Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>C1COCC1>[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=[CH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:36][CH:35]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: c1ccc([P+](Cc2cccc3ccccc23)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccc(C=Cc2cccc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An oven-dried 500 ml three-neck flask was purged with nitrogen and charged with (naphthalen-1-ylmethyl)triphenylphosphonium (11.67 g, 26.6 mmol) and dry THF (200 ml). Sodium hydride (1.06 g, 26.6 mmol) was added and reaction mixture was left to stir overnight at room temperature. Solution was orange in the morning. A solution of 4-fluorobenzaldehyde (3.0 g, 24.2 mmol) in dry THF (30 ml) was added next day (16 h later) over the period of 45 minutes, bleaching the orange-red color. Reaction mixture was stirred at room temperature for 24 hours. THF was removed under reduced pressure. Crude product was purified by column chromoatography on silica gel with 5% CHCl3 in hexanes. The desired product is a mixture of cis- and trans-isomers. Yield 5.7 g (95%) of a viscous oil. The structure was confirmed by 1H NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[C:6]([N:7]([CH2:13][C:14]#[CH:15])[C:8](=[O:12])[CH2:9][NH:10][CH3:11])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:6]([N:7]([CH2:13][C:14]#[CH:15])[C:8](=[O:12])[CH2:9][N:10]([CH3:11])[S:23]([CH3:22])(=[O:25])=[O:24])=[CH:5][N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: C#CCN(C(=O)CNC)c1cn(-c2cccnc2)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCN(C(=O)CN(C)S(C)(=O)=O)c1cn(-c2cccnc2)nc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.3 %

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-(methylamino)-N-(prop-2-yn-1-yl)acetamide (0.100 g, 0.329 mmol) in DCM (0.65 ml) was added methanesulfonyl chloride (0.057 g, 0.494 mmol) followed by diisopropylethylamine (0.11 ml, 0.658 mmol) and the reaction was stirred at room temperature for 24 h. The reaction mixture was poured into a solution of saturated NaHCO3 and subsequently extracted with DCM. The organic layers were combined and concentrated, and the residue was purified using silica gel chromatography (50-100% EtOAc/hexanes) to afford the title compound as a yellow solid (0.091 g, 0.238 mmol, 72%): (IR thin film) 1678 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.97 (d, J=2.6 Hz, 1H), 8.65 (dd, J=4.8, 1.3 Hz, 1H), 8.15 (s, 1H), 8.04 (ddd, J=8.3, 2.7, 1.4 Hz, 1H), 7.48 (dd, J=8.4, 4.7 Hz, 1H), 3.77 (hept, J=6.9 Hz, 2H), 3.05 (s, 2H), 3.01 (s, 3H), 2.87 (s, 3H), 2.31 (t, J=2.5 Hz, 1H); ESIMS m/z 382 ([M+H]+).
Reaction SMILES: [CH3:1]I.C(OC([N:10]1[CH2:15][C@H:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[O:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:22]=3[CH:32]=2)[C@@H:13]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][O:40][CH2:41][C@H:42]([O:44][CH2:45][CH3:46])[CH3:43])=[CH:35][CH:34]=2)[C@H:12]([CH2:47][OH:48])[CH2:11]1)=O)(C)(C)C.[H-].[Na+]>>[CH3:1][O:48][CH2:47][C@@H:12]1[CH2:11][NH:10][CH2:15][C@H:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[O:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:22]=3[CH:32]=2)[C@H:13]1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][CH2:41][C@H:42]([O:44][CH2:45][CH3:46])[CH3:43])=[CH:35][CH:34]=1
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CO)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](COC)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.568 mmol of methyl iodide are added to a suspension of 0.642 mmol of (3S,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-hydroxymethyl-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester (example 1a) and 0.963 mmol of NaH (60% dispersion in oil) under argon at 0° C. After stirring for 1 h at 0° C. and 1 h at RT, the reaction mixture is partitioned between TBME and saturated aqueous NaHCO3 solution. The aqueous layer is extracted with TBME (2×)—the combined organic layers are washed successively with H2O and brine, dried with Na2SO4 and evaporated. The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[O:23][CH3:24])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[CH3:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc(N2CCCN(C(=O)OC(C)(C)C)CC2)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N2CCCNCC2)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 mg of 4-(2,4-dimethoxyphenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester was dissolved in 10 mL of 4 N HCl in dioxane. The mixture was stirred at room temperature for 2 hrs and evaporated to dryness to give the desired product (270 mg) as a hydrochloride salt. MS (ES) m/z 237.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH:16]1(C)CCC(C(C)C)C(O)C1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:16])=[O:10])=[CH:6][CH:7]=1
Reactant: CC1CCC(C(C)C)C(O)C1
Reactant: O=C(O)Cc1ccc(Br)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
To a solution of 2-(4-bromophenyl)acetic acid (10 g, 46.7 mmol) in menthol was added thionyl chloride (8.34 g, 70.07 mmol) dropwise. The mixture was then stirred at room temperature for 18 hours. The reaction mixture was concentrated, and obtained methyl 2-(4-bromophenyl)acetate (10.5 g, 99.8%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11](I)[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:11]([O:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:12]
Reactant: O=Cc1cc(O)ccc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(O)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.6 %

