Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH:15]([CH3:17])[CH3:16])=[C:11]([Cl:18])[NH:10][C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][Cl:30]>CN(C)C=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH:15]([CH3:16])[CH3:17])=[C:11]([Cl:18])[N:10]([CH2:27][CH2:28][CH2:29][Cl:30])[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: CC(C)c1c(Cl)[nH]c(=O)n(Cc2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(Cl)n(CCCCl)c(=O)n(Cc2ccccc2)c1=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a suspension of 20.91 g (75 mmol) of 3-benzyl-6-chloro-5-isopropylpyrimidine-2,4(1H,3H)-dione and 16.58 g (120 mmol) of potassium carbonate in 120 ml of N,N-dimethylformamide, 14.8 ml (150 mmol) of 1-bromo-3-chloropropane was added at room temperature. This mixture was stirred at 90° C. for 2 hours. After cooling, the reaction mixture was concentrated to dryness; the resulting residue was dissolved in chloroform-water. After the organic layer was washed with water and dried, the solvent was distilled off to yield an oily substance, which was then purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→3/1) to yield 8.06 g (30.1%, yellow oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])=O)[N:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:38][N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][N:10]([C:19]([NH:38][N:39]3[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]3)=[N:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)(=[O:24])=[O:23])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reactant: NN1CCCCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: O=S(=O)(N=C(NN1CCCCC1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.1 %

Procedure:
Part B: A mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamide (1.42 gram, 3.00 mmol) and phosphorus pentachloride (PCl5) (0.63 gram, 3.03 mmol) in chlorobenzene (15 mL) is heated at reflux temperature for 1 hour. After thorough concentration in vacuo, the formed 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride is suspended in dry dichloromethane (30 mL) and reacted with 1-aminopiperidine (1.08 mL, 10.0 mmol). After stirring at room temperature for 16 hours, the mixture is twice washed with water and concentrated in vacuo. The residue is crystallised from methyl-t-butyl ether (MTBE) to give pure 3-(4-chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-N-(piperidin-1-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (0.57 gram, 34% yield). Melting point (MP): 213-214° C. MS ESI+: 556 (MH+).
Reaction SMILES: [CH2:1]([N:4]([CH2:9][CH:10]=[CH2:11])[CH2:5][C:6]([OH:8])=O)[CH:2]=[CH2:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[F:24][C:25]1[CH:26]=[CH:27][C:28]2[N:34]3[CH:35]=[N:36][C:37]([C:38](=[N:40]O)[NH2:39])=[C:33]3[C@@H:32]3[CH2:42][CH2:43][N:31]3[C:30](=[O:44])[C:29]=2[CH:45]=1>CN(C)C=O>[CH2:9]([N:4]([CH2:5][C:6]1[O:8][N:40]=[C:38]([C:37]2[N:36]=[CH:35][N:34]3[C:28]4[CH:27]=[CH:26][C:25]([F:24])=[CH:45][C:29]=4[C:30](=[O:44])[N:31]4[CH2:43][CH2:42][C@H:32]4[C:33]=23)[N:39]=1)[CH2:1][CH:2]=[CH2:3])[CH:10]=[CH2:11]
Reactant: C=CCN(CC=C)CC(=O)O
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C=CCN(CC=C)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(F)ccc2-3)no1
Reaction time: 2 h
Yield: 37 %

