Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:10]([O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[NH2:23][C:24]1[CH:37]=[CH:36][C:27]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:29])=[C:26]([Cl:38])[CH:25]=1>>[ClH:2].[C:28]([C:27]1[CH:36]=[CH:37][C:24]([NH:23][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:18][CH2:19][CH2:20][O:21][CH3:22])=[C:10]([O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:11]=3)[N:6]=[CH:5][N:4]=2)=[CH:25][C:26]=1[Cl:38])(=[O:29])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Nc1ccc(C(=O)c2ccccc2)c(Cl)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCOC
Agent: Cl
Product: COCCOc1cc2ncnc(Nc3ccc(C(=O)c4ccccc4)c(Cl)c3)c2cc1OCCOC
Yield: 32 %

Procedure:
Using an analogous procedure to that described in Example 1, 4-chloro-6,7-di-(2-methoxyethoxy)quinazoline hydrochloride was reacted with 4-amino-2-chlorobenzophenone to give 4-(4-benzoyl-3-chloroanilino)-6,7-di-(2-methoxyethoxy)quinazoline hydrochloride salt in 32% yield, m.p. 242°-244° C.;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]([CH3:15])[CH3:14])[CH2:10][C@H:9]1[CH2:16][OH:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]([CH3:14])[CH3:15])[CH2:10][C@H:9]1[CH2:16][O:17][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: CN(C)[C@@H]1C[C@@H](CO)N(C(=O)OC(C)(C)C)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC[C@@H]2C[C@@H](N(C)C)CN2C(=O)OC(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
To a stirred solution of trans-1-tert-butoxycarbonyl-4dimethylamino-(2S)-hydroxymethyl pyrrolidine (180 mg, 0.73 mmol), methyl 4-hydroxybenzoate (114 mg, 0.75 mmol), and Ph3P (296 mg, 1.13 mmol) in THF (10 ml) was added DIAD (227 mg, 1.13 mmol) at 0° C. The reaction mixture was stirred at 70° C. for 18 hr. The mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (1:2, v/v) to MeOH—CH2Cl2(5:95, v/v) as eluent to give methyl 4-[trans-1-tert-butoxycarbonyl-4-dimethylamino(2S) -pyrrolidinyl]methoxybenzoate (180 mg, 68%) as a pale yellow oil. 1H-NMR (CDCl3) δ1.46 (s, 9H), 1.80-1.95 (m, 1H), 2.20-2.23 (m, 1H), 2.24 (s, 6H), 2.90-2.95 (m, 1H), 3.10-3.30 (m, 1H), 3.50-3.65 (m, 1H), 3.88 (s, 3H), 3.95-4.35 (m, 3H), 6.93-6.95 (m, 2H), 7.96-7.98 (m, 2H).
Reaction SMILES: [CH:1]([B:5]([O:10][CH:11]([CH3:13])[CH3:12])OC(C)C)([CH2:3][CH3:4])[CH3:2].[C:14]([Li])#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].Cl.[B]>C(OCC)C>[CH:1]([B:5]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[O:10][CH:11]([CH3:12])[CH3:13])([CH2:3][CH3:4])[CH3:2]
Reactant: [Li]C#CCCCCCC
Reactant: CCC(C)B(OC(C)C)OC(C)C
Agent: Cl
Agent: [B]
Solvent: CCOCC
Product: CCCCCCC#CB(OC(C)C)C(C)CC

