Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:25][C:26]([N:28]1[C:32]2[N:33]=[CH:34][N:35]=[C:36](Cl)[C:31]=2[CH:30]=[CH:29]1)=[O:27].C(Cl)(=O)C.[NH2:42][C:43]1[CH:44]=[C:45]([S:49]([NH2:52])(=[O:51])=[O:50])[CH:46]=[CH:47][CH:48]=1>C(O)CCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)=[CH:4][C:3]=1[NH:25][C:26]([N:28]1[C:32]2[N:33]=[CH:34][N:35]=[C:36]([NH:42][C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([S:49](=[O:51])(=[O:50])[NH2:52])[CH:44]=3)[C:31]=2[CH:30]=[CH:29]1)=[O:27]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1NC(=O)n1ccc2c(Cl)ncnc21
Solvent: CCCCO
Solvent: CC(=O)Cl
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1NC(=O)n1ccc2c(Nc3cccc(S(N)(=O)=O)c3)ncnc21
Temperature: 80 °C
Reaction time: 24 h
Yield: 55.1 %

Procedure:
4-Chloro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-benzoylamino]-phenyl}-amide resin (50 mg, 0.05 mmol), prepared as in reference 2, in n-butanol (2 mL) is mixed with acetyl chloride (17.8 μL, 0.25 mmol) and 3-aminobenzenesulfonamide (43 mg, 0.25 mmol), and shaken at 80° C. for 24 hours. The resulting mixture is filtered and the resin is treated with TFA/CH2Cl2/H2O (45/50/5) (600 μL) for 30 minutes before filtering and washing with CH2Cl2 (3×2 mL), MeOH (3×2 mL). The washes are then combined together with n-butanol and concentrated. The residue is purified by preparative HPLC-MS to give 4-(3-sulfamoyl-phenylamino)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid {2-methyl-5-[4-(4-methyl-piperazin-1-ylmethyl)-benzoylamino]-phenyl}-amide (18.0 mg, yield 55%); 1H NMR (400 MHz, DMSO-d6) δ 11.45 (s, 1H), 10.27 (s, 1H), 10.09 (s, 1H), 8.59 (s, 1H), 8.49 (s, 1H), 8.29 (s, 1H), 8.17 (d, J=7.95 Hz, 1H), 7.95 (d, J=7.94, 2H), 7.87 (d, J=3.85 Hz, 1H), 7.54 (dd, J=7.61, 15.51 Hz, 2H), 7.52 (s, 1H), 7.45 (d, J=7.88 Hz, 2H), 7.37 (s, 2H), 7.25 (d, J=8.30 Hz, 1H), 7.11 (d, J=3.88 Hz, 1H), 3.69 (s, 2H), 3.54-3.3.17 (m, 2H), 3.01-2.93 (m, 6H), 2.75 (s, 3H), 2.41 (s, 3H); ESIMS m/z 654.20 (M++1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][O:11][C:12]([CH:14]1[N:19]([C:20](=[O:34])[CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][C:17]2[N:35](CC(=O)C3C=CC=CC=3)[CH2:36][NH:37][C:16]=2[CH2:15]1)=[O:13].C(#N)C>CCOCC>[CH3:10][O:11][C:12]([CH:14]1[N:19]([C:20](=[O:34])[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18][C:17]2[N:35]=[CH:36][N:37]([CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([CH3:1])[CH:3]=3)[C:16]=2[CH2:15]1)=[O:13]
Reactant: COC(=O)C1CC2=C(CN1C(=O)C(c1ccccc1)c1ccccc1)N(CC(=O)c1ccccc1)CN2
Reactant: Cc1cccc(CBr)c1
Solvent: CCOCC
Solvent: CC#N
Product: COC(=O)C1Cc2c(ncn2Cc2cccc(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1

