Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=O)=[CH:11][CH:10]=1)#[N:2].P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:17]1[N:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]#[N:2])=[CH:10][CH:11]=2)[C:20]2[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1
Reactant: COC(=O)c1cccc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2nc(Cl)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Yield: 28 %

Procedure:
A mixture of methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-oxo-2,3-dihydrobenzimidazole-7-carboxylate (8.02 g) in phosphorus oxychloride (30 ml) was heated under reflux for 8 hours. The reaction mixture was concentrated and the resulting residue was poured into ice-water. The mixture was extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was purified by column chromatography on silica gel to give crystals, which were recrystallized from chloroform--methanol to afford colorless needles (2.2 g, 28%), m.p. 154-157° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.[H-].[Na+].[CH3:17]I.O>O1CCCC1>[CH3:17][O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1
Reactant: OCCCSc1cccc2nccn12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCSc1cccc2nccn12
Yield: 35.9 %

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (803 mg, 3.86 mmoles) in tetrahydrofuran (30 ml) was added 60% sodium hydride in oil (0.19 g, 4.6 mmoles) with stirring under ice-cooling and the mixture was further stirred under ice-cooling for 30 minutes. To the reaction mixture was added methyl iodide (0.36 ml, 5.8 mmoles), followed by stirring at room temperature overnight. The reaction mixture was poured into water, which was extracted with methylene chloride (30 ml×3). The methylene chloride layers were combined and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 308 mg of the desired product (35.9%, light brown oily product).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[CH3:7][N:8]([CH3:13])[S:9](Cl)(=[O:11])=[O:10].C(N(CC)CC)C>C(Cl)Cl>[CH3:7][N:8]([CH3:13])[S:9]([N:4]1[CH:3]=[C:2]([CH3:1])[CH:6]=[N:5]1)(=[O:11])=[O:10]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1cn[nH]c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnn(S(=O)(=O)N(C)C)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Into a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-methyl-1H-pyrazole (10.4 g, 127.2 mmol) in CH2Cl2 (200 mL). N,N-dimethylsulfamoyl chloride (17.14 mL, 167.1 mmol) and triethylamine (35 mL, 251.1 mmol) were added to the reaction. The reaction mixture was stirred for 30 min at 0° C. in a water/ice bath and then stirred overnight at room temperature. The reaction was quenched with NaHCO3 (sat.) (40 mL) and the aqueous phase was extracted with 3×200 mL of EtOAc. The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/hexanes (1:6) as the eluent to afford the title compound (22.2 g, 92%) as a light yellow oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32].F[C:34](C1C(F)=C(F)C(F)=C(F)C=1F)([S:38]([C:41](F)(F)F)(=[O:40])=[O:39])[C:35]([O-])=[O:36]>C(Cl)Cl>[F:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:17]3[CH2:21][CH:20]([CH:22]4[CH2:23][CH2:24][N:25]([C:35](=[O:36])[CH2:34][S:38]([CH3:41])(=[O:40])=[O:39])[CH2:26][CH2:27]4)[O:19][N:18]=3)[N:14]=[C:13]([CH3:28])[N:12]=2)=[O:10])=[CH:5][C:4]=1[O:31][CH3:32]
Reactant: O=C([O-])C(F)(c1c(F)c(F)c(F)c(F)c1F)S(=O)(=O)C(F)(F)F
Reactant: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCNCC4)C3)nc(C)n2)ccc1F
Agent: Cl
Solvent: ClCCl
Product: COc1cc(CNC(=O)c2cc(C3=NOC(C4CCN(C(=O)CS(C)(=O)=O)CC4)C3)nc(C)n2)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.6 %

