Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:22]3[CH2:27][CH:26]4[CH:24]([CH:25]4[NH:28]C(=O)OCC4C5C=CC=CC=5C5C4=CC=CC=5)[CH2:23]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>CN(C=O)C>[NH2:28][CH:25]1[CH:24]2[CH:26]1[CH2:27][N:22]([C:20](=[O:21])/[CH:19]=[CH:18]\[N:15]1[CH:16]=[N:17][C:13]([C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:46])[F:47])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=3)=[N:14]1)[CH2:23]2
Reactant: O=C(NC1C2CN(C(=O)/C=C\n3cnc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)n3)CC21)OCC1c2ccccc2-c2ccccc21
Solvent: CN(C)C=O
Product: NC1C2CN(C(=O)/C=C\n3cnc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)n3)CC12
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.5 %

Procedure:
(Z)-(9H-Fluoren-9-yl)methyl (3-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (0.3 g, 1.0 eq.) in was dissolved in DMF (0.75 ml). TEA (0.75 ml) was added dropwise and the reaction mixture was stirred at room temperature for 4 h, quenched with water (10 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure (25° C., 20 mmHg) to afford 0.2 g of the crude product, which was purified by chromatography (10% Methanol in DCM) to obtain (Z)-1-(6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)prop-2-en-1-one (0.1 g; 50% yield). 1H NMR (400 MHz, DMSO) δ=9.10 (s, 1H), 8.49 (s, 2H), 8.30 (s, 1H), 7.30-7.32 (d, J=10 Hz, 1H), 6.07-6.09 (d, J=10 Hz, 1H), 3.65-3.68 (d, 1H), 3.48 (s, 1H), 3.35-3.45 (m, 1H), 3.29-3.30 (d, 1H), 2.28 (s, 1H), 1.48-1.49 (m, 2H), 1.22 (s, 1H); LCMS calcd. for C18H16F6N5O [M+H]+ 432.34. found 432.19 at 2.1 min retention time.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][O:8][CH:7]([CH:11]=O)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([N:5]1[CH2:10][CH2:9][O:8][CH:7]([CH2:11][N:27]2[CH2:26][CH2:25][N:24]([C:22]([NH:21][C:16]3[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=3)=[O:23])[CH2:29][CH2:28]2)[CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)N1CCOC(C=O)C1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)N1CCOC(CN2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Reaction time: 8 h
Yield: 19.4 %

Procedure:
A solution of 4-tert-butylmorpholine-2-carbaldehyde (154 mg) and N-(3,4-dichlorophenyl)piperazine-1-carboxamide (247 mg) in dichloromethane (20 mL) was stirred at room temperature under argon. Sodium triacetoxyborohydride (381 mg) was added and the mixture was stirred overnight. The reaction was quenched with water and partitioned between water and dichloromethane. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and then brine, dried (Na2SO4), filtered and concentrated. The residue was purified on the Isco™ Companion (12 g column: 0-11% MeOH in DCM) to give the title compound as a white solid (75 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[C:15]([O:17]C2CCCCO2)[CH:14]=[C:13]([CH3:24])[C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:2][O:3][C:4]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([CH3:24])[C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1cc(OC2CCCCO2)cc(C)c1CN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(O)cc(C)c1CN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
1N Hydrochloric acid (10 mL) was added to 1-[2-methoxy-6-methyl-4-(tetrahydropyran-2-yloxy)-benzyl]-piperidine (2.33 g, 7.3 mmol) in methanol (30 mL) and the reaction mixture was stirred at ambient temperature for 2 h. The pH of the solution was adjusted to 9 by the addition of saturated aqueous sodium carbonate solution (20 mL) and the aqueous phase was extracted with DCM (3×30 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford a colourless oil. The resultant oil was purified by flash chromatography (silica, 12 g column, ISCO, 0-15% (2N ammonia in MeOH) in DCM) to afford the title compound as a white solid (570 mg, 33%). NMR (CDCl3, 400 MHz): 6.14 (d, J=2.4 Hz, 1H), 5.99 (s, 1H), 3.68 (s, 3H), 3.49 (s, 2H), 2.56-2.46 (m, 4H), 2.25 (s, 3H), 1.65-1.51 (m, 4H), 1.48-1.36 (s, 2H).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].C([O-])(O)=O.[Na+].I[C:11]1[CH:18]=[CH:17][C:14]([CH2:15][OH:16])=[CH:13][CH:12]=1.CCOC(C)=O>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].O>[OH:16][CH2:15][C:14]1[CH:17]=[CH:18][C:11]([CH2:3][CH2:2][CH:1]=[O:4])=[CH:12][CH:13]=1
Reactant: OCc1ccc(I)cc1
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=CCCc1ccc(CO)cc1
Temperature: 60 °C

