Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]2[C:8]([CH3:11])=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[O:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(O)CCC>[Br:1][C:2]1[N:7]2[C:8]([CH3:11])=[CH:9][N:10]=[C:6]2[C:5]([NH:23][C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:17][CH2:18][O:13][CH2:14][CH2:15]3)=[CH:25][CH:24]=2)=[N:4][CH:3]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1cnc2c(Br)ncc(Br)n12
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cnc2c(Nc3ccc(N4CCOCC4)cc3)ncc(Br)n12
Yield: 52.6 %

Procedure:
5,8-Dibromo-3-methylimidazo[1,2-a]pyrazine (270 mg, 0.93 mmol) and 4-morpholinoaniline (200 mg, 1.1 mmol) are combined in nBuOH (10 mL) and DIPEA (240 μL, 1.4 mmol) is added. The mixture is heated at reflux for 10 h, cooled and the solvent removed under reduced pressure. The residue is purified by silica chromatography, eluting with 12% -100% EtOAc in cyclohexane, to afford the title compound as a red-brown solid (190 mg).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]3[C:18]4[CH:19]=[C:20]([OH:25])[C:21]([Br:24])=[C:22]([Br:23])[C:17]=4[O:16][CH:15]=3)=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[N+]([O-])(O)=[O:27].O>CC(O)=O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]([C:14]3[C:18]4[C:19](=[O:27])[C:20](=[O:25])[C:21]([Br:24])=[C:22]([Br:23])[C:17]=4[O:16][CH:15]=3)=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(c1ccc(-n2ccnc2)cc1)c1coc2c(Br)c(Br)c(O)cc12
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=C1C(=O)c2c(C(=O)c3ccc(-n4ccnc4)cc3)coc2C(Br)=C1Br
Temperature: 60 °C
Yield: 74.1 %

Procedure:
To a solution of (4-(1H-imidazol-1-yl)phenyl)(6,7-dibromo-5-hydroxybenzofuran-3-yl)methanone (55 mg, 0.119 mmol) in AcOH (1 mL) was added nitric acid—69% (36.7 μl, 0.595 mmol) at room temperature. The mixture was heated to 60° C. for 1 hour then cooled to room temperature, poured onto iced water (3 mL) and the suspension filtered under vacuum to furnish 42 mg of a red/orange solid. 1H NMR (DMSO-d6) was consistent with two species—product and starting material. The material was re-subjected to the above conditions for a further hour and then worked up as before to afford compound x (25 mg, 44%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Br.BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@:23]2([C:41]3[C:32](=[CH:33][C:34]4[O:39][CH2:38][CH2:37][O:36][C:35]=4[CH:40]=3)[O:31][CH2:30]2)[C:22]1=[O:42]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1ccccc1CBr
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccc2C(F)(F)F)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(trifluoromethyl)benzyl bromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, (8S)-1′-[2-(trifluoromethyl)benzyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (82%) as a colorless solid: mp 137-138° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ 7.72 (d, J=7.7 Hz, 1H), 7.52-7.33 (m, 2H), 7.22-7.12 (m, 3H), 7.07-7.00 (m, 1H), 6.61 (d, J=7.7 Hz, 1H), 6.52 (s, 1H), 6.31 (s, 1H), 5.26 (d, J=17.1 Hz, 1H), 5.07 (d, J=17.1 Hz, 1H), 4.97 (d, J=8.9 Hz, 1H), 4.70 (d, J=8.9 Hz, 1H), 4.23-4.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.9, 155.4, 144.8, 141.8, 138.4, 133.9, 132.5, 132.1, 129.0, 127.9 (q, 2JC-F=30.8 Hz), 127.6, 126.8, 126.4 (q, 5JC-F=5.8 Hz), 124.4 (q, 1JC-F=273.8 Hz), 124.1, 123.8, 120.8, 111.6, 109.2, 99.6, 80.3, 64.5, 64.0, 58.2, 40.6 (q, J=3.4 Hz); MS (ES+) m/z 454.0 (M+1); Anal. Calcd. for C25H18F3NO4: C, 66.22; H, 4.00; N, 3.09. Found: C, 66.06; H, 3.98; N, 3.12.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:52])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[C:43]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)=[CH:42][N:41]=[N:40]2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:21])([F:22])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:52])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N:39]2[C:43]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)=[CH:42][N:41]=[N:40]2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J12) (173 mg, 0.5 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K5) (250 mg, 0.62 mmol) according to the general procedure M. Obtained as an orange foam (168 mg).
Reaction SMILES: [O:1]=[Sb:2]([O:4][Sb:5](=[O:7])=[O:6])=[O:3].[N+]([O-])([O-])=[O:9].[In+3:12].[N+]([O-])([O-])=[O:14].[N+]([O-])([O-])=O.N>O>[OH-:1].[In+3:12].[OH-:9].[OH-:14].[O:1]=[Sb:2]([O:4][Sb:5](=[O:7])=[O:6])=[O:3]
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=[Sb](=O)O[Sb](=O)=O
Agent: [In+3]
Solvent: O
Product: [OH-]
Temperature: 25 °C

