Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[N:7]([CH3:15])[C:6](=[O:16])[CH:5]=1.[N:17]1([C:23]2[C:28]3[CH:29]=[CH:30][S:31][C:27]=3[CH:26]=[CH:25][N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])O.[Na+]>C(#N)C>[ClH:1].[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:15])[C:6](=[O:16])[CH:5]=[C:4]2[CH2:3][CH2:2][N:20]1[CH2:21][CH2:22][N:17]([C:23]2[C:28]3[CH:29]=[CH:30][S:31][C:27]=3[CH:26]=[CH:25][N:24]=2)[CH2:18][CH2:19]1
Reactant: c1cc2sccc2c(N2CCNCC2)n1
Reactant: Cn1c(=O)cc(CCCl)c2cc(F)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: Cl
Product: Cn1c(=O)cc(CCN2CCN(c3nccc4sccc34)CC2)c2cc(F)ccc21
Temperature: 57.5 °C
Yield: 26.3 %

Procedure:
1.4 g (5.8 mmol) of 4-(2-chloroethyl)-6-fluoro-1-methyl-2(1H)-quinolone are added to a mixture of 1.3 g (5.9 mmol) of 4-(1-piperazinyl)thieno[3,2-c]pyridine and 0.50 g (5.95 mmol) of sodium hydrogen carbonate in 20 ml of acetonitrile, and the reaction medium is heated to 55-60° C. for 18 hours. The solvent is evaporated off and the residue is taken up in 100 ml of dichloromethane. It is washed with saturated aqueous sodium bicarbonate solution and then with water. The organic phase is dried over sodium sulphate and filtered and the filtrate is condensed. The crude product is purified by flash chromatography on silica, eluting with a methanol/dichloromethane (5:95) mixture containing traces of aqueous ammonia. 0.70 g of the expected product is obtained in base form.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:10])=[C:5]2[CH2:9][NH:8][CH2:7][C:6]=12.[CH:11]([N:14](CC)[CH:15]([CH3:17])C)([CH3:13])C.[ClH:20].C[N:22](C)C=O>C(O)(C)C>[ClH:1].[ClH:20].[Cl:1][C:2]1[S:3][C:4]([Cl:10])=[C:5]2[CH2:9][N:8]([CH2:13][C:11]3[NH:14][CH2:15][CH2:17][N:22]=3)[CH2:7][C:6]=12
Reactant: CN(C)C=O
Reactant: Clc1sc(Cl)c2c1CNC2
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: CC(C)O
Product: Clc1sc(Cl)c2c1CN(CC1=NCCN1)C2

Procedure:
A solution of 2.13 g (0.011 mol) of 1,3-dichloro-5,6-dihydro-4H-thieno[3,4-c]pyrrole and 2.5 ml of N,N-diisopropylethylamine in 25 ml of dimethylformamide is poured onto a mixture of 1.95 g (0.0125 mol) of 2-chloromethyl-1H-4,5-dihydroimidazole hydrochloride, 2.5 ml of N,N-diisopropylethylamine and 25 ml of dimethylformamide. The mixture is subjected to ultrasound for 8 h and is then evaporated under vacuum. The residue is dissolved in 75 ml of salt solution and extracted with 5 times 50 ml of methylene chloride. The organic solution is dried and then concentrated to produce a residue which is dissolved in 50 ml of isopropanol and treated with 14 ml of a 1N solution of hydrochloric acid in isopropanol. The crystals formed by cooling are filtered and washed with diethyl ether. 0.5 g of product is obtained. Melting point: 206°-213° C. (with decomposition).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[C:16](=[O:31])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])[C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N-:39]=[N+:40]=[N-:41].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]([C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=4)[C:16](=[O:31])[C:17]4[CH:22]=[N:21][N:20]([C:23]5[CH:30]=[CH:29][CH:28]=[C:25]([C:26]6[NH:41][N:40]=[N:39][N:27]=6)[CH:24]=5)[C:18]=4[N:19]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)nc5)cc4)nc32)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2ccc(-c3nc4c(cnn4-c4cccc(-c5nnn[nH]5)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)cn1
Temperature: 90 °C

