Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[S:26][C:25]([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([CH:35]=2)[C:32](O)=[O:33])=[CH:24][CH:23]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:32](=[O:33])[C:31]3[CH:35]=[C:27]([C:25]4[S:26][C:22]([C:20](=[O:21])[C:19]([F:36])([F:18])[F:37])=[CH:23][CH:24]=4)[CH:28]=[N:29][CH:30]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cncc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Product: CC(C)(CNC(=O)c1cncc(-c2ccc(C(=O)C(F)(F)F)s2)c1)c1coc(-c2ccc(F)cc2)n1
Yield: 26 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinic acid as described in example 8 step 6 (45 mg, yield 26%). 1H NMR (400 MHz, DMSO-d6) δ 9.21 (d, J=2.1 Hz, 1H), 9.01 (s, 1H), 8.66-8.60 (m, 1H), 8.52-8.51 (t, J=2.0 Hz, 1H), 8.21-8.20 (m, 1H), 8.02-7.98 (m, 4H), 7.36-7.30 (m, 2H), 3.53-3.52 (d, J=6.1 Hz, 2H), 1.30 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.C1COCC1.[Cl:20][C:21]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>[Cl-].[Cl-].[Zn+2].CC([O-])=O.CC([O-])=O.[Cu+2].CCOC(C)=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([C:23]([C:22]2[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:21]=2[Cl:20])=[O:24])[CH:3]=1
Reactant: Cc1ccc(Br)cc1I
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC(C)[Mg]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Br)cc1C(=O)c1ccc([N+](=O)[O-])cc1Cl
Temperature: -35 °C
Reaction time: 0.5 h

Procedure:
A dry flask was charged with 4-bromo-2-iodo-1-methyl-benzene (6.85 g, 23.1 mmol) and the flask was evaporated and then filled with argon and this process repeated twice. Dry THF (20 mL) was added, and the solution cooled to −35° C.; then isopropylmagnesium chloride (11.5 mL, 2.0 M in diethyl ether, 23 mmol) was added slowly over 40 min keeping the temperature below −35° C. On completion of the addition the reaction mixture was stirred at −35° C. for 30 min. A THF solution of ZnCl2 (3.93 g, 28.9 mmol, 0.7 M) was added dropwise over 20 min. The reaction mixture was stirred at 0° C. for 20 min; then 2-chloro-4-nitro-benzoyl chloride (5.33 g, 24.2 mmol) and Cu(OAc)2 (92 mg, 0.46 mmol) were added and the reaction mixture was allowed to warm to room temperature. After 16 h the reaction mixture was poured into a mixture of EtOAc/water, then shaken and separated. The aqueous phase was extracted with more EtOAc. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by flash chromatography using EtOAc/petroleum ether 1:14 as the eluent to give the title compound as almost white solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][CH:5]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].[OH-].[Na+]>COC(C)(C)C>[CH3:11][O:10][C:7]1[N:6]=[CH:5][C:4]([CH2:3][OH:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OC)nc1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: COc1ccc(CO)cn1
Reaction time: 0.33 h
Yield: 110.3 %

