Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([CH2:20][CH2:21][C:22]2[N:23]=[C:24]([S:27][C:28]([CH3:36])([CH3:35])[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])=[O:30])[S:25][CH:26]=2)[C:12]2[N:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][N:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[C:31]([C:29](=[O:30])[C:28]([S:27][C:24]1[S:25][CH:26]=[C:22]([CH2:21][CH2:20][N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=2)[C:12]2[N:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][N:17]=2)[N:23]=1)([CH3:35])[CH3:36])([CH3:32])([CH3:33])[CH3:34]
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)C(C)(C)C)n2)Cc2ccc(C(=O)OC)cc2)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)C(C)(C)C)n2)Cc2ccc(C(=O)O)cc2)nc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
4-{[(2-{2-[(2-tert-Butyl-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethyl)(5-ethylpyrimidin-2-yl)amino]methyl}benzoic acid methyl ester (2.2 g) synthesized in Example 437-1 was dissolved in methanol (50 mL) and tetrahydrofuran (50 mL), 1N aqueous sodium hydroxide solution (16 ml) was added, and the mixture was stirred at 60° C. for 4 hr. Aqueous 10% citric acid solution was added, and the mixture was extracted with chloroform. The insoluble material was filtered off, and the filtrate was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (2.0 g) as an oil.
Reaction SMILES: [CH:1]1(O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.C1(P([N:28]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.O>C1(C)C=CC=CC=1>[CH:1]1([NH2:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: OC1CC2CCCc3cccc1c32
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: NC1CC2CCCc3cccc1c32
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of 2a,3,4,5-tetrahydro-2H-acenaphthylen-1-ol and diphenylphosphoryl azide (9.31 g) in toluene (90 ml) was added DBU (diazabicycloundecene) (5.04 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with toluene. The combined organic layer was washed with water, dried over magnesium sulfate, and concentrated. The crude product was dissolved in a mixed solvent (77 ml) of THF/water (10:1), triphenylphosphine (9.61 g) was added, and the mixture was heated under reflux for 1 hr. After cooling to room temperature, the solvent was evaporated, 1N hydrochloric acid (100 ml) was added to the residue, and unnecessary substances were removed by extraction with ethyl acetate. The aqueous phase was alkalified with potassium carbonate, and extracted with chloroform. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated to give 1,2,2a,3,4,5-hexahydroacenaphthylen-1-ylamine.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5].N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[N-:27]=[N+:28]=[N-].[Na+]>C(O)(=O)C.Cl.O>[N:1]([C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[O:5])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: O
Product: [N-]=[N+]=Nc1ccc(Cl)cc1C(=O)c1ccccc1F
Temperature: 0 °C

Procedure:
10 G (0.04 mol) of 2-amino-5-chloro-2'-fluorobenzophenone are dissolved in a mixture of 40 ml of glacial acetic acid and 10 ml of concentrated hydrochloric acid and diazotised with 10 ml (0.04 mol) of 4 M sodium nitrite solution. The mixture is then diluted with 200 ml of ice-cold water and neutralised by addition of 16.3 g (0.12 mol) of crystalline sodium acetate. The turbid solution is clarified by filtration using active charcoal and a solution of 8.5 g (0.13 mol) of sodium azide in 100 ml of water is then added. The reaction product which has precipitated is filtered off and washed with water until neutral. After drying over potassium hydroxide/calcium chloride in a desiccator, 2-azido-5-chloro-2'-fluorobenzophenone of decomposition point 90°C is obtained.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C:6](=[O:8])[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][C@H:3]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:34][C:35]([CH3:37])=[CH2:36].[I-].[Na+]>O1CCCC1.CN1CCCC1=O.O>[CH3:1][C@H:2]1[N:7]([CH2:36][C:35]([CH3:37])=[CH2:34])[C:6](=[O:8])[C@@H:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][C@H:3]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=C(C)CBr
Reactant: C[C@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: C=C(C)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@@H](c2ccccc2)[C@H]1C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a pre-cooled 0° C. solution of tert-butyl [(3S,5S,6R)-6-methyl-2-oxo-5-phenylpiperidin-3-yl]carbamate (described in Intermediate 9, step C, 0.20 g, 0.657 mmol) in tetrahydrofuran:N-methyl-2-pyrrolidinone (2:1, 4.0 mL) was added lithium bis(trimethylsilyl)amide (0.735 mL, 0.735 mmol, 1 M in THF) and the mixture was stirred at 0° C. for 10 min. 3-Bromo-2-methylpropene (0.31 mL, 3.29 mmol) and sodium iodide (0.098 g, 0.66 mmol) were added and the resulting mixture was stirred at 0° C. for 2 h and then warmed to 23° C. and stirred for an additional 18 h. The mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic extracts were washed with water, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (20% ethyl acetate→80% ethyl acetate/hexane) afforded the title compound. MS: m/z=381.3 (M+Na).
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7](Cl)([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8]>C1C=CC=CC=1>[C:7]([NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:8]
Reactant: C=C(C)C(N)=O
Reactant: CCOC(=O)C(=O)Cl
Solvent: c1ccccc1
Product: C=C(C)C(=O)NC(=O)C(=O)OCC
Reaction time: 2.5 h
Yield: 42.9 %

