Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:18])[C@@H:6]([NH2:17])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:3].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[CH2:2]([O:4][C:5](=[O:18])[C@@H:6]([NH:17][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
(S)-Ethyl-2-amino-3-(4-nitrophenyl)propionate hydrochloride (1.23 g, 4.47 mmol) was suspended in dichloromethane (25 mL) and to this suspension was added benzoyl chloride (0.628 g, 4.47 mmol) and triethylamine (1.36 g, 13.4 mmol). The mixture was stirred overnight at room temperature under nitrogen. The crude reaction was washed with 5% HCl, water, brine, dried (Na2SO4), concentrated and purified by flash chromatography (silica gel, 2:1 hexanes:EtOAc) to afford the title compound as a white powder (0.865 g, 57%): MS(ES+) m/e 343 [M+H]; mp 99-101° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:5]2[N:6]([C:8]([C:12](O)=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:7]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[CH3:54][C:55]([NH2:59])([CH3:58])[CH2:56][NH2:57]>CN(C=O)C>[NH2:59][C:55]([CH3:58])([CH3:54])[CH2:56][NH:57][C:12]([C:8]1[N:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:5]2=[N:10][C:9]=1[CH3:11])=[O:13]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)O
Reactant: CC(C)(N)CN
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(Cl)cn2c1C(=O)NCC(C)(C)N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
70 mg of 6-chloro-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid (0.20 mmol), 96 mg (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU, 0.30 mmol) and 80 mg of 4-methylmorpholine (0.79 mmol) were initially charged in 1 ml of DMF. 35 mg of 2-methylpropane-1,2-diamine (0.40 mmol) were then added, and the mixture was stirred at RT overnight. The reaction solution was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product was taken up in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with ethyl acetate, the combined organic phases were dried over sodium sulphate and filtered. The filtrate was concentrated and lyophilized. This gave 38 mg of the title compound (45% of theory).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[NH2:18])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=1.C[Si](Cl)(C)C>C(O)CCC>[NH2:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]1[NH:11][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])=[CH:24][CH:25]=2)[N:3]=1
Reactant: CC(=O)N(C)c1ccc(N)cc1
Reactant: NC1CCCCC1Nc1nc(Cl)nc2[nH]ccc12
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(NC3CCCCC3N)c3cc[nH]c3n2)cc1
Temperature: 116 °C
Yield: 9 %

Procedure:
A mixture of N1-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclohexane-1,2-diamine (44 mg, 0.17 mmol), N-(4-aminophenyl)-N-methylacetamide (56 mg, 0.34 mmol) and trimethylsilyl chloride (0.146 mL, 1.15 mmol) in nBuOH (2 mL) was heated at 116° C. for 4 h. It was then purified by HPLC to give the titled compound (6 mg). MS 394.2 (M+H); UV 201.4, 262.7, 306.7 nm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:16][C@H:17]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:24])=[O:23])[C:18](O)=[O:19])[CH:5]=[CH:6][C:7]=1[CH:8]1[S:12](=[O:14])(=[O:13])[NH:11][C:10](=[O:15])[CH2:9]1.F[P-](F)(F)(F)(F)F.[N:38]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=N1.C(N(CC)C(C)C)(C)C.C1(N)C(N)=CC=CC=1>CN(C=O)C>[NH2:38][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[NH:40][C:18](=[O:19])[CH:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24])[CH2:16][C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[S:12](=[O:13])(=[O:14])[NH:11][C:10](=[O:15])[CH2:9]2)=[C:2]([Br:1])[CH:3]=1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C1CC(c2ccc(C[C@H](NS(=O)(=O)c3ccccc3)C(=O)O)cc2Br)S(=O)(=O)N1
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)C(Cc1ccc(C2CC(=O)NS2(=O)=O)c(Br)c1)NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
(2S)-3-[3-Bromo-4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]-2-[(phenylsulfonyl)-amino]propanoic acid (20.7 mg, 0.040 mmol) in DMF (1 mL) was treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (21.2 mg, 0.0480 mmol). After stirring 5 minutes at rt a solution of N,N-diisopropylethylamine (34.8 μL, 0.200 mmol) and 1,2-benzenediamine (6.49 mg, 0.0600 mmol) in DMF (1.0 mL) was added. The solution stirred at rt for 2 h. Purification by preparative LCMS afforded product as a white solid (18.1 mg, 75%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CC(C)=O>[C:20]1([S:26][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(Sc2ccccc2)c([N+](=O)[O-])c1
Yield: 56 %

