Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>CCOCC>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:18](=[O:19])[CH2:17][Cl:16])[CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: Cc1ccnc(N)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccnc(NC(=O)CCl)c1
Reaction time: 1 h

Procedure:
A solution of 2-amino-4-methylpyridine (10.8 grams) in ether (150 ml), and triethylamine (10 grams) are placed in a reaction flask equipped with stirrer, thermometer and addition funnel. The reaction mixture is cooled to a temperature of about 0° C and chloroacetyl chloride (11.3 grams) dissolved in ether (30 ml) is slowly added thereto resulting in the formation of a precipitate. Stirring is continued for a period of about 1 hour. After this time the reaction mixture is filtered to recover the precipitate that has formed. The precipitate is washed with aqueous potassium carbonate and with water. The washed precipitate is then dried to yield the desired product N-(4-methyl-2-pyridyl)-α-chloroacetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH2:16])=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH:16][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C(=O)Nc2cccc(Cl)c2)c(N)s1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2cccc(Cl)c2)c(NC(=O)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
A solution of 5-amino-2-methyl-thiazole-4-carboxylic acid (3-chloro-phenyl)-amide (0.04 g, 0.17 mmol) in dry dioxane (0.50 ml) and pyridine (0.02 ml) was cooled to 0° C. and treated with benzoyl chloride (0.02 g, 0.17 mmol). The mixture was then left to warm to room temperature and stirred overnight. After evaporation of the solvent, the residue was triturated in acetonitrile to yield the title compound (0.003 g, 4%) as a white solid, MS (ISP): m/e=372.3 (M+H+)
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([CH2:20]O)[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>CN1C(=O)CCC1.C(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([CH2:20][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: OCc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1N1CCOCC1
Reactant: C1CCNC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Clc1ccc2c(Nc3ccc(N4CCOCC4)c(CN4CCCC4)c3)ccnc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To a suspension of {5-[(7-chloroquinolin-4-yl)amino]-2-(morpholin-4-yl)phenyl}methanol hydrochloride (0.105 g, 0.26 mmol) in 4 mL of NMP at 0° C. was added thionyl chloride (90 μL, 1.23 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 h. The reaction mixture was then slowly added to pyrrolidine (0.65 mL, 7.75 mmol) in 1 mL of NMP at 0° C. and then stirred at room temperature for 2 h. This solution was diluted in 100 mL of CH2Cl2 and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, evaporated and purified by flash chromatography (DCM/MeOH/NH4OH//90/10/1) to yield expected compound as a yellow solid (105 mg, 96% yield). LC-MS: m/z (ESI) 423.3 [M+H]+. mp=187-188° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](N(OC)C)=[O:17])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C=[O:23].[O-:24][CH2:25]C.[Na+].[OH-].[K+]>CS(C)=O.O.CCO>[Br:1][C:2]1[CH:7]=[N:6][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]([CH2:16][OH:17])[C:25]([OH:24])=[O:23])=[CH:13][CH:14]=2)=[N:4][CH:3]=1
Reactant: CC[O-]
Reactant: CON(C)C(=O)Cc1ccc(Nc2ncc(Br)cn2)cc1
Reactant: C=O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCO
Product: O=C(O)C(CO)c1ccc(Nc2ncc(Br)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(4-(5-Bromopyrimidin-2-ylamino)phenyl)-N-methoxy-N-methylacetamide 23 (2.0 mmol), paraformaldehyde (6.0 mmol) and sodium ethoxide (12.0 mmol) are dissolved in DMSO (10 mL). The reaction mixture is stirred at rt for 1 h. Then a solution of KOH (12.0 mmol) in H2O (5.0 mL) and EtOH (5.0 mL) is added. The reaction mixture is heated at 50° C. for 5 h. After the reaction is completed, the reaction mixture is washed with DCM (50 mL). The aqueous phase is acidified to pH ˜5 and extracted with DCM (2×50 mL). The organic layer is separated, dried and concentrated to yield 2-(4-(5-bromopyrimidin-2-ylamino)phenyl)-3-hydroxypropanoic acid 25, which is used in the next step without further purification. 1H NMR (400 MHz, d6-DMSO) δ 12.30 (bs, 1H), 9.84 (s, 1H), 8.57 (s, 2H), 7.61 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 3.90 (t, J=8.8 Hz, 1H), 3.49-3.61 (m, 2H), 3.35 (bs, 1H). MS (m/z) (M+1)+: 338.0, 340.0.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]([Br:7])=[CH:5][N:6]=1.[H-].[Na+].[CH3:10][Si:11]([CH2:14][CH2:15][O:16][CH2:17]Cl)(C)[CH3:12]>CN(C=O)C>[Br:1][C:2]1[N:3]([CH2:17][O:16][CH2:15][CH2:14][SiH:11]([CH3:12])[CH3:10])[C:4]([Br:7])=[CH:5][N:6]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cnc(Br)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[SiH](C)CCOCn1c(Br)cnc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2,5-dibromo-1H-imidazole (1 eq.) in DMF at 0° C. under Ar was added NaH (1.2 eq.) and the mixture stirred for 30 min at 0° C. Then SEM-Cl (1.1 eq.) was added dropwise, and the mixture stirred 16 h warming to RT. The reaction was quenched by slow addition of H2O and the desired product was extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude was purified by column chromatography eluting with 10% EtOAc/Petroleum ether to afford the desired product. 1H NMR (300 MHz, CD3CN) δ: 7.10 (1H, s), 5.21 (2H, s), 3.53 (2H, t, J=7.3 Hz), 0.90 (2H, t, J=7.3 Hz), 0.10 (9H, s). MS (ES) C9H16Br2N2OSi requires: 354:356:358 [1:2:1], found: 355:357:359 [1:2:1] (M+H)+.
