Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:2][CH2:3]2)=[O:26])=[CH:28][CH:29]=1)([O-:20])=[O:19]
Reactant: COC(=O)c1cccc(CN2CCNCC2)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1cccc(CN2CCN(C(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
A mixture of methyl 3-(piperazin-1-ylmethyl)benzoate (2.47 g, 10.542 mmol), 4-nitrobenzoic acid (1.77 g, 10.542 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.03 g, 15.813 mmol), triethylamine (2.94 mL, 21.084 mmol) and acetonitrile (40 mL) were stirred together, at ambient temperature, for 4 hours before being concentrated under vacuum. The residue was dissolved in ethyl acetate, filtered, washed with water (×2) and treated with strong cation exchange column chromatography to afford the title compound (3.12 g). MS (ESI) m/z 384.3 [M+H]+
Reaction SMILES: [CH2:1]([NH:3][C:4]([C@@H:6]1[C@H:10]2[O:11][C:12]([CH3:15])([CH3:14])[O:13][C@H:9]2[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([C:40]([O:42]CC)=[O:41])=[N:20][C:21]=3[NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:7]1)=[O:5])[CH3:2].[OH-].[Na+]>CO>[CH2:1]([NH:3][C:4]([C@@H:6]1[C@H:10]2[O:11][C:12]([CH3:15])([CH3:14])[O:13][C@H:9]2[C@H:8]([N:16]2[CH:24]=[N:23][C:22]3[C:17]2=[N:18][C:19]([C:40]([OH:42])=[O:41])=[N:20][C:21]=3[NH:25][CH2:26][CH:27]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:7]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)OCC)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)O)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
To a solution of ethyl 9-{(3aR,4R,6S,6aS)-6-[(ethylamino)carbonyl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl}-6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 69) (16.47 g, 0.0274 moles) in methanol (164 ml) was added aqueous sodium hydroxide (30.2 ml of a 1M solution, 0.0302 moles) and the resultant mixture was stirred at ambient temperature under an atmosphere of nitrogen for 1.5 hours. The reaction mixture was then concentrated in vacuo and to the residue was added dichloromethane (160 ml) and deionised water (160 ml). The pH of this mixture was adjusted to pH 4 by the addition of aqueous 2M hydrochloric acid with stirring. The organic phase was separated and the aqueous layer was extracted with dichloromethane (75 ml). The organic phases were then combined, dried over anhydrous magnesium sulphate and concentrated in vacuo to give the title compound (15.5 g) as a cream coloured foam that was used as such for the next step. If necessary, this crude product can be purified by standard means, such as flash chromatography on silica gel.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:20])[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]1(C)[CH:26]=CC(S(Cl)(=O)=O)=C[CH:22]=1.COC(OC)(C)C>C(Cl)Cl>[CH2:1]([O:8][CH2:9][CH:10]1[CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[O:12][C:21]([CH3:26])([CH3:22])[O:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC(COCc1ccccc1)C(O)c1ccccc1Cl
Solvent: ClCCl
Solvent: COC(C)(C)OC
Product: CC1(C)OC(COCc2ccccc2)C(c2ccccc2Cl)O1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8262.7 %

Procedure:
To a solution of (±)-3-(benzyloxy)-1-(2-chlorophenyl)propane-1,2-diol (Preparation example 370, 2.4 g, 8.2 mmole) in CH2Cl2 (40 mL) was added p-toluenesulfonyl chloride (15.2 g, 0.08 mmole), and dimethoxypropan (8.4 mL, 9.84 mmole) at 0° C. sequently. The mixture was stirred for 1.5 hr at room temperature. The TLC showed complete consumption of SM. The reaction mixture was quenched with H2O then extracted with EtOAc. The aqueous layer was extracted with EtOAc and separated. The combined organic layer was washed with H2O, then dried over MgSO4 and evaporated under reduced pressure. The crude compound was purified by silica ge column to produce the title compound (2.2 g, 75˜90%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][C:31]1([CH2:36][OH:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][C:31]2([CH2:36][OH:37])[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NC1(CO)CCCC1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNC3(CO)CCCC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL), and the solution was treated with 1-amino-1-cyclopentanemethanol (23 mg, 0.20 mmol) and sodium triacetoxyborohydride (48 mg, 0.23 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(1-hydroxymethylcyclopentyl)aminomethyl]indol-2-yl}isoindolinone was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:20])[O:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][Cl:23].C([Li])CCC.S([O-])(O)(=O)=O.[K+]>CCCCCC.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]([CH2:22][Cl:23])([OH:20])[O:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCBr
Reactant: CC(C)(C)OC(=O)N1COC(=O)[C@@H]1Cc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1COC(O)(CCl)[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
(4S)-N-tert-butoxycarbonyl-4-phenylmethyloxazolidin-5-one (0.34 g) and bromochloromethane (0.10 ml) were added to dehydrated tetrahydrofuran (12 ml). After cooling to −78° C., 1.53 M solution (1.03 ml) of n-butyllithium in hexane was added to the obtained mixture, and they were stirred for 1 hour. 10% aqueous potassium hydrogensulfate solution was added to the reaction mixture to terminate the reaction. The temperature of the reaction mixture was elevated to room temperature. After the extraction with ethyl acetate twice, the obtained ethyl acetate layer was dried over anhydrous magnesium sulfate and then magnesium sulfate was removed. The solvent was evaporated under reduced pressure to obtain intended (4S)-N-tert-butoxycarbonyl-5-chloromethyl-5-hydroxy-4-phenylmethyloxazolidine (0.40 g) in a yield of 100%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[O:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.[CH3:13]O.[O:15]1CCOC[CH2:16]1>>[CH3:13][O:7][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:1][CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:15][CH3:16]
Reactant: CO
Reactant: C1COCCO1
Product: COCCOCCOCCOCCOC

