Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[S:24][C:25]([CH:28]=O)=[CH:26][N:27]=1>>[OH:1][C:2]1([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:7][CH2:6][N:5]([CH2:28][C:25]2[S:24][C:23]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)=[N:27][CH:26]=2)[CH2:4][CH2:3]1
Reactant: O=Cc1cnc(-c2ccccn2)s1
Reactant: CC(C)(C)OC(=O)NCC1(O)CCNCC1
Product: CC(C)(C)OC(=O)NCC1(O)CCN(Cc2cnc(-c3ccccn3)s2)CC1

Procedure:
According to the same procedure described in Example 101, starting with the compound prepared in Example 251 instead of the compound prepared in Example 226 and the compound prepared in Example 139 instead of 2-phenylthiazole-5-carbaldehyde, the title compound having the following physical data was obtained.
Reaction SMILES: CO[N:3]=[C:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([CH2:14][C:15](OCC)=[O:16])[CH:8]=[CH:7][C:6]=2[CH2:5]1.C(O)C.[ClH:23].C(O)C>O1CCCC1>[ClH:23].[NH2:3][CH:4]1[CH2:13][CH2:12][C:11]2[CH:10]=[C:9]([CH2:14][CH2:15][OH:16])[CH:8]=[CH:7][C:6]=2[CH2:5]1
Reactant: CCOC(=O)Cc1ccc2c(c1)CCC(=NOC)C2
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: NC1CCc2cc(CCO)ccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.5 ml of 2M borane-methylsulfide complex in tetrahydrofuran are added to a solution of 1.31 g of ethyl 6-methoxyimino-5,6,7,8-tetrahydronaphthalene-2-acetate in tetrahydrofuran under argon at -5° to 0° C., and the mixture is stirred at room temperature overnight. Ethanol and 9% hydrogen chloride-ethanol are added to the mixture under cooing and stirring, and the mixture is stirred at room temperature for 30 minutes. After the solvent is distilled off, the residue is crystallized with a mixture of ethanol and ether to give 990 mg of 2-(6-amino-5,6,7,8-tetrahydronaphthalene-2-yl)ethanol hydrochloride as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]5O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.C(N(S(F)(F)F)CC)C>C(Cl)Cl>[C@@H:20]1([NH:19][C:17]2[S:18][C:14]3[CH:13]=[C:12]([CH2:11][N:8]4[C:5]5=[N:6][CH:7]=[C:2]([F:1])[CH:3]=[C:4]5[N:10]=[CH:9]4)[CH:28]=[CH:27][C:15]=3[N:16]=2)[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1
Reactant: O[C@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Fc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@H]3C=CCCC3)sc2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 3.3 %

Procedure:
To a stirred mixture of (1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (156 mg, 0.4 mmol) from Example 162 in CH2Cl2 (10 mL) at −78° C. under argon was added diethylaminosulfur trifluoride (63 μL, 0.5 mmol). After stirring the mixture for 3 h, additional diethylaminosulfur trifluoride (63 μL, 0.5 mmol) was added. After the mixture was stirred for a further 3 h, it was poured over ice. Additional CH2Cl2 (50 mL) was added and the mixture was stirred until the ice was melted. The layers were separated and the organic layer was washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (R)—N-(cyclohex-2-en-1-yl)-6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-amine (5 mg, 3%) as a white powder. 1H NMR (500 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.41 (s, 1H), 8.03-8.13 (m, 2H), 7.68 (s, 1H), 7.32 (d, J=8.3 Hz, 1H), 7.24 (dd, J=1.3, 8.3 Hz, 1H), 5.83 (m, 1H), 5.72 (m, 1H), 5.48 (s, 2H), 4.40 (br s, 1H), 1.95-2.03 (m, 2H), 1.90 (m, 1H), 1.70 (m, 1H), 1.54-1.62 (m, 2H); LCMS (ESI) m/z 380 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][Cl:22]>C(#N)C>[Cl:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[CH:11]=[N:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Oc1cnc2c(n1)CCCC2
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: ClCCCOc1cnc2c(n1)CCCC2
Yield: 64.8 %

