Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][Cl:7])([O-:3])=[O:2].[CH2:12]=[O:13].C1CCN2C(=NCCC2)CC1>CS(C)=O.CC(O)=O.C(Cl)Cl>[Cl:7][CH:6]([C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])[CH2:12][OH:13]
Reactant: O=[N+]([O-])c1ccccc1CCl
Reactant: C=O
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccccc1C(Cl)CO
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-nitrobenzyl chloride (4.3 g, 25 mmol) in DMSO (3.5 ml, synthesis quality, additionally dried for 2 d over molecular sieve 4 Å) was mixed with paraformaldehyde (750 mg, 25 mmol) and DBU (0.5 ml, 3.3 mmol) and stirred at room temperature for 20 min. The pH value of the reaction mixture was adjusted to about pH 3 by means of a few drops of conc. AcOH. The mixture was diluted with CH2Cl2 (120 ml), washed with H2O (80 ml) and post-extracted with CH2Cl2 (2×100 ml).
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[CH:6]1([CH2:12][NH2:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1>CO>[CH:6]1([CH:12]([CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[NH:13][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: ClCC1CO1
Reactant: NCC1CCCCC1
Solvent: CO
Product: OC(CCl)CNC(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.7 Grams of epichlorohydrin and 10.2 g of cyclohexylmethylamine are dissolved in 50 ml of methanol. The mixture is stirred for 8 hours at room temperature. Methanol is removed by evaporation under reduced pressure. The resulting crude oily substance is purified by a silica gel column chromatography (chloroform:methanol =8:1) to obtain 8.2 g of N-(dicyclohexylmethyl)-N-(3-chloro-2-hydroxypropyl)amine.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=1>>[CH3:12][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=4)=[CH:20][CH:21]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: Cc1ccc2ccc(N)cc2n1
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Product: Cc1ccc2ccc(NC(=O)c3ccc(-c4ccccn4)cc3)cc2n1

Procedure:
Using the procedure outlined in Example 56, the title compound was prepared from 7-amino-2-methylquinoline (D66) (33 mg, 0.21 mmol) and 4-(2-pyridyl)benzoic acid (D67) (50 mg, 0.25 mmol) as a white solid. MS (ES): MH+ 340, M-H+ 338.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:16])[CH2:4][CH:5]2[CH2:11][CH2:10][S:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6]=12.BrBr.O>C(O)(=O)C>[N:1]1[NH:2][C:3](=[O:16])[CH:4]=[C:5]2[CH2:11][CH2:10][S:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6]=12
Reactant: O=C1CC2CCSc3ccccc3C2=NN1
Agent: BrBr
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc2c(n[nH]1)-c1ccccc1SCC2
Yield: 93.2 %

Procedure:
To a mixture of 92 g of 4,4a,5,6-tetrahydro[1]benzothiepino[5,4-c]pyridazin-3(2H)-one in 920 ml of acetic acid is added 64 g of bromine dropwise at 50°-60° C., and the mixture is kept at the same temperature for an hour and poured into a large quantity of water. The precipitated crystals are collected by filtration, and washed with warm water and then with ethanol. The crystals are dried to give 85 g of 5,6-dihydro-[1]benzothiepino[5,4-c]pyridazin-3(2H)-one, melting at 311°-313° C. with decomposition.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=O)[C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(OCC)(=O)C.CCCCCC>[CH:1]1[C:11]2[CH:10]=[C:9]([C:12]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:14])[C:8]3[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C1COCCN1
Reactant: O=C(O)C1=Cc2ccccc2Oc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(C1=Cc2ccccc2Oc2ccccc21)N1CCOCC1
Yield: 62 %

Procedure:
Preparation analogous to Example 10a from dibenz[b,f]oxepine-10-carboxylic acid and morpholine; yield: 62%; yellow oil; 1H-NMR (CDCl3, 200 MHz): 3.30 (mbr, 4H); 3.62 (mbr, 4H); 6.90-7.28 (m, 9H); MS: 307 (M+), 221, 193, 165; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.17.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:20]2[C:19]3[CH2:18][CH2:17][C@@:15]4([CH3:16])[C@@H:11]([CH2:12][CH2:13][C:14]4=[O:23])[C:10]=3[CH2:9][CH2:8][C:7]=2[CH:6]=1.C(O)(=O)C.O>C(O)C>[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:20]2[C:19]3[CH2:18][CH2:17][C@@:15]4([CH3:16])[C@@H:11]([CH2:12][CH2:13][C@@H:14]4[OH:23])[C:10]=3[CH2:9][CH2:8][C:7]=2[CH:6]=1
Reactant: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CCC1=C2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Yield: 93.1 %

