Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9](=[O:11])[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:32]=[CH:31][C:23]3[N:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:26][C:22]=3[CH:21]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.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>[O:11]=[C:9]1[NH:8][C:7]2[C:2]([C:20]3[CH:32]=[CH:31][C:23]4[N:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:26][C:22]=4[CH:21]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[S:10]1
Reactant: O=c1[nH]c2c(Br)cccc2s1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(=O)Nc1nc2ccc(-c3cccc4sc(=O)[nH]c34)cc2s1
Temperature: 85 °C
Reaction time: 7 h

Procedure:
4-Bromobenzo[d]thiazol-2(3H)-one (69.9 mg, 0.304 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (124.9 mg, 3.925 mmol), dichlorobis(triphenyl-phosphine)palladium (II) (39.7 mg, 56.6 μmol), and sodium carbonate (0.30 mL, 2.0 M in water, 0.60 mmol) were suspended in 1,2-dimethoxyethane (1.4 mL) and ethanol (0.39 mL). The reaction flask was fit with a reflux condensor and the solution was heated in a preheated oil bath (85° C.) and stirred under nitrogen for 7 hours, at which time the reaction was slowly allowed to cool to RT. After sitting at RT for 4 days, more PdCl2(PPh3)2 (37.3 mg) was added, and stirring was resumed at 85° C. for 4 hours. Then, the reaction was cooled to RT and filtered through a silica gel plug with 10:1 DCM/MeOH. The filtrate was concentrated and purified on HPLC (10-95% MeCN/water with 0.1% TFA over 40 minutes) to provide N-(6-(2-oxo-2,3-dihydrobenzo[d]thiazol-4-yl)benzo[d]thiazol-2-yl)acetamide. MS (ESI pos. ion) m/z: 342 (MH+). Calculated exact mass for C16H11N3O2S2: 341.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[N:6]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)[CH3:3].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:55]1[CH2:60][CH2:59][CH:58]([N:61]2[CH2:64][C:63]([CH2:87][C:88]#[N:89])([N:65]3[CH:69]=[C:68]([C:70]4[C:71]5[CH:78]=[CH:77][N:76](COCC[Si](C)(C)C)[C:72]=5[N:73]=[CH:74][N:75]=4)[CH:67]=[N:66]3)[CH2:62]2)[CH2:57][CH2:56]1>CN(C)C=O>[CH3:3][N:2]([CH2:4][C:5]1[N:6]=[C:7]([C:15]([F:18])([F:17])[F:16])[C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([N:55]1[CH2:56][CH2:57][CH:58]([N:61]2[CH2:62][C:63]([CH2:87][C:88]#[N:89])([N:65]3[CH:69]=[C:68]([C:70]4[C:71]5[CH:78]=[CH:77][NH:76][C:72]=5[N:73]=[CH:74][N:75]=4)[CH:67]=[N:66]3)[CH2:64]2)[CH2:59][CH2:60]1)=[O:12])[CH3:1]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Reactant: CN(C)Cc1cc(C(=O)O)c(F)c(C(F)(F)F)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)Cc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)c(F)c(C(F)(F)F)n1
Reaction time: 1 h

Procedure:
A solution of 6-[(dimethylamino)methyl]-3-fluoro-2-(trifluoromethyl)isonicotinic acid (0.0776 g, 0.291 mmol, from Step C) in N,N-dimethylformamide (1 mL) was treated with N,N-diisopropylethylamine (0.3 mL, 2 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.15 g, 0.35 mmol). This mixture was pre-stirred for 1 hour, followed by the addition of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (0.158 g, 0.320 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base). After 3 hours, additional N,N-diisopropylethylamine (0.507 mL, 2.91 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.26 g, 0.58 mmol) were added and the mixture was stirred for 48 hours. The SEM-protected product was purified by preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Solvent was removed from fractions containing desired product by rotary evaporation. The product was deprotected by stirring with a 1:1 mixture of TFA:DCM for 1 hour, followed by evaporation, and stirring with ethylenediamine (0.2 mL) in methanol for 30 minutes. The product was purified by preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH). Fractions containing desired product were frozen and lyophilized. Yield: 0.006 g (3%); LC-MS: 611.2 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 8.69 (s, 1H), 8.67 (s, 1H), 8.40 (s, 1H), 7.77 (d, 1H), 7.51 (d, 1H), 6.98 (d, 1H), 4.33-4.21 (m, 1H), 3.87-3.71 (m, 4H), 3.68 (s, 2H), 3.59-3.45 (m, 3H), 3.44-3.10 (m, 2H), 2.71-2.58 (m, 1H), 2.31 (s, 6H), 1.97-1.85 (m, 1H), 1.85-1.72 (m, 1H), 1.56-1.24 (m, 2H). 19F NMR (300 MHz, CD3OD): δ −67.26 (d, 3F), −132.8 (m, 1F).
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1)(=O)C.CO.[OH-].[Na+]>C1COCC1.O>[I:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[CH:22][CH:21]=1
Reactant: CC(=O)OCCCCCCCCCCCCc1ccc(I)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: OCCCCCCCCCCCCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 0.1 %

