Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].CCN(CC)CC.[CH3:14][O:15][C:16]([C:18]1[C:23]([NH2:24])=[N:22][C:21]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[C:20](Br)[N:19]=1)=[O:17].COC(C1C(N)=NC(NCCOC)=C(Cl)N=1)=O>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:14][O:15][C:16]([C:18]1[C:23]([NH2:24])=[N:22][C:21]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[C:20]([C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4])[N:19]=1)=[O:17]
Reactant: COCCNc1nc(N)c(C(=O)OC)nc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: COCCNc1nc(N)c(C(=O)OC)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCNc1nc(N)c(C(=O)OC)nc1C#C[Si](C)(C)C
Temperature: 80 °C

Procedure:
To a solution of ethynyl-trimethyl-silane (1.05 g, 10.7 mmol), bis(triphenylphosphine)palladium(II) chloride (150 mg, 0.214 mmol), Copper(I) iodide (41 mg, 0.214 mmol) and NEt3 (2.09 ml, 14.98 mmol) in THF (17 ml) was added under an argon atmosphere a mixture (about 1:1) of 3-amino-6-bromo-5-(2-methoxy-ethylamino)-pyrazine-2-carboxylic acid methyl ester and 3-amino-6-chloro-5-(2-methoxy-ethylamino)-pyrazine-2-carboxylic acid methyl ester (651 mg, 2.14 mmol) and the mixture was heated to 80° C. for 17 h. The reaction mixture was filtered through Hyflo and the solvent evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 60:40) to provide the title compound as brown solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:21]1([CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)CCCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(CCCc1ccccc1)NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A suspension of 0.32 mmol rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) in 5 ml acetonitrile was treated successively with 0.32 mmol 4-phenylbutyric acid, 1.61 mmol DIPEA and 0.35 mmol TBTU. The reaction mixture was stirred for 1 hour at room temperature and concentrated. Chromatography (SiO2; dichloromethane/methanol) gave the title compound as a colorless solid. Yield=71%. MS (m/e): 419.3 (MH−, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClCCCl>[Br:14][CH2:13][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)c2ccccc2n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: COc1cc(CBr)c2ccccc2n1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
0.95 g (5.48 mmol) of 2-methoxy-4-methyl quinoline was dissolved in 10 mL of 1,2-dichloroethane, and then 1.17 g (6.58 mmol) of N-bromosuccinimide and 44 mg (0.27 mmol) of 2,2′-azobisisobutyronitrile were added, and stirred for 2 hours while heated at 90° C. After stirring was completed, the solution was cooled to a normal temperature, and the solvent was removed under reduced pressure to obtain 4-(bromomethyl)-2-methoxyquinoline. The obtained 4-(bromomethyl)-2-methoxyquinoline was used in a next step without any particular isolation and purification.
