Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[C:14](N1C=CN=C1)([N:16]1C=CN=C1)=[S:15].N>ClCCl.CO>[CH2:1]([O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:11][C:14]([NH2:16])=[S:15])=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CCCCCOc1ccc(N)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCCCCOc1ccc(NC(N)=S)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Pentyloxyaniline (370 ml, 2 mmol) in dichloromethane (3 ml) is added to a solution of 1,1′-thiocarbonyldiimidazole (537 mg, 3 mmol) in dichloromethane (5 ml) at room temperature and the mixture is stirred at room temperature for 30 minutes. 2 N Ammonia in methanol (30 ml) is added to the solution, and the solution is stirred for additional 1 hour at room temperature. The solvent is removed, and the product extracted with ethylacetate and H2O. The crude product is recrystallized from dichloromethane and hexane to afford the thiourea as a white solid. 1H NMR (300 Hz, CDCl3) δ 7.92 (s, 1H, NH), 7.15 (d, J=8.4 Hz, 2H, Aryl H), 6.92 (d, J=8.4 Hz, 2H, Aryl H), 6.0 (br s, 2H, NH2), 3.95 (t, J=6.6 Hz, 2H, CH2), 1.79 (m, 2H, CH2), 1.44-1.38 (m, 4H, (CH2)2), 0.94 (t, J=7.2 Hz, 3H, CH3). MS (APCI) m/z 239 [M+H]±.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:9]=1)[C:6]#[CH:7].I[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[O:31][C:32]([CH3:35])=[N:33][N:34]=2)[CH:25]=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:1][O:2][C:3](=[O:22])[CH2:4][CH:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:9]=1)[C:6]#[C:7][C:28]1[CH:29]=[CH:24][CH:25]=[C:26]([C:30]2[O:31][C:32]([CH3:35])=[N:33][N:34]=2)[CH:27]=1
Reactant: C#CC(CC(=O)OC)c1ccc(OC)c(OC2CCCC2)c1
Reactant: Cc1nnc(-c2cccc(I)c2)o1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)CC(C#Cc1cccc(-c2nnc(C)o2)c1)c1ccc(OC)c(OC2CCCC2)c1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
To a solution of the compound from Example 7 (0.15 g, 0.5 mmol) and 1-iodo-3-(5-methyl-[1,3,4]oxadiazol-2-yl)benzene (0.14 g, 0.5 mmol) in triethylamine (5 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0) and trace copper(I) iodide. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. Purification by flash chromatography (silica gel, 50% EtOAc/hexane) provided the titled compound as a yellow oil (0.19 g, 80%). Anal. (C27H28N2O5· 0·375 H2O) calcd: C, 69.40; H, 6.20; N, 6.00. found: C, 69.23; H, 6.13;N,5.69.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:12][N:11]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=O)[CH:16]=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:7]=2[N:8]=1.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1>>[CH3:29][C:25]1[CH:24]=[C:23]([NH:22][C:19]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([N:11]3[CH2:10][CH2:9][C:7]4[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[CH2:12]3)[N:18]=2)=[O:21])[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccc(N)c1
Reactant: CSc1ncc2c(n1)CCN(c1cccc(C(=O)O)n1)C2
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)Nc3cccc(C)c3)n1)C2

Procedure:
In a manner similar to that described in Example 108, a mixture of 6-[2-(methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]pyridine-2-carboxylic acid and m-toluidine were converted to the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:22][C@@:21]2([CH3:23])[C@@H:13]([CH2:14][CH2:15][C@:16]2([OH:24])[C:17](=[O:20])[CH2:18][OH:19])[C@H:12]2[C@H:3]1[C@:4]1([CH3:26])[C:9]([CH2:10][CH2:11]2)=[CH:8][C:7](=[O:25])[CH:6]=[CH:5]1.[CH2:27]([O:29][CH2:30][C:31](Cl)=[O:32])[CH3:28]>>[CH2:27]([O:29][CH2:30][C:31]([O:19][CH2:18][C:17](=[O:20])[C@:16]1([OH:24])[C@:21]2([CH3:23])[C@H:13]([C@H:12]3[C@H:3]([C@@H:2]([OH:1])[CH2:22]2)[C@:4]2([CH3:26])[C:9](=[CH:8][C:7](=[O:25])[CH:6]=[CH:5]2)[CH2:10][CH2:11]3)[CH2:14][CH2:15]1)=[O:32])[CH3:28]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CO
Reactant: CCOCC(=O)Cl
Product: CCOCC(=O)OCC(=O)[C@@]1(O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
10.0 g of 11β,17,21-trihydroxy-1,4-pregnadiene-3,20-dione is reacted analogously to Example 2(a) with ethoxyacetic acid chloride, worked up, and purified, thus isolating 10.4 g of 21-ethoxyacetoxy-11β,17-dihydroxy-1,4-pregnadiene-3,20-dione.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>C1COCC1>[N:32]1([C:29]2[CH:28]=[CH:27][C:26]([NH:25][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])[CH:10]=4)[NH:5][C:4]3=[O:24])=[CH:31][CH:30]=2)[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)C(=CNc2ccc(N4CCOCC4)cc2)C(=O)N3)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 68.9 %

