Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([OH:17])=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH:24]1([CH2:27]Br)[CH2:26][CH2:25]1.[Cl-].[NH4+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([O:17][CH2:27][CH:24]2[CH2:26][CH2:25]2)=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(OCc2ccccc2)c1O
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccccc2)c1OCC1CC1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
To a mixture of 3-benzyloxy-2-hydroxy-benzaldehyde (129, 1.0 g, 4.38 mmol) and cesium carbonate (2.14 g, 6.57 mmol) in N,N-dimethylformamide (50 mL), cyclopropylmethyl bromide (1.77 g, 13.1 mmol) was added at room temperature. The mixture was stirred at 40° C. for 3 days. The reaction mixture was poured into a solution of saturated ammonium chloride and was extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over magnesium sulfate. After removal of solvent, a viscous liquid was obtained (130, 1.21 g, 98%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[NH2:23]>>[CH3:28][O:27][C:25]1[CH:24]=[C:22]([CH:21]=[C:20]([O:19][CH3:18])[CH:26]=1)[NH:23][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: COc1cc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)cc(OC)c1

Procedure:
The title compound was prepared from 4-chloro-2-(2-pyridinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol) and 3,5-dimethoxyaniline (26 mg, 0.172 mmol) similar to Example 180 and was isolated as a light yellow solid (16 mg, 37% yield). 1H NMR (CDCl3): 8.85 (dd, J=4.8, 1.5 Hz, 1H), 8.56 (d, J=6.9 Hz, 1H), 7.89 (ddd, J=9.3, 7.5, 1.5 Hz, 1H), 7.65 (brs, 1H), 7.45 (dd, J=9.3, 4.5 Hz, 1H), 7.09 (s, 1H), 6.51 (d, J=1.8 Hz, 1H), 6.37 (t, J=1.8 Hz, 1H), 3.93 (s, 6H).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH2:12])[CH2:4][CH2:3]1.[CH3:13][N:14]=[C:15]=[O:16]>>[CH3:13][NH:14][C:15]([NH:12][CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:16]
Reactant: NC1CCC(O)c2ccccc21
Reactant: CN=C=O
Product: CNC(=O)NC1CCC(O)c2ccccc21

Procedure:
Similarly, 1,2,3,4-tetrahydro-4-hydroxy-1-naphthylamine is allowed to react with an equivalent amount of methyl isocyanate to afford 1-methyl-3-(1,2,3,4-tetrahydro-4-hydroxy-1-naphthyl)urea, m.p. 172° C. to 180° C.
Reaction SMILES: C1([C@@H]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[CH2:16][OH:17])C)C=CC=CC=1>[Pd].CO>[NH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[CH2:16][OH:17]
Reactant: C[C@H](N[C@H]1CCCC[C@@H]1CO)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CCCC[C@@H]1CO
Temperature: 60 °C
Yield: 108.4 %