Procedure:
300 g of water was added to 600 g of the diantimony pentoxide sol (specific gravity: 1.198, Sb2O5 concentration: 18.4 wt %) prepared in Preparation Example 1 for dilution. Then, an aqueous indium nitrate solution having 242.2 g of indium nitrate (In(NO3)3.3H2O, In2O3 content: 39.1 wt %, guaranteed reagent, manufactured by Mitsuwa Kagaku Yakuhin K.K.) dissolved in 241.5 g of water, was added thereto with stirring at room temperature. Then,. the mixture was heated to 90° C. and maintained at that temperature for 10 hours. Then, 125.8 g of 28% aqueous ammonia (guaranteed reagent) was added thereto to adjust the pH of the slurry to 7.05, to obtain a mixed slurry of indium hydroxide and diantimony pentoxide. This slurry had an In2O3 concentration of 6.27 wt %, a Sb2O, concentration of 7.31 wt % and an In2O3 /Sb2O5 molar ratio of 1.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[C:16]([C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20])#[N:17]>N1C=CC=CC=1>[C:16]([C:18]([CH3:23])([CH3:22])[C:19]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:20])#[N:17]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CC(C)(C#N)C(=O)Cl
Solvent: c1ccncc1
Product: CC1CC(=O)NN=C1c1ccc(NC(=O)C(C)(C)C#N)cc1
Temperature: 0 °C
Yield: 68.7 %

Procedure:
20.3 g (0.1 mole) of 6-(p-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone were stirred with 15.8 g (0.12 mole) of 2-cyano-2-methylpropionyl chloride in 100 ml of pyridine for 3 hours at 0° C. 100 g of ice were added, after which the crystals were filtered off under suction, and the product was recrystallized from dimethylformamide/water and dried at 50° C. under greatly reduced pressure. 20.5 g (57%) of 6-[p-(2-cyano-2-methylpropionylamino)-phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone were obtained. Mp.: 225°-227° C.
Reaction SMILES: O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+].[Br:15][C:16]1[CH:17]=[C:18]([NH2:22])[CH:19]=[N:20][CH:21]=1.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.CC(O)=O>ClCCCl>[Br:15][C:16]1[CH:17]=[C:18]([NH:22][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:30]=2)[CH:19]=[N:20][CH:21]=1
Reactant: Nc1cncc(Br)c1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ccc(CNc2cncc(Br)c2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Sodium triacetoxyl-borohydride (245 mg, 1.16 mmol) was added to the solution of 5-bromo-pyridine-3-amine(100 mg, 0.57 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (127 mg, 0.57 mmol) in 10 ml of 1,2-dicloroethtane (DCE), of HOAc (66 μL, 2eq. 1.16 mmol) was added, the mixture was stirred overnight at room temperature, followed by addition of 15 ml of DCE. The organic phase was washed with water, and dried over sodium sulfate. The solvent was removed by under reduced pressure to give 200 mg of crude 5-bromo-N-(3-(cyclopentyloxy)-4-methoxybenzyl)pyridin-3-amine, which was used for the next step without further purification.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]#[N:15])=[CH:11]2)=[CH:6][CH:5]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CS(C)=O>[CH2:16]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([C:14]#[N:15])=[CH:11]2)=[CH:6][CH:5]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc2ccc(O)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc2ccc(OCc3ccccc3)cc2c1
Reaction time: 4 h
Yield: 90.3 %

