Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[O:5][N:4]=1)[CH3:2].ClCl.[Cl:14]C(Cl)(Cl)Cl.O>C(O)(=O)C>[CH2:1]([C:3]1[C:7]([Cl:14])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[O:5][N:4]=1)[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCc1cc(NC(C)=O)on1
Agent: ClCl
Solvent: O
Solvent: CC(=O)O
Product: CCc1noc(NC(C)=O)c1Cl
Temperature: 25 °C
Yield: 203.3 %

Procedure:
3-Ethyl-5-acetylaminoisoxazole (1) (1.98 g) was dissolved in acetic acid (15 ml), chlorine-tetrachloromethane (18 ml, containing 1.09 g of chlorine) was added thereto under stirring at room temperature and after addition of water the mixture was extracted with chloroform after 5 minutes. The extract was washed with water, dried over sodium sulfate and evaporated. The resulting crystalline residue was recrystallized from ether/hexane to give 3-ethyl-4-chloro-5-acetylaminoisoxazole (2) (1.86 g), mp. 113°-114° C.
Reaction SMILES: CI.[C:3](=O)([O-])[O-].[K+].[K+].[Cl:9][C:10]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:33]([O-:35])=[O:34])=[C:17]([N:19]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[N:21]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:20]2=[O:32])[CH:18]=1.[Cl-].[NH4+]>CN(C)C=O>[Cl:9][C:10]1[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([N+:33]([O-:35])=[O:34])=[C:17]([N:19]2[C:24](=[O:25])[N:23]([CH3:3])[C:22](=[O:26])[N:21]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:20]2=[O:32])[CH:18]=1
Reactant: COC(=O)Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ccc(Cl)cc3Cl)ccc2[N+](=O)[O-])c1=O
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cn1c(=O)n(C)c(=O)n(-c2cc(Oc3ccc(Cl)cc3Cl)ccc2[N+](=O)[O-])c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (0.15 mL, 2.41 mmol) and potassium carbonate (0.19 g, 1.34 mmol) are added to a solution of methyl 3-[5-(2,4-dichlorophenoxy)-2-nitrophenyl]-tetrahydro-2,4,6-trioxo-s-triazine-1(2H)-acetate (0.40 g, 0.83 mmol) in N,N-dimethylformamide. The reaction mixture is stirred overnight at room temperature and poured into a saturated ammonium chloride solution. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a yellow oil. Column chromatography of the oil using silica gel and an ethyl acetate/hexanes (1:3) solution gives the title product as a yellow foam which is identified by NMR spectral analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([CH2:40][OH:41])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][CH2:37][CH:36]([CH2:40][OH:41])[CH2:35]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(c1ccccc1Br)N1CCCC(CO)C1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCCC(CO)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and racemic (1-((2-bromophenyl)sulfonyl)piperidin-3-yl)methanol. MS (ESI): mass calcd. for C22H23FN4O3S, 442.15; m/z found, 443.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.33 (d, J=8.7, 2H), 8.10-8.06 (m, 1H), 7.96 (m, 1H), 7.73-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.44-7.40 (m, 1H), 7.36-7.29 (m, 2H), 3.43-3.32 (m, 2H), 3.27-3.16 (m, 2H), 2.43-2.34 (m, 1H), 2.22-2.14 (m, 1H), 1.68-1.54 (m, 2H), 1.53-1.42 (m, 1H), 1.35-1.21 (m, 1H), 1.03-0.91 (m, 1H).
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH2:20][O:21]C(=O)C)[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:10]1=[N:11][C:12]([NH2:19])=[N:13][C:14]=2Cl)(=O)C.[OH-:25].[Na+]>Cl>[OH:4][CH2:5][CH:6]([CH2:20][OH:21])[CH2:7][CH2:8][N:9]1[CH:17]=[N:16][C:15]2[C:14](=[O:25])[NH:13][C:12]([NH2:19])=[N:11][C:10]1=2
Reactant: CC(=O)OCC(CCn1cnc2c(Cl)nc(N)nc21)COC(C)=O
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Yield: 85 %

