Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]2C3CCN(C(OC(C)(C)C)=O)CC3O[C:4]=2[CH:3]=1.[C:22]([N:29]1[CH2:34][CH:33]=[CH:32][CH:31]([OH:35])[CH2:30]1)([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].BrC1C=C(OC)C=CC=1O>>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:35][CH:31]3[CH2:30][N:29]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:34][CH2:33][CH:32]3[C:6]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(I)cc3OC2C1
Reactant: CC(C)(C)OC(=O)N1CC=CC(O)C1
Agent: COc1ccc(O)c(Br)c1
Product: CC(C)(C)OC(=O)N1CCC2c3cc(I)ccc3OC2C1

Procedure:
Tert-butyl 6-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate was synthesized as described for tert-butyl 7-iodo-3,4,4a,9a-tetrahydro[1]benzofuro[2,3-c]pyridine-2(1H)-carboxylate P01 starting from N-boc-3-hydroxy-1,2,3,6-tetrahydropyridine and 2-bromo-4-methoxyphenol. MS m/z 402 [M+H]+
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:23]=[CH:22][C:21]3[CH:20]([N:24]([CH:26]4[CH2:28][CH2:27]4)[CH3:25])[CH2:19][CH2:18][C:17]([CH3:30])([CH3:29])[C:16]=3[CH:15]=2)=[CH:8][C:7]=1[F:31])C.CO.O.[OH-].[Li+]>O>[CH:26]1([N:24]([CH3:25])[CH:20]2[CH2:19][CH2:18][C:17]([CH3:30])([CH3:29])[C:16]3[CH:15]=[C:14]([C:13]#[C:12][C:9]4[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:32])=[O:3])=[C:7]([F:31])[CH:8]=4)[CH:23]=[CH:22][C:21]2=3)[CH2:28][CH2:27]1
Reactant: CCOC(=O)Cc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C1CC1)C1CCC(C)(C)c2cc(C#Cc3ccc(CC(=O)O)c(F)c3)ccc21

Procedure:
Following general procedure J and using [4-(5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-ylethynyl)-2-fluoro-phenyl]-acetic acid ethyl ester (Compound 17, 0.025 g, 0.059 mmol), methanol (1 mL), tetrahydroftiran (1 mL), water (0.5 mL) and lithium hydroxide monohydrate (0.060 g, 1.43 mmol), the title compound was obtained as a white solid (0.023 g, 95%).
Reaction SMILES: [NH2-].[Na+].[CH2:3]([C:10]1([OH:20])[CH2:15][CH:14]2[C:16]([CH3:18])([CH3:17])[C:11]1([CH3:19])[CH2:12][CH2:13]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.N.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26]Cl.C(O)(=O)C(C(C(O)=O)O)O.Cl.[OH-].[NH4+]>C1C=CC=CC=1.O>[CH2:3]([C:10]1([O:20][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:22])[CH2:15][CH:14]2[C:16]([CH3:17])([CH3:18])[C:11]1([CH3:19])[CH2:12][CH2:13]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CN(C)CCCCl
Reactant: CC1(C)C2CCC1(C)C(O)(Cc1ccccc1)C2
Agent: Cl
Agent: N
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: O
Solvent: c1ccccc1
Product: CN(C)CCCOC1(Cc2ccccc2)CC2CCC1(C)C2(C)C
Temperature: 30 °C

Procedure:
A suspension of 3.9 g (0.1 mole) of sodium amide in 100 ml of anhydrous benzene is heated to boiling, and a solution of 24.4 g (0.1 mole) of (±)-2-benzyl-1,7,7-trimethyl-bicyclo(2,2,1)-heptan-2-ol in 100 ml of anhydrous benzene is added dropwise, under continuous stirring. When the addition of the above solution is completed the reaction mixture is boiled until the formation of ammonia gas is ceased, and while further continuing the stirring, a solution of 13.4 g (0.11 mole) of 1-dimethylamino-3-chloro-propane in 20 ml of anhydrous benzene is added. After boiling the mixture for further 6 hours it is cooled to 30° C., washed three times with 40 ml of water each, and extracted with a solution of 15 g (0.1 mole) of tartaric acid in 50 ml of water or with 0.11 mole of diluted aqueous hydrochloric acid. The aqueous solution cooled to 0°-5° C. is made alkaline to pH 10 with concentrated ammonium hydroxide. The base separated as an oil is extracted with dichloroethane. On distilling off the solvent, the residue is fractionated in vacuo.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:24])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(O)ncnc2cc1OCc1ccccc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Temperature: 120 °C
Yield: 71.5 %