Procedure:
To a stirred mixture of 2,4-dinitrofluorobenzene, 5.69 ml (45 mmol) and potassium carbonate 6.3 g (45 mmol) in acetone was added benzenethiol 4.65 ml (45 mmol). The mixture was heated to reflux for 2 hours, cooled and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with saturated potassium carbonate, dried over sodium sulfate, filtered and the solvent removed under reduced pressure to give 7.0 g (56%) of 2,4-dinitrophenyl phenyl sulfide.
Reaction SMILES: F[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6].[H-].[Na+].[CH3:18][O:19][CH2:20][CH2:21][SH:22]>CN(C=O)C>[CH3:18][O:19][CH2:20][CH2:21][S:22][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([F:14])([F:13])[F:12])[C:5]([OH:7])=[O:6]
Reactant: COCCS
Reactant: Cc1c(C(=O)O)ccc(C(F)(F)F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCSc1c(C(F)(F)F)ccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1.45 g (6.53 mmol) of 3-fluoro-2-methyl-4-trifluoromethylbenzoic acid were initially charged in 40 ml of DMF. 809 mg (20.2 mmol) of NaH were added a little at a time. After the evolution of gas had ceased, 1.20 g (13.1 mmol) of 2-methoxyethanethiol were added a little at a time. The mixture was stirred at RT for 10 minutes and then heated at 80° C. for 15 h. The reaction mixture was cooled and concentrated under reduced pressure, and for work-up water was added and the mixture was acidified with 1M HCl. The product precipitated and was removed by filtration. The product was then washed with water and n-heptane. What was isolated were 1.7 g of the pure product.
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].N1C=C(C#C[C:23]2[CH:24]=[C:25]([CH:47]=[CH:48][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])N2C=CN=CC=12>>[N:5]1[CH:4]=[C:3]([C:1]#[C:2][C:48]2[CH:47]=[C:25]([CH:24]=[CH:23][C:49]=2[CH3:50])[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]3)=[C:31]([C:43]([F:46])([F:45])[F:44])[CH:30]=2)=[O:27])[N:7]2[C:6]=1[CH:11]=[CH:10][CH:9]=[N:8]2
Reactant: C#Cc1cnc2cccnn12
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cnccn12
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cnc2cccnn12

Procedure:
The title compound was synthesized in a manner similar to that described for Example 14, from 3-ethynylimidazo[1,2-b]pyridazine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (Prepared as described in Example 2). The product was obtained as a solid: 533 m/z (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([NH:35]C(=O)C)=[CH:33][CH:32]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][C:31]2[CH:40]=[CH:39][C:34]([NH2:35])=[CH:33][CH:32]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNc3ccc(N)cc3)ccc21
Yield: 95.9 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (30.0 mg, 0.0730 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4′-aminoacetanilide (44 mg, 0.29 mmol), acetic acid (0.084 mL, 1.5 mmol) and sodium triacetoxyborohydride (46 mg, 0.22 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(4-aminophenylaminomethyl)indol-2-yl]isoindolinone (35.2 mg, yield 88%).
Reaction SMILES: [C:1]([NH:3][C:4](=[N:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])SC)#[N:2].[CH2:18]([NH2:21])[CH2:19][CH3:20]>C(O)C>[C:1]([NH:3][C:4]([NH:7][CH2:8][CH2:9][S:10][CH2:11][C:12]1[NH:16][CH:15]=[N:14][C:13]=1[CH3:17])=[N:21][CH2:18][CH2:19][CH3:20])#[N:2]
Reactant: CSC(=NCCSCc1[nH]cnc1C)NC#N
Reactant: CCCN
Solvent: CCO
Product: CCCN=C(NC#N)NCCSCc1[nH]cnc1C
Yield: 71.4 %

