Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:25])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:25][C:39]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2nc3ccccc3s2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2nc3ccccc3s2)CC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g (0.56 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(benzothiazol-2-yl)-piperazin-1-yl]-ethyl}-amine and 0.16 mL (1.12 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.086 g (0.59 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane (2 mL). The reaction mixture was allowed to stir under nitrogen for one hour at 0° C. and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.20 g (70%) as a white solid; mp=229–232° C.; MS (+) ESI m/z=469 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([OH:24])=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:25][N:26]1[CH2:31][CH2:30][N:29]([C:22]([C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[O:24])[CH2:28][CH2:27]1
Reactant: O=C(O)C1(c2ccc(OCCCN3CCCC3)cc2)CCCCC1
Reactant: CN1CCNCC1
Product: CN1CCN(C(=O)C2(c3ccc(OCCCN4CCCC4)cc3)CCCCC2)CC1
Yield: 8 %

Procedure:
The title compound (10 mg, 8%) was prepared using 1-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]cyclohexanecarboxylic acid and 1-methylpiperazine similarly to the procedure used for example 149. 1H NMR (400 MHz, CD3OD) δ 1.32 (m, 1H), 1.64-1.69 (m, 7H), 1.81-1.85 (m, 4H), 1.98-2.03 (m, 2H), 2.05-2.13 (m, 4H), 2.15 (s, 3H), 2.25-2.28 (m, 2H), 2.59-2.62 (m, 4H), 2.69 (t, 2H), 3.33-3.42 (m, 4H), 4.01 (t, 2H), 6.90 (d, 2H), 7.16 (d, 2H). HRMS ESI+ m/z 414.3107 [MH]+.
Reaction SMILES: COC1C=CC(B2OC(C)(C)C(C)(C)O2)=CN=1.[C:18]([N:21]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[CH:25][C:24]2[N:33]=[C:34]([C:38]3[CH:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)[C:35](F)=[CH:36][C:23]=2[CH2:22]1)(=[O:20])[CH3:19]>>[C:18]([N:21]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[CH:26]=[CH:25][C:24]2[N:33]=[C:34]([C:38]3[CH:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=3)[CH:35]=[CH:36][C:23]=2[CH2:22]1)(=[O:20])[CH3:19]
Reactant: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Agent: COc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: COc1ccc(-c2ccc3c(n2)C=Cc2ccccc2N(C(C)=O)C3)cn1
Yield: 59 %

Procedure:
The title compound (14.8 mg, 59%) was prepared from 13C (20.0 mg, 0.07 mmol) and 2A (24.7 mg, 0.105 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.612 min; LCMS Found: (M+H)+=358.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][C:21]([OH:23])=[CH:22][C:16]=3[S:15](=[O:25])(=[O:24])[CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:27][CH2:28][CH2:29][OH:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([N:12]2[CH2:18][C:17]3[CH:19]=[CH:20][C:21]([O:23][CH2:27][CH2:28][CH2:29][OH:30])=[CH:22][C:16]=3[S:15](=[O:25])(=[O:24])[CH2:14][CH2:13]2)[CH:3]=1
Reactant: OCCCBr
Reactant: O=S1(=O)CCN(c2cc(Cl)c3ccccc3n2)Cc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S1(=O)CCN(c2cc(Cl)c3ccccc3n2)Cc2ccc(OCCCO)cc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A mixture of 4-(4-chloroquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-ol 1,1-dioxide (374.0 mg, 1.0 mmol), 3-bromo-propan-1-ol (0.37 mL, 3.0 mmol) and potassium carbonate (415.0 mg, 3.0 mmol) in N,N-dimethylformamide (1.5 mL) was heated with stirring at 70° C. for 2 hours. After being cooled to room temperature, the resulting mixture was extracted with ethyl acetate (150 mL×2). The combined organic layers were washed with water (50 mL×2) and a saturated aqueous ammonium chloride solution (50 mL×2), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 421.6 mg of the crude product as a yellow oil which was used for next step without further purification. MS obsd. (ESI+) [(M+H)+] 433.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[S:12][C:13](I)=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[CH2:1]([O:8][C:9](=[O:20])[NH:10][C:11]1[S:12][C:13]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])=[CH:14][C:15]=1[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: NC(=O)c1cc(I)sc1NC(=O)OCc1ccccc1
Product: NC(=O)c1cc(-c2ccccc2F)sc1NC(=O)OCc1ccccc1

