Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:41])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:34])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[O:23])=[CH:17][C:16]=1[Cl:33].[CH3:42][C:43]([CH3:59])([O:45][C:46]([N:48]1[C:52]2[CH:53]=[CH:54][C:55]([CH:57]=O)=[CH:56][C:51]=2[N:50]=[N:49]1)=[O:47])[CH3:44]>O1CCCC1>[CH3:9][O:10][C:11](=[O:41])/[C:12](/[NH:13][C:14](=[O:34])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[O:23])=[CH:17][C:16]=1[Cl:33])=[CH:57]/[C:55]1[CH:54]=[CH:53][C:52]2[N:48]([C:46]([O:45][C:43]([CH3:42])([CH3:59])[CH3:44])=[O:47])[N:49]=[N:50][C:51]=2[CH:56]=1
Reactant: CC(C)(C)OC(=O)n1nnc2cc(C=O)ccc21
Reactant: COC(=O)C(NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1ccc2c(c1)nnn2C(=O)OC(C)(C)C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 42 h
Yield: 88 %

Procedure:
1,1,3,3-Tetramethylguanidine (60 μL, 0.48 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 132; 109 mg, 0.22 mmol) in tetrahydrofuran (3 mL) at room temperature. 1-(1,1-dimethylethoxycarbonyl)-1H-benzotriazole-5-carboxaldehyde (Example 40; 55 mg, 0.22 mmol) was added and the solution was stirred at room temperature for 42 h. After the solvents were removed under reduced pressure, the residue was partitioned between ethyl acetate (10 mL) and pH 6 phosphate buffer (5 mL). The organic phase was washed with pH 6 phosphate buffer, brine, 10% aqueous sodium bicarbonate solution and brine. Each of the aqueous layers was extracted in turn with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and evaporated to give crude (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-[1-(1,1-dimethylethoxycarbonyl)-1H-benzotriazol-5-yl]propenoic acid methyl ester (120 mg) which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[CH3:10][O:9][C:7]([C:6]1[S:5][C:4]2[CH:11]=[CH:12][CH:13]=[CH:14][C:3]=2[C:2]=1[N:1]=[CH:17][N:18]([CH3:20])[CH3:19])=[O:8]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1sc2ccccc2c1N
Product: COC(=O)c1sc2ccccc2c1N=CN(C)C
Temperature: 25 °C
Yield: 93 %

Procedure:
A mixture of 3.38 g (16.32 mmol) of methyl 3-aminobenzo[b]thiophene-2-carboxylate (J. Org. Chem. 37, 3224 (1972)) in 8 mL of N,N,-dimethylformamide dimethyl acetal is heated at reflux temperature for 2 hours, then cooled to room temperature. The solid is collected by filtration, washing with hexane and ethyl acetate to provide 3.96 g (93%) of a white solid, mp 73-74° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH2:14])=[S:13])=[CH:7][C:5]=2[N:6]=1.[CH2:15](O)[CH3:16]>>[S:13]1[CH:16]=[CH:15][N:14]=[C:12]1[NH:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([NH2:1])=[N:6][C:5]=2[CH:7]=1
Reactant: NC(=S)Nc1ccc2sc(N)nc2c1
Reactant: CCO
Product: Nc1nc2cc(Nc3nccs3)ccc2s1
Temperature: 25 °C

Procedure:
To a solution of ethanol (12 mL) was added the urea compound (Example 18, 50 mg, 0.22 mmol) along with chloroacetyaldehyde (0.12 mL, 0.94 mmol). The resulting mixture was heated at reflux for 24 hours. The mixture was then cooled to room temperature and the solvent was evaporated. Water (25 mL) was added to the residue and the pH was adjusted to 9 using sodium carbonate solution. The mixture was extracted using ethyl acetate (3×15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated (18.8 mg, 33%).%). 1H-NMR (CDCl3) δ: 7.66 (d, 1H, J=2.2 Hz), 7.47 (d, 1H, J=8.54), 7.21–7.18 (m, 2H), 6.73 (d, 1H, J=3.9 Hz); MS (ESI) 248.8 (M+1, 100%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:19][C@H:18](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:17][C@H:9]1[C:10]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[C:1]([O:5][C:6]([N:8]1[CH2:19][C@@H:18]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:17][C@H:9]1[C:10]([NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2C[C@@H](C(=O)NC(C)(C)C)N(C(=O)OC(C)(C)C)C2)cc1
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](N2CCOCC2)CN1C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 80.6 %

