Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10].[CH2:11]([NH:18][C@@H:19]([CH3:22])[CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:11]([N:18]([C@@H:19]([CH3:22])[CH2:20][OH:21])[CH2:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:10])[OH:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@@H](CO)NCc1ccccc1
Reactant: [O-][n+]1ccccc1C1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@H](CO)N(Cc1ccccc1)CC(O)c1cccc[n+]1[O-]
Reaction time: 24 h
Yield: 47.8 %

Procedure:
To a solution of 2-(oxiran-2-yl)pyridine 1-oxide (6.6 g, 48.48 mmol) in ethanol (150 mL) were added (S)-2-(benzylamino)propan-1-ol (16 g, 96.96 mmol) and potassium carbonate (13.3 g, 96.96 mmol), After 24 h, the mixture was concentrated under reduced pressure and the resulting residue was purified via alumina chromatography (1% methanol in dichloromethane) to afford 2-(2-(benzyl((S)-1-hydroxypropan-2-yl)amino)-1-hydroxyethyl)pyridine 1-oxide as a yellow liquid (7 g, 22%).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:13][CH2:12][NH:11][C:10]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1>C1COCC1>[Si:1]([O:8][C@H:9]1[CH2:13][CH2:12][N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[C:10]1=[O:14])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Reactant: Cc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(CN2CC[C@H](O[Si](C)(C)C(C)(C)C)C2=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 88 %

Procedure:
(S)-3-((tert-butyldimethylsilyl)oxy)pyrrolidin-2-one (5 g, 23.22 mmol, intermediate G) was dissolved in anhydrous THF (46.4 ml) and the reaction mixture was cooled to 0° C. under a nitrogen atmosphere. Sodium hydride (1.393 g, 34.8 mmol) was then added in one portion and the reaction mixture was allowed to stir for 5 min before the dropwise addition of 1-(bromomethyl)-4-methylbenzene (5.37 g, 29.0 mmol) in anhydrous THF (46.4 ml). The reaction was allowed to stir at 0° C. for 5 min, then the cooling bath was removed and mixture was allowed to warm to rt overnight. The reaction was cautiously quenched with water (100 mL) and then extracted with ethyl acetate (3×100 mL). The combined organic layers were then washed with brine (200 mL) and dried (MgSO4). Evaporation of the solvent in vacuo gave the crude product (9.6 g, oil) which was then purified by silica gel chromatography (330 g of silica) eluting with a gradient of 0% to 20% ethyl acetate in hexanes to provide 6.53 g (88%) of the desired product. LC/MS (Conditions B), RT=4.320 min, (M+H)+=320.3. 1H NMR (400 MHz, chloroform-d) δ 7.15 (s, 4H), 4.42 (s, 2H), 4.37 (t, J=7.6 Hz, 1H), 3.32-3.18 (m, 1H), 3.10 (dt, J=9.7, 7.5 Hz, 1H), 2.36 (s, 3H), 2.29 (dtd, J=12.6, 7.6, 3.1 Hz, 1H), 1.97-1.84 (m, 1H), 0.95 (s, 9H), 0.20 (d, J=10.3 Hz, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][C:5]([Cl:15])=[CH:4][N:3]=1>C(O)(=O)C>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][O:8][C:7]1[CH:2]=[N:3][CH:4]=[C:5]([Cl:15])[CH:6]=1)[CH3:14]
Reactant: CCOC(=O)COc1cc(Cl)cnc1Cl
Solvent: CC(=O)O
Product: CCOC(=O)COc1cncc(Cl)c1

