Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.CN.[CH2:15]([N:17](CC)CC)C.CCOC(C)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH3:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
4-Chlorobenzenesulfonyl chloride (10 g, 47 mmol) was added to a solution of methylamine hydrochloride (3.5 g, 52 mmol) and triethylamine (16.5 ml, 12.0 g, 119 mmol) in dichloromethane (100 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was reduced and chromatography (30% EtOAc/70% hexanes) afforded 4-chloro-N-methylbenzenesulfonamide (7.9 g, 81%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([N:23]1[C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[CH:25]=[C:24]1[CH2:32][N:33]1[CH2:37][CH2:36][C@H:35]([NH2:38])[C:34]1=[O:39])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C:31]2[CH:30]=[CH:29][N:28]=[CH:27][C:26]=2[CH:25]=[C:24]1[CH2:32][N:33]1[CH2:37][CH2:36][C@H:35]([NH:38][S:12]([C:9]2[S:8][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:11][CH:10]=2)(=[O:14])=[O:13])[C:34]1=[O:39])=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)n1c(CN2CC[C@H](N)C2=O)cc2cnccc21
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Cl)s2)s1
Product: CC(C)(C)OC(=O)n1c(CN2CC[C@H](NS(=O)(=O)c3ccc(-c4ccc(Cl)s4)s3)C2=O)cc2cnccc21

Procedure:
The title compound is prepared as described in EXAMPLE 56, Part A using 5′-chloro-[2,2′]bithiophenyl-5-sulfonyl chloride and 2-[3-(S)-amino-2-oxo-pyrrolidin-1-ylmethyl)-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester as starting material. The crude product can be purified by column chromatography eluting with 5% MeOH/CH2Cl2 to give the title compound as a white solid or used in the subsequent step after an aqueous work-up without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH3:16])[N:4]=[C:5]2[C:14]=1[C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:7]=[C:6]2[NH2:15].[OH-].[Na+]>Cl>[CH3:1][C:2]1[N:3]([CH3:16])[N:4]=[C:5]2[C:14]=1[C:13]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=1[N:7]=[C:6]2[NH2:15]
Reactant: Cc1c2c(nn1C)c(N)nc1ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c2c3c(nc(N)c2nn1C)CCCC3
Reaction time: 0.5 h
Yield: 72.8 %

Procedure:
A modification of the method described in Example 13 was used to reduce 1,2-dimethyl-2H-pyrazolo[3,4-c]quinolin-4-amine (1.0 g, 4.7 mmol), prepared as described in Example 5. During the work-up procedure, the residue from the filtrate was suspended in 6 M hydrochloric acid and stirred for 30 minutes. The suspension was adjusted to pH 13 with the addition of 50% sodium hydroxide. The resulting solid was isolated by filtration, washed with water, air-dried, and recrystallized from acetonitrile to provide 0.74 g of 1,2-dimethyl-6,7,8,9-tetrahydro-2H-pyrazolo[3,4-c]quinolin-4-amine as an off-white solid, mp 258-259° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@H:14](O)[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:35]=[N+:36]=[N-:37])[C:13]=2[CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@@H]2O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)COc1cccc2c1CCC[C@H]2N=[N+]=[N-]
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
The toluene solution of chiral alcohol XI prepared above (36.19 mmol, assumed 100% conversion) was diluted with an additional 100 mL of toluene, and cooled in an ice-water bath, then treated with diphenylphosphoryl azide (13.64 g, 49.57 mmol). To this solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 8.0 g, 52.46 mmol), dropwise over 20 minutes at such a rate so as to maintain the internal temperature between 1-4° C. The reaction mixture was then stirred at an internal temperature of 1-2° C. for an additional 45 minutes, then warmed to room temperature (with a water bath), and stirred at room temperature overnight. After 20 hours, the reaction mixture was treated with ice-cold water (50 mL), while maintaining the internal temperature below 24° C. The organic layer was separated and washed with 1 M aqueous citric acid solution (50 mL), saturated aqueous sodium bicarbonate (50 mL), and water (50 mL). The resulting organic phase was then concentrated under vacuum at 20 mmHg/26° C., to provide 15 g of an oil, which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:12]2[NH:13][CH:14]=[C:15]([CH2:17][C:18]([CH3:22])([CH3:21])[CH2:19][CH3:20])[N:16]=2)[NH:10][CH3:11])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1>CN(C)C=O.O.O>[CH3:21][C:18]([CH3:22])([CH2:19][CH3:20])[CH2:17][C:15]1[N:16]=[C:12]([CH:9]([NH:10][CH3:11])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)=[CH:3][CH:4]=2)[NH:13][CH:14]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(Br)cc2)NC)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(-c3cnn(C)c3)cc2)NC)n1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (35 mg, 0.04 mmol) was added to a degassed, ambient temperature solution of 2-(4-bromophenyl)-1-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]-N-methylethanamine (157 mg, 0.43 mmol), sodium carbonate (138 mg, 1.3 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (180 mg, 0.86 mmol) in N,N-dimethylformamide/water (2:1) (9 mL). After stirring at 80° C. overnight, the reaction mixture was cooled, diluted with water and extracted with diethyl ether. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded the title compound. (M+H) found: 366.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([N:14]=[C:15](SC)SC)#[N:13]>O1CCOCC1.ClCCl>[CH2:1]([N:8]1[CH2:9][CH2:10][NH:11][C:15]1=[N:14][C:12]#[N:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=NC#N)SC
Reactant: NCCNCc1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#CN=C1NCCN1Cc1ccccc1
Yield: 95 %

