Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12](=O)[CH2:13][CH3:14])=[C:4]([NH:8][C:9]([NH2:11])=[O:10])[S:5][C:6]=1[CH3:7].[OH-].[Na+].CC(O)=O>CCO>[CH2:13]([C:12]1[C:3]2[C:2]([CH3:1])=[C:6]([CH3:7])[S:5][C:4]=2[NH:8][C:9](=[O:10])[N:11]=1)[CH3:14]
Reactant: CCC(=O)c1c(NC(N)=O)sc(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1nc(=O)[nH]c2sc(C)c(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
To a solution of 1-(4,5-dimethyl-3-propionylthiophen-2-yl)urea (Example 51a) (15.4 mg, 0.068 mmol) in dry EtOH (10 mL) was added sodium hydroxide (8.4 mg, 0.20 mmol). The reaction mixture was then stirred at RT for 30 minutes under nitrogen. The reaction mixture was neutralized with 10% AcOH and then concentrated to dryness. The residue was purified by chromatography on silica gel (Gradient 0-10% MeOH in dichloromethane) to give the title compound (2.7 mg, 19%). 1H NMR (400 MHz, CDCl3) δ 1.42 (t, J=7.6 Hz, 3H), 2.31 (s, 3H), 2.33 (s, 3H), 3.06 (q, J=7.6 Hz, 2H). MS 209 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[C:18](=O)[C@H:17]1[C@@H:12]2[CH2:13][NH:14][CH2:15][CH2:16]1.[SiH](CC)(CC)CC>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[CH2:18][C@H:17]1[C@@H:12]2[CH2:13][NH:14][CH2:15][CH2:16]1
Reactant: O=C1c2ccc(-c3ccc(Cl)cc3Cl)cc2[C@H]2CNCC[C@@H]12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-c2ccc3c(c2)[C@H]2CNCC[C@H]2C3)c(Cl)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of cis-6-(2,4-dichloro-phenyl)-1,2,3,4,4a,9a-hexahydro-3-aza-fluoren-9-one (40 mg, 0.12 mmol) in trifluoroacetic acid (2.0 mL) was added Et3SiH (62 mg, 0.53 mmol). The reaction mixture was stirred at 20° C. for 15 h then concentrated in vacuo. The residue was basified with NH4OH then extracted with CH2Cl2. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the crude title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][C@H:13]([CH3:16])[CH2:14][OH:15]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:15][CH2:14][C@@H:13]([CH3:16])[CH2:12][O:11][CH3:10])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Br)cc1
Reactant: COC[C@H](C)CO
Product: COC[C@H](C)COCc1ccc(Br)cc1

Procedure:
According to general method E, 1-bromo-4-chloromethyl-benzene [589-17-3] and (R)-3-methoxy-2-methyl-propan-1-ol are used to afford the title compound as a yellow oil. Rf=0.44 (EtOAc-heptane 1:6); Rt=5.29 (gradient I).
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][O:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:11][CH:10]=1.[CH:27]([N:30](CC)C(C)C)(C)C.N#CBr>C(#N)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][O:14][CH2:15][C@@H:16]2[CH2:18][C@@H:17]2[CH:19]2[CH2:24][CH2:23][N:22]([C:27]#[N:30])[CH2:21][CH2:20]2)=[CH:25][CH:26]=1
Reactant: Brc1ccc(COC[C@@H]2C[C@@H]2C2CCNCC2)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: N#CBr
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: N#CN1CCC([C@H]2C[C@H]2COCc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from step B (1.00 g, 3.08 mmol) and N,N-diisopropylethylamine (1.61 mL, 9.25 mmol) were dissolved in acetonitrile (20 mL). Cyanogen bromide (5M in acetonitrile, 0.746 mL, 3.7 mmol) was added and the reaction was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned between CH2Cl2 and water. The organic layer was saved and the aqueous layer was extracted with CH2Cl2. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered and evaporated to yield a crude material, which was purified by silica gel column chromatography (gradient elution 0% to 100% EtOAc in hexanes) to yield the title compound as a viscous oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[O:8][C:9]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[C:10](=[O:12])[CH:11]=2)=[CH:3][CH:2]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:24][C:11]1[C:10](=[O:12])[C:9]2([CH2:16][CH2:15][CH2:14][CH2:13]2)[O:8][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=C1C=C(c2ccncc2)OC12CCCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C1C(Br)=C(c2ccncc2)OC12CCCC2
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a stirred solution of afford 2-(pyridin-4-yl)-1-oxaspiro[4.4]non-2-en-4-one (0.18 g, 0.84 mmol) in CHCl3 (10 mL) was added NBS (0.22 g, 1.25 mmol) portionwise at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with DCM (30 mL), washed with water (10 mL), brine (10 mL), dried over Na2SO4, filtered and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 3-bromo-2-(pyridin-4-yl)-1-oxaspiro[4.4]non-2-en-4-one (0.18 g, 40%) as an oil.