Reaction SMILES: [OH:1][C@H:2]([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[Cl-].[NH4+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Si:16]([O:8][CH2:7][C@@H:2]([OH:1])[C:3]([O:5][CH3:6])=[O:4])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)[C@H](O)CO
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
The compound of Example 68-1 (308 mg, 2.57 mmol) was dissolved in methylene chloride (10 ml), and thereto were added triethylamine (704 mg, 6.95 mmol), 4-dimethylaminopyridine (33 mg, 0.27 mmol), and t-butyldimethylsilyl chloride (524 mg, 3.48 mmol). The mixture was stirred at room temperature for 2 hours, and thereto was added a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography to give the title compound (356 mg, 57%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])=[C:12](Br)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:30][S:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([O:16][CH2:17][CH2:18][C@H:19]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH3:20])=[C:12]([C:35]3[CH:36]=[CH:37][C:32]([S:31][CH3:30])=[CH:33][CH:34]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@H](CCOc1c(Br)cnn(-c2ccc(F)c(F)c2)c1=O)O[Si](C)(C)C(C)(C)C
Reactant: CSc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CSc1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2OCC[C@@H](C)O[Si](C)(C)C(C)(C)C)cc1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Under a nitrogen atmosphere, a mixture of the product from Example 545C (0.98 g, 2 mmol), 4-(methylthio)benzeneboronic acid (0.4 g, 2.4 mmol), K3PO4 (1.2 g, 6 mmol), PdCl2(PPh3)2 (28 mg, 0.04 mmol), isopropanol (9 mL), and water (1 mL) was stirred at 70° C. for 4 hours. The reaction mixture was then cooled to room temperature, water (30 mL) was added and stirring was continued for 2 hours. The crude black precipitate was collected by filtration then Washed with water (10 mL) and hexane (10 mL). This title intermediate was used without further purification in the following oxidation/deprotection step.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([NH2:25])[CH:22]=[CH:21][C:3]=1[C:4]([N:6]1[CH2:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)=[O:5].C(N(CC)C(C)C)(C)C.[CH3:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C(Cl)Cl>[CH:17]1[C:8]2[CH2:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[CH2:12][N:6]([C:4]([C:3]3[CH:21]=[CH:22][C:23]([NH:25][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=4[CH3:35])=[CH:24][C:2]=3[Cl:1])=[O:5])[C:7]=2[CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.9 %

Procedure:
A mixture of 0.31 g of 5-(2-chloro-4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine and 0.15 g of N,N-diisopropylethylamine in 10 ml of methylene chloride is cooled in an ice bath while 0.18 g of 2-methylbenzoyl chloride is added. The bath is removed and the reactants stirred at room temperature for 18 hours. The mixture is washed with water, 1N HCl, water, 1M NaHCO3, brine and dried (Na2SO4). The methylene chloride is removed in vacuo to give 0.34 g of the desired product as crystalline solid, m.p. 138°-150° C. M+ =467.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.C(Cl)Cl.[CH2:23]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2](=[O:3])[NH:35][C@@H:32]2[CH2:33][CH2:34][N:30]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: N[C@@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(N[C@@H]1CCN(Cc2ccccc2)C1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Nitro-phenyl chloroformate (1 eq.) is added dropwise to a solution of pyridine/DCM (1:5) at 0° C. The reaction mixture is kept at 0° C. and a solution of (R)-1-benzyl-pyrrolidin-3-ylamine (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at room temperature overnight. The reaction mixture is partitioned between (0.2 M) HCl(aq) and DCM. The organics are washed with water, saturated sodium hydrogen carbonate solution and brine. The combined organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound. MS (ES+) m/e 342.10 (MH+).
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)=[N:10][CH2:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:19]3)=[CH:14][CH:13]=2)=CC=1.C[Si](C)(C)N[Si](C)(C)C.[Na].Cl[C:47]1[C:52]([Cl:53])=[N:51][CH:50]=[CH:49][N:48]=1.Cl>C1COCC1>[Cl:53][C:52]1[C:47]([CH:11]([NH2:10])[C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:19]3)=[CH:14][CH:13]=2)=[N:48][CH:49]=[CH:50][N:51]=1
