Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11](=O)/[CH:12]=[C:13]3/[C:14](=O)[C@:15]4([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:18]/3[CH2:17][CH2:16]4)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[NH2:26][NH2:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]12([C:11]3[CH:12]=[C:13]4[C:14]([C@:15]5([CH3:22])[C:19]([CH3:21])([CH3:20])[C@H:18]4[CH2:17][CH2:16]5)=[N:27][N:26]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)/C2=C/C(=O)C12CC3CC(CC(C3)C1)C2
Reactant: NN
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)[C@H]2CC[C@]1(C)c1nnc(C34CC5CC(CC(C5)C3)C4)cc12

Procedure:
This material was prepared according to example 1 step C] (1S,4R)-3-[2-adamantan-1-yl-2-oxo-eth-(E)-ylidene]-1,7,7-trimethyl-bicyclo[2.2.1]heptan-2-one (0.2 g) and hydrazine monohydrate (0.117 g) with the following modifications: toluene as solvent (5 ml) in the presence of p-toluene sulfonic acid (0.117 g), heating for 12 h at reflux temperature and isolation of desired product by chromatography (no further NaOMe treatment as in example 1 step C]. This gave (1S,8R)-5-adamantan-1-yl-1,11,11-trimethyl-3,4-diaza-tricyclo[6.2.1.02,7]undeca-2,4,6-triene (0.027 g) as an amorphous light yellow solid. MS (EI): 322.4 (M+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@:8]([NH:14][C:15](=[O:18])[CH2:16]Cl)([CH2:12][OH:13])[CH:9]([F:11])[F:10])[C:5]([F:19])=[C:4]([Si](CC)(CC)CC)[CH:3]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.C(OCC)(=O)C>[Br:1][C:2]1[N:7]=[C:6]([C@@:8]2([CH:9]([F:11])[F:10])[NH:14][C:15](=[O:18])[CH2:16][O:13][CH2:12]2)[C:5]([F:19])=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)c1cc(Br)nc([C@](CO)(NC(=O)CCl)C(F)F)c1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: O=C1COC[C@](c2nc(Br)ccc2F)(C(F)F)N1
Temperature: 100 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
To a solution of N—[(R)-1-(6-bromo-3-fluoro-4-triethylsilanyl-pyridin-2-yl)-2,2-difluoro-1-hydroxymethyl-ethyl]-2-chloro-acetamide (2.32 g, 4.88 mmol) in t-butanol (50 ml) was added potassium tert-butoxide (7.31 ml, 7.31 mmol, 1M in THF) and the solution was stirred in a closed vial for 18 h at 100° C. The reaction mixture was diluted with ethyl acetate, washed with water, sat. NaHSO4 solution and brine, dried over sodium sulfate, filtered and evaporated. The crude product (2.36 g) was chromatographed over silica gel (24 g redisep column, cyclohexane/ethyl acetate 10-80%) to give the title compound. 1.13 g (71% yield). Triethylsilylated lactam (640 mg) was recovered.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH:21]=[O:22].FC(F)(F)S(O[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Si](C)(C)C)(=O)=O.[F-].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH:21]1[O:22][CH:2]2[CH:3]=[CH:4][C:5]3[C:10]([N:1]2[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]1=2)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: O=Cc1ccc2ccccc2c1
Reactant: C[Si](C)(C)c1ccccc1OS(=O)(=O)C(F)(F)F
Reactant: c1ccc2ncccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: C1=CC2OC(c3ccc4ccccc4c3)c3ccccc3N2c2ccccc21
Yield: 50 %

Procedure:
Following the general procedure, treatment of quinoline (0.064 g, 59 μL, 0.50 mmol) and 2-naphthaldehyde (0.117 g, 0.75 mmol) with 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.179 g, 146 μL, 0.60 mmol) in the presence of KF (0.070 g, 1.2 mmol) and 18-crown-6 (0.317 g, 1.2 mmol) in THF (2.0 mL) at −10° C. to room temperature for 12 hrs followed by flash column chromatography (Pet. ether/EtOAc=75/25) of the crude reaction mixture afforded 5-(naphthalen-2-yl)-5H,6aH-benzo[4,5][1,3]oxazino[3,2-a]quinoline as a yellow solid (0.091 g, 50% yield, dr determined by 1H NMR analysis of crude reaction mixture is >20:1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30](O)=[O:31])[CH:28]=2)[CH:23]=[CH:22]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:30]([C:27]3[CH:28]=[C:29]4[C:24]([CH:23]=[CH:22][NH:21]4)=[CH:25][CH:26]=3)=[O:31])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc2cc[nH]c2c1

Procedure:
1H-Indole-6-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1H-Indole-6-carboxylic acid. MS calcd. for C25H19ClN3O2 [(M+H)+] 428.1, obsd. 427.9.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:17][C:18](=[O:27])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:13]=2)[CH:8]=1)(=O)=O.[CH:30]1[C:39]2[C:34](=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>O1CCOCC1.O>[CH:30]1[C:39]2[C:34](=[C:35]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[CH:13]=[C:12]([NH:17][C:18](=[O:27])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:11]=[CH:10]4)[CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][N:31]=1
Reactant: COc1ccc(C(=O)Nc2ccc3cc(OS(=O)(=O)C(F)(F)F)ccc3c2)cc1
Reactant: OB(O)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccc3cc(-c4cccc5cnccc45)ccc3c2)cc1
Reaction time: 0.17 h
Yield: 3 %

Procedure:
To a microwave vial containing 6-(4-methoxybenzamido)naphthalen-2-yl trifluoromethanesulfonate (0.100 g, 0.2 mmol), in 1,4-Dioxane (3 mL), was added isoquinolin-5-ylboronic acid (0.129 g, 0.8 mmol), Fibrecat catalyst (0.005 g, 5% by wt.), 2 M Potassium Carbonate (0.50 mL, 1 mmol). The vial was capped and placed into CEM Microwave for 10 minutes at 80° C., while supplying 50 Watts of power through power-max. The diluted the mixture [with DCM (2 mL) and water (2 mL)] was extracted with DCM (3×10 mL). The dried organics (over sodium sulfate) was filtered, and concentrated in-vacuo. The crude was purified from reverse-phase HPLC. This gave a tan colored amorphous solid, which was titled product (0.0023 g, 0.006 mmol) MS (ESI pos. ion) m/z: 405 (M+H). Calc'd Exact Mass for C27H20N2O2: 404.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][S:4][N:3]=1.[CH2:13]([NH2:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CS(C)=O>[CH2:13]([NH:19][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][S:4][N:3]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCN
Reactant: Clc1nsnc1-c1cccnc1
Solvent: CS(C)=O
Product: CCCCCCNc1nsnc1-c1cccnc1

Procedure:
A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (0.59 g, 3 mmol) and hexylamine (1.52 g, 15 mmol) in DMSO (5 ml) was heated at 100° C. for 48 h. After evaporation, water was added to the residue and extracted with ether. The combined organic extracts were dried and evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.[Li][CH2:12]CCC.CI>C(OCC)C>[CH2:1]([C:2]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][CH:8]=[C:9]2[CH:10]=1)[CH3:12]
Reactant: Cc1cc2cccnc2[nH]1
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CI
Product: CCc1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-methyl-7-azaindole (1.32 g, 10 mmol) in dry diethyl ether (60 ml) at room temperature under an inert atmosphere is added n-BuLi (18.8 ml of a 1.6 M solution in hexanes, 30 mmol) followed by f-BuOK (2.24 g, 20 mmol). The reaction mixture is stirred at room temperature for 40 minutes and then cooled to −70° C. whereupon methyl iodide (1.25 ml, 20 mmol) is added dropwise. Stirring continues for a further 2 hours after which time, the reaction mixture is quenched with water (2 ml) and is allowed to slowly warm to room temperature. The cooled solution is poured onto water (200 ml), neutralized with 1N HCl and then extracted with diethyl ether (80 ml). The organic portion is washed with water (2×60 ml), dried (Na2SO4) and concentrated in vacuo to yield the titled compound as orange crystals. [MH+CH3CN]+=188)
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:17]=[CH:16][C:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15][C:9]=3[CH:8]=2)=[CH:5][C:4]([CH3:18])=[N:3]1.Br[CH2:20][CH2:21][CH2:22][Cl:23]>C1COCC1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[Cl:23][CH2:22][CH2:21][CH2:20][N:13]1[CH2:12][CH2:11][C:10]2[CH:16]=[CH:17][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:18])[CH:5]=3)=[CH:8][C:9]=2[CH2:15][CH2:14]1
Reactant: Cc1cc(-c2ccc3c(c2)CCNCC3)n(C)n1
Reactant: ClCCCBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ccc3c(c2)CCN(CCCCl)CC3)n(C)n1
Temperature: 25 °C