Procedure:
A small screw cap test tube was charged with N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (prepared below, 52 mg, 0.161 mmol) and THF (2 mL). To the resulting solution was added N-(4-aminophenyl)morpholine (43 mg, 0.242 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 69% (54 mg, 0.111 mmol) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:5]([C:6]([O:8]C)=[O:7])=[C:4]([NH:13]C(OC(C)(C)C)=O)[CH:3]=1>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[CH:11]=[C:10]([F:12])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1c(F)cc(Cl)cc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(Cl)cc(F)c1C(=O)O
Reaction time: 72 h
Yield: 69 %

Procedure:
A solution of methyl 4-chloro-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-6-fluorobenzoate in methylene chloride (150 mL) and trifluoroacetic acid (25 mL) was stirred for six hours. All solvents were removed under reduced pressure on a rotoevaporator, and the resulting residue was dissolved in THF (150 mL) and water (100 mL) and lithium hydroxide (2.5 g) were added. The biphasic mixture was stirred rapidly for three days, at which time no starting materials remain by TLC. The organic layer was washed with 2.0N sodium hydroxide and then the organic layers are discarded. The aqueous layer was adjusted to pH=2 by careful addition of 1.0N hydrochloric acid and then extracted with ethyl acetate. The combined ethyl acetate washes were dried over sodium sulfate, and volatiles were removed under reduced pressure to afford 2-amino-4-chloro-6-fluorobenzoic acid as a white solid (3.3 g, 69% yield) of sufficient purity for use in the next transformation. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.38 (dd, J=11.17, 1.47 Hz, 1 H), 6.60 (s, 1 H).
Reaction SMILES: N1C=CN=C1.[CH3:6][C:7]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH2:14]([C:16]1[O:17][C:18]([CH2:21][CH2:22][OH:23])=[CH:19][CH:20]=1)[CH3:15]>CN(C=O)C.C(OCC)C>[C:7]([Si:10]([O:23][CH2:22][CH2:21][C:18]1[O:17][C:16]([CH2:14][CH3:15])=[CH:20][CH:19]=1)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:6]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1ccc(CCO)o1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCc1ccc(CCO[Si](C)(C)C(C)(C)C)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80 %

Procedure:
Imidazole (255 mg, 3.75 mmol) and TBSCl (414 mg, 2.75 mmol) were added to the solution of 245A (350 mg, 2.5 mmol) in DMF (4 mL). The mixture was stirred at rt for 15 hr and then 100 mg (0.66 mmol) of additional TBSCl was added to drive the reaction to completion. After stirring for an additional hour, the reaction mixture was diluted with diethylether (100 mL) and washed with water (20 mL), 1 N HCl (20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give 509 mg of compound 434A (80.3%) as a yellow oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:4]=[C:5]([NH:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=[CH:11][N:10]=2)[S:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].O>CN(C=O)C>[CH3:2][C:3]1[N:4]=[C:5]([NH:8][C:9]2[C:14]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=3)[O:23][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:13][CH:12]=[CH:11][N:10]=2)[S:6][CH:7]=1
Reactant: Cc1csc(Nc2ncccc2OCc2cccc(O)c2)n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)OC(C)(C)C)c2)n1
Reaction time: 3 h
Yield: 55.4 %