Procedure:
Sodium hydride (151 mg, 60% in mineral oil, 3.77 mmol) is added to a stirring solution of 7-hydroxy-2-naphthonitrile (530 mg, 3.14 mmol) in DMSO (10 mL). After the bubbling subsides, benzyl bromide (448 μL, 3.77 mmol) is added and the resulting mixture is allowed to stir for 4 hours. The reaction mixture is poured into water and extracted with ether. The ether layer is dried (Na2SO4), filtered, and concentrated to dryness. The product is purified by column chromatography (step gradient, 25 to 50% CH2Cl2 in hexanes) to give 7-benzyloxy-2-naphthonitrile (735 mg, 90%) as a white solid. HRMS (EI) calculated for C18H13NO: 259.0997, found 259.0993.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:49]1[CH2:54][CH2:53][O:52][CH2:51][CH2:50]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:49]3[CH2:54][CH2:53][O:52][CH2:51][CH2:50]3)=[O:25])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc2[nH]1
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc2[nH]c(C(=O)N3CCOCC3)cc2c1)N1CCN(C2CCCC2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), morpholine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C2C(=CC=CC=2)CCC1>CCOCC.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NCCc3cc(C)ccc32)cc1OC
Agent: [Pd]
Solvent: CCOCC
Solvent: c1ccc2c(c1)CCCC2
Product: COc1ccc(-c2nccc3cc(C)ccc23)cc1OC
Reaction time: 3.75 h
Yield: 107.4 %

Procedure:
A mixture of 1-(3,4-dimethoxyphenyl)-6-methyl-3,4-dihydroisoquinoline (C2) (5.0 g, 0.018 mol), 10% Pd/C (400 mg) and tetralin (50 ml) was boiled under nitrogen for 3.75 h. The cooled reaction mixture was diluted with ether and filtered The filtrate was treated with HCl gas to give 5.4 g (98%) of the title compound as the hydrochloride. A sample was recrystallized from i-PrOH to give pure 1-(3,4-dimethoxyphenyl)-6-methylisoquinoline hydrochloride, mp 225° dec.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([CH3:23])=[N:21][CH:22]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:15][C:10]1[N:11]=[C:12]([CH3:14])[N:13]=[C:8]([C:7]2[C:2]([NH:16][C:17]3[CH:18]=[C:19]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:20]([CH3:23])=[N:21][CH:22]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)[N:9]=1
Reactant: Cc1ncc(N)cc1NS(C)(=O)=O
Reactant: Cc1nc(N)nc(-c2cccnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1nc(N)nc(-c2cccnc2Nc2cnc(C)c(NS(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.4 %

Procedure:
To a 15 mL round-bottom flask was added 4-(2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.045 g, 0.219 mmol), N-(5-amino-2-methylpyridin-3-yl)methanesulfonamide (0.049 g, 0.241 mmol), and DMF (2.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (0.178 mL, 0.877 mmol) was then added to the solution in one portion. The now burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl and partitioned between water and CHCl3. The aqueous layer was extracted with more CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (16 g, 5% to 10% MeOH in DCM) to afford the desired product as a yellow solid (35 mg). MS (ESI pos. ion) m/z: 387.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.46 (d, J=9.06 Hz, 6H) 3.06 (s, 3H) 3.33 (s, 3H) 6.96 (dd, J=7.60, 4.68 Hz, 1H) 7.75 (br. s., 1H) 7.87 (br. s., 1H) 8.27-8.41 (m, 2H) 8.67 (d, J=2.05 Hz, 1H) 8.79 (dd, J=7.82, 1.53 Hz, 1H) 9.30 (br. s., 1H) 12.03 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Br[CH2:13][CH3:14].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:13][CH3:14])=[O:10])=[CH:6][CH:7]=1
Reactant: CCBr
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)Cc1ccc(Cl)cc1
Reaction time: 18 h
Yield: 623.3 %

