Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][N:10]=2)=[CH:6][C:5]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])=[C:4]([F:25])[CH:3]=1>C(O)(=O)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[C:2]([Cl:1])=[CH:3][C:4]([F:25])=[C:5]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:21])[F:22])[CH:6]=2)=[N:10][CH:11]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cn2)c(Cl)cc1F)C(F)(F)F
Solvent: CC(=O)O
Product: Nc1ccc(Oc2cc(NC(=O)C(F)(F)F)c(F)cc2Cl)nc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 64.6 %

Procedure:
A mixture of N-{4-chloro-2-fluoro-5-[(5-nitropyridin-2-yl)oxy]phenyl}-2,2,2-trifluoroacetamide (600 mg, 1.58 mmol), reduced iron (452 mg, 8.09 mmol) and acetic acid (10 mL) was stirred at 60° C. for 1.5 hr. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL), washed with saturated aqueous sodium hydrogen carbonate solution (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20→34/66) to give the title compound (357 mg, 65%) as a white powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][C:7]1[C:12](C(OCC)=O)=[CH:11][N:10]=[C:9]2[CH:18]=[N:19][NH:20][C:8]=12.[OH-].[Na+]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:18]=[N:19][NH:20][C:8]=12
Reactant: CCOC(=O)c1cnc2cn[nH]c2c1Nc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1csc(Nc2ccnc3cn[nH]c23)c1

Procedure:
Ethyl 7-thienylamino-1H-pyrazolo[4,3-b]pyridine-6-carboxylate (0.600 g) was converted to the corresponding acid by heating under reflux with a 2% sodium hydroxide solution in ethanol (50 ml). The ethanol was removed under reduced pressure and the residue diluted with water (5 ml) and acidified to pH5 with dilute hydrochloric acid. The resulting acid was filtered off and dried, mp 255°-259° C.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Cl[CH2:41][CH2:42][CH2:43][N:44]1[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=2[N:46]([CH:53]2[CH2:55][CH2:54]2)[C:45]1=[O:56]>CC(=O)CC>[CH:53]1([N:46]2[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[N:44]([CH2:43][CH2:42][CH2:41][N:9]3[CH2:10][CH2:11][C:6]4([N:5]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH2:4][N:3]([CH2:18][C:19]5[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=5)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]4=[O:1])[CH2:7][CH2:8]3)[C:45]2=[O:56])[CH2:55][CH2:54]1
Reactant: O=c1n(CCCCl)c2ccccc2n1C1CC1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)n(C5CC5)c5ccccc54)CC3)C2=O)c1
Temperature: 78 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
To a solution of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.2 g, 0.47 mmol), potassium carbonate (0.097 g, 0.7 mmol) and sodium iodide (0.021 g, 0.14 mmol) in 2-butanone (5 mL), was added 1-(3-chloropropyl)-3-cyclopropyl-1H-benzo[d]imidazol-2(3H)-one (0.119 g, 0.47 mmol). After stirring at 78° C. for 18 hours, the reaction mixture was filtered, concentrated and isolated by preparatory TLC (10% methanol/dichloromethane) to obtain the title compound (0.27 g, 90%); 1H NMR (DMSO-d6): δ 0.84-0.88 (m, 2H), 1.01 (d, 2H, J=5.6 Hz), 1.51 (s, 9H), 1.61 (d, 2H, J=14.4 Hz), 1.81 (br, 2H), 2.34 (t, 2H, J=6.8 Hz), 2.48-2.55 (m, 2H), 2.67-2.71 (m, 4H), 2.85-2.88 (m, 1H), 3.86 (t, 2H, J=6.4 Hz), 4.59 (d, 4H, J=10 Hz), 6.77 (t, 1H, J=7.2 Hz), 6.85 (d, 2H, J=8 Hz), 7.03-7.05 (m, 2H), 7.18-7.24 (m, 4H), 7.48-7.54 (m, 2H), 7.79 (s, 1H), 7.83 (d, 1H, J=7.2 Hz); MS for C38H45N5O4 m/z 636.26 (M+H)+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8]Cl.[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[OH:17]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][C:27]=3[O:29][CH2:30][C@@H:31]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])[CH3:32])[N:22]=[CH:21][N:20]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1
Reactant: ClCc1ccccn1
Reactant: CC(=O)N(C)[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Agent: Cl
Product: CC(=O)N(C)[C@@H](C)COc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 34 %

