Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:38])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])[CH2:17][CH2:16]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[Cl:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:22]([NH:21][CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(NC1CCNCC1)c1ccccc1Oc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Trifluoroacetic acid (TFA, 9 mL) was added to a solution of 4-[2-(2,4-dichlorophenoxy)-benzoylamino]piperidine-1-carboxylic acid tert-butyl ester (AMR01070, 900 mg, 1.93 mmol) in dry DCM (20 mL) at 0° C. After stirring at 0° C. for 1 h, the mixture was poured into solid K2CO3 (2.5 g) and water (100 mL) was added. The solution was extracted with DCM (3×30 mL) and the organic layer was dried (MgSO4), filtered and evaporated to give 4-[2-(2,4-dichlorophenoxy)-N-piperidin-4-ylbenzamide (AMR01077, 705 mg, 100%) as a white solid, which was used in the next step without further purification. Rf: 0.25 (DCM/MeOH 9:1) 1H NMR (270 MHz, CDCl3) δ 1.87 (2H, m, CH2), 2.21 (2H, d, J=11.4 Hz, CH2), 3.01 (2H, q, J=10.9 Hz, CH2), 3.43 (2H, d, J=13.1 Hz, CH2), 4.22 (1H, m, CH), 6.76 (1H, dd, J=8.4, 1.0 Hz, ArH), 6.95 (1H, d, J=8.7 Hz, ArH), 7.21-7.27 (2H, m, ArH), 7.41 (1H, m, ArH), 7.51 (1H, d, J=2.5 Hz, ArH), 8.14 (1H, dd, J=7.9, 2.0 Hz, ArH), 9.25 (1H, br d, J=8.5 Hz, NH) and 9.56 (1H, br d, J=7.4 Hz, NH). 13C NMR (270 MHz, CDCl3) δ 28.61 (CH2), 43.11 (CH2), 44.90 (CH), 117.10, 123.43, 124.53, 126.40, 128.58, 130.83, 130.98, 132.53, 133.24, 149.35, 154.00 (ArC) and 164.38 (C═N).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1)[CH3:6].O.[OH-].[Li+].Cl>CO.O>[CH3:1][O:2][CH2:3][CH2:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=1)[CH3:6]
Reactant: COCCC(C)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCCC(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.5 %

Procedure:
To the solution of methyl 4-(4-methoxybutan-2-yl)benzoate (211 mg, 0.95 mmol) in methanol (30 mL) and water (5 mL) was added lithium hydroxide hydrate (100 mg, 2.4 mmol) were added. The mixture was stirred at room temperature for 12 hours. Then the reaction mixture was acidified by hydrochloric acid aqueous solution (1N) to adjust pH=6 and extracted with dichloromethane (10 mL×3). The organic layers were combined and concentrated to give 4-(4-methoxybutan-2-yl)benzoic acid (177 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([OH:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1.[CH2:23]([N:25]([CH2:29][CH3:30])[C:26](Cl)=[O:27])[CH3:24].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([O:21][C:26]([N:25]([CH2:29][CH3:30])[CH2:23][CH3:24])=[O:27])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CCN(CC)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCN(CC)C(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 48 h
Yield: 57.5 %

Procedure:
The procedure of Example 21 is followed but starting with 2-(7-chloro-1,8-naphthyridin-2-yl)-3-hydroxy-isoindolin-1-one (6.2 g.) in methylene chloride (300 cc.), diethylcarbamoyl chloride (8.15 g.), triethylamine (8.4 cc.) and pyridine (30 cc.). Water (250 cc.) is added to the reaction mixture after it has been stirred for 48 hours at a temperature of about 20° C. The precipitate formed is filtered off and recrystallised from diisopropyl ether (800 cc.) to give 2-(7-chloro-1,8-naphthyridin-2-yl)-3-diethylaminocarbonyloxy-isoindolin-1-one (4.7 g.) melting at 142°-144° C.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])([O:3][CH3:4])=[O:2].[CH3:12][C:13]([C:16]1[CH:17]=[C:18]([CH2:26]Cl)[CH:19]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1)([CH3:15])[CH3:14]>>[CH3:25][C:22]([C:20]1[CH:19]=[C:18]([CH2:26][C:5]2([C:1]([O:3][CH3:4])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]2=[O:11])[CH:17]=[C:16]([C:13]([CH3:15])([CH3:14])[CH3:12])[CH:21]=1)([CH3:23])[CH3:24]
Reactant: CC(C)(C)c1cc(CCl)cc(C(C)(C)C)c1
Reactant: COC(=O)C1CCCCC1=O
Product: COC(=O)C1(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)CCCCC1=O

