Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31].[CH2:32]([NH2:35])[CH2:33][CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([S:29][CH3:30])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:35][CH2:32][CH2:33][CH3:34])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:31]
Reactant: CSc1nc(-c2cc(C(=O)O)ccc2C)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: CCCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CCCNC(=O)c1ccc(C)c(-c2nc(SC)nc3c2CNC(=O)N3c2c(F)cccc2F)c1
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To the solution of 3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methylbenzoic acid (1.2 g, 2.71 mmol) in CH2Cl2 (60 mL) was added propylamine (0.7 mL, 8.51 mmol), HATU (1.08 g, 2.84 mmol) and diisopropyl ethyl amine (1.2 mL, 6.9 mmol). The reaction mixture was stirred overnight. The reaction mixture was diluted with CH2Cl2 (50 mL) and water (50 mL) and shaken. The layers were separated and the organic layer was washed with brine (75 mL), dried over Na2SO4, filtered and concentrated. CombiFlash chromatography (load column with DCM, mobile phase EtOAc/Hexane) then provided the title compound as a white solid 1.10 g (84%). LC-MS m/z 484 (M+H)+.
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:25][CH2:24]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[CH2:29]([N:26]1[CH2:25][CH2:24][CH:23]([O:22][C:17]2[CH:16]=[CH:15][C:14]([NH:13][C:6]([C:5]3[O:1][C:2]4[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=4[CH:4]=3)=[O:8])=[CH:21][C:18]=2[C:19]#[N:20])[CH2:28][CH2:27]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: N#Cc1cc(N)ccc1OC1CCN(Cc2ccccc2)CC1
Product: N#Cc1cc(NC(=O)c2cc3ccccc3o2)ccc1OC1CCN(Cc2ccccc2)CC1
Yield: 40.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using benzo[b]furan-2-carboxylic acid (1.2 g) and 5-amino-2-(1-benzylpiperidin-4-yloxy)benzonitrile (2.2 g), the title compound (1.3 g) was obtained. melting point: 175° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[CH3:26].S([O-])(O)=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[OH:13][CH2:14][CH2:15][O:16][C:17]1[C:24]([CH3:25])=[CH:23][C:20]([C:21]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([O:11][CH3:12])[CH:7]=3)[N:1]=2)=[CH:19][C:18]=1[CH3:26]
Reactant: COc1ccc(N)c(C(N)=O)c1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc2nc(-c3cc(C)c(OCCO)c(C)c3)[nH]c(=O)c2c1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 2-amino-5-methoxy-benzamide (2.62 g, 15.80 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (3.23 g, 16.60 mmol) in N,N-dimethyl acetamide (20 mL), were added sodium hydrogen sulfite (58.5 wt %, 3.44 g, 19.00 mmol) and p-toluenesulfonic acid monohydrate (0.60 g, 3.20 mmol) and the reaction mixture was stirred at 115° C. for 16 hours. Solvent was evaporated in vacuo, water (50 mL) was added, and the separated solid was filtered. The solid was triturated with ether to give 2-[4-(2-hydroxy-ethoxy)-3,5-dimethyl-phenyl]-6-methoxy-3H-quinazolin-4-one as a white solid. Yield: 3.56 g (66%).
