Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:17][CH2:16][CH2:15][C:14]([C:18]([OH:20])=O)=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.C(Cl)(C(Cl)=O)=O.O1CCCCC1[O:34][CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1.C(N(CC)CC)C>O1CCCC1.O.CN(C=O)C>[OH:34][CH2:35][C:36]1[CH:42]=[CH:41][C:39]([NH:40][C:18]([C:14]2[CH2:15][CH2:16][CH2:17][C:11]3[CH:10]=[CH:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=4)=[CH:21][C:12]=3[CH:13]=2)=[O:20])=[CH:38][CH:37]=1
Reactant: Nc1ccc(COC2CCCCO2)cc1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCC3)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CO)cc2)CCC3)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
To a solution of 2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxylic acid (35.0 g, 0.126 mol) in tetrahydrofuran (THF) (280 ml) were added (COCl)2 (21.9 ml, 0.251 mol) and DMF (0.7 ml) at 0° C. Under nitrogen atmosphere, the mixture was stirred at room temperature for 4 hours. After the reaction completed, The solvent was evaporated, and to the residue was added THF (315 ml). To a solution of the acid chloride was added a solution of 4-(2-tetrahydropyranyloxymethyl)aniline (28.1 g, 0.138 mol) and triethylamine (Et3N) (26.3 ml, 0.189 mol) in THF (105 ml) at 0° C., and the mixture was stirred under nitrogen atmosphere, at room temperature for 2 hours. After the reaction completed, to the mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated NaCl solution and dried with MgSO4. The solvent was evaporated and the residue was dissolved in methanol (MeOH) (470 ml). To the mixture was dropwise added 6N HCl (5.9 ml) at room temperature, and the mixture was stirred for 1 hour. After the reaction completed, the mixture was neutralized with saturated NaHCO3 solution, and the solvent was removed. The residue was washed with water and then acetone/isopropylether (10:1; 60 ml), and the resulting precipitate was filtered, which was dissolved in THF. The mixture was dried with MgSO4, and the solvent was evaporated. The resulting powder was washed twice with hexane:ethyl acetate (10:1; 50 ml) to give N-(4-hydroxymethylphenyl)-2-(4-methylphenyl)-6,7-dihydro-5H-benzocycloheptene-8-carboxamide (26.8 g, 56%) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][CH:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[CH2:11][CH2:10][N:9]2C)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[CH2:11][CH2:10][NH:9]2)=[CH:19][CH:20]=1
Reactant: COc1ccc(CC2C3=C(CCCC3)CCN2C)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(CC2NCCC3=C2CCCC3)cc1

Procedure:
N-Alkyl allylic tertiary amines are dealkylated as illustrated by treatment of (-)-1-(p-methoxybenzyl)-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline in cold methylene chloride with m-chloroperbenzoic acid followed by the addition of aqueous ferrous chloride to provide a good yield of (+)-1-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline with substantial if not complete retention of optical activity. The product is an intermediate in a synthesis of the analgesic known as butorphanol.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]([CH:14]1[CH2:16][CH2:15]1)#[CH:13]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:14]1([C:12]#[C:13][C:2]2[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH2:16][CH2:15]1
Reactant: C#CC1CC1
Reactant: Nc1ccc([N+](=O)[O-])cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: Nc1ccc([N+](=O)[O-])cc1C#CC1CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 23243.2 %