Procedure:
To a solution of 3-[6-[4-(5-amino-pyridin-2-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-benzonitrile (prepared as described in example 28, 0.375 g, 0.726 mmol) in N,N-dimethylformamide (7 mL), sodium azide (0.236 g, 3.63 mmol), ammonium chloride (0.19 g, 3.63 mmol) are added. The reaction mixture is then heated at 90° C. for 14 h. The reaction mixture is concentrated to a dry residue. It is purified by column chromatography to afford 6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-1-[3-(1H-tetrazol-5-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one. 1H NMR (DMSO-d6, 400 MHz) δ 8.81 (s, 1H), 8.57 (s, 1H), 8.50 (br, 1H), 8.38 (m, 1H), 8.27 (m, 1H), 8.07 (d, 1H), 7.79 (m, 2H), 7.55 (m, 2H), 7.39-7.46 (m, 5H), 6.59 (d, 1H), 6.54 (br, 1H); LC-MS calculated for C29H19ClN10O (M+H+) 559.1, found 559.1.
Reaction SMILES: F[C:2]1[C:9]([F:10])=[C:8]([C:11]#[N:12])[C:7]([F:13])=[C:6]([F:14])[C:3]=1[C:4]#[N:5].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C>CC(C)=O.O>[C:4]([C:3]1[C:6]([F:14])=[C:7]([F:13])[C:8]([C:11]#[N:12])=[C:9]([F:10])[C:2]=1[N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]1)#[N:5]
Reactant: N#Cc1c(F)c(F)c(C#N)c(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2c(F)c(C#N)c(F)c(F)c2C#N)CC1
Temperature: 55 °C
Yield: 51.2 %

Procedure:
2,3,5,6-tetrafluoroterephthalonitrile (1 g, 5 mmol) was dissolved in acetone (15 mL) in a 2-necked flask under Nitrogen. A solution of tert-butyl piperazine-1-carboxylate (1.39 g, 7.5 mmol) in water (3 mL) was then added followed by triethylamine (1.01 g, 10 mmol). The solution was heated to 55° C. for 8 h then cooled to rt. The resulting solid was filtered then washed with acetone. The filtrate was concentrated under vacuum and the residue was dissolved again in DCM (30 mL) and washed once with 1M HCl (30 mL) and once with brine (30 mL). The organics were dried over Na2SO4, filtered and the solvent removed in vacuo to give tert-butyl 4-(2,5-dicyano-3,4,6-trifluorophenyl)piperazine-1-carboxylate as a bright yellow solid (0.938 g, 51% yield).
Reaction SMILES: C(OC([C:6]1[C:7]([N:18]([CH3:26])[CH2:19][CH2:20][C:21]([O:23]CC)=O)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=2)=O)C.[CH3:27][CH2:28][O-:29].[Na+].[C:31](O)(=[O:33])C.O>C(O)C>[CH2:28]([O:29][CH:20]1[C:19](=[C:31]=[O:33])[N:18]([CH3:26])[C:7]2[N:8]=[C:9]3[CH:10]=[C:11]([F:17])[C:12]([F:16])=[CH:13][C:14]3=[CH:15][C:6]=2[C:21]1=[O:23])[CH3:27]
Reactant: CC(=O)O
Reactant: CCOC(=O)CCN(C)c1nc2cc(F)c(F)cc2cc1C(=O)OCC
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC1C(=O)c2cc3cc(F)c(F)cc3nc2N(C)C1=C=O
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of 94 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(β-ethoxycarbonylethyl)amino]quinoline in 300 cm3 of absolute ethanol is added in the course of 80 minutes to a solution of 26.6 g of sodium ethylate brought to reflux in 900 cm3 of absolute ethanol. The suspension obtained, still refluxing, is stirred for a further 15 minutes. 38 cm3 of glacial acetic acid are then introduced in the course of 30 minutes. The reaction mixture is stirred for a further 15 minutes and, with the mixture still refluxing, 500 cm3 of water are then introduced in the course of 45 minutes. The suspension obtained is cooled to approximately 20° C. The precipitate is drained at approximately 20° C. and washed with twice 300 cm3 of water. The wet product is dried under reduced pressure (20 kPa) at approximately 60° C. 71.5 g of 3-ethoxy-carbonyl-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydrobenzo[b][1,8]naphthyridine are isolated in the form of a yellow solid, melting point 188° C.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=O.C([O-])(=O)C.[NH4+:19].C([N:22](CC)[CH2:23][CH3:24])C>>[NH:19]1[CH:24]=[CH:23][N:22]=[C:1]1[C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: CCN(CC)CC
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc[nH]1
Temperature: 140 °C
Reaction time: 2 h
Yield: 136.9 %

