Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.BrCC1CCCCO1.[CH3:19][N:20]([CH3:48])[C:21]1[N:26]=[CH:25][C:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[C:29]2([C:40]4=[CH:41][C:42]5[O:46][CH2:45][O:44][C:43]=5[CH:47]=[C:39]4[O:38][CH2:37]2)[C:30](=[O:36])[NH:31]3)=[CH:23][CH:22]=1>>[CH3:19][N:20]([CH3:48])[C:21]1[N:26]=[CH:25][C:24]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[C:29]2([C:40]4=[CH:41][C:42]5[O:46][CH2:45][O:44][C:43]=5[CH:47]=[C:39]4[O:38][CH2:37]2)[C:30](=[O:36])[N:31]3[CH2:2][C:3]2[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=2)=[CH:23][CH:22]=1
Reactant: CN(C)c1ccc(-c2cccc3c2C2(COc4cc5c(cc42)OCO5)C(=O)N3)cn1
Reactant: CC(C)c1nc(CCl)cs1
Agent: BrCC1CCCCO1
Product: CC(C)c1nc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3c(-c4ccc(N(C)C)nc4)cccc32)cs1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 4-(chloromethyl)-2-isopropylthiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-[6-(dimethylamino)pyridin-3-yl]spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1H)-one, 4′-[6-(dimethylamino)pyridin-3-yl]-1′-{[2-(1-methylethyl)-1,3-thiazol-4-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (73%) as a colorless solid: mp 164-165° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ7.58 (d, J=2.3 Hz, 1H), 7.49 (s, 1H), 7.32 (dd, J=7.8, 7.8 Hz, 1H), 7.06 (d, J=7.9 Hz, 1H), 6.82-6.76 (m, 2H), 6.42-6.37 (m, 3H), 5.96 (d, J=19.0 Hz, 2H), 5.11 (d, J=16.0 Hz, 1H), 4.89 (d, J=16.0 Hz, 1H), 4.57 (d, J=9.4 Hz, 1H), 4.42 (d, J=9.4 Hz, 1H), 3.29-3.20 (m, 1H), 2.99 (s, 6H), 1.31 (d, J=6.9 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 177.5, 176.9, 157.9, 155.4, 149.9, 148.3, 146.6, 142.6, 141.5, 136.8 (2C), 129.2, 128.8, 125.2, 121.7, 121.1, 115.3, 108.6, 104.3, 102.6, 101.3, 93.2, 77.2, 57.8, 37.6, 32.4, 22.8, 22.7; MS (ES+) m/z 541.3 (M+1).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][N:33]([CH3:38])[CH2:34][CH2:35][CH2:36][OH:37].[N+:39]([C:42]1[CH:47]=[CH:46][C:45](O)=[CH:44][CH:43]=1)([O-:41])=[O:40]>>[CH3:32][N:33]([CH2:34][CH2:35][CH2:36][O:37][C:45]1[CH:46]=[CH:47][C:42]([N+:39]([O-:41])=[O:40])=[CH:43][CH:44]=1)[CH3:38]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CN(C)CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CN(C)CCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.2 %

Procedure:
A stirred solution of diethyl azodicarboxylate (4.6 ml, 0.029 mole) and triphenylphosphine (7.60 g, 0.029 mole) in dry TBF (100 ml) was cooled to 0° C. 3-(Dimethylamino)propanol (3.43 ml, 0.029 mole) was added, followed by 4-nitrophenol (4.0 g, 0.029 mole) and the reaction mixture was stirred for 18 h at room temperature. The solvent was removed in vacuo, and the residue partitioned between 5N HCl and ethyl acetate. The aqueous layer was basified with 10% NaOH solution and extracted into ethyl acetate, dried (MgSO4) and evaporated in vacuo to leave the title compound as a yellow oil (3.2 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([OH:12])[CH3:11].O[C:14]1[C:15]([N+:20]([O-:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:14]1[C:15]([N+:20]([O-:22])=[O:21])=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:11]
Reactant: CC(O)c1c(Cl)ccc(F)c1Cl
Reactant: O=[N+]([O-])c1ncccc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1cccnc1[N+](=O)[O-])c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
1-(2,6-dichloro-3-fluorophenyl)ethanol (29.1 g, 139 mmol) and 3-hydroxy-2-nitropyridine (24.1 g, 153 mmol) were dissolved in anhydrous tetrahydrofuran (300 mL), and triphenylphosphine (PPh3, 51.1 g, 195 mmol) was added and the mixture was stirred for 1 h at room temperature. At 0° C., to the reaction liquid was added diisopropyl azodicarboxylate (DIAD, 38.4 mL, 195 mmol) dropwise. The resultant mixture was stirred overnight at room temperature. The resultant mixture was evaporated under reduced pressure to remove solvent, then purified via silica gel column chromatography (petroleum ether:ethyl acetate=3:1) to yield the target product as white crystals (41.2 g, 124 mmol; yield=89%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[CH3:9][C:10]1[CH:18]=[C:17]([C:19]([F:28])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])[CH:16]=[C:15]([CH3:29])[C:11]=1[C:12](Cl)=[O:13]>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:12](=[O:13])[C:11]2[C:10]([CH3:9])=[CH:18][C:17]([C:19]([F:28])([C:20]([F:21])([F:22])[F:23])[C:24]([F:25])([F:26])[F:27])=[CH:16][C:15]=2[CH3:29])[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(N)c1
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1C(=O)Nc1cccc(N)c1
Temperature: 70 °C
Reaction time: 48 h
Yield: 0.1 %

