Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C2C(=CC=1)[N:7](S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(Cl)(=O)=O.ClS(C1C2C(=C([N+]([O-])=O)C=CC=2)N(S(C2C=CC=CC=2)(=O)=O)C=1C(OCC)=O)(=O)=O.ClC1C=C2C(=CC=1)N(S(C1C=CC=CC=1)(=O)=O)C(C(OCC)=O)=C2S(N1CCOCC1)(=O)=O.[N:92]1([S:98]([C:101]2[C:109]3[C:104](=[C:105]([N+:110]([O-:112])=[O:111])[CH:106]=[CH:107][CH:108]=3)[NH:103][C:102]=2[C:113]([O:115]CC)=O)(=[O:100])=[O:99])[CH2:97][CH2:96][O:95][CH2:94][CH2:93]1>>[N:92]1([S:98]([C:101]2[C:109]3[C:104](=[C:105]([N+:110]([O-:112])=[O:111])[CH:106]=[CH:107][CH:108]=3)[NH:103][C:102]=2[C:113]([NH2:7])=[O:115])(=[O:100])=[O:99])[CH2:97][CH2:96][O:95][CH2:94][CH2:93]1
Reactant: CCOC(=O)c1c(S(=O)(=O)Cl)c2cc(Br)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOC(=O)c1[nH]c2c([N+](=O)[O-])cccc2c1S(=O)(=O)N1CCOCC1
Agent: CCOC(=O)c1c(S(=O)(=O)Cl)c2cccc([N+](=O)[O-])c2n1S(=O)(=O)c1ccccc1
Agent: CCOC(=O)c1c(S(=O)(=O)N2CCOCC2)c2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Product: NC(=O)c1[nH]c2c([N+](=O)[O-])cccc2c1S(=O)(=O)N1CCOCC1

Procedure:
Following the procedures described in Steps B and C of Example 2 and E of Example 1, replacing in Step B of Example 2 ethyl 5-bromo-3-(chlorosulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(chlorosulfonyl)-7-nitro-1-(phenylsulfonyl)-1H-indole-2-carboxylate, and replacing in Step E of Example 1 ethyl 5-chloro-3-(morpholin-4-ylsulfonyl)-1-(phenylsulfonyl)-1H-indole-2-carboxylate with ethyl 3-(morpholin-4-ylsulfonyl)-7-nitro-1H-indole-2-carboxylate, the title compound was obtained. HRMS (ES) exact mass calculated for C13H15N4O6S (M+H+): 355.0707. Found 355.0713.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)=[C:5]([NH:22][CH2:23][CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:4]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:51][O:52][CH:53]1[CH2:58][CH2:57][C:56](=O)[CH2:55][CH2:54]1.C(O)(=O)C>O1CCCC1>[C:25]1([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:23][NH:22][C:5]2[N:4]=[C:3]([CH2:2][NH:1][CH:56]3[CH2:57][CH2:58][CH:53]([O:52][CH3:51])[CH2:54][CH2:55]3)[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][O:20][CH3:21])[O:13]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC1CCC(=O)CC1
Reactant: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@H](O)[C@@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNC4CCC(OC)CC4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared by a similar method to example 6 using (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino}-9H-purin-9-yl}-5-(methoxymethyl)tetrahydro-3,4-furandiol (400 mg, 0.78 mmol) (example 1), sodium triacetoxyborohydride (260 mg, 1.23 mmol), 4-methoxycyclohexanone (100 mg, 0.78 mmol) (J. Am. Chem. Soc. 5190, 89, 1967) and acetic acid (56 mg, 0.93 mmol) in tetrahydrofuran (30 ml). The product was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane:methanol:ammonia (94:6:0.3) to give the title compound as a mixture (3:2 ratio) of diastereoisomers (118 mg) as a foam. MS: 603 (MH+).
Reaction SMILES: C([Li])(C)(C)C.CCCCC.[CH3:11][O:12][CH:13]([C:15]1[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[CH3:14].[C:29](=[O:31])=[O:30]>CCOCC>[CH3:11][O:12][CH:13]([C:15]1[CH:20]=[C:19]([C:29]([OH:31])=[O:30])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])[CH3:14]
Reactant: COC(C)c1cc(Br)ccc1-c1ccccc1C
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: COC(C)c1cc(C(=O)O)ccc1-c1ccccc1C
Temperature: -78 °C
Reaction time: 0.42 h

