Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH3:25])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[F:26].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:27])=[O:2])=[C:5]([F:26])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH3:25])=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(-c2ncnc(C)c2C#Cc2ccc(N)nc2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncnc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 2.28 g (6.29 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-methyl-pyrimidin-4-yl]-2-fluoro benzoic acid methyl ester using 1.32 g (31.5 mmol.) LiOH in 5 mL water and 50 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5 is reached. The precipitated product is filtered off and taken up in water. After freeze drying 2.7 g of crude product is obtained which is used for the next step without further purification.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C1COCC1.[C:14](Cl)(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[C:14]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCCCCCCBr
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)OCCCCCCBr
Yield: 53 %

Procedure:
7 g of 6-bromohexanol was dissolved in a mixed solution of 5 ml of triethylamine as base and 50 ml of THF, and then, cinnamoyl chloride was added dropwise thereto at 0° C. The resultant was filtered to remove the solvent and the residue was purified with a SiO2 column chromatography (EA:n-Hexane=1:5) to obtain 8 g of 6-bromohexyl cinnamate (yield: 53%).
Reaction SMILES: [OH:1][CH:2]([CH2:21][OH:22])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[K+].C[O:26][C:27](=O)[CH:28]([OH:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[OH:1][CH:2]([CH2:21][OH:22])[CH2:3][N:4]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:27](=[O:26])[CH:28]([OH:35])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCC(O)C(=O)OC
Reactant: CCCCCCCCCCCCCCCCNCC(O)CO
Agent: [K+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCN(CC(O)CO)C(=O)C(O)CCCCCC

Procedure:
N-(2,3-dihydroxypropyl)-N-hexadecylamine (1.0 g, 0.0032 mole) and potassium hydroxide (0.01 g, 0.18 mmole) were heated to 85° C. under vacuum and methyl-2-hydroxyoctanoate (0.55 g, 0.0032 mole) was heated and added dropwise to the reaction. The reaction was heated under vacuum for 6 hours. A waxy off-white solid was obtained (crude yield=1.39 g). The waxy solid was recrystalized from hot hexane (yield=0.88 g).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.Cl.[CH3:28][NH:29][CH3:30]>>[CH:1]1([C:4]2[C:5]([O:21][CH2:22][C:23]([F:24])([F:25])[F:26])=[CH:6][C:7]([C:10]([NH:12][CH:13]([C:17]([CH3:19])([CH3:18])[CH3:20])[C:14]([N:29]([CH3:30])[CH3:28])=[O:16])=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(=O)O
Reactant: CNC
Agent: Cl
Product: CN(C)C(=O)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C(C)(C)C

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-3,3-dimethyl-butanoic acid (Example 194b) and dimethylamine hydrochloride as starting materials and isolated (24 mg, 46%); MS (ESI, m/z): 402.6 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[F:36][C:37]([F:41])([F:40])[CH2:38][NH2:39]>O1CCCC1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:39][CH2:38][C:37]([F:41])([F:40])[F:36])[N:3]=3)[N:25]=2)=[CH:30][CH:31]=1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Reactant: NCC(F)(F)F
Solvent: C1CCOC1
Product: N#Cc1c(NCC(F)(F)F)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
140 mg (0.260 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 52 mg (0.519 mmol) of 2,2,2-trifluoro-1-aminoethane were dissolved in 2 ml of tetrahydrofuran and stirred at room temperature overnight. A further 52 mg (0.519 mmol) of 2,2,2-trifluoro-1-aminoethane were added and stirring was continued for 6 hours, after which the reaction mixture was heated to 50° C. and stirred at this temperature overnight. A further 52 mg (0.519 mmol) of 2,2,2-trifluoro-1-aminoethane were added. The mixture was then stirred initially at 50° C. for 2 hours and then under reflux for four hours. Without further work-up, the reaction mixture was purified by preparative HPLC. 36 mg (yield: 23%) of the target compound were obtained.
Reaction SMILES: CC1N(C(OC2C(C)=CC(C3N=NN(C)N=3)=CC=2C)CC)N=CN=1.O(C(O[CH2:35][C:36]1[N:40]([CH2:41][CH2:42][CH2:43][O:44][C:45]2[C:50]([CH3:51])=[CH:49][C:48]([C:52]3[N:53]=[N:54][N:55]([CH3:57])[N:56]=3)=[CH:47][C:46]=2[CH3:58])[N:39]=[CH:38][N:37]=1)=S)C1C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C.C([SnH](CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:35][C:36]1[N:40]([CH2:41][CH2:42][CH2:43][O:44][C:45]2[C:46]([CH3:58])=[CH:47][C:48]([C:52]3[N:53]=[N:54][N:55]([CH3:57])[N:56]=3)=[CH:49][C:50]=2[CH3:51])[N:39]=[CH:38][N:37]=1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1ncnc1COC(=S)Oc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCC(Oc1c(C)cc(-c2nnn(C)n2)cc1C)n1ncnc1C
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCn1ncnc1C
Temperature: 75 °C
Reaction time: 6.5 h
Yield: 23.6 %

