Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=1)=[O:12])[CH2:6]2.Cl.[CH3:27][N:28]([CH2:32][CH2:33]Cl)[CH2:29][CH2:30]Cl.C(=O)([O-])O.[Na+]>C(O)CCC>[CH3:27][N:28]1[CH2:32][CH2:33][N:1]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH:5]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=2)=[O:12])[CH2:6]3)[CH2:30][CH2:29]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cccc2c1CC(C(=O)Nc1ccc(N3CCOCC3)cc1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2cccc3c2CC(C(=O)Nc2ccc(N4CCOCC4)cc2)C3)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
A mixture of 4-amino-N-(4-morpholinophenyl)indan-2-carboxamide (1.1 g, 3 mmol), N-methyl-bis-(2-chloroethyl)amine hydrochloride (2.0 g, 10 mmol) and sodium hydrogen carbonate (8.0 g, 95 mmol) in 1-butanol (100 mL) was stirred overnight at 120° C. The mixture was filtered and the solvent was evaporated in vacuo. The crude residue (oil) was purified on a silica gel column using methylene chloride as the eluent to afford 100 mg of the title compound: mp 248-249° C.; EIMS (70 eV) m/z (relative intensity) 420 (47, M+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])=[CH:5][CH:4]=1
Reactant: C1CCNC1
Reactant: COc1ccc(C(=O)O)c2c(C)cccc12
Product: COc1ccc(C(=O)N2CCCC2)c2c(C)cccc12

Procedure:
4-Methoxy-8-methyl-1-naphthoic acid (Step-5 of Intermediate-22) was reacted with pyrrolidine by following the similar procedure as described in Step-6 of Intermediate-22.
Reaction SMILES: [N:1]1([C:7]2[C:12]([C:13]#[N:14])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[CH2:25][C:26]([NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=1)=[O:27]>C1(C)C=CC=CC=1>[C:13]([C:12]1[C:7]([N:1]2[CH2:2][CH2:3][N:4]([CH2:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=3)=[O:27])[CH2:5][CH2:6]2)=[N:8][CH:9]=[CH:10][CH:11]=1)#[N:14]
Reactant: N#Cc1cccnc1N1CCNCC1
Reactant: O=C(CCl)Nc1cccc([N+](=O)[O-])c1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: N#Cc1cccnc1N1CCN(CC(=O)Nc2cccc([N+](=O)[O-])c2)CC1
Temperature: 90 °C
Yield: 24.6 %

Procedure:
2-(1-Piperazinyl)-3-pyridinecarbonitrile (640 mg, 3.40 mmol) and N,N-diisopropylethylamine (1.0 mL) in toluene (15 mL) at room temperature were treated with N-chloroacetyl-3-nitroaniline (Lancaster, 610 mg, 2.84 mmol) and the reaction was heated at 90° C. for 18 hours. The mixture was allowed to cool to room temperature, transferred to a separatory funnel and washed with saturated aqueous sodium bicarbonate. The organic phase was dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (elution with 85% hexanes:ethyl acetate) to provide 256 mg (25% yield) of the title compound as a light tan solid. mp 143-145° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.69 (m, 4H), 3.27 (s, 2H), 3.70 (m, 4H), 6.93 (dd, 1H, J=7.4, 5.0 Hz), 7.61 (dd, 1H, J=8.1, 8.1 Hz), 7.93 (br d, 1H, J=8.2 Hz), 8.06 (dd, 2H, J=7.8, 7.8 Hz), 8.42 (m, 1H), 8.70 (br s, 1H), 10.28 (br s, 1H); MS (DCI/NH3) m/e 367 (M+H)+; Anal. calcd for C18H18N6O3: C, 59.01; H, 4.95; N, 22.94. Found: C, 59.31; H, 5.25; N, 22.66.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:28])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:27])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[C:5](=[O:12])[CH2:6]C(OCC)=O.Br[CH2:30][C:31]([CH3:58])=[CH:32][CH2:33][CH2:34][C:35]([CH3:57])=[CH:36][CH2:37][CH2:38][C:39]([CH3:56])=[CH:40][CH2:41][CH2:42][C:43]([CH3:55])=[CH:44][CH2:45][CH2:46][C:47]([CH3:54])=[CH:48][CH2:49][O:50]C(=O)C>CCOCC>[CH3:54][C:47]([CH2:46][CH2:45][CH:44]=[C:43]([CH3:55])[CH2:42][CH2:41][CH:40]=[C:39]([CH3:56])[CH2:38][CH2:37][CH:36]=[C:35]([CH3:57])[CH2:34][CH2:33][CH:32]=[C:31]([CH3:58])[CH2:30][CH2:6][C:5](=[O:12])[CH:4]([CH3:3])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:28])[CH2:17][CH2:18][CH:19]=[C:20]([CH3:27])[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[CH:48][CH2:49][OH:50]