Procedure:
To a deoxygenated solution of 2-bromo-4-nitroaniline (2.17 g, 0.01 mmol), ethynyl-cyclopropane (1 g, 15 mmol) and CuI (10 mg, 0.05 mmol) in triethylamine (20 mL) was added Pd(PPh3)2Cl2 (210 mg, 0.3 mmol) under N2. The mixture was heated at 70° C. and stirred for 24 hours. The solid was filtered off and washed with EtOAc (50 mL×3). The filtrate was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to give 2-(cyclopropylethynyl)-4-nitroaniline (470 mg, 23%). 1H NMR (300 MHz, CDCl3) δ 8.14 (d, J=2.7 Hz, 1H), 7.97 (dd, J=2.7, 9.0 Hz, 1H), 6.63 (d, J=9.0 Hz, 1H), 4.81 (brs, 2H), 1.55-1.46 (m, 1H), 0.98-0.90 (m, 2H), 0.89-0.84 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(N)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A flask was charged with 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation, see example 4) (739 mg, 2 mmol), [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (570 mg, 2.60 mmol), potassium carbonate (691 mg, 5.00 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (146 mg, 0.200 mmol) then filled with 1,4-dioxane (9 mL) and water (3 mL) and purged with nitrogen. The mixture was stirred under microwave irradiation for 30 min at 120° C. then cooled to room temperature. Most of the 1,4-dioxane was removed in vacuo and the residue was partitioned between water and AcOEt. The layers were separated and the aqueous phase extracted twice with AcOEt. The combined organic phases were washed twice with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 25 G silica cartridge (gradient: 13 to 63% AcOEt in Hexanes) gave 1-methylethyl[(2S,4R)-1-acetyl-6-(4-aminophenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (660 mg, 1.730 mmol, 87% yield) as a pale yellow foam.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][NH:35][C:34](=[O:38])[CH2:33]1>>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:35]3[CH2:36][CH2:37][N:32]([CH2:31][CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH2:33][C:34]3=[O:38])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CCC2
Reactant: O=C1CN(CCc2ccccn2)CCN1
Product: Cn1c2c(c3ccc(N4CCN(CCc5ccccn5)CC4=O)cc31)CN(C(=O)OC(C)(C)C)CCC2
Yield: 19.6 %

Procedure:
tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (200 mg, 0.528 mmol) and 4-(2-(pyridin-2-yl)ethyl)piperazin-2-one (118 mg, 0.576 mmol) were reacted following the procedure for Example 53 (step b) to provide the title compound (52 mg, 20%) as a white solid: ESI MS m/z 504 [M+H]−.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[O:31]1CCC[CH2:32]1>>[CH2:21]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH:32]=[O:31])=[CH:11][CH:10]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc2cccc(N(Cc3ccccc3)Cc3ccccc3)c2c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2c(C=O)ccc(N(Cc3ccccc3)Cc3ccccc3)c2c1
Temperature: 50 °C
Reaction time: 120 h
Yield: 98 %

Procedure:
A mixture of 4 (17.88 g, 43 mmol) and 10% aqueous sodium hydroxide solution (860 mL) in tetrahydrofuran (500 mL) was stirred at 50° C. for 5 days. The mixture was cooled to 0° C. and neutralized with concentrated hydrochloric acid. The mixture was concentrated under reduced pressure, and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated to give tert-butyl 4-bromo-7-hydroxynaphthalen-1-ylcarbamate (5). (14.32 g, 98% yield)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26](O)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CC1C=CC(S([O-])(=O)=O)=CC=1.[O:85]1[CH2:89][CH2:88][C@@H:87]([NH3+:90])[CH2:86]1>C(Cl)Cl.CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=[C:13]([C:21]4[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=4)[O:24][CH2:25][C:26]([NH:90][C@@H:87]4[CH2:88][CH2:89][O:85][CH2:86]4)=[O:27])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: [NH3+][C@@H]1CCOC1
Reactant: O=C(O)COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)N[C@@H]1CCOC1
Reaction time: 0.5 h

Procedure:
A suspension of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)acetic acid (70 mg, 0.14 mmol), PyBOP® (40 mg, 0.077 mmol), DIEA (24 μL, 0.14 mmol) in dry CH2Cl2:DMF (2:0.1 mL) was stirred at RT for 15 minutes. To this solution of activated acid was added (R)-tetrahydrofuran-3-aminium 4-methylbenzenesulfonate (24 mg, 0.091 mmol). After 30 minutes, 1.0 equivalent of DIEA and 0.55 equivalents of PyBOP® were added. After stirring the solution for 15 minutes, 0.65 equivalents of (R)-tetrahydrofuran-3-aminium 4-methylbenzenesulfonate were added and the mixture was stirred for an additional 30 minutes. The solvent was removed in vacuo and the crude product was purified using prep HPLC (15-40—90 mins) to afford 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N—((R)-tetrahydrofuran-3-yl)acetamide. (41 mg, 0.085 mmol, 61%).
Reaction SMILES: [C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][NH:20][C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1.O=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]1([CH3:24])[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:23][CH2:22][CH2:21][N:20]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:3][CH:2]=1
Reactant: Cc1ccc(-c2nc3c(nc2-c2ccc(C)cc2)NCCC3)cc1
Reactant: CCOC(=O)CCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOC(=O)CCCCCN1CCCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21

