Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:12]1([CH:19]=[CH:18][C:16]([OH:17])=[CH:15][CH:14]=1)[OH:13].Cl>N1C=CC=CC=1>[CH2:2]([C:1]([O:13][C:12]1[CH:19]=[CH:18][C:16]([OH:17])=[CH:15][CH:14]=1)=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(=O)Cl
Reactant: Oc1ccc(O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCC(=O)Oc1ccc(O)cc1

Procedure:
After adding 17 g of nonanic acid chloride to 200 ml of pyridine dissolved with 47 g of hydroquinone, the mixture was heated for 2 hours. Following neutralization of hydrogen chloride, the crude of 4-octylcarbonyloxyphenol was obtained by extracting with chloroform. The crude compound was purified by passing through silica-gel column to obtain pure 4-octylcarbonyloxyphenol (J). (I) was reacted with (J) to obtain the compound (G) same procedure as example 14. (G) was a smectic liquid crystal compound having the SC* phase. The phase transition points of (G) were shown in table 4.
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:9][N:8]=[C:7](SC)[N:6]=2)[CH2:3][CH2:2]1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>CS(C)=O>[CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:9][N:8]=[C:7]([NH:29][CH:26]([CH3:28])[CH3:27])[N:6]=2)[CH2:3][CH2:2]1
Reactant: CSc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Reactant: CC(C)N
Solvent: CS(C)=O
Product: CC(C)Nc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Yield: 39.4 %

Procedure:
To a solution of 4′-(cyclopropylmethyl)-2′-(methylsulfanyl)-N-pyridin-4-yl-4,5′-bipyrimidin-2-amine (11) (35 mg, 0.096 mmol) in DMSO (1 mL), isopropylamine (24.55 μl, 0.287 mmol) was added and the reaction was microwaved for 20 minutes at 160° C. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 10% MeOH/DCM] to afford the title compound as a pale-yellow solid (13.67 mg, 39.6% yield). 1H NMR (400 MHz, MeOD) δ ppm 0.04-0.17 (m, 2H) 0.31-0.50 (m, 2H) 0.97-1.17 (m, 1H) 1.27 (d, J=6.57 Hz, 6H) 2.88 (d, J=7.07 Hz, 2H) 4.22 (ddd, J=13.01, 6.44, 6.32 Hz, 1H) 7.10 (d, J=5.05 Hz, 1H) 7.84 (d, J=7.07 Hz, 2H) 8.30 (d, J=6.57 Hz, 2H) 8.42 (s, 1H) 8.55 (d, J=5.05 Hz, 1H). HRMS (ES+) for C20H23N7.H+ [MH+]: calcd, 362.2093; found, 362.2083. UV-LC: 100% UV purity at 254/214 nm; tR=3.39 minutes over 7.75 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH2:48])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:56][S:57](Cl)(=[O:59])=[O:58]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:48][S:57]([CH3:56])(=[O:59])=[O:58])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCN)CCC3)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCNS(C)(=O)=O)CCC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To an ice-cooled solution of 0.250 g (0.379 mmol) (3R,4R)-3-[1-(2-amino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 15(b)] and 0.049 g (0.493 mmol, 1.3 equiv.) triethylamine in 5 ml of dichloromethane was added dropwise at 0° C. 0.047 g (0.417 mmol, 1.1 equiv.) methanesulfonyl chloride. After stirring for 30 min at 0° C., the reaction mixture was poured into 50 ml of an ice/water mixture and extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 25 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 1:2 v/v mixture of hexane and ethyl acetate as eluent to yield 0.247 g (0.335 mmol, 88.3% of theory) of (3R,4R)-3-[1-(2-methanesulfonylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 736 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10]C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C1COCC1.CO>[C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl phenylacetate (5.03 g, 33.5 mmol) was treated with 1N aqueous NaOH (22 mL, 22 mmol) in THF (40 mL) and MeOH (4 mL), and stirred overnight at room temperature. Additional 1N aqueous NaOH (22 mL, 22 mmol) was added, and the reaction was stirred for 6 hours at room temperature. The mixture was acidified with 1N aqueous HCl to pH 3-4 and extracted with EtOAc three times. The combined organic layers were dried and concentrated to give phenyl-acetic acid.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.[CH:31]1([CH2:34][O:35][C:36]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH3:46])[CH2:39][NH:38][CH2:37]2)[CH2:33][CH2:32]1.[C:47]([O:51][C:52]([NH:54][C@H:55]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH3:67])=[CH:62][CH:61]=1)[C:56](O)=[O:57])=[O:53])([CH3:50])([CH3:49])[CH3:48]>CN(C)C=O.CCCCCCC.C(OCC)(=O)C>[CH:31]1([CH2:34][O:35][C:36]2([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[CH3:46])[CH2:37][N:38]([C:56](=[O:57])[C@H:55]([NH:54][C:52](=[O:53])[O:51][C:47]([CH3:48])([CH3:49])[CH3:50])[CH2:59][C:60]3[CH:61]=[CH:62][C:63]([O:66][CH3:67])=[CH:64][CH:65]=3)[CH2:39]2)[CH2:32][CH2:33]1
Reactant: Cc1ccccc1C1(OCC2CC2)CNC1
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)N2CC(OCC3CC3)(c3ccccc3C)C2)cc1
Temperature: 25 °C
Reaction time: 38 h
Yield: 41.8 %

