Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH2:13](C([Sn])=C(CCCC)CCCC)[CH2:14]CC.[Cl-].[Li+].[F-].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:12][C:4]1[CH:3]=[C:2]([CH:13]=[CH2:14])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)cc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(=O)OC)c(O)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-bromo-2-hydroxybenzoate (3.0 g) in DMF (50.0 mL) were added tributylvinyltin (6.18 g), bis(triphenylphosphine)palladium(II) chloride (0.46 g) and lithium chloride (4.07 g), and the mixture was stirred at 90° C. for 2 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound. This compound was used in the next step without an additional purification.
Reaction SMILES: ClC1C=CC(C(C2C=CC(Cl)=CC=2)=O)=CC=1.[OH-].[K+].[N+]([C:22]1[CH:23]=[C:24]([C:30]#[N:31])[C:25](=[CH:28][CH:29]=1)[C:26]#[N:27])([O-])=O.Cl>C1(C)C=CC=CC=1.CS(C)=O>[C:30](#[N:31])[C:24]1[C:25](=[CH:28][CH:29]=[CH:22][CH:23]=1)[C:26]#[N:27]
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: Cl
Agent: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: N#Cc1ccccc1C#N
Temperature: 140 °C
Yield: 95 %

Procedure:
To a 2000 mL, three-necked flask fitted with a thermometer, a Dean-Stark trap with condenser, and a nitrogen inlet were added bisphenol A6F (100 g, 0.298 mol), 4,4′-dichlorobenzophenone (26.5 g, 0.106 mol), potassium hydroxide (36.7 g, 0.656 mol), toluene (15 mL), and dimethylsulfoxide (DMSO) (500 mL). Toluene was used to control the refluxing azeotropic removal of water and to control the temperature of the reaction content. The resulting mixture was degassed with nitrogen at ambient temperature and the Dean-Stark trap was filled with toluene. The mixture was refluxed at 135-145° C. under a nitrogen atmosphere for 8-16 h or until no more water was observed being collected in the Dean-Stark trap. The toluene was then slowly distilled off causing the temperature to rise in the reaction vessel to enhance the yield of the intermediate hydroxyl salt and high conversion to this intermediate. The mixture was cooled to 50° C. At this time, 4-nitrophthalonitrile (69.4 g, 0.401 mol) was added in one portion and the reaction mixture was heated at 80° C. for 6-8 h. The mixture was allowed to cool to ambient temperature and poured into a 5% aqueous HCl solution resulting in the formation of a solid. The material was broken up and collected using a Büchner funnel. The white solid was washed with 200 mL of a 5% aqueous KOH solution, with 200 mL portions of distilled water until neutral, with 200 mL of a 5% aqueous HCl solution, and finally with 200 mL portions of water until neutral. The isolated solid was vacuum dried to yield the 2:1 oligomeric phthalonitrile and the bisphenol A6F phthalonitrile composition (159 g, 95% yield). IR [cm−1]: ν 3074 (C═CH), 2232 (CN), 1652 (C═O), 1587 (C═C), 1476 (aromatic), 1306 (aromatic), 1308 (C—O), 1245 (CH3), 1160 (C—O), 929 (C—O), 842 (aromatic).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH3:12][N:13]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]1[C:19]#[N:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:12][N:13]1[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]1[C:19]1[S:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[N:20]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cc1ccc(C#N)n1C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc(=O)c3ccccc3s2)n1C
Yield: 42.6 %

Procedure:
A mixture of methyl thiosalicylate (2.20 g, 13.3 mmol), 1,5-dimethyl-2-pyrrolecarbonitrile (1.40 g, 11.9 mmol), triethylamine (2.50 ml, 17.9 mmol) and toluene (7.0 ml) was refluxed for 24 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-ethanol to give the titled compound (1.30 g, 41%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:12]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13]1>Cl>[F:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:19])=[CH:8][CH:7]=1
Reactant: Fc1ccccc1
Reactant: O=C1CCCC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)CCCC(=O)c1ccc(F)cc1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 79.2 %