Procedure:
Add sodium borohydride (8.5 g) to 3-methoxyestra-1,3,5(10),8-tetraen-17-one (40 g) in ethanol (500 ml) and reflux the mixture for 90 minutes. Acidify the cooled solution with acetic acid, add water and extract with benzene. Wash, dry and evaporate the organic extract to obtain dl-3-methoxyestra-1,3,5(10),8-tetraen-17β-ol (37.5 g), m.p. 130°-133°; ultraviolet absorption peak at 280 mμ (ε16,100); infrared maxima at 3.1 μ, 3.58 μ, 6.25 μ, 6.4 μ, 6.7 μ
Reaction SMILES: [CH3:1][S:2][C:3]1[N:12]2[C:6]([CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:25])C=1>ClCCl>[CH3:1][S:2]([C:3]1[N:12]2[C:6]([CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]=[CH:11]2)=[N:5][N:4]=1)=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nnc2n1C=Cc1ccccc1C2
Solvent: ClCCl
Product: CS(=O)c1nnc2n1C=Cc1ccccc1C2
Reaction time: 0.67 h

Procedure:
A solution of 4.6 g of 3-methylthio-11H-s-triazolo[3,4-b][3]benzazepine in 100 ml of dichloromethane was stirred under ice-cooling and 5.2 g of m-chloroperbenzoic acid was added. The mixture was further stirred for 40 minutes, after which it was washed with a solution of sodium sulfite, a saturated solution of sodium hydrogen carbonate and water in the order mentioned, and followed by drying over Na2SO4. The solvent was then evaporated off and the crystalline residue was collected by filtration and washed with ethyl ether. The above procedure provided 3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine as crystals. Recrystallization from methanol yielded colorless needles melting at 176°-177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:12])[O:6][CH2:5]2.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:13][CH:5]1[C:4]2[C:8](=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[C:7](=[O:12])[O:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2cc(Cl)c(Cl)cc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C1OC(Br)c2cc(Cl)c(Cl)cc21
Yield: 90.5 %

Procedure:
A suspension of 5,6-Dichloro-3H-isobenzofuran-1-one (1.45 g), N-bromosuccinimide (1.27 g) and catalytic benzoyl peroxide in chloroform (30 mL) was heated to reflux for 1 hour. After cooling, the reaction mixture was washed with water, brine, dried (magnesium sulfate), filtered and concentrated to give the sub-title compound as a white solid (1.82 g, 91%); 1H NMR (400 MHz, CDCl3) δ 7.36 (1H, s), 7.77 (1H, s), 8.03 (1H, s).
Reaction SMILES: O=C1NC2C=CC=CC=2S[C@H](C2C=CC=CC=2)[C@@H]1NC(=O)[C@H](C)NC(=O)CC1C=CC=CC=1.Br.[NH2:35][C@H:36]1[C:42](=[O:43])[NH:41][C:40]2[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=2[S:38][C@H:37]1[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.[F:54][C:55]1[CH:56]=[C:57]([CH2:62][C:63]([NH:65][C@H:66]([C:71](O)=[O:72])[CH2:67][CH2:68][S:69][CH3:70])=[O:64])[CH:58]=[C:59]([F:61])[CH:60]=1>>[F:54][C:55]1[CH:56]=[C:57]([CH2:62][C:63]([NH:65][C@H:66]([C:71]([NH:35][C@@H:36]2[C:42](=[O:43])[NH:41][C:40]3[CH:44]=[CH:45][CH:46]=[CH:47][C:39]=3[S:38][C@@H:37]2[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:72])[CH2:67][CH2:68][S:69][CH3:70])=[O:64])[CH:58]=[C:59]([F:61])[CH:60]=1
Reactant: N[C@H]1C(=O)Nc2ccccc2S[C@H]1c1ccccc1
Reactant: CSCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Br
Agent: C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1
Product: CSCC[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2ccccc2S[C@@H]1c1ccccc1

