Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20]([NH:23][CH:24]([CH2:27]O)[CH2:25][CH3:26])=[N:19][C:18](=[O:29])[N:17]([CH2:30][CH2:31][CH3:32])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2>O=S(Cl)Cl>[CH2:25]([CH:24]1[N:23]=[C:20]2[N:19]([C:18](=[O:29])[N:17]([CH2:30][CH2:31][CH3:32])[C:16]3[N:15]=[C:14]([C:9]45[CH2:12][CH2:13][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:33])([CH2:7][CH2:8]4)[CH2:11][CH2:10]5)[NH:22][C:21]=32)[CH2:27]1)[CH3:26]
Reactant: CCCn1c(=O)nc(NC(CC)CO)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Solvent: O=S(Cl)Cl
Product: CCCN1C(=O)N2CC(CC)N=C2c2[nH]c(C34CCC(CCC(=O)O)(CC3)CC4)nc21
Temperature: 25 °C

Procedure:
3-{4-[6-(1-Hydroxymethyl-propylamino)-2-oxo-3-propyl-3,7-dihydro-2H-purin-8-yl]-bicyclo[2.2.2]oct-1-yl}-propionic acid methyl ester (30 mg) was dissolved in 1 mL of SOCl2 and stirred under reflux for 15 min. The reaction mixture was then cooled to rt and concentrated under reduced pressure. The resulting residue was dissolved in a solution containing 1 mL of water, 0.5 mL of MeOH, and 0.1 mL of 10% aq. NaOH. The reaction mixture was stirred at rt for 30 min. It was then acidified to pH 2 with dilute 1 N HCl and concentrated. The resulting crude product was purified by preparative HPLC to afford the titled compound.
Reaction SMILES: [CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[N:31][CH:32]=1>>[CH2:1]([C@@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:29]3[CH:30]=[N:31][CH:32]=[C:27]([F:26])[CH:28]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Reactant: OB(O)c1cncc(F)c1
Product: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3cncc(F)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one and 5-fluoropyridine-3-boronic acid using a procedure analogous to that described in Example 64. LC-MS Method 1 tR=1.84 min, m/z=417 (M+1); 1H NMR (CDCl3) 8.58 (s, 1H), 8.45 (d, 1H, J=3 Hz), 7.57-7.54 (m, 1H), 7.39-7.30 (m, 5H), 7.27-7.25 (m, 2H), 6.93 (d, 2H, J=8 Hz), 5.80-5.68 (m, 2H), 5.11-5.03 (m, 2H), 2.97-2.91 (m, 1H), 2.69-2.55 (m, 2H), 2.41-2.21 (m, 3H), 1.55 (d, 3H, J=7 Hz).
Reaction SMILES: CN(C)C=O.[C:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.I[CH2:21][CH2:22][CH2:23][CH2:24]I.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:13][CH:6]([C:14]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: ICCCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(O)c2ccccc2)CCCC1
Temperature: 60 °C
Reaction time: 15.5 h
Yield: 76.4 %

Procedure:
To N,N-dimethylformamide (400 ml) were added ethyl benzoylacetate (25.1 g, 0.13 mol), 1,4-diiodobutane (40.47 g) (0.13 g) and anhydrous sodium carbonate (82.7 g, 0.78 mol) and the mixture was stirred at 60° C. for 15.5 h. The reaction mixture was poured into 1 L of water and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dehydrated over anhydrous sodium sulfate and concentrated. A red residual solution (33.5 g) was purified by silica gel column chromatography (ethyl acetate/hexane=1/4) to give the title compound (24.67 g) as a colorless oil (yield 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:35]1[CH2:36][CH2:37][CH:32]([CH2:31][NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[NH:10]2)=[O:28])[CH2:33][CH2:34]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCC2CCOCC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 4-aminomethyl tetrahydropyran (34.5 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (10.8 mg, 10.2%) as an off-white powder. HRMS (ES+) m/z Calcd for C29H35Cl2N3O2S+H [(M+H)+]: 528.2179. found: 528.2180.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:22][C:21]([C:23](=[O:25])[CH3:24])=[CH:20][CH:19]=3)=[CH:7][CH:8]=2)[N:3]=1.[F:26][C:27]1[CH:37]=[C:36]([NH:38][C:39]([NH:41][C:42]2[CH:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][CH:43]=2)=[O:40])[CH:35]=[CH:34][C:28]=1[C:29]([N:31]([CH3:33])[CH3:32])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.CCO>[C:23]([C:21]1[O:22][C:18]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:45]4[CH:46]=[CH:47][C:42]([NH:41][C:39](=[O:40])[NH:38][C:36]5[CH:35]=[CH:34][C:28]([C:29]([N:31]([CH3:33])[CH3:32])=[O:30])=[C:27]([F:26])[CH:37]=5)=[CH:43][CH:44]=4)=[N:3]3)=[CH:8][CH:7]=2)=[CH:19][CH:20]=1)(=[O:25])[CH3:24]
Reactant: CN(C)C(=O)c1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1F
Reactant: CC(=O)c1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(=O)c1ccc(-c2ccc3c(N4CCOCC4)nc(-c4ccc(NC(=O)Nc5ccc(C(=O)N(C)C)c(F)c5)cc4)nc3c2)o1
Temperature: 75 °C
Reaction time: 3 h
Yield: 5.7 %