Procedure:
To a solution of methyl-6-methoxynicotinate (1) (650 g, 3.89 mol) in t-butyl methyl ether (hereinafter abbreviated as “MTBE”) (6.5 L) cooled in an ice bath was added sodium bis(2-methoxyethoxy)aluminum hydride (65% solution in toluene, 1.45 kg, 4.67 mol) under a nitrogen atmosphere over a period of 1.3 hours. After stirring for 20 minutes, a 3.5 N aqueous solution of sodium hydroxide (2.6 L) was added to the reaction mixture while keeping the temperature 15° C. or below. The reaction mixture was stirred at 32° C. for 45 minutes and then the organic layer was separated and the aqueous layer was re-extracted with MTBE (2.3 L). The organic layers were combined and concentrated under reduced pressure to dryness, and then toluene (1.3 L) was added to the residue and azeotropic distillation was carried out. Azeotropic distillation with toluene (1.3 L) was repeated three times to give 597 g of the title compound as a pale yellow oil (yield 100%).
Reaction SMILES: O.[NH2:2][NH2:3].[C:4]([O:8][C:9](=[O:24])[NH:10][C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)([CH3:16])[C:12](=O)[C:13]#[CH:14])([CH3:7])([CH3:6])[CH3:5]>CCO>[C:4]([O:8][C:9](=[O:24])[NH:10][C:11]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)([C:12]1[CH:13]=[CH:14][NH:3][N:2]=1)[CH3:16])([CH3:7])([CH3:6])[CH3:5]
Reactant: NN
Reactant: C#CC(=O)C(C)(NC(=O)OC(C)(C)C)c1cccc(Br)c1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(c1cccc(Br)c1)c1cc[nH]n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
Hydrazine hydrate (2.48 mL, 51.10 mmol) was added to a solution of rac-[1-(3-bromo-phenyl)-1-methyl-2-oxo-but-3-ynyl]-carbamic acid tert-butyl ester (1.8 g, 5.11 mmol) in EtOH (30 mL) and the mixture was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residue was dissolved in DCM and washed with water. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; AcOEt in DCM 0/100 to 50/50). The desired fractions were collected and concentrated in vacuo to yield rac-[1-(3-bromo-phenyl)-1-(1H-pyrazol-3-yl)-ethyl]-carbamic acid tert-butyl ester (1.62 g, 87% yield) as a white solid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].C(OCC)C.[CH2:14]([C:16]1[C:30]([O:31][CH3:32])=[CH:29][C:19]2[C@@H:20]3[C@H:24]([CH2:25][C:26](=[O:27])[C:18]=2[C:17]=1[OH:33])[CH2:23][N:22]([CH3:28])[CH2:21]3)[CH3:15]>C(O)C>[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH2:14]([C:16]1[C:30]([O:31][CH3:32])=[CH:29][C:19]2[CH:20]3[CH:24]([CH2:25][C:26](=[O:27])[C:18]=2[C:17]=1[OH:33])[CH2:23][N:22]([CH3:28])[CH2:21]3)[CH3:15]
Reactant: CCc1c(OC)cc2c(c1O)C(=O)C[C@@H]1CN(C)C[C@H]21
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CCOCC
Product: CCc1c(OC)cc2c(c1O)C(=O)CC1CN(C)CC21
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.9 %

Procedure:
168 mg (1.45 mmol) of fumaric acid and 50 ml of diethyl ether were added while stirring to a solution of 0.4 g (1.45 mmol) of cis-7-ethyl-6-hydroxy-8-methoxy-2-methyl-1,2,3,3a,4,9b-hexahydro-benzo[e]isoindol-5-one in 0.5 ml of ethanol. The mixture was stirred at room temperature for a further 17 hours and the solid was subsequently filtered off. 0.55 g (97%) of 7-ethyl-6-hydroxy-8-methoxy-2-methyl-1,2,3,3a,4,9b-hexahydro-benzo[e]isoindol-5-one fumarate (1:1) was obtained as a white solid with m.p. 195°.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:14]([O-])=O)[C:8]=2Cl)[N:3]=1>[Pd]>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:14])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(N)c2c(Cl)c([N+](=O)[O-])ccc2n1
Agent: [Pd]
Product: Nc1ccc2nc(N)nc(N)c2c1

Procedure:
In a similar manner 2,4,6-triaminoquinazoline and 2,4,6-triamino-5-chloroquinazoline can be prepared. This is accomplished by the nitration of, for example, 2,4-diamino-5-chloroquinazoline (above) with 90% nitric acid and sulfuric acid, yielding the corresponding 2,4-diamino-5-chloro-6-nitroquinazoline. The 6-nitroquinazoline is in turn reduced by either hydrogenation in the presence of 10% palladium on carbon or by treatment with stannous chloride dihydrate, affording the corresponding 2,4,6-triaminoquinazoline. Steps A and B of Example 15 describe in detail these two steps in the reaction sequence.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][S:30]([CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:32])=[O:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]1[C:10]([CH2:11][N:38]2[CH2:37][CH2:36][N:35]([CH2:34][CH2:33][S:30]([CH3:29])(=[O:31])=[O:32])[CH2:40][CH2:39]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(CCS(C)(=O)=O)CC3)n(C)c2n1
Reaction time: 64 h