Procedure:
A solution of 9-(4-acetoxy-3-acetoxymethyl-but-1-yl)-2-amino-6-chloropurine (15.5 g, 43.6 mmol) in 2 M hydrochloric acid (150 ml) was heated under reflux for 2 hours. The solution was then cooled to room temperature and neutralised with 10% sodium hydroxide solution, left to stand at 4° C., and the resulting precipitate filtered off, washed with cold water and recrystallized from water to give 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine as a white crystalline solid (9.4 g, 85%) mp 275°-277°.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:12])[S:4][N:3]=1.[CH2:13](Br)[CH:14]=[CH2:15]>>[CH3:12][C:5]1[S:4][N:3]=[C:2]([NH:1][CH2:13][CH2:14][CH3:15])[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: C=CCBr
Reactant: CCOC(=O)c1c(N)nsc1C
Product: CCCNc1nsc(C)c1C(=O)OCC

Procedure:
Ethyl 3-amino-5-methylisothiazole-4-carboxylate, prepared by the method of Hartke and Peshkar, Arch. Pharm.- Weinheim, 301(8), 611 (1968), is reacted with allyl bromide using the conditions described in Example 15A. This product is then hydrogenated using the procedure described in Example 15B to give ethyl 5-methyl-3-propylaminoisothiazole-4-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:18][CH:17]=[N:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[C:24](OC)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[S:18][C:17]([C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cncs2)CC1
Reactant: COC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2cnc(C(=O)c3ccccc3)s2)CC1
Reaction time: 0.33 h
Yield: 26.4 %

Procedure:
To 30 mg of 1-t-butyloxycarbonyl-4-(thiazol-5-yl)piperidine (prepared by method of example 291) in 3 ml THF at −78° C. was added 0.123 mmol of n-BuLi. The reaction was stirred for 20 min, then 18 mg of methyl benzoate was added. The reaction was stirred for 1 hr at −78° C. The solvent was evaporated under reduced pressure. The residue was dissolved in 1:1 MeOH:Et2O then purified by prep TLC with 1:1 hexane:EtOAc to give 11 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([OH:20])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:24].O>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([O:20][CH3:24])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-hydroxy-4-phenylpiperidine-1-carboxylic acid tert-butyl ester (7.1 g) in N,N-dimethylformamide (71 ml) was added 60% sodium hydride in mineral oil (1.13 g) under ice-cooling, and stirred for 1 hour at ambient temperature. The suspension was then stirred for 1.5 hours at 60° C. To the reaction mixture was added iodomethane (32 ml) at 40° C., and stirred for 30 minutes at 45° C. Water and ethyl acetate were added with stirring, and the organic layer was separated, washed with brine, dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography over silica using n-hexane/ethyl acetate (4:1) as the elution to give 4-methoxy-4-phenylpiperidine-1-carboxylic acid tert-butyl ester (6.63 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:29])([F:28])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:23]([CH2:24][C:25]([OH:27])=O)[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[N:16]=2)=[CH:11][CH:10]=1.[CH3:30][NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>O.CN(C)C=O>[CH3:30][N:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:25](=[O:27])[CH2:24][N:23]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[N:16]=[C:15]1[C:12]1[CH:13]=[CH:14][C:9]([C:8]([F:29])([F:28])[F:7])=[CH:10][CH:11]=1
Reactant: O=C(O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21
Reactant: CNc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C(=O)Cn1c(-c2ccc(C(F)(F)F)cc2)nc2cccnc21)c1ccccc1
Yield: 26.1 %

