Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[K].[CH3:25]C(C)([O-])C.CI.[Cl-].[Na+]>CS(C)=O>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH3:25])[C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: CC(C)(C)[O-]
Reactant: O=C(Nc1cccc2ccccc12)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Solvent: CI
Solvent: CS(C)=O
Product: CN(C(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.2 g (0.01 mol) of 4-chloro-3-nitro-N-(naphthalen-1-yl)-benzamide and 1.1 g (0.01 mol) of potassium-tert.-butoxide are dissolved in 50 ml dimethylsulphoxide and stirred for 30 minutes at ambient temperature. Then 1 ml methyl iodide is added thereto and the mixture is stirred for a further 3 hours at ambient temperature. The solution is poured onto saturated sodium chloride solution and extracted with ethyl acetate. The combined organic extracts are dried over sodium sulphate and concentrated by evaporation. The residue is chromatographed on silica gel and eluted with methylene chloride.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH2:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH3:10][C:11]([CH3:13])=O>O>[CH3:10][C:11]1([CH3:13])[NH:1][CH:2]([C:7]([NH2:9])=[O:8])[C:3]([CH3:5])([CH3:4])[S:6]1
Reactant: CC(C)(S)[C@H](N)C(N)=O
Reactant: CC(C)=O
Solvent: O
Product: CC1(C)NC(C(N)=O)C(C)(C)S1
Yield: 92 %

Procedure:
Penicillaminamide (74.0 g, 0.50 mol) was dissolved in distilled water (800 ml) and added with acetone (58.0 g, 1.00 mol). The mixture was allowed to react at 30° C. for 1 hour with stirring under normal pressure and cooled. Then, water and acetone were evaporated by using an evaporator. The residue was washed with acetone to obtain white crystals (86.5 g, 0.46 mol) of 2,2,5,5-tetramethyl-1,3-thiazolidine-4-carboxylic acid amide. The yield to penicillaminamide was 92.0 mole %.
Reaction SMILES: [OH-].[K+].[O:3]=[C:4]([CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:5]([OH:7])=[O:6].O1CCC[CH2:17]1>>[O:3]=[C:4]([C:8]([CH3:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:5]([OH:7])=[O:6]
Reactant: C1CCOC1
Reactant: CC(C(=O)C(=O)O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CC(C)(C(=O)C(=O)O)c1ccccc1
Yield: 11 %

Procedure:
Example 14 was repeated except that 4.0 ml (9.0 mmoles) of a 2.25N aqueous solution of potassium hydroxide was used instead of lithium hydroxide as a base, and 8 ml of tetrahydrofuran was used as a solvent. A mixture of 2-oxo-3-phenylbutanoic acid (65 %) and 2-oxo-3-methyl-3-phenylbutanoic acid (11 %) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.[F:10][C:11]([F:23])([F:22])[C:12](=O)[CH2:13][C:14]([C:16]1[O:17][CH:18]=[CH:19][CH:20]=1)=O>C(O)(=O)C>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[N:9]=[C:12]([C:11]([F:10])([F:22])[F:23])[CH:13]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccco1
Reactant: NNc1cccc(I)c1
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(-c2ccco2)n(-c2cccc(I)c2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a stirred suspension of 61 (3.63 g, 8.57 mmol) in acetic acid (34 mL) was added 4,4,4-trifluoro-1-(2-furyl)-1,3-butanedione (1.3 mL, 8.57 mmol). The resulting suspension was allowed to stir at 120° C. overnight turning clear upon heating. The mixture was then evaporated to dryness. The crude product was added to a silica gel column and eluted with 5% to 10% EtOAc/hexanes. The title product 62 (3.00 g, 87% yield) was isolated as a colorless oil that solidified upon standings. LRMS (ESI): calc. 404.1; found 405.2 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]([C:25]2[N:26]=[CH:27][O:28][CH:29]=2)[O:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([CH:17]=[C:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])[CH2:12]2)=[C:6]([CH3:8])[CH:7]=1>C(OCC)(=O)C.CO.[Pd]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:9]([C:25]2[N:26]=[CH:27][O:28][CH:29]=2)[O:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:24])[CH2:12]2)=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1ccc(C(O[C@@H]2CCC[C@H](C=C3SC(=O)NC3=O)C2)c2cocn2)c(C)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(C(O[C@@H]2CCC[C@H](CC3SC(=O)NC3=O)C2)c2cocn2)c(C)c1
Yield: 85.3 %

Procedure:
