Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])[CH:7]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[P:25](Cl)(Cl)(=[O:29])[O:26][CH2:27][CH3:28].ClCCl>C(#N)C>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][P:25]([O:26][CH2:27][CH3:28])(=[O:29])[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:8]=2[CH:7]=1)(=[O:4])=[O:3]
Reactant: CC(C)(CO)c1cc(OS(C)(=O)=O)ccc1O
Reactant: CCOP(=O)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: CCOP1(=O)OCC(C)(C)c2cc(OS(C)(=O)=O)ccc2O1
Reaction time: 6 h
Yield: 44.6 %

Procedure:
4-Hydroxy-3-(2-hydroxy-1,1-dimethylethyl)phenyl methanesulphonate (10 g) from Example 1 was suspended in acetonitrile (100 ml) and triethylamine (8 g) was added. The mixture was cooled in ice, and ethyl phosphorodichloridate (6.9 g) was added dropwise with vigorous stirring. Stirring was continued for 6 hours prior to the addition of dichloromethane (200 ml), after which the solution was washed with water, dilute sodium hydroxide solution and water again, dried over magnesium sulphate and run down. The crude product was recrystallised from toluene, yielding 6.0 g of the desired product, melting point 113°-115° C.
Reaction SMILES: [CH3:1][C:2]1(C)C(C)(C)OB(C=C)O1.Br[C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[N:23]1[CH2:28][CH2:27][O:26][C:25]2[CH:29]=[C:30]([S:33]([N:36]([CH2:42][C:43]3[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=3)[C:37]3[S:38][CH:39]=[CH:40][N:41]=3)(=[O:35])=[O:34])[CH:31]=[CH:32][C:24]1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:50][O:49][C:46]1[CH:47]=[CH:48][C:43]([CH2:42][N:36]([C:37]2[S:38][CH:39]=[CH:40][N:41]=2)[S:33]([C:30]2[CH:31]=[CH:32][C:24]3[N:23]([C:14]4[CH:15]=[CH:16][C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:13]=4[CH:1]=[CH2:2])[CH2:28][CH2:27][O:26][C:25]=3[CH:29]=2)(=[O:35])=[O:34])=[CH:44][CH:45]=1
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(F)(F)F)cc2Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Temperature: 100 °C
Yield: 83.9 %

Procedure:
In a reaction vial flushed with nitrogen, 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.080 ml, 6.38 mmol), 4-(2-bromo-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (EXAMPLE 53, Step 1; 1.022 g, 1.596 mmol), PdCl2(dppf)-CH2Cl2 adduct (0.065 g, 0.080 mmol), and cesium carbonate (1.560 g, 4.79 mmol) were combined in dioxane (7.18 ml) and water (0.798 ml). The vial was sealed and heated at 100° C. overnight. The reaction was diluted with ethyl acetate and extracted with water. The aqueous layer was then back extracted with ethyl acetate (×3). The organics were combined and dried over sodium sulfate, filtered and concentrated to yield crude material, which was then purified via silica gel chromatography (eluting with 0-100% ethyl acetate in heptanes) to yield N-(4-methoxybenzyl)-N-(thiazol-2-yl)-4-(4-(trifluoromethyl)-2-vinylphenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.787 g, 1.339 mmol, 84% yield) as a light yellow solid. m/z (ESI) 588.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].CN(C=O)C>>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:19][CH:20]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 95.3 %

