Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:17])[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[C:18]1([CH2:24][O:25][C:26]([NH:28][CH2:29][CH:30]=[CH2:31])=[O:27])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.[OH-].[Na+].OO>Cl[Pd]Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:31][CH2:30][CH2:29][NH:28][C:26]([O:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:27])=[CH:3][CH:4]=1)[CH2:9][NH:10][S:11]([CH:14]([CH3:16])[CH3:15])(=[O:13])=[O:12]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(I)cc1
Reactant: C=CCNC(=O)OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: OO
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(CCCNC(=O)OCc2ccccc2)cc1
Yield: 98.1 %

Procedure:
Scheme Vc, step A: 2-(4-Iodophenyl) propyl isopropylsulfonamide (1.5 g, 4.1 mmol), (phenylmethoxy)-N-prop-2-enylcarboxamide (0.94 g, 4.9 mmol, prepared in example 8), 9-BBN dimer (0.8 g, 3.28 mmol), [1,1′bis(diphenylphosphino)-ferrocene] dichloropalladium (II), PdCl2(dppf) (0.17 g, 0.2 mmol), 3N sodium hydroxide (3 mL), and pH=7 buffer: hydrogen peroxide (2:1, 15 mL) were combined in a manner analogous to the procedure described in example 6 to provide the intermediate title compound, N-{3-[4-(1-methyl-2-{[(methylethyl)sulfonyl]amino}ethyl)phenyl]propyl}(phenylmethoxy)carboxamide, (1.74 g, 99%). Electron spray M.S. 431 (M*−H).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=1.O[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[O:17][N:16]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CO)on1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccccc1OCc1cc(OCc2nc(-c3ccccc3)oc2C)no1
Reaction time: 15 h

Procedure:
To a mixture of 3-(5 methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethanol (0.859 g), methyl 2-(2-hydroxyphenyl)acetate (0.499 g), triphenylphosphine (0.944 g) and tetrahydrofuran (15 mL) was dropwise added a solution (40%, 1.74 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred for 15 hrs. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography to give methyl 2-[2-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]phenyl]acetate as an oil from a fraction eluted with ethyl acetate-hexane (1:2, v/v). This oil was dissolved in methanol-tetrahydrofuran (1:1, 20 mL) and a 1N aqueous sodium hydroxide solution (10 mL) was added. The mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water, 1N hydrochloric acid (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of 2-[2-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazoly]methoxylphenyl]acetic acid. Recrystallization from ethanol-hexane gave colorless needle crystals (0.651 g, 52%). melting point: 152-153° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])[S:6][CH:7]=1.[OH:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:27][CH:28]=1.CN(C)C=O.[H-].[Na+]>O>[CH3:15][C:14]1[O:13][C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:11][C:10]=1[CH2:9][CH2:8][C:5]1[S:6][CH:7]=[C:3]([CH2:2][O:22][C:23]2[CH:24]=[C:25]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:26]=[CH:27][CH:28]=2)[N:4]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCc1nc(CCl)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(OCc2csc(CCc3nc(-c4ccccc4)oc3C)n2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 38.3 %

Procedure:
To a mixture of 4-[2-(4-chloromethyl-2-thiazolyl)ethyl]-5-methyl-2-phenyloxazole (0.64 g), methyl 2-(3-hydroxyphenyl)acetate (0.30 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 0.09 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water, 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-[3-[[2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethyl]-4-thiazolyl]methoxy]phenyl]acetate as a colorless oil (0.31 g, 38%) from a fraction eluted with ethyl acetate-hexane (1:3, v/v).
Reaction SMILES: O.[SH-].[Na+:3].C([S:11][C:12]1[N:17]=[C:16]([N:18]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[S:19]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:15]=[C:14]([NH:35][C@H:36]([CH3:39])[CH2:37][OH:38])[N:13]=1)C1C=CC=CC=1>CS(C)=O>[OH:38][CH2:37][C@H:36]([NH:35][C:14]1[CH:15]=[C:16]([N:18]([S:19]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=[O:20])=[O:21])[CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[N:17]=[C:12]([S-:11])[N:13]=1)[CH3:39].[Na+:3]
Reactant: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCCC2)nc(SCc2ccccc2)n1
Agent: [Na+]
Agent: [SH-]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCCC2)nc([S-])n1
Reaction time: 1 h

