Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:22]=[CH:21][C:16]4[N:17]=[CH:18][N:19]([CH3:20])[C:15]=4[CH:14]=3)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][CH2:31][N:32]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[N:33]1>COCCOC>[CH3:20][N:19]1[C:15]2[CH:14]=[C:13]([CH:11]([C:8]3[N:6]4[N:7]=[C:2]([C:35]5[CH:34]=[N:33][N:32]([CH2:31][CH2:30][O:29][CH:24]6[CH2:25][CH2:26][CH2:27][CH2:28][O:23]6)[CH:36]=5)[CH:3]=[CH:4][C:5]4=[N:10][CH:9]=3)[CH3:12])[CH:22]=[CH:21][C:16]=2[N:17]=[CH:18]1
Reactant: CC(c1ccc2ncn(C)c2c1)c1cnc2ccc(Cl)nn12
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Solvent: COCCOC
Product: CC(c1ccc2ncn(C)c2c1)c1cnc2ccc(-c3cnn(CCOC4CCCCO4)c3)nn12
Temperature: 90 °C

Procedure:
(rac)-6-Chloro-3-[1-(3-methyl-3H-benzoimidazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (Stage 185.2, 525 mg, 1.381 mmol) was introduced in a microwave reactor together with 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3 ,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 667 mg, 2.071 mmol) and DME (9 mL). The mixture was purged with Argon for 5 min. Pd(PPh3)2Cl2 (38.8 mg) and 2 M K2CO3 (1.864 mL) were added and the mixture was flushed with Argon before being sealed. It was then heated at 90° C. for 4,5 h. The RM was diluted with EtOAc and washed with water, brine, dried over Na2SO4, filtered and evaporated. The residue was purified by flash chromatography (CombiFlash® Companion System®, with 40 g RediSep® silica gel column, DCM/MeOH=100:0->92:8 in 25 min). The collected fractions containing product were evaporated and the residue was dried under vacuum to afford the title compound as an oil (tR 2.39 min (conditions 8), MH+=472).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Br:6][C:7]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[C:13]2[C:8]=1[CH2:9][CH2:10][CH2:11][O:12]2>>[Br:6][C:7]1[C:16]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[C:13]2[C:8]=1[CH2:9][CH2:10][CH2:11][O:12]2
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccc(Br)c2c1OCCC2
Product: O=C(O)c1cc(S(=O)(=O)Cl)c(Br)c2c1OCCC2

Procedure:
817 ml of chlorosulphonic acid were introduced into a 2-liter round-bottomed flask and 210 g of 5-bromochroman-8-carboxylic acid were then added in small amounts. The temperature rose to 40° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[C:24]([F:25])[CH:23]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Product: O=S(=O)(NCCCCCO)c1ccc(-c2ccc(F)c(F)c2)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 3,4-difluorophenyl boronic acid were reacted to give the title compound as a white solid. δC (CDCl3, 62.9 MHz): 22.7, 29.3, 31.9, 43.1, 62.5, 116.4 (d, J 17.6), 118.0 (d, J 17.6), 123.5 (d, J 4.9), 127.6, 127.8, 136.4 (m), 139.2, 143.3, 150.5 (d, J 250.0) and 150.7 (d, J 250.0).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:21])[CH:8]=[CH:7][C:6]([CH:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1>O1CCCC1>[CH3:13][O:12][C:10](=[O:11])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH3:21])=[CH:4][CH:5]=1)([C:14]1[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)[OH:30]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)C(c1ccc(C)cc1)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(O)(c1ccc(C)cc1)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of NaH (255 mg, 10.6 mmol) in tetrahydrofuran (50 mL) was cooled to 0° C. and treated with a solution of 21 (2.29 g, 9.00 mmol) in tetrahydrofuran. The cooling bath was removed and DMF (1 mL) was added to the reaction. The resulting mixture was stirred at room temperature overnight. The mixture was treated with TMS-Cl (10 mL of 1M THF solution) and stirred at room temperature (2 h). The reaction was treated with solid MCPBA (85%, 3.49 g, 17.2 mmol) and stirred at room temperature overnight. The reaction was quenched with tetrabutylammonium fluoride and diluted with ethyl acetate and water. The aqueous layer was extracted with two additional portions of ethyl acetate and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (dichloromethane/hexane) afforded the title compound (22).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N+:23]([O-:25])=[O:24])=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:5][CH2:4]1.CC1(C)C(C)(C)OB([C:34]2[CH2:39][C:38]([CH3:41])([CH3:40])[CH2:37][C:36]([CH3:43])([CH3:42])[CH:35]=2)O1>COCCOC.O>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[CH:11][C:12]([N+:23]([O-:25])=[O:24])=[C:13]([C:34]3[CH2:39][C:38]([CH3:41])([CH3:40])[CH2:37][C:36]([CH3:43])([CH3:42])[CH:35]=3)[CH:14]=2)[CH2:5][CH2:4]1
Reactant: COC1CCN(c2ccc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)c2)CC1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)C1
Solvent: COCCOC
Solvent: O
Product: COC1CCN(c2ccc([N+](=O)[O-])c(C3=CC(C)(C)CC(C)(C)C3)c2)CC1

