Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C:13]2([CH2:23][O:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[CH2:18][CH2:17][C:16](OC)([O:19]C)[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C:13]2([CH2:23][O:24][S:25]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=3)(=[O:27])=[O:26])[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COC1(OC)CCC(COS(=O)(=O)c2ccc(C)cc2)(COS(=O)(=O)c2ccc(C)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCC2(COS(=O)(=O)c3ccc(C)cc3)CCC(=O)CC2)cc1
Yield: 87.5 %

Procedure:
To a solution of (4,4-dimethoxycyclohexane-1,1-diyl)bis(methylene) bis(4-methylbenzenesulfonate) (5.4 g, 10.53 mmol) in THF (20 mL) was added 1 N aq HCl (60 mL, 60.0 mmol) and the reaction mixture was refluxed for 3 h. Volatiles were removed in vacuo, and the aqueous layer was extracted with EtOAc (5×10 mL). The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 50% EtOAc:hexanes) to afford the title compound (4.3 g, 87% yield) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J=8.3 Hz, 4H), 7.39 (d, J=8.0 Hz, 4H), 3.97 (s, 4H), 2.50 (s, 6H), 2.25 (t, J=7.0 Hz, 4H), 1.75 (t, J=7.0 Hz, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)[CH:18]=[CH:17][C:15]=2[N:16]=1.O(CC)CC.[ClH:39]>C1COCC1>[ClH:39].[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[CH:20]=[C:19]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3nc(-c4ccc(S(C)(=O)=O)cc4F)oc3c2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2nc3ccc(C4CCNCC4)cc3o2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl 4-{2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-6-yl}piperidine-1-carboxylate (270 mg, 5.7 mmol) dissolved in THF (5 ml) and added Et2O.HCl (10 ml). Reaction mixture stirred at rt for 3 h. Ether removed on rotavapour to obtain crude. Crude was triturated with ether to obtain 2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(piperidin-4-yl)-benzo[d]oxazole hydrochloride (225 mg). 2-[2-fluoro-4-(methylsulfonyl)phenyl]-6-(piperidin-4-yl)-benzo[d]oxazole hydrochloride (70 mg, 0.17 mmol) was dissolved in DCM (5 ml) and added TEA (0.11 ml, 0.85 mmol). This mixture stirred at rt for 30 mins and added isopropylchloro formate in toluene (42 mg, 0.34 mmol). After 30 mins reaction mixture quenched with water and extracted with DCM. DCM removed on rotavapour to obtain the crude. Crude was purified by combiflash using EtOAC and Petether (1:3) as eluent to afford the titled compound (30 mg) as a white solid. M.P.: 170.3-174.3° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.47-8.44 (m, 1H), 7.90-7.83 (m, 2H), 7.78 (d, J 8.3, 1H), 7.49 (s, 1H), 7.28 (dd. J 1.5, 8.3, 1H), 4.96 (septet, J 6.2, 1H), 4.40-4.28 (m, 2H), 3.13 (s, 3H), 2.92-2.80 (m, 3H), 1.96-1.88 (m, 2H), 1.75-1.62 (m, 2H), 1.28 (d, J 6.2, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]2[N:18]([CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][C:10]=1[N:31]1[S:35](=[O:37])(=[O:36])[N:34](CC[Si](C)(C)C)[C:33](=[O:44])[CH2:32]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C:17]2[N:18]([CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:19]=[CH:20][CH:21]=2)[CH:12]=[CH:11][C:10]=1[N:31]1[S:35](=[O:37])(=[O:36])[NH:34][C:33](=[O:44])[CH2:32]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/c3ccnn3COCc3ccccc3)cc2OCc2ccccc2)S1(=O)=O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: O=C1CN(c2ccc(/C=C/c3ccnn3COCc3ccccc3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 60 °C

