Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15].ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl.CO>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N+:11]([O-:26])[CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15]
Reactant: Cc1ccc(-c2cncc(C(=O)O)c2)c(F)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(-c2cc(C(=O)O)c[n+]([O-])c2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To a solution of 5-(2-fluoro-4-methylphenyl)nicotinic acid (0.15 g, 0.43 mmol) in dichloromethane (5 mL) and methanol (3 mL) was added 3-chloroperbenzoic acid (70%; 0.16 g, 0.65 mmol). The mixture was stirred at ambient temperature. After 18 h, additional 3-chloroperbenzoic acid (70%; 0.19 g, 0.86 mmol) was added. The mixture was continued to stir at ambient temperature. After 24 h, additional 3-chloroperbenzoic acid (70%; 0.19 g, 0.86 mmol) was added. After 18 h, the mixture was concentrated. Purification by reverse chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (70 mg). MS 248.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:17][C:18]1[CH:39]=[CH:38][C:21]([O:22][C:23]2[CH:24]=[CH:25][C:26]3[N:27]([CH:29]=[C:30]([NH:32][C:33]([CH:35]4[CH2:37][CH2:36]4)=[O:34])[N:31]=3)[CH:28]=2)=[C:20]([F:40])[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:35]1([C:33]([NH:32][C:30]2[N:31]=[C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]4[CH:38]=[CH:39][C:18]([NH:17][C:7]([C:5]5[C:4](=[O:10])[N:3]([C:11]6[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=6)[N:2]([CH3:1])[CH:6]=5)=[O:9])=[CH:19][C:20]=4[F:40])=[CH:28][N:27]3[CH:29]=2)=[O:34])[CH2:36][CH2:37]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1ccccc1
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: CN(C)C=O
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccccc1
Yield: 14.4 %

Procedure:
Using 1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (220 mg, 0.99 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (220 mg, 0.66 mmol), HATU (380 mg, 0.99 mmol), diisopropylethylamine (260 mg, 2.0 mmol) and N,N-dimethylformamide (6 mL) as starting materials and in the same manner as in Example 35, the title compound (50 mg, 15%) was obtained as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=2)=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.Cl>C(OCC)C>[CH3:32][O:31][C:25]1[CH:24]=[C:23]([C:19]2[CH:20]=[C:21]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:22]3)[CH:28]=[CH:27][C:26]=1[O:29][CH3:30]
Reactant: COc1ccc(-c2ccc3[nH]c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3c2)cc1OC
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(-c2ccc3[nH]c(C4CCNCC4)cc3c2)cc1OC
Reaction time: 2 h

Procedure:
A 50 mL round bottom flask was charged with 4-[5-(3,4-dimethoxy-phenyl)-1H-indol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.15 mmol), dichloromethane (5.8 mL), and 1M hydrochloric acid in diethyl ether (5.8 mL) and the resulting mixture stirred for 2 h. The resulting mixture was then concentrated in vacuo, the residue triturated with diethyl ether, and then placed under high vacuum to yield 5-(3,4-dimethoxyphenyl)-2-(piperidin-4-yl)-1H-indole. 1H NMR (300 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.29-7.37 (m, 2H), 7.09-7.22 (m, 2H), 6.99 (d, J=8.2 Hz, 1H), 6.22 (s, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 3.67-3.74 (m, 1H), 3.02-3.15 (m, 4H), 2.50-2.61 (m, 2H), and 1.81-2.01 (m, 2H); MS (ES+) 337 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([C:15]#[C:16][C:17]3[CH:22]=[C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[CH:19][N:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:31])=[CH:4][N:3]=1>CO.O1CCCC1.[Pd]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][C:17]3[CH:22]=[C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH:20]=[CH:19][N:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:31])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(C#Cc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccnc(CCc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Yield: 88.2 %

