Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=O)=[O:14].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:45]1([C:51]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:61])[F:60])=[O:52])[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C=O)C.O>[OH:10][C:11]1[CH:23]=[CH:22][CH:21]=[CH:20][C:12]=1[C:13]([NH:15][CH2:16][C:17](=[O:19])[N:48]1[CH2:49][CH2:50][N:45]([C:51](=[O:52])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[C:59]([F:62])([F:60])[F:61])[CH2:46][CH2:47]1)=[O:14]
Reactant: O=C(O)CNC(=O)c1ccccc1O
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
DIPEA (0.239 mL, 1.39 mmol) was added drop wise to (2-hydroxy-benzoyl amino)-acetic acid (90 mg, 0.46 mmol) in DMF (7 mL). EDCI (221 mg, 1.15 mmol) and HOBT (74 mg, 0.55 mmol) were added consecutively and after 5 minutes, piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone (162 mg, 0.55 mmol) was added. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (silica gel of mesh size of 60-120 using 70:30 EtOAc:hexane as eluent) afforded 2-hydroxy-N-[2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazine-1-yl]-ethyl]-benzamide in 25% yield. LC-MS purity: 97%, 1H NMR (DMSO-D6): δ 12.0 (s, 1H), 9.1 (t, 1H), 7.9 (m, 3H), 7.7 (d, 1H), 7.6 (m, 1H), 7.4 (t, 1H), 6.9 (t, 2H), 4.2 (dd, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [C:1]([NH:11][C@H:12]([C@@H:20]([OH:42])[C@H:21]([OH:41])[C@@H:22]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[CH3:43][S:44](Cl)(=[O:46])=[O:45].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([NH:11][C@H:12]([C@@H:20]([O:42][S:44]([CH3:43])(=[O:46])=[O:45])[C@H:21]([O:41][S:44]([CH3:43])(=[O:46])=[O:45])[C@@H:22]([NH:30][C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@@H](O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@@H]([C@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 15 h
Yield: 90 %

Procedure:
A slurry of 1.50 g (2.64 mmol) of (2S,3R,4R,5S)-2,5-bis-(N-Cbz-amino)-3,4-dihydroxy-1,6-diphenylhexane in 50 ml of anhydrous dichloromethane was cooled to 0° C. and treated sequentially with 0.43 ml of methanesulfonyl chloride, 64 mg of 4-dimethylaminopyridine and 1.1 ml of triethylamine. The resulting mixture was stirred for 15 h with the temperature being allowed to slowly climb to ambient temperature. After treatment with aqueous NH4Cl, the separated organic layer was washed with aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo to provide 1.70 g (90%) of the desired compound, m.p. 153°-155° C. 1H NMR (CDCl3) δ2.73 (m, 2 H), 2.92 (m, 2 H), 3.09 (s, 6 H), 4.61 (m, 2 H), 4.83-5.06 (m, 8 H), 7.12-7.37 (m, 20 H).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:21])[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:7]2[C:12]([C:13]=1O)=[CH:11][CH:10]=[CH:9][N:8]=2)(=O)[CH3:2].O.[NH2:23][NH2:24]>C(O)(=O)C>[CH3:2][C:1]1[C:4]2[C:5](=[O:21])[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]3[N:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[NH:24][N:23]=1
Reactant: CC(=O)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: Cc1n[nH]c2c1c(=O)n(-c1ccccc1)c1ncccc21
Temperature: 25 °C
Yield: 44.3 %

Procedure:
Compound 102 in an amount of 1.2 g (4.3 millimoles) was suspended in 10 ml of glacial acetic acid, and 0.46 ml (9.4 millimoles) of hydrazine monohydrate was added to the suspension. Thereafter, the mixture was heated under reflux for 3 hours. The reaction solution was cooled to room temperature, and the precipitate was collected by filtration and recrystallized from DMF-water to give 530 mg (yield: 44.3%) of Compound 2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=O)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21].[NH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:23][CH2:24][S:25][CH3:26])[NH:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:9][C:8]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21]
Reactant: NCCN1CCCCC1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=O)cc1-c1ccccc1C
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CNCCN2CCCCC2)cc1-c1ccccc1C

