Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)C(=O)C3C=NN(C4C=CC=C(C)C=4S)C=3N=2)=[CH:4][CH:3]=1.BrC1C=CC(C(Cl)=[O:39])=CC=1.C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:9][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[O:39])=[CH:4][CH:3]=1
Reactant: Cc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(Br)cc4)nc32)c1S
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-N-(4-chloro-phenyl)-benzamide (4) used is prepared by the following procedure. To a solution of 4-chloroaniline (2, 66.0 g, 517.4 mmol) and 4-bromobenzoyl chloride (3, 109.0 g, 497.5 mmol) in dichloromethane (1200 mL) is added triethyl amine (83.2 mL, 597.0 mmol). The reaction mixture is then poured into 0.05 N sodium hydroxide solution and the resulted suspension is stirred at rt for 1 h. The solid formed is filtered and washed well with water. It is dried in vacuo and used for the next step.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=2)O1>>[C:9]([NH:8][C:6]1[N:7]=[C:2]([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)[CH:3]=[CH:4][CH:5]=1)(=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C(=O)Nc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(C)C(=O)Nc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
Prepared by Procedure W and Scheme AF using N-(6-bromo-2-pyridinyl)-2-methylpropanamide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate: ESMS m/e: 245.8 (M - 100)+.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:5]1[S:9][C:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:7][CH:6]=1)[CH3:4].[F:17][C:18]([F:30])([F:29])[C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>CN(C)C=O>[F:30][C:18]([F:17])([F:29])[C:19]1[CH:20]=[CH:21][C:22]([S:25]([NH:2][C@@H:3]([C:5]2[S:9][C:8]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[CH:7][CH:6]=2)[CH3:4])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H](N)c1ccc(C(=O)OC(C)(C)C)s1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](NS(=O)(=O)c1ccc(C(F)(F)F)cc1)c1ccc(C(=O)OC(C)(C)C)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To the vial containing (R)-tert-butyl 5-(1-aminoethyl)thiophene-2-carboxylate hydrochloride from Step 1 was added N,N-dimethylaminopyridine (3.91 mg, 0.0320 mmol), 4-(trifluoromethyl)benzenesulfonyl chloride (0.059 g, 0.24 mmol), N,N-dimethylformamide (2 mL), and triethylamine (0.178 mL, 1.28 mmol). The mixture was stirred at rt for 16 h and then evaporated. To the residue was added 1,2-dichloroethane (3 mL), sat. NaHCO3 solution (0.5 mL), and water (0.5 mL). After separation, the aqueous layer was extracted with 1,2-dichloroethane (2×3 mL). The combined organic phases were evaporated to dryness to give crude (R)-tert-butyl 5-(1-(4-(trifluoromethyl)phenylsulfonamido)ethyl)thiophene-2-carboxylate as a brown solid. LC-MS: (FA) ES− 434.
Reaction SMILES: OS(O)(=O)=O.N([O-])=O.[Na+].C(O)(=O)C.N[C:15]1[C:22]([F:23])=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[F:24].[BrH:25]>>[Br:25][C:15]1[C:22]([F:23])=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[F:24]
Reactant: N#Cc1cc(F)c(N)c(F)c1
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cc(F)c(Br)c(F)c1
Temperature: 40 °C

Procedure:
While stirring 420 cm3 of concentrated H2SO4 on an ice water bath, 54 g (0.78 mol) of pulverized NaNO2 was added at a rate that maintained a temperature under 40° C., and after the addition it was stirred in a hot water bath at 50° C. until the crystals dissolved completely. While stirring this solution on an ice water bath, 700 cm3 of glacial acetic acid was added dropwise, then 108 g (0.7 mol) of 4-amino-3,5-difluorobenzonitrile was added at a rate maintaining the temperature at 20°-25° C., and after the addition was completed it was stirred at this temperature until the crystals were completely dissolved to prepare a diazonium salt solution. A solution with 143 g (1.0 mol) of CuBr dissolved in 420 cm3 of 47% HBr was stirred in an ice water bath while the previously prepared diazonium salt solution was added dropwise for 2 hours, and after the dropping was completed, it was stirred on an ice water bath for 1 hour and at room temperature overnight. The crystals formed were filtered, and after washing the crystals in glacial acetic acid, they were recrystallized from a mixture of acetone and methanol to obtain 98 g (0.44 mol) of 4-bromo-3,5-difluorobenzonitrile.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][O:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH2:22][OH:23])=[C:16]([CH:24]([CH3:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=1>C(Cl)Cl.CCOCC>[CH3:12][O:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH:22]=[O:23])=[C:16]([CH:24]([CH3:32])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:15]=1
Reactant: COc1cc(CO)c(C(C)Cc2ccccc2)cc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(C=O)c(C(C)Cc2ccccc2)cc1OC
Reaction time: 0.75 h
Yield: 76.1 %

