Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:37])([CH3:36])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])[CH3:4].FC(F)(F)C(O)=O.C(N)CN>ClCCl>[OH:1][C:2]([CH3:36])([CH3:37])[C@H:3]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=4)[N:19]([CH3:27])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])[CH3:4]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(C)(C)O
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(C)(C)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 58.3 %

Procedure:
In a round-bottomed flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1,2-dimethyl-propyl)-amide (121 mg, 0.22 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.7 ml, 9.0 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The residue was redissolved in dichloromethane (1 ml) and ethylenediamine (0.9 ml, 13.3 mmol) was added. The solution was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resultant suspension was filtered, rinsed with hot water and ethyl acetate then dried under high vacuum to provide 53 mg (58%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-2-hydroxy-1,2-dimethyl-propyl)-amide as an off-white powder. MS: (M+H)+=413; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 12.83 (br. s., 1H), 9.14 (s, 1H), 8.75 (d, J=8.7 Hz, 1H), 8.42 (s, 1H), 8.16 (d, J=9.4 Hz, 1H), 7.95 (d, J=1.1 Hz, 1H), 7.36 (dd, J=8.7, 1.1 Hz, 1H), 4.78 (s, 1H), 4.17 (s, 3H), 4.03-4.16 (m, 1H), 1.22-1.28 (m, 6H), 1.16 (s, 3H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.Cl.Cl.[N:12]1[C:21]2[C:16](=[CH:17][C:18]([C:22]3([C:25]4[N:29]5[CH:30]=[C:31]([C:34]6[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=6)[CH:32]=[N:33][C:28]5=[N:27][CH:26]=4)[CH2:24][CH2:23]3)=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[CH:43]1([NH2:47])[CH2:46][CH2:45][CH2:44]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O.CO>[CH:43]1([NH:47][C:38](=[O:39])[C:37]2[CH:36]=[CH:35][C:34]([C:31]3[CH:32]=[N:33][C:28]4[N:29]([C:25]([C:22]5([C:18]6[CH:17]=[C:16]7[C:21](=[CH:20][CH:19]=6)[N:12]=[CH:13][CH:14]=[CH:15]7)[CH2:24][CH2:23]5)=[CH:26][N:27]=4)[CH:30]=3)=[CH:42][CH:41]=2)[CH2:46][CH2:45][CH2:44]1
Reactant: NC1CCC1
Reactant: O=C(O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CCC1)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N,N-Diisopropylethylamine (30.0 μL, 0.172 mmol) was added to a mixture of 4-[3-(1-quinolin-6-ylcyclopropyl)imidazo[1,2-a]pyrimidin-6-yl]benzoic acid dihydrochloride (18.5 mg, 0.0386 mmol), cyclobutanamine (4.12 mg, 0.0579 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (20.5 mg, 0.0463 mmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at RT for 3 h, and diluted with methanol (0.8 mL). The resulting solution was purified by RP-HPLC (pH 10) to give the desired product. LCMS: (M+H)=460.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH:11]([F:13])[F:12])=[CH:4][CH:3]=1.O[C:15]1[CH2:19][O:18][C:17](=[S:20])[CH:16]=1>C(O)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:10][CH:11]([F:13])[F:12])[C:15]2[CH2:19][O:18][C:17](=[S:20])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: FC(F)CNCc1ccc(Cl)nc1
Reactant: OC1=CC(=S)OC1
Solvent: CC(=O)O
Product: FC(F)CN(Cc1ccc(Cl)nc1)C1=CC(=S)OC1
Temperature: 25 °C
Reaction time: 336 h
Yield: 29.1 %

Procedure:
105 mg (0.506 mmol) of N-[(6-chloropyridin-3-yl)methyl]-2,2-difluoroethanamine (which can be prepared according to: WO 2007/115644 A1, WO 2008/009360 A2) were added to 20 mg (0.169 mMol) of 4-hydroxyfuran-2(5H)-thione (known from: R. Labruère et al., Synthesis 4163-4166, 2006) in 0.5 ml of acetic acid, and the mixture was stirred at room temperature for 14 days. Concentration under reduced pressure and purification of the residue by preparative HPLC (RP18, CH3CN—H2O) gave 15 mg (yield: 28.8% of theory) of 4-{[(6-chloropyridin-3-yl)methyl](2,2-difluoroethyl)amino}furan-2(5H)-thione.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([N:12]2[C@@H:19]3[C@@H:14]([CH2:15][CH2:16][NH:17][CH2:18]3)[CH2:13]2)[CH:3]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:36][C:37]1[CH:38]=[CH:39][C:40]([N:46]2[N:50]=[CH:49][CH:48]=[N:47]2)=[C:41]([CH:45]=1)[C:42](O)=[O:43].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[F:36][C:37]1[CH:38]=[CH:39][C:40]([N:46]2[N:50]=[CH:49][CH:48]=[N:47]2)=[C:41]([C:42]([N:17]2[CH2:16][CH2:15][C@@H:14]3[C@@H:19]([N:12]([C:4]4[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[N:5]=4)[CH2:13]3)[CH2:18]2)=[O:43])[CH:45]=1
Reactant: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(C(F)(F)F)n1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)nc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(6-methyl-2-trifluoromethyl-pyrimidin-4-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 9) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C21H19F4N7O, 461.422; m/z found 462.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.09-7.71 (m, 2H), 7.55-6.50 (m, 3H), 6.14 (d, J=81.2, 1H), 4.76-3.62 (m, 6H), 3.50-2.85 (m, 2H), 2.78-1.92 (m, 5H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C(N(CC)CC)C.[CH3:25][C:26]([CH3:28])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:2][C:3]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][N:15]([CH:26]([CH3:28])[CH3:25])[CH2:14][CH2:13]2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: CC(C)=O
Reactant: N#Cc1ccc(OC2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCC(Oc2ccc(C#N)c(Cl)c2)CC1
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
2-Chloro-4-(4-piperidinyloxy)benzonitrile hydrochloride (D30) (1.5 g) was dissolved in DCM (40 ml) and triethylamine (2.29 ml) was added followed by acetone (0.64 g). The mixture was stirred for 5 min and then sodium triacetoxyborohydride (1.94 g) was added and the reaction stirred at rt under argon overnight. The reaction mixture was then washed with saturated potassium carbonate solution (2×40 ml) and brine (40 ml). The organic layer was dried (MgSO4) and evaporated to give the title compound (D31) as a white solid (1.51 g). MS electrospray (+ion) 279 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[S:9][C:8]([CH3:16])([CH3:15])[CH2:7][C:6]2=[O:17])#[CH:2].I[C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>CCN(CC)CC.C1COCC1.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.[Cu]I>[CH3:16][C:8]1([CH3:15])[CH2:7][C:6](=[O:17])[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([C:1]#[C:2][C:19]3[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=3)[CH:4]=2)[S:9]1
Reactant: C#Cc1cc2c(cc1OC)SC(C)(C)CC2=O
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2cc3c(cc2OC)SC(C)(C)CC3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A solution of 6-ethynyl-7-methoxy-2,2-dimethylthiochroman-4-one (Compound 208, 217.0 mg, 0.88 mmol) and ethyl 4-iodobenzoate (245.0 mg, 0.89 mmol) in 10.0 mL Et3N and 2 mL THF was purged with argon for 15 minutes. To this solution was added bis(triphenylphosphine)-palladium(II) chloride (154.0 mg, 0.22 mmol) and copper(I) iodide (42.0 mg, 0.22 mmol). After sparging for an additional 10 minutes with argon, the solution was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and filtered through a pad of Celite using an EtOAc wash. Concentration of the filtrate under reduced pressure, followed by column chromatography (5 to 10% EtOAc/hexanes) of the residual solid afforded 320.0 mg (92%) of the title compound as an orange solid. 1H NMR (300 MHz, CDCQ3)δ: 8.29 (1H, s), 8.03 (2H, d, J=8.4 Hz), 7.60 (2H, d, J=8.4 Hz), 6.70 (1H, s), 4.40 (2H, q, J=7.1 Hz), 3.96 (3H, s), 2.86 (2H, s), 1.50 (6H, s), 1.41 (3H, t, J=7.1 Hz).