Reaction SMILES: C=O.[O:3]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@@H:10]2[NH:15][CH2:14][CH2:13][N:12]([C:16]3[C:25]4[CH:24]=[C:23]([CH3:26])[S:22][C:21]=4[NH:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[N:17]=3)[CH2:11]2)=[CH:4]1.[C:31](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[O:3]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@@H:10]2[N:15]([CH3:31])[CH2:14][CH2:13][N:12]([C:16]3[C:25]4[CH:24]=[C:23]([CH3:26])[S:22][C:21]=4[NH:20][C:19]4[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=4[N:17]=3)[CH2:11]2)=[CH:4]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccoc2)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCc2ccoc2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
Add formaldehyde (49 μL, 0.61 mmol, 37% in water) to a solution of (S)-10-[3-(2-furan-3-yl-ethyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (219 mg, 0.56 mmol) in methylene chloride (20 mL). Stir 15 min at ambient temperature. Add sodium triacetoxyborohydride (177 mg, 0.56 mmol) and stir 1 h at ambient temperature. Dilute with saturated sodium bicarbonate solution and extract with methylene chloride. Dry the extracts with sodium sulfate, filter and concentrate the filtrate. Purify by radial silica gel chromatography using a 2 mm plate and 2N ammonia in methanol-methylene chloride (1%–2.5%) as the eluent to give 179 mg (79%) of the title compound: mass spectrum (ion spray): m/z=407 (M+1), 405 (M−1). HPLC: Symmetry C18 column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.4 min; 100% pure;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([CH2:7][N:8]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=[O:22])[N:10]=2)=[CH:5][CH:4]=1.CO.[C:47](O)(=[O:49])C.[C-]#N.[Na+]>C1COCC1.[O-2].[O-2].[Mn+4]>[CH3:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:44][CH:43]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:24][C:25]4[CH:26]=[N:27][C:28]([O:32][CH3:33])=[C:29]([F:31])[CH:30]=4)=[N:18][CH:19]=[C:20]([CH:23]=3)[C:21]([O:49][CH3:47])=[O:22])[N:10]=2)=[CH:40][CH:39]=1
Reactant: CC(=O)O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: [Mn+4]
Agent: [C-]#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cnc(Nc2cnc(OC)c(F)c2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Reaction time: 72 h
Yield: 50.9 %

Procedure:
A slurry of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinaldehyde (Example 143, 0.200 g, 0.336 mmol), manganese dioxide (0.584 g, 6.72 mmol), methanol (0.068 mL, 1.679 mmol), acetic acid (0.029 mL, 0.504 mmol), and sodium cyanide (0.082 g, 1.679 mmol) in 4 mL THF was stirred rapidly overnight. Manganese dioxide (0.584 g, 6.72 mmol) was added, the reaction was sealed, and stirred rapidly for 3 days. The reaction was filtered through Celite® (diatomaceous earth), rinsing with 10% MeOH/DCM. The residue was adsorbed onto 2 g silica gel, dried, and purified by silica gel chromatography (40 g column) using 0-100% EtOAc/hexane. The product-containing fractions were concentrated to afford methyl 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)nicotinate (0.107 g, 0.171 mmol, 50.9% yield) as a orange solid. m/z (ESI, +ve ion) 626 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 12.33 (br. s., 1H), 9.41 (d, J=2.3 Hz, 1H), 8.92 (d, J=2.3 Hz, 1H), 7.98 (d, J=2.3 Hz, 1H,) 7.90-7.97 (m, 1H), 7.16-7.25 (m, 4H), 6.82-6.92 (m, 4H), 4.90 (s, 2H), 4.84 (s, 2H,) 4.04 (s, 3H), 3.92 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 2.61 (s, 3H).
