Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[CH2:47]O.P(Br)(Br)[Br:50].N1C=CC=CC=1>CCOCC>[CH2:31]([O:30][C@H:11]1[C@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:47][Br:50])[CH:4]=2)[O:9][C@@H:10]1[CH2:38][O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Temperature: 25 °C
Reaction time: 15 h
Yield: 203.6 %

Procedure:
To a solution of alcohol 105 (5.33 g, 8.01 mmol) in ether (50 mL) were added phosphorus tribromide (0.26 mL, 2.80 mmol) and catalytic amount of pyridine at 0° C. The mixture was allowed to warm to room temperature and stirred at room temperature for 15 hours. The mixture was extracted with EtOAc/H2O (100 mL/150 mL). The combined organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the title bromide 106 (4.15 g, 71%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH2:12]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>CCOC(C)=O.O>[CH2:25]([O:24][C:22]([N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)[CH2:12]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2ccc([N+](=O)[O-])cc2C1
Yield: 91.8 %

Procedure:
To a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (11.0 g, 51.25 mmol) in EtOAc (150 mL) at 0° C. in an ice bath add a solution of K2CO3 (15.65 g, 113.25 mmol) in water (150 mL) followed by benzyl chloroformate (8.37 mL, 56.37 mmol) and vigorously stir the reaction at room temperature for 24 h. Separate the layers and extract the aqeuous with more EtOAc (150 mL). Wash the organics with sat. NaHCO3 (200 mL), sat. NH4Cl (200 mL) and water (200 mL), then dry (Na2SO4). Concentrate in vacuo to give 14.70 g of 7-nitro-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as an oil which partially crystallizes.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH:5]1[NH:9]C(=O)N[C:6]1=[O:11].N1C=CN=C1.[OH2:17]>>[NH2:9][C@H:5]([C:6]([OH:11])=[O:17])[CH2:4][CH2:3][S:2][CH3:1]
Reactant: O
Reactant: CSCCC1NC(=O)NC1=O
Agent: c1c[nH]cn1
Product: CSCC[C@H](N)C(=O)O
Yield: 80 %

Procedure:
A mixture of 1.74 g. of 5-(β-methylthioethyl)hydantoin, 68 mg. of imidazole and 20 ml. of water was heated to 160° C. in a 50 ml. autoclave, and was allowed to react at 160° C. for 6 hours. After the reaction was over, the autoclave was rapidly cooled. The reaction mixture was treated by the same after-treatment as in Example 1 and methionine was obtained in yield of 80%.
Reaction SMILES: [CH:1]1([CH2:4][C:5](=O)/[C:6](/[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:12]=2)=[CH:7]\N(C)C)[CH2:3][CH2:2]1.Cl.[NH2:26][C:27]([NH2:29])=[NH:28].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][C:5]2[C:6]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[N:12]=3)=[CH:7][N:26]=[C:27]([NH2:29])[N:28]=2)[CH2:3][CH2:2]1
Reactant: CN(C)/C=C(\C(=O)CC1CC1)c1ccnc(Nc2ccncc2)n1
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ncc(-c2ccnc(Nc3ccncc3)n2)c(CC2CC2)n1
Temperature: 60 °C
Yield: 31.3 %

