Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[NH:9][C:8]3[C:11](Cl)=[N:12][C:13]([Cl:15])=[N:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:17][CH2:18][O-:19].[Na+]>C(O)C>[Br:1][C:2]1[C:10]2[NH:9][C:8]3[C:11]([O:19][CH2:18][CH3:17])=[N:12][C:13]([Cl:15])=[N:14][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC[O-]
Reactant: Clc1nc(Cl)c2[nH]c3c(Br)cccc3c2n1
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Cl)nc2c1[nH]c1c(Br)cccc12
Temperature: 25 °C
Yield: 86.1 %

Procedure:
1.0 g (3.2 mmol) 6-bromo-2,4-dichloro-5H-pyrimido[5,4-b]indole was suspended in 5 ml absolute ethanol and mixed with 6 ml (6.4 mmol) 1M sodium ethylate solution (EtOH). The mixture was refluxed for 15 h. Having cooled down to room temperature, the solvent was concentrated and water was added. The resulting precipitate was sucked off and washed with water. 0.9 g (86%) 6-bromo-2-chloro-4-ethoxy-5H-pyrimido[5,4-b]indole was obtained. ESI-MS [m/z]: 324, 326 [M−H]−
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH2:15])=[S:14])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.Br[CH:17]1[CH2:22][CH2:21][CH2:20][CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18]1=O>C(O)C>[C:19]1([CH:23]2[C:24]3[N:15]=[C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[N:4][CH:3]=[N:2]5)=[CH:11][CH:10]=4)[S:14][C:25]=3[CH2:26][CH2:27][CH2:28]2)[CH:20]=[CH:21][CH:22]=[CH:17][CH:18]=1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: NC(=S)Nc1ccc(-n2cncn2)cc1
Solvent: CCO
Product: c1ccc(C2CCCc3sc(Nc4ccc(-n5cncn5)cc4)nc32)cc1
Temperature: 25 °C
Yield: 64.3 %

