Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:37])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:49]([O:56][C:57](=[O:60])[CH2:58]Br)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>O>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:37])[C@@H:13]([NH:23][C:24]([C:26]2[CH:35]=[C:34]([O:36][CH2:58][C:57]([O:56][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:60])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(O)c3ccccc3n2)CC1
Reactant: O=C(CBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(OCC(=O)OCc3ccccc3)c3ccccc3n2)CC1
Reaction time: 2 h

Procedure:
To a solution of 6.2 g of 4-{(S)-4-tert-Butoxycarbonyl-2-[(4-hydroxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester 80 ml of DMF, 4.3 g of cesium carbonate and 2.5 g of Bromo-acetic acid benzyl ester was added and stirred for 2 h. Then, the reaction mixture was diluted with water and extracted with ethyl acetate (3×150 ml). The combined organic phases were dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 4.4 g.
Reaction SMILES: [OH:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][O:11][N:12]=[C:13]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=1)[CH3:14].N1C=CC=CC=1.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:29]([O:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:10][O:11][N:12]=[C:13]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[N:16]=1)[CH3:14])(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1cccc(CON=C(C)c2cc(C)cc(C)n2)c1O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cccc(CON=C(C)c2cc(C)cc(C)n2)c1OC(=O)C(C)(C)C
Reaction time: 5 h

Procedure:
0.2 g (0.67 mmol) of 1-(4,6-dimethyl-2-pyridinyl)ethanone O-[(2-hydroxy-3-methoxyphenyl)methyl]oxime was dissolved in 5 ml of methylene chloride. The resultant solution was added with 0.11 g (1.34 mmol) of pyridine, 5 mg of 4-(N,N-dimethylamino)pyridine and 0.12 g (1.00 mmol) of pivalic chloride. The obtained mixture was heated to reach the reflux temperature and stirred for 5 hours to complete a reaction. The reacted solution was washed with water and saturated saline solution in sequence, and the resultant nonaqueous layer was dried with anhydrous magnesium sulfate. The mixture was then condensed under reduced pressure to obtain a crude product. The crude product was then purified by means of silica gel column chromatography (eluate; hexane:ethyl acetate=9:1 (v/v)) to obtain the target compound in an amount of 0.2 g.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:22][C:23]([F:36])([F:35])[C:24]1[S:28][C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[N:26][CH:25]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:32]2[CH2:33][CH2:34][N:29]([C:27]3[S:28][C:24]([C:23]([F:36])([F:22])[F:35])=[CH:25][N:26]=3)[CH2:30][CH2:31]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1)C(F)(F)F
Yield: 57 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A16) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in pentane to yield the title compound as an off-white crystalline solid (yield 57%). MS (m/e): 532.0 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:20][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCC1
Reactant: COc1cccc2cc(C(=O)O)oc12
Product: COc1cccc2cc(C(=O)NC3CCCC3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-Methoxybenzofuran-2-carboxylic acid, and cyclopentylamine to give N-cyclopentyl-7-methoxybenzofuran-2-carboxamide (Compound 299a). Successively, it was formylated to give N-cyclopentyl-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 299b), then compound 299b was reacted with methylamine hydrochloride to give compound 299 as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2].Cl[CH2:19]CN1CCCC1.Cl.[H-].[Na+]>CN(C=O)C>[N:3]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:19])=[O:14])=[CH:16][CH:17]=2)[CH2:4][CH2:5][CH2:2][CH2:1]1
Reactant: ClCCN1CCCC1
Reactant: CCN(CC)CCOc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCN2CCCC2)cc1

