Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:28][CH:27]=4)[C:15](=[O:25])[NH:16]3)=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:42](Cl)[CH2:43]Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:10]([C@@H:19]1[CH2:20][CH2:21][C@@H:42]([CH3:43])[CH2:17][C@H:18]1[O:23][C:22]([C@@H:21]1[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:28][CH:27]=4)[C:15](=[O:25])[NH:16]3)=[CH:11][C:10]=2[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:24])([CH3:11])[CH3:9]
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2CC1C(=O)O)NC(=O)[C@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)O3
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (8.0 g, 13.3 mmol) was suspended in 30 mL DCM and 1R-2S-5R(−)-menthol (26.6 mmol), EDC (26.6 mmol) and DMAP (cat.) added. The mixture was stirred at r.t. for 6 h and the mixture was diluted with DCM. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The residue purified over silica with hexanes-EtOAc gradient (0% EtOAc to 30%) to provide (3S,7S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-((1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl) ester (2.4 g, 1H NMR (400 MHz, CDCl3): 8.2 (m, 1H), 7.5 (m, 1H), 7.42 (d, 1H), 7.35 (m, 2H), 7.25 (m, 1H), 6.9 (m, 2H), 6.7 (m, 1H), 6.6 (s, 1H), 5.55 (m, 1H), 4.8-5.1 (m, 1H), 5.0 (s, 2H), 4.3-4.6 (m, 3H), 3.1 (m, 2H), 1.8 (m, 1H), 1.6 (m, 3H), 1.5 (d, 9H), 1.3 (m, 2H), 0.7-1.0 (m, 9H), 0.4 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O.C([O-])=O.[NH4+]>O1CCOCC1.ClCCl.[Ni]>[NH2:1][C:4]1[CH:5]=[C:6]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1
Reactant: CS(=O)(=O)Nc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: [Ni]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cc(N)cc(C(F)(F)F)c1
Temperature: 140 °C

Procedure:
N-(3-nitro-5-trifluoromethyl-phenyl)-methylsulfonamide (0.1 g; 0.4 mmol) ammonium formate (0.1 g; 1.8 mmol) and Raney-Nickel (16 mg) were dissolved in 0.4 mL of dioxane. The reaction was heated to 140° C. for 6 minutes in a micro wave reactor. The mixture was then diluted with dichloromethane, filtrated and the filtrate concentrated. 70 mg (0.27 mmol; 68% yield) of an orange oil were obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[O:7][CH2:8][CH2:9][OH:10].[H-].[Na+].Br[C:19]1[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:26]2[C:25](=[O:36])[N:24]([CH2:37][CH2:38][CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[C:23](=[O:47])[N:22]([CH3:48])[C:21]=2[N:20]=1>C1COCC1>[CH3:48][N:22]1[C:21]2[N:20]=[C:19]([O:10][CH2:9][CH2:8][O:7][C:6]3[CH:11]=[CH:12][CH:13]=[C:4]([O:3][C:2]([F:14])([F:15])[F:1])[CH:5]=3)[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:33])[CH3:34])[C:26]=2[C:25](=[O:36])[N:24]([CH2:37][CH2:38][CH2:39][O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[C:23]1=[O:47]
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2COCC[Si](C)(C)C
Reactant: OCCOc1cccc(OC(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(OCCOc1cccc(OC(F)(F)F)c1)n2COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(3-(trifluoromethoxy)phenoxy)ethanol (0.64 g, 2.9 mmol, intermediate 5) in THF (15 mL) was added sodium hydride (0.23 g, 9.67 mmol) at 0° C. it was stirred at 0° C. for 30 min, then 8-bromo-3-methyl-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (1.0 g, 1.93 mmol, intermediate 16 step 1) was added. The mixture was stirred 16 h. The reaction was quenched with aq. ammonium chloride (2 mL) at 0° C.; then it was partitioned between ethyl acetate and water. The organic phases were combined, dried over sodium sulfate, filtered and concentrated to give a crude product which was used without purification. LCMS retention time 2.144; LCMS MH+-THP 575.
Reaction SMILES: CO.[Cl:3][C:4]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].[BH4-].[Na+]>[OH-].[Na+]>[Cl:3][C:4]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7]
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.5 %

