Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[N:20]=[CH:19][C:18]([C:21](OC)=[O:22])=[CH:17][CH:16]=1.[H-].[Na+].O>CN(C)C=O>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:15]3[CH:16]=[CH:17][C:18]([CH2:21][OH:22])=[CH:19][N:20]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1csc(-c2ccccc2)n1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
To a solution of 2-phenyl-4-thiazolylmethanol (6.69 g) and methyl 6-chloro-3-pyridinecarboxylate (6.01 g) in N,N-dimethylformamide (100 ml) was added sodium hydride (60% in oil, 1.40 g) at 0° C. and the mixture was stirred for 30 min. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. To a solution of the residue in tetrahydrofuran (150 ml) was added aluminum lithium hydride (1.33 g) at 0° C. and the mixture was stirred at room temperature for 10 min. Sodium sulfate 10 hydrate (11.3 g) was added to the reaction mixture and the mixture was stirred at room temperature for 30 min. The precipitate was filtered off and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and 2-(2-phenyl-4-thiazolylmethoxy)-5-pyridylmethanol (5.81 g, yield 56%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran. The crystals were recrystallized from tetrahydrofuran-hexane. melting point: 134–135° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]3)=[O:18])[CH2:13][C@H:12]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][N:20]3[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:42])=[O:18])[CH2:13][C@H:12]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)C2CCCCN2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)C2CCCCN2C(=O)c2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in Example 545 and benzoyl chloride, and by the reaction and purification in the same manner as in Example 39, the title compound was obtained.
Reaction SMILES: [Si:1]([N:8]1[CH:11]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C:9]1=[O:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH:33]1[C:37]([C:38]([O:40]CC)=O)=[N:36][N:35]=[N:34]1.[N+](=[CH2:45])=[N-].N1CCC1=O>C(Cl)Cl>[Si:1]([N:8]1[CH:11]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:10]([C:38]([C:37]2[N:36]([CH3:45])[N:35]=[N:34][N:33]=2)=[O:40])[C:9]1=[O:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1nnn[nH]1
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C1CCN1
Solvent: ClCCl
Product: Cn1nnnc1C(=O)C1C(=O)N([Si](C)(C)C(C)(C)C)C1SC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
1-t-Butyldimethylsilyl-4-tritylthioazetidin-2-one (1) (9.18 g, 20 mmol) was reacted with an approximately 1:1 mixture of ethyl 1- and 2-methyltetrazole-5-carboxylate (3.94 g, 24.8 mmol) (prepared by treating ethyl tetrazole-5-carboxylate [D. Moderhack, Chem. Ber., 1975, 108, 887]with excess diazomethane [cf 0. Gryszkiewicz-Trochimourski, Compt. Rendu, 1958, 246, 2627]) using the method described in Preparation 4(a). The crude reaction mixture was chromatographed on silica eluting with ethyl acetate/hexane mixtures to give two fractions. The less polar fraction contained a regioisomer of the title azetidinone (123) (3.48 g, 30%) νmax (CH2Cl2) 1750, 1690 cm-1 ; δ(CDCl3) 0.34 (6H, s), 1.00 (9H, s), 4.10 (3H, s), 4.90 (2H, s), 6.77-7.50 (15H, m); The more polar fraction contained the other regioisomer of the title compound ( 124) (3.5g, 30%) (mp. 158°-161°, needles ex ether/hexane) νmax (CH2Cl2) 1750, 1700 cm-1 ; δ(CDCl3) 0.37 (6H, s), 1.00 (9H, s), 4.37 (3H, s), 4.57 (1H, d, J2 Hz), 4.97 (1H, d, J2 Hz), 6.80-7.60 (15H, m). (Found C, 65.3; H; 6.3; N, 12.2; S, 5.6. C31H35N5O2SSi requires C, 65.4; H, 6.2; N, 12.3; S, 5.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([OH:13])=O.[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[NH2:21]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH:10][C:11]([NH:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH:15]1[CH3:14])=[O:13]
Reactant: COc1ccccc1C=CC(=O)O
Reactant: CC1CCCCC1N
Product: COc1ccccc1C=CC(=O)NC1CCCCC1C

