Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]([NH2:16])=[NH:15])=[N:6]1.[CH2:21]([C:24]#[N:25])[C:22]#[N:23].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].N1CCCCC1>CC(O)CCC>[NH2:23][C:22]1[C:21]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:24]([NH2:25])[N:16]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[F:1])[N:6]=2)[N:15]=1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Reactant: N#CCC#N
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCNCC1
Solvent: CCCC(C)O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(N)c1Cc1ccccc1

Procedure:
At 110° C., 200 mg (0.74 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboxamidine from Example 25A, 125 mg (0.8 mmol) of 2-benzylmalonodinitrile (preparable from malonodinitrile and benzyl bromide using a base such as potassium carbonate), 0.68 mg (0.8 mmol) of piperidine and 20 ml of 2-pentanol are stirred for 12 h. After cooling, the solvent is evaporated under reduced pressure and the residue is chromatographed over silica gel. This gives 165 mg (52.2% of theory) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH2:11])=[CH:2]1.[CH3:12][N:13]([CH3:27])[C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.[C:28](O)(=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH3:12][N:13]([CH3:27])[C:14]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH:17]([NH:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:1]([CH3:28])[CH:2]=2)[CH2:16][CH2:15]1
Reactant: NCc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CN(C)C1(c2ccccc2)CCC(NCc2cn(C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 5.1 %

Procedure:
450 mg C-(1H-indol-3-yl)-methylamine were partly dissolved in dry 1,2-dichloroethane (10 ml) under argon. After addition of 609 mg 4-dimethylamino-4-phenylcyclohexanone, glacial acetic acid (5.6 mmol), sodium sulfate (2 g) and sodium triacetoxyborohydride (770 mg), the suspension was stirred for five days at room temperature. For working up, water (20 ml) was added to the reaction mixture. The organic phase was separated off and the aqueous phase was washed twice with ether (5 ml) and then rendered strongly alkaline with sodium hydroxide solution. It was extracted with ether (2×5 ml) and ethyl acetate (4×10 ml), the combined extracts were dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained was chromatographed over silica gel with methanol/triethylamine (100:1). 52 mg N,N-dimethyl-N′-(1-methyl-1H-indol-3-ylmethyl)-1-phenyl-cyclohexane-1,4-diamine were obtained as a cis/trans mixture.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:16]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2
Reactant: Oc1cc2cccnc2nc1-c1ccccn1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4cccnc4nc3-c3ccccn3)c2cc1OC
Temperature: 140 °C
Reaction time: 48 h
Yield: 12.1 %

Procedure:
2-Pyridin-2-yl-[1,8]naphthyridin-3-ol (9 mg), 4-chloro-6,7-dimethoxyquinoline (27 mg), and 4-dimethylaminopyridine (16 mg) were suspended in o-dichlorobenzene (1.5 ml), and the mixture was stirred at 140° C. for 48 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (2 mg, yield 12%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:11]=1)[C:5]([O:7]C)=[O:6].[N:18]1([C:22]([C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][N:25]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.O>[N:18]1([C:22]([C:24]2[N:25]=[CH:26][C:27]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[CH:11]=3)[C:5]([OH:7])=[O:6])=[CH:28][CH:29]=2)=[O:23])[CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(O)c1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(O[C@H]2CCOC2)c1
Temperature: 160 °C
Yield: 58 %

