Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].O[CH:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(Cl)Cl>[OH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]=1[CH:13]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCCCCC(O)c1ccccc1
Reactant: Oc1ccc2ccccc2c1
Solvent: ClCCl
Product: CCOC(=O)CCCCCC(c1ccccc1)c1c(O)ccc2ccccc12
Reaction time: 5 h

Procedure:
2-Naphthol (1.152 g) and ethyl 7-hydroxy-7-phenyl-heptanoate (2g) were dissolved in methylene chloride (20 ml) followed by dropwise addition of boron trifluoride-ether complex (0.56 g). After 5 hours of stirring, the reaction mixture was extracted with chloroform and the extract was washed with water, dried, and concentrated. The residue was applied to a silica gel column (hexane-ethyl acetate) to provide the title compound (1.94 g).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([CH2:17][CH2:16][CH2:15][C:9]3[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:28][CH2:27]2)=[CH:24][CH:25]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(Cl)cc3)CC2)nn1-c1ccccc1

Procedure:
69 mg (45%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg, 0.330 mmol), 1-(4-chlorophenyl)piperazine (89 mg, 0.330 mmol), DIPEA (0.090 mL, 0.495 mmol) and NaBH(OAc)3 (210 mg, 0.990 mmol).
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[C:13]([OH:22])(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16]>>[C:3]1([CH2:2][S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[C:13]([OH:22])=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: ClCc1nccc2ccccc12
Reactant: O=C(O)c1ccccc1S
Product: O=C(O)c1ccccc1SCc1nccc2ccccc12

Procedure:
Following the procedure described in Example 16 but starting from 1.8 g. of 1-chloromethyl-isoquinoline and 1.54 g. of thiosalicylic acid, 1.1 g. of S-(1-isoquinolyl-methyl)-2-mercapto-benzoic acid are obtained, melting at 170° to 172° C.
Reaction SMILES: [ClH:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25](I)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:30]1[CH2:34][CH2:33][O:32][CH:31]1[C:35]1[O:39][C:38]([Sn](CCCC)(CCCC)CCCC)=[CH:37][CH:36]=1>CCOC(C)=O>[ClH:1].[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([C:38]5[O:39][C:35]([CH:31]6[O:32][CH2:33][CH2:34][O:30]6)=[CH:36][CH:37]=5)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Ic1ccc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5cc(-c6ccc(C7OCCO7)o6)ccc45)ccc32)cc1

Procedure:
Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl(7-iodoquinazolin-4-yl)-amine hydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tri-n-butylstannyl)furan; tic Rf, 0.25 (100% EtOAc on silica); m/z (M+1+) 490.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH2:6][CH2:5][C:4]1=[O:60])[CH3:2].[CH:61](OC)=[O:62]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:58])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][CH:61]=[O:62])[CH:46]([O:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[CH2:45]2)[CH:7]([CH3:59])[CH2:6][CH2:5][C:4]1=[O:60])[CH3:2]
Reactant: COC=O
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC=O)C(Oc4ccccc4)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 17-ethyl-1-hydroxy-12-[2'-(4"-amino-3"-phenoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (30 mg) is mixed with methyl formate (0.5 ml) and is stirred at 0° C. for 1 hr. The reaction mixture is allowed to warm to room temperature and then is stirred overnight. The excess methylformate is removed with nitrogen flow and the crude mixture is purified by preparative tlc on silica gel to give the title compound.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[Br:23]Br>C(Cl)Cl.ClC1C=CC=CC=1>[Br:23][C:18]1[CH:17]=[C:16]([CH:13]2[CH2:14][CH2:15][CH:10]([CH:7]3[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:8]3)[CH2:11][CH2:12]2)[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: CCCC1CCC(C2CCC(c3ccc(O)cc3)CC2)CC1
Reactant: BrBr
Solvent: ClCCl
Solvent: Clc1ccccc1
Product: CCCC1CCC(C2CCC(c3ccc(O)c(Br)c3)CC2)CC1
Temperature: 0 °C
Yield: 39.6 %

