Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][CH:34]([CH3:37])[CH2:35][OH:36])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33]([CH:34]([CH3:37])[CH2:35][OH:36])=[O:9])[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(-c2nc(SC(C)CO)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2nc(S(=O)C(C)CO)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At room temperature, a solution of 2.16 g. of 3-chloroperbenzoic acid in 150 ml. of chloroform is added dropwise to a solution of 3.71 g. of [4,5-bis(4-methoxyphenyl)]-2-(2-hydroxy-1-methylethylthio)imidazole in 200 ml. of chloroform. The mixture is stirred overnight at room temperature and washed with saturated sodium bicarbonate solution. The organic solution is dried over sodium sulfate and concentrated under vacuum. The residue is purified by chromatography on 200 g. of silica gel with ethyl acetate as the eluent. After evaporation of the solvent, 2.67 g. of [4,5-bis(4-methoxyphenyl)]-2-(2-hydroxy-1-methylethylsulfinyl)imidazole is obtained as an amorphous foam.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([N:10]2[C:14]([CH:15]([CH3:17])[CH3:16])=[N:13][N:12]=[N:11]2)[CH:7]=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][N:19]=2)[CH:5]=1.[Li+].[OH-].Cl>CO.O.C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[CH:5]=[C:4]([CH:9]=[C:8]([N:10]3[C:14]([CH:15]([CH3:17])[CH3:16])=[N:13][N:12]=[N:11]3)[CH:7]=2)[C:3]([OH:25])=[O:2])=[N:19][CH:20]=1
Reactant: COC(=O)c1cc(-c2ccc(Cl)cn2)cc(-n2nnnc2C(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)c1nnnn1-c1cc(C(=O)O)cc(-c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
3-(5-Chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid methyl ester (1.84 g, 5.14 mmol) was dissolved in a mixture of MeOH (15 mL), water (2 mL) and THF (2 mL), and LiOH 308 mg, 12.86 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours, made pH neutral by addition of 1N HCl, and then extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give 1.70 g of 3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid, Mp=179.5-181.2° C., MS (M+H)=344.
Reaction SMILES: [OH:1][C:2]1[N:6]2[C:7](=[O:19])[C:8]3[NH:9][CH:10]=[N:11][C:12]=3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:5]2=[N:4][N:3]=1.[Br:20]N1C(=O)CCC1=O>C1COCC1>[Br:20][C:10]1[NH:9][C:8]2[C:7](=[O:19])[N:6]3[C:2]([OH:1])=[N:3][N:4]=[C:5]3[N:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:12]=2[N:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(O)nnc12
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(O)nnc12
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
The mixture of solution of 3-hydroxy-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (100 mg, 0.381 mmol) and N-bromosuccinimide (204 mg, 1.14 mmol) in THF (2 ml) was stirred in a microwave reactor at 70° C. for 10 min. The reaction mixture was filtrated and the filtrate was purified by prep LCMS to yield the desired product. LCMS calculated for C11H14BrN6O2 (M+H) 341.0; found: 341.0, 343.0.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH2:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:7][C:5]=2[N:6]=1.C1(O)C=CC=CC=1.Br.CCOCC>O>[CH3:1][C:2]1[S:3][C:4]2[CH2:9][NH:8][CH2:7][C:5]=2[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3nc(C)sc3C2)cc1
Agent: Br
Solvent: Oc1ccccc1
Solvent: O
Solvent: CCOCC
Product: Cc1nc2c(s1)CNC2
Reaction time: 0.17 h

Procedure:
To the product from Step B (100 mg) was added phenol (32 mg) followed by hydrogen bromide solution in water (48%, 2 mL). The mixture was refluxed for 90 min and cooled to ambient temperature Water (2 mL) and ether (5 mL) were added and the mixture stirred for 10 min and the ether layer removed. This wash was repeated and the aqueous layer was then treated with acetonitrile and filtered to give a pale brown solid. The solid was purified by preparative thin layer chromatography using an Analtech® 1500 micron plate (10% methanol/ethyl acetate, 1% ammonium hydroxide) to give the title compound as a dark solid. LC/MS 141.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[S:9][C:10]([CH3:13])=[CH:11][CH:12]=2)[CH2:5][C:4](=[O:14])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[CH3:4][C:3]1[C:3]2[C:4](=[O:14])[CH2:5][CH:6]([C:8]3[S:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[CH2:7][C:2]=2[N:1]=[CH:7][CH:2]=1
Reactant: Cc1ccc(C2CC(=O)C=C(N)C2)s1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(C2CC(=O)c3c(C)ccnc3C2)s1
Temperature: 115 °C
Yield: 172.7 %