Procedure:
Methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (875 mg, 3.68 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (1.06 g, 4.41 mmol), caesium carbonate (3.59 g, 11.03 mmol), and bromotris(triphenylphosphine)copper (0.69 g, 0.735 mmol) were added together in DMA (16 mL) and heated in a microwave reactor at 160° C. for 9 hours. The mixture was taken up in water (25 mL) and washed with ethyl acetate (2×20 mL). The aqueous layer was acidified with 1N hydrochloric acid (30 mL) and extracted with ethyl acetate (5×30 mL). The combined organic extract was washed with water (30 mL), brine (30 mL), dried (MgSO4), filtered and evaporated to give a brown solid which was triturated with diethyl ether to give the desired compound as a beige solid (820 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:14])([CH3:13])[N:9]=[CH:10]2)=[CH:5][C:4]=1[OH:15].[BH4-].[Na+].O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][C:8]([CH3:13])([CH3:14])[NH:9][CH2:10]2)=[CH:5][C:4]=1[OH:15]
Reactant: COc1cc2c(cc1O)CC(C)(C)N=C2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc2c(cc1O)CC(C)(C)NC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
To a solution of 223 (1.67 mg, 8.2 mmol) in ethanol (30 ml) at 0° C. was added sodium borohydride (618 mg, 16.3 mmol). The reaction mixture was stirred at rt for 3 h. Water (50 ml) was added and the aqueous layer neutralised (2M HCl) and extracted with ethyl acetate (3×60 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and concentrated in vacuo to afford the title compound (1.34 mg, 80%) as a white solid. mp=170-173° C. 1H NMR (270 MHz; DMSO-d6) 1.04 (6H, s, 2×CH3), 2.42 (2H, s, CH2), 3.70 (3H, s, OCH3), 3.72 (2H, s, CH2), 6.43 (1H, s, CH), 6.54 (1H, s, CH), 8.60 (1H, brs, NH). LC/MS (ES+) tr=1.19 min, m/z 208.23 (M++H). HRMS (ES+) calcd. for C12H17NO2 (M++H) 208.1332, found 208.1322.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:11][O:10][C:9]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]3[O:17][C:16]([CH3:26])([CH3:25])[CH2:15][CH2:14][C:13]=3[C:12]2=[O:27])[O:8]1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C=O)C.C(Cl)Cl>[N:28]([CH2:6][CH:7]1[CH2:11][O:10][C:9]2([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[C:18]3[O:17][C:16]([CH3:26])([CH3:25])[CH2:15][CH2:14][C:13]=3[C:12]2=[O:27])[O:8]1)=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(COS(C)(=O)=O)O1)C2=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CCC2=C(O1)c1ccccc1C1(OCC(CN=[N+]=[N-])O1)C2=O
Temperature: 100 °C
Yield: 14.6 %

Procedure:
To a solution of 4′-(hydroxymethyl)-2,2-dimethyl-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-5-one (316 mg, 1.0 mmol) in dichloromethane (2 mL) is added methanesulfonyl chloride (0.095 mL, 1.3 mmol) and triethylamine (0.163 mL, 1.24 mmol). The mixture is stirred at room temperature for 2 hours. The reaction mixture is washed with water (2×1.0 mL), dried over sodium sulfate and concentrated to provide (2,2-dimethyl-5-oxo-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-4′-yl)methyl methanesulfonate as a white solid (99% by LC/MS, UV 254 nm). The (2,2-dimethyl-5-oxo-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-4′-yl)methyl methanesulfonate (197 mg, 0.5 mmol) is dissolved in DMF (2 mL) followed by the addition of sodium azide (97 mg, 1.5 mmol). The reaction is heated at 80° C. for 24 hour and 100° C. for 12 h. The mixture is diluted with CH2Cl2 (4 mL), washed with water (2 ml) and concentrated. The organic layer is dried with sodium sulfate, concentrated under reduced pressure and purified by flash column chromatography (SiO2, 30% EtOAc in hexane) to provide 4′-(azidomethyl)-2,2-dimethyl-3,4-dihydro-2H,5H-spiro[benzo[h]chromene-6,2′-[1,3]dioxolan]-5-one (25 mg, 15%) as a white solid. 400 MHz 1H NMR (CDCl3) δ: 7.78-7.56 (m, 1H), 7.60-7.57 (m, 1H), 7.44-7.40 (m, 2H), 4.68-4.62 (m, 1H), 4.46-4.42 (m, 1H), 4.23 (t, J=8 Hz, 1H). 3.96-3.91 (m, 1H), 3.54-3.49 (m, 1H), 2.48-2.42 (m, 2H), 1.79 (t, J=6.8 Hz, 2H), 1.42 (d, J=3.2 Hz, 6H); LCMS: 342 [M+H].
Reaction SMILES: [S-2].[Na+].[Na+].[CH3:4][C:5]1[C:12]([C:13]#[N:14])=[C:11]([S:15]C#N)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>O.CO>[CH3:4][C:5]1[C:12]([C:13]#[N:14])=[C:11]([SH:15])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: Cc1c(C#N)ccc(SC#N)c1C#N
Agent: [Na+]
Agent: [S-2]
Solvent: CO
Solvent: O
Product: Cc1c(C#N)ccc(S)c1C#N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
At 25-35° C., a solution of 110.5 g (0.85 mol) of 60 percent pure sodium sulfide in 425 ml of water was added dropwise to a solution of 170 g (0.85 mol) of 2-methyl-4-thiocyanoisophthalonitrile in 850 ml of methanol, and the mixture was stirred at room temperature for 3 hours. The mixture was then admixed with 1000 ml of water and extracted with methyl tert-butyl ether. The aqueous phase was acidified to pH 1 using HCl, and the thiophenol was extracted with methylene chloride. The extract was washed three times with water, and the organic phase was then separated off, dried over sodium sulfate and concentrated. Yield: 150 g (99%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:9][C@@:8]2([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[C@H:4]([CH2:5][CH2:6][CH2:7]2)[CH2:3]1.Br[CH2:21][CH2:22][CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:24]Br.[CH:32](N(CC)C(C)C)(C)C.O>C(#N)C>[C:26]1([CH:23]2[CH2:24][CH2:32][N:1]([C@H:2]3[CH2:9][C@@:8]4([C:10]([O:12][CH2:13][C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=5)=[O:11])[C@H:4]([CH2:5][CH2:6][CH2:7]4)[CH2:3]3)[CH2:21][CH2:22]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: N[C@@H]1C[C@H]2CCC[C@@]2(C(=O)OCc2ccccc2)C1
Reactant: CCN(C(C)C)C(C)C
Reactant: BrCCC(CBr)c1ccccc1
Solvent: O
Solvent: CC#N
Product: O=C(OCc1ccccc1)[C@@]12CCC[C@@H]1C[C@@H](N1CCC(c3ccccc3)CC1)C2

