Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].CO>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H]1C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 205.5 %

Procedure:
A cooled (0° C.) solution of 30A (15.0 g, 64.8 mmol) and imidazole (22.0 g, 324 mmol) in dry DMF (110 ml) was treated with tert-butyldimethylsilyl chloride (24.3 g, 162 mmol), warmed to RT and stirred for 24 h. The reaction mixture was treated with methanol (150 ml), stirred at RT for another 24 h then partitioned between 10% aqueous citric acid (225 ml) and EtOAc (3×1.0 L). The extracts were washed with brine (200 ml), dried (Na2SO4) and filtered. The filtrate was concentrated to dryness to give a thick colorless syrup (46.0 g). Purification of a portion (20 g) by using automated flash chromatography (135 g silica gel column, EtOAc/hexane gradient) gave the title compound as a thick clear syrup (9.7 g, 99.7%).
Reaction SMILES: [CH2:1]([S:13]([OH:16])(=[O:15])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:17][C:18]([N:20]([OH:55])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([CH2:29][CH2:30][C:31]([N:33]([OH:54])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([CH2:42][CH2:43][C:44]([N:46]([OH:53])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH2:52])=[O:45])=[O:41])=[O:32])=[O:28])=[O:19]>>[CH2:1]([S:13]([O-:16])(=[O:14])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:17][C:18]([N:20]([OH:55])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27]([CH2:29][CH2:30][C:31]([N:33]([OH:54])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][NH:39][C:40]([CH2:42][CH2:43][C:44]([N:46]([OH:53])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][NH2:52])=[O:45])=[O:41])=[O:32])=[O:28])=[O:19]
Reactant: CCCCCCCCCCCCS(=O)(=O)O
Agent: CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN
Product: CCCCCCCCCCCCS(=O)(=O)[O-]

Procedure:
Following a procedure analogous to that of Example 1, dodecane-1-sulphonic acid and desferrioxamine-B are reacted to give the dodecane-1-sulphonate salt of desferrioxamine-B, Mp 151° C. C37H74O11N6S Calcd C: 54.79%, H: 9.20%, N: 10.36%, S: 3.95%; Found C: 54.74%, H: 9.15%, N: 10.21%, S: 4.07%.
Reaction SMILES: [C:1]([NH:14][C@H:15]([C:17]([OH:19])=[O:18])[CH3:16])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:20]([CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:29]O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>>[CH2:20]([CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:29][O:18][C:17](=[O:19])[C@H:15]([CH3:16])[NH:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCC(=O)N[C@@H](C)C(=O)O
Reactant: CCCCCCCCCCC(CO)CCCCCCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCCCCCCCC(=O)N[C@@H](C)C(=O)OCC(CCCCCCCC)CCCCCCCCCC
Temperature: 130 °C
Yield: 91.1 %

Procedure:
N-Lauroylalanine (10 g) and 9.5 g of 2-octyldodecanol were charged in a 200-ml flask, and thereto was added 0.5 g of p-toluenesulfonic acid as the catalyst. The mixture was maintained at 130° C. for 3 hours for reaction. To the reaction mixture was added about 200 ml of a aqueous saturated solution of sodium hydrogen carbonate, and the resulting aqueous layer was removed. The oily layer was further washed with water. The extracted oily layer was well dried by adding 5 g of anhydrous magnesium sulfate thereto, and the magnesium sulfate was then filtered off to give 16 g (yield: 82%) of a liquid product.
Reaction SMILES: Br[C:2]1[C:13]2[CH2:12][C:11]([CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:10][C:9]=2[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH2:6]2.[C:21]([C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O.C1(C)C=CC=CC=1>[C:21]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:13]3[CH2:12][C:11]([CH2:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)=[CH:10][C:9]=3[CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][CH2:6]3)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Brc1c2c(cc3c1CCC3)C=C(CC1CCCCC1)C2
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(-c2c3c(cc4c2CCC4)C=C(CC2CCCCC2)C3)cc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
In argon atmosphere, a mixture of 34.6 g (105 mmol) of 4-bromo-6-(cyclohexylmethyl)-1,2,3,5-tetrahydro-s-indacene, 22.4 g (126 mmol) 4-tert-butylphenylboronic acid, 66.8 g (315 mmol) of K3PO4, 1.21 g (21 mmol) of Pd(dba)2, 1.73 g (42 mmol) of dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine and 350 ml of toluene was stirred for 12 h at 100° C. The resulting mixture was cooled to room temperature, and then 600 ml of water was added. The organic layer was separated, and the aqueous layer was extracted with 3×100 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and then evaporated to dryness. The target product was isolated by flash chromatography on silica gel 60 (40-63 um; eluent: hexanes). Yield 24.0 g (62%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:20]([NH2:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21].C(N(CC)CC)C.C([BH3-])#N.[Na+]>ClCCl.C(OCC)(=O)C.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(O)C>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:29][C:20]([CH3:22])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH3:21])=[CH:13][CH:14]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(NC(C)(C)c2ccccc2)c2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38 %

