Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(NC(C)C)(C)C.[Li].[N:16]1([C:20]2[C:29]3[C:24](=[N:25][C:26](Cl)=[C:27]([Cl:30])[N:28]=3)[N:23]=[C:22]([Cl:32])[N:21]=2)[CH2:19][CH2:18][CH2:17]1.O>O1CCCC1>[N:16]1([C:20]2[C:29]3[C:24](=[N:25][C:26]([O:1][CH:2]4[CH2:7][CH2:6][O:5][CH2:4][CH2:3]4)=[C:27]([Cl:30])[N:28]=3)[N:23]=[C:22]([Cl:32])[N:21]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: Clc1nc(N2CCC2)c2nc(Cl)c(Cl)nc2n1
Reactant: OC1CCOCC1
Agent: [Li]
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Clc1nc(N2CCC2)c2nc(Cl)c(OC3CCOCC3)nc2n1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 42.8 %

Procedure:
a)+b) 56 μl (0.59 mmol) 4-hydroxytetrahydropyran are dissolved in 2 ml of tetrahydrofuran and under protective gas at −10° C. mixed with 293 μl (0.59 mmol) of a 2 molar solution of lithium diisopropylamine in tetrahydrofuran. The mixture is stirred for 30 minutes at −10° C., then for one hour at ambient temperature. The mixture is cooled to −10° C. again and combined with a suspension of 170 mg (0.59 mmol) 4-azetidin-1-yl-2,6,7-trichloro-pteridine in 5 ml of tetrahydrofuran. The mixture is stirred for one hour at −10° C., slowly allowed to come up to ambient temperature and stirred for approx. another 16 hours. The reaction mixture is mixed with water and extracted with dichloromethane. The organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. The residue is purified by chromatography (reversed phase). 90 mg of 4-azetidin-1-yl-2,6-dichloro-7-(tetrahydropyran-4-yloxy)-pteridine are obtained, which is dissolved in 5 ml dioxane and slowly added dropwise to a solution of 109 mg (1.27 mmol) piperazine in 5 ml dioxane at a temperature of 80° C. The mixture is stirred for approx. another 1 hour at 80° C., cooled to ambient temperature and the reaction mixture is combined with water. It is extracted with dichloromethane, the organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. Yield 70 mg (68% of theoretical)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:18][CH2:17][C@@H:16]2[CH2:19][C@H:13]1[C:14](=[O:27])[N:15]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[BH4-].[Na+].[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:18][CH2:17][C@@H:16]([NH:15][C:20](=[O:21])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:19][C@H:13]1[CH2:14][OH:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.2 %

Procedure:
A solution of (1R,2S,5R)-tert-butyl 2-(benzyloxycarbonylamino)-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate (2.0 g, 5.34 mmol) in tetrahydrofuran (40 mL) was treated with water (8 mL) and then with NaBH4 (1.01 g, 26.7 mmol). The mixture was stirred at rt for 5 h, then was treated with aqueous NaOH (1.0 M, 100 mL) and stirred for 60 min. The mixture was extracted four times with ethyl acetate. The combined extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated under vacuum. The residue was recrystallized from ethyl acetate-hexane to provide tert-butyl (1R,3R,4S)-4-benzyloxycarbonylamino-3-(hydroxymethyl)cyclohexylcarbamate as a white solid (1.438 g). MS found: (M+H)+=379.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][C:37]([F:40])([F:39])[F:38])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:31][CH:32]3[CH2:34][CH2:33]3)[C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:35])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][C:37]([F:40])([F:38])[F:39])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH2:31][CH:32]3[CH2:33][CH2:34]3)[C:15]([NH:17][C:18]3[CH:30]=[CH:29][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)=[O:16])[C:10](=[O:35])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)C(CC2CC2)n2ccc(-c3cc(Cl)ccc3OC(F)(F)F)cc2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(NC(=O)C(CC2CC2)n2ccc(-c3cc(Cl)ccc3OC(F)(F)F)cc2=O)cc1

