Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:23]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[N:34][N:35](C(OC(C)(C)C)=O)[CH:36]=2)O1>>[CH:20]([N:19]1[C:15]([C:13]2[N:14]=[C:7]3[C:6]4[CH:23]=[C:2]([C:32]5[CH:33]=[N:34][NH:35][CH:36]=5)[CH:3]=[CH:4][C:5]=4[O:11][CH2:10][CH2:9][N:8]3[CH:12]=2)=[N:16][CH:17]=[N:18]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(-c3cn[nH]c3)ccc1OCC2

Procedure:
Following Example 182, 10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 187 was coupled with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate to give 160. MS: 362.3. 1H NMR (400 MHz, DMSO) δ 8.57 (t, J=4.0, 1H), 7.99-7.94 (m, 4H), 7.56 (dt, J=11.2, 5.6, 1H), 7.06 (t, J=8.6, 1H), 5.81 (p, J=6.6, 1H), 4.53 (d, J=9.5, 4H), 1.53 (d, J=6.6, 7H).
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23](O)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[NH2:41].CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]([NH:19][C:20]4[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=4)[C:23]([NH:41][C:32]4[CH:33]=[CH:34][C:35]5[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=5)[CH:31]=4)=[O:24])=[O:18])=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: Nc1ccc2ccccc2c1
Reactant: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(C(=O)Nc2ccc3ccccc3c2)c1
Yield: 61.5 %

Procedure:
To a solution of 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid (20 mg, 0.049 mmol), 2-naphthylamine (10.59 mg, 0.073 mmol) and DIPEA (9.56 mg, 0.073 mmol) in DMF 1 mL was added EDC (14.18 mg, 0.073 mmol) and HOBt (9.99 mg, 0.073 mmol) at room temperature and continued string for 16 h at room temperature. Reaction mixture was diluted with ethyl acetate and sequentially washed with aqueous sodium bicarbonate, brine and water, and dried over MgSO4. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by column chromatography on silica gel (n-Hexane:EtoAC=1:9˜4:6) to give 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-N-naphtalene-2-yl-benzamide as a colorless crystals (16 mg, 61.53% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25][C:26]([CH3:28])=O.S(=O)(=O)(O)O>C(O)(=O)C>[CH2:31]([O:30][C:24]([C:25]1[C:26]([CH3:28])=[N:1][C:2]2[C:3]([C:4]=1[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=[CH:16][C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)=[O:29])[CH3:32]
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Reactant: CCOC(=O)CC(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Yield: 83 %

Procedure:
To a mixture of 2-amino-4,5,3',4'-tetramethoxybenzophenone, ethyl acetoacetate and acetic acid, concentrated sulfuric acid was added, followed by the same treatment as in Reference Example 1, to yield 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-methylquinoline-3-carboxylic acid ethyl ester (83%), which was then recrystallized from ethanol to yield a colorless prismatic crystal having a melting point of 147° to 148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[NH2:23][CH2:24][C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:23][CH2:24][C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: NCc1cccnc1
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(NCc3cccnc3)nc21

Procedure:
This compound was prepared by a procedure similar to that described in Example 49 starting with 0.165 g (0.47 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37 and 1.08 g (10.0 mmol) of 3-(aminomethyl)-pyridine yielding 0.053 g of pure product; mp 224°-226° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH:20]1([CH2:26][N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][CH:20]4[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:28][CH2:29]3)=[O:17])[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: C1CCC(CN2CCNCC2)CC1
Product: O=C(Nc1nc(CC(=O)N2CCN(CC3CCCCC3)CC2)cs1)c1ccc(Cl)cc1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with (1-cyclohexyl-methyl)piperazine to give 4-chloro-N-{4-[2-(4-cyclohexylmethyl-piperazin-1-yl)-2-oxo-ethyl]-thiazol-2-yl}-benzamide, using general procedure A. Colorless amorphous solid. MS 461.0 ([M+H]+)
Reaction SMILES: [OH-].[Li+].I[CH3:4].[O:5]=[C:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[C:11]#[N:12]>O.CO>[CH3:4][C:7]1([C:11]#[N:12])[CH2:8][CH2:9][CH2:10][C:6]1=[O:5]
Reactant: N#CC1CCCC1=O
Reactant: CI
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C#N)CCCC1=O
Temperature: 50 °C
Yield: 78.3 %

