Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:33])[C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[C:18](=[O:22])[N:17]([CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26])[CH:16]=[C:15]4[CH:29]=[O:30])[C:9]([CH3:31])=[C:8]([F:32])[CH:7]=2)[CH2:3][CH2:2]1.[C:34]([Si:38]([CH3:41])([CH3:40])Cl)([CH3:37])([CH3:36])[CH3:35].N1C=CN=C1>CN(C=O)C.O>[Si:38]([O:26][CH2:25][C:24]([CH3:27])([CH3:28])[CH2:23][N:17]1[CH:16]=[C:15]([CH:29]=[O:30])[C:14]2[C:19](=[CH:20][CH:21]=[C:12]([C:10]3[CH:11]=[C:6]([CH:7]=[C:8]([F:32])[C:9]=3[CH3:31])[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)=[O:33])[CH:13]=2)[C:18]1=[O:22])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:41])[CH3:40]
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(C=O)c2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc(C=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A solution of N-cyclopropyl-3-fluoro-5-[4-formyl-2-(3-hydroxy-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinolin-6-yl]-4-methylbenzamide (Example 26e, 14.54 g) in DMF (120 mL) was treated with tert-butyldimethylchlorosilane (4.86 g) and imidazole (2.19 g) under nitrogen. The resulting mixture was stirred at room temperature for 1 h. More tert-butyldimethylchlorosilane (1.2 g) was added and the reaction mixture stirred at room temperature for 30 min, diluted with water (300 mL) and extracted with DCM (250 mL×2). The organics were dried (MgSO4), filtered and evaporated. The residue was purified (SiO2 chromatography, elution with 100% diethyl ether) to give the subtitle compound (15.20 g) as a gum.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O+:10]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1.[C:25]([C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1C=O)([OH:27])=[O:26].[C:36](O)(=O)C>Cl(O)(=O)(=O)=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[C:25]([C:28]1[CH:29]=[CH:32][C:33]([CH:36]=[CH:6][C:7]2[CH:8]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O+:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=2)=[CH:34][CH:35]=1)([OH:27])=[O:26]
Reactant: Cc1cc(-c2ccccc2)[o+]c(-c2ccccc2)c1
Reactant: O=Cc1ccccc1C(=O)O
Reactant: CC(=O)O
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: O=C(O)c1ccc(C=Cc2cc(-c3ccccc3)[o+]c(-c3ccccc3)c2)cc1

Procedure:
A mixture solution of the compound b (4.3 g), carboxybenzaldehyde (2 g), 70% perchloric acid (one drop), and acetic acid (10 ml) was refluxed for one hour. The precipitant was collected and recrystallized with a mixture solvent of ethanol and ether to obtain 4-(4-carboxystyryl)-2,6-diphenylpyrylium perchlorate (compound d).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:8](=[O:18])[C:9]2[C:14]([C:15](=[O:17])[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[CH2:19](O)[CH2:20][OH:21]>[Zn].C1(C)C=CC=CC=1>[OH:21][CH2:20][CH2:19][O:17][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:18])=[C:7]([CH3:6])[CH:16]=1
Reactant: CC1=CC(=O)c2ccccc2C1=O
Reactant: OCCO
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: Cc1ccccc1
Product: Cc1cc(OCCO)c2ccccc2c1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
4.9g of concentrated sulfuric acid were added dropwise, with stirring, to a mixture of 4.75 g (27.6 mmole) 2-methyl-1,4 naphthoquinone, 2.71 g (41.4 mmole) of zinc powder, 15 mL of ethylene glycol and 15 mL of toluene in an ice bath. After the addition was complete, the reaction mixture was stirred for 5 hours at 100° C. The reaction product was extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered, then evaporated under reduced pressure to give 4.21 g (70% yield) of the above product. That product had a melting point of 136.3-136.8° C. and an 1HNMR as follows: (300 MHz, DMSO-d6) δ 2.37 (s, 3H), 3.86 (m, 2H), 4.10 (t, 2H, J=4.8 Hz), 4.98 (t, 1H, J=5.4 Hz), 6.76 (s, 1H), 7.42 (m, 2H), 8.14 (d, 1H, J=9.0 Hz), 8.17 (d, 1H, J=9.0 Hz), 8.51 (s, 1H). The mass spectrum showed a molecular ion at m/z 218.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([C:17]2[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=2)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:25][NH2:26]>C(O)C>[C:1]1([S:7]([N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]2[C:17]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[NH:26][N:25]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C(c1cccnc1Cl)c1cccn1S(=O)(=O)c1ccccc1
Solvent: O
Solvent: CCO
Product: O=S(=O)(c1ccccc1)n1cccc1-c1n[nH]c2ncccc12
Temperature: 90 °C