Reactant: CCOC(=O)CC(=O)C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Reactant: CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)C(=O)CCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a suspension of sodium hydride (2.64 g) in ether (100 ml), a solution of ethyl 3,7,11,15-tetramethyl-6,10,14-hexadecatrien-2-one-1-carboxylate (18.1 g) in ether (18 ml) is dropwise added, and the resulting mixture is dropwise added, and the resulting mixture is stirred for 30 minutes. Then, a solution of 1-bromo-2,6,10,14,18-pentamethyl-20-acetoxy-2,6,10,14,18-eicosapentaene (26 g) in ether (26 ml) is dropwise added thereto. The reaction mixture is poured into ice water. The ether layer is washed with water, dried and evaporated. The residual material is treated as in Example 1 (4) to give 3,7,11,15,19,23,27,31, 35-nonamethyl-2,6,10,14,18,26,30,34-hexatriacontaoctaen-22-on-1-ol (29 g). IR: 3400, 1000 cm-1 (OH); 1705 cm-1 (C=O); 1668 cm-1 (C=C). NMR (carbon tetrachloride): δ 1.59 (s), 1.66 (s), 2.01 (m), 2.7 (m), 4.1 (m), 5.05 (m).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([CH:9]1[CH2:27][CH2:26][N:12]2[C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:11]2[CH2:10]1)#[N:8].O>CCOCC.C1COCC1>[NH2:8][CH2:7][CH:9]1[CH2:27][CH2:26][N:12]2[C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH:11]2[CH2:10]1
Reactant: N#CC1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: NCC1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
To a suspension of 10 g LiAlH4 in 400 ml of dry ether a solution of 8 g of 2-cyano-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine (axial) in 300 ml of THF is added. Then the mixture is refluxed for 30 minutes, whereupon it is cooled by means of ice. After that 40 ml of water are added to the mixture carefully so as to hydrolyse the excess of LiAlH4. The resulting precipitate is filtered off after which the filtrate is evaporated.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[C:7]#[N:8])(=[O:3])[CH3:2].[OH-].[Na+]>C1(C)C=CC=CC=1.C(C(CC)=O)C.N1CCCC1>[CH2:1]([C:4]1([CH2:11][CH3:10])[CH2:2][C:1](=[O:3])[C:4]2[CH:5]=[C:6]([C:7]#[N:8])[CH:9]=[CH:10][C:11]=2[O:12]1)[CH3:2]
Reactant: CC(=O)c1cc(C#N)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Solvent: CCC(=O)CC
Product: CCC1(CC)CC(=O)c2cc(C#N)ccc2O1
Temperature: 25 °C

Procedure:
A solution of 16,1 g of 3-acetyl-4-hydroxybenzonitrile in 200 ml of toluene, 21 ml of diethylketone and 10 ml of pyrrolidin is refluxed for 31/2 hours in a Dean-Stark apparatus. The reaction solution cooled to room temperature is made alkaline with a 2N aq. sodium hydroxide solution and extracted with dichloroethane. The combined organic phases are washed with sodium hydroxidesolution and water, dried over sodiumsulfate and concentrated. The obtained residue is chromatographed on silica gel/dichloromethane. Recristallisation of the eluate from ether/hexane yields 2,2-diethyl-3,4-dihydro-4-oxo-2H-1-benzopyran-6-carbonitrile having a m.p. of 71°-72° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH2:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:32]1([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:39][C:40]([CH3:56])=[C:41]([CH2:43][CH2:44]OS(C3C=CC(C)=CC=3)(=O)=O)[N:42]=2)[CH:33]=1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5]([CH3:24])([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:44][CH2:43][C:41]2[N:42]=[C:38]([C:34]3[CH:33]=[C:32]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[CH:37]=[CH:36][CH:35]=3)[O:39][C:40]=2[CH3:56])=[C:9]([CH2:14][CH2:15][CH3:16])[CH:8]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccc(-c4ccccc4)c3)oc2C)cc1
