Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5](=[CH:9][C:10]=1[Cl:11])[C:6]([OH:8])=O>C(OC(=O)C)(=O)C>[Cl:11][C:10]1[CH:9]=[C:5]2[C:6](=[O:8])[O:14][C:12](=[O:13])[C:4]2=[CH:3][C:2]=1[Cl:1]
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A suspension of 4,5-dichlorophthalic acid [(XVII), X=4-Cl, Y=5-Cl, 50.0 g, 0.213 mol] and acetic anhydride (70 mL) was heated to reflux until dissolution occurred. A distilling head was then attached and 30 mL of distillate was removed. The solution was cooled to room temperature whereupon a precipitate appeared. This solid was filtered, washed with anhydrous ether and dried in vacuo to provide the product (40.4 g, 87%) as a tan solid, m.p. 189°-192° C.
Reaction SMILES: S(Cl)(Cl)=O.CC1SC(C(O)=O)=CC=1.CC1SC(C(Cl)=O)=CC=1.[CH3:23][C:24]1[S:28][C:27]([C:29]([N:31]=[C:32]=[S:33])=[O:30])=[CH:26][CH:25]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[N:42]=[CH:41][CH:40]=[C:39]2[O:48][C:49]1[CH:55]=[CH:54][C:52]([NH2:53])=[CH:51][C:50]=1[F:56]>C(O)C.C1(C)C=CC=CC=1>[CH3:34][O:35][C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][C:45]=1[O:46][CH3:47])[N:42]=[CH:41][CH:40]=[C:39]2[O:48][C:49]1[CH:55]=[CH:54][C:52]([NH:53][C:32]([NH:31][C:29]([C:27]2[S:28][C:24]([CH3:23])=[CH:25][CH:26]=2)=[O:30])=[S:33])=[CH:51][C:50]=1[F:56]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: Cc1ccc(C(=O)N=C=S)s1
Agent: Cc1ccc(C(=O)Cl)s1
Agent: Cc1ccc(C(=O)O)s1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)s4)cc3F)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 5-methyl-2-thiophenecarboxylic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 5-methyl-2-thiophenecarbonyl isothiocyanate was prepared using the resultant 5-methyl-2-thiophenecarbonyl chloride as a starting compound according to the description of the literature. 5-Methyl-2-thiophenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (49 mg, yield 62%).
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH2:16][CH2:17]C(O)=O)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([NH2:33])[CH:27]=1.ClCCl.[OH-].[Na+]>C[Si](OP(=O)=O)(C)C>[CH3:23][O:24][C:25]([C:26]1[CH:31]=[CH:30][C:29]2[O:32][C:17]([CH2:16][O:15][C:14]3[CH:13]=[CH:12][C:11]([C:1]45[CH2:10][CH:5]6[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]6)[CH2:2]4)[CH2:8]5)=[CH:22][CH:21]=3)=[N:33][C:28]=2[CH:27]=1)=[O:34]
Reactant: O=C(O)CCOc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1ccc(O)c(N)c1
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Temperature: 140 °C
Yield: 64.1 %

Procedure:
A mixture of (4-adamantan-1-yl-phenoxymethyl)-acetic acid (200.0 mg, 0.70 mmol) and 3-amino-4-hydroxy-benzoic acid methyl ester (164.3 mg, 0.98 mmol) in PPSE (3 mL) was heated at 140° C. for 2 h. At the end of the reaction period, the mixture was taken to dichloromethane and neutralized with 1 N NaOH solution. The organic layer was separated and the aqueous solution extracted with dichloromethane. The combined extracts were dried over anhydrous MgSO4, filtered and the solvent was removed with rotary evaporator under reduced pressure. The residue was purified by flash chromatography (n-Hexane:EtoAc:MeOH=6:3:1) to afford 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid methyl ester as a white solid (187.3 mg, 64.1% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C@@H:12]([O:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([C:25]3[C:26](=[O:35])[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:21][CH2:20]2)=[O:18])[C:13](O)=[O:14])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.C(N(C(C)C)CC)(C)C.[CH:45]1([N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O.ClCCl>[O:35]=[C:26]1[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C@H:12]([CH2:11][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)[C:13]([N:54]3[CH2:55][CH2:56][N:51]([CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]4)[CH2:52][CH2:53]3)=[O:14])=[O:18])[CH2:20][CH2:21]2)=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]1