Procedure:
Prepared in a similar manner as described in example 4 from 3-(2-methoxy-phenyl)-acrylic acid and 2-methyl-cyclohexylamine. MS (M+H, 274.2).
Reaction SMILES: F[C:2]1C=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[O:15]1[CH2:20][CH2:19][CH:18]([CH2:21][NH2:22])[CH2:17][CH2:16]1.FC1(C[NH2:31])CCOCC1>>[N+:12]([C:3]1[CH:4]=[C:5]([S:8]([NH2:11])(=[O:9])=[O:10])[CH:6]=[N:31][C:2]=1[NH:22][CH2:21][CH:18]1[CH2:19][CH2:20][O:15][CH2:16][CH2:17]1)([O-:14])=[O:13]
Reactant: NS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1(F)CCOCC1
Reactant: NCC1CCOCC1
Product: NS(=O)(=O)c1cnc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared by substituting EXAMPLE 364D for 4-fluoro-3-nitrobenzenesulfonamide and (tetrahydro-2H-pyran-4-yl)methanamine for (4-fluorotetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 138D.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([CH3:21])([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:11][CH:10]=1)[CH3:7])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C)C=O.CS(O)(=O)=O.[CH3:38][NH:39][C:40]([N:42]([CH2:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:47][CH:46]=1)[NH2:43])=[O:41].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]([CH3:7])([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][C:18]([NH:43][N:42]([CH2:44][C:45]2[CH:46]=[CH:47][C:48]([C:51]([CH3:54])([CH3:53])[CH3:52])=[CH:49][CH:50]=2)[C:40]([NH:39][CH3:38])=[O:41])=[O:20])=[CH:13][CH:14]=1)[CH3:21])=[O:5])[CH3:2]
Reactant: CNC(=O)N(N)Cc1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(CCCC(=O)NN(Cc2ccc(C(C)(C)C)cc2)C(=O)NC)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.6 %

Procedure:
4-[4-(1-Ethoxycarbonyl-1-methyl-ethoxy)-phenyl] butyric acid (0.89 g, 3.02 mmol) was dissolved in ethyl acetate (10 mL). Oxalyl chloride (316 μL, 3.62 mmol) was added to this solution dropwise in the presence of a catalytic amount of N,N-dimethylformamide (17 μL, 0.24 mmol). Completion of acid chloride formation was verified by HPLC. The solution was then concentrated to remove excess oxalyl chloride and then redissolved in ethyl acetate (7 mL). This solution was then added dropwise to a suspension of N-Methyl-1-(4-t-butylphenylmethyl)hydrazine carboxamide methanesulfonate (1.02 g, 3.07 mmol) and pyridine (256 μL, 6.14 mmol) in ethyl acetate (10 mL) at 0° C. After stirring at 0° C. for 3 h, an additional charge of pyridine (256 μL, 6.14 mmol) was added and the solution was stirred at 0° C. for 1 h. The solution was warmed to rt and washed with 1N HCl (2×10 mL) and then with 5% aq. NaHCO3 (2×10 mL). The organic layer was dried (MgSO4), filtered and concentrated to an orange oil. Column chromatography (SiO2, ethyl acetate) afforded the title compound as a clear oil (1.06 g, 68%): 1H NMR (DMSO-d6, 60° C.) δ 9.50 (s, 1H), 7.29 (d, 2H, J=8 Hz), 7.16 (d, 2H, J=8 Hz), 7.01 (d, 2H, J=8 Hz), 6.71 (d, 2H, J=8 Hz), 6.27 (br s, 1H), 4.52 (br s, 2H), 4.15 (q, J=7 Hz), 2.58 (d, 3H, J=4 Hz), 2.44 (t, 2H, J=7 Hz ), 2.07 (t, 2H, J=7 Hz ), 1.72 (quint, 2H, J=7 Hz), 1.48 (s, 6H), 1.25 (s, 9H), (1.17 (t, 3H, J=7 Hz); 13C NMR (DMSO-d6) δ 174.0, 172.0, 158.7, 153.8, 149.9, 135.9, 129.7, 128.7, 125.6, 119.5, 79.2, 61.6, 50.8, 34.8, 34.4, 33.4, 31.8, 27.7, 27.1, 25.7, 14.6.; IR (CHCl3) 3009, 2966, 1671, 1509, 1211 cm−1; Anal. Calcd. for C29H41N3O5: C, 68.08; H, 8.08; N, 8.21. Found:,C, 67.70; H, 7.86; N, 8.11.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]([C@H:7]([C:31]([O:33]C)=[O:32])[CH2:8][N:9]([C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)[S:10]([CH3:13])(=[O:12])=[O:11])[CH3:6].Cl.CCCCCC>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]([C@H:7]([C:31]([OH:33])=[O:32])[CH2:8][N:9]([C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=2)=[CH:18][CH:19]=1)[S:10]([CH3:13])(=[O:11])=[O:12])[CH3:6]
Reactant: COC(=O)[C@H](CN(c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)S(C)(=O)=O)N(C)CCCCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(CCCCl)[C@@H](CN(c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)S(C)(=O)=O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
To a mixture of N-{(2S)-2-[N-(3-Chloropropyl)-N-methylamino]-2-methoxy-carbonylethyl}-N-[4-(4-trifluoromethylphenoxy)phenyl]methanesulfonamide (350 mg, 0.67 mmol) from Step D in THF (1.5 mL) was added lithium hydroxyl (1.0 M in H2O, 1.34 mL, 1.34 mmol) at room temperature. The mixture was stirred at rt for 3 h. Then, HCl(aq) (2 N, 0.67 mL, 0.67 mmol) and hexane (15 mL) were added sequentially. The resulting solid was filtered and was washed with H2O (50 mL) and hexane (100 mL). The solid was then dried to give 317 mg of the titled compound (92%) as a pale brown solid. 1H NMR (300 MHz, d6-DMSO) δ 12.60 (br s, 1H), 7.76 (d, J=9.0 Hz, 2H), 7.46 (d, J=9.0 Hz, 2H), 7.19 (d, J=9.0 Hz, 2H), 7.16 (d, J=9.0 Hz, 2H), 3.96-3.80 (m, 2H), 3.59 (t, J=9.0 Hz, 2H), 3.20 (t, J=7.5 Hz, 1H), 3.00 (s, 3H), 2.67-2.46 (m, 2H), 2.20 (s, 3H), 1.82-1.70 (m, 2H); MS (EI) 509 (M++1), 507 (M+−1, 100).
Reaction SMILES: Br[N:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([NH2:5])=[O:4].N1[CH:18]=[C:17](B(O)O)[CH:16]=[N:15][CH:14]=1.[CH3:22]N(C=O)C.CCN(CC)CC>CCOC(C)=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]>[N:15]1[CH:14]=[CH:22][CH:18]=[CH:17][C:16]=1[N:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([NH2:5])=[O:4]
Reactant: NC(=O)N(Br)Nc1ccccc1
Reactant: OB(O)c1cncnc1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: NC(=O)N(Nc1ccccc1)c1ccccn1
Temperature: 90 °C
Yield: 10 %

