Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][S:6][CH2:7][CH:8]1[CH2:10][CH2:9]1)[CH2:3][OH:4].CO[CH:13](O)[C:14]([F:17])([F:16])[F:15].O>C1(C)C=CC=CC=1>[CH:8]1([CH2:7][S:6][CH2:5][CH:2]2[CH2:3][O:4][CH:13]([C:14]([F:17])([F:16])[F:15])[NH:1]2)[CH2:10][CH2:9]1
Reactant: COC(O)C(F)(F)F
Reactant: N[C@H](CO)CSCC1CC1
Solvent: O
Solvent: Cc1ccccc1
Product: FC(F)(F)C1NC(CSCC2CC2)CO1
Yield: 86.6 %

Procedure:
A solution of 2(R)-amino-3-cyclopropylmethylsulfanylpropan-1-ol (3.2 g, 20.0 mmol), prepared as described in Example 2, Steps 1 and 2 above, and trifluoroacetaldehyde methyl hemiacetal (2.6 g, 20.0 mmol) in toluene (20 mL) was heated at reflux with Dean Stark trapping of water for 24 h. The reaction mixture was concentrated to give 4-cyclopropylmethylsulfanylmethyl-2-trifluoromethyloxazolidine (4.18 g) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:11])[CH:9]=[CH2:10]
Reactant: C=CC(=O)Cl
Reactant: Brc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccc(Br)cc1

Procedure:
Bromobenzene (0.5 mL), acryloyl chloride (110 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (1207.0 mg).
Reaction SMILES: [Br:1]C1C(C(C)C)=CC(OC)=C(C=O)C=1C1C=CC(F)=CC=1.OC(CC(O)C/C=C/C1C=CC=CC=1)CC(O[C:28]([CH3:31])([CH3:30])[CH3:29])=O.[F:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[C:55]([CH:57]([CH3:59])[CH3:58])[CH:54]=[C:53]([OH:60])[C:52]=2[OH:61])=[CH:47][CH:46]=1.CC(=O)CC(=O)C>>[Br:1][C:56]1[C:51]([C:48]2[CH:47]=[CH:46][C:45]([F:44])=[CH:50][CH:49]=2)=[C:52]([OH:61])[C:53]2[O:60][C:28]([CH3:31])([CH3:30])[CH2:29][C:54]=2[C:55]=1[CH:57]([CH3:59])[CH3:58]
Reactant: CC(C)c1cc(O)c(O)c(-c2ccc(F)cc2)c1
Reactant: COc1cc(C(C)C)c(Br)c(-c2ccc(F)cc2)c1C=O
Reactant: CC(C)(C)OC(=O)CC(O)CC(O)C/C=C/c1ccccc1
Solvent: CC(=O)CC(C)=O
Product: CC(C)c1c(Br)c(-c2ccc(F)cc2)c(O)c2c1CC(C)(C)O2

Procedure:
Mass (m/z, %): 380 (M+, 100), 378 (M+, 100), 365 (54), 363 (56), 284 (41), 256 (25), 242 (13), 183 (10), 149 (5).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:16][NH:17][C:18](=[O:36])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27](=[O:35])[NH:28][C:29]2[NH:30][CH2:31][CH2:32][CH2:33][N:34]=2)=[CH:21][CH:20]=1)[C:13]([OH:15])=[O:14])=O)C1C=CC=CC=1.C(O)(=O)C.[H][H].CO>O1CCOCC1.[Pd]>[NH2:11][C@@H:12]([CH2:16][NH:17][C:18](=[O:36])[C:19]1[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][C:27](=[O:35])[NH:28][C:29]2[NH:34][CH2:33][CH2:32][CH2:31][N:30]=2)=[CH:23][CH:24]=1)[C:13]([OH:15])=[O:14]
Reactant: O=C(CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1)NC1=NCCCN1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: N[C@@H](CNC(=O)c1ccc(CCC(=O)NC2=NCCCN2)cc1)C(=O)O
Reaction time: 2 h