Procedure:
A mixture of 5-{2-benzyloxy-4-[(E)-2-(2-benzyloxymethyl-2H-pyrazol-3-yl)-vinyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (330 mg, 0.50 mmol)) and CsF (400 mg, 2.6 mmol) in DMF (5 mL) is heated at 60° C. for 18 h. The mixture is partitioned between aqueous NH4Cl and EtOAc and the organic layer is concentrated to afford the title compound which is used directly in the next step: (M+1)+=531.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][O:8][C@@H:9]2[CH2:12][C@H:11]([C:13]([O:15]CC)=[O:14])[CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+]>O1CCOCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C@@H:9]2[CH2:12][C@H:11]([C:13]([OH:15])=[O:14])[CH2:10]2)=[CH:18][CH:19]=1)#[N:2]
Reactant: CCOC(=O)[C@H]1C[C@@H](OCc2ccc(C#N)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: N#Cc1ccc(CO[C@H]2C[C@@H](C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of cis-ethyl 3-(4-cyanobenzyloxy)cyclobutanecarboxylate (0.44 g, 1.70 mmol) in 1,4-dioxane (10 mL) was added aqueous NaOH (1 N, 2.0 mL). The reaction was stirred at about 25° C. for about 16 h. The reaction was partitioned between 10% aqueous AcOH (20 mL) and EtOAc (25 mL). The layers were separated and the aqueous layer was extracted with additional EtOAc (25 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered then concd in vacuo to give cis-3-(4-cyanobenzyloxy)-cyclobutanecarboxylic acid (0.24 g, 60%): LC/MS (Table 1, Method b) Rt=1.67 min; MS m/z: 232 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:22]1[N:27]=[C:26]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([NH2:37])=[O:36])[CH:25]=[CH:24][CH:23]=1>>[NH2:9][C:7]([C:6]1[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:17])[CH3:18])=[CH:12][C:11]=2[F:20])[S:3][C:2]=1[NH:1][C:22]1[N:27]=[C:26]([CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[C:35]([NH2:37])=[O:36])[CH:25]=[CH:24][CH:23]=1)=[O:8]
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: NC(=O)C1COCCN1Cc1cccc(Br)n1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCOCC4C(N)=O)n3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (80 mg, 0.27 mmol) and 4-[(6-bromopyridin-2-yl)methyl]morpholine-3-carboxamide (82 mg, 0.27 mmol) as starting materials.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:20]=[CH:19][C:18]([C:21]([NH2:23])=[O:22])=[C:17]2[C:9]=1[C:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=1[NH:16]2.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:16][C:17]=2[C:18]([C:21]([NH2:23])=[O:22])=[CH:19][CH:20]=1
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c3c([nH]c12)CCCC3
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 19 %

Procedure:
A solution of 5-(2-fluorophenyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (Example 47-1, 0.024 g, 0.078 mmol) in toluene (0.39 mL) was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.039 g, 0.171 mmol), and the mixture was heated to reflux. After 4 h, the mixture was cooled to rt. The solid was removed by filtration and rinsed with EtOAc. The filtrate was concentrated, diluted with methanol and subjected to preparative HPLC. The product-containing effluent was treated with NaHCO3 (aq) and concentrated. The residue was extracted three times with DCM, and the combined organic layers were dried and concentrated to give 4-(2-fluorophenyl)-9H-carbazole-1-carboxamide (0.0045 g, 19%) as a light tan solid. Mass spectrum m/z 305.0 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]1([CH3:14])[CH3:13]>CN(C=O)C.C(Cl)Cl.O=[Mn]=O>[CH3:13][C:3]1([CH3:14])[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12]
