Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:16][C:15]([C:17]#[N:18])=[N:14][N:13]=2)[CH2:8][CH2:7]1.[N-:25]=[N+:26]=[N-:27].[Na+].Cl.[NH+]1C=CC=CC=1.Cl>CN1C(=O)CCC1>[N:18]1[NH:25][N:26]=[N:27][C:17]=1[C:15]1[S:16][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([O:5][C:4]3[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=3[C:2]([F:1])([F:23])[F:24])[CH2:7][CH2:8]2)=[N:13][N:14]=1
Reactant: N#Cc1nnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccccc1OC1CCN(c2nnc(-c3nn[nH]n3)s2)CC1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
A suspension of 5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazole-2-carbonitrile (4.99 g, 14.1 mmol), NaN3 (4.65 g, 71.5 mmol) and pyridinium hydrochloride (3.43 g, 29.7 mmol) in NMP (50 mL) was heated at 130° C. for 18 h. The reaction mixture was cooled to room temperature and poured into aqueous 0.5 N HCl, extracted with EtOAc, washed three times with aqueous 0.5 N HCl, and with aqueous brine solution. The organic layer was dried (Na2SO4) and filtered. Evaporation of the solvent was followed by trituration in a mixture of MeOH/Et2O/heptane (1:1:6) (v/v) with stirring for 4 h at room temperature. After this time, the suspension was cooled with an ice-water bath and the title compound was collected by filtration as a white solid. The material was dried under high vacuum by heating at 50° C. for 1-2 h.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[Cl-].[CH:13](=[N+:20]([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:13]([N:20]([CH3:22])[CH3:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[N+](C)=Cc1ccccc1
Reactant: COc1ccc2[nH]ccc2c1
Agent: [Cl-]
Product: COc1ccc2[nH]cc(C(c3ccccc3)N(C)C)c2c1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-methoxy-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][C@H:12]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]2)=[CH:3][CH:2]=1>ClCCl.FC(F)(F)C(O)=O>[NH:14]1[CH2:15][CH2:16][C@H:12]([NH:11][C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2ccnc3ccccc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c(N[C@H]3CCNC3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl (3S)-3-(4-quinolylamino)pyrrolidine-1-carboxylate (231 mg, 0.68 mmol) was dissolved in a 1:1 mixture of dichloromethane and trifluoroacetic acid (2 ml) and stirred at room temperature for 15 minutes. The mixture was evaporated to dryness under reduced pressure and the residue obtained was used directly in the next step.
Reaction SMILES: [CH:1]1([C:4]2[S:25][C:7]3[NH:8][C:9](=[O:24])[N:10](CC4C=CC(OC)=CC=4OC)[C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1.Br[CH2:27][C:28]1[C:33]([F:34])=[CH:32][C:31]([C:35]2[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:30][C:29]=1[F:43].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([C:4]2[S:25][C:7]3[N:8]([CH2:27][C:28]4[C:33]([F:34])=[CH:32][C:31]([C:35]5[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=5)=[CH:30][C:29]=4[F:43])[C:9](=[O:24])[NH:10][C:11](=[O:12])[C:6]=3[CH:5]=2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccccc1-c1cc(F)c(CBr)c(F)c1
Reactant: COc1ccc(Cn2c(=O)[nH]c3sc(C4CC4)cc3c2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccccc1-c1cc(F)c(Cn2c(=O)[nH]c(=O)c3cc(C4CC4)sc32)c(F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A mixture of 6-cyclopropyl-3-(2,4-dimethoxybenzyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (0.37 g), 4′-(bromomethyl)-3′,5′-difluorobiphenyl-2-carbonitrile (0.38 g), potassium carbonate (0.29 g) and acetonitrile (30 mL) was stirred at 50° C. for 2 hr. Insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in trifluoroacetic acid (10 mL), and the mixture was stirred at 50° C. for 2 hr. To the reaction mixture was added toluene (10 mL), and the mixture was concentrated under reduced pressure. To the obtained residue was added ethyl acetate (10 mL), and the mixture was concentrated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.42 g, 94%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-])=O.Cl>C(O)C.[Fe]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[NH2:12]
Reactant: CS(=O)(=O)c1ccc(Br)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Br)c(N)c1
Reaction time: 24 h