Procedure:
A solution of tert-butyllithium in pentane (1.5M, 8.05 mL, 12.1 mmol) was added into anhydrous Et2O (40 mL) cooled at −78° C. under nitrogen atmosphere. Then a solution of 1-(4-bromo-2′-methylbiphenyl-2-yl)ethyl methyl ether (1.84 g, 6.03 mmol) in anhydrous Et2O (10 mL) was added dropwise over 10 minutes. The resulting mixture was stirred at −78° C. for 25 minutes, and then a large excess of dry ice was added and the cooling bath was removed. The reaction mixture was stirred until the temperature came back at RT, then diluted with water (20 ml) and a 5N aqueous solution of NaOH (0.5 mL). The layers were separated and the aqueous layer was washed with Et2O (20 ml). The organic layers were extracted with a 0.1N aqueous solution of NaOH (20 mL). The combined aqueous layers were acidified with a 5N aqueous solution of HCl (until pH˜1) and extracted with MTBE (2×50 mL). The organic layers were washed with brine (30 mL), combined, dried (Na2SO4) and concentrated under vacuum to give a pale yellow solid. After crystallization from a mixture of Et2O and heptane, the title compound was obtained as a white powder. HPLC (Method A) Rt 4.2 min (Purity: 98.2%). LC/MS (Method B): 269.1 (M−H)−. 1H NMR (DMSO-d6, 300 MHz) δ 13.03 (s, 1H), 8.09 (d, J=1.8 Hz, 0.4H), 8.07 (d, J=1.8 Hz, 0.6H), 7.89 (dd, J=7.9, 1.8 Hz, 1H), 7.36-7.24 (m, 3H), 7.22 (d, J=7.9 Hz, 0.4H), 7.20 (d, J=7.9 Hz, 0.6H), 7.13 (d, J=6.9 Hz, 0.4H), 7.07 (d, J=6.9 Hz, 0.6H), 4.12 (q, J=6.4 Hz, 0.4H), 3.92 (q, J=6.4 Hz, 0.6H), 3.05 (s, 1.2H), 3.04 (s, 1.8H), 2.03 (s, 1.8H), 1.98 (s, 1.2H), 1.19 (d, J=6.4 Hz, 1.8H), 1.13 (d, J=6.4 Hz, 1.2H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[CH2:21]([N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1)[CH3:22].C([O-])([O-])=O.[K+].[K+]>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>[CH2:21]([N:23]1[CH:27]=[C:26]([C:2]2[N:3]=[C:4]3[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]3=[N:6][CH:7]=2)[CH:25]=[N:24]1)[CH3:22]
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: O
Product: CCn1cc(-c2cnc3c(n2)c(C=O)cn3COCC[Si](C)(C)C)cn1
Temperature: 100 °C
Yield: 80.8 %

Procedure:
To a solution of 2-bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (1.33 g, 3.73 mmol) and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (995 mg, 4.48 mmol) in 1,2-DME (20 mL) were added Pd(Ph3P)4 (0.22 g, 0.19 mmol) and 2.0 M aqueous K2CO3 (5.6 ml, 11.2 mmol). The reaction mixture was degassed by bubbling N2 for 15 min then heated at 100° C. overnight. The resultant maroon reaction mixture was cooled and diluted with H2O then extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated. The crude residue was purified by SiO2 chromatography (30% to 80% EtOAc/hexanes) to afford 1.12 g (81%) of 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as a light orange-brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].[F:28][CH:29]([F:38])[O:30][C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:34]3[CH:35]=[CH:36][C:31]([O:30][CH:29]([F:38])[F:28])=[CH:32][CH:33]=3)=[CH:16][CH:17]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Reactant: FC(F)Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cc(COc2ccc(-c3ccc(OC(F)F)cc3)cc2)c(C)o1
Temperature: 80 °C
Reaction time: 4 h
Yield: 57.2 %

Procedure:
A degassed mixture of 5-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-furan-2-carboxylic acid methyl ester (119) (200 mg, 0.54 mmoles), 4-difluoromethoxy-1-iodo-benzene (175 mg, 0.65 mmoles), 2M aqueous cesium carbonate (0.81 ml) and), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (20 mg) in 1,4-dioxan (10 ml), under an argon atmosphere was heated at 80° C. for 20 h. Further quantities of 4-difluoromethoxy-1-iodo-benzene (87.5 mg, 0.0.27 mmoles) and [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (10 mg) were added and heating at 80° C. was continued for 4 hours. After cooling, the mixture was concentrated. The residue was dissolved in dichloromethane and washed with water and brine, and dried. The solvent was evaporated and the residue was purified by flash chromatography using petrol (40–60°)/diethyl ether 9:1v/v as eluent to afford compound 128(120 mg) as a wax. LC/MS System A; Rt=4.14 mins.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[N:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=2)=[CH:6][CH:7]=1.O.[NH2:22][NH2:23]>C(O)C>[CH3:18][Si:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][O:14][CH2:13][N:11]1[CH:12]=[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:22][NH2:23])=[CH:7][CH:6]=2)[CH:9]=[N:10]1
Reactant: NN
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc(Cl)nn2)cn1
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2ccc(NN)nn2)cn1
Temperature: 50 °C
Reaction time: 18 h
Yield: 77.7 %

