Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14][O:15]C3C=CC=CC=3F)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[CH:42][C:41]([CH:44](Br)[CH3:45])=[CH:40][CH:39]=1>>[CH3:35][O:36][C:37](=[O:47])[C:38]1[CH:43]=[CH:42][C:41]([CH:44]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH3:45])=[CH:40][CH:39]=1
Reactant: COC(=O)c1ccc(C(C)Br)cc1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COc3ccccc3F)C3CCCCC3)c2cc1F
Product: COC(=O)c1ccc(C(C)OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1

Procedure:
The title compound was prepared in analogy to Example 34, from 1-(2-bromo-1-cyclohexyl-ethyl)-2-(4-chloro-phenyl)-5,6-difluoro-1H-benzoimidazole (Example 34, intermediate) and 4-(1-bromo-ethyl)-benzoic acid methyl ester (CAS RN: 16281-97-3). The residue was purified by preparative HPLC chromatography (phenomenex gemini column) eluting with a gradient of water:acetonitrile (100:0 to 5:95). Light yellow foam (22%). MS (Turbo Spray): m/z=553.3 [M+H].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][CH:17]1[O:21][C:20](=[O:22])[N:19]([CH3:23])[CH2:18]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>C(O)CCC.CC(O)C>[CH3:23][N:19]1[CH2:18][CH:17]([CH2:16][CH2:15][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[O:21][C:20]1=[O:22]
Reactant: CN1CC(CCCl)OC1=O
Reactant: Cc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Solvent: CC(C)O
Product: Cc1ccc(N2CCN(CCC3CN(C)C(=O)O3)CC2)cc1
Yield: 69.2 %

Procedure:
This compound was prepared according to the procedure of Example 2. A mixture of 3.5 g (0.02 mol) of 1-(4-methylphenyl)piperazine, 3.3 g (0.02 mol) of 5-(2-chloroethyl)-3-methyl-2-oxazolidinone, 6.4 g (0.06 mol) of anhydrous sodium carbonate and 0.3 g of potassium iodide in 100 mL of 1-butanol gave 4.2 g (69%) of white solid, mp 96°-97° C. (2-propanol).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:11][C:4]=2[NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:42][S:43][CH2:44]Cl>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH3:42][S:43][CH2:44][N:3]1[C:2](=[O:1])[CH2:7][O:6][C:5]2[N:8]=[C:9]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:34])[CH3:33])[CH2:25][CH2:26][CH2:27]4)=[CH:20][CH:19]=3)[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:11][C:4]1=2
Reactant: CSCCl
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 80 °C
Yield: 44.4 %

Procedure:
In a 15 mL reaction tube was added tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (150 mg, 0.318 mmol), potassium carbonate (132 mg, 0.954 mmol) and chloromethyl methyl sulfide (0.079 mL, 0.954 mmol) in anhydrous N,N-dimethylformamide (2 mL) to give a yellow suspension. The reaction mixture was heated to 80° C. under a nitrogen atmosphere for 2 hours, then allowed to cool to room temperature, diluted with saturated sodium bicarbonate solution (10 mL) and extracted into dichloromethane (3×5 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil. This was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 80:20) to give the desired product as a white solid (75 mg, 44% yield). 1H-NMR (500 MHz, CDCl3) δ 7.43 (1H, s), 7.23-7.35 (7H, m), 7.19-7.23 (2H, m), 5.09 (3H, br s), 4.94 (2H, s), 2.30-2.55 (4H, m), 2.26 (3H, s), 2.00-2.15 (1H, m), 1.75-1.90 (1H, m), 1.10-1.50 (9H, br s). LCMS (Method A) RT=7.42 min, M+H+=532.14.
Reaction SMILES: [F:1][C:2]1[C:3](=O)[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:3]1[C:2]([F:1])=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1ccc2cc(F)c(=O)[nH]c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2cc(F)c(Cl)nc2c1
Reaction time: 1 h
Yield: 35.9 %