Procedure:
12-(p-Iodophenyl)dodecyl acetate 34 (872 mg, 2.03 mol) was dissolved in THF (4 ml) and MeOH (4 ml) mixture, and a solution of NaOH (325 mg, 8.11 mmol) in H2O (1 ml) was added. The mixture was stirred at room temperature for 5 h, quenched with 1 N HCl to pH 7, diluted with NaHCO3 solution and extracted with EtOAc. The extract was dried over Na2SO4 and the solvent was evaporated. Silica gel chromatography of the residue in hexane-ethyl acetate (95:5, 90:10) yielded the product (682 mg, 87%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13]C)=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1Br
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
To a mixture of 1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethanone (1.0 g, 3.6 mmol) in methylene chloride (20 mL) was added 1.0 M boron tribromide in methylene chloride (3.8 mL, 3.8 mmol) at −78° C. After stirring at −78° C. for 10 minutes, the reaction was allowed to warm to 0° C. and was then quenched with water at 0° C. and extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. The volatiles were removed under reduced pressure to afford 1-(3-Bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (0.91 g, 96%). 1H NMR (CDCl3, 300 MHz) δ 12.96 (1H, s), 7.72 (1H, s), 2.64 (3H, s), 2.59 (3H, s) ppm.
Reaction SMILES: [F:1][C:2]([F:18])([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].N1C=CC=CC=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl>O>[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:18])([F:1])[C:11]([F:16])([F:17])[C:12]([F:14])([F:15])[F:13])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: OCCOCCOCC(F)(F)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCC(F)(F)C(F)(F)C(F)(F)F)cc1
Reaction time: 3 h
Yield: 103.2 %

Procedure:
5.0 g (17.3 mM) of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecanol and 4.8 ml of pyridine were stirred under cooling on an ice bath. To the mixture, 4.0 g (20.8 mM) of p-toluenesulfonyl chloride was added, followed by stirring for 3 hours. The reaction mixture was poured into water and acidified by hydrochloric acid, followed by extraction with ethylacetate, washing with water, drying with anhydrous sodium sulfate and distilling-off of the solvent to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=10/1) to obtain 7.92 g of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecyl p-toluenesulfonate (Yield: 99.8%).
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[OH-].[Na+].[CH3:14][C:15]1[O:16][C:17](=[O:29])[C:18](=[CH:20][C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[N:19]=1>CC(C)=O>[C:15]([NH:19][C:18](=[CH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]#[N:26])=[CH:27][CH:28]=1)[C:17]([NH:11][C@@H:7]([CH:4]1[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)[C:8]([OH:10])=[O:9])=[O:29])(=[O:16])[CH3:14]
Reactant: N[C@H](C(=O)O)C1CCCCC1
Reactant: CC1=NC(=Cc2ccc(C#N)cc2)C(=O)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(=O)NC(=Cc1ccc(C#N)cc1)C(=O)N[C@H](C(=O)O)C1CCCCC1
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
(S)-Cyclohexylglycine (3.14 kg, 20 mol) in acetone (70 l) was heated with stirring at 35° C. With stirring, 1 N aqueous sodium hydroxide solution (20 l) was then added over a period of 10 min. The mixture was heated to 40° C., and at an internal temperature of 40° C., solid 4-(2-methyl-5-oxooxazol-4-ylidenemethyl)benzonitrile (4.66 kg, 22 mol) was metered in in portions, with vigorous stirring, over 20 min. After the addition had been ended, the reaction mixture was stirred at an internal temperature of 40° C. for 1 h. The reaction solution was then filtered through a pressure nutsch covered with a Seitz filter K1000 and activated carbon (1 kg), and the filter residue was washed with 10 l of acetone. The filtrate was then cooled to 14° C. With stirring, 2N hydrochloric acid (about 10 l) was then added over a period of 10 min until a pH of 2.3 had been reached. Stirring was continued for 15 min, and the pH was readjusted using 2N HCl. Over a period of 20 min, the solution was then admixed with stirring with deionized water (160 l), whereupon the title compound precipitated. With stirring, the mixture was cooled to 0° C. and stirred at this temperature for 1 h. For isolation, the product was pumped onto a centrifuge, washed three times with water (10 l each), tumble-dried and dried at 40° C. under reduced pressure. Yield: 4.21 kg (11.4 mol, 57% of theory). M.p.: 196–198° C.; MS(ESI+): m/z=370.2 [M+H+]; 1H-NMR (200 MHz, DMSO-d6): δ=0.98–1.35 (m 1.48–1.90 (m, 6H), 1.99 (s, 3H), 4.20 (dd, 1H), 6.98 (s, 1H), 7.72 (d, 2H), 7.88 (d, 2H), 8.02 (d, 1H), 9.58 (s, 1H), 12.65 (br s, 1H).
Reaction SMILES: C([S:8][CH2:9][CH:10]([CH3:21])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12])C1C=CC=CC=1.[Na].S([O-])([O-])(=O)=O.[NH4+].[NH4+]>N>[SH:8][CH2:9][CH:10]([CH3:21])[C:11]([N:13]1[CH2:20][CH2:19][CH2:18][C@H:14]1[C:15]([OH:17])=[O:16])=[O:12]
Reactant: CC(CSCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: N
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
1-[3-(benzylthio)-2-methylpropanoyl]-L-proline (0.1 g.) is suspended in boiling liquid ammonia (10 ml.) and small pieces of sodium are added with stirring until persistent blue color. The color is discharged with a few crystals of ammonium sulfate and the ammonia is allowed to evaporate under a current of nitrogen. The residue is dissolved in a mixture of dilute hydrochloric acid and ethyl acetate. The organic layer is dried and concentrated to dryness in vacuo to yield 1-(3-mercapto-2-methylpropanoyl)-L-proline. Rf : 0.35 (Silica gel; Benzene/acetic acid 3:1), Rf 0.5 (Silica gel; Methyl-ethylketone/acetic acid/pyridine/water 14:1:2:1) identical to the compound of Example 34.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C=Cc1ccccn1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.3 %