Procedure:
A mixture of 2,5-dihydroxybenzaldehyde (9.81 g), ethyl iodide (13.29 g), anhydrous potassium carbonate (14.72 g) and N,N-dimethylformamide (100 mL) was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column a chromatography to give crystals (4.20 g, 36%) of 2-ethoxy-5-hydroxybenzaldehyde from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 108-109° C.
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10](NCCCCCC(ON2C(=O)C(S([O-])(=O)=O)CC2=O)=O)=[O:11])[C@H:3]2[NH:32][C:33]([NH:35][C@@H:2]12)=[O:34].[Na+].C(=O)([O-])[O-:38].[Na+].[Na+]>>[OH:38][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:4]1[C@@H:3]2[C@@H:2]([NH:35][C:33]([NH:32]2)=[O:34])[CH2:1][S:5]1)=[O:11]
Reactant: O=C(CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)NCCCCCC(=O)ON1C(=O)CC(S(=O)(=O)[O-])C1=O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 8 h

Procedure:
The RA-NAH (10 mg) obtained in the above was dissolved in 0.5 ml of 0.1 M sodium carbonate aqueous solution, subsequently adding 3 mg of sulfo-NHS-LC-biotin (mfd, by Pierce Chemical Company) thereto followed by overnight incubation at 4° C. After overnight dialysis against distilled water thereafter, the dialyzed liquid was lyophilized to obtain the polysaccharide of the present invention in which biotin is bound to the reducing end of NAH (to be referred to as “NAH-biotin” hereinafter) (8 mg).
Reaction SMILES: N1([C:6]2[CH:7]=[C:8]([C:16]3[S:20][C:19]([NH:21][C:22]([N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[O:23])=[N:18][C:17]=3[CH3:29])[CH:9]=[CH:10][C:11]=2[S:12]([CH3:15])(=[O:14])=[O:13])C=CN=C1.[F:30]C1C=C(C2SC(N)=NC=2C)C=CC=1S(C)(=O)=O>>[F:30][C:6]1[CH:7]=[C:8]([C:16]2[S:20][C:19]([NH:21][C:22]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)=[O:23])=[N:18][C:17]=2[CH3:29])[CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(F)c1

Procedure:
The title compound is prepared by the same procedure as imidazole-1-carboxylic acid [5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide (Example 150a) by replacing 5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 148) with 5-(3-fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (Example 72)
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14]>CCCCCC>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=[N:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8]2
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1C2CC3CC(C2)CC1C3
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NN=C1C2CC3CC(C2)CC1C3