Procedure:
In using the dioxane solvent of "H", it is preferred to develop first with dioxane alone, followed by a mixture of dioxane and alkanol and finished with alkanol alone (for example, dioxane/dioxane:methanol mixture/methanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH2:17][C:16]3[CH2:15][CH:14]([C:18]([O:20]CC)=[O:19])[C:13]4=[N:23][NH:24][N:25]=[C:11]([C:12]=34)[C:10]([S:26][CH3:27])=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:17][C:16]3[CH2:15][CH:14]([C:18]([OH:20])=[O:19])[C:13]4=[N:23][NH:24][N:25]=[C:11]([C:12]=34)[C:10]([S:26][CH3:27])=[N:9]2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1CC2=C3C(=NNN=C31)C(SC)=NN(Cc1ccc(OC)cc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(CN2CC3=C4C(=NNN=C4C(C(=O)O)C3)C(SC)=N2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
The crude ethyl 6-(4-methoxybenzyl)-4-(methylthio)-6,7,8,9-tetrahydro-2H-1,2,3,5,6-pentaazabenzo[cd]azulene-9-carboxylate (24 g), was dissolved in ethanol (250 mL) and sodium hydroxide (27.11 g, 677.75 mmol) in water (250 mL) was added to it. The reaction mixture was then stirred at 60° C. for 2 h. Ethanol was removed under reduced pressure and the aqueous layer was acidified using 10% citric acid solution. The aqueous layer was then extracted with dichloromethane (250 mL×3); the combined organic layer was washed with water (500 mL×2) followed by brine (500 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give a residue as 6-(4-methoxybenzyl)-4-(methylthio)-6,7,8,9-tetrahydro-2H-1,2,3,5,6-pentaazabenzo[cd]azulene-9-carboxylic acid. To the residue (24 g) was added 4M HCl indioxane—(500 mL) and the mixture was refluxed for 16 h. Solvent was removed under reduced pressure and saturated NaHCO3 solution (250 mL) was added to the residue. The mixture was then extracted using dichloromethane (200 mL×3). The combined organic layer was washed with water (500 mL), brine (500 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (using 0-10% tetrahydrofuran in dichloromethane) to give a solid and the solid was further titurated with n-pentane to provide pure 6-(4-methoxybenzyl)-4-(methylthio)-6,7,8,9-tetrahydro-2H-1,2,3,5,6-pentaazabenzo[cd]azulene (6.0 g, 29.2% yield over four steps). LCMS [M+H]: 342, HPLC: 97.65% (254 nm), 1H NMR (DMSO-d6, 400 MHz): δ 12.97 (bs, 1H), 7.24 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 4.91 (s, 2H), 3.72 (s, 3H), 3.55 (d, J=7.2 Hz, 2H), 2.90-2.80 (m, 2H), 2.45 (s, 3H), 2.0-1.9 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C@@H:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:14]([Cl:46])=[C:15]([NH:21][C:22]3[N:27]=[C:26]([N:28]([CH:38]4[CH2:40][CH2:39]4)[CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[C:25]4=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:24]4[N:23]=3)[CH:16]=[C:17]([C:19]#[N:20])[CH:18]=2)[CH2:9][C@H:8]1[O:47][Si:48]([C:51]([CH3:54])([CH3:53])[CH3:52])([CH3:50])[CH3:49].C(N(CC)CC)C>ClCCl>[Si:48]([O:47][C@H:8]1[C@H:7]([NH:6][C:3](=[O:4])[CH2:2][Cl:1])[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([NH:21][C:22]3[N:27]=[C:26]([N:28]([CH:38]4[CH2:40][CH2:39]4)[CH2:29][C:30]4[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)[C:25]4=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:24]4[N:23]=3)[C:14]=2[Cl:46])[CH2:9]1)([C:51]([CH3:53])([CH3:54])[CH3:52])([CH3:49])[CH3:50]
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](N)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CC[C@@H](NC(=O)CCl)[C@H](O[Si](C)(C)C(C)(C)C)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
2-chloroacetyl chloride (7.56 mg, 0.067 mmol) in dichloromethane (0.5 mL) was added to a mixture of (+/−)-2-((3-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (Example 171D), (39 mg, 0.056 mmol) and triethylamine (0.016 mL, 0.112 mmol) in dichloromethane (1 mL) at 0° C. and the reaction mixture was stirred at for 1 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel using an automated ISCO system (12 g column, eluting with 5-40% ethyl acetate/dichloromethane to afford (+/−)-N-((3R,4R)-3-((tert-butyldimethylsilyl)oxy)-1-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)piperidin-4-yl)-2-chloroacetamide (43 mg) as a white solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]1[C:14]2=[CH:15][N:16]([CH2:24][CH2:25][S:26]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:13]2[C:12](=[O:46])[N:11]([CH3:47])[C:10]1=[O:48].C([SiH](CC)CC)C>C(Cl)Cl>[SH:26][CH2:25][CH2:24][N:16]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:13]2[C:14]([N:9]([CH3:8])[C:10](=[O:48])[N:11]([CH3:47])[C:12]2=[O:46])=[CH:15]1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3ccccc3)n(CCS)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
TFA (5.975 ml, 78 mmol) was added to a solution of 1,3-dimethyl-5-phenyl-6-(2-tritylsulfanyl-ethyl)-1,6-dihydro-pyrrolo[3,4-d]pyrimidine-2,4-dione (step 1) (865 mg, 1.551 mmol) and triethylsilane (2.477 ml, 15.51 mmol) in DCM (20 ml) and the mixture stirred at RT for 3 hours. The solvent was evaporated under reduced pressure. The residue was partitioned between DCM (10 mL) and sat. NaHCO3 (10 mL) and the phases separated. The organic phase was dried over magnesium sulfate and the solvent evaporated under reduced pressure. The residue was triturated with diethyl ether and the solid collected by filtration. The title compound was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1O[CH:21]=[CH:22][CH:23]=1)(=[O:14])=[O:13].ClC1C2C(=CC=CC=2)C=CC=1SC[CH2:37][NH:38]CC1N(C)C=CC=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[S:12]([CH2:15][CH2:16][NH:17][CH2:18][C:19]1[N:38]([CH3:37])[CH:21]=[CH:22][CH:23]=1)(=[O:14])=[O:13]
Reactant: Cn1cccc1CNCCSc1ccc2ccccc2c1Cl
Reactant: O=S(=O)(CCNCc1ccco1)c1ccc2ccccc2c1Cl
Product: Cn1cccc1CNCCS(=O)(=O)c1ccc2ccccc2c1Cl
Yield: 76 %

