Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]#[N:9])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([S:26](Cl)(=[O:28])=[O:27])[S:23][C:22]=2[CH:30]=1>C(Cl)Cl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]2[CH:25]=[C:24]([S:26]([N:4]3[CH2:5][CH2:6][N:1]([CH2:7][C:8]#[N:9])[CH2:2][CH2:3]3)(=[O:28])=[O:27])[S:23][C:22]=2[CH:30]=1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: N#CCN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#CCN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of piperazin-1-yl-acetonitrile (0.32 g, 2.3 mmol) and Et3N (350 mg, 3.4 mmol) is added 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (615 mg, 2.3 mmol) at 0° C. The reaction is warmed to room temperature and stirred 4 h. The reaction is diluted with CH2Cl2, washed with 1 N HCl, NaHCO3 and dried over MgSO4. The solution is concentrated and the residue is triturated with PE, triturated with Et2O, and pumped to yield [4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-1-yl]-acetonitrile which can be used without further purification. 1H NMR (300 MHz, CDCl3) δ7.89-7.84 (m, 3H), 7.48 (dd, 1H), 4.36 (s, 2H), 3.92 (s, 2H), 3.64-3.61 (m, 2H), 3.57-3.54 (m, 2H); MS (Ion Spray) 444 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:70][N:71]1[CH2:76][CH2:75][CH:74]([NH2:77])[CH2:73][CH2:72]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:38])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([CH3:28])([C:25](=[O:26])[NH:77][CH:74]4[CH2:75][CH2:76][N:71]([CH3:70])[CH2:72][CH2:73]4)[CH3:27])[CH2:14][C:13](=[O:29])[NH:12][CH:11]3[C:30]3[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=3[CH3:37])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)CO)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CN1CCC(N)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Cl)ccc2OC(C)(C)C(=O)NC2CCN(C)CC2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-6-chloro-4′-[5-chloro-2-(2-hydroxy-1,1-dimethyl-ethoxy)-phenyl]-2′-[5-fluoro-2-methylphenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (35 mg, 0.06 mmol), EDCl (18 mg, 0.094 mmol), HOBt (14 mg, 0.094 mmol) and DIPEA (23 mg, 0.2 mmol) in THF (1 mL) was added 1-methyl-piperidin-4-ylamine (21 mg, 0.18 mmol). The mixture was stirred at room temperature overnight, purified by prep-HPLC to give the title compound as a white solid (7 mg).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]2[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C([N-]C(C)C)(C)C.[Li+].[CH2:34]=[O:35]>O1CCCC1>[OH:1][C:2]1[C:3]([C:11]2([CH2:34][OH:35])[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: C=O
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ncccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ncccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 112 %

Procedure:
To a solution of 3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (1.60 g, 4.70 mmol) in anhydrous tetrahydrofuran (30.0 mL) was added a solution of pre-prepared lithium diisopropylamide (10.3 mmol) in anhydrous tetrahydrofuran (30.0 mL) at −78° C. The reaction mixture was stirred at −78° C. for 0.5 h followed by the addiotion of para-formaldehyde (0.85 g, 28.2 mmol) in one portion. The reaction was stirred at −78° C. for 2 h and quenched with saturated ammonium chloride (20.0 mL). After the organic solvent was removed under reduced pressure, the residue was diluted with ethyl acetate (50.0 mL). The organic layer was washed with brine (30.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to give the title compound (1.95 g, 100%): 1H NMR (300 MHz, CDCl3) δ 8.22 (dd, 1H), 7.22-7.12 (m, 2H), 6.51 (s, 1H), 6.06 (s, 1H), 5.83 (d, 2H), 4.89 (s, 2H), 3.83-3.61 (m, 2H), 1.75-1.61 (m, 2H), 1.39-1.29 (m, 4H), 0.89 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])=[C:16]([O:33][CH3:34])[CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:36]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH3:36][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)(=[O:25])=[O:24])=[C:16]([O:33][CH3:34])[CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COc1cc(C(=O)Nc2ccc(C(=O)O)c(Cl)c2)cc2c1CCN2S(=O)(=O)c1cccc(F)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: COC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cccc(F)c2)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(3-fluoro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 505.29 (M+H+.), was prepared in analogy to example 21, steps 1 to 6. Step 5 was performed using 3-fluoro-benzenesulfonyl chloride, yielding 2-chloro-4-{[1-(3-fluoro-benzenesulfonyl)-4-methoxy-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:30]([C:31]5[N:32]=[CH:33][N:34]([CH3:36])[CH:35]=5)[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.Cl>C1COCC1>[CH3:36][N:34]1[CH:35]=[C:31]([C:30]2[N:17]3[C:18]([C:19]4[CH:20]=[C:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:12]([C:9]5[CH:10]=[CH:11][C:6]([CH:2]=[O:1])=[CH:7][CH:8]=5)=[N:13][C:14]=4[CH:15]=[CH:16]3)=[N:28][N:29]=2)[N:32]=[CH:33]1
Reactant: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C6OCCO6)cc5)nc4ccn23)c1
Agent: Cl
Solvent: C1CCOC1
Product: Cn1cnc(-c2nnc3c4cc(-c5ccccc5)c(-c5ccc(C=O)cc5)nc4ccn23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 13-1 (2 g, 4.2 mMol) in THF (32 mL) was added 1N HCl (32 mL). A suspension developed as the reaction stirred at room temperature for 1 hour. The reaction was then quenched with 100 mL of a saturated NaHCO3 solution. The suspension was filtered and washed with water. The collected solid was dried azeotropically with toluene three times to yield 13-2 as a tan solid. Mass (M+1) calculated: 431.1615 observed: 431.1616
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1ccc(F)cc1Br
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1ccc(F)cc1Br
Reaction time: 2 h