Procedure:
77 mg (purity 92%, 0.12 mmol) of tert-butyl 4-[(2-{4-[5-chloro-2-(trifluoromethoxy)phenyl]-2-oxopyridin-1(2H)-yl}-3-cyclopropylpropanoyl)amino]benzoate (racemate) (Example 6.2C) were hydrolysed with TFA according to General Method 2. Yield: 41 mg (64% of theory)
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.I.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](SC)=[NH:24].N>CCO.CO>[CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:23]([C:19]3[S:18][CH:22]=[CH:21][CH:20]=3)=[NH:24])=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: CSC(=N)c1cccs1
Reactant: CN(C)CCN1CCCc2cc(N)ccc21
Agent: I
Agent: N
Solvent: CO
Solvent: CCO
Product: CN(C)CCN1CCCc2cc(NC(=N)c3cccs3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1-(2-(dimethylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-amine (900 mg, 4.10 mmol) in 25 mL EtOH was treated with methyl thiophene-2-carbimidothioate hydroiodide (2.34 g, 1.43 mmol) and stirred overnight at room temperature. Argon was bubbled through the mixture for 20 minutes then it was partitioned between CH2Cl2 (100 mL) and saturated sodium bicarbonate (20 mL). The organic layer was separated and the aqueous layer was extracted with an additional 50 mL CH2Cl2. The combined organic layers were rinsed with water, dried over sodium sulfate, filtered and concentrated to give a dark oil which was subjected to flash chromatography on silica gel using 5% MeOH/CH2CH2then 5% 2M NH3 in MeOH/CH2C12 to give an orange solid. 1H-NMR (DMSO-d6) δ: 7.66 (d, J=3.6 Hz, 1H), 7.55 (d, J=4.8 Hz, 1H), 7.08-7.05 (m, 1H), 6.57-6.48 (m, 3H), 6.25 (brs, 2H), 3.29-3.21 (m, 4H), 2.65 (t, J=6.3 Hz, 2H), 2.39 (t, J=6.3 Hz, 2H), 2.19 (s, 6H), 1.85-1.82 (m, 2H).
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:5]=[CH:6][C:7]([C@@H:10]([NH2:12])[CH3:11])=[N:8][CH:9]=1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([CH3:21])=[CH:16][N:15]=1.C(N(C(C)C)CC)(C)C>C(O)CCC.C(OCC)(=O)C>[Cl:13][C:14]1[N:19]=[C:18]([NH:12][C@H:10]([C:7]2[CH:6]=[CH:5][C:4]([F:3])=[CH:9][N:8]=2)[CH3:11])[C:17]([CH3:21])=[CH:16][N:15]=1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: Cc1cnc(Cl)nc1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc(Cl)nc1N[C@@H](C)c1ccc(F)cn1
Temperature: 110 °C
Yield: 60.9 %

Procedure:
A mixture of (S)-1-(5-fluoropyridin-2-yl)ethanamine dihydrochloride (prepared as described in WO2006/123113, 560 mg, 2.63 mmol), 2,4-dichloro-5-methylpyrimidine (620 mg, 2.63 mmol) and diisopropylethylamine (1.4 mL, 7.9 mmol) in n-butanol (1 mL) was stirred and heated for 45 min at 110° C. in a microwave oven. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate. The organic solution was washed with water and brine, dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography (2:1 hexanes/ethyl acetate) to give the title compound (427 mg, 61%) as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:20](B3OC(C)(C)C(C)(C)O3)=[N:19][N:18]([C:30]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:15]2=[N:16][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O.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]>[Cl:11][C:12]1[CH:13]=[C:14]2[C:20]([C:2]3[N:7]=[C:6]([S:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=3)=[N:19][N:18]([C:30]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:15]2=[N:16][CH:17]=1
Reactant: CSc1nc(Cl)ncc1F
Reactant: CC1(C)OB(c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(Cl)cc23)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CSc1nc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ncc(Cl)cc23)ncc1F
Temperature: 125 °C

