Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.FC(F)(F)S(O[C:25]1[CH2:26][O:27][C:28](=[O:33])[C:29]=1[CH:30]([CH3:32])[CH3:31])(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:30]([C:29]1[C:28](=[O:33])[O:27][CH2:26][C:25]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1])([CH3:32])[CH3:31]
Reactant: CC(C)C1=C(OS(=O)(=O)C(F)(F)F)COC1=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 66 °C

Procedure:
A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (I-11) (200 mg, 0.786 mmol), 4-isopropyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (259 mg, 0.944 mmol), Xantphos (46 mg, 0.079 mmol), palladium (II) acetate (8.8 mg, 0.039 mmol), water (0.043 mL, 2.4 mmol), and potassium carbonate (217 mg, 1.57 mmol) in toluene (20 mL) was heated at 66° C. for 16 h. After filtration through CELITE®, the filtrate was concentrated and the residue was purified on a silica gel column to give the title compound. LC/MS: (M+1)+: 379.21.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.Br[CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19]>>[C:12]([C:11]1[C:3]([C:2]([F:14])([F:1])[F:15])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:17]([CH3:22])[C:18]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5]2)#[N:13]
Reactant: N#Cc1ccc2[nH]ccc2c1C(F)(F)F
Reactant: COC(=O)C(C)Br
Product: COC(=O)C(C)n1ccc2c(C(F)(F)F)c(C#N)ccc21

Procedure:
Synthesized as described in Example 4 from 4-(trifluoromethyl)-1H-indole-5-carbonitrile and methyl 2-bromopropanoate: MS (APCI) m/z 297 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[C:18]([O:22][C:23](=[O:36])[CH:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[C:29]([F:35])[CH:28]=1)[CH3:25])([CH3:21])([CH3:20])[CH3:19].O1C2C=CC(OC3N=CC=CC=3C(O)=O)=CC=2OC1.COC(=O)COC1C=CC(CN)=C(F)C=1>>[C:18]([O:22][C:23](=[O:36])[CH:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:9]([C:8]2[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)=[N:15][CH:14]=[CH:13][CH:12]=2)=[O:11])=[C:29]([F:35])[CH:28]=1)[CH3:25])([CH3:19])([CH3:20])[CH3:21]
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Reactant: CC(Oc1ccc(CN)c(F)c1)C(=O)OC(C)(C)C
Agent: COC(=O)COc1ccc(CN)c(F)c1
Agent: O=C(O)c1cccnc1Oc1ccc2c(c1)OCO2
Product: CC(Oc1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1)C(=O)OC(C)(C)C

Procedure:
The compound of Formula (5.0.24) was prepared in a manner analogous to that described in Preparation 20, substituting 2-(4-fluoro-phenoxy)-nicotinic acid and (±)-2-(4-aminomethyl-3-fluoro-phenoxy)-propionic acid tert-butyl ester for the corresponding 2-(benzo-[1,3]-dioxol-5-yloxy)-nicotinic acid and (4-aminomethyl-3-fluoro-phenoxy)-acetic acid methyl ester materials, respectively.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:14][CH3:15])[C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[Sn].[CH2:23]([C:30]1[O:31][C:32]([CH3:36])=[C:33]([CH3:35])[CH:34]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([C:30]1[O:31][C:32]([CH3:36])=[C:33]([CH3:35])[C:34]=1[C:6]([C:5]1[CH:9]=[C:10]([CH2:14][CH3:15])[C:11]([O:12][CH3:13])=[C:3]([CH2:1][CH3:2])[CH:4]=1)=[O:8])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCc1cc(C(=O)O)cc(CC)c1OC
Reactant: Cc1cc(Cc2ccccc2)oc1C
Agent: O=C(Cl)C(=O)Cl
Agent: [Sn]
Product: CCc1cc(C(=O)c2c(Cc3ccccc3)oc(C)c2C)cc(CC)c1OC