Reactant: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(CC(C)(Oc2ccccc2)C(=O)OCC)ccc1OCCc1nc(-c2cccc(-c3ccccc3)c2)oc1C
Temperature: 55 °C
Yield: 52.2 %

Procedure:
A solution of 3-(4-hydroxy-3-propylphenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (266 mg, 1.0 mmol) in DMF (10 mL) was treated with cesium carbonate (407 mg, 1.25 mmol) and toluene-4-sulfonic acid 2-(2-biphenyl-3-yl-5-methyl-oxazol-4-yl)-ethyl ester (520 mg, 1.20 mmol) (see Ex. 2, Part F) and then heated at 55° C. for 18 h. After cooling to ambient temperature, the mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and then the organic phases were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (100 mL SiO2, hexanes to 30% ethyl acetatelhexanes) to provide the desired product (315 mg, 60%) as a clear, colorless oil: 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.68–7.63 (m, 3H), 7.51 (t, J=7.6 Hz, 1H), 7.46 (t, J=8.0 Hz, 2H), 7.38 (t, J=7.2 Hz, 1H), 7.25–7.21 (m, 2H), 7.04–6.96 (m, 3H), 6.85–6.69 (m, 3H), 4.26 (t, J=6.4 Hz, 2H), 4.21 (q, J=6.8 Hz, 2H), 3.26 (A of AB, J=13.6 Hz, 1H), 3.09 (B of AB, J=13.6 Hz, 1H), 3.01 (t, J=6.4 Hz, 2H), 2.54 (t, J=7.6 Hz, 2H), 2.41 (s, 3H), 1.54 (sextet, J=7.6 Hz, 2H), 1.41 (s, 3H), 1.23 (t, J=6.8 Hz, 3H), 0.91 (t, J=7.2 Hz, 3H); MS (EI) 604.3 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:24]=[C:23]([CH3:25])[O:22][N:21]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26]>O1CCOCC1>[ClH:26].[CH3:25][C:23]1[O:22][N:21]=[C:20]([C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:19][CH:18]=2)[N:24]=1
Reactant: Cc1nc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)no1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(-c2ccc(N3CCNCC3)cc2)no1
Reaction time: 2 h

Procedure:
1 mmol of 4-[4-(5-Methyl-[1,2,4]oxadiazol-3-yl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester was stirred in 3 ml of 1,4-dioxane saturated with gaseous HCl. After 2 h at room temperature, the reaction mixture was evaporated to dryness to yield the title compound as a colorless solid. MS (m/e): 245.1 (MH+, 100%)
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][N:12]([C:25](=[O:28])[CH2:26][CH3:27])[N:13]=[C:14]([C:20]([O:22]CC)=O)[C:15]([O:17]CC)=[O:16].O>C1COCC1>[OH:22][C:20]1[C:14]([C:15]([OH:17])=[O:16])=[N:13][N:12]([CH3:11])[C:25](=[O:28])[C:26]=1[CH3:27]
Reactant: CCOC(=O)C(=NN(C)C(=O)CC)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(O)c(C(=O)O)nn(C)c1=O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 47.3 %

Procedure:
To a solution of LiHMDS (331 mL, 331 mmol, 1 M solution in THF) in THF (430 mL) at −78° C. was added a solution of diethyl 2-(2-methyl-2-propionylhydrazono)malonate (21.40 g, 82.86 mmol) prepared by the procedure described in Example 168 (step B) in THF (10 mL). The resulting mixture was slowly warmed to 40° C. over 1 hour and stirred for 1.5 hours at −40° C. To the −40° C. reaction mixture was added water (500 mL). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the THF. The resulting aqueous mixture was quenched with 6 N aqueous HCl at 0° C., and acidified to pH 1 to 2. The resulting mixture was stirred for 16 hours at room temperature. The precipitates were filtered off and triturated with CH2Cl2 to afford 7.21 g (47%) of the desired product. The filtrate was extracted with EtOAc (3×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was triturated with CH2Cl2 to afford 3.56 g (23%) of additional desired product. The aqueous layer was extracted again with EtOAc (3×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude material that was triturated with CH2Cl2 to afford 1.32 g (9%) of additional desired product. A total of 12.09 g (79%) of the desired product was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.C(N(CC)CC)C.[C:23](=[N:26]O)([NH2:25])[CH3:24].CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C1COCC1>[CH3:24][C:23]1[N:26]=[C:10]([CH2:9][O:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=2)[O:12][N:25]=1
Reactant: O=C(O)COc1ccc([N+](=O)[O-])cc1
Reactant: CC(N)=NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1noc(COc2ccc([N+](=O)[O-])cc2)n1
Yield: 60.4 %

Procedure:
A mixture of 4-nitrophenoxyacetic acid (12) (2.25 g, 11.4 mmol), acetamide oxime triethylamine hydrochloride salt (11, 5.85 g, 27.62 mmol), EDCI.HCl (4.37 g, 22.79 mmol) and diisopropylethylamine (7.42 g, 10 mL, 57.40 mmol) in anhydrous tetrohydrofuran (THF) (250 mL) was refluxed for 18 hours. The heterogeneous brown reaction mixture was then quenched with water and extracted with EtOAc (3×300 mL). The combined organic layers were washed successively with aqueous sodium bicarbonate (NaHCO3) and brine. The resulting organic phase was dried over anhydrous Na2SO4 and solvent was removed by using rotary evaporator. The resulting residue was purified by silica gel column chromatography to yield 1.62 g (60%) of the desired product, 3-methyl-5-(4-nitrophenoxymethyl)-1,2,4-oxadiazole (13a) as a white solid. 1H NMR (CDCl3, 300 MHz): δ 8.24 (d, 2H, J=8.8 Hz), 7.08 (d, 2H, J=8.8 Hz), 5.36 (s, 2H), 2.44 (s, 3H); LCMS (m/z): 236 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)([O:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23]N(C)C=O.C(Cl)(=O)C(Cl)=O>ClCCl>[CH3:23][O:16][C:15](=[O:17])[CH2:14][O:13][C:10]1([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(OCC(=O)O)(c2nccs2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)COC1(c2nccs2)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 4 h

Procedure:
To a cooled (0° C.) solution of 2-(1-(tert-butoxycarbonyl)-3-(thiazol-2-yl)pyrrolidin-3-yloxy)acetic acid (7.5 g, 22.84 mmol) in dichloromethane (150 mL) was added N,N-dimethylformamide (1 mL) followed by dropwise addition of oxalyl chloride (1.999 mL, 22.84 mmol). The cold bath was then removed, and the reaction was stirred for 4 hours. Methanol (30 mL) was added to the ambient reaction, and the reaction was stirred for an additional 0.5 hours. The reaction was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 0 to 50% ethyl acetate in hexane, to give the product. MS ESI(+) m/z 342.8 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([OH:5])=O.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+].[BH4-].[Na+]>>[CH3:14][C:2]1([CH3:1])[CH:3]([OH:5])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[S:7][CH2:6]1
Reactant: CC(C)(CSc1ccccc1)C(=O)O
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [BH4-]
Product: CC1(C)CSc2ccccc2C1O