Procedure:
A mixture of 2-chloro-5-fluoro-4-methylsulfanyl-pyrimidine (0.26 g, 1.44 mmol) and 5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-pyrazolo[3,4-b]pyridine, 33, (0.75 g, 1.44 mmol) and K3PO4 (0.96 g, 4.53 mmol) in water (1.5 mL) and 2-Me-THF (7.5 mL) was degassed with nitrogen bubbling for 15 min. Then, X-Phos (0.07 g, 0.14 mmol) and Pd2(dba)3 (0.03 g, 0.04 mmol) was added and the vessel was sealed and heated to 125° C. with microwave irradiation for 30 min. After cooling to room temperature, water was added and the mixture was extracted and with ether and 2-Me-THF. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-100% EtOAc-hexanes, gradient elution) provided 230 mg of the desired product which was used without further purification: LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=3.46 min (M+H) 538.01.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C@H:9]([C:11](=[O:30])[NH:12][C@H:13]([C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[CH:28]=O)=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][C:33]=1[NH2:42].C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:31])[N:7]([CH3:8])[C@H:9]([C:11](=[O:30])[NH:12][C@H:13]([C:17]([N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21][C@H:20]1[CH2:28][NH:42][C:33]1[CH:34]=[CH:35][C:36]2[C:41](=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:32]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])[CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C=O
Reactant: Nc1ccc2ccccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CNc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
To a stirred solution of {(S)-1-[(S)-1-((S)-2-formyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (30 mg, 0.07 mmol) in dry MeOH (1.0 mL) was added 2-napthylamine (20 mg, 0.14 mmol) was the reaction was stirred at rt for 18 h. Acetic acid was added to adjust to pH ˜4. NaCNBH3 (8.7 mg, 0.139 mmol) was added and the reaction was stirred at rt for 18 h. The reaction mixture was concentrated in vacuo. The residue was taken up in EtOAc (25 mL) and washed with saturated aqueous NaHCO3 (10 mL×2), water (10 mL×2) and brine (4 mL×2) and concentrated in vacuo. The crude material was purified by preparative HPLC (X Bridge Prep C18 (250×19 0 mm) 5μ, acetonitrile and 5 mM NH4OAc) to give methyl-((S)-1-{(S)-2-methyl-1-[(S)-2-(naphthalen-2-ylaminomethyl)-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl]-propylcarbamoyl}-ethyl)-carbamic acid tert-butyl ester (32 mg), m/z=560 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:11][CH2:12][CH2:13][NH2:14].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:14][CH2:13][CH2:12][F:11])=[O:9]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: NCCF
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCF)c1cncc(Br)c1

