Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:33][C@@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[C:29](=[O:31])[N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Reactant: C1CCNC1
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)N1CCCC1
Yield: 60.5 %

Procedure:
Using the same procedure as in Example 26, methyl (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with pyrrolidine (0.36 ml, 4.3 mmol) to give the title compound as a solid (130 mg, 60%), except that the mixture was heated at 45° C. for 20 hours and purified by chromatography on silica gel (eluant: 3% methanol in DCM). NMR Spectrum 1.60 (d, 3H), 1.81 (m, 2H), 1.94 (m, 2H), 3.47-3.38 (m, 3H), 3.77 (m, 1H), 5.62 (q, 1H), 5.79 (s, 2H), 7.26 (d, 1H), 7.35 (d, 1H), 7.51 (s, 1H), 7.77-7.71 (m, 2H), 7.83 (m, 1H), 8.11 (s, 1H), 8.53 (m, 2H), 9.04 (s, 1H), 11.07 (br s, 1H); Mass spectrum MH+ 500.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([OH:22])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([NH2:33])[C:29]([NH2:32])=[CH:30][CH:31]=1.C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20](=[O:22])[NH:32][C:29]2[CH:30]=[CH:31][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:27][C:28]=2[NH2:33])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)O)CC1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)Nc2ccc(C(F)(F)F)cc2N)CC1
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
4-(2-Carboxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester, (0.060 g, 0.195 mmol) is dissolved in 5 mL of dry CH2Cl2 under argon. The solution is cooled to 4° C. and a 2 M solution of oxallyl chloride (0.10 mL, 0.21 mmol) is added in a drop-wise fashion resulting in gas evolution. After stirring the mixture for 30 min, 1 drop of DMF is added and the mixture is stirred at room temperature for 30 min. The reaction mixture is cooled to 4° C. and 4-trifluoromethyl-benzene-1,2-diamine (0.069 g, 0.390 mmol) and diisopropylethyl amine (0.092 mL, 0.500 mmol) are added. The reaction is warmed to room temperature and stirred for 1 h. The mixture is diluted with 50 mL EtOAc followed by 20 mL of sat. NH4Cl. The organic phase is washed with 2×20 mL of H2O and 1×20 mL of brine. The organic phase is dried with MgSO4, filtered and concentrated. The residue is applied to a SiO2 prep plate and eluted with 50% EtOAc/hexanes to give 0.045 g of 4-[2-(2-amino-4-trifluoromethyl-phenylcarbamoyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:21][CH3:22])[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:21][CH3:22])[CH:13]([OH:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)[C@H](CC)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)CC(O)[C@H](CC)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of ethyl(4S)-4-{[(benzyloxy)carbonyl]amino}-3-oxohexanoate (70.68 g) in methanol (500 mL) was added sodium borohydride (9.66 g) at −78° C., and the mixture was stirred at −78° C. for 1 hr and at room temperature for 1 hr. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate) to give ethyl(4S)-4-{[(benzyloxy)carbonyl]amino}-3-hydroxyhexanoate (yield: 63.2 g, 89%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:12]=[CH:11][C:5]2[CH:6]([OH:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1CCOc2cc(F)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC1CCOc2cc(F)ccc21
Reaction time: 18 h
Yield: 87.2 %

Procedure:
To a stirred solution of 5.0 grams (0.03 mole) of 3,4-dihydro-7-fluoro-2H-1-benzopyran-4-one in 100 mL of methanol was added portionwise 3.4 grams (0.09 mole) of sodium borohydride during a one hour period, after which the reaction mixture was stirred for about 18 hours. The reaction mixture was then concentrated under reduced pressure to a residue, which was slurried in water and extracted with methylene chloride. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with 1:4 ethyl acetate:hexane as the eluant. The product-containing fractions were combined and concentrated under reduce pressure, yielding 4.4 grams of 3,4-dihydro-7-fluoro-4-hydroxy-2H-1-benzopyran. The NMR spectrum was consistent with the proposed structure. This reaction was repeated several times.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][C:10](=[O:12])[CH3:11])[CH:8]=1
Reactant: Cc1ccc(F)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(F)ccc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 5 g of 5-fluoro-2-methylaniline in 30 mL of pyridine was added 4.6 mL of acetic anhydride, and stirred at room temperature for 4 hours. After distilling off the pyridine under reduced pressure, the residue was dissolved in 250 mL of ethyl acetate, and washed successively with water, 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and saturated brine. The solution was dried over anhydrous magnesium sulfate, allowed to pass though a silica gel pad, and then the solvent was evaporated. The residue was recrystallized from ethyl acetate-diethyl ether, to afford 5.34 g of the title compound as white needle crystals. The mother liquor was further concentrated, and triturated with diethyl ether, to afford 907 mg of the title compound as purple needle crystals.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>CC(C)=O.O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(NC1CCCCC1O)OCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1CCCCC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.4 %