Procedure:
The mixture of Example 48D, (3-bromo-1-bromomethyl-propyl)-benzene (1.82 g, 5.9 mmol) and N,N-diisopropylethyl amine (2.1 g, 16.2 mmol) in acetonitrile (10 ml) was stirred at 120° C. in a microwave reactor for 2 hours. Water (15 mL) was added and extracted with ethyl acetate. The combined organics were dried and concentrated. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate from 50:1 to 10:1) to provide the title compound as an oil. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.10-7.31 (m, 10H), 5.01-5.08 (s, 2H), 3.17 (d, 2H), 2.76 (q, 1H), 2.52-2.69 (m, 1H), 2.35-2.48 (m, 1H), 2.17-2.22 (m, 1H), 1.82-2.15 (m, 5H), 1.61-1.80 (m, 6H), 1.39-1.60 (m, 5H), 1.17-1.27 (m, 1H).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([C:10](=O)[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15]C=2)=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:20]([OH:22])C.Cl.[CH3:24][NH:25][C:26]([NH2:28])=[NH:27].C([O-])([O-])=O.[K+].[K+]>O>[NH2:28][C:26]1[N:25]([CH3:24])[C:20](=[O:22])[C:10]([C:8]2[S:9][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=2)([C:11]2[CH:13]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:27]=1
Reactant: CCCCc1ccc(C(=O)C(=O)c2ccccc2)s1
Reactant: CCO
Reactant: CNC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCc1ccc(C2(c3ccccc3)N=C(N)N(C)C2=O)s1
Temperature: 25 °C

