Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:38][O:39][C:40]1[CH:47]=[CH:46][C:43]([CH2:44]Cl)=[CH:42][CH:41]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:44][C:43]2[CH:46]=[CH:47][C:40]([O:39][CH3:38])=[CH:41][CH:42]=2)[CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Agent: Cl
Product: COc1ccc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.78 g) and 4-methoxybenzyl chloride (0.41 mL) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methoxyphenyl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.69 g) was obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([NH2:15])=[O:14])=[C:9]([O:16]C)[CH:8]=[CH:7][CH:6]=2)[CH3:2].B(Br)(Br)Br>>[CH2:1]([C:3]1[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]2[C:10]([C:11]=1[CH2:12][C:13]([NH2:15])=[O:14])=[C:9]([OH:16])[CH:8]=[CH:7][CH:6]=2)[CH3:2]
Reactant: CCc1c(CC(N)=O)c2c(OC)cccc2n1Cc1ccccc1
Agent: BrB(Br)Br
Product: CCc1c(CC(N)=O)c2c(O)cccc2n1Cc1ccccc1

Procedure:
2-Ethyl-4-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (483 mg, 1.5 mmol) and 6 mL of BBr3 were reacted as described in Example 56, Part C, to give after chromatography on silica gel (eluted with ethyl acetate) 156 mg (34% yield) of 2-ethyl-4-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]12[CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][CH:10]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[C:26]([CH:31]([F:33])[F:32])=[N:27][N:28]([CH3:30])[CH:29]=1)=S.O.C1CCCCC1.C(OCC)(=O)C>CN(C)C=O.CO>[CH:9]12[CH2:15][CH:12]([CH2:13][CH2:14]1)[CH2:11][CH:10]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([C:25]1[C:26]([CH:31]([F:33])[F:32])=[N:27][N:28]([CH3:30])[CH:29]=1)=[N:8][NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1cc(C(=S)Nc2ccccc2C2CC3CCC2C3)c(C(F)F)n1
Reactant: NNc1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1cc(C(=NNc2ccccc2)Nc2ccccc2C2CC3CCC2C3)c(C(F)F)n1
Temperature: 70 °C
Reaction time: 16 h
Yield: 35.6 %

Procedure:
0.9 g (8.4 mmol) of phenylhydrazine in 10 ml of dimethylformamide is added to a solution consisting of 1.0 g (2.7 mmol) of N-(2-bicyclo[2.2.1]hept-2-ylphenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-thiocarboxamide in 10 ml of methanol. The reaction mixture is stirred at 70° C. for 16 hours. For work-up, the reaction mixture is poured into water and extracted three times with in each case 20 ml of dichloromethane. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. Column chromatography (gradient cyclohexane/ethyl acetate) gives 0.42 g (0.96 mmol, 35% of theory) of N-(2-bicyclo[2.2.1]hept-2-ylphenyl)-3-(difluoromethyl)-1-methyl-N′-phenyl-1H-pyrazole-4-carbohydrazonamide [logP (pH 2.3)=3.66].
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=5)=[O:56])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cccnc4C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cccnc4C)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 53.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methyl-3-pyridinyl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.27 g) in methylene chloride (8.1 ml) was added dropwise a solution of m-chloroperbenzoic acid (86 mg) in methylene chloride (5.4 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, and recrystallized from ethanol, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(2-methyl-3-pyridinyl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 251) (148 mg).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)(=[O:25])=[O:24])=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[CH3:32][C:33](=O)[CH2:34][CH2:35][CH3:36].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[C:20]([S:23]([N:26]5[CH2:27][CH2:28][N:29]([CH:34]([CH2:35][CH3:36])[CH2:33][CH3:32])[CH2:30][CH2:31]5)(=[O:24])=[O:25])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCNCC3)ccc1OCC2
Reactant: CCCC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCC(CC)N1CCN(S(=O)(=O)c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Reaction time: 20 h
Yield: 24.3 %

