Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[C@H:38]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH2:37][CH2:36][C:35]1=[O:48]>>[Si:41]([O:40][CH2:39][C@H:38]1[CH2:37][CH2:36][C:35](=[O:48])[N:34]1[C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:20])[CH3:21])=[O:23])([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC(=O)N1c1cc(F)ccc1CN
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1N1C(=O)CC[C@@H]1CO[Si](C)(C)C(C)(C)C)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and (S)-1-(2-(aminomethyl)-5-fluorophenyl)-5-((tert-butyldimethylsilyloxy)methyl)pyrrolidin-2-one, derived from reduction of intermediate 122, (R)-2-(2-((tert-butyldimethylsilyloxy)methyl)-5-oxopyrrolidin-1-yl)-4-fluorobenzonitrile 1HNMR 400 MHz (DMSO) δ ppm: 8.82 (1H, broad s), 7.47 (2H, m), 7.35 (4H, m), 7.00 (1H, broad s), 5.09 (2H, s), 4.60–4.10 (3H, m), 4.02 (3H, m), 3.88 (2H, m), 3.53 (2H, broad s), 2.42–2.35 (2H, m), 1.94 (1H, m), 1.56 (3H, s), 1.55 (3H, s), 0.82 (9H, broad s), −0.01 (6H, s). LCMS (M+H)+ m/z 665.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]CC/C=C/C=C\CCCC)(=O)C.[CH2:20]([OH:29])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].O1C=CCCC1.Cl>ClCCl>[O:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[O:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][OH:29]
Reactant: CCCC/C=C\C=C\CCCCCCCOC(C)=O
Reactant: OCCCCCCCCO
Agent: C1=COCCC1
Agent: Cl
Solvent: ClCCl
Product: OCCCCCCCCOC1CCCCO1

Procedure:
The synthesis of compound I, the major component of the attractant composition of the invention is illustrated in FIG. 1. In brief, 1,8-octanediol is reacted with dihydropyran in dichloromethane catalyzed by hydrochloric acid to give 8-[(tetrahydro-2H-pyran-2-yl)oxy]-1-octanol, which is reacted with pyridinium chlorochromate to give 8-[(tetrahydro-2H-pyran-2-yl)oxy]octanal (A). The octanal (A) is then reacted with diethylcyanomethylphosphate and sodium hydride to produce 10-[(tetrahydro-2H-pyran-2-yl)oxy]-2-decenitrile (B). Diisobutylaluminum hydride reduces the nitrile (B) to an imine which upon hydrolysis yields the aldehyde (C). Wittig coupling of (C) with n-pentyl triphenylphosphorane gives the mixture of conjugated dienes (D) which upon hydrolysis and acetylation give the two isomeric pentadecadien-1-ol acetates (E). The (E,E)-8,10-isomer is removed by Diels-Alder reaction with tetracyanoethylene to give pure (E,Z)-8,10-pentadecadien- 1-ol acetate (I). A detailed description of the synthesis of I is given in Example 4, below.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:29])[C:11]([OH:28])([C:20]1[CH:25]=[CH:24][CH:23]=[C:22](OC)[CH:21]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](OC)[CH:13]=1)[CH2:2]2.O[C:31](C1C=CC=C(OC)C=1)(C1C=CC=C(OC)C=1)C(O)=O.OC(C1C=CC=CC=1)(C1C=CC=CC=1C)C(O)=O>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:29])[C:11]([OH:28])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:31])[CH2:2]2
Reactant: COc1cccc(C(O)(C(=O)O)c2cccc(OC)c2)c1
Reactant: COc1cccc(C(O)(C(=O)O[C@H]2CN3CCC2CC3)c2cccc(OC)c2)c1
Agent: Cc1ccccc1C(O)(C(=O)O)c1ccccc1
Product: Cc1ccccc1C(O)(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1