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of 2,2-dimethyl-3-phenylsulfanyl-propionic acid (290 mg, 1.38 mmol) and Eaton's reagent (7 mL) is stirred for overnight at 65° C. The mixture is poured onto ice and basified by the addition of 1M aqueous NaOH. The mixture is extracted three times with dichloromethane. The combined extracts are dried with Na2SO4, filtered and concentrated. The resulting residue is then dissolved in ethanol (10 mL). The resulting solution is charged with NaBH4 (82.6 mg, 2.18 mmol). The mixture is stirred for 48 hours, quenched with 10% aqueous HCl, and concentrated to dryness. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 1:4) to afford (3,3-dimethyl-thiochroman-4-ol); 1H NMR (400 MHz, CDCl3) δ ppm 0.98 (s, 3 H), 1.21 (s, 3 H), 1.58 (d, J=5.1 Hz, 1 H), 2.50 (d, J=13.4 Hz, 1 H), 3.26 (d, J=12.4 Hz, 1 H), 4.17 (d, J=4.6 Hz, 1 H), 6.99-7.09 (m, 1 H) 7.11-7.20 (m, 2 H), 7.27 (m, 1 H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](Cl)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:19][NH:20][CH2:21][CH2:22][CH2:23][OH:24].C(N(CC)CC)C>ClCCl.[Cl-].[Na+].O>[OH:24][CH2:23][CH2:22][CH2:21][N:20]([CH3:19])[C:16](=[O:17])[O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: CNCCCO
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(CCCO)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Yield: 100 %

Procedure:
A solution of 9-fluorenylmethoxycarbonyl chloride (15.22 g, 58.85 mmol) in dichloromethane (100 ml) was added over 1 h to an ice-cooled solution of 3-methylamino-1-propanol (5.25 g, 58.85 mmol) and triethylamine (9.0 ml, 64.74 mmol) in dichloromethane (50 ml). The resultant suspension was left overnight at −18° C., and then diluted with brine. The organic phase was separated, dried over MgSO4 and concentrated in vacuo. The residue was purified on silica eluting with 1:4 ethyl acetate/dichloromethane to give (9H-fluoren-9-yl)methyl 3-hydroxypropylmethylcarbamate (100% yield). p-Toluoyl chloride (4.26 g, 27.56 mmol) was added dropwise over 10 min to an ice-cooled solution of (9H-fluoren-9-yl)methyl 3-hydroxypropylmethylcarbamate (7.8 g, 25.05 mmol) in pyridine (100 ml). The resultant mixture NA as stirred for 2 h at 0° C., concentrated in vacuo and redissolved in ethyl acetate. The solution was washed with 10% citric acid and brine, then separated, dried over MgSO4 and concentrated in vacuo. The residue was purified on silica eluting with 30% ethyl acetate/hexane to give (9H-fluoren-9-yl)methyl 3-(4-methylbenzoyloxy)propylmethylcarbamate (97% yield). A solution of (9H-fluoren-9-yl)methyl 3-(4-methylbenzoyloxy)propylmethylcarbamate (0.91 g, 2.12 mmol) and triethylamine (5.0 ml) in DMF (5 ml) was stirred for 1 h at +80° C. The resultant mixture was cooled to room temperature and compound 1 (2.01 g, 1.74 mmol) was added. The reaction was diluted with DMF (5), stirred for 2 days, and then diluted with ether (100 ml). The precipitated solid was isolated by filtration, washed with ether and vacuum dried to afford compound 2b (89% yield) as a pale solid, which was sufficiently pure to be used in the next step without additional purification.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C@H:12]([NH:14][C:15](=[O:17])[CH3:16])[CH3:13])[C:5]([O:7][CH3:8])=[O:6].N([O-])=O.[Na+].[ClH:22]>C(O)(=O)C.S(=O)(=O)(O)O.[Cu]Cl>[C:15]([NH:14][C@@H:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Cl:22])[CH3:13])(=[O:17])[CH3:16]
