Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([CH2:15][CH3:16])[CH2:8]2)(=[O:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([NH:4][C:5]1[C:6]([Br:17])=[C:7]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[CH:9]([CH2:15][CH3:16])[CH2:8]2)(=[O:3])[CH3:2]
Reactant: CCC1Cc2cc(NC(C)=O)ccc2C1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCC1Cc2c(ccc(NC(C)=O)c2Br)C1=O
Temperature: 60 °C
Yield: 93.1 %

Procedure:
A solution of 5-(acetylamino)-2-ethyl-1-indanone (2.32 g, 10.7 mmol) in anhydrous N,N-dimethylformamide (10.7 mL) was treated with N-bromosuccinimide (2.00 g, 11.21 mmol). The mixture was placed under a N2 atmosphere, stirred, and heated in an oil bath at 60° C. for 100 minutes. After cooling to room temperature, the mixture was partitioned between EtOAc (200 mL) and water (200 mL). The organic phase was washed with water (4×200 mL) and brine (100 mL), dried over MgSO4, filtered, and evaporated under vacuum to afford crude 5-(acetylamino)-4-bromo-2-ethyl-1-indanone as a yellow solid (2.95 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[NH2:21][C:22]([CH3:27])([CH3:26])[CH2:23][CH2:24][OH:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:25][CH2:24][CH2:23][C:22]([NH:21][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6])([CH3:27])[CH3:26]
Reactant: O=C(OCc1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CC(C)(N)CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(CCO)Nc1cc(C(=O)OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 11.4 %

Procedure:
A stirred solution of benzyl 3-fluoro-4-nitrobenzoate (2.67 g, 9.69 mmol) and 3-amino-3-methylbutan-1-ol (1.00 g, 9.69 mmol) in acetonitrile (20 mL) containing potassium carbonate (1.34 g, 9.69 mmol) is heated to 80° C. for 16 h. The solvent is evaporated, water (100 mL) is added, and the mixture is extracted with EtOAc (3×100 mL). The combined organic layers are dried (MgSO4), concentrated and purified by flash chromatography in heptanes/EtOAc to afford the title compound (395 mg, 1.10 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([S:20][CH3:21])[CH:3]=1.O.OO.CC[O:27]CC>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)(=[O:8])=[O:9])=[C:4]([S:20]([CH3:21])=[O:27])[CH:3]=1
Reactant: CSc1cc(Cl)ccc1N(C)S(=O)(=O)c1ccc(C)cc1
Reactant: CCOCC
Agent: OO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Cl)cc2S(C)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74 %

Procedure:
To a suspension of 4′-chloro-N-methyl-2′-methylthio-p-toluenesulfonanilide (0.35 g (1.02 mmol)) in acetic acid (2.0 ml), 30% hydrogen peroxide water (0.12 g (1.06 mmol)) was added dropwise with stirring at room temperature. The mixture was stirred at 50° C. for 15 minutes to get a homogeneous solution, and then stirring was continued at room temperature for 18 hours. Then, the resulting solution was dissolved in ethyl acetate, washed with aqueous sodium hydroxide solution, and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude crystals. Disopropyl ether was added to these crystals. The crystals were filtered and washed to give 0.27 g (74%) of the title compound as white crystals.
Reaction SMILES: [O:1]=[C:2]=[N:3][CH:4]1[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:6]([CH3:16])([CH2:7][N:8]=[C:9]=[O:10])[CH2:5]1.[CH2:17]=[CH:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[C:36]([OH:38])[CH:35]=[CH:34][CH:33]=1.[OH2:39].CN([CH:43]=[O:44])C>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[CH2:17]=[CH:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22]/[CH:23]=[CH:24]\[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]1[CH:37]=[C:36]([OH:38])[CH:35]=[CH:34][CH:33]=1.[CH3:14][C:12]1([CH3:15])[CH2:11][C:6]([CH2:7][N:8]=[C:9]=[O:10])([CH3:16])[CH2:5][CH:4]([N:3]=[C:2]=[O:1])[CH2:13]1.[CH3:15][C:12]([C:13]([O:38][CH2:36][CH2:43][OH:44])=[O:39])=[CH2:14]
Reactant: O
Reactant: CN(C)C=O
Agent: C=CC/C=C\C/C=C\CCCCCCCc1cccc(O)c1
Agent: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: CCCCCCCCCCCC(=O)[O-]
Product: C=C(C)C(=O)OCCO
Temperature: 55 °C

