Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)=[N:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: OB(O)c1cccnc1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Nc1nc(-c2cccnc2)ccc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 77.1 %

Procedure:
An oven dried resealable Schlenk tube was charged with 6-chloro-3-nitropyridin-2-amine (5 g, 28.81 mmol), 3-pyridineboronic acid (5.31 g, 43.2 mmol), dioxane (250 mL) and a 2M aqueous solution of cesium carbonate (43 mL, 86.4 mmol). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (2.3 g, 2.81 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 100° C. oil bath. After 3 h, the mixture was cooled, partitioned between water and ethyl acetate, the aqueous phase extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (95:5 dichloromethane/methanol) to give the title compound (4.8 g, 77%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)=[C:4]([C:18]#[N:19])[CH:3]=1.O1CCCC1.[CH3:25][NH2:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:26][CH3:25])=[O:17])=[C:4]([C:18]#[N:19])[CH:3]=1
Reactant: CN
Reactant: N#Cc1cc(Cl)ccc1NC(=O)Oc1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(Cl)cc1C#N

Procedure:
(Step 1) Using phenyl (4-chloro-2-cyanophenyl)carbamate obtained in Example 47, Steps 1 and 2N methylamine tetrahydrofuran solution, and in the same manner as in Example 47, Step 2, 1-(4-chloro-2-cyanophenyl)-3-methylurea was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-])[CH3:3].[K+].[C:7]1([CH2:13][CH2:14][C:15]2[N:25]3[C:26]4C(C(=O)C[CH2:24]3)=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH2:1]=[C:2]1[C:5]2[C:26]3=[C:17]([N:16]=[C:15]([CH2:14][CH2:13][C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[N:25]3[CH2:24][CH2:3]1)[CH:18]=[CH:19][CH:20]=2
Reactant: O=C1CCn2c(CCc3ccccc3)nc3cccc1c32
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
Methyltriphenylphosphonium bromide (1.29 g) was suspended in anhydrous tetrahydrofuran (10 mL) and a solution of potassium t-butoxide (0.45 g) in tetrahydrofuran (10 mL) was added dropwise at room temperature, followed by stirring for 1 hr at room temperature. Subsequently, 0.50 g of 4,5-dihydro-2-(2-phenylethyl)-6H-imidazo[4,5,1-ij]quinolin-6-one obtained in Example 1 was dissolved in anhydrous tetrahydrofuran (10 mL) and the solution was added dropwise and the mixture was stirred at room temperature for 1 hr. To the reaction solution, a saturated aqueous solution of sodium hydrogencarbonate (50 mL) and ethyl acetate (50 mL) were added and then two layers were separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: dichloromethane/ethyl acetate) to yield the titled compound as colorless crystals (0.41 g).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:46])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][O:21][CH2:22][C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=4[O:30][C@H:31]([CH2:33]C=C)[CH3:32])[CH:19]=[C:15]3[N:14]=[C:13]([CH3:36])[C:12]=2[C@H:37]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[C:38]([OH:40])=[O:39])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]>ClCCCl.C1(C)C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru](Cl)(Cl)=CC1C=CC=CC=1OC(C)C.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.[Cu]I>[C:42]([O:41][C@@H:37]([C:12]1[C:13]([CH3:36])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:46])([O:4][CH2:1][CH:2]=[CH:3][CH2:32][C@H:31]([CH3:33])[O:30][C:24]2[C:23]([CH2:22][O:21][CH2:20]3)=[CH:28][C:27]([F:29])=[CH:26][CH:25]=2)[CH2:6][CH2:7]1)[C:38]([OH:40])=[O:39])([CH3:43])([CH3:44])[CH3:45]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(COCc4cc(F)ccc4O[C@@H](C)CC=C)nn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [Cu]I
Agent: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OC/C=C\C[C@H](C)Oc1ccc(F)cc1COC3
Solvent: ClCCCl
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1ccc(F)cc1COC3
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((5-fluoro-2-((S)-pent-4-en-2-yloxy)benzyl)oxy)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (20 mg, 0.031 mmol) in DCE (75 mL) were added (1,3-dimesitylimidazolidin-2-ylidene)(2-isopropoxybenzylidene)ruthenium(VI) chloride/Hoveyda-Grubbs II (4.90 mg, 7.83 μmol) and copper(I) iodide (5.96 mg, 0.031 mmol) and the mixture was stirred at 90° C. After 3 h, the reaction was concentrated. The crude material was purified via preparative HPLC to afford (2S)-2-(tert-butoxy)-2-[(20S,22Z)-15-fluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17,22-octaen-3-yl]acetic acid (9.8 mg, 0.016 mmol, 50.2% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.19-6.92 (m, 3H), 6.57-6.38 (m, 1H), 6.11-5.87 (m, 1H), 5.81-5.64 (m, 1H), 5.59-5.46 (m, 1H), 4.94-4.47 (m, 4H), 4.45-4.31 (m, 1H), 4.01-3.78 (m, 1H), 3.74-3.47 (m, 1H), 2.51 (br. s., 13H), 1.71-1.49 (m, 1H), 1.33-1.06 (m, 14H). LCMS (M+H) calcd for C33H44FN4O6: 611.32. found: 611.5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[CH:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:28]([CH2:31][CH3:32])([O-])=[O:29].C1(N=C=O)C=CC=CC=1.[ClH:42]>C(N(CC)CC)C.C(OCC)(=O)C.ClCCl>[ClH:42].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[O:29][N:28]=[C:31]([CH3:32])[CH:27]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Reactant: CC[N+](=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=C=Nc1ccccc1
Solvent: ClCCl
Product: Cc1cc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)on1
Yield: 11 %