Procedure:
A mixture of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-9-(piperazine-1-sulfonyl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (35 mg, 0.08 mmol), pentanone (25 μL, 0.24 mmol), AcOH (9 μL, 0.16 mmol) and 4 Å molecular sieves in DCE (2 mL) was stirred at RT for 1 h before the addition of sodium triacetoxyborohydride (33 mg, 0.16 mmol). The resulting mixture was stirred for 16 h before further pentanone (100 μL, 0.92 mmol) and sodium triacetoxyborohydride (198 mg, 0.96 mmol) were added. The mixture was stirred for 20 h then loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-10% MeOH in DCM) to afford 134 (10 mg, 25%) as a white solid. LCMS: RT 3.13 min [M+H]+ 514.4. 1H NMR (CDCl3, 400 MHz): δ 8.95 (1H, d, J=2.36 Hz), 7.88 (1H, s), 7.70 (1H, s), 7.65 (1H, dd, J=8.59, 2.37 Hz), 7.17 (1H, d, J=8.60 Hz), 5.94-5.85 (1H, m), 4.59-4.58 (2H, m), 4.52-4.51 (2H, m), 3.05 (4H, s), 2.61 (4H, s), 2.13-2.10 (1H, m), 1.60 (6H, d, J=6.64 Hz), 1.46-1.35 (2H, m), 1.29-1.27 (2H, m), 0.83 (6H, t, J=7.36 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([NH:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[C:27]([Cl:34])[CH:26]=1.CCN(CC)CC>ClCCCl>[CH3:22][O:23][C:24](=[O:35])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:17]([C:16]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[C:10]3[C:15]=2[CH:14]=[CH:13][CH:12]=[CH:11]3)[CH:18]2[CH2:21][CH2:20][CH2:19]2)=[O:33])=[C:27]([Cl:34])[CH:26]=1
Reactant: COC(=O)c1ccc(N=C=O)c(Cl)c1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 1.2, [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclobutyl-amine was reacted with 3-chloro-4-isocyanato-benzoic acid methyl ester (example 9.1) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 3 days under reflux conditions to give the title compound as yellow oil. MS: m/e=509.4 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:11])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1>>[Br:1][C:2]1[C:3]([NH:11][C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[N:7][C:6]=12
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: Nc1nn2cccnc2c1Br
Product: O=C(Cc1ccc(F)cc1)Nc1nn2cccnc2c1Br

Procedure:
The product from Example 110A and 4-fluorophenylacetic acid were processed using the method analogous to that described in Example 137 to provide the title compound. MS (APCI) m/z 349/351 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:45]([F:48])([F:47])[F:46])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:17][C:16]=3[F:40])[C:10]([CH2:41][CH2:42][CH2:43][CH3:44])=[N:9]2)[CH:7]=1.[C:49](Br)(=[O:52])[CH2:50][CH3:51].C1CCN2C(=NCCC2)CC1>C(Cl)Cl.CO>[CH2:41]([C:10]1[N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:38])(=[O:39])[NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:17][C:16]=2[F:40])[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:49](=[O:52])[CH2:50][CH3:51])[CH:3]=[CH:4][C:5]=2[C:45]([F:46])([F:47])[F:48])[N:9]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCC(=O)Br
Reactant: CCCCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nn(-c2cc(NC(=O)CC)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1F
Yield: 60 %

Procedure:
The title compound was synthesized by reaction of 2-[5-amino-2-(trifluoromethyl)phenyl]-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step G) with propionyl bromide (3 equivalents) and DBU (1.1 equiv) according to the method of Example 69. The material was obtained in 60% yield as a pale yellow solid, mp 181°-183° C.; homogeneous by TLC in 9:1 CH2Cl2 -MeOH; mass spectrum (FAB) m/e 796 (M+K)+.
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:10]([CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH2:21][CH:10]2[CH:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH2:12][NH:8][CH2:9]2)=[CH:28][CH:27]=1
Reactant: Clc1ccc(OCC2CN(Cc3ccccc3)CC2c2ccc(Cl)c(Cl)c2)cc1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: Clc1ccc(OCC2CNCC2c2ccc(Cl)c(Cl)c2)cc1
Reaction time: 2 h
Yield: 75.5 %