Procedure:
2.57 g of 4-methoxyphenyl 3-nitrophenyl ketone, 1.35 g of cumyl amine and 1.35 g of triethylamine were dissolved in 50 ml of dichloromethane, and then 30 ml of a solution of 1.65 ml of titanium tetrachloride in dichloromethane was added dropwise whilst ice cooling. The reaction mixture was stirred at room temperature for 2 hours and was then heated under reflux for 3 hours. The reaction mixture was allowed to cool, after which it was diluted with 150 ml of ethyl acetate. The insoluble matter was then filtered off. The filtrate was washed with a saturated solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. Following a similar reaction, separation and purification procedure to that described in Example (1a), the resulting brown oil, 100 ml of ethanol 2.51 g of sodium cyanoborohydride and 2.58 ml of acetic acid were reacted, to obtain 1.43 g of the title compound as a yellow oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1>O1CCCC1>[N+:1]([C:11]1[CH:12]=[C:7]([O:6][CH3:5])[CH:8]=[CH:9][C:10]=1[OH:13])([O-:4])=[O:2]
Reactant: COc1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: C1CCOC1
Product: COc1ccc(O)c([N+](=O)[O-])c1

Procedure:
6.3 9 of nitric acid were added dropwise at room temperature with stirring to 12.4 g of 4-methoxyphenol in 120 ml of tetrahydrofuran. The reaction mixture was then stirred for half an hour. The solvent was subsequently evaporated and the residue remaining was purified by chromatography using dichloromethane as an eluent. 6.2 g of 2-nitro-4-methoxyphenol were obtained as a yellow powder having a melting point of 72° C.
Reaction SMILES: [OH:1][CH2:2][C:3]12[CH2:10][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH:2]([C:3]12[CH2:10][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])([CH2:8][CH2:9]1)[CH2:6][CH2:5][CH2:4]2)=[O:1]
Reactant: CC(C)(C)OC(=O)NC12CCCC(CO)(CC1)C2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC12CCCC(C=O)(CC1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
To a stirred solution of tert-butyl 5-(hydroxymethyl)bicyclo[3.2.1]octan-1-ylcarbamate (7.0 g, 24.8 mmol) in DCM (50 mL) was added PCC (8.0 g, 37.2 mmol) in portions under N2 and the reaction mixture was stirred at room temperature for two hours. The mixture was filtered through a pad of silica gel and the filtrate was concentrated under reduced pressure to give 6.44 g (92%) of the crude title compound, tert-butyl 5-formylbicyclo[3.2.1]octan-1-ylcarbamate, as a brown oil, which was used in the next step without further purification. ESI-MS m/z: 198 (M-55)+.
Reaction SMILES: [CH2:1]([C:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12](N(OC)C)=[O:13])[O:7][CH2:6][CH2:5][O:4]1)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:24]1COCC1>>[CH2:1]([C:3]1([CH:8]([CH3:24])[CH2:9][CH2:10][CH2:11][CH:12]=[O:13])[O:4][CH2:5][CH2:6][O:7]1)[CH3:2]
Reactant: CCC1(CCCCC(=O)N(C)OC)OCCO1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCC1(C(C)CCCC=O)OCCO1
Temperature: 25 °C

