Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:12]([NH:14][CH2:15][C:16](N)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32].Cl.N[CH2:35][C:36](N)=O>>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([C:12]([N:14]3[CH2:36][CH2:35][C@H:16]([OH:17])[CH2:15]3)=[O:13])[CH:19]=[CH:20][C:21]=2[CH3:22])[CH:5]=[N:4][C:3]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=1[F:32]
Reactant: Cc1ccc(C(=O)NCC(N)=O)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O
Reactant: NCC(N)=O
Agent: Cl
Product: Cc1ccc(C(=O)N2CC[C@H](O)C2)cc1-n1cnc(OCc2ccc(F)cc2F)c(Cl)c1=O

Procedure:
The title compound was prepared using a procedure similar to that used in Step 4 of the synthesis of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide by substituting (S)-3-hydroxypyrrolidine for glycineamide HCl. 1H NMR (CD3OD/400 MHz) δ8.31 (d, 1H, J=7.6 Hz), 7.62 (m, 2H), 7.52 (m, 2H), 7.01 (m, 2H), 5.59 (m, 2H), 4.42 .(m, 1H), 3.64 (m, 4H), 2.19 (s, 3H), 2.00 (m, 2H). ESHRMS m/z 476.1147 (M+H calculated for C23H21ClF2N3O4 requires 476.1183).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(=O)(O)[O-].[Na+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[C:23]([N:5]1[CH2:6][CH:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: O=C(O)[C@@H]1CC(O)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)[C@@H]1CC(O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
To 20 g (152.5 mmol) of 4-hydroxy-L-proline in 35 ml of water was added 36.7 g (436.8 mmol) of sodium bicarbonate and the mixture was cooled to 10° C. before 32.5 g (190.5 mmol) of benzylchloroformate wa added dropwise. The cooling bath was then removed and the mixture was allowed to stir for 24 hours at room temperature. The pH of the reaction was then adjusted to 1 with concentrated HCl solution and the mixture was extracted with 3×100 ml portions of methylene chloride. The organic layers were dried over Na2SO4 and evaporated in vacuum to provide 36.4 g of the product as an oil (90% yield). NMR(CDCl3): 7.30 (m,5H, aromatic), 5.12 (m,2H), 4.50 (m,2H), 4.36 (m,2H), 3.6 (m,2H), 2.38 (m,2H).
Reaction SMILES: COC1C=CC(C[NH:8][CH:9]2[C:15]3=[N:16][C:17]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)=[CH:18][C:19](=[O:20])[N:14]3[CH2:13][CH2:12][O:11][CH2:10]2)=CC=1.[N+]([O-])([O-])=O.[Ce].[NH4+]>C(#N)C.O>[NH2:8][CH:9]1[C:15]2=[N:16][C:17]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[CH:18][C:19](=[O:20])[N:14]2[CH2:13][CH2:12][O:11][CH2:10]1
Reactant: COc1ccc(CNC2COCCn3c2nc(-c2ccncc2)cc3=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: NC1COCCn2c1nc(-c1ccncc1)cc2=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2.00 g (1.32 mmol) of 9-(4-methoxy-benzylamino)-2-pyridin-4-yl-5,6,8,9-tetrahydro-7-oxa-1,4a-diaza-benzocyclohepten-4-one in acetonitrile/water (20/10 mL) was added 2.17 g (3.96 mmol) of ammonium cerium nitrate. The reaction was stirred at room temperature for 15 hours. After an acido-basic work-up and extraction with dichloromethane, the organic phase was washed with a saturated solution of sodium chloride, dried over sodium sulphate and concentrated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 98/2/0.2 to give 0.226 g (5%, 3 steps) of product as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[CH3:28][N:25]1[CH2:26][CH2:27][N:22]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:2]([O:1][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:3][C:4]=3[C:32]([F:35])([F:34])[F:33])[N:8]=[CH:9]4)[C:18](=[O:29])[N:19]=2)[CH2:23][CH2:24]1
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(O)cc4C(F)(F)F)c3)S2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(OS(C)(=O)=O)cc4C(F)(F)F)c3)S2)CC1
Reaction time: 1 h

