Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1.[CH3:31][NH:32][CH3:33].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH2:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:32]([CH3:33])[CH3:31])=[CH:25][CH:24]=1)[CH:12]1[C:21]2[N:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)Cc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 42.3 %

Procedure:
Using General Procedure B: Reaction of 4-{[(1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzaldehyde (AMD9882) (157 mg, 0.40 mmol) and dimethylamine (2.0 M in THF, 0.4 mL, 0.80 mmol) with NaBH(OAc)3 (0.179 g, 0.84 mmol) in CH2Cl2 (4 mL) overnight followed by purification of the crude material by radial chromatography on silica gel (2 mm plate, 50:1:1 CH2Cl2—CH3OH—NH4OH) provided the free base of the title compound (72 mg, 43%) as a colorless oil.
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([CH:6]([CH:15]=[CH2:16])[CH2:7]/[CH:8]=[CH:9]/[C:10]([O:12]CC)=[O:11])[CH3:5]>O1CCCC1.CO.O>[CH2:15]([CH:6]([CH:4]=[CH2:5])[CH2:7]/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH3:16]
Reactant: C=CC(CC)C/C=C/C(=O)OCC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CC(CC)C/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (4.39 g, 104 mmol) was added to a tetrahydrofuran:methanol:water (3:3:1, 100 mL) mixed solution of ethyl (2E)-5-ethylhepta-2,6-dienoate (9.52 g, 52.2 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. To the residue, water was then added, followed by washing with diethyl ether. The aqueous layer was made acidic by the addition of 5 M hydrochloric acid, followed by extraction with ethyl acetate. Then, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure to obtain the compound of interest as an oil substance (8.00 g, >99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH2:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].Cl[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.C(N(CC)C(C)C)(C)C>CS(C)=O.O>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@@H:10]([NH:12][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N)C1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](Nc2nc3ccccc3s2)C1
Temperature: 110 °C

Procedure:
A mixture of tert-butyl(cis-3-aminocyclobutyl)carbamate (1.26 g, 6.77 mmol), 2-chlorobenzothiazole (0.965 mL, 6.77 mmol) and N,N-diisopropylethylamine (2.354 mL, 13.53 mmol) in DMSO (5 mL) was heated to 110° C. in a sealed microwave vial for 4 h, cooled to room temperature, diluted with water and extracted with EtOAc. EtOAc extract was concentrated and crude material purified with ISCO using silica gel column eluting with 0-80% EtOAc/hexane to give the desired product tert-butyl(cis-3-(benzo[d]thiazol-2-ylamino)cyclobutyl)carbamate (1.5 g, 4.70 mmol, 69.4% yield). m/z: 320.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:22][CH3:23])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:24][C:25]1[C:26]([O:41][CH3:42])=[N:27][C:28]([O:39][CH3:40])=[C:29]([Cl:38])[C:30]=1[C:31](=O)[C:32]([O:34]CC)=O.CC(O)=O>COCCO.CCOC(C)=O>[Cl:38][C:29]1[C:28]([O:39][CH3:40])=[N:27][C:26]([O:41][CH3:42])=[C:25]([Cl:24])[C:30]=1[C:31]1[C:32](=[O:34])[N:22]([CH3:23])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:10]=[CH:11][C:12]([C:15]([N:17]([CH2:18][CH3:19])[CH2:20][CH3:21])=[O:16])=[CH:13][CH:14]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCN(CC)C(=O)c1ccc(Nc2ncc(N)c(NC)n2)cc1
Reactant: CCOC(=O)C(=O)c1c(Cl)c(OC)nc(OC)c1Cl
Solvent: CCOC(C)=O
Solvent: COCCO
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccc(Nc2ncc3nc(-c4c(Cl)c(OC)nc(OC)c4Cl)c(=O)n(C)c3n2)cc1
Yield: 50.1 %

Procedure:
A mixture of 0.47 g (1.5 mmol) of 5-amino-2-[[4-(diethylaminocarbonyl)-phenyl]amino]-4-(methylamino)pyrimidine, 0.62 g (2 mmol) of ethyl 2-(3,5-dichloro-2,6-dimethoxypyridin-4-yl)-2-oxoacetate and 1.0 mL of HOAc in 20 mL of 2-methoxyethanol is heated under reflux for 16 hours. Workup in EtOAc, followed by chromatography on silica, eluting with hexane/EtOAc (1:1), gives 0.42 g (56%) of the title compound (Compound 22): mp (EtOH) 274–276° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].O.[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>C1C=CC=CC=1.C(O)C>[CH2:17]([O:13][C:12](=[O:14])[CH:11]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=1)[CH3:15])[CH3:18]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Solvent: O
Solvent: CCO
Solvent: c1ccccc1
Product: CCOC(=O)C(C)c1ccc(CC(C)C)cc1
Yield: 563.9 %

