Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:7]#[CH:8])[CH2:6][CH2:5][NH:4][CH2:3]1.[C:9]([C:12]1[CH:13]=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:29])[NH:20][C:21]3[C:26]\2=[C:25](I)[C:24]([F:28])=[CH:23][CH:22]=3)[NH:15][CH:16]=1)(=[O:11])[CH3:10]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[C:9]([C:12]1[CH:13]=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:29])[NH:20][C:21]3[C:26]\2=[C:25]([C:8]#[C:7][C:2]2([OH:1])[CH2:6][CH2:5][NH:4][CH2:3]2)[C:24]([F:28])=[CH:23][CH:22]=3)[NH:15][CH:16]=1)(=[O:11])[CH3:10]
Reactant: C#CC1(O)CCNC1
Reactant: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(C#CC4(O)CCNC4)c32)c1

Procedure:
Using Method C above, rac-3-hydroxy-3-ethynyl-pyrrolidine (35.1 mg, 0.32 mmol) (Example 97C) was coupled with (Z)-3-[(4-acetyl-1H-pyrrol-2-yl)methylene]-1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (50 mg, 0.13 mmol) (see Example 90B) using (Ph3P)4Pd (15 mg) and CuI (3.0 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 85° C. for 5 h. (Yield 10 mg, 21%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([OH:24])[CH:17]=2)[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[CH2:34][CH2:35]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:35][CH2:34][C:28]3[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=3[F:26])[CH:17]=2)[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:13]1)=[O:4]
Reactant: OCCc1cc(F)ccc1F
Reactant: COC(=O)C1(NC(=O)c2ccc(OC)c(O)c2)Cc2ccccc2C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C1(NC(=O)c2ccc(OC)c(OCCc3cc(F)ccc3F)c2)Cc2ccccc2C1
Reaction time: 8 h
Yield: 80.2 %

Procedure:
300.1 mg (0.88 mmol) of 2-(3-hydroxy-4-methoxy-benzoylamino)-indane-2-carboxylic acid methyl ester, 208.6 mg (1.32 mmol) of 2-(2,5-difluoro-phenyl)-ethanol and 346 mg (1.32 mmol) of triphenylphosphine were dissolved in 10 ml of THF. The mixture was cooled in an ice bath, and 355.5 mg (1.76 mmol) of DIAD were added. After stirring overnight, the mixture was evaporated to dryness and the residue was purified by preparative RP HPLC (water/ACN gradient). 340 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C([O:17][C:18](=O)[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[N:24]=1)CCC>C1COCC1>[CH3:4][O:3][P:2]([CH2:1][C:18](=[O:17])[CH2:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=2)[N:24]=1)(=[O:7])[O:5][CH3:6]
Reactant: COP(C)(=O)OC
Reactant: CCCCOC(=O)CCCCc1cccc(NCc2ccc(OC)cc2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CNc2cccc(CCCCC(=O)CP(=O)(OC)OC)n2)cc1
Reaction time: 0.75 h
Yield: 89 %