Procedure:
A solution of pyridinium chlorochromate (1.253 g, 5.8 mmol) in 40 mL CH2Cl2 was cooled to 0° C. [4,5-Dimethoxy-2-(1-methyl-2-phenyl-ethyl)-phenyl]-methanol (1.110 g, 3.88 mmol) in 5.0 mL CH2Cl2 was added drop-wise and allowed to stir for 45 minutes. The mixture was diluted in 200 mL Et2O, filtered through celite and concentrated in vacuo to afford a dark brown oil. Purification via flash chromatography (9:1 hexane/ethyl acetate) gave 4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-benzaldehyde (0.840 g, 76%) as a clear oil.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C>CS(C)=O>[CH:1]1([NH:4][C:5]2[S:6][CH:7]=[C:8]([CH:10]=[O:11])[N:9]=2)[CH2:3][CH2:2]1
Reactant: OCc1csc(NC2CC2)n1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1csc(NC2CC2)n1

Procedure:
The reaction described in Preparation 44 was repeated, but using 1.1 g of 2-cyclopropylaminothiazol-4-ylmethanol, 3.1 g of sulfur trioxide pyridine complex, 2 g of triethylamine and 15 ml of dimethyl sulfoxide, giving the title compound as pale yellow prisms.
Reaction SMILES: C([O-])(C)(C)C.[K+].ClC1C=CC(O[CH2:13][C:14]#[N:15])=CC=1.[N+:18]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)([O-:20])=[O:19].Cl>CN(C)C=O.O>[N+:18]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1[CH2:13][C:14]#[N:15])([O-:20])=[O:19]
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc2ccccc2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1c([N+](=O)[O-])ccc2ccccc12
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Prepare a solution of 53.5 g (0.477 mol) of potassium tert.-butanolate in 400 ml of dimethylformamide. Cool the resulting solution to −10° C. and add thereto, over the course of about 1 hour, a solution of 40 g of 4-chlorophenoxyacetonitrile (0.24 mol) and 37 g of 2-nitronaphthalene (0.213 mol) in 200 ml of dimethylformamide. After 2 hours at −5° C., pour the mixture into 4 litres of water containing 1 litre of concentrated hydrochloric acid and extract the aqueous phase with 3×500 ml of dichloromethane. Wash the organic phase with 300 ml of water, dry it over magnesium sulphate, filter and then evaporate off the solvent.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[CH2:24]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:36][C:35]4[CH:37]=[CH:38][C:32]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:33][CH:34]=4)=[O:2])([CH2:11][CH2:10]2)[CH2:9][CH2:8]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: CCCCCCCCc1ccc(N)cc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: CCCCCCCCc1ccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)cc1
Yield: 20 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 4-octylaniline (70.5 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-octylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (15.8 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC/C=C/c1cccc(Br)c1
Solvent: CCO
Product: O=C(O)CCCCc1cccc(Br)c1
Reaction time: 5 h
Yield: 98.5 %

Procedure:
Example 1, (E)-5-(3-Bromophenyl)pent-4-enoic acid (4 g, 15.8 mmol), was dissolved in absolute ethanol (200 mL) and flushed with nitrogen before addition of 5% platinum sulfide on carbon (2.5 g). The solution was flushed with hydrogen at atmospheric pressure and stirred 5 hours. The catalyst was removed by filtration through diatomaceous earth (Celite®) and the solvent immediately removed by rotory evaporation (in order to minimized esterification) to give Example 2, 5-(3-bromophenyl)pentanoic acid 4 g (99%) which was carried forward without further purification. 1H NMR (500 MHz, CDCl3) δ 7.31-7.30 (m, 2H), 7.13 (t, J=7.6 Hz, 1H), 7.09-7.07 (d, J=7.6 Hz, 1H), 2.60 (t, J=7.0 Hz, 2H), 2.37 (t, J=7.0 Hz, 2H), 1.68-1.65 (m, 4H). RT=2.1 minutes (condition 1); LRMS: Anal. Calcd. for C11H13BrO2: 255.00. found: 254.99 (M−H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([Cl:10])[CH:3]=1.[C-:11]#[N:12].[K+]>ClC(Cl)C.O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([Cl:10])[CH:3]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC(Cl)Cl
Product: N#CCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 290.2 %