Procedure:
A solution of 2,3-di-p-tolyl-5,6,7,8-tetrahydropyrido[2,3-b]pyrazine (Intermediate B) (2.0 g, 6.34 mmol) and ethyl 6-oxohexanoate (Intermediate A) (2.508 g, 12.68 mmol) in 1,2-dichloroethane (50 ml) was treated with sodium triacetoxyborohydride (3.36 g, 15.85 mmol) and the resultant suspension was stirred at room temperature overnight. The solution was treated with sat.NaHCO3 and extracted with DCM (×3). The organic extracts were dried (MgSO4) and evaporated under reduced pressure. The residue was loaded onto an Isolute® SCX-2 cartridge and eluted with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions were concentrated under reduced pressure and further purified by chromatography on silica eluting with 10-50% EtOAc in iso-hexane to afford the titled compound;
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[N:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)=[CH:6][CH:5]=1.[CH3:25]I.O>C1COCC1>[Cl:3][C:4]1[N:9]=[N:8][C:7]([N:10]([CH3:25])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([CH:21]=[O:22])=[CH:23][CH:24]=2)=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=Cc1ccc(OCCCCCNc2ccc(Cl)nn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCCCCOc1ccc(C=O)cc1)c1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
Sodium hydride (10 mg, 0.24 mmol) was added to a solution of 4-{N-(6-Chloro-3-pyridazinyl)-5-aminopentan-1-oxy}benzaldehyde (51 mg, 0.16 mmol) in THF (3.5 ml) and the mixture was stirred at room temperature for 30 minutes. Methyl iodide (50 μl, 0.8 mmol) was added to the reaction mixture and the suspension was stirred at room temperature for 48 hours. The reaction mixture was poured into water (1.5 ml) and concentrated under reduced pressure. The residue was partitioned between water (2 ml) and ethyl acetate (40 ml), shaken thoroughly and the organic layer was separated, dried and evaporated to give a yellow solid. Purification by chromatography on silica gel (6 g, 30% ethyl acetate/hexane) gave 4-{N-(6-Chloro-3-pyridazinyl)-N-methyl-5-aminopentan-1-oxy}benzaldehyde (16 mg, 30%) as a pale yellow oil.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:32][C:33]1[C:40]([O:41][CH3:42])=[CH:39][C:36]([CH:37]=O)=[CH:35][C:34]=1[O:43][CH3:44])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:37][C:36]1[CH:39]=[C:40]([O:41][CH3:42])[C:33]([O:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:34]([O:43][CH3:44])[CH:35]=1
Reactant: COc1cc(C=O)cc(OC)c1OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(C=C(Br)Br)cc(OC)c1OCc1ccccc1