Procedure:
To a suspension of ethyl 3-(pyridin-2-yl)acrylate (2.8 g) in methanol (150 ml) was added 10% palladium on carbon (230 mg) and the mixture was stirred under hydrogen gas atmosphere for 3 hours at room temperature and then filtered to remove an insoluble. Evaporation of solvent from the filtrate yielded ethyl 3-(pyridin-2-yl)propionate (2.5 g, 88%).
Reaction SMILES: [CH2:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:1]([CH2:3][C:4]([N:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: Ic1ccccc1
Reactant: CCCC(=O)Nc1ccccc1
Product: CCCC(=O)N(c1ccccc1)c1ccccc1
Yield: 56 %

Procedure:
Using 2-ethylacetanilide (4.9 g) and iodobenzene (12.4 ml), a reaction as made in the same manner as in 1) of Production Example 2. The subsequent purification by silica gel column chromatography (developing solvent, ethyl acetate:hexane=1:3) produced 2-ethyl-N-phenylacetanilide (4.0 g; yield, 56%) as a brown oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][C@@H:34]([CH3:38])[CH2:35][NH:36][CH3:37])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][C@@H:34]([CH3:38])[CH2:35][N:36]([CH3:37])[C:4](=[O:6])[CH2:3][O:2][CH3:1])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: COCC(=O)O
Reactant: CNC[C@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: COCC(=O)N(C)C[C@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 39 %