Procedure:
A solution of N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]-S-methylisothiourea (2.69 g.) and n-propylamine (1.1 g.) in ethanol (50 ml.) was heated under reflux for 6 hours. Concentration, followed by chromatographic purification on a column of silica gel with ethyl acetate-isopropyl alcohol (4:1) as eluant and final recrystallisation from aqueous isopropyl alcohol afforded N-cyano-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]N"-propylguanidine (2.0 g.) m.p. 108°-110°. (Found: C, 51.4; N, 7.4; N, 30.0; S, 11.4. C12H20N6S requires: C, 51.4; H, 7.2; N, 30.0; S, 11.4).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][CH:28]4[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]4)[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>ClCCl>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][CH:28]4[CH2:29][NH:30][CH2:31]4)[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CN(C(=O)OC(C)(C)C)C4)c4cc(F)ccc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CC4CNC4)c4cc(F)ccc34)nc12
Yield: 17 %

Procedure:
To a stirred solution of tert-butyl 3-((3-(7-(tert-butylcarbamoyl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)-6-fluoro-1H-indazol-1-yl)methyl)azetidine-1-carboxylate (70 mg, 107 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL). After 15 h the mixture was concentrated in vacuo and the residue dissolved in 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0-6% methanol containing 10% ammonium hydroxide in dichloromethane) followed by SFC chromatography (eluent contained TFA) gave 2-(1-azetidin-3-ylmethyl-6-fluoro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butyl amide trifluoroacetate (10 mg, 17%). MS (M+H)+=422; 1H NMR (DMSO-d6) δ: 9.09 (s, 1H), 8.49 (dd, J=8.9, 5.4 Hz, 1H), 8.40 (s, 1H), 7.92 (s, 1H), 7.77 (dd, J=9.8, 1.9 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 4.77 (d, J=7.0 Hz, 2H), 3.87-4.18 (m, 4H), 1.52 (s, 9H), 1.24 (d, J=4.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][CH:3]=1.Cl.[CH3:25][O:26][C:27]1[CH:31]=[C:30]([CH2:32][NH2:33])[O:29][N:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:17][C@@H:18]([CH3:23])[C:19]([F:20])([F:21])[F:22])=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:33][CH2:32][C:30]2[O:29][N:28]=[C:27]([O:26][CH3:25])[CH:31]=2)=[O:14])=[CH:6][CH:7]=1
Reactant: COc1cc(CN)on1
Reactant: C[C@H](Oc1ncc(C(=O)O)cc1-c1ccc(Cl)cc1)C(F)(F)F
Agent: Cl
Product: COc1cc(CNC(=O)c2cnc(O[C@@H](C)C(F)(F)F)c(-c3ccc(Cl)cc3)c2)on1

Procedure:
The title compound was synthesized in analogy to Example 1, using (S)-5-(4-chlorophenyl)-6-(1,1,1-trifluoropropan-2-yloxy)nicotinic acid (Example AO) and 3-methoxy-5-isoxazolemethanamine hydrochloride as starting materials. MS: 456.1 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:9]([N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Product: N#Cc1ccc(N(Cc2ccccc2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and benzyl bromide
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OCC)(OCC)(OCC)[CH3:26].C(OC1C=C2C(C(N)=C(NCC(C)C)C=N2)=CC=1)C1C=CC=CC=1>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:25]([CH3:26])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reactant: CCOC(C)(OCC)OCC
Agent: CC(C)CNc1cnc2cc(OCc3ccccc3)ccc2c1N
Solvent: CCOCC
Product: Cc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Temperature: 160 °C