Procedure:
The title compound was prepared according to the procedure in Example 5, step 2, using 3,5-diethyl-4-methoxybenzoic acid (10.66 g, 51.3 mmol), oxalyl chloride (4.90 mL, 56.3 mmol), N,N-DMF (2 drops), tin IV chloride (6.60 mL, 56.3 mmol) and 2-benzyl-4,5-dimethylfuran (11.4 g, 61.3 mmol) to give 22.0 g, of the title compound. 1H NMR δ1.13 (t, 6H), 1.83 (s, 3H), 2.19 (s, 3H), 2.61 (q, 4H), 3.74 (s, 3H), 3.82 (s, 2H), 7.05 (d, 2H), 7.23-7.27 (m, 3H), 7.42 (s, 2H). mass spectrum (EI), m/z 376 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:6]=2[CH:13]=1.[ClH:14].Cl.[NH2:16][C@@H:17]1[CH:22]2[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]2)[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[ClH:14].[N:19]12[CH2:24][CH2:23][CH:22]([CH2:21][CH2:20]1)[C@@H:17]([NH:16][C:10]([C:8]1[O:9][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=3[CH:7]=1)=[O:12])[CH2:18]2
Reactant: O=C(O)c1cc2cc(Br)ccc2o1
Reactant: N[C@H]1CN2CCC1CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cc(Br)ccc2o1

Procedure:
240 mg (0.98 mmol) of 5-bromobenzofuran-2-carboxylic acid, 200 mg (0.98 mmol) of (R)-3-aminoquinuclidine dihydrochloride, 450 mg (1.18 mmol) of HATU, 460 mg (3.54 mmol) of N,N-diisopropylethylamine and 2.0 ml of DMF are reacted by general method C. The reaction mixture is purified by preparative HPLC. Finally, an excess of 1N hydrochloric acid is added to the product. The solvent is removed under reduced pressure. 202 mg (53% of theory) of the title compound are isolated.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[CH3:11].CN(C)CCCN=C=NCC.[NH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[O:7])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: C[Si](C)(C)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)NC[Si](C)(C)C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a suspension of 4-bromo-3-methylbenzoic acid (25 g) and 4-(dimethylamino)pyridine (“DMAP”, 2.1 g) in CH2Cl2 (320 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (“EDC”, 22.4 g) portionwise. Then, (aminomethyl)trimethylsilane (8.6 mL) was added, while cooling to keep the internal temperature below 20° C. The reaction was stirred at room temperature overnight. Water was added under vigorous stirring, and the layers were separated. The aqueous layer was extracted twice with CH2Cl2, and the combined organic phase dried (Na2SO4), and filtered over silica gel using CH2Cl2 and methyl tert-butyl ether (MTBE) to afford the title compound (32.8 g, 94%).
Reaction SMILES: C(OC([NH:8][S:9](=[O:26])(=[O:25])[O:10][CH2:11][CH2:12][NH:13][S:14]([NH:17]C(OC(C)(C)C)=O)(=[O:16])=[O:15])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl>ClCCl>[S:9](=[O:26])(=[O:25])([O:10][CH2:11][CH2:12][NH:13][S:14]([NH2:17])(=[O:15])=[O:16])[NH2:8]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)NCCOS(=O)(=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)NCCOS(N)(=O)=O
Temperature: 20 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
To 1.5 g of 2-({[(tert-butoxycarbonyl)amino]sulfonyl}amino)ethyl tert-butoxycarbonylsulfamate in 30 ml of dichloromethane are added 30 ml of a 1/1 trifluoroacetic acid/dichloromethane mixture. After stirring for 4 hours at 20° C., the reaction mixture is concentrated under reduced pressure and taken up 3 times in ether and reevaporated. The white solid is taken up in dichloromethane and filtered under vacuum to give 700 mg of the desired product: 2-[(aminosulfonyl)amino]ethyl sulfamate.
Reaction SMILES: [N:1]1[C:10]2[CH:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][C:13]1[C:14]([CH:20]=O)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:12][C:13]1[C:14]([CH2:20][NH:11][CH:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: NC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CNC2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of 5,6,7,8-Tetrahydro-quinolin-8-ylamine and 3,5-dimethyl-pyridine-2-carboxaldehyde with NaBH(OAc)3 in CH2Cl2 gave (3,5-Dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]([O:30][C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[CH3:36])[C:11]([NH:14][C:15]2[S:19][N:18]=[C:17]([C@H:20]3[CH2:24][O:23]C4(CCCCC4)[O:21]3)[N:16]=2)=[N:12][CH:13]=1.[ClH:39].C(=O)(O)[O-].[Na+]>C(O)C>[ClH:39].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][C:8]1[CH:9]=[C:10]([O:30][C:31]2[C:32]([CH3:38])=[N:33][N:34]([CH3:37])[C:35]=2[CH3:36])[C:11]([NH:14][C:15]2[S:19][N:18]=[C:17]([C@H:20]([OH:21])[CH2:24][OH:23])[N:16]=2)=[N:12][CH:13]=1
Reactant: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(C)c(C)c1Oc1cc(Sc2ccccn2)cnc1Nc1nc([C@H](O)CO)ns1
Temperature: 75 °C
Yield: 66 %