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:16])=[C:6]2[C:11](=[C:12]([Cl:14])[CH:13]=1)[S:10][CH2:9][CH2:8][C:7]2=[O:15])([OH:3])=[O:2].S(Cl)(Cl)=O.[CH2:21]([N:23]1[C:27](O)=[CH:26][CH:25]=[N:24]1)[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:12]1[CH:13]=[C:4]([C:1]([O:3][C:27]2[N:23]([CH2:21][CH3:22])[N:24]=[CH:25][CH:26]=2)=[O:2])[C:5]([CH3:16])=[C:6]2[C:11]=1[S:10][CH2:9][CH2:8][C:7]2=[O:15]
Reactant: CCn1nccc1O
Reactant: Cc1c(C(=O)O)cc(Cl)c2c1C(=O)CCS2
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CCn1nccc1OC(=O)c1cc(Cl)c2c(c1C)C(=O)CCS2
Temperature: 40 °C
Yield: 83.7 %

Procedure:
A mixture containing 2.0 g (7.8 mmol) of 6-carboxy-8-chloro-5-methylthiochroman-4-one and 2.8 g (3.0 eq., 24 mmol) of thionyl chloride was stirred under heat at 40° C. for 2 hours. After the completion of the reaction, excess thionyl chloride was removed under reduced pressure. Then, the resultant acid chloride was dissolved in 10 ml of methylene chloride, and 0.96 g (1.1 eq., 8.6 mmol) of 1-ethyl-5-hydroxypyrazole and 0.95 ml (9.41 mmol) of triethylamine were added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with methylene chloride, washed with diluted hydrochloric acid and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, and the solvent was distilled off to give 2.29 g (yield 84%) of 8-chloro-6-(1-ethylpyrazol-5-yl)oxycarbonyl-5-methylthiochroman-4-one.
Reaction SMILES: [NH2:1][C@@H:2]1[C:9](=[O:10])[N:8]2[C@@H:3]1[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]1[C:21]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([OH:29])[CH:23]=3)=[CH:20][N:19]=[CH:18][N:17]=1)=[C:7]2[C:11]([OH:13])=[O:12].[OH-:30].[K+].[C:32](#[N:34])[CH3:33]>O>[NH2:8][C:3]1[S:4][CH:33]=[C:32]([C:9](=[O:10])[C:2]([NH:1][C@@H:2]2[C:9](=[O:10])[N:8]3[C@@H:3]2[S:4][CH2:5][C:6]([CH2:14][S:15][C:16]2[C:21]([C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([OH:29])[CH:23]=4)=[CH:20][N:19]=[CH:18][N:17]=2)=[C:7]3[C:11]([OH:13])=[O:12])=[O:30])[N:34]=1
Reactant: [OH-]
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3ncncc3-c3ccc(O)c(O)c3)CS[C@H]12
Reactant: CC#N
Agent: [K+]
Solvent: O
Product: Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4ncncc4-c4ccc(O)c(O)c4)CS[C@H]23)cs1

Procedure:
(6R,7R)-7-Amino-3-[[[5-(3,4-dihydroxyphenyl)-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (215 mg) (0.5 mmol) are suspended in 10 ml of water and 5 ml of acetonitrile. At 0° C. there are added dropwise thereto while stirring 7.5 ml of 0.1N aqueous potassium hydroxide solution and after 30 minutes there are added portionwise thereto within one hour 210 mg (0.65 mmol) of 2-amino-4-thiazoleglyoxylic acid S-(2-benzothiazolyl) ester. After a further 5 hours 0.1N aqueous potassium hydroxide solution is added thereto until pH 7.8 has been reached. The suspension obtained is filtered, the filtrate is washed with ethyl acetate and acidified (pH 5) with dilute aqueous hydrochloric acid. The precipitated product is filtered off under suction and washed with water and diethyl ether. After drying in a high vacuum there are obtained 200 mg of (6R,7R)-7-(2-amino-4-thiazoleglyoxylamido)-3-[[[5-(3,4-dihydroxyphenyl)-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [CH:1]1([CH2:7][Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CON(C)[C:13]([C:15]1[N:16]=[C:17]([CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)[S:18][CH:19]=1)=[O:14].