Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH2:4][NH:5][C:6]1[C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1.[C:20]1([NH:26][N:27]=[C:28]([C:32](Cl)=[O:33])[C:29](Cl)=[O:30])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C1COCC1>[C:20]1([NH:26][N:27]=[C:28]2[C:32](=[O:33])[N:5]([CH2:4][CH2:3][CH:2]([CH3:19])[CH3:1])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:29]2=[O:30])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)CCNc1ccccc1Nc1ccccc1
Reactant: O=C(Cl)C(=NNc1ccccc1)C(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)CCn1c(=O)c(=NNc2ccccc2)c(=O)n(-c2ccccc2)c2ccccc21
Yield: 96.8 %

Procedure:
Solutions of N1 -(3-Methylbutyl)-N2 -phenyl-1,2-benzenediamine (12.45 g) in dry THF (100 ml) and (phenylhydrazono)propandioyl dichloride (12.0 g) in dry THF (100 ml) were added dropwise concurrently to a flask of dry THF (100 ml) cooled in an ice-methanol bath under nitrogen. After 30 min more diacid chloride (1.0 g) in dry THF (30 ml) was added and the mixture was allowed to warm to 23°. After 24 h the mixture was poured into dilute HCl and extracted with EA. The combined extracts were washed with dilute sodium carbonate and saturated brine then dried and evaporated. The residue was chromatographed on TEA deactivated silica with EA as eluent to give the title compound (20.2 g) as a yellow solid, m.p. 143°
Reaction SMILES: [C:1]([N:9]=[C:10]=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:12]([O:19][C:20]1[C:21]([NH2:34])=[N:22][CH:23]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[C:1]([NH:9][C:10]([NH:34][C:21]1[C:20]([O:19][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:25][C:24]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])=[CH:23][N:22]=1)=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ncc(Oc2ccccc2Cl)cc1OCc1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ncc(Oc2ccccc2Cl)cc1OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
Benzoyl isothiocyanate (0.330 g, 2.02 mmol) was added to a solution of 3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-amine (0.660 g, 2.02 mmol) in THF (4 mL). The reaction mixture was stirred for 2 hours at room temperature, diluted with hexanes, filtered, and washed with hexanes to afford 1-benzoyl-3-(3-(benzyloxy)-5-(2-chlorophenoxy)pyridin-2-yl)thiourea (0.92 g, 93.0% yield) as a light yellow powder. 1H NMR (CDCl3) δ 5.16 (s, 2H), 6.95 (s, 1H), 7.00-8.04 (m, 17H).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:13]([C:12]3[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][N:3]4[CH2:4][CH2:5][CH2:6][S:2]4(=[O:1])=[O:18])=[CH:17][CH:16]=3)=[O:15])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: O=C(O)c1ccc(CCN2CCCS2(=O)=O)cc1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(CCN4CCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 89.8 %

Procedure:
Using 4-[2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)ethyl]benzoic acid (162 mg) described in Preparation Example 41 and 1-(3,5-dimethylpyridin-2-yl)piperazine (115 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 87, the title compound (239 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([NH:9][NH2:10])=[O:8])=[N:4][N:3]=1.[C:11](Cl)(Cl)=[S:12]>O1CCOCC1>[SH:12][C:11]1[O:8][C:7]([C:5]2[O:6][C:2]([CH3:1])=[N:3][N:4]=2)=[N:9][N:10]=1
Reactant: Cc1nnc(C(=O)NN)o1
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Product: Cc1nnc(-c2nnc(S)o2)o1
Reaction time: 5 h

Procedure:
3.6 g of 5-methyl-1,3,4-oxadiazole-2-carboxylic acid hydrazide of melting point 150°-151° C., prepared in the customary manner from the corresponding ethyl ester [Canad.J.Chem. 65, 166 (1987)], are stirred in 100 ml of dioxane with 2.9 g of thiophosgene at room temperature overnight and then at 55° C. for 5 hours. After cooling, undissolved solids are filtered off and 200 ml of hexane are added to the filtrate, the desired product (4 g of decomposition point 225°) crystallizing out.
Reaction SMILES: [CH3:1][C:2]1[O:12][C:5]2[CH2:6][N:7]([CH3:11])[CH2:8][CH:9]([OH:10])[C:4]=2[CH:3]=1.[C:13]([C:16]1[CH:17]=[C:18](F)[CH:19]=[CH:20][C:21]=1[Cl:22])(=[O:15])[NH2:14]>>[ClH:22].[C:13]([C:16]1[CH:17]=[C:18]([O:10][CH:9]2[CH2:8][N:7]([CH3:11])[CH2:6][C:5]3[O:12][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:19]=[CH:20][C:21]=1[Cl:22])(=[O:15])[NH2:14]
Reactant: Cc1cc2c(o1)CN(C)CC2O
Reactant: NC(=O)c1cc(F)ccc1Cl
Product: Cc1cc2c(o1)CN(C)CC2Oc1ccc(Cl)c(C(N)=O)c1
Product: Cl

