Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH3:18])[CH:8]=1)=O.Cl.[NH:21]([C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1)[C:22]([NH2:24])=[NH:23]>>[CH2:16]([N:9]1[C:10]2=[CH:11][N:12]=[CH:13][CH:14]=[C:15]2[C:7]([C:5]2[CH:4]=[CH:3][N:24]=[C:22]([NH:21][C:25]3[CH:26]=[C:27]([S:31]([NH2:34])(=[O:32])=[O:33])[CH:28]=[CH:29][CH:30]=3)[N:23]=2)=[CH:8]1)[CH2:17][CH3:18]
Reactant: N=C(N)Nc1cccc(S(N)(=O)=O)c1
Reactant: CCCn1cc(C(=O)/C=C/N(C)C)c2ccncc21
Agent: Cl
Product: CCCn1cc(-c2ccnc(Nc3cccc(S(N)(=O)=O)c3)n2)c2ccncc21

Procedure:
Prepared by treatment of (E)-3-(dimethylamino)-1-(1-propyl-1H-pyrrolo[2,3-c]pyridin-3-yl)prop-2-en-1-one and 3-guanidinobenzenesulfonamide hydrochloride as described above. 1H-NMR (DMSO-d6) δ: 0.89 (t, 3H, J=7.2 Hz, CH3), 1.91 (m, 2H, CH2), 4.36 (t, 2H, J=7.2 Hz, CH2), 6.56 (s, 2H, NH2), 7.34 (m, 2H, Pyrimidin-H and Ph-H), 7.44 (m, 1H, Ar—H or Ph-H), 7.91 (m, 1H, Ar—H or Ph-H), 8.33 (d, 1H J=5.2 Hz, Ar—H), 8.45 (d, 1H, J=5.6 Hz, Pyrimidin-H), 8.52 (m, 2H, Ar—H or Ph-H), 9.02 (s, 1H, Ar—H or Ph-H), 9.84 (s, 1H, Ar—H or Ph-H). MS (ESI+) m/z 409.1514 (M+H)+.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH:22]([CH3:24])[CH3:23])[CH3:6])C.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>C(OCC)(=O)C>[CH:22]([C:8]1[N:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=2)[O:11][C:7]=1[CH:5]([CH3:6])[CH2:4][OH:3])([CH3:23])[CH3:24]
Reactant: CCOC(=O)C(C)c1oc(-c2ccc(C(F)(F)F)cc2)nc1C(C)C
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1nc(-c2ccc(C(F)(F)F)cc2)oc1C(C)CO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propionic acid ethyl ester (1.11 g, 3.12 mmol) and tetrahydrofuran (50 mL) are cooled to 0° C. Lithium aluminum hydride (0.24 g, 6.25 mmol) is added and the resulting mixture is stirred 20 hr at room temperature. The mixture is cooled to 0° C. and 1M aqueous hydrochloric acid (50 mL) is carefully added. The mixture is then diluted with ethyl acetate (100 mL) and the layers are separated. The aqueous layer is washed with ethyl acetate (100 mL) and the organic ishes are combined, washed with water and brine (50 mL each), dried over anhydrous magnesium sulfate, filtered and concentrated to constant weight to give 2-[4-Isopropyl-2-(4-trifluoromethyl-phenyl)-oxazol-5-yl]-propan-1-ol as a pale orange oil, 1.03 g, 100%. MS (M++1) 314.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:21]=[CH:20][CH:19]=[CH:18][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=1)=[O:9])=[O:4].C(=O)([O-])[O-].[K+].[K+].[N:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1.O>ClCCl>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:18]=[CH:19][CH:20]=[CH:21][C:6]=2[NH:5][C:3]([CH2:2][N:37]2[CH2:38][CH2:39][N:34]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][CH:30]=3)[CH2:35][CH2:36]2)=[O:4])=[N:12][CH:13]=1
