Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[N:10]1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[NH:31][S:32]([CH3:35])(=[O:34])=[O:33].[H-].[Na+].[CH3:38]I.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:24])[N:10]1[CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[N:31]([CH3:38])[S:32]([CH3:35])(=[O:33])=[O:34]
Reactant: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2NS(C)(=O)=O)C1c1ccc(Cl)cc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1c2ccccc2C(=O)N(C2CCCCC2N(C)S(C)(=O)=O)C1c1ccc(Cl)cc1Cl
Reaction time: 0.17 h

Procedure:
To a solution of 1.4 g of ethyl(3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate in 20 ml of DMF was added 229 mg of sodium hydride under ice-cooling, followed by stirring at the same temperature for 10 minutes, and then 0.17 ml of methyl iodide was added thereto, followed by stirring under ice-cooling for 30 minutes. Water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol) to obtain 545 mg of ethyl (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[methyl(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate as a colorless amorphous substance.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[F:10][C:11]([F:18])([F:17])[CH:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.CCN(C(C)C)C(C)C>CC#N>[Cl:8][C:6]1[CH:5]=[C:4]([N:13]2[CH2:14][CH2:15][CH2:16][CH:12]2[C:11]([F:18])([F:17])[F:10])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: FC(F)(F)C1CCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(Cl)cc(N2CCCC2C(F)(F)F)n1
Yield: 36.6 %

Procedure:
2-Amino-4,6-dichloropyrimidine (143 mg, 0.870 mmol) was added to a stirring mixture of 2-trifluoromethylpyrrolidine (121 mg, 0.870 mmol) and Hunig's base (0.23 mL, 1.31 mmol) in CH3CN (2.5 mL) in a microwave vessel. The reaction was capped and heated in a microwave reactor for 1 hour. Silica gel chromatography (Analogix RS-12 g cartridge) eluting with 5-10% EtOAc—CHCl3 gave the title compound (85 mg) as a white solid. 1H NMR (400 MHz, CDCl3, * denotes minor rotamer): δ 1.96-2.15 (m, 2H), 2.15-2.32 (m, 2H), 3.37-3.52 (m, 1H), 3.54-3.65 (m, 1H), 4.82, 5.60* (bs, 1H), 5.00 (bs, 2H), 5.94, 6.72* (s, 1H).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][CH:5]([C:8]2[S:25][C:11]3[N:12]=[C:13]([CH3:24])[N:14]=[C:15]([CH2:16][NH:17][C:18]([CH3:23])([CH3:22])[CH2:19][O:20][CH3:21])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.N1(CO)C2C=CC=C[C:30]=2N=N1.ClCCCl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>O>[F:26][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[S:25][C:11]3[N:12]=[C:13]([CH3:24])[N:14]=[C:15]([CH2:16][N:17]([CH3:30])[C:18]([CH3:23])([CH3:22])[CH2:19][O:20][CH3:21])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: COCC(C)(C)NCc1nc(C)nc2sc(C3CCC(F)(F)CC3)cc12
Reactant: OCn1nnc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: COCC(C)(C)N(C)Cc1nc(C)nc2sc(C3CCC(F)(F)CC3)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a mixture of N-{[6-(4,4-difluorocyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-1-methoxy-2-methylpropan-2-amine (110 mg), 1H-benzotriazole-1-methanol (86 mg), and DCE was added NaBH(OAc)3 (182 mg), followed by stirring at room temperature for 4 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by basic silica gel column (hexane/EtOAc) to obtain N-{[6-(4,4-difluorocyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-1-methoxy-N,2-dimethylpropan-2-amine (93 mg). This product was dissolved in MeOH, and fumaric acid (27 mg) was added thereto, followed by concentration under reduced pressure to obtain N-{[6-(4,4-difluorocyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-1-methoxy-N,2-dimethylpropan-2-aminefumarate (117 mg).
