Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=S)([O-:3])=[O:2].[N:13]#[C:14][NH2:15].[Na].C(N(C(C)C)CC)(C)C.[NH2:26][CH:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:28].Cl.CN(C)CCCN=C=NCC>O1CCOCC1.CN(C)C=O>[C:14]([N:15]=[C:11]([NH:26][CH:27]([CH3:28])[C:29]([CH3:32])([CH3:31])[CH3:30])[NH:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])#[N:13]
Reactant: O=[N+]([O-])c1ccccc1N=C=S
Reactant: CC(N)C(C)(C)C
Reactant: N#CN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(NC(=NC#N)Nc1ccccc1[N+](=O)[O-])C(C)(C)C
Temperature: 85 °C
Reaction time: 1 h
Yield: 57.1 %

Procedure:
A mixture of 2-nitrophenyl isothiocyanate (6.00 g, 33 mmol) and monosodium cyanamide (1.92 g, 30 mmol) in dioxane (15 ml) was heated at 85° C. (oil bath) overnight under argon. The reaction was then diluted with dimethylformamide (15 ml). Diisopropylethylamine (2.76 ml, 33 mmol) and 2-amino-3,3-dimethyl butane (2.36 ml, 33 mmol) were added, and the resulting mixture was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.68 g, 44 mmol). After stirring for 1 hour, the reaction was partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase was washed with water (four times) and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated. The crude product was flash chromatographed (4% EtOAc/CH2Cl2) over Merck silica (650 g). The fractions containing the desired product were combined and evaporated to give the title compound as a yellow oil (4.96 g) which was crystallized to give free-flowing yellow crystals (2.31 g), m.p. 116°-118° C. TLC (40% Acetone/Hexane) single spot, Rf =0.33. TLC (10% EtOAc/CH2Cl2) single spot, Rf =0.49.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:18]2[C:19]([O:24]C)=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br.C([O-])(O)=O.[Na+]>CC(O)=O>[C:1]([C:5]1[CH:6]=[C:7]([C:18]2[C:19](=[O:24])[NH:20][CH:21]=[CH:22][CH:23]=2)[CH:8]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ncccc1-c1cc(Oc2ccccc2)cc(C(C)(C)C)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(Oc2ccccc2)cc(-c2ccc[nH]c2=O)c1
Temperature: 25 °C

Procedure:
step 2—A solution of 124 (52 mg, 0.157 mmol), 48% HBr (50 □L, 0.436 mmol) and HOAc (3 mL) in sealed tube was heated at 70° C. overnight. The reaction mixture was cooled to RT, carefully poured into a cold saturated aqueous NaHCO3 and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 66% EtOAc/hexanes to afford 48 mg (96%) of I-45 as a foam.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=1)[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:15])[N:5]=2.C([N:32]([CH2:35][CH3:36])[CH2:33][CH3:34])C.C(Cl)(=O)OC1C=CC([N+]([O-])=O)=CC=1.NC1CC[N:54]([C:57](OC(C)(C)C)=[O:58])[CH2:53]C1.[F:64][C:65]([F:70])([F:69])[C:66]([OH:68])=[O:67]>ClCCl>[NH:32]1[CH2:33][CH2:34][CH:53]([NH:54][C:57](=[O:58])[NH:1][C:2]2[S:3][C:4]3[C:9]([N:10]=2)=[CH:8][CH:7]=[C:6]([C:11]2[CH:12]=[C:13]([CH:27]=[CH:28][CH:29]=2)[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[O:15])[N:5]=3)[CH2:36][CH2:35]1.[C:66]([OH:68])([C:65]([F:70])([F:69])[F:64])=[O:67]
Reactant: CCN(CC)CC
Reactant: Nc1nc2ccc(-c3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)nc2s1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1nc2ccc(-c3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)nc2s1)NC1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-aminothiazolo[5,4-b]pyridin-5-yl)-N-(3-(trifluoromethyl)phenyl)benzamide (50 mg, 0.12 mmol) and triethylamine (25 μL, 0.18 mmol) in dichloromethane (1.0 mL) was added 4-nitrophenyl carbonochloridate (26 mg, 0.13 mmol) at 0° C. The reaction mixture was stirred at room temperature for 1 h. Tert-butyl 4-aminopiperidine-1-carboxylate (36 mg, 0.18 mmole) and triethylamine (25 μL, 0.18 mmol) were added to the reaction mixture. The reaction mixture was stirred for 4 h after which time the solvent was removed in vacuo. The reaction mixture was diluted with dichloromethane (5 mL) and washed with 1N aqueous HCl and brine. The organic layer was dried over MgSO4 and concentrated in vacuo. To a solution of the crude mixture in dichloromethane (1 mL) was added trifluoroacetic acid (40 μL, 0.60 mmol). The reaction mixture was stirred for 4 h. The majority of the organic solvent was removed in vacuo and the crude product was diluted with DMSO (1 mL) and purified by preparative HPLC to give title compound in a TFA salt form.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([CH:12]([CH:14]3[CH2:16][CH2:15]3)[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1>CCCCCC.C(O)C>[NH2:1][C:2]1[C:6]2[C:7](=[O:17])[N:8]([C@H:12]([CH:14]3[CH2:15][CH2:16]3)[CH3:13])[CH:9]=[C:10]([Br:11])[C:5]=2[NH:4][N:3]=1
Reactant: CC(C1CC1)n1cc(Br)c2[nH]nc(N)c2c1=O
Solvent: CCCCCC
Solvent: CCO
Product: C[C@@H](C1CC1)n1cc(Br)c2[nH]nc(N)c2c1=O
Yield: 48.5 %