Procedure:
4-(4-(4-Propylcyclohexyl)cyclohexyl)phenol (0.5 g) was dissolved in a mixed solvent of methylene chloride (5 ml) and chlorobenzene (1 ml), to which was then added dropwise a solution of bromine (0.28 g) in methylene chloride (2 ml) under ice cooling while stirring. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 30 minutes, added in ice water, and then extracted with methylene chloride. An organic layer was washed with water, rinsed with a sodium thiosulfate aqueous solution, and then dried over anhydrous magnesium sulfate. The methylene chloride solution was concentrated in vacuo and then subjected to isolation and purification by silica gel column chromatography, thereby obtaining a white crystal (0.25 g) of 2-bromo-4-(4-(4-propylcyclohexyl)cyclohexyl)phenol.
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])C.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>>[OH:28][CH2:27][C:26]([NH:25][C:4]([C:6]1[S:10][C:9]([O:11][CH2:12][C:13]2[C:14]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:8][CH:7]=1)=[O:5])([CH3:30])[CH3:29]
Reactant: CCOC(=O)c1cnc(OCc2c(-c3ccccc3)noc2C)s1
Reactant: CC(C)(N)CO
Product: Cc1onc(-c2ccccc2)c1COc1ncc(C(=O)NC(C)(C)CO)s1
Yield: 23 %

Procedure:
As described for example 127, 2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-thiazole-5-carboxylic acid ethyl ester (95 mg, 0.28 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (25 mg, 23%) which was obtained as a colourless gum after purification by chromatography (silica, 0 to 3% methanol in dichloromethane). MS: m/e=388.3 [M+H]+.
Reaction SMILES: C(Cl)Cl.[NH2:4][C:5]1[C:10]2=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=4[F:40])=[O:28])=[C:22]([F:41])[CH:21]=3)[CH:12]=[C:13]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:9]2[N:8]=[CH:7][N:6]=1.[CH3:42][N:43]=[C:44]=[O:45]>C1COCC1>[NH2:4][C:5]1[C:10]2=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:28])[NH:29][C:30]4[CH:35]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:33]=[CH:32][C:31]=4[F:40])=[C:22]([F:41])[CH:21]=3)[CH:12]=[C:13]([CH:14]3[CH2:19][CH2:18][N:17]([C:44]([NH:43][CH3:42])=[O:45])[CH2:16][CH2:15]3)[N:9]2[N:8]=[CH:7][N:6]=1
Reactant: CN=C=O
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c12
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)N1CCC(c2cc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)c(F)c3)c3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.3 %

