Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:33]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])(=[O:36])[CH:34]=[CH2:35]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:38]([O:37][C:33](=[O:36])[CH2:34][CH2:35][N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:31])([F:30])[F:32])[CH:23]=3)=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)([CH3:41])([CH3:40])[CH3:39]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CCN1CCC(c2ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc2)CC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
4-[4-(4-Chloro-3-trifluoromethyl-benzyloxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (1 eq) is dissolved in 10% TFA/DCM and stirred for 30 minutes. After concentration, the residue is re-dissolved in DCM and washed with saturated NaHCO3 and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is then dissolved in MeOH and t-butyl acrylate (2 eq) is added. The resulting solution is heated at 90° C. in microwave for 10 minutes. After concentration, purification by flash column chromatography (80% EtOAc/hexane) gave 3-{4-[4-(4-Chloro-3-trifluoromethyl-benzyloxy)-phenyl]-piperidin-1-yl}-propionic acid tert-butyl ester. [MS: (ES+) 498.2 (M+1)+].
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([CH2:39][C:40]2[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[C:42]([C:50]([F:53])([F:52])[F:51])[CH:41]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>C(OCC)(=O)C>[F:49][C:46]([F:47])([F:48])[C:44]1[CH:45]=[C:40]([CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)[CH:41]=[C:42]([C:50]([F:51])([F:53])[F:52])[CH:43]=1
Reactant: FC(F)(F)c1cc(Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc(C(F)(F)F)c1
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{[3,5-bis(trifluoromethyl)phenyl]-methyl}pyridazine (Intermediate 58a) except that the solvent used for the hydrogenation was tetrahydrofuran and the final compound was recrystallised from a mixture of ethyl acetate and heptanes (27% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.O1[CH2:15][CH2:14][NH:13]C1=O.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:15][CH2:14][NH:13][C:9]2=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NCCO1
Reactant: O=C=Nc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C1NCCN1c1cccc(Cl)c1
Temperature: 195 °C
Yield: 74 %

Procedure:
A mixture of 3-chlorophenyl isocyanate (50 mmoles), 2-oxazolidinone (50 mmoles) and anhydrous AlCl3 (40 mg, 0.3 mmole) is heated at 195° C. for 6 hours with stirring. The reaction mixture is dissolved in dichloromethane and the resulting solution is washed with water twice. The dichloromethane solution is dried and evaporated and the residue distilled at reduced pressure. The distillate is recrystallized from hot hexane to give a yield of 74 percent of the desired product, m.p. 121° C.-123° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:12][N:13]([CH3:18])[CH2:14]N(C)C>CC(O)=O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:12][N:13]([CH3:18])[CH3:14])=[CH:5][NH:6]2
Reactant: CN(C)CN(C)C
Reactant: Cc1cc(C)c2cc[nH]c2c1
Solvent: CC(=O)O
Product: Cc1cc(C)c2c(CN(C)C)c[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4,6-dimethyl-1H-indole (Cho et al., Tetrahedron, 2001, 57, 3321-3330) (93.0 mg, 0.640 mmol) and N,N,N′,N′-tetramethylmethanediamine (98.0 mg, 0.961 mmol) in AcOH (3 mL) was stirred at ambient temperature for 2 h. The reaction mixture was partitioned between EtOAc (20 mL) and saturated NaHCO3 (10 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]2)=[O:10])=[N:7][CH:8]=1.COC(=O)[C:23]1[CH:28]=[CH:27][C:26](C(N2CCN(C(C)C)CC2)=O)=[N:25][CH:24]=1.C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+]>C1COCC1>[CH:17]([N:14]1[CH2:15][CH2:16][N:11]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:25]3[CH2:26][CH2:27][CH2:28][CH2:23][CH2:24]3)=[CH:8][N:7]=2)=[O:10])[CH2:12][CH2:13]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CCN(C(=O)c2ccc(CO)cn2)CC1
Reactant: COC(=O)c1ccc(C(=O)N2CCN(C(C)C)CC2)nc1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)c2ccc(CN3CCCCC3)cn2)CC1
Reaction time: 18 h
Yield: 61 %

