Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.CS[C:15](=[N:20][CH3:21])[S:16]([O-:19])(=[O:18])=[O:17]>C(#N)C>[Cl:1][C:2]1[C:3]([CH2:8][S:9][CH2:10][CH2:11][NH:12][C:15]([S:16]([OH:19])(=[O:17])=[O:18])=[N:20][CH2:21][CH2:10][S:9][CH2:8][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN=C(SC)S(=O)(=O)[O-]
Reactant: NCCSCc1ncccc1Cl
Solvent: CC#N
Product: O=S(=O)(O)C(=NCCSCc1ncccc1Cl)NCCSCc1ncccc1Cl
Reaction time: 1 h

Procedure:
A solution of 2-(3-chloropyrid-2-ylmethylthio)ethylamine (4.06 g) in dry acetonitrile (200 ml) was added dropwise, with stirring, to a solution of 1-methylthio-1-methyliminomethanesulphonate (1.69 g) in dry acetonitrile (150 ml) at 50°. The mixture was stirred at 60° for 1 hour and then allowed to cool. The mixture was evaporated to dryness, dissolved in methanol and absorbed onto silica gel. Chromatography on a column of silica gel produced a viscous oil which was collected by eluting the column with a chloroform/methanol mixture and evaporating off the solvent. The viscous oil analysed by microanalysis and nuclear magnetic resonance spectroscopy to the title compound.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CC(C)([O-])C.[Na+].[C:20]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27]1[CH:39]=[CH:38][C:37]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([CH3:41])([CH3:40])[C:29]=2[CH:28]=1.Br[C:49]1[CH:61]=[CH:60][C:59]2[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:52]3([C:73]4[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=4[C:67]4[C:62]3=[CH:63][CH:64]=[CH:65][CH:66]=4)[C:51]=2[CH:50]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:20]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]([C:27]1[CH:39]=[CH:38][C:37]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([CH3:40])([CH3:41])[C:29]=2[CH:28]=1)[C:49]1[CH:61]=[CH:60][C:59]2[C:58]3[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=3)[C:52]3([C:73]4[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=4[C:67]4[C:62]3=[CH:63][CH:64]=[CH:65][CH:66]=4)[C:51]=2[CH:50]=1
Reactant: CC1(C)c2ccccc2-c2ccc(Nc3ccccc3-c3ccccc3)cc21
Reactant: Brc1ccc2c(c1)C1(c3ccccc3-c3ccccc31)c1ccccc1-2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(N(c3ccc4c(c3)C3(c5ccccc5-c5ccccc53)c3ccccc3-4)c3ccccc3-c3ccccc3)cc21
Temperature: 25 °C

Procedure:
Tri-tert-butylphosphine (4.4 ml of a 1.0 M solution in toluene, 4.4 mmol), palladium acetate (248 mg, 1.1 mmol) and sodium tert-butoxide (16.0 g, 166 mmol) are added to a solution of biphenyl-2-yl-(9,9-dimethyl-9H-fluoren-2-yl)amine (40.0 g, 111 mmol) and 2-bromo-9,9′-spirobifluorene (56.9 g, 144 mmol) in degassed toluene (500 ml), and the mixture is heated under reflux for 2 h. The reaction mixture is cooled to room temperature, diluted with toluene and filtered through Celite. The filtrate is evaporated in vacuo, and the residue is crystallised from ethyl acetate/heptane. The crude product is extracted in a Soxhlet extractor (toluene) and purified by zone sublimation in vacuo twice (p=3×104 mbar, T=298° C.). Biphenyl-2-yl-(9,9-dimethyl-9H-fluoren-2-yl)-(9,9′-spirobifluoren-2-yl)amine is isolated in the form of a pale-yellow solid (20.4 g, 27% of theory, purity >99.99% according to HPLC).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16]C(O)=O)[CH:12]=[CH:13][CH:14]=1.S(Cl)(Cl)=O.C[N:25](C)[CH:26]=[O:27].[N-]=[N+]=[N-].[Na+]>O.O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[C:26](=[O:27])[NH:25][CH:16]=[CH:15]2
Reactant: CN(C)C=O
Reactant: COCCOCCOc1cccc(C=CC(=O)O)c1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: COCCOCCOc1ccc2c(=O)[nH]ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To 3-{3-[2-(2-methoxyethoxy)ethoxy]phenyl}acrylic acid (10.7 g, 40.4 mmol) was added thionyl chloride (60 mL) and N,N-dimethylformamide (5 mL) and the reaction solution was refluxed under nitrogen atmosphere for 15 h. The reaction solution was dried, concentrated and the resulting oil was taken up in 1,4-dioxane (25 mL) and added dropwise during 15 min to a solution of sodium azide (7.87 g, 121 mmol) in water/dioxane (28 mL, 1:1) at 0° C. The suspension was stirred 30 min at 0° C., after which the precipitate was filtered off and washed with ethyl acetate. The filtrate was extracted with ethyl acetate (3×150 mL) and the combined organic layer was washed with water (75 mL) and brine (75 mL), dried over sodium sulphate and filtered. The azide containing solution volume was reduced in vacuo, diphenyl ether (20 mL) was added and the remaining ethyl acetate was removed in vacuo. The diphenyl ether solution of the azide was added dropwise during 20 min to hot diphenyl ether (65 mL, 230° C.) and the obtained solution was heated 2 h at reflux (˜260° C.) and then left stirring at room temperature over night. Hexane was added to the reaction solution and the product precipitated out as a black oil. The oil was pre-absorbed on silica gel and purified by flash chromatography (solvent gradient:methanol/methylene chloride, 2:98→4:96) giving, after concentration and drying of the appropriate fractions, 3.4 g (32% yield) of the title compound as a yellow solid. MS (AP+) m/z 264 (M++1).
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[NH:3]1.FC(F)(F)C(O)=O>ClCCl>[C:19]1([C:4]2[NH:3][C:2](=[O:1])[C:6]3([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]3)[N:5]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(c1ccccc1)NC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(c2ccccc2)=NC12CCNCC2

