Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]12[CH2:8][C:5]([NH:9]C(=O)OCC3C=CC=CC=3)([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.CO.[H][H].[OH-].[NH4+].CO.C(Cl)[Cl:29]>[Pd].O>[ClH:29].[NH2:9][C:5]12[CH2:8][C:2]([OH:1])([CH2:7][CH2:6]1)[CH2:3][CH2:4]2
Reactant: ClCCl
Reactant: O=C(NC12CCC(O)(CC1)C2)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cl
Product: NC12CCC(O)(CC1)C2
Yield: 97 %

Procedure:
A 2-L Parr bottle was charged with benzyl 4-hydroxybicyclo[2.2.1]heptan-1-ylcarbamate (61 g, 233 mmol), methanol (400 mL), and water (200 mL). The Parr bottle was flushed with nitrogen and charged with 10% palladium on carbon (25 g, 11.65 mmol, 50% wet with water). The reaction was run under 30 gpsi hydrogen on a parr shaker for 3 h when TLC analysis (15% methanol/DCM with 2% ammonium hydroxide) indicated a complete reaction. The reaction was filtered through a celite plug and concentrated to remove methanol. The resulting aqueous mixture was treated with 2 N hydrochloric acid (115 mL) until it reached pH 1-2. The aqueous mixture was extracted using ethyl acetate (5×400 mL) to remove an impurity. The aqueous mixture was concentrated to dryness and dried in a vacuum oven at 40° C. overnight to provide 36.91 g (97%) of 4-aminobicyclo[2.2.1]heptan-1-ol hydrochloride; MS (ESI) m/z 128.1 [M+1]+
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23.[F:16]C1C=CC(C)=C(C=1)C(O)=O>>[Br:1][C:2]1[NH:3][C:4]2[CH:5]=[C:6]([F:16])[CH:7]=[C:8]3[C:14](=[O:15])[NH:13][CH2:12][CH2:11][C:10]=1[C:9]=23
Reactant: Cc1ccc(F)cc1C(=O)O
Reactant: O=C1NCCc2c(Br)[nH]c3cccc1c23
Product: O=C1NCCc2c(Br)[nH]c3cc(F)cc1c23

Procedure:
The title compound was prepared in a manner similar to that used for 2-bromo-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, starting from 5-fluoro-2-methylbenzoic acid. 2-Bromo-8-fluoro-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one was isolated as an orange solid: m.p. 203-204° C. (dec); 1H NMR (300 MHz, d6-DMSO) δ2.79 (m, 2H), 3.41 (m, 2H), 7.29 (dd, J=8.7, 1.2 Hz, 1H), 7.74 (dd, J=10.8, 1.5 Hz, 1H), 8.23 (br t, 1H), 12.12 (br s, 1H). MS (electrospray, [M+Na]+) 305/307.
Reaction SMILES: [CH3:1]I.[CH2:3]([N:10]1[C:14]([C:15]([F:18])([F:17])[F:16])=[C:13]([CH3:19])[C:12]([Br:20])=[C:11]1[C:21]([NH:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+]>C1COCC1>[CH2:3]([N:10]1[C:14]([C:15]([F:18])([F:16])[F:17])=[C:13]([CH3:19])[C:12]([Br:20])=[C:11]1[C:21]([N:23]([CH3:1])[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:22])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: Cc1c(Br)c(C(=O)NCC(C)(C)C)n(Cc2ccccc2)c1C(F)(F)F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(Br)c(C(=O)N(C)CC(C)(C)C)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
HATU (12.6 g, 33.24 mmol) and DIPEA (12.4 ml, 69.25 mmol) were added to the ice cold solution of 1-benzyl-3-bromo-4-methyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid (10 g, 27.77) in DMF (110 mL) and it was stirred for 10 min at same temperature and then neopentyl amine (3.92 ml, 33.24 mmol) was added to the reaction mixture warmed to RT and then stirred for 15 h. Reaction mixture was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc (2×300 mL). Combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to yield crude mass of 1-benzyl-3-bromo-4-methyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide (11 g, 91.9% yield, white color solid) which directly used without further purification. Methyl iodide (3.17 mL, 51.04 mmol) was added to the ice cold solution of 1-benzyl-3-bromo-4-methyl-N-neopentyl-5-(trifluoromethyl)-1H-pyrrole-2-carboxamide (11 g, 25.52 mmol), (100%) NaH (1.2 g, 51.04 mmol) in THF (100 mL) and stirred for 2 h at RT. The reaction mass was poured onto crushed ice, extracted with EtOAc (2×200 mL). Combined organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to yield crude mass which was then purified by column chromatography (100-200 mesh Silica gel; 10% ethyl acetate/hexane Rf-value 0.6) to afford title compound (10 g, 88.05% yield, white solid).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][OH:23].O>CC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:21][CH2:22][OH:23])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: OCCBr
Reactant: Brc1cnc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: OCCN1CCN(c2ncc(Br)cn2)CC1
Yield: 46.2 %