Procedure:
1.5 g (10 mmol) of 2-hydroxy-5,6,7,8-tetrahydroquinoxaline was dissolved in 40 ml of acetonitrile. To the resultant solution were added 2.76 g (20 mmol) of potassium carbonate and 1.19 ml (12 mmol) of 1-bromo-3-chloropropane. The resultant mixture was heated under reflux for 2 hours and then, subjected to filtration to thereby filter off insoluble substances. The solvent of the filtrate was distilled off in vacuo to thereby obtain a residue. The obtained residue was purified by silica gel column chromatography. That is, the residue was charged in a column of 42 g of silica gel (Art7734, manufactured and sold by E. Merck, Darmstadt) and eluted with chloroform, to thereby obtain 1.47 g of 2-(3-chloropropoxy)-5,6,7,8-tetrahydroquinoxaline (yield: 67%).
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[CH:6]=[C:7]([C:11]2[NH:16][C:15](=O)[CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1)C.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:15]1[CH:14]=[CH:13][N:12]=[C:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[CH:4]=[O:3])[N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(OCC)c1cccc(-c2nccc(=O)[nH]2)c1
Product: O=Cc1cccc(-c2nccc(Cl)n2)c1

Procedure:
A 5.3 g portion of 2-(3-diethoxymethylphenyl)- 4(3H)-pyrimidinone and 30 ml of phosphorous oxychloride was heated on a steam bath overnight. The excess phosphorous oxychloride was removed under vacuum and the residue taken up in chloroform and passed through a hydrous magnesium silicate pad. Evaporation of the filtrate left 3.1 g of residue which had two spots by TLC (chloroform-silica gel). Trituration of the residue with ether gave 0.4 g of 3-(4-chloro-2-pyrimidinyl)benzaldehyde, mp 136°-138° C. (the slower moving spot) which was identified by analysis, PMR and IR.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:19][CH:20]([C:22]([OH:24])=[O:23])[CH3:21].Cl>[OH-].[Na+]>[C:1]([NH:19][CH:20]([CH3:21])[C:22]([OH:24])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCC(=O)NC(C)C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
The compound may be prepared using the Schotten-Baumann procedure. Palmitoyl chloride (44.0 g, 0.16 mol) is added dropwise to a solution of DL-alanine (21.4 g, 0.24 mol) in 10% aqueous sodium hydroxide (200 ml) heated at 50° C. The pH of the reaction is monitored such that the pH does not drop below 10. After the addition is complete, the reaction is stirred for a further 1 hour before it is allowed to cool to room temperature and neutralised with concentrated hydrochloric acid. The resultant precipitate is collected by filtration, washed with water and allowed to dry in air. The product is recrystallised from ether-petrol to give 2-palmitoylaminoproprionic acid as a white solid (36.4 g, 70%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:5]([CH3:19])=[C:4]([CH3:20])[N:3]=1.[O-:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Na+]>>[CH3:20][C:4]1[C:5]([CH3:19])=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:7]([N+:8]([O-:10])=[O:9])=[C:2]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: [O-]c1ccccc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCCCO)c1C
Agent: [Na+]
Product: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCCCCCCO)c1C

Procedure:
Using the general method of Example 90 Part B, 6-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]hexan-1-ol (14.00 g, 46.39 mmol) was reacted with sodium phenoxide to provide 12.40 g of 6-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]hexan-1-ol as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10](I)[C:5]2=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH:23]=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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[N:7]=[C:6]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[N:9]=[C:10]([C:22]3[CH:21]=[N:20][N:19]([CH3:18])[CH:23]=3)[C:5]2=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(I)nn(C3CCCCO3)c2n1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2nn(C3CCCCO3)c3nc(Cl)ccc23)cn1
Temperature: 80 °C
Reaction time: 3 h
Yield: 68.7 %

Procedure:
A mixture of 6-chloro-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine (200 mg, 0.6 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (110 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (30 mg, 0.03 mmol), and cesium carbonate (540 mg, 1.6 mmol) in 1,4-dioxane (1 mL) and water (0.12 mL) was degassed and sealed. It was stirred at 80° C. for 3 h. After cooling it was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.12 g). LCMS (M+H)+=318.0.
Reaction SMILES: C(=[C:5]1[C:10]([CH2:11][NH2:12])=[CH:9][CH:8]=[CH:7][NH:6]1)C(C)C.[CH3:13][C:14]([O-])([CH3:16])[CH3:15].[K+]>C1(C)C=CC=CC=1>[N:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[N:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:5]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)C=C1NC=CC=C1CN
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)CN=Cc1cccnc1
Yield: 2062.8 %

