Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:40])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH2:21]Br)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[NH:41]1[CH:45]=[CH:44][N:43]=[CH:42]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[OH:1][CH:2]([CH3:40])[CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:23]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=3)[O:24]2)[CH:10]=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][N:41]2[CH:45]=[CH:44][N:43]=[CH:42]2)[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5]
Reactant: c1c[nH]cn1
Reactant: CCCOc1c(OCCCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCOc1c(OCCCCn2ccnc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of trans-2-[-3-(2-hydroxy-n-propylsulfonyl)-4-n-propoxy-5-(4-bromobutoxy)phenyl]-5-(3,4,5-trimethoxyphenyl) tetrahydrofuran (64 mg, 0.10 mmol)(Example 19C), imidazole (27 mg, 0.40 mmol) and potassium carbonate (55 mg, 0.40 mmol) in acetone (3 mL) was heated with stirring at 60° C. under nitrogen for 24 h. The reaction mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water and brine, dried, and evaporated to a residue. Purification by preparative TLC (CH2Cl2 -MeOH; 92.8, v/v) gave the title compound: Rf 0.5; MS, m/z 632 M+. ; NMR (CDCl3) δ 1.28 (bd, CH2CHOHCH3), 6.94 & 7.08 (bs, NCH=CHN).
Reaction SMILES: [F-:1].[K+].O[CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:7]=2[NH:6][C:5]1=[O:22].N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[F:1][CH:4]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:7]=2[NH:6][C:5]1=[O:22]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1O
Reactant: [F-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1F

Procedure:
First, 1.2 of KF and then 2.9 g. of 3-hydroxy-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one are added to a mixture of 35 g. of HF and 15 ml. of pyridine and the mixture is stirred for 1 hour more. Working up in the customary manner using sodium carbonate solution/ethyl acetate gives 3-fluoro-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepin-2-one, m.p. 235° (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2].[CH3:54][N:55](C)C=O.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([C:54]#[N:55])=[CH:13][CH:14]=2)[C@@H:9]([NH:24][C:25]2[N:30]=[C:29]([CH2:31][C:32]3[CH:33]=[C:34]([C:42]([F:45])([F:43])[F:44])[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=3)[C:28]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)=[CH:27][N:26]=2)[CH2:8][C@H:7]1[CH2:52][CH3:53])=[O:5])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCOC(=O)N1c2ccc(OS(=O)(=O)C(F)(F)F)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1c2ccc(C#N)nc2[C@@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 95 °C
Reaction time: 8 h

Procedure:
A mixture of (2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (732 mg), tetrakis(triphenylphosphine)palladium (catalytic amount), zinc cyanide (142 mg) and N,N-dimethylformamide (10 ml) is stirred at 95° C. under nitrogen flow for 8 hours. After cooling to room temperature, water and ethyl acetate are added to the reaction solution. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane: ethyl acetate=4:1→2:1) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-6-cyano-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (572 mg). MS (m/z): 664 [M+H]+
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.[C:12]1([C:18]2([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[S:21](=[O:27])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:34][N:35]([CH3:50])[CH2:36][CH:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47](O)=[O:48])[CH3:38].CN(C)CCCN=C=NCC>ClCCl>[CH3:50][N:35]([CH3:34])[CH2:36][CH:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:46][C:47]([N:24]1[CH2:25][C@H:26]2[C:18]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:19][CH2:20][S@@:21](=[O:27])[C@H:22]2[CH2:23]1)=[O:48])[CH3:38]
Reactant: CC(CN(C)C)Oc1ccccc1CC(=O)O
Reactant: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: ClCCl
Product: CC(CN(C)C)Oc1ccccc1CC(=O)N1C[C@@H]2[C@H](C1)[S@](=O)CCC2(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
0.03 g of hydroxybenzotriazole hydrate is added to a solution, cooled to 0° C., of 1.06 g of (1R*, 4aR*, 7aR*) -(-) -4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide and 0.81 g of 2-[(3-dimethylamino-2-propoxy)phenyl]acetic acid in 60 cm3 of dry dichloromethane, followed by 0.77 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. After stirring for 2 hours at 0° C. and 20 hours at 20° C., the reaction mixture is washed with 20 cm3 of water and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (particle size 0.04-0.06 mm, diameter 2.4 cm, height 35 cm), eluting under a nitrogen pressure of 0.6 bar with an ethyl acetate, acetic acid and water mixture (60/10/10 by volume) and collecting fractions of 50 cm3. Fractions 8 to 19 are pooled and concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in 60 cm3 of dichloromethane, the solution is washed with 20 cm3 of a 1N aqueous solution of sodium hydroxide, dried over magnesium sulphate and then concentrated to dryness. The solid obtained is recrystallized from an ethyl acetate and ethyl ether mixture, the crystals are washed with diisopropyl oxide, drained and dried. 0.99 g of (1R*,4aR*,7aR*)-(-)-6-{2-[(3-dimethylamino2-propoxy)phenyl]acetyl}-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole 1-oxide is obtained in the form of a white solid; melting point 120° C. [α]D20 =-323° ; (c=0.5; acetic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[N:7]=[C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=3)[S:9][C:5]=2[C:4]=1[N+:22]([O-])=O.[H][H]>CO.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[N:7]=[C:8]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:11]=3)[S:9][C:5]=2[C:4]=1[NH2:22]
Reactant: COc1ccc2nc(-c3ccc4ccccc4c3)sc2c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2nc(-c3ccc4ccccc4c3)sc2c1N
Yield: 52.8 %