Procedure:
A solution of lithium hydroxide (0.2226 g, 9.30 mmol) in water (5 mL) and iodomethane (0.591 mL, 9.46 mmol) were added to a stirred solution of 2-oxocyclopentanecarbonitrile (0.86 g, 7.88 mmol) in methanol (5 mL) at room temperature. The resulting mixture was heated to 50° C. for 1.5 h. The methanol solvent was removed in vacuo. The aqueous residue was extracted with ether (2×25 mL). The combined ether extracts were dried (Na2SO4), decanted and concentrated to give 1-methyl-2-oxocyclopentanecarbonitrile (0.76 g, 78% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 2.63-2.74 (1 H, m), 2.43 (2 H, t, J=7.21 Hz), 1.59-1.93 (4 H, m), 1.34 (3 H, d, J=6.94 Hz).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[OH-].[K+].ClC(OC(Cl)(Cl)Cl)=[O:15]>O>[NH:1]1[C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7](=[O:8])[O:9][C:10]1=[O:15]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1ccsc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c2sccc2c(=O)o1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Methyl 2-amino-thiophene-3-carboxylate (5 g, 31.72 mmol) was added to a solution of potassium hydroxide (3.55 g, 63.45 mmol) in 10 mL water. The solution was heated at 90° C. until to get a clear solution. The solution was then cooled to 0° C. and trichloromethyl chloroformate (5.74 mL, 47.57 mmol) was added slowly. The solution was allowed to come to room temperature and further stirred for 30 min. The precipitated solid was collected by vacuum filtration to yield 4.7 g (88%) of 1H-thieno[2,3-d][1,3]oxazine-2,4-dione. MP 233° C. 1H-NMR (DMSO-d6) δ 7.15 (d, J=6.0 Hz, 1H), 7.19 (d, J=6.0 Hz, 1H) ppm.
Reaction SMILES: [N:1]1([C@:4]23[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.[CH3:44][S:45]([N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:47])=[O:46].CCN(C(C)C)C(C)C>O1CCOCC1>[CH3:22][C@:19]12[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:24])([CH3:25])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7][C@@H:6]1[C@H:5]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:4]1([NH:1][CH2:2][CH2:3][N:51]1[CH2:52][CH2:53][N:48]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:49][CH2:50]1)[CH2:21][CH2:20]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCN(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C

Procedure:
To a flask containing the crude ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.094 g, 0.16 mmol), was added 1-Methanesulfonyl-piperazine (0.131 g, 0.800 mmol). The mixture was diluted with 1,4-dioxane (2 mL) and Hunig's base (0.168 mL, 0.960 mmol) was added. The mixture was attached to a reflux condensor and was heated to 100° C. for 24 h then was cooled to rt, concentrated under reduced pressure, and adsorbed to silica gel. The mixture was purified by flash chromatography using a 12 g silica gel column and a 20-80% ethyl acetate in hexanes gradient. The fractions containing the product were combined and concentrated under reduced pressure to give ethyl 4-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13 aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-(4-(methylsulfonyl)piperazin-1-yl)ethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate as an off-white solid. LCMS: m/e 752.8 (M+H)+, 2.22 min (method 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:21])[C:15](=[N+]=[N-])[C:16](=[O:18])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][OH:23]>CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:21])[CH:15]([O:23][CH3:22])[C:16](=[O:18])[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(=O)C(=[N+]=[N-])C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Rh]
Solvent: CC(=O)O
Product: COC(C(C)=O)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 65 °C