Procedure:
A mixture of (1-benzenesulfonyl-1H-pyrrol-2-yl)-(2-chloro-pyridin-3-yl)-methanone (150 mg) and hydrazine hydrate (0.15 mL) in ethanol (3.5 mL) was heated at 90° C. for overnight. The reaction was concentrated, diluted with ethyl acetate, washed with base and water, dried and concentrated to give 75 mg of the titled compound as a white solid.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13]2)(=O)=O)=CC=1.[C-:27]#[N:28].[Na+]>CS(C)=O.[Cl-].[Na+].O>[C:27]([CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:13]1)#[N:28]
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OCc3ccccc3)C2)cc1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CC1CCN(C(=O)OCc2ccccc2)C1
Temperature: 80 °C
Yield: 83 %

Procedure:
To a solution of 13.4 g (35.7 mmol) of benzyl 3-(p-methylbenzenesulfonyloxy)pyrrolidine-1-carboxylate in 49 mL of DMSO were added 2.58 g (50.6 mmol) of finely powdered sodium cyanide. The reaction mixture was heated at 80° C. for 3.5 hours and then cooled to room temperature. The crude was diluted with 100 mL of brine and extracted with diethyl ether (5×250 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with 60% ethyl acetate/hexanes to give 6.8 g (83%) of benzyl 3-cyanopyrrolidine-1-carboxylate as a clear oil. Rf=0.46 in 100% ethyl acetate; Mass Spectrum (FD+): M+=230; IR (CHCl3, cm-1): 882, 912, 986, 1030, 1119, 1169, 1292, 1347, 1362, 1424, 1451, 1468, 1486, 1498, 1702, 2891, 2962, 3021; UV (C2H5OH) λmax =206 (ε=9299), 258 (ε=214); Anal. Calcd. for C13 H14N2O2 : C,67.81; H,6.13; N,12.17; Found: C, 67.58; H. 6.26; N, 12.43; 1H NMR (300 MHz, CDC13) δ2.25-2.31 (m, 2H); 3.11 (t, J=6.5 Hz, 1H); 3.48-3.75 (m, 3H); 5.15 (s, 2H); 7.37 (s, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([CH2:8][S:9][C:10]2[N:19]=[C:18]([NH:20][C@H:21]([CH3:31])[CH2:22][NH:23]C(=O)OC(C)(C)C)[C:17]3[N:16]=[CH:15][C:14](=[O:32])[NH:13][C:12]=3[N:11]=2)[CH:5]=[CH:6][CH:7]=1>O1CCOCC1.Cl.O>[ClH:1].[NH2:23][CH2:22][C@H:21]([NH:20][C:18]1[C:17]2[N:16]=[CH:15][C:14](=[O:32])[NH:13][C:12]=2[N:11]=[C:10]([S:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:33])[N:19]=1)[CH3:31]
Reactant: C[C@H](CNC(=O)OC(C)(C)C)Nc1nc(SCc2cccc(Cl)c2F)nc2[nH]c(=O)cnc12
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](CN)Nc1nc(SCc2cccc(Cl)c2F)nc2[nH]c(=O)cnc12
Reaction time: 2 h
Yield: 175.2 %

