Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:9]([N:12]2[C:16]([C:17]3C=CC=CC=3)=[N:15][N:14]=[N:13]2)[CH2:10][OH:11])=[CH:4][CH:3]=1.FC1C=CC(C(C2C=CC(F)=CC=2)=C(N2C(C)=NN=N2)CO)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[C:9]([N:12]2[C:16]([CH3:17])=[N:15][N:14]=[N:13]2)[CH:10]=[O:11])=[CH:6][CH:7]=1
Reactant: OCC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Agent: Cc1nnnn1C(CO)=C(c1ccc(F)cc1)c1ccc(F)cc1
Product: Cc1nnnn1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1

Procedure:
The general procedure of Example 6 was repeated, except that the 3,3-bis(4-fluorophenyl)-2-(5-phenyl-1H-tetrazol-1-yl)-2-propenol utilized therein was replaced by 4.45 g of 3,3-bis(4-fluorophenyl)-2-(5-methyl-1H-tetrazol-1-yl)-2-propenol [prepared in Example 15] and there was thereby produced 3.76 g of the title compound which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[O:9]=[C:10]1[NH:18][CH:17]=[N:16][C:15]2[N:14]([CH2:19][CH2:20][C:21](OCC)=[O:22])[CH:13]=[N:12][C:11]1=2>C(#N)C>[O:9]=[C:10]1[NH:18][CH:17]=[N:16][C:15]2[N:14]([CH2:19][CH2:20][C:21]([NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:22])[CH:13]=[N:12][C:11]1=2
Reactant: CCN(CC)CCN
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Product: CCN(CC)CCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
0.500 g (4.30 mmol) of N,N-diethylethylenediamine was placed into a 10 ml round bottom flask equipped with a magnetic stirring bar. The amine was heated to 110° C. and 0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to the stirring solution. The solution was heated for one hour at 110° C. and was allowed to cool to room temperature. 10 ml of acetonitrile was added and the solution was stirred for 15 minutes. The white precipitate was obtained by filtration and was washed with acetonitrile and then with ether. Upon drying, 195 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[2-(diethylamino)ethyl]propanamide (AIT-0064) as a white solid was obtained. Yield: 60%.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][N:4]1[CH3:17])=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[CH3:2].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:41]#[C:42][C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1>C1(C)C=CC=CC=1>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([C:42]#[C:41][N:9]2[C:10]3[C:15](=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[C:7]3[CH2:6][CH2:5][N:4]([CH3:17])[CH:3]([CH2:1][CH3:2])[C:8]2=3)=[CH:44][CH:45]=1
Reactant: CCC1c2[nH]c3ccc(C)cc3c2CCN1C
Reactant: Clc1ccc(C#CBr)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: CCC1c2c(c3cc(C)ccc3n2C#Cc2ccc(Cl)cc2)CCN1C
Temperature: 80 °C

Procedure:
1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (228 mg, 1 mmol) was mixed with CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg, 0.4 mmol), K3PO4 (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10 ml). The reaction mixture was flushed with nitrogen and heated at 80° C. for 16 h. The reaction mixture was filtered through Celite, and the Celite bed was rinsed with dichloromethane. Combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain 9-((4-chlorophenyl)ethynyl)-1-ethyl-2,6-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as brown semi solid (30 mg). 1H NMR (CDCl3) FREE BASE 7.50-7.40 (m, 3H), 7.37-7.33 (m, 2H), 7.28 (s, 1H), 7.20-7.15 (d, 1H), 5.25-5.20 (t, 1H), 3.06 (s, 3H), 3.02 (s, 3H), 2.98-2.88 (m, 2H), 2.80-2.60 (m, 2H), 1.20-1.18 (m, 2H), 1.10-1.07 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@@H:4](O)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:27](C(OC(C)(C)C)=O)=[N:28]C(OC(C)(C)C)=O.[ClH:43]>O1CCCC1.O>[ClH:43].[ClH:43].[NH:27]([C@H:4]1[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]1)[NH2:28]
Reactant: CN1CC[C@@H](O)C1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CN1CC[C@H](NN)C1
Reaction time: 1 h

