Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:29][O:30][CH3:31])[S:8][C:7]=2[CH:32]=1.C1(S)C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.CCOC(C)=O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([O:11][C:12]3[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:14][CH:13]=3)=[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH2:29][O:30][CH3:31])[S:8][C:7]=2[CH:32]=1
Reactant: COCc1ccccc1-c1sc2cc(OC)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COCc1ccccc1-c1sc2cc(O)ccc2c1Oc1ccc(/C=C/C(=O)O)cc1
Yield: 6.3 %

Procedure:
To a solution of (E)-3-(4-((6-methoxy-2-(2-(methoxymethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (45.9 mg, 0.103 mmol) in N-methyl-2-pyrrolidone (1.0 mL) was added thiophenol (0.016 mL, 0.154 mmol) and K2CO3 (14.21 mg, 0.103 mmol). The resulting mixture was subjected to microwave irradiation at 200° C. for 90 min after which time the reaction was diluted with EtOAc and filtered. The filtrate was concentrated in vacuo and the crude material was purified by was purified by reverse phase HPLC (basic condition, 0.1% NH4OH in CH3CN/H2O) to afford (E)-3-(4-((6-hydroxy-2-(2-(methoxymethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (3.0 mg, 0.00645 mmol, 6% yield). 1H NMR (400 MHz, CD3OD) δ ppm=7.47 (d, J=7.7 Hz, 1H), 7.40-7.31 (m, 4H), 7.31-7.21 (m, 4H), 6.86 (dd, J=8.7, 2.1 Hz, 1H), 6.79 (d, J=8.4 Hz, 2H), 6.35 (d, J=15.9 Hz, 1H), 4.53 (s, 2H), 3.29 (s, 3H). HRMS (m/z. M+H2O): 450.1355.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:7][N:8]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1.[Li]CCCC.[CH:32](=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:33]1([CH:32]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH:19]=[CH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:7][N:8]3[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=2)[OH:39])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(I)cc21
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nc(C=Cc2ccccc2)c2ccc(C(O)c3ccccc3)cc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of 6-iodo-3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazole, prepared in Example 14, step (i), (143 mg, 0.3 mmol) in THF (1 mL) cooled to −78° C. under an atmosphere of argon was added n-BuLi (0.2 mL, 0.315 mmol) dropwise. The resulting mixture was stirred at −78° C. for 30 min, then a solution of benzaldehyde (0.035 mL, 0.33 mmol) in THF (0.5 mL) was added rapidly via a cannula. After 0.5 h the reaction was quenched with saturated NH4Cl (aq) and diluted with EtOAc (10 mL) and H2O (3 mL). The phases were separated and the aqueous was extracted 2×10 mL EtOAc. The pooled EtOAc was washed with brine (5 mL), dried with Na2SO4, decanted and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (eluting with hexane:EtOAc 4:1) to give phenyl-{3-styryl-1-[2-(trimethyl-silanyl)-ethoxymethyl]-1H-indazol-6-yl}-methanol (68 mg, 50% yield). Rf sm=0.72; Rf p=0.39 (7:3 hexane:EtOAc); FTIR (thin film) 3368, 2952, 2893, 1621, 1478, 1449, 1374, 1307, 1249, 1216, 1078, 960, 859, 835 cm−1. MS (ESI) [M+H]/z Calc'd 457. found 457.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.[Br:15]N1C(=O)CCC1=O.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:15])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 61 %

Procedure:
To a solution of 4-methyl-3-nitrobenzoic acid (5.52 g, 30.5 mmol) in MeOH (100 mL) was added 98% sulfuric acid (2 mL) and the resultant mixture was refluxed overnight, then cooled to room temperature. The mixture was concentrated and the residue was dissolved in CH2Cl2 (50 mL) and water (20 mL). Solid Na2CO3 was added until the aqueous phase was basic to litmus paper. The phases were separated and the aqueous phase was extracted with CH2Cl2 (5×20 mL). The combined organic extracts were dried (Na2SO4) and concentrated and provided 5.79 g (97%) of 4-methyl-3-nitrobenzoic acid methyl ester as a white solid. To a solution of 4-methyl-3-nitrobenzoic acid methyl ester (5.01 g, 25.7 mmol) in CCl4 (65 mL) was added N-bromosuccinimide (5.04 g, 28.3 mmol) followed by 1,1′-azobis(cyclohexanecarbonitrile) (1.21 g, 4.96 mmol). The resultant mixture was refluxed for 24 hours then cooled to room temperature, filtered through filter paper, and concentrated. Purification of the crude material by column chromatography on silica gel (9:1:hexanes-EtOAc) provided 4.30 g (61%) of 4-bromomethyl-3-nitrobenzoic acid methyl ester as a yellow oil. 1H NMR (CDCl3) δ 3.98 (s, 3H), 4.85 (s, 2H), 7.67 (d, 1H, J=7.8 Hz), 8.25 (d, 1H, J=7.8, 1.5 Hz), 8.66 (d, 1H, J=1.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:33])[CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:10][O:11][C:12](=[O:33])[CH:13]=[CH:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(Cl)nc1
Yield: 90.7 %