Procedure:
Into a reaction vessel equipped with a stirrer, a cooler, an nitrogen gas introducing inlet and a dropping funnel, benzene (288.5 ml) and methacrylamide (49.1 g; 0.577 mol) were charged, and the resulting mixture was heated with reflux. Refluxing and bubbling with nitrogen gas were continued, during which ethoxalyl chloride (78.5 g; 0.577 mol) was dropwise added thereto in 2.5 hours. After the dropwise addition was completed, refluxing was continued for 5 hours. The benzene was distilled off, hydroquinone (0.01 g) was added thereto, and distillation under reduced pressure was carried out to give N-ethoxalylmethacrylamide (45.8 g). Yield, 43%. B.P., 110°-115° C./0.3 mmHg. Refractive index, 1.473.
Reaction SMILES: [CH3:1][C:2]1[N:3]([NH2:11])[C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.Cl.Cl[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[F:20]>CN1CCCC1=O>[F:20][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:14]=1[NH:11][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[C:2]1[CH3:1]
Reactant: Fc1cnccc1Cl
Reactant: Cc1cc2ccccc2n1N
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cc2ccccc2n1Nc1ccncc1F

Procedure:
The title compound was prepared from 2-methyl-1H-indol-1-amine and 4-chloro-3-fluoropyridine hydrochloride in 1-methyl-2-pyrrolidone for 1 hour in substantially the same manner as in Example 17, m.p. 157°-158° C.
Reaction SMILES: F[Sb-](F)(F)(F)(F)F.[CH2:8]([O:18][C:19]1[CH:24]=[CH:23][C:22]([I+:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].BrCCCCCCCCCC.C1(OCCCCCCCCCC)C=CC=CC=1.[S:60]([C:72]1[CH:78]=[CH:77][C:75]([CH3:76])=[CH:74][CH:73]=1)([O:63][IH](C1C=CC=CC=1)=O)(=[O:62])=[O:61]>ClCCl.C(O)(=O)C>[S:60]([C:72]1[CH:78]=[CH:77][C:75]([CH3:76])=[CH:74][CH:73]=1)([O-:63])(=[O:62])=[O:61].[CH2:8]([O:18][C:19]1[CH:24]=[CH:23][C:22]([I+:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Cc1ccc(S(=O)(=O)O[IH](=O)c2ccccc2)cc1
Agent: CCCCCCCCCCBr
Agent: CCCCCCCCCCOc1ccc([I+]c2ccccc2)cc1
Agent: CCCCCCCCCCOc1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
The procedure of Example 1 was repeated to prepare (4-decyloxyphenyl)phenyliodonium hexafluoroantimonate. 1-bromodecane was used and the yield of decyl phenyl ether was 98.9%. In accordance with Example 1, 196 grams (0.5 mol) of phenyliodoso tosylate, 117 grams (0.5 mol) of the decyl phenyl ether, 50 ml of acetic acid and 200 ml of dichloromethane were stirred at 40° C. for 2 hours. The reaction mixture was filtered and a solution triturated with ether. The crystallized product was isolated by suction filtration and washed with ether and then dried under vacuum. There was obtained, 205.3 grams (67.5% yield of (4-decyloxyphenyl)phenyliodonium tosylate.
Reaction SMILES: FC1C=C[C:5]([CH2:6][N:7]2[C@@H:11](C)[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19]([O:21]CC)=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:24])=[CH:4][CH:3]=1.C(N1CCN(C2SC(C(OCC)=O)=C(C)N=2)C1=O)CC=C>>[CH2:6]([N:7]1[CH2:11][CH2:10][N:9]([C:13]2[S:14][C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=2)[C:8]1=[O:24])[CH2:5][CH:4]=[CH2:3]
Reactant: CCOC(=O)c1sc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)nc1C
Agent: C=CCCN1CCN(c2nc(C)c(C(=O)OCC)s2)C1=O
Product: C=CCCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O