Procedure:
A flask was charged with (S)—N-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (1.38 g, 2.50 mmol), ethanol (50 mL), and 3M HCl (1.67 ml, 5.00 mmol) and heated to 75° C. for 1 hour. The reaction was cooled to ambient temperature, and saturated aqueous sodium bicarbonate was added slowly. The mixture was extracted with ethyl acetate and dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified over silica gel (50 to 100% ethyl acetate in hexanes followed 5% methanol in ethyl acetate). The product was dissolved in 10% methanol in dichloromethane and 5 mL 2M HCl in ether was added. The solution was concentrated and dried in a vacuum oven to afford (S)-1-(5-(5-(pyridin-2-ylthio)-3-(1,3,5-trimethyl-1H-pyrazol-4-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol hydrochloride (0.958 g, 1.65 mmol, 65.9% yield) as yellow solid. Mass Spectrum (apci) m/z=472.1 (M+H−HCl).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.[I-].[K+].C1OCCOCCOCCOCCOCC[O:33][CH2:32]1.C(N(CC)CC)C.C([SiH](CCCCCC)CCCCCC)CCCCC>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C(C2C=CC=CC=2)CCP)C=CC=CC=1>[Cl:27][C:19]1[CH:18]=[C:17]([CH:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([CH:32]=[O:33])=[CH:7][N:6]=2)=[O:28])[CH:22]=[CH:21][C:20]=1[S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)cc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCC[SiH](CCCCCC)CCCCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C=O)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 146.2 %

Procedure:
A mixture of N-(5-bromo-pyrazin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (prepared as in Example 6, 5.73 g, 11.8 mmol), potassium iodide (2.2 g, 13.0 mmol), 18-crown-6 (0.62 g, 2.4 mmol), triethylamine (4.2 mL, 29.5 mmol), diphenylpropylphosphine (81 μL, 0.35 mmol), and palladium(II) acetate (80 mg, 0.35 mmol) in anhydrous N,N-dimethylformamide (95 mL) in a pressure tube was stirred under carbon monoxide at 65 psi at 25° C. for 30 min. At this time, the reaction was treated with trihexylsilane (8.42 mL, 23.6 mmol) and was stirred under carbon monoxide at 65 psi at 110° C. for 4 h. The reaction was then allowed to cool to 25° C. and was extracted with ethyl acetate (2×200 mL). The combined organic layers were successively washed with a saturated aqueous sodium bicarbonate solution (3×50 mL) and water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 1/9 to 7/3 ethyl acetate/hexanes) afforded racemized 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl-pyrazin-2-yl)-propionamide (1.53 g, 30%) as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([CH:13]2[CH2:18][CH2:17][CH:16]([C:19](O)=[O:20])[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[C:7]1([CH:13]2[CH2:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)C1CCC(c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 136 %