Reaction SMILES: [CH:1](=O)[CH3:2].ClC(Cl)C.[C:8]1([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([C:24]4[N:25]=[C:26]([CH2:34][CH:35]5[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]5)[N:27]5[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]=45)=[CH:19][CH:20]=3)[N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:1]([N:38]1[CH2:39][CH2:40][CH:35]([CH2:34][C:26]2[N:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH2:33])[C:28]3=[C:24]([C:18]3[CH:17]=[C:16]4[C:21]([CH:22]=[CH:23][C:14]([C:8]5[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=5)=[N:15]4)=[CH:20][CH:19]=3)[N:25]=2)[CH2:36][CH2:37]1)[CH3:2]
Reactant: CC=O
Reactant: Nc1nccn2c(CC3CCNCC3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCN1CCC(Cc2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetaldehyde (6.76 mg, 0.15 mmol) in dichloroethane (5 mL, 2 equiv) was added to 1-(2-Phenyl-quinolin-7-yl)-3-piperidin-4-ylmethyl-imidazo[1,5-a]pyrazin-8-ylamine (100.00 mg, 0.23 mmol) and sodium triacetoxyborohydride (65.0 mg, 306.8 mmol). The reaction mixture was stirred at rt overnight. The crude product was purified by a 5 g Jones silica gel (dry loaded with silica, wetted with 100% CH2Cl2, eluted with 100% CH2Cl2→3% (7N NH3) in MeOH/CH2Cl2→6% (7N NH3) in MeOH/CH2Cl2) and afforded the desired product. 1H NMR (400 MHz, METHANOL-d) δ 8.38 (1 H, d, J=8.66), 8.25 (1 H, s), 8.08 (2 H, dd, J=1.64 Hz, J=1.08), 8.00 (2 H, m), 7.79 (1 H, dd, J=2.06, J=1.70), 7.51 (1 H, d, J=5.15), 7.44 (3 H, m), 7.00 (1 H, d, J=5.12), 3.06 (2 H, d, J=10.88), 2.97 (2 H, d, J=7.08), 2.54 (2 H, d, J=5.80), 2.18 (2 H, m), 1.98 (1H, m), 1.75 (2 H, d, J=13.12), 1.43 (2 H, m), 1.07 (3 H, t); MS (ES+): m/z 435.12/436.10 (15/5) [MH+]; HPLC: tR=1.71 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([C:4]1[C:8]2[CH:9]=[C:10]([C:13]([OH:15])=O)[CH:11]=[CH:12][C:7]=2[O:6][N:5]=1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:49][C@@H:50]([CH2:64][C:65]1[CH:70]=[C:69]([F:71])[CH:68]=[C:67]([F:72])[CH:66]=1)[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1>C(Cl)Cl>[F:71][C:69]1[CH:70]=[C:65]([CH:66]=[C:67]([F:72])[CH:68]=1)[CH2:64][C@H:50]([NH:49][C:13]([C:10]1[CH:11]=[CH:12][C:7]2[O:6][N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[C:8]=2[CH:9]=1)=[O:15])[C@H:51]([OH:63])[CH2:52][NH:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([CH2:61][CH3:62])[CH:56]=1
Reactant: CCCc1noc2ccc(C(=O)O)cc12
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
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: CCCc1noc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.2 %

Procedure:
To a stirred solution of 3-propyl-1,2-benzisoxazole-5-carboxylic acid (70 mg, 0.3 mmol) and HATU (130 mg, 0.3 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (110 μL, 0.6 mmol). In a separate flask, N,N-diisopropylethylamine (110 μL, 0.6 mmol) was added to (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (EXA xxx) (140 mg, 0.3 mmol) in methylene chloride (2 mL). This solution was added to the above solution containing the acid and the resulting reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between methylene chloride and water. The organic layer was washed with water, dried (sodium sulfate), filtered, and concentrated under reduced pressure to afford a crude oil. Purification by flash column chromatography (silica, gradient 97:3 to 94:6 methylene chloride/methanol) provided N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-3-propyl-1,2-benzisoxazole-5-carboxamide (30 mg). ESI-MS m/z 522 [M+H]+
Reaction SMILES: [C:1]([C:5]1C=C(C2N=C(C)C3C(C=2)=CC([O:21]C)=C(OC)C=3)[CH:8]=[CH:9][CH:10]=1)(C)(C)[CH3:2].[O:26]1[CH2:31][CH2:30]O[CH2:28][CH2:27]1>>[CH3:28][CH2:27][O:26][C:31]([CH3:30])=[O:21].[CH3:2][CH2:1][CH2:5][CH2:10][CH2:9][CH3:8]
Reactant: COc1cc2cc(-c3cccc(C(C)(C)C)c3)nc(C)c2cc1OC
Reactant: C1COCCO1
Product: CCCCCC
Product: CCOC(C)=O
Temperature: 25 °C
Yield: 62 %

Procedure:
3-(3-(tert-Butyl)phenyl)-6,7-dimethoxy-1-methylisoquinoline (153 mg) and SeO2 (61 mg, 1.2 eq.) in 5 mL anhydrous dioxane were refluxed at 102° C. for 3 hours. Solution was then cooled to room temperature and filtered to remove precipitate. Resulting filtrate was concentrated. Chromatography achieved using ISCO max gradient 30% EtOAc/hexane yielding product as a yellow solid (97 mg, 62% yield). 1H NMR (400 MHz) (CDCl3) δ 10.40 (s, 1H), 8.67 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.90 (dt, J=4 Hz, J=4 Hz, 1H), 7.42-7.40 (m, 2H), 7.13 (s, 1H), 4.04 (s, 3H), 4.00 (s, 3H), 1.36 (s, 9H). 13C NMR (100 MHz) (CDCl3) δ 196.96, 153.20, 152.67, 151.82, 150.35, 146.98, 138.51, 135.43, 128.67, 125.91, 124.05, 123.78, 122.07, 120.08, 104.95, 103.49, 56.30, 56.07, 34.95, 31.46.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:6][CH:5]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl-:1].[Cl:1][CH2:2][CH2:3][C:4]1[CH:23]=[CH:22][C:7]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][NH3+:14])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCCOCCOc1ccc(CCCl)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [Cl-]
Product: [NH3+]CCOCCOc1ccc(CCCl)cc1
Reaction time: 1 h

Procedure:
tert-butyl 2-{2-[4-(2-chloroethyl)phenoxy]ethoxy}ethylcarbamate (1.7 mmol) was dissolved in 5 ml dichloromethane and triethylsilane (0.5 ml, 5% v/v) was added. At this point trifluoroacetic acid (5 ml) was added dropwise to the solution at room temperature. The reaction mixture turned golden brown upon addition and was allowed to stir for one hour. All volatiles were removed under reduced atmosphere, the residue was re-dissolved in CH2Cl2, and washed twice with dilute HCl. The aqueous fractions were lyophilized overnight. The remaining oily residue was dissolved in anhydrous DMF to be used as a stock solution in further reactions.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][CH2:8][CH:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([C:37]4[O:38][CH:39]=[CH:40][C:41]=4[CH3:42])=[O:36])[CH:29]=3)[CH:24]=[CH:23][N:22]=2)[NH:18][CH:17]=1)=[O:15])[C:10](O)=[O:11])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:52]1N=N[C:54]2C=CC=N[C:53]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>O1CCCC1.O>[CH2:53]([NH:52][C:10](=[O:11])[CH:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([C:21]2[CH:26]=[C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([NH:34][C:35]([C:37]4[O:38][CH:39]=[CH:40][C:41]=4[CH3:42])=[O:36])[CH:29]=3)[CH:24]=[CH:23][N:22]=2)[NH:18][CH:17]=1)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:43])[CH3:54]
Reactant: Cc1ccoc1C(=O)Nc1cccc(Oc2ccnc(-c3cc(C(=O)NC(CCC(=O)OC(C)(C)C)C(=O)O)c[nH]3)c2)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C(CCC(=O)OC(C)(C)C)NC(=O)c1c[nH]c(-c2cc(Oc3cccc(NC(=O)c4occc4C)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a stirred suspension of 5-tert-butoxy-2-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoic acid (100 mg, 0.17 mmol) in 10 ml of anhydrous tetrahydrofuran were added HATU (76 mg, 0.20 mmol) and N,N-diisopropylethylamine (66 mg, 0.51 mmol). The mixture was heated at 60° C. for 15 minutes and cooled to room temperature, followed by addition of 2-Methylamine solution in THF (0.25 ml, 0.50 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water with vigorous stirring. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give the crude, which was purified by silica gel chromatography eluting with 3˜5% methanol in chloroform to give tert-butyl 5-(ethylamino)-4-({[5-(4-{3-[(3-methyl-2-furoyl)amino]phenoxy}pyridin-2-yl)-1H-pyrrol-3-yl]carbonyl}amino)-5-oxopentanoate as white solid. Yield: 82 mg, 78%.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C@@H:13]2[CH2:15][C@H:14]2[CH2:16][NH2:17])=[N:5]1.C(N(CC)CC)C.