Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>CN(C=O)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:13][O:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(O)c1C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: CI
Product: COC(=O)c1cccc(OC)c1C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
A solution of 13.98 g (0.0841 mol) of methyl 3-hydroxy-2-methylbenzoate in 120 mL of DMF was cooled in ice and treated dropwise with 200 mL (0.1 mol) of a 0.5 M solution of KHMDS in toluene. After stirring for 10 minutes, 7.8 mL (0.126 mol) of methyl iodide was added and the solution allowed to stir at room temperature overnight. The solution was diluted with EtOAc and washed twice with 6% HCl, 3 times with H2O, 10% NaHSO3, then saturated NaCl. Drying over MgSO4 and removal of the solvent under reduced pressure left 14.22 g (93.8% yield) of the product as a golden oil. The structure was confirmed by NMR and mass spectroscopy. MS m/z 181 (M+H+).
Reaction SMILES: C(O[C:4](=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)[CH3:5])C.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CC1C=CC=CC=1>[N:17]1([C:4](=[N:6][NH:7][C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH3:5])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: CCOC(C)=NNc1ccc([N+](=O)[O-])cc1
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: CC(=NNc1ccc([N+](=O)[O-])cc1)N1CCOCC1
Yield: 67 %

Procedure:
A mixture of 10 parts of 1-(1-ethoxyethylidene)-2-(4-nitrophenyl)hydrazine, 13 parts of morpholine and 135 parts of methylbenzene was stirred and refluxed for 72 hours. The reaction mixture was cooled. The precipitated product was filtered off, washed with methylbenzene and dried, yielding 8 parts (67%) of 1-[1-(4-morpholinyl)ethylidene]-2-(4-nitrophenyl)hydrazine; mp. 175.9° C. (int. 19)
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:15][C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:13][N:12]=3)[CH:9]=2)[N:4]([S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH:3]=1.[CH:36]1([NH:39][C:40]2[CH:45]=[N:44][CH:43]=[C:42]([Sn](C)(C)C)[N:41]=2)[CH2:38][CH2:37]1>CN(C=O)C.C(Cl)Cl.[Cu]I.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>[CH:36]1([NH:39][C:40]2[N:41]=[C:42]([C:2]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([C:11]5[S:15][C:14]([NH:16][CH2:17][C:18]6[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=6)=[N:13][N:12]=5)[CH:9]=4)[N:4]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:3]=3)[CH:43]=[N:44][CH:45]=2)[CH2:38][CH2:37]1
Reactant: C[Sn](C)(C)c1cncc(NC2CC2)n1
Reactant: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nnc(-c3ccc4c(c3)c(-c3cncc(NC5CC5)n3)cn4S(=O)(=O)c3ccc(C)cc3)s2)cc1
Temperature: 100 °C
Yield: 23.6 %

Procedure:
A glass microwave reaction vessel was charged with 5-(3-iodo-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (543 mg, 0.881 mmol) and N-cyclopropyl-6-(trimethylstannyl)pyrazin-2-amine (350 mg, 1.175 mmol) in DMF (3 mL) followed by copper(i) iodide (223 mg, 1.175 mmol) and Pd(PPh3)4 (67.9 mg, 0.059 mmol). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 100° C. for 1 h, then diluted with DCM and washed with H2O. The organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 20-60% EtOAc in Hex) to give 5-(3-(6-(cyclopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (130 mg, 0.208 mmol, 17.74% for two steps). MS (ESI, pos. ion) m/z: 624 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:17])/[CH:5]=[CH:6]\[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)C.[OH-].[Li+]>O1CCCC1.O>[CH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1/[CH:6]=[CH:5]\[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)/C=C\c1ccc2ccccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)/C=C\c1ccc2ccccc2c1
Temperature: 60 °C