Procedure:
To a solution of benzyl (2-hydroxycyclohexyl)carbamate (4.200 g, 16.8 mmol) in acetone (15 mL) was added Jones reagent dropwise over several minutes (with room temperature water bath cooling of reaction), and the reaction mixture was stirred at room temperature for 2.5 hrs. Solutions of saturated aqueous sodium carbonate and then saturated aqueous sodium bicarbonate were added until the solution was adjusted to neutral pH, and the resulting mixture extracted with ethyl acetate (3×). The combined organic layers were washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (10-50% ethyl acetate/hexanes) to give a clear liquid (3.3 g). 1H NMR (300 MHz, CDCl3) δ 7.36-7.29 (m, 5H), 5.75 (br s, 1H), 5.10 (s, 2H), 4.29-4.25 (m, 1H), 2.65 (m, 1H), 2.57-2.50 (m, 1H), 2.43-2.33 (m, 1H), 2.17-2.10 (m, 1H), 1.88-1.60 (m, 3H), 1.48-1.34 (m, 1H). ESI (m/z): 248.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:27]=1.[C:28]([C@:30]1([OH:37])[CH2:34][CH2:33][N:32]([CH3:35])[C:31]1=[O:36])#[CH:29]>>[OH:37][C@@:30]1([C:28]#[C:29][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[C:12]([C:18]([NH:20][CH:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:27]=2)[CH2:34][CH2:33][N:32]([CH3:35])[C:31]1=[O:36]
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: NC(=O)c1nc2n(c1C(=O)NC1CCOCC1)CCOc1ccc(Br)cc1-2
Product: CN1CC[C@@](O)(C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)C1=O
Yield: 11 %

Procedure:
10-bromo-2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-3-carboxylic acid was reacted with tetrahydro-pyran-4-ylamine hydrochloride similarly to as described in example 2 with non-critical modifications to afford 117 mg (63%) 10-bromo-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide. 10-bromo-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 14 mg (11%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-N3-tetrahydropyran-4-yl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reaction time: 0.75 h
Yield: 100.1 %

Procedure:
A solution of 4-bromophenyl sulphonyl chloride (53.76 g) in dichloromethane (700 ml) was added to a stirred solution of ethyl piperidine-4-carboxylate (32.97 g) in dichloromethane (500 ml) containing triethylamine (36 ml) at 0° C. and under argon over 0.75 hours. The reaction was stirred for 18 hours. The reaction mixture was washed with water (2×500 ml), saturated brine (1×500 ml), dried and evaporated. The residual solid was triturated in isohexane (500 ml) for 1 hour, collected by filtration and dried to give, as a colourless solid, ethyl 1-(4-bromophenylsulphonyl)piperidine-4-carboxylate (79 g); mp 132-3° C.; NMR (CDCl3): 1.21(t, 3H), 1.70-1.90(m, 2H), 1.90-2.05(m, 2H), 2.18-2.33(m, 1H), 2.45-2.60(m, 2H), 3.53-3.67(m, 2H), 4.10(q, 2H), 7.55-7.70(m, 4H); EI-MS m/z 376 (M+H).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:36])/[C:6](/[NH:15][C:16](=[O:35])[C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:33])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:19][C:18]=1[Cl:34])=[CH:7]/[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[CH3:14]>CO.O1CCCC1>[Cl:34][C:18]1[CH:19]=[C:20]([C:23](=[O:33])[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[CH:21]=[CH:22][C:17]=1[C:16]([NH:15]/[C:6](=[CH:7]\[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[CH3:14])/[C:5]([OH:36])=[O:4])=[O:35]
Reactant: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C)c(/C=C(\NC(=O)c2ccc(C(=O)CCc3cccc(O)c3)cc2Cl)C(=O)O)s1
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.5 %

