Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClS([N:5]=C=O)(=O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13](O)=O.CN(C)C=O>ClCCl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[CH3:19])[C:13]#[N:5]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: COc1cc(C(=O)O)ccc1C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(C#N)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A solution of chlorosulphonyl isocyanate (5.35 ml.) in dichloromethane (3 ml.) was added over 45 minutes to a stirred suspension of 3-methoxy-4-methylbenzoic acid (9.97 g.) in dichloromethane (18 ml.) at reflux under an atmosphere of nitrogen. The resulting bright-red homogeneous solution was heated under reflux for 45 minutes, chilled in an ice-bath, and treated dropwise with N,N-dimethylformamide (9.5 ml.), over 15 minutes. After stirring for 30 minutes at 0° C., the orange solution was poured onto ice. The organic layer was separated, washed with water (5×20 ml.), dried (MgSO4) and evaporated. The residue was purified by preparative HPLC (SiO2, 10:90 v/v hexane: toluene) to give 3-methoxy-4-methylbenzonitrile (5.28 g., 60%) as a white solid, m.p. 51°-52.5° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[N:28]=[CH:27][CH:26]=[CH:25][C:19]=3[N:20]3[C:24]=2[CH2:23][CH2:22][CH2:21]3)=[CH:13][CH:12]=1.[C:29]([O-])([O-])=O.[K+].[K+].CI.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:29][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18]3[N:28]=[CH:27][CH:26]=[CH:25][C:19]=3[N:20]3[C:24]=2[CH2:23][CH2:22][CH2:21]3)=[CH:13][CH:12]=1
Reactant: c1ccc2[nH]c(Oc3ccc(-c4c5n(c6cccnc46)CCC5)cc3)nc2c1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(Oc2ccc(-c3c4n(c5cccnc35)CCC4)cc2)nc2ccccc21
Temperature: 40 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a mixture of 9-[4-(1H-benzimidazol-2-yloxy)phenyl]-7,8-dihydro-6H-pyrido[2,3-b]pyrrolizine (70 mg) and K2CO3 (79 mg) in DMF (1 mL) was added MeI (0.024 mL). The mixture was stirred at 40° C. overnight. The mixture was poured into saturated NaHCO3 aqueous solution and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (38.1 mg).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:12][C:13]1[CH:14]=[C:15]([OH:34])[C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=2[CH2:32][I:33])=[CH:17][C:18]=1[CH:19]([CH3:21])[CH3:20].[O:35]1[CH:40]=[CH:39][CH2:38][CH2:37][CH2:36]1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:12][C:13]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=2[CH2:32][I:33])=[C:15]([O:34][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][O:35]2)[CH:14]=1
Reactant: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2CI)c(O)cc1F
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2CI)c(OC2CCCCO2)cc1F
Reaction time: 72 h

Procedure:
p-Toluenesulfonic acid (2.8 mg, 0.0145 mmol) was added to a solution of 4-fluoro-2′-(iodomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-ol (63.4 mg, 0.145 mmol) and 3,4-dihydro-2H-pyran (60.8 mg, 66 μL, 0.723 mmol) in dry CH2Cl2 (7.2 mL) at room temperature under N2 and the reaction was stirred for 3 days. The reaction mixture was diluted with saturated NaHCO3 (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) to afford 2-{[4-fluoro-2′-(iodomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-yl]oxy}tetrahydro-2H-pyran. Rf=0.74 (10% EtOAc in hexanes). 1H NMR (500 MHz, CDCl3) δ 7.75 (s, 1H), 7.62 (d, J=8.3 Hz, 0.5H), 7.59 (d, J=8.3 Hz, 0.5H), 7.53 (t, J=7.3 Hz, 0.5H), 7.41 (s, 0.5H), 7.32 (d, J=7.9 Hz, 0.5H), 7.25 (d, J=7.9 Hz, 0.5H), 7.15 (t, J=9.4 Hz, 0.5H), 6.99 (d, J=12.2 Hz, 0.5H), 6.94 (d, J=12.2 Hz, 0.5H), 6.69 (d, J=11.0 Hz, 0.5H), 5.37 (s, 0.5H), 5.23 (s, 0.5H), 5.13 (s, 1H), 4.45 (d, J=9.6 Hz, 0.5H), 4.40 (d, J=9.6 Hz, 0.5H), 4.31 (d, J=9.6 Hz, 0.5H), 4.23 (d, J=9.6 Hz, 0.5H) 3.76 (m, 0.5H), 3.66-3.54 (m, 1.5H), 3.29-3.21 (m, 1H), 1.68-1.44 (m, 4H) 1.32-1.26 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:21][CH:22]([CH2:26][CH3:27])[CH2:23][O:24][CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH:21][CH:22]([CH2:23][O:24][CH3:25])[CH2:26][CH3:27])=[O:15])=[CH:6][CH:7]=1
Reactant: CCC(N)COC
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Product: CCC(COC)NC(=O)c1ccc(OC)c(/C=C/c2ccc(Cl)cc2)c1