Procedure:
A solution of 2.7 mL 3-methylbenzyl bromide, 5.0 g methyl-5-diphenylacetyl-3-(2-oxo-2-phenyl- ethyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate and 50 mL acetonitrile is heated at reflux 4 hr. The cooled solution is added dropwise to 750 mL vigorously stirred ether and the resulting precipitate is collected by filtration. This precipitate is dissolved in 75 mL methanol and treated with 16 g zinc dust and 75 mL acetic acid. The resulting suspension is sonicated 6 hr then the solution is filtered from excess zinc. The filtrate is dissolved in 400 mL dichloromethane and treated dropwise with 650 mL 10% Na2CO3 with vigorous stirring. The organic phase is separated, dried, concentrated and the major product is isolated by chromatography on silica gel (chloroform-methanol, 99.5:0.5) as a crisp foam. NMR (CDCl3) 4.97 (s,2H,NCH2Ar).
Reaction SMILES: [C:1]([N:8]1[C@@H:13]([CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:22])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>C(O)C.[Pd]>[C:1]([N:8]1[C@@H:13]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:22])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[C@H]1CCC[C@H](C=Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CCC[C@H](CCc2ccccc2)N1C(=O)OC(C)(C)C

Procedure:
A solution of trans-N-Boc-2-methyl-6-(2-phenylethenyl)piperidine (3.8, 12.54 mmol) in 6 mL of ethanol was shaken under 58 psi of H2 pressure over 0.70 g Pd/C catalyst overnight, and then the mixture was filtered through Celite and concentrated to give 3.81 g (quantitative) of the product. No further purification was necessary. 1H NMR (250 MHz)δ7.30-7.14 (m, 5 H), 3.93-3.89 (m, 2 H), 2.64-2.59 (t, 2 H), 1.98-1.20 (m, 20 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[Cl:13]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].O>CN(C)C=O>[NH2:1][C:2]1[C:7]([Cl:13])=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(N)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N)c(Cl)c(Cl)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
The compound prepared in Example 404 (3.120 g) and N-chlorosuccinimide (2.456 g) were suspended in dimethyl formamide (100 mL) and stirred at 50° C. overnight. The reaction mixture was heated at 70° C. for a further 3 hours. The reaction mixture was added drop-wise to a stirred solution of 1:1 saturated aqueous sodium bicarbonate and water. The slurry was filtered and the solids dried under high vacuum to furnish the title compound (2.438 g), possessing the following physical data.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:29])[CH2:9][CH:10]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])=[CH:4][CH:3]=1.C[Si]([N:34]=[N+:35]=[N-:36])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:29])[CH2:9][CH:10]([C:21]2[CH:28]=[CH:27][CH:26]=[C:23]([C:24]3[NH:36][N:35]=[N:34][N:25]=3)[CH:22]=2)[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cccc(C(CC(=O)c2ccc(F)cc2)CC(=O)c2ccc(F)cc2)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=C(CC(CC(=O)c1ccc(F)cc1)c1cccc(-c2nnn[nH]2)c1)c1ccc(F)cc1
Yield: 88.1 %

Procedure:
A mixture of 3-[3-(4-fluorophenyl)-1-[2-(4-fluorophenyl)-2-oxoethyl]-3-oxopropyl]-benzonitrile (1 g, 2.1 mmol), trimethylsilylazide (0.48 g, 4.2 mmol), and dibutyltin oxide (0.05 g) is heated under N2 in toluene (25 mL) at 100° C. for 18 hours. The toluene is removed under vacuum and the residue is dissolved in a small amount of methanol. The methanol is removed under vacuum and the residue chromatographed over SiO2 eluting with dichloromethane:2-propanol (4:1). Pure fractions are combined, concentrated, and triturated with diethyl ether to provide 0.8 g of the title compound; mp 162°-164C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[C:6]([C:19]([NH2:21])=O)[C:5]2=[O:22].N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[CH:7]=[C:6]([C:19]#[N:21])[C:5]2=[O:22]
Reactant: NC(=O)c1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cn(-c2ccc(F)cc2)c2ccc(Br)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.5 %

