Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][C:15]#[N:16])[C:8](=[O:17])[C:7]12[O:22][CH2:21][CH2:20][CH2:19][O:18]1)([O-])=O.N.C1COCC1>[Ni].CCO>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][CH2:15][NH2:16])[C:8](=[O:17])[C:7]12[O:22][CH2:21][CH2:20][CH2:19][O:18]1
Reactant: N#CCCN1C(=O)C2(OCCCO2)c2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Product: NCCCN1C(=O)C2(OCCCO2)c2cc(N)ccc21
Yield: 73 %

Procedure:
A mixture of 3-(5′-nitro-2′-oxospiro[1,3-dioxane-2,3′-indol]-1′(2′H) -yl)propanenitrile (2.12 g, 7.76 mmol) and wet Raney Nickel (2.29 g) in 2M EtOH.NH3 (95 mL) and THF (35 mL) was hydrogenated in a Parr Hydrogenation Bottle at 50 lb/in2 H2 for 17 hr. The Raney Nickel was removed by filtration through Celite and the filtrate was concentrated. The crude product was purified on Biotage KP silica gel eluting with a step gradient of CH2Cl2/CH3OH/NH4OH (95/3/2) to (85/10/5) to give the title compound as a yellow foam (1.57 g, 73% yield). NMR (300 Mz, DMSO-d6): consistent
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][NH:6][C:7](=[O:28])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[CH:24][C:23](Br)=[C:22]([Cl:27])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[Cl:30][C:31]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=1B(O)O>>[CH3:18][CH:16]([CH3:17])[CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:29])=[O:28])=[CH:9][CH:10]=1)[O:19][C:20]1[CH:25]=[CH:24][C:23]([C:34]2[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][C:35]=2[Cl:37])=[C:22]([Cl:27])[CH:21]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2ccc(Br)c(Cl)c2)cc1
Product: CC(C)CC(Oc1ccc(-c2ccc(Cl)cc2Cl)c(Cl)c1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compounds are prepared in a manner substantially similar to Example 24 starting from 3-{4-[1-(4-bromo-3-chloro-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester and 2,4-dichlorophenyl boronic acid. The isomers are resolved by methods described herein or known to one skilled in the art. Isomer 1 MS: 533.2 [M−H]−; Isomer 2 MS: 533.2 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:20]([C:17]3[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=3)(=[O:22])=[O:21])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2[nH]cc(I)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 3.4 %

Procedure:
To a stirred solution of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (16.82 g, 52.23 mmol) in 522 mL of anhydrous THF cooled to 0° C. with an ice bath was added NaH [60% dispersion in mineral oil] (3.76 g, 156.7 mmol). The reaction mixture was stirred for 20 min at 0° C., after which p-toluenesulfonyl chloride (14.88 g, 78.3 mmol) was added. The resulting mixture was stirred at 0° C. for 1.5 hr, after which cold 0.5 M HCl (20 mL) was added. The mixture was partitioned between EtOAc and 0.5 M HCl, after which the organic layer was separated, dried over MgSO4, filtered, and evaporated in vacuo to yield a residue that was triturated with 20% CH2Cl2 in hexanes to yield the title compound (0.84 g, 81%) as a light yellow powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.51 (d, J=2.1 Hz, 1H), 8.22 (s, 1H), 8.02 (d, J=1.2 Hz, 1H), 8.00 (d, J=5.1 Hz, 2H), 7.44 (dd, J=8.7 Hz, 0.6 Hz, 2H), 2.35 (s, 3H); MS ESI (m/z): 477.0/479.0 (M+1)+, calc. 476.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[NH:12][C:11]2[C:10](=[O:13])[N:9]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[C:8](=[O:18])[N:7]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:6]=2[N:5]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl>O1CCCC1.O>[CH:15]1([CH2:14][N:9]2[C:10](=[O:13])[C:11]3[NH:12][C:4]([NH:3][S:31]([C:28]4[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=4)(=[O:33])=[O:32])=[N:5][C:6]=3[N:7]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:8]2=[O:18])[CH2:16][CH2:17]1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc2c([nH]1)c(=O)n(CC1CC1)c(=O)n2CC1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)Nc2nc3c([nH]2)c(=O)n(CC2CC2)c(=O)n3CC2CC2)cc1
Reaction time: 0.5 h
Yield: 30.8 %