Procedure:
To a mixture of (3R)-1-methylpyrrolidin-3-ol and 35 mL of tetrahydrofuran was added 18.2 g of triphenylphosphine, and a solution of 13.2 g of di-tert-butyl azodicarboxylate in 10 mL of a tetrahydrofuran was added dropwise thereto under ice-cooling, followed by stirring for 1 hour, and further stirring at room temperature for 1 hour. To the reaction mixture was added 40 mL of a 6 M hydrochloric acid, followed by stirring at room temperature overnight. To the reaction mixture was added 40 mL of water, tetrahydrofuran was evaporated under reduced pressure, and then 20 mL of dichloromethane was added thereto and the organic layer was separated. The obtained aqueous layer was washed with 20 mL of dichloromethane twice, and the aqueous layer was evaporated under reduced pressure, and then coevaporated with isopropanol. After forming a precipitate, the obtained solid was collected by filtration and dried under reduced pressure to obtain 7.92 g of (3S)-3-hydrazino-1-methylpyrrolidine dihydrochloride.
Reaction SMILES: Br[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:9][N:10]=2)[CH:7]=1.[CH3:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[K+].[K+].ClC1C=CC(C2C(C3C=CC(Cl)=CC=3Cl)=CN3C(CC4C=NC(C(F)(F)F)=CC=4)=NN=C3C=2)=CC=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:3]2[C:2]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH3:30])=[CH:7][N:6]3[C:8]([CH2:11][C:12]4[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=4)=[N:9][N:10]=[C:5]3[CH:4]=2)=[CH:28][CH:27]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cc1nnc2cc(-c3ccc(Cl)cc3)c(Br)cn12
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: FC(F)(F)c1ccc(Cc2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccc(Cl)cc4Cl)cn23)cn1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1-c1cn2c(Cc3ccc(C(F)(F)F)nc3C)nnc2cc1-c1ccc(Cl)cc1
Yield: 63.9 %

Procedure:
The title compound (6.3 mg, 65%) as a white powder was prepared from 6-bromo-7-(4-chlorophenyl)-3-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (9.5 mg, 0.020 mmol), 2-methylphenylboronic acid (5.4 mg, 0.039 mmol), K2CO3 (8.2 mg, 0.059 mmol) and Pd(PPh3)4 (2.8 mg, 0.002 mmol) in 1,4-dioxane (0.28 mL) and H2O (0.09 mL) by the procedures analogous to those described for 7-(4-chlorophenyl)-6-(2,4-dichlorophenyl)-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridine (Example 56E). LC/MS (method B): retention time=1.97 min, [M+H]+=543.3.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Br:12]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.S(=O)(=O)(O)O>[Br:12][C:8]1[C:9]([NH2:11])=[CH:10][C:5]2[O:4][CH2:3][CH2:2][O:1][C:6]=2[CH:7]=1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cc2c(cc1Br)OCCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 115.6 %

Procedure:
A solution of 2,3-dihydro-benzo[1,4]dioxin-6-ylamine (80 g, 530 mmol, 1 eq) in tetrahydrofuran (1000 mL) at −78° C. was treated with concentrated sulfuric acid (50 drops) then N-bromosuccinimide (94.2 g, 530 mmol, 1 eq) was added over 0.5 hour. After the addition the mixture was stirred at −78° C. for 1 hour then treated with solid sodium carbonate (12 g, 113 mmol, 0.21 eq). The mixture was evaporated and the residue partitioned between ether and water. The organic extract was dried, filtered and evaporated to give to oil that was chromatographed on silica gel eluting with dichloromethane to afford oil (141 g, 92%). LC/MS (ES) m/z 230 (MH+ 91%); 1H-NMR (400 MHz, d6-DMSO), 6.85 (1H, s, CHCNH2), 6.34 (1H, s, CHCBr), 4.79 (2H, s, NH2), 4.16 (4H, dd, J=16, 2×(CH2O))
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:14]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl-].[NH4+].C(N(C(C)C)CC)(C)C>O.CS(C)=O>[NH2:1][C:2]1[N:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:14])=[O:5]
Reactant: Nc1ccc(C(=O)O)c(N)n1
Reactant: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc(N)nc1N
Yield: 73.8 %

