Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]([C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([O:19][CH3:20])[CH:13]=2)=[O:9].CN([CH:24]=[O:25])C>>[CH:24]([C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:19][CH3:20])=[CH:15][CH:16]=2)[NH:11][C:10]=1[C:8]([O:7][CH3:6])=[O:9])=[O:25]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc2ccc(OC)cc2[nH]1
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1[nH]c2cc(OC)ccc2c1C=O
Reaction time: 0.5 h

Procedure:
General Procedure I. POCl3 (2.94 ml, 32.2 mmol) was added dropwise to anhydrous DMF (10 ml) at 0° C. under argon. After stirred for 30 min, this solution was added dropwise to a solution of methyl6-methoxy-1H-indole-2-carboxylate (Aldrich, 2.2 g, 10.7 mmol) in anhydrous DMF (20 ml) at 0° C. under argon. The reaction was stirred for 20 h at room temperature, quenched with ice, diluted with EtOAc, a precipitate formed and was filtered and washed with H2O (×3) to give the title compound as an off-white solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])[C@@H:25]([OH:33])[C@H:24]3[OH:34])=[C:16]([NH:35]C(CC)CC)[N:15]=2)[CH2:10]1.FC(F)(F)C(O)=O.ClC1N=C2C(N=CN2[C@@H]2C[C@H](NC(=O)CC)[C@@H](O)[C@H]2O)=C(N[CH2:71][C:72]2[C:81]3[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=3)[CH:75]=[CH:74][CH:73]=2)N=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[CH:19][N:20]3[C@@H:23]3[CH2:27][C@H:26]([NH:28][C:29](=[O:32])[CH2:30][CH3:31])[C@@H:25]([OH:33])[C@H:24]3[OH:34])=[C:16]([NH:35][CH2:71][C:72]3[C:81]4[C:76](=[CH:77][CH:78]=[CH:79][CH:80]=4)[CH:75]=[CH:74][CH:73]=3)[N:15]=2)[CH2:10]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(CC)CC)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCc4cccc5ccccc45)nc(N4CC[C@@H](N)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to N-{(1S,2R,3S,4R)-4-[2-((R)-3-Amino-pyrrolidin-1-yl)-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide trifluoroacetate by replacing N-{(1S,2R,3S,4R)-4-[2-chloro-6-(1-ethyl-propylamino)-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-propionamide with N-((1S,2R,3S,4R)-4-{2-chloro-6-[(naphthalen-1-ylmethyl)-amino]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-propionamide trifluoroacetate.
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[CH3:14][O:15][C:16]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=1[NH2:18]>C(O)CO>[CH3:14][O:15][C:16]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:17]=1[NH:18][C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5]
Reactant: COc1ccc(N)c(OC)c1
Reactant: C#CCNC(=O)c1cccnc1Cl
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccc(OC)cc1OC
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and 2,4-dimethoxyaniline (9e, 153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10g as pure product. To a solution of 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10 g, 150 mg, 0.48 mmol) and 1-(azidomethyl)-4-methoxybenzene (12c, 86 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 5g (180 mg, 79%); mp: 178-180° C.; 1H NMR (500 MHz, CDCl3) δ 10.30 (s, 1H), 8.23 (m, 2H), 7.74 (dd, J=6.0, 2.0 Hz, 2H), 7.51 (s, 1H), 7.34 (brs, 1H), 7.20 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 6.56-6.48 (m, 3H), 5.45 (s, 2H), 4.64 (d, J=6.0 Hz, 2H), 3.87 (s, 3H), 3.79 (s, 3H), 3.79 (s, 3H); MS (ESI m/z): 475 [M+H]+. Yield: 79%
Reaction SMILES: C(O[C:6]([C:8]1[C:9]([OH:24])=[C:10]2[C:22]([CH3:23])=[N:21][S:20][C:11]2=[C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:13]=1)=[O:7])CCC.[NH2:25][CH2:26][C:27]([OH:29])=[O:28]>>[OH:24][C:9]1[C:8]([C:6]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:7])=[N:13][C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:11]2[S:20][N:21]=[C:22]([CH3:23])[C:10]=12
Reactant: CCCCOC(=O)c1nc(-c2cccnc2)c2snc(C)c2c1O
Reactant: NCC(=O)O
Product: Cc1nsc2c(-c3cccnc3)nc(C(=O)NCC(=O)O)c(O)c12