Procedure:
In a mixture of ethanol (30 ml) and toluene (90 ml) was dissolved 1-amino-5-(5-methyl-2-thienyl)cyclohexen-3-one (1.66 g). To the solution were added 3-oxobutylaldehydedimethylacetal (2.6 g) and granulated potassium hydroxide (430 mg), and the mixture was stirred at 115° C. (bath temperature). To the mixture were added granulated potassium hydroxide (80 mg), 30 minutes later; 1 hour later; 1.5 hours later; respectively. The reaction solution was stirred at the same temperature for 1 hour and cooled. Under reduced pressure, the solvent was evaporated, and to the residue were added ethyl acetate (50 ml) and water (10 ml). The mixture was shaken, and the separated upper layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) and eluted with ethyl acetate/hexane to give 4-methyl-7-(5-methyl-2-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (1.78 g) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Nc1n[nH]cc1-c1cccnc1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc2c(-c3cccnc3)cnn12
Yield: 67 %

Procedure:
Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (285 mg, 1.0 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-(3-pyridinyl)-pyrazole [CAS No. 40545-68-2; prepared from 3-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (274 mg, 67%). MS (ISP) 409.1 [(M+H)+]; mp 224° C.
Reaction SMILES: [C:1]1([CH2:11][NH:12][C:13](=[O:20])[NH:14][O:15][CH2:16][C:17]([OH:19])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:21][C@@H:22]([CH3:45])[C:23]([N:25]([CH2:35][C:36]1[C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=2[S:39][CH:40]=1)[C@@H:26]([CH3:34])[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])=[O:24]>>[S:39]1[CH:40]=[C:36]([CH2:35][N:25]([C@@H:26]([CH3:34])[CH:27]([O:31][CH2:32][CH3:33])[O:28][CH2:29][CH3:30])[C:23](=[O:24])[C@@H:22]([NH:21][C:17](=[O:19])[CH2:16][O:15][NH:14][C:13]([NH:12][CH2:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:20])[CH3:45])[C:37]2[CH:44]=[CH:43][CH:42]=[CH:41][C:38]1=2
Reactant: O=C(O)CONC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)N
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](C)NC(=O)CONC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(naphthalen-1-ylmethyl)ureidooxy)acetic acid (Compound VI-12) 113 mg (0.41 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-12) 100 mg (0.27 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([CH:31]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C([BH3-])#N.[Na+].[CH3:40][NH:41][CH3:42]>CO.[Cl-].[Zn+2].[Cl-]>[CH3:40][N:41]([CH2:31][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:7][CH2:8]2)[CH:26]=[C:25]([O:27][CH3:28])[C:24]=1[O:29][CH3:30])[CH3:42]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C=O)c(OC)c(OC)c4)cc23)CC1
Reactant: CNC
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(CN(C)C)c(OC)c(OC)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4,5-bis(methyloxy)phenyl]-1H-indole-7-carboxamide (30 mg, 0.06 mmol) in methanol (2 mL), zinc chloride (5 mg, 0.03 mmol), sodium cyanoborohydride (5 mg, 0.06 mmol) and dimethylamine (100 μL, 0.30 mmol). The mixture was stirred at room temperature for 2 h then reacted in the microwave at 100° C. for 30 min. The resulting mixture was purified by Gilson Preparatory HPLC to give 11 mg of the title compound (34.7%).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[N:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:29][NH2:30]>>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([N:16]4[CH:20]=[CH:19][C:18]([C:21]([NH:30][CH3:29])=[O:23])=[N:17]4)[N:12]=[CH:11][C:10]=3[N:9]([CH3:24])[C:8](=[O:25])[C@H:7]2[CH2:26][CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccc(C(=O)O)n3)nc2N1C1CCCC1
Agent: Cl
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccc(C(=O)NC)n3)nc2N1C1CCCC1