Procedure:
To a solution of N-benzylethane-1,2-diamine (3.00 g, 19.96 mmol) in anhydrous dioxane (15 mL) was added dimethyl cyanocarbonimidodithioate (3.50 g, 23.96 mmol). The mixture was refluxed for 16 hours, then diluted with dichloromethane (200 mL), washed with water (200 mL) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/4) to afford the title compound as a colorless solid in 95% yield (3.88 g): mp 120-122° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.36-7.22 (m, 5H), 6.86 (br s, 1H), 4.38 (s, 2H), 3.58-3.52 (m, 2H), 3.44-3.88 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 164.0, 135.5, 128.8, 128.1, 127.9, 119.4, 48.3, 46.1, 40.2; MS (ES+) m/z 201.2 (M+1).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][CH2:13][S:14][C:15]1[N:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1>C(Cl)(Cl)Cl>[Cl:12][CH2:13][S:14]([C:15]1[N:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:9]
Reactant: ClCSc1ncc(Cl)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=S(CCl)c1ncc(Cl)cn1
Temperature: -5 °C
Yield: 73 %

Procedure:
90% m-chloroperbenzoic acid (4.2 mmol) in chloroform (7 ml) was added dropwise over 40 min to a solution of 2-(chloromethyl)thio-5-chloropyrimidine (3.9 mmol) in chloroform (6 ml) with stirring at -5° C. The mixture was allowed to reach room temperature and stirred overnight, washed with 1 M K2CO3, the dried (MgSO4) chloroform solution evaporated and the residue recrystallized from benzene/petroleum ether (60°-80° C.); yield 73%, m.p. 90° C. 1H NMR (CDCl3): δ4.70 and 5.00 (2H-CO2SO, Jgem 10 Hz), 8.84 (H-4, H-6).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:24].[NH4+].[OH-]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:24])=[C:6]2[CH:5]=[N:4]1)=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=3)[CH3:2]
Reactant: CCn1nccc1Nc1cc(OC)c(OC)cc1C(=O)O
Reactant: O=P(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: CCn1ncc2c(Cl)c3cc(OC)c(OC)cc3nc21
Temperature: 25 °C
Yield: 62 %

