Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br)([O-:3])=[O:2].[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:22][CH2:23][CH3:24])[C:20]=1[OH:21])[CH:16]=[O:17].C([O-])([O-])=O.[K+].[K+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CN(C=O)C.C(OCC)(=O)C>[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:22][CH2:23][CH3:24])[C:20]=1[O:21][CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH:16]=[O:17]
Reactant: CCOc1cc(C=O)cc(Br)c1O
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc(Br)c1OCc1cccc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 3-nitrobenzylbromide (2 g), 3-bromo-5-ethoxy-4-hydroxy benzaldehyde (2.06 g), K2CO3 (2.55 g) and Bu4NI (186 mg) in DMF (50 ml) was stirred at 60° C. for 2 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was recrystallized from heptane.
Reaction SMILES: [I:1]I.[CH2:3]([O:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1)[C:4]#[CH:5].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[I:1][CH:3]([O:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1)[C:4]#[CH:5]
Reactant: II
Reactant: C#CCOn1cccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: C#CC(I)On1cccn1
Reaction time: 8 h
Yield: 98.5 %

Procedure:
41.6 g of iodine are added, a little at a time, to 20 g of 1-pyrazolyl propargyl ether and 20 g of sodium carbonate in 400 g of acetonitrile at 40° C., while stirring. Stirring is continued for 8 hours at 40° C., after which undissolved material is filtered off under suction, and the filtrate is evaporated down in a rotary evaporator at 30° C. and under 20 mbar. The residue is dissolved in 200 g of dichloromethane, the solution is extracted twice with 200 g of 10% strength aqueous sodium thiosulfate solution, and the organic phase is dried with magnesium sulfate and evaporated down. 40 g (99% of theory) of 1-pyrazolyl iodopropargyl ether are obtained as an oil (H1 --NMR, in ppm: 5.1, s, 2H; 6.2, m, 1H; 7.4, m, 2H).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[OH2:7]>>[C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[CH3:3].[OH:7][C:2]([CH3:4])([CH3:3])[C:1]([OH:6])=[O:5]
Reactant: O
Solvent: CC(C)C(=O)O
Product: CC(C)(O)C(=O)O

Procedure:
In Examples 1-10 which follow in Table form, an aqueous solution of isobutyric acid (IBA) was prepared by weighing the desired quantities of the isobutyric acid and water into a 500 ml round bottom glass reaction flask equipped with a mechanical stirrer, a thermometer and reflux condenser. A molar equivalent quantity of a TlX3 salt compound, calculated according to the above-mentioned reaction formula, was added and the reaction mixture heated on an oil bath to the desired temperature with stirring for the desired time. The contents of the flask were then cooled and filtered to remove any insoluble TlX. The filtrate was titrated for unconverted Tl+3 and the product α-hydroxyisobutyric acid (α HIBA) determined by high pressure liquid chromatographic analysis. The α-hydroxyisobutyric acid yield (mol percent) is calculated as follows: ##EQU1##
Reaction SMILES: [O:1]([C:8]1[C:16]([S:17](=[O:30])(=[O:29])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][C:26](=[O:28])[CH3:27])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[NH2:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32](=O)[C:33]1[O:37][CH:36]=[CH:35][CH:34]=1>>[O:1]([C:8]1[C:16]([S:17](=[O:30])(=[O:29])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][C:26](=[O:28])[CH3:27])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[NH:31][CH2:32][C:33]1[O:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)Nc1ccccc1NS(=O)(=O)c1cc(C(=O)O)cc(N)c1Oc1ccccc1
Reactant: O=Cc1ccco1
Product: CC(=O)Nc1ccccc1NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccco2)c1Oc1ccccc1
Reaction time: 16 h