Procedure:
100 mg (0.2 mmol) of (2S)-2-benzyloxycarbonylamino-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)ethyl)benzoylamino)propionic acid (step e) were dissolved in 15 ml of dioxane, treated with 0.012 ml of glacial acetic acid and hydrogenated at room temperature under 1 bar of hydrogen over palladium/charcoal (5%). After 2 h, 15 ml of methanol were added and the mixture was hydrogenated at room temperature under 1 bar of hydrogen for further 5 h. It was then filtered and the solvent was evaporated in vacuo. Yield: 67.4 mg (93%).
Reaction SMILES: CO[C:3]1[CH:10]=[C:9]([O:11]CC=C(C)C)[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[CH3:17][O:18][C:19]1[CH:26]=[C:25]([OH:27])[C:24]([C:28]([CH3:32])([CH3:31])[CH:29]=[CH2:30])=[CH:23][C:20]=1[CH:21]=O.O[C:34]1C=CC(C=O)=CC=1>>[CH3:31][C:28]([C:24]1[CH:23]=[C:20](/[CH:21]=[CH:34]/[C:5]([C:4]2[CH:3]=[CH:10][C:9]([OH:11])=[CH:8][CH:7]=2)=[O:6])[C:19]([O:18][CH3:17])=[CH:26][C:25]=1[OH:27])([CH:29]=[CH2:30])[CH3:32]
Reactant: C=CC(C)(C)c1cc(C=O)c(OC)cc1O
Reactant: COc1cc(OCC=C(C)C)ccc1C=O
Reactant: O=Cc1ccc(O)cc1
Product: C=CC(C)(C)c1cc(/C=C/C(=O)c2ccc(O)cc2)c(OC)cc1O

Procedure:
The Claisen rearrangement of 2-methoxy-4-(3-methylbut-2-enyloxy)benzaldehyde and the Claisen condensation of the resulting 2-methoxy-4-hydroxy-5-(1,1-dimethyl-prop-2-enyl)benzaldehyde with 4-hydroxybenzaldehyde to give licochalcone A was performed according to the Chinese procedure:
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[C:15]([O:17][CH3:18])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>CO.O>[CH3:18][O:17][C:15]1[C:14]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)=[CH:13][C:9]2[CH:10]([CH3:12])[CH2:11][NH:5][CH2:6][CH2:7][C:8]=2[CH:16]=1
Reactant: COc1cc2c(cc1-c1cccs1)C(C)CN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1-c1cccs1)C(C)CNCC2
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
A solution of N-trifluoroacetyl-7-methoxy-1-methyl-8-(2-thienyl)-2,3,4,5-tetrahydro-1H-3-benzazepine (28 mg, 0.076 mmol) in methanol (2 mL) was treated with 15% aqueous NaOH (2 mL), and stirred 0.5 hours at 50 C. The product mixture was diluted with water (5 mL), extracted twice with EtOAc (5 mL), the combined organic phases were washed with brine (5 mL), dried with Na2SO4 and concentrated to give 18 mg of a yellow oil. 1H NMR (400 MHz, CDCl3) d 7.45 (d, J=4 Hz, 1 H), 7.39 (s, 1 H), 7.27 (d, J=6 Hz, 1 H), 7.07 (dd, J=4, 6 Hz, 1 H), 6.71 (s, 1 H), 3.90 (s, 3 H), 3.1−2.9 (m, 6 H), 2.80 (m, 1 H), 2.22 (bs, 1 H), 1.38 (d, J=7 Hz, 3 H). MS calculated for C16H19NOS+H: 274, observed: 274.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Cl:11][C:12]1[C:13]([F:20])=[N:14][C:15](F)=[C:16]([F:18])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:10][C:15]2[C:16]([F:18])=[CH:17][C:12]([Cl:11])=[C:13]([F:20])[N:14]=2)[CH:3]=1)[C:8]#[N:9]
Reactant: Fc1cc(Cl)c(F)nc1F
Reactant: N#Cc1cc(O)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc(Cl)cc(Oc2nc(F)c(Cl)cc2F)c1
Temperature: 25 °C

Procedure:
A solution of 3-chloro-5-cyanophenol (1-4; 218 mg; 1.41 mmol) and 3-chloro-2,5,6-trifluoropyridine (1-5; 250 mg; 1.49 mmol) in anhydrous DMF (2 mL) was cooled to −40° C. under a nitrogen atmosphere. The reaction mixture was then treated with 260 mg (1.94 mmol) of anhydrous potassium carbonate added in one portion, and the reaction mixture was vigorously stirred and allowed to warm to room temperature slowly over 90 minutes. The reaction mixture was then stirred for another hour at room temperature. The reaction mixture was diluted with a large excess of water, and a thick precipitate formed. After trituration, the suspension was filtered and the solid dried to give the title compound as an off white amorphous solid. 1H NMR (CDCl3): 7.91 (m, 2H), 7.99 (t, 1H), 8.60 (q, 1H). MS M+1=302.
Reaction SMILES: [Br:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH:6]=[N:5]2.[N+]([O-])([O-])=[O:18].[K+]>>[Br:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:18])[NH:5]2
Reactant: O=[N+]([O-])[O-]
Reactant: O=c1cnc2c([N+](=O)[O-])c(Br)c(Cl)cc2[nH]1
Agent: [K+]
Product: O=c1[nH]c2cc(Cl)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C
Reaction time: 65 h
Yield: 38.1 %

