Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[CH2:10]([O:14][CH2:15][CH:16]1[O:18][CH2:17]1)[CH2:11][CH2:12][CH3:13].Cl(O)(=O)(=O)=O>CCOCC>[CH2:10]([O:14][CH2:15][CH:16]([OH:18])[CH2:17][O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(CC)CO
Reactant: CCCCOCC1CO1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: CCCCOCC(O)COCC(CC)CCCC
Temperature: 100 °C

Procedure:
260 g (2 mol) of 2-ethylhexanol and 130 g (1 mol) of 1-butoxy-2,3-epoxypropane were stirred together and 0.25 ml of 70% aqueous perchloric acid was added thereto. The mixture was heated for 4 h at 100° C. and then cooled. Next, 1 l of ether was added. The mixture was rinsed twice with water and dried over potassium carbonate. After filtration and concentration by evaporation the crude product was fractionated under reduced pressure. The excess 2-ethylhexanol was removed. Yield: 151 g of oil-former 10 (58.2%) boiling at 146° C./12 mm Hg.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=4)=[O:18])=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:2][C:3]1[CH:32]=[CH:31][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:29])([F:30])[F:28])[CH:21]=4)=[O:18])=[CH:12][CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2c(c1)ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Agent: Cl
Product: CCOC(=O)Nc1ccc2c(c1)ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be synthesized from 1-[4-[5-aminobenzimidazol-1-yl]phenyl]-3-(4-chloro-3-(trifluoro-methyl)phenyl)urea hydrochloride and ethyl chloroformate by the same method as in Example 41.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1.[C:19](Cl)(=[O:22])[CH2:20][CH3:21]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:22])[CH2:20][CH3:21])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: CCC(=O)Cl
Reactant: Cc1nc(-c2sc(N)nc2-c2ccccc2)no1
Product: CCC(=O)Nc1nc(-c2ccccc2)c(-c2noc(C)n2)s1

Procedure:
Prepared from 5-(5-methyl-[1,2,4]oxadiazol-3-yl)-4-phenyl-thiazol-2-ylamine and propionyl chloride.
Reaction SMILES: [C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26]O)=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28]CCl.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O>>[C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:26][Cl:28])=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][N:20]=[CH:19]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CO)OC(=O)c1ccccc1
Reactant: ClCCl
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1CCl)OC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
(R)-3-(7-chloro-4-(hydroxymethyl)-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-yl benzoate (6.5 g, 16.72 mmol) in dichloromethane (100.0 ml, 1554 mmol) was added Diisopropylethyl amine (2.59 g, 20.06 mmol) followed by methanesulfonyl chloride (1.433 ml, 18.39 mmol). After 2 h, the reaction mixture was quenched with aqueous NaHCO3, dried (Na2SO4) and the solvent was removed. MS (ESI) 407 (M+H); Rf=1.69.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2O)=[CH:14][CH:13]=[CH:12][C:11]=3[C:18]([F:21])([F:20])[F:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrC1C=N[C:26]2[C:31](C=1O)=[CH:30][CH:29]=[CH:28][C:27]=2C(F)(F)F.C1(B(O)O)C=CC=CC=1.C([O-])(O)=O.[Na+]>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.O.CO.C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([C:16]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[C:18]([F:21])([F:20])[F:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1c(-c2ccccc2)cnc2c(C(F)(F)F)cccc12
Reactant: Oc1c(Br)cnc2c(C(F)(F)F)cccc12
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: OB(O)c1ccccc1
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc2c(-c3ccccc3)c(-c3ccccc3)cnc12
Yield: 59 %