Procedure:
1.9 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.2 mmol), 1.4 g of N-hydroxybenzotriazole (10.2 mmol), 3.8 ml of triethylamine (27.2 mmol) and then 2.2 g (8.7 mmol) of 3-cyclopropylmethoxy-3-o-tolylazetidine hydrochloride dissolved in 35 ml of N,N-dimethylformamide are successively added to a solution of 2.7 g (9.2 mmol) of (R)-2-tert-butoxycarbonylamino-3-(4-methoxyphenyl)propanoic acid in 55 ml of N,N-dimethylformamide. The reaction medium is stirred at room temperature for 38 hours. A 1/1 heptane/ethyl acetate mixture is added and the reaction medium is washed with aqueous 1N sodium hydroxide solution. The organic phase is then washed with aqueous 1N hydrochloric acid solution, dried over sodium sulfate, filtered and concentrated under vacuum. 2.7 g of crude residue are obtained and are purified by chromatography on silica gel eluted with a heptane/ethyl acetate mixture, the polarity being increased from 95/5 to 60/40. 1.8 g (41%) of tert-butyl [(R)-2-(3-cyclopropylmethoxy-3-o-tolylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]carbamate are obtained in the form of a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CS(C)=O>O.C(Cl)Cl.CO>[O:8]=[C:4]1[CH:3]=[C:2]([O:1][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:7]=[CH:6][NH:5]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: O=c1cc(O)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc[nH]c(=O)c2)CC1
Temperature: 100 °C
Yield: 44.8 %

Procedure:
A 250 mL round bottom flask was charged with 4-hydroxypyridin-2(1H)-one (6.13 g, 55.1 mmol), tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (12.83 g, 45.9 mmol) (prepared according to the procedure described in patent application WO-2009/012275), K2CO3 (14.60 g, 106 mmol) and DMSO (56 mL). The mixture was heated to 100° C. for 3 hours and then allowed to cool to room temperature overnight. The resulting mixture was diluted with H2O (300 mL) and extracted with EtOAc (2×150 mL). The organic layers were combined and concentrated in vacuo to a white solid. The solid was purified by flash chromatography (SiO2, 0-100% EtOAc in CH2Cl2 and then SiO2, 0-10% MeOH in CH2Cl2) to yield tert-butyl 4-(2-oxo-1,2-dihydropyridin-4-yloxy)piperidine-1-carboxylate (6.05 g, 45% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ 12.34 (br. s., 1H) 7.21 (d, J=7.28 Hz, 1H) 5.96 (dd, J=7.28, 2.51 Hz, 1H) 5.87 (d, J=2.26 Hz, 1H) 4.35-4.58 (m, 1H) 3.59-3.80 (m, 2H) 3.17-3.41 (m, 2H) 1.87-2.08 (m, 2H) 1.65-1.87 (m, 2H) 1.47 (s, 9H). MS (ESI) 295 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH2:12])=[CH:7][CH:6]=[CH:5]2.[CH2:13]([N:20]([CH2:24][CH2:25]Cl)[CH2:21][CH2:22]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.C(O)(C)C>C(OCC)(=O)C>[CH2:13]([N:20]1[CH2:24][CH2:25][N:12]([C:8]2[C:9]3[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: Nc1cccc2cc(F)ccc12
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc2c(N3CCN(Cc4ccccc4)CC3)cccc2c1
Yield: 75.4 %