Procedure:
A mixture of 3-fluoro-7-methoxyquinolin-2(1H)-one (1.40 g, 7.25 mmol) and POCl3 (13.3 ml, 145 mmol) was stirred at 110 C (bath) for 1 hour. The POCl3 was removed under reduced pressure. Ethyl acetate (30 mL) and saturated sodium bicarbonate (30 mL) were added and stirred for 10 minutes. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (10:1 hexane/ethyl acetate) to give 2-chloro-3-fluoro-7-methoxyquinoline (0.55 g, 2.60 mmol, 36% yield) as white solid.
Reaction SMILES: [C:1](=[O:4])([O-])N.[SiH3]O[SiH3].[CH2:8]([O:11][C:12]([N:14]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:15]1[C:20]([O:22]C)=[O:21])=[O:13])[CH:9]=[CH2:10]>C(Cl)(Cl)Cl>[CH2:8]([O:11][C:12]([N:14]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@:15]1([CH2:1][OH:4])[C:20]([OH:22])=[O:21])=[O:13])[C:9]1[CH:10]=[CH:17][CH:16]=[CH:15][CH:20]=1
Reactant: NC(=O)[O-]
Reactant: C=CCOC(=O)N1C[C@H](O)C[C@H]1C(=O)OC
Agent: [SiH3]O[SiH3]
Solvent: ClC(Cl)Cl
Product: O=C(OCc1ccccc1)N1C[C@H](O)C[C@]1(CO)C(=O)O

Procedure:
Lithium borohydride (1.57 g, 73 mmol) was added portionwise to a solution of (2S,4R)—N-(benzoxycarbonyl)-2-methyoxycarbonyl-4-hydroxyproline (46) (20.17 g, 73 mmol) in THF (350 ml) at 0° C. The reaction mixture was allowed to warm to room temperature and stir overnight. The resulting suspension was cooled to 0° C. and quenched with water (2-3 mL) until effervescence ceased, at which point 2 M HCl (15 mL) was added to dissolve the precipitate. The product was extracted with ethyl acetate (3×150 mL) and the combined organic phases washed with brine (1×100 mL) and then dried (MgSO4). Concentration in vacuo afforded a white gum (18.25 g, 100%). [α]22.3D=−404° (C=0.043, CHCl3). 1H NMR (CDCl3): δ 1.24-1.26 (m, 1H, H1), 1.73-2.08 (m, 1H, H1), 3.40-4.30 (m, 6H, H2, H3, H11, H11a), 5.06 (bs, 1H, OH), 5.09 (s, 2H, H6) 7.25-7.31 (m, 5H, H arom). 13C NMR (CDCl3): δ 36.7 (C1), 55.2 (C3), 58.7 (C2), 65.0 (C11), 67.0 (C6), 68.7 (C11a), 127.0, 127.5 (C arom), 127.8 (C arom), 128.2 (C arom). IR (thin film): ν=3390 (OH), 3065, 3033, 2953 (OH), 1681 (C═O carbamate), 1586, 1538, 1498, 1454, 1192, 1122, 978, 914, 862, 770, 698, 673 cm−1. MS (FAB)′ m/z (relative intensity): 252 (M+., 58), 208 (33), 176 (5), 144 (6), 118 (8), 116 (7), 92 (13), 91 (100). HRMS calcd. for C13H17NO4=251.1158 found 251.1230.
Reaction SMILES: NN.[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-])=O>[Pd].C(O)C>[NH2:3][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc2[nH]ccc2c1
Yield: 81 %

