Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([CH3:19])=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:4][CH:3]=1.[Br:21]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:19][C:7]1[C:6](=[O:20])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cn(-c2ccccc2Cl)c2cc(Cl)ccc2c1=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=c1c(CBr)cn(-c2ccccc2Cl)c2cc(Cl)ccc12
Temperature: 25 °C

Procedure:
To a 25 mL round-bottom flask was added 7-chloro-1-(2-chloro-phenyl)-3-methyl-1H-quinolin-4-one (324 mg, 1.07 mmol), N-bromosuccinimide (219 mg, 1.23 mmol), AIBN (33.0 mg, 201 μmol) and carbon tetrachloride (9 mL). The mixture was heated at reflux for 2 hr. The reaction mixture was cooled to room temperature and then placed in an ice bath. The solvent was decanted and the residue was then rinsed with a very small amount of dichloromethane. The supernatant was concentrated and the crude 3-bromomethyl-7-chloro-1-(2-chloro-phenyl)-1H-quinolin-4-one was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[C:11](O)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]1=[O:19].P(Cl)(Cl)(Cl)(Cl)Cl.[NH2:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[C:11](/[NH:26][C:27]2[CH:34]=[CH:33][CH:32]=[C:29]([C:30]#[N:31])[CH:28]=2)\[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)/[C:3]1=[O:19]
Reactant: CN1C(=O)C(=C(O)c2ccccc2)c2ccccc21
Reactant: N#Cc1cccc(N)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Product: CN1C(=O)/C(=C(\Nc2cccc(C#N)c2)c2ccccc2)c2ccccc21

Procedure:
Prepared analogously to Example 2 from 1-methyl-3-(1-hydroxy-1-phenyl-methylidene)-2-indolinone, phosphorus pentachloride and 3-aminobenzonitrile.
Reaction SMILES: C([NH:5][S:6]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[N:21](COCC[Si](C)(C)C)[CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])=[C:13]([C:35]2[CH2:40][CH2:39][C:38]([CH3:42])([CH3:41])[CH2:37][CH:36]=2)[CH:12]=1)(=[O:8])=[O:7])(C)(C)C.CCO.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[CH3:41][C:38]1([CH3:42])[CH2:39][CH2:40][C:35]([C:13]2[CH:12]=[C:11]([CH2:10][CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH:16]=[CH:15][C:14]=2[NH:17][C:18]([C:20]2[NH:21][CH:22]=[C:23]([C:25]#[N:26])[N:24]=2)=[O:19])=[CH:36][CH2:37]1
Reactant: CC1(C)CC=C(c2cc(CCS(=O)(=O)NC(C)(C)C)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: CCO
Solvent: COc1ccccc1
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(CCS(N)(=O)=O)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.6 %

Procedure:
A solution of 311 mg (0.506 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-(2-tert-butylsulfamoyl-ethyl)-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in the previous step) in CH2Cl2 (6 mL) was treated with EtOH (175 μL), anisole (80.0 μL), and TFA (1.8 mL). Additional TFA (0.5 mL each) was added at 3.5 and at 26 h. The mixture stirred at RT for a total of 48 h. MeOH (3 mL) was added, the mixture was concentrated in vacuo, and the residue was purified by RP-HPLC (C18) with 20-100% CH3CN in 0.1% TFA/H2O over 30 min to afford 70.5 mg (32%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 8.17 (d, 1H, J=8.0 Hz), 8.01 (s, 1H), 7.21 (dd, 1H, J=8.0, 2.0 Hz), 7.13 (d, 1H, J=2.0 Hz), 5.79-5.73 (m, 1H), 3.40-3.34 (m, 1H), 3.16-3.07 (m, 2H), 2.37-2.29 (m, 2H), 2.13-2.07 (m, 2H), 1.65-1.57 (m, 2H), 1.10 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C21H25N5O3S, 428.2 (M+H), found 428.1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1.O.C(OCC)C>CS(C)=O>[N:1]([C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1)=[N+:2]=[N-:3]
Reactant: CCOC(=O)C1(Br)CCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1(N=[N+]=[N-])CCC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
Sodium azide (3.14 g, 48.3 mmol) was partially dissolved in dry DMSO (50 mL), under nitrogen at ambient temperature. Ethyl 1-bromocyclobutanecarboxylate (3.91 mL, 24.2 mmol, Aldrich) was then added via syringe. After heating to 40° C. for 7 hours, the homogenous solution was allowed to cool to ambient temperature and stirring was continued overnight. The reaction mixture was then poured into water (700 mL), along with diethyl ether (200 mL). The ether layer was washed three times with half brine and then once with brine. The organic layer was dried over sodium sulfate, filtered and then evaporated under reduced pressure to provide ethyl 1-azidocyclobutanecarboxylate (4.00 g) as a clear oil.
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:10][C:11]([C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[C@H:14]1[C:28]1[CH:33]=[CH:32][C:31]([NH:34]C(OC(C)(C)C)=O)=[CH:30][CH:29]=1)=[O:12])[CH3:9].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:8]([O:10][C:11]([C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[C@H:14]1[C:28]1[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2C)[C@H]1c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2C)[C@H]1c1ccc(N)cc1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
4N HCl in 1,4-dioxane (5 mL, 20 mmol) was slowly added to a 0° C. solution of the above crude product (2R,3S)-2-(4-tert-Butoxycarbonylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester (840 mg, 1.72 mmol) in dry CH2Cl2 (4 mL). After the addition of the HCl, the reaction mixture was allowed to attain r.t and stirred for 1 h. It was diluted with CH2Cl2 (30 mL), cooled to 0° C. and neutralized with saturated aqueous NaHCO3 to get the (2R,3S)-2-(4-aminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester (612 mg) in 97% yield over two steps.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=2)=[C:7]([Cl:24])[CH:6]=1)C.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Cl:11][C:9]1[CH:10]=[C:5]([CH2:4][OH:3])[CH:6]=[C:7]([Cl:24])[C:8]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=1
Reactant: CCOC(=O)c1cc(Cl)c(Oc2ccc(OC)c(C(C)C)c2)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1C(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 84.5 %

