Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][C@H:8]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:17][C:16]=1[O:26][CH2:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1)(=[O:14])=[O:13])[CH:9]=[O:10])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:29]1([CH2:28][CH2:27][O:26][C:16]2[CH:17]=[C:18]([N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[CH:19]=[CH:20][C:15]=2[S:12]([NH:11][C@H:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:39])=[O:5])(=[O:13])=[O:14])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](C=O)NS(=O)(=O)c1ccc(N2CCCC2)cc1OCCc1cccc2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C[C@H](CC(=O)O)NS(=O)(=O)c1ccc(N2CCCC2)cc1OCCc1cccc2ccccc12
Yield: 34.8 %

Procedure:
A solution of (S)-3-[2-(2-naphthalen-1-yl-ethoxy)-4-pyrrolidin-1-yl-benzenesulfonylamino]-4-oxo-butyric acid tert-butyl ester (0.60 g, 1.10 mmol) in TFA (2 mL) and CH2Cl2 (20 mL) was stirred for 3 h. After the solvent was removed under vacuum, the residue was subjected to preparative reverse-phase HPLC (VYDAC, C18) using linear gradient of water containing 0.1% TFA and acetonitrile containing 0.1% TFA (20-65% acetonitrile, in 120 min) at a flow rate of 20 mL/min. Fractions containing the major peak were pooled and lyophilized to yield 0.190 g (60%) of (S)-3-[2-(2-naphthalen-1-yl-ethoxy)-4-pyrrolidin-1-yl-benzenesulfonyl amino]-4-oxo-butyric acid. MS (APCI) m/z 496.1 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH2:16][O:17][CH3:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][O:17][CH2:16][CH2:15][O:14][C:12]1[C:11]([C:19]([F:20])([F:22])[F:21])=[CH:10][C:9]2[NH:23][C:24](=[O:40])[CH2:25][C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]4[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=4)[CH:28]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: COCCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3)c1)=N2

Procedure:
The title compound was prepared from {5-(2-methoxy-ethoxy)-2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M188) (278 mg, 0.49 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (153 mg, 69%).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([CH2:8][C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])[CH3:3].O[N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28].C1CCC(N=C=NC2CCCCC2)CC1>O1CCOCC1>[CH3:4][C:2]([O:5][C:6]([CH2:8][C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([O:12][N:22]1[C:26](=[O:27])[CH2:25][CH2:24][C:23]1=[O:28])=[O:11])=[O:7])([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resulting 11.45 g (39.7 mmoles) of oily BOC--Asp(OtBu)--OH and 4.6 g (40 mmoles) of N-hydroxy-succinimide are dissolved in 100 ml of dry dioxane. The solution is cooled until freezing, and then 8.25 g (40 mmoles) of DCC are added. The reaction mixture is stirred at room temperature overnight, the separated DCU is filtered off, and the filtrate is evaporated. The oily residue is solidified with a mixture of n-hexane and diisopropyl ether. The resulting crude product, weighing 13.8 and melting at 98°-102° C., is recrystallized from a threefold amount of isopropanol. 12.1 g (78.3%) of white, crystalline BOC--Asp (OtBu)--OSu are obtained; m.p.: 103°-105° C., [α]D : -25.6° (c: 1.0, in dioxane).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([O:10][CH3:11])=[O:9].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[CH3:11][O:10][C:8](=[O:9])[CH:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1
Reactant: COC(=O)Cc1cccn1C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc([N+](=O)[O-])cc1)c1cccn1C
Temperature: 0 °C
Yield: 96.6 %

