Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][CH2:26][NH:27][CH2:28][C:29]4[C:30]5[N:37]([CH2:38][CH3:39])[C:36]([C:40]6[C:44]([NH2:45])=[N:43][O:42][N:41]=6)=[N:35][C:31]=5[CH:32]=[N:33][CH:34]=4)[CH2:20][CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>ClCCl>[CH2:38]([N:37]1[C:30]2[C:29]([CH2:28][NH:27][CH2:26][CH2:25][CH2:24][N:21]3[CH2:22][CH2:23][NH:18][CH2:19][CH2:20]3)=[CH:34][N:33]=[CH:32][C:31]=2[N:35]=[C:36]1[C:40]1[C:44]([NH2:45])=[N:43][O:42][N:41]=1)[CH3:39]
Reactant: CCn1c(-c2nonc2N)nc2cncc(CNCCCN3CCN(C(=O)OCC4c5ccccc5-c5ccccc54)CC3)c21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CCn1c(-c2nonc2N)nc2cncc(CNCCCN3CCNCC3)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.4 %

Procedure:
The product from step 4 (0.17 g, 0.28 mmole) was dissolved in dichloromethane (3 ml) and treated with piperidine (0.3 ml, 2.8 mmole). The mixture was stirred at room temperature under argon for 4 hours. The solvent was removed in vacuo and the residue purified by column chromatography on silica gel eluting with ammonia/methanol/dichloromethane (1:9:90) to afford the title compound (0.063 g). MS (ES+) m/e 386 [M+H]+.
Reaction SMILES: [P:1]([NH:11][CH2:12][CH3:13])([NH:8][CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:14](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN([CH2:33][CH3:34])CC>C(Cl)Cl>[P:14]([N:11]([P:1]([N:8]([P:14]([C:34]1[CH:33]=[CH:26][CH:21]=[CH:22][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:9][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH3:13])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCN(CC)CC
Reactant: CCNP(NCC)c1ccccc1
Reactant: ClP(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCN(P(c1ccccc1)c1ccccc1)P(c1ccccc1)N(CC)P(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 86.7 %

Procedure:
A solution of PPh(NHEt)2 (0.301 g, 1.5 mmol) in CH2CH2 (20 cm3) was added to PPh2Cl (0.677 g, 3.0 mmol) dissolved in CH2Cl2 (5 cm3) containing NEt3 (0.466 g, 4.6 mmol) and stirred for two hours. The solvent was removed in vacuo affording an off white solid. The solid was washed with 3×20 cm3 aliquots of diethylether, the washings combined and the solvent then removed in vacuo yielding a white solid characterised as Ph2PN(Et)P(Ph)N(Et)PPh2 (0.54 g 1.3 mmol) 31P [H] NMR (CD2Cl2)=53.5 [d, PPh2, 2P, J (PP) 25]. 105.1 [t, PPh, J(PP) 25 Hz] ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:13][C:14]([F:25])([F:26])[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=[N:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1cncc(Br)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CCOC(=O)c1cncc(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
3.35 g (14.6 mmol) of ethyl 5-bromonicotinate, 4.50 g (21.9 mmol) of 4-(trifluoromethoxy)-phenylboronic acid, 0.84 g (0.73 mmol) of tetrakis(triphenylphosphine)palladium(0) and 3.01 g (29.1 mmol) of sodium carbonate were dissolved in a mixture of 38 ml of 1,2-dimethoxyethane, 7.5 ml of water and 91 ml of dimethylformamide and stirred at 85° C. for 18 h. For work-up, some of the dimethylformamide was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulphate and the crude product was purified by flash chromatography (dichloromethane/acetonitrile 100:0→100:5). Yield: 2.64 g (55% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:11]3([O:15][N:14]([CH3:16])[C:13]([NH2:17])=[N:12]3)[CH2:10][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[O:8][C:5]2=[CH:6][CH:7]=1.[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[NH2:17][C:13]1[N:14]([CH3:16])[O:15][C:11]2([C:4]3[C:5](=[CH:6][CH:7]=[C:2]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]#[N:25])[CH:3]=3)[O:8][CH:9]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:10]2)[N:12]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1OC2(CC(C3CCOCC3)Oc3ccc(Br)cc32)N=C1N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1OC2(CC(C3CCOCC3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 4.8 %