Procedure:
A stirred mixture of 7-(benzyloxy)-6-methoxyquinazolin-4-ol (5.10 g, 18.09 mmol) and phosphorous oxychloride (10 mL, 109 mmol) in dry toluene (30 mL), was heated to 120° C. for 2 h. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed with sat aqueous NaHCO3 solution (2×100 mL). The organic layer was separated and dried over MgSO4 then concentrated under reduced pressure to afford 7-(benzyloxy)-4-chloro-6-methoxyquinazoline as a cream solid (3.89 g, 72%) which was taken into the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.85 (s, 1H), 7.49 (m, 2H), 7.33-7.43 (m, 5H), 5.33 (s, 2H), 4.07 (s, 3H); LC-MS (ESI) m/z 301 (M+H)+.
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9](N)=[CH:8][CH:7]=1.[ClH:15]>O.[Cu](Cl)Cl>[Br:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([Cl:15])=[CH:8][CH:7]=1
Reactant: Cl
Reactant: COc1nc(Br)ccc1N
Agent: Cl[Cu]Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1nc(Br)ccc1Cl
Reaction time: 0.17 h
Yield: 85 %

Procedure:
A solution of sodium nitrite (7.04 g) in water (10 mL) was added dropwise to a suspension of 6-bromo-2-methoxypyridin-3-amine (10.4 g) in concentrated hydrochloric acid (35 mL) under ice-cooling. After stirring for 10 minutes, the reaction system was added dropwise to a suspension of copper chloride (12.7 g) in concentrated hydrochloric acid (15 mL) under ice-cooling, and the mixture was stirred at 65° C. for one hour and 15 minutes. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→7:3) to give the title compound as a yellow powder (9.69 g, 85%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](C3(CCC(O)=O)C4C(=CC=CC=4)N(CCCCC)C3=O)=[CH:9][C:4]=2[O:3][CH2:2]1.O1C2C=C[C:37]([C:39]3(CC(O)=O)[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:41]([CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[C:40]3=[O:53])=[CH:38][C:33]=2[O:32]C1>>[CH2:48]([N:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39]2([CH2:37][CH2:38][C:33](=[O:32])[C:8]3[C:7]2=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=3)[C:40]1=[O:53])[CH2:49][CH2:50][CH2:51][CH3:52]
Reactant: CCCCCN1C(=O)C(CC(=O)O)(c2ccc3c(c2)OCO3)c2ccccc21
Reactant: CCCCCN1C(=O)C(CCC(=O)O)(c2ccc3c(c2)OCO3)c2ccccc21
Product: CCCCCN1C(=O)C2(CCC(=O)c3cc4c(cc32)OCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 21, and making non-critical variations using 3-[3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]propanoic acid to replace [3-(1,3-benzodioxol-5-yl)-2-oxo-1-pentyl-2,3-dihydro-1H-indol-3-yl]acetic acid, the title compound was obtained (32%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.57 (s, 1H), 7.37-7.28 (m, 1H), 7.08-7.03 (m, 2H), 6.95 (d, 1H), 6.02 (s, 1H), 5.95-5.91 (m, 2H), 3.73 (t, 2H), 3.37-3.24 (m, 1H), 2.79-2.67(m, 1H), 2.41-2.32 (m, 2H), 1.76-1.64 (m, 2H), 1.38-1.28 (m, 4H), 0.87 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 195.4, 177.4, 152.3, 148.0, 142.7, 138.9, 133.6, 128.8, 128.4, 124.1, 122.9, 108.9, 106.9, 106.6, 101.9, 51.7, 40.2, 33.1, 32.8, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 400.1 (M+23), 378.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[NH:14][C:13]2=O)=[C:4]([F:25])[CH:3]=1.P(Cl)(Cl)([Cl:28])=O>N1C=CC=CC=1>[Cl:28][C:13]1[N:12]([C:5]2[CH:6]=[C:7]([O:8][CH:9]([CH3:11])[CH3:10])[C:2]([Cl:1])=[CH:3][C:4]=2[F:25])[C:17](=[O:18])[C:16]([F:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[N:14]=1
Reactant: CC(C)Oc1cc(-n2c(=O)[nH]c(C(F)(F)F)c(F)c2=O)c(F)cc1Cl
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)Oc1cc(-n2c(Cl)nc(C(F)(F)F)c(F)c2=O)c(F)cc1Cl