Procedure:
Compound 23-2 (2 g, 11.8 mmol) and chloroethylpyrrolidine·HCl (Aldrich) (1.8 g, 11.8 mmol) were treated with NaH (0.94 g, 23.6 mmol) in DMF (30 mL) as described for 27-1 to give 27-6 as a clear oil. Rf (10% MeOH/CHCl3 saturated with NH3) 0.4
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CN(C=O)C>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:22][C:21](=[O:23])[N:10]([C:11]3[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=3[F:18])[C:6]=2[N:5]=[C:4]([S:19][CH3:20])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CSc1nc(Cl)c(C=O)c(Nc2c(F)cccc2F)n1
Solvent: CN(C)C=O
Product: CSc1nc(Cl)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Yield: 51 %

Procedure:
A solution of 4-chloro-6-[(2,6-difluorophenyl)amino]-2-(methylthio)-5-pyrimidinecarbaldehyde (200 mg, 0.63 mmol) in DMF (4.0 mL) and acetic anhydride (2.0 mL) was heated with a microwave (160° C.) for about 30 minutes. The resultant mixture was then concentrated. Flash chromatography (EtOAc/Hexane, 1:5) provided the title compound (109 mg, 51%): LC-MS m/z 340 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:51]([O:55][C:56]([NH:58][CH2:59][C:60](O)=[O:61])=[O:57])([CH3:54])([CH3:53])[CH3:52]>O1CCCC1>[C:51]([O:55][C:56]([NH:58][CH2:59][C:60]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:61])=[O:57])([CH3:54])([CH3:53])[CH3:52]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Solvent: C1CCOC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)CNC(=O)OC(C)(C)C
Yield: 61 %

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-oleamide and N-tert-butyloxycarbonyl-glycine. Yield 61%. [α]D 32 +1.2° (c=0.86, tetrahydrofuran).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[NH:19][C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:30])([CH3:29])[CH2:13][C:14]([NH:16][CH:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]#[N:46])=[CH:37][CH:38]=2)[C:18]1=[O:28])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(CC(=O)NC1CCc2ccccc2NC1=O)NC(=O)OCc1ccccc1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Product: CC(C)(CC(=O)NC1CCc2ccccc2N(Cc2ccc(-c3ccccc3C#N)cc2)C1=O)NC(=O)OCc1ccccc1

Procedure:
Prepared from 3-benzyloxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3-yl]-butanamide (Example 51, Step A) and 4'-bromomethyl-1,1'-biphenyl-2-nitrile (Example 69, Step C) by the procedure described in Example 1, Step K. FAB-MS: calculated for C37H36N4O4 600; found 601 (M+H,100%).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21](O)[N:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(OC([N:31]1[CH2:35][C@H:34]([C:36]#[N:37])[CH2:33][C@H:32]1[C:38](=[O:40])[NH2:39])=O)(C)(C)C.CO>C(Cl)Cl>[C:36]([C@H:34]1[CH2:35][N:31]([C:21]2[N:20]=[CH:19][C:16]3[C:17]4[N:11]([CH:10]=[C:9]([C:8]5[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=[CH:6][N:7]=5)[N:18]=4)[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)[C@H:32]([C:38]([NH2:39])=[O:40])[CH2:33]1)#[N:37]
Reactant: CC(C)(C)OC(=O)N1C[C@H](C#N)C[C@H]1C(N)=O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(O)cc1OCC2
Solvent: CO
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(N3C[C@H](C#N)C[C@H]3C(N)=O)cc1OCC2
Yield: 72 %