Procedure:
10.5 mL (152.8 mmol) allylalcohol, 18.8 g (62.2 mmol) Tetrabutylammonium chloride monohydrate, 12.8 g (152.8 mmol) NaHCO3 and 0.75 g (3.1 mmol) Pd(OAc)2 is added to a solution of 15.0 g (62.2 mmol) 4-iodobenzylalcohol in 100 mL DMF at RT under an N2 atmosphere and the reaction solution is heated to 60° C. for 3 h. The solvent is eliminated i.vac., the residue combined with 250 mL EtOAc and 80 mL water and suction filtered through a fibreglass filter. 80 mL NaCl solution are added to the filtrate, the phases are separated and the organic phase is dried over MgSO4. After the desiccant and solvent have been eliminated the residue is purified by column chromatography on silica gel (gradient: cyc/EtOAc 3:1 after cyc/EtOAc 1:1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([CH2:25][OH:26])=[CH:9]2)=[N:6][CH:7]=1.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:15]=3)[C:10]([CH2:25][OH:26])=[CH:9]2)=[N:6][CH:7]=1
Reactant: OB(O)c1ccccc1F
Reactant: O=C(c1ccc2c(CO)cn(-c3ncc(Br)cn3)c2c1)N1CCOCC1
Product: O=C(c1ccc2c(CO)cn(-c3ncc(-c4ccccc4F)cn3)c2c1)N1CCOCC1

Procedure:
Prepared from 27c) (400 mg, 0.959 mmol, 1.0 eq) and (2-fluorophenyl)boronic acid (133 mg, 0.959 mmol, 1.0 eq) according to general procedure 1. White solid. Yield: 230 mg (55% of theory). Melting range: 190-194° C. HPLC (method 1): Rt=9.69 min. Mass spectroscopy: m/z: [M+H]+=433.0
Reaction SMILES: [F:1][C:2]([C:5]1[S:9][C:8]([N:10]=[C:11]=[O:12])=[N:7][N:6]=1)([F:4])[F:3].[CH3:13][NH:14][CH2:15][CH2:16][CH:17]=[O:18]>C1C=CC=CC=1>[CH3:13][N:14]([CH2:15][CH2:16][CH:17]=[O:18])[C:11]([NH:10][C:8]1[S:9][C:5]([C:2]([F:3])([F:1])[F:4])=[N:6][N:7]=1)=[O:12]
Reactant: O=C=Nc1nnc(C(F)(F)F)s1
Reactant: CNCCC=O
Solvent: c1ccccc1
Product: CN(CCC=O)C(=O)Nc1nnc(C(F)(F)F)s1

Procedure:
A mixture of 5 trifluoromethyl-1,3,4-thiadiazol-2-yl isocyanate dimer (9.5 grams), the dimethyl acetal of 3-methylaminopropionaldehyde (5.8 grams) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This product is recrystallized to yield the desired product the dimethyl acetal of 3-[1-methyl-3-(5-trifluoromethyl-1,3,4-thiadiazol-2-yl)ureido]propionaldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11].C(N(CC)CC)C.O>C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(OCC)(=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:11]#[C:10][CH2:9][CH2:8][OH:12])[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: OCCC#Cc1cccnc1
Yield: 12.3 %

Procedure:
To a stirred solution of 3-bromopyridine (3.75 g, 23.8 mmol), 3-butyn-1-ol (2.0 g, 28.5 mmol) and triethylamine (12 ml) in anhydrous DCM was added bis(triphenylphosphine)palladium dichloride (0.05 g, 0.07 mmol) and copper(I) iodide (0.05 g, 0.26 mmol). The mixture was refluxed for 20 h under argon. After cooling, water (20 ml) was added and the product extracted into DCM. The combined organics were dried over anhydrous potassium carbonate, filtered and evaporated to give a brown oil. Column chromatography (flash silica gel, ethyl acetate) gave 4-(3-pyridyl)-1-but-3-ynol (0.43 g, 12%) as a colourless oil.
Reaction SMILES: [Na].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](Cl)=[O:18]>C(O)C>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([CH:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[NH:2][C:3]1=[O:11])=[O:18]
Reactant: O=C(Cl)c1ccco1
Reactant: O=C1Cc2ccccc2N1
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2ccccc2C1C(=O)c1ccco1
Reaction time: 0.21 h
Yield: 36.5 %