Procedure:
An aqueous 1N solution of sodium hydroxide (0.6 mL, 0.6 mmol) was added to a solution of (Z)-2-[[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester (Example 227; 95 mg, 0.19 mmol) in methanol/tetrahydrofuran (1:1; 2.4 mL). The solution was stirred at room temperature for 6 h and the solvent was evaporated. Water (5 mL) was added and the mixture was extracted with diethyl ether. The organic extract was discarded and the aqueous layer was acidified with 1N hydrochloric acid solution (0.6 mL) and stirred for 30 min at room temperature. The resulting precipitate was filtered off, washed with water, dried and crystallized from tetrahydrofuran/methanol/water to furnish (Z)-2-[[2-chloro-4-[3-(3-hydroxyphenyl)-1-oxopropan-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid (65 mg, 71% yield) as a colorless solid.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]O)=[CH:18][CH:17]=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][CH3:14].C(#N)C.N1C=CC=CC=1.P(Br)(Br)[Br:34]>C(Cl)Cl>[Br:34][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[CH:17][CH:18]=1
Reactant: BrP(Br)Br
Reactant: CCCCCCCCCCCCCCOc1ccc(CO)cc1
Solvent: CC#N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCOc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a room temperature slurry of 2.5 g of product from Example 19, 10 ml of acetonitrile and 0.339 g of pyridine is added dropwise, over 3 minutes, 2.11 g of phosphorus tribromide. The reaction is stirred at room temperature for 1 hour, diluted with methylene chloride and concentrated in vacuo. The residue is dissolved in methylene chloride, filtered through a silica gel pad and concentrated in vacuo to give 2.65 g of the desired product as pale yellow crystals.
Reaction SMILES: CC(C)(OC([N:7]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[O:39][C:38]([CH2:40][CH2:41][CH:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[N:37][CH:36]=3)=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:21][CH:20]=1)[CH2:8][C@H:9]([OH:16])[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O)C.Cl>>[OH:16][C@H:9]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:8][NH:7][CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[O:39][C:38]([CH2:40][CH2:41][CH:42]4[CH2:46][CH2:45][CH2:44][CH2:43]4)=[N:37][CH:36]=3)=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(NS(=O)(=O)c2ccc(-c3cnc(CCC4CCCC4)o3)cc2)cc1)C[C@H](O)c1cccnc1
Agent: Cl
Product: O=S(=O)(Nc1ccc(CCNC[C@H](O)c2cccnc2)cc1)c1ccc(-c2cnc(CCC3CCCC3)o2)cc1
Yield: 89.2 %

Procedure:
(R)-N-[4-[2-[N-(1,1-dimethylethoxycarbonyl)-N-[2-hydroxy-2-(pyridin-3-yl)ethyl]amino]ethyl]phenyl]-4-[2-(2-cyclopentylethyl)oxazol_ 5-yl]benzenesulfonamide (740 mg, 1.12 mmol) from Step D was treated with freshly prepared methanolic hydrogen chloride (5 mL) overnight. The solvent was removed under reduced pressure and the free base was isolated by column chromatography on silica gel (eluent: 1:9 10% ammonium hydroxide in methanol:methylene chloride) to afford the title compound as a white solid (560 mg, 89.3%): 1H NMR (500 MHz, CD3OD) δ8.52 (d, 1H, J=2.0 Hz), 8.43 (dd, 1H, J=1.5, 5 Hz), 7.81 (bd, H), 7.77 (d, 2H, J=8.5 Hz), 7.74 (d, 2H, J=8.5 Hz), 7.52 (s, 1H), 7.38 (dd, 1H, J=5, 7.5 Hz), 7.08 (d, 2H, J =8.5 Hz), 7.02 (d, 2H,J=8.5 Hz), 4.80 (m, 1H), 2.94-2.70 (m, 8H), 1.79 (m, 5H), 1.62 (m, 2H), 1.54 (m, 2H), 1.12 (m, 2H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][NH:2]1.[OH-].[Na+]>O1CCCC1.O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: C1=Cc2ccccc2CN1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)CCNC2
Temperature: -30 °C