Procedure:
1.06 g (3.15 mmol) of 6-methoxy-2-(2-naphthyl)-7-nitro-1,3-benzothiazole are put into suspension in 50 ml of methanol and 5 ml of acetic acid. 105 mg (10%) of palladium on carbon is added to the reaction mixture which is maintained under stirring under 2.5 bars of hydrogen for 24 hours. The catalyst is filtered, then the solvents are evaporated under reduced pressure. 0.51 g (yield=53%) of 6-methoxy-2-(2-naphthyl)-1,3-benzothiazol-7-amine is obtained and used in the following stage without other purification.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([N:15]2[C@H:19]([C:20]([O:22]C)=[O:21])[CH2:18][S:17][CH:16]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[Li+].[OH-]>O1CCOCC1>[C:1]1([O:11][CH2:12][C:13]([N:15]2[C@H:19]([C:20]([OH:22])=[O:21])[CH2:18][S:17][CH:16]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1CSC(c2ccccc2)N1C(=O)COc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CSC(c2ccccc2)N1C(=O)COc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a solution of (2RS,4R)-3-((1-naphthyloxy)acetyl)-2-phenylthiazolidine-4-carboxylic acid, methyl ester (2.50 g, 6.14 mmol) in dioxane(15 mL)-water(5.0 mL) at room temperature was added 1.0 N LiOH solution (6.75 mL, 6.75 mmol). After stirring at room temperature for 16 hrs, The mixture was partitioned between EtOAc-5% KHSO4. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated to give the title compound (2.42 g, 100%) as a viscous oil. TLC(MeOH—CH2Cl2; 1:9) Rf=0.38.
Reaction SMILES: C(N1CCN(C(C2C=C3C(=CC=2)NC(C(O)=O)=C3)=O)CC1)(C)C.[CH:24]1([N:29]2[CH2:34][CH2:33][N:32]([C:35]([C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[NH:42][C:41]([C:46]([N:48]3[CH2:53]CS(=O)(=O)CC3)=[O:47])=[CH:40]4)=[O:36])[CH2:31][CH2:30]2)[CH2:28]CC[CH2:25]1.[F:56][C:57]1(NC)[CH2:60][O:59][CH2:58]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:56][C:57]1([CH2:53][NH:48][C:46]([C:41]2[NH:42][C:43]3[C:39]([CH:40]=2)=[CH:38][C:37]([C:35]([N:32]2[CH2:33][CH2:34][N:29]([CH:24]([CH3:25])[CH3:28])[CH2:30][CH2:31]2)=[O:36])=[CH:45][CH:44]=3)=[O:47])[CH2:60][O:59][CH2:58]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: CNC1(F)COC1
Agent: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)NCC4(F)COC4)cc3c2)CC1
Yield: 42 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride (example 1, intermediate b), (3-fluoro-oxetan-3-yl)-methylamine (commercially available), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a colorless solid (42%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:17]([O:19][CH3:20])=[O:18])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.[N:22]1([CH2:28][C:29]2[S:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH3:20][O:19][C:17](=[O:18])[C:12]1[C:11]([NH:10][C:8]([C:7]2[C:2]([NH2:1])=[N:3][CH:4]=[C:5]([C:32]3[S:33][C:29]([CH2:28][N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:30][CH:31]=3)[CH:6]=2)=[O:9])=[CH:16][CH:15]=[N:14][CH:13]=1
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Reactant: COC(=O)c1cnccc1NC(=O)c1cc(Br)cnc1N
Product: COC(=O)c1cnccc1NC(=O)c1cc(-c2ccc(CN3CCOCC3)s2)cnc1N

