Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:29][C:30]1[N:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:36][C:33]3[CH:34]=[N:35][C:30]([Cl:29])=[CH:31][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc(Cl)nc4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 6-chloropyridine-3-carbaldehyde to the procedure of step 1, Example 66. MS (ESI) m/z 504.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:28]2([CH3:29])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:23])[CH2:21][OH:22])[CH2:11][C@@H:10]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:9]1.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][CH:39]=1>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:28]2([CH3:29])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:23])[CH2:21][O:22][S:44]([C:41]2[CH:42]=[CH:43][C:38]([CH3:48])=[CH:39][CH:40]=2)(=[O:46])=[O:45])[CH2:11][C@@H:10]([O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)[CH2:9]1
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](C)[C@H]2CC[C@H]3[C@@H]4CC=C5C[C@@H](OC6CCCCO6)C[C@H](OC6CCCCO6)[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 0 °C
Reaction time: 2.75 h
Yield: 72.6 %

Procedure:
To a stirred solution of 3.7 g of (20S)-1α,3β-bis[(tetrahydro-2H-pyran-2-yl)oxy]-20-methylpregn-5-en-21-ol in 5 ml of pyridine at 0° was added a solution of 1.77 g of p-toluenesulfonyl chloride in 3 ml of pyridine dropwise over 10 min. After 165 min. at 0°, the mixture was poured into ice water and extracted with ether. The ether extract was washed with water, dried (Na2SO4) and evaporated under reduced pressure. The residue was dissolved in 100 ml of toluene, concentrated in a 50° bath at 11 mm and applied to 80 g of silica gel containing 1% pyridine. Elution with hexane--ether, 7:3, afforded 3.49 g (73%) of (20S)-1α,3β-bis[(tetrahydro-2H-pyran-2-yl)oxy]-20-methyl-21-(p-toluenesulfonyloxy)pregn-5-ene as a white amorphous solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[O:15][CH3:16].O.C(C(O)=[O:23])(F)(F)F>CC#N>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH2:13][OH:23])=[CH:8][C:7]=1[O:15][CH3:16]
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)CO)ccc1OCCCCl

Procedure:
A solution of 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4.3 g, 17.7 mmol), [bis(trifluoroacetoxy)iodolbenzene (15.6 g, 36.2 mmol), H2O (18 ml), CF3CO2H (2.8 ml) and CH3CN (90 ml) was refluxed for 3 hours. The CH3CN was removed under reduced pressure and the resulting yellow liquid was partitioned between H2O and CH2Cl2. The biphasic mixture was filtered, the organic phase collected, washed with saturated NaHCO3 solution and concentrated to afford 1.5 g of an amorphous brown solid. The solid was flash chromatographed on silica gel, eluting the column with 5% EtOAc/CH2Cl2. Concentration of similar fractions afforded 0.7 g of the compound as a pale yellow solid, m.p. 99°-101° C.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][C:15]([NH:19][CH2:20][CH2:21][OH:22])=[N:16][CH:17]=3)[NH:12][N:11]=2)[CH:7]=[CH:6][N:5]=1)=O.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>>[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:28][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[N:14][C:15]([NH:19][CH2:20][CH2:21][OH:22])=[N:16][CH:17]=3)[NH:12][N:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CS(=O)c1nccc(-c2n[nH]c3nc(NCCO)ncc23)n1
Reactant: NCc1cccc(Cl)c1
Product: OCCNc1ncc2c(-c3ccnc(NCc4cccc(Cl)c4)n3)n[nH]c2n1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
The mixture of 2-[3-(2-methane sulfinyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-ethanol (from Example 21 supra) (1.9 g, crude, 2.31 mmol) and 3-chlorobenzylamine (797 mg, 4.62 mmol) was heated at 130° C. with stirring for 3 hours. The solvent was removed under reduced pressure and the solid was purified by prep-TLC and prep-HPLC. Concentrated HCl was added to the fractions with product and concentrated under reduced pressure to give 2-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-ethanol; hydrochloride. (Yield 28 mg, 3.1% of the 3 steps).
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19][C:20]([NH2:22])=[O:21])=[C:9]1[CH3:23].C(OC(=O)CC1C2C(=CC=C(OC)C=2)[N:37](CC2C=CC=CC=2C2C=CC=CC=2)C=1C)C.NN.O>C(O)C>[C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH2:19][C:20]([NH:22][NH2:37])=[O:21])=[C:9]1[CH3:23]
Reactant: CCOC(=O)Cc1c(C)n(Cc2ccccc2-c2ccccc2)c2ccc(OC)cc12
Reactant: COc1ccc2c(c1)c(CC(N)=O)c(C)n2Cc1ccccc1-c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)c(CC(=O)NN)c(C)n2Cc1ccccc1-c1ccccc1