Procedure:
A mixture of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (60 mg, 0.16 mmol), 1-(2-methanesulfonylethyl)piperazine (37 mg, 0.19 mmol) and 4 Å powdered molecular sieves (100 mg) in DCE (4 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (67 mg, 0.32 mmol). The reaction mixture was stirred for 64 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 329 as a cream solid (55 mg, 62%). LCMS (Method G): RT 5.54 min [M+H]+ 554.3. 1H NMR (CDCl3, 400 MHz): δ 8.11-8.06 (m, 1 H); 7.74-7.70 (m, 1 H); 7.30-7.25 (m, 2 H); 4.35 (m, 4 H); 3.90-3.82 (m, 7 H); 3.76 (s, 2 H); 3.15 (t, J=6.4 Hz, 2 H); 3.04 (s, 3 H); 2.95 (s, 3 H); 2.90 (t, J=6.4 Hz, 2 H) and 2.57 (m, 8 H)
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][NH:14][CH2:15][C@@H:16]([OH:24])[CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=O)C.O.[OH-].[Li+]>>[OH:24][C@@H:16]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:15][N:14]1[CH2:13][CH2:12][C:7]2[NH:8][CH:9]=[C:10]([CH3:11])[C:6]=2[C:4]1=[O:3]
Reactant: CCOC(=O)c1c(C)c[nH]c1CCNC[C@@H](O)CN1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1c[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Yield: 33537.8 %

Procedure:
(R)-2-[2-(2-Hydroxy-3-morpholin-4-yl-propylamino)-ethyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 5d (2.1 g, 6.2 mmol) and lithium hydroxide monohydrate (1.56 g, 37 mmol) were dissolved in 25 mL of glycol under stirring under an argon atmosphere. The reaction system was stirred at 140° C. in an oil bath for 50 minutes. The reaction was completed until TLC showed the disappearance of starting materials. After thin lay chromatography showed the starting material disappeared, the solvent was evaporated under reduced pressure, and 50 mL of saturated brine was then added to the residue. The mixture was extracted with dichloromethane (80 mL×3). The combined organic extracts were washed with saturated brine (80 mL), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 5e (610 g, yield 33.9%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2CCN2CCCC2)c1
Temperature: 60 °C

Procedure:
A mixture of 5-nitroindazole (3.00 g, 18.4 mmol) and potassium carbonate (7.50 g, 54.4 mmol) in DMF (60 mL) was stirred for 30 minutes after which 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (4.80 g, 28.4 mmol) was added. The mixture was heated to 60° C. for 6 hours, cooled to room temperature and filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure and the residue purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.60 (m, 4H), 2.44 (m, 4H), 2.90 (t, 2H, J=6.45), 4.59 (t, 2H, J=6.45), 7.90 (m, 1H), 8.20 (m, 1H), 8.39 (s, 1H), 8.80 (s, 1H); MS (DCI/NH3) m/z 261 [M+H]+.
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[Cl:14][CH2:15][C:16](Cl)=[O:17]>CCOCC>[Cl:14][CH2:15][C:16]([N:3]1[CH2:4][CH2:5][CH2:6][O:2]1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: C1CNOC1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCCO1
Reaction time: 4 h

Procedure:
To a stirred slurry of finely powdered isooxazolidine hydrochloride (H. King, J. Chem. Soc. 433,1942) (11.0 g) in dry ether (200 ml) at 0° C. was added triethylamine (28.0 ml) and a solution of chloroacetyl chloride (8.0 ml) in ether (50 ml). The reaction mixture was stirred for a further 4 hours, whilst the temperature rose to room temperature. The precipitate triethylamine hydrochloride was filtered off through diatomaceous earth and the filter bed washed well with ether. The combined ether solutions were evaporated to give N-chloroacetyl isooxazolidine as an oil (11.5 g) NMR (CDCl3) 2.38[quintet, 2H, CH2 ], 3.78[t,2H, NCH2 ], 4.05[t,2H, OCH2 ]and 4.22 [s,2H, ClCH2CO].
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:48]=[CH:47][C:10]([CH2:11][N:12]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:13]2[N:18]=[C:17]([C:19]3[C:20]([NH:28][C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)=[N:21][CH:22]=[C:23]([C:25]([CH3:27])=[CH2:26])[CH:24]=3)[N:16]=[C:15]([CH3:37])[N:14]=2)=[CH:9][CH:8]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[N:1]([C:25]([C:23]1[CH:24]=[C:19]([C:17]2[N:16]=[C:15]([CH3:37])[N:14]=[C:13]([N:12]([CH2:11][C:10]3[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:48][CH:47]=3)[CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[N:18]=2)[C:20]([NH:28][C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[N:21][CH:22]=1)([CH3:27])[CH3:26])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C=C(C)c1cnc(Nc2ccc(OC)nc2)c(-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)N=[N+]=[N-])cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.3 %