Procedure:
To a solution of 5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one (10 mg, 0.02 mmol) in 1 mL CH2Cl2 was added DIEA (7.7 mg, 0.06 mmol) and methanesulfonyl chloride (4 mg, 0.03 mmol). The mixture was stirred for 1 h and loaded onto a silica gel-packed column. The desired product was eluted with 0-100% gradient of CH2Cl2/EtOAc, followed by 10% MeOH/EtOAc (8.6 mg, 74%).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[O:17][CH3:18])[C:10]([C:19]([NH2:21])=[O:20])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:22][CH2:23][C:24]([CH2:26]Cl)=O>C1(C)C=CC=CC=1.ClCCl>[Cl:22][CH2:23][C:24]1[N:21]=[C:19]([C:10]2[C:11]3[C:16](=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH:9]=2)[O:20][CH:26]=1
Reactant: O=C(CCl)CCl
Reactant: COc1cccc2c(C(N)=O)cn(CC3CCCCC3)c12
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cccc2c(-c3nc(CCl)co3)cn(CC3CCCCC3)c12
Yield: 81.1 %

Procedure:
To a solution of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid amide (500 mg, 1.75 mmol) in toluene (4 ml) was added 1,3-dichloroacetone (333 mg, 2.62 mmol) and the reaction mixture subjected to microwave irradiation at 150° C. for 30 minutes. The resulting black solution was diluted with dichloromethane (50 ml) and washed with 5% aqueous sodium carbonate solution (5×20 ml), dried over magnesium sulfate, filtered and the solvent removed in vacuo. The resulting brown oil was purified by flash column chromatography using 5% (v/v) acetone in petroleum ether 40-60 to give 3-(4-chloromethyl-oxazol-2-yl)-1-cyclohexylmethyl-7-methoxy-1H-indole (510 mg, 1.42 mmol) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.[NH2:10][NH2:11].CC(O)CC>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][NH2:11])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: NN
Solvent: CCC(C)O
Solvent: O
Product: NNc1ccc(Br)cn1
Reaction time: 20 h
Yield: 87 %

Procedure:
A 12 L three-necked round-bottomed flask equipped with a mechanical stirrer and a condenser, connected on top with a nitrogen bubbler and a thermometer, was charged with 2,5-dibromopyridine (442 g, 1.87 moles), hydrazine hydrate (55% wt., 1057 ml, 18.7 moles), poly(ethylene glycol) (average Mn about 300, 1.87 L), 2-butanol (373 ml) and water (1.87 L). The mixture was heated at reflux for 29 hours. The heating source was removed and the mixture was stirred for an additional 20 hours. To the resulting slurry, cold water (2.2 L) was added. The slurry was stirred for an additional 30 minutes and filtered. The cake was washed with cold water (3×200 ml) and dried in a vacuum-oven (40° C.) for 48 hours. The title compound was obtained as off-white flakes (305 g, yield 87%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[N:13]([CH3:14])[C:12]2[C:15]3[CH2:16][C:17]([CH3:26])([CH3:25])[O:18][C:19]=3[C:20]([C:22]([OH:24])=O)=[CH:21][C:11]=2[N:10]=1.[CH:28]1([CH2:31][NH2:32])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN(C=O)C>C1COCC1>[CH:28]1([CH2:31][NH:32][C:22]([C:20]2[C:19]3[O:18][C:17]([CH3:26])([CH3:25])[CH2:16][C:15]=3[C:12]3[N:13]([CH3:14])[C:9]([NH:8][C:7]4[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=4[Cl:27])=[N:10][C:11]=3[CH:21]=2)=[O:24])[CH2:30][CH2:29]1
Reactant: NCC1CC1
Reactant: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)O)c3c(c21)CC(C)(C)O3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cn1c(Nc2c(Cl)cncc2Cl)nc2cc(C(=O)NCC3CC3)c3c(c21)CC(C)(C)O3
Yield: 18.6 %

