Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:25](Cl)=[O:26])[C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3.[NH4+:28].[OH-].C(OCC)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:25]([NH2:28])=[O:26])[C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3
Reactant: COc1ccc(C2Cc3c(C(=O)Cl)cc(OC)cc3C3CCCCC23)cc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1ccc(C2Cc3c(C(N)=O)cc(OC)cc3C3CCCCC23)cc1

Procedure:
Combine 3-Methoxy-9-(4-methoxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthrene-1-carbonyl chloride (0.08 g, 0.18 mmol), NH4OH (2 ml), and diethyl ether (1 ml) at 0-5° C. and stir as such 2 hours. Dilute with ethyl acetate and wash with water. Dry over anhydrous sodium sulfate, and remove solvent in vacuo at 40° C. to yield preparation 121 (0.069 g, 100%). MS m/z 366 (M+1).
Reaction SMILES: N([O-])=O.[Na+].[CH3:5][O:6][C:7]([C:9]1[C:10]([CH3:20])=[C:11]([CH:15]=[CH:16][C:17]=1[S:18][CH3:19])[C:12](N)=[O:13])=[O:8].S(=O)(=O)(O)[OH:22]>O.C(O)(=O)C>[CH3:5][O:6][C:7]([C:9]1[C:10]([CH3:20])=[C:11]([CH:15]=[CH:16][C:17]=1[S:18][CH3:19])[C:12]([OH:22])=[O:13])=[O:8]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1c(SC)ccc(C(N)=O)c1C
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1c(SC)ccc(C(=O)O)c1C

Procedure:
Sodium nitrite (2.4 g) was added dropwise to a stirred solution of 3-methoxycarbonyl-2-methyl-4-methylsulphenylbenzamide (4.2 g) in a mixture of concentrated sulphuric acid (50 ml), water (40 ml) and glacial acetic acid (70 ml) whilst maintaining the temperature below 5° C. The mixture was stirred without cooling for 0.5 hours. The brown solution was recooled to 0° C. and water (200 ml) was added. The mixture was extracted with ether (3×150 ml). The combined organic extracts were washed with water (2×150 ml), dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 3-methoxycarbonyl-2-methyl-4-methylsulphenylbenzoic acid (4.6 g) as a sticky orange solid NMR (CDCl3) 2.1(s,3H), 2.5(s,3H), 3.9(s,3H), 7.0(d,1H), 7.85(d,1H), 9.0(bs,1H).
Reaction SMILES: C(OC1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18](O)=CC=2)C(=O)C=1)C1C=CC=CC=1.[CH3:23][C:24]([O:27][C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]2[CH:41]=[CH:40][N:39]([C:42]3[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=3)[C:38](=[O:49])[CH:37]=2)=[CH:30][CH:29]=1)([CH3:26])[CH3:25]>>[CH3:26][C:24]([O:27][C:28]1[CH:29]=[CH:30][C:31](/[CH:34]=[CH:35]/[C:36]2[CH:41]=[CH:40][N:39]([C:42]3[CH:43]=[CH:44][C:45]([O:48][CH2:14][CH2:13][N:12]4[CH2:15][CH2:20][CH2:19][CH2:18]4)=[CH:46][CH:47]=3)[C:38](=[O:49])[CH:37]=2)=[CH:32][CH:33]=1)([CH3:23])[CH3:25]
Reactant: CC(C)(C)Oc1ccc(/C=C/c2ccn(-c3ccc(O)cc3)c(=O)c2)cc1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Product: CC(C)(C)Oc1ccc(/C=C/c2ccn(-c3ccc(OCCN4CCCC4)cc3)c(=O)c2)cc1