Procedure:
A solution of 467 mg (3.5 mmol) of AlCl3 in 10 ml of THF is added dropwise at room temperature to a suspension of 400 mg (10.5 mmol) of LiAlH4 in 20 ml of tetrahydrofuran (THF), as a result of which AlH3 is formed. After 15 minutes the solution is cooled to -30° C. and a solution of 2.5 g (6.74 mmol) of the dihydroisoquinoline according to b. in 100 ml of THF is added dropwise in 15 minutes. The reaction mixture is then slowly heated to room temperature. After 1.5 hours an NaOH solution in H2O is added until everything has dissolved. The organic phase is separated, and the aqueous phase is washed once with ethyl acetate/ether and four times with ether. The combined organic phases are washed with saline solution and dried with Na2SO4. After evaporation the tetrahydroisoquinoline (melting-point 160° C.) is obtained as a light-yellow powder (2.45 g, i.e. (2.45 g, i.e. 97%).
Reaction SMILES: S([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1C(O)=O)(O)(=O)=O.S(C1C=C(C(O)=O)C(=CC=1)C(O)=O)(O)(=O)=[O:18]>>[OH:18][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(S(=O)(=O)O)cc1C(=O)O
Reactant: O=C(O)c1cccc(S(=O)(=O)O)c1C(=O)O
Product: O=C(O)c1cccc(O)c1

Procedure:
Within the framework of the process according to the invention, sulphophthalic acid are 3-sulphophthalic acid and 4-sulphophthalic acid. They can be reacted according to the invention either on their own or as a mixture, to give 3-hydroxybenzoic acid. Preferably, a mixture of the two isomeric sulphophthalic acids such as is obtained from the sulphonation of phthalic anhydride with oleum is used for the process according to the invention. The mixture obtained from the said sulphonation is a mixture of 3-sulphophthalic acid and 4-sulphophthalic acid in a ratio of 1:4 to 1:6.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C#CCCCCCCCCCCC
Reactant: COC(=O)CCc1ccccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC#Cc1ccccc1CCC(=O)OC

Procedure:
Palladium acetate (60 mg) was added to a deaerated solution of methyl 3-(2-bromophenyl)propanoate (11.10 g, 25 mmole), 1-tridecyne (6.75 g) and triphenylphosphine (200 mg) in anhydrous triethylamine (100 ml) and the mixture was stirred at reflux under nitrogen for 24 hrs. After cooling, the precipitated triethylamine hydrobromide was filtered off and the filtrate was evaporated to a red oil. Chromatography on silica eluting with 1:1 dichloromethane-petrol (bp 60°-80° C.) gave the title product, 1.91 g (22%) as an oil, νmax (film) 2920, 2850, 1745 cm-1, δ(CDCl3) 0.84 (3H, distorted t, terminal CH3), 1.28 (18H, m, alkylene chain), 2.39 (2H, t, J 7 Hz; C=C--CH2), 2.62 (2H, m, ArCH2), 3.04 (2H, m, CH2CO2), 3.62 (3H, s, ester CH3), 7.12 (3H, m, arom), 7.31 (1H, m, arom).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][N:5]2[C:6](=[O:15])[C:7]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[N:9]=[C:4]2[CH:3]=1.[C:18]1([C:24]2[N:25]=[CH:26][NH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.[Cu]I>[C:18]1([C:24]2[N:25]=[CH:26][N:27]([C:2]3[CH:17]=[CH:16][N:5]4[C:6](=[O:15])[C:7]5[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:8]=5[N:9]=[C:4]4[CH:3]=3)[CH:28]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=c1c2c(nc3cc(Br)ccn13)CCCCC2
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(nc3cc(-n4cnc(-c5ccccc5)c4)ccn13)CCCCC2
Yield: 38 %