Reactant: CC1(C)C(=O)Nc2ccccc2C1O
Agent: O=[Mn]=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2ccccc2C1=O
Yield: 68.6 %

Procedure:
A mixture of 4-Hydroxy-3,3-dimethyl-3,4-dihydro-1H-quinolin-2-one (1.0 g, 5.2 mmol) and MnO2 (4.5 g, 52 mmol) in DMF-CH2Cl2 (10%, v/v, 20 mL) is heat to reflux for overnight (˜16 h). The insoluble material is removed by filtration through a pad of celite (˜1 cm), and washed with CH2Cl2. The combined solution is concentrated under vacuum, and yields the title compound as colorless solid (675 mg, yield 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:17])[C:11]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[C:5]([NH:7][OH:8])=[NH:6].[CH2:18](S(Cl)(=O)=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH3:17])[C:11]=1[NH:12][S:13]([CH2:16][CH3:18])(=[O:15])=[O:14])[C:5]([NH:7][OH:8])=[NH:6]
Reactant: CCS(=O)(=O)Cl
Reactant: Cc1cc(C(=N)NO)cc(Cl)c1NS(C)(=O)=O
Product: CCS(=O)(=O)Nc1c(C)cc(C(=N)NO)cc1Cl

Procedure:
The title compound is prepared in analogy to 3-chloro-N-hydroxy-4-methanesulfonylamino-5-methyl-benzamidine using ethanesulfonylchloride; LC-MS**: tR=0.27 min, [M+1]+=292.13; 1H NMR (D6-DMSO): δ 1.36 (t, J=7.5 Hz, 3H), 2.40 (s, 3H), 3.22 (q, J=7.5 Hz), 5.88 (s, 2H), 7.57 (d, J=1.5 Hz, 1H), 7.63 (d, J=1.5 Hz, 1H), 9.18 (s, 1H), 9.78 (s, 1H).
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([OH:26])=O)=[C:22]([O:30][CH3:31])[CH:21]=1.[C:32]([NH:36][C:37](=[O:51])[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH:39]=1)([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>ClCCl>[NH2:19][C:20]1[C:28]([Cl:29])=[CH:27][C:23]([C:24]([N:48]2[CH2:47][CH2:46][N:45]([CH2:44][C:40]3[CH:39]=[C:38]([CH:43]=[CH:42][CH:41]=3)[C:37]([NH:36][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:51])[CH2:50][CH2:49]2)=[O:26])=[C:22]([O:30][CH3:31])[CH:21]=1
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N)c(Cl)cc1C(=O)N1CCN(Cc2cccc(C(=O)NC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
1-Propanephosphonic acid cyclic anhydride (6.31 g, 9.92 mmol, 5.91 ml) was added dropwise to a solution of 4-amino-5-chloro-2-methoxybenzoic acid (1 g, 5 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (1.5150 g, 5,5 mol) and triethylamine (1.508 g, 14.88 mmol, 2.068 mL) in dichloromethane. The reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure and the residue was taken up with ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic phase was concentrated under vacuum to afford the title compound (1.71 g). MS (ESI) m/z 459.7 [M+H]+
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:15]1([CH2:14][C:10]2[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][N:11]=2)[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(CN2CCOCC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccnc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a stirred solution of 45 (150 mg, 0.513 mmol) in DCM (5 mL) was added TFA (1 mL) at 0° C. and allowed to stir at rt for 2 h. The reaction mixture was concentrated, the residue was dissolved in MeOH and treated with Ambersep-900-OH resin to basify the solution, then filtered to separate the resin and concentrated the filtrate to obtain the desired amine (90 mg, 88%) as a gummy liquid. (m/z): 194 [MH]+; 1H NMR (400 MHz, DMSO-d6) δ 7.87 (1H, d, J=5.6 Hz), 6.57 (1H, d, J=2.4 Hz), 6.33 (1H, dd, J=5.2, 2.4 Hz), 5.90 (2H, br s), 3.58-3.56 (4H, m), 3.34 (2H, s), 2.38-2.36 (4H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH3:11])[N:8]([C:12]3[N:17]=[CH:16][N:15]=[C:14]([NH2:18])[N:13]=3)[C:7]=2[CH:19]=1)#[CH:2].