Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([I:15])=[CH:9][CH:8]=3.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[I:15][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[C:5]3[C:13]([C:12]=2[CH:11]=1)=[CH:14][C:2]([I:1])=[CH:3][CH:4]=3
Reactant: OCCCCCCCCCCCBr
Reactant: Ic1ccc2[nH]c3ccc(I)cc3c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCCCCCCCCCCn1c2ccc(I)cc2c2cc(I)ccc21
Reaction time: 24 h
Yield: 88.2 %

Procedure:
To a solution of 3,6-diiodocarbazole (10.0 g, 23.87 mmol) and 11-bromo-1-undecanol (7.0 g, 27.87 mmol) in DMF (100.0 ml) was added K2CO3 (32.0 g, 231.33 mmol). The reaction was carried out at room temperature for 24 h. Water (300 ml) was added. The precipitate was filtered. The crude product was purified by silica gel column using Hexane/ethyl acetate (7:3) as solvent. 12.4 g (87.9%) of pure product as white solid was obtained.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])OC1=O.[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[CH2:28][CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][NH2:37])[CH2:31][CH2:30]1>CN(C)C=O>[NH2:1][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]([NH:37][CH2:36][CH2:35][N:32]1[CH2:33][CH2:34][CH:29]([CH2:28][C:20]2[N:19]([CH2:18][C:14]3[O:13][CH:17]=[CH:16][CH:15]=3)[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=2)[CH2:30][CH2:31]1)=[O:11]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)NCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Reaction time: 4 h
Yield: 73 %

Procedure:
To a stirred mixture of 4.9 parts of 2H-3,1-benzoxazine-2,4(1H)-dione and 45 parts of N,N-dimethylformamide were added dropwise 10.15 parts of 4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidineethanamine and 45 parts of C at 50° C. Upon completion, stirring was continued for 4 hours at 70° C. After cooling, the reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 1,1'-oxybisethane. The product was filtered off and dried, yielding 10 parts (73%) of 2-amino-N-[2-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]benzamide; mp. 125.7° C. (466).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=O.Cl.[C:18]([NH:22][NH2:23])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C.C(O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)/[C:5](/[C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:23]/[NH:22][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)NN
Reactant: O=C(c1cccc(Br)c1)c1ncccc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: CC(C)(C)N/N=C(/c1cccc(Br)c1)c1ncccc1O
Yield: 24.3 %

Procedure:
A mixture of 2-(3-bromobenzoyl)-3-hydroxypyridine (0.79 g), t-butylhydrazine hydrochloride (0.53 g), triethylamine (1.2 mL) and ethanol (13 mL) was refluxed for 5 hours. The reaction mixture was poured into water, and subjected to extraction with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate), followed by evaporating the solvent under reduced pressure. The residue was purified by means of a silica gel column (ethyl acetate--hexane) to afford (E)-2-(3-bromo-α-t-butylhydrazinobenzyl)-3-hydroxypyridine (0.60 g) and (Z)-2-(3-bromo-α-t-butylhydrazonobenzyl)-3-hydroxypyridine (0.24 g) (compounds 27 and 26).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].Br[C:9]1[CH:10]=[C:11]2[CH:29]=[C:27]([CH:28]=1)[NH:26][C:25]1=[N:30][C:21](=[C:22]([Cl:31])[CH:23]=[N:24]1)[NH:20][C:19]1=[CH:32][C:15](=[CH:16][CH:17]=[CH:18]1)[O:14][CH2:13][CH2:12]2.[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:31][C:22]1[CH:23]=[N:24][C:25]2[NH:26][C:27]3[CH:28]=[C:9]([C:36]4[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=4)[CH:10]=[C:11]([CH:29]=3)[CH2:12][CH2:13][O:14][C:15]3[CH:32]=[C:19]([NH:20][C:21]=1[N:30]=2)[CH:18]=[CH:17][CH:16]=3
Reactant: OB(O)c1ccncc1
Reactant: Clc1cnc2nc1Nc1cccc(c1)OCCc1cc(Br)cc(c1)N2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1cnc2nc1Nc1cccc(c1)OCCc1cc(cc(-c3ccncc3)c1)N2
Temperature: 85 °C
Yield: 12.9 %