Procedure:
3-((2-(4-Methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenol (prepared according to Example 22; 900 mg, 2.87 mmol), potassium carbonate (992 mg, 7.18 mmol), and tert-butyl 2-bromoacetate (0.424 mL, 2.87 mmol) were added to a 100 mL round bottom flask and dissolved in DMF (10 mL). The reaction mixture was stirred for 3 hours, then water (90 mL) was added and the reaction mixture was stirred at room temperature for 1 hour. The resultant solids were filtered and purified over silica gel (20% ethyl acetate in hexanes) to afford tert-butyl 2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetate (680 mg, 55.4% yield) as a white foam. 1H NMR (CDCl3) δ 8.60 (bs, 1H), 7.94 (dd, 1H), 7.32 (t, 1H), 7.07 (dd, 1H), 7.03 (m, 1H), 6.95 (m, 1H), 6.89 (dd, 1H), 6.80 (dd, 1H), 6.39 (q, 1H), 5.08 (s, 2H), 4.53 (s, 2H), 2.33 (s, 3H), 1.48 (s, 9H). Mass spectrum (apci) m/z=372 (100), 428 (20).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=O.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH:9]=[N:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1
Reactant: CN(C)CCCOc1ccccc1C=O
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCCOc1ccccc1C=Nc1ccccc1
Yield: 45.4 %

Procedure:
A solution of 32.5 g (0.156 mole) of 2-(3-dimethylaminopropoxy)benzaldehyde and 14.6 g (0.157 mole) of aniline in 150 ml of toluene is refluxed for 9 hours. Water which is formed very slowly is collected in a Dean-Stark trap. The bulk of solvent is removed on a rotary evaporator and the oily residue is fractionated to give 20.0 g of product; boiling point 165°-170° C./0.2 mm of Hg.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])=[N:4][N:3]=[N:2]1.[CH2:14]=[C:15]([CH3:17])[CH3:16].CS(O)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:15]([N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])=[N:4]1)([CH3:17])([CH3:16])[CH3:14]
Reactant: C=C(C)C
Reactant: O=Cc1cccc(-c2nnn[nH]2)c1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)n1nnc(-c2cccc(C=O)c2)n1

Procedure:
In an autoclave, 3.2 g (18.4 mmol) of 3-(tetrazol-5-yl)-benzaldehyde (see Step 59.1) in 22 ml of toluene are heated at 110° C. for 1.5 hours with ≈1.5 g of isobutene and 0.216 ml of methanesulfonic acid. When cold the reaction mixture is diluted with 200 ml of ethyl acetate, washed four times with water and once with brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/ethyl acetate=3:1) and crystallization from diethyl ether/hexane (−15° C.) yield 3-(2-tert-butyl-tetrazol-5-yl)-benzaldehyde; TLC: Rf=0.41 (hexane/ethyl acetate=3:1); FAB-MS: (M+H)+=231.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=[C:3]([N:13]([CH2:17][CH2:18][Cl:19])[CH2:14][CH2:15][Cl:16])[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:26](OC(=O)C)(=[O:28])[CH3:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O.O1CCOCC1>[CH3:27][C:26]([NH:12][CH:8]([C:9]([OH:11])=[O:10])[CH2:7][C:6]1[CH:5]=[CH:4][C:3]([N:13]([CH2:14][CH2:15][Cl:16])[CH2:17][CH2:18][Cl:19])=[CH:2][CH:1]=1)=[O:28]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](Cc1ccc(N(CCCl)CCCl)cc1)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NC(Cc1ccc(N(CCCl)CCCl)cc1)C(=O)O

