Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[NH3:6].[NH2-].[Li+].[CH3:9][C:10]([C:13]1[CH:14]=[C:15]([C:24]2[S:28][C:27]([C:29]([O:31]C)=O)=[N:26][N:25]=2)[CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])([CH3:12])[CH3:11]>CCCCCC.O1CCCC1>[CH3:21][C:20]([C:17]1[CH:16]=[C:15]([C:24]2[S:28][C:27]([C:29]([NH2:6])=[O:31])=[N:26][N:25]=2)[CH:14]=[C:13]([C:10]([CH3:11])([CH3:12])[CH3:9])[C:18]=1[OH:19])([CH3:22])[CH3:23]
Reactant: COC(=O)c1nnc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Reactant: N
Agent: [Li+]
Agent: [Li]CCCC
Agent: [NH2-]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(-c2nnc(C(N)=O)s2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2.0 ml (3.20 mmol) of 1.6M n-butyllithium in hexane is added dropwise to liquid ammonia (3-5 ml) at -78° C. over 10 minutes under a nitrogen atmosphere. The resulting white slurry is treated slowly with 10 ml of tetrahydrofuran and the resulting mixture of lithium amide at -78° C. is treated dropwise with a solution of 1.08 g (3.10 mmol) of 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-carboxylic acid, methyl ester in 3 ml of tetrahydrofuran. The reaction is allowed to warm slowly to room temperature and stirred for a total of 18 hours. The reaction is quenched with 100 ml of saturated aqueous NH4Cl and extracted with t-butylmethylether (3×). The combined organic extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo to give a yellow solid. Chromatography (flash, SiO2, 70-230 mesh, 30% ethyl acetate-hexane) followed by recrystallization from toluene gives 0.68 g (1.03 g theor., 66%) of the desired product as a pale yellow solid, mp 200°-201° C.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[N:7][CH:8]=1.P(Br)(Br)([Br:22])=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:22][C:3]1[CH:4]=[C:5]([O:9][C:10]2[N:14]([CH3:15])[N:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=[N:7][CH:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: COc1cnnc(Oc2cc(C(F)(F)F)nn2C)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1nc(C(F)(F)F)cc1Oc1cc(Br)cnn1
Yield: 46.8 %

Procedure:
5-Methoxy-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine(Compound No. 5, 5.0 g, 0.0182 mole) and phosphorus oxybromide (5.7 g, 0.02 mole) were refluxed under N2 in toluene (100 mL) for 3.5 hours. The mixture was poured into ethyl acetate and extracted 2×200 mL with water. The organic layer was then extracted with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and evaporated in vacuo to give a crude oil. The oil was purified by chromatography on silica gel to give 5-bromo-3-[[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5yl]oxy]pyridazine (2.75 g, 47% yield) as a brown solid which was used directly in the following step.
Reaction SMILES: C([O-])=O.[NH4+].C(OC([N:15]1[CH2:20][CH2:19][C:18]([CH2:27][C:28](=[O:39])[NH:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1)=O)C1C=CC=CC=1>CO.[Pd]>[F:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][CH2:30][NH:29][C:28](=[O:39])[CH2:27][C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1
Reactant: O=C(CC1(c2ccccc2)CCN(C(=O)OCc2ccccc2)CC1)NCCc1ccccc1F
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: O=C(CC1(c2ccccc2)CCNCC1)NCCc1ccccc1F
Reaction time: 4 h
Yield: 87.6 %

Procedure:
Ammonium formate (1.00 g) was added to a solution of 4-{[2-(2-fluoro-phenyl)-ethylcarbamoyl]-methyl}-4-phenyl-piperidine-1-carboxylic acid benzyl ester (0.520 g, 1.10 mmol) in methanol (50 mL) containing 10% palladium/carbon (0.500 g) and stirred for 4 h. The reaction mixture was filtered through celite and concentrated under reduced pressure. The crude product was taken up in 1M sodium hydroxide (100 mL) and extracted with ethyl acetate (3×50 mL). The organic layers were collected and concentrated under reduced pressure to give 0.328 g (87%) of N-[2-(2-fluoro-phenyl)-ethyl]-2-(4-phenyl-piperidin-4-yl)-acetamide. LRMS m/z 341.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([N:20]1[CH2:21][CH2:22][CH:17]([N:15]2[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]3[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=3)=[N:16]2)[CH2:18][CH2:19]1)(=[O:35])=[O:34]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4Br)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-bromobenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([S:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)=[N:19][N:20]=3)[N:17]=2)[CH:9]=[N:8]1.FC(F)(F)C(O)=O.C(N)CN>ClCCl.CO>[NH:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([S:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)=[N:19][N:20]=3)[N:17]=2)[CH:9]=[N:8]1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccc3nnc(Sc4ccc5ncccc5c4)n3n2)cn1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cnc2ccc(Sc3nnc4ccc(-c5cn[nH]c5)nn34)cc2c1
Temperature: 50 °C
Yield: 53.1 %