Procedure:
2.03 g (10 mmol) 5-bromonicotinic acid, 1 g (1 eq.) 2-fluoroethylamine, 2.31 g (1.2 eq.) EDC.HCl, 123 mg (0.1 eq.) DMAP and 5.6 mL (4 eq.) triethylamine are stirred in 60 mL dichloromethane for 20 hours at room temperature. The reaction mixture is extracted with dichloromethane and water, the combined organic phases are washed with brine, dried with sodium sulfate and evaporated. The residue is triturated in diethylether and hexane to yield after filtration the desired product as a white powder. MS(ES+): 347 and 349 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:14]C)([CH3:4])([CH3:3])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)O)ccc1C(C)(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)O)cc1O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 4-tert-butyl-3-methoxy-benzoic acid (400 mg, 1.92 mmol) in anhydrous DCM (9 mL) under N2 at −78° C. was added BBr3 (5.76 mL of 1M in DCM, 5.763 mmol) dropwise over 30 minutes. The mixture was allowed to stir at −78° C. for 1 hour, allowed to warm to room temperature over 1 hour and then stirred at room temperature for 1 hour. The mixture was poured onto crushed ice and was stirred for 10 minutes. The organic layer was removed and the aqueous layer was extracted with DCM (3×). The combined organics were combined, dried over Na2SO4 and then concentrated under reduced pressure to give 4-tert-butyl-3-hydroxybenzoic acid. ESI-MS m/z calc. 194.1. found 195.1 (M+1)+; Retention time: 1.45 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 12.50 (s, 1H), 9.71 (s, 1H), 7.39 (d, J=1.1 Hz, 1H), 7.32 (dd, J=8.0 Hz, 1.1 Hz, 1H), 7.24 (d, J=8.1 Hz, 1H), 1.35 (s, 9H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[CH2:22][CH2:23][NH2:24].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C(O)C>[O:8]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH:24][CH2:23][CH2:22][C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([O:18][CH3:17])[CH:20]=2)=[CH:15][CH:16]=1)[C:1]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc(CCNCc2ccc(Oc3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A solution of 4-benzoxybenzaldehyde (2.5 g, 12.6 mmol), 3-methoxyphenethyl amine (1.9 g, 12.6 mmol), a catalytic amount of p-toluenesulfonic acid monohydrate in absolute ethanol (12 mL) was stirred at 80° C. for 1.5 hours. After cooling to room temperature, NaBH4 (0.49 g, 13.0 mmol) was added in portions. The reaction mixture was stirred at 80° C. for 1 hour, then cooled to room temperature, and the ethanol was removed in vacuo. Water was added to the residue and the mixture was extracted with ethyl acetate. The combined extracts were washed with saturated NaCl, dried over MgSO4, filtered, and solvent removed in vacuo to afford a colorless oil which was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane saturated with NH3 to afford the title compound (3.2 g, 76%) as a colorless oil. MS (DCl/NH3) m/e 334 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ2.82 (t, 2H), 2.92 (t, 2H), 3.77 (s, 2H), 3.80 (s, 3H), 6.80 (m, 3H), 6.98 (m, 3H), 6.08 (t, 1H), 7.22 (m, 3H), 7.32 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(Cl)(=O)C(Cl)=O.CS(C)=O>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCC=Cc1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CC=Cc1ccc(Cl)c(Cl)c1
Yield: 90.9 %

Procedure:
3-(3,4-Dichlorophenyl)prop-2-en-1-ol(1.0 g)(prepared by analogy to Example 2(i) and Example 1(ii)) was oxidised using the procedure of Swern (oxalyl chloride, 0.5 ml; dimethyl sulphoxide, 0.7 ml; triethylamine 3.4 ml) to give 3-(3,4-dichlorophenyl)-prop-2-enal (0.9 g). NMR 1H: 9.76(1H,d), 7.53(3H,m), 7.41(1H,d), 6.68(2H,dd).
Reaction SMILES: [ClH:1].C(O)(=O)/C=C\C(O)=O.C1(C2[O:21][C:20]3[CH:22]=[CH:23][C:24]([CH:26]([OH:33])[CH2:27][NH:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[N:25][C:19]=3[CH2:18][O:17]2)C=CC=CC=1>CO>[ClH:1].[ClH:1].[OH:17][CH2:18][C:19]1[C:20]([OH:21])=[CH:22][CH:23]=[C:24]([CH:26]([OH:33])[CH2:27][NH:28][C:29]([CH3:31])([CH3:30])[CH3:32])[N:25]=1
Reactant: CC(C)(C)NCC(O)c1ccc2c(n1)COC(c1ccccc1)O2
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc(O)c(CO)n1