Procedure:
Racemic 3-amino-7-bromo-5-(1-cyclopropylethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]pyridin-4-one obtained in Example 164 (1.1 g) was resolved by HPLC (column: CHIRALPAD AD, 50 mmID×500 mmL, manufactured by Daicel Chemical Industries, mobile phase: hexane/ethanol=800/200(v/v)) to give the title compound (533 mg) having a shorter retention time.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:26])[C:7]=1[CH2:8][O:9][C:10]1[C:11]2[N:12]([C:17]([C:21]([O:23]CC)=[O:22])=[C:18]([CH3:20])[N:19]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1.[OH-].[Na+].Cl>O1CCOCC1>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([F:26])[C:7]=1[CH2:8][O:9][C:10]1[C:11]2[N:12]([C:17]([C:21]([OH:23])=[O:22])=[C:18]([CH3:20])[N:19]=2)[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cncc3F)cc(C)cn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(OCc2c(F)cncc2F)c2nc(C)c(C(=O)O)n2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5.34 g (14.78 mmol) of ethyl 8-[(3,5-difluoropyridine-4-yl)methoxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate from Example 130A were initially charged in 160 ml of dioxane, 147.8 ml (147.8 mmol) of 1 M aqueous sodium hydroxide solution were added and the mixture was stirred at RT overnight. The reaction mixture, cooled to RT, was adjusted to about pH 4 using 1 N aqueous hydrochloric acid, the solvent was concentrated to half of its original volume and the precipitated solid was filtered off with suction and dried under reduced pressure. This gave 4.61 g (93% of theory) of the target compound.
Reaction SMILES: [NH:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:22][C:23]([CH3:29])([CH2:27][CH3:28])[C:24](Cl)=[O:25]>>[CH3:22][C:23]([CH3:29])([CH2:27][CH3:28])[C:24]([N:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:25]
Reactant: C1COCCOCCOCCOCCOCCOCCN1
Reactant: CCC(C)(C)C(=O)Cl
Product: CCC(C)(C)C(=O)N1CCOCCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10,13,16,19-hexaoxacycloheneicosane and 2,2-dimethylbutyryl chloride.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1c2n(c3c(-c4ccc(C(F)(F)F)cc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (74 mg, 82%), MS (ISP) m/z=363.4 [(M+H)+], mp 269.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-trifluoromethyl-phenylboronic acid (61.7 mg, 0.325 mmol).
Reaction SMILES: C[O-].[Na+].C([O:12][CH:13]([CH2:55][O:56][C@H:57]1[O:86][C@H:85]([CH2:87][O:88][CH2:89][C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[C@H:76]([O:77][CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[C@H:67]([O:68][CH2:69][C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C@H:58]1[O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:14][O:15][C@H:16]1[O:45][C@H:44]([CH2:46][O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@H:35]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:17]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C1C=CC=CC=1>CO.ClCCl>[CH2:19]([O:18][C@@H:17]1[C@@H:26]([O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C@@H:35]([O:36][CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C@@H:44]([CH2:46][O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:45][C@@H:16]1[O:15][CH2:14][CH:13]([CH2:55][O:56][C@H:57]1[O:86][C@H:85]([CH2:87][O:88][CH2:89][C:90]2[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=2)[C@H:76]([O:77][CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[C@H:67]([O:68][CH2:69][C:70]2[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=2)[C@H:58]1[O:59][CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[OH:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OC(CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: OC(CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 78.6 %