Procedure:
using 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-5-fluoro-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with phosphorus oxychloride and pyridine within 15 minutes at 20°-40° C. and thereafter for 1 hour at 70° C. there is obtained 2-chloro-1-(4-chloro-2-fluoro -5-isopropoxyphenyl)-5-fluoro-4-trifluoromethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 60 MHz): 7.42 ppm (d,1H), 6.84 ppm (d,1H), 4.50 ppm (m,1H), 1.44 ppm (d,6H);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH2:25][CH3:26])[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1.[Cu][C:28]#[N:29]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N:6]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:5]2([CH2:25][CH3:26])[C:18]1[CH:23]=[CH:22][C:21]([C:28]#[N:29])=[CH:20][CH:19]=1
Reactant: N#C[Cu]
Reactant: CCC1(c2ccc(Br)cc2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Solvent: CN(C)C=O
Product: CCC1(c2ccc(C#N)cc2)c2cc(Cl)ccc2NC(=O)N1CC(F)(F)F
Temperature: 200 °C

Procedure:
To a solution of 0.062 g (0.14 mmol) 6-chloro-4-ethyl-4-(4-bromophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one in 1 mL DMF was added 0.015 g (0.17 mmol) copper(I) cyanide and the mixture heated in a sealed tube at 200° C. for 2 hours. After cooling to room temperature, the mixture was filtered and the resulting DMF solution purified by preperative reverse phase chromatography (linear gradient 5 to 95% CH3CN/H2O over 30 min, 0.05% added TFA, C18 SunFire 19×150 mm) to provide 6-chloro-4-ethyl-4-(4-cyanophenyl)-3-(2,2,2-trifluoroethyl)-3,4-dihydroquinazolin-2(1H)-one. 1H NMR (CDCl3, 400 MHz) δ 8.06 (s, NH); 7.71 (br d, 2H, J=8.24 Hz); 7.55 (br d, 2H, J=8.43 Hz); 7.14 (dd, 1H, J=8.61 and 2.20 Hz); 6.69 (d, 1H, J=8.61 Hz); 6.43 (d, 1H, J=2.02 Hz); 3.78 (dq, 1H, J=8.97 and 18 Hz); 3.60 (dq, 1H, J=8.43 and 17 Hz); 2.44 (dq, 1H, J=7.15 and 14 Hz); 2.27 (dq, 1H, J=7.14 and 14 Hz); 0.93 (t, J=7.15 Hz, 3H); MS (Electrospray): exact mass calculated for C19H15ClF3N3O+H 394.0929 found 394.0937
Reaction SMILES: [O:1]=[C:2]1[C@H:6]([NH:7][C:8]([C:10]2[C:14]([CH3:15])=[C:13](/[CH:16]=[C:17]3\[C:18](=[O:27])[NH:19][C:20]4[C:25]\3=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[NH:12][C:11]=2[CH3:28])=[O:9])[CH2:5][O:4][NH:3]1.[H-].[Na+].Br[CH2:32][C:33]([N:35]([CH3:37])[CH3:36])=[O:34]>>[CH3:36][N:35]([CH3:37])[C:33]([CH2:32][N:3]1[C:2](=[O:1])[C@H:6]([NH:7][C:8]([C:10]2[C:14]([CH3:15])=[C:13](/[CH:16]=[C:17]3\[C:18](=[O:27])[NH:19][C:20]4[C:25]\3=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[NH:12][C:11]=2[CH3:28])=[O:9])[CH2:5][O:4]1)=[O:34]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)N[C@@H]1CONC1=O
Reactant: CN(C)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)N[C@@H]1CON(CC(=O)N(C)C)C1=O
Yield: 13.6 %

Procedure:
To the solution of 42b (1.0 eq.) cooled on ice bath was added NaH (4.0 or 1.5 eq.). The resulting mixture was stirred for an hour and was then added 2-bromo-N,N-dimethylacetamide (1.0 eq.), the reaction mixture was stirred at room temperature for several hours. LC/MS detection was applied to determine completion of the reaction. DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine/methanol under sonication. The solid was collected by filtration, washed with methanol twice, and further purified by column chromatography to obtain title compound (30 mg, 13.6% yield) as orange solids: 1H NMR (300 MHz, DMSO-d6): δ=13.73 (s, 1H), 10.93 (s, 1H), 8.05-8.08 (d, 1H), 7.74-7.80 (m, 2H), 6.82-6.97 (m, 2H), 5.06-5.15 (q, 1H), 4.39-4.58 (m, 3H), 4.05-4.11 (q, 1H), 2.97 (s, 3H), 2.84 (s, 3H), 2.44-2.47 (ds, 6H). LC/MS: 468.2 [M−H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:40]([NH:42][C@H:43]([C:48]([OH:50])=[O:49])[CH2:44][CH2:45][S:46][CH3:47])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:27])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=O)(C)(C)C.[ClH:51]>O1CCOCC1>[ClH:51].[NH2:8][C@H:9]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH2:25][C:26]([NH:28][C@H:29]([C:40]([NH:42][C@H:43]([C:48]([OH:50])=[O:49])[CH2:44][CH2:45][S:46][CH3:47])=[O:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)=[O:27])=[O:23])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CNC(=O)CNC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O