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>O1CCCC1>[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:17][CH2:16][C@@H:14]2[CH2:15][C@H:13]2[C:10]2[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=2)=[N:5][N:4]([CH3:3])[CH:12]=3)=[O:31])=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Cn1cc2c([C@@H]3C[C@H]3CN)cccc2n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1cc2c([C@@H]3C[C@H]3CNC(=O)c3ccc(Br)cc3)cccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of 1-[(1R,2R)-2-(2-methyl-2H-indazol-4-yl)cyclopropyl]methanamine dihydrochloride (200 mg, 0.729 mmol) and triethylamine (407 μL, 2.92 mmol) in tetrahydrofuran (7 mL) was added 4-bromobenzoyl chloride (192 mg, 0.875 mmol), and the mixture was stirred at room temperature for 1 hr. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=40/60→90/10) to give the title compound (247 mg, yield 88%).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.[CH3:41][N:42]1[CH2:47][CH2:46][CH2:45][CH:44]([CH2:48]O)[CH2:43]1.C(P(CCCC)CCCC)CCC>C(Cl)Cl.CCOCC>[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:48][CH:44]4[CH2:45][CH2:46][CH2:47][N:42]([CH3:41])[CH2:43]4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: CN1CCCC(CO)C1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCC1CCCN(C)C1
Reaction time: 18 h
Yield: 32.5 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (560 mg, 2.2 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (240 mg, 0.75 mmol), (prepared as described for the starting material in Example 2), 1-methyl-3-piperidinemethanol (115 mg, 0.89 mmol) and tributylphosphine (440 mg, 2.2 mmol) in methylene chloride (10 ml). The mixture was stirred for 18 hours, diluted with ether and the resulting precipitate was removed by filtration. The volatiles were removed from the filtrate by evaporation, and the residue was dissolved in acetone and ethereal hydrogen chloride (1.5 ml of a 1M solution, 1.5 mmol) was added. The precipitated product was collected by filtration and purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (75/8/1). The purified solid product was triturated with ether collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)quinazoline (105 mg, 33%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:26]([F:29])([F:28])[F:27])[O:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:25])[CH2:24][NH:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:39][S:40]([CH2:43][C:44](O)=[O:45])(=[O:42])=[O:41].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2([C:26]([F:27])([F:29])[F:28])[O:14][CH:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([F:25])[CH2:22][N:23]([C:44](=[O:45])[CH2:43][S:40]([CH3:39])(=[O:42])=[O:41])[CH2:24]4)=[CH:17][CH:16]=3)[CH2:11]2)[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: FC1(c2ccc(C3=COC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)CNC1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)CC(=O)N1CC(F)(c2ccc(C3=COC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 54.1 %

Procedure:
To a stirred solution of 3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-3-yl)phenyl)-3-fluoroazetidine hydrochloride (Example 1, Intermediate 3) (0.25 g, 0.535 mmol) in THF (5 mL) was added DIPEA (0.933 mL, 5.35 mmol) at room temperature and stirred for 10 minutes at room temperature. Methane sulfonyl acetic acid (0.147 g, 1.07 mmol), T3P (50% solution in ethyl acetate, 1.6 mL, 2.675 mmol) were added at room temperature. Resulting reaction mixture was stirred for 16 hours at room temperature under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (5×25 mL). Combined organic layer was washed with saturated solution of NaHCO3 (2×100 mL), dried over sodium sulphate and concentrated in vacuo to get pale yellow oil (0.32 g, crude). Crude was purified by column chromatography using 100-200 mesh silica gel. Desired product gets eluted in 0.6% MeOH in DCM to afford white semisolid (0.160 g), which was triturated with DCM: n-pentane (1:10; 2×5 mL) to afford product as off white solid. Yield: 0.145 g (49.15%). 