Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:32]1[O:33][N:34]=[C:35]2[C:40](S([Cl:44])(=O)=O)=[CH:39][CH:38]=[CH:37][C:36]=12>>[ClH:44].[N:32]1[O:33][N:34]=[C:35]2[C:40]([NH:22][S:23]([C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]4)=[CH:4][C:3]=3[NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])(=[O:25])=[O:24])=[CH:39][CH:38]=[CH:37][C:36]=12
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: O=S(=O)(Cl)c1cccc2nonc12
Product: Cl
Product: O=S(=O)(Nc1cc(N2CCCNCC2)ccc1S(=O)(=O)Nc1cccc2nonc12)c1ccccc1

Procedure:
N-(2,1,3-benzoxadiazol4-yl)-4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]benzenesulfonamide hydrochloride was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)- phenyl}benzenesulfonamide (0.072 g, 0.16 mmol) and 2,1,3-benzoxadiazol-4-yl sulfonyl chloride (0.072 g, 0.21 mmol) to give 38.0 mg of a light purple solid; M+1 537.2 Calcd 537.15; 1HNMR δ 8.21 (d, 1H), 7.80 (d, 1H), 7.68-7.46 (m, 6H), 6.92 (d, 1H), 6.49 (dd, 1H), 6.12 (d, 1H), 3.57 (app t, 2H), 3.34 (app t, 2H), 3.17 (app t, 2H), 3.11 (app t, 2H), 2.03-1.95 (m, 2H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6]N=O.[CH2:9]=[C:10]=[O:11].[C]=O>ClC1C=CC=CC=1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:10]([CH3:9])=[O:11]
Reactant: C=C=O
Reactant: CCCCCON=O
Agent: [C]=O
Solvent: Clc1ccccc1
Product: CCCCCOC(C)=O
Reaction time: 3 h
Yield: 28.3 %

Procedure:
To the same reaction vessel as in Example 9 were charged bistriphenylphosphinedibromopalladium (0.791 g, 1 mmole), stannous bromide (0.558 g, 2 mmoles) and tetra-n-ethylammonium bromide (0.420 g, 2 mmoles), together with n-amyl nitrite (50 ml, 356.0 mmoles) and chlorobenzene (200 ml). Then, nitrogen gas containing 10.0 vol.% of ketene and carbon monooxide were introduced to the mixture at the rate of 116.1 ml/min and 200 ml/min, respectively, and the reaction was performed at 90° C. for 3 hours. The reaction mixture was analyzed to reveal that di-n-amyl malonate (63.0 mmoles, 49.4%) and n-amyl acetate (36.5 mmoles, 28.3%) were obtained.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([N:18]2[CH:22]=[CH:21][CH:20]=[CH:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[C:12]1([N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: c1ccc(-n2cccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: O=C(O)c1ccccc1C(=O)c1cccn1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2.96 g (0.02 mole) of phthalic anhydride and 5.72 g (0.04 mole) of N-phenylpyrrole in 50 ml of chlorobenzene, maintained at 0°-5° C. in an ice bath, 810 g (0.06 mole) of aluminum chloride was added in small portions. The reaction mixture was held at 0°-5° C. for approximately two hours. The reaction was allowed to warm to room temperature and then set aside overnight at ambient temperature. The reaction mixture was worked up in a manner similar to that described in part A of Example 15 to obtain 2-[(1-phenyl-2-pyrrolyl)carbonyl]benzoic acid (Formula IX: Ro =R1 =R2 =R3 =H; R7 =C6H5) which melted over the range 159°-168° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.Cl[C:16]1[N:21]2[N:22]=[C:23]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[C:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:20]2[N:19]=[C:18]([CH3:39])[N:17]=1.O>CN(C=O)C>[CH2:1]([NH:5][C:16]1[N:21]2[N:22]=[C:23]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[C:24]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)=[C:20]2[N:19]=[C:18]([CH3:39])[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNc1nc(C)nc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reaction time: 40 h

