Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][C:13]2([CH3:18])OCC[O:14]2)[CH:3]=1>C(O)(=O)C.O>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][CH2:12][C:13](=[O:14])[CH3:18])[CH:3]=1
Reactant: CC1(CCc2cc(O)n3nccc3n2)OCCO1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)CCc1cc(O)n2nccc2n1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
The compound obtained in step (1), 22 g, was dissolved in 500 ml of acetic acid-water (4:1) and stirred at 50° C. for 3 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the remaining acetic acid-water was azeotropically distilled off with benzene. The residue was recrystallized from ethanol-n-hexane to provide 11 g of 7-hydroxy-5-(3-oxobutyl)pyrazolo[1,5-a]pyrimidine as colorless crystals.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:12]([C:14]2[CH:15]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=O.[CH2:30]([NH2:33])[CH2:31][CH3:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[N+:9]([C:8]1[CH:7]=[CH:6][C:5]([S:12]([C:14]2[CH:15]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:22])=[O:23])[CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:4][C:3]=1[CH2:1][NH:33][CH2:30][CH2:31][CH3:32])([O-:11])=[O:10]
Reactant: CCCN
Reactant: O=Cc1cc(S(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNCc1cc(S(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
The following reaction was run under N2. A mixture of N-[3-(3-formyl-4-nitro-benzenesulfinyl)-phenyl]-benzenesulfonamide (0.0023 mol) and propylamine (0.0025 mol) in DCE (50 mL) was stirred at room temperature and NaBH(OAc)3 (0.8 g) was added. The reaction mixture was stirred overnight at room temperature, and then a NaHCO3 solution was added. The organic layer was separated, dried, and filtered, and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25](O)=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[Cl-].[NH4+:30]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:28])[C:10]([C:12]1[S:24][C:23]2[C:22]3[CH:21]=[C:20]([C:25]([NH2:30])=[O:26])[CH:19]=[CH:18][C:17]=3[O:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OC2)c1ccc(F)cc1F
Reactant: [NH4+]
Agent: [Cl-]
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(N)=O)ccc1OC2)c1ccc(F)cc1F

Procedure:
Following the procedure of Example 15 and General Procedure C, 2-((2,4-difluorophenyl)(methyl)carbamoyl)-4H-thieno[3,2-c]chromene-8-carboxylic acid and ammonium chloride were coupled to give 119bp. LCMS (ESI) m/z: 401.1
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[C:6]2[C:9]([CH:15]([CH3:17])[CH3:16])=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:5]=2[S:4]1(=[O:19])=[O:18].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]1[C:32](=[O:33])[CH2:31][C:30]([C:34]#[N:35])=[N:29]1.[F-].[K+].CN(C=O)C>O>[CH:15]([C:9]1[C:6]2[C:7](=[O:8])[N:3]([CH2:2][O:33][C:32]3[N:28]([C:22]4[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=4[Cl:20])[N:29]=[C:30]([C:34]#[N:35])[CH:31]=3)[S:4](=[O:19])(=[O:18])[C:5]=2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=1)([CH3:17])[CH3:16]
Reactant: N#CC1=NN(c2ccc(Cl)cc2Cl)C(=O)C1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COc1cc(C#N)nn1-c1ccc(Cl)cc1Cl)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
A mixture of 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (410 mg, 1.18 mmol), 2,4-dihydro-2-(2,4-dichlorophenyl)-5-cyano-3H-pyrazol-3-one (300 mg, 1.18 mmol), KF (68.44 mg, 1.18 mmol) and DMF (20 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (100 mL) and was extracted with ether (3×50 mL). The ether extracts were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20% ethyl acetate/hexane to afford 310 mg of 4-isopropyl-6-methoxy-2-[1-(2, 4-dichlorophenyl)-3-cyanopyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =2,4-Cl2 --Ph; R2 =CN; R3 =H; R4 =CH(CH3)2 ; R5 =6-OCH3), m.p. 183°-184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][C:6]([CH2:7][N:8]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[N:50]1([CH2:56][CH2:57][OH:58])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>>[CH3:47][O:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:49][CH:48]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([N:53]6[CH2:54][CH2:55][N:50]([CH2:56][CH2:57][OH:58])[CH2:51][CH2:52]6)=[O:35])=[CH:32][CH:31]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:41][CH:42]=1
Reactant: OCCN1CCNCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(CCO)CC4)cc3)cn2)cc1
Yield: 83.2 %