Procedure:
Under a nitrogen atmosphere, oxalyl chloride (1.91 g, 0.015 mole) was added dropwise (slowly) to a stirred and chilled (5°-10° C.) solution of 2-(4-trifluoromethylphenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (4.5 g, 0.014 mole) and anhydrous dimethylformamide (50 ml). The reaction mixture was heated at 55°-60° C. for 4 hours, cooled, and added dropwise to a stirred and chilled (5°-10° C.) solution of N-methylaniline (1.60 g, 0.015 mole), triethylamine (1.52 g, 0.015 mole), and anhydrous dimethylformamide (50 ml). The reaction mixture was stirred at room temperature overnight and then poured into water (300 ml). The mixture was extracted with methylene chloride (3×50 ml). The combined organic extracts were washed with potassium bicarbonate solution (2×30 ml), water (30 ml), dried over sodium sulfate and concentrated in vacuo. Recrystallization twice from isopropyl ether-petroleum ether gave 1.5 g (24%) of off-white needles, mp 158°-159° C.
Reaction SMILES: [C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]1)([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.[CH:25]1([CH2:30][C@H:31]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)[C:32](Cl)=[O:33])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[C:1]([Si:5]([CH3:16])([CH3:15])[O:6][CH2:7][CH2:8][N:9]1[CH:13]=[CH:12][C:11]([NH:14][C:32](=[O:33])[C@@H:31]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=2)[CH2:30][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)=[N:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
In a round bottom flask was placed 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (prepared in Example 67, 86 mg, 0.36 mmol), 2,6-lutidine (57 μL, 0.49 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionyl chloride in methylene chloride (prepared as in Example 102, ˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes) afforded (R)—N-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionamide (128 mg, 77%) as a white foam: [α]30589=−74.3° (c=0.14, methylene chloride); ES-HRMS m/e calcd for C25H37N3O2SiCl2 (M+H)+ 510.2105, observed 510.2105; 1H NMR (300 MHz, DMSO-d6) δ −0.09 (s, 6H, 2×SiCH3), 0.77 (s, 9H, 3×CH3), 1.10 (m, 2H, CH2), 1.35-1.80 (m, 8H, 4×CH2), 2.05 (m, 1H, CH), 3.81 (m, 1H, ArCHCO), 3.84 (t, J=5.4 Hz, 2H, OCH2), 4.04 (t, J=5.4 Hz, 2 H, NCH2), 6.40 (d, J=2.3 Hz, 1H, Ar), 7.34 (dd, Jm=2.1 Hz, Jo=8.3 Hz, 1H, Ar), 7.51 (d, J=2.3 Hz, 1H, Ar), 7.58 (d, Jo=8.3 Hz, 1H, Ar), 7.59 (d, Jm=2.1 Hz, 1H, Ar), 10.68 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:11])[N:5]=[C:4]([O:20]COCC[Si](C)(C)C)[C:3]=1[NH:29][C@@H:30]1[CH2:35][C@@H:34]2[CH2:36][C@@H:32]([C:33]2([CH3:38])[CH3:37])[C@H:31]1[CH3:39].Cl.CO>CO>[ClH:1].[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[O:11])[N:5]=[C:4]([OH:20])[C:3]=1[NH:29][C@@H:30]1[CH2:35][C@@H:34]2[CH2:36][C@@H:32]([C:33]2([CH3:38])[CH3:37])[C@H:31]1[CH3:39]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1c(OCOCC[Si](C)(C)C)nn(CC(=O)NCc3ccncc3)c(=O)c1Cl)C2(C)C
Agent: Cl
Solvent: CO
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1c(O)nn(CC(=O)NCc3ccncc3)c(=O)c1Cl)C2(C)C

Procedure:
2-[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}-3-{[2-(trimethylsilyl)ethoxy]methoxy}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (12 mg, 0.0208 mmol) in methanol (1 mL) was stirred with 10 mass % hydrogen chloride-methanol (5 mL) at 60° C. for 5 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure and purified by preparative HPLC to give the desired product.
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[N:19]([C:35]3[C:36]4[C@H:43]([CH3:44])[CH2:42][CH2:41][C:37]=4[N:38]=[CH:39][N:40]=3)[CH2:18]2)[CH2:14][CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[CH3:44][C@H:43]1[C:36]2[C:35]([N:19]3[C:20]4[C:25](=[C:24]([CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:23]=[CH:22][CH:21]=4)[C:15]4([CH2:14][CH2:13][NH:12][CH2:17][CH2:16]4)[CH2:18]3)=[N:40][CH:39]=[N:38][C:37]=2[CH2:41][CH2:42]1
Reactant: C[C@@H]1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: C[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c(CNC(=O)OC(C)(C)C)cccc43)c21
Yield: 77.7 %

