Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].CON(C)[C:20](=[O:32])[CH:21]([O:30][CH3:31])[C:22]1[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:20](=[O:32])[CH:21]([O:30][CH3:31])[C:22]3[CH:23]=[N:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Reactant: COc1ccc(C(OC)C(=O)N(C)OC)cn1
Product: COc1ccc(C(OC)C(=O)c2ccc(-c3cc(OC)c(Br)c(OC)c3)o2)cn1

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(6-methoxypyridin-3-yl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and N,2-dimethoxy-2-(6-methoxypyridin-3-yl)-N-methylacetamide according to the procedure used in Example 30. Purification by chromatography (50% EtOAc/hexanes) gave the product as a pale yellow solid (0.092 g, 28% yield). MS: m/z 462.2 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1>>[F:32][C:31]([F:33])([F:34])[O:30][C:26]1[CH:25]=[C:24]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)[CH:29]=[CH:28][CH:27]=1
Reactant: FC(F)(F)Oc1cccc(Br)c1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1cccc(OC(F)(F)F)c1)CC2

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 1-bromo-3-trifluoromethoxy-benzene. Light yellow solid. MS (ESI): 475.1 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]4)[C:6]=2[CH:24]=1.[ClH:25].Cl.Cl.[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1>>[ClH:1].[ClH:25].[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH:45][C:21]([C:15]3[NH:16][C:17]4[C:13]([CH:14]=3)=[C:12]([O:11][CH2:10][C:7]3[C:6]5[CH:24]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[O:9][CH:8]=3)[CH:20]=[CH:19][CH:18]=4)=[O:23])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: CS(O[CH2:6][CH:7]1[N:17]2[CH:18]3[CH:13]([N:14]=[CH:15][C:16]2=[O:19])[CH:12]=[CH:11][C:10](=[O:20])[N:9]3[CH2:8]1)(=O)=O.N1C=CC=CC=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29][CH2:28]1.CO>C(#N)C.C(Cl)Cl>[O:19]=[C:16]1[CH:15]=[N:14][C:13]2=[C:18]3[N:17]1[CH:7]([CH2:6][N:27]1[CH2:28][CH2:29][CH:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:38])([CH3:37])[CH3:39])[CH2:31][CH2:32]1)[CH2:8][N:9]3[C:10](=[O:20])[CH:11]=[CH:12]2
Reactant: CS(=O)(=O)OCC1CN2C(=O)C=CC3N=CC(=O)N1C32
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CC2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Yield: 58 %

Procedure:
Crude (3,8-dioxo-1,2,5a,8b-tetrahydro-3H,8H-2a,5,8a-triazaacenaphthylen-2-yl)methyl methanesulfonate (6.950 g, 23.38 mmol) was dissolved in dry acetonitrile (200 ml) and the mixture was treated with pyridine (7.55 ml, 94.0 mmol) followed by 1,1-dimethylethyl 4-piperidinylcarbamate (10.30 g, 51.4 mmol). The mixture was stirred at reflux under argon for 3 h then at 50° C. over the weekend. The mixture was then stirred at 90° C. for 2 hours, then the volatiles were removed under reduced pressure and the residue was partitioned between DCM (600 ml) and water (100 ml). The organic phase was separated and the aqueous phase was extracted with DCM (2×200 ml). The combined organic extracts were washed with water (2×100 ml) dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to give a dark tan solid; this was taken up in a minimum of 5% MeOH in DCM and chromatographed on silica, eluting with 0-10% MeOH in DCM. Appropriate fractions were combined and evaporated under reduced pressure to give the title compound as an amorphous pale tan solid (5.444 g, 56.8%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[C:10]([O:13][C@@H:14]1[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:26]([O:32][C:33](=[O:35])[CH3:34])[CH2:25][S:24][C@H:15]1[O:16][C:17]1[CH:18]=[N:19][C:20](Br)=[CH:21][CH:22]=1)(=[O:12])[CH3:11]>>[C:10]([O:13][C@@H:14]1[C@@H:27]([O:28][C:29](=[O:31])[CH3:30])[C@H:26]([O:32][C:33](=[O:35])[CH3:34])[CH2:25][S:24][C@H:15]1[O:16][C:17]1[CH:18]=[N:19][C:20]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=2)=[CH:21][CH:22]=1)(=[O:12])[CH3:11]
Reactant: COc1cncc(Br)c1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Product: COc1cncc(-c2ccc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cn2)c1