Procedure:
A solution of 1-bromo-4-(methylsulfonyl)-2-nitrobenzene (1.0 eq.), iron powder (3.0 eq.), and concentrated HCl (1.04 eq.) were mixed together in ethanol (0.64 M) and heated to reflux. The reaction was stirred for 24 hours, and the solvent was evaporated. The resulting residue was diluted with ethyl acetate and saturated aqueous ammonium chloride solution. The aqueous layer was extracted three times with ethyl acetate, and the combined organic layers were washed with water, brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude material was purified by triturating in 1:1 hexane/ether to give a light yellow solid.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([OH:14])=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH:2]=[CH:3][CH3:4].[CH2:16](Br)[CH:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:11]=2)[C:6]1=[O:15])[CH:2]=[CH:3][CH3:4]
Reactant: CC(C)CBr
Reactant: CC=CCC1Cc2ccc(O)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC=CCC1Cc2ccc(OCC(C)C)cc2C1=O
Yield: 93 %

Procedure:
A solution of 4.74 g of (RS)-2-(2-buten-1-yl)-6-hydroxy-1-indanone, 5.18 ml of isobutyl bromide and 5.98 g of potassium carbonate in 40 ml of N,N-dimethylformamide was heated to 60° for 48 hours. After cooling, the solution was poured into 100 ml of water and extracted twice with 70 ml of ethyl acetate each time. The combined organic phases were washed once with 70 ml of water and once with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. 5.2 g (93%) of (RS)-2-(2-buten-1-yl)-6-isobutoxy-1-indanone were obtained as a red-brown oil which was used directly in the next reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:14])[CH3:2].C([N-]C(C)C)(C)C.[Li+].CON(C)[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)=[O:27]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH2:14][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=1)=[O:27])[CH3:2]
Reactant: CCOc1ccc2nccc(C)c2c1
Reactant: CON(C)C(=O)c1cccc(C)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1ccc2nccc(CC(=O)c3cccc(C)n3)c2c1
Reaction time: 1 h
Yield: 19.6 %

Procedure:
To a solution of 6-ethoxy-4-methyl-quinoline (360 mg, 2.0 mmol) in THF at −78° C. add 1.5M lithium diisopropylamide (4.6 ml, 7.0 mmol) dropwise and stir for 1 hour. 6-Methyl-pyridine-2-carboxylic acid methoxy-methyl-amide (430 mg, 2.4 mmol) is then added, and the mixture stirred for 30 minutes at −78° C. before quenching with 1N HCl (5 ml). Neutralize with saturated aqueous NaHCO3 and extract with EtOAc (3×50 ml). The organic phase is then dried with MgSO4 and concentrated in vacuo. The crude product was chromatographed on silica gel (elute with 50/50 Hexane/EtOAc) to give 120 mg (20%) of the title compound. MS ES+ m/e 307.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[OH:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C([O-])([O-])=O.[Na+].[Na+]>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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([CH2:32][OH:31])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: OCc1ccc(B(O)O)cc1
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: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(CO)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 61.5 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (200 mg, 0.42 mmol) and 4-(hydroxymethyl)phenylboronic acid (96 mg, 0.63 mmol) in dioxane (2.5 mL), aqueous 2M Na2CO3 solution (0.75 mL, 1.51 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (48 mg, 0.04 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the title compound (130 mg, 62%). LCMS: 504.15 (M+1)+; HPLC: 98.86% (@254 nm) (Rt; 4.240; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.19 (t, 1H), 7.57 (d, 2H, J=7.2 Hz), 7.39 (s, 1H), 7.37 (d, 2H), 7.21 (s, 1H), 5.85 (s, 1H), 5.20 (t, 1H, J=5.2 Hz), 4.52 (d, 2H, J=5.6 Hz), 4.28 (d, 2H, J=3.6 Hz), 3.81-3.84 (m, 2H), 3.22-3.32 (m, 2H), 3.08-3.09 (m, 2H), 3.01 (m, 1H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.65-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.4 Hz).
Reaction SMILES: C([N:8]1[C:12]2[C:13]([C:17]([NH:19][C:20]3[CH:51]=[CH:50][C:23]([C:24]([N:26]([CH3:49])[C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=4[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([N:42]4[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]4)=[O:41])=[O:25])=[CH:22][C:21]=3[O:52][CH3:53])=[O:18])=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:54][O:55][CH3:56])C1C=CC=CC=1.C(O)=O>CO>[CH3:53][O:52][C:21]1[CH:22]=[C:23]([CH:50]=[CH:51][C:20]=1[NH:19][C:17]([C:13]1[C:12]2[N:8]=[C:9]([CH2:54][O:55][CH3:56])[NH:10][C:11]=2[CH:16]=[CH:15][CH:14]=1)=[O:18])[C:24]([N:26]([CH3:49])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][C:28]=1[O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([N:42]1[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]1)=[O:41])=[O:25]
Reactant: COCc1nc2cccc(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)c2n1Cc1ccccc1
Solvent: O=CO
Solvent: CO
Product: COCc1nc2c(C(=O)Nc3ccc(C(=O)N(C)c4ccc(C)cc4OCCCCCC(=O)N4CCN(C)CC4)cc3OC)cccc2[nH]1
Yield: 27.2 %

