Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Sn](C)(C)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.CN(C)C=O.Br[C:17]1[N:25]2[C:20]([CH:21]=[N:22][C:23]([S:26][CH3:27])=[N:24]2)=[CH:19][CH:18]=1>CCOC(C)=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>[CH3:27][S:26][C:23]1[N:22]=[CH:21][C:20]2=[CH:19][CH:18]=[C:17]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[N:25]2[N:24]=1
Reactant: CSc1ncc2ccc(Br)n2n1
Reactant: C[Sn](C)(C)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1ncc2ccc(-c3ccccn3)n2n1
Temperature: 80 °C
Yield: 70 %

Procedure:
2-Trimethylstannanyl-pyridine (0.557 g, 2.30 mmol) in N,N-Dimethylformamide (7.6 mL, 98 mmol) was added 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.250 g, 1.02 mmol) and Tetrakis(triphenylphosphine)palladium(0) (67 mg, 0.058 mmol) in a vial, and the mixture was heated in a block at 80° C. The reaction mixture was then diluted with EtOAc (30 mL) and washed with water (1×, 10 mL), 2.5M KF (2×, 10 mL), and brine (1×, 10 mL), followed by drying with sodium sulfate, filtering, and conc. in vacuo. The crude product was purified by ISCO column chromatography (0-25, 25-100% EtOAc/Hex) to give 2-Methylsulfanyl-7-pyridin-2-yl-pyrrolo[2,1-f][1,2,4]triazine (0.173 g, 70%). 1H-NMR (DMSO-d6): 9.09 (s, 1H), 8.71 (m, 2H), 7.98 (dt, 1H, J=7.80 Hz), 7.63 (d, 1H, J=4.74 Hz), 7.38 (dt, 1H, J=6.40), 7.12 (d, 1H, 4.98 Hz), 2.65 (s, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:14]([I:17])=[C:13]2[C:9]=1[CH:10](O)[N:11](C(C)(C1C=CC=CC=1)C)[C:12]2=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>[N+](C)([O-])=O>[O:1]([C:8]1[CH:16]=[CH:15][C:14]([I:17])=[C:13]2[C:9]=1[CH2:10][NH:11][C:12]2=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccccc1)N1C(=O)c2c(I)ccc(Oc3ccccc3)c2C1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: C[N+](=O)[O-]
Product: O=C1NCc2c(Oc3ccccc3)ccc(I)c21
Yield: 73 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-phenoxy-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (700 mg, 1.44 mmol) was dissolved in nitromethane (28 mL), and the solution was treated with trifluoroacetic acid (1.10 mL, 14.4 mmol) and triethylsilane (0.460 mL, 2.88 mmol), followed by purification by slurry using diisopropylether to obtain 4-phenoxy-7-iodoisoindolinone (369 mg, yield 73%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]=[O:18])=[C:9]2Cl)[CH:5]=[CH:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH:17]=[O:18])=[C:9]2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1c(Cl)n(-c2cccc(Br)c2)c2ccccc12
Reactant: C1CNCCN1
Product: O=Cc1c(N2CCNCC2)n(-c2cccc(Br)c2)c2ccccc12
Yield: 31 %

Procedure:
1-(3-bromo-phenyl)-2-chloro-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 to afford 1-(3-bromophenyl)-2-piperazin-1-yl-1H-indole-3-carboxaldehyde (31% yield). ESI/MS 384 (M), 386 (M+2); RT 2.70 min; NMR (CDCl3) 10.31 (1H, s); 8.28 (1H, d, J=9 Hz); 7.67 (2H, m); 7.63-7.16 (5H, m); 7.01 (1H, d, J=9 Hz); 3.31 (4H, m); 2.82 (4H, m).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([S:23][CH3:24])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH:31](I)([CH3:33])[CH3:32].O>CC(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:31]([CH3:33])[CH3:32])=[C:18]([S:23][CH3:24])[CH:17]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)I
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(O)c(SC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC(C)C)c(SC)c1
Yield: 62.8 %

