Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[CH:10]=[N:9][N:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[C:6]=2[N:7]=1.[CH3:28][C:29]1([CH3:46])[CH2:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][C:31]([CH3:45])([CH3:44])[NH:30]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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>[CH:11]1([N:8]2[C:6]3[N:7]=[C:2]([C:33]4[CH2:32][C:31]([CH3:45])([CH3:44])[NH:30][C:29]([CH3:46])([CH3:28])[CH:34]=4)[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]4[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=4[CH3:25])=[O:16])[C:5]=3[CH:10]=[N:9]2)[CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)N1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C2CCC2)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(C3=CC(C)(C)NC(C)(C)C3)nc3c2cnn3C2CCC2)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 6-bromo-1-cyclobutyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), 2,2,6,6-tetramethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane was purged with argon for 10 min. Then, 2 M Na2CO3 (3.6 equiv.) solution was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (80% yield). LCMS: 489.30 (M+1)+; HPLC: 95.97% (@ 254 nm) (Rt;5.425); 1H NMR (DMSO-d6, 400 MHz) δ 11.55 (s, 1H), 8.89 (t, 1H), 8.31 (s, 1H), 7.79 (s, 1H), 6.81 (s, 1H), 5.89 (s, 1H), 5.52-5.44 (m, 1H), 4.37 (d, 2H, J=4.8 Hz), 2.73-2.63 (m, 2H), 2.43 (m, 4H), 2.22 (s, 3H), 2.12 (s, 3H), 1.94-1.88 (m, 2H), 1.24 (d, 6H, J=6 Hz), 1.15 (s, 6H).
Reaction SMILES: [C:1]([C:9]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:10]=1[O:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[C:1]([C:9]1[CH:26]=[C:25]([CH2:27][Br:28])[CH:24]=[CH:23][C:10]=1[O:11][CH:12]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(Oc1ccc(C)cc1C(=O)c1ccccc1)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1ccc(CBr)cc1C(=O)c1ccccc1)c1ccccc1
Yield: 35.6 %

Procedure:
To a solution of 0.314 g (0.87 mmol) of the product of Step A dissolved in 10 mL of CCl4 was added 0.155 g (0.87 mmol) of N-bromosuccinimide and 15 mg (catalytic amount) of AIBN. The mixture was stirred at reflux for 7 hours, then cooled filtered and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 15% ethyl acetate/hexane to afford 0.136 g (36%) of the title compound.
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl[CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1>>[CH2:7]([O:6][C:1](=[O:5])[C:2]([CH3:4])([CH3:3])[CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[CH3:8]
Reactant: CCOC(=O)C(C)C
Reactant: ClCc1cccs1
Product: CCOC(=O)C(C)(C)Cc1cccs1
Yield: 95 %

Procedure:
Ethyl isobutyrate (10.9 mL, 81.7 mmol) is alkylated with 2-(chloromethyl)thiophene according to general procedure F to give the product 44 as a yellow liquid (16.4 g, 95%). 1H NMR (CDCl3) 7.15-7.10 (m, 1), 6.95-6.90 (m, 1), 6.77 (d, 1, J=3.6), 4.15 (t, 2, J=7.0), 3.07 (s, 2), 1.26 (t, 3, J=7.0), 1.21 (s, 6); 13C NMR (CDCl3) 176.96, 139.80, 126.74, 126.42, 123.94, 60.59, 43.65, 40.30, 25.07, 14.22; MS (MW=212.3, CI/CH4, eE=70 eV) m/z 213 [(M+H)30 , base peak], 193, 179, 167, 140, 139, 125, 98, 97.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[C:11](=[O:22])[NH:10][C:8]=2[N:9]=1.Br[CH2:24][C:25]1[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:32]>CN(C)C=O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:13]=[C:12]([C:14]3[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=3[Cl:20])[C:11](=[O:22])[N:10]([CH2:24][C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])[C:8]=2[N:9]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)[nH]c2n1
Reactant: Clc1cccc(Cl)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(Cc3c(Cl)cccc3Cl)c2n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
To a suspension of NaH (60% in mineral oil, 36 mg) in 8 mL of dimethylformamide was added 2-amino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (208 mg, 0.68 mmol). The mixture was heated at 70° C. for 10 minutes and then at 50° C. for 30 minutes, resulting in a clear solution. α-Bromo-2,6-dichlorotoluene (215 mg, 0.90 mmol) was added, and the reaction mixture was heated at 50° C. for 25 minutes, then poured onto ice water. The resulting precipitate was removed by filtration and washed with water. The solid was purified by flash chromatography, eluting with 1:1 hexane:ethyl acetate then dried in vacuo to provide 112 mg (35%) of 2-amino-8-(2,6-dichlorobenzyl)-6-(2,6-dichlorophenyl)-8H-pyrido[2,3-d]pyrimidin-7-one; mp 274°-276° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10](O)[C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=3)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)[CH:17]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(O)nc(-c3ccc(F)cc3)cc2c1
Product: COc1ccc2c(Cl)nc(-c3ccc(F)cc3)cc2c1
Yield: 90.9 %