Procedure:
To a solution of 5-bromo-2-(piperazin-1-yl)pyrimidine (0.20 g, 0.83 mmol) in acetone (10.0 mL) was added K2CO3 (0.58 g, 4.17 mmol) followed by the addition of 2-bromoethanol (0.01 g, 1.66 mmol). The resulting reaction mixture was heated to reflux for 3 h. After the completion of reaction (TLC monitoring), the reaction mixture was cooled, added water and extracted with EtOAc (2×100 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (100-200 M, 2% MeOH-DCM) to obtain the desired product (0.11 g, 47%). MS: 287.10 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([F:17])=[C:15]([CH2:18]Br)[CH:14]=[C:13]([Br:20])[C:12]=2[Br:21])[CH:9]=1)[C:5]#[N:6].[NH3:22].CO>ClCCl>[NH2:22][CH2:18][C:15]1[C:16]([F:17])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[C:12]([Br:21])=[C:13]([Br:20])[CH:14]=1
Reactant: N
Reactant: N#Cc1cc(Cl)cc(Oc2c(F)c(CBr)cc(Br)c2Br)c1
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(F)c(CN)cc(Br)c2Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.5 %

Procedure:
A mixture of 3-chloro-5-{[2,3-dibromo-5-(bromomethyl)-6-fluorophenyl]oxy}benzonitrile (0.185 g, 0.371 mmol) and 7M ammonia in methanol (5 mL, 35.0 mmol) in dichloromethane (5 mL) was stirred at RT overnight. The solvent was evaporated and the residue was purified by chromatography (MeOH:dichloromethane) to give the desired product (37 mg, 19.5%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 7.80 (d, 1H), 7.52 (t, 1H), 7.25 (t, 1H), 7.20 (d, 1H), 3.82 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:19](N1C=CN=C1)([N:21]1[CH:25]=[CH:24][N:23]=[CH:22]1)=[O:20]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][C:15]([NH:17][C:19]([N:21]3[CH:25]=[CH:24][N:23]=[CH:22]3)=[O:20])=[N:14][C:13]=2[CH3:18])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Solvent: ClCCl
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 40 °C

Procedure:
A suspension of 5-(3-Fluoro-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (17.5 mmol) and 1,1′-carbonyldiimidazole (4.26 g, 26.3 mmol, 1.5 equivalents) in CH2Cl2 (100 ml) was heated at 40° C.-reflux under argon until no starting material remains (30 min-5 hours) as determined by HPLC and NMR. When cool the solid precipitate was removed by filtration.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([O:10][C:11](=[O:24])[NH:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[C:15]([O:21][CH3:22])[C:14]=1[CH3:23])([CH3:9])([CH3:8])[CH3:7].C([O-])(O)=O.[Na+].CCOC(C)=O>C(Cl)Cl.C1COCC1>[C:6]([O:10][C:11](=[O:24])[NH:12][C:13]1[C:14]([CH3:23])=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([O:19][CH3:20])[C:18]=1[Cl:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(C)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(NC(=O)OC(C)(C)C)c1C
Temperature: -15 °C
Reaction time: 3 h