Procedure:
A mixture of 6-bromo-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazol]-3′-amine (50 mg, 0.131 mmol), 3-cyanophenylboronic acid (40 mg, 0.222 mmol), Cs2CO3 (2 M, 0.5 mL) and Pd(PPh3)2C12 (15 mg) in 1,4-dioxane (3 mL) under Ar was stirred in a microwave reactor at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified preparative TLC and HPLC to give 3-(3′-amino-2′-methyl-2-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[chroman-4,5′-[1,2,4]oxadiazole]-6-yl)benzonitrile (2.54 mg, 5%). 1H-NMR (CDCl3): 1.54 (m, 2H), 1.62 (m, 1H), 1.88 (m, 1H), 2.10 (m, 1H), 2.48 (m, 1H), 3.39 (m, 3H), 3.42 (m, 3H), 4.03 (m, 3H), 6.90 (m, 1H), 7.45 (m, 2H), 7.58 (m, 2H), 7.62 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:1][C:2]2[O:6][N:5]=[C:4]([CH3:7])[C:3]=2[Br:8])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: Cc1noc(NS(=O)(=O)c2ccc(F)cc2)c1Br
Yield: 71 %

Procedure:
4-Fluoro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared in the same manner as described in Example 5 from 5-amino-4-bromo-3-methylisoxazole and 4-fluorobenzenesulfonyl chloride in 71% yield. Purification was achieved by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 142°-144° C.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=2[S:17]([CH3:20])(=[O:19])=[O:18])[N:7]([C:21](OC2C=CC([N+]([O-])=O)=CC=2)=[O:22])[C:6](=[O:33])[N:5]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)[C:4]=1[CH3:44])#[N:2].[OH:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1>C(#N)C>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C@@H:8]2[C:3]([C:1]#[N:2])=[C:4]([CH3:44])[N:5]([C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:41])([F:43])[F:42])[CH:35]=3)[C:6](=[O:33])[N:7]2[C:21]([N:51]2[CH2:52][CH2:53][N:48]([CH2:47][CH2:46][OH:45])[CH2:49][CH2:50]2)=[O:22])=[C:10]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:11]=1)#[N:16]
Reactant: OCCN1CCNCC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1c1cccc(C(F)(F)F)c1
Solvent: CC#N
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(C(=O)N2CCN(CCO)CC2)C(=O)N1c1cccc(C(F)(F)F)c1

Procedure:
According to the General Procedure 1, 4-nitrophenyl (6S)-5-cyano-6-[4-cyano-2-(methylsulfonyl)phenyl]-4-methyl-2-oxo-3-[3-(trifluoromethyl)phenyl]-3,6-dihydropyrimidine-1(2H)-carboxylate (78 mg, 0.125 mmol; Example 6A) was reacted with N-(2-hydroxyethyl)piperazine (48.7 mg, 0.374 mmol) in acetonitrile (1.0 ml) to give the target compound (68 mg, 85% of theory).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](/[CH:31]=[CH:32]/[C:33]([O:35]CC)=[O:34])[CH:5]=[C:6]([CH3:30])[C:7]=1[O:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[Na+].Cl>C1COCC1.CO>[CH3:30][C:6]1[CH:5]=[C:4](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])[CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][CH:9]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:24][CH:25]=2)[N:15]=1)[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(Oc1c(C)cc(/C=C/C(=O)OCC)cc1C)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCC(Oc1c(C)cc(/C=C/C(=O)O)cc1C)c1cccc(-c2ccc(C(F)(F)F)cc2)n1
Reaction time: 2 h
Yield: 82.7 %

