Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([C:21]1[CH:22]=[CH:23][C:18]([C:16]([O:15][CH3:14])=[O:17])=[CH:19][CH:20]=1)[CH:11]=[CH:10]2
Reactant: COc1ccc2nc(Cl)ccc2c1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc3cc(OC)ccc3n2)cc1
Temperature: 120 °C

Procedure:
A mixture of 2-chloro-6-methoxyquinoline (see U.S. 61/391,225 for synthesis) (200 mg, 1.0 mmol), 4-(methoxycarbonyl)phenylboronic acid (205 mg, 1.1 mmol), Pd(dppf)Cl2 (366 mg, 0.5 mmol) and sodium carbonate (212 mg, 2.0 mmol) in 1,4-dioxane/water (3 mL/0.6 mL) was heated to 120° C. by microwave for 1 h. The precipitates were filtered; washed with EtOAc (10 mL), acetone (10 mL) and water (10 mL) separately; dried to give the product as a black solid. (120 mg, 40.9%).
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH:6](CS([O-])(=O)=O)[CH2:5][O:4]2)[CH2:2]1.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]4[C:35](=[O:47])[N:36]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:37]([CH3:40])[C:38]=4[CH3:39])=[O:33])=[CH:27][C:26]=3[F:48])=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH2:2]1[C:3]2([CH2:7][CH:6]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18]([O:24][C:25]5[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]6[C:35](=[O:47])[N:36]([C:41]7[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=7)[N:37]([CH3:40])[C:38]=6[CH3:39])=[O:33])=[CH:27][C:26]=5[F:48])=[CH:19][CH:20]=[N:21]4)=[CH:16][CH:15]=3)[CH2:5][O:4]2)[CH2:1]1
Reactant: O=S(=O)([O-])CC1COC2(CC2)C1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC5COC6(CC6)C5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C

Procedure:
The title compound was prepared according to the procedure described in Example 6 by using (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (220 mg, 1.14 mmol), N-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (300 mg, 0.62 mmol), and cesium carbonate (450 mg, 2.4 mmol, Aladdin) in DMA (6 mL). The title compound was purified by a silica gel column chromatography (5:1 (v/v) EtOAc/n-hexane) and was obtained as a white solid (68 mg, 19%).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][O:7][CH2:8][C@:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:15][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH:10]=[CH:11][N+:12]([O-])=O>[Pt](=O)=O.CO>[F:36][C:2]([F:1])([F:37])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][O:7][CH2:8][C@:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O:15][Si:16]([CH2:19][CH3:20])([CH2:21][CH3:22])[CH2:17][CH3:18])[CH2:10][CH2:11][NH2:12]
Reactant: CC[Si](CC)(CC)O[C@](C=C[N+](=O)[O-])(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Agent: O=[Pt]=O
Solvent: CO
Product: CC[Si](CC)(CC)O[C@](CCN)(COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1
Reaction time: 2 h

Procedure:
A flask was charged with (S)-(1-(3,5-bis(trifluoromethyl)benzyloxy)-4-nitro-2-phenylbut-3-en-2-yloxy)triethylsilane (35 mg, 64 μmol), methanol (1.5 mL), and platinum dioxide (20 mg, 88 μmol). The flask was purged with hydrogen and stirred under a balloon of hydrogen for 2 h. The reaction was filtered through celite and concentrated. Column chromatography (5% methanol/dichloromethane) gave 20 mg (60%) as a colorless oil. Retention time: 1.98 min. (Phenomenex C18 3.0×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=2 min., Flow rate=5 mL/min.) Mass spec.: 522.16 (MH)+.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([NH2:13])=[C:4]([F:14])[CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][N:17]=1>C(Cl)Cl.CC(N(C)C)=O>[Br:1][C:2]1[C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:6][C:5]([NH:13][C:22](=[O:23])[C:19]2[CH:20]=[CH:21][C:16]([F:15])=[N:17][CH:18]=2)=[C:4]([F:14])[CH:3]=1
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: Nc1cc(OC(F)(F)F)c(Br)cc1F
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc(OC(F)(F)F)c(Br)cc1F)c1ccc(F)nc1