Procedure:
The title compound was synthesized in analogy Example 1 from 4-hydroxy-3-methyl-7-pyridin-3-yl-isothiazolo[5,4-c]pyridine-5-carboxylic acid butyl ester and glycine: MS (m/z) 345.1 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].[Cl:35][C:36]1[CH:46]=[C:45](F)[C:44]([F:48])=[CH:43][C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39]>C(#N)C>[Cl:35][C:36]1[CH:46]=[C:45]([O:27][C:25]2[CH:24]=[C:14]([C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)=[O:16])[CH:13]=[C:12]([O:11][C@@H:10]([CH3:28])[CH2:9][OH:8])[CH:26]=2)[C:44]([F:48])=[CH:43][C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CN(C)C(=O)c1cc(F)c(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](CO)Oc1cc(Oc2cc(Cl)c(C(=O)N(C)C)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 16.7 %

Procedure:
A suspension of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (200 mg, 0.477 mmol), potassium carbonate (136 mg, 0.95 mmol) and 2-chloro-4,5-difluoro-N,N-dimethylbenzamide (106 mg, 0.45 mmol) in acetonitrile (3.5 mL) was heated in a microwave reactor at 160° C. for 2 hours. The reaction mixture was quenched with water and extracted with DCM (2×6 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was then chromatographed by preparatory reverse phase HPLC using a gradient of 5-95% acetonitrile in water (containing 0.2% TFA) on a Phenomenex Luna 10u C18 (2) 100A (150×21.2 mm) column to give the title compound (37 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH3:8][C:5]1[N:4]=[N:3][C:2]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][OH:17])[CH2:11][CH2:10]2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: OCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(N2CCC(CCO)CC2)nn1
Temperature: 150 °C
Reaction time: 5 h
Yield: 95 %

Procedure:
A mixture of 19.3 parts of 3-chloro-6-methylpyridazine, 19.4 parts of 4-piperidineethanol, 16 parts of sodium carbonate and 0.9 parts of N,N-dimethylacetamide was stirred for 5 hours at about 150° C. After cooling, the reaction mixture was diluted with water and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated, yielding 31.5 parts (95%) of 1-(6-methyl-3-pyridazinyl) -4-piperidineethanol (int. 83).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[N:16]=[C:15]3[CH2:32][CH2:33][CH2:34][C:14]=23)=[CH:8][CH:7]=1)C.[NH3:36]>CO>[NH2:36][C:4](=[O:3])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)[N:16]=[C:15]3[CH2:32][CH2:33][CH2:34][C:14]=23)=[CH:8][CH:7]=1
Reactant: CCOC(=O)Cc1ccc(Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)nc3c2CCC3)cc1
Reactant: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Nc3ccc(CC(N)=O)cc3)c3c(n2)CCC3)CC1

Procedure:
Following general procedure C, tert-butyl 4-(4-((4-(2-ethoxy-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)piperazine-1-carboxylate (0.034 g, 0.071 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL) to afford crude product (0.031 g) as an orange oil. MW=451.56. APCI MS m/z 452 [M+H]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([Cl:10])=[N:8][C:7]([S:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:6][C:5]=2[N:19]=1.[NH2:20][CH2:21][CH2:22][C:23]1[N:27]=[CH:26][NH:25][CH:24]=1>>[Cl:10][C:9]1[C:4]2[S:3][C:2]([NH:20][CH2:21][CH2:22][C:23]3[N:27]=[CH:26][NH:25][CH:24]=3)=[N:19][C:5]=2[N:6]=[C:7]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=1
Reactant: NCCc1c[nH]cn1
Reactant: Clc1nc(SCc2ccccc2)nc2nc(Br)sc12
Product: Clc1nc(SCc2ccccc2)nc2nc(NCCc3c[nH]cn3)sc12