Procedure:
The title compound was prepared following the procedure described for Example-1 by using 2-((3,5-dichloropyridin-4-yl)amino)-1,7,7-trimethyl-7,8-dihydro-1H-benzofuro[4,5-d]imidazole-5-carboxylic acid (Intermediate-61, 0.100 g, 0.245 mmol), cyclopropylmethanamine (0.025 g, 0.363 mmol), TBTU (0.157 g, 0.49 mmol), DMF (5 mL), THF (3 mL) to afford 0.021 g of the desired product. 1HNMR (DMSO-d6): δ 0.22 (d, J=4.2 Hz, 2H), 0.44 (d, J=6.6 Hz, 2H), 1.02 (m, 1H), 1.54 (s, 6H), 3.19 (m, 2H), 3.44 (s, 2H), 3.56 (s, 3H), 7.22 (s, 1H), 7.80 (m, 1H), 8.45 (s, 2H), 10.79 (s, 1H); MS [M+]+: 459.03.
Reaction SMILES: CC1(C)[C@H]2CC[C@]1(CS(O)(=O)=O)C(=O)C2.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@H:21]([NH2:26])[CH2:20]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>CCOC(C)=O.O>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@H:21]([NH:26][C:34](=[O:35])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:20]2
Reactant: N[C@H]1Cc2ccc(Br)cc2C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC1(C)[C@H]2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(N[C@H]1Cc2ccc(Br)cc2C1)OCc1ccccc1
Reaction time: 8 h
Yield: 107.7 %

Procedure:
(S)-5-bromo-2,3-dihydro-1H-inden-2-amine((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (18.47 mmol, 8.21 g) was dissolved in EtOAc (30 mL)/water (30 mL) and potassium carbonate (55.4 mmol, 7.66 g) added. The mixture was cooled in an ice bath and benzyl chloroformate (20.32 mmol, 2.89 mL, 3.47 g) added dropwise. Stirring was continued overnight during which time the reaction came to room temperature. The crude reaction mixture was diluted with water and ethylacetate and the phases mixed and separated. The aqueous layer was further extracted with EtOAc (×2). Combined organics were dried and concentrated to give (S)-benzyl 5-bromo-2,3-dihydro-1H-inden-2-ylcarbamate as a colourless solid (6.89 g, 108%). 1H NMR (400 MHz, CDCl3) δ 2.79 (m, 2H) 3.26 (m, 2H) 4.53 (bm, 1H) 4.93 (bm, 1H) 5.10 (bs, 2H) 7.07 (m, 1H) 7.26-7.37 (m, 7H)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl>[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1ccc(N)cc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 4-amino-2-chlorobenzonitrile (5.02 g, 32.9 mmol) in dichloromethane (80 mL) was added N,N-diisopropylethylamine (17.0 mL, 97.8 mmol) and methanesulfonyl chloride (3.0 mL, 38.8 mmol) at −78° C. The reaction was then allowed to warm to room temperature slowly. After stirring at room temperature for 12 h, the reaction was quenched with 1 N hydrochloric acid. The organic phase was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 50:50 hexanes/ethyl acetate) to give the desired product.
Reaction SMILES: C1(OC)C=CC=CC=1.C(OC([N:19]1[CH2:24][CH2:23][N:22]([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21][CH2:20]1)=O)C1C=CC=CC=1.[BrH:35].C(O)(=O)C>>[BrH:35].[N:22]1([NH:25][C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[CH2:21][CH2:20][NH:19][CH2:24][CH2:23]1
Reactant: O=C(NN1CCN(C(=O)OCc2ccccc2)CC1)c1ccc(F)cc1
Agent: Br
Solvent: COc1ccccc1
Solvent: CC(=O)O
Product: O=C(NN1CCNCC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 25% hydrogen bromide-acetic acid (30 ml) and anisole (1.6 ml) was added N-(4-benzyloxycarbonyl-1-piperazinyl)-p-fluorobenzamide (10 g) dropwise for 15 minutes under nitrogen atmosphere. The reaction mixture was stirred at ambient temperature for 3 hours. The resulting precipitate was collected and washed with diethyl ether (10 ml) to give N-piperazinyl-p-fluorobenzamide hydrobromide (10.2 g) as white hydroscopic solid.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:17][CH2:18][N:19](CC)CC.ClCC#N>C1COCC1>[C:7]1([N:1]2[CH2:2][CH2:3][N:4]([CH2:17][C:18]#[N:19])[CH2:5][CH2:6]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][N:8]=1
Reactant: CCN(CC)CC
Reactant: c1ccc2c(N3CCNCC3)nccc2c1
Agent: N#CCCl
Solvent: C1CCOC1
Product: N#CCN1CCN(c2nccc3ccccc23)CC1
Reaction time: 3 h
Yield: 34.9 %