Procedure:
A solution of 25 grams (0.147 mole) of 4-chlorophenylacetic acid in 250 ml of acetonitrile was stirred and 15.0 grams (0.0147 mole) of bromoethane, followed by 22.0 grams (0.147 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene, were added. Upon completion of addition the reaction mixture was cooled in a water bath while being stirred for 18 hours. The reaction mixture was concentrated under reduced pressure to one-half volume and then was added to 50 ml of water. The mixture was extracted with two portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 18.2 grams of ethyl (4-chlorophenyl)acetate.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]1[CH2:8][CH:7]([C:9]2[NH:14][C:13]3=[CH:15][CH:16]=[N:17][C:12]3=[CH:11][N:10]=2)[CH2:6][CH:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:4]1.[Br:24]Br>CC(O)=O.O>[ClH:1].[Br:24][C:15]1[CH:16]=[N:17][C:12]2[C:13]=1[NH:14][C:9]([CH:7]1[CH2:6][CH:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:4][CH:3]([CH3:2])[CH2:8]1)=[N:10][CH:11]=2
Reactant: CC1CC(c2ncc3nccc-3[nH]2)CC(c2ccccc2)N1
Reactant: BrBr
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC1CC(c2ncc3ncc(Br)c-3[nH]2)CC(c2ccccc2)N1
Temperature: 45 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
To an oven-dried, 50-mL, round-bottomed flask was added 2-methyl-6-phenyl-4-(piperidinyl)pyrrolo[3,2-d]pyrimidine (Example 35)) (500 mg, 1.71 mmol) which was dissolved in glacial AcOH (15 mL). To this solution was added Br2 (Aldrich Chemical Company) (90.0 mL, 1.8 mmol) dropwise over 2 min. The resulting dark mixture was diluted with H2O (10 mL) and the mixture was warmed to 45° C. and stirred for 2 h. The reaction was allowed to cool to room temperature and the crude material was extracted with EtOAc (50 mL) and washed with saturated NaHCO3 (3×50 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered and evaporated in vacuo to give an oily residue. The residue was purified by silica gel chromatography with 50% EtOAc/hexanes as eluant to give 500 mg (79.4% yield) of a yellow solid. Mp: 239-240 ° C. 1H NMR (DMSO-d6; 400 MHz): d 1.74 (s, 6), 2.63 (s, 3), 3.83 (s, 4), 7.44 (t, 1, J=2.4), 7.5 (t, 2, J=7.0), 7.80 (d, 2, J=7.1). MS m/z: 373.0 (M+1); 369.0, 371.0 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:8]2[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]2=[O:19])[CH:7]=1.[CH3:21][C:22]1[N:23]=[CH:24][S:25][CH:26]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(=O)([O-])[O-].[Ag+2].O.C(#N)C>[CH3:20][C:5]1[CH:4]=[CH:3][C:2]([C:24]2[S:25][CH:26]=[C:22]([CH3:21])[N:23]=2)=[CH:7][C:6]=1[CH:8]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[O:11][C:10]([CH3:18])([CH3:17])[C:9]1=[O:19]
Reactant: Cc1ccc(Br)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Reactant: Cc1cscn1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: Cc1csc(-c2ccc(C)c(C3C(=O)C(C)(C)OC(C)(C)C3=O)c2)n1
Temperature: 65 °C
Yield: 17.1 %

Procedure:
To a mixture of 4-(5-bromo-2-methylphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (200 mg, 0.589 mmol), 4-methylthiazole (70 mg, 0.707 mmol), silver carbonate (814 mg, 2.94 mmol), triphenylphosphine (15 mg, 0.0589 mmol) and [1,1-bis(diphenylphosphino)-ferrocene]palladium(II)chloride (24 mg, 0.0294 mmol) is added a degassed solvent mixture of water/acetonitrile (1.5 ml, 1:1 ratio), followed by subsequent purging with nitrogen then heating at 65° C. for 65 hours with shaking. After cooling to room temperature the reaction mixture is then partitioned between 2M aqueous hydrochloric acid and dichloromethane, and the organic phase is separated. The aqueous layer is washed with a further aliquot of dichloromethane, and the combined organic layers are evaporated under reduced pressure to give a brown solid which is purified by preparative reverse phase HPLC to give 4-[2-methyl-5-(4-methylthiazol-2-yl)phenyl]-2,2,6,6-tetramethylpyran-3,5-dione as a pale yellow solid (36 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][N:3]=1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.Cl>>[F:9][C:8]([F:11])([F:10])[C:6]1[C:5]([C:12]([F:15])([F:14])[F:13])=[CH:4][N:3]=[C:2]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:7]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1cnc(Cl)cc1C(F)(F)F
Agent: Cl
Product: FC(F)(F)c1cnc(N2CCNCC2)cc1C(F)(F)F
Yield: 65.2 %

Procedure:
Working as described in Example 1, but starting with 10 g (0.04 mol) of 2-chloro-4,5-bis(trifluoromethyl)pyridine and 10.3 g (0.12 mol) of piperazine, the base having a boiling point B.p. 0.04 of 100-102° C. was obtained, and then, after conversion to the hydrochloride, 7.8 g of the title compound .
Reaction SMILES: [C:1]1([S:7]([C:10]([CH:15]2[CH2:27][CH2:26][C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([Cl:28])[CH:23]=4)[N:18](COC)[C:17]=3[CH2:16]2)([CH3:14])[CH2:11][O:12][CH3:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+]>CO.C1COCC1.Cl>[C:1]1([S:7]([C:10]([CH:15]2[CH2:27][CH2:26][C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([Cl:28])[CH:23]=4)[NH:18][C:17]=3[CH2:16]2)([CH3:14])[CH2:11][O:12][CH3:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCn1c2c(c3cc(Cl)ccc31)CCC(C(C)(COC)S(=O)(=O)c1ccccc1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COCC(C)(C1CCc2c([nH]c3ccc(Cl)cc23)C1)S(=O)(=O)c1ccccc1
Temperature: 55 °C
Reaction time: 6 h
Yield: 13.2 %