Procedure:
To a stirred solution of 5.5 g (0.24 mole) of sodium in 150 ml of ethanol was added 13.3 g (0.10 mole) of 2-oxindole at room temperature. The resulting slurry was cooled to ice-bath temperature, and then 15.7 g (0.12 mole) of 2-furoyl chloride was added, dropwise, during 10-15 minutes. The ice-bath was removed, and an additional 100 ml of ethanol was added and then the reaction mixture was heated under reflux for 7 hours. The reaction mixture was allowed to stand overnight and then the solid was filtered off. The solid was added to 400 ml of water and the resulting mixture was acidified using concentrated hydrochloric acid. The mixture was cooled with ice and the solid was collected by filtration. The solid residue was recrystallized from 150 ml of acetic acid, affording 8.3 g of yellow crystals, m.p. 209°-210° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18](C)=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2C)[CH2:4][O:3]1.[OH:22][C:23]1C=CC(C#N)=C(OC)C=1.CC1(C)O[C@H](CO)CO1>>[CH3:21][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[C:17]([O:22][CH3:23])[CH:18]=2)[CH2:4][O:3]1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Reactant: COc1cc(O)ccc1C#N
Agent: CC1(C)OC[C@@H](CO)O1
Product: COc1cc(OC[C@@H]2COC(C)(C)O2)ccc1C(=N)NO

Procedure:
The title compound is obtained as a beige oil (2.46 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 4-hydroxy-2-methoxy-benzonitrile and L-α,β-isopropylidene glycerol. LC-MS: tR=0.62 min, [M+H]+=296.97.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[C:12]([CH3:30])[CH:11]=1)(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[CH3:30][C:12]1[CH:11]=[C:10]([S:7]([NH:6][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][N:32]=2)(=[O:8])=[O:9])[CH:15]=[CH:14][C:13]=1[O:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]1[C:24]1[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCCC[C@@H]3c3ccnn3C)c(C)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)ccc1O[C@H]1CCCCC[C@@H]1c1ccnn1C
Yield: 73.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-3-methyl-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (182 mg, 0.31 mmol) prepared in Example 57a, triethylsilane (0.15 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (100 mg, 74%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1.CS(O[CH2:27][C:28]1[CH:33]=[N:32][CH:31]=[CH:30][N:29]=1)(=O)=O.C(=O)([O-])O.[Na+]>CC(=O)C>[NH2:1][C:2]1[C:18]([Cl:19])=[CH:17][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:27][C:28]3[CH:33]=[N:32][CH:31]=[CH:30][N:29]=3)[CH2:11][C@H:10]2[O:15][CH3:16])=[O:7])=[C:4]([O:20][CH3:21])[CH:3]=1
Reactant: CS(=O)(=O)OCc1cnccn1
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCNC[C@H]1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(Cc2cnccn2)C[C@H]1OC

Procedure:
4.7 Parts of cis-4-amino-5-chloro-2-methoxy-N-(3-methoxy-4-piperidinyl)benzamide were dissolved in 160 parts of 2-propanone. Then there were added successively 3.2 parts of [(2-pyrazinyl)methyl] methanesulfonate (ester) and 1.7 parts of sodium hydrogen carbonate. The whole was stirred and refluxed for 18 hours while nitrogen gas was introduced. The precipitated product was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized twice from acetonitrile, yielding 1.16 parts of cis-4-amino-5-chloro-2-methoxy-N-[3-methoxy-1-(2-pyrazinylmethyl)-4-piperidinyl]-benzamide; mp. 203.5° C. (compound 144).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[C:9]([CH2:11][O:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)[N:10]=[C:6]2[C:5]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:4][CH:3]=1.[NH:29]1[C:33]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)=[N:32][N:31]=[N:30]1>>[NH:32]1[C:33]([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[N:7]4[CH:8]=[C:9]([CH2:11][O:12][C:13]5[CH:22]=[CH:21][C:20]6[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=6)[N:14]=5)[N:10]=[C:6]4[C:5]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:4][CH:3]=3)=[CH:36][CH:35]=2)=[N:29][N:30]=[N:31]1
Reactant: OB(O)c1ccc(-c2nnn[nH]2)cc1
Reactant: Brc1cnc(N2CCOCC2)c2nc(COc3ccc4ccccc4n3)cn12
Product: c1ccc2nc(OCc3cn4c(-c5ccc(-c6nnn[nH]6)cc5)cnc(N5CCOCC5)c4n3)ccc2c1

