Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[NH:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([N:27]([C:35](=[O:37])[CH3:36])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH2:19][C@@H:18]2[CH3:38])=[O:16])=[CH:11][CH:10]=1.[H-].[Na+].[CH2:42](I)[CH3:43]>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3](=[O:39])[N:4]([CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([N:27]([C:35](=[O:37])[CH3:36])[C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:19][C@@H:18]2[CH3:38])=[O:16])=[CH:13][CH:14]=1)[CH2:42][CH3:43]
Reactant: CCI
Reactant: COC(=O)NCCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCN(CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 35.1 %

Procedure:
(2S,4R)-[3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-propyl]-carbamic acid methyl ester (41 mg, 0.074 mmol) was dissolved in THF/DMF (10:1, 3 mL). To this solution was added Sodium Hydride (2 mg, 0.089 mmol), followed by ethyl iodide (14 mg, 0.089 mmol). The reaction was stirred at room temperature for 7 hours and was quenched by adding 1 mL of water. The mixture was concentrated under reduced pressure and dissolved in DCM (15 mL). The reaction mixture was washed with sat. aq. NaHCO3 (15 mL), water (15 mL) and brine (15 mL). The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (5/95 ethyl acetate/hexane—50/50 ethyl acetate/hexane gradient) to afford slightly yellow solid product (15 mg, 35%).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[O:12][CH3:13])[CH2:3][OH:4].[CH2:14]([O:21][C:22](Cl)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+].CO>C1COCC1.O.C(Cl)Cl>[CH2:14]([O:21][C:22](=[O:23])[NH:1][C@H:2]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[O:12][CH3:13])[CH2:3][OH:4])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COc1cc(O)ccc1[C@@H](N)CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(O)ccc1[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A mixture of 4-((R)-1-amino-2-hydroxy-ethyl)-3-methoxy-phenol (542 mg, 2.96 mmol), benzylchloroformate (634 uL, 4.44 mmol) and NaHCO3 (497 mg, 5.92 mmol) in THF/H2O (15/10 mL) was stirred at rt for overnight. After aqueous work up, the titled compound (736.3 mg, 79%) was obtained by flash column (5-7% MeOH in DCM).
Reaction SMILES: [CH:1]([C:3]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](O)=[O:11])=[O:2].C([N:20](CC)CC)C.ClC(OCC)=O.[Cl-].[NH4+]>O1CCCC1.O.CCOCC.C(OCC)(=O)C.Cl>[CH:1]([C:3]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH2:20])=[O:11])=[O:2]
Reactant: O=Cc1c(O)cccc1OCCCCC(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: NC(=O)CCCCOc1cccc(O)c1C=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
5-(2-Formyl-3-hydroxyphenoxy)pentanoic acid (595 mg, 0.0025 M) was dissolved in dry tetrahydrofuran (5.5 ml) and immersed in a cooling bath kept at -10° C. To the stirred solution under nitrogen was added dropwise from a syringe triethylamine (0.35 ml, 0.0025 M). After 5 minutes was then similarly added ethyl chloroformate (0.25 ml, 0.0025 M). After 15 minutes was then added a solution of ammonium chloride (0.4 g) in water (1.1 ml) and tetrahydrofuran (1.6 ml) previously cooled to 0° C. The vigorously stirred mixture was allowed to come to room temperature over 30 minutes, stirred at room temperature (15 minutes), and then diluted with ether/ethyl acetate (1:1) and 1 N hydrochloric acid. The layers were separated and the organic layer washed with dilute sodium bicarbonate solution and then quickly extracted with 2 N sodium hydroxide (1×25 ml). The layers were separated and the aqueous phase immediately acidified with dilute hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with dilute sodium bicarbonate solution, water, dried (sodium sulphate) and evaporated to give 5-(2-formyl-3-hydroxyphenoxy)pentanamide, m.p. 94°-95° C. from ethyl acetate/petrol.
Reaction SMILES: C(OC([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@@H:43]([C:45]4[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]5[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=5)=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl>[CH3:39][O:38][C:36](=[O:37])[C@@H:20]([NH:19][C:18]([C@@H:17]1[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@@H:43]([C:45]4[CH:50]=[CH:49][C:48]([O:51][CH2:52][C:53]5[CH:58]=[CH:57][C:56]([Cl:59])=[C:55]([Cl:60])[CH:54]=5)=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9][NH:8]1)=[O:40])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=2[CH3:35])=[CH:24][CH:23]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.5 %