0.35 g of 5-[1-[cis-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexyl]-methylidene]thiazolidine-2,4-dione is dissolved in 12 ml of a solvent mixture of ethyl acetate and methanol (3:1), and 20 mg of palladium-on-carbon are added. The mixture is then hydrogenated at room temperature under a hydrogen pressure of 3 bar for 2 hours. The catalyst is filtered off and the solvent is then removed under reduced pressure and the residue is taken up in acetonitrile. The product can be filtered off, giving 0.3 g of 5-[cis-3-(5-methyl-2-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]thiazolidine-2,4-dione as a white solid. C22H26N2O4S (414.52), MS (ESI): 415 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][NH:25][CH2:26]2>>[NH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH2:23][CH2:24][N:25]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=3)[N:3]=1)[CH2:26]2
Reactant: Nc1cccc2c1CCNC2
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: Nc1cccc2c1CCN(c1ncnc(Nc3cccc(CS(N)(=O)=O)c3)n1)C2

Procedure:
B41 was prepared following the general procedure reported for B10 using A1 and 5-amino-1,2,3,4-tetrahydroisoquinoline; yield: 61.5 mg (15%), pale yellow solid. MS (ES) C19H21N7O2S requires: 411. found: 412 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][N:27]=1)CCC>C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:23]4[S:24][CH:25]=[CH:26][N:27]=4)[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: c1ccccc1
Product: Cc1c(-c2nccs2)c(F)c2oc(C3CC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 30 h
Yield: 32.4 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (100 mg, 0.34 mmol) was dissolved in benzene (3 ml), then 2-tributylstannylthiazole (140 μl, 0.37 mmol) and 2,6-di-tert-butylcresol (1 mg) and bis(triphenylphosphine)palladium(II) dichloride (3 mg, 0.003 mmol) were added, followed by heating under reflux for 20 hours under nitrogen atmosphere. The reaction liquid was cooled, the insoluble matter was separated by filtration through Celite, the solvent was concentrated under reduced pressure. The resulting residue was fractionated with ethyl acetate and water, followed by washing with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was dissolved in methylene chloride, potassium fluoride (20 mg) and water (0.1 ml) were added, followed by vigorously stirring at room temperature for 30 hours. The insoluble matter was separated by filtration through Celite, followed by fractionation with methylene chloride and water and by washing with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure. The resulting residue was subjected to preparative silica gel column chromatography, eluted with a mixed solvent of n-hexane/ethyl acetate (3:1, v/v) to obtain 2-cyclopropyl-7-fluoro-5-methyl-6-(1,3-thiazol-2-yl)-1,3-benzoxazole-4-carbonitrile (31 mg, 0.11 mmol, 31%) as a white solid. This was dissolved in dimethyl sulfoxide (0.7 ml), triethylamine (37 μl, 0.26 mmol) and (3S)-3-(dimethylamino)pyrrolidine (17 μl, 0.14 mmol) were added, followed by stirring at 90° C. under nitrogen atmosphere for 22 hours. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated away, the resulting residue was subjected to preparative thin-layer silica gel column chromatography and eluted with a mixed solvent of chloroform/methanol (20:1, v/v) to obtain the entitled compound (13 mg, 32%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])/[CH:5]=[CH:6]/[C:7]1[CH:24]=[CH:23][C:10]2[N:11]([CH2:21][CH3:22])[C:12](=[O:20])[C:13]([CH3:19])([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:9]=2[CH:8]=1)[CH3:2]>[Pd].CO>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH2:6][C:7]1[CH:24]=[CH:23][C:10]2[N:11]([CH2:21][CH3:22])[C:12](=[O:20])[C:13]([CH3:19])([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2CC
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1ccc2c(c1)N(C)C(=O)C(C)(C)C(=O)N2CC
Yield: 80.1 %

Procedure:
10% Palladium on carbon(0.1 g) was added to a methanol solution(10 ml) of (E)-3-(1-ethyl 3,3,5-trimethyl 2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yl) acrylic acid ethyl ester(0.36 g). The mixture was subjected to catalytic reduction at room temperature and under normal pressure. The catalyst was removed by celite filtration, followed by concentration under reduced pressure to give the title compound(0.29 g) as a brown solid.
