Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].CO.[I:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([NH:14][CH:15]([C:21]([O:23]CC)=O)[C:16]([O:18][CH2:19]C)=[O:17])=[O:13])=[CH:8][CH:7]=1>CO>[I:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:13])[NH:14][CH:15]([C:21]([NH:2][CH3:1])=[O:23])[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=1
Reactant: CCOC(=O)C(NC(=O)c1ccc(I)cc1)C(=O)OCC
Reactant: CN
Solvent: CO
Product: CNC(=O)C(NC(=O)c1ccc(I)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 19 h
Yield: 39 %

Procedure:
A 40% methylamine-methanol solution (0.80 mL) was added to a methanol (90 mL) solution of diethyl {[(4-iodophenyl)carbonyl]amino}propandioate (4.1 g) obtained by the same method as the synthesis method described in the literature (Organic & Biomolecular Chemistry, 2005, Vol. 3(19), pp. 3531-3539), and the mixture was stirred for 19 hours at room temperature. Further, a 40% methylamine-methanol solution (0.24 mL) was added, and the mixture was stirred for 19 hours at the same temperature, followed by concentrating the reaction mixture. The resulting residue was purified by OH type silica gel column chromatography (gradient elution with chloroform/ethanol=95/5→90/10) to obtain 1-iodo-4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl]carbamoyl}benzene (white solid) (1.5 g, 39%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[C:28](O)(=[O:32])[CH2:29][CH2:30][CH3:31]>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[CH2:29][CH2:30][CH3:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: CCCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: CCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (54 mg, 67%), MS (ISP) m/z=401.5 [(M+H)+], mp 191° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and butyric acid.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[C:20]=1[Cl:26])=[O:17].O>C1COCC1>[Br:25][C:21]1[C:20]([Cl:26])=[C:19]([N:18]2[C:16](=[O:17])[C:15]3[C:14](=[C:30]([F:31])[CH:29]=[CH:28][CH:27]=3)[NH:13][C:2]2=[O:4])[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1c(F)cccc1C(=O)Nc1cccc(Br)c1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2c(F)cccc2c(=O)n1-c1cccc(Br)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
Triphosgene (453 mg, 1.53 mmol) was added in one portion to a solution of amino-N-(3-bromo-2-chlorophenyl)-3-fluorobenzamide (350 mg, 1.019 mmol) in THF (10 mL) at 0° C. The mixture was stirred at room temperature for 1 h, then was cooled to 0° C. and treated with water until no more gas evolution was observed. The mixture was concentrated and the residue was dissolved in EtOAc, washed sequentially with saturated aqueous NaHCO3, water and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel (24 g), eluting with EtOAc-hexanes (gradient from 0-50%), to provide 3-(3-bromo-2-chlorophenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione as a yellow solid (320 mg, 85% yield). Mass spectrum m/z 369, 371 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 8.54 (br. s., 1H), 7.97 (d, J=8.1 Hz, 1H), 7.77 (dd, J=6.8, 2.6 Hz, 1H), 7.46 (ddd, J=9.8, 8.3, 1.2 Hz, 1H), 7.36-7.29 (m, 2H), 7.24 (td, J=8.0, 4.8 Hz, 1H).
Reaction SMILES: [N+:1]([NH:4][C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[N:8][O:7][N:6]=1)([O-:3])=[O:2].[NH2:13][NH2:14]>O>[NH:4]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[N:8][O:7][N:6]=1)[N+:1]([O-:3])=[O:2].[NH3+:13][NH2:14]
Reactant: NN
Agent: O=[N+]([O-])Nc1nonc1[N+](=O)[O-]
Solvent: O
Product: N[NH3+]
Reaction time: 0.17 h