Procedure:
Compound 31b was subjected to Suzuki coupling reaction conditions with (4-(1H-tetrazol-5-yl)phenyl)boronic acid using the methods described in Example 1, Step G to obtain compound 31c. 1H-NMR (400 MHz, DMSO-d6) 8.26 (d, J=8.6 Hz, 1H), 8.21 (d, J=8.6 Hz, 2H), 8.17 (s, 1H), 7.88-7.93 (m, 3H), 7.80 (d, J=8.6 Hz, 1H), 7.65-7.71 (m, 1H), 7.55 (s, 1H), 7.45 (t, J=7.0 Hz, 1H), 7.06 (d, J=9.0 Hz, 1H), 5.58 (s, 2H), 4.21-4.28 (m, 4H), 3.75-3.80 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C27H23N9O2: 506.2 (M+H). Found 506.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:20]=1)[CH:18]=[O:19]>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:21])=[C:17]([CH:18]([C:9]2[S:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:11][CH:10]=2)[OH:19])[CH:20]=1
Reactant: c1ccc(-c2cccs2)nc1
Reactant: O=Cc1cc(Br)ccc1Cl
Product: OC(c1ccc(-c2ccccn2)s1)c1cc(Br)ccc1Cl

Procedure:
2-(2-Pyridyl)thiophene and 5-bromo-2-chlorobenzaldehyde obtained in Reference Example 16-(1) were treated in a manner similar to Reference Example 7-(1) to give 5-bromo-2-chlorophenyl-5-(2-pyridyl)-2-thienylmethanol as colorless powder. APCI-Mass m/Z 380/382 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH2:20][CH2:21][CH3:22])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:23][CH3:24].[Cl:25][C:26]1[N:27]=[C:28]([C:33](O)=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.CC(N(C)C)=O>[Cl:25][C:26]1[N:27]=[C:28]([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH2:20][CH2:21][CH3:22])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:23][CH3:24])=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OC)C2)oc1CCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)oc1CCC
Yield: 44.4 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-methoxypiperidin-1-yl)-5-propyl-1,3-oxazole-4-carboxylate obtained in Example (116c) (0.69 g, 2.0 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.2 g, 1 mmol), WSC hydrochloride (0.5 g, 2.5 mmol), HOBt (0.2 g, 1.5 mmol), DMA (3 mL) and dichloromethane (3 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/4, 2/3, 3/2, 4/1) to obtain 0.22 g of the title compound as a colorless solid (44%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17](I)[S:18][C:11]=12)[NH2:5].C(=O)([O-])[O-].[Cs+].[Cs+].[N:26]1([C:32]([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.COCCOC>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>[NH2:5][C:4]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[CH:16]=[C:17]([C:37]4[CH:36]=[CH:35][C:34]([C:32]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[O:33])=[CH:39][CH:38]=4)[S:18][C:11]=23)=[C:2]([F:1])[CH:3]=1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Temperature: 85 °C
Yield: 13.3 %

Procedure:
A sealable tube was charged with 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (Example 6, Step A, 0.200 g, 0.518 mmol), cesium carbonate (0.253 g, 0.777 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (0.183 g, 0.777 mmol) and DME (2 mL). The mixture was degassed under nitrogen for 10 minutes and Pd(PPh3)4 (0.0299 g, 0.0259 mmol) was added as a solid. The mixture was heated to 85° C. for 18 hours. The crude was diluted with water (300 mL), extracted with EtOAc/MeOH (4:1, 2×300 mL), dried organic over sodium sulfate, filtered and concentrated. The crude product was purified by preparative TLC (2.0 mm thickness) eluting with EtOAc/MeOH (9:1) to give product (31 mg, 12%) as a white solid. LRMS (APCI+) 450 m/z (M+1) detected.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[C:9]([F:18])[CH:10]=[CH:11][C:12]=2[O:14][CH2:15][CH2:16][CH3:17])[C:7](=[O:19])[C:6]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:5]1.[SH:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].[I-].[Na+].CN(C=O)C>C(OCC)(=O)C.O>[F:18][C:9]1[CH:10]=[CH:11][C:12]([O:14][CH2:15][CH2:16][CH3:17])=[C:13]2[C:8]=1[C:7](=[O:19])[C:6]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[CH:5][N:4]2[CH2:3][CH2:2][S:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCCl)c12
Reactant: COC(=O)CCS
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OC)cc3)cn(CCSCCC(=O)OC)c12
Temperature: 80 °C
Reaction time: 5 h
Yield: 75.2 %