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.Cl[CH2:39][C:40]([NH:42][CH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH:43]1([NH:42][CH2:40][CH2:39][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[CH:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)NC1CCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCNC3CCCCC3)cc2)c1
Yield: 6.1 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N-cyclohexylacetamide (17 mg) according to an analogous synthetic method to Example 567 and purified by LC-MS, the title compound (0.8 mg) was obtained.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.ClCl.N#N>C(O)(=O)C>[ClH:1].[Cl:1][C:5]1[CH:6]=[C:7]([CH2:8][NH2:9])[CH:10]=[CH:11][C:4]=1[O:3][CH3:2]
Reactant: COc1ccc(CN)cc1
Agent: Cl
Agent: ClCl
Agent: N#N
Solvent: CC(=O)O
Product: COc1ccc(CN)cc1Cl
Yield: 144.2 %

Procedure:
Chlorine gas was bubbled into 400 mL glacial acetic acid with stirring until the weight gained equaled 7% of the starting acetic acid. In a 2 L round bottom flask, 4-methoxybenzylamine hydrogen chloride (32.0 g, 0.18 mol) was suspended in 400 mL glacial acetic acid with vigorous stirring. The chlorine solution (1.5 eq Cl2) was added in rapid drops in 30 min at room temperature. The resulted suspension was stirred for another 20 min before N2 was bubbled in to remove Cl2 and HCl into a 6 N NaOH trap. The acetic acid was evaporated under reduced pressure to 100 mL. To this white slurry, diethyl ether (300 mL) was used to loosen the solid which was then filtered. The solid was resuspended with 50 mL acetic acid followed by the addition of 50 mL diethyl ether and filtration. This process was repeated twice. The white solid was transferred to a 1 L Erhlenmeyer flask and suspended in 400 mL THF. This suspension was heated to boiling for 10 min before filtration. The undissolved solid was filtered, and twice resuspended in boiling THF (100 mL) with filtration to afford the title compound (27.0 g, 71%) as a white solid. This material contained <2% starting material and <2% dichlorinated material.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19]>O>[CH:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)COc1ccccc1C=O
Temperature: 65 °C
Reaction time: 24 h

Procedure:
2. Approximately 509 g of the starting compound, salicylaldehyde (1) was introduced into a 4-liter Erlenmeyer flask with powdered potassium carbonate (569 g), dimethylformnamide (1,000 ml), and methyl chloroacetate (478 g) and mechanically stirred at 65° C. for about 24 hours. The stirring was stopped and the reaction mixture cooled to 25° C. The mixture was poured into cold water (0° C.) while stirring vigorously. An oil separated that suddenly solidified. Stirring was continued for 30 minutes and the solid isolated by filtration. The product was washed with water (2×1,000 ml) and pressed dry. The product can also be dried in vacuo at 25° C. A small sample (approx. 2 g) was purified by distillation. The boiling range of the pure product is 124-128° C. at 2 mm Hg and has a melting temperature range of about 50.2-50.6° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-])=O.Cl>[Fe].CO>[CH3:1][NH:2][C:3]1[C:4]([NH2:11])=[CH:5][C:6]([CH3:10])=[C:7]([CH3:9])[CH:8]=1
Reactant: CNc1cc(C)c(C)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CNc1cc(C)c(C)cc1N
Yield: 42 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-28 by using N1,4,5-trimethyl-2-nitroaniline (0.350 g, 1.9 mmol), methanol (20 mL), Iron powder (1.75 g, 9.75 mmol), conc. HCl (5 mL) to afford 0.120 g of desired product.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][CH:5]=1.C([Li])CCC.[Si:18]([O:35][C:36]1[N:41]=[CH:40][CH:39]=[CH:38][N:37]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1.CCOCC.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][C:7]([C:39]2[CH:40]=[N:41][C:36]([O:35][Si:18]([C:31]([CH3:34])([CH3:33])[CH3:32])([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:37][CH:38]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)[Si](Oc1ncccn1)(c1ccccc1)c1ccccc1