Procedure:
A mixture of 1.0 g (2.27 mmol) of (4R)-1-t-butoxycarbonyl-4-(p-toluenesulfonyloxy)-N-t-butyl-L-prolinamide [prepared as described in step (a) above] and 5 g of morpholine was heated at 80° C. for 3 hours, whilst stirring. At the end of this time, the excess morpholine was removed by distillation under reduced pressure, and the residue was mixed with a saturated aqueous solution of sodium hydrogencarbonate. It was then extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was recrystallized from a mixture of methylene chloride and diethyl ether, to give 650 mg of the title compound as colorless crystals, melting at 172°-173° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH2:11])=[C:4]([CH3:12])[CH:3]=1.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:11])=[C:4]([CH3:12])[CH:3]=1
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(Br)cc(N)c1N
Temperature: 25 °C
Yield: 59.3 %

Procedure:
To a suspension of 4-bromo-2-methyl-6-nitro-phenylamine (20 g, 0.086 mol) in ethanol (200 mL) was added tin chloride dihydrate (49.2 g, 0.258 mol). The reaction mixture was heated to reflux for 14 h, cooled to room temperature, and concentrated in vacuo. The residue was diluted with ethyl acetate (150 mL) and treated with triethylamine (40 mL). The resulting slurry was filtered through a pad of celite, and the filtercake was rinsed with three portions ethyl acetate (50 mL). The filtrate was washed with saturated NaHCO3, water, and brine, then dried over Na2SO4 and filtered. After removal of the solvent, the residue was purified by flash chromatography on silica gel (30% EtOAc/hexane, then 5% MeOH/CH2Cl2) to yield the title compound (10.26 g, 59%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 6.77 (1H, d, J=2.0 Hz), 6.74 (1H, d, J=2.0 Hz), 2.16 (3H, s). LCMS (M+H)+ m/z 201. (t=0.83 min.).
Reaction SMILES: C([O:3][C:4]([C:6]1([F:19])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=O)C.[Li+].[BH4-]>C1COCC1>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6]([F:19])([CH2:4][OH:3])[CH2:11][CH2:10]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C1(F)CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 86.7 %

Procedure:
To a stirred solution of 4-fluoro-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (0.9 mmol, 0.25 g), in anhydrous THF (3 mL) under N2 atmosphere, was added LiBH4 (2.0 mmol, 1.0 mL, 2N solution in THF) dropwise and reaction was stirred at room temperature for 10 h. The reaction was quenched with slow addition of water (1 mL) and the product was extracted with ethyl acetate (2×5 mL), Organic layer was washed with water, (5 mL), brine (5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on a SiO2 cartridge with 30% ethyl acetate in hexanes to provide 4-fluoro-4-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.182 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].[O:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:20][CH:19]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[OH:18])[C:7]3[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1cccc2c3c([nH]c12)CCN(C)C3
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2c3c(n(CC(O)c4ccncc4)c12)CCN(C)C3
Reaction time: 0.17 h