Procedure:
The starting material is prepared as follows: The mixture of 3.5 g of 4-phenoxy-3-amino-5-(2-acetamidophenylsulfamoyl)-benzoic acid and 30 ml of furfural is heated to 100° for five hours and allowed to stand at room temperature for 16 hours. It is evaporated under reduced pressure, the residue triturated with diethyl ether and dissolved in 75 ml of ethanol. Thereupon 2 g of sodium borohydride are added while stirring and cooling followed by another 0.5 g thereof after 4 hours and another 0.5 g thereof after 16 hours and stirring is continued for one hour. Thereupon 100 ml of water are added, the mixture filtered and the filtrate acidified with hydrochloric acid to a pH of 2-3. The precipitate formed is filtered off and recrystallized from 30% aqueous ethanol to yield the 4-phenoxy-3-furfurylamino-5-(2-acetamidophenylsulfamoyl)-benzoic acid melting at 207°-210° with decomposition.
Reaction SMILES: [NH2:1][C@H:2]([C@H:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.[NH:15]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[C@H:16]([C@H:21]([CH2:23][C:24]([NH:26][C@H:27]([C:29](O)=[O:30])[CH3:28])=[O:25])[OH:22])[CH2:17][CH:18]([CH3:20])[CH3:19].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C1CCC(N=C=NC2CCCCC2)CC1>O>[NH:15]([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[C@H:16]([C@H:21]([CH2:23][C:24]([NH:26][C@H:27]([C:29]([NH:1][C@H:2]([C@H:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:30])[CH3:28])=[O:25])[OH:22])[CH2:17][CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)N[C@@H](C)C(=O)O
Reactant: COC(=O)C[C@H](O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1

Procedure:
In a manner analogous to that described in stage 13.1, using as starting materials 150 mg of H-Sta-OMe×HCl (from stage 13.4), 253 mg of Z-Sta-Ala-OH (from stage 13.2), 102 mg of HOBt×H2O, 67 mg of N-methylmorpholine and 178 mg of DCCI, Z-Sta-Ala-Sta-OMe is obtained; Rf (chloroform/methanol ]9:1])=0.37.
Reaction SMILES: [CH2:1]([Zn]CC)C.ClCI.C[O:10][C:11](=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH:20]=[CH2:21].[Cl-].[NH4+].[OH-].[Na+]>ClCCCl.C1COCC1>[CH:20]1([O:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][C:11]([OH:10])=[O:22])[CH2:1][CH2:21]1
Reactant: CC[Zn]CC
Reactant: C=COc1ccccc1CC(=O)OC
Agent: ClCI
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCCl
Product: O=C(O)Cc1ccccc1OC1CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 53 %