Procedure:
To a solution of (3SR,4RS)-1-benzyl-3-(4-chloro-phenoxymethyl)-4-(3,4-dichloro-phenyl)-pyrrolidine 350 mg (0.78 mmol) dissolved in CH3CN (8 mL) was added 0.12 mL (0.86 mmol) of 2,2,2-trichloroethyl chloroformate and stirring was continued for 2 hours at RT. Volatiles were removed under vacuo, and the crude residue was dissolved in AcOH (5 mL) before a total of 200 mg of Zn dust was added portion wise. After three hours at RT, the reaction mixture was filtered on celite, the solvent removed under vacuo, followed by an extraction with EtOAc/aq. NaHCO3 (basic pH). The organic phases were dried on Na2SO4 and column chromatography (SiO2, CH2Cl2/MeOH 9:1 to 8:2) yielded 210 mg (75%) of the title compound as a colorless oil. ES-MS m/e: 357.1 (M+H+).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([NH2:10])(=[O:9])=[O:8].C(N=[C:22]=[O:23])CCC.N12CCN(CC1)CC2.ClC(OC(Cl)(Cl)Cl)=O>C1(C)C(C)=CC=CC=1>[C:1]1([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([N:10]=[C:22]=[O:23])(=[O:9])=[O:8]
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Reactant: CCCCN=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)c1ccccc1-c1ccccc1
Yield: 85 %

Procedure:
23.3 g of 2-biphenylylsulfonamide, 10.9 g of n-butyl isocyanate, a catalytic amount of 1,4-diazabicyclo[2,2,2]-octane and 150 ml of xylene were refluxed with stirring for an hour. Then, a solution of 11.9 g of trichloromethyl chloroformate in 30 ml of xylene was added dropwise over 2.5 hours while maintaining the internal temperature at 120°-125° C. After this addition, the mixture was held at this temperature for a while, and thereafter the mixture was refluxed for a short period to complete the reaction. At the end of the reaction, the xylene and n-butyl isocyanate were distilled off under reduced pressure, to obtain 22.0 g of 2-biphenylylsulfonylisocyanate of high purity. B.pt. 135°-137° C./0.7-0.8 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[N+:16]([O-])=O)[O:5][CH2:6][CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10].ClCCl.CO>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[O:5][CH2:6][CH2:7][N:8]([CH2:9][CH3:10])[CH2:11][CH3:12]
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])c(Cl)c1
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(N)c(Cl)c1