Procedure:
Isophorone diisocyanate [IPDI] (0.73 g, 0.003 moles) in 10 ml dry DMF was taken in a 100 ml two necked flask. Cardanol (1 g, 0.0033 moles) in 10 ml DMF was added drop wise with constant stirring under nitrogen. The reaction mixture was allowed to proceed under room temperature for 1 and a half hours. Then 3 drops of dibutyl tin dilaurate [DBTDL] was added as catalyst followed by drop wise addition of 2-Hydroxy ethyl methacrylate [HEMA][0.43 g, 0.003 moles]. It was left stirring at room temperature for further 2 hours. It was then heated to 55° C. and maintained at that temperature for 2 hours. Then, the contents were poured to 150 ml water and extracted with dichloromethane. It was then washed with plenty of water and dried in vacuum oven at 60° C. for 12 hours. Yield=90% (1.95 g)
Reaction SMILES: N(C(OC)=O)=NC([O-])=O.[C:10]([OH:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH2:38](O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C1COCC1>[C:10]([O:18][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccccc1
Reactant: OCc1ccccc1
Agent: COC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
Methyl azodicarboxylate resin (6.55 g of 0.61 meq/g ~4.0 meq) was suspended in dry THF (100 ml) and allowed to swell for ~15 minutes. Benzoic acid (0.366 g, 3.0 mmol) was dissolved in THF (10 ml) and added to the resin. To the stirred mixture at 25° C. was added dropwise a solution of Ph3P (0.786 g, 3.0 mmol) and benzyl alcohol (0.361 ml, 3.5 mmol) in THF (5 ml). This mixture was left to stir at 25° C. for 16 hours. Resin was then filtered and washed with CH2Cl2 (4×150 mL) and Et2O. The filtrate and washings were concentrated in vacuo at 30° C. and flash chromatographed (3.5% EtOAC/hexane) to yield benzyl benzoate (0.417 g, 65%): IR (film) 1720 (vs), 1451 (m), 1272 (vs), 1110 (m), 710 (s), 697 (m) cm-1 ; 1H NMR (80 MHz, CDCl3) δ8.25-8.05 (m, 2H, o-PhCOO), 7.65-7.25 (m, 8H, m-, p-PhCOO, OCH2PH), 5.32 (s, 2H, OCH2Ph); EI-MS: 212.0839 (M+, 212.0837 calcd. for C14H12O2), 105.0343 (Base Peak, phC=O).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][O:21][CH2:20][CH2:19][O:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH2:35]([O:37][CH:38]1[CH2:41][NH:40][CH2:39]1)[CH3:36].C(Cl)(Cl)Cl>CN(C=O)C>[O:18]1[CH2:19][CH2:20][O:21][CH2:22][CH:17]1[C:16]1[C:10]2[S:9][C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:40]4[CH2:41][CH:38]([O:37][CH2:35][CH3:36])[CH2:39]4)[CH:3]=3)=[N:12][C:11]=2[C:13]([O:23][CH3:24])=[CH:14][CH:15]=1
Reactant: CCOC1CNC1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCOC1CN(c2cc(C(=O)Nc3nc4c(OC)ccc(C5COCCO5)c4s3)ccn2)C1

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 3-ethoxy-azetidine hydrochloride in DMF. [α]D20=+44.3° (c=0.57, CHCl3), ES-MS m/e (%): 471 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2=[N:9][C:10]3[C:15]([C:14](=O)[NH:13][CH2:12][N:11]=3)=[C:5]2[CH:4]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:14]1[C:15]2[C:5]3[C:6](=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:9][C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: COc1ccc2c(c1)=C1C(=O)NCN=C1N=2
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c3ncnc(Cl)c3c2c1
Temperature: 90 °C