Procedure:
A solution of (Z)-naphthalene-2-acrylic acid ethyl ester (1.38 g, 6.0 mmole) in a mixture of tetrahydrofuran (10 ml) and water (10 ml) was treated with lithium hydroxide (0.88 g, 37 mmol) and heated to 60° C. for 6 hours. On cooling, the organic phase was separated and the. aqueous phase was acidified and extracted with diethyl ether. The ethereal phase was dried and the solvent removed in vaccuo to give (Z)-3-(2-naphthyl)prop-2-enoic acid as a white solid which was used without further purification, Mp 207-209° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH:5]=[N+]=[N-])[CH3:2].[F:11][C@@H:12]1[C:32]2[C@:27]([CH3:34])([CH:28]=[CH:29][C:30](=[O:33])[CH:31]=2)[C@@H:26]2[C@H:14]([C@H:15]3[C@:23]([CH3:36])([CH2:24][C@@H:25]2[OH:35])[C@@:18]([OH:37])([C:19](=[O:22])[CH2:20][OH:21])[C@H:17]([OH:38])[CH2:16]3)[CH2:13]1>>[F:11][C@@H:12]1[C:32]2[C@:27]([CH3:34])([CH:28]=[CH:29][C:30](=[O:33])[CH:31]=2)[C@@H:26]2[C@H:14]([C@H:15]3[C@:23]([CH3:36])([CH2:24][C@@H:25]2[OH:35])[C@@:18]([OH:37])([C:19](=[O:22])[CH2:20][OH:21])[C@H:17]([O:38][CH2:5][CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])[CH2:16]3)[CH2:13]1
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](O)[C@]2(O)C(=O)CO
Reactant: CCOC(C=[N+]=[N-])OCC
Product: CCOC(CO[C@@H]1C[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO)OCC

Procedure:
A solution of 2,2-diethoxy-1-diazoethane (prepared from 0.18 mole of precursor as described in Example 2A) in methanolether at 0°C is treated with 6α-fluoro-11β,16α,17,21-tetrahydroxypregna-1,4-diene-3,20-dione, 16,17-cycloborate until nitrogen evolution ceases. The solution is evaporated to give the title compound.
Reaction SMILES: BrC1C=C[C:5]([N:8]2[CH2:13][C@H:12](C)[NH:11][C@H:10](C)[CH2:9]2)=CC=1.I[C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][CH:18]=1.CN(C)CCNC>>[I:23][C:20]1[CH:21]=[CH:22][C:17]([N:11]([CH3:12])[CH2:10][CH2:9][N:8]([CH3:13])[CH3:5])=[CH:18][CH:19]=1
Reactant: C[C@@H]1CN(c2ccc(Br)cc2)C[C@H](C)N1
Reactant: Ic1ccc(I)cc1
Agent: CNCCN(C)C
Product: CN(C)CCN(C)c1ccc(I)cc1

Procedure:
The title compound was synthesized according to the synthesis of 1-(4-bromophenyl)-cis-3,5-dimethylpiperazine, except reacting 1,4-diiodobenzene (1.06 g, 3.21 mmol) with N,N,N′-trimethylethylenediamine (0.5 mL, 3.9 mmol). The title compound was purified by silica gel chromatography (MeOH/CH2Cl2, 5:95 to 1:5) to give a pale orange solid (0.62 g, 64%). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=8.0 Hz, 2H), 6.55 (d, J=8.2 Hz, 2H), 3.77-3.76 (m, 2H), 2.99 (s, 3H), 2.99-2.92 (m, 2H), 2.65 (s, 6H); MS ESI 305.0 [M+H]+, calcd for [C11H17IN2+H]+ 305.04.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:14]([CH3:15])[CH:13](OCC)[O:12][N:11]=3)=[C:7]([C:19]([NH:21][CH3:22])=[O:20])[C:6]=2[CH:23]=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:3]([N:24]([CH3:29])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:4][C:5]2[O:9][C:8]([C:10]3[C:14]([CH3:15])=[CH:13][O:12][N:11]=3)=[C:7]([C:19]([NH:21][CH3:22])=[O:20])[C:6]=2[CH:23]=1
Reactant: CCOC1ON=C(c2oc3cc(N(C)S(C)(=O)=O)c(Br)cc3c2C(=O)NC)C1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1c(-c2nocc2C)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Yield: 90.4 %