Procedure:
To solution of MeOH (150 mL) containing 2,3-dichlorobenzaldehyde (20 g, 0.11 mole), cooled in ice bath, was added a solution of NaBH4 (4.54 g, 0.12 mole) in 0.2 M NaOH (15 mL) slowly over 15 min under nitrogen atmosphere. After completion of the addition, the mixture was allowed to warm up gradually to rt, and stirred for 2.5 h at rt. The reaction was quenched by cooling the mixture and pouring it slowly to ice water (˜700 mL). The mixing led to formation of white precipitates. After stirring for 30 min, the precipitates were collected on Bòchner funnel; and the collected solid was dissolved in EtOAc (200 mL). The organic solution was washed with 0.1 M NaOH (150 mL), dried over Na2SO4, and concentrated to dryness in vacuo, yielding 2,3-dichlorobenzylalcohol as white solid (19.57 g, 97%). Rf=0.46 in EtOAc/hexane (1/3). 1H-NMR (CD3OD, 299.96 MHz): δ (ppm) 7.52-7.49 (dd, 1H), 7.45-7.42 (dd, 1H), 7.33-7.27 (t, 1H), 4.70 (s, 2H). Retention time (anal. HPLC: 10 to 70% MeCN/H2O over 6 min)=4.00 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([CH3:7])([SH:6])[CH3:5].C(N(CC)CC)C.[C:15]1(=[O:21])[O:20][C:18](=[O:19])[CH2:17][CH2:16]1>C(Cl)Cl>[CH3:5][C:4]([SH:6])([CH3:7])[CH2:3][NH:2][C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:21]
Reactant: CC(C)(S)CN
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(S)CNC(=O)CCC(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
To an ice-cooled suspension of 1-amino-2-methylpropan2-thiol hydrochloride (5.06 g, 35.72 mmol) in methylene chloride (100 mL) was added triethylamine (5.0 mL, 35.87 mmol) followed by succinic anhydride (3.50 g, 34.96 mmol). The resulting clear solution was stirred at 0° C. or 10 minutes, then at room temperature for 2 hours. Evaporation of the volatiles under reduced pressure gave a residue which was partitioned between 2 N hydrochloric acid (100 mL) and ethyl acetate (100 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (5 mL), dried over sodium sulfate and evaporated to dryness. The residue was triturated with ether-hexane to afford the title compound as a white solid (6.78 g, 94.4%). Mp. 86-87° C.; 1H NMR (300 MHz, CDCl3): δ 1.34 (s, 6H), 1.55 (s, 1H), 2.59 (t, J=6.6 Hz, H), 2.70 (t, J=6.6 Hz, 2H), 3.32 (d, J=8.0 Hz, 2H), 6.58 (br t, J=5.9 Hz, 1H), 10.73 (br s, 1H); 13C NMR (75 MHz, CDCl3): δ 29.57, 29.79, 30.79, 172.50, 176.81; LCMS (m/e): 223 (M+H2O), 206 (M+1).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[S:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:20]1[S:19][CH:23]=[CH:22][N:21]=1)([O-:3])=[O:2]
Reactant: c1cscn1
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCNC(=C[N+](=O)[O-])NCCSCc1nccs1

Procedure:
Reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene with an excess of 2-[2-aminoethyl)thiomethyl]thiazole according to the procedure of Example 3, results in the production of 1-nitro-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-2-[2-(2-thiazolylmethylthio)ethylamino]ethylene, m.p. 119°-120° (from acetonitrile). By the same procedure, reaction of 1-nitro-2-methylthio-2-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]ethylene with the following compounds
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH:19](OCC)[O:20]CC)[NH:11][CH:10]=[C:9]1[C:26]([O:28][CH3:29])=[O:27].Cl>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH:19]=[O:20])[NH:11][CH:10]=[C:9]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC=C(C(=O)OC)C1c1ccccc1Cl
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)C1=C(C=O)NC=C(C(=O)OC)C1c1ccccc1Cl
Yield: 27.2 %

Procedure:
To a mixture of a yellow oil (360 mg) of methyl 4-(2-chlorophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate in acetone (10 ml) was added 6N hydrochloric acid (0.3 ml) and the resultant mixture was stirred for 1.5 hours at room temperature, and the acetone was removed. Water was added to the residue and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated. The resultant orange oil (0.26 g) was crystallized and the crystals were washed with n-hexane to give yellowish-orange powder (80.7 mg) of methyl 4-(2-chlorophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate.
Reaction SMILES: [CH3:1][NH:2][S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13]([OH:15])[C:12]([CH3:17])([CH3:16])[C:11]=2[CH:18]=1)(=[O:5])=[O:4].[CH3:19]O>S(=O)(=O)(O)O.C(N(CC)CC)C>[CH3:1][NH:2][S:3]([O:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH:13]([O:15][CH3:19])[C:12]([CH3:16])([CH3:17])[C:11]=2[CH:18]=1)(=[O:4])=[O:5]
Reactant: CO
Reactant: CNS(=O)(=O)Oc1ccc2c(c1)C(C)(C)C(O)O2
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)Oc1ccc2c(c1)C(C)(C)C(OC)O2
Reaction time: 0.5 h

