Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][C@H:28]([O:31][Si](C(C)(C)C)(C)C)[C@@H:27]1[CH2:39][O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1.C(OCC)(=O)C>[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][C@@H:28]([OH:31])[C@H:27]1[CH2:39][O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1COCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](O)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
A solution of 2.01 g (7.68 mmol) of tetrabutylammonium fluoride in 5 ml of tetrahydrofuran was added, whilst ice-cooling, to a solution of 2.16 g (5.12 mmol) of (2S,3S)-1-t-butoxycarbonyl-2-benzyloxymethyl-3-t-butyldimethylsilyloxypyrrolidine in 5 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 4 hours. At the end of this time, the reaction mixture was diluted with ethyl acetate, and the organic extract was washed with 0.5N aqueous hydrochloric acid, with a 5% w/v aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The reaction mixture was then dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was then purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.57 g of the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:49][O:50][C:51]1[CH:59]=[CH:58][C:54]([CH:55]([OH:57])[CH3:56])=[CH:53][CH:52]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:38](=[O:40])[O:57][CH:55]([C:54]2[CH:58]=[CH:59][C:51]([O:50][CH3:49])=[CH:52][CH:53]=2)[CH3:56])=[CH:18][CH:17]=1
Reactant: COc1ccc(C(C)O)cc1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(C)OC(=O)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)cc1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (68 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (102 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-methoxy-α-methylbenzyl alcohol (52 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (61 mg, yield 52%).
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16]([CH3:19])([OH:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20]I.[H-].[Na+]>CN(C=O)C>[CH:1]([N:14]1[CH2:17][C:16]([O:18][CH3:20])([CH3:19])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC1(O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(C)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 1 h
Yield: 29.2 %

Procedure:
To a DMF (2 mL) solution of 1-benzhydryl-3-methylazetidin-3-ol (123 mg, 0.486 mmol), methyl iodide (33.2 μl, 0.534 mmol) and 60% sodium hydride (29 mg, 0.729 mmol) were added at 0° C. under a nitrogen stream, and the mixture was stirred for one hour at the same temperature. The reaction liquor was poured onto ice water, and the mixture was extracted with ethyl acetate. The extract was washed with ice water and saturated brine in this order, and then dried over anhydrous sodium sulfate. Sodium sulfate was removed, and then the solvent was concentrated under reduced pressure. The obtained residue was purified by thin layer chromatography (ethyl acetate/n-hexane=10/1, v/v), to obtain the title compound (38 mg, 29%) as an oily matter.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[H-].[Na+].[C:11]([C:13]1[CH:14]=[C:15]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1F)#[N:12].Cl>O1CCCC1.O>[C:11]([C:13]1[CH:14]=[C:15]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1[O:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)#[N:12]
Reactant: N#Cc1cc(S(N)(=O)=O)ccc1F
Reactant: OCC1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(S(N)(=O)=O)ccc1OCC1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To (tetrahydro-2H-pyran-4-yl)methanol (0.206 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.284 g) and the reaction stirred at room temperature for 20 minutes. The reaction was cooled to 0° C. and 3-cyano-4-fluorobenzenesulfonamide (0.355 g) in tetrahydrofuran (2 mL) was added dropwise and the reaction was allowed to warm to room temperature. After 3 hours, the reaction was poured into water, made acidic (pH=1) with 1N HCl and extracted with dichloromethane (2×75 mL). The organics were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10]([NH2:12])=[O:11])[CH2:3][CH2:2]1.[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([N:33](C(OC4C=CC=CC=4)=O)[C:34](=O)[O:35]C4C=CC=CC=4)[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]>CN(C)C=O>[CH3:13][NH:14][C:15]([N:17]1[C:25]2[C:20](=[CH:21][C:22]([O:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([NH:33][C:34]([N:1]4[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][C:10](=[O:11])[NH2:12])[CH2:3][CH2:2]4)=[O:35])[CH:28]=3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1)=[O:16]