Procedure:
Compound E (30 mg, 0.083 mmol, 1.0 eq) and cyanuric chloride (15 mg, 0.083 mmol, 1.0 eq) were dissolved in DMF (0.5 mL) and the reaction was stirred at room temperature for 30 minutes. The reaction was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. Purification by reverse phase chromatography afforded 10.1 mg (68%) of the title compound as white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.30 (d, J=2.4 Hz, 1H), 7.86 (dd, J=9.0, 2.4 Hz, 1H), 7.75-7.72 (m, 2H), 7.53 (t, J=8.7 Hz, 2H), 6.96 (d, J=9.1 Hz, 1H); ES-MS [M+1]+: 343.2.
Reaction SMILES: [ClH:1].N1C=CC=NC=1C(N)CC.[F:12][C:13]([F:35])([F:34])[C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:17]=[CH:16][C:15]=1[C@H:24]([NH:27][S@](C(C)(C)C)=O)[CH2:25][CH3:26]>>[ClH:1].[F:35][C:13]([F:12])([F:34])[C:14]1[CH:19]=[C:18]([C:20]([F:22])([F:23])[F:21])[N:17]=[CH:16][C:15]=1[CH:24]([NH2:27])[CH2:25][CH3:26]
Reactant: CC[C@@H](N[S@@](=O)C(C)(C)C)c1cnc(C(F)(F)F)cc1C(F)(F)F
Agent: CCC(N)c1ncccn1
Agent: Cl
Product: CCC(N)c1cnc(C(F)(F)F)cc1C(F)(F)F

Procedure:
(R)-1-(4,6-Bis-trifluoromethyl-pyridin-3-yl)-propylamine hydrochloride was obtained in analogy to comp. no. 15a from (S)-2-methyl-propane-2-sulfinic acid [(R)-1-(4,6-bis-trifluoromethyl-pyridin-3-yl)-propyl]-amide (Comp. No. 14n). LC/MS (method 7): Rt=0.93 min; m/z=273.1 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5][C:4]=1[N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:23](O)=[O:24])=[CH:20][CH:21]=2)[CH:16]=[CH:15]1)#[N:2].C(N(CC)CC)C.C(Cl)(=O)C(Cl)=O.[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[CH2:47][CH2:48][NH2:49]>C(Cl)Cl.CN(C=O)C>[Cl:39][C:40]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:41]=1[CH2:47][CH2:48][NH:49][C:23]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[N:14]([C:4]1[CH:5]=[CH:6][C:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:3]=1[C:1]#[N:2])[CH:15]=[CH:16]2)=[O:24]
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1ccc(-n2ccc3cc(C(=O)O)ccc32)c(C#N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(-n2ccc3cc(C(=O)NCCc4ccc(Cl)cc4Cl)ccc32)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(2-cyano-4-(2-methoxy-2-oxoethyl)phenyl)-1H-indole-5-carboxylic acid (0.020 g, 0.078 mmol, triethylamine (0.013 mL, 0.090 mmol) and oxalyl chloride (0.010 g, 0.079 mmol) was combined in 1 mL of DCM and 1 drop of DMF was added. The reaction mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture was added 2-(2,4-dichlorophenyl)ethanamine.The reaction mixture was stirred for 1 hour then loaded onto a silica gel column. The product was eluted with solvent system of 5% EtOAc/Hexanes to 100% EtOAc to provide methyl 2-(4-(5-((2,4-dichlorophenethyl)carbamoyl)-1H-indol-1-yl)-3-cyanophenyl)acetate (0.170 g, 0.034 mmol). MS(APCI)=506.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7]CC1C=CC=CC=1>[Pd].C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[C:21]([F:23])[C:20]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[N:26]([CH3:35])[C:25]2=[O:36])=[CH:19][C:3]=1[O:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[OH:7]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3OCc3ccccc3)c(Cl)cc2F)c1=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3O)c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
To 4.5 g of ([2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene were added 230 ml of ethyl acetate and 0.46 g of 10% palladium/carbon, and the mixture was stirred at room temperature under an atmosphere of hydrogen gas for 5 hours. The gas in the atmosphere on the reaction system was replaced with nitrogen gas, and the reaction mixture was filtered through Celite. The filtrate was concentrated to give 3.57 g of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][N:12]=2)[CH2:3][CH2:2]1.[F:17][C:18]([F:29])([F:28])[O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>ClCCCl>[F:17][C:18]([F:28])([F:29])[O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]2[S:9][C:10]([C:13]([F:16])([F:14])[F:15])=[N:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cccc(OC(F)(F)F)c1
Reactant: FC(F)(F)c1nnc(NC2CCNCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: ClCCCl
Product: FC(F)(F)Oc1cccc(CN2CCC(Nc3nnc(C(F)(F)F)s3)CC2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
A mixture of piperidin-4-yl-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amine (D4) (0.025 g, 0.10 mmol), 3-trifluoromethoxy-benzaldehyde (0.034 ml, 0.29 mmol) and polymer supported triacetoxyborohydride (2.07 mmol/g) (0.165 g, 0.29 mmol) in 1,2-dichloroethane (2 ml) was shaken at room temperature for 16 h. After this period, the reaction mixture was filtered through an Isolute SCX-2 cartridge. The cartridge was washed with methanol. The crude product was eluted with a 7M solution of ammonia in methanol. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 5% ammonia in methanol (7M)/dichloromethane) to yield E13 (0.029 g, 68%) as a white solid. C16H16F6N4OS requires 426. Found 427 (MH+).
Reaction SMILES: [O-:1][CH2:2][CH3:3].CN(P(=N[P+](N=P(N(C)C)(N(C)C)N(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=[PH2]N(CC[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])CCCCCCCC)(N(C)C)N(C)C)C>P(N(C)C)(N(C)C)N(C)C>[CH2:2]([O:1][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH3:3]
Reactant: CC[O-]
Reactant: CCCCCCCCN(CCCCCCCC)[PH2]=N[P+](N=P(N(C)C)(N(C)C)N(C)C)(N=P(N(C)C)(N(C)C)N(C)C)N=P(N(C)C)(N(C)C)N(C)C
Agent: CN(C)P(N(C)C)N(C)C
Product: CCOc1ccccc1
Yield: 86 %