Procedure:
1-([1,1'-Biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetamide. A mixture of 1.18 g (2.86 mmol) of 1-([1,1'-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester and 3 mL of hydrazine in 20 mL of ethanol was heated to maintain reflux for 16 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4), and concentrated to give 1.02 g of 1-([1,1'-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid hydrazide. A mixture of 576 mg (1.44 mmol) of this material and 300 mg of Raney Ni in 20 mL of ethanol was heated to maintain reflux for 3 hours. After cooling the solvent was decanted and the Raney Ni washed twice with methylene chloride. The combined organic solvents were concentrated at reduced pressure and the residue chromatographed on silica gel and eluted with ethyl acetate to give 369 mg (67% yield) of 1-([1,1'-biphenyl]-2-ylmethyl)-5-methoxy-2-methyl-1H-indole-3-acetamide.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH2:12][C@@H:13]([NH:17][C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]3[CH:32]=[CH:31][C:30]([C:33]4[N:34]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:35]=[CH:36][N:37]=4)=[CH:29][CH:28]=3)=[C:20]2[N:19]=1)[CH:14]([CH3:16])[CH3:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:56](OC(Cl)(Cl)Cl)=[O:57]>ClCCl>[Si:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:12][C@H:13]([CH:14]([CH3:16])[CH3:15])[N:17]([C:18]2[CH:23]=[CH:22][N:21]3[N:24]=[CH:25][C:26]([C:27]4[CH:28]=[CH:29][C:30]([C:33]5[N:34]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:44])([CH3:45])[CH3:43])[CH:35]=[CH:36][N:37]=5)=[CH:31][CH:32]=4)=[C:20]3[N:19]=2)[C:56]1=[O:57])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)[C@@H](CNCCO[Si](C)(C)C(C)(C)C)Nc1ccn2ncc(-c3ccc(-c4nccn4COCC[Si](C)(C)C)cc3)c2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[C@H]1CN(CCO[Si](C)(C)C(C)(C)C)C(=O)N1c1ccn2ncc(-c3ccc(-c4nccn4COCC[Si](C)(C)C)cc3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
To a stirred solution of (S)—N1-(2-(tert-butyldimethylsilyloxy)ethyl)-3-methyl-N2-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)butane-1,2-diamine (0.055 mmol) in dichloromethane (1 mL) was added diisopropylethylamine (0.019 mL, 0.14 mmol). Trichloromethyl chloroformate (0.010 mL, 0.083 mmol) was added dropwise at 0° C. under N2. The reaction mixture was stirred at 0° C. for 30 minutes, then diluted with dichloromethane, washed with aqueous saturated NaHCO3 and brine, dried and concentrated. The residue was purified by silica gel chromatography (dichloromethane:MeOH, 100:1) to give (S)-1-(2-(tert-butyldimethylsilyloxy)ethyl)-4-isopropyl-3-(3-(4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)imidazolidin-2-one (15 mg, 40% for two steps). LCMS (APCI+) m/z 676.9 [M+H]
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]1[C:13](OCC)=[N:12][S:11](=[O:18])(=[O:17])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[CH3:31][C:32]1[CH:33]=[C:34]([NH:38][C:39]([NH:41][CH2:42][CH2:43][NH2:44])=[O:40])[CH:35]=[CH:36][CH:37]=1.C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6](=[O:27])[C@H:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[NH:8][C:9]1[C:13]([NH:44][CH2:43][CH2:42][NH:41][C:39]([NH:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([CH3:31])[CH:33]=2)=[O:40])=[N:12][S:11](=[O:17])(=[O:18])[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC1=NS(=O)(=O)N=C1N[C@@H](Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Reactant: Cc1cccc(NC(=O)NCCN)c1
Agent: O=C[O-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)NCCNC2=NS(=O)(=O)N=C2N[C@@H](Cc2ccc(O)cc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a solution of N-(4-ethoxy-1,1-dioxo-1,2,5-thiadiazol-3-yl)-L-tyrosine tert-butyl ester from Step A (150 mg, 0.38 mmol) and the formate salt of 2-(3-methylphenylaminocarbonylamino)eth-1-ylamine from Step B (210 mg, 0.89 mmol) in ethanol (10 mL) was added triethylamine (133 mg, 1.44 mmol). The reaction was stirred at room temperature overnight. Solvent was removed under reduced pressure and the residue purified by flash column chromatography (silica, 5% MeOH in EtOAc)to give the title compound (130 mg, 91%).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][C@@H:5]([NH:7][C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:4][N:3]1C(OC(C)(C)C)=O.Cl>CO.O1CCOCC1>[CH3:1][C@@H:2]1[NH:3][CH2:4][C@H:5]([NH:7][C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[CH2:6]1
Reactant: C[C@H]1C[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H]1C[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 121.5 %