Procedure:
Prepared as described for compound 25 from 2-[(1-chloronaphthalen-2-yl)sulfanyl]-N-[(1-methyl-1H-pyrrol-2-yl)methyl]ethanamine and in 76% yield as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[C:6]([C:8]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)=[O:9])[CH:7]=1.Cl[C:24]1[N:29]=[C:28]([N:30]([CH3:32])[CH3:31])[CH:27]=[C:26]([CH3:33])[N:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[C:6]([C:8]([N:10]2[CH2:11][CH:12]3[CH2:13][N:14]([C:24]4[N:29]=[C:28]([N:30]([CH3:32])[CH3:31])[CH:27]=[C:26]([CH3:33])[N:25]=4)[CH2:15][CH:16]3[CH2:17]2)=[O:9])[CH:7]=1
Reactant: Cc1cc(N(C)C)nc(Cl)n1
Reactant: O=C(c1cc(F)ccc1-n1nccn1)N1CC2CNCC2C1
Product: Cc1cc(N(C)C)nc(N2CC3CN(C(=O)c4cc(F)ccc4-n4nccn4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 21 and (2-chloro-6-methyl-pyrimidin-4-yl)-dimethyl-amine. MS (ESI): mass calculated for C22H25FN8O, 435.49; m/z found 437.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.99-7.93 (m, 1H), 7.73 (s, 2H), 7.23-7.18 (m, 1H), 7.15-7.12 (m, 1H), 5.69 (s, 1H), 3.88-3.80 (m, 2H), 3.71-3.62 (m, 2H), 3.59-3.52 (m, 1H), 3.49-3.32 (m, 2H), 3.15-2.83 (m, 9H), 2.24 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(N(CC)CC)C.[CH3:22][N:23]([CH2:25][CH:26]([OH:28])[CH3:27])[CH3:24]>C(Cl)(Cl)Cl>[C:1]([O:28][CH:26]([CH3:27])[CH2:25][N:23]([CH3:24])[CH3:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC(O)CN(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)OC(C)CN(C)C

