Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[F:40][C:41]1[C:46]([F:47])=[CH:45][CH:44]=[C:43]([O:48][C@H:49]([CH2:51][CH:52]=[CH2:53])[CH3:50])[C:42]=1B1OC(=O)CN(C)CC(=O)O1.C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=C(F)C(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C(C)=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:1]([O:4][C:5]1([CH3:39])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:42]5[C:43]([O:48][C@H:49]([CH2:51][CH:52]=[CH2:53])[CH3:50])=[CH:44][CH:45]=[C:46]([F:47])[C:41]=5[F:40])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[C:14]([CH3:27])=[C:13]([CH3:28])[C:12]=2[C@H:29]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:30]([O:32][CH3:33])=[O:31])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@H](C)Oc1ccc(F)c(F)c1B1OC(=O)CN(C)CC(=O)O1
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(Br)c4)cn23)CC1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5cc(F)c(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)c(C)c3nc(-c4cccc(-c5c(O[C@@H](C)CC=C)ccc(F)c5F)c4)cn23)CC1
Yield: 45 %

Procedure:
Prepared from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate and (S)-2-(2,3-difluoro-6-(pent-4-en-2-yloxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione in 45% yield following the same procedure as (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′,5′-difluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7,8-dimethylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 716.7.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>ClCCl.C(OCC)(=O)C>[CH2:32]([O:31][C:29]([N:11]1[CH2:12][CH2:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:9][CH2:10]1)=[O:30])[CH3:33]
Reactant: CCOC(=O)Cl
Reactant: Clc1ccc(C2(c3ccc(Br)cc3)CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Reaction time: 3 h
Yield: 94 %

Procedure:
To a stirring suspension of 4-(4-Bromo-phenyl)-4-(4-chloro-phenyl)-piperidine* (0.28 g, 0.80 mmol) in dichloromethane (10 ml), were added triethylamine (0.45 ml, 3.2 mmol) and ethyl chloroformate (0.085 ml, 0.88 mmol). The reaction mixture was stirred for 3 hours, diluted with ethyl acetate and washed with 1N HCl, saturated sodium hydrogen carbonate and brine. The organic layer was separated, dried (MgSO4), filtered and concentrated to afford the title compound (0.29 g, 94% yield). LCMS: (PS-A2), Rt 4.02 [M÷H]+422, 424. *This starting material can be made by the method described in Example 14A
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(=O)(OC)[O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[CH3:14]>S(=O)(=O)(O)O>[F:13][C:10]1[C:11]([N+:1]([O-:4])=[O:2])=[CH:12][C:7]([OH:6])=[C:8]([CH3:14])[CH:9]=1
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Oc1ccc(F)cc1C
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c([N+](=O)[O-])cc1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
A mixture of concentrated nitric acid (6 ml) and concentrated sulphuric acid (6 ml) was added slowly to a solution of 4-fluoro-2-methylphenyl methyl carbonate (11.34 g, 62 mmol) in concentrated sulphuric acid (6 ml) such that the temperature of the reaction mixture was kept below 50° C. The mixture was stirred for 2 hours, then ice/water was added and the precipitated product collected by filtration. The crude product was purified by chromatography on silica eluting with methylene chloride/hexane progressing through increasingly polar mixtures to methanol/methylene chloride (1/19) to give 4fluoro-2-methyl-5-nitrophenol (2.5 g, 22%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[F:36][C:37]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:38]=1[CH2:39][NH2:40]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:36][C:37]1[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:38]=1[CH2:39][NH:40][C:28]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][C:18]=1[F:23])=[O:34]
Reactant: NCc1ccc(F)cc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(F)c3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NCc4ccc(F)cc4F)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-fluoroaniline (50 mg) was dissolved in chloroform (3 ml) and triethylamine (0.3 ml), and a solution of triphosgene (47 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, 2,4-difluorobenzylamine (28 μl) was added to the reaction solution, and the mixture was further stirred at room temperature overnight. The precipitated crystal was collected by filtration and was washed to give 20 mg (yield 26%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)=[CH:6][CH:5]=1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([N:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:19])[F:20])=[CH:5][CH:6]=1)[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1)=[O:25]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: O=C(O)c1csc(Nc2ccc(OC(F)(F)F)cc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(O)c1csc(N(C(=O)c2ccccc2Cl)c2ccc(OC(F)(F)F)cc2)n1
Temperature: 50 °C
Reaction time: 48 h
Yield: 71.9 %