Procedure:
A solution of 3-(4-fluorophenyl)-6-methoxyisoquinolin-1-ol (350 mg, 1.300 mmol) in POCl3 (1.82 ml, 19.50 mmol) was refluxed (90° C.) for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in Hexanes as eluent. The product fractions were collected and the solvent removed under vacuum to give 1-chloro-3-(4-fluorophenyl)-6-methoxyisoquinoline (340 mg, 91% yield). MS: MS m/z 288.1 (M++1).
Reaction SMILES: C(C(C(C(O)=O)O)O)(O)=O.[CH3:11][C@@H:12]1[CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S(O[CH2:34][CH2:35][C:36]2[O:37][C:38]3[CH:44]=[CH:43][C:42]([Br:45])=[CH:41][C:39]=3[CH:40]=2)(=O)=O)=CC=1>C(#N)C.C1(C)C=CC=CC=1>[Br:45][C:42]1[CH:43]=[CH:44][C:38]2[O:37][C:36]([CH2:35][CH2:34][N:13]3[CH2:14][CH2:15][CH2:16][C@H:12]3[CH3:11])=[CH:40][C:39]=2[CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3cc(Br)ccc3o2)cc1
Reactant: C[C@@H]1CCCN1
Agent: O=C(O)C(O)C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2o1
Temperature: 60 °C
Yield: 60.8 %

Procedure:
(2R)-2-Methylpyrrolidine tartrate (0.70 g, 3.0 mmol) and potassium carbonate (0.82 g, 6.0 mmol) were combined in acetonitrile (12 mL). The slurry was heated at 60° C. for 1 hour, treated with the product from Example 4B (790 mg, 2.0 mmol). The mixture was heated at about 60° C. for 6 hours, cooled to 25° C., and diluted with toluene (30 mL). The mixture was washed with 5% NaHCO3 (40 mL×2) and extracted with H2O: N-methylpyrrolidinone: MSA (methanesulfonic acid)=70:20:10 (30 mL). The aqueous solution was adjusted to pH about 12 with 50% NaOH and extracted with IPAC (45 mL). The organic phase was washed with 5% NaHCO3 (50 mL×3), water (50 mL, 2×), dried over MgSO4, filtered, and the filtrate was concentrated to dryness to provide 375 mg (60%) of the title compound. MS (esi): 308, 310 (M+H)+; 1H-NMR (CDCl3) δ 7.58 (1H, d, J=1.7 Hz), 7.27 (2H, m), 6.38 (1H, s), 3.20 (2 H, m), 2.95 (2H, m), 2.43 (1H, m), 2.28 (1H, m), 2.19 (1H, q, J=8.8 Hz), 1.95 (1 H, m), 1.75 (2H, m), 1.42 (1H, m), 1.13 (3H, d, J=6.2 Hz); 13C-NMR (CDCl3) δ 158.8, 152.9,130.6, 125.7, 122.6, 115.2,111.9, 101.8, 60.0, 53.9, 51.9, 32.9, 28.4, 22.0, 19.3.
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][CH2:10][CH2:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:23]([O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Cl)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C.C1(C)C=CC=CC=1>[CH2:23]([O:30][C:31]1[CH:32]=[CH:33][C:34]([CH2:35][C:12]([CH2:11][CH2:10][CH2:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:37][CH:38]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C(CCCc1ccccc1)C(=O)OCC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(CCCc1ccccc1)(Cc1ccc(OCc2ccccc2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Sodium hydride (55% suspension in oil, 0.48 g) was added to a solution of diethyl 2-(3-phenylpropyl)malonate (2.78 g) in a mixture of N,N-dimethylacetamide (10 ml) and toluene (20 ml). The mixture was stirred at ambient temperature for 30 minutes. To the reaction mixture 4-benzyloxybenzyl chloride (2.45 g) was added and the mixture was stirred at ambient temperature for 30 minutes and then at 60° C. for 30 minutes. At the end of this time the reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate and concentrated. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=9/1 as the eluant to afford the desired compound (3.91 g) as a syrup.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:8]=23)=[C:4]([F:22])[CH:3]=1.Cl.Cl.N1C2C(=NC=CC=2OC2C=CC(N[C:42]([NH:44][C:45](=[O:55])[CH2:46][C:47]3[C:52]([Cl:53])=[CH:51][CH:50]=[CH:49][C:48]=3Cl)=[S:43])=CC=2F)C=C1.C1(CC(N=C=S)=O)C=CC=CC=1>>[ClH:53].[F:22][C:4]1[CH:3]=[C:2]([NH:1][C:42]([NH:44][C:45](=[O:55])[CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[S:43])[CH:21]=[CH:20][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:8]=12
Reactant: O=C(Cc1c(Cl)cccc1Cl)NC(=S)Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Reactant: COC(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: Cl
Agent: O=C(Cc1ccccc1)N=C=S
Product: COC(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Yield: 72 %