Procedure:
The same method as in Example 3 was conducted using 2,6-dimethyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 2) instead of 6-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridin-4-ol (Reference Example 1) and was conducted using 3-carbamoyl-4-chloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]3[NH:17][N:18]=[C:19]4[C:24]=3[CH2:23][CH2:22][C:21]3[CH:25]=[C:26]([CH:29]=C)[CH:27]=[CH:28][C:20]4=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[C:11]([C:12]([F:13])([F:14])[F:15])=[C:10]([C:16]3[NH:17][N:18]=[C:19]4[C:24]=3[CH2:23][CH2:22][C:21]3[CH:25]=[C:26]([CH:29]=[O:35])[CH:27]=[CH:28][C:20]4=3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1ccc2c(c1)CCc1c-2n[nH]c1-c1onc(-c2ccccc2)c1C(F)(F)F
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc2c(c1)CCc1c-2n[nH]c1-c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 109 %

Procedure:
To 3-phenyl-4-(trifluoromethyl)-5-(7-vinyl-4,5-dihydro-2H-benzo[g]indazol-3-yl)isoxazole (Preparation 22B, 0.15 g, 0.368 mmol) in THF (2 mL) were added sequentially N-methylmorpholine N-oxide (50% aq., 0.17 mL, 0.368 mmol) and osmium tetroxide (4% aq. 0.058 mL, 7.36 μmol) at room temperature under a nitrogen atmosphere. The reaction was stirred at room temperature for 45 min. and sodium periodate (0.118 g, 0.552 mmol) in water (1 mL) was added over a period of 1 min. at room temperature. The milky heterogeneous reaction mixture was stirred at room temperature for 45 min., concentrated, and partitioned between ethyl acetate (20 mL) and water (10 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield 3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydro-2H-benzo[g]indazole-7-carbaldehyde (0.164 g, 0.401 mmol, quantitative yield) as a dark brown oil. LC/MS M+1=410.1.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:17]([CH3:28])[CH2:16]1)(=[O:14])=[O:13].[C:29](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.CCOC(C)=O>O1CCOCC1.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>[CH3:28][C@H:17]1[CH2:16][N:15]([S:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[CH3:29])(=[O:14])=[O:13])[CH2:20][CH2:19][N:18]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: O=C([O-])[O-]
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2Br)CCN1C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(C(F)(F)F)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C)C1
Temperature: 100 °C
Yield: 90.6 %

