Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:15][CH:14]=3)[CH:9]=[C:8]3[C:24](=[O:35])[N:25]([C:27]4[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=4[CH:29]=O)[N:26]=[C:7]3[C:6]=2[C:5]([F:36])=[CH:4][CH:3]=1.[CH2:37]([NH2:39])[CH3:38].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(#N)C.ClCCl>[CH2:37]([NH:39][CH2:29][C:28]1[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=1[N:25]1[C:24](=[O:35])[C:8]2=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH:23]=[CH:22][CH:21]=[N:20]4)=[CH:17][CH:18]=3)[C:11]3[C:2]([F:1])=[CH:3][CH:4]=[C:5]([F:36])[C:6]=3[C:7]2=[N:26]1)[CH3:38]
Reactant: O=Cc1ccccc1-n1nc2c3c(F)ccc(F)c3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: CCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CC#N
Product: CCNCc1ccccc1-n1nc2c3c(F)ccc(F)c3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(6,9-Difluoro-3-oxo-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-3,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)benzaldehyde [(Example 39) 15 mg, 0.031 mmol] was suspended in acetonitrile (1.5 mL), treated with ethylamine (0.15 mL, 0.15 mmol, 1.0 M tetrahydrofuran solution, 5 equiv), acetic acid (10 μL, 0.17 mmol, 5.6 equiv) and powdered 4 Å molecular sieves (15 mg, 1 wt equiv) and stirred for 30 minutes at ambient temperature. Sodium triacetoxyborohydride (6.6 mg, 0.031 mmol, 1 equiv) was added and the mixture was stirred for 3 hours at ambient temperature. The mixture was diluted with dichloromethane (5 mL), filtered and concentrated in vacuo. The residue was diluted with dimethylsulfoxide (1 mL) and water (0.1 mL) and treated with 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 7.0 mg, 0.031 mmol, 1 equiv). After stirring for 30 minutes, the mixture was filtered and purified by preparative reverse phase HPLC (5:95 to 95:5; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid:acetonitrile), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.24 (1H, s), 8.80 (2H, br s), 8.47 (1H, d, J=2.5 Hz), 7.82 (2H, d, J=8.7 Hz), 7.73-7.68 (3H, m), 7.64-7.58 (2H, m), 7.55-7.50 (2H, m), 7.35 (2H, d, J=8.6 Hz), 6.54 (1H, dd, J=2.4, 1.9 Hz), 5.86 (2H, d, J=3.2 Hz), 4.16 (2H, br m), 2.97-2.92 (2H, m), 0.91 (3H, t, J=7.5 Hz) ppm; high resolution mass spectrometry (ES+) m/z 511.2035 [(M+H)+; calculated for C29H25F2N6O: 511.2053].
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]([CH3:16])[C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([N:13]([CH3:15])[CH3:14])[CH:12]=1)[C:8]#[N:9].Cl>CCO>[NH2:9][CH2:8][C:7]1[CH:6]=[C:5]([N:4]([CH3:16])[CH3:3])[CH:12]=[C:11]([N:13]([CH3:14])[CH3:15])[CH:10]=1
Reactant: CN(C)c1cc(C#N)cc(N(C)C)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1cc(CN)cc(N(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.3 %