Procedure:
To a solution of 2,6-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.0 g, 5.00 mmol) in DMF (10 mL) was added sodium hydride (600 mg, 15 mmol) under nitrogen atmosphere at 0° C. and stirred for 10 min. 4-(Oxiran-2-yl)pyridine (1.08 g, 8.92 mmol) was added dropwise under nitrogen atmosphere. The reaction mixture was stirred at RT for 12 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was poured in ice-cold water and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (5×50 mL), dried over anhydrous sodium sulfate and concentrated. The residue was crystallized with diethyl ether to yield 2-(2,6-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol. 1H NMR (CDCl3, freebase) δ (ppm): 8.58 (d, 2H), 7.23 (m, 3H), 7.0 (t, 1H), 6.9 (d, 1H), 4.81 (t, 1H), 4.3-4.4 (m, 2H), 3.5 (dd, 2H), 3.0 (m, 1H), 2.8 (m, 1H), 2.75 (s, 3H), 2.7 (m, 1H), 2.6 (m, 1H), 2.43 (s, 3H). Separation by chiral HPLC provides enantiomers 82a and 82b.
Reaction SMILES: CC(C)(C(=O)CC1CCCCC1)CCCO[C:7]1[CH:8]=[CH:9][C:10]2[O:15][CH:14]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:13]([C:24]3[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=3)=[CH:12][C:11]=2[CH:30]=1.FC1C=CC(CCC2C(C3N(C)C=CN=3)=CC3C=C([O:66][CH2:67][CH2:68][CH2:69][C:70]4([C:75](=[O:84])[CH2:76][C:77]5[CH:82]=[CH:81][C:80](F)=[CH:79][CH:78]=5)[CH2:74]CC[CH2:71]4)C=CC=3O2)=CC=1>>[CH3:71][C:70]([CH3:74])([C:75](=[O:84])[CH2:76][CH:77]1[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]1)[CH2:69][CH2:68][CH2:67][O:66][C:8]1[CH:7]=[CH:30][C:11]2[CH:12]=[C:13]([C:24]3[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=3)[CH:14]([CH2:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[O:15][C:10]=2[CH:9]=1
Reactant: Cn1ccnc1C1=Cc2cc(OCCCC3(C(=O)Cc4ccc(F)cc4)CCCC3)ccc2OC1CCc1ccc(F)cc1
Reactant: Cn1ccnc1C1=Cc2cc(OCCCC(C)(C)C(=O)CC3CCCCC3)ccc2OC1CCc1ccccc1
Product: Cn1ccnc1C1=Cc2ccc(OCCCC(C)(C)C(=O)CC3CCCCC3)cc2OC1CCc1ccccc1