Procedure:
To a mixture of butylamine (0.17 ml, 0.15 mmol) and diisopropylethylamine (0.037 ml, 0.21 mmol) in DMF (0.75 ml) was added a solution of 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 54 mg, 0.14 mmol) in DMF (1.3 ml). After stirring for 40 hours, the reaction was treated with water, dropwise, until a precipitate formed. After several more hours of stirring, the resultant solid was collected by vacuum filtration, and then washed with water and a small amount of isopropyl alcohol to afford 7A-1 (46 mg, 77%) as a solid: +APcI MS (M+1) 426.2; 1H NMR (400 MHz, CD3OD) δ 7.51-7.30 (m, 6H), 7.22-7.18 (m, 2H), 3.63 (t, J=7.1 Hz, 2H), 2.50 (s, 3H), 1.70 (quintet, J=7.3 Hz, 2H), 1.44 (hextuplet, J=7.5 Hz, 2H), 0.98 (t, J=7.5 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]([CH3:14])([CH2:12][CH3:13])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:24][CH2:25][CH2:26][O:27]CC1C=CC=CC=1.O>CN(C=O)C.CO.[Pd]>[OH:27][CH2:26][CH2:25][CH2:24][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:14])([CH2:12][CH3:13])[C:8]([O:10][CH3:11])=[O:9])=[CH:15][CH:16]=1
Reactant: CCC(C)(Oc1ccc(O)cc1)C(=O)OC
Reactant: BrCCCOCc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCC(C)(Oc1ccc(OCCCO)cc1)C(=O)OC
Temperature: 45 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
To a solution of methyl 2-(4-hydroxyphenoxy)-2-methylbutanoate (5 g, 22.32 mmol) in 30 mL DMF was added cesium carbonate (8.7 g, 26.7 mmol) followed by benzyl 3-bromopropyl ether (7.7 g, 33.6 mmol). The solution was stirred at 45° C. for 24 hr, cooled and poured over water. Extraction with AcOEt followed by washing the extracts with water, drying over anhydrous Na2SO4 and concentrating under reduced pressure gave the crude residue. Purification over silica gel using AcOEt/hexanes furnished the desired alkylated derivative (8.25 g). This product was taken up in MeOH (75 mL) and hydrogenated over 10% Pd/C at 40 psi to provide methyl 2-(4-(3-hydroxypropoxy)phenoxy)-2-methylbutanoate (6.23 g, quantitative).
Reaction SMILES: OC[CH2:3][NH:4][CH2:5][CH2:6][NH2:7].C(=S)=[S:9].Cl.[CH2:12]([OH:14])[CH3:13].O>>[OH:14][CH2:12][CH2:13][N:4]1[CH2:5][C:6](=[S:9])[N:7]=[CH:3]1
Reactant: S=C=S
Reactant: CCO
Reactant: NCCNCCO
Agent: Cl
Solvent: O
Product: OCCN1C=NC(=S)C1

Procedure:
(Hydroxyethyl)ethylenediamine (25 ml) is dissolved in 1:1 ethyl alcohol-water (85 mL) and heated to 40°-50° C. Carbon disulfide (16.5 ml) is added dropwise over a period of about 15 minutes. After about half of the amount is added, the exothermic reaction starts and the reaction mixture solidifies. After the addition of all of the carbon disulfide, the mixture is refluxed gently for about 1 hour. Concentrated hydrochloric acid (2 ml) is then added and the reaction mixture is refluxed overnight. The solid which separates after the addition of carbon disulfide redissolves. The solution is cooled in an ice bath, and the solid separates, is filtered out, washed well with isopropyl alcohol and t-butyl methyl ether and dried to give 23.3 g of 1-(2-hydroxyethyl)-2-imidazolinethione, melting point 137°-138° C.
Reaction SMILES: [O:1]1C=C[CH:3]=[C:2]1CCCC(OC(C)C)=O.[O:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].[CH2:28]([OH:31])[CH2:29]C>[PH4+].C(O)C>[CH2:2]([O:1][C:16]1([CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:17]=[CH:18][CH:19]([O:31][CH2:28][CH3:29])[O:15]1)[CH3:3]
Reactant: CCCO
Reactant: CC(C)OC(=O)CCCc1ccco1
Reactant: COC(=O)CCCCc1ccco1
Agent: [PH4+]
Solvent: CCO
Product: CCOC1C=CC(CCCCC(=O)OC)(OCC)O1