Procedure:
(5-Hydroxymethyl-pyridin-2-yl)-(4-isopropyl-piperazin-1-yl)-methanone. A solution of 6-(4-isopropyl-piperazine-1-carbonyl)-nicotinic acid methyl ester (0.500 g, 1.72 mmol) in THF (15 mL) was cooled to −78° C. in a dry ice bath. A solution of lithium tri-tert-butoxyaluminohydride (1 M in THF, 3.44 mL) was then added drop-wise to the reaction mixture. The resulting solution was allowed to come to rt and was stirred for 18 h. The reaction was quenched with satd. aq. potassium sodium tartrate (Rochelle's salt, 15 mL) and extracted with DCM (3×50 mL). The organic layers were combined, dried (Na2SO4), and concentrated to give the title compound (0.275 g, 61%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH2:21])=[CH:17][CH:16]=1>CCO>[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([CH2:19][CH2:20][NH:21][CH2:2][CH:3]2[CH2:12][CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4]2)=[CH:17][CH:16]=1
Reactant: BrCC1CCc2ccccc2C1
Reactant: COc1ccc(CCN)cc1
Solvent: CCO
Product: COc1ccc(CCNCC2CCc3ccccc3C2)cc1
Yield: 59 %

Procedure:
A solution of 2-bromomethyl-1,2,3,4-tetrahydronaphthalene (1.33 g, 5.91 mmol) and 4-methoxyphenethylamine (1.79 g, 11.8 mmol) in 50 ml of EtOH was refluxed for 48 hours. After removal of EtOH in vacuo, the residue was dissolved in 100 ml of CHCl3, washed with 10% K2CO3, H2O, sat'd brine, and then dried over Na2SO4. Filtration followed by evaporation of solvent gave a yellow oil, which was purified by chromatography (SiO2, MeOH:CHCl3, 5:95) to a give a yellowish oil (1.03 g, 58.9%). The product was converted to HCl salt, crystallization with MeOH/Et2O gave a white powder. mp 274-275° C..; Calcd for C20H25NO.HCl: C 72.37, H 7.91, N 4.22; Found C 72.40, H 7.76, N 4.13.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])[O:9][N:8]=1
Reactant: COc1ccc(Br)cc1-c1nc(-c2ccccn2)no1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccn2)cc1-c1nc(-c2ccccn2)no1
Temperature: 100 °C
Yield: 25.4 %

Procedure:
In a similar fashion, a mixture of 3-(2-pyridyl)-5-(5-bromo-2-methoxyphenyl)-1,2,4-oxadiazole (110 mg, 0.331 mmol), pyridine-2-tributyltin (138.8 mg, 0.663 mmole) and Pd(PPh3)4 (38.5 mg, 0.0333 mmole) in tetrahydrofuran (1 mL) was heated in a sealed vial overnight at 100° C. Standard work up afforded 13.9 mg (13%) 3-(2-pyridyl)-5-[2-methoxy-5-(2-pyridyl)phenyl]-1,2,4-oxadiazole.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]([NH:11][CH2:12][CH2:13][C:14]1[C:18]2[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=2[NH:16][CH:15]=1)=[O:10]>C1C=CC=CC=1>[CH3:24][O:23][C:20]1[CH:19]=[C:18]2[C:17](=[CH:22][CH:21]=1)[NH:16][CH:15]=[C:14]2[CH2:13][CH2:12][N:11]([C:1]([CH3:2])=[O:3])[C:9](=[O:10])[CH3:8]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Solvent: c1ccccc1
Product: COc1ccc2[nH]cc(CCN(C(C)=O)C(C)=O)c2c1
Yield: 50 %

Procedure:
Acetic anhydride (7 ml) is added with stirring to melatonin (500 mg) dissolved in benzene (50 ml). The mixture is heated for 72 h in refluxing benzene. The solvent is evaporated off and the crude product is taken up in water and then neutralized with sodium carbonate solution (pH>8). After extraction (dichloromethane), washing (water) and drying (magnesium sulphate), the crude product is flash-chromatographed (EtOAc eluent). N-[2-(5-Methoxyindol-3-yl)ethyl]diacetamide (4) (300 mg, 50% yield) is obtained.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:19][NH2:20]>CC(O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([NH:20][CH3:19])[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: CN
Solvent: CC(C)O
Product: CNc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)o1
Yield: 86 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), an aqueous solution of 30% methylamine (4.0 ml) and 2-propanol (20 ml) was stirred in a sealed tube at 100° C. for 4 hours. The reaction mixture was concentrated, and water was added to the resulting residue. The pH was then adjusted 3 with 2 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-methylamino-5-oxazolepropionic acid (1.21 g, 86%). This was recrystallized from ethanol to give colorless prisms. mp 217-218° C.
Reaction SMILES: [OH:1][C:2]1([CH2:18][C:19]#[N:20])[C:13]2[C:12]3[O:11][C:10]([CH3:14])=[N:9][C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH:3]1[CH:15]([CH3:17])[CH3:16].N.[CH2:22]([OH:24])[CH3:23].C(N(CC)CC)C.C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C(O)C.[Co]>[OH:1][C:2]1([CH2:18][CH2:19][NH:20][C:22](=[O:24])[CH3:23])[C:13]2[C:12]3[O:11][C:10]([CH3:14])=[N:9][C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH:3]1[CH:15]([CH3:17])[CH3:16]
Reactant: Cc1nc2ccc3c(c2o1)C(O)(CC#N)C(C(C)C)C3
Reactant: CCO
Agent: [Co]
Agent: N
Agent: O=C([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCC1(O)c2c(ccc3nc(C)oc23)CC1C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 19 %