Procedure:
To a solution of 3,5-dichloro-4-(3-isopropyl-4-methoxy-phenoxy)-benzoic acid ethyl ester (prepared as described in Example 1, Step A) (100 mg, 0.26 mmol) in methylene chloride (3 mL) at −78° C. under nitrogen was added diisobutylaluminum hydride (1M in hexane, 0.6 ml, 0.6 mmol). The reaction mixture was warmed to room temperature and stirred for about 19 hours. The reaction was quenched with methanol (1 ml) and sodium potassium tartrate (0.5M aqueous solution, 2 ml). After stirring for about 15 minutes, the solution was extracted with methylene chloride (3×10 mL). The combined organic extracts were washed with saturated sodium bicarbonate and brine, dried, filtered, and concentrated. The crude product was purified by preparative TLC (methylene chloride) to afford the title compound (75 mg) as a solid. NMR (400 MHz, CDCl3) δ 7.39 (s, 2H), 6.85 (d, 1H), 6.69 (d, 1H), 6.43-6.46 (dd, 1H), 4.68 (s, 2H), 3.77 (s, 3H), 3.26-3.30 (sept, 1H), 2.03 (bs, 1H), 1.18 (d, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C@H:7]2[N:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C@H:7]2[N:12]1[CH2:17][CH2:16][CH:15]([NH:25][C:20]2[C:19]([NH2:26])=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1
Reactant: Nc1ccccc1N
Reactant: Cc1cccc2c1CCC[C@H]2N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1cccc2c1CCC[C@H]2N1CCC(Nc2ccccc2N)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
(R)-1-(5-Methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidin-4-one (1.84 g) was dissolved in dichloroethane (55 ml), and 1,2-phenylenediamine (1.23 g) was added. To the solution were added sodium triacetoxyborohydride (3.61 g) and acetic acid (0.97 ml). The mixture was stirred at room temperature for 24 hr, alkalified with saturated sodium hydrogen carbonate, and extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give (R)-N-[1-(5-methyl-1,2,3,4-tetrahydronaphthalen-1-yl)piperidin-4-yl]-benzene-1,2-diamine (1.83 g) as a pale-brown solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:27])[NH2:26].Br[CH2:29][CH2:30][C:31](OCC)=[O:32].CN(C)C=O>[Cl-].[Na+]>[O:32]=[C:31]1[CH2:30][CH2:29][S:27][C:25]([N:3]2[CH:2]([CH3:1])[CH2:8][C:7]3[CH:9]=[C:10]4[O:15][CH2:14][O:13][C:11]4=[CH:12][C:6]=3[C:5]([C:16]3[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=3)=[N:4]2)=[N:26]1
Reactant: CCOC(=O)CCBr
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(N)=S)OCO3
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C1=NC(=O)CCS1)OCO3
Temperature: 85 °C
Reaction time: 3 h
Yield: 58.8 %