Procedure:
The procedure is carried out as in Example 1 (b) but with the use of 80.1 g (0.495 mol) of isobutylidene-3-aminomethylpyridine, 2.5 g (0.0223 mol) of potassium tert-butylate and 75 ml of toluene. After a reaction time of 1 hour at 30°-35° C., distillation yields 74.5 g (0.46 mol) of 3-pyridylmethylidene-isobutylamine; yield 93% of theory; b.p. 108° C./2×103Pa; nD20 =1.5198.
Reaction SMILES: Cl[C:2]1[N:10]2[C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:12][O:13][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[C:20]2[C:21]([CH3:26])=[N:22][O:23][C:24]=2[CH3:25])[N:3]=1.[CH3:27][C:28]1(C)C(C)(C)OB(C=C)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.NC1C=CC=CC=1C1C=CC=CC=1[Pd]Cl>[CH3:26][C:21]1[C:20]([C:7]2[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[N:10]4[C:2]([CH:27]=[CH2:28])=[N:3][C:4]([C:9]=34)=[CH:5][CH:6]=2)=[C:24]([CH3:25])[O:23][N:22]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Cc1noc(C)c1-c1ccc2nc(Cl)n3c2c1OC[C@@H]3c1ccccn1
Agent: Nc1ccccc1-c1ccccc1[Pd]Cl
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1nc2ccc(-c3c(C)noc3C)c3c2n1[C@@H](c1ccccn1)CO3
Temperature: 80 °C
Yield: 77.6 %

Procedure:
(4S)-2-Chloro-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazine (277 mg, 0.755 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (0.19 mL, 1.1 mmol) [Aldrich, cat. #633348], and potassium phosphate (0.3 g, 2 mmol) [Aldrich, cat. #P5629], were dissolved in water (2.4 mL) and 1,4-dioxane (10 mL). The reaction mixture was deoxygenated with nitrogen and dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine-(2′-aminobiphenyl-2-yl)(chloro)palladium (1:1) (0.03 g, 0.04 mmol) [Aldrich, cat. #741825] was added. The resulting mixture was deoxygenated with nitrogen and heated at 80° C. for 3 h. The reaction mixture was then allowed to cool to room temperature. Ethyl acetate was added, and the mixture was washed with water and brine, then dried over sodium sulfate and concentrated. The resulting residue was purified by flash chromatography eluting ethyl acetate in hexanes (75-100%, ethyl acetate containing 20% MeOH) to afford the desired product (0.21 g, 78%). LCMS for C21H19O2N4 (M+H)+: calculated m/z=359.2. found 359.3; 1H NMR (400 MHz, CD3OD) δ 8.61-8.53 (m, 1H), 7.74 (m, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.34 (dd, J=7.7, 4.8 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 6.75 (d, J=4.1 Hz, 1H), 6.69 (d, J=11.4 Hz, 1H), 6.34 (dd, J=17.5, 1.0 Hz, 1H), 6.09 (dd, J=2.5 Hz, 2H), 5.68 (dd, J=11.4, 1.0 Hz, 1H), 4.96 (dd, J=11.6, 2.1 Hz, 1H), 4.64 (dd, J=11.6, 3.1 Hz, 1H), 2.29 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH:7](O)[CH3:8])=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Br:1][C:2]1[S:6][C:5]([CH2:7][CH3:8])=[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:3]=1
Reactant: CCOC(=O)c1cc(Br)sc1C(C)O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(Br)sc1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To a solution of ethyl 5-bromo-2-(1-hydroxyethyl)thiophene-3-carboxylate (11.0 g) synthesized above in trifluoroacetic acid (100 mL) was added dropwise triethylsilane (18.8 mL). After stirring at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19, volume ratio) to give the title compound (9.67 g, 94%) as a pale-yellow oil.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[CH:14]=[C:13]3[C:8]([CH:9]=[C:10]([C:15]4[CH:16]=[C:17]([CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[N:18]5[C:23]=4[C:22]([NH2:24])=[N:21][CH:20]=[N:19]5)[CH:11]=[CH:12]3)=[N:7]2)[CH2:4][CH2:3][CH2:2]1.Cl[CH2:32][C:33](N(C)C)=[O:34]>>[C:33]([N:28]1[CH2:29][CH2:30][CH:25]([C:17]2[N:18]3[C:23]([C:22]([NH2:24])=[N:21][CH:20]=[N:19]3)=[C:15]([C:10]3[CH:11]=[CH:12][C:13]4[C:8]([CH:9]=3)=[N:7][N:6]([CH2:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)[CH:14]=4)[CH:16]=2)[CH2:26][CH2:27]1)(=[O:34])[CH3:32]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(CC5CCC5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Product: CC(=O)N1CCC(c2cc(-c3ccc4cn(CC5CCC5)nc4c3)c3c(N)ncnn23)CC1
Yield: 62 %