Procedure:
A mixture of 4-(3-benzyl-2-methoxymethyl-3 H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]-phenyl]benzamide (200 mg) and 5% formic acid in methanol solution (10 ml) was refluxed for 24 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in chloroform. The solution was washed with saturated aqueous sodium bicarbonate solution and the organic layer was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 3-methoxy-4-(2-methoxymethyl-1 H-benzimidazol-4-yl)carbonylamino-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (48 mg) as a powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:10]1([CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:9](=[O:17])[C:8]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])=[C:7]2[OH:29].C(O)(C(F)(F)F)=O>O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:10]1([CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:9](=[O:17])[C:8]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[C:7]2[OH:29]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccc(F)c2C2(CCOCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CNC(=O)C1=C(O)c2cccc(F)c2C2(CCOCC2)C1=O
Reaction time: 0.25 h

Procedure:
In a flask was combined 1,1-dimethylethyl N-((8-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (1.7 g, 4.2 mmol) and TFA (50 mL). The reaction was stirred for 15 minutes and then concentrated to afford an oil. Water was added, affording a white precipitate that was filtered off and washed with water and ether. The solid was dried under vacuum at 50° C. (1.4 g, 98%). MS m/e=348 (M−1)−. Calculated for C17H16FNO6 349.1.
Reaction SMILES: [CH:1](=O)[CH3:2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:18][C:19]1[CH:28]=[C:27]([C:29]#[N:30])[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])O.[Na+]>C(O)(=O)C>[C:29]([C:27]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([NH:18][CH2:1][CH3:2])[CH:28]=1)#[N:30]
Reactant: CC=O
Reactant: COC(=O)c1ccc(C#N)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCNc1cc(C#N)ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
Acetaldehyde (90%)(10 mL) and sodium triacetoxyborohydride (7.71 g, 36.4 mmol) were added to an acetic acid solution (10 mL) of methyl 2-amino-4-cyanobenzoate (3.04 g, 17.3 mmol) under ice cooling. The mixture was stirred at the same temperature for an hour and at room temperature for 2 hours. Ice water was added to the reaction mixture, the mixture was neutralized with sodium hydrogencarbonate, followed by extraction with ethyl acetate. The combined organic layers were washed with water and then saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crystals obtained were washed with diisopropyl ether-hexane to give the title compound (800 mg, 23%). The residue was applied to silica gel column chromatography (hexane/ethyl acetate=50:1 and then 30:1). The crystals obtained were washed with hexane to give the title compound (920 mg, 26%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[N+:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]=[C:40]=[O:41])([O-:32])=[O:31]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:40]([NH:39][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N+:30]([O-:32])=[O:31])=[O:41])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-nitrophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 554.8.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:12])=[CH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>C(O)(=O)C.C(O)(C(F)(F)F)=O>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:12])=[C:9]([C:17]2[CH2:18][CH2:19][N:14]([CH3:13])[CH2:15][CH:16]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CN1CCC(=O)CC1
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1[nH]c(C)c(C2=CCN(C)CC2)c1C
Temperature: 95 °C
Yield: 85.4 %