Procedure:
The (N,N-disubstituted amino)-alkanol alkanoates are readily prepared by reacting the corresponding aminoalkinol with lauroyl chloride in the presence of triethylamine. A solvent such as chloroform is optional but preferred. For example, 1-(N,N-dimethylamino)-2-propanol can be reacted with lauroyl chloride in chloroform and in the presence of triethylamine to form 1-(N,N-dimethylamino)-2-propanol dodecanoate.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH2:11])OCC[O:3]1.[ClH:15]>CO>[ClH:15].[C:2]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][NH2:11])(=[O:3])[CH3:1]
Reactant: CC1(c2cccc(CN)c2)OCCO1
Agent: Cl
Solvent: CO
Product: CC(=O)c1cccc(CN)c1

Procedure:
A solution of 3-(2-methyl-1,3-dioxolan-2-yl)benzylamine (57.2 g) in 1N hydrochloric acid (500 ml) and methanol (500 ml) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in methanol. The resulting precipitate was removed by filtration. The solvent was removed under reduced pressure. Recrystallization from a mixture of ethanol and acetone afforded 3-acetylbenzylamine hydrochloride (31.2 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[CH3:27][C:28]1([CH3:52])[C:32](=[O:33])[N:31]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:35]=2)[C:30](=[O:46])[N:29]1[CH2:47][CH2:48][CH2:49][CH2:50]O>C(Cl)Cl>[CH3:27][C:28]1([CH3:52])[C:32](=[O:33])[N:31]([C:34]2[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[C:36]([C:42]([F:45])([F:44])[F:43])[CH:35]=2)[C:30](=[O:46])[N:29]1[CH2:47][CH2:48][CH2:49][CH2:50][I:25]
Reactant: II
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCO
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1CCCCI
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
787 mg of triphenyl phosphine, 204 mg of imidazole, 762 mg of iodine and 5 ml of methylene chloride are introduced, the suspension is agitated for 45 minutes at ambient temperature, then over about 3 minutes, 1.1 g of 4-(4,4-dimethyl-2,5-dioxo-3-(4-hydroxybutyl)-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile obtained in Example 1 of EP 0,580,459 in 7 ml of methylene chloride is added. Rinsing is carried out with 1 ml of methylene chloride followed by agitation for 4 hours at ambient temperature.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5](=[N:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:14][CH2:15][CH2:16][NH:17]C(=O)OC(C)(C)C)[C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>O1CCOCC1>[NH2:17][CH2:16][CH2:15][CH2:14][N:4]1[C:3]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:2]([CH3:1])[S:6][C:5]1=[N:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1sc(=Nc2ccccc2)n(CCCNC(=O)OC(C)(C)C)c1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1sc(=Nc2ccccc2)n(CCCN)c1-c1ccccc1
Yield: 115.7 %

Procedure:
t-Butyl 3-[5-methyl-4-phenyl-2-(phenylimino)thiazol-3(2H)-yl]propylcarbamate (370 mg) and a 4N solution of hydrogen chloride in dioxane (4 ml) were treated in a similar manner to in Example 9 (2) to give the title compound (327 mg) as hydrochloride.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:38])[C@@H:10]([NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:35])[F:34])[C:26]=1[CH3:37])[C:11]1[O:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[N:14][N:15]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([C:13]2[O:12][C:11]([C@H:10]([NH:24][C:25]3[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:34])([F:36])[F:35])[C:26]=3[CH3:37])[C@@H:9]([OH:8])[CH3:38])=[N:15][N:14]=2)=[CH:21][CH:20]=1)#[N:23]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O[Si](C)(C)C(C)(C)C)ccc(C#N)c1C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](c2nnc(-c3ccc(C#N)cc3)o2)[C@H](C)O)ccc(C#N)c1C(F)(F)F
Temperature: -55 °C
Yield: 60.2 %

