Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[Br:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:12])=[C:8]([CH:11]=1)[CH2:9][NH2:10].C(N(CC)CC)C.[C:20](Cl)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>ClCCl.C1(C)C=CC=CC=1.O>[Br:3][C:4]1[CH:11]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:12]=[C:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[N:10]=[CH:9]2
Reactant: NCc1cc(Br)ccc1N
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Brc1ccc2nc(-c3ccccc3)ncc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a suspension of 5-bromo-2-amino-benzylamine dihydrochloride (38 g, 0.138 mol) in dichloromethane (DCM) (1 l) was added at 0° C. triethylamine (TEA) (67.5 ml, 0.485 mol) and a solution of benzoyl chloride (17 ml, 0.145 mol) in DCM (200 ml). The mixture was stirred for 1 h at r.t. Water was added and the organic phase was separated, washed with water and dried over Na2SO4. The solvent was removed in vacuum (i.v.) and the residue suspended in POCl3 (200 ml). The mixture was heated at reflux for 1 hour, then the solvent was removed i.v., and the residue partitioned between AcOEt and 0.1 N NaOH. The organic layer was washed with 0.1 N NaOH and water, then dried over Na2SO4 and concentrated i.v. to provide a solid. A mixture of the obtained solid and chloranil (35 g, 0.138 mol) in toluene (600 ml) was heated at reflux for 4 hours. The mixture was concentrated i.v. and the residue was treated with DCM. The insoluble was filtered off and washed with DCM. The combined filtrates were washed with 0.1 N NaOH and then with water. The solution was dried over Na2SO4 and concentrated i.v. The obtained solid was triturated with methanol and dried i.v. (22 g, 56% yield). C14H9BrN2; MW: 285.15; 1H NMR (DMSO-d6) 9.70 (s, 1H), 8.49-8.56 (m, 3H), 8.17 (dd, 1H), 8.02 (d, 1H), 7.58-7.61 (m, 3H); TLC (AcOEt:PE 2:8) Rf=0.70.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]12[CH2:15][CH:14]1[CH2:13][CH2:12][S:11][C:10]([NH2:16])=[N:9]2.S(=O)(=O)(O)O.[N+:22]([O-])([OH:24])=[O:23].[OH-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:22]([O-:24])=[O:23])=[CH:4][C:3]=1[C:8]12[CH2:15][CH:14]1[CH2:13][CH2:12][S:11][C:10]([NH2:16])=[N:9]2
Reactant: NC1=NC2(c3ccccc3F)CC2CCS1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC1=NC2(c3cc([N+](=O)[O-])ccc3F)CC2CCS1
Temperature: 0 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
(1SR,7SR)-1-(2-Fluorophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-amine (intermediate A5a) (1.22 g, 5.16 mmol, Eq: 1.00) was dissolved in conc. sulfuric acid (20.3 g, 11.0 ml, 207 mmol, Eq: 40), then at 0° C. fuming nitric acid (488 mg, 321 μl, 7.74 mmol, Eq: 1.5) was added dropwise with an Eppendorf pipette. The light brown solution was stirred at 0° C. for 2 hours. The reaction mixture was poured on ice and basified with conc NaOH (pH=10) followed by the extraction with dichloromethane. The organic layer was separated, dried over Na2SO4, filtered and evaporated to dryness to give the (1SR,7SR)-1-(2-fluoro-5-nitrophenyl)-4-thia-2-azabicyclo[5.1.0]oct-2-en-3-amine (995 mg, 3.54 mmol, 68.5% yield). as a yellow solid. The crude product was used in the next step without further purification. MS (ISP): m/z=237.2 [(M+H)+].
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:28](=[CH:29][CH:30]=1)[C:9]1=[N:10][O:11][C:12]([C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]=3[C:24]([F:27])([F:26])[F:25])=[C:8]1[CH2:7][CH2:6]2>ClCCl>[C:18]1([C:15]2[C:14]([C:24]([F:27])([F:26])[F:25])=[C:13]([C:12]3[O:11][N:10]=[C:9]4[C:28]5[C:5]([CH2:6][CH2:7][C:8]=34)=[CH:4][C:3]([OH:2])=[CH:30][CH:29]=5)[O:17][N:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Solvent: ClCCl
Product: Oc1ccc2c(c1)CCc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 39.3 %