Procedure:
The procedure described in Example 3 was repeated using picolyl chloride hydrochloride and N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-N-methylacetamide to give the title compound in 34% yield; NMR spectrum (DMSO-d6, 373K) 1.20 (d, 3H), 1.85 (s, 3H), 2.80 (s, 3H), 3.00 (m, 1H), 4.30 (m, 1H), 4.40 (m, 1H), 5.30 (s, 2H), 7.20 (m, 2H), 7.40 (m, 2H), 7.50 (d, 1H), 7.60 (d, 1H), 7.70 (t, 1H), 7.80 (m, 1H), 7.90 (d, 1H), 8.40 (s, 1H), 8.60 (d, 1H), 9.60 (s, 1H); Mass spectrum MH+ 492.2.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3]C1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@@:4]([CH2:1][CH3:3])([OH:12])[CH2:8][CH2:7][N:6]1[C:20]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:13])[CH:21]=1)[CH3:11]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(F)c2)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (196 mg), 2,4-difluorobenzonitrile (284 mg) and lithium carbonate (202 mg), the title compound was obtained as pale-yellow oil (yield: 208 mg, yield: 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH2:13])[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[C:27](O)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[C:12]2[N:11]=[C:10]([NH:13][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=3)[N:9]3[CH2:14][CH2:15][N:16]=[C:8]3[C:7]=2[CH:6]=[CH:5][C:4]=1[O:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:22][CH2:23][O:24][CH2:25][CH2:26]1
Reactant: O=C(O)c1cccnc1
Reactant: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(NC(=O)c1cccnc1)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
7-Methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Step 5, 1.0 g, 2.2 mmol) was dissolved in DMF (15 mL), and nicotinic acid (0.44 g, 3.3 mmol) was added. PyBOP (1.73 g, 3.3 mmol) and diisopropylethylamine (1.6 mL, 8.9 mmol) were subsequently added, and the mixture was stirred at rt overnight. EtOAc was added, and the solids were isolated by vacuum filtration to give the title compound (0.43 g, 40%): HPLC MS RT=1.15 min, MH+=463.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 9.01 (2H, s), 8.04 (1H, d), 7.43 (1H, d), 4.54 (2H, m), 4.34 (2H, br t), 4.23 (2H, m), 4.04 (2H, m), 4.00 (3H, s), 3.65 (2H, br t), 3.52 (2H, m), 3.31 (2H, m), 3.18 (2H, m), 2.25 (2H, m).
Reaction SMILES: Cl.[O:2]1[C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:20]([C:22]1[N:23]=[C:24]([C:27](O)=[O:28])[S:25][CH:26]=1)[CH3:21].C(N(CC)CC)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)Cl.C1COCC1.O>[CH2:20]([C:22]1[N:23]=[C:24]([C:27]([N:5]2[CH2:6][C:7]3([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]3)[O:2][CH2:3][CH2:4]2)=[O:28])[S:25][CH:26]=1)[CH3:21]
Reactant: CCc1csc(C(=O)O)n1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCc1csc(C(=O)N2CCOC3(CCN(C(=O)OC(C)(C)C)CC3)C2)n1
Temperature: 16 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
A mixture of tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate hydrochloride (limiting reagent), and 4-ethylthiazole-2-carboxylic acid (1 molar equivalent) was suspended in DCM (4.5 volumes) and cooled to 16° C. To this was added triethylamine (5 molar equivalents) in portions. The thick suspension was cooled to 6° C. and T3P (1.1 molar equivalents of a 1.57M in THF) was added drop-wise at 5-15° C. over 0.5 hr. The reaction mixture was allowed to warm to 22° C. and stirred at 22° C. for 2 hr. The mixture was diluted with water (6.5 volumes, 4° C. exotherm) and the mixture was stirred for 10 mins; the aqueous was separated and extracted with DCM (4.5 volumes). The combined organics were washed saturated aq sodium bicarbonate solution (5.5 volumes) and 20% brine solution (1.5 volumes). The organics were dried over anhydrous sodium sulphate, filtered and evaporated to give a brown oil. Yield: 96% of theoretical.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18].[H-].[Na+]>C1COCC1>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([N:1]2[CH2:13][CH2:14][CH2:15][NH:16][C:17]2=[O:18])=[CH:11][CH:10]=1
Reactant: O=C=NCCCCl
Reactant: COC(=O)c1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N2CCCNC2=O)cc1
Reaction time: 3.5 h
Yield: 45.9 %