Procedure:
A suspension of 6-methoxy-3H-indolo[2,3-d]pyrimidine-4-one (800 mg, 3.08 mmol, ˜83% pure) and POCl3 (7 mL) is heated at 90° C. for 6 h. The suspension is concentrated to a solid that is evacuated at 1 mm for 1 h. The solids are cooled in a −78° C. bath then treated dropwise with cold H2O. The bath is removed and the frozen solids are allowed to gradually melt. The solids are filtered, washed well with cold H2O, and dried to leave 4-chloro-6-methoxyindolo[2,3-d]pyrimidine dine (733 mg, 81%) that is about 80% pure. 1H NMR (DMSO): δ12.64 (1H, br s, exchanges with D2O), 8.74 (1H, s), 7.74 (1H, d, J=2.4 Hz), 7.57 (1H, d, J=8.9 Hz), 7.28 (1H, dd, J=8.9, 2.4 Hz), 3.88 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[CH:3]=1.Cl[Sn]Cl.O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Cl)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(N)cc(Cl)c1
Yield: 97.4 %

Procedure:
An ethanol solution (75 mL) containing 1-chloro-3-methyl-5-nitro-benzene (5.0 g, 29 mmol) are added with SnCl2.2 H2O (32.8 g, 146 mmol). The reaction mixture was reflux for 3.0 h. The solution was concentrated under vacuum, and the residue was re-dissolved in aqueous NaOH, filtered, and extracted with EtOAc. The organic layer was collected, washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give 3-chloro-5-methyl-phenylamine (4.0 g) as light yellow solids in 97% yield: 1H NMR (500 MHz, CDCl3) δ 6.56 (s, 1 H), 6.48 (s, 1 H), 6.36 (s, 1 H), 3.66 (bs, 2 H), 2.23 (s, 3 H); ESI-MS: m/z 141.7 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[Sn:20](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24].C([O-])(O)=O.[Na+]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Sn:20]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:21][CH2:22][CH2:23][CH3:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccccc1NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 2 h
Yield: 48.5 %

Procedure:
To a solution of N-(t-butoxycarbonyl)aniline (2.0 g, 10.35 mmol) in dry THF (50 mL) at 78° C., a solution of t-BuLi (2.7M in pentane, 26 mL, 25.88 mmol) was added dropwise over 30 min. The resulting yellow solution was warmed to −20° C. and stirred at this temperature for 2.5 h. n-Bu3SnCl (4.2 mL, 15.52 mmol) in dry THF (10 mL) was added over 20 min, and the solution stirred at −20° C. for 2 h, then at room temperature for 12 h. The reaction mixture was poured into NaHCO3 solution and extracted with ether. The extract was washed with water, brine, and dried over MgSO4. The solvent was evaporated and the resulting oil purified by flash chromatography in hexanes/ether (20: 1) to give 2-tributylstannylphenylcarbamic acid t-butyl ester (2.42 g, 54%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH:38]=[C:39]([O:41][CH3:42])[CH:40]=1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:46]1[CH2:45][CH2:44][N:43]([C:37]2[CH:38]=[C:39]([O:41][CH3:42])[CH:40]=[C:35]([O:34][CH3:33])[CH:36]=2)[CH2:48][CH2:47]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: COc1cc(OC)cc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4ccc(F)cc4F)CN3Cc3ccccc3)CC2)c1
Yield: 3.1 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(3,5-dimethoxy-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (2.3 mg, 3.1%) as light yellow oil. MS m/e=551.5 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)=[O:4].[OH-].[Na+].O>O1CCCC1>[O:14]=[C:11]1[NH:10][C:9]2[CH:15]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[S:13][CH2:12]1
Reactant: COC(=O)c1ccc2c(c1)NC(=O)CS2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1CSc2ccc(C(=O)O)cc2N1
Reaction time: 2.5 h
Yield: 98.2 %

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid methyl ester (6.74 g) was suspended in tetrahydrofuran (100 ml) and 2M sodium hydroxide (30 ml) was added followed by water (20 ml). The solution was stirred for 2.5 hours, evaporated to half volume and acidified with 2M hydrochloric acid. The product was collected, washed with water and dried in vacuo, to give a white solid (6.2 g).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6](C[C@H]1COC(C)(C)O1)[C:7]2=[O:12].ClC1C=CC(N)=CC=1C1NC(C2C=CC=CC=2)=CN=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:7]1(=[O:12])[C:8]2[C:3](=[CH:2][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:5][NH:6]1
Reactant: CC1(C)OC[C@H](CN2CCc3c(Br)cccc3C2=O)O1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Nc1ccc(Cl)c(-c2ncc(-c3ccccc3)[nH]2)c1
Solvent: C1COCCO1
Product: O=C1NCCc2ccccc21
Temperature: 96 °C
Reaction time: 18 h