Procedure:
To a stirred solution of 4-bromo-1-bromomethyl-2-chlorobenzene (16, 62.5 g, 0.22 mol) in dichloroethane (522 mL) and water (480 mL) was added tetrabutylammonium chloride (5.05 g), followed by a solution of potassium cyanide (43.2 g, 75.8 mmol) in water (523 mL). and the solution was stirred for 4 h at room temperature. The layers were separated and the aqueous layer was extracted with dichloroethane (100 mL). The combined organic layers were washed with water (100 mL), dried over sodium sulfate filtered and evaporated. The crude product (52 g) was distilled under reduced pressure (1 mmHg), affording (4-bromo-2-chlorophenyl)-acetonitrile (45.5 g, 0.220 mol, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH:10]=[CH:9][CH2:8][CH:7]1[CH2:12][CH2:13][NH:14][C:15]1[NH:16][C:17]2[C:22]([C:23](=[O:25])[CH:24]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2>C(O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[CH2:12][CH2:13][NH:14][C:15]1[NH:16][C:17]2[C:22]([C:23](=[O:25])[CH:24]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2
Reactant: O=c1cc(NCCC2CC=CCN2Cc2ccc(Cl)c(Cl)c2)[nH]c2ccccc12
Agent: O=[Pt]=O
Solvent: CCO
Product: O=c1cc(NCCC2CCCCN2Cc2ccc(Cl)c(Cl)c2)[nH]c2ccccc12

Procedure:
2-{2-[1-(3,4-Dichlorobenzyl)-1.2,3,6-tetrahydropyridin-2-yl]ethylamino}-1H-quinolin-4-one (62 mg, 0.15 mmol) dissolved in ethanol (15 mL) was hydrogenated over platinum dioxide for 24 h at room temperature and atmospheric pressure. The reaction mixture was filtered and evaporated to yield the title compound as a colourless gum. δH (CD3OD) 1.16-1.80 (8H, m), 2.33-2.51 (1H, m), 2.57-2.71 (1H, m), 2.81-2.96 (1H, m), 3.16-3.37 (2H, m), 3.71-3.88 (2H, m), 5.55 (1H, s), 7.44-7.69 (6H, m,), 7.97 (1H, d, J=7.78 Hz); MS (ES+) 430 (100%) MH+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([O:9][C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: Oc1ccc(Cl)cc1Cl
Product: O=C(O)C1=Cc2cc(Cl)c(Oc3ccc(Cl)cc3Cl)cc2OC1C(F)(F)F

Procedure:
The title compound was prepared from 2,4-dichlorophenol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 233.0–234.0° C. 1H NMR (acetone-d6/300 MHz) 7.90 (s, 1H), 7.73 (s, 1H), 7.69 (d, 1H, J=2.6 Hz), 7.47 (dd, 1H, J=8.7 Hz, 2.6 Hz), 7.28 (d, 1H, J=8.7 Hz), 6.57 (s, 1H), 5.81 (q, 1H, J=7.0 Hz). 19F NMR (acetone-d6/282 MHz) −79.4 (d, J=6.5 Hz). FABLRMS m/z 437 (M−H). ESHRMS m/z 436.9379 (M−H, Calc'd 436.9362). Anal. Calc'd for C17H9Cl3F3O4: C, 46.45; H, 1.83; Cl, 24.19. Found: C, 46.38; H, 1.59; Cl, 24.46.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[O:1]([CH2:8][CH2:9][CH2:10][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccccc1
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(OCCCN2CCOCC2)cc1