Procedure:
Trifluoromethanesulfonic acid 5-(4-methoxypiperidin-1-yl)-2-nitrophenyl ester (3 g, 7.81 mmol) prepared in Example (7c) was used as the starting material. 4,4,5,5-Tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)-[1,3,2]dioxaborolane prepared in Example (4b) was used instead of 4-t-butylcyclohex-1-enyl-(4,4,5,5-tetramethyl)-[1,3,2]dioxaborolane, and a mixed solvent of 1,2-dimethoxyethane-water was used as the solvent, for reaction in a manner similar to Example (7e) and treated in a similar manner, to give 2.89 g of the title compound as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[C:24]=4[OH:31])[CH2:18][CH2:17]3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Li+].Cl.C(OCC)(=O)C>CO>[Cl:30][C:25]1[C:24]([OH:31])=[C:23]([CH:28]=[C:27]([Cl:29])[CH:26]=1)[CH2:22][N:19]1[CH2:18][CH2:17][CH:16]([CH2:15][NH:14][C:11]2[NH:10][C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)[CH2:21][CH2:20]1
Reactant: COC(=O)c1cccc2[nH]c(NCC3CCN(Cc4cc(Cl)cc(Cl)c4O)CC3)nc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc2[nH]c(NCC3CCN(Cc4cc(Cl)cc(Cl)c4O)CC3)nc12
Temperature: 50 °C
Reaction time: 2 h

Procedure:
After suspending 2-{[1-(3,5-dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylic acid methyl ester (993 mg, 2.14 mmol) in methanol (10 ml), an aqueous lithium hydroxide solution (4M, 5.4 ml, 21.4 mmol) was added. The reaction mixture was stirred at 50° C. for 2 hours and then cooled to room temperature. 1N hydrochloric acid was added dropwise to adjust the pH to approximately 6.0. Ethyl acetate (1 ml) was then added and the mixture was stirred for 3 hours, after which the precipitate was filtered out to obtain 2-{[1-(3,5-dichloro-2-hydroxy-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazole-4-carboxylic acid. The compound was identified by LC-MS.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.CCCCCC.[CH2:17]([O:20][C:21]1[C:22](/[C:35](/[CH2:43][CH3:44])=[C:36](/[F:42])\[C:37](OCC)=[O:38])=[CH:23][C:24]2[C:25]([CH3:34])([CH3:33])[CH2:26][CH2:27][C:28]([CH3:32])([CH3:31])[C:29]=2[CH:30]=1)[CH2:18][CH3:19]>C1COCC1>[CH2:17]([O:20][C:21]1[C:22](/[C:35](/[CH2:43][CH3:44])=[C:36](/[F:42])\[CH2:37][OH:38])=[CH:23][C:24]2[C:25]([CH3:33])([CH3:34])[CH2:26][CH2:27][C:28]([CH3:32])([CH3:31])[C:29]=2[CH:30]=1)[CH2:18][CH3:19]
Reactant: CCCOc1cc2c(cc1/C(CC)=C(/F)C(=O)OCC)C(C)(C)CCC2(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCOc1cc2c(cc1/C(CC)=C(/F)CO)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
A solution of diisobutylaluminum hydride and hexane (40 mL, 1 M, 40 mmol) was added to a stirring solution of ethyl (E)-3-(3-n-propoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-fluoropent-2-enoate (Intermediate 8, 3.52 g, 9.36 mmol) in THF (60 mL) at −78° C. under argon. The solution was stirred at −78° C. for 3 h, and the reaction was quenched at −78° C. by adding methanol. The solution was warmed to room temperature and stirred for 1.5 h. The solution was treated with 1 M aqueous HCl, and the products were extracted three times with ether. The combined organic layers were washed with water, brine and dried over magnesium sulfate. The solvent was removed in vacuo to give the title compound after purification by silica gel chromatography (15% ethyl acetate in hexane).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:7]([CH:10]([OH:23])[C:11](C)([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:32](OC(=O)C)(=[O:34])[CH3:33].O>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[C:32]([O:23][CH:10]([C:7]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][CH:8]=1)[CH:11]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1ncc(C(O)C(C)(C(=O)OC)c2ccncc2)n1Cc1ccccc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCCCc1ncc(C(OC(C)=O)C(C(=O)OC)c2ccncc2)n1Cc1ccccc1Cl
Reaction time: 2 h
Yield: 113.5 %