Procedure:
Diethyl zinc (2.34 mL, 2.34 mmol, 1M in heptane) was cooled to 0° C. under nitrogen then chloroiodomethane (0.35 mL, 4.68 mmol) in DCE (1 mL) was added drop-wise. The mixture was stirred under nitrogen at 0° C. for 20 minutes then methyl[2-(vinyloxy)phenyl]acetate (Preparation 156, 150 mg, 0.78 mmol) in DCE (1 mL) was added. The reaction mixture was stirred at 00° C. for 30 minutes then stirred at room temperature for 17 hours. Saturated aqueous ammonium chloride (10 mL) was added and the mixture was extracted with DCM (4×8 mL). The combined organic phases were dried over magnesium sulphate and evaporated in vacuo. Sodium hydroxide (3.28 mL, 3.28 mmol, 1 M) was added to the residue in THF (3 mL). The mixture was heated at 80° C. for 17 hours then evaporated in vacuo. Hydrochloric acid (10 mL, 1 M) was added to the residue then extracted with EtOAc (10 mL). The organic phase was evaporated in vacuo to afford the title compound as a yellow oil in 53% yield, 83 mg.
Reaction SMILES: [CH2:1]([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][Si](C(C)(C)C)(C)C)[CH:10]=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Cl:6][C:7]1[CH:8]=[C:9]([CH:10]=[CH2:1])[CH:12]=[CH:13][C:14]=1[OH:15]
Reactant: [Li]CCCC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1Cl
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1ccc(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a slurry of methyltriphenylphosphonium bromide (0.23 g) in dry THF (5 ml) under nitrogen at −78° C., n-butyl lithium (1.6M in hexanes, 0.37 ml) was added dropwise over 2 min. The mixture was allowed to warm to 0° C., stirred for 20 min, cooled to −78° C. and a solution of 3-chloro-4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzaldehyde* (0.134 g) in dry THF (5 ml) added. The reaction mixture was allowed to reach room temperature overnight and quenched with saturated aqueous ammonium chloride. The resultant mixture was extracted with diethyl ether and the combined organic extracts were concentrated under reduced pressure. The residue was purified using SPE (silica, eluting with cyclohexane, followed by 5% to 25% ethyl acetate:cyclohexane) to give the title compound (0.049 g) as an oil. *Boukouvalas, J; Maltais, F; Lachance, N., Tetrahedron Lett. (1994), 35(43), 7897-900.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:27][O:28][C:29](=[O:35])[C@H:30]([CH:32]([CH3:34])[CH3:33])[NH2:31].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([NH:31][C@H:30]([C:29]([O:28][CH3:27])=[O:35])[CH:32]([CH3:34])[CH3:33])=[O:10]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: Cc1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C)C(C)C
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
3-Methyl-4′-nitrobiphenyl-4-carboxylic acid (0.50 g, 1.0 mmol) was dissolved in methylene chloride (10 mL), and then oxalyl chloride (0.25 mL, 0.29 mmol) was added, followed by one drop of DMF. The resulting mixture was stirred at 50° C. for 45 min and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cold mixture of L-valine methyl ester hydrochloride (0.39 g, 2.3 mmol), methylene chloride (10 mL), and triethylamine (1.08 mL, 7.75 mmol). The resulting solution was stirred at rt for 18 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (50% EtOAc in hexanes). This yielded 0.653 g (91%) of the title compound. LC/MS m/z 370.9 (MH+), retention time 3.29 min. 1H NMR (400 MHz, CD2Cl2) δ 1.06 (dd, 6H), 2.32-2.39 (m, 1H), 2.55 (s, 3H), 3.78 (s, 3H), 4.71-4.78 (m, 1H), 6.33 (d, 1H), 7.42-7.52 (m, 3H), 7.82 (d, 2H), 8.26 (d, 2H).
Reaction SMILES: [Br-].[Cl:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[Cl:20])[NH:6][C:7]1[CH:16]=[CH:15][N+:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[OH-].[Na+]>O>[Cl:2][C:3]1[CH:4]=[C:5]([N:6]=[C:7]2[CH:16]=[CH:15][N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[CH:8]2)[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Clc1ccc(Nc2cc[n+]3ccccc3c2)cc1Cl
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1ccc(N=c2ccn3ccccc3c2)cc1Cl

Procedure:
A solution of 2-(3,4-dichloroanilino)quinolizinium bromide (23 g, 0.062 mole) in water (1 l.) was warmed to 50°. The warm solution was stirred and treated with a 2 N solution of NaOH (400 ml). The solution precipitated a yellow-orange product and the aqueous solution was warmed at 50° for 1 hour. After cooling and filtration the air dried product weighed 18 g (100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.C(O)(=O)C.[N:14]([O-])=[O:15].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:14]=[O:15])=[C:4]([NH2:9])[N:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(N)nc(N)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(N)c(N=O)c(N)n1