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)O)cc2cn[nH]c12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCN(C3CCCCC3)CC2)cc2cn[nH]c12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-(7-methyl-1H-indazol-5-yl)-2-(4-(2-oxo-1,2-dihydroquinolin-3-yl)piperidine-1-carbonyloxy)propanoic acid (50 mg, 0.11 mmol), diisopropylethylamine (37 μL, 0.21 mmol), and 1-cyclohexylpiperazine (35.5 mg, 2.0 equiv) in dimethylformamide (0.50 mL) and dichloromethane (0.50 mL) at 0° C. was added PyBOP® (57.6 mg, 0.11 mmol). The reaction was stirred at 0° C. for 4 h. The reaction was concentrated and purified by column chromatography (95:5:1 to 90:10:1 dichloromethane/methanol/triethylamine). The resulting residue was dissolved in 5% methanol/dichloromethane and passed through a basic alumina column to give 62.3 mg (92%) as a white powder. 1H-NMR (CD3OD, 500 MHz) δ 0.75-2.10 (m, 20H), 2.29 (m, 1H), 2.47 (m, 1H), 2.56 (s, 3H), 2.77-3.41 (m, 9H), 3.73 (m, 1H), 4.04-4.49 (m, 2H), 5.52 (dd, J=8.2, 7.3, 1H), 7.11 (s, 1H), 7.22 (dd, J=7.0, 7.0, 1H), 7.33 (d, J=7.9, 1H), 7.42-7.53 (m, 2H), 7.53-7.76 (m, 2H), 8.01 (s, 1H). Mass spec.: 625.33 (MH)+.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]([O:42]CC4C=CC=CC=4)=[C:37]([CH3:50])[CH:36]=3)[C:19]([N:21]3[CH2:26][CH2:25][N:24](CC4C=CC=CC=4)[CH2:23][CH2:22]3)=[O:20])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1.[H][H]>CO.[Pd]>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:34][C:35]3[CH:40]=[C:39]([CH3:41])[C:38]([OH:42])=[C:37]([CH3:50])[CH:36]=3)[C:19](=[O:20])[N:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]3)=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:51]=[CH:52][CH:53]=[CH:54][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(Cc3ccccc3)CC2)cc(C)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCNCC2)cc(C)c1O

Procedure:
1.62 g (2.22 mmol) (R)-1-(4-benzyloxy-3,5-dimethyl-benzyl)-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 40 mL MeOH were combined with 150 mg 10% Pd/C and hydrogenated at RT and 3 bar hydrogen until the reaction came to an end. The catalyst was removed by suction filtering and the solvent was concentrated by evaporation i. vac. The residue was purified by chromatography (silica gel, EtOAc/MeOH/NH3 85:13.5:1.5).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:9]([CH:20](Cl)[CH3:21])=[CH:8]2.CN(C=O)C.[C:28]1(=[O:38])[NH:32][C:31](=[O:33])[C:30]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:29]12.[K]>>[Cl:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[C:14]([CH3:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:9]([CH:20]([N:32]1[C:28](=[O:38])[C:29]3[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:31]1=[O:33])[CH3:21])=[CH:8]2