Procedure:
To a solution of benzene-1,3-diamine (4.48 g, 41.4 mmol) in anhydrous tetrahydrofuran (3 ml) under an atmosphere of nitrogen was added 2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzoyl chloride (4.40 g, 13.8 mmol) (Example I4) dissolved in anhydrous tetrahydrofuran (3 ml). The reaction mixture was stirred at 70° C. for 48 hours. Then the reaction mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate (saturated). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to give N-(3-amino-phenyl)-2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzamide (3.4 mg, 61% yield). 1H-NMR (CDCl3, 400 MHz): 7.34 (t, 1H), 7.30 (s, 2H), 7.15 (t, 1H), 6.75 (d, 2H), 6.52 (d, 2H), 2.46 (s, 6H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[Br:27]Br>C(Cl)(Cl)Cl>[Br:27][C:14]1[CH:13]=[CH:12][C:11]2[N:10]([N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[CH:15]=1
Reactant: BrBr
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3ccccc23)cc1
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3cc(Br)ccc23)cc1
Yield: 33 %

Procedure:
A mixture of 4-[2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide (0.062 g 0.17 mmol) and bromine (0.03 g 0.17 mmol) in chloroform (3 ml) was heated under reflux for 24 hours. The reaction mixture was diluted with chloroform (20 ml), washed with M sodium thiosulphate (10 ml), water (10 ml) and dried. Removal of solvent gave a brown solid which was purified by SPE chromatography. Elution with cyclohexane/ethyl acetate (10/1) gave the title compound as a white solid (0.025 g 32%). MH+: 446, 448; NMR: (d6-acetone): δ 6.55 (2H, br) 7.05 (2H, t) 7.30 (1H, d) 7.45 (2H, d) 7.50 (2H, m) 7.55 (1H, d) 7.80 (2H, d) 8.80 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[C:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)(=[O:18])[CH3:17]>>[C:16]([C:19]1[CH:20]=[CH:21][C:22]([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:23][CH:24]=1)(=[O:18])[CH3:17]
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: COc1ccc(CNc2ccc(C(C)=O)cc2)cc1
Product: COc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)=O)cc2)cc1
Yield: 24.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.63 g) and (4-acetylphenyl)[(4-methoxyphenyl)methyl]amine (0.78 g) as starting materials, N-(4-acetylphenyl)-7-methoxy-N-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.33 g) was obtained.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH:30]4[CH2:32][CH2:31]4)=[CH:28][C:27]([C:33]([F:36])([F:35])[F:34])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:37])[CH:11]=1>>[CH:30]1([C:29]2[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:7]5[C@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]5=[O:8])=[CH:11][C:12]=4[F:37])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=[C:27]([C:33]([F:35])([F:36])[F:34])[CH:28]=2)[CH2:32][CH2:31]1
Reactant: O=C1CC[C@@H](CO)N1
Reactant: O=C(c1ccc(Br)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Product: O=C(c1ccc(N2C(=O)CC[C@H]2CO)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one and (4-bromo-2-fluorophenyl)[4-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazin-1-yl]methanone (945 mg) described in Preparation Example 123 and by the reaction and treatment in the same manner as in Example 1, the title compound (371 mg) was obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[CH3:11][O:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][C:18](=O)[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:11][O:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=1
Reactant: COC(=O)CCCCC(=O)Nc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1I
Product: COC(=O)CCCCc1nc2ccccc2n1-c1ccccc1
Yield: 88.2 %