Procedure:
A mixture of 4 (11.09 g, 25.3 mmol), ammonium acetate (29.25 g, 38.0 mmol) and triethylamine (38.45 g, 38.0 mmol) in xylenes (600 mL) in a sealed tube was stirred at 140° C. for 2 h. After being cooled, the reaction mixture was transferred into a flask and concentrated to dryness. The residue was partitioned between chloroform and H2O, and the organic layer was washed with H2O and concentrated. The crude product was purified by silica gel column chromatography (NH4OH/acetonitrile/ethyl acetate: 1/8/100=(v/v/v)) to afford 5 (8.22 g, 75% yield) as a white solid. LC-MS (ESI): m/z 420.1 (M+H)+.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].Cl[C:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=[O:21].C(N(CC)CC)C.O1CCCC1>O>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:20]([C:22]2[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=2)=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)c1ccccc1N1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)c1ccc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cc1
Temperature: 25 °C
Yield: 96 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)piperazine dihydrochloride obtained in Reference Example 1 (0.5 g), methyl 4-(chlorocarbonyl)benzoate (397 mg), triethylamine (0.836 mL), and tetrahydrofuran (10 mL) was stirred at room temperature for over-night. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (NH-silica gel, 90:10-50:50 hexane/ethyl acetate) to provide the title compound (628 mg, 96%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[C:11]([S:12]CC2C=CC(OC)=CC=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:3]=1[F:30].C([C:33]1[C:39](=O)[C:38](Cl)=[C:37]([Cl:42])[C:35](=O)[C:34]=1C#N)#N.[OH2:45]>C(Cl)Cl>[S:12]([C:11]1[C:2]([NH2:1])=[C:3]([F:30])[C:4]([NH:22][C:35]2[CH:34]=[CH:33][CH:39]=[CH:38][C:37]=2[Cl:42])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:45])[S:12][C:11]1[C:2]([NH2:1])=[C:3]([F:30])[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N)c(F)c1Nc1ccccc1Cl
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O
Solvent: ClCCl
Product: COC(=O)c1cc(SSc2cc(C(=O)OC)c(Nc3ccccc3Cl)c(F)c2N)c(N)c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 32.3 %

Procedure:
To a solution of methyl 4-amino-5-(4-methoxybenzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate (19.93 g, 44.6 mmol) in CH2Cl2 (180 mL) was added DDQ (11.25 g, 53.73 mmol) followed by water (20 mL). After stirring at ambient temperature for 10 h, the reaction was quenched by saturated sodium bicarbonate (aq., 100 mL). The aqueous layer was extracted by CH2Cl2 (100 mL×3). The combined organic phase was washed with water (100 mL) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the desired product (pale yellow solid, 9.39 g, 32.3% yield). 1H NMR (400 MHz, CDCl3): δ 9.33 (s, 2H), 7.46 (s, 2H), 7.40 (m, 2H), 7.15 (m, 2H), 6.92 (m, 2H), 6.76 (m, 2H), 4.86 (br, 4H), 3.80 (s, 6H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.Cl.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:12][C:11]1([CH3:13])[C:8]([CH3:9])([CH3:10])[O:7][B:6]([C:4]2[CH:3]=[N:2][N:1]([CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:5]=2)[O:14]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: ClCCN1CCCCC1
Agent: Cl
Product: CC1(C)OB(c2cnn(CCN3CCCCC3)c2)OC1(C)C
Temperature: 90 °C