Procedure:
5% Palladium on carbon (0.05 g) was added to a solution of (1S,2S)-2-[(S)-1-phenylethyl amino]cyclohexyl)methanol (11, 0.5 g, 0.002 mol) dissolved in methanol (15 mL). The mixture was heated at 60° C. under hydrogen (14.5 psi) atmosphere for NLT 3 h. The mixture was cooled to room temperature, flushed with nitrogen, the catalyst was filtered and washed with fresh methanol (10 mL). The combined filtrate was concentrated under vacuum to afford 0.28 g of ((1S,2S)-2-aminocyclohexyl)methanol (17) in quantitative yield as a white solid. [α]23D 9.1 (c, 0.0107 CHCl3), 1H NMR (CDCl3, 400 MHz): δ 3.61-3.54 (m, 2 H), 2.71 (bs, 3H), 2.45 (dt, 1H, J=10.6, 1.2 Hz), 1.85-1.78 (m, 1H), 1.74-1.65 (m, 1H), 1.62-1.53 (m, 1H), 1.40-1.30 (m, 1H), 1.25-1.06 (m, 3H), 0.91-0.80 (m, 1H), 13C NMR (CDCl3): δ 70.2, 57.4, 45.5, 40.1, 28.6, 25.5, 25.5, For NMR of its enantiomer, ((1R,2R)-2-Aminocyclohexyl)methanol, see reference J. Am. Chem. Soc. 1996, 118, 5502.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][O:14][C:15](=[O:22])[C:16]([N:19]=[C:20]=[O:21])([CH3:18])[CH3:17]>>[CH3:13][O:14][C:15](=[O:22])[C:16]([CH3:18])([CH3:17])[NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)C(C)(C)N=C=O
Product: COC(=O)C(C)(C)NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
9.75 g (50 mmol) of 5-amino-2-chlorobenzotrifluoride and 7.15 g (50 mmol) of 2-isocyanato-2-methylpropionic acid methyl ester were admixed and melted at 80° C. The melt was maintained at 80° C. for 30 minutes. The resulting product which was crystallized during the process, was recrystallized from isopropanol/methylene chloride and dried at 50° C. for 20 hours, under greatly reduced pressure, to yield N-[(3-Trifluoromethyl-4-chloro-phenyl)-carbamoyl]-2-methylalanine methyl ester, m.p. 141°-142° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[S:32][C:33]2[CH2:60][CH2:59][CH2:58][CH2:57][C:34]=2[C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][C:47]2[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=2)=[CH:41][CH:40]=1)=[O:37]>CN(C=O)C.ClCCl.N1C=CC=CC=1>[CH3:54][O:53][C:51]([C:50]1[CH:49]=[CH:48][C:47]([CH2:46][CH2:45][C:42]2[CH:41]=[CH:40][C:39]([NH:38][C:36]([C:35]3[C:34]4[CH2:57][CH2:58][CH2:59][CH2:60][C:33]=4[S:32][C:31]=3[NH:30][C:18]([C:17]3[CH:16]=[C:15]([S:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=4)(=[O:14])=[O:13])[CH:23]=[CH:22][CH:21]=3)=[O:19])=[O:37])=[CH:44][CH:43]=2)=[CH:56][CH:55]=1)=[O:52]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)O)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Nc5ccc(C(=O)OC)cc5)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A mixture of 347 mg of 3-{[4-(methoxycarbonyl)phenyl]sulfamoyl}benzoic acid, 0.090 mL of oxalyl chloride, 3.0 mL of dichloromethane, and one drop of DMF was stirred at room temperature for 2 hours, and then the reaction mixture was concentrated under reduced pressure. A mixture of the obtained crude product and 3.0 mL of dichloromethane was added to a mixture of 0.071 mL of pyridine, 300 mg of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, and 2.5 mL of dichloromethane, followed by stirring at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 505 mg of methyl 4-({[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)phenyl]sulfonyl}amino)benzoate as a yellow foamed solid. ESI+: 752
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([OH:22])[CH2:20][CH2:19][O:18][CH:17]([CH3:21])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]I>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([O:22][CH3:23])[CH2:20][CH2:19][O:18][CH:17]([CH3:21])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC1CC(O)(c2cccc(OCc3ccccc3)c2)CCO1
Product: COC1(c2cccc(OCc3ccccc3)c2)CCOC(C)C1
Yield: 66 %