Reaction SMILES: [ClH:1].[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[ClH:1].[C:2]1([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=C(c2ccccc2)CCNC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: c1ccc(C2CCNCC2)cc1
Temperature: 45 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
1,2,3,6-Tetrahydro-4-phenylpyridine hydrochloride (70 mg) was dissolved in methanol (1.4 ml), added with 10% palladium/carbon (35 mg) and stirred at 45° C. for 5 hours under hydrogen gas atmosphere. After insoluble matters were removed by filtration, the solvent was evaporated under reduced pressure to obtain 70.0 mg of the title compound. Yield: 99%.
Reaction SMILES: C[C:2]([C:4]([C:14]([CH3:16])=[O:15])=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[Cl:13])=O.C1(C)C=CC(S([CH2:26][N+:27]#[C-])(=O)=O)=CC=1.C[O-].[Na+].O>CO>[CH3:16][C:14]([C:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=2[Cl:13])=[CH:26][NH:27][CH:2]=1)=[O:15]
Reactant: CC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)c1c[nH]cc1-c1cccc(Cl)c1Cl
Yield: 50 %

Procedure:
With stirring, 20 g of 1,1-di(methylcarbonyl)-2-(2,3-dichlorophenyl)ethene are added at 0° C. to 65 g of a 23.2% by weight solution of (p-tolylsulfonyl)methyl isocyanide prepared according to Example P1 (a). Then 28.1 g of a 30 % solution of sodium methylate in methanol are added dropwise over 3 hours. The mixture is stirred for 60 minutes at a temperature of +10° C. and then 170 ml of water are added dropwise and the product is subsequently isolated by filtration. The filter residue is recrystallised from a 1:1 mixture of methanol/ethanol and dried under vacuum, affording 8.3 g (50% of theory) of 4-methylcarbonyl-3-(2,3-dichlorophenyl)pyrrole which melts at 192°-194° C.
Reaction SMILES: C(O[C:4]1[C:5](=[O:16])[C:6](=[O:15])[C:7]=1[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C.[O:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1>C(O)C>[O:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:4]3[C:5](=[O:16])[C:6](=[O:15])[C:7]=3[NH:8][C:9]3[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:36][CH:37]=2)[CH2:21][CH2:22]1
Reactant: NCCCCCCOc1ccc(CN2CCOCC2)cc1
Reactant: CCOc1c(Nc2cccnc2)c(=O)c1=O
Solvent: CCO
Product: O=c1c(NCCCCCCOc2ccc(CN3CCOCC3)cc2)c(Nc2cccnc2)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-ethoxy-4-(pyridin-3-yl-amino)-3-cyclobutene-1,2-dione (350 mg, 1.6 mmol) in ethanol (1.4 mL) was added 6-[4-(morpholinomethyl)-phenoxy]-hexylamine (469 mg, 1.6 mmol) in ethanol (5 mL). The reaction was allowed to stir at r.t. for 18 h, then filtered. The solid was washed with cold ethanol, then ether to give the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[O:8]([C:15]1[CH:16]=[C:17]([N:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32](Br)[CH:31]=2)[CH2:22][CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])[CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].O(C1C=C(CC(NCC2C=C([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=3[C:77]([F:80])([F:79])[F:78])C=CC=2)(O)C(F)(F)F)C=CC=1)C1C=CC=CC=1>CCO.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.O.CN(C=O)C>[O:8]([C:15]1[CH:16]=[C:17]([N:21]([CH2:29][C:30]2[CH:31]=[C:32]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][C:72]=3[C:77]([F:80])([F:79])[F:78])[CH:33]=[CH:34][CH:35]=2)[CH2:22][CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])[CH:18]=[CH:19][CH:20]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OC(CN(Cc1cccc(Br)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F