Procedure:
A solution of 2-(4-isobutylphenyl)-propionic acid (Ibuprofen, 9.6 g, 46.5 mmol) and p-toluenesulfonic acid monohydrate (1.52 g, 7.9 mmol) in benzene (100 mL) and ethanol (75 mL) was heated to reflux using a Dean-Stark apparatus for 4 h. The solvent was removed under reduced pressure and the residue was taken up in Et2O (100 mL). The solution was extracted with saturated aqueous NaHCO3 solution (2×100 mL) and water (2×100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated, affording 204 (10.44 g, 96%) as a clear oil. 1H NMR (CDCl3): δ 7.19 (d, 2 H, J=8.0), 7.08 (d, 2 H, J=8.0), 4.10 (m, 2 H), 3.66 (q, 1 H, J=7.0), 2.44 (d, 2 H, J=7.0), 1.84 (m, 1 H), 1.47 (d, 3 H, J=7.0), 1.19 (t, 3 H, J=7.3), 0.89 (d, 6 H, J=7.0). 13C NMR (CDCl3): δ 174.92, 140.59, 138.07, 129.45, 127.29, 60.79, 45.32, 45.21, 30.35, 22.55, 18.78, 14.29. HRMS (LSIMS, nba): Calcd for C15H23O2 (MH+): 235.1698, found: 235.1688.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([OH:18])=O.[CH3:19][C@H:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([CH3:26])[N:21]1[CH2:27][CH2:28][NH2:29]>>[NH3:3].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[C:16]([NH:29][CH2:28][CH2:27][N:21]1[C@H:22]([CH3:26])[CH2:23][CH2:24][CH2:25][C@@H:20]1[CH3:19])=[O:18]
Reactant: C[C@@H]1CCC[C@H](C)N1CCN
Reactant: O=C(O)[C@@H]1CCCCN1c1nc2ccccc2o1
Product: C[C@@H]1CCC[C@H](C)N1CCNC(=O)[C@@H]1CCCCN1c1nc2ccccc2o1
Product: N

Procedure:
The title compound was prepared by a similar method to Example 1 from (2S)-1-(1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid [see Preparation 3] and 2-[(cis)-2,6-dimethyl-1-piperidinyl]ethylamine [J. Med. Chem., 27; 5, (1984), 684-691]. The crude product was purified by column chromatography on silica gel eluting with a solvent system of 93:7:1, by volume, dichloromethane:methanol:0.88 aqueous ammonia solution, to afford (2S)-1-(1,3-benzoxazol-2-yl)-N2-2-[(cis)-2,6-dimethyl-1-piperidinyl]ethyl-2-piperidinecarboxamide as a colourless gum.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12](Br)=[CH:11][C:10]=1[F:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:23]([Si:26]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])[N:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[C:29]([CH:36]=[O:37])=[CH:28]1)([CH3:25])[CH3:24].O>O1CCCC1.CCOCC>[CH2:1]([O:8][C:9]1[C:10]([F:17])=[CH:11][C:12]([C:28]2[N:27]([Si:26]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:39])[CH3:40])[CH:23]([CH3:25])[CH3:24])[C:31]3=[N:32][CH:33]=[CH:34][CH:35]=[C:30]3[C:29]=2[CH2:36][OH:37])=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc(OCc2ccccc2)c(F)cc1Br
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C=O)c2cccnc21
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)[Si](C(C)C)(C(C)C)n1c(-c2cc(F)c(OCc3ccccc3)cc2F)c(CO)c2cccnc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To 1-Benzyloxy-4-bromo-2,5-difluoro-benzene (47, 0.84 g, 2.80 mmol) in tetrahydrofuran (15.0 mL) and ether (15.0 mL), under an atmosphere of nitrogen at −78° C., n-butyllithium (1.20 mL, 2.50 M in hexane) was added slowly. After 20 minutes, 1-Triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (8, 0.82 g, 0.0027 mol, prepared as described in Example 5) was added to the reaction. After 20 minutes, the reaction was allowed to warm to room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with silica gel column chromatography eluting with 20% ethyl acetate in hexane to a white solid (48, 10 g, 70.0%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]1[C:7]([C:8]([C:17]([O:19]C)=[O:18])=[CH:9][CH:10]=[CH:11]1)=[N:6]2>CO.O>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]1[C:7]([C:8]([C:17]([OH:19])=[O:18])=[CH:9][CH:10]=[CH:11]1)=[N:6]2
Reactant: COC(=O)c1cccc2cc3ccc(C(F)(F)F)cc3nc12
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2cc3ccc(C(F)(F)F)cc3nc12
Yield: 81 %