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 1-(2-chloroethyl)piperidine hydrochloride according to Method AC (heating to 90° C. for 6 days before addition of further 1-(2-chloroethyl)piperidine hydrochloride, and heating to 90° C. for a further 3 days) and was isolated as a brown gum (69%). LCMS (ES+) 305 (M+H)+, RT 1.91 minutes (Method 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[CH:30]=[C:29]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[N:28]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[N:27]=1)([CH3:25])[CH3:24]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:29]2[N:28]([C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)[N:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:30]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccc(-n2nc(C(C)C)cc2NC(=O)Oc2ccccc2)cc1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(C)C)cc2NC(=O)Nc2cccc(Oc3ncnc4cc(OC)c(OC)cc34)c2)cc1
Yield: 39.1 %

Procedure:
Using the procedure described in Example 306A, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), prepared as described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-ylcarbamate (105 mg, 0.3 mmol), described in the previous step, to afford 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)urea (65 mg, 39%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (d, J=7 Hz, 6H), 2.85 (m, 1H), 3.81 (s, 3H), 3.97 (s, 6H), 6.27 (s, 1H), 6.91 (d, J=7.5 Hz, 1H), 7.07 (d, J=9 Hz, 2H), 7.16 (d, J=9 Hz, 1H), 7.33-7.41 (m, 4H), 7.55 (s, 2H), 8.35 (s, 1H), 8.55 (s, 1H), 9.18 (s, 1H); LC-MS (ESI) m/z 555 (M+H)+.
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1.C(N(CC)CC)C.[CH3:28][S:29]C>O1CCCC1.O>[CH3:28][S:29][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=1
Reactant: Brc1cncc(C#Cc2ccccc2)c1
Reactant: CSC
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.3 %