Procedure:
To a flask containing 3 ml of methylene chloride was added 1-[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-2-fluorophenyl]-3-[2-fluoro-5-(trifluoromethyl)phenyl]urea (Example 111) (75 mg, 0.141 mmol, 1.0 eq). To this suspension was added THF dropwise until complete dissolution occurs. To this solution was added methyl isocyanate (8.8 μl, 0.148 mmol, 1.05 eq.) and reaction allowed to stir at room temperature for 17 h. Reaction solution was concentrated to dryness and residue dissolved in EtOAc. Wash 2× with saturated sodium bicarbonate, 1× brine, layers separated, organics dried (Na2SO4), filtered, condensed and purified via flash chromatography (1:1 THF:hexanes). The purified fractions collected and concentrated to dryness. Residue was stirred in hexanes and filtered to obtain title compound (50 mg, 60.2% yield). 1H-NMR (DMSO-d6) δ 9.41 (d, J=2.8 Hz, 1H), 9.25 (d, J=2.3 Hz, 1H), 8.65 (dd, J=7.5, 2.4 Hz, 1H), 8.25 (t, J=8.6 Hz, 1H), 7.90 (s, 1H), 7.51 (m, 1H), 7.41 (m, 1H), 7.32 (dd, J=12.4, 2.0 Hz, 1H), 7.23 (dd, J=8.5, 1.4 Hz, 1H), 6.57 (s, 1H) 6.44 (q, J=4.3 Hz, 1H), 4.05 (d, J=13.3 Hz, 2H), 3.28 (m, 1H), 2.80 (t, J=12.2 Hz, 2H), 2.56 (d, J=4.5 Hz, 3H), 1.95 (d, J=11.3 Hz, 2H), 1.52 (m, 2H); MS [M+H]+=589; LCMS RT=3.11 min.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+]>C1COCC1>[CH:5]([C:1]1[CH:5]=[CH:4][CH2:3][CH:2]=1)=[CH:1][CH2:2][CH3:3]
Reactant: c1cc[cH-]c1
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC=CC1=CCC=C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
To a solution of 25.0 g (110 mmol) 3-buten-1-tosylate prepared according to step (a) above in 200 ml THF cooled to 0° C. was added 68.9 ml of 2.0M (138 mmol) sodium cyclopentadienylide in THF. The reaction mixture was allowed to warm to room temperature and was stirred for 16 h. 100 ml concentrated aqueous saline solution was added and the product extracted with ether (3×75 ml). The combined organic fractions were dried over magnesium sulphate for 2 hours, filtered and the solvents removed under reduced pressure using a rotary evaporator to yield a dark brown oil. The crude product was distilled under reduced pressure (b.p. 50°-51° C. @15 mm Hg) to give 5.71 g of a colourless oil (47.6 mmol, 43.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[NH:15][NH:16]C(OC(C)(C)C)=O.[Cl:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([N:31]=[C:32]=[O:33])=O)=[C:27]([F:36])[CH:26]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([CH:12]2[CH2:14][CH2:13]2)=[O:11])=[CH:4][C:3]=1[N:15]1[C:32](=[O:33])[NH:31][C:29]([C:28]2[CH:34]=[CH:35][C:25]([Cl:24])=[CH:26][C:27]=2[F:36])=[N:16]1
Reactant: O=C=NC(=O)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C2CC2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(-n2nc(-c3ccc(Cl)cc3F)[nH]c2=O)c1)C1CC1
Yield: 55.9 %

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(2-chloro-5-(cyclopropanecarboxamidomethyl)phenyl)hydrazinecarboxylate (step-7 of Intermediate-48, 0.060 g, 0.17 mmol), 4-chloro-2-fluorobenzoyl isocyanate (Intermediate-58, 0.035 g, 0.71 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.040 g of desired product. 1H NMR (400 MHz, DMSO d6): δ 0.67-0.69 (m, 4H), 1.59-1.60 (m, 1H), 4.31 (d, J=5.9 Hz, 2H), 7.36 (dd, J=6.24 Hz, 1H), 7.45 (dd, J=8.5 Hz, 2H), 7.59 (d, J=8.3 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.83 (t, J=8.3 Hz, 1H), 7.64 (t, J=6 Hz, 1H), 12.51 (br s, 1H); MS (m/z): 421.08 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[C:6]([C:8]2[O:9]CC(C)(C)N=2)[CH:7]=1.Cl.[O:23]1CCOCC1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:4][CH:3]=1)[C:8]([OH:9])=[O:23]
Reactant: C1COCCO1
Reactant: Cc1ccccc1-c1ccc(Cl)cc1C1=NC(C)(C)CO1
Agent: Cl
Product: Cc1ccccc1-c1ccc(Cl)cc1C(=O)O