Procedure:
Following the procedure as described in Preparation 6, making variations as required to replace (S)-ethyl 2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with ethyl 2-(3-(but-3-enyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colourless solid (85%): mp 205-207° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.70 (s, 1H), 5.86-5.72 (m, 1H), 5.16-5.02 (m, 2H), 4.01-3.96 (m, 2H), 3.60-3.54 (m, 2H), 3.31 (t, J=7.1 Hz, 2H), 2.50 (s, 3H), 2.32-2.26 (m, 2H); MS (ES+) m/z 281.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:37])=[C:9]([N:11]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[S:12]([C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[N:10]=2)[CH:7]=1.[OH-].[Na+:39]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:37])=[C:9]([N:11]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:28][CH:27]=3)[S:12]([C:15]3[CH:16]=[CH:17][C:18]([C:19]([O-:21])=[O:20])=[CH:23][CH:24]=3)(=[O:14])=[O:13])[N:10]=2)[CH:7]=1.[Na+:39]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc(OC(F)(F)F)cc2)c2nc3ccc(Cl)cn3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(N(Cc2ccc(OC(F)(F)F)cc2)S(=O)(=O)c2ccc(C(=O)[O-])cc2)nc2ccc(Cl)cn12
Temperature: 60 °C
Yield: 100.8 %

Procedure:
To a solution of Compound 110 (0.067 g, 0.12 mmol) in methanol (1.2 mL) was added 3N NaOH (42.33 μL, 0.13 mmol) and the reaction mixture was heated at 60° C. for 13 h. The reaction mixture was cooled to room temperature, the solvent evaporated under reduced pressure to give Compound 113 as a white solid (0.068 g, 99%); 1H NMR (MeOD): δ 8.21-8.31 (m, 1H), 8.05-8.14 (m, J=8.31 Hz, 2H), 7.68-7.78 (m, J=8.31 Hz, 2H), 7.36-7.40 (m, J=9.54 Hz, 1H), 7.34 (d, J=8.56 Hz, 2H), 7.28 (dd, J=1.71, 9.54 Hz, 1H), 7.12 (d, J=8.07 Hz, 2H), 4.81 (s, 2H), 2.23 (s, 3H); MS m/z (M+H+) 540.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=O.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([N:14]([CH3:13])[C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:12]
Reactant: O=C(O)Cc1ccc(F)cc1Cl
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)Cc1ccc(F)cc1Cl)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (2-chloro-4-fluorophenyl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 429.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([CH3:21])([CH2:19][SH:20])[C:10]([NH:12][C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][SH:15])=[O:11].II>C(Cl)Cl>[CH3:8][C:9]1([CH3:21])[CH2:19][S:20][S:15][CH2:14][C@@H:13]([C:16]([OH:18])=[O:17])[NH:12][C:10]1=[O:11]
Reactant: CC(C)(CS)C(=O)N[C@@H](CS)C(=O)O
Agent: II
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CSSC[C@@H](C(=O)O)NC1=O
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of triethylamine (13.3 g) in methylene chloride (0.5 l), N-(2,2-dimethyl-3-mercaptopropionyl)-L-cysteine (15.6 g) dissolved in methylene chloride (0.5 l) and iodine (18.3 g) dissolved in methylene chloride (0.5 l) were added dropwise simultaneously under ice-salt cooling. After the addition, the reaction mixture was stirred for 1 hr at the same temperature. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Separated crystals were collected by filtration to give 8.5 g (55%) of the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=1)[CH3:2].C1COCC1>[Pd].CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1cccc(/C=C/C(=O)O)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cccc(CCC(=O)O)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of (2E)-3-{3-[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]phenyl}acrylic acid (10.40 g) in a mixed solvent(THF:EtOAc=150 mL:100 mL) was added 10% Palladium on activated carbon (50% wet, 1.6 g) at ambient temperature. The reaction mixture was stirred under hydrogen atmosphere at ambient temperature for 5 hours and was filtered through celite. The filtrate was evaporated in vacuo to afford 3-[3-(3-ethoxy-3-oxopropyl)phenyl]propanoic acid (10.57 g) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:13](=O)([O-:15])[O-:14].[K+].[K+].C(=O)=O>O>[Cl:1][C:2]1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(Cl)c2cccnc12
Agent: O=C=O
Agent: [K+]
Solvent: O
Product: O=C(O)c1cc(Cl)c2cccnc2c1O
Temperature: 170 °C
Yield: 23.8 %

