Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([OH:12])=O)[S:7][C:6]=2[C:13]=1[N+:14]([O-:16])=[O:15].S(Cl)(Cl)=O.[C:23]1([CH3:29])C=CC=CC=1>CN(C)C=O>[OH:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]2[CH:9]=[C:8]([C:10]([N:14]3[CH2:29][CH2:23][O:1][CH2:2][CH2:13]3)=[O:12])[S:7][C:6]=2[C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: COc1cc2cc(C(=O)O)sc2c([N+](=O)[O-])c1O
Reactant: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2cc(C(=O)N3CCOCC3)sc2c([N+](=O)[O-])c1O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
6-Hydroxy-5-methoxy-7-nitro-benzo[b]thiophene-2-carboxylic acid (2.7 g) was dissolved in toluene (45 ml). Thionyl chloride (1.2 ml) and N,N-dimethylformamide (4 drops) were added. The solution was stirred at 80° C. for two hours and after that it was evaporated. The residue was dissolved into dichloromethane (45 ml) and morpholine (1.4 ml) and triethylamine (1.2 ml) added. The reaction solution was stirred at room temperature overnight. The solution of water and 2M HCl was added to the solution. The solid was washed with water and dried under vacuum.
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.Br[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:11]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: Brc1ccccn1
Product: O=C(O)COc1ccc(Cl)cc1C#Cc1ccccn1

Procedure:
Following the general method as outlined in Example 10, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and 2-bromopyridine (Acros), the title compound was obtained as a beige powder after purification by precipitation in acetonitrile.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][OH:7])[CH2:4][OH:5])[CH3:2].[CH:8](=O)[CH2:9][CH2:10]C>C(O)CCC>[CH2:1]([CH:3]([CH:6]([OH:7])[CH2:8][CH2:9][CH3:10])[CH:4]=[O:5])[CH3:2]
Reactant: CCC(CO)CO
Reactant: CCCC=O
Solvent: CCCCO
Product: CCCC(O)C(C=O)CC
Yield: 52.6 %

Procedure:
JP patent publication 1 299 240 discloses a process for the preparation of 2-ethyl-1,3-propane diol from n-butyraldehyde by aldol condensation by using alkali metal alkoxides as the catalyst. The reaction was performed in the presence of sodium methoxy in a butanol solution at 40° C. 2-Ethyl-3-hydroxyhexanal formed with a yield of 52.6%, and it was hydrogenated with Raney nickel at a temperature of 100° C. and a pressure of 50 atm.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[C:9]#[C:10][Si](C)(C)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:9]([C:3]1[CH:4]=[CH:5][C:6]([NH2:8])=[N:7][C:2]=1[CH3:1])#[CH:10]
Reactant: Cc1nc(N)ccc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc(N)nc1C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a mixture of 6-methyl-5-trimethylsilanylethynyl-pyridin-2-ylamine (450 mg, 1.9 mmol) described in Manufacturing Example 187-1-1 and methanol (5 mL) was added potassium carbonate (390 mg, 2.8 mmol), which was stirred for 30 minutes at the same temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (220 mg, 88%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[C:9]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:10]3=[CH:11][CH:12]=[C:13]([C:21]3[CH:22]=[N:23][N:24]([CH3:32])[C:25]=3[CH:26]3[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]3)[CH:14]=2)[N:4]([CH:33]([CH3:35])[CH3:34])[N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[CH2:43]1COCC1>>[CH:33]([N:4]1[C:5]([C:7]2[N:8]=[C:9]3[C:10]4[CH:11]=[CH:12][C:13]([C:21]5[CH:22]=[N:23][N:24]([CH3:32])[C:25]=5[CH:26]5[CH2:31][CH2:30][CH2:29][N:28]([CH3:43])[CH2:27]5)=[CH:14][C:15]=4[O:16][CH2:17][CH2:18][N:19]3[CH:20]=2)=[N:6][C:2]([CH3:1])=[N:3]1)([CH3:35])[CH3:34]
Reactant: C1CCOC1
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCNC4)cc2OCC3)n(C(C)C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C)c4C4CCCN(C)C4)cc2OCC3)n(C(C)C)n1
Yield: 79 %