Procedure:
Ammonium formate (1.82 g, 28.9 mmol) and 10% Pd/C (0.31 g, 20% weight) was added to a solution of (R)-tert-butyl (1′-benzyl-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (1.56 g, 2.89 mmol) in MeOH (28 mL). The mixture was allowed to stir at reflux for 4 hours. After cooling, the reaction mixture was filtered through Celite. The filtrate was evaporated in vacuo. The crude product was taken up in DCM, washed with saturated aqueous NaHCO3 solution and brine, dried and concentrated. The residue was puffed by column chromatography (5% 7N ammonia in MeOH/DCM) to give (R)-tert-butyl (1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methylcarbamate (1.01 g, 78%). LCMS (APCI+) m/z 450 [M+H]+; Rt=2.15 min.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1)(=O)C.[OH-].[Na+].[ClH:34]>C(Cl)Cl.CO.CO>[ClH:34].[OH:4][C:5]1[CH:6]=[C:7]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3[CH:27]=[CH:26][S:25][CH:24]=3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][N:10]=1
Reactant: COc1cc2c(Nc3ccc(C)c(OC(C)=O)c3)ncnc2cc1OCc1ccsc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc2c(Nc3ccc(C)c(O)c3)ncnc2cc1OCc1ccsc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 66 %

Procedure:
To a solution of 4-(3-acetoxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline (200 mg, 0.45 mmol) in methylene chloride/methanol (1/1) (20 ml) was added, a 2M aqueous sodium hydroxide solution (0.67 ml, 1.35 mmol). The mixture was stirred for 35 minutes at ambient temperature, the solvents were evaporated, water was added to the residue and the solution was extracted with ethyl acetate. The organic layer was washed with water, brine, then dried (MgSO4) and evaporated to give a white solid. This solid was then dissolved into a saturated solution of hydrochloric acid in methanol (10 ml) and stirred for 10 minutes. The solid product was filtered and dried under a vacuum, to give 4-(3-hydroxy-4-methylanilino)-6-methoxy-7-(3-thienylmethoxy)quinazoline hydrochloride (127 mg, 66%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[N:3]=1>[Zn].O1CCOCC1>[C:8]([C:7]1[CH:2]=[N:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)=[N:5][CH:6]=1)#[N:9]
Reactant: CCCc1ccc(-c2ncc(C#N)c(Cl)n2)cc1
Agent: [Zn]
Solvent: C1COCCO1
Product: CCCc1ccc(-c2ncc(C#N)cn2)cc1

Procedure:
5.0 G. of 4-chloro-5-cyano-2-(4-n-propylphenyl)-pyrimidine are boiled under reflux for 1 hour while stirring in 255 ml. of 50% dioxane with 22.4 g. of zinc dust (treated with hydrochloric acid and washed with water). Then, the zinc is separated and washed with dioxane. The filtrate and washings are freed from dioxane in vacuo and the aqueous suspension is extracted with methylene chloride. The extract is dried and concentrated and the residue chromatographed on silica gel. Elution with methylene chloride and methylene chloride/2% acetone yields the 5-cyano-2-(4-n-propylphenyl)-pyrimidine, which is recrystallized from acetone/hexane up to a constant melting point and sublimed at 120° C. in a high vacuum. There are obtained colorless crystals of melting point 125.9°-126.0° C, which on cooling are liquid crystalline (monotropic) at 106.4° C. The substance is identical with the compound obtained according to Example 6.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1)([O-])=O.NN>CCO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccco1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccccc1-c1ccco1

