Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13](O)=[O:14])[CH2:10][CH:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O1CCCC1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[CH2:10][C@H:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1CC(C(=O)O)CN1C(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](CO)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 27.5 %

Procedure:
To a solution of pyrrolidine-1,2,4-tricarboxylic acid 1,2-di-tert-butyl ester (Preparation 44, 501 mg, 1.59 mmol) in anhydrous tetrahydrofuran (10 ml) at 0° C. under a nitrogen atmosphere was added borane-tetrahydrofuran complex (1M in tetrahydrofuran, 3.16 ml, 3.18 mmol) dropwise and allowed to stir to room temperature over 18 hours. The solvent was removed under reduced pressure and the residue dissolved in ethyl acetate (10 ml) and washed with 1M hydrochloric acid (10 ml), saturated sodium hydrogen carbonate (10 ml) and then dried (MgSO4), filtered and evaporated under reduced presssure to give the title compound as a colourless gum (single diastereonier 132 mg, 27%)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[C:17]3[CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:10]=2)[CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O>C(COC)OC>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[C:17]3[CH2:25][N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH:10]=2)[CH:3]=1
Reactant: Clc1cc(Nc2cccc(Cn3c(CN4CCOCC4)nc4ccccc43)c2)ncn1
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1-c1cc(Nc2cccc(Cn3c(CN4CCOCC4)nc4ccccc43)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.2 %

Procedure:
330 mg (6-Chloro-pyrimidin-4-yl)-[3-(2-morpholin-4-ylmethyl-benzoimidazol-1-ylmethyl)-phenyl]-amine (prepared in Example 92) (0.70 mmol) was suspended in 30 cm3 dimethoxyethane and the flask was filled with argon properly. 58 mg Tetrakis(thriphenylphosphine) palladium[0] (0.05 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Then 152 mg 2-methoxyphenyl-boronic acid (1 mmol), 424 mg anhydrous Na2CO3 (4 mmol) and 6 ml water were added. The mixture was ferluxed overnight while slow argon flow was being applied. The reaction mixture was poured to 80 cm3 1M NaH2PO4 solution and it was extracted three times with 50-50 cm3 of ethyl-acetate. The combined organic layer was washed with brine, dried over MgSO4, decolorized with activated carbon and evaporated to dryness. The residual solid was recrystallized from minimal amount of acetonitrile and air-dried to give the desired product (132 mg, 37% yield). For analitical results and compound identification see Table 1.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[NH4+].[OH-].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[C:19]1[NH:20][C:21]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:22]([C:24]2[N:29]=[C:28]([NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:27]([N+:35]([O-])=O)=[CH:26][CH:25]=2)[N:23]=1.O>C1COCC1.CCOC(C)=O>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[C:19]1[NH:20][C:21]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[C:22]([C:24]2[N:29]=[C:28]([NH:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:27]([NH2:35])=[CH:26][CH:25]=2)[N:23]=1
Reactant: CC(C)CNc1nc(-c2nc(-c3c(Cl)cccc3Cl)[nH]c2-c2ccccc2)ccc1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)CNc1nc(-c2nc(-c3c(Cl)cccc3Cl)[nH]c2-c2ccccc2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Add sodium dithionite (2.58 g, 14.82 mmol) followed by 32% NH4OH (9 mL) to a solution of {6-[2-(2,6-dichlorophenyl)-5-phenyl-1H-imidazol-4-yl]-3-nitropyridin-2-yl}isobutylamine (1.43 g, 2.96 mmol) in 50 mL of 1:1 THF:water mixture. Stir the mixture at RT for 2 h. Dilute with EtOAc. Wash the organic layer with saturated aqueous NaCl and dry the organic phase over Na2SO4. Concentrate to yield the title compound (1.32 g, 98%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[S:11][CH:12]=1.Cl>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[S:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3F)cs2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccccc1-c1csc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.4 %