Reactant: NC(=O)CCCC1CCNCC1
Reactant: CNC(=O)n1ccc2cc(Oc3ccnc(N(C(=O)Oc4ccccc4)C(=O)Oc4ccccc4)c3)ccc21
Solvent: CN(C)C=O
Product: CNC(=O)n1ccc2cc(Oc3ccnc(NC(=O)N4CCC(CCCC(N)=O)CC4)c3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(Piperidin-4-yl)butanamide (547 mg, 1.41 mmol) was dissolved in N,N-dimethylformamide (3 ml); phenyl N-(4-(1-(methylamino)carbonyl-1H-indol-5-yloxy)-pyridin-2-yl)-N-(phenoxycarbonyl)carbamate (210 mg, 0.402 mmol, the product of Production example 5-2) was added thereto; and the reaction mixture was stirred at room temperature for 1.5 hour. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate-methanol system). The obtained amorphous solid was crystallized by adding diethyl ether. After addition of a small amount of ethanol to make a suspension, this was diluted with hexane. After separation by filtration to obtain crystals, these were rinsed with diethyl ether and dried under aeration. Thus, the title compound was obtained as colorless crystals (157 mg, 0.328 mmol, 81.7%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22](OC)=[O:23])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][CH2:22][OH:23])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CSc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCO)c2CC1
Temperature: -30 °C
Yield: 93.8 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-methoxycarbonylmethylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (750 mg, 1.94 mmol) in THF (25 mL) at −78° C. under nitrogen, add 1M DIBAL in toluene (5.0 mL, 5.0 mmol) dropwise with stirring. Warm to −30° C. over 1 h and quench carefully with water. Extract with EtOAc, dry over anhydrous MgSO4, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (4:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(2-hydroxy-ethylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (651 mg, 94%).
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH:29](=O)[CH2:30][CH2:31][CH2:32][CH2:33]C>>[CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[C:21]=4[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2]
Reactant: CCCCCC=O
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Product: CCCCCc1c2c(nc3cc(F)ccc13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 2 is treated with hexanal according to a procedure similar to Stage 13e in order to produce the expected solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.[C:26]([C:28]1[N:32]([CH3:33])[CH:31]=[N:30][CH:29]=1)#[CH:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[ClH:1].[ClH:1].[CH3:33][N:32]1[C:28]([C:26]#[C:27][C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]4[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=4)=[CH:9][N:10]=[C:4]3[CH:3]=2)=[CH:29][N:30]=[CH:31]1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)ccn23)c1
Reactant: C#Cc1cncn1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Cl
Product: Cn1cncc1C#Cc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Temperature: 100 °C
Yield: 63.1 %

Procedure:
A mixture of 1-[3-(7-Chloro-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (3.08 g, 8.3 mmol), 5-Ethynyl-1-methyl-1H-imidazole (1.78 g, 10 mmol) and cesium carbonate (5.43 g, 16.7 mmol) in dry DMSO (31 ml) was deoxygenated by evacuation /refill with N2 (×3). PdCl2(PCy3)2 (185 mg, 0.25 mmol) was added and the mixture was deoxygenated again (×3) then stirred and heated at 100° C. under N2 for 16 hours. The reaction was allowed to cool to RT, diluted with water (65 ml) and the mixture was extracted with EtOAc (3×50 ml). The combined organic extracts were washed with brine (40 ml) then dried (MgSO4), filtered and evaporated. The residue was mixed with dichloromethane (20 ml), cooled in ice and filtered to give the title compound (1.34 g, yellow solid). 1H NMR (400 MHz, Me-d3-OD): 8.59 (1H, d), 7.87-7.74 (4H, m), 7.50 (1H, t), 7.42 (1H, d), 7.37 (1H, s), 7.32 (1H, d), 7.10 (1H, dd), 3.95 (2H, q), 3.85 (3H, s). A solution of the title compound in methanol (10 ml) was cooled in ice and was treated with a solution of saturated hydrogen chloride in ethyl acetate (15 ml). The mixture was evaporated to give the bis-HCl salt (1.59 g, yellow foam). 1H NMR (400 MHz, Me-d3-OD): 9.06 (1H, s), 8.88 (1H, d), 8.34-8.27 (2H, m), 8.08 (2H, d), 7.65 (1H, d), 7.59 (1H, t), 7.47-7.35 (2H, m), 4.09 (3H, s), 3.96 (2H, q).