Procedure:
A solution of 1,1-dimethylethyl(2S)-4-{[2-bromo-4-(trifluoromethyl)phenyl]sulfonyl}-2-methyl-1-piperazinecarboxylate (1.00 g, 2.05 mmol) (may be prepared as described in Description 26), potassium carbonate (0.737 g, 5.34 mmol) in 1,4-dioxane (43 ml) were stirred for 5 min then trimethylboroxin (0.743 ml, 5.34 mmol) and Pd(Ph3P)4 (0.403 g, 0.349 mmol) were added and the reaction mixture heated at 100° C. overnight. EtOAc (100 ml) was added then the mixture washed aqueous sodium bicarbonate (100 ml), water (100 ml) and concentrated under vacuum. Flash chromatography (silica; linear gradient (0-20%) EtOAc in isohexane) gave 1,1-dimethylethyl(2S)-2-methyl-4-{[2-methyl-4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate (0.785 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:55][S:56](Cl)(=[O:58])=[O:57].O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([C:19]([C:22]5[CH:28]=[CH:27][C:25]([NH:26][S:56]([CH3:55])(=[O:58])=[O:57])=[CH:24][CH:23]=5)=[CH:20][N:21]=4)[CH:18]=3)=[CH:11][N:10]([C:29]([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Nc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-c2cnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cn23)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
While 7 mL solution of 68 mg 4-{6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]imidazo[1,2-a]pyridin-3-yl}aniline obtained in Example 19 and 34 mg triethylamine in dichloromethane was stirred in a stream of nitrogen, 20 μL methylsulfonyl chloride was added thereto. Then, the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution which was then extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the concentrated residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 52 mg of the title compound as a pale yellow amorphous.
Reaction SMILES: C(O)C.[CH2:4]([N:7]1[C:13]2[CH:14]=[CH:15][C:16](Br)=[CH:17][C:12]=2[CH:11]=[C:10]([C:19]([O:21][CH3:22])=[O:20])[CH2:9][CH2:8]1)[CH:5]=[CH2:6].B([O-])([O-])O[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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.O>[CH2:4]([N:7]1[C:13]2[CH:14]=[CH:15][C:16]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:26]=3)=[CH:17][C:12]=2[CH:11]=[C:10]([C:19]([O:21][CH3:22])=[O:20])[CH2:9][CH2:8]1)[CH:5]=[CH2:6]
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: C=CCN1CCC(C(=O)OC)=Cc2cc(Br)ccc21
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: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=CCN1CCC(C(=O)OC)=Cc2cc(-c3ccc(OCCOCCC)cc3)ccc21
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
In toluene (20 ml), ethanol (2 ml) and water (2 ml) were suspended methyl 1-allyl-7-bromo-2,3-dihydro-1-benzazepine-4-carboxylate (274 mg), 4-propoxyethoxyphenyl borate (248 mg) and potassium carbonate (307 mg), and the suspension was stirred under argon atmosphere for 30 minutes, Then, tetrakistriphenylphosphinepalladium (69 mg) was added thereto, and the mixture was heated under argon atmosphere at 100° C. for 8 hours. After allowing to cool, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=4:1) to give methyl 1-allyl-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (269 mg) as yellow oil.
Reaction SMILES: C([Cl:4])(=O)C.[CH3:5][N:6]1[C:10]2[NH:11][CH2:12][CH2:13][S:14][CH:15]([CH:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)[C:9]=2[C:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:7]1>CO>[ClH:4].[ClH:4].[CH3:5][N:6]1[C:10]2[NH:11][CH2:12][CH2:13][S:14][CH:15]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:9]=2[C:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[N:7]1
Reactant: Cn1nc(-c2ccccn2)c2c1NCCSC2C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(=O)Cl
Solvent: CO
Product: Cl
Product: Cn1nc(-c2ccccn2)c2c1NCCSC2C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Acetyl chloride (0.3 mL, 4.2 mmol) was added dropwise to methanol (20 mL), at about 0° C. Tert-butyl 4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]piperidine-1-carboxylate (0.45 g, 1.1 mmol, prepared using General Procedure C from Example #2 step B with 1-Boc-piperidine-4-carboxaldehyde and thioglycolic acid followed by D) was added in portions and the resulting mixture was stirred at rt overnight. Subsequently, the mixture was concentrated in vacuo to afford 1-methyl-4-(4-piperidyl)-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine dihydrochloride as a yellow solid which was used as such.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH:31]([N:34]=[C:35]=[O:36])([CH3:33])[CH3:32]>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:34]([CH:31]([CH3:33])[CH3:32])[C:35]2=[O:36])(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Reactant: CC(C)N=C=O
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3C(C)C)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and isopropyl isocyanate to give the title compound as a colorless solid. MS: 485.2 ([M+H]+)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:10][C:11](=[O:13])[CH3:12])[CH:8]=2)[CH:3]=[CH:2]1.[CH2:14]=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>O1CCOCC1.C(O)(=O)C>[N:16]1([CH2:14][C:3]2[C:4]3[C:9](=[CH:8][C:7]([O:10][C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: CC(=O)Oc1ccc2cc[nH]c2c1
Reactant: C=O
Reactant: C1COCCN1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CC(=O)Oc1ccc2c(CN3CCOCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.8 %