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)-4,5-dimethoxy anthranilic acid (12.8 g, 44 mmol) and POCl3 (75 ml) was refluxed for 8 hours. The reaction mixture was cooled to room temperature, poured into ice-water and neutralized with concentrated NH4OH. The mixture was extracted with CH2Cl2 and the CH2Cl2 layer was dried over MgSO4 and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with CH2Cl2 /ether (9/1) to afford 8.0 g (62%) of 1-ethyl-4-chloro-6,7-dimethoxy-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: Br.[Br:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>[C:15]([NH:6][CH2:5][CH2:4][CH2:3][Br:2])([O:14][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16]
Reactant: NCCCBr
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(NCCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a stirred solution of 1-bromo-3-propylamine hydrobromide (5 g, 22.84 mmol) in saturated aqueous sodium carbonate (100 mL) and ethyl acetate (200 mL) at 0° C., was added benzylchloroformate (3.2 mL, 22.84 mmol) and the resulting mixture was warmed to room temperature and stirred overnight. The aqueous layer was separated and extracted with ethyl acetate (2×100 mL) and the combined organic layers were washed with brine (2×100 mL), dried over sodium sulfate and evaporated to dryness under reduced pressure. Silica gel chromatography using ethyl acetate/hexanes (1:9) provided the title compound as a colorless oil (4.7 g, 79%).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([Cl:27])[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[N:39][CH:38]=2)O1>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([Cl:27])[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13]([CH3:28])[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([C:37]2[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH:40]=[N:39][CH:38]=2)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cncc3ccccc23)OC1(C)C
Agent: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Product: Cn1c(CN2CCN(C(C)(C)C)CC2)nc2c(N3CCOCC3)nc(-c3cncc4ccccc34)nc21

Procedure:
4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine was prepared following General Procedure E of amine SN2 alkylation. Following General Procedure A Suzuki coupling, 4-(8-((4-tert-butylpiperazin-1-yl)methyl)-2-chloro-9-methyl-9H-purin-6-yl)morpholine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline were reacted to give 445. LCMS: M+H +=501.3
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:9])[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: CC(=O)c1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CC1(c2cccc(Br)c2)OCCO1

Procedure:
1-(3-bromophenyl)ethanone (60.6 g), ethylene glycol (83.7 mL), and p-toluenesulfonic acid (0.15 g) were dissolved in benzene (250 mL) and heated at reflux overnight in a Dean-Stark apparatus. The mixture was cooled and washed with water. The aqueous layer was further extracted twice with chlorobutane and the combined organic layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 75.0 g of a yellow oil. The oil was purified by distillation under reduced pressure (19-24 Pa, 64-74° C.) to afford 70.1 g of the title compound of Step A as an oil. 1H NMR (CDCl3): δ 7.64 (s,1H), 7.40 (m,2H), 7.20 (m,1H), 4.0 (m,2H), 3.7 (m,2H), 1.63 (s,3H).
Reaction SMILES: [C:1]([C:3]1[C:7]([C:8]#[N:9])=[N:6][S:5][N:4]=1)#[N:2].[OH-:10].[K+]>O>[C:1]([C:3]1[C:7]([C:8](=[O:10])[NH2:9])=[N:6][S:5][N:4]=1)#[N:2]
Reactant: N#Cc1nsnc1C#N
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: N#Cc1nsnc1C(N)=O

Procedure:
First, one mole of solid 3,4-dicyano-1,2,5-thiadiazole (II) is suspended in a quantity of water sufficient to obtain an easily stirrable mixture. Then, under stirring, there are admixed from 0.01 to 0.8 mole of KOH in the form of an aqueous solution. There occurs an exothermic reaction which is controlled by cooling so as to maintain a temperature of about 20° to 50° C. At this stage the 3,4-dicyano-1,2,5-thiadizole (II) passes into solution, hydrating to form 3-cyano-4-carbamoyl-1,2,5-thiadiazole (III), which may be separated as a solid if one operates at 20° to 35° C, or which will remain in solution if one operates at higher temperatures up to 50° C. This ends the first stage of the reaction.
Reaction SMILES: [C:1](=[NH:25])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][C:21]([F:24])([F:23])[F:22])[CH:14]=2)=[CH:8][CH:7]=1)[NH2:2].[OH:26]/[CH:27]=[C:28](/[CH2:33][C:34]1[CH:35]=[N:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=1)\[C:29](OC)=O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:29]=[C:28]([CH2:33][C:34]4[CH:35]=[N:36][C:37]([O:40][CH3:41])=[N:38][CH:39]=4)[C:27](=[O:26])[N:25]=3)=[CH:11][CH:10]=2)=[CH:14][C:15]=1[O:20][C:21]([F:24])([F:22])[F:23]
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(OC(F)(F)F)c2)cc1
Reactant: COC(=O)/C(=C\O)Cc1cnc(OC)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1ncc(Cc2c[nH]c(OCCc3ccc(Oc4ccc(Cl)c(OC(F)(F)F)c4)cc3)nc2=O)cn1
Reaction time: 4 h
Yield: 15.7 %

