Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:22])[CH2:20]Cl)=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6]=1[NH:23][C:24](=[O:35])[C@:25]([O:31]C(=O)C)([CH3:30])[C:26]([F:29])([F:28])[F:27]>O.CC(C)=O>[Cl:4][C:5]1[CH:10]=[C:9]([S:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:22])[CH2:20][N:2]([CH3:3])[CH3:1])=[CH:16][CH:17]=2)[CH:8]=[CH:7][C:6]=1[NH:23][C:24](=[O:35])[C@:25]([OH:31])([CH3:30])[C:26]([F:28])([F:29])[F:27]
Reactant: CC(=O)O[C@](C)(C(=O)Nc1ccc(Sc2ccc(NC(=O)CCl)cc2)cc1Cl)C(F)(F)F
Reactant: CNC
Solvent: O
Solvent: CC(C)=O
Product: CN(C)CC(=O)Nc1ccc(Sc2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2)cc1

Procedure:
Dimethylamine (0.17 ml of a 40% solution in water) was added to a solution of (R)-N-{2-chloro-4-[4-(2-chloroacetylamino)phenylsulphanyl]phenyl}-2-acetoxy-2-methyl-3,3,3-trifluoropropanamide (Method 19) (0.25 g) in acetone (1.5 ml). After 24 hours volatile material was removed by evaporation and the residue was dissolved in ethyl acetate, washed with water, and the organic layer was poured onto a Varian Chem Elut column. Elution with ethyl acetate gave the title compound (0.25 g) as a foam. NMR: 1.6 (s, 3H), 3.1 (s, 2H), 3.3 (s, 6H), 7.2 (d, 1H), 7.3 (s, 1H), 7.4 (d, 2H), 7.7 (m, 3H), 7.9 (d, 1H), 9.7 (s, 1H) 9.9 (s, 1H); MS (ESP−): 474.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:35])=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][NH:6][C:7]([C@@H:9]1[CH2:14][C@:13]2(CO)[C@@H:11]([CH2:12]2)[N:10]1[C:17](=[O:31])[CH2:18][N:19]1[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[C:21]([C:28](=[O:30])[CH3:29])=[CH:20]1)=[O:8].[C:36]([O:40]C(N1[C@H](C(=O)N[C@@H](C2C=CC=C(Cl)C=2F)CO)C[C@@H]2[C@H]1C2)=O)(C)(C)C.ClCl.CCOC(C)=O>>[Cl:1][C:2]1[C:3]([F:35])=[C:4]([C@H:5]([NH:6][C:7]([C@@H:9]2[CH2:14][C@@H:13]3[C@@H:11]([CH2:12]3)[N:10]2[C:17](=[O:31])[CH2:18][N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28](=[O:30])[CH3:29])=[CH:20]2)=[O:8])[CH2:36][OH:40])[CH:32]=[CH:33][CH:34]=1
Reactant: CC(=O)c1cn(CC(=O)N2[C@H](C(=O)NCc3cccc(Cl)c3F)C[C@@]3(CO)C[C@@H]23)c2ncccc12
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)N[C@H](CO)c1cccc(Cl)c1F
Agent: ClCl
Solvent: CCOC(C)=O
Product: CC(=O)c1cn(CC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)N[C@H](CO)c2cccc(Cl)c2F)c2ncccc12

Procedure:
The title compound was prepared in 2 steps according to the procedure described for the preparation of Example 610 (1R,3S,5S)-2-[2-(3-acetyl-pyrrolo[2,3-b]pyridin-1-yl)-acetyl]-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid 3-chloro-2-fluoro-benzylamide from (1R,3S,5R)-3-[(S)-1-(3-chloro-2-fluoro-phenyl)-2-hydroxy-ethylcarbamoyl]-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (prepared as described in Scheme B9). White powder. TLC, Rf (CH2/Cl2/EtOAc 9:1)=0.70; MS (UPLC/MS): 499.3/501.3 [M+H]+, 543.2/545.3 [M+HCOO]−; tR (HPLC conditions a): 3.02 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][C:12]1([OH:18])[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[CH3:11][C:12]1([OH:18])[CH2:17][CH2:16][CH2:15][N:14]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:13]1
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CC1(O)CCCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1(O)CCCN(c2ccncc2[N+](=O)[O-])C1