Procedure:
A solution of 19-bromo-6-chloro-14-oxa-2,4,8,23-tetraazatetracyclo[15.3.1.1(3,7).1(9,13)]tricosa-1(21),3(23),4,6,9(22),10,12,17,19-nonaene trifluoroacetate (40 mg, 96 μmol), 4-pyridinylboronic acid (13 mg, 0.11 mmol), and 2 M sodium carbonate (0.14 mL, 0.29 mmol) in toluene (0.36 mL) and ethanol (0.36 mL) was degassed with nitrogen, treated with tetrakis(triphenylphosphine)palladium(O) (8 mg, 6.7 μmol), and heated at 85° C. for 12 h. The reaction mixture was concentrated and purified by preparative LCMS to give the desired product (4 mg, 7%) as a white solid. LCMS for C23H19ClN5O (M+H)+: m/z=416.0. 1H NMR (400 MHz, DMSO-d6): δ 9.62 (s, 1H), 9.20 (s, 1H), 8.90 (br s, 2H), 8.19 (s, 1H), 8.13-8.05 (m, 3H), 7.65 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.24 (dd, J=8.2, 8.0 Hz, 1H), 6.94-6.86 (m, 2H), 4.57-4.54 (m, 2H), 2.85-2.78 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[C:13](=[O:29])[NH:14][C:15](=[O:28])[C:16]=1[C:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][OH:27])=[CH:25][C:20]=2[O:19][CH:18]=1.[H-].[Na+].[CH3:32]I>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[CH:6]=[C:5]2[C:12]1[C:13](=[O:29])[N:14]([CH3:32])[C:15](=[O:28])[C:16]=1[C:17]1[C:21]2[CH:22]=[CH:23][C:24]([CH2:26][OH:27])=[CH:25][C:20]=2[O:19][CH:18]=1
Reactant: CI
Reactant: Cn1cc(C2=C(c3coc4cc(CO)ccc34)C(=O)NC2=O)c2cc(F)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)C(c2coc3cc(CO)ccc23)=C(c2cn(C)c3ccc(F)cc23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of 3-(5-fluoro-1-methyl-1H-indol-3-yl)-4-(6-hydroxymethyl-benzofuran-3-yl)-pyrrole-2,5-dione (0.035 g, 0.090 mmol) in dry THF was added sodium hydride (0.005 g, 0.011 mmol, 55% in mineral oil) and methyliodide (0.006 mL, 0.090 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with ice water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, evaporated in vacuo and purified by preparative TLC (methanol:dichloromethane; 5:95) to afford the product (0.012 g, 34%) as an orange solid. 1H NMR (CDCl3, 400 MHz) 3.19 (s, 3H), 3.86 (s, 3H), 4.71 (s, 2H), 6.62 (dd, J=2.3, 10.0 Hz, 1H), 6.83-6.90 (m, 3H), 7.21 (dd, J=4.3, 8.9 Hz, 1H), 7.51 (s, 1H), 7.81 (s, 1H), 8.11 (s, 1H), 13C NMR (CDCl3, 100 MHz) 23.9, 33.4, 64.8, 104.7, 106.5, 106.8, 109.6, 110.0, 110.1, 110.6, 110.8, 111.3, 121.4, 121.7, 122.1, 124.5, 126.1, 126.2, 130.8, 133.2, 134.4, 137.8, 147.0, 154.8, 156.6, 158.9, 170.9, 171.3.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:15]1[CH2:19][C@H:18]([OH:20])[CH2:17][C@H:16]1[C:21]([OH:24])([CH3:23])[CH3:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH2:8]([N:15]1[CH2:19][C@H:18]([O:20][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:17][C@H:16]1[C:21]([OH:24])([CH3:22])[CH3:23])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(O)[C@@H]1C[C@@H](O)CN1Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of triethylamine (4.32 ml) and (2S,4R)-1-benzyl-2-(1-hydroxy-1-methylethyl)-4-hydroxypyrrolidine (4.87 g) in dichloromethane (50 ml) was added methanesulfonyl chloride (2.4 ml) at 0° C. After stirring at room temperature for 4 hours, the mixture was quenched with water and extracted with ethyl acetate (×2). The combined extracts were washed with brine, dried over magnesium sulfate, evaporated under reduced pressure, and purified with column chromatography (silica gel, 500 ml, methanol:dichloromethane=4:96) to give (2S,4R)-1-benzyl-2-(1-hydroxy-1-methylethyl)-4-(methanesulfonyloxy)pyrrolidine (3.34 g) as a pale yellow solid.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:10])[CH2:8][OH:9])[C@H:4]([C:11]#[N:12])[CH2:3]1.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14]>>[F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:10])[CH2:8][O:9][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])[C@H:4]([C:11]#[N:12])[CH2:3]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CO
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)COS(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 15.1 %