Procedure:
To a suspension of 3-chloro-6-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-pyridazine (640 mg, 2.06 mmol) in ethanol (5 mL) was added hydrazine monohydrate (1.34 mL, 1.4 g, 28 mmol). The reaction mixture was stirred at 50° C. for 18 h, then cooled to room temperature. The precipitate was collected via filtration, washed with cold ethanol and dried in vacuo to provide title compound as a white solid (500 mg, 1.6 mmol, 79% yield): 1H NMR (DMSO-d6) δ 0.00 (9H, s), 0.89 (2H, t), 3.61 (2H, t), 4.34 (2H, bs), 5.48 (2H, s), 7.09 (1H, d), 7.69 (1H, d), 7.94 (1H, bs), 8.08 (1H, s), 8.44 (1H, s); MS (m/z) 307 [M+H+]+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[O:12][CH3:13])(=[O:3])[CH3:2].[I:14]Cl>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[C:9]([I:14])[C:8]([F:11])=[CH:7][C:6]=1[O:12][CH3:13])(=[O:3])[CH3:2]
Reactant: COc1cc(F)ccc1OC(C)=O
Reactant: ClI
Solvent: ClCCl
Product: COc1cc(F)c(I)cc1OC(C)=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 85.5 %

Procedure:
To a solution of 64A (850 mg, 4.6 mmol) in CH2Cl2 (5.0 mL) was added ICl (1.0 M in CH2Cl2, 10.2 mL, 10.2 mmol). The mixture was stirred at 50° C. for 4 h and then at rt for 18 h. The reaction was quenched by a sat. solution of NaHCO3. After extraction with CH2Cl2, the organic layer was washed with a solution of Na2S2O3, brine and dried over Na2SO4. After evaporation of the solvent, the crude product was purified by column chromatography (EtOAc:hexanes=1:4) to give 64B (1.22 g, 80% yield) as a solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.29 (s, 3H) 3.81 (s, 3H) 6.73 (d, J=9.23 Hz, 1H) 7.35 (d, J=6.59 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][O:20][CH:19]([C:23](O)=O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:23]([CH:19]3[O:20][CH2:21][CH2:22][N:17]([CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:18]3)=[N:9][C:4]=2[CH:3]=1
Reactant: O=C(O)C1CN(Cc2ccccc2)CCO1
Reactant: Nc1ccc(F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1ccc2[nH]c(C3CN(Cc4ccccc4)CCO3)nc2c1
Temperature: 140 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
A mixture of 4-fluorobenzene-1,2-diamine (2.0 g, 15.86 mmol) and 4-benzylmorpholine-2-carboxylic acid (5.26 g, 23.78 mmol) in polyphosphoric acid (20 mL) was stirred at 140° C. overnight. The reaction mixture was cooled to room temperature and treated with 100 mL of water. The aqueous phase was adjusted to weakly basic with 2 N aqueous sodium hydroxide and extracted with EtOAc. The organic phase was dried over MgSO4 and evaporated in vacuo to give the crude product as a red solid. The residue was triturated with Hexanes/EtOAc (1×25 mL). The resulting solid was filtered, rinsed with n-hexane, and collected. The solvent was evaporated in vacuo to afford the title compound (3.0 g). LC-MS (ES) m/z=312 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:13][C:14]([C:16]1[N:17]=[C:18]([N:21]2[CH2:24][CH:23]([OH:25])[CH2:22]2)[S:19][CH:20]=1)=[O:15])[CH2:11][CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@@H:10]([NH:13][C:14]([C:16]1[N:17]=[C:18]([N:21]2[CH2:22][CH:23]([O:25][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:24]2)[S:19][CH:20]=1)=[O:15])[CH2:11][CH3:12])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(O)C2)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
To a solution of 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)propylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (1.00 mg, 2.59 mmol) (obtained as described in Reference Example 34(4)) in methylene chloride (50 ml) were added methanesulfonyl chloride (602 μl, 7.78 mmol) and triethylamine (1.09 ml, 7.78 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 3 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1→1:2) as the eluant to afford 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)propylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (1.02 g, yield 85%) as a pale yellow oil.
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][C:10]=1[Cl:28])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:28][C:10]1[CH:11]=[C:12]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C2CCNCC2)cc1Cl