Procedure:
To a solution of 3,5-dimethyl-1H-pyrrole-2-carboxylic acid ethyl ester (836 mg, 5 mmol) in acetic acid (10 mL) and TFA (5 mL) under nitrogen was added 1-methyl-piperidin-4-one (0.8 mL, 6.67 mmol). The mixture was then heated in a 95° C. oil bath for overnight. The reaction was concentrated, dissolved in ethyl acetate, washed with NaHCO3, brine, dried and concentrated. The residue was purified on a silica gel column to give 1.12 g (85%) of 3,5-dimethyl-4-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-pyrrole-2-carboxylic acid ethyl ester.
Reaction SMILES: [Na].C(C1(CCOC2C=CN=C(C[S:24]([C:26]3[NH:30][C:29]4[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=4[N:27]=3)=O)C=2C)OCC2(OCCO2)CO1)C.[CH3:36]C1(CCO)OCC2(OCCO2)CO1>>[CH3:36][C:33]1[CH:32]=[CH:31][C:29]2[NH:30][C:26]([SH:24])=[N:27][C:28]=2[CH:34]=1
Reactant: CCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCC2(CO1)OCCO2
Reactant: CC1(CCO)OCC2(CO1)OCCO2
Agent: [Na]
Product: Cc1ccc2[nH]c(S)nc2c1

Procedure:
The same procedure as in the steps (4f) to (4j) of Example 4 was repeated using 2-(8-methyl-1,4,7,9-tetraoxaspiro[4.5]dec-8-yl)ethanol obtained in the step (73b) above and 5-methyl-1H-benzimidazole-2-thiol obtained in the step (47a) to obtain the title compound (188 mg, total 12.4% yield) as a white solid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23]#[N:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].P([O-])(OCC)(SCC)=[S:26]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3([C:23](=[S:26])[NH2:24])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCOP([O-])(=S)SCC
Reactant: CC(C)N1CCC(Oc2ccc(C3(C#N)CCOCC3)cc2)CC1
Product: CC(C)N1CCC(Oc2ccc(C3(C(N)=S)CCOCC3)cc2)CC1
Yield: 74 %

Procedure:
The title compound (320 mg, 74%) was prepared from 4-[4-(1-isopropylpiperidin-4-yloxy)phenyl]tetrahydropyran-4-carbonitrile and diethyl dithiophosphate similarly to the procedure used for intermediate 50. LRMS APCI+ m/z 363 [MH]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[CH3:33][N:34]([CH3:44])[C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=[O:40])=[CH:37][CH:36]=1.C(O)(=O)/C=C\C(O)=O>N1C=CC=CC=1.CCOC(C)=O>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:39](=[O:40])[C:38]4[CH:37]=[CH:36][C:35]([N:34]([CH3:33])[CH3:44])=[CH:43][CH:42]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Agent: O=C(O)/C=C\C(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(N(C)C)cc1
Reaction time: 8 h

