Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[CH3:19][CH:20]([NH2:35])[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[O:22][N+:23]([O-:25])=[O:24].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=1)=[N:35][CH:20]([CH3:19])[CH:21]([C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1)[O:22][N+:23]([O-:25])=[O:24])#[N:2]
Reactant: CC(C)OC(=NC#N)c1ccncc1
Reactant: CC(N)C(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: CC(N=C(NC#N)c1ccncc1)C(O[N+](=O)[O-])c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 5 %

Procedure:
Isopropyl N-cyano-4-pyridinecarboximidate (0.31 g, 1.6 mmol) was dissolved in methanol (15 ml), and 1-methyl-2-(4-nitrophenyl)-2-nitroxyethylamine nitrate (0.50 g, 1.8 mmol) and sodium methoxide (0.09 g, 1.7 mmol) were added. The mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform (50 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was sub3ected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (60:1). The eluted fractions were concentrated under reduced pressure and crystallized from diethyl ether to give the title compound (0.03 g, 0.08 mmol, yield: 5%) as colorless crystals.
Reaction SMILES: [NH3:1].[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:11]([O:17][CH3:18])(=[O:16])[CH2:12][C:13]([CH3:15])=O>CO>[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]1[C:12]([C:11]([OH:17])=[O:16])=[C:13]([CH3:15])[N:1]=[C:13]([CH3:15])[C:12]=1[C:11]([OH:17])=[O:16].[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]1[C:12]([C:11]([O:17][CH3:18])=[O:16])=[C:13]([CH3:15])[NH:1][C:13]([CH3:15])=[C:12]1[C:11]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1ccccc1F
Reactant: N
Solvent: CO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1c1ccccc1F
Product: Cc1nc(C)c(C(=O)O)c(-c2ccccc2F)c1C(=O)O

Procedure:
As shown hereinbelow in Example 1, the intermediate 4-(2-fluorophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylic acid was prepared in very good yield by first adding concentrated aqueous ammonia to a mixture of 2-fluorobenzaldehyde and methyl acetoacetate in methanol to produce dimethyl 4-(2-fluorophenyl)-1,4-dihyro-2,6-dimethyl-3,5-pyridinedicarboxylate, oxidizing the 1,4-dihydro compound with 4N nitric acid to produce dimethyl 4-(2-fluorophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate and saponifying the latter ester by heating it with sodium hydroxide in aqueous methanol at about 60°-65° C. to produce 4-(2-fluorophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]2)[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]=[C:9]([CH2:11][N:19]3[CH2:22][CH:21]([N:23]4[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]4)[CH2:20]3)[S:8][C:6]=2[N:7]=1
Reactant: O=S1(=O)CCN(C2CNC2)CC1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=S1(=O)CCN(C2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)C2)CC1
Reaction time: 65 h
Yield: 89 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine-2-carbaldehyde (400 mg, 1.40 mmol), 4-azetidin-3-ylthiomorpholine-1,1-dioxide (321 mg, 1.69 mmol) and 4 Å powdered molecular sieves (600 mg) in DCE (20 mL) was stirred at room temperature for 4 h before the addition of sodium triacetoxyborohydride (595 mg, 2.80 mmol). The reaction mixture was stirred for 65 h then filtered through celite, washing with DCM. The organic phase was washed with brine (×1) and concentrated in vacuo affording 5-Chloro-2-[3-(1,1-Dioxo-1-thiomorpholin-4-yl)azetidin-1-ylmethyl]-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine as an orange powder (572 mg, 89%). LCMS (Method H): RT 2.43 min [M+H]+ 459.2
Reaction SMILES: [CH2:1]([C:5]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22]Br)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:8]2[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].[CH2:28]([NH2:32])[CH2:29][CH2:30][CH3:31].O>CS(C)=O>[CH2:1]([C:5]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][N:32]([CH2:5][CH2:1][CH2:2][CH3:3])[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:8]2[CH:24]=[CH:25][CH:26]=[CH:27][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1S(=O)(=O)c1ccc(OCCCBr)cc1
Reactant: CCCCN
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc2ccccc2n1S(=O)(=O)c1ccc(OCCCN(CCCC)CCCC)cc1
Reaction time: 17 h