Procedure:
Sodium hydrosulfide hydrate (2.15 g) was added to a solution of the subtitle product of step iii) (4.5 g) in DMSO (37.8 ml) and the green solution stirred for 1 h. A further aliquot of sodium hydrosulfide hydrate (0.1 g) was added and stirred for 1 h. A further aliquot of sodium hydrosulfide hydrate (0.1 g) was added and stirred for 2 h before the addition of a final aliquot of sodium hydrosulfide hydrate (0.05 g). The resulting reaction solution was used directly in the following step. The subtitle compound was also kept as a stock solution for further reaction with alkyl halides, described in Examples 112-113.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:30])[C:16]([NH:18][C@H:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N(CCO)(CCO)CCO.O>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]([OH:30])[CH2:16][NH:18][C@H:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CCc2ccc(O)cc2C1)[C@H](O)c1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Solvent: OCCN(CCO)CCO
Solvent: O
Product: Oc1ccc2c(c1)C[C@@H](NC[C@H](O)c1ccc(OCc3ccccc3)cc1)CC2
Yield: 59.9 %

Procedure:
(2R)-2-(4-Benzyloxyphenyl)-2-hydroxy-N-((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)acetamide (605 mg) was dissolved in tetrahydrofuran (7.5 ml), and 2M borane-dimethyl-sulfide complex in tetrahydrofuran (2.25 ml) was added to the solution at room temperature with stirring. After the mixture was heated under reflux for 3 hours, a solution of triethanolamine (1.12 g) in tetrahydrofuran (2.5 ml) was added to the reaction mixture and the mixture was heated under reflux for 15 hours. After cooling, water was poured into the reaction mixture and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. Recrystallization of the residue from ethyl acetate gave (1R)-1-(4-benzyloxyphenyl)-2-[((2S)-7-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)-amino]ethanol (350 mg) having a melting point of 132-134° C.
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@H:19]4[CH2:24][CH2:23][C@@H:22]([CH3:25])[CH2:21][CH2:20]4)[CH:14]=3)[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.C(O)C.O.[OH-].[Li+]>O>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@H:19]3[CH2:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH2:24]3)[CH:14]=2)[CH:9]=1)([CH3:1])[CH2:6][OH:5]
Reactant: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@@H](C)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1ccc2cc(O[C@H]3CC[C@@H](C)CC3)ccc2c1
Temperature: 80 °C