Reaction SMILES: C([O:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][NH:13][CH2:14]2)C1C=CC=CC=1>[C].[Pd].CO>[OH:8][C:9]1[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][NH:13][CH2:14]2
Reactant: COc1ccc2c(c1OCc1ccccc1)CCNC2
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1O)CCNC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Palladium carbon (10%) (200 mg), methanol (10 mL) and 5-(benzyloxy)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (800 mg, 2.97 mmol, 1.00 equiv). To the above H2 (enough, amount) was introduced in. The resulting solution was stirred for 2 h at room temperature. The solids were filtered out. The resulting solution was diluted with 12 mL of tetrahydrofuran. To this was HCl (gas) (enough amount) was introduced in. The resulting mixture was concentrated under vacuum. The solids were collected by filtration. The filter cake was washed with 2×20 mL of dichloromethane. This resulted in 0.5 g (crude) of 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride as a off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 2.88-3.92 (t, 2H), 3.40-3.44 (t, 2H), 3.77 (s, 3H), 4.20 (s, 2H), 6.68-6.70 (d, 1H), 6.88-6.91 (d, 1H); MS (ESI) m/z 180 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH2:10][O:11][CH3:12])[CH:3]=1.[Mg].[F:14][C:15]([F:26])([C:22]([F:25])([F:24])[F:23])[C:16](N(OC)C)=[O:17].Cl>C1COCC1>[F:14][C:15]([F:26])([C:22]([F:25])([F:24])[F:23])[C:16]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][CH2:10][O:11][CH3:12])[CH:3]=1)=[O:17]
Reactant: CON(C)C(=O)C(F)(F)C(F)(F)F
Reactant: COCOCc1cccc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COCOCc1cccc(C(=O)C(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
In THF (15 mL), a Grignard reactant was prepared from 1-bromo-3-((methoxymethoxy)methyl)benzene (2.54 g) and magnesium (292 mg). Under a nitrogen atmosphere, the obtained Grignard reactant (entire amount) was added to a solution of 2,2,3,3,3-pentafluoro-N-methoxy-N-methylpropanamide (3.70 g) in THF (10 mL) at 0° C., and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1N hydrochloric acid at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.28 g) as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]([C:51]3[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=3)=[C:45]3[NH:46][NH:47][CH2:48][CH2:49][N:44]3[N:43]=2)=[CH:38][CH:37]=1>CN(C)C=O.O>[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]([C:51]3[CH:56]=[CH:55][N:54]=[CH:53][CH:52]=3)=[C:45]3[NH:46][N:47]([C:11](=[O:13])[CH2:10][C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][CH:2]=4)[CH2:48][CH2:49][N:44]3[N:43]=2)=[CH:38][CH:37]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: Fc1ccc(-c2nn3c(c2-c2ccncc2)NNCC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Cc1c[nH]c2ccccc12)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A mixture of 3-indolylacetic acid (57 mg, 0.325 mmol), 3-(3-dimethylaminopropyl)-1-ethylcarbodiimide (50 mg, 0.325 mmol) and 1-hydroxybenzotriazole (44 mg, 0.325 mmol) in N,N-dimethylformamide (0.6 ml) was stirred for 1 hour at ambient temperature. Then to the mixture was added 