Reactant: O=C(CBr)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: c1cc(N2CCNCC2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CN1CCN(c2ccncc2)CC1)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of 2-(bromoacetyl)amino-N-(5-chloro-pyridin-2-yl)benzamide (0.369 g, 1 mmol) in dichloromethane (10 ml) was added potassium carbonate (0.169 g, 1.22 mmol) and 1-(4-pyridyl)piperazine (0.171 mg, 1.05 mmol). The reaction was stirred overnight at room temperature. Water (2 mL) was added and the mixture was passed through a column of flux-calcined, high purity, inert diatomaceous earth packed into a polypropylene tube (article number CE 1103 from Varian) to remove water. The solvent was removed and the residue was purified by RPHPLC (CH2Cl2/5% 2 N ammonia in methanol) to give 0.08 g of pure title product.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([NH2:20])=[CH:13][C:12]=2[F:21])[CH2:5][CH2:4]1.FC1C=C(N)C([N+]([O-])=O)=CC=1C(O)=O.FC(F)(F)[C@H]1CC[C@H](N)CC1>[Pd]>[F:24][C:2]([F:1])([F:23])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:10](=[O:22])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH2:20])=[CH:13][C:12]=2[F:21])[CH2:7][CH2:8]1
Reactant: Nc1cc(F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: Nc1cc(F)c(C(=O)O)cc1[N+](=O)[O-]
Product: Nc1cc(F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N

Procedure:
The subtitle compound is prepared from N-(trans-4-trifluoromethyl-cyclohex-1-yl)-2-fluoro-4-amino-5-nitro-benzoic acid amide (prepared from 2-fluoro-4-amino-5-nitro-benzoic acid, trans-4-trifluoromethyl-cyclohexylamine in analogy to the example 2d) with Pd/C and H2 in analogy to example 1f.
Reaction SMILES: C(Cl)CCl.C1C=[CH:7][C:8]2[N:13](O)N=N[C:9]=2[CH:10]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][N:26]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][N:30]=3)[C:27]=2[OH:28])=[CH:19][CH:18]=1)#[N:16].Cl.CC1(N)CC1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[C:15]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[N:25][N:26]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([NH:13][C:8]4([CH3:7])[CH2:10][CH2:9]4)=[O:35])=[CH:31][N:30]=3)[C:27]=2[OH:28])=[CH:21][CH:22]=1)#[N:16]
Reactant: On1nnc2ccccc21
Reactant: N#Cc1ccc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)cc1
Agent: CC1(N)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CC1(NC(=O)c2ccc(-n3ncc(-c4ccc(C#N)cc4)c3O)nc2)CC1
Yield: 51.1 %

Procedure:
Combined EDC (56.3 mg, 0.294 mmol), HOBT (39.7 mg, 0.294 mmol) and 6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid (45 mg, 0.147 mmol) in DMF (0.8 mL) then added 1-methylcyclopropanamine hydrochloride (47.4 mg, 0.441 mmol) and Hunig's base (0.180 mL, 1.028 mmol) and stirred at 20° C. for 16 h. The reaction mixture was diluted with 100 uL DMSO and purified by prep HPLC (ACN/water with formic acid) to give the title compound (27 mg, 51.1% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.60-0.68 (m, 2 H) 0.73-0.81 (m, 2 H) 1.40 (s, 3 H) 7.75 (d, J=8.6 Hz, 2H) 8.06-8.16 (m, 2 H) 8.35 (dd, J=8.6, 2.3 Hz, 1 H) 8.46 (d, J=8.8 Hz, 1 H) 8.54 (s, 1 H) 8.82-8.90 (m, 2 H) 13.53 (br. s., 1 H). MS m/z 360 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(Cl)Cl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:14])[CH3:13])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(Cl)c([N+](=O)[O-])c1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.9 %

Procedure:
To a stirred solution of 4-chloro-3-nitroaniline (51.8 g, 0.36 mol) in anhydrous DCM (300 mL) was added dropwise acetic anhydride (45 mL, 0.48 mol) at room temperature, and the resulting solution was stirred at room temperature for 3 h. The solvent was removed in vacuo, and Et2O was added to the residue. The precipitates were collected by filtration, washed thoroughly with Et2O, and dried under high vacuum to give 4′-chloro-3′-nitroacetanilide (78.7 g, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[N:5][N:4]=[C:3]1[C:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])=[N:5][N:4]=[C:3]1[C:14]1([NH:19][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: Cc1ccccc1-c1nnc(C2(N)CCCC2)n1C
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1nnc(C2(NC(=O)c3ccccc3)CCCC2)n1C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
1-[4-Methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]cyclopentanamine (270 mg) was dissolved in chloroform (5 ml) and then diisopropylethylamine (1.7 ml) and benzoyl chloride (0.48 ml) were added thereto, followed by stirring at room temperature for 19 hours. The reaction solution was diluted with a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform (10 ml×2). The organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The resulting residue was purified by column chromatography (methanol:chloroform=1:19) and the resulting solid was dissolved in ethanol (1 ml) and then a 1M aqueous sodium hydroxide solution (2 ml) was added thereto, followed by stirring at room temperature for 6 days. The resulting solid was collected by filtration and washed with water to obtain 51 mg of N-{1-[4-methyl-5-(2-methylphenyl)-1,2,4-triazol-3-yl]cyclopentyl}benzamide (white solid).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.S([O-])([O-])(=O)=O.[Mg+2].[Cl-].[C:18]([O:22][C:23](=[O:26])[CH2:24][Zn+])([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.C(OCC)(=O)C>[CH2:18]([O:22][C:23](=[O:26])[CH:24]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)[CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH3:19]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: O=S(=O)([O-])[O-]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 65 %

Procedure:
To a solution/suspension of 5-aminoindazole (1.01 g, 7.6 mmol) in tetrahydrofuran (20 mL) was added ethyl glyoxlate solution (ca. 50% in toluene, 1.7 mL, 1.1 equiv) in one portion followed by magnesium sulfate (4.6 g). The mixture was stirred at room temperature overnight (23 h) and then filtered and concentrated in vacuo. The resulting crude imine intermediate (1.3 g, 6 mmol) was dried by azeotroping with anhydrous benzene and further dried under high vacuum. The residue was then dissolved in tetrahydrofuran (20 mL) and cooled at 0° C. A solution of 2-tert-butoxy-2-oxoethylzinc chloride (0.5 M in ether, 24 mL, 2 equiv) was then slowly added. After stirring at 0° C. for 1 h, the mixture was stored at 4° C. overnight. The mixture was then diluted with ethyl acetate and quenched with half-saturated ammonium chloride solution along with a minimum amount of 0.5 N HCl to dissolve the precipitated solids. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel, eluting with 10% methanol in methylene chloride, to afford the desired product (1.3 g, 65%) as a tan oil. 1H-NMR (400 MHz, CDCl3) δ 7.89 (1H, s), 7.40-7.27 (1H, m), 6.98-6.77 (2H, m), 4.42-4.35 (1H, m), 4.30-4.12 (3H, m), 2.80 (2H, d, J=4.4 Hz), 1.43 (9H, s), 1.27-1.17 (4H, m). Mass spec.: 356.24 (M+Na)+, 278.23 (M−tBu)+, tR=1.287 min.