Procedure:
NaBH4 (0.067 g, 1.77 mmol, 3 eq) was added to a stirred solution of 3,5-bis(dimethylamino)benzonitrile (0.1145 g, 0.59 mmol, 1 eq) and CoCl2.6H2O (0.0161 g, 0.059 mmol, 10 mol %) in 5 ml EtOH at 50° C. After 2 h the reaction was not complete. Additional NaBH4 (0.0245 g, 0.64 mmol, 1.1 eq) was added. After 2 h the reaction was cooled to room temperature and 3 N HCl was added to pH=1-2. After stirring for 1 h the reaction was concentrated in vacuo. The residue was extracted with EtOAc (×2). The aqueous layer was adjusted to pH=8-9 with 1 N NaOH. The water was removed in vacuo. The residue was stirred with CHCl3, filtered through Celite, and dried over Na2SO4. The inorganics were filtered off, and the solvent was removed in vacuo yielding 0.0807 g (0.22 mmol, 37% yield) of the product.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([NH:8]C(=O)C)[CH:7]=1.O1CCOCC1>Cl>[Cl:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc([N+](=O)[O-])c(NC(C)=O)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])c(N)cc1Cl
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(5-chloro-4-methoxy-2-nitrophenyl)-acetamide (2 g, 8.2 mmol) in 5N HCl (20 mL) is added 1,4-dioxane (10 mL), and the mixture is stirred at 60° C. for 1.5 hours. The reaction mixture is concentrated and partitioned between EtOAc/2 N NaOH. The aqueous layers are washed with EtOAc (3×), brine, dried (MgSO4), adsorbed onto silica gel, and chromatographed (70% EtOAc/hexanes) to provide an orange powder.
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:6]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)[CH:7]=[CH2:8].C(O)(C(F)(F)F)=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH2:6]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C@H:3]([CH3:4])[CH2:2][CH:1]=[O:5])=[CH:10]1)[CH:7]=[CH2:8]
Reactant: C=CCn1ccc2ccccc21
Reactant: C/C=C/C=O
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCn1cc([C@H](C)CC=O)c2ccccc21
Yield: 70.4 %

Procedure:
Prepared according to general procedure from crotonaldehyde (125 μL, 1.50 mmol), 1-allyl-1H-indole (78.5 mg, 0.500 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −72° C. for 21 h to provide, after silica gel chromatography (7:93 EtOAc/hexanes), the title compound as a colorless oil (80 mg, 70% yield, 92% ee). IR (film) 3041, 2966, 2919, 2822, 2834, 2712, 1722, 1469, 1375, 1328, 1309, 1262, 192, 1018, 995, 929, 736 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.76 (dd, J=2.1, 2.1 Hz, 1H, CHO), 7.64 (dt, J=0.9, 7.8 Hz, 1H, ArH), 7.33-7.20 (m, 2H, ArH), 7.13 (ddd, J=0.9, 6.9, 7.8 Hz, 1H, ArH), 6.89 (s, 1H, NCH), 5.98 (ddd, J=5.4, 9.9, 22.5 Hz, 1H, CH2CHCH2), 5.20 (dd, J=1.5, 10.2 Hz, 1H, CH2CHCH2), 5.10 (dt, J=1.5, 17.1 Hz, 1H CH2CHCH2), 4.68 (d, J=5.4 Hz, 2H NCH2), 3.69 (dt, J=6.9, 21.3 Hz, 1H, ArCH), 2.88 (ddd, J=2.4, 6.6, 16.2 Hz, 1H, CH2CO); 2.71 (ddd, J=2.1, 7.2, 16.2 Hz, 1H, CH2CO); 1.44 (d, J=6.9 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ 202.8, 136.7, 133.5, 126.8, 124.1, 121.8, 119.3, 119.2, 119.0, 117.4, 109.8, 51.1, 48.9, 26.1, 21.8; HRMS (CI) exact mass calcd for (C15H17NO) requires m/z 227.1310, found m/z 227.1309. [α]D=−4.4 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AD and AD guard column (2:98 ethanol/hexanes, 1 mL/min); S isomer tr=38.7 min and R isomer tr=42.2 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]([NH:18][C@H:19]([C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=2)[CH3:20])=[O:17])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH:30]1([S:36]([NH2:39])(=[O:38])=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:4]([CH:3]=1)[C:16]([NH:18][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:39][S:36]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:38])=[O:37])=[O:27])=[CH:28][CH:29]=1)[CH3:20])=[O:17]
Reactant: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Reactant: NS(=O)(=O)C1CCCCC1
Product: C[C@H](NC(=O)c1cc(Cl)cnc1Oc1ccc(F)cc1)c1ccc(C(=O)NS(=O)(=O)C2CCCCC2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 103 from 4-[(1S)-1-({[5-chloro-2-(4-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid (step 5 of Example 44) and cyclohexanesulfonamide (Helv. Chim. Acta 1975, 58, 2321): 1H-NMR (CDCl3) δ 8.53 (1H, d, J=2.6 Hz), 8.14 (1H, d, J=2.6 Hz), 8.15–8.08 (1H, m), 7.81 (2H, d, J=8.3 Hz), 7.49 (2H, d, J=8.3 Hz), 7.22–7.10 (4H, m), 5.42–5.30 (1H, m), 3.80–3.65 (1H, m), 2.26–2.16 (2H, m), 1.98–1.85 (2H, m), 1.78–1.50 (4H, m), 1.60 (3H, d, J=7.0 Hz), 1.43–1.15 (2H, m); MS (ESI) m/z 560 (M+H)+, 558 (M−H)−.
Reaction SMILES: C(S(C[C@@H](CC1C=CC=CC=1)C(N[C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C(C)C)=[O:15])=O)(=O)=O)(C)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)(C)C=O.C(Cl)Cl.CCOCC>[NH:36]1[CH:37]=[C:33]([CH2:32][CH2:13][C:14]([NH2:16])=[O:15])[N:34]=[CH:35]1
Reactant: CC(C)[C@H](O)[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C
Agent: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: NC(=O)CCc1c[nH]cn1
Reaction time: 24 h