Procedure:
N-[3-(Phenoxy)propyl] morpholine was prepared by a reaction of 3-(phenoxy)propyl bromide with morpholine. For example, 3-(phenoxy)propyl bromide (7.8 ml, 50 mmole) was added to morpholine (8 ml) in toluene (50 ml) and refluxed overnight. NaOH solution (2 g of NaOH in 20 ml of water) was added and additionally refluxed for 4 hr. Toluene was removed by distillation under reduced pressure. Residue was treated with dichloromethane(200 ml) and water(200 ml). Dichloromethane layer was dried and concentrated. Residue was treated with dichloromethane-heptane to give 7 g of 4-[3-(phenoxy)propyl] morpholine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20]OS(C)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[NH:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][CH2:19][CH2:20][N:26]([CH2:30][CH2:31][OH:32])[CH2:27][CH2:28][OH:29])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: OCCNCCO
Reactant: CS(=O)(=O)OCCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1
Product: OCCN(CCO)CCCCc1ccc2c(-c3ccc(Cl)cc3)nsc2c1

Procedure:
According to the method in example 23, Methanesulfonic acid 4-[3-(4-chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl ester and Diethanolamin were converted to yield 2-[{4-[3-(4-Chloro-phenyl)-benzo[d]isothiazol-6-yl]-butyl}-(2-hydroxy-ethyl)-amino]-ethanol, MS: 405 (MH+, 1Cl).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)=[CH:23][CH:22]=1)[CH3:19]
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: CCOc1ccc(B(O)O)cc1
Product: CCOc1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-ethoxy-phenylboronic acid to give [1-(4-ethoxy-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 331(MH+).
Reaction SMILES: [O:1]=[O+][O-].[OH:4][CH:5]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]([CH3:27])[C:15]1=[O:28])/[CH:6]=C/C1C=CC=CC=1>CO.ClCCl>[OH:4][CH:5]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH:16]([CH3:27])[C:15]1=[O:28])[CH:6]=[O:1]
Reactant: O=[O+][O-]
Reactant: CC1C(=O)C(C(O)/C=C/c2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: CC1C(=O)C(C(O)C=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ozone gas was bubbled into a solution of 0.450 g (1.30 mmol) of tert-butyl 4-[(2E)-1-hydroxyl-3-phenylprop-2-enyl]-2-methyl-3-oxopiperidine-1-carboxylate (Step D) in 10 mL of methanol and 10 mL of dichloromethane at −78° C. until the solution turned blue. The reaction was quenched with dimethyl sulfide, warmed to ambient temperature, and stirred for 1 h. The mixture was concentrated in vacuo and purified by flash chromatography on a Biotage® system (silica gel, eluting with 20% ethyl acetate/hexane to 60% ethyl acetate/hexane), affording the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][C:3]=1[O:12][CH3:13].Cl.C([O:19][N:20]=O)CCC>CO>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[N:20][OH:19])[C:8]2=[O:11])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc2c(cc1F)C(=O)CC2
Reactant: CCCCON=O
Agent: Cl
Solvent: CO
Product: COc1cc2c(cc1F)C(=O)C(=NO)C2
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of 6-Fluoro-5-methoxy-indan-1-one (4.8 g) in 65 ml of MeOH was added 2.7 ml of concentrated HCl, then a solution of n-butylnitrite (3.47 ml) at room temperature. The resulting mixture was stirred for 2 hrs, the precipitate was collected and dried to yield the product as a white solid (3.9 g, 70% yield). LC-MS: m/e 210 (MH+)
Reaction SMILES: [F:1][C:2]([F:18])([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([NH:14][NH2:15])=[O:13])=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].[CH:19](OC)(OC)OC.C(O)(=O)C>CO>[F:1][C:2]([F:18])([O:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]2[O:13][CH:19]=[N:15][N:14]=2)=[CH:10][CH:9]=1)[C:3]([F:5])([F:4])[F:6]
Reactant: COC(OC)OC
Reactant: NNC(=O)c1ccc(OC(F)(F)C(F)(F)F)cc1
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)C(F)(F)Oc1ccc(-c2nnco2)cc1
Temperature: 120 °C
Yield: 5.1 %