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-benzoic acid (70.0 mg, 0.106 mmol) obtained in Step A in Example 1-D-19 and 1-piperazineethanol (26.0 μl, 0.212 mmol) instead of 3-(aminomethyl)pyridine, in the same manner as Step B in Example 1-D-19, amidation was carried out, to obtain a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone as a yellow solid (68.1 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-111) as a yellow powder (24.7 mg, 44%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1.CCN(C(C)C)C(C)C.Cl[C:25]([O:27][CH3:28])=[O:26]>C(Cl)Cl>[NH2:14][C:3]1[N:4]=[CH:5][C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:25]([O:27][CH3:28])=[O:26])[CH2:12][CH2:13]2)=[N:7][C:2]=1[Br:1]
Reactant: COC(=O)Cl
Reactant: Nc1ncc(C2CCNCC2)nc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N1CCC(c2cnc(N)c(Br)n2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromo-5-(piperidin-4-yl)pyrazin-2-amine (60 mg, 0.233 mmol) in DCM (2 mL) in ice bath was added DIEA (408 μl, 2.333 mmol) and methyl chloroformate (18.07 μl, 0.233 mmol). The reaction mixture was stirred under ice bath for 30 min. The reaction mixture was partitioned between DCM and water. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered off, and evaporated in vacuo. The crude methyl 4-(5-amino-6-bromopyrazin-2-yl)piperidine-1-carboxylate was used for next step. LCMS (m/z): 315.0/317.0 (MH+), 0.647 min.
Reaction SMILES: [Br:1][C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1I.[CH3:12][N:13](C=O)C>[C-]#N.[Zn+2].[C-]#N.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>[Br:1][C:2]1[C:10]2[S:9][N:8]=[CH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:12]#[N:13]
Reactant: CN(C)C=O
Reactant: Brc1c(I)ccc2cnsc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2cnsc2c1Br
Temperature: 80 °C
Yield: 50 %

Procedure:
A suspension of 7-bromo-6-iodo-1,2-benzothiazole (43.2 mg, 0.127 mmol), zinc cyanide (13.6 mg, 0.116 mmol), and Pd(PPh3)4 (15.9 mg, 0.0138 mmol) in DMF (1.6 mL) was heated to 80° C. in a microwave for 15 min. The reaction mixture was concentrated in vacuo. Purification of the residue by ISCO chromatography (20 to 100% dichloromethane:heptane) to afford 16.4 mg (50%) of the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 9.25 (s, 1H), 7.77 (d, J=7.58 Hz, 1H), 7.69 (d, J=8.08 Hz, 1H); MS (ESI): 237.15, 239.14 [M−H]+; HPLC tR=0.90 min (HPLC: nonpolar—2 min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])/[CH:4]=[CH:5]/[C:6]1[C:7]([O:23][CH3:24])=[C:8]2[C:12](=[C:13]([F:15])[CH:14]=1)[N:11]([CH2:16][CH3:17])[CH:10]=[C:9]2[CH2:18][C:19]([NH:21][CH3:22])=[O:20].[CH3:26]O>[Pd]>[CH3:22][N:21]([CH3:26])[C:19](=[O:20])[CH2:18][C:9]1[C:8]2[C:12](=[C:13]([F:15])[CH:14]=[C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:25])[C:7]=2[O:23][CH3:24])[N:11]([CH2:16][CH3:17])[CH:10]=1
Reactant: CCn1cc(CC(=O)NC)c2c(OC)c(/C=C/C(=O)OC)cc(F)c21
Reactant: CO
Agent: [Pd]
Product: CCn1cc(CC(=O)N(C)C)c2c(OC)c(CCC(=O)OC)cc(F)c21
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 27-1 (200 mg, 0.57 mmol) in 20 mL of MeOH was added 0.1 g of Pd/C (10%). The mixture was stirred over night under H2 atmosphere at room temperature. The mixture was filtered and the filtrate was to afford 27-2 (150 mg, 0.42 mmol, 74%) as a white solid. LRMS: calc 364.1 and found: 365.1 [MH]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:39])[NH:25][C@H:26]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O[CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][F:65])(=O)=O)=CC=1.C1(C)C=CC=CC=1>CN(C=O)C>[F:65][CH2:64][CH2:63][O:62][CH2:61][CH2:60][O:59][CH2:58][CH2:57][O:38][C:34]1[CH:33]=[C:32]([C@@H:26]([NH:25][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]3)[CH2:19]2)=[O:39])[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:37]=[CH:36][CH:35]=1
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cccc(OCCOCCOCCF)c1
Temperature: 25 °C
Yield: 61.8 %