Procedure:
To a solution of 4-bromo-2-fluoro-5-trifluoromethoxy-phenylamine (500 mg, 2 mmol) dissolved in DCM (1 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (290 mg, 1.8 mmol) in DCM (1 mL). A few drops of DMA were added and the reaction mixture was concentrated to form N-(4-bromo-2-fluoro-5-trifluoromethoxy-phenyl)-6-fluoro-nicotinamide as a purple solid.
Reaction SMILES: O.[OH-].[Li+].CC([Si](C)(C)[O:9][C:10]1[CH:11]=[C:12]([CH:23]=[C:24]([O:26][C@@H:27]([CH3:37])[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH:25]=1)[C:13]([NH:15][C:16]1[CH:21]=[N:20][C:19]([CH3:22])=[CH:18][N:17]=1)=[O:14])(C)C>O.C1COCC1>[CH3:34][C:33]([Si:30]([CH3:31])([CH3:32])[O:29][CH2:28][C@@H:27]([O:26][C:24]1[CH:23]=[C:12]([CH:11]=[C:10]([OH:9])[CH:25]=1)[C:13]([NH:15][C:16]1[CH:21]=[N:20][C:19]([CH3:22])=[CH:18][N:17]=1)=[O:14])[CH3:37])([CH3:35])[CH3:36]
Reactant: Cc1cnc(NC(=O)c2cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)c2cc(O)cc(O[C@@H](C)CO[Si](C)(C)C(C)(C)C)c2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 0.1 %

Procedure:
Lithium hydroxide monohydrate (0.38 g, 9.12 mol) in water (20 mL) was added to a solution of 3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-5-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide (1.94 g, 3.65 mol) in THF (40 mL) and stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous layer was adjusted to pH7. Ethyl acetate (50 mL) and water (50 mL) were added then the aqueous layer re-extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered and reduced in vacuo. The crude material was chromatographed on silica, eluting with 20-50% ethyl acetate in isohexane, to give the desired material as a white solid (0.8 g). 1H NMR δ (CDCl3): 0.04 (s, 3H), 0.08 (s, 3H), 0.87 (s, 9H), 1.30 (d, 3H), 2.56 (s, 3H), 3.65-3.81 (m, 2H), 4.46-4.51 (m, 1H), 5.63 (s, 1H), 6.63 (t, 1H), 6.98 (t, 1H), 7.04 (t, 1H), 8.15 (s, 1H), 8.41 (s, 1H), 9.57 (s, 1H); m/z 418 (M+H)+
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[CH:25][NH:24][C:23]=1[CH:36]=O>C(O)C.N1CCCCC1>[CH3:21][C:22]1[C:26]([C:27]([N:29]2[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)=[O:28])=[CH:25][NH:24][C:23]=1[CH:36]=[C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:19])[F:20])[CH:4]=2)[NH:13][C:12]1=[O:18]
Reactant: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=O
Reactant: O=C1Cc2c(cccc2-c2cccc(C(F)(F)F)c2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(C(=O)N2CCN(C)CC2)c[nH]c1C=C1C(=O)Nc2cccc(-c3cccc(C(F)(F)F)c3)c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.9 %

Procedure:
To a solution of 4-(3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (61.2 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-(3-methyl-4-(4-methyl-piperazine-1-carbonyl)-1H-pyrrol-2-ylmethylene]-4 (3-trifluoromethyl-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (46.9 mg, 38%).
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>C1C=CC=CC=1>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]=[N:18][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[CH:5][C:4]=2[O:9]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: NC1CCCCC1
Solvent: c1ccccc1
Product: C(=NC1CCCCC1)c1ccc2c(c1)OCO2
Yield: 77.6 %