Procedure:
A solution of methyl 3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-3-hydroxy-2-(4-pyridyl)-methylpropanoate (3.32 g, 7.5 mmol) methylene chloride (50 mL), 4-dimethylaminopyridine (150 mg, 1.3 mmol) and acetic anhydride (7.1 mL, 75 mmol) was stirred at ambient temperature for 18 hours. Water (5 mL) was added, the mixture was stirred for 2 hours and then diluted with methylene chloride and 5% sodium bicarbonate solution. The organic phase was washed with 5% sodium bicarbonate solution and brine, dried and concentrated to give 4 g of the crude title compound. TLC on silica gel with 5% methanol ethyl acetate showed essentially one spot material with an Rf of 0.86. No starting material was detected. This material was not purified further.
Reaction SMILES: N12CCCN=C1CCCCC2.[C:12]([OH:16])(=[O:15])[C:13]#[CH:14].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>C(Cl)Cl>[C:12]([O:16][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=1)(=[O:15])[C:13]#[CH:14]
Reactant: C#CC(=O)O
Reactant: COc1ccc(CCl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C#CC(=O)OCc1ccc(OC)cc1
Reaction time: 2 h

Procedure:
64 ml (0.43 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene were added to a solution of 26.4 ml (0.43 mol) of propiolic acid in 400 ml of methylene chloride at 25°, where required while cooling with ice. The mixture was stirred at 25° for 2 hours, then 56 ml (415 mmol) of 4-methoxybenzyl chloride were added and the mixture was finally stirred at 25° for a further 2 days. The reaction mixture was washed in succession with 200 ml of saturated sodium hydrogen carbonate solution and twice with 200 ml of water each time. The organic phase was dried over sodium sulphate and concentrated. The residue was purified by flash chromatography on 1000 g of silica gel (elution agent hexane/ethyl acetate 9:1). There was obtained 4-methoxybenzyl propiolate as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[N+]=[N-])[CH:5]=[CH:6][CH:7]=1.[O:18]=[CH:19][C:20](=[CH2:22])[CH3:21]>ClCCl.CCCCCC.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=3)[CH2:21][C:20]2([CH3:22])[CH:19]=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=C(c1cccc(F)c1)c1cccc(F)c1
Reactant: C=C(C)C=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC1(C=O)CC1(c1cccc(F)c1)c1cccc(F)c1
Temperature: 43 °C

