Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[Se:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)([CH3:3])[CH3:2].[Li]CCCC.[CH:28](N1CCOCC1)=[O:29].Cl>C(OCC)C.O>[CH:20]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:17]([CH3:19])[CH3:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[Se:13][C:14]([CH:28]=[O:29])=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)([CH3:22])[CH3:21]
Reactant: O=CN1CCOCC1
Reactant: CC(C)[Si](Oc1ccc(-c2ccc[se]2)cc1)(C(C)C)C(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: CC(C)[Si](Oc1ccc(-c2ccc(C=O)[se]2)cc1)(C(C)C)C(C)C
Temperature: -70 °C
Reaction time: 1 h

Procedure:
11.0 g (27.9 mmol) of triisopropyl-(4-selenophen-2-ylphenoxy)silane are initially introduced in 200 ml of diethyl ether, and 20 ml (31.8 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 30 min and subsequently cooled to −70° C. 15.0 ml (0.15 mol) of N-formylmorpholine in 50 ml of diethyl ether are added, and the mixture is warmed to RT and stirred for 1 h. The mixture is added to water, and 2 N hydrochloric acid is added. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, toluene). 5-(4-Triisopropylsilanyloxyphenyl)selenophene-2-carbaldehyde is obtained as a red solid.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:9])([CH2:7][CH3:8])[C:4]([OH:6])=[O:5].O.[CH2:11](O)[CH3:12]>>[CH2:11]([O:5][C:4](=[O:6])[C:3]([CH3:9])([CH3:2])[CH2:7][CH3:8])[CH3:12]
Reactant: CCC(C)(C)C(=O)O
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCOC(=O)C(C)(C)CC
Temperature: 25 °C

Procedure:
Add 0.2 mL of concentrated hydrochloric acid to 2,2-dimethyl-butanoic acid (5.0 g, 43.0 mmol) in ethanol (43 mL) and heat to reflux for 5 hours. Cool to room temperature. Pour the reaction into water and extract with diethyl ether. Wash the combined organics with saturated aqueous sodium bicarbonate and water, dry over magnesium sulfate, filter, and concentrate under reduced pressure to afford the title compound which was used without further purification (4.0 g, 64.4%): 1H NMR (CDCl3) δ 0.82 (t, 3H, 1.14 (s, 3H), 1.23 (t, 3H), 1.55 (q, 2H), 4.1 (q, 2H).
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1.[CH3:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH2:25][S:26][CH2:27][CH2:28][NH2:29]>>[CH3:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH2:25][S:26][CH2:27][CH2:28][NH:29][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1
Reactant: Cc1[nH]cnc1CSCCN
Reactant: COc1cccc(Cc2nnc(SC)[nH]c2=O)c1
Product: COc1cccc(Cc2nnc(NCCSCc3nc[nH]c3C)[nH]c2=O)c1
Reaction time: 0.08 h
Yield: 41.4 %

