Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[N:22]1([C:28]2[N:33]=[C:32]([C:34](O)=[O:35])[CH:31]=[N:30][CH:29]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:34]([C:32]4[CH:31]=[N:30][CH:29]=[C:28]([N:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[N:33]=4)=[O:35])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1cncc(N2CCOCC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cncc(N3CCOCC3)n2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Yield: 92.7 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4carboxamide (75 mg, 0.27 mmol), 6-morpholin-4-ylpyrazine-2-carboxylic acid (55.9 mg, 0.27 mmol), HATU (101.5 mg, 0.27 mmol), HOBT (36 mg, 0.27 mmol) and DIPEA (140 μl, 0.80 mmol) in DMF (3 ml) were stirred at room temperature for 18 h. The reaction was diluted with ethyl acetate (150 ml), washed with hydrochloric acid (0.5M, 2×20 ml), aqueous sodium hydrogen carbonate (20 ml) and dried (magnesium sulphate). Evaporation of the solvents under vacuum gave N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-6-morpholin-4-ylpyrazine-2-carboxamide (118 mg, 94%). NMR; δH [2H6]—DMSO 10.17,(1H, s), 8.62,(1H, t), 8.54,(1H, s), 8.47,(1H, s), 7.93,(2H, d), 7.80,(1H, dd), 7.70,(1H, d), 7.45,(2H, d), 7.31,(1H, d), 3.73,(8H, m), 3.16,(2H, t), 2.21,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.20 min, MH+472.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4](C1C=CC(C)=CC=1)=[O:5].O.C1(C)C=CC(S(O)(=O)=[O:26])=CC=1.OO>O1CCCC1.O>[Cl:1][C:2]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:3]=1[C:4]([OH:5])=[O:26]
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: OO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(F)cc1Cl
Temperature: 20 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
12.4 g (0.05 mol) of 2-chloro-4-fluoro-4'-methylbenzophenone in 30 ml of tetrahydrofuran were added dropwise to a solution of 19.0 g (0.1 mol) of toluene-4-sulfonic acid hydrate and 3.8 g (0.1 mol) of 90% hydrogen peroxide in 100 ml of tetrahydrofuran. The mixture was subsequently stirred for 12 h at 20° C. and then diluted with 100 g of water. Further processing as described in Example 22 gave 7.6 g (43.5 mmol, 87%) of 2-chloro-4-fluorobenzoic acid (m.p. 181°-186° C.).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][NH2:15])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]1([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:31]=[C:30]([CH:39]=O)[CH:29]=3)=[CH:24][CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:31]=[C:30]([CH2:39][NH:15][CH2:14][CH2:13][N:10]4[CH2:9][CH2:8][N:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH2:12][CH2:11]4)[CH:29]=3)=[CH:24][CH:23]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=Cc1cc(-c2ccc(C3CCCCC3)cc2)n(-c2ccccc2)n1
Reactant: NCCN1CCN(c2ccccc2)CC1
Product: c1ccc(N2CCN(CCNCc3cc(-c4ccc(C5CCCCC5)cc4)n(-c4ccccc4)n3)CC2)cc1
Yield: 71.2 %

Procedure:
Compound 12 was prepared using the same method as that of Example 1 except that 4-phenylpiperazin-1-ylethylamine and 5-(4-cyclohexylphenyl)-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:3]=1[C:22](=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:31]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[C:4]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:3]=1[C:22](=[O:24])[CH3:23])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COCCOCOc1cc(O)c(C(C)=O)c(OCOCCOC)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOCOc1cc(OCOCCOC)c(C(C)=O)c(OCc2ccccc2)c1
Reaction time: 8 h
Yield: 73 %