Procedure:
To a solution of acetic acid 1H-indol-6-yl ester (2.0 g, 11.4 mmol) in dioxane/acetic acid (1:1, 114 mL) was added formaldehyde (0.85 mL, 0.93 g, 11.4 mmol) and morpholine (1 mL, 1 g, 11.4 mmol) and the resulting mixture was stirred (rt, 16 h). The reaction mixture was concentrated in vacuo, diluted with DCM (200 mL) and washed with 1N NaOH (20 mL), 4 N NaOH (20 mL) and brine (2×10 mL). The organic layer was dried, filtered and concentrated in vacuo to provide the title compound (2.87 g, 92%). MS (ESI): mass calculated for C15H18N2O3, 274.1; m/z found, 275.1 [M+H]+. 1H NMR (600 MHz, CDCl3): 8.09 (s, 1H), 7.73 (d, J=8.5, 1H), 7.11 (dd, J=11.7, 2.1, 2H), 6.85 (dd, J=8.5, 2.0, 1H), 3.71-3.68 (m, 4H), 3.67 (s, 2H), 2.48 (s, 4H), 2.32 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].[C:14]([C:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23])([CH3:18])[CH3:17])#[N:15]>O1CCCC1>[C:14]([C:16]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=1)=[O:23])([CH3:18])[CH3:17])#[N:15]
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(O)c2)c1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)benzoic acid (10 g, 52.8 mmol) in tetrahydrofuran (100 mL) were added N,N-dimethylformamide (80 μL) and oxalyl chloride (6.28 mL, 72.0 mmol), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure to give 3-(cyano-1-methylethyl)benzoyl chloride as a pale-brown oil. To a solution of 3-aminophenol (5.24 g, 48.0 mmol) in tetrahydrofuran (40 mL) was added an aqueous suspension (60 mL) of sodium hydrogen carbonate (6.05 g, 72.0 mmol), and the mixture was vigorously stirred at room temperature. To this mixture was added dropwise a solution of 3-(cyano-1-methylethyl)benzoyl chloride in tetrahydrofuran (60 mL) synthesized above under ice-cooling, and the mixture was stirred at room temperature for 5 hr. The aqueous layer of the reaction mixture was separated, and the organic layer was diluted with ethyl acetate (200 mL) and washed with saturated brine (200 mL). The extract was dried over anhydrous magnesium sulfate and decolored with activated carbon. The insoluble material was filtered off through a pad packed with silica gel and celite in two layers. The solvent was evaporated under reduced pressure, and the obtained solid was washed with ethyl acetate-hexane mixture to give the title compound (13.03 g, 96%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH2:12])=[NH:11].[C:13](OC(=O)C)(=[O:15])[CH3:14].O.[O:21]1CC[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([C:22](=[O:21])[CH3:23])[C:10]([NH:12][C:13](=[O:15])[CH3:14])=[NH:11]
Reactant: CC(=O)OC(C)=O
Reactant: C1CCOC1
Reactant: N=C(N)Nc1c(Cl)cccc1Cl
Solvent: O
Product: CC(=O)NC(=N)N(C(C)=O)c1c(Cl)cccc1Cl
Reaction time: 48 h

Procedure:
A solution of 5 g (0.024 mole) of 2.6-dichlorophenylguanidine in 50 ml of tetrahydrofuran is chilled in an ice bath while 2.56 g (0.24 mole) of acetic anhydride is added dropwise. The mixture is then stirred for 48 hours and then poured into 1 liter of water. The mixture is then stirred for 8 hours and the precipitate is collected to obtain 1-(2,6-dichlorophenyl)-1,3-diacetylguanidine 3 g of this material is stirred at room temperature with 15 ml of conc. hydrochloric acid. The reaction mixture is poured into ice and basicified with cold conc. sodium hydroxide solution. The precipitate is cooled and recrystallized from ethanol: water to obtain 1-(2,6-dichlorophenyl)-3-acetylguanidine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C@H:5]([CH2:16][C@@H:17]([CH:33]([CH3:35])[CH3:34])[CH2:18][C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3[CH2:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:21][CH:20]=2)[N:6]=C(OCC)[C@@H](C(C)C)N=1)[CH3:2].Cl.C([O-])(O)=[O:38].[Na+]>CC#N>[NH2:6][C@@H:5]([CH2:16][C@H:17]([CH2:18][C:19]1[CH:27]=[C:26]2[C:22]([CH:23]=[N:24][N:25]2[CH2:28][CH2:29][CH2:30][O:31][CH3:32])=[CH:21][CH:20]=1)[CH:33]([CH3:35])[CH3:34])[C:4]([O:3][CH2:1][CH3:2])=[O:38]
Reactant: O=C([O-])O
Reactant: CCOC1=N[C@H](C(C)C)C(OCC)=N[C@H]1C[C@H](Cc1ccc2cnn(CCCOC)c2c1)C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)[C@@H](N)C[C@H](Cc1ccc2cnn(CCCOC)c2c1)C(C)C
Reaction time: 5 h
Yield: 95 %