Procedure:
This compound is prepared by an analogous method to hydroxy-bis-(3-methoxy-phenyl)-acetic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Intermediate K) by replacing hydroxy-bis-(3-methoxy-phenyl)-acetic acid (Intermediate J) with hydroxy-phenyl-o-tolyl-acetic acid (Intermediate M).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=O)[O:17]C3C=CC=CC=3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[C:35]1([S:45]([NH2:48])(=[O:47])=[O:46])[CH:40]=[CH:39][CH:38]=[C:37]([S:41]([NH2:44])(=[O:43])=[O:42])[CH:36]=1>>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16]([NH:44][S:41]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([S:45]([NH2:48])(=[O:47])=[O:46])[CH:36]=3)(=[O:43])=[O:42])=[O:17])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:25]([F:26])([F:27])[F:28])[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1cccc(S(N)(=O)=O)c1
Product: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)NS(=O)(=O)c2cccc(S(N)(=O)=O)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-{4-[5-methyl-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 7 of Example 52) and 1,3-benzenedisulfonamide: MS (ESI) m/z 608 [M+H]+, 606 [M−H]−, 1H-NMR (CDCl3) δ 8.62 (1H, br.s), 8.14 (2H, br.s), 7.70 (1H, br.s), 7.39-7.21 (9H, m), 6.18 (1H, br.s), 3.35 (2H, br.s), 2.76 (2H, br.s), 2.15 (3H, s).
Reaction SMILES: [OH:1]O.[OH-].[Na+].[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]3[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])=[CH:13][C:8]=2[O:7][CH2:6]1>CO>[O:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16][CH:15]3[O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35](=[O:1])[NH2:36])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(OCc2ccccc2C#N)C1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)OCO3)C(OCc2ccccc2C(N)=O)C1
Yield: 57 %

Procedure:
0.5 ml of hydrogen peroxide (33%) and 0.2 ml of 2N sodium hydroxide solution were added to a solution of 236 mg (0.54 mmol) of tert-butyl (3RS,4RS)-4-benzo[1,3]dioxol-5-yl-3-(2-cyano-benzyloxy)-piperidine-1-carboxylate in 5 ml of methanol. The reaction solution was heated under reflux for 2 hours. Subsequently, the same amounts of hydrogen peroxide and sodium hydroxide solution were again added and the solution was heated for a further 2 hours. Thereafter, the solution was cooled and evaporated under reduced pressure. For purification, the residue was chromatographed on silica gel using a 9:1 mixture of methylene chloride and ether as the eluent. There were obtained 140 mg (57% of theory) of tert-butyl (3RS,4RS)-4-benzo[1,3]dioxol-5-yl-3-(2-carbamoyl-benzyloxy)-piperidine-1-carboxylate as a colourless solid; MS: 455 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:11][CH:10]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>CCOCC>[C:19]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH2:11][CH:10]=1)(=[O:21])[CH3:20]
Reactant: OCCCCCCCC1=CC1
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OCCCCCCCC1=CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A solution of 2.5 mmol of 1-(7-hydroxyheptyl)-cyclopropene in 5 ml of ether was cooled in an ice bath. Triethylamine (0.44 ml) and 0.21 g (2.7 mmol) of acetyl chloride were added, and the reaction mixture was stirred 1 hour at 5° C. Additional acetyl chloride (0.11 g), ether and triethylamine were added, and the reaction was stirred at 5° C. until GC analysis indicated 95% conversion. The reaction was worked up by adding more ether and washing the organic phase with water, dilute HCl solution (diluted 1M aqueous HCl), potassium carbonate solution (2×), water and brine. The ether phase was dried over magnesium sulfate and stripped. Hexane was added and the reaction was stripped again to give 1-(7-acetoxyheptyl)-cyclopropene.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[NH:10][CH:9]=[C:8]([C:14]#[N:15])[C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:7]1[C:6]2[C:11](=[N:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:14]#[N:15]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c[nH]c2ncc([N+](=O)[O-])cc2c1=O
Product: N#Cc1cnc2ncc([N+](=O)[O-])cc2c1Cl