Procedure:
To a solution of methanol (11.3 l.)--hydrogen chloride gas (620 g., 17 moles) at 20° C. is added, with stirring, 2-phenyl-6-(1-hydroxy-2-t-butylaminoethyl)-4-H-pyrido-[3,2-d]-1,3-dioxin maleate (1880 g., 4.24 moles) over a five minute period. The resulting solution is then stirred for 2 hours at 20°-25° C. and is then concentrated under reduced pressure to a volume of about 3 liters. Acetone (16 liters) is added to the concentrate and the resulting precipitate granulated at 25° C. for a half-hour. The white crystalline solid is separated by filtration and washed with acetone (4 liters). Yield = quantitative. M.P. 183°-187° C. (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([I:10])[CH:3]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[CH:13]=[CH:12]1>C(O)(=O)C>[O:15]=[C:14]1[CH:13]=[CH:12][C:11](=[O:16])[N:1]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([I:10])[CH:3]=1
Reactant: O=C1C=CC(=O)O1
Reactant: N#Cc1ccc(N)cc1I
Solvent: CC(=O)O
Product: N#Cc1ccc(N2C(=O)C=CC2=O)cc1I
Temperature: 25 °C
Yield: 90.5 %

Procedure:
Compound 489C (3.97 g, 16.3 mmol) and maleic anhydride (2.41 g, 24.4 mmol) were refluxed in glacial acetic acid (15 mL) for 5 h. The reaction was cooled to 25° C. and then poured onto ice (100 mL). The resulting precipitate was isolated by filtration and washed with water (2×25 mL) and dried under vacuum to yield 4.78 g (90%) of compound 489D as a tan solid. HPLC: 82% at 2.68 min (retention time) C Shimadzu VP-ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.1% trifluoroacetic acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 325.04 [M+H]+.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH:27]=O>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:27][C:26]3[CH:29]=[C:30]([O:34][CH3:35])[C:31]([O:32][CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=3)[C:10]([O:14][CH2:15][C:16]#[CH:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: C#CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C#CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-prop-2-ynyloxy-8-acetylcoumarin (1.92 g, 0.0075 mol) and 3,4,5-trimethoxy-benzaldehyde (1.47 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by ethanol to give 1.1 of product m.p. 191-93° C., 1H-NMR (CDCl3) δ: 2.45 (s, 3H); 2.53-2.56 (m, 1H); 3.83-3.85 (m, 9H); 4.82 (d, 2H, J=2.2 Hz); 6.20 (s, 1H); 6.72 (s, 2H); 6.92 (d, 1H, J=16 Hz); 7.12 (d, 1H, J=8.9 Hz); 7.15 (d, 1H, J=16 Hz); 7.67 (d, 1H, J=8.9 Hz).
Reaction SMILES: [N:1]1[N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[N:22][C:7]=3[O:8][C:9]3([CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]3)[C:4]2=[CH:3][CH:2]=1.[ClH:26].O1CCOCC1>C(Cl)Cl.CO>[ClH:26].[N:1]1[N:5]2[C:6]3[CH:25]=[CH:24][CH:23]=[N:22][C:7]=3[O:8][C:9]3([CH2:10][CH2:11][NH:12][CH2:13][CH2:14]3)[C:4]2=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ncccc1-n1nccc12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: c1cnc2c(c1)-n1nccc1C1(CCNCC1)O2
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl spiro[piperidine-4,4′-pyrazolo[1,5-d]pyrido[2,3-b][1,4]oxazine]-1-carboxylate (35 mg, 0.10 mmol) in CH2Cl2 (1 mL) and MeOH (0.1 mL) was added HCl in dioxane (256 μL of 4 M, 1.02 mmol) and the mixture was stirred at 40° C. for 4 hours. The reaction mixture was evaporated and the hydrochloric acid salt of the product was used without further purification. ESI-MS m/z calc. 242.1. found 243.5 (M+1)+. Retention time: 0.32 minutes (3 min run).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[CH2:2][C:3]([NH:5][C@H:6]([C:24]([N:26]1[CH2:65][CH2:64][CH2:63][C@H:27]1[C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:53]([O:55]CC1C=CC=CC=1)=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41]C(OCC1C=CC=CC=1Cl)=O)=[O:34])[CH3:32])=[O:29])=[O:25])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:23])[NH:12]S(C1C=CC(C)=CC=1)(=O)=O)=[O:4].C1(OC)C=CC=CC=1>>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:24]([N:26]1[CH2:65][CH2:64][CH2:63][C@H:27]1[C:28]([NH:30][C@H:31]([C:33]([NH:35][C@H:36]([C:53]([OH:55])=[O:54])[CH2:37][CH2:38][CH2:39][CH2:40][NH2:41])=[O:34])[CH3:32])=[O:29])=[O:25])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:23])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)CNC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Solvent: COc1ccccc1
Product: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)CN)C(=O)N[C@@H](CCCCN)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
The solution of 300 mg (0.289 mmol) of Boc-Gly-Arg(Tos)-Pro-Ala-Lys(ClZ)OBzl (SEQ ID NO: 14), 1 ml of anisole and 2 ml of HF was stirred at 0° C. for 2 h. The reaction mixture was evaporated under reduced pressure to remove HF. To the residue 2 ml of HF were added and the solution was stirred at 0° C. for another 1 h. The reaction mixture was evaporated under reduced pressure to remove HF. The residue was triturated with ether and the resulted solid was purified on the Sephadex G-10 column. The collected fractions were lyophilized to provide 109 mg (80%) of the title compound. Mp. 168–170° C., FAB-MS (m/e) 528[M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH2:7][C:8]([CH2:10][Cl:11])=[O:9])([CH3:4])([CH3:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[CH2:7][C@@H:8]([OH:9])[CH2:10][Cl:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)CCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)C[C@@H](O)CCl