Procedure:
A solution of ethyl (2,5-dichloropyrid-3-yloxy)-acetate (200mg.) in glacial acetic acid (8ml.) was stirred overnight under reflux with acid washed zinc powder (1.0g.). The solution was cooled and filtered and the filtrate was evaporated to dryness. The residue was purified by chromatography on silica gel to yield ethyl(5-chloropyrid-3-yloxy)acetate, m.p. 38°-40° C. (ether-pentane).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[CH2:13](Br)[CH:14]=[CH2:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:15]([O:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([Cl:8])=[CH:7][C:2]=1[NH2:1])[CH:14]=[CH2:13]
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cc([N+](=O)[O-])c(Cl)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a mixture of 2-amino-4-chloro-5-nitrophenol (10 g, 0.053 mol) and allyl bromide (5.05 mL, 0.058 mol) in DMF (100 mL) was added K2CO3. The reaction mixture was stirred at room temperature for 3 hours, and then the inorganic salts were filtered off. The filtrate was concentrated, and the residue was dissolved in ethyl acetate and washed with aqueous NH4Cl. The organic layer was dried over MgSO4 and concentrated to provide the desired product (10.9 g, 90%) as yellow solid. MS (DCI/NH3) m/z 246.04 (M+NH4)+; 1H NMR (500 MHz, DMSO-D6) δ ppm 4.68 (d, J=4.99 Hz, 2 H) 5.29 (dd, J=10.60, 1.56 Hz, 1 H) 5.48 (dd, J=17.47, 1.56 Hz, 1 H) 6.05 (m, 1 H) 6.48 (s, 2 H) 6.76 (s, 1 H) 7.59 (s, 1 H).
Reaction SMILES: [C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([C:14]#[C:15][C:16](O)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(N=C=NC2CCCCC2)CCCCC1.O>ClCCl>[C:1]1([NH:7][C:16](=[O:17])[C:15]#[C:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)C#Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: O=C(C#Cc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61 %

Procedure:
Phenylamine (1.86 g, 20 mmol) and phenylpropiolic acid (3.22 g, 22 mmol) were dissolved in dichloromethane (50 ml) and 1,3-dicyclohexylcarbodiimide (4.8 g, 23.2 mmol) was added in one portion at 0° C. The mixture was stirred room temperature for 14 h. The mixture was poured into water and extracted with dichloromethane (3×15 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded 3-phenyl-propynoic acid phenylamide 2.7 g (62%).
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH3:13])[CH:9]=[C:8]([C:14]([OH:16])=[O:15])[C:7]2=[O:17].C(OC([NH:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][N:30]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:17])[C:8]([C:14]([OH:16])=[O:15])=[CH:9][N:10]3[CH2:12][CH3:13])=[CH:5][C:4]=2[F:18])[CH2:29]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(Cl)c21
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@@H](N)[C@@H](C)C3)c(Cl)c21
Yield: 31.3 %