Procedure:
A suspension of LiAlH4 (0.56 g, 14.8 mmol, 2.0 equiv) was prepared under argon in 50 mL of anhydrous THF (50 mL) kept at 0° C. A solution of 4-phenyl-cyclohexanecarboxylic acid (1.5 g, 7.34 mmol, 1.0 equiv) in 50 mL of THF was added dropwise over a 20 min period. The reaction mixture was stirred at ambient temperature for 1.5 h and then cooled to 0° C. The excess hydride reagent was carefully quenched under argon by dropwise addition of 1 N HCl. After quenching, the reaction mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give the title product as a colorless oil (1.9 g crude) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([O:9]C1CCCO1)([C:4]#[C:5][CH:6]1[CH2:8][CH2:7]1)[CH3:3].C(O)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C[O-].[Na+]>O>[CH3:1][C:2]([OH:9])([C:4]#[C:5][CH:6]1[CH2:8][CH2:7]1)[CH3:3]
Reactant: CC(C)(C#CC1CC1)OC1CCCO1
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(O)C#CC1CC1
Temperature: 25 °C
Yield: 93.8 %

Procedure:
In a dried flask (300 ml volume), the inside of which had been flushed with nitrogen, were placed 2-methyl-2-tetrahydrofuranoxy-4-cyclopropyl-3-butyne (13.4 g, purity 97.5%, 67.3 mmol.) prepared in Example 4, ethanol (120 ml) and pyridinium p-toluenesulfonate (6.7 mg), and the resulting mixture was heated at 50° C. to 60° C. for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, 10 mg of sodium methoxide (25% methanol solution) was added to the cooled mixture and ethanol was distilled through a rotary evaporator. To the concentrate obtained was added 100 ml of water, and the mixture was subjected to extraction with two 100 ml portions of ethyl acetate. The extract was washed with an aqueous saturated sodium bicarbonate solution and a saturated saline solution, dried over anhydrous sodium sulfate and concentrated by distillation of the solvent through a rotary evaporator to give 10.8 g of a crude product. The crude product was purified by silica gel column chromatography to give 2-methyl-2-hydroxy-4-cyclopropyl-3-butyne (7.84 g, purity 98.6%, yield 92.6%) having the following physical data:
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:5]([C:29]([O:31][CH3:32])=[O:30])[CH:4]=1.C1CCN2C(=NCCC2)CC1.[CH3:44][O:45][C:46]1[C:47]([CH3:54])=[C:48]([CH:51]=[CH:52][CH:53]=1)[CH:49]=O>C(#N)C>[CH3:32][O:31][C:29](=[O:30])[C:5]1[CH:4]=[C:3]([Br:2])[CH:28]=[CH:27][C:6]=1[CH:7]=[CH:49][C:48]1[CH:51]=[CH:52][CH:53]=[C:46]([O:45][CH3:44])[C:47]=1[CH3:54]
Reactant: COc1cccc(C=O)c1C
Reactant: COC(=O)c1cc(Br)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc(Br)ccc1C=Cc1cccc(OC)c1C
Yield: 83.6 %

Procedure:
To a stirred mixture of (4-bromo-2-methoxycarbonylbenzyl)-triphenylphosphonium bromide (4) (34.2 g; 60.0 mmol), DBU (1,8-diazabicyclo(5.4.0) undec-5-ene; 20.1 g; 132 mmol), and 3-methoxy-2-methylbenzaldehyde (7.21 g; 48.0 mmol) in acetonitrile were heated at reflux temperature for 2 hours. The mixture was cooled and the solvent was evaporated. The residue was partitioned between water and ethyl acetate and the organic phase was washed with 0.1 N HCl, water, and brine. The solution was dried over MgSO4, filtered, and evaporated. The residue was crystallized from ethyl acetate and hexane to yield compound 5 (14.5 g; 84%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])[C:5]([C:17]#[N:18])=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[Br:24]N1C(=O)CCC1=O>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Br:16])[C:5]([C:17]#[N:18])=[C:4]([C:19]2[O:20][C:21]([Br:24])=[CH:22][CH:23]=2)[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: N#Cc1c(NCc2ccccc2Br)nc(N)nc1-c1ccco1
Solvent: CN(C)C=O
Product: N#Cc1c(NCc2ccccc2Br)nc(N)nc1-c1ccc(Br)o1