Procedure:
To a solution of 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-12-[1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1 (14),2,4,10,12-pentaene, also named as 2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-9-(1-methyl-5-(piperidin-3-yl)-1H-pyrazol-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (220 mg, 0.39 mmol) in dry THF (5.0 mL), was added LiAlH4 (59.3 mg, 1.56 mmol) in small portions at room temperature. The resultant mixture was heated to reflux for 1 h. Water (2.0 mL) was added to quench the reaction. The organic layer was dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give racemic 246 (150 mg, 79% yield), which was separated by chiral SFC (Cellulose-2 column, 0.1% DEA in MeOH isocratic) to give: 5.5 mg of one enantiomer and 70 mg of the other (39% total yield). LCMS (ESI): RT=4.96 min, m/z: 487.4 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.42 (d, J=2.0 Hz, 1H), 7.91 (s, 1H), 7.43 (s, 1H), 7.09-7.06 (m, 1H), 6.93 (d, J=1.5 Hz, 1H), 5.87-5.84 (m, 1H), 4.54 (d, J=6.0 Hz, 4H), 3.90 (s, 3H), 3.17 (s, 1H), 2.78-2.74 (m, 2H), 2.26 (s, 3H), 2.18-2.13 (m, 3H), 1.64-1.48 (m, 5H), 1.45 (d, J=7.0 Hz, 6H)
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.C1COCC1.[CH3:20][NH:21][CH3:22]>>[CH3:20][N:21]([CH3:22])[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNC
Reactant: COc1ccc2c(O)nc(Cl)nc2c1
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(N(C)C)nc2c1
Temperature: 100 °C

Procedure:
2-chloro-7-methoxyquinazolin-4-ol (288 mg, 1.368 mmol) was dissolved in Dimethylamine 2 M in THF (2 ml, 4.00 mmol) and heated to 100° C. for 1 h in a sealed tube. The reaction was cooled and the volatiles were removed under vacuum. The crude solid was collected and washed with water, filtered and dried to give 2-(dimethylamino)-7-methoxyquinazolin-4-ol which was carried to the next step without further purification. MS: MS m/z 220.1 (M++1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2[N:8]=[C:9]([NH2:11])[S:10][C:4]=2[CH2:3]1.Br[C:13]1[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=[C:17]([Br:19])[CH:18]=1>>[Br:19][C:17]1[CH:18]=[C:13]([NH:11][C:9]2[S:10][C:4]3[CH2:3][N:2]([CH3:1])[CH2:7][CH2:6][C:5]=3[N:8]=2)[C:14](=[O:21])[N:15]([CH3:20])[CH:16]=1
Reactant: CN1CCc2nc(N)sc2C1
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: CN1CCc2nc(Nc3cc(Br)cn(C)c3=O)sc2C1
Yield: 52.6 %

Procedure:
Following Example 110c, 3 g of 141a and 4 g of 3,5-dibromo-1-methylpyridin-2(1H)-one were reacted to give 141b as a yellow solid (2.8 g, 52%). LCMS: [M+H]+ 357
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14]([O:17]CC)=[CH:13][C:12]1=[O:20])=[O:6]>C(Cl)Cl.C(OCC)C>[CH3:1][NH:2][C:3]1[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=1[C:5]([O:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][C:12]1=[O:20])=[O:6]
Reactant: CCOC1=CC(=O)C(CCCOC(=O)c2ccccc2NC)CC1
Solvent: CCOCC
Solvent: ClCCl
Product: CNc1ccccc1C(=O)OCCCC1CCC(=O)CC1=O