Procedure:
Cyclization of this as above, followed by immediate hydrolysis of the crude methyl 6-trifluoromethylacridine-4-carboxylate, gave 6-trifluoromethylacridine-4-carboxylic acid (81%), mp (MeOH/H2O) 244-246° C. 1H NMR [(CD3)2SO] δ 7.93 (t, J=7.9 Hz, 1 H, H-3), 7.98 (dd, J=8.9, 1.5 Hz, 1 H, ArH), 8.56 (d, J=8.8 Hz, 1 H, ArH), 8.60 (d, J=8.5 Hz, 1 H, ArH), 8.79 (dd, J=7.0, 1.1 Hz, 1 H, ArH), 8.86 (s, 1 H, H-5), 9.66 (s, 1 H, H-9).
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH2:12][CH2:11][CH2:10][C:9](=[O:13])[CH:8]=1)[C:4]([NH2:6])=[O:5])#[N:2].[CH3:14]N(C)C=O.C(OC(OCC)N(C)C)C>O>[O:5]=[C:4]1[C:3]([C:1]#[N:2])=[C:7]2[C:8]([C:9](=[O:13])[CH2:10][CH2:11][CH2:12]2)=[CH:14][NH:6]1
Reactant: N#CC(C(N)=O)C1=CC(=O)CCC1
Reactant: CN(C)C=O
Agent: CCOC(OCC)N(C)C
Solvent: O
Product: N#Cc1c2c(c[nH]c1=O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution consisting of 40 parts of α-cyano-3-oxo-1-cyclohexen-1-acetamide in 125 parts by volume of dimethylformamide, in an atmosphere of nitrogen, is added dropwise, over a period of 10-15 minutes, 40 parts of dimethylformamide diethyl acetal. After the reaction mixture is stirred at room temperature for about 18 hours, 10 parts of water is added and the organic solvents are removed by distillation under reduced pressure. The residual oily product is extracted with dilute aqueous sodium hydroxide and the extract is washed several times with chloroform, then filtered to remove the small amount of insoluble material. Neutralization of the alkaline solution by the addition of dilute hydrochloric acid results in precipitation of the product, which is purified by recrystallization from aqueous acetone to afford 2,3,5,6,7,8-hexahydro-3,8-dioxo-4-isoquinolinecarbonitrile, melting above 290°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=O)[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:24]=1.Cl.[NH2:26][OH:27].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[C:22]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[C:15](=[N:26][OH:27])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:24]=1
Reactant: O=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Cl)cc2[nH]1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: ON=C1c2ccccc2-c2c1cccc2-c1nc2ccc(Cl)cc2[nH]1
Temperature: 25 °C
Yield: 89.9 %

Procedure:
Stir, at room temperature under argon, a mixture of 2.0 g of 4-(6-chloro-1H-benzimidazol-2-yl)-9H-fluoren-9-one, 1.26 g of hydroxylamine hydrochloride and 2.48 g of sodium acetate in 100 ml of ethanol. The following day, evaporate the reaction medium to dryness under vacuum, take the residue up with 100 ml of dichloromethane and wash with 100 ml of water. The organic phase is dried over magnesium sulphate and evaporated to dryness under vacuum. After drying at 40° C. under vacuum, we obtain 1.88 g of 4-(6-chloro-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z, E) in the form of a beige solid with the following characteristics:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:35]=[CH:34][C:13]([C:14]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:17]=3)=[O:15])=[CH:12][C:11]=2[O:36][CH2:37][CH2:38][CH2:39]Cl)=[CH:4][CH:3]=1.[CH3:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:35]=[CH:34][C:13]([C:14]([C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]([S:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)(=[O:27])=[O:26])[CH:17]=3)=[O:15])=[CH:12][C:11]=2[O:36][CH2:37][CH2:38][CH2:39][N:52]2[CH2:51][CH2:50][N:49]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=3[O:42][CH3:41])[CH2:54][CH2:53]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(COc2ccc(C(=O)c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)cc2OCCCCl)cc1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCOc2cc(C(=O)c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)ccc2OCc2ccc(C)cc2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 51.8 %