Procedure:
Step (3) of Example 12 was repeated except that 4-benzyloxy-1-(4-hydroxyphenyl)-1H-pyridin-2-one was replaced with 4-((E)-2-{4-[(2-methyl-2-propyl)oxy]phenyl}vinyl)-1-(4-hydroxyphenyl)-1H-pyridin-2-one, to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[CH:25]=[C:26]([C:34]4[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=4)[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=3)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:42][N:43](C)C=O>[C-]#N.[Zn+2].[C-]#N>[C:40]([C:37]1[CH:38]=[CH:39][C:34]([C:26]2[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=[C:24]([CH2:23][O:22][CH2:21][C:8]3([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:42]#[N:43])[CH:3]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[CH:25]=2)=[CH:35][CH:36]=1)#[N:41]
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2cccc(Br)c2)CC1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2cccc(C#N)c2)CC1
Temperature: 120 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
A mixture of tert-Butyl 4-(3-bromophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate (150 mg, 0.238 mmol), zinc cyanide (33.6 mg, 0.286 mmol), palladium tetrakis triphenylphosphine (27.5 mg, 0.024 mmol), and dimethylformamide (1 mL) was charged to a conical vial and purged with nitrogen for 5 minutes. The vial was sealed and heated at 120° C. for 2 hours and then held at room temperature overnight. The resulting mixture was filtered through a syringe tip filter and applied directly to a silica gel column. Gradient elution with 5-40% ethyl acetate/hexanes afforded the product as a clear oil (83 mg, 61%). 1H-NMR (CDCl3, 500 MHz) δ ppm 7.76 (m, 2H), 7.68 (s, 1H), 7.56-7.64 (m, 4H), 7.45-7.49 (m, 1H), 7.38-7.43 (m, 2H), 7.34 (s, 1H), 3.69 (m, 2H), 3.45 (s, 2H), 3.05 (m, 2H), 2.10 (m, 2H), 1.88 (m, 2H), 1.42 (s, 9H). Mass spec.: 576.17 (MH)+.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[S:13](Cl)(=[O:16])(=[O:15])[NH2:14].ClS(N=C=O)(=O)=O.C(N(CC)CC)C>C(#N)C>[N:1]1([C:6]2[CH:7]=[C:8]([O:12][S:13](=[O:16])(=[O:15])[NH2:14])[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Oc1cccc(-n2ccnc2)c1
Reactant: NS(=O)(=O)Cl
Agent: O=C=NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)Oc1cccc(-n2ccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3(1H-imidazol-1-yl)phenol (8 g, 0.05 mole) in acetonitrile was treated in an ice bath with sulfamoyl chloride generated from 0.075 mole of chlorosulfonyl isocyanate (Preparation 19) followed by 0.075 mole of triethylamine. After stirring overnight at room temperature, TLC, and 1H NMR of a sample showed starting material still present. The reaction was then treated with another 0.075 mole each of sulfamoyl chloride and triethylamine for another night.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][N:5]1[C:11](=[O:12])[C@@H:10]([NH:13][C:14](=[O:23])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][NH:8][C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]1=2.O.[OH-].[Li+]>CO.O>[C:17]1([CH2:16][CH2:15][C:14]([NH:13][C@@H:10]2[C:11](=[O:12])[N:5]([CH2:4][C:3]([OH:28])=[O:2])[C:6]3[CH:27]=[CH:26][CH:25]=[CH:24][C:7]=3[NH:8][CH2:9]2)=[O:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)CCc2ccccc2)CNc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CN1C(=O)[C@@H](NC(=O)CCc2ccccc2)CNc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
(3(S)-(3-Phenylpropionylamino)-2-oxo-2,3,4,5-tetrahydro-benzo[b] [1,4]diazepin-1-yl)acetic acid methyl ester (104a) was dissolved in 90% methanol. Lithium hydroxide hydrate was added to the reaction and the reaction was stirred at room temperature for 4 h. The reaction was evaporated in vacuo to give a white solid. This was dissolved in 20 ml of water and acidified to pH 5 and extracted with ethyl acetate to afford 304 mg (88%) of the title compound as a white solid. 1H NMR (CDCl3) δ7.5-6.9 (11H, m), 4.92-4.8 (1H, m), 4.7-4.58 (1H, d), 4.38-4.25 (1H, d), 3.88-3.78 (1H, m), 3.45-3.25 (1H, m), 3.05-2.85 (2H, m), 2.55-2.45 (2H, m).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[CH3:20][N:21]([CH3:30])[C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][CH:23]=1>>[ClH:19].[CH3:20][N:21]([CH3:30])[C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH:29][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])=[CH:24][CH:23]=1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: CN(C)c1ccc(CN)cn1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccc(N(C)C)nc3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 55 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with [(6-dimethylaminopyridin-3-yl)methyl]amine as described in Steps 5 and 6, Example 24 to give the title compound as a yellow solid (55% yield). LC/MS: RT 2.07 min; m/e 433; 1H NMR (δ, ppm): 11.86 (1H, br), 8.57 (1H, t), 7.80-7.95 (2H, m), 7.54 (1H, d), 7.43 (1H, s), 7.21 (1H, d), 7.14 (1H, d), 4.03 (2H, d), 3.17 (6H, d), 2.41 (2H, q), 2.30 (3H, s), 1.10 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:15][C:16]2[C:17]([CH3:25])=[N:18][C:19]([O:23][CH3:24])=[C:20]([CH3:22])[CH:21]=2)[C:5](=[O:14])[N:6]([CH2:8][C@H:9](C2CC2)[OH:10])[CH:7]=1.[H-].[Na+].[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[CH2:37]1[CH2:41]OC[CH2:38]1>>[C:28]1([NH:34][C:35](=[O:36])[O:10][CH2:9][C@@H:8]([N:6]2[CH:7]=[C:2]([Cl:1])[N:3]=[C:4]([NH:15][C:16]3[C:17]([CH3:25])=[N:18][C:19]([O:23][CH3:24])=[C:20]([CH3:22])[CH:21]=3)[C:5]2=[O:14])[CH:38]2[CH2:37][CH2:41]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COc1nc(C)c(Nc2nc(Cl)cn(C[C@@H](O)C3CC3)c2=O)cc1C
Reactant: C1CCOC1
Reactant: O=C=Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COc1nc(C)c(Nc2nc(Cl)cn([C@H](COC(=O)Nc3ccccc3)C3CC3)c2=O)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of (S)-5-chloro-1-(cyclopropyl-2-hydroxyethyl)-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)pyrazin-2(1H)-one (20 mg, 0.055 mmol) from Part M in THF (1 mL) at 0° C. was treated with NaH (7 mg, 0.275 mmol, prewashed with hexanes). The cooling bath was removed and the mixture was allowed to warm to room temperature and was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. and a solution of phenyl isocyanate (9 μL, 0.083 mmol) in 0.5 mL THF was added via cannula. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature and was stirred at room temperature for 20 min. The reaction mixture was then cooled to 0° C. and was quenched by the addition of saturated aqueous NaHCO3. The mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 (5 mL) and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The product was purified by column chromatography on silica gel (20% 30% ethyl acetate in hexanes) to furnish (S)-2-(5-chloro-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)-2-oxopyrazin-1(2H)-yl)-2-cyclopropylethyl phenylcarbamate (14 mg, 52% yield) as a colorless amorphous solid: 1H NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.92 (s, 1H), 7.30-7.26 (m, 4H), 7.06 (t, J=8.3 Hz, 1H), 6.82 (s, 1H), 6.63 (s br, 1H), 4.58 (dd, JAB=11.9, JAX=4.1 Hz, 1H), 4.48 (dd, JBA=11.9, JBX=7.6 Hz, 1H), 4.26-4.21 (m, 1H), 4.05 (s, 3H), 2.51 (s, 3H), 2.19 (s, 3H), 1.26-1.21 (m, 1H), 0.88-0.80 (m, 1H), 0.67-0.57 (m, 2H), 0.40-0.36 (m, 1H); HRMS (ESI) m/e 484.1753 [(M+H)+, calcd for C24H27N5O4Cl 484.1752].
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:8][N:7]([CH:9]2[CH2:13][CH2:12][C@@H:11]([CH3:14])[CH2:10]2)[C:6]2[N:15]=[C:16]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=3[O:29][CH3:30])[N:17]=[CH:18][C:5]=2[N:4]([CH3:31])[C:3]1=[O:32].[CH3:34][N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:33][C:2]1([F:1])[CH2:8][N:7]([CH:9]2[CH2:13][CH2:12][C@@H:11]([CH3:14])[CH2:10]2)[C:6]2[N:15]=[C:16]([NH:19][C:20]3[CH:28]=[CH:27][C:23]([C:24]([NH:41][CH:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)=[O:26])=[CH:22][C:21]=3[O:29][CH3:30])[N:17]=[CH:18][C:5]=2[N:4]([CH3:31])[C:3]1=[O:32]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CC[C@@H](C)C1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CC[C@@H](C)C1)CC(F)(F)C(=O)N2C
Reaction time: 0.5 h