Procedure:
A solution of 3-bromo-7,8,9,10-tetrahydrocyclohepta[d]pyrido[1,2-a]pyrimidin-11(6H)-one (50 mg, 0.17 mmol), 4-phenyl-1H-imidazole (37.4 mg, 0.26 mmol), CuI (8 mg, 0.04 mmol) and Cs2CO3 in DMF was stirred at 80° C. under nitrogen. The completion of the reaction was monitored by TLC. After the suspension was diluted with water (30 mL) and extracted with ethyl acetate (3×50 mL), the combined organic phases were concentrated to crude product and 23 mg desired product was obtained by column chromatography purification. MS (ESI): 357 (MH+); MS (ESI): 357 (MH+); 1H NMR (300 MHz, CDCl3) δ 9.15-9.13 (d, J=7.83 Hz, 1H), 8.16 (s, 1H), 7.87-7.85 (d, J=7.38 Hz, 2H), 7.72 (s, 1H), 7.57-7.56 (d, J=2.19 Hz, 1H), 7.48-7.44 (t, J=7.35 Hz, 2H), 7.38-7.35 (d, J=7.08 Hz, 1H), 7.26 (m, 1H), 3.00-2.97 (m, 4H), 1.93-1.91 (m, 2H), 1.79-1.77 (m, 2H), 1.71-1.69 (m, 2H).
Reaction SMILES: [CH2:1]([O:10][C:11](=[O:44])[CH:12]([NH:36]C(OC(C)(C)C)=O)[CH2:13][C:14]1[CH:15]=[C:16]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH:17]=[C:18]([CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:10][C:11](=[O:44])[CH:12]([NH2:36])[CH2:13][C:14]1[CH:15]=[C:16]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH:17]=[C:18]([CH2:20][P:21]([O:26][CH2:27][CH3:28])([O:23][CH2:24][CH3:25])=[O:22])[CH:19]=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOP(=O)(Cc1cc(CC(NC(=O)OC(C)(C)C)C(=O)OCC=Cc2ccccc2)cc(-c2ccc(Cl)cc2)c1)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(Cc1cc(CC(N)C(=O)OCC=Cc2ccccc2)cc(-c2ccc(Cl)cc2)c1)OCC

Procedure:
5.5 g of the product of step c) and 50 ml aqueous trifluoroacetic acid (70%) are stirred at room temperature 20 hours. To the mixture are added CH2Cl2 and dropwise aqueous KHCO3 solution. The organic phase is dried (Na2SO4) and evaporated. The residue is taken up in diethyl ether, filtered and evaporated to dryness, to give the heading compound as an oil.
Reaction SMILES: [C:1]([CH2:4][CH:5]([CH3:19])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:18])[NH:13]2)([OH:3])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH2:33]([NH:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH3:34]>O.C(OCC)(=O)C>[CH:36]1([N:35]([CH2:33][CH3:34])[C:1]([CH2:4][CH:5]([CH3:19])[CH2:6][O:7][C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][C:12](=[O:18])[NH:13]3)=[O:3])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(COc1cccc2c1CCC(=O)N2)CC(=O)O
Reactant: CCNC1CCCCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(C(=O)CC(C)COc1cccc2c1CCC(=O)N2)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.6 Grams of 5-(3-carboxy-2-methylpropoxy)-3,4-dihydrocarbostyril and 1.6 ml of triethylamine are added to 200 ml of ethyl acetate, followed by dropwise addition of 1.0 ml of ethyl chloroformate under external ice cooling and agitation while maintaining the internal temperature at 10° to 20° C. Thereafter, the mixture is agitated at room temperature for 1 hour, added with 1.4 g of N-ethylcyclohexylamine and further agitated for 1.5 hours. The reaction solution is poured into water to separate the liquid, and the organic layer is washed with dilute aqueous NaOH solution, diluted hydrochloric acid and water in that order and then dried with anhydrous Na2SO4. After filtering off the inorganic matter, the mother liquor is concentrated and the residue is recrystallized from ligroin-benzene, obtaining 1.5 g of 5-[3-(N-cyclohexyl-N-ethylaminocarbonyl)-2-methylpropoxy]-3,4-dihydrocarbostyril in the form of colorless needle-like crystals with melting point of 114°-115.5° C.