Reaction SMILES: [F-:1].[K+].I([C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:9]([NH:11][CH2:12][C:13]([O-:15])=[O:14])=[O:10])(=O)=O.[K+].C1OCCOCCOCCOCCOCCOC1>CS(C)=O>[F:1][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])[C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10]
Reactant: [F-]
Reactant: O=C([O-])CNC(=O)c1ccc([N+](=O)[O-])c(I(=O)=O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)CNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 105 °C
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
A mixture of spray-dried KF (138 mg, 2.3 mmol), intermediate 9 (100 mg, 0.23 mmol), catalytic amount of 18-crown-6 in dry DMSO (4 mL) was stirred at 100-110° C. for 15 min. Work-up of the reaction mixture as described in example 1 gave the product as a colorless solid (40 mg, 69%), mp 136-138° C. 1H NMR (400 MHz, DMSO-d6): δ 8.76 (1H, br s), 8.25 (1H, t, J=7.8 Hz), 8.00 (1H, d, J=12.0 Hz), 7.90 (1H, d, J=8.4 Hz), 3.75 (2H, d, J=4.4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[CH2:13][N:14]([CH3:16])[CH3:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:23][CH3:24].Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39]([N:42]([CH3:44])[CH3:43])(=[O:41])=[O:40])[C:29]([Cl:45])=[CH:28][N:27]=1.C(O)(C(F)(F)F)=O>>[Cl:45][C:29]1[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[S:39](=[O:41])(=[O:40])[N:42]([CH3:43])[CH3:44])=[N:31][C:26]([NH:1][C:2]2[CH:22]=[CH:21][C:5]3[N:6]([CH2:19][CH3:20])[C:7](=[O:18])[CH:8]([NH:11][C:12](=[O:17])[CH2:13][N:14]([CH3:15])[CH3:16])[CH2:9][CH2:10][C:4]=3[C:3]=2[O:23][CH3:24])=[N:27][CH:28]=1
Reactant: CCN1C(=O)C(NC(=O)CN(C)C)CCc2c1ccc(N)c2OC
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Solvent: O=C(O)C(F)(F)F
Product: CCN1C(=O)C(NC(=O)CN(C)C)CCc2c1ccc(Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n1)c2OC

Procedure:
Following a procedure analogous to Example 113, N-(7-Amino-1-ethyl-6-methoxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-2-dimethylamino-acetamide (50 mgs) and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide was converted to the title compound as the TFA salt (24 mgs). 1H NMR (400 MHz, (CD3)2SO) δ 9.44 (s, 1H), 8.94 (d, J=7.3 Hz, 1H), 8.77 (s, 1H), 8.54 (d, J=7.6 Hz, 1H), 8.30 (s, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.31 (t, J=7.6 Hz, 1H), 7.17 (d, J=9.1 Hz, 1H), 4.14-4.30 (m, 2H), 3.92 (s, 2H), 3.70 (s, 3H), 3.54 (m, 1H), 3.07 (m, 1H), 2.78 (s, 6H), 2.66 (s, 6H), 2.42 (m, 1H), 2.20 (m, 1H), 2.07 (m, 1H), 1.04 (t, J=7.1 Hz, 3H). LCMS: found 646.18 (m+1).
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][CH:23]([NH2:28])[C:24]([F:27])([F:26])[F:25]>>[F:25][C:24]([F:27])([F:26])[C@H:23]([NH:28][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20])[CH3:22]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: CC(N)C(F)(F)F
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)N[C@H](C)C(F)(F)F)s1
Yield: 46 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using L-2,2,2,-trifluoro-1-(methyl)ethylamine instead of rac-2-amino-1-butanol, to the title compound (92 mg, 46%) which was obtained as a white solid after purification by chromatography (silica, 50 to 100% ethyl acetate in heptane and recrystallization from ethyl acetate/heptane. MS: m/e=402.3 [M+H]+.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].[C:10]([CH:13]1[CH2:18][CH2:17][O:16][C:14]1=[O:15])(=O)[CH3:11]>C(O)CCC>[NH2:8][C:7]1[N:6]([NH2:5])[C:14](=[O:15])[C:13]([CH2:18][CH2:17][OH:16])=[C:10]([CH3:11])[N:9]=1
Reactant: N=C(N)NN
Reactant: CC(=O)C1CCOC1=O
Agent: O=C(O)O
Solvent: CCCCO
Product: Cc1nc(N)n(N)c(=O)c1CCO
Yield: 65.2 %

Procedure:
A mixture of 13.6 g of aminoguanidine bicarbonate and 12.8 g of 2-acetyl butyrolactone in 80 ml of n-butanol was heated at reflux until a clear solution was obtained. This solution was cooled, evaporated to dryness in vacuo and the residue was triturated with 200 ml of a 50/50 ether-chloroform mixture, giving 12 g of the desired intermediate, mp 126°-135° C.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([O:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(F)(F)F.CCOCC>C(OCC)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[CH2:5]([O:12][C:13]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]1([NH2:16])[CH2:2][CH2:1]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC[Mg]Br
Reactant: N#Cc1cccc(F)c1OCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2cccc(F)c2OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of ethylmagnesium bromide, 3M in diethyl ether (28.2 mL) was added as a slow stream to a mechanically stirred mixture of tetraisopropyl orthotitanate (13.09 mL,) and 2-(benzyloxy)-3-fluorobenzonitrile (Example 283a, 9.6 g) in diethyl ether (400 mL) cooled to −78° C. The resulting solution was stirred at −78° C. for 15 min and then warmed to room temperature over 1 h 30 min. An ice bath was placed around the reaction and boron trifluoride etherate (10.71 mL) was added as a slow stream (caution exothermic) and the mixture was stirred for 30 min. The reaction was cooled (ice bath) and quenched with 1 M aqueous HCl (400 mL added portionwise). The aqueous layer was separated and the diethyl ether layer further extracted into 1M HCl (2×200 mL) (ethyl acetate added to the diethyl ether to aid solubility). The aqueous layer was cooled in an ice bath and basified with stirring with a 10M aqueous NaOH solution. The resulting precipitate was filtered through Celite, washing the pad with water (200 mL) then DCM (4×200 mL) then DCM/MeOH (90:10, 300 mL). The combined filtrates were separated and the aqueous layer further extracted with DCM (2×200 mL). The combined organics were dried (MgSO4) and evaporated, the residue was purified on SCX resin (50 g) eluting with DCM, methanol (discarded) and flushing with 20% ammonia in methanol to give the subtitle compound as an oil (2.54 g).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[Cl-].[Cl-].[Cl-].[Al+3].ClC(N(C)C)=C(C)C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][C:26]=1[C:35]([N:37]1[CH2:42][CH2:41][CH:40]([O:43][CH3:44])[CH2:39][CH2:38]1)=[O:36].Cl>C(Cl)Cl>[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([C:5]2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:2]([CH3:1])[NH:3][C:4]=2[CH3:11])=[O:33])=[CH:27][C:26]=1[C:35]([N:37]1[CH2:38][CH2:39][CH:40]([O:43][CH3:44])[CH2:41][CH2:42]1)=[O:36]
Reactant: COC1CCN(C(=O)c2cc(CC(=O)O)ccc2F)CC1
Reactant: COC(=O)c1cc(C)[nH]c1C
Agent: CC(C)=C(Cl)N(C)C
Agent: Cl
Agent: [Al+3]
Solvent: ClCCl
Product: COC(=O)c1c(C)[nH]c(C)c1C(=O)Cc1ccc(F)c(C(=O)N2CCC(OC)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
A solution of methyl 2,5-dimethyl-1H-pyrrole-3-carboxylate (0.114 g, 0.74 mmol) in anhydrous DCM (5 mL) was added dropwise to a stirred suspension of aluminum trichloride (0.226 g, 1.69 mmol) in anhydrous DCM (10 mL) at 0° C., under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes. A solution of the requisite acid chloride [prepared earlier; 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.090 mL, 0.68 mmol) was added to a solution of 2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetic acid (43) (0.200 g, 0.68 mmol) in anhydrous DCM (5 mL) at 0° C. and stirred for 2 hours] was added dropwise to the stirred suspension at 0° C. The resulting suspension was allowed to warm to room temperature and then stirred at room temperature for a further 18 hours. The reaction was incomplete and further aluminum trichloride (0.226 g, 1.69 mmol) was added and the solution was stirred at room temperature for a further 1 hour. The reaction mixture was poured onto ice (50 mL) and conc HCl (2 mL). The layers were separated and the aqueous layer extracted with DCM (2×50 mL). The combined organics were washed sequentially with 2M HCl (2×75 mL), water (50 mL), and saturated NaHCO3 (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford methyl 4-(2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (0.223 g, 76% yield) as a cream solid. 