Procedure:
A suspension of the ethyl (RS)-(4-cyano-phenylamino)-(4-hydroxy-3-methylsulphanyl-phenyl)-acetate (198 mg, 0.58 mmol) described in Example 168.1, Cs2CO3 (227 mg, 0.64 mmol) and isopropyl iodide (58 μl, 0.58 mmol) in acetone (3 ml) was heated under reflux for 4 h. Water was added and the mixture was extracted with CH2Cl2. Die organic phase was dried, filtered and concentrated. The residue was purified by chromatography (SiO2, hexane/EtOAc 2:1). Ethyl (RS)-(4-cyano-phenylamino)-(4-isopropoxy-3-methylsulphanyl-phenyl)-acetate (140 mg, 63%) was obtained as a colorless oil; MS: 443 ([M+OAc]−).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].[C:18](N1C=CN=C1)(N1C=CN=C1)=[S:19]>CN(C)C=O>[N:17]([C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][CH2:7]2)=[CH:16][CH:15]=1)=[C:18]=[S:19]
Reactant: CC(C)CN1CCN(c2ccc(N)cc2)CC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)CN1CCN(c2ccc(N=C=S)cc2)CC1
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
A solution of 4-[4-(isobutyl)-1-piperazinyl]benzenamine (7.8 g, 33.4 mmol) (from Step B above) in N,N-dimethylformamide (75 mL) was added dropwise over 20 min to a cooled (−15° C.) solution of thiocarbonyldiimidazole (5.97 g, 33.5 mmol) (Aldrich) in N,N-dimethylformamide (25 mL). After the addition was complete, the mixture was stirred at −15° C. for 20 min, the cooling bath was removed and the solution was stirred for 1 h. Ice-water (700 ml) was added and the mixture was stirred for 30 min. The solid was filtered off and washed with water and dried under vacuum to give 1-(4-Isothiocyanatophenyl)-4-(1-isobutyl)piperazine (8 g, 87%)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:18]=[C:17]([O:19][C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:15][C:14]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+]>CO.Cl[Pd]Cl>[F:12][C:13]1[CH:18]=[C:17]([O:19][C:20]([F:21])([F:22])[F:23])[CH:16]=[CH:15][C:14]=1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: CC1(C)OB(c2ccc(OC(F)(F)F)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1ccnc(-c2ccc(OC(F)(F)F)cc2F)c1
Temperature: 100 °C
Yield: 81.3 %