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.[F:12][C:13]1[C:18]([OH:19])=[C:17]([CH:20]=[O:21])[CH:16]=[CH:15][C:14]=1[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1>CN(C=O)C>[Br:1][C:15]1[C:14]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:13]([F:12])[C:18]([OH:19])=[C:17]([CH:20]=[O:21])[CH:16]=1
Reactant: O=Cc1ccc(-c2ccc(F)cc2)c(F)c1O
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Solvent: CN(C)C=O
Product: O=Cc1cc(Br)c(-c2ccc(F)cc2)c(F)c1O
Reaction time: 3 h
Yield: 122.3 %

Procedure:
Dibromoisocyanuric acid (24.8 g) was added to a solution of 2,4′-difluoro-3-hydroxybiphenyl-4-carbaldehyde (33.7 g) in DMF (400 mL) at room temperature. The mixture was stirred at the same temperature under nitrogen atmosphere for 3 hours. The mixture was quenched with aqueous saturated sodium thiosulfate solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (33.1 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([N+:22]([O-])=O)[CH:5]=1.[H][H]>C(OCC)(=O)C.[Ni]>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[C:6]([NH2:22])[CH:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccc(C)cc2)c(S(N)(=O)=O)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)c(Oc2ccc(C)cc2)c(S(N)(=O)=O)c1

Procedure:
45 g of 3-nitro-4-(4'-methylphenoxy)-5-sulphamoylbenzoic acid methyl ester are suspended in 150 ml of ethyl acetate and hydrogenated for 5 hours with Raney nickel at 50° C and a hydrogen pressure of 100 atmospheres gauge. After cooling, the Raney nickel is separated and the solution is concentrated to dryness. The 3-amino-4-(4'-methylphenoxy)-4-sulphamoylbenzoic acid methyl ester is recrystallised from methanol/H2O. Crystals melting at 183°-185° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.C([Li])CCC.[Br:26][C:27]1[CH:41]=[CH:40][C:30]([C:31]([C:33]2[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][CH:34]=2)=O)=[CH:29][CH:28]=1>O1CCCC1.C(O)(=O)C.S(=O)(=O)(O)O>[Br:26][C:27]1[CH:41]=[CH:40][C:30]([C:31]2([C:33]3[CH:38]=[CH:37][C:36]([Br:39])=[CH:35][CH:34]=3)[C:19]3[C:20]4=[C:15]([C:14]5[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=5[N:8]4[C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=4)[CH:16]=[CH:17][CH:18]=3)=[CH:29][CH:28]=1
Reactant: O=C(c1ccc(Br)cc1)c1ccc(Br)cc1
Reactant: Brc1ccccc1-n1c2ccccc2c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Brc1ccc(C2(c3ccc(Br)cc3)c3ccccc3-n3c4ccccc4c4cccc2c43)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
6.96 g of 9-(2-bromophenyl)-9H-carbazole as the intermediate of Preparation Example 8 was dissolved in 10 mL of purified tetrahydrofuran, and the resulting solution was cooled to −78° C. and 8.64 mL of butyllithium was slowly added dropwise. The mixture was stirred at the same temperature for 30 min, and 6.12 g of 4,4′-dibromobenzophenone was added. The mixture was stirred at the same temperature for 40 min and then further stirred at room temperature for an additional 3 hours. The reaction was terminated with aqueous ammonium chloride, and the reaction mixture was extracted with ethyl ether. The organic layer was dewatered using anhydrous magnesium sulfate, and the organic solvent was then removed. The resulting solid was dispersed in ethanol, stirred for one day, filtered, and vacuum dried, thus obtaining an intermediate material. The solid thus obtained was dispersed in 10 mL of acetic acid, and 10 drops of concentrated sulfuric acid were added, after which the mixture was refluxed for 4 hours. The resulting solid was filtered, washed with ethanol, and vacuum dried, yielding a 8,8-bis(4-bromophenyl)-8H-indolo[3,2,1-de]acridine compound.