Procedure:
A suspension of 4-(1,2,4-triazol-1-yl)phenylthiourea (109.6 mg, 0.5 mmol) and of 2-bromo-6-phenyl-cyclohexanone (253.1 mg, 1.00 mmol) in ethanol (4 mL) was heated for two days to reflux under an atmosphere of nitrogen. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was treated with dichloromethane, diethyl ether and heptane. The product precipitated as a solid and was filtered off to yield the title compound (120 mg, 64%) as a pale-brown solid. MS ISP (m/e): 374.3 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=10.4 (s, 1H), 9.38 (s, 1H), 8.29 (s, 1H), 8.02 (d, 2H), 7.56 (d, 2H), 7.30 (t, 2H), 7.10-7.19 (m, 5H), 4.00 (m, 1H), 2.72 (m, 2H), 2.14 (m, 1.70-1.89 (m, 3H).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:11][C:12]([O-:14])=[O:13].[Na+].Cl>>[C:12]([CH2:11][N:1]1[CH2:9][CH2:8][N:7]([CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5][N:4]([CH2:11][C:12]([OH:14])=[O:13])[CH2:3][CH2:2]1)([OH:14])=[O:13]
Reactant: O=C([O-])CCl
Reactant: C1CNCCNCCN1
Agent: Cl
Agent: [Na+]
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To an aqueous solution of TACN (0.16 mols in 58 mL water) is added an aqueous solution of sodium chloroacetate (0.71 mols sodium chloroacetate in 68 mL of water). This solution is stirred at 80° C. overnight while maintaining the pH at 9-10. After cooling to ambient temperature the pH of the solution is adjusted to 2.5 with aqueous HCl. The resulting precipitate is collected by filtration, washed with acetone, and dried in vacuo to afford the mono-hydrochloride salt of 1,4,7-tricarboxymethyl-1,4,7-triazacyclononane.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=NCCCCCCCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: NCCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 7-phenylheptylazide (3.97 g, 18.3 mmol) in EtOH (15 mL) was added to palladium on carbon (200 mg) in EtOH (35 mL) under an atmosphere of Hydrogen. The mixture was stirred for 24 h at r.t. The mixture was filtered through celite and the solvent was removed under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.[H-].[Na+].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20](Br)[CH:21]=1)[C:17]#[N:18]>CN(C=O)C.C(OCC)(=O)C>[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:21]=1)[C:17]#[N:18]
Reactant: COc1ccc(CO)cc1
Reactant: N#Cc1cc(Br)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cc(Br)cc(C#N)c2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
p-Methoxybenzyl alcohol (2.6 mL) was dissolved in anhydrous DMF (50 mL) and NaH (808 mg, 60% dispersion in oil) was added in several portions. After gas evolution ceased, 3,5-dibromobenzonitrile (5.0 g) was added and the reaction mixture was stirred at 70° C. After 2 h additional amount of NaH (147 mg) was added and heating was continued for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 3.1 g of the title compound (51% yield). HRMS calcd for C15H12O2BrN M+ 371.0051, observed 371.0048.
Reaction SMILES: [I-].[Na+].Cl[Si](C)(C)C.O[CH:9]([C:21]1[O:22][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[CH:24][CH:25]=1)[C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1.O>C(#N)C>[F:34][C:32]([F:33])([F:35])[C:28]1[CH:27]=[C:26]([C:23]2[O:22][C:21]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=3)=[CH:25][CH:24]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1ccc(C(O)c2ccc(-c3cccc(C(F)(F)F)c3)o2)cc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1ccc(Cc2ccc(-c3cccc(C(F)(F)F)c3)o2)cc1
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Sodium iodide (0.49 g) was suspended in acetonitrile (2 mL), and the suspension was cooled in an ice bath. Chlorotrimethylsilane (0.42 mL), and then a solution of the compound (0.26 g) obtained in Example 222b in acetonitrile (2 mL) were added. The reaction mixture was stirred at the same temperature for 30 min, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.22 g) as an oil.
Reaction SMILES: C([N:8]1[C:16]2[C:15]3=[N:17][C@H:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:19][N:14]3[C:13](=[O:27])[N:12]([CH2:28][CH2:29][CH3:30])[C:11]=2[N:10]=[C:9]1[C:31](O)=[O:32])C1C=CC=CC=1.S(Cl)(Cl)=O.[NH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>C(Cl)(Cl)Cl>[CH2:20]([C@@H:18]1[CH2:19][N:14]2[C:15]([C:16]3[NH:8][C:9]([C:31]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:32])=[N:10][C:11]=3[N:12]([CH2:28][CH2:29][CH3:30])[C:13]2=[O:27])=[N:17]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C1CCNCC1
Reactant: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2c1nc(C(=O)O)n2Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCN1C(=O)N2C[C@@H](Cc3ccccc3)N=C2c2[nH]c(C(=O)N3CCCCC3)nc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
Compound 47a (70 mg, 0.158 mmol) obtained in Example 47 was dissolved in chloroform (2 mL), to the solution was added thionyl chloride (40 μL, 0.548 mmol, 3.4 equivalents), and the mixture was stirred at 60° C. for 30 minutes. To the reaction solution was added piperidine (320 μL, 3.24 mmol, 20 equivalents) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and directly purified by silica gel column chromatography (chloroform:methanol=98:2). Thereafter, the title compound (17 mg, 26%) was obtained in a manner similar to the method by which Compound 40 was obtained from Adduct 40a in Example 40.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=1)[CH3:6])[CH3:2].[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)#[CH:16]>C(#N)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.CCOC(C)=O>[CH2:1]([NH:3][C:4](=[O:14])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:16]#[C:15][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)[CH3:6])[CH3:2]
Reactant: C#Cc1ccc(OC)cc1
Reactant: CCNC(=O)C(C)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCNC(=O)C(C)c1ccc(C#Cc2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
300 mg (0.99 mmol) N-Ethyl-2-(4-iodo-phenyl)-propionamide (XVIII.1) are added to 148 μL (1.14 mmol) 1-ethynyl-4-methoxybenzene in 8 mL ACN under inert gas atmosphere. 276 μL (1.99 mmol) TEA as base, 6 mg (0.03 mmol) copper(I)iodide and 42 mg (0.060 mmol) bis(triphenylphosphine)palladium(II)chloride as catalyst are added and the mixture is stirred at rt under inert gas atmosphere for 5 h. After that time, the mixture is diluted with EtOAc, washed with saturated ammonium chloride solution and brine, and the organic layer is dried over sodium sulphate. The solvent is evaporated and the residue is purified by column chromatography (silicia gel; heptane:EtOAc 50:50).
Reaction SMILES: [K].[OH:2][C:3]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([OH:25])(=O)=[O:23])=[CH:18][CH:17]=2)=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].CN(C)C=O.S(Cl)([Cl:33])=O.[Cl-].[Na+]>C1(C)C=CC=CC=1>[OH:2][C:3]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([Cl:33])(=[O:25])=[O:23])=[CH:18][CH:17]=2)=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)O)cc2)ccc1O
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Cl)cc2)ccc1O