Procedure:
A mixture of 8-chloro-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.25 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.21 g), DBU (0.15 g) and anhydrous acetonitrile (4 ml) was refluxed for 2.5 hours. Then, the reacting mixture was treated as described in example 22 to give the title compound (0.1 g) as white powder, mp 222°-224° C. (decompd.).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9](S(C)(=O)=O)[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH3:25])[C:17]=2[F:26])[N:6]=1)=[O:4].[NH3:27].CO>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]([Cl:11])=[C:9]([NH2:27])[N:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH2:24][CH3:25])[C:17]=2[F:26])[N:6]=1)=[O:4]
Reactant: CCOc1c(Cl)ccc(-c2nc(C(=O)OC)c(Cl)c(S(C)(=O)=O)n2)c1F
Reactant: N
Solvent: C1COCCO1
Solvent: CO
Product: CCOc1c(Cl)ccc(-c2nc(N)c(Cl)c(C(=O)OC)n2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
5-Chloro-2-(4-chloro-3-ethoxy-2-fluorophenyl)-6-methane-sulfonylpyrimidine-4-carboxylic acid methyl ester (350 mg, 0.83 mmol) was dissolved in 10 mL p-dioxane and 7N ammonia in methanol (0.43 mL, 3 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated. The residue was partitioned between ethyl acetate and water and the organic phase was dried and concentrated. The product was purified by column chromatography to yield 6-amino-5-chloro-2-(4-chloro-3-ethoxy-2- fluorophenyl)-pyrimidine-4-carboxylic acid methyl ester (160 mg, 54% yield): 1H NMR (CDCl3): δ 7.65 (dd, 1H), 7.24 (dd, 1H), 5.67 (br s, 2H), 4.22 (q, 2H), 4.03 (s, 3H), 1.46 (t, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7]C)=[O:5])#[N:2].C[O-].[Na+].Cl[CH2:13][C:14](=[O:16])[CH3:15]>CO>[CH3:7][O:6][C:4](=[O:5])[CH:3]([C:1]#[N:2])[CH2:13][C:14](=[O:16])[CH3:15]
Reactant: CCOC(=O)CC#N
Reactant: CC(=O)CCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C#N)CC(C)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cooled (0° C.) solution of ethyl cyanoacetate (6.58 g, 58.1 mmol) in MeOH (20 mL) was slowly added a solution of NaOMe (25% w/v; 58.1 mmol). After 10 min, chloroacetone (5 mL; 62.8 mmol) was slowly added. After 4 h, the solvent was removed. The brown oil was diluted the EtOAc (100 mL) and washed with H2O (100 mL). The organic fraction was dried, filtered, and concentrated to a brown oil (7.79 g; 79%). The oil was a mixture of methyl/ethyl ester products (9/1), and was used without further purification. 1H NMR (200 MHz, CDCl3): δ 1.26 (t, J=7.1 Hz), 2.44 (s, 3H), 3.02 (dd, 1H, J=15.0, 7.0 Hz), 3.42 (dd, 1H, J=15.0, 7.1 Hz), 3.62 (s, 3H), 3.91 (dd, 1H, J=7.2, 7.0 Hz), 4.24 (q, J=7.2 Hz).
Reaction SMILES: [CH3:1][S:2]([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[N:6]2[N:5]=1)=[O:3].[C:25](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>>[CH3:1][S:2]([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=3[N:20]([CH3:25])[S:21]([CH3:24])(=[O:23])=[O:22])[N:6]2[N:5]=1)=[O:3]
Reactant: Cc1ccc(-c2ccc3cnc(S(C)=O)nn23)c(NS(C)(=O)=O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3cnc(S(C)=O)nn23)c(N(C)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-methyl-phenyl]-methanesulfonamide (530 mg, 1.4 mmol) was dissolved in 20 mL of dry and warm DMF. The solution was cooled (ice bath). Potassium carbonate (0.80 g, 5.8 mmol) in N,N-Dimethylformamide (20 mL, 200 mmol) was added followed by methyl iodide (270 uL, 4.4 mmol). After 18 h, the mixture was stirred at room temperature overnight. The mixture was filtered and the solvent was evaporated. The product was purified by flash chromatography (ISCO, EtOAc to EtOAc: MeOH 90:10). The product, N-[2-(2-Methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-methyl-phenyl]-N-methyl-methanesulfonamide, was obtained as a solid (320 mg, 58%). LCMS (E/I+) 379 (M+H).
Reaction SMILES: C(OCC[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)C.C(O)C.[OH-].[Na+].[C:21]([O:24][CH2:25][CH3:26])(=O)[CH3:22]>O.[Zn]>[CH2:21]([O:24][CH2:25][CH2:26][C:7]1([NH2:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]1[NH2:13])[CH3:22]
Reactant: CCOC(C)=O
Reactant: CCOCCNc1ccccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: CCOCCC1(N)C=CC=CC1N
Reaction time: 0.5 h

Procedure:
Combine N-(2-ethoxyethyl)-2-nitroaniline (85.4 g, 406 mmol) and ethanol (300 mL). Add a solution of sodium hydroxide (6 g) in water (60 mL). Heat to reflux. Remove the heating and add portionwise zinc metal (106 g, 1.62 mol) at a rate such that the reaction is maintained at reflux. After the addition of zinc metal is complete stir for 30 minutes. Filter the reaction mixture and rinse with water. Extract the filtrate three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with ethyl acetate to give 1-(2-ethoxyethyl)-1,2-phenylenediamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([NH2:12])[C@H:9]([OH:13])[C@H:8]([O:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:7]=1)=[O:5])[CH3:2].[Na+:20].[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([O-:32])(=[O:31])=[O:30])=O>C(O)C>[Na+:20].[CH2:1]([O:3][C:4]([C:6]1[CH2:11][C@@H:10]([N:12]=[CH:21][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([O-:32])(=[O:31])=[O:30])[C@H:9]([OH:13])[C@H:8]([O:14][CH:15]([CH2:16][CH3:17])[CH2:18][CH3:19])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=Cc1ccccc1S(=O)(=O)[O-]
Reactant: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@@H](O)[C@H](N)C1
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@@H](O)[C@H](N=Cc2ccccc2S(=O)(=O)[O-])C1
Yield: 99.4 %