Procedure:
The intermediate of step F (0.6 g, 1.4 mmol) was dissolved in MeOH (3 mL) and a solution of 4 N HCl in dioxane (3 mL). After being stirred at room temperature for 4 hours, the solution was concentrated to give 0.56 g of the title compound. MS calculated (M+H)+ 330. found 330.2.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[C:25]([C:35]([F:38])([F:37])[F:36])[CH:24]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:29]1([C:26]2[CH:27]=[CH:28][C:23]([CH2:22][O:21][C:18]3[CH:19]=[CH:20][C:15]([CH:12]4[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]([OH:39])=[O:5])[CH2:14][CH2:13]4)=[CH:16][CH:17]=3)=[CH:24][C:25]=2[C:35]([F:38])([F:36])[F:37])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)CCN1CCC(c2ccc(OCc3ccc(C4CCCCC4)c(C(F)(F)F)c3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCN1CCC(c2ccc(OCc3ccc(C4CCCCC4)c(C(F)(F)F)c3)cc2)CC1
Reaction time: 2 h

Procedure:
3-{4-[4-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-phenyl]-piperidin-1-yl}-propionic acid tert-butyl ester is dissolved in DCM and treated with TFA (50% v/v). After 2 h at room temperature, it is concentrated to give a residue which is purified by RP LC-MS to give 3-{4-[4-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-phenyl]-piperidin-1-yl}-propionic acid. 1HNMR (400 MHz, CD3OD) δ 7.83 (1H, s), 7.65 (1H, d), 7.55 (1H, d), 7.20 (4H, m), 5.45 (2H, s), 3.66 (2H, d), 3.44 (2H, m), 3.20 (2H, m), 2.81 (2H, m), 2.68 (2H, m), 1.84 (9H, m), 1.36 (5H, m). MS (ES+): 490.3 (M+1)+.
Reaction SMILES: [OH-:1].[Na+].[CH:3]([C:5]1[CH2:11][C:10]2[CH:12]=[C:13]3[O:18][CH2:17][O:16][C:14]3=[CH:15][C:9]=2[C:8]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[N:7][N:6]=1)=[O:4]>O.O1CCOCC1.[N+]([O-])([O-])=O.[Ag+]>[N+:25]([C:22]1[CH:21]=[CH:20][C:19]([C:8]2[C:9]3[CH:15]=[C:14]4[O:16][CH2:17][O:18][C:13]4=[CH:12][C:10]=3[CH2:11][C:5]([C:3]([OH:1])=[O:4])=[N:6][N:7]=2)=[CH:24][CH:23]=1)([O-:27])=[O:26]
Reactant: O=CC1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Reactant: [OH-]
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C1=NN=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
42 ml of a 4% NaOH solution is added to a solution of 3.0 g of AgNO3 in water (50 ml). The solution of 3.0 g of 8-formyl-5-(4-nitrophenyl)-9H-1,3-dioxolo[4,5-h-][2,3]-benzodiazepine in 120 ml of dioxane is slowly added to the heterogeneous mixture, and the reaction mixture is stirred for 30 minutes at 25° C. After activated carbon is added, it is filtered, the filtrate is concentrated by evaporation in a vacuum at 50-60° C., the suspension that is produced is diluted with 30 ml of water and cooled. After standing overnight, it is filtered off, the precipitate is washed with 2×10 ml of ice water, and 1.94 g of sodium salt, which is dissolved in 60 ml of hot water and, after cooling, acidified with 1 ml of acetic acid, is obtained. After filtration and washing with water, 1.66 g (53%) of product with a melting point of 196-198° C. (decomposition) is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.S(=O)(=O)(O)O.[CH2:16](O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:7])=[CH:4][N:3]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc(O)nc1
