Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:35]=[CH:34][C:33]([CH2:36][CH2:37]C(O)=O)=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=CC=1.C(O[C:57]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)=[O:58])(C)(C)C>>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[C:16]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([CH2:36][CH2:37][C:57]([N:59]5[CH2:60][CH2:61][NH:62][CH2:63][CH2:64]5)=[O:58])=[CH:32][CH:31]=4)[C:17]=3[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=2)=[CH:11][N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(CCC(=O)O)cc3)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: Nc1ncc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccc(CCC(=O)N3CCNCC3)cc2)cn1
Yield: 30.6 %

Procedure:
Using 3-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-propionic acid (61 mg) and piperazine-1-carboxylic acid tert-butyl ester (20 mg) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, 3-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-tert-butyl-piperazin-1-yl)-propan-1-one was obtained, and further PMB group and BOC group were removed according to the above Deprotection method 2, to obtain the desired compound (D-168) as a pale yellow powder (14 mg, 31%).
Reaction SMILES: [CH:1]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>CN(C)C1C=CN=CC=1.ClCCl.N1C=CC=CC=1.Cl>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:7][CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 74.6 %

Procedure:
To a mixture of cyclopentylmethanol (8.7 g, 87 mmol) and 4-(dimethylamino)pyridine (0.5 g, 4.3 mmol) in dichloromethane (30 mL) and pyridine (30 mL) was added 4-methylbenzene-1-sulfonyl chloride (16.6 g, 87 mmol). The mixture was stirred at ambient temperature for 20 hours then diluted with 2 N aqueous HCl and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried with NaSO4, concentrated and the filtered thru a silica plug using hexanes:EtOAc (3:1) to afford the title compound (16.5 g, 64.9 mmol, 76% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.12-1.27 (m, 2H), 1.47-1.61 (m, 4H), 1.64-1.78 (m, 2H), 2.12-2.30 (m, 1H), 2.45 (s, 3H), 3.90 (d, J=7.1 Hz, 2H), 7.32-7.36 (m, 2H), 7.76-7.81 (m, 2H); MS (DCI/NH3) m/z 272.1 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Cl)=[CH:5][C:3]=1[NH2:4].[CH3:13][O-:14]>>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:14][CH3:13])=[CH:5][C:3]=1[NH2:4]
Reactant: C[O-]
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Product: COc1cc(N)c(Cl)cc1[N+](=O)[O-]

Procedure:
Similarly, 2,5-dichloro-4-nitroaniline is allowed to react with methoxide ion to afford 2-chloro-4-nitro-5-methoxyaniline, m.p. 150°-152° C. Also by allowing 2,3-dichloro-4-nitroaniline to react with sodium ethoxide, sodium propoxide, sodium butoxide and sodium benzyloxide, 3 ethoxy-, 3-propoxy-, 3-isopropoxy-, 3-butoxy- and 3-benzyloxy-4-nitroaniline are obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O.Cl[CH2:15][C:16]([O:18][C:19](=O)[CH2:20]Cl)=O.O1C=CC=C1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:16]1[O:18][CH:19]=[CH:20][CH:15]=1)=[O:12])=[O:13]
Reactant: COC(=O)CCCCCCC(=O)O
Reactant: O=C(CCl)OC(=O)CCl
Solvent: Cc1ccccc1
Solvent: c1ccoc1
Product: COC(=O)CCCCCCC(=O)c1ccco1
Temperature: 60 °C
Reaction time: 3 h
Yield: 84.8 %