Procedure:
6-(4,4-dimethyl-6-cyclohexyl-5-oxohexyl)oxy-2-(2-phenylethyl)-3-(1-methyl-1H-imidazol-2-yl)-2H-1-benzopyran, and 1-[3-[2-(2-(4-fluorophenyl)-ethyl)-3-(1-methyl-1H-imidazol-2-yl)-2H-1-benzopyran-6-yl]oxypropyl]-1-[1-oxo-2-(4-fluorophenyl)ethyl]cyclopentane.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:9]2[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:16])=[N:5][O:6][C:7]=1[CH3:8].C[O:18][C:19](=[O:32])[CH2:20][O:21][C:22]1[CH:30]=[CH:29][C:28]([SH:31])=[C:27]2[C:23]=1[CH2:24][CH2:25][CH2:26]2>>[Cl:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:9]=1[C:4]1[C:3]([CH2:2][S:31][C:28]2[CH:29]=[CH:30][C:22]([O:21][CH2:20][C:19]([OH:32])=[O:18])=[C:23]3[C:27]=2[CH2:26][CH2:25][CH2:24]3)=[C:7]([CH3:8])[O:6][N:5]=1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1CBr
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1CSc1ccc(OCC(=O)O)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using commercially available 4-bromomethyl-3-(2,6-dichloro-phenyl)-5-methyl-isoxazole and 12C. MS m/z 478 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].[ClH:26]>CO.O>[ClH:26].[CH3:23][N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][O:15][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)[CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cc2cc(OCC3CCN(C)CC3)ccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCC(COc2ccc3[nH]c(C(=O)O)cc3c2)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
A suspension of ester 26 (1.00 g, 3.16 mmol) in MeOH (8 mL) was treated with a solution of NaOH (155 mg, 3.88 mmol) in water (4 mL) and heated at reflux for 3.5 h. After cooling to room temperature, the solution was adjusted to pH 6 with 2 M HCl and the solvent was removed under reduced pressure. The residue was dissolved in MeOH, 2 M HCl was added dropwise, and the formed precipitate was collected by filtration to give 27 (712 mg, 69%) as a brown solid. The residue obtained after evaporation of the mother liquor was purified by column chromatography (CH2Cl2/MeOH, 6:1, 1% cone. HCl) to provide a second batch of 27 (226 mg, 22%). 1H NMR (300 MHz, DMSO-d6): δ=1.56-1.77 (m, 2 H, 3′-Hax, 5′-Hax), 1.89-2.09 (m, 3 H, 3′-Heq, 41-H, 5′-Heq), 2.69 (s, 3 H, NMe), 2.87-3.05 (m, 2 H, 2′-Hax, 6′-Hax) 3.24-3.48 (m, 2 H, 2′-Heq, 6′-Heq), 3.79-3.92 (m, 2 H, ArOCH9), 6.90 (dd, J=9.0, 2.2 Hz, 1 H, 6-H), 6.98 (d, J=1.7 Hz, 1 H, 3-H), 7.12 (d, J=2.2 Hz, 1 H, 4-H), 7.34 (d, J=9.0 Hz, 1 H, 7-H), 10.84 (sbr, 1H, NH+), 11.59 (s, 1H, NH), 12.74 (sbr, 1 H, CO2H) ppm. —13C NMR (75.5 MHz, DMSO-d6): δ=25.8 (C-3′, C-5′), 32.8 (C-4′), 42.5 (NMe), 52.8 (C-2′, C-6′), 71.6 (OCH2), 103.4 (C-4), 106.8 (C-3), 113.3 (C-7), 116.0 (C-6), 127.1 (C-2), 128.7 (C-3a), 132.6 (C-7a), 152.9 (C-5), 162.5 (C═O) ppm. −MS (70 eV, EI): m/z (%)=288 (14) [M−HCl]+, 112 (100) [C7H14N]+. —C16H21ClN2O3 (324.80): calcd. 288.1474 [M−HCl]+; found 288.1474.
Reaction SMILES: N.[Li].[CH3:3][O:4][C:5]1[CH:18]=[C:17]([CH:19]([CH3:21])[CH3:20])[C:16]([O:22][CH3:23])=[C:15]2[C:6]=1[C:7]1([CH3:26])[C:12]([CH2:13][CH2:14]2)=[C:11]([CH3:24])[C:10](=[O:25])[CH2:9][CH2:8]1>C1COCC1>[CH3:3][O:4][C:5]1[CH:18]=[C:17]([CH:19]([CH3:20])[CH3:21])[C:16]([O:22][CH3:23])=[C:15]2[C:6]=1[C:7]1([CH3:26])[CH:12]([CH2:13][CH2:14]2)[CH:11]([CH3:24])[C:10](=[O:25])[CH2:9][CH2:8]1
Reactant: COc1cc(C(C)C)c(OC)c2c1C1(C)CCC(=O)C(C)=C1CC2
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(OC)c2c1C1(C)CCC(=O)C(C)C1CC2
Reaction time: 0.08 h
Yield: 53.7 %

Procedure:
To 15.6 ml of liquid ammonia was added 28.5 mg of lithium metal at -78° C. and the mixture was stirred for 5 minutes. Then, 15.6 ml of a THF solution containing 500 mg of the compound obtained in Example 1 was slowly added dropwise. After the mixture was stirred at -78° C. for 1.5 hours, the ammonia was distilled off and the residue was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent=diethyl ether:n-hexane:chloroform=5:50:1) to provide 270 mg of the object compound.
Reaction SMILES: N=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[NH:5][C:4](=[S:13])[N:3]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1.Cl.[OH-:27].[NH4+].[Cl-].[Na+]>C(OCC)(=O)C.CO>[CH3:12][N:9]1[CH2:10][CH2:11][C:6]2([NH:5][C:4](=[S:13])[N:3]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=3)[C:2]2=[O:27])[CH2:7][CH2:8]1
Reactant: CN1CCC2(CC1)NC(=S)N(c1ccc(C#N)c(C(F)(F)F)c1)C2=N
Reactant: [OH-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCC2(CC1)NC(=S)N(c1ccc(C#N)c(C(F)(F)F)c1)C2=O