Procedure:
A solution of 10.9 g. (0.05 mole) of 2-bromo-4-fluorobenzamide in 50 ml. of dry pyridine is stirred and cooled in an ice-bath while 11.2 g. (0.0525 mole) of trifluoroacetic anhydride is added dropwise. After 2 hours at room temperature, the bulk of the solvent is evaporated under reduced pressure and the residue is dissolved in ether. Evaporation of the washed and dried ethereal extract under reduced pressure leaves the product as the residual solid. Sublimation at 55°C. and 0.05 mm. yields white crystals, m.p. 75°-76.5°C. A sample from a previous experiment was resublimed for analysis, m.p. 77°-78°C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:22]=[C:23]=[O:24])[CH2:19][CH2:20][CH3:21]>>[CH2:18]([NH:22][C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CCCCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 95.8 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 11.1 mg (0.131 mMol) n-butyl isocyanate, 20.6 mg (96%) of the title compound were recovered.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21](NCCN(C)C)=[CH:20][C:19]2=[O:29])=[CH:4][CH:3]=1.ClC1C=CC(C2N=[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][N:40]3C=2CN2CC(OC)=CC2=O)=CC=1.N1CCCCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]3[C:16]=2[CH2:17][N:18]2[CH2:22][C:21]([N:40]3[CH2:41][CH2:42][CH2:43][CH2:44][CH2:39]3)=[CH:20][C:19]2=[O:29])=[CH:6][CH:7]=1
Reactant: CN(C)CCNC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Reactant: COC1=CC(=O)N(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)C1
Solvent: C1CCNCC1
Product: O=C1C=C(N2CCCCC2)CN1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to the experimental for compound 237 from 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-4-methoxy-1H-pyrrol-2(5H)-one and piperidine. (62 mg, 54%) m/e+=407 (M+H+). 1H-NMR (400 MHz, CDCl3, δ): 8.49 (d, 1H, D, J=7.0 Hz), 7.73 (d, 2H, D, J=8.4 Hz), 7.62 (d, 1H, D, J=9.2 Hz), 7.47 (d, 2H, D, J=8.4 Hz), 7.25 (t, 1H, D, J=7.3 Hz), 6.85 (t, 1H, D, J=7.3 Hz), 5.09 (s, 2H), 4.69 (s, 1H), 3.56 (s, 2H), 2.99 (m, 4H), 1.63 (m, 2H), 1.53 (m, 4H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19].[CH2:20]([NH2:22])[CH3:21]>CO>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH2:11][N:6]1[CH:5]=[N:4][C:3]2[C:7]1=[N:8][CH:9]=[N:10][C:2]=2[NH:22][CH2:20][CH3:21]
Reactant: Clc1cccc(Cl)c1Cn1cnc2c(Cl)ncnc21
Reactant: CCN
Solvent: CO
Product: CCNc1ncnc2c1ncn2Cc1c(Cl)cccc1Cl
Yield: 79 %