Procedure:
Add a 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (0.96 mL, 1.94 mmol) to a solution of 3-bromo-5-phenylethynylpyridine, (prepared as described in EXAMPLE 9), (500 mg, 1.94 mmol) in anhydrous tetrahydrofuran (2 mL) and stir under nitrogen at room temperature for 2 h. Add triethylamine (0.27 mL, 1.94 mmol) and dimethyl sulfide (0.175 mL, 1.94 mmol). Stir for an additional 2 h, dilute with water, extract with dichloromethane, dry (magnesium sulfate), filter and concentrate. Purify the residue by silica gel chromatography, eluting from 100:0 to 100:50 with hexanes:ethyl acetate, to give the title compound (10.1 mg, 2.3%).
Reaction SMILES: C([Zn]CC)C.[CH:6]1([C:9]#[CH:10])[CH2:8][CH2:7]1.[Li]CCCC.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26].[H][H]>C1(C)C=CC=CC=1.C1COCC1.C1(C)C=CC=CC=1>[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[C@@:24]([OH:29])([C:10]#[C:9][CH:6]1[CH2:8][CH2:7]1)[C:25]([F:26])([F:27])[F:28]
Reactant: Cc1ccc(N)c(C(=O)C(F)(F)F)c1
Reactant: C#CC1CC1
Reactant: [H][H]
Agent: CC[Zn]CC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(N)c([C@@](O)(C#CC2CC2)C(F)(F)F)c1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of (1R,2S)-PNE (17.6%-w/w, 21.0 g, 18.0 mmol) in a THF/toluene mixture (9:1-w/w) was charged in a vessel at room temperature. A solution of diethylzinc in toluene (29.9%-w/w, 6.10 g, 14.8 mmol) was added at 17 to 25° C. and the mixture was aged at said temperature range for 30 min. A solution of cyclopropylacetylene (compound of formula III, wherein R2 is cyclopropyl) in toluene (69.6%-w/w, 8.55 g, 90.0 mmol) was added at 18° C. and the resulting mixture was aged at 20° C. for 60 min. A solution of BuLi in toluene (3.09 mol/kg, 17.6 g, 54.4 mmol) and a solution of 1-(2-amino-5-methylphenyl)-2,2,2-trifluoroethanone (CN46217, compound of formula IV, wherein R1 is trifluoromethyl, R8 is 5-methyl, R9 is hydrogen and R10 is hydrogen) (36.5%-w/w, 33.4 g, 60.0 mmol) in toluene/THF (1:1-w/w) were added in parallel to the reaction mixture at 20° C. within 3 h. The addition of BuLi was started 10 min in advance of the CN46217 addition. After completed addition of CN46217 the reaction mixture was stirred for 30 min at 20° C., then heated to 30° C. over a period of 60 min and aged for 6 h at 30° C. The reaction mixture was stirred at 0° C. overnight. HPLC (Method B) indicated 72.3% conversion and 96.7% enantiomeric purity. The reaction mixture was diluted with toluene (25.8 g) and quenched by addition of aqueous citric acid (1 M, 73.9 g). After stirring for 15 min the phases were separated and the aqueous phase was discarded. The organic phase was successively washed with water (9.1 g), aqueous NaHCO3 solution (5%-w/w, 24.0 g), and water (12.0 g). The organic phase was partially concentrated (60 g residual solution), diluted with toluene (30 g), and partially concentrated again (52 g residue). The residue was diluted with toluene (65 g), cooled to 5° C. and aged over night. The crystals were filtered, washed with cold (approx. 5° C.) toluene (10 g) and dried under vacuum at 40° C. The wet product (10.8 g) obtained as off-white solid with a purity of 99.2 and 100% ep according to method B. The crude product was purified by slurring it in a mixture of toluene (10 mL) and heptane (40 mL) at room temperature for 1 h, filtered and dried at 40° C. in vacuo. The product (compound of formula II, wherein R1 is trifluoromethyl, R2 is cyclopropyl, R8 is 5-methyl, R9 is hydrogen and R10 is hydrogen) was obtained as white solid (10.6 g, 38 mmol, 64% yield) with a purity of 99.4% and 100% ep according to method B. The assay was 97.0%-w/w according to 1H-NMR.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@@H:4]([NH:25][C:26](=[O:35])[C:27]1[CH:32]=[C:31]([Br:33])[CH:30]=[CH:29][C:28]=1[OH:34])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[Br:33][C:31]1[CH:30]=[CH:29][C:28]([OH:34])=[C:27]([CH:32]=1)[C:26]([NH:25][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[C:3]([OH:36])=[O:2])=[O:35]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)NC(=O)c1cc(Br)ccc1O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)C(=O)O)c1cc(Br)ccc1O
Yield: 104.4 %

