Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH3:35])[C:2]1[C:7]([S:8]([N:11]2[CH2:12][CH2:13][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:21]=[CH:22][C:23]([O:26][C:27]([F:30])([F:28])[F:29])=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)[CH2:31][CH2:32]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Product: CN(C)c1ncccc1S(=O)(=O)N1CCC2(CCN(c3ccc(OC(F)(F)F)cc3)C2=O)CC1

Procedure:
The title compound was prepared in analogy to example 189 from 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188) and dimethyl amine (7.9M in H2O). Off-white solid. MS (ESI): 499.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42](Br)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[C:52]1(B(O)O)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)C.O.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>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccccc5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added phenylboronic acid (143 mg, 0.8 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol), and Cs2CO3 (390 mg, 1.2 mmol). The reaction was heated to 60° C. for 16 h, then cooled to RT, filtered through celite and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Br:26])[CH:20]=3)[C:17](=[O:27])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)(=O)=O.[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O>[N:28]([CH2:6][CH2:7][NH:8][C:9]1[C:13]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Br:26])[CH:20]=3)[C:17](=[O:27])[O:16][N:15]=2)=[N:12][O:11][N:10]=1)=[N+:29]=[N-:30]
Reactant: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCNc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1
Temperature: 50 °C
Yield: 77 %

Procedure:
To a solution of 2-({4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}amino)ethyl methanesulfonate (2.13 kg, 4.6 mol, containing also some of the corresponding bromo-compound) in dimethylformamide (4 L) stirring in a 22 L flask was added sodium azide (380 g, 5.84 mol). The reaction was heated at 50° C. for 6 h, poured into ice/water (8 L), and extracted with 1:1 ethyl acetate:heptane (20 L). The organic layer was washed with water (5 L) and brine (5 L), and the solvents removed in vacuo to afford the desired product (1464 g, 77%) as a tan solid. LCMS for C12H8BrFN8O3Na (M+Na)+: m/z=433.0, 435.0. 1H NMR (400 MHz, DMSO-d6): δ 8.08 (dd, J=6.2, 2.5 Hz, 1 H), 7.72 (m, 1H), 7.58 (t, J=8.7 Hz, 1 H), 6.75 (t, J=5.7 Hz, 1 H), 3.54 (t, J=5.3 Hz, 2 H), 3.45 (dd, J=11.1, 5.2 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:10]=[C:11]3[C:16]([OH:17])=[N:15][C:14]([CH2:18][CH3:19])=[N:13][C:12]=23)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:33]([CH2:37]I)([F:36])([F:35])[F:34]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[N:10]=[C:11]3[C:16](=[O:17])[N:15]([CH2:37][C:33]([F:36])([F:35])[F:34])[C:14]([CH2:18][CH3:19])=[N:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: FC(F)(F)CI
Reactant: CCc1nc(O)c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc2c(=O)n1CC(F)(F)F
Temperature: 100 °C
Reaction time: 18 h
Yield: 60.4 %

Procedure:
A mixture of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-2H-pyrazolo[4,3-d]pyrimidin-7-ol (I-3A-1a, 15 mg, 0.039 mmol), Cs2CO3 (52 mg, 0.16 mmol) and CF3CH2I (39 μl, 0.4 mmol) in DMF (1 ml) was stirred at 100° C. for 18 h. The reaction mixture was cooled to room temperature, quenched with saturated aqueous sodium chloride, and extracted with ethyl acetate (2×). The combined extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by radial chromatography (Chromatotron) using a 1 mm silica gel plate and a solvent gradient of 25% ethyl acetate/hexanes to 50% ethyl acetate/hexanes to provide the desired product, 3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-ethyl-6-(2,2,2-trifluoroethyl)-2,6-dihydropyrazolo[4,3-d]pyrimidin-7-one 3A-1 (11 mg): MS 467.4 (M+1); 1H NMR (400 MHz, CD2Cl2): δ 7.57-7.43 (m, 4H), 7.44-7.40 (m, 2H), 7.34-7.30 (m, 2H), 5.00-4.80 (br m, 2H), 2.87 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[O:22][CH3:23].[CH2:24]1[O:32][C:31]2[CH:30]=[CH:29][C:28]([CH2:33][C:34]#[N:35])=[CH:27][C:26]=2[O:25]1>>[O:32]1[C:31]2[CH:30]=[CH:29][C:28](/[C:33](=[CH:18]/[C:17]3[CH:20]=[CH:21][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])=[C:15]([O:22][CH3:23])[CH:16]=3)/[C:34]#[N:35])=[CH:27][C:26]=2[O:25][CH2:24]1
Reactant: COc1cc(C=O)ccc1OCCCCCCCCCCCO
Reactant: N#CCc1ccc2c(c1)OCO2
Product: COc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCCCCCCO
Yield: 65 %