Procedure:
25 mL of hydrazine (98-100%) are added slowly to a mixture of 25.0 g of 5-nitroindole, 1.2 g of 10% palladium on carbon and 200 mL of absolute ethanol. After the addition, the resulting reaction mixture is then taken to reflux for 2 hours. The catalyst is eliminated by filtration and the filtrate is evaporated in order to produce a solid yellow residue. The crystals are washed with 200 ml of water and they are dried under vacuum in order to produce 16.5 g (81%) of 5-aminoindole. Melting point: 131-134° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=2[Cl:18])[C:5]([Cl:8])=[N:6][CH:7]=1.[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[NH:21][NH2:22].CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[CH2:25]([O:24][C:20]([NH:21][N:22]=[C:9]([C:4]1[C:5]([Cl:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:12]=1[Cl:18])=[O:23])[CH3:26]
Reactant: O=C(Cc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl
Reactant: CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)NN=C(Cc1cccc(Cl)c1Cl)c1cc(Br)cnc1Cl

Procedure:
To a solution of 1-(5-bromo-2-chloropyridin-3-yl)-2-(2,3-dichlorophenyl)ethanone (1.14 g, 3.03 mmol) in EtOH (40 mL) was added ethyl carbazate (0.95 g, 9.09 mmol) and TsOH (2 mg). The reaction mixture was heated for 3 hours, followed by evaporated of the volatiles to give ethyl-2-(1-(5-bromo-2-chloropyridin-3-yl)-2-(2,3-dichlorophenyl)ethylidene)hydrazinecarboxylate as a yellow oil, which was used directly in the next step.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:29])[CH2:18][N:19]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:28])([F:27])[F:26])=[N:20]3)[CH2:13][CH2:12]2)[S:9][CH:10]=1)(=[O:5])[CH3:4].[F:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:32]=1[CH:33]=O>CO.O>[F:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:32]=1/[CH:33]=[CH:4]/[C:3]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:12][CH2:13][N:14]([C:17](=[O:29])[CH2:18][N:19]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([F:26])([F:28])[F:27])=[N:20]3)[CH2:15][CH2:16]2)[S:9][CH:10]=1)=[O:5]
Reactant: O=Cc1c(F)cccc1F
Reactant: CC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)/C=C/c3c(F)cccc3F)cs2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, a solution of sodium hydroxide (19 mg) in methanol (0.25 ml) and water (0.05 ml) was added to a solution of 1-[4-(4-acetyl-1,3-thiazol-2-yl)piperidin-1-yl]-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone (190 mg) and 2,6-difluorobenzaldehyde (67 mg) in methanol (0.12 ml). The reaction mixture was stirred at room temperature overnight. After aqueous work-up, the mixture was extracted with ethyl acetate and the extracts were dried with sodium sulphate and concentrated under reduced pressure. The residue was purified chromatographically. This gave (2E)-3-(2,6-difluorophenyl)-1-[2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazol-4-yl]prop-2-en-1-one (160 mg).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:12]=[C:11]([Cl:13])[S:10][C:9]=2[Cl:14])[CH2:5][C:4](=[O:15])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[Cl:14][C:9]1[S:10][C:11]([Cl:13])=[CH:12][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:7][CH:2]=[C:3]([CH3:4])[C:3]=2[C:4](=[O:15])[CH2:5]1
Reactant: NC1=CC(=O)CC(c2cc(Cl)sc2Cl)C1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Reaction time: 2 h
Yield: 148 %