Procedure:
3-Phenyl-8-(trifluoromethyl)quinolin-4-ol: A solution of 3-bromo-8-(trifluoromethyl)quinolin-4-ol (3.2 g, 10.95 mmol) and phenyl boronic acid (2.67 g, 21.91 mmol) in 2:1 toluene:methanol (120 mL) and sat aq NaHCO3 (40 mL) is treated with Pd(PPh3)4 (760 mg) and heated at reflux overnight. The reaction is poured into water and extracted with ethyl acetate. The combined extracts are washed with 2N aq NaOH, water, brine, and dried with magnesium sulfate. The extracts are concentrated and the residue is chromatographed with 1:4 ethyl acetate:hexanes to afford the title compound as a yellow solid (6.4 g, 59%). mp 272-275° C.; MS (ESI) m/z 290; MS (ESI) m/z 288; HRMS: calcd for C16H10NF3O+H, 290.07927; found (ESI_FT, [M+H]1+), 290.07816.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19](Cl)[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:29][O:30][CH2:31][C:32]#[C:33][CH2:34][OH:35].C(O)C#CCO.COS(OC)(=O)=O.[H-].[Na+]>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[C:19]([O:35][CH2:34][C:33]#[C:32][CH2:31][O:30][CH3:29])[N:18]=[CH:17][N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCC#CCO
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: OCC#CCO
Agent: [H-]
Solvent: COS(=O)(=O)OC
Product: COCC#CCOc1ncnc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.6 %

Procedure:
To a mixture of 300 mg of 4-tert.-butyl-N-[6-chloro-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide (Example 12c) and 1.8 g of 4-methoxy-2-butyn-1-ol (prepared starting from 2-butyn-1,4-diol and dimethylsulfate following the procedure given in Bull. Chem. Soc. Japan 28 (1955), 80-83) was added 288 mg of 55% NaH in mineral oil. After evolution of gas had ceased, the brown suspension was stirred at room temperature for 24 h. Another 288 mg of 55% NaH in mineral oil was added and the mixture was stirred at 60° C. for 18 h. The mixture was cooled, diluted with 50 ml of 10% aqueous citric acid and extracted 4 times with 50 ml of ethyl acetate. The combined organic phases were washed with water, dried over MgSO4 and evaporated. The crude product was purified by column chromatography on silica gel eluting with hexane:ethyl acetate 1:1 and precipitated from diethyl ether to give 213 mg of 4-tert.-butyl-N-[6-(4-methoxy-2-butynyloxy)-5-(p-tolyl)-4-pyrimidinyl]-benzene sulfonamide as a white powder. LC-MS: tR=5.61 min, [M+1]+=480.30, [M−1]−=478.39.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH2:26][CH2:27][CH2:28][CH3:29])[C:3](=[O:25])/[CH:4]=[CH:5]/[C@H:6]1[CH2:10][O:9][C:8](=[O:11])[N:7]1[CH2:12][CH2:13][S:14][C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1.[BH4-].[Na+].C(O)(=O)C.O>CO>[OH:25][C@@H:3]([C:2]([CH3:1])([CH3:30])[CH2:26][CH2:27][CH2:28][CH3:29])/[CH:4]=[CH:5]/[C@H:6]1[CH2:10][O:9][C:8](=[O:11])[N:7]1[CH2:12][CH2:13][S:14][C:15]1[S:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=1
Reactant: CCCCC(C)(C)C(=O)/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)OCC)cs1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CCCCC(C)(C)[C@H](O)/C=C/[C@H]1COC(=O)N1CCSc1nc(C(=O)OCC)cs1
Yield: 70 %

Procedure:
To a solution of the compound 6 (124 mg) in anhydrous methanol (1.40 mL) were added sodium borohydride (10.4 mg) and a catalytic amount of acetic acid at −78° C. and the solution was stirred at the same temperature for 1 hour. After return to room temperature, to the reaction solution was added water and the solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1), to give the title compound (87.2 mg) having the following physical data.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:15][C:16]1[N:21]=[C:20]2[NH:22][C:23]([C:25]([NH:27][C@@H:28]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:29](O)=[O:30])=[O:26])=[CH:24][C:19]2=[CH:18][CH:17]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[F:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][C@H:28]([NH:27][C:25]([C:23]2[NH:22][C:20]3=[N:21][C:16]([Cl:15])=[CH:17][CH:18]=[C:19]3[CH:24]=2)=[O:26])[C:29](=[O:30])[N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:38][CH:37]=1
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2ccc(Cl)nc2[nH]1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCCC1)c1cc2ccc(Cl)nc2[nH]1