Procedure:
To a 125 ml round-bottomed flask equipped with condenser and N2 inlet were added 1.0 g (6.21 mmol) of 6-fluoro-1-amino naphthalene, 1.8 g (7.76 mmol) of N-benzyl bis(2-chloroethyl)amine, 3.3 ml (19.2 mmol) of diisopropylethylamine, and 50 ml isopropanol. The reaction was refluxed 24 hours, cooled, and evaporaated to an oil. The oil was taken up in ethyl acetate, washed with waterand brine, dried over sodium sulfate, and evaporated to an oil. The oil was chromatographed on silica gel using methylene chloride as eluent to afford 1.5 g (75.5%) of an oil.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Li+].[OH-].O>CO>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C(=O)OC)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCc1ccc(C#Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.8 %

Procedure:
To a solution of methyl 4-[(4-butylphenyl)ethynyl]benzoate (23.0 g, 0.078 mol) in MeOH (200 ml) was added LiOH (3.6 g, 0.157 mol) followed by water (50 mL) and the reaction mixture was stirred for 5 hrs at rt. The solvents were removed under reduced pressure. The residue was acidified with an aqueous solution of HCl (1.5M) and a solid precipitated out. The precipitate was filtered and dried to yield 19.5 g (89%) of the title compound. 1H NMR (DMSO-d6) δ: 13.1 (brs, 1H), 7.96 (dd, J=1.6 and 6.7 Hz, 2H), 7.64 (d, J=6.8 Hz, 2H), 7.49 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.2 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H), 1.55 (m, 2H), 1.29 (m, 2H), 0.88 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[F:21][C:22]([F:30])([F:29])[C:23](=O)[CH2:24][C:25](=O)[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:25]([CH3:26])=[CH:24][C:23]([C:22]([F:30])([F:29])[F:21])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Reactant: CC(=O)CC(=O)C(F)(F)F
Product: Cc1cc(C(F)(F)F)nn1-c1nc(Nc2ccc(Cl)cc2)c2ncn(C)c2n1

Procedure:
Was prepared according to Example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine and 1,1,1-trifluoro-2,4-pentanedione.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:9][C:10]([S:13]([C:16]3[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH2:23][CH2:24][CH2:25][N:26]1[C:30]([CH3:32])([CH3:31])[C:29](=[O:33])[NH:28][C:27]1=[O:34].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:31][C:30]1([CH3:32])[N:26]([CH2:25][CH2:24][NH:23][C:2]2[N:7]=[C:6]([C:8]3[S:9][C:10]([S:13]([C:16]4[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=4)(=[O:15])=[O:14])=[CH:11][CH:12]=3)[CH:5]=[CH:4][N:3]=2)[C:27](=[O:34])[NH:28][C:29]1=[O:33]
Reactant: CC1(C)C(=O)NC(=O)N1CCN
Reactant: Cc1ccc(S(=O)(=O)c2ccc(-c3ccnc(Cl)n3)s2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)c2ccc(-c3ccnc(NCCN4C(=O)NC(=O)C4(C)C)n3)s2)cc1
Temperature: 160 °C
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
A mixture of 2-chloro-4-(5-tosylthiophen-2-yl)pyrimidine (100 mg, 0.23 mmol), 1-(2-aminoethyl)-5,5-dimethylimidazolidine-2,4-dione (33 mg, 0.26 mmol) and triethylamine (28 mg, 0.27 mmol) in toluene (3 mL) was heated at 160° C. for 35 min in a Personal Chemistry microwave reactor. Upon cooling to rt the precipitate was filtered and washed with diethyl ether. The solid was put into 2 mL of methanol and the suspension was stirred for about 15 min and filtered to afford the title compound as pale yellow crystals (56 mg, 50%). MS (M+H)+ 486.
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][NH:9][C:10]([NH:18][C:19]#[N:20])=[N:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:1]1([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[C:10](=[N:18][C:19]#[N:20])[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CNC(=Nc1ccncc1)NCC(O)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CN=C1NCC(c2ccccc2)N1c1ccncc1
Temperature: 25 °C