Procedure:
Starting from the amine 287, following the procedure described above for the synthesis of compound 269b (scheme 561, example 222) and replacing 2-(2,6-dichlorophenyl)acetyl isothiocyanate with 2-phenylacetyl isothiocyanate, title compound 288 was obtained in 72% yield as a yellowish solid. 1H NMR (d-DMSO) δ (ppm): 12.51(s, 1H), 11.84(s, 1H), 8.64(dd, 1H, J1=5.1 Hz, J2=0.4 Hz), 8.24(s, 1H, J=0.4 Hz), 8.02(dd, 1H, J1=1.8 Hz, J2=13.4 Hz), 7.56-7.54(m, 2H), 7.36-7.31(m, 1H), 7.28-7.25(m, 1H), 6.81 (d, 1H, J=5.5 Hz), 3.91 (s, 3H), 3.81 (s, 2H). MS (m/z):496.3 (M+H) (found).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([O:28]CC)=[O:27])=[C:19]3[N:18]=2)[C:6]1=[O:31].C1COCC1.CO.[Li+].[OH-].Cl>CO>[NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([C@H:12]2[CH2:16][CH2:15][CH2:14][N:13]2[C:17]2[CH:22]=[CH:21][N:20]3[N:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[C:19]3[N:18]=2)[C:6]1=[O:31]
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(CCCN)c3=O)nc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: NCCCn1cc(F)cc([C@H]2CCCN2c2ccn3ncc(C(=O)O)c3n2)c1=O
Temperature: 70 °C
Yield: 96.1 %

Procedure:
To a solution of (R)-ethyl 5-(2-(1-(3-aminopropyl)-5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.11 g, 0.26 mmol) in 3:1 THF/MeOH (8 mL) was added LiOH (1 N, 1.5 mL, 1.5 mmol), and the reaction mixture was heated at 70° C. for 20 hours. After cooling, the reaction mixture was treated with MeOH, acidified with 1N HCl (1.5 mL), and concentrated to afford the desired product (0.1 g, 100% yield). MS (apci) m/z=401.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:7]2[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1.[S:25]1[CH:29]=[C:28]([CH:30]=O)[C:27]2[CH:32]=[CH:33][CH:34]=[CH:35][C:26]1=2>>[S:25]1[C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([CH2:30][NH:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:7]3[C:6]4[C:11](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=[N:9][C:8]=3[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:19]=2)=[CH:29]1
Reactant: O=Cc1csc2ccccc12
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Product: Clc1cccc2c(-c3cccc(NCc4csc5ccccc45)c3)c(-c3ccccc3)nnc12