Procedure:
Following the procedure for Example 339, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulen-8-ol from Example 93 and (2S,4R)-2-carbamoyl-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester were reacted. The crude product was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 430 as an off-white solid (41 mg, 72%). LCMS: RT=2.85 min, [M+H]+=435. 1H NMR 400 MHz (DMSO-d6) δ: 9.08 (1H, s), 7.88 (1H, d, J=0.63 Hz), 7.85 (1H, s), 7.56 (1H, br, s), 7.11 (1H, br, s), 6.04 (1H, s), 5.94-5.93 (1H, m), 4.51 (4H, d, J=15.42 Hz), 4.44 (1H, d, J=5.97 Hz), 3.92 (1H, dd, J=10.05, 7.55 Hz), 3.72 (1H, t, J=8.49 Hz), 3.61-3.53 (1H, m), 2.55-2.54 (1H, m), 2.35 (1H, ddd, J=12.61, 6.87, 3.63 Hz), 1.47 (6H, dd, J=6.59, 3.21 Hz)
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:15][CH2:14][C:13]2([C:17]3[CH:18]=[C:19]([NH:23][S:28]([CH2:27][CH2:26][O:25][CH3:24])(=[O:30])=[O:29])[CH:20]=[CH:21][CH:22]=3)[CH2:16][CH:9]1[CH2:10][CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Reactant: COCCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COCCS(=O)(=O)Nc1cccc(C23CCCC(C2)N(Cc2ccccc2)CC3)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-Benzyl-2-aza-bicyclo[3.3.1]non-5-yl)-phenylamine (2.71 g, 8.84 mmol) stirred in pyridine (25 ml) at 0° C. was charged with 2-methoxy-ethanesulfonyl chloride (2.1 g, 13.26 mmol) dropwise causing a color change from yellow to bright orange. The reaction was allowed to warm to room temperature gradually and stirred 18 h. The reaction mixture was diluted with toluene and concentrated in vacuo. The residue was dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3 solution (100 mL). The aqueous layer was extracted with CH2Cl2 (2×50 ml) and the organic layer was concentrated to an oil. This was dissolved in EtOAc which caused an oil to separate. The EtOAc layer was separated and washed with saturated aqueous NaHCO3 solution (100 mL). The aqueous layer was extracted with EtOAc (2×50 ml) and the combined organic layer was washed with saturated aqueous NaCl solution (50 ml), dried over Na2SO4, filtered and concentrated to a crude orange liquid (3.77 g, ˜100%). (TLC 75% EtOAc/hexanes Rf 0.48);
Reaction SMILES: [OH-].[Na+].C(O)(=O)C.[CH3:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:39])[CH:25]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36](=[NH:38])[NH2:37])[CH:31]=2)[CH2:26][CH2:27][CH3:28])=[CH:19][CH:18]=1)(=[O:10])=[O:9].Cl[C:41]([O:43][CH3:44])=[O:42]>ClCCl>[CH3:44][O:43][C:41](=[O:42])[NH:38][C:36](=[NH:37])[C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([O:29][CH:25]([C:24](=[O:39])[NH:23][C:20]2[CH:19]=[CH:18][C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:8]([CH3:7])(=[O:9])=[O:10])=[CH:22][CH:21]=2)[CH2:26][CH2:27][CH3:28])[CH:31]=1
Reactant: COC(=O)Cl
Reactant: CCCC(Oc1cccc(C(=N)N)c1)C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCC(Oc1cccc(C(=N)NC(=O)OC)c1)C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1

Procedure:
1 N NaOH is added up to a pH of 9 to a solution of 500 mg (1.07 mmol) of 2-(3-carbamimidoylphenoxy) pentanoic acid (2′-methanesulfonylbiphenyl-4-yl)amide acetate (3) in 40 ml of dichloromethane kept at 5° C. 0.108 ml (1.40 mmol) of methyl chloroformate is then added. During the following hour, the pH is kept at a value of 9 by addition of further 1 N NaOH. The organic phase is then separated off, washed with water, dried over sodium sulfate and evaporated. A colourless solid is obtained; FAB 524
Reaction SMILES: [F:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:4][C:5]2[C:10]([C:11]=1I)=[CH:9][CH:8]=[CH:7][CH:6]=2.CC(C)([O-])C.[Na+].[NH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.O>[F:1][C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[N:4][C:5]2[C:10]([C:11]=1[NH:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1ccncc1
Reactant: Fc1ccccc1-c1nc2ccccc2c(I)c1F
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccccc1-c1nc2ccccc2c(Nc2ccncc2)c1F
Temperature: 110 °C
Yield: 72 %