Procedure:
The procedure described in Example 1 was repeated using methoxyacetic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[(1S)-1-methyl-2-(methylamino) ethoxy]quinazolin-4-amine (obtained as described for the R-antipode in Example 2.3, preparation of starting materials) to give the title compound in 39% yield; NMR spectrum (DMSO-d6) 1.38 (d, 3H), 2.99 (s, 3H), 3.16 (s, 3H), 3.27 (1H obscured by H2O), 4.03 (s, 2H), 4.23 (m, 1H), 5.11 (m, 1H), 5.29 (s, 2H), 7.24 (m, 2H), 7.30 (d, 1H), 7.35 (m, 1H), 7.57 (d, 1H), 7.65, (dd, 1H), 7.71 (t, 1H), 7.86 (dt, 1H), 8.12 (d, 1H), 8.44 (s, 1H), 8.58 (d, 1H), 9.90 (s, 1H); Mass Spectrum MH+ 522.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:21]([OH:22])[C@H:20]([OH:23])[C@@H:19]([CH2:24][OH:25])[O:18][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][C:9]=1[O:16][CH3:17])(=[O:3])[CH3:2].[I-:26].[CH3:27][N+:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([CH3:38])=[CH:30][CH:29]=1.C([O-])(=O)C.[NH4+].N>C(O)C.C(Cl)(Cl)Cl.CO>[I-:26].[C:1]([NH:4][C@@H:5]1[C@@H:21]([OH:22])[C@H:20]([OH:23])[C@@H:19]([CH2:24][OH:25])[O:18][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:38][C:31]2[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[N+:28]([CH3:27])=[CH:29][CH:30]=2)=[CH:10][C:9]=1[O:16][CH3:17])(=[O:3])[CH3:2]
Reactant: COc1cc(C=O)ccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Reactant: Cc1cc[n+](C)c2ccccc12
Agent: CC(=O)[O-]
Agent: N
Agent: [I-]
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(C=Cc2cc[n+](C)c3ccccc23)ccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1NC(C)=O
Reaction time: 1.5 h

Procedure:
A stirred suspension of 4-formyl-2-methoxyphenyl 2-acetamido-2deoxy-β-D-glucopyranoside (1b)(0.25 g, 0.70 mmol), 1,4-dimethylquinolinium iodide (0.20 g, 0.70 mmol) in ethanol (20 ml) containing ammonium acetate (0.16 g, 2.1 mmol) and ammonia (conc.) (0.12 ml) was heated at 60°-70° C. The mixture soon turned orange and reaction was complete after 1.5 h as indicated by t.l.c. (chloroform-methanol, 5:4). The solid material was filtered off and washed sequentially with ethanol, acetone and ether to give (23b) as a fine yellow solid {0.34 g, 78%, m.p. 207°-212° C. (decomp.), [α]D +28° (c 1, DMOS)}(Found: C, 52.12; H, 5.01; N, 4.78. C27H31IN2O7 calc. C, 52.10; H, 5.02; N, 4.50%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: C1CCNCC1
Product: O=C(O)c1ccc(Cl)c(S(=O)(=O)N2CCCCC2)c1
Yield: 89 %

Procedure:
Compound 3.2 was prepared from 4-chloro-3-chlorosulfonyl-benzoic acid 2.2 and piperidine a1 in 89% yield according to general method B. MS (M−1)=302.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13](Cl)[N:12]=[C:11]([Cl:16])[N:10]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[Cl:16][C:11]1[N:10]=[C:9]([NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:14]=[C:13]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:12]=1
Reactant: Clc1ccc(Nc2nc(Cl)nc(Cl)n2)cc1
Reactant: Nc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ccc(Nc2nc(Cl)nc(Nc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 46 %

Procedure:
To a mixture of (4-chloro-phenyl)-(4,6-dichloro-[1,3,5]triazin-2-yl)-amine (3.97 g, 14.4 mmol), potassium carbonate (2.20 g, 15.9 mmol) and 18-crown-6 (46 mg, 0.17 mmol) in toluene (25 ml), cooled in an ice bath, was added a solution of aniline (1.4 ml, 15.4 mmol) in toluene (10 ml) over 15 minutes. After stirring at room temperature for 24 hours, the mixture was treated with ethyl acetate (35 ml) and filtered through a pad of celite under suction. The filtrate was concentrated under vacuum and the residue was recrystallized (chloroform) to give 6-Chloro-N-(4-chlorophenyl)-N′-phenyl-[1,3,5]triazine-2,4-diamine (2.20 g, 46% yield) as a white solid. 1H NMR (d6-DMSO) δ 10.1–10.4 (2H, br s), 7.5–7.8 (4H, br s), 7.3–7.5 (4H, m), 7.15–7.05 (1H, m), ESMS m/z 330 (M-H)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1B(O)O.I[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1
Reactant: OB(O)c1cc(F)c(F)cc1F
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(-c2cc(F)c(F)cc2F)cc1
Temperature: 50 °C
Yield: 74.8 %