Procedure:
The N-t-butoxycarbonyl-L-tyrosylglycylglycyl-L-tryptophyl-L-methionine is dissolved in 100 parts dioxane and stirred with a ten-fold excess of 2 N hydrochloric acid at room temperature for 15 minutes. The solvent is then removed under reduced pressure and the residue is triturated with ethyl ether. The resulting solid is precipitated from the mixture of methanol and ether to afford L-tyrosylglycylglycyl-L-tryptophyl-L-methionine hydrochloride. This compound is represented by the following formula
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[O:22][CH2:23][CH:24]3[CH2:26][CH2:25]3)[C:9]=2[NH:8][C:7]=1[CH3:27])=[O:5])[CH3:2].Cl[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34]>>[CH:24]1([CH2:23][O:22][C:16]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=2[C:14]2[C:9]3[N:8]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:7]([CH3:27])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:10]=3[N:11]=[CH:12][N:13]=2)[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1c(C)[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1c(C)n(COCC[Si](C)(C)C)c2c(-c3ccc(F)cc3OCC3CC3)ncnc12

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid ethyl ester (example D.a2) and commercially available (2-chloromethoxy-ethyl)trimethyl-silane the title compound is prepared as pale yellow viscous oil.
Reaction SMILES: [H-].[Na+].O1CCC[CH2:4]1.[CH3:8][C:9]([NH:12][C:13]1[O:14][C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1)([CH3:11])[CH3:10].CI>>[CH3:11][C:9]([N:12]([CH3:4])[C:13]1[O:14][C:15]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([C:18]([F:20])([F:21])[F:19])[N:17]=1)([CH3:8])[CH3:10]
Reactant: CCOC(=O)c1oc(NC(C)(C)C)nc1C(F)(F)F
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CCOC(=O)c1oc(N(C)C(C)(C)C)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 50% oil dispersion of sodium hydride (0.38 g; 7.9 mmol) was washed three times with petroleum ether under a nitrogen atmosphere. The oil-free sodium hydride was suspended in 15 mol anhydrous tetrahydrofuran in a reaction vessel cooled in an ice bath. Then, with the sodium hydride suspension at 0° C. and stirred, there was added dropwise 25 ml anhydrous tetrahydrofuran containing 2.0 g (7.15 mmol) of ethyl 2-[(1,1-dimethylethyl)amino]-4-trifluoromethyl-5-oxazolecarboxylate (as prepared in Example 6. The reaction mixture was stirred for 1/2 hour at 0° C. and then 15 ml of anhydrous tetrahydrofuran containing 2.54 g (20 mmol) of methyl iodide was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 3 hours. An additional 0.2 g (4 mmol) of 50% oil dispersion of sodium hydride (washed as before) was added and the mixture was stirred at room temperature for one hour. The reaction mixture was heated at reflux for 45 minutes, then stirred overnight at ambient temperature. The mixture was partitioned between ethyl ether and 5% hydrochloric acid solution. The organic phase was dried with sodium sulfate and concentrated under reduced pressure to yield 2.1 g of a reddish-brown product which was subjected to Kugelrohr distillation (100°-120° C. @ 2.5 mm Hg) to yield 1.7 g of a brown oil. This brown oil was dissolved in methylene chloride, washed with 10% sodium bisulfite, and concentrated under reduced pressure to yield 1.3 g of a colorless oil which was subjected to Kugelrohr distillation (100° C. @ 4 mm Hg) to yield 1.25 g of a pale yellow oil identified in Table I.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][N:33]([CH2:21][CH2:20][CH2:19][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:32][CH2:31]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4ccccc4F)CC3)nn2-c2ccccc2)cc1

Procedure:
105 mg (77%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-(2-fluorophenyl)piperazine (50 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:40]([CH2:42]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:41]>CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:42]=[N:40][CH:41]=2)[C:5]2[C:10]([O:32][CH3:33])=[N:11][N:12]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C=O)c12
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(-c3cnco3)c12
Temperature: 65 °C
Reaction time: 8 h