Procedure:
The preparation of 7-benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine is described in Parts A-F of Example 1. Under a nitrogen atmosphere, triethyl orthoacetate (4.59 mL, 25.0 mmol) was added to a solution of 7-benzyloxy-N-(2-methylpropyl)quinoline-3,4-diamine (8.05 g, 25.0 mmol) in xylenes (130 mL), and the resulting solution was heated at reflux (160° C.) overnight. The solvent volume was reduced to 70 mL using a Dean-Stark trap. Over a period of a few days, a precipitate formed. Diethyl ether was added, and the precipitate was isolated by filtration and washed with diethyl ether to provide 6.81 g of 7-benzyloxy-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline as a light-brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[CH:17][S:16][C:10]=2[NH:11][C:12](=[O:15])[CH2:13][N:14]=1.[I:19]Cl.C([O-])(=O)C.[Na+].S(=O)(O)[O-].[Na+].N>O.CO.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([I:19])[S:16][C:10]=2[NH:11][C:12](=[O:15])[CH2:13][N:14]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2ccsc2N1
Reactant: ClI
Agent: CC(=O)[O-]
Agent: N
Agent: O=S([O-])O
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: O=C1CN=C(c2ccccc2Cl)c2cc(I)sc2N1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 54.8 g of 5-(2-chlorophenyl)-1,3-dihydro-2H-thieno[2,3-e][4,1]diazepin-2-one [NL patent 7,205,730, Nov. 1972, Hoffmann-La Roche & Co., AG, Basle]in 350 ml of acetic acid and 350 ml of methanol was treated with 64.4 g of iodine monochloride and 16.2 g of sodium acetate. The mixture was stirred for 15 minutes at room temperature. A solution of 65 g of sodium bisulfite in 350 ml of water was then added and stirring was continued for 10 minutes. The mixture was neutralized by addition of 500 ml of conc. ammonia and 1 kg of ice. The precipitated product was filtered off and washed with water and ethanol. Recrystallization from tetrahydrofuran/ ethanol gave off-white crystals of the title compound with m.p. 229°-231°.
Reaction SMILES: [Cl-].[C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH+:10]=[C:9]([CH3:14])[C:8]2([CH3:16])[CH3:15])([OH:4])=[O:3].[CH3:17][N:18]([CH3:29])[C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH:25]=O)=[CH:21][CH:20]=1>C(#N)C>[CH3:17][N:18]([CH3:29])[C:19]1[CH:28]=[CH:27][C:22]([C:23]2[CH:24]=[CH:25][N+:10]3[C:11]4[C:7]([C:8]([CH3:16])([CH3:15])[C:9]=3[CH:14]=2)=[CH:6][C:5]([C:2]([O-:4])=[O:3])=[CH:13][CH:12]=4)=[CH:21][CH:20]=1
Reactant: CC1=[NH+]c2ccc(C(=O)O)cc2C1(C)C
Reactant: CN(C)c1ccc(C=CC=O)cc1
Agent: [Cl-]
Solvent: CC#N
Product: CN(C)c1ccc(-c2cc[n+]3c(c2)C(C)(C)c2cc(C(=O)[O-])ccc2-3)cc1
Temperature: 60 °C