Procedure:
To a mixture of tert-butyl [2-({3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}ethynyl)pyridin-4-yl]carbamate (740 mg, 1.6 mmol) in methanol (15 mL) and tetrahydrofuran (15 mL) was added 10% palladium on carbon (148 mg, 0.139 mmol). The resultant mixture was hydrogenated at 55 psi for 20 hours. The crude mixture was filtered and concentrated to give the desired product as a light yellow solid (0.65 g, 87%). LCMS for C22H24Cl2N5O2 (M+H)+: m/z=460.0, 462.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1[N+](=O)[O-]
Agent: [Ni]
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N

Procedure:
Prepared from (4′-fluoro-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example B12) by catalytic hydrogenation with Raney-Nickel according to the general procedure G (method a). Obtained as a light yellow solid (3.40 g). MS (ISP) 303 [(M+H)+].
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:12]=[CH:11][N:10]=[CH:9][C:5]2=[N:6][C:7]=1[Cl:8].[F:13][C:14]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:15]=1[CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:7]1[N:6]=[C:5]2[CH:9]=[N:10][CH:11]=[CH:12][C:4]2=[N:3][C:2]=1[N:20]1[CH2:19][CH2:18][N:17]([CH2:16][C:15]2[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:14]=2[F:13])[CH2:22][CH2:21]1
Reactant: Fc1ccc(CN2CCNCC2)c(F)c1
Reactant: Clc1nc2ccncc2nc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(CN2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a mixture of 2,3-dichloropyrido[3,4-b]pyrazine (8 g, 40.0 mmol) and 1-(2,4-difluorobenzyl)piperazine (8.49 g, 40.0 mmol) in DCM (100 mL) was added triethylamine (16.72 mL, 120 mmol) at room temperature. Then the mixture was stirred at room temperature for 0.5 h. The reaction mixture was diluted with 30 mL of DCM, washed with brine twice, dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography, eluting with a gradient of 50:1 to 5:1 PE:EtOAc to give the title compound (12 g, 80%). ESI-MS m/z [M+H]+ 376.0.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:6]([C:11]2[CH:12]=[C:13]([Cl:19])[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=2)[C:7](=[O:10])[C:8]=1O)(=O)[CH3:2].Cl.[CH:28]([NH:31][NH2:32])([CH3:30])[CH3:29]>CCOC(C)=O>[Cl:19][C:13]1[C:14](=[O:18])[N:15]([CH3:17])[CH:16]=[C:11]([N:6]2[CH:5]([C:20]3[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=3)[C:4]3[C:1]([CH3:2])=[N:32][N:31]([CH:28]([CH3:30])[CH3:29])[C:8]=3[C:7]2=[O:10])[CH:12]=1
Reactant: CC(C)NN
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(Cl)c(=O)n(C)c2)C1c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nn(C(C)C)c2c1C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described in Example 58 using 5-(3-acetyl-2-(4-chlorophenyl)-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-3-chloro-1-methyl-pyridin-2(1H)-one (Step 58.1) and isopropylhydrazine hydrochloride. tR: 4.69 min (HPLC 1); tR: 1.09 min (LC-MS 2); ESI-MS: 431/433 [M+H]+ (LC-MS 2); Rf=0.55 (EtOAc); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.45-1.57 (m, 6H) 1.93 (s, 3H) 3.44 (s, 3H) 4.67-4.79 (m, 1H) 6.11 (s, 1H) 7.28 (d, J=8.2 Hz, 2H) 7.40 (d, J=8.2 Hz, 2H) 7.91 (d, J=2.0 Hz, 1H) 7.95 (d, J=2.4 Hz, 1H).
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[O:43][C:44]3[CH:54]=[C:53]([N:55]([CH3:60])[S:56]([CH3:59])(=[O:58])=[O:57])[C:52](B4OC(C)(C)C(C)(C)O4)=[CH:51][C:45]=3[C:46]=2[C:47]([NH:49][CH3:50])=[O:48])=[CH:38][CH:37]=1.[CH2:70]([O:77][C:78]1[C:79]([C:85]([O:87][CH3:88])=[O:86])=[N:80][C:81](Br)=[CH:82][CH:83]=1)[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:70]([O:77][C:78]1[C:79]([C:85]([O:87][CH3:88])=[O:86])=[N:80][C:81]([C:52]2[C:53]([N:55]([CH3:60])[S:56]([CH3:59])(=[O:58])=[O:57])=[CH:54][C:44]3[O:43][C:42]([C:39]4[CH:38]=[CH:37][C:36]([F:35])=[CH:41][CH:40]=4)=[C:46]([C:47](=[O:48])[NH:49][CH3:50])[C:45]=3[CH:51]=2)=[CH:82][CH:83]=1)[C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COC(=O)c1nc(Br)ccc1OCc1ccccc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc(OCc4ccccc4)c(C(=O)OC)n3)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.4 %