Procedure:
5-Methyl-1-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]3-propyl]-1,2,4-triazole (I, Azo=5-methyl-1,2,4-triazol-1-yl, Y=1,3-propylene, R1,R2 =3,5-dimethyl, R3 =2-methyl-tetrazol-5-yl) p To a solution of 5-phenoxythiocarbonyloxymethyl-1-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole (130 mg, 0.79 mmol) in 20 ml of toluene was added AIBN (130 mg, 0.79 mmol) and tributyltin hydride (3.2 g, 11 mmol) and the mixture was stirred at 75° C. for 6.5 h. The solvent was concentrated in vacuo and the residue was purified by silica column chromatography (13 cm column, ethyl acetate/hexane, 1/1-5/1; methylene chloride/acetone, 4/1-0/1) to afford 61 mg (19%) of 5-methyl-1-[3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-propyl]-1,2,4-triazole, m.p. 126°-128° C.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[N:42]1[CH:47]=[CH:46][CH:45]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:43]=1>O1CCCC1.O>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:48]([C:44]3[CH:43]=[N:42][CH:47]=[CH:46][CH:45]=3)(=[O:50])=[O:49])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (4 mL) were added dropwise a solution (2 mL) of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (330 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and pyridine-3-sulfonyl chloride (266 mg) under ice-cooling and the mixture was stirred for 1 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→3:2) to give the title compound as a pale-yellow oil (yield 421 mg, 89%).
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](O)(=[O:9])=[O:8])=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:18]>O>[C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7]([Cl:18])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=S(=O)(O)c1ccc(-c2ccccc2)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-Biphenyl sulfonic acid (2.4 g, 10 mmol) was heated to 100 C with phosphorus pentachloride (2.1 g, 10 mmol) overnight. The reaction was cooled to RT, diluted with water, filtered and washed with water. The solid was then triturated with EtOAc-ether and the beige solid was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:53])([F:52])[C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]([CH2:26][CH2:27][CH3:28])[CH2:23][CH2:24][CH3:25])[CH:19]=[CH:18][C:17]=2[NH:29][C:30]([C:32]2[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=2)[CH2:35][S:36][CH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40])=[O:31])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[CH2:26]([N:22]([CH2:23][CH2:24][CH3:25])[C:20]1[CH:19]=[CH:18][C:17]([NH:29][C:30]([C:32]2[CH:33]=[C:34]([CH:46]=[CH:47][CH:48]=2)[CH2:35][S:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:31])=[C:16]([C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:49]=[CH:50][CH:51]=[C:3]([C:2]([F:53])([F:1])[F:52])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)[CH:21]=1)[CH2:27][CH3:28]
Reactant: CCCN(CCC)c1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(CCC)c1ccc(NC(=O)c2cccc(CSCCC(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of tert-butyl 3-(3-((2-(4-((3-(trifluoromethyl)-benzyl)carbamoyl)pyridin-2-yl)-4-(dipropylamino)phenyl)carbamoyl)benzylthio)-propanoate (320 mg, 0.43 mmol, 1.00 equiv) in dichloromethane (10 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred overnight at 25° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 108 mg (30%) of a yellow solid. 1H-NMR (300 MHz, DMSO, ppm): δ 9.52 (t, J=6 Hz, 1H), 8.96 (d, J=5.1 Hz, 1H), 8.27 (s, 2H), 7.85 (s, 2H), 7.74 (m, 2H), 7.53 (m, 5H), 7.02 (s, 2H), 4.61 (d, J=5.7 Hz, 2H), 3.87 (s, 2H), 3.39 (s, 4H), 2.61 (m, 2H), 2.50 (m, 2H), 1.53 (t, J=9.3 Hz, 4H), 0.89 (t, J=7.2 Hz, 6H). MS (ES, m/z): 693 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:21])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([CH3:21])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:26]4[CH:27]=[CH:28][C:23]([NH2:22])=[N:24][CH:25]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(Cl)cc2)cc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-methyl-pyridine (example E.32) (0.15 g, 0.42 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.101 g, 0.46 mmol) according to the general procedure VI. Obtained as a white solid (0.045 g, 29%). MS (ISP) 372.1 [(M+H)+] and 374 [(M+2+H)+]; mp 76-95° C.
Reaction SMILES: [Mg].[CH2:2]([O:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[B:18](OC(C)C)([O:23]C(C)C)[O:19]C(C)C.Cl>O1CCCC1>[CH2:2]([O:10][C:11]1[CH:16]=[CH:15][C:14]([B:18]([OH:23])[OH:19])=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCOc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(B(O)O)cc1
Reaction time: 8 h
Yield: 94.9 %