Procedure:
Compound 4 was stirred in a mixture of THF/3N HCl (1/1) at rt for 3 h and the mixture was concentrated. The crude product was washed with EtOAc/hexane/MeOH (1/2/0.5) to afford 6 as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.83 (1H, m), 7.34 (1H, m), 6.55 (2H, m), 4.22 (2H, t, J=6.3 Hz), 3.60 (2H, m), 2.84 (3H, s), 2.52-1.50 (9H, m); 13C NMR (75MHz, CDCl3) δ 204.3, 203.8, 168.6, 151.6, 134.9, 131.7, 131.5, 115.2, 111.6, 110.5, 64.1, 58.4, 49.1, 39.9, 30.1, 26.4, 26.0, 24.7; ESI MS m/z 326 (M++Na+).
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]=1[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C.[OH:25][CH:26]([CH:29]1[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30]1)[CH2:27][NH2:28]>C(O)C>[OH:25][CH:26]([CH:29]1[CH2:33][O:32][C:31]([CH3:35])([CH3:34])[O:30]1)[CH2:27][NH:28][C:4](=[O:3])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C:12]([F:13])([F:14])[F:15])[C:6]=1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cc(F)cc(C(F)(F)F)c1OCc1ccccc1
Reactant: CC1(C)OCC(C(O)CN)O1
Solvent: CCO
Product: CC1(C)OCC(C(O)CNC(=O)c2cc(F)cc(C(F)(F)F)c2OCc2ccccc2)O1
Temperature: 100 °C

Procedure:
3.42 g (10 mmol) of 2-benzyloxy-5-fluoro-3-(trifluoromethyl)-benzoic acid ethyl ester is dissolved in 10 ml of ethanol, 2.43 g (15 mmol) of 2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamine is added, the ethanol is distilled off and the remaining oil is warmed to 100° C. in a vacuum in 2 hours. The reaction mixture is then dissolved in 50 ml of ethyl acetate, shaken out twice with 10 ml of 1N hydrochloric acid each, the organic phase is dried on sodium sulfate, concentrated by evaporation and the residue is chromatographed on silica gel 60 with ethyl acetate/hexane. 2.18 g (7.18 mol) =47.68% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [P:1]([O-:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].C(=O)(O)[O-:14].[K+].[Mn]([O-])(=O)(=O)=O.[K+]>O>[P:1]([OH:14])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])([O:2][C:3]([CH3:5])([CH3:6])[CH3:4])=[O:12]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OP([O-])OC(C)(C)C
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OP(=O)(O)OC(C)(C)C
Temperature: 25 °C
Yield: 76.8 %