Procedure:
To a stirred suspension of 1-{2-hydroxy-4,6-bis[(2-methoxyethoxy)methoxy]phenyl}ethanone (3.53 g, 10 mmol), potassium carbonate (1.7 g, 14 mmol) in DMF (15 mL) was added benzylbromide (2.1 g, 12 mmol). After stirring overnight, the reaction mixture was diluted with ethyl acetate (100 mL) and thoroughly washed with brine. The organic phase was dried and evaporated to dryness. The crude was chromatographed on a small pad of silica gel eluting with hexane/ethyl acetate 7/1, to provide the title compound (g 3.25, yield 73%).
Reaction SMILES: [N:1]#[C:2]Br.C(O[C:7](=[O:20])[CH2:8][NH:9][CH2:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([Cl:18])[C:12]=1[Cl:19])C>COCCO>[ClH:18].[Cl:19][C:12]1[C:13]([Cl:18])=[CH:14][CH:15]=[C:16]2[C:11]=1[CH2:10][N:9]1[CH2:8][C:7](=[O:20])[NH:1][C:2]1=[N:17]2
Reactant: N#CBr
Reactant: CCOC(=O)CNCc1c(N)ccc(Cl)c1Cl
Solvent: COCCO
Product: Cl
Product: O=C1CN2Cc3c(ccc(Cl)c3Cl)N=C2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
A solution of cyanogen bromide (3.2 g, 0.030 mol) in 100 ml. 2-methoxyethanol was added to a solution of N-(6-amino-2,3-dichlorobenzyl)glycine ethyl ester (8.2 g, 0.030 mol) in 250 ml. 2-methoxyethanol. The solution was stirred at room temperature for 1 hour, heated at reflux for 22 hours, and cooled. The precipitate was filtered off, washed with ether and air dried to give 3.11 gms. of the crude title product (31% yield as the hydrobromide salt). Recrystallization from ethanolic HCl gave the pure title product in 71% recovery (22% overall yield); m.p. >250°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[OH:17][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([C@@H:8]([NH:7][C:6](=[O:18])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:9])=[CH:11][CH:12]=1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)cc1
Reactant: Cl[Mg]Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C(O)Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
70 mg of the compound [15-1] was dissolved in 5 mL of tetrahydrofuran and cooled to 0° C. Thereafter, 300 μL of benzylmagnesium chloride (2.0M tetrahydrofuran solution) was added thereto, and the mixture was stirred overnight while gradually heating back to room temperature. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the solution was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then the resulting residue was purified by preparative thin-layer chromatography, to obtain 11 mg of the tert-butyl {(1S)-1-[4-(1-hydroxy-2-phenylethyl) phenyl]ethyl}carbamate [16-1] (hereinafter, referred to as the compound [16-1]) as a colorless oily product.
Reaction SMILES: O.O.[Sn](Cl)Cl.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:28](=[O:29])[C:18]3=[CH:19][NH:20][C:21]4[C:22]([F:27])=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]3=[N:16]2)=[CH:11][CH:10]=1)([O-])=O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:6][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:28](=[O:29])[C:18]3=[CH:19][NH:20][C:21]4[C:22]([F:27])=[CH:23][CH:24]=[CH:25][C:26]=4[C:17]3=[N:16]2)=[CH:11][CH:10]=1
Reactant: O=c1c2c[nH]c3c(F)cccc3c-2nn1-c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(-n2nc3c4cccc(F)c4[nH]cc-3c2=O)cc1
Temperature: 80 °C
Yield: 104.7 %

Procedure:
Tin (II) chloride dihydrate (12.5 g, 0.055 mol) was added in one portion to a stirred solution of 2-(4-nitro-phenyl)-6-fluoro-2,5-dihydro-pyrazolo[4,3-c]quinolin-3-one (intermediate 1) (3.59 g, 0.011 mol) in ethyl alcohol (110 ml) at room temperature. The mixture was then heated to 80° C. for 8 h, cooled to room temperature and filtered to leave a yellow solid. The solid was suspended in a bi-phasic solution of ethyl acetate (1L), a saturated solution of Rochelles salt (500 ml) and a saturated solution of sodium bicarbonate (500 ml) and stirred at room temperature for 2 h. The mixture was filtered and the remaining solid was washed with water and dried under vacuum to afford the title compound (3.39 g, 99%) as a bright yellow solid, LCMS m/z 295.30 [M+H]+ @ RT 0.84 min.
Reaction SMILES: [CH3:1][C@H:2]1[N:6]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][C:8]=3[N:17]=[C:5]2[NH:4][CH2:3]1.Cl.Cl.[NH2:20]C[C@H](N)C.Cl.Cl.NC[C@@H](N)C>>[CH3:1][C@H:2]1[N:6]2[C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[C:9]([NH2:20])[C:8]=3[N:17]=[C:5]2[NH:4][CH2:3]1
Reactant: C[C@@H](N)CN
Reactant: C[C@@H]1CNc2nc3cnc4ccccc4c3n21
Agent: C[C@H](N)CN
Agent: Cl
Product: C[C@@H]1CNc2nc3c(N)nc4ccccc4c3n21