Procedure:
To a solution of trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (500 mg, 1.15 mmol) in pyridine (5 ml) was added 4-(dimethylamino)benzoylchloride (420 mg, 2.28 mol) dropwise. The solution was stirred overnight, the solvent evaporated and the residue partitioned between dichloromethane and 2N NaOH solution. The aqueous layer was extracted with dichloromethane (×3). The organics were dried, filtered and evaporated to leave a solid which was triturated with EtOAc/Et2O (1:4) to leave a solid which was dissolved in EtOAc and treated with maleic acid (3 eqs.) to give trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide (320 mg, 30%). 1H NMR (d6-DMSO)): δH 9.05 (1H, s), 8.25 (1H, s), 8.18 (1H, d, J=8 Hz), 7.84 (2H, d, J=9.2 Hz), 7.29 (1H, s), 7.25 (1H, d, J=8 Hz), 6.78 (2H, d, J=8.8 Hz), 6.17 (6H, s), 4.71 (1H, m), 3.95 (3H, s), 3.01 (6H, s), 2.83-3.18 (9H, m), 2.68 (3H, s), 2.08 (6H, m), 1.56 (2H, m). HPLC (5.23 mins, 100%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([O:18]C)=[O:17])=[CH:8]2)[CH:4]=[N:3][CH:2]=1.[OH-].[K+].Cl>O.CO>[N:3]1[CH:4]=[C:5]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([OH:18])=[O:17])=[CH:8]2)[CH:6]=[N:1][CH:2]=1
Reactant: COC(=O)c1cn(-c2cncnc2)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(-c2cncnc2)c2ccccc12
Temperature: 80 °C

Procedure:
To a solution of methyl 1-(pyrimidin-5-yl)-1H-indole-3-carboxylate (16 mg, 0.063 mmol) in water MeOH (316 μl) was added 2M KOH (158 μl, 0.316 mmol). The mixture was heated at 80° C. for 4 h then neutralized with 1M HCl. The precipitate was collected by filtration to afford the title compound as a white solid, which was used without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH2:18][C:19]#[CH:20])[C:9]1[S:10][CH:11]=[C:12]([C:14](OC)=[O:15])[N:13]=1.O>O1CCCC1>[CH3:7][N:8]([CH2:18][C:19]#[CH:20])[C:9]1[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=1
Reactant: C#CCN(C)c1nc(C(=O)OC)cs1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCN(C)c1nc(CO)cs1
Yield: 86.5 %

Procedure:
Lithium aluminum hydride (900 mg) was added to anhydrous tetrahydrofuran (20 ml) and a solution of 2-(N-methyl-2-propynylamino)-4-methoxycarbonylthiazole (h) (5.0 g) in tetrahydrofuran (30 ml) was added dropwise thereto with stirring under ice-cooling. The mixture was refluxed for 2 hours, to which water was carefully added under ice-cooling, and evaporated to remove the tetrahydrofuran. The residue was extracted with chloroform. The extract was washed with water, dried and recrystallized from ether-hexane to give 2-(N-methyl-2-propynylamino)-4-hydroxymethylthiazole (i) (3.75 g, yield 86.5%): mp. 69°-70° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]([NH:16][C@@H:17]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]([O:20][CH3:21])=[O:19])=[O:15])=[CH:9][CH:8]=[CH:7]2)([O-])=O.C(O)C.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([C:14]([NH:16][C@@H:17]([CH2:22][CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]([O:20][CH3:21])=[O:19])=[O:15])=[CH:9][CH:8]=[CH:7]2
Reactant: [H][H]
Reactant: COC(=O)[C@H](CCS(C)(=O)=O)NC(=O)c1cccc2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)[C@H](CCS(C)(=O)=O)NC(=O)c1cccc2cc(N)ccc12

Procedure:
0.04 g of 10% palladium-on-charcoal is added to a solution of 0.42 g of methyl ester of methyl 2(S)-(6-nitro-1-naphthoylamino)-4-(methylsulphonyl)butanoate dissolved in 30 cm3 of ethyl acetate and 20 cm3 of ethanol and the solution is subjected to a hydrogen pressure of 1.5 atmosphere for 3 hours at a temperature in the region of 20° C. The reaction mixture is filtered on sintered glass covered with Celite and concentrated to dryness under reduced pressure. 0.6 g of methyl 2(S)-(6-amino-1-naphthoylamino)-4-(methylsulphonyl)-butanoate is obtained, the characteristics of which are the following: