Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[O:16]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of p-fluorobenzaldehyde (1.6 mmol, 0.2 g) in dimethylformamide (8 mL) was added phenol (3.52 mmol, 0.33 g) and cesium carbonate (3.52 mmol, 1.15 g). The reaction mixture was headed to 90° C. for 3 hours at which time the reaction mixture was cooled to room temperature and filtered through a medium fritted funnel. The reaction mixture was then diluted with 125 mL of ethyl acetate and extracted with eight 15 mL portions of water followed by one 10 mL portion of brine. The organic layer was then dried with magnesium sulfate and evaporated to dryness. The title product was purified by column chromatography and 0.237 g (1.2 mmol) was recovered. 1H NMR (300 MHz, CDCl3) δ 9.91 (s, 1H), 8.02 (s, OH), 7.92-7.79 (m, 2H), 7.49-7.37 (m, 2H), 7.23 (t, J=8.0, 2H), 7.14-7.01 (m, 4H), 6.89 (t, J=8.3, 2H). 13C NMR (75 MHz, CDCl3) δ 191.28, 163.56, 156.41, 155.26, 132.28, 131.38, 130.41, 129.79, 125.23, 120.69, 120.45, 117.79, 115.61.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[ClH:9].[CH3:10][C:11]1[N:12]=[C:13]([NH:16][C:17]2[CH:25]=[C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]([C:21](O)=[O:22])=[CH:19][N:18]=2)[S:14][CH:15]=1>>[ClH:9].[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:21]([C:20]2[CH:19]=[N:18][C:17]([NH:16][C:13]3[S:14][CH:15]=[C:11]([CH3:10])[N:12]=3)=[CH:25][C:24]=2[O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:22])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: Cc1csc(Nc2cc(Oc3ccccc3)c(C(=O)O)cn2)n1
Agent: Cl
Product: CCN1CCN(C(=O)c2cnc(Nc3nc(C)cs3)cc2Oc2ccccc2)CC1

Procedure:
Prepared according to the method of Example 32 from 1-ethylpiperazine and 6-(4-methylthiazol-2-ylamino)-4-phenoxynicotinic acid hydrochloride (Example 59). Yield: 0.055 g, 43.07%. 1H NMR (CDCl3) δ 8.34 (s, 1H), 7.47 (t, 2H), 7.33 (t, 1H), 7.06 (s, 1H), 7.04 (s, 1H), 6.38 (s, 1H), 6.26 (s, 1H), 3.97 (m, 3H), 2.97 (m, 7H), 2.27 (s, 3H), 1.46 (t, 3H).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:68][N:69]([CH3:81])[CH2:70][CH2:71][O:72][C:73]1[CH:80]=[CH:79][C:76]([CH:77]=O)=[CH:75][CH:74]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:77]([C:76]3[CH:79]=[CH:80][C:73]([O:72][CH2:71][CH2:70][N:69]([CH3:68])[CH3:81])=[CH:74][CH:75]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CN(C)CCOc1ccc(C=O)cc1
Reactant: CC(c1ccncc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(c1ccncc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(OCCN(C)C)cc4)nc23)CC1
Reaction time: 6 h
Yield: 22.1 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.074 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.22 mmol, 0.22 mL) and 4-(2-(dimethylamino)ethoxy)benzaldehyde (1.1 eq, 0.088 mmol, 17 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 85:15) gave the product (9 mg, 21%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.35 (d, J=6.7 Hz, 3H, CHCH3), 2.25 (s, 6H, N(CH3)2), 2.51-2.55 (m, 2H, piperazine NCH2), 2.63-2.65 (m, 2H, piperazine NCH2), 2.67 (t, J=5.6 Hz, 2H, Me2NCH2), 3.57 (q, J=6.7 Hz, 1H, CHCH3), 3.63-3.66 (m, 4H, piperazine N(CH2)2), 4.14 (q, J=5.8 Hz, 2H, OCH2), 7.10 (d, J=8.9 Hz, 2H, phenyl H-3 & H-5), 7.39 (d, J=6.0 Hz, 2H, pyridine H-3 & H-5), 8.11 (d, J=8.8 Hz, 2H, phenyl H-2 & H-6), 8.19 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.54 (d, J=5.9 Hz, 2H, pyridine H-2 & H-6), 13.33 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][C:13]=2[C:21](=[O:23])[CH3:22])=O)[S:7][CH:8]=1)([CH3:3])[CH3:2].OC1C2C(=C(C)C(OC)=CC=2)N=C(C2SC=CN=2)C=1>>[Cl:18][C:17]1[C:16]([O:19][CH3:20])=[CH:15][CH:14]=[C:13]2[C:12]=1[N:11]=[C:9]([C:6]1[S:7][CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1)[CH:22]=[C:21]2[OH:23]
Reactant: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1Cl
Agent: COc1ccc2c(O)cc(-c3nccs3)nc2c1C
Product: COc1ccc2c(O)cc(-c3nc(C(C)C)cs3)nc2c1Cl

Procedure:
The title product 46 was prepared (58%) from 2′-[[(4-isopropylthiazole-2-yl)(oxo)-methyl]amino]-3′-chloro-4′-methoxyacetophenone (45) following the procedure reported for 4-hydroxy-7-methoxy-8-methyl-2-(thiazol-2-yl)quinoline (24): m/z=335 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:8]=2)[CH2:5][CH:4]([C:21]([O:23]C)=[O:22])[CH2:3]1.[OH-].[Na+].[OH-].[Na+].O.C1COCC1.CO>O.C1COCC1.CO>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[CH:8]=2)[CH2:5][CH:4]([C:21]([OH:23])=[O:22])[CH2:3]1
Reactant: COC(=O)C1CC(=O)N(c2cccc(CNc3ccccn3)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CC(=O)N(c2cccc(CNc3ccccn3)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-oxo-1-{3-((2-pyridylamino)methyl)phenyl}pyrrolidine-3-carboxylate in water/THF/MeOH was added 1.0 eq 1N NaOH. The volume ratio of NaOH/water/THF/MeOH was 1:3:4:4. The reaction was stirred at room temperature overnight, and then concentrated in vacuo. The compound was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([NH:15][C:16]([C:18]3[C:22]([O:23][CH3:24])=[C:21]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[N:20]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])[N:19]=3)=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:4][CH:3]=1.O.C(OCC)(=O)C.[CH3:46][N:47](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[C:46]([C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:10][CH2:11][N:12]([NH:15][C:16]([C:18]3[C:22]([O:23][CH3:24])=[C:21]([C:25]4[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=4)[N:20]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[Cl:38])[N:19]=3)=[O:17])[CH2:13][CH2:14]2)=[O:8])=[CH:4][CH:3]=1)#[N:47]
Reactant: CN(C)C=O
Reactant: COc1c(C(=O)NN2CCN(C(=O)c3ccc(Br)s3)CC2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(C(=O)NN2CCN(C(=O)c3ccc(C#N)s3)CC2)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Temperature: 180 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a solution of the compound obtained in Example 24A (49 mg) in dimethylformamide (1 mL) was added zinc cyanide (6 mg), tris(dibenzylideneacetone)-dipalladium (1.5 mg) and 1,1′-bis(diphenylphosphino)ferrocene (DPPF, 1.8 mg) and the mixture was stirred at 180° C. for 15 minutes in a microwave reactor. After cooling to room temperature, to the reaction mixture was added water and ethyl acetate. The mixture was stirred and the organic layer was extracted by diatomaceous earth column (CHEM ELUTE, VARIAN Inc.) and the extract was concentrated in vacuo. The extract was concentrated in vacuo and the crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=30/70 to 0/100) to obtain 3-[N-[4-(5-cyano-2-thenoyl)piperazin-1-yl)carbamoyl]-1-(2-chlorophenyl)-5-(4-chloro-phenyl)-4-methoxy-1H-pyrazole (79 mg; yield: 83%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].[CH3:12][S:13]SC.Cl>CCCCCC.O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([S:13][CH3:12])[C:3]=1[F:11]
Reactant: CSSC
Reactant: O=C(O)c1ccc(Cl)c(F)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1c(C(=O)O)ccc(Cl)c1F
Temperature: -40 °C
Reaction time: 3 h
Yield: 69.3 %

Procedure:
n-Butylithium (2.5M in hexane, 180 ml) was added dropwise to a stirred, cooled solution of 4-chloro-3-fluorobenzoic acid (37.5 g) in tetrahydrofuran while maintaining the temperature below -40° C. The mixture was stirred at -40° C. for 3 hours. Dimethyl disulphide (60.5 g) in tetrahydrofuran was added dropwise and the mixture was stirred at -40° C. for half an hour and at room temperature overnight. Hydrochloric acid (2M) was added and the layers were separated. The aqueous layer was extracted with ether and the combined organic layers were extracted with aqueous sodium hydroxide (2M). The aqueous extract was acidified to pH1 and extracted with ether. washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was triturated with n-hexane and filtered to give 4-chloro-3-fluoro-2-(methylsulphenyl)benzoic acid (32.84 g) as a white solid m.p. 149.5°-150.50° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([O:30]CC)=[O:29])[CH:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([OH:30])=[O:29])[CH:23]=3)[CH2:20][CH2:21]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cccc(N2CCN(CCC3CCN(C(=O)OC(C)(C)C)CC3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(CCN2CCN(c3cccc(C(=O)O)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of 2.8 g (12.8 mmol) of 4-{2-[4-(3-ethoxycarbonylphenyl)piperazin-1-yl]ethyl}piperidine-1-carboxylic acid tert-butyl ester are added 12.8 mL of 1N aqueous sodium hydroxide solution. The mixture is stirred overnight at room temperature then concentrated under reduced pressure. The residue is acidified with 12.8 mL of 1N aqueous hydrochloric acid solution. The product is extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 2.5 g (47%) of 4-{2-[4-(3-carboxyphenyl)piperazin-1-yl]ethyl}piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: CC([SiH:12]([CH2:23]CCCCCCCCC)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=CCCCCCCCC.[CH3:33][CH:34]([SiH](CCCCCCCCCC)CCCCCCCCCC)[CH:35]=CCCCCCCC>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:23][SiH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCC=C(C)[SiH](CCCCCCCCCC)CCCCCCCCCC
Reactant: CCCCCCCC=CC(C)[SiH](CCCCCCCCCC)CCCCCCCCCC
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCCCCCCCC[SiH2]C
Yield: 85 %

Procedure:
The test of Example 20 was repeated using 0.005 gram of chlorotris(triphenylphosphine)rhodium(I). The reaction was over in one hour at 50° C., and produced an 85 percent yield of methyltridecylsilane and 15 percent of methyldidecylsilyl-1-decene and methyldidecylsilyl-2-decene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.[CH:11]1([CH2:14][N:15]2[C:23]3[N:22]=[C:21]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([NH:31][CH3:32])=[CH:27][CH:26]=4)[NH:20][C:19]=3[C:18](=[O:33])[N:17]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:16]2=[O:42])[CH2:13][CH2:12]1.C(N(CC)CC)C>>[CH:11]1([CH2:14][N:15]2[C:23]3[N:22]=[C:21]([CH2:24][C:25]4[CH:26]=[CH:27][C:28]([N:31]([CH3:32])[C:8](=[O:10])[CH2:7][C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)=[CH:29][CH:30]=4)[NH:20][C:19]=3[C:18](=[O:33])[N:17]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[C:16]2=[O:42])[CH2:13][CH2:12]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: O=C(O)Cc1cccnc1
Solvent: CCN(CC)CC
Product: CN(C(=O)Cc1cccnc1)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1

Procedure:
This compound was prepared by a method similar to that described in example 79 except that commercially available 3-pyridylacetic acid was used in place of N-acetyl-6-amino-2-pyridine carboxylic acid, the reaction was performed using 0.69 equivalents of 3-cyclopropylmethyl-8-[4-(methylamino)-benzyl]-1-(2-fluorobenzyl)-3,7-dihydropurine-2,6-dione and 0.78 equivalents of triethylamine was added as the final reagent to the reaction mixture. The product was purified by chromatography using silica gel eluted with 93:7 chloroform/methanol followed by crystallization from acetonitrile. MS, m/z(M+)=553.2364.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1([OH:19])[CH2:10][CH:9]2[CH2:11][CH2:12][CH:6]1[CH:7]=[C:8]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][O:21][CH2:22][C:23]([CH2:32][O:33][CH3:34])([CH3:31])[C:24]([NH:26][CH2:27][CH2:28][CH:29]=O)=[O:25].C([BH3-])#N.[Na+]>C(Cl)Cl.CC(O)=O>[OH:19][C@@:5]1([CH2:4][CH2:3][N:2]([CH3:1])[CH2:29][CH2:28][CH2:27][NH:26][C:24](=[O:25])[C:23]([CH2:32][O:33][CH3:34])([CH3:31])[CH2:22][O:21][CH3:20])[CH2:10][C@H:9]2[CH2:11][CH2:12][C@@H:6]1[CH:7]=[C:8]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COCC(C)(COC)C(=O)NCCC=O
Reactant: CNCCC1(O)CC2CCC1C=C2c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COCC(C)(COC)C(=O)NCCCN(C)CC[C@]1(O)C[C@H]2CC[C@@H]1C=C2c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55 %

Procedure:
50 mg of rac-(1R*,2R*,4R*)-2-(2-methylamino-ethyl)-5-phenyl-bicyclo[2.2.2]oct-5-en-2-ol were dissolved in DCM/AcOH. 46 mg of 3-methoxy-2-methoxymethyl-2-methyl-N-(3-oxo-propyl)-propionamide and 50 mg of sodium cyanoborohydride were added. The reaction mixture was stirred for 3 days at room temperature, quenched with sat.-NaHCO3 and extracted with DCM. The organic phase was washed with brine, dried over anh. Na2SO4 and concentrated in vacuo. The resulting crude material was purified by CC using EtOAc/MeOH/NEt3 90/10/1 as eluant to yield 49 mg of rac-N-(3-{[2-((1R*,2R*,4R*)-2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)-ethyl]-methyl-amino}-propyl)-3-methoxy-2-methoxymethyl-2-methyl-propionamide as a yellow oil.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:16][CH:15]=1)=O>C(O)C>[C:2]1([C:1]2[S:8][CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:16][CH:15]=3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NCCc1ccc(C(=O)CBr)cc1
Reactant: NC(=S)c1ccccc1
Solvent: CCO
Product: CC(=O)NCCc1ccc(-c2csc(-c3ccccc3)n2)cc1
Temperature: 80 °C
Yield: 100 %

Procedure:
In a round-bottomed flask, thiobenzamide (357 mg, 2.60 mmol) and N-[2-(4-bromoacetyl-phenyl)-ethyl]-acetamide (740 mg, 2.60 mmol) were combined in ethanol (30 ml) and heated to about 80° C. for about three hours. The reaction mixture was then concentrated in vacuo to yield an off-white solid. The resulting material (838 mg, 100% yield) was ascertained to be pure by NMR and was carried into the next step directly without further purification. LRMS ([M+H]+)=323.2.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1([O:15][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)=[C:18]([NH2:31])[N:17]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O>C(Cl)(Cl)Cl>[Br:1][C:21]1[N:22]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:23]2[C:19]([N:20]=1)=[C:18]([NH2:31])[N:17]=[C:16]([O:15][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)[N:24]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1nc(OC2CCCCC2)nc2c1ncn2C1CCCCO1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc(OC2CCCCC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
N-Bromosuccinimide (0.214 g, 1.2 mmol) was added to a stirred solution of 2-(cyclohexyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.254 g, 0.80 mmol) in chloroform (5 ml) at 0° C. The resultant mixture was stirred at 0° C. for 1.5 hours and then warmed to room temperature and stirred for a further 2 hours. Water (5 ml) was added and the phases separated using a hydrophobic frit. The organic phase was evaporated and the residue dissolved in dichloromethane and purified on a 70 g aminopropyl (NH2) cartridge eluting with a 0-100% ethyl acetate in cyclohexane gradient over 40 mins. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (0.252 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O:18]C)=[O:17])[CH:14]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[OH-].[K+:21].CO.O>C1COCC1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([O-:18])=[O:17])[CH:14]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[K+:21]
Reactant: COC(=O)c1ccc2[nH]nc(-c3ccncc3)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1ccc2[nH]nc(-c3ccncc3)c2c1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
Methyl 3-pyridin-4-yl-1H-indazole-5-carboxylate (305 mg, 1.204 mmol) and KOH (88 mg, 1.566 mmol) were stirred in THF (9 mL)/MeOH (1.5 mL)/water (1.5 mL) at 70° C. for 24 hours. Additional KOH (87 mg, 1.551 mmol) was added and stirring at 70° C. continued for 20 hours. Room temperature was attained and the solvent was removed in vacuo to give potassium 3-(pyridin-4-yl)-1H-indazole-5-carboxylate as a brown solid (˜67 wt %).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(-c2ccc(Cl)nn2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 10.4 %

Procedure:
To a suspension of 3,6-dichloropyridazine (2.98 g), 3-nitrophenylboronic acid (1.67 g) and tetralis(triphenylphosphine)-palladium (578 mg) in 1,2-dimethoxyethane (30 ml) was added an aqueous solution of sodium carbonate (2M, 15 ml), and the mixture was stirred at 80° C. for 3 hours. The mixture was diluted with ethyl acetate, and then washed with water and brine. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 30% ethyl acetate in n-hexane to give 3-chloro-6-(3-nitro-phenyl)-pyridazine (0.246 g, 10.4%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]#[CH:16].Br[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:13][CH2:14]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]#[C:16][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[CH3:24]
Reactant: C#Cc1ccc2c(nnn2CC2CC2)c1Cl
Reactant: Cc1ccncc1Br
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccncc1C#Cc1ccc2c(nnn2CC2CC2)c1Cl
Temperature: 90 °C
Reaction time: 18 h

Procedure:
A solution of 4-chloro-1-(cyclopropylmethyl)-5-ethynyl-1H-benzotriazole (20 mg, 0.086 mmol), 3-bromo-4-methylpyridine (30 mg, 0.17 mmol), copper (I) iodide (5 mg, 0.026 mmol), and triethylamine (156 μL, 1.12 mmol) in DMF (0.54 mL) was sparged under nitrogen and heated at 90° C. for 18 hours. The mixture was treated with Quadrapure TU, stirred for 18 hours and filtered. The filtrated was concentrated in vacuo and the residue was purified by preparative reverse-phase HPLC, providing the titled compound: 1H-NMR (500 MHz, d6-DMSO) δ 8.78 (s, 1H), 8.53 (s, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.44 (s, 1H), 4.67 (d, J=7.3 Hz, 2H), 2.56 (s, 3H), 1.40 (m, 1H), 0.58 (d, J=7.7 Hz, 2H), 0.50 (d, J=5.0 Hz, 2H) ppm; high resolution mass spectrometry (ES+) m/z 323.1058 [(M+H)+; calculated for C18H16ClN4: 323.1058].
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:50]1[C:58]2[C:53](=[C:54]([C:59]3[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=3)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]1>CN(C=O)C>[NH:50]1[C:58]2[C:53](=[C:54]([C:59]3[CH:60]=[C:61]([NH:65][C:23]([C:18]4[C:19](=[O:22])[O:20][C:21]5[C:16]([CH:17]=4)=[CH:15][CH:14]=[CH:13][C:12]=5[O:11][CH3:10])=[O:25])[CH:62]=[CH:63][CH:64]=3)[CH:55]=[CH:56][CH:57]=2)[CH:52]=[CH:51]1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2cccc3[nH]ccc23)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cccc5[nH]ccc45)c3)c(=O)oc12
Temperature: 25 °C
Yield: 67.5 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-indol-4-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.018 g of product in 70% yield: LCMS (ESI) m/z 411 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].[CH:11]([Mg]Br)=[CH2:12].C([O-])(=O)C.[NH4+]>C1COCC1>[OH:7][CH:6]([C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[C:1]#[N:2])[CH:11]=[CH2:12]
Reactant: N#Cc1cccc(C=O)c1
Reactant: C=C[Mg]Br
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)c1cccc(C#N)c1
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To 3-cyanobenzaldehyde (25 g, 0.190 mmol) in THF (576 mL) was added dropwise at -10° C. vinyl magnesium bromide in THF (202 mL, 0.201 mmol). After 15 min, the reaction mixture was poured on cold 25% aqueous ammonium acetate solution and extracted with EtOAc. The resulting mixture was purified by flash chromatography to provide 17.5 g (60%) of the title product.