Procedure:
To a solution of (R)-4-Methyl-4-[6-(cis4-methyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one (0.4420 g, 0.001302 mol) in ethanol (5.00 mL, 0.0856 mol) in a capped 40 mL vial was added 4.2 M Lithium hydroxide, monohydrate in water (2.8 mL). The mixture was heated overnight at 80° C. TLC analysis showed the reaction was complete. The mixture was concentrated to dryness under vacuum. Methylene chloride (5 mL) and water (5 mL) were added and the layers were separated (2×). The organic layer was concentrated under vacuum and purified by HPLC to give 0.0233 g of the title compound (6% yield). MS: m/z=297.29 [M−NH2]+. 1H NMR (400 MHz, MeOD) δ 0.98 (d, J=6.02 Hz, 3H), 1.40-1.51 (m, 2H), 1.51-1.60 (m, 3H), 1.64-1.74 (m, 2H), 1.79 (s, 3H), 2.03-2.14 (m, 2H), 3.83 (d, J=11.55 Hz, 1H), 3.93 (d, J=11.55 Hz, 1H), 4.69-4.77 (m, 1H), 7.23 (dd, J=8.91, 2.38 Hz, 1H), 7.27 (d, J=2.51 Hz, 1H), 7.53 (dd, J=8.78, 2.01 Hz, 1H), 7.79-7.89 (m, 3H)
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[S:26]([O:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:4]1)([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1(CO)CN(C(=O)OC(C)(C)C)CCO1
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C1(COS(=O)(=O)c2ccc(C)cc2)CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
E3 (3.2 g, 11.62 mmol) was dissolved in pyridine (75 mL), p-toluenesulfonyl chloride (2.66 g, 13.95 mmol) was added in 4 portions in ca. 10 minutes and the solution was stirred for 15 h at RT. The reaction mixture was poured into water and extracted twice with EtOAc. The organic layer was washed with 1 N HCl and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by flash column chromatography (heptane:EtOAc 100:0 to 40:60) yielding the title compound (4.0 g, 80%). MS (ES) C19H27NO8S requires: 429. found: 452.1 [M+Na]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:30][CH:29]=2)[C@H:10]([CH2:48]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[NH:62]1[CH:66]=[CH:65][N:64]=[CH:63]1.[H-].[Na+]>O1CCCC1.ClCCl.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH3:27])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[C@@H:11]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][CH2:37][O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[O:46][CH3:47])=[CH:32][CH:33]=2)[C@H:10]([CH2:48][N:62]2[CH:66]=[CH:65][N:64]=[CH:63]2)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2[C@H](CO)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2cc(OC)c3ccccc3c2)cc1
Agent: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccccc1COCCCOc1ccc([C@H]2[C@H](Cn3ccnc3)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2cc(OC)c3ccccc3c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
To a solution of 1.5 g (2.2 mmol) of (3S,4R,5R)-3-hydroxymethyl-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester [Example 13 (h)] in 40 ml of tetrahydrofurane were added 0.9 ml (6.7 mmol) of triethylamine and thereafter dropwise at 0° C. 512 mg (4.5 mmol) of methanesulphonyl chloride. The reaction solution was stirred at room temperature for 2 hours. For the working-up, the reaction solution was diluted with 50 ml of dichloromethane, extracted with 20 ml of saturated sodium hydrogencarbonate solution, dried over sodium sulfate and evaporated under reduced pressure. The solid crude mesylate was dissolved in 30 ml of N,N-dimethylformamide and thereafter added dropwise to a solution beforehand prepared of 456 mg (6.7 mmol) of imidazole and 322 mg (about 6.7 mmol) of sodium hydride dispersion in refined oil (55-65%) in 10 ml of N,N-dimethylformamide. The reaction mixture was stirred at 100° C. for 6 hours and thereafter evaporated under reduced pressure. The residue was taken up in 50 ml of dichloromethane and then extracted with 20 ml of saturated sodium hydrogencarbonate solution. The organic phase was separated and dried over sodium sulfate and subsequently evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 98:2 mixture of dichloromethane and methanol as the eluent. There were obtained 1.4 g of (3R,4R,5R)-3-imidazol-1-ylmethyl-4-{4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl}-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as a yellowish foam; MS: 722 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C:22]1[N:23]=[CH:24][S:25][CH:26]=1)[C@H:9]([C:17]([O:19]C)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([N:8]([CH2:21][C:22]1[N:23]=[CH:24][S:25][CH:26]=1)[C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccccc1)N(Cc1cscn1)C(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1cscn1)[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 83.1 %

Procedure:
Ester 34.8.D (2.75 g, 7.3 mmol) was dissolved in THF/H2O. LiOH hydrate (646 mg, 15.4 mmol) was added and the mixture was stirred at room temperature. The THF was removed on a rotavap and the resulting aqueous layer was acidified with 1.0 N HCl and then conc. HCl. A white sticky solid formed which was extracted with EtOAc. The organic layers were dried with sodium sulfate, filtered, and concentrated to yield 34.8.E as a sticky foam (2.20 g).
Reaction SMILES: [S:1]([CH:5]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7])([OH:4])(=[O:3])=[O:2].[Cl:16][CH:17](OC(Cl)Cl)Cl>S(=O)(=O)(O)O>[S:1]([CH:5]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:17][Cl:16])[CH:10]=1)[C:6]([OH:8])=[O:7])([OH:4])(=[O:3])=[O:2]
Reactant: O=C(O)C(c1ccc(O)cc1)S(=O)(=O)O
Reactant: ClC(Cl)OC(Cl)Cl
Agent: O=S(=O)(O)O
Product: O=C(O)C(c1ccc(O)c(CCl)c1)S(=O)(=O)O