Procedure:
The title compound was prepared from 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine and benzo[b]thiophene-3-carbaldehyde according the procedure of Example 5 Step 5.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C@H:4]([NH2:12])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]([O:18][C:19](=[O:24])[NH:20][CH2:21][CH:22]=O)([CH3:17])([CH3:16])[CH3:15].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C@H:4]([NH:12][CH2:22][CH2:21][NH:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC=O
Reactant: COC(=O)[C@H](N)Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H](Cc1ccccc1)NCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
(2R)-2-Amino-3-phenylpropionic acid methyl ester (3.2 g; 15.0 mmol) and (2-oxoethyl)carbamic acid tert-butyl ester (3.2 g; 20.0 mmol) (prepared as in Dueholm et al, Org. Prep. Proced. Int. 25(4), 457-61 (1993)) were dissolved in a mixture of methanol (100 ml) and acetic acid (5 ml). Molecular sieves (3 Å; 100 g) were added and the reaction mixture was cooled to 0° C. Sodium cyanoborohydride (1.38 g; 22.0 mmol) was added portionwise and the reaction mixture was left without stirring for 12 h. The reaction mixture was filtered and water (100 ml), aqueous sodium hydrogencarbonate/sodium carbonate (10%; 100 ml; pH 9) and methylene chloride (50 ml) were added to the filtrate. The aqueous phase was extracted with methylene chloride (2×50 ml) and the combined organic phases were dried over magnesium sulfate. The organic phase was evaporated in vacuo and the residue was chromatographed on silica (4×40 cm) using ethyl acetate/heptane (3:2) as eluent to afford 2.07 g of (2R)-2-(2-(tert-butoxycarbonylamino)ethylamino)-3-phenylpropionic acid methyl ester.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:20])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[CH:5][CH:4]=1)[CH3:2].[Al](C(C)C)(C(C)C)C(C)C.CC(O)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]([OH:20])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C(=O)[C@H](C)NC(=O)OC(C)(C)C)cc1
Agent: CC(C)[Al](C(C)C)C(C)C
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCc1ccc([C@@H](O)[C@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 50 °C

Procedure:
The procedure described by J. Yin et al., J. Org. Chem. 2006, 71, 840-843) was used. A mixture of tert-butyl [(1S)-2-(4-ethylphenyl)-1-methyl-2-oxoethyl]carbamate (555 mg, 2 mmol), Al(iPr)3 (81 mg, 0.4 mmol), 2-propanol (1.32 g, 22 mmol), and toluene (2.6 ml, 1.3 ml/mmol) was heated in a sealed vial at 50° C. overnight. Then the reaction mixture was cooled to r.t., quenched with aqueous HCl (1 N, 10 ml), and diluted with ethyl acetate (10 ml). The layers were separated, the organic layer was washed with water (80 ml), dried with Na2SO4, and concentrated. Trituration with n-heptane (30 ml) afforded the subtitle compound as colourless precipitate, 137 mg. n-Heptane solution was concentrated under reduced pressure, and the residue purified by flash chromatography in silica gel to give the second crop of the subtitle compound, 318 mg. Overall yield 455 mg (81%).
Reaction SMILES: [CH2:1]([Cl:4])[CH2:2][OH:3].CCOCC.[CH2:10]([S:14](Cl)(=[O:16])=[O:15])[CH:11]([CH3:13])[CH3:12]>C(N(CC)CC)C>[CH2:10]([S:14]([O:3][CH2:2][CH2:1][Cl:4])(=[O:16])=[O:15])[CH:11]([CH3:13])[CH3:12]
Reactant: OCCCl
Reactant: CC(C)CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)CS(=O)(=O)OCCCl
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
A mixture was formed containing 6.7 ml. of ethylene chlorohydrin, 70 ml. of ether and 15.6 g. of isobutane sulfonyl chloride. Then, 14 ml. of triethylamine was added dropwise to the mixture with stirring in an ice bath over a period of 30 minutes at 12°-14° C. While stirring the mixture was allowed to warm to 23° C. (1 hour) and was then washed with water (100 ml.), dried over magnesium sulfate and evaporated to yield 19.7 g. of a colorless oil. nD30 1.4502.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.[CH2:31]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])[CH3:32].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:31]([O:33][C:34]([N:36]1[CH2:37][CH2:38][N:39]([C:12](=[O:14])[C@@H:11]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:40][CH2:41]1)=[O:35])[CH3:32]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)OC(C)(C)C)CC1
Reaction time: 12 h

Procedure:
To a solution of 900 mg (S)-4-benzyloxy-2-tert-butoxycarbonylamino-butyric acid in 10 ml DMF were added 1.5 ml N-ethylmorpholine, 0.43 ml 1-ethoxycarbonylpiperazine and 955 mg TOTU. The solution was stirred for 12 h before being diluted with ethyl acetate and extracted subsequently with aqueous LiCl (4%), 0.1 M HCl and saturated NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 1.23 g.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:17]1([CH2:23][CH:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.CCCCCC>[C:17]1([CH2:23][C:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=CCc1ccccc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 24 %