Procedure:
3-Methylthio-6-(3-methoxybenzyl)-1,2,4-triazin-5-one (1.07 g) and 2-(5-methyl-4-imidazolylmethylthio)ethylamine (0.77 g) were heated together on an oil bath (160°-70°) for 3/4 hour. The solidified mass was broken up under methanol (ea 15 ml) and boiled for 5 minutes. After cooling the white solid was filtered off and recrystallised from dimethylformamide to give the title compound as a colourless solid (0.65 g) m.p. 203°-4°.
Reaction SMILES: CN([CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[NH:7][CH:6]=1)C.[C:17](#[N:19])C.CI.[C-]#N.[Na+]>O>[N+:14]([C:12]1[CH:13]=[C:8]2[C:9]([C:5]([CH2:4][C:17]#[N:19])=[CH:6][NH:7]2)=[CH:10][CH:11]=1)([O-:16])=[O:15]
Reactant: CC#N
Reactant: CN(C)Cc1c[nH]c2cc([N+](=O)[O-])ccc12
Agent: [C-]#N
Agent: [Na+]
Solvent: CI
Solvent: O
Product: N#CCc1c[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To a stirred solution of 44.27 g (0.204 mol) of 6-nitrogramine (12) [Jackson B. Hester J. Org. Chem., 29: 1158 (1964)] in 450 ml of acetonitrile 44.59 g (0.31 mol) of methyl iodide was added at 0-5° C. over a period of an hour. The reaction mixture was stirred at room temperature for three hours, then a solution of 26.6 g (0.543 mol) of sodium cyanide in 225 ml of water added at once. The reaction mixture was heated at 32° C. overnight, cooled to room temperature and the product extracted 3 times with a total of 800 ml of ethyl acetate and 300 ml of water. The combined extracts were washed with water, 1N-HCl solution, a saturated sodium bicarbonate solution, dried on MgSO4 and the solvent evaporated in vacuo. The orange-brown residue (41.3 g) was dissolved in 200 ml of warm ethyl acetate and passed through a small pad of silica gel to produce 28.9 g (70.4%) of (6-nitro-1H-indolyl-3-yl)-acetonitrile (13) as a yellow solid after evaporation of the solvent.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[NH2:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22]>>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([NH:19][CH:20]([CH2:23][OH:24])[CH2:21][OH:22])=[O:8]
Reactant: NC(CO)CO
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NC(CO)CO)c1I
Yield: 95 %

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride was reacted with serinol according to the conditions in Example 24 g. The product was isolated in 95% yield.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-:20])=[O:19])[C:9]1=[O:21])[C:4]([O:6][CH3:7])=[O:5].C(Cl)Cl.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>>[Si:30]([O:1][CH2:2][C@@H:3]([N:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:18]([O-:20])=[O:19])[C:9]1=[O:21])[C:4]([O:6][CH3:7])=[O:5])([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: COC(=O)[C@@H](CO)n1ccc2c([N+](=O)[O-])cccc2c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A round bottom flask was charged with (R)-methyl 3-hydroxy-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)propanoate (4 g, 0.01 mol), methylene chloride (40 mL, 0.5 mol) and 1H-imidazole (1.6 g, 0.023 mol) and tert-butyldimethylsilyl chloride (2.3 g, 0.015 mol) were added at 0° C. and the reaction allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with water and extracted with methylene chloride. Solvent was removed under reduced pressure to recover the pure product as an orange solid. MS m/z=407.5 (M+H).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].Br[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Cl>C1COCC1.C(O)(C)C>[CH3:2][N:3]([CH3:4])[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10]
Reactant: CNC
Reactant: COC(=O)/C=C/CBr
Agent: Cl
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=O)/C=C/CN(C)C
Yield: 52.2 %

Procedure:
Trithylamine (37.5 ml, 0.27 mol, 2.8 equiv) was dissolved in THF (100 ml), and dimethylamine hydrochloride (9.3 g, 0.114 mol, 1.2 equiv) was added. Methyl 4-bromocrotonate (20 g, 85% purity, 0.095 mol, 1.00 equiv) in 100 ml of THF was added drop-wise to the resulting solution at room temperature while stirring. The reaction mixture was allowed to react overnight at room temperature. The reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to give yellow oil. The oil was dissolved in 50 ml of isopropanol, and hydrogen chloride was added until pH 2.0 was reached. The white solid was formed and filtered and dried to give 7.1 g product. MS (ESI) m/z: 563 (M+1).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]2[NH:16][C:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][N:13]=2)[C:9]([OH:25])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:26][S:27]([OH:29])=[O:28].[Na].O>CN1CCCC1=O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:15]2[NH:16][C:12]([C:10]3[C:9]([OH:25])=[C:8]4[C:3]([CH:4]=[CH:5][CH:6]=[N:7]4)=[C:2]([S:27]([CH3:26])(=[O:29])=[O:28])[N:11]=3)=[N:13][N:14]=2)=[CH:19][CH:20]=1
Reactant: CS(=O)O
Reactant: Oc1c(-c2nnc(Cc3ccc(F)cc3)[nH]2)nc(Br)c2cccnc12
Agent: [Na]
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)c1nc(-c2nnc(Cc3ccc(F)cc3)[nH]2)c(O)c2ncccc12
Yield: 37.6 %