Procedure:
To a solution of 6-{6-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazol-4-yl]-[1,2,4]triazolo[4,3-b]pyridazin-3-ylsulfanyl}-quinoline (150 mg, 0.32 mmol) in dichloromethane (8 mL) at 0° C. was added trifluoroacetic acid. After 3 hours the mixture was concentrated to dryness and taken Up in dichloromethane and neutralized via the addition of aqueous NaHCO3. To this emulsion was added a chloroform/methanol (95/5) mixture (20 mL) and brine (30 mL). The organic phase was separated and the organic phase filtered and the solid residue washed with water then Et2O and dried to return a yellow solid (64 mg). This solid was taken up in methanol (2 mL) to which ethylenediamine (1 mmol) was added and heated at 50° C. for 1 hour. The mixture was cooled to ambient temperature and the solid collected via filtration and dried to return title compound as a white solid (57 mg, 0.17 mmol, 53% yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[C:9]([C:11]1([CH3:15])[CH2:14][CH2:13][NH:12]1)=[O:10].[CH3:25][C:26]1[CH:27]=[C:28]([N:33]=[C:34]=[O:35])[CH:29]=[C:30]([CH3:32])[CH:31]=1>C1COCC1>[CH3:2][O:3][C:4](=[O:24])[CH2:5][CH2:6][CH2:7][N:8]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=1)[C:9]([C:11]1([CH3:15])[CH2:14][CH2:13][N:12]1[C:34](=[O:35])[NH:33][C:28]1[CH:29]=[C:30]([CH3:32])[CH:31]=[C:26]([CH3:25])[CH:27]=1)=[O:10]
Reactant: Cc1cc(C)cc(N=C=O)c1
Reactant: COC(=O)CCCN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)CCCN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)Nc1cc(C)cc(C)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 4-[(4-chloro-benzyl)-(2-methyl-azetidine-2-carbonyl)-amino]-butyric acid methyl ester hydrochloride, Intermediate 23 (1 eq.) and TEA (5 eq.) in THF under nitrogen was added 3,5-dimethyl-phenyl-isocyanate (1.5 eq.). The reaction was stirred for 15 h at 20° C. The crude was partitioned between a saturated aqueous solution of NaHCO3 and EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 75/25 to 40/60) to afford 4-{(4-chloro-benzyl)-[1-(3,5-dimethyl-phenylcarbamoyl)-2-methyl-azetidine-2-carbonyl]-amino}-butyric acid methyl ester.
Reaction SMILES: Cl[C:2]1[C:3](NC(=S)COC)=[C:4]2[C:9](=[CH:10][C:11]=1Cl)[N:8]=[C:7](OC)[C:6](OC)=[N:5]2.C(NN)(=O)C1C=CC=NC=1>[Hg]=O.O1CCOCC1>[N:5]1[C:4]2[C:9](=[CH:10][CH:11]=[CH:2][CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: COCC(=S)Nc1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: NNC(=O)c1cccnc1
Agent: O=[Hg]
Solvent: C1COCCO1
Product: c1ccc2nccnc2c1
Yield: 127.5 %