Procedure:
Methyl 4-aminobenzoate (3.0 g, 20.0 mmol) and 1-chloro-3-isocyanato-propane (2.0 mL, 20.0 mmol) were stirred in THF (50 mL) at room temperature overnight. The solvents were evaporated. A THF (50 mL) solution of the residue (5.0 g, 18.51 mmol) was added to a stirred solution of NaH (60%, 0.93 g, 23.25 mmol) in THF (60 mL) portionwise at room temperature. The mixture was stirred for 3.5 h. It was evaporated. H2O was added. It was extracted with CH2Cl2, dried over MgSO4, filtered, and concentrated to dryness to give pure 4-(2-oxo-tetrahydro-pyrimidin-1-yl)-benzoic acid methyl ester as a white solid (2.15 g, yield: 49.6%). 1H NMR (DMSO-d6) δ 7.88 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 6.82 (s, br, 1H), 3.68 (m, 2H), 3.34 (s, 3H), 3.23 (m, 2H), 1.96 (m, 2H) ppm. LC-MS (ESI) 235.23 (M+H), tR=2.17 min (10–90% MeOH in H2O in a 4-min run).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-])=O)=[CH:4][N:3]=1.N12CCCN=C1CCCCC2.O.[C:24](OCC)(=O)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(OCC)(=O)C.[Fe]>[CH2:28]([O:27][C:25]([C:24]1[NH:9][C:5]2=[CH:4][N:3]=[C:2]([Br:1])[CH:7]=[C:6]2[CH:8]=1)=[O:26])[CH3:29]
Reactant: Cc1cc(Br)ncc1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOC(=O)c1cc2cc(Br)ncc2[nH]1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Route B: To a solution of 2-bromo-4-methyl-5-nitropyridine (Preparation 24, 5.7 g, 26.3 mmol) in diethyl oxalate (17.9 mL) under argon was added 1,8-diazabicyclo[5,4,0]undec-7-ene (4.5 mL, 30.2 mmol) to give a dark red precipitate. Reaction mixture was stirred at rt for 4.5 h and concentrated in vacuo. Acetic acid (140 mL) was added to the residue under argon and heated to 60° C. Iron (2.94 g, 52.6 mmol) was added in small portions over a period of 1 h. The reaction mixture was heated at 80° C. for 4 h. The reaction mixture was cooled to rt and poured into water (300 mL) which gave a beige precipitate. The precipitate was isolated and washed with water. The solid obtained was dissolved in ethyl acetate (700 ml) and filtered. The filtrate was concentrated in vacuo to give the title compound. m/z (ES+)=269 [M+H]+; RT=3.39 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([S:11][CH3:12])=[CH:10][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([S:11]([CH3:12])=[O:22])=[CH:10][C:4]=2[O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc2c(c1)OC(C)(C)O2
Solvent: ClCCl
Product: CS(=O)c1ccc2c(c1)OC(C)(C)O2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 19.6 g of 2,2-dimethyl-5-(methylthio)-1,3-benzodioxol in 500 ml of methylene chloride was treated at 0° C. with 20.3 g of 85% m-chloroperbenzoic acid. The mixture was subsequently stirred at 0° C. for 1 hour. A white precipitate resulted. The reaction mixture was extracted with 400 ml of 17% aqueous sodium carbonate solution and 400 of water. The organic phase was dried over sodium sulphate and freed from solvent in a vacuum. The residue was taken up in a small amount of methylene chloride and chromatographed on silica gel, with elution being carried out with ethyl acetate/n-hexane/methylene chloride (1:1:1, v/v/v). After crystallization from ethyl acetate/n-hexane, there was obtained 2,2-dimethyl-5-(methyl-sulphinyl)-1,3-benzodioxol as white crystals having a melting point of 87°-88° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:21][O:22][CH2:23][C@H:24]1[C@H:33]2[CH2:34][CH2:35][N:36]([C:37]([C@H:39]3[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]3[NH2:45])=[O:38])[C@H:32]2[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:25]1>>[CH3:21][O:22][CH2:23][C@H:24]1[C@H:33]2[CH2:34][CH2:35][N:36]([C:37]([C@H:39]3[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]3[NH:45][C:14]([C:13]3[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:18][CH:17]=3)=[O:16])=[O:38])[C@H:32]2[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[NH:25]1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1N
Agent: Cl
Product: COC[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1