Procedure:
Reaction of methyl 4-[(2-amino-5-bromo-pyridine-3-carbonyl)amino]pyridine-3-carboxylate with 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives compound “A35”; HPLC/MS: 1.36 min, [M+H]=454;
Reaction SMILES: [CH3:1][C:2]([CH3:5])([O-:4])[CH3:3].[K+].Br[CH2:8][C:9]([OH:11])=[O:10].O>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:5])([O:4][CH2:8][C:9]([OH:11])=[O:10])[CH3:3]
Reactant: O=C(O)CBr
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OCC(=O)O
Temperature: 25 °C
Yield: 46.3 %

Procedure:
To a 3-neck 2-liter round-bottom flask equipped with a mechanical stirrer, reflux condenser and addition funnel was added potassium tert-butoxide (100.00 g, 0.891 moles) and 1500 ml of toluene under nitrogen. A solution of bromoacetic acid (61.90 g, 0.446 moles) in 100 ml of toluene was then added dropwise and the mixture then heated at reflux for 24 hours. After cooling the mixture to room temperature, water (100 ml) was added and the layers separated. The aqueous layer was washed with ether (2×50 ml) and then acidified to pH 1 with concentrated hydrochloric acid. The resulting mixture was extracted with ether (3×100 ml) and the combined extracts washed with saturated sodium chloride solution (1×75 ml), dried over magnesium sulfate and concentrated in vacuo to give 27.3 g of the product as a yellow oil.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:17])([F:16])[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:3][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[C:6]([F:17])([F:16])[F:5]
Reactant: Oc1ccccc1C(O)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Oc1ccccc1C(Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thionyl chloride (2.28 ml) was added to a solution of 2-(2,2,2-trifluoro-1-hydroxyethyl)phenol (3.0 g) and pyridine (1.23 ml) in toluene (50 ml). The reaction was stirred at room temperature for 1 hr, after which time the toluene was removed in vacuuo and the residue partitioned between ethyl acetate (100 ml) and 1 n HCl (100 ml). The organics were separated and dried over magnesium sulfate, filtered and solvent removed in vacuuo to afford the title compound as a clear oil (3.0 g). 1H NMR (CDCl3): δ 5.93 (m, 1H), 6.90 (d, J=4.52 Hz, 1H), 7.10 (m, 1H), 7.35 (m, 1H), 7.69 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH:10]=[CH2:11])[NH2:6].B.[OH-:15].[Na+].OO>O1CCCC1>[OH:15][CH2:11][CH2:10][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:2]([F:12])([F:13])[F:1]
Reactant: C=Cc1ccc(N)cc1C(F)(F)F
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ccc(CCO)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
3-Trifluoromethyl-4-vinylaniline (2.47 g, 13.2 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and borane.dimethyl sulfide complex (2.75 mL, 30.0 mmol) was dropwise added thereto under argon atmosphere. The mixture was stirred at room temperature for 4 hours, and then a sodium hydroxide aqueous solution (1 N, 5 mL) and a 30% hydrogen peroxide aqueous solution (3 mL) were added thereto. The resulting mixture was stirred at 0° C. for 1 hour. The reaction solution was concentrated, and the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and concentrated under reduced pressure. The resulting product was purified by silica-gel column chromatography (n-hexane:ethyl acetate=2:1) to give 4-(2-hydroxyethyl)-3-(trifluoromethyl)aniline (1.3 g, 48%) as a light-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][CH:10]=[O:11])=[CH:4][N:3]=1.[BH4-].[Na+]>CO.C1COCC1>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]=[CH:9][CH2:10][OH:11])=[CH:6][N:7]=1
Reactant: Cc1ncc(C=CC=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ncc(C=CCO)cn1
Reaction time: 0.08 h