Procedure:
A stirred mixture of (4-benzyloxy-phenyl)-(6-ethynylquinazolin-4-yl)-amine (0.20 g, 0.57 mmol), nitroethane (0.20 g, 2.7 mmol), phenylisocyanate (0.15 ml , 0.164 g, 1.38 mmol), and triethylamine (3 drops) in a mixture of ethyl acetate (10 ml) and dichloromethane (5 ml) was heated at reflux for 18 hours. After cooling the mixture was filtered to remove solid, and the concentrated filtrate was purified by silica gel chromatography, eluting with 50% ethyl acetate/i-hexane. After concentration of the appropriate fractions, the material obtained was treated with methanolic HCl, the solvent was removed in vacuo and the residue was triturated with ether to give the title compound as a yellow solid (0.027 g, 0.061 mmol, 11%); δH [2H6]DMSO 12.0 (1H, s), 9.55 (1H, s), 8.91 (1H, s), 8.48 (1H, d), 8.03 (1H, d), 7.68 (2H, d), 7.32-7.55 (5H, m), 7.22 (1H, s), 7.15 (2H, d), 5.18 (2H, s), 2.35 (3H, s); m/z (M+1+) 409.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(Cl)Cl>O>[Cl:15][C:10]1[CH:9]=[C:8]([C:7]2[C:2]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:3][CH:4]=[CH:5][N:6]=2)[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: Clc1ccc(-c2nccnc2Cl)cc1Cl
Reactant: C1CNCCN1
Solvent: O
Solvent: ClCCl
Product: Clc1ccc(-c2nccnc2N2CCNCC2)cc1Cl
Temperature: 25 °C

Procedure:
Combine 2-chloro-3-(3,4-dichloro-phenyl)-pyrazine (0.124 g, 0.477 mmol) and piperazine (1.40 gm; 16.3 mmol) and heat the mixture for 2 hr. at 120° C. Cool to room temperature, and add DCM (50 mL) and water (50 mL). Separate the layers and extract the aqueous layer with DCM (2×25 mL). Combine the organic layers, wash with brine, dry (MgSO4) and concentrate. Purify via chromatography on silica gel eluting 0-15% methanol in DCM to give the title preparation (0.118 gm, 80%). MS (ES+) m/z: 310 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][C:10]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[S:11])=[CH:4][CH:3]=1.[O-]CC.[Na+].O>CN1CCCC1=O>[Br:1][C:2]1[N:7]=[C:6]2[S:11][C:10]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:9][C:5]2=[CH:4][CH:3]=1
Reactant: O=C(NC(=S)Nc1ccc(Br)nc1Cl)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(Nc1nc2ccc(Br)nc2s1)c1ccccc1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A solution of N-(6-bromo-2-chloropyridin-3-ylcarbamothioyl)benzamide (1.5 g, 4.0 mmol) and sodium ethoxide (0.54 g, 8.0 mmol) in 1-methyl-2-pyrrolidinone (10 mL) was heated to 120° C. for 8 hours. After cooling the reaction mixture to room temperature the mixture was poured into water. The resulting solid was collected by filtration, then washed sequentially with water and diethyl ether. The filter cake was dried to give N-(5-bromothiazolo[5,4-b]pyridin-2-yl)benzamide (1.02 g, 76%). 1H NMR (400 MHz, d6-DMSO): 13.2 (br s, 1H), 8.16-8.10 (m, 3H), 7.72 (d, 1H), 7.70 (t, 1H), 7.59 (t, 2H). MS (EI) for C13H8BrN3OS: 336 (MH+).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[CH:3][C:2]=1[C:10]([OH:12])=[O:11]>CO.[Rh]>[N:1]1[N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]2=[CH:3][C:2]=1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)c1cc2ccccn2n1
Agent: [Rh]
Solvent: CO
Product: O=C(O)c1cc2n(n1)CCCC2

