Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[F:5][C:6]([F:26])([F:25])[O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:18][CH2:17][C:16]3([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:15]2=[O:24])=[CH:10][CH:9]=1.[C:27]1([CH:33]([CH2:37][CH3:38])[C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH:33]([CH2:37][CH3:38])[C:34]([N:21]2[CH2:20][CH2:19][C:16]3([C:15](=[O:24])[N:14]([C:11]4[CH:12]=[CH:13][C:8]([O:7][C:6]([F:5])([F:25])[F:26])=[CH:9][CH:10]=4)[CH2:18][CH2:17]3)[CH2:23][CH2:22]2)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: CCC(C(=O)Cl)c1ccccc1
Solvent: CC(=O)O
Product: CCC(C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)c1ccccc1

Procedure:
The title compound was prepared in analogy to example 7 step A from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one acetic acid salt (described in example 180 step C) and 2-phenyl-butyryl chloride. Off-white solid. MS (ESI): 461.4 (MH+).
Reaction SMILES: [OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26]C4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1.Cl.CNC1COC1>>[OH:1][C@:2]([C:32]1[CH:36]=[C:35]([CH3:37])[O:34][N:33]=1)([CH3:31])[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[O:14][CH2:13][CH2:12][N:11]3[C:15]([C:21]([NH:23][CH2:24][CH:29]4[CH2:26][O:27][CH2:28]4)=[O:22])=[C:16]([C:18]([NH2:20])=[O:19])[N:17]=[C:10]3[C:9]=2[CH:30]=1
Reactant: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NC4CCOCC4)n2CCO3)no1
Agent: CNC1COC1
Agent: Cl
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(=O)NCC4COC4)n2CCO3)no1

Procedure:
Prepared as described for (R)-10-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-yn-1-yl)-N3-(tetrahydro-2H-pyran-4-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2,3-dicarboxamide replacing oxan-4-amine hydrochloride with 3-methylaminooxetane hydrochloride. off-white solid (6.7 mg, 2%).
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.CO.O.C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O.CCOCC>[OH:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(OCCOC2CCCCO2)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: O=C(O)c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixture of 7.7 g (37.7 mmol) of 4-(2-tetrahydropyranyloxyethoxy)benzoic acid and 31 ml (754 mmol) of anhydrous methanol, at RT, is added 2 drops of conc. sulfuric acid. The mixture is stirred at RT for 1 day and is then rotoevaporated to near dryness. To the residue is added 100 ml water, 50 ml ether and 30 ml aqueous 15% potassium carbonate, and the mixture is stirred until the solid is dissolved. The organic phase is separated and discarded; 150 ml of ethyl acetate and 50 ml of aqueous 3 N sulfuric acid are added to the remaining aqueous phase. The aqueous phase is then separated and extracted with ethyl acetate (80 ml, 3X). The combined organic phases are washed with aqueous saturated sodium chloride (50 ml, 2X) and then dried over calcium sulfate. Removal of solvent by rotoevaporation gives 4-(hydroxyethoxy)benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][CH:13]=[N:12][C:11]=2[NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(NC(=O)C2C=CC=NC=2NC2CC(C)(C)NC(C)(C)C2)C=CC=1.[CH2:51](Cl)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.BrCCO>>[CH2:51]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([NH:16][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:23])[CH2:18]1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1
Reactant: ClCc1ccccc1
Reactant: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@H]1CCCNC1
Agent: CC1(C)CC(Nc2ncccc2C(=O)Nc2cccc(Cl)c2)CC(C)(C)N1
Agent: OCCBr
Product: O=C(Nc1cccc(Cl)c1)c1cccnc1N[C@@H]1CCCN(Cc2ccccc2)C1
Yield: 64.4 %