Reaction SMILES: Cl.[NH:2]1[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.[Cl:19][C:20]1[CH:29]=[CH:28][C:23]([CH:24]=[CH:25][CH2:26]Cl)=[CH:22][CH:21]=1>C(#N)C>[Cl:19][C:20]1[CH:29]=[CH:28][C:23](/[CH:24]=[CH:25]/[CH2:26][N:2]2[CH2:8][CH2:7][CH2:6][C:5](=[O:9])[CH2:4][CH2:3]2)=[CH:22][CH:21]=1
Reactant: O=C1CCCNCC1
Reactant: ClCC=Cc1ccc(Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCCN(C/C=C/c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.3 %

Procedure:
4-Perhydroazepinone hydrochloride (2.5 g, prepared according to Synth. Commun. 1992, 1249-1258) was suspended in acetonitrile (80 ml); diisopropylethylamine (4.4 ml) and 4-chlorocinnamyl chloride (2.7 g) were successively added at room temperature and the resulting reaction mixture was stirred at room temperature for 20 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography (eluent cyclohexane:ethyl acetate 6:4) to afford 1-(trans-3-(4-chlorophenyl)allyl)-perhydroazepin-4-one (1.84 g) as a foam. MS (ES+) 264/266 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH:13]3[CH2:14][CH2:15][CH:9]2[CH2:10][N:11](C(OC(C)(C)C)=O)[CH2:12]3)=[N:4][CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([N:8]2[CH:9]3[CH2:15][CH2:14][CH:13]2[CH2:12][NH:11][CH2:10]3)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC2CCC(C1)N2c1ncccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cccnc1N1C2CCC1CNC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 8-(3-chloro-2-pyridinyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (285 mg, 880 μmol) in dry dichloromethane (2 mL) was treated with trifluoroacetic acid (2 mL). After stirring at ambient temperature for 30 minutes, the mixture was concentrated under reduced pressure and the residue was treated with 1N sodium hydroxide solution. The mixture was extracted with ethyl acetate and the organic phase was concentrated under reduced pressure to provide the title compound. MS (DCI/NH3) m/z: 224 (M+H)+; 1H NMR (CDCl3) δ 1.87 (m, 2H), 1.97 (m, 2H), 2.75 (dd, 2H), 3.24 (dd, 2H), 4.44 (dd, 2H), 6.73 (dd, 1H), 7.54 (dd, 1H), 8.08 (dd, 1H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([OH:24])=O)[S:18][CH:19]=2)=[CH:11][CH:10]=1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]=[C:17]([NH:20][CH2:21][C:22]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:24])[S:18][CH:19]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)CNc1nc(-c2ccc(F)cc2)cs1
Reactant: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nc(-c2ccc(F)cc2)cs1)N1CCCCC1

Procedure:
The title compound was prepared analogously as described in Example 30(d) from 100 mg (0.27 mmol) of [4-(4-fluoro-phenyl)-thiazol-2-ylamino]-acetic acid trifluoroacetic acid salt and 46.5 mg (0.54 mmol) of piperidine. Yield: 58 mg.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].O=[C:14]([CH2:20][CH3:21])[CH2:15][C:16]([O:18][CH3:19])=[O:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:20]([C:14]1[O:4][C:3]([C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)=[CH:2][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:21]
Reactant: CCC(=O)CC(=O)OC
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1oc(-c2ccc(OC)cc2)cc1C(=O)OC
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
To a solution of 2-bromo-4′-methoxyacetophenone (13.7 g) and methyl 3-oxopentanoate (7.8 g) in toluene (100 mL) was added dropwise 1,8-azabicyclo[5.4.0]-7-undecene (9.1 mL) over 30 min or more under ice-cooling. After the completion of the dropwise addition, the mixture was stirred for 30 min under ice-cooling, and then at room temperature for 2 hr. The resulting precipitate was filtered, and washed with toluene. The obtained toluene solution was passed through silica gel, and the silica gel was washed with ethyl acetate-hexane (1:1). The collected solutions were concentrated under reduced pressure to remove ethyl acetate-hexane to give a toluene solution. To this toluene solution was added 4-toluenesulfonic acid monohydrate (2.3 g), and the mixture was stirred at 100° C. for 2 hr. The reaction mixture was washed with aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layers were collected, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 5% ethyl acetate/hexane) to give the title compound (9.2 g, 59%) as an oil.
