Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[I-].[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][CH2:23][C:16]=3[C:15]2=[O:24])=[CH:10][C:9]=1[OH:25].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:15](=[O:24])[C:16]3[CH2:23][CH2:22][CH2:21][CH2:20][C:17]=3[C:18]2=[O:19])=[CH:10][C:9]=1[O:25][CH2:2][C:3]#[N:4]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Br)c(O)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br
Reaction time: 5 h

Procedure:
A mixture of 1.0 g. of chloroacetonitrile, 2.2 g. of potassium iodide and 25 ml. of acetone was stirred at room temperature for 1 hour and then, 3.5 g. of N-(4-bromo-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide and 1.8 g. of potassium carbonate were added and the mixture was refluxed with stirring for 5 hours. The solvent was distilled off under a reduced pressure and 2N-HCl was added to the residue to precipitate the product. The precipitate was separated by a filtration and washed with water and dried and recrystallized from ethanol to obtain 2.7 g. of Compound No. 229 shown in Table 1.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([C:11]#[N:12])[CH:2]=1.B1([O-])O[O:14]1.O.O.O.O.[Na+]>C(O)(=O)C>[C:11]([C:3]1[CH:2]=[N+:1]([O-:14])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)#[N:12]
Reactant: [O-]B1OO1
Reactant: N#Cc1cnc2c(c1)CCCC2
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cc2c([n+]([O-])c1)CCCC2
Temperature: 40 °C
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To a solution of 5,6,7,8-tetrahydroquinoline-3-carbonitrile (633 mg, 4.00 mmol) in acetic acid (5 ml) at 40° C. was portionwise added sodium perborate tetrahydrate (677 mg, 4.4 mmol) and the mixture was stirred at 40° C. for 16 hours. The acetic acid was removed by evaporation at reduced pressure, the residue was basified with a saturated aqueous solution of sodium hydrogencarbonate, and the mixture extracted thrice with ethyl acetate. The combined extracts were dried over sodium sulphate and the solvent removed in vacuum to give the 3-cyano-5,6,7,8-tetrahydroquinoline 1-oxide (645 mg, 93% yield) as a white solid. MS (ISP): m/z=175.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.[Cu]I>[N:11]1([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=2)[C:5]([OH:7])=[O:6])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=C(O)c1ccnc(Br)c1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=C(O)c1ccnc(-n2ccnc2)c1
Temperature: 125 °C
Reaction time: 18 h
Yield: 108 %

Procedure:
To a solution of 2-bromoisonicotinic acid (1.87 g, 9.26 mmol), 1H-imidazole (573 mg, 8.42 mmol) and Cs2CO3 (6.03 g, 18.5 mmol) in DMSO (18.6 mL), was added CuI (176 mg, 0.926 mmol). The mixture was heated to 125° C., stirred for 18 hours, cooled to room temperature, filtered and purified by preparative HPLC (10-90% acetonitrile in water) to give the title compound as a light pink solid (1.72 g, 98%). MS 190 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[N:8]=[C:9]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.[CH3:20][NH2:21]>O>[Cl:19][C:15]1[CH:14]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([CH2:2][NH:21][CH3:20])=[N:4][N:5]=3)[N:8]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CN
Reactant: ClCc1nnc2ccc(Nc3cccc(Cl)c3)nn12
Solvent: O
Product: CNCc1nnc2ccc(Nc3cccc(Cl)c3)nn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
(Step 3-ii) 3-(Chloromethyl)-N-(3-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (210 mg, 0.71 mmol) was suspended in 2 mL of 40% methyl amine in water and the suspension microirradiated at 100° C. for 10 min. The reaction mixture was allowed to cool to room temperature and a brown solid was filtered off and dried in vacuo to yield the product, N-(3-chlorophenyl)-3-((methylamino)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (126 mg, 0.43 mmol, 61% yield): MH+=289.02.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]([CH2:23][C:24]2[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=2)[C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.C1COCC1>[CH:1]1([CH2:4][CH2:5][N:6]([CH2:23][C:24]2[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=2)[C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)COc1ccc(CN(CCC2CC2)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(CN(CCC2CC2)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)ccc1OCC(=O)O
Yield: 84.9 %