Procedure:
Piperonal (500 g) and cyclohexylamine (330 g) are dissolved in benzene, and the mixture is refluxed for about 3 hours while dehydrating with Diene Schtark device. The solvent is distilled off from the reaction mixture, and the residue is recrystallized from a mixture of isopropyl ether and hexane to give N-(3,4-methylenedioxybenzylidene)-N-cyclohexylamine (597 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(CCC)=CC(CCC)=CC=1CCC)(C)(C)C.[CH2:56]1[O:65][C:64]2[CH:63]=[CH:62][C:60]([NH2:61])=[CH:59][C:58]=2[O:57]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[O:65]1[C:64]2[CH:63]=[CH:62][C:60]([NH:61][C:2]3[CH:3]=[C:4]([C:8]4([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[CH2:12][O:11][C:10]([NH2:13])=[N:9]4)[CH:5]=[CH:6][CH:7]=3)=[CH:59][C:58]=2[O:57][CH2:56]1
Reactant: NC1=NC(c2ccccc2)(c2cccc(Br)c2)CO1
Reactant: Nc1ccc2c(c1)OCO2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(CCC)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: NC1=NC(c2ccccc2)(c2cccc(Nc3ccc4c(c3)OCO4)c2)CO1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
An oven dried pressure tube was charged with (RS)-4-(3-bromo-phenyl)-4-phenyl-4,5-dihydro-oxazol-2-ylamine (Building Block A, 100 mg, 0.315 mmol), sodium tert-butoxide (61 mg, 0.63 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-1-propyl-1,1′biphenyl (12 mg, 0.028 mmol), tris(dibenzylideneacetone)dipalladium (7 mg, 0.008 mmol) and 3,4-(methylendioxy)-aniline (86 mg, 0.631 mmol). After three vacuum-nitrogen cycles, toluene was introduced (0.7 mL), the tube was scaled and stirred at 100° C. for 16 hours. After cooling to room temperature, water (1 mL) and ethyl acetate (1 mL) were added. The organic fraction of the reaction mixture was placed on an SCX column. This was then washed with dichloromethane/methanol. The desired product was obtained by eluting with 2M ammonia in methanol. Fractions containing the compound were combined and the product purified further using preparative HPLC to yield 32 mg (26% yield) of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH3:30])[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([C:21]2[NH:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C=O)C.Br[CH2:37][C:38]#[CH:39]>[Cl-].[NH4+].C(OCC)(=O)C>[CH2:3]([N:10]([CH3:30])[C:11]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([C:21]2[N:22]([CH2:39][C:38]#[CH:37])[C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C#CCBr
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CCn1c(C(=O)N2CCC(C(=O)N(C)Cc3ccccc3)CC2)cc2ccccc21
Reaction time: 8 h

Procedure:
sodium hydride (12.78 mg, 0.320 mmol) was added to an oven dried flask and placed under nitrogen. It was then suspended in 1.0 mL of DMF. The suspension was placed in a 70° C. oil bath before adding N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (100 mg, 0.266 mmol) as a 0.5 mL DMF solution. The reaction was allowed to stir for 20 minutes before the addition of 3-bromoprop-1-yne (0.047 ml, 0.533 mmol) dropwise. The reaction was allowed to stir overnight. The reaction was cooled and diluted with saturated ammonium chloride and ethyl acetate. The organic layer was washed with saturated ammonium chloride followed by saturated sodium chloride. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The yellow crude material was purified via Biotage column 30-70% ethyl acetate:hexanes 4 gram silicycle column to obtain white solid. (Yield: 50 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.64-7.53, 7.40-7.05, 6.75-6.65, 5.16-5.04, 4.65, 4.58-3.99, 3.23, 3.10-2.93, 2.76, 1.85-1.52
Reaction SMILES: [C:1]([N:8]1[CH2:11][C:10](=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(O)(=O)C>[CH2:15]([N:14]([CH3:13])[CH:10]1[CH2:11][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)C1CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.6 %

Procedure:
To a solution of 1-Boc-azetidin-3-one 1d (1.0 g, 5.85 mmol) and N-methyl-benzylamine 6a (1.02 g, 8.43 mmol) in 1,2-dichloroethane (12 mL) and acetic acid (1 mL) was added Na(OAc)3BH (1.30 g, 6.13 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction was quenched by the addition of aq. NaHCO3. The resulting mixture was extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, 40% EtOAc/heptane) gave compound 6b (1.40 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23](=[O:32])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:21](Cl)[N:20]=[C:19]([C:34]#[N:35])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:37]1[C:39]2([CH2:44][CH2:43][CH:42]([CH2:45][NH2:46])[CH2:41][CH2:40]2)[CH2:38]1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[C:22]([C:23](=[O:32])[NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:21]([NH:46][CH2:45][CH:42]3[CH2:43][CH2:44][C:39]4([CH2:37][CH2:38]4)[CH2:40][CH2:41]3)[N:20]=[C:19]([C:34]#[N:35])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(Cl)c2C(=O)NCc2ccccc2)CC1
Reactant: NCC1CCC2(CC1)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2nc(C#N)nc(NCC3CCC4(CC3)CC4)c2C(=O)NCc2ccccc2)CC1
Temperature: 70 °C