Procedure:
A mixture of 2.00 g (5.20 mmol) of the starting material I, 1.89 g (10.44 mmol) of ethyl 3-bromopropionate and 20 ml of dimethylformamide was stirred at 80-90° C. for 3 h. The reaction mixture was diluted with 25% sodium chloride solution and extracted with dichloromethane. After drying and concentration the crude product was purified by column chromatography using silica gel (MN Kieselgel 60) as adsorbent and a mixture of ethyl acetate-methanol (2:1) as eluent to yield 1.34 g (59%) of the title compound; Mp.: 220-221° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([CH2:26][CH:27]4[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)=[O:25])[CH2:20][CH2:19]3)[C:5]2=[N:6][CH:7]=1.OS(O)(=O)=O.[OH-].[Na+]>CO.O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:12][CH2:11][C:10]3[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:9]=3[CH:8]([N:18]3[CH2:19][CH2:20][N:21]([C:24](=[O:25])[CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH2:22][CH2:23]3)[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)N2CCN(C3c4ccc(Cl)cc4CCc4cc(Br)cnc43)CC2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(CC1CCNCC1)N1CCN(C2c3ccc(Cl)cc3CCc3cc(Br)cnc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
The title compound from Step A above (4.61 g) (7.5 mmoles) was dissolved in methanol (40 mL) and a 10% (v/v) conc. H2SO4 in dioxane solution (100 mL) was added. The mixture was stirred at 25° C. for 2 h and then basified with conc. aqueous NaOH. The mixture was extracted with dichloromethane and the latter was washed with water, dried over MgSO4, filtered and evaporated to dryness. The product was chromatographed on silica gel using 10% (10% conc. NH4OH in methanol)dichloromethane as the eluant to give the title compound (Yield: 2.86 g; 74%)
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:20]=[C:19]([C:21]3[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.N1C=CC=C[C:32]=1C.B.C(=O)([O-])O.[Na+]>C(O)(=O)C.CN(C)C=O>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]2[CH:20]=[C:19]([C:21]3[C:22]([NH2:28])=[N:23][C:24]([NH:27][CH3:32])=[CH:25][CH:26]=3)[O:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccn1
Reactant: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Agent: B
Agent: C=O
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CNc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)c(N)n1
Reaction time: 8 h
Yield: 4.6 %

Procedure:
To a mixture of 3-(3-(6-benzyloxy-pyridin-3-ylmethyl)-isoxazol-5-yl)-pyridine-2,6-diamine (50 mg, 0.13 mmol) described in Example 25 and N,N-dimethylformamide (0.5 mL) were added a formaldehyde aqueous solution (14 mg, 0.17 mmol, content: 37%), α-picoline-borane (17 mg, 0.16 mmol), and acetic acid (50 μL) at room temperature, which was stirred overnight at the same temperature. A saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, after which the organic layer was concentrated under a reduced pressure. The residue thus obtained was purified by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain a crude product, and then purified by silica gel thin-layer chromatography (diethyl ether:hexane=2:1) to obtain the title compound (2.3 mg, 4.4%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[C:11]([CH3:28])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[Cl:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[Cl:46])[C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][C:45]=1[Cl:46])[C:40]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)[CH2:19][CH2:18]3)=[O:16])[C:11]([CH3:28])=[N:10]2)[CH:4]=1)=[O:41]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Cc1nn(-c2cccc(N)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn(-c2cccc(NC(=O)c3ccc(Cl)c(Cl)c3)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 25 °C

Procedure:
A solution of 0.080 g (0.20 mmol) of [1-(3-amino-phenyl)-3,5-dimethyl-1H-pyrazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone hydrochloride and 0.11 ml (0.79 mmol, 4 eq) of triethylamine in 3 ml of CH2Cl2 was treated at 0° C. with 0.050 g (0.24 mmol, 1.2 eq) of 3,4-dichlorobenzoyl chloride. The reaction was stirred over night at RT, then partitioned three times between EtOAc and aqueous saturated NaHCO3, dried over Na2SO4 and evaporated to give 0.115 g (quant.) of the title compound as light yellow solid. MS: 540.4 (MH+, 2 Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2=[O:12].C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9]([S:8][CH2:7][C:6](=[CH:16][N:17]([CH3:19])[CH3:18])[C:5]2=[O:12])=[CH:10][CH:11]=1
Reactant: CCOC(OCC)N(C)C
Reactant: O=C1CCSc2ccc(Cl)cc21
Product: CN(C)C=C1CSc2ccc(Cl)cc2C1=O