Reactant: OC(Cc1cccc(Oc2ccccc2)c1)(NCc1cccc(-c2ccccc2C(F)(F)F)c1)C(F)(F)F
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: [K+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: OC(CN(Cc1cccc(-c2ccccc2C(F)(F)F)c1)c1cccc(Oc2ccccc2)c1)C(F)(F)F

Procedure:
To a toluene (8 mL) solution of 3-[(3-phenoxyphenyl)[[3-bromophenyl]methyl]-amino]-1,1,1-trifluoro-2-propanol (0.51 g, 1.1 mmol) from EX-595B was added 2-(tii-fluoromethyl)phenylboronic acid (0.33 g, 1.7 mmol) and DMF (3 mL). To the resulting solution was added K2CO3 (0.31 g, 2.2 mmol) and Pd(PPh3)4 (0.060 g, 0.05 mmol). The slurry was heated to reflux under argon for 18 h. The cooled mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 20% ethyl acetate in hexane gave an oil which was dissolved in EtOH, stripped and dried in vacuo to give 0.32 g (55%) of the desired 3-[(3-phenoxyphenyl) [[(2′-(trifluoromethyl)[1,1′-biphenyl]-3-yl]methyl]amino]-1,1,1-tri-fluoro-2-propanol product as a colorless oil. Anal. calcd. for C29H23NO2F6.0.8 EtOH: C, 64.67; H, 4.93; N, 2.46. Found: C, 64.53; H, 4.69; N, 2.49. HRMS calcd. 532.1711 [M+H]+, found: 532.1708. 1H NMR (C6D6) δ 1.72 (d, 11H), 3.17 (dd, 11H), 3.46 (dd, 11H), 3.72 (m, 1H), 4.23 (s, 2H), 6.33 (dd, 1H), 6.43 (dd, 1H), 6.52 (t, 1H), 6.82 (m, 2H), 6.9-7.1 (m, 11H), 7.43 (d, 11H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2=[C:8]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:9]=[CH:10][N:6]2[CH2:5][CH2:4][O:3]1.[CH3:15][O:16][C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH:24][C:25](=O)[O:26]C2C=CC=CC=2)[N:18]=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.C(OCC)C.O>[CH3:15][O:16][C:17]1[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH:24][C:25]([NH:14][S:11]([C:8]2[CH:9]=[CH:10][N:6]3[CH2:5][CH2:4][O:3][C:2](=[O:1])[C:7]=23)(=[O:13])=[O:12])=[O:26])[N:18]=1
Reactant: NS(=O)(=O)c1ccn2c1C(=O)OCC2
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccn3c2C(=O)OCC3)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 56.5 %

Procedure:
A solution of 40 mg (0.185 mmol) of 3,4-dihydro-1-oxo-1H-pyrrolo[2,1-c][1,4]oxazine-8-sulfonamide and 53 mg (0.204 mmol) of phenyl (4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate in 0.8 mL acetonitrile was treated with 0.03 mL 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and then stirred 40 minutes at ambient temperature. Water (5 mL) plus 0.5 mL 1N HCl was added with stirring followed by ca. 1 mL of ethyl ether. The product crystallized from the two phase mixture and was collected by filtration to afford 40 mg of the title compound, m.p. 204°-207° C. dec.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[F:8][C:9]([F:20])([F:19])[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1>CC#N>[F:8][C:9]([F:19])([F:20])[O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:13][CH:12]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(OC(F)(F)F)cc1
Solvent: CC#N
Product: CC(C)(C)C(=O)NCc1ccc(OC(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A solution of pivaloyl chloride (2.1 mL, 17 mmol) in MeCN (10 mL) was added dropwise over 10 min to a solution of 4-trifluoromethoxy-benzylamine (2.6 mL, 17 mmol) and TEA (4.0 mL, 29 mmol) in MeCN (20 mL) at 0° C. The mixture was stirred for 30 min, filtered and concentrated. The residue was treated with water and filtration gave the sub-title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.C([Li])CCC.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1>O1CCCC1.CCCCCC>[Br:8][C:4]1[CH:3]=[C:2]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC1(c2cccc(Br)c2)CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