Procedure:
sec-Butyl(1-octynyl)isopropoxyborane was prepared following the method of Example 12 with sec-butyldiisopropoxyborane (10.79 g, 58 mmol) in ethyl ether (58 mL) and added to a solution of 1-octynyllithium (64 mmol in 64 mL, THF) and quenched with HCl in ethyl ether (18.82 mL, 64 mmol). Yield: 10.1 g (74%), bp 68°-70° C. (0.1 mm Hg); n20D 1.4366; proton NMR (CDCl3) δ4.60 (septet, J=18 Hz, 1H), 2.23 (triplet, 2H), 1.17 (d, J=18 Hz, 6H), 0.87 (m, 9H); boron NMR (CDCl3) δ+41.6 ppm(s); mass spectrum (chemical ionization, isobutee) m/e 237 (M+H, 15%); IR (thin film) 2183, 1324 cm1. Anal. Calcd. for C15H29BO: C, 76.77; H, 12.38; B, 4.58. Found: C, 76.30; H, 12.39; B, 4.63.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([CH:16]=O)[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)[CH3:2].[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25]>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([CH:16]=[C:23]3[S:19][C:20](=[O:25])[NH:21][C:22]3=[O:24])[CH:14]=[CH:15][C:10]=2[O:9][CH:8]=1)[CH3:2]
Reactant: O=C1CSC(=O)N1
Reactant: CCOC(=O)CCc1coc2ccc(C=O)cc12
Product: CCOC(=O)CCc1coc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 3-(5-Formyl-benzofuran-3-yl)-propionic acid ethylester (intermediate 71) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[C:13]([Cl:20])=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=2[C:10]([CH3:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)C.N1CCOCC1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:12]2=[C:13]([Cl:20])[N:14]=[CH:15][C:16]([C:17]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:19])=[C:11]2[C:10]([CH3:21])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)O)c12
Reactant: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCN1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-chloro-3-methyl-pyrrolo[2,3-c]pyridine-1,4-dicarboxylic acid 1-tert-butyl ester (80 mg) in dimethylformamide (2 ml) was added 4-ethylmorpholine (131 μl), morpholine (46 μl), 1-hydroxybenzotriazole hydrate (54 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (60 mg) and the solution stirred at room temperature overnight. The dimethylformamide was evaporated and the residue dissolved in ethyl acetate (20 ml). The organic layer was then washed with 5% sodium hydrogen carbonate solution (2×4 ml) and water (2×10 ml). The organic layer was dried (MgSO4) and evaporated to give a yellow oil (107 mg) which was used without further purification.
Reaction SMILES: C(OCC1[N:6](CCC)C2C3C=C(O)C=CC=3N=CC=2N=1)C.[CH2:22]([O:24][CH2:25][C:26]1[N:27]([CH2:45][CH2:46][CH3:47])[C:28]2[C:37]3[CH:36]=[C:35]([O:38][CH:39]4[CH2:43][CH2:42][O:41][CH2:40]4)[CH:34]=[CH:33][C:32]=3[N:31]=[CH:30][C:29]=2[N:44]=1)[CH3:23].OC1CCOC1.OCCCN1CCCC1=O.C(OCC1N(CCC)C2C3C=C(OC4CCOC4)C=CC=3N=C(N)C=2N=1)C.[OH-].[NH4+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>>[CH2:22]([O:24][CH2:25][C:26]1([NH2:6])[NH:44][C:29]2[CH:30]=[N:31][C:32]3[CH:33]=[CH:34][C:35]([O:38][CH:39]4[CH2:43][CH2:42][O:41][CH2:40]4)=[CH:36][C:37]=3[C:28]=2[N:27]1[CH2:45][CH2:46][CH3:47])[CH3:23]
Reactant: CCCn1c(COCC)nc2cnc3ccc(O)cc3c21
Reactant: CCCn1c(COCC)nc2cnc3ccc(OC4CCOC4)cc3c21
Agent: CCCn1c(COCC)nc2c(N)nc3ccc(OC4CCOC4)cc3c21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C1CCCN1CCCO
Product: CCCN1c2c(cnc3ccc(OC4CCOC4)cc23)NC1(N)COCC