Procedure:
300 mg of the product of Example 20, 6 ml of methanol and 1.5 ml of 2N hydrochloric acid were mixed together and refluxed for one hour, then returned to ambient temperature. The reaction medium was poured into 20 ml of 50% ammonium hydroxide saturated with sodium chloride and extraction was carried out 3 times with ethyl acetate. The extracts were dried and purification was carried out on silica with methylene chloride-methanol: 9-1 as eluant to obtain 260 mg of the expected product (white crystals) melting at 229-230° C.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[CH:28][S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:29]([CH3:30])=[CH:28][S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1csc2nc(-c3ccccn3)nc(Cl)c12
Product: Cc1csc2nc(-c3ccccn3)nc(NCCc3ccc4c(c3)OCCO4)c12

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:11][CH:10]=[CH:9][C@@H:8]([OH:12])[C@H:7]1[OH:13])(=[O:3])[CH3:2].[Cl:14][CH2:15][C:16](OC=C)=[O:17]>COCCOC>[C:1]([O:4][CH2:5][C@H:6]1[O:11][CH:10]=[CH:9][C@@H:8]([O:12][C:16](=[O:17])[CH2:15][Cl:14])[C@H:7]1[OH:13])(=[O:3])[CH3:2]
Reactant: C=COC(=O)CCl
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](O)[C@H]1O
Solvent: COCCOC
Product: CC(=O)OC[C@H]1OC=C[C@@H](OC(=O)CCl)[C@H]1O
Yield: 80 %

Procedure:
1.03 g (5.5 mmol) of 6-O-acetylgalactal are taken up in 10-15 ml of DME and 20-25 ml of vinyl chloroacetate and stirred with 1 g of lipase P (Pseudomonas spec.) at room temperature for 5-6 h. Filtering off the reusable enzyme, concentration of the solution and chromatography (SiO2, ether/hexane 1:2) result in 6-O-acetyl-3-O-chloroacetylgalactal in 80% yield.
Reaction SMILES: [CH:1]1([NH:4][CH:5]=[C:6]([C:12](=[O:26])[C:13]2[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([F:22])[C:16]([F:23])=[C:15]([CH3:24])[C:14]=2F)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[H-].[Na+].O>O1CCOCC1>[CH:1]1([N:4]2[C:14]3[C:13](=[C:18]([N+:19]([O-:21])=[O:20])[C:17]([F:22])=[C:16]([F:23])[C:15]=3[CH3:24])[C:12](=[O:26])[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 27.1 g of ethyl 3-cyclopropylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate in 270 ml of 1,4-dioxane, 3.2 g of sodium hydride (60% mineral oil dispersion) was added by portions and stirred at room temperature for one hour. 300 ml of water was added to the reaction mixture and the deposited crystals were collected by filtration to give 19.5 g of the desired compound as colorless crystals, which was recrystallized from N,N-dimethylformamide to provide colorless needles, m.p. 260°-263° C.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:48]([O:52][C:53](=[O:62])[NH:54][CH2:55][C@@H:56]1[CH2:61][CH2:60][CH2:59][CH2:58][NH:57]1)([CH3:51])([CH3:50])[CH3:49]>C(#N)C>[C:48]([O:52][C:53](=[O:62])[NH:54][CH2:55][C@@H:56]1[CH2:61][CH2:60][CH2:59][CH2:58][N:57]1[C:7]([C:5]1[N:6]=[C:2]([Br:1])[S:3][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)=[O:9])([CH3:51])([CH3:49])[CH3:50]
Reactant: O=C(O)c1nc(Br)sc1-c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1C(=O)c1nc(Br)sc1-c1ccc(F)cc1
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
2-bromo-5-(4-fluoro-phenyl)-thiazole-4-carboxylic acid (1.02 g, 3.38 mmol) was dissolved in acetonitrile (20 ml) followed by the addition of TBTU (1.19 g, 3.72 mmol) and DIPEA (547 mg, 4.22 mmol). Stirring was continued for 30 min. at rt. A solution of (S)-piperidin-2-ylmethyl-carbamic acid tert-butyl ester (725 mg, 3.38 mmol) in acetonitrile (20 ml) was added to the reaction mixture within 10 minutes and stiring was continued at rt for 24 h. The reaction mixture was concentrated under reduced pressure followed by the addition of aq. HCl (0.5 M, 50 ml). Stirring was continued for 30 min. The precipitated product was filtered off, washed with cold water and dried at HV to give the expected product (1.57 g). LC-MS: tR=1.03 min; [M+H]+=500.38.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][CH:7]=1)=[O:5])[CH3:2].C(OC(=O)C)(=O)C.C(O)(=O)C.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[CH:35]=O>O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](/[CH:11]=[CH:35]/[C:25]2[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[N:27][O:28][C:24]=2[CH3:23])=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(C)s1
Reactant: Cc1onc(-c2ccccc2)c1C=O
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cnc(/C=C/c2c(-c3ccccc3)noc2C)s1
Temperature: 120 °C
Reaction time: 144 h
Yield: 19.2 %