Procedure:
A solution of dimethyl methylphosphonate (2.48 g, 20 mmol) in anhydrous THF (30 mL) was cooled to −78° and treated dropwise with 2.5 M n-BuLi (8.0 mL). After stirring at −78° for 45 min, a solution of ester 6-6 (1.85 g, 5.0 mmol) in THF (10 mL) was added dropwise and the resulting solution stirred for 30 min at −78°, quenched with sat. NH4Cl (25 mL), then extracted with ethyl acetate (3×75 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford a yellow oil. Chromatography on silica gel (5% MeOH/CH2Cl2) afforded 6-7 as a yellow oil in 89% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[CH:11]=[CH:10][NH:9][C:5]2=[N+:6]([O-])[CH:7]=1.C[Si](C)(C)N[Si](C)(C)C.[Cl:21]C(OC)=O.[OH-].[Na+].Cl>C1COCC1>[Cl:21][C:7]1[N:6]=[C:5]2[NH:9][CH:10]=[CH:11][C:4]2=[CH:3][C:2]=1[F:1]
Reactant: COC(=O)Cl
Reactant: [O-][n+]1cc(F)cc2cc[nH]c21
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1cc2cc[nH]c2nc1Cl
Temperature: 5 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a stirred solution of 5-fluoro-1H-pyrrolo[2,3-b]pyridine 7-oxide (4.317 g, 28.38 mmol) in THF (150 mL) is added hexamethyldisilazane (6.54 mL, 31.22 mmol). The reaction mixture is cooled to 5° C. and methyl chloroformate (5.49 mL, 70.94 mmol) added dropwise. After stirring at 5° C. for 3 h, 2M sodium hydroxide (80 mL, 0.16 mol) is added dropwise, keeping temperature below 10° C. After 2 h, 2M hydrochloric acid solution is added until the mixture is at pH7. The reaction is poured onto brine (ca. 500 mL) and product extracted with CHCl3 (ca. 4×300 mL). The combined organic extracts are dried over magnesium sulphate, filtered, and concentrated in vacuo to give the title compound as a light brown solid (4.15 g, 24.33 mmol). MS (m/z): 171/173 (M+1). The following compounds are prepared essentially by the method of Preparation 31.
Reaction SMILES: [C:1]1([C:7]([OH:9])=O)([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.O=S(Cl)Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1>C1COCC1.CC(=O)OCC>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:7]([C:1]2([C:4]([OH:6])=[O:5])[CH2:2][CH2:3]2)=[O:9])=[CH:25][CH:24]=1
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: COc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)C2(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound was prepared according to literature procedure. To a solution of cyclopropane-1,1-dicarboxylic acid (390.0 mg, 3.0 mmol) in dry THF (20 mL) in ice bath was added triethylamine (TEA; 0.40 mL, 3.1 mL) dropwise. The solution was stirred for 15 min and SOCl2 (0.20 mL, 2.9 mmol) was added to it. After 15 min reaction at such temperature, a solution of p-anisidine (387.0 mg, 3.1 mmol) in THF (5 mL) was added slowly. Reaction mixture was allowed to warm to rt and stirred for additional 18 h. After that, reaction mixture was diluted by EA; unconsumed diacid was quenched by 10% NaOH (0.5 mL). Crude product was extracted by EA and washed by water and brine. Organic portions were concentrated in vacuo. Solid precipitated by addition of n-heptane was collected by filter. Prolonged drying in vacuo gave the title compound. YD: 82%; mp 133-136° C. 1H-NMR (400 MHz, DMSO-d6) δ: 1.40 (s, 4H, 2×CH2), 3.71 (s, 3H, OCH3), 6.85 (d, J=8.8 Hz, 2H, ArH), 7.49 (d, J=8.8 Hz, 2H, ArH), 10.42 (s, 1H, NH). Anal. (C13H13NO4.0.5; H2O) C, H, N. MS (ESI) 233.8 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=2)[CH:6]=1.P(Br)(Br)[Br:17]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Br:17][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][N:5]2[CH:6]=[C:2]([Cl:1])[CH:3]=[N:4]2)=[CH:9][CH:10]=1
Reactant: OCc1ccc(Cn2cc(Cl)cn2)cc1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cnn(Cc2ccc(CBr)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A solution of (4-((4-chloro-1H-pyrazol-1-yl)methyl)phenyl)methanol (0.375 g, 1.68 mmol) in methylene chloride (7 mL) at 0° C. under a nitrogen atmosphere was treated with PBr3 (0.456 g, 1.68 mmol) and the mixture was warmed to rt and stirred for 1 h. After this time, the mixture was diluted with saturated aqueous sodium bicarbonate and ice and then extracted with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/dichloromethane) to afford the title compound (0.342 g, 91%) as a white solid. MW=285.57. 1H NMR (CDCl3, 500 MHz) δ 7.46 (s, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.35 (s, 1H), 7.19 (d, J=8.1 Hz, 2H), 5.24 (s, 2H), 4.47 (s, 2H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([SH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=3)=[CH:4][C:3]=2[N+:21]([O-:23])=[O:22])=[CH:27][CH:26]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of the product of Example 255A (2.00 g, 5.80 mmol), 4-hydroxythiophenol (0.732 g, 5.80 mmol) and potassium carbonate (1.604 g, 11.6 mmol) in N,N-dimethylformamide (40 mL) was heated to 80° C. for 2 hours. After cooling to room temperature the mixture was poured into ice water (100 mL). The solution was then extracted with ethyl acetate (3×150 mL), the combined extracts dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (2.52 g, 100%).
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]1.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.I[C:39]1[CH:49]=[CH:48][C:42]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:41][CH:40]=1>O1CCCC1.[Zn]>[CH2:46]([O:45][C:43]([C:42]1[CH:48]=[CH:49][C:39]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)=[CH:40][CH:41]=1)=[O:44])[CH3:47]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CCOC(=O)c1ccc(C2CN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 68 %