Procedure:
To a solution of N-(2-phenyl-2-hydroxyethyl)-N′-cyano-N″-4-pyridylguanidine (1.0 g, 3.56 mmol) and triphenylphosphine (1.86 g, 7.12 mmol) in THF (30 mL) at 0° C. was added diisopropyl azodicarboxylate (3.8 mL, 7.12 mmol) dissolved in 15 mL (THF) by syringe pump over 30 min. The resulting mixture was kept stirring and warmed to room temperature for 70 h. The product was precipitated from ether to form the white solid. The solid thus obtained was washed sequentially with ether, methanol and acetone to give the product (i.e., Compound 14) as a white solid (0.67 g, 72%).
Reaction SMILES: C1OC2C(=CSC=2)[O:3]C1CO.[CH:12]1([N:18]=[C:19]=[N:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(C1C=CC(C2C=CC(OC(CC)C(O)=O)=CC=2)=CC=1)#N>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:21]1([NH:20][C:19]([NH:18][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: OCC1COc2cscc2O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCC(Oc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1.06 g of a mixture of 80% of EDT-methanol and 20% of hydroxy-PDT (corresponding to 6.19 mmol; 4.95 mmol based on the main component EDT-methanol), 1.04 g (5.04 mmol) of N,N′-dicyclohexylcarbodiimide and 0.15 g (1.22 mmol) of 4-(dimethylamino)pyridine are dissolved in 50 ml of CH2Cl2 and cooled in an ice bath. 1.42 g (5.05 mmol) of [(4′-cyano-1,1′-biphenyl-4-yl)oxy]-butyric acid (see formula) are added in small doses while stirring to the ice-cooled solution. After 1 hour, the reaction is continued at room temperature. After a further 64 hours, the colourless precipitate (N,N′-dicyclohexylurea) formed is filtered off. The clear, colourless solution is washed in succession with 2×75 ml of 1 N HCl, 2×75 ml of saturated NaHCO3 solution and 2×75 ml of NaCl solution. The clear organic phase is dried over MgSO4, the desiccant is filtered off and the solvent is removed on a rotary evaporator. This gives 2.38 g of crude product.
Reaction SMILES: [CH3:1][N:2]1[CH2:5][C:4]2([CH2:14][C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18](O)=[O:19])[CH:11]=3)[O:6]2)[CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:35][O:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][O:38]1>C(Cl)Cl>[CH3:1][N:2]1[CH2:3][C:4]2([CH2:14][C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10](/[CH:16]=[CH:17]/[C:18]([NH:35][O:36][CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][O:38]4)=[O:19])[CH:11]=3)[O:6]2)[CH2:5]1
Reactant: NOC1CCCCO1
Reactant: CN1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Yield: 70.8 %

Procedure:
A suspension of (E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (400 mg, 1.29 mmol) in DCM (16 ml) was treated with TEA (0.30 ml, 2.2 mmol) and then with EDC (420 mg, 2.20 mmol), HOBt (297 mg, 2.20 mmol) and NH2OTHP (204 mg, 1.75 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-methyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (340 mg) as a light yellow solid.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([N:26]([CH2:32][C@H:33]1[C@@H:37]([F:38])[CH2:36][N:35](C(OCC2C=CC=CC=2)=O)[CH2:34]1)[C:27](=[O:31])[C@@H:28]([OH:30])[CH3:29])[C:22]([CH3:25])([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)C.C(#N)C.[Pd]>[CH2:1]([C:8]1[S:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[C@H:21]([N:26]([CH2:32][C@H:33]1[C@@H:37]([F:38])[CH2:36][NH:35][CH2:34]1)[C:27](=[O:31])[C@@H:28]([OH:30])[CH3:29])[C:22]([CH3:25])([CH3:23])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](O)C(=O)N(C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: C[C@H](O)C(=O)N(C[C@@H]1CNC[C@@H]1F)[C@@H](c1nc(-c2cc(F)ccc2F)sc1Cc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of (3R,4R)-benzyl 3-(((S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)-2-hydroxypropanamido)methyl)-4-fluoropyrrolidine-1-carboxylate (108 mg, 0.159 mmol) in degassed ethanol (3 mL, 0.05 M solution) was added Pd/C (17.2 mg) under anhydrous N2 atmosphere. After flushed with hydrogen gas, the reaction mixture equipped with a hydrogen gas balloon was stirred at room temperature for 30 min. The reaction mixture was filtered through Celite® pad that was washed with methanol and EtOAc. The volatile organic filtrate was removed in vacuo to give the crude amine, which was purified by preparative reverse phase HPLC. The combined fractions of the product were neutralized with saturated NaHCO3 solution, which was then extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The product obtained was then dissolved in acetonitrile and water (1:1 ratio) and lyophilized for 48 h. The white powdery (S)-N-((R)-1-(5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)-2,2-dimethylpropyl)-N-(((3S,4R)-4-fluoropyrrolidin-3-yl)methyl)-2-hydroxypropanamide was obtained in 75% yield (66 mg, over 2 steps) as the free amine. 1H NMR (CD3Cl, 400 MHz): δ 7.87 (1H, m), 7.33-7.27 (4H, m), 7.22-7.14 (2H, m), 7.08 (1H, m), 6.08 (1H, s), 4.71-4.62 (1H, m), 4.60-4.40 (1H, m), 4.23 (2H, s), 3.95 (1H, m), 3.63 (2H, m), 3.01-2.86 (1H, m), 2.70-2.46 (2H, m), 2.14-2.06 (2H, m), 1.45 (3H, m), 1.03 (9H, s). LC/MS (uplc): MH+ 546.4, 1.00 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]([NH:19]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([N:29](CC)CC)C.COC1C=CC(CN)=CC=1>CS(C)=O>[NH2:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:29])[N:7]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)n2)c2ccccc12
Reactant: CCN(CC)CC
Agent: COc1ccc(CN)cc1
Solvent: CS(C)=O
Product: Nc1nccc(Oc2ccc(N)c3ccccc23)n1
Temperature: 95 °C