Procedure:
A solution of 5-bromo-7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-1,6-naphthyridin-8-ol (9 mg, 0.02 mmol) and sodium methanesulfinic acid (100 mg) in 1-methylpyrrolidin-2-one (2 mL) was heated at 150° C. for 3 hours. The resultant solution was cooled to room temperature and water was added. The solids which formed were removed by filtration and further purified by preparative HPLC to give 7-[5-(4-fluorobenzyl)-4H-1,2,4-triazol-3-yl]-5-(methylsulfonyl)-1,6-naphthyridin-8-ol (3 mg, 33%) as a white solid. 1H NMR (CDCl3): δ 9.32 (d, J=8.4 Hz, 1 H), 9.25(d, J=4.4 Hz, 1 H), 7.75 (dd, J=8.4, 4.4 Hz, 1 H), 7.36 (dd, J=8.4, 5.6 Hz, 2 H), 7.03 (t, J=8.4 Hz, 2 H). 4.24 (s, 2 H), 3.42 (s, 3 H); MS m/z 400 (M+1).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.CN(/[CH:12]=[N:13]/[C:14]1[C:23]([C:24]([O:26]C)=O)=[CH:22][C:21]2[C:16](=[CH:17][C:18]([O:30][CH3:31])=[C:19]([O:28][CH3:29])[CH:20]=2)[N:15]=1)C.C(O)(=O)C>O1CCCC1>[CH3:29][O:28][C:19]1[C:18]([O:30][CH3:31])=[CH:17][C:16]2=[N:15][C:14]3[NH:13][CH:12]=[C:2]([C:1]#[N:3])[C:24](=[O:26])[C:23]=3[CH:22]=[C:21]2[CH:20]=1
Reactant: CC#N
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2nc1/N=C/N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc2cc3c(=O)c(C#N)c[nH]c3nc2cc1OC
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 43.8 %

Procedure:
Acetonitrile (1.3 mL, 24.9 mmol) is added to a −78° C. solution of 9.0 mL of 2.5 M n-butyllithium (22.5 mmol) in 40 mL of tetrahydrofuran. After stirring at −78° C. for 15 min, a solution of 2.86 g (9.02 mmol) of methyl 2-{[(E)-(dimethylamino)methylidene]amino}-6,7-dimethoxy-3-quinolinecarboxylate in 100 mL of tetrahydrofuran is added dropwise over 30 minutes. After stirring at −78° C. for 30 minutes, the reaction mixture is allowed to warm to room temperature and then stirred at room temperature for 1 hour. The reaction mixture is cooled to −78° C. and 3.0 mL of acetic acid is added. The mixture is then stirred at room temperature for 40 min. The solids are collected by filtration washing with water, methanol and ethyl acetate to provide 1.11 g (44%) of 7.8-dimethoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carbonitrile as a light yellow solid, mp>300° C.
Reaction SMILES: C([Li])(CC)C.[CH3:6][O:7][C:8]1[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=1[C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11].CN(C)CCN(C)C.[CH:29](=[O:32])[CH2:30]C>O1CCCC1.C(OCC)C>[OH:32][CH:29]([C:17]1[C:9]([C:10]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[O:11])=[C:8]([O:7][CH3:6])[CH:20]=[CH:19][CH:18]=1)[CH3:30]
Reactant: CCC=O
Reactant: CCN(CC)C(=O)c1ccccc1OC
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCN(CC)C(=O)c1c(OC)cccc1C(C)O
Temperature: -78 °C