Procedure:
To tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(3-hydroxyphenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (26 mg, 50 μmol) in DMF (6.6 mL) was added cesium carbonate (38.8 mg, 120 μmol) and 2-[2-(2-fluoroethoxy)ethoxy]ethyl 4-methylbenzenesulfonate (22 mg, 70 μmol) while stirring at room temperature. After 5 hours toluene was added and the mixture was concentrated in vacuum. The DMF free residue was purified by preparative thin layer chromatography on silica gel (dichloromethane in ethyl acetate 30%) to yield 21 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-1-(3-{2-[2-(2-fluoroethoxy)ethoxy]ethoxy}phenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: Cl.[C:2]([C:4]1([NH:7][C:8]([C@@H:10]2[CH2:14][C@@H:13]([S:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])(=[O:17])=[O:16])[CH2:12][NH:11]2)=[O:9])[CH2:6][CH2:5]1)#[N:3].Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>>[CH:29]([O:28][C:26]([N:11]1[CH2:12][C@H:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])(=[O:17])=[O:16])[CH2:14][C@H:10]1[C:8](=[O:9])[NH:7][C:4]1([C:2]#[N:3])[CH2:6][CH2:5]1)=[O:27])([CH3:31])[CH3:30]
Reactant: CC(C)OC(=O)Cl
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: Cl
Product: CC(C)OC(=O)N1C[C@H](S(=O)(=O)c2ccccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
(2S,4R)-4-(2-chloro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide hydrochloride from experiment K4 was acylated with isopropyl chloroformate in analogy to experiment L21 to give (2S,4R)-4-(2-chloro-benzenesulfonyl)-2-(1-cyano-cyclopropylcarbamoyl)-pyrrolidine-1-carboxylic acid isopropyl ester as a colorless oil. MS: 440.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13]([NH:15]C(=O)C3C=CC=CC=3)=[S:14])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>CO.[OH-].[Na+]>[C:1]1([C:7]2[N:8]=[C:9]([NH:12][C:13]([NH2:15])=[S:14])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(NC(=S)Nc1nc(-c2ccccc2)cs1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: NC(=S)Nc1nc(-c2ccccc2)cs1
Yield: 3.6 %

Procedure:
4.20 g N-{[(4-phenyl-1,3-thiazole-2-yl)amino]carbonothioyl}benzamide (339 mmol) were suspended in 40 ml methanol, were dissolved in aqueous sodium hydroxide (550 mg NaOH dissolved in 3 ml H2O) and were heated for 3 hours at reflux. The reaction mixture was evaporation-concentrated, the residue obtained was stirred with water and the precipitated solid was suction-isolated. After drying, 2.90 g of a light yellow solid were obtained.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CC([O-])(C)C.[Na+].[CH3:16][O:17][C:18]([C:20]1[S:32][C:23]2[C:24]3[CH:25]=[CH:26][C:27]([Cl:31])=[CH:28][C:29]=3[S:30][C:22]=2[C:21]=1[OH:33])=[O:19].O>CN(C=O)C>[CH3:16][O:17][C:18]([C:20]1[S:32][C:23]2[C:24]3[CH:25]=[CH:26][C:27]([Cl:31])=[CH:28][C:29]=3[S:30][C:22]=2[C:21]=1[O:33][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:19]
Reactant: COC(=O)c1sc2c(sc3cc(Cl)ccc32)c1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1sc2c(sc3cc(Cl)ccc32)c1OCC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 67.8 %