Procedure:
To pyrrolidine (11.5 mg, 0.14 mmol) was added a solution of DIPEA (60 μL, 0.35 mmol) in DMF (500 μL) followed by 2-(S)-[(6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl) propionic acid (EXAMPLE 272, 50 mg, 0.14 mmol) in DMF (500 μL) and HOBt (23 mg, 0.15 mmol) in DMF (500 μL) and the mixture stirred. After 5 min EDCI (34.5 mg, 0.18 mmol) in DMF (500 μL) was added and the reaction stirred for 16 hr. Solvent was removed in vacuo then crude material purified by mass-directed purification to give the title compound. m/z (ES+)=414.93 [m+H]+; RT=3.77 min.
Reaction SMILES: [Li+].[OH-].[CH3:3][C:4]1([C:20]([O:22]CC)=[O:21])[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1>C(O)C>[CH2:13]([O:12][C:10]([N:6]1[CH2:7][CH2:8][CH2:9][C:4]([CH3:3])([C:20]([OH:22])=[O:21])[CH2:5]1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1(C)CCCN(C(=O)OCc2ccccc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C(=O)O)CCCN(C(=O)OCc2ccccc2)C1
Temperature: 86 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
LiOH (15.0 mL, 30.1 mmol) was added to 1-benzyl 3-ethyl 3-methylpiperidine-1,3-dicarboxylate (3.0 g, 10.0 mmol) in ethanol (15 mL), and the reaction mixture was stirred at 86° C. for 1 hour. The ethanol was removed, and ether (30 mL) was added. The aqueous layer was separated and acidified with saturated potassium hydrogen sulfate to a pH of about 3 to about 4, extracted with ethyl acetate (50 mL), washed with brine and dried over sodium sulfate. After removal of the solvent, 1-(benzyloxycarbonyl)-3-methylpiperidine-3-carboxylic acid (2.6 g, 92% yield) was isolated as an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:5]=1[CH2:6][OH:7].Cl[C:14]1[C:15]2[N:16]([C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=2)[CH:17]=[CH:18][N:19]=1>C(#N)C>[CH3:23][C:21]1[N:22]=[C:15]2[C:14]([O:7][CH2:6][C:5]3[C:8]([CH3:12])=[CH:9][CH:10]=[CH:11][C:4]=3[CH3:3])=[N:19][CH:18]=[CH:17][N:16]2[C:20]=1[CH3:24]
Reactant: Cc1nc2c(Cl)nccn2c1C
Reactant: Cc1cccc(C)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cccc(C)c1COc1nccn2c(C)c(C)nc12
Yield: 50 %