Procedure:
The title compound was synthesized from benzyl[3-(aminocarbonyl)-5-iodo-2-thienyl]carbamate (Intermediate 1, Step 2) (300 mg, 0.746 mmol) and 2-fluorophenyl boronic acid (157 mg, 1.12 mmol) as the starting materials as described in Intermediate 1 Step 3.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]=[N:16][C:17]([O:20][C@@H:21]3[CH:26]4[CH2:27][CH2:28][N:23]([CH2:24][CH2:25]4)[CH2:22]3)=[CH:18][CH:19]=2)=[CH:10][C:9]=1[N+:29]([O-:31])=[O:30])(C)(C)C.Cl>CCO>[N:23]12[CH2:24][CH2:25][CH:26]([CH2:27][CH2:28]1)[C@@H:21]([O:20][C:17]1[N:16]=[N:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([NH2:7])=[C:9]([N+:29]([O-:31])=[O:30])[CH:10]=3)=[CH:19][CH:18]=1)[CH2:22]2
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: Nc1ccc(-c2ccc(O[C@H]3CN4CCC3CC4)nn2)cc1[N+](=O)[O-]

Procedure:
The product of Example 28C (350 mg, 0.79 mmol) was treated with HCl (Aldrich, 4 M in dioxane, 2 mL, 8 mmol) in EtOH (5 mL) at ambient temperature for 1 h. The mixture was concentrated and the title compound was purified by chromatography (SiO2, EtOAc:MeOH (v. 2% NH3.H2O), 50:50, Rf. 0.1) as white solid (250 mg, 93%). 1H NMR (300 MHz, MeOH-D4) δ 1.54-1.66 (m, 1H), 1.72-2.02 (m, 2H), 2.07-2.24 (m, 1H), 2.35-2.57 (m, 1H), 2.79-3.18 (m, 5H), 3.48-3.69 (m, 1H), 5.27-5.47 (m, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.22 (d, J=9.5 Hz, 1H), 7.66 (s, 1H), 7.98 (d, J=9.2 Hz, 1H), 8.08 (dd, J=9.0, 2.2 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H) ppm. MS (DCI/NH3): 342 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([S:7][CH3:8])([CH3:6])[CH:3]=[N:4][OH:5].[CH3:9][N:10]=[C:11]=[O:12]>O>[CH3:1][C:2]([S:7][CH3:8])([CH3:6])[CH:3]=[N:4][OH:5].[CH3:9][NH:10][C:11]([O:5][N:4]=[CH:3][C:2]([CH3:6])([S:7][CH3:8])[CH3:1])=[O:12]
Reactant: CN=C=O
Agent: CSC(C)(C)C=NO
Solvent: O
Product: CNC(=O)ON=CC(C)(C)SC

Procedure:
The process of this invention can be conducted by mixing 2-methyl-2-(methylthio) propionaldehyde oxime with water at a temperature of from about 0° C. to about 30° C. after which a catalyst is optionally added to the mixture. While maintaining the reaction temperature between about 0° C. and 30° C., methyl isocyanate is added with vigorous stirring over a sufficient period of time to provide for substantially complete conversion of 2-methyl-2-(methylthio) propionaldehyde oxime to 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime as a solid in aqueous slurry which is then filtered to give a water-wet cake. The process of this invention can provide 2-methyl-2-(methylthio) propionaldehyde O-(methylcarbamoyl) oxime on a yield basis in excess of 90 percent based on the weight of 2-methyl-2-(methylthio) propionaldehyde oxime.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]CC)=O)[N:6]=1.Cl.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[C:24]2[CH2:30][CH2:31][NH:32][C:10]([C:7]1[N:6]=[C:5]([CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[Cl:1])[O:9][N:8]=1)=[O:12]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1noc(Cc2ccccc2Cl)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccccc2Cl)n1
Yield: 23.4 %