Procedure:
600 mg of melphalan (63) is suspended in 25 ml of water containing 500 mg of sodium carbonate. 10 ml of dioxane is added and 1 ml of acetic anhydride. After stirring at ambient temperature for 1 h citric acid is added and the mixture extracted with ethyl acetate. After washing with water and brine the organic phase is dried (sodium sulfate) and concentrated in vacuum. Removal of all volatiles yields the crude N-acetylmelphalan that is carried on to the next step without further purification.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[O:12][CH2:11][N:10]([C:13]([CH3:25])([CH3:24])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C:9](=[O:26])[C:8]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOCC.O1CCCC1>[Br:2][CH2:6][C:7]1[O:12][CH2:11][N:10]([C:13]([CH3:25])([CH3:24])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C:9](=[O:26])[C:8]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C(=O)OCc1ccccc1)N1COC(CO)=C(c2ccccc2)C1=O
Reactant: BrP(Br)Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C(=O)OCc1ccccc1)N1COC(CBr)=C(c2ccccc2)C1=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of phosphorus tribromide (5.1 ml) in ether was added during 0.5 hour to a solution of benzyl 2-(2,3-dihydro-6-hydroxymethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (61.1 g) in a mixture of ether and tetrahydrofuran at -78° C. The mixture was then stirred at -10° C. for 4 hours and at room temperature for 1 hour, then washed (water), dried (magnesium sulphate) and evaporated. Purification of the residue by dry column chromatography on silica gel gave benzyl 2-(6-bromomethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoate (46.1 g), NMR(CDCl3) 1.5(s,6H), 3.8(s,2H), 5.05(s,2H), 5.3(s,2H), 7.2(s,5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:20])[C:17](F)=[CH:18][C:13]=2[NH:12][C:11](=[O:21])[CH2:10][N:9]=1.[CH3:22][OH:23].[H-].[Na+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([F:20])[C:17]([O:23][CH3:22])=[CH:18][C:13]=2[NH:12][C:11](=[O:21])[CH2:10][N:9]=1
Reactant: CO
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(F)c(F)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1F)C(c1ccccc1Cl)=NCC(=O)N2
Temperature: 100 °C

Procedure:
A mixture of 0.10 g (0.00033 mole) of 5-(2-chlorophenyl)-7,8-difluoro-1,3-dihydro-2H-1,4-benzodiazepin-2-one (Imm), 2 mL of methanol and 0.03 g of sodium hydride was heated at 100° C. for 40 minutes using microwave heating in a sealed reaction vessel. The mixture was then cooled. diluted with ethyl acetate and washed successively with water and then brine. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 0.103 g of 5-(2-chlorophenyl)-1,3-dihydro-7-fluoro-8-methoxy-2H-1,4-benzodiazepin-2-one (Ia) as a white solid. MH+/Z=319.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[CH3:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:20])=[O:19])[CH:15]=[CH:14][CH:13]=1>C(O)(=O)C>[CH2:8]([O:7][C:3](=[O:10])[CH2:20][C:18](=[O:19])[C:16]1[CH:17]=[C:12]([CH3:11])[CH:13]=[CH:14][CH:15]=1)[CH3:9]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)c1cccc(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CC(=O)c1cccc(C)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Sodium hydride (3.1 g, 77.1 mmol) and diethyl carbonate were combined with 3-methylacetophenone (4.5 g, 33.54 mmol). The mixture was stirred for 2 hours at 80° C. After the reaction was completed, ice water and acetic acid were added thereto. Then, the mixture was extracted with ethyl acetate/saturated sodium chloride. The extract was dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography to obtain 3-oxo-3-m-tolylpropionate ethyl ester (5.8 g, yield 84%).
Reaction SMILES: C[O:2][C:3]1([CH2:9][N:10]2[C:14]([CH3:15])=[CH:13][CH:12]=[N:11]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:16]N1C(=O)CCC1=O>CN(C)C(=O)C.C(OCC)(=O)C>[Br:16][C:13]1[CH:12]=[N:11][N:10]([CH2:9][C:3]2([OH:2])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[C:14]=1[CH3:15]
Reactant: COC1(Cn2nccc2C)CCCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: Cc1c(Br)cnn1CC1(O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 165B (10.6 g) in N,N-dimethylacetamide (30 mL) was added N-bromosuccinimide (9.72 g). The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (400 mL) and washed with aqueous sodium bisulfite, water, and brine. Evaporation of the solvent gave the crude product which was used in the next reaction without further purification.
Reaction SMILES: Br[CH:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[OH:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>C1COCC1>[OH:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][CH:18]=1)[CH:2]=[C:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(=CBr)CC1
Reactant: OB(O)c1cccc(O)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(O)c2)CC1
Temperature: 50 °C
Yield: 66.1 %