Procedure:
Into a clean 250 ml 3 neck round bottom flask equipped with a nitrogen port, magnetic stirring bar, and thermocouple was placed 3-nitroamino-4-nitrofurazan ("ANF"; 4.44 grams 0.025M). Thirty-five mls of distilled water was then added and the flask set into an ice bath. Fuming hydrazine (95%; 0.942 g; 0.028M) was preweighed into a vial, then added over three minutes while not letting the reaction temperature exceed +8° C. The reaction mixture was kept cold for 10 minutes, then the ice bath was withdrawn and the reaction mixture was stirred 2.5 hrs. After transfer to a tarred one neck flask, the water was removed in vacuo at 40° C. to obtain crystals (94% yield). The crystals were dissolved in approximately 200 ml THF at 40° C. then the amount of solvent present was reduced and thereafter the solution was refrigerated at -20° C. for 16 hrs. The resulting yellow green crystals were collected and placed over high vacuum (68.5% theoretical yield). DSC: decomposition at 184° C. FTIR 3500-3000 (m), 1583 (s), 1467, 1422, 1395, 1348, 1296 (m). The density of the hydrate (X-ray analysis) was 1,704 g/ml.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][CH2:15]O>>[CH2:14]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH3:15]
Reactant: CCO
Reactant: Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Product: CCOC(=O)c1ccc(C)c([N+](=O)[O-])c1
Temperature: 90 °C

Procedure:
4-Methyl-3-nitro-benzoic acid (71 g, 0.39 mol) was dissolved in dry EtOH (600 mL) and dry HCl gas was bubbled into the solution for 5 min. The reaction was heated to 90° C. under N2 for 20 h, then cooled and concentrated to give 4-methyl-3-nitro-benzoic acid ethyl ester as a straw-color liquid (80.0 g, yield 98%).
Reaction SMILES: Cl.[CH2:2]([NH:10][C:11]1[N:19]=[C:18]([C:20]#[N:21])[N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2C1CCCCO1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[CH2:2]([NH:10][C:11]1[N:19]=[C:18]([C:20]#[N:21])[N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][NH:15]2)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#Cc1nc(NCCc2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Solvent: CCO
Product: N#Cc1nc(NCCc2ccccc2)c2nc[nH]c2n1
Temperature: 25 °C
Yield: 83.6 %

Procedure:
2 Molar hydrochloric acid (10 ml) was added to a stirred solution of 6-(phenethylamino)-9-tetrahydro-2H-pyran-2-yl-9H-purine-2-carbonitrile (10.2 g, 27.6 mmol) (preparation 44) in ethanol (250 ml) at 60° C. The solution was allowed to cool to room temperature and the white solid that had been formed filtered off. After drying, this gave the title compound (6.1 g) as a white crystalline solid. MS: 265 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10]3)=[N:5][N:4]=[C:3]1[CH2:18][CH2:19][CH2:20][CH:21]=O.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:39]=[CH:38][C:32]3[CH2:33][CH2:34][NH:35][CH2:36][CH2:37][C:31]=3[CH:30]=2)[CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:39]=[CH:38][C:32]3[CH2:33][CH2:34][N:35]([CH2:21][CH2:20][CH2:19][CH2:18][C:3]4[N:2]([CH3:1])[C:6]([C:7]5[CH:8]=[C:9]6[C:14](=[CH:15][CH:16]=5)[N:13]=[C:12]([CH3:17])[CH:11]=[CH:10]6)=[N:5][N:4]=4)[CH2:36][CH2:37][C:31]=3[CH:30]=2)[CH:25]=1
Reactant: Cc1ccc2cc(-c3nnc(CCCC=O)n3C)ccc2n1
Reactant: Cc1cc(-c2ccc3c(c2)CCNCC3)no1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc2cc(-c3nnc(CCCCN4CCc5ccc(-c6cc(C)on6)cc5CC4)n3C)ccc2n1
Yield: 21.4 %