Procedure:
tert-Butyl bromoacetate (0.10 ml, 0.65 mmol, 1.3 equiv) was added to a mixture of NaOt-Bu (60 mg, 1.2 equiv) and 6-chloro-1-hydroxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (150 mg, 0.5 mmol) in DMF (6 ml) and stirred at 60° C. for 2.5 hr then at RT for 3 days. Water was added and the mixture was extracted with EtOAc. After removal of solvent, purification by column chromatography gave 140 mg (68%) of 1-tert-butoxycarbonylmethoxy-6-chloro-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester as orange solids.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9]2=[N:15][CH:16]=[N:17][N:8]2[C:7]1=[O:18])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:19]N1C(=O)CCC1=O>C1COCC1>[Br:19][C:12]1[NH:11][C:10]2[C:9]3=[N:15][CH:16]=[N:17][N:8]3[C:7](=[O:18])[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:14]=2[N:13]=1
Reactant: CCCCCn1c(=O)n2ncnc2c2[nH]cnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n2ncnc2c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-pentyl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (20 mg, 0.081 mmol) in THF (5 mL) was added N-bromosuccinimide (19 mg, 0.11 mol). The reaction mixture was stirred at room temperature for 1 hour and then quenched by phenol. After removing solvent, the residue was purified by preparative LCMS (method B) to yield the desired product. 1HNMR (400 MHz, CD3OD): δ 8.30 (s, 1H), 4.30 (t, J=7.4 Hz, 2H), 1.86 (m, 2H), 1.41 (m, 4H), 0.93 (t, J=7.0 Hz, 3H). LCMS calculated for C11H14BrN6O (M+H): 325.0; found: 325.0, 327.0.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.S([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)(C)(=O)=O>CN(C=O)C>[I:3][C:4]1[CH:5]=[N:6][N:7]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:8]=1
Reactant: Ic1cn[nH]c1
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(I)cn2)CC1
Reaction time: 1 h

Procedure:
NaH (60% suspension, 1.13 g, 28.4 mmol) was added portion wise to a solution of 4-iodopyrazole (5 g, 25.7 mmol) in anhydrous DMF (30 mL) at 0° C.; and it was stirred for 1 h. Finally, tert-butyl 4-mesylpiperidine-1-carboxylate (CAS: 141699-59-4) (6.5 g, 32.7 mmol) was added to the reaction mixture and it was stirred at 100° C. for 16 h. It was, then, cooled and quenched with saturated solution of NH4Cl (100 mL). Extraction was carried out using EtOAc (50 mL×2); the combined organic layers were washed with water (100 mL); brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide crude product, which was further purified by silica gel column chromatography (20% EtOAc in hexanes) to give title compound Va-1-I (4 g, 41%). LCMS: m/z 378.1 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:15][NH:16][CH3:17]>CN(C)C=O>[CH3:15][N:16]([CH3:17])[C:2]1[C:3]2[N:4]([CH:12]=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Clc1nc2ccccc2n2cnnc12
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)c1nc2ccccc2n2cnnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
A slurry of 2.0 g. (0.01 mole) of 4-chloro-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 2) in N,N-dimethylformamide (30 ml.) was saturated with dimethylamine gas and stirred at room temperature overnight. The mixture was poured over ice and the precipitate was removed by filtration. Recrystallization from ethanol gave 640 mg. (44% yield) of 4-dimethylamino-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 184°-186° C. Mass spectrum: m/e, 213 (P).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([C:15]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)(Cl)Cl>[Br:1][C:22]1[CH:21]=[CH:20][C:18]2[O:19][C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:16][C:17]=2[CH:23]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(C2(c3ccccc3)Oc3ccccc3O2)cc1
Solvent: ClC(Cl)Cl
Product: Brc1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2