Procedure:
5-Chloro-8-hydroxyquinoline (5.00 g) and potassium carbonate (11.54 g) are mixed together in a stainless steel bomb and heated to 170° C. under 800 p.s.i. CO2 for 7 days. The reaction is cooled and the resulting solid is dissolved in 800 mL water. The insoluble material is filtered and partitioned between 800 mL water and 400 mL EtOAc in a separatory funnel. The aqueous layer is washed with EtOAc (3×400 mL). The aqueous layer is then acidified to pH 4.5 with conc. HCl. The resulting solid is collected, washed with water and dried. The crude product is triturated with i-PrOH and dried to yield 1.481 g of the title product as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:7][CH:6]=1
Reactant: ClCc1ccccn1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(OCc2ccccn2)cc1
Temperature: 50 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
To a solution of 4-hydroxyphenylacetic acid methyl ester (8.4 g; 50 mmol) in DMF (100 ml)were added potassium carbonate (14.0g; 100 mmol) and 2-chloromethylpyridine hydrochloride (8.2 g; 50 mmol), and the resulting mixture was stirred at 50° C. for 24 h. The mixture was then poured into water, extracted with ethyl acetate, the acetate layer was washed with water, brine and concentrated in vacuo. The residue was purified on silica gel column (hexane-ethyl acetate 1:1) to provide 9.5 g of 4-(2-pyridylmethoxy)phenylacetic acid methyl ester.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]3[C:12](=[CH:13][C:4]=2[N:3]=1)[C:11]([CH3:15])([CH3:14])[C:10](=[O:16])[C:9]3([CH3:18])[CH3:17].C([O-])(C)(C)C.[K+].Cl[CH2:26][C:27]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=1.C(OCC)(=O)C.CCCCCC>C(O)(C)(C)C>[CH3:15][C:11]1([CH3:14])[C:12]2[C:8](=[CH:7][C:5]3[NH:6][C:2]([S:1][CH2:26][C:27]4[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]=4)=[N:3][C:4]=3[CH:13]=2)[C:9]([CH3:18])([CH3:17])[C:10]1=[O:16]
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Reactant: Cc1cccnc1CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(C)(C)O
Product: Cc1cccnc1CSc1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)C3(C)C
Reaction time: 18 h

Procedure:
A suspension of 5.2 g of 5.7-dihydro-2-mercapto-5,5,7,7 -tetramethylindeno[5,6-d]imidazol-6(1H )-one and 2.6 g of potassium t-butanolate is treated under argon with a solution of 3 g of 2-chloromethyl-3-methylpyridine in 30 ml of t-butanol and the mixture is stirred for 18 hours. After concentrating the mixture the residue is acidified with glacial acetic acid and dissolved in methylene chloride, whereupon 10% sodium bicarbonate solution is added thereto. the mixture is extracted and the methylene chloride solutlon is dried and concentrated. The thus-obtained crude product is chromatographed on silica gel and purified with methylene chloride/ethyl acetate (1:1), the medium pressure flash chromatography method being used and the pressure being produced with nitroqen gas. The 5,7-dihydro-5,5,7,7-tetramethyl-2-[[(3-methyl-2 -pyridyl)methyl]thio]indeno[5,6-d]imidazol-6(1H )-one which is obtained from ethyl acetate-n-hexane melts at 161°-164°.
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[N:4]=1.Cl.[C:18]([Cl:26])(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[ClH:26].[CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1)[C:3]1[N:4]=[C:5]([NH:9][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CN1CCC(N(C)c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: CN1CCC(N(C)c2cccc(NC(=O)c3ccncc3)n2)CC1
Yield: 86 %

