Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][C@@H:11]1[CH3:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Cl)[N:20]=1>CS(C)=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][C@H:13]([O:16][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[N:20]=2)[CH2:12][C@@H:11]1[CH3:17])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: C[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@H]1C[C@@H](Oc2cccc(Cl)n2)CCN1C(=O)OC(C)(C)C
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Add sodium hydride (95%, 0.318 g) to a solution of 4-hydroxy-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 3, 2.465 g) in DMSO (100 mL) and heat in an oil bath at 65° C. After 30 min., add 2,6-dichloropyridine (1.864 g) and beat at 100° C. After 4 hr., partition between ethyl acetate-hexane (1:4) and saturated aqueous NaCl aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a 35 g silica gel column eluting with ethyl acetate-hexane (1:39) to give the title compound (3.26 g). 1H NMR (CDCl3): 7.50 (t, 1H), 6.87 (d, 1H), 6.61 (d, 1H), 5.38 (m, 1H), 4.35 (m, 1H), 3.89 (m, 1H), 3.22 (m, 1H), 1.93 (m, 3H), 1.75 (m, 1H), 1.46 (s, 9H), 1.26 (d, 3H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[C:12]([O:16][C:17](=[O:45])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2[C:39]3[C:38]4[CH:37]=[CH:36][C:35]([Br:40])=[CH:34][C:33]=4[N:32]=[CH:31][C:30]=3[N:29]=[C:28]2[CH2:41][O:42][CH2:43][CH3:44])=[CH:22][CH:21]=1)([CH3:15])([CH3:14])[CH3:13].[OH-].[NH4+:47].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[C:12]([O:16][C:17](=[O:45])[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][N:27]2[C:39]3[C:38]4[CH:37]=[CH:36][C:35]([Br:40])=[CH:34][C:33]=4[N:32]=[C:31]([NH2:47])[C:30]=3[N:29]=[C:28]2[CH2:41][O:42][CH2:43][CH3:44])=[CH:24][CH:25]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Reaction time: 1 h

Procedure:
3-Chloroperoxybenzoic acid (2.91 g, 9.3 mmol, 55% pure) was added to a solution of tert-butyl[4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-ylmethyl)benzyl]carbamate (3.2 g, 6.1 mmol) in chloroform (60 mL). The reaction was stirred for 1 hour and then cooled with an ice bath. Ammonium hydroxide (40 mL) was added and the reaction was stirred for 10 minutes. p-Toluenesulfonyl chloride (1.16 g, 6.1 mmol) was added in two portions. The cooling bath was removed and the mixture was stirred for an additional 16 hours. The layers were separated and the aqueous fraction was extracted with dichloromethane. The combined organic fractions were washed sequentially with water and saturated aqueous sodium chloride, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification of the residue by flash column chromatography (CMA/chloroform) and subsequent recrystallization from acetonitrile yielded 1.15 g of tert-butyl[4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo [4,5-c]quinolin-1-ylmethyl)benzyl]carbamate as a tan solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]4[CH2:53][CH2:52]4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH:54]=[O:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:56]=[O:57].[OH-].[Na+].[BH4-].[Na+]>O1CCOCC1.O>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]4[CH2:52][CH2:53]4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:56][OH:57])[CH2:54][OH:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)O[C@H](C=O)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 23.7 %

Procedure:
Crude (2S,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-6-methoxy-tetrahydropyran-2-carbaldehyde 1e (1.3 g, 1.7 mmol) was dissolved in 15 mL 1,4-dioxane, followed by addition of 37% formaldehyde solution (2.6 mL, 34 mmol) and a solution of sodium hydroxide (204 mg, 5.1 mmol) in 5.1 mL water into the reaction mixture. The reaction mixture was stirred for 4 hours at 70° C., then cooled to 50° C. and stirred for 16 hours. The reaction mixture was extracted with ethyl acetate (20 mL×3) after 20 mL saturated sodium chloride solution were added. The organic extract was washed with saturated sodium bicarbonate solution (20 mL), saturated sodium chloride solution (20 mL), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. Then 20 mL of mixed solution (THF and MeOH, v:v=1:1) were added into the residue, before sodium borohydride (130 mg, 3.4 mmol) was added. The reaction mixture was stirred for 30 minutes and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 mL) and partitioned. The organic extract was washed with saturated sodium chloride solution (10 mL×2), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, then the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 1f (320 mg, colorless oil), yield: 23.7%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)=[CH:11][C:10]([C:28]([F:31])([F:30])[F:29])=[N:9]1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34](B(O)O)[CH:33]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>CCOC(C)=O.O>[CH3:27][S:24]([C:20]1[CH:19]=[C:18]([C:15]2[S:14][C:13]([C:12]3[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[C:34]4[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=4)[N:9]=[C:10]([C:28]([F:31])([F:30])[F:29])[CH:11]=3)=[CH:17][CH:16]=2)[CH:23]=[CH:22][CH:21]=1)(=[O:26])=[O:25]
Reactant: OB(O)c1cccnc1
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3Br)s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3ccccc3-c3cccnc3)s2)c1
Temperature: 75 °C
Reaction time: 20 h
Yield: 41 %