Procedure:
By carrying out the operation analogously to example 137, starting from 3-bromo-5-methoxypyridine and 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, the desired product is obtained in the form of a white solid (yield=48%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)=[C:5]([CH3:18])[CH:4]=1)#[N:2].[CH3:19][N:20]([CH3:35])[CH2:21][CH2:22][O:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[CH:29][NH:30]2)=[CH:26][C:25]=1[O:33][CH3:34].C(C1C=CC(C2C=CC(C(O)=O)=CC=2)=CC=1C)(=O)C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([N:30]3[C:31]4[C:27](=[CH:26][C:25]([O:33][CH3:34])=[C:24]([O:23][CH2:22][CH2:21][N:20]([CH3:19])[CH3:35])[CH:32]=4)[CH:28]=[CH:29]3)=[O:17])=[CH:13][CH:14]=2)=[C:5]([CH3:18])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1ccc(C(=O)O)cc1
Reactant: COc1cc2cc[nH]c2cc1OCCN(C)C
Agent: CC(=O)c1ccc(-c2ccc(C(=O)O)cc2)cc1C
Product: COc1cc2ccn(C(=O)c3ccc(-c4ccc(C#N)cc4C)cc3)c2cc1OCCN(C)C

Procedure:
The title compound was prepared from 4'-cyano-2'-methylbiphenyl-4-carboxylic acid (D15) and 6-(2-dimethylaminoethoxy)-5-methoxy-1H-indole (D13) using a similar procedure to Example 4 as a white solid mp 140°-142° C. (42%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)=[N:6]2)[CH2:3][CH2:2]1.[Cl:27][C:28]1C=CC(CN2C(=O)C(CO)=CC(C3C=CC4OCCC=4C=3)=N2)=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:3]=[CH:2][C:1]([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][O:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:8][C:7]([C:18]3[CH:19]=[CH:20][C:21]4[O:25][CH2:24][CH2:23][C:22]=4[CH:26]=3)=[N:6]2)=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(CC2CC2)c1=O
Reactant: O=c1c(CO)cc(-c2ccc3c(c2)CCO3)nn1Cc1ccc(Cl)cc1
Product: CS(=O)(=O)OCc1cc(-c2ccc3c(c2)CCO3)nn(Cc2ccc(Cl)cc2)c1=O
Yield: 96.6 %

Procedure:
The general procedure of Example 1 (5) was carried out by use of 2-(4-chlorobenzyl)-6-(2,3-dihydro-1-benzofuran-5-yl)-4-hydroxymethyl-2H-pyridazin-3-one, to thereby yield the title compound as a yellow powder (yield: 96.6%).
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.C(O)(=O)/C=C/C(O)=O.[CH3:17][N:18]1[C:22]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]([NH2:28])[CH2:20][CH2:19]1.C([O-])(O)=O.[Na+].[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[Cl:44])[C:38](Cl)=[O:39]>C(Cl)(Cl)Cl>[CH3:17][N:18]1[C:22]2([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[CH:21]([NH:28][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][C:43]([Cl:44])=[C:35]([Cl:34])[CH:36]=2)[CH2:20][CH2:19]1
Reactant: CN1CCC(N)C12CCCCC2
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1CCC(NC(=O)c2ccc(Cl)c(Cl)c2)C12CCCCC2
Temperature: 25 °C
Yield: 44.8 %

