Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(C)[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:1]1([C:10]2[CH:9]=[CH:8][C:13]([OH:14])=[CH:12][CH:11]=2)([C:4]2[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccccc1O
Reactant: Oc1ccccc1
Product: Oc1ccc(C2(c3ccc(O)cc3)CCCCC2)cc1

Procedure:
The procedure of Example 1 was repeated, except that 10500 g (111.6 moles) of phenol was substituted for o-cresol. The crude crystals that separated out were rinsed with methylene chloride; after airdrying they weighed 5170 g or 87% of theoretical. Recrystallization from methanol-water yielded pure CDP, mp 188-189° C., that was 99.8% pure by gas chromatography.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]1[N:15]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:16]=[C:17]([CH3:19])[CH:18]=1)=[O:4].[OH-].[Li+]>>[CH3:13][S:10]([C@H:8]1[CH2:7][N:6]([C:14]2[N:15]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=3)[N:16]=[C:17]([CH3:19])[CH:18]=2)[C@H:5]([C:3]([OH:4])=[O:2])[CH2:9]1)(=[O:11])=[O:12]
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1c1cc(C)nn1-c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(N2C[C@H](S(C)(=O)=O)C[C@H]2C(=O)O)n(-c2ccc(C(F)(F)F)cc2)n1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-4-methanesulfonyl-1-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound which was used in the next step without further purification. MS (ESI): m/z=418.4 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]([CH:22]=[CH:23][CH:24]=1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1.O>[CH2:1]([O:8][C:9]1[C:10]([CH3:25])=[C:11]([CH:22]=[CH:23][CH:24]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(OCc2ccccc2)cccc1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(OCc2ccccc2)cccc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a solution of benzyl 3-(benzyloxy)-2-methylbenzoate (2.90 g) in methanol (50 ml) and THF (50 mL) was added a solution of sodium hydroxide (3.40 g) in water (50 mL), and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture and the mixture was concentrated. Water (30 ml) was added to the residue, and the mixture was adjusted with 2N hydrochloric acid to pH<2. The precipitated crystals were collected by filtration, and dried to give the title compound (2.00 g) as a white solid. This compound was used for the next step without further purification.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[CH:20]1[CH:25]=[CH:24][C:23]([C@H:26]([NH2:29])[CH2:27][OH:28])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>>[OH:28][CH2:27][C@@H:26]([NH:29][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1)[C:23]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@H](CO)c2ccccc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (S)-(+)-phenylglycinol and DIEA to give 2-((S)-2-hydroxy-1-phenyl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 376 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][N:3]=1.[CH2:11]([N:18]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22](Br)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:30]([N:18]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C@@H:19]1[CH2:28][CH2:27][C:26]2[C:21](=[C:22]([C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[N:7][CH:6]=3)[CH:23]=[CH:24][CH:25]=2)[CH2:20]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ncc(B(O)O)cn1
Reactant: Brc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CC2
Product: Cc1ncc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CC3)cn1
Yield: 58 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 58% yield, starting from (2-methylpyrimidin-5-yl)boronic acid and (2R)-N,N-dibenzyl-8-bromo -1,2,3,4-tetrahydronaphthalen-2-amine; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.68 (s, 2 H), 7.22-7.32 (m, 8 H), 7.11-7.21 (m, 4 H), 7.03 (dd, 1 H), 3.50-3.70 (m, 4 H), 2.88-3.02 (m, 2 H), 2.71 (s, 3 H), 2.66-2.83 (m, 2 H), 2.42-2.53 (m, 1 H, obscured by DMSO), 2.05-2.14 (m, 1 H), 1.64-1.79 (m, 1 H); MS (ESI) m/z 420[M+H+].
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=[O:26])C>O>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([NH2:23])=[O:26])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CCOC(C)=O
Solvent: O
Product: NC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Temperature: 25 °C
Yield: 26 %

Procedure:
4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (400 mg, 1.27 mmol) was treated with polyphosphoric acid at 80° C. overnight. After allowing the mixture to cool to room temperature, ethyl acetate and water were added. The organic layer was separated. The aqueous layer was basified to pH 10 with concentrated NaOH and extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered, concentrated in vacuo and purified by column chromatography on silica gel eluting to give the title compound (88 mg, 26%). 1H NMR (400 MHz, CDCl3) δ7.29 (d, 2H), 6.91 (d, 2H), 5.64-5.30 (d, 2H), 4.02 (t, 2H), 3.76 (t, 4H), 2.62 (t, 2H), 2.52 (m, 4H), 2.37-2.30 (m, 2H), 2.08-1.96 (m, 4H), 1.81-1.75 (m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][O:9][C:10]2=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][NH:15][CH3:16]>C(O)C>[OH:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]=1[C:10]([N:15]([CH3:16])[CH3:14])=[O:11]
Reactant: CNC
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Solvent: CCO
Product: CN(C)C(=O)c1cc([N+](=O)[O-])ccc1CO
Reaction time: 5 h

