Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Li+].Cl.[NH2:13]O.Cl>C(O)C.O>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:13]=1
Reactant: NO
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
In a 100 ml. round bottom 3-neck flask there was placed 2 g. of pivalyl acetonitrile, 25 ml. of ethanol, and 10 ml. of water. While this mixture was refluxed, a solution of 0.89 g. of lithium hydroxide and 1.5 g. of hydroxylamine hydrochloride in 25 ml. of water was added. At the end of the addition, the pH of the reaction mixture was about 7.2. The pH was adjusted to about 6.8 using concentrated aqueous hydrochloric acid. After 30 minutes the pH was about 6.0 and was readjusted to about 6.5 using an aqueous solution of lithium hydroxide. After 1 hour the pH was about 6.2 and was adjusted to about 6.8 using an aqueous solution of lithium hydroxide. At 1.5 hours the pH was about 6.6. At 2 hours the pH was about 6.7. At 21/2 hours the pH was about 6.8. At 3 hours the pH was about 7.0 and was adjusted to about 6.5 using concentrated aqueous hydrochloric acid. After 20 hours the pH was about 7.0. The reaction mixture was cooled and the ethanol stripped on the rotovapor. The solid which precipitated was filtered off and dried. It weighed 1.4 g., had a melting point of about 105°-106° C., and was determined by vpc to contain 98.5% of 3-amino-5-(t-butyl)isoxazole and 1% of 5-amino-3-(t-butyl)isoxazole. Yield: 62.5% of desired isomer.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[C:8]([OH:15])=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11].C(=O)([O-])[O-].[Na+].[Na+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:25])=[C:5]([C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20])[CH2:6][C:7]1[C:8]([O:15][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=[O:11]
Reactant: BrCc1ccccc1
Reactant: COc1c(C)c(Cc2cccc(C=O)c2O)c(OC)c(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1c(C)c(Cc2cccc(C=O)c2OCc2ccccc2)c(OC)c(OC)c1OC
Yield: 82.6 %

Procedure:
3-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzaldehyde (1.16 g, 3.35 mol) was dissolved in acetone (5 ml) and after adding thereto anhydrous sodium carbonate (1.02 g, 7.38 mmol) and benzyl bromide (0.69 g, 4.02 mmol), the solution was refluxed under heating for 3 hours. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (1.45 g, 3.32 mmol, 99%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH2:11][S:12][CH3:13].[CH:14]([Mg]Br)=[CH2:15].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[C:3]([CH2:11][S:12][CH3:13])=[C:4]2[C:5]([CH:14]=[CH:15][NH:8]2)=[CH:6][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: CSCc1c(F)cccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSCc1c(F)ccc2cc[nH]c12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 11.42 g (56.7 mmol) of the compound from Example 2A in 127 ml of tetrahydrofuran was slowly added dropwise to 284 ml (283.7 mmol) of a 0.7N solution of vinylmagnesium bromide in tetrahydrofuran under argon at −78° C., and the solution was then stirred at −78° C. for 2 h. The reaction mixture was added to an ice-cold, saturated aqueous ammonium chloride solution, some ethyl acetate was added, the phases were separated, and the aqueous phase was extracted three times with ethyl acetate. Washing of the combined organic phases with saturated aqueous sodium chloride solution was followed by drying over sodium sulfate, filtration and removal of the solvents in vacuo. Purification of the residue by flash chromatography (mobile phase: cyclohexane/toluene/dichloromethane 10/10/1) afforded 6.31 g (57% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:11]([CH3:13])[CH3:12])[CH:9]=[CH2:10])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:9]2[CH2:10][O:22]2)[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: C=CC(c1ccc(Cl)cc1)C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)C(c1ccc(Cl)cc1)C1CO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4 g of the product of Example 1 and 4.5 g of m-chloroperbenzoic acid in 50 mL of chloroform was stirred overnight at room temperature and filtered. The filtrate was washed with aqueous NaHSO3, aqueous NaHCO3, brine, dried (Na2SO4), and concentrated. The residue was a mixture of diastereomeric epoxides.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[F:20][C:21]1[C:27]([F:28])=[C:26]([F:29])[CH:25]=[CH:24][C:22]=1[NH2:23].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C1(C)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)(C)(C)C>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][CH2:10][C:4]3[CH:3]=[C:2]([NH:23][C:22]4[CH:24]=[CH:25][C:26]([F:29])=[C:27]([F:28])[C:21]=4[F:20])[CH:19]=[CH:18][C:5]=3[C:6](=[O:17])[C:7]=2[CH:14]=1
Reactant: COc1ccc2c(c1)C(=O)c1ccc(Cl)cc1CC2
Reactant: Nc1ccc(F)c(F)c1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)C(=O)c1ccc(Nc3ccc(F)c(F)c3F)cc1CC2
Yield: 72 %

Procedure:
In accordance with general method AA, 0.50 g (1.8 mmol) of 2-chloro-7-methoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one (34), 0.27 g (1.8 mmol) of 2,3,4-trifluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)2, 0.10 g (0.21 mmol) of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.60 g (6.2 mmol) of Na—O-tert-butylate, 5 ml of toluene and 1 ml of tert-BuOH are used. Reaction time: 1 h. Purification is carried out via flash chromatography (SiO2, hexane/ethyl acetate 8+2). Yield: 72%; melting point: 128° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]([CH2:30][CH2:31][CH:32]=O)([CH2:17][CH2:18][CH2:19][CH2:20][B:21]1[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]([CH3:34])[C:9]([CH2:30][CH2:31][CH2:32][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)([CH2:17][CH2:18][CH2:19][CH2:20][B:21]1[O:25][C:24]([CH3:26])([CH3:27])[C:23]([CH3:29])([CH3:28])[O:22]1)[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C1CCNC1
Reactant: CN(C(=O)OC(C)(C)C)C(CCC=O)(CCCCB1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C(=O)OC(C)(C)C)C(CCCCB1OC(C)(C)C(C)(C)O1)(CCCN1CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A solution of tert-butyl 2-(tert-butoxycarbonyl(methyl)amino)-2-(3-oxopropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (193 mg, 0.40 mmol, 1.0 equiv) and pyrrolidine (43 mg, 0.60 mmol, 1.5 equiv) in 1,2-dichloroethane (2 mL) was treated with sodium triacetoxyborohydride (168 mg, 0.80 mmol) in one portion. After stirring at room temperature overnight, the reaction mixture was quenched with saturated aqueous NaHCO3 (1 mL) and stirred for an additional 5 min. The resulting mixture was added to a separatory funnel, diluted with saturated aqueous NaCl (5 mL) and extracted with dichloromethane (2×10 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography eluting with gradient 1-10% methanol in chloroform gave tert-butyl 2-(tert-butoxycarbonyl(methyl)amino)-2-(3-(pyrrolidin-1-yl)propyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as an oil (186 mg, 88%). Rf 0.35 (10% methanol in dichloromethane). ESI MS found for C29H55BN2O6 m/z [539.4 (M+1)].
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:17])(=[O:16])[N:13]([CH3:15])[CH3:14])[CH:6]=1)=[O:4].[BH4-].[Na+].Cl>CO>[Br:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:16])(=[O:17])[N:13]([CH3:14])[CH3:15])[CH:6]=1)[OH:4]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)S(=O)(=O)c1cc(C(O)CBr)ccc1Cl

Procedure:
To a solution of 6.4 g of 2-bromo-4'-chloro-3'-dimethylsulfamoylacetophenone in 28 ml of methanol were added dropwise, at a reaction temperature of 5° C, a solution of 0.6 g of sodium borohydride in 5 ml of methanol and the solution was then stirred for 1 hour at room temperature. The reaction mixture was acidified while cooling (+5° C) with 2 N HCl and the solvent was distilled off under reduced pressure. After adding 70 ml of water, extraction followed with 200 ml of diethyl ether, the organic phase was dried over sodium sulfate, the solvent was distilled off and 2-bromo-1-(4-chloro-3-dimethylsulfamoylphenyl)-ethanol was obtained as fair yellow to colorless oil.
Reaction SMILES: [Cl-].[C:2]([C@@H:5]([O:24][CH2:25][CH3:26])[CH2:6][C:7]1[CH:23]=[CH:22][C:10]([O:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH3+:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([OH:4])=[O:3].C(N(CC)C(C)C)(C)C.[C:36]([O:40][C:41]([NH:43][C:44](=[N:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])SC)=[O:42])([CH3:39])([CH3:38])[CH3:37]>C(O)(C)C>[C:51]([O:50][C:48]([NH:47][C:44]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:22]=[CH:23][C:7]([CH2:6][C@H:5]([O:24][CH2:25][CH3:26])[C:2]([OH:4])=[O:3])=[CH:8][CH:9]=2)=[CH:20][CH:19]=1)=[N:43][C:41]([O:40][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:42])=[O:49])([CH3:54])([CH3:53])[CH3:52]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CCO[C@@H](Cc1ccc(OCCCc2ccc([NH3+])cc2)cc1)C(=O)O
Agent: [Cl-]
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCO[C@@H](Cc1ccc(OCCCc2ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)cc1)C(=O)O
Reaction time: 0.08 h
Yield: 26.9 %

Procedure:
4-(3-{4-[(2S)-2-Carboxy-2-ethoxyethyl]phenoxy}propyl)benzenaminium chloride (152 mg, 0.4 mmol) was in isopropyl alcohol (3 ml). N,N-diisopropylethylamine (0.28 ml, 1.6 mmol) was added. The mixture was stirred for 5 minutes, then 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (290 mg, 0.4 mmol) was added. The mixture was stirred at room temperature for 7 days and thereafter evaporated in vacuum to dryness. Water and ethyl acetate were added into the residue. The mixture was acidified with 1% hydrochloric acid, pH˜5 and there was some precipitation. The two phase mixture was filtered and then separated. The pH of the water phase was further adjusted to ˜3 and the water phase was extracted with ethyl acetate (×2). All organic phases were combined and washed with brine and dried with magnesium sulfate. The solvent was evaporated in vacuum. Chromatography of the residue on an ISOLUTE column (SI, 2 g/6 ml) using heptane/DCM (50:50), then DCM and MeOH/DCM (0.5: 99.5) as eluant gave the desired product (63 mg), yield 27%.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([CH2:21][CH2:22][NH:23][CH3:24])=[C:4]1[CH3:25].C=O.[C:28]([BH3-])#N.[Na+]>C(#N)C>[CH3:2][N:3]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([CH2:21][CH2:22][N:23]([CH3:28])[CH3:24])=[C:4]1[CH3:25]
Reactant: [BH3-]C#N
Reactant: CNCCc1c(C)n(C)c2ccc(S(=O)(=O)c3ccccc3)cc12
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: Cc1c(CCN(C)C)c2cc(S(=O)(=O)c3ccccc3)ccc2n1C
Temperature: 25 °C
Reaction time: 60 h
Yield: 24.7 %

Procedure:
A solution of 2-[1,2-dimethyl-5-(phenylsulfonyl)-1H-indol-3-yl]-N-methylethanamine hydrochloride (0.34 g, 0.91 mmol) and formaldehyde (37%, 1.4 mL, 18.80 mmol) in acetonitrile was treated with sodium cyanoborohydride (0.92 g, 14.69 mmol) in portions. The reaction was stirred at room temperature for 2.5 days. The reaction mixture was concentrated in vacuo and the residue partitioned between CHCl3 and NH4OH. The layers were separated and the aqueous layer was extracted with CHCl3. The organic layers were combined, washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo and subjected to column chromatography (silica gel, 75% EtOAc/hexane) to give 0.08 g (23%) of white solid as the title compound: mp 169.6-171.9° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.93-7.91 (m, 2H), 7.63-7.55 (m, 5H), 3.67 (s, 3H), 2.86-2.82 (m, 2H), 2.41-2.37 (m, 2H), 2.36 (s, 3H), 2.24 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ 142.8, 137.9, 136.8, 132.7, 130.3, 129.3, 126.8, 126.7, 118.7, 118.0, 110.2, 110.0, 59.9, 44.9, 29.7, 21.8, 9.9; IR (diffuse reflectance) 2936, 2776, 2760, 1482, 1449, 1377, 1303, 1285, 1153, 1143, 1094, 729 (s), 687, 651, 619 cm−1; HRMS (FAB) calcd for C20H24N2O2S+H 357.1637, found 357.1649; Anal. Calcd for C20H24N2O2S: C, 65.72; H, 6.88; N, 7.66. Found: C, 65.52; H, 6.71; N, 7.73.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:32])[N:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[C:19]([CH3:33])[CH:18]=1)[NH:5]C(OCC1C=CC=CC=1)=O.C1CCCCC=1>[Pd].C(O)C>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:32])[N:25]([CH3:31])[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[C:19]([CH3:33])[CH:18]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COC(=O)[C@@H](N)Cc1ccc(-c2cn(C)c(=O)n(C)c2=O)c(C)c1
Yield: 85.2 %

Procedure:
A mixture of N-(benzyloxycarbonyl)-4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester (0.34 mmol, 159 mg), cyclohexene (1 mL) and 10% palladium on carbon (100 mg) in ethanol (3 mL) was heated to reflux for 20 min. Then, it was filtered through a pad of celite and the pad was washed with ethanol (10 mL). The combined filtrate was concentrated and the residue was dried under high vacuum to afford 96 mg (85% yield) of 4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)-3-methyl-L-phenylalanine methyl ester as a sticky yellow solid. ES-HRMS m/e calcd for C17H21N3O4 (M+Na) 354.1424, found 354.1424.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2O.P(Br)(Br)[Br:15]>CN(C=O)C>[Br:15][C:5]1[C:4]2[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: BrP(Br)Br
Reactant: Oc1ccnc2c(F)cc(F)cc12
Solvent: CN(C)C=O
Product: Fc1cc(F)c2nccc(Br)c2c1

Procedure:
6,8-Difluoro-quinolin-4-ol (commercially available) (7.43 g) in DMF (200 mL) was treated with phosphorus tribromide (4.24 mL) by the method of Example (28a) to give a solid (9.03 g).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:21][C:22]([C:24]2[C:33]([NH:34]C(=O)OCC3C=CC=CC=3)=[CH:32][C:31]3[C:26](=[CH:27][C:28]([CH:45]=O)=[CH:29][CH:30]=3)[N:25]=2)=[O:23])[CH2:10]1)=O)(C)(C)C.[NH:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Br.CC(O)=O>C(Cl)Cl>[NH2:34][C:33]1[C:24]([C:22]([NH:21][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[N:11]2[CH2:12][CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10]2)=[O:23])=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([CH2:45][N:47]1[CH2:51][CH2:50][CH2:49][CH2:48]1)[CH:27]=2
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccncc2NC(=O)c2nc3cc(C=O)ccc3cc2NC(=O)OCc2ccccc2)C1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1cc2ccc(CN3CCCC3)cc2nc1C(=O)Nc1cnccc1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzyl (2-{[(4-{(3S)-3-[(tert-butoxycarbonyl)amino]piperidin-1-yl}pyridin-3-yl)amino]carbonyl}-7-formylquinolin-3-yl)carbamate (0.008 g, 0.01 mmol) (from Example 15, step 5) was mixed with pyrrolidine, DCM (0.20 mL) and sodium triacetoxyborohydride (0.020 g, 0.094 mmol). The reaction mixture was stirred at room temperature for 2 h. HBr in AcOH (8.0 M; 0.20 mL, 1.6 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. After concentration to remove the solvent, the crude product was diluted with MeOH and neutralized with a small amount of NH4OH. The mixture was filtered and purified by preparative LC-MS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with NH4OH) to give the title compound. LCMS calc. for C25H32N7O (M+H)+: m/z=446.2. Found: 446.1.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][C:14]=3[F:25])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br.Br[CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([F:25])[CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH:11]=2)=[O:9])=[CH:26][CH:27]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(F)cc(C#CCO)cc2c1O
Reactant: CCN(CC)CCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)CCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)cc(F)c21
Temperature: 95 °C

Procedure:
A solution of N-(4-chlorobenzyl)-8-fluoro-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 15 (0.96 g) is dissolved in DMF (7 mL), and K2CO3 (1.38 g) and 2-bromo-N,N-diethylethylamine hydrobromide (1.30 g) are added. The reaction mixture is heated to 95° C. for 16. Water is added and an oily solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-3% MeOH/CHCl3) gave 0.373 g of the title compound which is crystallized from ethyl acetate to give 0.163 g of a solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[S:15][C:14]2[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=2[C:12]=1[C:20]#[N:21].Cl>N1C=CC=CC=1>[C:1]([NH:10][C:11]1[S:15][C:14]2[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=2[C:12]=1[C:20]#[N:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1c(N)sc2c1CCCC2
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: N#Cc1c(NC(=O)c2ccccc2)sc2c1CCCC2
Reaction time: 2 h
Yield: 97 %