Procedure:
To a solution of 1-(piperazin-1-yl)isoquinoline (459 mg, 2.15 mmol) in THF (15 mL) was added NEt3 (3.6 mL, 27 mmol) and chloroacetonitrile (1.8 mL, 28 mmol) and the reaction was stirred 3 h. The reaction mixture was filtered, concentrated and the residue purified by silica gel chromatography (Biotage 25-short, 25% EtOAc/hexanes to 100% EtOAc/hex) to yield 38 (188 mg, 0.75 mmol, 35%) as a white solid. LC/MS: (ES+) m/z (M+H)+=253; HPLC Rt=1.23 min., column Q, conditions B.
Reaction SMILES: OC1C=C(CNC=C2C3C(=CC=C(I)C=3)C(=O)NC2=O)C=CC=1C1C=CC=CC=1.[CH:30]1([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[C:41](=[O:45])[NH:40][C:39](=[O:46])[C:38]3=[CH:47]OC)[CH2:34][CH2:33][CH2:32][CH2:31]1.[NH2:50][CH2:51][C:52]1[CH:53]=[CH:54][C:55]([C:59]2[CH:63]=[CH:62][O:61][CH:60]=2)=[C:56]([OH:58])[CH:57]=1>>[CH:30]1([C:35]2[CH:36]=[C:37]3[C:42](=[CH:43][CH:44]=2)[C:41](=[O:45])[NH:40][C:39](=[O:46])[C:38]3=[CH:47][NH:50][CH2:51][C:52]2[CH:53]=[CH:54][C:55]([C:59]3[CH:63]=[CH:62][O:61][CH:60]=3)=[C:56]([OH:58])[CH:57]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: NCc1ccc(-c2ccoc2)c(O)c1
Reactant: COC=C1C(=O)NC(=O)c2ccc(C3CCCC3)cc21
Agent: O=C1NC(=O)c2ccc(I)cc2C1=CNCc1ccc(-c2ccccc2)c(O)c1
Product: O=C1NC(=O)c2ccc(C3CCCC3)cc2C1=CNCc1ccc(-c2ccoc2)c(O)c1
Yield: 78 %

Procedure:
Following the same procedure for the preparation of 4-{[(2-hydroxy-biphenyl-4-ylmethyl)-amino]-methylene}-6-iodo-4H-isoquinoline-1,3-dione, the title compound (purified through chromatography) is prepared from 6-cyclopentyl-4-methoxymethylene-4H-isoquinoline-1,3-dione (108 mg, 0.398 mmol) and 5-Aminomethyl-2-furan-3-yl-phenol (109 mg, 0.57 mmol) in 78% yield: MS (ESI): 427.1 (M−1)−1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OC([C:26]2[CH:38]=[CH:37][C:29]3[N:30]=[C:31]([NH:33]C(=O)C)[S:32][C:28]=3[CH:27]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:33][C:31]1[S:32][C:28]2[CH:27]=[C:26]([C:2]3[N:7]=[C:6]([NH:8][S:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)(=[O:11])=[O:10])[CH:5]=[CH:4][CH:3]=3)[CH:38]=[CH:37][C:29]=2[N:30]=1
Reactant: CC(=O)Nc1nc2ccc(C3OC(C)(C)C(C)(C)O3)cc2s1
Reactant: O=S(=O)(Nc1cccc(Cl)n1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc2ccc(-c3cccc(NS(=O)(=O)c4ccccc4)n3)cc2s1
Temperature: 95 °C
Reaction time: 8 h