Procedure:
To a solution of (3Z)-1-cyclopropyl-4-(dimethylamino)-3-[2-(pyridin-4-ylamino)pyrimidin-4-yl]but-3-en-2-one (9) (80 mg, 0.247 mmol) in DMF (2061 μl), Guanidine HCl (35.3 mg, 0.371 mmol) and potassium carbonate (103 mg, 0.742 mmol) were added and the reaction was heated at 60° C. for 4 hours. The crude product was purified by reverse-phase HPLC [30-90% organic phase over 15 minutes] followed by Biotage™ silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product as a white solid (24.72 mg, 31.3% yield). 1H NMR (400 MHz, MeOD) δ ppm 0.01-0.14 (m, 2H) 0.39 (q, J=6.06 Hz, 2H) 0.94-1.10 (m, 1H) 2.87 (d, J=7.07 Hz, 2H) 7.10 (d, J=5.05 Hz, 1H) 7.83 (d, J=6.57 Hz, 2H) 8.30 (d, J=6.57 Hz, 2H) 8.41 (s, 1H) 8.57 (d, J=5.05 Hz, 1H). HRMS (ES+) for C17H17N7.H+ [MH+]: calcd, 320.1624; found, 320.1636. UV-LC: 100% UV purity at 254/214 nm; tR=4.67 minute over 7.75 minutes.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])(=O)C>CO.Cl>[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:12]
Reactant: CC(=O)Nc1ccccc1C(=O)C1CCCCC1
Agent: Cl
Solvent: CO
Product: Nc1ccccc1C(=O)C1CCCCC1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of (2-acetamidophenyl) cyclohexyl methanone (0.53 g) in methanol (5 ml) and concentrated hydrochloric acid (15 ml) was heated at 80° C. for 1 hour. After this time the solution was cooled to ambient temperature and the solvents removed in vacuo. The residue was dissolved in water (10 ml) and basified with 4N sodium hydroxide solution (20 ml). The mixture was then extracted into ethyl acetate (4×20 ml) and the organic layers combined and dried (MgSO4). The solvent was evaporated and the residue chromatographed on silica gel using petrol:ethyl acetate (2:1), to afford the title compound (0.40 g) as a solid. The spectroscopic properties of this material were identical to those described in Method A.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[C:12]([C:14]#[N:15])[N:13]=1.CO>[Pd].CCOC(C)=O>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:11]2[O:10][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])=[N:13][C:12]=2[C:14]#[N:15])=[CH:22][CH:21]=1
Reactant: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1nc(-c2c(F)cccc2F)oc1Nc1ccc(N)cc1
Yield: 90.7 %

Procedure:
A solution of 2-(2,6-difluorophenyl)-5-(4-nitrophenylamino)oxazole-4-carbonitrile (0.435 g, 1.271 mmol) in 50:50 MeOH:EtOAc (10 ml) was hydrogenated using a 10% Pd/C catalyst at 30° C. at atmospheric pressure using the Thales H-Cube at a flow rate of 1 ml/min. The organic layer was then reduced in vacuo to yield 5-(4-aminophenylamino)-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.360 g, 1.153 mmol, 90%). 1H NMR (CD3OD) δ 6.74 (2H, d), 7.10 (2H, d), 7.14 (2H, t), 7.55 (1H, m). LCMS (2) Rt: 2.47 min; m/z (ES+) 313.
Reaction SMILES: [C:1]1([CH2:14][C:15]#[N:16])[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[O:3][CH:2]=1)[O:10][CH2:9][CH:8]=[CH:7]3.[H][H]>C(O)C.N.[Ni]>[C:1]1([CH2:14][CH2:15][NH2:16])[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[O:3][CH:2]=1)[O:10][CH2:9][CH2:8][CH2:7]3
Reactant: N#CCc1coc2ccc3c(c12)C=CCO3
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCCc1coc2ccc3c(c12)CCCO3

Procedure:
1.4 mmol of compound obtained in stage E are dissolved in 30 ml of ethanol saturated with ammonia, in the presence of 400 mg of Nickel (Raney). The reaction mixture is stirred at 50° C. under 50 atm of hydrogen during 5 hours. After cooling and filtration of the catalyst, the filtrate is concentrated, dissolved in a mixture of ether/water and extracted. The organic layer is dried over magnesium sulfate and concentrated to yield the title product.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[N:21]1([CH2:26][C@@H:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(OCC)(=O)C>C(O)C>[N:21]1([CH2:26][C@@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1Nc2cccnc2N(C(=O)CN2CCC[C@H]2CN2CCCC2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 31 from 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and (S)-(+)-2-[(1-pyrrolidinyl)methyl]pyrrolidine to give colorless crystals, mp. 192°-193° C. (ethyl acetate). [α]D20 =-18.1° (ethanol).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[CH2:4][C@H:3]1[OH:14].C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[Cl:22][CH2:23][C:24]([NH:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:12][CH3:13])[CH2:4][C@H:3]1[OH:14])=[O:25]
Reactant: O=C(Cl)CCl
Reactant: COc1cccc2c1C[C@@H](N)[C@H](O)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1C[C@@H](NC(=O)CCl)[C@H](O)C2
Reaction time: 2 h