Procedure:
The same procedure as E177 from 4-(4-chloro-3-(trifluoromethoxy)phenoxy)phenethyl carbamimidate (100 mg, 0.267 mmol), (Z)-methyl 3-hydroxy-2((2-methoxypyrimidin-5-yl) methyl)acrylate (180 mg, 0.803 mmol) and Cs2CO3 (260 mg, 0.798 mmol) in 1,4-dioxane (2 mL), except that the reaction temperature was 120° C. and the time was 4 h, to afford the title compound (28 mg, 0.042 mmol, 15.83% yield). LCMS: rt=3.63 min, [M+H+]=549
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]2[N:20]=[N:21][N:22]([C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:23]=2)=[CH:9][CH:8]=1)(=O)=O.[CH2:43]([C:47]1[NH:48][C:49]([CH:53]=[O:54])=[C:50]([Cl:52])[N:51]=1)[CH2:44][CH2:45][CH3:46].[BH4-].[Na+]>O>[CH2:43]([C:47]1[N:48]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[N:20]=[N:21][N:22]([C:24]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:23]=3)=[CH:11][CH:12]=2)[C:49]([CH2:53][OH:54])=[C:50]([Cl:52])[N:51]=1)[CH2:44][CH2:45][CH3:46]
Reactant: CS(=O)(=O)OCc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the reaction mixture of Example 10 was added 2-n-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (0.01 m=1.86 g). The reaction was stirred overnight at room temperature. Water (0.87 mL) was added dropwise followed by sodium borohydride pellets (0.37 g). After stirring for 5 hours, the reaction mixture was added slowly to 100 mL water containing 3 mL acetone. The temperature was maintained at about 25° C. during the addition. The resultant slurry was stirred for an additional 45 minutes, then filtered. The solid was rinsed with two 50 mL portions of water. The wet cake was recrystallized first from 50 mL of n-butyl chloride, then from 30 mL of ethyl acetate to give 1.95 g title compound in 28% overall yield; mp 168°-169° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]1[CH2:21][NH:20][CH2:19][CH:18]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[NH:17][C:16](=O)[CH2:15][O:14][CH2:13][C:12](=O)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[CH2:24]([O:23][CH2:22][CH:18]1[CH2:19][NH:20][CH2:21][CH:10]([CH2:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][NH:17]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1COCC(=O)NC(COCc2ccccc2)CNCC(COCc2ccccc2)N1
Agent: Cl
Solvent: C1CCOC1
Product: c1ccc(COCC2CNCC(COCc3ccccc3)NCCOCCN2)cc1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
5,9-Bis-(benzyloxymethyl)-1-oxa-4,7,10-triazacyclododecane-3,11-dione (0.250 g, 0.566 mmol) was dissolved in dry tetrahydrofuran (10 ml) cooled to 0° C. A 1M solution of borohydride-THF complex in tetrahydrofuran (5 ml) was added under nitrogen and the mixture was stirred at ambient temperature for 14 hours. 2M Hydrochloric acid (3 ml) was added and the mixture was concentrated in vacuo to approximately 1 ml volume. 25% Ammonia solution (2 ml) was added and the mixture was extracted four times with 4 ml of chloroform. The extracts were concentrated in vacuo and gave a yellow oil which showed an absence of carbonyl bands in IR. Yield 0.227 g (97%), FAB MS: 414 (M+1).
Reaction SMILES: Cl.[C:2]12([NH2:12])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>O1CCOCC1>[C:2]12([NH:12][S:30]([C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:29][CH:28]=3)(=[O:32])=[O:31])[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)NC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 80 °C
Yield: 30.3 %