Procedure:
6-Chloro-9-(2,6-dichlorobenzyl)purine (314 mg), 322 mg of 70% aqueous ethylamine and 25 ml of methanol were treated in the same manner as Example 2, whereby 255 mg (yield 79%) of 9-(2,6-dichlorobenzyl)-6-ethylaminopurine was obtained as needles melting at 222°-223° C.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6](CC2C=CC(OC)=CC=2)[C:5]([C:18](=[O:32])[CH:19]([C:25]2(O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:4]([CH3:33])[CH:3]=1.FC(F)(F)C(O)=O>ClCCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:5](=[C:4]([CH3:33])[CH:3]=1)[C:18](=[O:32])[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]12[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)C(C(=O)c1c(C)cc(Br)c(=O)n1Cc1ccc(OC)cc1)C1(O)CCCCC1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1C(=O)c2c(C)cc(Br)c(=O)n2C12CCCCC2

Procedure:
To a solution of ethyl 3-(5-bromo-1-(4-methoxybenzyl)-3-methyl-6-oxo-1,6-dihydropyridin-2-yl)-2-(1-hydroxycyclohexyl)-3-oxopropanoate (5, 1.0 mmol, 1.0 eq) in 1,2-dichloroethane (15 mL), add trifluoroacetic acid (10 mmol, 10 eq) and heat the reaction at 60° C. for 16 h. After completion, remove the solvent and quench the reaction with ammonia and extract with dichloromethane. Remove the solvent under reduced pressure and purify the crude using silica gel column chromatography to afford ethyl 6′-bromo-8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-indolizine]-2′-carboxylate (6).
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH:8][CH2:9][CH2:10][Cl:11])=[O:7])[CH:2]([CH3:4])[CH3:3].C(O)C.[N:15]([O-])=[O:16].[Na+]>Cl.O>[CH2:1]([NH:5][C:6]([N:8]([CH2:9][CH2:10][Cl:11])[N:15]=[O:16])=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: O=N[O-]
Reactant: CC(C)CNC(=O)NCCCl
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)CNC(=O)N(CCCl)N=O
Reaction time: 2 h
Yield: 70 %

Procedure:
A 2 g (11.2 mmol) quantity of 1-isobutyl-3-(2-chloroethyl) urea was dissolved in 25 ml of concentrated HCl:ethanol, 2:1, and cooled to 5° C. A solution of 773 mg (11.2 mmol) of sodium nitrite in 5 ml of water was added in portions and the mixture was stirred at this temperature for 2 hrs. The crystalline yellow solid was filtered and dried in vacuo overnight giving 1.6 g (70%) of the product, MP 51° C. (decomposes). IR analysis showed peaks at 1705/cm (C=O) and 1525/cm (C--N=O). NMR: Doublet (6H, J=6.8 Hz) at 0.9 ppm, multiplet (1H) at 2.0 ppm, multiplet (6H) at 3.7 ppm.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.C(OO)(=[O:11])C>CC(C)=O>[CH3:8][C:3]1[CH:4]=[CH:5][C:6]([OH:7])=[C:1]([OH:11])[CH:2]=1
Reactant: CC(=O)OO
Reactant: Cc1ccc(O)cc1
Solvent: CC(C)=O
Product: Cc1ccc(O)c(O)c1

Procedure:
Five-neck flasks having a volume of 500 ml and provided with a stirrer, a reflux condenser, a sampling tube, a test specimen inlet and a thermometer were charged with 108.1g (1.0 mol) of paracresol and a different kind of peracid stabilizer as the catalyst shown in Table 1. Each flask was placed in a constant temperature bath kept at a temperature indicated in Table 1. Into the flask contents, 7.61g (0.1 mol) of peracetic acid in the form of about 35 weight% acetone solution was introduced through a micro-feeder over 20 minutes. Within 75 hours after the start of the addition of the peracetic acid, the contents of the flask were subjected to distillation under reduced pressure to obtain a fraction of 4-methyl-1,2-dihydroxybenzene having a boiling point of 124 - 125°C/6 mmHg. The results of this reaction are shown in the following table.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11]1.[CH:19]1([C:23]2[N:24]=[C:25](/[CH:28]=[CH:29]/[C:30]3[CH:31]=[C:32]([NH2:36])[CH:33]=[CH:34][CH:35]=3)[S:26][CH:27]=2)[CH2:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1([C:15]([NH:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30](/[CH:29]=[CH:28]/[C:25]3[S:26][CH:27]=[C:23]([CH:19]4[CH2:22][CH2:21][CH2:20]4)[N:24]=3)[CH:31]=2)=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: COC(=O)c1ccccc1C1(C(=O)O)CCCC1
Reactant: Nc1cccc(/C=C/c2nc(C3CCC3)cs2)c1
Product: COC(=O)c1ccccc1C1(C(=O)Nc2cccc(/C=C/c3nc(C4CCC4)cs3)c2)CCCC1