Procedure:
A hexane solution containing 2-adamantanone (2 g) and tert-butyl carbazate (1.76) was heated to reflux for 3 hours. When the solution cooled, the title compound crystallized and was filtered (3.28 g). M. p. 175-177°.
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][OH:19].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[OH:19][CH2:18][CH2:17][N:13]1[CH2:14][CH2:15][CH:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11][CH2:12]1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(NC1CCN(CCO)CC1)c1ccccc1
Yield: 62.4 %

Procedure:
A mixture of 2.04 grams (0.01 mole) of 4-benzamidopiperidine, 1.25 grams (1 equivalent) of 2-bromoethanol and 2.76 grams (4 equivalents) of potassium carbonate were stirred at 100° C in 2 milliliters of methyl etyl ketone for 2 hours. The mixture was filtered hot and the inorganic residue was washed well with hot methyl ethyl ketone. The filtrate was evaporated to dryness and the resulting white solid recrystallised from ethyl acetate to give 1.55 grams (62%) of 1-(2-hydroxyethyl)-4-benzamidopiperidine.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:15]=[CH:14][C:7]2[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1.[Cl:17][C:18]1[CH:23]=[C:22]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:21]=[C:20]([Cl:30])[C:19]=1[CH:31]([F:33])[F:32]>CN(C=O)C>[Cl:17][C:18]1[CH:23]=[C:22]([C:24]2([C:26]([F:29])([F:27])[F:28])[O:1][N:2]=[C:3]([C:4]3[CH:15]=[CH:14][C:7]4[B:8]([OH:13])[O:9][C:10]([CH3:12])([CH3:11])[C:6]=4[CH:5]=3)[CH2:25]2)[CH:21]=[C:20]([Cl:30])[C:19]=1[CH:31]([F:32])[F:33]
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)cc21
Reactant: C=C(c1cc(Cl)c(C(F)F)c(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)c(C(F)F)c(Cl)c4)(C(F)(F)F)C3)cc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 28 %

Procedure:
To a solution of crude N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (156 mg, 0.65 mmol) and 1,3-dichloro-2-(difluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (210 mg, 0.72 mmol) in DMF (8 mL) at rt was added TEA (100 μL, 0.72 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 5-(5-(3,5-dichloro-4(difluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-isoxazol-3-yl)-3,3-dimethyl-benzo[c][1,2]oxaborol-1(3H)-ol (90 mg; yield 28% over 3 steps) as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.268 (s, 1 H), 7.796 (s, 2H), 7.757-7.771 (m, 2 H), 7.694-7.710 (m, 1H), 7.389 (t, J=52.0 Hz, 1 H), 4.451 (d, J=18.0 Hz, 1 H), 4.344 (d, J=18.0 Hz, 1 H), 1.476 (s, 6 H); HPLC purity: 99.28% at 220 nm and 100% at 254 nm; MS: m/z=494.0 (M+1, ESI+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:21]([CH3:31])=[C:20]([C:32]([OH:34])=O)[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[N:22]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:21]([CH3:31])=[C:20]([C:32]([NH:35][CH:36]4[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40][CH2:41]4)=[O:34])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc(-c2ncnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c5) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:14]([O:16][CH3:17])=[O:15])[N:9]=[C:10]2[CH3:13])=[CH:5][CH:4]=1.[H][H]>[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:14]([O:16][CH3:17])=[O:15])[NH:9][CH:10]2[CH3:13])=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COC(=O)C1Cc2ccc(OC)cc2C(C)=N1
Agent: [Pd]
Product: COC(=O)C1Cc2ccc(OC)cc2C(C)N1
Yield: 94 %