Procedure:
Adaption of the above-described procedures to the preparation of the other compounds of this invention essentially involves the lengthening or shortening of, or the introduction of one or two lower alkyl groups into, the side-chains in furans (I) or (XVII) or in phosphonium derivative (III). These adaptations can be accomplished by procedures well-known to the art. For example, isopropyl γ-(2-furyl)butyrate provides 2,5-dihydro-2,5-di-n-propoxy-2-(3'-carbo-isopropoxypropyl)furan in n-propanol whereas methyl δ-(2-furyl)valerate provides 2,5-dihydro-2,5-diethoxy-2-(4'-carbomethoxybutyl)furan in ethanol when treated in the manner described for the conversion of (I) to (II). Similarly, ω-(2-furyl)caproic acid and ω-(2-furyl)enanthic acid provide 2,5-dihydro-2,5-diethoxy-2-(5'-carboxyentyl)furan and 2,5-dihydro-2,5-diethoxy-2-(6'-carboxyhexyl)furan when treated in ethanol in the manner described for the conversion of (XVII) to (XVIII). Optionally, the furyl acids may be first esterified prior to oxidative alkoxylation, and all 2,5-dihydro-2,5-dialkoxy-2-(carboalkoxyalkyl)furans may be converted to the corresponding aldehydes in the manner described for the conversion of (II) to (IV). Also, the reaction of 3-carboxypropyltriphenylphosphonium bromide and 5-carboxy-3,4-dimethylamyltriphenylphosphonium bromide with 2,5-dihydro-2,5-diethoxy-2-(4'-oxobutyl)furan and 2,5-dihydro-2,5-diethoxy-2-(2'-oxoethyl)furan, respectively, provides the 2,5-dihydro-2,5-diethoxy-2-(7'-carboxy-4'-cis-heptenyl)furan and 2,5-dihydro-2,5-diethoxy-2-(7'-carboxy-5',6'-dimethyl-2-cis-heptenyl)furan.
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH:4]([OH:6])[CH3:5].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11](S(O)(=O)=O)=[CH:10][CH:9]=1.[C:19]1(C)C=CC=CC=1>>[CH3:5][CH:4]1[CH2:3][CH:2]([CH3:1])[O:7][C:9]2([CH:10]([CH3:19])[CH2:11][CH2:12][CH2:13][CH:8]2[CH3:18])[O:6]1
Reactant: CC(O)CC(C)O
Reactant: Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1CC(C)OC2(O1)C(C)CCCC2C
Temperature: 120 °C

Procedure:
A reaction flask equipped with a Dean Stark trap was charged with 2,6-dimethyl cyclohehanone (252 g), 2,4-pentanediol (312 g), p-toluenesulfonic acid (6 g) and toluene (300 mL). The reaction mass was heated to reflux (110-130° C.). Water (36 mL) was collected in the Dean Stark trap. When no water was recovered, the reaction mass was cooled to an ambient temperature, neutralized with 10% aqueous sodium carbonate (100 mL) and washed with brine. Purification by vacuum distillation afforded 2,4,7,11-tetramethyl-1,5-dioxaspiro[5,5]undecane (339 g), which had a boiling point of 124° C. at a pressure of 40 mmHg.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:2]1.[Br:12][C:13]1[CH:18]=[C:17](F)[CH:16]=[C:15]([F:20])[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:12][C:13]1[CH:18]=[C:17]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)=[CH:2]2)[CH:16]=[C:15]([F:20])[CH:14]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: c1ccc(-c2cc[nH]c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cc(Br)cc(-n2ccc(-c3ccccn3)c2)c1
Temperature: 140 °C
Yield: 27.8 %