Procedure:
A solution of pyrazolo[1,5-a]pyridine-2-carboxylic acid (1 g, 6.17 mmol) in methanol (100 mL) was hydrogenated at 3½ bar over 5% rhodium on carbon (100 mg) overnight. The mixture was filtered through Celite and the pad was washed with methanol. The filtrates were evaporated to give the sub-title compound as a cream powder. Yield: 0.953 g
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH:21]1[C:29]2[CH2:28][CH2:27][CH2:26][C:25](=[O:30])[C:24]=2[CH:23]=[CH:22]1.[O-]CC.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[O:19]1[C:20]2[C:12]([C:2]([CH3:1])([CH3:11])[CH2:3][C:4]([OH:5])([C:7]([F:8])([F:10])[F:9])[CH2:6][N:21]3[C:29]4[CH2:28][CH2:27][CH2:26][C:25](=[O:30])[C:24]=4[CH:23]=[CH:22]3)=[CH:13][CH:14]=[CH:15][C:16]=2[CH2:17][CH2:18]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cccc2c1OCC2
Reactant: O=C1CCCc2[nH]ccc21
Agent: CC[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CC(O)(Cn1ccc2c1CCCC2=O)C(F)(F)F)c1cccc2c1OCC2
Temperature: 85 °C
Yield: 66 %

Procedure:
To a suspension of 7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-2,3-dihydrobenzofuran (59.2 mg, 0.21 mmol) and 1,5,6,7-tetrahydroindol-4-one (56.0 mg, 0.41 mmol) in 0.4 mL of anhydrous ethanol was added 0.077 mL of sodium ethoxide solution (21 wt % in ethanol). The reaction mixture was then heated at 85° C. for 16 hours. The resulting mixture was poured into half-saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with 35% ethyl acetate-hexanes) to give 58.4 mg (66% yield) of the title compound as a white solid, m.p. 145° C.-146° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][N:10]([CH2:15][C:16]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:25])[CH:17]=1)[C:11](=[O:14])[CH:12]=[CH2:13].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:13]=[CH:12]/[C:11]([N:10]([CH3:9])[CH2:15][C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH3:25])[CH:17]=2)=[O:14])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cn1
Reactant: C=CC(=O)N(C)Cc1cn(C)c2ncccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN(Cc1cn(C)c2ncccc12)C(=O)/C=C/c1cnc(N)nc1
Temperature: 25 °C
Yield: 20 %

Procedure:
A solution of 2-amino-5-bromopyrimidine (0.27 g, 1.55 mmole), N-methyl-N-(1-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)acrylamide (0.5 g, 2.33 mmole), Pd(OAc)2 (0.037 g, 0.163 mmole), P(o-tolyl)3 (0.085 g, 0.28 mmole), and (i-Pr)2NEt (0.42 mL, 2.33 mmole) in propionitrile (20 mL) was degassed then heated to reflux. After 18 hr the mixture was cooled to RT and concentrated. Flash chromatography on silica gel (10% MeOH/CH2Cl2) gave the title compound (0.100 g, 18%): MS (ES) m/e 363 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][NH:7]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:10][CH2:9][CH2:8][N:7]1[S:17]([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: c1csc(C2CCCN2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2cccs2)cc1

Procedure:
The title compound, white solid, m.p. 108° C. and MS: m/e=308.2 (M+H+) was prepared in accordance with the general method of example 1e from (RS)-2-thien-2-yl-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH2:25].CCN(CC)CC.Cl[C:34](=[O:39])[C:35]([O:37][CH3:38])=[O:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[CH:9]/[CH:10]([C:15]2[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[C:17]([Cl:23])[CH:16]=2)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:24][NH:25][C:34](=[O:39])[C:35]([O:37][CH3:38])=[O:36]
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Reactant: COC(=O)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a stirred solution of (E)-(2-chloro-4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)phenyl)methanamine (0.2 g, 0.5 mmol) in CH2Cl2 (5 mL) at 0° C. were added Et3N (0.141 mL, 1 mmol) and methyl 2-chloro-2-oxoacetate (0.09 g, 0.75 mmol), and the reaction mixture was stirred for 1 h at 0° C. The reaction mixture was diluted with CH2Cl2. The organic layer was washed with H2O and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 100-200 mesh; 20% EtOAc in hexane) afforded the title compound as a solid (0.12 g, 50%): 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 1H). 7.43 (m, 3H), 7.38 (m, 1H), 7.23 (s, 1H), 6.55 (d, J=16.0 Hz, 1H), 6.36 (dd, J=16.0, 8.0 Hz, 1H), 4.60 (d, J=4.4 Hz, 2H), 4.18 (m, 1H), 3.85 (s, 3H); ESIMS m/z 512.22 ([M−H]−); IR (thin film) 1740, 1701, 1114, 808 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[CH:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[CH:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: C#Cc1ccc(Cl)cc1-c1ccn(C(C)C(=O)O)c(=O)c1
Product: C#Cc1ccc(Cl)cc1-c1ccn(C(C)C(=O)Nc2ccc(C(=O)OC)cc2)c(=O)c1