Procedure:
N-(6-Chloropyridin-2-yl)benzenesulfonamide (0.480 g, 1.90 mmol) was dissolved in 1,4-dioxane (6 mL). Then N-(6-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.7 g, 2 mmol), 2M Na2CO3 (2 mL, 4 mmol), and tetrakis(triphenylphosphine)palladium (0) (0.3 g, 0.2 mmol) was added to the mixture. The flask was fit with a reflux condensor, then placed into a pre-heated (95° C.) bath and allowed to stir under inert atmosphere overnight. The flask was removed from the heat bath and allowed to cool to ambient temperature. The mixture was filtered through a fritted funnel and the crude filtrate was purified by reverse-phase HPLC. This gave N-(6-(2-aminobenzo[d]thiazol-6-yl)pyridin-2-yl)benzenesulfonamide. MS (ESI pos. ion) m/z: 383 (MH+). Calculated exact mass for C18H14N4O2S2: 382. 1H NMR (400 MHz, acetone-d6): 8.19 (s, 1H), 8.08 (d, J=8.0 Hz, 2H), 7.86 (d, J=8.0 Hz, 1H), 7.74 (t, J=8.0 Hz, 1H), 7.53-7.64 (m, 4H), 7.44 (d, J=8.5 Hz, 1H), 7.13 (d, J=8.0 Hz, 1H), 6.98 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)(C)C.O1CCOCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:10][C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)[N:7]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccnc(Cl)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: C1COCCO1
Product: COc1ccnc(Nc2ccc(C#N)cc2)n1
Temperature: 105 °C
Reaction time: 14 h
Yield: 55.3 %

Procedure:
1,4-Dioxane (100 ml) was added to a mixture of 2-chloro-4-methoxypyrimidine (20 gm), 4-aminobenzonitrile (16.33 gm) and p-toluene sulfonic acid (42.12 gm). The mixture was then heated to 100 to 110° C. and stirred for 14 hours. The solution was then cooled to room temperature and basified with saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and then concentrated to obtain a residual solid. The residual solid obtained was slurried in isopropyl alcohol at room temperature for 30 minutes and filtered. The solid obtained was then dried to give 17.3 gm of 4-(4-methoxypyrimidin-2-ylamino)benzonitrile.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([OH:21])=O)[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][O:23][CH2:24][C@@H:25]1[CH2:29][CH2:28][CH2:27][N:26]1[NH2:30]>>[CH:1]1([C:7]2[CH:8]=[C:9]([C:19]([NH:30][N:26]3[CH2:27][CH2:28][CH2:29][C@H:25]3[CH2:24][O:23][CH3:22])=[O:21])[CH:10]=[N:11][C:12]=2[O:13][CH2:14][C:15]([F:17])([F:16])[F:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Reactant: COC[C@@H]1CCCN1N
Product: COC[C@@H]1CCCN1NC(=O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-3-pyridinecarboxylic acid (example 12c) and (2S)-2-(methoxymethyl)-1-pyrrolidinamine (CAN 59983-39-0) as starting materials; LC-MS (UV peak area/ESI) 98.8%, 416.2159 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][OH:9])=[N:6][CH:5]=[N:4]1)[CH3:2].Cl[C:11]1[C:12]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:13][C:14]2[N:15]([C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[N:18][N:19]=2)[N:16]=1.[H-].[Na+]>CN(C=O)C.O>[CH3:30][C:27]([C:12]1[C:11]([O:9][CH2:8][C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][N:6]=2)=[N:16][N:15]2[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])=[N:18][N:19]=[C:14]2[CH:13]=1)([CH3:28])[CH3:29]
Reactant: CCn1ncnc1CO
Reactant: CC(C)(C)c1cc2nnc(-c3ccccc3F)n2nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.9 %

Procedure:
To a solution of (2-ethyl-2H-1,2,4-triazol-3-yl)methanol (0.094 g, 0.74 mmol) and 6-chloro-7-(1,1-dimethylethyl)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (0.15 g. 0.49 mmol) in DMF (10 ml) was added sodium hydride (0.024 g of a 60% dispersion in oil, 1.1 mol eq.) and the reaction mixture was stirred at room temperature for 30 minutes. After this time, the reaction mixture was diluted with water (80 ml) and the solid that precipitated was collected by filtration and washed several times with water in the sinter funnel. The solid was recrystallised from ethyl acetate/hexane to give pure title compound (0.085 g, 44%). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ1.40-1.47 (12H, m), 4.14 (2H, t, J=7.3 Hz), 5.26 (2H, s), 7.26-7.38 (2H, m), 7.53-7.58 (1H, m), 7.86-7.90 (1H, m), 7.93 (1H, s), 7.99 (1H, s); MS (ES+) m/e 396 [MH]+. Anal. Found C, 61.02; H, 5.45; N, 24.75%. C20H22FN7O requires C, 60.75; H, 5.61; N, 24.79%.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10](N)=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:15][B-](F)(F)F.N#[O+]>ClCCl>[F:15][C:10]1[CH:11]=[C:12]2[C:7]([CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13]2)=[CH:8][CH:9]=1
Reactant: Nc1ccc2ccc([N+](=O)[O-])cc2c1
Reactant: F[B-](F)(F)F
Agent: N#[O+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2ccc(F)cc2c1
Temperature: 25 °C