Procedure:
To a stirred solution of 6-bromo-7-chloro-5-nitroquinoxaline-2(1H)-one (0.025 g, 0.082 mmol) in conc. H2So4 (0.5 mL) was added KNO3 (0.011 g, 0.11 mmol) and the resulting dark red solution was stirred at r.t. for 65 h. The solution was then cooled in an ice-bath and diluted with ice to a total volume of 5.0 mL. The precipitated solid was filtered, washed with water (2.0 mL) and dried under vacuum to give 0.019 g (72%) of crude product. It was purified as follows. Crude product (0.016 g) was taken up in 1N NaOH (1.1 mL). The mixture was centrifuged and the supernatant liquid was acidified with conc. HCl to pH~2. The precipitated solid was filtered, washed with water (1.0 mL) and dried under vacuum to furnish 0.010 g (50%) of pure title compound as a cream colored powder; m.p. 338°-343° C. (decomposed); 1H NMR (DMSO-d6): 7.351 (s, 1H), 12.251 (s overlapped by a br s, 2H).
Reaction SMILES: [H-].[Na+].F[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[OH:21]>CN(C)C=O.O.Cl[Cu]>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Oc1cc(F)ccc1F
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl[Cu]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cc(F)ccc2F)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 80.5 %

Procedure:
Into a 500 mL 3-necked round-bottom flask, was placed a solution of sodium hydride (3.9 g, 162.50 mmol, 1.7 equiv) in N,N-dimethylformamide (200 mL). This was followed by the addition of a solution of 1-fluoro-4-nitrobenzene (13.6 g, 96.39 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL) dropwise with stirring at 0° C. over 20 min. The reaction mixture was stirred for 2 hr at 25° C. and then CuCl (9.6 g, 96.97 mmol, 1.0 equiv) was added, followed by addition of a solution of 2,5-difluorophenol (15.5 g, 119.15 mmol, 1.2 equiv) in N,N-dimethylformamide (50 mL) dropwise with stirring at 25° C. over 10 min. The resulting solution was stirred for 12 h at 100° C. in an oil bath and then diluted with water and washed with ether, water and brine. The reaction mixture was dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and eluted with ethyl acetate/petroleum ether (1/8) to give 19.5 g (81%) of 1,4-difluoro-2-(4-nitrophenoxy)benzene as a brown solid,
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[S:22][C:12]=2[N:13]=[C:14]([C:16]2[CH:21]=[N:20][CH:19]=[CH:18][N:17]=2)[N:15]=1>>[N:17]1[CH:18]=[CH:19][N:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:10]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]2[CH:24]=[C:23]([C:25]([F:27])([F:28])[F:26])[S:22][C:12]=2[N:13]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCc1ccccc1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(pyrazin-2-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)- 4-benzylamino-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22](=[O:47])[C@H:23]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH:24][C:25](=[O:39])[C@H:26]([CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[NH2:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22](=[O:47])[C@H:23]([CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[NH:24][C:25](=[O:39])[C@H:26]([CH2:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[NH:27][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)NCCC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
N-(t-butoxycarbonyl)-β-alanine was coupled with N-[3-[(benzyloxy)-carbonyl]-L-alanyl]-3-phenyl-L-alanine benzyl ester to give N-[3-[(benzyloxy)carbonyl]-N-[N-(t-butoxycarbonyl)-β-alanyl]-L-alanyl]-3-phenyl-L-alanine benzyl ester, m.p. 124°-125° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1Br.[NH2:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:13])([F:12])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: FC(F)(F)COc1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: FC(F)(F)COc1ccccc1Nc1ccccc1
Temperature: 90 °C

Procedure:
To a solution of 1.0 g (3.93 mmol) of 2-trifluoroethoxyphenyl bromide (Example 2, Step A) in 39 mL of toluene was added 0.136 g (0.118 mmol) of tetrakis(triphenylphosphine)palladium(0), 0.56 g (4.31 mol) of 3-aminophenylboronic acid, 47 mL (94.1 mmol) of a 2M solution of sodium carbonate and 8 mL of ethanol and the reaction mixture was heated at 90° C. for 22 hr. The reaction mixtur was colld to RT, and partitioned between water and EtOAc. The aqueous fraction was extracted with EtOAc nd the combined organic fractions were washed with water and brine and dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, 4:1 hexanes:EtOAc) to give the title compound. Mass Spectrum (ESI) m/e M+1 268.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]([CH2:7][CH3:8])[NH:5][N:6]=1.[Br:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]#[N:24])=[CH:13][CH:12]=1>CO>[BrH:9].[CH2:7]([C:4]1[S:3][C:2](=[NH:1])[N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])=[CH:15][CH:16]=2)[N:5]=1)[CH3:8]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCC1NN=C(N)S1
Solvent: CO
Product: Br
Product: CCc1nn(Cc2ccc(-c3ccccc3C#N)cc2)c(=N)s1
Yield: 110.6 %