Procedure:
To a solution tert-butyl 4-[4-(2-fluorophenyl)-1,3-thiazol-2-yl]piperazine-1-carboxylate (3.83 g, 10.5 mmol) in ethyl acetate (100 ml) was added a 4N solution (100 ml) of hydrogen chloride in ethyl acetate, and the mixture was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in water. The solution was neutralized with 1N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give the desired product (2.61 g, 94.1%) as an oil.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.[CH3:19][O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23].CN(C)CCCN=C=NCC.[CH2:37]([C:40]1([C:55](O)=[O:56])[CH2:44][CH2:43][CH2:42][N:41]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])[CH:38]=[CH2:39]>CN(C=O)C>[CH3:19][O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:55](=[O:56])[C:40]1([CH2:37][CH:38]=[CH2:39])[CH2:44][CH2:43][CH2:42][N:41]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46]
Reactant: C=CCC1(C(=O)O)CCCN1C(=O)OCc1ccccc1
Reactant: COC(=O)[C@H](C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C=CCC1(C(=O)N[C@@H](C)C(=O)OC)CCCN1C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 83.2 %

Procedure:
HOBT (7.7 g), N-methylmorpholine (6.6 g), L-alanine methyl ester hydrochloride (4.5 g) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide (5.7 g) was added to (RS)-2-allyl-N-(benzyloxycarbonyl)proline (6.5 g) in DMF (30 ml) and the mixture was stirred for 18 hours and then evaporated. The residue was partitioned between ether and water, filtered to remove HOBt and the organic layer separated. The organic layer was evaporated and the residue was purified by chromatography on silica using a gradient of 20% ethyl acetate in hexane increasing to 50% ethyl acetate in hexane. The appropriate fractions were combined and evaporated to dryness to give [(RS)-2-allyl-N-(benzyloxycarbonyl)prolyl]-(S)-alanine methyl ester (7 g); NMR (d6-DMSO (373K)): some doubling of peaks due to the mixture of diastereoisomers, 1.25 and 1.3 (2d, 3H), 1.75 (m, 2H), 2.2 (m,2H), 2.65 (m, 1H), 2.9 (m, 1H), 3.4 (m, 1H), 3.65 (2s, 3H), 3.7 (m, 1H), 4.3 (2q, 1H), 5.0 (m, 4H), 5.7 (m,1H), 7.3 (m, 5H), 7.4 and 7.5 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:17]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30]I)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[C:17]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][N:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCCOCCI)c1ccccc1
Reactant: Clc1ncnc2cc[nH]c12
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.659 g) in N,N-dimethylformamide (5.0 mL) was added cesium carbonate (3.13 g) under ice-cooling, and the reaction mixture was stirred while warming to room temperature for 15 min. To the reaction mixture was added 2-(2-iodoethoxy)ethyl benzoate (1.45 g) prepared above, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into 5% aqueous sodium hydrogen carbonate solution (100 mL), and extracted with ethyl acetate (150 mL×3). The organic layer was washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel chromatography (eluent:hexane/ethyl acetate=95/5→60/40). The object fraction was concentrated under reduced pressure and dried to give the title compound (0.822 g) as a colorless transparent oil.
Reaction SMILES: Br[C:2]1[O:3][C:4]2[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:12][C:5]=2[C:6](=[O:11])[C:7]=1[NH:8][CH:9]=[O:10].O.Cl.[CH3:30][N:31](C)C=O>>[C:30]([C:2]1[O:3][C:4]2[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:13]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:12][C:5]=2[C:6](=[O:11])[C:7]=1[NH:8][CH:9]=[O:10])#[N:31]
Reactant: CS(=O)(=O)Nc1cc2oc(Br)c(NC=O)c(=O)c2cc1Oc1ccccc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: O
Product: CS(=O)(=O)Nc1cc2oc(C#N)c(NC=O)c(=O)c2cc1Oc1ccccc1
Reaction time: 2 h
Yield: 55.3 %

Procedure:
4.25 g of 2-bromo-3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was dissolved in 50 ml of N,N-dimethylformamide. 1.97 g of cuprous cyanide was added thereto, and the resulting mixture was stirred for 2 hours at 85°-90° C. The reaction mixture was introduced into 300 ml of water, adjusted to pH 4 with 4N hydrochloric acid, and extracted with two 200-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure. The resulting residue was recrystallized from acetonitrile to obtain 2.05 g (yield: 55.3%) of 2-cyano-3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one having a melting point of 229°-230° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.F[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.[H-].[Na+]>O>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccccn1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(CN2CCC(Oc3ccccn3)CC2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 106.3 %