Procedure:
A slurry of sodium azide (0.075 g, 1.160 mmol) and N,N-bis(4-methoxybenzyl)-4-(2-(6-methoxypyridin-3-ylamino)-5-(prop-1-en-2-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.171 g, 0.290 mmol) in CHCl3 (1 mL) at −15° C. was treated with a solution of trifluoroacetic acid (0.223 mL, 2.90 mmol) in CHCl3 (1 mL) added via syringe over 10 min. The cooling reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The reaction was sealed and heated at 60° C. After 2 h, the reaction was poured onto ice and basified with 10 N NaOH. The reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3×), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-(5-(2-azidopropan-2-yl)-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.184 g, 0.291 mmol, 100% yield). m/z (ESI, +ve ion) 633 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.67 (br. s., 1H); 8.90 (d, J=2.7 Hz, 1H); 8.38 (d, J=2.5 Hz, 1H); 8.26 (d, J=2.5 Hz, 1H); 7.91 (dd, J=8.8, 2.7 Hz, 1H); 7.18-7.26 (m, 4H); 6.81-6.94 (m, 4H); 6.73 (d, J=8.8 Hz, 1H); 4.90 (s, 2H); 4.81 (s, 2H); 3.94 (s, 3H); 3.82 (s, 3H); 3.78 (s, 3H); 2.59 (s, 3H); 1.64 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:21](OCC)=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH2:21][OH:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2cc(OC)ccc2n1Cc1ccc(C(C)(C)C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: COc1ccc2c(c1)cc(CO)n2Cc1ccc(C(C)(C)C)cc1

Procedure:
The title compound was prepared from ethyl 1-(4-tert-butylbenzyl)-5-methoxy-1H-indole-2-carboxylate and lithium aluminum hydride in substantially the same manner, as described in step 3 of Example 1. The product was obtained as an oil. Mass spectrum (ESI, [M−H]−) m/z 322. 1H NMR (400 MHz, DMSO-d6) δ 7.27 (d, 2H, J=8.14 Hz), 7.20 (d, 1H, J=8.70 Hz), 7.01 (d, 1H, J=2.45 Hz), 6.94 (d, 2H, J=8.24 Hz), 6.68 (dd, 1H, J=8.85 and 2.44 Hz), 6.34 (s, 1H), 5.37 (s, 2H), 5.26 (t, 1H), 4.56 (d, 2H, J=4.43 Hz), 3.72 (s, 3H), and 1.21 ppm (s, 9H).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][CH3:27])=[CH:20][C:19]=2[Cl:28])[CH2:9][CH2:8][CH2:7]1)=[O:4].[OH-].[Na+].Cl>C(O)C>[C:3]([CH2:5][CH:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([C:17](=[O:29])[C:18]2[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][CH3:27])=[CH:20][C:19]=2[Cl:28])[CH2:9][CH2:8][CH2:7]1)([OH:4])=[O:2]
Reactant: CCCNc1ccc(C(=O)N2CCCC(CC(=O)OC)c3ccccc32)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCNc1ccc(C(=O)N2CCCC(CC(=O)O)c3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
The above product, 5-methoxycarbonylmethyl-1-(4-n-propylamino-2-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (880 mg) is dissolved in ethanol (20 ml), and thereto is added a 6N aqueous sodium hydroxide solution (1 ml), and the mixture is stirred overnight at room temperature. The mixture is acidified with hydrochloric acid, and extracted with ethyl acetate. The extract is dried, and concentrated to give 5-carboxymethyl-1-(4-n-propylamino-2-chlorobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (800 mg) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([Cl:33])=[CH:14][C:15]([F:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=3)[CH:17]=1)[N:5]=2.CC(N(C)C)=O.[C:40]1(/[CH:46]=[CH:47]/[C:48](Cl)=[O:49])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:33][C:13]1[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:48](=[O:49])/[CH:47]=[CH:46]/[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:17][C:16]([NH:18][C:19](=[O:31])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=2)=[C:15]([F:32])[CH:14]=1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(N)sc4n3)c(Cl)cc2F)c1
Reactant: O=C(Cl)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)/C=C/c5ccccc5)sc4n3)c(Cl)cc2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a suspension of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-chloro-2-fluorophenyl}-3-(1-cyano-1-methylethyl)benzamide (80 mg, 0.166 mmol) produced in Example C52(v) in pyridine (1.0 mL) were added dimethylacetamide (0.5 mL) and (2E)-3-phenylprop-2-enoyl chloride (55 mg, 0.332 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate (20 mL), washed with 5% aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/hexane to give the title compound (87.5 mg, 86%) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=2)[N:3]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+].COC=COC>C(O)C.O>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:32]3[C:27]([F:26])=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:12]=2)[N:3]=1
Reactant: OB(O)c1cccnc1F
Reactant: N#Cc1ccc(C2(c3cccc(Br)c3)N=C(N)c3ccccc32)cc1
Agent: COC=COC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C2(c3cccc(-c4cccnc4F)c3)N=C(N)c3ccccc32)cc1
Temperature: 25 °C
Yield: 69.7 %