Procedure:
Following procedure A, 2-chloro-5-nitropyridine (501 mg, 3.16 mmol, 1.00 eq) and 4-tert-butylphenol (611 mg, 4.07 mmol, 1.29 eq) were dissolved in DMF (6.0 mL) Anhydrous K2CO3 (654 mg, 4.73 mmol, 1.50 eq) was added and the reaction mixture was stirred at room temperature for 14 h. After extraction with Et2O, the crude product was purified by flash column chromatography (SiO2; EtOAc/petrolether 1:100 to 1:50) to afford the title compound as colourless solid (820 mg, 3.01 mmol, 95% yield). Rf=0.40 (EtOAc/PE 1:20). HRMS (ESI) calcd. for C15H17N2O3+[M+H]+ 273.1234. found: 273.1229. 1H NMR (400 MHz, CDCl3) δ 9.06 (d, J=2.8 Hz, 1H, aromatic H), 8.46 (dd, J=9.1, 2.8 Hz, 1H, aromatic H), 7.53-7.42 (m, 2H, aromatic H), 7.17-7.05 (m, 2H, aromatic H), 7.01 (d, J=9.1 Hz, 1H, aromatic H), 1.35 (s, 9H, C(CH3)3). 13C NMR (101 MHz, CDCl3) δ 167.20, 150.49, 148.98, 145.26, 140.29, 134.95, 126.99, 120.84, 111.38, 34.72, 31.57.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][N:4]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:3]1.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26].C([O-])(O)=O.[Na+]>C(#N)C>[CH:8]1([C@@H:7]2[CH2:6][CH2:5][N:4]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:3][C@H:2]2[NH:1][C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C1CCCCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C1CCCCC1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(3S,4S)-benzyl 3-amino-4-cyclohexylpiperidine-1-carboxylate (23 mg, 0.073 mmol), 4-nitrophenyl chloroformate (16 mg, 1.1 equiv) and powdered NaHCO3 (13 mg, 2 equiv) were mixed with acetonitrile (3 mL). The mixture was stirred 1 h at rt. LC-MS showed the reaction was complete. The reaction mixture was concentrated to afford (3S,4S)-benzyl 4-cyclohexyl-3-((4-nitrophenoxy)carbonylamino)piperidine-1-carboxylate which was used directly in the next step. LC-MS (3 min) tR=2.24 min., m/z 482 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH2:8][C:9]2=O)=[CH:4][CH:3]=1.[C:15]([Mg]Cl)([CH3:18])([CH3:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:14])([CH3:13])[CH2:7][CH:8]=[C:9]2[C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Mg]Cl
Reactant: CC1(C)CCC(=O)c2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: CC(C)(C)C1=CCC(C)(C)c2ccc(Br)cc21

Procedure:
Reaction Scheme 9 discloses the preferred method of synthesis of a starting material from which certain examples for compounds of the invention within the scope of Formula 6 are preferably made. In accordance with this scheme 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G) is reacted with t-butylmagnesium chloride in tetrahydrofuran in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(H)-pyrimidinone (DMPU). Thereafter, the resulting intermediate tertiary alcohol is heated in the presence of acid (p-toluenesulfonic acid) to give 7-bromo-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene (Compound C42). Compound C42 is reacted with 1-ethoxyvinyltributyltin (EVTB) in the presence of Pd(0) catalyst to yield after acidic work-up 7-acetyl-1-(1,1-dimethylethyl)-3,4-dihydro-4,4-dimethylnaphthalene (Compound C43). Compound C43 is subjected to a sequence of reactions of the type described above in connection with Reaction Scheme 8, starting with a Horner Emmons reaction with diethyl cyanomethylphosphonate, to eventually provide ethyl 7-[4,4-dimethyl-3,4-dihydro-1-(1,1-dimethylethyl)-naphth-7-yl]-3,7-dimethyl-hepta-2(E),4(E),6(E)-trienoate (Compound C46). Compound C46 of the invention is within the scope of Formula 6. ##STR24##
Reaction SMILES: O[C:2]1[C:7]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[C:12]([CH3:19])[CH:11]=2)=[C:6](O)[N:5]=[C:4]([S:22][CH3:23])[N:3]=1.S(=O)(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:32])=O>>[Cl:32][C:2]1[C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[C:14]([CH3:16])[C:13]([O:17][CH3:18])=[C:12]([CH3:19])[CH:11]=3)[O:20][C:6]=2[N:5]=[C:4]([S:22][CH3:23])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1c(C)cc(C(=O)Nc2c(O)nc(SC)nc2O)cc1C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: COc1c(C)cc(-c2nc3c(Cl)nc(SC)nc3o2)cc1C
Temperature: 70 °C
Reaction time: 0.17 h

Procedure:
At room temperature, 45.95 g of N-(4,6-dihydroxy-2-methylsulfanylpyrimidin-5-yl)-4-methoxy-3,5-dimethylbenzamide were suspended with stirring in 125 ml of phosphorus oxychloride, and the mixture was heated at 70° C. for 36 hours. After cooling, the reaction mixture was sucked through a glass frit, giving a yellow solid which was introduced with stirring into a saturated aqueous sodium bisulfate solution and stirred for 10 min. The solid was then filtered off with suction, washed until neutral and dried. This gave 10.47 g (22%) of the title compound, which was reacted further without any further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH:27]=[CH2:28])=[CH:19][N:18]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:28][CH2:27][C:20]3[C:21]4[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17]([CH3:16])=[N:18][CH:19]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: C=Cc1cnc(C)c2ccccc12
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc(C)c3ccccc23)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 1-methyl-4-vinylisoquinoline and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [C:1]([C:3](=[CH:17][NH:18][C:19]1[CH:23]=[CH:22][S:21][CH:20]=1)[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=O)#[N:2].P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:16][C:8]1[CH:9]=[C:10]([Cl:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=1[NH:6][C:4]1[C:3]([C:1]#[N:2])=[CH:17][N:18]=[C:19]2[CH:23]=[CH:22][S:21][C:20]=12
Reactant: COc1cc(NC(=O)C(C#N)=CNc2ccsc2)c(Cl)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: COc1cc(Nc2c(C#N)cnc3ccsc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
A suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-(thien-3-ylamino)prop-2-enamide (500 mg, 1.35 mmol) in 35 mL of acetonitrile was heated to reflux and phosphorous oxychloride (0.84 mL, 8.98 mmol) was added dropwise. The mixture was heated at reflux overnight. The resultant solution was concentrated in vacuo and the residue was cooled to 0° C. Ice water was added followed by the slow addition of saturated aqueous sodium bicarbonate. The mixture was stirred for 10 minutes then partitioned between ethyl acetate and additional saturated aqueous sodium bicarbonate. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate and hexane to provide 337 mg (71%) of 7-[(2,4-dichloro-5-methoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile, mp 208-210° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.85 (s, 3H), 7.39 (s, 1H), 7.46 (d, J=5 Hz, 1H), 7.76 (s, 1H), 8.11 (d, J=5 Hz, 1H), 8.61 (s, 1H), 9.74 (s, 1H); MS (ES) m/z348.1, 350.0 (M−H)−
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[N+:11]([C:14]1[CH:24]=[CH:23][CH:22]=[C:16]2[C:17]([O:19][C:20](=O)[C:15]=12)=[O:18])([O-:13])=[O:12]>C(O)(=O)C>[N+:11]([C:14]1[CH:24]=[CH:23][CH:22]=[C:16]2[C:15]=1[C:20](=[O:19])[N:1]([CH:2]([CH2:3][CH2:4][C:5](=[O:7])[NH2:6])[C:8]([OH:10])=[O:9])[C:17]2=[O:18])([O-:13])=[O:12]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CC(=O)O
Product: NC(=O)CCC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O

Procedure:
A mixture of glutamine (10 mmol) and 3-nitrophthalic anhydride (10 mmol) in 15 ml of acetic acid is heated to reflux. The cooled reaction mixture is concentrated and the residue purified by chromatography to afford 2-(4-nitro-1,3-dioxoisoindolin-2-yl)-4-carbamoylbutanoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.[CH:15]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])OCC>CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]([O:10][CH3:11])=[C:6]([CH:15]([O:19][CH2:20][CH3:21])[O:22][CH2:23][CH3:24])[CH:9]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1c(C=O)cc(Br)cc1C(C)C
Solvent: CCCCCC
Product: CCOC(OCC)c1cc(Br)cc(C(C)C)c1OC

Procedure:
5-bromo-3-isopropyl-2-methoxybenzaldehyde (26.76 g) was dissolved in n-hexane (50 mL) and triethyl orthoformate (22 mL), and Amberlyst-15 (2.68 g) was added to the solution, and then the mixture was refluxed for 4 hours. The reaction solution was filtered, and then the solvent was distilled off under reduced pressure to obtain the title compound (31.55 g) as a brown oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1B(O)O>COCCOC>[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: Cc1ccc(C)c(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccc(C)c(-c2ccccc2CCC(=O)N(NC(=O)c2ccccc2)C(C)C)c1
Yield: 26 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 2,5-dimethyl-phenylboronic acid (29 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (14 mg, 26%). LC-MS m/e 415.36 (M+H+)
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH2:22][CH3:23])[C:10]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:24])[CH:3]=1.[NH3:25]>CO>[CH2:22]([C:9]1[C:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:24])[CH:3]=[C:2]([NH2:25])[N:7]2[N:8]=1)[CH3:23]
Reactant: N
Reactant: CCc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(OC)cc1
Solvent: CO
Product: CCc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1ccc(OC)cc1

Procedure:
In an analogous manner to that described in Example 4, from 7-chloro-2-ethyl-3-(4-methoxy-benzenesulphonyl)-5-methyl-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 2-ethyl-3-(4-methoxy-benzenesulphonyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 186-188°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH2:5].CO.[CH2:8]=[C:9]([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11]>O>[F:11][C:10]([F:13])([F:12])[CH:9]([C:14]([F:17])([F:16])[F:15])[CH2:8][NH:1][CH2:2][CH2:3][CH2:4][NH:5][CH2:8][CH:9]([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11]
Reactant: NCCCN
Reactant: C=C(C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: CO
Product: FC(F)(F)C(CNCCCNCC(C(F)(F)F)C(F)(F)F)C(F)(F)F

Procedure:
To a mixture of 1,3-diaminopropane (3.5 g) and methanol (4 mL) was added HFIB in several portions over a period of about 0.5 h until a gentle reflux of HFIB was observed which did not dissipate. A dry-ice condenser was used to obtain the gentle reflux of HFIB at 20° C. for 15 h. The mixture was poured into water (100 mL) and the bottom layer washed with water to provide 1,3-di-(2-trifluoromethyl-3,3,3-trifluoropropylamino)propane (13 g): MS (m/e) 402 (M+, 0.5%), 251 (12%), 221 (82%), 208 (23%),194 (100%); 1H NMR (CDCl3): 1.66 (quintet, J=6.5 Hz, 2H), 2.72 (t, J=6.5 Hz, 4H), 3.08 (m, 6H) ppm.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:26][CH2:25][CH2:24]3)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:30]1[S:31][CH:32]=[CH:33][N:34]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([CH2:27][CH3:28])=[N:19][N:20]3[CH:23]3[CH2:24][CH2:25][CH2:26]3)=[CH:16][CH:15]=2)[CH2:11][CH2:12][N:13]1[C:30]1[S:31][CH:32]=[CH:33][N:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1nccs1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCN[C@@H](Cc4ccccc4)C3)ccc12
Product: CCc1nn(C2CCC2)c2cc(N3CCN(c4nccs4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 64 %