Procedure:
To 6-chloro-pyridine-3-carboxaldehyde (300 mg, 2.12 mmol) in toluene was added methyl(triphenylphosphoranylidene)acetate (708 mg, 2.12 mmol) and the solution was refluxed for 6 hrs. The reaction mixture was diluted with EtOAc and then washed three times with H2O, brine, dried. Na2SO4, filtered and concentrated under reduced pressure. The obtained residue was column-chromatographed to yield 3-(6-chloro-pyridin-3-yl)-acrylic acid methyl ester (380 mg, 90%).
Reaction SMILES: CCOP(OCC)([CH2:6][C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])=O.[H-].[Na+].[S:18]1[CH:22]=[C:21]([CH:23]=O)[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]1=2>C1COCC1>[S:18]1[CH:22]=[C:21](/[CH:23]=[CH:6]/[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])[C:20]2[CH:25]=[CH:26][CH:27]=[CH:28][C:19]1=2
Reactant: O=Cc1csc2ccccc12
Reactant: CCOP(=O)(CC(=O)N(C)OC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CON(C)C(=O)/C=C/c1csc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
Diethyl (N-methoxy-N-methylcarbamoylmethyl)phosphonate (6.13 g, 25.6 mmol) was added dropwise via syringe to a stirred suspension of sodium hydride (1.02 g, 25.6 mmol) in anhydrous THF (75 ml) at 0° C. The reaction was warmed to room temperature and was stirred for 1 h. After cooling to 0° C., benzo[b]thiophene-3-carbaldehyde (3.78 g, 23.3 mmol) was added. The resulting mixture was stirred at room temperature for 1 hr. The reaction was quenched with 100 mL aqueous HCl (0.1 N) and extracted with ethyl acetate (250 ml). The combined organic layers were washed with brine (50 ml) and dried over anhydrous magnesium sulfate. The filtrate was concentrated in vacuo and triturated with hexane to give (E)-3-benzo[b]thiophen-3-yl-N-methoxy-N-methyl-acrylamide (5.38 g, 93%) as a yellow solid. 1H NMR (500 MHz, CDCl3) 8.06-8.01 (2H, 2 superimposed d, J=8.24, 15.87 Hz), 7.89 (1H, d, J=7.94 Hz), 7.78 (1H, s), 7.47 (1H, t, J=7.93 Hz), 7.41 (1H, t, J=8.24 Hz), 7.13 (1H, d, J=15.87 Hz), 3.79 (3H, s), 3.34 (3H, s); MS m/e 248.07 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[S:9][C:6]=2[NH:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:22])=O>CN(C)C=O>[CH3:18][O:17][C:15](=[O:16])[CH2:14][CH2:13][CH2:12][C:10]1[S:9][C:6]2=[N:7][CH:8]=[C:3]([C:1]#[N:2])[C:4]([Cl:22])=[C:5]2[CH:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)CCCc1cc2c(=O)c(C#N)c[nH]c2s1
Solvent: CN(C)C=O
Product: COC(=O)CCCc1cc2c(Cl)c(C#N)cnc2s1