Procedure:
To a solution of 3,4-dihydro-7-methoxy-3-methoxycarbonyl-1-methyl-isoquinoline (2.0 g. 8.57 mmol). obtained from the previous step, in veOH (I 50 mL) was added Pd/C (0.g). The reaction mixture was hydrogenated for 21 hr at 4 atm hydrogen pressure. The catalyst was filtered off and the filtrate was concentrated in vacuo. The oily residue (2 g) was purified by a silica gel column using (1: 1) ethyl acetate/ hexane to yield a yellowish oil (94 %): IR (MIC) U 3340, 2951, 1739, 1616, 1503, 1436, 1290, 1228, 1035 cm-1 ; 1H-NMR (CDCl3, δ): 1.51 (d.J=6.6 Hz, 3H). 2.75 (broad s, 1H), 2.89- 3.03 (m. 2H), 3.72 (dd, J=4.5, 11.1 Hz, 1H). 3.79 (s. 6H), 4.14 (q. J=6.6 Hz, 1H), 6.71- 6.75 (m, 2H), 7.02 (d, J=7.8 Hz, I H): MS showed (M+H) +@ 236; Anal. Calcd for C13Hl7NO3 . HCl: C, 57.46; H, 6.68; N, 5.15; Found: C, 57.42; H, 6.64; N, 5.02.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([Cl:15])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:22]1(C)C=CC=C[CH:23]=1>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>[Cl:15][C:4]1[CH:3]=[C:2]([CH:22]=[CH2:23])[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1Cl
Reactant: Cc1ccccc1
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+]
Product: C=Cc1ccc(C(=O)OC(C)(C)C)c(Cl)c1
Yield: 46 %

Procedure:
To a stirred solution of tert-butyl 4-bromo-2-chlorobenzoate (1.6 g, 5.50 mmol) in toluene (20 mL) was added tetrakis(triphenylphospine)palladium(0) (Pd(PPh3)4; (0.31 mg, 0.27 mmol), K2CO3 (2.27 g, 16.5 mmol) and vinylboronic anhydride pyridine complex (2.0 g, 8.3 mmol) and the reaction mixture was heated to reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 5-6% EtOAc in n-hexane) afforded the title compound as a liquid (0.6 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J=8.1 Hz, 1H), 7.44 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.69 (dd, J=17.6, 10.8 Hz, 1H), 5.85 (d, J=17.6 Hz, 1H), 5.40 (d, J=10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m/z 238.95 ([M+H]+); IR (thin film) 2931, 1725, 1134 cm−1.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)=[O:14])[CH:5]=[N:4][C:3]1=2>C1C=CC=CC=1>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([O:22][CH:3]([CH3:2])[CH2:7][N:6]([CH3:11])[CH3:5])=[O:21])=[CH:18][CH:17]=3)=[O:14])[CH:5]=[N:4][C:3]1=2
Reactant: O=C(CCn1cnc2c(=O)[nH]cnc21)Nc1ccc(C(=O)O)cc1
Solvent: c1ccccc1
Product: CC(CN(C)C)OC(=O)c1ccc(NC(=O)CCn2cnc3c(=O)[nH]cnc32)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 33 %

Procedure:
2.0 g (5.78 mmol) of 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]benzoic acid (AIT-0082) were placed into a 100 ml round bottom flask equipped with a magnetic stirring bar, reflux condenser and a drying tube. 16 ml of thionyl/chloride were added and the mixture was slowly heated to 55°-60° C. for six hours. The reaction mixture was allowed to cool to room temperature. 50 ml of benzene were added to break up the crystal mass. The solid was collected by filtration, washed twice with 10 ml of benzene and was allowed to dry under the hood for two hours. While the product was being dried, 20 ml of dimethylamino-2-propanol were placed in a 100 ml round bottom flask equipped with a magnetic stirring bar and drying tube. The mass was slowly added under stirring conditions. The drying tube was replaced on the flask and the stirring continued for six hours at room temperature. The reaction mixture was poured into a 500 ml Erlenmeyer flask containing 300 ml of acetonitrile. The solution was stirred for five minutes. The flask was covered with parafilm and was allowed to stand in the hood overnight at room temperature. The solid material was removed by filtration, washed twice with 15 ml of acetonitrile and air dried under the hood for three hours. The weight of the product 4-[[3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-1-oxopropyl]amino]benzoic acid, 1-(dimethylamino)-2-propyl ester (AIT-0084) was 830 mg. Yield: 33%
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.CN([CH:34]=[O:35])C>>[C:1]1([C:7]2[N:8]=[C:9]([CH:34]=[O:35])[N:10]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccccc2)c1-c1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1c(C=O)nc(-c2ccccc2)c1-c1ccccc1
Yield: 78 %