Procedure:
Sodium hydride (0.31 g of a 60% suspension in oil, 2.1 eq) was added to a suspension of 8-amino-1,3-di(cyclopropylmethyl)xanthine (1 g, 3.64 mmol) in tetrahydrofuran (25 ml). After 30 minutes, 4-methoxybenzenesulphonyl chloride (0.82 g, 1.1 eq) was added and stirring continued for 48 hours. The reaction mixture was poured into water, acidified with dilute hydrochloric acid and extracted into ethyl acetate. The combined organic solutions were dried (MgSO4), filtered and concentrated. The crude residue was purified by column chromatography over silica in 2-5% methanol/dichloromethane to afford 1,3-di(cyclopropylmethyl)-8-(4-methoxybenzenesulphonylamino )xanthine (0.50 g, 31%) as a white solid m.pt>200° C. (decomp.)
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([C:17]#[N:18])=[CH:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[BH4-].[Na+].[OH-].[Na+].C(OCC)(=O)C>CO>[CH2:1]([O:3][P:4]([CH:9]([C:17]#[N:18])[CH2:10][CH:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(OCC)C(C#N)=CC1CCOCC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCOP(=O)(OCC)C(C#N)CC1CCOCC1
Reaction time: 2 h

Procedure:
To a solution of [1-cyano-2-(tetrahydro-pyran-4-yl)-vinyl]-phosphonic acid diethyl ester (7.45 g, 27.1 mmol) in methanol (200 mL) was added sodium borohydride (5 g, 135 mmol, 5 pellets), portion wise over 1.5 hours. The resulting mixture was stirred an additional 2 hours. The solvent was evaporated in vacuo to yield an oil, to which was added 0.1N NaOH and ethyl acetate. The layers were separated, and the organic layer was dried with MgSO4 and filtered. The solvent was removed to yield an oil which was purified via silica column chromatography (50% EtOAc/heptane) to yield an oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[C:27]1([C:34](=[NH:36])[NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]1[CH3:33]>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:36]=[C:34]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: CC1C=CC=CC1(O)C(=N)N
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4C)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 33 mg (0.22 mmol, 1.1 eq.) of 1-hydroxy-2-methylbenzenecarboximidamide were reacted according to the General Method 1. Yield: 62 mg (68% of theory)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[OH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[C:5]([C:11]#[N:12])=[C:6]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[N:7]=1
Reactant: OCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. ES-MS m/e (%): 294 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:20]4=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]4[CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:4][CH2:3]1.CC(O)=O>C1COCC1.[Pt](=O)=O>[CH3:1][C:2]1([CH3:27])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[C:20]4=[N:21][S:22](=[O:26])(=[O:25])[CH2:23][CH2:24][N:19]4[CH2:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CC=C(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)CC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)CCC(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.9 %

Procedure:
Platinum(IV) oxide (40 mg) was added to a solution of 9-{4-[(4,4-dimethylcyclohex-1-en-1-yl)oxy]phenyl}-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (340 mg) in THF (dry) (30 mL), NeOH (30 mL) and AcOH (10 mL). The mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc, to remove catalytic poison). Platinum(IV) oxide (40 mg) was added and the mixture was stirred at 50° C. under hydrogen for 6 hr. Platinum(IV) oxide was added and the mixture was stirred 50° C. under hydrogen for 12 hr. The insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo with silica-gel. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo. The residue was crystallized from EtOAc/hexane. This was dissolved in THF, silica-gel was added to the solution and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc). The residue was crystallized from THF-EtOAc/IPE to give the title compound (37.6 mg) as colorless crystals.
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:18][CH2:19][C:20]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:21]=2[C:22](Cl)=[O:23])[CH:17]=1>[OH-].[Na+].C(OCC)C.O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:30][CH3:31])=[C:16]([CH2:18][CH2:19][C:20]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:21]=2[C:22]([NH:10][C:8](=[NH:9])[S:7][CH3:6])=[O:23])[CH:17]=1
Reactant: COc1ccc(Br)cc1CCc1c(F)cccc1C(=O)Cl
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(Br)cc1CCc1c(F)cccc1C(=O)NC(=N)SC
Reaction time: 3.5 h

Procedure:
A solution of 2-methyl-2-thiopseudourea sulfate (1.6 g, 5.75 mmol, 2.5 equiv) in 1N NaOH (10 mL) was cooled to 0° C. To this solution was added dropwise a solution of 2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorobenzoyl chloride (2.3 mmol, 1 equiv) in diethyl ether (4 mL). The solution was allowed to stir for 3.5 hr and then diluted with H2O. The aqueous solution was extracted with dichloromethane and the combined organic phases were dried over Na2SO4, filtered, and concentrated to give 1-{2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorobenzoyl}-2-methylisothiourea in quantitative yield. The crude product was used without further purification. 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.2 Hz, 1H), 7.07-7.30 (m, 4H), 6.68 (d, J=8.1 Hz, 1H), 3.73 (s, 3H), 3.27-3.33 (m, 2H), 2.84-2.90 (m, 2H), and 2.52 (s, 3H).
Reaction SMILES: [O:1]1[CH2:18][C@H:2]1[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10].[C:19]1([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C.[C:41]1([CH3:51])[CH:46]=[CH:45][C:44]([S:47]([OH:50])(=[O:49])=[O:48])=[CH:43][CH:42]=1>CO>[C:41]1([CH3:51])[CH:42]=[CH:43][C:44]([S:47]([OH:50])(=[O:48])=[O:49])=[CH:45][CH:46]=1.[OH:1][C@@H:2]([CH2:18][N:32]1[CH2:33][CH2:34][CH:29]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:30][CH2:31]1)[CH2:3][O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[CH:7]=[C:8]1[CH2:13][CH2:12][O:11][C:9]1=[O:10]
Reactant: O=C1OCCC1=Cc1ccccc1OC[C@@H]1CO1
Reactant: c1ccc2c(C3CCNCC3)cccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1OCCC1=Cc1ccccc1OC[C@@H](O)CN1CCC(c2cccc3ccccc23)CC1

Procedure:
The reaction was performed in same manner as in Example 307 using (S)-α-(2′-(2,3-epoxypropan-1-yloxy)benzylidene)-γ-butyrolactone (5.8 g) and 4-(naphthalen-1-yl)piperidine (5.0 g) in methanol (100 ml) and the obtained oil was treated with ethyl acetate/p-toluenesulfonic acid to give the title compound (7.8 g), melting point 119–121° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:29])C=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:12]([O:29]2)[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(c3ccc(Cl)cc3)OC2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-(4-Chloro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.8 g, 13 mmol) in CH2Cl2 (50 mL) was added 3-chloroperbenzoic acid (3.8 g, 17.0 mmol) and triethylamine (3.6 mL, 20 mmol). The solution was stirred at room temperature for about 4 hours. A white precipitate was observed. The reaction was quenched with aqueous sodium bicarbonate, extracted with CH2Cl2, and the organic layers were evaporated in vacuo. The residue was purified by flash chromatography on silica gel (35 g SiO2, gradient elution from 100% hexane to 100% ethyl acetate) to yield the title compound as a colorless oil.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[F:14][C:15]([F:25])([F:24])[C:16]1[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=[CH:20][CH:21]=1.B(OC)(OC)[O:27]C.N>CCCCCC>[CH3:23][O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([F:24])([F:25])[F:14])[C:17]=1[OH:27]
Reactant: COB(OC)OC
Reactant: COc1cccc(C(F)(F)F)c1
Agent: CN(C)CCN(C)C
Agent: N
Agent: [Li]CCCC
Solvent: CCCCCC
Product: COc1cccc(C(F)(F)F)c1O
Temperature: -78 °C

Procedure:
A solution containing 160 ml of 1.6 molar butyllithium in hexane, 300 ml oftetrahydrofuran and 40 ml of N,N,N',N'-tetramethylethylenediamine was cooled to -78° C. and 43.3 g of 3-trifluoromethylanisole was added with stirring under nitrogen atmosphere. The solution was allowed to warm up to room temperature and cooled then again to -78° C. after which35 ml of trimethyl borate was added. The solution was warmed up to 20° C. and 50 ml of conc. ammonia solution was added. The solvents were evaporated in reduced pressure and to the residue 60 ml of 98-100% formic acid followed with 25 ml of 35% hydrogen peroxide were added. The solution was extracted with ether-petroleum ether (1:1). The organic phasewas separated and the product was extracted with 2.5 N NaOH-solution. The aqueous phase was acidified with hydrochloric acid and the product was extracted in dichloromethane. The solvent was removed for the most part invacuo after which petroleum ether was added. The crystalline product was filtered, yield 8.5 g (18%), m.p. 51°-53° C.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([N:14]2[C:18]3=[N:19][C:20]([C:23](=O)[CH3:24])=[CH:21][N:22]=[C:17]3[N:16]=[N:15]2)[CH3:13])=[C:10]([F:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[NH2:28][O:29][CH2:30][CH2:31][OH:32]>CO>[OH:32][CH2:31][CH2:30][O:29]/[N:28]=[C:23](/[C:20]1[N:19]=[C:18]2[N:14]([CH:12]([C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:26])[N:7]=[CH:6][CH:5]=[CH:4]4)[CH3:13])[N:15]=[N:16][C:17]2=[N:22][CH:21]=1)\[CH3:24]
Reactant: NOCCO
Reactant: CC(=O)c1cnc2nnn(C(C)c3c(F)cc4ncccc4c3F)c2n1
Agent: Cl
Solvent: CO
Product: C/C(=N\OCCO)c1cnc2nnn(C(C)c3c(F)cc4ncccc4c3F)c2n1
Temperature: 45 °C
Yield: 63.8 %