Procedure:
13.7 ml of sec-butyllithium (1.4M in cyclohexane/isopentane) are added dropwise to a solution of 5.2 g of 2-methoxy-N,N-diethyl-benzamide and 2.91 g of tetramethylethylenediamine in 50 ml of absolute tetrahydrofuran in such a manner that the temperature does not exceed -68° C. When the addition is complete, the reaction mixture is stirred at -78° C. for a further hour and then 2.5 ml of propionaldehyde are added. The reaction mixture is allowed to warm slowly to room temperature, is subsequently stirred for one hour and is diluted with 300 ml of diethyl ether. The organic phase is washed with 2N hydrochloric acid and then with saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated by evaporation to yield 6-(1-hydroxyethyl)-2-methoxy-N,N-diethyl-benzamide in the form of a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:38][O:39][C:40](=[O:46])[CH:41]([CH3:45])[CH2:42][CH2:43]Cl>CN(C=O)C>[CH3:38][O:39][C:40](=[O:46])[C@@H:41]([CH3:45])[CH2:42][CH2:43][O:29][C:26]1[CH:25]=[CH:24][C:23]([C:22]([N:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@H:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:13][CH:14]2[CH3:31])=[O:30])=[CH:28][CH:27]=1
Reactant: COC(=O)C(C)CCCl
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)CCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)CC2C)cc1
Reaction time: 8 h

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (230 mg, 0.531 mmol) was dissolved in DMF (5 mL) at room temperature. Cs2CO3 (433 mg, 1.33 mmol) was added followed by 4-chloro-2-methyl-butyric acid methyl ester (120 mg, 0.796 mmol) and the reaction was allowed to stir overnight. The mixture was partitioned between methylene chloride and water; the organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (1/1 hexanes/ethyl acetate—ethyl acetate gradient) to afford the product.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[N:9]1([CH2:14][C@@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([C:22]2[CH:27]=[CH:26][C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=2)=[O:21])[CH2:13][CH2:12][CH2:11][CH2:10]1>>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([C:25]2[CH:26]=[CH:27][C:22]([C:20]([N:16]3[CH2:17][CH2:18][CH2:19][C@H:15]3[CH2:14][N:9]3[CH2:10][CH2:11][CH2:12][CH2:13]3)=[O:21])=[CH:23][CH:24]=2)=[CH:3][CH:4]=1
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)OC1(C)C
Reactant: Nc1ccc(I)cn1
Product: Nc1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)cn1

Procedure:
The title compound is prepared starting with 5-iodo-pyridin-2-ylamine and (2-(S)-Pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone following a procedure significantly analogous to Procedure FF. MS (m/e): 351.2 (M+1)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[S:7][CH:8]=[C:9]([Br:11])[CH:10]=1)[OH:5].[F:12][C:13]([F:20])([F:19])[C:14](OCC)=[O:15]>C(Cl)Cl>[Br:11][C:9]1[CH:10]=[C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:14](=[O:15])[C:13]([F:20])([F:19])[F:12])[S:7][CH:8]=1
Reactant: NCCC(O)c1cc(Br)cs1
Reactant: CCOC(=O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCCC(O)c1cc(Br)cs1)C(F)(F)F

Procedure:
3-Amino-1-(4-bromothiophen-2-yl)propan-1-ol and ethyl trifluoroacetate (2.0 mL) were stirred in CH2Cl2 (10 mL) at room temperature overnight. Concentration under reduced pressure gave N-(3-(4-bromothiophen-2-yl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide which was used in the next step without additional purification. Yield (0.77 g, 28% in three steps); 1H NMR (400 MHz, DMSO-d6) δ 9.36 (br.s, 1H), 7.51 (d, J=1.5 Hz, 1H), 6.90-7.00 (m, 1H), 5.86 (d, J=5.0 Hz, 1H), 4.75-4.83 (m, 1H), 3.20-3.30 (m, 2H), 1.80-1.94 (m, 2H).
Reaction SMILES: [OH-].[Na+].[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:29]([O:31]C)=[O:30])=[CH:14][C:15]=3[N:16]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20][C:19]4[CH:25]=[CH:26][CH:27]=[CH:28][C:18]=4[C:17]=23)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl>CO.O1CCCC1>[CH:3]1([C:9]2[C:10]3[CH:11]=[CH:12][C:13]([C:29]([OH:31])=[O:30])=[CH:14][C:15]=3[N:16]3[CH2:22][CH:21]([CH2:23][OH:24])[CH2:20][C:19]4[CH:25]=[CH:26][CH:27]=[CH:28][C:18]=4[C:17]=23)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)Cc1ccccc1-3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)Cc1ccccc1-3
Temperature: 100 °C
Yield: 69.4 %