[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[CH:1]1([CH2:7][C:13]([C:15]2[N:16]=[C:17]([CH:20]3[CH2:21][CH2:22][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:24][CH2:25]3)[S:18][CH:19]=2)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CON(C)C(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: Cl[Mg]CC1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)CC3CCCCC3)cs2)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon and at −78° C., cyclohexylmethylmagnesium chloride 0.5M in diethyl ether (2.7 ml) was added dropwise to a solution of tert-butyl 4-{4-[methoxy(methyl)carbamoyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (480 mg) in tetrahydrofuran (5 ml). The reaction mixture was stirred at −78° C. for one hour. The reaction mixture was then stirred at room temperature for one hour. Saturated ammonium chloride solution was then added to the reaction mixture, and the aqueous phase was separated off. After extraction of the aqueous phase with ethyl acetate, the combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. This gave tert-butyl 4-[4-(cyclohexylacetyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (335 mg).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:15])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[BH4-].[Na+].C(OCC)(=O)C.Cl>O1CCCC1.CO>[OH:15][CH:3]([CH2:2][Br:1])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C(CBr)CC(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CC(O)CBr)OCc1ccccc1
Temperature: 0 °C
Yield: 86.2 %

Procedure:
The product of step 1 (500 mg, 1.84 mmoles) was dissolved in a mixture of tetrahydrofuran (9 mL) and methanol (1 mL), the solution was cooled in an ice-bath, and sodium borohydride (72 mg, 1.90 mmoles) was added in one portion. Stirring was continued in the ice-bath for 15 min, and ethyl acetate (50 mL) and M hydrochloric acid (1.5 mL) were added. The aqueous layer was separated, extracted with ethyl acetate (20 mL), and the combined organic layers were washed with saturated sodium bicarbonate (40 mL), dried over anhydrous magnesium sulfate and evaporated to give benzyl 3-hydroxy-4-bromobutanoate (433 mg, 86%). 1HMR (CDCl3, δ): 7.36 (5H, s), 5.17 (2H, s), 4.26 (1H, m), 3.50 (1H, dd, 5.0, 10.5 Hz), 3.47 (1H, dd, 5.6, 10.5 Hz), 3.06 (1H, d, 541 Hz), 2.72 (1H, dd, 5.0, 16.6 Hz), 2.69 (1H, dd, 7.3, 16.6 Hz). IR (neat): 3443, 3064, 1731, 1624 cm−1. Mass spectum (CI,m/z): 273, 275 (M+1, M+3). Calcd. for C11H13BrO3.0.5H2O: C 53.75; H 5.88. Found: C 53.65; H 5.60.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:31])[CH:12]2[CH2:30][N:16]3[C:17]4[C:22]([C:23]([C:24](=O)[C:25]([O:27][CH3:28])=[O:26])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+].CC(O)=O>CO.C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:31])[CH:12]2[CH2:30][N:16]3[C:17]4[C:22]([C:23]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)C(=O)c1c2n(c3ccccc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1c2n(c3ccccc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