Procedure:
Prepared according to the method of Example 231 using the product of Example 219 and histamine.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH:36]([OH:53])[CH2:37][N:38](CC2C=CC=CC=2)CC2C=CC=CC=2)=[CH:32][C:31]=1[NH:54][S:55]([CH3:58])(=[O:57])=[O:56])C1C=CC=CC=1>>[OH:53][CH:36]([C:33]1[CH:34]=[CH:35][C:30]([OH:29])=[C:31]([NH:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH:32]=1)[CH2:37][NH:38][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH2:19][CH2:20][CH3:21])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN(Cc2ccccc2)Cc2ccccc2)ccc1OCc1ccccc1
Reactant: CCCCS(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Product: CCCCS(=O)(=O)Nc1ccc(N2CCC(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from butane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-amide (which was obtained in Example 228) and N-[2-benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanesulfonamide (which was obtained in Example 7) according to the procedure of Example 255 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.83(t, J=7.2 Hz, 3 H), 1.20–1.40 (m, 2 H), 1.50–1.70 (m, 4 H), 1.95–2.10 (m, 2 H), 2.40–2.60 (m, 2 H), 2.94 (s, 3 H), 2.90–3.20 (m, 5 H), 3.62–3.75 (m, 2 H), 4.70–4.80 (m, 1 H), 5.95 (brs, 1 H), 6.85–6.95 (m, 3 H), 7.00–7.10 (m, 3 H), 7.24 (d, J=2.0 Hz, 1 H), 8.70 (brs, 1 H), 9.33 (brs, 1 H); MS (ES) m/z: 541.0 (MH+); HRMS Calcd. for C24H37N4O6S2 (MH+): 541.2155. Found: 541.2161.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:17]([OH:22])(=[O:21])[C:18]([CH3:20])=O.[OH-].[Na+]>O>[N:12]1([C:6]2[CH:11]=[CH:10][C:9]([C:18]([C:9]3[CH:8]=[CH:7][C:6]([N:12]4[CH2:13][CH2:14][CH2:15][CH2:16]4)=[CH:11][CH:10]=3)([CH3:20])[C:17]([OH:22])=[O:21])=[CH:8][CH:7]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(=O)C(=O)O
Reactant: c1ccc(N2CCCC2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)(c1ccc(N2CCCC2)cc1)c1ccc(N2CCCC2)cc1
Yield: 74.7 %

Procedure:
Into 40 ml of 20% aqueous solution of sulfuric acid was dissolved 20 g of N-phenylpyrrolidine. To the solution was added 7.2 g of pyruvic acid and the mixture was heated with reflux for 16 hours. The reaction mixture was, after cooled, diluted with 300 ml of water and adjusted to pH 6 with addition of 20% aqueous solution of sodium hydroxide. The precipitated crystal was collected by filtration. The crystal was recrystallized from benzene to obtain 18.5 g (yielded 75%) of 2,2-bis(4-pyrrolidinophenyl)propionic acid as white crystal, having a melting point of 174°~176° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11]1[C:19]2[C:18](=O)[N:17]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([F:33])[CH:22]=3)[CH:16]([OH:34])[C:15]=2[C:14]([O:35][CH2:36][CH3:37])=[C:13]2[CH:38]=[CH:39][CH:40]=[CH:41][C:12]=12)[CH3:9].C([SiH](CC)CC)C>ClCCl>[CH2:8]([O:10][C:11]1[C:19]2[CH2:18][N:17]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:23]([F:33])[CH:22]=3)[C:16](=[O:34])[C:15]=2[C:14]([O:35][CH2:36][CH3:37])=[C:13]2[CH:38]=[CH:39][CH:40]=[CH:41][C:12]=12)[CH3:9]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2O)cc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 94.7 %

Procedure:
Trifluoroacetic acid (1900 mL) was added to a stirred solution of ethyl {4-[4,9-bis(ethyloxy)-1-hydroxy-3-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetate (898 g, 1.92 mol) in dichloromethane (1900 mL) at 0° C. under a nitrogen atmosphere. Triethylsilane (465 mL, 2.92 mol) was added dropwise to the deep red solution ensuring that the temperature was maintained below 3° C. The reaction mixture was then stirred at 0° C. for 45 minutes, over which time the solution turned yellow and all ethyl {-4-[4,9-bis(ethyloxy)-1-hydroxy-3-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetate was shown to be consumed by TLC analysis (silica, dichloromethane:methanol, 99:1). The reaction mixture was evaporated to dryness under reduced pressure, slurried in hexane (2×2.5 L) and then isopropanol (2.5 L) at 40° C. and dried under vacuum to give the desired product as a white solid (821 g, 95% yield).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:7]([C:8]#[C:9][Sn](CCCC)(CCCC)CCCC)[CH2:6][CH:5]([O:23][CH3:24])[O:4]1.I[C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:30]([C:29]1[CH:32]=[CH:33][C:26]([C:9]#[C:8][CH:7]2[CH2:6][CH:5]([O:23][CH3:24])[O:4][CH:3]2[O:2][CH3:1])=[CH:27][CH:28]=1)#[N:31]
Reactant: CCCC[Sn](C#CC1CC(OC)OC1OC)(CCCC)CCCC
Reactant: N#Cc1ccc(I)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC1CC(C#Cc2ccc(C#N)cc2)C(OC)O1
Temperature: 100 °C
Reaction time: 5.5 h
Yield: 102.3 %