Procedure:
A mixture of 2.0 g (6.6 mmol) 2-(4-(trifluoromethoxy)phenylamino)-thiazole-4-carboxylic acid, 2.87 g (16.4 mmol) 2-chlorobenzoyl chloride and 0.92 g (6.6 mmol) potassium carbonate in 50 mL THF was stirred at 50° C. for 48 h. After evaporation of the volatiles the residue was partitioned between water and ethyl acetate. Organic phases were pooled, dried with MgSO4 and the solvent was removed in vacuo. Crystallisation from n-heptane yielded 2.1 g (72%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.Cl.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH2:21]1>>[F:17][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([N:20]2[CH2:24][CH2:23][CH:22]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[CH2:21]2)=[O:16])=[CH:7][CH:8]=1
Reactant: c1cc(C2CCNC2)ccn1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Product: O=C(c1cnoc1-c1ccc(C(F)(F)F)cc1)N1CCC(c2ccncc2)C1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and 4-pyrrolidin-3-ylpyridine hydrochloride (11.1 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (11.6 mg). Calcd for C20H16F3N3O2: 387.1195, found 387.1193.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[C:8]([C:13]([OH:15])=O)=[N:9][CH:10]=[CH:11][CH:12]=2)[O:4][N:3]=1.[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]2[CH2:31][CH:30]3[CH:26]([CH2:27][NH:28][CH2:29]3)[CH2:25]2)[N:18]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[NH3:3].[CH3:16][C:17]1[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]2[CH2:31][CH:30]3[CH:26]([CH2:27][N:28]([C:13]([C:8]4[C:7]([C:5]5[O:4][N:3]=[C:2]([CH3:1])[N:6]=5)=[CH:12][CH:11]=[CH:10][N:9]=4)=[O:15])[CH2:29]3)[CH2:25]2)[N:18]=1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: Cc1noc(-c2cccnc2C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ncccc4-c4nc(C)no4)CC3C2)n1
Product: N
Temperature: 25 °C
Reaction time: 14 h
Yield: 80.6 %
Yield: 8 %

Procedure:
To a solution of the product of Step C (60 mg, 0.30 mmol) in DCM (3 mL) was added Intermediate 23 (65 mg, 0.30 mmol) followed by EDCl (85 mg, 0.44 mmol), HOBt (60 mg, 0.44 mmol) and TEA (0.08 mL, 0.59 mmol). The mixture was stirred at room temperature for 14 h and then concentrated in vacuo. Chromatography (DCM to 8% 2 M NH3 in MeOH/DCM) afforded the desired compound as a colorless foam (49 mg, 41%). MS (ESI) mass calculated for C21H23N7O2, 405.19; m/z found, 406.2. 1H NMR (500 MHz, CDCl3): 8.82-8.75 (m, 1H), 8.42-8.36 (m, 1H), 7.52-7.47 (m, 1H), 6.31-6.26 (m, 1H), 4.02-3.90 (m, 2H), 3.86-3.79 (m, 1H), 3.76-3.69 (m, 2H), 3.66-3.54 (m, 2H), 3.24-3.18 (m, 1H), 3.14-2.99 (m, 2H), 2.48-2.42 (m, 3H), 2.33-2.24 (m, 6H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6]([CH:8]=[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:7])#[N:2].[CH2:22]([Mg]Br)[CH3:23].C(OCC)(=O)C.[Cl-].[NH4+]>O1CCCC1.CCOCC>[C:1]([CH2:3][CH2:4][O:5][C:6]([CH2:8][C:9]1([CH2:22][CH3:23])[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]1)=[O:7])#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=CC(=O)OCCC#N)CC1
Reactant: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCC1(CC(=O)OCCC#N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2.00 g (6.79 mmol) of tert-butyl 4-(cyanoethoxycarbonylmethylene)piperidine-1-carboxylate (WO 2006/001 752) in 33 mL of tetrahydrofuran are added dropwise, at −5° C. under argon, 4.53 mL (13.59 mmol) of a 3M solution of ethylmagnesium bromide in ether. The reaction medium is then stirred at room temperature for 12 hours. Ethyl acetate is added and the medium is cooled in a bath of ice/water, followed by addition of saturated ammonium chloride solution. The aqueous phase is separated out and extracted three times with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the filtrate is concentrated under reduced pressure. The residue is chromatographed on silica gel, eluting with a 95/5 mixture of cyclohexane and ethyl acetate to give 1.63 g of pure product in the form of a white powder.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[C:8]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[CH:9][CH:10]=[C:11]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:17]=2)[CH:12]=1)=[O:6]>O.O1CCOCC1>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:13]([C:11]3[CH:12]=[C:7]([C:5]([OH:6])=[O:4])[C:8]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[N+:32]([O-:34])=[O:33])=[CH:9][CH:10]=3)[S:14][CH:15]=2)=[CH:23][CH:22]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(OC)cc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2csc(-c3ccc(-c4ccccc4[N+](=O)[O-])c(C(=O)O)c3)n2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
Sodium hydroxide (200 mg, 5 mmol) was added to a suspension of 4-[4-(4-methoxy-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid methyl ester (187 mg) in a mixture of water (8 mL) and dioxane (8 mL). The reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was evaporated to dryness and water (15 mL) was added. The mixture was filtered and the filtrate was made acidic to pH 3-4 by the addition of concentrated HCl. The precipitate was collected by filtration and dried to give 4-[4-(4-methoxy-phenyl)-thiazol-2-yl]-2′-nitro-biphenyl-2-carboxylic acid (100 mg, 37% for two steps). 1H NMR (300 MHz, DMSO-d6) δ 13.17 (br s, 1H), 8.56 (d, J=1.8 Hz, 1H), 8.24 (dd, J=8.0, 1.9 Hz, 1H), 8.11-8.16 (m, 2H), 8.01 (d, J=8.8 Hz, 2H), 7.76-7.81 (m, 1H), 7.63-7.68 (m, 1H), 7.41-7.47 (m, 2H), 7.05 (d, J=8.8 Hz, 2H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[CH2:16][C:17]#[C:18][CH2:19]C.Cl.[CH2:22]1COCC1>O>[C:8]([C:2]([CH3:22])([CH2:1][C:16]#[C:17][CH2:18][CH3:19])[C:3]([O:5][CH2:6][CH3:7])=[O:4])([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: CCC#CCBr
Reactant: C1CCOC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCC#CCC(C)(C(=O)OCC)C(=O)OCC

