Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(=O)([O-])O.[Cs+].[C:15]([O:23][CH:24](Cl)[CH:25]([CH3:27])[CH3:26])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O:6][CH:24]([O:23][C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:22])[CH:25]([CH3:27])[CH3:26])=[O:5]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: CC(C)C(Cl)OC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Cs+]
Product: COC(=O)/C=C/C(=O)OC(OC(=O)c1ccccc1)C(C)C
Yield: 15.4 %

Procedure:
Following general procedure A, methyl hydrogen fumarate (0.50 g, 3.82 mmol) was reacted with CsHCO3 (5.76 mmol) and chloroisobutyl benzoate (1.1 g, 5.17 mmol) at ca. 55° C. to afford 0.18 g (15% yield) of the title compound (46) after purification by silica gel flash chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:7). 1H NMR (CDCl3, 400 MHz): δ 8.04-8.01 (m, 2H), 7.58-7.55 (m, 1H), 7.45-7.41 (m, 2H) 6.98 (d, J=4.8 Hz, 1H), 6.90 (d, J=16.0 Hz, 1H), 6.84 (d, J=16.0 Hz, 1H), 3.78 (s, 3H), 2.25-2.21 (m, 1H), 1.10-1.07 (m, 6H); MS (ESI): m/z 307.11 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[N+:10]([O-])([O-:12])=[O:11].[K+].S(=O)(=O)(O)O>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:4]([CH:3]=1)[C:5]#[N:6]
Reactant: N#Cc1cccc(F)c1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: N#Cc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 55.4 %

Procedure:
3-Fluorobenzonitrile (25 g) was added dropwise to a stirred mixture of potassium nitrate (21.1 g) and concentrated sulphuric acid (150 ml) which had been cooled in a mixture of salt and ice. The mixture was stirred at ambient temperature for 45 minutes. The mixture was poured onto ice (800 ml) and the precipitate was isolated. The solid so obtained was dissolved in methylene chloride, dried (MgSO4) and the solution was evaporated to give 5-fluoro-2-nitrobenzonitrile (19 g).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([NH2:29])[CH:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])[CH:20]=4)[C:9]3=[N:10][CH:11]=2)[N:3]=[N:2]1.N1C=CC=CC=1.[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]3[N:14]=[CH:13][N:12]([C:15]4[CH:16]=[C:17]([NH:29][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])[CH:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])[CH:20]=4)[C:9]3=[N:10][CH:11]=2)[N:3]=[N:2]1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4c[nH]nn4)cnc32)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4c[nH]nn4)cnc32)c1
Yield: 9.3 %

Procedure:
To a solution of 5-(6-(1H-1,2,3-triazol-4-yl)-3H-imidazo[4,5-b]pyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (70 mg, 0.179 mmol) in DCM was added pyridine (42 mg, 0.53 mmol, 3.0 eq.) followed by ethanesulfonyl chloride (20 mg, 0.179 mmol, 1.0 eq.). The reaction was monitored by LCMS. After completion of the reaction the solvent was distilled off and the crude product was purified by preparative HPLC to give the product in 9.3% yield (8 mg). 1H NMR (300 MHz, DMSO): δ 10.4 (s, 1H) 9.0-8.97 (m, 2H), 8.64 (d, 1H), 7.92 (s, 1H), 7.75-7.64 (m, 3H), 7.47-7.43 (m, 3H), 3.31-3.24 (q, 2H), 1.39-1.34 (t, 3H); LC-MS (ESI): Calculated mass: 481.4; Observed mass: 481.8 [M+H]+ (rt: 1.36 min).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[CH:17]([N:30]1[CH2:33][CH:32](OS(C)(=O)=O)[CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[C:18]1([CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:30]2[CH2:33][CH:32]([O:1][C:2]3[C:7]4[CH:8]=[C:9]([CH3:11])[O:10][C:6]=4[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=3)[CH2:31]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2cc(C)oc2c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 63.1 %