Procedure:
The captioned compound was synthesized from 3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid and 2-amino-1-methoxybutane in accordance with the same procedure as in the manufacturing method described in step C of Example 1-2-3.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[CH:16]=[C:15]([CH3:17])[NH:14][C:13]=1[CH:18]=O>N1CCCCC1.C(O)C>[CH3:18][C:13]1[NH:14][C:15]([CH:17]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:16][C:12]=1[CH3:11]
Reactant: Cc1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C=C2C(=O)Nc3ccccc32)[nH]c1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A reaction mixture of 134.0 mg of oxindole, 147.8 mg of the 3,5-dimethylpyrrole-2-carboxaldehyde, and 3 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 136.7 mg (57%) of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C@:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)=O.S(C)C>C1COCC1>[C:15]1([C@@:2]([NH2:1])([CH3:14])[CH2:3][CH2:4][NH:6][C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccc(NC(=O)C[C@@](C)(N)c2ccccc2)c1
Solvent: CSC
Solvent: C1CCOC1
Product: Cc1cccc(NCC[C@@](C)(N)c2ccccc2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 24.3 %

Procedure:
A solution of (R)-3-amino-3-phenyl-N-m-tolylbutanamide (218 mg, 0.81 mmol) in THF (5 mL) was cooled to 0° C. under N2 and 2M BH3.Me2S (1 mL, 2 mmol) was added. Then the mixture was stirred at 80° C. overnight. The reaction mixture was quenched with MeOH and concentrated. The residue was purified by preparative TLC to afford (R)-3-phenyl-N1-m-tolylbutane-1,3-diamine (50 mg, 24%). 1H NMR (CDCl3): 1.59-1.62 (m, 7H), 1.30-1.35 (m, 4H), 2.15-2.20 (m, 3H), 2.40-2.65 (m, 2H), 2.98-3.05 (m, 2H), 3.35-3.45 (m, 1H), 3.60-3.65 (m, 6H), 3.75-3.80 (m, 1H), 6.40-6.60 (m, 2H), 6.90-7.01 (m, 1H), 7.25-7.40 (m, 4H), 7.45-7.52 (m, 2H).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2].C(O)C.[CH2:40]([NH:42][CH2:43]C)C>CN(C=O)C>[C:1]([N:3]=[C:4]([N:42]([CH3:43])[CH3:40])[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2]
Reactant: CCNCC
Reactant: CSC(=NC#N)NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Solvent: CN(C)C=O
Solvent: CCO
Product: CN(C)C(=NC#N)NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
100 mg of the product of Example 50 were treated with 10 ml of ethanol, 10 ml of DMF and 20 ml of 40% aqueous diethylamine for 16 hours. The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with 10% methanol in dichloromethane to give 53 mg of 3-[1-[3-(2-cyano-3,3-dimethylguanidino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p 150°-153° C.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[CH:15]([NH2:18])([CH3:17])[CH3:16].C(O)(=O)C>CO>[CH:15]([NH:18][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)([CH3:17])[CH3:16]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(C)N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)NCc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 38.3 %

Procedure:
Under a nitrogen atmosphere, add sodium cyanoborohydride (5.77 g, 91.6 mmol) to a solution of 4-cyanobenzaldehyde (3 g, 22.9 mmol), iso-propylamine (2.03 g, 34.4 mmol) and acetic acid (1.37 g, 22.9 mmol) in methanol (30 mL) at 0° C. with stirring. Warm the mixture to room temperature and stir overnight. Add water (100 mL), saturated aqueous K2CO3 (50 mL), and extract with DCM. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (300 g) eluting with 9:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the desired intermediate (1.53 g, 38%). MS (APCI+) m/z: 175 (M+H)+.
Reaction SMILES: Cl.OC(COC1C=CC([Cl:26])=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.[OH:28][CH:29]([CH2:44][O:45][C:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)C=[CH:48][CH:47]=1)[CH2:30][NH:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1.Cl.OC(COC1C=CC(OC)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:28][CH:29]([CH2:44][O:45][C:46]1[CH:47]=[CH:48][C:51]([CH2:52][CH2:53][CH3:54])=[CH:50][CH:55]=1)[CH2:30][NH:31][C:32]([CH3:43])([CH3:42])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2cccc3ccccc23)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Agent: Cl
Product: CCCc1ccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 356 (M-15,.8), 251(18), 250 (100), 163 (5), 121 (19), 114 (7), 110 (5), 107 (7), 91 (6).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@H:15]([CH3:16])[N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12][N:11]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22])C1C=CC=CC=1>O1CCOCC1.CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:8][CH2:9][C@H:10]1[C@H:15]([CH3:16])[N:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH2:13][CH2:12][N:11]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: COc1ccc(S(=O)(=O)N2CCN(S(C)(=O)=O)[C@@H](C)[C@@H]2COCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2CCN(S(C)(=O)=O)[C@@H](C)[C@@H]2CO)cc1
Yield: 94.9 %