Procedure:
A mixture of 2,5-dimethoxy-3-(2-tributylstannylethynyl)-tetrahydrofuran (1.86 g, 4.18 mmol), 4-iodobenzonitrile (1.15 g, 5.02 mmol), and tetrakis(triphenylphosphine) palladium(0) (145 mg, 0.125 mmol) in toluene (25 mL) was heated at 100° C. After 5.5 hours, the resultant red solution was allowed to cool, and the solvent was removed under reduced pressure. Flash column chromatography twice with 10% EtOAc/hex provided 1.10 g (100%) of 3-[2-(4-cyanophenyl)-ethynyl]-2,5-dimethoxy-tetrahydrofuran as an orange oil. A mixture of diastereomers was observed by 1H NMR, which was used without further purification. 1H NMR (CDCl3): 3.12 (ddd, J=2.8, 6.6, 9.0 Hz), 2.57 (ddd, J=5.6, 9.3, 13.4 Hz), 2.08 (dd, J=2.5, 4.7 Hz), 2.04 (dd, J=3.1, 4.3 Hz). IR: 2227, 1603, 1216, 1102, 1012, 841 cm−1. Anal. Calculated for C15H15NO3.0.1EtOAc: C, 69.51; H, 5.98; N, 5.26. Found: C, 69.52; H, 5.76; N, 5.32.
Reaction SMILES: [N+](C1C=CC(O[C:11]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:14]2)=[O:12])=CC=1)([O-])=O.[CH3:32][NH2:33]>C1COCC1>[CH2:25]([O:24][C:22]([C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:13]([C:11](=[O:12])[NH:33][CH3:32])[CH:14]=1)=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN
Reactant: O=C(OCc1ccccc1)c1cn(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc12
Solvent: C1CCOC1
Product: CNC(=O)n1cc(C(=O)OCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of indole-1,3-dicarboxylic acid 3-benzyl ester 1-(4-nitro-phenyl)ester (45 mg, 0.108 mmol) in dry THF (1 mL) was added methylamine (2 M in THF, 270 μl, 0.54 mmol) and the reaction was stirred at RT for 15 min. The mixture was concentrated and the residue was taken up in Et2O and filtered to give the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.52; MS (LC/MS): 309.1 [M+H]+, 331.1 [M+Na]+, 639.2 [2M+Na]+, 353.2 [M+HCOO]−; tR (HPLC conditions a): 3.86 min.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[NH2:30]>>[CH3:13][C:12]1[C:7]([NH:30][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]2[CH3:23])=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: CC1CCCCC1N
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2C)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using 2-methylcyclohexanamine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 0.93 (bs, 3H), 1.28-1.42 (m, 6H), 1.62-1.70 (m, 1H), 1.78-1.89 (m, 2H), 1.93 (s, 3H), 2.07 (s, 3H), 2.95-3.04 (m, 1H), 4.43 (bs, 2H), 7.22 (t, J=7.30 Hz, 1H), 7.56 (d, J=7.76 Hz, 1H), 7.68-7.75 (m, 1H), 8.65 (d, J=4.92 Hz, 1H); MS (ESI) m/z 326.4.0 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25]([O:27][CH2:28][CH2:29]Cl)[CH3:26]>>[CH2:25]([O:27][CH2:28][CH2:29][N:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=[C:16]1[C:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:15])[CH3:26]
Reactant: CCOCCCl
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Product: CCOCCn1c(C(=O)C2CCNCC2)nc2ccccc21

Procedure:
Prepare by the method of Preparation 6 using 1-(t-butoxycarbonyl)-4-(1H-benzoimidazole-2-carbonyl)-piperidine and 2-chloroethyl ethyl ether to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[N:15]=1.O1CCOCC1>C(Cl)Cl>[NH2:13][C:14]1[N:15]=[C:16]([NH:20][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][C:9]([F:11])=[CH:8][C:7]=2[F:12])[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Reactant: Nc1cccc(N)n1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Nc1cccc(NC(=O)c2c(F)cc(F)cc2F)n1
Temperature: 40 °C
Yield: 73.9 %

