Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5](Cl)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[F:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH:23][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COc1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(C(=O)O)c(Nc2cccc(F)c2)c1

Procedure:
4-methoxy-2-chloro-benzoic acid (2.0 g), potassium carbonate (1.78 g), 3-fluoroaniline (6.7 mL) and Cu powder (100 mg) were combined and heated at 125 C for 1 h. The reaction was cooled and partitioned between saturated aqueous sodium carbonate and ethyl ether. The aqueous solution was extracted once with ether, then the combined organic solutions were washed with saturated aqueous sodium carbonate (2×). The combined aqueous solutions were acidified to pH 3.5 with conc HCl and extracted with EtOAc (4×). The combined organic solutions were dried (MgSO4) and concentrated. Flash chromatography (0 to 10% MeOH in CH2Cl2) provided a solid, which was recrystallized from CH2Cl2/hexanes to give 1.9 g of 2-(3-fluoro-anilino)-4-methoxybenzoic acid.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH2:7][CH2:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])(=[O:6])=[O:5].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18]([CH2:17][N:9]([CH2:8][CH2:7][S:4]([CH3:3])(=[O:5])=[O:6])[C:10](=[O:15])[C:11]([F:12])([F:14])[F:13])=[O:19])[CH3:22]
Reactant: CS(=O)(=O)CCNC(=O)C(F)(F)F
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCS(C)(=O)=O)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.190 g, 4.75 mmol) was added to a solution of N-(2-methylsulphonylethyl)trifluoroacetamide (0.986 g, 4.50 mmol) in dry DMF (10 ml) and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Ethyl bromoacetate (0.55 ml, 0.828 g, 4.96 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was poured into ice-water, and extracted with ethyl acetate. This solution was washed with water, dried (MgSO4), and concentrated in vacuo to give the title compound as a white solid (1.239 g, 4.03 mmol, 90%); δH CDCl3 4.17 (4H, m), 3.91 (2H, t), 3.46 (2H, t), 2.98 (3H, s), 1.30 (3H, t).
Reaction SMILES: C(OC1C=C2C(C=CC(O)=C2)=CC=1C1N=NC(N(C)C2CC(C)(C)NC(C)(C)C2)=CC=1)C1C=CC=CC=1.[H-].[Na+].CI.[CH2:42]([O:49][C:50]1[C:51]([C:62]2[N:67]=[N:66][C:65]([N:68]([CH3:80])[CH:69]3[CH2:74][C:73]([CH3:76])([CH3:75])[N:72](C)[C:71]([CH3:79])([CH3:78])[CH2:70]3)=[CH:64][CH:63]=2)=[CH:52][C:53]2[C:58]([CH:59]=1)=[CH:57][C:56]([O:60][CH3:61])=[CH:55][CH:54]=2)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C=O)C>[CH2:42]([O:49][C:50]1[C:51]([C:62]2[N:67]=[N:66][C:65]([N:68]([CH3:80])[CH:69]3[CH2:74][C:73]([CH3:75])([CH3:76])[NH:72][C:71]([CH3:79])([CH3:78])[CH2:70]3)=[CH:64][CH:63]=2)=[CH:52][C:53]2[C:58]([CH:59]=1)=[CH:57][C:56]([O:60][CH3:61])=[CH:55][CH:54]=2)[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: COc1ccc2cc(-c3ccc(N(C)C4CC(C)(C)N(C)C(C)(C)C4)nn3)c(OCc3ccccc3)cc2c1
Agent: CN(c1ccc(-c2cc3ccc(O)cc3cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2cc(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)c(OCc3ccccc3)cc2c1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a reaction mixture of 7-(benzyloxy)-6-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)naphthalen-2-ol (Intermediate 5-1, 500 mg, 1.01 mmol) in DMF (3 mL) was added 60% wt NaH (48.3 mg, 1.21 mmol) at 0° C. The mixture was stirred for 0.5 h, then methyl iodide (0.063 mL, 1.01 mmol) was added. The mixture was stirred at RT for 1.5 hours, then another portion of methyl iodide (0.063 mL, 1.01 mmol) was added. The reaction mixture was stirred at RT overnight, then slowly quenched with water. The residue was partitioned between water and DCM, and the aqueous layer was further extracted with DCM. The combined organic layers were dried over Na2SO4, and concentrated in vacuo. The residue was purified via silica gel flash column chromatography (0-20% 1.5 M NH3 in MeOH/DCM) to give a mixture of Intermediate 5-4 and 6-(3-(benzyloxy)-6-methoxynaphthalen-2-yl)-N-methyl-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyridazin-3-amine which was used without further purification (412 mg, 80% yield). MS (M+1)=511.5.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:16]([O:15][C:11](=[O:14])/[CH:12]=[CH:13]/[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6])[CH3:17]