Procedure:
To 7-methoxy-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 8A, 0.125 g, 0.303 mmol) in dichloromethane (4 mL) was added borontribromide (1.0 M in dichloromethane, 3.03 mL, 3.03 mmol) at 0° C. over a period of 3 min. The contents were allowed to come to room temperature over a period of 15 min. and stirred at room temperature for 1 h. Additional borontribromide (4 mL) was added at room temperature over a period of 2 min. and the reaction was stirred for 3 h. The reaction mixture was concentrated and kept on the high vacuum pump for 10 min. Dichloromethane (5 mL) was added followed by 3 mL of borontribromide at room temperature. The contents were stirred at room temperature for 60 h. The reaction mixture was cooled to 0° C. and quenched by the slow addition of methanol (˜0 mL). The contents were stirred for 10 min. and concentrated under reduced pressure. The resulting residue was partitioned between dichloromethane (25 mL) and water (10 mL). The dichloromethane layer was washed with brine (20 mL), dried over sodium sulfate and concentrated. The resulting solid was triturated with ethyl acetate (5 mL), collected by filtration, washed with ethyl acetate (2×3 mL) and dried to yield 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol (0.050 g, 0.119 mmol, 39.3% yield) as a white solid. The compound had an HPLC retention time=3.77 min (condition C); LC/MS M+1=399.
Reaction SMILES: O[CH:2]([CH3:17])[CH2:3][C:4]([CH:6]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:7]21[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:5].OC(C)CC(C1C2(CC=CC=1C)CCCC2)=O.OC(C)CC(C1C(=C)C=CCC21CCCC2)=O.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>C([O-])(O)=O.[Na+]>[CH3:16][C:15]1[CH:6]([C:4](=[O:5])/[CH:3]=[CH:2]/[CH3:17])[C:7]2([CH:12]=[CH:13][CH:14]=1)[CH2:8][CH2:9][CH2:10][CH2:11]2
Reactant: CC1=CC=CC2(CCCC2)C1C(=O)CC(C)O
Agent: C=C1C=CCC2(CCCC2)C1C(=O)CC(C)O
Agent: CC(=O)[O-]
Agent: CC1=C(C(=O)CC(C)O)C2(CC=C1)CCCC2
Solvent: CC(=O)OC(C)=O
Product: C/C=C/C(=O)C1C(C)=CC=CC12CCCC2
Temperature: 80 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
A 81:14:3 mixture of 3-hydroxy-1-(7-methylspiro[4.5]deca-7,9-dien-6-yl)butan-1-one, 3-hydroxy-1-(7-methylspiro[4.5]deca-6,8-dien-6-yl)butan-1-one, and 3-hydroxy-1-(7-methylenespiro[4.5]dec-8-en-6-yl)butan-1-one (0.2 g, 0.85 mmol), acetic anhydride (0.17 ml, 1.8 mmol) and sodium acetate (77 mg, 3.0 mmol) was stirred at 80° C. for 16 h, treated with sodium acetate (30 mg, 0.37 mmol), stirred at 80° C. for 2 h, cooled to 0° C., poured into cold saturated aqueous NaHCO3 (20 ml), and extracted three times with MTBE (10 ml). The combined organic phases were washed twice with a saturated aqueous solution of NaCl, dried (MgSO4), and concentrated. FC (30 g SiO2, hexane/MTBE 60:1) of the crude product (0.2 g) gave (E)-1-(7-methylspiro[4.5]deca-7,9-dien-6-yl)but-2-en-1-one (0.139 g, 77%). Boiling point: 100° C. (0.07 mbar).
Reaction SMILES: I[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C@@H:8]2[CH2:13][O:12][C:11]3=[N:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][N:10]3[CH2:9]2)=[CH:4][CH:3]=1.[C:22]([Si](C)(C)C)#[CH:23]>CN(C=O)C.CCN(CC)CC.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:22]([C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C@@H:8]2[CH2:13][O:12][C:11]3=[N:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][N:10]3[CH2:9]2)=[CH:4][CH:3]=1)#[CH:23]
Reactant: C#C[Si](C)(C)C
Reactant: O=[N+]([O-])c1cn2c(n1)OC[C@@H](OCc1ccc(I)cc1)C2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc(CO[C@@H]2COc3nc([N+](=O)[O-])cn3C2)cc1
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
A mixture of iodide 43 (see Example 2C) (1.00 g, 2.49 mmol) and copper iodide (51 mg, 0.27 mmol) in DMF (10 mL) and Et3N (10 mL) was purged with N2. Ethynyltrimethylsilane (1.0 mL, 7.1 mmol) and PdCl2(PPh3)2 (93 mg, 0.13 mmol) were added and the mixture was stirred under N2 for 0.5 h. The resulting mixture was partitioned between EtOAc and water, the organic fraction was dried, and the solvent was removed. The residue was dissolved in THF (50 mL) and tetra-n-butylammonium fluoride (5 mL of a 1M solution in THF, 5 mmol) was added. The solution was stirred for 2 h and then concentrated. The residue was partitioned between EtOAc and water, and the organic fraction was dried and concentrated. Column chromatography of the residue on silca gel using gradient elution (1:1 hexanes EtOAc to EtOAc) gave (6S)-6-[(4-ethynylbenzyl)oxy]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (129) (0.530 g, 71%) as a white solid: mp 162-164° C.; 1H NMR [(CD3)2SO] δ 8.01 (s, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H), 4.62-4.71 (m, 3H), 4.47 (d, J=11.9 Hz, 1H), 4.20-4.30 (m, 3H), 4.14 (s, 1H). Anal. (C15H13N3O4) C, H, N.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[OH-].[K+:15].C(O)C>>[C:1]([O-:13])(=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[K+:15]
Reactant: C=CCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCCCCCCCCC(=O)[O-]