Procedure:
In the same manner as in Reference Example 19 and using 4-{[(tert-butoxycarbonyl)amino]methyl}benzoic acid and (1R,2S)-2-{[(3aR,4R,9bR)-4-(methoxymethyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexaneamine dihydrochloride, the title compound was synthesized.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[N:8]=1.[CH2:15]([O:22][N:23]=[CH:24][CH:25]1[CH2:27][CH2:26]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.B(F)(F)F.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1(C)C=CC=CC=1.O>[CH2:15]([O:22][NH:23][CH:24]([CH:25]1[CH2:27][CH2:26]1)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[N:8]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C(=NOCc1ccccc1)C1CC1
Reactant: COc1cccc(Br)n1
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cccc(C(NOCc2ccccc2)C2CC2)n1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
8.8 ml (22 mmol) of n-BuLi (2.5 M in toluene) were added to 3.76 g (20 mmol) of 2-bromo-6-methoxypyridine in 20 ml of THF at −78° C. After 30 min, this dark red solution was added to a solution of 1.4 g (8 mmol) of cyclopropanecarbaldehyde O-benzyloxime (see a) and 2.52 ml (20 mmol) of BF3 etherate in 40 ml of toluene which had been stirred at −78° C. for 15 min. The mixture was stirred at −78° C. for 4 h, slowly warmed to RT and, after addition of water, made alkaline with saturated Na2CO3 solution.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:34]([NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])=[O:35])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: COc1ccccc1N=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccccc1NC(=O)Nc1cc(C)c(Oc2ccnc3cc(OC)c(OC)cc23)cc1C

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethyl-aniline (100 mg) was dissolved in chloroform (10 ml), and 2-methoxyphenyl isocyanate (49 μl) was added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/acetone (2/1) to quantitatively give the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:27]=[CH:26][C:6]2[CH2:7][C@@H:8]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:9](=[O:20])[N:10]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][C:5]=2[CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:27]=[CH:26][C:6]2[CH2:7][C@@H:8]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:9](=[O:20])[N:10]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][C:5]=2[CH:4]=1
Reactant: COC(=O)C[C@@H]1Cc2ccc(OC)cc2CN(CCc2ccccc2)C1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: COC(=O)C[C@@H]1Cc2ccc(O)cc2CN(CCc2ccccc2)C1=O
Yield: 86.1 %

Procedure:
To a solution of methyl (S)-8-methoxy-3-oxo-2-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (2.61 g, 7.1 mmole) in CH2Cl2 (40 mL) was added BBr3 (21.3 mL, 1M in CH2Cl2, 21.3 mmole) at −20° C. After 45 minutes the mixture was quenched with MeOH (200 mL) and concentrated. The residue was filtered through a silica gel plug using 50% EtOAc/hexanes as eluent. The resulting orange solid was recrystallized from MeOH/H2O to give the title compound as an off-white solid (2.16 g, 81%): MS (ES) m/e 376 (M+Na)+.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:21]=[CH:22][C:23]4[NH:28][CH2:27][CH2:26][O:25][C:24]=4[CH:29]=3)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:30][CH3:31])C1C=CC=CC=1>C(O)C.[Pd]>[O:25]1[CH2:26][CH2:27][NH:28][C:23]2[CH:22]=[CH:21][C:20]([O:19][C:13]3[C:12]4[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:30][CH3:31])[CH:11]=4)[N:16]=[CH:15][CH:14]=3)=[CH:29][C:24]1=2
Reactant: COc1cc2c(Oc3ccc4c(c3)OCCN4)ccnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(Oc3ccc4c(c3)OCCN4)ccnc2cc1O
Reaction time: 20 h
Yield: 102.8 %

Procedure:
Palladium, 10 wt % on activated carbon (0.050 g, 0.47 mmol) was added to a solution of 7-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.250 g, 0.60 mmol) in ethanol (10.0 mL). The system was evacuated and purged with hydrogen (g) three times and then stirred under a H2 (g) atmosphere for 20 h. The reaction mixture was filtered through a pad of Celite and concentrated to afford 4-(3,4-dihydro-2H-benzo[b][1,4]oxazin-7-yloxy)-6-methoxyquinolin-7-ol (0.200 g, 102% yield) as a yellow-green solid. MS (MH+) 325.0; Calculated 324 for C18H16N2O4.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:29])[C:14]([CH2:24][CH2:25][CH:26]4[CH2:28][CH2:27]4)([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[CH:26]1([CH2:25][CH2:24][C:14]2([CH3:23])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]([OH:22])=[C:12]([C:7]3[NH:6][C:5]4[CH:30]=[CH:31][C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:3][C:4]=4[S:9](=[O:11])(=[O:10])[N:8]=3)[C:13]2=[O:29])[CH2:28][CH2:27]1
Reactant: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(CCC2CC2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reaction time: 12 h
Yield: 77.5 %