Procedure:
To a stirring suspension of 3.0 g (0.017 mole) of 1-methyl-4-amino-1-azaspiro[4.5]decane of Example 2 and 5.0 g of NaHCO3 in 50 ml of CHCl3 was added dropwise 3.8 g (0.018 mole) of 3,4-dichlorobenzoyl chloride in 25 ml of CHCl3. The reaction was refluxed for 3 hours, cooled to room temperature, filtered, and the solvent evaporated to give an oil. The residue was triturated with boiling hexane and decanted, the hexane solution afforded 2.6 g of 1-methyl-4-(3,4-dichlorobenzamido)-1-azaspiro[4.5]decane on standing. The solid was dissolved in ether and a solution of ethereal HCl was added. The resulting solid was collected and recrystallized three times from ethanol to give 2.2 g (35%) m.p. 227°-228° C. of 1-methyl-4-(3,4-dichlorobenzamido)-1-azaspiro[4.5]decane hydrochloride.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH2:13][CH2:14][OH:15].C(N(CC)CC)C>ClCCl>[CH3:16][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:11])[CH2:13][CH:14]=[O:15]
Reactant: CC(C)(CCO)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(CC=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
Step B To a solution of oxalyl chloride (1.7 g, 13 mmol) (Aldrich) in dichloromethane (50 mL) at −78° C. was added the solution of dimethyl sulfoxide (1.9 mL, 27 mmol) in dichloromethane (10 mL) dropwise. After 5 mins, the solution of 3-methyl-3-phenyl-butan-1-ol (2 g, 12 mmol) in dichloromethane (10 mL) was added dropwise. The reaction mixture was stirred at −78° C. for 15 min. Triethylamine (6.1 mL, 44 mol) was added and the reaction mixture was slowly warmed up to room temperature and stirred at room temperature for 45 min. The water was added. The organic layers were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with 10% of HCl, saturated NaHCO3, brine, dried over MgSO4, and concentrated to give 3-methyl-3-phenyl-butyraldehyde as a colorless oil (Yield: 1.8 g, 90%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[Cl:26][C:27]1[C:28]([O:42][CH3:43])=[N:29][CH:30]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.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>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[C:3]([CH3:25])=[CH:4][CH:5]=[C:6]([NH:8][C:9]([C:11]3([C:14]4[CH:24]=[CH:23][C:17]5[O:18][C:19]([F:21])([F:22])[O:20][C:16]=5[CH:15]=4)[CH2:13][CH2:12]3)=[O:10])[N:7]=2)[CH:30]=[N:29][C:28]=1[O:42][CH3:43]
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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: ClCCl
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1Cl
Temperature: 80 °C
Yield: 27.4 %

Procedure:
To N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.2 mmol) in 1,2-dimethoxyethane (2 mL) was added 3-chloro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65 mg, 0.24 mmol), tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.01 mmol), and 2 M sodium carbonate (0.20 mL, 0.4 mmol). The reaction mixture was heated to 80° C. in an oil bath overnight. The reaction mixture was diluted with dichloromethane (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (26 mg, 27%). ESI-MS m/z calc. 473.86. found 474.3 (M+1)+. Retention time 2.27 minutes.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C1C(=O)N(Cl)C(=O)C1.[Cl:21][C:22]1[C:30]([F:31])=[C:29]2[C:25]([CH:26]=[CH:27][N:28]2[C:32]2[CH:33]=[N:34][N:35]([CH2:37][CH2:38][CH3:39])[CH:36]=2)=[CH:24][CH:23]=1>C(Cl)Cl.O>[Cl:21][C:22]1[C:30]([F:31])=[C:29]2[C:25]([C:26]([S:1][C:2]3[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=3)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:27][N:28]2[C:32]2[CH:33]=[N:34][N:35]([CH2:37][CH2:38][CH3:39])[CH:36]=2)=[CH:24][CH:23]=1
Reactant: CCCn1cc(-n2ccc3ccc(Cl)c(F)c32)cn1
Reactant: CCOC(=O)c1cccc(S)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: CCCn1cc(-n2cc(Sc3cccc(C(=O)OCC)c3)c3ccc(Cl)c(F)c32)cn1
Reaction time: 0.83 h
Yield: 60.7 %