Procedure:
A mixture of 4-(perfluoroethoxy)benzohydrazide (3.17 g, 11.7 mmol) in trimethyl orthoformate (11.6 mL, 106 mmol) and acetic acid (0.13 mL, 2.35 mmol) was heated at 120° C. for 5 hours. The reaction was diluted with MeOH (15 mL) and poured into a beaker containing ice water (150 mL). The white precipitate was vacuum filtered and dried in a vacuum oven to provide 166 mg of 2-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazole as an off-white solid. An orange precipitate had formed in the aqueous filtrate and was collected by vacuum filtration and adsorbed onto silica gel. Purification by flash chromatography (0-40% EtOAc/hexanes) provided 2.02 g of 2-(4-(perfluoroethoxy)phenyl)-1,3,4-oxadiazole as an off-white solid giving a combined yield of 2.186 g (67%): mp 87-89° C.; 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.28-8.05 (m, 2H), 7.40 (d, J=8.9 Hz, 2H); 19F NMR (376 MHz, CDCl3) δ −85.98, −87.82; ESIMS m/z 280 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19]>O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)C(C)Br
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)C(C)Oc1ccc(C=O)cc1
Temperature: 60 °C
Yield: 71.4 %

Procedure:
A mixture consisting of 45 gm (0.37 mol) of 4-hydroxy-benzaldehyde, 111 gm (0.81 mol) of potassium carbonate, 89 ml (0.81 mol) of methyl 2-bromo-propionate and 300 ml of dimethylformanide was heated at 60° C. for 16 hours, while stirring. Thereafter, the reaction mixture was poured into 1 liter of water, and the aquous mixture was extracted with ether. The ethereal extract solution was washed with 1 N potassium hydroxide and then with water, dried and evaporated, leaving 55 gm of methyl 2-(4-formyl-phenoxy)-propionate as an oil, which was purified by passing it through a silicagel column with chloroform as the flow agent.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:19](=[C:20]([C:22]([NH2:24])=[O:23])[CH:21]=2)[NH:18][CH:17]=[C:16]3[CH:25]2[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:33])=[O:32])[CH2:27][CH2:26]2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].Br[C:37]1[CH:42]=CC(CCNC(=O)C)=C[CH:38]=1>>[CH:2]1([C:1]([NH:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]=[C:15]4[C:19](=[C:20]([C:22]([NH2:24])=[O:23])[CH:21]=3)[NH:18][CH:17]=[C:16]4[CH:25]3[CH2:30][CH2:29][N:28]([S:31]([CH2:34][CH3:35])(=[O:32])=[O:33])[CH2:27][CH2:26]3)=[CH:9][CH:8]=2)=[O:3])[CH2:42][CH2:37][CH2:38]1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CCNC(C)=O)cc4)cc23)CC1
Reactant: CC(=O)NCCc1ccc(Br)cc1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CCNC(=O)C5CCC5)cc4)cc23)CC1
Yield: 48.3 %

Procedure:
The title compound was prepared according to the general procedure of 5-{4-[2-(acetylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, substituting N-[2-(4-bromophenyl)ethyl]cyclobutanecarboxamide (100 mg, 0.324 mmol) for N-[2-(4-bromophenyl)ethyl]acetamide. Purified by flash chromatography to afford 28 mg of the title compound (48.3%).
Reaction SMILES: [CH2:1]([N:3]([CH2:17][CH3:18])[C:4](=O)[CH:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH3:6])[CH3:2].O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:3]([CH2:4][CH:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[CH3:6])[CH2:17][CH3:18])[CH3:2]
Reactant: CCN(CC)C(=O)C(C)Nc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CC(C)Nc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 93.7 %

Procedure:
2.31 g of N,N-diethyl 2-(3,4-dichloroanilino)propionamide were dissolved in 15 ml of dry tetrahydrofuran. This solution was added dropwise in 5 minutes to a stirred suspension of 0.61 g of lithium-aluminium-hydride in 25 ml of dry tetrahydrofuran. The reaction mixture was refluxed for 6 hours and was left to stand overnight. The next day 0.6 ml of water, 1.5 ml of 15% sodium hydroxide solution and 1.5 ml of water were added successively. After filtration the organic layer was washed with water, dried and filtered. After evaporating the solvent, 2.06 g of the desired product were obtained; identification by means of thin-layer chromatography. The product was purified by means of columnchromatography (acetone as an eluent), after which 1.41 g or an orange oil was obtained; nD25 =1.5404.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13])[CH3:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][Cl:19]>>[Cl:19][CH2:18][CH2:17][CH2:16][CH2:15][C:3]1([CH2:1][CH3:2])[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:13]
Reactant: CCC1C(=O)Nc2cc(F)ccc21
Reactant: ClCCCCBr
Product: CCC1(CCCCCl)C(=O)Nc2cc(F)ccc21

Procedure:
The title compound is prepared according to process E starting from 3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1-bromo-4-chloro-butane.