Procedure:
A solution of 5-(2,5-dichlorothiophen-3-yl)cyclohexane-1,3-dione (42.0 g) and ammonium acetate (36.9 g) in ethanol (840 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added water. The crystals were filtered, washed with toluene and dried to give 1-amino-5-(2,5-dichlorothiophen-3-yl)cyclohexen-3-one (40.3 g). To a solution of 1-amino-5-(2,5-dichlorothiophen-3-yl)cyclohexen-3-one (37.0 g) in ethanol (700 ml) and toluene (1400 ml) were added 3-oxobutylaldehydedimethylacetal (46.6 g) and powdery potassium hydroxide (7.7 g), and the mixture was refluxed. To the mixture was added powdery potassium hydroxide (1.6 g) 30 minutes later; powdery potassium hydroxide (1.6 g) and 3-oxobutylaldehydedimethylacetal (3.7 g) 1 hour later; and powdery potassium hydroxide (1.6 g) 1.5 hours later; and then the mixture was stirred at the same temperature for 2 hours. After the mixture was cooled, the solvent was evaporated under reduced pressure and to the residue was added ethyl acetate. The mixture was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, ethyl acetate was evaporated, and the thus obtained oil containing crystals were subjected to silica gel column (EtOAc/hexane) to remove starting materials. The thus obtained crystals were recrystallized from ethyl acetate-hexane to give 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (32.6 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27]([OH:29])=O)[C:23]([CH3:30])=[N:22]1.ClN1C(=O)CCC1=O.[CH:39]1([CH2:42][N:43]2[C:51]3[N:50]=[C:49]([CH2:52][C:53]4[CH:58]=[CH:57][C:56]([NH:59][CH2:60][CH3:61])=[CH:55][CH:54]=4)[NH:48][C:47]=3[C:46](=[O:62])[N:45]([CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=3[F:70])[C:44]2=[O:71])[CH2:41][CH2:40]1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:39]1([CH2:42][N:43]2[C:51]3[N:50]=[C:49]([CH2:52][C:53]4[CH:54]=[CH:55][C:56]([N:59]([CH2:60][CH3:61])[C:27]([C:24]5[C:23]([CH3:30])=[N:22][N:21]([CH3:20])[C:25]=5[CH3:26])=[O:29])=[CH:57][CH:58]=4)[NH:48][C:47]=3[C:46](=[O:62])[N:45]([CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=3[F:70])[C:44]2=[O:71])[CH2:41][CH2:40]1
Reactant: Cc1nn(C)c(C)c1C(=O)O
Reactant: CCNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Agent: CN(C)c1ccncc1
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(C(=O)c1c(C)nn(C)c1C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
A suspension of triphenylphosphine (59.3 mg, 0.226 mmol) and 1,3,5-trimethyl-1H-pyrazole-4-carboxylic acid (SALOR) (26.8 mg, 0.174 mmol) in dichloromethane was cooled to 0° C. and N-chlorosuccinimide added. The mixture was stirred at 0° C. for 0.5 h then ambient temperature for an additional 0.5 h. 3-Cyclopropylmethyl-8-[4-(ethyl-amino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione (93.4 mg, 0.209 mmol) was added followed by triethylamine (30.2 mg, 0.226 mmol) and 4-dimethylaminopyridine (a few crystals). The reaction was left to stir at ambient temperature overnight before washing with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, drying the organic extract (sodium sulfate) and concentrating in vacuo. Purification by chromatography using silica eluted with 5:9 methanol/dichloromethane gave the product as a colorless solid (83.5 mg, 69%). MS, m/z(M+H)=584.2787.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:21][C:22]([F:37])([F:36])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1([OH:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>C(Cl)Cl>[OH:35][C:29]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([F:37])([F:21])[F:36])[CH2:34][CH2:33][N:32]([C:14]([C@@:11]2([CH:17]([CH3:19])[CH3:18])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]2)=[O:16])[CH2:31][CH2:30]1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: OC1(c2ccccc2C(F)(F)F)CCNCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@]1(C(=O)N2CCC(O)(c3ccccc3C(F)(F)F)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 2.5 h