Procedure:
2,6-Diaminonicotinic acid (1.5 g), WSC (2.8 g), HOBt (2.0 g), ammonium chloride (1.6 g), diisopropylethylamine (7.6 g), and DMSO (45 mL) were stirred for 15 hours at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was concentrated and purified by silica gel chromatography (ethyl acetate, then ethyl acetate:methanol=4:1). The organic layer thus obtained was concentrated and purified by NH silica gel column chromatography (ethyl acetate). Ethyl acetate and hexane were added to the residue thus obtained, and the solids were filtered off to obtain the titled compound (1.1 g).
Reaction SMILES: C([O-])(=O)C.[K+].[Cl:6][C:7]1[CH:12]=[C:11](Cl)[N:10]=[C:9]2[N:14]([CH3:17])[N:15]=[CH:16][C:8]=12.[C:18]([C:20]1[C:21]([F:29])=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19]>CN(C=O)C.C(#N)C>[Cl:6][C:7]1[CH:12]=[C:11]([C:22]2[C:21]([F:29])=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:18]#[N:19])[N:10]=[C:9]2[N:14]([CH3:17])[N:15]=[CH:16][C:8]=12
Reactant: N#Cc1cccc(B(O)O)c1F
Reactant: Cn1ncc2c(Cl)cc(Cl)nc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cn1ncc2c(Cl)cc(-c3cccc(C#N)c3F)nc21
Temperature: 125 °C
Yield: 26.8 %

Procedure:
Potassium acetate (4 mL, 1M, 4 mmol) was added to a mixture of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine 5 (0.115 g, 0.569 mmol), 3-cyano-2-fluorophenylboronic acid 14 (0.075 g, 0.455 mmol) in DMF (2 mL) and acetonitrile (2 mL). Nitrogen was bubbled through the mixture followed by the addition of 10 mole % tetrakis(triphenylphosphine) palladium (0) and the reaction was heated at 125° C. in a microwave for 20 minutes. Solvent was removed, and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and brine (15 mL). The organic portions were pooled and dried over anhydrous sodium sulfate and the solvent was removed. The crude material was purified by reverse phase chromatography (Biotage) using ethyl acetate and hexanes as solvents to give 15 as white solid (0.035 g, 20%)
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([CH3:13])[CH:7]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.[N-:41]=[N+:42]=[N-:43].[Na+]>ClC(Cl)(Cl)Cl.C(O)(=O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([N:5]2[C:3]([C:2]([F:15])([F:14])[F:1])=[N:43][N:42]=[N:41]2)=[CH:7][C:8]=1[CH3:13]
Reactant: Cc1cc(NC(=O)C(F)(F)F)ccc1F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: Cc1cc(-n2nnnc2C(F)(F)F)ccc1F
Temperature: 100 °C
Reaction time: 17 h
Yield: 95.5 %

Procedure:
A mixture of 2,2,2-trifluoro-N-(4-fluoro-3-methylphenyl)acetamide (14.3 g) and triphenylphosphine (19.5 g) in tetrachloromethane (140 ml) was stirred for 17 hours at 100° C. An additional triphenylphosphine (5 g) was added to the mixture and the whole was stirred for 5 hours and finally triphenylphosphine (5 g) was added to the mixture, and the whole was stirred further for 15 hours at 100° C. After being cooled to room temperature hexane was added to the reaction mixture and the whole was stirred for 0.5 hour under ice-cooling. The resulting precipitate was removed by filtration and washed with hexane. The combined filtrate and washing were evaporated under reduced pressure below 20° C. A mixture of the syrup obtained and sodium azide (10.6 g) in acetic acid (100 ml) was stirred at room temperature for 7 hours, followed by at 70° C. for 17 hours. After being cooled to room temperature, the mixture was poured into ice-water, and extracted with dichloromethane. The organic layer was separated, dried over magnesium sulfate, and evaporated under reduced pressure. The syrup was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (100:1-5:1). The fractions containing the objective compound were collected to give 1-(4-fluoro-3-methylphenyl)-5-(trifluoromethyl)-1H-tetrazole (15.2 g) as a syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[N:14]=[CH:15]2)=[C:10]([C:24]#[CH:25])[N:9]=1>C(O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])[N:14]=[CH:15]2)=[C:10]([CH2:24][CH3:25])[N:9]=1
Reactant: C#Cc1nc(-c2ccccc2Cl)cc2cnc(NC(=O)C3CC3)cc12
Agent: O=[Pt]=O
Solvent: CCO
Product: CCc1nc(-c2ccccc2Cl)cc2cnc(NC(=O)C3CC3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.8 %