Procedure:
A mixture of ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate (252c) (1.70 g, 7.72 mmol), 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (193a) (2.95 g, 9.29 mmol) and Cs2CO3 (6.29 g, 19.3 mmol) in DMF (10 mL) was stirred for 4 hours at 100° C. The reaction was cooled to room temperature, diluted with EtOAc and washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The product was purified via gradient silica gel chromatography using EtOAc/Hexanes (10/90 to 40/60) to give the desired compound (2.15 g, 63%) as a white solid after evaporation of the solvent. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.32-1.49 (m, 3 H) 2.42-2.57 (m, 3 H) 3.10-3.29 (m, 2 H) 3.75-3.94 (m, 2 H) 4.27-4.42 (m, 2 H) 4.43-4.52 (m, 1 H) 4.91-5.10 (m, 1 H) 6.50 (s, 1 H) 7.05 (s, 1 H) 7.15-7.25 (m, 2 H) 7.24-7.35 (m, 4 H) 7.39-7.54 (m, 4 H) 7.74 (s, 1 H); MS (ESI, pos): 442.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.[Fe]>[NH2:1][C:4]1[C:9]2[N:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cccc2oc(C(F)(F)F)nc12
Agent: [Fe]
Solvent: CCOC(C)=O
Product: Nc1cccc2oc(C(F)(F)F)nc12
Temperature: 65 °C
Reaction time: 6 h
Yield: 75 %

Procedure:
Compound 476A (10.75 g, 46.30 mmol) was dissolved in 1:1 EtOAc/10% HOAc (250 mL) and heated to 65° C. Iron powder (12.93 g, 231.5 mmol) was added portionwise and the reaction was stirred for 6 h at 65° C. After cooling, the mixture was filtered through Celite rinsing with EtOAc. The organic layer was separated, washed with H2O (3×100 mL), brine (100 mL), dried over MgSO4, and concentrated in vacuo to give a brown oil. The crude material was purified by flash chromatography on silica gel eluting with 70/30 CH2Cl2/hexanes to give compound 476B (7.02 g, 75%) as a yellow crystalline solid. HPLC: 96.7% at 2.68 min (retention time) (YMC S5 ODS column, 4.6×50 mm, eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm).
Reaction SMILES: O[C@@H:2]1[C@H:8]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH2:6][CH3:7])[C:4](=[O:21])[CH2:3]1)[C@@H:17]1[C:12](=[CH:13][CH2:14][CH2:15][CH2:16]1)[CH2:11][CH2:10]3.CS(Cl)(=O)=O.CN(C)C=O.C([O-])(=O)C.[Na+]>N1C=CC=CC=1>[CH3:7][CH2:6][C@:5]12[CH2:20][CH2:19][C@H:18]3[C@@H:9]([CH2:10][CH2:11][C:12]4[C@@H:17]3[CH2:16][CH2:15][CH2:14][CH:13]=4)[C@@H:8]1[CH:2]=[CH:3][C:4]2=[O:21]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1C=CC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.7 %

Procedure:
In an ice bath, 7.8 g of 15α-hydroxy-18-methyl-4-estren-17-one in 50 ml of pyridine is combined with 10 ml of methanesulfonic acid chloride. After 1 hour, 50 ml of dimethylformamide (DMF) is added thereto, along with 23 g of anhydrous sodium acetate. The mixture is stirred for another 20 hours at room temperature. The mixture is introduced into ice/water. The thus-precipitated product is vacuum-filtered, washed with water, dissolved in ethyl acetate, and dried. Crystallization from ethyl acetate yields 5.1 g of 18-methyl-4,15-estradien-17-one, mp 125.2° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]=1[C:19](O)=[O:20].[NH2:22][CH2:23][CH:24]([OH:31])[CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28]>>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]([C:19]([NH:22][CH2:23][CH:24]([OH:31])[CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:20])=[C:3]2[O:2][CH3:1]
Reactant: CCN(CC)CC(O)CN
Reactant: COc1c(C(=O)O)n(-c2ccccc2)c2ccc(C)cc12
Product: CCN(CC)CC(O)CNC(=O)c1c(OC)c2cc(C)ccc2n1-c1ccccc1