Procedure:
To a solution of ethyl [4-({(2-cyclopropylethyl)[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amino}methyl)-2-methylphenoxy]acetate (141 mg, 0.28 mmol) in MeOH (2 mL) and THF (2 mL) at room temperature was added 2M NaOH (1 mL, 2 mmol). The resultant mixture was stirred for 1.5 h, then the solvents were removed in vacuo. The residue was partitioned between CH2Cl2 (2×20 mL) and 2M HCl (20 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed, affording the title compound as a white solid (115 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C:4]2[CH:5]=[C:6]([N:8]3[CH:17]([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:19]5[CH:24]=[N:23][C:22]([C:25]([N:35]6[CH2:39][CH2:38][CH2:37][CH2:36]6)=[O:26])=[CH:21][CH:20]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:7]=[C:2]([NH2:1])[N:3]=2)[CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Product: CC1Cc2ccc(-c3ccc(C(=O)N4CCCC4)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50B starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50B, Step 1) and pyrrolidine. LCMS (M+H)+: m/z=513.3.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1.NC(N)=[S:16]>C(O)C>[SH:16][C:2]1[N:7]=[N:6][C:5]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:4]=2[CH:3]=1
Reactant: NC(N)=S
Reactant: Clc1cc2c(nn1)CCCCCC2
Solvent: CCO
Product: Sc1cc2c(nn1)CCCCCC2
Reaction time: 20 h

Procedure:
59.1 g of 3-chloro-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine and 25.2 g of thiourea are heated at reflux in 250 cc of absolute ethanol while stirring for 20 hours. The reaction mixture is subsequently concentrated and divided between chloroform and water. After concentrating the chloroform phase, crude 3-mercapto-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine is obtained and is recrystallized from 250 cc of absolute ethanol with the addition of carbon.
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[N:8]([CH:19]=[N:20][N:21]=3)[C:9]3[CH:17]=[CH:16][C:15](=[O:18])[CH2:14][C:10]=3[N:11]3[CH:12]=[CH:13][C:4]([C:5]=23)=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[CH:29]=[CH2:30]>CN(C)C=O>[CH2:30]([CH:14]1[C:10]2[N:11]3[CH:12]=[CH:13][C:4]4[C:5]3=[C:6]([CH2:1][CH2:2][CH:3]=4)[C:7]3[N:8]([CH:19]=[N:20][N:21]=3)[C:9]=2[CH:17]=[CH:16][C:15]1=[O:18])[CH:29]=[CH2:28]
Reactant: C=CCBr
Reactant: O=C1C=CC2=C(C1)n1ccc3c1=C(CCC=3)c1nncn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCC1C(=O)C=CC2=C1n1ccc3c1=C(CCC=3)c1nncn12
Temperature: 95 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,2,4]triazolo[4,3-d][1,4]benzodiazepin-8(7H)-one (2.5 g) was dissolved in dimethylformamide (50 ml). Potassium carbonate (0.5 g) was added followed by allyl bromide (2.2 g). The reaction mixture was stirred at 95° C. overnight, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by high performance liquid chromatography (2% methanol/dichloromethane) to yield 1.9 g (65.9%) of product. Recrystallization from methanol gave the analytical sample, mp 109°-110° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=1[S:22](=[O:25])(=[O:24])[NH2:23])(=[O:11])=[O:10].[CH2:26](O)[CH3:27]>S(Cl)(Cl)=O>[CH2:26]([O:18][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][C:13]([NH:12][S:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])(=[O:10])=[O:11])=[C:14]([S:22](=[O:24])(=[O:25])[NH2:23])[CH:15]=1)[CH3:27]
Reactant: CCO
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1NS(=O)(=O)c1cccc(Cl)c1Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(NS(=O)(=O)c2cccc(Cl)c2Cl)c(S(N)(=O)=O)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 4-(2,3-dichloro-benzenesulfonylamino)-3-sulfamoyl-benzoic acid (1.3 g, 3.05 mmol) in ethanol (20 mL) was stirred at RT and a few drops of thionyl chloride were added. The reaction mixture was heated at reflux for 7 h, cooled to RT and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate/hexane (1:1) as eluent to afford the title compound (1.4 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][OH:12])=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:5][C:4]1[C:3]2[CH:6]=[C:7]3[C:8]([O:12][CH2:11][O:10]3)=[CH:9][C:2]=2[O:1][C:14]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])=[O:16]
Reactant: N#Cc1cc(OCO)ccc1O
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3c(cc12)OCO3
Yield: 60.9 %