Procedure:
2,4,6-triamino-5-nitrosopyrimidine was prepared by dissolving 1.0 mole of 2,4,6-triaminopyrimidine in 1040 ml of water and 1.5 moles of acetic acid, maintaining the temperature in the range of about 0°-16° C. Then 1.0 mole of sodium nitrite was added to the reaction mixture while controlling the reaction temperature in the range of 0°-20° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13](SC)[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[O:30][N:29]=[C:28]([CH:31]([CH3:33])[CH3:32])[CH:27]=1)=[O:24].[NH2:34][C@H:35]([CH2:37][OH:38])[CH3:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:19](=[O:20])[N:18]([CH3:21])[C:11]3[N:12]=[C:13]([NH:34][C@@H:35]([CH3:36])[CH2:37][OH:38])[N:14]=[CH:15][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:22][C:23]([NH:25][C:26]1[O:30][N:29]=[C:28]([CH:31]([CH3:33])[CH3:32])[CH:27]=1)=[O:24]
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cc(C(C)C)no4)c3)c(=O)n(C)c2n1
Reactant: C[C@H](N)CO
Product: CC(C)c1cc(NC(=O)Nc2cc(-c3cc4cnc(N[C@@H](C)CO)nc4n(C)c3=O)ccc2F)on1
Yield: 42 %

Procedure:
Using a procedure analogous to Example A1, 1-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea (0.150 g, 0.322 mmol, 1.00 eq) was oxidized and reacted with L-alaninol (41.4 μL, 0.533 mmol, 2.00 eq) to afford (S)-1-(2-fluoro-5-(2-(1-hydroxypropan-2-ylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)-3-(3-isopropylisoxazol-5-yl)urea (67 mg, 51% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 8.73 (brs, 1H), 8.65 (brs, 1H), 8.39 (dd, J=2.4 and 8.0 Hz, 1H), 7.87 (s, 1H), 7.60-7.57 (m, 1H), 7.35-7.25 (m, 2H), 6.06 (s, 1H), 4.70 (t, J=6.0 Hz, 1H), 4.09 (brs, 1H), 3.58-3.49 (m, 4H), 3.35 (brs, 1H), 2.89 (m, 1H), 1.23 (s, 9H), 1.17-1.15 (m, 9H); MS (ESI) m/z: 496.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][NH:9][CH2:10][C:4]=2[CH:3]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[Br:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][CH2:8][N:9]([S:14]([CH3:13])(=[O:16])=[O:15])[CH2:10][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Brc1cnc2c(c1)CNCCN2
Solvent: ClCCl
Product: CS(=O)(=O)N1CCNc2ncc(Br)cc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.6 %

Procedure:
To a solution of 7-bromo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine (432 mg, 1.89 mmol) and TEA (0.28 mL, 2.02 mmol) in anhydrous CH2Cl2 (20 mL) under argon was added methanesulfonyl chloride (0.16 mL, 2.06 mmol). The mixture was stirred for 12 h at room temperature. Mixture was then concentrated to a brown solid and redissolved in a 2:1 MeOH:DMSO mixture. Purification by preparative HPLC (water/acetonitrile/0.05% TFA mixture) gave the title compound (7-bromo-4-(methylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepine) (281 mg, 48%) as a yellow solid: 1H NMR (200 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.68 (s, 1H), 4.39 (s, 2H), 3.48 (s, 2H), 3.39 (s, 2H), 2.79 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:19]=[CH:20][C:21]=1[Cl:22])[O:14][CH2:15][C:16](N)=[NH:17].C(O)C.CN(C)C=O>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:16]([CH2:15][O:14][C:13]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:11]([Cl:10])[CH:12]=2)[N:17]=1
Reactant: N#Cc1nccnc1N
Reactant: N=C(N)COc1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(COc2ccc(Cl)c(Cl)c2)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 9.6 g (0.080 mole) of 3-amino-2-pyrazinecarbonitrile and 26.3 g (0.12 mole) of 2-(3,4-dichlorophenoxy)acetamidine in 520 ml of absolute ethanol. Refluxing time: 3 hours. Yld: 18.0 g (70%), m.p. 261°-263° C. (ethanol/N,N-dimethylformamide).
Reaction SMILES: [ClH:1].C(OC([N:9]1[C@H:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]=[C:10]1[N:26]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:27])=O)(C)(C)C>CCOC(C)=O>[ClH:1].[C:14]1([C@H:13]2[C@@H:12]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:11][C:10]([N:26]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH3:27])=[N:9]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CN(Cc1ccccc1)C1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(Cc1ccccc1)C1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Hydrogen chloride is bubbled into a solution of 81 (110 mg, 0.25 mmol) in EtOAc (10 mL) for 1 min, and the solution is stirred at RT for 6 h. The solvent is removed by rotary evaporation, and the residue triturated with Et2O. The insoluble material is dissolved in dichloromethane and Et2O is added, and the precipitate is filtered to give 43 mg of the product 82. 1H NMR (DMSO-d6) δ 9.28 (s, 2H), 7.60-7.30 (m, 5H), 7.25-6.95 (m, 10H), 5.58 (s, 2H), 4.78 (s, 2H), 3.15 (s, 3H); MS: m/z 342 (M++1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]2[S:9][CH:10]=[C:11]([C:12](O)=[O:13])[C:7]=2[CH:6]=1)(=[O:3])[CH3:2].CN(C)C=O.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[C:1]([O:4][C:5]1[CH:16]=[CH:15][C:8]2[S:9][CH:10]=[C:11]([C:12]([Cl:24])=[O:13])[C:7]=2[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc2scc(C(=O)O)c2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccc2scc(C(=O)Cl)c2c1