Procedure:
The above 3-methoxy-5-methyl-1-phenylindole-2-carboxylic acid is converted into its acid chloride analogously to Example 1H, and this is reacted with 1-amino-3-diethylamino-2-hydroxypropane. The title compound is obtained as an oily base. This base is dissolved in isopropanol, and citric acid is added to the solution. The citrate of the title compound which has precipitated is filtered off with suction and recrystallised from isopropanol. Melting point: 126°-128° C., yield: 7.7 g.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][N:14]([CH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=2)[CH2:18]1)[CH3:15].[N+:28]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35]O)=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:15][N:14]([CH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=3)[CH:23]=2)[CH2:18]1)[CH3:13]
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CC1CCc2cc(OCc3ccc([N+](=O)[O-])cc3)ccc2C1
Reaction time: 24 h
Yield: 51.9 %

Procedure:
Diethyl azodicarboxylate (40% toluene solution, 9.53 g) was added dropwise to THF solution (15 ml) of 2-[(N,N-dimethylamino)methyl]-6-hydroxytetralin (1.5 g), 4-nitrobenzylalcohol (3.35 g), and triphenylphosphine (5.74 g) at room temperature, which was stirred for 24 hours. The reaction mixture was concentrated, and the residue was purified using alumina column chromatography (development solvent; hexane˜hexane:ethyl acetate=8:1), and recrystallized (ethyl acetate-hexane) to give the titled compound (1.29 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][N:6]([C:8](=[O:20])[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([NH:18][CH3:19])[CH:10]=2)[CH2:5][CH2:4][N:3]1[C:21]([C:23]1[N:27]=[CH:26][N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]=1)=[O:22]>[Ni].CO>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([N:6]2[CH2:5][CH2:4][N:3]([C:21]([C:23]3[N:27]=[CH:26][N:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:24]=3)=[O:22])[C:2]([CH3:34])([CH3:1])[CH2:7]2)=[O:20])=[CH:10][C:11]=1[NH:18][CH3:19]
Reactant: CNc1cc(C(=O)N2CCN(C(=O)c3ncn(-c4ccccc4)n3)C(C)(C)C2)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CNc1cc(C(=O)N2CCN(C(=O)c3ncn(-c4ccccc4)n3)C(C)(C)C2)ccc1N
Reaction time: 7.5 h

Procedure:
A mixture of 445 mg (0.960 mmol) [2,2-dimethyl-4-(3-methylamino-4-nitro-benzoyl)-piperazin-1-yl]-(1-phenyl-1H-[1,2,4]-triazol-3-yl)-methanone and 300 mg Raney nickel in 50 mL MeOH was hydrogenated at RT for 7.5 h. The catalyst was removed by filtration and the solvent was evaporated in vacuo.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:14]=[N:13]1)[CH2:9][C:10]#[CH:11]>N1C=CC=CC=1>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:14]=[N:13][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:16]=2)=[CH:22][CH:21]=1
Reactant: C#CCCn1cc(-c2ccc(F)cc2)nn1
Reactant: Brc1ccccn1
Solvent: c1ccncc1
Product: Fc1ccc(-c2cn(CCC#Cc3ccccn3)nn2)cc1

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-pyridine (65 mg, 0.41 mmol) and 1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-[1,2,3]triazole (80 mg, 0.37 mmol). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98.5:1.5) to yield 28 mg (96 μmol, 26%) of 2-(4-(4-fluorophenyl)-1H-1,2,3-triazol-1-yl)but-1-ynyl)pyridine as a brown solid (M.P.=120-122° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:18][O:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:21]#[N:22].[Na+].O.C(OCC)(=O)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:21]#[N:22])[CH2:10][C@H:9]1[CH2:18][O:19][CH3:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COC[C@@H]1C[C@H](C#N)CN1C(=O)OC(C)(C)C
Yield: 97.5 %