Procedure:
To a 50 mL round bottom flask, 1-(5-(2-chloro-4-morpholino-quinazolin-7-yl)furan-2-yl)ethanone (0.1 g, 0.00028 mol), 2-fluoro-N,N-dimethyl-4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)-benzamide (0.144 g, 0.00034 mol), cesium carbonate (0.228 g, 0.0007 mol), toluene (7 mL) and EtOH (7 mL), and water (3 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd(PPh3)2Cl2 (0.0098 g, 0.000014 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 75° C. for 3 h. The reaction mixture was cooled, diluted with chloroform, washed with water, brine and dried over anhydrous sodium sulfate. The organic layer was evaporated under reduced pressure to afford the crude product. The crude product was purified by column chromatography using 60-120 silica gel and 4% MeOH in chloroform. The compound was further purified by prep HPLC using 10 mM ammonium acetate in water and ACN to obtain the title compound [0.01 g, 6%]. 1H NMR (400 MHz, DMSO-d6): δ 9.04 (s, 1H), 8.96 (s, 1H), 8.46 (d, J=8.4 Hz, 2H), 8.28 (s, 1H), 8.13 (d, 1H, J=8.8 Hz), 7.92 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 3H), 7.55-7.52 (m, 3H), 7.38 (d, J=8.0 Hz, 2H), 3.85 (s, 8H), 2.97 (s, 6H), 2.56 (s, 3H). LC-MS (ESI): Calculated mass: 622.2; Observed mass: 623.2 (RT: 0.45 min).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH3:39])[CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[CH:15]=[C:16]([NH2:29])[C:17]([N:22]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH3:23])=[CH:18][C:19]=2[O:20][CH3:21])=[N:11][CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:6][C:7]1[C:8]([C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([CH3:39])[CH:31]=2)=[N:9][C:10]([NH:13][C:14]2[C:19]([O:20][CH3:21])=[CH:18][C:17]([N:22]([CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[CH3:23])=[C:16]([NH:29][C:1](=[O:4])[CH:2]=[CH2:3])[CH:15]=2)=[N:11][CH:12]=1
Reactant: C=CC(=O)Cl
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2ncc(Cl)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Yield: 77 %