Procedure:
A solution of 532 mg (1.8 mmol) of 1-(tert-butoxycarbonyl)-4-(2-diazo-1,3-dioxo-but-1-yl)piperidine in 5 mL of MeOH was treated with 25 mg (0.056 mmol) of rhodium (II) acetate dimer. The reaction was slowly warmed to 65° C. over 2 hours. Upon cooling, volatiles were removed under reduced pressure. The residue was partitioned between 100 mL of EtOAc and 100 mL of H2O. After separating phases, the organic layer was washed with 100 mL of brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 19:1 v/v hexanes/acetone as the eluant to afford the title compound as a yellow oil: RF: 0.39 (4:1 v/v hexanes/acetone); 1H-NMR (500 MHz) δ 1.45, 1.47 (2s, 9H), 1.68–1.71 (m, 3H), 2.19, 2.22 (2s, 3H), 2.78–2.89 (m, 2H), 3.44, 3.58 (2s, 3H), 4.03–4.3 (m, 2H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]=[N:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:17][NH:18][CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: C(=NCCc1ccccc1)c1ccccc1OCCCN1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: c1ccc(CCNCc2ccccc2OCCCN2CCOCC2)cc1

Procedure:
N-[[2-[3-(4-Morpholinyl)propoxy]phenyl]methylene]-benzeneethanamine (17g) is reduced with 5.4g of sodium borohydride in 85 ml of methanol following the procedure described in Example 1B to yield 12.8g of product as an oil, boiling point 219°-223° C at 0.1-0.2 mm of Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=3[CH3:26])[CH:12]=[CH:11][C:10]=2[O:27]C)=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[C:21]([CH3:22])=[CH:20][C:19]([N+:23]([O-:25])=[O:24])=[CH:18][C:17]=3[CH3:26])[CH:12]=[CH:11][C:10]=2[OH:27])=[CH:6][CH:7]=1
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1Cc1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(O)c(Cc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.7 g (4.5 mmol) of 1-[(4-fluorophenyl)methyl]-2-methoxy-5-(2,6-dimethyl-4-nitrophenoxy)benzene in 100 ml methylene chloride is added 13.5 ml (13.5 mmol) 1.0N boron tribromide in methylene chloride. The solution is stirred overnight at room temperature, poured into ice water (300 ml) and stirred 1 hour. The organic layer is separated, washed with water, dried (CaSO4) and evaporated. Flash chromatography of the residue gives 2-[(4-fluorophenyl)methyl]-4-(2,6-dimethyl-4-nitrophenoxy)phenol, m.p. 127°-132°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])=[CH:34][CH:33]=3)[CH2:27][CH2:26]2)[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+].Cl.[OH-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][C:32]3[CH:33]=[CH:34][C:35]([CH:38]([OH:42])[CH:39]([CH3:40])[CH3:41])=[CH:36][CH:37]=3)[CH2:27][CH2:26]2)[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:19])=[O:20])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)C(=O)c1ccc(CC2CCN(CCCN(C(=O)C3CCN(S(C)(=O)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C(O)c1ccc(CC2CCN(CCCN(C(=O)C3CCN(S(C)(=O)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of the title compound of example 335 (318 mg, 0.50 mmol) in a mixture of methanol (5 mL) and THF (5 mL) was added sodium borohydride (38 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 16 hours before the addition of 1N hydrochloric acid (2 mL). After being stirred at room temperature for 30 minutes, 1N aqueous sodium hydroxide (4 mL) was added and the mixture was evaporated under reduced pressure. Water (15 mL) was added and extracted with dichloromethane (30 mL, 2×15 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. A mixture of ethanol and ethyl acetate was added to the residue, the resulting precipitate, was collected by filtration, washed with ethyl acetate and dried under reduced pressure to afford the title compound (280 mg, 0.44 mmol, yield 88%) as a white solid.
Reaction SMILES: C1C([N+]([O-])=[O:8])=CC=C(O)C=1.[CH:11]1([N:17]=[C:18]=[N:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>C(OCC)(=O)C>[C:18]([NH:17][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([NH:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)=[O:8]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCOC(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Temperature: 5 °C
Reaction time: 16 h