To a solution of 1,3-dibromo-benzene (2.36 grams, 10 mmol) in tetrahydrofuran at −78° C. was added a 1.6M solution of n-butyllithium (6.3 ml, 10 mmol) in hexane and stirred for 4 hours. Cyclobutanone (700 mg, 10 mmol) was then added in one portion. After stirring for 2 hours at −78° C., the reaction was quenched with 2N hydrochloric acid. The reaction was warmed to room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was dried and evaporated to give 2.5 grams of crude product which was purified on silica gel eluting with 50% methylene chloride in hexane to give 1.5 grams of the titled compound.
Reaction SMILES: C1COCC1.[CH3:6][N:7]1[CH2:25][CH2:24][C:10]2[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:9]=2[CH2:8]1.[OH-].[Na+].[ClH:28]>C(OCC)C.C(O)C>[ClH:28].[CH3:6][N:7]1[CH2:25][CH2:24][C@H:10]2[N:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C@@H:9]2[CH2:8]1
Reactant: CN1CCc2c(c3ccccc3n2-c2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CC[C@@H]2[C@@H](C1)c1ccccc1N2c1ccccc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 180 ml 1 molar BH3 in THF (0.18 mole BH3) which was cooled in an ice bath, was added a solution of 7.9 grams 2,3,4,5-tetrahydro-2-methyl-5-phenyl-1H-pyrido[4,3-b]indole (0.03 mole) in 200 ml freshly chromatographed THF, dropwise with stirring over 30 minutes in a nitrogen atmosphere. The ice bath was then replaced with a heating mantle and the mixture was refluxed for 19 hours in the nitrogen atmosphere. The mixture was cooled and evaporated under vacuum to a clear gel. The gel was then refluxed in 75 ml of a 1:1 mixture of glacial acetic acid and 5 N HCl. A clear light brown solution was obtained after about 1/2 hour and refluxing was continued for a total of 1 hour. The resulting solution was cooled to about 50° C. and treated with 50% aqueous NaOH until basic, during which time the temperature rose to 80° C. The mixture was cooled again and a light purple oil was extracted into CHCl3. The mixture was again extracted with CHCl3, the extracts were combined and washed with saturated NaCl solution, then dried over Na2SO4. The CHCl3 was then evaporated under vacuum, leaving a purple oily residue which was taken up in about 50 ml diethyl ether and some ethanol. Ethereal HCl was added and 8.1 grams of pale greenish-white powder were obtained by filtration and drying. Recrystallization from methanol provided 6.2 grams of the title compound, m.p. 256°-258° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH2:8]CC)([OH:7])[CH2:5][CH2:4][NH:3]1.[Cl:11][C:12]1[C:19]([CH3:20])=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:11][C:12]1[C:19]([CH3:20])=[C:18]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH3:8])[C@@H:2]2[CH3:1])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: Cc1c(F)ccc(C#N)c1Cl
Reactant: CCC[C@]1(O)CCN[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1c(N2CC[C@](C)(O)[C@@H]2C)ccc(C#N)c1Cl

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-dimethylpyrrolidin-3-ol 0.5 oxalate (260 mg), 2-chloro-4-fluoro-3-methylbenzonitrile (550 mg) and lithium carbonate (240 mg), the title compound was obtained as a colorless solid (yield: 320 mg, yield: 75%).