Procedure:
The title compound was prepared in the same manner as in Example 21, with the exception that (S)—N-(3-chlorophenyl)-2-(3-piperidylamino)nicotinamide of Example 20-A, instead of N-(3-chlorophenyl)-2-(2,2,6,6-tetramethylpiperidin-4-ylamino)nicotinamide, and benzylchloride, instead of 2-bromoethanol, were used in the same molar amounts (Yield: 64.4%). 1H NMR (CDCl3) δ 8.33 (d, 1H), 8.24 (d, 1H), 7.83 (s, 1H), 7.74 (s, 1H), 7.68 (d, 1H), 7.47-7.13 (m, 7H), 6.53-6.46 (m, 1H), 4.39-4.27 (m, 1H), 2.69 (d, 1H), 2.53-2.34 (m, 3H), 1.85-1.58 (m, 6H) ppm.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][SH:7])(=[O:3])[CH3:2].[H-].[Na+].Cl[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[N:16]=1>C(O)C>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[N:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCCS
Reactant: Clc1ccc2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)NCCSc1ccc2nccn2n1
Yield: 77.2 %

Procedure:
To 30 ml of ethanol is added 1.79 g of N-acetylcysteamine and with ice-cooling and stirring, 720 mg of sodium hydride (oily, 60 wt.%) is added. Then, 1.54 g of 6-chloroimidazo[1,2-b]pyridazine is further added and the mixture is stirred at 50° C. for 4 hours. The solvent is distilled off under reduced pressure and the residue is diluted with a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The extract is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is subjected to silica gel (50 g) column chromatography and after the column is washed with ethyl acetate, elution is carried out with acetone. The eluate is concentrated under reduced pressure to give 1.83 g of 6-(2-acetylaminoethylthio)imidazo[1,2-b]pyridazine as colorless powders.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Br:12])[N+:8]([O-])=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:19])[NH:5]2.P(Cl)(Cl)Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Br:12])[N:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:19])[NH:5]2
Reactant: CCOC(=O)c1c(=O)[nH]c2cc(Cl)c(Br)cc2[n+]1[O-]
Solvent: ClP(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1nc2cc(Br)c(Cl)cc2[nH]c1=O
Temperature: 0 °C

Procedure:
One gram of ethyl 6-chloro-7-bromo-3,4-dihydro-3-oxo-2-quinoxaline carboxylate N-oxide was dissolved in 50 ml. of THF. Six ml. of phosphorus trichloride were added and the resulting mixture heated gently at refluxing temperature overnight. The reaction mixture was poured into 500 ml. of an ice-water mixture. A solid, comprising ethyl 6-chloro-7-bromo-3,4-dihydro-3-oxo-2-quinoxaline carboxylate formed in the above reaction, was separated by filtration; melting point=203°-205° C.; yield=0.6 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13].[Li]CCCC.CN([CH:23]=[O:24])C>>[Cl:12][C:10]1[CH:11]=[C:2]([CH:23]=[O:24])[CH:3]=[C:4]2[C:9]=1[S:8][CH2:7][CH2:6][C:5]2([CH3:14])[CH3:13]
Reactant: CC1(C)CCSc2c(Cl)cc(Br)cc21
Reactant: CN(C)C=O
Agent: [Li]CCCC
Product: CC1(C)CCSc2c(Cl)cc(C=O)cc21

Procedure:
Using essentially the same procedure as Example 5-20, Step 3, 6-bromo-8-chloro-4,4-dimethyl-3,4-dihydro-2H-thiochromene (954 mg, 3.27 mmol), n-BuLi (1.57 mL, 3.93 mmol) and DMF (1.01 mL, 13.1 mmol) afforded the desired product as a pale-yellow oil.
Reaction SMILES: [C:1]1([C:7]2[NH:12][C:11](=[O:13])[C:10]3[CH2:14][CH2:15][CH2:16][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:19](Br)[C:20]#[CH:21]>O1CCCC1.C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]1([C:7]2[N:12]([CH2:21][C:20]#[CH:19])[C:11](=[O:13])[C:10]3[CH2:14][CH2:15][CH2:16][C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=c1[nH]c(-c2ccccc2)nc2c1CCC2
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#CCn1c(-c2ccccc2)nc2c(c1=O)CCC2
Yield: 5.1 %