Procedure:
To a solution of tert-butyl 4-oxo-2-phenyl-1,3,8-triazaspiro[4.5]dec-1-ene-8-carboxylate (45 mg, 0.137 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (2 mL). After 2 h the reaction was concentrated to give the title compound. MS: m/z=230.1 (M+1).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](O)(=[O:39])[CH:36]([CH3:38])[CH3:37].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[F:17][C:15]1[CH:14]=[N:13][C:12]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)=[C:11]([CH:16]=1)[C:10]([NH:9][C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH:2][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH2:4][CH2:5]1)=[O:27]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Reactant: CC(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)C(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 101.6 %

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (100 mg, 0.243 mmol) was dissolved in dimethylformamide (1 ml) and triethylamine (100 μl, 0.729 mmol) was added followed by isobutyric acid (27 μl, 0.291 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56 mg, 0.291 mmol) and 1-hydroxybenzotriazole (39 mg, 0.291 mmol). The reaction was stirred under nitrogen at room temperature for 64 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (5 ml) and ethyl acetate (10 ml) and the aqueous phase was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with water (2×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was triturated with diethylether (5 ml) to give 5-Fluoro-N-(cis-4-isobutyrylamino-cyclohexyl)-2-(3-methylsulfanyl-phenoxy)-nicotinamide (110 mg) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19])([O-])=O.C1COCC1>CO.[C].[Pd]>[NH2:1][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]
Reactant: N#Cc1cccc(Nc2ccc3ccccc3c2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(Nc2ccc3ccccc3c2N)c1
Yield: 93.6 %

Procedure:
3-(1-Nitro-2-naphthylamino)benzonitrile (1.16 g, 3.99 mmol) was hydrogenated in methanol (20 mL)/THF (40 mL) for 4 hours at room temperature using 10% palladium-carbon (220 mg) as a catalyst. After removal of the catalyst by filtration, the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (chloroform/methanol=99/1), to give the titled compound as a yellow crystal (968 mg, yield 93%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:29][CH2:30][CH2:31][CH2:32][C@@H:3]12.[Li+].[OH-]>O1CCOCC1>[O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:29][CH2:30][CH2:31][CH2:32][C@@H:3]12
Reactant: COC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
(S)-methyl 4-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)benzoate (152 mg, 0.349 mmol) was taken up in dioxane (2 ml) and LiOH (1N, 2 ml, 2.000 mmol) was added. The reaction was stirred 16 h at room temperature. The reaction was concentrated in-vacuo and the residue was taken up in water (5 mL) and acidified (4.5N HCl) to pH 4. A white precipitate formed. The precipitate was filtered off and dried in vacuum to afford the title compound (122.8 mg, 83%) as a white solid. [M+H] calc'd for C23H27N5O3, 422; found, 422.
Reaction SMILES: Cl[C:2]1[N:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:3]=1[C:4]([NH:6][C:7](=[NH:19])[CH2:8][O:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:5].CC([O-])(C)C.[K+]>>[Cl:24][C:21]1[CH:22]=[N:23][C:2]2[N:19]=[C:7]([CH2:8][O:9][CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[NH:6][C:4](=[O:5])[C:3]=2[CH:20]=1
Reactant: N=C(COCCc1ccc(Cl)cc1)NC(=O)c1cc(Cl)cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=c1[nH]c(COCCc2ccc(Cl)cc2)nc2ncc(Cl)cc12