Procedure:
To a mixture of the 4-(7,7-difluoro-5-methyl-9-((3R)-3-methylcyclopentyl)-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid, 1-methylpiperidin-4-amine (1.1 equivalent) and DIEA (3-6 equivalent) in 20 mL of anhydrous DMF, was added HATU (1.5 to 2 equivalent). The reaction mixture was stirred for 30 min. The reaction mixture was then diluted with ethyl acetate, washed with water and brine. The organic layer dried over Na2SO4 followed by HPLC purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.06 (m, 3H) 1.06-2.12 (m, 13H) 2.16 (s, 3H) 2.77 (d, J=11.87 Hz, 2H) 3.32 (br. s., 3H) 3.65-3.80 (m, 1H) 3.93 (s, 3H) 3.97-4.12 (m, 2H) 4.73-4.96 (m, 1H) 7.44-7.52 (m, 2H) 7.97 (d, J=6.06 Hz, 1H) 8.12 (d, J=7.83 Hz, 1H) 8.25 (d, 2H). [M+H] calc'd for C28H37F2N7O3 558. found 558.
Reaction SMILES: [C:1]([C:4]1[CH:32]=[CH:31][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]3[CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:28][CH2:29][CH3:30])=[C:6]([CH2:33][CH2:34][CH3:35])[C:5]=1O)(=[O:3])[CH3:2].[CH3:37]C(C)=O.S([O:46][CH3:47])(OC)(=O)=O>[OH-].[K+]>[C:1]([C:4]1[CH:32]=[CH:31][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:27]=[CH:26][C:16]3[CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][C:23]([O:25][CH3:37])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:28][CH2:29][CH3:30])=[C:6]([CH2:33][CH2:34][CH3:35])[C:5]=1[O:46][CH3:47])(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CCCc1c(OCCCOc2ccc3c(c2CCC)OC(CCC(=O)O)CC3)ccc(C(C)=O)c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Product: CCCc1c(OCCCOc2ccc(C(C)=O)c(OC)c2CCC)ccc2c1OC(CCC(=O)OC)CC2
Temperature: 40 °C