Procedure:
A solution of sulfurylchloride (6.7 ml, 79.8 mmol, 1.05 equiv) in DCM (140 mL) is added dropwise (75 min) to a cold (−15° C.) solution of (3,5-dimethoxy-2-methyl-phenyl)-carbamic acid tert-butyl ester (20.4 g, 76.3 mmol) in THF (330 ml), under an argon atmosphere. The reaction mixture is allowed to stir for 3 h at −15° C. and then poured onto a mixture of ice/H2O (400 mL), a saturated aqueous solution of NaHCO3 (400 ml), and EtOAc (400 mL). The layers are separated and the aqueous phase is extracted with EtOAc (2×200 mL). The combined organic phase is washed with H2O (3×200 mL) and brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue is purified by trituration in diethyl ether followed by silica gel column chromatography (Hex/acetone, 95:5) to afford the title compound. ESI-MS: 302.2 [MH]+, TLC: Rf=0.13 (Hex/acetone, 9:1).
Reaction SMILES: [OH-].[K+].[CH2:3]([O:10][CH2:11][C:12]([CH3:20])([CH3:19])[C:13]#[C:14][Si](C)(C)C)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O>[CH2:3]([O:10][CH2:11][C:12]([CH3:20])([CH3:19])[C:13]#[CH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C#C[Si](C)(C)C)COCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#CC(C)(C)COCc1ccccc1
Temperature: 5 °C
Reaction time: 3.5 h

Procedure:
A 30 L jacketed reactor was charged with methanol (6 vol) which was then cooled to 5° C. Potassium hydroxide (85%, 1.3 equiv) was added to the reactor. A 15-20° C. exotherm was observed as the potassium hydroxide dissolved. The jacket temperature was set to 25° C. A solution of 4-benzyloxy-3,3-dimethyl-1-trimethylsilylbut-1-yne (1.0 equiv) in methanol (2 vol) was added and the resulting mixture was stirred until reaction completion, as monitored by HPLC. Typical reaction time at 25° C. is 3-4 h. The reaction mixture is diluted with water (8 vol) and then stirred for 0.5 h. Hexanes (6 vol) was added and the resulting mixture was stirred for 0.5 h. The phases were allowed to settle and then the aqueous phase (pH 10-11) was drained off and discarded. The organic phase was washed with a solution of KOH (85%, 0.4 equiv) in water (8 vol) followed by water (8 vol). The organic phase was then concentrated down using a rotary evaporator, yielding the title material as a yellow-orange oil. Typical purity of this material is in the 80% range with primarily a single impurity present. 1H NMR (400 MHz, C6D6) δ 7.28 (d, 2 H, J=7.4 Hz), 7.18 (t, 2 H, J=7.2 Hz), 7.10 (d, 1H, J=7.2 Hz), 4.35 (s, 2 H), 3.24 (s, 2 H), 1.91 (s, 1 H), 1.25 (s, 6 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([OH:9])[C:3]=1[C:10](=[O:12])[CH3:11].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24]Cl.[O:26]1[CH2:30]CC[CH2:27]1>>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:22][O:23][CH3:24])[CH:5]=[C:4]([O:9][CH2:27][O:26][CH3:30])[C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)c1c(O)cc(O)cc1O
Reactant: COCCl
Reactant: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(O)c(C(C)=O)c(OCOC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.4 %