Procedure:
The reaction was carried out completely in the same manner as in Example 1, except that tris[tris(dimethylamino)phosphoranylideneamino](dioctylamino)phosphoranylideneamino phosphonium ethoxide: [(Me2N)3P═N]3P+{N═P[N(C8H17)2]}, C2H5O− was used instead of tetrakis[tris(dimethylamino)phosphoranylideneamino]phosphonium methoxide in Example 1. Objective ethoxybenzene was produced in the yield of 86%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:24])=[C:4]([C:18]([CH3:23])=[C:19]([F:22])[C:20]=1[F:21])[C:5]([CH:7](C(OCC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:3]([F:24])=[C:4]([C:18]([CH3:23])=[C:19]([F:22])[C:20]=1[F:21])[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1c(C)c(F)c(F)c(Cl)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)CC(=O)c1c(C)c(F)c(F)c(Cl)c1F
Yield: 116.7 %

Procedure:
Employing diethyl 3-chloro-2,4,5-trifluoro-6-methylbenzoylmalonate (320 mg) and p-toluenesulfonic acid (3 mg), the procedure of Reference Example 19 is repeated to give ethyl 3-chloro-2,4,5-trifluoro-6-methylbenzoylacetate (300 mg), as brown oil.
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:24])=[C:20]([F:33])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14](C)(C)C)=[O:12])[CH2:7][CH2:6]1.Cl.ClC(OC)=O.CCN(CC)CC>CO.O1CCOCC1>[F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:26]2[CH:27]=[N:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[O:24])=[C:20]([F:33])[CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1
Reactant: Cc1ccc(NC(=O)Nc2c(F)ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)cn1
Agent: COC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)N1CCN(Cc2ccc(F)c(NC(=O)Nc3ccc(C)nc3)c2F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.3 %

