Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[C:5]([NH:11]S(C2C=CC(C)=CC=2)(=O)=O)=[C:4]([CH:22]([CH3:24])[CH3:23])[CH:3]=1.Br[CH2:26][CH2:27][O:28][CH2:29][CH2:30]Br.C(N(CC)C(C)C)(C)C.CN1CCCC1>C(OCC)(=O)C>[CH:22]([C:4]1[CH:3]=[C:2]([N:1]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[C:5]=1[NH2:11])([CH3:23])[CH3:24]
Reactant: BrCCOCCBr
Reactant: Cc1ccc(S(=O)(=O)Nc2c(C(C)C)cc(N)cc2C(C)C)cc1
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)c1cc(N2CCOCC2)cc(C(C)C)c1N
Temperature: 180 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A mixture of N-(4-amino-2,6-diisopropyl-phenyl)-4-methyl-benzenesulfonamide (346 mg), bis-(2-bromoethyl)ether (151 μL), N,N-diisopropyl-ethylamine (0.53 mL) and N-methylpyrrolidine (1.0 mL) was heated to 180° C. for 20 minutes in a sealed microwave process vial. The mixture was diluted with ethyl acetate (20 mL), washed with brine (30 mL) and saturated aqueous potassium carbonate (30 mL) and dried over sodium sulfate. The organic phase was concentrated in vacuo and redissolved in a mixture of sulfuric acid (1.9 mL) and water (0.1 mL) and stirred at 40° C. for 3 hours. Ice (30 mL) and water (30 mL) were added and the mixture was basified with solid potassium carbonate. The mixture was extracted with ethyl acetate (3×20 mL) and the combined organic phases were dried over sodium sulfate and concentrated in vacuo to furnish 260 mg (99%) of the title compound as a while solid. 1H NMR (500 MHz, CDCl3): 1.26 (d, 12H), 2.95 (m, 2H), 3.06 (m, 4H), 3.49 (b, 2H), 3.87 (m, 4H), 6.69 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[C:5]([Cl:18])=[CH:4][C:3]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[CH:27]=[CH2:28]>CC(C)=O>[CH2:28]([O:19][C:3]1[CH:4]=[C:5]([Cl:18])[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH3:17])=[CH:13][CH:14]=2)=[CH:7][C:2]=1[Br:1])[CH:27]=[CH2:26]
Reactant: C=CCBr
Reactant: CCOc1ccc(Cc2cc(Br)c(O)cc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1Br
Temperature: 65 °C
Yield: 94.5 %

Procedure:
To a solution of 2-Bromo-5-chloro-4-(4-ethoxybenzyl)phenol (7, 55 mmol) in acetone (180 mL) were added potassium carbonate (15.2 g, 110 mmol) and allyl bromide (7 mL, 83 mmol) and heated at 65° C. for 3 h. The insoluble material was removed by filter and the filtrate was evaporated under reduced pressure. The crude residue was purified on Biotage® purification apparatus (silica gel, 3 to 10% ethyl acetate in hexanes) to yield the title compound (21 g, 52 mmol, 95%) as colorless oil.
Reaction SMILES: [CH2:1]([NH2:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:8]1([C:14]2[N:15]=[C:16]([C:26](O)=[O:27])[N:17]([CH3:25])[C:18]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:1]([NH:7][C:26]([C:16]1[N:17]([CH3:25])[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:15]=1)=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN
Reactant: Cn1c(C(=O)O)nc(-c2ccccc2)c1-c1ccccc1
Product: CCCCCCNC(=O)c1nc(-c2ccccc2)c(-c2ccccc2)n1C