Procedure:
7-[3-(4-Acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propionic acid (1 mmol) is dissolved in acetone containing 2.5 equivalents of potassium hydroxide and 3 equivalents of dimethyl sulfate. The mixture is heated at 40° C. for about 10 hours then cooled. The solvent is removed in vacuo, and the residue is partitioned between ethyl acetate and water. The organic layer is separated and dried over magnesium sulfate. Removal of the volatiles in vacuo gives the product.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(#N)C>[Br-:1].[C:8]([O:7][C:6]([NH:5][CH2:4][CH2:3][CH2:2][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCCCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Yield: 64 %

Procedure:
A mixture of tert-butyl (3-bromopropyl)carbamate (5.45 g, 22.88 mmol) and triphenylphosphine (6.0 g, 22.88 mmol) in 100 ml of acetonitrile was heated to reflux for 2 days. Upon cooling to room temperature, the compound was purified with silica chromatography using methylene chloride/methanol as an eluent to give a yield of 64% (6.15 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:20]=[C:14]2[C:15](=[O:19])[NH:16][CH2:17][CH2:18][N:13]2[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:22][CH:23]1[CH2:25][CH2:24]1>CN(C=O)C.O>[CH2:3]([O:10][C:11]1[CH:20]=[C:14]2[C:15](=[O:19])[N:16]([CH2:22][CH:23]3[CH2:25][CH2:24]3)[CH2:17][CH2:18][N:13]2[N:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C1NCCn2nc(OCc3ccccc3)cc21
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cc(OCc3ccccc3)nn2CCN1CC1CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.5 %