Procedure:
To a solution of (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (150 mg, 0.55 mmol), 4-[2-(trifluoromethyl)phenyl]piperidin-4-ol hydrochloride (170 mg, 0.60 mmol), and triethylamine (0.17 g, 1.6 mmol) in methylene chloride (3 mL) was added (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.31 g, 0.60 mmol). After being stirred for 2.5 h, the reaction was quenched by addition of a saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered, and concentrated. The crude product was carried on to the next step without purification. MS calculated for C26H37F3N2O4:(M+H) 499; found 499.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[C:10]2[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH2:21][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(C)(C)C(=O)N(Br)C1=O.O>CS(C)=O>[CH3:16][O:15][C:13]([C:11]1[C:10]2[C:17](=[O:22])[CH:18]([Br:23])[CH2:19][CH2:20][CH2:21][C:9]=2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:12]=1)=[O:14]
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CCCC2
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
To a solution of 4-Oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole1,3-dicarboxylic acid 3-methyl ester 1-tert-butyl ester(l.1 g, 3.6 mmol) in DMSO(20 mL) is added 1,3-dibromo-5,5-dimethylhydantoin(1.5 g, 5.4 mmol) portion wise with the aid of a cooling bath and the resulting mixture is stirred for 18 h at RT. Water is added and the reaction mixture is extracted with ether . The combined ether layers are washed with saturated brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified by flash chromatography on silica gel (10% EtOAc/Hex to 25% EtOAc/Hex) to yield 915 mg of 5-Bromo-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester as a bright yellow oil (66%). 1H NMR(CDCl3) 1.59 (s, 9H), 1.72-1.84 (m, 1H), 2.12-2.25 (m, 2H), 2.43-2.58 (m, 1H), 3.05-3.14 (m, 1H), 3.40-3.49 (m, 1H), 3.80 (s, 3H), 4.75 (m, 1H), 7.79 (s, 1H)
Reaction SMILES: FC1C=C(F)C=CC=1NC1C=CC(C(C2C=C(N3C=C(CCO)N=N3)C=CC=2C)=O)=C(C)C=1.Br[C:35]1[CH:40]=[CH:39][C:38]([C:41]([C:43]2[CH:48]=[C:47]([N:49]3[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]3)[CH:46]=[CH:45][C:44]=2[CH3:57])=[O:42])=[C:37]([Cl:58])[CH:36]=1.[Cl:59][C:60]1[C:65]([Cl:66])=[CH:64][CH:63]=[CH:62][C:61]=1[NH2:67]>>[Cl:58][C:37]1[CH:36]=[C:35]([NH:67][C:61]2[CH:62]=[CH:63][CH:64]=[C:65]([Cl:66])[C:60]=2[Cl:59])[CH:40]=[CH:39][C:38]=1[C:41]([C:43]1[CH:48]=[C:47]([N:49]2[CH:53]=[C:52]([CH2:54][CH2:55][OH:56])[N:51]=[N:50]2)[CH:46]=[CH:45][C:44]=1[CH3:57])=[O:42]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Br)cc1Cl
Agent: Cc1cc(Nc2ccc(F)cc2F)ccc1C(=O)c1cc(-n2cc(CCO)nn2)ccc1C
Product: Cc1ccc(-n2cc(CCO)nn2)cc1C(=O)c1ccc(Nc2cccc(Cl)c2Cl)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 148, using compound 471 (0.13 mmol) and 2,3-dichloro-phenylamine (0.13 mmol). The crude product was purified by flash chromatography using MeOH/DCM 1:20 as the eluent to afford the title compound. 13C NMR (CDCl3) δ 194.9, 146.4, 140.4, 139.1, 138.5, 135.1, 134.8, 134.0, 133.5, 132.7, 130.0, 127.6, 124.3, 123.2, 122.5, 121.0, 119.9, 118.6, 117.4, 115.2, 61.5, 28.7, 20.1
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:15])[N:3]=1.[I:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1>>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[C:4]([CH3:15])[N:3]=[C:2]([N:20]3[CH:21]=[C:17]([I:16])[N:18]=[CH:19]3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(Cl)n1
Reactant: Ic1c[nH]cn1
Product: Cc1cc(-c2ccc(Cl)cc2)cc(-n2cnc(I)c2)n1