Procedure:
A mixture of 5-bromo-2-(5-ethoxy-4-methyl-4,5-dihydroisoxazol-3-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (50 mg, 0.10 mmol) in DCM/TFA (1 mL/2 mL) was stirred at reflux for 16 h. It was washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by prep-TLC (DCM:MeOH=20:1) to get 5-bromo-N-methyl-2-(4-methylisoxazol-3-yl)-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (40 mg, yield: 88%). 1H-NMR (CDCl3, 400 MHz) δ 9.14 (br s, 1H), 8.84 (s, 1H), 8.39 (s, 1H), 7.76 (s, 1H), 3.35 (s, 3H), 3.10 (s, 3H), 3.04 (d, J=4.8 Hz, 3H), 2.36 (s, 3H). MS (M+H)+: 442/444.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:22][CH2:21][C:20]([C:28](O)=[O:29])=[CH:19][C:18]=3[CH:31]=2)=[CH:10][CH:9]=1)[CH3:2].S(Cl)(Cl)=O.[CH3:36][N:37]([CH:39]=O)[CH3:38]>C1COCC1>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:23]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:22][CH2:21][C:20]([C:28]([NH:23][C:17]4[CH:18]=[CH:31][C:14]([CH2:39][N:37]([CH3:36])[CH:38]5[CH2:5][CH2:4][O:3][CH2:1][CH2:2]5)=[CH:15][CH:16]=4)=[O:29])=[CH:19][C:18]=3[CH:31]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3S(C)(=O)=O)cc1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCOCCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In THF (5 ml) was dissolved 7-[4-(3-ethoxypropoxy)phenyl]-1-methanesulfonyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.20 g). To the solution were added, under ice-cooling, thionyl chloride (0.06 ml) and DMF (catalytic amount), and the mixture was stirred at room temperature for 2 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in THF (15 ml). The solution was added dropwise to a solution of 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline (0.11 g) and triethylamine (0.19 ml) in THF (5 ml), under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature overnight. Under reduced pressure, the solvent was evaporated. To the residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate, and the solvent was evaporated to give crude crystals, which were recrystallized from ethyl acetate/hexane to give 7-[4-(3-ethoxypropoxy)phenyl)-1-methanesulfonyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 8) (0.22 g) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:21](=O)[CH3:22])=[C:6]([CH3:20])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][C:11]=2[CH3:19])[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:24][NH2:25]>>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:8]([CH3:9])=[C:4]3[C:5]([C:21]([CH3:22])=[N:24][N:25]=[C:1]3[CH3:2])=[C:6]2[CH3:20])=[C:11]([CH3:19])[CH:12]=1)[CH3:18]
Reactant: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(C)=O)c2C)c(C)c1
Reactant: NN
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(C)c3c2C)c(C)c1

Procedure:
Utilizing the general procedure outlined in Example 48, 1-[4-acetyl-1-(4-ethoxy-2-methyl-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone and hydrazine reacted to give 6-(4-ethoxy-2-methyl-phenyl)-1,4,5,7-tetramethyl-6H-pyrrolo[3,4-d]pyridazine as light yellow solid: 1H NMR (CDCl9, 500 MHz) δ 7.06 (d, 1H), 6.94 (s, 1H), 6.90 (m, 1H), 4.12 (q, 2H), 2.81 (s, 6H), 2.38 (s, 6H), 1.80 (s, 3H), 1.50 (t, 3H); MS (ESI) 310 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19]4)[C:14]([F:32])=[CH:13][N:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.ClC1C=C2C(C3N=C(N[C@H]4CCCN(C(OC(C)(C)C)=O)C4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.[Li+].[OH-]>C1COCC1.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:19]4)[C:14]([F:32])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(CC(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(Cl)cnc32)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CN1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1

Procedure:
To a solution of tert-butyl 2-[(3S)-3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-1-piperidyl]acetate, 2a, (0.27 g, 0.44 mmol) in THF was added 1N LiOH solution. The reaction mixture was heated in microwave at 120 degrees for 10 minutes. The reaction mixture diluted with brine, extracted with EtOAc, then with 20% isopropanol/CH2Cl2. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The resulting product, 2b, was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12](=O)[C:13]([O:15]C)=O)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:26]=2)[C:21]([CH2:34][C:35]([NH2:37])=[O:36])=[CH:20]1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[C:13](=[O:15])[NH:37][C:35](=[O:36])[C:34]=3[C:21]3[C:22]4[C:27](=[CH:26][C:25]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[CH:24][CH:23]=4)[N:19]([CH3:18])[CH:20]=3)=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: COC(=O)C(=O)c1cn(C)c2cc(Br)ccc12
Reactant: Cn1cc(CC(N)=O)c2ccc(N3CCOCC3)cc21
Product: Cn1cc(C2=C(c3cn(C)c4cc(N5CCOCC5)ccc34)C(=O)NC2=O)c2ccc(Br)cc21
Yield: 48.7 %

