Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([CH:20]([CH3:22])[CH3:21])[N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)O1>>[CH:20]([N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2]([C:33]5[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][C:17]([CH3:19])=[N:16]1)([CH3:22])[CH3:21]
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cccnc4)cc2OCC3)n(C(C)C)n1

Procedure:
8-Bromo-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine to give 244. MS (ESI+) 387.2
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:24](O)[CH2:25][OH:26].O>C1(C)C=CC=CC=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[CH2:24]1[CH2:25][O:26][C:2]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:1]1
Reactant: OCCO
Reactant: CCCCCCCCCCCCCCCC(=O)CC(=O)OCC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCC1(CC(=O)OCC)OCCO1
Yield: 61.4 %

Procedure:
26(a) A solution of 42.57 g of ethyl 3-oxostearate (prepared as described in Preparation 25). 9.71 g of ethylene glycol and 1 g of camphorsulfonic acid in 200 ml of toluene was heated under reflux for 24 hours, and the water produced was removed through a side arm attached to a water separator. The mixture was allowed to cool, and then washed, in turn, with a saturated aqueous solution of sodium bicarbonate and with water. It was then dried and concentrated by evaporation under reduced pressure, to give 29.66 g of crude ethyl 3,3-ethylenedioxystearate.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.OC(C(F)(F)F)=O.[F:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[CH:18]=1>C(#N)C>[Br:1][C:22]1[C:17]([F:16])=[CH:18][C:19]([NH2:23])=[N:20][CH:21]=1
Reactant: Nc1cc(F)ccn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(F)c(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
N-Bromosuccinimide (126 mg, 0.71 mmol) was added to a solution of 4-fluoropyridin-2-amine TFA salt (162 mg, 0.72 mmol) in acetonitrile (4 mL) in an aluminum foil-wrapped flask in a darkened hood. The reaction solution was stirred at room temperature in darkness for 2 hours. After evaporation of the solvent, the crude product was purified on a silica gel column eluting with EtOAc to give 5-bromo-4-fluoropyridin-2-amine as an ivory solid (92 mg, 67%). LC/MS (m/z): 190.9/192.9 (MH+), Rt 1.02 minutes.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:33]([F:36])([F:35])[F:34])=[C:11]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[C:28]4[CH2:29][NH:30][CH2:31][CH2:32][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[F:15].[O:37]1[CH2:40][C:39](=O)[CH2:38]1>>[F:8][C:9]1[C:10]([C:33]([F:34])([F:35])[F:36])=[C:11]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([C:24]3[C:28]4[CH2:29][N:30]([CH:39]5[CH2:40][O:37][CH2:38]5)[CH2:31][CH2:32][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:20][CH2:21]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C1COC1
Reactant: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1n[nH]c2c1CN(C1COC1)CC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1

Procedure:
Following general procedure GP-D1, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone (36) and 3-oxetanone were converted to (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(5-(oxetan-3-yl)-4,5,6,7-tetrahydro-Hpyrazolo[4,3-c]pyridin-3-yl)methanone as a white solid (28 mg, 27%): mp 212-215° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.847 (s, 1H), 7.796-7.684 (m, 1H), 7.546-7.458 (m, 1H), 5.151 (d, 1H), 4.737-4.554 (m, 3H), 4.554-4.423 (m, 2H), 3.755-3.600 (m, 1H), 3.379 (s, 2H), 3.222-3.050 (br s, 2H), 2.844-2.643 (m, 3H), 1.898-1.515 (br s, 4H); ESI MS m/z 471.2 [M H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.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>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:20]1[CH:19]=[CH:18][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
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
Product: COC(=O)c1c(O)c2ccc(-c3ccc4ccccc4c3)cc2sc1=O
Yield: 46.9 %