Reactant: COC(OC)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(OC)c1ccc(-c2cnc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
To a cooled (−78° C.) solution of 4-bromo-benzaldehyde dimethyl ketal (2.31 g 10 mmol) in THF (30 mL) is added, dropwise, n-butyl lithium (4.4 mL, 2.5 M in hexanes). On complete addition, the reaction mixture is stirred for 5 min then ZnCl2 solution (20 mL, 0.5M in THF) is added. The cold bath is removed and stirring continued for 5 min. then a solution comprising of 5-bromo-(2-[t-butyldiphenylsilyloxy]-pyrimidine (4.13 g, 10 mmol) and (Ph3P)4Pd (1.1 g, 1 mmol) in THF (20 mL) is added. This mixture is warmewd to 60° C. and stirred at this temperature for 2 h. The resulting solution is cooled to room temperature, diluted with ether, washed, sequentially, with 5% aqueous ammonia solution, water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 10% ethyl acetate, 10% dichloromethane in hexanes) to give 2.28 g of the title compound as an oil. 1H NMR (CDCl3) δ 1.18 (s, 9H), 3.35 (s, 6H), 5.44 (s, 1H), 7.38 (m, 6H), 7.44 (d, J=8 Hz, 2H), 7.53 (d, J=8 Hz, 2H), 7.8 (m, 4H), 8.59 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][O:15][C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)=[CH:10][CH:11]=2)[C:6]([CH3:32])([CH3:31])[CH2:5][CH2:4]1)[CH3:2].O.[OH-].[Li+]>C1COCC1.O.CCOCC>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:14][O:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=3)=[CH:10][CH:11]=2)[C:6]([CH3:31])([CH3:32])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCCCCC(COc1ccc(C(=O)OC)cc1)c1ccc2c(c1)C(C)(C)CCN2CC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCC(COc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCN2CC
Temperature: 40 °C
Reaction time: 6 h
Yield: 49.3 %

Procedure:
1 g of (RS)-2-(N-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-heptanol dissolved in 20 ml THF were treated with 950 mg of triphenylphosphine, 550 mg of methyl 4-hydroxybenzoate and 0.57 ml of diethyl azodicarboxylate. The reaction mixture was heated to reflux for 6 hours. The mixture was diluted with 100 ml of ether and washed with two portions of 25 ml of water and one portion of 25 ml of sat. aq. sodium chloride solution. The organic phase was dried over MgSO4. The solvents were removed in vacuo and the resulting yellow oil was purified by flash chromatography (SiO2, 3% ethyl acetate/hexanes), giving 670 mg (RS)-methyl 4-[2-(N-ethyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-6-yl)-heptyloxy]-benzoate as a pale yellow oil. The ester (670 mg), dissolved in 5 ml THF/5 ml H2O/5 ml methanol, was treated with 260 mg of lithium hydroxide hydrate. The mixture was stirred at 40° C. for 6 hours. The mixture was diluted with 5 ml water and acidified to pH 2 with 1N hydrochloric. The resulting suspension was taken in 20 ml ether and the phases were separated. The aqueous phase was extracted with three portions of 10 ml ether. The combined extracts were dried over MgSO4. The solvent was removed in vacuo and the crude product was purified by preparative tlc (10% methanol/methylene chloride), yielding 320 mg of a pale yellow oil. 1H NMR (CDCl3): 8.01 (d, J=9.0 HZ, 2H), 6.98 (d, J=2.1 Hz, 1H), 6.95-6.85 (m, 3H), 6.52 (d, J=8.4 Hz, 1H), 4.64 (quint, J=5.8 Hz, 1H), 3.32 (q, J=7.1 Hz, 2H), 3.25-3.15 (m, 2H), 2.88 (dd, J=14.1, 5.9 Hz, 1H), 2.78 (dd, J=14.1, 5.9 Hz, 1H), 1.80-1.65 (m, 4H), 1.55-1.25 (m, 6H), 1.24 (s, 3H), 1.18 (s, 3H), 1.11 (t, J=7.1 Hz, 3H), 0.86 (t, J=6.7 Hz, 3H).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH2:4].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[F:27])N>>[F:27][C:26]1[CH:25]=[CH:24][C:22]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])=[CH:21][C:20]=1[C:19]([F:18])([F:28])[F:29]
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Reactant: CS(=O)(=O)NCCNc1nonc1C(N)=NO