Procedure:
2-(2-Nitrophenyl)furan (0.51 g) was dissolved in 10 mL of EtOH. To this solution was added 0.07 g of 10% Pd/C and 1 mL of EtOH. This mixture was stirred and treated dropwise with 1.4 mL of 35% hydrazine. The suspension was filtered, and the filtrate was evaporated. The resulting residue was taken up in 50 mL of toluene and re-evaporated to give 2-(2-aminophenyl)furan. [This compound was reported in Smith et al.; J. Am. Chem Soc. 1953, 75, 6335.]
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH2:10])=O)[N:6]=1.P(Cl)(Cl)(Cl)=O>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]#[N:10])[N:6]=1
Reactant: NC(=O)Cc1csc(N)n1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCc1csc(N)n1

Procedure:
To a solution of 2.0 g (13.0 mmol) of 2-(2-Amino-thiazol-4-yl)-acetamide in 30 ml of dry DMF was added Phosphorus oxychloride (2.3 ml, 25.0 mmol, 2.0 equiv.) dropwise at 0° C.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.[Cl:9]N1C(=O)CCC1=O>C1C=CC=CC=1>[C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([S:7][Cl:9])=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc(S)cc1
Solvent: c1ccccc1
Product: Cc1ccc(SCl)cc1
Yield: 88.2 %

Procedure:
By the method of Preparation 5, 6.2 g. of p-toluenethiol (6.2 g., 50 mmoles) was reacted with N-chlorosuccinimide (6.67 g., 50 mmoles) in 100 ml. of benzene to yield p-toluenesulfenyl chloride (7.0 g.) as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C[O-].[Na+].O.[C:19](OCC)(=[O:21])C>O1CCCC1>[CH3:19][O:21][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C

Procedure:
1-Fluoro-4-nitro-2-trifluoromethylbenzene 67 (0.1 mol), was dissolved in tetrahydrofuran (100 mL). The solution was cooled to 0° C. and sodium methoxide (0.1 mol) was added. The reaction was warmed to room temperature over 2 hours. Water and ethyl acetate were added. The organic phase was dried and concentrated to afford 1-methoxy-4-nitro-2-trifluoromethylbenzene 68. This material was dissolved in methylene chloride (100 mL) and the solution was cooled to −78° C. Boron tribromide (0.1 mol) was added. The mixture was warmed to room temperature. Water was added, and the organic phase was dried and concentrated. Chromatography then afforded the title compound 69.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][C:15]#[N:16])[CH2:10]1)[CH3:8].O.[OH-].[Na+]>C1COCC1>[CH2:7]([N:9]1[CH2:13][CH2:12][C@@H:11]([CH2:14][CH2:15][NH2:16])[CH2:10]1)[CH3:8]
Reactant: CCN1CC[C@@H](CC#N)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCN1CC[C@@H](CCN)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 51.1 %

Procedure:
Lithium aluminium hydride (1.0 g) was added in portions to a stirred, cooled solution of 2-((S)-1-ethylpyrrolidin-3-yl)acetonitrile (Intermediate 204, 3.8 g) in THF (20 mL) at 0° C. On completion of the addition, the mixture was stirred at room temperature for 4 hours. Water was added cautiously, followed by addition of 15% aqueous sodium hydroxide solution and more water. The solid was filtered off and the filtrate was evaporated to dryness. The residue was dissolved in DCM, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 2-((R)-1-ethylpyrrolidin-3-yl)ethylamine (2.0 g) as a colourless oil, which was used without further characterisation.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[CH3:36][NH:37][C:38]([C:40]1([C:43]2[CH:48]=[CH:47][CH:46]=[C:45](Br)[N:44]=2)[CH2:42][CH2:41]1)=[O:39]>>[CH3:36][NH:37][C:38]([C:40]1([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([C:16]3[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]4[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[O:9][C:8]4=[O:10])[CH3:12])=[CH:18][CH:17]=3)[N:44]=2)[CH2:42][CH2:41]1)=[O:39]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CNC(=O)C1(c2cccc(Br)n2)CC1
Product: CNC(=O)C1(c2cccc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)n2)CC1
Yield: 74 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-ethyl}-1,3-oxazinan-2-one and 1-(6-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid methylamide following a procedure analogous to that described in Example 1. Yield: 74% of theory; LC (method 1): tR=1.96 min; Mass spectrum (ESI+): m/z=528 [M+H]+.