Procedure:
To a mixture of 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5 e) (220 mg, 0.70 mmol) in dimethoxyethane (DME) (3.1 mL) was added naphthalen-2-yl-boronic acid (144 mg, 0.84 mmol), Pd(PPh3)4 solid (64 mg, 0.06 mmol) and then 2M aqueous Na2CO3 solution (0.86 mL). The resulting mixture was purged with nitrogen gas for 1 min and heated to reflux for 3 h. After cooling, the reaction mixture was diluted with water (100 mL) and acidified using 1 N HCl to pH 3-4. The precipitate was collected by filtration, rinsed with CH2Cl2 and the solid dried to provide 4-hydroxy-7-naphthalen-2-yl-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (119 mg). MS ESI(+) m/e: 363.19 (M+1).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[C:3]=1[CH3:21].[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[NH:25][CH2:24]1>C1(C)C=CC=CC=1>[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[N:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]3=[O:20])[C:3]=2[CH3:21])[CH2:24]1
Reactant: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Br
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 1-(4-bromo-5,7-difluoro-3-methylquinolin-2-yl)piperidin-2-one (53.0 mg, 0.150 mmol) and 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine in toluene to give 1-(4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-quinolinyl)-2-piperidinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.60-7.69 (1H, m), 7.50-7.59 (1H, m), 6.89-7.09 (1H, m), 6.06 (1H, d, J=2.0 Hz), 4.21-4.36 (1H, m), 4.00 (1H, d, J=8.8 Hz), 3.68-3.92 (4H, m), 3.50-3.68 (2H, m), 3.11 (3H, dd, J=5.9, 3.7 Hz), 2.92-3.06 (2H, m), 2.52-2.70 (2H, m), 1.94-2.18 (6H, m), 1.49-1.64 (6H, m). Mass Spectrum (ESI) m/e=508.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[NH:37][CH3:38].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[NH:37][CH3:38])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CNc1cc(C(C)=O)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CNc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 47.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.3 g, 10.3 mmol), K2CO3 (1.4 g, 10.3 mmol), 1-[4(3-chloropropoxy)-3-(methylamino)phenyl]ethanone (2.5 g, 10.3 mmol), KI (0.10 g), and acetonitrile (100 ml) was stirred at reflux under nitrogen for 23 hours. The reaction was cooled to ambient temperature, poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate yield 4.8 g of a damp, brown solid. The compound was isolated by preparative HPLC (Waters Associates prep LC/System 500, utilizing 2 silica gel columns and 4% methanol-methylene chloride as eluent). Concentration of appropriate fractions afforded 2.4 g. Recrystallization from ethanol gave 2.1 g of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-(methylamino)phenyl]ethanone as a beige solid, m.p.=151°-153° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:8](O)=[O:9])(=[O:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:24])=O>C(Cl)Cl>[Cl:24][C:8]([C:7]1[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=1)=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C(=O)O)cc1OC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)cc1OC(C)=O

Procedure:
700 mg of 3-acetoxy-4-methoxy-benzoic acid were suspended in 6 ml of anhydrous DCM and 24 μl of DMF were added. Then 5.0 ml of a 2 M solution of oxalyl chloride in DCM were added dropwise. The mixture was stirred until the evolution of gas had ceased (about 30 min). The volatiles were removed in vacuo, the residue was dissolved in 10 ml of DCM and evaporated to yield 750 mg of the title compound which was used in the subsequent step without further purification.
Reaction SMILES: OC1C(C)=NC([Br:9])=CN=1.O[C:11]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][C:14]([Br:23])=[CH:13][N:12]=1>>[Br:9][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][C:14]([Br:23])=[CH:13][N:12]=1
Reactant: Oc1ncc(Br)nc1-c1ccccc1
Reactant: Cc1nc(Br)cnc1O
Product: Brc1cnc(Br)c(-c2ccccc2)n1

Procedure:
By replacing the 2-hydroxy-3-methyl-5-bromopyrazine used in Step A of Preparation 87 by an equivalent quantity of 2-hydroxy-3-phenyl-5-bromopyrazine and following substantially the same procedure there is obtained 2,5-dibromo-3-phenylpyrazine.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[C:15]=3[CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=O)OCC>C(COC)OC>[CH:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[C:14]([CH2:17][OH:18])[CH:13]=[CH:12][CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cccc2ncc(C3CCCCC3)cc12
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: OCc1cccc2ncc(C3CCCCC3)cc12
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
33.6 g (131.7 mmol) of the compound from Example VI are dissolved in 320 ml of dimethoxyethane and the solution is stirred with 197.6 mmol (27.6 ml) of triethylamine. After 30 minutes, 19.75 ml (197.5 mmol) of ethyl chlorocarbonate are added dropwise at 20°-30° C. The mixture is subsequently stirred for 30 minutes and the salt is filtered off with suction and washed with dimethoxyethane. The filtrate is concentrated end the residue is dissolved in a mixture of 320 ml of ethanol and 160 ml of water, and a solution of 9.25 g of sodium borohydride in 54 ml of water is added dropwise at 15°-18° C. The mixture is stirred at room temperature for 1 hour and the salt is filtered off with suction and washed with ethanol and water. The filtrate is concentrated to one third, methylene chloride and water are added and the phases are separated. The organic phase is washed 3 times with water, dried and concentrated. 26 g of a pale brown oil are obtained, which is employed without further purification.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][CH3:22])[C:13]=2[CH3:23])=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)(O)=[O:2].[CH2:24]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])[CH:32]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>C(OC(=O)C)(=O)C>[CH2:40]([N:37]([CH2:38][CH3:39])[C:33]1[CH:34]=[CH:35][C:36]([C:10]2([C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH2:21][CH3:22])[C:13]=3[CH3:23])[C:5]3[C:4](=[CH:9][CH:8]=[CH:7][N:6]=3)[C:1](=[O:2])[O:11]2)=[C:31]([O:30][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:32]=1)[CH3:41]
Reactant: CCCCCCOc1cccc(N(CC)CC)c1
Reactant: CCn1c(C)c(C(=O)c2ncccc2C(=O)O)c2ccccc21
Solvent: CC(=O)OC(C)=O
Product: CCCCCCOc1cc(N(CC)CC)ccc1C1(c2c(C)n(CC)c3ccccc23)OC(=O)c2cccnc21
Temperature: 25 °C

