Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].C1OC1C.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([Cl:28])=[O:27])=[CH:24][CH:23]=1>C(O)C>[ClH:28].[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:2][C:3]2[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=2)[C:6]([CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[O:7])=[O:27])=[CH:24][CH:23]=1
Reactant: Nc1cccc(C(=O)C2CCNCC2)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: CC1CO1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1cccc(C(=O)C2CCNCC2)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.9 %

Procedure:
4-(3-aminobenzoyl)piperidine HCl (10.87 g (45.15 mmol)) was suspended in absolute ethanol (220 mL) in presence of propylene oxide (3.185 g, 3.84 mL, 54.84 mmol) at room temperature for 15 min. p-fluorobenzoyl chloride (8.93 g, 6.65 mL, 56.44 mmol) was then added dropwise. During the addition, a partial dissolution was observed before the formation of a thick precipitate. The temperature rose from 22° C. to 33° C. during the acylation. The suspension was post-agitated at room temperature for 4 h. Then, the precipitate was filtered, washed with ethanol (22 mL) and diethylether (40 mL). 15.38 g (94%) of 4-[3-(4-fluorobenzamidyl)benzoyl]piperidine HCl were obtained after drying at 50° C. under vacuum for 12 hours.
Reaction SMILES: [C:1]([Cl:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg]Cl>>[CH2:4]1[CH2:5][CH2:6][CH2:7][CH:2]([C:1]([Cl:9])=[O:8])[CH2:3]1
Reactant: O=C(Cl)c1ccccc1
Agent: C[Mg]Cl
Product: O=C(Cl)C1CCCCC1

Procedure:
Compound of formula (XI) where all R5s are H and R7 and R8 are methyl was prepared by reacting 4-PgO benzoic acid chloride, prepared as in the above paragraph, in a Grignard reaction with CH3MgCl in a procedure similar that employed in Example I for producing (1-methyl-l-hydroxy) ethyl-3-cyclohexene from 3-cyclohexane carboxylic acid chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.Br[CH:13]([CH:20]=O)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>ClCCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[S:8][C:13]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][N:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(Br)C=O
Reactant: COc1ccc(C(N)=S)cc1
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cnc(-c2ccc(OC)cc2)s1
Yield: 66.5 %