Procedure:
4.7 ml (40 mmol) of benzoyl chloride were added to a solution of 5.34 g (30 mmol) of 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene in 50 ml of pyridine. Stirring was carried out for 2 hours at 80° C. after which 150 ml of 10 mol % aqueous hydrochloric acid were added to the mixture. The solid formed was isolated in a conventional manner. Yield: 97%; mp.: 168°-170° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:21])C(=O)C1>CC#N.C(OCC)(=O)C>[Br:21][C:9]1[C:10]([NH2:13])=[N:11][CH:12]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[N:8]=1
Reactant: Nc1cnc(C2CCOCC2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1ncc(C2CCOCC2)nc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine (2.8 g, 15.6 mmol) in CH3CN (52 mL) was added NBS (2.78 g, 15.62 mmol) in two portions at 0° C. The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with ethyl acetate and was washed with saturated sodium carbonate solution, water, brine, dried and concentrated. The crude 3-bromo-5-(tetrahydro-2H-pyran-4-yl)pyrazin-2-amine (3.9 g, 97%) was used for the next step without further purification. LCMS (m/z): 258/260 (MH+), 0.52 min; 1H NMR (400 MHz, CDCl3) δ ppm 7.83 (s, 1H), 4.90 (br. s., 2H), 4.14-4.02 (m, 2H), 3.59-3.43 (m, 2H), 2.83 (d, J=5.5 Hz, 1H), 1.91-1.77 (m, 4H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[NH:2]1[CH:3]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([N:32]5[CH2:33][CH2:34][N:29]([C:24]6[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=6)[CH2:30][CH2:31]5)=[O:20])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:5]=[N:1]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCN(c2ccccn2)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-(pyridine-2-yl)piperazine (1.2 equiv) to give 168 (19.8 mg, M+1 459.1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH2:10]1[C:9]2[NH:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]=2[CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCCCC1
Reactant: Nc1ccccc1
Product: c1ccc2c3c([nH]c2c1)CCCC3
Yield: 87 %

Procedure:
Aniline was reacted with cyclohexanone in the same way as in Example 3. Tetrahydrocarbazole was formed in a yield of 87% of the theoretical yield.
Reaction SMILES: [OH:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:19]([O:1][C@H:2]1[CH2:16][CH:15]=[C:14]2[C@:4]([CH3:17])([CH2:5][C:6]3[C:7](=[CH:13]2)[O:8][C:9](=[O:12])[C:10]=3[CH3:11])[C@H:3]1[CH3:18])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1=C2C[C@@]3(C)C(=CC[C@H](O)[C@@H]3C)C=C2OC1=O
Reactant: O=C(Cl)c1ccccc1
Product: CC1=C2C[C@@]3(C)C(=CC[C@H](OC(=O)c4ccccc4)[C@@H]3C)C=C2OC1=O

Procedure:
The title compound was prepared in the same manner as in Example B2, except that the compound prepared in Example B1 was reacted with benzoyl chloride.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([N+:9]([O-])=[O:10])[C:6]([Br:12])=[CH:5][C:4]=1[F:13].[C:14](O)(=O)C.C(O)C.C(=O)([O-])[O-].[K+].[K+]>O.[Fe]>[Br:12][C:6]1[CH:5]=[C:4]([F:13])[CH:3]=[CH:8][C:7]=1[NH:9][O:10][CH3:14]
Reactant: COc1cc([N+](=O)[O-])c(Br)cc1F
Reactant: CC(=O)O
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CONc1ccc(F)cc1Br
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of 4-bromo-2-fluoro-5-nitrophenyl methyl ether (25.5 g, 102 mmol), acetic acid (250 mL), ethanol (250 mL) and iron powder (22.7 g, 408 mmol) was heated to 100 C for 4 hours. The reaction mixture was cooled to room temperature, diluted with water, neutralised by addition of potassium carbonate and filtered through Celite. The aqueous layer was extracted thrice with DCM. The combined organic layers were dried over magnesium sulfate and evaporated under vacuum to afford the title compound (15 g, 67%) as a white solid. LC-MS (ES) (M+H)+ m/z=220.