Procedure:
To a solution of 3-fluoro-2-(2-fluoro-phenyl)-4-iodo-quinoline (from Step F, 0.02 g, 0.05 mmol) in toluene (1 mL) was added S-BINAP (0.007 g, 0.01 mmol), sodium tert-butoxide (0.105 g, 1 mmol) and 4-aminopyridine (0.015 g, 0.05 mmol). The resulting mixture was degassed for 5 min., after which tris(dibenzylidineacetone) dipalladium(0) (0.0025 g, 0.0025 mmol) was added. The reaction mixture was heated to 110° C. for 48 h. and then diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in rotary evaporator. The residue was purified using HPLC over a gradient of acetonitrile and water containing 0.1% trifluoroacetic acid to yield the desired compound (0.012 g, 65%). MS (ES) 334.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.[C:17]1([NH:23][C:24]([C:26]2[O:27][C:28](Br)=[CH:29][CH:30]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[CH3:1][C:2]1[N:3]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:28]3[O:27][C:26]([C:24]([NH:23][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:25])=[CH:30][CH:29]=3)[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: O=C(Nc1ccccc1)c1ccc(Br)o1
Solvent: O
Product: Cc1cccc(C#CC=C2CCN(c3ccc(C(=O)Nc4ccccc4)o3)CC2)n1
Yield: 19.3 %

Procedure:
A well homogenised mixture of the Compound of Example 3 (100 mg, 0.47 mmol) and N-phenyl-5-bromofuran-2-carboxamide (125 mg, 0.47 mmol) was stirred at 120° C. for 8 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with brine, dried on Na2SO4 and evaporated to dryness in vacuo to afford a residue, which was purified by flash chromatography eluting with Petroleum Ether-EtOAc 7:3, affording the title product (36 mg) as a brown solid.
Reaction SMILES: Cl.O[CH2:3][C:4]1[N:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]2=[N:6][CH:5]=1.[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)([O-:15])=[O:14].[OH-].[Na+]>C(O)(=O)C.Cl>[N+:13]([C:16]1[CH:21]=[CH:20][C:19]([S:22][CH2:3][C:4]2[N:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]3=[N:6][CH:5]=2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: OCc1cnc2ccccn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(SCc2cnc3ccccn23)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 69.9 %

Procedure:
A mixture of 3-hydroxymethylimidazo[1,2-a]pyridine hydrochloride (0.50 g) and 4-nitrothiophenol (0.42 g) in acetic acid (10 ml) and concentrated hydrochloric acid (10 ml) was stirred for 5 hours at 100° C. The reaction solution was cooled to 0° C., 8N aqueous solution of sodium hydroxide was added dropwise to adjust pH to 8. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether, to give 3-(4-nitrophenylthiomethyl) imidazo[1,2-a]pyridine (0.54 g) as yellow crystals.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][C:11]([CH3:18])([CH3:17])[S:12][C:13]([CH3:16])([CH3:15])[CH:14]=2)O1.Br[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1>>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([C:9]2[CH2:10][C:11]([CH3:18])([CH3:17])[S:12][C:13]([CH3:15])([CH3:16])[CH:14]=2)=[N:22][CH:23]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)S1
Product: CC1(C)C=C(c2ccc([N+](=O)[O-])cn2)CC(C)(C)S1

Procedure:
The title compound was prepared from 4,4,5,5-tetramethyl-2-(2,2,6,6-tetramethyl-3,6-dihydro-2H-thiopyran-4-yl)-[1,3,2]dioxaborolane (as prepared in the previous step) and 2-bromo-5-nitro-pyridine according to the procedure of Example 15, step (c). Mass spectrum (ESI, m/z): Calcd. for C14H18N2O2S, 279.1 (M+H), found 279.2.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1.[C:23](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH3:23])=[CH:6][C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])=[C:4]([F:22])[CH:3]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Br)cc2F)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: COc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Br