Procedure:
The synthesis of 2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol is described in Parts A-I of Example 2. A modification of the method described in Part A of Example 405 was used to convert 2-ethoxymethyl-1-propyl-1H-imidazo[4,5-c]quinolin-8-ol into 2-(ethoxymethyl)-1-propyl-8-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinoline using 3-hydroxytetrahydrofuran in lieu of 1-(3-hydroxypropyl)pyrrolidin-2-one. Modifications of the methods described in Parts B and C of Example 405 were used to convert 2-(ethoxymethyl)-1-propyl-8-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinoline into 2-(ethoxymethyl)-1-propyl-8-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolin-4-amine. Parts B and C were combined by omitting the aqueous work up of Part B, in other words, the ammonium hydroxide and p-toluenesulfonyl chloride reagents used in Part C were added to the reaction mixture in Part B. The reaction was worked up as described in Part C of Example 405. 2-(Ethoxymethyl)-1-propyl-8-(tetrahydrofuran-3-yloxy)-1H-imidazo[4,5-c]quinolinamine was isolated as tan needles, mp 173-175° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([OH:9])=O)=[CH:3][CH:2]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl.CCOC(C)=O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]([N:35]2[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:37][CH2:36]2)=[O:9])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccncc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A sample of 4-pyridinecarboxylic acid (1.32 g, 10.7 mmol) was dissolved in 50 mL of CH2Cl2. To this solution under N2 was added N-methylmorpholine (1.21 mL, 11.0 mmol) before it was cooled to -78° C. and isobutylchloroformate (1.39 mL, 10.7 mmol) was added. The reaction was allowed to warm to 0° C. and stirred at this temperature for 30 minutes before it was cooled again to -78° C. and t-butyloxycarbonyl piperazine (2.0 g, 10.7 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 18 hours. All solvent was removed under reduced pressure to give a residue that was dissolved in EtOAc, washed with saturated NaHCO3 and brine, and dried (Na2SO4). After all solvent was removed in vacuo, the residue was chromatographed to generate 1.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[O:6][C:7]2[C:13]([CH2:14][CH:15]=[CH2:16])=[CH:12][C:11]([Cl:17])=[CH:10][C:8]=2[N:9]=1.C(BCCC(C)C)CC(C)C.CC(=CC)C.[OH-:38].[Na+].OO>C1COCC1.ClCCl.O>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][C:5]1[O:6][C:7]2[C:13]([CH2:14][CH2:15][CH2:16][OH:38])=[CH:12][C:11]([Cl:17])=[CH:10][C:8]=2[N:9]=1
Reactant: C=CCc1cc(Cl)cc2nc(Cc3ccccc3Cl)oc12
Reactant: [OH-]
Agent: CC(C)CCBCCC(C)C
Agent: CC=C(C)C
Agent: OO
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: OCCCc1cc(Cl)cc2nc(Cc3ccccc3Cl)oc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(2-chlorobenzyl)-5-chloro-7-allylbenzoxazole (40 g, 0.126 mol) in THF (63 ml) was added to a solution at 0° C. of di-iso-amylborane prepared in THF from 10.8 g of borane-tetrahydrofuran complex and 19.5 g of 2-methyl-2-butene. The reaction mixture was allowed to warm to room temperature. After 16 hours, the reaction mixture was cooled to 5° C. and 3 N sodium hydroxide (50 ml) was added slowly followed by the slow addition of 30% hydrogen peroxide (50 ml). After 3 hours, the reaction mixture was diluted with dichloromethane (300 ml) and water (300 ml). The layers were separated and the aqueous solution was extracted with dichloromethane (2×150 ml). The dichloromethane extracts were combined and washed with water (3×200 ml) and evaporated under reduced pressure to give an oil. The crude product was purified by flash chromatography (silica gel; 300 g). Elution with 2 l of 1:1 hexane/dichloro-methane gave starting material (3.5 g). Elution with dichloromethane (5 l) afforded 32 g of the title compound, mp 87-89° C. (from toluene).
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:33]=[CH:32][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][NH:16][CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][C:5]=1[F:34].C(N(CC)C(C)C)(C)C.Cl[C:46]1[S:47][C:48]2[C:53]([Cl:54])=[N:52][C:51]([C:55]([F:58])([F:57])[F:56])=[N:50][C:49]=2[N:59]=1>C(Cl)(Cl)Cl>[F:35][CH:2]([F:1])[O:3][C:4]1[CH:33]=[CH:32][C:7]([CH2:8][NH:9][C:10]([C@H:12]2[CH2:17][N:16]([C:46]3[S:47][C:48]4[C:53]([Cl:54])=[N:52][C:51]([C:55]([F:58])([F:57])[F:56])=[N:50][C:49]=4[N:59]=3)[CH2:15][CH2:14][N:13]2[S:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:31])[F:30])=[CH:25][CH:26]=2)(=[O:20])=[O:19])=[O:11])=[CH:6][C:5]=1[F:34]
Reactant: O=C(NCc1ccc(OC(F)F)c(F)c1)[C@H]1CNCCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)c1nc(Cl)c2sc(Cl)nc2n1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(OC(F)F)c(F)c1)[C@H]1CN(c2nc3nc(C(F)(F)F)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(OC(F)(F)F)cc1
Yield: 79 %

Procedure:
To a solution of the compound (796 mg) obtained in Step 5 in chloroform (8 ml) were successively added, with stirring under ice-cooling, N,N-diisopropylethylamine (234 mg) and 2,7-dichloro-5-trifluoromethyl-thiazolo[4,5-d]pyrimidine (414 mg). After stirring at room temperature for 1 hr, the mixture was partitioned by adding chloroform and water. The aqueous layer was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=6:1-1:2) to give the title compound (912 mg).
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][N:5]=[C:4]([C:9]([OH:11])=[O:10])[CH:3]=1.[CH2:12](O)[CH3:13]>>[CH2:12]([O:10][C:9]([C:4]1[CH:3]=[C:2]([OH:1])[C:7]([OH:8])=[CH:6][N:5]=1)=[O:11])[CH3:13]
Reactant: CCO
Reactant: O=C(O)c1cc(O)c(O)cn1
Product: CCOC(=O)c1cc(O)c(O)cn1