Procedure:
(3R,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]-isoquinoline-7-carboxylic acid tert-butyl ester (300 mg) was dissolved in 15 mL DCM and 7.5 mL 4N HCl (in dioxane) added. The reaction was stirred at room temperature for 2.5 hours, DCM was added and mixture was concentrated. The solid was suspended in EtOAc-THF (9:1) and washed with a 10% sodium carbonate solution. The organic layer was washed with brine, nd dried over sodium sulfate and concentrated. DCM added and the mixture concentrated to provide 0.2 g of the product. LCMS: m/z 753.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[S:3]([N:6]1[C:10]([CH3:11])=[C:9]([CH2:12][N:13]([CH2:20][CH2:21][C:22]2[N:23]([CH3:32])[C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[CH:26][C:25]=3[F:31])C(=O)C(F)(F)F)[N:8]=[CH:7]1)(=[O:5])=[O:4].C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[F:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:24]=1[N:23]([CH3:32])[C:22]([CH2:21][CH2:20][NH:13][CH2:12][C:9]1[N:8]=[CH:7][N:6]([S:3]([N:2]([CH3:33])[CH3:1])(=[O:4])=[O:5])[C:10]=1[CH3:11])=[CH:30]2
Reactant: Cc1c(CN(CCc2cc3cccc(F)c3n2C)C(=O)C(F)(F)F)ncn1S(=O)(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(CNCCc2cc3cccc(F)c3n2C)ncn1S(=O)(=O)N(C)C
Yield: 59.5 %

Procedure:
To a solution of N-[[1-[(dimethylamino)sulphonyl]-5-methyl-1H-imidazol -4-yl]methyl]-2,2,2-trifluoro-N-[2-(7-fluoro-1-methyl-1H-indol-2-yl)-ethyl]acetamide (230 mg) in methanol (10 ml) was added potassium carbonate (350 mg), and the mixture was heated at reflux for 2 h. The mixture was then diluted with ethyl acetate (100 ml), washed with 8% sodium bicarbonate solution (100 ml), dried, and evaporated in vacuo to leave an oil. This was purified by FCC eluting with System A (200:8:1) to give the title compound (110 mg) as a solid, m.p. 114°-115.5°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C:8]2OC(=O)[S:10][N:9]=2)=[CH:5][CH:4]=1.[C:16]1([CH3:27])[CH:21]=[CH:20][C:19]([S:22]([C:25]#[N:26])(=[O:24])=[O:23])=[CH:18][CH:17]=1>C1(C)C=C(C)C=C(C)C=1>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][C:8]2[N:26]=[C:25]([S:22]([C:19]3[CH:18]=[CH:17][C:16]([CH3:27])=[CH:21][CH:20]=3)(=[O:23])=[O:24])[S:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: COc1ccc(Cc2nsc(=O)o2)cc1
Solvent: Cc1cc(C)cc(C)c1
Product: COc1ccc(Cc2nsc(S(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 150 °C
Yield: 85.4 %

Procedure:
To a suspension of 5-(4-methoxy-benzyl)-[1,3,4]oxathiazol-2-one (335 mg, 1.50 mmol) in mesitylene (3 mL) was added 4-toluenesulfonylcyanide (572 mg, 3.00 mmol) and the resulting mixture heated to 150° C. for 135 min. The resulting brown solution was cooled and purified by flash chromatography (silica gel, 0% to 33% ethyl acetate/hexanes) which afforded 3-(4-methoxy-benzyl)-5-(toluene-4-sulfonyl)-[1,2,4]thiadiazole (462 mg, 86%) as a dark yellow solid.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CN=C1.[OH:14][C@H:15]1[CH2:19][N:18]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C@H:17]([C:33]([O:35][CH3:36])=[O:34])[CH2:16]1>CN(C=O)C>[Si:1]([O:14][C@H:15]1[CH2:19][N:18]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:30])([F:31])[F:32])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C@H:17]([C:33]([O:35][CH3:36])=[O:34])[CH2:16]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 4 h
Yield: 93.6 %