Procedure:
A suspension of 5-carboxy-2,3,3-trimethyl-3H-indolium chloride (14.5 g, 60.5 mmol) and 4-dimethylamino cinnamaldehyde (10.6 g, 60.5 mmol) in 200 ml of acetonitrile was heated to 60° C. for 24 h. The solvent was removed under vacuum and the resulting residue was subjected to silica gel chromatography twice. Then, recrystallization from methanol and ether afforded 10 g of target compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:27])([CH3:26])[C:4]#[C:5][C:6]1[CH:7]=[C:8]2[C:19]3([CH2:23][O:22][C:21]([NH2:24])=[N:20]3)[C:18]3[C:13](=[N:14][CH:15]=[C:16](Br)[CH:17]=3)[O:12][C:9]2=[CH:10][CH:11]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:1][O:2][C:3]([CH3:27])([CH3:26])[C:4]#[C:5][C:6]1[CH:7]=[C:8]2[C:19]3([CH2:23][O:22][C:21]([NH2:24])=[N:20]3)[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH:17]=3)[O:12][C:9]2=[CH:10][CH:11]=1
Reactant: COC(C)(C)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(Br)cnc1O2
Reactant: OB(O)c1cccnc1
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: [K+]
Solvent: C1CCOC1
Product: COC(C)(C)C#Cc1ccc2c(c1)C1(COC(N)=N1)c1cc(-c3cccnc3)cnc1O2
Temperature: 110 °C
Yield: 78.7 %

Procedure:
7-(3-Methoxy-3-methyl-1-butyn-1-yl)-3-bromo-spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (300 mg, 0.700 mmol), tetrakis(triphenylphosphine)palladium (81 mg, 0.070 mmol), 3-pyridineboronic acid (172 mg, 1.401 mmol) and THF (7005 μL, 0.700 mmol) were combined in a sealable tube. Potassium carbonate (1.5 M) (1401 μL, 2.101 mmol) was added to the tube, which was then flushed with argon, sealed and heated at 110° C. for 1.5 hours. The reaction was diluted with water (50 mL) and poured into a separatory funnel containing ethyl acetate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (40 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide 7-(3-methoxy-3-methyl-1-butyn-1-yl)-3-(3-pyridinyl)spiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazol]-2′-amine (235 mg, 0.551 mmol, 79% yield) as a light yellow solid. MS m/z=427.2 [M+H]+. Calc'd for C25H23N4O3: 427.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.C1(N=C=N)CCCCC1.Cl.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:39]2C(=O)C3C(=CC=C(OC4C=CC=CC=4)C=3)C2=O)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:8])[N:39]([C:27]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)=[C:25]([O:24][CH3:23])[CH:26]=1)[C:9]2=[O:10]
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: COc1cc(N2C(=O)c3ccc(Oc4ccccc4)cc3C2=O)ccc1OCCN1CCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N=C=NC1CCCCC1
Solvent: ClCCl
Product: COc1cc(N2C(=O)c3ccc(F)cc3C2=O)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Fluorophthalic anhydride [Acros] (0.84 g, 5 mmol) was dissolved in dichloromethane (30 ml) and polymer bound N-cyclohexylcarbodiimide [Argonaut Technologies] (1.69 mol. eq./g, 3 g) was added, followed by a solution of 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine [Example A4] (1.18 g, 5.0 mmol) and a catalytic amount of 4-dimethylaminopyridine. The mixture was stirred for 16 h at ambient temperature. The resin was filtered off over filter-aid, and washed with dichloromethane. The filtrate was evaporated in vacuo and purified by chromatography using a Biotage Flash40M cartridge, eluting with dichloromethane-methanol to give the 5-fluoro-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione;
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:17]([OH:26])[C:16]([Br:27])=[CH:15][CH:14]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[NH2:12][C:13]1[C:18]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[C:17]([O:26][S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[C:16]([Br:27])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)c1c(N)ccc(Br)c1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2c(Br)ccc(N)c2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 80.2 %

Procedure:
4-Methylbenzenesulfonyl chloride (2.26 g) was added to a solution of tert-butyl 6-amino-3-bromo-2-hydroxybenzoate (Intermediate 51, 2.85 g), DMAP (1.21 g), and triethylamine (1.5 g) in DCM (40 mL) and left at room temperature for 1 hour. The resulting solution was washed with water, filtered through a phase separator and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-15% to give tert-butyl 6-amino-3-bromo-2-(4-methylbenzenesulfonyloxyl)benzoate (3.51 g) as an off-white solid.