Procedure:
Methyl 2-chloroisonicotinate (3 g, 17.48 mmol), 2-(2-fluoro-4-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.37 g, 17.55 mmol), potassium carbonate (1.812 g, 13.11 mmol) and PdCl2 (dppf) (0.380 g, 0.52 mmol) were mixed in methanol (30 mL) in two separate 20 mL microwave vials. The vials were capped and heated at 100° C. for 10 min in a single node microwave reactor. Water and DCM were added and the phases were separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated to yield a dark-brown solid. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 340 g column. A gradient from 8:1 to 3:1 of EtOAc in heptane over 10 CV was used as mobile phase. Methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)isonicotinate (4.48 g, 81%) was yielded as a colorless solid. 1H NMR (600 MHz, cdcl3) δ 3.96 (s, 3H), 7.07 (d, 1H), 7.14 (d, 1H), 7.79-7.84 (m, 1H), 8.03-8.09 (m, 1H), 8.31 (s, 1H), 8.82-8.88 (m, 1H). MS m/z 316 (M+H)+
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:19])[N:3]=1)=[C:11]([F:16])[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=3.[F:20][C:21]1[C:22]([CH3:30])=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>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>[F:16][C:11]1[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=[C:7]2[C:12]=1[N:13]=[C:14]([CH3:15])[C:5]1[N:6]2[C:2]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([F:20])[C:22]=2[CH3:30])=[N:3][C:4]=1[CH3:19]
Reactant: COc1cc(F)c2nc(C)c3c(C)nc(Br)n3c2c1
Reactant: Cc1c(F)cccc1B(O)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: [K+]
Product: COc1cc(F)c2nc(C)c3c(C)nc(-c4cccc(F)c4C)n3c2c1
Yield: 42.4 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 6A (65 mg, 0.2 mmol), 3-fluoro-2-methylphenylboronic acid (46 mg, 0.3 mmol), K2CO3 (82 mg, 0.6 mmol) and Pd(PPh3)4 (5 mg, 0.004 mmol) provided the coupling product as an off-white powder (30 mg, 43% yield). EIMS 354.1 [M+H]+.
Reaction SMILES: [C:1]([NH2:9])(=[NH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:12][C:13](=O)[C:14](=[CH:17]OCC)[C:15]#[N:16])C>CN(C=O)C>[OH:12][C:13]1[C:14]([C:15]#[N:16])=[CH:17][N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:8]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CN(C)C=O
Product: N#Cc1cnc(-c2ccccc2)nc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of benzamidine (1.0 g, 8.32 mmol) in anhydrous DMF (20 mL ) was added Ethyl(ethoxymethylene)cyanoacetate (11) (1.41 g, 8.32 mmol, 1.0 equiv ) under argon at 0° C. The mixture was stirred at 0° C. for 2 h and increase to 105° C. for 60 h. The reaction mixture was then cooled to ambient temperature. The mixture was extracted with ethyl acetate (2×100 mL ). The combined organic extracts were washed with water (1×50 mL) and brine (1×50 mL), dried (Na2SO4), filtered, and evaporated in vacuo. The residue was washed with water (1×60 mL), dichloromethane (1×60 mL) then dried in the vacuum oven to obtain the light yellow solid as product (0.77 g, 47%). 1H-NMR (CD3CN) δ8.25 (s, 1H ), 8.06 (d, 2H ), 7.70 (t, 1H ), 7.61 (t, 2H). MS LC-MS (MH+=198).
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:12]=[C:11]([F:21])[CH:10]=1)(C)(C)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:21][C:11]1[CH:10]=[C:9]([CH2:8][NH:7][CH3:6])[CH:14]=[C:13]([CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)[CH:12]=1
Reactant: CC(C)(C)OC(=O)NCc1cc(F)cc(CN2CCCC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCc1cc(F)cc(CN2CCCC2)c1
Temperature: 0 °C
Reaction time: 40 h

Procedure:
tert-butyl[3-fluoro-5-(pyrrolidin-1-ylmethyl)benzyl]carbamate (0.72 mmol) was dissolved in anhydrous THF (2 mL) under N2 and the solution was cooled to 0° C. LiAlH4 (1 M in THF, 1.62 mL) was added and the reaction was stirred at between 0° C. and 40° C. for 40 h. The reaction was partitioned between 1:1 saturated aqueous NaHCO3: 30% aqueous Rochelle's salt (20 mL) and DCM (3×15 mL) and the combined organic extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound as a yellow oil. No further purification was required.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)[CH2:27][CH2:26]3)[N:9]=[C:10]([C:11]3[CH:12]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=3)[C:3]=12.FC(F)(F)C(O)=O>ClCCl>[NH2:17][C:13]1[CH:12]=[C:11]([C:10]2[C:3]3[C:4](=[N:5][CH:6]=[N:7][C:2]=3[NH2:1])[N:8]([C@H:25]3[CH2:30][CH2:29][C@@H:28]([N:31]4[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]4)[CH2:27][CH2:26]3)[N:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(NC(=O)OC(C)(C)C)c4)c4c(N)ncnc43)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4cccc(N)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 0 °C
Yield: 100 %