Procedure:
In 50 ml of toluene were dissolved 9.41 g (0.05 mole) of suberic acid monomethyl ester and 9.83 g (0.0575 mole) of monochloroacetic anhydride. To the resulting solution were added 4.43 g (0.065 mole) of furan and 1.0 g of boron trifluoride-acetic acid complex and the resulting mixture was then stirred at 60° C. for 3 hours. After completion of the reaction, the reaction solution was cooled and washed successively with 5% aqueous sodium carbonate solution and water. The organic layer was concentrated under reduced pressure and the resulting concentrated residue was then purified by silica gel-filled column chromatography to obtain 10.1 g of 2-(7-methoxycarbonyl-1-oxoheptyl)furan.
Reaction SMILES: CN(C)[CH2:3][CH2:4]N(C)C.N#N.CCO.[Li]C(CC)C.[Cl:19][C:20]1[CH:28]=C[C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1>C1COCC1>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[C:3]([CH3:4])[CH:28]=1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: CN(C)CCN(C)C
Agent: N#N
Agent: [Li]C(C)CC
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1C(=O)O
Temperature: -50 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
In a dry round-bottomed flask (3 L) equipped with a mechanical stirrer under N2, anhydrous N,N,N′,N′-tetramethylethylenediamine (TMEDA, 99.7 mL, 660 mmol, 2.2 eq.) and anhydrous THF (600 mL) were added and the mixture was cooled to −90° C. in a bath of liquid N2/EtOH. Freshly titrated sec-BuLi (550 mL, 1.2M in cyclohexane, 660 mmol., 2.2 eq.) was added slowly via cannula as to maintain the temperature at −50° C. The solution was cooled to −90° C. and 4-chlorobenzoic acid (47.0 g in 400 mL anhydrous THF, 300 mmol) was added slowly via cannula, while stirring carefully to maintain the temperature at −90° C. The reaction mixture was stirred at −90° C. for 1 h before allowed to warm-up to −80° C. and CH3l (80 mL, 1.28 moles) was added very slowly. The reaction mixture was stirred for 10 min at −80° C., then quenched slowly with H2O (600 mL) and allowed to warm-up to room temperature. The aqueous layer was separated, washed with Et2O (2×500 mL) and then acidified with HCl (2.5 N, 600 mL) while cooling in an ice bath; cooling was continued for 16 h at 4° C. to allow crystallization of the desired product. The crude product was dried under vacuum and over anhydrous P2O5 and then re-crystallized from hot toluene (700 mL) to obtain pure 4-chloro-2-methylbenzoic acid (40 g, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[N:25][C:24]=1[CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:30][CH2:29][C:24]2[N:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[O:15])=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1
Reactant: NCc1ncccn1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)O)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(SC)ncc2C(=O)NCc2ncccn2)cc1Cl
Temperature: 60 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
In DMF (60 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio) pyrimidine-5-carboxylic acid (1.0 g, 2.95 mmol), pyrimidine 2-ylmethylamine (570 mg, 5.22 mmol) and HATU (2-(7-azabenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 2.64 g, 6.96 mmol), then DIEA (152 mg, 1.2 mmol) was added dropwisely. The reaction mixture was stirred at 60° C. overnight, extracted with DCM after water was added and washed with brine. The organic phase was dried over sodium sulfate. The solvent was removed by rotary evaporation, then the solid obtained was purified by silica gel column chromatography (DCM/methanol=50/1) to give 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylthio)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (350 mg, 13% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].C(N(CC)C(C)C)(C)C.[NH2:23][CH:24]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)[CH2:25][C:26]([O:28][CH3:29])=[O:27]>CO>[C:33]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:34]=[CH:35][C:30]([CH:24]([NH:23][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:31][CH:32]=1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)CC(N)c1ccc(-c2ccccc2)cc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2,4-dinitrofluorobenzene (247 mg, 847 μmol) in methanol (2 mL) was added N,N-diisopropylethylamine (147 μL, 844 μmol) and methyl 3-amino-3-(1,1′-biphenyl)-4-ylpropanoate (158 mg, 849 μmol). The solution was stirred at room temperature for 72 hours, then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of petroleum ether and dichloromethane (1:1 to 0:1), to afford the title compound, [LCMS (Method B, Mobile Phase I) RT=3.81 min, MH+ 422].
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[CH:11]([N:14]=[N:15][C:16]1(Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:13])[CH3:12].O>CO>[CH:11]([N:14]=[N:15][C:16]1([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:13])[CH3:12]
Reactant: O=S([O-])c1ccccc1
Reactant: CC(C)N=NC1(Cl)CCCCC1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)N=NC1(S(=O)(=O)c2ccccc2)CCCCC1
Reaction time: 1 h