Procedure:
Sodium hydride (0.15 g, 3 mmol) (50% in oil) was added to a stirred solution of 2,6-dimethylbenzylalcohol in acetonitril (10 ml). 8-chloro-2,3-dimethylimidazo[1,2-a]pyrazine (0.4 g, 3 mmol) was added and the reaction mixture was refluxed for 20 h. The solvent was evaporated under reduced pressure and the residue was solved in methylene chloride and washed with water. The organic layer was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using ethylacetate:petroleum ether(40-60) 1:1 as eluent. Crystallization from petroleum ether gave 0.42 g (50%) of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[Al+3].[Cl-].[Cl-].[Cl-].[CH3:11][O:12][C:13]1[C:22]2[C:23](=[O:36])[C:24]3[CH:25]=[C:26]4[CH:35]=[CH:34][CH:33]=[CH:32][C:27]4=[N:28][C:29]=3[N:30]([CH3:31])[C:21]=2[C:20]2[CH:19]=[CH:18][C:17]([CH3:38])([CH3:37])[O:16][C:15]=2[CH:14]=1.Cl>ClCCl>[C:1]([C:18]1[C:17]([CH3:38])([CH3:37])[O:16][C:15]2[CH:14]=[C:13]([O:12][CH3:11])[C:22]3[C:23](=[O:36])[C:24]4[CH:25]=[C:26]5[CH:35]=[CH:34][CH:33]=[CH:32][C:27]5=[N:28][C:29]=4[N:30]([CH3:31])[C:21]=3[C:20]=2[CH:19]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: COc1cc2c(c3c1c(=O)c1cc4ccccc4nc1n3C)C=CC(C)(C)O2
Reactant: CCCC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCC(=O)C1=Cc2c(cc(OC)c3c(=O)c4cc5ccccc5nc4n(C)c23)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 0.81 mmol of butyryl chloride and 0.673 mmol of AlCl3 in 2 ml of anhydrous dichloromethane is added in small portions to 0.135 mmol of the product of Example 2 in 2 ml of dichloromethane at 0° C. The reaction mixture is stirred for 4 hours at ambient temperature and then poured into a 10% solution of HCl. Following conventional treatment of the organic phases, and evaporation thereof under reduced pressure, chromatography of the residue on silica gel (dichloromethane/methanol gradient) allows the expected product to be isolated.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@:6]([C:12]([N:14]1[C@@H:18]([CH3:19])[CH2:17][CH2:16][C@H:15]1[C:20]1[NH:21][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]4[NH:41][C:40]([C@@H:42]5[CH2:46][C@H:45]([CH2:47][O:48][CH3:49])[CH2:44][N:43]5[C:50](=[O:61])[C@@H:51]([NH:56][C:57](=[O:60])[O:58][CH3:59])[C@H:52]([O:54][CH3:55])[CH3:53])=[N:39][CH:38]=4)=[CH:33][CH:32]=3)=[CH:27][CH:26]=2)=[CH:23][N:24]=1)=[O:13])([C@@H:8]([CH3:11])[O:9][CH3:10])[NH2:7])=[O:4].[Cl:62]N1C(=O)CCC1=O>CN(C=O)C>[Cl:62][C:38]1[N:39]=[C:40]([C@@H:42]2[CH2:46][C@H:45]([CH2:47][O:48][CH3:49])[CH2:44][N:43]2[C:50](=[O:61])[C@@H:51]([NH:56][C:57](=[O:60])[O:58][CH3:59])[C@H:52]([O:54][CH3:55])[CH3:53])[NH:41][C:37]=1[C:34]1[CH:35]=[CH:36][C:31]([C:28]2[CH:27]=[CH:26][C:25]([C:22]3[NH:21][C:20]([C@@H:15]4[CH2:16][CH2:17][C@H:18]([CH3:19])[N:14]4[C:12](=[O:13])[C@@:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])([C@@H:8]([CH3:11])[O:9][CH3:10])[NH2:7])=[N:24][CH:23]=3)=[CH:30][CH:29]=2)=[CH:32][CH:33]=1
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc(-c4ccc(-c5cnc([C@@H]6CC[C@H](C)N6C(=O)[C@@](N)(NC(=O)OC)[C@@H](C)OC)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2nc(Cl)c(-c3ccc(-c4ccc(-c5cnc([C@@H]6CC[C@H](C)N6C(=O)[C@@](N)(NC(=O)OC)[C@@H](C)OC)[nH]5)cc4)cc3)[nH]2)N(C(=O)[C@@H](NC(=O)OC)[C@@H](C)OC)C1
Temperature: 45 °C
Yield: 4.6 %