Procedure:
To a stirring solution of Example 158 (0.400 g, 0.914 mmol) and pyridine (0.591 mL, 7.312 mmol) in dichloromethane was added methanesulfonyl chloride (0.141 mL, 1.829 mmol) dropwise over 5 minutes and the resulting reaction mixture stirred for 12 hours. The solution was concentrated in. vacuo and purified by flash chromatography on SiO2 eluting with a 0-100% ethyl acetate/hexane gradient yielding the title compound (0.365 g, 77% yield) as a light yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm -0.22 (m, 2H) 0.24 (m, 2H) 0.85 (m, 2H) 1.57 (s, 3H) 2.14 (m, 1H) 2.32 (m, 1H) 3.08 (s, 3H) 7.56 (m, 4H) 7.73 (m, 4H) 8.14 (d, J=8.09 Hz, 1H) 10.23 (m, 1H) 13.79 (m, 1H). MS (ESI+) m/z=416 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[CH2:8]([PH:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH:9]([CH3:11])[CH3:10]>>[CH2:8]([P:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]1[CH2:4][CH2:5][CH2:6][C:1](=[O:7])[CH2:2]1)[CH:9]([CH3:11])[CH3:10]
Reactant: O=C1C=CCCC1
Reactant: CC(C)CPCC(C)C
Product: CC(C)CP(CC(C)C)C1CCCC(=O)C1
Temperature: 45 °C

Procedure:
A 250 ml round-bottomed flask fitted with a condenser, nitrogen purge, and addition funnel was charged with 29.9 g (0.3 mol) 2-cyclohexen-1-one and heated to 45° C. with stirring. Di-(iso-butyl)phosphine (28.8 g, 0.2 mol) was gradually added to the flask via the addition funnel, over a period of 0.5 hour. When addition was complete, the temperature of the contents of the flask was slowly raised to 70° C. and maintained at that temperature for 3 hours, then cooled. Unreacted starting materials were removed by evaporation under reduced pressure at 120° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])(=[O:3])[CH3:2].[CH3:13][O:14][CH2:15][C:16](=O)[CH3:17].N1CCCC1.C1(C)C=CC=CC=1>O>[CH3:13][O:14][CH2:15][C:16]1([CH3:17])[CH2:2][C:1](=[O:3])[C:4]2[C:11](=[CH:10][CH:9]=[C:6]([C:7]#[N:8])[CH:5]=2)[O:12]1
Reactant: CC(=O)c1cc(C#N)ccc1O
Reactant: COCC(C)=O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Solvent: O
Product: COCC1(C)CC(=O)c2cc(C#N)ccc2O1

Procedure:
a mixture of 50 g of 3-acetyl-4-hydroxybenzonitrile, 70 ml of methoxy-2-propanone, 6 ml of pyrrolidine and 300 ml of toluene is boiled in a water separator for 3 hours. The mixture is evaporated, the residue is worked up in the customary manner (ethyl acetate/dil. hydrochloric acid) and 2-methoxymethyl-2-methyl-6-cyano-4-chromanone is obtained, m.p. 79°-81° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[F:4][C:5]([F:22])([F:21])[C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][C:17]([CH:19]=O)=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[CH3:1][N:2]([CH2:19][C:17]1[CH:16]=[CH:15][C:12]2[CH2:13][CH2:14][N:8]([C:6](=[O:7])[C:5]([F:22])([F:4])[F:21])[CH2:9][CH2:10][C:11]=2[CH:18]=1)[CH3:3]
Reactant: CNC
Reactant: O=Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)Cc1ccc2c(c1)CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
11.7 mL (23.4 mmol) of a 2 M dimethylamine solution in THF were added to a solution of 4.5 g (16.59 mmol) 3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-7-carbaldehyde in 150 mL THF and the solution was adjusted to pH 5 with 1 mL glacial acetic acid. After 30 min 4.62 g (21.79 mmol) sodium triacetoxyborohydride were added and the reaction mixture was stirred overnight at RT. The reaction solution was carefully combined with saturated NaHCO3 solution, stirred for 30 min, exhaustively extracted with EtOAc, the organic phase was separated off and dried over Na2SO4. After the desiccant and solvent had been eliminated the desired product was obtained, which was further reacted without purification.