Procedure:
50 mg (purity 82%, 0.32 mmol) of 2-[4-(5-chloro-2-ethynylphenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.2 eq. of methyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 15 mg (25% of theory)
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=5)[N:27]([CH3:35])[N:26]=4)[N:23]=3)[N:18]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:17]=2)=[O:15])[CH2:9]1)C1C=CC=CC=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.ClC(OC(Cl)C)=O>ClCCCl>[NH:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[C:22]([C:25]4[C:33]5[C:28](=[CH:29][C:30]([F:34])=[CH:31][CH:32]=5)[N:27]([CH3:35])[N:26]=4)[N:23]=3)[N:18]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[CH:17]=2)=[O:15])[CH2:9]1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCN(Cc4ccccc4)C2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCCl
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)N[C@@H]2CCNC2)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Temperature: 25 °C

Procedure:
To a 100 ml round bottom flask containing 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-benzyl-pyrrolidin-3-yl)-amide (530 mg, 0.88 mmol) and proton sponge (132 mg, 0.62 mmol) was added 1,2 dichloroethane (20 ml). The clear solution was stirred under nitrogen and cooled in an ice bath for 10 min. To this was added 1-chloroethyl chloroformate (0.19 ml, 1.77 mmol). The reaction was stirred in the ice bath for 5 min, the bath removed and the reaction warmed to room temperature for 20 min. The reaction was placed in an oil bath and heated at 85° C. for 4 h then allowed to cool to room temperature overnight and concentrated. The residue was suspended in methanol (20 ml) and heated at reflux for 3 h then removed from the heat and allowed to cool to room temperature. Some product precipitated during cooling and was filtered off and washed with methanol. The remaining product was recovered from the mother liquor. The liquid was concentrated, suspended in ethyl acetate and washed with aqueous sodium bicarbonate. The aqueous solution with solids was extracted four times with dichloromethane. The organic layers were combined and washed with brine (100 ml), dried over magnesium sulfate, filtered, concentrated, and dried from a mixture of ethyl acetate and hexanes. The crude was suspended in boiling ethyl acetate (20 ml), cooled, filtered and washed with ethyl acetate and hexanes to afford 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (R)-pyrrolidin-3-ylamide as a white solid. This material was combined with the product that precipitated from the reaction and was used without further purification. LC-MS: (M+H)+=510.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[S:3]Cl.[F:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10].[NH2:14][CH2:15][CH:16]([Cl:24])[CH2:17]S(C(F)(F)F)=O.FC(F)(F)C(O)=[O:28].NCC(Cl)CS(Cl)(C(F)F)=O.FC(F)(F)C(O)=O.NCC(Cl)CS(Cl)(Cl)(CF)=O>>[F:7][C:8]([F:13])([F:12])[C:9]([OH:11])=[O:10].[NH2:14][CH2:15][CH:16]([Cl:24])[CH2:17][S:3]([C:2]([Cl:6])([Cl:5])[Cl:1])=[O:28]
Reactant: ClSC(Cl)(Cl)Cl
Reactant: NCC(Cl)CS(=O)C(F)(F)F
Agent: NCC(Cl)CS(=O)(Cl)(Cl)CF
Agent: NCC(Cl)C[SH](=O)(Cl)C(F)F
Solvent: O=C(O)C(F)(F)F
Product: NCC(Cl)CS(=O)C(Cl)(Cl)Cl