Procedure:
3-[4-(4-Methylphenylmethoxy)-3-(3-chloropropoxy) benzoyl]-1-(phenylsulfonyl)indole (0.44 g) obtained in Step 2 was dissolved in N,N-dimethylformamide (5 ml). 1-(2-Methoxyphenyl)piperazine (0.20 g), potassium carbonate (0.14 g), and potassium iodide (0.38 g) were added to the resultant solution and the mixture was stirred overnight at 60° C. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The resultant extract was washed with brine and then dried. The solvent was distilled off. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:3), obtaining 0.29 g of 3-{4-(4-methylphenylmethoxy)-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzoyl}-1-(phenylsulfonyl)indole (0.29 g) as a light yellow oily substance.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[N:8][O:9][C:10]=3[CH3:11])[N:3]=[CH:2]2)=[CH:23][CH:22]=1)[CH3:19]
Reactant: Cc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: CCOc1ccc(B(O)O)cc1
Product: CCOc1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C)c2)cc1
Yield: 29 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-phenyl-isoxazole (112.6 mg, 0.5 mmol) was converted, using 4-ethoxyphenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (50 mg, 29%) which was obtained as a white solid. MS (ESI): m/e=346.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.O.CO>[C:1]([O:5][C:6]([N:8]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(N(C(=O)OC(C)(C)C)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N(c1ccccc1)c1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methyl 3-(4-(tert-butoxycarbonyl(phenyl)amino)phenyl)propanoate (S34), 390 mg, 1.10 mmol) in a mixture of THF/H2O/MeOH (3/1/0.4, 4 mL), was treated with NaOH (100 mg, 2.5 mmol) and was stirred for 4 h at 25° C. The reaction mixture was concentrated, diluted with aqueous 1 N HCl and extracted with CH2Cl2. The organic layer was washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to afford S35 (370 mg, 1.08 mmol, 99%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) 7.34-7.29 (m, 2H), 7.23-7.15 (m, 7H), 2.94 (t, 2H, J=7.6 Hz), 2.66 (t, 2H, J=7.6 Hz), 1.46 (s, 9H); 13C NMR (CDCl3, 100 MHz) 178.7, 153.9, 142.9, 141.2, 137.6, 128.6, 128.5, 126.9 (2C), 125.6, 81.1, 35.5, 30.0, 28.2.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[NH2:17][C:18]1[N:19]=[N:20][N:21]([CH3:23])[N:22]=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH2:6][NH:17][C:18]1[N:19]=[N:20][N:21]([CH3:23])[N:22]=1
Reactant: Cn1nnc(N)n1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: Cn1nnc(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Temperature: 25 °C

Procedure:
A solution (70 ml) of 3,5-bis(trifluoromethyl)benzaldehyde (6.71 g) and 5-amino-2-methyltetrazole (3.30 g) in toluene was heated under reflux for 4 hr. The reaction solution was concentrated and the obtained residue was dissolved in ethanol (70 ml), and sodium borohydride (2.10 g) was added with stirring at room temperature. The reaction solution was stirred at room temperature for 30 min, and saturated aqueous ammonium chloride was added. The mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine. The organic layer was dried over sodium sulfate and sodium sulfate was filtered off. The filtrate was concentrated and the obtained residue was recrystallized from isopropanol-water (3:7, 50 ml) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([N:18]4[CH2:23][CH2:22][CH:21]([C:24]5[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][CH:25]=5)[CH2:20][CH2:19]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[N:3]=1.[CH3:40][NH2:41]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([N:18]4[CH2:23][CH2:22][CH:21]([C:24]5[CH:25]=[CH:26][C:27]([C:28]([NH:41][CH3:40])=[O:30])=[CH:31][CH:32]=5)[CH2:20][CH2:19]4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[N:3]=1
Reactant: CN1CCN(c2cc(N3CCc4ccc(N5CCC(c6ccc(C(=O)O)cc6)CC5)cc4C3)nc(N)n2)CC1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(C2CCN(c3ccc4c(c3)CN(c3cc(N5CCN(C)CC5)nc(N)n3)CC4)CC2)cc1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 4-(1-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}piperidin-4-yl)benzoic acid and methylamine in THF (2.0 M). LCMS (M+H)+: m/z=541.3.
Reaction SMILES: N[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])C.N1C=CC=C[CH:10]=1.Cl[CH2:16][CH:17]=[O:18].Cl>>[CH3:10][O:8][C:6]([C:2]1[CH:3]=[CH:5][O:18][C:17]=1[CH3:16])=[O:7]
Reactant: c1ccncc1
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=CCCl
Agent: Cl
Product: COC(=O)c1ccoc1C
Temperature: 70 °C
Reaction time: 6.5 h