Procedure:
Prepare according to procedure in Example 69 starting with N-methyl-N-(1-methyl-piperidin-4-yl)-pyridine-2,6-diamine (Preparation 34) (175 mg, 0.794 mmol), isonicotinoyl chloride hydrochloride (212 mg, 1.19 mmol), and pyridine (15 mL) to yield 247 mg (86%) of the title compound: mass spectrum (ion spray): m/z=326.1 (M+1); Analysis Calcd for C18H24N5OCl.0.5H2O: C, 58.29; H, 6.79; N, 18.88. Found: C, 58.49; H, 6.79; N, 19.22. mp 274–7° C.
Reaction SMILES: [C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32](O)=[O:33])[CH:31]=1)[NH:28][CH:27]=[CH:26]2.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:1]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:32]([C:30]2[CH:31]=[C:23]([Cl:22])[CH:24]=[C:25]3[C:29]=2[NH:28][CH:27]=[CH:26]3)=[O:33])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)cc2)C(=O)c2cc(Cl)cc3cc[nH]c23)cc1
Yield: 60.5 %

Procedure:
140 mg (0.5 mmol) of (4-tert-butyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]-amine, 97 mg (0.5 mmol) of 5-chloro-1H-indole-7-carboxylic acid and 115 mg (0.6 mmol) of EDC.HCl were stirred over night at rt in 10 ml DCM. The product was purified by column chromatography (20 silica gel; DCM) to yield 140 mg (64%) product as a colorless oil. MS (EI) 462.2 (27), 463.2 (14), 464.2 (12) (M)+.
Reaction SMILES: O1CCCC1.[CH3:6][S:7]([C:10]1[N:15]=[C:14]([CH3:16])[C:13]([C:17]([O:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:18])=[CH:12][N:11]=1)(=O)=O.[C:27]1(S)[CH:32]=[CH:31]C=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:16][C:14]1[C:13]([C:17]([O:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:18])=[CH:12][N:11]=[C:10]([S:7][C:6]2[CH:31]=[CH:32][CH:27]=[CH:28][CH:29]=2)[N:15]=1
Reactant: CC(CCOC(=O)c1cnc(S(C)(=O)=O)nc1C)=C(F)F
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(CCOC(=O)c1cnc(Sc2ccccc2)nc1C)=C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To 5 ml of tetrahydrofuran were dissolved 0.56 g (1.8 mmol) of 4,4-difluoro-3-methyl-3-butenyl 2-methanesulfonyl-4-methylpyrimidine-5-carboxylate and 0.21 g (1.9 mmol) of thiophenol, followed by the addition of 0.30 g (2.8 mmol) of sodium carbonate and stirring at room temperature for 1 hour. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:8) to obtain 0.54 g (yield: 88%) of 4,4-difluoro-3-methyl-3-butenyl 4-methyl-2-(phenylthio)pyrimidine-5-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].Cl.Cl[CH2:14][C:15]1[N:16]=[CH:17][S:18][CH:19]=1.C([O-])(=O)C.[K+]>C(O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:14][C:15]2[N:16]=[CH:17][S:18][CH:19]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: ClCc1cscn1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCCO
Product: O=S(=O)(Cc1cscn1)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 21 h

Procedure:
To 1-propanol (10 ml) were added sodium 4-chlorobenzenesulfinate (359 mg, 1.81 mmol), 4-(chloromethyl)thiazole hydrochloride (307 mg, 1.81 mmol) and potassium acetate (354 mg, 3.61 mmol) and the mixture was stirred at 70° C. for 21 hours. After cooling the reaction mixture to room temperature, the solvent was concentrated under reduced pressure. Ethyl acetate was added to the residue. The mixture was washed successively with water and brine and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate eluate (=3:2) was concentrated under reduced pressure. The resulting solid was washed with hexane-ether and then collected by filtration, whereby the title compound (154 mg, 31%) was obtained as a white powder.