Procedure:
To a stirred mixture of 5-(2-ethyl-1,3-dioxolan-2-yl)-N-methoxy-N-methyl-pentanamide (1 eq.) [Prepared by coupling 7-oxononanoic acid with N, O-dimethylhydroxylamine and subsequent ketal protection] in anhydrous THF at −78° C. was added a 1 M LiAlH4 solution in THF (1.6 eq.) slowly over 5 min. After 45 min the reaction was quenched by addition of Et2O and then aq. Rochelle's salt solution (10% w/v). The mixture was warmed to RT with a vigourous stirring. The organic phase was separated, washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by column chromatography eluting with 5% EtOAc/Petroleum ether to afford the desired aldehyde. 1H NMR (300 MHz, CD3CN) δ: 9.77 (1H, s), 4.00 (4H, s), 2.44 (2H, t, J=7.0 Hz), 1.75-1.48 (6H, m), 1.46-1.25 (4H, m), 1.00-0.80 (3H, t, J=7.0 Hz).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([CH2:16][C:17]#[N:18])[C:9]=2[CH3:19])[CH2:5][C:4](=[O:20])[C:3]=1[C:21](=[O:24])[CH2:22][CH3:23].C(N)(=[S:27])C.Cl>>[OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([CH2:16][C:17](=[S:27])[NH2:18])[C:9]=2[CH3:19])[CH2:5][C:4](=[O:20])[C:3]=1[C:21](=[O:24])[CH2:22][CH3:23]
Reactant: CC(N)=S
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CC#N)c2C)CC1=O
Agent: Cl
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CC(N)=S)c2C)CC1=O

Procedure:
A solution of 3-hydroxy-2-propionyl-5-(3-cyanomethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (0.77 g, 2.37 mmol) and thioacetamide (0.36 g, 4.74 mmol) in dmf (10 ml) was saturated with anhydrous hydrogen chloride. The solutuion was then heated under a distillation head at 110° for 45 m. Most of the dmf was then distilled off under reduced pressure. The dark red residue was cooled, saturated sodium bicarbonate solution was added, and the aqueous layer extracted with ethylacetate. The organic layer was washed extensively with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield an orange solid. The crude material was purified by chromatography on silica gel (elution with an increasing gradient of ethylacetate in methylene chloride) to give 3-hydroxy-2-propionyl-5-(3-thiocarbamoylmethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one as a colourless solid (0.40, 47%). Proton magnetic resonance spectrum (CDCl3 ; δ in ppm); 1.15 (3H, t); 2.22 (3H,s); 2.28 (3H,s); 2.36 (3H,s); 2.4-4.2 (9H,m); 6.70 (1H,brs); 6.90 (1H,s); 8.25 (1H,brs); 18.20 (1H,s).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:8])=[C:5]([OH:20])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29](=[O:31])[CH3:30].O>CN(C=O)C>[NH2:2][C:3]1[C:18]([Cl:19])=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[CH2:15][CH3:16])=[O:8])=[C:5]([O:20][CH2:28][C:29](=[O:31])[CH3:30])[CH:4]=1
Reactant: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1O
Reactant: CC(=O)CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCNC(=O)c1cc(Cl)c(N)cc1OCC(C)=O
Reaction time: 5 h
Yield: 76.1 %

Procedure:
To a stirred suspension of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (5.0 g, 16 mmoles) and potassium carbonate (10.62 g, 77 mmoles) in DMF (25 ml) was added chloroacetone (2.32 g of 90%, 22 mmoles) and the mixture stirred vigorously for 5 hours, followed by pouring into water (130 ml) and filtration to give, after drying, 4.57 g of crude product. This was dissolved in methylene chloride and filtered over a short alumina column, followed by concentration and recrystallization of the residue from toluene to give 4.16 g (78%) of the title compound as white solid, mp 105°-106.5°. The NMR (90 MHz) in CDCl3 gave the following resonances: ε 8.44 (s, 1H); 8.24 (s, 1H); 6.16 (s, 1H); 4.72 (s, 2H); 4.4 (s, 2H); 3.6 (m, 2H); 2.68 (m, 6 H); 2.28 (s, 3H); 1.08 (t, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14](O)(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([F:18])[CH:3]=1.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:33])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([S:14]([Cl:33])(=[O:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:4]([F:18])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccccc1-c1ccc(Br)cc1F
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccccc1-c1ccc(Br)cc1F

Procedure:
4′-Bromo-2′-fluorobiphenyl sulfonic acid (5 g) was refluxed in thionyl chloride (30 mL) with a catalytic quantity of DMF (0.5 mL) for 4 hours. Toluene was added and the solvents evaporated under vacuum. The residue collected was recrystallised from petrol/ethyl acetate to give white crystals.
Reaction SMILES: [C:1]1(=[O:8])[NH:6][C:5](=[O:7])[CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CC(C)=O.[N+](CCCC)(CCCC)(CCCC)CCCC.[I-]>[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:6]2[C:5](=[O:7])[CH2:4][CH2:3][CH2:2][C:1]2=[O:8])=[CH:19][CH:18]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CCCC(=O)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: COc1ccc(CN2C(=O)CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.2 %