Procedure:
Charged 260 g of anhydrous AlCl3 (1.87 moles) to a 2 L 3-neck round bottom flask, added 300 mL fluorobenzene (307.5 g; 3.2 moles) and cooled the mixture in an ice bath to 5° C. Added a hazy suspension of 100 g glutaric anhydride (0.86 mole) in 400 mL fluorobenzene (4.3 moles) through an addition funnel over a period of 45 min., and maintained the temperature below 12° C. The reaction mixture was warmed to ambient temperature gradually and agitated at r.t. for about 90 min.; checked for completion by NMR. Cooled the reaction mixture to 0 to 5° C., then added a cold aqueous solution (700 ml) of 1N HCl carefully to the mixture to destroy any unreacted AlCl3, keeping the temperature of the mixture below 20° C. during the early part of the acid addition, and below 40° C. for the rest of the time. Poured the entire mixture into a 2 L 1:1 mixture of water and ice (v/w) to precipitate out crude products, filtered the white suspension and washed well with water. Added the white residue to 3 L of aqueous saturated solution (˜5%) of NaHCO3, heated the basic mixture on a steam bath for one hour and filtered the batch while hot through a thin pad of celite. Cooled the filtrate to r.t., added about 320 mL of concentrated HCl dropwise into the filtrate to pH 1 to crystallize out products, and agitated the white suspension in an ice bath for 30 min. Filtered the batch, washed the wet cake with ice cold water and dried in a vacuum oven at 50° C. for 16 h to obtain 143.2 g of 4-(4-fluorobenzoyl)-butyric acid; m.p. 141 to 142° C., isolated yield: 79.3%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O.[NH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][NH:18][CH2:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:11]=1
Reactant: O=Cc1cccc(CCOC2CCCCO2)c1
Reactant: NCCc1ccccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CCNCc2cccc(CCOC3CCCCO3)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 3-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-benzaldehyde (Example 50, step A, 6.1 g) and 2-(2-aminoethyl)pyridine (3.18 g, 3.1 ml) in toluene (150 mL) was added p-toluene sulfonic acid (100 mg). The reaction was heated at reflux in a Dean-Stark apparatus for couple of hours. Around 2 mL water were displaced. The mixture was cooled and washed with aqueous bicarbonate and concentrated in vacuo. The residue was taken up in ethanol (100 ml) and cooled. Sodium borohydride (1.0 g) was added slowly and the reaction left 1 hour to warm to room temperature. Water was added (100 mL) and ethanol removed by distillation. The reaction was partitioned between aqueous bicarbonate and ethyl acetate. The organic layers were dried over sodium sulfate and concentrated in vacuo to give yellow oil (6.5 g). The material was used in the next step without further purification.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[OH:5][C:6]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15]>>[C:1]([CH2:2][CH2:3][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([OH:5])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]1=[O:15])#[N:4]
Reactant: O=C1Nc2ccccc2C1(O)c1ccccc1
Reactant: C=CC#N
Product: N#CCCN1C(=O)C(O)(c2ccccc2)c2ccccc21

Procedure:
Reaction of acrylonitrile with 3-hydroxy-3-phenyl-indolin-2-one by a procedure analogous to that of Example 1 gives 1-(2-cyanoethyl)-3-hydroxy-3-phenyl-indolin-2-one Hydrogenation of the 1-(2-cyanoethyl)-3-hydroxy-3-phenyl-indolin-2-one by a procedure analogous to that of Example 2 gives 1-(3-aminopropyl)-3-hydroxy-3-phenyl-indolin-2-one. Cyclodehydration of 1-(3-aminopropyl)-3-hydroxy-3-phenylindolin-2-one by a procedure analogous to that of Example 3 gives 2,3,4,10-tetrahydro-10-phenylpyrimido [1,2-a] indol-10-ol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>ClCCl>[F:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:18]([CH:15]2[CH2:17][CH2:16]2)=[O:19])=[CH:7][N:6]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc(F)nc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)nc1)C1CC1
Reaction time: 1 h
Yield: 72.4 %