Procedure:
Pd2(dba)3 (45 mg, 0.05 mmol) and X-phos (48 mg, 0.1 mmol) were added to a mixture of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (500 mg, 1 mmol), methyl 3-(benzyloxy)-6-bromopicolinate (350 mg, 1.1 mmol) and K3PO4.3H2O (798 mg, 3 mmol) in 1,4-dioxane/H2O (5 mL/0.5 mL) under N2. The mixture was stirred at 80° C. for 8 h, and after being filtered through celite, the filtrate was concentrated in vacuo, diluted with water and extracted with EtOAc. The residue was purified by column chromatography (DCM:EtOAc=40:1 to 10:1) to obtain methyl 3-(benzyloxy)-6-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)picolinate (540 mg, yield: 88%). 1H-NMR (CDCl3, 400 MHz) δ 7.88˜8.04 (m, 3H), 7.70 (d, J=8.8 Hz, 1H), 7.62 (s, 1H), 7.45˜7.56 (m, 3H), 7.41 (t, J=7.2 Hz, 2H), 7.32˜7.38 (m, 1H), 7.20 (t, J=8.4 Hz, 2H), 5.90 (d, J=4.0 Hz, 1H), 5.27 (s, 2H), 3.97 (s, 3H), 3.22 (s, 3H), 2.98 (d, J=4.8 Hz, 3H), 2.72 (s, 3H). MS (M+H)+: 618.
Reaction SMILES: [Li]CCCC.[S:6]1[CH:10]=[CH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]1=2.[Sn:15](Cl)([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:24]([Sn:15]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:20][CH2:21][CH2:22][CH3:23])[C:10]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH:9]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccc2sccc2c1
Agent: [Li]CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cc2ccccc2s1

Procedure:
2.5 M of n-BuLi (3.1 mL/hexane, 7.67 mmol) was added to benzo[b]thiophene (1.05 g, 7.67 mmol/THF (20 mL)) and reacted at 0° C. for 1 hour under a dry and anaerobic operation condition to form a solution. SnBu3Cl (2.38 mL, 8.44 mmol) was then added to the solution and reacted at 0° C. for 30 minutes. After returning to room temperature, the solution was continuously reacted for 8 hours. After the reaction was completed, the solution was extracted by ether (30 mL) and deionized water (50 mL). An organic phase was collected. After removal of ether by a rotary concentrator, the organic phase was purified by reduced-pressure distillation to form a transparent pale yellow oily product (23, 1.76 g, 54%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21]([OH:23])=O)=[CH:15][CH:16]=2)[NH:11][N:10]=1.Cl.[CH:29]([O:32][NH2:33])([CH3:31])[CH3:30].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:29]([O:32][NH:33][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1)([CH3:31])[CH3:30]
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: CC(C)ON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)ONC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 50.1 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), O-isopropyl-hydroxylamine hydrochloride (18.7 mg, 0.17 mmol), triethylamine(58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 17.4 mg (50%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.23 (1H, s), 8.69 (H, d, J=2.1), 8.03 (4H, m), 7.50 (5H, m), 7.23 (1H, s), 7.04 (1H, d, J=6.7 Hz), 6.92 (1H, m), 5.98 (1H, m), 4.13 (1H, m), 1.29 (6H, d, J=8.1). ESIMS (M+H+): 414.1.
Reaction SMILES: C(C1NC=CN=1)(=S)N.[CH2:9]1[NH:14][C:12](=[O:13])[NH:11][CH2:10]1.[CH2:15]([N:22]=[C:23]=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([N:11]1[CH2:10][CH2:9][NH:14][C:12]1=[O:13])=[S:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: S=C=NCc1ccccc1
Reactant: O=C1NCCN1
Agent: NC(=S)c1ncc[nH]1
Product: O=C1NCCN1C(=S)NCc1ccccc1
Reaction time: 6 h