Reactant: O=C(O)c1cccc(I)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cccc(C(=O)O)c1
Temperature: 25 °C
Yield: 104.3 %

Procedure:
A solution of 3-iodobenzoic acid (20.2 g, 81.4 mmol), ethyl acrylate (9.0 g, 90.2 mmol), triethylamine (24 mL) and palladium acetate (92 mg, 0.41 mmol) in DMF (130 mL) was stirred at 140° C. for 3 hr. The reaction mixture was cooled to room temperature, partitioned between ethyl acetate and 1N hydrochloric acid, and the ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 50:50-0:100) to give the title compound (18.7 g, quant.) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:14](Cl)[N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]3)=[C:4]2[N:3]=1.O.O1CCCC1.[Cl-].[NH4+]>C(O)C.[Zn]>[Cl:1][C:2]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][N:5]2[N:6]=[C:7]3[C:12]([CH:11]=[C:10]([F:13])[CH:9]=[CH:8]3)=[C:4]2[N:3]=1
Reactant: Fc1ccc2nn3c(Cl)c(-c4ccccc4)c(Cl)nc3c2c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: Fc1ccc2nn3cc(-c4ccccc4)c(Cl)nc3c2c1
Temperature: 25 °C

Procedure:
7.2 g (21.7 mmol) 2,4-Dichloro-9-fluoro-3-phenylpyrimido[1,2-b]indazole were suspended in a mixture of 551 mL ethanol, 392 mL water and 211 mL tetrahydrofuran. After addition of 5.5 g (102.7 mmol) ammonium chloride and 9.1 g (138.7 mmol) zinc the mixture was stirred over night at room temperature. The mixture was filtered via a glass fibre filter, and the organic solvents were removed. The product which precipitated was filtered off (3.4 g=51.9%). 3.4 g (42.2%) of the starting material wereregained by stirring the zinc slurry with 1 L ethyl acetate, filtration of the zinc via a glass fibre filter and evaporation of the organic solvent. The product was contaminated with 9-fluoro-3-phenylpyrimido[1,2-b]indazole (25%).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]3[N:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:52]([N:71]1[CH:75]=[C:74]([C:76]2[CH:77]=[C:78]([NH2:82])[CH:79]=[CH:80][CH:81]=2)[N:73]=[CH:72]1)([C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1)([C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(N(CC)CC)C>CN(C=O)C.O>[O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]3[N:15]=[C:14]([C:16]([NH:82][C:78]4[CH:79]=[CH:80][CH:81]=[C:76]([C:74]5[N:73]=[CH:72][N:71]([C:52]([C:65]6[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=6)([C:59]6[CH:60]=[CH:61][CH:62]=[CH:63][CH:64]=6)[C:53]6[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=6)[CH:75]=5)[CH:77]=4)=[O:18])[CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12
Reactant: O=C(O)c1ccc2cc3n(c2n1)CCCNC3=O
Reactant: Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1)c1ccc2cc3n(c2n1)CCCNC3=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
A solution of 6-Oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxylic acid (Intermediate E, 50 mg, 0.20 mmol) and PyBOP (159 mg, 0.31 mmol) in DMF (1.5 mL) is stirred for 30 min. 3-(1-Trityl-1H-imidazol-4-yl)-phenylamine (86 mg, 0.21 mmol) and triethylamine (57 μL, 0.41 mmol) are added and the reaction is stirred at room temperature for 16 h. The mixture is poured into H2O and the resulting white solid is collected by filtration and dried in vacuo to afford the title compound (86 mg, 67%) which was used in the next step without further purification.