To a solution of 0.8 g of the product of Step 10 in 100 mL of MeOH and 20 mL of THF was added 0.3 g of NaBH4. After stirring for 1 h at room temperature, 2 mL of AcOH was added and the reaction mixture was concentrated and the residue was portioned between 50 mL of brine and 150 mL of EtOAc. The organic layer was separated and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was dissolved in 5 mL of CH2Cl2, and treated with 5 mL of Et3SiH and 3 mL of TFA. After stirring for 30 min at room temperature, the reaction mixture was concentrated and the residue was purified by Combiflash eluted with a gradient up to 70% EtOAc/hexane to give 0.3 g of the title compound. 1H NMR (500 MHz, acetone-d6) δ 8.10 (m, 2H), 7.45-7.52 (m, 3H), 7.27 (d, 1H), 7.10 (m, 1H), 7.01 (m, 1H), 4.53 (m, 1H), 4.18 (m, 1H), 3.88 (t, 1H), 3.60 (s, 3H), 3.13 (m, 1H), 2.97 (s, 3H), 2.86 (m, 1H), 1.90-2.00 (m, 1H), 1.70 (m, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]2[S:15][C:16]([C:19]3[C:23]([CH3:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[O:21][N:20]=3)=[CH:17][CH:18]=2)=[O:13])[CH2:7]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(#N)C>[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:2][C:3]([NH:5][C@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]3[S:15][C:16]([C:19]4[C:23]([CH3:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[O:21][N:20]=4)=[CH:17][CH:18]=3)=[O:13])[CH2:7]2)=[O:4])[CH2:38][CH2:37]1
Reactant: CN1CCNCC1
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@H](NC(=O)CCl)C3)s2)noc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](NC(=O)CN4CCN(C)CC4)C3)s2)noc1C(F)(F)F
Reaction time: 72 h
Yield: 85.1 %

Procedure:
2-Chloro-N-{(S)-1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-acetamide (35 mg, 0.08 mmol, as prepared in Example 56) was dissolved in acetonitrile (3 mL) containing anhydrous K2CO3, treated with N-methylpiperazine (18 μL, 0.16 mmol), and stirred for 3 days. The reaction mixture was then evaporated and treated with water to provide a homogeneous solution which was extracted with EtOAc (2×4 mL), dried over MgSO4, filtered, and evaporated to afford product as an foam (34 mg, 85%). 1H NMR (CDCl3) 1.60-1.76 (m, 3 H), 1.88-1.98 (m, 1 H), 2.22 (s, 3 H), 2.29 (d, J=1.3, 3 H), 2.32-2.52 (m, 8 H), 2.92 (s, 2 H), 3.52 (br s, 1 H), 3.48 (br s, 2 H), 3.72-4.46 (m, 3 H), 7.32-7.44 (br m, 3 H). 19F NMR −63.1. LC/MS 4.59 min, [M+1]+ 500.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:18][CH2:19][CH2:20][CH2:21][SH:22].CN(C)C=O>O>[CH2:21]([S:22][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[CH2:20][CH2:19][CH3:18]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCSc1ccc(C=O)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-nitrobenzaldehyde (10.0 g), potassium carbonate (10.0 g), n-butylthiol (12.5 ml) and dimethylformamide (12.5 ml) was heated at 100° C. for a period of 16 hours, cooled and poured into water (250 ml). The aqueous mixture was extracted with diethyl ether (4×250 ml) and the combined organic phases were washed with aqueous 2% sodium hydroxide solution (5×100 ml) and finally with water. The organic phase was dried over anhydrous sodium sulfate and the solvent was removed by distillation to give 4-(n-butylthio)benzaldehyde (10.8 g) as a reddish coloured oil. The product was characterized by proton nuclear magnetic resonance spectroscopy. Pmr (CDCl3 ; δ in ppm): 0.97 (3H, t); 1.60 (4H, m); 3.03 (2H, t); 7.32 (2H, d); 7.77 (2H, d); 9.89 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[OH:11][C:12]1[CH:19]=CC=C[C:13]=1C#N>>[NH2:8][C:7]1[C:6]2[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:10][C:13]=1[C:12](=[O:11])[CH3:19]
Reactant: N#Cc1cc(Cl)ccc1O
Reactant: N#Cc1ccccc1O
Product: CC(=O)c1oc2ccc(Cl)cc2c1N

Procedure:
The procedure was similar to step S1A, while the starting material was 5-chloro-2-hydroxy-benzonitrile (5A) in stead of 2-hydroxy-benzonitrile.