Procedure:
To 1/2 N-potassium hydroxide/ethanol (200 mL) is added undecylenic acid (18.8 g, 0.102 mol) slowly dropwise at 0° C. with constant stirring. The volatile matter is then distilled off to give a crude product. This crude product is washed with acetone and heated in vacuo to provide potassium undecylenate of the following formula as white solid (8.88 g, yield 88%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([CH2:23][C:24](OC)=[O:25])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[BH4-].[Na+]>CCO>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3([CH2:23][CH2:24][OH:25])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: COC(=O)CC1(c2ccccc2)C(=O)Nc2ccc(-c3c(C)noc3C)cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1noc(C)c1-c1ccc2c(c1)C(CCO)(c1ccccc1)C(=O)N2
Temperature: 0 °C
Yield: 22.1 %

Procedure:
To a solution of methyl 2-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)acetate (50 mg, 0.13 mmol) in EtOH (20 mL) was added NaBH4 (49 mg, 1.3 mmol), the reaction mixture was stirred at reflux for 3.0 h. After cooling to 0° C., the reaction was quenched by addition of aq. saturated NH4Cl (2 mL) solution. The mixture was diluted with water (10 mL) and extracted with EtOAc (15 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to yield crude product which were purified on flash column chromatography to afford the title compound as a white solid (10 mg, 22%). 1H NMR (400 MHz, DMSO-d6): δH 10.59 (s, 1H), 7.22-7.35 (m, 7H), 6.98 (d, J=8.0 Hz, 1H), 4.48-4.51 (m, 1H), 3.15-3.17 (m, 2H), 2.44-2.48 (m, 2H), 2.32 (s, 3H), 2.20 (s, 3H). MS (ESI) m/e [M+1]+ 349.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10].N(OC(C)(C)C)=O.N[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>[Cu](F)F.C(#N)C>[O:1]([N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][C:3]1([CH3:11])[CH3:10])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: CC1(C)CCCC(C)(C)N1O
Agent: F[Cu]F
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CC1(C)CCCC(C)(C)N1Oc1ccccc1
Yield: 42.9 %