Procedure:
A mixture the product of Example 60C (100 mg) and trifluoroacetic acid (1 mL) in dichloromethane (4 mL) was stirred at ambient temperature for 3 hours. The mixture was concentrated and the crude title compound was used in the next step without further purification. MS: 211 (M+H+).
Reaction SMILES: ClC1C=CN=C(C(Cl)=O)C=1.C(N)C.Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH:23][CH2:24][CH3:25])=[O:22])[CH:16]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[CH2:24]([NH:23][C:21]([C:17]1[CH:16]=[C:15]([O:33][C:30]2[CH:31]=[CH:32][C:27]([NH2:26])=[CH:28][CH:29]=2)[CH:20]=[CH:19][N:18]=1)=[O:22])[CH3:25]
Reactant: Nc1ccc(O)cc1
Reactant: CCNC(=O)c1cc(Cl)ccn1
Agent: CCN
Agent: O=C(Cl)c1cc(Cl)ccn1
Product: CCNC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 88: 4-Chloropyridine-2-carbonyl chloride was reacted with ethylamine according to Method A2, Step 3b. The resulting 4-chloro-N-ethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N-ethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]#[N:13])=[CH:7][CH:6]=2)=O.C1(P(=[CH:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[C:12]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](/[CH:1]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:11]2)#[N:13]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1ccc2[nH]c(C=O)cc2c1
Solvent: CC#N
Product: CCOC(=O)/C=C/c1cc2cc(C#N)ccc2[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 70.8 %

Procedure:
2-Formyl-1H-indole-5-carbonitrile (D28) (230 mg) was dissolved in acetonitrile (50 mL). Ethyl (triphenyl-λ5-phosphanylidene)acetate (522 mg) was added to the solution. The reaction was heated to 60° C. and was stirred at 60° C. for 1 hour. The reaction mixture was concentrated. The residue was purified by Biotage (25%→33% EtOAc in hexane) to afford ethyl (2E)-3-(5-cyano-1H-indol-2-yl)-2-propenoate (D29) (230 mg) as a white solid. MS (ES): C14H12N2O2 requires 240; found 239.1 (M−H+).
Reaction SMILES: [Br-].[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[Zn+].FC(F)(F)S(O[C:14]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:16][CH:15]=1)(=O)=O>O1CCCC1>[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:16]1[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:14][CH:15]=1
Reactant: [Zn+]c1nccs1
Reactant: CC(C)(C)OC(=O)N1CCC=C(OS(=O)(=O)C(F)(F)F)C1
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC=C(c2nccs2)C1
Temperature: 50 °C
Yield: 52.6 %

Procedure:
To the mixture of 2-thiazolylzinc bromide (20 mL, 10 mmol) in dry tetrahydrofuran (30 mL) at 0° C. was added the product from Example 328B (3.3 gm, 10 mmol) and tetrakis(tripehynlphosphine) palladium (0) (10% mole 1.1 g). The mixture was heated at 50° C. for 1 hour, cooled to room temperature, quenched with brine and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 25% ethyl acetate:hexanes) to obtain desired product 1.4 g (60%) as colorless oil. MS (DCI/NH3) m/e 265 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]([CH2:13][NH2:14])[OH:12]>CO>[N+:8]([C:5]1[N:6]=[CH:7][C:2]([NH:14][CH2:13][CH2:11][OH:12])=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(Br)cn1
Reactant: NCCO
Solvent: CO
Product: O=[N+]([O-])c1cnc(NCCO)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
A mixture of 2-bromo-5-nitropyrazine (500 mg, 2.45 mmol) and ethanolamine (225 mg, 3.67 mmol) in methanol (15 mL) was stirred at 25° C. for 5 h. After such time, the reaction was concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 20/80 hexanes/ethyl acetate to 97/3 ethyl acetate/methanol) afforded 2-(5-nitro-pyrazin-2-ylamino)-ethanol (375 mg, 83%) as a yellow solid: mp 157.5–159.8° C.; EI-HRMS m/e calcd for C6H8N4O3 (M+) 184.0596, found 184.0603.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10].[N+:11]([O-])([OH:13])=[O:12]>CCOCC>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[OH:10]
Reactant: COc1ccccc1O
Reactant: O=[N+]([O-])O
Solvent: CCOCC
Solvent: O
Product: COc1cccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 50 ml of water, 150 ml of ether and 15.0 g of 2-methoxyphenol was added dropwise 12.7 ml of 61% nitric acid, and the mixture was stirred at room temperature for 15 minutes. The ether layer was separated from the aqueous layer and dried over anhydrous sodium sulfate. After the drying agent was filtered off, the solvent was distilled off under reduced pressure. The residue was purified by silica-gel column-chromatography using Wakogel® C-200 [eluent: chloroform-n-hexane (1:1)] to give 4.72 g of 2-methoxy-6-nitrophenol.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:23]#[N:24])=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[S:25](Cl)(=[O:28])(=[O:27])[NH2:26]>>[NH2:24][C:23]1[C:3]2[C:4]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:20][CH:21]=[CH:22][C:2]=2[NH:1][S:25](=[O:28])(=[O:27])[N:26]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCOc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)NCCCCCCOc1cccc2c1C(N)=NS(=O)(=O)N2
Yield: 59.5 %