Procedure:
To a solution of tert-butyl 4-(2,4-difluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (790 mg, 1.71 mmol, 1.0 equiv) in MeOH (5 mL) was added by syringe HCl (71 (4.0 M in dioxane, 4.5 mL, 17 mmol, 10 equiv) After 30 minutes, the reaction mixture was concentrated in vacuo. The resulting solid was then suspended in DCM (20 mL) and methyl chloroformate (158 μL, 2.05 mmol, 1.2 equiv) and Et3N (716 μL, 5.13 mmol, 3.0 equiv) were added by syringe. The reaction mixture was allowed to stir at room temperature for 1.5 h and then quenched by the addition of aq. satd. NaHCO3. The organic layer was separated, dried over sodium sulfate and purified by preparative thin layer chromatography (10% MeOH/DCM) to provide methyl 4-(2,4-difluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (275 mg, 38%). LCMS m/z (APCI)=420.2 (M+H).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2].[F:19][C:20]1[CH:21]=[C:22]([CH:27]([OH:31])[C:28](O)=[O:29])[CH:23]=[C:24]([F:26])[CH:25]=1>>[CH2:1]([CH:3]([N:6]1[CH:10]=[C:9]([NH:11][C:12](=[O:18])[CH:13]([NH:17][C:28](=[O:29])[CH:27]([C:22]2[CH:23]=[C:24]([F:26])[CH:25]=[C:20]([F:19])[CH:21]=2)[OH:31])[CH2:14][CH2:15][CH3:16])[N:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C(O)C(O)c1cc(F)cc(F)c1
Reactant: CCCC(N)C(=O)Nc1cn(C(CC)CC)cn1
Product: CCCC(NC(=O)C(O)c1cc(F)cc(F)c1)C(=O)Nc1cn(C(CC)CC)cn1

Procedure:
2-Amino-pentanoic acid [1-(1-ethyl-propyl)-1H-imidazol-4-yl]-amide was coupled with (3,5-Difluoro-phenyl)-hydroxy-acetic acid to provide the title compound: C13 NMR (100 MHz, CDCl3) 10.7, 13.7, 13.7, 19.0, 19.1, 35.5, 35.7, 52.9, 53.2, 62.9, 73.4, 73.5, 103.4, 103.7, 105.0, 105.2, 109.6, 109.8, 109.9, 110.1, 132.5, 132.6, 137.4, 137.5, 144.1, 161.7, 161.9, 164.3, 169.2, 169.6, 171.8, 172.0; MS 423.21 m/z (M+1).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]([C:18]2[C:26]3[C:21](=[C:22]([C:27]([O:29]C)=[O:28])[CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:17])[C@H:11]([CH3:32])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>[C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:31])[C:16]([CH:18]2[C:26]3[C:21](=[C:22]([C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=3)[NH:20][CH2:19]2)=[O:17])[C@H:11]([CH3:32])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)C[C@H]3C)c[nH]c12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(=O)C1CNc2c(C(=O)O)cccc21
Reaction time: 10 h
Yield: 11.3 %

Procedure:
1-(benzoyl)-3-(R)-methyl4-[(7-(methoxycarbonyl)indol-3-yl)-2-oxoacetyl]piperazine (50 mg) was dissolved in a solution of triethylsilane (Et3SiH, 0.5 mL) in TFA (5 mL). The reaction was stirred for 10 hours. Solvents were removed under vaccum, and the residue was purified using Shimadzu automated preparative HPLC System to give 1-benzoyl-3-(R)-methyl-4-[(7-carboxyindolin-3-yl)-2-oxoacetyl]piperazine (5.5 mg).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8]O)=[CH:4][CH:3]=1.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:36]I>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][I:36])=[CH:4][CH:3]=1
Reactant: II
Reactant: OCCOc1ccc(Br)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(OCCI)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
To a sol. of compound 4 (39.2 g, 181 mmol) in dry toluene (500 mL) was added imidazole (61.5 g, 903 mmol), PPh3 (90 g, 343 mmol), and iodine (87.1 g, 343 mmol). This mixture was stirred at 60° C. for 2 h. The mixture was filtered over Celite, and the filtrate was concentrated under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:5→1:4→1:3→1:2→1:1) yielded the title compound (39.9 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])(=[O:17])=[O:16])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl.CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:34])=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[F:25])(=[O:17])=[O:16])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)CCSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C(O)CCS(=O)c1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
To a solution of 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoic acid (91 mg, 0.21 mmol) in CH2Cl2 (2 ml) and acetone (2 ml) was added mCPBA (50 mg, ˜0.21 mmol). The reaction was stirred at room temperature for 1 hour and was concentrated. The solid residue was rinsed with Et2O to yield the title compound (88 mg, 94%).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].[OH-].[Na+].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[Na+].[Cl-]>[CH2:16]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: OCCOCCOCCOCCO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Product: OCCOCCOCCOCCOCc1ccccc1
Temperature: 100 °C
Yield: 70.9 %