Procedure:
A mixture of 19.3 g (89.3 mmol) of 6-nitro-4-oxo-1,4-dihydro-[1.8]naphthyridine-3-carbonitrile in 386 ml of phosphorous oxychloride was refluxed for 24 hr. Excess phosphorous oxychloride was removed. The residue is mixed with ethyl acetate and 15 g of potassium hydroxide in 200 ml of ice water. The organic layer was separated and the aqueous layer was extract several more times with ethyl acetate. The combined volume of extracts was 4000 ml. The extracts were dried of magnesium sulfate and the solution was filter through a short silica gel column. The solvent was removed. The residue was stirred with ether and the solid was collected giving 15.7 g of the title compound as an orange solid: mass spectrum (electrospray, m/e): M+H 235.
Reaction SMILES: [CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27](=[O:31])[N:28]([CH3:30])[CH3:29])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C@H:32]12[C@H:38]([OH:39])[C@H:35]([CH2:36][CH2:37]1)[CH2:34][NH:33]2>>[CH:1]1([N:8]2[C:12]3[N:13]=[C:14]([NH:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([N:33]5[CH2:34][C@@H:35]6[C@@H:38]([OH:39])[C@H:32]5[CH2:37][CH2:36]6)=[O:24])=[CH:20][N:19]=4)[N:15]=[CH:16][C:11]=3[CH:10]=[C:9]2[C:27]([N:28]([CH3:30])[CH3:29])=[O:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCCCC1
Reactant: O[C@@H]1[C@@H]2CC[C@H]1NC2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4C[C@H]5CC[C@@H]4[C@@H]5O)cn3)nc2n1C1CCCCCC1
Yield: 77 %

Procedure:
Following general amide formation method 3, 6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid was combined with (1R,4R,7R)-2-azabicyclo[2.2.1]heptan-7-ol which gave 7-cycloheptyl-2-(5-((1R,4R,7R)-7-hydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (50 mg) in 77% yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([NH2:16])[S:8][C:7]=1[NH2:17])=[O:5])[CH3:2].[CH:18]([C:20]1[S:24][C:23]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)=[CH:22][CH:21]=1)=O.C(O)(C(F)(F)F)=O>C(O)(C)C>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([N:16]=[CH:18][C:20]2[S:24][C:23]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)=[CH:22][CH:21]=2)[S:8][C:7]=1[NH2:17])=[O:5])[CH3:2]
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: CCOC(=O)c1c(N)sc(N=Cc2ccc(-c3cccs3)s2)c1C(=O)OCC

Procedure:
2,5-Diamino-thiophene-3,4-dicarboxylic acid diethyl ester (30 mg, 0.25 mmol) was mixed with 5-formyl-2,2′bithiophene (40 mg, 0.25 mmol) in isopropanol and refluxed for five hours following the catalytic addition of TFA. The solvent was removed and the product isolated as a yellow solid after purification by flash chromatography (42 mg, 64%). 1H-NMR (300 MHz, [D] DMSO): δ=8.19 (s, 1H), 7.89 (s, 2H), 7.58 (d, 1H, 3J=5.2 Hz), 7.50 (d, 1H, 3J=3.9 Hz) 7.41 (d, 1H, 3J=3.6 Hz), 7.34 (d, 1H, 3J=3.9 Hz), 7.11 (t, 1H, 3J=3.6 Hz), 4.25 (q, 2H, 3J=7.1 Hz), 4.12 (q, 2H, 3J=7.2 Hz), 1.31 (t, 3H, 3J=7.2 Hz), 1.19 (t, 3H, 3J=7.0 Hz). 13C-NMR (300 MHz, [D] acetone): δ=165.5, 164.8, 161.7, 146.1, 142.3, 141.9, 137.7, 137.6, 133.5, 133.4, 131.1, 129.2, 126.9, 125.8, 125.3, 61.5, 60.5, 14.8, 14.6. EI-MS: m/z 434.9 ([M]+, 96%).
Reaction SMILES: Cl.[OH:2][NH2:3].C(=O)([O-])[O-].[Na+].[Na+].[O:10]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:13][CH2:12][C@@H:11]1[CH:20]=O>O.C1COCC1>[O:10]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:13][CH2:12][C@@H:11]1[CH:20]=[N:3][OH:2]
Reactant: O=C[C@H]1COC2(CCCCC2)O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: ON=C[C@H]1COC2(CCCCC2)O1
Reaction time: 0.08 h
Yield: 99.3 %