Procedure:
To a stirred solution of ethyl 3-mercaptobenzoate (66 mg, 0.36 mmol) in CH2Cl2 (5 mL) under inert atmosphere was added NCS (48.2 mg, 0.36 mmol) at RT and stirred for 50 min. To this, compound 3 (100 mg, 0.36 mmol) was added at RT and stirred for 16 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (25 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 9% EtOAc/Hexanes to afford compound 4 (100 mg, 61%) as a colorless syrup. 1H NMR (500 MHz, CDCl3): δ 7.88 (s, 1H), 7.77-7.76 (m, 1H), 7.69 (s, 1H), 7.67 (s, 1H), 7.43 (s, 1H), 7.27-7.24 (m, 3H), 7.15-7.12 (m, 1H), 4.33 (q, J=7.5 Hz, 2H), 4.15 (t, J=7.0 Hz, 2H), 1.98-1.94 (m, 2H), 1.35 (t, J=7.5 Hz, 3H), 0.98 (t, J=7.0 Hz, 3H); LC-MS: 94.6%; m/z 458.4 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.91 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:3]=2[O:2]1.C1N2CN3CN(C2)CN1C3.Cl.FC(F)(F)[C:24](O)=[O:25]>>[OH:10][C:7]1[C:8]([CH:24]=[O:25])=[CH:9][C:3]2[O:2][CH2:1][O:5][C:4]=2[CH:6]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: O=Cc1cc2c(cc1O)OCO2

Procedure:
In a 500 mL recovery flask, 10.0 g (72.4 mmol) of sesamol (manufactured by Tokyo Chemical Industry Co., Ltd.) and 15.2 g (109 mmol, 1.5 eq) of hexamethylenetetramine (manufactured by Tokyo Chemical Industry Co., Ltd.) were dissolved in 100 ml of trifluoroacetic acid (manufactured by Kanto Chemical Co., Inc.) and reacted at 95° C. for 10 hours. After the reaction was completed, in an ice bath, 200 ml of 1 N hydrochloric acid was added thereto and the resultant was stirred for minutes. After the stirring was completed, the resultant was extracted with chloroform to obtain an extract. The extract was washed with hydrochloric acid and saturated saline, thereby obtaining 2.38 g (14.3 mmol) of 6-hydroxy-3,4-methylenedioxybenzaldehyde.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](C4C=CC=C5C=4CC(=O)N5C)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[C:45]1[CH:46]=[C:47]2[C:51](=[CH:52][CH:53]=1)[N:50]([CH3:54])[C:49](=[O:55])[CH2:48]2>>[C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:45]4[CH:46]=[C:47]5[C:51](=[CH:52][CH:53]=4)[N:50]([CH3:54])[C:49](=[O:55])[CH2:48]5)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1C(=O)Cc2cc(Br)ccc21
Reactant: Cc1cc2nc(-c3ccnc(-c4cccc5c4CC(=O)N5C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2nc(-c3ccnc(-c4ccc5c(c4)CC(=O)N5C)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-2-oxoindolin-5-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetic acid was prepared using in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(1-methyl-2-oxoindolin-4-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetic acid, except 5-bromo-1-methylindolin-2-one was used instead of 4-bromo-1-methylindolin-2-one. LCMS-ESI+: calc'd for C34H31ClN3O4S: 612.1 (M+H+); Found: 612.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ: 8.61 (d, 1H), 8.36 (s, 1H), 7.94 (d, 1H), 7.89 (m, 1H), 7.84 (m, 2H), 7.61-7.59 (m, 1H), 7.54-7.50 (m, 3H), 7.03 (d, 1H), 5.18 (s, 1H), 3.55 (s, 2H), 3.14 (s, 3H), 2.53 (s, 3H), 0.89 (s, 9H).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[C:17](=O)([O-])[O-].[Na+].[Na+]>O.CCOCC>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[CH2:12][CH2:13]1
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1