Procedure:
The 7-chloro-3,4-dihydro-2-(dimethylaminomethylene)-4-thia-1(2H)-naphthalenone starting material was prepared from 6-chloro-thiochroman-4-one (3.97 g, 20 mmol) and N,N-dimethylformamide diethyl acetal (20 ml, 80 mmol) to give the desired product as yellow crystals (4.38 g) m.p. 127-128°. MS (ES+) 256 (MH+, 37Cl, 33%), 254 (MH+, 35Cl, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([O:19][C:20]1[C:21](=[O:36])[O:22][CH:23]([CH2:33][CH2:34]O)[C:24]=1[O:25]CC1C=CC=CC=1)C1C=CC=CC=1>>[OH:19][C:20]1[C:21](=[O:36])[O:22][CH:23]([CH2:33][CH2:34][O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[C:24]=1[OH:25]
Reactant: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Reactant: Oc1ccc2ccccc2n1
Product: O=C1OC(CCOc2ccc3ccccc3n2)C(O)=C1O
Yield: 17.4 %

Procedure:
Mitsunoble coupling of 0.17 g (1.2 mmol) of 2-hydroxyquinoline with 0.34 g (1.0 mmol) of 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and subsequent benzyl group deprotection by hydrogenation were performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 50 mg (17% yield) of 3,4-dihydroxy-5-[2-(quinoline-2-oxy)ethyl]-2(5H)-furanone as a fluffy white solid after recrystallization from ether and hexanes: 1H NMR (acetone-d6) δ 8.25-8.17 (m, 1H); 7.88-7.38 (m, 4H), 7.01-6.93 (m, 1H); 4.97 (dd, J=4.9, 8.7 H, 1H), 4.81-4.55 (m, 2H); 2.62-2.45 (m, 1H), 2.20-1.95 (m, 1H). Anal Calcd for C15H13NO5 +0.5H2O: C, 60.81; H, 5.10; N, 4.72. Found: C, 61.04; H 5.04: N, 4.32.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:20])([CH3:19])[C:7](=[O:18])[N:8]2[CH2:11][CH2:12][CH2:13][O:14][CH:15]2[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:30]=[N:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25]>>[CH:15]1([O:14][CH2:13][CH2:12][CH2:11][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:24](=[O:25])[C:23]4[CH:27]=[CH:28][N:29]=[CH:30][C:22]=4[F:21])[CH:10]=3)[C:6]([CH3:20])([CH3:19])[C:7]2=[O:18])[CH2:16][CH2:17]1
Reactant: O=C(O)c1ccncc1F
Reactant: CC1(C)C(=O)N(CCCOC2CC2)c2cc(N)ccc21
Product: CC1(C)C(=O)N(CCCOC2CC2)c2cc(NC(=O)c3ccncc3F)ccc21

Procedure:
Prepared in analogy to example 26 from 6-amino-1-(3-cyclopropoxypropyl)-3,3-dimethylindolin-2-one and 3-fluoroisonicotinic acid. The title compound was obtained as yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][OH:10].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br.[OH-].[Na+]>O>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:10][CH2:9][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCCc1ccccn1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCCCCCOCCCc1ccccn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-pyridinepropanol (15.8 g), 1,6-dibromohexane (60 ml), 50% (w/v) sodium hydroxide (60 ml) and TAB (1.5 g) was stirred at room temperature for 5 h. Water (200 ml) was added and the mixture was extracted with ether (2×200 ml). The organic extracts were washed with water and brine, dried and concentrated to an oil which was purified by FCC eluting with hexane→hexane-ether (1:1) to give the title compound as a colourless oil (18.1 g), t.l.c. (hexane-ether 1:1) Rf 0.19.
Reaction SMILES: ClC(N(C)C)=C(C)C.[F:9][CH:10]([F:27])[CH2:11][O:12][C:13]1[N:21]=[C:20]([NH:22][CH3:23])[C:19]([N+:24]([O-:26])=[O:25])=[CH:18][C:14]=1[C:15]([OH:17])=O.N1C=CC=CC=1.[Br:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1>C(Cl)Cl.C1COCC1>[Br:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39][C:15](=[O:17])[C:14]2[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[C:20]([NH:22][CH3:23])=[N:21][C:13]=2[O:12][CH2:11][CH:10]([F:9])[F:27])=[CH:37][CH:36]=1
Reactant: CNc1nc(OCC(F)F)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Br)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNc1nc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(1-Chloro-2-methyl-propenyl)-dimethylamine (1.54 mL, 5.63 mmol) is added to 2-(2,2-difluoro-ethoxy)-6-methylamino-5-nitro-nicotinic acid (880 mg, 5.12 mmol) in DCM (15 mL) and THF (15 mL) and stirred at rt for 15 min. Pyridine (607 μL, 7.67 mmol) followed by 4-bromoaniline are added to the reaction mixture and it is stirred for 1 h at rt. The mixture is concentrated, diluted with water and filtered. The filtercake is washed with water and dried to give the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]=1[CH3:10])=[O:4].[Br:15]N1C(=O)CCC1=O.[Al]>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:9]=1[CH2:10][Br:15])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cnn(C(C)(C)C)c1C
Agent: [Al]
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cnn(C(C)(C)C)c1CBr
Yield: 95.2 %