Procedure:
To a solution of 4-[2-(5-benzylcarbamoyl-6-chloro-2-cyanopyrimidin-4-yloxy)ethyl]piperidine-1-carboxylic acid tert-butyl ester (0.23 mmol) in CH3CN (5 mL), C-spiro[2.5]oct-6-yl-methylamine hydrochloride (0.25 mmol) and K2CO3 (0.7 mmol) are added at room temperature. After warmed up to 70° C., the reaction mixture is stirred over night. The mixture is diluted with H2O and AcOEt, and extracted twice with AcOEt. The organic layer is dried over Na2SO4, filtered, and concentrated to give 4-(2-{5-benzylcarbamoyl-2-cyano-6-[(spiro[2.5]oct-6-ylmethyl)amino]pyrimidin-4-yloxy}ethyl)piperidine-1-carboxylic acid tert-butyl ester as a white solid; 1H-NMR (CDCl3), δ 0.17-0.30 (4H, m), 0.89-1.06 (4H, m), 1.14-1.38 (3H, m), 1.46 (9H, s), 1.49-1.79 (9H, m), 2.51 (2H, br t), 3.42 (2H, t), 4.00 (2H, m), 4.45 (2H, t), 4.55 (2H, d), 7.30-7.39 (5H, m), 8.12 (1H, t), 10.16 (1H, t).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[OH-].[Na+].[N+:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)([O-:11])=[O:10]>>[N+:9]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:17])=[CH:19][CH:20]=1)([O-:11])=[O:10]
Reactant: C[C@H](N)C(=O)O
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)O

Procedure:
A solution of 7 g. alanine in 65 ml. of 10% aqueous sodium hydroxide solution was treated portionwise, while stirring, with 12.5 g. finely powdered 4-nitrobenzoyl chloride. The reaction mixture was stirred at 5° C. for 20 hours, acidified and the precipitate isolated, washed with water and suction dried. Repeated fractional crystallisation from acetone-diethyl ether (2:1 v/v) gave 4-nitrobenzoylalanine; m.p. 199°-200° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:18])=[C:10]([CH2:12][CH:13]([CH3:17])[C:14](Cl)=[O:15])[CH:11]=1>ClCCl>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:18])=[C:10]2[C:11]=1[C:14](=[O:15])[CH:13]([CH3:17])[CH2:12]2
Reactant: Cc1ccc(Br)cc1CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(Br)c2c1CC(C)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To a stirred suspension of 49.5 g (0.371 mol, 1.2 eq.) of AlCl3 in 300 ml of dichloromethane a solution of 85.3 g (0.310 mol) of 3-(5-bromo-2-methylphenyl)-2-methylpropanoyl chloride in 50 ml of dichloromethane was added dropwise. This mixture was stirred overnight at room temperature and then poured on 500 g of ice. The organic layer was separated, and the aqueous layer was additionally extracted with 3×75 ml of dichloromethane. The combined organic extract was washed by aqueous K2CO3, dried over K2CO3, passed through a short pad of silica gel, and then evaporated to dryness. This procedure gave 74.0 g (>99%) of 7-bromo-2,4-dimethylindan-1-one as a light-orange liquid, solidified at room temperature, which was further used without an additional purification.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[CH:18]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([CH3:32])=[C:17]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[CH:18]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: COc1ccc(C(=O)Nc2cc(N)ccc2C)cc1OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3ccc(CCl)cc3)ccc2C)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
4-(Chloromethyl)benzoyl chloride (0.73 g) was added dropwise to a stirred mixture of N-(5-amino-2-methylphenyl)-3,4-dimethoxybenzamide (1 g), triethylamine (0.98 ml) and methylene chloride (80 ml) and the mixture was stirred at ambient temperature for 16 hours. A 1N hydrochloric acid solution (10 ml) was added and the resultant solution was stirred at ambient temperature for 1 hour. The resultant white solid was filtered off, washed with water and with diethyl ether, dried under vacuum at 40° C. to give the title compound (1.35 g); NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 3.82 (s, 6H), 4.82 (s, 2H), 7.06 (d, 1H). 7.21 (d, 1H). 7.58 (m, 5H), 7.81 (s, 1H), 7.94 (d, 2H), 9.76 (s, 1H), 10.23 (s, 1H);
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:15](Br)=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:20])([CH3:19])[C:8]=2[CH:7]=1.[Cl-].[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][Zn+]>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[C:15]([CH2:25][C:24]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:23]=2[F:22])=[CH:14][C:13]2[C:12]([CH3:18])([CH3:17])[CH2:11][CH2:10][C:9]([CH3:20])([CH3:19])[C:8]=2[CH:7]=1
Reactant: Fc1ccc(C[Zn+])c(F)c1
Reactant: CC1(C)CCC(C)(C)c2cc(C3OCCO3)c(Br)cc21
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(C3OCCO3)c(Cc3ccc(F)cc3F)cc21
Yield: 85.7 %