Procedure:
A mixture of 6,7-dichloro-2,3-dimethoxy-5-methoxythioacetamido-quinoxaline (25.3 g, 69.9 mmol), nicotinic acid hydrazide (19.3 g, 140.8 mmol), mercury(II) oxide (15.1 g, 69.7 mmol) and 1,4-dioxane (600 ml) was heated under reflux for 18 hours. After cooling, the mixture was filtered through ARBOCEL (trade mark) filter aid and the residue washed with dichloromethane. The filtrate was concentrated under reduced pressure to afford a light brown solid which was partitioned between ethyl acetate and 2M aqueous hydrochloric acid solution. The layers were separated and the aqueous layer was extracted with dichloromethane (2×500 ml, 4×100 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was crystallised from ethyl acetate/methanol to give (±)-6,7-dichloro-2,3-dimethoxy-5-[3-methoxymethyl-5-(3-pyridyl)-4H-1,2,4-triazol-4-yl)]quinoxaline (11.6 g, 37%) as a pale yellow solid. mp 189-191° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]3[B:12]([OH:15])[O:13][CH2:14][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.CCN(CC)CC>C(Cl)Cl>[OH:15][B:12]1[C:11]2[CH:16]=[CH:17][C:8]([O:7][C:6]3[CH:18]=[CH:19][C:3]([CH2:2][NH:1][S:27]([C:24]4[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=4)(=[O:29])=[O:28])=[CH:4][CH:5]=3)=[CH:9][C:10]=2[CH2:14][O:13]1
Reactant: NCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCc2ccc(Oc3ccc4c(c3)COB4O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial containing 5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (144 mg, 0.56 mmol, 1.1 eq.), 4-methyl-benzenesulfonyl chloride (118.4 mg, 0.62 mmol, 1.1 eq.) in DCM (10.0 mL) was added Et3N (160 μL, 1.12 mmol, 2.0 eq.) drop wise. The mixture was stirred at room temperature overnight. The mixture was carefully treated with aqu. NH4Cl (10 mL) and the layers were separated. The aqueous was extracted with DCM (2×5 mL), combined organic phase was washed with H2O (10 mL), brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with EtOAc/Heptanes (0:100 to 80:20) to give N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-4-methyl-benzenesulfonamide as a white solid. LCMS (m/z) 432 (M+23); 1H NMR (400 MHz, DMSO-d) δ ppm 1H NMR (DMSO-d6) δ: 9.11 (s, 1H), 8.08 (t, J=6.3 Hz, 1H), 7.65-7.74 (m, 3H), 7.38 (d, J=8.0 Hz, 2H), 7.23-7.31 (m, J=8.6 Hz, 2H), 6.95-7.00 (m, 2H), 6.89-6.95 (m, 2H), 4.92 (s, 2H), 3.95 (d, J=6.3 Hz, 2H), 2.38 (s, 3H).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH:6]([C:9]1[CH:13]=[CH:12][NH:11][N:10]=1)([CH3:8])[CH3:7].[Br:14]Br>C(O)(=O)C.O>[Br:14][C:13]1[C:9]([CH:6]([CH3:8])[CH3:7])=[N:10][NH:11][CH:12]=1
Reactant: BrBr
Reactant: CC(C)c1cc[nH]n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1n[nH]cc1Br
Reaction time: 15 h
Yield: 80.9 %

Procedure:
To a stirred solution of sodium acetate (19.7 g., 0.24 mole) in acetic acid (100 ml.) and water (15 ml.), 3-isopropylpyrazole (11.0 g., 0.1 mole) was added, followed by dropwise addition of bromine (16.0 g., 0.11 mole) keeping the internal temperature below 15° C. The mixture was kept at 25° C. for 15 hours, treated with water (200 ml.) and extracted with ethyl ether (3 × 50 ml.), and the ether layer washed with water (1 × 50 ml.) dried, (sodium sulfate) and evaporated under reduced pressure. The resultant pale yellow oil was distilled to give 4-bromo-3-isopropylpyrazole (15.3 g., 81%) with a boiling point of 85° C. at 0.06 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN(C)C=O.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: Clc1ccccc1Cl
Solvent: CN(C)C=O
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Yield: 0.72 %