Procedure:
Prepared analogously to Example 3.1.b. from [2-(3-chloro-4-nitrophenoxy)ethyl]diethylamine in ethyl acetate. Yield: 1.05 g (95.4% of theory); C12H19ClN2O (M=242.75); calc.: molecular ion peak (M+H)+: 243/245; found: molecular ion peak (M+H)+: 243/245; Rf value: 0.41 (silica gel, dichloromethane/methanol (90:10)).
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]([C:14]2[N:18]3[N:19]=[C:20]([C:23](=O)[CH3:24])[CH:21]=[CH:22][C:17]3=[N:16][N:15]=2)[CH3:13])=[C:10]([F:26])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl.[NH2:28][O:29][CH2:30][CH2:31][OH:32].[OH-].[Na+]>CO>[OH:32][CH2:31][CH2:30][O:29]/[N:28]=[C:23](/[C:20]1[CH:21]=[CH:22][C:17]2[N:18]([C:14]([CH:12]([C:11]3[C:2]([F:1])=[C:3]4[C:8](=[CH:9][C:10]=3[F:26])[N:7]=[CH:6][CH:5]=[CH:4]4)[CH3:13])=[N:15][N:16]=2)[N:19]=1)\[CH3:24]
Reactant: CC(=O)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Reactant: NOCCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C/C(=N\OCCO)c1ccc2nnc(C(C)c3c(F)cc4ncccc4c3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
To a suspension of 1-{3-[1-(5,7-difluoro-quinolin-6-yl)-ethyl]-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}-ethanone (4.2 g, 11.9 mmol) in methanol (250 mL) was added 2-(aminooxy)ethanol hydrochloride (intermediate S) (2.70 g, 23.8 mmol). The mixture was stirred at rt overnight. LC-MS showed the reaction was complete. An aqueous 1N NaOH solution was added slowly until pH 8-9. The mixture was concentrated, extracted with EtOAc, washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and purified by gradient column chromatography (EtOAc:hexane=2:1, then 100% EtOAc, and then MeOH:EtOAc=1:12 as eluent) to afford 4.8 g (98%) of the title compound as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.97 (dd, 1H), 8.44 (m, 1H), 8.25 (d, 1H), 7.64-7.70 (m, 2H), 7.59 (dd, 1H), 5.25 (q, 1H), 4.70 (t, 1H), 4.19 (t, 2H), 3.62 (dd, 2H), 2.02 (d, 3H), 1.88 (s, 3H). LCMS (method A): [MH]+=413, tR=5.09 min.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C:3]([NH:5][C:6]1[N:15]=[C:14]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:4].[Cl:25]N1C(=O)CCC1=O>CN(C)C=O>[Cl:25][C:13]1[C:14]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:15][C:6]([NH:5][C:3](=[O:4])[C:2]([CH3:24])([CH3:23])[CH3:1])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(NC(=O)C(C)(C)C)nc1NC(=O)C(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)c(NC(=O)C(C)(C)C)nc1NC(=O)C(C)(C)C
Temperature: 70 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of methyl 2,6-bis[(2,2-dimethylpropanoyl)amino]nicotinate (Example 2, Step 1, 186 g, 555 mmol) in anhydrous N,N-dimethylformamide (930 mL) was added a solution of N-chlorosuccinimide (81.5 g, 610 mmol) in anhydrous N,N-dimethylformamide (560 mL) dropwise from a dropping funnel (1 L) during the period of 2.5 h at 70° C. (internal temperature) under nitrogen atmosphere. The resulting pale yellow solution was stirred at 70° C. for 2 h and allowed to cool to room temperature. The reaction solution was quenched with a solution of 250 g of ammonium chloride and 100 g of sodium hydrogen sulfite in 3 L of water and extracted with a mixture of ethyl acetate and hexane (3 L, 3:1). After the layers were separated, the organic layer was washed with water (2 L), dried over sodium sulfite (300 g) and evaporated. The residual pale yellow solid was added isopropylether (1.4 L) and the resulting mixture was stirred at 60° C. for 2 h. After the mixture was cooled to room temperature, the mixture was filtered through paper filter, and the cake was washed with isopropylether (200 mL), dried under reduced pressure at room temperature to give (153.9 g, 416 mmol) of the title compound as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:16]=1)[N:13]=[CH:12][CH:11]=[CH:10]2)(=O)=O.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C.[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:28]1([C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=4)[N:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc(OS(=O)(=O)C(F)(F)F)cc3cccnc23)c1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(-c2nc(-c3ccccc3)cc3cccnc23)c1
Reaction time: 20 h