Procedure:
A method similar to the one described for (97) was used except that (2,3-cis)-3-amino-2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-one hydrobromide (9d) (105 mg) was used as the amine component and N-[(3,5-difluorophenyl)acetyl]-L-methionine (109b) (91 mg) was used as the acid component to afford the title compound as a 1:1 mixture with the (2S,3S) diastereomer (63 mg), white solid, m.p. 85-90° C. 1H NMR (300 MHz, d6-DMSO) δ 1.55 (m, 4H), 2.20 (s, 3H), 2.40 (m, 12H), 3.03 (m, 4H), 4.26 (m, 1H), 4.72 (m, 1H), 5.17 (d, 1H, J=7 Hz), 5.829 (d, 1H, j=6 Hz), 6.89-7.79 (m, 12H), 8.21 (m, 1H), 10.53 (m, 1H). MS APCI, m/z=556(M+1). LC/MS: 2.55 min.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:19][OH:20]>C(Cl)Cl.[OH-].[Na+]>[CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:17][C@@H:18]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:19][OH:20])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H](CO)Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(N[C@H](CO)Cc1ccccc1)c1ccccc1Cc1ccccc1
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
At 0° C., 2.1 g (9.2 mmol) of 2-benzylbenzoyl chloride dissolved in a little methylene chloride were added dropwise to 1.3 g (8.6 mmol) of (S)-2-amino-3-phenylpropan-1-ol in 35 ml of methylene chloride and 20 ml of 2M aqueous sodium hydroxide solution. The mixture was stirred for about 30 min. The organic phase was separated off, dried and concentrated under reduced pressure. 2.7 g (91%) of the product were obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:33])[N:27]2[CH2:30][CH:31]=O)=[N:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[F:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][C:26](=[O:33])[N:27]2[CH2:30][CH2:31][N:5]2[CH2:6][C@@H:2]([OH:1])[C@@H:3]([CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:4]2)=[N:22][CH:21]=1
Reactant: O=C(NC[C@H]1CNC[C@H]1O)OCc1ccccc1
Reactant: O=CCn1c(=O)ccc2ncc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NC[C@H]1CN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Phenylmethyl {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (1.17 g; 4.560 mmol) and (7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde (as the methyl hemiacetal)) (855 mg, 4.17 mmol) were combined in anhydrous DCM (5 ml) and anhydrous MeOH (1 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 1 h then sodium triacetoxyborohydride (2.76 g; 12.44 mmol) was added and stirred overnight. The reaction mixture was concentrated and the title compound was obtained as a pale yellow oil (1.69 mg, 87%) after column:chromatography (90:10: DCM:MeOH).
Reaction SMILES: [Cl-:1].[Cl-].[Cl-].[CH:4]1([Ti+3:9])[CH:8]=[CH:7][CH:6]=[CH:5]1.[OH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C(N(CC)CC)C>CCOCC>[Cl-:1].[Cl-:1].[CH:4]1([Ti+2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][CH:6]=[CH:5]1
Reactant: [Ti+3]C1C=CC=C1
Reactant: Oc1ccccn1
Agent: [Cl-]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C1=CC([Ti+2]Oc2ccccn2)C=C1
Reaction time: 8 h

Procedure:
To a solution of 0.002 moles of cyclopentadienyl titanium trichloride in 50 mL of ether a solution of 2-hydroxy pyridine (0.002 moles) and triethylamine (0.002 moles) in 50 mL of ether was added at 0° C. and stirred overnight. The product was recovered from the ether filtrate. The product has the formula:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9]CC)=O.[CH3:13][Mg]Br.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>CCOCC>[C:7]([C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:12]=1)(=[O:9])[CH3:13]
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: C[Mg]Br
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)c1cncc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of ethyl 5-bromonicotinate (3.9 g, 16.9 mmol) in ether (50 ml) at 0° C. was added a 3M solution of methylmagnesium bromide (16.9 ml, 50.8 mmol). The resulting thick slurry was warmed slowly to room temperature and after 1.5 hours it was poured slowly into an excess of 1M aqueous monobasic sodium phosphate. The mixture was partitioned between ether and water and the product from the organic phase was chromatographed on silica gel, eluting with a 1:1:2 mixture of ether, pentane and ammonia-saturated methylene chloride to afford the 3-acetyl-5-bromopyridine compound. This preparation also afforded 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine described in Example 25.
Reaction SMILES: [C:1]([O:6]CC)(=O)[CH:2]([CH3:4])[OH:3].[CH2:9]([CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][NH2:13])[CH3:10]>>[CH2:9]([CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][NH:13][C:1](=[O:6])[CH:2]([CH3:4])[OH:3])[CH3:10]
Reactant: CCOC(=O)C(C)O
Reactant: CCCCC(CC)CN
Product: CCCCC(CC)CNC(=O)C(C)O