Procedure:
This compound was prepared according to method F with ethyl 5-(2-chlorobenzyl)-1,2,4-oxadiazole-3-carboxylate (0.115 g; 0.433 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), HATU (0.164 g; 0.432 mmol), N,N diisopropylethylamine (0.075 mL; 0.432 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and preparative HPLC method 2 to yield 0.042 g (24%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2-chlorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: C[O:2][C:3]1[C:11]([O:12]C)=[CH:10][C:6]2[N:7]=[CH:8][NH:9][C:5]=2[CH:4]=1.[H-].[Na+].[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.B(Br)(Br)Br>CCOC(C)=O.C(Cl)Cl>[Cl:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][N:7]2[C:6]3[CH:10]=[C:11]([OH:12])[C:3]([OH:2])=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:19][CH:18]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COc1cc2nc[nH]c2cc1OC
Agent: BrB(Br)Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1cc2ncn(Cc3ccc(Cl)cc3)c2cc1O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5,6-dimethoxybenzimidazole (0.100 g, 0.8 mmol) was added 60% NaH (0.021 g, 0.88 mmol). After stirring for 30 min, the 4-chlorobenzylbromide (0.171 g, 0.8 mmol) was added and the solution was heated to 60° C. for 2 h. The reaction solution was diluted with EtOAc (10 mL) and washed with aqueous saturated NaHCO3 (2×10 mL). The organic layer was dried with Na2SO4 and concentrated in vacuo. To a solution of the crude alkylated intermediate (0.8 mmol) in CH2Cl2 (10 mL) was added 1 M BBr3 in CH2Cl2 (1 mL, 1 mmol). After stirring for 16 h, the solvent was removed in vacuo and the crude product was purified by reverse-phase preparative HPLC to provide 1-(4-chloro-benzyl)-1H-benzoimidazole-5,6-diol.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)[CH2:2][CH:3]=[CH2:4].O.CC[O:16]CC>C1COCC1.[Cl-].[Na+].O>[OH:16][CH2:4][CH2:3][CH2:2][CH2:1][C:5]1[CH:6]=[CH:7][C:8]([C:9]#[N:10])=[CH:11][CH:12]=1
Reactant: CCOCC
Reactant: C=CCCc1ccc(C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CCCCO)cc1
Temperature: 0 °C

Procedure:
4-(3-Butenyl)benzonitrile (from step (i) above, 10.8 g, 69 mmol) was dissolved in dry THF (140 mL) and was cooled to 0° C. BH3-MeS complex (20 mL, 2 M) was added dropwise over 45 minutes at 0° C. and, after 7 hours, water (70 mL) and NaBO3-4H2O (25 g) were added and the mixture was stirred overnight before dilution with ether (700 mL) and brine (satd., 250 mL). After separation, the aqueous phase was extracted with ether (2×200 mL) and the combined extracts were dried, filtered and evaporated to give crude sub-title compound. Purification by flash chromatography on SiO2 (300 g) with heptane:EtOAc (3:1 to 1:1) gave the sub-title compound (6.99 g)
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].[C:27]([O-:31])(=[O:30])[CH2:28][CH3:29].[K+]>CC(C)=O.O>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][O:31][C:27](=[O:30])[CH2:28][CH3:29])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CCC(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCC(=O)OCC(=O)O[C@H]1[C@@H](CC)C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@@]21C
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.4 %

Procedure:
In a mixture of 50 ml of acetone and 12 ml of water are dissolved 2.5 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 0.7 g of potassium propionate. The solution is stirred at room temperature (17°-25° C.) for 3 days and concentrated under reduced pressure. The residue is extracted with 200 ml of ethyl acetate. The organic layer is separated, washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is subjected to column chromatography. Following passage of 1000 ml isopropyl ether-n-hexane (2:3), elution is carried out with 2000 ml of the same solvent system. The eluate is evaporated under reduced pressure to remove the solvent, giving 0.87 g of the above-identified compound as white crystals.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:2]1[C:11]2[C:6](=[C:7]([F:13])[CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2c(F)cc(F)cc12
Product: Fc1cc(F)c2nccc(Cl)c2c1