Procedure:
In analogy to the procedure described in example 78.4, 2,5-dichloro-N-{2-[2-(4-chloro-phenyl)-ethoxy]-1-imino-ethyl}-nicotinamide was treated with KOtBu to obtain 6-chloro-2-[2-(4-chloro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one as orange crystals. MS: m/e=350.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:10](I)=[CH:11][C:3]=12.CC1(C)C(C)(C)OB([C:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=2)O1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:10]([C:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=3)=[CH:11][C:3]=12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=S(=O)(c1ccccc1)n1c(I)cc2c(Cl)c(F)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)c(F)cnc3n2S(=O)(=O)c2ccccc2)CC1
Temperature: 80 °C

Procedure:
A mixture of Example 231B (6.70 g, 15.34 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (4.89 g, 15.81 mmol), tetrakis(triphenylphosphine)palladium (0.532 g, 0.460 mmol), and sodium bicarbonate solution (40 mL, 15.34 mmol) in N,N-dimethylformamide (160 mL) was degassed and heated at 80° C. overnight. The mixture was diluted with water/brine and extracted with ethyl acetate (twice). The combined organic layers were washed with water, dried over magnesium sulfate, filtered, concentrated, and purified on silica gel using an ISCO Companion eluting with heptanes/ethyl acetate (8:2 to 7:3) to give the title compound. MS (ESI+) m/z 492.0 (M+H)+.
Reaction SMILES: C([Si](C)(C)[O:6][C@H:7]1[C@:11]([C:14]#[CH:15])([CH2:12][OH:13])[O:10][C@@H:9]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:8]1)(C)(C)C.[CH3:27]O>>[CH2:14]([C@:11]1([CH2:12][OH:13])[O:10][C@@H:9]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:8][C@@H:7]1[OH:6])[CH:15]=[CH2:27]
Reactant: C#C[C@@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: CO
Product: C=CC[C@]1(CO)O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O

Procedure:
Physical data for 10b: mp 96-98° C.; UV (MeOH): λmax 267 nm (ε9300), λmin 235 nm (ε1700). 1H NMR (CDCl3) δ0.08 and 0.13 (6H, each as s, SiMe), 0.89 (9H, s, SiBu-t), 1.93 (3H, d, J6,CH3=0.9 Hz, Me), 2.12-2.17 (1H, m, H-2′a), 2.63 (1H, br, OH), 2.71-2.77 (1H, m, H-2′b), 2.75 (1H, s, ethynyl), 3.67 (1H, d, Jgem=11.5 Hz, H-5′a), 3.74 (1H, d, Jgem=11.5 Hz, H-5′b), 4.47 (1H, t, J2′a,3′=J2′b,3′=5.3 Hz, H-3′), 6.30 (1H, dd, J1′,2′a=4.8 Hz and J1′,2′b=6.9 Hz, H-1′), 7.80 (1H, d, J6,CH3=0.9 Hz, H-6), 9.00 (1H, brs, NH); FAB-MS m/z 381 (M++H). Anal. Calcd for C18H28N2O5Si: C, 56.82; H, 7.42; N, 7.36. Found: C, 56.57; H, 7.58; N, 7.19.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[OH-].[Na+].CN(C)[CH:20]=[O:21]>>[CH3:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([CH:20]=[O:21])=[CH:10][NH:11]2
Reactant: Cc1cccc2[nH]ccc12
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cccc2[nH]cc(C=O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of N,N-dimethylformamide (6 ml) and phosphorus oxychloride (1.78 g) was stirred at room temperature for 30 minutes. 4-Methylindole (1.0 g) was added to the reaction solution, followed by stirring at room temperature for one hour. A 5N aqueous solution of sodium hydroxide (15 ml) was added thereto, followed by stirring at 100° C. for further 30 minutes. The reaction solution was cooled, and the precipitated crystals were collected by filtration to give 4-methylindole-3-carboxaldehyde (Compound III-1, 1.14 g).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH:3]=[CH:4][N+:5]([O-:7])=[O:6].C(O)(C(F)(F)F)=O.[CH3:16][S:17]([C:20]1[CH:28]=C2[C:23]([CH:24]=CN2)=[CH:22][CH:21]=1)(=[O:19])=[O:18]>>[N+:5]([CH:4]=[CH:3][N:2]1[C:8]2[C:23](=[CH:22][CH:21]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:28]=2)[CH:24]=[CH:1]1)([O-:7])=[O:6]
Reactant: CN(C)C=C[N+](=O)[O-]
Reactant: CS(=O)(=O)c1ccc2cc[nH]c2c1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc2ccn(C=C[N+](=O)[O-])c2c1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
Combine 1-dimethylamino-2-nitroethylene (892.1 mg, 7.68 mmol) and TFA (9.0 ml) and stir until dissolved. Add 6-methanesulfonyl-1H-indole (1.5 g, 7.68 mmol) and stir at ambient temperature. After 24 hours, pour the reaction mixture into ice/water, extract with ethyl acetate, then wash ethyl acetate with brine and saturated sodium bicarbonate. Filter, wash, and dry the precipitate to give the title compound as a yellow powder: mp >250° C. MS (ACPI): m/e 267.0 (M+1). Analysis for C11H10N2O4S: Calcd: C, 49.62; H, 3.79; N, 10.52; found: C, 49.86; H, 3.97; N, 10.25.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7]/[C:8](=[CH:13]\[C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)/[C:9]2=[O:12])=[CH:5][C:4]=1[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=3)[C:9]2=[O:12])=[CH:5][C:4]=1[N:24]1[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(C(F)(F)F)cc1)C2=O
Agent: [Pd]
Solvent: CO
Product: COc1cc2c(cc1N1CCOCC1)CC(Cc1ccc(C(F)(F)F)cc1)C2=O
Reaction time: 6 h

Procedure:
The 85 (50 mg, 0.123 mmol) was dissolved in methanol 20 mL, Pd/C 20 mg added, and the reaction stirred under hydrogen balloon for 6 h, then filtered through celite bed and washed with excess methanol. The organic layer was concentrated to get the crude 86 which was purified by flash chromatography using 100-200 mesh silica gel. The compound 86 was eluted at 25% ethyl acetate in hexane as half white coloured solid compound 6-methoxy-5-morpholino-2-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one 86. 1HNMR (400 MHz, CDCl3) δ ppm 7.53 (d, 2H), 7.34 (d, 2H), 7.18 (s, 1H), 6.80 (s, 1H), 3.89 (m, 3H), 3.86 (m, 4H), 3.38 (m, 1H), 3.15 (m, 4H), 3.08 (m, 1H), 2.96 (m, 1H), 2.68 (m, 2H); MS (ESI) m/z 406.0 (M+H).
Reaction SMILES: CO[C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH3:11])[N:4]=1.[CH3:12][NH2:13].C(O)(=O)C>O>[CH3:10][O:9][C:7]1[N:6]=[C:5]([CH3:11])[N:4]=[C:3]([NH:13][CH3:12])[N:8]=1
Reactant: COc1nc(C)nc(OC)n1
Reactant: CN
Solvent: O
Solvent: CC(=O)O
Product: CNc1nc(C)nc(OC)n1
Reaction time: 4 h
Yield: 93 %

Procedure:
5000 g of a 40% by weight strength methanolic solution of 2,4-dimethoxy-6-methyl-1,3,5-triazine are initially charged and then, at from 5 to 10° C., admixed with a 40% by weight strength aqueous methylamine solution to neutralize the acetic acid, establishing a pH of from 7.2 to 7.5 (glass electrode). At from 13 to 15° C., 1500 g of a 40% by weight strength aqueous methylamine solution are then introduced over a period of 8 hours. After the addition of the methylamine solution has ended, stirring is continued at 14° C. for another 4 hours and then with water-cooling for 12 hours. The reaction product is subsequently filtered off with suction using a nutsch filter and washed with 5×900 ml of a 2% by weight strength methylamine solution and finally with 4×900 ml of water. The yield of 2-methoxy-4-methyl-6-methylamino-1,3,5-triazine, based on the dried product, is 1850 g (yield: about 93%).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH:29]=[C:28]([CH2:31][C:32](OC)=[O:33])[C:27]([CH3:37])([CH3:36])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O)C>O1CCCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH:29]=[C:28]([CH2:31][CH2:32][OH:33])[C:27]([CH3:37])([CH3:36])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)CC1=CCN(C(=O)OC(C)(C)C)CC1(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(CCO)C(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
A solution of 1 M diisobutylaluminum hydride in toluene (14.0 mL, 14.1 mmol) was slowly dropped into a cooled (−78° C.) solution of 1.6 g (5.7 mmol) of 4-methoxycarbonylmethyl-3,3-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester obtained in the above 1) of PREPARATION EXAMPLE 20 in tetrahydrofuran (70 mL) under an atmosphere of argon. After dropping, the solution was stirred for 2 hours at the same temperature. After the reaction was completed, ethanol (10 mL) was added at 0° C. and the solution was allowed to warm to room temperature gradually. The reaction mixture was then concentrated under a reduced pressure, treated with an aqueous solution of 20% sodium potassium tartrate (50 mL), and stirred for 30 minutes. After stirring, it was extracted with ether, and dried over anhydrous sodium sulfate. After drying, the extract was filtered and the filtrate was concentrated under a reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent, hexane:ethyl acetate=2:1) to obtain 1.1 g (yield 76.4%) of 4-(2-hydroxylethyl)-3,3-dimethyl-3,6-dihydro-2H-pyridine-1-carboxylic acid t-butyl ester. Its physical property is shown below.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.ClCCl.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O[CH2:34][CH3:35])(=O)C>COCCOC.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:3][C:2]1[CH:10]=[C:9]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=3)[N:4]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[N:3]=2)[CH:8]=[CH:34][CH:35]=1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Reactant: CCOC(C)=O
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOC
Product: N#Cc1ccc2c(c1)c(-c1cccc(N)c1)nn2C1CCCCO1