Procedure:
Using the procedure described in Example 3, (2RS,4SR)-4-(3-benzyloxyphenyl)-4-hydroxy-2-methyltetrahydropyran (1.22 g; obtained as described within Note k. below Table IX in Example 44) was reacted with methyl iodide (0.5 ml), to give (2RS,4SR)-4-(3-benzyloxyphenyl)-4-methoxy-2-methyltetrahydropyran (0.84 g, 66%), as an oil.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.[F:47][C:48]1[CH:58]=[CH:57][C:51](/[C:52](=[N:55]/[H])/[NH:53]O)=[CH:50][CH:49]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[F:47][C:48]1[CH:58]=[CH:57][C:51]([C:52]2[N:55]=[C:20]([CH2:19][N:3]3[CH2:4][CH2:5][C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:2]3=[O:1])[O:21][N:53]=2)=[CH:50][CH:49]=1
Reactant: [H]/N=C(\NO)c1ccc(F)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3ccc(F)cc3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)-4-fluoro-N-hydroxybenzimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 8.02-7.96 (m, 2H), 7.45-7.27 (m, 10H), 7.18-7.11 (m, 2H), 4.88 (s, 2H), 3.57 (t, J=6.5, 2H), 2.88 (t, J=6.5, 2H); MS (DCI) m/z 414.1 (M+H)+.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[C:21]1([SH:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[C:21]1([S:27][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: Sc1ccccc1
Solvent: CO
Product: COC(=O)C(Sc1ccccc1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
Methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate (7.11 g) is reacted with 2.75 g of thiophenol in methanol, as in Example 16, to yield a yellow oil. After a brief distillation at 0.02 mm to remove volatile impurities, the residue is evaporatively distilled (173° C. @ 0.01 mm) to afford the product as a colorless oil which solidifies, mp 64°-68.5° C. A portion is recrystallized from hexane to give white plates, mp 71.5°-72.5° C.
Reaction SMILES: [CH3:1][N:2]1C2C(=CC=CC=2)C=C1CNC.[CH2:14]1[C:18]2=[C:19]([CH:26]=O)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:17]2[CH2:16][CH2:15]1.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[CH3:1][NH:2][CH2:26][C:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[N:17]2[CH2:16][CH2:15][CH2:14][C:18]=12
Reactant: CNCc1cc2ccccc2n1C
Reactant: O=Cc1c2n(c3ccccc13)CCC2
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1c2n(c3ccccc13)CCC2
Yield: 54 %

Procedure:
According to the procedure of Preparation 40 (c), except substituting 2,3-dihydro-1H-3a-azacyclopenta[α]indene-8-carboxaldehyde (0.17 g, 0.92 mmole) for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (0.1 g, 54%) was prepared as a yellow oil: MS (ES) m/e 201 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:21].C(=O)([O-])[O-].[K+].[K+]>N1CCCCC1>[N:5]1([CH2:2][CH2:3][CH2:4][N:5]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:21])[CH2:14][CH2:13][CH2:12][CH2:7][CH2:6]1
Reactant: O=c1c2ccccc2c(-c2ccccc2)cn1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCNCC1
Product: O=c1c2ccccc2c(-c2ccccc2)cn1CCCN1CCCCC1
Yield: 180 %

Procedure:
Then, 14.9 g of 2-(3-chloropropyl)-4-phenyl-1(2H)-isoquinolone, 7 g of anhydrous potassium carbonate and 40 ml of piperidine were mixed and heated at reflux for 5 hours. Thereafter, any excess of piperidine was distilled off and the residue was dissolved in dichloromethane. The solution was washed with water, dried and the solvent was distilled off. The resulting crystals were recrystallized from a mixture of diethyl ether and petroleum ether to obtain 15.6 g of 2-(3-piperidinopropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 117.5° C. as colorless prisms.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][O:7][CH2:8][C:9]([CH3:17])([CH3:16])[CH:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][O:7][CH2:8][C:9]([CH3:17])([CH3:16])[C:10](=[O:15])[C:11]([CH3:13])([CH3:14])[CH3:12]
Reactant: COc1cccc(COCC(C)(C)C(O)C(C)(C)C)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1cccc(COCC(C)(C)C(=O)C(C)(C)C)c1
Yield: 94 %