Procedure:
A solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-methanesulfonyloxy-2-methoxymethylpyrrolidine (3.3 g) and sodium cyanide (1.75 g) in dimethyl sulfoxide (35 ml) was heated for three hours and forty minutes at 92° C. The reaction mixture was poured into a mixture of water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (200 ml) eluting with a mixture of hexane and ethyl (1:1, V/V) to give (2S,4S)-1-(tert-butoxycarbonyl)-4-cyano-2-methoxymethylpyrrolidine (2.5 g).
Reaction SMILES: [N:1]1[NH:2][N:3]=[C:4]([CH2:6][C:7]2[N:11]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]3=[N:9][C:8]=2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:5]=1.Cl.Cl[C:26]1C=CC2N(C(CCl)=C(C3C=CC(Cl)=CC=3)N=2)C=1.C([Mg]Br)#CC>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([C:7]([CH2:6][C:4]3[C:5]([CH3:26])=[N:1][NH:2][N:3]=3)=[C:8]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:9]=2)[CH:12]=1
Reactant: Clc1ccc(-c2nc3ccc(Cl)cn3c2Cc2cn[nH]n2)cc1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12
Agent: CC#C[Mg]Br
Agent: Cl
Product: Cc1n[nH]nc1Cc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cn12

Procedure:
The title compound was prepared according to the experimental described for compound 227 from 6-chloro-3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and prop-1-ynylmagnesium bromide. m/e+ 359 for C17H14Cl2N5 (M+H)+.
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:11]([O:13][C:14](=[O:15])[C:7]3=[C:8]2[C:3](=[C:4]([OH:16])[CH:5]=[CH:6]3)[CH:2]=1)=[O:12].C=O.S(=O)(=O)(O)O.[O:24]1[CH2:29]COC[CH2:25]1>>[CH:2]1[C:3]2[C:8]3[C:9]([C:11](=[O:12])[O:13][C:14](=[O:15])[C:7]=3[CH:6]=[C:5]3[C:4]=2[O:16][CH2:29][O:24][CH2:25]3)=[CH:10][CH:1]=1
Reactant: C1COCCO1
Reactant: O=C1OC(=O)c2ccc(O)c3cccc1c23
Agent: C=O
Agent: O=S(=O)(O)O
Product: O=C1OC(=O)c2cc3c(c4cccc1c24)OCOC3

Procedure:
To a suspension of 620 mg (2.9 mmol) of 4-hydroxy-1,8-naphthalic anhydride (from Example S3) and 1.60 g (53.0 mmol) of paraformaldehyde in 20 mL dioxane was added 5.2 mL of concentrated sulfuric acid. The reaction mixture was refluxed for 1 hour and quenched with 100 mL water. The precipitate was isolated, dried, recrystallized from DMSO, washed with acetone, and dried again to yield 0.50 g of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15]>>[CH2:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH3:15]
Reactant: CCOCCCCCl
Reactant: O=C1CCNCC1
Product: CCOCCCCN1CCC(=O)CC1

Procedure:
1-(4-Ethoxybutyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-4-ethoxybutane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:22]4[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[Br:29][C:30]1[CH:31]=[C:32]2[C:43]3([CH2:48][CH2:47][O:46][C:45]([NH2:49])=[N:44]3)[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([C:50]4[C:51]([F:56])=[N:52][CH:53]=[CH:54][CH:55]=4)[CH:41]=3)[O:36][C:33]2=[N:34][CH:35]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:20][CH2:19][O:18][C:17]([NH2:21])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:22]4[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[Br:29][C:30]1[CH:31]=[C:32]2[C@@:43]3([CH2:48][CH2:47][O:46][C:45]([NH2:49])=[N:44]3)[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([C:50]4[C:51]([F:56])=[N:52][CH:53]=[CH:54][CH:55]=4)[CH:41]=3)[O:36][C:33]2=[N:34][CH:35]=1
Reactant: NC1=NC2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Agent: NC1=N[C@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Product: NC1=N[C@@]2(CCO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12