Procedure:
To a 15 mL pressure vessel was added 42 (250 mg, 0.594 mmol, 1.0 eq.), 5-pyrimidine boronic acid (74 mg, 0.594 mmol, 1.0 eq.), PdCl2(dppf)2 (43 mg, 0.0594 mmol, 0.1 eq.), DMF (5 mL), and Et3N (166 μL, 1.19 mmol, 2.0 eq.). The vessel was sealed and heated at 90° C. overnight upon which the reaction mixture turned from dark red to black. The reaction mixture was cooled and then diluted with EtOAc (100 mL) and the organic phase was washed with 10% aq LiCl (3×50 mL), and brine (50 mL). The combined aqueous phases were extracted with EtOAc (50 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give a black oil. The crude material was purified via flash chromatography (30% to 70% EtOAc/Hex) to give a white powder (32 mg, 10%). 1H-NMR, Varian 400 MHz, (DMSO-d6) δ 9.38 (s, 1H), 9.18 (s, 1H), 9.10 (s, 1H), 8.78 (s, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.56 (d, 1H), 7.40 (t, 1H), 7.24 (m, 2H), 7.00 (d, 1H), 3.17 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4].[N+](=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-].C(OCC)(=O)C.O>C(Cl)Cl.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]#[N:36])=[CH:27][CH:28]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reaction time: 3 h