Procedure:
Into 200 ml of acetic anhydride, 15.4 g of (1-ethyl-2-methylindol-3-yl) (3-carboxypyridin-2-yl) ketone and 13.7 g of 1-n-hexyloxy-3-diethylaminobenzene were added, and the resultant mixture was stirred for 3 hours to 60° to 65° C. After cooling the reaction mixture to room temperature, the cooled reaction mixture was treated by the same manner as in Synthetic Example 1 and as a result, 18.9 of the objective compound of the melting point of 154° to 156° C. as pale blue crystals was obtained. The elementary analytical data of the product were as follows.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)=[C:8]([N+:25]([O-])=O)[CH:7]=1>CO.C(Cl)Cl>[CH3:3][O:4][C:5](=[O:28])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)=[C:8]([NH2:25])[CH:7]=1
Reactant: COC(=O)c1ccc(NCc2cc(-c3ccc(Cl)s3)on2)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(NCc2cc(-c3ccc(Cl)s3)on2)c(N)c1

Procedure:
97.1 mg (0.41 mmol) NiCl2.6H2O were dissolved in 10 mL MeOH and treated under ultrasonic conditions. 46.4 mg (1.24 mmol) NaBH4 were added. After 15 minutes a solution of 214.0 mg (0.54 mmol) 4-{[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-amino}-3-nitro-benzoic acid methyl ester in 20 mL CH2Cl2 was added. After further 15 minutes 55.6 mg (1.48 mmol) NaBH4 were added in three portions. The reaction mixture was treated under ultrasonic conditions for 2 h. Addition of NaBH4 (55.6 mg each time) and treatment under ultrasonic conditions had to be repeated three times to achieve complete conversion. The reaction mixture was filtered over “Celite” and the filtrate was concentrated under reduced pressure. The residue was suspended in 30 mL MeOH. After filtration the filtrate was concentrated under vacuo and the residue was taken up in 100 mL CH2Cl2. The organic layer was washed four times with water, dried over anhydrous MgSO4 and concentrated under reduced pressure to afford crude 3-Amino-4-{[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-amino}-benzoic acid methyl ester as a brown oil.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[O:22]([C:2]1[S:3][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1sc(Cl)nc1C(F)(F)F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(Oc2ccccc2)nc1C(F)(F)F
Yield: 75.6 %

Procedure:
A mixture of 5.2 g (0.02 mole) of ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarboxylate, 1.88 g (0.02 mole) of phenol, 2.76 g (0.02 mole) of K2CO3 and 50 ml. of acetone was held at reflux for 3 days. Acetone was removed under reduced pressure. The residue was treated with water, extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residual solid was heated with hexane, cooled and filtered to give 4.8 g (76%) of the desired product, m.p. 52°-54° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[C:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:47]>C(Cl)Cl>[Br:47][CH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][S:9][C:7]2[CH:6]=[CH:5][C:4]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:3]([C:2]([F:26])([F:25])[F:1])[CH:8]=2)=[CH:12][CH:13]=1
Reactant: OCc1ccc(CSc2ccc(-c3ccccc3)c(C(F)(F)F)c2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1cc(SCc2ccc(CBr)cc2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of [4-(2-trifluoromethyl-biphenyl-4-ylsulfanylmethyl)-phenyl]-methanol (162 mg, 0.4327 mmol, 1 eq.) in anhydrous DCM (5 mL) is added PPh3 (148 mg, 0.5625 mmol, 1.3 eq). The mixture is stirred at room temperature for 5 min. at which point the reaction is cooled to 0° C. To the reaction mixture at 0° C. is added a solution of CBr4 (187 mg, 0.5625 mmol, 1.3 eq.) in anhydrous DCM (2 mL). The reaction is allowed to slowly warm to room temperature and is stirred for 12 h. The reaction mixture is applied directly to silica gel chromatography (6:1 hexanes/EtOAc) to give 4-(4-bromomethyl-benzylsulfanyl)-2-trifluoromethyl-biphenyl.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].[C:10]([N:17]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]1)([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]>C(OCC)C>[F:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[C:19]1([OH:22])[CH2:20][CH2:21][N:17]([C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:18]1
Reactant: Fc1cccc(Br)c1F
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(F)c2F)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Preparation according to Preparation 23: 1-bromo-2,3-difluorobenzene (3.12 g, 16.2 mmol), dry diethyl ether (30 mL), N-butyl lithium (2.5 M, 6.5 mL, 16.2 mmol), 1-N-boc-3-pyrrolidinone (2.0 g, 10.8 mmol). Stirred 2 h at −78° C. before addition, and 1 h at ambient temperature after addition of 1-N-boc-3-pyrrolidinone. Yield: 1.72 g. MS m/z (rel. intensity, 70 eV) 299 (M+, 1), 243 (46), 226 (38), 198 (68), 57 (bp).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1.C([O-])(O)=O.[Na+]>COCCOC.CCOC(C)=O.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>[F:29][CH2:30][C:31]1[N:32]=[CH:33][C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([O:16][C:17]([F:19])([F:18])[F:20])=[CH:14][CH:15]=3)=[O:8])[CH:21]=2)=[CH:35][CH:36]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: CC1(C)OB(c2ccc(CF)nc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2ccc(CF)nc2)c1
Temperature: 90 °C