Procedure:
Intermediates ((S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) (intermediate 26A, 350 mg), and its enantiomer ((R)-3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine (intermediate 26 B, 500 mg) were obtained from racemic (3-bromo-7-(2-fluoropyridin-3-yl)-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-2′-amine) using similar chiral separation conditions as described herein for intermediate 10. MS (m/z) 441/443 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:17]=[C:16]([S:18][CH3:19])[CH:15]=[CH:14][C:9]=1[C:10](OC)=[O:11]>O1CCCC1.C(OCC)C.Cl>[Cl:7][C:8]1[CH:17]=[C:16]([S:18][CH3:19])[CH:15]=[CH:14][C:9]=1[CH2:10][OH:11]
Reactant: COC(=O)c1ccc(SC)cc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CSc1ccc(CO)c(Cl)c1
Reaction time: 1 h
Yield: 103.3 %

Procedure:
To a suspension of lithium aluminum hydride (139 mg) in tetrahydrofuran (8 ml) was added dropwise methyl 2-chloro-4-(methylthio)benzoate (806 mg) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was diluted with diethyl ether and 1N hydrochloric acid (10 ml) was added dropwise. The resulting product was extracted 3 times with diethyl ether. The organic layers were combined and washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 2-chloro-4-(methylthio)benzyl alcohol (725 mg) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([CH:16]=[C:17]([CH3:19])[CH3:18])[CH:14]=3)[N:9]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:8]=2)[CH:4]=[N:3]1>CO.[OH-].[OH-].[Pd+2]>[CH2:16]([C:13]1[CH:14]=[C:15]2[C:7]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:8][N:9]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:10]2=[N:11][CH:12]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)=Cc1cnc2c(c1)c(-c1cnn(C)c1)cn2S(=O)(=O)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)Cc1cnc2c(c1)c(-c1cnn(C)c1)cn2S(=O)(=O)c1ccccc1
Reaction time: 93 h

Procedure:
A mixture of olefin 61 (118 mg, 3.00 mmol) and moist Pd(OH)2 on carbon (96 mg of catalyst containing 20% wt Pd) in MeOH (6 mL) was stirred vigorously under H2 for 93 h. The catalyst was removed by filtration through a pad of Celite. The pad was washed sequentially with MeOH, CH2Cl2 and AcOH and the combined filtrates were concentrated to afford azaindole 62 as brown oil that was used directly without purification in the next step. 1H NMR (400 MHz; CDCl3) δ 0.90 (s, 3H), 0.91 (s, 3H), 1.87 (m, 1H), 2.58 (d, J=7.2 Hz, 2H), 3.96 (s, 3H), 7.34 (s, 1H), 7.41-7.46 (m, 2H), 7.50-7.55 (m, 1H), 7.59 (s, 1H), 7.62-7.67 (m, 2H), 7.73 (s, 1H), 7.86 (d, J=1.8 Hz, 1H), 7.99 (d, J=1.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][CH3:12])[N:3]=1.C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.[B:41](OC(C)C)([O:46]C(C)C)[O:42]C(C)C.FC1N=C(OCCOC)C(B(O)O)=CC=1>C1COCC1>[F:1][C:2]1[C:7]([B:41]([OH:46])[OH:42])=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH2:10][O:11][CH3:12])[N:3]=1
Reactant: COCCOc1cccc(F)n1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: COCCOc1nc(F)ccc1B(O)O
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: COCCOc1ccc(B(O)O)c(F)n1
Temperature: -60 °C
Reaction time: 1 h
Yield: 15.9 %