Procedure:
To a 50 mL round bottom flask attached with condenser was added 1-(2-Bromo-phenyl)-5-[5-(3-methanesulfonyl-phenyl)-thiophen-2-yl]-3-trifluoromethyl-1H-pyrazole (prepared following the described in Example 1c) (110 mg, 210 μmol), 3-pyridylboronic acid (31 mg, 525 μmol), PdCl2dppf (25 mg, 10 mol %), K2CO3 (58 mg, 410 μmol), 1,4-dioxane (8 mL) and H2O (1.5 mL). The reaction solution was allowed to stir at 75° C. for 20 hrs. The reaction solution was diluted with EtOAc (150 mL) and transferred to a separator), funnel and washed with aq NH4Cl (100 mL) and aq NaCl (100 mL). The organic phase was dried over Na2SO4, filtered, concentrated on the Rotavapor and chromatographed through a 25 g SiO2 column using a mobile phase gradient of 100% Hx to 90% EtOAc to afford 45 mg (41% yield) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.41 (m, 1H), 7.99 (m, 2H), 7.51-7.90 (m, 8H), 7.24 (s, 1H), 7.17-7.23 (m, 2H), 6.87 (d, 1H), 3.28 (s, 3H); 19F NMR (400 MHz, DMSO-d6) δ −61.2 ppm. MS (ES) 526.5 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[NH:10][N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].Br[C:18]1[C:19]([CH:35]=[O:36])=[C:20]([N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]([C:33]#[N:34])=[CH:25]2)[CH:21]=[CH:22][CH:23]=1.C(=O)(O)[O-].[Na+]>CS(C)=O.O.ClCCl.[Cu](I)I>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:18]1[C:19]([CH:35]=[O:36])=[C:20]([N:24]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]([C:33]#[N:34])=[CH:25]3)[CH:21]=[CH:22][CH:23]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Reactant: N#Cc1cn(-c2cccc(Br)c2C=O)c2ccccc12
Agent: I[Cu]I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccccc54)c3C=O)ncc2c1
Temperature: 110 °C
Yield: 77 %