Procedure:
To a solution of methyl {(2S,3R)-1-((2S,4S)-2-(5-(4′-(2-((2S,5S)-1-((2S,3R)-2-(methoxycarbonylamino)-O-methyl-L-threonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-yl}carbamate (0.12 g, 0.15 mmol) in DMF (1.5 mL) was added N-chlorosuccinimide (0.05 g, 0.38 mmol). The resulting solution was heated to 45° C. for 3 h and cooled to room temperature. The reaction solution was purified by preparative HPLC (Gemini C18, 20-75% MeCN/H2O (0.1% TFA)). The desired fractions were combined and lyophilized to provide methyl {(2S,3R)-1-((2S,4S)-2-(4-chloro-5-(4′-(2-((2S,5S)-1-((2S,3R)-2-(methoxycarbonylamino)-O-methyl-L-threonyl)-5-methylpyrrolidin-2-yl)-1H-imidazol-5-yl)biphenyl-4-yl)-1H-imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-yl}carbamate (0.006 g, 5%).
Reaction SMILES: [C:1]([C:3]1[C:4]([S:10][CH:11]([CH2:23][CH3:24])[CH2:12][CH2:13][N:14](C)[C:15](=O)OC(C)(C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[ClH:25]>O1CCOCC1>[ClH:25].[CH2:23]([CH:11]([S:10][C:4]1[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[C:6]([CH3:9])[N:5]=1)[CH2:12][CH2:13][NH:14][CH3:15])[CH3:24]
Reactant: CCC(CCN(C)C(=O)OC(C)(C)C)Sc1nc(C)ccc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: CCC(CCNC)Sc1nc(C)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,1-Dimethylethyl [3-[(3-cyano-6-methyl-2-pyridinyl)thio]pentyl]methylcarbamate (110 mg) was dissolved in 4M HCl in dioxane (10 ml). The resulting solution was stirred at room temperature for 1 h, then the solvent was evaporated off. The residue was recrystallised from diethyl ether/ethanol to give the title compound (90 mg) as a white solid.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[CH3:8][C:9]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]1[NH:14][CH2:15][CH2:16][N:17]=1.S(Cl)Cl>C(Cl)Cl.O>[CH3:8][C:9]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:10]=1[O:11][CH2:12][C:13]1[N:17]([CH2:12][O:11][C:10]2[CH:9]=[CH:21][CH:20]=[C:19]([CH3:18])[C:6]=2[CH3:7])[CH2:16][CH2:15][N:14]=1
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Reactant: CCN(CC)CC
Agent: ClSCl
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(OCC2=NCCN2COc2cccc(C)c2C)c1C
Reaction time: 2 h

Procedure:
11 g of triethylamine are added slowly dropwise at 0° C. to a solution of 20.4 g of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline in 200 ml of methylene chloride, followed by the slow dropwise addition of 5.15 g of freshly distilled sulfur chloride. The reaction mixture is then stirred for about 2 hours in an ice bath, the resultant solution is diluted with water and the organic phase is washed repeatedly with water, dried over sodium sulfate and concentrated completely. The residue is stirred in hexane and recrystallisation of the solid precipitate yields bis-(2,3-dimethylphenoxymethyl)-2-imidazoline)-1,1'-sulfide (compound 1) of the formula ##STR5## in the form of a light beige-coloured powder with a melting point of 112°-114° C.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=[CH2:18])=[CH2:10].Cl[CH:20](Cl)[CH3:21]>>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]=[CH2:18])=[CH2:10].[CH3:10][CH2:9][CH2:11][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:17][CH:20]([CH3:21])[CH3:1]
Reactant: CC(Cl)Cl
Agent: C=Cc1ccccc1C=C
Solvent: C=Cc1ccccc1
Product: CCCCCCCCCC(C)C

Procedure:
436 g of the succinic acid ester prepared in this manner are dissolved in 1200 g of dichloroethane. 160 g of a macroporous styrene bead polymer crosslinked with 8 % of divinyl benzene (obtained by bead polymerisation of styrene and divinyl benzene in the presence of 60 % by weight of isododecane based on the sum total of monomers) are swollen in this solution over a period of 30 minutes at 60° C, 100 g of concentrated sulphuric acid are then added dropwise with stirring over a period of 3 hours. After stirring the reaction mixture for 20 hours at reflux temperature, the reaction product is separated off. The product is freed form adherent dichloroethane by suspending it in 10 % aqueous ammonia solution and azeotropic destillation as is described in Example 1. The polymer is then heated for 10 hours to 180° C with 40 % sodium hydroxide solution in an autoclave. After the sodium hydroxide has been washed out, 585 ml of a weakly basic anion exchanger are obtained with an acid binding capacity of 2,72 Val/1 for N/10 hydrochloric acid and a nitrogen content of 10,9 % in the dry material.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5]Br.C(=O)([O-])[O-].[Cs+].[Cs+].[C:13]([O:17][C:18]([N:20]1[CH2:25][C:24](=[O:26])[N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])[CH2:22][C:21]1([CH3:35])[CH3:34])=[O:19])([CH3:16])([CH3:15])[CH3:14].O>CN(C)C=O>[C:13]([O:17][C:18]([N:20]1[CH2:25][C:24](=[O:26])[N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:22][C:21]1([CH3:35])[CH3:34])=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2O)CC1(C)C
Reactant: COCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCCOc1ccccc1N1CC(C)(C)N(C(=O)OC(C)(C)C)CC1=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 70.2 %