Procedure:
A mixture of (2R,3S)-2-benzyloxymethyl-4-methanesulfonyl-1-(4-methoxybenzenesulfonyl)-3-methylpiperazine (330 mg) and palladium hydroxide (40 mg) in dioxane (5 ml) and MeOH (5 ml) was hydrogenated in hydrogen at 3.5 atm and ambient temperature for 1 day. The catalyst was removed by filtration through a celite pad and the pad was washed with MeOH. The filtrate and combined washings were concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: AcOEt/n-hexane 60%, then MeOH/AcOEt 1%) to give 253 mg of (2R,3S)-2-hydroxymethyl-4-methanesulfonyl-1-(4-methoxybenzenesulfonyl)-3-methylpiperazine.
Reaction SMILES: II.C(Br)C.Br[C:7]1[CH:24]=[CH:23][C:10]([O:11][CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:9][CH:8]=1.[OH:25][C:26]1[CH:27]=[CH:28][C:29]([C:32](N(OC)C)=[O:33])=[N:30][CH:31]=1>C1COCC1>[OH:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([C:7]2[CH:24]=[CH:23][C:10]([O:11][CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:9][CH:8]=2)=[O:33])=[N:30][CH:31]=1
Reactant: CN(CCOc1ccc(Br)cc1)C(=O)OC(C)(C)C
Reactant: CON(C)C(=O)c1ccc(O)cn1
Agent: II
Solvent: CCBr
Solvent: C1CCOC1
Product: CN(CCOc1ccc(C(=O)c2ccc(O)cn2)cc1)C(=O)OC(C)(C)C
Temperature: 55 °C
Reaction time: 0.5 h

Procedure:
Mg (3.5 eq) was added to a 3-neck round bottom flask containing 50 mL anhydrous THF. The mixture was heated to 55° C. Iodine chips (2 grains) were added in one lot followed by addition of 0.1 mL ethyl bromide. Tert-butyl 2-(4-bromophenoxy)ethyl(methyl)carbamate (3.0 eq) was dissolved in 30 mL anhydrous THF, 3 mL of this solution was added at once to Mg-THF suspension. The reaction was initiated after 30 min and reflux started. The remaining solution of tert-butyl 2-(4-bromophenoxy)ethyl(methyl)carbamate was added dropwise in such speed that the reaction mixture remained reflux. After addition, the reaction mixture was further reflux for 2 h and cooled to rt. 5-Hydroxy-N-methoxy-N-methylpicolinamide (1.0 eq) in 20 mL THF was added dropwise at rt, stirred for 30 min. at rt., quenched with sat NH4Cl (aq), and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[N+:8]([C:11]1[CH:12]=[C:13]([CH:36]=[CH:37][CH:38]=1)[CH2:14][C:15]1[C:16](=[O:35])[O:17][C:18]2[CH:28]=[C:27]([O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:26]=[CH:25][C:19]=2[C:20]=1[CH2:21][C:22]([OH:24])=[O:23])([O-:10])=[O:9].ClCCl>CO>[CH3:1][O:23][C:22](=[O:24])[CH2:21][C:20]1[C:19]2[CH:25]=[CH:26][C:27]([O:29][C:30](=[O:34])[N:31]([CH3:32])[CH3:33])=[CH:28][C:18]=2[O:17][C:16](=[O:35])[C:15]=1[CH2:14][C:13]1[CH:36]=[CH:37][CH:38]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CN(C)C(=O)Oc1ccc2c(CC(=O)O)c(Cc3cccc([N+](=O)[O-])c3)c(=O)oc2c1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Trimethylsilyl diazomethane (0.82 mL, 2.0 M in hexane) was added to a solution of {3-(3-nitrobenzyl)-7-dimethylcarbamoyloxy-2-oxo-2H-1-benzopyran-4-yl}acetic acid (compound 7f-1-1COOH) (350 mg, 0.82 mmol) in methanol (5.0 mL)/dichloromethane (8.0 mL), and the mixture was stirred at room temperature for 10 minutes. Aacetic acid (2.0 mL) was added to the reaction mixture, and the title compound (338 mg, 94%) was obtained by vacuum concentration as a pale yellow powder.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[NH:11][C:10](=[O:19])[C:9]([C:20]([OH:22])=O)=[CH:8]2)(=[O:3])[CH3:2].S(Cl)([Cl:25])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[NH:11][C:10](=[O:19])[C:9]([C:20]([Cl:25])=[O:22])=[CH:8]2)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1cc2cc(C(=O)O)c(=O)[nH]c2cc1OC(C)=O
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Oc1cc2cc(C(=O)Cl)c(=O)[nH]c2cc1OC(C)=O