Procedure:
4 drops of concentrated sulfuric acid was added to a solution of 22.5 parts of 2,3-dihydro-3,3-dimethyl-2-hydroxybenzofuran-5-yl methylaminosulfonate in 200 parts of methanol. The mixture was subsequently boiled for 30 minutes under reflux, and then cooled. The mixture was neutralized with triethylamine and concentrated to dryness in vacuo. Treatment of the viscous residue with a mixture of ether and n-hexane gave crystals of 2,3-dihydro-3,3-dimethyl-2-methoxybenzofuran -5-yl methylaminosulfonate; melting point: 89° to 91°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH2:34][CH3:35])[C:16]2[C:17]([CH3:33])=[C:18]([C:29]([O:31][CH3:32])=[O:30])[CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:21]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:37][CH2:38][O:39][CH3:40].C([O-])([O-])=O.[Cs+].[Cs+].O>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH2:34][CH3:35])[C:16]2[C:17]([CH3:33])=[C:18]([C:29]([O:31][CH3:32])=[O:30])[CH:19]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH2:37][CH2:38][O:39][CH3:40])=[CH:26][CH:27]=3)[CH:21]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(c1cc(-c2ccc(O)cc2)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCN(c1cc(-c2ccc(OCCOC)cc2)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To a stirred solution of methyl 5-(((trans)-4-((tert-butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-4′-hydroxy-4-methyl-[1,1′-biphenyl]-3-carboxylate (0.6 g, 1.24 mmol) and 1-bromo-2-methoxyethane (0.519 g, 3.73 mmol) in acetonitrile (6 mL), Cs2CO3 (0.485 g, 1.49 mmol) was added and reaction was stirred at 80° C. for 12 h. On completion, water was added to it and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by column chromatography to afford the title compound (0.6 g, 76.5% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=1.[Cl:27][C:28]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]>>[Cl:27][C:28]1[CH:33]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])=[CH:18][CH:17]=2)[CH:31]=[C:30]([Cl:43])[C:29]=1[OH:44]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CCN(C)C)cc1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CCN(C)C)cc1
Yield: 55.1 %