Reactant: Cc1ncccc1-c1nc2c(Cl)cccc2cc1C(C)Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1ncccc1-c1nc2c(Cl)cccc2cc1C(C)N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution of 8-chloro-3-(1-chloroethyl)-2-(2-methylpyridin-3-yl)-quinoline hydrochloride (1.3130 g, 3.712 mmol) in DMF (18.56 mL, 3.712 mmol) at 100° C. was added potassium phthalimide (1.719 g, 9.281 mmol) at 100° C. and the mixture was stirred at 100° C. After 1.5 h, the mixture was concentrated under reduced pressure and triturated with water (50 mL). The resulting solid was filtered and washed with 2 N NaOH (50 mL) and then with water (500 mL), and air-dried to give 2-(1-(8-chloro-2-(2-methylpyridin-3-yl)quinolin-3-yl)ethyl)-isoindoline-1,3-dione as a tan solid: LC-MS (ESI) m/z 428.0 [M+H]+. The impure product was carried on crude without purification for the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:11]([O-:14])(O)=[O:12].S(=O)(=O)(O)O.[CH2:20](Cl)Cl>>[N+:11]([C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[C:5]([CH3:20])[CH:6]=[CH:7][CH:8]=1)([O-:14])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: ClCCl
Reactant: Cc1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Product: Cc1cccc([N+](=O)[O-])c1[N+](=O)[O-]
Reaction time: 1 h
Yield: 99 %

Procedure:
68.6 g (0.5 mol) of 4-nitrotoluene were dissolved in 80 ml of methylene chloride and 38.6 g (0.6 mol) of 98% by weight nitric acid, followed by the addition with stirring over a period of 1 hour at reflux temperature of 40 g of 100% by weight sulphuric acid. After stirring under reflux for another 2 hours, the methylene chloride phase was separated off without cooling and washed three times while still hot with 3 × 200 ml of water. After the washing water had been carefully separated off, the methylene chloride was distilled off, leaving 90.2 g of dinitrotoluene containing 99% of 2,4-dinitrotoluene (98% of the theoretical yield).
Reaction SMILES: CO[C:3](=[O:20])[CH2:4][CH2:5][C@H:6]1[CH2:10][O:9][C:8]([CH3:12])([CH3:11])[N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[Mg]([CH2:23][CH2:24][CH2:25][CH2:26][Mg]Br)Br>C1COCC1>[OH:20][C:3]1([CH2:4][CH2:5][C@H:6]2[CH2:10][O:9][C:8]([CH3:11])([CH3:12])[N:7]2[C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: Br[Mg]CCCC[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CCC2(O)CCCC2)COC1(C)C
Temperature: -10 °C
Reaction time: 2 h

Procedure:
The (S)-tert-butyl 4-(3-methoxy-3-oxopropyl)-2,2-dimethyloxazolidine-3-carboxylate (1.02 g, 3.55 mmol, 1.0 equiv) was dissolved in 50 mL of THF and cooled to −10° C. A 1.0 M solution of BrMg(CH2)4MgBr (7.1 mL, 2.0 equiv) was added and the mixture stirred for 2 h. After this time a second portion of BrMg(CH2)4MgBr was added and the mixture stirred for 1 h. The mixture was quenched by addition of saturated NH4Cl and the mixture transferred to a separatory funnel, and the organic layer was washed with brine, then dried over Na2SO4, filtered, and evaporated to provide crude (S)-tert-butyl 4-(2-(1-hydroxycyclopentyl)ethyl)-2,2-dimethyloxazolidine-3-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15](S(C)=O)=[N:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].O.[NH2:22][NH2:23]>O1CCCC1>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[N:16][C:15]([NH:22][NH2:23])=[N:14][CH:13]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(-c2cnc(S(C)=O)nn2)cc1F
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2cnc(NN)nn2)cc1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of methyl 2-fluoro-4-[3-(methylsulfinyl)-1,2,4-triazin-6-yl]benzoate (0.19 g, 0.00064 mol) in tetrahydrofuran (20 mL) was added hydrazine hydrate (63 μL, 0.0013 mol) slowly. The mixture was stirred at RT for 1.5 h. The mixture was concentrated under reduced pressure to yield the desired product. Analytical LCMS: (M+H)+=264.1.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([O:44][CH2:45][C@H:46](O)[CH3:47])(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:15]=1)[C:10]([O:12][C@H:46]([CH3:47])[CH2:45][O:44][C:36]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:43])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](O)COC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C[C@H](COC(=O)c1ccccc1)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 45.1 %