Procedure:
Under argon atmosphere a solution of diethyl methylmalonate (20.0 g, 0.114 mol) in anhydrous THF (20 ml) was added dropwise into a stirred solution of sodium hydride (60% mineral oil dispersion, 4.6 g, 0.114 mol) in anhydrous THF (200 ml) over one hour at room temperature. A solution of 1-bromo-2-pentyne (14.0 g, 0.095 mol) in anhydrous THF (15 ml) was then added dropwise over 20 min. at room temperature. To the resulting mixture was added water (30 ml), and the mixture was neutralized with 3N hydrochloric acid, and concentrated. The residue was extracted with ethyl acetate (200 ml×2). The combined ethyl acetate layers were washed with water (50 ml) and with brine (30 ml), dried over anhydrous sodium sulfate, and concentrated to give a crude material of ethyl 2-carboethoxy-2-methyl-4-heptynoate (26.0 g). To a stirred solution of the crude material in ethanol (200 ml) was added 0.994N aqueous NaOH solution (169 ml, 0.168 mol) under ice-cooling and the mixture was stirred for 14 hrs. at room temperature. After dilution with water (30 ml), the resulting mixture was concentrated, neutralized with 6N hydrochloric acid under ice-cooling and extracted with ethyl acetate (100 ml×3). The combined ethyl acetate layers were washed with brine (50 ml), dried over anhydrous sodium sulfate, and concentrated to give a crude material of 2-carboethoxy-2-methyl-4-heptynoic acid (22.1 g). The crude material was heated at 180° C. for 2 hrs., cooled and dissolved in 100 ml of ether. A solution of diazomethane in ether was added to the solution excessively. The resulting mixture was concentrated and distilled in vacuo to give ethyl 2-methyl-4-heptynoate (12.21 g, 0.073 mol, 76%, B.p.: 118°-125° C./56 mmHg) containing methyl 2-methyl-4-heptynoate in an amount of 10% by weight.
Reaction SMILES: N1C=CC=CC=1.CS(C)=O.[Cl:11][C:12]1[N:17]=[C:16]([O:18][CH3:19])[N:15]2[N:20]=[C:21]([S:23](Cl)(=[O:25])=[O:24])[N:22]=[C:14]2[CH:13]=1.[NH2:27][C:28]1[C:32]([Br:33])=[CH:31][N:30]([CH3:34])[N:29]=1>C(#N)C>[Br:33][C:32]1[C:28]([NH:27][S:23]([C:21]2[N:22]=[C:14]3[N:15]([C:16]([O:18][CH3:19])=[N:17][C:12]([Cl:11])=[CH:13]3)[N:20]=2)(=[O:25])=[O:24])=[N:29][N:30]([CH3:34])[CH:31]=1
Reactant: COc1nc(Cl)cc2nc(S(=O)(=O)Cl)nn12
Reactant: Cn1cc(Br)c(N)n1
Solvent: CS(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: COc1nc(Cl)cc2nc(S(=O)(=O)Nc3nn(C)cc3Br)nn12
Temperature: 25 °C

