Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([I:17])=[C:5]([C:14]([OH:16])=[O:15])[C:6]([I:13])=[C:7]([C:11]=1[I:12])[C:8]([OH:10])=[O:9])#[N:2].[OH-:18].[Na+].Cl>O>[C:1]([C:3]1[C:11]([I:12])=[C:7]([C:8]([OH:10])=[O:9])[C:6]([I:13])=[C:5]([C:4]=1[I:17])[C:14]([OH:16])=[O:15])(=[O:18])[NH2:2]
Reactant: [OH-]
Reactant: N#Cc1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NC(=O)c1c(I)c(C(=O)O)c(I)c(C(=O)O)c1I
Yield: 95 %

Procedure:
100 g of 5-cyano-2,4,6-triiodoisophthalic acid is suspended in 400 ml of water and dissolved by adding 20 g of sodium hydroxide. The solution is maintained at +60° C. for 3 hours, then poured under stirring into 60 ml of concentrated hydrochloric acid. After several hours of agitation in an ice bath the precipitated product is vacuum-filtered, washed with a small amount of ice-cold water, and dried at 50° C., thus obtaining 98 g of 5-carbamoyl-2,4,6-triiodoisophthalic acid as a white powder having a decomposition point of above 280° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:10][C:5]2[NH:6][C:7](=O)[NH:8][C:4]=2[CH:3]=1.O=P(Cl)(Cl)[Cl:19].[OH-].[Na+]>>[Cl:19][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([Cl:1])[C:11]([O:12][C:13]([F:16])([F:15])[F:14])=[CH:10][C:5]=2[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(Cl)c(OC(F)(F)F)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)Oc1cc2nc(Cl)[nH]c2cc1Cl
Temperature: 25 °C
Yield: 96 %

Procedure:
Thoroughly dried 5-chloro-6-trifluoromethoxy-1,3-dihydro-benzoimidazol-2-one (154.6 g, 0.61 mol, 1.0 equiv.) was suspended in POCl3 (450 mL, 8.0 equiv.). The reaction solution was heated to reflux temperature for 6 hours and cooled to room temperature. The solution was poured into crushed ice/water (˜3 L) slowly with sufficient stirring. The solution was neutralized to pH=6.0 with NaOH. The precipitated solid was collected by filtration, washed with water, and dried to afford the title compound (159.97 g, 96%). The crude product was used in the following reaction without further purification.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH2:19]([N:26]1[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[NH:29][CH:28]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:27]1=[O:43])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:19]([N:26]1[C:30]2([CH2:31][CH2:32][N:33]([S:15]([C:12]3[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)(=[O:17])=[O:16])[CH2:34][CH2:35]2)[NH:29][CH:28]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:27]1=[O:43])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C(Cc2ccccc2)NC2(CCN(S(=O)(=O)c3ccc(Cl)cc3)CC2)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
Triethylamine (0.12 ml, 0.89 mmol) and subsequently 4-chlorobenzenesulfonyl chloride (314 mg, 1.49 mmol) were added to a solution of 1,3-dibenzyl-1,4,8-triaza-spiro[4,5]decan-2-one (249 mg, 0.75 mmol) in CH2Cl2 (6.7 ml) with stirring under a blanket of nitrogen at RT. The reaction mixture was stirred overnight. The organic phase was rendered alkaline using saturated aqueous sodium carbonate solution (20 ml) and the aqueous phase was extracted with CH2Cl2 (15 ml). The combined organic phases were dried over Na2SO4. After filtration, removal of the solvent and column chromatography, the desired product 1,3-dibenzyl-8-(4-chlorobenzene-sulfonyl)-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 382 mg (100% of theory).