Procedure:
The title compound was prepared similarly to the methods described in Example 39, with (R)-1-(8-cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-pyrazole-3-carboxylic acid (Example 56) used instead of (R)-1-(8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-5,6,7,8-tetrahydropteridin-2-yl)-1H-pyrazole-4-carboxylic acid (Example 44) and methylamine hydrochloride instead of dimethylamine hydrochloride. LCMS: 384.2 m/z (M+H)+; ret. Time: 3.65 min (Analytical Method A).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([NH:8][C:9]([C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][CH:12]=2)=[O:10])[CH:7]=1.CC([O-])=O.[K+].Br[C:27]#[N:28]>CO>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([NH:8][C:9]([C:11]2[N:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]3=[N:13][CH:12]=2)=[O:10])[CH:7]=1)[C:27]#[N:28]
Reactant: N#CBr
Reactant: Cc1ccc(N)cc1NC(=O)c1cnc2ccccn12
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: Cc1ccc(NC#N)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To N-(5-amino-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (67) (4.53 g, 15 mmol) in MeOH (100 mL) was added KOAc (4.41 g, 45 mmol) and the mixture was stirred at room temperature for 5 minutes then cooled to 0° C. before a solution of BrCN (1.62 g, 15 mmol) in MeOH (30 mL) was added dropwise. The resulting mixture was slowly warmed to room temperature and stirred overnight. The solvent was evaporated and to the residue was added water (150 mL). The mixture was stirred at room temperature for 1 hour, filtered and washed with water (2×20 mL), then air dried to give N-(5-cyanamido-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (68) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:11](=[O:13])[CH3:12])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[F:14][CH:15]([F:21])[C:16](OCC)=[O:17].C[O-].[Na+].[O-]CC.[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([C:11](=[O:13])[CH2:12][C:16](=[O:17])[CH:15]([F:21])[F:14])=[CH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C(F)F
Reactant: CCOC(=O)c1ccc(C(C)=O)s1
Agent: CC[O-]
Agent: C[O-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(C(=O)CC(=O)C(F)F)s1
Yield: 85 %

Procedure:
Prepared from 5-Acetyl-thiophene-2-carboxylic acid ethyl ester and ethyl difluoroacetate by the method described in Preparative Example 3. Sodium methoxide was substituted with sodium ethoxide. The product was obtained as a crude oil (5.4 g, 85%). An approx. 5:1 isomer mixture was observed in the NMR spectra of product. 1H NMR (CDCl3) 1.41 (t, J=7.0, 3H), 3.63 (q, J=7.0, 2H), 5.98 (t, minor isomer, J=53.2, 1H), 6.05 (t, major isomer, J=54.0, 1H), 6.45 (s, 1H), 7.74 (d, J=4.0, 1H), 7.80 (d, J=4.0, 1H). 19F NMR −127.8 (minor isomer, J=53.5), −127.1 (major isomer, J=55.5). LC/MS 5.18 min, [M+1]+ 277.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH:13]=2)=[O:10])[C:6]=1[O:7][CH3:8].[N:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.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>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([NH:11][C:9]([C:5]2[C:6]([O:7][CH3:8])=[C:2]([C:30]3[CH:31]=[CH:32][N:27]=[CH:28][CH:29]=3)[S:3][CH:4]=2)=[O:10])=[CH:13][C:14]=1[N:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(NC(=O)c2csc(Br)c2OC)cc1N1CCN(C)CC1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(NC(=O)c2csc(-c3ccncc3)c2OC)cc1N1CCN(C)CC1

Procedure:
2-Bromo-N-[4-methoxy-3-(4-methyl- 1-piperazinyl)phenyl]-3-methoxythiophene-4-carboxamide (0.20 g;0.45 mmol) was stirred with 4-pyridylboronic acid (0.056 g;0.45 mmol), tetrakis(triphenylphosphine)palladium(0) (0.024 g) and anhydrous sodium carbonate (0.053 g;0.50 mmol) in water (5 ml) and DME (5 ml) and the whole heated at reflux under Ar (18 hours). The reaction mixture was poured into 10% Na2CO3 (aq) (20 ml) and extracted into CHCl3. The organic extracts were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 4%MeOH/CHCl3 to yield a orange gum (0.088;44%).
Reaction SMILES: C(OC(C1C=CC(C2C=CC(O)=CC=2)=CC=1)=O)C.[OH-].[K+].CC(OS(C1C=CC(C)=CC=1)(=O)=O)CCCCCC.Cl.C([O:43][C:44]([C:46]1[CH:51]=[CH:50][C:49]([C:52]2[CH:57]=[CH:56][C:55]([O:58][CH:59]([CH3:66])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])=[CH:54][CH:53]=2)=[CH:48][CH:47]=1)=[O:45])C.[OH-].[Na+]>C(O)C.O.C1(C)C=CC=CC=1>[CH3:66][CH:59]([O:58][C:55]1[CH:56]=[CH:57][C:52]([C:49]2[CH:48]=[CH:47][C:46]([C:44]([OH:45])=[O:43])=[CH:51][CH:50]=2)=[CH:53][CH:54]=1)[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65]
Reactant: CCCCCCC(C)Oc1ccc(-c2ccc(C(=O)OCC)cc2)cc1
Agent: CCCCCCC(C)OS(=O)(=O)c1ccc(C)cc1
Agent: CCOC(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCCCCC(C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 65.8 %