Procedure:
Sodium methoxide (30%, ca 0.1 mL) was added dropwise to a stirred solution of benzoate 41 (209 mg, 0.168 mmol) in dry methanol (6 mL) and dichloromethane (2 mL) under argon. After 12 hrs the reaction mixture was partitioned between ether (50 mL) and 2M HCl (50 mL). The aqueous phase was re-extracted with ether (50 mL) and the combined ethereal extract washed with H2O (60 mL). After drying (MgSO4) and filtration the solvent was removed at reduced pressure to give the crude product that was purified by column chromatography on silica gel. Gradient elution with ethyl acetate/petroleum ether (30:70→50:50) afforded the title compound 42 (150 mg, 0.132 mmol, 79%) as a thin film; [α]D22 +61.3 (c 3.00, CH2Cl2); 1H NMR (300 MHz, CDCl3) δ 7.35-7.15 (m, 40H), 4.90-4.35 (m, 18H), 4.10-3.82 (m, 9H), 3.70-3.42 (m, 9H); 13C NMR (75 MHz, CDCl3) δ 139.2, 139.1, 139.0, 138.9, 138.4, 128.8, 128.7, 128.6, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 99.4, 99.2, 79.5, 77.1, 77.0, 75.5, 75.2, 73.9, 73.8, 73.6, 73.5, 71.1, 71.0, 70.2, 69.7, 69.6, 69.5; HRMS-ESI (+ve) (Found: m/z 1154.5579 (MNH4+). C71H80NO14 requires m/z 1154.5624).
Reaction SMILES: Br[C:2]1[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]2[O:9][C:8]([CH2:11][OH:12])([CH3:10])[CH2:7][C:6]=2[C:13]=1[CH3:14].[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1)([CH3:19])[CH3:18]>>[CH3:10][C:8]1([CH2:11][OH:12])[CH2:7][C:6]2[C:13]([CH3:14])=[C:2]([N:29]3[CH2:30][CH2:31][N:26]([C:23]4[CH:24]=[CH:25][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:21][CH:22]=4)[CH2:27][CH2:28]3)[C:3]([CH3:16])=[C:4]([CH3:15])[C:5]=2[O:9]1
Reactant: CC(C)c1ccc(N2CCNCC2)cc1
Reactant: Cc1c(C)c2c(c(C)c1Br)CC(C)(CO)O2
Product: Cc1c(C)c(N2CCN(c3ccc(C(C)C)cc3)CC2)c(C)c2c1OC(C)(CO)C2
Yield: 6.3 %

Procedure:
By using (5-bromo-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl)methanol (330 mg, 1.16 mmol) synthesized in Reference example 123 and 1-(4-isopropylphenyl)piperazine (774 mg, 3.78 mmol), the reaction was carried out in the same manner as Example 1 to obtain the title compound 30 mg (yield 6%). Melting point was 160 to 163° C. (ethyl acetate-hexane).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH:24]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38][OH:39])=[CH:36][C:35]=1[CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(Cl)Cl>[CH3:42][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][C:34]=1[C:24](=[O:23])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:38]=[O:39]
Reactant: CCCCCCCCCC(O)c1ccc(CO)cc1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCCCCCCCCC(=O)c1ccc(C=O)cc1C
Reaction time: 0.33 h
Yield: 83.2 %

Procedure:
Dess-Martin periodinane (1.00 g, 2.37 mmol) was added to a solution of 4-(1-hydroxydec-1-yl)-3-methylbenzyl alcohol (0.300 g, 1.07 mmol, from Step B) in methylene chloride (5.0 mL). After 20 min, the reaction was filtered and concentrated in vacuo. Silica gel chromatography eluting with 5% ethyl acetate/hexane gave 0.24 g (0.89 mmol, 83%) of product: 1H NMR (500 MHz) δ 10.0 (s, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.74 (s, 1H), 7.66 (d, J=7.8 Hz, 1H), 2.87 (t, J=7.5 Hz, 2H), 2.51 (s, 3H), 1.66-1.74 (m, 2H), 1.22-1.38 (m, 12H), 0.87 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=O.C(Cl)(=O)C(Cl)=O.[OH:19][C:20]([CH3:24])([CH3:23])[CH2:21][NH2:22].C(N(CC)CC)C>ClCCl.CN(C)C=O.Cl>[OH:19][C:20]([CH3:24])([CH3:23])[CH2:21][NH:22][C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(C)(O)CN
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(O)CNC(=O)c1ccc(B(O)O)cc1
Reaction time: 3 h