Procedure:
A slurry of 8.3 g (39.1 mmol) of 2-phenyl-3,5,6,7-tetrahydro-4H-cyclopentapyrimidin-4-one in 60 mL of tetrahydrofuran was added to 1.9 g (48 mmol) of 60% sodium hydride, with external cooling. A 6.4 g (43.0 mmol) portion of 80% by weight of propargyl bromide in toluene was added to the cooled solution. The ice bath was removed and the reaction was refluxed for 6 hours. The solvent was removed in vacuo, ether was added to the residue and the reaction was washed 3 times with water and once with brine. The organic layer was dried over MgSO4 and concentrated to yield 5.0 g of crude semisolid product. The crude product was dissolved in a small amount of methylene chloride and passed through a 6 inch plug of silica gel, washing with 1 of methylene chloride. The silica gel was washed further with 1 L of ether. The ether was removed in vacuo to yield 0.5 g (5.1%) of 2-phenyl-3-propargyl-3,5,6,7-tetrahydro-4H-cyclopentapyrimidin-4-one (Compound 1) as a white solid. 1H-NMR (CDCl3) δ 2.15 (2H,m), 2.35 (1H,t), 2.95 (4H,t), 4.65 (2H,t), 7.55 (3H,m), 7.7 (2H,m).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][N:3]=1.[C:13](=[NH:26])(C1C=CC=CC=1)[C:14]1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Cl.C(=O)([O-])O.[Na+].ClCC=O>C1(C)C=CC=CC=1.CC(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:8][C:7]1[C:2]2[N:3]([CH:14]=[CH:13][N:26]=2)[CH:4]=[CH:5][C:6]=1[C:9]([F:12])([F:11])[F:10]
Reactant: Fc1c(C(F)(F)F)ccnc1Cl
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Fc1c(C(F)(F)F)ccn2ccnc12
Temperature: 115 °C
Yield: 42 %

Procedure:
A mixture of 2-chloro-3-fluoro-4-trifluoromethylpyridine (3.50 g, 17.5 mmol), benzophenone imine (3.50 g, 19.3 mmol), palladium(II) acetate (0.158 g, 0.70 mmol), caesium carbonate (8.00 g, 24.6 mmol) and BINAP (0.66 g, 1.05 mmol) was suspended in toluene (35 ml) and degassed with nitrogen for 1 h. The mixture was then heated at 115° C. for 18 h. The mixture was allowed to cool to ambient temperature, diluted with toluene (100 ml) and the organic phase was washed with water (100 ml) and brine (100 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give an orange oil. The oil was dissolved in propan-2-ol (60 ml), 5N hydrochloric acid (10 ml) added and the mixture heated at 50° C. for 30 min. The mixture was cooled to ambient temperature and solid sodium hydrogencarbonate (7.14 g, 85 mmol) added portionwise over 10 min, followed by addition of chloroacetaldehyde (2.75 g, 35.08 mmol). On complete addition the mixture was heated at 95° C. for 24 h. The mixture was allowed to cool to ambient temperature, filtered through a glass microfibre filter paper, the solid washed with ethanol (30 ml) and the filtrate evaporated. The residue was diluted with ethyl acetate (200 ml) and extracted with 5N hydrochloric acid (2×75 ml). The organics were filtered and then washed with ethyl acetate (2×100 ml). The aqueous phase was then made basic by the addition of solid sodium hydrogen-carbonate and extracted with ethyl acetate (2×150 ml). The organics were washed with brine (100 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give a brown oil. The oil was purified by flash column chromatography on silica eluting with dichloromethane on a gradient of methanol (0-2%). Collecting appropriate fractions gave 8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridine (1.5 g, 42%) as a pale yellow solid: δH (360 MHz, CDCl3) 6.92 (1H, dd, J 7 and 7), 7.75 (1H, d, J 3), 7.80 (1H, d, J 3), 8.04 (1H, d, J 7).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:9]=[C:8]([OH:10])[N:7]([CH3:11])[N:6]=1)([CH3:4])[CH3:3].Cl[C:13]1[N:14]=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CS(C)=O>[CH3:4][C:2]([C:5]1[CH:9]=[C:8]([O:10][C:13]2[N:14]=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=2)[N:7]([CH3:11])[N:6]=1)([CH3:1])[CH3:3]
Reactant: COc1cnnc(Cl)c1
Reactant: Cn1nc(C(C)(C)C)cc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cnnc(Oc2cc(C(C)(C)C)nn2C)c1
Temperature: 95 °C
Reaction time: 7 h
Yield: 61.2 %

