Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([O:25][CH3:26])=[CH:9][CH:10]=2)[O:5][CH:4]=1)#[N:2]>CCOC(C)=O>[C:1]([CH:3]1[CH:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([O:25][CH3:26])=[CH:9][CH:10]=2)[O:5][CH2:4]1)#[N:2]
Reactant: COc1ccc2c(c1)OC=C(C#N)C2c1cc(OC)c(OC)c(OC)c1
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)OCC(C#N)C2c1cc(OC)c(OC)c(OC)c1

Procedure:
3-Cyano-7-methoxy-4-(3,4,5-trimethoxy-phenyl)-4H-chromene (25 mg, 0.07 mmol) was dissolved into EtOAc (1 mL). The solution was purged with nitrogen, and a catalytic amount of Pd/C 10% was added. The reaction was put under H2 pressure at 60 psi for 5 h. The solution was flushed with nitrogen, filtered on a Celite pad, and the pad was washed with EtOAc (5 mL). The solution was concentrated. Purification with bond elute silica gel using 20% EtOAc/hexane yielded 24 mg (72%) as a white solid. 1H NMR (CDCl3): 6.83 (d, J=8.3 Hz, 1H), 6.51 (d, J=2.6 Hz, 1H), 6.48 (dd, J=2.5, 5.1 Hz, 1H), 6.45 (s, 2H), 4.38-4.33 (m, 3H), 3.86 (s, 3H), 3.80 (s, 9H), 3.40-3.37 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]([CH3:15])[C:13](=[O:16])[C:12]([CH3:18])([CH3:17])[C:11]2=[O:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[NH4+].[CH2:22]1COCC1>>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[C:11](=[O:19])[C:12]([CH3:18])([CH3:17])[C@:13]([OH:16])([CH3:22])[C@H:14]2[CH3:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C1CCOC1
Reactant: CC1C(=O)C(C)(C)C(=O)N1c1ccc(C#N)c(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Product: C[C@H]1N(c2ccc(C#N)c(Cl)c2)C(=O)C(C)(C)[C@@]1(C)O
Temperature: 25 °C
Yield: 30 %

Procedure:
A solution of 2-chloro-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (90 mg) in THF (5 mL) was cooled to −78° C., methylmagnesium bromide-ether solution (0.22 mL, 3 mol/L) was added under a nitrogen atmosphere, and the reaction mixture was warmed to room temperature. The reaction mixture was again cooled to −78° C., a 3mol/L methylmagnesium bromide-ether solution (0.89 mL) was added, and the reaction mixture was warmed to room temperature. The reaction mixture was added to saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid (yield: 29 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:16][CH2:15][CH2:14][C:13]3[C:9]2=[CH:10][N:11]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[N:12]=3)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:13]([CH2:14][CH2:15][CH:16]=2)=[N:12][N:11]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH:10]=3)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c(n2)CCCC3(O)c2ccc(Cl)cc2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc3c(n2)CCC=C3c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
4-(4-Chlorophenyl)-2-(p-tolylsulfonyl)-6,7-dihydro-5H-indazol-4-ol (0.76 g, 1.89 mmol) is added to dichloromethane (20.0 mL), triethylsilane (6.04 mL, 37.7 mmol), and TFA (0.16 mL, 2.07 mmol) and stirred at room temperature for 2.0 h. The reaction is quenched with saturated NaHCO3, separated, the organics washed with brine dried over Na2SO4, filtered, and evaporated to dryness to give the title compound (0.622 g, 86%). 1H NMR (CDCl3) δ 2.42 (s, 3H), 2.55 (m, 2H), 2.82 (t, 2H), 5.98 (t, 1H), 7.37-7.31 (m, 6H), 7.81 (s, 1H), 7.87 (d, 2H).
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[C:8]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(=[NH:10])[NH2:9].CO[CH:26]=[C:27]([C:32]([CH3:34])=O)[C:28]([O:30][CH3:31])=[O:29]>CO>[CH2:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:9]=[C:32]([CH3:34])[C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][N:10]=2)[CH2:12][CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Reactant: COC=C(C(C)=O)C(=O)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cnc(N2CCN(Cc3ccccc3)CC2)nc1C
Yield: 87.9 %