Procedure:
A solution of 5-amino-2-fluoropyridine (6.63 g, 0.059 mol) and pyridine (5.16 g, 0.065 mol) in dichloromethane (120 ml) was stirred at room temperature. Cyclopropane carboxylic acid chloride (6.2 g, 0.059 mol) was added dropwise to the reaction mixture at such a rate to maintain the temperature at 20°-30° C. After complete addition the reaction mixture was stirred at temperature for a further one hour, then washed with 5% sodium hydroxide (100 ml), water (100 ml) and dried over anhydrous magnesium sulphate. Removal of the solvent gave a dark brown solid which was purified by column chromatography (silica eluted with dichloromethane : tetrahydrofuran=9:1) to give N-(2-fluoro-5-pyridyl)cyclopropane carboxamide (7.7 g, 72%) as an orange brown solid m.p. 116°-117° C.
Reaction SMILES: [OH:1][C:2]1[C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][C:5]([CH:6]=[N:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH2:13][CH2:14][CH3:15])=[CH:4][C:3]=1[C:22]([CH3:25])([CH3:24])[CH3:23].Cl.[H][H]>CO.[Pd]>[OH:1][C:2]1[C:17]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:16][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH2:13][CH2:14][CH3:15])=[CH:4][C:3]=1[C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: [H][H]
Reactant: CCCc1nccn1N=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCc1nccn1NCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
9.9 g of 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)-2-propylimidazole are hydrogenated at normal pressure and room temperature in 200 ml of methanol and 29 ml of 1N hydrochloric acid in the presence of 1 g of a palladium catalyst (5% on carbon). After 700 ml of hydrogen have been taken up, the catalyst is removed by filtration and the filtrate is evaporated. The residue is taken up with 100 ml of water, and saturated sodium bicarbonate solution is added up to a neutral reaction (pH=7). The separated crystals are removed by filtration and taken up in 300 ml of methylene chloride. The methylene chloride solution is washed once with water, dried and evaporated. The residue is dissolved in 50 ml of hot isopropyl ether. The crystals which separate upon cooling are removed by filtration, washed with isopropyl ether and n-hexane and dried at 60° in a vacuum. There is obtained 1-(4-hydroxy-3,5-di-tert.-butylbenzylamino)-2-propylimidazole of m.p. 122°-123°.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.[C:17]1([CH:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:24]2[CH2:27][CH2:26][C:25]2=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+].[Cl-].[Na+]>CO.[Cl-].[Zn+2].[Cl-]>[C:17]1([CH:23]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:24]2[CH2:27][CH:26]([N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=5[NH:9][C:8]4=[O:16])[CH2:5][CH2:6]3)[CH2:25]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCN1C(c1ccccc1)c1ccccc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: CO
Product: O=c1[nH]c2ccccc2n1C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Reaction time: 8 h
Yield: 133.1 %

Procedure:
In 7 ml of methanol, 217 mg of 1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one, 300 mg of 1-(diphenylmethyl)azetidin-2-one, 94 mg of sodium cyanoborohydride and 102 mg of zinc chloride were dissolved and stirred overnight. The reaction liquid was added to a saturated aqueous solution of sodium hydrogencarbonate to which sodium chloride had been added, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate and concentrated. Thus obtained residue was purified by silica gel column chromatography (chloroform, chloroform/methanol=50/1) to provide 583 mg of crude 1-[1-[1-(diphenylmethyl)azetidin-3-yl]piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one.
Reaction SMILES: [CH3:1][C:2]([CH3:16])([O:4][C:5]([NH:7][C@H:8]([C:13](O)=[O:14])[C:9]([SH:12])([CH3:11])[CH3:10])=[O:6])[CH3:3].O[N:18]1[C:22]2C=CC=CC=2N=N1.Cl.CN.CN1CCOCC1.C(Cl)CCl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C1C=CN=CC=1.CN(C)C=O>[CH3:22][NH:18][C:13](=[O:14])[C@H:8]([C:9]([SH:12])([CH3:11])[CH3:10])[NH:7][C:5]([O:4][C:2]([CH3:16])([CH3:3])[CH3:1])=[O:6]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)S
Reactant: On1nnc2ccccc21
Agent: CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)S
Yield: 83.6 %

Procedure:
A solution of (R)-N-(1,1-dimethylethoxy)carbonylpenicillamine (14 g, 56.1 mmol), N-hydroxybenzotriazole (7.6 g, 56.1 mmol), methylamine hydrochloride (18.9 g, 280 mmol), N-methylmorpholine (34 ml, 308 mmol), 4-dimethylaminopyridine (685 mg, 5.6 mmol) and EDC (11.8 g, 62 mmol) in anhydrous dimethylformamide (300 ml) was stirred at RT overnight. The mixture was poured into 10 w/v citric acid (750 ml) and extracted with ether (3×500 ml). The combined extracts were then washed with 8% sodium bicarbonate (2×500 ml) and brine (500 ml), dried (MgSO4) and evaporated in vacuo to provide the title compound (12.3 g, 83%)
Reaction SMILES: [I-].O1CCNC1=O.[F:8][C:9]1[CH:10]=[C:11]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:12]=[CH:13][C:14]=1[Sn](C)(C)C.Br[C:31]1[CH:37]=[CH:36][C:35](=[O:38])[C:34]([O:39][CH3:40])=[CH:33][CH:32]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:8][C:9]1[CH:10]=[C:11]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:12]=[CH:13][C:14]=1[C:31]1[CH:37]=[CH:36][C:35](=[O:38])[C:34]([O:39][CH3:40])=[CH:33][CH:32]=1
Reactant: COc1ccc(Br)ccc1=O
Reactant: CC(=O)NC[C@H]1CN(c2ccc([Sn](C)(C)C)c(F)c2)C(=O)O1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C1NCCO1
Agent: [I-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)ccc1=O
Temperature: 80 °C
Yield: 57 %