Procedure:
To a solution of 0.0017 mol of 2-n-butyl-1-(4-bromopropoxy-benzenesulphonyl) benzimidazole in 15 ml of dimethylsulphoxide was added 0.0034 mol of n-butylamine. The reaction medium was allowed to stand for 17 hours at room-temperature and then poured into 50 ml of water. After extraction, the ethereal phase was dried and evaporated to dryness. The residue so obtained was purified by chromatography on a silica column (eluent : dichloromethane/ethyl acetate) to obtain an oil which 10 was the desired product in the form of the free base (yield : 50%). The oxalate of the base so provided was formed by dissolving the base in question into ethyl ether and adding an ethereal solution of oxalic acid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)#[CH:12].N>>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[O:1][N:2]=2)[CH:5]=1
Reactant: ON=C(Cl)c1cccnc1
Reactant: C#Cc1cccnc1
Agent: N
Product: c1cncc(-c2cc(-c3cccnc3)on2)c1

Procedure:
The titled compound was prepared as the bishydrochloride salt according to Method CA using the product of Example 1A (0.78 g, 5.0 mmol) and 3-ethynylpyridine (Aldrich, 0.52 g, 5.0 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.76 (dd, J=8.1, 5.1 Hz, 1H), 7.79-7.86 (m, 1H), 7.98 (s, 1H), 8.44 (dt, J=8.0, 2.0, 1.9 Hz, 1H), 8.55 (dt, J=8.1, 1.9 Hz, 1H), 8.80 (dd, J=4.9, 1.5 Hz, 1H), 8.86 (dd, J=5.1, 1.7 Hz, 1H), 9.21 (d, J=2.0 Hz, 1H), 9.23 (d, J=2.0 Hz, 1H) ppm; MS (DCI/NH3) m/z 224 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]=O)[C:6]#[N:7])[CH3:2].[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17].C(O)(=O)C.N1CCCCC1>ClCCl>[C:16]([C:15]([C:14](=[O:19])[CH3:13])=[CH:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:1][CH3:2])(=[O:18])[CH3:17]
Reactant: CC(=O)CC(C)=O
Reactant: CCc1cc(C#N)ccc1C=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCc1cc(C#N)ccc1C=C(C(C)=O)C(C)=O

Procedure:
885 mg (5.55 mmol) of 3-ethyl-4-formylbenzonitrile, 0.62 ml (6.11 mmol) of 2,4-pentanedione, 0.47 ml (8.33 mmol) of acetic acid and 0.11 ml (1.11 mmol) of piperidine in 40 ml of anhydrous dichloromethane are stirred under reflux with a water trap for 24 h. After cooling, the reaction solution is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue (1.07 g) is reacted further without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1.Cl.O1CCOCC1>C(O)C>[Cl:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:4][N:3]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Clc1ncc(CCc2cccnc2)c2ccccc12
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: Clc1ccc(Nc2ncc(CCc3cccnc3)c3ccccc23)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Under an N2 atmosphere, 250 mg (0.93 mmol) of 1-chloro-4-(2-pyridin-3-yl-ethyl)isoquinoline in 2.9 ml of abs. ethanol are mixed with 131 mg (1.02 mmol) of 4-chloro-aniline and 0.23 ml of 4 N HCl/dioxane, and stirred for 8 h at 80° C. The mixture is cooled to RT, filtered and the residue washed with acetonitrile. The residue is dissolved in 4 ml of water, then 0.9 ml of sat. NH3 solution are added, stirring is effected for 10 min, the precipitate is filtered off and washed with water. Recrystallisation from acetonitrile yields 1-(4chloroanilino)-4-[2-(pyridin-3-yl)-ethyl]-isoquinoline; m.p.157-158° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH:13]=2)=[CH:5][CH:4]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][C:21]([C:24](Cl)=[O:25])=[CH:20][CH:19]=1.C(Cl)Cl>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[C:13]=2[C:24](=[O:25])[C:21]2[CH:22]=[CH:23][C:18]([CH3:27])=[CH:19][CH:20]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccccc3o2)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(C)cc2)cc1
Reaction time: 1.5 h

Procedure:
To a cooled (0°) mixture of 4.07 g. (0.018 mol.) of 2-p-methoxyphenylbenzofuran and 4.17 g. (0.027 mol.) of p-toluic acid chloride in 100 ml. of methylene chloride was added dropwise 11.25 g. (0.043 mol.) of stannic chloride. The reaction mixture was stirred for 1.5 hours at 0°, then for 0.5 hour at 25 °. The mixture was poured into water and stirred vigorously, the layers were separated and the organic phase was washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and concentrated to give 2-p-methoxyphenyl-3-p-methylbenzoylbenzofuran.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C(NC1C2C(=CC=CC=2)CCC1)(=[O:18])C>>[C:1]([NH:4][C:5]1[C:10]2[C:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1CCCc2ccccc21
Reactant: CC(=O)Nc1cccc2c1CCCCC2
Product: CC(=O)Nc1cccc2c1C(=O)CCCC2