Procedure:
t-Butyldimethylsilyl chloride (TBSCl) (4.07 g, 27.03 mmol) and imidazole (2.58 g, 37.8 mmol) were added to a solution of (3) (9.55 g, 27.03 mmol) in DMF (60 ml) at RT. The reaction was stirred for 4 hours and concentrated in vacuo. The residue was dissolved in EtOAc and washed with 0.1M aqueous HCl, sat. sodium bicarbonate solution and brine. The organic layers were dried with sodium sulfate and concentrated in vacuo to yield (2S,4R)-methyl 4-(tert-butyldimethylsilyloxy)-1-(4-(trifluoromethyl)phenylsulfonyl)pyrrolidine-2-carboxylate (4) (11.83 g, 94%) as a yellow oil. It was used without further purification in the next step. MS m/z 490.2. (M+Na)+; retention time=3.159 min, method [1].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1.[Li]CCCC.[C:22](=[O:24])=[O:23]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]([F:14])([F:15])[F:16])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[C:8]=1[C:22]([OH:24])=[O:23]
Reactant: O=C=O
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 1-methoxy-3,5-bis(trifluoromethyl)benzene (48, 0.56 g, 2.33 mmol) in anhydrous ether (5 mL) was slowly added n-BuLi (1.6 M solution in hexanes, 3 mL, 4.66 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. Dry ice was added into the yellow suspension until the starting material was completely consumed as monitored by TLC. The reaction was quenched with H2O (3 mL) and organic layer was separated. The aqueous layer was acidified with concentrated HCl, and then extracted with Et2O (3×5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 2-methoxy-4,6-bis(trifluoromethyl)benzoic acid (49, 0.38 g, 50%): 1H NMR (300 MHz, DMSO-d6) δ 13.94 (s, 1H), 7.76 (s, 1H), 3.97 (s, 1H).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1.[F:29][C:30]1[CH:40]=[CH:39][C:33](/[CH:34]=[CH:35]/[C:36](O)=[O:37])=[CH:32][CH:31]=1>>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH:19]([CH:23]3[CH2:24][CH2:25][N:26]([C:36](=[O:37])/[CH:35]=[CH:34]/[C:33]4[CH:39]=[CH:40][C:30]([F:29])=[CH:31][CH:32]=4)[CH2:27][CH2:28]3)[C:20]([NH2:22])=[O:21])[CH2:14][CH2:13]2)=[CH:4]1
Reactant: O=C(O)/C=C/c1ccc(F)cc1
Reactant: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCNCC1
Agent: Cl
Product: NC(=O)C(NC1CCC(c2c[nH]c3ccccc23)CC1)C1CCN(C(=O)/C=C/c2ccc(F)cc2)CC1

Procedure:
The title compound was prepared from the product of Example 1, step J (0.50 mmol), and trans-4-fluorocinnamic acid, by the method of Example 1, step K, giving the title compound as a white solid that was mostly the more polar cyclohexyl diastereomer by LCMS. Mass spectrum (LCMS, ESI pos.) calcd. for C30H35FN4O2: 503 (M+H). Found: 503
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:33]([F:36])([F:35])[F:34])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24](OC4C=CC=CN=4)=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([SiH](CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:33]([F:35])([F:34])[F:36])[O:13][N:12]=[C:11]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH:24]=[O:25])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(Oc1ccccn1)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: CN(C)C=O
Product: O=Cc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 70.2 %