Procedure:
A solution of di-tert-butyl phosphite (175 g), potassium bicarbonate (54.2 g), and deionized water (788 mL) was cooled to 0° C. Potassium permanganate (99.7 g) was divided into three equal portions of 33.2 g and each portion was added over one hour. During the addition, the maximum temperature observed was 21.6° C. Once the addition was complete, the reaction was allowed to warm to room temperature and was stirred for thirty minutes. Decolorizing carbon (13.4 g) was added and the reaction was heated to 60° C. for fifteen minutes. The suspension was filtered (very slowly) and washed with deionized water (250 mL). The filtrate was again heated to 60° C. with decolorizing carbon (22.4 g) for 20 min. The suspension was filtered and the filter cake was washed with deionized water (250 mL). The filtrate was cooled to 0° C. in an ice/water bath. The pH of the solution was 8-9. Concentrated HCl (157.2 mL) was added to acidify the solution to pH=1. A white precipitate immediately formed. The slurry was continued to stir at 0° C. for ten minutes. The white solid was filtered and washed with cold deionized water (219 mL). The filter cake was dissolved in chloroform (500 mL) and was dried over sodium sulfate. The dried solution was filtered, washed with chloroform, and concentrated in vacuo to afford a white solid (87.4 g, 46.2% yield). NMR analysis indicated pure product. 1H NMR (300 MHz): δ 1.45 (s, 18H); 31P NMR (121 MHz): δ −604.30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:19]=[C:18]([OH:20])[C:17]3[C:12](=[C:13](Br)[CH:14]=[C:15]([CH3:24])[C:16]=3[N+:21]([O-:23])=[O:22])[N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=[CH2:27].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)C(C)C)(C)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:31]1[CH:32]=[CH:33][C:28](/[CH:26]=[CH:27]/[C:13]2[CH:14]=[C:15]([CH3:24])[C:16]([N+:21]([O-:23])=[O:22])=[C:17]3[C:12]=2[N:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[N:19]=[C:18]3[OH:20])=[CH:29][CH:30]=1
Reactant: Cc1cc(Br)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1[N+](=O)[O-]
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(/C=C/c2ccncc2)c2nc(Nc3ccc(Cl)c(Cl)c3)nc(O)c2c1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
To a solution of 2-((3,4-dichlorophenyl)amino)-8-bromo-6-methyl-5-nitroquinazolin-4-ol (65 mg) in N,N-dimethylformamide (2 mL) was added 4-vinylpyridine (0.040 mL), followed by palladium acetate (14 mg), tri-o-tolylphosphine (30 mg) and N,N-diisopropylethylamine (0.44 mL). The mixture was heated at 120° C. for 22.5 h, then was cooled to room temperature. The supernatant was concentrated in vacuo to a dark oil which was triturated with a 50% (v/v) methanol/dichloromethane (5 mL). The solid product was isolated by filtration, washed with 50% (v/v) methanol/dichloromethane (5 mL) and dried to give the title compound (12 mg). 1H NMR (300 MHz, DMSO-d6) δ11.55 (s, 1H), 9.23, 8.59 (d, J=4.5 Hz, 2H), 8.43 (d, J=2.4 Hz, 1H), 8.21 (s, 1H), 8.08 (d, J=16.8 Hz, 1H), 7.62-7.31 (m, 5H), 2.26 (s, 3H). HPLC (Method B) 9.3 min. MS (APCI+): m/z 468.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:16]=[C:15]([F:17])[C:14]([N+:18]([O-:20])=[O:19])=[CH:13]C=1C(O)=O.C(Cl)Cl>CN(C)C=O>[F:7][C:8]1[CH:16]=[C:15]([F:17])[C:14]([N+:18]([O-:20])=[O:19])=[CH:13][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1F
Temperature: 25 °C
Yield: 101.8 %

Procedure:
Oxalyl chloride (94.0 g, 0.739 mol) is added dropwise to a mixture of 2,4-difluoro-5-nitrobenzoic acid (100.0 g, 0.492 mol), methylene chloride and N,N-dimethylformamide (0.600 ml). The resultant mixture is stirred 3.25 hours at reflux, cooled to room temperature, and concentrated in vacuo to afford the title compound as a brown oil (111 g, 95.2%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[NH:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C(=O)C>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([N:12]2[CH2:17][CH2:16][S:15][CH2:14][CH2:13]2)=[CH:8][C:6]=1[NH2:7])([O-:11])=[O:10]
Reactant: C1CSCCN1
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Nc1cc(N2CCSCC2)ccc1[N+](=O)[O-]
Temperature: 135 °C
Reaction time: 24 h
Yield: 91.4 %

Procedure:
A mixture of 5-chloro-2-nitroaniline (5.6 g, 32 mmol), thiomorpholine (10.0 g, 97 mmol) and anhydrous potassium carbonate (4.98 g, 36 mmol) in N,N-dimethylacetamide (10 ml) was stirred at 135° C. under nitrogen for 1 day. Sample NMR analysis showed complete conversion of the starting material. The resultant mixture was then cooled to room temperature, poured into cold water and stirred vigorously for 3 hours. The resulting brown precipitate was collected by filtration, washed well with water then dried on the filter funnel. The resulting brown solid was washed with diethyl ether, filtered, washed with additional diethyl ether, dried to afford 2-Nitro-5-thiomorpholin-4-yl-phenylamine (7.0 g, 91.5%) as a brown powder, and used in the next step without further purification.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14]C(C)C)=O)(C)(C)C.[CH3:21][Si](C=[N+]=[N-])(C)C>C(O)C.CCOCC>[NH2:8][C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(C)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)[C@@H](N)CCCCN