Procedure:
2.32 g (15 mmol) of diallylglycine were dissolved in 15 ml of N,N-dimethylformamide and treated with 2.75 g (17 mmol) of 1,1'-carbonyldiimidazole. After stirring at 50° C. for 20 minutes 3.01 (10 mmol) of (S)-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime were added and the mixture was stirred at 90° for 16 hours and at 120° for 2 hours. The solution was concentrated and the residue was purified by chromatography on 320 g of silica gel while eluting with ethyl acetate. There were obtained 1.54 g (37%) of (S)-1-(5-diallylaminomethyl-1,2,4-oxadiazol-3-yl)-7-fluoro-12,12a-dihydro-9H,11H-azeto[2,1-c]-imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 100°-105°.
Reaction SMILES: C(C=C([NH:9][C@@H:10]1[C:35](=[O:36])[N:12]2[C@@H:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[C@@:14]([Cl:18])([CH3:17])[CH2:15][S:16][C@H:11]12)C)(OCC)=O.Cl>C(Cl)(Cl)Cl.CC(C)=O>[NH2:9][C@@H:10]1[C:35](=[O:36])[N:12]2[C@@H:13]([C:19]([O:21][CH:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:20])[C@@:14]([Cl:18])([CH3:17])[CH2:15][S:16][C@H:11]12
Reactant: CCOC(=O)C=C(C)N[C@@H]1C(=O)N2[C@@H]1SC[C@@](C)(Cl)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: C[C@@]1(Cl)CS[C@@H]2[C@H](N)C(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
A solution of benzhydryl 7β-(1-carbethoxy-1-propen-2-ylamino)-3β-chloro-3α-methylcepham-4α-carboxylate (107 mg) and 1N hydrochloric acid (0.1 ml) in a mixture of chloroform and acetone (1:1; 2 ml) is stirred at room temperature for 1 hour. The reaction mixture is washed with water, dried, and evaporated to remove the solvent. The residue is treated with a mixture of ether and petroleum ether to give solid benzhydryl 7β-amino-3β-chloro-3α-methylcepham-4α-carboxylate (60 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:17])=[C:13]([CH2:14][CH2:15][CH3:16])[C:8]=2[O:7][N:6]=1)[CH3:4].CS(O[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=1)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:17][CH:24]([CH3:23])[CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=3)=[C:13]([CH2:14][CH2:15][CH3:16])[C:8]=2[O:7][N:6]=1)[CH3:4]
Reactant: CCCc1c(O)ccc2c(CC)noc12
Reactant: COC(=O)Cc1ccc(CCCCOS(C)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1c(OC(C)CCc2ccc(CC(=O)OC)cc2)ccc2c(CC)noc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.2 %

Procedure:
A suspension of sodium hydride (15 mg, 0.36 mmole) in DMF (1.5 mL) was treated with 3-ethyl-6-hydroxy-7-propylbenz-[4,5]-isoxazole (68 mg, 0.33 mmole) and the mixture stirred at room temperature for 10 minutes under a nitrogen atmosphere. A solution of methyl 4-(4-methansulfonyloxybutyl)phenylacetate (100 mg, 0.33 mmole) in DMF (0.5 mL) was added and the mixture stirred at 80° C. for 5 hours. The cooled reaction mix was dissolved in ethyl acetate and washed with water (twice), brine, dried over magnesium sulfate and concentrated in vacuo to an oil. The crude product was purified by thin layer chromatography on silica gel eluting with hexane:ethyl acetate (4:1) to give the title compound (80 mg) as an oil. NMR (CDCl3): δ 0.97 (t, 3H); 1.44 (t, 3H); 1.71 (m, 2H); 1.87 (m, 4H); 2.71 (t, 2H); 2.88 (t, 2H); 2.97 (q, 2H); 3.62 (s, 2H); 3.71 (s, 3H); 6.89 (d, 1H); 7.18 (d, 2H); 7.22 (d, 2H); 7.39 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[CH:19]([OH:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: Cc1cccc(CNc2c3c(nc4ccccc24)CCCC3=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(CNc2c3c(nc4ccccc24)CCCC3O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3,4-Dihydro-9-(3-methylbenzylamino)acridin-1(2H)-one (3.70 g) was dissolved in 100 ml of dry THF and chilled in ice-water. 1M lithium aluminum hydride in THF (7.0 ml) was added and the reaction stirred 30 minutes in the cold. The reaction mixture was quenched by the sequential addition of 0.5 ml of water, 0.5 ml of 15% sodium hydroxide and 1.5 ml of water. The inorganic salts were filtered from the reaction mixture and the organic phase was evaporated to an oil. Trituration with ether gave a solid that was recrystallized from ethyl acetate/pentane to obtain 3.22 g, mp 133°-134° C.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:6]=[C:5]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:4]=1)=[O:2].[BH4-].[Na+]>CO>[OH:2][CH2:1][C:3]1[N:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[N:6]=[C:5]([O:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(C=O)nc(C(F)(F)F)n2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(CO)nc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl 4-{[6-formyl-2-(trifluoromethyl)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (202 mg, 0.538 mmol) in methanol (2.0 mL) was added sodium tetrahydroborate (20.4 mg, 0.538 mmol). The reaction solution was stirred at room temperature for 4 hours. The reaction was quenched with water and extracted with ethyl acetate (2×). The organic solutions were washed with brine, dried over Na2SC4, filtered and concentrated. The crude was purified with silica gel column to give the desired product. LCMS (M+H)+: 378.2.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1[CH:29]=[C:30]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[CH:31]=[CH:32][CH:33]=1)(C(C)(C)C)(C)C>C1COCC1>[N:34]1([C:30]2[CH:29]=[C:28]([CH2:27][OH:26])[CH:33]=[CH:32][CH:31]=2)[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CCCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cccc(N2CCCC2)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Tetrabutylammonium fluoride (1.0 M solution in THF, 3.8 ml) was added to a solution of 1-[3-(tert-butyldimethylsilyloxymethyl)phenyl]pyrrolidine in THF (20 ml) and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (557 mg).
Reaction SMILES: [ClH:1].C(OC([N:12]([CH2:25][CH:26]1[C:35]2[C:30](=[CH:31][C:32]([OH:37])=[C:33]([OH:36])[CH:34]=2)[CH2:29][CH2:28][NH:27]1)[C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=1)=O)C1C=CC=CC=1.Cl>C(O)(=O)C>[ClH:1].[CH3:24][O:23][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22])[NH:12][CH2:25][CH:26]1[C:35]2[C:30](=[CH:31][C:32]([OH:37])=[C:33]([OH:36])[CH:34]=2)[CH2:29][CH2:28][NH:27]1
Reactant: COc1cc(N(CC2NCCc3cc(O)c(O)cc32)C(=O)OCc2ccccc2)cc(OC)c1OC
Agent: Cl
Solvent: CC(=O)O
Product: COc1cc(NCC2NCCc3cc(O)c(O)cc32)cc(OC)c1OC
Yield: 69.9 %