Procedure:
A mixture of cis-tert-butyl N-(3-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)carbamate (1.7 g, 3.3 mmol, 1 equiv) and dichloromethane (40 mL) was cooled at 0° C. and then trifluoroacetic acid (10.5 mL, 137 mmol, 41 equiv) was added. The reaction mixture was allowed to warm to ambient temperature over 3 h, the solvent was removed under reduced pressure, and the residue was partitioned between CH2Cl2 (50 mL) and water (50 mL). The organic layer was separated and treated with saturated aqueous sodium bicarbonate solution (50 mL). The organic extract was dried over MgSO4, filtered, and concentrated to afford cis-3-(3-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (1.34 g, 3.30 mmol): 1H NMR (d6 DMSO, 400 MHz): δ H 8.21 (1H, s), 7.17-7.21 (1H, m), 6.85 (1H, s), 6.72-6.74 (1H, m), 6.65-6.68 (1H, m), 5.36 (2H, bs), 4.75-4.80 (1H, m), 2.22-2.51 (11H, m), 2.20 (3H, s), 2.06-2.08 (2H, m), 1.58-1.68 (4H, m); RP-HPLC (Delta Pak C18, 5 μm, 300 Å, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 20 min, 1 mL/min) Rt 9.06 min. MS: MH+ 407.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[N:21]=1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:22]3[N:21]=[C:20]([CH3:19])[O:24][N:23]=3)[CH:26]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: Cc1nc(-c2cccc(C=O)c2)no1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2noc(C)n2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 394.03 g/mol.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].[N+:9]([O-])([OH:11])=[O:10]>C(O)(=O)C>[N+:9]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1c[nH]cn1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
430 mL of acetic acid and 188 g of 4-nitroimidazole were charged into a 2 L-volume reactor and stirred. While stirring the mixture, 100% nitric acid(137 mL) was slowly added dropwise to the mixture at the reaction temperature of 35° C. Anhydrous acetic acid(318 mL) was added dropwise thereto at 25° C. over 1 hour. After stirring the reaction mixture at 25° C. for 2 days, the resultant was poured into 3 kg of ice cubes to obtain 1,4-dinitroimidazole as white precipitates. Then the precipitates, still cool, were immediately filtered out, washed with cold water so as to remove the residual acid, and then dried, resulting in 178.6 g(68% yield) of 1,4-dinitroimidazole in a fine white powder form. The structure of the resulted 1,4-dinitroimidazole was determined by NMR analysis, 1H-NMR and 13C-NMR. The results are shown below:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=3[C:38]3[CH2:39][CH2:40][NH:41][CH2:42][CH:43]=3)[CH:19]=2)(=[O:17])=[O:16])=[N:10][CH:9]=1.C=O.[Na]>CO>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:2][N:41]1[CH2:40][CH:39]=[C:38]([C:29]2[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:28]=2[C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:25]=2[CH:26]=[CH:27][C:18]([S:15]([NH:14][C:11]2[CH:12]=[CH:13][N:8]=[CH:9][N:10]=2)(=[O:17])=[O:16])=[CH:19]3)[CH2:43][CH2:42]1
Reactant: O=S(=O)(Nc1ccncn1)c1ccc2c(-c3ccc(C(F)(F)F)cc3C3=CCNCC3)cccc2c1
Agent: C=O
Agent: [Na]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3cc(S(=O)(=O)Nc4ccncn4)ccc23)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 182.3 %