Procedure:
130 mg of (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-4-methylpentyl]imidazole-4-propionamide and 130 mg of p-toluenesulphonic acid in 1 ml of trimethylacetaldehyde and 10 ml of methylene chloride are left to stand at room temperature for 24 hours. Thereafter, the reaction mixture is taken up in ether and the organic phase is washed in succession with 2N sodium bicarbonate solution and water, dried and evaporated. Chromatography of the residue on 30 g of silica gel using a 200:10:1 mixture of methylene chloride, methanol and ammonia yields (S)-N-[(S)-1-[(2R or S,4R,5S)-2-t-butyl-5-isopropyl-1,3-dioxolan-4-yl]-2-cyclohexylethyl]-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]imidazole-4-propionamide as a foam, MS: 701 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C:16]=3[CH:29]=2)=[CH:8][CH:7]=1>CO.Cl.O1CCOCC1>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]=3[CH:29]=2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(-c4ncc[nH]4)nc3)cc2C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1c[nH]c(-c2ccc(-c3ccc4c(c3)CNCCO4)cn2)n1
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethylethyl 7-[6-(1H-imidazol-2-yl)pyridin-3-yl]-2,3-dihydro-1,4-benzoxazepin-4(5H)-carboxylate (50 mg, 0.13 mmol) in a mixture of methanol (2 mL) and 4N hydrochloric acid in dioxane (2 mL) was refluxed for 5 min. After cooling to room temperature and the reaction mixture was concentrated. The residue was then concentrated from chloroform (3×) and dried to give crude 7-[6-(1H-imidazol-2-yl)pyridin-3-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[N:21][OH:22])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C(O)CCC(=O)c1ccc(-c2ccc(Cl)s2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCC(=NO)c1ccc(-c2ccc(Cl)s2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.7 %

Procedure:
A stirred mixture of 4-[4-(5-chloro-thiophen-2-yl)-phenyl]-4-oxo-butyric acid (0.065 g, 0.00022 mol), hydroxylamine hydrochloride (0.0181 g, 0.000260 mol), sodium carbonate (0.0280 g, 0.000260 mol), and absolute ethanol was refluxed under nitrogen for 17 hours and allowed to cool. The resulting suspension was stirred at room temperature for 2 days and filtered. The filtercake was dissolved in methanol (5 mL) and water (5 mL), and the solution was filtered to remove a small amount of fines. The filtrate was acidified with 1.0 M aqueous hydrochloric acid (0.24 mL, 0.00024 mol), and the resulting suspension was rotary evaporated to remove methanol. The resulting aqueous suspension was filtered, washed with water, and dried in vacuo to give 0.0584 g of 4-[4-(5-chloro-thiophen-2-yl)-phenyl]-4-hydroxyimino-butyric acid as a pale yellow solid; mp 172-174° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]=[C:8]=[O:9])[CH:2]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[CH3:20])[NH:16][CH2:15][CH2:14]2>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][C:19]=1[CH3:20])[N:16]([C:8](=[O:9])[NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:15][CH2:14]2
Reactant: O=C=Nc1cccnc1
Reactant: Cc1cc2c(cc1Cl)CCN2
Product: Cc1cc2c(cc1Cl)CCN2C(=O)Nc1cccnc1