Procedure:
N-(2-Ethylhexyl)lactamide was prepared in accordance with example 1 by amidation of ethyl lactate with 2-ethylhexylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][C:26]([O:28]CC)=[O:27])([OH:24])[CH2:19]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.[Li+].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][C:26]([OH:28])=[O:27])([OH:24])[CH2:19]4)[C:14]([F:31])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCOC(=O)C[C@@]1(O)CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C[C@@]1(O)CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1

Procedure:
To a solution of ethyl 2-((1R,3S)-3-(2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-ylamino)-1-hydroxycyclohexyl)ethanoate, 60c, (0.14 g, 0.22 mmol) in THF (5.0 mL) was added LiOH (1.12 mL of 1 M aqueous solution, 1.12 mmol). The reaction was microwaved at 130° C. for 30 min, neutralized with HCl (0.56 mL of 2 M, 1.12 mmol) and concentrated under reduced pressure, diluted in toluene and concentrated (2×) to give 60d which was used without further purification. LC MS+: 420.30 at 3.05 min (10-90% MeOH, 3/5 grad/run, Formic Acid).
Reaction SMILES: [CH2:1]([O:7][C:8]1[C:13]([F:14])=[C:12]([F:15])[CH:11]=[C:10]([F:16])[C:9]=1[F:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.CCCCCC.[C:29](=[O:31])=[O:30].Cl>C1COCC1>[CH2:1]([O:7][C:8]1[C:9]([F:17])=[C:10]([F:16])[C:11]([C:29]([OH:31])=[O:30])=[C:12]([F:15])[C:13]=1[F:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1c(F)c(F)cc(F)c1F
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCOc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
27.5 g of the compound (4) dissolved in 250 mL of THF were cooled at −78° C. in an argon atmosphere; thereto were then dripped 82 mL of a 1.6 M/L n-butyllithium/hexane solution, with stirring for 2 hours at the same temperature. After addition of a suitable amount of crushed dry ice, the temperature was raised to room temperature, followed by stirring overnight. 200 mL of 3N hydrochloric acid were then added under ice cooling, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, were washed with saturated brine, and were then dried over anhydrous magnesium sulfate. After evaporating the solvent, the organic layer was recrystallized from hexane to yield 25.9 g (88 mmol) of 4-hexyloxy-2,3,5,6-tetrafluorobenzoic acid (5).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2([CH3:14])[CH2:13][CH2:12]2)=[C:5]([CH:15]([CH3:17])[CH3:16])[CH:4]=1)#[CH:2].[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>C(N(CC)CC)C.[Cu]I.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>[CH:15]([C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:25]2[CH:26]=[CH:27][C:22]([CH2:21][C:20]([O:19][CH3:18])=[O:29])=[CH:23][CH:24]=2)[CH:8]=[CH:7][C:6]=1[CH2:9][O:10][C:11]1([CH3:14])[CH2:12][CH2:13]1)([CH3:17])[CH3:16]
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: C#Cc1ccc(COC2(C)CC2)c(C(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(C#Cc2ccc(COC3(C)CC3)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 60.2 %