Procedure:
A solution of 1-(3-nitrophenyl)piperazine hydrochloride (1.80 g) in water (7 ml) was basified with anhydrous sodium carbonate (0.8 g) and the mixture evaporated to dryness in vacuo. The solid was mixed with formic acid (17 ml) and a solution of formaldehyde 36% in water (1.3 ml, ≡0.47 g CH2O) added and the mixture heated at 95°-98° for 3 h. The mixture was diluted with water (35 ml) and basified with anhydrous sodium carbonate. The suspension was extracted with ethyl acetate (2×80 ml) and the extract dried for 1 h. The mixture was filtered and the filtrate evaporated to dryness to give a dark red oil which was dissolved in ether (20 ml) and filtered. The filtrate was evaporated to dryness to give a red oil which was purified by FCC eluting with System A (500:8:1) to give an orange oil which was dried in vacuo. Upon scratching, crystallisation began and the oil was left to stand until crystallisation of the title compound was complete (1.10 g) m.p. 53°-54° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([NH:12][C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15](O)=O)=[CH:10][CH:9]=[N:8]1.P(Cl)(Cl)([Cl:24])=O.[OH-].[Na+]>O>[Cl:24][C:15]1[C:14]2[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:12]=[C:11]2[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:8]=[CH:9][C:10]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)c1ccccc1Nc1ccnn1-c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Clc1c2ccccc2nc2c1cnn2-c1ccccn1
Temperature: 25 °C
Yield: 76.4 %

Procedure:
A solution of 2-[[1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (62.0 g, 0.221 mol) in phosphorous oxychloride (166 g, 1.08 mol) was heated under reflux for 1 hour. The solution was allowed to cool to room temperature and poured into water. The solution was neutralized by addition of a sodium hydroxide solution, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform) to give the title compound (47.4 g, 76% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 98.8 %

Procedure:
3-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N,N-dimethylformamide (60 mL). Benzyl bromide (3.21 mL, 27.1 mmol) was added to this suspension, and stirred for 14 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-1:1) to obtain the title compound (5.16 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Cs+].I[CH:11]([CH3:13])[CH3:12]>CN(C=O)C>[CH:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:13])[CH3:12]
Reactant: CC(C)I
Reactant: Nc1ccccc1
Agent: [Cs+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)Nc1ccccc1
Temperature: 30 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
A mixture of aniline (0.46 mls, 5 mmol) and cesium hydroxide (0.61 mls, 15 mmol) was stirred at 25° C. for 30 mins in DMF (25 mls). 2-iodopropane (2.5 mls, 25 mmol) was added dropwise over 5 mins, the reaction was heated to 30° C. and stirred for 16 hours. The solvent was evaporated and the residue was quenched with 100 mL water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with CH2Cl2 and the combined organic layer was washed with water and then brine and was dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide the intermediate 4a (55 mg, 4 mmol, 81.4% yield) as an orange oil. 1H NMR (400 MHz, CDCl3) δ 7.11-7.02 (t, J=7.9 Hz, 2H), 6.63-6.54 (t, J=7.3 Hz, 2H), 6.54-6.45 (d, J=7.8 Hz, 1H), 3.60-3.45 (hept, J=6.3 Hz, 1H), 3.41-3.25 (s, 1H), 1.14-1.06 (d, J=6.3 Hz, 6H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:34])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[NH:33][N:32]=[CH:31][CH:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:34][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[NH:33][N:32]=[CH:31][CH:30]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccn[nH]5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccn[nH]5)cc4)CC3)n2CCS1
Yield: 66.4 %

Procedure:
A solution of the compound (295 mg, 0.60 mmol) obtained in Example 83-1) and 4 M hydrochloric acid (1,4-dioxane solution, 3 mL) in methanol (6 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, a 5 M aqueous sodium hydroxide solution (10 mL) was added to the residue, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=20:80) to obtain the title compound (152 mg, 66%) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:4].[C:25](Cl)(=[O:35])[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1>>[OH:24][C:13]1([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:14][CH2:15][CH:10]([N:8]2[CH2:9][CH:6]([NH:5][C:3]([CH2:2][NH:1][C:25]([C:26]3[CH:34]=[CH:33][C:32]4[O:31][CH2:30][O:29][C:28]=4[CH:27]=3)=[O:35])=[O:4])[CH2:7]2)[CH2:11][CH2:12]1
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)CN)C3)CC2)cn1
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4ccc5c(c4)OCO5)C3)CC2)cn1

Procedure:
The title compound was prepared as yellow solid from coupling of 2-amino-N-{1-[4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-acetamide, as prepared in Step D of Example 16, and piperonoyl chloride (Aldrich) using the procedure described in Example 18.