Procedure:
Alternatively, the oxazolidinone iodide described above can be converted to (S)-N-[[3-[3-fluoro-4-(trimethylstannyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, employing conditions disclosed for the corresponding racemic material in TR 7246-92-050. This tin-substituted intermediate (0.180 g, 0.43 mmol) and 5-bromo-2-methoxycyclohepta-2,4,6-trien-1-one (0.103 g, 0.48 mmol) were dissolved in dry DMF (3 mL) and the resultant solution degassed by repeated evacuation and filling with nitrogen. Bis(triphenylphosphine)palladium(II) chloride (0.015 g, 0.02 mmol) was added, the reaction again degassed, and the mixture heated to 80° C. for 2 h. TLC revealed some starting material still remained, so additional palladium catalyst (0.015 g) was added and the mixture heated a further 5 h. The reaction mixture was concentrated in vacuo and the residue chromatographed over silica gel, eluting with a methanol/chloroform gradient, to afford 0.096 g (57%) of the title compound, identical in all respects to material prepared via the above protocol.
Reaction SMILES: C(O)=O.[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([NH:27]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[O:16])=[CH:5]1>C(Cl)Cl>[NH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][CH:14]([NH2:27])[C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])=[O:16])=[CH:5]1
Reactant: COc1ccccc1CNC(=O)C(Cc1c[nH]c2ccccc12)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=CO
Product: COc1ccccc1CNC(=O)C(N)Cc1c[nH]c2ccccc12
Reaction time: 4 h
Yield: 90 %