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)=[C:4]([CH2:16][CH3:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[CH:32])=[N:29][CH:30]=2)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]#[C:32][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)=[C:4]([CH2:16][CH3:17])[CH:3]=3)=[N:29][CH:30]=2)=[CH:23][CH:24]=1
Reactant: CCc1cc(I)ccc1OCCN1CCCC1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: CCc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CCCC1

Procedure:
The product was obtained analogously to Example 7.1e starting from 1-[2-(4-iodo-2-ethylphenoxy)ethyl]pyrrolidine and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 44 mg (12% of theoretical); C27H27ClN2O (M=430.969); calc.: molpeak (M+H)+: 431/433 (Cl); found: molpeak (M+H)+: 431/433 (Cl); HPLC-MS: 5.74 minutes (method A).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH:10]([CH3:12])[CH3:11])=[N:5][CH:6]=[CH:7][CH:8]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[C:22]=1[CH3:29])=[O:17])C>>[CH:10]([S:9][C:4]1[C:3]([CH2:2][O:27][C:24]2[CH:25]=[CH:26][C:21]([CH:19]3[CH2:20][CH:18]3[C:16]([OH:17])=[O:15])=[C:22]([CH3:29])[C:23]=2[CH3:28])=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:12])[CH3:11]
Reactant: CCOC(=O)C1CC1c1ccc(O)c(C)c1C
Reactant: CC(C)Sc1ncccc1CCl
Product: Cc1c(OCc2cccnc2SC(C)C)ccc(C2CC2C(=O)O)c1C
Yield: 81.3 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-pyridine (0.030 g, 0.149 mmol) obtained in Step C of Preparation Example 1 and 2-(4-hydroxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester (0.035 g, 0.149 mmol) obtained in Step C of Preparation Example 48 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.045 g, 81%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH3:28])=[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:13]=3)=[C:9]([C:25]#[N:26])[CH:8]=[N:7][N:6]2[CH:27]=1.CCN(C(C)C)C(C)C.[C:38]1([S:44](Cl)(=[O:46])=[O:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl>[C:25]([C:9]1[CH:8]=[N:7][N:6]2[CH:27]=[C:3]([NH:2][S:44]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)(=[O:46])=[O:45])[C:4]([CH3:28])=[C:5]2[C:10]=1[NH:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)#[N:26]
Reactant: Cc1c(N)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(NS(=O)(=O)c2ccccc2)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12

Procedure:
To 6-Amino-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-3-carbonitrile hydrochloride (8.2 mg, 0.021 mmol) and DIEA (5.4 mg, 0.042 mmol) in dichloromethane (1.0 ml) was added benzenesulfonyl chloride (3.7 mg, 0.021 mmol) at RT for 2 hrs. The reaction mixture was quenched with pH 7 phosphate buffer (2 ml), dried over Na2SO4, concentrated and purified by silica gel flash chromatography to isolate 377 as a yellow film (3 mg, 29%). [M+H]+=496.1.