Procedure:
N-(7-(2-chlorophenyl)-5-ethynyl-2,6-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg, 0.1 mmol) was dissolved in ethanol (15 mL) and treated with platinum dioxide (3 mg, 0.01 mmol). The reaction flask was flushed with nitrogen and evacuated three times and then flushed with hydrogen gas, evacuated once, and then left under a balloon of hydrogen. The reaction mixture was stirred for 16 hours at room temperature and then filtered over a pad of Celite. The filtrate was evaporated in vacuo to afford a residue that was purified by reverse phase HPLC (5-85% acetonitrile in water with 0.1% ammonium hydroxide over 14 min) to afford the title compound as an off-white solid (20 mg, 50%). 1H NMR (400 MHz, DMSO) δ 11.16 (s, 1H), 9.31 (s, 1H), 8.78 (s, 1H), 8.08 (s, 1H), 7.77-7.69 (m, 1H), 7.61 (m, 1H), 7.54-7.42 (m, 2H), 3.24 (dd, J=15.2, 7.7 Hz, 2H), 2.15-2.07 (m, 1H), 1.38 (t, J=7.4 Hz, 3H), 0.95-0.80 (m, 4H). LCMS (Method E): RT=5.052 min, M+H+=352.1.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[NH:6]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16]O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>>[NH:6]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:16][Cl:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: OCc1ccc(F)c(Nc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(CCl)cc1Nc1ccccc1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
Two grams of phosphorus oxychloride was added to 470 mg of 3-anilino-4-fluorobenzyl alcohol with ice-cooling, and the mixture was stirred for 1 hour and then for further 12 hours at 15° C. Thereafter, the reaction solution was poured into a 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium chloride liquor and dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation to obtain 450 mg of 3-anilino-4-fluorobenzyl chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[C:19]([Cl:32])[CH:18]=2)=[C:6]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=O)[CH:7]=1.[NH2:33][CH2:34][CH:35]([OH:38])[CH2:36][OH:37]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH3:30])=[C:19]([Cl:32])[CH:18]=2)=[C:6]([NH:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([NH:33][CH2:34][CH:35]([OH:38])[CH2:36][OH:37])=[O:14])[CH:7]=1
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2NC(=O)CCC(=O)O)cc1Cl
Reactant: NCC(O)CO
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2NC(=O)CCC(=O)NCC(O)CO)cc1Cl

Procedure:
The reaction and work up was conducted as described in the preparation of compound 211. Starting compounds were N-(5-bromo-2-{[3-chloro-4-(2-methylbenzoyl)phenyl]amino}phenyl)-succinamic acid (600 mg, 1.16 mmol) (prepared as described in WO 01/05746) and 3-amino-1,2-propane-diol (117 mg, 1.28 mmol). The crude product was purified by flash chromatography using EtOAc followed by EtOAC/MeOH 95:5 as the eluent to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[C:2]([CH:24]([NH:23][S:21]([C:17]([CH3:19])([CH3:18])[CH3:20])=[O:22])[CH2:25][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:7]([O:8][CH3:9])[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)C(C)CC=NS(=O)C(C)(C)C
Reactant: COc1ccnc(OC)c1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1c(OC)ccnc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A cooled (−78° C.) solution of commercially available 3-bromo-2,4-dimethoxypyridine (1.390 g; 5.74 mmol) in anh. THF (70 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (3.60 ml; 5.74 mmol). The resulting solution was further stirred at −78° C. for 15 min. A solution of ethyl 4-((tert-butylsulfinyl)imino)-2-methylbutanoate (1.290 g; 5.22 mmol) in anh. THF (5 ml) was then added to the cooled reaction mixture, and stirring at −78° C. was continued for 30 min. The resulting reaction mixture was treated successively with aq. sat. NH4Cl (35 ml), Et2O (75 ml) and water (20 ml). The separated organic layer was then washed with brine (30 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded ethyl 4-(2,4-dimethoxypyridin-3-yl)-4-(1,1-dimethylethylsulfinamido)-2-methylbutanoate as a yellow oil. LC-MS (conditions B): tR=0.78 min. and [M+H]+: 386.68 g/mol; tR=0.80 min. and [M+H]+: 386.76 g/mol (mixture of diastereoisomers).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[C:14]1(=[O:18])[CH2:17][CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2([OH:18])[CH2:17][CH2:16][CH2:15]2)=[N:3][CH:4]=1
Reactant: O=C1CCC1
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: OC1(c2ccc(Br)cn2)CCC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 68.2 %