Procedure:
A mixture of 1,349 mg of the above obtained 5-acetoxybenzo[b]thiophene-3-carboxylic acid (4), a drop of dimethylformamide, 1.22 ml of (17.13 mmol) of thionyl chloride and 25 ml of toluene was refluxed for 1.5 hours and then concentrated under reduced pressure to give 1,454 mg of the objective compound (5).
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)([CH3:6])[CH3:5])=[N+]=[N-]>[Ni].C(O)C>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([C:4]([NH2:1])([CH3:5])[CH3:6])[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc(C(C)(C)N=[N+]=[N-])c1
Agent: [Ni]
Solvent: CCO
Product: COc1cccc(C(C)(C)N)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 60.9 %

Procedure:
A mixture of 1-(1-azido-1-methylethyl)-3-methoxybenzene (34.1 g, 178 mmols), Raney nickel (100 g) and ethanol (300 ml) was stirred at room temperature for 24 hours. The catalyst was removed through decantation, and the resulting supernatant was concentrated under reduced pressure. 1 N hydrochloric acid was added to the residue, which was then washed with diethyl ether. After neutralized, the aqueous layer was made alkaline with sodium hydroxide added thereto, and extracted with ethyl acetate. The extract was washed with brine, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure to give an oil of 1-(3-methoxyphenyl)-1-methylethylamine (17.9 g, 60%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([OH:17])[C:9]2[N:10]=[CH:11][N:12]3[CH:16]=[CH:15][S:14][C:13]=23)[CH:5]=[N:6][CH:7]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>[O-2].[O-2].[Mn+4].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:18]1([C:2]2[CH:3]=[C:4]([C:8]([C:9]3[N:10]=[CH:11][N:12]4[CH:16]=[CH:15][S:14][C:13]=34)=[O:17])[CH:5]=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC(c1cncc(Br)c1)c1ncn2ccsc12
Reactant: OB(O)c1ccccc1
Agent: [Mn+4]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Product: O=C(c1cncc(-c2ccccc2)c1)c1ncn2ccsc12
Yield: 47.4 %