Procedure:
From 2-amino-4-(2-bromo-benzylamino)-6-furan-2-yl-pyrimidine-5-carbonitrile and N-bromosuccinimide in DMF. ES-MS m/e (%): 451 (M{81Br}+H+, 100), 449 (M{79Br}+H+, 95).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[C:9](=O)[CH2:8][CH2:7][CH2:6][C:5]2=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Nc1ccccc1
Reactant: O=C1CCCc2c1[nH]c1ccc(Cl)cc21
Product: Clc1ccc2[nH]c3c(c2c1)CCCC3Nc1ccccc1

Procedure:
6-Chloro-N-phenyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-one and aniline in a similar manner as described in Example 13 to give 200 mg (74% yield) of a yellow solid. 1H-NMR (CDCl3): δ 8.04 (s, 1H), 7.46 (d, 1H), 7.27-7.20 (m, 2H), 7.17 (dd, 1H), 7.10 (dd, 1H), 6.79 (m, 1H), 6.74 (m, 2H), 4.81 (m, 1H), 3.85 (s, 1H), 2.70 (m, 2H), 2.25 (m, 1H), 2.03 (m, 1H), 1.93-1.78 (m, 2H); MS m/z 295 (M−1).
Reaction SMILES: [CH:1]12[N:8]([C:9]3C=N[C:16]4[C:11](=[CH:12]C=[CH:14][CH:15]=4)[N:10]=3)[CH2:7][CH:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.C(OC([N:26]1CCC2C(NC2)C1)=O)(C)(C)C.ClC1N=C(C)C=C(C)N=1.ClC1C=NC2C(=CC=CC=2)N=1>>[CH3:14][C:15]1[CH:16]=[C:11]([CH3:12])[N:10]=[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][NH:3][CH2:2]3)[CH2:7]2)[N:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC2CNC2C1
Reactant: c1ccc2nc(N3CC4CCNCC43)cnc2c1
Agent: Cc1cc(C)nc(Cl)n1
Agent: Clc1cnc2ccccc2n1
Product: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 2, substituting (1R,6S)3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester for 3,8-diaza-bicyclo[4.2.0]octane-3-carboxylic acid tert-butyl ester and 2-chloro-4,6-dimethyl-pyrimidine for 2-chloro-quinoxaline in Step A. MS (ESI) mass calcd. for C12H18N4, 218.3; m/z found, 219.2 [M+H]+. 1H NMR (CDCl3): 6.32 (s, 1H), 4.25-4.16 (m, 1H), 4.03 (t, J=7.6, 1H), 3.75 (dd, J=7.9, 3.1, 1H), 3.62 (dd, J=14.5, 1.6, 1H), 3.15-3.05 (m, 1H), 2.94 (dd, J=14.5, 3.8, 1H), 2.67-2.56 (m, 2H), 2.28 (s, 6H), 2.11-1.98 (m, 2H), 1.77-1.64 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[CH2:6]2.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)=[C:22]=[O:23].Cl>C(#N)C>[CH3:33][O:32][C:26]1[CH:25]=[C:24]([NH:21][C:22]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[N:7]([CH:13]2[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]2=[O:20])[CH2:6]3)=[O:23])[CH:29]=[CH:28][C:27]=1[O:30][CH3:31]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: COc1ccc(N=C=O)cc1OC
Agent: Cl
Solvent: CC#N
Product: COc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
TEA (0.28 ml, 2 mmol) was added to a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione (0.37 g, 1 mmol) and 4-isocyanato-1,2-dimethoxy-benzene (0.15 ml, 1 mmol) in acetonitrile (10 mL) under nitrogen. The mixture was stirred at ambient temperature for 1 h, during which time it remained a suspension. The reaction was then monitored and determined to be complete. A 3.5% aqueous HCl solution (10 mL) was added, and the mixture stirred for 10 minutes. The solid was isolated by filtration, and the solid was washed with additional 3.5% aq. HCl (20 mL) and acetonitrile (20 mL), yielding the 1-(3,4-Dimethoxy-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (400 mg, 91%). HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 30/70 CH3CN 0.1% H3PO4 in H2O: tR=2.43 min (97%); mp. 216-218° C. 1H NMR (DMSO-d6) δ 1.79-2.12 (m, 1H, CHH), 2.25-2.47 (m, 1H, CHH), 2.62 (br. s., 1H, CHH), 2.81-3.01 (m, 1H, CHH), 3.69 (d, J=6.0 Hz, 6H, OCH3+OCH3), 4.24-4.53 (m, 4H, CH2+CH2), 5.11 (dd, J=5.0, 13.1 Hz, 1H, CHN), 6.64 (t, J=5.9 Hz, 1H, Ar), 6.82 (s, 2H, Ar), 7.18 (s, 1H, Ar), 7.44 (d, J=7.7 Hz, 1H, Ar), 7.51 (s, 1H, NH), 7.69 (d, J=7.9 Hz, 1H, Ar), 8.46 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.49, 31.20, 42.77, 47.12, 51.56, 55.28, 55.88, 103.55, 109.60, 112.56, 121.83, 122.91, 126.85, 130.25, 134.15, 142.36, 143.51, 145.03, 148.73, 155.35, 167.95, 170.99, 172.85. LCMS MH=453. Anal Calcd for: C23H24N4O6: C, 61.06; H, 5.35; N, 12.38. found: C, 59.84; H, 4.87; N, 12.13.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]1[NH:12][C:10](=[O:11])[NH:9][CH2:8]1.Br[CH2:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[CH3:22][O:21][C:19]([C:18]1[CH:23]=[CH:24][C:15]([CH2:14][N:9]2[CH2:8][CH2:7][NH:12][C:10]2=[O:11])=[CH:16][CH:17]=1)=[O:20]
Reactant: O=C1NCCN1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN2CCNC2=O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 57.4 %