Procedure:
To a solution of (8-hydroxy-7-isopropyl-2-methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)acetonitrile (584 mg, 2.16 mmol) in ethanol (11 mL) were added Raney cobalt (5.84 g) and 2M ammonia/ethanol solution (11 mL), and the mixture was stirred at room temperature for 24 hr under a hydrogen atmosphere. The catalyst was filtered off using celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (11 mL), triethylamine (82.9 μL, 0.594 mmol) and acetic anhydride (51.0 μL, 0.540 mmol) were added under ice-cooling, and the mixture was stirred for 5 min. To the reaction solution was added saturated aqueous sodium hydrogencarbonate solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (132 mg, yield 19%).
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][O:3]2.C1(C)C=CC=CC=1.C[Al](C)C.[Cl:20][C:21]1[C:22]2[N:23]([C:31]([C:34](OCC)=[O:35])=[N:32][N:33]=2)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.Cl>C1COCC1>[C@H:2]12[CH2:8][C@H:5]([N:6]([C:34]([C:31]3[N:23]4[CH:24]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:26]=[C:21]([Cl:20])[C:22]4=[N:33][N:32]=3)=[O:35])[CH2:7]1)[CH2:4][O:3]2
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: CCOC(=O)c1nnc2c(Cl)cc(C(F)(F)F)cn12
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(c1nnc2c(Cl)cc(C(F)(F)F)cn12)N1C[C@@H]2C[C@H]1CO2
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a mixture of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (100 mg) and anhydrous THF (4 mL) was added dropwise trimethylaluminium toluene solution (1.8 M, 0.410 mL) in an ice bath. The reaction solution was stirred at the same temperature for 1 hr under argon gas atmosphere, ethyl 8-chloro-6-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (180 mg) was added thereto, and the mixture was stirred at room temperature for 2 days. The reaction mixture was slowly added to 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (47 mg).
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[C:11]([O:19][CH2:20][CH3:21])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH2:20]([O:19][C:11]1[C:10]([NH:9][C:8]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:22])=[CH:15][C:14]([CH2:16][CH3:17])=[C:13]([CH3:18])[N:12]=1)[CH3:21]
Reactant: CCOc1nc(C)c(CC)cc1NC(=O)Oc1ccccc1
Reactant: Clc1cccc(N2CCNCC2)c1
Product: CCOc1nc(C)c(CC)cc1NC(=O)N1CCN(c2cccc(Cl)c2)CC1
Yield: 83 %