Procedure:
A solution of bis(3-fluorophenyl)diazomethane, prepared as in Example 84 by the action of activated manganese dioxide (33 g) on 3,3'-difluorobenzophenone hydrazone (21.76 g) in dichloro-methane (105 mL), was added to a solution of methacrolein (15 mL) in hexane (100 mL). The mixture was heated at 43° C. for 20 hours then the amber solution was evaporated in vacuo. The crude solid was triturated with hexane to yield 23.1 g of 2,2-bis(3-fluorophenyl)-1-methylcyclopropanecarboxaldehyde, mp 92°-93° C. Recrystallization of a sample from hexane furnished the analytical specimen, mp 92°-93.5° C.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][C:15]3[N:16]([CH3:23])[CH2:17][N:18]([CH3:22])[C:19](=[O:21])[C:20]=3[N:12]2[C:11]([OH:24])=[CH:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[CH2:33]([C:10]1[C:9](=[O:25])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]2[N:12]([C:11]=1[OH:24])[C:20]1[C:19](=[O:21])[N:18]([CH3:22])[CH2:17][N:16]([CH3:23])[C:15]=1[N:14]=2)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: BrCc1ccccc1
Reactant: CN1CN(C)c2nc3n(Cc4ccccc4)c(=O)cc(O)n3c2C1=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CN1CN(C)c2nc3n(Cc4ccccc4)c(=O)c(Cc4ccccc4)c(O)n3c2C1=O

Procedure:
To a suspension of 7.1 g. (0.021 mole) of 9-benzyl-2,3-dihydro-1,3-dimethyl-6-(hydroxy)pyrimido[2,1-f]purine-4,8(1H,9H)-dione in 200 ml. of acetone, add 2.3 g. (0.023 mole) of triethylamine, and stir the mixture for 5 minutes at room temperature under a nitrogen atmosphere to obtain a clear solution. Add dropwise to the solution 4.7 g. (0.027 mole) of benzyl bromide, and reflux the mixture for 5 hours under a nitrogen atmosphere. Remove the acetone under reduced pressure, and triturate the gummy residue with methanol. Remove the resultant white solid by filtration, pour the filtrate into water, acidify to pH 4-5 with dilute hydrochloric acid, and decant the aqueous supernatant. Dissolve the gummy residue in the chloroform, wash the solution with water, and dry over anhydrous magnesium sulfate. Remove the drying agent by filtration, and evaporate solvent from the filtrate under reduced pressure. Chromatograph the residual oil on silica gel, eluting with chloroform(96)-methanol(4), to obtain the title compound as a solid with m.p. 176°-179° C.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH2:11])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].C1(C)C=CC=CC=1.C[O:20][C:21](=O)[CH:22]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:24][CH3:25]>C1COCC1>[C:30]([O:29][C:27](=[O:28])[NH:26][CH:22]([C:21](=[O:20])[NH:11][C:8]1[CH:7]=[C:6]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:10][N:9]=1)[CH2:23][CH2:24][CH3:25])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCCC(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: CC(C)(C)c1cc(N)no1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCC(NC(=O)OC(C)(C)C)C(=O)Nc1cc(C(C)(C)C)on1
Reaction time: 1 h
Yield: 141.2 %