Procedure:
95 mg (0.20 mmol) of (RS,SR)-2-(1-benzenesulfonyl-2-methoxy-1-methyl-ethyl)-6-chloro-9-methoxymethyl-2,3,4,9-tetrahydro-1H-carbazole were dissolved in 8 mL of MeOH/THF 1:1, and 5 drops of HCl 12M were added. The temperature was raised to 55° C. and the solution was stirred for 6 hours. By adding 2M NaHCO3 the solution was neutralized to pH=7, and the mixture was extracted with EtOAc. Column chromatography on silica gel with heptane/EtOAc 2:1 yielded 11 mg (13%) of (RS,SR)-2-(1-benzenesulfonyl-2-methoxy-1-methyl-ethyl)-6-chloro-2,3,4,9-tetrahydro-1H-carbazole as a white solid, MS: 418 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:15][CH3:16])[C:11](=O)[NH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.P(Cl)(Cl)([Cl:19])=O.CCN(C(C)C)C(C)C.[OH-].[Na+]>>[Cl:19][C:11]1[N:12]=[N:13][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[CH:9][C:10]=1[CH2:15][CH3:16]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1cc(-c2cccc(Cl)c2)n[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(-c2cccc(Cl)c2)nnc1Cl
Temperature: 110 °C

Procedure:
A RBF was charged with 6-(3-chlorophenyl)-4-ethylpyridazin-3(2H)-one (1.50 g, 6.4 mmol) and phosphorus oxychloride (6.0 ml, 64 mmol). Hunig's base (1.2 ml, 7.0 mmol) was added to the mixture dropwise (slightly exothermic). The flask was fitted with a reflux condenser and a nitrogen inlet and the mixture was heated at 110° C. for 3 h. Upon cooling the reaction mixture was poured onto ice. 6N NaOH was added dropwise until pH 9 while keeping the mixture cold by gradual addition of ice. The solids were filtered, washed with water and dried to provide 3-chloro-6-(3-chlorophenyl)-4-ethylpyridazine as a peach colored solid. MS m/z=253 [M]+. Calc'd for C12H10Cl2N2: 253.13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][C:9]#N)=[CH:5][CH:4]=1.O.CC(O)=[O:16]>[Ni].N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH:7]=[CH:8][CH:9]=[O:16])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC#N)cc1
Reactant: CC(=O)O
Agent: [Ni]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C=CC=O)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
To 2 g (12.6 mmol) 4-methoxycinnamonitrile in 10:10:20 ml H2O:HOAc:pyridine was added 5 g (47 mmol) NaH2PO2 (hypophosphite) followed by 2 g Ra-Ni. After stirring 3 hours at 50° C., the reaction mixture was filtered, extracted with CH2Cl2, washed with dilute HCl, washed with H2O and evaporated to give 0.7 g (35% yield) 4-methoxycinnamaldehyde, a yellow solid, m.p. 47° C.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[CH:23](O)[CH:24]1[CH2:26][CH:25]1[C:27]#[N:28].[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([CH2:40][S:41]([CH3:44])(=[O:43])=[O:42])[CH:39]=1)[NH:36][CH:35]=[CH:34]2>ClCCCl>[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[C:38]([CH2:40][S:41]([CH3:44])(=[O:42])=[O:43])[CH:39]=1)[NH:36][CH:35]=[C:34]2[CH:23]([C:14]1[CH:15]=[CH:16][C:17]([C:19]([F:22])([F:21])[F:20])=[CH:18][C:13]=1[F:12])[CH:24]1[CH2:26][CH:25]1[C:27]#[N:28]
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: N#CC1CC1C(O)c1ccc(C(F)(F)F)cc1F
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(C(F)(F)F)cc3F)C3CC3C#N)c[nH]c12

Procedure:
1.63 g (7.35 mmol) of indium(III) chloride and 0.85 ml (11.0 mmol) of trifluoroacetic acid were added to 1.59 g (6.13 mmol) of the compound from Example 164A and 1.90 g (7.35 mmol) of the compound from Example 87A in 100 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 763 mg (27% of theory) of the title compound as mixture of diastereomers.