Procedure:
To a stirred solution of 6-nitrophthalide (2 g.) in ethanol (120 ml.) at room temperature was added dimethylamine (in ethanol 33.3% solution: 50 ml.). After stirring for 5 hours the solvent was evaporated off. The resulting gum was dissolved in ethyl acetate. On addition of petrol 60°-80° a white solid crystallised out.
Reaction SMILES: S([O-])([O-])(=O)=O.[Mg+2].[F:7][C:8]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:9]=1[NH2:10].[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.B.[Na]>CO.C(O)(=O)C>[CH2:16]([NH:10][C:9]1[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:8]=1[F:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=Cc1ccccc1
Agent: B
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: CO
Product: Fc1ccc(NCc2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
Magnesium sulfate (5.59 g) and a minor amount of acetic acid were added to a solution of 2,4-difluoroaniline (2.37 ml) and benzaldehyde (2.36 ml) in methanol (46 ml). The mixture was stirred at room temperature for 45 min. Sodium boron hydride (2.64 g) was added thereto under ice cooling, and the mixture was stirred at room temperature for one hr. The solvent was removed by distillation under the reduced pressure. Water and ethyl acetate were added to the residue. The mixture was stirred and was filtered through Celite. The organic layer was extracted with ethyl acetate and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with hexane/acetone (30/1) to give 3.04 g (yield 60%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[C:11](#[N:15])/[CH:12]=[CH:13]/[CH3:14]>CO>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([CH:13]([CH3:14])[CH2:12][C:11]#[N:15])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: C/C=C/C#N
Solvent: CO
Product: CC(CC#N)N1CCC2(CC1)OCCO2
Temperature: 50 °C
Yield: 100 %

Procedure:
To a solution of 1,4-dioxa-8-azaspiro[4.5]decane (8.00 g, 55.9 mmol) in MeOH (70 ml) was added crotononitrile (18.74 g, 279 mol). The mixture was heated at 50° C. for 16 hours. MeOH and excess crotononitrile were removed by evaporation under reduced pressure to give 3-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-butyronitrile (11.75 g, 100%) as a pale yellow oil.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][NH:16][CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2].[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]([CH:30]=O)[CH:21]=1>>[CH:1]([N:4]1[C:8]2[N:9]=[C:10]([C@H:14]3[C@H:18]([CH3:19])[CH2:17][N:16]([CH2:30][C:22]4[CH:21]=[N:20][C:29]5[C:24]([CH:23]=4)=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:15]3)[NH:11][C:12](=[O:13])[C:7]=2[CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=Cc1cnc2ccccc2c1
Reactant: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CNC[C@H]3C)nc21
Product: CC(C)n1ncc2c(=O)[nH]c([C@@H]3CN(Cc4cnc5ccccc5c4)C[C@H]3C)nc21

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-isopropyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and quinoline-3-carbaldehyde provided the title compound. 400 MHz 1H NMR (CD3OD) δ 11.0 (brs, 1H), 8.87 (d, J=2.1 Hz, 1H), 8.29 (s, 1H), 8.07 (d, J=8.3 Hz, 1H), 8.02 (s, 1H), 7.90-7.88 (m, 1H), 7.70-7.66 (m, 1H), 7.56-7.51 (m, 1H), 5.01-4.92 (m, 1H), 4.03-3.83 (m, 2H), 3.40 (t, J=8.7 Hz, 1H), 3.07 (d, J=9.5 Hz, 1H), 2.89-2.86 (m, 1H), 2.68-2.67 (m, 1H), 2.48-2.47 (m, 1H), 2.08-2.02 (m, 1H), 1.48 (dd, J=6.6, 16.59 Hz, 6H), 1.20 (J=7.1 Hz, 3H). MS: (M+H m/z 403.1).
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[CH:27][CH:26]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[C:31]([C:28]1[CH:27]=[CH:26][C:25]([C@H:24]2[CH:23]=[CH:22][N:21]([S:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=3)(=[O:20])=[O:19])[C:2](=[O:1])[C@H:3]2[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:30][CH:29]=1)(=[O:33])[CH3:32]
Reactant: COc1ccc(S(=O)(=O)N=C/C=C/c2ccc(C(C)=O)cc2)cc1
Reactant: CCOC(=O)/C=C/C=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C[C@@H]1C(=O)N(S(=O)(=O)c2ccc(OC)cc2)C=C[C@@H]1c1ccc(C(C)=O)cc1
Yield: 55 %