Procedure:
1-Adamantanamine hydrochloride (0.0114 mol) and triethylamine (0.0114 mol) are added to a solution of 4-acetamidophenylsulfonyl chloride (1.34 g, 0.0057 mol) in dioxane (5 mL). The mixture is heated for 1 hour at 80° C., then part of the solvent is removed by evaporation at reduced pressure, and water is added until precipitation of the resulting sulfonamide. The product is collected by filtration as a pink solid in 30.3% yield and used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[C:16]1([C:22]2[O:23][CH:24]=[N:25][N:26]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:24]2[O:23][C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:26][N:25]=2)[OH:15])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: c1ccc(-c2nnco2)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1nnc(-c2ccccc2)o1

Procedure:
Prepared according to the procedure described in Example 30, Step 1, using 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 2-phenyl-[1,3,4]oxadiazole.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:29][C:30]1([F:41])[O:34][C:33]2[CH:35]=[CH:36][C:37]([CH2:39]O)=[CH:38][C:32]=2[O:31]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O.C(Cl)Cl>[Br:1][C:2]1[C:3](=[O:9])[N:4]([CH2:39][C:37]2[CH:36]=[CH:35][C:33]3[O:34][C:30]([F:41])([F:29])[O:31][C:32]=3[CH:38]=2)[C:5](=[O:8])[NH:6][N:7]=1
Reactant: O=c1[nH]nc(Br)c(=O)[nH]1
Reactant: OCc1ccc2c(c1)OC(F)(F)O2
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: O=c1[nH]nc(Br)c(=O)n1Cc1ccc2c(c1)OC(F)(F)O2
Temperature: 0 °C
Yield: 20.4 %

Procedure:
According to Scheme 2 Step 2: A mixture of 6-bromo-1,2,4-triazine-3,5(2H,4H)-dione 2(A) (943 mg, 4.91 mmol), CH2Cl2 (40 mL), triphenylphosphine (1.76 g, 6.69 mmol), (2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol (840 mg, 4.46 mmol) was stirred at 0° C. under nitrogen atmosphere. Di-tertbutyl azodicarboxylate (2.05 g, 8.93 mmol) was added portionwise and the mixture was stirred for 16 hours at room temperature. 200 mL of water were added and the aqueous layer was extracted thrice with 200 mL of DCM. The organic layers were combined and were successively dried over MgSO4, filtered and concentrated under reduce pressure to afford a brown solid. The crude solid was purified by flash chromatography with silica gel (Merck Flashmart prepacked column SiO2) using AcOEt/cyclohexane 3/7 as eluant to afford 6-bromo-4-((2,2-difluorobenzo[d][1,3]dioxol-5-yl)methyl)-1,2,4-triazine-3,5(2H,4H)-dione 5(A) (330 mg, 20%) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:21]=[C:22]([O:24]C)[CH:23]=1)[CH2:6][C:7]1[N:16]2[N:17]=[C:18]([NH2:20])[N:19]=[C:15]2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:8]=1.B(Br)(Br)Br>ClCCl>[NH2:20][C:18]1[N:19]=[C:15]2[N:16]([C:7]([CH2:6][C:5]3[CH:4]=[C:3]([OH:2])[CH:23]=[C:22]([OH:24])[CH:21]=3)=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:17]=1
Reactant: COc1cc(Cc2nc3ccccc3c3nc(N)nn23)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1nc2c3ccccc3nc(Cc3cc(O)cc(O)c3)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 759.3 %

Procedure:
To a stirred suspension of 5-(3,5-dimethoxy-benzyl)-[1,2,4]triazolo[1,5-c]quinazolin-2-ylamine (0.10 g, 0.30 mmol), prepared as described in Example 4, in anhydrous dichloromethane (10 mL) was added dropwise, under argon, 1M BBr3 solution (3 mL, 3 mmol) in DCM at 0-5° C. The ice bath was removed and the mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate and washed with NaHCO3 satured solution, then with water and brine. After drying over Na2SO4, the solvent was removed to give a crude that was crystallized twice from ethyl acetate to afford the title compound (0.70 g, 70% yield).