Procedure:
The starting material is prepared as follows: To the mixture of 31.5 g of carbon tetrabromide and 65 ml of methylene chloride the solution of 50.0 g of triphenylphosphine in 175 ml of methylene chloride is added dropwise while stirring at 0°-5° under nitrogen. After 20 minutes the solution of 13.5 g of 4-benzyloxy-3,5-dimethoxybenzaldehyde in 50 ml of methylene chloride is added dropwise and the mixture stirred at room temperature for 2 hours. It is washed with 200 ml of water, dried and evaporated. The residue is extracted with hexane-diethyl ether (5:1), the extract evaporated, the residue chromatographed on silica gel, eluted with diethyl ether, the eluate evaporated and the residue recrystallized from hexane, to yield the β,β-dibromo-4-benzyloxy-3,5-dimethoxy-styrene melting at 76°-77°.
Reaction SMILES: [C:1](#[N:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:10][CH:11](O)[CH:12]=[CH2:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:13][CH:12]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]#[N:9])[CH:11]=[CH2:10]
Reactant: C=CC(C)O
Reactant: N#Cc1ccccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CC(C)Oc1ccccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
To a mixture of salicylonitrile (2.0 g, 16.8 mmol) and but-3-en-2-ol (1.5 ml, 16.8 mmol) in tetrahydrofuran (100 ml) was added triphenylphosphine (4.4 g, 16.8 mmol), followed by diisopropyl azodicarboxylate (3.3 ml, 16.8 mmol) in tetrahydrofuran (15 ml), added dropwise ensuring the reaction temperature did not rise above 20° C. The reaction mixture was stirred at room temperature for 18 h and then concentrated in vacuo. To the residue was added diethyl ether (20 ml) and the solution was washed with aqueous sodium hydroxide solution (1N), dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography (silica) with gradient elution, diethyl ether:cyclohexane [1:9 to 1:1]. The appropriate fractions were combined and concentrated to give the title compound (1.9 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:23]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]2[C:32]([O:34][C:35](=O)[C:25]=2[CH:24]=1)=[O:33]>>[C:17]1([C:14]2[CH:15]=[CH:16][C:10]3[O:9][C:8]([C:4]4[CH:3]=[C:2]([N:1]5[C:32](=[O:33])[C:26]6[C:25](=[CH:24][CH:23]=[C:28]([C:29]([OH:31])=[O:30])[CH:27]=6)[C:35]5=[O:34])[CH:7]=[CH:6][CH:5]=4)=[N:12][C:11]=3[CH:13]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(-c2nc3cc(-c4ccccc4)ccc3o2)c1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: O=C(O)c1ccc2c(c1)C(=O)N(c1cccc(-c3nc4cc(-c5ccccc5)ccc4o3)c1)C2=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-aminophenyl)-5-phenylbenzoxazole (40 mg, 0.14 mmol) and 1,2,4-benzenetricarboxylic anhydride (30 mg, 0.16 mmol) the title compound was obtained, 45 mg (70%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.38(d, 2H), 8.30(dt, 1H), 8.12(m, 2H), 7.9(d, 1H), 7.78(m, 5H), 7.51(t, 2H), 7.40(t, 1H). MS 459 m/z (M−H)−.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](N2CCCC2)=[O:11])=[C:5]([CH3:17])[C:4]=1[CH3:18].[OH-].[Na+].C(OCC)(=[O:23])C>Br.C(O)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:11])=[O:23])=[C:5]([CH3:17])[C:4]=1[CH3:18]
Reactant: COc1ccc(CC(=O)N2CCCC2)c(C)c1C
Reactant: CCOC(C)=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1c(O)ccc(CC(=O)O)c1C

Procedure:
2-(4-Methoxy-2,3-dimethylphenyl)-1-(pyrrolidin-1-yl)ethanone was suspended in a mixture of 48% HBr (aq) (15 mL) and acetic acid (15 mL) and the reaction was heated to reflux for 24 h. The reaction was poured over ice and brought to pH 4 with 1 N NaOH. Ethyl acetate was added and the layers were separated. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was taken up in dioxane (100 mL) and 1 N HCl (15 mL) was added. The reaction was heated to reflux for 4 days. Ethyl acetate and 1N HCl were added. The layers were separated, and the aqueous layer was washed with additional ethyl acetate. The organics were combined, dried (Na2SO4), filtered and concentrated in vacuo. Flash column chromatography of the residue, eluting 0% to 7% methanol in dichloromethane, afforded the title compound. LC-MS ESI (neg.) m/z: 179.2 (M−H).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:6]=[C:7](/[CH:17]=[CH:18]/[C:19](=[NH:23])OCC)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]1.Cl.Cl[CH2:26][CH2:27][CH2:28][CH:29]([CH:34]1[CH2:39][CH2:38][CH2:37][C:36]([CH3:41])([CH3:40])[O:35]1)[C:30]([NH:32][NH2:33])=O>>[CH3:40][C:36]1([CH3:41])[O:35][CH:34]([CH:29]2[CH2:28][CH2:27][CH2:26][N:32]3[N:33]=[C:19](/[CH:18]=[CH:17]/[C:7]4[CH:8]=[CH:9][C:10]([N:11]5[CH:15]=[C:14]([CH3:16])[N:13]=[CH:12]5)=[C:5]([O:4][CH3:3])[CH:6]=4)[N:23]=[C:30]23)[CH2:39][CH2:38][CH2:37]1
Reactant: CCOC(=N)/C=C/c1ccc(-n2cnc(C)c2)c(OC)c1
Reactant: CC1(C)CCCC(C(CCCCl)C(=O)NN)O1
Agent: Cl
Product: COc1cc(/C=C/c2nc3n(n2)CCCC3C2CCCC(C)(C)O2)ccc1-n1cnc(C)c1