Procedure:
To a solution of (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoic acid (15.9 g, 33.3 mmol), (2R)-2-hydroxypropyl benzoate (5.0 g, 27.7 mmol), and 4-(dimethylamino)pyridine (340 mg) in 250 mL of anhydrous dichloromethane, 1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (EDAC) (8.0 g, 41.6 mmol) was slowly added. The resulting mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with dichloromethane and washed with 0.5N HCl twice, followed by the addition of brine. The organic layer was separated, dried through a MgSO4 pad and concentrated under reduced pressure. Chromatography (silica gel, 1:5 then 1:4 ethyl acetate/hexane) of the residue followed by crystallization from 1:5 ethyl acetate/hexane afforded 8.0 g (45%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3I)=[C:13]([C:26]#[N:27])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[N:38][NH:39][CH:40]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:1][C:2]1[S:6][C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:36]3[CH:37]=[N:38][NH:39][CH:40]=3)=[C:13]([C:26]#[N:27])[CH:12]=2)(=[O:10])=[O:9])=[N:4][CH:3]=1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1Oc1ccc(F)cc1I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(S(=O)(=O)Nc2ncc(Cl)s2)ccc1Oc1ccc(F)cc1-c1cn[nH]c1
Temperature: 90 °C

Procedure:
N-(5-Chloro-1,3-thiazol-2-yl)-3-cyano-4-(4-fluoro-2-iodophenoxy)benzenesulfonamide (Preparation 240, 50 mg, 0.09 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (27 mg, 0.14 mmol) palladium (0) tetrakis(triphenylphosphine) (10 mg, 0.009 mmol) and sodium carbonate (30 mg, 0.28 mmol) were dissolved in dimethylformamide:water (2:1, 1.5 ml.) and heated to 90° C. for 18 hours. The reaction was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo to afford a brown oil. Purification by preparative HPLC afforded the title compound. Yield 12.5 mg 30%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24]3)=[CH:18][CH:17]=2)[CH2:10][C:11]([O:13]CC)=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.[Li+].[OH-].Cl>C1COCC1.C(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH:23]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24]3)=[CH:20][CH:21]=2)[CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CCOC(=O)CC(c1ccc(OC2Cc3ccccc3C2)cc1)c1cc(F)cc(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CC(c1ccc(OC2Cc3ccccc3C2)cc1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(+/−)3-(3,5-Difluoro-phenyl)-3-[4-(indan-2-yloxy)-phenyl]-propionic acid ethyl ester 35 (25 mg) was dissolved in 3 mL THF-EtOH-H2O (1/1/1), and LiOH (20 mg) was added. The mixture was stirred at room temperature for 6 hours. 1N HCl was added to acidify the mixture to pH 2-3. The mixture was extracted with EtOAc (2×20 mL). The organic solution was washed with water and brine, dried over Na2SO4, concentrated, and flash chromatographed (0-60% EtOAc in hexane). (+/−)-3-(3,5-Difluorophenyl)-3-(4-(2,3-dihydro-1H-inden-2-yloxy)phenyl) propanoic acid 36 was obtained as a colorless oil. MS ESI (neg.) m/e: 393 (M−H). 1H NMR (500 MHz) (CDCl3) δ 7.25-7.31 (m, 2H); 7.20-7.22 (m, 2H); 7.14 (d, J =8.4 Hz, 2H); 6.87 (d, J=8.4 Hz, 2H); 6.78 (d, J =6.5 Hz, 2H); 6.67 (t, J =8.9 Hz, 1H); 5.16 (m, 1H); 4.47 (t, J=7.8 Hz, 1H); 3.38 (dd, J =16.7, 6.3 Hz, 2H); 3.19 (dd, J=16.7, 2.6 Hz, 2H); 3.06 (d, J =7.9 Hz, 2H).