Procedure:
In 200 ml of anhydrous tetrahydrofuran were dissolved 30 g of 2',4',6'-trihydroxyacetophenone and 115.0 g of N,N-diisopropylethylamine, and 50.2 g of chloromethyl methyl ether was gradually added to the solution under ice cooling over a period of 20 minutes and the reaction mixture was stirred under ice cooling for 1 hour and at room temperature for 4 hours to effect reaction. After the reaction, the reaction mixture was extracted with 3 l of ether, and the ether layer was washed with water (500 ml×3 times), shaken with a saturated aqueous solution of sodium chloride (300 ml×2 times), dried with anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate by distillation and the obtained residue was recrystallized from a mixed solvent of methanol and water to obtain 18.9 g (yield=41.4%) of 2'-hydroxy-4',6'-bis(methoxymethoxy)acetophenone in the form of a colorless prism.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([Br:16])[N:6]=1)=[O:4].[C:17]1(C)[CH:22]=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1.C(CC(=O)C)C(C)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10]([N:11]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:22]2[CH3:21])=[CH:9][C:8]([C:12]([F:15])([F:13])[F:14])=[C:7]([Br:16])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(Br)c(C(F)(F)F)cc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1nc(Br)c(C(F)(F)F)cc1-n1c(C)ccc1C
Temperature: 25 °C

Procedure:
3-Amino-6-bromo-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (Intermediate A4) (2 g, 6.69 mmol) was suspended in toluene (8 ml), then p-toluenesulfonic acid (TsOH) (0.115 g, 0.669 mmol) and acetonylacetone (0.941 ml, 8.03 mmol) was added. The reaction mixture was heated at reflux for 2 hrs and allowed to cool to RT overnight. The resulting dark red/black solution was concentrated in vacuo to remove toluene and the crude residue diluted with 200 ml EtOAc, washed with NaHCO3 (50 ml), dried (MgSO4) and concentrated in vacuo to give a brown solid; LC-MS Rt=5.58 min [M+H]+ 377/379 (Method 10minLC_v002).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:18]([NH2:21])[CH2:19][CH3:20]>>[C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([NH:21][CH2:18][CH2:19][CH3:20])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)Cl)(c1ccccc1)c1ccccc1
Reactant: CCCN
Product: CCCNC(=O)C(C)(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 62° C. and MS: m/e=267 (M+) was prepared in accordance with the general method of example 1 from 2,2-diphenylpropionyl chloride and propylamine.
Reaction SMILES: [F:1][C:2]1[C:23]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][CH:21]=[C:20](F)[C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH:29]([O-:32])([CH3:31])[CH3:30].[Na+]>>[F:1][C:2]1[C:23]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:21]=[C:20]([O:32][CH:29]([CH3:31])[CH3:30])[C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]#[N:17])=[CH:18][CH:19]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)[O-]
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)N2CCN(c3ccc(C#N)cc3)CC2)c1F
Agent: [Na+]
Product: CC(C)Oc1ccc(S(C)(=O)=O)c(F)c1C(=O)N1CCN(c2ccc(C#N)cc2)CC1

Procedure:
The compound was prepared in analogy to example 359 from 4-[4-(2,6-difluoro-3-methanesulfonyl-benzoyl)-piperazin-1-yl]-benzonitrile and sodium isopropanolate. MS (m/e): 446.0 (MH+, 49%)
Reaction SMILES: C(O[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)C.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]#[N:21]>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:4]([C:5]1[CH:6]=[CH:7][N:8]=[CH:9][CH:10]=1)=[O:11].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH:20]([NH2:21])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: N#CCc1ccccc1F
Reactant: CCOC(=O)c1ccncc1
Product: NC(Cc1ccccc1F)c1ccncc1
Product: O=C(Cc1ccccc1F)c1ccncc1