Procedure:
3-(1,1-Dimethylethyl)-1-methyl-1H-pyrazol-5-ol (1.12 g, 0.0073 moles) which is a known compound, 3-chloro-5-methoxypyridazine (1.02 g, 0.0071 mole), potassium carbonate (1.87 g, 0.0136 mole), and CuBr (1.05 g, 0.0073 mole) were added to dry dimethyl-sulfoxide (12 mL). The mixture was stirred under N2 at 95° C. for 7 h. The mixture was then poured into saturated ammonium chloride and extracted 2×100 mL with ethyl acetate. The organic layer was dried (MgSO4), filtered through silica gel with ethyl acetate and evaporated in vacuo. The crude oil was flash chromatographed to give 3-[[3-(1,1-dimethylethyl)-1-methyl-1H-pyrazol-5-yl]oxy-5-methoxypyridazine (1.14 g, 62% yield) as an oil which solidified upon standing to a white solid.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8]2)(=[O:4])=[O:3].[OH-].[NH4+:22]>C1COCC1.O>[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8]2)(=[O:4])(=[O:3])[NH2:22]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(S(=O)(=O)Cl)cc2C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccc(S(N)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of tert-butyl 5-(chlorosulfonyl)isoindoline-2-carboxylate (D97) (400 mg, 1.259 mmol) in THF (12 mL) was added ammonium hydroxide (0.490 mL, 12.59 mmol) at 0° C. The mixture was left to stir for 1 hour at RT. The mixture was concentrated in vacuo and the residue obtained taken up in water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were dried and concentrated down to afford the title compound (335 mg). LCMS (A): m/z (M−H)− 297, C13H18N2O4S requires 298 (acidic).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:14])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:15])[CH:5]=1.Cl.[N:17]1([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[NH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([N:17]2[CH2:18][CH2:19][N:20]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([N:10]([CH3:14])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:15])[CH:5]=3)[CH2:21][CH2:22]2)=[N:24]1
Reactant: c1ccc2c(N3CCNCC3)n[nH]c2c1
Reactant: CC(=O)N(C)c1ccc(CCCl)cc1C
Agent: Cl
Product: CC(=O)N(C)c1ccc(CCN2CCN(c3n[nH]c4ccccc34)CC2)cc1C
Yield: 45 %

Procedure:
Starting with N-[4-(2-chloro-ethyl)-2-methyl-phenyl]-N-methyl-acetamide (0.195 g, 0.863 mmol) and 3-piperazin-1-yl-1H-indazole hydrochloride (0.309 g, 1.24 mmol) and following the procedure as outlined in Example 501, N-(4-{2-[4-(1H-indazol-3-yl)-piperazin-1-yl]-ethyl}-2-methyl-phenyl)-N-methyl-acetamide was obtained as its hydrochloride salt (0.152 g, 0.388 mmol). Yield=45%. 100% purity @ 254 nm; LCMS (APCI): 392.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.57 (bs, 1H), 7.79 (d, J=8.91 Hz, 1H), 7.37 (d, J=8.91 Hz, 1H), 7.32–7.24 (m, 2H), 7.24–7.13 (m, 2H), 6.99 (t, J=6.93 Hz, 1H), 3.97 (bd, J=9.77 Hz, 2H), 3.64 (bm, 2H), 3.48 (bs, DMSO-H2O), 3.44–3.24 (m, 6H), 3.10–3.02 (m, 2H), 3.00 (s, 3H), 2.47 (DMSO), 2.15 (s, 3H), 1.60 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26]([O:28]C(C)(C)C)=[O:27])=[CH:17][C:16]=1[C:33]([F:36])([F:35])[F:34])=[O:13].C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[C:3]1[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2[C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:33]([F:36])([F:35])[F:34])=[O:13]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1c1ccc(NC(=O)c2c[nH]c3ccccc3c2=O)c(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCC[C@@H]2C(=O)O)cc1C(F)(F)F)c1c[nH]c2ccccc2c1=O
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (2R)-1-[4-[(4-oxo1H-quinoline-3-carbonyl)amino]-3-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylate (35 mg, 0.06979 mmol) in DCM (500 μL) was added TFA (1 mL) at room temperature and the reaction mixture was stirred for 3 h. The solvents were evaporated under reduced pressure and the residue was purified via reverse phase HPLC to give (2R)-1-[4-[(4-oxo-1H-quinoline-3-carbonyl)amino]-3-(trifluoromethyl)phenyl]pyrrolidine-2-carboxylic acid. LC/MS: m/z 466.3 (M+H)+ at 1.46 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][C:8]=1[S:17](=[O:20])(=[O:19])[NH2:18].C[O-].[Na+].[Na]>CO>[ClH:6].[Cl:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([NH:4][C:3]([NH2:5])=[NH:2])=[O:12])=[CH:9][C:8]=1[S:17](=[O:19])(=[O:20])[NH2:18]
Reactant: N=C(N)N
Reactant: COC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(N)NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1

Procedure:
8.5 g of guanidine hydrochloride and then 5 g of methyl 4-chloro-3-sulfamoylbenzoate are added to a methanolic sodium methoxide solution, prepared from 1.9 g of sodium in 90 ml of methanol. After heating this mixture to 50°-60° C. under inert gas (nitrogen or argon) over the course of 30 hours, the solvent is removed by distillation, the solution is adjusted to pH 6 after taking up the residue with 2 N acetic acid and is extracted with ethyl acetate. After acidifying the dried extract (drying over magnesium sulfate) using ethereal hydrochloric acid, the title compound is filtered off.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([O:23][C@H:24]4[CH2:29][CH2:28][C@@H:27]([C:30]([CH3:34])([CH3:33])[CH2:31][CH3:32])[CH2:26][CH2:25]4)[CH:19]=3)[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Li+].O1CCCC1.O>>[C:30]([C@@H:27]1[CH2:28][CH2:29][C@H:24]([O:23][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([CH2:12][N:9]2[CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10]2)[CH:22]=[CH:21]3)[CH2:25][CH2:26]1)([CH2:31][CH3:32])([CH3:33])[CH3:34]
Reactant: CCOC(=O)C1CCN(Cc2ccc3cc(O[C@H]4CC[C@@H](C(C)(C)CC)CC4)ccc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)(C)[C@H]1CC[C@@H](Oc2ccc3cc(CN4CCC(C(=O)O)CC4)ccc3c2)CC1

Procedure:
A solution of 1-{6-[cis-4-(1,1-dimethyl-propyl)-cyclohexyloxy]-naphthalen-2-ylmethyl}-piperidine-4-carboxylic acid ethyl ester (0.382 g, 0.820 mmol) and lithium hydroxide (196 mg, 8.20 mmol) in tetrahydrofuran (3.32 mL, 41.0 mmol) and water (0.738 mL, 41.0 mmol) was stirred at room temperature overnight. LCMS showed a single desired product peak Rt=1.78 min, m/z=438.40 [M+1], 100%. The solvent was concentrated and neutralized with concentrated HCl. The solid was suspended with water and filtered and washed thoroughly with water and ether then dried to give a white solid (86.9 mg, 24%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.81-0.90 (m, 9H), 1.19-1.70 (m, 10H), 2.19 (d, J=13.99 Hz, 2H), 2.67 (s, 2H), 4.45 (s, 2H), 4.78 (t, J=2.45 Hz, 1H), 7.26 (dd, J=8.91, 2.45 Hz, 1H), 7.31 (d, J=2.26 Hz, 1H), 7.53 (dd, J=8.50, 1.73 Hz, 1H), 7.86 (dd, J=8.69, 3.42 Hz, 2H), 7.96 (s, 1H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][S:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>>[Br:28][C:25]1[CH:24]=[CH:23][C:22]([S:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:27][CH:26]=1
Reactant: O=C(CSc1ccc(Br)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NCCc1ccc(O)cc1
Product: O=C(NCCc1ccc(O)cc1)c1ccc2n1Cc1ccccc1N(C(=O)CSc1ccc(Br)cc1)C2

Procedure:
The title compound was synthesized in the manner of Example 81 from 2,2,2-trichloro-1-[10-{[(4-bromophenyl)thio]acetyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-yl]-ethanone of Example 80 and 4-(2-aminoethyl)-phenol, m.p. 168-169° C. MS [(+)ESI, m/z]: 574 [M+H]+
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N+]([O-])=O)[C:3]=1[C:4]#[N:5].[Cl-:14].[Ca+2].[Cl-].ClCl>>[Cl:14][C:6]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: [Cl-]
Reactant: N#Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: ClCl
Agent: [Ca+2]
Product: N#Cc1c(Cl)ccc(F)c1F
Temperature: 190 °C
Yield: 987.8 %

Procedure:
24.8 g (0.135 mol) of 2,3-difluoro-6-nitrobenzonitrile and 1 g of anhydrous calcium chloride are placed in a 50 ml flask with a finely drawn-out gas inlet tube, and heated to 190° C. Chlorine is introduced at this temperature with a throughput of 2-3 l/h so that a uniform production of nitrous gases occurs. After a reaction time of 12 h, the starting material has been substantially converted (<10% residual content of nitro compound). The remaining nitrous gases are purged with air and the residue is distilled off under vacuum over a short Vigreux column to give 15.5 g (89 mmol, 66%) of 2-chloro-5,6-difluorobenzonitrile as a light yellowish, oily liquid boiling at 70°-75° C./3 Torr (purity (GC)>95%).
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]([C:16](=O)[CH2:17]Cl)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][C:21]([NH2:23])=[S:22].C([O-])(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O.C(O)C>[NH2:23][C:21]1[S:22][CH:17]=[C:16]([C:10](=[N:9][O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:20]=1
Reactant: CCOC(=O)C(=NOCc1ccccc1)C(=O)CCl
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=NOCc1ccccc1)c1csc(N)n1
Reaction time: 2.5 h
Yield: 71.9 %

Procedure:
A solution of ethyl 2-benzyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 51.4 g.), thiourea (17.5 g.) and sodium acetate (31.3 g.) in a mixture of water (130 ml.) and ethanol (130 ml.) was stirred at 40° to 45° C. for 2.5 hours. The resultant solution was adjusted to pH 6.5 with aqueous sodium bicarbonate and the precipitates were collected by filtration and washed with diisopropyl ether to give ethyl 2-(2-aminothiazol-4-yl)-2-benzyloxyiminoacetate (syn isomer, 39.78 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.[ClH:25].Cl.FC1C=C(NC(NC(=O)CC2C=CC=CC=2F)=S)C=CC=1OC1C=CN=C2C=C(C3N(C)C=CN=3)SC=12.[CH3:64][O:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[CH2:72][C:73]([N:75]=[C:76]=[S:77])=[O:74]>>[ClH:25].[ClH:25].[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:76]([NH:75][C:73](=[O:74])[CH2:72][C:67]2[CH:68]=[CH:69][CH:70]=[CH:71][C:66]=2[O:65][CH3:64])=[S:77])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: COc1ccccc1CC(=O)N=C=S
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: Cl
Agent: Cn1ccnc1-c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4F)cc3F)c2s1
Product: COc1ccccc1CC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1

Procedure:
Starting from the compound 219, following the procedure described above for the synthesis of 303a (example 232) but replacing 2-(2-fluorophenyl)acetyl isothiocyanate with 2-(2-methoxyphenyl)acetyl isothiocyanate, title compound 303b was obtained in 44% as an off-white solid. 1H NMR (d-DMSO) δ (ppm): 12.55 (s, 1H), 11.73 (s, 1H), 8.62 (m, 1H), 8.09(m, 1H), 7.65 (s, 1H), 7.57 (m, 1H), 7.43 (s, 1H), 7.27-7.20 (m, 1H), 6.98(d, 1H, J=8.2 Hz), 6.90(dt, 1H, J1=10 Hz, J2=7.4 Hz), 6.79 (m, 1H), 4.02 (s, 3H), 3.81 (s, 2H), 3.77 (s, 3H). MS (m/z): 548.3 (M+H) (found).