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21]C)=[CH:18][CH:19]=3)[CH2:14][CH2:13][N:12]2[C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CO>C(Cl)Cl>[CH:5]1([CH:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13][N:12]2[C:23](=[O:28])[C:24]([F:25])([F:26])[F:27])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: COc1ccc2c(c1)CCN(C(=O)C(F)(F)F)C2C1CCCCC1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: O=C(N1CCc2cc(O)ccc2C1C1CCCCC1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 113.4 %

Procedure:
A 1M solution of BBr3 in CH2Cl2 (0.77 ml, 0.77 mmol) was added slowly to a solution of 1-(1-cyclohexyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (0.176 g, 0.52 mmol) in anhydrous CH2Cl2 (10 ml) at 0° C. under N2. The reaction mixture was stirred at 0° C. for 30 min, then warmed to rt and stirred at rt for 21 hr. MeOH (10 ml) was slowly added with stirring and the resulting solution was concentrated in vacuo to a orange oil. Purification by flash chromatography, eluting with hexane:EtOAc (8:2) gave 0.193 g (100% yield) of white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[Cl:16].[CH3:17][Mg]Br>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[CH3:17])=[CH:4][C:3]=1[Cl:16]
Reactant: C[Mg]Br
Reactant: O=C(c1ccccc1)c1ccc(Br)c(Cl)c1
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccc(Br)c(Cl)c1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of (4-bromo-3-chlorophenyl)-phenylmethanone (200 mg, 0.677 mmol) in THF (6 mL) was added 1.4 M of methylmagnesium bromide in THF (1.8 mL, 2.5 mmol) slowly at −78° C. The reaction was stirred at −78° C. for 4 h. The reaction was quenched with sat. aq. NaHCO3 at −78° C. The crude material was extracted with DCM and concentrated in vacuo to afford the title compound as a colorless oil which was used for next step without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][CH2:10][C:9]2[CH:18]=[CH:19][CH:20]=[CH:21][C:8]1=2.[NH:22]1[CH2:27][CH2:26][CH2:25][C@@H:24]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23]1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:31]([O:30][C:28]([C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][CH2:10][C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]2=3)[CH2:23]1)=[O:29])[CH3:32]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: ClCCOCCN1c2ccccc2CCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CCCN(CCOCCN2c3ccccc3CCc3ccccc32)C1
Temperature: 150 °C
Yield: 50 %

Procedure:
A mixture of sodium hydride (0.40 g, 0.010 mol, 60% oil dispersion) and 10,11-dihydro-5H-dibenz[b,f]azepine (1.95 g, 0.010 mol) in dry dibutylether (30 ml) was heated at reflux temperature for 3.5 h under an atmosphere of nitrogen. The reaction mixture was cooled to 100° C. and bis-2-chloro-ethyl ether (4.7 ml) was added and the mixture was heated at reflux temperature for 16 h. The reaction mixture was cooled and water (50 ml) was added. The mixture was extracted with toluene (100 ml). The organic extract was dried over sodium sulphate and the solvent evaporated in vacuo to give 2.8 g of an oily residue containing 2-chloro-1-(2-(10,11-dihydro-5H-dibenz[b,f]-azepin-5-yl)ethoxy)ethane. To this oil was added ethyl (R)-3-piperidinecarboxylate (3.0 g, 0.019 mol) and the mixture was heated at 150° C. for 1.5 h. The reaction mixture was allowed to cool to 80° C. and toluene (100 ml) was added. The mixture was then allowed to cool to room temperature and a solution of potassium carbonate (1.4 g) in water (100 ml) was added. The phases were separated and the organic phase was washed successively with water, an aqueous sodium acetate solution (pH 5) and an aqueous citric acid solution (pH 5). The organic phase was then extracted with a 5% aqueous citric acid solution (50 ml). The acidic (pH 1) aqueous extract was washed with toluene (2×50 ml) and then a 4 N sodium hydroxide solution was added until pH 6-7. The aqueous mixture was extracted with toluene and the organic extract was treated with charcoal and dried over sodium sulphate. The solvent was evaporated in vacuo to give 2.1 g (50%) of (R)-N-(2-(2-(10,11-dihydro-5H-dibenz[b,f]azepin-5-yl)ethoxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.20 (SiO2 ; n-heptane/THF=7:3).