Procedure:
In nitrogen atmosphere at a room temperature, 9.9 g of Celite and 4.61 g (16.5 mmol) of 1-(3-methoxybenzyloxy)-2,2,4,4-tetramethyl-3-pentanol (Compound [48]) were added to 75 ml of dichloromethane and the mixture was stirred. After adding 4.26 g (19.7 mmol) of PCC and stirring for 7 hours, 800 mg (3.71 mmol) of PCC was added and then the reaction mixture was stirred over night. Adding ether to the reaction mixture, the resulting mixture was filtrated by Celite and the filtrate was concentrated. The concentrate was applied to a silica gel column and the elution was carried out with the mixture of hexane and ethyl acetate (hexane:ethyl acetate=10:1) to obtain 4.32 g of 1-(3-methoxybenzyloxy)-2,2,4,4-tetramethyl-3-pentanon (Compound [49]) as a colorless compound. Yield 94.4%.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][CH:12]([C:14]3([CH2:17][CH3:18])[CH2:16][CH2:15]3)O)=[CH:4][C:3]=2[O:2]1.P(Br)(Br)[Br:20].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[CH2:17]([C:14](=[CH:12][CH:11]=[CH:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH2:15][CH2:16][Br:20])[CH3:18]
Reactant: BrP(Br)Br
Reactant: CCC1(C(O)C=Cc2ccc3c(c2)OCO3)CC1
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: CCC(=CC=Cc1ccc2c(c1)OCO2)CCBr

Procedure:
3-Ethyl-6-(3,4-methylenedioxyphenyl)-3,5-hexadienyl bromide [VIII; Ar is 3,4-methylenedioxyphenyl, R is C2H5 ] was prepared from 3.6 g. of 2-(3,4-methylenedioxyphenyl)vinyl 1-ethylcyclopropyl carbinol (Preparation B9), 3.5 g. of phosphorus tribromide, 4.5 g. of lithium bromide and 3.5 g. of zinc bromide according to the procedure given above in Preparation C1, affording 2 g. of product as an oil.
Reaction SMILES: [OH:1][C@H:2]([C@@H:13]([NH:18]C(=O)OC(C)(C)C)[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][NH:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:6].O[C@@H]([C@@H](NC(=O)OC(C)(C)C)CCCC)CNC(N1CCOCC1)=O.Cl.C(N(CC)C(C)C)(C)C.[C:61](=[O:94])(OC1C=CC([N+]([O-])=O)=CC=1)[O:62][C@H:63]([CH2:68][N:69]1[CH:73]=[CH:72][C:71]([C:74]2[CH:79]=[CH:78][C:77]([C:80]([F:83])([F:82])[F:81])=[CH:76][CH:75]=2)=[N:70]1)[C:64]([CH3:67])([CH3:66])[CH3:65]>O1CCOCC1.CN(C)C=O.C(OCC)(=O)C>[OH:1][C@H:2]([C@@H:13]([NH:18][C:61](=[O:94])[O:62][C@H:63]([CH2:68][N:69]1[CH:73]=[CH:72][C:71]([C:74]2[CH:79]=[CH:78][C:77]([C:80]([F:81])([F:83])[F:82])=[CH:76][CH:75]=2)=[N:70]1)[C:64]([CH3:66])([CH3:65])[CH3:67])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][NH:4][C:5]([N:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)=[O:6]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CNC(=O)N1CCOCC1
Reactant: CC(C)(C)[C@@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CCCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)CNC(=O)N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@@H](O)CNC(=O)N1CCOCC1
Reaction time: 2 h
Yield: 55.8 %