Procedure:
To a stirred solution of N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide hydrochloride (0.20 g, 0.43 mmol Preparation #K. 1) in DCM (10 mL) was added TEA (0.13 g, 1.29 mmol, Spectrochem) and perfluorophenyl-2-(methylsulfonyl)acetate (0.196 g, 0.645 mmol, See Ref: US 20090312338). The resulting solution was stirred at RT for about 16 h. The crude reaction mixture was purified by preparative HPLC (Table 2, Method f) to afford N-(4-fluoro-3-methoxybenzyl)-2-methyl-6-(5-(1-(2-(methylsulfonyl)acetyl)piperidin-4-yl)-4,5-dihydroisoxazol-3-yl)pyrimidine-4-carboxamide 0.072 g (31.3%); LC/MS (Table 1, Method d) Rt=0.55 min; MS m/z: 548.3 (M+H)+.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][C@H:3]([C:7]([O:9]C)=O)[CH2:2]1.Cl.[O:19]([C:21]#[N:22])[K]>O1CCOCC1.O>[O:9]=[C:7]1[C@@H:3]2[CH2:2][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][N:4]2[C:21](=[O:19])[NH:22]1
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Reactant: N#CO[K]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN2C(=O)NC(=O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 1-tert-butyl 3-methyl (3S)-piperazine-1,3-dicarboxylate (AA3) (1.0 eq.) and 6 N aq. HCl sol. (1.0 eq.) in 1,4-dioxane (1 M) was added a sol. of KOCN (2.0 eq.) in H2O (2 M). The reaction mixture was stirred at RT for 2 h, then the organic solvent was removed under reduced pressure. The desired product precipitated from H2O: it was filtered off, washed with cold water and dried at the high vacuum pump. Mother liquors were extracted with EtOAc, the organic phase was washed with brine, dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified by flash chromatography on silica gel eluting with 10-100% EtOAc/petroleum ether to afford the desired product (H1) as a white powder which was combined with the previously isolated precipitate. 1H-NMR (300 MHz, DMSO-d6, 300K) δ 10.95 (1H, bs), 4.15-4.00 (2H, m), 3.97-3.75 (2H, m), 2.97-2.67 (3H, m), 1.42 (9H, s). MS (ES) C11H17N3O4 requires: 255, found: 256 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2([CH2:10][CH2:9][NH:8][CH2:7]2)[O:5][CH2:4][CH2:3][CH2:2]1.C([O:13][C:14]([C:16]1[CH2:17][N:18]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=2[F:35])[C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([F:26])=[C:21](Cl)[N:20]=2)=[O:15])C>>[F:35][C:29]1[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=1[N:18]1[C:19]2[C:24](=[CH:23][C:22]([F:26])=[C:21]([N:8]3[CH2:9][CH2:10][C:6]4([O:5][CH2:4][CH2:3][CH2:2][O:1]4)[CH2:7]3)[N:20]=2)[CH:25]=[C:16]([C:14]([OH:15])=[O:13])[CH2:17]1
Reactant: CCOC(=O)C1=Cc2cc(F)c(Cl)nc2N(c2ccc(F)cc2F)C1
Reactant: C1COC2(CCNC2)OC1
Product: O=C(O)C1=Cc2cc(F)c(N3CCC4(C3)OCCCO4)nc2N(c2ccc(F)cc2F)C1
Temperature: 45 °C

Procedure:
Following the procedure of Step 2 Example 331 a 0.168 g (1.17 mmol) of 1,5-dioxa-8-azaspiro[5.4]decane, from Step 2 Example 14, was reacted with 0.300 g (0.78 mmol) of 1-(2,4-difluorophenyl)-7-chloro-6-fluoro-1,8-naphthyridine-3-carboxylic acid ethyl ester by heating at 40° C. instead of 45° C. for 10 instead of 24 hours. The solvent was removed by evaporation to afford the title product which was purified by column chromatography over silica gel (0% increasing to 4% methanol/methylene chloride) to afford 0.252 g of the title compound. The ester was not further purified, but was taken directly to the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>>[N:11]12[CH2:17][CH:15]3[CH2:14][CH:13]([CH2:18][CH:9]([N:8]([C:4]4[CH:3]=[C:2]([C:24]5[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=5)[CH:7]=[N:6][CH:5]=4)[CH2:16]3)[CH2:10]1)[CH2:12]2
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1