Procedure:
To a stirring solution of ethyl (2E)-3-{3,5-dimethyl-4-[(1-{6-[4-(trifluoromethyl)phenyl]-2-pyridinyl}pentyl)oxy]phenyl}-2-propenoate (35 mg, 0.07 mmol) in THF (5 mL) and MeOH (5 mL) at ambient temperature was added NaOH (2N, 5 mL) and the mixture stirred for 2 h and then left to stand overnight. HCl (2N, 5 mL) was then added and the mixture reduced under vacuum. The residue was then purified by SPE (silica, 5 g cartridge) with a pad of celite on the top, eluting with cyclohexane:EtOAc (gradient 3:1 to 0:1) the EtOAc:MeOH (gradient 95:5 to 0:1) to give the title compound (28 mg).
Reaction SMILES: C(=O)=O.CC(C)=O.[Li]CCCC.Br[C:14]1[CH:15]=[CH:16][C:17]([F:20])=[N:18][CH:19]=1.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C>CC(OC)(C)C>[F:20][C:17]1[N:18]=[CH:19][C:14]([B:25]([OH:26])[OH:24])=[CH:15][CH:16]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: O=C=O
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: OB(O)c1ccc(F)nc1
Temperature: 6 °C
Reaction time: 0.83 h
Yield: 79 %

Procedure:
To stirred and cooled (dry ice-acetone bath) anhydrous [TBME] (620 mL; in a 3 L three-necked round-bottomed flask equipped with mechanical stirrer, temperature probe with adapter, and nitrogen inlet) was added (via syringe) 2 M BuLi (352 mL, 0.704 mol, 1.2 eq). To this rapidly stirred and cooled (<−75° C.) mixture was added a solution of 3 (102.2 g, 0.581 mol) in anhydrous TBME (100 mL) over a period of 13 min during which time the internal temperature rose to −62° C. The reaction was stirred for another 45 min (the temperature was maintained between −62° C. and −80° C.), followed by the rapid and sequential addition of four portions of triisopropylborate (total of 180 g, 0.957 mol, 1.65 eq). At the end of the addition the internal temperature had risen to −33° C. After stirring an additional 45 min over the cold bath (internal temperature lowered from −33° C. to −65° C.), the cold bath was removed and the stirred mixture on its own rose to −22° C. over a period of 50 min. After warming (via water bath) to 6° C. over a period of 15 min, the stirred reaction mixture was placed in an ice-water bath and then quenched under nitrogen with a cooled solution of NaOH (160 g) in water (500 mL). Once the addition was complete, the internal temperature was 20° C. This mixture was stirred at room temperature for 1.5 h. The aqueous layer was removed, neutralized to pH 7 with ˜350 mL concentrated HCl, and then extracted with EtOAc (3×1 L). Because the pH was now 8-9, the aqueous layer was adjusted to pH 7 using ˜15 mL concentrated HCl and extracted further (2×1 L) with ethyl acetate. The combined EtOAc extracts were dried (Na2SO4), filtered, and concentrated to a volume of ˜150 mL. With swirling of the concentrate, heptane was added in portions (total volume of 300 mL) resulting in the precipitation/crystallization of the product. Filtration, washing of the solid with heptane (100 mL, 300 mL, then another 300 mL), and air drying gave the title product as an off-white solid (68.6 g, yield of 79-90%*; LC purity of 96.4%, NMR showed an estimated 5.5% w/w of heptane), which was used successfully without further purification. LC/MS showed it to be a mixture of the two following entities, the intensity of the higher molecular weight entity being major (*Note: yield of reaction is 79% if the boronic acid is assumed to be the only constituent and is 90% if it is assumed that the cyclic borate is the only constituent):
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:14][C:15]1[C:24]2[C:19](=[C:20]([O:29][CH3:30])[C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[CH2:18][CH2:17][N:16]=1.C(N(CC)CC)C>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([N:16]1[CH2:17][CH2:18][C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[C:20]=2[O:29][CH3:30])[C:15]1=[CH2:14])=[O:6]
Reactant: COc1cc2c(c(OC)c1OC)CCN=C2C
Reactant: COc1ccc(OC)c(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C=C1c2cc(OC)c(OC)c(OC)c2CCN1C(=O)c1cc(OC)ccc1OC
Reaction time: 2 h
Yield: 88 %