Procedure:
To a round-bottom flask under argon containing (S)-5-bromo-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one (227 mg, 0.79 mmol), 4-chloro-3-(5-phenyl-1H-imidazol-2-yl) aniline (213 mg, 0.79 mmol), Pd2(dba)3 (143 mg, 0.158 mmol), xantphos (260 mg, 0.316 mmol), potassium phosphate (505 mg, 2.37 mmol) is added anhydrous dioxane (1.6 ml). The mixture is stirred at 96° C. for 18 hours, cooled to room temperature, filtered through a celite pad and washed with THF. The crude product is purified by flash column chromatography using 1% methanol in dichloromethane as eluent to give S)-5-(4-Chloro-3-(5-phenyl-1H-imidazol-2-yl)phenylamino)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3,4-dihydroisoquinolin-1(2H)-one as a dark brown solid. LC-MS m/z: 530.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:19])[CH2:17][CH3:18])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]([F:20])([F:21])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([OH:19])[CH2:17][CH3:18])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCC(=O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCC(O)Cc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To an ethanol (2 mL) solution of 1-(4′-trifluoromethyl-biphenyl-4-yl)-butan-2-one (0.093 g, 0.32 mmol) is added sodium borohydride (0.048 g, 1.27 mmol) at 0° C. The reaction mixture is stirred one hour at 0° C., quenched by saturated sodium bicarbonate solution (1 mL) and stirred for five minutes, extracted with ethyl acetate. Organic phase is washed with saturated sodium bicarbonate and brine dried over sodium sulfate, filtered and concentrated to give 0.088 g (0.30 mmol, 94%) of title compound.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9](Cl)=[C:8]([Cl:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][Mg]Br.Cl>CCOCC>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:14])=[C:8]([Cl:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Mg]Br
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Agent: Cl
Solvent: CCOCC
Product: Cc1c(Cl)cnn(C(C)(C)C)c1=O
Temperature: 5 °C
Reaction time: 2 h

Procedure:
2-tert-butyl-4,5-dichloro-3(2H)-pyridazinone (5 g, 22.72 mmol) dissolved in 12 ml of ether was added dropwise to 15 ml of a ether solution of methylmagnesium bromide (3M in ether) at 5° C. was added. After completion of addition the solution was stirred at 5° C. for 2 hours. 10 ml of 6N HCl solution is then added slowly to it and the solution is stirred for 10 minutes. The mixture is then extracted with diethyl ether. The ether layer is then washed with water and dried. The crude product obtained after concentrating the ether is subjected to flash chromatography (silica gel; ethyl acetate/hexanes: 9:1) to give the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.ClCCl.O.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>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[C:4]([NH:8][CH2:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Brc1cccc(NCc2cccnc2)c1
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: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1ccc(-c2cccc(NCc3cccnc3)c2)cc1
Temperature: 25 °C