Procedure:
Using (2S,4S)-4-fluoro-1-(2-hydroxyacetyl)pyrrolidine-2-carbonitrile (259 mg) and 2-nitrobenzenesulfonyl chloride (366 mg), the same procedure was followed as in Reference Example 3 to give (2S,4S)-4-fluoro-1-[2-[(2-nitrophenyl)sulfonyloxy]acetyl]pyrro lidine-2-carbonitrile as a pale yellow solid (81.2 mg, 15% yield).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[Cl:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:19][NH2:20]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:20][CH2:19][C:18]1[CH:21]=[CH:22][C:23]([Cl:24])=[C:16]([Cl:15])[CH:17]=1)#[N:2]
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCc1ccc(Cl)c(Cl)c1)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.8 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 3,4-dichlorobenzylamine (0.51 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from diethyl ether to give the title compound (0.42 g, 1.4 mmol, yield: 52%) as colorless crystals.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:15]([OH:17])=O)[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=O)(C)(C)C.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)=[C:23]([CH:33]=1)[CH2:24][NH:25][C:26](=[O:32])[C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:14][C:11]([CH3:12])([CH3:13])[CH2:10][C@H:9]([C:15]([N:28]1[CH2:29][CH2:30][CH2:31][C@H:27]1[C:26]([NH:25][CH2:24][C:23]1[CH:33]=[C:19]([Cl:18])[CH:20]=[CH:21][C:22]=1[N:34]1[CH:38]=[N:37][CH:36]=[N:35]1)=[O:32])=[O:17])[NH2:8]
Reactant: CC(C)(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(NCc1cc(Cl)ccc1-n1cncn1)[C@@H]1CCCN1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H](N)C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cncn1

Procedure:
The title compound was prepared from N-(tert-butoxycarbonyl)-4-methyl-D-leucine (32 mg, 0.13 mmol), N-[5-chloro-2-(1H-1,2,4-triazol-1-yl)benzyl]-L-prolinamide (Example 27, Step B, 50 mg, 0.21 mmol, 1.0 equiv), EDC (38 mg, 0.20 mmol, 1.5 equiv) and HOAt (9 mg, 0.07 mmol, 0.5 equiv) in DMF (1 mL) followed by deprotection in TFA-CH2Cl2 essentially according to the procedure described in Example 27, Step C. Purification by reverse phase chromatography [95:5 water (+0.1% TFA)/CH3CN (+0.1% TFA) to 50:50 water (+0.1% TFA)/CH3CN (+0.1% TFA)] followed by lyophilization of the fractions afforded the title compound as a white powder. 1H NMR (400 MHz, CDCl3): δ 8.81 (s, 1 H), 8.35 (br s, 2 H), 8.23 (s, 1 H), 8.09 (t, J=5.6Hz, 1 H), 7.50 (d, J=2.0 Hz, 1 H), 7.35 (dd, J=2.0, 8.4 Hz, 1 H), 7.24 (d, J=8.4 Hz, 1 H), 4.41–4.38 (m, 1 H), 4.29 (dd, J=5.6, 15.6 Hz, 1 H), 4.20–4.12 (m, 2 H), 3.87–3.83 (m, 1 H), 3.50–3.45 (m, 1 H), 2.12–2.02 (m, 3 H), 1.85–1.72 (m, 3 H), 0.96 (s, 9 H). HRMS (APCI) M+H: calculated for (C21H29N6O2Cl)+ 433.2113, found 433.2104.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][O:6][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: OCc1cccc(I)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Ic1cccc(COC2CCCCO2)c1
Temperature: 25 °C
Yield: 103.6 %