Procedure:
To a stirred solution of 6.57 grams (.04 moles) of sodium benzenesulfinate in 60 ml of 70% aqueous methanol in a 125 ml erlenmeyer flask was added 6.4 grams (.034 moles) of 1-isopropylazo-1-chlorocyclohexane (from Example 3-2) dropwise over 25 minutes while holding the temperature at 0° to 5° C with an ice bath. After the addition was complete, the reaction was stirred for 60 minutes at 0° to 5° C, poured into 200 ml cold water and extracted into 100 ml of pentane. The pentane solution was separated, washed with 50 ml of water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 5.95 grams (59.5% crude yield). The infrared spectrum of the product was in agreement with the structure of 1-isopropylazo-1-(benzenesulfonyl)-cyclohexane.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:16])[CH2:14][CH3:15].Br[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1>C1COCC1>[Cl:24][C:23]1[C:18]([CH:14]([CH3:15])[C:13]#[N:16])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCC#N
Reactant: Clc1cccnc1Br
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C#N)c1ncccc1Cl
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 91.2 %

Procedure:
To a −78° C. solution of diisopropylamine (3.04 g, 4.28 mL, 30 mmol) was added n-butyl lithium (13.2 mL, 2.5M in hexane, 33 mmol). The reaction mixture was stirred for 20 minutes at −78° C., followed by the addition of propionitrile (1.65 g, 2.15 mL, 30 mmol). The reaction mixture was stirred for an additional 50 minutes, followed by the slow addition of 2-bromo-3-chloropyridine (1.92 g, 10 mmol) in THF (10 mL). The reaction was then allowed to warm to ambient temperature and stirred overnight. The reaction mixture was quenched with water and extracted with two portions of diethyl ether. The combined organic phases were washed with brine, concentrated, and the residue chromatographed on silica gel eluting with 30% ethyl acetate-hexane to obtain the title compound (1.52 g, 91%). 1H NMR (300 MHz, DMSO-d6) δ ppm 8.59 (dd, J=1.5, 4.7, 1H), 8.02 (dd, J=1.5, 8.1, 1H), 7.48 (dd, J=4.7, 8.1, 1H), 4.73 (q, J=7.1, 1H), 1.59 (d, J=7.1, 3H). MS (DCI) m/z 167 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.CCOC(C)=O>[C:16]1([S:22]([N:8]2[C:9]3[C:5](=[C:4]([CH3:13])[CH:3]=[C:2]([Cl:1])[C:10]=3[O:11][CH3:12])[CH:6]=[N:7]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1c(Cl)cc(C)c2cn[nH]c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1c(Cl)cc(C)c2cnn(S(=O)(=O)c3ccccc3)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-Chloro-7-methoxy-4-methyl-1H-indazole (1.55 g, 9.2 mmol) is dissolved in THF (50 mL) and cooled to 0° C. Sodium hydride (60% in mineral oil, 0.40 g, 10 mmol) is added and the reaction is stirred 10 min. Benzenesulfonyl chloride (1.2 mL, 9.7 mmol) is added and the reaction is stirred 20 min. The reaction is diluted with EtOAc, washed with a solution of NH4Cl, water, brine and dried with MgSO4. The solution is concentrated and triturated with hexane to provide 1-benzenesulfonyl-6-chloro-7-methoxy-4-methyl-1H-indazole which is used without further purification.
Reaction SMILES: C(O)C(O)C.[CH3:6][CH:7]([OH:11])[CH:8]([OH:10])[CH3:9].[CH2:12]([NH2:15])[CH2:13][NH2:14]>O>[CH3:6][CH:7]([OH:11])[CH:8]([OH:10])[CH3:9].[CH3:6][C:7]1[C:8]([CH3:9])=[N:15][CH:12]=[CH:13][N:14]=1
Reactant: NCCN
Agent: CC(O)C(C)O
Solvent: CC(O)CO
Solvent: O
Product: Cc1nccnc1C

Procedure:
The procedure in Example 2 was repeated except that propylene glycol was replaced by 2,3-butanediol, water was not used and the mixing (molar) ratio of the mixed gas was changed to ethylene diamine: 2,3-butanediol:nitrogen=1:1.2:0.7 to produce 2,3-dimethylpyrazine. The rate of conversion was 100% and the yield of 2,3-dimethylpyrazine was 72%.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([F:11])[CH:5]=1)=[O:3].[Se](=O)=[O:13]>>[Cl:10][C:8]1[CH:9]=[C:4]([C:2](=[O:3])[CH:1]=[O:13])[CH:5]=[C:6]([F:11])[CH:7]=1
Reactant: CC(=O)c1cc(F)cc(Cl)c1
Reactant: O=[Se]=O
Product: O=CC(=O)c1cc(F)cc(Cl)c1
Yield: 83 %