Procedure:
To a solution of 45.0 g of 1-bromo-4-(trifluoromethyl)benzene in 300 mL of THF cooled to -78° C. was added 77.0 mL of 2.5M n-butyl lithium in hexane dropwise. An exothermic reaction to -55° C. was observed. The reaction was then stirred for 20 minutes after which time phenyl acetaldehyde (23.5 mL, 0.2 mol) was added dropwise. The reaction was then stirred for an additional hour with gradual warming to room temperature. The mixture was then partitioned between ether and water, dried over anhydrous magnesium sulfate and concentrated to 52.6 g of a yellow oil. The crude oil was dissolved in 600 mL of methylene chloride and 100 g of pyridinium dichromate was added in several portions over 20 minutes and the mixture was then stirred at room temperature overnight. The reaction was then diluted with ether and filtered through magnesium sulfate and concentrated. The crude product was dissolved in hot n-butyl chloride, insoluble material was filtered off and the mixture was cooled to 0° C. Filtration and drying of the precipitate afforded 12.7 g of the title compound as a white solid, mp 127°-128° C.
Reaction SMILES: Cl.[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:12][NH:11][CH2:10]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[C:26]1([NH:32][C:33]([N:11]2[CH2:12][CH:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:3][CH:4]=3)[CH2:10]2)=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(-c2ccc(OC3CNC3)cc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)N1CC(Oc2ccc(-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 102.5 %

Procedure:
To a stirred suspension of 3-(1,1′-biphenyl-4-yloxy)azetidine hydrochloride (100 mg, 382 μmol) in dichloromethane (2.5 mL) was added triethylamine (63 μL, 48 mg, 478 μmol) followed by phenyl isocyanate (35 μL, 38 mg, 320 μmol) and the reaction stirred at room temperature for 2.5 hours. The mixture was loaded directly onto a 2 g pre-packed SCX-2 cartridge and the product eluted with 1:1 dichloromethane:methanol (15 mL). The solvents were evaporated to give the urea (113 mg, 100%) as a white powder; LCMS retention time 2.57 minutes, m/z 345.2 [M+H]+; 1H nmr (400 MHz; DMSO-d6) δ 8.54 (s, 1H), 7.62 (d, 4H, J=7.6 Hz), 7.50 (d, 2H, J=8.0 Hz), 7.44 (t, 2H, J=7.6 Hz), 7.32 (t, 1H, J=7.2 Hz), 7.23 (t, 2H, J=7.8 Hz), 7.98-7.91 (m, 3H), 5.09 (m, 1H), 4.46-4.42 (m, 2H) and 3.95-3.91 (m, 2H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].Br[CH2:20][C:21]([NH2:23])=[O:22].O>CN(C=O)C>[O:13]=[C:12]1[C:11]2[C:10](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:18])[N:8]1[O:7][CH2:20][C:21]([NH2:23])=[O:22]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.4 %

Procedure:
Potassium carbonate (2.67 g, 19.31 mmol) was added to a solution of N-hydroxyphthalimide (3.0 g, 18.39 mmol) in anhydrous DMF (37 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 min and then at room temperature for 1 h. The reaction mixture was cooled to 0° C. and 2-bromoacetamide (2.79 g, 20.23 mmol) was added. The reaction mixture was stirred at 0° C. for 10 min and then at room temperature overnight. The reaction mixture was poured into rapidly stirring water and the precipitated solid was collected by filtration and dried to afford 2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]acetamide (2.0 g, 49%) as a yellow solid: 1H NMR (300 MHz, CD3OD) δ4.63 (2H, s), 7.85-7.88 (4H, m); ESI MS m/z 221 [C10H8N2O4+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])=[C:6]2[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=12.[F:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([F:29])[CH:28]=1)[NH2:25]>>[F:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:3]=[CH:4][C:5]([C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])=[C:6]3[C:10]([CH3:11])=[CH:9][N:8]([CH3:12])[C:7]=23)[CH:26]=[C:27]([F:29])[CH:28]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: Cc1cn(C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Product: Cc1cn(C)c2c(Nc3cc(F)cc(F)c3)ncc(C(=O)N3CCOCC3)c12
Yield: 25.1 %

Procedure:
Prepared in a similar manner to Example 4(d) from 1-(7-chloro-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridine-4-yl)-1-morpholin-4-yl-methanone (100 mg) and using 3,5-difluoroaniline (88 mg) instead of 3-bromoaniline and heating for 15 rather than 30 minutes to give 1-[7-(3,5-difluoro-phenylamino)-1,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-4-yl]-1-morpholin-4-yl-methanone (33 mg).