Procedure:
4,5-Dihydroxy-pyridine-2-carboxylic acid (844 mg, 5.45 mmol) was dissolved in ethanol (20 mL). Gaseous hydrochloric acid was bubbled through the mixture for 5 minutes whilst it was cooled in an ice bath. The solution was then heated to reflux for 2 hours. This procedure was repeated a further two times and then the mixture heated for 24 hours. The volatiles were removed in vacuo and water added (5 mL). This was also removed under reduced pressure. The hydrochloride salt of the desired product was produced in this way and used without further purification.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([Mg]Br)#[CH:10].[Cl-].[NH4+]>C1COCC1.C(OCC)C>[C:2]1([CH:1]([OH:8])[C:9]#[CH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C#C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C#CC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2.65 g of benzaldehyde (Formula 26) in 50 mL of THF at room temperature was added 100 mL of 0.5M ethynylmagnesium bromide in THF. The mixture was stirred at room temperature for 2 hours. Then, the mixture was diluted with diethylether and a saturated solution of ammonium chloride. The mixture was extracted with ethyl acetate. Combined ethyl acetate was washed with brine, dried over sodium sulfate and concentrated. Column chromatography (20% ethyl acetate/hexane) gave 3.17 g of 1-phenyl-prop-2-yn-1-ol (Formula 27) as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ 2.68 (m, 1H), 5.46-5.49 (m, 1H), 7.34-7.43 (m, 3H), 7.55-7.57 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:12].[I-].[Na+].[Al+3].[Cl-].[Cl-].[Cl-]>C(#N)C>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[OH:2])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=O)c2ccc(F)cc2)c(OC)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [I-]
Solvent: CC#N
Product: COc1ccc(C(=O)c2ccc(F)cc2)c(O)c1
Reaction time: 1.5 h
Yield: 88.4 %

Procedure:
The above prepared (2,4-Dimethoxy-phenyl)-(4-fluoro-phenyl)-methanone (7.75 g, 29.8 mmol) was dissolved in 150 mL of acetonitrile and treated successively with sodium iodide (6.70 g, 1.5 eq.) and AlCl3 (3.97 g, 1.0 eq.), and the mixture kept at 80° C. for 1.5 h. Cooling, pouring onto crashed ice, twofold extraction with AcOEt, washing with water and brine, drying over sodium sulfate, and evaporation of the solvents, followed by a short flash chromatography (SiO2, hexane/AcOEt=9/1), gave 6.49 g of the title compound as yellow solid.
Reaction SMILES: [N:1]([N:3]1[C:26]2[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=2)[C:5]2([CH2:10][CH2:9][N:8]([CH2:11]/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH2:7][CH2:6]2)[CH2:4]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[NH2:1][N:3]1[C:26]2[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=2)[C:5]2([CH2:10][CH2:9][N:8]([CH2:11]/[CH:12]=[CH:13]/[C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[CH2:7][CH2:6]2)[CH2:4]1
Reactant: O=NN1CC2(CCN(C/C=C/c3ccc(Cl)cc3)CC2)c2cc(F)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NN1CC2(CCN(C/C=C/c3ccc(Cl)cc3)CC2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 105.8 %

Procedure:
A solution of 1-nitroso-5-fluoro-1′-[trans-3-(4-chlorophenyl)allyl]spiro[indoline-3,4′-piperidine] (5 g) in tetrahydrofuran (60 ml) was added dropwise to a suspension of lithium aluminium hydride (1.47 g) in tetrahydrofuran (60 ml) at 0° C. and the resulting mixture was stirred at room temperature for 2.5 hours. Water (4.8 ml) was carefully added, followed by 15% aqueous sodium hydroxide (4.8 ml), and finally water (14.4 ml). The mixture was stirred for 0.5 hours, diluted with ethyl acetate, dried over sodium sulfate, and filtered. The solvents were evaporated in vacuo to afford 5.1 g (100%) of the desired amino-indoline as a solid. MS (ES+) 372.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13]Br)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:15][S-:16].[Na+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH2:11][CH2:12][CH2:13][S:16][CH3:15])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(CCCCBr)CCCC1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(CCCCSC)CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 50.6 %