Procedure:
4-[4-Methyl-5-(2-methyl-quinolin-6-yl)-4H-[1,2,4]triazol-3-yl]-butyraldehyde (76 mg, 0.25 mmol) and 7-(5-Methyl-isoxazol-3-yl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (55 mg, 0.24 mmol) were stirred at room temperature in dichloromethane (5 ml) for 30 min. Sodium triacetoxyborohydride (55 mg, 0.26 mmol) was then added and the mixture stirred over the weekend. The mixture was diluted with dichloromethane (50 ml) and washed with saturated sodium bicarbonate solution (30 ml). The aqueous was extracted with further dichloromethane (50 ml) and the combined organic portions were dried (Na2SO4), filtered and evaporated to give the desired compound as an off-white solid (26 mg).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:41])[N:10]([CH2:20][CH:21]([OH:40])[CH:22]([NH:32]C(OC(C)(C)C)=O)[CH2:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:32][C@@H:22]([CH2:23][C:24]1[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=1)[C@H:21]([OH:40])[CH2:20][N:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)[C:9](=[O:41])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(CN(CC(O)C(Cc2cc(F)cc(F)c2)NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(CN(C[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 20 ml solution of [3-tert-butoxycarbonylamino-4-(3,5-difluoro-phenyl)-2-hydroxy-butyl]-(3-methoxybenzyl)-carbamic acid benzyl ester (0.5 g, 0.9 mmol) at 0° C. was added trifluoroacetic acid (4 ml). The cold bath was removed and the mixture stirred at r.t. for 1 h. The solvent was removed in vacuo and the residue dissolved in 10% aq. NaHCO3, extracted with EtOAc (3×115 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to yield an amorphous solid. MS (ESI+) for C26H28F2N2O4 m/z 471.2 (M+H)+. The crude amine was used in subsequent steps without purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH3:18][N:19]([CH3:32])[C:20]1([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1.FC(F)(F)S(O)(=O)=O>ClCCl>[CH3:18][N:19]([CH3:32])[C:20]1([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH2:25][CH2:24][C:23]([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:22][CH2:21]1
Reactant: CN(C)C1(c2cccs2)CCC(=O)CC1
Reactant: c1ccc2c(CCc3ccncc3)c[nH]c2c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C1(c2cccs2)CCC(c2[nH]c3ccccc3c2CCc2ccncc2)(c2[nH]c3ccccc3c2CCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
3-(2-pyridin-4-ylethyl)-1H-indole (667 mg, 3 mmol, synthesis cf. WO2008009415, indole unit Ind-14) together with 4-(dimethylamino)-4-(thiophen-2-yl)cyclohexanone (671 mg, 3 mmol, synthesis cf. WO2008009415, ketone unit Ket-12) was dissolved in abs. dichloromethane (45 ml) and mixed with trifluoromethane sulphonic acid (0.660 ml, 7.43 mmol). The batch was stirred for 64 h at RT, and a brown oil separated out. For work up the reaction solution was mixed with 1N NaOH (30 ml) and methanol (10 ml). The mixture was stirred a further 60 min. After separation of the phases the aqueous phase was extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over Na2SO4 and then concentrated to low volume. The raw product obtained (1.33 g) was purified by column chromatography [silica gel 60 (100 g); ethyl acetate/methanol 10:1, (1650 ml), ethyl acetate/methanol (5:1, (600 ml)].
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])=[O:4].C(=O)([O-])[O-].[K+].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][S:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CBr)c1ccccc1F
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(CSc1ccccc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a suspension of 2-bromo-1-(2-fluorophenyl)ethanone (3.0 g) and potassium carbonate (2.0 g) in ethanol (30 mL) was added dropwise thiophenol (1.4 mL) at 0° C. The mixture was stirred at room temperature for 8 hr, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=15:1) to give the title compound as a pale-yellow solid (yield 2.2 g, yield 64%).
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+]>>[CH2:25]([N:1]1[CH2:9][CH2:8][CH:4]([C:5]([NH2:7])=[O:6])[CH2:3][CH2:2]1)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: NC(=O)C1CCNCC1
Reactant: CCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCCCCCCCN1CCC(C(N)=O)CC1
Yield: 85.2 %

Procedure:
Prepared from isonipecotamide (2.0 g, 15.6 mmol), 1-bromopentadecane (4.5 g, 15.6 mmol) and potassium carbonate (2.16 g, 15.6 mmol) according to procedure used for Example 8 (Step A) to give 4.5 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][NH:20][OH:21])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1.Cl[C:26]([O:28][CH3:29])=[O:27].C([O-])(=O)C.[Na+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][N:20]([OH:21])[C:26](=[O:27])[O:28][CH3:29])=[C:9]2[CH3:22])=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CNO)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: COC(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)N(O)Cc1c(C)n(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Yield: 63 %

Procedure:
According to the procedure of Example 62, 1-(4-chlorobenzoyl)-N-hydroxy-5-methoxy-2-methyl-lH-indole-3-methanamine is reacted with 1.1 eq of methyl chloroformate in dioxane/water (2:1) in the presence of sodium acetate (2.5 eq). The crude product is recrystallized from isopropyl ether:cyclohexane to give pure [[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-yl]methyl]hydroxycarbamic acid, methyl ester (63%); mp 113°-114° C.
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3](O)[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].Cl>>[O:8]=[C:7]1[O:9][C@H:3]([C@H:2]([CH2:1][OH:13])[OH:12])[C:4]([OH:10])=[C:5]1[OH:6]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Cl
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Yield: 87 %