Procedure:
The title compound was generated from commercially available isonicotinic acid ethyl ester and (2-fluoro-phenyl)-acetonitrile according to the general procedure D described above. The intermediates 2-(2-fluoro-phenyl)-1-pyridin-4-yl-ethanone and 2-(2-fluoro-phenyl)-1-pyridin-4-yl-ethylamine were isolated and characterized.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:32])[N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:22]([CH3:25])[C:23]=3[CH3:24])=[O:18])=[C:11]([Cl:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.Cl[C:42](OC1C=CC=CC=1)=[O:43].[NH:51]1[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1>C1COCC1>[Cl:33][C:11]1[C:12]([NH:16][C:17]([C:19]2[C:20](=[O:32])[N:21]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:22]([CH3:25])[C:23]=2[CH3:24])=[O:18])=[CH:13][C:14]([F:15])=[C:9]([CH:10]=1)[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:42]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[O:43])[CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(N)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(NC(=O)N4CCOCC4)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
To a suspension of N-(4-((2-aminopyridin-4-yl)oxy)-2-chloro-5-fluorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (234 mg, 0.5 mmol) and Et3N (0.1 mg, 1 mmol) in THF (5 mL) was added phenyl chloroformate (0.16 mg, 1 mmol). The mixture was stirred at rt for 2 hours, then morpholine (0.44 mL, 5 mmol) was added. The reaction mixture was stirred rt for 24 hours, then partitioned between aq NH4Cl (30 mL) and DCM (30 mL). The organic phase was separated and the aqueous phase extracted with DCM (30 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=50/1) to give the title compound as a white solid (145 mg, 49.9%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:29]1([S:35]([CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[ClH:20].[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][S:35]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)(=[O:36])=[O:37])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=S(=O)(CCCCCCl)c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCS(=O)(=O)c2ccccc2)CC1
Yield: 48.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.48 g) as starting compound, potassium carbonate (0.80 g) and 5-phenylsulfonylpentyl chloride (0.40 g) were reacted and treated in the same manner as in Example 199 to give 0.17 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-phenylsulfonylpentyl)piperidin-4-yl)methyl)-benzamide hydrochloride.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.Br[CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(CC)CC)C.Cl.[CH3:28][N:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:32]3[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][C:31]=3[C:5]=2[CH:4]=1
Reactant: CN1CCC(=O)CC1
Reactant: BrCCC1CCCCC1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCC2CCCCC2)C1

Procedure:
Preparation of the title compound was carried out according to General Method 8. 4-Chlorophenylhydrazine hydrochloride (1 g, 5.5 mmol), 1-bromo-2-cyclohexylethane (0.87 ml, 5.5, mmol), triethyl amine (2.31 ml, 16.6 mmol) and N-methyl-4-piperidone hydrochloride (810 mg, 5.5 mmol) were combined in ethanol (10 ml) to obtain 16 mg of 8-chloro-5-(2-cyclohexylethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole after purification on silica gel (230-400 mesh) chromatography eluting with acetone-hexane gradient. The free base was converted into its oxalate salt by treatment of oxalic acid (1 equiv.) in anhydrous THF.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3].[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=1[O:30]C>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:11])=[C:6]([C:7]([C:27]2[CH:28]=[C:23]([F:22])[C:24]([OH:30])=[C:25]([F:29])[CH:26]=2)=[O:9])[CH:10]=1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Reactant: COc1c(F)cccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1cc(F)c(O)c(F)c1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a solution of 5-bromo-2-chlorobenzoic acid (3.2 g, 13.5 mmol) in dichloromethane (40 mL), oxalyl dichloride (1.7 mL, 27.1 mmol) was added. Then N,N-dimethylformamide (50 mL) was added dropwise. After the vigorous evolution of gas ceased, the mixture was stirred at 25° C. overnight prior to removal of the volatiles under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and cooled to 0° C. Aluminum trichloride (2.7 g, 20.4 mmol) was added in portions, and the mixture was stirred for 10 minutes. Then 1,3-difluoro-2-methoxybenzene (2.0 g, 13.8 mmol) was added, and the mixture was stirred at 0° C. for 2 hours. Then the reaction was allowed to warm to 25° C. overnight. The reaction was quenched with ice-water (30 mL) and extracted with dichloromethane (2×20 mL). The combined organic layers were washed with sodium hydroxide (2 M), water, hydrochloric acid (10%), and brine prior to drying over sodium sulfate. Crude product was obtained after dichloromethane was removed under reduced pressure. The sample was dissolved in tetrahydrofuran/methanol/water (30 mL, v/v/v=2:3:1), and lithium hydroxide monohydrate (700 mg) was added. The mixture was stirred for 1 hour at 25° C. The solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×30 mL), and the extracts were washed with brine, dried over sodium sulfate, and concentrated to a crude product under reduced pressure. The residue was purified by silica column chromatography to give 1.46 g of white solid (30% yield, purity: 95%). 1H-NMR (CDCl3, 400 MHz): δ 7.59-7.62 (m, 1H), 7.49-7.50 (m, 1H), 7.36-7.42 (m, 3H); HPLC-MS method: Method 2, retention time 3.81 min; MS ES+ (m/z): 345 (M−1)−.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:4][CH:3]1[OH:33].[CH3:34][O:35][C:36]1[CH:45]=[CH:44][C:39]([CH2:40][N:41]=[C:42]=S)=[CH:38][CH:37]=1.CI.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:9]([O:8][CH:7]1[CH:2]2[N:1]=[C:42]([NH:41][CH2:40][C:39]3[CH:44]=[CH:45][C:36]([O:35][CH3:34])=[CH:37][CH:38]=3)[O:33][CH:3]2[CH2:4][CH:5]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:6]1[O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(CN=C=S)cc1
Reactant: NC1C(O)CC(COCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(CNC2=NC3C(CC(COCc4ccccc4)C(OCc4ccccc4)C3OCc3ccccc3)O2)cc1
Temperature: 25 °C
Reaction time: 28 h
Yield: 66.6 %