Procedure:
A solution of 2-hydroxy-5-hydroxymethoxy-benzonitrile (0.10 g, 0.61 mmol), 2,2′,4′-trichloroacetophenone (0.16 g, 0.74 mmol, 1.2 eq) and potassium carbonate (0.13 g, 0.92 mmol, 1.5 eq) in 1 mL DMF was stirred overnight at 80° C. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried with sodium sulfate and filtered through a plug of silica. Concentration in vacuo provided an orange solid, purification of which by RP-HPLC (H2O-MeCN gradient) provided 0.13 g (61%) of (7-amino-1,3,5-trioxa-s-indacen-6-yl)-(2,4-dichloro-phenyl)-methanone as a yellow solid. 1H-NMR (DMSO-d6) δ 7.70–7.69 (m, 1 H), 7.51–7.49, (m 2H), 7.42, (s, 1H) 7.30 (bs, 2H), 7.03 (s, 1H), 6.07 (s, 2H); MS LC-MS (MH+=350.2/352.1), LC-MS RT=3.21 min.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[P:22](Cl)(Cl)=[O:23]>>[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[P:22]1(=[O:23])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][N:8]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccccc1P(=O)(Cl)Cl
Reactant: c1ccc(CNc2ccccc2)cc1
Product: Cc1ccccc1P1(=O)c2ccccc2CN1c1ccccc1
Yield: 8 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and 2-methylphenyl phosphonic dichloride. The reaction of the dilithio compound and the 2-methylphenyl phosphonic dichloride was conducted at 0° C. to yield 1-(2-methylphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (0.8 g, 8% yield) as a yellow solid having a melting point of 181°-183° C. and the following analysis:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:16][CH2:15][C:14](=O)/[C:13](=[CH:18]/[N:19](C)C)/[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:31]N>C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([C:11]2([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])[CH2:16][CH2:15][C:14]3[C:13](=[CH:18][NH:19][N:31]=3)[CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NN
Reactant: CN(C)/C=C1\CC(NC(=O)OC(C)(C)C)(c2cccc(C(C)(C)C)c2)CCC1=O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2cccc(C(C)(C)C)c2)CCc2n[nH]cc2C1
Reaction time: 3 h
Yield: 67 %

Procedure:
To a stirred solution of (E)-tert-butyl 1-(3-tert-butylphenyl)-3-((dimethylamino) methylene)-4-oxocyclohexylcarbamate (801 mg, 2.0 mmol) in 6 mL of ethanol was added hydrazine monohydrate (150 μL, 3.0 mmol). The reaction was allowed to stir for 3 h. The reaction was concentrated and purified using a biotage 40S column eluting with DCM/MeOH (95:5) to afford 500 mg (67% yield) of an off white foam. LCMS corresponded to the desired material: retention time (min)=2.45 (method [8]); MS (ESI) 370.0.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][O:53][CH2:54][C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([O:65][Si](C(C)(C)C)(C)C)[CH2:5][C:4]1=[O:73])[CH3:2]>C(#N)C.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:63])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][O:53][CH2:54][C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH:46]([O:61][CH3:62])[CH2:45]2)[CH:7]([CH3:64])[CH:6]([OH:65])[CH2:5][C:4]1=[O:73])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOCc4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCOCc4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.9 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2'"-benzyloxyethoxy)-3"-methoxycyclo-hexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone(10 mg) in acetonitrile (500 μl) was added a solution of 2% HF in aqueous acetonitrile (200 μl), and the mixture stirred at room temperature. After 2.5 hours, the solution was diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and the organic phase dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([OH:17])[CH:13]=[CH:14][C:15]=1[NH2:16]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:17][C:12]2[CH:13]=[CH:14][C:15]([NH2:16])=[C:10]([F:9])[CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: Nc1ccc(O)cc1F
Product: Nc1ccc(Oc2ccnc(Cl)c2)cc1F
Yield: 86 %

Procedure:
Using a procedure analogous to Example A2, 2,4-dichloropyridine (8.0 g, 54 mmol) and 3-fluoro-4-aminophenol (8.0 g, 62.9 mmol) were combined to provide 4-(2-chloro-pyridin-4-yloxy)-2-fluorophenylamine (11g, 86% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.24 (d, J=5.7 Hz, 1H), 7.00 (dd, J=9.0, 2.7 Hz, 1H), 6.89-6.73 (m, 4H), 5.21 (br s, 2H); MS (ESI) m/z: 239.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:5]=[CH:6][C:7]=1[F:8].[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1Cc2c(cccc2-c2ccc(F)c(Cl)c2)N1
Reactant: Cc1cc(C(=O)NCCN2CCCC2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(F)c(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.2 %

Procedure:
To a solution of 4-(3-chloro 4-fluoro-phenyl)-1,3-dihydro-indol-2-one (65.4 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide (64.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-chloro-4-fluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)amide as a yellow solid (89 mg, 72%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]=1.[I-:19].[Na+]>CC(C)=O>[I:19][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]=1
Reactant: [I-]
Reactant: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CCl
Agent: [Na+]
Solvent: CC(C)=O
Product: Cn1nc(-c2ccc(C(F)(F)F)cc2)cc1CI

Procedure:
In analogy to the procedure described in example 20 a], 5-chloromethyl-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole (example 9 a]) was treated with sodium iodide in acetone to obtain 5-iodomethyl-1-methyl-3-(4-trifluoromethyl-phenyl)-1H-pyrazole as yellow solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:26]([O-])=O)=[C:7]([CH:25]=1)[CH2:8][N:9]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:26][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][C:7]=1[CH2:8][N:9]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1
Reactant: CCOC(=O)CN(Cc1cc(OC)ccc1[N+](=O)[O-])C(=O)c1ccc(Cl)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)CN(Cc1cc(OC)ccc1N)C(=O)c1ccc(Cl)cc1