Procedure:
The desired compound was prepared using the method described in Example 403H starting with N-[4-formyl-2-(2-methylphenyl)benzoyl]methionine methyl ester, prepared as in Example 403G, and 1-(2-aminoethyl)piperidine. m/e (ESI) 498 (MH+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Cl[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[CH:26]=2)[CH:21]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:16]([CH2:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH3:31])[CH:26]=3)[CH:21]=2)[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: COc1ccc2cc(CCl)ccc2c1
Product: COc1ccc2cc(CN3C(=O)CCCC3c3c(OC)cccc3OC)ccc2c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with 2-(chloromethyl)-6-methoxynaphthalene. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.80 min.; [M+H]+: 406.18 g/mol.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:9][CH2:10][C:11]([CH2:13][Cl:14])=[O:12].C(O)(=O)C.O>CCOCC>[Cl:9][CH2:10][C:11]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:12])[CH2:13][Cl:14]
Reactant: O=C(CCl)CCl
Reactant: Br[Mg]c1ccccc1
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: OC(CCl)(CCl)c1ccccc1
Reaction time: 0.17 h
Yield: 51 %

Procedure:
289 ml (0.866 mol) of a 3M solution of phenylmagnesium bromide in ether are run, over a period of 1.50 h, into a solution of 100 g (0.787 mol) of 1,3-dichloroacetone in 1000 ml of anhydrous ether under a nitrogen atmosphere and at -60° C. After 10 minutes, a solution of 83.5 g of acetic acid in 126 ml of ether is added to the reaction medium. The temperature is allowed to rise to +4° C. and 315 ml of water are run in. The ether phase is decanted, washed with water and dried over MgSO4. It is filtered, the filtrate is evaporated to dryness and the evaporation residue is distilled in vacuo to give 82.3 g (yield: 51%) of 1,3-dichloro-2-phenylpropan-2-ol. B.p. (0.5 mm Hg)=102° C. (0.5 mm Hg corresponds to 66.6 Pa).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:26][CH2:25][C:20]5(OCC[O:21]5)[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][C:15]([C:17]4[CH2:26][CH2:25][C:20](=[O:21])[CH2:19][CH:18]=4)=[CH:16][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1-c1ccnc2[nH]c(C3=CCC(=O)CC3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 241A (3.7 g, 9.73 mmol) in 30 mL dichloromethane was added excess trifluoroacetic acid (6 mL). The mixture was stirred at room temperature overnight and the solvent was removed in vacuo. The residue was dissolved in 50 mL ethyl acetate and washed with saturated sodium bicarbonate, water, and brine, dried over magnesium sulfate, filtered and concentrated. The crude material was triturated with ethyl acetate and the solid was filtered and dried in vacuo to give the title compound. MS (ESI): 337.2 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[CH2:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:14][O:15][C:16]=3[N:17]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.Cl[C:33]([O:35][CH3:36])=[O:34].O>C1COCC1>[CH3:36][O:35][C:33]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[CH2:11][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:14][O:15][C:16]=3[N:17]=2)[CH2:2][CH2:3]1)=[O:34]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2nc(N3CCNCC3)ccc2C1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)N1CCN(c2ccc3c(n2)OCCN(C(=O)OC(C)(C)C)C3)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of the compound (0.26 g) obtained in step 1 and Et3N (0.21 mL) in THF (10 mL) was added methyl chloroformate (0.12 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→50% ethyl acetate/hexane) to give tert-butyl 8-[4-(methoxycarbonyl)piperazin-1-yl]-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4(5H)-carboxylate (0.21 g, 69%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[C@@H:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:31]([O:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:32]>>[CH:34]1([O:33][C:31](=[O:32])[N:14]([C@@H:13]2[C@@H:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12]2)[CH3:15])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: CN[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)OC1CCCC1)[C@H]1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)C[C@@H]1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 2 (step b), the title compound rac-{(3R,4S)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid cyclopentyl ester was prepared from rac-{4-[(3S,4R)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using cyclopentyl chloroformate instead of 4-fluorophenyl chloroformate and was obtained as a white solid. MS m/e: 550.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][NH:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=1.[CH3:21][N:22]([CH3:39])[S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](O)=[O:30])(=[O:25])=[O:24]>>[CH3:21][N:22]([CH3:39])[S:23]([C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=1)[C:29]([N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:20])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:30])(=[O:24])=[O:25]
Reactant: CN(C)S(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COC(=O)CNc1cnccc1-c1cccnc1OC
Product: COC(=O)CN(C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)N(C)C)c1)c1cnccc1-c1cccnc1OC