Procedure:
A solution of acryloyl chloride (0.026 mL, 0.32 mmol) in CH2Cl2 (1 mL) was added to a mixture of N4-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-N1-(2-dimethylamino-ethyl)-5-methoxy-N1-methylbenzene-1,2,4-triamine (Intermediate 97, 130 mg, 0.27 mmol) and DIPEA (0.090 mL, 0.54 mmol) in CH2Cl2 (2 mL) at 0° C. The mixture was stirred at 0° C. for 2.5 h (during this time a further 0.2 eq acryloyl chloride was added). The mixture was then diluted with CH2Cl2, washed twice with sat. NaHCO3 and then with water, dried (MgSO4), and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (111 mg, 77%) as a yellow solid; 1H NMR: (CDCl3) 2.26 (6H, s), 2.23-2.33 (2H, m), 2.70 (3H, s), 2.86-2.89 (2H, m), 3.88 (3H, s), 3.91 (3H, s), 5.67 (1H, d), 6.25-6.44 (2H, m), 6.79 (1H, s), 7.20-7.37 (3H, m), 7.57 (1H, s), 8.36-8.45 (3H, m), 9.54 (1H, s), 10.11 (1H, s); m/z: ES+ MH+ 534, 536.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:19]#[N:20])[CH:13]=[C:14]([C:15]([F:18])([F:17])[F:16])[C:9]=2[NH:8][C:7]1=[O:21])[CH3:2].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([C:19]#[N:20])[CH:13]=[C:14]([C:15]([F:16])([F:17])[F:18])[C:9]=2[N:8]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[C:25]([F:24])([F:34])[F:35])[C:7]1=[O:21])[CH3:23]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCN(CC)CCn1c(=O)[nH]c2c(C(F)(F)F)cc(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCn1c(=O)n(Cc2ccccc2C(F)(F)F)c2c(C(F)(F)F)cc(C#N)cc21
Temperature: 80 °C
Yield: 9.9 %

Procedure:
A mixture of 3-[2-(diethylamino)ethyl]-2-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-benzimidazole-5-carbonitrile (19.1 mg), 2-trifluoromethylbenzyl bromide (30.4 mg) and potassium carbonate (16.5 mg) in N,N-dimethylformamide (3 ml) was stirred with heating at 80° C. for 1.5 hours. To the mixture was further added 2-trifluoromethylbenzyl bromide (46.8 mg), and the mixture was stirred with heating at 80° C. for 1 hour. 2-Trifluoromethylbenzyl bromide (160.3 mg) and potassium carbonate (43.2 mg) were further added, and the mixture was stirred with heating 80° C. for 1 hour. The reaction mixture was concentrated in vacuo. The resultant residue was purified by preparative TLC (1 mm, 20×20 cm, chloroform:methanol=25:1) to give the title compound (2.8 mg, 10%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1.[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)#[N:23]>>[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH:3]=1)#[N:23]
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Reactant: N#Cc1ccccc1B(O)O
Product: N#Cc1ccccc1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Example 272 from methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate and 2-cyanophenylboronic acid. colorless crystals (yield 6%). MS (APCI−): 356 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]1([C:17](Cl)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.C(N(CC)CC)C>>[C:11]1([C:17]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C1=CCCCC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)O)cc1)C1=CCCCC1

Procedure:
88.0%. B. 4-(1-cyclohexene-1-carbonylamino)-benzoic acid was prepared as described in Example 1 from 16.6 g (0.121 mol) of p-aminobenzoic acid with 22.0 g (0.152 mol) of 1-cyclohexene-1-carboxylic acid chloride and 21.3 ml (0.152 mol) of triethylamine. Recrystallization from THF/n-pentane.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)[CH2:13][CH2:14]O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:46].O>C(#N)C>[Br:46][CH2:14][CH2:13][CH:12]([C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:5])[N:3]([CH2:24][CH3:25])[CH2:1][CH3:2])=[CH:7][CH:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: CCN(CC)C(=O)c1ccc(C(CCO)c2cccc(OC)c2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc(C(CCBr)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
3-(4-Diethylcarbamoylphenyl)-1-hydroxy-3-(3-methoxyphenyl)propane (215 mg) was dissolved in acetonitrile (4 ml), added with triphenylphosphine (304 mg) and carbon tetrabromide (385 mg) under ice cooling and stirred at room temperature for 30 minutes. The reaction mixture was added with water (5 ml) and extracted twice with dichloromethane (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane: ethyl acetate=2:1) to obtain 189 mg of the title compound. Yield: 74%.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[C:4]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]4[O:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=4[CH:33]=3)[CH2:18][CH2:17]2)[CH:3]=1.[Cu][C:35]#[N:36]>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:35]#[N:36])=[CH:3][C:4]=2[O:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]4[O:31][CH2:30][C:29](=[O:32])[NH:28][C:27]=4[CH:33]=3)[CH2:20][CH2:21]2)[N:9]=1
Reactant: N#C[Cu]
Reactant: Cc1ccc2c(OCCN3CCC(Cc4ccc5c(c4)NC(=O)CO5)CC3)cc(I)cc2n1
Product: Cc1ccc2c(OCCN3CCC(Cc4ccc5c(c4)NC(=O)CO5)CC3)cc(C#N)cc2n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 23.5 %