Procedure:
To 10 ml of methanol, 2.7 g of 2-amino-5-ethyl-1,3,4-thiadiazoline and 1.3 g of 4'-bromomethyl-2-cyanobiphenyl were added, followed by heating under reflux for 20 hours. After the reaction mixture was cooled, crystals so precipitated were collected by filtration. The resulting crystals were washed successively with methanol and diethyl ether and then dried, whereby 2.12 g of the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[CH2:5]([OH:12])[C:6]#[C:7][C:8]#[C:9][CH2:10][OH:11].[CH2:13]([OH:22])[CH2:14][C:15]#[C:16][C:17]#[C:18][CH2:19][CH2:20][OH:21]>>[CH3:1][NH:2][C:3]([O:11][CH2:10][CH3:9])=[O:4].[CH3:1][NH:2][C:3]([O:21][CH2:20][CH3:19])=[O:4].[CH2:5]([OH:12])[C:6]#[C:7][C:8]#[C:9][CH2:10][OH:11].[CH3:1][NH:2][C:3]([O:11][CH2:10][CH3:9])=[O:4].[CH3:1][NH:2][C:3]([O:11][CH2:10][CH3:9])=[O:4].[CH2:13]([OH:22])[CH2:14][C:15]#[C:16][C:17]#[C:18][CH2:19][CH2:20][OH:21]
Reactant: CN=C=O
Agent: OCC#CC#CCO
Agent: OCCC#CC#CCCO
Product: CCOC(=O)NC

Procedure:
The limitation in this process is that the total number of diols and isocyantes or diols and organic sulfonic acid agents is at least three, thereby resulting in a co-crystallized composition directly recoverable from the reaction mixture. For example, methylisocyanate can be reacted with a mixture of 2,4-hexadiyn-1,6-diol and 3,5-octadiyne-1,8-diol to yield a co-crystallized composition of (1) 2,4-hexadiyn-1,6-diol bis(methylurethane) and (2) 3,5-octadiyn-1,8-diol bis(methylurethane). Similarly, methylisocyanate and ethylisocyanate can be reacted with 2,4-hexadiyn-1,6-diol to yield a co-crystallized composition of (1) 2,4-hexadiyn-1,6-diol bis(methylurethane), (2) 2,4-hexadiyn-1,6-diol bis(ethylurethane) and (3) 2,4-hexadiyn-1-ol-methylurethane-6-ol-ethylurethane.
Reaction SMILES: [C:1]([OH:16])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:20])=O>ClCCl>[C:1]([Cl:20])(=[O:16])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCC/C=C/C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCCCCCCCC/C=C/C(=O)Cl
Temperature: 25 °C
Yield: 99 %

Procedure:
(E)-tetradec-2-enoic acid (18.7 g) was dissolved in anhydrous dichloromethane (200 ml) under nitrogen with stirring. The solution was cooled in ice-water bath for 30 min. Oxalyl chloride (9.1 ml) was added dropwise. The reaction mixture was slowly warm up to room temperature overnight. The solvent was removed under vacuum. The product was obtained as clear oil (20.0 g, 99%) and used in next step synthesis without further purification.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.Cl.[SH:20][C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([S:20][C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: Cc1ccnc(S)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccnc(Sc2nc(-c3ccc(Cl)cc3)c(CCC(=O)O)o2)n1
Yield: 87.8 %