Procedure:
The methods described in Parts A through C of Example 23 were used to prepare (10R)-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline with (R)-(−)-1,2-diaminopropane dihydrochloride used in lieu of (S)-(−)-1,2-diaminopropane dihydrochloride in Part A. The methods described in Parts A through D of Example 27 were used to convert (10R)-10-methyl-9,10-dihydro-8H-imidazo[1′,2′:1,2]imidazo[4,5-c]quinoline to the title compound, which was obtained as a white solid, m.p. 272-274° C.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Br:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[C:22]([CH3:27])([CH3:26])[CH2:23][CH:24]=[O:25])=[O:12].Cl>O.CC(C)=O>[Br:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[C:22]([CH3:27])([CH3:26])[CH2:23][C:24]([OH:2])=[O:25])=[O:12]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1cc(C)c(C(C)(C)CC=O)c(OC(=O)CCCBr)c1
Agent: Cl
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C)c(C(C)(C)CC(=O)O)c(OC(=O)CCCBr)c1
Reaction time: 24 h
Yield: 114.9 %

Procedure:
A solution of 1 g of potassium permanganate in a mixture of 46 cm3 of distilled water and 30 cm3 of acetone is added dropwise, at 20° C., to 2.3 g of 3-[2-(4-bromobutyryloxy)4,6-dimethylphenyl]-3,3-dimethylpropanal in solution in 200 cm3 of acetone. After stirring for 24 hours, the reaction mixture is supplemented with 100 cm3 of distilled water, acidified to pH 1–2 by addition of a 1 N aqeuous hydrochloric acid solution, and then extracted with five times 100 cm3 of dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa). 2.7 g of 3-[2-(4-bromobutyryloxy)4,6-dimethylphenyl]-3,3-dimethylpropionic acid are obtained in the form of a colorless oil.
Reaction SMILES: C1C=CC(N)=CC=1.Cl.C(O[C:17]([N:19]([CH2:21][C:22]([NH:24][C@H:25]([C:34]([NH:36][C@H:37]([C:39]([NH:41][C@H:42]([P:44](=[O:47])([OH:46])[OH:45])[CH3:43])=[O:40])[CH3:38])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)=[O:23])C)=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[NH:19]([CH2:21][C:22]([NH:24][C@H:25]([C:34]([NH:36][C@H:37]([C:39]([NH:41][C@H:42]([P:44](=[O:45])([OH:47])[OH:46])[CH3:43])=[O:40])[CH3:38])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)=[O:23])[CH3:17]
Reactant: C[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CN(C)C(=O)OCc1ccccc1)C(=O)N[C@@H](C)P(=O)(O)O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: Nc1ccccc1
Solvent: CC(=O)O
Product: CNCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](C)C(=O)N[C@@H](C)P(=O)(O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The aniline salt of (1R)-1-[(N-benzyloxycarbonyl-sarcosyl-L-tyrosyl-L-alanyl)amino]-ethylphosphonic acid was suspended in acetic acid and 10% palladium-on-carbon was added under argon. Acetic acid was then added. The mixture was stirred overnight at room temperature and then hydrogenated until the uptake of hydrogen ceased. The catalyst was filtered off and the filtrate was evaporated. The residual solid was triturated with methanol, filtered off, washed and dried. The solid was purified by reprecipitation from aqueous hydrochloric acid/ethanol with propylene oxide to give (1R)-1-(N-sarcosyl-L-tyrosyl-L-alanylamino)-ethylphosphonic acid of melting point 275°-277° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([NH2:15])=[CH:11][CH:12]=[CH:13][CH:14]=1.[S:16](N)(N)(=[O:18])=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][S:16]1(=[O:18])=[O:17]
Reactant: NS(N)(=O)=O
Reactant: Nc1ccccc1Nc1ccccc1F
Product: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Yield: 39.4 %