Procedure:
To a suspension of 2-2 (0.5 g, 3.7 mmol) in MeOH (5 mL) and THF (15 mL) at −78° C. was added sodium borohydride (0.042 g, 1.11 mmol) in one portion. After 5 minutes, the cooling bath was removed, and the mixture allowed to warm and stir for 10 minutes. Concentrated HCl (0.3 mL) was added dropwise, and the volume of the mixture reduced to 2 mL by evaporation. Following the addition of sat. NaHCO3 (10 mL), the mixture was extracted with chloroform, the organics dried over MgSO4, and the solvents evaporated to give alcohol 2-3 as a white solid.
Reaction SMILES: [C:1]([C:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:29])=[C:13]([NH:15][C:16]2[NH:17][C:18]3[CH:24]=[C:23]([C:25](O)=[O:26])[C:22]([Cl:28])=[CH:21][C:19]=3[N:20]=2)[CH:14]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[F:30][C:31]([F:35])([F:34])[CH2:32][NH2:33].CCCP(O)(O)=O>CC#N>[C:1]([C:5]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:29])=[C:13]([NH:15][C:16]2[NH:17][C:18]3[CH:24]=[C:23]([C:25]([NH:33][CH2:32][C:31]([F:35])([F:34])[F:30])=[O:26])[C:22]([Cl:28])=[CH:21][C:19]=3[N:20]=2)[CH:14]=1)=[O:6])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(C(=O)O)cc3[nH]2)c1
Reactant: NCC(F)(F)F
Agent: CCCP(=O)(O)O
Solvent: CC#N
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(Cl)c(C(=O)NCC(F)(F)F)cc3[nH]2)c1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of 2-[5-(tert.butylcarbonylaminomethyl)-2-chlorophenylamino]-6-chloro-benzimidazole-5-carboxylic acid (0.15 g, 0.345 mmol), 2,2,2-Trifluoroethylamine (2×0.027 ml, 0.345 mmol), 1-propylphosphonic-acid cyclic anhydride (PPA, 0.244 ml, 50% in EtOAc), 0.12 ml TEA and 10 ml MeCN was stirred for 48 h at 60° C. an concentrated. The residue was purified by chromatography to give the title compound. Yield 17 mg (10%) m/z: 516 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[N:19]=[C:18]([NH:20][CH3:21])[N:17]=[C:16]([N:22]2[C@H:27]([CH3:28])[CH2:26][O:25][C@H:24]([CH2:29][OH:30])[CH2:23]2)[CH:15]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:8][S:9]([O:30][CH2:29][C@H:24]1[O:25][CH2:26][C@@H:27]([CH3:28])[N:22]([C:16]2[CH:15]=[C:14]([Cl:13])[N:19]=[C:18]([NH:20][CH3:21])[N:17]=2)[CH2:23]1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)Cl
Reactant: CNc1nc(Cl)cc(N2C[C@@H](CO)OC[C@H]2C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNc1nc(Cl)cc(N2C[C@@H](COS(C)(=O)=O)OC[C@H]2C)n1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 96.2 %