Procedure:
To a solution of 130 mg (0.36 mmol) of tert-butyl (1S)-1-{(1S)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate & tert-butyl (1S)-1-{(1R)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate in 1 mL of dioxane was added 5 mL of 4M hydrochloric acid in dioxane. The reaction mixture was stirred for 2 h and concentrated under reduced pressure. Half of the product was carried forward. This material was slurried in N,N-dimethylformamide before 0.094 mL (0.54 mmol) of N,N-diisopropylethylamine was added, followed by 86 mg (0.18 mmol) of (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl 4-nitrophenyl carbonate. The reaction mixture was stirred at room temperature for 18 h, and then diluted with ethyl acetate before being washed with 1M sodium hydroxide and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate to afford 60 mg (55%) of (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1S)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate & (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1R)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate. 1H-NMR (300 MHz, DMSO-d6): δ 7.99 (m, 2H), 7.74 (d, J=8 Hz, 2H), 6.77 (s, 1H), 6.58 (d, J=9 Hz, 1H), 6.33 (m, 1H), 4.95–4.75 (m, 2H), 4.48 (d, J=13 Hz, 1H), 4.19 (t, J=12 Hz, 1H), 3.45–3.10 (m, 13H), 1.25 (m, 1H), 0.99 (m, 14H), 0.67 (m, 3H); ES-LCMS m/z 620 (M+Na).
Reaction SMILES: [CH:1]1([CH2:4][C:5](=[O:20])[CH2:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:8]=2)[CH2:3][CH2:2]1.[CH3:21][N:22]([CH:24](OC)OC)[CH3:23]>>[CH:1]1([CH2:4][C:5](=[O:20])/[C:6](/[C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:21]\[N:22]([CH3:24])[CH3:23])[CH2:2][CH2:3]1
Reactant: O=C(Cc1ccnc(Nc2ccncc2)n1)CC1CC1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 98.7 %

Procedure:
1-Cyclopropyl-3-[2-(pyridin-4-ylamino)pyrimidin-4-yl]propan-2-one (8) (269 mg, 1.003 mmol) was taken up in DMF-DMA (5.369 mL, 40.1 mmol) and stirred at 80° C. for 30 minutes. The solvent was evaporated and the residue partitioned between DCM and water. The organic layer was washed with saturated sodium bicarbonate and brine, dried with sodium sulfate, and concentrated in vacuo. The crude residue was purified by Biotage™ silica gel chromatography [1-13% MeOH in DCM with 1% triethylamine] to afford the desired product as an orange/brown foam (320 mg, 99% yield). MS (ES+): m/z=324.3 (100) [MH+2]. HPLC: tR=0.88 minute over 3 minutes. Purity: >90% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [NH2:1][C:2]([C:4]1[NH:8][CH:7]=[N:6][C:5]=1[NH:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[F:20])[N:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:12]=1)=[O:3].C(N=[C:37]=[S:38])(=O)C1C=CC=CC=1>C(Cl)Cl>[F:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:11]([CH2:10][N:9]1[C:5]3[N:6]=[CH:7][NH:8][C:4]=3[C:2](=[O:3])[NH:1][C:37]1=[S:38])=[CH:12][N:13]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)n1cc(CNc2nc[nH]c2C(N)=O)c2c(F)cccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cc(Cn2c(=S)[nH]c(=O)c3[nH]cnc32)c2c(F)cccc21
Temperature: 80 °C
Yield: 47.6 %

Procedure:
A solution of tert-butyl 3-({[5-(aminocarbonyl)-1H-imidazol-4-yl]amino}methyl)-4-fluoro-1H-indole-1-carboxylate (0.17 g, 0.45 mmol, obtained from Example 11(b)) and benzoyl isothiocyanate (0.073 mL, 0.54 mmol) in CH2Cl2 (5 mL) was stirred for 3 h 20 minutes and then evaporated. Ammonia (7 M in MeOH, 4 mL) was added to the residue and the mixture was heated to 80° C. for 2 h and then evaporated. Purification by flash chromatography using MeOH (2%) in CHCl3 gave the title compound (0.089 g, 48%).
Reaction SMILES: N1C2C(=CC=CC=2)[C:3]2([O:20][C:12]3[CH:13]=CC4OCOC=4[C:11]=3[CH2:10]2)C1=O.Br[C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[C:25]1([C:36]3=[CH:37][C:38]4[O:42][CH2:41][O:40][C:39]=4[CH:43]=[C:35]3[O:34][CH2:33]1)[C:26](=[O:32])[NH:27]2.ClCC1OC=CC=1.BrCC1OC(C(F)(F)F)=CC=1>>[O:20]1[CH:3]=[CH:10][CH:11]=[C:12]1[CH2:13][N:27]1[C:28]2[C:24](=[CH:23][CH:31]=[CH:30][CH:29]=2)[C:25]2([C:36]3=[CH:37][C:38]4[O:42][CH2:41][O:40][C:39]=4[CH:43]=[C:35]3[O:34][CH2:33]2)[C:26]1=[O:32]
Reactant: O=C1Nc2ccccc2C12Cc1c(ccc3c1OCO3)O2
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCO3
Agent: ClCc1ccco1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccco2)c2ccccc2C12COc1cc3c(cc12)OCO3
Yield: 40 %