Agent: O=S(=O)(O)O
Product: O=C(OCc1ccccc1)c1ccc(O)nc1
Temperature: 0 °C

Procedure:
30 g of 6-hydroxynicotinic acid were treated with 500 ml of benzyl alcohol and 1 ml of concentrated sulfuric acid. After boiling at reflux for 3 days, the reaction mixture was poured on to ice-water, extracted several times with ethyl acetate, washed with water, dried over sodium sulfate and evaporated, firstly in a water-jet vacuum and then in a high vacuum. The semi-crystalline residue was filtered over silica gel (eluent hexane/ethyl acetate=2:1, then ethyl acetate) and recrystallized from ethyl acetate/hexane. There were obtained 19 g of benzyl 6-hydroxy-nicotinate in colourless crystals, m.p. 178-179° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][NH:26][C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=4)[C:27]([NH:26][CH3:25])=[O:28])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CNC(=O)c1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CNC(=O)c1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)c1
Temperature: 120 °C
Yield: 4.2 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(methylcarbamoyl)phenylboronic acid (18.6 mg, 0.104 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and preparative HPLC to give pure 3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N-methylbenzamide (0.96 mg, 4%). 1H-NMR (CDCl3): 2.36 (d, 1H), 2.57 (t, 1H), 2.73 (s, 3H), 2.97 (s, 3H), 5.87 (d, 1H), 7.11 (m, 2H), 7.45 (m, 8H), 7.51 (m, 1H), 7.60 (s, 1H), 7.78 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].Cl[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[N:29]=[C:30]([NH2:32])[S:31][C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26]2[N:29]=[C:30]([NH:32][C:7]([O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:8])[S:31][C:25]=2[CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)sc2C1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)Oc3ccccc3)sc2C1
Reaction time: 15 h
Yield: 81.6 %

Procedure:
39 g calcium carbonate and 36.8 g phenyl chloroformate in 250 mL THF was added to a stirred solution of 50 g 2-amino-6,7-dihydro-4H-thiazolo (5,4-c)pyridine-5-carboxylic acid tert-butyl ester in 1 L THF. The reaction mixture was allowed to stir for 15 h. The reaction mixture was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate and the organic layer was dried over magnesium sulfate. The organic layer was concentrated under reduced pressure. The residue was washed with 20% ethyl acetate in hexane to give 60 g of the desired product.
Reaction SMILES: [CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=O)[NH2:23])=[CH:18][N:17]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)(Cl)(Cl)Cl>[CH2:1]([CH:7]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][N:17]=3)[CH:13]=2)[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCC1Cc2ccc(-c3ccc(C(N)=O)cn3)cc2C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CCCCCCC1Cc2ccc(-c3ccc(C#N)cn3)cc2C1
Reaction time: 10 h
Yield: 36.5 %