Procedure:
2.40 g (99.0 mmol) of magnesium and 25.56 g (89.6 mmol) of 4-octyloxybromobenzene in 250 ml of tetrahydrofuran are used to prepare, at 60° C. for 3 hours, the solution of the Grignard compound, which is added dropwise to a solution, cooled to -70° C., of 18.62 g (99.00 mmol) of triisopropyl borate in 100 ml of tetrahydrofuran, and the mixture is stirred overnight. 130 ml of 10% strength hydrochloric acid are subsequently added dropwise, the mixture is stirred at room temperature for 1 hour and partitioned between sodium chloride solution and ether, and the organic phase is washed with sodium chloride solution, dried over sodium sulfate and evaporated, giving 21.26 g of 4-octyloxybenzeneboronic acid. ##STR14##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:20])[CH2:16][C:17](=O)[CH3:18])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)[O:26][CH2:27][C:28]([NH2:30])=O.C1(C)C=CC=CC=1.[NH4+].[Cl-]>C1(C)C(C)=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[C:15](=[O:20])[CH:16]=[C:17]([CH3:18])[N:30]=[C:28]2[CH2:27][O:26][C:25]2[CH:31]=[CH:32][CH:33]=[C:23]([O:22][CH3:21])[CH:24]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(F)c1
Reactant: COc1cccc(OCC(N)=O)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: Cc1ccccc1C
Product: COc1cccc(OCc2nc(C)cc(=O)n2-c2ccc(N3CCOCC3)c(F)c2)c1
Temperature: 165 °C
Reaction time: 24 h
Yield: 40.2 %

Procedure:
A mixture of N-(3-fluoro-4-morpholinophenyl)-3-oxobutanamide (1.0 g, 3.57 mmol), 2-(3-methoxyphenoxy)acetamide (1.29 g, 7.12 mmol) and titanium tetraisopropanolate (8.11 g, 28.5 mmol) in xylene (30 mL) was stirred at 165° C. for 24 h. The mixture was cooled to rt and 80 mL of toluene and 100 mL of saturated NH4Cl aqueous solution were added. The resulting mixture was stirred at rt overnight and filtered and the filtrate was extracted with DCM (150 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as a yellow solid (0.61 g, 40%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][C@H:23]2[C:32]3[C:27](=[C:28]([F:34])[CH:29]=[C:30]([F:33])[CH:31]=3)[O:26][CH2:25][CH2:24]2)[C:19]([N+:35]([O-])=O)=[CH:18][N:17]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].CO>C1COCC1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][C@H:23]2[C:32]3[C:27](=[C:28]([F:34])[CH:29]=[C:30]([F:33])[CH:31]=3)[O:26][CH2:25][CH2:24]2)[C:19]([NH2:35])=[CH:18][N:17]=1
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc([N+](=O)[O-])c(N[C@@H]3CCOc4c(F)cc(F)cc43)n2)c(OC)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc(N)c(N[C@@H]3CCOc4c(F)cc(F)cc43)n2)c(OC)c1
Reaction time: 0.25 h