Procedure:
18.75 g of N-bromosuccinimide are added to a solution of 27.4 g of 2,2-diphenyl-1,3-benzodioxol in 80 ml of chloroform and the mixture was boiled at reflux for 20 hours. The reaction mixture was cooled and the separated succinimide was filtered off. The filtrate was washed with water, dried over sodium sulphate and the solvent was removed in a vacuum. By crystallization of the residue from ethanol, there was obtained 5-bromo-2,2-diphenyl-1,3-benzodioxol as white crystals of melting point 88°-89° C.
Reaction SMILES: [C:1]12([C:11]3[C:12]([OH:32])=[CH:13][C:14]([OH:31])=[C:15]([CH:30]=3)[C:16]([NH:18][CH2:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28]C)[CH:21]=3)=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.B(Br)(Br)Br.CO>ClCCl>[C:1]12([C:11]3[C:12]([OH:32])=[CH:13][C:14]([OH:31])=[C:15]([CH:30]=3)[C:16]([NH:18][CH2:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([OH:28])[CH:21]=3)=[O:17])[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COc1cc(CNC(=O)c2cc(C34CC5CC(CC(C5)C3)C4)c(O)cc2O)cc(OC)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: COc1cc(O)cc(CNC(=O)c2cc(C34CC5CC(CC(C5)C3)C4)c(O)cc2O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.2 %

Procedure:
5-Adamantan-1-yl-N-(3,5-dimethoxybenzyl)-2,4-dihydroxybenzamide (0.27 g) is dissolved in dichloromethane (3 mL). After adding BBr3 (1.7 mL in CH2Cl2 1.0 M solution, 3 eq.) and stirring at room temperature for 2 hours, methanol (5 mL) is added and extraction is carried out using water and dichloromethane. The organic layer is dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography to obtain 0.045 g of the target compound as white solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([O:24][CH3:25])[C:18]=3[C:17](I)=[CH:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:35]2[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)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>[Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:23]3[CH:22]=[CH:21][N:20]=[C:19]([O:24][CH3:25])[C:18]=3[C:17]([C:35]3[CH:40]=[CH:39][C:38]([S:41]([NH2:44])(=[O:43])=[O:42])=[CH:37][CH:36]=3)=[CH:16]2)[CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(S(N)(=O)=O)cc2)OC1(C)C
Reactant: COc1nccc2c1c(I)cn2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)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: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)cn2[C@H]1CC[C@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 130 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(trans-4-((tert-butyl(dimethyl)silyl)oxy)cyclohexyl)-3-iodo-4-methoxy-1H-pyrrolo[3,2-c]pyridine (30.0 mg) in DMF (2 mL)/water (0.20 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (25.8 mg), tetrakis(triphenylphosphine)palladium(0) (7.13 mg) and potassium carbonate (17.2 mg). The reaction mixture was stirred under microwave irradiation at 130° C. for 1 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (13.1 mg).
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](NC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][C@@H:37]([CH3:40])[CH2:38][OH:39]>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:36][C@@H:37]([CH3:40])[CH2:38][OH:39])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](N)CO
Reactant: CNc1ncc2cc(-c3cc(NC(=O)Nc4cnn(C(C)(C)C)c4)c(F)cc3C)c(=O)n(C)c2n1
Solvent: C1CCOC1
Product: Cc1cc(F)c(NC(=O)Nc2cnn(C(C)(C)C)c2)cc1-c1cc2cnc(N[C@@H](C)CO)nc2n(C)c1=O
Yield: 74.2 %

Procedure:
Using general method E, 1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 109 (0.081 g, 0.16 mmol) and (S)-2-aminopropan-1-ol (0.036 g, 0.48 mmol) were combined in THF (1 mL) to provide (S)-1-(1-tert-butyl-1H-pyrazol-4-yl)-3-(2-fluoro-5-(2-(1-hydroxypropan-2-ylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)urea as a white solid (0.062 g, 75% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.60 (s, 1H), 8.40 (d, J=1.6 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.77 (s, 1H), 7.64 (s, 1H), 7.59 (d, J=8.0 Hz, 1H) 7.36 (s, 1H), 7.10 (d, J=12.4 Hz, 1H), 4.72 (t, J=5.6 Hz, 1H), 4.10-4.06 (m, 1H), 3.65-3.53 (m, 3H), 2.05 (s, 3H), 1.45 (s, 9H), 1.17 (d, J=6.4 Hz, 3H); (ESI) m/z: 523.2 (M+H+).