Procedure:
The procedure of Example 1 is repeated using 3.9 g (25 mmol) of 1-oxyl-2,2,6,6-tetramethylpiperidine, 7.84 g (76 mmol) of tert-butyl nitrite, 25 mg (0.25 mmol) of copper(II) fluoride, 120 mL of acetonitrile and 4.65 g (50 mmol) of aniline at ambient temperature for 72 hours. The crude product is purified by vacuum flash chromatography (heptane) to give 2.5 g of colorless oil in a 43% yield based on nitroxyl.
Reaction SMILES: CCN=C=NCCCN(C)C.C(Cl)Cl.[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH3:25])=[C:17]1[C:26]([NH:28][C@H:29]([C:33]([OH:35])=O)[CH:30]([CH3:32])[CH3:31])=[O:27].[NH2:36][CH:37]([CH:46]([OH:58])[CH2:47][O:48][CH2:49][C:50]1[C:55]([Cl:56])=[CH:54][CH:53]=[CH:52][C:51]=1[Cl:57])[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>C(OCC)(=O)C.CCCCCC>[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([CH3:25])=[C:17]1[C:26]([NH:28][C@H:29]([C:33]([NH:36][CH:37]([CH:46]([OH:58])[CH2:47][O:48][CH2:49][C:50]1[C:51]([Cl:57])=[CH:52][CH:53]=[CH:54][C:55]=1[Cl:56])[CH2:38][C:39]([O:41][C:42]([CH3:44])([CH3:43])[CH3:45])=[O:40])=[O:35])[CH:30]([CH3:31])[CH3:32])=[O:27]
Reactant: CC(C)(C)OC(=O)CC(N)C(O)COCc1c(Cl)cccc1Cl
Reactant: Cc1c(C(=O)N[C@H](C(=O)O)C(C)C)n(C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)COCc2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
1-tlydroxybenzotriazole hydrate (153 mg, 1.0 mmol) and EDAC (268 mg, 1.4 mmol) were added to a methylene chloride solution of N-(1,3-dimethylindole-2-carbonyl)valine (288 mg, 1.0 mmol, in 3 mL of methylene chloride). The resultant mixture was stirred for 10 minutes under a nitrogen atmosphere at room temperature. A methylene chloride solution of 3-amino-5-(2′,6′-dichlorobenzyloxy)-4-hydroxypentanoic acid, t-butyl ester (364 mg, 1.0 mmol, in 2 mL of methylene chloride) was added to the reaction mixture and the mixture was first stirred for one hour under a nitrogen atmosphere at 0° C., and then for 16 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated to give crude product (583 mg). The crude product was subjected to flash chromatography on silica gel with ethyl acetate/hexane (2/3) to give the title product as a white solid (260 mg). TLC (ethyl acetate/hexanes 1:1): Rf=0.38.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[N:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31]O)[CH2:27][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)(C(OCC)=O)=[N-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:31][CH:28]2[CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:24])[CH2:26][CH2:27]2)=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 16 h
Yield: 39.5 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-hydroxybenzamide (200 mg, 0.806 mmol), 1-tert-butoxycarbonylpiperidine-4-methanol (191 mg, 0.887 mmol), and triphenylphosphine (232 mg, 0.887 mmol) in THF was treated dropwise with a THF solution of diethyl diazodicarboxylate (DEAD) (0.14 mL, 0.887 mmol in 1 mL of THF). After 16 h, the mixture was treated with an additional equivalent of triphenylphosphine and DEAD. After 2 h, the mixture was concentrated, diluted with methylene chloride, and filtered. The solid collected was the desired product (128 mg, 36%). The filtrate was purified by column chromatography (SiO2; 4:1 hexanes:EtOAc) providing an additional 142 mg (40%) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]1)=[O:12])=[O:4].[CH3:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39](F)[CH:38]=1)[CH3:35].[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C.O>[CH3:33][N:34]([CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[C:39]([O:26][C@H:23]2[CH2:24][CH2:25][C@H:20]([N:10]([C:11]([CH:13]3[CH2:18][CH2:17][C:16]([CH3:19])=[CH:15][CH2:14]3)=[O:12])[C:9]3[CH:8]=[C:7]([C:27]#[C:28][C:29]([CH3:30])([CH3:31])[CH3:32])[S:6][C:5]=3[C:3]([OH:2])=[O:4])[CH2:21][CH2:22]2)[CH:38]=1)[CH3:35]
Reactant: CN(C)Cc1ccnc(F)c1
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)C1CC=C(C)CC1)[C@H]1CC[C@H](O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1=CCC(C(=O)N(c2cc(C#CC(C)(C)C)sc2C(=O)O)[C@H]2CC[C@H](Oc3cc(CN(C)C)ccn3)CC2)CC1
Temperature: 90 °C