Procedure:
A mixture of methyl 4-(5-cyano-4-oxo-4,7-dihydrothieno[2,3-b]pyridin-2-yl)butanoate (136 mg) and 2 drops of N,N-dimethylformamide in 5 mL of phosphorous oxychloride is heated at reflux for 10 minutes and concentrated. To the residue is added dichloromethane and the solution is washed with 1% aqueous sodium bicarbonate solution. The organic layer is dried and concentrated. The residue is purified by flash column chromatography eluting with dichloromethane to provide 126 mg of 4-(4-chloro-5-cyano-thieno[2,3-b]pyridin-2-yl)-butyric acid methyl ester as a tan solid, mp 55-57° C.; 1H NMR (DMSO-d6) δ 1.98 (quintet, J=7 Hz, 2H), 2.42 (t, J=7 Hz, 2H), 3.04 (t, J=7 Hz, 2H), 3.59 (s, 3H), 7.42 (s, 1H), 8.94 (s, 1H); MS 295.1 (M+H)+.
Reaction SMILES: [C:1]([O:20][C@H:21]1[C@H:25]([O:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:24][NH:23][CH2:22]1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.[CH3:47][N:48]([CH3:53])[CH2:49][C:50](O)=[O:51]>>[C:1]([O:20][C@H:21]1[C@H:25]([O:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37]/[CH:38]=[CH:39]\[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:24][N:23]([C:50](=[O:51])[CH2:49][N:48]([CH3:53])[CH3:47])[CH2:22]1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O[C@@H]1CNC[C@H]1OC(=O)CCCCCCC/C=C\C/C=C\CCCCC
Reactant: CN(C)CC(=O)O
Agent: Cl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)O[C@@H]1CN(C(=O)CN(C)C)C[C@H]1OC(=O)CCCCCCC/C=C\C/C=C\CCCCC

Procedure:
Compound 26 (297 mg, 87.2%) was obtained in the same manner as that in Example 25, by using compound 2 (300 mg, 0.478 mmol) obtained in Example 2, and N,N-dimethylglycine hydrochloride (Tokyo Chemical Industry Co., Ltd.; 133 mg, 0.955 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH2:25][O:26][C:27]4[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:28]=4[CH:29]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:35])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CO>[ClH:34].[Cl:34][C:32]1[CH:31]=[CH:30][C:28]2[CH:29]=[C:24]([S:21]([N:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[C:16](=[O:35])[CH2:17]3)(=[O:22])=[O:23])[CH2:25][O:26][C:27]=2[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)C2=Cc3ccc(Cl)cc3OC2)CCN1CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 198.4 %

Procedure:
To 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone (1.856 g) were added 4N hydrochloric acid in ethyl acetate (40 ml) and methanol (25 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give colorless crystals of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride (1.618 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:55]12[CH2:62][CH2:61][CH:58]([CH2:59][CH2:60]1)[C@@H:57](O)[CH2:56]2>C1COCC1>[N:55]12[CH2:62][CH2:61][CH:58]([CH2:59][CH2:60]1)[C@@H:57]([O:12][C:11](=[O:13])[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:56]2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: COc1ccc(C(Nc2ccccc2)C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(Nc2ccccc2)C(=O)O[C@H]2CN3CCC2CC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.1 %

Procedure:
(4-Methoxy-phenyl)-phenylamino-acetic acid hydrochloride (I92) (300 mg, 1.02 mmol), DCC (253 mg, 1.23 mmol), and HOBT (188 mg, 1.23 mmol) are dissolved in THF (10 mL). DIPEA (0.36 mL, 2.04 mmol) and (R)-quinuclidin-3-ol (130 mg, 1.02 mmol) are added. The mixture is stirred ad RT for 16 hours. Then DCC (25.3 mg, 0.12 mmol), HOBT (18.8 mg, 0.12 mmol), DIPEA (36 uL, 0.204 mmol) and (R)-quinuclidin-3-ol (13.0 mg, 0.10 mmol) are added again and reaction is stirred for additional 32 hours. THF is evaporated and the residue is dissolved in EtOAc and washed with sat. NaHCO3, H2O and brine. The organic layer is dried (Na2SO4), filtered and evaporated. The crude residue is purified by flash chromatography (DCM/MeOH=97/3 to 92/8) to obtain the title compound as a yellow solid (90 mg, 24% yield, mixture of diastereoisomers).
Reaction SMILES: [C:1]([O:9][C:10]1[C:15](=[O:16])[N:14]2[CH2:17][CH2:18][CH2:19][CH:20](Br)[C:13]2=[N:12][C:11]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:9][C:10]1[C:15](=[O:16])[N:14]2[CH2:17][CH2:18][CH:19]=[CH:20][C:13]2=[N:12][C:11]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CCCC2Br
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CCC=C2
Temperature: 100 °C