Procedure:
In a manner analogous to Example 7a and 7b, when 2-(1-carboxycyclopentyl)benzoic acid methyl ester is reacted with (E)-3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]benzeneamine, there is obtained (E)-2-[1-[[[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenyl]amino]carbonyl]cyclopentyl]benzoic acid methyl ester which is converted to (E)-2-[1-[[[3-[2-[4-(cyclobutyl)-2-thiazolyl]ethenyl]phenyl]amino]carbonyl]cyclopentyl]benzoic acid.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].O=[C:9]([CH2:21][CH2:22][CH3:23])[CH:10]=[CH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>C(O)(=O)C>[O:6]=[C:5]1[C:7](=[C:9]([CH2:21][CH2:22][CH3:23])[CH:10]=[CH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[S:1][C:2](=[S:3])[NH:4]1
Reactant: O=C1CSC(=S)N1
Reactant: CCCC(=O)C=Cc1ccc(C(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCC(C=Cc1ccc(C(=O)O)cc1)=C1SC(=S)NC1=O

Procedure:
A mixture of 0.73 g (0.0055 mol) of rhodanine, 1.09 g (0.005mol) of 4-(3-oxo-hexen-1-yl)benzoic acid, 0.39 g (0.005 mol) of ammonium acetate and 10 ml of toluene was heated under reflux for 5 hours. After cooling, acetic acid was added to the reaction mixture and the precipitate was recovered by filtration. The precipitate was recrystallized from chloroform-methanol to give 0.10 g of the isomer A of the desired 4-[3-(4-oxo-2- thioxo-5-thiazolidinylidene)-1-hexen-1-yl]benzoic acid. To the filtrate was added water and the resulting mixture was extracted with chloroform (100 ml×3). The chloroform layer was washed three times with water and then once with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent, chlorform : methanol=10:1) to give 0.10 g of the isomer B of the desired product.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:29])[CH2:24][O:25]C(=O)C)[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1.[OH-].[Na+]>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:29])[CH2:24][OH:25])[S:20][CH:21]=3)[CH2:14][CH2:15]2)=[CH:2]1
Reactant: CC(=O)OCC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(CO)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Reaction time: 1 h
Yield: 34.6 %

Procedure:
To a suspension of 4-[4-(3-indolyl)piperidinomethyl]-2-(2-acetoxyacetylamino)thiazole (0.9 g) in ethanol (20 ml) was added 1N aqueous solution of sodium hydroxide (3 ml). After one hour of stirring, the reaction mixture was concentrated and the resulting precipitate was collected by filtration and recrystallized from a mixture of water and ethanol to give 4-[4-(3-indolyl)piperidinomethyl]-2-glycoloylaminothiazole (0.28 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:3]=1[C:4]([O:6][CH2:17][CH3:18])=[O:5]
Reactant: Cc1cc(Br)c(N)c(C(=O)O)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(C)cc(Br)c1N
Yield: 64 %

Procedure:
Ethanol (10 mL) was added to 2-amino-3-bromo-5-methylbenzoic acid (1.00 g, 4.4 mmol). While the mixture was stirred, thionyl chloride (1.03 g, 8.7 mmol) was added at room temperature, followed by stirring at 80° C. overnight. The reaction solution was concentrated, and then diluted with water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=0/10, 4/6) to obtain 715 mg of the title compound as a pale yellow solid (64%).
Reaction SMILES: O=O.[C:3]([O:6][CH:7]=[C:8]([CH3:11])[CH:9]=[CH2:10])(=[O:5])[CH3:4].[C:12]([OH:15])(=[O:14])[CH3:13]>>[C:3]([O:6][CH:7]([O:6][C:3](=[O:5])[CH3:4])[C:8]([CH3:11])=[CH:9][CH2:10][O:14][C:12](=[O:15])[CH3:13])(=[O:5])[CH3:4]
Reactant: CC(=O)O
Reactant: C=CC(C)=COC(C)=O
Agent: O=O
Product: CC(=O)OCC=C(C)C(OC(C)=O)OC(C)=O
Yield: 58.8 %