Procedure:
To a stirred mixture of the title compound of Step A (690 mg, 1.30 mmol), palladium(II) acetate (9 mg, 0.04 mmol) and triphenylphosphine (31 mg, 0.12 mmol) in DMF (4 mL) was added triethylsilane (0.42 mL, 2.60 mmol). The resulting mixture was stirred at 60° C. for 5 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted with 20% ethyl acetate in hexane. The organic layer was washed with brine, dried with Na2SO4 and concentrated, and the residue was purified by column chromatography on silica gel using hexane/EtOAc as eluent to provide the title product as a yellow solid (400 mg, 70% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=[O:21])[CH:18]=3)[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:12]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][OH:21])[CH:18]=3)[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:12]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(C=O)ccc2n1Cc1cccc(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(CO)ccc2n1Cc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Ethyl 3-(4-tert-butylphenyl)-5-formyl-1-(3-methoxybenzyl)-1H-indole-2-carboxylate (Example 140, 700 mg, 1.493 mmol) was dissolved in ethanol (15 mL) and cooled to 0° C. Sodium borohydride (57 mg, 1.50 mmol) was added, and the solution was stirred for 1 hour. Water (27 μL, 1.5 mmol) was added, and the mixture was allowed to warm to room temperature. The mixture was concentrated via rotary evaporation, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The resulting crude oil was purified by flash chromatography on silica gel eluted with hexane then 20% ethyl acetate/hexane. The title compound was collected as a foam (530 mg, 75%). The product had: 1H NMR (300 MHz, acetone-d6) δ 7.56-7.55 (m, 1 H), 7.53-7.51 (m, 1 H), 7.50-7.47 (m, 2 H), 7.41-7.39 (m, 1 H), 7.37-7.34 (m, 2 H), 7.18-7.16 (m, 1 H), 6.77-6.75 (m, 1 H), 6.68-6.70 (m, 2 H), 5.85 (s, 2 H), 4.65 (d, 2 H), 4.09 (q, 2 H), 4.06-4.04 (m, 1 H), 3.70 (s, 3 H), 1.38 (s, 9 H), 0.96 (t, 3 H); mass spectroscopy gave MH+=472.2 (calc'd exact mass for C30H33NO4=471.24).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[CH2:25][C@H:24]2[CH2:26][C@H:22]([C:23]2([CH3:28])[CH3:27])[CH:21]1[NH2:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:30][C:31]1[CH:32]=[C:33]2[C:39]([C:40]3[N:45]=[C:44](S(C)=O)[C:43]([F:49])=[CH:42][N:41]=3)=[CH:38][N:37]([S:50]([C:53]3[CH:59]=[CH:58][C:56]([CH3:57])=[CH:55][CH:54]=3)(=[O:52])=[O:51])[C:34]2=[N:35][CH:36]=1.C(N(C(C)C)CC)(C)C.[NH4+].[Cl-]>CN(C=O)C>[Si:1]([O:18][CH2:19][C@H:20]1[CH2:25][C@H:24]2[CH2:26][C@H:22]([C:23]2([CH3:28])[CH3:27])[C@@H:21]1[NH:29][C:42]1[C:43]([F:49])=[CH:44][N:45]=[C:40]([C:39]2[C:33]3[C:34](=[N:35][CH:36]=[C:31]([Cl:30])[CH:32]=3)[N:37]([S:50]([C:53]3[CH:59]=[CH:58][C:56]([CH3:57])=[CH:55][CH:54]=3)(=[O:52])=[O:51])[CH:38]=2)[N:41]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Reactant: CC1(C)[C@H]2C[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(N)[C@@H]1C2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4[C@@H](CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)C[C@H]5C[C@@H]4C5(C)C)n3)c3cc(Cl)cnc32)cc1
Temperature: 75 °C

Procedure:
To a solution of (1R,3S,5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-6,6-dimethyl-bicyclo[3.1.1]heptan-2-amine, 77e, (0.20 g, 0.46 mmol) and 5-chloro-3-(5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (0.14 g, 0.30 mmol) in DMF (1.5 mL) was added diisopropylethylamine (0.11 mL, 0.61 mmol). The reaction was heated to 75° C. for 18 hours. The mixture was diluted into aqueous saturated NH4Cl solution and extracted twice with EtOAc. The combined organic phases were washed twice with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified via silica gel chromatography (0-5% MeOH/CH2Cl2 gradient) to afford 78 mg of the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[CH3:32])[C:19]4[CH2:25][CH2:24][NH:23][CH2:22][C:20]=4[N:21]=3)=[CH:12][CH:11]=2)[NH:4][C:3]1=[O:33].CN(C)C=O.N1C=CC=CC=1.[S:45]1[CH:49]=[CH:48][N:47]=[C:46]1[C:50](Cl)=[O:51]>>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:17]=[C:18]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[CH3:32])[C:19]4[CH2:25][CH2:24][N:23]([C:50]([C:46]5[S:45][CH:49]=[CH:48][N:47]=5)=[O:51])[CH2:22][C:20]=4[N:21]=3)=[CH:12][CH:11]=2)[NH:4][C:3]1=[O:33]
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cc(=O)n(C)c(=O)[nH]3)cc2)nc2c1CCNC2
Reactant: O=C(Cl)c1nccs1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nc(-c2ccc(Nc3cc(=O)n(C)c(=O)[nH]3)cc2)nc2c1CCN(C(=O)c1nccs1)C2
Reaction time: 8 h