Procedure:
To a stirred suspension of 27.1 g (100 mmol) (3R,4S,5R)-5-amino-3-(1-ethylpropoxy)-4-hydroxycyclohexene-1-carboxylic acid ethyl ester and 20.8 g (100 mmol) 2-formylbenzenesulfonic acid sodium salt in 270 ml ethanol was heated to reflux under argon for 2 hours. The brown, turbid reaction mixture was evaporated in a rotary evaporator and the residue was treated twice with 135 ml of ethyl acetate and evaporated in a rotary evaporator at 50° C. to dryness to yield 45.88 g (99%) of (1R,5R,6S)-2-{[3-ethoxycarbonyl-5-(1-ethyl-propoxy)-6-hydroxy-cyclohex-3-enylimino]-methyl}-benzenesulfonic acid sodium salt as a yellow amorphous solid. IR (film): 3417,2924, 2726, 1714, 1638, 1464, 1378, 1237, 1091, 970 cm−1; MS (ISP-MS):438.3 (M+−Na) m/z.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][C:9]([C:11]3[S:12][C:13]4[C:19]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=4[N:15]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:28][NH:29][CH3:30]>>[CH3:27][O:26][C:16]1[C:14]2[N:15]=[C:11]([C:9]3[NH:8][C:6]4=[N:7][C:2]([N:29]([CH3:30])[CH3:28])=[CH:3][CH:4]=[C:5]4[N:10]=3)[S:12][C:13]=2[C:19]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:18][CH:17]=1
Reactant: CNC
Reactant: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccc(Cl)nc4[nH]3)nc12
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccc(N(C)C)nc4[nH]3)nc12
Temperature: 200 °C
Yield: 29 %

Procedure:
0.03 g 5-Chloro-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3H-imidazo[4,5-b]pyridine (0.07 mmol) was dissolved in dimethylamine (5 ml) in an autoclave and heated to 200° C. for 16 h. The residue was triturated in water whereupon a precipitate formed, which was isolated and dried in vacuo. 0.08 g [2-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl]-dimethyl-amine (29%) were obtained as a brown solid; M.p.: 120–130° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:8](=[O:25])[N:9]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:3]=12.[H-].[Na+].I[CH3:29].O>O1CCCC1>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:9]2[C:10]3([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[C:3]3[C:2](=[O:1])[CH:7]=[CH:6][N:5]([CH3:29])[C:4]=3[C:8]2=[O:25])=[CH:22][CH:21]=1
Reactant: CI
Reactant: COc1ccc(CN2C(=O)c3nccc(O)c3C23CCCCC3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)c3c(c(=O)ccn3C)C23CCCCC3)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 4′-hydroxy-6′-(4-methoxybenzyl)spiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridin]-7′(6′H)-one (1.0 mmol, 1 eq) in tetrahydrofuran (25 mL), add sodium hydride (2.5 mmol, 2.5 eq) at 0° C. and stir for 20 min. Add iodomethane (2.5 mmol, 2.5 eq) to the above mixture and stir for 16 h. After completion add water to the reaction and extract with ethyl acetate. Remove the solvent under reduced pressure to get the crude which is purified by column chromatography to give 6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione (6).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][NH2:29])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1.C1COCC1.[CH3:37][N:38]([CH3:42])[C:39](Cl)=[O:40]>C(N(CC)CC)C>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:22]4[CH:27]=[C:26]([CH2:28][NH:29][C:39]([N:38]([CH3:42])[CH3:37])=[O:40])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)NCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1

Procedure:
To a solution of 5-(6-aminomethyl-pyrimidin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (50 mg, 0.12 mmol), THF (5 mL), and dimethylcarbamyl chloride (50 mg) is added triethylamine (50 mg). After 10 min the solution is partitioned between EtOAc and water. The organic layer is separated and washed further with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)[CH3:2].[CH3:22]C(C)([O-])C.[K+]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:18][CH2:17][CH:16]([CH:19]=[CH2:22])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)CCC1CCC(C2CCC(C=O)CC2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CCC(C2CCC(CCC(=O)OCC)CC2)CC1
Reaction time: 8 h

Procedure:
To 3-(4′-formyl-bicyclohexyl-4-yl)-propionic acid ethyl ester (7.8 g, 25 mmol) and methyltriphenylphosphoniumbromide (9.5 g, 26 mmol) in THF (150 ml) is added potassium-tert-butoxide portionwise at −10° C. The reaction mixture is stirred overnight, quenched with water and acidified with hydrochloric acid. The aq. layer is separated and extracted twice with MTB ether. The combined org. layers are washed with brine, dried (Na2SO4) and evaporated. The crude product is purified with heptane/ethyl acetate (19:1) on silica to give 3-(4′-vinyl-bicyclohexyl-4-yl)-propionic acid ethyl ester as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][CH:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15]([OH:17])=O)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:24][N:25]([CH3:40])[CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]([NH2:39])[CH2:34][CH2:33][CH2:32]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][CH:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][C:15]([NH:39][CH:35]2[C:36]3[C:31](=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:25]([CH3:40])[CH3:24])=[CH:38][CH:37]=3)[CH2:32][CH2:33][CH2:34]2)=[O:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1
Reactant: CN(C)CCOc1ccc2c(c1)CCCC2N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CN(C)CCOc1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1ccc(Cl)c(Cl)c1)c1ccccc1