Procedure:
The starting material is prepared as follows: The mixture of 17 g of 2-(5-chloro-2-o-tolylphenyl)-4,4-dimethyl-2-oxazoline (prepared as shown in Example 2), 150 ml of p-dioxane, and 160 ml of 5 N aqueous hydrochloric acid is refluxed for 3 days while stirring. It is evaporated, the residue taken up in diethyl ether, the organic phase separated, dried, evaporated and the residue crystallized from hexane to yield the 3-chloro-6-o-tolylbenzoic acid melting at 135°-137°.
Reaction SMILES: O[CH:2]1[NH:8][C:7](=O)[C:6]2[S:10][CH:11]=[CH:12][C:5]=2[N:4]2[CH:13]=[CH:14][CH:15]=[C:3]12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>ClCCl.C(OCC)C>[CH:12]1[C:5]2[N:4]3[CH:13]=[CH:14][CH:15]=[C:3]3[CH2:2][NH:8][CH2:7][C:6]=2[S:10][CH:11]=1
Reactant: O=C1NC(O)c2cccn2-c2ccsc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Product: c1cc2n(c1)-c1ccsc1CNC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
A solution of 5.3 g (0.024 mol) of 6-hydroxy-5,6-dihydro-4-oxo-4H-pyrrolo[1,2-a]thieno[2,3-f][1,4]diazepine in 400 ml of dichloromethane is added in small portions to a suspension of 3.66 g (0.096 mol) of lithium aluminum hydride in 20 ml of ethyl ether. The reaction mixture is stirred at room temperature for 30 minutes and then heated to reflux for 6 hours. After cooling, the solution obtained is poured onto 250 g of ice. The emulsion formed is drained and the organic phase is then separated after settling has taken place. The aqueous phase is extracted with 200 ml of dichloromethane. The organic phases are combined, dried over calcium chloride, purified with animal charcoal and evaporated under vacuum. The residual oil is dissolved in 300 ml of ethyl ether and a stream of gaseous HCl is bubbled into this ethereal solution for 15 seconds. The precipitate is drained, washed with ether and recrystallized. 3.2 g of 5,6-dihydro-4H-pyrrolo[1,2-a]thieno -[2,3-f][1,4]diazepine are thereby obtained in the form of beige crystals, melting point 260° C. (isopropanol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:7]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)[CH:8]1[O:10][CH2:9]1>>[C:12]1([O:11][CH2:7][CH:8]([OH:10])[CH2:9][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: C1CNCCN1
Reactant: c1ccc2c(OCC3CO3)cccc2c1
Product: OC(COc1cccc2ccccc12)CN1CCNCC1
Yield: 64.7 %

Procedure:
In the same manner as described in Example 1A, 9.1 g of piperazine is allowed to react with 10.8 g of α-naphthyl glycidyl ether to yield 10.0 g of N-[3-(naphth-1-yloxy)-2-hydroxypropyl]-piperazine. Five grams of this compound and 2.3 g of triethylamine are dissolved in 20 ml of benzene and, with stirring and at room temperature, 3.16 g of N,N-diethylcarbamyl chloride are added dropwise over a period of 30 minutes. When the addition is complete, the mixture is heated at reflux for 2 hours and, after cooling, washed with water and dried. The solvent is removed by distillation, the residue dissolved in ethanol and hydrogen chloride bubbled through the solution. The title compound is thus obtained as the hydrochloride which is recrystallized from isopropyl alcohol. Yield: 2.44 g; m.p. 152°-156° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13](O)[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:11]#[N:12].O=P(Cl)(Cl)[Cl:26]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[C:13]([Cl:26])[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:11]#[N:12]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#CC(=C(O)c1ccc([N+](=O)[O-])cc1)c1nc2ccccc2s1
Product: N#CC(=C(Cl)c1ccc([N+](=O)[O-])cc1)c1nc2ccccc2s1
Temperature: 100 °C
Yield: 95 %

Procedure:
The above prepared 2-benzothiazol-2-yl-3-hydroxy-3-(4-nitrophenyl)-acrylonitrile (500 mg, 1.55 mmol) was suspended in POCl3 (12 mL). The suspension was heated at 100° C. for 4 hrs and was then poured into ice water (25 mL). The pH of the aqueous phase was adjusted to neutral. The solids were isolated by filtration and dried to yield 505 mg (95%) of 2-benzothiazol-2-yl-3-chloro-3-(4-nitrophenyl)-acrylonitrile. MS (m/z, ES+): 341.92 (Cl35M+1, 100%), 343.92 (Cl37M+1, 45%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[CH2:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]O)[CH:26]=1)[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=2)[CH:26]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: Cc1cccc(CC(C)C)c1-c1cccc(CO)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Product: Cc1cccc(CC(C)C)c1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Reference Example 230 from methyl 3-(4-hydroxyphenyl)propanoate and (2′-isobutyl-6′-methylbiphenyl-3-yl)methanol. colorless oil (yield 58%). MS (APCI−): 401 (M−H).
Reaction SMILES: [P:1]([Cl:5])(Cl)([Cl:3])=[O:2].[CH2:6]([OH:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl>>[P:1]([Cl:5])([Cl:3])(=[O:2])[O:14][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCO
Reactant: O=P(Cl)(Cl)Cl
Agent: Cl
Product: CCCCCCCCOP(=O)(Cl)Cl
Temperature: 10 °C
Reaction time: 1.5 h

