Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[CH2:14]1)=[O:12])=[CH:5]2.[CH2:20]=O.[Na]>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:20])[CH:15]([CH3:19])[CH2:14]1)=[O:12])=[CH:5]2
Reactant: CC1CN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1
Reactant: C=O
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1CN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product of Example 64, (5-Chloro-1H-indol-2-yl)-(3-methyl-piperazin-1-yl)-methanone (0.19 g) was dissolved in dichloromethane (10 mL). At room temperature, paraformaldehyde (0.031 g) was added, followed by acetic acid (1 drop). The reaction mixture was stirred at ambient temperature for 5 h. Sodium triacetoxybrohydride (0.318 g) was added. The reaction mixture was stirred at ambient temperature for 16 h and poured into dichloromethane (20 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% methanol/dichloromethane) to give the title compound (0.22 g). 1H NMR (400 MHz, CDCl3): δ 10.69 (br s, 1H), 7.56 (d, J=1.76 Hz, 1H), 7.33 (d, J=8.80 Hz, 1H), 7.16 (dd, J=1.96, 6.66 (d, J=1.57 Hz, 1H), 4.63-4.36 (m, 2H), 3.63-2.67 (m, 3H), 2.30 (s, 3H), 2.30-2.20 (m, 1H), 2.18-2.09 (m, 1H), 1.12 (d, J=5.87 Hz, 1H). MS (electrospray): exact mass calculated for C15H18ClN3O, 291.11; m/z found, 292.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[N+:25]([O-])=O)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[C].[Pd]>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[NH2:25])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3c(c2[N+](=O)[O-])CCCC3)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2ccc3c(c2N)CCCC3)cc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 94.9 %

Procedure:
tert-Butyl[4-[(1-nitro-5,6,7,8-tetrahydro-2-naphthyl)amino]phenyl]carbamate (7.66 g, 20 mmol) was dissolved in tetrahydrofuran (77 mL) and methanol (77 mL), the solution was added with 10% palladium-carbon (0.77 g), and the mixture was stirred at room temperature for 42 hours under a hydrogen atmosphere. The catalyst was separated by filtration, then the solvent was evaporated under reduced pressure, and the residue was washed with hexane to obtain the title compound (6.71 g, yield 95%) as pale brown crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[CH3:10][C:11]1[CH:15]=[C:14]([CH3:16])[N:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]([OH:28])[C:24]([F:27])([F:26])[F:25])[N:12]=1.[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[CH:5]=[C:4]([O:28][CH:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:13]2[C:14]([CH3:16])=[CH:15][C:11]([CH3:10])=[N:12]2)[C:24]([F:25])([F:27])[F:26])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(C)n(-c2ccccc2C(O)C(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)n(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)n1
Temperature: 42.5 °C
Reaction time: 6 h
Yield: 108.9 %

Procedure:
2-Amino-4,6-dichloro pyrimidine (0.074 g, 0.45 mmol), 1-[2-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethanol (0.120 g, 0.45 mmol), NaH (0.022 g, 0.59 mmol) were added to anhydrous THF (10 ml) under nitrogen atmosphere. The reaction was stirred at 40-45° C. for 6 h, and then cooled to room temperature, and quenched with water (0.2 ml). The reaction mixture was concentrated to give crude 4-chloro-6-{1-[2-(3,5-dimethyl-pyrazol-1-yl)-phenyl]-2,2,2-trifluoro-ethoxy]-pyrimidin-2-ylamine (0.195 g, >90% pure by LCMS) which was directly used in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:18])=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=2)[CH:7]=1.[CH2:21]([O:23][C@@H:24]([CH2:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22]>>[CH2:21]([O:23][C@@H:24]([CH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:17][CH2:16]/[CH:15]=[C:14](/[C:11]2[CH:12]=[CH:13][C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:19][CH3:20])=[CH:9][CH:10]=2)\[CH3:18])=[CH:35][CH:36]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22]
Reactant: COc1ccc(Cl)cc1-c1ccc(/C(C)=C/CO)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Cl)ccc3OC)cc2)cc1)OCC
Yield: 61.3 %

Procedure:
The title compound (0.54 g, 61% yield) was prepared from (E)-3-(5′-chloro-2′-methoxy-biphenyl-4-yl)-but-2-en-1-ol (0.50 g, 1.73 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (0.433 g, 1.82 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:9]1[N:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[N+:16]([O-])=O.[CH3:19]OC(OC)OC.C(O)(C(F)(F)F)=O>CO.[Ni]>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[C:9]2=[N:14][C:13]([OH:15])=[CH:12][CH:11]=[C:10]2[N:16]=[CH:19]1
Reactant: CC1CCCCC1Nc1nc(O)ccc1[N+](=O)[O-]
Reactant: COC(OC)OC
Agent: [Ni]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC1CCCCC1n1cnc2ccc(O)nc21
Yield: 40.2 %

Procedure:
6-(2-Methylcyclohexylamino)-5-nitropyridin-2-ol (100 mg, 0.398 mmol) and nickel (11.68 mg, 0.199 mmol) in MeOH (10 mL) were stirred at 22° C. for 24 hr under H2. After filtration through Celite®, the solution was concentrated in the presence of a few drops of TFA. The residue was dissolved in trimethoxymethane (2112 mg, 19.90 mmol) and stirred overnight with a drop of TFA. The mixture was concentrated. The residue was diluted with water, neutralized with NaHCO3 solution and extracted with EtOAC. The EtOAc extract was concentrated and the residue was purified by column chromatography to give the title compound as a brown oil (37 mg). LCMS m/z=232.10 [M+H]+, 1H NMR (400 MHz, CDCl3) major isomer; δ ppm 0.75 (d, J=6.3 Hz, 3H), 1.22-2.20 (m, 9H), 4.18-4.27 (m, 1H), 6.89 (d, J=8.9 Hz, 1H), 8.17 (d, J=8.9 Hz, 1H), 8.52 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH:3]=1.[NH:19]1[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1.C1(O)C=CC=CC=1>O>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:3]=[C:2]([N:19]3[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)=[CH:13][CH:14]=1
Reactant: Fc1ccc(-c2cc(Cl)c3ccccc3n2)cc1
Reactant: NC(=O)C1CCNCC1
Solvent: O
Solvent: Oc1ccccc1
Product: NC(=O)C1CCN(c2cc(-c3ccc(F)cc3)nc3ccccc23)CC1

Procedure:
A mixture of 1.44 g of 4-chloro-2-(4-fluorophenyl)quinoline 1.3 g (10 mmol) of isonipecotamide, and 3 g of phenol was stirred and heated in an oil bath at 165°-170° for 4.5 hr. It was then cooled and diluted with water. It wa made alkaline with 3N sodium hydroxide, and crystallization was induced by the addition of ether and scratching. The solid was collected and washed with ether to give 1.6 g of crude product. Recrystallization from ethanol/water gave white needles (0.42g). mp 218°-220° dec.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:13]=[C:12]([NH:14][C:15]3[S:16][C:17]([C:23]4[N:24]=[N:25][N:26]([CH2:28][Si](C)(C)C)[CH:27]=4)=[CH:18][C:19]=3[C:20]([NH2:22])=[O:21])[CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[CH3:28][N:26]1[CH:27]=[C:23]([C:17]2[S:16][C:15]([NH:14][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:13]=3)=[C:19]([C:20]([NH2:22])=[O:21])[CH:18]=2)[N:24]=[N:25]1
Reactant: C[Si](C)(C)Cn1cc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCOCC4)n3)s2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(-c2cc(C(N)=O)c(Nc3cccc(CN4CCOCC4)n3)s2)nn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-{[6-(morpholin-4-ylmethyl)pyridin-2-yl]amino}-5-{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}thiophene-3-carboxamide (65 mg, 0.14 mmol) in THF (2.0 mL) was added TBAF (1.0 M in THF, 0.276 ml, 0.276 mmol). The reaction was stirred at room temperature for 4 h. The solution was diluted with water and extracted with 5:1 CH2Cl2:MeOH (3×). The combined organic layers were dried (MgSO4), filtered, and evaporated. The crude solid was triturated with CH2Cl2 and filtered to isolate the title compound as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>>[CH3:14][Si:15]([C:18]#[C:19][C:4]1[CH:5]=[CH:6][C:1]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:2][CH:3]=1)([CH3:17])[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc(-c2ccccc2)nc1
Product: C[Si](C)(C)C#Cc1ccc(-c2ccccn2)cc1
Yield: 88 %

Procedure:
To explain the synthesis in more detail, the Suzuki reaction between phenylboronic acid and 2,5-dibromopyridine gave 2-phenyl-5-bromopyridine in an 86% yield (see scheme 1 above). The reaction occurred preferentially on the 2 position on the pyridine ring, which is activated by the adjacent nitrogen. Reaction of 2-phenyl-5-bromopyridine with trimethylsilylacetylene under Sonogashira conditions gave the 2-phenyl-5-(trimethylsilylethynyl)pyridine (2) in an 88% yield, which could be deprotected to 2-phenyl-5-ethynylpyridine (3) in a yield of 93% using tetra-n-butylammonium hydroxide. The Diels-Alder reaction between (3) and the difluorenylcyclopentadienone (10) gave the dendronised ligand in a 48% yield, after purification by precipitation of the ligand from a dichloromethane solution by pouring the solution into ethanol. The complex was formed by the two-step procedure via the bis(chloro)-bis(iridium) dimer in a yield of 50%. This yield is no lower than those obtained from the complexation of ligands dendronised only on the phenyl ring, showing that the presence of the bulky dendron on the pyridine ring does not inhibit complexation.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22](C)=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[Cl:26]C1C2C=CC(Cl)=CC=2SC=1C(O)=O>>[Cl:1][C:2]1[C:3]2[CH:24]=[CH:23][C:22]([Cl:26])=[CH:21][C:4]=2[S:5][C:6]=1[C:7]([NH:9][C@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8]
Reactant: Cc1ccc2c(Cl)c(C(=O)N[C@H](Cc3ccccc3)C(=O)O)sc2c1
Reactant: O=C(O)c1sc2cc(Cl)ccc2c1Cl
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)c1sc2cc(Cl)ccc2c1Cl

Procedure:
Following the 2a synthetic method, using 3,6-dichlorobenzo[b]thiophene-2-carboxylic acid (123.55 mg, 0.5 mmol) instead of 3-chloro-6-methylbenzo[b]thiophene-2-carboxylic acid gave 3a as a white powder; (182.94 mg, 92.8%). [α]D25: −23.2 (c=0.24, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 8.79 (s, 1H), 7.78 (d, J=1.5 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.59 (d, J=6.9 Hz, 1H), 7.42 (dd, J=1.8, 8.7 Hz, 1H), 7.37-7.25 (m, 5H), 5.16-5.14 (m, 1H), 3.41-3.28 (m, 2H); 13C NMR (300 MHz, CDCl3): δ 175.51, 160.41, 138.97, 135.33, 135.18, 134.21, 132.38, 129.47, 128.82, 127.52, 126.51, 124.16, 122.38, 119.64, 54.12, 37.28; HRMS (ESI): calcd for: C18H13Cl2NO3S [M−H]−=391.9920, obsd [M−H]−=391.9921.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[N+:17]([C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[CH2:10][N:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=1)[S:21]([CH3:20])(=[O:23])=[O:22])([O-:19])=[O:18]
Reactant: CSc1cccc(NCc2cccc([N+](=O)[O-])c2)c1
Reactant: CS(=O)(=O)Cl
Product: CSc1cccc(N(Cc2cccc([N+](=O)[O-])c2)S(C)(=O)=O)c1

Procedure:
The product of Example 4 is treated with methane sulfonyl chloride according to known procedures to yield the title product (Compound No. 6).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:3]=1[C:4]([NH2:6])=[O:5].O=[CH:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21]>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:5])[NH:6][CH:15]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[NH:11]2
Reactant: NC(=O)c1c(Cl)cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCC1NC(=O)c2c(Cl)cccc2N1
Yield: 21.4 %

Procedure:
A mixtre of 2-chloro-6-nitrobenzamide (0.3 g), iron powder (0.5 g) and t-butyl (N-2-oxoethyl)carbamate (1.0 g) in glacial acetic acid (5 mL) was heated at 50-55° C. for 2 h. The mixture was concentrated and the residue was partitioned between sat. NaHCO3 and EtOAc. The organic layer was dried (MgSO4), concentrated, and the residue was subjected to flash chromatography (silica gel/heptane-EtOAc 100:0 to 20:80 gradient) to afford the title compound as an off-white solid (0.1 g).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]3[C:11]([C:12]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[CH:15]=[CH:14][C:13]3[C:4](=[C:5]([C:22]4[CH:23]=[CH:24][C:25]5[C:26](=[CH:22][CH:5]=[CH:6][CH:7]=5)[CH:27]=4)[C:6]4[C:11]([C:12]=3[C:16]3[CH:17]=[CH:18][C:19]5[C:20](=[CH:15][CH:2]=[CH:3][CH:4]=5)[CH:21]=3)=[CH:10][C:9]([C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)=[CH:8][CH:7]=4)[CH:3]=2)=[CH:31][CH:30]=1
Reactant: Brc1ccc2c(-c3ccccc3)c3ccccc3c(-c3ccccc3)c2c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Clc1ccc(-c2ccc3c(-c4ccc5ccccc5c4)c4cc(-c5ccc(Cl)cc5)ccc4c(-c4ccc5ccccc5c4)c3c2)cc1
Yield: 173.3 %

Procedure:
5.0 g (8.5 mmol) of 2-bromo-9,10-diphenylanthracene, 2.9 g (18.7 mmol) of 4-chlorophenylboronic acid, and 0.20 g (0.17 mmol) of tetrakis(triphenylphosphine)palladium were dissolved into 50 mL of 1,2-dimethoxyethane. Then, 25 mL of a 2 M aqueous solution of sodium carbonate were added, and the whole was refluxed under heating for 8 hours in an argon atmosphere. The resultant was stood to cool. After the completion of the reaction, the resultant was filtered, and the resultant solid was washed with water, methanol, and toluene to obtain 4.8 g of 2,6-bis(4-chlorophenyl)-9,10-di(2-naphthyl)anthracene (86% yield).
Reaction SMILES: [NH2:1][C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[OH:24])[C:15]2[CH:14]=[C:13]([Cl:16])[N:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][C:5]([Br:17])=[CH:6][CH:7]=2.C([O-])(=O)C.[K+].[N:30]#[C:31]Br.C(Cl)Cl>CO>[Br:17][C:5]1[CH:4]=[C:3]2[C:8](=[CH:7][CH:6]=1)[O:9][C:10]1[CH:11]=[N:12][C:13]([Cl:16])=[CH:14][C:15]=1[C:2]12[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][C:31]([NH2:30])=[N:1]1
Reactant: NC1(c2ccccc2O)c2cc(Br)ccc2Oc2cnc(Cl)cc21
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: NC1=NC2(c3ccccc3O1)c1cc(Br)ccc1Oc1cnc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-amino-7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-yl)phenol (0.406 g, 1.006 mmol) in MeOH 5 mL was added potassium acetate (0.126 mL, 2.012 mmol) followed by the dropwise addition of cyanogen bromide, 3.0M solution in DCM (0.402 mL, 1.207 mmol). The resulting mixture was stirred at RT overnight. The reaction mixture was concentrated, washed with sat. NaHCO3, extracted with DCM, dried over Na2SO4 and concentrated. The resulting product was dissolved in 1,2-dichloroethane followed by the addition of 4.0 M HCl in dioxane (15 mL) and stirred at RT for 1.5 h. The reaction mixture was concentrated, diluted with dichloromethane and washed with saturated NaHCO3 solution, brine, dried over Na2SO4, filtered, concentrated. The crude material was purified by chromatography on silica gel using gradient of 0-100% EtOAc/hexanes to give the desired product. MS m/z=429.8 [M+H]+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: COc1ccccc1-c1cc(Cl)cc2c1OC(COS(=O)(=O)c1ccc(C)cc1)C2
Product: CNCC1Cc2cc(Cl)cc(-c3ccccc3OC)c2O1

Procedure:
The title compound was prepared (0.037 g, 29%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.39 g, 0.88 mmol) and methylamine (0.271 g, 8.8 mmol). mp 100-102° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1Br)=[O:9])([CH3:6])[CH3:5].[Cl:22][C:23]1[CH:28]=[CH:27][C:26](/[CH:29]=[CH:30]/B(O)O)=[CH:25][CH:24]=1.[F-].[Cs+]>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:21])[C:4]([NH:7][C:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1/[CH:30]=[CH:29]/[C:26]1[CH:27]=[CH:28][C:23]([Cl:22])=[CH:24][CH:25]=1)=[O:9])([CH3:6])[CH3:5]
Reactant: OB(O)/C=C/c1ccc(Cl)cc1
Reactant: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1/C=C/c1ccc(Cl)cc1
Yield: 65.3 %

Procedure:
50 mg 2-[(1-bromo-naphthalene-2-carbonyl)amino]-2-methyl-propionic acid methyl ester, 49.5 mg tetrakis(triphenylphosphine)palladium (0), 28.7 mg trans-2-(4-chloro-phenyl)vinylboronic acid and 43 mg CsF were suspended in 1 ml of MeOH and 3 ml of dimethoxyethane, deoxygenated with Argon, and heated to 80° for 14 h. The reaction was filtered, purified by RP-HPLC and freeze-dried to give 38 mg of 2-({1-[(E)-2-(4-Chloro-phenyl)-vinyl]-naphthalene-2-carbonyl}-amino)-2-methyl-propionic acid methyl ester (65%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:8]=2)[CH:3]=1.[OH-].[Na+].[CH3:17]OS(OC)(=O)=O>O>[CH3:17][O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:8]=2)[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: CC(C)c1ccc2cc(O)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2cc(C(C)C)ccc2c1
Temperature: 60 °C

Procedure:
To a suspension of 31.71 g 2-hydroxy-6-(1-methylethyl)naphthalene in 500 ml water and under a nitrogen atmosphere was added 61.5 g of 14.4% (by weight) sodium hydroxide (NaOH). The mixture was heated to 60° C. and 30.02 g of dimethylsulfate was added in one portion to the dark cloudy solution. In 20 minutes the pH of the reaction had dropped from 13 to 2. Another 20 g 14.4% NaOH was added. After 45 minutes 10 g additional dimethylsulfate was added. After 1 hour 20 g of 14.4% NaOH was added and the reaction was heated at 80° C. overnight. The brown suspension was then extracted with toluene and the extract was dried over magnesium sulfate (MgSO4), filtered, and concentrated in vacuum to give a crude solid which was recrystallized from isopropanol to give 2-methoxy-6-isopropylnaphthalene, melting point 63.5° to 64.5° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=[O:20])[C:8]#[C:9]C2(O[Si](C)(C)C)CCCC2)=[CH:3][CH:2]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.O>[N:1]1[CH:6]=[CH:5][C:4]([C:7](=[O:20])[C:8]#[CH:9])=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)OC1(C#CC(=O)c2ccncc2)CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: C#CC(=O)c1ccncc1
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a stirred solution of 1-(pyridin-4-yl)-3-(1-(trimethylsilyloxy)cyclopentyl) prop-2-yn-1-one (1.1 g, 3.8 mmol) in DCM (15 mL) was added PTSA (0.87 g, 4.6 mmol) at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (2 mL), the organic layer was washed with a saturated NaHCO3 solution, water, dried over Na2SO4, filtered and then concentrated in vacuo to afford 341-hydroxycyclopentyl)-1-(pyridin-4-yl) prop-2-yn-1-one (0.42 g, 51%) as an oil.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:28][CH:29]=1.CCN(C(C)C)C(C)C>CN(C)C=O>[C:16]1([C:3]2[C:2]([N:33]3[CH2:34][CH2:35][N:30]([C:27]4[CH:26]=[CH:25][C:24]([C:23]([F:37])([F:22])[F:36])=[CH:29][N:28]=4)[CH2:31][CH2:32]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc(C(F)(F)F)cn4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 1-(5-(trifluoromethyl)pyridin-2-yl)piperazine (203.28 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv), N,N-dimethylformamide (3 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 4×30 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 210.8 mg (97%) of methyl 2-phenyl-3-(4-(5-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([C:13]([O:15]CC)=[O:14])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].C(O)C.[O-]CC.[Na+]>O>[N:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([C:13]([OH:15])=[O:14])[CH2:11][CH2:12]2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: CCOC(=O)C1CCC(N2CCCC2=O)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CCC(N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 65.7 %

Procedure:
To ethyl 4-(2-pyrrolidon-1-yl)cyclohexylcarboxylate (5.0 g, mixture of cis and trans isomers, cis:trans=61:39) are added ethanol (25.0 mL, 5V/W) and sodium ethoxide (2.0 equiv. 0.0132 mol), and the mixture is stirred at room temperature for 20 hours. After adding water (5.0 mL, 1V/W), the reaction solution is stirred at room temperature for 2 hours, and evaporated to remove ethanol under reduced pressure. The residue is acidified by adding 2 N hydrochloric acid, and thereto is added an excessive amount of crystalline sodium chloride followed by extraction with methylene chloride. The extract is dried, and evaporated to remove the solvent under reduced pressure. The resulting crystals are collected with toluene to give 4-(2-pyrrolidon-1-yl)cyclohexylcarboxylic acid (2.9 g, trans:cis=88:12, yield 58%).