Procedure:
A two-phase mixture of the product from Example 9 (76 mg) in 1,4-dioxane (3 ml) and conc. HCl (0.3 ml) was stirred for 2 hours, then diluted with water (10 ml) and lyophilised. The residue was dissolved in water (10 ml), washed with ethyl acetate (5 ml), and lyophilised to give the titled compound as a pale yellow solid (58 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11](SC)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O[O:18][S:19]([O-:21])=O.[K+].[CH3:23]O>O.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([S:19]([CH3:23])(=[O:21])=[O:18])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CS[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CO
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of trans (4-methylsulfanyl-cyclohexyl)-carbamic acid tert-butyl ester (0.51 g, 2.10 mmol) in methanol (7 mL) was cooled to 0° C. and treated with a suspension of oxone (1.28 g, 4.20 mmol) in water (3.1 mL). The mixture was stirred at ambient temperature for 20 minutes, then diluted with ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate (×2). The combined organic extracts were washed with 10% aqueous citric acid solution, saturated sodium hydrogen carbonate solution, and brine, dried with sodium sulphate and concentrated under vacuum to give 412 mg (71%) of trans (4-methanesulfonyl-cyclohexyl)-carbamic acid tert-butyl ester as a white solid which was used without further purification. 1H NMR (400 MHz, CDCl3) δ: 4.39 (br s, 1H), 3.43 (br s, 1H), 2.83 (s, 3H), 2.78 (m, 1H), 2.25 (m, 4H), 1.67 (m, 2H), 1.44 (s, 9H), 1.28-1.12 (m, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=[O:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2].[CH3:13][Mg]Br.[Cl-].[NH4+]>C(OCC)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([CH3:13])([OH:12])[CH3:11])=[CH:5][CH:4]=1)[CH3:2]
Reactant: C[Mg]Br
Reactant: CCc1ccc(CC(C)=O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCc1ccc(CC(C)(C)O)cc1

Procedure:
14.8 g (90 mmol) of 1-(4-ethylphenyl)propan-2-one dissolved in diethyl ether is added dropwise to 39 mL of a 3 molar solution of methylmagnesium bromide in diethyl ether while being cooled with an ice bath in such a way that the temperature does not exceed 30° C. After the addition has ended, the reaction mixture is refluxed for 1.5 hours and then hydrolyzed with 10% ammonium chloride solution. After the removal of the organic phase, the aqueous phase is extracted with diethyl ether. The combined ether phases are washed with water, dried with sodium sulfate, and evaporated down. The oil thus obtained is further reacted directly. Yield: 15.5 g (90%).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:20][CH2:19][C:18]2[C@@:5](O)([CH2:6][CH2:7][C@@H:8]3[C:17]=2[C@@H:16]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]4OCC(C)(C)C[O:28]4)=[CH:23][CH:22]=2)[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:35])[CH2:4]1.[BH4-].[Na+].O>CO.C1COCC1>[OH:35][C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C:17]([C@@H:16]([C:21]4[CH:22]=[CH:23][C:24]([CH:27]=[O:28])=[CH:25][CH:26]=4)[CH2:15][C@:13]12[CH3:14])=[C:18]1[C:5](=[CH:4][C:3](=[O:2])[CH2:20][CH2:19]1)[CH2:6][CH2:7]3
Reactant: COC1(OC)CCC2=C3[C@@H](CC[C@@]2(O)C1)[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]3c1ccc(C2OCC(C)(C)CO2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12C[C@H](c3ccc(C=O)cc3)C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73 %

Procedure:
2.1 g of 3,3-dimethoxy-11β-[4-(5,5-dimethyl-1,3-dioxan-2-yl)phenyl]-5α-hydroxy-estr-9-en-17-one is dissolved in 25 ml of methanol/THF (1:1, V/V) and reduced at 23° C. with 303 mg of sodium borohydride. After 45 minutes, it is stirred into water, and the aqueous phase is extracted several times with methylene chloride. The organic phase is dried and evaporated under reduced pressure. The crude product [4-(3,3-dimethoxy-5α,17β-dihydroxy-estr-9-en-11β-yl)benzaldehyde-neopentylketal] is dissolved in 25 ml of acetone, and stirred with 2 ml of water and 283 mg of p-toluenesulfonic acid at room temperature for 8 hours. Then, it is poured into water and the precipitate is suctioned off. The purification of the crude product is carried out by chromatography with a toluene/acetone gradient on silica gel. 1.1 g of 4-(17β-hydroxy-3-oxoestra-4,9-dien-11β-yl)benzaldehyde is obtained.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15]>>[CH3:8][C:2]1[C:1]([N+:14]([O-:16])=[O:15])=[C:6]([OH:7])[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(O)c1
Agent: O=S(=O)(O)O
Product: Cc1cccc(O)c1[N+](=O)[O-]

Procedure:
Furthermore, there is disclosed in Journal of Chemical Society, 1277 (1923) that m-cresol is sulfonated with a fuming sulfuric acid and then the resulting sulfonated m-cresol is nitrated with a mixed acid (nitric acid plus sulfuric acid), but by this method 3-methyl-2-nitrophenol is obtained as a main product and only a small amount of 5-methyl-2-nitrophenol is obtained as a by-product, the total yield being very poor for the reason as mentioned above.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](O)=O>>[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccc(F)cc1F
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(F)cc2F)o1
Yield: 64 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2,4-difluorobenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 199 mg, 64%) which was obtained as a white solid. MS: m/e=340.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25]C[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.N1CC(O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][C:26]([CH3:28])([OH:25])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Agent: OC1CNC1
Product: CC1(O)CN(c2nc(C(C)(C)C)nc3c2nnn3Cc2ccccc2Cl)C1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and azetidin-3-ol hydrochloride and isolated as light-yellow solid (8.0 mg, 46%). MS(m/e): 373.4 (MH+).
Reaction SMILES: [C:1]1(=O)[O:7][C:4]([Cl:6])([Cl:5])[C:3]([Cl:9])([Cl:8])[O:2]1.[FH:11].S(F)(F)(F)[F:13]>>[Cl:8][C:3]1([Cl:9])[C:4]([Cl:6])([Cl:5])[O:7][C:1]([F:13])([F:11])[O:2]1
Reactant: O=C1OC(Cl)(Cl)C(Cl)(Cl)O1
Reactant: F
Reactant: FS(F)(F)F
Product: FC1(F)OC(Cl)(Cl)C(Cl)(Cl)O1
Temperature: 200 °C
Reaction time: 10 h

Procedure:
A 360 mL "Hastelloy" C shaker tube was charged with 113 g (0.5 mole) of tetrachloroethylene carbonate, sealed under nitrogen, cooled in a dry ice acetone mixture, evacuated, flushed with nitrogen, reevacuated and charged with 18 g (0.9 mole) of hydrogen fluoride and 194 g (1.8 mole) of sulfur tetrafluoride. The tube was agitated for 10 hours at 200° C. The tube was next chilled in an ice-water bath and then slowly vented to remove the excess SF4 and HF. The product was dumped from the tube into wet ice and allowed to stand a day. The organic phase was separated from the aqueous phase in a polyethylene separatory funnel, then stirred with a 30% aqueous solution of potassium carbonate to neutralize free acid. The product was dried over potassium carbonate and distilled at a reduced pressure. It boils at 126° C. at atmospheric pressure. The best yield of 4,4,5,5-tetrachloro-2,2,-difluoro-1,3-dioxolane was 73%. Infrared and nuclear magnetic resonance (NMR) spectra support the chemical structure (4) of this dioxolane.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.[I:22]N1C(=O)CCC1=O.N1C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[I:22]
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(I)c(Br)c12
Yield: 23 %

Procedure:
A mixture of 4-bromo-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [synthesized according to the procedure described in U.S. Pat. No. 8,084,620, Example 73-2] (2.00 g, 5.76 mmol), N-iodosuccinimide (1.69 g, 7.49 mmol), and pyridine (1.9 mL, 23.0 mmol) in DMF (20 mL) was heated at 65° C. for 2 days. The cooled mixture was diluted with EtOAc, washed twice with 10% aqueous LiCl and then with brine. The aqueous layers were extracted with EtOAc. The combined organic layers were dried and concentrated, and the residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (gradient from 50%-65%), to provide 4-bromo-7-(2-hydroxypropan-2-yl)-3-iodo-9H-carbazole-1-carboxamide as a yellow solid (0.609 g, 23% yield). Mass spectrum m/z 473, 475 (M+H—H2O)+. 1H NMR (500 MHz, DMSO-d6) δ 11.66 (s, 1H), 8.49 (d, J=8.6 Hz, 1H), 8.38 (s, 1H), 8.26 (br. s., 1H), 7.94 (d, J=1.1 Hz, 1H), 7.58 (br. s., 1H), 7.40 (dd, J=8.6, 1.4 Hz, 1H), 5.09 (s, 1H), and 1.51 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:18]=[C:17](O)[C:16]2[C:15](=[O:20])[N:14]([C:21]3[CH:26]=[C:25]([CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:22]=3[CH3:30])[CH2:13][CH2:12][C:11]=2[N:10]=1.C(=O)(O)[O-].[Na+].[OH-].[Na+].C(Cl)[Cl:39]>>[Cl:39][C:17]1[C:16]2[C:15](=[O:20])[N:14]([C:21]3[CH:26]=[C:25]([CH:27]([CH3:28])[CH3:29])[CH:24]=[CH:23][C:22]=3[CH3:30])[CH2:13][CH2:12][C:11]=2[N:10]=[C:9]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:8])[CH:18]=1
Reactant: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)cccc3C)cc(O)c2C1=O
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)cccc3C)cc(Cl)c2C1=O
Temperature: 25 °C

Procedure:
To a solution of crude 2-(2,6-dimethylphenyl)-4-hydroxy-6-(5-isopropyl-2-methylphenyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (1.4 g, 3.50 mmol) in DCM (35.0 mL) was added Vilsmeier's reagent (0.895 g, 6.99 mmol) as a solid in one portion and the reaction mixture stirred at room temperature. After 2 h 500 mg of Vilsmeier's reagent was added and stirring continued. After 35 min an additional portion of 200 mg of Vilsmeier's reagent was added and stirring continued. After 15 min the reaction mixture was diluted with DCM and poured into saturated aqueous sodium bicarbonate solution containing 1 N NaOH. The layers were separated and the aqueous layer was extracted with DCM (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by FCC (0-20% EtOAc/heptane) to provide 4-chloro-2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one. MS (ESI+) m/z 419.2 (M+H)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11](=[N:13]O)[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.CO.N.[H][H]>CCO.[Ni]>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([NH2:13])[CH3:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=NO)c1ccc2ncccc2c1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: CCO
Product: CC(N)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
To a solution of 1-quinolin-6-yl-ethanone oxime (4.54 g, 24.4 mmol) in EtOH (50 mL) was added methanol solution of NH3 (7N, 12 mL, 80 mmol). A slurry of Raney Nickel (washed 3× with EtOH) about 2 g was added followed by a hydrogen-filled balloon. The reaction was stirred at ambient temperature for 16 hours under hydrogen-filled balloon. The reaction mixture was filtered over a pad of celite and the mother liquor was concentrated to give quantitative 1-quinolin-6-yl-ethylamine (4.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]#[C:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: CN1CCN(CC#Cc2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCO
Product: CN1CCN(CCCc2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)CC1
Yield: 62.2 %

Procedure:
A mixture of 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.057 g, 0.12 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-chloro-5-[3-(4-methyl-piperazin-1-yl)-propyl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.036 g, 63%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.79 (m, 2H), 2.22-2.60 (m, 13H), 2.66 (t, 2H), 4.20 (s, 2H), 4.76 (s, 2H), 7.08-7.38 (m, 6H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:32])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28](O)(=[O:30])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.O=S(Cl)[Cl:35].CN(C=O)C>O=P(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH3:32])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([Cl:35])(=[O:30])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(S(=O)(=O)Cl)cc1
Temperature: 75 °C

Procedure:
5′-[(1-Benzo[1,3]dioxol-5-yl-cyclopropanecarbonyl)-amino]-2′-methylbiphenyl-4-sulfonic acid (1.9 g, 4.3 mmol) was dissolved in POCl3 (30 mL) followed by the addition of SOCl2 (3 mL) and DMF (100 μl). The reaction mixture was heated at 70-80° C. for 15 min. The reagents were evaporated and re-evaporated with chloroform-toluene. The residual brown oil was diluted with chloroform (22 mL) and immediately used for sulfonylation. ESI-MS m/z calc. 469.0. found 470.1 (M+1).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)=O.[NH2:20][C:21]1[CH:25]=[CH:24][NH:23][N:22]=1>C(O)(=O)C>[F:1][C:2]([F:19])([F:18])[C:3]1[N:22]2[N:23]=[CH:24][CH:25]=[C:21]2[N:20]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[CH:4]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cc[nH]n1
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3nccc3n2)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 4,4,4-trifluoro-1-(4-trifluoromethyl-phenyl)-butane-1,3-dione (Example C.1, method 1, step 1) (2.84 g, 10 mmol) and 3-aminopyrazole (0.83 g, 10 mmol) in acetic acid (20 mL) were refluxed for 4 h. The reaction mixture was cooled to rt and poured into ice water (200 mL), extracted with EtOAc, dried over MgSO4, filtered and concentrated, and triturated with toluene, and dried to give 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-α]pyrimidine (3.28 g, 99%) as a yellow solid. MS (ISP) 332.1 [(M+H)+]; mp 110-111° C.