Procedure:
Then, 2.00 g (6.20 mM) of 2-hexyl-5-(5-carbamoylpyridine-2-yl)indan was dissolved in 20 ml of dry THF. To the solution, a solution of 4.89 g (18.6 mM) of triphenylphosphine in 15 ml of carbon tetrachloride was added, followed by stirring 10 hours to obtain an insoluble matter. The insoluble matter was recovered by filtration and washed with toluene. The resultant mixture was added to the filtrate and evaporated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=100/1), followed by distilling-off of the solvent and addition of methanol to obtain an insoluble matter. The insoluble matter was recovered by filtration to obtain 0.69 g of 2-hexyl-5-(5-cyanopyridine-2-yl)indan (Yield: 36.5%). ##STR303## (2) Production of 2-hexyl-5-(5-decanoylpyridine-2-yl)indan
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2.CC(C)([O-])C.[K+].C[N:25]1CCCC1=O.[NH2:31][O:32][S:33]([OH:36])(=[O:35])=[O:34].CN1CCCC1=O>CN1CCCC1=O>[NH2:31][O:32][S:33]([OH:36])(=[O:35])=[O:34].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([NH2:25])[CH:13]=[CH:12]2
Reactant: CN1CCCC1=O
Reactant: COc1ccc2[nH]ccc2c1
Agent: CC(C)(C)[O-]
Agent: NOS(=O)(=O)O
Agent: [K+]
Product: COc1ccc2c(ccn2N)c1
Reaction time: 1.43 h
Yield: 87 %

Procedure:
A solution of 10.0 g (9.7 g corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) in 33.7 g of N-methylpyrrolidinone (NMP) is prepared and chilled to 0–5° C. A second solution is prepared from 20.1 g (19.1 g corrected for 95% purity) of potassium tert-butoxide and 34.4 g of NMP. An amination vessel is charged with 5.9 g of 5-methoxyindole, 17.8 g of NMP and an initial charge of 0.7 g of the potassium tert-butoxide/NMP solution. The HOSA/NMP solution and the remaining potassium tert-butoxide/NMP solution are then simultaneously and proportionally metered into the amination vessel over a period of 86 minutes while maintaining a reaction temperature of 15–22° C. to yield a solution containing 5.6 g (87% yield) of 5-methoxy-1H-indol-1-amine as determined by internal standard HPLC assay.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1)[NH2:5].[O:23]=[C:24]1[N:28]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH2:27][CH2:26][N:25]1[C:35](Cl)=[O:36].O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:5][C:35]([N:25]2[CH2:26][CH2:27][N:28]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:24]2=[O:23])=[O:36])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1
Reactant: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3Cl)ccn2)cn1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Solvent: ClCCl
Solvent: O
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)c(F)c3Cl)ccn2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
A mixture of 3-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.250 g, 0.784 mmol) and TEA (0.150 mL, 1.076 mmol) in DCM (5 mL) was treated drop-wise with a solution of Example B2 (0.219 g, 0.941 mmol) in DCM (5 mL), warmed to RT and stirred overnight. The mixture was treated with water, extracted with DCM (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with MeCN, sonicated and the resulting solid collected via filtration to afford N-(3-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (242 mg, 60%). 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.26 (s, 1 H), 8.18 (t, J=8.9 Hz, 1 H), 7.97 (s, 1 H), 7.25-7.20 (m, 2 H), 6.65 (dd, J=5.7, 2.4 Hz, 1 H), 3.90 (m, 3 H), 3.84 (s, 3 H), 3.81 (m, 2 H), 3.47 (m, 2 H), 3.38 (m, 2 H), 1.77-1.65 (m, 2 H), 1.59 (m, 2H); MS (ESI) m/z: (M+H+): 515.1.