Procedure:
A ketone compound (1.96 g) was prepared in substantially the same manner as in step b) of Synthesis Example 1, except that 2.77 g of 7-[(5-bromopyridin-3-yl)hydroxymethyl]imidazo[5,1-b]thiazole and 2.00 g of manganese dioxide were used as the starting compounds. 7-(5-Phenylpyridin-3-yl)carbonylimidazo[5,1-b]thiazole (285 mg) was prepared in substantially the same manner as in step b) of Synthesis Example 11, except that 308 mg of the ketone compound, 240 mg of phenylboronic acid, 116 mg of tetrakis(triphenylphosphine)palladium(0), and 276 mg of potassium carbonate were used as the starting compounds.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:19][CH2:20][CH3:21])[C@H:14]([OH:18])[C:15](O)=[O:16])=[O:11])([CH3:8])([CH3:7])[CH3:6].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.C([O-])(O)=O.[Na+]>O.C(OCC)(=O)C>[CH:1]1([NH:4][C:15](=[O:16])[C@@H:14]([OH:18])[C@@H:13]([NH:12][C:10]([O:9][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[CH2:19][CH2:20][CH3:21])[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC[C@H](NC(=O)OC(C)(C)C)[C@H](O)C(=O)NC1CC1
Temperature: 40 °C

Procedure:
Cyclopropylamine (1.99 g, 34.94 mmol) was dropwise added to a mixed solution of (2S,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid (7.2 g, 29.12 mmol), ethyl acetate (144 g) and water (7.2 g). The mixture was cooled by ice. HOBt monohydrate (4.68 g, 30.58 mmol) and EDC hydrochloride (6.14 g, 32.03 mmol) were added thereto, and the mixture was stirred with cooling by ice for 22 hours. Next, 5% NaHCO3 aqueous solution (72 g) was added thereto, and the mixture was heated up to 40° C. Then, the aqueous layer was removed. The organic layer was washed twice with 5% NaHCO3 aqueous solution (72 g) at 40° C., and finally the organic layer was washed with water (72 g), to obtain an ethyl acetate solution of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (yield: 90 mol %, chemical purity: 96.1 area %, optical purity: 99.3% ee). The obtained organic layer (140.2 g) was concentrated under reduced pressure to be 62.5 g, using a rotary evaporator. The obtained slurry was heated up to 60° C. so as to dissolve the contents, and then cooled to 51° C. Seed crystals of (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (2 mg) were added to the solution. As a result, crystals were gradually precipitated. The mixture was aged at the same temperature for 1 hour, and then was cooled to 2° C., taking about 5 hours. The precipitated crystals were separated and dried to obtain (2S,3S)—N-cyclopropyl-3-(tert-butoxycarbonyl)amino-2-hydroxyhexanoic acid amide (6.45 g, isolation yield: 78 mol %, chemical purity: 100.0 area %, optical purity: 100% ee).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([NH:10][C:11](=[O:18])OCC(Cl)(Cl)Cl)=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:2].[C:19]1([C:25]2[N:29]=[C:28]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[S:27][N:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[CH2:1]([O:3][C:4]1[C:9]([NH:10][C:11]([N:33]2[CH2:34][CH2:35][N:30]([C:28]3[S:27][N:26]=[C:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:29]=3)[CH2:31][CH2:32]2)=[O:18])=[CH:8][N:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ncncc1NC(=O)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCOc1ncncc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl (4-ethoxypyrimidin-5-yl)carbamate (315 mg, 1.00 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (246 mg, 1.00 mmol), diisopropylethylamine (0.174 ml, 1.00 mmol) and dimethylsulfoxide (5 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (290 mg, 70.6%) as a solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH3:7][C:8]1[C:9]([CH:15]=O)=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=1.[BH4-].[Na+]>CO>[CH3:7][C:8]1[C:9]([CH2:15][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[N:10][CH:11]=[C:12]([CH3:14])[CH:13]=1
Reactant: NCCCCO
Reactant: Cc1cnc(C=O)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cnc(CNCCCCO)c(C)c1

Procedure:
Using General Procedure B, 4-amino-butan-1-ol and 3,5-dimethyl-pyridine-2-carbaldehyde in MeOH were reacted with NaBH4 to give 4-[(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butan-1-ol as a pale yellow oil.