Procedure:
5.2 mg of a diastereomer mixture, 8-(6,6-dimethyltetrahydropyran-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine, was obtained according to the method in Example 113 from ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride obtained in Example 1 (47 mg) and 5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)-valeric acid hydrazide hydrochloride (36 mg). The diastereomer mixture was separated by CHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm, mobile phase: 30% ethanol-hexane) to obtain the title optically active compound with a retention time of 13 minutes and positive optical rotation (0.75 mg), the title optically active compound with a retention time of 14 minutes and positive optical rotation (0.21 mg), the title optically active compound with a retention time of 16 minutes and negative optical rotation (0.13 mg) and the title optically active compound with a retention time of 24 minutes and negative optical rotation (0.54 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:18]#[N:19].[Na+]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH2:16][C:18]#[N:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: BrCc1cc(Br)ccc1OCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
A mixture of 2-bromomethyl-4-bromophenyl benzyl ether (0.28 moles) and NaCN (16 g) in DMF (200 ml) was stirred at ambient temperature for 16 hours, then heated at 100° C. for 5 hours. A further 2 g of NaCN was added and the reaction heated for 5 hours at 100° C. The mixture was diluted with water (200 ml) and stirred (1 hour). The resulting solid was filtered off and recrystallised from methanol to give 4-bromo-2-cyanomethylphenyl benzyl ether (48 g) mpt. 75°-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[CH:25]=[C:24]([CH2:26][CH:27]([O:29]C4CCCCO4)[CH3:28])[O:23][N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[CH:25]=[C:24]([CH2:26][CH:27]([OH:29])[CH3:28])[O:23][N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(Cc1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1)OC1CCCCO1
Agent: Cl
Solvent: CCO
Product: CC(O)Cc1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Temperature: 25 °C
Yield: 51.7 %

Procedure:
N—((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-(tetrahydro-2H-pyran-2-yloxy)propyl)isoxazole-3-carboxamide (0.1 g, 0.201 mmol), ethanol (2 ml) and hydrogen chloride, 10% in EtOH (0.5 ml, 1.350 mmol) were mixed together and stirred over the weekend at RT. The mixture was evaporated, more ethanol was added and evaporated again. The product was pure enough without further purifications. Yield 51.7%. 1H-NMR (400 MHz; DMSO-d6): δ 1.09 (dd, 3H), 1.15 (d, 3H), 2.82-2.86 (m, 2H), 3.91-3.98 (m, 1H), 4.29-4.34 (m, 2H), 4.41-4.50 (m, 1H), 6.48-6.50 (m, 1H), 6.94 (d, 1H), 7.82 (d, 1H), 7.92 (dd, 1H), 7.97 (d, 1H), 8.08-8.10 (m, 1H), 8.73 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=O.[F:10][C:11]1[C:17]([F:18])=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][C:12]=1[NH2:13]>>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:13][C:12]1[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[C:17]([F:18])[C:11]=1[F:10])=[O:9]
Reactant: O=C(O)c1sccc1Br
Reactant: COc1ccc(N)c(F)c1F
Product: COc1ccc(NC(=O)c2sccc2Br)c(F)c1F
Yield: 100.3 %

Procedure:
Following Step 1 from General Procedure A, 3-bromothiophene-2-carboxylic acid (1.3 g, 6.3 mmol) was reacted with 2,3-difluoro-4-methoxyaniline (960 mg, 7.5 mmol) to afford the desired product (2.2 g, >99%): ESI MS m/z 349 [C12H8BrF2NO2S+H]+.
Reaction SMILES: [CH2:1]([NH:9][C:10]([NH2:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[CH:14]([C:20]([C:22]([F:25])([F:24])[F:23])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:1]([NH:9][C:10]1[O:11][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([C:22]([F:23])([F:25])[F:24])[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(N)=O
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Product: CCCCCCCCNc1nc(C(F)(F)F)c(C(=O)OCC)o1
Yield: 17.8 %

Procedure:
By the procedure of Example 4, 5.16 g (30 mmol) of n-octyl urea was reacted with 5.4 g (25 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 18 hours. The product was separated and then recrystallized from petroleum ether to yield 1.5 g of a white powder product (m.p.=36°-37° C.) identified in Table I.