Reaction SMILES: [CH2:1]([N:5]1[CH2:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]1=O)[CH2:2][CH2:3][CH3:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[CH2:1]([N:5]1[CH2:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1Cc2c([nH]c3ccccc23)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCN1Cc2[nH]c3ccccc3c2C1

Procedure:
2-n-Butyl-1,4-dihydropyrrolo[3,4-b]indol-3(2H)-one, 20 g., in dry tetrahydrofuran, 400 ml., is added slowly to a slurry of LiAlH4, 14 g., in tetrahydrofuran, 250 ml. After refluxing twenty hours, the reaction mixture is hydrolyzed with 30 ml. of water, and filtered. After the solvent is removed, one obtains 20.1 g. of a reddish-brown solid. Recrystallization from methanol, 200 ml., gives 11 g. of the title compound, m.p. 151°-2°.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]([CH2:48][CH2:49][O:50][Si](C)(C)C(C)(C)C)[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:47])[C:30](=[O:46])[C:31]4[N:39]5[C:34]([CH:35]=[CH:36][CH:37]=[CH:38]5)=[CH:33][C:32]=4[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH:13]=[CH:12][CH:11]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:6][CH2:7][CH2:8][N:9]([CH2:48][CH2:49][OH:50])[C:10]1[N:15]=[C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:47])[C:30](=[O:46])[C:31]4[N:39]5[C:34]([CH:35]=[CH:36][CH:37]=[CH:38]5)=[CH:33][C:32]=4[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)=[CH:24][CH:23]=3)[CH2:20][CH2:21]2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(CCO[Si](C)(C)C(C)(C)C)c1cccc(N2CCN(c3ccc(NC(=O)C(=O)c4c(-c5ccccc5)cc5ccccn45)cc3)CC2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Nc1ccc(N2CCN(c3cccc(N(CCO)CCO)n3)CC2)cc1)C(=O)c1c(-c2ccccc2)cc2ccccn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of N-{4-[4-(6-{bis-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-amino}-pyridin-2-yl)-piperazin-1-yl]-phenyl}-2-oxo-2-(2-phenyl-indolizin-3-yl)-acetamide (0.7 g, 0.81 mmol) in THF (10 mL) was added tetra-n-butylammonium fluoride (1.28 g, 4.06 mmol) at 0° C. The reaction mixture was stirred at r.t. for 1 h. The solvent was evaporated in vacuo, the residue diluted with dichloromethane and washed with water, brine, dried over sodium sulfate filtered and concentrated. The crude compound was purified by column chromatography over silica gel (60-120 mesh) using 3% methanol/chloroform to yield N-[4-(4-{6-[bis-(2-hydroxy-ethyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-phenyl]-2-oxo-2-(2-phenyl-indolizin-3-yl)-acetamide (180 mg, 36%) as a light yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]#[N:16])=[CH:5][CH:4]=1.C([O-])(=[O:19])C.[Na+]>C(O)(=O)C>[C:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:19])=[CH:4][CH:5]=1)#[N:16]
Reactant: CC(=O)[O-]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccccc1-c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
250 g of 4-bromomethyl-2'-cyano-biphenyl, 150 g of sodium acetate and 2.5 1 of glacial acetic acid are heated to reflux overnight. The mixture is then concentrated in a high vacuum, and the residue is taken up in ethyl acetate. This ethyl acetate mixture is extracted in succession with water, sodium hydrogencarbonate solution and brine and then evaporated on a rotary evaporator. The crude product is dissolved in 3.1 l of ethanol, the solution is treated with 430 ml of 2N NaOH, the mixture is stirred overnight at room temperature and then concentrated, and the residue is taken up in ethyl acetate. The mixture is washed in succession with water and sodium carbonate solution and concentrated. The residue is suspended in hexane, the suspension is filtered with suction, and the filter cake is washed and dried at 60° in a high vacuum for 20 hours. 2'-Cyano-4-hydroxymethyl-biphenyl is thus obtained in the form of a white powder [1H-NMR (DMSO-d6): 4.58 ppm (d, 2H); 5.3 ppm (t, 1H); 7.6 to 8.0 ppm (m, 8H)].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[N:11][CH:12]=1)=[O:5].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>Cl.O1CCOCC1.O>[CH3:27][S:28]([N:16]1[CH2:17][CH2:18][N:13]([C:10]2[N:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]([O:2][CH3:1])=[O:26])=[CH:8][CH:9]=2)[CH2:14][CH2:15]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(=O)Nc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C(=O)Nc1ccc(N2CCN(S(C)(=O)=O)CC2)nc1