1H NMR (400.132 MHz, CDCl3) δ 1.57-1.90 (4H, m), 1.98 (3H, s), 2.31 (3H, s), 3.07 (1H, m), 3.29 (3H, s), 3.36-3.55 (3H, m), 3.75 (3H, s), 3.92 (1H, m), 3.97 (2H, s), 6.93 (1H, t), 7.07 (1H, m), 7.17 (1H, m), 8.50 (1H, s); m/z (LC-MS, ESI+), RT=1.89 min (M+H=431.19).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:12](=[CH:13][CH:14]=1)[C:8]([CH2:9][CH2:10][NH2:11])=[CH:7][NH:6]2.[C:15](O)(=[O:21])[CH2:16][CH2:17][C:18]([CH3:20])=O>C(OC(O)C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:12]([C:8]3[CH2:9][CH2:10][N:11]4[C:18]([CH3:20])([CH2:17][CH2:16][C:15]4=[O:21])[C:7]=3[NH:6]2)=[CH:13][CH:14]=1
Reactant: COc1ccc2c(CCN)c[nH]c2c1
Reactant: CC(=O)CCC(=O)O
Agent: CCOC(C)O
Product: COc1ccc2c3c([nH]c2c1)C1(C)CCC(=O)N1CC3
Temperature: 25 °C
Yield: 71.8 %

Procedure:
A mixture of 6-methoxytryptamine (0.95 g, 5 mmol) and levulinic acid (0.7 g, 6 mmol) in ethoxyethanol is heated at ruflux temperature for 16 hours, cooled to room temperature and concentrated in vacuo to give 9-methoxy-11b-methyl-1,2,5,6,11,11b-hexahydro-indolizino[8,7-b]indol-3-one (0.97 g) identified by NMR, HPLC and MS [271.2 m/e (M+H)].
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:23]=1[C:15]1[N:16]([CH2:19][CH:20](O)[CH3:21])[CH:17]=[CH:18][C:14]=1[CH2:13]2.C(N(CC)CC)C.[N-:31]=[N+:32]=[N-:33].[Na+]>ClCCl.C(OCC)C.CN(C)C=O.O>[N:31]([CH:20]([CH3:21])[CH2:19][N:16]1[CH:17]=[CH:18][C:14]2[CH2:13][C:12]3[C:23]([C:15]1=2)=[C:8]([O:7][CH3:6])[CH:9]=[CH:10][CH:11]=3)=[N+:32]=[N-:33]
Reactant: COc1cccc2c1-c1c(ccn1CC(C)O)C2
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1-c1c(ccn1CC(C)N=[N+]=[N-])C2
Yield: 56.1 %

Procedure:
0.7 ml of methanesulfonyl chloride was added dropwise while stirring to a solution, cooled to 0°, of 1.1 g of (RS)-1-(8-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol and 2.5 ml of triethylamine in 25 ml of dichloromethane and the mixture was stirred at this temperature for an additional 1.5 hours. The reaction mixture was subsequently diluted with 200 ml of diethyl ether, washed twice with 70 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 140 ml of diethyl ether. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The brown oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 526 mg of sodium azide and the reaction mixture was heated to 60° while stirring for 29 hours. After cooling, the solution was poured into 140 ml of water and extracted twice with 140 ml of diethyl ether each time. The combined organic phases were washed once with 140 ml of water and once with 140 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (toluene). 0.68 g (56%) of (RS)-1-(2-azido-propyl)-8-methoxy-1,4-dihydro-indeno[1,2-b]-pyrrole was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:12][C:13]1[CH:25]=[CH:24][C:16]([O:17][CH:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=1>>[CH3:22][O:21][C:19](=[O:20])[CH:18]([O:17][C:16]1[CH:24]=[CH:25][C:13]([O:12][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:14][CH:15]=1)[CH3:23]
Reactant: Clc1ccc2ccccc2n1
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Product: COC(=O)C(C)Oc1ccc(Oc2ccc3ccccc3n2)cc1

Procedure:
Methyl-2-[4-(2-quinolinyloxy)phenoxy]propionate (24) was prepared from 2-chloroquinoline and methyl 2-(4-hydroxyphenoxy)propionate following essentially the same procedure as that described in Example 1. The compound had a melting point of 95°-100° C.