Procedure:
Following general procedure D, 1-(6-bromo-4-(4-(2-(dimethylamino)ethyl)phenylamino)quinolin-3-yl)ethanone (76 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (81 mg, 0.28 mmol) to afford the desired product (49 mg, 55%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.30 (s, 1H), 8.19 (dd, J=8.8, 2.0 Hz, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.60 (d, J=8.3 Hz, 2H), 7.49 (d, J=8.3 Hz, 2H), 7.13 (s, 2H), 3.45-3.37 (m, 2H), 3.29-3.20 (m, 2H), 3.00 (s, 6H), 2.82 (s, 3H); ESI MS m/z 494 [C27H25Cl2N3O2+H]+; HPLC 96.9% (AUC), tR=12.01 min.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]3)[C:12]2=O)=[CH:8][CH:7]=1.[CH3:22][C:23]([S:26]([NH2:28])=[O:27])([CH3:25])[CH3:24].CCOC(C)=O>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.O>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9](=[CH:8][CH:7]=1)[CH2:10][C:11]1([CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)[C:12]2=[N:28][S:26]([C:23]([CH3:25])([CH3:24])[CH3:22])=[O:27]
Reactant: O=C1c2cc(OCCCF)ccc2CC12CCC(O)CC2
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)N=C1c2cc(OCCCF)ccc2CC12CCC(O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
6′-(3-Fluoropropoxy)-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 21, 0.91 g, 3.11 mmol), 2-methylpropane-2-sulfinamide (0.566 g, 4.67 mmol) and titanium(IV) ethoxide (1.283 mL, 6.23 mmol) were dissolved in 2-Me THF (8 mL) and heated to reflux over a weekend. More 2-methyl-2-propanesulfinamide (0.189 g, 1.56 mmol) and titanium(IV) ethoxide (0.325 mL, 1.56 mmol) were added, and the mixture was refluxed overnight. The reaction was cooled to r.t. EtOAc (50 mL) and water (10 mL) were added under stirring. The mixture were let to stand still for 1 h. The organic phase was collected by filtration, dried, and concentrated. The residue was purified by flash column chromatography using a gradient of 0-40% EtOAc in heptane, to give 0.278 g (23% yield) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.33 (s, 9 H) 1.45-1.54 (m, 4 H) 1.87 (br. s., 1 H) 2.03 (dd, 2 H) 2.14-2.19 (m, 1 H) 2.20-2.25 (m, 1 H) 2.93-3.01 (m, 2 H) 3.71-3.80 (m, 1 H) 4.13-4.18 (m, 2 H) 4.59-4.66 (m, 1 H) 4.69-4.75 (m, 1 H) 7.11 (dd, 1 H) 7.29 (s, 1 H); MS (ES+) m/z 396.11 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)#[N:2].[Li]CCCC.[O:21]1[CH:23]([CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22]1.O>C1COCC1>[OH:21][CH:23]([CH2:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:22][N:7]1[C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2
Reactant: c1ccc(OCC2CO2)cc1
Reactant: N#Cc1ccc2[nH]c3ccccc3c2c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)c1ccccc1n2CC(O)COc1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyano-9H-carbazole (0.4998 g, 2.6 mmol, 1 equiv) in THF (40 mL) was added nBuLi (1.6 M in hexane, 3.25 mL, 5.2 mmol, 2 equiv). The mixture was stirred at −78° C. for 2 hours. 1,2-epoxy-3-phenoxypropane (0.7809 g, 5.2 mmol, 2 equiv) was added and the mixture was stirred at 45° C. overnight. Water (50 mL) was added and the mixture was extracted by dichloromethane (3×30 mL). The combined dichloromethane layers were washed by brine (2×30 mL) and then dried over Na2SO4. The solvent was removed under reduced pressure, and the product was chromatographed on silica gel with dichloromethane to yield 0.7736 g white foamed solid (86%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[O:14]1[CH2:17][CH:16]([NH2:18])[CH2:15]1.CCN(C(C)C)C(C)C>>[N+:11]([C:6]1[CH:7]=[C:8]2[CH2:9][N:18]([CH:16]3[CH2:17][O:14][CH2:15]3)[CH2:2][CH2:3][N:4]2[N:5]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Reactant: NC1COC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc2n(n1)CCN(C1COC1)C2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 250 mL round-bottomed flask, 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (1.54 g, 4.92 mmol, Eq: 1.00) was combined with CH3 CN (60 ml) to give a light yellow solution. To this oxetan-3-amine (432 mg, 5.91 mmol, Eq: 1.20) and dropwise DIPEA (1.14 g, 1.55 ml, 8.86 mmol, Eq: 1.80) were added and the reaction mixture was stirred at room temperature for 24 hr.
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[F:16])[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=3)=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C1CCCCC=1>>[CH:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[F:16])[C:9]([C:17]3[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=3)=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(-c2nn(C3CCCCC3)c3c(F)cccc23)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Oc1ccc(-c2nn(C3CCCCC3)c3c(F)cccc23)cc1
Yield: 25.8 %

Procedure:
Prepared according to Method C step B from 1-cyclohexyl-7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.9 g, 0.5 mmol), boron tribromide (0.094 mL, 1.0 mmol) and 0.5 mL of cyclohexene to give the product (0.040 g) as a tan solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:18][CH:15]2[CH2:17][CH2:16]2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Reactant: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCCO)nc1NC1CC1

Procedure:
In analogy to the procedure described in example 38b, 4,6-dichloro-2-(2-hydroxy-ethyl-amino)-pyrimidine-5-carbonitrile was treated with cyclopropylamine in dioxane in the presence of N-ethyl-diisopropylamine at 90° C. to yield 4-chloro-6-cyclopropylamino-2-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=254.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:20]=[CH:19][C:18]([C:21]4[O:22][C:23]5[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=5[N:25]=4)=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[Br:37]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:37][C:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]3[O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:19][CH:20]=2)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2
Reactant: c1ccc2c(-c3ccc(-c4nc5ccccc5o4)cc3)c3ccccc3cc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1c2ccccc2c(-c2ccc(-c3nc4ccccc4o3)cc2)c2ccccc12
Reaction time: 25 h
Yield: 83.3 %