Reaction time: 3 h

Procedure:
A solution of tert-butyl 4-(5-{[methoxy(oxo)acetyl]amino}pyridin-2-yl)piperazine-1-carboxylate (Intermediate 16, 4 g, 11 mmol) in 4N HCl/dioxan (25 mL) was stood for 16 h then concentrated by evaporation. The residue was dissolved in a mixture of DMF (20 mL) and pyridine (7 mL) then methanesulphonyl chloride (1.28 mL, 16.48 mmol) was added. The mixture was stirred for 3 hours then was diluted with water (50 mL) and extracted with dichloromethane (2×100 mL). The organic extracts were dried and concentrated by evaporation to give the title compound as a solid that was used without further purification; MS m/e MH+ 343.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([OH:12])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH2:13](N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1C(=O)O
Reactant: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(Cl)cnc1OC

Procedure:
By the procedure of Example 1, 5-chloro-2-methoxypyridine-3-carboxylic acid [Sarges et al., J. Med. Chem. 19, 709 (1976); 10 g.] was converted to its acid chloride, which was added in one portion to 150 ml. of methanol (slight exotherm), then made basic with triethylamine (approximately 1.1 equivalents). The reaction mixture was evaporated to solids and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was washed with fresh water and then brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product [9.75 g., m.p. 79°-81° C.; pnmr/CDCl3 /delta (ppm) 3.8 (s, 3H), 4.1 (s, 3H), 8.1 (d, 1H), 8.3 (d, 1H)].
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6](F)[C:5]([C:13](=[N:25][OH:26])[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:13]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:25][O:26][C:6]=2[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1c(Cl)ccc(C(=NO)Nc2cccc(C(F)(F)F)c2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)ccc2c(Nc3cccc(C(F)(F)F)c3)noc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 6-chloro-2-fluoro-3-(N′-hydroxy-N-(3-(trifluoromethyl)phenyl)carbamimidoyl)benzoate (1.1 g, 2.8 mmol) in DMF cooled to 0° C. was added NaH (0.136 g, 3.39 mmol) portionwise. The resulting orange solution was stirred at 0° C. for 2 h. The reaction was partitioned between EtOAc (50 ml), brine (30 mL), and water (20 mL). The aqueous layer was back exacted with EtOAc (3×20 mL) and the combined EtOAc layer was dried (Na2SO4) and concentrated to provide the title compound as a crude product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][O:17][C:18]([C:20]1[N:21]([CH2:26][C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[N:22]=[C:23]([NH2:25])[CH:24]=1)=[O:19]>>[CH3:16][O:17][C:18]([C:20]1[N:21]([CH2:26][C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[N:22]=[C:23]([NH:25][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([C:7]#[N:8])[CH:9]=2)[CH:24]=1)=[O:19]
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: COC(=O)c1cc(N)nn1Cc1cc(F)c(F)c(F)c1
Product: COC(=O)c1cc(Nc2ccc(-n3cnc(C)c3)c(C#N)c2)nn1Cc1cc(F)c(F)c(F)c1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 5-amino-2-(3,4,5-trifluoro-benzyl)-2H-pyrazole-3-carboxylic acid methyl ester. The title compound was obtained as a colorless solid (Yield=15%). MS ISP (m/e): 467.2 (100) [(M+H)+].