Procedure:
Phenyl-N-(2-ethoxy-5-ethyl-6-methylpyridin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C(OC(C)C)(=O)C.[F:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([C:22]([OH:24])=O)[CH2:13][C:12]2=1.[OH-].[NH4+:26].C(Cl)(=O)C(Cl)=O>O.CN(C=O)C>[F:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH:14]([C:22]([NH2:26])=[O:24])[CH2:13][C:12]2=1
Reactant: [NH4+]
Reactant: O=C(O)C1CCc2[nH]c3ccc(F)cc3c2C1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)C1CCc2[nH]c3ccc(F)cc3c2C1
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Isopropyl acetate (570 mL, 488 g) was charged to a (3-L) four-necked reactor (reactor A) equipped with mechanical stirrer, condenser with nitrogen inlet, powder addition funnel, and a thermocouple. 6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (Example 90) was charged to the reactor with stirring. The reaction mixture was cooled to 5-10° C. with an ice-bath and DMF (13.8 g) was added. Ammonium hydroxide (28% aqueous, 607 g) and water (144 g) were added to another (5-L), 4-neck reactor (reactor B) equipped with an overhead stirrer, thermocouple, and condenser under nitrogen. The contents of reactor B were cooled 5-10° C. Reactor B was connected to a caustic scrubber. Oxalyl chloride (94.3 g, 0.74 mol) was added through an addition funnel to the stirring slurry in reactor A maintaining temperature between 5 and 15° C. The funnel was rinsed with 50 mL of isopropyl acetate and the reaction mixture was allowed to warm to 10-15° C. The reaction mixture was stirred for an additional 30 min after addition of oxalyl chloride and an aliquot (3 drops) of the reaction mixture was quenched with 0.11 mL of 28% aq. ammonium hydroxide then diluted with CH3CN to 2 mL, and monitored for disappearance of the acid by HPLC (<10-11 area % of the acid). When the reaction was complete, the contents of reactor A were cooled to 5-10° C. The acid chloride from reactor A was transferred to the cooled ammonium hydroxide solution in reactor B over 30 min to 45 min maintaining temperature between 5-15° C. followed by a 50 mL isopropyl acetate rinse. The reaction mixture was stirred at 5-10° C. for 30 min when solids separated out. Heptane (540 mL) was charged at 10-15° C. and stirring continued for 30 min. The slurry was filtered through a funnel lined with polypropylene and the collected solid washed with 800 mL of cold water followed by 800 mL of n-heptane. The solid was dried under vacuum (<20 mm Hg) at 40° C. to give 140.4 g of 6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid amide (94% yield). Chiral purity is 99.4% by HPLC and MW 232(LC/MS).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].O>CN1C(=O)CCC1>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[C:4]([NH2:18])[N:3]=2)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1nc(N)nc(Cl)c1C#Cc1ccc(N)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1nc(N)nc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
The title compound is synthesized according to general procedure GP7 starting from 5.0 g (19.3 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidin-2-ylamine and 3.94 g (21.2 mmol) N-Boc-piperazine using 2.94 mL (21.2 mmol) triethylamine in 30 mL NMP. Work up is performed by addition of 500 mL water to the reaction mixture and stirring for 30 min. The solid material is filtered off, washed with water (50 mL three times) yielding 7.25 g (17.7 mmol) of the desired product with sufficient purity.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:8]=[N:7][C:6]([C:9]([O:11]CCCC)=O)=[CH:5][CH:4]=1>CO>[Cl:2][C:3]1[N:8]=[N:7][C:6]([C:9]([NH2:1])=[O:11])=[CH:5][CH:4]=1
Reactant: N
Reactant: CCCCOC(=O)c1ccc(Cl)nn1
Solvent: CO
Product: NC(=O)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.5 %

Procedure:
Excess gaseous ammonia was added to an ice bath cooled solution of n-butyl 6-chloropyridazine-3-carboxylate (40 g) in methanol (280 ml). The mixture was stirred at ambient temperature for 4 hours and the resulting residue filtered off, washed with methanol (20 ml) and dried to give 6-chloropyridazine-3-carboxamide (28.05 g, 95.5% yield), mpt. 243°-5° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][CH2:11][C:12]([NH:14][C@@H:15]([C:17]([NH:19][CH2:20][C:21]([O:23]CC1C=CC=CC=1)=[O:22])=[O:18])[CH3:16])=[O:13])=[O:9])[CH3:7])=[O:4].[ClH:31]>C(O)(=O)C>[NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:8]([NH:10][CH2:11][C:12]([NH:14][C@@H:15]([C:17]([NH:19][CH2:20][C:21]([OH:23])=[O:22])=[O:18])[CH3:16])=[O:13])=[O:9])[CH3:7])=[O:4].[ClH:31]
Reactant: C[C@H](NC(=O)CN)C(=O)NCC(=O)N[C@H](C)C(=O)NCC(=O)OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: C[C@H](NC(=O)CN)C(=O)NCC(=O)N[C@H](C)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 100 %

Procedure:
To Gly-Ala-Gly-DAla-Gly-OBzl prepared as in Example 34C (13.4 g, 25.7 mol) in glacial acetic acid (400 ml) was added concentrated HCl (100 ml) and the reaction mixture was stirred at room temperature for 24 h. The solution was concentrated in vacuo, dissolved in water (100 ml) and the resulting aqueous solution was washed with ether (2×50 ml) and concentrated again in vacuo. Drying at high vacuum afforded 9.70 g (100% yield) of the product as a white powder: 1H NMR (D2O) δ 1.38 (d, J=7.2 Hz, 3 H), 1.39 (d, J=7.2 Hz, 3 H), 3.84 (s, 2 H), 3.92 (s, 2 H), 3.96 (s, 2 H), 4.34 (m, 2 H).
Reaction SMILES: Cl.CN.[CH:4]([N:7](C(C)C)CC)(C)C.[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]2[CH2:25][O:24]2)[CH:20]=[CH:21][CH:22]=1.C(OCC)(=O)C>CO>[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]([OH:24])[CH2:25][NH:7][CH3:4])[CH:20]=[CH:21][CH:22]=1
Reactant: COCOc1cccc(C2CO2)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCC(O)c1cccc(OCOC)c1
Temperature: 25 °C
Yield: 20 %