Procedure:
A mixture of 1-(N-benzyloxycarbonyl-3,4,5-trimethoxyanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (4.4 g), conc. hydrochloric acid (45 ml) and acetic acid (45 ml) was refluxed for 1.5 hours in a stream of nitrogen. The reaction mixture was concentrated to dryness and the residue was washed with ether and acetone and crystallized with methanol to give 1-(3,4,5-trimethoxyanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (2.3 g). The product was recrystallized from water to give a pure product, mp 223° to 225° C.
Reaction SMILES: C(OC(N1CC[CH:14]([CH:17]([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH:28]=[C:27]([C:33]2[N:34]([CH:39]([CH3:41])[CH3:40])[N:35]=[C:36]([CH3:38])[N:37]=2)[N:26]=4)[CH2:18]C)CC1)=O)C1C=CC=CC=1.[CH3:44][C:45]1[S:46][C:47](C(O)C)=[C:48](C)[N:49]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCOCC1>[CH3:44][C:45]1[S:46][C:14]([CH:17]([O:20][C:21]2[CH:43]=[CH:42][C:24]3[C:25]4[N:29]([CH:28]=[C:27]([C:33]5[N:34]([CH:39]([CH3:40])[CH3:41])[N:35]=[C:36]([CH3:38])[N:37]=5)[N:26]=4)[CH2:30][CH2:31][O:32][C:23]=3[CH:22]=2)[CH3:18])=[C:48]([CH3:47])[N:49]=1
Reactant: CCC(Oc1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1nc(C)c(C(C)O)s1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(C)c4sc(C)nc4C)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-ol from Example 4 (345 mg, 1.06 mmol), 1-(2,4-dimethylthiazol-5-yl)ethanol (250 mg, 1.59 mmol) and triphenylphosphine (0.84 g, 3.18 mmol) in dioxane (15 mL) was added dropwise DEAD (0.63 mL, 3.18 mmol) and the reaction mixture was stirred at RT for 18 h. Additional amounts of 1-(2,4-dimethylthiazol-5-yl)ethanol (100 mg, 0.63 mmol) and triphenylphosphine (0.42 g, 1.59 mmol) were added, followed by DEAD (0.31 mL, 1.59 mmol) and stirring at RT was continued for 72 h. Volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was further purified by column chromatography (Si-PCC, gradient 0-6% MeOH in EtOAc then C18, gradient 15-70% MeOH in H2O) and finally loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH affording 188 as a white solid (60 mg, 12%). LCMS: RT 4.42 min [M+H]+ 465.1. 1H NMR (CDCl3, 400 MHz): δ 8.33 (1H, d, J=9.33 Hz), 7.53 (1H, s), 6.65 (1H, dd, J=9.33 and 2.56 Hz), 6.46 (1H, d, J=2.71), 5.91-5.81 (1H, m), 5.54-5.48 (1H, m), 4.44-4.29 (4H, m), 2.57 (3H, s), 2.39 (3H, s), 2.37 (3H, s), 1.65 (3H, d J=6.22 Hz), 1.52 (6H, d, J=6.72 Hz)
Reaction SMILES: [Si:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:14](#[N:17])[CH:15]=[CH2:16]>>[Si:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:16][CH2:15][C:14]#[N:17])[CH2:10][CH2:9]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)N1CCNCC1
Reactant: C=CC#N
Product: CC(C)(C)[Si](C)(C)N1CCN(CCC#N)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 160.3 g (0.8 mol) of 1-t-butyldimethylsilylpiperazine (Synthesis Example 1) and heated at 70° C. Once the internal temperature became steady, 46.7 g (0.88 mol) of acrylonitrile was added dropwise over 2 hours. Stirring was continued for 4 hours at the temperature. On distillation of the reaction solution, 194.1 g of a fraction having a boiling point of 145-147° C./0.4 kPa was collected.
Reaction SMILES: [C:1]([CH:4]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)([OH:3])=O.[S:22]1[CH:26]=[CH:25][N:24]=[C:23]1[NH2:27]>>[O:9]1[CH2:10][CH2:11][CH:6]([CH2:5][CH:4]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[C:1](=[O:3])[NH:27][C:23]2[S:22][CH:26]=[CH:25][N:24]=2)[CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1
Reactant: Nc1nccs1
Product: COC(=O)c1ccc(C(CC2CCOCC2)C(=O)Nc2nccs2)cc1