Procedure:
The title compound was prepared in analogy to example 90, from (2-methoxy-[3,4′]bipyridinyl-3′-ylamino)-acetic acid methyl ester and 3-dimethylsulfamoyl-5-trifluoromethyl-benzoic acid (Buttpark Ltd.) after a reaction time of 72 hours. The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 20:80). The product-containing fractions were pooled and evaporated and the residue poured on 30 mL 1M aqueous HCl and 30 mL EtOAc. The layers were separated and the aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed twice with 30 mL 1M aqueous HCl followed by 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. Light yellow solid (30%). MS (ESI): m/z=553.135 [M+H]+.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][S:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]([O:20]C)=[O:19])[CH:9]=1)=[O:4].[Li+].[OH-]>CO>[C:3]([CH2:5][CH2:6][S:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=[C:10]([C:18]([OH:20])=[O:19])[CH:9]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCSc1cc(C(=O)OC)nc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCSc1cc(C(=O)O)nc2ccccc12
Temperature: 25 °C

Procedure:
This methyl 4-(2-methoxycarbonylethylthio)quinoline-2-carboxylate is hydrolyzed by the addition of 3 equivalents of aqueous lM LiOH in MeOH/H20 and stirring at RT. After stirring for 16 hours, the methanol is evaporated, the residue diluted with water and extracted 2x with ethyl acetate. The aqueous layer is acidified to pH 1.5 by the addition of aqueous lN HCl and the solid obtained is filtered, washed with water, and dried to afford 4-(2-carboxyethylthio)quinoline-2-carboxylic acid.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:12][CH:13]([O:20]CC)[CH2:14][C:15](OCC)=O)[CH3:11]>[Ti](Cl)(Cl)(Cl)Cl.[N+](C)([O-])=O>[CH:15]1([CH2:14][C:13]([O:12][CH2:10][CH3:11])=[O:20])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][O:9]1
Reactant: CCOC(=O)CC(OCC)OCC
Reactant: OCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)CC1OCCc2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Titanium tetrachloride (1M in methylene chloride, 90 ml, 90.0 mmol) is added over a period of 20 minutes to an ice-cooled mixture of phenethyl alcohol (XLV, 4.9 ml, 41.0 mmol), ethyl 3,3-diethoxypropionate (LXXV, 9.1 ml, 46.8 mmol) and nitromethane (17 ml). The mixture is stirred for 2 hr and then concentrated, diluted with ether, poured into ice/hydrochloric acid (1N), and allowed to stir. The phases are separated and the aqueous phase is extracted three times with ether. The combined organic phases are backwashed with saline, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel eluting with ethyl acetate/hexane (10/90). The appropriate fractions are pooled and concentrated to give ethyl (±)-(isochroman-1-yl)acetate (LXXVII), NMR (CDCl3) 1.28, 2.68-3.04, 3.82, 4.13, 4.22, 5.26, 7.05 and 7.16 δ.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:15][CH:16]=1)=[O:8].[O:24]([C:26]#[N:27])[K]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:21]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([S:17]([NH:18][C:26]([NH2:27])=[O:24])(=[O:19])=[O:20])=[CH:15][CH:16]=1)=[O:8]
Reactant: N#CO[K]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(N)(=O)=O)s1
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)NCCc1ccc(S(=O)(=O)NC(N)=O)s1