Reaction SMILES: [C:1]1([CH:7]([CH2:11][CH3:12])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([O:19]C)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[OH-].[Na+].[Al+3].[Cl-].[Cl-].[Cl-]>CCOC(C)=O.O.C1(C)C=CC=CC=1>[OH:19][C:13]1[CH:18]=[CH:17][C:16]([C:8](=[O:10])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][CH3:12])=[CH:15][CH:14]=1
Reactant: CCC(C(=O)O)c1ccccc1
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(C(=O)c1ccc(O)cc1)c1ccccc1
Temperature: 10 °C
Reaction time: 72 h
Yield: 76 %

Procedure:
A 5.0 L round bottom flask was charged with 164.2 (1.00 mol) (±)-2-phenylbutyric acid (III) and 110.3 g (1.02 mol) anisole and anhydrous toluene (575 mL) and stirred until dissolved. The resulting solution was cooled to 10° C. and 367.5 g (1.75 mol) TFAA added such that the temperature did not rise above 15° C. The solution was heated to 35° C. for 1 h then at 40° C. for 72 h. The solution was cooled to 20° C. and toluene (1300 mL) added followed by 2N NaOH (1.80 mol) with external cooling and vigorous stirring at a rate such that the reaction temperature did not rise above 35° C. The mixture was stirred for 1 h and the pH then adjusted to 10 by addition of 2N NaOH. The aqueous layer was removed and the upper organic layer was washed with H2O (900 mL). The aqueous layer was removed and the toluene layer concentrated to ˜1000 mL via atmospheric distillation. This solution was then quickly added to a stirred mixture of 266.7 g AlCl3 (2.00 mol) and anhydrous toluene (900 mL) at 70° C. The solution was stirred at 70° C. for 1 h, cooled to 15° C., and then added to water (1000 mL, 15° C.) with cooling such that the temperature did not exceed 40° C. After complete addition and cooling to 25° C., EtOAc (900 mL) was added and then stirred for 5 minutes. The lower aqueous layer was removed and the organic layer washed with water (1000 mL). The organic layer was concentrated under reduced pressure (˜60° C.) to ˜1000 mL. The solution was then cooled to 50° C. and hexanes (660 mL) added while maintaining an internal temperature of >50° C. The solution was then cooled slowly to 10° C. during which time crystallization occurred. The mixture was stirred for an additional 30 minutes and filtered through a medium glass fritted funnel and the filter cake washed with cold hexanes (330 mL). The material was dried to constant weight in a vacuum oven at 40° C. to yield 183.1 g (76%) of 8 as a cream solid; mp 127-129° C.; 1HNMR (400 MHz, DMSO-d6): δ 0.80 (t, J=7.3 Hz, 3H), 1.69 (h, J=7.2 Hz, 1H), 2.04 (h, J=7.2 Hz, 1H), 4.62 (t, J=7.2 Hz, 1H), 6.79 (d, J=8.7 Hz, 2H), 7.15-7.33 (m, 5H), 7.91 (d, J=8.7 Hz, 2H), 10.32 (s, 1H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([C:25]#[C:26][C:27]2[C:35]3[C:30](=[N:31][CH:32]=[N:33][C:34]=3[NH2:36])[NH:29][N:28]=2)[CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1.[C:37]([N:44]1[CH2:48][CH2:47][CH:46]([CH2:49]O)[CH2:45]1)([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[NH2:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([CH2:49][CH:46]3[CH2:47][CH2:48][N:44]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:45]3)[N:28]=[C:27]([C:26]#[C:25][C:19]3[CH:18]=[C:17]([O:16][CH3:15])[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=3)[C:35]=12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)C1
Reactant: COc1cc(C#Cc2n[nH]c3ncnc(N)c23)cc(OC)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C#Cc2nn(CC3CCN(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
DIAD (197 μl) was added to a suspension of 3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (148 mg) obtained in Example 1 (Step 1), N-Boc-3-hydroxymethylpyrrolidine (154 mg), polymer supported triphenylphosphine (up to 3.0 mmol/g, 334 mg) in THF (5.0 ml), followed by stirring at room temperature for 3 hours. The insoluble matter was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain the title compound as a colorless, amorphous substance (94.5 mg). Physical properties: m/z [M+H]+ 479.1
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20][N:19]=2)=[CH:4][CH:3]=1.Cl.ClCC1N2C=C([F:40])C=CC2=NC=1C1C=CC(Cl)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([F:40])=[CH:12][N:11]3[C:16]=2[CH2:17][C:18]2[N:22]=[C:21]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[O:20][N:19]=2)=[CH:6][CH:7]=1
Reactant: Fc1ccc2nc(-c3ccc(Cl)cc3)c(CCl)n2c1
Reactant: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)no1
Agent: Cl
Product: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)no1

Procedure:
The title compound was prepared according to the experimentals described for compound 212 from 3-(chloromethyl)-2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridine hydrochloride. m/e+ 401 for C19H15ClFN4O3 (M+H)+.