Procedure:
Nα-tert-Butyloxycarbonyl-Nε-isopropyl lysine (SennChem) was reacted with trimethylsilyldiazomethan in ethanol. The resulting methyl ester amine was reacted with 2-(pinacolborono)benzyl bromide in ether and TEA to give Nα-tert-butyloxycarbonyl, Nε-isopropyl, Nε-(2-pinacolboronobenzyl) methyl lysinate:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]([CH3:17])=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:21](=[O:22])[C:20]2[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:19]=2[Cl:18])[C:9]2[S:10][C:11]([CH3:17])=[C:12]([C:14]([OH:16])=[O:15])[N:13]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Cc1sc(Nc2ccc(Cl)cc2)nc1C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1sc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2)nc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2.0 g (7.4 mmol) 2-(4-Chloro-phenylamino)-5-methyl-thiazole-4-carboxylic acid, 1.56 ml (11.1 mmol) 2,4-Dichlorobenzoyl chloride and 3.09 ml (22.3 mmol) NEt3 in 30 ml DCM was stirred at room temperature for 2 h. After removal of all volatiles the resulting yellow foam was used without further purification in the consecutive step. MS (m/e): 441.0 (MH+, 100%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][C:27]=2[NH2:28])[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:29][C:27]=2[NH:28][C:2]2[C:11]3[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[C:3]=2[CH3:19])[CH2:24][CH2:25][O:20][CH2:21][CH2:22]1
Reactant: Cc1c(-c2ccccn2)nc2c(F)cccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2ccccn2)nc2c(F)cccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-8-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (95 mg, 0.348 mmol), 2,5-dimorpholinoaniline (92 mg, 0.348 mmol) and a 4.0M solution of HCl in dioxane (0.09 mL, 0.348 mmol) in MeOH (2.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-8-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.72 (1H, dd, J=4.7, 1.6 Hz), 7.87-8.00 (2H, m), 7.64-7.71 (1H, m), 7.31-7.45 (4H, m), 7.11 (1H, d, J=8.6 Hz), 6.47 (1H, d, J=7.4 Hz), 6.04 (1H, br. s.), 3.90 (4H, t, J=4.9 Hz), 3.68-3.79 (4H, m), 2.99-3.14 (4H, m), 2.86-2.98 (4H, m), 2.42 (3H, s). Mass Spectrum (ESI) m/e=500.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:20][C:21]1[C:33]([O:34][CH3:35])=[CH:32][C:24]2[CH2:25][CH2:26][O:27][C:28](=[O:31])[N:29]([CH3:30])[C:23]=2[CH:22]=1>>[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([NH:14][CH3:15])=[O:13])=[N:4][C:5]([NH:20][C:21]2[C:33]([O:34][CH3:35])=[CH:32][C:24]3[CH2:25][CH2:26][O:27][C:28](=[O:31])[N:29]([CH3:30])[C:23]=3[CH:22]=2)=[N:6][CH:7]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Br
Reactant: COc1cc2c(cc1N)N(C)C(=O)OCC2
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)CCOC(=O)N3C)ncc1Br
Yield: 30 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from 2-(5-Bromo-2-chloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 3-Amino-2-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product triturated from Et2O to obtain a white solid (28 mg, 30%). mp: 251-253° C., MS (ESI+): 527 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 10.86 (s, 1H), 8.45 (s, J=8 Hz, 1H), 8.33 (s, 1H), 8.25 (s, 1H), 7.57 (s, 1H), 7.51 (d, J=7 Hz, 1H), 7.41 (t, J=7 Hz, 1H), 7.16 (t, J=7 Hz, 1H), 6.73 (s, 1H), 6.24 (br s, 1H), 4.53 (t, 7 Hz, 2H), 3.93 (s, 1H), 3.06 (d, J=5 Hz, 3H), 2.97 (s, 3H), 2.93 (t, J=7, 2H).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[Si:11]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[C:26]([CH:36]([NH2:38])[CH3:37])=[CH:27][C:28]([Cl:35])=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C>C(O)C>[Si:11]([O:18][CH:19]1[CH2:20][CH2:21][N:22]([C:25]2[C:26]([CH:36]([NH:38][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:37])=[CH:27][C:28]([Cl:35])=[C:29]3[C:34]=2[N:33]=[CH:32][CH:31]=[CH:30]3)[CH2:23][CH2:24]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:13])[CH3:12]
Reactant: Brc1ncnc2[nH]cnc12
Reactant: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(Nc1ncnc2[nH]cnc12)c1cc(Cl)c2cccnc2c1N1CCC(O[Si](C)(C)C(C)(C)C)CC1