Procedure:
The reaction was carried out in the same manner as in Example 1-(1), except that 200 mg of the compound prepared in (1) above was used instead of 1-acetylaminotetraline of Example 1-(1). The reaction product was post-treated to produce 55 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N:11]2[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]2)=[C:9]([Cl:18])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:21])=O>CN(C)C=O.ClCCCl>[Cl:1][C:2]1[C:10]([N:11]2[C:15](=[O:16])[N:14]([CH3:17])[N:13]=[N:12]2)=[C:9]([Cl:18])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: Cn1nnn(-c2c(Cl)ccc(C(=O)O)c2Cl)c1=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cn1nnn(-c2c(Cl)ccc(C(=O)Cl)c2Cl)c1=O
Yield: 100.3 %

Procedure:
2,4-Dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoic acid (3.42 g) and thionylchloride (4.22 g) were added to 1,2-dichloroethane (50 ml). The mixture, after adding several drops of N,N-dimethylformamide, was refluxed upon heating for 4 hours. After cooling, the solvent was distilled off to obtain crude 2,4-dichloro-3-(4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl)benzoyl chloride (3.65 g).
Reaction SMILES: CC(C)C[CH:4]1[C:9]2=[CH:10][CH:11]=[CH:12][N:8]2[C:7](=[O:13])[CH2:6][O:5]1.Cl.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-:27].[Na+]>O>[C:7]([CH:6]([O:5][CH2:4][C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:24]([O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:25])[CH2:16][CH:17]([CH3:22])[CH3:18])([OH:13])=[O:27]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)CC1OCC(=O)n2cccc21
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)CC(OC[C@@H]1CCCN1C(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(8a S)-Tetrahydro-3-(2-methylpropyl-1H-pyrrolo [2,1-c][1,4] oxazine-4(3H)-one, 5.1 g (0.026 mol), is suspended in a solution of 50 ml of concentrated hydrochloric acid and 50 ml of water and refluxed for four hours, cooled to room temperature and extracted with 200 ml of dichloromethane. The aqueous layer is separated, evaporated in vacuo, the residue dissolved in 200 ml of water, and the pH adjusted with a 10% aqueous solution of sodium hydroxide to pH 10-10.5. The solution is cooled to 5° C. and 4.44 g (0.026 mol) of benzylchloroformate is added dropwise while the pH is maintained at pH 10 with a 10% aqueous solution of sodium hydroxide. The mixture is stirred one hour, extracted with 100 ml of diethylether, the aqueous layer is separated and the pH is adjusted to pH 3-4 by the addition of a 10% aqueous solution of hydrochloric acid. The mixture is extracted with dichloromethane, 3×200 ml. The dichloromethane layer is separated, washed with a saturated aqueous solution of sodium chloride, 3×200 ml, separated, dried over sodium sulfate, evaporated, and the residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give (2S)-phenylmethyl 2-[(1-carboxy-3-methylbutoxy)methyl]-1-pyrrolidinecarboxylate (center on side chain is R, S mixture), 4.3 g; [α]D25 -78.7° (c 0.33, methanol).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[N:12]([CH2:15][CH2:16][CH2:17][CH3:18])=[C:13]=[O:14]>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:15]([NH:12][C:13]([N:1]1[C:9]2[C:4](=[C:5]([CH:10]=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: CCCCN=C=O
Reactant: O=Cc1cccc2[nH]ccc12
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CCCCNC(=O)n1ccc2c(C=O)cccc21

Procedure:
To 1H-Indole-4-carbaldehyde (518, 1.57 g, 10.8 mmol) in acetonitrile (20 mL) was added 1-isocyanatobutane (1.81 mL, 16.2 mmol), followed by 4-dimethylaminopyridine (130 mg, 1.1 mmol). The reaction was refluxed for 48 hours. The reaction solution was quenched with 1 M HCl (aq.) and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtrated and concentrated to give a light yellow solid (519, 2.62 g, 45%). MS (ESI) [M+H+]+=245.2.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:28][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[C:20]([CH3:27])=[N:19]4)(=O)=O)=CC=1.[NH:29]1[CH2:34][CH:33]=[C:32]([C:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[NH:37][CH:36]=2)[CH2:31][CH2:30]1>CS(C)=O.C(OCC)(=O)C>[NH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:35]([C:32]2[CH2:33][CH2:34][N:29]([CH2:12][CH:13]3[O:28][C:17]4=[C:18]5[C:23](=[CH:24][CH:25]=[C:16]4[O:15][CH2:14]3)[N:22]=[C:21]([CH3:26])[C:20]([CH3:27])=[N:19]5)[CH2:30][CH:31]=2)=[CH:36]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)c(C)nc4c3O2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc3c(c2nc1C)OC(CN1CC=C(c2c[nH]c4ccccc24)CC1)CO3
Temperature: 80 °C