Procedure:
2-Methyl-thiazole-5-carboxylic acid ethyl ester (547 mg, 2.92 mmol) was dissolved in acetic anhydride (0.15 mL, 15.5 mmol) and acetic acid (0.04 mL, 2.54 mmol) then 5-methyl-3-phenyl-4-isoxazolecarbaldehyde (500 mg, 2.92 mmol) was added and the reaction mixture warmed to 120° C. After 6 days, the reaction mixture was cooled to room temperature then diluted with water and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated then purified by chromatography (silica, 0 to 30% ethyl acetate in heptane) to give the title compound (191 mg, 19%) as an off-white solid after trituration with isopropylether. MS: m/e=341.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(Cl)(=O)C.C(N(CC)CC)C>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12](=[O:14])[CH3:13])[CH2:6][CH2:5]2
Reactant: Oc1ccc2c(c1)CCNC2
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2cc(O)ccc2C1

Procedure:
5.0 g of 6-hydroxy-1,2,3,4-tetrahydroisoquinoline are converted into the bisacetyl compound using acetic anhydride or acetyl chloride/triethylamine, and, without purification, this compound is heated under reflux for 6 hours with 10 ml of diethylamine in 50 ml of ethanol. The mixture is evaporated in vacuo in a rotary evaporator, and the residue is chromatographed on silica gel using ethyl acetate/methanol in the ratio 9:1. A yellow oil which crystallizes on trituration with diethyl ether is obtained. Yield: 5.2 g (78% of theory), melting point: 129°-130°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[C:6]([F:14])[C:5]=1[F:15])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:36].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][Br:36])=[C:6]([F:14])[C:5]=1[F:15])[CH3:2]
Reactant: CCOc1ccc(CCCO)c(F)c1F
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1ccc(CCCBr)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
3-(4-Ethoxy-2,3-difluorophenyl)propanol (s21) (9.4 g) and triphenylphosphine (17.1 g) were dissolved in methylene chloride (100 ml). Carbon tetrabromide (17.3 g) in methylene chloride (100 ml) solution was slowly added dropwise to the solution at room temperature, and the mixture was stirred at room temperature for another 3 hours. The reaction mixture was treated with a saturated aqueous solution of sodium hydrogencarbonate, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to leave a residue, pale yellow solids. The residue was purified by column chromatography with heptane as an eluent and silica gel as a stationary phase powder to give 3-(4-ethoxy-2,3-difluorophenyl) bromopropane (s22) (11.5 g). The yield based on the compound (s21) was 94.8%.