Procedure:
A solution of compound 45 (746 mg, 3.7 mmol) in anhydrous benzene (2 mL) was slowly added at room temperature to a solution of compound 44 (880 mg, 3.7 mmol) in anhydrous benzene (10 mL) containing triethylamine (568 mg, 5.6 mmol, 0.78 mL). The resulting solution was heated at reflux with stirring under Ar for 2 h. White NH4Cl precipitated and was removed by filtration. The filtrate was evaporated to dryness and the residue was subjected to flash chromatography (ether:triethylamine, 99:1 by volume, silica gel 230-300 mesh) to give compound 46 as an oil (1.3 g, 87.8%): 1H NMR (CDCl3, 200 MHz) δ6.87 (s, 1H), 6.85 (d, 1H, J=10 Hz), 6.80 (d, 1H, J=3 Hz), 6.70 (d, 1H, J=10 Hz), 5.21 (s, br 1H), 4.55 (s, br, 1H), 3.90 (s, 6H), 3.88 (s, 3H), 3.84 (s, 3H), 3.75 (s, 3H), 3.41 (s, br, 2H), 2.88 (t, 2H, J=6 Hz). CIMS (isobutane) m/e 400 (MH+, 100).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1.O>CC(C)=O>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:13][S:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)(=[O:11])=[O:12])=[O:25])=[CH:19][CH:18]=1
Reactant: NS(=O)(=O)c1ccc2c(c1)CCC2
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccc(Cl)cc1)NS(=O)(=O)c1ccc2c(c1)CCC2
Yield: 87.4 %

Procedure:
To a mixture of 93.2 g of indane-5-sulfonamide in 300 ml of acetone were added 490 ml of 1N sodium hydroxide. A solution of 79.36 g of 4-chlorophenylisocyanate in 250 ml of acetone was added to the reaction mixture with stirring. After stirring at room temperature for about 18 hours, the reaction mixture was filtered and 490 ml of 1N hydrochloric acid were added to the filtrate, thereby providing a fine white precipitate. One liter of water was added, and the solid was recovered by filtration to provide 144.86 g of the desired title product. m.p. 169-172° C.
Reaction SMILES: [S:1]=[C:2](C(S)C(OCC)=O)[CH3:3].[NH:11]([C:13]([O:15][CH3:16])=[O:14])[NH2:12].C(Cl)(Cl)Cl.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>ClCCl>[S:1]=[C:2]([NH:12][NH:11][C:13]([O:15][CH3:16])=[O:14])[CH3:3]
Reactant: CCOC(=O)C(S)C(C)=S
Reactant: COC(=O)NN
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COC(=O)NNC(C)=S
Yield: 65.3 %

Procedure:
A mixture of 129 g of 2-(1-thioxoethyl)thioglycolic acid, ethyl ester, 67.5 g of methyl hydrazinocarboxylate and 500 ml of chloroform was heated at reflux for 8 hours, then concentrated in vacuo. The oily residue was concentrated further under high vacuum, giving a yellow oil. This oil was dissolved in 500 ml of dichloromethane and passed through a bed of hydrous magnesium silicate, washing with additional dichloromethane. The resulting light yellow oil was crystallized from toluene-methylcyclohexane, giving 70 g of the desired compound as ivory crystals, mp 99°-100.5° C. Proton nuclear magnetic resonance (δ [ppm], CDCl3) 90 MHz: 2.42 (s, 3H, CH3CS); 3.76 (s, 3H, OCH3); 8.55 (bs, 1H, NH); 9.56 (bs, 1H, NH).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Br:12][CH2:13][CH2:14][CH2:15][CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C=O)C>[Br-:12].[C:17]1([CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:15][CH2:14][CH2:13][N+:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[OH:1])[CH:7]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1cccc2cnccc12
Reactant: BrCCCC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Oc1cccc2c[n+](CCCC(c3ccccc3)c3ccccc3)ccc12
Product: [Br-]
Temperature: 80 °C
Reaction time: 16 h
Yield: 69.6 %