Procedure:
To a stirred solution of 6-((S)-2-(((2S,5R)-3,6-diethoxy-5-isopropyl-2,5-dihydropyrazin-2-yl)methyl)-3-methylbutyl)-1-(3-methoxypropyl)-1H-indazole (300 mg, 0.62 mmol) in CH3CN (5 mL) was added 1 N aq HCl (5 mL) at rt. The mixture was stirred for 5 h, poured into ice-cold, satd aq NaHCO3 and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated to give (2S,4S)-ethyl 2-amino-4-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-5-methylhexanoate (220 mg, 95%).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])O)=[C:16]([F:30])[CH:15]=1.FC1C=CC(C(C2C=CC(F)=CC=2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)=[C:16]([F:30])[CH:15]=1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: OC(c1ccc(Cl)cc1F)c1ccc(Cl)cc1F
Agent: CSCc1cccc2c(C(c3ccc(F)cc3)c3ccc(F)cc3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3F)c3ccc(Cl)cc3F)c[nH]c12

Procedure:
The title compound was prepared starting from 750 mg (4.23 mmol) of the compound from Example 8A and 1.22 g (4.23 mmol) of the compound from Example 179A in analogy to the synthesis of the compound from Example 278. 97 mg (5% of theory) of the target compound were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[C:12]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([C:31](=[O:43])[CH2:32][O:33][CH2:34][C:35]1[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=1[Cl:42])[CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13].C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1.C(Cl)Cl>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[C:3]1[C:12]([NH:14][C@H:15]([C:19]([NH:21][CH:22]([C:31](=[O:43])[CH2:32][O:33][CH2:34][C:35]1[C:40]([Cl:41])=[CH:39][CH:38]=[CH:37][C:36]=1[Cl:42])[CH2:23][C:24]([OH:26])=[O:25])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13]
Reactant: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COCc2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCl
Product: Cc1c(C(=O)N[C@H](C(=O)NC(CC(=O)O)C(=O)COCc2c(Cl)cccc2Cl)C(C)C)n(C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.1 %

Procedure:
A solution of N-[(1,3-Dimethylindole-2-carbonyl)valinyl]-3-amino-4-oxo-5-(2′,6′-dichloro-benzyloxy)pentanoic acid, t-butyl ester (49 mg) in anisole (0.2 mL) and methylene chloride (2 mL) was treated with TFA (1 ml) and stirred for 30 minutes under a nitrogen atmosphere at room temperature. The resultant solution was concentrated and chased with methylene chloride to give a white solid as the crude product. The crude product was triturated with ether to yield the title product as a white powder (34 mg). MS(EI) for C28H31Cl2N3O6; MH+=576/578; (MH)−=574/576.
Reaction SMILES: C(C1C=CC=C(C(C)(C)C)C=1O)(C)(C)C.C([C:20]1[CH:21]=[C:22]([C:31]2[CH:36]=[C:35](C(C)(C)C)[C:34]([OH:41])=[C:33](C(C)(C)C)[CH:32]=2)[CH:23]=[C:24](C(C)(C)C)[C:25]=1[OH:26])(C)(C)C>C1(O)C=CC=CC=1.S(=O)(=O)(O)O>[CH:23]1[C:22]([C:31]2[CH:36]=[CH:35][C:34]([OH:41])=[CH:33][CH:32]=2)=[CH:21][CH:20]=[C:25]([OH:26])[CH:24]=1
Reactant: CC(C)(C)c1cc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: O=S(=O)(O)O
Solvent: Oc1ccccc1
Product: Oc1ccc(-c2ccc(O)cc2)cc1

Procedure:
A starting material which was a mixture of 3,3',5,5'-tetra-t-butyl-4,4'-diphenoquinone (0.46 g), 2,6-di-t-butylphenol (0.34 g) and 3,3',5,5'-tetra-t-butyl-4,4'-dihydroxybiphenyl (8.56 g) was subjected to reaction at 180° C. for 6 hours in a nitrogen gas atmosphere using 20 g of phenol as a solvent and 0.04 g of sulfuric acid as a catalyst. As a result, p,p'-biphenol was obtained in an amount of 3.35 g (yield, 79.9%).