Procedure:
Ethyl 2-hydroxy-5-[(4-sulfophenyl]ethynyl]benzoate potassium salt (19 g, 50 mmol) was suspended in toluene (100 ml). Dimethylformamide (1 ml) and thionyl chloride (12 g) were added and the suspension was refluxed for 1 h. The reaction mixture was added to a nearly saturated sodium chloride solution and the precipitated oil was extracted with toluene. The solution was dried and taken to dryness. The product was sufficiently pure for the next step. Yield 16 g, 88%.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([NH:12][CH2:13][C:14]([OH:16])=O)=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:38][O:39][C:40](=[O:50])[C@H:41]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH2:42]>C1COCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:38][O:39][C:40](=[O:50])[C@H:41]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH:42][C:14](=[O:16])[CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To N-Boc-glycylglycine (696 mg, 3.00 mmol, 1.00 equiv) in THF (10.0 mL) at 0° C. was added EDCI (1.15 g, 6.00 mmol, 2.00 equiv), HOBt (810 mg, 6.00 mmol, 2.00 equiv), n,n-diisopropylethyl amine (1.56 mL, 9.00 mmol, 3.00 equiv) and 4-(Dimethylamino)pyridine (36 mg, 0.030 mmol, 0.10 equiv) and L-phenylalanine methyl ester (647 mg, 3.00 mmol, 1.00 equiv). The reaction mixture was stirred for 1 hr at 0° C. and stirred for 12 h at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and dried (Na2SO4). The filtrate is concentrated in vacuo and the residue is purified by chromatography on silica gel eluting with DCM/MeOH 10:1 (v/v) to afford 1.10 g of the title compound as a colorless oil (93% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[Br:10]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:10][C:6]1[CH:5]=[CH:4][C:3]([O:8][CH3:9])=[C:2]([CH3:1])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)cc1C
Yield: 47.1 %

Procedure:
A solution of 24 g of 2-methylanisole, 35 g of N-bromosuccinimide and 1.24 g of dibenzoyl peroxide in 150 ml of carbon tetrachloride was heated to boiling under reflux for 12 hours. After cooling the solution was filtered and the filtrate is evaporated. The residue was recrystallized from hexane. There were obtained 18.6 g (47%) of 4-bromo-2-methylanisole as a colorless solid; m.p. 66°-68°.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[OH:6][CH:7]([CH3:11])[C:8](=O)[CH3:9].C(NCC)C>CO>[NH2:4][C:3]1[O:6][C:7]([CH3:11])=[C:8]([CH3:9])[C:2]=1[C:1]#[N:5]
Reactant: N#CCC#N
Reactant: CC(=O)C(C)O
Solvent: CO
Solvent: CCNCC
Product: Cc1oc(N)c(C#N)c1C
Temperature: 10 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
To a solution of malononitrile (28.2 g) in methanol (30 mL) is added a suspension of acetoin (25 g) in methanol (30 mL) and thereto is added dropwise diethylamine (11 mL) under ice-cooling (internal temp.: 10° C.). The mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ice water (300 mL) and the precipitated crystals are collected by filtration to give 2-amino-4,5-dimethyl-3-furonitrile (28.91 g, yield; 75%) as colorless crystals.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC.[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1>CS(C)=O>[CH2:1]([O:8][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
Benzyl alcohol (2.22 g, 20 mmol) was added to a slurry of hexane-washed NaH (60% oil suspension, 820 mg, 20.5 mmol) in DMSO (20 mL), stirred under nitrogen at 20° C., producing strong gas evolution. After 30 minutes, 1-fluoro-4-nitrobenzene (2.826 g, 20 mmol) was added dropwise to the light grey slurry. The reaction mixture became a bright orange red and quite strongly exothermic, and a lot of gas was evolved. After 2 hours, the reaction mixture was poured onto ice-water (200 mL), and the solid was collected by Buchner filtration, rinsed with water (2×50 mL), and air dried to give 1-benzyloxy-4-nitrobenzene (4.188 g, 91.3%) as canary yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[N:13][OH:14])[CH2:8][CH2:7][CH2:6]2.C([Li])CCC.[C:20]1([C:26]2[C:30]([C:31]([F:34])([F:33])[F:32])=[C:29]([C:35](OC)=O)[O:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S(=O)(=O)(O)O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]1=[N:13][O:14][C:35]([C:29]3[O:28][N:27]=[C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:30]=3[C:31]([F:34])([F:32])[F:33])=[C:8]1[CH2:7][CH2:6]2
Reactant: COC(=O)c1onc(-c2ccccc2)c1C(F)(F)F
Reactant: COc1ccc2c(c1)CCCC2=NO
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 26.6 %