Procedure:
(4-Hydroxy-6,8-difluoro-quinoline, 29.1 g, 0.160 mol) was dissolved in POCl3(183 mL) and heated at reflux for 12 h. On complete consumption of starting material (tic) the contents were brought to RT and excess POCl3 was removed under reduced pressure. Crude mass was azeotroped with toluene and product was diluted with ethyl acetate, organics were washed with sodium bicarbonate and solvent removed under reduced pressure. Crude product was purified by column chromatography at 100-200 mesh size silica in 0-2% EtOAc-hexane. Mass: 199.99 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][CH2:42][NH:43][C:44](=[O:46])[CH3:45])=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[C:44]([NH:43][CH2:42][CH2:41][O:40][C:39]1[CH:38]=[C:37]([CH3:50])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:48]([CH3:49])[CH:47]=1)(=[O:46])[CH3:45]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: CC(=O)NCCOc1cc(C)c(Br)c(C)c1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCNC(C)=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and N-(2-(4-bromo-3,5-dimethylphenoxy)ethyl)acetamide following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.50 min; Mass spectrum (ESI+): m/z=548 [M+H]+.
Reaction SMILES: CC[N:3](C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:20][C:21]1[S:47][C:24]2[NH:25][C:26]([C:28]([NH:30][CH:31]3[CH2:40][C:39]4[C:34](=[CH:35]C=[CH:37][CH:38]=4)[N:33](CC(O)CO)[C:32]3=[O:46])=[O:29])=[CH:27][C:23]=2[CH:22]=1.ClC1SC2NC(C(NC3CC4C(=CC=CC=4)N(CC4ON=C(C)N=4)C3=O)=O)=CC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:20][C:21]1[S:47][C:24]2[NH:25][C:26]([C:28]([NH:30][CH:31]3[CH2:40][C:39]4[C:34](=[CH:35][N:3]=[CH:37][CH:38]=4)[NH:33][C:32]3=[O:46])=[O:29])=[CH:27][C:23]=2[CH:22]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(NC1Cc2ccccc2N(CC(O)CO)C1=O)c1cc2cc(Cl)sc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1noc(CN2C(=O)C(NC(=O)c3cc4cc(Cl)sc4[nH]3)Cc3ccccc32)n1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NC1Cc2ccncc2NC1=O)c1cc2cc(Cl)sc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.9 %

Procedure:
DIPEA (297 mg, 2.3 mmol), HOBT (128 mg, 0.95 mmol), 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (Method 9, 154 mg., 0.767 mmol) and 3-amino-3,4-dihydro-1,7-naphthyridin-2(1H)-one (Method 28, 300 mg, 0.767 mmol) were suspended in DCM (10 mL). EDCI (183 mg, 0.95 mmol) was then added and the reaction mixture stirred at ambient temperature for 2 hrs. The reaction mixture was filtered and the filtrate was diluted with ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate (2×25 mL) and brine (25 mL), dried (MgSO4) and evaporated under reduced pressure to give a light brown solid which was washed with methanol (20 mL) and dried to give the title compound (45 mg, 17%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11](Cl)=[O:12])[S:10][C:3]=12.[CH3:14][N:15]([CH3:17])[NH2:16]>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([NH:16][N:15]([CH3:17])[CH3:14])=[O:12])[S:10][C:3]=12
Reactant: O=C(Cl)c1cc2nccc(Cl)c2s1
Reactant: CN(C)N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)NC(=O)c1cc2nccc(Cl)c2s1
Reaction time: 5 h
Yield: 72.3 %

Procedure:
To a suspension of 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride 20 (1 g, 4.33 mmol) (scheme 6) in DCM (22 mL), 1,1-dimethylhydrazine (0.33 mL, 4.33 mmol) was added in one portion and the mixture was stirred for 5 h. More 1,1-dimethylhydrazine (0.33 mL, 4.33 mmol) was added and the mixture was stirred overnight at room temperature. The crude was diluted with EtOAc, extracted with 1N HCl, the aqueous solution basified to pH˜11 by addition of 1N NaOH, extracted with EtOAc, the organic phase dried over anhydrous Na2SO4 and concentrated under reduced pressure affording 237 (798 mg, 3.13 mmol, 72%) as a crude mixture that was used in the next step without further purification. MS (m/z): (M+1) 255.9 (100%), 257.9 (39%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4].[Cl:15]CCCl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:15][CH2:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: ClCCCl
Reactant: O=C(CBr)c1cccc2ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Product: O=C(CCl)c1cccc2ccccc12

Procedure:
A solution of 2-bromoacetylnaphthalene (7.00 g) and tetra-n-butyl ammonium bromide (0.905 g) in 1,2-dichloroethane (226 ml) was refluxed for 3.5 hours, evaporated in vacuo and extracted with dichloromethane. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was washed with n-hexane to afford 2-chloroacetylnaphthalene (5.43 g) as a yellow powder.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])[CH:23]=3)[C:17]([O:19]C)=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].O>C1COCC1.CO>[N:1]1([C:5]([C:7]2[N:8]=[CH:9][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:21]=[C:22]([O:24][C@H:25]4[CH2:29][CH2:28][N:27]([CH3:30])[C:26]4=[O:31])[CH:23]=3)[C:17]([OH:19])=[O:18])=[N:11][CH:12]=2)=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(O[C@H]2CCN(C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN1CC[C@H](Oc2cc(Oc3cnc(C(=O)N4CCC4)cn3)cc(C(=O)O)c2)C1=O
Yield: 90.5 %