Procedure:
Following the procedure described in EXAMPLE 10.47, and making non-critical variations using spiro[furo[2,3-][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and 2-chloromethylfuran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, the title compound (40%) as a colorless solid: mp 110-112° C.; 1H NMR (300 MHz, CDCl3) δ 7.35-7.33 (m, 1H), 7.29-7.23 (m, 1H), 7.15 (d, 1H), 7.06-7.00 (m, 2H), 6.50 (s, 1H), 6.34-6.31 (m, 2H), 6.10 (s, 1H), 5.85 (dd, 2H), 4.92 (ABq, 2H), 4.79 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ 177.1, 155.9, 149.0, 148.9, 142.6, 142.3, 141.8, 132.2, 128.9, 123.8, 123.5, 119.5, 110.6, 109.3, 108.7, 103.1, 101.5, 93.6, 80.4, 58.2, 37.1; MS (ES+) m/z 362.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)[CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH:23](Cl)[CH3:24]>NC1C2C(=CC=CC=2)CC1.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=3)[O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:7][CH:6]3[C:23]4[C:24](=[CH:3][CH:2]=[CH:21][CH:20]=4)[CH2:4][CH2:5]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3cccc(OC[C@H]4CO4)c3)noc2c1
Reactant: CC(Cl)Cl
Agent: NC1CCc2ccccc21
Solvent: CCO
Product: O[C@H](CNC1CCc2ccccc21)COc1cccc(-c2noc3cc(F)ccc23)c1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(3-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dichloroethane, 1-aminoindan and ethanol, essentially as described above in Example 57. Purity by LC/MS=91%, [M+H]+=419.
Reaction SMILES: B(F)(F)F.CCOCC.[F:10][C:11]([F:30])([F:29])[C:12]1[CH:28]=[CH:27][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][C:22]2([CH3:26])[CH2:25][O:24][CH2:23]2)=[O:19])=[CH:14][CH:13]=1>ClCCl>[CH3:23][C:22]12[CH2:25][O:24][C:18]([CH2:17][O:16][C:15]3[CH:27]=[CH:28][C:12]([C:11]([F:30])([F:29])[F:10])=[CH:13][CH:14]=3)([O:19][CH2:26]1)[O:20][CH2:21]2
Reactant: CC1(COC(=O)COc2ccc(C(F)(F)F)cc2)COC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC12COC(COc3ccc(C(F)(F)F)cc3)(OC1)OC2
Reaction time: 3 h

Procedure:
Boron trifluoride diethyl etherate (1.48 ml) was added to a solution of the product from step (ii) (14.2 g) in dichloromethane at −78° C. The cooling bath was removed, the mixture, stirred for 3 h then triethylamine (6.2 ml) added. The mixture was reduced to half the volume under reduced pressure then filtered. The filtrate was evaporated under reduced pressure then the residue purified by chromatography on silica (pre-eluted with one column volume of neat triethylamine) eluting with dichloromethane, yield 11.1 g.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2F)=[CH:10][CH:9]=1)[OH:7]>C1C=CC=CC=1.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][S:4][CH2:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[OH:7]
Reactant: OCCSCC(O)c1ccc(-c2ccccc2F)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: OCCSCC(O)c1ccc(-c2ccccc2)cc1

Procedure:
2-Hydroxyethyl-[2-(2'-fluoro-4-biphenylyl)-2-hydroxyethyl]-sulfide, an oil, Rf -value: 0.3 on silicagel-polygram-plates with benzene/ethyl acetate = 1:1 as the eluant, was prepared in analogous manner.