Procedure:
To a solution of 7-(1,3-dimethyl-1H-pyrazol-5-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine (0.5 g) in dry THF (10 ml), diisopropylethylamine (0.85 ml) and 1-bromo-3-chloropropane (0.47 mL) were added and the resulting mixture was refluxed for 7 hours. After cooling at room temperature it was diluted with ethyl acetate (30 ml) washed twice with a saturated solution of NaHCO3 in water (20 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by biotage chromatography using a silica 25 M+ cartridge and eluting with cHex/EtOAc 8:2 to give the title compound as a colourless oil (0.57 g).
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:30])[CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=[C:18]([C:27]([OH:29])=O)[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH2:50]([O:54][C:55]([N:57]1[CH2:62][CH2:61][N:60]([C:63](=[O:73])[C@@H:64]([NH2:72])[CH2:65][CH2:66][C:67]2[N:68]=[N:69][NH:70][N:71]=2)[CH2:59][CH2:58]1)=[O:56])[CH2:51][CH2:52][CH3:53]>CN(C=O)C.C(Cl)CCl>[CH2:50]([O:54][C:55]([N:57]1[CH2:58][CH2:59][N:60]([C:63](=[O:73])[C@@H:64]([NH:72][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)=[O:30])[C:25]3[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=3)[N:19]=2)=[O:29])[CH2:65][CH2:66][C:67]2[N:71]=[N:70][NH:69][N:68]=2)[CH2:61][CH2:62]1)=[O:56])[CH2:51][CH2:52][CH3:53]
Reactant: Cc1ccc2c(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)cc(C(=O)O)nc2c1
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCc2nn[nH]n2)CC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)c3ccc(C)cc3n2)CC1
Reaction time: 48 h

Procedure:
To a solution of 600 mg 4-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid in 60 ml DMF were added 279 μl DIPEA, 294 mg EDC and 234 mg HOBt. After 5 minutes 661 mg 4-[(S)-2-amino-4-(2H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate were added and the mixture stirred for 48 h.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:15][CH:16]=2)[C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: Cc1cc(Cl)ccc1O
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1cc(Cl)cc(Cc2ccc(C(C)(C)C)cc2)c1O

Procedure:
106.5 g (0.75 mol) 4-chloro-2-methylphenol and 45.67 g (0.25 mol) 4-tert. butylbenzylchloride are dissolved in 200 ml chloroform, and 22.5 g water-free zinc chloride are added as Friedel-Crafts catalyst. Thereafter the reaction mixture is stirred, whereby indeed at room temperature to the start of the reaction intense gas development, i.e. intense reaction, is to be noted. Subsequently the reaction mixture is stirred at 60° C. 5-6 h and washed three times each with 200 ml water for the purpose of removing the zinc chloride. The organic phase is dried across magnesium sulfate and the chloroform is driven off in a vacuum. At 182°-185° C./0.3 Torr the 4-chloro-2-methyl-6-(4'-tert. butylbenzyl)-phenol distills over as water-clear, viscous, nearly odorless liquid.
Reaction SMILES: [C:1](#[N:5])[CH2:2][CH2:3][CH3:4].[ClH:6].[CH3:7][CH2:8][OH:9]>>[ClH:6].[CH2:8]([O:9][C:1](=[NH:5])[CH2:2][CH2:3][CH3:4])[CH3:7]
Reactant: CCO
Reactant: CCCC#N
Agent: Cl
Product: CCCC(=N)OCC
Reaction time: 18 h
Yield: 48 %

Procedure:
A solution of butyronitrile (15 g, 0.21 mol) in EtOH (150 mL) was cooled in an ice bath. The cold solution was then saturated with hydrogen chloride. The reaction mixture was refrigerated for 18 hours. The ethanol was evaporated under vacuum. The residual oily substance was then treated with ether to obtain the title compound (15.5 g, 48% yield) which was used in the next reaction.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)CN(S(C3C=CC(C)=CC=3)(=O)=O)[C@@H](CCOS(C)(=O)=O)[CH2:15]2)=[CH:10][CH:9]=1)[CH3:2].[N-]=[N+:56]=[N-:57].[Na+].[CH3:59][N:60]1[C:65](=O)[N:64]([CH3:67])[CH2:63][CH2:62][CH2:61]1>CC(OC)(C)C>[CH2:1]([O:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:15][C@H:63]([CH2:62][CH2:61][N:60]3[CH:65]=[N:57][N:56]=[CH:59]3)[NH:64][CH2:67][C@@H:19]2[O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CCOS(C)(=O)=O)N(S(=O)(=O)c3ccc(C)cc3)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: CN1CCCN(C)C1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CCO[C@H](C)COCc1ccc([C@H]2C[C@H](CCn3cnnc3)NC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 25 °C