Procedure:
450 mg of 3-methoxypropyl bromide (2.94 mmol) and 958 mg of cesium carbonate (2.94 mmol) were added to a solution of 573 mg of 4-(2-hydroxyphenyl)-2,2-dimethyl-5-oxopiperazine-1-carboxylic acid t-butyl ester obtained in Example (10d) (1.96 mmol) in N,N-dimethylformamide (20 ml), and the mixture was stirred at 100° C. for four hours. The reaction mixture was cooled and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=1/1) to obtain 540 mg of the title compound (yield: 70%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:25]([O-])=O)[CH:9]=2)[N:4]=1.ClC1C2C(=CC=C([N+]([O-])=O)C=2)N=C(CCl)[N:30]=1.C(OC1C=CC(NC)=CC=1)(C)C.C(Cl)Cl>CC(O)C.Cl>[NH2:30][CH2:2][C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:25])[CH:9]=2)[N:4]=1
Reactant: CC(C)Oc1ccc(N(C)c2nc(CCl)nc3ccc([N+](=O)[O-])cc23)cc1
Reactant: O=[N+]([O-])c1ccc2nc(CCl)nc(Cl)c2c1
Agent: CNc1ccc(OC(C)C)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)Oc1ccc(N(C)c2nc(CN)nc3ccc(N)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
(2-Chloromethyl-6-nitro-quinazolin-4-yl)-(4-isopropoxy-phenyl)-methyl-amine: A suspension of 4-chloro-2-chloromethyl-6-nitroquinazoline (200 mg, 0.77 mmol) and (4-isopropoxy-phenyl)-methyl-amine (140 mg, 0.84 mmol) in i-PrOH (1.5 mL) was treated with HCl (12 M, 6 drops) and stirred at rt overnight. CH2Cl2 was added and the reaction washed with 5% NaOH, dried (MgSO4), filtered and concentrated. The residue was purified by gradient MPLC (SiO2, EtOAc/hexanes, 0-100%) to provide 203 mg (71%) of the title compound. 1H NMR (DMSO-d6) δ 8.35 (dd, 1H), 7.86 (dd, 1H), 7.71 (dd, 1H), 7.32-7.40 (m, 2H), 7.08-7.12 (m, 2H), 4.78 (s, 2H), 4.71 (sept, 1H), 3.63 (s, 3H), 1.31 (d, 6H); LC-MS (ESI+; 387 ([M+H]+)).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][CH2:7][CH:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[C:4]([N+:15]([O-])=O)[CH:3]=1>C(O)C.[Ni]>[NH2:15][C:4]1[CH:3]=[C:2]([Cl:1])[CH:14]=[CH:13][C:5]=1[NH:6][CH2:7][CH:8]([CH2:9][CH3:10])[CH2:11][CH3:12]
Reactant: CCC(CC)CNc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCC(CC)CNc1ccc(Cl)cc1N
Yield: 98.9 %

Procedure:
40 g (0.156 mol) of 4-chloro-N-(2-ethylbutyl)-2-nitroaniline were dissolved in 500 ml of ethanol and, after addition of 4 g of Raney nickel, hydrogenated under 1 atm at room temperature. The mixture was then filtered and the filtrate was concentrated under reduced pressure to yield 35 g (98%) of the product.