Procedure:
1-(5-butyl-thiophen-2-yl)-2-phenyl-ethane-1,2-dione was dissolved in a solution containing ethanol (15 mL) and water (3 mL). Into this mixture was added 1-methylguanidine hydrochloride (0.32 g, 3 mmol), and followed by K2CO3 (1.2 g, 0.9 mmol). The reaction was set to reflux 3 h, and then cooled to room temperature and the ethanol removed under reduced pressure. The crude product was taken in water (50 mL) and extracted with CHCl3 (3×). The organic layers were separated and combined, then dried over MgSO4, filtered and stripped. The crude product was purified by flash chromatography on silica gel in 10% methanol/ethyl acetate. A white solid was obtained. MS m/e 328 (M)+; 1HNMR (DMSO-d6, 300 MHz) δ 0.9 (m, 3H), 1.2 (m, 2H), 1.5 (m, 1H), 2.6 (t, 2H), 2.95 (s, 3H), 6.5 (s, 1H), 6.6 (b, 2H), 6.8 (s, 1H), 7.2 (m, 3H), 7.5 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14](O)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:59][N:60]1[C:64]([NH2:65])=[CH:63][C:62]([CH3:66])=[N:61]1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:65][C:64]3[N:60]([CH3:59])[N:61]=[C:62]([CH3:66])[CH:63]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: Cc1cc(N)n(C)n1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)[C@H]2CCCN(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)n(C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
In a 100 mL round-bottomed flask, To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol) and HATU (201 mg, 0.527 mmol) in DMF (3 mL) was added Hunig's base (0.15 mL, 0.88 mmol), and the mixture was stirred at room temperature for 15 minutes. 1,3-Dimethyl-1H-pyrazol-5-amine (59 mg, 0.53 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed the reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (190 mg) as a yellow solid. LC-MS (ES) m/z=435 [M+H]+.
Reaction SMILES: FC1C(F)=CC(C2C=CC(OCC3C=CC=C4C=3C=CN4C(=O)CCC(O)=O)=CC=2)=C(OC)C=1.[F:35][C:36]1[C:41]([F:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH2:50][C:51]3[CH:59]=[CH:58][CH:57]=[C:56]4[C:52]=3[CH:53]=[CH:54][NH:55]4)=[CH:45][CH:44]=2)=[C:38]([O:60][CH3:61])[CH:37]=1.[CH3:62][C:63]1([CH3:70])[CH2:68][C:67](=[O:69])[O:66][C:64]1=[O:65]>>[F:35][C:36]1[C:41]([F:42])=[CH:40][C:39]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH2:50][C:51]3[CH:59]=[CH:58][CH:57]=[C:56]4[C:52]=3[CH:53]=[CH:54][N:55]4[C:67](=[O:69])[CH2:68][C:63]([CH3:70])([CH3:62])[C:64]([OH:66])=[O:65])=[CH:45][CH:44]=2)=[C:38]([O:60][CH3:61])[CH:37]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3[nH]ccc23)cc1
Reactant: CC1(C)CC(=O)OC1=O
Agent: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2ccn3C(=O)CCC(=O)O)cc1
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2ccn3C(=O)CC(C)(C)C(=O)O)cc1

Procedure:
4-[4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-2,2-dimethyl-4-oxo-butyric acid was synthesized by a procedure similar to 4-[4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-indol-1-yl]-4-oxo-butyric acid from starting materials 4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indole and 2,2-dimethyl-succinic anhydride to yield the product as a white solid (13 mg, 27%). LC-MS (ES) calculated for C28H25F2NO5, 493.2; found m/z 494 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1.Cl.[CH:21]12[CH2:27][CH:24]([CH2:25][CH2:26]1)[CH2:23][CH:22]2[NH2:28].C(N(CC)CC)C.O1CCOCC1>O>[C@H:21]12[CH2:27][C@H:24]([CH2:25][CH2:26]1)[CH2:23][C@@H:22]2[NH:28][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:13])=[CH:4][N:3]=1
Reactant: NC1CC2CCC1C2
Reactant: O=C(c1cnc(Cl)nc1C(F)(F)F)N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1cnc(N[C@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
A mixture of 4-{[2-chloro-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}morpholine (150 mg), rac-(1S,2R,4R)-bicyclo[2.2.1]heptan-2-amine hydrochloride (300 mg), triethylamine (354 μL), and 1,4-dioxane (1.5 mL) was stirred at room temperature for 3 hours. To the reaction mixture was added water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate), and the obtained colorless oil was solidified from hexane-ethyl acetate to obtain rac-N-[(1R,2S,4S)-bicyclo[2.2.1]hept-2-yl]-5-(morpholin-4-ylcarbonyl)-4-(trifluoromethyl)pyrimidin-2-amine (132 mg) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][NH:7][C:6](=[O:15])[C:5]=3[C:4]=2[CH2:3]1.[F:16][C:17]1[CH:18]=[C:19]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]1[CH2:24][CH2:23][CH:22]([CH:30]=O)[CH2:21][C:20]2=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25]1[CH2:24][CH2:23][CH:22]([CH2:30][NH:1][CH:2]3[CH2:14][O:13][C:12]4[CH:11]=[CH:10][C:9]5[CH2:8][NH:7][C:6](=[O:15])[C:5]=5[C:4]=4[CH2:3]3)[CH2:21][C:20]2=1
Reactant: NC1COc2ccc3c(c2C1)C(=O)NC3
Reactant: O=CC1CCc2[nH]c3ccc(F)cc3c2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C1NCc2ccc3c(c21)CC(NCC1CCc2[nH]c4ccc(F)cc4c2C1)CO3
Reaction time: 0.67 h