Procedure:
On the other hand, 4-hydroxy-4'-biphenylcarboxylic acid ethyl ester (38.7 g, 0.160 mol) was dissolved in ethanol (200 ml), followed by further adding and dissolving KOH (9 g, 0.160 mol), adding optically active p-toluenesulfonic acid 1-methyl-heptyl ester obtained above (50 g, 0.176 mol), keeping the mixture under reflux for 4 hours, cooling, adding toluene (200 ml) and 6N-HCl (50 ml), washing the toluene layer with a 2N-NaOH aqueous solution, washing with water till the washing water became neutral, and distilling off toluene to obtain as a residue, optically active 4'-(1-methyl-heptyloxy)-4-biphenylcarboxylic acid ethyl ester (38.6 g, 0.109 mol), which was dissolved in ethanol (6 ml), NaOH (5.3 g, 0.130 mol) and water (26 ml), following by heating the solution under reflux for 10 minutes to deposit crystals, cooling, adding 6N-HCl (20 ml), separating crystals by filtering, and recrystallizing from acetic acid to obtain optically active 4'-(1-methyl-heptyloxy)-4-biphenylcarboxylic acid (23.4 g). This product exhibited liquid crystal phases and its phase transition points, C-SC* point, SC*-Ch point and Ch-I point were 160° C., 177° C. and 196° C., respectively.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]([F:35])=[C:6]([CH:31]=[CH:32][C:33]=1[F:34])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:29][CH3:30])=[C:15]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]([OH:28])=O)[CH2:21][CH2:20]3)[CH:16]=2)[N:11]=[CH:10][N:9]=1.[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[Cl:3][C:4]1[C:5]([F:35])=[C:6]([CH:31]=[CH:32][C:33]=1[F:34])[NH:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:29][CH3:30])=[C:15]([O:18][CH:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)=[O:28])[CH2:21][CH2:20]3)[CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CCN(CC(=O)O)CC1
Reactant: CN1CCNCC1
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3F)c2cc1OC1CCN(CC(=O)N2CCN(C)CC2)CC1
Yield: 56 %

Procedure:
[4-({4-(3-chloro-2,4-difluoroanilino)-7-methoxyquinazolin-6-yl}oxy)piperidin-1-yl]acetic acid dihydrochloride salt and N-methylpiperazine were converted to the title compound (126 mg, 56%) using the procedure according to Examples 6 to 10.
Reaction SMILES: [NH2:1][C:2]1[C:17](Br)=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[Cl:19].[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:17](/[CH:22]=[CH:21]/[C:20]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[C:3]=1[Cl:19]
Reactant: CCOC(=O)N1CCc2cc(Br)c(N)c(Cl)c2CC1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc2c(c(Cl)c1N)CCN(C(=O)OCC)CC2
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 4.37 g of ethyl 7-amino-8-bromo-6-chloro-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate in 40 ml of DMF were added 2.1 ml of ethyl acrylate, 230 mg of tris-o-tolylphosphine, 85 mg of palladium(II) acetate, and 3.6 ml of triethylamine, followed by stirring at 120° C. for 3 hours. The reaction mixture was diluted with EtOAc, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure. The resulting yellow solid was stirred and washed in diisopropylether to obtain 3.125 g of ethyl 7-amino-6-chloro-8-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate as a pale yellow solid.
Reaction SMILES: CC(C)(OC([NH:7][C@H:8](C(O)=O)[CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])=O)C.ClC(Cl)(Cl)C[O:29][C:30](NCCCC[C@@H](C(O)=O)N)=[O:31].Cl.N[C@H](C(O)=O)CCCCN.ClC(OCC(Cl)(Cl)Cl)=O.C(=O)([O-])[O-].[Na+].[Na+].[Na+].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=O.C(N(CC)CC)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O.C(=O)([O-])[O-].[Cu+2].O1CCOCC1>[Cl:21][C:18]([Cl:19])([Cl:20])[CH2:17][O:16][C:14]([NH:13][C@H:12]([C:30]([OH:31])=[O:29])[CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])=[O:15]
Reactant: N[C@@H](CCCCNC(=O)OCC(Cl)(Cl)Cl)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC(Cl)(Cl)Cl)C(=O)O
Agent: [Cu+2]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: NCCCC[C@H](NC(=O)OCC(Cl)(Cl)Cl)C(=O)O
Temperature: 20 °C
Reaction time: 20 h
Yield: 55 %