Procedure:
The title compound was prepared 2-chloro-4-(4-chloro-phenyl)-6-methyl-pyridine (example A.27) (2.3 g, 10 mmol) and commercially available 4-iodo-imidazole (2.248 g, 12 mmol) according to the general procedure IVa. Obtained as an off-white solid (2.1 g, 55%). MS (ISP) 396.0 [(M+H)+].
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[CH2:6]([Cl:12])[CH2:7][O:8]CCO.C(OC=C)=C.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:1]([O:3][CH2:4][CH2:5][O:8][CH2:7][CH2:6][Cl:12])=[CH2:2]
Reactant: OCCOCCCl
Reactant: C=COCC
Agent: C=COC=C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C=COCCOCCCl

Procedure:
315 ml (3.3 moles) of ethyl vinyl ether and 12.5 mmoles of mercuric acetate, which rapidly dissolves, are fed into a three-neck flask of 500 ml capacity provided with a reflux condenser and mechanical stirrer and maintained under a nitrogen stream. 0.660 moles of diethylene chlorohydrin are dripped into the solution, the mixture then being heated under reflux until the ratio (gas-chromatographic analysis) of the chlorohydrin to the corresponding vinyl ether remains constant (20 hours). The mixture is then treated with anhydrous potassium carbonate (20 grams), most of the excess ethyl vinyl ether and by-product ethyl alcohol are removed under vacuum and the remaining mixture is filtered through a Gooch crucible. The filtrate is diluted with chloroform and extracted with water, the organic phase being dried with anhydrous sodium sulphate and filtered. After evaporating the solvent, the crude product is purified by preparative HPLC (stationary phase silica gel).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:14])=[C:11]([OH:13])[CH:12]=2)[N:5]=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH:25](O)[CH3:26])[CH2:21][CH2:20]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.O>[C:15]([C:4]1[CH:3]=[C:2]([NH2:1])[N:6]([C:7]2[CH:8]=[CH:9][C:10]([Cl:14])=[C:11]([O:13][CH2:26][CH2:25][N:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)[CH:12]=2)[N:5]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(O)N1CCOCC1
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(O)c2)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(N)n(-c2ccc(Cl)c(OCCN3CCOCC3)c2)n1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirred solution of 5-(5-amino-3-tert-butyl-pyrazol-1-yl)-2-chloro-phenol (WO2007/091152, which is incorporated herein by reference; 200 mg, 0.75 mmol), 2-N morpholino ethanol (137 μL, 1.13 mmol) and Ph3P (394 mg, 1.50 mmol) in THF (7.5 mL) at 0° C. was added DEAD (236 μL, 1.50 mmol). After 1 h, the reaction mixture was diluted with water and extracted with DCM. The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the title compound (228 mg, 80%). LCMS (Method 3): Rt 2.28 min, m/z 379 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]3)[C:7]=2[N:29]=1.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O.CO>C(Cl)Cl.FC(F)(F)C(O)=O.C(Cl)Cl>[NH2:21][CH:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH2:13][N:8]2[C:9](=[O:12])[CH:10]=[N:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:29][C:7]2=3)[CH2:20][CH2:19]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1
Yield: 96.1 %

Procedure:
A solution of 1,1-dimethylethyl (1-{2-[6-(methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]ethyl}-4-piperidinyl)carbamate (470 mg, 1.2 mmol) in DCM/trifluoroacetic acid (10 ml/10 ml) was stirred at rt for 30 minutes then evaporated to dryness. The residue was triturated with ether and then resultant solid dried in vacuo. The solid was dissolved in DCM/MeOH (20 ml/20 ml) and treated with MP-carbonate resin (2.3 mmol of carbonate per gram, 3 g, ca 8 mmol). After 1.5 hours the mixture was filtered, washing alternatively with small volumes of DCM and MeOH. The combined filtrates were evaporated affording a yellow oil (contaminated with particulate material from the resin). This residue was treated with 20% MeOH in DCM (20 ml) filtered and evaporated affording a yellow oil (350 mg, 100%).