Procedure:
Combine 2,4,6-trifluorobenzoyl chloride (3.891 g, 20 mmol), 2,6-diaminopyridine (6.548 g, 60 mmol) and dioxane (25 mL) and stir for 1 hr. at room temperature followed by heating at 40° C. overnight. Dilute the reaction mixture with CH2Cl2 (100 mL), and wash with 0.1N NaOH solution. Extract the aqueous layer three times with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate to a residue. Chromatography on silica gel, eluting with a gradient of 40–50% ethylacetate in hexanes gives the title intermediate (3.95 g, 74%): mass spectrum (ion spray): m/z=267.9 (M+1); 1H NMR (CDCl3, ppm):8.28 (s, br, 1H), 7.66 (d, 1H), 7.52 (t, 1H), 6.78 (m, 2H), 6.31 (d, 1H), 4.36 (s, br, 2H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1.[CH3:16][O:17][C:18]1[CH:27]=[CH:26][C:21]([CH:22]=[CH:23][CH:24]=[O:25])=[CH:20][CH:19]=1>O1CCCC1>[OH:25][CH:24]([CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][C:18]([O:17][CH3:16])=[CH:27][CH:26]=1)[CH2:9][C:10]1[CH:15]=[N:14][CH:13]=[CH:12][N:11]=1
Reactant: COc1ccc(C=CC=O)cc1
Reactant: Cc1cnccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C=CC(O)Cc2cnccn2)cc1
Temperature: 25 °C

Procedure:
To a solution of lithium diisopropylamide (1.5 Molar, 73.3 mL, 0.11 mole) in 150 mL of tetrahydofuran at -78° C. is added slowly to a solution of 2-methylpyrazine (9.4 g, 0.1 mole) in 100 mL of tetrahydrofuran. The mixture is allowed to warm to room temperature and then cooled to -78° C. A solution of p-methoxycinnamaldehyde (17.8 g, 0.11 mole) in 100 mL of tetrahydrofuran is added dropwise over 15 minutes. The reaction product mixture is then worked up according to the procedure of Example I to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH2:12][CH3:13].C1COCC1.O.[Cl-].[NH4+]>[Fe].O>[CH2:12]([O:11][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[CH3:1])[NH2:8])[CH3:13]
Reactant: CCOc1cc([N+](=O)[O-])ccc1C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc(N)ccc1C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
Fe powder (609 mg, 10.90 mmol) was added to a solution of ethyl 2-methyl-5-nitrophenyl ether (Intermediate 88, 395 mg) in a mixture THF/water (15 mL/5 mL) followed by ammonium chloride (583 mg, 10.90 mmol). The reaction mixture was stirred overnight under nitrogen. The reaction mixture was poured into water (20 mL) and the iron was filtrated. Ethyl acetate was used to wash the solid filtrated. The filtrate was extracted with ethyl acetate (3 times). The combined ethyl acetate layers were dried over sodium sulphate and concentrated to give the title compound (303 mg) which was directly used in the next step.
Reaction SMILES: CN(C)C1C=CC=CC=1.[N+:10]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][NH:19][C:18]2=O)([O-:12])=[O:11].O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:18]1[C:17]2[C:22](=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[CH:15][CH:16]=2)[N:21]=[CH:20][N:19]=1
Reactant: O=c1[nH]cnc2c([N+](=O)[O-])cccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: O=[N+]([O-])c1cccc2c(Cl)ncnc12
Temperature: 65 °C
Yield: 59.6 %

Procedure:
N, N-dimethylaniline (0.37 ml, 1.23 mmol) was added dropwise to a solution of 8-nitro-3H-quinazolin-4-one 476 (200 mg, 1.04 mmol) in POCl3 (1.25 ml, 10.5 mmol) at 0° C. The mixture was heated at 65° C. for 1.5 h. After cooling, the mixture was concentrated in vacuo. The residue was quenched with sat. NaHCO3 solution and the aqueous phase was extracted with EtOAc (25 ml, ×2). The combined organic phase was dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with n-hexane/DCM (80:20) to give the title compound (130 mg, 59.63%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][C:35](=[O:42])[C:36]([CH3:41])([CH3:40])[CH:37](Cl)C)[CH2:24][CH:23]2[OH:43])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].[H-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:34]3[CH2:37][C:36]([CH3:41])([CH3:40])[C:35]3=[O:42])[CH2:24][CH:23]2[OH:43])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:11]
Reactant: CC(Cl)C(C)(C)C(=O)Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CN(c2ccccc2N2CCC(NC(=O)C3(NC(=O)c4cc5ccccc5o4)CCCCC3)C(O)C2)C1=O
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
The solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-[2-(3-chloro-2,2-dimethylbutyryl)aminophenyl]piperidin-3-ol (4.1 g) obtained in Step 3 in 50 ml of dimethylformamide was cooled to 0° C. Sodium hydride (NaH, 60%; 640 mg) was added to the reaction mixture, which was then stirred overnight at 50° C., diluted with ethyl acetate, washed with a brine, and then dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 2.1 g of the titled compound.