Procedure:
A mixed solution of 3-[2-chloro-4-(4-chlorophenyl)-5-oxazolyl]propionic acid (1.43 g), 2-mercapto-4-methylpyrimidine hydrochloride (1.05 g), potassium carbonate (2.76 g) and N,N-dimethylformamide (20 mL) was stirred at 110° C. under a nitrogen atmosphere for 10 hrs. The reaction mixture was diluted with water, and acidified with 2N aqueous hydrochloric acid solution. The precipitated crystals were collected by filtration and recrystallized from methanol to give 3-[4-(4-chlorophenyl)-2-[(4-methylpyrimidin-2-yl)sulfanyl]-5-oxazolepropionic acid (1.65 g, yield 88%) as colorless prism crystals. melting point: 174–175° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[NH2:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.O.Cl>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:6][CH:7]=1
Reactant: NCCN1CCCC1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: O=[N+]([O-])c1cc(Br)cnc1NCCN1CCCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
0.86 mL (5.05 mmol) ethyldiiopropylamine are added to a solution of 600 mg (2.53 mmol) 5-bromo-2-chloro-3-nitropyridine and 0.32 mL (2.53 mmol) 1-(2-aminoethyl)-pyrrolidine in 3 mL n-butanol. The reaction is heated to 50° C. and stirred for one hour at this temperature. The solvent is eliminated i.vac. and the residue is combined with 40 mL water and acidified with 1 M HCl. The aqueous phase is extracted with 20 mL EtOAc and the aqueous phase is then made alkaline with saturated K2CO3 solution. The aqueous phase is extracted with 40 mL EtOAc. The organic phase is dried over Na2SO4 and the solvent is eliminated i.vac.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:36]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:9][CH:10]=1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCOC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
(aa) In an analogous manner to that described in Example 22 (k), by acylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 24 (t)] with benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzoyloxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as an almost colourless solid; MS: 580 (M+H)+.
Reaction SMILES: I[CH3:2].[CH:3]1([CH:6]([OH:33])[C:7]2[N:11]3[CH2:12][C@H:13]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=4[F:32])[CH2:14][CH2:15][C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]3=[N:9][CH:8]=2)[CH2:5][CH2:4]1.[H-].[Na+]>O1CCCC1>[CH:3]1([CH:6]([O:33][CH3:2])[C:7]2[N:11]3[CH2:12][C@H:13]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=4[F:32])[CH2:14][CH2:15][C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:10]3=[N:9][CH:8]=2)[CH2:5][CH2:4]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(O)C3CC3)cnc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(c1cnc2n1C[C@H](c1cccc(F)c1F)CC[C@H]2NC(=O)OC(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
Iodomethane (9.0 μL, 0.15 mmol) was added to a solution of tert-butyl (6S,9R)-3-[cyclopropyl(hydroxy)methyl]-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-ylcarbamate (66 mg, 0.15 mmol) and sodium hydride (60% dispersion in mineral oil; 8.3 mg, 0.23 mmol) in tetrahydrofuran (1 mL) at 0° C. After 1 h, the mixture was allowed to warm to ambient temperature. After 2 h, additional iodomethane (6.0 μL, 0.10 mmol) and sodium hydride (60% dispersion in mineral oil; 3.0 mg, 0.08 mmol) were added. After 1 h, the reaction was quenched with water and the mixture was extracted with dichloromethane (3×). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (23 mg). MS 448.2 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@@:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:7])[C:3]1([CH3:18])[CH3:17].[Br:19][C:20]1[CH:21]=[C:22]2[C:27](Cl)=[C:26]([C:29]([NH2:31])=[O:30])[CH:25]=[N:24][N:23]2[CH:32]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[Br:19][C:20]1[CH:21]=[C:22]2[C:27]([NH:1][C@@H:2]3[CH2:6][CH2:5][C@@:4]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:7])[C:3]3([CH3:18])[CH3:17])=[C:26]([C:29](=[O:30])[NH2:31])[CH:25]=[N:24][N:23]2[CH:32]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Reactant: CC(C)(C)OC(=O)NC[C@@]1(C)CC[C@@H](N)C1(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC[C@@]1(C)CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C1(C)C
Temperature: 90 °C
Yield: 72.1 %

Procedure:
To a solution of tert-butyl (((1S,3R)-3-amino-1,2,2-trimethylcyclopentyl)methyl)carbamate (417 mg, 1.626 mmol) and 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (446 mg, 1.626 mmol, from preparation 5) in DMF (4.07 ml) was added DIEA (625 μl, 3.58 mmol). The reaction mixture was heated at 90° C. for 2 hrs. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (100 ml). The ethyl acetate solution was washed with water (3×100 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure, yielding a light yellow oil. The solid was dissolved in 50% EtOAc/hexanes (5 ml) and loaded directly on a pre-packed silica gel column. The crude product was purified via medium pressure chromatography (10-60% EtOAc-hexanes solvent system over 30 minutes) to afford tert-butyl (((1S,3R)-3-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-1,2,2-trimethylcyclopentyl)methyl)carbamate (580 mg, 1.173 mmol, 72.1% yield) as a yellow solid. ESI-MS m/z 496.1 ([M+H]+).