Procedure:
To a solution of 4′-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.9 g) and rhodium acetate (dimer, 0.070 g) in methylene chloride (15 mL) was added dropwise a solution of ethyl diazoacetate (3.1 mL) in methylene chloride (3 mL), and the mixture was stirred for 3 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (2.1 g, 61%).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)=[N:9][CH:10]=1.C(N(CC)C(C)C)(C)C.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34]([Cl:36])=[O:35]>ClCCl>[ClH:36].[CH3:32][C:33]([CH3:38])([CH3:37])[C:34]([NH:3][CH2:4][C:5]1[CH:10]=[N:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)=[CH:7][CH:6]=1)=[O:35]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NCc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(-n2[nH]cc(-c3cccnc3)c2=O)nc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
100 mg (0.3 mmol) of the compound from Example 13 are suspended in 3 ml of dichloromethane. 152 mg (1.2 mmol) of N,N-diisopropylethylamine (Hünig base) are added, and the mixture is stirred at RT for 5 min. 43 mg (0.4 mmol) of 2,2-dimethylpropanoyl chloride are then added, and the mixture is stirred at RT for 16 h. The mixture is then concentrated on a rotary evaporator, the residue is taken up in 5 ml of dioxane and 1 ml 1 N aqueous sodium hydroxide solution is added. This mixture is then purified by preparativer HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA to the water). The product-containing fractions are combined and concentrated on a rotary evaporator. The residue is dissolved in 1 N hydrochloric acid, and the solution is lyophilized. The solid is then stirred in tert-butyl methyl ether for 30 min, filtered off and dried under high vacuum.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:15]=2[N+:21]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]OC(OC)N(C)C.N1CCCC1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:15]=2[NH:21][CH:24]=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: Cc1cccc(N2CCN(C(=O)OC(C)(C)C)CC2)c1[N+](=O)[O-]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cc[nH]c23)CC1
Reaction time: 6 h
Yield: 26.8 %

Procedure:
A solution of 4-(3-methyl-2-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester (10 g, 31 mmol), N,N-dimethylformamide dimethyl acetal (13.2 mL, 100 mmol) and pyrrolidine (4 mL, 50 mmol) in 45 mL of DMF was heated under reflux for 20 h. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The ethyl acetate was dried and evaporated. The residue was hydrogenated in 200 mL of THF containing 2.5 g of 10% Pd-C at 50 psi for 6 h. The mixture was filtered, concentrated in vacuo, and partitioned between ethyl acetate and aqueous HCl. The ethyl acetate was washed with brine, dried and evaporated. Silica gel chromatography (10% ethyl acetate-hexane) afforded 2.5 g of 4-(1H-Indol-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (19) as a white solid, m.p. 150-151° C.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=1)(=O)=O.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][C:32]([NH:35][S:36]([CH3:39])(=[O:37])=[O:38])=[CH:33][CH:34]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(NS(C)(=O)=O)cc1

Procedure:
A mixture of 2,2-diphenyl-5-methylaminopentanamide (0.3 g--see Preparation 3), N-[4-(2-methanesulphonyloxyethyl)phenyl]-methanesulphonamide (0.3 g--see Preparation 18), sodium bicarbonate (0.5 g) and acetonitrile (10 ml) was heated under reflux for 8 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.12 g.
Reaction SMILES: CO[C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: NCc1ccccc1
Product: O=C(Cc1ccc(O)cc1)NCc1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 80 g of 4-hydroxyphenylacetic acid methyl ester and 51.6 g of benzylamine is brought to 180° C. for 8 hours. The mixture is allowed to return to room temperature and the crystals are filtered off and washed with ethanol and then ethyl ether.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9]([C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10])([CH3:7])[C:3]([O:5]C)=[O:4].[Li+].[OH-]>CO.O.CCOC(C)=O>[CH3:7][C:2]([NH:8][C:9]([C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=[O:10])([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)NC(=O)c1cnccn1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)c1cnccn1)C(=O)O
Temperature: 22 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
A solution of methyl 2-methyl-2-[(pyrazin-2-ylcarbonyl)amino]propanoate (0.36, 1.6 mmol) in MeOH/H2O (2:1) (6.0 mL) was treated with LiOH (0.08 g, 3.2 mmol) and stirred at 22° C. After 12 h, the reaction was diluted with 1-O and EtOAc and the layers were separated. The aqueous layer was acidified with 1 M HCl in water (28 mL) to an approximate pH˜2. The aqueous was extracted with EtOAc (3×). These three combined extracts were dried (Na2SO4), filtered and concentrated to obtain the title compound (0.286 g, 88%).
Reaction SMILES: [CH3:1][C@:2]12[C@@:18]3(C[O:19]3)[CH2:17][CH2:16][C@@H:15]1[CH2:14][C@H:13]1[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:12]1[CH2:11][CH2:10][C@@H:9]([OH:21])[CH2:8]3)[CH2:3]2.C(N(CC)C(C)C)(C)C.[CH3:31][O:32][CH2:33]Cl.O>ClCCl>[CH3:31][O:32][CH2:33][O:21][C@H:9]1[CH2:8][C@H:7]2[C@@H:12]([C@@H:13]3[C@@H:4]([CH2:5][CH2:6]2)[CH2:3][C@@:2]2([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16][C@@H:15]2[CH2:14]3)[CH2:11][CH2:10]1
Reactant: COCCl
Reactant: C[C@@]12C[C@@H]3CC[C@H]4C[C@H](O)CC[C@@H]4[C@H]3C[C@H]1CC[C@]21CO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCO[C@@H]1CC[C@H]2[C@@H](CC[C@H]3C[C@@]4(C)C(=O)CC[C@@H]4C[C@@H]32)C1
Reaction time: 16 h
Yield: 99.7 %