Procedure:
Methylamine hydrochloride (275 mg, 4.08 mmol) and diisopropylethylamine (601 mg, 4.66 mmol) were sequentially added to a solution of 2-(3-methoxymethoxy-phenyl)-oxirane (210 mg, 1.16 mmol) in anhydrous methanol (5 mL). The resulting mixture was maintained at ambient temperature for about 12 hours. Following standard extractive workup with ethyl acetate, the crude product was purified by flash column chromatography on silica gel (1×15 cm, dichloromethane/methanol/NH4OH=90/8/1 elution) to give the title product (49 mg, 20%). 1H NMR (300 MHz, CDCl3) δ 7.26-7.23 (m, 1H), 7.06 (s, 1H), 7.00 (d, 1H, J=7.5 Hz), 6.95 (d, 1H, J=6.9 Hz), 5.18 (s, 2H), 4.71 (d, 1H, J=5.7 Hz), 3.48 (s, 3H), 2.84-2.62 (m, 2H), 2.46 (s, 3H); LC-MS: m/z=212 (MH)+.
Reaction SMILES: [CH3:1]I.[H-].[Na+].[CH:5]([C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:11]([CH2:26][OH:27])=[C:10]([CH:28]([CH3:30])[CH3:29])[N:9]=1)([CH3:7])[CH3:6].O>O1CCCC1>[CH:5]([C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:11]([CH2:26][O:27][CH3:1])=[C:10]([CH:28]([CH3:29])[CH3:30])[N:9]=1)([CH3:7])[CH3:6]
Reactant: CI
Reactant: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C(C)C)nc(C(C)C)c(COC)c1-c1ccc(F)cc1
Reaction time: 2 h

Procedure:
0.57 ml (9.2 mmol) of methyl iodide and, at -50° C. 327 mg (10.9 mmol) of 80% strength sodium hydride are added under a nitrogen atmosphere to 3 g (8.4 mmol) of the compound from Example 4 in 100 ml of dry tetrahydrofuran. The mixture is stirred for 2 hours and the temperature is allowed to rise to 25° C. in the course of this. Water is cautiously added to the mixture and it is extracted several times using ether, and the organic phase is dried over sodium sulphate and concentrated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[O:19][CH3:20].C1COCC1>C(O)C>[F:1][C:2]1[CH:24]=[C:23]([CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[O:19][CH3:20])[NH2:25]
Reactant: COc1cc(C#Cc2ccccn2)ccc1Oc1ccc([N+](=O)[O-])cc1F
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(CCc2ccccn2)ccc1Oc1ccc(N)cc1F

Procedure:
According to the procedure of example 20(b) except substituting 4-ethyl-2-methoxy-1-[4-nitro-2-(trifluoromethyl)phenoxy]benzene by 2-{[4-(2-fluoro-4-nitrophenoxy)-3-methoxy phenyl]ethynyl}pyridine (0.23 mmol; 84 mg) and THF by ethanol, the title compound was obtained as a clear oil (68%, 53 mg) 10 after purification on preparative TLC (cyclohexane/ethyl acetate: 6/4).
Reaction SMILES: B(F)(F)F.CCOCC.[CH2:10]([O:17][C@@H:18]1[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:26]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:25]([CH2:44][O:45]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:24][C@@H:19]1[O:20][CH2:21][CH:22]=[CH2:23])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[SiH](CC)(CC)CC.C([O-])(O)=O.[Na+]>CC#N.C(Cl)Cl.O>[CH2:10]([O:17][C@@H:18]1[C@@H:27]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:26]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:25]([CH2:44][OH:45])[O:24][C@@H:19]1[O:20][CH2:21][CH:22]=[CH2:23])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CCO[C@H]1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CC#N
Solvent: O
Product: C=CCO[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of BF3.OEt2 (5.0 ml, 39.8 mmol) in MeCN (90 ml) was added dropwise to a cooled (0°) solution of 3 (13.4 g, 18.3 mmol) and Et3SiH (14.5 ml, 91.5 mmol) in dry CH2Cl2 (150 ml). After 10 min., a sat. aq. solution of NaHCO3 (100 ml) and H2O (200 ml) were added. The mixture was shaken vigorously, the aq. layer was extracted with CH2Cl2, the combined organic layers were extracted with brine, dried (MgSO4), and evaporated. FC (400 g SiO2, EtOAc/hexane 1:5→EtOAc/hexane 1:1) affored 8.35 g (93%) of 4. Rf (EtOAc/hexane 1:2) 0.20.