Procedure:
299 mg (0.8 mmol of 2-[2-(5-chloro-2-methoxybenzoylamino)ethyl]-5-sulfamoylthiophene were treated with 448 mg of KOCN and 0.6 ml of triethylamine, and the mixture was then heated to reflux for 4 h. The cooled solution was filtered and evaporated to dryness. The residue was stirred with 40 ml of H2O, 25 ml of triethylamine and 25 ml of ethyl acetate. The organic phase was extracted 3 times with water/1% triethylamine. The combined aqueous phases were acidified with 2N hydrochloric acid. The precipitate formed was stirred in an ice bath for 3 hours and filtered off with suction.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]1[CH2:11][C@H:7]2[O:8][CH2:9][CH2:10][C@@:6]2([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[OH:26])=[O:13])[CH2:5]1.[C:27]1(=O)[O:32][C:30](=[O:31])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.CCN(C(C)C)C(C)C.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl>C(Cl)(Cl)Cl>[O:31]=[C:30]1[C:29]2[C:28](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27](=[O:32])[N:3]1[C@@H:4]1[CH2:11][C@H:7]2[O:8][CH2:9][CH2:10][C@@:6]2([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[CH:18][C:17]=2[OH:26])=[O:13])[CH2:5]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)NCc2cc(C(F)(F)F)ccc2O)C1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H]2OCC[C@@]2(C(=O)NCc2cc(C(F)(F)F)ccc2O)C1
Temperature: 25 °C

Procedure:
A solution of the product of Step B (8.58 g, 18.74 mmol, 1 eq), phthalic anhydride (5.55 g, 37.5 mmol, 2 eq) and DIEA (11.3 mL, 55.6 mmol, 3.5 eq) in chloroform (150 mL) was heated to 70° C. for 2 hours. The solution was cooled to rt and carbonyl diimidazole (2.24 g 13.82 mmol, 3 eq) was added and the solution heated to 60° C. for 2 hours. The solution was cooled to rt, 1 N HCl was added, the aqueous extracted with DCM, the organics combined, dried over MgSO4 and concentrated. Purification by chromatography (200 g column) eluting with 30 to 60 to 80% EA/heptane afforded the product of Step C. Calculated for C24H21F3N2O5: 474.1 (M+1). found: 475.1.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([O:15][C:16]1[CH:27]=[CH:26][C:19]([CH2:20][N:21]([C:23](=[O:25])[CH3:24])[OH:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.CCOCC>C(Cl)Cl.CN(C1C=CC=CN=1)C>[CH2:8]([O:15][C:16]1[CH:27]=[CH:26][C:19]([CH2:20][N:21]([O:22][C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])=[O:6])[C:23](=[O:25])[CH3:24])=[CH:18][CH:17]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)N(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1ccc(OCc2ccccc2)cc1)OC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Pivaloylchloride (1.36 ml) was added dropwise to a solution of N-(4-benzyloxybenzyl)acetohydroxamic acid (2.71 g) and triethylamine (1.7 ml) in methylene dichloride (15 ml) and dimethylaminopyridine (100 ml). The mixture was stirred for 2 hours at room temperature, then neutral material was isolated with ether. The product, N-(4-(Benzyloxybenzyl)-N-(t-butylcarbonyloxy)acetamide, was a colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:4][N:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:33])(=[N:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:26])=[CH:21][CH:20]=1>>[CH2:31]([O:30][C:28]([N:27]=[S:25]([C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:2]2[N:7]=[C:6]([NH:8][C@H:9]([CH3:12])[CH2:10][OH:11])[C:5]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[CH:4][N:3]=2)=[CH:24][CH:23]=1)([CH3:33])=[O:26])=[O:29])[CH3:32]
Reactant: CCOC(=O)N=S(C)(=O)c1ccc(N)cc1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: CCOC(=O)N=S(C)(=O)c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](C)CO)n2)cc1
Yield: 27 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)propan-1-ol (178 mg, 0.7 mmol) with (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-methyl-sulfoximide (145 mg, 0.6 mmol) according to procedure 5a, the desired product is obtained in 27% yield (85 mg) after chromatographic purification (silica gel, ethyl acetate/hexane (0%-80% ethyl acetate)).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH3:9])[C:6](=[O:10])[N:5]([CH2:11][CH2:12][CH3:13])[C:4](=[O:14])[C:3]=1[N:15]=O>CO.[Pd]>[NH2:15][C:3]1[C:4](=[O:14])[N:5]([CH2:11][CH2:12][CH3:13])[C:6](=[O:10])[N:7]([CH2:8][CH3:9])[C:2]=1[NH2:1]
Reactant: CCCn1c(=O)c(N=O)c(N)n(CC)c1=O
Agent: [Pd]
Solvent: CO
Product: CCCn1c(=O)c(N)c(N)n(CC)c1=O
Reaction time: 2 h