Procedure:
To a solution of 5-tert-butyl-isoxazol-3-ylamine hydrochloride (1.22 g, 8.69 mmol) in THF was added 2 M AIMe3 in toluene (4.3 ml, 8.6 mmol) at room temperature and stirred for 1 hr. A solution of 2-tert-butoxycarbonylamino-pentanoic acid methyl ester (1.005 g, 4.34 mmol) in THF was added and the resulting mixture was stirred at room temperature over the weekend. The mixture was quenched with Rochelle salt and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give 2.08 g of the title compound as a crude oil. The oil was purified by silica gel column chromatography using 1% methanl in methylenechloride as eluent to give the title compound as a white solid (0.554 g). 1H NMR (CDCl3) □ 8.8 (brs, 1H), 6.7 (s, 1H), 4.85 (brs, 1H), 4.22 (m, 1H), 1.9 (m, 1H), 1.4-1.7 (m, 3H), 1.45 (s, 9H), 1.44 (s, 9H), 0.97 (t, 3H) ppm. LC-MS M+1=340.3.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[N:19]=[C:18]([NH:23][C@@H:24]3[CH2:28][CH2:27][CH2:26][C@@H:25]3[NH:29]C(=O)OC(C)(C)C)[N:17]=[CH:16]4)=[C:9]([O:37][CH3:38])[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Cl>O1CCOCC1.ClCCl>[NH2:29][C@H:25]1[CH2:26][CH2:27][CH2:28][C@H:24]1[NH:23][C:18]1[N:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH:1]4[CH2:3][CH2:2]4)=[O:6])=[CH:8][C:9]=3[O:37][CH3:38])[CH:14]=2)[N:19]=1
Reactant: COc1cc(C(=O)NC2CC2)ccc1-c1ccc2nc(N[C@@H]3CCC[C@@H]3NC(=O)OC(C)(C)C)ncc2c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc(C(=O)NC2CC2)ccc1-c1ccc2nc(N[C@@H]3CCC[C@@H]3N)ncc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl ((1S,2R)-2-((6-(4-(cyclopropylcarbamoyl)-2-methoxyphenyl)quinazolin-2-yl)amino)cyclopentyl)carbamate (58 mg, 0.11 mmol) and 4M HCl in Dioxane (0.8 mL) in dichloromethane (1.5 mL) was stirred at room temperature for 120 minutes. LC-MS indicated complete consumption of SM. The reaction mixture was concentrated and used without further purification in the next step.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]([OH:20])=[O:19]>>[C:23]([NH:22][CH2:21][CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[C:18]([OH:20])=[O:19])(=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC(CNC(=O)c1ccccc1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(NCC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O)c1ccccc1

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-benzoylamino-propionic acid to provide the title compound in good yield.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]2[O:6][CH2:7][C:8]3([CH2:22][O:23][C:4]=2[CH:3]=1)[O:12][CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:10]([CH:19]([CH3:21])[CH3:20])[CH2:9]3.N12CCN(CC1)CC2.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>CCOCC>[CH:19]([N:10]1[CH2:9][C:8]2([CH2:7][O:6][C:5]3[CH:24]=[CH:25][C:2]([NH:1][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:3][C:4]=3[O:23][CH2:22]2)[O:12][CH:11]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:20])[CH3:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)N1CC2(COc3ccc(N)cc3OC2)OC1c1ccccc1
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: CC(C)N1CC2(COc3ccc(NS(C)(=O)=O)cc3OC2)OC1c1ccccc1

Procedure:
The crude 7-amino-3'-isopropyl-2'-phenyl-3,4-dihydro-2H-1,5-benzodioxepin-3-spiro-5'-oxazolidine (352 mg.) is dissolved in dry ether (23 ml.) and 1,4-diazabicyclo[2,2,2]-octane (118 mg.; 1.065 mmole) is added. Methane sulphonyl chloride (105 mg.; 1.065 mmole) dissolved in dry ether (5 ml.) is added dropwise with stirring and the reaction mixture then is stirred at room temperature for 1 hour. The solid is filtered off and discarded: evaporation of the mother liquors affords 387.2 mg. (91%) of crude product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[N:8]O.[Cl:10]NC(=O)CCC(N)=O>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([Cl:10])=[NH:8]
Reactant: NC(=O)CCC(=O)NCl
Reactant: ON=Cc1ccccn1
Solvent: CN(C)C=O
Product: N=C(Cl)c1ccccn1
Temperature: 30 °C
Reaction time: 2 h