Procedure:
Prepared as in Example 224 from tert-butyl 6-(3-amino-2-cyanophenoxy)hexylcarbamate (Example 229a) and sulfamoyl chloride in 59.5% yield. 1H NMR (400 MHz, DMSO-d6) δ 1.274 (m, 2H), 1.339 (s, 9H), 1.361 (m, 4H), 1.779 (pentet, J=7 Hz, 2H), 2.878 (q, J=6 Hz, 2H), 4.122 (t, J=6 Hz, 2H), 6.580 (d, J=8 Hz, 1H), 6.722 (d, J=8 Hz, 1H), 6.75 (br t, J=6 Hz, 1H), 7.428 (t, J=8 Hz, 1H), 7.798 (br. s, 1H), 8.323 (br. s, 1H), 10.921 (s, 1H). MS 413 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([O:24][C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][C:28]([CH3:36])([CH3:35])[C:29]([NH:31][CH2:32][CH2:33][OH:34])=[O:30])=[CH:22][CH:21]=1.COC(C1C(C)=C2C(NC3C=CC(OC4C=CC=CC=4OC(C(OC(C)(C)C)=O)(C)C)=CC=3)=C(C#N)C=NN2C=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([NH:19][C:20]3[CH:42]=[CH:41][C:23]([O:24][C:25]4[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=4[O:27][C:28]([C:29](=[O:30])[NH:31][CH2:32][CH2:33][OH:34])([CH3:35])[CH3:36])=[CH:22][CH:21]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Reactant: CC(C)(Oc1ccccc1Oc1ccc(N)cc1)C(=O)NCCO
Agent: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)OC(C)(C)C)cc3)c2c1C
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCCO)cc3)c2c1C
Yield: 55 %

Procedure:
Compound 433E (146 mg, 83%) was prepared from 4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (Example 1D) (126 mg, 0.476 mmol) and 433D (165 mg, 0.500 mmol) by a route analogous to that used for the preparation of compound 388D. It is a cream-colored crystalline solid. LCMS Found: (M+H)+=558.1
Reaction SMILES: [C:1]([C:4]1[C:12]2[N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]4[CH2:23][CH2:22][CH2:21][N:20]4C(OC(C)(C)C)=O)=[CH:15][CH:14]=3)[NH:9][C:8]=2[CH:7]=[C:6]([Cl:31])[CH:5]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:6]1[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:12]2[N:11]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:23][CH2:22][CH2:21][NH:20]4)=[CH:17][CH:18]=3)[NH:9][C:8]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2nc3c(C(N)=O)cc(Cl)cc3[nH]2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1cc(Cl)cc2[nH]c(-c3ccc(C4CCCN4)cc3)nc12
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 44C (410 mg) in dichloromethane (20 mL) was treated with TFA (4 mL), stirred for 1 hour and concentrated. The concentrate was purified by HPLC (Zorbax, C-18, 250×2.54 column, mobile phase A: 0.1% TFA in water; B: 0.1% TFA in CH3CN; 0-100% gradient). 1H NMR (DMSO-d6) δ 2.04-2.20 (m, 3H), 2.41-2.52 (m, 2H), 3.33-3.46 (m, 2H), 4.65-4.71 (m, 1H), 7.72 (d, J=8.29 Hz, 2H), 7.81-7.84 (m, 1H), 7.95 (s, 1H), 8.34 (d, J=8.29 Hz, 2H), 8.94 (s, 1H), 9.14 (s, 1H), 9.73 (s, 1H).