7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (80 mg, 0.271 mmol) in N,N-dimethylformamide (1 ml). After stirring for 2 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by crystallization from ethyl acetate to give 7-(4-fluorophenyl)-2-(3-indolylacetyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (87 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41](Br)=[CH:40][CH:39]=1)[CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7].CCCC[Sn]([C:59]1[N:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)(CCCC)CCCC>>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:10]([NH:12][N:13]([CH2:14][C@:15]([OH:36])([C:23](=[O:35])[NH:24][C@H:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][C@H:26]1[OH:34])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:63]2[CH:62]=[CH:61][CH:60]=[CH:59][N:64]=2)=[CH:40][CH:39]=1)=[O:11])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: COC(=O)N[C@H](C(=O)NN(Cc1ccc(Br)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C
Product: COC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2ccccn2)cc1)C[C@@](O)(Cc1ccccc1)C(=O)N[C@H]1c2ccccc2C[C@H]1O)C(C)(C)C

Procedure:
The title compound was prepared according to Method A, using compound 19 (100 mg, 0.147 mmol), 2-(1,1,1-tributylstannyl)pyridine (220 mg, 0.598 mmol), Pd(PPh)3Cl2 (5.12 mg, 0.0072 mmol) and CuO (11.7 mg, 0.147 mmol). Purification by RP-LC-MS (40 min gradient of 10-100% CH3CN in 0.05% aqueous formic acid) gave the product (17.2 mg, 17%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][O:15][C:16]2[C:21]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][C@H:23]3[CH3:28])=[N:20][CH:19]=[CH:18][N:17]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C=O.[OH-].[Na+]>ClCCCl.O>[CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][O:5][C:6]1[C:11]([O:12][CH2:13][CH2:14][O:15][C:16]2[C:21]([N:22]3[CH2:27][CH2:26][N:25]([CH3:30])[CH2:24][C@H:23]3[CH3:28])=[N:20][CH:19]=[CH:18][N:17]=2)=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: C[C@@H]1CNCCN1c1nccnc1OCCOc1cccnc1OCCN(C)C
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: O
Product: C[C@@H]1CN(C)CCN1c1nccnc1OCCOc1cccnc1OCCN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{2-[{2-[2-(dimethylamino)ethoxy]pyridin-3-yl}oxy]ethoxy}-3-[(2R)-2-methylpiperazin-1-yl]pyrazine (from Example 1; 0.48 g, 1.19 mmol) in 1,2-dichloroethane (4 mL) was added sodium triacetoxyborohydride (1.3 g, 6.2 mmol) and 37% aqueous formaldehyde (0.072 g, 2.4 mmol), the slightly exothermic reaction was stirred at ambient temperature overnight. Water was added and the mixture was made basic (pH>13) by addition of 8 M NaOH. After being stirred for five minutes, the phases were separated and the aqueous phase was extracted twice with CHCl3. The combined organic phases were dried (MgSO4) and the solvent was removed under reduced pressure. The resulting oil was chromatographed on a column of silica (80 mm, i.d.=30 mm) with CHCl3/MeOH/NH4OH (95:5:0.2; 100 mL, followed by 90:10:0.2) as eluent to give 0.33 (67%) of the title compound as a colorless oil. HRMS m/z calcd for C21H32N6O3 (M)+ 416.2536. found 416.2523.