Procedure:
(2Z)-2-(1,3-benzodioxol-5-yl)-3-{4-[(11-hydroxyundecyl)oxy]-3-methoxyphenyl}prop-2-enenitrile is prepared starting from 4-[(11-hydroxyundecyl)oxy]-3-methoxybenzaldehyde and commercial [3,4-(methylenedioxy)phenyl]acetonitrile according the same procedure following for example 1 in 65% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12](Br)=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]1)=[O:16])=O)(C)(C)C.[F:38][C:39]1[C:44]([O:45][CH2:46][CH3:47])=[CH:43][CH:42]=[C:41]([F:48])[C:40]=1B(O)O.C(O)(C(F)(F)F)=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[NH2:8][C:9]1[S:13][C:12]([C:40]2[C:41]([F:48])=[CH:42][CH:43]=[C:44]([O:45][CH2:46][CH3:47])[C:39]=2[F:38])=[N:11][C:10]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][CH2:27][C@H:26]([NH2:30])[CH2:25]1)=[O:16]
Reactant: CCOc1ccc(F)c(B(O)O)c1F
Reactant: CC(C)(C)OC(=O)Nc1sc(Br)nc1C(=O)Nc1cnccc1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOc1ccc(F)c(-c2nc(C(=O)Nc3cnccc3N3CCC[C@H](N)C3)c(N)s2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12 %

Procedure:
A septum sealed microwave tube was charged with (S)-tert-butyl 1-(3-(5-(tert-butoxycarbonylamino)-2-bromothiazole-4-carboxamido)pyridin-4-yl)piperidin-3-ylcarbamate (50 mg, 0.084 mmol), 2,6-difluoro-3-ethoxyphenyl-boronic acid (169 mg, 0.84 mmol), Pd(dppf)Cl2 (13.6 mg, 0.016 mmol) 1M Na2CO3 (0.6 mL, 14.1 mmol) and acetonitrile (3 mL). The mixture was irradiated for 30 min at 120 C. Upon completion of the reaction, the solvent was distilled off and the crude material was dissolved in CH2Cl2 (5 mL) and transferred to a scintillation vial. TFA (0.77 g, 6.7 mmol) was added and the mixture was stirred at room temperature for 30 min. The solvent was distilled off and the crude product was purified via reverse phase HPLC 40% to 80% MeOH in water with 0.1% NH4OH to afford (S)-5-amino-N-(4-(3-aminopiperidin-1-yl)pyridin-3-yl)-2-(3-ethoxy-2,6-difluorophenyl)thiazole-4-carboxamide as a white solid (4.8 mg, 12%). 1H NMR (400 MHz, DMSO) δ 9.35 (s, 1H), 8.27-8.16 (m, 1H), 7.66 (s, 2H), 7.28 (td, J=9.2, 5.1, 1H), 7.23-7.09 (m, 2H), 4.15 (q, J=7.0, 2H), 3.06 (dd, J=41.9, 10.8, 5H), 2.65 (dd, J=15.7, 5.1, 1H), 1.89 (d, J=10.1, 1H), 1.82-1.67 (m, 2H), 1.36 (t, J=7.0, 3H). ESIMS m/z=475.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])([O-])=O.[C:19]([O:22][CH2:23][CH3:24])(=[O:21])C>O=[Pt]=O>[CH2:23]([O:22][C:19]([NH:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[CH:8]1[N:14]([CH3:17])[CH2:15][CH2:16][C:7]21[CH3:18])=[O:21])[C:24]1[CH:6]=[CH:5][CH:4]=[CH:12][CH:11]=1
Reactant: CN1CCC2(C)c3cc([N+](=O)[O-])ccc3N(C)C12
Reactant: CCOC(C)=O
Agent: O=[Pt]=O
Product: CN1CCC2(C)c3cc(NC(=O)OCc4ccccc4)ccc3N(C)C12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,2,3,3a,8,8a-Hexahydro-5-nitro-1,3a,8-trimethylpyrrolo[2,3-b]indole (2.2 g) was dissolved in ethyl acetate (100 ml) and hydrogenated in a Parr apparatus at 45 psi using PtO2 (220 mg) as a catalyst. The reduction was complete within 2 hours. The reduction was filtered directly into a nitrogen flushed flask. 4-Dimethylaminopyridine (0.100 g) and triethylamine (0.9 g) were added, the mixture was cooled to 0° C. and a solution of benzylchloroformate (1.5 g) in ethyl acetate (100 ml) was added over a period of 1.5 hours. The mixture was washed with water (2×100 ml), dried (Na2SO4), concentrated and purified by flash chromatography on silica gel (eluting with 15% MeOH/EtOAc). The pure fractions were concentrated to give 5-(benzoxycarbonylamino)-1,2,3,3a,8,8a-hexahydro-1,3a,8-trimethylpyrrolo-[2,3-b]indole (1.2 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([OH:26])=O)[CH2:21][N:22]=1)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[N:40](C)CCCN=C=NCC.[NH4+].ON1C2C=CC=CC=2N=N1.CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][CH:29]=2)[CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]1[S:19][CH:20]([CH2:23][C:24]([NH2:40])=[O:26])[CH2:21][N:22]=1)=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C4=NCC(CC(=O)O)S4)cc3c2)cc1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OCc3ccccc3)c3[nH]c(C4=NCC(CC(N)=O)S4)cc3c2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.1 %