Procedure:
(S)-5-Bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1, 92 mg, 0.2 mmol) and 2-(fluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (prepared as described in US20090571601) (316 mg 30% ig, 0.4 mmol) were dissolved in DME (0.8 mL). A solution of 2 M NaHCO3 (0.3 mL, 0.6 mmol) was added, the RM was flushed with argon, heated to 90° C. and Pd(PPh3)2Cl2 (14.0 mg, 0.02 mmol) was added. The RM was heated for 2 h at 90° C. After cooling at RT, the RM was dissolved in EtOAc and water, and extracted with EtOAc. The combined extracts were dried over Na2SO4 and evaporated to dryness under reduced pressure. The crude product was first purified by flash chromatography (RediSep® Silica gel column, DCM/MeOH from 2% to 5% MeOH), treated with Si-Thiol (100 mg) in MeOH and further purified by reverse phase chromatography (MPLC, Lichroprep 15-25 μm column, water+0.1% formic acid/MeCN+0.1% formic acid, gradient 10% to 38% MeCN+0.1% formic acid). The combined pure fractions were neutralized with NaHCO3 and extracted with EtOAc. The combined organic phases were dried over Na2SO4 and evaporated to afford the title compound as an off-white amorphous solid. HPLC (Condition 4) tR=4.96 min, UPLC-MS (Condition 3) tR=1.07 min, m/z=491.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.62 (m, 1H) 1.77-1.89 (m, 1H) 2.15-2.29 (m, 1H) 2.92-3.02 (m, 1H) 3.07-3.38 (m, 4H) 3.42-3.53 (m, 2H) 4.60 (t, J=5.08 Hz, 1H) 5.47 (s, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.58 (d, J=7.82 Hz, 1H) 7.77-7.92 (m, 3H) 8.02 (d, J=2.35 Hz, 1H) 8.64 (d, J=1.56 Hz, 1H) 8.75 (d, J=2.74 Hz, 1H) 10.16 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Temperature: 0 °C
Yield: 101.2 %

Procedure:
A mixture containing 6.5 g of 4-methyl-2'-nitrobiphenyl and 5.42 g of NBS in 50 ml of carbon tetrachloride is refluxed for 5 hours. It is cooled to 0° C. and filtered and the filtrate is concentrated to give 9 g of an oily product, which is used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:10]=[C:11]3[C:16]([OH:17])=[N:15][C:14]([CH3:18])=[N:13][C:12]=23)=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:36][C:37]([F:48])([F:47])[CH2:38]OS(C(F)(F)F)(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:10]=[C:11]3[C:16](=[O:17])[N:15]([CH2:38][C:37]([F:48])([F:47])[F:36])[C:14]([CH3:18])=[N:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: Cc1nc(O)c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc2c(=O)n1CC(F)(F)F
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a mixture of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-ol (I-4A-1a, 1.86 g, 5.0 mmol) in anhydrous THF (30 ml) at room temperature was added lithium hexamethyidisilazide (7.5 ml, 7.5 mmol). A reddish solution was formed. Trifluoromethanesulfonic acid 2,2,2-trifluoroethyl ester (2,2 ml, 15 mmol) was subsequently added in one portion. The reaction mixture was stirred at 60° C. for 1.5 h, quenched with water, and concentrated under vacuum. MeOH was added to the residue to give a slurry which was then cooled to 0° C. A yellowish solid was formed and collected by filtration to give the desired product 4A-1 (1.63 g, 72%): MS (m/z) 453.1 (M+H)+; 1H NMR (400 MHz, CDCl3): δ 7.55-7.52 (m, 1H), 7.46-7.40 (m, 2H), 7.39-7.32 (m, 2H), 7.31-7.28 (m, 2H), 5.00-4.80 (br m, 2H), 2.87 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H).