Procedure:
To a mixture of 2-(1,3-dioxolan-2-yl)-3-bromo-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene (250 mg, 0.74 mmol) and tetrakis(triphenylphospine)palladium(0) (21 mg, 0.018 mmol) under an argon atmosphere was added a 0.5 M tetrahydrofuran solution of 2,4-difluorobenzylzinc chloride (7.3 mL, 3.68 mmol). The reaction was stirred at reflux overnight and partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified by preparative thin layer chromatography on silica gel (5% ethyl acetate/hexane) to give 2-(1,3-dioxolan-2-yl)-3-(2,4-difluorobenzyl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene as a white crystalline solid (245 mg, 96%).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C1C(=O)N([Cl:22])C(=O)C1.CO>CN(C=O)C>[Cl:22][C:5]1[N:4]([CH2:1][CH:2]=[CH2:3])[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=1
Reactant: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CO
Product: C=CCn1c(Cl)nc2[nH]c(=O)[nH]c(=O)c21
Temperature: 20 °C
Reaction time: 6 h
Yield: 62 %

Procedure:
To a solution of 7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione) (10.52 g, 54.7 mmol) in anhydrous DMF (60 ml) was added NCS (8.04 g, 60.2 mmol). The reaction mixture was left to stir under nitrogen at 20° C. for 6 hours. The reaction mixture was concentrated in vacuo to give an amber oil. MeOH was added and left to stand for 18 hours. The resulting residue was filtered and dried under vacuum to give the title compound (7.69 g, 62%). m/z 227.2 [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>C(O)C>[Cl:10][C:9]1[CH:8]=[CH:7][C:4](/[CH:5]=[CH:14]/[N+:11]([O-:13])=[O:12])=[CH:3][C:2]=1[Cl:1]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])/C=C/c1ccc(Cl)c(Cl)c1
Yield: 38.4 %

Procedure:
Using analogous conditions and workup as described for the preparation of intermediate I-1a above, 3,4-dichlorobenzaldehyde (10 g, 74.074 mmol) in ethanol (100 mL) was reacted with nitro methane (4.12 mL, 74.074 mmol) and 10N NaOH (2.96 g in 7.4 mL of H2O, 74.074 mmol) to afford 6.2 g of the product (39% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][C:12]=3[CH:22]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][C:12]=3[CH:22]=2)=[CH:23][CH:24]=1
Reactant: COC(=O)C1=Cc2cc(OCc3ccc(C)cc3)ccc2CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(COc2ccc3c(c2)C=C(C(=O)O)CCC3)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
To methyl 2-(4-methylbenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (2.34 g, 7.26 mmol) dissolved in a mixed solvent of methanol (25 ml) and THF (25 ml) was added a 1N aqueous solution of sodium hydroxide (23 ml), and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was mixed with 1 N hydrochloric acid (23 ml) at room temperature, was concentrated under reduced pressure and was mixed with water, and an insoluble material was collected by filtration. The insoluble material was washed successively with water and hexane, and was dried under reduced pressure to obtain 2-(4-methylbenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (2.11 g, 6.84 mmol, 94%).
Reaction SMILES: N[C@H](C(O)=O)[C@@H](C)O.N1CCC[C@H]1C(O)=O.C([S:20][CH2:21][CH:22]([CH2:33][S:34]C(=O)C)[C:23]([NH:25][C@H:26]([C:30]([OH:32])=[O:31])[C@@H:27]([CH3:29])[OH:28])=[O:24])(=O)C>>[SH:20][CH2:21][CH:22]([CH2:33][SH:34])[C:23]([NH:25][C@H:26]([C:30]([OH:32])=[O:31])[C@@H:27]([CH3:29])[OH:28])=[O:24]
Reactant: CC(=O)SCC(CSC(C)=O)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Agent: C[C@@H](O)[C@H](N)C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: C[C@@H](O)[C@H](NC(=O)C(CS)CS)C(=O)O

Procedure:
By substituting L-threonine for the L-proline in the procedure of Example 3B, and then submitting the product to the procedure of Example 4, N-[2-(acetylthiomethyl)-3-(acetylthio)propanoyl]-L-threonine and 1-[2-(mercaptomethyl)-3-mercaptopropanoyl]-L-threonine are obtained.