Procedure:
One hundred milliliters of a 1M solution of sodium hydroxide in methanol were added to a suspension (60 ml) of 26.8 g (0.1 mol) of 1-amidino-4-benzylpiperazine sulfate [which had been synthesized in accordance with the process disclosed in J. Am. Chem. Soc., 66, 263 (1944)] in methanol, followed by a dropwise addition of 15.8 g (0.1 mol) of methyl α-methoxymethyleneacetoacetate. After stirring the resultant mixture overnight at room temperature, the precipitated sodium sulfate was filtered off. After distilling off methanol, the residue was dissolved in 500 ml of ethyl acetate. The resultant solution was washed twice with 100 ml of water. The ethyl acetate layer was washed with saturated saline and then dried with anhydrous magnesium sulfate. Upon distilling off ethyl acetate, 28.7 g of the intended compound was obtained as an orange-colored oily substance (yield: 88%). When the oily substance was left over at room temperature subsequent to its distillation under a reduced pressure, it was crystallized.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:16]2[CH2:21][C:20](=[O:22])[C:19]([C:23](=O)[CH2:24][CH3:25])=[C:18]([OH:27])[CH2:17]2)=[C:4]2[C:9](=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13])[C:8](=[O:15])[CH2:7][CH2:6][CH2:5]2.Cl.[CH2:29]([O:31][NH2:32])[CH3:30].C([O-])(=O)C.[Na+].Cl>>[CH3:1][C:2]1[C:3]([CH:16]2[CH2:21][C:20](=[O:22])[C:19]([C:23](=[N:32][O:31][CH2:29][CH3:30])[CH2:24][CH3:25])=[C:18]([OH:27])[CH2:17]2)=[C:4]2[C:9](=[C:10]([CH3:14])[C:11]=1[O:12][CH3:13])[C:8](=[O:15])[CH2:7][CH2:6][CH2:5]2
Reactant: CCC(=O)C1=C(O)CC(c2c(C)c(OC)c(C)c3c2CCCC3=O)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Product: CCON=C(CC)C1=C(O)CC(c2c(C)c(OC)c(C)c3c2CCCC3=O)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 5-(6,8-dimethyl-7-methoxy-1-oxo-1,2,3,4-tetrahydronaphth-5-yl)-3-hydroxy-2-propionylcyclohex-2-en-1-one (0.48 g), ethoxyamine hydrochloride (1 equiv), anhydrous sodium acetate (1 equiv) and absolute alcohol (30 ml) was stirred at room temperature for 1 hr. The mixture was poured into a very dilute aqueous hydrochloric acid solution which was then immediately extracted with diethyl ether. The dried (MgSO4) organic fraction was evaporated to give 5-(6,8-dimethyl-7-methoxy-1-oxo-1,2,3,4-tetrahydronaphth-5-yl)-2[1-(ethoxyimino)propyl]-3-hydroxycyclohex-2-en-1-one (6) as a pale yellow oil. Pmr spectrum (CDCl3 ; δ in ppm): 1.11-1.42 (6H,2xt); 1.9-3.8 (15H,m); 2.41 (3H,s); 2.52 (3H,s); 3.66 (3H,s); 4.14 (2H, q); OH not observed.
Reaction SMILES: [C:1]1([CH:7]([CH3:14])[CH2:8][O:9][CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:22]>C1(C)C=CC=CC=1>[C:1]1([CH:7]([CH3:14])[CH2:8][O:9][CH2:10][C:11]([NH2:22])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(COCC(=O)O)c1ccccc1
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(COCC(N)=O)c1ccccc1

Procedure:
The subtitle compound (4.39 g) was prepared according to the procedure in example 5 part b using 2-(2-phenyl-1-propoxy)acetic acid (5.0 g), oxalyl chloride 4.5 ml), concentrated ammonium hydroxide (20 ml), and toluene (30 ml).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:19][C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)=[C:17]([C:27](=[O:30])[NH:28][CH3:29])[C:16]=3[C:31]=2[F:32])[C:10]=1[CH3:11])[C:5](O)=[O:6].Cl.Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1([NH2:45])[CH2:44][O:43][CH2:42]1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:32][C:31]1[C:16]2[C:17]([C:27]([NH:28][CH3:29])=[O:30])=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[O:19][C:15]=2[CH:14]=[CH:13][C:12]=1[C:9]1[CH:8]=[C:4]([C:5](=[O:6])[NH:45][C:41]2([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=3)[CH2:42][O:43][CH2:44]2)[CH:3]=[C:2]([F:1])[C:10]=1[CH3:11]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(F)c3C)c(F)c12
Reactant: NC1(c2ccccn2)COC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)COC4)cc(F)c3C)c(F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-fluoro-5-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.050 g, 0.114 mmol, 1.0 eq) and 3-(pyridin-2-yl)oxetan-3-amine 2HCl (0.03 g, 0.134 mmol, 1.2 eq) in DMF at 0° C. was added TEA (0.15 ml, 1.08 mmol, 9 eq) and BOP reagent (0.06 g, 0.136 mmol, 1.2 eq). The reaction mixture was stirred as rt overnight. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 filtered and the filtrate concentrated. The crude product was purified by preparative HPLC. Yield: 0.010 g (15.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Cl)=[CH:5][C:3]=1[NH2:4].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1cc(Oc2ccccc2)c([N+](=O)[O-])cc1Cl
Temperature: 100 °C
Yield: 39.1 %