Procedure:
Prepared according to the general procedure from ethyl trans-4-oxo-2-butenoate and trans-N-(4-methoxybenzenesulfonyl)-1-(4-(3-iminoprop-1-enyl)phenyl)ethanone using 10 mol % 9 as the catalyst in 55% yield as a yellow oil. [α]D20 (c 1.22, CHCl3)=+168.2; 1H NMR (400 MHz, CDCl3) δ 8.04 (dd, 2H, J=6.9, 2.1 Hz), 7.59 (dd, 2H, J=6.5, 1.9 Hz), 7.19 (d, 1H, J=8.0 Hz), 7.07 (dd, 2H, J=6.9, 2.1 Hz), 6.69 (dd, 2H, J=6.6, 1.7 Hz), 5.59 (dd, 1H, J=8.0, 6.6 Hz), 4.14-4.11 (m, 2H), 3.95 (s, 3H), 3.74 (t, 1H, J=6.9 Hz), 3.58-3.53 (m, 1H), 2.58 (dd, 1H, J=17.4, 6.0 Hz), 2.52 (s, 3H), 1.90 (dd, 1H, J=17.4, 7.8 Hz), 1.22 (t, 3H, J=7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 197.5, 171.5, 168.6, 164.5, 142.3, 136.6, 131.4, 128.9, 128.2, 125.3, 114.3, 112.7, 94.6, 61.1, 56.1, 43.9, 41.7, 31.4, 26.7, 14.3; IR (thin film) ν 3020, 2983, 2842, 1723, 1682, 1594, 1497, 1363, 1267, 1167, 1091, 1024 cm−1; HRMS (ESI) calcd for C24H25NO7S [M+Na]+ 494.1243, found 494.1265; >99% ee (3S,4S)-isomer as determined by HPLC(OD-H, 4:1 hexanes/i-PrOH), tr (3S,4S)=28.6 min, tr (3R,4R)=35.1 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18](CC)(C)C)[CH:15]=[C:14](C(CC)(C)C)[C:13]=1[OH:28])([O-])=O.[N+](C1C=CC=CC=1N=NC1C=C(C)C=CC=1O)([O-])=O>[Ni].[Mo]>[OH:28][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[N:11]1[N:1]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:10]1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Agent: [Mo]
Agent: [Ni]
Agent: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Product: Cc1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 60.3 %

Procedure:
When using the procedure of Example 1, the 2-nitro-2'-hydroxy-3',5'-di-tert-amylazobenzene was replaced by an equivalent amount of 2-nitro-2'-hydroxy-5'-methylazobenzene and a total of 9% molybdenum-promoted Raney nickel catalyst was used, the above named compound was obtained in a 60.3% yield.
Reaction SMILES: [CH:1]1[C:5]2[CH2:6][CH:7]3[CH:12]([C:4]=2[S:3][CH:2]=1)[CH2:11][CH2:10][NH:9][CH2:8]3.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:9]1[CH2:10][CH2:11][CH:12]2[CH:7]([CH2:6][C:5]3[CH:1]=[CH:2][S:3][C:4]=32)[CH2:8]1)=[O:22])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: c1cc2c(s1)C1CCNCC1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC2c3sccc3CC2C1
Temperature: 22 °C
Yield: 71 %