[Li+].CC([N-]C(C)C)C.[N:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:34](=[O:36])[CH3:35]>C1COCC1>[NH2:18][C:14]1[N:15]=[CH:16][N:17]=[C:12]([N:8]2[C:7]3[CH:19]=[C:3]([C:1]#[C:2][C:34]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][N:28]=4)([OH:36])[CH3:35])[CH:4]=[CH:5][C:6]=3[N:10]=[C:9]2[CH3:11])[N:13]=1
Reactant: CC(=O)c1cnccn1
Reactant: C#Cc1ccc2nc(C)n(-c3ncnc(N)n3)c2c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2ccc(C#CC(C)(O)c3cnccn3)cc2n1-c1ncnc(N)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 13.9 %

Procedure:
To a solution of 4-(6-ethynyl-2-methyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine (80 mg, 0.29 mmol) in THF (0.5 mL) at −78° C. under N2 (g) was added 2M LDA in THF (0.43 mL, 0.86 mmol). After 5 min 1-pyrazin-2-yl-ethanone (105 mg, 0.86 mmol) in THF (0.5 mL) was added. After 20 min, the mixture was allowed to warm to RT and was stirred for 1 hr. The reaction mixture was quenched by addition of sat aq NH4Cl (0.5 mL). The volatiles were removed by evaporation under reduced pressure. The mixture was diluted with EtOAc (10 ml) and washed with water (2 mL), dried (Na2SO4), filtered and concentrated in vacuo. Purification by Biotage chromatography (100% DCM to 8% MeOH/DCM) gave the title compound (15 mg, 14% yield); 1H NMR (250 MHz, DMSO) delta 1.86 (3H, s), 2.89 (3H, s), 6.63 (1H, s), 7.32 (1H, dd, J=8.22, 1.52 Hz), 7.58 (1H, d, J=8.22 Hz), 7.96 (1H, s), 7.98 (1H, s), 8.39 (1H, d, J=1.22 Hz), 8.59-8.63 (1H, m), 8.63-8.67 (2 H, m), 9.02 (1H, d, J=1.37 Hz); LC-MS: m/z+373.4 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][OH:11])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][N:16]=1>CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][CH2:10][O:11][C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][N:16]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CN1CCC(CCCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(CCCOc2ccc(C#N)cn2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 49 %

Procedure:
To a stirred solution of 3-(1-methyl-piperidin-4-yl)-propan-1-ol (5.0 g, 31.7 mmol) in DMF (200 mL), was added NaH (60%; 1.73 g, 43.3 mmol) portion wise. Once the initial effervescence had subsided, the mixture was heated at 60° C. for 1 h, and then was cooled to rt. A solution of 6-chloronicotinonitrile (4.0 g, 28.9 mmol) in DMF (20 mL) was then added and the mixture was stirred for 16 h before quenching with saturated (satd.) aq. NaHCO3 (50 mL) and brine (50 mL). A precipitate was formed and was collected by vacuum filtration to afford 3.67 g of the product. The filtrate was concentrated to half the volume and a second crop of precipitate was recovered. The precipitates were combined to give 5.64 g (76%) of an orange solid, which was used without further purification. MS (ESI): mass calcd for C15H21N3O, 259.17; m/z found, 260.4 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.46 (dd, J=2.3, 0.8, 1H), 7.77 (dd, J=8.6, 2.3, 1H), 6.80 (dd, J=8.6, 0.8, 1H), 4.34 (t, J=6.6, 2H), 2.96-2.82 (m, 2H), 2.25 (s, 3H), 1.92-1.68 (m, 7H), 1.37-1.34 (m, 2H), 0.89-0.81 (m, 2H).