Procedure:
To 6-methoxy-3,4-dihydronaphthalen-1(2H)-one oxime (Intermediate 2, 0.328 g, 1.715 mmol) in 3 mL of THF, cooled to 0° C. was added butyllithium (1.372 mL, 3.43 mmol) dropwise over a period of 3 min. The contents were stirred at 0° C. for 30 min. A solution of methyl 3-phenyl-4-(trifluoromethyl)isoxazole-5-carboxylate (Intermediate 3, 0.31 g, 1.14 mmol) dissolved in 2 mL of THF was added over a period of 3 min. The pale yellow reaction mixture was allowed to come to room temperature and stirred for 20 min. To the reaction mixture was added 0.5 mL of conc. sulfuric acid dropwise over a period of 3 min. at 0° C. and the contents were allowed to come to room temperature over a period of 10 min., then stirred at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure. Dioxane (5 mL) was added and the contents were heated at 100° C. for 1.5 h, and at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (25 mL) and water (10 mL). The ethyl acetate layer was washed with sat. aq. sodium bicarbonate (15 mL), dried over sodium sulfate, concentrated and purified by silica gel column chromatography using hexane/ethyl acetate to yield 7-methoxy-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (0.125 g, 0.303 mmol, 26.5% yield) as pale yellow solid. LC/MS M+1=413.0.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH3:16].C(OCC)(=O)C>C(O)(C)C>[Br:1][C:2]1[C:3]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][C:5]([NH2:16])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(NC2CCOCC2)n1
Reactant: N
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Nc1ncc(Br)c(NC2CCOCC2)n1
Temperature: 130 °C
Yield: 77 %

Procedure:
To a suspension of compound 32 (6.60 g, 23 mmol) in isopropyl alcohol (40 ml) was added ammonia (aq. 28%, 80 ml). This reaction mixture was heated to 130° C. for 14 hours in a pressure vessel. The reaction mixture was cooled down to room temperature and to this mixture was added ethyl acetate. The reaction mixture was washed with water and brine. The ethyl acetate layer was dried with sodium sulfate and concentrated to give compound 33 (4.75 g, 77%). 1H NMR (500 MHz, CD3OD) δ ppm 7.79 (1 H, s), 4.24 (1 H, m), 3.99-4.02 (2 H, dd, J=11.0, 2.2 Hz), 3.52 (2 H, td, J=11.9, 2.0 Hz), 1.92-1.96 (2 H, m), 1.69 (2 H, m); LCMS-ESI (POS), M/Z, M+1: Found 273, Calculated 273.0
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:4][C:3]1=2.[Cl:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[Cl:20][C:21]1[CH:26]=[C:25]([C:6]2[CH:7]=[C:8]3[C:3](=[CH:4][CH:5]=2)[C:2](=[O:1])[CH2:11][CH2:10][CH2:9]3)[CH:24]=[CH:23][CH:22]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Product: O=C1CCCc2cc(-c3cccc(Cl)c3)ccc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester and 3-chlorophenyl boronic acid according to the coupling procedure as described in example 6. MS (ES) m/z 257.1.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][CH3:17])=[O:15])#[N:2].[OH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[C:23]([C:22]1[CH:26]=[CH:27][C:19]([O:18][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:20][CH:21]=1)(=[O:24])[NH2:25]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3)c(C#N)cc21
Temperature: 110 °C
Yield: 22.2 %