Procedure:
3-(6-Bromo-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-morpholin-4-yl-1H-indol-3-yl)pyrrole-2,5-dione (139 mg, 49%) was prepared from methyl (6-bromo-1-methyl-1H-indol-3-yl)glyoxylate (190 mg, 0.64 mmol) and (1-methyl-6-morpholin-4-yl-1H-indol-3-yl)acetamide (150 mg, 0.55 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1I.[C:17]([CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1)#[CH:18]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:18]#[C:17][CH:19]1[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:24]1
Reactant: CC(C)(C)C(=O)Nc1ncc(F)c(Cl)c1I
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2c(NC(=O)C(C)(C)C)ncc(F)c2Cl)CC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of N-(4-chloro-5-fluoro-3-iodopyridin-2-yl)pivalamide (1 g, 2.80 mmol), tert-butyl 4-ethynylpiperidine-1-carboxylate (0.880 g, 4.21 mmol), copper(I) iodide (0.053 g, 0.28 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.197 g, 0.280 mmol) in 50 mL tetrahydrofuran was degassed with nitrogen. The mixture was stirred at room temperature for 48 hours and at 50° C. for 8 hours. The mixture was filtered and the filtrate was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica-gel column chromatography eluting with 0-40% ethyl acetate in heptane to afford the title compound. MS (ESI(+)) m/e 438 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[N+]([C:10]1[CH:17]=[CH:16][CH:15]=[C:12]([C:13]#[N:14])[C:11]=1[C:18]#[N:19])([O-])=O.C([O-])([O-])=O.[K+].[K+].C1C=CC=CC=1>CS(C)=O.CC#N>[C:18](#[N:19])[C:11]1[C:12](=[CH:15][CH:16]=[CH:17][CH:10]=1)[C:13]#[N:14].[C:18](#[N:19])[C:11]1[C:12](=[CH:15][CH:16]=[CH:17][CH:10]=1)[C:13]#[N:14].[NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: NC(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CS(C)=O
Solvent: CC#N
Product: N#Cc1ccccc1C#N
Temperature: 25 °C
Reaction time: 90 h

Procedure:
A mixture of serinol (45.8 mg, 0.50 mmol, 1 equiv.), 3-nitrophthalonitrile (258.1 mg, 1.5 mmol, 2.5 equiv.) and K2CO3 (277.4 mg, 2.0 mmol, 4 equiv.) in 3 mL DMSO was stirred at room temperature and monitored periodically by TLC (9:1 benzene:CH3CN). The reaction mixture changed from orange to brown as the reaction occurred. After 90 h, the reaction mixture was heated to 70° C. TLC analysis showed the gradual disappearance of 3-nitrophthalonitrile over the next 8.5 h. The reaction mixture was partitioned between EtOAc and water, and the two layers were separated. The aqueous layer was extracted with EtOAc. This organic extract was combined with the phase-separated organic layer from the original separation, and then this mixture was washed twice with saturated NaHCO3, twice with water, and once with saturated NaCl. TLC analysis of the crude material showed no ninhydrin positive spot. The crude material was purified by flash chromatography using benzene:CH3CN (95:5) to extract the major UV-active spot.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:24]=[CH:23][CH:22]=[C:7]2[C:8]([N:10]([C:13]3([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11](=[O:12])[C:6]=12)=[O:9])(=[O:3])[CH3:2].[CH3:25][NH2:26]>>[C:1]([NH:4][C:5]1[CH:24]=[CH:23][CH:22]=[C:7]2[C:8]([N:10]([C:13]3([C:19]([NH:26][CH3:25])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11](=[O:12])[C:6]=12)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C1(C(=O)Cl)CCCCC1)C2=O
Reactant: CN
Product: CNC(=O)C1(N2C(=O)c3cccc(NC(C)=O)c3C2=O)CCCCC1

Procedure:
Using the same procedure as described in Example 3 but replacing the ammonia with methylamine gives the title mono-methylamide, m.p. 168.5°-170°C. Similarly, reacting 1-(3-acetamidophthalimido)-cyclohexanecarbonyl chloride with methylamine yields 1-(3-acetamidophthalimido)-N-methylcyclohexanecarboxamide, m.p. 205°-207.5°C.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]([C:20]2[N:21]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:22]=[C:23]3[C:28]=2[CH:27]=[CH:26][CH:25]=[CH:24]3)[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[C:6]([Cl:36])[CH:5]=1.[OH-].[Li+]>C(OC(C)=O)(C)C.[Cl-].[Na+].O>[Cl:36][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[NH:10][C:11]([N:13]([C:20]1[N:21]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[N:22]=[C:23]2[C:28]=1[CH:27]=[CH:26][CH:25]=[CH:24]2)[CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:12])[C:3]([OH:37])=[O:2]
Reactant: COC(=O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: O=C(O)c1ccc(NC(=O)N(c2c3ccccc3nn2-c2ccc(Cl)cc2)C2CCCCC2)c(Cl)c1

