[C:42]([I:43])=[C:41]([NH:44][C:45](=[O:51])[CH2:46][OH:47])[C:40]([I:52])=[C:39]([C:53](=[O:66])[NH:54][CH:55]([CH2:56][OH:57])[CH2:61][OH:62])[C:38]=2[I:67])=[O:69])[C:15]([I:70])=[C:14]([C:19]=1[I:20])[C:13]([NH:12][CH:6]([CH2:7][OH:8])[CH2:5][OH:4])=[O:71])=[O:28]
Reactant: CC(=O)OCC(=O)Nc1c(I)c(C(=O)NCCCNC(=O)c2c(I)c(NC(=O)COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c2I)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Agent: N
Solvent: O
Solvent: CO
Product: O=C(CO)Nc1c(I)c(C(=O)NCCCNC(=O)c2c(I)c(NC(=O)CO)c(I)c(C(=O)NC(CO)CO)c2I)c(I)c(C(=O)NC(CO)CO)c1I
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The crude Acetic acid 3-acetoxy-2-[3-{3-[3-(2-acetoxy-1-acetoxymethyl-ethylcarbamoyl)-5-(2-acetoxy-acetylamino)-2,4,6-triiodo-benzoylamino]-propylcarbamoyl}-5-(2-acetoxy-acetylamino)-2,4,6-triiodo-benzoylamino]-propyl ester (1.5 g) was dissolved in methanol (10 ml) and water (10 ml) was added. Concentrated aqueous ammonia (3 ml) was added and the solution stirred at ambient temperature for 18 h. The reaction was evaporated to dryness, the residue dissolved in water and purified by preparative hplc to give the title product as a white solid after freeze drying.
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][C:21]=1[O:29][CH3:30])=[O:7])[CH2:2][CH2:3][CH3:4].Cl.CN(C)CCCN=C=NCC.[CH3:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([NH2:53])(=[O:52])=[O:51]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([NH:5][C:6]([CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH3:18])[CH:13]=[C:12]2[CH2:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:53][S:50]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=2[CH3:43])(=[O:52])=[O:51])=[O:25])=[CH:22][C:21]=1[O:29][CH3:30])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: CCCCNC(=O)Cc1ccc2c(c1)c(Cc1ccc(C(=O)O)cc1OC)cn2C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCCNC(=O)Cc1ccc2c(c1)c(Cc1ccc(C(=O)NS(=O)(=O)c3ccccc3C)cc1OC)cn2C
Yield: 84.8 %

Procedure:
A solution of 4-[5-(butylcarbamoyl)methyl-1-methylindol-3-ylmethyl]-3-methoxybenzoic acid (0.18 g), 4-(dimethylamino)pyridine (0.06 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.10 g), and 2-methylbenzenesulfonamide (0.08 g) in methylene chloride (3 ml) was stirred under a nitrogen atmosphere for 36 hr. The mixture was diluted with methylene chloride; washed (10% v/v hydrochloric acid, water), evaporated and dried under vacuum to give the title compound (0.21 g, 86%) as a pale pink powder: mp 108°-110°.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)O[C:12](=O)[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)=O.[CH3:23]COCC.[OH-:28].[Na+]>C(Cl)Cl>[CH3:23][CH:9]([CH2:10][CH2:11][CH3:12])[C:8](=[O:28])[CH:7]=[CH2:6]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CCOCC
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)C(C)CCC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of Intermediate 13.1 (700 mg, 5.5 mmol) in DCM (10 ml) was added Dess-Martin periodinane reagent (2.57 g, 6.6 mmol) and the solution was stirred at room temperature for 20 minutes. Ether (20 mL) was added to the mixture, and later 15 ml of 1.3 M NaOH solution was added. The mixture was stirred for an additional 10 minutes. After all the precipitate was dissolved into aqueous layer, the solution was extracted with ether (3×50 mL). The combined organic layer was washed with 1.3′ M NaOH solution, brine, dried, and concentrated to afford the title compound (500 mg) as colorless oil used in the next step without purification.