Procedure:
A mixture of 2,4,5-trifluorophenylboronic acid (43.8 g, 249.2 mmol), 4-iodophenol (50 g, 226.5 mmol), potassium carbonate (78 g, 556.3 mmol), Pd(dppf)Cl2 methylene chloride complex (5.5 g, 6.8 mmol), DMF (150 mL), and water (38 mL) was degassed, purged with nitrogen, and heated at 50° C. overnight. The mixture was then diluted with EtOAc and water, acidified with conc. HCl under cooling with ice-water bath, stirred with charcoal, and filtered through Celite. The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered, and evaporated to afford a deep red oily crude product. The crude product in EtOAc was passed through silica gel to give 2′,4′,5′-trifluoro-biphenyl-4-ol as a light brown solid (38 g, 75%). LC-MS (ES) calculated for C12H7F3O, 224.18; found m/z 224 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH:30]1[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:10]=2[N:11]=[C:12]([NH:36][CH:33]2[CH2:34][CH2:35][NH:30][CH2:31][CH2:32]2)[N:13]=1
Reactant: CS(=O)(=O)c1nc(-c2ccccc2Cl)c2ccc(=O)n(-c3ccccc3Cl)c2n1
Reactant: NC1CCNCC1
Product: O=c1ccc2c(-c3ccccc3Cl)nc(NC3CCNCC3)nc2n1-c1ccccc1Cl

Procedure:
The product of Example 47, and piperidin-4-ylamine were reacted by the procedure of Example 60 to afford the title compound 4,8-bis-(2-chloro-phenyl)-2-(piperidin-4-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3) δ 1.21 (m, 2H), 1.84 (m, 2H), 2.38 (m, 2H), 3.01 (m, 2H), 3.30 (m, 1H), 5.36 (s, 1H), 6.40 (d, 1H, J=9.8 Hz), 7.20-7.62 (m, 9H). LC MS (m/e)=466 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[CH:9][NH:10][C:4]=2[CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1.Cl[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C.O.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[CH:9][N:10]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:4]=2[CH:3]=1
Reactant: Clc1cc2[nH]ccc2cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2cnc(Cl)cc21
Reaction time: 2 h

Procedure:
6-chloro-1H-pyrrolo[3,2-c]pyridine (1 g, 6.6 mmol) was dissolved in DMF (5 mL) under Ar and the solution was cooled in an ice water bath. A 1 M solution of NaHMDS in THF (7.5 mL, 7.5 mmol) was added over 1.5 min and the reaction mixture was stirred 20 min. (2-(chloromethoxy)ethyl)trimethylsilane (1.3 mL, 7.5 mmol) was then added and the reaction mixture was stirred for 2 h. The mixture was then diluted with water and DCM, and the aqueous phase was extracted with DCM (2×). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified by silica gel chromatography (0-50% EtOAc in hexanes) to afford 6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,2-c]pyridine. LCMS-ESI+ (m/z): [M+H]+ calcd for C13H20ClN2OSi: 283.10; found: 283.03.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[NH2:19][CH2:20][C:21]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[OH:26][C:21]1([CH2:20][NH:19][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCC1(O)CCCC1
Reactant: O=C(O)c1cc(OCC2CC2)c(C2CC2)cn1
Agent: Cl
Product: O=C(NCC1(O)CCCC1)c1cc(OCC2CC2)c(C2CC2)cn1

Procedure:
The title compound was synthesized in analogy to Example 54, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and 1-(aminomethyl)cyclopentanol hydrochloride (CAN 76066-27-8) as starting materials and isolated (71 mg, 63%) as a white solid; MS (ESI, m/z): 331.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Na].O>C(O)C>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: Cc1ccc2ccccc2n1
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC1CCc2ccccc2N1
Temperature: 25 °C

Procedure:
2-Methylquinoline (10 g, 0.070 mol) was refluxed in 250 ml ethanol. While refluxing, sodium (22.9 g, 1.0 mol) was added cautiously over a period of 1 hour. The mixture was refluxed for an additional 3.5 hours, cooled to room temperature, poured into 500 ml H2O, and extracted 3×500 ml toluene. The organic layers were combined, dried (K2CO3) and stripped to yield title produce as an oil, 9.2 g.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1>CN(C=O)C>[N:10]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][N:15]2[C:14]3[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=3[S:12][C:11]=12
Reactant: Nc1nc2ccccc2s1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(n1)sc1ccccc12
Temperature: 25 °C

Procedure:
Ethyl bromopyruvate (9.8 g, 50 mmol) was added dropwise to a stirred solution of 2-aminobenzothiazole (7.5 g, 50 mmol) in DMF (100 ml) at room temperature. After the addition, the reaction mixture was heated to reflux for 6 h. The reaction mixture was cooled to room temperature and quenched with ice cold water. The aqueous layer was neutralized with NH4OH and the separated solid was fitered. It was washed well with water and dried. The crude product obtained was taken to next step without purification.