Procedure:
The title compound was prepared as described in example 161 using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (1.7 g, 5.55 mmol), in ethylene glycol dimethyl ether (60 mL), 3-amino boronic acid (1.72 g, 11.10 mmol), [1,1′-bis(diphenylphosphino)-ferrocene] complex with dichloromethane (1:1) (0.641 g, 0.555 mmol), and potassium phosphate (5.89 g, 27.75 mmol). A second batch was prepared using 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (2.0 g, 6.53 mmol), in ethylene glycol dimethyl ether (70 mL), 3-amino boronic acid (2.025 g, 13.06 mmol), [1,1′-bis(diphenylphosphino)-ferrocene] complex with dichloromethane (1:1) (0.755 g, 0.653 mmol), and potassium phosphate (6.92 g, 32.65 mmol). The crude compounds were combined and purified by column chromatography using 30% ethyl acetate in hexanes (3.2 g, 82% yield): ES-MS (m/z) 319 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.ClCCCl>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:11][CH2:12][CH:13]([C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[CH2:14][CH2:15]1
Reactant: O=C(O)C1CCN(c2cccc(CO)c2F)CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: O=C(C1CCN(c2cccc(CO)c2F)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
1-[2-Fluoro-3-(hydroxymethyl)phenyl]piperidine-4-carboxylic acid (100 mg) and morpholine (50 mg) were mixed with DCE (3 ml), and WSC hydrochloride (140 mg) and HOBt (95 mg) were added thereto, followed by stirring at room temperature for 3 hours. A saturated aqueous sodium hydrogen carbonate solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain {1-[2-fluoro-3-(hydroxymethyl)phenyl]piperidin-4-yl}(morpholin-4-yl)methanone (126 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C@H:3]([NH:8][C:9]([N:11]1[C:19]2[CH2:18][CH2:17][N:16]([CH3:20])[CH2:15][C:14]=2[C:13]([C:21]2[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:22]=2F)=[N:12]1)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].FC1C=C(C2C3CN(C(OC(C)(C)C)=O)CCC=3NN=2)C=CC=1F>>[F:27][C:25]1[CH:26]=[C:21]([C:13]2[C:14]3[CH2:15][N:16]([CH3:20])[CH2:17][CH2:18][C:19]=3[N:11]([C:9]([NH:8][C@@H:3]([C:2]([CH3:31])([CH3:30])[CH3:1])[C:4]([NH:6][CH3:7])=[O:5])=[O:10])[N:12]=2)[CH:22]=[CH:23][C:24]=1[F:28]
Reactant: CNC(=O)[C@@H](NC(=O)n1nc(-c2cc(F)c(F)cc2F)c2c1CCN(C)C2)C(C)(C)C
Agent: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(F)c(F)c3)c2C1
Product: CNC(=O)[C@@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCN(C)C2)C(C)(C)C

Procedure:
Compound 42 was prepared according to the procedure described for the synthesis of compound 37 by replacing intermediate 19 with intermediate 15. 1H NMR (CDCl3) δ 7.89 (d, J=9.4 Hz, 1H), 7.49-7.55 (m, 1H), 7.39-7.43 (m, 1H), 7.19-7.25 (m, 1H), 5.80 (br, 1H), 4.11 (d, J=9.4 Hz, 1H), 3.57 (s, 2H), 3.16-3.20 (m, 2H), 2.84 (d, J=4.8 Hz, 3H), 2.73 (t, J=5.8 Hz, 2H), 2.53 (s, 3H), 1.08 (s, 9H). LCMS (+ESI) m/z=420 [M+H]+.