Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[I:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[CH2:16][C:17]([OH:19])=O.[CH3:20][NH:21][CH3:22].C(Cl)Cl>C1(C)C=CC=CC=1.CN(C=O)C>[CH3:20][N:21]([CH3:22])[C:17](=[O:19])[CH2:16][C:9]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:8]=1[I:7]
Reactant: CNC
Reactant: COc1ccc(I)c(CC(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(I)c(CC(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A 16.7 g (0.19 mole) sample of oxalyl chloride was added dropwise at 0° C. to a solution of 50.0 g (0.17 mole) of 2-iodo-5-methoxybenzeneacetic acid in 310 ml dry toluene and 31.7 ml of DMF. The mixture was allowed to warm to room temperature and stir for 16 hours. The solution was cooled to 0° C. and dimethylamine gas was admitted until the mixture was strongly basic. The mixture was allowed to warm to room temperature and stir for three hours and methylene chloride was added. The organic layer was washed with water, dilute hydrochloric acid, and sodium hydroxide. The organic layer was dried with MgSO4 and evaporated in vacuo to give 54.2 g of N,N-dimethyl-2-iodo-5-methoxybenzeneacetamide, mp 86°-89° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2].[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][Br:28]>>[Br-:28].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]=2[Cl:24])[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH3:22])[CH:17]=2)[C:12]1=[O:23])(=[O:3])[CH3:2]
Reactant: Clc1ccccc1CBr
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1C(C)=O)C2=O
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3ccccc3Cl)cc1C(C)=O)C2=O
Product: [Br-]

Procedure:
The title compound 126 is prepared according to the procedure reported in Example 38.1 with compound 103 (62 mg, 0.2 mmol) and 2-chlorobenzyl bromide (39 μL, 0.3 mmol) as reactants. White solid. (Yield 72.3 mg, 70%).
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=1[CH3:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[C:21]=3[CH3:27])[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Reactant: Cc1cccc(CBr)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To the mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.4 g, 1.351 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)-2,3-dimethylbenzene (0.323 g, 1.621 mmol) and potassium carbonate (0.560 g, 4.05 mmol). The resulting reaction mixture was stirred at 80° C. for 3 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜90% EtOAc in Hexane) to give the product as solid (0.4 g, 71%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.33 (s, 3H) 2.37 (s, 3H) 2.53 (s, 3H) 2.98-3.14 (m, 4H) 3.66-3.93 (m, 4H) 5.24 (s, 2H) 6.24 (d, J=7.58 Hz, 1H) 6.53 (d, J=2.27 Hz, 1H) 6.89-7.00 (m, 1H) 7.06-7.17 (m, 2H); MS (ES+) m/e 414.1 [M+H]+
Reaction SMILES: N12CCCN=C1CC[CH2:4][CH2:3][CH2:2]2.[Cl:12][C:13]1[CH:14]=[C:15]([CH2:19][CH:20]([OH:39])/[CH:21]=[CH:22]/[C@H:23]2[CH2:28][CH2:27][CH2:26][C:25](=O)[N:24]2[CH2:30][CH2:31][CH2:32][CH2:33][O:34][CH2:35][C:36]([OH:38])=[O:37])[CH:16]=[CH:17][CH:18]=1.IC(C)C.CC(C)=[O:46]>>[CH:3]([O:38][C:36](=[O:37])[CH2:35][O:34][CH2:33][CH2:32][CH2:31][CH2:30][N:24]1[CH2:25][CH2:26][CH2:27][C:28](=[O:46])[C@H:23]1/[CH:22]=[CH:21]/[CH:20]([OH:39])[CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[CH:14]=1)([CH3:4])[CH3:2]
Reactant: C1CCC2=NCCCN2CC1
Reactant: CC(C)=O
Reactant: O=C(O)COCCCCN1C(=O)CCC[C@@H]1/C=C/C(O)Cc1cccc(Cl)c1
Solvent: CC(C)I
Product: CC(C)OC(=O)COCCCCN1CCCC(=O)[C@H]1/C=C/C(O)Cc1cccc(Cl)c1
Reaction time: 0.08 h
Yield: 50 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 16 μL, 0.11 mmol) was added to a solution of (4-{(R)-2-[(E)-4-(3-chlorophenyl)-3-hydroxy-but-1-enyl]-6-oxo -piperidin-1-yl)-butoxy)-acetic acid (29 mg, 0.071 mmol) in acetone (0.5 mL). After 5 min, 2-iodopropane (35 μL, 0.35 mmol) was added. After 17 h, the reaction mixture was concentrated in vacuo, EtOAc (15 mL) was added and the resultant mixture was washed with 0.5 M aqueous HCl (5 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL). The organic phase was then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2 →5% MeOH/CH2Cl2, gradient) afforded 16 mg (50%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]1[C:18]1[CH:19]=[CH:20][C:21]2[C:22]3[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28][CH2:27][C:23]=3[NH:24][C:25]=2[CH:26]=1.[ClH:39]>CO.CCOCC>[ClH:39].[CH2:31]1[C:22]2[C:21]3[CH:20]=[CH:19][C:18]([N:3]4[CH:4]=[CH:5][C:6]([C:8]5[N:9]=[N:10][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:12][CH:13]=5)=[CH:7][C:2]4=[O:1])=[CH:26][C:25]=3[NH:24][C:23]=2[CH2:27][CH2:28][CH2:29][NH:30]1
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]c3cc(-n4ccc(-c5ccc(C(F)(F)F)nn5)cc4=O)ccc3c2C1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=c1cc(-c2ccc(C(F)(F)F)nn2)ccn1-c1ccc2c3c([nH]c2c1)CCCNC3
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
tert-Butyl 8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (54 mg, 0.10 mmol) was treated with 1.25 M HCl in MeOH (9.9 mL), and the resulting solution was stirred at ambient temperature for 18 h. The solution was diluted with Et2O. The resulting solids were collected by filtration, washed with Et2O and dried to yield the title compound (33 mg, 70%) as a yellow powder: mp 310-315° C. decomp.; 1H NMR (500 MHz, DMSO-d6) δ 11.54 (s, 1H), 8.90 (s, 2H), 8.70 (d, J=9.0 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.43 (d, J=1.5 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.16 (dd, J=7.0, 2.0 Hz, 1H), 7.08 (dd, J=8.5, 2.0 Hz, 1H), 4.44 (s, 2H), 3.48-3.46 (m, 2H), 3.05 (t, J=5.5 Hz, 2H), 2.03-2.01 (m, 2H); ESI MS m/z 426 [M+H]+; HPLC (Method A) 97.3% (AUC), tR=12.3 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:45]([N:48]1[CH2:53][CH2:52][CH:51]([NH2:54])[CH2:50][CH2:49]1)([CH3:47])[CH3:46]>C(Cl)Cl>[CH:45]([N:48]1[CH2:53][CH2:52][CH:51]([NH:54][C:8]([C:4]2[NH:5][C:6]([CH3:7])=[C:2]([Br:1])[C:3]=2[CH3:11])=[O:10])[CH2:50][CH2:49]1)([CH3:47])[CH3:46]
Reactant: Cc1[nH]c(C(=O)O)c(C)c1Br
Reactant: CC(C)N1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1[nH]c(C(=O)NC2CCN(C(C)C)CC2)c(C)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.3 %

Procedure:
To 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (570 mg) in DCM (15 mL) was added DIEA (2.11 g), HATU (994 mg) and 1-isopropyl-piperidin-4-ylamine (372 mg). The mixture was stirred for 16 h at RT after which it was concentrated. The residue was purified by preparative HPLC to give 4-bromo-3,5-dimethyl-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide (65 mg) which was directly used in the next step.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:12][CH2:13][C:14]([O:16]C)=[O:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CN(C)C=O.[OH-].[Li+].Cl>CS(C)=O.O>[OH:1][C:2]1[C:3]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)CCc1nc2ccccc2nc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)CCc1nc2ccccc2nc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Methyl 3-(3-hydroxyquinoxaline-2-yl)propanoate (701 mg) was dissolved in dimethylsulfoxide (8 ml), dimethylformamide (8 ml), dimethylformamide (20 ml) and water (10 ml), and then lithium hydroxide (80 mg) was added to the solution, followed by stirring the mixture overnight at room temperature. Then lithium hydroxide (110 mg) was further added and the mixture was stirred for 2 days. To the reaction solution, 1N hydrochloric acid was added and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were combined and washed with brine. The resultant was dried over anhydrous sodium sulfate and then concentrated to obtain 642 mg of 3-(3-hydroxyquinoxaline-2-yl)propanoic acid Yield: 97%.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][N:8]([S:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:23])[CH:19]=3)[CH:14]=2)(=[O:12])=[O:11])[CH2:7][CH2:6][N:5]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[C-:31]#[N:32].[Na+]>CN(C)C=O>[C:27]([O:26][C:24]([N:5]1[CH2:6][CH2:7][N:8]([S:10]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([Cl:23])[CH:19]=3)[CH:14]=2)(=[O:12])=[O:11])[CH2:9][CH:4]1[CH2:3][CH2:2][C:31]#[N:32])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CCBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1CCC#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In N,N-dimethylformamide (20 ml) was dissolved 2-(2-bromoethyl)-1-(tert-butoxycarbonyl)-4-[(6-chloronaphthalen -2-yl)sulfonyl]piperazine (980 mg), followed by the addition of sodium cyanide (102 mg). The resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue and the resulting mixture was washed with water and saturated aqueous NaCl solution, each once. The organic layer thus extracted was dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (842 mg) was obtained as a colorless foam.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH:14]=[CH:18][CH:17]=[CH:16]2)=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2]
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(-n2cccc2)c(O)c1
Yield: 44.9 %

Procedure:
In a manner similar to Example 1, Step A, the reaction of 10.0 g (0.06 mole) of 5-nitro-2-aminophenol with 9.8 g (0.07 mole) of 2,5-dimethoxytetrahydrofuran in 20 ml of glacial acetic acid produced 5.5 g of 5-nitro-2-(1H-pyrrol-1-yl)phenol.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N+:13]([C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([NH:20][NH2:21])=[O:19])([O-:15])=[O:14]>C(O)(=O)C>[N+:13]([C:16]1[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=1[C:18]([NH:20][N:21]=[C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=2)[NH:7][C:6]1=[O:11])=[O:19])([O-:15])=[O:14]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 73 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3dione in acetic acid was added 2-nitrobenzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 159 mg of the title compound (73%) as a yellow solid in 99.2% purity by HPLC (Rt: 5.67, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)C=C.N([C:17]1[CH:22]=CC=C[CH:18]=1)(CC)CC>CCOC(C)=O>[CH2:22]([C:6]1[C:7]([Br:11])=[CH:8][CH:9]=[CH:10][C:5]=1[OH:4])[CH:17]=[CH2:18].[CH2:22]([C:10]1[CH:9]=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[OH:4])[CH:17]=[CH2:18]
Reactant: C=CCOc1cccc(Br)c1
Reactant: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1c(O)cccc1Br
Product: C=CCc1ccc(Br)cc1O
Temperature: 220 °C
Reaction time: 5 h
Yield: 34 %
Yield: 47 %

Procedure:
A mixture of 1-(allyloxy)-3-bromobenzene (3.53 g, 16.6 mmol) and Et2NPh (7.4 mL) was heated in a 220° C. oil bath. After 5 hr, the reaction mixture was cooled to room temperature, diluted with EtOAc (80 mL), and washed with 2N aq HCl (3×20 mL), water (2×20 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Flash chromatography (0%-1 0% EtOAc/hexanes) gave 1.64 g (47%) of the title compound as the late eluting component, and 1.19 g (34%) of 2-allyl-5-bromophenol. 1HNMR (300 MHz, CDCl3) δ 7.17 (dd, J=8.0, 1.1, 1H), 6.97 (t, J=8.0, 1H), 6.77 (dd, J=8.0, 1.0, 1H), 6.04-5.90 (m, 1H), 5.15 (t, J=1.7, 1H), 5.13-5.07 (m, 2H), 3.63 (dt, J=6.0, 1.6, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(O[Cl:15])(C)(C)C>CC(O)=O>[Cl:15][C:3]1[C:2]([OH:1])=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: CC(C)(C)OCl
Reactant: O=Cc1cccc(O)c1
Solvent: CC(=O)O
Product: O=Cc1cccc(O)c1Cl
Yield: 55 %

Procedure:
To a suspension of 3-hydroxybenzaldehyde (20.12 g, 160 mmol) in HOAc (40 mL) was added carefully tBuOCl (20 mL, 176 mmol) with stirring. The reaction became a clear solution and strongly exothermic. It was allowed to cool and stirred for 16 hours, resulting in a white precipitate. The solid was filtered, washed with H2O and dried to give 2-chloro-3-hydroxybenzaldehyde (13.77 g, 55%), GCMS (EI) m/z 156, 158 (M+).
Reaction SMILES: [O:1]=[C:2]1[NH:10]/[C:9](=[N:11]\[NH:12][C:13](=O)[CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:19]=[N:18]2)/[N:8]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:7]2[N:6]=[CH:5][NH:4][C:3]1=2>C1(C)C=CC=CC=1>[CH2:29]([N:8]1[C:7]2[N:6]=[CH:5][NH:4][C:3]=2[C:2](=[O:1])[N:10]2[C:13]([CH2:14][CH2:15][CH2:16][N:17]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:19]=[N:18]3)=[N:12][N:11]=[C:9]12)[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCn1/c(=N/NC(=O)CCCn2cc(-c3ccccc3)cn2)[nH]c(=O)c2[nH]cnc21
Solvent: Cc1ccccc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(CCCn3cc(-c4ccccc4)cn3)nnc12
Temperature: 25 °C
Yield: 66 %

Procedure:
A mixture of N′-[(2E)-6-oxo-3-pentyl-1,3,6,7-tetrahydro-2H-purin-2-ylidene]-4-(4-phenyl-1H-pyrazol-1-yl)butanohydrazide (369 mg, 0.823 mmols) in toluene (20 ml) was refluxed for 2 hours. After cooling to room temperature, the solid formed was filtered, washed with EtOAc/Hexane (1:9) and dried to give the desired product (234 mg, 66% yield) as off pink solid. LCMS calculated for C23H27N8O (M+H): 431.2; found: 431.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[N:9]=[N:8]1.[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].CCN(CC)CC>C1COCC1.C(Cl)Cl>[Cl:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: c1ccc(-n2nnc3c2CCNC3)nc1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(nnn2-c2ccccn2)C1

Procedure:
A solution of 1-(pyridin-2-yl)-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (13 mg, 0.065 mmol) in THF (1 mL) was treated with 2-chloro-3-(trifluoromethyl)benzoyl chloride (19 mg, 0.078 mmol) followed by Et3N (0.013 mL, 0.097 mmol). After 5 min the reaction was diluted with CH2Cl2 and the organic portion washed with NaHCO3. The organic portion was then dried over Na2SO4, concentrated and purified on 4 g SiO2 to yield 20 mg (75%) of: 5-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-1-pyridin-2-yl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine. MS (ESI): mass calcd. for C18H13ClF3N5O, 407.1. m/z found, 408.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.49 (dddd, J=32.1, 4.9, 1.8, 0.8 Hz, 1H), 8.17 (ddt, J=17.3, 8.3, 1.0 Hz, 1H), 7.93 (ddt, J=8.4, 7.5, 1.7 Hz, 1H), 7.79 (ddd, J=6.6, 4.4, 2.2 Hz, 1H), 7.57-7.42 (m, 2H), 7.35 (dddd, J=12.3, 7.5, 4.9, 1.0 Hz, 1H), 5.25-4.96 (m, 1H), 4.35 (dt, J=13.3, 5.4 Hz, 1H), 4.11-3.95 (m, 1H), 3.61-3.53 (m, 1H), 3.51-3.44 (m, 1H), 3.36 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([N:6]1[CH2:11][C:10]2[CH:12]=[C:13]([S:16][CH3:17])[CH:14]=[CH:15][C:9]=2[NH:8][S:7]1(=[O:19])=[O:18])[CH3:5].[H][H].Br[CH2:23][CH2:24][Cl:25]>CN(C=O)C.CCCCCC>[Cl:25][CH2:24][CH2:23][N:8]1[C:9]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][C:10]=2[CH2:11][N:6]([CH:4]([CH3:3])[CH3:5])[S:7]1(=[O:19])=[O:18]
Reactant: ClCCBr
Reactant: [H][H]
Reactant: CSc1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CSc1ccc2c(c1)CN(C(C)C)S(=O)(=O)N2CCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 250 ml 3 necked flask equipped thermometer, pressure equalised dropping funnel, nitrogen bubbler and magnetic stirrer bar was added 60% sodium hydride (1.77 g, 1.062 g, 0.04425 mol,) hexane washed, to dry DMF (75 ml). To this stirred suspension was added dropwise a solution of 3,4-dihydro-3-(1-methylethyl)-6-methylthio-1H-2,1,3-benzothiadiazine-2,2-dioxide (10.0 g, 0.0368 mol) in dry DMF (75 ml) (slight exotherm). The suspension was stirred under nitrogen for 2 hr until hydrogen evolution ceased. 1-Bromo-2-chloroethane (6.33 g, 3.77 ml, 0.04425 mol) was added dropwise and the reaction mixture allowed to stir at room temperature under nitrogen overnight. The reaction mixture was poured onto ice-water (800 ml) with stirring for 1 hr, filtered and washed with water (200 ml) to leave a white solid which was dried in vacuo at 50° C. to give a solid. Mp 74-75° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[C:10]([F:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(Cl)(Cl)=O.C([N:25]([CH2:28][CH3:29])CC)C.[OH2:30]>C1(C)C=CC=CC=1.C(Cl)Cl>[Si:1]([O:8][C:9]1[C:10]([F:18])=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:25][CH2:28][C@H:29]([C:9]1[CH:10]=[CH:11][CH:15]=[CH:16][CH:17]=1)[OH:30])=[O:14])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)O)c1F