Procedure:
To a round bottom flask charged with N-(pyrimidin-4-yl)-5-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonamide (EXAMPLE 48, 167.0 mg, 0.327 mmol) was added MeOH (3271 μl), then formaldehyde (265 μl, 3.27 mmol). The solution was maintained at rt for 15 min, then sodium triacetoxyhydroborate (693 mg, 3.27 mmol) was added portionwise. After 10 min, the reaction mixture was partitioned between ice and saturated NaHCO3 and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (1×25 mL). The combined organic extracts were washed with brine (1×20 mL) and dried over Na2SO4 and concentrated under a vacuum. The residue was taken up in minimal MeOH and purified by reverse phase preparative HPLC (20 to 80% CH3CN:H2O (1% TFA modifier) over 15 min). Clean fractions were combined and concentrated to afford 5-(2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide 2,2,2-trifluoroacetate (190 mg, 0.298 mmol) as a off-white amorphous solid. 1H NMR (400 MHz, MeOH) δ ppm 1.98-2.47 (m, 2H) 2.49-2.90 (m, 4H) 3.08-3.28 (m, 1H) 3.37-3.58 (m, 1H) 3.64-3.90 (m, 1H) 5.68 (d, J=8.51 Hz, 1H) 7.16 (dd, J=6.36, 0.98 Hz, 1H) 7.54 (d, J=8.02 Hz, 1H) 7.58-7.69 (m, 2H) 7.70-7.85 (m, 3H) 7.94 (d, J=8.61 Hz, 1H) 8.18 (d, J=8.31 Hz, 1H) 8.30 (d, J=6.36 Hz, 1H) 8.60 (s, 1H) 8.72 (d, J=1.37 Hz, 1H); m/z (ESI, +ve ion) 525.2 (M+H)+.
Reaction SMILES: CO[C:3]1[C:8]([CH3:9])=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1.[CH2:21]([Mg]Cl)[CH3:22]>C1COCC1>[CH2:21]([C:3]1[C:8]([CH3:9])=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:14]1[O:15][CH2:16][C:17]([CH3:20])([CH3:19])[N:18]=1)[CH3:22]
Reactant: CC[Mg]Cl
Reactant: COc1c(C2=NC(C)(C)CO2)ccc(C(F)(F)F)c1C
Solvent: C1CCOC1
Product: CCc1c(C2=NC(C)(C)CO2)ccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled solution of 355 mg (1.17 mmol) 2-(2-methoxy-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole in 4 ml THF were added at <10° C. drop-wise over 20 min 2.35 ml (4.7 mmol) 2M ethylmagnesium chloride solution in THF. The resulting brown solution was stirred at ambient temperature for 1 h, then quenched with saturated aqueous NH4Cl solution (cooling with ice bath) and extracted three times with tert-butyl methyl ether. The combined organic phases were washed three times with brine, dried over Na2SO4, filtered and evaporated. 2-(2-Ethyl-3-methyl-4-trifluoromethyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole was obtained as yellow oil: MS (ISP): 286.1 ((M+H)+.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]=O)=O)=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:17]([NH2:18])[CH:16]=[N:15][N:14]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:10]=[N:18][N:17]3[CH:16]=[N:15][N:14]=[C:13]3[N:12]=2)=[CH:4][CH:3]=1
Reactant: Nc1nncn1N
Reactant: O=CC(=O)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1ccc(-c2cnn3cnnc3n2)cc1

Procedure:
A solution of 11.9 g. of p-fluorophenylglyoxal, 9.5 g. of 3,4-diamino-4H-1,2,4-triazole and 5.74 g. of sodium acetate in 120 ml. of 67% acetic acid is heated on a steam bath and then filtered through celite. The filtrate is heated for an additional hour and the resulting solid is collected by filtration giving the desired product as cream-colored plates, m.p. >300° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]2[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=O.[O:22]1[C:26]2([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[O:25][CH2:24][CH2:23]1>CO.C(Cl)Cl>[O:22]1[C:26]2([CH2:31][CH2:30][N:29]([CH2:1][C:3]3[CH:4]=[C:5]4[C:9](=[CH:10][CH:11]=3)[NH:8][C:7]([C:12]([NH2:14])=[O:13])=[C:6]4[S:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:28][CH2:27]2)[O:25][CH2:24][CH2:23]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: NC(=O)c1[nH]c2ccc(C=O)cc2c1Sc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1[nH]c2ccc(CN3CCC4(CC3)OCCO4)cc2c1Sc1ccccc1