Procedure:
Sodium hydroxide (0.2 mL of 1 N, 0.2 mmol) was added to a solution of methyl (±)-13-cyclohexyl-6,7-dihydro-6-hydroxymethyl-5H-indolo[2,1-a][2]benzazepine-10-carboxylate (15.0 mg, 0.037 mmol) in methanol (0.5 mL) and tetrahydrofuran (0.5 mL) in a microwave vial. The vial was sealed and the contents heated at 100° C. for 10 min in a microwave apparatus. The solution was acidified with dilute hydrochloric acid to precipitate the crude acid. The solid was collected and purified on the Shimadzu preparative liquid chromatograph. The product containing fraction was concentrated on a Speed Vac® to leave the titled compound as a white solid (10.0 mg, 69%). ESI-MS m/z 390 (MH+); 1H NMR (500 MHz, MeOD) δ 1.19–1.34 (m, 1 H) 1.36–1.56 (m, 2 H) 1.63 (m, 1 H) 1.74–1.87 (m, 2 H) 1.91–2.21 (m, 5 H) 2.37–2.60 (m, 1 H) 2.74 (m, 1 H) 2.97 (m, 1 H) 3.36 (m, 1 H) 3.47–3.67 (m, 2 H) 4.59 (m, 1 H) 7.38–7.50 (m, 4 H) 7.72 (m, 1 H) 7.88 (m, 1 H) 8.18 (m, 1 H).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:40]=[CH:39][C:14]([CH2:15][NH:16][C:17]2[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:27])[F:26])[N:20]=[C:19]([NH:29][C:30]3[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=3)[CH:18]=2)=[CH:13][CH:12]=1.[C:41]([O:45][C:46](=[O:54])[NH:47][CH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][NH2:51])([CH3:44])([CH3:43])[CH3:42].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C1COCC1>[OH:10][C:11]1[CH:40]=[CH:39][C:14]([CH2:15][NH:16][C:17]2[N:22]=[C:21]([O:23][CH2:24][C:25]([F:28])([F:26])[F:27])[N:20]=[C:19]([NH:29][C:30]3[CH:38]=[CH:37][C:33]([C:34]([NH:51][CH2:50][C:49]([CH3:53])([CH3:52])[CH2:48][NH:47][C:46](=[O:54])[O:45][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:35])=[CH:32][N:31]=3)[CH:18]=2)=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)nc1
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2cc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
iPr2NEt (0.5 mL) was added into a solution of 6-((6-((4-hydroxybenzyl)amino)-2-(2,2,2-trifluoroethoxyl)pyrimidin-4-yl)amino)nicotinic acid (340 mg), tert-butyl(3-amino-2,2-dimethylpropyl)carbamate (316 mg) and TBTU (501 mg) in THF (10 mL). The reaction was stirred at room temperature for 16 hours before being quenched by water (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum to give the crude product, tert-butyl 3-(6-(6-(4-hydroxybenzylamino)-2-(2,2,2-trifluoroethoxyl)pyrimidin-4-ylamino)nicotinamido)-2,2-dimethylpropylcarbamate, which was purified by silica gel chromatography.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[C:19]([O:23][C:24]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:36][O:37][CH3:38])[CH:32]=2)[CH:27]1[C:39](O)=[O:40])=[O:25])([CH3:22])([CH3:21])[CH3:20].[F:42][C:43]1[CH:44]=[C:45]([NH2:54])[CH:46]=[C:47]2[C:51]=1[C:50]([CH3:53])([CH3:52])[CH2:49][CH2:48]2.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[F:42][C:43]1[CH:44]=[C:45]([NH:54][C:39]([CH:27]2[C:28]3[C:33](=[CH:32][C:31]([CH2:36][O:37][CH3:38])=[CH:30][CH:29]=3)[CH2:34][CH2:35][N:26]2[C:24]([O:23][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:25])=[O:40])[CH:46]=[C:47]2[C:51]=1[C:50]([CH3:52])([CH3:53])[CH2:49][CH2:48]2
Reactant: COCc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)O
Reactant: CC1(C)CCc2cc(N)cc(F)c21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COCc1ccc2c(c1)CCN(C(=O)OC(C)(C)C)C2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 60 °C
Reaction time: 48 h
Yield: 71.1 %