Procedure:
In analogy to the procedure described in example 2.2, 3-chloro-4-{3-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-3-cyclohexyl-ureido}-benzoic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF/MeOH 1/1 for 14 h at ambient temperature to give the title compound as yellow solid. MS: m/e=521.0 [M−H−].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[N:10]([O-])=O.[Na+].O.O.[Sn](Cl)Cl.[OH-].[K+]>Cl.O.C(OCC)C>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1)[NH2:10]
Reactant: O=N[O-]
Reactant: COc1ccc(N)cn1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(NN)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
5-Amino-2-methoxypyridine (5.0 g, 40 mmol) was dissolved in 6 N HCl (10 mL), cooled to 0° C., and vigorously stirred throughout the procedure. Sodium nitrite (2.8 g, 41 mmol) was dissolved in water (10 mL) and this solution was added to the reaction solution. After 30 min, tin (II) chloride dihydrate (52 g, 230 mmol) in 6 N HCl (20 mL) was added, and the reaction slurry was stirred at 0° C. for 2.5 h. The pH was adjusted to 13 with 40% aqueous potassium hydroxide solution. Ethyl ether was added and the mixture was extracted with EtOAc (4×70 mL), dried (MgSO4) and concentrated to give 5-hydrazino-2-methoxypyridine as an orange solid (5.1 g).
Reaction SMILES: [NH:1]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:17]([CH3:19])[CH3:18]>C(#N)C>[CH3:18][CH:17]([N:1]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=[N:2]1)[CH3:19]
Reactant: CC(C)I
Reactant: COC(=O)c1ccn[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1ccnn1C(C)C
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 1H-pyrazole-5-carboxylate (0.6 g) (available from Fluorochem), in acetonitrile (50 ml) was added cesium carbonate (1.55 g) followed by 2-iodopropane (0.476 ml) and the mixture stirred at 20° C. for 18 h. The solvent was removed in vacuo and the residue was partitioned between water (20 ml) and DCM (20 ml) and separated by hydrophobic frit. Purification by chromatography on silica gel (50 g silica), eluting with a gradient of 0-100% ethyl acetate in cyclohexane gave methyl 1-(1-methylethyl)-1H-pyrazole-5-carboxylate (0.24 g) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][O-:13].[Na+].CO>C(Cl)Cl>[CH3:12][O:13][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
To 4-bromo-2-fluoro-1-nitrobenzene (8.0 g, 36.4 mmol) was added 0.5 N sodium methoxide (105 mL, 52.5 mmol). The mixture was stirred at 60° C. for 1 h. The MeOH was rotovaped down. The crude product was dissolved in DCM (100 mL), washed with H2O, dried (Na2SO4), filtered, and rotovaped down to give the title compound of step A (8.1 g, 34.9 mmol, 96%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (d, J=8.61 Hz, 1H), 7.23 (d, J=2.01 Hz, 1H), 7.16 (dd, J=8.61, 1.83 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: O[N:2]([OH:10])[C:3]([CH3:9])([C:5]([CH3:8])([NH2:7])[CH3:6])[CH3:4].I([O-])(=O)(=O)=[O:12].[Na+].C(Cl)(Cl)Cl.CO>O>[CH3:4][C:3]1([CH3:9])[C:5]([CH3:8])([CH3:6])[N+:7]([O-:12])=[N+:2]1[O-:10]
Reactant: CC(C)(N)C(C)(C)N(O)O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O
Product: CC1(C)[N+]([O-])=[N+]([O-])C1(C)C

Procedure:
The product could also be obtained by oxidation of the dihydroxylamino precursor with sodium periodate. Thus, N,N-dihydroxy 2,3-dimethyl-2,3-diaminobutane (1.5 g) in water (50 ml) was stirred for 30 min. with aqueous sodium periodate (4.5 g in ca. 100 ml water). The product precipitated out and was washed with water, dried (MgSO4), and evaporated to give the product (800 mg. 65°) T.L.C. (silica, CHCl3 /MeOH;4/1) one spot, Rf 0.8
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[C:25]([NH:29][S:30]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[C:25]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=4)[CH:11]=[C:10]([CH3:24])[N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:38]=1)(=[O:32])=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
The title compound was prepared from 2′-chloro-6-methyl-4-(4-trifluoromethyl-phenyl)-[2,4′]bipyridinyl (example E.28) (0.200 g, 0.6 mmol) and commercially available 3-(tert-butylsulfamoyl)-benzeneboronic acid (0.177 g, 0.7 mmol) according to the general procedure VI. Obtained as an off-white solid (0.286 g, 95%). MS (ISP) 526.2 [(M+H)+]; mp 189° C.