Procedure:
The title compound was prepared from the product of Example 65A and 4-cyanophenylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 331.0 (M+H)+, retention time 1.26 minutes.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[I:34][C:35]1[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[NH:37][N:36]=1.O[C@H:51]1[CH2:55][O:54][CH2:53][C@@H:52]1[NH:56][C:57](=[O:63])[O:58][C:59]([CH3:62])([CH3:61])[CH3:60]>C1COCC1>[C:59]([O:58][C:57]([NH:56][C@@H:52]1[CH2:53][O:54][CH2:55][C@@H:51]1[N:37]1[C:38]([C:45]([O:47][CH2:48][CH3:49])=[O:46])=[C:39]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:35]([I:34])=[N:36]1)=[O:63])([CH3:62])([CH3:60])[CH3:61]
Reactant: CC(C)(C)OC(=O)N[C@H]1COC[C@@H]1O
Reactant: CCOC(=O)c1[nH]nc(I)c1C(=O)OCC
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(I)nn([C@H]2COC[C@H]2NC(=O)OC(C)(C)C)c1C(=O)OCC
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
To a solution of PPh3 (2.72 g, 10.35 mmol) in THF (10 mL) at 0° C. was added DIAD (2.013 mL, 10.35 mmol) dropwise and stirred for 15 min. A solution of Intermediate 104C (1.4 g, 4.14 mmol) in THF (10 mL) was added to the above reaction mixture and was stirred at 0° C. for 45 min. A solution of tert-butyl ((3S,4R)-4-hydroxytetrahydrofuran-3-yl)carbamate (1.683 g, 8.28 mmol) in THF (10 mL) was added dropwise at 0° C. and the reaction mixture was stirred at RT for 12 h. The reaction mixture was then concentrated and the crude compound was purified by silica gel chromatography (24 g REDISEP® column, eluting with 30% EtOAc in hexanes). Fractions containing the product were combined and evaporated to afford Intermediate 352A (1.7 g, 81%) as a white solid. MS(ES): m/z=522 [M−H]+; The crude product was taken to the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:10])[CH2:4][CH2:3]1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:10][C:22]2[CH:23]=[CH:24][C:19]([C:18]([F:27])([F:26])[F:17])=[CH:20][CH:21]=2)[CH2:4][CH2:3]1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CN1CCN(CC(O)c2ccccc2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CCN(CC(Oc2ccc(C(F)(F)F)cc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
2-(4-Methyl-piperazin-1-yl)-1-phenyl-ethanol (38) (2.0 g, 9.09 mmol) was dissolved in 50 mL of THF. 4-trifluoromethyl phenol was added to the solution and then triphenylphosphine. After complete dissolution, the mixture was cooled to 0° C. and after 10 minutes DIAD was added dropwise. Ice-bath was removed and the reaction mixture was stirred at room temperature for 48 hours. The product was purified using flash chromatography, using pure ethyl acetate. The product 14a (2.78 g, 7.64 mmol, 84%) was afforded as a yellow oil. H-NMR (CDCl3): δ 7.39 (2H, d, J=8.62), 7.36 (5H, m), 6.91 (2H, d, J=8.58), 5.38 (1H, dd, J=3.11, 3.10 Hz), 3.03 (1H, dd, J=8.39, 8.38), 2.71 (1H, dd, J=3.14, 3.14), 2.63 (4H, b), 2.44 (4H, b), 2.27 (3H, s).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F-:12].[Cs+]>CS(C)=O.O>[F:12][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: [F-]
Reactant: Clc1ccc2ccccc2n1
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Fc1ccc2ccccc2n1
Temperature: 130 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of 2-chloroquinoline (4.9 g, 30 mmol) in 200 mL of anhydrous DMSO was added cesium fluoride (9.13 g, 60 mmol), and the resulting mixture was stirred at 130° C. overnight, when LC-MS showed completion of the reaction. After cooling, the reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was then washed with brine, dried over anhy. Na2SO4, and concentrated in vacuo. Column chromatography (6% EtOAc/PE) afforded 3.34 g of title compound. 1H NMR (CHLOROFORM-d) δ: 8.23 (d, J=8.6 Hz, 1H), 7.89 (d, J=8.6 Hz, 1H), 7.82-7.86 (m, 1H), 7.67 (d, J=8.5, 7.0, 1.5 Hz, 1H), 7.47-7.53 (m, 1H), 7.35 (d, J=8.6 Hz, 1H). LC-MS: m/z 148.2 (M+H)+
Reaction SMILES: [BH4-].[Na+].C(O)(C(F)(F)F)=O.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[C:24]#[N:25])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])[CH2:24][NH2:25])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)c2ccccc2Cl)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.6 %