Reaction SMILES: CS(Cl)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:20](O)=O.[N:27]1C=CC=CC=1>>[Cl:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]1[C:20]#[N:27]
Reactant: c1ccncc1
Reactant: O=C(O)c1cc2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: CS(=O)(=O)Cl
Product: N#Cc1cc2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
Methanesulphonyl chloride (1 ml) added to a solution of N-(3,4-dichlorobenzyl)indole-2-carboxylic acid (0.23 g) in pyridine at 0° C., and reaction stirred for 2 hours. Ammonia gas was then bubbled through the reaction mixture for 15 mins and then concentrated in vacuo. The residue was dissolved in fresh pyridine, cooled to 0° C. and methanesulphonyl chloride (1 ml) added dropwise. The reaction was stirred for 16 hours, then concentrated in vacuo and residue partitioned between 1N HCl and dichloromethane. Combined organic extracts were dried (MgSO4) and concentrated and the resulting solid purified by column chromatography using dichloromethane-10% ethyl acetate as eluent to give N-(3,4-dichlorobenzyl)-2-cyanoindole as yellow crystals (58 mg, 27%); NMR δ (CD3SOCD3) 5.82 (s, 2H), 6.95-7.70 (m, 7H), 8.03 (m, 1H); M/z (+) 300 (M+), 161, 159; followed by N-(3,4-dichlorobenzyl)indole-2-carboxamide as yellow crystals (37 mg, 16%); M/z (+) 318 (M+), 274, 161, 159, 71, 57.
Reaction SMILES: CN1CCOCC1.[Br:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=1.Cl.Cl.[CH3:19][O:20][C:21](=[O:32])[CH:22]([NH:25][C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[CH2:23][NH2:24].ON1C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:19][O:20][C:21](=[O:32])[CH:22]([NH:25][C:26]1[N:27]=[CH:28][CH:29]=[CH:30][N:31]=1)[CH2:23][NH:24][C:14]([C:12]1[S:13][C:9]([Br:8])=[CH:10][CH:11]=1)=[O:16]
Reactant: O=C(O)c1ccc(Br)s1
Reactant: COC(=O)C(CN)Nc1ncccn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C(CNC(=O)c1ccc(Br)s1)Nc1ncccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
4-methylmorpholine (0.23 mL, 2.10 mmol) was added to a mixture of 5-bromothiophene-2-carboxylic acid (124 mg, 0.60 mmol), 3-amino-2-(pyrimidin-2-ylamino)-propionic acid methyl ester bis-hydrochloride salt (161 mg, 0.60 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarboiimide hydrochloride (115 mg, 0.60 mmol) and 1-hydroxybenzotriazole (81 mg, 0.60 mmol) in dry DMF (2 mL). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, solvent removed in vacuo and the residue chromatographed. Elution with 5% methanol in dichloromethane gave compound G-2 as a yellow foam (186 mg, 81% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]3[C:10]4[CH:24]=[CH:23][S:22][C:11]=4[C:12](=[O:21])[NH:13][C:14]=3[C:15]([CH3:20])=[CH:16][C:17]=2[O:18][CH3:19])[CH:5]=[CH:4][C:3]=1[C@H:25]([CH3:35])[CH2:26][NH:27]C(=O)OC(C)(C)C.[ClH:36]>>[ClH:36].[NH2:27][CH2:26][C@H:25]([C:3]1[CH:4]=[CH:5][C:6]([C:8]2[C:9]3[C:10]4[CH:24]=[CH:23][S:22][C:11]=4[C:12](=[O:21])[NH:13][C:14]=3[C:15]([CH3:20])=[CH:16][C:17]=2[O:18][CH3:19])=[CH:7][C:2]=1[F:1])[CH3:35]
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CNC(=O)OC(C)(C)C)c(F)c1
Agent: Cl
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@H](C)CN)c(F)c1
Yield: 74 %

Procedure:
Following General Procedure D1, (S)-tert-butyl 2-(2-fluoro-4-(8-methoxy-6-methyl-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (520 mg, 1.1 mmol) was reacted with HCl (25 ml) to afford desire product (300 mg, 74%) as an off-white solid: 1H NMR (500 MHz, MeOD) δ 7.63 (d, J=5.4 Hz, 1H), 7.51 (dt, J=23.5, 7.8 Hz, 1H), 7.29 (s, 1H), 7.14-7.02 (m, 2H), 6.16-6.05 (m, 1H), 3.76 (s, 3H), 3.54 (ddd, J=46.9, 14.5, 7.3 Hz, 1H), 3.43-3.20 (m, 2H), 1.51 (d, J=7.0 Hz, 3H); ESI MS m/z 397 [C22H21FN2O2S+H]+; HPLC 98.9% (AUC), tR=10.75 min.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH2:14])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.[OH-].[Na+]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][C:18]([CH3:17])=[CH:19][CH:20]=3)[CH2:9]2)=[O:7])=[CH:15][CH:16]=1
