Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:12])=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:15]([N:17]([CH2:25][CH3:26])[C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH2:24])[CH3:16]>O1CCCC1>[ClH:12].[CH2:25]([N:17]([CH2:15][CH3:16])[C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@H:19]1[NH:24][C:10](=[O:11])[C:9]1[CH:13]=[CH:14][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=1)[CH3:26]
Reactant: CCN(CC)[C@@H]1CCCC[C@H]1N
Reactant: CS(=O)(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: CCN(CC)[C@@H]1CCCC[C@H]1NC(=O)c1ccc(NS(C)(=O)=O)cc1
Product: Cl
Reaction time: 1 h

Procedure:
To a solution of 6.31 g (27 mmole) of 4-[(methylsulfonyl)amino]benzoyl chloride in 25 ml of tetrahydrofuran (THF) cooled to 0° C. under a nitrogen atmosphere, add dropwise a solution of 4.26 g (25 mmole) of trans-N,N-diethyl-1,2-cyclohexanediamine in 10 ml of THF. Stir the reaction mixture for 1 hr, then collect the resulting solid by filtration. Recrystallize the solid from ethanol to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[C:16]([O:22][CH:23]([CH3:25])[CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=O>>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:17]([C:16]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[C:18]([CH3:20])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: O=Cc1ccccc1F
Reactant: CC(=O)CC(=O)OC(C)C
Reactant: Nc1cc[nH]n1
Product: CC1=C(C(=O)OC(C)C)C(c2ccccc2F)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-fluorobenzaldehyde, 3-aminopyrazole and isopropyl acetoacetate in the same manner as in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:7]1[S:11][C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)[CH2:5][OH:6].C(N(CC)CC)C.FC(F)(F)S(O[Si:40]([CH:47]([CH3:49])[CH3:48])([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])(=O)=O>ClCCl.C1COCC1>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:7]1[S:11][C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)[CH2:5][O:6][Si:40]([CH:47]([CH3:49])[CH3:48])([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COC(=O)C(CO)c1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(CO[Si](C(C)C)(C(C)C)C(C)C)c1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1

Procedure:
To a mixture of compound 73.1 (1.67 mmol) and triethylamine (2.2 equivalent) in 1:1 dichloromethane/THF (12.0 mL) was added triisopropylsilyl trifluoromethanesulfonate (2.2 equivalents) dropwise at 0° C. After complete consumption of the starting material (TLC 30% EtOAc in hexanes) the reaction mixture is diluted with EtOAc and washed with 0.5 N HCl, saturated sodium bicarbonate, dried and concentrated to give a residue that was purified by flash column chromatography on silica gel (0 to 60% EtOAc in hexanes) to provide 2-{2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-3-triisopropylsilanyloxy-propionic acid methyl ester (compound 73.2) as a foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:13][CH3:14])[C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#N.[OH:15]S(O)(=O)=O.[OH2:20]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:13][CH3:14])[C:9]=1[N+:10]([O-:12])=[O:11])[C:5]([OH:15])=[O:20]
Reactant: O=S(=O)(O)O
Reactant: COc1cc(C#N)cc(F)c1[N+](=O)[O-]
Reactant: O
Product: COc1cc(C(=O)O)cc(F)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 75 %

Procedure:
A suspension of 3-fluoro-5-methoxy-4-nitrobenzonitrile (940 mg, 4.8 mmol) in a mixture of concentrated H2SO4 and water (2 mL/2 mL) was heated at 100° C. overnight. The reaction mixture was then cooled down, solid filtered and dried to give the product as brown solid (770 mg, 75%).
Reaction SMILES: [C:1]1([C:7]2[C:8]3[S:17][CH:16]=[CH:15][C:9]=3[N:10]=[C:11]([NH2:14])[CH2:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](=[O:21])(O)[O-].[Na+].Cl[CH2:24][C:25](CCl)=O.[OH-].[Na+]>O1CCOCC1>[C:1]1([C:7]2[C:8]3[S:17][CH:16]=[CH:15][C:9]=3[N:10]3[CH:24]=[C:25]([CH2:18][OH:21])[N:14]=[C:11]3[CH2:12][N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=Nc2ccsc2C(c2ccccc2)=NC1
Reactant: O=C([O-])O
Reactant: O=C(CCl)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: OCc1cn2c(n1)CN=C(c1ccccc1)c1sccc1-2
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.3 %

Procedure:
A suspension of 2.9 g of 5-phenyl-3H-thieno[3,2-e][1,4]diazepin-2-ylamine, 11.7 g of sodium bicarbonate and 1.83 g of 1,3-dichloroacetone in 80 ml of dioxan was stirred at room temperature under argon for 48 h. Thereafter, the temperature of the reaction mixture was increased to 80° C. and the suspension was stirred under argon for a further 27 h. After cooling to 60° C. 19.2 g of 2.5N sodium hydroxide solution were added and the reaction mixture was stirred under argon for a further 20 h. Subsequently, a further two 19.2 g portions of 2.5N sodium hydroxide solution were added at intervals of twenty hours. The suspension was extracted with dichloromethane/saturated sodium chloride solution in the presence of a small amount of methanol. The dichloromethane extracts were dried with sodium sulphate, filtered and evaporated in a vacuum. The residue was suspended twice in succession in methanol and triturated. There were obtained 2.14 g of crude 4-phenyl-6H-imidazo[1,2-a]thieno[2,3-f][1,4]diazepin-8-ylmethanol which was used without further purification as the free base for the preparation of the dihydrochloride.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:7]([CH:10]([OH:23])[C:11](C)([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[C:32](OC(=O)C)(=[O:34])[CH3:33].O>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(=O)(O)[O-].[Na+]>[C:32]([O:23][CH:10]([C:7]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][CH:8]=1)[CH:11]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:12]([O:14][CH3:15])=[O:13])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCc1ncc(C(O)C(C)(C(=O)OC)c2ccncc2)n1Cc1ccccc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCc1ncc(C(OC(C)=O)C(C(=O)OC)c2ccncc2)n1Cc1ccccc1Cl
Reaction time: 2 h
Yield: 113.5 %

Procedure:
A solution of methyl 3-[2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-yl]-3-hydroxy-2-(4-pyridyl)-methylpropanoate (3.32 g, 7.5 mmol) methylene chloride (50 mL), 4-dimethylaminopyridine (150 mg, 1.3 mmol) and acetic anhydride (7.1 mL, 75 mmol) was stirred at ambient temperature for 18 hours. Water (5 mL) was added, the mixture was stirred for 2 hours and then diluted with methylene chloride and 5% sodium bicarbonate solution. The organic phase was washed with 5% sodium bicarbonate solution and brine, dried and concentrated to give 4 g of the crude title compound. TLC on silica gel with 5% methanol ethyl acetate showed essentially one spot material with an Rf of 0.86. No starting material was detected. This material was not purified further.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].II.CO>O1CCCC1>[CH3:11][NH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CNCCCc1ccccc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CNCCCc1ccccc1
Temperature: 7 °C
Yield: 53 %

Procedure:
N-(3-Phenylpropyl)formamide (5.70 g, 34.9 mmol) was dissolved in tetrahydrofuran (50 ml) and added dropwise to a suspension of sodium borohydride (1.58 g, 41.91 mmol) in tetrahydrofuran (100 ml), which was cooled to 7° C. A solution of iodine (4.42 g, 17.46 mmol) in tetrahydrofuran was added dropwise, while the temperature was kept at 7° C. After the addition was finished, the reaction mixture was warmed to reflux for 16 h. The reaction mixture was cooled to 7° C., and methanol (250 ml) was added dropwise. The solvent was removed in vacuo. The residue was dissolved in 20% aqueous sodium hydroxide solution (250 ml) and tert-butyl methyl ether (100 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (400 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1) as eluent to give 2.76 g of N-methyl-N-(3-phenylpropyl)amine.
Reaction SMILES: C(O[C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:21]=[CH:20][C:19]=3[N:32]=2)=[C:11]([F:33])[CH:10]=1)C1C=CC=CC=1.[F:34][C:35]1([F:40])[CH2:37][CH:36]1[CH2:38][OH:39]>>[F:34][C:35]1([F:40])[CH2:37][CH:36]1[CH2:38][O:39][C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:21]=[CH:20][C:19]=3[N:32]=2)=[C:11]([F:33])[CH:10]=1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCc4ccccc4)cc3F)nc2cn1
Reactant: OCC1CC1(F)F
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCC4CC4(F)F)cc3F)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-2,5-difluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (2,2-difluorocyclopropyl)methanol, and in the same manner as in Step A and Step B of Example 4, the title compound was obtained.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23]Br)[CH3:20]>CCCCCC.CCOCC>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][CH:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:8]([O:16][CH2:17][CH3:18])=[O:15])[CH3:20]
Reactant: CCOC(CBr)OCC
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(CC(OCC)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
A mixture of 10.6 gms (0.25 moles) sodium hydride 57% oil dispersion and 75 mL hexane was stirred under argon for 10 minutes. The hexane solvent was replaced by 125 mL of dry dimethylformamide, and to this suspension was added dropwise 40.5 gms (0.25 moles) diethyl malonate over 30 minutes. 49 gms (0.25 moles) bromoacetaldehyde diethyl acetal was then added dropwise over 20 minutes. After the addition was complete, the reaction mixture was stirred at 86 degrees Celsius for 18 hours, then cooled to room temperature and diluted with 600 mL of an ice-water mixture. The mixture was 4×200 mL ether extracted. The ether extracts were combined, washed twice with 50 mL cold 5% HCl, twice with 50 mL 5% NaHCO3 solution, twice with saturated NaCl solution, dried over magnesium sulfate, and filtered. The ether was evaporated in vacuo to give 55.2 gms of oil. The crude oil was purified by two successive vacuum distillations to finally give 18 gms of pure product, b.p. 81-83 degrees/0.1 mmHg. Elemental analysis: calculated C 56.51, H 8.75; found C 57.11, H 9.09.
Reaction SMILES: F[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][NH:15][CH2:14]1.N12CCCN=C1CCCCC2>N1C=CC=CC=1>[CH3:11][N:12]([CH3:18])[CH:13]1[CH2:17][CH2:16][N:15]([C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])[CH2:14]1
Reactant: O=C(O)c1cccnc1F
Reactant: CN(C)C1CCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CN(C)C1CCN(c2ncccc2C(=O)O)C1
Temperature: 100 °C
Reaction time: 12 h
Yield: 116.9 %

Procedure:
To a suspension of resin B (1.2 mmol/g, 5.0 g, 8.0 mmol) in pyridine (12 mL) was added dimethyl-pyrrolidin-3-yl-amine (1.37 mL, 12 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.2 mL, 14.4 mmol) at room temperature. The mixture was agitated at 100° C. for 12 hours under a nitrogen atmosphere. The resin was washed with DCM then MeOH (3×), and dried under vacuum. Compound C was cleaved off the resin with the addition of 50% trifluoroacetic acid in DCM. The mixture was agitated at room temperature for 30 minutes. The resin was washed with DCM (3×), and the filtrate was concentrated using a rotary evaporator. 1 N HCl aqueous solution (2 mL) was added and then lyophilized to yield compound C as a light pink gum (2.2 g). The compound was taken onto the next step without further purification. 1H-NMR δ (CDCl3): 10.85 (s, 1H), 8.26 (dd, 1H, J=4.8 Hz, J=1.6 Hz), 7.96 (dd, 1H, J=7.2 Hz, J=2.0 Hz), 6.81 (dd, 1H, J=7.6 Hz, J=4.8 Hz), 3.92-3.94 (m, 1H), 3.70-3.80 (m, 2H), 3.52-3.54 (m, 1H), 3.43 (m, 1H), 2.80 (m, 6H), 2.20 (m, 1H), 2.17 (m, 1H). ESMS: 236.0 [M+H]+.
Reaction SMILES: [Cl:1]CC(OC(=O)CCl)=O.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH2:13][CH2:14][CH2:15][CH2:16]2.[CH2:21]([O:23]CC)[CH3:22]>>[Cl:1][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][CH2:19][CH2:20][CH:11]2[NH:10][C:21]([CH3:22])=[O:23]
Reactant: CCOCC
Reactant: Nc1cccc2c1CCCC2
Reactant: O=C(CCl)OC(=O)CCl
Product: CC(=O)NC1CCCc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An ethereal solution of 90 g of chloroacetic acid anhydride is added dropwise to 73.6 g of 5-amino-1,2,3,4-tetrahydronapthalene in 1000 ml of diethyl ether. The temperature should not exceed 30°. The mixture is stirred for a further half hour at room temperature, then cooled to 0° and the precipitated product filtered off. After recrystallisation from ethanol, there is obtained 100 g of 5-chloroacetamino-1,2,3,4-tetrahydronaphthalene having a melting point of 155° - 157° (compound No. 2).
Reaction SMILES: I[C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[N:25][C:26]([C:29]#[CH:30])=[CH:27][CH:28]=2)=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:24]=[N:25][C:26]([C:29]#[C:30][C:2]3[CH:15]=[CH:14][C:5]([O:6][CH2:7][CH2:8][N:9]4[CH2:13][CH2:12][CH2:11][CH2:10]4)=[CH:4][CH:3]=3)=[CH:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)nn1
Reactant: Ic1ccc(OCCN2CCCC2)cc1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(OCCN4CCCC4)cc3)nn2)cc1

Procedure:
Prepared according to general working method I from 1-[2-(4-iodo-phenoxy)-ethyl]-pyrrolidine (200 mg, 0.63 mmol) and 3-(4-chloro-phenyl)-6-ethynyl-pyridazine (135 mg, 0.63 mmol).
Reaction SMILES: [C:1]1([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][OH:8])[CH:2]=1.N1C=CN=C1.[Cl-].[C:17]([SiH:21]([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18]>CN(C)C=O.CCOCC>[Si:21]([O:8][CH2:7][C:3]1[CH:2]=[C:1]([CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: C[SiH](C)C(C)(C)C
Reactant: OCc1cccc(CO)c1
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)c1
Reaction time: 12 h

Procedure:
A solution of 1,3-benzenedimethanol (2 g; 14.47 mmol) in 50 ml of dimethylformamide is stirred at ambient temperature. Imidazole (1.97 g; 28.94 mmol) and tert-butyl(dimethyl)silane chloride (2.18 g; 14.47 mmol) are added in succession. After stirring for 12 hours, the reaction mixture is diluted with ether and washed with a saturated aqueous sodium chloride solution. After extraction, the ethereal phase is dried over magnesium sulphate and concentrated to yield the expected compound.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[N:56]=[C:55]([O:57][CH3:58])[C:54]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:53][N:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[N:56]=[C:55]([O:57][CH3:58])[C:54]([C:59]2[CH:60]=[C:61]([NH:65][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:62]=[CH:63][CH:64]=2)=[CH:53][N:52]=1
Reactant: COc1ncc(-c2cccc(N)c2)c(OC)n1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)c(OC)n1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2,4-dimethoxy-pyrimidin-5-yl)-phenylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.010 g of product in 39% yield: LCMS (ESI) m/z 420 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:22])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])=[C:10]([F:21])[CH:9]=2)[CH:7]=1.[CH2:23]([O:25][C:26](=[O:29])[CH2:27]Br)[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:29])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:15])=[C:10]([F:21])[CH:9]=2)[CH:7]=1
Reactant: O=C(c1ccc(-c2cc(Cl)ccc2O)cc1F)N1CCCC1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cl)cc1-c1ccc(C(=O)N2CCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product of step c) (0.11 g) was dissolved in DMF (5 ml), ethylbromoacetate (0.04 ml) and potassium carbonate (0.1 g) were added. The reaction mixture was stirred for 16 h at RT. Water and ethyl acetate were added. The organic layer was removed, dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography eluting with isohexane:ethyl acetate (1:1) to give the sub-title compound. Yield 0.12 g.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:6]=[CH:7][C:8]([O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:45][CH2:44][CH2:43][C:42]2=[O:46])=[C:9](/[CH:11]=[CH:12]/[CH:13]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([O:35]C)=[O:34])=[CH:29][CH:28]=2)[CH2:14][CH2:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)[CH:10]=1.Cl>C1COCC1.O>[C:33]([C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH:13](/[CH:12]=[CH:11]/[C:9]2[CH:10]=[C:5]([F:4])[CH:6]=[CH:7][C:8]=2[O:37][CH2:38][CH2:39][CH2:40][N:41]2[CH2:45][CH2:44][CH2:43][C:42]2=[O:46])[CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:32][CH:31]=1)([OH:35])=[O:34]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2cc(F)ccc2OCCCN2CCCC2=O)Cc2ccc(C(=O)OC)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CCC(/C=C/c2cc(F)ccc2OCCCN2CCCC2=O)Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.57 mg (61.3 mmol) of lithium hydroxide monohydrate are added to a solution of 12 mg (10.4 μmol) of methyl 4-{(4E)-5-{5-fluoro-2-[3-(2-oxopyrrolidin-1-yl)propoxy]phenyl}-3-[4-(methoxy-carbonyl)benzyl]pent-4-en-1-yl}benzoate (Example 29A) in 0.3 ml of THF and 0.3 ml of water, and the mixture is stirred at room temperature for 16 h. The mixture is then adjusted to pH 2 using 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is purified by preparative HPLC. This gives 5.0 mg (8.93 μmol, 43.8% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(Cl)(Cl)Cl.O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[Br:8][C:6]1[CH:7]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:3]=[N:4][CH:5]=1
Reactant: C1COCCN1
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Brc1cncc(N2CCOCC2)c1
Yield: 64.8 %

Procedure:
To a solution of 3,5-dibromopyridine (XL) (1.68 g, 7.1 mmol) in dioxane (14 mL) was added morpholine (682 mg, 7.8 mmol), CsCO3 (3.24 g, 9.93 mmol) and xantphos (123 mg, 0.21 mmol). The solution was degassed before adding Pd2(dba)3 (195 mg, 0.21 mmol). The reaction was microwaved at 90° C. for 4 h. The reaction was poured into a mixture of CHCl3/H2O; the aqueous layer was separated, washed with water, then brine and concentrated under vacuum. The crude product was purified on a silica gel column (100% hexane→1:3 EtOAc:hexane) to give 4-(5-bromopyridin-3-yl)morpholine (XLI) as a yellow solid (1.12 g, 4.6 mmol, 65% yield). ESIMS found C9H11BrN2O m/z 244 (M+H).
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:15][N:16]1[C:21]2[CH:22]=[N:23][C:24]([Cl:26])=[CH:25][C:20]=2[CH:19]=[N:18][CH2:17]1>>[ClH:15].[Cl:26][C:24]1[N:23]=[CH:22][C:21]2[N:16]=[CH:17][N:18]=[C:19]([NH:12][C:11]3[CH:13]=[CH:14][C:8]([S:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:9][CH:10]=3)[C:20]=2[CH:25]=1
Reactant: Nc1ccc(Sc2ccccc2)cc1
Reactant: Clc1cc2c(cn1)N(Cl)CN=C2
Product: Cl
Product: Clc1cc2c(Nc3ccc(Sc4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure A from 4-(phenylthio)aniline (commercially available from Salor) and 1,6-dichloropyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 8.94 (1H,s), 8.85 (1H,s), 8.25 (1H,s), 7.96 (2H,d), 7.24-7.49 (7H,m); m/z (M+1)+365.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]([N:14]([CH2:16][C:17]([OH:19])=O)[CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1[CH2:23][OH:24].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:20])[CH2:10][CH2:11][C:12]([N:14]([CH2:16][C:17]([N:21]1[CH2:27][CH2:26][CH2:25][C@H:22]1[CH2:23][OH:24])=[O:19])[CH3:15])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC[C@@H]1CCCN1
Reactant: CN(CC(=O)O)C(=O)CCC(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(=O)N1CCC[C@H]1CO)C(=O)CCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
N-(benzyloxysuccinyl)sarcosine (139.5 g, 0.5 mol), L-prolinol (50.5 g, 0.5 mol) and triethylamine (200 ml) are dissolved in methylene chloride (2 l), and a solution of DMC (127 g, 0.75 mol) in methylene chloride (500 ml) is added dropwise thereto under water-cooling over a period of thirty minutes. The mixture is stirred at room temperature for a further three hours, and the reaction liquid is washed successively with water (1 l), a saturated aqueous solution of sodium hydrogen carbonate (1 l), 1N hydrochloric acid (1 l) and water (1 l). The organic layer is dried over anhydrous magnesium sulfate and filtered. The filtrate is then concentrated to dryness under reduced pressure, and the residue is purified by column chromatography on silica gel (chloroform:methanol) to give N-(benzyloxysuccinyl)sarcosyl-L-prolinol (88.4 g, 48.8%).