Procedure:
In a manner similar to the procedure described for Example 369 and using 5-[2-(cyclobutylmethyl)-2H-indazol-6-yl]-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine and substituting acetyl chloride for 2-chloro-N,N-dimethylacetamide as starting materials, 48 mg, (62%) of the desired product was isolated. LC-MS [M+H]+=444.3, RT=2.37 min.
Reaction SMILES: C[O-].[Na+].[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[S:15])[N:9](C(OCC)=O)[C:8]2=[O:21].C(O)(=O)C>CO.C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[S:15])[NH:9][C:8]2=[O:21]
Reactant: CCOC(=O)n1c(=S)[nH]c2ccc(Br)cc2c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=c1[nH]c(=S)[nH]c2ccc(Br)cc12
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of sodium methoxide (0.5 M, 36.1 mmol) in methanol (72 mL) was added to a solution of 3a (10.8 g, 32.8 mmol) in 150 mL of dry THF and the mixture was heated at reflux for 90 min. The mixture was allowed to reach room temperature and quenched by addition of acetic acid (2.1 mL, 36.1 mmol). The mixture was concentrated under reduced pressure and 200 mL of ethyl alcohol and 100 mL of water was added and the mixture was heated at reflux for 30 min. The slurry was cooled to rt. and filtrated to give 4 white solid (8.43 g, 100%). mp: 350° C. (decomp.),
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[O:8][C:9]3[C:10](=[C:12]([C:16]([OH:18])=O)[CH:13]=[CH:14][CH:15]=3)[N:11]=2)=[C:5]([CH3:19])[O:4][N:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][C@H:45]1[CH:50]2[CH2:51][CH2:52][N:47]([CH2:48][CH2:49]2)[CH2:46]1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[N:47]12[CH2:52][CH2:51][CH:50]([CH2:49][CH2:48]1)[C@H:45]([NH:44][C:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:9]3[O:8][C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:19])=[N:11][C:10]=13)=[O:18])[CH2:46]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: Cc1noc(C)c1-c1nc2c(C(=O)O)cccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1noc(C)c1-c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
A mixture of 2-(3,5-dimethylisoxazol-4-yl)benzoxazole-4-carboxylic acid (136 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (201 mg, 1.05 mmol), 1-hydroxybenzotriazole (142 mg, 1.05 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (131 mg, 0.66 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.56 mL, 4.0 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (100 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organics were washed with water (5×25 mL), brine (25 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 methylene chloride/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(3,5-dimethylisoxazole-4-yl)benzoxazole-4-carboxamide (91 mg, 47%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 9.09 (d, J=6.5 Hz, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 7.72 (dd, J=8.1, 1.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 4.33-4.29 (m, 1H), 3.58-3.53 (m, 1H), 3.00-2.90 (m, 3H), 2.89 (s, 3H), 2.76-2.71 (m, 1H), 2.69 (s, 3H), 2.15-2.10 (m, 1H), 1.97-1.85 (m, 2H), 1.80-1.70 (m, 2H), 1.61-1.50 (m, 1H); MS (ESI+) m/z 367 (M+H); HPLC>99% (AUC), tR=11.69 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[CH:18][C:19](OC)=[O:20])=[CH:14][CH:15]=2)[CH:10]=[C:9]1C)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=[CH:18][CH2:19][OH:20])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C=Cc1ccc2c(c1)cc(C)n2C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1ccc2cc(C=CCO)ccc21
Temperature: -5 °C
Yield: 69.1 %