Procedure:
A solution of N-(3-bromophenyl)pyridin-3-ylmethylamine (364 mg, 1.38 mmol), 4-cyanophenylboronic acid (305 mg, 2.08 mmol), sodium carbonate (2.15 ml of a 2M aqueous solution, 4.3 mmol), and tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmol), under a nitrogen atmosphere was refluxed in dioxane (15 ml) for 6 h, then cooled to room temperature. The mixture was diluted with dichloromethane (70 ml) and water (15 ml). The organics were separated, dried over sodium sulfate, filtered, and concentrated to a brown solid. The solid was purified by radial chromatography eluting with 2 to 4% methanol/dichloromethane to afforded the title compound. MS calcd. 285.3; MS (M+1) 286.3.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([C:13]1[CH:14]=[C:15]([C:29]2[N:34]=[C:33]([CH3:35])[N:32]=[C:31]([NH2:36])[N:30]=2)[C:16]([NH:19][C:20]2[CH:21]=[N:22][C:23]([O:27][CH3:28])=[C:24]([F:26])[CH:25]=2)=[N:17][CH:18]=1)([CH3:12])[CH3:11])(C(C)(C)C)(C)C>C1COCC1>[NH2:36][C:31]1[N:32]=[C:33]([CH3:35])[N:34]=[C:29]([C:15]2[CH:14]=[C:13]([C:10]([CH3:12])([CH3:11])[CH2:9][OH:8])[CH:18]=[N:17][C:16]=2[NH:19][C:20]2[CH:21]=[N:22][C:23]([O:27][CH3:28])=[C:24]([F:26])[CH:25]=2)[N:30]=1
Reactant: COc1ncc(Nc2ncc(C(C)(C)CO[Si](C)(C)C(C)(C)C)cc2-c2nc(C)nc(N)n2)cc1F
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)(C)CO)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
Tetra(N-butyl)ammonium fluoride (1.0M in THF) (Fluka, St. Louis, Mo.; 0.432 mL, 0.432 mmol) was added to an orange solution of 4-(5-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (88.8 mg, 0.173 mmol) in THF (2.0 mL) at 0° C., and the resulting mixture was stirred at 0° C. for 10 min, then at 25° C. for 3 h. The reaction mixture was subsequently concentrated onto silica gel and chromatographically purified (silica gel, 0 to 100% EtOAc/hexanes) to provide 2-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)-2-methylpropan-1-ol (44.0 mg, 0.110 mmol, 63.7% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.87 (s, 1H), 8.81 (d, J=2.7 Hz, 1H), 8.37-8.43 (m, 3H), 7.86 (br. s., 1H), 7.72 (br. s., 1H), 4.75 (br. s., 1H), 3.93 (s, 3H), 3.43 (s, 2H), 2.44 (s, 3H), 1.27 (s, 6H). 19F NMR (377 MHz, d6-DMSO) δ −139.89 to −139.79 (m, 1 F). m/z (ESI, +ve) 400.3 (M+H)+.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH2:22]([NH:29][C:30]([NH2:32])=[S:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:32]=[C:30]([NH:29][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:31][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: NC(=S)NCc1ccccc1
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(-c2sc(NCc3ccccc3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 168 h
Yield: 69.2 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (Example 26, Step 2) (0.415 g, 1.12 mmol) in isopropanol (12 mL) in a 25 mL round bottom flask was added N-benzyl thiourea (0.186 g, 1.12 mmol). The solution was heated to reflux (30 hours), cooled to room temperature and let stand for 7 days. The resulting suspension was concentrated in vacuo. The resulting residue was suspended in methylene chloride (100 mL) and washed with NaHCO3 saturated solution (3×10 mL), dried over sodium sulfate, filtered and reconcentrated in vacuo yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminothiazole as a pale yellow solid (0.34 g, 69%): mp 112° C. 1H NMR (CDCl3 400 mHz δ7.74 (d, J=8.56 Hz, 2H), 7.43-7.25 (m, 10H), 6.92 (t, J=8.56 Hz, 2H), 4.33 (s, 2H), 3.02 (s, 3H). MS (EI-thermospray): m/z 439 (MH+). HRMS Δ=1.6 mmu.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:45])[CH2:5][C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:44])[CH2:28]/[CH:29]=[CH:30]/[C:31]4[CH:36]=[CH:35][C:34]([CH2:37][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:45])[CH2:5][C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:44])[CH2:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([CH2:37][C:38]5[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=5)=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4ccc(Cc5ccccc5)cc4)cc3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CCCc4ccc(Cc5ccccc5)cc4)cc3)cc2)CC1
Reaction time: 8 h

Procedure:
[1-(4′-{4-[(E)-4-(4-Benzyl-phenyl)-1-hydroxy-but-3-enyl]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropyl]-acetic acid ethyl ester (0.203 g, 0.340 mmol) was dissolved in EtOH and palladium on carbon (0.020 g, 10% wt., wet: 50% w/w H2O) was added. The reaction was stirred under H2 (g) atmosphere overnight then filtered through Celite to afford the title compound in EtOH solution, which was brought to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[CH:6]2.FC(F)(F)C(O)=O.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(ccn2C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN2C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 5-methoxy-1-methylindole (182 mg, 1.13 mmol) in 2.3 mL of acetic acid was added trifluoroacetic acid (1.1 mL). After the reaction mixture was added sodium cyanoborohydride (142 mg, 2.26 mmol) at 0° C., the reaction mixture was stirred at the same temperature for 2 h. After the reaction mixture was basified by 50% sodium hydroxide aqueous solution, the solution was extracted with diethyl ether (20 mL) twice. The combined extracts were washed with brine (5 mL), and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain 5-methoxy-1-methylindoline (131 mg, 71%).