Procedure:
Glutarimide (5 g, 44.2 mmol) was suspended in acetone (Volume: 100 mL) and then K2CO3 (12.22 g, 88 mmol), Bu4NI (3.27 g, 8.84 mmol) and 4-methoxybenzyl chloride (6.02 mL, 44.2 mmol) were added. The mixture was agitated at room temperature overnight and filtered through celite and then concentrated in vacuo and the residue purified by flash chromatography (0-50% EtOAc/heptane) to afford 8.99 g of the desired product as a colorless solid. LCMS (m/z): (MH+), 234.2, 0.66 min.
Reaction SMILES: [CH3:1][C:2]1([NH2:15])[CH2:14][C:5]2=[CH:6][C:7]3[CH2:8]CC[CH2:11][C:12]=3[CH:13]=[C:4]2[CH2:3]1>CC1C=CC=CC=1C>[CH3:1][C:2]1([NH2:15])[CH2:14][C:5]2[C:4](=[CH:13][C:12]([CH3:11])=[C:7]([CH3:8])[CH:6]=2)[CH2:3]1
Reactant: CC1(N)Cc2cc3c(cc2C1)CCCC3
Solvent: Cc1ccccc1C
Product: Cc1cc2c(cc1C)CC(C)(N)C2

Procedure:
2,5,6-Trimethyl-indan-2-ylamine is prepared from 1,2-dimethylbenzene by procedures analogous to those used for 2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-ylamine.
Reaction SMILES: Br[C:2]1[C:7]([NH2:8])=[C:6]([Br:9])[CH:5]=[C:4]([CH2:10][CH3:11])[N:3]=1.[S-:12][CH2:13][CH3:14].[Na+].O>CN(C=O)C>[Br:9][C:6]1[CH:5]=[C:4]([CH2:10][CH3:11])[N:3]=[C:2]([S:12][CH2:13][CH3:14])[C:7]=1[NH2:8]
Reactant: CC[S-]
Reactant: CCc1cc(Br)c(N)c(Br)n1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc(CC)cc(Br)c1N
Temperature: 50 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
2,4-Dibromo-6-ethyl-pyridin-3-ylamine (105 mg, 0.38 mmoles) was combined with 80% sodium thioethoxide (50 mg, 0.48 mmoles) in anhydrous DMF (2 mL) and was stirred at 50° C. under nitrogen for 2 hours. After this period the reaction mix was combined with water (20 mL) and was extracted with EtOAc (3×20 mL). The combined EtOAc layer was washed with water (3×1 5 mL) and brine. After drying over anhydrous Na2SO4 the organic layer was evaporated in vacuo to yield crude product. The crude product was purified using flash silica chromatography (0-15% EtOAc/Hexane) to yield 4-bromo-6-ethyl-2-ethylsulfanyl-pyridin-3-ylamine (83 mg, 84%) as a clear residue. 1H-NMR (CDCl3): δ 6.94 (s, 1H), 4.34 (br s, 2H), 2.95 (q, J=7.3 Hz, 2H), 2.68 (q, J=7.6 Hz, 2H), 1.33 (t, J=7.3 Hz, 3H), 1.24 (t, J=7.6 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([F:35])[S:9]([N:12](CC2C=CC(OC)=CC=2OC)CC2C=CC(OC)=CC=2OC)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.C[Li].[CH3:38][C:39]([CH3:41])=[O:40].FC(F)(F)C(O)=O>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:35])([S:9]([NH2:12])(=[O:10])=[O:11])[C:39]([OH:40])([CH3:41])[CH3:38])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2OC)S(=O)(=O)C(F)c2cccc(Br)c2)c(OC)c1
Agent: [Li]C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)C(F)(c1cccc(Br)c1)S(N)(=O)=O
Reaction time: 0.17 h