Procedure:
A mixture of 60.65 H (318 mmoles) 1-phenylmethyl-4-piperidinol, 500 ml dimethylformamide, 46.25 g, that is 41 ml (475 mmoles) 2-fluoropyridine and 17 g 50% sodium hydride in mineral oil is heated at 100° C. for 1 h. The mixture is cooled in an ice bath, 20 ml water are added, the mixture is stirred for 30 min and concentrated to a residual volume of about 200 ml. 1 1 iced water is added, the mixture is stirred at 0° C. for 30 min, and the precipitate is filtered off, washed and dried. 90.71 g 1-phenylmethyl-4-(2-pyridinyloxy)piperidine are thus isolated. Melting point: 75° C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12](I)[CH:11]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[NH2:14][C:13]1[CH:15]=[CH:16][C:10]([Br:9])=[CH:11][C:12]=1/[C:3](/[CH3:4])=[CH:2]\[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: Nc1ccc(Br)cc1I
Reactant: C/C=C/C(=O)OCC
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)/C=C(/C)c1cc(Br)ccc1N
Yield: 40 %

Procedure:
A solution of Pd(Amphos)2Cl2 (1.188 g, 1.678 mmol), ethyl crotonate (5.01 ml, 40.3 mmol), 4-bromo-2-iodoaniline (Spectrum Bioscience, 10.000 g, 33.6 mmol), and n,n-diisopropylethylamine (7.03 ml, 40.3 mmol) in 6 mL DMF was heated to 90° C. for 6 hours. The reaction mixture was then poured into water and was extracted with DCM. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0-100% EtOAc/heptane) gave (Z)-ethyl 3-(2-amino-5-bromophenyl)but-2-enoate (3.817 g, 13.43 mmol, 40.0% yield) with minor impurities. m/z (ESI) 286.1 (M+H)+.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]2[O:11][CH2:12][C:13](=[O:15])[NH:14][C:9]=2[N:8]=[C:7]([CH3:16])[N:6]=1>C(O)CCC>[NH:2]([C:5]1[C:10]2[O:11][CH2:12][C:13](=[O:15])[NH:14][C:9]=2[N:8]=[C:7]([CH3:16])[N:6]=1)[NH2:3]
Reactant: NN
Reactant: Cc1nc(Cl)c2c(n1)NC(=O)CO2
Solvent: O
Solvent: CCCCO
Product: Cc1nc(NN)c2c(n1)NC(=O)CO2
Temperature: 25 °C
Yield: 56.3 %

Procedure:
12.8 ml of 98% hydrazine hydrate dissolved in 40 ml of n-butanol are dropped to a solution of 20 g of 4-chloro-2-methyl-6,7-dihydro-8H-pyrimido[5,4-b][1,4]oxazin-7-one in 320 ml of n-butanol at 117° C. within 30 minutes while stirring. The mixture is stirred for an additional 45 minutes at 117° C., then cooled to room temperature. The precipitate is filtered and washed with water to give 11.66 g (56.3%) of the product, m.p.: 262°-264° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[N+:24]([C:27]1[CH:36]=[CH:35][C:30]([C:31](=[O:34])[CH2:32]Br)=[CH:29][CH:28]=1)([O-:26])=[O:25]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:32]=1[C:31](=[O:34])[C:30]1[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:36][CH:35]=1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Product: COC(=O)Cc1c(C(=O)c2ccc([N+](=O)[O-])cc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 4-nitrophenacyl bromide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][N:7]=1.[F:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.C(OCC)(=O)C>ClCCl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([F:14])=[CH:16][CH:17]=2)=[CH:8][N:7]=1
Reactant: COC(=O)COc1ccc(N)cn1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)COc1ccc(NC(=O)c2ccc(F)cc2)cn1
Yield: 67.2 %