Procedure:
Using essentially the same procedure as Example 4, Step B, but using n-hexylamine (0.025 mL), 4,5-diphenyl-1-methylimidazole-2-carboxylic acid (30 mg, 0.10 mmol) from Example 4, Step A was converted to the title compound.
Reaction SMILES: O1C[CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:47])([F:46])[F:45])[CH:39]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)[CH2:3][CH2:2]1.[CH3:49][O:50][CH:51]1CCNC[CH2:52]1>C(N(CC)CC)C>[CH3:49][O:50][CH:51]1[CH2:52][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[CH2:19][S:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:15])=[C:9]([C:29]3[CH:34]=[C:33]([C:35](=[O:48])[NH:36][CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[C:40]([C:44]([F:45])([F:46])[F:47])[CH:39]=4)[CH:32]=[CH:31][N:30]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)CCSCc1cccc(C(=O)Nc2ccc(N3CCOCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: COC1CCNCC1
Solvent: CCN(CC)CC
Product: COC1CCN(c2ccc(NC(=O)c3cccc(CSCCC(=O)O)c3)c(-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1

Procedure:
This compound was prepared according to the procedure described for the synthesis of 3-((3-((4-morpholino-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)-carbamoyl)benzyl)thio)propanoic acid 14, using 4-methoxypiperidine in place of morpholine and using triethylamine in place of potassium carbonate in the nucleophilic aromatic substitution step. 1H-NMR (300 MHz, CD3OD, ppm) δ 8.98 (d, J=4.1 Hz, 1H), 8.47 (d, J=9 Hz, 1H) 8.33 (s, 1H), 7.94 (s, 1H), 7.84 (m, 2H), 7.72-7.46 (m, 7H), 7.38 (d, J=7.5 Hz, 1H), 4.71 (s, 3H), 3.89 (s, 2H), 3.72 (m, 2H), 3.55 (m, 1H), 3.33 (s, 3H), 3.26 (m, 2H), 2.74 (t, 2H), 2.56 (t, 2H), 2.20 (m, 2H), 1.88 (m, 2H). MS (ES, m/z): 707 [M+H]+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:7]>C(Cl)Cl>[OH:2][CH2:1][CH2:3][NH:4][C:6](=[O:7])[O:8][CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)COC(=O)Cl
Reactant: NCCO
Solvent: ClCCl
Product: CC(C)COC(=O)NCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
42.8 g of ethanolamine are placed in 350 ml of methylene chloride. 47.8 g of isobutyl chloroformate are then added dropwise during 1 hour at 5°-15° C. while cooling with ice. After stirring at room temperature for a further 4 hours, the methylene chloride is removed by evaporation and the residue is distilled. There is obtained pure isobutyl 2-hydroxyethylcarbamate; b.p. 111°-113° C./0.07 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6](=[O:12])[C:5]2([NH:20][C:21](=[O:30])[CH2:22][N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[H-].[Na+].[C:33]1([C:39](Cl)=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C=O)C>[C:39]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[C:10]([Cl:11])[CH:9]=2)[C:5]([NH:20][C:21](=[O:30])[CH2:22][N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:6]1=[O:12])(=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCN(CC(=O)NC2(c3ccc(Cl)cc3)C(=O)Nc3cc(Cl)c(Cl)cc32)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(CC(=O)NC2(c3ccc(Cl)cc3)C(=O)N(C(=O)c3ccccc3)c3cc(Cl)c(Cl)cc32)CC1

Procedure:
0.14 g of the compound of Example 1 is placed in 9 ml of DMF in a round-bottomed flask equipped with a magnetic stirrer, and under a stream of nitrogen. 0.01 g of 60% NaH is added, at 0° C. PhCOCl is then added dropwise and the mixture is left to react at room temperature for 2 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. 120 mg of oil are obtained, which product is purified on a column by flash chromatography, eluting with 95/5 ethyl acetate/methanol, to isolate 20 mg of white solid.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C:30]([O:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:19]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)OCc3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.5 h