Procedure:
4-Carboxyphenylboronic acid (0.5 g, 3.0 mmol) is suspended in dry dichloromethane (8 mL) and oxalylchloride (2 M in dichloromethane, 3.0 mL, 6.0 mmol) is added followed by 2 drops of N,N-dimethylformamide. The mixture is stirred for 3 hours then the solvent removed under vacuum. 2-Hydroxy-2-methylpropylamine (step 1, 800 mg, 9.0 mmol) and triethylamine (2.0 mL, 13.8 mmol) in dichloromethane (12 mL) are added to the residue and the mixture stirred for 30 minutes. The mixture is diluted with 1 M HCl and the phases separated. The aqueous layer is extracted several times with ethyl acetate. The combined organic phases are dried and the solvent removed to give the title compound as a crude product. LC (METHOD 5): tR=0.55 min; Mass spectrum (ES+): m/z=238 [M+H]+.
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])[CH3:3].[ClH:6].[CH2:7]([OH:9])[CH3:8]>>[ClH:6].[C:1](=[NH:5])([O:9][CH2:7][CH3:8])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C#N
Reactant: CCO
Agent: Cl
Product: CCOC(=N)C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 82 %

Procedure:
Isobutyronitrile (1 g, 14.5 mmol) was dissolved in anhydrous ethanol (30 mL) under an atmosphere of Ar. The solution was cooled to 0° C., saturated with HCl gas, stirred for 6 h, allowed to warm to RT, and stirred for 6 h. The solvent was removed in vacuo to afford ethyl isobutyrimidate hydrochloride (1.8 g, 82%) as a colorless solid. 1H NMR (400 MHz, DMSO-d6): δ 11.78 (br s, 1H), 11.05 (br s, 1H), 4.40 (q, J=7.0 Hz, 2H), 2.93-2.92 (m, 1H), 1.33 (t, J=7.0 Hz, 3H), 1.16 (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.C(O[C:32]1(O[Si](C)(C)C)[CH2:34][CH2:33]1)C.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20][N:19]1[CH:32]1[CH2:34][CH2:33]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CCCC1CCNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCC1CCC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(C2CC2)CC1
Yield: 59 %

Procedure:
5-propyl-azepane-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide prepared as described in example 47 (68 mg, 0.16 mmol) in MeOH (2 mL), acetic acid (0.1 mL) was added, followed by 1-[(ethyoxycyclopropyl)oxy]trimethylsilane (0.2 mL, 0.96 mmol), sodium cyanoborohydride (41 mg, 0.64 mmol), and 3 Å molecular sieves, heated to reflux for 3 h. Molecular sieves were filtered out and the reaction solvent was removed to obtain the crude material. Purification was carried by silica gel column chromatography (10% MeOH/DCM) and HPLC to provide the title compound (44 mg, 59%).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6](=O)[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][N:30]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][NH2:43])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:29][CH2:28]1)=[O:26])[CH3:23].C(N(CC)CC)C>CO>[CH2:22]([O:24][C:25]([CH:27]1[CH2:32][CH2:31][N:30]([S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH2:42][N:43]3[C:4]([C:1](=[O:3])[CH3:2])=[C:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([Br:20])[CH:11]=4)[C:6]3=[O:5])=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH2:29][CH2:28]1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(CN)cc2)CC1
Reactant: CC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCOC(=O)C1CCN(S(=O)(=O)c2ccc(Cn3c(C(C)=O)c(-c4ccccc4)c4cc(Br)ccc4c3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 14 %

Procedure:
[Step 3] To a solution of 3-acetyl-6-bromo-4-phenylisochromen-1-one (343 mg) in methanol (20 ml) were added 1-(4-aminomethylbenzenesulfonyl)piperidine-4-carboxylic acid ethyl ester (979 mg) and triethylamine (1.4 ml), and the mixture was stirred at room temperature for 72 hrs. The solvent was evaporated under reduced pressure, and partitioned between 1N hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, 4N hydrochloric acid ethyl acetate solution (5 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=7/3→2/3) to give the title compound (91 mg, 14%). 1H-NMR (CDCl3) δ: 1.21 (3H, t, J=7.0 Hz), 1.37 (3H, s), 1.65-2.01 (4H, m), 2.11 (1H, m), 2.38-2.56 (2H, m), 3.50-3.66 (2H, m), 4.09 (2H, q, J=7.0 Hz), 5.47 (2H, s), 7.24-7.50 (8H, m), 7.67-7.76 (3H, m), 8.41 (1H, d, J=8.4 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[CH3:9][N:10]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[CH3:11]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:15]2[CH2:16][CH2:17][CH:12]([N:10]([CH3:11])[CH3:9])[CH2:13][CH2:14]2)=[N:6][CH:7]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CN(C)C1CCNCC1
Product: CN(C)C1CCN(c2ccc(Br)cn2)CC1
Temperature: 80 °C
Yield: 92.3 %