Procedure:
Reaction of 4,5-diphenyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (304 mg, 0.87 mmol), 2.5 M n-BuLi (452 uL, 1.13 mmol), and DMF (269 uL, 3.48 mmol) for 1 h at −40° C. gave the title compound (257 mg, 78%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.89 (t, 2H, J=9.0 Hz), 3.58 (t, 2H, J=7.5 Hz), 5.61 (s, 2H), 7.26 (br s, 5H), 7.47 (br s, 5H), 9.95 (s, 1H).
Reaction SMILES: CC([N:5]([C@@:9]([CH3:34])([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[C:27]3[C:28]4([CH2:31][O:32][CH2:33][C:26]=3[CH:25]=[CH:24][CH:23]=2)[CH2:30][CH2:29]4)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[C:28]12([C:27]3[C:22]([O:21][C:18]4[N:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[C@:9]([CH3:34])([CH2:10][CH3:11])[NH2:5])=[CH:20][CH:19]=4)=[CH:23][CH:24]=[CH:25][C:26]=3[CH2:33][O:32][CH2:31]1)[CH2:29][CH2:30]2
Reactant: CC[C@](C)(C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)COC3)nc1)N(C(=O)[O-])C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@](C)(N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)COC3)nc1
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of 1,1-dimethylethyl[(1R)-1-methyl-1-({[6-(1H-spiro[2-benzopyran-4,1′-cyclopropan]-5-yloxy)-3-pyridinyl]amino}carbonyl)propyl]carbamate (Intermediate 140, 62 mg) in dry dichloromethane (6 mL) at 0° C. TFA (2 ml, 26.0 mmol) was slowly added and the reaction mixture was stirred for 3 hours at the same temperature. The reaction mixture was diluted with dichloromethane (15 ml) and an aqueous saturated solution of NaHCO3 was added while the pH was allowed to reach ˜8. Two phases were separated and the organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and dichloromethane/methanol as eluents from 99:1 to 95:5. This afforded the title compound as a white solid (42 mg, 86% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:20][CH2:21][N:22]([C@H:25]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]3)[CH2:23][CH:24]=2)=[CH:15][C:3]=1[NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])[CH3:6].Cl>C(O)C.[Pt](=O)=O>[N:22]1([C@H:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:21][CH2:20][CH:19]([C:16]2[CH:17]=[CH:18][C:2]([Cl:1])=[C:3]([CH:15]=2)[NH:4][C@@H:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[CH3:6])[CH2:24][CH2:23]1
Reactant: C[C@@H](Nc1cc(C2=CCN([C@H]3CCCNC3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: C[C@@H](Nc1cc(C2CCN([C@H]3CCCNC3)CC2)ccc1Cl)c1ccc(Cl)cc1Cl
Reaction time: 0.75 h

Procedure:
A mixture of the crude 2-chloro-N-((1R)-1-(2,4-dichlorophenyl)ethyl)-5-(1-((3S)-3-piperidyl)-3,6-dihydro-2H-pyridin-4-yl)aniline (0.30 g, 0.63 mmol), platinum(IV) oxide (PtO2) (5% by weight, 0.045 g) in ethanol (3 mL) containing concentrated hydrochloric acid (conc. HCl) (0.20 mL, 2.20 mmol) in a Paar shaker flask was hydrogenated at 40 psi for 45 min. The reaction mixture was diluted with ethanol, and filtered through the Celite. The filtrate was concentrated in vacuo, and the resulting residue was diluted with dichloromethane (25 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was used without further purification (0.27 g, 0.058 mmol). MS: (ES) m/z calculated for C24H31Cl3N3 [M+H]+466.2. found 466.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Reactant: C#Cc1cccc(F)c1
Product: CC(C)(C)c1cc2ncc(C#Cc3cccc(F)c3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=294.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-3-fluoro-benzene.