Procedure:
In 1000 mL of DI water was added hydroxyl amine hydrochloride (51.0 g, 734 mol) and the reaction was stirred for 5 minutes. Sodium carbonate (38.1 g, 360 mmol) was added in 3 large portions and the reaction was stirred for 15 minutes. THF (700 mL) was added to the reaction and (R)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde (125 g, 734 mmol) was added in 1 portion in 800 mL of THF. The reaction was stirred for 4 hours and poured into a 4 L separatory funnel and the layers separated. The aqueous layer was extracted twice with MTBE (3000 mL total). The combined organic layers were washed with water (700 mL) and brine (300 mL), dried over MgSO4 and concentrated in vacuo to afford (S)-1,4-dioxaspiro[4.5]decane-2-carbaldehyde oxime (135 g, 99%) as a clear viscous oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=[C:9]2[C:17]([OH:19])=[O:18])([O-:3])=[O:2].[CH2:20](O)[CH3:21]>Cl>[CH2:20]([O:18][C:17]([C:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[C:12]([C:14]([OH:16])=[O:15])=[CH:11][CH:10]=1)=[O:19])[CH3:21]
Reactant: CCO
Reactant: O=C(O)c1ccc(C(=O)O)c2c([N+](=O)[O-])cccc12
Agent: Cl
Product: CCOC(=O)c1ccc(C(=O)O)c2c([N+](=O)[O-])cccc12

Procedure:
52 parts of 8-nitro-naphthalene-1,4-dicarboxylic acid are dissolved in 700 parts of absolute ethyl alcohol and the solution is boiled under reflux for 12 hours whilst continuously passing in hydrogen chloride gas. The resulting solution is evaporated in vacuo. The 4-ethoxycarbonyl-8-nitro-naphthalene-1-carboxylic acid of the formula ##STR27## which is obtained in this way, melts at 178° to 180°.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[CH:5]=[C:4]([OH:12])[CH:3]=1.C([Mg]Cl)(C)C.[C:18]1([CH:24]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[O:34])[C:26]2=[O:35])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>ClCCl.O1CCCC1>[C:36]1([CH:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([C:3]3[C:4]([OH:12])=[CH:5][C:6]4[O:11][CH2:10][CH2:9][O:8][C:7]=4[C:2]=3[F:1])([OH:34])[C:26]2=[O:35])[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1cc(F)c2c(c1)OCCO2
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1c(O)cc2c(c1F)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.8 %