Procedure:
A mixture of 6-{1-[2-(7-Iodo-2-methyl-quinolin-5-yloxy)-ethyl]-piperidin-4-ylmethyl}-4H-benzo[1,4]oxazin-3-one (155 mg, 0.28 mmol) and copper (I) cyanide (50 mg, 0.56 mmol) in N-methylpyrrolidinione (2 mL) was stirred at 90° C. for 18 hrs. Upon cooling to room temperature the reaction mixture was partitioned between dichloromethane (5 mL) and ammonia (0.880, 5 mL). The organic layer was separated and applied directly to a 10 g pre-packed silica column eluting with 0-20% methanol in ethyl acetate to afford the title compound as a yellow oil (30 mg, 23%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[Br:10]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:10][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([O:8][CH3:9])=[N:5][CH:6]=1
Reactant: COc1cc(Cl)ccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Cl)c(Br)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.6 %

Procedure:
5.76 g (40.1 mmol) of 4-chloro-2-methoxypyridine was dissolved in 20 ml of dimethylformamide, and a dimethylformamide (20 ml) solution of 8.01 g of N-bromosuccinimide (98%, 44.1 mmol) was dropwise added over a period of 30 minutes. After stirring at room temperature for 2 days, an unreacted material was confirmed, and thus 2.85 g of N-bromosuccinimide (98%, 16 mmol) was further added, followed by stirring at room temperature further for 3 days. The reaction mixture was poured into 250 ml of water, followed by extraction with ethyl ether (100 ml each) three times. The organic layer was washed with water (100 ml), a sodium thiosulfate aqueous solution (100 ml) and then a saturated sodium chloride solution (100 ml), dried over magnesium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography to obtain 7.10 g (yield: 80%) of 5-bromo-4-chloro-2-methoxypyridine.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([N:11]=[C:12]=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2].Cl.[F:28][CH2:29][CH2:30][CH2:31][NH2:32].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:4][C@H:5]1[C@H:10]([NH:11][C:12]([NH:32][CH2:31][CH2:30][CH2:29][F:28])=[S:13])[C@@H:9]([O:14][C:15](=[O:17])[CH3:16])[C@H:8]([O:18][C:19](=[O:21])[CH3:20])[C@@H:7]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:6]1)(=[O:3])[CH3:2]
Reactant: NCCCF
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=C=S)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=S)NCCCF)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-isothiocyanatotetrahydro-2H-pyran-2,4,5-triyl triacetate (0.850 g, 2.19 mmol) and 3-fluoropropylamine hydrochloride (0.251 g, 2.21 mmol) in DCM (10 mL), was added DIPEA (0.415 g, 4.00 mmol). The reaction mixture was stirred at room temperature for 30 min, and then concentrated under reduced pressure. The residue was purified on silica gel by flash column chromatography (EtOAc/hexanes, 2:1 in), affording (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(3-(3-fluoropropyl)thioureido)tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white solid (0.91 g, 88%).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[CH2:3][CH2:4][N:5]([CH3:32])[C:6]1[C:7]([NH2:31])=[CH:8][C:9]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH3:30])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)=[C:10]([O:12][CH3:13])[CH:11]=1.Cl[CH2:35][CH2:36][C:37](Cl)=[O:38].[OH-].[Na+].CO>C1COCC1.O>[CH3:33][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:32])[C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH3:30])[CH:22]=3)[CH:18]=[CH:17][N:16]=2)=[CH:8][C:7]=1[NH:31][C:37](=[O:38])[CH:36]=[CH2:35]
Reactant: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Reactant: O=C(Cl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cn(C)c4ccccc34)n2)c(OC)cc1N(C)CCN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
To a stirred solution of N1-(2-dimethylaminoethyl)-5-methoxy-N1-methyl-N4-[4-(1-methylindol-3-yl)pyrimidin-2-yl]benzene-1,2,4-triamine (Intermediate 100, 10 g, 21.32 mmol) in THF (95 mL) and water (9.5 mL) at 0° C. was added the 3-chloropropanoyl chloride (3.28 g, 25.59 mmol). The mixture was stirred at r.t. for 15 minutes then NaOH (3.48 g, 85.28 mmol) was added. The resulting mixture was heated to 65° C. for 10 h. The mixture was then cooled to r.t. and CH3OH (40 mL) and water (70 mL) were added. The resulting mixture was stirred overnight. The resulting solid was collected by filtration, washed with water (25 mL) and dried at 50° C. for 12 h to give the title compound (7.0 g, 94%) as a solid form identified herein as polymorphic Form D. 1H NMR: 2.69 (3H, s) 2.83 (6H, d) 3.35 (4H, s) 3.84 (3H, s) 3.91 (3H, s) 5.75 (1H, d) 6.28 (1H, d) 6.67 (1H, dd) 7.05-7.23 (2H, m) 7.29 (1H, t) 7.43 (1H, d) 7.56 (1H, d) 8.21 (2H, s) 8.81 (1H, s) 9.47 (1H, s) 9.52 (1H, s) ES+ MH+ 500.26.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:22])[NH:17][CH:18]1[CH2:21][CH2:20][CH2:19]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[CH:18]1([NH:17][C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[O:22])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C(NC1CCC1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(NC1CCC1)[C@@H]1CCCN1
Reaction time: 12 h