Procedure:
A mixture of 5-hydroxyisoquinoline (2.17 g, 14.95 mmol) and 1-bromo-4,4-diphenylbutane (4.79 g, 16.56 mmol) in 75 mL of anhydrous DMF was stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature. Ethyl acetate (200 mL) was added to precipitate product. The solid was collected by filtration and washed with ethyl acetate (1×70 mL). The solid was air-dried to give 4.52 g of product as an off-white solid.
Reaction SMILES: C(S([C:11]1[N:20]=[CH:19][C:18]2[CH2:17][CH2:16][C:15]3[C:21]([C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:26])=[N:22][N:23]([CH3:24])[C:14]=3[C:13]=2[N:12]=1)(=O)=O)C1C=CC=CC=1.[CH:33]1([NH2:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CS(C)=O>[CH:33]1([NH:39][C:11]2[N:20]=[CH:19][C:18]3[CH2:17][CH2:16][C:15]4[C:21]([C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:26])=[N:22][N:23]([CH3:24])[C:14]=4[C:13]=3[N:12]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.[CH:33]1([NH:39][C:11]2[N:20]=[CH:19][C:18]3[CH:17]=[CH:16][C:15]4[C:21]([C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[O:26])=[N:22][N:23]([CH3:24])[C:14]=4[C:13]=3[N:12]=2)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: Cn1nc(C(=O)c2ccccc2)c2c1-c1nc(S(=O)(=O)Cc3ccccc3)ncc1CC2
Reactant: NC1CCCCC1
Solvent: CS(C)=O
Product: Cn1nc(C(=O)c2ccccc2)c2c1-c1nc(NC3CCCCC3)ncc1CC2
Product: Cn1nc(C(=O)c2ccccc2)c2ccc3cnc(NC4CCCCC4)nc3c21
Reaction time: 16 h
Yield: 70 %

Procedure:
83 mg (0.19 mmol) of [8-(benzylsulfonyl)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl](phenyl)methanone were dissolved in 3 mL of dimethylsulfoxide and cyclohexylamine (0.033 mL, 0.29 mmol) and the solution was heated at 100° C. under stirring for 16 hours. The solvent was then removed under reduced pressure and the crude purified by chromatography on a silica gel column (eluant dichloromethane/acetone) giving 31 mg of [8-(cyclohexylamino)-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazolin-3-yl](phenyl)methanone and 15 mg of [8-(cyclohexylamino)-1-methyl-1H-pyrazolo[4,3-h]quinazolin-3-yl](phenyl)methanone (70% yield overall).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[N:27]=2)[CH:20]=1.O>CN1C(=O)CCC1.[Cu]I>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([O:11][C:19]3[N:24]=[CH:23][N:22]=[C:21]([NH:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[N:27]=4)[CH:20]=3)[CH:9]=[CH:10][C:2]1=2
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Reactant: Oc1ccc2c(c1)OCCO2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1cccc(Nc2cc(Oc3ccc4c(c3)OCCO4)ncn2)n1
Temperature: 100 °C
Yield: 29 %