Procedure:
The above compound (8.2 g) and p-nitrophenol (3.3 g) are dissolved in 200 ml of ethyl acetate and cooled to 5° C. N,N'-Dicyclohexylcarbodiimide (5.0 g) is added portionwise and the reaction mixture is stirred at 5° C. for about 16 hours. The dicyclohexylurea is filtered off and the ethyl acetate filtrate is concentrated in vacuo for 1 hour. Diisopropyl ether (4 ml) and ethyl acetate (4 ml) are added to the pot residue. A second crop of dicyclohexylurea is obtained. The filtrate is concentrated in vacuo to yield 8.7 g of crude active ester.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:7][C:6]=1[CH2:20][N:21](CC1C=CC(OC)=CC=1OC)[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])C.CCC([O-])(C)C.[K+].S(Cl)(Cl)=O>C1COCC1.C(Cl)Cl>[CH2:26]([O:25][C:23]([C:22]1[N:21]=[CH:20][C:6]2[C:5]([C:4]=1[OH:3])=[CH:10][CH:9]=[C:8]([O:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[Cl:19])[CH:7]=2)=[O:24])[CH3:27]
Reactant: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1cc(Oc2cc(F)ccc2Cl)ccc1C(=O)OCC
Agent: CCC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.6 %

Procedure:
To an ice-water bath cooled solution of 4-(2-chloro-5-fluoro-phenoxy)-2-{[(2,4-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}-benzoic acid ethyl ester (1.59 g) in THF (20 mL) was added a solution of potassium tert-pentoxide (2.83 mL, 1.7 M in toluene); the mixture was stirred for 2 h at rt after addition; then the mixture was quenched with 2 M HCl, diluted with EtOAc and water, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulphate, filtered off, concentrated to give the desired cyclized intermediate. This intermediate was then dissolved in DCM (20 mL) and treated with thionyl chloride (0.42 mL) overnight. Then concentrated, the residue was dissolved in EtOAc, washed with water, diluted NaCl solution, then dried over sodium sulphate, filtered, concentrated and the residue was column purified to give the desired product (530 mg). LC MS ESI: 362 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1)[NH2:6].[C:12](OC(=O)C)(=[O:14])[CH3:13].O>N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>[CH3:11][O:10][C:8]1[CH:7]=[C:5]([NH:6][C:12](=[O:14])[CH3:13])[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(N)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(NC(C)=O)cc(OC)c1