Procedure:
A mixture of 6,7-diacetoxy-1,2-dihydro-2-oxoquinoline-3-carboxylic acid (100 mg), thionyl chloride (70 μL), and dimethylformamide (one drop) was heated under reflux for 4.5 hours in 50 mL of benzene, and the solvent was distilled off. Benzene (30 mL) was added to the residue and the benzene was distilled off again, followed by vacuum drying, to yield 6,7-diacetoxy-1,2-dihydro-2-oxoquinoline-3-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([C:18]([C:17]1[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=1[O:15][CH:12]([CH3:14])[CH3:13])=[O:19])[CH2:8][CH2:7]2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Clc1cccc2c1CNCC2
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cccc(Cl)c2C1

Procedure:
Prepared in analogy to example 1.1 from 8-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [61563-33-5]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:20]#[N:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49]O.N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[CH:17][C:16]([O:19][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46])=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:20]#[N:21]
Reactant: CN(C)CCO
Reactant: N#Cc1cnc2cc3ccc(O)cc3cc2c1Nc1ccc(Cl)cc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)CCOc1ccc2cc3ncc(C#N)c(Nc4ccc(Cl)cc4Cl)c3cc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.5 %

Procedure:
To a suspension of 189.1 mg (0.50 mmol) of 4-(2,4-dichloroanilino)-7-hydroxybenzo[g]quinoline-3-carbonitrile, 207.2 mg (0.79 mmol) of triphenylphosphine and 66.9 mg (0.75 mmol) of 2-(dimethylamino)-ethanol in 3.0 mL of anhydrous methylene chloride at 0° C. is added dropwise diethyl azodicarboxylate. The resulting reaction mixture is stirred at room temperature under nitrogen for 2 days. The solvent is concentrated in vacuo and the residue is purified on preparative thin layer chromatography (developing solvent: 9:1 methylene chloride/methanol) to provide 46.3 mg (20.5%) of 4-(2,4-dichloroanilino)-7-[2-(dimethylamino)ethoxy]benzo[g]quinoline-3-carbonitrile as a yellow solid, mp 115–117° C.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=4[CH3:23])[CH:11]=[C:10]([C:24]([NH:26][CH2:27][C:28]4[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=4[CH3:34])=[O:25])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:37]5[CH2:42][CH2:41][O:40][CH2:39][CH2:38]5)=[CH:17][C:16]=4[CH3:23])[CH:11]=[C:10]([C:24]([NH:26][CH2:27][C:28]4[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=4[CH3:34])=[O:25])[C:9]=3[CH:8]=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)cc3C)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3C)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(4-formyl-2-methylphenyl)-1H-indazole-4-carboxamide (0.15 g, 0.31 mmol) in methanol (5 mL), morpholine (0.081 g, 0.93 mmol) and acetic acid (0.01 g, 0.311 mmol) were added at room temperature and reaction stirred at room temperature for 18 h. Then NaBH3CN (0.023 g, 0.37 mmol) was added and reaction stirred again at room temperature for 18 h. On completion, methanol was removed under reduced pressure and water added to the residue. The aqueous phase was extracted with 10% MeOH/DCM and the combined organic layers dried over sodium sulfate and concentrated to obtain crude material which was purified by column chromatography to afford 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(2-methyl-4-(morpholinomethyl)phenyl)-1H-indazole-4-carboxamide (34% yield). LCMS: 554.30 (M+1)+; HPLC: 95.54% (@ 254 nm) (Rt; 5.595); 1H NMR (DMSO-d6, 400 MHz) δ 11.49 (s, 1H), 8.52 (t, 1H), 8.38 (s, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.02-7.28 (m, 3H), 5.86 (s, 1H), 5.22-5.26 (m, 1H), 4.34 (d, 2H, J=4.4 Hz), 3.58 (t, 4H), 3.47 (s, 2H), 2.37 (s, 4H), 2.25 (s, 3H), 2.18 (s, 3H), 2.09-2.06 (m, 2H), 2.09 (s, 3H), 1.98-2.03 (m, 2H), 1.86 (m, 2H), 1.66-1.69 (m, 2H).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:28])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:9]([C:26]#[N:27])[CH:8]=1)=[O:5].[C:29](OCC)(OCC)(OCC)[CH3:30]>>[CH2:14]([N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[CH:3]=[C:2]([CH3:28])[N:1]=[C:29]2[CH3:30])=[CH:8][C:9]=1[C:26]#[N:27])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCN(CCCCCC)c1ccc(NC(=O)/C=C(/C)N)cc1C#N
Reactant: CCOC(C)(OCC)OCC
Product: CCCCCCN(CCCCCC)c1ccc(-n2c(C)nc(C)cc2=O)cc1C#N
Temperature: 150 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
A mixture of (Z)-3-amino-N-(3-cyano-4-(dihexylamino)phenyl)but-2-enamide (1.30 g, 3.38 mmol) and triethyl orthoacetate (30 mL) was stirred at 150° C. overnight. The mixture was then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=50:1) to give the title compound as pale yellow oil (60 mg, 4%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:9][CH3:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:11][C@H:12](CO)[CH:13]([CH3:15])[CH3:14]>[Zn].ClC1C=CC=CC=1>[CH:13]([C@H:12]1[CH2:10][O:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:11]1)([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccccc1
Reactant: CC(C)[C@H](N)CO
Agent: [Zn]
Solvent: Clc1ccccc1
Product: CC(C)[C@H]1COC(c2ccccc2)=N1
Yield: 83 %