Procedure:
Treat 5-formyl-3-phenylsulfanyl-1H-indole-2-carboxylic acid amide 13 (m=0, R3=Ph) (80 mg, 0.27 mmol) with 1,4-dioxa-8-aza-spiro[4,5]decane (71.6 mg, 0.50 mmol) as described in General Procedure X to afford Iz (51.0 mg, 44.7%) as a tan solid, tlc Rf=0.35 (10% MeOH/CH2Cl2−0.20% Et3N), m/z obs=424 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([O:11][C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH2:9]([O:11][C:12](=[O:23])[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[C:19]([C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:20]=1)[CH3:10]
Reactant: CCOC(=O)CCc1ccc(OC)cc1
Reactant: CCCCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCCCCC(=O)c1cc(CCC(=O)OCC)ccc1OC
Temperature: 50 °C

Procedure:
98 ml (0.7 mol) of hexanoyl chloride are added dropwise to a solution of 70 g (0.336 mol) of ethyl3-(4-methoxyphenyl)propanoate in 280 ml of dichloromethane. 89 g (0.67 mol) of aluminium chloride are then added in small amounts, and the mixture is heated for one hour at 50° C. The mixture is poured into cold water and extracted with ether. The organic phase is washed with sodium bicarbonate solution. After drying (Na2SO4) and evaporating off the solvents, a yellow liquid is obtained, and then distilled: Bp0.4 mmHg=160° C. (74 g; 72%);
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[N:11]([CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:10]2=[O:27])[CH:6]=[CH:7][CH:8]=1.ClC1C=C(C=CC=1)C(OO)=[O:33]>C(Cl)Cl>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([N:9]2[C:14]3[N:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12](=[O:19])[N:11]([CH2:20][C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[C:10]2=[O:27])[CH:6]=[CH:7][CH:8]=1)=[O:33]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cccc(-n2c(=O)n(Cc3ccncc3)c(=O)c3cccnc32)c1
Solvent: ClCCl
Product: CS(=O)c1cccc(-n2c(=O)n(Cc3ccncc3)c(=O)c3cccnc32)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
1-(3-Methylthiophenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (100 mg, 0.27 mmole), prepared, e.g., as described in Example 5B, was dissolved in methylene chloride (20 ml) and cooled to 0° C. m-Chloroperoxybenzoic acid (45 mg, 0.27 mmole) was added to the solution. The solution was stirred for 2 hours at 0° C. The solution was then washed with a 10% solution of Na2SO3 (2 ml) followed by a wash with saturated NaHCO3 (10 ml). The organic and aqueous phases were separated and the organic phase was dried with MgSO4. The solvents were removed and the residue purified by preparative thin-layer chromatography (ethyl acetate as eluent) yielding 51 mg (0.13 mmole, 48% yield) of 1-(3-methylsulfinylphenyl)-3-(4-pyridylmethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, as a white solid, (mp 218°-219° C.).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-])=O)[C:5]([F:12])=[C:4]([Cl:13])[C:3]=1[OH:14].[H][H]>CO.[Ni]>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([NH2:9])[C:5]([F:12])=[C:4]([Cl:13])[C:3]=1[OH:14]
Reactant: O=[N+]([O-])c1c(F)c(Cl)c(O)c(Cl)c1F
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: Nc1c(F)c(Cl)c(O)c(Cl)c1F

Procedure:
18 g of 2,6-dichloro-3,5-difluoro-4-nitrophenol are hydrogenated in 100 ml of methanol in the presence of 1.5 g of Raney nickel at 25°-45° C. using 30-50 bar of hydrogen until the take-up of hydrogen is complete. After filtration, the solution is freed from solvent under recuced pressure. 13 g of aminophenol (GC purity 98.4%) remain; m.p. 151° C.