Procedure:
(3-Chloro-5-fluorophenyl)(oxo)acetaldehyde (27 g, 84%) was prepared from 3-chloro-5-fluoro acetophenone (30.0 g, 174.4 mmol) and selenium dioxide (21.28 g, 191.8 mmol) according to the typical procedure used for Preparation 1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Cl.[CH:22]1([CH2:25][C:26]([NH2:34])([CH3:33])[C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH2:24][CH2:23]1>>[CH:22]1([CH2:25][C:26]([NH:34][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])([CH3:33])[C:27]2[N:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH2:24][CH2:23]1
Reactant: Cc1nc(C(C)(N)CC2CC2)no1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cl
Product: Cc1nc(C(C)(CC2CC2)NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and 2-cyclopropyl-1-methyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine hydrochloride as starting materials. MS (D): m/e=448.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH2:9])=[N:4][CH:5]=[CH:6][N:7]=1.Cl.[N:11]1([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13](O)=[O:14].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:13]([C@@H:12]2[CH2:16][CH2:17][CH2:18][N:11]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[O:14])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: NCc1nccnc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1nccnc1Cl)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
To a solution of (3-chloropyrazin-2-yl)methanamine.HCl (9.57 g, 21.26 mmol, 40% wt) and Z-Pro-OH (5.3 g, 21.26 mmol) in dichloromethane (250 mL) was added triethylamine (11.85 mL, 85 mmol) and the reaction mixture was cooled to 0° C. After 15 min stirring at 0° C., HATU (8.49 g, 22.33 mmol) was added. The mixture was stirred for 1 hour at 0° C. and then overnight at room temperature. The mixture was washed with 0.1 M HCl-solution, 5% NaHCO3, water and brine, dried over sodium sulfate and concentrated in vacuo. The product was purified using silica gel chromatography (heptane/ethyl acetate=1/4 v/v %) to give 5 g of (S)-benzyl 2-((3-chloropyrazin-2-yl)methylcarbamoyl)pyrrolidine-1-carboxylate (62.7%).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7](Br)[S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[H][H]>CO.[Pd]>[C:1]([NH:4][C:5]1[N:6]=[CH:7][S:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Nc1nc(Br)sc1-c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ncsc1-c1ccccc1
Yield: 12.8 %

Procedure:
A solution of 4-acetamido-2-bromo-5-phenylthiazole (U.S. Pat. No. 3,244,723) (5.5 g) and sodium acetate (1.55 g) in methanol (110 ml) was hydrogenated at atmospheric pressure over 10% Pd/C catalyst until the theoretical uptake of hydrogen had occurred. The catalyst was removed by filtration and washed with methanol and the filtrate was evaporated to dryness. The residue was recrystallised three times from benzene-petroleum ether (b.p. 60°-80° C.) to give 4-acetamido-5-phenylthiazole (1.5 g) m.p. 105°-7° C. (Found: C, 60.3; H, 4.65; N, 12.7. C11H10N2OS requires: C, 60.5; H, 4.6; N, 12.8%).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31]C(CCCC(O)=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]([C:48]([O:50]C(C)(C)C)=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[NH2:46].Cl>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:21]([CH2:22][CH2:23][CH2:24][C:25]([NH:41][C@H:42]([C:48]([OH:50])=[O:49])[CH2:43][CH2:44][C:45](=[O:47])[NH2:46])=[O:26])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)CCC(N)=O
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)N[C@@H](CCC(N)=O)C(=O)O)cc2)cc1

Procedure:
The product from Example 100 (56 mg, 0.1 mmole) and H-Gln-OtBu HCl (48 mg, 0.2 mmole) were processed as in Example 213A-B to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ11.53-13.22 (br.s, 1 H), 8.95 (s, 1 H), 8.06 (d, 1 H), 7.26 (m, 6 H), 7.18 (m, 3 H), 7.04 (m, 1 H), 6.96 (m, 2 H), 6.88 (m, 4 H), 6.73 (br.s, 2 H), 4.15 (m, 1 H), 4.06 (s, 2 H), 4.02 (s, 2 H), 2.91 (s, 3 H), 2.54 (t, 2 H), 2.39 (s, 3 H), 2.13 (m, 4 H), 1.93 (m, 1 H), 1.75 (m, 3 H); MS (APCI+) m/z 687 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH:18]2[OH:23])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>C(OCC)(=O)C>[OH:23][CH:18]1[CH:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=3[O:2][CH3:1])=[CH:12][CH:13]=2)[CH2:22][CH2:21][N:20]([C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:35])[CH2:19]1
Reactant: O=COCc1ccccc1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCNCC2O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Reaction time: 0.17 h