Reaction SMILES: [CH:1]([CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2([CH3:31])[CH2:15][C:14]3[C:16]([CH3:30])=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:18]([CH3:21])=[C:19]([CH3:20])[C:13]=3[O:12]2)[CH2:6][CH2:5]1)=O.[C:32]1([CH:38]([NH2:45])[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C([BH3-])#N.[Na+].CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.Cl.C(=O)([O-])O.[Na+]>C(O)C>[C:32]1([CH:38]([NH:45][CH2:1][CH2:3][CH:4]2[CH2:5][CH2:6][N:7]([CH2:10][C:11]3([CH3:31])[CH2:15][C:14]4[C:16]([CH3:30])=[C:17]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[C:18]([CH3:21])=[C:19]([CH3:20])[C:13]=4[O:12]3)[CH2:8][CH2:9]2)[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CN1CCC(CC=O)CC1)O2
Reactant: NC(c1ccccc1)c1ccccc1
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1NC(=O)OC(C)(C)C)CC(C)(CN1CCC(CCNC(c3ccccc3)c3ccccc3)CC1)O2
Reaction time: 1 h
Yield: 77 %

Procedure:
A solution of tert-butyl [2-[[4-(formylmethyl)-1-piperidinyl]methyl]-2,3-dihydro-2,4,6,7-tetramethylbenzofuran-5-yl]carbamate (1.5 g) and 1,1-diphenylmethylamine (0.60 mL) in ethanol (20 mL) was stirred on an ice bath for 30 minutes. Then, 0.26 g of sodium cyanoborohydride and a small amount of bromocresol green were added. Thereafter, 4N-HCl solution in ethanol was added until the reaction mixture had turned yellow. The mixture was stirred for 1 hour, after which it was poured in an excess of aqueous sodium hydrogen carbonate. The mixture was extracted with ethyl acetate and the extract was washed with saturated aqueous NaCl and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=4:1 to ethyl acetate) to provide 1.6 g of the title compound. Yield 77%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH:14]([S:18][CH3:19])[C:15]([OH:17])=O)=[CH:8][CH:7]=2)#[CH:2].ON1C2N=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH2:52][C:53]([CH3:58])([CH2:56][OH:57])[C:54]#[N:55]>C(#N)C.[Cl-].[Na+].O.C(OCC)(=O)C.C(N(CC)CC)C>[C:54]([C:53]([NH:52][C:15](=[O:17])[CH:14]([O:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:1]#[CH:2])=[CH:12]2)[S:18][CH3:19])([CH3:58])[CH2:56][OH:57])#[N:55]
Reactant: CC(N)(C#N)CO
Reactant: C#Cc1cnc2ccc(OC(SC)C(=O)O)cc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC(C)(C#N)CO)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.8 %

Procedure:
To a solution of (3-ethynyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid (4.0 g) and triethylamine (6 ml) in dry acetonitrile (50 ml) at room temperature were added successively a 1-hydroxy-7-azabenzotriazole (2.39 g) and O-(1H Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (5.64 g) and a solution of 2-amino-3-hydroxy-2-methyl-propionitrile (1.76 g) in dry acetonitrile (20 ml). The reaction mixture was stirred at room temperature for 18 hrs and then poured onto a mixture of ethyl acetate and brine. The two layers were separated and the aqueous layer was extracted thrice with ethyl acetate. The organic layers were combined, washed once with brine and then, dried over sodium sulphate. After filtration and concentration under reduced pressure, the crude residue was dissolved in 50 ml of THF/H2O (1/1) and treated with 260 mg of LiOH monohydrate at room temperature for 1 hr. The crude mixture was extracted (pH=11) thrice with ethyl acetate. The organic layers were combined, washed with water, with brine and then dried over sodium sulphate. After filtration and concentration under reduced pressure, the crude residue was purified by flash chromatography on silica gel (hexane/ethyl acetate 1:4, 0:1) to provide 2.02 g of N-(1-cyano-2-hydroxy-1-methyl-ethyl)-2-(3-ethynyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide as a white solid (m.p. 78-80° C.