Procedure:
The reaction of 2-keto-L-gulonic acid with 36% hydrochloric acid is described, for example, in DE 29 39 052. After reaction at 100° C. and after removal of the hydrochloric acid by distillation, a yield of 87% of theory of L-ascorbic acid is obtained. The disadvantage of the process, however, is the rapid decomposition of the ascorbic acid at 100° C., so that an increased formation of by-products and an intense black coloration of the solution occurs. On account of the large amount of by-products, isolation of the ascorbic acid is associated with further, not inconsiderable losses of material.
Reaction SMILES: C(NC(C)C)(C)C.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([Li])CCC.[F:27][C:28]([F:52])([F:51])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:38]2[CH2:42][CH:41]([CH3:43])[C:40]([C:44]3[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=3)=[N:39]2)=[O:37])=[CH:31][CH:30]=1.C([O:56][CH2:57][CH3:58])(=O)C>O1CCCC1.CCCCCC>[F:52][C:28]([F:27])([F:51])[C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:38]2[CH2:42][C:41]([CH3:43])([C:57](=[O:56])[CH3:58])[C:40]([C:44]3[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=3)=[N:39]2)=[O:37])=[CH:31][CH:30]=1
Reactant: CCOC(C)=O
Reactant: CC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Agent: [Li]CCCC
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(=O)C1(C)CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Temperature: -70 °C
Reaction time: 0.67 h

Procedure:
To 14 ml (102 mmole) of diisopropyl amine and 1 mg of phenanthroline in 150 ml of tetrahydrofuran cooled to -30° C. was added 40 ml (100 mmole) of 2.5M n-butyllithium in hexane. After stirring for 5 minutes a solution of 15 g (39 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide (U.S. Pat. No. 4,663,341, see experimental for compound 149) in 25 ml of tetrahydrofuran was added while maintaining the internal temperature between -30° C and -40° C. After stirring for 40 minutes the mixture was cooled to -70° C. and 20 ml of ethyl acetate was added. After stirring for 15 minutes the mixture was quenched with 20 ml of acetic acid, warmed to 0° C. and 25 ml of water was added. The organic layer was separated, concentrated in vacuo, dissolved in 200 ml of diethyl ether, washed with dilute aqueous hydrochloric acid, dilute aqueous sodium hydroxide, and brine. The mixture was dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and crystallized from diethyl ether yielding 6.5 g of the title compound containing a small amount of starting material.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[N:4]([CH3:10])[C:3]1=[O:11].ClC1C=CC=CC=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>[Cl-].[Zn+2].[Cl-].CCOC(C)=O>[C:19]([C:6]1[C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[N:2]([CH3:1])[C:7]=1[CH3:8])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1cc(=O)n(C)c(=O)n1C
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: Clc1ccccc1
Solvent: O
Product: Cc1c(C(=O)c2ccccc2)c(=O)n(C)c(=O)n1C
Temperature: 110 °C

Procedure:
1,3,6-Trimethylpyrimidine-2,4(1H,3H)-dione (step 1) (5 g, 32.4 mmol) and chlorobenzene (50 mL) were charged to a 3 necked flask, and the vessel evacuated with nitrogen. Benzoyl chloride (commercial) (11.2 mL, 97 mmol) was added followed by zinc (II) chloride (5 g, 36.7 mmol) in one portion and the reaction was heated to 110° C. for 16 h. The reaction was cooled to RT then poured into water (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous extracted with EtOAc (2×150 mL). The combined organics were washed with water (100 mL) and dried (Na2SO4), filtered under reduced pressure and evaporated to leave an orange solid. The solid was washed with hexane followed by hot diethyl ether, affording the product as an off white solid. The mother liquors were further purified by chromatography on silica, eluting with 10%-100% EtOAc/hexane. The title product was obtained as a pale orange solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:11]1([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1.Br[CH2:32][CH2:33][Cl:34]>O1CCCC1>[Cl:34][CH2:33][CH2:32][C:14]1([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12][N:11]([C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:16][CH2:15]1
Reactant: COC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: ClCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(CCCl)CCN(C(=O)OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Lithium bis(trimethylsilyl)amide (LiHMDS) in THF (1.0 M, 7.2 mL, 0.0072 mol) was added to a solution of 1-benzyl 4-methyl piperidine-1,4-dicarboxylate (1.00 g, 0.00360 mol) in tetrahydrofuran (10.0 mL) at −78° C. The reaction mixture had been stirred at −78° C. for 1 hr, then 1-bromo-2-chloroethane (0.45 mL, 0.0054 mol) was slowly added to the mixture. The reaction mixture was allowed to warm to room temperature and stirred for 2 hrs. The reaction was quenched with saturated NH4Cl, extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, concentrated. The residue was flash chromatographed (ethyl acetate in hexane: 20%) to afford 1-benzyl 4-methyl 4-(2-chloroethyl)piperidine-1,4-dicarboxylate.
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[C:3]=1[CH3:18].Br[CH2:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>>[Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([CH2:20][C:21]4[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=4[C:23]#[N:24])[CH2:15][CH2:16]3)[C:4]=2[C:3]=1[CH3:18]
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1c(Cl)sc2ncnc(NC3CCNCC3)c12
Product: Cc1c(Cl)sc2ncnc(NC3CCN(Cc4ccccc4C#N)CC3)c12