Procedure:
To a mixture of pyridin-2-carbaldehyde-oxime (15 gm) and N-chlorosuccinamide (25 gm) in DMF (30 ml) was stirred at 30° C. over a period of 2 h. The reaction mixture was quenched with ice cold water (150 ml). The suspension was filtered and the wet cake washed with small quantity of water to provide pure title compound in 7 gm quantity (55%) as a white solid.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11]1([OH:21])[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1.[C:22](=[O:24])=[O:23].Cl>C1COCC1.O>[OH:21][C:11]1([C:7]2[S:6][CH:10]=[C:9]([C:22]([OH:24])=[O:23])[N:8]=2)[CH2:12][CH2:13][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:19][CH2:20]1
Reactant: OC1(c2nccs2)CCC2(CC1)OCCO2
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1csc(C2(O)CCC3(CC2)OCCO3)n1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of n-butyllithium (17.1 mL of 1.6 M solution in hexane, 27.35 mmol) was added to 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol (3.00 g, 12.43 mmol) in THF (50 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, dry ice (10 g, 227 mmol) was added to the lithiated compound solution and stirred for 2 h at −78° C. Water was added and the solution was warmed to room temperature. The mixture was then treated with 1N HCl to pH 3 to 4 and extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), and concentrated and chromatographed EtOAc to 1% AcOH/EAOAc) to give 3.23 g of 2-(8-hydroxy-1,4-dioxaspiro[4.5]dec-8-yl)-1,3-thiazole-4-carboxylic acid. MS (EI) calcd: (M+H)+=286.1; found: 286.0.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[O:7][CH2:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][CH:10]=1)([O-])=O.Cl.[OH-].[NH4+]>O.C(OCC)(=O)C>[C:15]1([C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][C:6]3[CH:5]=[C:4]([NH2:1])[CH:23]=[CH:22][CH:21]=3)[N:14]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1cccc(OCc2cccc(-c3ccccc3)n2)c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cccc(OCc2cccc(-c3ccccc3)n2)c1
Yield: 86.9 %

Procedure:
A supension of 6.2 g (0.02 mol) of 6-[(3-nitrophenoxy)methyl]-2-phenylpyridine in a solution of 50.0 g (0.18 mol) of ferrous sulfate heptahydrate and 0.3 ml of concentrated hydrochloric acid in 100 ml of water is heated on a steambath of 90° C. Concentrated ammonium hydroxide is added in 3 increments of 10 ml over a period of 10 minutes. Heating is discontinued and the reaction mixture is allowed to cool over a period of 45 minutes while vigorously stirring. The reaction mixture is diluted with 300 ml of water/300 ml of ethyl acetate and filtered through Celite. The filter cake is extracted once with 300 ml of ethyl acetate, and the combined ethyl acetate solution is concentrated in vacuo to obtain an oil (4.8 g). The oil is chromatographed with ethyl acetate/hexane as eluent. Fractions 8-11 are combined and concentrated to obtain 2.0 g (37%) of an oil, MS (CI) 277 (N+H). The product is used without further purification in subsequent reactions.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][C:6]=12.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([CH:11]([Br:20])[CH3:12])=[CH:7][C:6]=12
Reactant: CCc1ccn2ncc(Br)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC(Br)c1ccn2ncc(Br)c2c1
Temperature: 77 °C
Reaction time: 2 h
Yield: 28697.2 %

Procedure:
To a stirred solution of 3-bromo-5-ethylpyrazolo[1,5-a]pyridine (I-17, 2.1 g, 0.0094 mmol) in CCl4 (20 mL) at rt was added NBS (2 g, 0.01 mmol) followed by benzoyl peroxide (1.1 g, 0.004 mmol). The resulting reaction mixture was heated to 77° C. After 2 h, the reaction mixture was allowed to cool to rt and subsequently water (20 mL) was added followed by extraction with dichloromethane (2×20 mL). The combined organic layers were washed with water (1×20 mL), sat NaHCO3 solution (1×10 mL), brine (1×10 mL), dried over Na2SO4 and the solvent was removed under reduced pressure. The resulting crude product was purified by column chromatography over silica gel (petroleum ether/EtOAc, 0-5% EtOAc) to afford 820 mg (29%) of 3-bromo-5-(1-bromoethyl)pyrazolo[1,5-a]pyridine (I-18) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=7.91 Hz, 1H), 7.93 (s, 1H), 7.46 (d, J=1.32 Hz, 1H), 6.90-6.92 (dd, J=1.76, 5.71 Hz, 1H), 5.19-5.24 (m, 2H), 2.08 (d, J=7.04 Hz, 3H); ESI-LC/MS (m/z): [M+H]+ 302.9, [(M+2)+H]+ 304.9, [(M+4)+H]+ 306.9, RT 2.65 min