Procedure:
A solution of (R)-4-(2,4-dimethoxybenzylamino)-3-(4-(6,8-difluorochroman-4-ylamino)-5-nitropyrimidin-2-ylamino)benzonitrile (358 mg) in THF (25 mL) was treated with a solution of sodium hydrosulfite (1.5 g) and sodium bicarbonate (1.5 g) in 20 mL of distilled water. Methanol (5 mL) was added to maintain a homogeneous solution. After 15 minutes, the mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous NaCl (2×100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo to provide the intermediate (R)-4-(2,4-dimethoxybenzylamino)-3-(5-amino-4-(6,8-difluorochroman-4-ylamino)pyrimidin-2-ylamino)benzonitrile. The intermediate was dissolved in THF (5 mL) and treated with carbonyldiimidazole (0.55 g) for 16 hours. The mixture was diluted with EtOAc (100 mL) and washed twice with saturated aqueous NaCl (2×100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated in vacuo. Column chromatography (2→3% MeOH/DCM) provided 230 mg of the title compound.
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15]([Sn:19]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:21][CH2:22][CH2:23][CH3:24])Cl)[CH2:16][CH2:17][CH3:18].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:25]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:21][CH2:22][CH2:23][CH3:24])[C:2]1[S:1][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1cnc2sccc2c1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc2cccnc2s1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a cold (−78° C.) solution of thieno[2,3-b]pyridine (2.000 g, 14.79 mmol) in anhydrous THF (50 mL) was added n-butyllithium (10.17 mL, 16.27 mmol) dropwise. The reaction mixture was stirred for 60 minutes at −78° C. A solution of tributylchlorostannane (4.79 mL, 17.75 mmol) in anhydrous THF (10 mL) was added and the reaction mixture was stirred for 30 minutes at −78° C. The solution was allowed to warm to room temperature over a period of 2 to 3 hours. Saturated aqueous sodium bicarbonate was added. The aqueous phase was extracted with ether (3×200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The crude product was purified by silica gel column chromatography, eluting with a gradient of 10-50% EtOAc and hexane over a period of 60 minutes. The desired fractions were collected and the solvent removed in vacuo to give the title compound (4.5 g, 72%) 1H NMR (500 MHz, DMSO-d6) δ ppm 0.87 (t, J=7.32 Hz, 9H), 1.13-1.20 (m, 6H), 1.32 (dq, J=14.64, 7.32 Hz, 6H), 1.52-1.64 (m, 6H), 7.34-7.42 (m, 1H), 7.51 (s, 1H), 8.25 (dd, J=7.81, 1.46 Hz, 1H), 8.50 (dd, J=4.39, 1.46 Hz, 1H).
Reaction SMILES: [C:1]([C@@:6]12[N:13]([CH3:14])[C@@H:10]([CH2:11][CH2:12]1)[C@H:9]([N:15]=[N+]=[N-])[CH2:8][CH2:7]2)([O:3][CH2:4][CH3:5])=[O:2].[H][H]>[Pd].C(O)C>[C:1]([C@@:6]12[N:13]([CH3:14])[C@@H:10]([CH2:11][CH2:12]1)[C@H:9]([NH2:15])[CH2:8][CH2:7]2)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)[C@]12CC[C@@H](N=[N+]=[N-])[C@H](CC1)N2C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@]12CC[C@@H](N)[C@H](CC1)N2C
Yield: 112.2 %