Procedure:
Pyridine (1.08 g, 8.0 mmol) and dimethyl sulfoxide (0.2 g) were added to a solution of 7-chloro-5-methoxy-1,2,4-triazolo[1,5-c]pyrimidine-2-sulfonyl chloride (1.0 g, 4.0 mmol) and 3-amino-4-bromo-1-methylpyrazole (0.70 g, 4.0 mmol) in 10 mL of acetonitrile with stirring at ambient temperature and the mixture was allowed to react overnight. The mixture was then concentrated by evaporation under reduced pressure and the residue was taken up in methylene chloride. The resulting solution was extracted with water and dried over magnesium sulfate. The volatile materials were then removed by evaporation under reduced pressure and the solid residue was extracted with diethyl ether and with water, recovered by filtration, and dried under reduced pressure to obtain 0.38 g (25 percent of theory) of the title compound as a white solid melting at 230°-232° C.
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[C:8]([C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)(=[O:10])[CH3:9].CN(C=O)C.C>C(#N)C.C(OCC)(=O)C>[C:6]([C:14]1[CH:15]=[C:11]([C:8](=[O:10])[CH3:9])[NH:12][CH:13]=1)#[N:5]
Reactant: CC(=O)c1ccc[nH]1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=O)c1cc(C#N)c[nH]1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of chlorosulfonylisocyanate in acetonitrile (25 mL) was added dropwise to a solution of 2-acetylpyrrole (10.9 g, 100 mmol) in acetonitrile (25 mL) at 0° C. The reaction mixture turned from yellow to black and was allowed to stir at ambient temperature for 2.5 h. The reaction mixture was cooled to 0° C. and DMF (10 mL) was added. The resulting reaction mixture was then heated to 50° C. for 10 minutes and then poured onto ice to afford a dark colored product. The product was dissolved in ethyl acetate and treated with activated charcoal and filtered. The ethyl acetate was evaporated to afford a tan-colored product. Recrystallization from ethyl acetate afforded 4-cyano-2-acetylpyrrole (4.5 g) as a tan solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([CH3:20])([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.Cl.[NH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@@:9]([CH3:20])([C:17]([NH:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)[C@@](C)(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a stirring solution of (R)-N-(tert-butyloxycarbonyl)-α-methylphenylalanine (0.72 g, 2.6 mmol) in dry CH2Cl2 (16 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.69 g, 4.4 mmol) and 1-hydroxybenzotriazole hydrate (0.39 g, 2.9 mmol). The reaction was stirred at ambient temperature for 30 min and then glycine, ethyl ester hydrochloride (0.62 g, 5.2 mmol) and triethylamine (0.85 ml, 5.7 mmol) were added. After stirring at ambient temperature for 3 h, the reaction was transferred to a separatory funnel with CH2Cl2. Extraction with CH2Cl2 and washing of the organic layer with water, saturated NaHCO3, and brine and drying with MgSO4 afforded 0.94 g of crude product after evaporation of the solvent. Purification by flash chromatography (SiO2, 0.2 to 10% MeOH in CH2Cl2) afforded pure product (0.87 g, 93% yield). MS (ESI) 365 (M+H).
Reaction SMILES: [CH3:1][N:2]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[N:12]=[C:11]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])[C:10](B(O)O)=[CH:9][CH:8]=1)=[O:5].Br[C:37]1[N:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]2=[N:39][C:38]=1[CH3:46].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:32]([O:31][C:29](=[O:30])[N:2]([CH3:1])[CH:3]([CH3:28])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:37]2[N:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]3=[N:39][C:38]=2[CH3:46])=[C:11]([C:13]#[C:14][Si:15]([CH:22]([CH3:24])[CH3:23])([CH:16]([CH3:18])[CH3:17])[CH:19]([CH3:21])[CH3:20])[N:12]=1)=[O:5])([CH3:34])([CH3:33])[CH3:35]
Reactant: Cc1nc2ccccn2c1Br
Reactant: CC(C(=O)Nc1ccc(B(O)O)c(C#C[Si](C(C)C)(C(C)C)C(C)C)n1)N(C)C(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc2ccccn2c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#C[Si](C(C)C)(C(C)C)C(C)C
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of [6-[2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoylamino]-2-[2-tri(propan-2-yl)silylethynyl]pyridin-3-yl]boronic acid D1a (1.5 g, 3.0 mmol), 3-bromo-2-methylimidazo[1,2-a]pyridine (842 mg, 3.9 mmol), Na2CO3 (0.95 g, 8.9 mmol), Dichlorobis(triphenylphosphine)palladium(II) (209 mg, 0.3 mmol), dioxane (30 ml) and water (5 ml) is stirred under argon atmosphere for 2 h at 60° C. The mixture is diluted with water and extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 0.6 g (34%). HPLC-MS: M+H=590; tR=2.05 min (*Method—3).
Reaction SMILES: C(C=C)=O.[N+](C(C)C)([O-])=O.[CH3:11][C:12]([N+:18]([O-:20])=[O:19])([CH3:17])[CH2:13][CH2:14][CH:15]=[O:16].[Br:21]Br>C(O)(=O)C.O>[CH3:11][C:12]([N+:18]([O-:20])=[O:19])([CH3:17])[CH2:13][CH2:14][CH:15]=[O:16].[Br:21][CH:14]([CH2:13][C:12]([CH3:17])([N+:18]([O-:20])=[O:19])[CH3:11])[CH:15]=[O:16]
Reactant: BrBr
Agent: C=CC=O
Agent: CC(C)(CCC=O)[N+](=O)[O-]
Solvent: CC(C)[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(CC(Br)C=O)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 163.1 %