Procedure:
To a solution of 6-tert-butyl-8-fluorophthlazine-1(2H)-one (prepared according to US2010/0222325) 36 mg, 0.16 mmol) and 1-(3-bromo-2-formylphenyl)-1H-indole-3-carbonitrile (59 mg, 0.18 mmol) in dry dimethylsulfoxide (1.8 mL) was added sodium bicarbonate (31 mg, 0.36 mmol) under an argon atmosphere. Next copper iodide (35 mg, 0.18 mmol) was added and the mixture was heated to 110° C. for 2 hours. The reaction was cooled to ambient and taken up in water (40 ml) and dichloromethane (40 ml). The material was filtered through a plug of celite, rinsing well with dichloromethane. The filtrate was transferred to a reparatory funnel and the dichloromethane phase was collected. This was washed with a 50% solution of diluted brine (40 ml). The organic phase was collected and the aqueous phases back extracted with dichloromethane (2×35 ml). The dichloromethane phases were combined, dried (MgSO4), filtered and stripped. Then the identical reaction was repeated on a larger scale using 1-(3-bromo-2-formylphenyl)-1H-indole-3-carbonitrile (290 mg, 0.89 mmol) and similar scaled amounts of the reagents described above and under identical procedure and work up. The crude from the two reactions was combined and purified by HPLC (silica gel, eluting with 100% CH2Cl2 to 1% MeOH/CH2Cl2) to provide a semi-pure product. The material was further purified by preparative thin layer chromatography (3 plates, eluting with 0.5% MeOH/CH2Cl2 and then re-eluting with 0.75% and then 1% MeOH/CH2Cl2). The product band was collected to provide 1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-formylphenyl)-1H-indole-3 carbonitrile as a yellow foamy solid. (384 mg, 77% yield). LC/MS calcd for C28H21FN4O2 (m/e) 464.49, obsd 465.0 (M+H, ES+): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9H) 7.24-7.32 (m, 1H) 7.34-7.41 (m, 2H) 7.46-7.60 (m, 3H) 7.75 (d, J=7.55 Hz, 1H) 7.81 (s, 1H) 7.83-7.87 (m, 1H) 7.90 (t, J=7.96 Hz, 1H) 8.25 (d, J=2.64 Hz, 1H) 9.56 (s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1.O.ON1C2C=CC=CC=2N=N1.[CH3:28][NH:29][C:30]1[S:31][C:32]([S:36]([NH2:39])(=[O:38])=[O:37])=[C:33]([CH3:35])[N:34]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[NH2:39][S:36]([C:32]1[S:31][C:30]([N:29]([CH3:28])[C:14](=[O:16])[CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:12][CH:11]=2)=[N:34][C:33]=1[CH3:35])(=[O:37])=[O:38]
Reactant: CNc1nc(C)c(S(N)(=O)=O)s1
Reactant: O=C(O)Cc1ccc(-c2ccccn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(N(C)C(=O)Cc2ccc(-c3ccccn3)cc2)sc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
300 mg (1.41 mmol) of [4-(2-pyridyl)phenyl]acetic acid and 190 mg (1.41 mmol) of 1-hydroxy-1H-benzotriazole hydrate are introduced into 4 ml of dimethylformamide at room temperature. 307 mg (1.48 mmol) of 2-methylamino-4-methyl-1,3-thiazole-5-sulfonamide and 284 mg (1.48 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride are added, and the mixture is stirred at room temperature for 18 h. The solvent is then removed in vacuo, the residue is taken up in toluene, and the solvent is again removed in vacuo. The residue is stirred with 15 ml of water and 3 ml of methanol and then filtered off, and the filtrate is back-extracted with 20 ml of dichloromethane. Solid and dichloromethane phase are combined, and the solvent is removed in vacuo. The compound of Example 38 is obtained in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15].CCCCCC.C(OCC)(=O)C>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]([CH2:16][CH2:17][OH:18])[CH2:13][CH2:14][OH:15]
Reactant: OCCNCCO
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N(CCO)CCO)c(F)c1
Temperature: 140 °C
Yield: 90.4 %

Procedure:
In 4 ml of DMSO, 5.0 g (31.4 mmol) of 3,4-difluoronitrobenzene and 8.3 g (78.5 mmol) of diethanolamine were dissolved, followed by stirring under heat at 140° C. for one hour. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was dried and concentrated. To the reddish brown syrup so obtained, n-hexane/ethyl acetate was added for crystallization, whereby 6.93 g of the title compound were obtained as yellow powder (yield: 90%).
Reaction SMILES: [CH2:1]([C:4]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([O:41]C(C)(C)C)=[O:40])=[CH:29][CH:28]=2)[C:7]2[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:9]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[C:39]([OH:41])=[O:40])=[CH:29][CH:28]=2)[C:7]2[CH:8]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:9]([C:12](=[O:19])[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)OC(C)(C)C)cc1)C(C(=O)OCC)N(C(=O)CC(=O)OCC)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3C(=O)O)cc1)C(C(=O)OCC)N(C(=O)CC(=O)OCC)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
The mixture of ethyl 2-n-propyl-3-[2'-(t-butoxycarbonyl)biphenyl-4-yl]methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (657 mg), trifluoroacetic acid (3 ml) and methylene chloride (10 ml) is stirred overnight at room temperature. The reaction mixture is washed with a saturated sodium hydrogen carbonate solution and brine, dried, and evaporated. The crude product is purified by silica gel column chromatography (solvent; chloroform/methanol) to give ethyl 2-n-propyl-3-(2'-carboxybiphenyl-4-yl)methyl-5-ethoxycarbonylacetyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (516 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:3][CH:2]=1.[CH3:16][OH:17].[H][H]>[Pd].C(O)(=O)C>[CH:16]([NH:8][CH2:7][C:4]([C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:8][C:9]=2[CH:15]=1)([CH3:5])[CH3:3])=[O:17]
Reactant: CO
Reactant: c1ccc2[nH]c(-c3ccncc3)nc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(CNC=O)c1ccc2nc(C3CCNCC3)[nH]c2c1