Procedure:
To a stirred solution of dehydroepiandrosterone (2.88 g, 10 mmol) in methylene chloride (100 mL) is added dropwise benzylchloroformate, over a period of 30 min following the known procedure (F. Reber and T. Reichstein, Helv. Chim. Acta, 28, 1164, 1945). After stirring for 3 h, the mixture is washed with water and evaporated to dryness. The residue is then dissolved in acetone and precipitated in iced water. After 16 h, crystals are filtered and dried in vacuo.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]([OH:15])=O)=[O:7])=[CH:2]1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:41]1([CH2:47][C:48]2[CH:49]=[C:50]([CH:57]=[CH:58][CH:59]=2)[O:51][CH2:52]/[CH:53]=[CH:54]\[CH2:55][NH2:56])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>ClCCl>[N:41]1([CH2:47][C:48]2[CH:49]=[C:50]([CH:57]=[CH:58][CH:59]=2)[O:51][CH2:52]/[CH:53]=[CH:54]\[CH2:55][NH:56][C:13](=[O:15])[CH2:12][S:11][CH2:10][CH2:9][NH:8][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[O:7])[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1
Reactant: NC/C=C\COc1cccc(CN2CCCCC2)c1
Reactant: O=C(O)CSCCNC(=O)c1ccoc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(CSCCNC(=O)c1ccoc1)NC/C=C\COc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
There was suspended 3.52 g (0.0154 mol) of 2-[(3-furoylamino)ethylthio]acetic acid in 80 ml of dichloromethane and added 2.36 g (0.0154 mol) of HOBt and 3.17 g (0.0154 mol) of DCC under cooling with ice, and the mixture was stirred for 30 minutes under cooling with ice. Thereto was added 4.0 g (0.0138 mol) of 4-[3-(piperidinomethyl)phenoxy]-cis-2-butenylamine, and the mixture was stirred for 12 hours at room temperature. The precipitate was filtrated off, and the filtrate was washed with 10% aqueous solution of sodium hydroxide and with water and dried over Glauber's salt. Then the solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give 2.9 g of the titled compound as oily matter.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39](Cl)(=[O:41])=[O:40].N1C=CC=CC=1>ClCCl>[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[S:39]([NH:8][C:7]1[CH:6]=[CH:5][C:4]([F:9])=[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)[C:2]=1[F:1])(=[O:41])=[O:40]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccccc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. 2-chloro benzene-1-sulfonyl chloride (15 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16](Cl)[N:15]=[C:14]([N:19]([CH3:21])[CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:22][NH2:23]>C(O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([NH:23][CH3:22])[N:15]=[C:14]([N:19]([CH3:21])[CH3:20])[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CN(C)c1nc(Cl)cc(NS(=O)(=O)c2ccc(N)cc2)n1
Reactant: CN
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2ccc(N)cc2)nc(N(C)C)n1
Temperature: 130 °C
Reaction time: 4 h
Yield: 20.3 %