Procedure:
The title compound was prepared as in the method of (Example 2) from 3-pyridylisocyanate and 5-chloro-6-methylindoline (D45) to give (E23) (0.76 g, 73%) m.p. 217°-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:40])[CH2:37][CH2:38][CH3:39])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: CCCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Product: CCCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 53 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}butanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.58 (s, 1H), 7.49 (br s, 1H), 7.28–7.21 (m, 10H), 6.91 (m, 1H), 4.77 (s, 1H), 3.38 (dd, 2H, J=6.0, 11.6 Hz), 2.93 (d, 2H, J=11.6 Hz), 2.46 (m, 1H), 2.41 (t, 2H, J=6.0 Hz), 2.31 (t, 2H, J=7.2 Hz), 1.96 (dt, 2H, J=1.6, 12.0 Hz), 1.82–1.66 (m, 6H), 1.58–1.54 (m, 2H), 0.98 (t, 3H, J=7.6 Hz); ESMS m/e: 566.3 (M+H)+.
Reaction SMILES: [CH2:1]1[N:5]2[C:6]3[C:11]([NH:12][C:13](=[O:14])[CH:4]2[CH2:3][CH2:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([CH2:15][N:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]3[CH2:1][CH2:2][CH2:3][CH:4]3[C:13]2=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: O=C1Nc2ccccc2N2CCCC12
Product: O=C1C2CCCN2c2ccccc2N1Cc1ccccc1

Procedure:
Following the procedure of Example 2, 1,2,3,3a-tetrahydropyrrolo[1,2-a]quinoxalin-4(5H)-one is reacted with benzyl chloride to afford the title compound, m.p. 156°-157° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[C:16](=[O:17])[C@H:15]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[NH:14][C:13]2=[O:25])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][C:60]1[S:61][CH:62]=[CH:63][N:64]=1>CN1CCCC1=O.O>[CH:1]1([CH2:7][C@H:8]([N:12]2[C:16](=[O:17])[C@H:15]([CH2:18][CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)[NH:14][C:13]2=[O:25])[C:9]([NH:59][C:60]2[S:61][CH:62]=[CH:63][N:64]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1C(=O)N[C@@H](CC2CCCCC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A solution of (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl]propanoic acid [Step (iii); 25 mg, 0.071 mmol] in N-methylpyrrolidinone (1 mL) was treated with diisopropylethylamine (19 μL, 1.065 mmol) and HBTU (29.3 mg, 0.078 mmol). The reaction mixture was then treated with 2-aminothiazole (7.2 mg, 0.071 mmol) and stirred at ambient temperature overnight. The reaction mixture was then diluted with water (2 mL) and extracted with ethyl acetate (2×3 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The product was purified by using flash chromatography (Merck Silica gel 60, 230-400 mesh, 99/1 dichloromethane/methanol) to furnish (S,S)-3-cyclohexyl-2-[4-(cyclohexyl)methyl-2,5-dioxoimidazolidin-1-yl]-N-(thiazol-2-yl)propanamide (27 mg, 88%) as a white foam: EI-HRMS m/e calcd. for C22H32N4O3S (M+) 433.2273, found 433.2270.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.ClC(O[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=O.C(N(CC)CC)C.O>FC(F)(F)C(O)=O.ClCCl>[CH2:35]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:23][C:24]4[C:25]([CH3:30])=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ncccc1Oc1ncnc2c1cnn2C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
A solution of 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 92; 50 mg, 0.12 mmol) in a mixture of trifluoroacetic acid (0.5 mL) and dichloromethane (2 mL) was stirred at room temperature for 30 min, then the solvents were evaporated and the residue held under high vacuum. Dichloromethane (4 mL) was added, followed successively by benzyl chloroformate (26 μL, 0.18 mmol) and triethylamine (110 μL, 0.8 mmol). The mixture was stirred overnight at room temperature. Water was added and the mixture was extracted with three times with dichloromethane. The combined dichloromethane layers were evaporated and the residue was purified by C18 reversed phase HPLC using a gradient of 10-100% acetonitrile/water to give 4-[4-(2-methyl-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid benzyl ester (16 mg, 29%) as a white powder. HRMS Calcd. For C24H25N6O3 (MH+): 445.1983. Found: 445.1981.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].[F:15][C:16]1[CH:29]=[CH:28][C:19]([C:20]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>CCOCC.O>[F:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([CH:22]2[CH2:27][CH2:26][N:25]([CH2:2][CH2:3][CH2:4][C:5]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[CH3:14])[CH2:24][CH2:23]2)=[O:21])=[CH:28][CH:29]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Cc1[nH]c2ccccc2c1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c2ccccc2c1CCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 50 °C