Procedure:
Triethylamine (1.95 mL, 14.07 mmol) and methanesulfonyl chloride (0.52 mL, 6.67 mmol) were added dropwise to a solution of {(2S,5R)-4-[6-chloro-2-(methylamino)-4-pyrimidinyl]-5-methyl-2-morpholinyl}methanol (1.52 g, 5.57 mmol) in CH2Cl2 (50 mL) at 0° C., and the mixture was stirred at 0° C. under nitrogen for 45 minutes. It was then poured into saturated aqueous NaHCO3 (100 mL) and extracted with CH2Cl2 (3×100 mL). The extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (1.88 g) as a foam that was crushed into an off-white solid. LC-MS (ES) m/z=351, 353 [M+H]+.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:36]=[CH:37][CH:38]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:20]=[N:21][C:22]([NH:25][S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])=[CH:23][CH:24]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].C(N(C(C)C)C(C)C)C.I[CH2:49][C:50]([NH2:52])=[O:51]>CN(C)C=O>[NH2:52][C:50](=[O:51])[CH2:49][N:21]1[C:22](=[N:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:27])=[O:28])[CH:23]=[CH:24][C:19]([O:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:36]=[CH:37][CH:38]=[C:6]([C:3]4([C:1]#[N:2])[CH2:5][CH2:4]4)[CH:7]=3)[CH:17]=[CH:16][CH:15]=2)=[CH:20]1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)cn2)cc1
Reactant: NC(=O)CI
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(Oc3cccc(NC(=O)c4cccc(C5(C#N)CC5)c4)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.1 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)-N-{3-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}benzamide (2.5 g, 4.77 mmol) in N,N-dimethylformamide (15 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.90 mL, 5.01 mmol), and the mixture was stirred at room temperature for 15 min. 2-Iodoacetamide (927 mg, 5.01 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 48 hr. The reaction mixture was concentrated under reduced pressure, water (150 mL) was added to the residue, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with saturated brine (150 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (2.14 g, 77%) as a pale-yellow solid.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([F:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(#N)C>[F:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: C1COCCN1
Solvent: CC#N
Product: CS(=O)(=O)c1cc(F)c2c(c1)O[C@@H](CN1CCOCC1)CO2
Temperature: 120 °C

Procedure:
A mixture of [(2R)-5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.39 g, 0.95 mmol), morpholine (0.3 ml, 3.4 mmol) and ACN (3 ml) was heated under microwave radiation at 120° C. for 70 min. Purification on SCX-3 column (TEA/MeOH) and by flash column chromatography and (isooctane/EtOAc/MeOH). Yield: 0.17 g. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 251° C. MS m/z (rel. intensity, 70 eV) 331 (M+, 1), 207 (2), 101 (6), 100 (bp), 69 (2), 56 (5).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7].[CH:8]#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].O1CCCC1.C(NC(C)C)(C)C>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:8]([C:2]1[S:3][CH:4]=[CH:5][C:6]=1[Br:7])#[C:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: C#CCCCCC
Reactant: Brc1ccsc1Br
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCC#Cc1sccc1Br
Temperature: 70 °C
Yield: 99.4 %

Procedure:
2 ml (18.0 mmol) of 2,3-dibromothiophene, commercially available from Aldrich under the Product No. D4,390-5, and 3.5 ml (27.0 mmol) of 1-heptyne, commercially available from Aldrich under the Product No. 24,4414, were mixed with a solvent of tetrahydrofuran/diisopropylamine (1:1), and 0.23 g (0.36 mmol) of palladium dichlorodiphosphine, 70 mg (0.36 mmol) of copper iodide and 0.1 g (0.36 mmol) of triphenylphosphine were sequentially added thereto. The reaction solution was heated at 70° C. for 8 hours, and washed with an aqueous solution of ammonium chloride. The resulting organic layer was dried over magnesium sulfate, dried under reduced pressure, and purified using silica gel column chromatography, thus obtaining 4.6 g of 2-heptynyl 3-bromothiophene. The compound thus obtained was added with 3.3 ml (23.2 mmol) of trimethylsilylacetylene, commercially available from Aldrich under the Product No. 21,817-0, and then subjected to the above synthesis process, to prepare 2.7 g (9.84 mmol) of 2-heptynyl-3-trimethylsilylethynylthiophene, which was then mixed with 12.8 ml (12.8 mmol) of lithium diisopropylamide (1 M) at about −78° C. The reaction mixture was stirred at the same temperature for 30 minutes, then combined with 2.4 ml (11.8 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-oxaborolane, commercially available from Aldrich under the Product No. 41,714-9, and allowed to react in a bath while the temperature was increased to room temperature. The resultant reaction solution was poured into an aqueous solution of 1 N HCl, treated with chloroform to obtain an organic layer, which was then dried over magnesium sulfate 1 N HCl, treated with chloroform to obtain an organic layer, which was then dried over magnesium sulfate and distilled under reduced pressure, thus obtaining 4.1 g of a compound a in an oil phase. Analysis of the compound 1a produced the following NMR data: 1H NMR (300 MHz, CDCl3), δ(ppm) 0.24 (s, 9), 0.92 (t, 3H, J=7.2 Hz), 1.24-1.64 (m, 18), 2.49 (t, 2H, J=7.0 Hz), 7.47 (s, 1H).