Procedure:
A 100 mL round-bottom flask was charged with 8-fluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-ol (6.4 g, 37 mmol) and tetrahydrofuran (60 mL). A 2 M solution of isopropylmagnesium chloride in tetrahydrofuran (20.0 mL, 40.0 mmol) was added at 5° C. and the reaction mixture was stirred for 15 min. The reaction mixture was concentrated in vacuo and dichloromethane (60 mL) was added, followed by a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (10.9 g, 35.0 mmol) in dichloromethane (60 mL). The reaction mixture was heated at reflux for 5 h, allowed to cool to ambient temperature and stirred for a further 16 h. Saturated aqueous ammonium chloride (30 mL) was added and the phases were separated. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. Trituration of the residue in methanol (30 mL) afforded 1-(diphenylmethyl)-3-(5-fluoro-7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (10.8 g, 64%) as an off-white solid: MS (ES+) m/z 506.0 (M+23).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH:18]([CH3:20])[CH3:19])([C:15](O)=[O:16])[CH2:10]1.CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.[CH:35]1([C:38]2[CH:39]=[C:40]([NH2:48])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=2)[CH2:37][CH2:36]1>C1COCC1>[CH:35]1([C:38]2[CH:39]=[C:40]([NH:48][C:15]([C@@:11]3([CH:18]([CH3:19])[CH3:20])[CH2:12][C:13](=[O:14])[N:9]([C:3]4[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[CH2:10]3)=[O:16])[CH:41]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:43]=2)[CH2:36][CH2:37]1
Reactant: Nc1cc(C2CC2)cc(C(F)(F)F)c1
Reactant: Cc1cccc(C)c1N1C[C@](C(=O)O)(C(C)C)CC1=O
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1N1C[C@](C(=O)Nc2cc(C3CC3)cc(C(F)(F)F)c2)(C(C)C)CC1=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-1-(2,6-dimethylphenyl)-3-isopropyl-5-oxopyrrolidine-3-carboxylic acid (32 mg, 0.12 mmol) and methanesulfonyl chloride (12 μL, 0.15 mmol) in THF (0.6 mL) at 0° C. was added diisopropylethylamine (0.060 mL, 0.35 mmol). The solution was stirred 15 min at 0° C., warmed to ambient temperature, and 3-cyclopropyl-5-(trifluoromethyl)benzenamine (47 mg, 0.23 mmol) was subsequently added and the solution was heated at 55° C. overnight. The following day, the reaction mixture was purified via preparative HPLC to afford the desired amide as a white solid. 1H NMR (400 MHZ, CDCl): δ 9.89 (s, 1H), 7.86 (s, 1H), 7.56 (s, 1H), 7.05-7.17 (m, 4H), 3.97 (d, J=10.4 Hz, 1H), 3.67 (d, J=10.4 Hz, 1H), 3.04 (d, J=17.2 Hz, 1H), 2.65 (d, J=17.2 Hz, 1H), 2.36 (septet, J=6.8 Hz, 1H), 2.16 (s, 3H), 1.99-2.08 (m, 1H), 1.99 (s, 3H), 1.00-1.06 (m, 2H), 0.96 (t, J=6.8 Hz, 6H), 0.70-0.75 (m, 2H). LC-MS Rt (retention time): 3.02 min; MS: (ES) m/z 459 (M+H+).
Reaction SMILES: [C:1]([O:9][C@H:10]([CH2:15][C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([NH2:23])=[C:18]([CH3:24])[C:17]=1[CH2:25][O:26][C:27](=[O:29])[CH3:28])[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(O)(=O)C.[N:41](OCCC(C)C)=O.C([O-])(=O)C.[K+]>>[C:1]([O:9][C@H:10]([CH2:15][C:16]1[C:17]([CH2:25][O:26][C:27](=[O:29])[CH3:28])=[C:18]2[C:19](=[C:20]([Cl:22])[CH:21]=1)[NH:23][N:41]=[CH:24]2)[C:11]([O:13][CH3:14])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)OC(=O)c1ccccc1
Reactant: CC(C)CCON=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](Cc1cc(Cl)c2[nH]ncc2c1COC(C)=O)OC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
(R)-3-(2-(acetoxymethyl)-4-amino-5-chloro-3-methylphenyl)-1-methoxy-1-oxopropan-2-yl benzoate (16.33 g, 38.9 mmol) in toluene (100.0 ml, 939 mmol) was added acetic acid (5.0 ml, 87 mmol) followed by isoamyl nitrite (5.76 ml, 42.8 mmol) at 0° C. After 15 min, potassium acetate (7.64 g, 78 mmol) was added and the reaction mixture was stirred for 12 h. The solvent was removed and the crude product was dissolved in dichloromethane (250 mL) and washed with aqueous NaHCO3. The solvent was dried (Na2SO4), evaporated and the crude product was purified by flash chromatography using 40% EtOAc in hexane to give (R)-3-(4-(acetoxymethyl)-7-chloro-1H-indazol-5-yl)-1-methoxy-1-oxopropan-2-yl benzoate in 88% yield. MS (ESI) 453 (M+Na); Rf=2.46.
Reaction SMILES: C([O:4][C:5]([C:7]1[C:12]([C:13]#[N:14])=[CH:11][C:10]([Br:15])=[CH:9][N:8]=1)=[O:6])(C)C.O.[OH-].[Li+].Cl>C1COCC1.O>[Br:15][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[C:7]([C:5]([OH:6])=[O:4])=[N:8][CH:9]=1
Reactant: CC(C)OC(=O)c1ncc(Br)cc1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(Br)cnc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of 5-bromo-3-cyano-pyridine-2-carboxylic acid isopropyl ester (70 mg, 0.26 mmol) in a mixture of THF (3 ml) and water (3 ml) was added lithium hydroxide monohydrate (32.75 mg, 0.78 mmol, 3 equiv.). The reaction mixture was stirred for 2 hours at 25° C. The mixture was acidified with 2N aqueous HCl solution (pH 5) and extracted with EtOAc (2×15 ml). The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to dryness to give 5-bromo-3-cyano-pyridine-2-carboxylic acid (45 mg, 76%) as a yellow solid which was used in next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C([Li])CCC.[B:26](OC)([O:29]C)[O:27]C.Cl>CCCCCC.O1CCCC1>[CH:10]1[C:9]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([B:26]([OH:29])[OH:27])=[CH:7][CH:6]=3)[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(-n2c3ccccc3c3ccccc32)cc1
Reaction time: 2 h
Yield: 66 %