Procedure:
To a solution of 6-amino-1-ethyl-5-nitroso-3-propyl-1,3-dihydropyrimidine-2,4-dione (300 mg) in methanol (10 ml) was added 10% palladium on carbon catalyst (50 mg), and the mixture was hydrogenated under hydrogen at 30 psi for 2 hours. The mixture was filtered through celite, and solvent was removed from the filtrate under reduced pressure, to provide 5,6-diamino-1-ethyl-3-propyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (2).
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]1([OH:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(=O)(O)(O)O.O>C1(C)C(C)=CC=CC=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[CH3:4][C:3]1([CH3:5])[C:10]2[C:9](=[CH:8][CH:7]=[C:6]([OH:12])[CH:11]=2)[CH2:1][CH2:2]1
Reactant: C=CC(=C)C
Reactant: Oc1ccccc1
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Solvent: Cc1ccccc1C
Product: CC1(C)CCc2ccc(O)cc21
Temperature: 110 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
322 g of isoprene, stabilized with 1 g of phenothiazine, were added dropwise over the course of 8 hours to a solution of 403 g of phenol, 50 g of 85% strength phosphoric acid and 9 ml of water in 2.14 liters of xylene at 110° C. To complete the reaction, the mixture was stirred overnight at 110° C. The acid phase was separated off and the organic phase was washed until neutral. Fractional distillation gave 230 g of 3,3-dimethyl-5-hydroxy-indane, boiling point 132°-134° C/10 mm Hg; melting point 84.5° -86.5° C. ##STR30##
Reaction SMILES: [NH:1]([C:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])[C@H:2]([C:7]([O:9]CC1C=CC=CC=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H][H]>CO.[Pd]>[NH:1]([C:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18])[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@H](NC(=O)Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Yield: 74.9 %

Procedure:
A solution of N-phenylacetyl-L-Leu-OBzl (14 g) in methanol (140 ml) was hydrogenated over 10% palladium on carbon (1.4 g) at 3 atmospheric pressure of hydrogen for 2 hours. After removal of the catalyst by filtration, the filtrate was concentrated in vacuo. The residue was triturated with diisopropyl ether to give N-phenylacetyl-L-Leu-OH (7.7 g).
Reaction SMILES: B(Br)(Br)Br.[NH:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([N:16]3[C@@H:25]4[C@@H:20]([C:21]5[CH:29]=[CH:28][CH:27]=[C:26]([O:30]C)[C:22]=5[CH2:23][CH2:24]4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:13][C:8]=2[N:7]=[CH:6]1.C([O-])(O)=O.[Na+]>ClCCl>[NH:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]([N:16]3[C@@H:25]4[C@@H:20]([C:21]5[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[C:22]=5[CH2:23][CH2:24]4)[CH2:19][CH2:18][CH2:17]3)=[O:15])=[CH:13][C:8]=2[N:7]=[CH:6]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc2[nH]cnc2c1)N1CCC[C@@H]2c3cccc(O)c3CC[C@@H]21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boron tribromide (1 mol/L in dichloromethane, 0.5 mL) is added to a solution of (1H-benzo-imidazol-5-yl)-(cis-7-methoxy-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinolin-4-yl)-methanone (60 mg) in dichloromethane (5 mL) at room temperature. The resulting solution is stirred at room temperature for 2 h. Aqueous half-saturated NaHCO3 solution is added and the resulting neutral mixture is extracted with dichloromethane and dichloromethane/methanol (95:5). The combined extracts are washed with brine and dried (Na2SO4). The solvent is evaporated and the residue is triturated with diethyl ether and dried to give the title compound as a colorless solid. Yield: 30 mg (52% of theory); TLC: rf=0.45 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=348 [M+H]+.