Procedure:
Employing the procedure substantially as described in Example 4, but substituting for the trichloromethylsulfenyl chloride used in Step A thereof, an equimolecular amount of the sulfenyl chlorides of structure RSCl wherein R is F3C--, ClF2C--, and FCl2C--, there are produced respectively: 1-amino-2-chloro-3-(trifluoromethylsulfinyl)propane trifluoroacetic acid salt; 1-amino-2-chloro-3-(chlorodifluoromethylsulfinyl)propane trifluoroacetic acid salt; and 1-amino-2-chloro-3-(dichlorfluoromethylsulfinyl)propane trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C(N(C(C)C)CC)(C)C.[N+:20]([C:23]1[C:24]([C:28](Cl)=[O:29])=[N:25][NH:26][CH:27]=1)([O-:22])=[O:21]>ClCCl>[NH2:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[NH:10][C:28]([C:24]1[C:23]([N+:20]([O-:22])=[O:21])=[CH:27][NH:26][N:25]=1)=[O:29]
Reactant: O=C(Cl)c1n[nH]cc1[N+](=O)[O-]
Reactant: Cc1cc(N)c(N)cc1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N)c(NC(=O)c2n[nH]cc2[N+](=O)[O-])cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
Method A A stirred solution of 4,5-dimethylphenylenediamine (4.32 g) and diisopropylethylamine (30 ml) in dichloromethane (200 ml) was treated with 4-nitropyrazole-3-carboxylic chloride (5 g) portionwise at 0° C. The reaction mixture was warmed to ambient temperature and stirred for 30 minutes. The solvent was removed in vacuo and the oily residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated. The residual oil was re-crystallised from ethyl acetate and methanol (10%) to give 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethylphenyl)amide (6.58 g) as an orange solid. LC-MS (METHOD B): RT=2.36 minutes, 276.09 (M+H)+.
Reaction SMILES: I[C:2]1[C:11]([NH:12][C:13](=[O:15])[CH3:14])=[C:10]([Cl:16])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[OH:17].[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20]>CCN(CC)CC.O1CCOCC1.[Cu]I>[CH3:18][Si:19]([C:22]#[C:23][C:2]1[C:11]([NH:12][C:13](=[O:15])[CH3:14])=[C:10]([Cl:16])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[OH:17])([CH3:21])[CH3:20]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)c(I)c1O
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)c(NC(C)=O)c(C#C[Si](C)(C)C)c1O
Temperature: 40 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 3-iodo-4-acetamido-5-chlorosalicylate (2 g) in distilled Et3N (60 ml) and dioxane (40 ml), trimethylsilylacetylene (1 ml), CuI (23 mg), and PdCl2 (PPh3)2 (152 mg) were added. The reaction mixture was stirred at 40° C. for 1.5 hours, after which time the solvents were removed in vacuo. A sample of the residue was purified by column chromatography for analytical purposes eluting with diethyl ether/hexane mixtures to yield the intermediate methyl 3-trimethylsilylethynyl-4-acetamido-5-chloro-salic ylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([Br:10])=[CH:8][N:7]=[C:6]([NH2:11])[CH:5]=1.C([O-])(O)=O.[Na+].Cl[CH2:19][CH:20]=O>CCO>[CH3:1][O:2][C:3]([C:4]1[C:9]([Br:10])=[CH:8][N:7]2[CH:19]=[CH:20][N:11]=[C:6]2[CH:5]=1)=[O:12]
Reactant: O=CCCl
Reactant: COC(=O)c1cc(N)ncc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1cc2nccn2cc1Br
Temperature: 25 °C
Yield: 91.7 %

Procedure:
A mixture of 2-amino-5-bromo-isonicotinic acid methyl ester (500 mg, 2.16 mmol), NaHCO3 (309 mg, 3.68 mmol) and chloracetaldehyde (1.16 mL, 9.8 mmol) in EtOH (15 mL) was vigorously stirred and refluxed for 14 h. The reaction mixture was cooled to RT, concentrated under vacuum and the remaining residue was suspended in AcOEt (100 mL). The organic fraction was washed with water (2×50 mL), then dried over Na2SO4, filtered, and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, [hexane/DCM 1:1]/TBME 95:5-100% TBME) to yield the title compound (505 mg, 1.98 mmol, 91%). MS: 255 [M+1]+; HPLC: AtRet=0.58 TLC: RF 0.16 (hexane/DCM/TBME 1:1:2).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10](O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:18])=O>CN(C)C=O>[N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([Cl:18])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Cl

Procedure:
A mixture of 2-(4-nitrophenoxy)-propionic acid (40 g), thionyl chloride (80 ml) and dimethyl formamide (0.5 ml) was refluxed for 5 hours. Excess thionyl chloride was distilled off under reduced pressure. Dry toluene (20 ml) was added to the reaction mixture and solvent was removed under reduced pressure to obtain 2-(4-nitrophenoxy)-propionyl chloride (40 g) as light brown liquid.