Procedure:
A 60% dispersion of sodium hydride in mineral oils (8.14 mg, 0.2 mmol) was added to a stirred solution of 2-(benzyloxy)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.045 g, 0.18 mmol) in DMF (2.7 mL) at 0° C. The mixture was stirred at 0° C. for 15 minutes. Then (bromomethyl)cyclopropane (22 μL, 0.22 mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 hour and then allowed to warm to room temperature and stirred for 16 hours. The mixture was diluted with water and extracted with AcOEt. The organic layer was separated, washed with a saturated solution of NH4Cl, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 20/80). The desired fractions were collected, the solvents evaporated in vacuo and the residue was triturated with DIPE to yield 2-(benzyloxy)-5-(cyclopropylmethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (42 mg, 76% yield) as a white solid. C17H19N3O2. 1H NMR (500 MHz, CDCl3) δ ppm 0.25-0.36 (m, 2H), 0.51-0.62 (m, 2H), 0.98-1.08 (m, 1H), 3.43 (d, J=6.9 Hz, 2H), 3.83 (dd, J=6.9, 5.5 Hz, 2H), 4.23 (dd, J=6.9, 5.5 Hz, 2H), 5.20 (s, 2H), 6.26 (s, 1H), 7.29-7.35 (m, 1H), 7.37 (t, J=7.4 Hz, 2H), 7.41-7.48 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([F:40])[C:30]=1B1OC(C)(C)C(C)(C)O1)[NH2:27]>>[CH2:8]([NH:9][C:11](=[O:12])[NH:27][C:26]1[CH:28]=[C:29]([F:40])[C:30]([C:2]2[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[C:5]3[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[C:24]([F:23])[CH:25]=1)[CH3:6]
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Reactant: CC1(C)OB(c2c(F)cc(N)cc2F)OC1(C)C
Product: CCNC(=O)Nc1cc(F)c(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC)C3)c(F)c1
Temperature: 130 °C
Yield: 14 %

Procedure:
Method as described for example 47 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. Reaction mixture heated in by microwave at 130° C. for 1 h. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and the solvent removed in vacuo. The residue was purified by prep. HPLC at high pH, yielding the title compound (55 mg, 0.13 mmol, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C@@H:13]2[O:18][C:17]3[CH:19]=[CH:20][C:21]([CH:23]=O)=[CH:22][C:16]=3[O:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C1CCN2C(=NCCC2)CC1.[CH3:40][C:41]([O:44][C:45]([NH:47][CH:48](P(OC)(OC)=O)[C:49]([O:51][CH3:52])=[O:50])=[O:46])([CH3:43])[CH3:42]>C(Cl)Cl>[CH3:52][O:51][C:49](=[O:50])[C:48]([NH:47][C:45]([O:44][C:41]([CH3:42])([CH3:40])[CH3:43])=[O:46])=[CH:23][C:21]1[CH:20]=[CH:19][C:17]2[O:18][C@@H:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([O:6][CH2:5][C:4]4[CH:25]=[CH:26][C:27]([Cl:28])=[C:2]([Cl:1])[CH:3]=4)[CH:8]=3)[CH2:14][O:15][C:16]=2[CH:22]=1
Reactant: O=Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)C(=Cc1ccc2c(c1)OC[C@H](c1cccc(OCc3ccc(Cl)c(Cl)c3)c1)O2)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 60.7 %

Procedure:
(S)-2-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3-dihydro-benzo[1,4]dioxine-6 carbaldehyde (2.1 g) was dissolved in 8 mL dry DCM under nitrogen at rt and DBU (1.61 g) was added by syringe. A solution of Boc-phosphonoglycine trimethyl ester (1.58 g) in 4 mL of dry DCM was added to the reaction mixture and stirred at rt. for 12 hours. Reaction mixture was directly loaded on to silica gel column (40% hexanes in DCM to DCM) gave 1.8 g pure product. 1H NMR (400 MHz, CDCl3): 7.55 (d, 1H), 7.46 (d, 1H), 7.32-7.38 (m, 1H), 7.18-7.28 (m, 3H), 7.10-7.15 (m, 1H), 6.94-7.06 (m, 4H), 5.13 (m, 1H), 5.03 (s, 2H), 4.36 (m, 1H), 4.01 (m, 1H), 3.84 (s, 3H), 1.44 (s, 9H). LCMS (m/z): 587.
Reaction SMILES: [CH2:1]([CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]([OH:18])=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[CH:25]2>>[CH:25]1[C:26]2[C:21](=[C:20]([NH:19][C:16]([CH:12]3[CH2:13][CH2:14][CH2:15][CH:11]3[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:18])[CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:23][N:24]=1
Reactant: Nc1cccc2cnccc12
Reactant: CCCCCCCCCCC1CCCC1C(=O)O
Product: CCCCCCCCCCC1CCCC1C(=O)Nc1cccc2cnccc12