Reactant: Cc1ccc(C(=O)N2CCC[C@@H](N)C2)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(=O)N[C@@H]2CCCN(C(=O)c3ccc(C)cc3)C2)cc1
Temperature: 15 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To the aqueous solution of (R)-1-(p-methylbenzoyl)-3-amino piperidine obtained in Example 13 (amount: 3 g), p-Methylbenzoyl chloride (0.16 g) was added. The pH of the mixture was kept from 8.0 to 9.0 using sodium hydroxide. The mixture was stirred at 15° C. for 3 hours, and the precipitated crystal was filtered off. The crystal was dried under reduced pressure to obtain the title compound as white crystal (0.28 g, yield: 59%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]2[CH2:31][C@H:30]([NH2:32])[CH2:29][C@H:28]2[C:33]([O:35][CH3:36])=[O:34])[CH:21]=1.Cl.C(N(CC)CC)C.[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1>C(OCC)(=O)C.O>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]2[CH2:31][C@H:30]([NH:32][S:52]([C:49]3[CH:50]=[CH:51][C:46]([Cl:45])=[CH:47][CH:48]=3)(=[O:54])=[O:53])[CH2:29][C@H:28]2[C:33]([O:35][CH3:36])=[O:34])[CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1Cc1cccnc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1Cc1cccnc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In an atmosphere of nitrogen,(2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-azidopyrrolidine (49.4 g) was dissolved in ethyl acetate (500 ml) followed by addition of triphenylphosphine (60.75 g, 0.232 mol) at 20°-30° C. (foaming took place). After completion of addition, the mixture was warmed to 40°-45° C. and stirred for 30 minutes. The mixture was diluted with water (16.5 ml) and warmed and stirred at 60°-65° C. for 1.5 hours to provide a reaction mixture containing (2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-aminopyrrolidine. This reaction mixture was cooled to 5°-10° C. and adjusted to pH 3.5 with 1N hydrochloric acid (ca. 350 ml). After phase separation, the organic layer was washed with 1% hydrochloric acid (125 ml). The aqueous layer was combined and adjusted to pH 7.0 with triethylamine (ca. 20 ml) (pH prior to adjustment:1.5). This aqueous solution was cooled to 5° C. and ethyl acetate (475 ml) and triethylamine (70.5 g, 0.696 mol) were added thereto in that order. Then, at 5°-10° C., 4-chlorobenzenesulfonyl chloride (49 g, 0.232 mol) was added in 3 successive portions and the mixture was stirred at 5° C. for 1 hour. The reaction mixture was adjusted to pH 2.0 with 6N-hydrochloric acid. After phase separation, the organic layer was washed with 1% hydrochloric acid (125 ml). The aqueous layer was combined and adjusted to pH 7.0 with 24% aqueous sodium hydroxide solution. The aqueous solution was extracted with ethyl acetate (500 ml) and the extract was washed with a saturated aqueous sodium chloride solution (125 ml). The ethyl acetate layer was concentrated to 187.5 ml under reduced pressure and the concentrate was stirred at 20°-25° C. for 1.5 hours for crystallization and ripening. To this solution was added diisopropyl ether (562.5 ml) dropwise and the mixture was stirred for 1 hour. The resulting crystal was collected by filtration and washed with diisopropyl ether (100 ml). The washed crystal was dried in vacuo overnight to provide (2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-(4-chlorophenylsulfonylamino)pyrrolidine (51.51 g) as a crystal.