Procedure:
To a solution of methyl 3-(benzoyloxy)-9-bromo-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate (obtained following Example 2, Step 1) in anhydrous DMF was added triethylamine (2 eq.). The mixture was stirred and heated to 100° C. for 3 h. After cooling to room temperature the mixture was partitioned between 0.1 M HCl and EtOAc. The aq. phase was again extracted with EtOAc and the combined org. phases were dried over sodium sulfate, filtered, concentrated to dryness under vacuum. The crude product so obtained was used in the subsequent step without further purification. An analytical sample of the title compound was obtained by crystallization from methanol. A pale yellow solid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].C1([N:18]=C=NC2CCCCC2)CCCCC1.O.OC1C2N=NNC=2C=CC=1.[OH-].[NH4+]>CN(C)C=O>[NH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=1[C:6]([NH2:18])=[O:7]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: Oc1cccc2[nH]nnc12
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Cl)cc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-chloroanthranilic acid (70 g, 0.41 mol) in hot (60° C.) dimethylformamide (700 mL), dicyclohexylcarbodiimide (93 g, 0.451 mol, 1.1 equiv), hydroxybenzotriazole hydrate (60.9 g, 0.451 mol, 1.1 eq) and 30% aqueous ammonium hydroxide solution (350 mL) were added. The resulting solution was stirred at room temperature for 18 h. The formed urea was filtered off and the filtrate concentrated. The resulting mixture was partitioned between ethyl acetate and 5% K2CO3 solution. The organic phase was separated, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to dryness to give the desired product as a slightly yellow solid (58.1 g, 83%).
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2([CH2:27][NH2:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]2([CH2:27][NH:28][C:9](=[O:11])[CH2:8][S:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: O=C(O)CSc1ccccc1
Reactant: COc1ccc(C2(CN)CCCC2)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2(CNC(=O)CSc3ccccc3)CCCC2)cc1OC
Reaction time: 16 h
Yield: 14.6 %

Procedure:
Phenylsulfanyl-acetic acid (33.6 mg, 0.200 mmol) and C-[1-(3,4-Dimethoxy-phenyl)-cyclopentyl]-methylamine (47.1 g, 0.200 mmol) were dissolved in acetonitrile (1 mL) containing triethylamine (83.6 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (76.0 mg, 0.200 mmol) was added and the solution was allowed to stir for 16 hours. The mixture was then purified by reverse phase preparative liquid chromatography to yield the pure product (11.3 mg, 0.0293 mmol, 14.6%) ESI-MS m/z calc. 385.2, found 386.0 (M+1)+. Retention time of 3.12 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[N:13]([CH3:14])[CH3:12])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)C1CCc2ccc(Br)cc21
Temperature: 120 °C

Procedure:
(Method 1): 6-Bromo-indan-1-one (0.23 mmol) and dimethyl-amine (0.71 mmol) were mixed in 3 ml of 1,2-dichloroethane in a process vial, which was sealed with a septum. Sodium triacetoxyborohydride (0.47 mmol) was added under argon atmosphere. The suspension was subjected to microwave irradiating conditions (CEM Discover® equipped with a CEM Explorer® automated reaction handling module). The reaction mixture was heated for 5 min at 120° C. and then cooled. The crude was evaporated to dryness and then suspended in aqueous NaHCO3 The product was extracted with CH2Cl2 and washed with aqueous NaHCO3. The CH2Cl2 extract was dried with anhydrous Na2SO4, filtered and evaporated to dryness to give the crude product (6-bromo-indan-1-yl)-dimethyl-amine. The crude was purified by flash column chromatography (CH2Cl2-MeOH as eluents) by using a CombiFlash Companion™ system to yield the title compound (85%). MS [MH]+=240.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[C:21](=[O:22])[C:20]3[C@@H:19]4[C:23]([CH3:25])([CH3:24])[C@@:16]([CH3:26])([CH2:17][CH2:18]4)[C:15]=3[N:14]2[CH3:27])=[CH:8][CH:7]=1>CO.O1CCCC1>[CH3:27][N:14]1[C:15]2[C@@:16]3([CH3:26])[C:23]([CH3:24])([CH3:25])[C@H:19]([CH2:18][CH2:17]3)[C:20]=2[C:21](=[O:22])[N:13]1[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([C:5]([OH:28])=[O:4])=[CH:11][CH:10]=1
Reactant: COC(=O)c1ccc(Cn2c(=O)c3c(n2C)[C@]2(C)CC[C@H]3C2(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1c2c(c(=O)n1Cc1ccc(C(=O)O)cc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
1 M NaOH (1.1 mL, 1.1 mmol) was added to a solution of (4S,7R)-4-(1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-ylmethyl)-benzoic acid methyl ester (228 mg, 0.644 mmol) in methanol (0.9 mL) and tetrahydrofuran (1.8 mL). The reaction mixture was stirred at room temperature overnight, and it was then partitioned between water (100 mL) and ether (100 mL). The aqueous layer was acidified with 1 M HCl to pH<3 and the resulting mixture was extracted with chloroform (100 mL). The chloroform extract was washed with brine (100 mL), dried (magnesium sulfate), filtered, and evaporated to give (4S,7R)-4-(1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-ylmethyl)-benzoic acid (168 mg, 77%) as a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][N:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:12].[Cl:22][CH2:23][C:24](Cl)=[O:25].Cl>ClCCCl>[Cl:22][CH2:23][C:24]([C:9]1[CH:8]=[C:7]([C:11](=[O:12])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[N:6]([CH3:5])[CH:10]=1)=[O:25]
Reactant: Cn1cccc1C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cn1cc(C(=O)CCl)cc1C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.1 %