Procedure:
Prepared using the same procedure described in Example 413 from 6-((S)-3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole and 2-chlorothiazole to afford the title compound as a colorless solid (152 mg, 64%). LC/MS (Method B) 4.60 min, [M+1]+ 458.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([N:13]=[C:14]([SH:15])[N:9]3[CH2:8][CH2:7][CH2:6]2)[CH:12]=1.Cl.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10]3=[C:11]([N:13]=[C:14]([S:15][CH2:23][C:20]4[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=4)[N:9]3[CH2:8][CH2:7][CH2:6]2)[CH:12]=1
Reactant: ClCc1ccncc1
Reactant: COc1cc2c3c(c1)nc(S)n3CCC2
Agent: Cl
Solvent: CCO
Product: COc1cc2c3c(c1)nc(SCc1ccncc1)n3CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
To a suspension of 5,6-dihydro-8-methoxy-2-mercapto-4H-imidazo[4,5,1-ij]quinoline (2.2 g) in ethanol was added 4-picolyl chloride HCl (1.68 g) and the mixture was stirred at ambient temperature for 16 hours and at reflux for 2 hours. The solvent was removed by evaporation and the residue dissolved in water. The solution was washed with EtOAc and then basified (aqueous NaOH) and extracted with CHCl3. Following short column chromatography (SiO2 /CHCl3) the residue was crystallised from EtOAc to give the title compound (1.45 g, 43%) mp 99°-101° C. (Found: C,65.55; H,5.6; N,13.8. C17H17N3OS, requires C,65.6; H,5.5; N,13.5%).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:7]1[C:33]([F:34])=[CH:32][C:10]([O:11][C:12]2[CH:30]=[CH:29][C:15]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH2:27])=[O:26])[C:20](=[O:28])[CH2:19]3)=[O:17])=[CH:14][C:13]=2[F:31])=[C:9]([O:35]C)[CH:8]=1)[CH3:6].[Cl-].[NH4+]>ClCCl>[CH2:5]([C:7]1[C:33]([F:34])=[CH:32][C:10]([O:11][C:12]2[CH:30]=[CH:29][C:15]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH2:24][C:25]([NH2:27])=[O:26])[C:20](=[O:28])[CH2:19]3)=[O:17])=[CH:14][C:13]=2[F:31])=[C:9]([OH:35])[CH:8]=1)[CH3:6]
Reactant: CCc1cc(OC)c(Oc2ccc(C(=O)N3CCN(CC(N)=O)C(=O)C3)cc2F)cc1F
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCc1cc(O)c(Oc2ccc(C(=O)N3CCN(CC(N)=O)C(=O)C3)cc2F)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A commercial solution of boron tribromide (1N in DCM, 0.84 mL, 0.84 mmol) was added to a solution of 2-[4-(4-(4-ethyl-5-fluoro-2-methoxyphenoxy)-3-fluorobenzoyl]-2-oxopiperazin-1-yl)acetamide (which may be prepared in accordance with the experimental described in Example 6, step 1; 140 mg, 0.31 mmol) in dichloromethane (1 mL) placed under argon at −30° C. The reaction mixture was stirred at room temperature overnight and diluted by addition of dichloromethane (20 mL) and a saturated solution of ammonium chloride (20 mL). After separation, the aqueous layer was extracted with dichloromethane (2×20 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (95:5 to 90:10) as eluent. The title product was obtained as a white solid (30 mg, 22%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C:8]1[CH:9]=[C:10]([C:18]2[CH2:23][CH2:22][N:21]([C:24](OC(C)(C)C)=O)[CH2:20][CH:19]=2)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.O.[OH-].[Na+]>C1COCC1>[CH3:24][N:21]1[CH2:20][CH:19]=[C:18]([C:10]2[CH:9]=[C:8]([NH2:7])[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=2)[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(N)cc(C(F)(F)F)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CC=C(c2cc(N)cc(C(F)(F)F)c2)CC1

Procedure:
Into a 100 mL round bottom flask was placed LAH (1.518 g, 40 mmol) and suspended in THF (30 mL). Flask placed into an ice bath. Tert-butyl 4-(3-amino-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (1.368 g, 4 mmol) is added to THF (10 mL) and this solution is in turn added dropwise to the LAH suspension at 0° C. 15 min after addition was complete, flask is equipped with reflux condensor and allowed to reflux 15 h with stirring. Work up: Water (1.5 g) is added dropwise, then 15% NaOH(aq)(w/w)(1.5 g), followed by water (3 g). White precipitate forms after 20 h of stirring, filtered solids, removed solvent under reduced pressure. No further purification done. LC-MS(+) shows mass 257 (M+H), as expected for C13H15F3N2, mw 256.27.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH:9]1[C:28]([O:30]C)=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH:9]1[C:28]([OH:30])=[O:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(C(=O)O)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a mixture of methyl 1-tert-butoxycarbon-vl-4(3,4,5-trimethoxybenzoyl)piperazine-2-carboxylate (500 mg), methanol (3 ml) and water (3 ml) is added sodium hydroxide (100 mg), which is stirred for 30 minutes at room temperature. The reaction mixture is poured into a 5% aqueous solution of citric acid, followed by extraction with dichloromethane. The organic layer is dried and then concentrated to give a crude product, which is recrystallized from ethyl acetate to afford 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxy-benzoyl)piperazine-2-carboxylic acid (400 mg) as colorless crystals, m.p. 188-190° C.