Procedure:
The procedure of example 369 was repeated using t-butyl-4-chloroacetoacetate as the substrate to give t-butyl-4-chloro-3(R)-hydroxybutyrate, [α]D23 +18.09° (c, 5.1 CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[C:16](=[O:21])[C:17](=[CH2:20])[CH2:18][CH3:19].ClC1C=C([O:29]CCN2CCOCC2)C=CC=1C(=O)CCC>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][O:29][CH2:15][CH2:14]2)[CH:5]=[CH:4][C:3]=1[C:16](=[O:21])[C:17](=[CH2:20])[CH2:18][CH3:19]
Reactant: CCCC(=O)c1ccc(OCCN2CCOCC2)cc1Cl
Reactant: C=C(CC)C(=O)c1ccc(OCCN(CC)CC)cc1Cl
Product: C=C(CC)C(=O)c1ccc(OCCN2CCOCC2)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step B except that the 1-[2-chloro-4-(2-diethylaminoethoxy)phenyl]-1-butanone of Example 1, Step B is replaced by an equimolecular quantity of 1-[2-chloro-4-(2-morpholinoethoxy)phenyl]-1-butanone. The product is obtained as a yellow oil upon distillation in vacuo (0.3 mm.).
Reaction SMILES: C([O:3][C:4]([CH2:6][S:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)=[O:5])C.[C:17]([O:21][C:22](=[O:28])[NH:23][CH2:24][CH2:25][NH:26][CH3:27])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([NH:23][CH2:24][CH2:25][N:26]([CH3:27])[C:12]([C:11]1[CH:10]=[CH:9][C:8]([S:7][CH2:6][C:4]([OH:3])=[O:5])=[CH:16][CH:15]=1)=[O:14])=[O:28])([CH3:20])([CH3:19])[CH3:18]
Reactant: CNCCNC(=O)OC(C)(C)C
Reactant: CCOC(=O)CSc1ccc(C(=O)O)cc1
Product: CN(CCNC(=O)OC(C)(C)C)C(=O)c1ccc(SCC(=O)O)cc1

Procedure:
{4-[(2-Tert-butoxycarbonylaminoethyl)methylcarbamoyl]phenylthio}acetic acid was prepared in analogy to the procedure described in example 80 using 4-ethoxycarbonylmethylsulfanylbenzoic acid and commercially available (2-methylamino-ethyl)carbamic acid tert-butyl ester.