Reaction SMILES: C(O[C:4]([CH2:6][NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([O:26]C(=O)C(C)(C)C)[CH:20]=[CH:19][C:18]=2[CH2:17]1)=[O:5])C.C(O[C:38]([N:40]1[CH2:45][CH2:44][CH:43]([C:46]2[CH:51]=[CH:50][C:49]([C:52](O)=O)=[CH:48][CH:47]=2)[CH2:42][CH2:41]1)=O)(C)(C)C>>[OH:5][CH2:4][CH2:6][N:7]([CH2:52][C:49]1[CH:48]=[CH:47][C:46]([CH:43]2[CH2:44][CH2:45][N:40]([CH3:38])[CH2:41][CH2:42]2)=[CH:51][CH:50]=1)[C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[C@H:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[C:21]([OH:26])[CH:20]=[CH:19][C:18]=2[CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Reactant: CCOC(=O)CNc1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@H]2CCc3cc(O)ccc3C2)c(N(CCO)Cc2ccc(C3CCN(C)CC3)cc2)c1
Yield: 102.8 %

Procedure:
Synthesized from pivalic acid (S)-6-[2-(ethoxycarbonylmethylamino)-4-methoxyphenyl]-5,6,7,8-tetrahydronaphthalen-2-yl ester (35 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (73 mg) according to an analogous synthesis method to the above-mentioned Preparation Example 86 and Example 337, the title compound (41 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@@H:15]([NH:22][C:23]([C:25]3[O:29][C:28]([O:30]C)=[N:27][CH:26]=3)=[O:24])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C@@H:15]([NH:22][C:23]([C:25]3[O:29][C:28](=[O:30])[NH:27][CH:26]=3)=[O:24])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cnc(OC)o1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-methoxyoxazole-5-carboxamido)butanoate, intermediate 14, (103 mg, 0.23 mmol) in dioxane (3 mL) is added 4 N solution of HCl in dioxane (0.29 mL, 1.16 mmol). The crude was stirred at room temperature for 2 hrs. The crude is concentrated and is diluted in water and EtOAc. The organic layer is washed with brine, dried over MgSO4, filtered, and concentrated. 50% of the crude is purified via RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN) to give (R)-ethyl 4-(3′-chlorobiphenyl-4-yl)-3-(2-oxo-2,3-dihydrooxazole-5-carboxamido)butanoate (38 mg) as a white solid. HPLC retention time=1.66 minutes (condition A); MS (m+1)=429.4; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.1 Hz, 3 H) 2.51-2.69 (m, 2 H) 2.95 (dd, 1 H) 3.05 (dd, 1 H) 4.19 (q, 2 H) 4.58-4.75 (m, 1 H) 6.83 (d, J=8.8 Hz, 1 H) 7.26-7.33 (m, 4 H) 7.35 (t, J=7.7 Hz, 1 H) 7.45 (dt, J=7.6, 1.5 Hz, 1 H) 7.51 (d, J=8.3 Hz, 2 H) 7.56 (t, J=1.8 Hz, 1 H) 8.45 (br. s., 1 H).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:20](=O)(O)[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:20])=[O:11])=[O:7])=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 3-(4-fluorobenzoyl)-propionic acid (1.98 g, 10.0 =ol) in methanol (25 mL) was added 0.5 mL of conc. sulfuric acid. The resulting solution was stirred at room temperature under argon for 2 hours. The reaction mixture was neutralized with saturated sodium bicarbonate, the methanol was removed via rotary evaporator and the residue was dissolved in 50 mL of ethyl acetate. The resulting solution was washed with saturated sodium bicarbonate (3×50 nL) and brine (50 -mL), dried over sodium sulfate and the solvent was removed in vacuo to give Methyl 3-(4-fluorobenzoyl)-propionate (2 g, 94%). IR (film) 3448, 3111, 3076, 3003, 3958, 1734, 1678, 1601, 1423, 1300, 1240, 1155, 1099 cm−1; 1H-NMR (CDCl3) δ 7.97 (2H, dd, J=9.0, 5.5 Hz), 7.10 (2H, t, J=8.9 Hz), 3.67 (3H, s), 3.25 (2H, t, J=6.6 Hz), 2.73 (2H, t, J=6.6 Hz); 13C-NMR (CDCl3) δ 196.50, 173.34, 167.54, 164.17, 132.98, 130.77, 115.91, 115.62, 51.91, 33.31, 28.00.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:15][C:16]1[CH:40]=[CH:39][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:25]([C:35]([F:38])([F:37])[F:36])[CH:24]=3)[S:22][C:18]=2[CH:17]=1>CN(C=O)C.CCOC(C)=O>[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH:10][CH2:15][C:16]1[CH:40]=[CH:39][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[C:25]([C:35]([F:36])([F:37])[F:38])[CH:24]=3)[S:22][C:18]=2[CH:17]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: FC(F)(F)c1cc(-c2nc3ccc(CBr)cc3s2)ccc1-c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCNCc1ccc2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