Procedure:
1,2-Dibromoethane (0.286 mL, 3.32 mmol) was added to a suspension of zinc powder (2.12 g, 32.4 mmol) in tetrahydrofuran (10 mL) under nitrogen atmosphere at room temperature. The liquid mixture was stirred at 65° C. for 10 minutes. The reaction liquid was allowed to stand to cool to room temperature, then chlorotrimethylsilane (0.400 mL, 3.13 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. A solution of tert-butyl 3-iodoazetidine-1-carboxylate described in Production Example 26-3 (5.91 g, 20.9 mmol) in tetrahydrofuran (10 mL) was added to the reaction liquid over 5 minutes, and the mixture was stirred at room temperature for 40 minutes (a solution A). A solution of iris(dibenzylideneacetone)dipalladium(0) (382 mg, 0.418 mmol) and tri-2-furylphosphine (402 mg, 1.73 mmol) in tetrahydrofuran (10 mL) was stirred under nitrogen atmosphere at room temperature for 15 minutes, and then the previously prepared solution A was added at room temperature. Subsequently, a solution of ethyl 4-iodobenzoate (6.92 g, 25.1 mmol) in tetrahydrofuran (18.5 mL) was added under nitrogen atmosphere at room temperature. The reaction liquid was stirred at 65° C. overnight. The reaction liquid was allowed to stand to cool to room temperature, then was filtered with celite, and the resultant was washed with ethyl acetate. The filtrate was washed serially with a saturated aqueous sodium bicarbonate solution and a saturated saline solution and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration and then the filtrate was concentrated under vacuum. The residue was dissolved in dichloromethane, then the resultant was purified with silica gel column chromatography (n-heptane:ethyl acetate=9:1-4:1) to obtain the title compound (4.35 g, 68%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N:11]1([CH2:17][CH2:18][O:19][C:20]2[CH:21]=[N:22][C:23]([C:26]3[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=3)[C:29](OC)=[O:30])=[N:24][CH:25]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[Cl-].[NH4+]>C1COCC1>[N:11]1([CH2:17][CH2:18][O:19][C:20]2[CH:25]=[N:24][C:23]([C:26]3[CH:27]=[C:28]([CH2:29][OH:30])[CH:33]=[CH:34][CH:35]=3)=[N:22][CH:21]=2)[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: COC(=O)c1cccc(-c2ncc(OCCN3CCOCC3)cn2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cccc(-c2ncc(OCCN3CCOCC3)cn2)c1

Procedure:
138 ml of a 1 M solution of diisobutylaluminium hydride in THF are added dropwise with stirring to a solution, kept under nitrogen, of 9.5 g (27.5 mmol) of methyl 3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]benzoate in 180 ml of THF. After the mixture has been stirred at room temperature for 1 hour, 100 ml of a saturated aqueous ammonium chloride solution are added dropwise. The precipitate formed is filtered off with suction and washed a number of times with dichloromethane. The filtrate is dried over sodium sulfate and evaporated. The residue is recrystallised from a mixture of isopropanol/ether: {3-[5-(2-morpholin-4-ylethoxy)pyrimidin-2-yl]phenyl}-methanol as yellow crystals; m.p. 101-102°; ESI 316 (M+H); HPLC: Rt.=1.67 min (method A).
Reaction SMILES: [O:1]=[S:2]1(=[O:36])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:8]=[C:9]([C:25]2[C:30]([CH3:31])=[CH:29][N:28]=[C:27]([NH:32][C:33](=[O:35])[CH3:34])[CH:26]=2)[O:10][C:11]=1[C:12]1[N:16]=[CH:15][N:14](COCC[Si](C)(C)C)[N:13]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[O:36]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:8]=[C:9]([C:25]2[C:30]([CH3:31])=[CH:29][N:28]=[C:27]([NH:32][C:33](=[O:35])[CH3:34])[CH:26]=2)[O:10][C:11]=1[C:12]1[NH:16][CH:15]=[N:14][N:13]=1
Reactant: CC(=O)Nc1cc(-c2nc(N3CCCS3(=O)=O)c(-c3ncn(COCC[Si](C)(C)C)n3)o2)c(C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2nc(N3CCCS3(=O)=O)c(-c3nnc[nH]3)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
To a solution of N-{4-[4-(1,1-dioxidoisothiazolidin-2-yl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (from the previous step) in THF (10 mL) was added TBAF in THF (1M, 3.3 mL). The reaction mixture was allowed to stir at rt overnight. The mixture was concentrated to dryness and then diluted with EtOAc. The mixture was washed with water. The organic solution was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-{4-[4-(1,1-dioxidoisothiazolidin-2-yl)-5-(4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}acetamide (Compound I-50) (0.028 g, 12%). LCMS (FA): m/z=404.6 (M+H).
Reaction SMILES: [C:1]([CH:4]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)(O)=[O:2].C(=O)(O)[O-].[Na+]>C1COCC1>[C:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][CH:4]([CH2:1][OH:2])[CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)=[CH:23][CH:22]=1)#[N:25]
Reactant: COC(=O)c1ccc(CC(CCc2ccc(C#N)cc2)C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC(CO)CCc2ccc(C#N)cc2)cc1
Reaction time: 3 h
Yield: 83 %