Procedure:
para-Toluenesulfonic acid (100 mg, cat.) was added in one portion to a cooled solution (0 C) of 3-iodobenzyl alcohol (4.71 g, 0.02 mol) and dihydropyran (1.86 g, 0.022 mol) in dichloromethane (50 mL) under a nitrogen atmosphere. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature over 1 hr. Diethyl ether (100 mL) was then added followed by saturated sodium hydrogen carbonate solution (100 mL). The organic layer was separated, dried (MgSO4) and evaporated in vacuo to yield the crude product (6.59 g) A332.1, which was used immediately without further purification. HPLC YMC S-5 4.6×33 mm (2 min grad): retention time 2.16 min, no M+H+ observed.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2Cl)(=[O:3])[NH2:2].[F:17][C:18]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:19]=1[N:25]([CH3:36])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1)=[O:27].[H-].[Na+].O>CS(C)=O>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[CH:9][CH:8]=[C:7]2[O:24][C:22]1[CH:21]=[CH:20][C:19]([N:25]([CH3:36])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[O:27])=[C:18]([F:17])[CH:23]=1)(=[O:3])[NH2:2]
Reactant: COc1cc2nccc(Cl)c2cc1C(N)=O
Reactant: CN(C(=O)Nc1ccc(F)cc1)c1ccc(O)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(N(C)C(=O)Nc4ccc(F)cc4)c(F)c3)c2cc1C(N)=O
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
6-Carbamoyl-4-chloro-7-methoxyquinoline (41 mg, 0.1744 mmol) and N-(2-fluoro-4-hydroxyphenyl)-N′-(4-fluorophenyl)-N-methylurea (57 mg, 0.2048 mmol) were dissolved in dimethylsulfoxide (1.0 ml), and then sodium hydride (8.4 mg, 0.2093 mmol) was added and the mixture was heated and stirred at 85° C. for 30 minutes. After cooling the reaction solution to room temperature, water was added and the precipitated crystals were filtered out. The crystals were then suspended in acetone: diethyl ether=1:2 and refiltered out, washed with diethyl ether and dried by aspiration to obtain the title compound (46 mg, 0.0961 mmol, 55.13%) as yellow crystals.
Reaction SMILES: COB(OC)OC.B.CSC.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH:13]=1.Cl>C1COCC1>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C@H:18]([OH:22])[CH2:19][CH2:20][CH3:21])[CH:13]=1
Reactant: CCCC(=O)c1cccnc1
Agent: B
Agent: COB(OC)OC
Agent: Cl
Solvent: CSC
Solvent: C1CCOC1
Product: CCC[C@@H](O)c1cccnc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of S(−)-α,α-diphenyl-2-pyrrolidinemethanol (500 mg, 2 mmol) and trimethylborate (0.27 ml, 2.4 mmol) in THF (20 mL) was added borane-dimethylsulfide complex (20 mL, 2M in THF, 40 mmol). The mixture was cooled to 0° C. and 1-pyridin-3-ylbutan-1-one was added dropwise over 4 h. The solution was stirred at RT overnight and then treated with 2M HCl (175 mL) and stirring continued for 4 h. The-volatiles were removed under reduced pressure and the resulting cloudy solution basified to pH 11 with aqueous ammonia. The product was extracted into ethyl acetate (3×100 mL) and the combined organic layers washed with brine (100 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure afforded ˜3 g of product.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].[C:14]1(=O)[CH2:17][CH2:16][CH2:15]1.[Cl-].[NH4+]>O1CCCC1>[C:14]1(=[CH:7][C:5]([O:4][CH3:3])=[O:6])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCC1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C=C1CCC1
Reaction time: 1 h

Procedure:
Sodium hydride (>65% oil, 3.62 g, 95 mmol) was added to a tetrahydrofuran solution (200 mL) of trimethyl phosphonoacetate (18.21 g, 100 mmol) under ice cooling, and the mixture was stirred for 1 hour. To the reaction solution, a tetrahydrofuran solution (50 mL) of cyclobutanone (5.00 g, 71.4 mmol) was added dropwise, and the mixture was then brought to room temperature and stirred for 1.5 hours. To the reaction solution, a saturated aqueous solution of ammonium chloride was added, followed by extraction with hexane. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the compound of interest as a pale yellow oil substance (18.94 g, <100%).
Reaction SMILES: [CH2:1]([CH:6]([C:11]([O:13]C)=[O:12])[C:7]([O:9]C)=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4]>[OH-].[Na+]>[CH2:1]([CH:6]([C:11]([OH:13])=[O:12])[C:7]([OH:9])=[O:8])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: COC(=O)C(CCC(C)C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: CC(C)CCC(C(=O)O)C(=O)O

Procedure:
Dimethyl isoamylmalonate (71.7 g) was added to a 50% aqueous solution of sodium hydroxide (60 ml), and the mixture was heated under reflux for 6 h. After cooling, the mixture was extracted with ether; the water layer was acidified with hydrochloric acid and, after saturation with sodium chloride, was extracted with ether. The extracts from the acidic aqueous layer were concentrated under reduced pressure to give isoamylmalonic acid. The obtained dicaboxylic acid was heated at 180° C. for 2 h. After distillation under reduced pressure, 5-mehyl-caproic acid was obtained. Yield: 30 g (75%), b.p. 107°-106° C./11 mmHg.
Reaction SMILES: Cl[C:2](=[N:10][N:11]=[C:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH3:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:22]=1[NH2:23].CN(C)C1C=CC=CC=1.Cl>ClCCl>[CH3:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]1[N:23]([C:22]2[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:21]=2[CH3:20])[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:11][N:10]=1
Reactant: Cc1cccc(C)c1N
Reactant: Cc1ccccc1C(Cl)=NN=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Cc1ccccc1-c1nnc(-c2ccccc2)n1-c1c(C)cccc1C
Temperature: 120 °C
Reaction time: 20 h
Yield: 30.6 %