Procedure:
2-(1H-Pyrrol-3-yl)pyridine (2.0 g, 17 mmol), 1-bromo-3,5-diflurobenzene (6.6 g, 34 mmol), potassium carbonate (2.4 g, 34 mmol) were combined in DMF (30 mL) under argon. The reaction mixture was heated at 140° C. overnight. The reaction mixture was allowed to cool to ambient temperature. TLC analysis showed no starting material present. The reaction mixture was diluted with EtOAc (300 mL), and washed with H2O (3×300 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a dark oil which solidified when pumped down under high vacuum. The crude product was purified by column chromatography eluting with 2:8 EtOAc:hexanes to afford 2-[1-(3-bromo-5-fluorophenyl)-1H-pyrrol-3-yl]pyridine (1.5 g, 35% yield) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ 8.61-8.62 (d, 1H), 8.50-8.53 (t, 1H), 8.40 (s, 1H), 8.35-8.36 (d, 1H), 7.78-7.81 (m, 2H), 7.57-7.62 (m, 1H), 7.54-7.57 (d, 1H), 7.43-7.46 (d, 1H), 7.11 (s, 1H), MS 319.1 (M++H).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13].C(N(CC)CC)C.[CH3:21][NH:22][CH2:23][CH:24]=[CH2:25]>C(O)C>[CH2:23]([N:22]([CH3:21])[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]=[O:13])[CH:24]=[CH2:25]
Reactant: Cn1c(Cl)c(C=O)c(=O)n(C)c1=O
Reactant: C=CCNC
Solvent: CCO
Solvent: CCN(CC)CC
Product: C=CCN(C)c1c(C=O)c(=O)n(C)c(=O)n1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 6-chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbaldehyde (0.500 g, 2.47 mmol) and triethyl-amine (0.52 ml, 3.71 mmol) in dry ethanol (10 ml), N-methylprop-2-en-1-amine (0.36 ml, 3.71 mmol) was added under argon. The resulting mixture was stirred at room temperature under argon overnight. After evaporation of the solvent in vacuo, water (15 ml) was added to the yellow oily residue, and the mixture was extracted with dichloromethane (4×15 ml). The combined organic phases were dried over anhydrous MgSO4. The solvent was evaporated in vacuo, and the crude product was purified by crystallization from a mixture of cyclohexane:isopropyl alcohol (4:1).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.[C:7]([NH:13][NH2:14])(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11].[CH3:15][N:16]1[CH2:20][CH2:19][CH2:18][C:17]1=O.Cl>ClCCl.CN(C)C=O.O>[C:7]([NH:13][NH:14][C:1]([CH:2]1[CH2:19][CH2:20][N:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:15][N:16]=2)[CH2:17][CH2:18]1)=[O:5])(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCC(=O)NN
Reactant: CN1CCCC1=O
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC(=O)NNC(=O)C1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.6 %

Procedure:
The carboxylic acid from Preparation 1 (1.5 g, 7.3 mmol) was suspended in dichloromethane (40 ml) containing N,N-dimethylformamide (2 drops) and oxalyl chloride (1.27 ml, 14 mmol) in dichloromethane (5 ml) was added drop wise. The mixture was stirred for 5 hours at room temperature and then was evaporated under reduced pressure. The residue was suspended in hexane and evaporated (3×20 ml). The residue was dissolved in dichloromethane and cooled to 0° C. and pentanoic acid hydrazide (1.7 g, 14.6 mmol) was added. 1-Methyl-pyrrolidin-2-one (1.6 ml, 14.6 mmol) in dichloromethane (10 ml) was added drop wise and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the residue was triturated with diethyl ether. The material obtained was dissolved in water and acidified to pH2 by addition of 2N hydrochloric acid. The acidic solution filtered and the filtrate was washed with ethyl acetate (3×20 ml) then basified with sodium carbonate. The solid formed was triturated with diethyl ether and isolated by filtration to give the title compound as a white solid (0.68 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:41])([C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:21]=3)[CH:14]([CH3:16])[CH3:15])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:42](OC)=[O:43].[F:46][C:47]([F:51])([F:50])[CH2:48][NH2:49]>>[OH:41][C:13]([C:9]1[CH:10]=[CH:11][C:12]2[C:3]3[CH2:2][N:49]([CH2:48][C:47]([F:51])([F:50])[F:46])[C:42](=[O:43])[C:4]=3[CH:5]=[CH:6][C:7]=2[CH:8]=1)([C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1CBr
Product: CC(C)C(O)(c1ccc2c3c(ccc2c1)C(=O)N(CC(F)(F)F)C3)c1c[nH]cn1