Procedure:
4-Methoxythiobenzamide (1.62 g, 9.7 mmol) and ethyl 3-bromo-4-oxobutanoate (2.02 g, 9.7 mmol) were suspended in 1,2-dichloroethane (25 ml), and the mixture was heated under reflux for 3 hours. The reaction mixture was diluted with ethyl acetate, successively washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=2/1) to give ethyl [2-(4-methoxyphenyl)-1,3-thiazol-5-yl]acetate (1.79 g, yield: 67%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3I)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]([Cu])#[N:35]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:34]#[N:35])[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: N#C[Cu]
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1C#N
Temperature: 100 °C
Reaction time: 14 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (500 mg, 0.837 mmol) in DMF (7.5 mL) was added CuCN (150 mg, 1.67 mmol). The reaction was heated to 100° C. and stirred at that temperature for 14 hours. The reaction was then cooled to room temperature, diluted with EtOAc (200 mL), and washed with 100 mL of 2.5 M aqueous ammonia. The organic layer was washed with brine (75 mL) and then filtered through a plug of silica gel. The filtrate was concentrated, and the residue was purified by flash chromatography on silica gel (5 to 50% EtOAc/hexanes) to afford 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzonitrile. Rf=0.29 (25% EtOAc/hexanes). LCMS=497.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.91 (s, 1H), 7.88 (s, 1H), 7.86 (d, J=8.2 Hz, 1H), 7.79 (s, 2H), 7.74 (d, J=8.2 Hz, 1H), 5.78 (d, J=7.8 Hz, 1H), 4.93 (d, J=16.1 Hz, 1H), 4.53 (d, J=15.8 Hz, 1H), 4.23 (m, 1H), 0.86 (d, J=6.7 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:22][C:21](=[O:23])[C:20]4[C:15](=[C:16]([C:27]#[N:28])[CH:17]=[C:18]5[CH:26]=[N:25][NH:24][C:19]5=4)[N:14]=3)=[CH:11][C:10]([C:29]([F:32])([F:31])[F:30])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:33]([NH2:36])([CH3:35])[CH3:34]>C(#N)C.O>[CH:33]([NH:36][C:21]([C:20]1[C:15]([NH:14][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:29]([F:30])([F:31])[F:32])[CH:11]=2)=[O:22])=[C:16]([C:27]#[N:28])[CH:17]=[C:18]2[C:19]=1[NH:24][N:25]=[CH:26]2)=[O:23])([CH3:35])[CH3:34]
Reactant: N#Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Reactant: CC(C)N
Solvent: CC#N
Solvent: O
Product: CC(C)NC(=O)c1c(NC(=O)c2cc(C(F)(F)F)nn2-c2ncccc2Cl)c(C#N)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 600 mg of the above 7-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-9-oxo-1,9-dihydro-8-oxa-1,2,6-triaza-cyclopenta[a]naphthalene-5-carbonitrile in 5 mL of acetonitrile/water (4:1, v/v) is added 1.1 mL (12.9 mmol) of isopropylamine. The reaction mixture is stirred during 4 hours at ambient temperature and then concentrated in vacuo. After purification by flash chromatography (SiO2, hexanes/ethyl acetate 4:1), 250 mg (38%) of a white solid are obtained; LC/MS:518/520 (M+H)+.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[H-].[Na+].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][C:22]=1[NH:29][C:30](=[O:48])[CH2:31][CH:32]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[C:39]=1[O:46][CH3:47])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.C(OCC)(=O)C>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:23][C:22]=1[NH:29][C:30](=[O:48])[CH2:31][CH:32]([C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[C:39]=1[O:46][CH3:47])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:18])([CH3:19])[CH3:20]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CCCCCC(CC(=O)Nc1cc(C=O)ccc1C(C)(C)C)c1cccc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(CCC(=O)OCC)ccc1C(C)(C)C)c1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
1.23 ml (6.22 mmol) of ethyl diethylphosphonoacetate were added dropwise, whilst ice-cooling, over a period of 3 minutes to a suspension of 271 mg (6.22 mmol) of sodium hydride (as a 55% w/w dispersion in mineral oil) in 7 ml of dimethylformamide, and the resulting mixture was then stirred at room temperature for 30 minutes. A solution of 1.37 g (3.11 mmol) of N-(2-t-butyl-5-formylphenyl)-3-(2,3-dimethoxyphenyl)octanamide (prepared as described in Preparation 24), in 6 ml of dimethylformamide was ice-cooled and then added dropwise to the mixture over a period of 3 minutes. The resulting mixture was stirred at room temperature for 1.5 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate, and the diluted solution was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. A solution of the residue in 20 ml of ethanol was stirred at room temperature for 8 hours in an atmosphere of hydrogen and in the presence of 400 mg of 10% palladiun-on-charcoal. At the end of this time, the reaction mixture was filtered using a Celite (trade mark) filter aid to remove the catalyst, and the filtrate was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.56 g (yield 98%) of the title compound as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[CH3:25][C:26]1[CH:30]=[CH:29][S:28][C:27]=1[C:31](Cl)=[O:32].C(N(CC)CC)C>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31]([C:27]4[S:28][CH:29]=[CH:30][C:26]=4[CH3:25])=[O:32])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: Cc1ccsc1C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccsc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Yield: 53.6 %

Procedure:
As described for Example 9, 0.314 g (1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is reacted with 0.177 g (1.1 mmol) of 3-methyl-2-thiophenecarbonyl chloride in 5 ml of dichloromethane and 0.111 g of triethylamine for 2 hours at room temperature to give crystals. Recrystallization from dichloromethane-hexane gives 0.235 g of crystals, m.p. 201°-204° C.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl[CH2:10][CH2:11][CH2:12][C:13](O)=[O:14]>Cl>[NH:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:8]=[C:10]1[CH2:11][CH2:12][CH2:13][OH:14]
Reactant: Nc1ccccc1N
Reactant: O=C(O)CCCCl
Agent: Cl
Product: OCCCc1nc2ccccc2[nH]1
Yield: 42.6 %