Procedure:
A mixture of (2-{7-(benzyloxy)-5-[4-(methylsulfonyl)phenoxy]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (500 mg), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride (356 mg), 1-hydroxybenzotriazole ammonium salt (283 mg) and N,N-dimethylformamide (20 mL) was stirred at room temperature for 14 hr. Water was added to the reaction solution, and the precipitated solid was collected by filtration, and washed successively with water, ethanol and diethyl ether. The obtained brown solid was recrystallized from ethanol to give the title compound (300 mg, yield 60%) as colorless crystals. melting point 134-135° C. MS 536 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=O)[CH:2]=1.[OH-].[K+].O.NN>C(O)CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:2]=1
Reactant: O=C(c1cccnc1)c1cccnc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: c1cncc(Cc2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dipyridin-3-ylmethanone (1-1, 2.630 g, 14.28 mmol) was suspended in ethylene glycol (28 mL). KOH (1.682 g, 29.98 mmol) was added and the reaction was stirred at RT for 1 hr until most of the solids were dissolved. Hydrazine monohydrate (1.596 mL, 32.84 mmol) was added and the mixture was heated to 185° C. After 1 hr 45 min, the reaction was cooled to RT, diluted with H2O (150 mL), and extracted with CH2Cl2 (4×100 mL). The combined organics were washed with water, washed with brine (2×), dried over Na2SO4, filtered, and concentrated in vacuo to afford 3-(pyridin-3-ylmethyl)pyridine as a light yellow solid. 1H NMR (CDCl3) δ 8.52-8.49 (m, 4H), 7.47-7.45 (m, 2H), 7.25-7.22 (m, 2H), 3.99 (s, 2H). [M+H]+=171.2.
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH2:23].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26]>ClCCl>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][CH:16]=[C:15]2[CH2:21][CH2:22][NH:23][C:25](=[O:26])[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.2 %