Procedure:
A 0° C. solution of the product from step g) (874 mg, 4.05 mmol) in CH2Cl2 (20 ml) was treated with triethylamine (1.69 ml, 12.15 mmol) and ethyl chloroformate (466 μl, 4.86 mmol) and the reaction was warmed to 22° C. Next, the reaction mixture was diluted with CH2Cl2 (50 ml) and washed with brine (25 ml). The organic layer was dried (MgSO4) and solvent evaporated in vacuo leaving the crude product that was purified by silica-gel chromatography (hexanes:EtOAc-50:50) to give 722 mg (71%) of the subtitle compound. MS calculated for C13H17NO2S+H 252, observed 252.
Reaction SMILES: [C:1]1([N:7]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C:8](=[O:50])[CH2:9][C@@H:10]2[O:15]C(C)(C)O[C@H:12]([CH2:18][CH2:19][N:20]3[C:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[C:23]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:22]([C:38]([NH:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:39])=[C:21]3[CH:47]([CH3:49])[CH3:48])[CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C[OH:59]>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:20]([CH2:19][CH2:18][CH2:12][CH:11]([OH:59])[CH:10]([OH:15])[CH2:9][C:8]([N:7]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:50])[C:21]([CH:47]([CH3:49])[CH3:48])=[C:22]([C:38]([NH:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[O:39])[C:23]=2[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:26][CH:27]=1
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)N(c2ccccc2)c2ccccc2)OC(C)(C)O1
Reactant: CO
Agent: Cl
Product: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CCCC(O)C(O)CC(=O)N(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(4R-cis)-1-[2-[6-[2-(diphenylamino)-2-oxoethyl]-2,2-dimethyl-1,3-dioxan-4-yl]ethyl]-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide is dissolved in methanol (300 mL) and reacted by adding 1.0N hydrochloric acid (100 mL) and stirring for 12 hours at room temperature. The white crystalline solid [R-(R*,R*)]-5-(4-fluorophenyl)-β,γ-dihydroxy-2-(1-methylethyl)-N,N,4-triphenyl-3-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanamide is isolated by filtration (mp 228.5°-232.9° C., uncorrected). FTIR (KBr) 3400 (broad), 2850, 1640 cm-1 ;
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([N:8]([CH2:4][CH2:3][CH:2]=[CH2:1])[CH2:10][CH2:11][CH:12]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCCBr
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCN(CCC=C)Cc1ccccc1
Temperature: 50 °C
Yield: 151.8 %

Procedure:
12 g Benzylamine and 25 g 4-bromo-1-buten were added to a suspension of 46 g potassium carbonate in 150 mL DMF and the mixture was heated at 50° C. for 16 h. The reaction mixture was cooled to RT, diluted with ethyl acetate, washed with water and brine, dried, concentrated, and purified by chromatographie on silica gel (hexane/ethyl acetate 50:1) to yield 18.3 g of the desired product. (M+H)+: 230
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[Cl:26][C:27]1[C:32]([C:33]2[CH:38]=[CH:37][N:36]=[C:35](S(C)(=O)=O)[N:34]=2)=[CH:31][CH:30]=[CH:29][N:28]=1>O>[Cl:26][C:27]1[C:32]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)=[CH:9][CH:10]=3)[N:34]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CS(=O)(=O)c1nccc(-c2cccnc2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc(Nc3nccc(-c4cccnc4Cl)n3)cc2)CC1
Temperature: 70 °C

Procedure:
In a 48 mL sealed pressure vessel, was added 4-(4-methylpiperazin-1-yl)benzenamine (0.851 g, 4.45 mmol), potassium carbonate (1.03 g, 7.42 mmol), N,N-dimethylformamide (10 mL) and 4-(2-chloropyridin-3-yl)-2-(methylsulfonyl)pyrimidine (Step 1, 1.0 g). the vessel was heated to 70° C. for 22 hours, cooled to room temperature, diluted with water, extracted into ethyl acetate, washed 1× with water and 1× with NaCl solution. The organics were dried over magnesium sulfate, filtered through fritted Buchner funnel, and concentrated. The crude was chromatographed on silica gel using 15-60% 90:10:1 (CH2Cl2:MeOH:NH4OH/CH2Cl2) as a gradient. Concentrated the product fractions to yield 4-(2-chloropyridin-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidin-2-amine as a brown solid. MS (M+H)+=381. Calc'd 380.87 for C20H21ClN6.
Reaction SMILES: [F:1][CH:2]([F:18])[C:3]1([CH3:17])[C:8]2[O:9][C:10]3[CH:15]=[C:14](I)[CH:13]=[CH:12][C:11]=3[C:7]=2[CH2:6][CH2:5][NH:4]1.[F:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=1[S:27][Si](C(C)C)(C(C)C)C(C)C.[F-].[Cs+].C(O)CO.CN(C=O)C>[Cu]I>[F:1][CH:2]([F:18])[C:3]1([CH3:17])[C:8]2[O:9][C:10]3[CH:15]=[C:14]([S:27][C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([F:26])[C:20]=4[F:19])[CH:13]=[CH:12][C:11]=3[C:7]=2[CH2:6][CH2:5][NH:4]1
Reactant: CC1(C(F)F)NCCc2c1oc1cc(I)ccc21
Reactant: CC(C)[Si](Sc1cccc(F)c1F)(C(C)C)C(C)C
Agent: [Cu]I
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: OCCO
Product: CC1(C(F)F)NCCc2c1oc1cc(Sc3cccc(F)c3F)ccc21
Temperature: 105 °C
Yield: 135.5 %