Procedure:
Methyl 4-tert-butoxycarbonylmethylbenzoate (1.71 g, 6.84 mmol) was alkylated with 4-iodomethyltetrahydropyran (1.86 g, 8.21 mmol), employing the method described in Preparation 41, to afford methyl 4-[1-tert-butoxycarbonyl-2-(tetrahydropyran-4-yl)ethyl]benzoate: RTA=3.86 min. A solution of this compound (1.37 g, 3.94 mmol) in CH2Cl2 (5 mL) was treated with TFA-CH2Cl2 (2:1, 15 mL) at 0° C. over 10 min. The mixture was stirred at 20° C. for 3 h, before being concentrated in vacuo. The residue was treated with PhMe and the solvents were evaporated off under reduced pressure. This process was repeated twice to provide crude methyl 4-[1-carboxy-2-(tetrahydropyran-4-yl)ethyl]benzoate. This carboxylic acid was condensed with thiazol-2-ylamine, utilizing the protocol outlined in EXAMPLE 65, to furnish methyl 4-[2-(tetrahydropyran-4-yl)-1-(thiazol-2-ylcarbamoyl)ethyl]benzoate: m/z (ES+)=375.2 [M+H]+. This ester (1.20 g, 3.21 mmol) was saponified with LiOH.H2O, using the procedure described in Preparation 22, to furnish the title compound: m/z (ES−)=359.2 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[OH:17])[CH:6]=[CH:7][CH:8]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27](O)[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([O:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1cccc(CCc2ccccc2O)c1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1cccc(CCc2ccccc2OC2CCCN(C(=O)OC(C)(C)C)C2)c1
Yield: 62.1 %

Procedure:
Following a procedure similar to that described in Example 36(a), 1.50 g of 2-[2-(3-methoxyphenyl)ethyl]phenol (prepared as described in Preparation 20), 2.64 g of 1-t-butoxycarbonyl-3-hydroxypiperidine, 3.44 g of triphenylphosphine and 2.29 g of diethyl azodicarboxylate were reacted. The mixture was then worked up as described in Example 36(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 7:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.68 g (yield 62%) of the title compound as a colorless oil.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[O:12][C:13]([C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([F:24])[CH:22]=2)[N:17]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:16]=1[CH2:34][N:35]([CH2:46][C:47]#[N:48])S(C1C=CC(C)=CC=1)(=O)=O)=O>C1COCC1>[C:28]1([S:25]([N:17]2[C:16]3[CH:34]=[N:35][C:46]([C:47]#[N:48])=[C:13]([OH:12])[C:15]=3[C:23]3[CH:22]=[C:21]([F:24])[CH:20]=[N:19][C:18]2=3)(=[O:27])=[O:26])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)c1c(CN(CC#N)S(=O)(=O)c2ccc(C)cc2)n(S(=O)(=O)c2ccccc2)c2ncc(F)cc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ncc2c(c1O)c1cc(F)cnc1n2S(=O)(=O)c1ccccc1
Temperature: -10 °C
Yield: 75.2 %