Procedure:
To a solution of (5-aminopyridin-2-yloxy)acetic acid methyl ester (0.16 g, 0.88 mmol) in dichloromethane (5 mL) was added 4-fluorobenzoyl chloride (0.11 mL, 0.97 mmol) and N,N-diisopropylethylamine (0.33 mL, 1.9 mmol). After 24 h the reaction was poured into ethyl acetate, washed with water, and dried over sodium sulfate. Removal of the solvent gave a white solid that was purified by trituation using ethyl acetate/hexanes to give the titled product 0.18 g (67%) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.30 (s, 1H); 8.40 (m, 1H); 8.03 (m, 3H); 7.35 (m, 2H); 6.92 (m, 1H); 4.87 (m, 2H); 3.64 (m, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][C:39]5[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:26][C:25]([C:45]([CH3:48])([CH3:47])[CH3:46])=[N:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:45]([C:25]1[CH:26]=[C:27]([NH:28][C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([O:38][C:39]3[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=3)=[CH:36][CH:37]=2)=[O:30])[N:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:18][CH:19]=2)[N:24]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3ccc(Oc4cccnc4)cc3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3cccnc3)cc2)n(-c2ccc(OCCC3CCNCC3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
To a solution of 4-{2-[4-(3-tert-butyl-5-{3-[4-(pyridin-3-yloxy)-phenyl]-ureido}-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (210 mg, 0.32 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.3 mL). The reaction mixture was stirred at room temperature for 16 h, concentrated at reduced pressure, re-dissolved in methanol and purified by preparative HPLC. The HPLC fraction containing the desired product was basified by addition of saturated aq Na2CO3 and then extracted with EtOAc. Evaporation of the solvent at reduced pressure gave the desired product 1-{5-tert-butyl-2-[4-(2-piperidin-4-yl-ethoxy)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-3-yloxy)-phenyl]-urea (46.6 mg, 26%). 1H-NMR (DMSO-d6) δ 9.20 (s, 1H), 8.30 (m, 3H), 7.45-7.35 (m, 5H), 7.00 (m, 3H), 6.30 (s, 1H), 4.0 (m, 4H), 2.40 (m, 2H), 1.70-1.60 (m, 6H), 1.40 (s, 9H), 1.05 (m, 1H); MS LC-MS [M+H]+=555.3, RT=2.73 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:5]2[S:10][C:9]([CH2:11]OS(C)(=O)=O)=[CH:8][C:6]=2[N:7]=1.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[C:5]2[S:10][C:9]([CH2:11][S:25][C:23](=[O:26])[CH3:24])=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1nc(N2CCOCC2)c2sc(COS(C)(=O)=O)cc2n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SCc1cc2nc(C)nc(N3CCOCC3)c2s1
Temperature: 60 °C
Reaction time: 16 h
Yield: 74.3 %

Procedure:
To a solution of methanesulfonic acid 2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl ester (300 mg) in DMF (8 mL) was added potassium thioacetate (113 mg). The reaction was stirred at 60° C. for 16 h and then allowed to cool to room temperature. The reaction mixture was then quenched with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (3×20 mL), dried (MgSO4), concentrated and purified using column chromatography to give thioacetic acid S-(2-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl) ester as an off-white solid (210 mg).
Reaction SMILES: O1[CH:11]2[C:2]1([CH3:14])[C:3](=[O:13])[C:4]1[C:9]([C:10]2=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH3:14][C:2]1[C:3](=[O:13])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:12])[CH:11]=1
Reactant: CC12OC1C(=O)c1ccccc1C2=O
Solvent: CCO
Product: CC1=CC(=O)c2ccccc2C1=O