Reaction SMILES: [CH3:1][C:2]1(O)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]2[CH2:11][CH2:12][CH2:13][N:14]=[C:3]12.S(=O)(=O)(O)O.O.C(=O)(O)[O-:23].[Na+].[C:27](#[N:29])[CH3:28]>CS(O)(=O)=O>[C:27]([NH:29][C:2]1([CH3:1])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]2[CH2:11][CH2:12][CH2:13][N:14]=[C:3]12)(=[O:23])[CH3:28]
Reactant: CC1(O)C2=NCCCN2c2ccccc21
Reactant: O=C([O-])O
Reactant: CC#N
Agent: CS(=O)(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)NC1(C)C2=NCCCN2c2ccccc21

Procedure:
A solution of 2,3,4,10-tetrahydro-10-methylpyrimido [1,2-a]indol-10-ol (0.444 g) in acetonitrile (4 ml) and methanesulphonic acid (10 drops) was adde dropwise over 5 min to stirred sulphuric acid 98% w/w (2.5 ml) at 50°-60°. After 2.5h, the solution was poured into water (100 ml), basified with sat. aqueous sodium bicarbonate, and extracted with chloroform (3×100 ml). The extracts were washed with water (200 ml), dried (MgSO4), and evaporated in vacuo to give the title compound as the free base (0.07 g).
Reaction SMILES: [NH2:1][C:2]1([C:12]([OH:14])=[O:13])[CH:9]2[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.[CH:15]1[C:24]2[C:19](=[C:20]([N:25]3[C:29]([C:30]4[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:31]=4[O:38][CH3:39])=[CH:28][C:27]([C:40](Cl)=[O:41])=[N:26]3)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1>N1C=CC=CC=1.ClCCl>[CH:15]1[C:24]2[C:19](=[C:20]([N:25]3[C:29]([C:30]4[C:31]([O:38][CH3:39])=[CH:32][CH:33]=[CH:34][C:35]=4[O:36][CH3:37])=[CH:28][C:27]([C:40]([NH:1][C:2]4([C:12]([OH:14])=[O:13])[CH:9]5[CH2:8][CH:7]6[CH2:6][CH:5]([CH2:4][CH:3]4[CH2:11]6)[CH2:10]5)=[O:41])=[N:26]3)[CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1
Reactant: NC1(C(=O)O)C2CC3CC(C2)CC1C3
Reactant: COc1cccc(OC)c1-c1cc(C(=O)Cl)nn1-c1cccc2cnccc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(OC)c1-c1cc(C(=O)NC2(C(=O)O)C3CC4CC(C3)CC2C4)nn1-c1cccc2cnccc12
Reaction time: 8 h

Procedure:
0.75 g of 2-amino-2-adamantanecarboxylic acid is dissolved in 20 ml of pyridine. 1.4 g of 1-(5-isoquinolyl)-5-(2,6-dimethoxyphenyl)-3-pyrazolecarbonyl chloride, dissolved in 20 ml of dichloromethane, are added and the reaction mixture is left overnight at room temperature. It is concentrated under vacuum, the residue is taken up with pH 2 buffer, the mixture is stirred and the precipitate is filtered off and rinsed with diisopropyl ether.