Procedure:
To a 20 mL vial equipped with stirring was added 3-(3,4-dichloro-benzenesulfonylamino)-3-phenyl-propionic acid (128 mg, 0.34 mmol), 6-(2-dimethylamino-ethoxy)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (40 mg, 0.17 mmol), EDC (Aldrich, 49 mg, 0.26 mmol), HOBt (Aldrich, 23 mg, 0.17 mmol), and CH2Cl2 (1 mL). The reaction was stirred at RT overnight and diluted with CH2Cl2 (50 mL). The organic phase was washed with saturated NaHCO3, and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by silica gel chromatography (4%-6% MeOH—CH2Cl2) to afford the title compound as a white solid. MS (ESI): 590 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]=[C:11]=[S:12])=[O:9].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.C1(C)C=CC=CC=1>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[N:21]=[CH:20][CH:19]=[C:18]2[O:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:11]([NH:10][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[S:12])=[C:30]([CH3:35])[CH:29]=1
Reactant: Cc1ccccc1C(=O)N=C=S
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3)c2cc1OC
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4C)c(C)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
Commercially available 2-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methylaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (46 mg, yield 59%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[H-].[Na+].[CH:26]12[NH:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][NH:28][C:27]2=[O:34].C(N(CC)CC)C>CN1C(=O)CCC1>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[N:20][C:21]([N:33]5[CH:30]6[CH2:31][CH2:32][CH:26]5[C:27](=[O:34])[NH:28][CH2:29]6)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: O=C1NCC2CCC1N2
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3C4CCC3C(=O)NC4)cc1OCC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 29.2 %

Procedure:
To a suspension of 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 (137 mg, 0.44 mmol) in NMP (1.2 mL) was added sodium hydride (60% in mineral oil, 21 mg, 0.53 mmol). The reaction mixture was stirred at RT for 45 min, then at 45° C. for 45 min then cooled to RT. Phenyl trifluorosulphonimide (189 mg, 0.53 mmol) was added and the reaction stirred at RT for 1 h. 3,8-diaza-bicyclo[3.2.1]octan-2-one (69 mg, 0.48 mmol) and triethylamine (77 μL, 0.44 mmol) were added and the reaction mixture heated at 100° C. for 72 h then 120° C. for 7 h. The reaction mixture was cooled to RT, quenched with water and the resulting solid filtered and dried in vacuo. The resultant solid was loaded onto an Isolute SCX-2 cartridge, washed with methanol and eluted with 2M ammonia in methanol. Basic fractions were combined and concentrated in vacuo, the resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 466 (54 mg, 29%). LCMS: RT=2.33 min, [M+H]+=421. 1H NMR 300 MHz (DMSO-d6) δ: 9.13 (1H, s), 7.88 (2H, d, J=8.29 Hz), 7.19 (1H, br, s), 6.42 (1H, s), 5.95 (1H, m), 4.53 (4H, d, J=10.45 Hz), 4.50 (1H, m), 3.49 (1H, m), 3.17 (1H, d, J=5.21 Hz), 2.98 (1H, m), 2.05-2.20 (2H, m), 1.99 (1H, m), 1.95-1.98 (1H, m), 1.48 (6H, dd, J=6.57, 2.41 Hz)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[Cl:21][C:22]1[C:23]([NH:31][CH2:32][CH2:33][OH:34])=[N:24][CH:25]=[C:26]([CH:30]=1)[C:27](O)=[O:28]>>[Cl:21][C:22]1[C:23]([NH:31][CH2:32][CH2:33][OH:34])=[N:24][CH:25]=[C:26]([CH:30]=1)[C:27]([NH:20][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)=[CH:7][C:2]=1[CH3:1])=[O:28]
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1cnc(NCCO)c(Cl)c1
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1cnc(NCCO)c(Cl)c1

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with 5-chloro-6-(2-hydroxy-ethylamino)-nicotinic acid. MS: 472.3 (M+H).