Procedure:
Method A applied to 1-iodo-2-nitrobenzene (125 mg, 0.5 mmol) and 5-phenylcarbamoyl-pentanoic acid methyl ester (141 mg, 0.6 mmol) yielded the title compound as brown oil (136 mg, 88%). 1H NMR (DMSO) δ 1.50-1.74 (m, 4H), 2.27 (d, J=7.2Hz, 2H), 2.89 (d, J=7.5Hz, 2H), 3.52 (s, 3H), 7.22 (d, J=8.1Hz, 1H), 7.38 (apparent t, J=7.6Hz, 1H), 7.46 (apparent t, J=7.6Hz, 1H), 7.52-7.72 (m, 5H), 7.79 (d, J=7.8 Hz, 1H); 13C NMR δ 23.3, 25.3, 25.4, 32.2, 50.9, 111.3, 115.6, 124.3, 124.4, 126.8, 130.0, 132.4, 133.2, 133.4, 153.9, 172.3. HRMS (FAB): cal. for C19H21N2O2 [M+H+]: 309.1603; found: 309.1595.
Reaction SMILES: [N:1]([CH2:4][CH3:5])=[C:2]=[O:3].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][C:16]3[N:17]([C:19]([CH2:22][C:23]4[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=4)[NH2:26])=[CH:20][N:21]=3)[N:18]=2)=[CH:9][C:8]=1[F:30].C(N(CC)CC)C>C(#N)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[N:15][C:16]3[N:17]([C:19]([CH2:22][C:23]4[CH:24]=[C:25]([NH:26][C:2]([NH:1][CH2:4][CH3:5])=[O:3])[CH:27]=[CH:28][CH:29]=4)=[CH:20][N:21]=3)[N:18]=2)=[CH:9][C:8]=1[F:30]
Reactant: CCN=C=O
Reactant: Nc1cccc(Cc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNC(=O)Nc1cccc(Cc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.6 %

Procedure:
Isocyanatoethane (1.3 μL, 0.019 mmol) were added to a mixture of 3-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]methylaniline (5 mg, 0.01 mmol) and triethylamine (7.0 μL, 0.050 mmol) in acetonitrile (0.5 mL). After the reaction mixture was stirred at RT for 30 min, it was purified by RP-HPLC (pH 10) to afford the desired product (2 mg, 30%). LCMS: (M+H)=469.0/470.8.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].[C:9]([O:13][C:14]([N:16]1C(C2C=CC(C#N)=CC=2)O1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C)C=O>[Br:1][C:2]1[N:3]=[CH:4][N:5]([NH:16][C:14](=[O:15])[O:13][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1OC1c1ccc(C#N)cc1
Reactant: Brc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nn1cnc(Br)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56.8 %

Procedure:
4-Bromo-1H-imidazole (3.2 g, 21.8 mmol) was weighed into a 500 mL round bottomed flask equipped with a magnetic stir bar under a nitrogen atmosphere. Anhydrous N,N-dimethylformamide (DMF, 12 mL) was added and the mixture was placed on ice. After 10 minutes the mixture was treated with sodium hydride (0.840 g, 21.0 mmol 60% dispersion in oil). After 5 minutes, the ice bath was removed and the reaction warmed to room temperature. After 15 minutes of vigorous stirring the ice bath was re-inserted and 3-(4-cyano-phenyl)-oxaziridine-2-carboxylic acid tert-butyl ester (1.92 g, 7.80 mmol) was added. The reaction was vigorously stirred for 5 minutes and the ice bath was removed. After 5 minutes the mixture was diluted with saturated sodium bicarbonate and extracted with ethyl acetate. The organics were washed with dilute sodium carbonate, dried over sodium sulfate, and concentrated. The residue was purified using silica gel chromatography (0-5% methanol/dichloromethane) to afford the title compound (1.16 g, 4.43 mmol, 57%) as a yellow oil: 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 7.36 (d, J=1.5 Hz, 1H), 6.97 (d, J=1.5 Hz, 1H), 1.48 (s, 9H); ESIMS m/z 262 ([M]+), 260 ([M−2]−).
Reaction SMILES: [Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][N:10]([CH:16]=O)[NH:11][C:12]([O:14][CH3:15])=[O:13].C([O-])(=O)C.[NH4+].C([NH2:26])=O.C(#N)C>O>[Br:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]1[N:26]=[CH:16][N:10]([NH:11][C:12](=[O:13])[O:14][CH3:15])[CH:9]=1
Reactant: COC(=O)NN(C=O)CC(=O)c1cnn(C)c1Br
Reactant: NC=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC(=O)Nn1cnc(-c2cnn(C)c2Br)c1
Temperature: 130 °C
Reaction time: 0.17 h