Procedure:
58.055 kg (500 mol) acetacetic acid methyl ester are introduced into a vessel with a stirrer and 22.5 kg (487.5 Val) of ground dolomite having a grain size of 30 μm are mixed therewith. Then 0.988 kg (12.5 mol=2.5 mol%) pyridine are added thereto and the mixture is heated to 70° C., whereupon 87.2 kg (500 mol) 45% aqueous chloracetaldehyde solution are metered in within one hour. The temperature in the reaction is maintained at 70° C. by slight cooling. About 4 hours after the onset of the reaction, light heating is required; after 6-7 hours, heating to 75°-80° C. is performed, and thereafter heating is discontinued and stirring is continued for some time at falling temperatures. To the reaction mixture cooled to room temperature, concentrated hydrochloric acid is added in portions in order to decompose excessive dolomite. After separation of phases the aqueous bottom layer is removed and the organic layer washed with 76 liters of water. For better phase separation, about 2 kg. salt are added. The organic phase, which is now the bottom phase, is separated and distilled under reduced pressure. The yield in 2-methyl-3-carboxylic acid methyl ester amounts to 53.6 kg=76.6% of the theoretical amount.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:22](=[O:23])[O:24][C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)=[CH:16][CH:15]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenamine (intermediate 30.7) (300 mg, 0.98 mmol, 1.00 equiv) in dichloromethane (10 mL). This was followed by the addition of 4-nitrophenyl chloroformate (230 mg, 1.14 mmol, 1.20 equiv) in several batches at room temperature. The resulting solution was stirred for 3 h at room temperature. The solids were collected by filtration. This resulted in 0.3 g (65%) of 4-nitrophenyl 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylcarbamate as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[N:10]#[C:11]Br.C(N(CC)CC)C>CC(C)=O>[CH3:9][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[O:8][C:11]#[N:10]
Reactant: N#CBr
Reactant: Cc1cc(Cl)ccc1O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Cc1cc(Cl)ccc1OC#N
Temperature: 0 °C
Reaction time: 2 h

Procedure:
4-chloro-2-methyl phenol (10g, 0.07 mol) and cyanogen bromide (7.4g, 0.07 mol) were stirred in acetone at 0° C. and triethylamine (9.7 ml, 0.07 mol) was added dropwise. The mixture was stirred at 0° C. for a further 2 hours, then filtered. The filtrate was concentrated using a rotary evaporator to leave the desired product as a fawn solid. This was used without further purification. The melting point of the product, after recrystallisation from ethyl acetate/hexane, was found to be 60° C.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([NH:15][C:16]1([CH:20](O)[CH2:21][CH3:22])[CH2:19][CH2:18][CH2:17]1)(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1C[O:27]CC1>O.C(OCC)(=O)C>[CH2:7]([NH:15][C:16]1([CH2:20][CH:21]([OH:27])[CH3:22])[CH2:19][CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC(O)C1(NC(=O)c2ccccc2)CCC1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(O)CC1(NCc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
LiAlH4 (1.20 g, 31.6 mmol) was added to a solution of 1-[1-(benzoylamino) cyclobutyl]propanol (2.64 g, 11.3 mmol) in THF (40 mL) at room temperature. The mixture was stirred at room temperature for 1 hour and refluxed for 30 minutes. The mixture was cooled in an ice-water bath and a few drops of water were added. The mixture was then diluted with ethyl acetate, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (AcOEt) of the residue gave the title compound as a colorless oil (2.25 g, 91%). 1H-NMR (400 MHz, CDCl3) δ 1.21 (3H, d, J=6.1 Hz), 1.63 (1H, dd, J=13.7 and 2.4 Hz), 1.73-1.90 (5H, m), 2.04-2.13 (1H, m), 2.18-2.27 (1H, m), 3.59 (1H, d, J=11.6 Hz), 3.81 (1H, d, J=11.6 Hz), 4.07-4.16 (1H, m), 7.22-7.35 (5H, m).