Procedure:
To a solution of 1-(4-bromobutyl)cyclopentane carboxylic acid methyl ester (38 mmol, 10 g) in DMF (100 mL) was added sodium thiomethoxide (72.6 mmol, 5.09 g). After addition of sodium thiomethoxide, the reaction was exothermic and the mixture became a light brown cloudy solution. The mixture was stirred for 15 h at room temperature and was poured into water (200 mL). The organic compound was extracted with ether (2×150 mL). The combined extracts were washed with brine (150 mL) and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solution was concentrated under vacuum and the resulting residue was purified by silica gel column chromatography to afford 4.43 g (51%) of a colorless oil. LR MS (C12H22O2S): 230 (M+).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O-:24])=[O:23])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Na+].Cl[CH2:29][CH2:30][CH2:31][CH2:32][OH:33].CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:1]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:29][CH2:30][CH2:31][CH2:32][OH:33])=[O:23])=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: OCCCCCl
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)[O-])cc1
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCCCCO)cc1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of 7.66 g of sodium 4-(n-hexadecylamino)benzoate, 7.55 g of 4-chloro-1-butanol, and 20.0 ml of hexamethylphosphoramide is stirred at 150° C. for two hours, allowed to cool, and poured into water. The solid is collected by filtration and then is dissolved in methylene chloride. The solution is washed with water, dried, and evaporated. The residual solid is crystallized from hexane to yield 4-hydroxybutyl 4-(n-hexadecylamino)benzoate as a white solid, mp 61°-63° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21].Cl.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>COCCO.CO>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:33][C:30]2[CH:31]=[CH:32][C:25]3[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:28][CH2:27][C:26]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CO
Solvent: COCCO
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)cc2CC1
Temperature: 120 °C

Procedure:
2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (650 mg/2.2 mmol), 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (500 mg/2.6 mmol) and 4 N HCl in dioxane (650 μL/2.6 mmol) were suspended in 2-methoxyethanol (5 mL) and heated to 120° C. until judged complete by HPLC. The resulting tan solution was cooled to room temperature, diluted with methanol (2 mL) and treated with solid potassium carbonate (carbon dioxide evolves). The mixture was filtered and the filtrate concentrated onto silica gel and purified by column chromatography to afford 2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide as a tan solid (200 mg/20%). 1H NMR (400 MHz, CDCl3) δ 11.02 (s, 1H), 8.68 (d, J=8.1 Hz, 1H), 8.06 (s, 1H), 7.52-7.40 (m, 2H), 7.33 (s, 1H), 7.23 (s, 1H), 7.09-6.98 (m, 2H), 6.87 (s, 1H), 6.20 (s, 1H), 3.05 (d, J=3.8 Hz, 3H), 2.91 (m, 4H), 2.60 (m, 6H), 1.11 (t, J=6.9 Hz, 3H). LC/MS found 451 (M+H). mp 201° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:4]=1[NH:5][CH2:6][CH:7]=[O:8])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:27][C:28](=[O:33])[CH:29](Cl)[CH2:30][CH3:31]>O>[Cl:27][C:28](=[O:33])[CH:29]([N:5]([CH2:6][CH:7]=[O:8])[C:4]1[C:9]([O:13][CH3:14])=[CH:10][CH:11]=[CH:12][C:3]=1[CH2:1][CH3:2])[CH2:30][CH3:31]
Reactant: CCC(Cl)C(=O)Cl
Reactant: CCc1cccc(OC)c1NCC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCc1cccc(OC)c1N(CC=O)C(CC)C(=O)Cl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-ethyl-6-methoxyanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0°C and α-chlorobutanoyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chlorobutanoyl-2-ethyl-6-methoxyanilino)acetaldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1C(O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC1C(OC(=O)C)=C(I=O)C=CC=1)(=[O:21])C.II.CO>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[O:21][CH3:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CC(=O)Oc1cccc(I=O)c1OC(C)=O
Agent: II
Solvent: CO
Solvent: ClCCl
Product: COC1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
To a mixture of (S)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester (purchased at Fluka, Ref 97090, 6 g, 1.0 eq.) in dichloromethane (300 mL) was added diacetoxyiodosobenzene (15.8 g, 2 eq.) and iodine (3.0 eq., 0.5 eq.). The mixture was stirred 5 h at room temperature. Methanol (12 mL) was added and the reaction mixture was stirred for an additional 1.5 h at room temperature, partitioned between an aqueous solution of sodium sulfite and dichloromethane. The organic layer was washed with an aqueous solution of sodium sulfite, brine, evaporated in vacuo and purified on silica eluting with 9:1 cyclohexane/ethyl acetate to yield 5.0 g (88%) of the desired product as light yellow oil. MS (m/e): 235.5 (MH+, 100%)