Procedure:
Methyl 2-[2-(5-bromo-1-methyl-1H-pyrazol-4-yl)-2-oxoethyl]-2-formylhydrazine carboxylate (1.20 g, 3.76 mmol) was mixed with ammonium acetate (1.16 g, 15.0 mmol), formamide (4 mL) and acetonitrile (5 mL). The reaction was heated to 130° C., and the acetonitrile was allowed to boil off for 10 minutes. Heating was continued for an additional 4 hours. After addition of water, the crude mixture was extracted eight times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo; purification via silica gel chromatography (Gradient: 0% to 100% [10% methanol in ethyl acetate] in heptane) afforded the product as a pinkish solid. Yield: 800 mg, 2.67 mmol, 19% over two steps. LCMS m/z 299.8 (M+1). 1H NMR (400 MHz, CD3OD) δ 3.80 (br s, 3H), 3.90 (s, 3H), 7.52 (d, J=1.3 Hz, 1H), 7.77 (d, J=1.3 Hz, 1H), 7.85 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:19]1([CH2:22][C:23]2[C:28]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](S(C)=O)[N:30]=3)=[CH:27][N:26]=[C:25]([NH:38][CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])[N:24]=2)[CH2:21][CH2:20]1>C1COCC1>[Cl:8][C:4]1[CH:3]=[C:2]([NH:1][C:31]2[N:30]=[C:29]([C:28]3[C:23]([CH2:22][CH:19]4[CH2:21][CH2:20]4)=[N:24][C:25]([NH:38][CH2:39][C:40]([CH3:43])([OH:42])[CH3:41])=[N:26][CH:27]=3)[CH:34]=[CH:33][N:32]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: CS(=O)c1nccc(-c2cnc(NCC(C)(C)O)nc2CC2CC2)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(O)CNc1ncc(-c2ccnc(Nc3ccnc(Cl)c3)n2)c(CC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.3 %

Procedure:
To a solution of 4-amino-2-chloropyridine (53.3 mg, 0.415 mmol) in THF (277 μl) cooled to −78° C. under nitrogen, LiHMDS (415 μl, 0.415 mmol) was added dropwise. The reaction mixture was warmed up to rt, then was stirred for 30 min. To the reaction mixture cooled back to −78° C., 1-(4′-(cyclopropylmethyl)-2-(methylsulfinyl)-4,5′-bipyrimidin-2′-ylamino)-2-methylpropan-2-ol (5-3) (50 mg, 0.138 mmol) was added, and the reaction mixture was warmed up to rt, then was stirred for additional 1 h. According to LC/MS, the reaction was complete. The crude product was purified by reverse-phase HPLC [30-100% organic phase over 15 min] followed by Biotage silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to obtain the desired product (29 mg, 49%).
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[SH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1>>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1)[S:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[CH3:7]
Reactant: CCOC(=O)C(Br)c1cccc(Cl)c1
Reactant: Oc1ccc(S)cc1
Product: CCOC(=O)C(Sc1ccc(O)cc1)c1cccc(Cl)c1
Yield: 82 %

Procedure:
Ethyl(3-chlorophenyl)[(4-hydroxyphenyl)sulfanyl]acetate was prepared according to the general method as outlined in example 1 (step 1), starting from ethyl bromo(3-chlorophenyl)acetate (6.16 g, 16.5 mmol) and 4-mercaptophenol (2.08 g, 16.5 mmol); 4.36 g clear oil. Yield 82%; MS: 321 (M−H)−
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:18][O:5][C:4](=[O:6])[CH2:3][CH:2]([NH2:1])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([I:13])[CH:8]=1
Reactant: NC(CC(=O)O)c1cccc(I)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CC(N)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a suspension of (±)-3-Amino-3-(3-iodo-phenyl)-propionic acid (3.1 g, 10.6 mmol) in methanol was added thionyl chloride (0.95 mL, 12.7 mmol) and the reaction was stirred at room temperature overnight. Concentration followed by trituration with ether gives a white solid. The solid is filtered, washed with ether and dried to afford the desired product (3.5 g, 10 mmol, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.79 (br, 2H), 8.01 (s, 1H), 7.74 (d, J=8.1 Hz, 1H). 7.57 (d, J=7.8 Hz, 1H), 7.21 (dd, J=8.1, 7.8 Hz, 1H), 4.56 (br, 1H), 3.54 (s, 3H), 3.23-3.17 (m, 1H), 3.04-2.98 (m, 1H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([Mg]Cl)(C)C.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[CH:27][N:28]3[C:37]=2[CH:36]=[C:35]2[C@@:30]([CH3:40])([C@@H:31]([CH:38]=[O:39])[CH2:32][CH2:33][CH2:34]2)[CH2:29]3)=[CH:21][CH:20]=1>C1COCC1>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[CH:27][N:28]3[C:37]=2[CH:36]=[C:35]2[C@@:30]([CH3:40])([C@@H:31]([CH:38]([OH:39])[C:2]4[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=4)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:32][CH2:33][CH2:34]2)[CH2:29]3)=[CH:21][CH:20]=1
Reactant: C[C@]12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCC[C@@H]2C=O
Reactant: CCOC(=O)c1cccc(I)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(C(O)[C@H]2CCCC3=Cc4c(-c5ccc(F)cc5)ncn4C[C@@]32C)c1
Reaction time: 1 h