Procedure:
3.0 g. of the 5-(2-formylaminomethyl)prop-2-yl)-2-(4-pyridinyl)-benzimidazole prepared in Example 2 are hydrogenated in 50 ml. methanol in the presence of 1 ml. glacial acetic acid and 1 g. 10% palladium on charcoal for 6 hours at 50° C. and 5 bar hydrogen pressure. The reaction mixture is filtered, the filtrate is evaporated in a vacuum, the residue is digested with ethyl acetate, filtered off with suction and the residue is dissolved in 40 ml. hot dimethylformamide and filtered. After cooling, the filtrate is mixed with the same amount of ethyl acetate. After crystallisation, the product is filtered off with suction and washed with ethyl acetate to give 1.8 g. (59% of theory) of the title compound as colourless crystals; m.p. 234°-237° C.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([OH:7])[CH2:3]1.[Br:8][C:9]1[C:10]([CH3:16])=[N:11][C:12](Cl)=[N:13][CH:14]=1.CCN(C(C)C)C(C)C>CCO>[Br:8][C:9]1[C:10]([CH3:16])=[N:11][C:12]([N:2]2[CH2:6][CH2:5][C@@H:4]([OH:7])[CH2:3]2)=[N:13][CH:14]=1
Reactant: Cc1nc(Cl)ncc1Br
Reactant: O[C@@H]1CCNC1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2CC[C@@H](O)C2)ncc1Br
Temperature: 70 °C
Yield: 89.5 %

Procedure:
In a 500 mL pear flask equipped with a magnetic stir bar were mixed (R)-pyrrolidin-3-ol hydrochloride (8.94 g, 72.3 mmol), 5-bromo-2-chloro-4-methylpyrimidine (15 g, 72.3 mmol), DIPEA (31.6 mL, 181 mmol), and EtOH (150 mL). The resulting yellow suspension was heated in a sand bath to 70° C. for 18 hours. At this time about half of the solvent was evaporated. Water (250 mL) was added to the flask while rapidly stirring the solution. An off-white precipitate formed and was filtered off, washed with water (100 mL) and dried to give the title compound (16.7 g, 89.5%).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:21]=[CH:22][C:14]1=2)[CH2:3][C:4]([O:6]C(C)(C)C)=[O:5].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(Cl)[Cl:47]>>[ClH:47].[ClH:47].[CH3:1][N:2]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][S:16][C:15]2[CH:19]=[C:20]([NH:23][C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[NH:25])[CH:21]=[CH:22][C:14]1=2)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: ClCCl
Reactant: CN(CCN1CCSc2cc(NC(=N)c3cccs3)ccc21)CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CN(CCN1CCSc2cc(NC(=N)c3cccs3)ccc21)CC(=O)O
Product: Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96 %