Procedure:
A stirred mixture of 2,3-dihydrobenzo[b][1,4]dioxin-6-ol (0.137 g, 0.90 mmol), Cs2CO3 (0.734 g, 2.25 mmol), CuI (0.02 g, 10% w/w), and N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine (0.29 g, 0.90 mmol) in NMP (1 mL) was heated at 100° C. for 16 h. The reaction mixture was cooled to rt and slowly added to demineralised water. The solid that precipitated was collected by filtration and was further purified by column chromatography (SiO2, 60-120, pet ether/ethyl acetate, 7/3) to give N2-(6-(2,3-dihydrobenzo[b][1,4]dioxin-6-yloxy)pyrimidin-4-yl)pyridine-2,6-diamine (0.088 g, 29%) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10].O>C(OCC)(=O)C>[CH2:7]([N:6]1[C:2]([NH:1][CH:19]=[C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:23])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][CH:4]=[N:5]1)[CH3:8]
Reactant: CCn1nccc1N
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CNc1ccnn1CC)C(=O)OCC
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of 5-amino-1-ethylpyrazole (1 gm, 0.0089 mole) and diethylethoxymethylenemalonate (1.9 ml, 0.0089 mole) was stirred at 120° C. for about 1 hour. The reaction mixture was poured into water and extraction was done with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give yellow oil. Yield: 2.5 g. m/z: (M++1) 282.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][NH:23][S:24]([C:27]3([CH3:30])[CH2:29][CH2:28]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([CH2:35][C:36]([O:38][CH3:39])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:40](P(CCCC)(CCCC)=CC#N)CCC>CO.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[N:12]([C@@H:21]([CH2:31][CH3:32])[CH2:22][N:23]([CH3:40])[S:24]([C:27]3([CH3:30])[CH2:28][CH2:29]3)(=[O:26])=[O:25])[C:11](=[O:33])[C@:10]([CH2:35][C:36]([O:38][CH3:39])=[O:37])([CH3:34])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Reactant: CC[C@@H](CNS(=O)(=O)C1(C)CC1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: CC[C@@H](CN(C)S(=O)(=O)C1(C)CC1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(1-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetate (21.7 mg, 0.036 mmol; Example 193), 2-(tributylphosphoranylidene)acetonitrile (8.8 mg, 0.036 mmol) and one drop of MeOH in toluene (0.5 mL) was stirred at 110° C. for 1 h. Flash column purification on silica gel (0 to 60% EtOAc in hexanes) gave methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,1-dimethylcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate. This was hydrolyzed with LiOH (1N solution in water, 0.3 mL) in ethanol (0.5 mL) for 3 h at rt. HPLC purification (C18 column, eluted with 10 to 95% CH3CN in water, with 0.1% TFA) gave the title compound.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][NH:6][CH:7]=1)#N.[CH2:8]([Mg]Br)[CH3:9].S(=O)(=O)(O)[OH:13].[OH-].[Na+]>C1COCC1.O>[NH:6]1[CH:7]=[C:3]([C:1](=[O:13])[CH2:8][CH3:9])[N:4]=[CH:5]1
Reactant: N#Cc1c[nH]cn1
Reactant: O=S(=O)(O)O
Reactant: CC[Mg]Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(=O)c1c[nH]cn1
Temperature: 20 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
A solution of 4-cyanoimidazole (2 g, 21.4 mmol) in THF (25 ml) was added dropwise to a solution (68.5 mL, 68.5 mmol, 3.2 equivalents) of 1 M ethyl magnesium bromide in THF at 0 to 10° C. under a nitrogen atmosphere. The mixture was stirred at 15 to 25° C. for 4 h. Water (20 ml) and 10% aqueous sulfuric acid solution (45 ml) were successively added dropwise, and the mixture was stirred for 1 h. A 30% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 8. After partitioning, the aqueous layer was extracted with ethyl acetate (15 ml×2). The organic layer was combined, and the mixture was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, and concentrated under reduced pressure. The concentration residue was broken up with n-hexane (6 ml), and the crystals were collected by filtration and washed with n-hexane. The crystals were dried in vacuo (40° C.) to give 1-(1H-imidazol-4-yl)-1-propanone (1.68 g, yield 63%).