Procedure:
1-(2-Chloroethyl)-5-fluoro-3-(4-methoxyphenyl)-8-propoxy-1H-quinolin-4-one (3.5 g, 8.98 mmol), methyl 3-mercaptopropionate (1.19 g, 9.88 mmol), and sodium iodide (1.48 g, 9.88 mmol) were added to DMF (30 ml) and stirred at 80° C. for 5 hours. Water and ethyl acetate were added to the reaction mixture, followed by separation. The thus-obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane). The purified product was concentrated to dryness under reduced pressure, giving a pale yellow powder of methyl 3-{2-[5-fluoro-3-(4-methoxyphenyl)-4-oxo-8-propoxy-4H-quinolin-1-yl]ethylsulfanyl}propionate (3.2 g, yield: 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:42])[C@@H:9]([C:33]([CH3:41])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:34])[CH2:10][NH:11][C@H:12]([C:17]([N:19]([CH3:32])[C@@H:20]([CH:29]([CH3:31])[CH3:30])/[CH:21]=[C:22](\[CH3:28])/[C:23]([O:25]CC)=[O:24])=[O:18])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCCC1.O.[OH-].[Li+]>CO>[C:1]([O:5][C:6]([N:8]([CH3:42])[C@@H:9]([C:33]([CH3:41])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH3:34])[CH2:10][NH:11][C@H:12]([C:17]([N:19]([CH3:32])[C@@H:20]([CH:29]([CH3:31])[CH3:30])/[CH:21]=[C:22](\[CH3:28])/[C:23]([OH:25])=[O:24])=[O:18])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)/C(C)=C/[C@H](C(C)C)N(C)C(=O)[C@@H](NC[C@@H](N(C)C(=O)OC(C)(C)C)C(C)(C)c1ccccc1)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C/C(=C\[C@H](C(C)C)N(C)C(=O)[C@@H](NC[C@@H](N(C)C(=O)OC(C)(C)C)C(C)(C)c1ccccc1)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Ethyl (2E,4S)-4-[(N-{(2S)-2-[(tert-butoxycarbonyl)(methyl)amino]-3-methyl-3-phenyl butyl}-3-methyl-L-valyl)(methyl)amino]-2,5-dimethyl-2-hexenoate (50 mg, 0.085 mmol, Reference Example 20) is dissolved in methanol (1 ml), tetrahydrofuran (1 ml). To this solution is added water (0.5 ml) and solid lithium hydroxide (4.1 mg). The resulting mixture is stirred at room temperature for 15 hours. The organic solvents are removed in vacuo, and the residual aqueous mixture is cooled with an ice water bath, and acidified to pH 5.5-6.0 with aqueous 1 N aqueous citric acid solution. The precipitate is collect by filtration, and the solid is washed with a cold water, and dried over high vacuum. Alternatively, the product can be purified by using preparative HPLC. (40 mg, 80%) MS [M+H] 588.2
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:20]2[CH2:21][CH2:22][CH:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:24][CH2:25]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(N3CCC(NC(=O)OC(C)(C)C)CC3)nc(-c3ccccc3O)nc2c1
Reaction time: 6 h
Yield: 101 %

Procedure:
To a suspension of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (2.0 g, 7.38 mmol) in CH2Cl2 (25 ml) at 0° C. under an N2 atmosphere was added dropwise a solution of tert-butyl piperidin-4-ylcarbamate (1.92 g, 9.6 mmol) in CH2Cl2 (10 ml) and triethylamine (2.0 ml, 14.76 mmol). The reaction was stirred for 6 hours, then it was quenched with water (25 ml), and the layers were separated. The aqueous phase was extracted twice with CH2Cl2 (10 ml), and the combined organic layers were dried over MgSO4, filtered, and concentrated to give tert-butyl 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-4-ylcarbamate as a yellow solid (3.24 g, 100%). LC/MS: m/z 435.3 (M+H)+ at 2.79 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).