Procedure:
4-Methyl-4-nitropentanal is prepared by condensation of acrolein and 2-nitropropane according to a known procedure (Synthesis 1986, 237). To a solution of 4-methyl-4-nitropentanal (8.5 g, 58.56 mmol) in acetic acid (125 ml) is added bromine (9.12 g, 57.07 mmol) dropwise while the temperature is kept below 15° C. After stirring for 15 minutes at room temperature the reaction is poured into a mixture of water and ice (250 ml) and extracted two times with dichloromethane. The combined organic extracts are washed with water and with brine, successively, dried over magnesium sulfate, and the solvent is removed under reduced pressure to leave 10.7 g of 2-bromo-4-methyl-4-nitropentanal which is used for the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[C:10]([F:11])=[C:9]([NH:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:8]=[C:7]([CH:32](OCC)[O:33]CC)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.CC#N>O>[NH2:12][C:9]1[C:10]([F:11])=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[N:6]=[C:7]([CH:32]=[O:33])[CH:8]=1
Reactant: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(C(C)(C)C)n1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1nc(C=O)cc(N)c1F
Yield: 76.2 %

Procedure:
Using the procedure for Example 12, 2-(tert-butyl)-6-(diethoxymethyl)-3-fluoro-N-tritylpyridin-4-amine (2461 mg, 4.8 mmol), conc H2SO4 (1 mL), CH3CN (35 mL) and H2O (35 mL) gave 4-amino-6-(tert-butyl)-5-fluoropicolinaldehyde (718 mg, 73.2%) as a white solid: mp 129-130° C.; 1H NMR (400 MHz, CDCl3) δ 9.86 (s, 1H), 7.26 (d, J=6.3 Hz, 2H), 4.37 (s, 2H), 1.43 (d, J=1.5 Hz, 9H); 13C NMR (101 MHz, CDCl3) δ 193.06, 149.83 (d, J=14.8 Hz), 148.90 (d, J=253.5 Hz), 148.71 (d, J=5.5 Hz), 141.32 (d, J=12.6 Hz), 107.56 (d, J=3.7 Hz), 33.32 (d, J=1.4 Hz), 21.85 (d, J=1.2 Hz), 13.90; 19F NMR (376 MHz, CDCl3) δ −137.45 (d, J=4.6 Hz); HRMS-ESI (m/z) [M+H]+ calcd for C10H13FN2O, 196.1012. found, 196.0994.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>CO>[OH:8][CH:9]([CH2:20][N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CN(CC(CN(C)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CN(CC(O)CN(C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 96.9 %

Procedure:
Di-tert-butyl 2-(tert-butyldimethylsilyloxy)propane-1,3-diylbis(methylcarbamate) (21 g, 48.6 mmol) was dissolved into 200 ml methanol at 0° C. Concentrated HCl (4 mL) was added dropwise and the reaction mixture was stirred at RT for 6 hrs. The mixture was placed over an ice water bath and 10 g of NaHCO3 was added slowly. Then the reaction mixture was dried with MgSO4, and then filtered. The filtrate was concentrated to yield 15.0 g of di-tert-butyl 2-hydroxypropane-1,3-diylbis(methylcarbamate) (97%).