Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([C:11](=[O:43])[NH:12][C@@H:13]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:14]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][C@H:17]1[C:25](=[O:36])[NH:26][CH2:27][C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=1[CH3:35])=[O:15])[CH3:10])C)(C)(C)C.Cl.C(Cl)[Cl:47]>O1CCOCC1>[ClH:47].[F:34][C:32]1[CH:31]=[CH:30][C:29]([CH3:35])=[C:28]([CH:33]=1)[CH2:27][NH:26][C:25]([C@@H:17]1[CH2:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:16]1[C:14](=[O:15])[C@@H:13]([NH:12][C:11](=[O:43])[C@@H:9]([NH:7][CH3:6])[CH3:10])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:36]
Reactant: Cc1ccc(F)cc1CNC(=O)[C@@H]1Cc2ccccc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)c1ccccc1
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ccccc2C[C@H]1C(=O)NCc1cc(F)ccc1C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
((S)-1-{(S)-2-[(S)-2-(5-Fluoro-2-methyl-benzylcarbamoyl)-2,3-dihydro-indol-1-yl]-2-oxo-1-phenyl-ethylcarbamoyl}-ethyl)-methyl-carbamic acid tert-butyl ester (48 mg) was suspended in a 1:1 mixture of 4 M HCl in dioxane) and DCM and stirred at rt for 1 h. The solvent was removed in vacuo and the resulting solid was dissolved in CH3CN and water (3:1), and lyophilized to give (S)-1-[(S)-2-((S)-2-methylamino-propionylamino)-2-phenyl-acetyl]-2,3-dihydro-1H-indole-2-carboxylic acid 5-fluoro-2-methyl-benzylamide hydrochloride salt as a white powder (44 mg), m/z=503 (M+H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1.[H][H]>C(O)C.[Pd]>[F:22][C:2]([F:1])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1cncc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CNCC(c2ccc(OC(F)(F)F)cc2)C1

Procedure:
2.5 g (7.6 mmol) of ethyl 5-[4-(trifluoromethoxy)phenyl]pyridine-3-carboxylate were dissolved in 60 ml of ethanol, 1.14 g of Pd/C (10%) were added and the mixture was hydrogenated in an autoclave at 60° C. at a hydrogen pressure of 50 bar overnight. The reaction mixture was filtered through silica gel. The resulting solution was concentrated under reduced pressure. Water was added to the residue, and the solution was adjusted to pH 8 using aqueous 1 N sodium hydroxide solution. The mixture was then extracted with dichloromethane. The organic phase was dried over sodium sulphate and concentrated. Yield: 1.76 g (66% of theory)
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][N:22]1[C:26]2[CH:27]=[CH:28][C:29]([C:31]3[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=3)=[CH:30][C:25]=2[N:24]=[C:23]1[CH3:38]>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][N:22]2[C:26]3[CH:27]=[CH:28][C:29]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:30][C:25]=3[N:24]=[C:23]2[CH3:38])=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Reactant: Cc1nc2cc(C3=NNC(=O)CC3)ccc2n1CCN
Product: Cc1nc2cc(C3=NNC(=O)CC3)ccc2n1CCNCC(O)COc1ccc(CCOCC(C)C)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxyethyl)-phenoxy]-2,3-epoxypropane and 6-[1-(2-aminoethyl)-2-methyl-benzimidazol-5-yl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[S:25][C:26]2[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:27]=2[N:28]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH:15]([CH2:14][N:13]([C:24]3[S:25][C:26]4[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:27]=4[N:28]=3)[CH2:12]2)[CH2:16]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: Cc1ccc2nc(Cl)sc2c1
Product: Cc1ccc2nc(N3CC4CN(C(=O)c5ccccc5-c5ccccc5)CC4C3)sc2c1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-6-methyl-benzothiazole. MS (ESI): mass calculated for C27H26N3OS, 439.57; m/z found 440.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])O.[Na+].[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>O1CCOCC1>[CH3:18][S:19]([NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:21])=[O:20]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc(NS(C)(=O)=O)c1
Reaction time: 120 h
Yield: 81.5 %

Procedure:
To a solution of ethyl 3-aminobenzoate (2.0 g, 12.1 mmol) and sodium hydrogen carbonate (1.2 g, 14.5 mmol) in 1,4-dioxane (24 ml) was added methanesulphonyl chloride (2.3 ml, 30.3 mmol). The mixture was stirred at room temperature for 3 h, before addition of water (10 ml), and the reaction mixture was stirred for a further 5 days. The mixture was partitioned between ethyl acetate and hydrochloric acid (2M) and the organic phase was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was passed through a plug of silica, eluting with ethyl acetate/cyclohexane [1:3] and the filtrate was concentrated in vacuo to give the title compound (2.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13](O)=[O:14])[CH:7]=1.O.O.[Sn](Cl)Cl.[OH-].[Na+].CCOC(C)=O>C(O)C.O.Cl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([NH:16][C:13](=[O:14])[CH:9]3[CH2:10][CH2:11][CH2:12][N:8]32)=[CH:4][CH:3]=1
Reactant: O=C(O)C1CCCN1c1cc(Br)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: O=C1Nc2ccc(Br)cc2N2CCCC12
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A solution of N-(5-bromo-2-nitro-phenyl)-pyrrolidine-2-carboxylic acid (6 g, 23 mmol) and tin(II) chloride dihydrate (16.5 g, 73 mmol) in ethanol (200 ml), water (30 ml) and concentrated HCl (10 ml) was heated to reflux for 6 hours. After cooling to room temperature, the mixture was diluted with water and was adjusted to pH 9 with 2N aqueous sodium hydroxide solution. After addition of EtOAc, the precipitated tin hydroxide was filtered off The layers were separated and the organic layer was washed with water, then brine, dried (MgSO4) and evaporated to afford 8-bromo-1,2,3,3a-tetrahydro-5H-pyrrolo[1,2-a]quinoxalin-4-one (3.7 g, 60%), which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[C:17]([C:18](=[O:20])[CH3:19])=[C:16]([CH3:21])[N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:14](=[O:32])[N:13]1[CH3:33].[OH-].[Li+].O.Cl>O1CCOCC1>[C:18]([C:17]1[CH:12]([C:5]2[CH:6]=[CH:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[C:3]([OH:34])=[O:2])[N:13]([CH3:33])[C:14](=[O:32])[N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:16]=1[CH3:21])(=[O:20])[CH3:19]
Reactant: COC(=O)c1cc(C#N)ccc1C1C(C(C)=O)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O

Procedure:
2-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-5-cyano-benzoic acid methyl ester (intermediate 5)(612 mg, 1.30 mmol) and lithium hydroxide (93.3 mg, 3.90 mmol) are stirred in 1,4-dioxane (12.0 ml) and water (6.0 mL) at room temperature for 20 min Water (200 mL) is added and the mixture is acidified with hydrochloric acid (1.0 M, 44 mL) to a pH value of 3. The aqueous phase is extracted with ethyl acetate. The organic phase is washed twice with water, dried over MgSO4 and concentrated. Yield: 665 mg. ESI mass spectrum: [M+H]+=472; Retention time HPLC: 1.09 min (HPLC method Z018_S04).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[CH:32]=[N:31][N:30]=1.C(=O)=O.CC(C)=O>C1COCC1.[Cl-].[NH4+].CCOC(C)=O>[Cl:28][C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39]([N:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=3[O:2][CH3:1])[C:7]3[S:8][CH:9]=[CH:10][N:11]=3)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[CH:32]=[N:31][N:30]=1
Reactant: COc1ccc(CNc2nccs2)c(OC)c1
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nncc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nncc3c2)c(OC)c1
Reaction time: 0.08 h
Yield: 35.8 %

Procedure:
A round-bottom flask was charged with N-(2,4-dimethoxybenzyl)thiazol-2-amine (181 mg, 0.723 mmol) and THF (3287 μl) to give a clear solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (723 μl, 0.723 mmol) was added. The flask was removed from the bath for 2 min, then resubmerged. After 5 min, a solution of perfluorophenyl 1-chlorophthalazine-6-sulfonate (270 mg, 0.657 mmol) in THF (0.7 mL with a 0.3 mL wash) was added drop wise. After 5 min, the dry ice-acetone bath was swapped out for an ice-water bath. After 1 h, the mixture was diluted with saturated aq ammonium chloride solution and EtOAc. The layers were separated, and the aq. layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40-g column, 20 to 70% EtOAc/Heptane) to give 1-chloro-N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)phthalazine-6-sulfonamide (112 mg, 0.235 mmol, 35.7% yield) as a cream-colored solid: m/z (ESI) 477.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:5][C@H:6]([NH:24]C(=O)OC(C)(C)C)[C@H:7]([OH:23])[CH2:8][NH:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH3:21])[CH:18]=2)[N:13]([CH3:22])[CH2:12][CH2:11]1.Cl>CO.CCOCC>[NH2:24][C@@H:6]([CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:34]=[C:33]([F:35])[CH:32]=1)[C@H:7]([OH:23])[CH2:8][NH:9][CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH3:21])[CH:18]=2)[N:13]([CH3:22])[CH2:12][CH2:11]1
Reactant: CCc1ccc2c(c1)C(NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C)CCN2C
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CCc1ccc2c(c1)C(NC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1)CCN2C
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-3-[(6-ethyl-1-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino]-2-hydroxypropylcarbamate (0.412 g) in MeOH (5 mL) was added 2N HCl in Et2O (2.1 mL). The mixture was stirred at room temperature for fifteen minutes. The mixture was stripped of solvent under reduced pressure. The residue was partitioned between dichloromethane and aqueous sodium bicarbonate, and the organic was extracted three times, washed with brine, dried with sodium sulfate, filtered, and concentrated. A silica gel column was run for purification using 5% MeOH in dichloromethane with as the solvent solution. 0.255 g of the title product were recovered. (78% yield). MS (ESI+) for C22H29F2N3O m/z 390.18 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[C:5]([O:10][CH3:11])=[C:4]([Cl:12])[N:3]=1.[C:13](=O)(O)[O-:14].[Na+].BrBr.[Na+].[Cl-]>CO.O.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:14][CH3:13])=[O:9])[C:5]([O:10][CH3:11])=[C:4]([Cl:12])[N:3]=1
Reactant: COc1c(Cl)nc(Cl)nc1C=O
Reactant: O=C([O-])O
Agent: BrBr
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)c1nc(Cl)nc(Cl)c1OC
Temperature: 0 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
The 2,6-dichloro-5-methoxy-pyrimidine-4-carbaldehyde crude material (32.5 mmol), prepared by Example 7, was cooled to 0° C. in an ice/water bath. It was assumed that approximately 60 mL of methanol was still present in the crude material. Additional methanol (60 mL) and water (13 mL) was added to the chilled crude material. Solid sodium bicarbonate (54.7 g) was added, and the solution stirred vigorously. A 2 M solution of bromine (81.4 mL, 163 mmol) in methanol and water (9:1) was dropwise added to the crude material solution over 30 minutes. The reacting mixture was stirred at 0° C. for 1 h. The mixture was then removed from the ice/water bath, and the reaction monitored using GCMS. About 6 h after initiating the reaction with bromine, a mixture of Na2S2O3.5H2O (4.5 g), saturated NaCl (150 mL), and ice (400 g) was prepared and, into this, the reaction mixture was poured. This was diluted with ethyl acetate (200 mL), and additional ethyl acetate (200 mL) was used to extract the product. The combined organic phases were dried over sodium sulfate, filtered, and toluene (50 mL) was then added. The product was then concentrated on a rotary evaporator with a bath temperature of less than or equal to 25° C. Obtained was a yellow oil comprising the title compound (3.1 g, 45% yield). The title compound was not isolated from the solution.