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[(4-hydroxy-trans-cyclohexyl)-(4-methyl-cyclohex-3-enecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (40 mg, 0.088 mmol) and (N,N-dimethyl)-(2-fluoro-pyridin-4-ylmethyl)amine (84 mg, 0.55 mmol) in DMF (1 mL) were treated with sodium hydride (22 mg, 60% oil dispersion, 0.55 mmol). After the bubbling slowed, the reaction mixture was sealed and heated by microwave (90° C.) for 70 min. The reaction mixture was treated with 10% citric acid (2-3 mL) followed by water (2-3 mL). The organics were extracted twice with ethyl acetate, dried over sodium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC to give the Compound 337, 18 mg (35% yield): MS (m/z): 578.0 [M+H]+; HPLC retention time 3.53 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CN(C=O)C.O>[N:20]1([C:2]2[S:3][C:4]3[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cccc2nc(Br)sc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc2nc(N3CCOCC3)sc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 36.7 %

Procedure:
To 0.200 g (0.77 mmol) of 2-bromo-7-nitro-1,3-benzothiazole in 2 mL of DMF was added 0.21 g (1.5 mmol) of potassium carbonate and 81 μL (0.93 mmol) of morpholine. The mixture was stirred at room temperature for 72 h and diluted with water. The precipitate that formed was collected by filtration and purified by flash chromatography eluting with a 33% ethyl acetate/hexanes mixture to give 0.075 g (37%) of the title compound as a cream colored powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12](COCC[Si](C)(C)C)[N:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[N:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1nncc1-c1cccc(Br)c1
Agent: Cl
Solvent: CCO
Product: Brc1cccc(-c2cnn[nH]2)c1
Temperature: 60 °C
Yield: 96.2 %

Procedure:
A mixture of 5-(3-bromophenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-[1,2,3]triazole (1.27 g, 3.6 mmol), 2 N HCl (30 ml) and ethanol (30 ml) was heated at 60° C. for 3 h. The reaction mixture was cooled to room temperature and concentrated to approximately 5 ml under reduced pressure. The resulting solid was filtered off and dried under vacuum to yield the title compound (776 mg, 97%): 1H NMR (360 MHz, DMSO-d6) δ 8.46 (1H, s), 8.07 (1H, s), 7.89 (1H, d, J 7.8 Hz), 7.55 (1H, d, J 7.8 Hz), 7.42 (1H, t, J 7.8 Hz).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:12])[N:6]([CH3:11])[N:7]=2)[CH:3]=1.[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC.N>CS(C)=O.[Cu]I>[Cl:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][N:23]([C:2]3[CH:10]=[CH:9][C:8]4[C:4](=[C:5]([CH3:12])[N:6]([CH3:11])[N:7]=4)[CH:3]=3)[C:22](=[O:26])[CH:21]=2)=[CH:16][CH:15]=1
Reactant: O=c1cc(OCc2ccc(Cl)cc2)cc[nH]1
Reactant: Cc1c2cc(Br)ccc2nn1C
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: Cc1c2cc(-n3ccc(OCc4ccc(Cl)cc4)cc3=O)ccc2nn1C
Temperature: 150 °C
Reaction time: 3 h
Yield: 31 %