Procedure:
First, 12.6 g (43.3 mmol) of N-[1-chloro-1-(2-methylphenyl)methylidene]-N′-[1-chloro-(1-phenyl)methylidene]hydrazine, 15.7 g (134.5 mmol) of 2,6-dimethylaniline, and 100 ml of N,N-dimethylaniline were put into a 500-ml recovery flask and heated and stirred at 120° C. for 20 hours. After reaction for the predetermined time, this reacted solution was slowly added to 200 ml of 1N hydrochloric acid. Dichloromethane was added to this solution and an objective substance was extracted to an organic layer. The obtained organic layer was washed with water and an aqueous solution of sodium hydrogen carbonate, and was dried with magnesium sulfate. The magnesium sulfate was removed by gravity filtration, and the obtained filtrate was concentrated to give a black liquid. This liquid was purified by silica gel column chromatography. A mixed solvent of ethyl acetate and hexane in a ratio of 1:5 was used as a developing solvent. The obtained fraction was concentrated to give a white solid. This solid was recrystallized with ethyl acetate to give 4.5 g of a white solid of Hmpptz-dmp in a yield of 31%. A synthesis scheme of Step 1 is shown below.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:18])[CH2:6][CH2:5][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3]1.[H-].[Na+].Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].[NH4+].[Cl-]>C1COCC1>[C:22]([O:21][C:19]([N:4]1[CH2:5][CH2:6][CH:7]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:18])[CH:2]([O:1][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:3]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc2c(c1)nc(C)n2[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)nc(C)n2C1CCN(C(=O)OC(C)(C)C)CC1OCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A stirring solution of racemic trans-3-hydroxy-4-[2,5-dimethylbenzimidazol-1yl]-N-Boc-piperidine (950 mg; 2.75 mmol) in THF (30 mL) under Ar cooled to 0° C. NaH (60% oil dispersion; 132 mg; 3.3 mmol) was added and the mixture was stirred for 15 min followed by addition of tert-butyl bromoacetate (516 μL; 3.5 mmol). The reaction mixture was warmed to rt and allowed to stir for 14 hours after which it was poured into satd NH4Cl and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. Filtration followed by removal of volatiles under reduced pressure yielded crude product. Racemic 3-tert-butoxycarbonylmethoxy-4-(2,5-dimethyl-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester was isolated as an oil by flash chromatography (470 mg; 37%)
Reaction SMILES: [F:1][CH:2]([F:15])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([OH:14])=O)[N:4]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[C:25]=1[CH:31]1[O:35][N:34]=[C:33]([C:36]2[N:37]=[C:38]([CH:41]3[CH2:46][CH2:45][NH2+:44][CH2:43][CH2:42]3)[S:39][CH:40]=2)[CH2:32]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C=O>[F:15][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:44]2[CH2:45][CH2:46][CH:41]([C:38]3[S:39][CH:40]=[C:36]([C:33]4[CH2:32][CH:31]([C:25]5[C:26]([OH:30])=[CH:27][CH:28]=[CH:29][C:24]=5[Cl:23])[O:35][N:34]=4)[N:37]=3)[CH2:42][CH2:43]2)=[O:14])[N:4]=1
Reactant: O=C(O)Cn1nc(C(F)F)cc1C(F)F
Reactant: Oc1cccc(Cl)c1C1CC(c2csc(C3CC[NH2+]CC3)n2)=NO1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4c(O)cccc4Cl)C3)cs2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3,5-bis-(difluoromethyl)-1H-pyrazol-1-yl]acetic acid (177 mg) in dichloromethane (40 ml) are added, at 0° C., oxalyl chloride (290 mg) and one drop of N,N-dimethylformamide. The reaction mixture is stirred at room temperature for 2 hours. The solvent and the excess reagent are removed under reduced pressure. The solid residue is again dissolved in dichloromethane and, at 0° C., added dropwise to a solution of 4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidinium chloride and triethylamine (5.0 eq.) in dichloromethane (25 ml). The reaction mixture is stirred at room temperature overnight. Then it is admixed with concentrated sodium hydrogencarbonate solution, and the aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-chloro-6-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (110 mg).