Procedure:
A mixture 7-nitro-2-aminonaphthalene (1 g, 5.31 mmol) and nitrosonium tetrafluoroborate (931 mg, 7.97 mmol) in dichloromethane (10 mL) is stirred at room temperature for 12 hours and at 110° C. for 1 hour. After cooling to room temperature, the reaction mixture is concentrated by rotary evaporator under high vacuum. The residual oil is purified by flash chromatography on silica gel (3:1 hexanes/EtOAc) to give 7-fluoro-2-nitronaphthalene as a dark red solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[CH:20][CH:21]=2)[C:16]1=[O:27]>CC(C)=O.[I-].[Cs+]>[CH3:26][O:25][C:19]1[CH:18]=[C:17]2[C:22]([CH2:23][CH2:24][CH:15]([O:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:16]2=[O:27])=[CH:21][CH:20]=1
Reactant: Oc1ccccc1
Reactant: COc1ccc2c(c1)C(=O)C(Br)CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: COc1ccc2c(c1)C(=O)C(Oc1ccccc1)CC2
Temperature: 0 °C
Reaction time: 15 h
Yield: 61 %

Procedure:
A mixture of 2.95 g (31.4 mmol) of phenol, 25.5 g (78.2 mmol) of cesium carbonate and 320 mg (1.23 mmol) of cesium iodide in 64 ml of acetone was heated at reflux for 40 minutes and then cooled to 0° C. To this 0° C. mixture was added 8.00 g (31.4 mmol) of 2-bromo-3,4-dihydro-7-methoxy-1(2H)-naphthalenone. The resultant reaction mixture was stirred 3 hours at 0° C. and 15 hours at 25° C., then filtrated. The filtrate was evaporated to an oil which was purified via column chromatography on 400 g of silica gel, eluting with 25% ether-hexane, to give 5.14 g (61%) of present title product as an oil, crystallized from ether-hexane, m.p. 94.5°-96.5° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([CH3:16])[CH:8]=1)(=O)=O.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1(C)C=CC=CC=1>[CH3:16][C:9]1[CH:8]=[C:7]([C:25]2[CH:26]=[CH:27][C:22]([N+:19]([O-:21])=[O:20])=[CH:23][CH:24]=2)[CH:12]=[CH:11][C:10]=1[C:13](=[O:15])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)cc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A mixture of 4-acetyl-3-methylphenyl trifluoromethanesulfonate (6.90 g, 24.0 mmol), 4-nitrophenylboronic acid (3.80 g, 24 mmol), 2 N aqueous sodium carbonate (88.0 mL), dioxane (88.0 mL), and toluene (296 mL) was purged with argon for 30 minutes before [1,1′-bis(diphenyl-phosphino)-ferrocene]dichloro palladium(II) (1:1 complex with dichloromethane, 1.90 g, 2.30 mmol) was added. The reaction mixture was heated at 85° C. and stirred overnight. The layers were separated and the organic layer was washed with water (2×50 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. This material was purified by flash chromatography (7 to 20% ethyl acetatethexane) to give 1-(3-methyl-4′-nitro-1,1′-biphenyl-4-yl)ethanone as a light yellow solid (6.12 g, 99% yield). GC-MS m/z 255 (M+), ret. time 9.89 min; 1H NMR (CDCl3) δ: 2.61 (s, 3H), 2.62 (s, 3H), 7.49-55 (m, 2H), 7.78 (d, 2H), 7.81 (d, 1H), 8.32 (d, 2H).