Procedure:
Methyl 6-cyano-7-fluorochroman-4-carboxylate (300 mg, 1.28 mmol), 4-hydroxybenzamide (227 mg, 1.66 mmol) and potassium carbonate (423 mg, 3.06 mmol) were diluted with dry NMP (4 mL). The reaction was bubbled with argon for 10 minutes and then heated at 110° C. for 12 hours. The reaction was cooled and loaded directly onto a biotage 40M cartridge (silica gel), eluting with 5% ethyl acetate/hexanes to 100% ethyl acetate to yield methyl 7-(4-carbamoylphenoxy)-6-cyanochroman-4-carboxylate (100 mg, 22.3% yield).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[O:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:36])([F:19])[F:37])[CH:23]=3)=[O:34])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(OC(F)(F)F)c1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(OC(F)(F)F)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.94 min; [M+H]+=478.03.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:19][C:20]([F:23])([CH3:22])[CH3:21])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:18]=1)(=[O:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:29].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:4][CH2:5][C:6]1[N:7]([CH2:19][C:20]([F:23])([CH3:22])[CH3:21])[C:8]2[C:17]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:11]([O-:29])=[CH:10][C:9]=2[N:18]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1nc2cnc3cccnc3c2n1CC(C)(C)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OCc1nc2c[n+]([O-])c3cccnc3c2n1CC(C)(C)F
Reaction time: 2 h
Yield: 99.9 %

Procedure:
[1-(2-Fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl acetate (1.59 g, 5.03 mmol) was dissolved in 50 mL of CH2Cl2 and treated with 3-chloroperoxybenzoic acid (1.52 g, 57-86% purity). After stirring for 2 hours, the reaction mixture was treated with 25 mL of CH2Cl2 and 20 mL of 5% Na2CO3 solution and the layers were separated. The organic layer was washed with H2O (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1.67 g of [1-(2-fluoro-2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]methyl acetate as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26]>>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]([N:10]1[CH2:11][CH:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH2:13]2)[CH2:9]1)=[O:26]
Reactant: Clc1ccc(C23CNCC2C3)cc1
Reactant: O=C(Cl)c1ccco1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(c1ccco1)N1CC2CC2(c2ccc(Cl)cc2)C1

Procedure:
Following the procedure of Example 8, 19.35 g. of 1-p-chlorophenyl-3-azabicyclo[3.1.0]hexane, 10.59 g. of sodium carbonate and 13.05 g. of 2-furoyl chloride are reacted to produce the product as a dark brown gum.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].[CH2:14]([O:16][C:17](=[O:25])[C:18](=[CH:21]OCC)[C:19]#[N:20])[CH3:15]>C(O)(=O)C.O>[NH2:20][C:19]1[N:10]([C:4]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=2[C:2]([F:1])([F:12])[F:13])[N:11]=[CH:21][C:18]=1[C:17]([O:16][CH2:14][CH3:15])=[O:25]
Reactant: NNc1ccc(Cl)cc1C(F)(F)F
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2C(F)(F)F)c1N
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of 31.58 g of 2-(trifluoromethyl)-4-chlorophenylhydrazine and 27.92 g of ethyl(ethoxymethylene)cyanoacetate dissolved in 225 of acetic acid and 75 ml of water was heated on a steam bath for approximately 16 hours. The reaction mixture was cooled to room temperature and placed in the refrigerator. The precipitated solid was collected by filtration and combined with the solids isolated from the filtrate to provide 43 g of 5-amino-1-[2-(trifluoromethyl)-4-chlorophenyl]-1H-pyrazole-4-carboxylic acid, ethyl ester. MP=114°-116° C.