Procedure:
4-[3-Amino-1-(3-bromophenyl)-1H-isoindol-1-yl]benzonitrile (0.086 g, 0.22 mmol) (Example 50), (2-fluoropyridin-3-yl)boronic acid (0.047 g, 0.33 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane adduct (0.018 g, 0.022 mmol), potassium carbonate (0.091 g, 0.66 mmol) and solvent (3 mL of a mixture of dimethoxyethene, water and ethanol in a ratio of 6:3:1) was irradiated under argon atmosphere in a microwave at 125° C. for 6 min. When cooled to ambient temperature the mixture was partitioned between ethyl acetate and water; the organic phase was dried over magnesium sulfate and evaporated. Purification by preparative HPLC to give 0.062 g (70% yield) of the title compound. 1H NMR (DMSO-d6) δ 8.22 (dd, J=3.28, 1.52 Hz, 1 H), 8.05-7.94 (m, 1 H), 7.84-7.75 (m, 2 H), 7.75-7.69 (m, 2 H), 7.56-7.34 (m, 9 H), 6.90 (br s, 2 H); MS (AP) m/z 405 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[C:11](Cl)(=[O:13])[CH3:12]>>[C:11]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[NH2:1])(=[O:13])[CH3:12]
Reactant: CC(=O)Cl
Reactant: Nc1c(Cl)cccc1CO
Product: CC(=O)OCc1cccc(Cl)c1N

Procedure:
This material was prepared from 2-amino-3-chlorobenzyl alcohol and acetyl chloride by the general procedure outlined in Example 82. The product was isolated as an amber oil and was characterized by IR and 'H NMR spectroscopy and combustion analysis.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][NH2:31])=[CH:28][C:23]=2[O:22][CH2:21]1.CCN(C(C)C)C(C)C>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][CH2:30][NH:31][C:3]3[S:4]/[C:5](=[CH:9]\[C:10]4[CH:11]=[C:12]5[C:17](=[CH:18][CH:19]=4)[N:16]=[CH:15][CH:14]=[CH:13]5)/[C:6](=[O:8])[N:7]=3)=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCCc1ccc2c(c1)OCO2
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCc2ccc3c(c2)OCO3)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-benzo[1,3]dioxol-5-yl-ethylamine and DIEA to give (2-benzo[1,3]dioxol-5-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 404 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](OCC#C)=[CH:5][C:4]=1[C:13]1[NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N:21]=1.C([O-])(=O)/[CH:23]=[CH:24]/[C:25]([O-])=[O:26]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:26][CH2:25][C:24]#[CH:23])[CH:6]=[CH:5][C:4]=1[C:13]1[NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N:21]=1
Reactant: C#CCOc1ccc(OC)c(-c2nc3cnccc3[nH]2)c1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Product: C#CCOc1ccc(-c2nc3cnccc3[nH]2)c(OC)c1

Procedure:
2-(2-Methoxy-5-propargyloxyphenyl)imidazo(4,5-c)-pyridine, fumarate, m.p. 210°.