Procedure:
The title compound is prepared by the method of Example 12, except that 2-carbomethoxycyclohexanone is used in place of 2-carbomethoxycyclopentanone, and that the title product of Example 3 is used in place of the title product of Example 11.
Reaction SMILES: FC1C=CC(N2C(C(O)=O)=CN=C2SCC2C(F)=CC=C(F)C=2F)=CC=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:38]([C:39]([O:41]CC)=[O:40])=[C:37]([CH3:44])[N:36]=[C:35]2[S:45][CH2:46][C:47]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([F:54])[C:48]=2[F:55])=[CH:30][CH:29]=1.[Li+].[OH-]>C1COCC1.CO>[F:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:38]([C:39]([OH:41])=[O:40])=[C:37]([CH3:44])[N:36]=[C:35]2[S:45][CH2:46][C:47]2[C:52]([F:53])=[CH:51][CH:50]=[C:49]([F:54])[C:48]=2[F:55])=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1c(C)nc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: O=C(O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(SCc2c(F)ccc(F)c2F)n(-c2ccc(F)cc2)c1C(=O)O

Procedure:
1-(4-Fluorophenyl)-4-methyl-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylic acid (59) was prepared in a similar manner as that described for the synthesis of compound 11 using ethyl 1-(4-fluorophenyl)-4-methyl-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylate (58) (300 mg, 0.71 mmol), 1N LiOH (5 mL) in THF (5 mL) and MeOH (5 mL).
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>CO>[OH:1][CH:2]([CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:3][O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)NOCC1CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)NOCC(O)CN1CCCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 88 %