Procedure:
20.6 ml (20.6 mmol) of a 1 M borane-THF complex solution are added dropwise to a solution of 4.2 g (12.98 mmol) of methyl 4-[2-carboxy-4-(4-cyanophenyl)butyl]benzoate in 40 ml of THF at −15° C., and the reaction mixture is stirred at this temperature for 3 hours. Then a further 10 ml (10 mmol) of 1 M borane-THF complex solution are added dropwise, and the mixture is stirred at −15° C. for a further 30 min. After reaction is complete, saturated sodium bicarbonate solution is added to the reaction mixture, and the solvent is evaporated to dryness. The residue is taken up in dichloromethane, dried over sodium sulphate and again freed of solvent. The resulting crude product is purified by flash chromatography on 150 g of silica gel (mobile phase: ethyl acetate/petroleum ether 1:1). 3.1 g (90% purity, 83% yield) of a colourless solid are obtained.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1>>[CH2:2]([C:1]1[NH:15][C:14]2[C:9]([N:8]=1)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:3][CH2:4][CH3:5]
Reactant: Nc1cccnc1N
Reactant: CCCCC(=O)O
Product: CCCCc1nc2ncccc2[nH]1
Temperature: 100 °C
Reaction time: 5 h
Yield: 94.8 %

Procedure:
A mixture of valeric acid (5.50 mL, 50.4 mmol), 2,3-diaminopyridine (5.0 g, 45.8 mmol), and polyphosphoric acid (50 g) was heated to 100° C. with stirring for 5 hours. Basification (NH4OH), extraction (EtOAc, 4×20 mL), drying (K2CO3), and concentration gave 7.61 g (95%) of the title compound as an amorphous tan solid which was judged pure by 1H NMR and tlc (mp ca 80° C. without recrystallization).
Reaction SMILES: C[O:2][C:3](=[O:33])[C@H:4]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:5]C(CC1N(CC2C=CC=CC=2Cl)C(SCCC)=NC=1)=O.[OH-].[K+]>C(O)C.O>[NH2:5][C@H:4]([C:3]([OH:33])=[O:2])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCSc1ncc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The methyl ester from Example 9 (i) (0.58 g, 1.2 mmol) was dissolved in ethanol (10 mL) and a solution of potassium hydroxide (0.223 g, 4 mmol) in water (4 mL) was added. This solution was stirred at room temperature for 1.5 hours. The ethanol was evaporated, the residue was diluted with water (10 mL) and the basic solution was extracted with ether. The aqueous layer was acidified to pH 3.5 with 10% hydrochloric acid solution, and the cooled suspension was then filtered, washed with water and dried in vacuum to provide 0.46 g (82%) of N-[1-(2-chlorophenyl)methyl-2-propylthio-1H-imidazol-5-yl}methylcarbonyl]-L-phenylalanine; mp 120°-121° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][N:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([Cl:32])[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=1>CCOC(C)=O>[Cl:32][C:26]1[C:27](=[O:31])[N:28]([CH3:30])[CH:29]=[C:24]([NH:23][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]2[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:11][N:12]([CH:14]3[CH2:16][CH2:15]3)[CH:13]=2)[CH:25]=1
Reactant: CCOC(=O)c1nn(C2CC2)cc1C(O)c1ccc(Cl)cc1
Reactant: Cn1cc(N)cc(Cl)c1=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1nn(C2CC2)cc1C(Nc1cc(Cl)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-1H-pyrazole-3-carboxylate (Step 37.3) and 5-amino-3-chloro-1-methylpyridin-2(1H)-one (Step 5.2). tR: 4.54 min (HPLC 1); tR: 1.03 min (LC-MS 2); ESI-MS: 461 [M+H]+ (LC-MS 2); Rf=0.18 (EtOAc).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][CH2:6]2.S(Cl)(Cl)=O.[F:27][C:28]([F:40])([F:39])[C:29]1[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][NH:31][N:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C=O)C.[NH4+].