Procedure:
A mixture of 2,5-dichloro-4-nitroaniline (7.0 g), phenol (3.2 g), potassium carbonate (9.7 g) and dry dimethylformamide (50 ml) is stirred and heated at 100° C. for 7.5 hours. The mixture is then poured into 500 ml of ice water and stirred. The aqueous mixture is extracted with ethyl acetate (5×200 ml), the extracts are dried and evaporated to dryness. The residual oil is stirred with methylene chloride (20 ml), the resulting solid is collected and dried to yield 3.5 g of title product, m.p. 122°-124° C.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[N:4]1)[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[Cl:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C(=O)C.O1CCCC1>[Cl:46][C:45]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH2:41]4)=[O:39])[N:36]=3)[N:33]=2)=[CH:25][C:24]=1[NH:23][C:8]([C:6]1[C:5]([CH3:11])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=1)=[O:10]
Reactant: CCn1cc(C(=O)O)c(C)n1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CCn1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2Cl)c(C)n1
Yield: 32.3 %

Procedure:
Using 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (188 mg, 1.22 mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (107 μL, 1.22 mmol), N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (300 mg, 0.87 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 249, the title compound (135 mg, 33%) was obtained as a white powder. melting point 200° C.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[F:13][C:14]([F:24])([F:23])[C:15]([F:22])([F:21])[C:16](OCC)=[O:17]>>[O:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=[C:4]1[C:1](=[O:3])[CH2:2][C:16](=[O:17])[C:15]([F:22])([F:21])[C:14]([F:24])([F:23])[F:13]
Reactant: CC(=O)c1cc2ccccc2o1
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Product: O=C(CC(=O)C(F)(F)C(F)(F)F)c1cc2ccccc2o1

Procedure:
The compound was synthesized according to example 1 using 2-acetylbenzofuran and ethyl pentafluoropropionate as starting materials. The product was crystallized from petroleum ether. 1H NMR (CDCl3): 6.75 (s, 1 H); 7.35 (ddd, 1H, J=0.9 & 7.1 & 7.9 Hz); 7.51 (ddd, 1H, J=1.3 & 7.1 & 8.4 Hz); 7.58-7.60 (m, 1 H); 7.67 (d, 1H, J=0.9 Hz); 7.71-7.73 (m, 1 H). IR (film): 1614 (C═O); 1211, 1200 (C—F).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.O1CCOCC1.O.CC1(C)C(C)(C)OB([C:36]2[CH2:37][CH2:38][O:39][CH2:40][CH:41]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O>[O:39]1[CH2:38][CH:37]=[C:36]([C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[C:10]4[C:15](=[N:16][CH:17]=3)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]4)[CH:5]=[N:6][CH:7]=2)[CH2:41][CH2:40]1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: NC(=O)N1CCCc2cc(-c3cncc(Br)c3)cnc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: NC(=O)N1CCCc2cc(-c3cncc(C4=CCOCC4)c3)cnc21
Temperature: 100 °C