Procedure:
A 150 mg (0.79 mmol) portion of tert-butyl N-(2,3-epoxypropoxy)carbamate was dissolved in 1 ml of methanol, and the solution was mixed with 0.08 ml (0.95 mmol) of pyrrolidine and stirred at room temperature for 14 hours. The reaction solution was mixed with a saturated ammonium chloride aqueous solution and extracted with chloroform. The chloroform layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain 181 mg (yield, 88%) of tert-butyl N-(2-hydroxy-3-pyrrolidinylpropoxy)carbamate.
Reaction SMILES: [NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25](O)=[O:26])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[NH2:56][C@H:57]([C:63]([NH:65][C@H:66]([C:74]([NH:76][C@H:77]([C:79]([NH:81][C@H:82]([C:87]([NH:89][CH2:90][C:91]([OH:93])=[O:92])=[O:88])[C@H:83]([CH2:85][CH3:86])[CH3:84])=[O:80])[CH3:78])=[O:75])[C@@H:67]([CH3:73])[O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:64])[CH2:58][CH2:59][C:60](=[O:62])[NH2:61].Cl>O1CCCC1.CN(C)C=O.O>[NH:1]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([NH:56][C@H:57]([C:63]([NH:65][C@H:66]([C:74]([NH:76][C@H:77]([C:79]([NH:81][C@H:82]([C:87]([NH:89][CH2:90][C:91]([OH:93])=[O:92])=[O:88])[C@H:83]([CH2:85][CH3:86])[CH3:84])=[O:80])[CH3:78])=[O:75])[C@@H:67]([CH3:73])[O:68][C:69]([CH3:70])([CH3:71])[CH3:72])=[O:64])[CH2:58][CH2:59][C:60](=[O:62])[NH2:61])=[O:26])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:7])([CH3:8])[CH3:6]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)CCC(N)=O)[C@@H](C)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C)[C@@H](C)OC(C)(C)C)C(=O)NCC(=O)O
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
2.8 g of Z-Thr(tBu)-Phe-Pro-OH and 0.77 ml of absolute triethylamine are dissolved in 30 ml of dry tetrahydrofurane and the solution, cooled to -10°C, is added dropwise to 700 mg of isobutyl chlorocarbonate, care being taken for the temperature not to exceed -5°C. The mixture is then left for 10 minutes at -10°C and is thereafter added to a solution, precooled to -20°C, of 2.5 g of H-Gln-Thr(tBu)-Ala-Ile-Gly-OH.HCl in 65 ml of dimethylformamide-water (9:1). 1.2 ml of triethylamine are then added dropwise and the mixture is left for 1 hour at -10°C and for 18 hours at 0°C. It is thereafter concentrated, in vacuo and then in a high vacuum at 40°C bath temperature, to a volume of about 15 ml and then precipitated by adding 100 ml of ice-cold 2 % strength acetic acid. The product is filtered off, washed with ice water, dried and twice reprecipitated from methanol-water to purify it; yield 3.9 g of octapeptide derivative.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[C:12](OC2C=CC(NC)=C(N)C=2)[CH:11]=[CH:10][N:9]=1)=[O:7])(C)(C)C.NC(N)=S.IC.C(OC(C1C=C([O:43][C:44]2[CH:62]=[CH:61][C:47]3[N:48]([CH3:60])[C:49]([NH:51][C:52]4[CH:57]=[CH:56][C:55]([CH2:58][CH3:59])=[CH:54][CH:53]=4)=[N:50][C:46]=3[CH:45]=2)C=CN=1)=O)(C)(C)C.FC(F)(F)C(O)=O>CO.C(Cl)Cl>[CH2:58]([C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:49]2[N:48]([CH3:60])[C:47]3[CH:61]=[CH:62][C:44]([O:43][C:8]4([C:6]([OH:7])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][NH:9]4)=[CH:45][C:46]=3[N:50]=2)=[CH:53][CH:54]=1)[CH3:59]
Reactant: CNc1ccc(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Reactant: CCc1ccc(Nc2nc3cc(Oc4ccnc(C(=O)OC(C)(C)C)c4)ccc3n2C)cc1
Agent: NC(N)=S
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CI
Product: CCc1ccc(Nc2nc3cc(OC4(C(=O)O)C=CC=CN4)ccc3n2C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl4-[3-amino-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-ethylbenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[4-ethylphenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluoroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[4-ethylphenylamino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH+=388.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1.[S:12]([OH:19])([O:15][CH2:16][CH2:17][NH2:18])(=[O:14])=[O:13]>CO.[OH-].[Na+]>[S:12]([OH:19])([O:15][CH2:16][CH2:17][NH:18][CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:14])=[O:13]
Reactant: NCCOS(=O)(=O)O
Reactant: c1ccc(CCC2CO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=S(=O)(O)OCCNCC(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1,2-epoxy-4-phenylbutane (1.48 g.) and 2-aminoethyl hydrogen sulphate (7.05 g.) in methanol (7.5 ml.) and sodium hydroxide solution (18N, 2.8 ml.) is stirred at ambient temperature for 2 hours. The 2-(2-hydroxy-4-phenylbutyl)aminoethyl hydrogen sulphate formed as intermediate is not isolated but is cyclised in situ as follows:
Reaction SMILES: [CH3:1][C@@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:11][CH2:12]O.Br>ClCCl>[CH3:1][C@@H:2]1[C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:12][CH2:11][NH:9]1
Reactant: OCCBr
Reactant: C[C@@H](N)c1ccccc1
Agent: Br
Solvent: ClCCl
Product: C[C@H]1NCCc2ccccc21
Temperature: 51 °C
Reaction time: 50 h
Yield: 137.5 %

Procedure:
76.61 g(630 mmole) of (R)-(+)-α-methylbenzylamine was dissolved in 77 ml of dichloromethane and 94.8 g(760 mmole) of 2-bromoethanol was added thereto. This mixture was stirred at 51° C. for 50 hours to complete the reaction. The reaction solution was concentrated under reduced pressure and 286.4 ml(2500 mmole) of 48% aqueous hydrobromic acid solution was added thereto and then allowed to react at 126° C. for 30 minutes under refluxing. The reaction solution was then distilled for 2 hours under normal pressure at constant temperature and 250 ml of aqueous hydrobromic acid and water, the reaction by-product, was removed. The residue was dissolved in 350 ml of isopropyl alcohol with refluxing for 30 minutes, and this solution was cooled to 10° C. and then allowed to stand for 3 hours. The resulting solid product was filtered, washed with 50 ml of ethyl acetate, and then dried to obtain 127.5 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1F)[C:5]([OH:7])=[O:6].[CH2:16]([N:18](CC)CC)C.CN.Cl>O.CN>[Cl:1][C:2]1[C:3]([F:15])=[C:4]([CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[C:10]=1[NH:18][CH3:16])[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(Cl)c1F
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: O
Product: CNc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 102.2 %