Procedure:
A suspension of 5-bromo-2,3-dimethyl-2H-indazole (287 mg), 4-[(4-chlorobenzyl)oxy]pyridin-2(1H)-one (300 mg), potassium carbonate (528 m g), copper(I) iodide (242 mg) and N,N′-dimethylethylenediamine (112 mg) in DMSO (10 ml) was stirred at 150° C. for 3 hr. The reaction mixture was cooled to room temperature, added to 28% aqueous ammonia, and extracted with a 1:1 mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (150 mg).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][CH:10]([C:13]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:9]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCOCC2)C1
Yield: 62 %

Procedure:
The subtitle compound was prepared by the method of Example 5(e) with (R/S)-1-Boc-pyrrolidine-3-carboxylic acid (MacLeod et al J. Med. Chem., 33, 2052 (1990)] and morpholine. The subtitle compound (62%) was obtained as an oil. Rf 0.69 (CH2Cl2/MeOH 95/5, v/v). MS m/z 285 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2C(OC(C)(C)C)=O)[CH:5]=[CH:6][CH:7]=1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][NH:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CNCc1cccc(F)c1
Agent: Cl
Solvent: C1CCOC1
Product: Fc1cccc(CNC[C@H]2CCCN2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 48.3 %

Procedure:
920 mg of tert-butyl (R)-2-{[(3-fluorophenyl)methylamino]methyl}pyrrolidine-1-carboxylate are dissolved in, 10 ml of THF, and 5 ml of ethanolic hydrochloric acid are added. The mixture is stirred at 80° C. for 4 h and, for work-up, partitioned between 50 ml of water and 50 ml of ethyl acetate at room temperature. Conventional work-up and purification by chromatography on silica gel gives 300 mg of (3-fluorophenyl)methyl-(R)-1-pyrrolidin-2-ylmethylamine; Rt.: 1.377 min; [M+H]+209.2.
Reaction SMILES: [Cl:1][C:2](Cl)=[CH:3][C:4]([CH3:7])([CH3:6])[CH3:5].[C:9]1([O-:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na+]>CN(C)C=O>[Cl:1][CH:2]=[C:3]([O:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: [O-]c1ccccc1
Reactant: CC(C)(C)C=C(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=CCl)Oc1ccccc1
Yield: 98 %

Procedure:
16.5 g (0.108 mols) of 1,1-dichloro-3,3-dimethyl-1-butene are heated under reflux with 23.2 g (0.2 mol) of sodium phenolate in 100 ml of dimethylformamide, during the course of 12 hours. The customary working-up according to Example A1(a) yields, with distillation at a boiling point of 80° C./0.5 mm Hg, 22.3 g of 1-chloro-3,3-dimethyl-2-phenoxy-1-butene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=23)[CH:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C@@H:27]([NH2:29])[CH3:28]>CN1C(=O)CCC1>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C@@H:27]([NH:29][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[N:12][N:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=23)[N:5]=[C:6]([S:8][CH3:9])[N:7]=1)[CH3:28]
Reactant: CSc1nc(Cl)cc(-c2cnn3cccnc23)n1
Reactant: C[C@H](N)c1ccc(F)cc1F
Solvent: CN1CCCC1=O
Product: CSc1nc(N[C@@H](C)c2ccc(F)cc2F)cc(-c2cnn3cccnc23)n1
Yield: 58.6 %

Procedure:
A 7 ml NMP solution of 3-(6-chloro-2-(methylthio)pyrimidin-4-yl)pyrazolo[1,5-a]pyrimidine (7h, 1.30 g) and (S)-1-(2,4-difluoro-phenyl)ethanamine (1.47 g) was heated in a microwave reactor at 220° C. for 20 min. LC/MS indicated the major peak was the desired product. The reaction mixture was partitioned between ethyl acetate and sat. NH4OAc. The organic phase was dried with MgSO4, filtered and the solvent was removed under reduced pressure. The product was purified by chromatography (SiO2, EtOAc-Hex, 1:1) (1.09 g, 58.6% yield).