Product: CS(=O)(=O)NCCNc1nonc1C(=NO)Nc1ccc(F)c(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure of Example 17 step E, using N′-hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide and 3-trifluoromethyl-4-fluoroaniline [Aldrich, product #217778] as the starting materials. LCMS for C13H15F4N6O4S (M+H)+: m/z=427.0. 1H NMR (400 MHz, DMSO-d6): δ 11.60 (s, 1H), 9.07 (s, 1H), 7.30 (t, J=10.1 Hz, 1H), 7.18 (t, J=6.0 Hz, 1H), 7.13 (dd, J=6.0, 2.7 Hz, 1H), 7.03 (m, 1H), 6.27 (t, J=6.3 Hz, 1H), 3.32 (m, 2H), 3.13 (q, J=6.0 Hz, 2H), 2.89 (s, 3H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[C:5]=2[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][CH:16]=2)=[CH:3][CH:2]=1.[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35].C(N(CC)CC)C>ClCCCl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34]([N:11]1[CH2:12][CH2:13][C:8]2[NH:7][C:6]3[N:1]=[CH:2][CH:3]=[C:4]([NH:14][C:15]4[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:29])[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][CH:20]=4)[C:5]=3[C:9]=2[CH2:10]1)=[O:35]
Reactant: O=C(Nc1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1)c1ccccc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(Nc1ccc(Nc2ccnc3[nH]c4c(c23)CN(C(=O)c2cccc(Cl)c2)CC4)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
N-[4-(6,7,8,9-Tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-ylamino)-phenyl]-benzamide (40 mg, 0.1 mmol), 3-chlorobenzoyl chloride (22 mg, 0.13 mmol), and triethylamine (0.04 mL, 0.31 mmol) were dissolved in 1,2-dichloroethane (2.0 mL), and stirred overnight at room temperature. The reaction mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with CH2Cl2/MeOH (9/1, v/v) to provide 12 (26 mg, 48% yield) as a brown solid. LC-MS (M+H=522, obsd.=522).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[CH3:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:12][C:13]1[N:14]=[CH:15][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[CH3:11])[CH:17]=1
Reactant: Cc1c[nH]cn1
Reactant: Cc1cc([N+](=O)[O-])ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2C)cn1
Yield: 48.7 %

Procedure:
A mixture of 2-chloro-5-nitro-toluene (2.0 g, 12 mmol), of 4-methylimidazole (1.0 g, 12 mmol) and of cesium carbonate (5.7 g, 17.5 mmol) in acetonitrile (20 mL) was refluxed overnight. The reaction mixture was cooled, quenched by addition of water and extracted with ethyl acetate. The solvent was removed under reduced pressure and the crude material was purified by column chromatography on silica gel using ethyl acetate as eluent to yield the title compound (1.27 g, 50%) as a slightly brownish solid. MS ISP (m/e): 218.3 (100) [(M+H)+].
Reaction SMILES: S(Cl)(Cl)=O.[OH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[OH:15])[C:9]([OH:11])=[O:10].[CH3:19]O>>[OH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([N+:16]([O-:18])=[O:17])[C:14]=1[OH:15])[C:9]([O:11][CH3:19])=[O:10]
Reactant: O=C(O)c1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Yield: 71.4 %

Procedure:
Thionyl chloride (6.07 mL, 83 mmol) was added drop wise to a stirred solution of 3,4-dihydroxy-5-nitrobenzoic acid (14.4 g, 72.3 mmol) in MeOH (70 mL) at room temperature for 1 h. The reaction mixture was refluxed for 3 h and concentrated. The residue was recrystallized from water and vacuum-dried to afford the desired ester (11.0 g, 51.6 mmol, 71.4% yield).
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:13][CH2:14][C:15]#[N:16]>>[C:14]([CH2:15][NH:16][C:1](=[O:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])#[N:13]
Reactant: N#CCN
Reactant: CCCCCCCCCC(=O)O
Product: CCCCCCCCCC(=O)NCC#N

Procedure:
General procedure F was used to couple 0.1 g (0.58 mmols) of decanoic acid and 0.065 g of amino acetonitrile. The title product was purified with flash chromatography using a solvent system of ethyl acetate and hexanes (2:3) to yield 0.104 g (0.38 mmols). 1H NMR (500 MHz, CDCl3) δ 6.09 (s, 1H), 4.18 (d, J=5.8, 2H), 2.35-2.14 (m, 2H), 1.78-1.55 (m, 2H), 1.27 (d, J=17.2, 12H), 0.87 (t, J=6.9, 3H). 13C NMR (126 MHz, CDCl3) δ 173.15, 116.12, 77.26, 77.01, 76.76, 36.06, 31.82, 29.38, 29.27, 29.23, 29.16, 27.34, 25.28, 22.63, 14.09.