Procedure:
A suspension of 5 g (21.05 mmol) of 3-chloro-2,4-difluoro-5-nitro-benzoic acid (known from WO 03/077914) in 50 mL of H2O is cooled to a temperature of 0° C. Then 5.86 ml (42.10 mmol) of triethylamine were added dropwise followed by the dropwise addition of 1.82 ml (21.05 mmol) of methylamine (40% in H2O). After 30 min of stirring at 0° C., 0.18 ml (2.11 mmol) of methylamine (40% in H2O) is added and the mixture is stirred again during 30 min at a temperature of 0° C. The pH of the mixture is adjusted to 1-0.5 by the addition of concentrated HCl at a temperature of 0° C. The product is extracted with tert-butyl methyl ether (2 times) and the organic phase is washed once with brine, dried on Na2SO4, filtrated and the solvent is evaporated. 5.35 g (21.52 mmol, 102%) of a crude yellow solid were obtained and used directly in the next step without purification. LC/MS: 247/249 (M−1)−.
Reaction SMILES: [H-].[Na+].[CH:3]([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15])(=[O:8])=[O:7])([CH3:5])[CH3:4].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([CH3:24])=[CH:19][N:18]=1>CN(C=O)C.CS(C)=O>[Cl:16][C:17]1[N:22]=[C:21]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6]([CH:3]([CH3:5])[CH3:4])(=[O:8])=[O:7])[C:20]([CH3:24])=[CH:19][N:18]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1cnc(Cl)nc1Nc1ccccc1S(=O)(=O)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 730 mg of NaH in a mixture of DMF/DMSO (25/2.5 ml) is added drop-wise at 0° C., 2.53 g (12.69 mmol) of 2-(iso-propylsulfonyl)benzenamine in DMF/DMSO (10 ml, ratio 9/1). The solution is stirred 30 minutes at 0° C. and 4.11 g (25.3 mmol, 2 eq.) of 2,4-dichloro-5-methylpyrimidine diluted in 10 ml of DMF/DMSO (ratio: 9/1) is added dropwise. The solution is warmed-up to room temperature and stirred overnight. After work-up, the crude product is directly crystallized from cold CH3CN in several batches to afford 2-chloro-N-(2-(iso-propylsulfonyl)phenyl)-5-methylpyrimidin-4-amine as pale creamy colored crystals: ESMS m/z 326.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a 1000 mL RB flask fitted with magnetic stirrer was charged 250 mL of DMF, 3-(4-Hydroxy-phenyl)-propanoic acid (25.0 g, 150.43 mmol) and K2CO3 (41.58 g, 300.87 mmol). The resulting mixture was stirred at RT for 30 minutes. Methyl Iodide (25.627 g, 180.51 mmol) was added to the resulting mixture which was precooled to 0° C. The resulting mixture was stirred at RT for 3 h. After completion of the reaction (reaction monitored by TLC), the solvent was removed under reduced pressure and the crude mass was dissolved in ethyl acetate (250 mL). The organic layer was washed with water (250 mL), saturated sodium bicarbonate solution (250 mL×2), and saturated brine solution (250 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as yellow color oil (26 g, Yield: 95.9%): MS (ESI, 120 eV): m/z=178.9 (M−H)+; 1H NMR (300 MHz, CDCl3): δ 6.97-7.00 (d, 2H), 6.66-6.69 (d, 2H), 4.94 (s, 1H), 3.59 (s, 3H), 2.78-2.83 (t, 2H), 2.50-2.55 (t, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[NH:11])[NH:9][CH3:10].[S:12](N1C=CN=C1)(N1C=CN=C1)(=[O:14])=[O:13]>O>[CH3:10][N:9]1[CH:8]([NH2:11])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][S:12]1(=[O:14])=[O:13]
Reactant: O=S(=O)(n1ccnc1)n1ccnc1
Reactant: CNC(=N)c1ccccc1O
Solvent: O
Product: CN1C(N)c2ccccc2OS1(=O)=O
Yield: 33.8 %

Procedure:
0.18 g (1.20 mmol) of 2-hydroxyl-N-methylbenzenecarboximidamide is stirred with 0.48 g (2.42 mmol) of 1,1′-sulphonyldiimidazole at 120° C. for 18 hours. Cooling is followed by stirring the mixture with water and then decanting off from the water. The remaining residue is chromatographed on silica gel (450 g, 40-63 μm) with dichloromethane/methanol=99/1. 87 mg of product are isolated.
Reaction SMILES: [CH2:1]([S:8][CH:9]([S:35]CC1C=CC=CC=1)[CH2:10][C@@H:11]([C@H:20]([CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)OS(C)(=O)=O)[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].C(=O)([O-])[O-].[Ba+2]>CC(C)=O>[CH2:13]([O:12][C@@H:11]1[C@@H:20]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[S:35][CH:9]([S:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)O[C@@H](COCc1ccccc1)[C@H](CC(SCc1ccccc1)SCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Agent: [I-]
Solvent: CC(C)=O
Product: c1ccc(COC[C@H]2SC(SCc3ccccc3)C[C@@H]2OCc2ccccc2)cc1