Procedure:
To a solution of the preceding compound, (2S)-(5-Bromo-2-hydroxy-benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid methyl ester (10 mg, 18 μmol) in THF/MeOH was added aqueous LiOH, as described in General procedure C which, after work-up afforded the title compound, (2S)-(5-Bromo-2-hydroxy-benzoylamino)-3-(4′-phenoxy-biphenyl-4-yl)-propionic acid (10 mg ) LCMS for C28H22BrNO5: 531, 533.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](Cl)=[O:14])=[CH:10][CH:11]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:5]1)(=O)C.[CH3:23][O:24]C(C)CN.O.[N:30]1C=C[CH:33]=[CH:32][CH:31]=1>>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:13]([NH:30][CH2:31][CH2:32][CH2:33][O:24][CH3:23])=[O:14])[CH:8]=3)[NH:4][N:5]=2)=[CH:21][CH:20]=1
Reactant: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)Cl)ccc21
Reactant: c1ccncc1
Reactant: COC(C)CN
Solvent: O
Product: COCCCNC(=O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
The title compound was prepared as described in Example 68. To a solution of 1-acetyl-3-(4-fluorophenyl)-1H-indazole-5-carbonyl chloride (0.200 g, 0.632 mmol) in pyridine (4 mL) was added 2-methoxypropylamine (0.274 mL, 3.16 mmol). The solution was stirred for 3 h at room temperature. Water (40 mL) was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with aqueous 1 N hydrochloric acid, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative HPLC (10–90% acetonitrile/water). The pure fractions were basified with ammonium hydroxide, evaporated at reduced pressure, diluted with water and filtered to give the title compound (0.073 g, 35% yield): 1H NMR (DMSO-d6) δ 13.42 (br s, 1H), 8.60 (t, 1H), 8.53 (s, 1H), 8.07 (AB quartet, 2H), 7.92 (dd, 1H), 7.62 (d, 1H), 7.40 (t, 2H), 3.40 (t, 2H), 3.34 (m, 2H), 3.25 (s, 3H), 1.79 (m, 2H); ES-MS (m/z) 328 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][CH:11]=1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN1CCCC1=O.O>[Si:23]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:10]2[N:15]=[C:14]([C:16]#[N:17])[CH:13]=[CH:12][CH:11]=2)=[CH:3][CH:4]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: N#Cc1cccc(Cl)n1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1ccc(O)cc1
Agent: c1c[nH]cn1
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Nc2cccc(C#N)n2)cc1
Temperature: 145 °C
Reaction time: 16 h

Procedure:
4-Aminophenol (3.3 g, 30.2 mmol) is added to a solution of 6-chloropyridine-2-carbonitrile (3.5 g, 25.3 mmol) in 1-methyl-2-pyrrolidinone (70 mL). The reaction mixture is heated at 140-150° C. for 16 hours in a sealed flask. The batch is then cooled to ambient temperature. Imidazole (3.4 g, 49.9 mmol) and tert-butyl(dimethyl)silyl chloride (7.6 g, 50.4 mmol) are subsequently added and the mixture is stirred for 16 hours at ambient temperature. The mixture is diluted with water (140 mL) and the product is extracted with AcOEt (4×50 mL). The organic phases are combined and washed with water (3×50 mL), and then brine (1×50 mL). The organic phase is then dried over MgSO4, filtered and concentrated in vacuo. The crude product is purified by chromatography over silica gel using ethyl acetate and heptane as eluants to obtain the title product.
Reaction SMILES: [NH2:1][C:2]1[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([N:21]=[C:22]=[O:23])[CH:18]=[CH:19][CH:20]=1.O>CS(C)=O>[O:12]=[C:8]1[NH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:22]([NH:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:13])([F:24])[F:25])[CH:16]=2)=[O:23])[C:10](=[O:11])[NH:9]1
Reactant: Nc1c(C(=O)O)[nH]c(=O)[nH]c1=O
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Solvent: CS(C)=O
Solvent: O
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1c(C(=O)O)[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Amino-orotic acid (0.86 g) was dissolved in DMSO (10 ml), treated with 3-trifluoromethylphenylisocyanate (0.9 ml) and after an hour with another 0.5 ml. The reaction was stirred for three days at room temperature. Water was added and the mixture was filtered and washed with water. The residue was slurried in water, treated with NaOH and worked through until basic. Filtration and acidification of the filtrate provided a precipitate, which was filtered, washed with water and dried. Recrystallisation from 96% EtOH provided 2,6-dioxo-5-[3-(3-trifluoromethyl-phenyl)-ureido]-1,2,3,6-tetrahydro-pyrimidine-4-carboxylic acid (330 mg). Mp. >300° C.