Procedure:
In an analogous manner to general procedure I, step 3, N-(2-fluorophenyl)benzene-1,2-diamine (1.0 g, 5.0 mmol) was treated with sulfamide (0.58 g, 6.0 mmol) to provide 0.52 g (40%) of 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. HRMS: calculated for C12H9FN2O2S+Na+, 287.02609; found (ESI, [M+Na]+), 287.0263; HPLC purity 100.0% at 210-370 nm, 8.4 minutes; Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/minutes 85/15-5/95 (Ammonium formate buffer pH=3.5/ACN+MeOH) for 10 minutes hold 4 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Cl)[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C.O>[CH2:17]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClCC=Cc1ccccc1
Reactant: NC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: NC(=O)c1cccc(OCC=Cc2ccccc2)c1

Procedure:
3-hydroxybenzamide (0.5 g 3.6 mmol) was dissolved in dry acetonitrile (50 ml). To this was added potassium carbonate (0.503 g; 3.6 mmol) and cinnamyl chloride (0.5 ml; 3.6 mmol). This was left to reflux for 3.5 hours. The acetonitrile was removed under reduced pressure yielding a white sold which was dissolved in water (80 ml). The organics were extracted in dichloromethane (3×30 ml), dried over magnesium sulphate, filtered and the solvent removed under reduced pressure leaving a white solid. The solid was recrystallised from ethyl acetate and petrol (45%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:16]([CH:21]=O)=[CH:17][CH:18]=[CH:19][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:12]1[CH2:11][CH2:10][N:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[CH2:14][CH2:13]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=Cc1ccccc1-c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1ccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)c(C)c1

Procedure:
201.6 mg of the target compound (0.57 mmol, 69.0%) was obtained using 1-(2,4-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-2-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][C:10]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:9]=2[S:8][CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:9]3[S:8][CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][C:10]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCSc2ccc(N)cc2C1
Reactant: CS(=O)(=O)N[C@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COCCN1CCSc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc2C1
Yield: 26.8 %

Procedure:
Following the procedure of 512f, 8-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamine (0.07 g, 0.00029 mol) and N-[(1S,2R)-2-(2,5-dichoro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (0.099 g, 0.00029 mol) were reacted. Purification was carried out by SiO2 prep plate chromatography giving N-((1R,2R)-2-{5-chloro-2-[8-(2-methoxy-ethyl)-6,7,8,9-tetrahydro-5-thia-8-aza-benzocyclohepten-2-ylamino]pyrimidin-4-ylamino}-cyclohexyl)-methanesulfonamide (0.042 g, 28%) as a grey solid. MP: 140-3° C.; 1H-NMR (DMSO-d6) 9.28 (s, 1H), 7.95 (s, 1H), 7.60-5 (s, 1H), 7.58 (d, 1H), 7.33-5 (d, 1H), 7.16-8 (d, 1H), 6.76-8 (d, 1H), 4.01 (s, 2H), 3.80-90 (m, 1H), 3.36-45 (m, 4H), 3.21 (m, 4H), 2.93 (s, 2H), 2.67 (s, 2H), 2.0010 (m, 2H), 1.65-80 (m, 2H), 1.20-45 (m, 4H); LC/MS (ESI+): 541 (M).
Reaction SMILES: O=P(Cl)(Cl)Cl.[C:6]1([C:12]2[O:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-].[Na+].CN([CH:22]=[O:23])C>>[C:6]1([C:12]2[O:13][C:14]([CH:22]=[O:23])=[CH:15][N:16]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CN(C)C=O
Reactant: c1ccc(-c2ncco2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cnc(-c2ccccc2)o1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a 50 mL flask charged with DMF (5 mL) was added POCl3 (0.7 g, 4.6 mmol) dropwise at 0° C. After stirring for 10 min, a solution of 2-phenyloxazole (0.6 g, 4.1 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was heated to 100° C. and stirred for 48 h. After cooling to room temperature, the reaction mixture was poured into ice water and the pH was adjusted to 10 with 10% aqueous NaOH. The aqueous mixture was extracted with EtOAc (20 mL×3). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated and purified by column chromatography to give 240 mg of the desired product. LC-MS: m/z 174 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][C:13]([CH3:16])=[N:12]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:17].[K+].[Mn]([O-])(=O)(=O)=O.[K+].[OH2:25]>>[C:4]([C:3]1[CH:7]=[CH:8][C:9]([N:11]2[CH:15]=[CH:14][C:13]([C:16]([OH:25])=[O:17])=[N:12]2)=[CH:10][C:2]=1[Cl:1])([OH:6])=[O:5]
Reactant: O
Reactant: [OH-]
Reactant: Cc1ccn(-c2ccc(C(=O)O)c(Cl)c2)n1
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)c1ccn(-c2ccc(C(=O)O)c(Cl)c2)n1
Temperature: 25 °C
Yield: 16 %