Procedure:
1.01 g (0.005M) of trans-3-amino-1,2,3,4-tetrahydro-5-methoxy-2-naphthalinol are dissolved in 50 ml of absolute methylene chloride. 0.81 g (0.008M) of triethylamine are added, and the mixture left to cool to 0°. At this temperature, 0.68 g (0.006M) of chloroacetyl chloride (dissolved in 5 ml of absolute methylene chloride) are then added in drops over the course of 5 minutes. Stirring is effected for 2 hours at room temperature. The reaction mixture is subsequently washed once with 1N hydrochloric acid and once with ice water. It is extracted three times, each with 20 ml of methylene chloride, the combined organic phases are dried, and the solvent is concentrated by evaporation. Trans-2-chloro-N-(1,2,3,4-tetrahydro-2-hydroxy-5-methoxy-3-naphthalinyl)-acetamide is obtained (m.p. 176°-178°, recrystallisation from methylene chloride/ether).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:10][CH:11]([CH2:14][OH:15])[CH2:12][OH:13])=[N:4][CH:5]=[N:6][C:7]=1[CH2:8][CH3:9].[CH3:16][C:17](=O)[CH2:18][CH2:19][CH2:20][CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:18]([C:17]1([CH3:16])[O:15][CH2:14][CH:11]([NH:10][C:3]2[C:2]([Cl:1])=[C:7]([CH2:8][CH3:9])[N:6]=[CH:5][N:4]=2)[CH2:12][O:13]1)[CH2:19][CH2:20][CH3:21]
Reactant: CCc1ncnc(NC(CO)CO)c1Cl
Reactant: CCCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC1(C)OCC(Nc2ncnc(CC)c2Cl)CO1

Procedure:
2.16 g (9 mmol) of 5-chloro-6-ethyl-4-(1,3-dihydroxy-2-propylamino)-pyrimidine (Example 1), 1.80 g (18 mmol) of 2-hexanone and 500 mg of p-toluenesulfonic acid were heated in 100 ml of toluene for 8 hours, using a water separator. After the mixture had been extracted by stirring with dilute sodium hydroxide solution, the organic phase was dried and concentrated. The cis/trans isomers were separated by chromatography over silica gel (mobile phase: ethyl acetate/petroleum ether 4:1). 0.29 g of trans isomer (10.3% of theory, colorless oil) was first eluted, followed by 0.49 g of the cis isomer (17.3% of theory, colorless oil).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([O:10]C1C=C(Cl)C(Cl)=CC=1Cl)=O.[NH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH2:29])[N:23]=1>CN(C)C=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:29][C:8](=[O:10])[CH2:7][N:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[N:23]=1)=[O:10]
Reactant: NCc1cccc(CN)n1
Reactant: O=C(CN1CCCC1=O)Oc1cc(Cl)c(Cl)cc1Cl
Solvent: CN(C)C=O
Product: O=C(CN1CCCC1=O)NCc1cccc(CNC(=O)CN2CCCC2=O)n1
Temperature: 60 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
0.02 mol of 2,4,5-trichlorophenyl 2-oxo-pyrrolidineacetate is dissolved in 50 ml of dimethylformamide and reacted with a solution of 0.01 mol of 2,6-diaminomethylpyridine in 20 ml of dimethylformamide, at -5° C., whilst stirring and with the exclusion of moisture. After leaving the reaction solution to stand at room temperature for three hours, it is warmed to 60° C. for 2 hours, the solvent is then evaporated off, ether is added to the residue and the crystals which precipitate are filtered off. Melting point: 149° C., yield 57% of theory
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:3]=1.Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(N(C(C)C)C(C)C)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:13]=[CH:12][C:10]([NH:11][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1nc(-c2ccc(N)cc2)no1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1ccc(-c2noc(C)n2)cc1

Procedure:
Prepared analogously to Example 9a from 4-(5-methyl-1,2,4-oxadiazol-3-yl)-aniline and ethyl bromoacetate in N-ethyl-diisopropylamine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.C1CCCCC1.[C:31](=[O:33])=[O:32]>C1COCC1>[C:1]([O:5][C:6]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[C:31]([OH:33])=[O:32])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1C(=O)O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A solution of (4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (2.31 g, 8.33 mMol) in anhydrous THF (50 mL) at −78° C. was treated with a 1.4 M solution of sec-butyllithium in cyclohexane (13 mL, 18.33 mMol), at a rate which did not allow the internal temperature to exceed −60° C. The solution was stirred at −78° C. for 15 minutes, then allowed to warm to −40° C. and stirred for 2.5 hours. The reaction was treated with gaseous CO2, stirred 30 minutes while warming to −20° C., then quenched with saturated ammonium chloride. The mixture was warmed to room temperature, and extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated in-vacuo. The residue was triturated with hot heptane to yield 1.9 g of white powder as product. NMR (500 MHz, DMSO) δ 12.89 (s, 1H), 8.24 (d, 1H, J=9 Hz), 7.84 (s, 1H), 7.21 (d, 1H, J=7 Hz), 1.51 (s, 9 Hz). Yield=72%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][C:12]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[Cl:23][CH2:24][C:25](Cl)=O>>[C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][CH2:9][N:10]1[C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:21]=[C:25]1[CH2:24][Cl:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Reactant: O=C(Cl)CCl
Product: CC(C)(C)OC(=O)NCCn1c(CCl)nc2cnc3ccccc3c21
Yield: 72 %