[Cl-].O>[CH2:15]([O:14][C:13]([NH:12][CH:8]1[C:9]2[C:5](=[CH:4][C:3]([CH2:2][N:31]3[CH:32]=[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:29]([C:28]([F:27])([F:39])[F:40])=[N:30]3)=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(NC1CCc2cc(CO)ccc21)OCc1ccccc1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccc3c(c2)CCC3NC(=O)OCc2ccccc2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of benzyl 5-(hydroxymethyl)-2,3-dihydro-1H-inden-1-ylcarbamate (6.73 mmol, 2.0 g) in DCM (15 ml) was added thionyl chloride (13.45 mmol, 0.0.98 mL) and the whole was stirred for 2 h at room temperature after which time LCMS suggested 100% conversion to product. The reaction mixture was concentrated under reduced pressure and the residue re-dissolved in DCM. This was repeated a further 4 times to give a light yellow solid. This was dissolved in DMF (25 mL) and ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1.29 g, 6.17 mmol) was added followed by potassium carbonate (18.52 mmol, 2.56 g). The resulting suspension was heated to 60° C. and this temperature was maintained for 2 h after the reaction mixture was diluted with sat NH4Cl followed by water and the organics extracted with EtOAc (2×100 mL), dried (1PS paper) and concentrated under reduced pressure. The residue was then purified by flash chromatography (40% EtOAc/heptane) to give a white solid (2.54, 5.21 mmol, 84%). 1H NMR (400 MHz, CDCl3) δ 1.34 (t, 3H) 1.85 (m, 1H) 2.12 (m, 1H) 2.85 (m, 1H) 2.95 (m, 1H) 4.28 (q, 2H) 4.95 (d, 1H), 5.16 (s, 1H) 5.25 (m, 1H) 5.29 (s, 2H) 7.13 (brs, 2H) 7.35 (m, 6H), 7.87 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([S:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+:20].[O:21]1CCOCC1>O>[NH2:3][C:4]1[C:5]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:21])=[O:1].[Na+:20]
Reactant: C1COCCO1
Reactant: O=C1Cc2cccc(Sc3ccccc3Cl)c2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)[O-])cccc1Sc1ccccc1Cl

Procedure:
A mixture of 2-oxo-7-(2-chlorophenylthio)indoline (5.0 g.), sodium hydroxide (1.5 g.), dioxane (15 ml.) and water (15 ml.) was refluxed for 14 hours with stirring. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from water twice and washed with diethyl ether to give crystals of the captioned compound (3.5 g.), mp 209° to 212° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:19]([O:22][CH2:23][C:24]1[C:25]([N:33]2[CH2:44][CH2:43][N:42]3[C:35](=[CH:36][C:37]4[CH2:38][C:39]([CH3:46])([CH3:45])[CH2:40][C:41]=43)[C:34]2=[O:47])=[N:26][CH:27]=[CH:28][C:29]=1B(O)O)(=[O:21])[CH3:20].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCCC1>[C:19]([O:22][CH2:23][C:24]1[C:25]([N:33]2[CH2:44][CH2:43][N:42]3[C:41]4[CH2:40][C:39]([CH3:46])([CH3:45])[CH2:38][C:37]=4[CH:36]=[C:35]3[C:34]2=[O:47])=[N:26][CH:27]=[CH:28][C:29]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][CH3:18])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:21])[CH3:20]
Reactant: CCc1nccc(Nc2cc(Br)cn(C)c2=O)n1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3COC(C)=O)cn(C)c2=O)n1
Temperature: 25 °C
Yield: 55.6 %

Procedure:
A 100-mL round-bottomed flask equipped with a reflux condenser was charged with 229b (277 mg, 0.90 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-2(6H)-yl)pyridin-4-yl)boronic acid 199e (358 mg, 0.90 mmol), Pd(dppf)Cl2 (74 mg, 0.090 mmol), K3PO4 (381 mg, 1.80 mmol), water (2 mL), and tetrahydrofuran (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 3 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 60:1 dichloromethane/methanol to afford 229c as white solid (291 mg, 50%). MS-ESI: [M+H]+ 582.4