Reaction SMILES: C([N:8]([C@H:16]([C@@H:24]([OH:42])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)CC1C=CC=CC=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.O.[Pd]>[NH2:8][C@H:16]([C@@H:24]([OH:42])[CH2:25][C@@H:26]([NH:34][C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of the product from Example 68C (150 gm, 250 mmol) dissolved in absolute EtOH (2 liters) was treated with 10% Pd/C (18 gm, pre-wetted), followed by addition of ammonium formate (78.6 gms, 1.25 moles) dissolved in H2O (200 ml). The resulting mixture was stirred at reflux for 2.5 hours. The mixture was cooled to room temperature and filtered through a pad of infusorial earth (20 g). The filter cake was washed 3 times with EtOH (70 ml each). The filtrate was concentrated in vacuo. The residue was dissolved into EtOAc (1L) and washed (1N NaOH, followed by H2O, followed by brine), dried (Na2SO4), filtered and concentrated in vacuo. to a constant weight of 95 gms. (99.2% of theory). The light yellow solid (91.5 gm of the 95 gm) was slurried in hot heptane (600 ml) (steam bath) and treated with isopropanol (45 ml), and swirled to effect solution. The solution was allowed to slowly cool to room temperature over 3 hours, kept at room temperature for 2 more hours and filtered. The filter cake was washed 10 times with 9/1 hexane-isopropanol (30 ml each) to give the desired product as an off-white finely crystalline solid which was dried to constant weight of 57.5 gm.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.[C:13]1([NH:19]N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.O>C(O)(=O)C>[CH3:1][C:2]1([CH3:12])[C:3]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:19][C:4]=2[C:5]2[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: NNc1ccccc1
Reactant: CC1(C)CC(=O)c2ccccc21
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)c2ccccc2-c2[nH]c3ccccc3c21
Reaction time: 2 h

Procedure:
A solution of 3,3-dimethyl-1-indanone (20,0 q, 0,125 mol) prepared by the method described by R. Knorr et al., Leibig's Annalen, 1207 (1980) and phenylhydrazine (12.3 cm3, 0.125 mol) in glacial acetic acid (200 cm3), was heated to reflux. Concentrated hydrochloric acid (10 cm3) was added via the condenser, and boiling continued for a further 2 hours. The solution was allowed to cool, and then poured into water (500 cm3). The water was extracted with diethylether three times, the combined extracts were washed with brine and water, and dried (MgSO4). The solvent was removed, and petrol (60°-80° C.) added to the residue. The suspension was heated until boiling, The solid product was filtered off and the mother liquor concentrated. On cooling, more solid was obtained, and additional product separated out as the mother liquor was concentrated further. The solids were combined and crystallised from petrol to give the title compound. Yield: 10,2 g (35%). M.p. 160 ° C. 1H NMR: (CDCl3) δ: 1.60 (6H, s,), 7.1-7.7 (8H, m,), 8.16 (1H, s,).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7].C([Li])(C)(C)C.CON(C)[C:23](=[O:40])[CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][C:32]2[C:33]([O:38][CH3:39])=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:27][CH2:26]1.O>O1CCCC1.C(OCC)C>[CH3:39][O:38][C:33]1[C:32]([CH2:31][N:28]2[CH2:27][CH2:26][CH:25]([CH2:24][C:23](=[O:40])[C:2]3[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=3[NH:4][C:5](=[O:10])[C:6]([F:9])([F:8])[F:7])[CH2:30][CH2:29]2)=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: COc1ncccc1CN1CCC(CC(=O)N(C)OC)CC1
Reactant: O=C(Nc1ccccc1Br)C(F)(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COc1ncccc1CN1CCC(CC(=O)c2ccccc2NC(=O)C(F)(F)F)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