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11]C(=O)OCC3C=CC=CC=3)=[CH:10][C:5]=2[CH2:4][CH2:3][O:2]1.CO.O(C(C)(C)C)[Li].[C:30]([O:33][C@H:34]([CH2:40]Cl)[CH2:35][NH:36][C:37](=[O:39])[CH3:38])(=[O:32])C>CN(C=O)C>[CH2:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:40][C@H:34]([CH2:35][NH:36][C:37](=[O:39])[CH3:38])[O:33][C:30]3=[O:32])=[CH:10][C:5]=2[CH2:4][CH2:3][O:2]1
Reactant: CC(=O)NC[C@@H](CCl)OC(C)=O
Reactant: O=C(Nc1ccc2c(c1)CCOC2)OCc1ccccc1
Agent: [Li]OC(C)(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CCOC3)C(=O)O1
Temperature: 25 °C
Reaction time: 66 h
Yield: 50.5 %

Procedure:
A solution of phenylmethyl (3,4-dihydro-1H-2-benzopyran-6-yl)carbamate (Step 1, 1.60 g, 5.65 mmol) and MeOH (0.458 mL, 11.3 mmol) in dry DMF (5.6 mL) under N2 is cooled in an ice bath and treated with LiOtBu (1M in THF, 16.95 mL, 16.95 mmol) dropwise over 2 mins. Then, the (1S)-2-(acetylamino)-1-(chloromethyl)ethyl acetate (2.19 g, 11.3 mmol) is added all at once, the cooling bath is removed and the mixture is stirred at ambient temperature for 2.75 days and is then diluted with H2O (20 mL) and extracted with EtOAc (4×50 mL). The combined organic phase is washed with brine (25 mL), dried over MgSO4 and concentrated under reduced pressure, and the residue is chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (1/99-2/98). Those fractions with an Rf=0.23 by TLC (MeOH/CHCl3, 5/95) are pooled and concentrated and the product triturated with EtOAc to give 828 mg (50%) of the title compound as a white solid, mp 142-145° C. [α]25D=−24° (c 1.01, DMSO).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(N(CC)CC)C.[CH2:19]([O:21][CH2:22][C:23](Cl)=[O:24])[CH3:20]>ClCCl>[CH2:19]([O:21][CH2:22][C:23]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])=[O:24])[CH3:20]
Reactant: CCOCC(=O)Cl
Reactant: COC(=O)c1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCC(=O)Nc1ccccc1C(=O)OC
Reaction time: 1 h
Yield: 107.6 %

Procedure:
To a solution of 4.53 g (30 mmol) of methyl anthranilate and 6.1 ml of triethylamine in 50 ml of dichloromethane was dropwise added a solution of 4.41 g (36 mmol) of ethoxyacetylchloride in 10 ml of dichloromethane under chilling with ice for a period of 15 min. The resulting mixture was stirred for 1 hr. at room temperature. The stirred mixture was washed sequentially with water, 4 N hydrochloric acid and 5% aqueous sodium carbonate, and then was dried over anhydrous sodium sulfate. The solvent was distilled off to leave 7.66 g of the desired compound (purity: 92.8 %) as a residual pale brown oil.
Reaction SMILES: [NH2:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][O:4]1.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:10]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C1COCC1>[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH:18]=[CH:19][C:20]([NH:1][O:2][CH:3]2[CH2:8][CH2:7][CH2:6][CH2:5][O:4]2)=[O:21])=[CH:10]1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1c[nH]c2ccccc12
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C=Cc1c[nH]c2ccccc12)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NH2OTHP (0.38 g, 3.21 mmol) was added to a solution of trans-3-indoleacrylic acid (17) (0.50 g, 2.67 mmol), PyBOP (1.47 g, 2.83 mmol), triethylamine (0.74 ml, 6.41 mmol) in THF (25 mL). The mixture was stirred at room temperature for 2 h and then was concentrated under reduced pressure. The residue was dissolved in EtOAc and quenched with water, followed by extraction with EtOAc (20 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc:n-hexane=1.5:1:1% NH3(aq)) to afford 18. 1H NMR (500 MHz, CD3OD): δ 1.58-1.70 (m, 3H), 1.79-1.90 (m, 3H), 3.63-3.65 (m, 1H), 4.03-4.08 (m, 1H), 4.97-4.98 (m, 1H), 6.47 (d, J=14.9 Hz, 1H), 7.15-7.21 (m, 2H), 7.41 (d, J=7.8 Hz, 1H), 7.59 (s, 1H), 7.84-7.87 (m, 2H).