Procedure:
By a ring closure reaction, a detritylation reaction and purification in the same manner as in Example 1 using methyl 1-bromomethyl-6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthoate (0.66 g) and 2,2,2-trifluoroethylamine (2.0 ml), the title compound (0.34 g) was obtained as a colorless amorphous solid.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[NH2:11][C:12]([CH3:32])([CH3:31])[CH2:13][C:14]1[N:15]([CH2:28][CH2:29][CH3:30])[N:16]=[C:17]2[C:26]=1[C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:19]=[C:18]2[NH2:27].C(N(CC)CC)C>ClCCl>[NH2:27][C:18]1[C:17]2=[N:16][N:15]([CH2:28][CH2:29][CH3:30])[C:14]([CH2:13][C:12]([NH:11][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=3)([CH3:32])[CH3:31])=[C:26]2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
Nicotinoyl chloride hydrochloride (1.62 g, 9.08 mmol) was added to a stirred solution of 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 1.08 g, 3.63 mmol) and triethylamine (2.8 mL, 20 mmol) in dichloromethane (32.4 mL). After 2 h, the solution was concentrated under reduced pressure. The residue was dissolved in methanol (20 mL). Concentrated hydrochloric acid (4 mL) was added and the solution was heated at reflux for 30 minutes, then was allowed to cool to ambient temperature. To the solution was added 2 M aqueous sodium carbonate until the pH was basic, then water was added. The mixture was extracted with chloroform four times. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to yield a brown oil that was purified by IFC (silica gel, elution with CMA in chloroform). The appropriate fractions were combined and concentrated to produce a yellow foam that was crystallized from ethyl acetate/hexanes. The solid was isolated by filtration and dried to yield 418 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]nicotinamide as a pale yellow solid, mp 203-205° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.C([Li])CCC.[CH3:20][C:21]1([O:24][CH2:23]1)[CH3:22]>O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:3]=[C:2]([CH2:1][CH2:20][C:21]([CH3:23])([OH:24])[CH3:22])[N:7]=1
Reactant: CC1(C)CO1
Reactant: Cc1nc(Cl)cc(N2CCOCC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)CCc1nc(Cl)cc(N2CCOCC2)n1
Temperature: -78 °C
Yield: 43.4 %

Procedure:
2-Methyl-4-chloro-6-morpholino-pyrimidine (10.7 g.; 50 mmol) was dissolved in tetrahydrofuran (200 mL). The reaction was chilled to −78° C. under an inert atmosphere. A solution of n-butyllithium in hexanes (25 mL, 2.5M, 62.50 mmol) was added, and the reaction mixture was stirred for thirty minutes. A solution of isobutylene oxide 6.6 mL, 75 mmol) was added, and the reaction was allowed to warm to room temperature while stirring overnight. The solvent was removed under reduced pressure, and the crude material was dissolved in methylene chloride (200 mL) and washed with saturated ammonium chloride (2×50 mL), dried with sodium sulfate, and evaporated to dryness. The compound was purified by column chromatography to give 4-(4-chloro-6-morpholin-4-yl-pyrimidin-2-yl)-2-methyl-butan-2-ol (6.2 g., 21.7 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10](Cl)(Cl)=[O:11].Cl.[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[C:26]([C:28]3[CH:37]=[C:36]4[C:31]([CH2:32][CH2:33][NH:34][CH2:35]4)=[CH:30][CH:29]=3)[N:25]=[C:24]([NH2:38])[N:23]=2)[CH2:18][CH2:17]1>>[NH2:38][C:24]1[N:25]=[C:26]([C:28]2[CH:37]=[C:36]3[C:31]([CH2:32][CH2:33][N:34]([C:10]([NH:1][C:2]4[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=4)=[O:11])[CH2:35]3)=[CH:30][CH:29]=2)[CH:27]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH3:15])[CH2:21][CH2:20]2)[N:23]=1
Reactant: O=C(Cl)Cl
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: COc1ccc(N)cn1
Agent: Cl
Product: COc1ccc(NC(=O)N2CCc3ccc(-c4cc(N5CCN(C)CC5)nc(N)n4)cc3C2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 5-amino-2-methoxypyridine (Aldrich, Cat. #A61209), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=475.2.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:28]=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:30]=1[OH:31])[C:8]([O:10][C:11]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([OH:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:36]([O:54][C:15](=[O:16])[C:14]1[CH:18]=[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]([O:10][C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:30]([OH:31])=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:28]=2)=[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:13]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)Cl)cc2C(C)(C)C)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1cc(C(C)(C)C)c(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C(C)(C)C)c1
Temperature: 25 °C
Yield: 102 %

