Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH:13]([OH:26])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]2)[CH2:7][CH2:6]1)([O:3][CH3:4])=[O:2].N>>[C:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH:13]([OH:26])[CH2:12][CH2:11][C:8]2[CH:7]=[CH:6][C:5]([C:1]([O:3][CH3:4])=[O:2])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1)([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1CCC(CCC(O)CCC2CCC(C(=O)OC)CC2)CC1
Agent: N
Product: COC(=O)c1ccc(CCC(O)CCc2ccc(C(=O)OC)cc2)cc1

Procedure:
To a stainless steel autoclave was added 143.9 g (0.404 moles) 1,5-bis-(4'-carbomethoxyphenyl)-3-pentanol, 14.4 grams of 0.5% Pd on alumina, and 1,150 mL of cyclohexane. The autoclave was pressurized to 500 psi with hydrogen and then heated to 225° C. Upon reaching temperature, the pressure was adjusted to 1500 psi and these conditions were maintained for 6 hrs. The reaction was then cooled and vented. The product is soluble in the cyclohexane and is separated from the catalyst by filtration. The product is isolated by simple solvent removal in vacuo to give 139.6 grams of product (0.379 moles, 94%) consisting of all three diastereomeric cyclohexyl isomers of 1,5-bis -(4'-carbomethoxycyclohexyl)-3-pentanol. 300 MHz NMR (CDCl3) δ=0.93 (m,2H), 1.10-1.65 (m, 20H), 1.82 (d,1H), 1.96 (d,4H), 2.23 (m,1H), 2.52 (m,1H), 3.53 (s(br), 1H), 3.67 (s,3H), 3.69 (s,3H). IR (neat): 1040, 1200, 1740, 3500 cm-1. GC-MS: (a) electron impact 50 eV: all three isomers with identical mass spectra: 368(<1%), 350, 337, 318, 290, 199, 170, 167, 138, 121, 108, 95, 94, 87, 81, 67. (NH3 chemical ionization): three peaks with M+=368.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)[CH:7]=[CH:6][N:5]=1.[C:20]1([N:26]=[C:27]=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[C:20]1([NH:26][C:27]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([NH2:3])[CH:9]=4)=[CH:19][CH:18]=3)[CH:14]=[CH:15]2)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Oc2ccc3c(ccn3C(=O)Nc3ccccc3)c2)ccn1
Reaction time: 0.08 h
Yield: 74.1 %

Procedure:
After adding 28 mg of sodium hydride (60% in oil) to a solution of 3.0 g of 5-[(2-amino-4-pyridyl)oxy]-1H-indole in dimethylformamide at room temperature and stirring the mixture for 5 minutes, 1.6 g of phenyl isocyanate was added and the mixture was stirred for 20 minutes. Water was added, extraction was performed with ethyl acetate and the organic layer was washed with water, and then silica gel was added and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel and purified by column chromatography (ethyl acetate), to obtain 3.4 g of a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH:30]=[CH:29][CH:28]=[N:27]2)=[CH:22][CH:21]=1>>[N:26]1([C:23]2[CH:24]=[CH:25][C:20]([CH2:19][N:16]3[CH:11]([C:4]4[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]3=[O:17])=[CH:21][CH:22]=2)[CH:30]=[CH:29][CH:28]=[N:27]1
Reactant: BrCc1ccc(-n2cccn2)cc1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(-n2cccn2)cc1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 1-(4-(bromomethyl)phenyl)-1H-pyrazole. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.73 min.; [M+H]+: 392.16 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[N:13][CH2:12][CH2:11][N:10]=2)=[CH:5][CH:4]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO.O>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[N:10][C:11]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:12][N:13]=2)=[CH:16][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccc(C2=NCCN=C2c2ccc(OC)cc2)cc1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2ncc(Cc3ccccc3)nc2-c2ccc(OC)cc2)cc1

Procedure:
The same procedures as in Example 3 were repeated using 2,3-bis(p-methoxyphenyl)-5,6-dihydropyrazine and benzaldehyde. 2,3-Bis(p-methoxyphenyl)-5-benzylpyrazine was obtained as colorless prisms, m.p. 107°-109° C. (recrystallized from methanol-water). Physical properties of the product support a chemical structure of the below formula (X).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([Li])CCC.[CH2:20]=[O:21]>C1COCC1>[OH:21][CH2:20][C:1]1([S:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: C=O
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)C1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)C1(CO)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of tert-butyl cyclopropylsulfonylcarbamate (30 g, 136 mmol) in 750 mL of THF was added dropwise butyllithium (1.6 M in hexane, 212 mL, 339 mmol) over 30 min at −78° C. and the resulting mixture was stirred at −78° C. for 1 h. Formaldehyde gas was generated from para-formaldehyde (by heating at 180° C.) and was purged in to the above reaction mass for 30 min at −30° C. The reaction was stirred at the same temperature for 1 h, then allowed to warm to room temperature. The reaction was quenched with aqueous ammonium chloride solution and diluted with water. The resulting mass was washed with ethyl acetate and the aqueous layer was acidified to pH ˜2 and extracted with ethyl acetate. The combined organics were dried over sodium sulfate and evaporated under reduced pressure to get desired compound (27 g, 79%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 10.90 (sb, 1H), 4.95 (sb, 1H), 3.75 (s, 2H), 1.42 (s, 9H), 1.27 (m, 2H), 1.08 (m, 2H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[C@@H:34]([OH:35])[CH2:33][CH2:32][NH:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[C@@H:34]([OH:35])[CH2:33][CH2:32][N:31]([C:39](=[O:40])[CH2:38][O:37][CH3:36])[CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CNCC[C@@H]4O)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COCC(=O)N1CC[C@H](O)[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-N-[(3S*,4S*)-4-hydroxypiperidin-3-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f39) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15](Cl)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:8][CH2:7]1)[CH3:2].Cl.Cl.[NH2:33][CH2:34][CH2:35][NH:36][C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][N:38]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15]([NH:33][CH2:34][CH2:35][NH:36][C:37]4[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][N:38]=4)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: N#Cc1ccc(NCCN)nc1
Reactant: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Temperature: 130 °C

Procedure:
120 mg (0.23 mmol) of ethyl{4-[5-chloro-7-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]piperidin-1-yl}acetate (Example 55A), 54.9 mg (0.28 mmol) of 6-[(2-aminoethyl)amino]-pyridine-3-carbonitrile dihydrochloride (Example 2A) and 0.24 ml (1.38 mmol) of N,N-diisopropylethylamine were initially charged in 2.33 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 113 mg (77% of theory) of the product as a solid.
Reaction SMILES: [C:1]1(=O)[NH:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[NH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]1[S:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: Nc1ccccc1S
Reactant: O=C1CCCCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: NCCCCCc1nc2ccccc2s1

Procedure:
A mixture of caprolactam (62 g; 0.55 mole) and o-aminothiophenol (68.8; 0.55 mole) was heated with p-toluenesulfonic acid (4.3 g) at 190°-260° for 41/2 hrs. while removing water by distillation. The product was essentially pure 2-(5-aminopentyl)benzothiazole.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[F:18])[CH:6]=[C:7]([F:9])[CH:8]=1.S(=O)(=O)(O)O.CC(O)=O.C1C(=O)N([I:36])C(=O)C1>C(Cl)Cl>[F:19][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([I:36])=[CH:12][C:11]=2[F:18])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(F)c(-c2cc(F)cc(C(F)F)c2)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(-c2cc(F)cc(C(F)F)c2)c(F)cc1I
Reaction time: 3 h
Yield: 81.9 %

Procedure:
To a 250-mL RBF was added 3′-(difluoromethyl)-2,5′-difluoro-5-methoxy-1,1′-biphenyl (642 mg, 2.376 mmol) and sulfuric acid (69.7 μl, 1.307 mmol). DCM (3960 μl) and AcOH (3960 μl) were added to give a colorless clear solution. To this solution was added n-iodosuccinimide (238 μl, 2.376 mmol) as a solid in a single portion to give a maroon-colored solution. After 3 h at rt, the mixture was diluted with DCM (30 mL), washed with water (10 mL), washed with saturated aq. sodium thiosulfate (10 mL, DCM was upper layer for separation), dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (50-g silica gel column, 0-5% EtOAc/Heptane) to provide 3′-(difluoromethyl)-2,5′-difluoro-4-iodo-5-methoxy-1,1′-biphenyl (771 mg, 1.946 mmol, 82% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.80-7.87 (m, 1H), 7.67-7.73 (m, 1H), 7.63-7.67 (m, 1H), 7.48-7.57 (m, 1H), 7.08-7.18 (m, 2H), 3.91 (d, J=2.54 Hz, 3H)
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=O)=O)=CC=1.[CH2:20]([NH:27][C:28]([C:30]1[S:31][C:32]([N:36]2[CH:41]=[CH:40][C:39](O)=[CH:38][C:37]2=[O:43])=[CH:33][C:34]=1[CH3:35])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([NH:27][C:28]([C:30]1[S:31][C:32]([N:36]2[CH:41]=[CH:40][C:39]([O:11][CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:38][C:37]2=[O:43])=[CH:33][C:34]=1[CH3:35])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2)cc1
Product: Cc1cc(-n2ccc(OCCc3ccccc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 59 %

Procedure:
Following the procedure as described in Example 9, making variations only as required to use phenethyl 4-methylbenzenesulfonate in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-5-(4-hydroxy-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxamide, the title compound was obtained as a colorless solid in 59% yield: mp 159-160° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (t, J=5.9 Hz, 1H), 8.12 (d, J=7.9 Hz, 1H), 7.35-7.20 (m, 11H), 6.18 (dd, J=7.9, 2.6 Hz, 1H), 6.06 (d, J=2.6 Hz, 1H), 4.41 (d, J=6.0 Hz, 2H), 4.27 (t, J=6.7 Hz, 2H), 3.04 (t, J=6.6 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.3, 162.4, 161.0, 139.6, 138.8, 137.7, 137.1, 135.0, 128.8, 128.3, 128.2, 127.3, 127.1, 126.6, 126.3, 120.5, 102.4, 96.8, 68.8, 42.5, 34.2, 15.5; MS (ES+) m/z 445.3 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:6]=[CH:7][CH:8]=1.[OH:18][C:19]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:29](=[O:31])[CH3:30]>>[C:29]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([S:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])[CH:6]=[CH:7][CH:8]=2)=[C:24]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:18])(=[O:31])[CH3:30]
Reactant: N#Cc1cncc(Sc2cccc(CO)c2)c1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2cccc(Sc3cncc(C#N)c3)c2)ccc(C(C)=O)c1O
Yield: 71.2 %

Procedure:
Using the method of Preparation 160 using 5-(3-(hydroxymethyl)phenylthio) nicotinonitrile (3.90 g, 16.1 mmol) and 1-(2,4-dihydroxy-3-propylphenyl)ethanone (3.13 g, 16.1 mmol) affords the title compound (4.80 g, 71%): 1H NMR (CDCl3) δ 0.92 (t, J=7.2 Hz, 3H), 1.50-1.59 (m, 2H), 2.57 (s, 3H), 2.68 (t, J=7.6 Hz, 2H), 5.18 (s, 2H), 6.43 (d, J=9.0 Hz, 1H), 7.44-7.49 (m, 3H), 7.53 (s, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.62 (dd, J=1.6, 2.3 Hz, 1H), 8.63 (dd, J=1.6, 2.3 Hz, 2H), 12.75 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH3:10].Cl.[NH2:12][OH:13].CC(C)([O-])C.[K+].O>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[NH:12][OH:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C#N)ccc1Br
Reactant: NO
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=N)NO)ccc1Br
Reaction time: 0.5 h
Yield: 309.2 %

Procedure:
A solution of 4-bromo-3-methylbenzonitrile (20.0 g) in methanol (100 ml) was treated with hydroxylamine hydrochloride (4×2.08 g) and potassium t-butoxide (4×3.25 g) over 6 hours and the resulting mixture heated at reflux for 18 h. After cooling, the reaction mixture was poured into water (800 ml), the suspension stirred for 30 min, and the white solid filtered off and dried in vacuo to give the title compound (21.2 g).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][C@@H:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:14][C:4]=1[C:5]=23)#[N:2].CCN(CC)CC.[C:29]1([C:35](Cl)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[C:35]([N:8]1[C:9]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[C:4]3[CH2:14][C@H:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:12][C@H:6]([C:5]=23)[CH2:7]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCN(CCC)[C@H]1Cc2c(C#N)ccc3c2[C@H](CN3)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)[C@H]1Cc2c(C#N)ccc3c2[C@@H](C1)CN3C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.5 %

Procedure:
To a sol of (2aR,4R)-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole (1 g, 3.5 mmol) and Et3N (354 mg, 3.5 mmol) in 50 mL of methylene chloride was added a sol of triphenylmethyl chloride (trityl chloride) (0.98 g, 3.5 mmol) in 10 mL of methylene chloride dropwise at RT. The reaction mixture was stirred for 16 hr at RT. The reaction mixture was extracted with water and cold 1 N HCl. The organic sol was washed with sat'd NaHCO3 sol and with sat'd brine sol. The organic sol was dried (MgSO4) and conc to dryness in vacuo to give a residue. The residue was slurried with warm hexanes, cooled and filtered to remove insolubles. The filtrate was conc to an oil. The oil was chromatographed (silica gel, 20% EtOAc in hexanes) to provide 1.5 g of (2aR,4R)-1-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole.
Reaction SMILES: [F:1][C:2]1[C:3]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)=[C:4]([C:10]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:11]([F:15])[C:12]=1[CH2:13][OH:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N1C=CN=C1.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36].O>ClCCl>[Si:35]([O:14][CH2:13][C:12]1[C:11]([F:15])=[C:10]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[C:2]=1[F:1])([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCOC(=O)c1c(NC(=O)C(C)(C)C)c(F)c(CO)c(F)c1OC1CCCCO1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(NC(=O)C(C)(C)C)c(F)c(CO[Si](C)(C)C(C)(C)C)c(F)c1OC1CCCCO1
Yield: 96.7 %

Procedure:
213 mg (0.50 mmol) of the above ethyl 3,5-difluoro-4-hydroxymethyl-6-pivaloylamino-2-(2-tetrahydropyranyloxy)benzoate was dissolved in 5 mL of dichloromethane, 68 mg (1.0 mmol) of imidazole and 302 mg (2.00 mmol) of tert-butyldimethylsilyl chloride were added and the mixture was heated at reflux for 30 minutes. The reaction solution was cooled on ice, water was added and the mixture was extracted once with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 256 mg of ethyl 4-tert-butyldimethylsilyloxymethyl-3,5-difluoro-6-pivaloylamino-2-(2-tetrahydropyranyloxy)benzoate (yield: 98%).
Reaction SMILES: C(O[CH:4]=[C:5]1[C:16]2[C:8](=[CH:9][CH:10]=[C:11]3[C:15]=2[S:14][CH:13]=[N:12]3)[NH:7][C:6]1=[O:17])C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:28][C:29]([NH2:31])=[NH:30])(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[NH2:31][C:29](=[NH:30])[NH:28][S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][CH:4]=[C:5]2[C:16]3[C:8](=[CH:9][CH:10]=[C:11]4[C:15]=3[S:14][CH:13]=[N:12]4)[NH:7][C:6]2=[O:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26]
Reactant: CCOC=C1C(=O)Nc2ccc3ncsc3c21
Reactant: N=C(N)NS(=O)(=O)c1ccc(N)cc1
Product: N=C(N)NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc4ncsc4c32)cc1
Yield: 26 %

Procedure:
The title compound was prepared in 26% yield from 8-ethoxymethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one and 4-amino-N-(amino-imino-methyl)-benzenesulfonamide according to Procedure J: 1H NMR (DMSO-d6): δ11.2 (d, 1H), 10.9 (s, 1H), 9.3 (s, 1H), 8.1 (d, 1H), 7.85 (d, 1H), 7.8 (d, 2H), 7.5 (d, 2H), 7.4 (d, 1H), 7.3 (d, 1H), 6.5 (d, 1H), 5.7 (s, 1H); C17H14N6O3S2: APCI−MS m/z 415 (M+H)+.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:7][CH:6](CS([O-])(=O)=O)[CH2:5][O:4]2)[CH2:2]1.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]([O:24][C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]4[C:35](=[O:47])[N:36]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:37]([CH3:40])[C:38]=4[CH3:39])=[O:33])=[CH:27][C:26]=3[F:48])=[CH:19][CH:20]=[N:21]2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O>[CH2:2]1[C:3]2([CH2:7][CH:6]([O:13][C:14]3[CH:23]=[C:22]4[C:17]([C:18]([O:24][C:25]5[CH:30]=[CH:29][C:28]([NH:31][C:32]([C:34]6[C:35](=[O:47])[N:36]([C:41]7[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=7)[N:37]([CH3:40])[C:38]=6[CH3:39])=[O:33])=[CH:27][C:26]=5[F:48])=[CH:19][CH:20]=[N:21]4)=[CH:16][CH:15]=3)[CH2:5][O:4]2)[CH2:1]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: O=S(=O)([O-])CC1COC2(CC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC5COC6(CC6)C5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C

Procedure:
The title compound was prepared according to the procedure described in Example 6 by using (4-oxaspiro[2.4]heptane-6-yl)methanesulfonate (220 mg, 1.14 mmol), N-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (300 mg, 0.62 mmol), and cesium carbonate (450 mg, 2.4 mmol, Aladdin) in DMA (6 mL). The title compound was purified by a silica gel column chromatography (5:1 (v/v) EtOAc/n-hexane) and was obtained as a white solid (68 mg, 19%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=2)O1>>[OH:1][CH2:2][CH2:3][N:4]([CH:22]([CH3:24])[CH3:23])[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[CH:19][C:18]([C:33]4[CH:38]=[N:37][C:36]([NH2:39])=[CH:35][CH:34]=4)=[CH:17][C:14]=3[C:15]=2[N:16]=1)=[O:6]
Reactant: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: CC(C)N(CCO)C(=O)c1nc2c(s1)CCOc1ccc(-c3ccc(N)nc3)cc1-2
Yield: 13.3 %

Procedure:
Following the procedure for 277, 9-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (2-hydroxy-ethyl)-isopropyl-amide (52.5 mg, 0.128 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (33.7 mg, 0.153 mmol) were reacted to give 279 (7.2 mg, 13% yield, M+1 425.1).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[C:26]1([CH2:25][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH2:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][NH:9]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1ccccc1CCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(CCc2ccccc2OCCC2CCCCN2)cc1
Reaction time: 2 h
Yield: 53 %

Procedure:
5 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 440 mg of 1-t-butoxycarbonyl-2-{2-[2-(2-phenylethyl)phenoxy]ethyl}piperidine [prepared as described in step (a) above] in 5 ml of dioxane, and the resulting mixture was allowed to stand at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting solid residue was dissolved in a small amount of methylene chloride; 20 ml of ethyl acetate was then added to the solution thus obtained, after which it was allowed to stand at room temperature. The crystals which precipitated were collected by filtration, to give 214 mg (yield 53%) of the title compound as colorless crystals, melting at 95°-97° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](Br)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=[CH:6]2.[F:18][C:19]([F:24])([F:23])C([O-])=O.[Na+]>[Cu]I.CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([C:19]([F:24])([F:23])[F:18])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:8][CH:7]=[CH:6]2
Reactant: O=C([O-])C(F)(F)F
Reactant: COC(=O)c1cccc2c(Br)c(OC)ccc12
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c(C(F)(F)F)c(OC)ccc12
Reaction time: 5 h
Yield: 76 %

Procedure:
Using the same general procedure as in Comparative Example A, one molar proportion of methyl 6-methoxy-5-bromo-1-naphthoate (MMBN) was reacted with 1.7 molar proportions of sodium trifluoroacetate in the presence of 2 molar proportions of CuI and molar proportions of N,N-dimethylformamide (DMF), with an additional 0.95 molar proportion of sodium trifluoroacetate being added during the course of the reaction. The total reaction time was 5 hours. After workup, the desired methyl 6-methoxy-5-trifluoromethyl-1-naphthoate (MMTN) was isolated in a 76% yield.