Reactant: COc1ccc(C(=NCc2ccc3ccc(-c4ccccc4)nc3c2)c2ccc(OC)cc2)cc1
Reactant: Clc1nccnc1Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: NC(c1ccc2ccc(-c3ccccc3)nc2c1)c1nccnc1Cl
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 87.8 %

Procedure:
N-[bis(4-methoxyphenyl)methylidene]-1-(2-phenylquinolin-7-yl)methanamine (100 mg, 0.22 mmol) was added to a flask and protected by nitrogen. THF (2 mL) was added and a clear solution was obtained. The solution was cooled to −5° C. and then 1.0 M 1,1,1,3,3,3-hexamethyldisilazane, sodium salt in THF (0.26 mL, 0.26 mol) was added. After 20 min, 2,3-dichloropyrazine (36 mg, 0.24 mmol) in THF (1.0 mL) was added. After a further 20 min, 2M HCl (2 mL) was added and the mixture was stirred at room temperature for 10 min. The aqueous mixture was washed with DCM (3×) and then basified to pH 10 with solid potassium carbonate. A white solid precipitated from the aqueous solution and the resulting suspension was extracted with DCM. The organic solution was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give a light yellow oil (67 mg). The yellow oil was further purified by silica gel chromatography (eluted with ethyl acetate/methanol/triethylamine, 10:0.5:1) to yield a colorless oil (63 mg, 83% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:13][NH2:14])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(N(CC)CC)C.[Br:22][CH:23]([CH3:27])[C:24](O)=[O:25].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[Cl:2][C:3]1[C:4]([CH2:13][NH:14][C:24](=[O:25])[CH:23]([Br:22])[CH3:27])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Reactant: CC(Br)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(Br)C(=O)NCc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (1.0 g) in tetrahydrofuran (5 ml) and triethylamine (0.41 g) which had been stirred at room temperature for 30 minutes, was added a mixture of 2-bromopropionic acid (0.62 g) and carbonyldiimidazole (0.65 g) in tetrahydrofuran (5 ml) which had also been stirred at room temperature for 30 minutes. The combined mixture was stirred at room temperature for 12 hours and then the solvent was removed. The residue was partitioned between diethyl ether and water and the layers separated. The organic phase was dried (MgSO4) and the solvent removed to give the title product.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:12]([OH:24])[CH:11]=1)=[O:5].ClC([O-])=O>C1COCC1>[C:4]([O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:12]([OH:24])[CH:11]=1)(=[O:5])[NH:1][NH2:2]
Reactant: O=C(Cl)OCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: NN
Agent: O=C([O-])Cl
Solvent: C1CCOC1
Product: NNC(=O)OCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
Into a 250 ml 3-neck flask was added 5.4 grams (0.11 mole) of 64% aqueous hydrazine and 50 mls of THF. The flask was equipped with a magnetic stirrer, thermometer, reflux condenser and a dropping funnel containing 9.6 grams (0.03 mole) of 2-(3-hydroxy-4-benzoylphenoxy)ethyl chloroformate dissolved in 50 ml of THF. The chloroformate solution was added dropwise to the stirring hydrazine solution over 1/2 hour. The temperature quickly exothermed to 36° C. and slowly subsided after the addition was over. The reaction was stirred an additional 1/2 hour and concentrated to 31 grams. The THF solution was added to 300 ml of water. A sticky solid formed. The solid was filtered off, taken up in methylene chloride, dried over Na2SO4, filtered and the methylene chloride stripped off. The residue was a viscous orange-brown liquid. The crude product was slurried in 150 ml of warm MtBE. Most of the crude product went into solution, leaving a dark brown liquid residue. The yellow MtBE layer was decanted off and the MtBE stripped off on a rotating evaporator, leaving 9.0 grams of a yellow viscous liquid. Liquid chromatography indicated it was about 92% pure. The residue was slurried in warm methanol and upon cooling, a solid formed. The solid was filtered off and after air drying, weighed 6.4 grams (67% yield) and had a melting point of 58°-61° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)#[N:2].[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CCOCC>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: Oc1ccccc1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: N#Cc1ccc(C(=O)Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 81.8 %