Procedure:
Using the general method of Example 5 Part A, tert-butyl[2-(3-aminoquinolin-4-ylamino)ethyl]carbamate (43.5 g, 144 mmol) was reacted with chloroacetyl chloride (17.72 g, 158 mmol) to provide 37.39 g of tert-butyl[2-(2-chloromethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]carbamate.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:17][C:18]([F:21])([F:20])[F:19])[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:5])C.[OH-].[Na+].Cl>CO>[C:11]1([C:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]([CH2:17][C:18]([F:19])([F:20])[F:21])[N:8]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)nn1CC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(-c2ccccc2)nn1CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid ethyl ester (360 mg, 1.21 mmol) and 1N aqueous sodium hydroxide solution (3.6 mL, 3.6 mmol) in methanol (10 mL) was stirred at room temperature overnight. The reaction mixture was acidified to pH˜2 with 1N aqueous hydrochloric acid and concentrated to give 5-phenyl-2-(2,2,2-trifluoro-ethyl)-2H-pyrazole-3-carboxylic acid as an off-white solid, which was directly used in the next step reaction without further purification. LCMS calcd for C12H9F3N2O (m/e) 270, obsd 271 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH2:3][CH2:2]1.[CH:18]12[NH:25][CH:22]([CH2:23][CH2:24]1)[CH2:21][CH:20]([OH:26])[CH2:19]2>>[OH:26][CH:20]1[CH2:19][CH:18]2[N:25]([C:12]([C:11]3[CH:15]=[CH:16][CH:17]=[C:9]([O:8][CH2:7][CH:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[CH:10]=3)=[O:14])[CH:22]([CH2:23][CH2:24]2)[CH2:21]1
Reactant: O=C(O)c1cccc(OCC2CCOCC2)c1
Reactant: OC1CC2CCC(C1)N2
Product: O=C(c1cccc(OCC2CCOCC2)c1)N1C2CCC1CC(O)C2

Procedure:
Prepared from 3-(tetrahydro-pyran-4-yl-methoxy)-benzoic acid and 8-aza-bicyclo[3.2.1]octan-3-ol. LC-MS (m/z): 346 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[N:6][N:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[N:4]=1.[S-:20][C:21]#[N:22].[K+].O1CCCC1>O>[Cl:19][C:9]1[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:5]1[N:6]=[C:7]([S:20][C:21]#[N:22])[C:3]([CH3:2])=[N:4]1
Reactant: N#C[S-]
Reactant: FC(F)(F)c1cc(Cl)c(-n2ncc(CBr)n2)c(Cl)c1
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1SC#N