1H NMR (400 MHz, DMSO-d6) δ: 3.11 (s, 3H), 3.20 (d, J=17.16 Hz, 1H), 3.65 (d, J=17.12 Hz, 1H), 4.24 (s, 2H), 4.34 (d, J=21.6 Hz, 2H), 4.70 (d, J=21.52 Hz, 2H), 7.27 (d, J=7.96 Hz, 2H), 7.47 (d, J=9.36 Hz, 2H), 7.73 (d, J=3.92 Hz, 3H). LC-MS (m/z): =550.1 (M−H). HPLC purity: 98.75%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[NH:19][CH:20]=[C:21]([CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[CH3:36]CN(C(C)C)C(C)C.CI>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][O:17][C:18]3[N:19]([CH3:36])[CH:20]=[C:21]([CH2:25][C:26]4[CH:31]=[N:30][CH:29]=[N:28][CH:27]=4)[C:22](=[O:24])[N:23]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Solvent: CI
Solvent: ClCCl
Product: Cn1cc(Cc2cncnc2)c(=O)nc1OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Yield: 43.8 %

Procedure:
To a solution of 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (45 mg, 0.089 mmol) in dichloromethane (DCM) (2 mL) was added DIPEA (0.031 mL, 0.179 mmol) and MeI (8.39 μL, 0.134 mmol). The mixture was purified by reverse phase biotage affording 2-{[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]oxy}-1-methyl-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (20 mg, 0.039 mmol, 43.2% yield) LCMS: rt=3.37 min, [M+H+]=517
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[N:22]=[C:23]1[N:27]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26](=[O:34])[CH2:25][S:24]1.[CH3:35][C:36]([CH3:38])=O.N1CCCCC1.C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:17])[F:18])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[N:22]=[C:23]1[N:27]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26](=[O:34])[C:25](=[C:36]([CH3:38])[CH3:35])[S:24]1
Reactant: CC(C)=O
Reactant: CCOC(=O)CN1C(=O)CSC1=Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)CN1C(=O)C(=C(C)C)SC1=Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A mixture of ethyl 2-{{2-chloro-5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4-fluorophenyl}imino}-4-oxo-3-thiazolidineacetate (2.0 g, 3.83 mmol), acetone (0.562 mL, 7.65 mmol), piperidine (0.20 mL, 2.02 mmol) and acetic acid (20 μL) in ethanol is refluxed for 90 minutes, treated with additional acetone (0.562 mL), refluxed for 3.5 hours, stirred at room temperature overnight, concentrated in vacuo, and chased with ethyl acetate to obtain a residue. Column chromatography of the residue using silica gel and an ethyl acetate/hexanes solution (1:3) gives the title product as a white solid (1.5 g, mp 67-80° C.).
Reaction SMILES: O=C(C[N:8]1C(=O)C2C=CC=CC=2NC2N=CC=CC1=2)CC([O-])=O.O=[C:25]([CH2:31][N:32]1[C:38](=O)[C:37]2[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=2[NH:35][C:34]2[N:44]=[CH:45][CH:46]=[CH:47][C:33]1=2)[CH2:26][C:27]([O:29][CH3:30])=[O:28].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N:8]1[C:25]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:31][N:32]2[C:38]=1[C:37]1[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=1[NH:35][C:34]1[N:44]=[CH:45][CH:46]=[CH:47][C:33]2=1
Reactant: O=C([O-])CC(=O)CN1C(=O)c2ccccc2Nc2ncccc21
Reactant: COC(=O)CC(=O)CN1C(=O)c2ccccc2Nc2ncccc21
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COC(=O)Cc1cn2c(n1)-c1ccccc1Nc1ncccc1-2
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a solution of 3-oxo-4-(6-oxo-6,11-dihydro-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-5-yl)butanoate (crude product from step 1, 0.36 g, 1 eq.) in acetic acid (5 mL) was added ammonium acetate (0.385 g, 20 eq. based on the amount of starting material used in step 1). The reaction was stirred at 120° C. for 2 hours. The reaction was poured onto water (25 mL) and extracted with dichloromethane (2×25 mL). The combined extracts were washed with water (1×25 mL), saturated sodium bicarbonate (25 mL), brine (1×25 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (10% methanol in dichloromethane) gave the methyl 2-(9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-2-yl)acetate (0.4 g). LCMS: 307 [M+H].