Procedure:
Methyl 1-methylpyrrole-2-acetate (5.32 g, 34.73 mmol) and 4-fluoro-nitrobenzene (4.9 g, 34.73 mmol) were dissolved in dry DMF (100 ml), and the solution was cooled to 0° C. under nitrogen. Sodium hydride powder (1.75 g, 72.93 mmol) was added in portions. After 30 min the reaction mixture was quenched with 1 M HCl and the product was extracted into ether. The organic extracts were washed with water and brine, and dried over magnesium sulfate. The solvent was removed in vacuo to give methyl-2-(1-methylpyrrol-2-yl)-2-(4-nitrophenyl)acetate (9.20 g, 97%) as a red oil. ##STR61##
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:22][CH2:21][C@@:12]34[C:13]5[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@@H:7]3[CH2:8][CH2:9][C:10](=O)[CH2:11]4)[CH2:3][CH2:2]1.[CH2:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>CS(C)=O>[CH:1]1([CH2:4][N:5]2[CH2:22][CH2:21][C@@:12]34[C:13]5[CH:14]=[C:15]([OH:20])[CH:16]=[CH:17][C:18]=5[CH2:19][C@@H:6]2[C@@H:7]3[CH2:8][CH2:9][C:10](=[CH2:24])[CH2:11]4)[CH2:2][CH2:3]1
Reactant: O=C1CC[C@H]2[C@H]3Cc4ccc(O)cc4[C@@]2(CCN3CC2CC2)C1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Product: C=C1CC[C@H]2[C@H]3Cc4ccc(O)cc4[C@@]2(CCN3CC2CC2)C1

Procedure:
Reaction of 17-cyclopropylmethyl-3-hydroxy-morphinan-6-one (1.58 g, 5 mmole) with methylenetriphenylphosphorane (20 mmole) in dimethyl sulfoxide gave a crude residue which was chromatographed using 10:1 chloroform-methanol containing 1% concentrated ammonium hydroxide. Pure fractions were pooled to give 909 mg (58%) of TR-5609 which crystallized from ethanol to give 532 mg of analytically pure TR-5609, mp 220°-223°.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][CH:18]=3)[CH:13]=2)[N:3]=1.COC1C=C2C(C=CC(OCCO)=C2)=CC=1.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C([O-])([O-])=O.[K+].[K+]>>[CH3:23][O:22][C:16]1[CH:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([O:11][CH2:10][CH2:9][O:8][C:4]3[CH:5]=[N:6][CH:7]=[C:2]([N:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)[N:3]=3)=[CH:13]2)=[CH:18][CH:17]=1
Reactant: C1CNCCN1
Reactant: COc1ccc2ccc(OCCOc3cncc(Cl)n3)cc2c1
Agent: COc1ccc2ccc(OCCO)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc2ccc(OCCOc3cncc(N4CCNCC4)n3)cc2c1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[2-(7-methoxy-naphthalen-2-yloxy)-ethoxy]pyrazine [1.19 g, 3.60 mmol; obtained according to the procedure of example 50, step 1, starting from 2-(7-methoxy-naphthalen-2-yloxy)ethanol*], piperazine (1.25 g, 14.5 mmol) and K2CO3 (0.60 g, 4.3 mmol) with the exception that the final filtration through alumina was omitted. The yield of the of the title compound was 0.98 g (71%) which was obtained as an oil that solidified when refrigerated. Purity 100% (HPLC). MS m/z 380 (M)+. HRMS m/z calcd for C21H24N4O3 (M)+ 380.1848, found 380.1851.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].CC1(C)C(C)(C)OB([C:31]2[CH:32]=[CH:33][C:34]([NH2:37])=[N:35][CH:36]=2)O1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:31]3[CH:36]=[N:35][C:34]([NH2:37])=[CH:33][CH:32]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccc(N)nc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 90 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
1-Methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (1 g, 2.71 mmol) (for a preparation see Example 4) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridinamine (0.487 g, 2.213 mmol) were combined in ethanol (4.7 ml) and toluene (4.70 ml) to give a light yellow solution. K2CO3 (0.449 g, 3.25 mmol) followed by tetrakis(triphenylphosphine)palladium(0) (0.156 g, 0.135 mmol) were added and the resulted mixture was stirred at 90° C. under nitrogen for 16 h then was cooled to room temperature and concentrated in vacuo. The residue was partitioned between water (40 mL) and EtOAc (50 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (50 mL) and the combined organic phases were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 12 to 63% AcOEt in Hexanes followed by 10% (2M NH3 in MeOH) in DCM) gave a residue which was further purified by flash chromatography on silica gel (gradient: 1 to 5% (2M NH3 in MeOH) in DCM) to give 1-methylethyl[(2S,4R)-1-acetyl-6-(6-amino-3-pyridinyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (0.74 g, 1.885 mmol, 69.6% yield) as a yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21][CH:22]=C(C)CCC(O)=O.CCCCCC.C(OCC)(=[O:38])C>>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21][CH:22]=[O:38]
Reactant: COCCOCOc1c(CC=C(C)CCC(=O)O)c(OC)c(C)c2c1C(=O)OC2
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: COCCOCOc1c(CC=O)c(OC)c(C)c2c1C(=O)OC2