Procedure:
To a solution of [(2R)-8,9-dimethyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoxalin-2-yl]methyl 4-methylbenzenesulfonate (0.400 g, 1.000 mmole) in methyl sulfoxide (20 mL) was added 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.495 g, 2.497 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (250 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.262 g (62%) of the (S)-enantiomer of the title compound as a pale yellow solid. Rf=0.32 (silica, methanol:ethyl acetate 1:9); mp 153–155° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])=[CH:4][CH:3]=1.[C:14]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[C:27](F)=[CH:26][C:25]([NH:29][C:30]([C:32]2[CH:37]=[N:36][CH:35]=[CH:34][N:33]=2)=O)=[C:24]([N+:38]([O-])=O)[CH:23]=1)(=[O:16])[CH3:15]>>[C:14]([N:17]1[CH2:21][CH2:20][CH2:19][CH:18]1[C:22]1[C:27]([O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:12][CH2:11][O:10][C:9]3=[O:13])=[CH:6][CH:7]=2)=[CH:26][C:25]2[N:29]=[C:30]([C:32]3[CH:37]=[N:36][CH:35]=[CH:34][N:33]=3)[NH:38][C:24]=2[CH:23]=1)(=[O:16])[CH3:15]
Reactant: O=C1OCCN1c1ccc(O)cc1
Reactant: CC(=O)N1CCCC1c1cc([N+](=O)[O-])c(NC(=O)c2cnccn2)cc1F
Product: CC(=O)N1CCCC1c1cc2[nH]c(-c3cnccn3)nc2cc1Oc1ccc(N2CCOC2=O)cc1

Procedure:
One chiral form of the entitled compound was obtained as a yellow oily substance in the same method as in Example 338 (step 5) or in accordance with the method or by combining it with an ordinary method but using 3-(4-hydroxyphenyl)-1,3-oxazolidin-2-one and N-(4-(1-acetylpyrrolidin-2-yl)-5-fluoro-2-nitrophenyl)pyrazin-2-carboxamide enantiomer A.
Reaction SMILES: [C:1]1([CH:7]2[CH2:11][N:10](CC3C=CC=CC=3)[CH2:9][CH:8]2[CH2:19][NH2:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>[Pd].CO>[C:1]1([CH:7]2[CH2:11][NH:10][CH2:9][CH:8]2[CH2:19][NH2:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: NCC1CN(Cc2ccccc2)CC1c1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCC1CNCC1c1ccccc1
Yield: 86.4 %

Procedure:
A mixture of 4.79 g (0.018 mole) of 4-phenYl-1-(phenylmethyl)-3-pyrrolidinemethanamine, 0.7 g of 20% palladium on carbon, and 250 ml of methanol was shaken in an atmosphere of hydrogen at about 50 psi and at room temperature for 24 hours. The catalyst was filtered and the filtrate evaporated under reduced pressure to give 2.74 g of 4-phenyl-3-pyrrolidinemethanamine.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[C:4](=[O:20])[NH:3]1.BrC1C=CC=CC=1CBr.[Br:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[CH2:39]Br>>[Br:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[CH2:39][N:3]1[C:2]([CH3:21])([CH3:1])[C:6](=[O:7])[N:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:17])[F:18])[CH:9]=2)[C:4]1=[O:20]
Reactant: Clc1ccc(CBr)c(Br)c1
Reactant: CC1(C)NC(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Agent: BrCc1ccccc1Br
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1Cc1ccc(Cl)cc1Br

Procedure:
Compound 109.2 was prepared as described for example 1.2, by reacting compound 1.1, instead of 2-bromobenzyl bromide, with 2-bromo-1-bromomethyl-4-chlorobenzene (prepared by N-bromosuccinimide bromination from 2-bromo-4-chloro-1-methylbenzene; 1H NMR: 7.82, d, 1H; 7.65, s, 1H, 7.5, d, 1H, 4.72, s, 2H). 4-[3-(2-Bromo-4-chlorobenzyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-trifluoromethylbenzonitrile was obtained. (Molecular weight 498.99 (C20H14BrClF3N3O2); retention time Rt=2.30 min. [B]; MS (ESI): 541.04 (MH++CH3CN).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:18][CH2:19][CH3:20])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].C(N(CC)C(C)C)(C)C.[Cl:30][CH2:31][CH2:32][CH2:33][S:34](Cl)(=[O:36])=[O:35].CN1CCCC1=O>C(Cl)(Cl)Cl>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][CH3:20])[C:4]([CH2:3][CH2:2][NH:1][S:34]([CH2:33][CH2:32][CH2:31][Cl:30])(=[O:36])=[O:35])=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CCN
Reactant: O=S(=O)(Cl)CCCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCCn1nc2c(N)nc3ccccc3c2c1CCNS(=O)(=O)CCCCl