Reactant: O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)NC[C@@H](O)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of 3-tert-butyldimethylsilyloxy-2-fluorobenzoic acid (3.3 g, 12 mmol, example 36B) in toluene (30 ml) was added thionyl chloride (1.3 ml, 18 mmol) carefully at ambient temperature. After addition was complete, the reaction mixture was heated at reflux for 40 min, then cooled and concentrated in vacuo. The residual oil was dissolved in CH2Cl2 (20 ml) and added dropwise to a solution of (+)-2-amino-1(S)-phenylethanol (1.7 g, 12 mmol, see A. I. Meyers and J. Slade. J. Org. Chem. 1980, 45, 2785.) and triethylamine (2.0 ml, 15 mmol) in CH2Cl2 (20 ml) cooled to 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred a further 30 min. The mixture was poured into water (100 ml) and extracted with CH2 Cl2 (3×10 ml). The combined organic extracts were washed with saturated aqueous NaHCO3 (100 ml), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (=3:2) to afford title compound (4.6 g, 97%) as a pale yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>CC(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:17]\[C:13]1[NH:12][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccc[nH]1
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: CC(C)O
Product: O=C1Nc2ccc(Br)cc2/C1=C/c1ccc[nH]1
Temperature: 23 °C

Procedure:
A mixture of 5-bromo-1,3-dihydro-2H-indol-2-one (3.10 g, 14.62 mmol) (Starting Material 6) and pyrrole-2-carboxaldehyde (1.46 g, 15.35 mmol) (Aldrich) in 2-propanol (73 mL) was treated with 10-12 drops of piperidne. The reaction mixture was heated at reflux for 20 h and then allowed to cool to 23° C., at which time, the reaction mixture was filtered. The resulting solid was washed well with hexanes, followed by petroleum ether, and then allowed to air dry to provide pure (Z)-5-bromo-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow solid which was used without further purification. (Yield 4.01 g, 95%; mp 267-268° C.).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3].[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C)C(=O)C.C(OCC)(=O)C>[F:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][S:2]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:4])=[O:3]
Reactant: CCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1F
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(S(=O)(=O)Nc2ccccc2F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To ethyl 3-(chlorosulfonyl)benzoate (1 g, 4.02 mmol) in N,N-dimethylacetamide (13.4 mL) was added 2-fluoroaniline (1.551 mL, 16.08 mmol) dropwise over 1 minute at room temperature. The mixture was stirred at room temperature for 1 hour and then diluted with ethyl acetate (35 mL). The organic solution was washed with 1 N HCl (2×13 mL) and saturated NaCl (13 mL). The organic layer was concentrated, ethanol (38 mL) was added to the reside, and the mixture was concentrated to give ethyl 3-{[(2-fluorophenyl)amino]sulfonyl}benzoate.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)=[O:19]>N1C=CC=CC=1>[CH3:15][C:16]1[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=1[C:18]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:6]2[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[O:26])=[CH:23][CH:22]=1)=[O:19]
Reactant: c1ccc2c(c1)CNc1ccccc1-2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
To a solution of 0.181 g (1.0 mmol) of 5,6-dihydrophenanthridine in 2 ml of warm pyridine is added 0.273 g (1.0 mmol) of 4-[(2-methylbenzoyl)amino]benzoyl chloride. The mixture is stirred overnight at room temperature, 1.2 ml of 2NHCl added. The solid which separates is filtered and washed with water. The solid is dissolved in dichloromethane and the solution washed with 2M sodium carbonate. The organic layer is concentrated and the residue chromatographed twice on silica gel with ethyl acetate-hexane as solvent to give 79 mg of crystals, m.p. 190°-194° C. Mass Spec-FAB 419 (M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)(C)(C)C.CO.[ClH:21]>>[ClH:21].[NH2:7][C:8]1([C:13]([CH:15]2[CH2:17][CH2:16]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)C2CC2)CCCC1
Agent: Cl
Solvent: CO
Product: NC1(C(=O)C2CC2)CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
In a 10 mL round-bottomed flask (1-cyclopropanecarbonyl-cyclopentyl)-carbamic acid tert-butyl ester (61 mg, 0.24 mmol) was dissolved in 1.0 M HCl solution in MeOH (1.5 mL, 1.5 mmol). The reaction mixture was stirred at room temperature overnight then concentrated under reduced pressure to afford 45 mg (98%) of (1-amino-cyclopentyl)-cyclopropyl-methanone hydrochloride as a white solid.