Procedure:
Formic acid (9.0 ml, 238.540 mmol) was added to a stirring solution of 3-(1H-indol-3-yl)-N-(2-methoxybenzyl)-2-(N-triphenylmethylamino)propanamide (14.11 g, 23.763 mmol) in anhydrous methylene chloride under a nitrogen atmosphere at 0° C. After 4 hours, the reaction mixture was concentrated to an oil on a rotary evaporator and redissolved in diethyl ether and 1.0N hydrochloric acid. The aqueous layer was washed twice with diethyl ether and basified with sodium hydroxide to a pH greater than 12. The product was extracted out with methylene chloride (4×). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated on a rotary evaporator to a white foam. The compound 3-(1H-indol-3-yl)-2-amino-N-(2-methoxybenzyl)propanamide (7.52 g, 21.397 mmols) was isolated giving a 90% yield. No further purification was necessary.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]3[CH2:31][CH:26]4[CH2:27][N:28]([CH3:30])[CH2:29][CH:25]4[CH2:24]3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1.C1(C)C=CC=CC=1.[C:40]1([CH2:46][C:47]([N:49]=[C:50]=[S:51])=[O:48])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:32][C:50]([NH:49][C:47](=[O:48])[CH2:46][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[S:51])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]3[CH2:24][CH:25]4[CH2:29][N:28]([CH3:30])[CH2:27][CH:26]4[CH2:31]3)=[C:16]([O:19][CH3:20])[CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCC1CC2CN(C)CC2C1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2c(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)ccnc2cc1OCC1CC2CN(C)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a round bottom flask equipped with a magnetic stir bar was added 3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenylamine (0.78 mg, 1.7 mmol, 1.0 eq.), toluene (10 ml), ethanol (10 ml) and phenyl-acetyl isothiocyanate (1.64 g, 9.2 mmol, 4.5 eq). The reaction mixture was stirred at room temperature overnight. After removal of the solvent the product was purified with a biotage system using an eluent EtOAc and 4% TEA (2L) then EtOAc, 4% TEA, 1% MeOH (1L). The solvent was removed to give 1-{3-fluoro-4-[6-methoxy-7-(2-methyl-octahydro-cyclopenta[c]pyrrol-5-ylmethoxy)-quinolin-4-yloxy]-phenyl}-3-phenylacetyl-thiourea (0.5 g, 50% yield). 1H NMR (400 MHz, DMSO): 8.48 (d, 1H), 7.92 (dd, 1H), 7.53 (s, 1H), 7.40 (m, 4H), 7.33 (d, 2H), 7.23 (m, 2H), 6,54 (d, 2H), 6.39 (d, 1H), 4.21 (d, 2H), 4.02 (s, 3H), 3.81 (m, 3H), 2.87 (d, 2H), 2.73 (m, 4H), 2.53 (m, 1H), 2.27 (m, 2H), 2.01 (s, 3H), 1.36 (m, 2H); MS (EI) for C34H35FN4O4S: 615 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([OH:17])[C@H:13]([F:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[CH2:25]([C:29]1[N:30]=[N:31][C:32](Cl)=[CH:33][C:34]=1[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:37][CH:36]=1)[CH2:26][CH2:27][CH3:28]>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C@@H:14]([O:17][C:32]2[N:31]=[N:30][C:29]([CH2:25][CH2:26][CH2:27][CH3:28])=[C:34]([C:35]3[CH:36]=[CH:37][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:39][CH:40]=3)[CH:33]=2)[C@H:13]([F:18])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)[C@H](F)C1
Reactant: CCCCc1nnc(Cl)cc1-c1ccc(OC2CCCCC2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nnc(O[C@@H]2CCN(C(=O)OCc3ccccc3)C[C@H]2F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a stirred solution of (±)-trans-3-fluoro-4-hydroxy-piperidine-1-carboxylic acid benzyl ester (100 mg, 0.4 mmol) at 0° C. in THF (2 mL) was added potassium tert-butoxide (1.0 M in THF, 0.5 mmol, 0.5 mL). After 15 min 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-pyridazine (120 mg, 0.34 mmol) in THF (2 mL) was added. The solution was stirred overnight at 40° C., diluted with EtOAc and washed with water. The organics were dried over sodium sulfate, filtered, concentrated, and purified by column chromatography using 20-40% EtOAc in hexanes to provide (±)-trans-4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxy]-3-fluoro-piperidine-1-carboxylic acid benzyl ester (65 mg).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH:10]([C:13](=[O:15])[NH2:14])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[F:23][C:24]([F:57])([F:56])[C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:34]2[C:42]3[C:37](=[CH:38][C:39]([O:43][C:44]4[N:49]=[CH:48][N:47]=[C:46](COS(C)(=O)=O)[CH:45]=4)=[CH:40][CH:41]=3)[CH:36]=[CH:35]2)=[O:33])[CH:28]=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:56][C:24]([F:23])([F:57])[C:25]1[CH:26]=[C:27]([NH:31][C:32]([N:34]2[C:42]3[C:37](=[CH:38][C:39]([O:43][C:44]4[CH:45]=[C:46]([CH2:6][N:8]5[CH2:12][CH2:11][CH:10]([C:13](=[O:15])[NH2:14])[CH2:9]5)[N:47]=[CH:48][N:49]=4)=[CH:40][CH:41]=3)[CH:36]=[CH:35]2)=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: CS(=O)(=O)OCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)C1CCN(Cc2cc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncn2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Carbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.22 g, 1.03 mmol) is dissolved in DCM (5 mL). TFA (2 mL, 26.0 mmol) is added and the reaction is allowed to stir at rt overnight. The solvent is removed in vacuo and THF (5.0 mL) is added followed by methanesulfonic acid 6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl ester (0.347 g, 0.685 mmol) and DIEA (0.60 mL, 3.42 mmol). The reaction is heated at 60° C. for 19 h. The solvent is removed in vacuo and the residue separated by FCC (0-15%, 10% NH3MeOH/DCM) to provide (±)-5-[6-(3-carbamoyl-pyrrolidin-1-ylmethyl)-pyrimidin-4-yloxy]-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 524.9 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.41 (s, 1H), 8.72 (s, 1H), 8.30 (d, J=8.84 Hz, 1H), 8.14 (d, J=3.79 Hz, 1H), 8.10 (s, 1H), 7.97 (s, 1H), 7.65 (t, J=8.08 Hz, 1H), 7.51 (d, J=2.53 Hz, 2H), 7.16 (dd, J=8.84, 2.27 Hz, 1H), 7.12 (s, 1H), 6.81 (d, J=3.54 Hz, 1H), 3.63 (br. S., 1H), 3.14 (d, J=7.33 Hz, 1H), 2.94 (br. S., 1H), 1.99 (br. S., 1H), 1.25 (d, J=6.06 Hz, 6H).