Procedure:
(S)-3-methyl-6-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenylamino)pyrimidine-2,4(1H,3H)-dione (0.0325 g, 0.0000723 mol) in dry N,N-Dimethylformamide (2.00 mL, 0.0258 mol) was added dry Pyridine (0.030 mL, 0.00037 mol) followed by 1,3-thiazole-2-carbonyl chloride (0.0300 g, 0.000203 mol). The reaction mixture was stirred overnight. The reaction mixture was concentrated, chromatographed through silica gel (4 g, 0-10% MeOH in dichloromethane), and then purifed by HPLC. 1H NMR (400 MHz, DMSO) δ 10.74 (s, 1H), 8.69 (s, 1H), 8.32 (t, J=7.8, 2H), 8.13-8.04 (m, 2H), 7.31 (dd, J=8.3, 4.7, 2H), 5.50 (dd, J=75.0, 18.3, 1H), 5.04 (d, J=2.8, 1H), 4.79 (dd, J=47.1, 18.7, 1H), 4.67-4.28 (m, 1H), 4.17 (d, J=6.1, 1H), 4.05-3.73 (m, 2H), 3.73-3.55 (m, 4H), 3.45 (dd, J=17.5, 7.1, 1H), 3.09 (s, 3H), 2.82 (d, J=22.7, 2H), 1.28 (d, J=6.7, 3H). LC/MS-m/z+561.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[CH3:27][C:28]([OH:32])([CH3:31])[C:29]#[CH:30]>>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[CH:3][C:2]([C:30]#[C:29][C:28]([OH:32])([CH3:31])[CH3:27])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[NH:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)n[nH]1)CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(-c3nc(C4CC4)n[nH]3)n1CCO2
Yield: 6.6 %

Procedure:
3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly to General Procedure G with slight modifications. 10-bromo-3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with 3-methyl-1-butyne-3-ol to afford 5.5 mg (6.6% yield). M+1=419.0.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]3[C:21](=[O:22])[C:20]([C:23]([O:25]CC)=O)=[CH:19][N:12]4[CH2:13][C:14](=O)[NH:15][C:16]([CH:17]=2)=[C:11]34)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>CO>[Cl:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][C:23]([C:20]2[C:21](=[O:22])[C:10]3[C:11]4[N:12]([CH:19]=2)[CH2:13][C:14]([NH:34][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([Cl:28])=[CH:30][CH:31]=2)=[N:15][C:16]=4[CH:17]=[C:8]([CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[CH:9]=3)=[O:25])=[CH:31][CH:30]=1
Reactant: CCOC(=O)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)NC(=O)C2
Reactant: NCc1ccc(Cl)cc1
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1cn2c3c(cc(CN4CCOCC4)cc3c1=O)N=C(NCc1ccc(Cl)cc1)C2
Temperature: 180 °C

Procedure:
A mixture of ethyl 9-(4-morpholinylmethyl)-2,7-dioxo-2,3-dihydro-1H,7H-pyrido[1,2,3-de]quinoxaline-6-carboxylate (Preparation 4, 280 mg) and 4-chlorobenzylamine (1 mL) is heated at 180° C. The solution is cooled, diluted with methanol (2 mL), and the precipitate is filtered off. The resulting solid is washed with methanol followed by ether and dried to give 117 mg of the title compound. Physical characteristics: 1H NMR (DMSO-d6) δ2.35, 3.49, 3.57, 4.56, 4.60, 5.08, 7.20, 7.34-7.40, 7.64, 8.21, 8.62, 10.6. Anal. Found: C, 62.90; H, 4.99; N, 11.81; Cl, 12.03.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=2)=[O:18])=[CH:20][CH:21]=1)([O-:12])=[O:11]
Reactant: Cc1cc(C)cc(N)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: Cc1cc(C)cc(NC(=O)c2ccc([N+](=O)[O-])cc2)c1

Procedure:
Using 3,5-xylidine (1.42 ml, 11.0 mmol) and 4-nitrobenzoic acid (1.76 g, 10.4 mmol), the procedure of Reference Example 16 was repeated to obtain 2.72 g (quantitative) of the title compound in the form of light yellow crystals.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)=[CH:9][CH:8]=1.[OH-].[Na+].CN(C)[CH:26]=[O:27]>>[Br:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[C:16]3[CH:26]=[O:27])=[CH:11][CH:12]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(-c2ccc3[nH]ccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(-c3ccc(Br)cc3)cc12
Temperature: 25 °C

Procedure:
In a 100-ml round-bottom flask is placed 2.8 mL of dimethylformamide (2.74 g, 3.74 mmol). The flask and the content was cooled in an ice-salt bath for about 0.5 hour and 0.86 mL (1.44 g, 94 mmol) of freshly distilled phosphorusoxychloride is subsequently added with stirring to the dimethylformamide dropwise. Then a solution of 1.0 g of 32 (85 mmol) in 1 mL of dimethylformamide is added to the above solution slowly. After the addition, the temperature of the solution is brought to 40° C. and allowed to stir for an hour. At this time, 1 N NaOH (10 mL) was added to the reaction mixture dropwise. The resulting mixture is heated rapidly to the boiling point and allowed to cool to room temperature. The resulting precipitate is collected on a filter and the solid was further washed with water. Compound 33 obtained from this procedure was pure enough for the next reaction. MS (Es+ve) m/z 300, (Es−ve) m/z 298.