Procedure:
Under inert gas, 310 mg of C-(3-bromophenyl)-N,N-bis(2,4-dimethoxybenzyl)-C-fluoromethanesulfonamide were initially charged in 10 ml of THF, and then, at a temperature of −78° C., 0.68 ml of a 1.6 N methyllithium solution in diethyl ether were added dropwise and the mixture was stirred at constant temperature for 10 minutes. Subsequently, 0.25 ml of acetone were added. After stirring for 10 minutes, the reaction solution was admixed with 0.10 ml of trifluoroacetic acid, and the reaction mixture was allowed to come to room temperature and concentrated by rotary evaporation. The residue was dissolved in 10 ml of dichloromethane, 1.5 ml of trifluoroacetic acid were added and the mixture was stirred at room temperature for 20 minutes. The reaction solution was freed of the solvent and the crude product was purified by means of normal phase chromatography using a Flashmaster with a dichloromethane/methanol gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (77.9 mg) with a molecular weight of 326.2 g/mol (C10H13BrFNO3S); MS (ESI): m/e=345 (M+H2O+H+).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1.[CH2:23]([N:25]=[C:26]=[O:27])[CH3:24]>O1CCOCC1>[CH2:23]([NH:25][C:26]([NH:1][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:3]=1)=[O:27])[CH3:24]
Reactant: CCN=C=O
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(N)c2s1
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(NC(=O)NCC)c2s1
Temperature: 100 °C

Procedure:
A stirred mixture of 1-(7-Amino-5-pyridin-3-yl-benzothiazol-2-yl)-3-ethyl-urea (15 mg, 0.048 mmol), ethyl isocyanate (0.03 ml) and dibutyltindiacetate (2 drops) in anhydrous 1,4-dioxane (2 ml) was heated in a sealed vessel at 100° C. for 16 h. After cooling to ambient temperature, the 1-Ethyl-3-[2-(3-ethyl-ureido)-5-pyridin-3-yl-benzothiazol-7-yl]-urea was isolated by Preparative HPLC as a white solid (5.4 mg, 29%).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][NH:38][CH:39]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:21]1([CH2:20][CH2:19][O:18][C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:5]3[C:6]4[N:7]([CH:8]=[CH:9][N:10]=4)[C:2]([C:35]4[CH:36]=[N:37][NH:38][CH:39]=4)=[CH:3][N:4]=3)=[CH:13][CH:14]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Brc1cnc(Nc2ccc(OCCN3CCOCC3)cc2)c2nccn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: c1cn2c(-c3cn[nH]c3)cnc(Nc3ccc(OCCN4CCOCC4)cc3)c2n1

Procedure:
In the same way as described for Compound 178, step 4 using (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine (113 mg, 0.27 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (105 mg, 0.541 mmol), 1.5M Na2CO3 (1.44 mL, 2.14 mmol), and Pd(PPh3)4 (0.78 g, 0.67 mmol) in dioxane (4.3 mL). Purification by silica gel column chromatography eluting with 96:4 DCM:NH3 (7M in MeOH) followed by trituration with diethyl ether, affords the title compound as a free base (0.071 g, 65%). LCMS: Rt 1.59 min (100%), m/z (APCI) 406 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm) 2.40-2.60 (4H, m), 2.70-2.73 (2H, t), 3.61-3.63 (4H, m), 4.10 (2H, m), 6.94-6.97 (2H, d), 7.58 (1H, s), 7.74 (1H, s), 7.97 (2H, d), 8.06 (1H, s), 8.13 (1H, s), 8.41 (1H, s), 9.45 (1H, s), 13.41 (1H, br s).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:12][C:11]=2[C:31]([O:33]C)=[O:32])=[CH:6][CH:5]=1.Cl>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:14][C:13](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]4)=[C:19]([O:29][CH3:30])[CH:18]=3)=[N:12][C:11]=2[C:31]([OH:33])=[O:32])=[CH:8][CH:9]=1
Reactant: COC(=O)c1nc(/C=C/c2ccc(-n3cnc(C)c3)c(OC)c2)[nH]c1-c1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(/C=C/c2nc(C(=O)O)c(-c3ccc(F)cc3)[nH]2)ccc1-n1cnc(C)c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 100.5 %

Procedure:
A 2 N sodium hydroxide solution (1 mL) was added to a solution of methyl 5-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-1H-imidazole-4-carboxylate (143 mg) in methanol (1 mL), and the reaction solution was stirred at room temperature for 1.5 hours and at 80° C. for 17 hours. The reaction solution was left to cool to room temperature. Then, 2 N hydrochloric acid (1 mL) was added to the reaction solution, which was then stirred at room temperature for 30 minutes. The solid precipitated from the reaction solution was collected by filtration to obtain 139 mg of the title compound.