Procedure:
According to Flowchart V, 2,3-epoxy-2-methyl-1,4-naphthoquinone 11 is reacted with an amine 2, where R2, R3, R4 and R5 are as described above, in absolute ethanol with heat for several hours, producing the 3-methyl-1,4-naphthalenedione derivatives 12.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:58])[C@@H:4]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=3)=[CH:35][CH:34]=2)[CH2:14][O:15][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:8]([Br:49])[CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][O:2][C:3](=[O:58])[C@@H:4]([NH:50][C:51]([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([Cl:47])=[C:43]([Cl:48])[CH:42]=3)=[CH:37][CH:38]=2)[CH2:14][OH:15])=[C:8]([Br:49])[CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c(Br)c1)NC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(OC(CO)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c(Br)c1)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
(S)-3-(3-Bromo-4-{2-(tert-butyl-diphenyl-silanyloxy)-1-[4-(3,4-dichloro-benzyloxy)-phenyl]-ethoxy}-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (5.0 g) was dissolved in 10 mL of anhydrous THF. TBAF (6 mL, 1.0 M solution in THF) was added drop-wise to the reaction mixture. After 2 h, the reaction mixture was concentrated to obtain a light brown oil. The oil was purified by silica gel chromatography (ethyl acetate/hexanes) to obtain the desired product as a white fluffy solid. 1H NMR (400 MHz, CDCl3): 7.51 (d, 1H), 7.43 (d, 1H), 7.3 (m, 3H), 7.23 (m, 2H), 6.92 (d, 2H), 6.84 (m, 1H), 6.62 (d, 1H), 5.17 (m, 1H), 4.99 (s, 1H), 4.93 (m, 1H), 4.48 (m, 1H), 3.94 (m, 1H), 3.76 (m, 1H), 3.66 (s, 3H), 2.84-3.02 (m, 2H), 2.47 (m, 1H), 1.41 (s, 9H). LCMS: 669.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C([O:13][C:14]([C:16]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[C:23]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:22]=2)=[C:19]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:18][C:17]=1[CH:41]([CH3:43])[CH3:42])=O)C.CC(C[AlH]CC(C)C)C.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.O>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:16]([CH2:14][OH:13])=[C:17]([CH:41]([CH3:43])[CH3:42])[O:18][C:19]=2[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:22][C:23]=1[O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1c(C(C)C)oc(-c2ccccc2)c1-c1ccc(F)c(Oc2ccccc2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1oc(-c2ccccc2)c(-c2ccc(F)c(Oc3ccccc3)c2)c1CO
Temperature: -70 °C
Reaction time: 1 h

Procedure:
70 ml (84 mmol) of a 1.2M diisobutylaluminum hydride solution in toluene are slowly added dropwise at -78° C. under an argon atmosphere to a solution of 31 g (70 mmol) of the compound from Example 23 in 350 ml of anhydrous toluene in such a way that the temperature does not exceed -65° C. After stirring for 1 hour at -70° C., a further 58 ml (70 mmol) of DIBAH solution are added and the mixture is stirred for 1 more hour. 240 ml of 1N hydrochloric acid are then added dropwise at about -30° C. and finally 400 ml of water and 200 ml of ethyl acetate are added, as a result of which the mixture warms to room temperature. The aqueous phase is extracted 3 times with 250 ml of ethyl acetate, and the washed organic phases are washed with 400 ml of water and 400 ml of saturated sodium chloride solution and dried over sodium sulphate. The solvent is removed and the residue is dried under high vacuum.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>CC(C)=O.C(Cl)Cl.CCOCC>[CH:2]([C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:7][CH:8]=1)=[O:1]
Reactant: NS(=O)(=O)c1ccc(CO)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CCOCC
Product: NS(=O)(=O)c1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
To a solution of 4-(hydroxymethyl)benzenesulfonamide (Step 3) (3.75 g, 20 mmol) in a mixture of acetone (250 ml) and methylene chloride (250 ml), pyridinium chlorochromate (6.47 g, 30 mmol) was added. After stirring at room temperature for 5 hours, the reaction mixture was diluted with ether and filtered through a short silica gel column. The column was eluted with hexane/ethyl acetate, (1/1). The fractions containing the desired material were combined and concentrated to give a white solid (2.0 g, 53%): mp 104-106° C. Anal Calc'd. for C7H7NSO3 : C, 45.40; H, 3.81; N, 7.56; S, 17.31. Found: C, 45.61; H, 3.59; N, 7.18; S, 16.27.