Reaction SMILES: [Na].[C:2]([N:5]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:9]=2[NH:8][C:7](=[O:23])[CH2:6]1)(=[O:4])[NH2:3].[CH3:24]O>>[CH3:24][N:8]1[C:9]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:10]=2[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]([C:2](=[O:4])[NH2:3])[CH2:6][C:7]1=[O:23]
Reactant: NC(=O)N1CC(=O)Nc2ccc(Cl)cc2C1c1ccccc1
Reactant: CO
Agent: [Na]
Product: CN1C(=O)CN(C(N)=O)C(c2ccccc2)c2cc(Cl)ccc21
Yield: 79.5 %

Procedure:
0.16 g. (6.85 mmoles) of metallic sodium are dissolved in 2 ml. of absolute methanol, and a suspension of 0.9 g. (2.86 mmoles) of 4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 50 ml. of absolute methanol is added to the solution at room temperature, with stirring. The suspension is stirred at room temperature for 30 minutes, and then evaporated under reduced pressure. The oily residue is dissolved in 9 ml. of dimethyl formamide, and 0.48 ml. of methyl iodide are added to the stirred solution at room temperature. The mixture is stirred for an additional 2 hours, then diluted with 50 ml. of water and extracted with 3×10 ml. of chloroform. The chloroform extracts are combined, dried over sodium sulfate, filtered, and the filtrate is evaporated under reduced pressure, to obtain 0.85 g. of a residue, which is recrystallized from ethanol. 0.75 g. (79.5%) of 1-methyl-4-carbamoyl-5-phenyl-7-chloro-1,3,4,5-tetrahydro-2H-1,4 -benzodiazepine-2-one are obtained; m.p.: 217°-220° C.
Reaction SMILES: C[O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][CH2:7][C:6](=[O:9])[N:5]1[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[Na+].O>CO>[N+:17]([C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:5]2[C:6](=[O:9])[CH2:7][CH2:8][C@H:4]2[C:3]([OH:20])=[O:2])=[CH:16][CH:15]=1)([O-:19])=[O:18]
Reactant: COC(=O)[C@@H]1CCC(=O)N1Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCC(=O)N1Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(S)-N-(4-Nitrobenzyl)pyroglutamic acid methyl ester (0.365 g, 1.31 mmol) was dissolved in 10 ml MeOH, cooled to 0° C., and 1N NaOH (5.2 ml, 5.2 mmol) was added. The reaction was stirred at room temperature for 1 h. Water (50 ml) was added and the aqueous was washed with 2×50 ml EtOAc. The aqueous was acidified with 1N HCl and extracted with 3×40 ml EtOAc. The organic layers were dried (MgSO4), filtered, and concentrated to give the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:28]2[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]2)=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1CNCCO1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 30.1 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.6 g, 1.2 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.3 g, 1.8 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.2 g, 30%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([OH:5])[C@@H:2]([OH:4])[CH3:3].[H-].[Na+].[CH2:8]([N:12]1[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[S:14]/[C:13]/1=[N:21]\[C:22](=[O:34])[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1F)[CH2:9][CH2:10][CH3:11]>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:8]([N:12]1[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][C:15]=2[S:14]/[C:13]/1=[N:21]\[C:22](=[O:34])[C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[O:5][CH2:1][C@@H:2]([OH:4])[CH3:3])[CH2:9][CH2:10][CH3:11]
Reactant: C[C@H](O)CO
Reactant: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)sc2ccncc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCn1/c(=N/C(=O)c2cc(C(F)(F)F)ccc2OC[C@H](C)O)sc2ccncc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 18.2 %

Procedure:
(S)-propane-1,2-diol (52 mg, 0.68 mmol) in THF (1 mL) was treated with NaH (60% dispersion; 27 mg, 0.68 mmol) at room temperature for 20 minutes. The mixture was cooled to 0° C. and a solution of Example 18B (90 mg, 0.23 mmol) in THF (1 mL) was added. The mixture was allowed to warm to room temperature, and stirred for 4 hours. The mixture was diluted with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 19 mg (19%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.04 (t, J=7.48 Hz, 3H) 1.28 (d, J=6.41 Hz, 3H) 1.47-1.59 (m, 2H) 1.88-1.98 (m, 2H) 3.87 (t, J=8.85 Hz, 1H) 4.21-4.31 (m, 1H) 4.35 (dd, J=9.15, 2.75 Hz, 1H) 4.51-4.59 (m, 2H) 7.12 (d, J=8.85 Hz, 1H) 7.72 (dd, J=8.54, 2.14 Hz, 2H) 8.51 (d, J=1.83 Hz, 2H) 8.75 (s, 1H); MS (DCI/NH3) m/z 454 (M+H)+.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[N:24]([CH2:28][CH3:29])[N:25]=[CH:26][CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)[CH2:34][CH2:33]1>C1COCC1>[CH3:31][N:32]1[CH2:33][CH2:34][N:35]([C:38]2[CH:43]=[CH:42][C:41]([NH:44][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[N:24]([CH2:28][CH3:29])[N:25]=[CH:26][CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:30])=[CH:40][CH:39]=2)[CH2:36][CH2:37]1
Reactant: CCn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CCn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(N3CCN(C)CC3)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 36 %

Procedure:
A small screw cap test tube was charged with 2-Ethyl-2H-pyrazole-3-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.249 mmol) and THF (2.5 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (47.9 mg, 0.250 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was redissolved in EtOAc (˜5 mL) and Hexane (˜40 mL) was added to the solution. The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (10 mL) to afford the title compound in 36% yield (0.0515 g, 0.089 mmol).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10][NH2:11])=[CH:8][CH:9]=1.[F:27][C:28]1[CH:29]=[C:30]2[C:35](=[C:36]([O:38][CH3:39])[CH:37]=1)[N:34]=[C:33]([CH:40]=O)[CH:32]=[CH:31]2>C(O)C>[F:26][C:2]([F:25])([F:1])[C@H:3]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:13]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:40]/[C:33]2[CH:32]=[CH:31][C:30]3[C:35](=[C:36]([O:38][CH3:39])[CH:37]=[C:28]([F:27])[CH:29]=3)[N:34]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc(NN)nc2)C(F)(F)F)C1
Reactant: COc1cc(F)cc2ccc(C=O)nc12
Solvent: CCO
Product: COc1cc(F)cc2ccc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc12

Procedure:
tert-Butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (200 mg, 0.533 mmol) and 6-fluoro-8-methoxyquinoline-2-carbaldehyde (109 mg, 0.533 mmol) were stirred in ethanol at ambient temperature for 24 hours. The reaction was concentrated and used as is in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][OH:17].CNC1C=CC=C(NC)N=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH2:16][O:17][S:36]([CH3:35])(=[O:38])=[O:37]
Reactant: COc1ccc(OC)c(C2CCCC2CO)c1
Reactant: CS(=O)(=O)Cl
Agent: CNc1cccc(NC)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c(C2CCCC2COS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
Dissolve [2-(2,5-dimethoxy-phenyl)-cyclopentyl]-methanol (3.6 g, 15 mmol) in dichloromethane (94 ml), add 2,6-dimethylaminopyridine (0.4 g, 0.31 mmol), add triethylamine (4.7 ml, 33.5 mmol), cool to 0° C., add methanesulfonyl chloride (1.9 g, 17 mmol), remove ice bath and stir 2 hours at room temperature. Quench with water and ethyl acetate, separate layers, wash with brine, dry and concentrate to give the title compound (4.8 g, 100%): 1H NMR (CDCl3) δ 6.78-6.69 (m, 3H), 3.86-3.82 (m, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.68-3.64 (m,1H), 3.53-3.47 (m, 1H), 2.83-2.76 (m, 1H), 2.69 (s,3H), 1.97-1.88 (m, 3H), 1.67-1.60 (m,3H).