Procedure:
Nα -(1,1-Dimethylethoxycarbonyl)-Nε -(2,2,2-trichloroethoxycarbonyl)lysine. In a modification of a literature method [Yajima, H.; Watanabe, H.; Okamoto, M., Studies on peptides. XXXIII. Nε -β,β,β-Trichloroethyloxycarbonyllysine, Chem. Pharm. Bull, 1971, 19, 2185-2189], lysine monohydrochloride (9.14 g, 50 mmol) was stirred under reflux with copper (II) carbonate (21.6 g, 75 mmol) in water (180 mL) for 3 h. The solution was filtered while hot and the filtrate was cooled to 20° C. 2,2,2-Trichloroethyl chloroformate (15.9 g, 75 mmol) and aqueous sodium carbonate (13.3 g, 125 mmol in 40 mL) were added alternately in portions to the filtrate during 30 min and the mixture was stirred vigorously at 0° C. for 20 h. The blue precipitate was collected and was boiled under reflux with ethylenediaminetetraacetic acid disodium salt (18.6 g, 100 mmol) in water (200 mL) for 2 h. The solution was cooled to 0° C. for 20 hrs and crude Nε -(2,2,2-trichloroethoxycarbonyl)lysine was collected as a gummy solid. This material was dissolved in water (75 mL) and triethylamine (20.2 g, 200 mmol) was added, followed by di-t-butyl dicarbonate (13.64 g, 62 mmol) and 1,4-dioxan (30 mL). The mixture was stirred vigorously for 3 d. The mixture was washed with diethyl ether. Ethyl acetate was added to the aqueous phase and the mixture was acidified by careful addition of cold 10% aqueous sulphuric acid. The ethyl acetate phase was washed with water and dried with anhydrous magnesium sulphate. The solvent was evaporated under reduced pressure to give Nα -(1,1-dimethylethoxycarbonyl)-Ne -(2,2,2-trichloroethoxycarbonyl)lysine (12.32 g, 55%).
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])C=CC=CC=1.[Na].[H-].[Na+].[CH2:31]1[CH2:43][O:42][C:33]2([CH2:40][C@@H:39]3[C@@H:35]([CH2:36][C:37](=O)[CH2:38]3)[CH2:34]2)[O:32]1.[Cl-].[Na+]>CS(C)=O.C(O)(=O)C>[C:13]([CH2:12][CH2:11][CH2:10][CH:9]=[C:37]1[CH2:38][C@@H:39]2[C@@H:35]([CH2:34][C:33]3([O:42][CH2:43][CH2:31][O:32]3)[CH2:40]2)[CH2:36]1)([OH:15])=[O:14]
Reactant: O=C1C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Cl-]
Agent: [H-]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=C(O)CCCC=C1C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Reaction time: 48 h
Yield: 312.2 %

Procedure:
An ylide solution was prepared from 440 g of triphenyl (4-carboxybutyl)phosphonium bromide and sodium dimsyl (prepared from 75.0 g of a 55% w/w suspension of sodium hydride in oil and 3 liters of dimethyl sulfoxide) in dimethyl sulfoxide. To this were added dropwise 36.0 g of 7,7-ethylenedioxy-3-oxo-cis-bicyclo[3,3,0]octane in 400 ml of dimethyl sulfoxide, and the mixture was left standing at room temperature for 48 hours under an atmosphere of nitrogen. Upon completion of the reaction, the reaction product was neutralized with acetic acid, and the mixture was poured into a saturated aqueous solution of sodium chloride. The mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, giving 164.3 g of residue. On purifying the residue by column chromatography through silica gel, 49.10 g of the title compound was obtained in the form of an oil, from the fractions eluted with hexane containing 30-40% by volume of ethyl acetate.