Procedure:
2-Fluoro-6-(2-methoxyethoxy)pyridine (1.13 g, 6.60 mmol) in THF (5 mL) was cooled to −60° C. and treated with lithium diisopropylamide, 2.0 M solution in heptane/tetrahydrofuran/ethylbenzene (4.95 mL, 9.90 mmol) (Aldrich) and stirred at −60° C. for 1 h. The mixture was then treated with triisopropyl borate (2.277 mL, 9.90 mmol) (Aldrich) and allowed to warm to RT over 30 min. It was then quenched by the addition of a saturated solution of ammonium chloride and stirred for 30 min. The reaction mixture was extracted with EtOAc (3×25 mL), dried over MgSO4, filtered and concentrated. Purification on the ISCO (12 g column, 5-100% EtOAc) gave a mixture of 2-fluoro-6-(2-methoxyethoxy)pyridin-3-ylboronic acid (226 mg, 1.051 mmol, 15.92% yield) and 6-fluoro-2-(2-methoxyethoxy)-pyridin-3-ylboronic acid as a semi-crystalline solid. m/z (ESI, +ve ion) 216.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([Cl:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[Cl:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][C:23]=2[Cl:25])[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(Cl)cc13)CCNC2=O
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: Cc1c2n(c3c(-c4ccc(Cl)cc4Cl)cc(Cl)cc13)CCNC2=O

Procedure:
The title compound, white solid (63 mg, 66%), MS (ISP) m/z=379.4 [(M+H)+], mp 213° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-chloro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 12) (78.4 mg, 0.25 mmol) and commercially available 2,4-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15](Br)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1.[NH2:18][C:19]1[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[C:15]([NH:18][C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)=[CH:14][CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cn1cc(N)cn1
Reactant: Cc1ccc(Br)c(C(=O)Nc2ccn(C)n2)n1
Product: Cc1ccc(Nc2cnn(C)c2)c(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 3-Bromo-6-methyl-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of Example 78, step 3 using 4-Amino-1-methyl-pyrazole instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a yellow solid, MS (ISP): m/e=312.1 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][C@@H:14](O)[CH2:15][CH:16]=[CH2:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[CH3:12][C:9]1[CH:10]=[CH:11][C:2]([O:1][C@H:16]([CH2:15][CH:14]=[CH2:13])[CH3:17])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(C)ccc1O
Reactant: C=CC[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC[C@H](C)Oc1ccc(C)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 89.9 %

Procedure:
To a solution of methyl 2-hydroxy-5-methylbenzoate (1.0 g, 6.02 mmol) in THF (14 ml) were added (R)-(−)-pent-4-en-2-ol (1.037 g, 12.04 mmol) and triphenylphosphine (2.052 g, 7.82 mmol). DIAD (1.521 ml, 7.82 mmol) was added dropwise (exotherm) and the mixture was stirred at rt. After 4.5 h, the mixture was diluted with Et2O and washed with 1N NaOH followed by water (3×'s) then brine, dried (Na2SO4), filtered and concentrated. The yellow oil was purified by flash chromatography (Biotage; 0%-100% EtOAc/hexane; 20 CV) to give (S)-methyl 5-methyl-2-(pent-4-en-2-yloxy)benzoate (1.2664 g, 5.41 mmol, 90% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=2.2 Hz, 1H), 7.23 (dd, J=8.3, 2.0 Hz, 1H), 6.90 (d, J=8.6 Hz, 1H), 6.03-5.77 (m, 1H), 5.21-4.99 (m, 2H), 4.61-4.35 (m, 1H), 3.89 (s, 3H), 2.60-2.46 (m, 1H), 2.46-2.34 (m, 1H), 2.34-2.25 (m, 3H), 1.34 (d, J=6.1 Hz, 3H).