Procedure:
A solution of 1.0 mmol of methanesulfonic acid 2-[(2R,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl) -phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-ethyl ester (example 6g) and 10 mmol of sodium azide in 1.5 ml of DMPU is stirred at 80° C. for 3 h. The solution is cooled to RT, diluted with 3 ml of TBME, filtered through 2 cm of SiO2 60 F, eluting with EtOAc-Heptane 1:1. The filtrate is concentrated under reduced pressure and purified by flash chromatography (SiO2 60 F), to afford the title compound as a yellow oil. Rf=0.45 (EtOAc/heptane 2:1); Rt=5.80 (gradient I).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].C(OCC)C.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[CH2:28][Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH2:28][C:19]1[CH:20]=[CH:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=1)[CH3:12]
Reactant: Br[Mg]Cc1ccc2ccccc2c1
Reactant: CCOC(=O)C(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(OCC)C(=O)Cc1ccc2ccccc2c1
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
Under an argon atmosphere, to a solution of ethyl diethoxyacetate (900 μL, 5.06 mmol) in THF (15 mL) was added slowly a diethyl ether solution of (2-naphtalenylmethyl)magnesium bromide (21) (0.25 M, 25.0 mL, 6.25 mmol) at −78° C. After stirring at for 2.5 h at −78° C., the mixture was gradually warmed to room temperature and stirred for 15 h. To this was added 20% aqueous solution of ammonium chloride (10 mL) and the product was extracted with ethyl acetate (×3). The organic layer was sequentially washed with water (×1) and saturated brine (×1), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography (n-hexane/ethyl acetate=19/1) to give 1,1-diethoxy-3-(2-naphthalenyl)propan-2-one (22) as a colorless oily substance (675 mg, 2.48 mmol, 49.0%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[NH:13][C:12]3[CH:11]=[N:10][CH:9]=[CH:8][C:7]=3[C:5]=2[CH:6]=1.[H-].[Na+].Cl[CH2:17][CH2:18][N:19]([CH2:39][CH2:40]Cl)[C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[N-:42]=[N+]=[N-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C1(C)C=CC=CC=1>[NH2:42][CH2:17][CH2:18][N:19]([C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:39][CH2:40][N:13]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]2[CH:8]=[CH:9][N:10]=[CH:11][C:12]1=2
Reactant: c1ccc2c(c1)[nH]c1cnccc12
Reactant: ClCCN(CCCl)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [H-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: NCCN(CCn1c2ccccc2c2ccncc21)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.5 %