Procedure:
In a 500 mL three-neck flask was put 21.8 g (67.5 mmol) of 9-(4-bromophenyl)-9H-carbazole. The atmosphere in the flask was replaced with nitrogen. To the mixture was added 200 mL of tetrahydrofuran (THF). The temperature of this solution was set to −78° C., and then 48.9 mL (74.3 mmol) of n-butyllithium (a 1.52 mol/L hexane solution) was dripped to the solution. The mixture was stirred at the same temperature for 2 hours. After that, 17.4 mL (155 mmol) of trimethyl borate was added to the mixture, followed by stirring for 1 hour at the same temperature. Then, the mixture was stirred for 24 hours while the temperature thereof is returned to room temperature. After that, 200 mL of 1.0 mol/L hydrochloric acid was added to this solution, followed by stirring for 1 hour at room temperature. The organic layer of the mixture was washed with water, and the aqueous layer was extracted with ethyl acetate. The extract and the organic layer were combined, washed with saturated brine, and then dried with magnesium sulfate. After that, this mixture was suction filtered. The resulting filtrate was concentrated to give a residue. This residue was recrystallized with a mixed solvent of chloroform and hexane to give 4-(9H-carbazol-9-yl)phenylboronic acid which was the desired substance as 13 g of a white powdered solid in a yield of 66%.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].BrC1C=CC(OC)=CC=1>>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([N:11]2[CH2:16][CH2:15][NH:14][C@H:13]([CH3:17])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCN[C@H](C)C2)cc1OC
Agent: COc1ccc(Br)cc1
Product: COc1ccc(N2CCN[C@H](C)C2)cc1

Procedure:
The title compound was prepared following the procedure of Intermediate 25, but starting from 1-bromo-4-methoxybenzene. Purification by flash chromatography (CHCl3/MeOH) gave the title compound as a yellow oil. M+(ESI): 207.2. HPLC (Condition A), Rt: 1.2 min (HPLC purity: 922%).
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH3:7].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH2:8]([C:4]1[O:3][C:2]([CH3:1])=[C:6]([CH3:7])[CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccoc1C
Reactant: BrCc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccccc2)oc1C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
At −78° C., to a stirred solution of commercial 2,3-dimethylfuran (50 g, 0.520 mol) in THF (2.6 L) was add dropwise 1.6M n-BuLi/hexanes (325 mL, 0.520 mol). After the addition was complete, the dry ice/acetone bath was removed and the reaction was stirred for 1 h. At −78° C., to the reaction was added dropwise commercial benzyl bromide (62 mL, 0.520 mol). After the addition was complete the reaction was stirred at −78° C. for 6 h, the dry ice/acetone bath was removed and the reaction was stirred for 7 days. The reaction was concentrated in vacuo and purified on silica gel eluting with hexane to give 75.70 g (78%) of the title compound as a clear oil; 1H NMR (DMSO-d6) δ 1.83 (s, 3H), 2.08 (s, 3H), 3.83 (s, 2H), 5.83 (s, 1H), 7.16-7.30 (m, 5H). mass spectrum (EI), m/z 186 (M+).