Reaction SMILES: C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:8])C=CC=CC=1.C([N:20]([CH2:23]C)CC)C.[CH3:25][O:26][C:27]([CH2:29][C@:30]1([CH2:36]C(O)=O)[CH2:34][CH2:33][C@@H:32]([CH3:35])[CH2:31]1)=[O:28]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:25][O:26][C:27](=[O:28])[CH2:29][C@:30]1([CH2:36][N:20]=[C:23]=[O:8])[CH2:34][CH2:33][C@@H:32]([CH3:35])[CH2:31]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COC(=O)C[C@]1(CC(=O)O)CC[C@@H](C)C1
Reactant: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)C[C@]1(CN=C=O)CC[C@@H](C)C1
Yield: 100.3 %

Procedure:
Diphenylphosphoryl azide (5.35 mL, 24.8 mmol), triethylamine (3.55 mL, 25.6 mmol), and [(1R,3R)-1-methoxycarbonylmethyl-3-methyl-cyclopentyl]-acetic acid (5.26 g, 24.5 mmol) were refluxed in toluene (80 mL) for 17 hours. The mixture was allowed to cool and then taken up in ethyl acetate (300 mL), washed with saturated aqueous sodium hydrogen carbonate solution (250 mL), brine (200 mL), and dried (MgSO4). The solvent was removed under reduced pressure to give 5.19 g (100%) of ((1S,3R)-1-isocyanatomethyl-3-methyl-cyclopentyl)-acetic acid methyl ester which was used without further purification;
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6](O)=O.COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=[C:27]([NH2:29])C=1.FC1C=C(C=CC=1CCCN1CCCCC1)CN[C:48]1[CH:53]=[C:52]([O:54][CH3:55])[CH:51]=[CH:50][C:49]=1[CH:56]1[CH2:65][CH2:64][C:63]2[C:58](=[CH:59][CH:60]=[C:61]([O:66][CH3:67])[CH:62]=2)[CH2:57]1>>[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:6][NH:29][CH2:27][C:48]1[CH:53]=[C:52]([O:54][CH3:55])[CH:51]=[CH:50][C:49]=1[CH:56]1[CH2:65][CH2:64][C:63]2[C:58](=[CH:59][CH:60]=[C:61]([O:66][CH3:67])[CH:62]=2)[CH2:57]1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(CCCN3CCCCC3)c(F)c1)C2
Reactant: O=C(O)c1ccc(CCCN2CCCCC2)c(F)c1
Agent: Cl
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CNCc1ccc(CCCN3CCCCC3)c(F)c1)C2

Procedure:
Synthesized from 3-fluoro-4-(3-piperidin-1-ylpropyl)benzoic acid hydrochloride and 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine according to an analogous synthetic method to Example 337 described below, [3-fluoro-4-(3-piperidin-1-ylpropyl)benzyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (311 mg) was used according to an analogous synthetic method to Preparation Example 18 to provide [3-fluoro-4-(3-piperidin-1-ylpropyl)benzyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamine (272 mg). This compound (270 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (147 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[O:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.[NH:19]1[CH2:26][CH2:25]C[C@H:20]1[C:21](O)=[O:22].N1CCOCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CS(C)=O.O.[Cu]I>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:8][C:6]3[C:5]([N:10]=2)=[CH:4][CH:3]=[C:2]([N:19]2[CH2:20][CH2:21][O:22][CH2:25][CH2:26]2)[N:7]=3)=[CH:12][CH:13]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COc1ccc(-c2nc3ccc(Cl)nc3o2)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCN1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2nc3ccc(N4CCOCC4)nc3o2)cc1
Temperature: 90 °C
Yield: 13.5 %

Procedure:
To a solution of 5-chloro-2-(4-methoxy-phenyl)-oxazolo[5,4-b]pyridine (25 mg, 0.096 mmol) in DMSO (1 mL) was added L-proline (11.04 mg, 0.096 mmol), CuI (18.27 mg, 0.096 mmol), morpholine (13 μL, 0.15 mmol) and K3PO4 (40.7 mg, 0.192 mmol). The reaction vessel was sealed and heated to 90° C. overnight, at which point the reaction was diluted with water and extracted with EtOAc. The organics were concentrated leaving a residue that was purified by reverse phase chromatography to afford 2-(4-methoxy-phenyl)-5-morpholin-4-yl-oxazolo[5,4-b]pyridine (4.3 mg, 0.013 mmol, 14% yield). ES MS (M+H+)=312; 1H NMR (499 MHz, DMSO-d6): δ 8.07-8.02 (d, J=8.7 Hz, 2H); 7.98-7.94 (m, 1 H); 7.17-7.11 (d, J=8.7 Hz, 2H); 6.91 (d, J=8.8 Hz, 1H); 3.86 (s, 3H); 3.73 (t, J=4.8 Hz, 4H); 3.51 (t, J=4.8 Hz, 4H); HRMS m/z 312.1352 (C17H17N3O3+H+ requires 312.1343)