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21](Br)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[OH:23][CH2:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([CH2:24][OH:23])[CH:30]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: OCc1cccc(B(O)O)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(CO)c3)c2s1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
200 mg (0.45 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 74.6 mg (0.49 mmol) of 3-(hydroxymethyl)phenylboronic acid are introduced into 3 ml of DMF. Addition of 0.67 ml of 2 M sodium carbonate solution and 1.8.2 mg (0.02 mmol) of PdCl2(dppf) is followed by heating to 80° C. After 14 h, the reaction mixture is filtered through kieselguhr and purified by separation by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 4N hydrogen chloride in dioxane, again concentrated. Drying under high vacuum results in 40 mg (19% of theory) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10](Cl)=[O:11].[OH:13][C:14]12[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[C:18]1([NH:27][C:28](=[O:30])[CH3:29])[C:17]1[CH:31]=[CH:32][C:33]([CH:35]([CH3:37])[CH3:36])=[CH:34][C:16]=1[O:15]2>C1COCC1>[C:10](=[O:11])([O:9][CH3:8])[O:15][C:16]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:17]=1[C:18]1([NH:27][C:28](=[O:30])[CH3:29])[C:19](=[O:26])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]1=[O:13]
Reactant: COC(=O)Cl
Reactant: CC(=O)NC12C(=O)c3ccccc3C1(O)Oc1cc(C(C)C)ccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Oc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 17.1 %

Procedure:
Triethylamine (0.24 ml, 1.77 mmol) and methylchloroformate (0.11 ml, 1.48 mmol) were added to N-(4b-hydroxy-7-isopropyl-10-oxo-9b,10-dihydro-4bH-benzo[d]indeno[1,2-b]furan-9b-yl)acetamide (0.50 g, 1.48 mmol) in THF (5 ml). The reaction mixture was stirred at room temperature for 12 hrs, concentrated in a vacuum to remove solvent. The reaction mixture was extracted with water and methylene chloride, and purified through silica gel column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.10 g, 14%).
Reaction SMILES: CN(C=O)C.FC(F)(F)C(O)=O.[Cl:13][CH2:14][CH2:15][CH2:16]/[C:17](=[CH:21]\[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]2)=[C:24]([O:34][CH3:35])[CH:23]=1)/[C:18]([OH:20])=O.[N:36]1([C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][CH:50]=2)[CH:47]([NH2:51])[CH2:46][CH2:45]3)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C1C=CC2N(O)N=NC=2C=1>C(N(C(C)C)CC)(C)C.C(Cl)CCl>[N:36]1([C:42]2[CH:43]=[C:44]3[C:48](=[CH:49][CH:50]=2)[CH:47]([NH:51][C:18](=[O:20])/[C:17](=[CH:21]/[C:22]2[CH:27]=[CH:26][C:25]([N:28]4[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]4)=[C:24]([O:34][CH3:35])[CH:23]=2)/[CH2:16][CH2:15][CH2:14][Cl:13])[CH2:46][CH2:45]3)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: NC1CCc2cc(N3CCOCC3)ccc21
Reactant: COc1cc(/C=C(\CCCCl)C(=O)O)ccc1-n1cnc(C)c1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(/C=C(\CCCCl)C(=O)NC2CCc3cc(N4CCOCC4)ccc32)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
To a DMF (5.0 mL) solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetic acid salt (3.0 g) obtained in Example 418 and 5-morpholin-4-yl-indan-1-ylamine (1.80 g), IPEA (5.18 mg), EDC (3.84 g) and HOBT (2.71 g) were added one by one, and the reaction solution was agitated at room temperature for 1 hour. After confirming disappearance of the starting materials, the solvent was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the organic layer was partitioned. After washed with a saturated saline solution the organic layer, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 2.80 g of the title compound was obtained by purifying the obtained residue by silica gel chromatography (elution solvent: heptane-ethyl acetate system). The physical properties of the compound are as follows.