Procedure:
The solution of 3.0 g of 4-{4-[3-(2-methoxybenyloxy)propoxy]phenyl}piperidin-3-ol in 30 ml of ethyl acetate is cooled to 0° C. with stirring and admixed with 30 ml of saturated aqueous sodium carbonate solution. At 0-5° C., 1.32 ml of benzyl formate are added dropwise. After 10 minutes, the reaction mixture is poured onto water (250 ml) and extracted with ethyl acetate (2×250 ml). The organic phases are washed with brine (1×250 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.35 (1:1 EtOAc-heptane); Rt=5.94. m.p. 71-73° C.
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[CH:11][N:10]=1)=[O:8]>C1COCC1>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([C:7](=[O:8])[CH3:1])=[N:10][CH:11]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1ccc(C(=O)N(C)OC)nc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCc1ccc(C(C)=O)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
MeMgBr (1.98 ml, 5.94 mmol) was added to a solution of 5-butyl-pyridine-2-carboxylic acid methoxy-methyl-amide (I-2A-38a; 880 mg, 3.96 mmol) in THF (10 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 1.5 h, quenched with saturated aqueous NH4Cl (1 ml), and saturated aqueous NaCl. The aqueous THF solution was extracted with EtOAc (2×), and the combined organic extracts were washed with saturated aqueous NaCl, dried, and concentrated under vacuum to yield the product I-2A-38b as an oil (680 mg): APcl MS 178.1 (M+1)+; 1H NMR (400 MHz, CDCl3) δ 8.47 (d, 1H, J=1.6 Hz), 7.95 (d, 1H, J=8.3 Hz), 7.60 (dd, 1H, J=1.6, 8.3 Hz), 2.69 (s, 3H), 2.67 (t, 2H, J=7.9 Hz), 1.65-1.56 (m, 2H), 1.40-1.30 (m, 2H), 0.92 (t, 3H, J=7.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]2[CH2:17][CH:16]2[NH:18]C(=O)OCC2C=CC=CC=2)[CH:12]=[N:13][CH:14]=1.B(Br)(Br)Br.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34].[NH4+].[Cl-]>C(Cl)Cl.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]2[CH2:17][CH:16]2[NH:18][S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH:12]=[N:13][CH:14]=1
Reactant: CCS(=O)(=O)Cl
Reactant: O=C(NC1CC1c1cncc(-c2cccc(Cl)c2Cl)c1)OCc1ccccc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Product: CCS(=O)(=O)NC1CC1c1cncc(-c2cccc(Cl)c2Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.5 %

Procedure:
To a solution of benzyl 2-(5-(2,3-dichlorophenyl)pyridin-3-yl)cyclopropylcarbamate (94 mg, 0.227 mmol) in DCM (3 ml) was added BBr3 (0.682 ml, 0.682 mmol) at 0° C. This reaction mixture was stirred for 1 h at 0° C. The reaction was quenched by addition of saturated NaHCO3 solution, and the mixture was extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in pyridine (3.00 ml), and ethanesulfonyl chloride (0.086 ml, 0.910 mmol) was added to the solution. This reaction mixture was stirred at room temperature. After 1 h, saturated NH4Cl solution in water was added. The mixture was extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column (EtOAc/Heptane=0-50%, v/v) gave N-(2-(5-(2,3-dichlorophenyl)pyridin-3-yl)cyclopropyl)ethanesulfonamide (6.2 mg, 0.017 mmol, 7% yield). ESI-MS m/z: 371[M+1]+. 1H NMR (CDCl3, 400 MHz) 1.31 (t, J=7.2 Hz, 3H), 1.38-1.43 (m, 2H), 2.35-2.38 (m, 1H), 2.86-2.91 (m, 1H), 3.14 (q, J=7.2 Hz, 2H), 7.41 (dd, J=7.6, 2.0 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.57 (t, J=2.0 Hz, 1H), 7.65 (dd, J=7.6, 2.0 Hz, 1H), 8.46 (d, J=2.4 Hz, 1H), 8.53 (d, J=2.4 Hz, 1H).