Procedure:
2-(Decyl)cyclopentane carboxylic acid, prepared according to the procedure of Hoefle, et. al. (U.S. Pat. No. 4,715,175), was coupled with 5-aminoisoquinoline according to the procedure outlined in Example 47 to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH3:14])[CH2:9]2)[N:5]=[C:4]([NH:15][CH3:16])[N:3]=1.[CH3:17][I:18]>O1CCOCC1>[I-:18].[CH3:17][N+:3]1[C:4]([NH:15][CH3:16])=[N:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([CH3:14])[CH2:9]2)=[N:7][C:2]=1[CH3:1]
Reactant: CI
Reactant: CNc1nc(C)nc(N2CCCC(C)C2)n1
Solvent: C1COCCO1
Product: CNc1nc(N2CCCC(C)C2)nc(C)[n+]1C
Product: [I-]
Yield: 72 %

Procedure:
A mixture of 2-methyl-6-methylamino-4-(3-methylpiperidino)-1,3,5-triazine (221 mg; 1 mM) and methyl iodide (0.5 ml; 8 mM) and dioxane (5 ml) was heated at reflux for 15 hours. The mixture was cooled, the solvent removed under reduced pressure and the residue was crystallised from a mixture of methanol and ether. There was thus obtained 1,2-dimethyl-6-methylamino-4-(3-methylpiperidino)-1,3,5-triazinium iodide (262 mg, 72% yield) m.p. 214°-214.5° C.; microanalysis found: C,39.7; H,5.8; N,19.3%; C12H22N5I requires: C,39.7; H,6.1; N,19.3%; NMR (200 MHz). (CDCl3): 0.95-1.05 (3H,q, piperidine 3--CH3), 1.2-2.0 (5H, complex, piperdine 3H, 4--CH2 and 5--CH2), 2.5-2.6 (3H, s, CH3), 2.6-3.15 (2H, complex, piperidine 2 --H axial and 6--H axial), 3.05-3.15 (3H,d, NHCH3), 3.9 (3H,s, N--CH3), 4.45-4.7 (2H, complex piperidine 2--H equatorial and 6--H equatorial), 8.6-8.8 (1H, br, NH). [Note: the site of quaternisation was confirmed by conventional nuclear Overhauser studies].
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:12]([OH:14])=O)[S:10][CH:11]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:37][C:32]1[CH:31]=[C:30]([CH2:29][C@H:16]([NH:15][C:12]([C:9]2[S:10][CH:11]=[C:7]([C:6]3[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=3)[CH:8]=2)=[O:14])[CH2:17][N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[CH:35]=[CH:34][C:33]=1[Cl:36]
Reactant: Cn1nccc1-c1csc(C(=O)O)c1
Reactant: N[C@@H](Cc1ccc(Cl)c(Cl)c1)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1nccc1-c1csc(C(=O)N[C@@H](Cc2ccc(Cl)c(Cl)c2)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.6 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (160 mg, 0.62 mmol) [prepared according to the procedure of Example 146], 2-[(2S)-2-amino-3-(3,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (0.26 g, 0.67 mmol) [prepared according to the procedure of Preparation 6 except substituting 3,4-dichloro-N-{[(1,1-dimethylethyl)oxy]carbonyl}-L-phenylalanine (2.03 g, 6.07 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (376 mg, 0.80 mmol) in chloroform (4 mL). DIEA (0.55 mL, 3.15 mmol) was added and the mixture stirred overnight at room temperature. The reaction mixture was adsorbed onto silica and purified via column chromatography (25-75% EtOAc/Hex) affording the title compound (149 mg, 30%): LC-MS (ES) m/z=539 (M+H)+