Procedure:
using 3-(4-bromo-2-fluoro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione with potassium carbonate and methyl iodide in acetonitrile there is obtained 3-(4-bromo-2-fluoro-5-methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione. m.p. 154° C.;
Reaction SMILES: CS[C:3](=[N:12][CH2:13][Si](C)(C)C)[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([CH3:11])[CH:5]=1.[Cl:18][C:19]1[CH:20]=[C:21]([C:26](=[CH2:31])[C:27]([F:30])([F:29])[F:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]2[CH2:31][C:26]([C:21]3[CH:22]=[C:23]([Cl:25])[CH:24]=[C:19]([Cl:18])[CH:20]=3)([C:27]([F:28])([F:30])[F:29])[CH2:13][N:12]=2)=[CH:5][C:6]=1[CH3:11]
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(Br)c(C)c1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1Br
Temperature: 25 °C
Yield: 75 %

Procedure:
To a solution of 4-bromo-3-methyl-N-trimethylsilanylmethyl-thiobenzimidic acid methyl ester (4.40 g, 13.3 mmol) in dry THF (60 mL) was added 2-(3,5-dichlorophenyl)-1,1,1-trifluoro-2-propene (4.35 g, 16.25 mmol) at −7° C. A solution of tetrabutyl ammoniumfluoride (5.32 mL, 1 M in THF, 5.33 mmol) was added at this temperature and the mixture was allowed to warm to room temperature over night. All volatiles were removed in vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (4.50 g, 75%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[CH2:16]=[O:17]>C(N(CC)CC)C.CC(C)=O>[F:15][C:2]([F:1])([F:14])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:16][OH:17])[CH:6]=1)=[O:4]
Reactant: O=C(c1c[nH]c2ccccc12)C(F)(F)F
Reactant: C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(c1cn(CO)c2ccccc12)C(F)(F)F
Temperature: 130 °C
Reaction time: 2 h
Yield: 97.9 %

Procedure:
The mixture of 4.80 g of 3-(trifluoroacetyl)-1H-indole, 1.35 g of paraformaldehyde and 0.10 g of triethylamine was stirred at 130° C. for 2 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered, and then the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and hexane was added to the residue, as a result, a crystal was formed. The crystal was collected to obtain 5.36 g of 3-(trifluoroacetyl)-1H-indole-1-ylmethanol.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]1=[O:12].[CH2:14](O)[CH:15]([CH3:17])[CH3:16].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][C:5]1[C:10](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=1[O:12][CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)CCC1C(=O)CCCC1=O
Reactant: CC(C)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(C)CCC1=C(OCC(C)C)CCCC1=O
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A solution of ketoenol 7 (68.0 g, 374 mmol), isobutanol (83.0 g, 1120 mmol), and p-toluenesulfonic acid (1.0 g, 1.2 mmol) in anhydrous benzene (730 mL) was refluxed overnight with azeotropic removal of water (Dean-Stark trap). The reaction mixture was cooled to room temperature, washed with saturated sodium bicarbonate solution (3×250 mL), brine (2×250 mL) and concentrated to give 88.0 g (98.9%) of 8 as a thick oil, which solidified upon cooling. MS m/z 239 (M+1); 1H NMR (300 MHz, CDCl3) δ 3.75 (d, 2H), 2.5 (t, 2H), 2.3-2.2 (m, 4H), 2.0-1.9 (m, 3H), 1.6-1.5 (m, 1H), 1.2-1.1 (m, 2H), 1.0 (d, 6H), 0.9 (d, 6H); 13C NMR (CDCl3) δ 198.4, 171.5, 120.1, 73.9, 38.0, 36.5, 28.8, 28.4, 25.5, 22.6, 21.1, 20.1, 19.1.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:12][C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Br:12])[CH:14]=1)=[O:21]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1cccc(Br)c1
Product: O=C(Nc1cccc(Br)c1)Nc1ccc([N+](=O)[O-])cc1O
Yield: 84.1 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-bromo phenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 3-bromo phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.96 g, 87%). EI-MS m/z 350 (M-H)-