Procedure:
To a solution of Intermediate B (180 mg, 0.403 mmol) in dry THF (3 mL) was added a solution of 4-methoxybenzyl isothiocyanate (94%, 96 mg, 0.50 mmol) in dry THF (2 mL). The mixture was stirred at room temperature for 28 h. Solvents were evaporated under reduced pressure. The residue was dissolved in acetone (3 mL). MeI (114 mg, 0.805 mmol) was added. The mixture was stirred at room temperature for 2 h. Satd. aqueous NaHCO3 (2 mL) was added and stirred at room temperature for 10 min. The mixture was further diluted with satd. aqueous NaHCO3 (20 mL), extracted with EtOAc (2×15 mL). The combined extracts were washed with brine and dried over Na2SO4. Solvents were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with 96:3:1 EtOAc-MeOH—NH4OH (28% aqueous) to give rac-(3aS,4R,5R,6R,7aS)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-N-(4-methoxybenzyl)-3a,4,5,6,7,7a-hexahydrobenzo[d]oxazol-2-amine (159 mg, 67%) as a syrup. 1H NMR (400 MHz, CDCl3) δ 7.37-7.25 (m, 15H), 7.21 (d, J=8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 4.80 (m, 1H), 4.79 (d, J=11.3 Hz, 1H), 4.77 (d, J=10.1 Hz, 1H), 4.66 (d, J=11.5 Hz, 1H), 4.45 (s, 2H), 4.44 (d, J=11.2 Hz, 1H), 4.35 (d, J=13.9 Hz, 1H), 4.25 (d, J=13.9 Hz, 1H), 4.07 (dd, J=7.9, 5.4 Hz, 1H), 3.76 (s, 3H), 3.64 (t, J=5.8 Hz, 1H), 3.56 (dd, J=10.2, 5.0 Hz, 1H), 3.51 (dd, J=8.2, 6.5 Hz, 1H), 3.47 (dd, J=9.1, 3.8 Hz, 1H), 2.17 (dt, J=14.7, 3.4 Hz, 1H), 2.06-1.97 (m, 1H), 1.88 (ddd, J=15.2, 12.1, 3.6 Hz, 1H).