Procedure:
6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbaldehyde (Intermediate 11B, 200 mg, 0.441 mmol), potassium carbonate (63.9 mg, 0.463 mmol) and 1-(isocyanomethylsulfonyl)-4-methylbenzene (90 mg, 0.463 mmol) were taken up in MeOH (1.8 ml) and were stirred at 65° C. overnight. The mixture was concentrated in vacuo while loading onto silica gel and purificied by MPLC 0-25% EtOAc/DCM to give 5-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)oxazole (54B). MS: [M+H]+ m/z 493.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH2:6][N:7]1[CH2:21][CH2:20][C:19]2[C:10](=[N:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[C:18]=2[CH3:22])[CH2:9][CH2:8]1)C.[ClH:24]>>[ClH:24].[ClH:24].[CH3:22][C:18]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=[C:10]2[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][C:4]([OH:23])=[O:3])[CH2:21][CH2:20][C:19]=12
Reactant: CCOC(=O)CCN1CCc2nc3ccccc3c(C)c2CC1
Agent: Cl
Product: Cc1c2c(nc3ccccc13)CCN(CCC(=O)O)CC2
Yield: 76 %

Procedure:
3-[1,2,4,5-Tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline-3-yl]propionic acid dihydrochloride was prepared by hydrolysis of 3-[1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline-3-yl]propionic acid ethyl ester with 2 N hydrochloric acid at reflux temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][CH2:26][OH:27]>CN(C=O)C.Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Cl:16])[C:3]=1[O:17][CH2:25][CH2:26][OH:27]
Reactant: Oc1c(Cl)cc(OCc2ccccc2)cc1Cl
Reactant: OCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCOc1c(Cl)cc(OCc2ccccc2)cc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 68.5 %

Procedure:
A mixture of 13 grams (0.048 mole) of 2,6-dichloro-4-phenylmethoxyphenol (known compound), 6.8 grams (0.048 mole) of potassium carbonate and 3.9 grams (0.048 mole) of 2-chloroethanol in 80 mL of DMF was heated to 70° C. where it stirred for three hours. After this time the reaction mixture was allowed to cool to ambient temperature. The reaction mixture was diluted with 100 mL of aqueous 10% hydrochloric acid then extracted with three 150 mL portions of ethyl acetate. The combined extracts were washed with an aqueous saturated sodium chloride solution, dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The crude residue was purified with column chromatography on silica gel using 6:4 heptane:ethyl acetate as an eluant. The appropriate fractions were combined and concentrated under reduced pressure, yielding 10.3 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:25]([O:27][C:28](=[O:35])[CH2:29][CH:30](Br)[CH2:31][CH2:32][CH3:33])[CH3:26]>CN(C=O)C>[CH2:25]([O:27][C:28](=[O:35])[CH2:29][CH:30]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:31][CH2:32][CH3:33])[CH3:26]
Reactant: c1cnc2nc(CCCc3ccc4[nH]ccc4c3)ccc2c1
Reactant: CCCC(Br)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1ccc2cc(CCCc3ccc4cccnc4n3)ccc21
Reaction time: 0.25 h
Yield: 17 %

Procedure:
To a solution of 2-[3-(1H-indol-5-yl)-propyl]-[1,8]naphthyridine (0.18 g, 0.62 mmol) in DMF (2 mL) was added sodium hydride (30.0 mg, 1.24 mmol) at room temperature. After stirring for 15 minutes, 3-bromo-hexanoic acid ethyl ester (276 mg, 1.24 mmol) was added. The reaction mixture was stirred overnight and quenched with water. The crude product was extracted with methylene chloride, washed with brine, and purified via column chromatography with silica gel (ethyl acetate/hexane1:1), to give the title product (17% yield). 1H NMR (CDCl3) δ 9.08 (dd, J=1.7, 4.0 Hz, 1H), 8.14 (m, 1H), 8.06 (m, 1H), 7.32–7.44 (m, 4H), 7.05–7.12 (m, 2H), 6.45 (d, J=3.2 Hz, 1H), 4.81 (m, 1H), 3.99 (m, 2H), 3.08 (m, 2H), 2.83 (m, 4H), 2.22 (m, 2H), 1.90 (m, 2H), 1.20 (m, 2H), 1.07 (m, 3H), 0.87 (m, 3H). Mass Spectrum (LCMS, ESI) calculated for C27H32N3O2 430.3 (M+H); found 430.3.
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:31](=[O:47])[N:32]([CH2:36][CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)[CH2:33][CH2:34][CH3:35])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH2:10][C:11]([C:31](=[O:47])[N:32]([CH2:36][CH2:37][CH2:38][OH:39])[CH2:33][CH2:34][CH3:35])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCC)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCCO)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCC)cc3)cc2N=C(N)C1
Reaction time: 1 h
Yield: 35.6 %

Procedure:
Ethyl 4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate (0.050 g, 0.075 mmol) was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) afforded 0.012 g (35%) of ethyl 4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate.