Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].[CH2:9]=O>O.[Pd]>[CH3:9][N:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@H]1CCCN1
Reactant: C=O
Agent: [Pd]
Solvent: O
Product: CN1CCC[C@@H]1C(=O)O
Temperature: 50 °C
Reaction time: 8 h
Yield: 36.5 %

Procedure:
To a solution of D-proline (30 g, 260.7 mmol, 1 eq) and 37% aqueous formaldehyde (80.5 mL, 782 mmol, 3eq) in H2O (900 mL) was added 10% Pd/C (30 g) under N2. The mixture was stirred at 50° C. under H2 (30 psi) overnight. The mixture was heated to boiling and filtered to remove the catalyst. The solution was concentrated under reduced pressure, and then water (150 mL) was added to the mixture and concentrated, the procedure was repeated three times so as to remove unreacted formaldehyde. The crude product was resuspended in ACN/H2O (1:1, v/v) and lyophilized. The solid product was recrystallized from EtOH/acetone, filtered, liberally washed with acetone, and dried under reduced pressure to give 1-methyl-D-proline (12.3 g, 40%) as white solid. 1H NMR (400 MHz, MeOHD) δ ppm 1.95-1.99 (s, 1H), 2.1-2.2(s, 2H), 2.4-2.5 (m, 1H), 3.05-3.15(m,1H),3.3-3.35(s,1H),3.65-3.75(m, 1H),3.75-3.85(m,1H).
Reaction SMILES: CC(C)=O.[CH3:5][C:6]1([CH3:16])[O:15][C:13](=O)[C:10](=CO)[C:8](=[O:9])[O:7]1>C1(C)C=CC=CC=1>[CH3:5][C:6]1([CH3:16])[O:7][C:8](=[O:9])[CH:10]=[CH:13][O:15]1
Reactant: CC1(C)OC(=O)C(=CO)C(=O)O1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CC1(C)OC=CC(=O)O1
Yield: 82.8 %

Procedure:
Acetone (2.9 g) was added to sufficiently dehydrated toluene (500 ml) and the mixture was heated under reflux in a reaction flask equipped with a reflux condenser. While the reflux was continued, a warm solution obtained by dissolving formyl Meldrum's acid (8.6 g) in toluene (500 ml) on heating was dropwise added over about 2 hours, followed by subjecting the reaction mixture to heating under reflux for additional one hour and then subjecting the resulting reaction mixture to purifying operation in the same manner as in Example 1 to obtain 2,2-dimethyl-1,3-dioxin-4-one (5.3 g, yield 82%).
Reaction SMILES: [OH:1][C:2]1[CH:32]=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]#[CH:18])=[CH:12][CH:13]=2)[C:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=[N:7][C:6]1=[O:28].C(=O)([O-])[O-].[K+].[K+].[CH3:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48]CS([O-])(=O)=O>CC(C)=O>[CH:25]([C:22]1[CH:21]=[CH:20][C:19]([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]#[CH:18])[CH:10]=3)[N:5]([CH2:4][C:3]3[CH:29]=[CH:30][CH:31]=[CH:32][C:2]=3[O:1][CH2:48][CH2:47][O:46][CH2:45][CH2:44][O:43][CH2:42][CH2:41][O:40][CH3:39])[C:6](=[O:28])[N:7]=2)=[CH:24][CH:23]=1)([CH3:26])[CH3:27]
Reactant: COCCOCCOCCCS(=O)(=O)[O-]
Reactant: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCOc1ccc2c(c1)c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1OCCOCCOCCOC
Temperature: 25 °C

Procedure:
To a solution of 125 mg (0.29 mmol) of 1-(2-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one in acetone (5 ml) is added potassium carbonate (407 mg, 2.94 mmol) followed by 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl-methanesulfonate (as prepared in Step A, Example RT-5) (357 mg, 1.47 mmol). The reaction mixture is heated at reflux overnight. After cooling to room temperature, the reaction mixture is quenched with water and extracted with EtOAc (2×20 ml). The combined organic layers are washed with brine, dried (Na2SO4), filtered and evaporated in vacuo to provide a yellow oil which is purified by preparative TLC chromatography on Silica gel using dichloromethane/ether (1:1) to provide the title compound as a yellow oil. Yield: 29 mg (17%).
Reaction SMILES: [Br:1]C1C=C2C(C(C=O)=CN2)=CC=1.C(O[C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([C:26]([NH2:28])=[O:27])[CH:21]=[C:20]2[N:29]=[C:30]=[O:31])C=C>>[Br:1][C:25]1[CH:24]=[C:23]2[C:19]([C:20]([N:29]=[C:30]=[O:31])=[CH:21][N:22]2[C:26]([NH2:28])=[O:27])=[CH:18][CH:17]=1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Reactant: O=Cc1c[nH]c2cc(Br)ccc12
Product: NC(=O)n1cc(N=C=O)c2ccc(Br)cc21

Procedure:
was prepared from 6-bromo-1H-indole-3-carbaldehyde using the protocol described for steps C, D and E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: Cl.Cl.[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=3)[CH3:18])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)#[N:4]>O1CCCC1>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][N:17]([CH:14]2[CH2:13][CH2:12][N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:3]#[N:4])=[CH:10][CH:9]=3)[CH2:16][CH2:15]2)[CH3:18])=[CH:22][CH:23]=1
Reactant: CN(CCc1ccc([N+](=O)[O-])cc1)C1CCN(c2ccc(C#N)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Product: CN(CCc1ccc(N)cc1)C1CCN(c2ccc(C#N)cc2)CC1
Yield: 99.7 %

Procedure:
1.2 g (3.3 mmol) of the product from Example 2 were hydrogenated on Pd/C (10%) in 100 ml of tetrahydrofuran and worked up in a conventional manner. 1.1 g of 4-(2-(4-aminophenyl)-N-methylethylamino)-1-(4-cyanophenyl)piperidine were obtained as an oil. 1H NMR (d6 -DMSO) δ=1.2-1.5 (2H); 1.8-1.9 (2H); 2.1 (3H); 2.4-2.7 (4H); 2.7-2.9 (2H); 3.3 (1H); 3.9 (2); 6.4 (2H); 6.8 (2H); 6.9 (2H) and 7.5 (2H) ppm.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].F[C:15]1[C:22]([F:23])=[C:21]([F:24])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18]>C1COCC1.Cl>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([C:15]1[C:16]([C:17]#[N:18])=[CH:19][CH:20]=[C:21]([F:24])[C:22]=1[F:23])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: N#Cc1ccc(F)c(F)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1c(C#N)ccc(F)c1F
Temperature: 2.5 °C
Yield: 97.5 %

Procedure:
To a mixture of NaH (16.6 g, 657 mmol, dry) in THF (150 mL) was added dropwise over 30 min with stirring at 0-5° C. a solution of diethyl malonate (104.7 g, 654 mmol) in THF (120 mL). To this translucent mixture was then immediately added a solution of 2,3,4-trifluorobenzonitrile (47.7 g, 304 mmol) in THF (50 mL) dropwise with stirring at 0-5° C. The ice bath was then removed and the mixture allowed to stir at room temperature for 4 days. The clear yellow reaction was then diluted with 1 M HCl (350 mL), 4 N HCl was added to pH ˜2 (paper), and the mixture was extracted with 1:1 ether/hexanes (1×350 mL, 1×200 mL). The combined organic layers were washed with brine (1×300 mL), dried (Na2SO4), and concentrated to afford the title compound (88.1 g, 98%) as a 1.35:1 mixture of regioisomers. 1H NMR of major (desired) regioisomer (300 MHz, CDCl3) δ 7.51 (ddd, J=8.7 Hz, 4.6 Hz, 1.8 Hz, 1H), 7.29 (dt, J=8.9 Hz, 7.2 Hz, 1H), 5.12 (s, 1H), 4.35-4.20 (m, 4H), 1.31 (t, 7.2 J=Hz, 6H).
Reaction SMILES: C([N:8]1[CH2:11][CH:10]([OH:12])[CH2:9]1)(OC(C)(C)C)=O.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[C:17](O)[CH:18]=[CH:19][CH:20]=1>>[F:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][CH:16]=1)[O:12][CH:10]1[CH2:9][NH:8][CH2:11]1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Product: FC(F)(F)c1cccc(OC2CNC2)c1
Yield: 8 %

Procedure:
The title compound (D53) (100 mg) was prepared according to the experimental procedure described in Description 52 starting from 1-Boc-3-hydroxyazetidine (1 g, 5.77 mmol) and 3-(Trifluoromethyl)phenol (0.69 ml, 5.77 mmol).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[Cl:9]N1C(=O)CCC1=O.N1C=CC=CC=1>C1C=CC=CC=1>[Cl:9][CH2:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1ccncc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: ClCSc1ccncc1
Temperature: 25 °C
Yield: 46.5 %

Procedure:
A solution of 4-methylthiopyridine (2.28 g, 18.2 mmol), N-chlorosuccinimide (3.0 g, 23 mmol) and pyridine (2.9 mL, 3.0 mmol) in benzene (40 mL) was heated at 50°-60° C. for 3 h. The mixture was allowed to cool to room temperature. The solvent was decanted and the residue was rinsed with benzene (2×10 mL). The organic phases were combined and evaporated. The residue was passed through a pad of silica gel (40 g) to give the title material (1.35 g) contaminated with the starting material. The impure product was repurified on silica gel preparative plates (eluted with CH2Cl2 /CH3CN: 1/1) to give the pure title material (926 mg, 32%) as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.O1CCCC1.C([Li])CCC.[C:20]1([C:26]2[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:30][CH:29]=[CH:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.CCCCCC>[F:9][C:4]1[CH:3]=[C:2]([C:29]2[N:30]=[C:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:27][CH:28]=2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: c1ccc(-c2nccnc2-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Fc1cc(F)cc(-c2cnc(-c3ccccc3)c(-c3ccccc3)n2)c1
Temperature: -78 °C
Reaction time: 2 h
Yield: 4 %

Procedure:
First, to a mixed solution of 4.02 g of 1-bromo-3,5-difluorobenzene and 40 mL of tetrahydrofuran was added dropwise 14 mL (1.61 mol/L) of hexane solution of n-butyllithium at −78° C. under an atmosphere of nitrogen, and the solution was stirred for 2 hours at −78° C. In addition, to this mixed solution was added 4.03 g of 2,3-diphenylpyrazine in five steps at −78° C., and the temperature of the solution was raised to room temperature. Water was added to this mixture and an organic layer was extracted using diethylether as an extraction solvent. The obtained organic layer was washed with water and dried with anhydrous magnesium sulfate. The solution after drying was filtrated, and the magnesium sulfate was removed. The solvent of the solution was distilled off and the residue obtained by distillation was purified by silica gel column chromatography using dichloromethane as a developing solvent, so that a pyrazine derivative Hdppr-3,5FP (an orange powder, yield: 4%), which was a target substance was obtained. A synthetic scheme of Step 2 is shown by a following (c-3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=2[CH3:18])[N:5]=[C:4]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:3]=1.O.C(O)C>[Pd].C(N(CC)CC)C>[CH3:18][C:10]1[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][C:9]=1[NH:8][C:6]1[N:5]=[C:4]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:3]=[CH:2][N:7]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nc(Cl)cc(-c2cccnc2)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Reaction time: 40 h

Procedure:
In an autoclave, 5 g 6-chloro-N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine, 0.5 g palladium on charcoal 5% wet with 50% water, 50 mL ethanol and 5 mL triethylamine is charged. The mixture is hydrogenated at 5 bars and room temperature for 40 hours. Once completed the conversion, the catalyst is filtered off and the filtrates is concentrated in vacuum. The residue is taken again with isopropyl acetate and an aqueous carbonate solution. The layers are separated, and the organic layer is concentrated, yielding, upon drying, 3 g of product with 85% HPLC purity (A %), which is identified through LC-MS and 1H-NMR.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([Cl:27])[CH:9]=[C:10]([N:11]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]2=[N:4][CH:3]=1.C([Li])CCC.[C:33](=[O:35])=[O:34]>C1COCC1>[Cl:27][C:8]1[CH:9]=[C:10]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[N:6]([C:2]([C:33]([OH:35])=[O:34])=[CH:3][N:4]=2)[N:7]=1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(Br)cnc23)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C(=O)O)cnc23)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To an oven dried 25 ml shlenk flask under nitrogen was added 3-bromo-6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (0.5 g, 1.1 mmol) from Example XXXI step (1a) and THF (5.0 ml). The solution was cooled to −78° C. and n-butyllithium was added drop-wise over 10 minutes. The reaction was allowed to stir at the depressed temperature for 1 hour. Carbon dioxide gas was then introduced via a needle purging the solution for 2 minutes. The reaction was allowed to warm to 25° C. and stir for an additional 30 minutes. Dilute 1N HCl was added taking the aqueous portion to pH=5. Ethyl acetate was added and the layers separated. The organic layer was washed with water (20 ml), then brine (10 ml), dried over Na2SO4, filtered and concentrated to provide 0.47 g of 6-chloro-8-((4-methoxybenzyl)(phenyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid (98%). m/z=(410, M+1).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][O:26]CC2C=CC(OC)=CC=2)=[O:8])[CH2:5][CH2:4]1)#[N:2].O>ClCCl>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[CH2:25][OH:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccc(COC[C@@H]2C[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)cc1
Solvent: ClCCl
Solvent: O
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CO)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.8 %

Procedure:
To a cold mixture of (1R,2R,4S)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-(4-methoxy-benzyloxymethyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 153, step 9, 171 mg) in dichloromethane (4 mL) was added water (0.2 mL) and dichlorodicyanoquinone (97 mg). The reaction mixture was stirred 90 min at room temperature. The suspension was filtered and the solid was washed with dichloromethane. The resulting liquor was partionned between dichloromethane and saturated aqueous solution of sodium hydrogenocarbonate. The aqueous layer was washed with dichloromethane. The combined organic layers were washed brine, dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of dichlormethane:methanol (98:2 to 19:1 v/v) as eluant to afford the title compound (101 mg, 77%) as a white solid. MS (EI): 401.1 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:36]=[CH:35][C:14]2[S:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:20]=3)=[C:17]([Cl:18])[C:13]=2[CH:12]=1)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:18][C:17]1[C:13]2[CH:12]=[C:11]([CH2:10][NH:9][CH2:8][CH2:7][C:6]([OH:37])=[O:5])[CH:36]=[CH:35][C:14]=2[S:15][C:16]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[C:21]([C:31]([F:33])([F:32])[F:34])[CH:20]=1
Reactant: CC(C)(C)OC(=O)CCNCc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)c(Cl)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNCc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)c(Cl)c2c1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
3-{[3-Chloro-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophen-5-ylmethyl]-amino}-propionic acid tert-butyl ester (43 mg, 0.079 mmol) is dissolved in TFA/CH2Cl2 (1/1) (1 mL). The solution is stirred at room temperature for an hour. The mixture is concentrated and purified by reversed phase preparative LC/MS to give 23 mg of 3-{[3-chloro-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophen-5-ylmethyl]-amino}-propionic acid: 1H NMR (CD3OD, 400 MHz) δ 8.10 (s, 1 H), 7.96-8.02 (m, 3 H), 7.54 (d, 1 H), 7.46 (d, 1 H), 7.35-7.37 (m, 3 H), 7.28-7.29 (m, 2 H), 4.37 (s, 2 H), 3.26(m, 2 H), 2.71 (m, 2 H), MS (ES+) 490.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]12[C:21](=[O:22])[NH:20][C:19](=O)[NH:18]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][C:5]12[C:21](=[O:22])[NH:20][C:19](=[S:33])[NH:18]1
Reactant: O=C1NC(=O)C2(CC(c3ccccc3)Sc3ccc(Br)cc32)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: O=C1NC(=S)NC12CC(c1ccccc1)Sc1ccc(Br)cc12
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A solution of 6′-bromo-2′-phenylspiro[imidazolidine-4,4′-thiochroman]-2,5-dione (237 mg, 0.61 mmol) and Lawesson's reagent (246 mg, 0.61 mmol) in 1,4-dioxane (3 mL) in a 10 mL CEM microwave test tube is heated in a CEM microwave reactor at 110° C. for 30 min. After cooled to rt, the solvent is removed in vacuo, and the residue is purified by flash chromatography column to give 6′-bromo-2′-phenyl-2-thioxospiro[imidazolidine-4,4′-thiochroman]-5-one (200 mg, 81%). MS ESI +ve m/z 405 (M+H)+.
Reaction SMILES: C([O:5][C:6](=[O:53])[C:7]([O:10]/[N:11]=[C:12](/[C:40]1[N:41]=[C:42]([NH:45]C(OC(C)(C)C)=O)[S:43][CH:44]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[N:30]=[C:29]([CH2:31][NH:32]C(OC(C)(C)C)=O)[CH:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(O)=O>[NH2:32][CH2:31][C:29]1[CH:28]=[N:27][N:26]([CH2:25][C@@H:17]2[C@H:16]([NH:15][C:13](=[O:14])/[C:12](=[N:11]\[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:53])=[O:5])/[C:40]3[N:41]=[C:42]([NH2:45])[S:43][CH:44]=3)[C:19](=[O:20])[N:18]2[S:21]([OH:24])(=[O:23])=[O:22])[N:30]=1
Reactant: CC(C)(C)OC(=O)NCc1cnn(C[C@@H]2[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c3csc(NC(=O)OC(C)(C)C)n3)C(=O)N2S(=O)(=O)O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: O=CO
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncc(CN)n1)c1csc(N)n1)C(=O)O
Temperature: 0 °C
Yield: 31.1 %