Procedure:
By following the procedure of part A and substituting methyl (E) 6(4-t-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate with (E) 6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid, there was obtained 2-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-acetaldehyde, m.p. 61°-63° C. (hexane-ethyl acetate).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([OH:42])[CH:38]=3)[CH:33]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21].[CH:43]12[CH2:49][CH:46]([CH:47]=[CH:48]1)[CH2:45][CH:44]2O.C1(C)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(OC(=O)C)C>[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[C:37]([O:42][CH:48]4[CH2:47][CH:46]5[CH2:49][CH:43]4[CH:44]=[CH:45]5)[CH:38]=3)[CH:33]=2)[CH2:27][CH2:26]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O)ccc3c2)CC1
Reactant: OC1CC2C=CC1C2
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(Cc2ccc3cc(OC4CC5C=CC4C5)ccc3c2)CC1
Yield: 8 %

Procedure:
Triphenylphosphine was added to a solution of 1-(6-Hydroxy-naphthalen-2-ylmethyl)-piperidine-4-carboxylic acid ethyl ester (0.4319 g, 0.001378 mol) and bicyclo[2.2.1]hept-5-en-2-ol (0.243 g, 0.00220 mol) in toluene (0.881 mL, 0.00827 mol) and the mixture was stirred for several minutes. Diisopropyl azodicarboxylate (0.434 mL, 0.00220 mol) was then added dropwise and the mixture was stirred at room temperature for 72 hours. The reaction mixture was then diluted in ethylacetate and washed with water, then brine. The organic phase was dried over MgSO4, filtered, concentrated under reduced pressure and purified by flash chromatography (0-40% EtOAc in heptanes) to give the title compound in 8% yield. ESI-MS (M+H+): 406.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])[C:18]([Cl:20])=[CH:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.C1COCC1.O[Li].O>O>[Cl:20][C:18]1[C:17]([S:21]([CH:24]([CH3:26])[CH3:25])(=[O:23])=[O:22])=[CH:16][C:14]2[NH:15][C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[N:12][C:13]=2[CH:19]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(S(=O)(=O)C(C)C)cc3[nH]2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)S(=O)(=O)c1cc2[nH]c(-n3cc(C(=O)O)cn3)nc2cc1Cl
Temperature: 23 °C
Reaction time: 56 h
Yield: 87.8 %

Procedure:
To a solution of 1-[5-chloro-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.179 mg, 0.451 mmol), THF (1.7 mL), and water (0.55 mL) was added LiOH.H2O (56.8 mg, 1.35 mmol). The mixture was sonicated briefly, and stirred at 23° C. for 56 h. The solvent was evaporated, water was added, and the resulting solution was acidified to pH 1 with 1M aq. HCl. The precipitate was collected to yield the titled compound (0.146 g, 86% yield). MS (ESI/CI): mass calcd. for C14H13ClN4O4S, 368.0; m/z found, 369.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6, tautomeric broadening): 14.07 (s, 1H), 13.03 (s, 1H), 8.95 (d, J=0.4 Hz, 1H), 8.36 (s, 1H), 8.16 (s, 1H), 8.09-7.64 (m, 1H), 3.88-3.76 (m, 1H), 1.22 (d, J=7.9 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Yield: 84.8 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.260 g, 0.92 mmol) was treated with 4-chlorophenyl isocyanate (0.144 g, 0.92 mmol, 1.0 equiv.) in CH2Cl2 (5 mL), in a similar manner as described in Example 1.2 to afford Compound 1 (0.340 g, 0.78 mmol, 84%) as a white solid. LCMS m/z (%)=435 (M+H79Br35Cl, 27), 437 (M+H81Br35Cl, 100), 439 (M+H81Br37Cl, 25). 1H NMR (400 MHz, CDCl3) δ: 7.56 (s, 1H), 7.44 (dd, J=2.7, 8.9 Hz, 1H), 7.34 (d, J=9.0 Hz, 1H), 7.29 (d, J=9.0 Hz, 1H), 7.19 (d, J=2.7 Hz, 1H), 6.59 (s, 1H), 6.47 (s, 1H), 3.84 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:20]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1cccnc1C
Solvent: ClCCl
Product: COC(=O)c1ccc[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-methylpyridine-3-carboxylate (10 g, 66.2 mmol) was taken up in DCM (140 mL) and mCPBA (16.31 g, 72.8 mmol) was added. The resulting solution was stirred at room temperature overnight. The reaction mixture was purified directly by silica gel chromatography (0-20% MeOH/EtOAc) to afford the title compound as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([Br:20])[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.N1C=CC=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:30]=1[S:36](Cl)(=[O:38])=[O:37].Cl>O1CCCC1>[Br:20][C:17]1[CH:18]=[C:19]2[C:11]([C:9]([C:4]3[C:3]([F:21])=[C:2]([NH:1][S:36]([C:30]4[CH:31]=[C:32]([F:35])[CH:33]=[CH:34][C:29]=4[F:28])(=[O:38])=[O:37])[CH:7]=[CH:6][C:5]=3[F:8])=[O:10])=[CH:12][NH:13][C:14]2=[N:15][CH:16]=1
Reactant: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Br)cc23)c1F
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(c1c(F)ccc(NS(=O)(=O)c2cc(F)ccc2F)c1F)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.9 %