Procedure:
10.0 grams of 4-(3,5-di-t-butyl-4-hydroxybenzoyloxy)-3,5-di-t-butylbenzoyl chloride (0.02 moles) 5.4 grams of n-octadecanol (0.02 moles) and 2.0 grams of triethylamine were stirred together in 100 ml. of benzene at room temperature for 2 hours and then heated for 1 hour at 60° to 70° C. The reaction mixture was cooled to room temperature and the precipitate filtered. The benzene solution was washed with water and dried over sodium sulfate. The benzene solution was then concentrated at reduced pressure yielding about 15 grams of the product. The product was crystallized twice from isopropanol yielding white crystals melting at 75° to 76° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:13]([CH2:14][O:15]C(=O)C)[O:12][C@H:11]2[C@H:7]([N:8]=[C:9]([NH:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[S:10]2)[C@H:6]1[O:30]C(=O)C)(=O)C.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C.C(OCC)(=O)C>CO>[CH2:23]([O:22][CH2:21][CH2:20][NH:19][C:9]1[S:10][C@H:11]2[O:12][C@H:13]([CH2:14][OH:15])[C@@H:5]([OH:4])[C@H:6]([OH:30])[C@H:7]2[N:8]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)OC[C@H]1O[C@@H]2SC(NCCOCc3ccccc3)=N[C@@H]2[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: OC[C@H]1O[C@@H]2SC(NCCOCc3ccccc3)=N[C@@H]2[C@@H](O)[C@@H]1O
Yield: 77.4 %

Procedure:
A solution of 129 (4.5 g, 9.4 mmol) in methanol (40 mL) was treated with potassium carbonate (260 mg, 2 mmol) for 3 hours at room temperature, then neutralized by the addition of acetic acid (0.5 mL). Volatiles were distilled out to give a residue, which was solidified from ethyl acetate. The solids were washed with ethyl acetate (3×20 mL) to give 130 as a light yellow solid (2.58 g, 80%). (ES, m/z) [M+H]+ 355.0; 1H NMR (300 MHz, D2O) δ 7.27-7.37 (m, 5H), 6.17 (d, J=6.3 Hz, 1H), 4.48 (s, 2H), 4.34-4.37 (m, 1H), 4.03-4.07 (m, 1H), 3.88-3.91 (m, 1H), 3.58-3.67 (m, 2H), 3.31-3.55 (m, 5H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].[O:17]1[CH:21]2[O:22][CH2:23][CH2:24][N:20]2[CH2:19][CH2:18]1>C(O)(C)C>[Br-:1].[C:8]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N+:20]23[CH2:24][CH2:23][O:22][CH:21]2[O:17][CH2:18][CH2:19]3)=[CH:6][CH:7]=1
Reactant: C1CN2CCOC2O1
Reactant: O=C(CBr)c1ccc(-c2ccccc2)cc1
Solvent: CC(C)O
Product: O=C(C[N+]12CCOC1OCC2)c1ccc(-c2ccccc2)cc1
Product: [Br-]
Yield: 90.2 %

Procedure:
A solution of 2.751 g (10 mmol) 2-bromo-4′-phenylacetophenone and 1.152 g (10 mmol) tetrahydro[1,3]oxazolo[2,3-b][1,3]oxazole in 20 ml of isopropanol was refluxed for 30 minutes. The reaction mixture was allowed to cool overnight and the precipitate was then filtered off, washed twice with dichloromethane and dried. 3.520 g (90.2%) of white fine crystalline product was obtained.