Procedure:
The title compound was prepared (100 mg, 75%) from 6-chloro-5-methyl-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (95 mg, 0.336 mmol) and 2-(bromomethyl) benzonitrile (73 mg, 0.37 mmol) by following the general procedure described for Preparation 12. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.65 (d, 1H), 7.55 (m, 2H), 7.35 (m, 1H), 5.30 (d, 1H), 4.25 (m, 1H), 3.7 (s, 2H), 2.85 (m, 2H), 2.50 (s, 3H), 2.40 (m, 2H), 2.10 (m, 2H), 1.40 (m, 2H). MS (ESI) m/z: Calculated: 397.92; Observed: 398.2 (M++1).
Reaction SMILES: [NH2:1][C:2](=[N:44][OH:45])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][O:7][NH:8][C:9]([CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:12]1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])=[O:10].CN(C=O)C.N1C=CC=CC=1.Cl[C:58]([O:60][CH2:61][CH:62]([CH2:67][CH3:68])[CH2:63][CH2:64][CH2:65][CH3:66])=[O:59]>C(OCC)(=O)C>[NH2:1][C:2](=[N:44][O:45][C:58]([O:60][CH2:61][CH:62]([CH2:67][CH3:68])[CH2:63][CH2:64][CH2:65][CH3:66])=[O:59])[C:3]1[CH:4]=[C:5]([CH:41]=[CH:42][CH:43]=1)[CH2:6][O:7][NH:8][C:9]([CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]2[NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:12]1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][C:34]=1[Cl:40])=[O:10]
Reactant: CS(=O)(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2cccc(C(N)=NO)c2)C1c1ccc(Cl)cc1Cl
Reactant: CCCCC(CC)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCC(CC)COC(=O)ON=C(N)c1cccc(CONC(=O)C2c3ccccc3C(=O)N(C3CCCCC3NS(C)(=O)=O)C2c2ccc(Cl)cc2Cl)c1

Procedure:
To a mixed liquid of 280 mg of (3RS,4RS)—N-({3-[amino(hydroxyimino)methyl]benzyl}oxy)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 10 ml of DMF were added 0.037 ml of pyridine and subsequently 0.084 ml of 2-ethylhexyl chloroformate under ice-cooling, followed by stirring under ice-cooling for 30 minutes. To the reaction solution was added ethyl acetate, followed by washing with water and a saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent:chloroform-methanol) to obtain 305 mg of (3RS,4RS)—N-[(3-{amino[({[(2-ethyl hexyl)oxy]carbonyl}oxy)imino]methyl}benzyl)oxy]-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white amorphous substance. To 290 mg of the present compound was added 6 ml of NMP, followed by stirring at 140° C. for 3 hours. The reaction solution was cooled, and 50 ml of water was then added thereto, followed by stirring. The precipitated solid was collected by filtration. This solid was purified by silica gel column chromatography (eluent: chloroform-methanol), then crystallized with acetonitrile-water, and collected by filtration to obtain 101 mg of (3RS,4RS)-3-(2,4-dichlorophenyl)-2-{(1SR,2SR)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-N-{[3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzyl]oxy}-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.