Procedure:
α-Sulfo-4-hydroxybenzeneacetic acid, 0.3 mole, is dissolved in aqueous sulfuric acid (50%). One equivalent of dichloromethyl ether is added to the solution maintained at between 35° to 45° C. Hydrogen chloride is then bubbled through this reaction mixture for 3 hours. The desired compound is recovered by pouring the reaction mixture into water and extracting the title compound with ethyl acetate. The ethyl acetate is dried over magnesium sulfate. The magnesium sulfate is removed by filtration and evaporation of the ethyl acetate gives the desired compound.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2Cl)=[N:13][C:12]([Cl:17])=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(=O)C.C(O)(=O)C.[CH3:26][N:27]([CH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([NH2:36])[CH2:32][CH2:31]1)[CH3:28]>>[Cl:17][C:12]1[N:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])=[C:15]2[NH:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([CH2:29][N:27]([CH3:28])[CH3:26])[CH2:31][CH2:32]1
Reactant: CN(C)C[C@H]1CC[C@H](N)CC1
Reactant: O=C(c1cnc2ccc(Cl)nc2c1Cl)C1CC1
Solvent: CC(=O)O
Product: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Cl)nc23)CC1

Procedure:
Following general procedure I, cyclopropyl(4,6-dichloro-1,5-naphthyridin-3-yl)-methanone (267 mg, 1.0 mmol) was reacted with trans-4-[(dimethylamino)methyl]cyclohexanamine diacetic acid salt (270 mg, 1.0 mmol) to afford the desired product (150 mg, 39%) as an off-white solid: 1H NMR (500 MHz, CDCl3) δ 10.85 (br s, 1H), 9.19 (s, 1H), 8.08 (d, J=8.7 Hz, 1H), 7.51 (d, J=8.7 Hz, 1H), 4.97 (br s, 1H), 2.72-2.62 (m, 1H), 2.31-2.24 (m, 2H), 2.22 (s, 6H), 2.13 (d, J=7.2 Hz, 2H), 1.96-1.89 (m, 2H), 1.55-1.46 (m, 1 H), 1.36 (qd, J=12.4, 3.3 Hz, 2H), 1.28-1.22 (m, 2H), 1.21-1.09 (m, 2H), 1.08-1.02 (m, 2H); ESI MS m/z 387 [M+H].+
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]3[N:18]=[C:17]([NH2:19])[CH:16]=[CH:15][N:14]3[CH:20]=2)[CH:8]=[CH:9][CH:10]=1.[CH2:21]([O:23][C:24]([C:26]1[CH:27]=[N:28][N:29]([CH3:34])[C:30]=1[C:31](O)=[O:32])=[O:25])[CH3:22].CCN(C(C)C)C(C)C>CCOC(C)=O>[CH2:21]([O:23][C:24]([C:26]1[CH:27]=[N:28][N:29]([CH3:34])[C:30]=1[C:31](=[O:32])[NH:19][C:17]1[CH:16]=[CH:15][N:14]2[CH:20]=[C:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH2:3][CH2:2][F:1])[CH:6]=3)[N:12]=[C:13]2[N:18]=1)=[O:25])[CH3:22]
Reactant: Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccn2cc(-c3cccc(OCCF)c3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(3-(2-Fluoroethoxy)phenyl)imidazo[1,2-a]pyrimidin-7-amine (1 eq.) was combined with EtOAc (7.50 ml) to give a light yellow suspension. 4-(Ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (1 eq.) and DIPEA (6 eq.) were added. The reaction mixture was cooled down to 0° C. and n-propylphosphonic acid anhydride, cyclic trimer (1.17 g, 1.1 ml, 1.84 mmol, 2.50 eq.) was added dropwise. After stirring at 0° C. during 30 min, the reaction mixture was stirred and allowed to warm-up to RT overnight. The reaction mixture (yellow solution) was poured into 50 ml EtOAc and extracted with H2O (1×30 ml). The aqueous layer was back-extracted with DCM (3×20 ml). The organic layers were combined and washed with sat. NaCl-solution (1×30 ml), dried over MgSO4, filtrated and concentrated under vacuum to give a yellow solid (207 mg). The crude material was purified by flash chromatography (silica gel, 20 g, CH2Cl2 to 50% CH2Cl2/MeOH/NH3 aq. 140:10:1). Yellow solid (332 mg, 31%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acid tert-butyl ester {CAS-No. [335255-58-0]} (245 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an orange foam (304 mg, 74%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si](C)(C)O[Si](C)(C)C.[CH3:24][S:25][C:26]1[S:30][C:29]([C:31]([NH2:33])=O)=[CH:28][C:27]=1[C:34]1[S:35][CH:36]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:38]=1.[Na+].[Cl-]>ClC(Cl)C>[CH3:24][S:25][C:26]1[S:30][C:29]([C:31]#[N:33])=[CH:28][C:27]=1[C:34]1[S:35][CH:36]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:38]=1
Reactant: CSc1sc(C(N)=O)cc1-c1nc(-c2ccccc2)cs1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: C[Si](C)(C)O[Si](C)(C)C
Product: CSc1sc(C#N)cc1-c1nc(-c2ccccc2)cs1
Temperature: 40 °C
Yield: 58.9 %

Procedure:
A slurry of P2O5 (2.7 g, 19 mmol) and hexamethyldisiloxane (6.7 mL) in dichloroethane (13 mL) was heated to 90° C., while stirring under a N2 atmosphere. After stirring for 2 h, the resulting clear solution was allowed to cool to 40° C. 5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carboxamide (0.9 g, 2.7 mmol) as prepared in previous step was added to this solution and the mixture was heated at 75° C. for 5 h. This solution was cooled to room temperature and stirred with aqueous NaCl (6 M, 100 mL) for 10 min. As the aqueous solution is added a yellow solid precipitated. After 10 min this solid was separated by filtration, and dried under vacuum to give (0.5 g, 59%) of 5-methylthio-4-(4-phenyl(1,3-thiazol-2-yl))thiophene-2-carbonitrile as a yellow solid. 1H-NMR (DMSO-d6; 300 MHz) δ2.76 (s, 3H), 7.35-7.40 (m, 1H), 7.45-7.50 (m, 2H), 8.05-8.08 (m, 2H), 8.22 (s, 1H), 8.51 (s, 1H).
Reaction SMILES: I[C:2]1[C:3]([NH:17][CH3:18])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])=[N:6][CH:7]=1.[C:19]([C@@H:21]1[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28](=[O:40])[C@@H:29]([N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH3:30])[CH2:22]1)#[CH:20].CN(C)C=O.C(=O)([O-])O.[Na+]>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.[Cu]I.C(OCC)(=O)C.C(N(CC)CC)C>[C:12]([C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][CH3:18])[C:2]([C:20]#[C:19][C@@H:21]3[CH2:26][CH2:25][CH2:24][C@H:23]([NH:27][C:28](=[O:40])[C@@H:29]([N:31]([CH3:39])[C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])[CH3:30])[CH2:22]3)=[CH:7][N:6]=2)[CH:16]=[CH:15][CH:14]=1)#[N:13]
Reactant: CNc1nc(Nc2cccc(C#N)c2)ncc1I
Reactant: C#C[C@@H]1CCC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNc1nc(Nc2cccc(C#N)c2)ncc1C#C[C@@H]1CCC[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C1
Reaction time: 4 h

Procedure:
To 3-((5-iodo-4-(methylamino)pyrimidin-2-yl)amino)benzonitrile (F219, 30 mg), tert-butyl ((S)-1-(((1S,3R)-3-ethynylcyclohexyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (U2, 39.5 mg), bis(triphenylphosphine)palladium(II) dichloride (5.96 mg) and copper(I) iodide (3.24 mg), N,N-dimethylformamide (1 mL) and triethylamine (59 μL) were added at room temperature, and the mixture was stirred at the same temperature for 4 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with saturated aqueous ammonium chloride, water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 84 to 25% hexane in ethyl acetate) to obtain tert-butyl ((S)-1-(((1S,3R)-3-((2-((3-cyanophenyl)amino)-4-(methylamino)pyrimidin-5-yl)ethynyl)cyclohexyl)amino)-1-oxopropan-2-yl)(methyl)carbamate (U3, 27.4 mg) as pale yellow solid.