Procedure:
A mixture of 1,2-Phenylenediamine (1.0 g, 12.0 mmol) and 4-chlorobutyric acid (1.5 mL, 15.17 mmol) were refluxed in 4N HCl (13 mL) for 16 hours under N2 to give the title compound as white solid (900 mg, 50%). 1H NMR (CD3OD) □ 2.04-2.08 (m, 2H), 2.97 (t, 2H, J=7.8 Hz), 5.64 (t, 2H, J=6.6 Hz), 7.15-7.21 (m, 2H), 7.47-7.49 (m, 2H); ES-MS m/z 177.1 (M+H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Cl[C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][N:23]([C:28]5[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][N:29]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@]1(C2CCN(c3ccc(C(F)(F)F)cn3)CC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-(trifluoromethyl)pyridine in dimethylsulfoxide at 100° C. in the presence of potassium carbonate. LC (method 4): tR=1.04 min; Mass spectrum (ESI+): m/z=523 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:24]3[CH2:27][C@H:26]([CH2:28]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:25]3)=[N:9][C:10]=2[C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:40][NH:41][CH3:42].C1COCC1>CO>[CH3:40][N:41]([CH2:28][C@@H:26]1[CH2:27][C@H:24]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][CH:12]=3)[N:9]=2)[CH2:25]1)[CH3:42]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C[C@@H](c3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)nccn43)C2)cc1
Reactant: CNC
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)C[C@H]1C[C@@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)C1
Temperature: 60 °C

Procedure:
A mixture of cis-toluene-4-sulfonic acid 3-[8-amino-1-(4-phenoxyphenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclobutylmethyl ester (30.0 mg, 0.0555 mmol), 2 M of dimethylamine in MeOH (2 mL) and THF (5 mL, 0.06 mol) was heated to 60° C. overnight in a sealed tube. The material was concentrated in vacuo, redissolved in minimal MeOH/DCM, and loaded onto a prep TLC plate, eluting with 6% (7N NH3 in MeOH)/DCM. The band containing the pure product was collected, and the product was filtered off using 1:1 MeOH/DCM. The filtrate was concentrated in vacuo, and hexanes was added. The mixture was sonicated until a white precipitate crashed out. The solid was filtered off, washing several times with hexanes, to afford the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ=2.23 (s, 6H), 2.26-2.33 (m, 2H), 2.42 (d, J=6.3 Hz, 2H), 2.57-2.70 (m, 3H), 3.60-3.71 (m, 1H), 5.03 (s, 2H), 7.03-7.17 (m, 7H), 7.34-7.41 (m, 2H), 7.61-7.65 (m, 2H). MS (ES+): m/z 414.19 (100) [MH+]. HPLC: tR=1.98 min (ZQ3, polar—5 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[OH:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[NH:26]1[C:27]2[C:23](=[C:22]([O:21][C:16]3[N:15]=[C:14]([NH:13][C:5]4[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=4)[CH:19]=[N:18][CH:17]=3)[CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:25]1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Reactant: Oc1cccc2[nH]ccc12
Product: COc1cc(Nc2cncc(Oc3cccc4[nH]ccc34)n2)cc(OC)c1OC
Yield: 17 %

Procedure:
Using Method X with 150 mg of 2-(3,4,5-trimethoxyphenylamino)-6-chloropyrazine and 4-hydroxyindole, the title compound was obtained (34 mg). Yield: 17%. 1H NMR (250 MHz, DMSO-d6) δ 3.24 (s, 6H), 3.49 (s, 3H), 6.10-6.12 (m, 1H), 6.66 (s, 2H), 6.79 (d, 1H, J=7.1 Hz), 7.07 (t, 1H, J=7.8 Hz), 7.25-7.29 (m, 2H), 7.79 (s, 1H), 7.92 (s, 1H), 9.44 (s, 1H), 11.26 (s, 1H). 13C NMR (62.9 MHz, DMSO-d6) δ 55.12, 59.96, 95.43, 98.04, 108.42, 109.87, 120.50, 120.91, 121.37, 125.36, 127.87, 131.91, 136.34, 138.13, 146.33, 150.59, 152.58, 157.84. m/z 393.1 [(M+H)+ calcd for C21H20N4O4 392.1].
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][NH2:7].C(=O)([O-])[O-].[Na+].[Na+].Br[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[N+:25]([O-:27])=[O:26])[C:17](=O)[O:16]1.O>CN(C=O)C>[N+:25]([C:23]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:24]=1[CH:15]=[N:6][NH:7][C:17]2=[O:16])([O-:27])=[O:26]
Reactant: NN
Reactant: O=C1OC(Br)c2c1cccc2[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]ncc2c([N+](=O)[O-])cccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 43.8 %