Procedure:
4-((1R,2S)-2-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl) propylamino)-3-methyl-2-(trifluoromethyl)benzonitrile (380 mg, 0.70 mmol) was dissolved in THF (20 mL) and cooled to −55° C. under N2 atmosphere. TBAF (1.0 M solution in THF, 0.84 mL, 0.84 mmol) was added to the pre-cooled solution slowly and the temperature was allowed to rise gradually. After the reaction was complete, saturated aqueous NH4Cl (100 mL) was added and the solution was extracted with EtOAc (3×100 mL). Purification by column chromatography on silica gel provided the desired product (180 mg): 1H NMR(500 MHz, acetone-d6, δ in ppm): 8.18 (d, J=9 Hz, 2H), 7.97 (d, J=9 Hz, 2H), 7.59 (d, J=9 Hz, 1H), 7.13 (d, J=9 Hz, 1H), 5.82 (d, J=9 Hz, 1H), 5.18 (m, 1H), 4.83 (d, J=6 Hz, 1H), 4.64 (m, 1H), 2.40 (m, 3H), 1.40 (d, J=6 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Na].[CH2:16]([NH:23][C:24](=[O:47])[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:36]3[N:37]=[C:38](S(C)(=O)=O)[N:39]=[C:40]([CH3:41])[C:35]=3[CH:34]=[CH:33][C:32]2=[O:46])=[CH:27][CH:26]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([NH:23][C:24]([C:25]1[CH:26]=[CH:27][C:28]([N:31]2[C:36]3[N:37]=[C:38]([O:1][C:2]4[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=4)[N:39]=[C:40]([CH3:41])[C:35]=3[CH:34]=[CH:33][C:32]2=[O:46])=[CH:29][CH:30]=1)=[O:47])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccc(C(=O)NCc2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(Oc2nc(C)c3ccc(=O)n(-c4ccc(C(=O)NCc5ccccc5)cc4)c3n2)cc1
Reaction time: 18 h

Procedure:
Ethyl 4-hydroxybenzoate (0.128 mmol) was suspended in THF (1 ml) and NaH (2.9 mg, 0.12 mmol) was added. After formation of the subsequent sodium salt, suspended in THF, the resin (A3) was added and shaking continued for 18 h. The resin was washed with THF (2×1 min), DMF (3×1 min, 60° C.) and with DCM (3×1 min).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[OH:22].C([O-])([O-])=O.[Cs+].[Cs+].CC(=O)OCC>CS(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[F:14]
Reactant: Oc1ccc(F)cc1F
Reactant: CCS(=O)(=O)c1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)c1ccc(Oc2ccc(F)cc2F)c(Br)c1
Yield: 81.2 %

Procedure:
2-bromo-1-fluoro-4-ethylsulfonylbenzene (130 mg, 0.49 mmol), 2,4-difluorophenol (78 mg, 0.60 mmol) and Cs2CO3 (478 mg, 1.47 mmol) in DMSO (5 mL) were heated at 100° C. for 12 h. EA extractive work up gave the title compound (150 mg, yield: 80.5%) as a grey solid. 1H NMR (CDCl3, 400 MHz) δ 8.18 (d, J=2.0 Hz, 1H), δ 7.75 (dd, J1=8.4 Hz, J2=1.6 Hz, 1H), 7.22-7.16 (m, 1H), 7.06-6.95 (m, 2H), 6.80 (d, J=8.8 Hz, 1H), 3.16 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.6 Hz, 3H). LCMS: 395.8 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([O:15]C)=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9]C)=[O:8].Cl>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([OH:15])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1ccc(OC)cc1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C(=O)O)c(C(=O)O)c1
Temperature: 25 °C

Procedure:
A solution of dimethyl 4-methoxyphthalate (20 g, 89 mmol) was heated at reflux in 10% aqueous sodium hydroxide (85 mL) for 1 hour. The mixture was cooled to room temperature then acidified to pH 1 using concentrated hydrochloric acid. The precipitate that formed was filtered off, washed with water and dried under vacuum to afford the title compound D22 (13.61 g). MH−195. 1H NMR δ (DMSO-de) 3.83 (3H, s), 7.05-7.10 (3H, m), 7.72 (1H, d).