Procedure:
To a solution of 9.00 g (S)-2-Cyclobutylcarbamoyl-pyrrolidine-1-carboxylic acid benzyl ester in 120 ml ethanol were added 1.0 g Pd/C (10%) and the suspension stirred under an atmosphere of hydrogen (3 bar) for 12 h. The reaction mixture was filtrated over a plug of Celite, washed with ethanol and concentrated to give the crude product which was used in the subsequent reaction. Yield: 3.3 g.
Reaction SMILES: [OH:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:3]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:10][N:11]=1)=[O:4].Cl.Br[CH2:33][C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH:2]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:3]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:33][C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)=[CH:14][CH:13]=2)=[N:10][N:11]=1)=[O:4]
Reactant: BrCc1ccncc1
Reactant: O=C(NCc1nnc(-c2ccc(O)cc2)s1)C(O)CCCCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NCc1nnc(-c2ccc(OCc3ccncc3)cc2)s1)C(O)CCCCCCc1ccccc1

Procedure:
A solution of 4-(5-(aminomethyl)-1,3,4-thiadiazol-2-yl)phenol (1.74 mmol), 2-hydroxy-8-phenyloctanoic acid (1.74 mmol), HOBt (2.1 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.1 mmol) and DIPEA (6.94 mmol) in DMF (4 mL) was stirred at room temperature overnight. The resulting mixture was diluted with NaHCO3 (saturated) and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4) and concentrated. The resulting residue was purified by chromatography (silica gel, methanol-CH2Cl2) to yield 2-hydroxy-N-((5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)methyl)-8-phenyloctanamide. A solution of 2-hydroxy-N-((5-(4-hydroxyphenyl)-1,3,4-thiadiazol-2-yl)methyl)-8-phenyloctanamide (0.18 mmol), 4-bromomethypyridine hydrochloride (0.26 mmol), and potassium carbonate (0.53 mmol) in DMF (4 mL) was stirred at room temperature overnight. The resulting mixture was diluted with ethyl acetate, washed with brine, dried (Na2SO4) and concentrated to yield 2-hydroxy-8-phenyl-N-((5-(4-(pyridin-4-ylmethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)octanamide, which was used in the next step without purification. To a solution of 2-hydroxy-8-phenyl-N-((5-(4-(pyridin-4-ylmethoxy)phenyl)-1,3,4-thiadiazol-2-yl)methyl)octanamide (0.16 mmol) in CH2Cl2 (5 mL) was added the Dess-Martin periodinane (0.23 mmol). The resulting mixture was stirred overnight, then quenched with an excess of a solution of sodium thiosulfate in saturated NaHCO3 (aqueous). The mixture was then extracted twice with ethyl acetate and the combined extracts were washed with brine, dried (Na2SO4) and concentrated. The resulting residue was purified by chromatography (silica gel, heptane-ethyl acetate) to yield the title compound.