Procedure:
18.25 g of hydrazine sulfate and 14.88 g of sodium carbonate are stirred in 300 ml of DMF at 100° C. for one hour. Then, 7.24 g of 3-bromo-4-nitro-phthalide in 100 ml of DMF is added, and it is stirred for another 4 hours at 100° C. It is added to water, extracted several times with ethyl acetate, and the organic phase is washed with water and brine. It is dried, and the solvent is removed in a vacuum. After recrystallization from ethyl acetate, 2.35 g of 5-nitro-phthalazin-1-one is obtained as a solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6](I)[CH:5]=1.O=[C:14]([CH3:18])[C:15]([OH:17])=[O:16].N12CCN(CC1)CC2>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:14]([C:15]([OH:17])=[O:16])=[CH:18]2)=[O:12]
Reactant: CC(=O)C(=O)O
Reactant: COC(=O)c1ccc(N)c(I)c1
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Product: COC(=O)c1ccc2[nH]c(C(=O)O)cc2c1

Procedure:
A solution of 25 g 4-Amino-3-iodo-benzoic acid methyl ester, 19 ml 2-Oxo-propionic acid, 30.4 g 1,4-Diaza-bicyclo[2.2.2]octane and 1 g Pd(OAc)2 was heated under argon to 100° C. After 5 h the reaction mixture was concentrated under reduced pressure and the residue was partitioned between 300 ml ethyl acetate and 200 ml 1 M hydrochloric acid. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure to yield a yellow solid (6.4 g). From the aqueous layer additional product slowly precipitated as a white solid (7.9 g) which was collected by filtration. Both fractions were combined, dried in vacuo and used in the next reaction without further purification. Yield: 14.3 g MS (ES+): m/e=220.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=O.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].CCOCC>C(OC(=O)C)(=O)C.[Cl-].[Cl-].[Zn+2]>[CH2:17]([O:16][C:8](=[O:15])[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:2]([C:1]([O:6][CH3:7])=[O:5])[CH3:4])[CH3:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COC(=O)C(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C(=O)OCC)=C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A mixture of ZnCl2 (42 g, 308 mmol) in acetic anhydride (100 mL) was stirred at r.t. for 2 h. The resulting solution was decanted, and to this solution was added methyl pyruvate (15.5 mL, 171 mmol) and diethyl malonate (26 mL, 171 mmol). The resulting mixture was heated at 100° C. for 1 h, then left standing at r.t. for 16 h. Ether (250 mL) was added and the mixture was washed with ice water and saturated NaHCO3. The organic layer was dried over MgSO4 and concentrated to give a dark brown oil, which was distilled under reduced pressure to give 32.3 g of the title compound as a yellow oil. 1H NMR (CDCl3, 200 MHz): δ=4.15-4.40 (m, 4H), 3.78 (s, 3H), 2.20 (s, 3H), 1.20-1.40 (m, 6H).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].Cl.[NH2:8][C:9]1[CH:38]=[CH:37][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:36])[C@:21]([CH3:35])([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1.N1C=CC=CC=1>CC(C)=O>[OH:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@:21]([CH3:35])([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C:20](=[O:36])[C:19]=1[C:14]1[NH:13][C:12]2[CH:37]=[CH:38][C:9]([NH:8][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:10][C:11]=2[S:16](=[O:18])(=[O:17])[N:15]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3[C@@](C)(CCC(C)C)C1=O)N2
Reaction time: 4 h
Yield: 94.7 %