Reaction SMILES: C([O-])(=O)C1C(=CC=CC=1)C([O-])=[O:5].[C:13]([C:15]1[CH:28]=[CH:27][C:26]2SC3C(=CC=CC=3)N(C[C@]([NH3+])(CCC)C3C=CC=CC=3)[C:17]=2[CH:16]=1)#[N:14].C([C:43]1[CH:56]=[CH:55][C:54]2[S:53][C:52]3[C:47](=[CH:48]C=CC=3)[N:46](C[C@@]([NH3+])(C3C=CC=CC=3)CCC)[C:45]=2[CH:44]=1)#N.[OH-].[K+].O>C(O)C>[OH:5][CH2:48][CH:47]([N:46]1[C:27]2[CH:28]=[C:15]([C:13]#[N:14])[CH:16]=[CH:17][C:26]=2[S:53][C:54]2[C:45]1=[CH:44][CH:43]=[CH:56][CH:55]=2)[CH3:52]
Reactant: O=C([O-])c1ccccc1C(=O)[O-]
Reactant: CCC[C@@]([NH3+])(CN1c2ccccc2Sc2ccc(C#N)cc21)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CO)N1c2ccccc2Sc2ccc(C#N)cc21
Reaction time: 0.17 h
Yield: 127 %

Procedure:
(-)-2-(2-cyano-10-phenothiazinyl)-1-propyl 1-phenyl-(S)-ethylammonium phthalate (95.4 g) is added to a solution of 23.5 g of potassium hydroxide in 1150 cc ethanol under reflux and reflux is continued while stirring for 10 minutes. The reaction mixture is then poured into iced water (1 liter) and extracted with ethyl acetate (2 liters and then 500 cc). The combined organic phases are washed successively with a 0.1N aqueous solution of hydrochloric acid (2×500 cc), with a saturated aqueous solution of sodium bicarbonate (2×500 cc) and with a saturated aqueous solution of sodium chloride (500 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow solid (44 g) is taken up in isopropyl ether (200 cc) under reflux and the product crystallizes whilst warm. The mixture is allowed to return to a temperature of about 20° C. and the solid is centrifuged, washed with isopropyl ether (20 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 20° C. D series 10-(1-hydroxy-2-propyl)-2-phenothiazinecarbonitrile (36.5 g) is thus obtained in the form of yellow crystals which melt at 135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:15]I>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][OH:12])[N:8]([CH3:15])[C:5]2=[N:6][CH:7]=1
Reactant: CI
Reactant: OCc1nc2cc(Cl)cnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CO)nc2cc(Cl)cnc21

Procedure:
A procedure similar to that described in Preparation 59 was repeated, except that 3.00 g of 6-chloro-2-hydroxymethyl-3H-imidazo[5,4-b]pyridine (prepared as described in Preparation 63), 0.71 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 1.03 ml of methyl iodide and 50 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 50:1 by volume as the eluent, to give 0.87 g of the title compound, melting at 141°-142° C.
Reaction SMILES: [K].[CH3:2][C:3]1([CH3:10])[O:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[C:11]1([C:21](Cl)=[O:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C(OCC)(=O)C>O1CCCC1>[CH3:2][C:3]1([CH3:10])[O:7][C:6](=[O:8])[N:5]([C:21]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:22])[C:4]1=[O:9]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC1(C)OC(=O)NC1=O
Agent: [K]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
5,5-Dimethyl-2,4-oxazolidinedione potassium salt (84 mg) was suspended in tetrahydrofuran (1 mL), 1-naphthoyl chloride (95 mg) was added, and the mixture was stirred at room temperature overnight. To the reaction solution was added 4 mL of ethyl acetate, and the solution was filtered with a membrane filter (0.25 μm). The resulting organic layer was purified by silica gel chromatography (hexane:ethyl acetate=2:1), and further recrystallized from ethyl acetate/IPE to obtain 61 mg of white crystals.