Procedure:
To a mixture of (1) (60 mg, 0.294 mmol), 6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3-carbaldehyde ((28), 64 mg, 0.294 mmol) in acetic acid (38 mg, 0.588 mmol) and methanol (3 ml) was added NaBH3CN (37 mg, 0.588 mmol) in portions. The resulting mixture was stirred for 40 min. The solvent was removed in vacuo and the residue was dissolved in methylene chloride. The organic solution was washed with 1N NaOH and saturated NaCl before being dried over with Na2SO4. The concentration of organic solution in vacuo gave crude (27), which was purified on silica gel eluting with 80% EtOAc/Hexane to give a white solid (71 mg, 60%). MS (ES) m/z 406.2
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:5]([C:13]([OH:15])=O)[CH2:4][N:3]1[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17].[CH3:29][C:30]1[C:31]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[N:32][C:33]([CH3:36])=[CH:34][N:35]=1>>[CH3:29][C:30]1[C:31]([N:37]2[CH2:38][CH2:39][N:40]([C:13]([CH:5]3[CH2:4][N:3]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:26])([F:28])[F:27])(=[O:18])=[O:17])[C:2](=[O:1])[N:6]3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[O:15])[CH2:41][CH2:42]2)=[N:32][C:33]([CH3:36])=[CH:34][N:35]=1
Reactant: Cc1cnc(C)c(N2CCNCC2)n1
Reactant: O=C(O)C1CN(S(=O)(=O)c2ccccc2C(F)(F)F)C(=O)N1c1ccccc1
Product: Cc1cnc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4C(F)(F)F)C(=O)N3c3ccccc3)CC2)n1

Procedure:
In analogy to example 1, (RS)-2-oxo-3-phenyl-1-(2-trifluoromethyl-benzenesulfonyl)-imidazolidine-4-carboxylic acid (example 11) was coupled with 3′,6′-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (CAS [59215-42-8]) to give the title compound as a colorless solid. MS: 589.0 ([M+H]+)
Reaction SMILES: C([O:8][C:9]([NH:11][C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([OH:16])=[O:15])=O)C1C=CC=CC=1.[CH3:19]C(C)(CC(OC)=O)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[N:11]([C:12]([CH3:18])([CH3:17])[CH2:13][C:14]([O:16][CH3:19])=[O:15])=[C:9]=[O:8]
Reactant: COC(=O)CC(C)(C)C(=O)O
Reactant: CC(C)(CC(=O)O)NC(=O)OCc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CC(C)(C)N=C=O
Temperature: 5 °C

Procedure:
3-(Benzyloxycarbonylamino)-3-methylbutanoic Acid. A solution of 2,2-dimethyl-3-carbomethoxypropionic acid (LeMaul, Bull. Soc. Chim. Fr., 828 (1965), 20 g, 0.125 mol), diphenylphosphorylazide (34.3 g, 0.125 mol) and triethylamine was heated in toluene (150 ml) at 100° C. for 2 h After cooling to 5° C., the toluene solution was washed successively with 0.5M HCl, aqueous NaHCO3 and brine. Evaporation of the dried solution gave a residue which was chromatographed on silica gel eluting with 60/40 hexane-ether. There was obtained 13 g of methyl 3-isocyanato-3-methylbutanoate as a mobile liquid. A solution of this material in toluene (20 ml) was treated with benzyl alcohol (13 ml) and the resulting mixture heated at reflux for 40 h. Evaporation of the toluene left a residue which was dissolved in methanol (125 ml) and then treated with a solution of NaOH (6.6 g, 0.165 mol) in 22 ml of water. After 5 h, the reaction mixture was partially evaporated, washed with ether and acidified with 6N HCl. Extraction with methylene chloride and evaporation gave 21 g of the desired product. NMR (300 MHz, CDCl3): 1.42 (s,6H), 2.78 (s,2H), 5.08 (s,2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14](OC)=[O:15])=O)(=[O:3])[CH3:2].O.[NH2:30][NH2:31].[OH-].[Na+]>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([C:10]2[CH2:12][CH2:13][C:14](=[O:15])[NH:30][N:31]=2)[CH:18]=1)(=[O:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC(O)CNC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(C2=NNC(=O)CC2)c1

Procedure:
A solution of methyl 3-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate (0.21 g) and hydrazine hydrate (0.12 ml) in glacial acetic acid (5 ml) was heated under reflux for 16 hours. Evaporation of the reaction mixture under reduced pressure gave a glassy residue to which was added sodium hydroxide solution (2N, 10 ml). The resulting solution was extracted well with chloroform, the combined organic phases washed with water, dried and evaporated to give a white brittle residue which was recrystallised from isopropanol/ether to give 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone as a white solid (0.16 g, 80% m.p. 102°-109°C; M+ 376, M 376).