Procedure:
To a solution of methyl 5-(2-methoxycarbonyl-vinyl)-indole-1-carboxylic acid tert-butyl ester (4.64 g, 15.3 mmol, 1.0 eq.) in THF (87 mL) at −30° C. was added LiAlH4 (I N in THF, 18.6 mL, 1.2 eq.) by syringe pump over 20 nm in and the resulting mixture was stirred and warmed to −5° C. After cooling back to −30° C., the reaction was then quenched by slow addition of acetone (10 mL) keeping temperature below −15° C., poured into Rochelle salt at 0° C., stirred for 1 h and the separated aqueous layer was extracted with EtOAc. The combined organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purification by column chromatography (methylene chloride to 2% acetone/methylene chloride) to give 5-(3-hydroxy-propenyl)-indole-1-carboxylic acid tert-butyl ester (2.89 g, 70%) or similarly 6-(3-hydroxy-propenyl)-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([Cl:21])=[C:16]([O:22][CH2:23][C:24]#[N:25])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO>C1COCC1>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([Cl:21])=[C:16]([O:22][CH2:23][CH2:24][NH2:25])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCOc1c(Cl)ccc2c1c1ccccc1n2Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: NCCOc1c(Cl)ccc2c1c1ccccc1n2Cc1ccccc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 69.7 %

Procedure:
To [(9-benzyl-3-chloro-9H-carbazol-4-yl)oxy]acetonitrile (0.292 g, 0.842 mmol) in THF (6 mL) is added borane-methyl sulfide complex (0.24 mL, 2.53 mmol). The mixture is stirred at 80° C. for 2.5 h and then allowed to cool. MeOH is carefully added to the residue until gas evolution ceased and then the mixture is concentrated under vacuum. MeOH addition/removal is repeated two more times and then MeOH-dichloromethane (about 2 mL each) is added, followed by several drops of conc. HCl. The mixture is stirred for about 15 min and then taken to dryness under vacuum. After partitioning with dichloromethane and aq. sodium bicarbonate and drying, the residue is chromatographed on silica gel (50 mL) using MeOH-dichloromethane (2/98 to 4/96) to give 0.206 g (70%) of 2-[(9-benzyl-3-chloro-9H-carbazol-4-yl)oxy]ethylamine. The methanesulfonate salt is prepared by dissolving 2-[(9-benzyl-3-chloro-9H-carbazol-4-yl)oxy]ethylamine in MeOH and dichloromethane and adding methanesulfonic acid (0.0581 g). The mixture is concentrated to dryness under vacuum and the residue is crystallized from dichloromethane-hexane to give 0.206 g of 2-[(9-benzyl-3-chloro-9H-carbazol-4-yl)oxy]ethylamine, methanesulfonate salt as a white crystalline solid. 1H NMR (CDCl3) δ1.9, 3.29, 4.31, 5.49, 7.07, 7.12, 7.27, 7.35-7.49, 8.32.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:34](=[O:35])[C:12]2=[CH:13][N:14]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[CH:31][CH:30]=[N:29]4)=[CH:24][C:23]=3F)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]2=[N:10]1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:42][N:43](C)C=O>[C-]#N.[Zn+2].[C-]#N.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:8][C:4]1[C:3]([N:9]2[C:34](=[O:35])[C:12]3=[CH:13][N:14]([CH2:21][C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH:32]=[CH:31][CH:30]=[N:29]5)=[CH:26][CH:27]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:42]#[N:43]
Reactant: O=c1c2cn(Cc3ccc(-n4cccn4)cc3F)c3ccccc3c-2nn1-c1c(F)cccc1Br
Reactant: CN(C)C=O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [C-]#N
Product: N#Cc1cccc(F)c1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2-Bromo-6-fluorophenyl)-5-{[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 666, 0.10 g, 0.19 mmol) and zinc(II) cyanide (46 mg, 0.39 mmol, 2 equiv) were dissolved in N,N-dimethylformamide (3.5 mL). The mixture was degassed, treated with bis(tri-tert-butylphosphine)palladium(0) (15 mg, 0.029 mmol, 0.15 equiv) and placed into an oil bath preheated to 100° C. for 1 hour. The mixture was cooled to ambient temperature, poured into sodium carbonate (15 mL, aqueous saturated) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate containing 5% methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.24 (1H, s), 8.46 (1H, d, J=2.5 Hz), 8.21 (1H, dd, J=7.9, 1.3 Hz), 7.91 (1H, d, J=8.0 Hz), 7.89-7.80 (4H, m), 7.76-7.70 (2H, m), 7.68-7.64 (1H, m), 7.56 (1H, ap t, J=7.3 Hz), 7.50 (2H, d, J=8.5 Hz), 6.53 (1H, m), 5.79 (2H, s) ppm; high resolution mass spectrometry (ES+) m/z 461.1503 [(M+H)+; calculated for C27H18FN6O: 461.1521].