Procedure:
6-(5-Bromo-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (100 mg, 0.30 mmol, which is prepared according to the procedure for Step 1 to Step 4 of Example 15) is dissolved into 2 mL of dioxane/water (9:1). 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (94.6 mg, 0.45 mmol), K3PO4 (318 mg, 1.50 mmol) and PdCl2(DPPF)CH2Cl2 (24.5 mg, 0.03 mmol) are added. The mixture is heated at 100° C. for 48 hrs. The mixture is diluted with 100 mL EtOAc and quenched with 100 mL of saturated aqueous NH4Cl. The organic phase is washed with 2×20 mL of H2O and 1×20 mL of brine. The organic phase is dried with MgSO4, filtered and concentrated. The crude material is applied to a silica preparative TLC plate and purified twice to give 52.1 mg of the titled product.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].Cl.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27].C(N(CC)CC)C.O>C(#N)C>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:27][CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: NCc1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: C=CCNc1nc(NCc2ccccn2)nc2ccc([N+](=O)[O-])cc12
Yield: 93.9 %

Procedure:
150 mg (0.57 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline was dissolved in 10 ml of acetonitrile, and then 165 mg (1.14 mmol) of 2-pyridylmethylamine hydrochloride and 0.40 ml (2.85 mmol) of triethylamine were added thereto, followed by heating under reflux overnight. To the reaction solution was added water, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 180 mg (93.9%) of the title compound.
Reaction SMILES: [C:1]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)([OH:3])=[O:2].S(Cl)(Cl)=O.CCOCC.[CH2:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:2][C:1]([CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][NH:6][CH2:5]1)=[O:3])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)C1CCCCNC1
Reactant: OCc1ccccc1
Solvent: CCOCC
Solvent: O=S(Cl)Cl
Product: O=C(OCc1ccccc1)C1CCCCNC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Suspend 1.15 g 3-carboxyperhydroazepine [P. Krogsgaard-Larsen et al., Acta Chem. Scand., B32, 327 (1978)] in 8 ml benzyl alcohol. Cool the mixture to 0° and add 1 ml thionyl chloride. Stir the mixture at room temperature for 48 hours, then add it dropwise to 300 ml ether with vigorous stirring. Decant the ether and dissolve the residue in H2O. Wash the aqueous solution with ether, then make it to pH 12 and extract with ethyl acetate. Dry the extracts and concentrate in vacuo to obtain 3-benzyloxycarbonylperhydroazepine.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([C:50]([F:53])([F:52])[F:51])[CH:39]=2)[C:35]([OH:37])=O)[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([C:50]([F:52])([F:51])[F:53])[CH:39]=2)[C:35]([NH:54][C:55]2[S:56][CH:57]=[CH:58][N:59]=2)=[O:37])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Nc1nccs1
Reactant: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of triphenylphosphine (213 mg, 0.84 mmol) in methylene chloride (12 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (144 mg, 0.84 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with the 3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-propionic acid (150 mg, 0.4 mmol). The clear solution was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 2 h. The reaction mixture was then treated with 2-aminothiazole (122 mg, 1.22 mmol), and the resulting suspension was stirred for 15 h at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (30 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×20 mL). The combined organic extracts were successively washed with a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/2 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(5-methyl-tetrazol-1-yl)-3-trifluoromethyl-phenyl]-N-thiazol-2-yl-propionamide (128 mg, 70%) as an amorphous solid: EI-HRMS m/e calcd for C20H21F3N6OS (M+) 450.1449, found 450.1454.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][N:5]=1)([O-])=O.O.[Cl-].[NH4+]>O1CCCC1.[Fe]>[CH3:13][Si:12]([C:11]#[C:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[N:5][CH:6]=1)([CH3:14])[CH3:15]
Reactant: C[Si](C)(C)C#Cc1ccc([N+](=O)[O-])nc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C[Si](C)(C)C#Cc1ccc(N)nc1
Temperature: 70 °C
Reaction time: 1.25 h
Yield: 91.1 %