Reaction SMILES: C([Mg]Br)C.[O:5]1CCC[CH2:6]1.[Cl:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1.C=O.CN(C)P(N(C)C)(N(C)C)=O>C(OCC)C.C1(C)C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[C:13]([OH:17])[C:14](=[CH:15][CH:16]=1)[CH:6]=[O:5]
Reactant: Oc1cccc(Cl)c1
Reactant: C1CCOC1
Agent: C=O
Agent: CC[Mg]Br
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: O=Cc1ccc(Cl)cc1O
Temperature: 80 °C
Yield: 73.5 %

Procedure:
A 2M solution of ethylmagnesium bromide in tetrahydrofuran (50 ml, 0.10 mole) was placed in a flask, and a solution of 12.85 g (0.10 mole) of 3-chlorophenol in 50 mL of diethyl ether was added slowly with stirring. The addition required two hours, after which the solvents were removed by evaporation under reduced pressure. Toluene (200 ml), 7.50 g (0.25 mole) of paraformaldehyde, and 17.92 g (0.10 mole) of hexamethylphosphoramide were added to the residue, and this mixture was heated at 80° C. for approximately 16 hours. The solvent was evaporated under reduced pressure, leaving a residue. This residue was washed successively with 50 mL of hydrochloric acid and 300 mL of water. Vacuum distillation of the washed residue yielded 11.50 g of 4-chlorosalicylaldehyde, b.p. 112° C. at 9 mm of Hg. This reaction was repeated several times.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([Cl:23])=[CH:17][C:16]=3[CH3:24])=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26].[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O>[N:28]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([Cl:23])=[CH:17][C:16]=3[CH3:24])=[C:7]([C:12]#[N:13])[CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:25]([O-:27])=[O:26])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(Cl)c([N+](=O)[O-])cc23)c(C)cc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cc(Nc2c(C#N)cnc3cc(N=[N+]=[N-])c([N+](=O)[O-])cc23)c(C)cc1Cl
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To 1.1 g (2.7 mmol) of 7-chloro-4-(4-chloro-5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile in 5 mL of anhydrous dimethyl sulfoxide (DMSO) is added 1.77 g (27 mmol) of sodium azide under a flow of nitrogen. The mixture is stirred at 55° C. for 3 hours. The reaction is cooled to room temperature and poured onto 30 g of crushed ice. This mixture is stirred for 30 minutes and the suspended solid collected by filtration. After drying, a 1 g portion of 7-azido-4-(4-chloro-5-methoxy-2-methylanilino)-6-nitro-3-quinolinecarbonitrile is obtained as a dark solid. The solid is dissolved in a 1:1 mixture of ethanol/tetrahydrofuran (50 mL) and to this is added 200 mg of 10% palladium on carbon under a flow of nitrogen. After hydrogenation of the mixture for 1.5 hours using a Parr shaker at 40 psi, the crude product is filtered through diatomaceous earth and the filtrate evaporated in vacuo. The residue obtained is purified by flash chromatography, eluting with 85:15 methylene chloride/methanol to provide a 0.638 g of a brown solid, mp 232-235° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@H:9]1[NH:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:37][C:38]([F:41])([F:40])[F:39])[C:17]3[C:22]([N:23]=2)=[C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:20]=[C:19]([C:30]2[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=2)[N:18]=3)[CH2:10]1.C([O:45][CH2:46][C:47](Cl)=[O:48])(=O)C.C[O-].[Na+].CO>C(Cl)Cl.CO.O1CCCC1.C(Cl)Cl.CO>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:19]2[N:18]=[C:17]3[C:22]([N:23]=[C:15]([N:11]4[CH2:12][CH2:13][N:14]([C:46](=[O:45])[CH2:47][OH:48])[C@H:9]([CH3:8])[CH2:10]4)[N:16]3[CH2:37][C:38]([F:41])([F:39])[F:40])=[C:21]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:20]=2)=[CH:31][N:32]=1
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1
Reactant: CC(=O)OCC(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)CCN1C(=O)CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
Triethylamine (55.9 μl, 0.40 mmol) was added to a methylene chloride suspension (3.0 ml) of 5-{8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl}pyrimidin-2-amine (87.2 mg, 0.18 mmol) at room temperature followed by the addition of acetoxyacetyl chloride (24.2 μl, 0.22 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 1 hour, then the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, a 25% by weight sodium methoxide-methanol solution (83.3 μl, 0.36 mmol) was added to a methanol-tetrahydrofuran (1:1) mixture solution (12.0 ml) of the resulting white solid, and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into methylene chloride and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (85.2 mg, 87%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([O:48][CH3:49])[C:34]=1[OH:50]>>[Cl:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:14])[CH3:15])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:22][CH2:23]2)[CH:36]=[C:35]([O:48][CH3:49])[C:34]=1[OH:50]
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Product: COc1cc(-c2ccc3ncc(C(=O)C(C)C)c(N[C@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)c3c2)cc(Cl)c1O

Procedure:
Following general procedure D, tert-butyl (trans-4-((6-bromo-3-isobutyrylquinolin-4-yl)amino)cyclohexyl)carbamate (49 mg, 0.10 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.15 mmol) to afford the desired product (77 mg, >99%) as a viscous brown oil. ESI MS m/z 568 [C31H38ClN3O5+H]+