Procedure:
Mix 5-bromo-2-fluoro-pyridine (1.00 g, 5.68 mmol) and N,N-dimethyl-piperidin-4-yl-amine (1.50 g, 11.70 mmol) together and heat to 80° C. for 64 h. Partition the reaction between CH2Cl2 (5 mL) and 1N NaOH (8 mL). Collect the organic phase and extract the aqueous phase with additional CH2Cl2 (2×20 mL). Combine the organic solutions, then dry, filter, and concentrate. Purify the crude material by flash chromatography using an eluent of 5% MeOH (2N NH3)/CH2Cl2 to give 1.49 g (92%) of the title compound as a white solid. 1H NMR (CDCl3) δ 1.46 (dq, 2H, J=4.0, 11.8 Hz), 1.86 (br d, 2H, J=12.8 Hz), 2.26 (s, 6H), 2.32 (m, 1H), 2.80 (dt, 2H, J=2.7, 12.8 Hz), 4.23 (br d, 2H, J=13.2 Hz), 6.53 (d, 1H, J=8.9 Hz), 7.46 (dd, 1H, J=2.8, 9.0 Hz), 8.13 (d, 1H, J=2.6 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[CH:17]=2)[C:5](O)=[N:6][CH:7]=1.CN([CH:21]=[O:22])C.O=P(Cl)(Cl)[Cl:25]>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:17]=2[CH:21]=[O:22])[C:5]([Cl:25])=[N:6][CH:7]=1
Reactant: Oc1ncc(Br)cc1-c1cn2ccccc2n1
Reactant: CN(C)C=O
Reactant: O=P(Cl)(Cl)Cl
Product: O=Cc1c(-c2cc(Br)cnc2Cl)nc2ccccn12
Temperature: 100 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
A solution of 5-bromo-3-(imidazo[1,2-a]pyridin-2-yl)pyridin-2-ol (500 mg, 1.72 mmol) in POCl3 (10 mL) was stirred at 100° C. overnight. Then DMF (10 mL) was added dropwise. The reaction mixture was stirred at 100° C. for 3 hours. The reaction mixture was concentrated in vacuo. The resulting residue was suspended with water, and saturated aqueous NaHCO3 solution was added until the solution was at pH 7. The mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified using column chromatography (eluted with dichloromethane:MeOH=50:1) to provide 2-(5-bromo-2-chloropyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde (300 mg, yield: 51%). 1H-NMR (CDCl3, 400 MHz) δ 9.87 (s, 1H), 9.62 (d, J=7.2 Hz, 1H), 8.61 (d, J=2.4 Hz, 1H), 8.12 (d, J=2.4 Hz, 1H), 7.84 (d, J=9.2 Hz, 1H), 7.63˜7.67 (m, 1H), 7.21˜7.24 (m, 2H). MS (M+H)+: 336/338.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=12.CCOC(C1C(=O)CCCC1)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1.[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][C:43]=1[N:49]=[C:50]=[O:51]>CS(C)=O.C1COCC1.O>[F:41][C:42]1[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][C:43]=1[NH:49][C:50]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:3]=23)=[CH:36][CH:35]=1)=[O:51]
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: COC(=O)c1cc2nccc(Br)c2s1
Reactant: Nc1ccc(O)cc1
Agent: CCOC(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)ccc4F)cc3)c2s1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a stirred solution of methyl 7-bromothieno[3,2-b]pyridine-2-carboxylate (200 mg, 0.74 mmol) in 8 ml of DMSO, were added CuBr (10 mg, 0.074 mmol), ethyl 2-cyclohexanonecarboxylate (26 mg, 0.15 mmol), cesium carbonate (500 mg, 1.54 mmol) and 4-aminophenol (96 mg, 0.88 mmol). The mixture was purged with nitrogen for 10 minutes, and then heated at 70° C. under N2 for 3 hours. The reaction was cooled to room temperature and poured into 100 ml of water. The precipitates were filtered, washed with water and dried to give the crude aniline intermediate as a pale green solid (˜140 mg). This crude material was dissolved in 10 ml of THF, and 2-fluoro-5-methylphenyl isocyanate (70 mg, 0.46 mmol) was added. The mixture was stirred at room temperature for 5 hours, and poured into 100 ml of water. The brown precipitates were filtered, washed with water and dried to give the crude product, which was purified by silica gel chromatography, eluting with 2-3% MeOH/CHCl3 to give methyl 7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxylate as light brown solid. Yield: 90 mg, 27%.