Procedure:
In a 1 L Meyer flask, 3.3 g (8.8 mmol) of 2-[4-(9-anthryl)phenyl]benzoxazole, 50 mL of toluene, and 200 mL of ethyl acetate were placed. Into the solution, 1.6 g (8.8 mmol) of N-bromosuccinimide was added little by little. This solution was stirred under air for 25 hours. After a certain period, the solution was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline, and then, the organic layer was dried with magnesium sulfate. The obtained mixture was gravity filtered, and the filtrate was condensed to give an oily substance. The oily substance was purified by silica gel column chromatography (toluene:hexane=5:1) to give a solid. The solid was recrystallized with toluene/methanol, giving 3.3 g of the target yellow powder in a yield of 82%.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[CH:8]1([C:14]([O:16][CH:17]([O:21][C:22](ON2C(=O)CCC2=O)=[O:23])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(#N)C.O>[CH:8]1([C:14]([O:16][CH:17]([O:21][C:22]([NH:7][C:3]2([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]2)=[O:23])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)C(OC(=O)ON1C(=O)CCC1=O)OC(=O)C1CCCCC1
Reactant: NC1(C(=O)O)CC1
Solvent: O
Solvent: CC#N
Product: CC(C)C(OC(=O)NC1(C(=O)O)CC1)OC(=O)C1CCCCC1
Yield: 25.6 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (0.533 g, 5.27 mmol) and 1-(2,5-dioxoazolidinyloxycarbonyloxy)-2-methylpropyl cyclohexanecarboxylate (1.5 g, 4.39 mmol) were reacted in the acetonitrile/water mixture to provide 0.368 g (27% yield) of the title compound (11) as a white powder after work-up and mass-guided preparative HPLC purification. M.p.: 156-158.5° C. 1H NMR (CDCl3, 400 MHz): δ=6.59 (d, 1H), 6.05 (br s, 0.3H), 5.41 (s, 0.7H), 2.38 (m, 1H), 2.13 (m, 1H), 1.96 (d, 2H), 1.78 (m, 2H), 1.6 (m, 3H), 1.44 (m, 2H), 1.23 (m, 5H), 0.99 (m, 6H). MS (ESI) m/z 350.05 (M+Na)+.
Reaction SMILES: Br[C:2]1[C:3]([NH2:18])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)[N:7]=1.[CH2:19]([NH:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][C:30]=1[F:38])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH2:18][C:3]1[C:2]([C:32]2[CH:33]=[CH:34][C:29]([C:27]([NH:26][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:28])=[C:30]([F:38])[CH:31]=2)=[N:7][C:6]([CH:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:5][N:4]=1
Reactant: O=C(NCc1ccccc1)c1ccc(B(O)O)cc1F
Reactant: Nc1ncc(C2CCC3(CC2)OCCO3)nc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1ncc(C2CCC3(CC2)OCCO3)nc1-c1ccc(C(=O)NCc2ccccc2)c(F)c1
Yield: 46.6 %

Procedure:
To 3-bromo-5-(1,4-dioxaspiro[4.5]decan-8-yl)pyrazin-2-amine (630 mg, 2.005 mmol) was added (4-(benzylcarbamoyl)-3-fluorophenyl)boronic acid (767 mg, 2.81 mmol), PdCl2(dppf)CH2Cl2 adduct (164 mg, 0.201 mmol), DME (9 mL) and then last sodium carbonate 2M (3.01 mL, 6.02 mmol). The reaction was microwaved at 115° C. for 12 min. To the reaction was added 400 mL of ethyl acetate washed with water (2×), dried with sodium sulfate, filtered and concentrated to residue. The crude was purified by silica gel chromatography using 40 gram column eluting with 20-100% ethyl acetate and heptane. The desired fractions were concentrated to constant mass to give 432 mg of the desired product as free base used as is, (47% yield). LCMS (m/z): 463.2 (MH+), 0.82 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.94-8.81 (m, 1H), 7.89 (s, 1H), 7.80-7.69 (m, 1H), 7.67-7.52 (m, 2H), 7.33 (d, J=4.3 Hz, 4H), 7.27-7.18 (m, 1H), 6.09 (s, 2H), 4.49 (d, J=5.9 Hz, 2H), 3.85 (s, 4H), 2.70-2.61 (m, 1H), 1.84-1.67 (m, 6H), 1.65-1.48 (m, 2H).