Reactant: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(N)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of methyl (R)-3-amino-4-(1-acetamidoethyl)benzoate (600 mg) in acetic acid (6 ml) was dropwise added to a solution of sodium nitrite (193mg) in conc. sulfuric acid (2 ml) at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was dropwise added to a solution of copper(I) chloride (550 mg) in conc. hydrochloric acid (6 ml) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. After the reaction, the reaction mixture was poured into ice water, dried, and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 460 mg of methyl (R)-4-(1-acetamidoethyl)-3-chlorobenzoate.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=2)=[C:5]([F:17])[CH:4]=1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1.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>CN(C=O)C>[F:17][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[C:9]1[CH:10]=[CH:11][C:12](=[O:16])[N:13]([CH3:15])[CH:14]=1)[CH2:2][NH:1][C:28](=[O:29])[C:27]1[CH:26]=[CH:25][C:24]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][N:18]=2)=[CH:32][CH:31]=1
Reactant: O=C(O)c1ccc(-c2cnccn2)cc1
Reactant: Cn1cc(-c2ccc(CN)cc2F)ccc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2ccc(CNC(=O)c3ccc(-c4cnccn4)cc3)cc2F)ccc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of the 5-(4-(aminomethyl)-2-fluorophenyl)-1-methylpyridin-2(1H)-one 21-7 (obtained in Step 4), 4-(pyrazin-2-yl)benzoic acid 18-3 (5.0 mg, 0.025 mmol), and HATU (9.5 mg, 0.025 mmol) were added N,N-diisopropylethylamine (DIEA, 17 μL, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to give N-(3-fluoro-4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)benzyl)-4-(pyrazin-2-yl)benzamide 21 (2.5 mg). MS m/z 415.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:25][C:11]3=[N:12][C:13]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[C:14](B(O)O)[CH:15]=[C:10]3[C:9]=2[C:26](=[O:29])[NH:27][CH3:28])=[CH:4][CH:3]=1.Cl[C:31]1[CH:40]=[CH:39][C:38]2[CH2:37][CH2:36][N:35]3[C:41]4[CH:42]=[CH:43][CH:44]=[C:45]([F:48])[C:46]=4[CH:47]=[C:34]3[C:33]=2[N:32]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:48][C:45]1[C:46]2[CH:47]=[C:34]3[C:33]4[N:32]=[C:31]([C:14]5[CH:15]=[C:10]6[C:9]([C:26]([NH:27][CH3:28])=[O:29])=[C:8]([C:5]7[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=7)[O:25][C:11]6=[N:12][C:13]=5[N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[CH:40]=[CH:39][C:38]=4[CH2:37][CH2:36][N:35]3[C:41]=2[CH:42]=[CH:43][CH:44]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(B(O)O)cc12
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2nc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a degassed solution of (2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)furo[2,3-b]pyridin-5-yl)boronic acid (100 mg, 0.24 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (60 mg, 0.21 mmol) and K2CO3 (98 mg, 0.72 mmol) in 1,4-dioxane (3 mL) and H2O (5 drops) was added Pd2(dba)3 (10 mg) and X-Phos (10 mg) under nitrogen atmosphere. The reaction mixture was stirred at 100° C. for 2 h, concentrated in vacuo to remove 1,4-dioxane. The residue was diluted with H2O and extracted with DCM. The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated and purified to give the desired product (80 mg, yield: 55%) through the prep-HPLC. 1H-NMR (CDCl3, 400 MHz) δ 8.60 (s, 1H), 8.00˜8.04 (m, 2H), 7.76 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 7.21 (t, J=8.8 Hz, 2H), 7.14˜7.16 (m, 2H), 6.75˜6.80 (m, 1H), 5.97 (br s, 1H), 4.33 (t, J=6.4 Hz, 2H), 3.25˜3.32 (m, 5H), 3.18 (s, 3H), 3.00 (d, J=4.8 Hz, 3H). MS (M+H)+: 614.