Procedure:
Phosphoryl trichloride (3113 g; 20.3 moles) is placed in a 5-liter flask fitted with a condenser and mechanical stirrer, and cooled down to about 10° C. (external ice bath). Octanol (2380 g; 18.3 moles; 0.9 equivalents with respect to POCl3) is added at a rate such that the reaction temperature remains below 15° C. The reaction is exothermic and the HCl gas that evolves during this reaction is vented out with a flow of nitrogen through an aspirator operated with a slight vacuum of about 0.5 inches of mercury. When addition of alcohol is completed (2-3 hours), the ice bath is removed and the reaction mixture is allowed to warm to room temperature and then warmed to 60°-70° C. and stirred at this temperature for 1.5 hours to drive out most of the HCl gas. The product, octyl phosphorodichloridate, is obtained as a clear light yellow free-flowing liquid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([O:7][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[C@@:3]1([CH3:26])[OH:25].[Cl:27][C:28]1[C:35]([CH2:36][CH3:37])=[C:34](F)[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]>>[Cl:27][C:28]1[C:35]([CH2:36][CH3:37])=[C:34]([NH:1][C@@H:2]2[CH2:6][CH2:5][C@@H:4]([OH:7])[C@:3]2([OH:25])[CH3:26])[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@H](N)[C@]1(C)O)(c1ccccc1)c1ccccc1
Reactant: CCc1c(F)ccc(C#N)c1Cl
Product: CCc1c(N[C@@H]2CC[C@@H](O)[C@@]2(C)O)ccc(C#N)c1Cl

Procedure:
The title compound is prepared by essentially following the procedure described in Example 20, using rel-(1S,2R,5R)-2-amino-5-(tert-butyl(diphenyl)silyl)oxy-1-methyl-cyclopentanol and 2-chloro-3-ethyl-4-fluoro-benzonitrile for the substitution reaction followed by TBDPS removal with TBAF. 1H-NMR (400 MHz, DMSO-d6) δ 7.44 (d, J=8.7 Hz, 1H), 6.87 (d, J=9.0 Hz, 1H), 5.74-5.70 (m, 1H), 4.74 (d, J=5.4 Hz, 1H), 4.27 (s, 1H), 3.82-3.79 (m, 1H), 3.58-3.51 (m, 1H), 2.80-2.78 (m, 2H), 2.03-2.02 (m, 1H), 1.88-1.86 (m, 1H), 1.69-1.68 (m, 1H), 1.52-1.51 (m, 1H), 1.01-0.97 (m, 3H), 0.93 (s, 3H). LC-ES/MS m/z 295 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([N:9]2[CH:14]=[CH:13][C:12](=[O:15])[NH:11][C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1.[Si:19]([O:36][CH2:37][C@H:38](O)[CH3:39])([C:32]([CH3:35])([CH3:34])[CH3:33])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[Si:19]([O:36][CH2:37][C@H:38]([N:11]1[C:12](=[O:15])[CH:13]=[CH:14][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:4]=2)[C:10]1=[O:16])[CH3:39])([C:32]([CH3:33])([CH3:34])[CH3:35])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)c(=O)[nH]1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)n1c(=O)ccn(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a solution of 1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 98 or 99) (740.0 mg) in tetrahydrofuran (10.0 ml) was added (R)-1-(tert-butyldiphenylsilyloxy)propane-2-ol (1.82 g), triphenylphosphine (1.5 g) and diethyl azodicarboxylate (2.7 ml:2.2 M toluene solution) and the resulting mixture was stirred at room temperature for twelve hours. To the reaction mixture was added water (50 ml), and the resulting mixture was extracted with ethyl acetate (30 ml×2) and the organic layer was washed with water (20 ml) and saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford (R)-3-[1-(tert-butyldiphenylsilyloxy)propane-2-yl]-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (969.8 mg).