Procedure:
To a solution of 1-(1-(1-(5,7-difluoroquinolin-6-yl)ethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (76.5 mg, 0.22 mmol) in MeOH (50 mL) was added 2-(aminooxy)ethanol hydrochloride (49.0 mg, 0.43 mol). The mixture was heated at 45° C. overnight. The solvent was removed under reduced pressure. The residue was purified by column chromatography with gradient (DCM/MeOH=10:1) to give the title compound as a white solid (58.0 mg, 62%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1H), 9.01 (dd, 1H), 8.52 (d, 1H), 7.74 (d, 1H), 7.63 (dd, 1H), 6.80 (q, 1H), 4.74 (t, 1H), 4.27 (t, 2H), 3.68 (m, 2H), 2.36 (d, 3H), 2.10 (s, 3H). LCMS (method A): [MH]+=414, tR=5.44 min.
Reaction SMILES: C(C1[C:12](=[O:13])C2C=CSC=2CC1)CC.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=O)[CH2:21][CH2:20][CH2:19]2.C(I)C>>[CH2:20]([CH:21]1[CH2:22][C:23]2[C:18](=[CH:17][C:16]([O:15][CH3:14])=[CH:25][CH:24]=2)[C:12]1=[O:13])[CH3:19]
Reactant: CCCC1CCc2sccc2C1=O
Reactant: COc1ccc2c(c1)CCCC2=O
Solvent: CCI
Product: CCC1Cc2ccc(OC)cc2C1=O

Procedure:
Following the procedure for the preparation of 5-propyl-6,7-dihydro-1-benzothiophen-4(5H)-one but substituting 6-methoxy 1-tetralone and ethyl iodide, and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.02, 1.55, 1.99, 2.68, 2.77, 3.27, 3.86, 7.21, 7.37; HRMS (FAB) calcd for C12H14O2+H 191.1072, found 191.1075.
Reaction SMILES: [C:1]([NH:9][C:10](=[N:13]C(OCCCC)=O)[S:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>>[C:1]([NH:9][C:10](=[NH:13])[S:11][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOC(=O)N=C(NC(=O)c1ccccc1)SC
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CSC(=N)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 128.7 %

Procedure:
To a mixture of 78b (160 mg, 0.54 mmol) and anisole (0.1 mL) was added TFA (1.0 mL). The resulting mixture was stirred for 30 min at room temperature, evaporated to dryness and put on vacuum line for 2 hours, and triturated with anhydrous Et2O to give 135 mg of 79b as a semi-solid. This crude product was used directly in the next step without further purification. 1HNMR (300 MHz, CD3OD): δ2.74 (3H, m); 7.55 (2H, t, J=7.8 Hz); 7.69 (1H, t, J=7.5 Hz); 8.02 (2H, d, J=7.5 Hz) ppm. IR (NaCl, film): 3226, 2936, 1695, 1680, 1540, 1188 cm-1.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C@H:8]1[C@H:17]2[CH2:18][CH2:19][N:20]([C:21]([C@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]3[NH2:29])=[O:22])[C@H:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9]1.C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>ClCCl>[CH3:2][C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C@H:8]1[C@H:17]2[CH2:18][CH2:19][N:20]([C:21]([C@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]3[NH:29][C:37](=[O:44])[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:22])[C@H:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9]1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1occc1[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1N
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1occc1[C@@H]1Nc2ccccc2[C@H]2[C@@H]1CCN2C(=O)[C@H]1CCCC[C@H]1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a suspension of (1R,2S)-2-{[(3aR,4R,9bR)-4-(2-methyl-3-furyl)-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinolin-1-yl]carbonyl}cyclohexaneamine hydrochloride (201 mg, 0.445 mmol) in dichloromethane (5 ml) were added triethylamine (0.203 ml, 1.47 mmol) and benzoylchloride (0.0568 ml, 0.490 mmol) under ice-cooling. The reaction mixture was stirred overnight at room temperature, water was added, and extracted with dichloromethane. The extract was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1-3:2, v/v) to give the title compound (176 mg, 82%) as an amorphous form.
Reaction SMILES: [C:1]1(=[O:14])[O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:15]>>[Br:15][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:13])=[O:14]
Reactant: Br
Reactant: O=C1CCCCCCCCCCCO1
Product: O=C(O)CCCCCCCCCCCBr
Reaction time: 16 h
Yield: 86 %