Procedure:
To a solution of 2-nitro-5-trimethylsilanylethynyl-pyridine (405 mg, 1.84 mmol) described in Manufacturing Example 28-1-1 in tetrahydrofuran (10 mL) and water (5 mL) were added iron powder (514 mg, 9.21 mmol) and ammonium chloride (197 mg, 3.69 mmol) at room temperature, which was stirred for 75 minutes at 70° C. The reaction solution was cooled to room temperature and filtered through a Celite pad, and the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (319 mg, 91%).
Reaction SMILES: [NH:1]([C:8]1[N:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([NH:12][NH2:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.O>CCO>[F:18][C:19]([F:28])([F:29])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[N:13][NH:12][C:10]([C:9]1[C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:17][CH:16]=[CH:15][CH:14]=1)=[O:11]
Reactant: NNC(=O)c1cccnc1Nc1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: O
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1cccnc1Nc1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred solution of 2-anilino-nicotinic acid hydrazide (0.31 g, 1.05 mmol) in 20 mL EtOH was added 3-trifluoromethyl-benzaldehyde (0.182 g, 1.05 mmol) in 5 mL EtOH at room temperature. The mixture was refluxed for 4 h and cooled to room temperature, then diluted by 100 mL water. The precipitate was collected by filtration, washed with MeOH, and dried to yield the title compound (0.343 g, 85%). 1H NMR (acetone-d6): 11.40 (S, 1H), 11.80 (S, 1H), 8.56 (s, 1H), 8.37 (d, J=4.8 Hz, 1H), 8.22 (d, J=8.1 Hz, 1H), 8.13 (s, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.80 (m, 3H), 7.12 (m, 1H), 7.32 (m, 2H), 7.0 (t, J=8.1 Hz, 1H), 6.86 (q, J=4.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C(F)(F)F)=[CH:4][CH:3]=1.[CH3:18][C:19]1[N:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:29]=2[F:35])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22]>>[F:35][C:29]1[C:30]([F:34])=[CH:31][CH:32]=[CH:33][C:28]=1[C:26]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][NH:9]3)=[CH:4][CH:3]=2)=[O:22])=[C:19]([CH3:18])[N:27]=1
Reactant: Cc1nc(-c2cccc(F)c2F)ccc1C(=O)O
Reactant: Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2
Product: Cc1nc(-c2cccc(F)c2F)ccc1C(=O)Nc1ccc2c(c1)NCCC2

Procedure:
Using the procedure outlined in Example 38, the title compound was prepared from 7-amino-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (D5) (48 mg, 0.20 mmol) and 2-methyl-6-(2,3-difluorophenyl)-nicotinic acid (D26) (54 mg, 0.22 mmol) as an off-white solid. MS(ES): MH+ 380, M-H+ 378.
Reaction SMILES: C(OC(=O)[N:7]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([NH:30][CH2:31][C:32]23[CH2:41][CH:36]4[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]4)[CH2:33]2)[CH2:39]3)=[O:29])[C:25]([Cl:42])=[CH:24][N:23]=1)[CH2:8][CH2:9][CH2:10][O:11][Si](C(C)(C)C)(C)C)(C)(C)C>Cl.O1CCOCC1>[ClH:42].[ClH:42].[C:32]12([CH2:31][NH:30][C:28](=[O:29])[C:26]3[C:25]([Cl:42])=[CH:24][N:23]=[C:22]([CH2:21][CH2:20][CH2:19][NH:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:27]=3)[CH2:39][CH:38]3[CH2:40][CH:34]([CH2:35][CH:36]([CH2:37]3)[CH2:41]1)[CH2:33]2
Reactant: CC(C)(C)OC(=O)N(CCCO[Si](C)(C)C(C)(C)C)CCCc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCO)ncc1Cl
Yield: 201.4 %

Procedure:
tert-Butyl[3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)propyl](3-{[tert-butyl(dimethyl)silyl]oxy}propyl)carbamate (Example 2(vi)) (0.46 g) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (10 ml of a 4M solution) and concentrated; the resultant solid was recrystallised from 1,4-dioxane/methanol and the solid collected by filtration to afford the titled compound (0.24 g) as a colourless powder.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH2:16][OH:17])[C:10]3[O:14][CH:13]=[CH:12][C:11]=3[CH:15]=2)[N:5]=[N:4][N:3]=1>O1CCOCC1.[O-2].[Mn+4].[O-2]>[CH3:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[O:17])[C:10]3[O:14][CH:13]=[CH:12][C:11]=3[CH:15]=2)[N:5]=[N:4][N:3]=1
Reactant: Cc1nnnn1-c1cc(CO)c2occc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: Cc1nnnn1-c1cc(C=O)c2occc2c1
Reaction time: 2 h
Yield: 62.6 %

Procedure:
[5-(5-Methyl-tetrazol-1-yl)-benzofuran-7-yl]-methanol (124 mg,) and manganese (IV) oxide (140 mg) in 1,4-dioxan (5 ml) was heated at reflux for 18 h. A further portion of manganese (IV) oxide (210 mg) was added and heating continued for 2 h. The reaction mixture was filtered through a plug of Hyflo, the pad was washed with chloroform (20 ml) and the filtrate was evaporated in vacuo to give the title compound as a white powder (77 mg).