Procedure:
To the oil of non-polydispersed tetraethylene glycol (19.4 g, 0.10 mol) was added a solution of NaOH (4.0 g in 4.0 mL) and the reaction was stirred for 15 mm. Then benzyl chloride (3.54 mL, 30.8 mmol) was added and the reaction mixture was heated to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature, diluted with sat. NaCl (250 mL), and washed CH2Cl2 (2×200 mL). The organic layers were combined, washed sat. NaCl, dried MgSO4, and chromatographed (silica, ethyl acetate) to afford the non-polydispersed title compound as a yellow oil (6.21 g, 71% yield).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=[NH:14])[O:11][CH2:12][CH3:13].[N:15]#[C:16]N>C(O)C.CCOCC>[C:16]([N:14]=[C:10]([O:11][CH2:12][CH3:13])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])#[N:15]
Reactant: N#CN
Reactant: CCOC(=N)Cc1ccccc1C
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: CCOC(Cc1ccccc1C)=NC#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.8 %

Procedure:
A solution of Example 26A (15 g, 70.2 mmol) in absolute ethanol (200 mL) was treated with a solution of cyanamide (2.95 g, 70.2 mmol) in dry ether (40 mL) and stirred at room temperature for 72 h. The resulting precipitate was filtered and the solution was concentrated to dryness under reduced pressure to give 10.2 g of the title compound.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([CH2:9][C:10]([OH:12])=O)[C:4]=1[CH3:13])=[O:2].[CH2:14]([N:16]([CH2:19][CH2:20][NH2:21])[CH2:17][CH3:18])[CH3:15]>>[CH2:14]([N:16]([CH2:17][CH3:18])[CH2:19][CH2:20][NH:21][C:10](=[O:12])[CH2:9][C:5]1[C:4]([CH3:13])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[CH3:8])[CH3:15]
Reactant: Cc1[nH]c(C=O)c(C)c1CC(=O)O
Reactant: CCN(CC)CCN
Product: CCN(CC)CCNC(=O)Cc1c(C)[nH]c(C=O)c1C

Procedure:
(5-Formyl-2,4-dimethyl-1H-pyrrol-3-yl)-acetic acid was reacted with diethylaminoethylamine using General Amidation Procedure 1 to give N-(2-diethylamino-ethyl)-2-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-acetamide. MS m/z 280 [M+1].
Reaction SMILES: Cl[C:2]1[CH:3]2[C:10]([I:11])=[CH:9][N:8]([CH:12]([CH3:14])[CH3:13])[CH:4]2[N:5]=[CH:6][N:7]=1.[CH3:15][NH2:16]>C1COCC1>[I:11][C:10]1[CH:3]2[CH:4]([N:5]=[CH:6][N:7]=[C:2]2[NH:16][CH3:15])[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=1
Reactant: CN
Reactant: CC(C)N1C=C(I)C2C(Cl)=NC=NC21
Solvent: C1CCOC1
Product: CNC1=NC=NC2C1C(I)=CN2C(C)C
Reaction time: 8 h
Yield: 85 %

Procedure:
4-Chloro-7,7a-dihydro-5-iodo-7-isopropyl-4aH-pyrrolo[2,3-d]pyrimidine (0.3 g, 0.93 mmol) from above was placed within a 15 ml pressure tube. 2 M methylamine in THF (15 ml) was added, and the reaction was left to stir overnight. The volatiles were removed in vacuo, and the residue was dissolved in methanol, 5 ml silica gel were added, and the volatiles were removed in vacuo. The adhered product was purified by silica gel chromatography (ethyl acetate:hexanes), and the requisite fractions were pooled and evaporated in vacuo to yield the desired product (0.25 g, 85% yield). 1H NMR (399.6 MHz, CDCl3) δ 1.43 (6H, d, J=6.8 Hz), 3.13 (3H, d, J=4.8 Hz), 5.0 (1H, sp, J=6.8 Hz), 7.02 (1H, s), 8.35 (1H, s).