Procedure:
0.50 g (0.00153 mol) of 4-amino-N-(2-dimethylamino-6-chloro-pyrimidin-4-yl)-benzenesulfonamide were dissolved in 20 ml (0.176 mol) of 8M methylamine in ethanol and stirred in an autoclave at 130° C. for 4 hours. The reaction mixture was freed from solvent and the residue was chromatographed on silica gel with methanol/dichloromethane 1:19. There was obtained 0.10 g (21%) of 4-amino-N-(2-dimethylamino-6-methylamino-pyrimidin-4-yl)-benzenesulfonamide as beige crystals; m.p: 253-254° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[CH:6][CH:7]=1.[N:29]#[C:30]Br.[OH-].[Na+]>ClCCl.CO>[I:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[C:30]([NH2:29])=[N:28][C:4]=2[CH:3]=1
Reactant: COc1ccc(COc2ccc(CNc3ccc(I)cc3N)cc2OC)cc1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(COc2ccc(Cn3c(N)nc4cc(I)ccc43)cc2OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a stirred suspension of 4-iodo-N1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)benzene-1,2-diamine (8.32 g, 16.97 mmol) in dichloromethane (100 mL) and methanol (50 mL) was added cyanogen bromide solution (5.0 M in acetonitrile, 17.0 mL, 85.00 mmol). The resulting brown reaction mixture was allowed to stir at room temperature. After 16 h, the mixture was treated with 1 N sodium hydroxide solution (250 mL) and was allowed to stir at room temperature. After 15 min, a precipitate formed. The solids were isolated by filtration, washed with water, and dried to afford 4.42 g (51%) of 5-iodo-1-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)-1H-benzo[d]imidazol-2-amine as a tan solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH2:7])[CH3:3].C(N(CC)CC)C.Br[CH2:18][C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:28]>C(O)C>[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH:7][CH2:18][C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:28])[CH3:3]
Reactant: O=[N+]([O-])c1cccc(Cl)c1CBr
Reactant: CCOC(=O)[C@H](C)N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](C)NCc1c(Cl)cccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
18.24 g of L-alanine ethyl ester hydrochloride in 60 ml of ethanol was added dropwise to a mixture of 25 ml of triethylamine in 60 ml of ethanol and the mixture was heated to 80° C. The resulting solution was added dropwise at this temperature to a solution of 15 g of α-bromo-2-chloro-6-nitrotoluene in 60 ml of ethanol. The mixture was stirred at 80° C. overnight and then evaporated to dryness. The residue was treated with 150 ml of deionised water and extracted twice with 100 ml of methylene chloride. The methylene chloride extracts were washed with water, dried and evaporated. The resulting product was purified by chromatography on silica gel with methylene chloride/5% methanol. There were obtained 15.75 g (91% of theory) of N-(2-chloro-6-nitrobenzyl)-L-alanine ethyl ester; nD20 =1.5267.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]([C:18]4[O:19][CH:20]=[CH:21][CH:22]=4)=[CH:16][C:15]([C:23](O)=[O:24])=[N:14]3)[CH:8]=2)=[CH:4][CH:3]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][C:34]2=[O:39])=[CH:29][CH:28]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC>[O:39]=[C:34]1[CH2:35][O:36][CH2:37][CH2:38][N:33]1[C:30]1[CH:29]=[CH:28][C:27]([NH:26][C:23]([C:15]2[CH:16]=[C:17]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[N:14]=2)=[O:24])=[CH:32][CH:31]=1
Reactant: O=C(O)c1cc(-c2ccco2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)c1cc(-c2ccco2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Reaction time: 16 h

Procedure:
To 100 mg 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-furan-2-yl-1H -pyrazole-3-carboxylic acid in 2 ml DCM and 0.1 ml NEt3, 62 mg 4-(4-Amino-phenyl)-morpholin-3-one and 67 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. The mixture was was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1)=[N+]=[N-].[H][H]>[Pd].CCO>[NH2:1][CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][N:6]=1
Reactant: [N-]=[N+]=NCc1n[nH]c2ncccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: NCc1n[nH]c2ncccc12
Reaction time: 2 h

Procedure:
A mixture of 286 mg (1.64 mmol) of 1-2 and 35 mg of 10% palladium on carbon catalyst in 2 mL of absolute EtOH was hydrogentated at 1 atmosphere pressure using a hydrogen filled balloon. After approximately 2 hours, the reaction was determined to be complete by LC-MS analysis. The reaction was filtered through a Celite pad, and the filtrate concentrated in vacuo to give the title product as a pale yellow oil. MS M+1=149.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9]1([O:15][CH2:14][CH2:13][O:12]1)[CH2:8][CH2:7]2.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.CC(C)([O-])C.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.N>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[CH2:10][C:9]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:8][CH2:7]3)[CH2:19][CH2:18]1
Reactant: Brc1cccc2c1CC1(CC2)OCCO1
Reactant: CN1CCNCC1
Agent: CC(C)(C)[O-]
Agent: N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN1CCN(c2cccc3c2CC2(CC3)OCCO2)CC1
Temperature: 85 °C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
8′-Bromo-3′,4′-dihydrospiro-[1,3-dioxolane-2,2′(1H)-naphthalene] (6.0 g, 22 mmol; described in Sunkyung L.; Stewart P. F.; David E. N. Synth. Commun. 1995, 25(18), 2775-2780) was dissolved in toluene (180 mL) and flushed with argon. N-Methylpiperazine (3.0 mL, 27 mmol), R(+)-bis(diphenylphosphino)-1,1′-binaphthyl (830 mg, 1.3 mmol), tetrakis(dibenzylideneacetone)dipalladium (0) (510 mg, 0.45 mmol) and sodium t-butoxide (3.0 g, 31 mmol) were added and the reaction mixture was stirred at 85° C. for 2.5 h. After cooling to room temperature ethyl acetate (400 mL) and 2 M ammonia (60 mL) were added. The phases were separated and the organic layer was washed with 2 M ammonia (30 mL), brine (40 mL) and dried (MgSO4). Evaporation of the solvent gave 7.5 g of a crude product. Purification by column chromatography on silica using chloroform/methanol/conc. NH3 (180:5:0.5) as eluent afforded 5.5 g (84% yield) of the title compound as a yellowish solid: mp 127-128° C.; EIMS (70 eV) m/z (relative intensity) 288 (43, M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[CH:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[CH3:12])=[CH:4][C:3]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H][H]>CO.[Ni]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)([C:13]([F:16])([F:15])[F:14])[CH3:12])=[CH:4][C:3]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(C(C)(C=CCc2ccc(F)c(Oc3ccccc3)c2)C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: COc1ccc(C(C)(CCCc2ccc(F)c(Oc3ccccc3)c2)C(F)(F)F)cc1
Yield: 61.9 %