Procedure:
A mixture of 3-(3-bromopropyl)-2-methylindole (13.8 g), 4-(4-fluorobenzoyl)piperidine (6.0 g), K2CO3 (4.0 g) and dimethylformamide (DMF) (100 ml) is stirred and heated at 50° C. under N2 for 16 hours. The mixture is poured into H2O, and the aqueous mixture extracted with benzene, the benzene extract is washed with H2O, dried (Na2SO4), and the solvent evaporated to leave an oil. The oil is taken up in ether and HCl (g) is bubbled into it to precipitate 10.6 g of a hydrochloride salt. The salt is converted to the free base (an oil). Upon trituration of the oil with ether 4.2 g of a solid is collected. The solid is recrystallized from EtOH-H2O (charcoal treatment), and then twice from isopropanol to yield 1.9 g (15%), m.p. 135°-137° of 3-{3-[4-(4-fluorobenzoyl)piperidyl]propyl} 2-methylindole.
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](Cl)=[O:5].[NH2:9]/[C:10](/[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[Cl:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH:9]/[C:10](/[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: CCOC(=O)/C=C(/C)N
Product: CCOC(=O)/C=C(/C)NC(=O)C(C)(C)CCl
Yield: 42 %

Procedure:
Ethyl N-(β-chloropivaloyl)-3-aminocrotonate was prepared in 42% yield from β-chloropivaloyl chloride and ethyl 3-aminocrotonate by the procedure used in Example 5. M.P. 76°-77.5° C. (after recrystallization from hexanes); IR (KBr) 1705, 1675 cm-1 ; 'HNMR δ 1.06-1.23 (9H, m), 2.3 (3H, s), 3.6 (2H, s), 4.0-4.23 (2H, q) 6.7 (1H, s), 6.8-7.1 (1H, br).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([N-]C(C)C)(C)C.[Li+].CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[CH3:1][C:2]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]1=[O:15]
Reactant: BrCc1ccccc1
Reactant: CC1CCCN(Cc2ccccc2)C1=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC1(Cc2ccccc2)CCCN(Cc2ccccc2)C1=O
Yield: 166.6 %

Procedure:
The reaction of 3-methyl-1-phenylmethyl-2-piperidinone (3.65 g, 18 mmol) with benzyl bromide (4.84 g, 28.3 mmol) in the presence of lithium diisopropylamide (prepared by treating diisopropylamine (2.73 g, 27 mmol) with butyllithium in hexanes (2.5M, 10.3 mL, 25.7 mmol)) in THF (45 mL) and HMPA (2.7 mL, 15.5 mmol) as described above in the preparation of Example 10, gave 8.80 g of pale yellow colored oil. Column chromatography over silica gel (hexanes-EtOAc, 9:1) afforded the product lactam (3.72 g, 71%) as a colorless viscous residue. Analytical sample was prepared by bulb-to-bulb distillation (pot temp. 150°-155° C. (1.3 mmHg)).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][N:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([OH:17])=O)=[CH:11]2.Cl.C([N:35]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[OH-].[NH4+]>CN(C)C=O>[CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][N:20]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([NH2:35])=[O:17])=[CH:11]2
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(=O)O)[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(N)=O)[nH]c12
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 100.2 %

Procedure:
A mixture of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylic acid (1.66 g), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.4 g), 1-hydroxybenzotriazole (1.0 g) and N,N-dimethylformamide (15 mL) was stirred at 50° C. for 30 min. The mixture was cooled to room temperature, and 25% ammonium hydroxide solution (1.5 mL) was added to the mixture. After stirring at room temperature for 14 h, the mixture was concentrated under reduced pressure. Water was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified by basic silica gel column chromatography (methanol/ethyl acetate/hexane=0/60/40 to 10/90/0, volume ratio) to give the title compound (1.66 g, 100%) as a colorless amorphous solid. MS 450 (MH+).