Procedure:
To a solution of 506 mg (3.01 mmol) of norharman in N,N-dimethylformamide (15 ml) was added 132 mg (3.3 mmol) of sodium hydride in small portions under ice cooling, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 3.84 g (10 mmol) of bis(2-chloroethyl)(triphenylmethyl)amine and the mixture was reacted at 110° C. for 3 hours. Then, 650 mg (10 mmol) of sodium azide was added, followed by reaction at 100° C. for 2 hours. After cooling to room temperature, the resulting suspension was diluted with toluene and then washed with water and saturated saline. The toluene layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was added with tetrahydrofuran (3 ml) and water (1 ml) to dissolve the former in the latter. To the resulting solution was added 787 mg (3.0 mmol) of triphenylphosphine and the mixture was reacted at 50° C. for 2 hours. Generation of a gas was observed for a while after the initiation of the reaction and it lasted for about 1.5 hours. After completion of the reaction, the reaction mixture was concentrated, followed by purification through chromatography on a silica gel column (mobile phase; chloroform:methanol:aqueous ammonia=90:9.7:0.3 (v/v)), whereby 306 mg (20.5%) of the title compound was obtained. The physical properties of the resulting compound are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.C([Li])CCC.CN(C)[CH:16]=[O:17]>C1COCC1.CCOCC>[Br:1][C:2]1[N:3]=[CH:4][C:5]([CH:16]=[O:17])=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
2,5-Dibromopyridine 9.48 g (40 mmol) was dissolved in 60 mL of THF and 150 mL of anhydrous ether. After the solution was cooled to −78° C., 16 mL of n-butyllithium (2.5 M, 40 mmol) was slowly dropped through a syringe in 30 min. After being stirred at −78° C. for 30 minutes, N,N-dimethylformamide (3.5 g, 48 mmol) was added. The reaction mixture was warmed up to room temperature during two hours and then quenched by addition of 10 ml water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 30-40% EtOAc in hexane, 2.80 g white solid was obtained (28% yield), MS: (M+H)+ 186.0, 188.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1.C1CCCCC1.C(OCC)(=[O:36])C>>[CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:36])[C:5]2[CH:14]=[C:15]([C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([I:25])[CH:20]=3)[CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3cccc(I)c3)ccc2O1
Reactant: CCOC(C)=O
Solvent: C1CCCCC1
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(=O)c3cccc(I)c3)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 21, from 3,4-dihydro-2,2-dimethyl-6-(3-iodobenzoyl)-4-(2-pyridyl)-2H-1-benzopyran there was obtained 2-[3,4-dihydro-2,2-dimethyl-6-(3-iodobenzoyl)-2-H-1-benzopyran-4-yl]pyridine N-oxide of melting point 128°-130° C. (from cyclohexane/ethyl acetate).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:19][Si](CC)(CC)CC)([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)[CH3:2].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[CH2:27]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:19])([C:11]([F:12])([F:13])[F:14])[C:15]([F:16])([F:17])[F:18])=[CH:8][CH:9]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCNc1ccc(C(O[Si](CC)(CC)CC)(C(F)(F)F)C(F)(F)F)cc1
Reactant: BrCc1ccccc1
Solvent: CN(C)C=O
Product: CCN(Cc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 0.5 g (1.24 mmol) of ethyl-[4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenyl]-amine in 2 mL of DMF were added 0.3 mL (2.5 mmol) of benzylbromide and the mixture was stirred overnight at 80° C. After distribution between a 2M aqueous solution of NaOH and Et2O, drying of the combined organic phases over Na2SO4 and evaporation, the resulting crude was dissolved in 5 mL of MeOH, treated with 1 mL of a 2M NaOMe-solution in MeOH and stirred for 30 min. Evaporation of the solvent and column chromatography on silica gel with n-heptane/EtOAc 95:5 gave 0.33 g (70%) of 2-[4-(benzyl-ethyl-amino)-phenyl]-1,1,1,3,3,3-hexafluoro-propan-2-ol, light yellow semisolid, MS: 378 (MH+).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([Cl:11])[CH:5]=1)=O.N1C=CC=CC=1.[NH2:18][OH:19].O>CCO>[Cl:11][C:6]1[CH:5]=[C:4]([C:2](=[N:18][OH:19])[CH3:1])[CH:9]=[CH:8][C:7]=1[Cl:10]
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NO
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: CC(=NO)c1ccc(Cl)c(Cl)c1
Temperature: 90 °C

Procedure:
A mixture of 3,4-dichloroacetophenone (1.0 eq), pyridine (5.0 eq) and hydroxylamine (5.0 eq) in EtOH (10 vol) was heated to a temperature of 90° C. for 80 minutes. To the cooled reaction mixture was added water (40 vol) and the precipitated solid was filtered, washed with water (2×10 vol) and dried to give 1-(3,4-dichloro-phenyl)-ethanone oxime.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH2:15]2)[CH:4]=1.[CH3:28][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[CH3:1][S:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH3:28])[CH2:16][CH2:15]2)[CH:4]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)c1ccc(SC)cc1O[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(SC)cc1O[C@H]1CC[C@@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 7 h
Yield: 41.8 %

Procedure:
To a mixture of methyl 4-methylthio-2-[cis-4-(t-butoxy-carbonylamino)cyclohexyloxy]benzoate (3.0 g, 7.59 mmol) in THF (15 mL) at −20° C. was added 1 M lithium hexamethyl-disilazide (LiHMDS)/hexane (8.0 ml, 7.97 mmol, 1.05 eq), and the mixture was warmed to 0° C. for 10 min. To the reaction mixture was added methyl iodide (0.5 mL, 7.97 mmol, 1.05 equivalent), the mixture was warmed to room temperature and stirred for 7 h, and the reaction was quenched with satd citric acid. The mixture was diluted with CH2Cl2 and partitioned. The organic layer was dried (Na2SO4) and concentrated. This material was combined with the crude product from a small scaled reaction (500 mg, 1.27 mmol), chromatographed (400 g, SiO2, hexanes to 20% EtOAc/hexanes) and triturated with Et2O to give the title compound as a white solid (1.3 g, 36%).