Procedure:
12,000 parts by volume of oxygen are introduced in the course of 4 hours into a solution, at 95° C., of 63 parts of 1-acetoxy-2-methyl-1,3-butadiene in 600 parts of glacial acetic acid, in which 25 parts of the catalyst prepared as described in Example 1a are suspended. The reaction mixture is worked up as described in Example 1b and fractional distillation gives 71.8 parts of 1,1,4-triacetoxy-2-methyl-2-butene (representing 58.8% conversion) of boiling point 118°-124° C./0.7 mbar and 19.5 parts of 4-acetoxytiglic aldehyde (representing 27.4% conversion) of boiling point 102°-107° C./25-27 mbar.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][C:12]([C:14]3[N:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:4]=2[CH2:3]1.[C:20]1(O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1.ClCCl>[CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([O:9][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[CH:10]=[CH:11][C:12]([C:14]3[N:15]=[N:16][CH:17]=[CH:18][CH:19]=3)=[CH:13][C:4]=2[CH2:3]1
Reactant: CN1CCC(O)c2ccc(-c3cccnn3)cc2C1
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CCC(Oc2ccccc2)c2ccc(-c3cccnn3)cc2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.6 %

Procedure:
To a solution of (+)-2-methyl-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-ol (65 mg, 0.25) from Step A in THF (5 mL) was added phenol (73 mg, 0.77 mmol), tributylphosophine (156 mg, 0.77 mmol) and 1,1′-(azodicarboyl)dipiperidine (192 mg, 0.77 mmol) at room temperature. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane and washed with water, brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography (98:2 to 95:5 ethyl acetate/methanol), followed by HPLC to give (−)-2-methyl-5-phenoxy-8-(pyridazin-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine (52 mg, 62%) as a gum-like solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C@H:11](O)[CH2:10][C@@H:9]1[CH3:19])=[O:7].[NH:25]1[C:34]2[C:29](=[CH:30][C:31]([NH:35][C:36](=[O:38])[CH3:37])=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([N:25]2[C:34]3[C:29](=[CH:30][C:31]([NH:35][C:36](=[O:38])[CH3:37])=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]2)[CH2:10][CH:9]1[CH3:19])=[O:7]
Reactant: CC(=O)Nc1ccc2c(c1)CCCN2
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](O)C[C@@H]2C)cc1OC
Product: COc1ccc(C(=O)N2c3ccccc3C(N3CCCc4cc(NC(C)=O)ccc43)CC2C)cc1OC
Yield: 7.1 %

Procedure:
Starting with cis-1-(3,4-dimethoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinol (350 mg, 1.07 mmol) prepared in Reference Example 1 and N-(1,2,3,4-tetrahydro-quinolin-6-yl)acetamide (475 mg, 2.50 mmol), the same procedure as shown in Example 1 was repeated to give the titled compound (38 mg, yield: 7%) as a colorless oil. (cis:trans=1:1.7)
Reaction SMILES: [Br:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]([NH2:23])=[S:22])=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1.C(N(CC)CC)C.Br[CH2:37][C:38]([CH:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1)=O>CCO>[Br:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:6]([NH:20][C:21]2[S:22][CH:37]=[C:38]([CH:40]3[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]3)[N:23]=2)=[N:7][CH:8]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[CH:10]=1
Reactant: COc1cccc(Sc2cnc(NC(N)=S)c(Oc3ccc(F)cc3Br)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CBr)CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cccc(Sc2cnc(Nc3nc(C4CCN(C(=O)OC(C)(C)C)CC4)cs3)c(Oc3ccc(F)cc3Br)c2)c1
Temperature: 70 °C
Yield: 82 %

Procedure:
A 50 mL flask was charged with 1-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-yl)thiourea (1.5 g, 3.12 mmol), triethylamine (0.740 mL, 5.31 mmol), tert-butyl 4-(2-bromoacetyl)piperidine-1-carboxylate (1.15 g, 3.75 mmol), and EtOH (25 mL). The reaction was heated to 70° C. for 2 hours. The reaction was partitioned between EtOAc and water. The organic layer was dried with sodium sulfate, filtered and concentrated. The residue was purified on silica (10% EtOAc in hexanes) to afford tert-butyl 4-(2-(3-(2-bromo-4-fluorophenoxy)-5-(3-methoxyphenylthio)pyridin-2-ylamino)thiazol-4-yl)piperidine-1-carboxylate (1.76 g, 82.0% yield).