Reaction SMILES: [C:1]1([C:7]2([N:13]3[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CC(O)C.O.O.C([O-])(=O)CC(CC([O-])=O)(C([O-])=O)O.[Na+].[Na+].[Na+]>C(O)(=O)C.S(=O)(=O)(O)O.O>[C:1]1([C:7]2([N:13]3[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCN(C2(c3ccccc3)CCCCC2)CC1
Agent: O=[Cr](=O)=O
Agent: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(C)O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: O=C1CCN(C2(c3ccccc3)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
1-(1-Phenylcyclohexyl)-4-hydroxypiperidine was dissolved in 15 ml glacial acetic acid and 0.3 ml concentrated sulfuric acid, and 1.9 ml Jones reagent (made from 26.72 g H2CrO4 and 23 ml H2SO4 diluted to 100 ml with water) was added dropwise. After stirring at room temperature for 20 minutes, 2 ml 2-propanol, Zn(Hg) (made from 1.5 g mossy zinc and 0.2 g mercuric chloride in 20 ml water and 0.25 ml concentrated hydrochloric acid at room temperature for 5 minutes), sodium citrate dihydrate (3.6 g) and 35 ml deionized water were added sequentially. After stirring the solution at room temperature for 30 minutes, the reaction was extracted with chloroform. The solvent was removed in vacuo. Distilled water was added and removed in vacuo. The residue was chromatographed on silica gel eluted with the appropriate mixture of methanol and chloroform to yield pure 1-(1-phenylcyclohexyl)-4-piperidone.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6](I)=[C:7]([CH:33]=1)[O:8][CH2:9][C@H:10]([NH:22][C:23](=[O:32])[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[CH2:11][C:12]([O:14][CH2:15][C:16]1C=CC=CC=1)=[O:13])#[N:2].[C:35]([NH:38][C:39](=[CH2:44])[C:40]([O:42][CH3:43])=[O:41])(=[O:37])[CH3:36].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:35]([NH:38][C:39](=[CH:44][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:33][C:7]=1[O:8][CH2:9][C@H:10]([NH:22][C:23](=[O:32])[C:24]1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=1)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:40]([O:42][CH3:43])=[O:41])(=[O:37])[CH3:36]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: N#Cc1ccc(C(=O)N[C@@H](COc2cc(C#N)ccc2I)CC(=O)OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H](COc1cc(C#N)ccc1C=C(NC(C)=O)C(=O)OC)NC(=O)c1ccc(C#N)cc1
Temperature: 90 °C
Reaction time: 12 h

Procedure:
1.28 g (2.27 mmol) of benzyl (3R)-4-(5-cyano-2-iodophenoxy)-3-(4-cyanobenzoylamino)butanoate, 975 mg (6.81 mmol) of methyl 2-acetamidoacrylate, 415 mg (1.36 mmol) of tris(2-methylphenyl)phosphine, 0.95 ml (6.81 mmol) of triethylamine and 0.5 ml of dimethylformamide were dissolved in 8.0 ml of acetonitrile. 56 mg (0.23 mmol) of palladium acetate was added to the solution at room temperature, and they were stirred at 90° C. for 12 hours. The solvent was distilled off, and the residue was purified by the silica gel column chromatography (volume ratio of chloroform:methanol=30:1) to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[N:16]=[C:15]([NH:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.[N:25]1([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[CH:32]=O)[CH:29]=[CH:28][CH:27]=[CH:26]1.[BH3-]C#N.[Na+]>CO.[Cl-].[Cl-].[Zn+2]>[N:25]1([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[CH2:32][N:21]2[CH2:20][CH2:19][CH:18]([NH:17][C:15]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=[C:7]([NH:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:1])[CH3:24])[N:16]=3)[CH2:23][CH2:22]2)[CH:26]=[CH:27][CH:28]=[CH:29]1