Procedure:
N,N-diisopropylethylamine (0.745; 4.33 mmol) was added to a mixture of 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.500 g; 2.16 mmol), and phenyl chloroformate (0.406 mL; 3.25 mmol) in dichloromethane (20 mL). The solution was stirred at room temperature. for 20 minutes, diluted in dichloromethane, washed with sodium hydrogen sulfate (1M, water), sodium carbonate (1M, water) and brine. The organic layer was dried and concentrated under reduced pressure to furnish 0.60 g (88%) of phenyl 2-(5-chloro-1H-indol-3-yl)ethylcarbamate as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].CC1C=CC(S(O[C@@H:36]2[CH2:40][CH2:39][O:38][CH2:37]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:13][N:10]1[CH:11]=[CH:12][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:3]=[C:2]([O:1][C@H:36]3[CH2:40][CH2:39][O:38][CH2:37]3)[CH:16]=[C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:14]=2)=[N:9]1
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OCc3ccccc3)c2)n1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1ccc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@H]3CCOC3)c2)n1
Temperature: 160 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
A suspension of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(phenylmethyl)oxy]benzamide (450 mg, 1.39 mmol), (3R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (507 mg, 2.09 mmol) and potassium carbonate (481 mg, 3.48 mmol) in acetonitrile (5 mL) was stirred in a Smith Creator microwave at 160° C. for 3 hours. The solvent was removed in vacuo and ethyl acetate added. The organics were washed with water (40 mL), brine (40 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow foam which was chromatographed on silica, eluting with a gradient of 0-100% ethyl acetate in iso-hexane, to give the title compound as a white foam (452 mg). 1H NMR δ (CDCl3): 2.09-2.14 (1H, m), 2.14-2.24 (1H, m), 3.68 (3H, s), 3.86-3.91 (1H, m), 3.94-3.98 (3H, m), 4.89 (1H, s), 5.03 (2H, s), 6.64 (1H, t), 6.85 (1H, s), 6.96 (1H, d), 7.07 (1H, t), 7.27 (1H, m), 7.33-7.41 (5H, m), 9.31 (1H, s); m/z 394 (M+H)+.
Reaction SMILES: Cl.C(OC(=O)[CH2:6][CH:7]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH2:10][NH2:11])C.C(=O)([O-])[O-:21].[K+].[K+]>C(O)C>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([CH:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:6]2=[O:21])=[CH:13][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CC(CCCN)c1ccc(Br)cc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: O=C1NCCCC1c1ccc(Br)cc1
Yield: 86 %

Procedure:
A solution of 6-amino-3-(4-bromo-phenyl)-hexanoic acid ethyl ester hydrochloride, potassium carbonate (1039 mg, 7.52 mmol) in ethanol (50 ml) was refluxed for 20 hr. Solvent was removed in vacuo after addition of dilute hydrochloric acid and water was added to the residue. Filtration, wash with water and dryness afforded 3-(4-Bromo-phenyl)-piperidin-2-one (1387 mg, 86%, 2 steps).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH:10](O)=[O:11].C(OC(=O)C)(=O)C>O>[CH:10]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8])=[O:11]
Reactant: O=CO
Reactant: O=C(O)C1COCCN1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=CN1CCOCC1C(=O)O
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
To a mixture of morpholine-3-carboxylic acid (5 g, 38.1 mmol) and formic acid (46.6 g, 1.01 mol) cooled at 0-5° C. was added acetic anhydride (26.7 g, 262 mmol) dropwise. The resulting mixture was stirred at room temperature for 2 h. An excess of water was added while cooling the mixture. The resulting mixture was then concentrated under reduced pressure. The crude product 4-formyl-morpholine-3-carboxylic acid (6 g) was used in the next step without further purification. LC/MS (method 7): Rt=0.13 min; m/z=160.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2Cl)[CH2:5][CH2:4]1.[F:26][C:27]1([F:32])[CH2:31][CH2:30][NH:29][CH2:28]1.Cl.CCN(C(C)C)C(C)C>O1CCOCC1>[F:1][C:2]([F:25])([F:24])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([NH:20][CH3:21])=[CH:13][C:12]=2[N:29]2[CH2:30][CH2:31][C:27]([F:32])([F:26])[CH2:28]2)[CH2:5][CH2:4]1
Reactant: CNc1cc(Cl)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reactant: FC1(F)CCNC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(N2CCC(F)(F)C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to procedure 6a from N-(trans-4-trifluoromethyl-cyclohexyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (190 mg, 0.50 mmol), 3,3-difluoro-pyrrolidine×HCl (143 mg, 1.00 mmol), DIPEA (0.34 mL, 2.0 mmol) and dioxane (10 mL).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][NH:10][C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl>[CH3:8][O:9][N:10]([C:11](=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:21](=[O:23])[CH3:22]
Reactant: CCCCCCCCC(=O)NOC
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=O)N(OC)C(C)=O
Reaction time: 8 h