Procedure:
The starting thiocarbamoylimidazole required for the above reaction is made as follows: 86g ethyleneurea and 149G benzylisothiocyanate are treated together with stirring for 6 hrs. at 150°. Upon cooling, a solid mass is obtained, which is triturated with ether and then with hot alcohol and filtered. Recrystallization from chloroform-methanol gives 1-(benzylthiocarbamoyl)-2-oxo-tetrahydroimidazole.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5](O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].[CH:32]1[CH:37]=[CH:36][C:35]([CH2:38][SH:39])=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([S:39][CH2:38][C:35]1[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCCCCCN(CCc1ccc(CC(O)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Reactant: SCc1ccccc1
Product: CCCCCCCN(CCc1ccc(CC(SCc2ccccc2)C(=O)OCC)cc1)C(=O)OC(C)(C)C

Procedure:
Synthesized from 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester using a procedure analogous to that used for Example 50 and substituting benzylthiol as the nucleophile to give an approximate 1:1 mixture of ethyl and methyl ester as a clear film (58 mg, 95%).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH2:25])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:26]1[CH:31]=[CH:30][N:29]=[CH:28][C:27]=1[C:32](Cl)=[O:33]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([NH:25][C:32]([C:27]5[CH:28]=[N:29][CH:30]=[CH:31][N:26]=5)=[O:33])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[N:12][CH:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1cncc(-n2cnc3cc(N)ccc32)n1)c1ccccc1
Reactant: O=C(Cl)c1cnccn1
Product: C[C@H](Nc1cncc(-n2cnc3cc(NC(=O)c4cnccn4)ccc32)n1)c1ccccc1
Yield: 55 %

Procedure:
In a procedure analogous to example 32, reaction of 1-(6-{[(1S)-1-phenylethyl]amino}pyrazin-2-yl)-1H-benzimidazol-5-amine (33 mg, 0.10 mmol) and pyrazine-2-carbonyl chloride (0.11 mmol) (prepared by reacting pyrazine-2-carboxylic acid with oxalyl chloride in dicloromethane at room temperature) furnished the product (24 mg, 55%) after chromatography.
Reaction SMILES: Cl[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[CH3:22])[C:3]([O:5][CH3:6])=[O:4].[N:23]([O-:25])=[O:24].[Na+].C1(C=C(O)C=C(O)C=1)O.O>CN(C)C=O>[CH3:22][C:16]1[CH:17]=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[O:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH:2]([N+:23]([O-:25])=[O:24])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)c1ccccc1COc1cc(C)ccc1C
Reactant: O=N[O-]
Agent: Oc1cc(O)cc(O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(c1ccccc1COc1cc(C)ccc1C)[N+](=O)[O-]
Yield: 22.1 %

Procedure:
A solution of methyl 2-chloro-2-[2-(2,5-dimethylphenoxymethyl)phenyl]acetate (0.35 g, 1.1 mmol), sodium nitrite (0.13 g, 1.9 mmol) and phloroglucinol (0.145 g, 1.1 mol) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 6 hours. Water was added to the mixture. The resulting mixture was extracted with ether, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/methylene chloride=1/1) to give the desired compound methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-nitroacetate (0.08 g, 22%) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:17])[CH:14]=[CH:15][CH3:16])=[CH:5][CH:4]=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[CH3:1][O:2][C:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]([C:13](=[O:17])[CH2:14][CH:15]([CH3:16])[N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:5][CH:4]=1
Reactant: CC=CC(=O)c1ccc(OC)c2c1CCCC2
Reactant: C1CCNC1
Solvent: CCO
Product: COc1ccc(C(=O)CC(C)N2CCCC2)c2c1CCCC2
Yield: 58.8 %