Procedure:
An oven dried round bottom flask, equipped with a magnetic stirbar under argon, was charged with tert-butyl 2-(methyl(2-(7-(thiophene-2-carboximidamido)-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethyl)amino)acetate (200 mg, 0.448 mmol) in CH2Cl2 (3 mL), and the solution was cooled to 0° C. (ice/water bath). To this solution was added anisole (0.098 mL, 0.896 mmol) followed by the dropwise addition of trifluoroacetic acid (2.92 mL, 26.9 mmol). The reaction was stirred at 0° C. for 20 minutes. The ice bath was then removed, and the mixture was stirred for 3 additional hours. At this time, the mixture was concentrated and treated with 4.0 M HCl in 1,4-dioxane (4 mL). The resulting suspension was diluted with Et2O (20 mL) and then stirred for 20 minutes. The mixture was filtered, and the solid was washed with Et2O (20 mL). The solid was dried under reduced pressure to give compound 17 as light yellow powder (200 mg, 96%). An HPLC analysis indicated that the sample contained ˜3.4% of the starting material. 1H-NMR (CD3OD) δ 7.99 (d, J=5.1 Hz, 1H), 7.97 (d, J=3.6 Hz, 1H), 7.31 (pseudo t, J=4.5 Hz, 1H), 7.11-6.99 (m, 2H), 6.95 (d, J=8.7 Hz, 1H), 4.16 (s, 2H), 3.81 (brt, J=6.9 Hz, 2H), 3.68 (brt, J=4.8 Hz, 2H), 3.52-3.39 (m, 2H), 3.10 (brt, J=4.8 Hz, 2H), 3.03 (s, 3H); ESI-MS (positive ion mode): 391 (MH+, free base, 100); ESI-MS (negative ion mode): 389 (M-1, free base, 100); ESI-HRMS calculated for C18H23N4O2S2 (MH+, free base): 391.1256, Observed: 391.1255; HPLC purity: 96.64% a/a.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=C1.S(Cl)(Cl)=O.[CH3:10][C:11]1[S:12][C:13]([C:19]([OH:21])=O)=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1.[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1NCC#N>O1CCCC1>[CH3:10][C:11]1[S:12][C:13]([C:19]([NH:3][CH:4]([C:23]2[S:22][CH:26]=[CH:25][CH:24]=2)[C:5]#[N:1])=[O:21])=[C:14]([CH:16]([CH3:17])[CH3:18])[N:15]=1
Reactant: Cc1nc(C(C)C)c(C(=O)O)s1
Reactant: c1c[nH]cn1
Reactant: N#CCNc1cccs1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc(C(C)C)c(C(=O)NC(C#N)c2cccs2)s1
Reaction time: 1 h
Yield: 48.8 %

Procedure:
To a solution of imidazole (2.72 g; 40 mmol) in dry tetrahydrofuran (60 ml) was added dropwise thionyl chloride (1.20 g; 10 mmol) under ice-cooling while stirring. After the resultant mixture was turned to room temperature, 2-methyl-4-isopropyl-5-thiazolecarboxylic acid (1.85 g; 10 mmol) was added thereto at once, and stirring was continued for 1 hour. To the mixture was added dropwise a solution of 2-(2-thienyl)aminoacetonitrile (1.65 g; 12 mmol) in dry tetrahydrofuran under ice-cooling, and the resultant mixture was stirred at room temperature for 3 hours. After completion of the reaction, tetrahydrofuran was removed under reduced pressure to separate the residue. Water was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude oil. The oil was purified by silica-gel column chromatography (eluent:n-hexane:ethyl acetate=2:1 volume) to give 1.49 g of 2-(2-methyl-4-isopropylthiazole-5-carboxamido)-2-(2-thienyl)acetonitrile as a viscous oil. 1H-NMR δ (CDCl3): 1.26 (6H, d, J=6 Hz), 2.62 (3H, s), 3.70 (1H, sep, J=6 Hz), 6.35 (1H, d, J=8 Hz), 6.8-7.1 (4H, m). Yield, 49%.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[C:11]1([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[O:2]1[C:10]2[CH2:9][CH2:8][N:7]([C:20](=[O:21])[CH2:19][CH2:18][CH2:17][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:6][C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(O)CCCc1ccccc1
Reactant: c1cc2c(o1)CCNC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CCCc1ccccc1)N1CCc2occc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.18 g (1.1 mmol) of 4-phenylbutyric acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate=3/1) to yield the desired product.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@@H:8]1[CH2:19][OH:20])([CH3:4])[CH3:3].[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C.O>C(OCC)(=O)C>[CH3:4][C:2]([Si:5]([CH3:22])([CH3:21])[O:6][C@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[C@@H:8]1[CH2:19][O:20][S:24]([CH3:23])(=[O:26])=[O:25])([CH3:1])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1CO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 1,1-dimethylethyl (2R,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-(hydroxymethyl)-1-pyrrolidinecarboxylate (Registry No. 156129-73-6, 4.0 g) in ethyl acetate (100 mL), methanesulfonyl chloride (1.12 mL) and triethylamine (2.19 mL) was added at 0° C. The reaction mixture was stirred at 0° C. for 15 minutes. The reaction mixture was added by water and then extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated, obtained the title compound (4.87 g) having the following physical properties.