482 mg of 2-bromo-N-(trifluoroacetyl)aniline was dissolved in a mixed solvent of 1.8 ml of tetrahydrofuran and 1.8 ml of diethyl ether, and a 1.14M methyllithium diethyl ether solution was added dropwise thereinto at 0° C. After stirring for 10 minutes, the mixture was slowly charged by a cannular to a solution of 2.4 ml of 1.51 M tert-butyllithium and 4 ml of a diethyl ether solution cooled at −78° C. The mixture was stirred for 1 hour. Then, a mixed solution of 500 mg of N1-methoxy,N1-ethyl-2-[1-(2-methoxy-3-pyridyl)methyl]-4-piperidyl]acetamide obtained in Example 55 and 2 ml of tetrahydrofuran was added dropwise thereinto, and the mixture was further stirred for 20 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (ethyl acetate), to give 150 mg of the above compound as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[CH2:16]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[S:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[ClH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:24][C:23](=[N:22][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[N:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: CCCCCCNC(=S)NCCCCCC
Reactant: NS(=O)(=O)c1cc(C(=O)CCl)ccc1Cl
Product: CCCCCCN=C1SCC(O)(c2ccc(Cl)c(S(N)(=O)=O)c2)N1CCCCCC
Product: Cl

Procedure:
5.2 g of 2,4'-dichloro-3'-sulfamoylacetophenone and 4.8 g of 1,3-di-n-hexyl-thiourea were reacted according to the prescription given in Example 12, the end product was precipitated with diethyl ether and the remaining oil was treated with cyclohexane. Colorless, amorphous solid body: decomposition beginning at 75° C., γ C=N 1615 cm-1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8]CC)=O)=[CH:2]1.[Br-].S(=O)(=O)(O)O.[CH2:17](OCC)[CH3:18]>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2([OH:8])[CH2:18][CH2:17]2)=[CH:2]1
Reactant: CCOC(=O)c1ccoc1
Reactant: CCOCC
Agent: O=S(=O)(O)O
Agent: [Br-]
Product: OC1(c2ccoc2)CC1
Reaction time: 1.5 h

Procedure:
2.50 g (17.84 mmol) ethyl furan-3-carboxylate and 0.53 ml (1.82 mmol) titanium tetra-isopropyloxide are placed in 56 ml diethyl ether, 12.61 ml (37.82 mmol) ethylmagnesum bromide (Grignard reagent in tetrahydrofuran) in 28 ml diethyl ether are added dropwise within 1 hour, while the temperature should not rise above 20° C. The reaction mixture is stirred for 1.5 hours, then hydrolysed with 180 ml 10% sulphuric acid. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried and evaporated to dryness. The residue is purified by chromatography. Yield: 1.05 g (47% of theoretical)
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH3:13][NH:14][CH2:15][C:16]1[S:24][C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=1.[NH2:25][C:26]1[N:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([OH:36])=O)=[CH:28][CH:27]=1.C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C>CN(C=O)C.O>[NH2:25][C:26]1[N:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([N:14]([CH3:13])[CH2:15][C:16]2[S:24][C:23]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[CH:17]=2)=[O:36])=[CH:28][CH:27]=1
Reactant: CNCc1cc2cnccc2s1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1cc2cnccc2s1)C(=O)/C=C/c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
EDC hydrochloride (118 mg, 0.62 mmol) was added to a solution of methyl-thieno[3,2-c]pyridine-2-ylmethyl-amine (100 mg, 0.56 mmol), (E)-3-(6-amino-pyridin-3-yl)acrylic acid (101 mg, 0.62 mmol), HOBt H2O (83 mg, 0.62 mmol) and triethylamine (235 μL, 1.68 mmol) in anhydrous DMF (5 mL). The mixture was stirred at room temperature overnight then diluted with H2O (10 mL) and extracted with CH2Cl2 (3×50 mL). The combined organic fractions were dried over MgSO4, filtered and evaporated to give a yellow residue which was subjected to flash chromatography on silica gel (10% MeOH: CH2Cl2) to yield the title compound (61.0%). 1H-NMR (300 MHz, CDCl3) δ 9.04 (s, 1H), 8.45 (d, J=5.3 Hz, 1H), 8.26 (s, 1H), 7.76-7.67 (m, 3H), 7.32 (d, J=15.0 Hz, 1H), 6.76 (d, J=15.2 Hz, 1H), 6.53 (d, J=8.3 Hz, 1H), 4.95 (s, 2H), 4.76 (br s, 2H), 3.22 (s, 3H); MS (ES) m/e 325.1 (M+H)+.