Procedure:
11.9 g (60.0 mmol) of 12-dodecanolide and 24.3 g (96.0 mmol, 1.6 equivalents) of a 32% (hydrogen bromide)/(acetic acid) solution were introduced into a 100-mL autoclave protected with Teflon (registered trademark), and the autoclave was purged with nitrogen and then sealed. The content in the autoclave was stirred with a magnetic stirrer for 16 hours by using an oil bath at 60° C. After cooling the mixture, 14 mL of water was added thereto, and the mixture was transferred into a separatory funnel by using 200 mL of hot hexane. The mixture was washed with ion-exchanged water, dried over magnesium sulfate, filtered, and crystallized from n-hexane. Thus, 14.4 g (yield: 86%) of 12-bromododecanoic acid was obtained.
Reaction SMILES: C([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:32])[CH:18]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[CH:19]([CH3:24])[C:20]([F:23])([F:22])[F:21])[C:11]=1[F:33])[C:6]([OH:8])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH:18]([CH:19]([CH3:24])[C:20]([F:23])([F:21])[F:22])[C:17]([NH:16][C:12]2[C:11]([F:33])=[C:10]([CH2:9][CH2:5][C:6]([OH:8])=[O:7])[CH:15]=[CH:14][CH:13]=2)=[O:32])=[CH:30][CH:29]=1
Reactant: CC(C(C(=O)Nc1cccc(CC(C(=O)O)C(C)(C)C)c1F)c1ccc(Cl)cc1)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C(C(=O)Nc1cccc(CCC(=O)O)c1F)c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
270 mg (0.553 mmol) of tert-butyl (+/−)-3-(3-{[2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}-2-fluorophenyl) propanoic acid (diastereomer 1, Example 102A) were dissolved in 0.2 ml of dichloromethane, and 0.85 ml of trifluoroacetic acid was added at RT. The reaction mixture was stirred at RT for 4 h and then concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (acetonitrile/water mixture). This gave 188 mg (78.7% of theory) of the target compound.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:12])=[C:7]([F:19])[CH:6]=1)(=O)C.C(N)C1C=CC=CC=1>C(O)C.CCOCC>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:12])=[C:7]([F:19])[CH:6]=1
Reactant: CCC(CC)OC(=O)c1ccc(OC(C)=O)cc1F
Solvent: CCOCC
Solvent: NCc1ccccc1
Solvent: CCO
Product: CCC(CC)OC(=O)c1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.5 Gram of the compound obtained in the above (3) was dissolved in 30 ml of ethanol, and 1.5 g of benzylamine was added dropwise thereto. Further, the mixture was stirred at room temperature for one day and diluted with 300 ml of ether, and the diluted mixture was washed with diluted hydrochloric acid and then with water and dried over magnesium sulfate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH2:10][C:11]#[N:12].[N+:13]([O-])([OH:15])=[O:14].OS(O)(=O)=O>C(O)(=O)C>[C:11]([CH2:10][C:3]1[C:4]([CH3:9])=[C:5]([N+:13]([O-:15])=[O:14])[C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])#[N:12]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C)c(CC#N)c(C)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cc(C)c([N+](=O)[O-])c(C)c1CC#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of 2,4,6-trimethylphenylacetonitrile (4.5 g) in acetic acid (40 mL) at RT was added dropwise 70% HNO3 (20 mL) and conc. H2SO4 (5 mL). The brown reaction mixture was stirred for 1 h, poured into ice-water (500 mL). The product was extracted into ethyl acetate, the extract was washed with water, dried over MgSO4 and concentrated to give 3-cyanomethyl-1-nitro-2,4,6-trimethylbenzene as an oil (5.8 g, quantitative yield).