Procedure:
A solution of 1-tert-butyl-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester (3.38 g, 17.22 mmol) (as described in Example 54, Step 2) in carbon tetrachloride (12.2 mL, 1.41M) at 25° C. was treated with N-bromosuccinimide (3.10 g, 17.41 mmol). The reaction flask was fitted with a reflux condenser. The set-up was wrapped with aluminum foil and was then illuminated with a 250 Watt sun lamp for 3 h. At this time, the reaction was filtered and was rinsed with carbon tetrachloride. The filtrate was transferred to a separatory funnel and was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL). The organics were dried over magnesium sulfate, filtered, rinsed with carbon tetrachloride and concentrated in vacuo to a light yellow oil. ISCO CombiFlash chromatography (120 g, 0-10% ethyl acetate/hexanes) afforded 5-bromomethyl-1-tert-butyl-1H-pyrazole-4-carboxylic acid methyl ester (4.51 g, 95%) as a clear oil. The material was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].C[Mg]Br.[Cl-].[Li+].[Cl-].[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][CH2:25][Mg]Br.C[Si](C)(C)CCCBr.[Mg]>CCOCC.O1CCCC1>[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][CH2:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: C[Si](C)(C)CCC[Mg]Br
Agent: C[Mg]Br
Agent: C[Si](C)(C)CCCBr
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[Si](C)(C)CCCCCCCCCCCCCC(=O)O
Reaction time: 0.5 h

Procedure:
A solution of 240 g. 11-bromoundecanoic acid in 1.15 l. dry tetrahydrofuran was cooled to -20° under nitrogen, and to this stirred solution was dropwise added 309 ml. of a 3M solution of methyl magnesium bromide in ether followed by a solution of 1.54 g. lithium chloride and 2.43 g. cuprus chloride in 90 ml. dry tetrahydrofuran. The mixture was stirred at -20° while a warm solution of 3-(trimethylsilyl)propyl magnesium bromide, prepared from 266 g. 3-(trimethylsilyl)propyl bromide and 33.7 g. magnesium turnings in 860 ml. dry tetrahydrofuran, was added dropwise. The reaction was stirred at -20° for 30 min. after addition was complete, then at room temperature for 18 hr. The mixture was poured into 4 l. toluene and washed twice with 4 l. of 10% sulfuric acid and once with 4 l. 1N hydrochloric acid containing 375 ml. methanol. Evaporation of the toluene and distillation at reduced pressure yielded the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH2:28]([NH2:31])[C:29]#[CH:30].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:28]([NH:31][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1)[C:29]#[CH:30]
Reactant: C#CCN
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C#Cc3ccccn3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCNC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A solution of 2-(3-Pyridin-2-ylethynyl-1H-indazol-6-ylamino)-benzoic acid (41 mg, 0.117 mmol), propargylamine (24 μL, 0.35 mmol), triethylamine (81 μl, 0.58 mmol), dissolved in DMF (0.5 mL), was treated with HATU (89 mg, 0.233 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 27 mg (59%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.78 (1H, s), 8.99 (1H, m), 8.61 (1H, d, J=2.1), 7.88 (1H, s), 7.72 (3H, m), 7.43 (4H, m), 7.29 (1H, s), 7.04 (1H, d, J=7.3), 6.91 (1H, t, J=5.2), 4.04 (2H, s), 3.04 (1H, s). ESIMS (M+H+): 392.1.