Procedure:
A solution of 15.3 g of 3,5-dimethoxyaniline and 57.5 ml of acetic anhydride in 40 ml of anhydrous pyridine is heated at reflux for 1 hour. The reaction mixture is then cooled and poured into 350 ml of water. The precipitate formed is suspended in 20% aqueous Na2CO3 solution and is then filtered off using a Buchner funnel, washed with water and dried under a phosphoric vacuum. A precipitate of 14.5 g of the expected product is obtained in the form of a white amorphous solid.
Reaction SMILES: [I:1]Cl.[CH2:3]([O:10][CH2:11][C@H:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH:21]=2)[NH:16][C:15]=1[Si](CC)(CC)CC)[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.CO.C1COCC1.F[B-](F)(F)F.[Ag+]>[CH2:3]([O:10][CH2:11][C@H:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH:21]=2)[NH:16][C:15]=1[I:1])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(C(C)(C)C(=O)OC)cc2c1[C@H](C)COCc1ccccc1
Reactant: ClI
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)c1cnc2[nH]c(I)c([C@H](C)COCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of iodine monochloride (2.83 g, 17.4 mmol) in MeOH (25 mL) was added over approximately 0.5 h via pressure equalizing addition funnel to a vigorously stirred mixture of methyl (S)-2-[3-(2-benzyloxy-1-methylethyl)-2-triethylsilyl-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoate (6.00 g, 13.4 mmol) and silver tetrafluoroborate (3.39 g, 17.4 mmol) in MeOH/THF (1:2; 75 mL) at 0° C. After an additional 0.5 h, the reaction was quenched with 1M Na2S2O3, warmed to room temperature and filtered through celite® washing copiously with ethyl acetate. The filtrate was concentrated under reduced pressure, poured into 1M Na2S2O3 and extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes as eluent) to give the title compound as a colourless solid (5.54 g, 84%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])[C:5]([Cl:21])=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:36]=[CH:35][C:26]2[N:27]([CH2:33][CH3:34])[C:28](=[O:32])[CH2:29][CH2:30][CH2:31][C:25]=2[C:24]=1[O:37][CH3:38].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)([O-])[O-]>C(O)(C)C>[Cl:21][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]([CH3:20])[S:16]([CH3:19])(=[O:18])=[O:17])=[N:7][C:2]([NH:22][C:23]2[CH:36]=[CH:35][C:26]3[N:27]([CH2:33][CH3:34])[C:28](=[O:32])[CH2:29][CH2:30][CH2:31][C:25]=3[C:24]=2[O:37][CH3:38])=[N:3][CH:4]=1
Reactant: CCN1C(=O)CCCc2c1ccc(N)c2OC
Reactant: CN([C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)S(C)(=O)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Product: CCN1C(=O)CCCc2c1ccc(Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3N(C)S(C)(=O)=O)n1)c2OC
Yield: 27.2 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-N-methyl-methanesulfonamide (79 mg, 0.22 mmol), 7-Amino-1-ethyl-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (52 mg, 0.22 mmol), and 10-Camphorsulfonic acid (80 mg, 0.34 mmol) in Isopropyl alcohol (3 mL) and was heated in a microwave vial for 2 h at 120° C. Upon cooling, the mixture was treated with MP-Carbonate (2.69 mmol/g loading; 0.29 g, 0.78 mmol) for 1 h, was filtered and was concentrated in vacuo. Chromatography (ISCO, 2×12 g silica gel, 0-80% EtOAc:Hex) afforded N-{(1R,2R)-2-[5-Chloro-2-(1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-N-methyl-methanesulfonamide as a white foam (33 mg, 27%). LCMS: 551 (M+H), 1H-NMR (CDCl3): 8.35 (d, 1H, J=8.9 Hz), 7.94 (s, 1H), 7.35 (s, 1H), 6.96 (d, 1H, J=8.9 Hz), 5.72 (d, 1H, J=7.4 Hz), 4.06 (m, 1H), 3.82 (m, 4H), 3.5 (br s, 1H), 3.0 (br s, 1H), 2.85 (s, 3H), 2.78 (s, 3H), 2.47 (m, 1H), 2.29 (m, 2H), 1.84 (m, 3H), 1.71 (m, 1H), 1.25-1.5 (m, 6H), 1.13 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([O:7][CH2:8][CH3:9])=[CH:5][CH3:6])[CH3:2].[C:10]([NH:13][CH:14]=[C:15]([C:20](=[O:22])[CH3:21])[C:16]([O:18][CH3:19])=[O:17])(=[O:12])[CH3:11]>C1(C)C=CC=CC=1>[C:10]([NH:13][C@@H:14]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:20]([CH3:21])[O:22][C:4]([O:7][CH2:8][CH3:9])([O:3][CH2:1][CH3:2])[C@H:5]1[CH3:6])(=[O:12])[CH3:11]
Reactant: CC=C(OCC)OCC
Reactant: COC(=O)C(=CNC(C)=O)C(C)=O
Solvent: Cc1ccccc1
Product: CCOC1(OCC)OC(C)=C(C(=O)OC)[C@@H](NC(C)=O)[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1,1-Diethoxyprop-1-ene (1.0 ml) was added to a solution of methyl 2-acetylaminomethylene-3-oxobutanoate (1.0 g) and tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octandionato)ytterbium (0.05 g) in toluene (3.0 ml) at 20° C. After stirring for 2 hr at ambient temperature, the reaction mixture was filtered to give methyl trans-4-acetylamino-2,2-diethoxy-3,6-dimethyl-3,4-dihydro-2H-pyran-5-carboxylate (1.05 g), m.p. 153°-4° C.