Procedure:
4-Bromomethyl-2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole (9.55 g), potassium thiocyanate (1 g) and tetrahydrofuran (50 ml) were heated under reflux for 3 hours. The mixture was poured into water, solid collected and recrystallised from ethyl aceteate/hexane to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-thiocyanato-methyl-2H-1,2,3-triazole, m.p. 115°-117°. (Compound 23)
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH3:15])[N:5]([C:7]2[CH:12]=[N:11][N:10]([CH3:13])[C:9](=[O:14])[CH:8]=2)[CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[Cl:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([C:49]#[CH:50])[CH:44]=1>[Cu]I>[Cl:42][C:43]1[CH:44]=[C:45]([C:49]#[C:50][C:2]2[N:3]=[C:4]([CH3:15])[N:5]([C:7]3[CH:12]=[N:11][N:10]([CH3:13])[C:9](=[O:14])[CH:8]=3)[CH:6]=2)[CH:46]=[CH:47][CH:48]=1
Reactant: Cc1nc(I)cn1-c1cnn(C)c(=O)c1
Reactant: C#Cc1cccc(Cl)c1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cnn(C)c(=O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
A solution of 8 mg bis(triphenyl-phosphine)palladium dichloride in 3 ml of DMF was degassed with argon. Then 52 mg (0.165 mmol) 5-(4-iodo-2-methyl-imidazol-1-yl)-2-methyl-2H-pyridazin-3-one, 1 mg (0.03 mmol) of triphenylphosphine, 0.046 ml (0.33 mmol) triethylamine were added and the mixture was stirred for 5 min at room temperature. Then 1 mg (0.005 mmol) of copper(I) iodide and 0.042 ml (0.33 mmol) of 1-chloro-3-ethynyl-benzene were added and the mixture was stirred for 2 h at 50° C. The mixture was evaporated to dryness in vaccuo, taken up in 5 ml of ethyl acetate. Then ca. 1 g of silicagel was added and the suspension was evaporated to dryness. The silicagel containing adsorbed product was loaded onto a 20 g flash chromatography column. The product was eluted with ethyl acetate. The pure fractions were concentrated to yield 36 mg (0.111 mmol, 67%) of the title compound as a light yellow crystalline solid, MS: m/e=325.2, 327.2 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:27]=[CH:26][C:11]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([CH3:25])=[C:22]([OH:24])[CH:23]=3)[N:15]=[N:14]2)=[CH:10][CH:9]=1.[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43]Br)[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]>O1CCCC1.CN(C)C=O>[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43][O:24][C:22]3[CH:23]=[C:18]([C:16]4[N:15]=[N:14][N:13]([CH2:12][C:11]5[CH:26]=[CH:27][C:8]([Cl:7])=[CH:9][CH:10]=5)[CH:17]=4)[CH:19]=[CH:20][C:21]=3[CH3:25])[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Reactant: Cc1ccc(-c2cn(Cc3ccc(Cl)cc3)nn2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4cn(Cc5ccc(Cl)cc5)nn4)ccc3C)csc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A suspension of cesium carbonate (1.11 g, 3.41 mmol), 5-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-2-methyl-phenol (0.75 g, 2.50 mmol) (from Example 34 supra) in tetrahydrofuran-N,N-dimethylformamide (5:2, 23 mL) was heated at 70° C. for 2 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.76 g, 2.27 mmol) (from Example 1 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The precipitate was filtered, washed with ethyl acetate and dried to give 4-chloro-3-{5-[1-(4-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-2-methyl-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.33 g, 26%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:4](=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:14][CH:15]=2)[N:5]=[CH:6][C:7]=1[C:8]([O:10]CC)=O.C(N(CC)CC)C.[C:28]1([NH:34][NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>C(O)C>[O:10]=[C:8]1[C:7]2[C:2]([C:3]3[C:4](=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:14][CH:15]=3)[NH:5][CH:6]=2)=[N:35][N:34]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cnc2c(C(=O)OCC)[nH]cc2c1Cl
Reactant: NNc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1[nH]cc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c12
Temperature: 75 °C

Procedure:
One equivalent of crude diethyl 4-chloro-6H-pyrrolo[3,4-b]pyridine-3,7-dicarboxylate was dissolved in ethanol (0.2 M) under an atmosphere of nitrogen. Following the addition of 2 equivalents of triethylamine and 1.2 equivalents of phenyl hydrazine, the reaction was heated at 75° C. for 21 hours. After cooling to room temperature a large excess of 1 N NaOH was added and after 5 hours the reaction was concentrated to dryness. 10% HCl (aq.) was added and the brown precipitate was collected by filtration and washed with methylene chloride to afford the product as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.35 (br. s., 3H) 4.23-4.52 (m, 2H) 6.96-7.22 (m, 1H) 7.26-7.54 (m, 2H) 7.64-7.89 (m, 1H) 7.99-8.27 (m, 3H) 11.60-11.89 (m, 1H) 13.04-13.29 (m, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([OH:13])[CH:10]=[CH:9]1.[C:14](OC(=O)C)(=[O:16])[CH3:15].CN(C1C=CC=CN=1)C.C(OCC)(=O)C>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([O:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:9]1
Reactant: CC(=O)OC(C)=O
Reactant: O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Yield: 81 %

Procedure:
Dissolve (-)-cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol (292 mg, 1.59 mmol, prepared in example 11) in pyridine (2.8 mL) and treat with acetic anhydride (0.39 mL) and dimethylaminopyridine (16 mg). Stir the reaction overnight. Concentrate the reaction under vacuum, dissolve the residue with ethyl acetate (10 mL). Wash with 0.5M hydrochloric acid that is 1/2 saturated with brine (2×10 mL), saturated sodium bicarbonate (10 mL), brine (10 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by chromatography (silica gel, 10 g, 1.5×4 cm column, 20% ethyl acetate/hexane) to provide the title compound (290 mg, 81%).