Reactant: CN(C)CCCNc1nc(NC2CCNCC2)c2ccccc2n1
Reactant: O=Cc1ccccc1-n1cccc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CN(C)CCCNc1nc(NC2CCN(Cc3ccccc3-n3cccc3)CC2)c2ccccc2n1

Procedure:
N2-(3-(Dimethylamino)propyl)-N4-(piperidin-4-yl)quinazoline-2,4-diamine (62 mg, 0.189 mmol), 2-(1H-pyrrol-1-yl)benzaldehyde (32 mg, 0.189 mmol), NaCNBH3 (12 mg, 0.190 mmol) and ZnCl2 (13 mg, 0.09 mmol) in MeOH (1 ml) was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography using 5% NH3 ca. 7 N MeOH in CH2Cl2 and 90% CH2Cl2 solution as eluent to produce the title compound as a brown oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.Br[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.Cl>>[CH3:1][CH:2]1[NH:3][CH2:4][CH2:5][N:6]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7]1
Reactant: CC1CNCCN1
Reactant: Brc1nccs1
Agent: Cl
Product: CC1CN(c2nccs2)CCN1
Yield: 90.2 %

Procedure:
30.06 g (300.0 mmol) of 2-methylpiperazine were combined with 4.51 ml (50.0 mmol) of 2-bromothiazole. This mixture was fused and refluxed 5 min. The reaction mixture was cooled and taken up in 10% strength hydrochloric acid and washed with EA. The aqueous phase was set to pH>12 with a 10% strength aq. NaOH solution and then extracted with EA. The organic phase was dried over MgSO4 and conc. in vacuo. There were obtained 8.26 g (45.1 mmol, 90%) of 3-methyl-1-thiazol-2-ylpiperazine.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:9]1[N:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:10]=1[CH3:19].O>O1CCCC1>[F:1][CH:2]([F:5])[CH2:3][O:4][C:9]1[N:14]=[C:13]([NH2:15])[C:12]([N+:16]([O-:18])=[O:17])=[CH:11][C:10]=1[CH3:19]
Reactant: Cc1cc([N+](=O)[O-])c(N)nc1Cl
Reactant: OCC(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])c(N)nc1OCC(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
2,2-Difluoro ethanol (418 mg, 5.1 mmol) was dissolved in tetrahydrofuran (15 ml), sodium hydride (60%) (180 mg, 4.5 mmol) was added thereto under nitrogen atmosphere, and the reaction mixture was stirred for 30 minutes at room temperature. A solution of 6-chloro-5-methyl-3-nitro-2-pyridineamine (600 mg, 3.20 mmol) in tetrahydrofuran (15 ml) was dropped, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution and extracted with ethyl acetate, and after washed with sodium bicarbonate solution, dried over magnesium sulfate. The residue obtained by evaporating the solvent was triturated with n-hexane to yield the title compound (685 mg, 3.1 mmol, 96%) as an orange solid.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:9](O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CC>S(=O)(=O)(O)O>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CCCCCCCCO
Reactant: CCOC(=O)C(C)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCOC(=O)C(C)O
Yield: 43.6 %

Procedure:
A 500 mL one neck round bottom flask equipped with a distillation apparatus and nitrogen inlet/outlet was charged with 100.0 g (0.85 moles) of ethyl lactate, 220.49 g (1.69 moles) of octyl alcohol and 0.42 g of sulfuric acid. The reaction was refluxed for 8 hours and ethanol was collected as formed. The acid was neutralized by washing three times with 100 mL saturated sodium bicarbonate solution. The organic layer was collected and dried over magnesium sulfate. Excess octyl alcohol was removed by high vacuum distillation, and three fractional distillations led to 75.0 g (44% yield) of clear colorless oil. According to GC, the product is 95% pure.