Procedure:
To NaBH4 (0.79 g, 20.84 mmol) in THF (20 mL) at 0° C. was added TFA (2.38 g, 20.84 mmol) dropwise. To this cooled mixture was added 4-[(2-Chloro-phenyl)-cyano-methyl)-piperazine-1-carboxylic acid tert-butyl ester (101) (1.40 g, 4.17 mmol) in THF (10 mL) dropwise. The reaction mixture was allowed to stir at room temperature for 18 h. The reaction was quenched with H2O (50 mL) and diluted with EtOAc (100 mL). The organic phase was washed with H2O (100 mL) and brine (100 mL). The crude material was purified by chromatography (silica gel 60 mesh, eluting with 10% TEA/10% MeOH in EtOAc) yielding 0.49 g (34%) pure product.
Reaction SMILES: Br[Mg][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1.Br[CH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:18]([C:22]([F:25])([F:24])[F:23])[O:19]2)=[CH:14][C:13]=1[Cl:31]>[Cl-].[Cl-].[Zn+2].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:31][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[CH2:11][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][N:4]=1)[O:19][CH:18]([C:22]([F:25])([F:24])[F:23])[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:16]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(CBr)cc2OC1C(F)(F)F
Reactant: Cc1ccnc([Mg]Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCOC(=O)C1=Cc2cc(Cl)c(Cc3cc(C)ccn3)cc2OC1C(F)(F)F
Temperature: -78 °C
Yield: 4.9 %

Procedure:
The bromo (4-methylpyridin-2-yl)magnesium (10.4 mL, 2.6 mmole) was diluted by 5 mL THF and the solution was cooled to −78° C. ZnCl2 (340 mg, 2.5 mmole) was added to above solution and the mixture was slowly warmed to r.t and heated to 50 OC for 3 hrs. The mixture was cooled to −78° C. again and ethyl 7-(bromomethyl)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylate from Example 16, Step 3 (1.0 g, 2.5 mmol) was added to above mixture and followed by PdCl2(PPh3)2 (18 mg, 0.025 mmole). The mixture was warmed to 50° C. for 3 hrs. LCMS indicated that around 40% product was formed. The reaction was quenched with 1 N HCl and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. The filtrate was concentrated to afford the crude product, which was purified by RPHPLC eluted with 10 to 95% ACN in water with 0.05% TFA to give 50 mg the desired product as a brown oil (yield 5%), which had suitable purity to use without further purification.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18][C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:14][CH:13]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Nc1ccc(Sc2nc3ccccc3o2)cc1
Yield: 79.4 %

Procedure:
2-Chlorobenzoxazole (0.065 moles, 10.0 g), 4-aminothiophenol (0.065 moles, 8.1 g) and potassium carbonate (0.065 moles, 9.0 g) were stirred for 3 days at room temperature in 250 ml ethanol, filtered, and concentrated. Ethyl acetate was added and the solution washed with water, dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with 50% ethyl acetate in hexane to yield 2-(4-aminophenylthio)benzoxazole 12.5 g, 79%. Mass spec (FD) 243. Calculated for C11H10N2OS: C, 64.44; H, 4.16; N, 11.56. Found: C, 64.53; H, 4.22; N, 11.58.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:19])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClC1C=CC=CC=1>[Br:19][CH2:11][C:6]1[CH:7]=[C:8]([Cl:10])[CH:9]=[C:2]([Cl:1])[C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)cc(Cl)c1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Clc1ccccc1
Product: N#Cc1c(Cl)cc(Cl)cc1CBr
Temperature: 78 °C
Reaction time: 2 h

Procedure:
A soln. of 2,4-dichloro-6-methylbenzonitrile (16.9 mmol) in 34 mL chlorobenzene was heated to 50° C. when NBS (18.6 mmol) was added. The flask was purged with Ar before AIBN (1.69 mmol) was added at once still at 50° C. The reaction mixture was then stirred at 78° C. After 2 h and 4 h, another portion of AIBN (1.69 mmol) was added and heating to 78° C. was continued overnight. The solvent was then evaporated off, the resulting residue was redissolved in Et2O and the remaining solid was removed by filtration. The filtrate was washed twice with 2N HCl solution and brine, it was dried over MgSO4 and conc. in vacuo. Purification with CC (0-100% EtOAc/Hept) gives the desired compound as yellowish solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][CH:15]([CH2:17]Cl)[CH2:14][S:13]1.[CH3:19][NH2:20]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][CH:15]([CH2:17][NH:20][CH3:19])[CH2:14][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC(CCl)CS1
Reactant: CN
Product: CNCC1CSC(=Nc2ccc([N+](=O)[O-])cc2C)N1