To a solution of β-alanine tert-butyl ester hydrochloride (47 mg, 1.1 eq.) in DMF (2 ml) is added NaH (60% in mineral oil) (28 mg, 3 eq.) at room temperature. The mixture is stirred at room temperature for 15 minutes before a solution of 6-bromomethyl-2-(2-trifluoromethyl-biphenyl-4-yl)benzothiazole (105 mg, 0.234 mmol) in DMF (1 ml) is added. The mixture is stirred at room temperature overnight, diluted with EtOAc, washed with 10% Na2S2O3, brine, dried over MgSO4, filtered and concentrated. Column chromatography (CH2Cl2/CH3OH, 95/5) gave 31 mg (26%) of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-benzothiazol-6-ylmethyl]-amino}-propionic acid tert-butyl ester.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:7]=[C:6]([NH:24][C@@H:25]([CH3:30])[C:26]([O:28]C)=[O:27])[CH:5]=1)(=[O:3])[NH2:2].O[Li].O>C1COCC1.O>[C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[N:7]=[C:6]([NH:24][C@@H:25]([CH3:30])[C:26]([OH:28])=[O:27])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)[C@H](C)Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](Nc1cc(C(N)=O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1)C(=O)O
Reaction time: 72 h
Yield: 40 %

Procedure:
To a solution of the (S)-methyl 2-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)propanoate (0.123 g, 0.300 mmol) in 5:1 THF/water (5 mL) was added LiOH.H2O (0.025 g, 0.60 mmol). After stirring 3 days, the reaction was quenched with 1N aqueous HCl (0.60 mL). The mixture was evaporated in vacuo then chromatographed using reverse-phase HPLC with a 40-100% acetonitrile in water (+0.1% TFA) gradient. The product fractions were pooled and concentrated to give a solid suspension. After cooling, the solid precipitate was filtered, rinsed with water and dried under vacuum at 50° C. to give (S)-2-((6-carbamoyl-2-(4-(4-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)propanoic acid as a white powder (0.049 g, 0.12 mmol, 41% yield). 1H NMR (400 MHz, DMSO-d6): 12.57 (1H, s), 8.50 (2H, d, J=8.8 Hz), 8.29 (1H, s), 8.12 (1H, d, J=6.1 Hz), 7.76 (1H, s), 7.31-7.24 (2H, m), 7.18-7.12 (2H, m), 7.07 (1H, s), 7.03 (2H, d, J=8.8 Hz), 4.56 (1H, m), 1.44 (3H, d, J=7.5 Hz). LC/MS: m/z=397.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:32]1[CH2:33][CH2:34][CH:30]([C:27]2[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)[CH2:31]1)=[O:15]
Reactant: COc1ccc(C2CCNC2)cc1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: O=C(O)C(=O)O
Product: COc1ccc(C2CCN(C(=O)c3cnoc3-c3ccccc3Cl)C2)cc1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(4-methoxyphenyl)pyrrolidine oxalat (16.0 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (5.4 mg). Calcd for C21H19ClN2O3: 382.1084, found 382.1083.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[C:8]([NH:17][S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)(=[O:20])=[O:19])[N:7]([CH3:27])[N:6]=1.[H-].[Na+].[Cl:30][C:31]1[CH:32]=[N:33][C:34](S(C)(=O)=O)=[N:35][CH:36]=1.O>O1CCCC1>[Cl:30][C:31]1[CH:32]=[N:33][C:34]([O:1][CH2:2][CH2:3][O:4][C:5]2[C:9]([C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[C:8]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)(=[O:19])=[O:20])[N:7]([CH3:27])[N:6]=2)=[N:35][CH:36]=1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccccn2)cc1
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2c(OCCOc3ncc(Cl)cn3)nn(C)c2NS(=O)(=O)c2ccccn2)cc1
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
To N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]-2-pyridine sulphonamide (Example 52) (200 mg) in dry tetrahydrofuran (2 ml) at room temperature was added sodium hydride (80% dispersion in oil, 35 mg) the mixture was stirred for 10 minutes. A solution of 5-chloro-2-methylsulphonylpyrimidine (134 mg) in dry tetrahydrofuran (2.5 ml) was then added and the mixture was stirred for a further 4 hours. The mixture was stirred for 4 hours. The reaction was treated with water (50 ml) and extracted with ethyl acetate (50 ml). The aqueous phase was neutralised to pH7 with 2N hydrochloric acid (aq.). The organic fraction was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with a solvent gradient of pentane:ethyl acetate (1:1 to 0:1) to yield the tile compound as a colourless foam (120 mg).