Procedure:
1.0 g (2.5 mmol) of ethyl [(5-methoxy-2-nitrobenzyl)-(4-chlorobenzoyl)amino]acetate was dissolved in a mixture of 10 ml of ethyl acetate and 10 ml of ethanol. 360 mg of 10% palladium/carbon was added to the obtained solution, and they were stirred in the presence of hydrogen at room temperature for 4 hours. The reaction mixture was filtered through Celite and the solvent was evaporated. The obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1>C(O)C>[OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc(O)cc1
Solvent: CCO
Product: Nc1ccc(NC(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 23.3 h

Procedure:
A portion (44.1 grams, 0.1708 mole) of 4-hydroxy-4'-nitrobenzanilide from A. above and ethanol (300 milliliters) are added to a 400 milliliter heavy walled glass bottle then sparged with nitrogen. After removal of air by nitrogen sparging, Raney nickel catalyst (5.5 grams of a 75% wt. slurry in water at pH 10) is added to the slurry in the glass bottle which is then stoppered and multiply purged with hydrogen to replace the nitrogen atmosphere. The bottle is then placed on a shaking type agitator, and pressurized to 48 psig hydrogen. Shaking of the pressurized slurry at room temperature (25° C.) commences until 23.3 hours later, the hydrogen pressure reading indicates that 47 psig of hydrogen has been consumed. By the completion of the hydrogenation, the light yellow colored reactant slurry became a light pink tan colored product slurry. The product slurry is recovered, diluted into dimethylsulfoxide (300 milliliters) to provide a solution of product containing precipitated Raney nickel, then filtered through a medium porosity fritted glass funnel. The recovered dimethylsulfoxide product solution is rotary evaporated at 130° C. under vacuum to provide a powder product. The powder product is further dried at 120° C. under vacuum to a constant weight of 38.94 grams (99.88% isolated yield). Fourier transform infrared spectrophotometric analysis of a nujol mull of a portion of the product on a sodium chloride plate revealed the presence of absorbances at 3376 (shoulder), 3351 (shoulder), 3316 (sharp) and 3282 (shoulder) cm-1 due to secondary amide group N--H stretching (solid state), primary amine N--H group stretching and hydroxyl group O--H stretching; the secondary amide carbonyl stretching (solid state) at 1645 cm-1 (sharp); and complete disappearance of the conjugated nitro group absorbances at 1537 and 1339 cm-1 (sharp). Proton magnetic resonance spectroscopy (250 MHz) further confirmed the product structure as 4-hydroxy-4'-aminobenzanilide.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6](O)[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:38]1(=[O:48])[NH:42][C:41](=[O:43])[C:40]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:39]12.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([N:42]2[C:38](=[O:48])[C:39]3[C:40](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:41]2=[O:43])[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(O)C1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)CC(c2ccncc2[N+](=O)[O-])=CC(N2C(=O)c3ccccc3C2=O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a homogeneous solution of 5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enol (1.0 eq), triphenyl phosphine (1.5 eq), and phthalimide (1.5 eq) in THF (0.2 M) cooled to 0° C., ditertbutyl azodicarboxylate (1.5 eq) in THF was added to the solution. The mixture was stirred at 0° C. for 2 hours. The reaction was concentrated in vacco. The residue was purified by column (5% methanol in 1:1 ethyl acetate and hexanes) to give 2-(5,5-dimethyl-3-(3-nitropyridin-4-yl)cyclohex-2-enyl)isoindoline-1,3-dione (99%). LC/MS (m/z): MH+=378.2, Rt=1.10 min.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2([C:16]3[S:17][CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=3)[CH2:15][CH2:14][C:9]3(OCC[O:10]3)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(C)=O.O>[CH:1]1([CH2:4][O:5][C:6]2([C:16]3[S:17][CH:18]=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[N:20]=3)[CH2:15][CH2:14][C:9](=[O:10])[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: c1ccc(-c2csc(C3(OCC4CC4)CCC4(CC3)OCCO4)n2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(OCC2CC2)(c2nc(-c3ccccc3)cs2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 80.6 %

Procedure:
8.3 g of 2-(8-cyclopropylmethoxy-1,4-dioxaspiro[4.5]dec-8-yl)-4-phenylthiazole and 5.5 g of p-toluenesulfonic acid were dissolved in 137 ml of acetone and 14 ml of water. The mixture was stirred at room temperature for 4 days, then poured onto 100 ml of a saturated aqueous sodium hydrogencarbonate solution. The acetone was distilled off and the residue extracted three times with 100 ml each of EA. The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. 5.9 g of the title compound were obtained as an amorphous solid.