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H) naphthalenylidene]methanamine (Ketimine) (50 g), dimethylformamide (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 12 to 13 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product<0.1%, yield 0.72 to 0.75%].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][C@H:19]([CH3:23])[C@H:20]([OH:22])[CH3:21])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][CH:4]=1.[C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:31]=[CH2:32].O>C1COCC1>[C:35]([O:34][C:30](=[O:33])[CH2:31][CH2:32][O:22][C@H:20]([CH3:21])[C@H:19]([O:18][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:10]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:11][C:12]=2[N:13]=[CH:14][N:15]=1)[CH3:23])([CH3:38])([CH3:37])[CH3:36]
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H](C)[C@@H](C)O)c23)cc1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H](C)[C@@H](C)OCCC(=O)OC(C)(C)C)c23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add 157 mg (1.37 mmol) potassium tert.-butylate to a solution of 535 mg (1.37 mmol) (2R,3R)-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}butan-2-ol in 5 ml THF. After stirring for 15 min at RT, add 1.0 ml (878 mg, 6.65 mmol) tert.-butyl acrylate. After three hours, add 10 ml water, and concentrate the reaction mixture by vacuum evaporation. Purify the residue by preparative RP-HPLC (gradient: water/acetonitrile). 346 mg (47% of theor.) of the desired product is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[N:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1=[O:17].[H-].[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22]([CH2:21][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3](=[O:17])[C:4]2[CH:16]=[CH:15][CH:14]=[N:13][C:5]1=2)=[O:23])[CH3:26]
Reactant: CN1C(=O)c2cccnc2Nc2ccccc21
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1c2ccccc2N(C)C(=O)c2cccnc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
To 1.0 g (4.4 mmoles) of 5,6-dihydro-6-methyl-11H-pyrido[2,3-b][1,5]benzodiazepin-5-one in 50 ml of dimethylformamide was added 0.25 g (5 mmol) of 50% sodium hydride in oil. The reaction mixture was then stirred at 50° C. for an additional 2 h and then 0.6 ml (5 mmol) of ethyl bromoacetate was added. The reaction mixture was then stirred at 50° C. for an additional 3 h. It was then cooled to room temperature and the solvent was evaporated. The residue was dissolved in methylene chloride, washed with water, dried over anhydrous sodium sulfate and evaporated to obtain 2.0 g of the crude product. It was further purified by column chromatography (silica gel) using 10% ethyl acetate/methylene chloride as eluent to obtain 250 mg of pure 5,6-dihydro-11-(ethoxy-carbonyl)methyl-6-methyl-11H-pyrido[2,3-b][1,5]benzodiazepin-5-one, m.p. 99°-100° C.
Reaction SMILES: C(O[C:4](=[O:20])[C:5]([CH3:19])([CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])C.[CH3:21][S:22]([NH:25][CH2:26][C:27]1[C:35]2[S:34](=[O:37])(=[O:36])[N:33]=[C:32]([CH2:38][C:39](O)=[O:40])[NH:31][C:30]=2[S:29][CH:28]=1)(=[O:24])=[O:23].Cl.CN(C)CCCN=C=NCC.[O-]CC.[Na+].C(O)C>CN(C)C=O>[OH:20][C:4]1[C:5]([CH3:19])([CH2:6][CH2:7][CH:8]([CH3:9])[CH3:10])[CH2:11][N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:39](=[O:40])[C:38]=1[C:32]1[NH:31][C:30]2[S:29][CH:28]=[C:27]([CH2:26][NH:25][S:22]([CH3:21])(=[O:23])=[O:24])[C:35]=2[S:34](=[O:37])(=[O:36])[N:33]=1
Reactant: CCOC(=O)C(C)(CCC(C)C)CNc1ccccc1
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CC[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)CCC1(C)CN(c2ccccc2)C(=O)C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)=C1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.9 %