Procedure:
To a solution of 6-trifluoromethylsulfonyloxy-8-(3-nitrophenyl)-1,7-naphthyridine (300 mg, 0.75 mmol; prepared according to example 8) in tetrahydrofuran (5 ml) is added phenylboronic acid (118 mg, 0.97 mmol, bis(dibenzylideneacetone) palladium (18 mg, 0.03 mmol), triphenylphosphine (16 mg, 0.06 mmol) and aqueous Na2CO3 (2N, 1.44 ml). The solution is kept at 60° C. for 20 h. The solution is diluted with ethyl acetate, filtered and washed with 1N NaOH and water. The solvent is removed in vacuo to give pure product. Mass M+H 328. mp 172-175° C.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:9][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)[CH2:7][CH3:8].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:16]([N:14]1[CH:10]([O:9][CH2:6][CH2:7][CH3:8])[CH2:11][CH2:12][C:13]1=[O:15])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCOC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCOC1CCC(=O)N1C(=O)c1ccccc1
Yield: 57.9 %

Procedure:
18.6 cm3 of a 1.5M solution of n-butyllithium in hexane is added to a solution of 4 g of 5-(1-propyloxy) pyrrolidin-2-one in tetrahydrofuran at -60° C., while maintaining the temperature between -55° C. and -60° C. After agitation for 15 minutes at -60° C. a solution of 3.93 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added at this temperature. After allowing the mixture to return to ambient temperature, the solvent is evaporated under reduced pressure. The residue is chromatographed on silica (eluent: ethyl acetate-n-hexane 1-3) and 4 g of the expected product is obtained. b.p. =200° C. under 0.1 mbar.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]12[O:18][CH2:17][CH2:16][CH2:15][O:14]1)([O-:3])=[O:2].[C:19](#[N:22])[CH:20]=[CH2:21].O>CN(C=O)C.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:21][CH2:20][C:19]#[N:22])[C:8](=[O:13])[C:7]12[O:18][CH2:17][CH2:16][CH2:15][O:14]1)([O-:3])=[O:2]
Reactant: C=CC#N
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C12OCCCO2
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCN1C(=O)C2(OCCCO2)c2cc([N+](=O)[O-])ccc21
Temperature: 52 °C
Yield: 101.4 %

Procedure:
At room temperature, to a mixture of 5′-nitrospiro[1,3-dioxane-2,3′-indol]-2′(1′H)-one(1.75 g, 6.99 mmol) and benzyltrimethylammonium hydroxide (40% aqueous solution, 0.110 mL, 0.699 mmol, 0.1 mole %) in DMF (31 mL) was added acrylonitrile (0.921 mL, 14.0 mmol, 2 eq) drop-wise. and the mixture was heated at 52° C. for 2 hr. The reaction was cooled to room temperature and poured into H2O (160 mL). The reaction mixture was extracted with Et2O. The combined organic extracts were washed with brine and concentrated. The crude product was purified on Biotage KP silica gel eluting with 96/4 CH2Cl2/CH3CN to give the title compound as a yellow solid (2.15 g, 100% ). NMR (300 Mz, DMSO-d6): consistent
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[CH3:39][S:40]([O:43][C:44]1[CH:49]=[C:48](B2OC(C)(C)C(C)(C)O2)[CH:47]=[C:46]([NH:59][S:60]([CH3:63])(=[O:62])=[O:61])[CH:45]=1)(=[O:42])=[O:41].CS(Cl)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].ClCCl.[Pd](Cl)Cl>[CH3:39][S:40]([O:43][C:44]1[CH:45]=[C:46]([NH:59][S:60]([CH3:63])(=[O:62])=[O:61])[CH:47]=[C:48]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:14]4[N:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:18](=[O:26])[C:17]5=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]5[N:15]=4)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=2)[CH:49]=1)(=[O:41])=[O:42]
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(NS(C)(=O)=O)cc(OS(C)(=O)=O)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)cc(OS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (170 mg, 0.29 mmol) was treated with 3-(methylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl methanesulfonate (300 mg, 0.67 mmol, prepared from the title compound of Preparation 105 and methanesulfonyl chloride according to Preparation 37), 2M cesium carbonate (450 μl, 0.90 mmols) and bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (50 mg, 0.06 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 80%, hexane-ethyl acetate) to give 169 mg (66% yield) of the title compound. Purity 87%.