Procedure:
A vigorously stirred solution of 2-chloro-4-(3-methyl-1 H-pyrazol-1-yl)benzoic acid (7.08 g, 30.0 mmol) and 1 N potassium hydroxide (30 mL, 30.0 mmol) in water (200 mL) was heated to between 60–65° C. and treated gradually over ninety minutes with several aliquots of solid potassium permanganate (Total: 49.78 g, 315 mmol, 5.25 equivalents). The mixture was heated for an additional 2.5 hours (4 hours total). After cooling to room temperature, the mixture was filtered and evaporated to a residue. The residue was dissolved in 2 N hydrochloric acid and extracted with ethyl acetate (3×). The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the solvent removed in vacuo to yield, after crystallization from a mixture of ethyl acetate-diethyl ether-hexane, the title compound (1.27 g, 4.8 mmol, 16%) as a homogeneous solid, m.p. 260–263° C.;
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4](C2CCC(F)(F)C3C=CC=CC=3N2)[CH:3]=1.ClC1C=C(Cl)C2C(=CC=C(C)C=2)N=1.[CH3:39][O:40][N:41]=[C:42]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[CH2:46][NH:45][CH2:44][CH2:43]1.NC1(CNC2C3C(=CC=C(C)C=3)N=C(N3CC/C(=N\OC)/C4C=CC=CC=4C3)C=2)COC1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:45]2[CH2:44][CH2:43]/[C:42](=[N:41]\[O:40][CH3:39])/[C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=3[CH2:46]2)[CH:3]=1
Reactant: CON=C1CCNCc2ccccc21
Reactant: Cc1ccc2nc(C3CCC(F)(F)c4ccccc4N3)cc(Cl)c2c1
Agent: CO/N=C1\CCN(c2cc(NCC3(N)COC3)c3cc(C)ccc3n2)Cc2ccccc21
Agent: Cc1ccc2nc(Cl)cc(Cl)c2c1
Product: CO/N=C1\CCN(c2cc(Cl)c3cc(C)ccc3n2)Cc2ccccc21

Procedure:
The title compound was prepared in analogy to 2-(4-chloro-6-methylquinolin-2-yl)-5,5-difluoro-2,3,4,5-tetrahydro-1H-benzazepine in Example 110-1 in Scheme 56 by using 2,4-dichoro-6-methylquinoline and N-methoxy-1,2,3,4-tetrahydro-5H-2-benzazepin-5-imine. N-[(3-Aminooxetan-3-yl)methyl]-2-[(5E)-5-(methoxyimino)-1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl]-6-methylquinolin-4-amine
Reaction SMILES: O.[C:2]1([CH:8]([CH3:26])[C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([O:23]CC)=[O:22])[C:15]=3[N:16]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:2]1([CH:8]([CH3:26])[C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:20][CH2:19][CH2:18][CH:17]([C:21]([OH:23])=[O:22])[C:15]=3[N:16]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCCc2sc(NC(=O)C(C)c3ccccc3)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C(=O)Nc1nc2c(s1)CCCC2C(=O)O)c1ccccc1

Procedure:
Water (20 mL) and MeOH (80 mL) were added to ethyl 2-(2-phenylpropionylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylate (R) (4.95 g, 13.8 mmol) and NaOH (5.52 g, 0.138 mol), and the resultant mixture was stirred at RT under a blanket of nitrogen as inert gas until completion of the reaction. Following removal of MeOH, 2N hydrochloric acid solution in water (250 mL) and DCM (250 mL) were added. The phases were separated, and the aqueous phase was extracted a number of times with DCM (a total of 200 mL). Following drying of the combined organic phases over Na2SO4 and filtration, there was obtained the product 2-(2-phenylpropionylamino)-4,5,6,7-tetrahydrobenzthiazol-4-carboxylic acid (S) in a yield of 4.6 g (corresponding to 100% of theory).