Procedure:
1-(4-Fluoro-3-phenoxyphenyl)-4-(4-methoxyphenyl)-4-trifluoromethyl-2-pentene (15.12 g; 37.76 mmol) was hydrogenated in methanol (200 ml) with hydrogen using Raney nickel (5 g) at room temperature and under atmospheric pressure. After the calculated amount of hydrogen had been taken up, the catalyst was filtered off and the solvent removed under reduced pressure. After chromatography on silica gel using ethyl acetate/hexane as eluant, there was obtained a 10.1 g of product (=61.8% of theory).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([NH:24][C:25]([C:27]3[N:28]=[C:29]([CH3:32])[S:30][CH:31]=3)=[O:26])[C:12]3[C:16]([CH:17]=2)=[N:15][N:14](C2CCCCO2)[CH:13]=3)[CH:5]=[N:6][C:7]=1[Cl:8].[CH3:33][C:34]1[CH:35]=[CH:36][C:37]([O:44][CH3:45])=[C:38]([S:40](Cl)(=[O:42])=[O:41])[CH:39]=1.Cl>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:8][C:7]1[N:6]=[CH:5][C:4]([C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[C:11]([NH:24][C:25]([C:27]3[N:28]=[C:29]([CH3:32])[S:30][CH:31]=3)=[O:26])[CH:10]=2)=[CH:3][C:2]=1[NH:1][S:40]([C:38]1[CH:39]=[C:34]([CH3:33])[CH:35]=[CH:36][C:37]=1[O:44][CH3:45])(=[O:42])=[O:41]
Reactant: Cc1nc(C(=O)Nc2cc(-c3cnc(Cl)c(N)c3)cc3nn(C4CCCCO4)cc23)cs1
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(C)cc1S(=O)(=O)Nc1cc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)cnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
N-[6-(5-Amino-6-chloro-3-pyridinyl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl]-2-methyl-1,3-thiazole-4-carboxamide (50 mg) was dissolved in pyridine (1 ml) and 5-methyl-2-(methyloxy)benzenesulfonyl chloride (35 mg) was added. The reaction was stirred at RT overnight. Further 5-methyl-2-(methyloxy)benzenesulfonyl chloride (35 mg) was added and the reaction was stirred at RT for 4 h. DMAP (3 mg) followed by 5-methyl-2-(methyloxy)benzenesulfonyl chloride (20 mg) was added and the reaction was stirred at RT overnight. The reaction was neutralised with 2M HCl (aq) and extracted into DCM. The DCM was evaporated and the residue was dissolved in DMSO:methanol (1 ml, 8:1, v/v) and purified by MDAP (method E). The desired fraction was evaporated to dryness and methanol (3 ml) and a few drops of 2M HCl (aq) were added and the reaction stirred for 2 h. The reaction was evaporated to dryness to give title compound (39 mg).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19](C)[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:24](O)(=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30]>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:10]2[CH2:15][CH2:14][N:13]([C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:12][CH2:11]2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:4][CH:3]=1
Reactant: O=C(O)CCCCC(=O)O
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Product: O=C(O)CCCCC(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (G) using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and adipic acid.