Procedure:
Potassium carbonate (7.88 g; 57 mmol) was added to a solution of 4.92 g of ethylene urea (57 mmol), 5.73 g of methyl 4-bromomethylbenzoate (25 mmol) and 1.85 g of tetra-n-butylammonium iodide (5.0 mmol) in 30 mL of DMF, and the mixture was heated with stirring at 80° C. for 5 hours. After cooling, the solid was collected by filtration and washed with ethyl acetate. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate:methanol=10:1). To the light yellow oil obtained-was-added diisopropyl ether, and the precipitated solid w-as collected by filtration and dried to give 3.36 g of N-(4-methoxycarbonylphenylmethyl)imidazolin-2-one (Yield: 57.4%) as a light brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=[CH:9][C:8]=2[C:7](=[O:19])[CH2:6]1)=[O:4].BrC(Cl)(Cl)Cl.N12CCCN=C1CCCCC2.CCCCCC>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([C:15]([F:18])([F:16])[F:17])=[N:12]2)=[C:7]([OH:19])[CH:6]=1)=[O:4]
Reactant: COC(=O)C1CC(=O)c2ccc(C(F)(F)F)nc2C1
Solvent: ClC(Cl)(Cl)Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(O)c2ccc(C(F)(F)F)nc2c1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 5-Oxo-2-trifluoromethyl-5,6,7,8-tetrahydro-quinoline-7-carboxylic acid methyl ester (50.0 g, 183.01 mmol) is dissolved in methylene chloride (500 ml) and treated drop wise with a solution of bromotrichloromethane (54.43 g, 274.51 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 55.72 g, 366.02 mmol) in methylene chloride (100 ml) at 0-5° C. After the addition is complete, the reaction mixture is allowed to warm to room temperature and stirred for 1 hr where TLC analysis (4:1 hexane:ethyl acetate) shows reaction completion. The reaction mixture is diluted with ethyl acetate and then washed successively with dilute aqueous hydrochloric acid and brine. The ethyl acetate phase is dried over anhydrous sodium sulphate, filtered, and concentrated in vacuo. The residue is purified by recrystallisation from hexane:ethyl acetate to give the title compound (47.13 g, 95%) as pale yellow crystals.