Procedure:
Under an argon atmosphere, a mixture of methyl benzoate (1.5 mmol), (L)-valinol (1.8 mmol), Zn4(OCOCF3)6O (0.15 mmol in terms of the number of moles of zinc atom; the number of moles of the zinc compound used in the following Examples is also shown in terms of the number of moles of zinc atom) and chlorobenzene (2.5 mL) was heated under reflux for 12 hours. From the resulting solution, the solvent was removed using an evaporator, and the residues were purified by silica gel column chromatography (hexane/ethyl acetate=10/1 (V/V)) to give (S)-4-isopropyl-2-phenyl-1,3-oxazoline in 83% yield.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH3:8])[CH2:6][CH2:5][C@@H:4]([NH:9][C:10]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=2)[CH2:3]1.[CH:22]1([NH2:25])[CH2:24][CH2:23]1>CN1C(=O)CCC1>[CH:22]1([NH:25][C:12]2[N:11]=[C:10]([NH:9][C@@H:4]3[CH2:5][CH2:6][C@@H:7]([CH3:8])[C@H:2]([OH:1])[CH2:3]3)[C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH2:24][CH2:23]1
Reactant: NC1CC1
Reactant: C[C@@H]1CC[C@@H](Nc2nc(S(C)(=O)=O)ncc2C#N)C[C@H]1O
Solvent: CN1CCCC1=O
Product: C[C@@H]1CC[C@@H](Nc2nc(NC3CC3)ncc2C#N)C[C@H]1O
Temperature: 80 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
To a solution of 4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (362 mg, 1.166 mmol; synthesis described herein) in NMP (5.832 mL), was added cyclopropanamine (0.485 mL, 7.00 mmol). The reaction was stirred at 80° C. for 5 h in a sealed vessel and then allowed to cool to ambient temperature overnight. The reaction mixture was concentrated under reduced pressure to an oil that was purified by silica gel chromatography (0-60% ethyl acetate/hexane) to afford 2-(cyclopropylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)pyrimidine-5-carbonitrile (265 mg, 0.922 mmol, 79% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.99-8.32 (m, 3H), 4.54 (d, J=5.08 Hz, 1H), 3.85-4.13 (m, 1H), 2.80-3.03 (m, 1H), 2.58-2.75 (m, 1H), 1.50-2.08 (m, 3H), 1.03-1.42 (m, 3H), 0.88 (d, J=6.25 Hz, 4H), 0.29-0.68 (m, 4H). MS (ESI) m/z 288.1 [M+1]+.