Procedure:
Lithium bis(trimethylsilyl)amide (100 mL of a 1N solution in THF, 100 mmol) was added dropwise to a cooled (−78° C.) suspension of 1-benzenesulfonyl-5-fluoro-2-{[cyanomethyl-(toluene-4-sulfonyl)amino]methyl}-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (16.5 g, 29.6 mmol) in dry THF (150 mL). The reaction mixture was allowed to slowly warm to −10° C. then slowly quenched into cold 1M hydrochloric acid. The layers were separated and the aqueous layer further extracted with THF. The combined organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The resultant residue was triturated with methanol then acetone and air dried to afford the title compound as a brown solid (8.2 g, 75%). 1H NMR (400 MHz, DMSO-d6): 9.25 (s, 1H), 8.76 (dd, J=2.8, 1.3 Hz, 1H), 8.50 (dd, J=8.2, 2.8 Hz, 1H), 8.20-8.17 (m, 2H), 7.75-7.75 (m, 1H), 7.63-7.62 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[H-].[Na+].[CH3:15]I.O>CN(C)C=O>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C(=O)O)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
1H-Indole-3-carboxylic acid (960 mg) was dissolved in N,N-dimethylformamide (15 ml) and cooled to 0° C. Sodiumhydride (720 mg) was added in two divided portions thereto, and the mixture was warmed to room temperature and stirred for 1 hour. The mixture was cooled again to 0° C., and a solution of methyl iodide (0.67 ml) in N,N-dimethylformamide (5 ml) was added slowly dropwise thereto, and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to 0° C., then ice was added thereto, water (50 ml) was further added thereto, and precipitated crystals were collected by filtration and washed with water and n-hexane. The product was dried under reduced pressure to give the title compound (910 mg, Y.:87%) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([NH2:9])[N:3]=1.[C:10]12([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2>C(O)C>[C:10]12([N:20]3[CH2:25][CH2:24][N:23]([C:6]4[CH:5]=[C:4]([NH2:9])[N:3]=[C:2]([NH2:1])[N:7]=4)[CH2:22][CH2:21]3)[CH2:17][CH:16]3[CH2:15][CH:14]([CH2:13][CH:12]([CH2:18]3)[CH2:11]1)[CH2:19]2
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: C1CN(C23CC4CC(CC(C4)C2)C3)CCN1
Solvent: CCO
Product: Nc1cc(N2CCN(C34CC5CC(CC(C5)C3)C4)CC2)nc(N)n1
Temperature: 170 °C
Yield: 80.2 %

Procedure:
A mixture of 2,6-diamino-4-chloropyrimidine (0.43 g, 3.0 mmol) and 1-(1-adamantyl)-piperazine (0.66 g, 3.0 mmol) in ethanol (30 ml) was heated in a sealed tube at 170° C. for 3 hours. After cooling the solvent was removed, the solid residue was dissolved in water (45 ml) and acidified to pH=3 with conc. HCl. The obtained mixture was heated to 50° C. the insolubles were filtered off and the clear solution was rendered alkaline with 10N NaOH under stirring and cooling. The precipitated crystals were collected, washed with water until neutral and dried. In this manner 0.79 g of the title compound was obtained in the form of its monohydrate, yield: 76.6%, mp. 265°-268° C.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=1)[CH2:3][NH2:4].[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH2:26][CH3:27])=[CH:20][CH:19]=1)([O:14][CH3:15])=[O:13]>>[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH:26]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]=2)[CH3:27])=[CH:22][CH:23]=1)([O:14][CH3:15])=[O:13]
Reactant: CCC(=O)Cc1ccc(/C=C/C(=O)OC)cc1
Reactant: NCC(O)c1cccc(Cl)c1
Product: COC(=O)/C=C/c1ccc(CCC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 22.3 %

Procedure:
This was prepared in an identical manner to the compound described in Example 1 using 2-hydroxy-2-(3-chlorophenyl) ethanamine (1.71 g) and 4-{(E)-2-carbomethoxyethenyl}phenylbutan-2-one (2.32 g). Elution with 1% methanolchloroform on Kieselgel 60 gave the title compound (0.86 g), m.p. 87°-89° C. (hexane) as a 50:50 mixture of diastereoisomers. τ(CDCl3), 8.9 (3H, d, J=6 Hz), 8.15-8.55 (2H, m), 6.9-7.7 (7H, m, 2H disappears with D2O), 6.3 (3H, s), 5.45 (1H, m), 3.65 (1H, d, J=16 Hz), 2.55-2.9 (8H, m), 2.4 (1H, d, J=16 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:41])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]2C(=O)C3=CC=CC=C3C2=O)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].O.NN>>[CH3:1][C:2]1[NH:3][C:4]([CH3:41])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][NH2:30])=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-:20])=[O:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCN2C(=O)c3ccccc3C2=O)C1c1ccccc1[N+](=O)[O-]
Agent: NN
Solvent: O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCCCCN)C1c1ccccc1[N+](=O)[O-]

Procedure:
Prepared by a method analogous to that of Example 1(b) from 9.1 g (16 mmol) of 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(2-nitrophenyl)-5-(6-phthalimidohexyloxy)carbonyl-pyridine and 2.4 ml (49 mmol) of hydrazine hydrate. 6.2 g (89%) of an orange coloured oil.