Procedure:
(2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((4-(((tert-butoxycarbonyl)amino)methyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidine-1-sulfonic acid (82 mg, 0.104 mmol) was stirred with formic acid (2.0 mL) at rt for 5 h, which removed both Boc groups. After concentration in vacuo, the material was dissolved in DCM (1.5 mL), cooled to 0° C. and treated with TFA (0.5 mL, 6.5 mmol) for 1 h, whereupon it was concentrated in vacuo. The crude residue was purified by reverse phase prep HPLC (T3, 30×150 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (17.2 mg, 31%) as a white solid. LCMS: m/z=529.9 (M−1); 1H NMR (400 MHz, D2O): δ 7.67 (s, 1H), 6.92 (s, 1H), 5.39 (d, J=5.6 Hz, 1H), 4.86-4.74 (m, 3H assumed; obscured by solvent residual peak), 4.16 (s, 2H), 1.25 (s, 3H), 1.23 (3H, s).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>>[N:19]1([C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: c1ccc2c(c1)CCN2
Reactant: COc1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Product: COc1ccc(-c2cc3c(N4CCc5ccccc54)ncnc3[nH]2)cc1

Procedure:
This product is prepared in a manner analogous to that described in Example 1 from 4-chloro-6-(4-methoxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 2,3-dihydroindole (1.1 equivalents). M.p. >300° C.; FAB-MS: (M+H)+ =343 (corresponds to C21H18N4O).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:35])[CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][C@@H:18]1[C@@H:22](/[CH:23]=[CH:24]/[C@@H:25]([OH:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])[C@H:21]([OH:33])[CH2:20][C@@H:19]1[OH:34].C(Cl)(Cl)Cl.O1CCCC1>C(OCC)(=O)C>[CH3:9][O:10][C:11](=[O:35])[CH2:12][CH2:13][CH2:14][CH:15]([Br:1])[CH:16]1[O:34][C@H:19]2[CH2:20][C@@H:21]([OH:33])[C@H:22](/[CH:23]=[CH:24]/[C@@H:25]([OH:32])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])[C@H:18]2[CH2:17]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCCCl)[C@H](O)C[C@@H]1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COC(=O)CCCC(Br)C1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCCCl)[C@H](O)C[C@@H]2O1
Yield: 78.8 %

Procedure:
Under an atmosphere of nitrogen, 85 mg of N-bromosuccinimide were added to a solution of 175 mg of (5Z,13E)-(9α,11α,15S)-9,11,15-trihydroxy-20-chloroprosta-5,13-dienoic acid methyl ester [prepared as described in Example 4 of British Patent Application No. 22090/75 and, e.g. the equivalent Belgian Specification No. 842113] in 3 ml of a mixture of chloroform and tetrahydrofuran (1:1) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (1:2) as eluent to give 165 mg of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[C:31](O)(=O)C.C=O.C([BH3-])#N.[Na+]>CO.ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: CC(=O)O
Reactant: Cc1cc(CC2CCNCC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(CC2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2

Procedure:
7-Methyl-5-piperidin-4-ylmethyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (50.0 mg, 0.124 mmol) was dissolved in methanol (0.2 mL) and acetic acid (0.2 mL) and 37% formaldehyde (0.2 mL) was added at room temperature. The mixture was stirred for ten minutes and sodium cyanoborohydride (1M in THF, 0.2 mL, 0.20 mmol) was added and the mixture was allowed to stir overnight at room temperature. The reaction was diluted with dichloromethane, washed with sodium bicarbonate (sat) and brine dried over sodium sulphate, filtered and concentrated. Column chromatography provided the title compound as an off white foam (23.8 mg, 44%). 1H NMR (300 MHz, CDCl3): δ 7.37 (d, 2H), 7.21 (d, 2H), 6.99 (d, 2H), 4.77 (s, 2H), 4.22 (s, 2H), 2.91 (d, 1H), 2.77 (m, 4H), 2.58 (d, 2H), 2.30 (m, 3H), 1.99 (m, 1H), 1.67-1.27 (m, 6H).