Procedure:
A suspension of 3,5-di-O-benzyl-2-deoxy-4-O-methanesulphonyl L-threo-pentose dibenzyl dithioacetal (29.4 g, 47.4 mmol), sodium iodide (74.0 g, 494 mmol), barium carbonate (148 g, 750 mmol) and dry acetone (1 L) was boiled under reflux for 42 hours. At the end of this time the suspension was filtered and the solids were washed with chloroform. The filtrate was sequentially washed with water, sodium thiosulphate solution (5%) and water, dried (magnesium sulphate) and evaporated. The resultant residue was applied to a silica gel column, eluted with hexane-ethyl acetate (9:1). Combination of the appropriate fractions gave the title product as a clear, slightly yellow, syrup, and recovered starting material.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:42])[C:34]2[CH:39]=[CH:38][C:37]([F:40])=[C:36]([F:41])[CH:35]=2)=[CH:28][CH:27]=1>>[F:41][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][C:37]=1[F:40])[C:33]([NH:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[C:15]([C:17]([NH:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18])[CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:31][CH:30]=1)=[O:42]
Reactant: Nc1ccc(NC(=O)c2ccc(F)c(F)c2)cc1
Reactant: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Cl)c3c2c1
Product: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Nc4ccc(NC(=O)c5ccc(F)c(F)c5)cc4)c3c2c1

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 267 using 296 (40 mg, 0.12 mmol), and N-(4-amino-phenyl)-3,4-difluoro-benzamide (36 mg, 0.12 mmol) to provide 298. LC-MS (M+H=557, obsd.=557).
Reaction SMILES: [F:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7](O)=[O:8].C(Cl)(C([Cl:22])=O)=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:3]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([Cl:22])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1sc2cc(C(F)(F)F)ccc2c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1sc2cc(C(F)(F)F)ccc2c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To compound 15b (0.14 g, 0.53 mmol) in CH2Cl2 (5 mL) at room temperature was added (COCl)2 (0.051 mL, 0.58 mmol), followed by 2 drops of DMF. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated to give compound 15c.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[N:42]1([CH2:46][C@@H:47]([NH:51][CH2:52][CH3:53])[CH:48]([CH3:50])[CH3:49])[CH2:45][CH2:44][CH2:43]1>CN(C=O)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[N:42]1([CH2:46][C@@H:47]([N:51]([CH2:52][CH3:53])[C:6](=[O:8])[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[CH:48]([CH3:50])[CH3:49])[CH2:45][CH2:44][CH2:43]1
Reactant: CCN[C@H](CN1CCC1)C(C)C
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C(=O)c1ccc(Cl)cc1)[C@H](CN1CCC1)C(C)C
Yield: 2.5 %

Procedure:
4-Chlorobenzoic acid (0.030 mL, 0.29 mmol), TBTU (113 mg, 0.35 mmol) and DIPEA (0.303 mL, 1.74 mmol) was stirred in DMF (2 mL). (S)-1-(azetidin-1-yl)-N-ethyl-3-methylbutan-2-amine (Compound V) (50 mg, 0.29 mmol) was added and the resultant mixture was stirred at rt overnight. The reaction mixture was diluted with DCM (10 mL) and NaHCO3 (saturated, 10 mL). The organic phase was isolated, filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (2.2 mg, 2%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.63-1.32, 1.60-1.76, 1.82-1.98, 2.0-3.5 (omitted signals), 7.27-7.51. HRMS (M+H)+: calculated 309.1725. found 309.1734.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:13](O)=O)[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C.[CH3:16][NH:17][CH3:18]>>[CH3:11][CH:10]([CH3:12])[C@@H:9]([NH2:8])[CH2:13][N:17]([CH3:18])[CH3:16]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNC
Product: CC(C)[C@@H](N)CN(C)C

Procedure:
The starting material (R)-3,N1,N1-trimethyl-butane-1,2-diamine was prepared in a route similar to that in Example A45 from N-tert-butoxycarbonyl D-valine and dimethylamine and used without further purification.