Procedure:
To a solution of compound 46 (200 mg, 0.72 mmol) in dry dichloromethane (10 mL) was added N,N-diisopropylethylamine (260 mg, 2.0 mmol) and chloromethyl methyl ether (241 mg, 3.0 mmol) at room temperature. After 16 h, water (30 mL) was added and the product extracted into dichloromethane (50 mL×3). The combined extracts were dried, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 10% EtOAc in hexanes) to give compound 47 (230 mg, 100%) as a white solid: [α]D25 −40.0 (c 0.20, CHCl3); 1H NMR (CDCl3) δ 4.60 (s, 2H), 3.83-3.82 (m, 1H), 3.31 (s, 3H), 0.81 (s, 3H); 13C NMR (CDCl3) δ 220.9, 94.5, 71.2, 55.0, 48.3, 47.7, 46.9, 45.6, 39.3, 38.1, 37.9, 36.6, 35.6, 33.9, 30.2, 28.3, 24.0, 2.39, 13.5; IR νmax 1740 cm−1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[OH-].[Na+].CO.[C:15](=O)=[O:16]>O>[CH3:15][O:16][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccnc2[nH]ccc12
Temperature: 170 °C

Procedure:
To 4-chloro-1H-pyrrolo[2,3-b]pyridine [2.3 g, Reference Example 64] in a stainless steel pressure vessel was added sodium hydroxide (2 g), and methanol (40 mL). The pressure vessel was sealed and heated at 170° C. for 4 hours. After cooling, water (100 mL) was added and the mixture was neutralised by addition of excess solid carbon dioxide pellets (30 g). After concentration to a slurry and filtration, the residue was washed twice with water (5 mL) to afford 4-methoxy-1H-pyrrolo[2,3-b]pyridine as a solid. To a mixture of 4-methoxy-1H-pyrrolo[2,3-b]pyridine (5.85 g) in toluene (150 mL) and water (150 mL) was added potassium hydroxide pellets (2.5 g), 4-methylbenzene sulfonyl chloride (7.53 g) and tetra-n-butyl ammonium hydrogen sulfate (0.02 g). This mixture was stirred at room temperature for 20 hours then extracted four times with ethyl acetate (100 mL). The combined organic extracts were concentrated and then subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and heptane (35:65, v/v) to afford the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:9]=1[O:10][CH3:11])=[O:4].[OH-].[K+]>O.CO>[CH3:11][O:10][C:9]1[CH:8]=[C:7]([C:12]([F:14])([F:15])[F:13])[S:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(C(F)(F)F)cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(F)(F)F)sc1C(=O)O
Yield: 88.4 %

Procedure:
A solution of 2 g (14 mmole) of methyl-3-methoxy-5-trifluoromethyl-2-thiophenecarboxylate , 2 g (28 mmole) of KOH in a mixture of 15 mL water and 50 mL of methanol was refluxed for 2 hr. The reaction mixture was partitioned with ether and dilute aqueous HCl. The organic phase was separated, dried over MgSO4, filtered and concentrated to give 2.8 g (87%) of a colorless solid. mp 131-132° C. 1H NMR (300 MHz, CDCl3): δ 7.2 (s, 1H); 4.1 (s, 3H). Anal. Calc'd for C7H5F3O3S: C, 37.17; H, 2.23; S, 14.18. Found: C, 36.96; H, 2.19; S, 14.08.