Procedure:
T3P (8.24 mL, 14.00 mmol) was added to a mixture of 2-(tert-butoxycarbonyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (1.5 g, 4.67 mmol), 7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-amine (0.837 g, 4.67 mmol), DIEA (4.08 mL, 23.34 mmol), DMAP (0.570 g, 4.67 mmol) and ethyl acetate (5 mL) at 60° C., and the mixture was stirred at 60° C. for 2 days. To the reaction mixture was added ethyl acetate, and the mixture was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 32→40% ethyl acetate/hexane) to give tert-butyl 1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-3,4-dihydroisoquinoline-2 (1H)-carboxylate (1.600 g, 3.32 mmol, 71.0%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:4][CH:3]=1.[CH2:19]([CH:21]1[O:23][CH2:22]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[O:23]1[CH2:22][CH:21]1[CH2:19][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH2:13][CH2:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: O=C1CCC(c2ccc(O)c3ccccc23)=NN1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=C1CCC(c2ccc(OCC3CO3)c3ccccc23)=NN1
Yield: 71.7 %

Procedure:
A mixture of 6-(4-hydroxy-1-naphthyl)-4,5-dihydro-3(2H)-pyridazinone (0.5 g, 0.002 mole), epichlorohydrin (2g, 0.02 mole), and piperidine (0.02 g) was heated on a steam bath for 1.5 hours. Evaporation under reduced pressure gave an oil which was dissolved in dichloromethane and shaken with dilute sodium hydroxide (5 ml). The organic phase was washed with water, dried and evaporated to an oil which with ethanol-ether gave crystalline 6-[4-(2,3-epoxypropoxy)-1-naphthyl]-4,5-dihydro-3(2H)-pyridazinone (0.425 g, 69%, m.p. 151°-155°C). Crystallisation from ethanol gave the pure epoxide, m.p. 153.5°-155.5°C.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([S:7][CH2:8][C:9]2[C:19]3[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14][C:13]=3[CH:12]=[CH:11][C:10]=2[Cl:27])=[N:4][N:3]=1.[CH:28]1([CH:31]=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C([O-])(O)=O.[Na+]>ClCCCl>[C:23]([O:22][C:20]([N:16]1[CH2:17][CH2:18][C:19]2[C:9]([CH2:8][S:7][C:5]3[S:6][C:2]([NH:1][CH2:31][CH:28]4[CH2:30][CH2:29]4)=[N:3][N:4]=3)=[C:10]([Cl:27])[CH:11]=[CH:12][C:13]=2[CH2:14][CH2:15]1)=[O:21])([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3nnc(N)s3)c2CC1
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3nnc(NCC4CC4)s3)c2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a solution of 6-(5-amino-[1,3,4]thiadiazol-2-ylthiomethyl)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.252 g, 0.59 mmol) in anhydrous DCE (1 mL), add a solution of cyclopropane carboxaldehyde (0.083 g, 1.2 mmol) in anhydrous DCE (1 mL) at room temperature. Add sodium tris(acetoxy)borohydride (0.38 g, 1.8 mmol) and a solution of glacial acetic acid (0.20 mL, 3.5 mmol) in anhydrous DCE (1 mL) to the reaction mixture at room temperature. Heat at reflux overnight, cool the reaction mixture to room temperature and add saturated aqueous NaHCO3 (25 mL) to the mixture. After stirring at room temperature for 1 h, extract the two-phase mixture with DCM (2×50 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 95:5 hexane/EtOAc over 33 min; 95:5 to 50:50 hexane/EtOAc over 33 min; 50:50 to 0:100 hexane/EtOAc over 30 min; 35 mL/min) to afford the desired intermediate (0.087 g, 31%). MS (ES+) m/z: 481.2 (M+H)+.