Procedure:
2-Amino-1,3-propanediol was reacted with excess SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-4-(chloromethyl)-1,3-thiazolidine. The thiazolidine was reacted with N-methylamine according to Method D13a to give 2-(2-methyl-4-nitrophenylimino)-4-(N-methylaminomethyl)-1,3-thiazolidine, which was reacted with isobutyl bromide according to Method D2a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-(N-isobutyl-N-methylaminomethyl)-1,3-thiazolidine.
Reaction SMILES: [O:1]1[C@H:7]2[C@@H:2]1[C:3]([CH3:17])([CH3:16])[O:4][C:5]1[C:11]([CH3:12])=[C:10]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:8][C:6]=12.Cl([O-])(=O)(=O)=O.[Li+].[Cl-].[NH4+:25]>O1CCOCC1>[CH3:16][C:3]1([CH3:17])[C@H:2]([OH:1])[C@@H:7]([NH:25][CH2:2][CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:5]=2)[C:6]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[C:11]([CH3:12])[C:5]=2[O:4]1
Reactant: Cc1c([N+](=O)[O-])ccc2c1OC(C)(C)[C@@H]1O[C@H]21
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1c([N+](=O)[O-])ccc2c1OC(C)(C)[C@H](O)[C@H]2NCCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution of (3R*,4R*)-3,4-epoxy-2,2,8-trimethyl-7-nitro-3,4-dihydro-2H-1-benzopyran (600 mg, 2.55 mmol) in 1,4-dioxane (1.2 mL), lithium perchlorate (271 mg, 2.55 mmol) and 2-(phenylethyl)amine (0.384 mL, 3.06 mmol) were added at room temperature and the mixture was stirred at 80° C. for 1 hour. Upon the completion of the reaction, saturated ammonium chloride was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=4/1) and the aimed product was obtained as orange oily substance (yield: 99%).
Reaction SMILES: [CH:1](=O)[CH3:2].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH:22][C:23]1[CH:50]=[CH:49][C:48]([CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:47][C:24]=1[C:25]([NH:27][C:28]1[CH:40]=[C:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:38]=[CH:37][C:29]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26]>C(Cl)Cl>[CH2:1]([N:54]1[CH2:53][CH2:52][CH:51]([C:48]2[CH:49]=[CH:50][C:23]([OH:22])=[C:24]([CH:47]=2)[C:25]([NH:27][C:28]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH:38]=[CH:37][C:29]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:26])[CH2:56][CH2:55]1)[CH3:2]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(C2CCNCC2)ccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCN1CCC(c2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Acetaldehyde (0.016 mL), acetic acid (0.024 mL), and sodium triacetoxyborohydride (0.11 g) were sequentially added to a methylene chloride (1.0 mL) suspension of tert-butyl 2-(2-hydroxy-5-(piperidin-4-yl)benzamido)-4-phenylbenzoate (0.10 g), followed by stirring at room temperature for 1 hour. Acetaldehyde (0.016 mL) and sodium triacetoxyborohydride (0.11 g) were sequentially added to the reaction mixture, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and ethyl acetate was added to the residue. After removal of the insoluble substance by filtration, a saturated aqueous solution of sodium bicarbonate was added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-90% chloroform/methanol] to obtain 0.045 g of tert-butyl 2-(5-(1-ethylpiperidin-4-yl)-2-hydroxybenzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:17]3[CH2:19][CH2:18]3)[C:11]3[N:12]([CH:14]=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[I:20]Cl>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:17]3[CH2:19][CH2:18]3)[C:11]3[N:12]([C:14]([I:20])=[CH:15][N:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cc(C3CC3)c3nccn3c2)cc1
Reactant: ClI
Product: Clc1ccc(-c2cc(C3CC3)c3ncc(I)n3c2)cc1

Procedure:
Prepared from 6-(4-chloro-phenyl)-8-cyclopropyl-imidazo[1,2-a]pyridine (example C.27 step 4) (3.1 g, 11.5 mmol) and iodine monochloride as described in example C.20 step 3. Obtained the title compound as an off-white solid (1.098 g, 24% pure material, crystallized from EtOAc/heptane; 2.001 g, 42% contains dicylopropyl material). MS (ISP) 394.8 [(M+H)+], 396.9 [(M+2+H)+].