Procedure:
Into a reaction flask, (3-amino-2,6-difluoro-phenyl)-(5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (7, 140 mg, 0.40 mmol) is stirred in 3 mL of tetrahydrofuran and pyridine (0.3 mL, 4.0 mmol) is added, followed by 2,5-difluoro-benzenesulfonyl chloride (25, 127 mg, 0.596 mmol). The reaction is stirred at room temperature for 24 hours, then adjusted to pH 4 with addition of 1M aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with brine, dried with sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material is purified by silica gel column chromatography to provide the desired compound (26, 190 mg, 90%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2].[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([S:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([NH2:25])[CH:24]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][C:23]1[CH:24]=[C:19]([CH3:18])[CH:20]=[CH:21][C:22]=1[S:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[CH:13][CH:12]=[C:11]([CH3:17])[N:10]=2)=[O:5])[CH3:2]
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1Cl
Product: CCOC(=O)c1cnc2nc(C)ccc2c1Nc1cc(C)ccc1Sc1ccccc1

Procedure:
The product from Example 10a (438 mg, 2.03 mmol) was reacted with the product from Example 1f (510 mg, 2.03 mmol) for 10 min following the procedure from Example 1g giving the title compound which was purified by silica gel column chromatography eluting with 4% MeOH/CH2Cl2 as a solid (114 mg, 57%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.33 (t, J=6.99 Hz, 3H) 2.16 (s, 3H) 2.62 (s, 3H) 4.29 (q, J=7.11 Hz, 2H) 6.86 (s, 1H) 7.04 (d, J=8.09 Hz, 1H) 7.15-7.34 (m, 6H) 7.39 (d, J=7.72 Hz, 1H) 7.69 (d, J=8.82 Hz, 1H) 9.17 (s, 1H) 10.13 (s, 1H); MS (ESI+) m/z 430 (M+H)+, (ESI−) m/z 428 (M−H)−.
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]1[CH2:15]O.[CH:18]1([N:21]2[C:29]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[NH:23][C:22]2=[O:30])[CH2:20][CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O>C1COCC1>[CH:18]1([N:21]2[C:29]3[CH:28]=[CH:27][N:26]=[CH:25][C:24]=3[N:23]([CH2:15][C:7]3[N:6]([CH2:5][CH2:4][CH2:3][CH:2]([F:17])[F:1])[C:14]4[C:9]([N:8]=3)=[N:10][CH:11]=[CH:12][CH:13]=4)[C:22]2=[O:30])[CH2:20][CH2:19]1
Reactant: OCc1nc2ncccc2n1CCCC(F)F
Reactant: O=c1[nH]c2cnccc2n1C1CC1
Agent: O=C([O-])N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1n(Cc2nc3ncccc3n2CCCC(F)F)c2cnccc2n1C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 59.4 %