Procedure:
Methyl 3-[5-(azetidine-1-carbonyl)pyrazin-2-yl]oxy-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-benzoate (Intermediate 7) (304 mg, 0.71 mmol) was dissolved in THF (6 mL) and methanol (2 mL); 1 N lithium hydroxide solution (0.85 mL) was added followed by water (8 mL), and the resultant solution was stirred for 1 hr at room temperature. The majority of the organic solvent was removed by distillation, the remaining aqueous solution was filtered and acidified with 2N hydrochloric acid and extracted with 1:1 ethyl acetate: DCM (2×40 mL). The combined organic extracts were washed with water (10 mL) and brine (20 mL) and dried (MgSO4) to afford the product (265 mg, 96%). 1H NMR δ (300 MHz, CDCl3) 2.12-2.27 (m, 1H), 2.38 (quintet, 2H), 2.52-2.67 (m, 1H), 2.95 (s, 3H), 3.36-3.57 (m, 2H), 4.27 (t, 2H), 4.68 (t, 2H), 4.97 (t, 1H), 7.10 (s, 1H), 7.45 (s, 1H), 7.62 (s, 1H), 8.31 (s, 1H), 8.84 (s, 1H); m/z 413 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH3:14])[C:9](OCC)=[O:10])=[C:5]([N+:18]([O-])=O)[CH:4]=1>[C].[Pd].C(O)C>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[O:7][C:8]([CH3:15])([CH3:14])[C:9](=[O:10])[NH:18][C:5]=2[CH:4]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)NC(=O)C(C)(C)O2
Yield: 65.5 %

Procedure:
5% palladium carbon (1.5 g) were added to an ethanol solution (250 ml) of ethyl 2-(4-methoxy-2-nitrophenoxy)-2-methylpropionate (14.6 g, 51.6 mmol) to perform catalytic reduction at room temperature. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. Water was added to the obtained residue, which was then extracted with ethyl acetate. The extraction solution was dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1). The purified product was concentrated to dryness under reduced pressure to obtain 6-methoxy-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (7.0 g) as white powder.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][C:24]=1[F:37])[C:3]([N:5]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=1)=[O:4].[CH2:38]([NH:45][C:46]([NH:48][N:49]([CH2:54][CH:55]=[CH2:56])[CH2:50][C:51](O)=[O:52])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO.C(OCC)(=O)C.ClCCl>[CH2:38]([NH:45][C:46]([NH:48][N:49]([CH2:54][CH:55]=[CH2:56])[CH2:50][C:51]([NH:1][C@@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:25][C:24]=1[F:37])[C:3]([N:5]([CH2:14][CH:15]([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[N:8]=1)=[O:4])=[O:52])=[O:47])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: C=CCN(CC(=O)O)NC(=O)NCc1ccccc1
Reactant: CCOC(CN(Cc1cccc(F)n1)C(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1F)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCN(CC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1F)C(=O)N(Cc1cccc(F)n1)CC(OCC)OCC)NC(=O)NCc1ccccc1
Yield: 101.2 %

Procedure:
To a mixed solution of (2S)-2-amino-3-(4-(benzyloxy)-2-fluorophenyl)-N-(2,2-diethoxyethyl)-N-((6-fluoropyridin-2-yl)methyl)propanamide (4.87 g, 9.48 mmol) described in Production Example 1-1-3 and dichloromethane (100 mL) were added a known substance (WO2009148192) 2-(((benzylcarbamoyl)amino)(prop-2-en-1-yl)amino)acetic acid (2.62 g, 9.95 mmol), triethylamine (2.64 mL, 19.0 mmol) and HBTU (3.96 g, 10.4 mmol) at room temperature. The resultant mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under a reduced pressure, and the resultant residue was purified by NH silica gel column chromatography (ethyl acetate and then ethyl acetate:methanol=30:1) to give the title compound (7.28 g, yield: quantitative).