Procedure:
2,5-Dimethyl-2-phenylaminomethyl-hexanoic acid ethyl ester (0.10 g, 0.36 mmol) was dissolved in N,N-dimethylformamide (4 mL). [7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.127 g, 0.36 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.083 g, 0.43 mmol). The mixture was stirred at 25° C. for 5 h. The solvent was removed in vacuo then re-dissolved in ethanol. A 21 wt. % solution of sodium ethoxide in ethanol (806 μL, 2.16 mmol) was added to the mixture and stirred at 60° C. for 16 h. Upon cooling to 25° C., the mixture was concentrated in vacuo to afford a thick oil. The oil was partitioned between dichloromethane (4 mL) and 1.0 M aqueous hydrochloric acid solution (6 mL). The organic phase was loaded directly onto a prepacked RediSep silica gel column and purified by flash column chromatography (Teledyne Isco RediSep column; 20-100% ethyl acetate in hexanes) to afford the desired product, N-{3-[4-hydroxy-5-methyl-5-(3-methyl-butyl)-2-oxo-1-phenyl-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.079 g, 0.1401 mmol, 39%), as an off white powder. 1H NMR (400 MHz, Acetone-d6) δ: 0.90 (6H, d, J=8.0 Hz), 1.25-1.38 (2H, m), 1.49-1.59 (1H, m), 1.80-1.89 (2H, m), 2.08 (3H, s), 2.96 (3H, s), 3.78-3.85 (2H, m), 4.44 (2H, d, J=6.1 Hz), 6.42 (1H, t, J=6.3 Hz), 7.31-7.48 (6H, m). LC-MS (ESI) calculated for C24H30N4O6S3 566.13. found 567.2 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:30]([O:32]C(C)(C)C)=[O:31])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(C(O)=O)=NC(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)=NC=1O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:10]([C:30]([OH:32])=[O:31])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3ccc(Cl)c(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1
Agent: O=C(O)c1nc(CC2(c3ccc(C(F)(F)F)cc3)CCCC2)nc(O)c1OCc1ccccc1
Product: O=C(O)c1nc(CC2(c3ccc(Cl)c(Cl)c3)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-(Benzyloxy)-2-((1-(3,4-dichlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylic acid (488) was synthesized as a white solid from tert-butyl 5-(benzyloxy)-2-((1-(3,4-dichlorophenyl)cyclopentyl)methyl)-6-hydroxypyrimidine-4-carboxylate (487) following the procedure described for 5-benzyloxy-2-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid (244).
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:35])[CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH:18]([C:24]2[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[C:26]([F:33])[C:25]=2[F:34])[C:19]([O:21]CC)=[O:20])=[O:15])=[CH:6][CH:5]=1.[OH-].[Li+].C(O)(C(F)(F)F)=O>O.C(#N)C>[NH2:1][N:2]=[CH:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11](=[O:35])[CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH:18]([C:24]2[C:25]([F:34])=[C:26]([F:33])[C:27]([F:32])=[C:28]([F:31])[C:29]=2[F:30])[C:19]([OH:21])=[O:20])=[O:15])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(CNC(=O)CCC(=O)Nc1ccc(C=NN)cc1)c1c(F)c(F)c(F)c(F)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: NN=Cc1ccc(NC(=O)CCC(=O)NCC(C(=O)O)c2c(F)c(F)c(F)c(F)c2F)cc1
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
Ethyl β[[4-[[4-(aminoiminomethyl)phenyl]-amino]-1,4-dioxobutyl]amino]-(pentafluorophenyl)propanoate prepared in Example 59 (600 mg) was added to water/acetonitrile (20 ml) followed by lithium hydroxide (100 mg) at 25° C. The mixture was stirred for 30 min. The course of the reaction was monitored by RPHPLC. After satisfactory acid was formed the reaction was neutralized with TFA and purified by reverse phase chromatography (water/acetonitrile) to result in 620 mg of a white solid: 1H NMR (d6 -DMSO) δ2.38 (t, 2H, J=7.3 Hz), 2.44 (d, 2H, J=6.4 Hz), 2.56 (t, 2H, J=7.3 Hz), 4.32 (m, 1H), 7.78 (s, 4H), 7.99 (d, 1H,J=8.1 Hz), 8.92 (bs, 2H), 9.16 (bs, 2H), 10.39 (s, 1H); MS (FAB) m/z 365.2 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=[O:34]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:34])=[CH:3][C:4]=3[S:25]([CH3:28])(=[O:27])=[O:26])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: O=C1CCCN1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3S(C)(=O)=O)CC2)c(C)c1

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (466 mg) described in Preparation Example 254 and pyrrolidin-2-one (115 μL) and by the reaction and treatment in the same manner as in Example 262, the title compound (420 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28]>C1(C)C=CC=CC=1>[CH3:28][CH:27]([NH:30][C:31]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)=[O:32])[CH3:29]
Reactant: CC(C)N=C=O
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Solvent: Cc1ccccc1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)NC(C)C)c4)CC3)cccc2n1

Procedure:
The title compound was prepared from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6, 30 mg), isopropyl isocyanate (10.2 μL) using toluene (1 mL) as solvent according to Method E. Yield 23 mg.