Procedure:
A mixture of 6-bromo-9H-purine (0.262 g, 1.31 mmol), 1-[8-(4-{[tert-butyl(dimethyl)silyl]oxy}piperidin-1-yl)-5-chloroquinolin-7-yl]ethanamine (0.276 g, 0.657 mmol), and N,N-diisopropylethylamine (0.23 mL, 1.31 mmol) in ethanol (2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resulting residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude product was used directly in the next step (0.20 g, 57%). LCMS calculated for C27H37ClN7OSi (M+H)+: m/z=538.2; Found: 538.2.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])[C:5]([N+:15]([O-])=O)=[C:4]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1>[Pt].C1(C)C=CC=CC=1.C(O)(C)C>[NH2:15][C:5]1[C:4]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:3][C:2]([CH3:1])=[C:7]([CH3:8])[C:6]=1[NH:9][CH2:10][C:11]([CH3:12])([OH:13])[CH3:14]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCC(C)(C)O)c1C
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Cc1nc(Oc2ccccc2)c(N)c(NCC(C)(C)O)c1C

Procedure:
To a 500 ml Parr hydrogenation flask was added 5% platinum on carbon (1.432 g) and a solution of 1-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]-2-methylpropan-2-ol in 90/10 toluene/isopropanol (105 ml). The flask was evacuated until the solvent bubbled, and hydrogen was pressured into the flask at 207 kPa. After three evacuation cycles the flask was pressurized with hydrogen to 345 kPa and mixed on a shaker for about 2 hours. The pressure was released, and thin layer chromatography (TLC) monitoring of the reaction mixture indicated complete reaction. The reaction mixture was filtered, and the solvent was removed under reduced pressure. The resulting product was used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2([CH:18]=[CH2:19])O.[CH3:20][OH:21].S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1[CH:8]=[N:9][C:10]([Cl:12])=[CH:11][C:6]=1[C:5]2=[CH:18][CH2:19][O:21][CH3:20]
Reactant: CO
Reactant: C=CC1(O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Agent: O=S(=O)(O)O
Product: COCC=C1c2cc(Br)ccc2Oc2cnc(Cl)cc21
Temperature: 50 °C
Yield: 92.3 %

Procedure:
To a sealed vessel was added 7-bromo-3-chloro-5-vinyl-5H-chromeno[2,3-c]pyridin-5-ol (2.50 g, 7.38 mmol), methanol (59.8 mL, 1477 mmol) and sulfuric acid (0.2M in water) (3.70 mL, 0.74 mmol). The clear solution was heated to 50° C. over the weekend. The reaction mixture became light yellow heterogenous. The solvent was removed by rotovap and the residue was diluted with 125 mL of EtOAc. The organic solution was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude material 7-bromo-3-chloro-5-(2-methoxyethylidene)-5H-chromeno[2,3-c]pyridine (2.40 g, 6.81 mmol, 92% yield) as a yellow solid.