Procedure:
Using General Procedure F; 4-ethynyl-2-isopropyl-1-(1-methyl-cyclopropoxymethyl)-benzene (Intermediate 166, 78.0 mg, 0.34 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 94.0 mg, 0.34 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (22.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (79 mg, 0.11 mmol) was added and the reaction mixture was stirred at room temperature for 3.5 hours. Column chromatography (2-5% EtOAc-hexanes) afforded 77.0 mg (60%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][C:21]([CH3:28])([C:23]1[O:24][CH:25]=[CH:26][N:27]=1)[NH2:22]>>[CH3:20][C:21]([NH:22][C:14]([C:12]1[CH:11]=[CH:10][C:9]([CH:17]2[CH2:19][CH2:18]2)=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])([C:23]1[O:24][CH:25]=[CH:26][N:27]=1)[CH3:28]
Reactant: O=C(O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1
Reactant: CC(C)(N)c1ncco1
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(-c2cccc(Cl)c2)n1)c1ncco1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyridine-2-carboxylic acid (Example 48 e) and α,α-dimethyl-2-oxazolemethanamine (CAN 1211519-76-4) as starting materials, MS (EI): m/e=382.1 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][O:22]C(=O)C)[CH:14]=[CH:15][CH:16]=1.O1CCOCC1.[OH-].[Na+].Cl>O.CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)[C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH2:19][CH2:20][CH2:21][OH:22])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)OCCCC=Cc1cccc(C(OC2CCN(C)CC2)c2nc3ccccc3s2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CN1CCC(OC(c2cccc(C=CCCCO)c2)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Acetic acid 5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-enyl ester (150 mg) in a mixture of water (1 mL), 1,4-dioxane (1 mL) and methanol (1 mL) is added 1N sodium hydroxide solution (0.6 mL). The reaction mixture is stirred at room temperature for 2 hours. After neutralization to pH 7 with addition of 1N hydrochloric acid, the reaction mixture is extracted with dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/1) to afford 5-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}pent-4-en-1-ol.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:36]2[CH2:35][CH2:34][N:33]([C:29]3[CH:28]=[C:27]([O:26][CH3:25])[CH:32]=[CH:31][N:30]=3)[CH2:38][CH2:37]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: COc1ccnc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1ccnc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2)c1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(4-Methoxy-pyridin-2-yl)-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.92 (d, 1H), 6.67 (s 1H), 6.63 (d, 1H), 5.42 (s, 2H), 3.96 (s, 3H), 3.88 (m, 2H), 3.73 (m, 4H), 3.62 (m, 2H), 2.19 (s, 3H) ppm; MS (ES) M+H expected=418.1, found=418.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15](C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.CC1(C)CC=C(OS(C(F)(F)F)(=O)=O)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2>>[CH3:32][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1), 203.8 mg (0.43 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) was converted into the title compound (colorless solid) using 58.2 mg (0.36 ml, 0.69 mmol) of phenyllithium (1.8M solution in cyclohexane/Et2O), 116.1 mg (0.85 mmol) of zinc chloride and 13.8 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium(0). PMR (CDCl3): δ 1.36 (6H, s), 1.40 (3H, t, J=7.1 Hz), 2.37 (2H, d, J=4.7 Hz), 4.38 (2H, q, J=7.1 Hz), 6.02 (1H, t, J=4.7 Hz), 7.20 (1H, d, J=1.5 Hz), 7.27 (1H, m), 7.39 (6H, m), 7.52 (2H, d, J=8.2 Hz), 7.98 (2H, d, J=8.2 Hz).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:11]=[C:12]([N:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=[C:17]2[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26])[CH:13]=[CH:14][CH:15]=1>CN(C=O)C.O>[Cl:1][C:18]1[C:19]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)[C:17]=1[CH:25]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH3:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(NC(=O)OC(C)(C)C)c1cc2cccnc2n1-c1cccc(F)c1
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC(=O)OC(C)(C)C)c1c(Cl)c2cccnc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.2 %

Procedure:
A solution of N-chlorosuccinimide (24 mg, 0.18 mmol) in DMF (0.1 mL) was added dropwise to an ice-cooled solution of tert-butyl {1-[1-(3-fluorophenyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]ethyl}carbamate (60 mg, 0.17 mmol) (5073-171) in N,N-dimethylformamide (1 mL). The resulting mixture was allowed to warm to room temperature and stirred overnight. The mix was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-10% EtOAc/hexane) to give the desired product (26 mg, 40%). LCMS calculated for C20H22ClFN3O2(M+H)+: m/z=390.1. Found: 390.1.