Reaction SMILES: [N+:1]([O-])([N+]([O-])=O)=[O:2].C([O-])(=O)C.[Na+].[Cl:12][CH2:13][CH2:14][NH:15][C:16]([N:18]=[N+:19]=[N-:20])=[O:17].CC(O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:12][CH2:13][CH2:14][N:15]([N:1]=[O:2])[C:16]([N:18]=[N+:19]=[N-:20])=[O:17]
Reactant: [N-]=[N+]=NC(=O)NCCCl
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: [N-]=[N+]=NC(=O)N(CCCl)N=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Nitrogen tetroxide (0,3 mole) was slowly added to a suspension of anhydrous sodium acetate (0.6 mole) in 300 ml of carbon tetrachloride at -10° C. After warming to 0° C., 2-chloroethylcarbamoyl azide (0.2) was slowly added with a spatula to the stirred suspension. A white precipitate was formed (AcOH). After 15 minutes, the reaction mixture was poured into ice water. The separated organic phase was extracted twice with 50 ml of a cold solution of NaHCO3 (1 molar) and was then washed neutral with 2×50 ml of ice cold water saturated with NaCl. It was then dried over anhydrous sodium sulfate. No attempt was made to isolate N-(chloroethyl)-N-nitrosocarbamoyl azide as it is potentially explosive. The NMR spectroscopic examination of the CCl4 solution (internal standard TMS) showed the complete absence of an NH-- signal and showed a pattern which is typical for the A2B2 system of the nitrosated 2-chloroethylamino group. δ=3.50 ppm (t, 2H, --CH 2 --N--NO); 4.15 ppm (t, 2H, Cl--CH2 --).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:10][S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[I:8].[H-].[Na+].[CH3:19][Si:20]([CH2:23][CH2:24][O:25][CH2:26]Cl)([CH3:22])[CH3:21]>CN(C=O)C>[F:1][C:2]1[C:3]([N:10]([CH2:26][O:25][CH2:24][CH2:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[S:11]([CH2:14][CH2:15][CH3:16])(=[O:13])=[O:12])=[N:4][CH:5]=[C:6]([F:9])[C:7]=1[I:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCCS(=O)(=O)Nc1ncc(F)c(I)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N(COCC[Si](C)(C)C)c1ncc(F)c(I)c1F
Reaction time: 0.17 h

Procedure:
To a solution of N-(3,5-difluoro-4-iodopyridin-2-yl)propane-1-sulfonamide (0.68 g, 1.88 mmol) in anhydrous DMF (25 ml) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.15 g, 3.8 mmol). The reaction mixture was stirred for 10 min, and then SEMCl (0.47 g, 2.8 mmol) was added. The mixture was stirred for 1 h and was then concentrated. Water was added and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel (5 to 20% ethyl acetate in hexanes eluant) to provide the title compound. MS m/z 515.1 (M+Na).
Reaction SMILES: O1C=C(CN)N=C1.[NH:8]1[CH:12]=[CH:11][C:10]([CH2:13][NH2:14])=[N:9]1.[F:15][C:16]1[CH:37]=[CH:36][C:19]([CH2:20][N:21]2[CH2:25][CH2:24][N:23]([C:26]3[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=3)[C:29](O)=[O:30])[C:22]2=[O:35])=[CH:18][CH:17]=1>>[NH:8]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][N:34]=[C:26]([N:23]3[CH2:24][CH2:25][N:21]([CH2:20][C:19]4[CH:18]=[CH:17][C:16]([F:15])=[CH:37][CH:36]=4)[C:22]3=[O:35])[CH:27]=2)=[N:9]1
Reactant: NCc1cc[nH]n1
Reactant: O=C(O)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Agent: NCc1cocn1
Product: O=C(NCc1cc[nH]n1)c1ccnc(N2CCN(Cc3ccc(F)cc3)C2=O)c1
Yield: 23 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace oxazol-4-ylmethanamine with (1H-pyrazol-3-yl)methanamine to react with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinic acid, N-((1H-pyrazol-3-yl)methyl)-2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)isonicotinamide was obtained as a colorless solid in 23% yield: mp 178-180° C.; 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.33-8.24 (m, 2H), 7.45-7.37 (m, 2H), 7.32-7.17 (m, 3H), 7.04-6.94 (m, 2H), 6.27 (s, 1H), 4.70 (d, J=5.7 Hz, 2H), 4.43 (s, 2H), 4.03 (t, J=8.1 Hz, 2H), 3.37 (t, J=8.1 Hz, 2H); MS (ES+) m/z 394.9 (M+1).