Procedure:
4-Cyano-benzoic acid (10.0 g, 68.0 mmol), phenol (6.40 g, 68.0 mmol), DCC (14.73 g, 71.4 mmol), DMAP (0.25 g, 2.04 mmol) and ether (200 mL) were mixed, and stirred at room temperature for 3 days. Ether was removed. To the residue was added CH2Cl2 (200 mL). The solid was filtered. The filtrate was concentrated, and purified by flash chromatography to give the desired product (12.41 g, 82%). MS (DCI/NH3) m/z 224 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 7.19-7.25 (m, 2H) 7.31 (m, 1H) 7.41-7.50 (m, 2H) 7.807.85 (m, 2H) 8.29-8.34 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[S:19]([CH3:22])(=[O:21])=[O:20])[C:3]=1[CH3:23].[Br:24][C:25]1[CH:26]=[C:27]2[NH:33][CH2:32][C:31]([CH3:35])([CH3:34])[C:28]2=[N:29][CH:30]=1.Cl.O1CCOCC1>CN1C(=O)CCC1>[Br:24][C:25]1[CH:26]=[C:27]2[N:33]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=4)[N:5]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[S:19]([CH3:22])(=[O:21])=[O:20])[C:3]=3[CH3:23])[CH2:32][C:31]([CH3:35])([CH3:34])[C:28]2=[N:29][CH:30]=1
Reactant: CC1(C)CNc2cc(Br)cnc21
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Temperature: 150 °C

Procedure:
Prepared according to procedure L using 4-chloro-7-fluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (242 mg, 0.69 mmol) (described herein), 6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine (157 mg, 0.69 mmol) (described herein), 4.0 M hydrochloric acid in 1,4-dioxane (0.17 mL, 0.69 mmol), and NMP (1.2 mL). The reaction mixture was stirred and heated in a microwave at 150° C. for 120 min. Chromatography afforded 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-(methylsulfonyl)-phenyl)quinoline as a dark oil. Mass Spectrum (ESI) m/e=541 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.CCN(C(C)C)C(C)C.[F:47][C:48]1[CH:56]=[CH:55][CH:54]=[CH:53][C:49]=1[C:50](Cl)=[O:51]>C(Cl)Cl>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:50](=[O:51])[C:49]2[CH:53]=[CH:54][CH:55]=[CH:56][C:48]=2[F:47])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:17]([CH3:34])[C:18]([CH2:21][N:22]([CH2:30][CH2:31][O:32][CH3:33])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][N:20]=3)[S:15][C:8]=12
Reactant: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCN(Cc1cnc(-c2cc3nccc(Oc4ccc(NC(=O)c5ccccc5F)cc4F)c3s2)n1C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.3 %

Procedure:
To a solution of aniline 46 (300 mg, 0.569 mmol) in DCM (10 mL) at 0° C. was added DIPEA (0.199 mL, 1.137 mmol) and 2-fluorobenzoyl chloride (135 mg, 0.853 mmol) and the suspension was stirred overnight at room temperature. The reaction mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was collected, dried and concentrated. The residue was purified using Biotage (eluent EtOAc, 25 g Silicycle HR column) to provide the title compound 356 (400 mg, 0.616 mmol, quantitative yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][F:21])[CH:12]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+].[N+:27]([CH3:30])([O-:29])=[O:28]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:30]/[N+:27]([O-:29])=[O:28])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][CH2:19][CH2:20][F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCCCF)c(OCc2ccccc2)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(OCCCF)c(OCc2ccccc2)c1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
3-(Benzyloxy)-4-(3-fluoropropoxy)benzaldehyde described in Production Example 33-2 (6.14 g, 21.3 mmol) was dissolved in acetic acid (17.0 mL), then ammonium acetate (1.97 g, 25.6 mmol) and nitromethane (2.8 mL, 51.7 mmol) were added under nitrogen atmosphere at room temperature, and the mixture was heated and stirred at 130° C. for 2 hours. The mixture was cooled to mom temperature, then the precipitate was collected by filteration and washed with a small quantity of ethanol to quantitatively obtain the title compound.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:28]([Cl:29])=[C:27]([O:30][CH3:31])[CH:26]=[C:25]([Cl:32])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH:44]=O)[CH3:43])[CH3:34]>>[CH2:33]([O:35][C:36](=[O:47])[CH:37]=[C:38]([CH3:46])[CH:39]=[CH:40][CH:41]=[C:42]([CH3:44])[CH:43]=[CH:5][C:4]1[C:25]([Cl:32])=[CH:26][C:27]([O:30][CH3:31])=[C:28]([Cl:29])[C:3]=1[Cl:2])[CH3:34]