Procedure:
To a stirred solution of ethyl 3-iodobenzoate (0.17 mL, 1 mmol) in anhydrous THF (2 mL) cooled in an acetonitrile-dry ice bath was added isopropylmagnesium chloride solution (2M in THF, 0.5 mL, 1 mmol) dropwise under nitrogen. The reaction mixture was stirred at the same temperature for 30 min before (5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinoline-6-carbaldehyde (Example 1g, 55 mg, 0.18 mmol) was added. The mixture was stirred in an acetonitrile-dry ice bath for 1 hr before being quenched by the addition of saturated aqueous ammonium chloride solution (3 mL) at the same temperature. The reaction mixture was extracted with ethyl acetate (3×3 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Silica gel flash chromatography (25-100% ethyl acetate in heptanes, then 0-10% methanol in ethyl acetate) gave ethyl 3-(((5aR,6S)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)(hydroxy)methyl)benzoate as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[C:15]([C:24]([O:26][CH3:27])=[O:25])=[N:14]1.S(OCC)(O[CH2:32][CH3:33])(=O)=O.[H-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][CH2:32][CH3:33])=[C:16]([S:19][C:20]([F:21])([F:22])[F:23])[C:15]([C:24]([O:26][CH3:27])=[O:25])=[N:14]1
Reactant: CCOS(=O)(=O)OCC
Reactant: COC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOc1c(SC(F)(F)F)c(C(=O)OC)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl

Procedure:
The intermediate was prepared according to process SCHEME I of EXAMPLE 1c by reacting 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methoxycarbonyl-4-trifluoromethylsulfenyl-5-hydroxypyrazole with diethyl sulfate and sodium hydride in dioxane. The following spectral data were obtained: MS, m/e=482(M+); NMR (CDCl3) δ1.43 (t, J=7.0 Hz, C2H5), 3.73 (s, OCH3), 4.4 (q, J=7.0, OCH2), and 7.76 (s, 2H aromatic).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH:18]1([C:21]([CH3:29])([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[NH2:22])[CH2:20][CH2:19]1>>[CH:18]1([C:21]([NH:22][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])([C:23]2[N:27]=[C:26]([CH3:28])[O:25][N:24]=2)[CH3:29])[CH2:20][CH2:19]1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(N)C2CC2)no1
Product: Cc1nc(C(C)(NC(=O)c2cnc(C3CC3)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.42 mmol) and α-cyclopropyl-α,5-dimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1155536-64-3, 106.88 mg, 0.64 mmol) as starting materials, and isolated (12 mg, 7.3%) as white solid; LC-MS (UV peak area, ESI) 83.46%, 384.0 (M+H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH3:18])([O:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H].C>C(O)C>[CH3:18][C:11]1([O:14][CH2:15][CH2:16][OH:17])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC1(OCCO)CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Solvent: CCO
Product: CC1(OCCO)CCNCC1
Yield: 73 %

Procedure:
A solution of 51.5 g of 2-(1-benzyl-4-methyl-4-piperidyloxy)-ethanol in 500 ml of absolute ethanol was reacted with hydrogen at 50° C in the presence of 5 g of 5% palladized charcoal until the theoretical amount of hydrogen was absorbed (about 31/2 hours) and the catalyst was then filtered off. The ethanol was evaporated and the residue was distilled under reduced pressure to obtain 24 g of 2-(4-methyl-4-piperidyloxy) -ethanol as a colorless oil boiling at 80°-86° C at 0.01 mm Hg and having a refractive index nD24 = 1.481.