Procedure:
Ethane sulfonylchloride (75.6 mg, 0.588 mmol) was added carefully dropwise to a solution of Example 39H (70.0 mg, 0.147 mmol) and pyridine (93.1 mg, 1.18 mmol) in acetone (7 mL). The reaction mixture was stirred for 4 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with a 0-25% ethyl acetate/hexane gradient to give the title compound (74 mg, 95%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.42 m, 1 H) 0.69 (d, J=6.62 Hz, 3H) 0.72 (d, J=6.62 Hz, 3 H) 0.80 m, 1 H) 1.22 (t, J=7.35 Hz, 3 H) 1.33 (m, 1 H) 1.57 (s, 3 H) 2.07 m, 1 H) 2.22 m, 1 H) 3.19 m, 2 H) 5.76 (s, 1 H) 7.53 (dd, J=7.91, 4.23 Hz, 1H) 7.57 (dd, J=8.82, 2.21 Hz, 1 H) 7.63 (d, J=2.21 Hz, 1 H) 7.71 (d, J=8.82 Hz, 1 H) 7.76 (d, J=3.68 Hz, 2 H) 8.16 (d, J=7.72 Hz, 1 H) 10.31 (s, 1 H) 13.77 (s, 1 H).). MS (ESI+) m/z 532.0 (M+H)+, 549.1 (M+NH4)+ (ESI−) m/z 530.1 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:10](=O)OC(C)(C)C.[Cl:24][CH2:25]C([O-])=O.[Na+]>Cl>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:17][CH2:18][CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:10]([CH2:25][Cl:24])=[N:1][C:2]=2[CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCCS(C)(=O)=O)c1ccc(Cl)cc1N
Reactant: O=C([O-])CCl
Agent: Cl
Agent: [Na+]
Product: CS(=O)(=O)CCCn1c(CCl)nc2cc(Cl)ccc21
Temperature: 100 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
A mixture of tert-butyl 2-amino-4-chlorophenyl(3-(methylsulfonyl)propyl)carbamate (320 mg, 0.92 mmol) and sodium chloroacetate (130 mg, 1.1 mmol) in 4 N HCl was heated to 100° C. After overnight stirring, the reaction solution was cooled to RT and concentrated. The residue was diluted with DCM (100 mL) and washed with sat. NaHCO3 (50 mL). The organic layer was dried and concentrated under vacuum. The residue was purified by prep-TLC (DCM/EtOAc=3:1) to give 5-chloro-2-(chloromethyl)-1-(3-(methylsulfonyl)propyl)-1H-benzo[d]imidazole (130 mg, yield: 44%) as pale solid. MS obsd. (ESI+) [(M+H)+]: 321.0.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][C@H:9]([CH2:13][CH3:14])[C:10]([NH2:12])=[O:11].[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>CC(C)=O.CCOCC>[NH2:12][C:10]([C@H:9]([NH:8][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][Cl:15])[CH2:13][CH3:14])=[O:11]
Reactant: CC[C@@H](N)C(N)=O
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CC[C@@H](NC(=O)CCCCl)C(N)=O
Temperature: 0 °C
Yield: 86 %

Procedure:
31.1 g (0.225 mole) of ground potassium carbonate are mixed with 12.47 g (0.09 mole) of (R)-2-aminobutanamide hydrochloride in 160 ml of acetone. The reaction mixture is cooled to 0° C. and a solution of 15.23 g (0.108 mole) of 4-chlorobutyryl chloride in 25 ml of acetone is introduced dropwise. After the addition, the reaction mixture is allowed to return to ambient temperature; the insoluble matter is filtered off and the filtrate evaporated under reduced pressure. The crude residue obtained is stirred in 100 ml of anhydrous ether for 15 minutes at a temperature between 5° and 10° C. The precipitate is filtered off, washed twice with 30 ml of ether, and dried in vacuo to obtain 16 g of (R)-N-[1-(aminocarbonyl)propyl]-4-chlorobutanamide. Melting point: 127°-129° C. [alpha]D25 : +22.2° (c=1, methanol). Yield: 86%.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](Cl)=[O:4].[NH:10]1[CH2:16][CH2:15][CH2:14][C@H:11]1[CH2:12][OH:13].C([O-])(=O)C.[Na+]>CC(C)=O.O>[Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([N:10]1[CH2:16][CH2:15][CH2:14][C@H:11]1[CH2:12][OH:13])=[O:4]
Reactant: CC(C)CC(Br)C(=O)Cl
Reactant: OC[C@@H]1CCCN1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)CC(Br)C(=O)N1CCC[C@H]1CO
Reaction time: 2 h

Procedure:
A solution of (±)-2-bromo-4-methyl-pentanoyl chloride, 21 g (0.099 mol), in 25 ml of acetone is added dropwise with stirring to a solution of 10 g (0.099 mol) of L-prolinol and 16.2 g (0.197 mol) of sodium acetate in a mixture of 150 ml of acetone and 75 ml of water at 0°-5° C. The mixture is stirred and allowed to reach room temperature over two hours, the solvent is evaporated in vacuo and the residue is suspended in 300 ml of chloroform and washed with water, 2×300 ml. The chloroform layer is separated, dried over sodium sulfate, evaporated in vacuo, and the residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give (2S)-1-(2-bromo-4-methyl-1-oxopentyl)2-pyrrolidinemethanol (2 position on side chain is R,S mixture), 21 g; mp 79°-82°; [α]D25 -54.0° (c 0.6, methanol).