Procedure:
A 100 mL round-bottom flask equipped with a magnetic stir bar, argon inlet and pressure equalizing addition funnel is charged with methylene chloride (22.5 mL), triethylamine (3.80 g, 2 eq) and N-methoxynonanamide (3.5 g, 1 eq). The reaction mixture is stirred and cooled in an ice bath. Acetic anhydride (2.88 g, 1.5 eq) is then added dropwise. The reaction slowly warms to room temperature overnight. The reaction mixture is diluted with methylene chloride (50 mL) and washed with 0.05 M hydrochloric acid solution (1×50 mL), saturated aqueous sodium bicarbonate solution (3×50 mL) and brine (1×50 mL). The organic layer is dried over sodium sulfate, filtered and concentrated under vacuum.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[N:4]([C@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([Cl:25])[CH:24]=1)[NH:21][CH2:20][CH2:19]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:21]2[C:22]3[C:18](=[CH:17][C:16]([Cl:15])=[CH:24][C:23]=3[Cl:25])[CH2:19][CH2:20]2)[C:3](=[O:14])[N:4]([C@H:9]([CH3:13])[CH2:10][O:11][CH3:12])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: COC[C@@H](C)n1cc(Cl)nc(Cl)c1=O
Product: COC[C@@H](C)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-2-methoxy-1-methylethyl]-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 93–95° C.; 1H NMR (300 MHz, CDCl3): δ 7.18 (s, 1 H), 7.11 (s, 1 H), 7.06 (s, 1 H), 4.35 (t, J=7.9 Hz, 2 H), 3.62–3.56 (m, 3 H), 3.36 (s, 3 H), 3.12 (t, J=8.1 Hz, 2 H), 0.90–0.86 (m, 3 H); HRMS (ESI) calcd for C16H17N3O2Cl3 (M+H)+: 388.0386; found m/z 388.0358.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:13]([O:15]CC)=[O:14])[CH2:12][CH:11]2[CH:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:5])C.CO.O>[OH-].[K+]>[CH:8]12[CH2:9][CH2:10][CH:11]1[CH2:12][C:6]([C:13]([OH:15])=[O:14])([C:4]([OH:5])=[O:3])[CH2:7]2
Reactant: CCOC(=O)C1(C(=O)OCC)CC2CCC2C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)C1(C(=O)O)CC2CCC2C1
Yield: 87.4 %

Procedure:
A solution of 10.3 g of 3,3-bis(ethoxycarbonyl)bicyclo[3.2.0]heptane in 68 ml of 16% potassium hydroxide in 1:1 methanol-water was refluxed for 16 hr under argon. The solvents were removed in vacuo and the residue dissolved in a minimum amount of water. The solution was acidified with concentrated hydrochloric acid and the precipitated acid isolated by vacuum filtration to yield 6.9 g of bicyclo[3.2.0]heptane-3,3-dicarboxylic acid as a white solid, mp 161°-170°.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([C:8]2[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10](OCC)=[O:11])=O)=[CH:4][N:3]=1.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2[C:8]3[C:9](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10](=[O:11])[NH:23][N:22]=2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1ccccc1C(=O)c1ccc(Cl)nc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc(-c2ccc(Cl)nc2)c2ccccc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 2-(6-chloronicotinoyl)benzoate (0.599 g, 2.1 mmol) and hydrazine hydrate (0.35 mL, 6.2 mmol) in ethanol (6 mL) was stirred at 75° C. for 1 hour, concentrated, and azeotroped with toluene to provide the title compound, which was used without purification: 1H NMR (300 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.65 (dd, J=2.7, 0.6, 1H), 8.44-8.25 (m, 1H), 8.13 (dd, J=8.3, 2.5, 1H), 8.08-7.82 (m, 2H), 7.82-7.59 (m, 2H).