Procedure:
To a solution of 2,5-dibromopyridine (4.74 g, 20.0 mmol) in toluene (200 mL) was added n-BuLi (1.2 eq) dropwise at −50° C. The mixture was stirred at that temperature for 40 min, then cooled to −78° C. before cyclobutanone (1.82 g, 26.0 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 1 h, then warmed to 0° C. and quenched with 40 mL of NH4Cl (sat.). The organic layer was separated and concentrated. The crude product was purified by a SiO2 column (0-40% EtOAc/Hexanes, Rf=0.7 in 50% EtOAc) to afford the titled compound as a red oil (3.11 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:47])[CH2:42][C:43]([O:45]C)=[O:44])=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[CH2:9]/[C:10](=[N:19]\[O:20]C(=O)CC(OC)=O)/[C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[CH:12]=2)=[C:4]([CH3:48])[CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:35]=[CH:36][C:37]([NH:40][C:41](=[O:47])[CH2:42][C:43]([OH:45])=[O:44])=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)[CH2:9]/[C:10](=[N:19]\[OH:20])/[C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[CH:12]=2)=[C:4]([CH3:48])[CH:3]=1
Reactant: COC(=O)CC(=O)Nc1ccc(-c2ccc(C(C/C(=N\OC(=O)CC(=O)OC)c3ccc(=O)n(C)c3)c3ccc(F)cc3C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(NC(=O)CC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 2.25 h

Procedure:
To a solution of (E)-methyl 3-(4′-(1-(4-fluoro-2-methylphenyl)-3-(3-methoxy-3-oxopropanoyloxyimino)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)propyl)biphenyl-4-ylamino)-3-oxopropanoate (0.044 g, 67.1 μmol, from example 399) in dioxane (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (7.04 mg, 168 μmol). The resulting clear solution was stirred at room temperature for 2.25 hours, and then the solvents were removed. The residue was dissolved in water (2 mL) and the pH of the solution was adjusted to approximately to pH 3 using 1M aqueous hydrochloric acid. The resulting suspension was filtered, washed with water and the filter cake dried in high vacuum. Colourless solid (0.023 g, 63%). MS (ESI+): m/z=542.2 ([M+H]+).
Reaction SMILES: C[N:2](C)[CH2:3][C:4]([CH3:37])([CH3:36])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:35]=[CH:34][C:14]([CH2:15][C:16]2[CH:17]=[C:18]([C@H:23]3[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([S:32][CH3:33])[O:24]3)[CH:19]=[CH:20][C:21]=2[CH3:22])=[CH:13][CH:12]=1.NCC(C)(C)C(N)=[O:43]>>[CH3:36][C:4]([CH3:37])([CH2:5][NH:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]2[CH:17]=[C:18]([C@H:23]3[C@H:28]([OH:29])[C@@H:27]([OH:30])[C@H:26]([OH:31])[C@@H:25]([S:32][CH3:33])[O:24]3)[CH:19]=[CH:20][C:21]=2[CH3:22])=[CH:34][CH:35]=1)[C:3]([NH2:2])=[O:43]
Reactant: CC(C)(CN)C(N)=O
Reactant: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCCNCC(C)(C)CN(C)C)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Product: CS[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(OCCCNCC(C)(C)C(N)=O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The same procedure was employed as for amine 50, using 3-amino-2,2-dimethylpropanamide, to provide the product 51. The material was purified by prep HPLC (C18 30×100 mm column, 5-60% CH3CN/10 mM aqueous ammonium formate, 45 mL/min) and lyophilized to give the formate salt the product as a white solid. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.11-7.21 (m, 3 H), 7.06 (d, J=8.1 Hz, 2 H), 6.88 (m, J=8.3 Hz, 2 H), 4.39 (d, J=9.3 Hz, 1H), 4.05-4.16 (m, 3 H), 3.94 (s, 2 H), 3.35-3.53 (m, 3 H), 3.23 (t, J=6.9 Hz, 2 H), 3.07 (s, 2 H), 2.20 (s, 3 H), 2.16-2.24 (m, 2 H), 2.14 (s, 3 H), 1.33 (s, 6 H); MS (ES+) [M+H]+=533.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].I[CH2:18][CH3:19].O>CN(C=O)C.C(OCC)C.C(OCC)(=O)C>[CH2:18]([N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]1=[O:1])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCN(C(=O)OC(C)(C)C)CC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a slurry of tert-butyl 3-oxopiperazine-1-carboxylate (10 g, 49.9 mmol) in 250 mL of DMF, NaH (60% in mineral oil) (2.1 g, 52.4 mmol) was added in portions. The mixture was stirred for 15 min after completion of addition, cooled to 0° C. and iodoethane (5.62 mL, 69.92 mmol) slowly added over ˜3 min. The resultant suspension was stirred at rt for 2 h. Water was slowly added (400 mL) and then 250 mL of 1:1 ethyl acetate:diethyl ether. The layers were separated and then the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to afford tert-butyl 4-ethyl-3-oxopiperazine-1-carboxylate as a colorless oil weighing 6.4 g which was used directly in the next step.