Procedure:
A solution of 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-2-butene-1-one (3.0 g) and pyrrolidine (1.85 g) in ethanol (100 ml) was stirred for 3 hours at room temperature. The mixture was evaporated in vacuo to give the residue. The residue was partitioned into water and ethyl ether The ethyl ether was washed with water. The organic layer was extracted with 2N hydrochloric acid. The aqueous layer was neutralized with ammonia water and then extracted with ethyl ether. The ethyl ether was dried over anhydrous magnesium sulfate and then filtered. The filtrate was evaporated in vacuo to give 1-(4-methoxy-5,6,7,8-tetrahydro-1-naphthyl)-3-methyl-3-pyrrolidino-1-propanone (2.31 g, Yield: 53.6%) as an oil.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([N:17]2[CH2:34][CH2:33][C:20]3[N:21]([CH2:28][C:29]([O:31]C)=[O:30])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:19]=3[CH2:18]2)=[O:16])=[O:8])[CH2:5][CH2:4]1)#[N:2].[I-].[Li+]>N1C=CC=CC=1>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[C:15]([N:17]2[CH2:34][CH2:33][C:20]3[N:21]([CH2:28][C:29]([OH:31])=[O:30])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:19]=3[CH2:18]2)=[O:16])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: COC(=O)Cn1c2c(c3ccccc31)CN(C(=O)[C@@H]1CCCC[C@H]1C(=O)NC1(C#N)CC1)CC2
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: N#CC1(NC(=O)[C@@H]2CCCC[C@H]2C(=O)N2CCc3c(c4ccccc4n3CC(=O)O)C2)CC1
Temperature: 150 °C

Procedure:
(1R,2R)-N-(1-cyanocyclopropyl)-2-[(5-methoxycarbonylmethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide (150 mg, 0.32 mmol) and lithium iodide (520 mg, 3.89 mmol) were suspended in pyridine (5 mL) in a capped microwave vessel. This was heated in a microwave at 150° C. for one hour (absorbance: N). Pyridine was removed in vacuo and the residue azeotroped once with toluene. It was taken up in 50% brine (20 mL), acidified with acetic acid and partitioned with ethyl acetate (2×80 mL). Combined organics were dried (magnesium sulphate), concentrated in vacuo, azeotroped once with toluene and adsorbed onto silica for purification by flash chromatography (0-20% methanol/DCM). This gave (1R,2R)-N-(1-cyanocyclopropyl)-2-[(5-hydroxycarbonylmethyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide as a pale yellow solid (84.0 mg, 59%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].[Cl:15][C:16]1[N:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1>CC#N.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>[Cl:15][C:16]1[N:21]=[C:20]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: Clc1nccc(-c2cccs2)n1
Temperature: 25 °C

Procedure:
A solution of 2.0 g (15.6 mmol) of 2-thiopheneboronic acid in 80 mL of a 5% (w/v) Na2CO3 aqueous solution was added drop wise to a refluxing solution of 4.7 g (31 mmol) of 2,4-dichloropyrimidine and 0.55 g (0.78 mmol) of bis(triphenylphosphine)palladium(II) chloride in 80 mL of MeCN. The reaction solution was heated at reflux for 6 h, then cooled to rt, the organic solvent removed in vacuo, and the resulting purple solid filtered and washed with water. The crude product was purified by flash chromatography eluting with a linear gradient of neat hexane to neat EtOAc to deliver the title compound. MS (M+H)+ 197.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[O:25])[C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: O=Cc1cc(Cl)cc(C(=O)O)c1O
Temperature: 100 °C

Procedure:
A mixture of 102 g of 5-chloro-2-hydroxybenzoic acid, 166 g of hexamethylenetetramine and 600 ml of trifluoroacetic acid is heated at 100° C. overnight. 2.95 liters of water and 1.48 liters of 10% hydrochloric acid are added to the mixture and said mixture is heated at the same temperature for 15 minutes. After cooling, the resultant crystals are collected by filtration to give 96.9 g of 5-chloro-3-formyl-2-hydroxybenzoic acid.