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([O:18]C(=O)C)[C:12]=1[CH3:22])(=O)C>CCOCC>[OH:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[C:13]([OH:18])[C:12]=1[CH3:22]
Reactant: CC(=O)Oc1ccc(C)c(OC(C)=O)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1ccc(O)c(C)c1O
Reaction time: 8 h
Yield: 62 %

Procedure:
To a slurry of lithium aluminum hydride (0.56 g, 14.76 mmol) in ether (35 mL) was added 1,3-diacetoxy-2,4-dimethylbenzene (the compound of Preparation 24, 1.65 g, 7.42 mmol in 40 mL of ether) via syringe. The mixture was stirred overnight; then it was carefully quenched with sodium sulfate decahydrate (excess). The mixture was dried with anhydrous sodium sulfate, filtered, and concentrated to give 0.62 g (62%) of 1,3-dihydroxy-2,4-dimethylbenzene as a waxy light yellow solid which had: NMR δ 6.83 (d, J=8 Hz, 1 H), 6.34 (d, J=8.1 Hz, 1 H), 4.71 (s, 2 H), 2.19 (s, 3 H), 2.17 (s, 3 H). There was also a small amount of an impurity observed in the NMR spectrum but the product was found to be suitable for use without further purification. The product was somewhat air sensitive and was used the same day it was synthesized.
Reaction SMILES: [F:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]2[N:26]=[CH:25][C:24]([C:27]([O:29]C)=[O:28])=[CH:23][CH:22]=2)=[O:20])=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[OH-].[Li+].O1CCCC1.Cl>O.CO>[F:1][C:2]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]2[N:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)=[O:20])=[CH:16][CH:17]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:6])=[O:7]
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(C(C)(F)CNS(=O)(=O)C(C)C)cc2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(F)c1ccc(NC(=O)c2ccc(C(=O)O)cn2)cc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
Methyl 6-{N-[4-(1-fluoro-1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]carbamoyl}pyridine-3-carboxylate (150 mg, 0.35 mmol, prepared in example 50), lithium hydroxide (52 mg, 1.24 mmol), tetrahydrofuran (6 mL), methanol (2 mL), and water (2 mL) were mixed together in a 25 mL 3 neck flask and stirred over night at room temperature. In the morning, the mixture was concentrated under reduced vacuum to yield a white solid. This material was taken into 1N HCl and the desired material was extracted into methylene chloride. The acidic solution was taken to pH 10 with 1N NaOH and the resulting precipitate was again extracted with methylene chloride. Both organic layers were combined and washed once with H2O, dried over MgSO4, filtered, and concentrated under reduced vacuum to yield the title compound (125 mg, 84%) as a tan solid. This material was used without further purification. Ion spray M.S. 403.9 (M*−19 Fluorine).