Procedure:
Into a Schlenk flask equipped with a magnetic stir bar was added 1-difluoromethyl-7-iodo-1-methyl-1,2,3,4-tetrahydro-benzofuro[2,3-C]pyridine (enantiomer 1, 100 mg, 0.30 mmol), (2,3-difluorophenylsulfanyl)-triisopropylsilane (125 mg, 0.43 mmol), CsF (189 mg, 1.24 mmol), CuI (25 mg, 0.13 mmol), ethylene glycol (85 μL, 1.5 mmol) and anhydrous DMF (3 mL, 0.30 mmol). The Schlenck flask was evacuated and flushed with argon three times. The reaction mixture was heated at 105° C. under argon for 17 h. Upon cooling, the reaction was diluted with DCM, filtered through celite and solvent was evaporated. Purification using preparative TLC (2000 micron silica gfel plate; elution with 15% EtOAc in dichloromethane) afforded 155 mg of product as a viscous, pale oil. MS m/z: 382 [M+H]+.
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=O.CN1CCOCC1.ClC(OCC)=O.[NH2:29][C@H:30]([C:38]([NH:40][C@H:41]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([NH:29][C@H:30]([C:38]([NH:40][C@H:41]([C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:5]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OC(C)(C)C
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.05 h

Procedure:
Z-Gly-OH (25.2 g., 132 mM) was dissolved in DMF (300 ml.) and the solution was cooled to -10° C. N-methylmorpholine (14.8 ml., 132 mM) was added, followed by ethyl chloroformate (12.1 ml., 126 mM). After 3 minutes at -10° C., a solution of H-Phe-Leu-OBut (40.1 g., 120 mM) in DMF (100 ml.) was added, and the mixture was stirred at 0° C. overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate (600 ml.) and washed successively with water (2×60 ml.), 2 N-aqueous potassium bicarbonate (3×60 ml.), and water (3×60 ml.). The solution was dried (MgSO4) and filtered. The solvent was evaporated to give Z-Gly-Phe-Leu-OBut.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:24]=[C:23]([CH3:25])[S:22][C:13]=2[N:14]=[C:15]([C:17]2[O:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[O:21]1[C:17]([C:15]2[N:16]=[C:11]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:12]3[CH:24]=[C:23]([CH3:25])[S:22][C:13]=3[N:14]=2)=[CH:18][CH:19]=[N:20]1
Reactant: Cc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccc(F)cc1
Product: Cc1cc2c(NCc3ccc(F)cc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(isoxazol-5-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(4-fluorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:29])[N:7]2[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1.Cl>C(Cl)(Cl)Cl.O1CCOCC1.CO>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:7]2[C:8]3[C:3](=[C:2]([F:1])[CH:11]=[C:10]([F:12])[CH:9]=3)[CH:4]=[CH:5][C:6]2=[O:29])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC1CCN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
1,1-Dimethylethyl {1-[2-(5,7-difluoro-2-oxo-1(2H)-quinolinyl)ethyl]-4-piperidinyl}carbamate (2 g; 4.9 mmol) was dissolved in chloroform (20 ml) and 4M HCl in 1,4-dioxane added (20 ml), this was stirred at rt for 1 h. The salts were then dissolved in MeOH and all solvents removed. The residues were redissolved in MeOH and stirred with amberlyst ion exchange resin until neutral pH was reached, the resin was filtered off and solvents removed. The crude residues were purified by column chromatography on silica gel using a 0-20% 2M NH3:MeOH/DCM gradient to give the desired product (970 mg; 65%).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[N:17]=[C:18]([NH2:27])[C:19]2[CH:25]=[C:24](N)[CH:23]=[N:22][C:20]=2[N:21]=1.CC(O)=O.CCN(CC)CC>CN(C=O)C.O>[NH2:15][C:16]1[N:17]=[C:18]([NH2:27])[C:19]2[CH:25]=[C:24]([NH:14][CH:1]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:23]=[N:22][C:20]=2[N:21]=1
Reactant: Nc1cnc2nc(N)nc(N)c2c1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(N)c2cc(NC(c3ccccc3)c3ccccc3)cnc2n1

Procedure:
A solution of benzhydrylamine (366 mg, 2.0 mmol) and 2,4,6-triaminopyrido[2,3-d]pyrimidine (350 mg, 2.0 mmol) in a mixture of DMF (40 mL) and glacial AcOH (4 mL) is treated with BH3.Et3N (75 mg, 6.6 mmol), and the mixture is stirred at room temperature overnight, then diluted with H2O (20 mL) to decompose any unreacted reducing agent. The solvents are evaporated under reduced pressure, and the residue is purified on a silica gel column using 5-15% CHCl3 in MeOH as the eluent. Pooling and evaporation of appropriate fractions yields the title compound, N-(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)benzhydrylamine.