Procedure:
To a suspension of (1-(4,4-difluorobutyl)-1H-imidazo[4,5-b]pyridin-2-yl)methanol 43-5 (470 mg, 1.9 mmol), 1-cyclopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one 10-d (431 mg, 2.3 mmol) and triphenylphosphine (613 mg, 2.3 mmol) in 14 ml dry THF was added (E)-diïsopropyl diazene-1,2-dicarboxylate (0.6 ml, 2.9 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 hours. The precipitate was filtered off and washed with some diethyl ether to obtain the title product as a white powder (450 mg, 58%). m/z=399 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10](Cl)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:21]=[C:22]([O:26][CH3:27])[C:23]=1[O:24][CH3:25])[NH2:20].Cl>CC(C)=O.O>[C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:20][C:19]3[CH:21]=[C:22]([O:26][CH3:27])[C:23]([O:24][CH3:25])=[C:17]([O:16][CH3:15])[CH:18]=3)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Clc1nccc(Nc2ccccc2)n1
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(Nc2nccc(Nc3ccccc3)n2)cc(OC)c1OC
Yield: 76.8 %

Procedure:
A solution of N-phenyl-2-chloro-4-pyrimidineamine (1.83 g, 8.91 mmol) and 3,4,5-trimethoxyaniline (1.83 g, 10.0 mmol) in acetone (10 ml) and water (15 ml) containing concentrated hydrochloric acid (0.2 ml) was heated at reflux for 10 h. On cooling the acetone was removed under reduced pressure, and the reaction taken to pH10 with 4N NaOH and extracted with ethyl acetate (2×75 ml). The combined organic layers were dried (MgSO4), concentrated under reduced pressure and the residue crystallised from ethyl acetate to give the title compound (2.41 g) as a colourless solid m.p. 191°. δH (CDCl3) 8.04 (1H, d, J 5.8 Hz), 7.37-7.34 (4H, m), 7.16-7.10 (1H, m), 7.05 (1H, br s), 6.85 (2H, s), 6.68 (1H, br s), 6.16 (1H, d, J 5.8 Hz), 3.82 (3H, s) and 3.81 (6H, s). MS m/z 353 (M+H)+. The pyrimidineamine used as starting material was prepared by heating a solution of 2,4-dichloropyrimidine (4.0 g, 26.8 mmol), aniline (2.46 ml, 27.0 mmol) and triethylamine (4.3ml, 30.0 mmol) in ethanol (50 ml) at reflux for 2 h. On cooling a white precipitate was collectd which was washed with cold ethanol (100 ml) and recrystallised from ethyl acetate to give the desired product (6.01 g) as a colourless solid m.p. 186°. MS/mz 206 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>CC(O)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH:10][NH2:11])[CH:7]=1
Reactant: NN
Reactant: Clc1cc(Cl)ncn1
Solvent: O
Solvent: CC(C)O
Product: NNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
A mixture of 4,6-dichloro-pyrimidine (18.68 g, 125 mmol), hydrazine monohydrate (18.28 mL, 376 mmol), and 2-propanol (300 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated, triturated with water, and filtered. The solid was washed with water, air-dried to give (6-chloro-pyrimidin-4-yl)-hydrazine (16.97 g, Yield 94%): 1H NMR 400 MHz (d6-DMSO) δ 8.83 (s, 1H), 8.17 (s, 1H), 6.76 (s, 1H), 4.50 (s, 2H); MS m/z 145.02 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C=O)C>[C:16]([Si:19]([CH3:21])([CH3:20])[O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[NH2:1])([CH3:18])([CH3:17])[CH3:15]
Reactant: Cc1ccc(N)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.5 %

Procedure:
To a solution of 2-amino-5-methyl-phenol (500 mg, 4.0 mmol) and imidazole (298 mg, 4.4 mmol) in DMF (5 ml) was added TBDMSCl (660 mg, 4.4 mmol). The reaction mixture was stirred at RT for 3 h then diluted into water and extracted with AcOEt. The organic fraction was dried over Na2SO4, filtered and evaporated to dryness. The resulting residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, heptane/TBME containing 5% of 7M NH3 in MeOH 95:5→8:2) to yield the title compound (724 mg, 3.1 mmol, 77%) as a reddish oil. TLC: RF=0.94 (heptane/DCM/TBME 1:1:2 containing 5% of 7M NH3 in MeOH); HPLC: AtRet=1.80 min; API-MS: m/z 238.1 [M+H]+; 1H NMR (400 MHz, CDCl3): 0.26 (s, 6H), 1.04 (s, 9H), 2.23 (s, 3H), 3.56 (br. s., 1H), 6.56-6.67 (m, 3H).