Procedure:
To a solution of tert-butyl 4-(2-chloropyrimidin-4-yloxy)naphthalen-1-ylcarbamate (1.00 g, 2.69 mmol) and triethylamine (0.374 mL, 2.69 mmol) in DMSO (10 mL) was added (4-methoxyphenyl)methanamine (350 μl, 2.69 mmol) and the reaction mixture was heated in a sealed tube at 95° C. for 16 hr. The resulting mixture was partitioned between water and EtOAc and the organic layer was separated and washed with brine and then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate in isohexane, 0-50%, gradient elution) to afford [as judged by LCMS] a 1:1 mixture of the desired compound: tert-butyl 4-(2-(4-methoxybenzylamino)pyrimidin-4-yloxy)naphthalen-1-ylcarbamate together with 2-chloro-N-(4-methoxybenzyl)pyrimidin-4-amine. This material was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:9][CH:10]([OH:14])[CH2:11][CH2:12]Br>>[C:2]1([N:1]2[CH2:12][CH2:11][CH:10]([OH:14])[CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: OC(CBr)CCBr
Product: OC1CCN(c2ccccc2)C1

Procedure:
Referring to the above reaction diagram, tetrahydroquinoline may be alkylated in methanol by adding excess bromoethanol, sodium iodide and potassium carbonate and refluxing the solution for 24 hours. The product is preferably isolated in water and purified by vacuum distillation. If phenylpiperazine is the starting material, it is alkylated under the same reaction conditions. A 1-phenyl-4-piperidinol structure is synthesized by preparing N-but-3-enyl--N-methylaniline, and treating with aqueous trifluoroacetic acid. N-but-3-enyl--N-methylaniline is provided by alkylation of N-methylaniline with 4-bromobut-1-ene. 1-Phenyl-3-pyrrolidinol is synthesized by the reaction of aniline with 1,4-dibromo-2-butanol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[C:29]3[CH:28]=[CH:27][S:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)(=O)C.O>CO>[S:26]1[CH:27]=[CH:28][C:29]2[C:21]([N:18]3[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][CH2:12][CH2:11][OH:10])[CH2:20][CH2:19]3)=[CH:22][CH:23]=[CH:24][C:25]1=2
Reactant: CC(=O)OCCCCN1CCN(c2cccc3sccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OCCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Potassium carbonate (3.87 g, 28 mmol) was added to a solution of 7.76 g (23.3 mmol) of 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butyl acetate in 90% methanol solution (150 ml). The solution mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was then extracted with dichloromethane. The extraction solution was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (n-hexane:ethyl acetate=2:1→1:1), and concentrated under reduced pressure to obtain 4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butan-1-ol (6.65 g) as colorless oil.