Procedure:
To a solution of tert-butyl 4-(bromomethylene)piperidine-1-carboxylate (38 g, 0.1376 mol) in dry THF (380 mL) was added 3-hydroxyphenyl boronic acid (22.77 g, 0.165 mol), potassium phosphate (88.2 g, 0.415 mol) and water (7.6 mL). The mixture was degassed with argon. 1,1′-Bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (11.23 g, 0.01376 mol) was added and the mixture was degassed again. The reaction was heated at 50° C. for 1.5 h and then allowed to cool to RT. Water was added and the mixture was extracted with ethyl acetate (3×). The total organic extract was washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography using 100-200 mesh silica gel (8% ethyl acetate in hexane) to give the title compound (26.3 g, 66%). 1H NMR (500 MHz, CDCl3): δ 7.16 (t, J=7.5 Hz, 1H), 6.74 (d, J=7.5 Hz, 1H), 6.68 (d, J=9 Hz, 1H), 6.68 (s, 1H), 6.30 (s, 1H), 5.37 (bs, 1H), 3.49 (m, 2H), 3.40 (m, 2H), 2.46 (m, 2H), 2.31 (m, 2H), 1.48 (s, 9H); 13C NMR (125 MHz, CDCl3): δ 156.09, 155.09, 138.87, 138.15, 129.31, 124.58, 120.98, 115.74, 113.54, 80.10, 45.45, 44.57, 36.08, 29.23, 28.50.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C@@H:7]1([NH2:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[CH2:5]([O:4][C:2](=[O:3])[NH:17][C@@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)[CH3:6]
Reactant: N[C@H]1CCCc2ccccc21
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)N[C@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl chloroformate (7.74 g, 71.3 mmol) is added dropwise to a mixture of (S)-1,2,3,4-tetrahydro-naphthalen-1-ylamine (10.0 g, 67.9 mmol) and K2CO3 (18.8 g, 136 mmol) in CH3CN (100 mL). The resulting mixture is stirred at room temperature overnight. Water (100 mL) is added and the mixture is extracted with ether (2×100 mL). The combined extract is washed with 1 N HCl (2×TO mL), water, dried (Na2SO4), and concentrated in vacuo to give (S)-(1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid ethyl ester as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=1)[C:5]([NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[O:6].[C:23]([O:27][C:28](=[O:48])[NH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([O:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43](Cl)[N:42]=2)=[CH:32][CH:31]=1)([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[C:23]([O:27][C:28](=[O:48])[NH:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([O:40][C:41]2[CH:46]=[CH:45][N:44]=[C:43]([NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH:18]=[C:19]([C:21]#[CH:22])[CH:20]=3)[N:42]=2)=[CH:32][CH:31]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc(Cl)n2)c2ccccc12
Reactant: C#Cc1cc(N)cc(C(=O)NCCOCCOCCOC)c1
Solvent: CN(C)C=O
Product: C#Cc1cc(Nc2nccc(Oc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)n2)cc(C(=O)NCCOCCOCCOC)c1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
To a stirred solution of the product from step (iv) above (1 g, 3.13 mmol) and tert-butyl(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun. 2010; 777 mg, 2.090 mmol) in DMF (60 mL) was added pTSA monohydrate (200 mg, 1.051 mmol). The resulting solution was stirred at 60° C. for 72 h. The reaction was cooled to rt, then partitioned between EtOAc (150 mL) and sat. aq. NaHCO3 (100 mL). The aqueous layer was further extracted with EtOAc (2×150 mL), then the combined organic extracts were washed with water (3×200 mL) and brine (200 mL), before being dried (MgSO4), filtered and concentrated to afford an orange oil (1.17 g). The crude product was purified by chromatography on silica gel (80 g column, 0-5% MeOH in EtOAc) to afford the sub-title compound (552 mg) as a light brown foam.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH:6]([CH2:12][N:13]1C(=O)C3=CC=CC=C3C1=O)[CH2:7]2.O.NN>C(O)C>[NH2:13][CH2:12][CH:6]1[CH2:5][CH2:4][C:3]2[C:2]([OH:1])=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:7]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CCc2c(O)cccc2C1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC1CCc2c(O)cccc2C1
Temperature: 25 °C
Yield: 76.9 %

Procedure:
A solution of N-[(1,2,3,4-tetrahydro-5-hydroxy-2-naphthyl)methyl]phthalimide (634 mg) and hydrazine monohydrate (309 mg) in ethanol (14 ml) was refluxed for 3 hours, cooled to room temperature, and evaporated in vacuo. The residue was chromatographed (methylene chloride-methanol) over basic alumina to afford 6-(aminomethyl)-5,6,7,8-tetrahydro-1-naphthol (281 mg) as a colorless powder. mp: 183°-192° C.