Procedure:
A 210 g (1.57 mole) sample of AlCl3 was added in portions to a solution of 145.4 g (0.63 mole) of (1 -methyl-1H-pyrrol-2-yl)(4-nitrophenyl)-methanone (1) in 450 mL of 1,2-dichloroethane (DCE). A solution of 125 mL (1.57 mole) of chloroacetyl chloride in 200 mL of DCE was added dropwise. The mixture was stirred 1 h at room temperature. The reaction was poured into 1N HCl and ice, the organics were separated, washed with H2O, 1N NaOH, H2O, brine and dried (MgSO4). The solvent was evaporated in vacuo and the residue was recrystallized from EtOAc/EtOH to give 116.2 g of solid. mp 173°-176° C. Mass spectrum (Cl-CH4) m/z 307 (M+1). NMR (Me2SO-d6)δ 8.4 (d, 2 H); 8.2 (s,1 H); 8.0 (d, 2 H); 7.1 (s, 1 H); 4.8 (s, 2 H); 4.0 (s, 3 H). Anal calcd for C14H11CIN2O4 : Calcd: C, 54.83; H, 3.61; N, 9.13. Found: C, 55.11;H, 3.70; N, 9.10.
Reaction SMILES: Cl[C:2]([O:4]CC)=[O:3].[CH3:7][CH2:8][N:9](C(C)C)C(C)C.[CH3:16][C:17]1[CH:18]=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1>C(Cl)Cl>[CH2:8]([NH:9][C:2](=[O:3])[O-:4])[CH3:7].[CH3:16][C:17]1[CH:18]=[CH:19][C:20]2[CH:21]([CH3:29])[CH:22]3[CH2:26][NH:25][CH2:24][CH:23]3[C:27]=2[CH:28]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)Cl
Agent: Cc1ccc2c(c1)C1CNCC1C2C
Solvent: ClCCl
Product: CCNC(=O)[O-]
Reaction time: 2 h

Procedure:
Ethyl chloroformate (0.29 mL, 3.0 mmol) and DIEA (1.6 mL, 9.0 mmol) were added to a solution of 5-methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (from Example 13, Step F) (0.56 g, 3.0 mmol) in CH2Cl2 (15 mL) at 0° C. The reaction was stirred for 2 hours from 0° C. to room temperature. The reaction was quenched with aqueous HCl (15 mL, 1M). The desired product was extracted with CH2Cl2 (3×15 mL). The organic extracts were washed with brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (SiO2) using a 10-60% EtOAc—hexanes gradient to afford 0.36 g (46%) of the subtitle compound. MS calculated for C16H21NO2+H: 260, observed: 260.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13].Cl>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:33])=[C:5]([C:24]([O:31][CH3:32])=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c(Cc2ccc(Oc3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.4 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-phenoxybenzoate (0.220 g, 0.487 mmol) was dissolved in a mixed solution of an aqueous 1N NaOH solution (3 ml) and 1,4-dioxane (5 ml) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was diluted with water, rendered acidic with concentrated hydrochloric acid and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the titled compound (0.210 g, 0.479 mmol, 98%).