Reactant: COc1cc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1Cl
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(Cl)cc(OC)c(Cl)c1Cl

Procedure:
By the procedure of Example 1, 2,3,6-trichloro-4-methoxy-benzyltriphenyl-phosphonium chloride is reacted with 7-formyl-3 -methyl-octa-2,4,6-trien-1-oic acid ethyl ester to obtain 9-(2,3,6-trichloro-4-methoxyphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester of melting point 126° - 128° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].CO[CH:17]1[CH2:21][CH2:20][CH:19](OC)O1.C(Cl)(Cl)Cl.[Cl-].[Na+]>C(O)(=O)C>[C:1]([O:4][CH:5]1[C:13]2[C:8](=[C:9]([N:14]3[CH:17]=[CH:21][CH:20]=[CH:19]3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCc2c(N)cccc21
Reactant: COC1CCC(OC)O1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)OC1CCc2c1cccc2-n1cccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.2 %

Procedure:
A stirred solution of 10.0 g (0.052 mole) of 4-amino-1-indanyl acetate (prepared as in Example 1, step F) and 7.5 g (0.056 mole) of 2,5-dimethoxytetrahydrofuran in 21.2 mL of acetic acid was heated under reflux for 3.5 hours. The reaction mixture was then allowed to cool to ambient temperature, and was stirred for 16 hours. The reaction mixture was poured into 200 mL of chloroform. An aqueous saturated solution of sodium chloride (200 mL) was added, and the mixture was stirred for 10 minutes. The aqueous layer was separated and washed with 50 mL of chloroform. The combined organic phases were washed with two portions of 50 mL each of an aqueous saturated solution of sodium chloride. The organic layer was dried over potassium carbonate, filtered, and the filtrate concentrated under reduced pressure to give 13.2 g of 4-(1-pyrrolyl)-1-indanyl acetate.
Reaction SMILES: [Mg].CN(CCN(C)C)C.Br[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18].Br[CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1.CCCCCC>[CH:22]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrC1CCCC1
Reactant: FC(F)(F)c1ccccc1Br
Agent: CN(C)CCN(C)C
Agent: [Mg]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: FC(F)(F)c1ccccc1C1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 10 L jacketed reactor was added dry THF (2.4 L) and magnesium turnings (81.0 g, 3.33 mol, 1.5 eq.) under N2. In a separate flask FeCl3 (36 g, 0.22 mol, 0.1 eq.) was dissolved in THF (150 mL) (caution, exothermic) under N2. This dark brown solution was allowed to cool to ambient temperature and then added over 10 min to the reactor content under N2 at an internal temperature of about 10° C. TMEDA (402 mL) was added to this yellow/green mixture keeping the internal temperature below about 20° C. (slightly exothermic). The resulting rust brown mixture was stirred at ambient temperature for 1 h under N2 then 1 h at 45° C. The reactor contents were allowed to cool below about 20° C. and a mixture of 1-bromo-2-(trifluoromethyl)benzene (500 g, 2.22 mol) and bromocyclopentane (397 g, 2.66 mol, 1.2 eq.) added dropwise under N2 at a rate as to maintain the internal temperature between about 25-30° C. After the addition, the reaction mixture was stirred at about 25° C. under N2 overnight, allowed to cool to an internal temperature of about 0° C. and quenched with 6 N HCl (2 L) at a rate as to maintain the internal temperature below about 15° C. (caution, exothermic). [Note: IPC's after completing the addition and stirring overnight were similar indicating that the reaction may have been completed much sooner.] After the quench, hexane (3 L) was added and the reactor contents were stirred at ambient temperature for 1 h. The phases were separated and the aqueous layer back extracted with hexane (1 L). The combined organic layers were dried (Na2SO4), slurried with silica (750 g) and filtered washing the solids with hexane (1 L). The filtrate was concentrated under reduced pressure (100 torr at 37° C.) to give an amber oil (317 g, 973 Area % by HPLC, 87.7 wt % by HPLC (contained residual hexane by NMR), corrected yield 58′%) which was used in the next step without further purification.