Procedure:
A mixture of 4.5 g of the 1-carbethoxy-4β-azidotropane, 300 mL of ethanol and 1 g of 10% palladium on carbon was shaken under 1 atm of hydrogen (balloon) for 18 h. The mixture was filtered and concentrated under reduced pressure. Drying under vacuum gave 4.5 g of 1-carbethoxy-4β-aminotropane as a gum: 1H NMR (400 MHz, CDCl3) 4.3 (br m, 2H), 4.18 (q, 2H), 3.15 (m, 1H), 1.95 (m, 2H), 1.82 (m, 2H), 1.7 (m, 2H), 1.4 (m, 2H), 1.30 (t, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=[C:4]([F:16])[C:3]=1[CH:17]([O:32][CH3:33])[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29]O)=[CH:24][CH:23]=1)=[O:19].[CH3:34][C:35]([OH:37])=[O:36]>[Pd]>[C:35]([OH:37])(=[O:36])[CH3:34].[C:28]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][NH:20][C:18](=[O:19])[CH:17]([C:3]2[C:4]([F:16])=[CH:5][CH:6]=[C:7]([C:8]([N:10]3[CH2:11][CH2:12][O:13][CH2:14][CH2:15]3)=[O:9])[C:2]=2[F:1])[O:32][CH3:33])=[CH:27][CH:26]=1)(=[NH:29])[NH2:31]
Reactant: COC(C(=O)NCc1ccc(C(=N)NO)cc1)c1c(F)ccc(C(=O)N2CCOCC2)c1F
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(C(=O)NCc1ccc(C(=N)N)cc1)c1c(F)ccc(C(=O)N2CCOCC2)c1F
Yield: 84 %

Procedure:
A solution of (RS)-2-[2,6-difluoro-3-(morpholine-4-carbonyl)-phenyl]-N-[4-(N-hydroxycarbamimidoyl)-benzyl]-2-methoxy-acetamide (125 mg) was hydrogenated 2 days at rt and 1 atm H2 in presence of 10% Pd/C (13 mg) and AcOH (143 mg). The catalyst was filtered away and the solvent was evaporated to obtain 115 mg of (RS)-N-(4-carbamimidoyl-benzyl)-2-[2,6-difluoro-3-(morpholine-4-carbonyl)-phenyl]-2-methoxy-acetamide acetate. Off-white solid, MS 447.1 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Cl[CH:12]([C:17]([CH3:19])=O)[C:13]([O:15][CH3:16])=[O:14]>C(O)C>[CH3:16][O:15][C:13]([C:12]1[O:7][C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[N:8][C:17]=1[CH3:19])=[O:14]
Reactant: NC(=O)c1ccc(F)cc1
Reactant: COC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: COC(=O)c1oc(-c2ccc(F)cc2)nc1C
Yield: 10.2 %

Procedure:
A solution of 4-fluorobenzamide (12 g, 86.3 mmol) and methyl 2-chloroacetoacetate (10.5 mL, 86.3 mmol) in ethanol (120 mL) was refluxed overnight. Subsequently the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic solution was washed with saturated sodium bicarbonate solution and brine, dried, and concentrated in vacuo. The residue was purified by flash chromatography eluting from silica gel with a gradient of 0-50% ethyl acetate in hexanes to give 2.08 g of the title compound as a white solid. MS: (+) m/z 236.2 (M+1).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:30][C:31](=[O:33])[CH3:32])[CH3:29])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1>C(#N)C>[CH:3]1([N:2]([CH3:1])[C:9]2[N:14]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([NH:30][C:31](=[O:33])[CH3:32])[CH3:29])=[CH:23][CH:22]=4)[CH2:19][CH2:20]3)[CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC(=O)NC(C)Cc1ccc(C2CCN(c3ccnc(Cl)n3)CC2)cc1
Reactant: CNC1CCCC1
Solvent: CC#N
Product: CC(=O)NC(C)Cc1ccc(C2CCN(c3ccnc(N(C)C4CCCC4)n3)CC2)cc1
Temperature: 150 °C

Procedure:
181 μL (1.61 mmol) N-Methyl-cyclopentylamine are added to 120 mg (0.32 mmol) N-(2-{4-[1-(2-chloro-pyrimidin-4-yl)-piperidin-4-yl]-phenyl}-1-methyl-ethyl)-acetamide (XIV.2) in 3 mL acetonitrile. The mixture is heated at 150° C. for 30 min under microwave irradiation. After that time, the solvent is evaporated and the residue is purified using reversed phase HPLC (eluent A: water+0.1% TFA, eluent B: acetonitrile+0.1% TFA) to yield the desired product.