Procedure:
Under a nitrogen atmosphere, a solution of 1-(2-aminoethyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (0.228 g, 0.848 mmol) and N,N-diisopropylethylamine (0.604 mL, 3.39 mmol) in chloroform (6.67 mL) was cooled to 0° C. A solution of 3-chloropropanesulfonyl chloride (0.113 mL, 0.933 mmol) in chloroform (10 mL) was added. An analysis by HPLC indicated that the reaction was not progressing. N-Methylpyrrolidone (12 mL) was added, and the reaction went to completion. The solvents were removed under reduced pressure to provide N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)ethyl]-3-chloropropane-1-sulfonamide.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[CH2:14][CH2:13][C:12]4[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=4[C:10]=3[NH:9][N:8]=2)=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:25]>O1CCCC1>[NH:9]1[C:10]2[C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[CH2:13][CH2:14][C:15]=2[C:7]([C:4]2[CH:3]=[CH:2][N+:1]([O-:25])=[CH:6][CH:5]=2)=[N:8]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc2c(c1)CCc1c(-c3ccncc3)n[nH]c1-2
Solvent: C1CCOC1
Product: [O-][n+]1ccc(-c2n[nH]c3c2CCc2ccccc2-3)cc1
Temperature: 57.5 °C

Procedure:
3-(4-Pyridyl)-4,5-dihydro-1H-benzo[g]indazole (100 mg, compound commercially available from Aldrich) was dissolved in tetrahydrofuran (5-10 ml) with warming and then 3-chloroperoxybenzoic acid (1.25 molar equivalents of 70-75% pure material) was added. The mixture was heated at 55-60° C. for 4 hours. A precipitate was collected by filtration, washed with tetrahydrofuran and then ether to give 4-(4,5-dihydro-1H-benzo[g]indazol-3-yl)pyridine 1-oxide.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:24]1[CH:29]=[CH:28][CH2:27][CH2:26][CH2:25]1.O.[NH3:31]>C(OCC)(=O)C.C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:29]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:4]([NH2:31])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: C1=COCCC1
Reactant: N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 2,6-dichloropurine (25 g) (available from, for example, Aldrich, UK) in dry ethyl acetate (200 ml) was added p-toluenesulfonic acid monohydrate (235 mg). The reaction was heated to 50° C. and 3,4-dihydro-2H-pyran (18.1 ml) was added in one go. The reaction was allowed to stir at 50° C. for 1 hour and the solvent was removed under reduced pressure. This afforded a yellow solid. A suspension of this solid (˜36 g) in 2.0M ammonia in isopropanol (460 ml) was heated under nitrogen at 60° C. for 4 hours with an attached condenser. The reaction was poured into water (50 ml) and left to cool overnight. The precipitate was filtered and dried on a rotary evaporator (60° C.) for 30 min. to afford the title compound as an off-white solid, 31 g (93%, 2 steps).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9]Br.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([C:21]([OH:24])([CH3:23])[CH3:22])[NH:18]2)=[C:14]([Cl:25])[N:13]=1>CN(C=O)C>[Cl:25][C:14]1[C:15]2[N:16]=[C:17]3[N:18]([CH2:8][CH2:9][O:24][C:21]3([CH3:23])[CH3:22])[C:19]=2[N:20]=[C:12]([Cl:11])[N:13]=1
Reactant: BrCCBr
Reactant: CC(C)(O)c1nc2c(Cl)nc(Cl)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OCCn2c1nc1c(Cl)nc(Cl)nc12
Temperature: 100 °C
Yield: 27.4 %

Procedure:
Cesium carbonate (9.3 g, 28.5 mmol) and 1,2-dibromoethane (4.1 mL, 47.6 mmol) were added to a solution of 2-(2,6-dichloro-9H-purin-8-yl)-propan-2-ol (3.3 g, 13.36 mmol) in DMF (100 mL) and the reaction mixture was heated at 100° C. for 2 h, then partitioned between water and ethyl acetate. The organic extract was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 10 to 20% ethyl acetate in cyclohexane) affording 1,3-Dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b,9-tetraaza-fluorene as a yellow solid (1.0 g, 27%). 1H NMR (400 MHz, CDCl3): δ 4.26 (2H, dd, J=6, 4 Hz), 4.19 (2H, dd, J=6, 4 Hz).