Procedure:
Method 1 of Example 1 was followed using 1 equivalent each of 4-chloro-3-nitropyridine, 3-methylpiperidin-3-ol and triethyl amine in DMF yielding 3-methyl-1-(3-nitropyridin-4-yl)piperidin-3-ol. LCMS (m/z): 238.1 (MH+); LC Rt=1.39 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:45])[O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: NCCCN1CCC(c2cccc(NC(=O)OCc3ccccc3)c2)CC1
Product: O=C(Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1)OCc1ccccc1

Procedure:
Example 141 was prepared from bis(4-fluorophenyl)acetic acid and benzyl 3-[1-(3-amino propyl)-4-piperidinyl]phenylcarbamate according to the procedures described in Scheme 9: ESMS m/e: 598.5 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:7][C:8]1[CH:9]=[CH:10][C:11]2[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:29])[CH3:28])[CH2:18][CH2:17]3)=[CH:14][S:13][C:12]=2[CH:30]=1.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[C:27]([N:26]([CH2:25][CH2:24][CH2:23][CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:15]2[C:11]3[CH:10]=[CH:9][C:8]([F:7])=[CH:30][C:12]=3[S:13][CH:14]=2)[CH2:21][CH2:20]1)[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])(=[O:29])[CH3:28]
Reactant: CC(C)C(=O)Cl
Reactant: CC(=O)NCCCCN1CCN(c2csc3cc(F)ccc23)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(CCCCN1CCN(c2csc3cc(F)ccc23)CC1)C(=O)C(C)C
Yield: 96.6 %

Procedure:
A solution of isobutyryl chloride (2.34 g, 21.9 mmol) in dry dichloromethane (8 mL) was added over 2 minutes to a solution of N-[4-[4-(6-fluorobenzo[b]thien-3-yl)-1-piperazinyl]butyl]-acetamide (2.51 g, 7.18 mmol), triethylamine (2.18 g, 21.5 mmol), 4-dimethylaminopyridine (0.877 g, 7.18 mmol), and dry dichloromethane (50 mL) at room temperature under a nitrogen atmosphere. After 2.5 hours the reaction solution was diluted with dichloromethane (100 mL), washed with water (75 mL), dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel with 5% methanol/dichloromethane as eluent to give 2.91 g of an amber solid. Recrystallization from tert-butyl methyl ether/heptane afforded 1.52 g (50%) of the title compound as tan crystals: m.p.=98 °-99° C.
Reaction SMILES: CN(P(N(C)C)(N(C)C)=O)C.O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:47])[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]([S:34]([C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=1[O:45][CH3:46])(=[O:36])=[O:35])[CH2:29][C:30]([O:32][CH3:33])=[O:31]>C1COCC1>[Cl:27][C:25]1[CH:26]=[C:21]2[C:22](=[CH:23][CH:24]=1)[N:28]([S:34]([C:37]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:38]=1[O:45][CH3:46])(=[O:36])=[O:35])[CH:29]([C:30]([O:32][CH3:33])=[O:31])[C:20]2([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])[OH:47]
Reactant: COC(=O)CN(c1ccc(Cl)cc1C(=O)c1ccccc1Cl)S(=O)(=O)c1cc(OC)ccc1OC
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1N(S(=O)(=O)c2cc(OC)ccc2OC)c2ccc(Cl)cc2C1(O)c1ccccc1Cl
Reaction time: 1 h

Procedure:
In a parallel procedure, 400 mg of the compound prepared in step B are dissolved in 3 ml of anhydrous THF at -78° C. under argon and 2.2 ml of the solution prepared above are added over 5 minutes, followed by 0.4 ml of HMPA. After 1 hour, a further 0.5 ml of the solution prepared above is added, the mixture is then left to stand for 1 hour at -78° C. and, finally, water is added and the mixture is extracted with ether.
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([IH+:17])=[CH:13][CH:12]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([IH+])=[CH:22][CH:21]=1.O.[S:28]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)([OH:31])(=[O:30])=[O:29].IC1C=CC(OC)=CC=1>C(#N)C>[S:28]([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)([O-:31])(=[O:30])=[O:29].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([I+:17][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc([IH+])cc1
Agent: CC(=O)[O-]
Agent: COc1ccc(I)cc1
Solvent: O
Solvent: CC#N
Product: COc1ccc([I+]c2ccc(OC)cc2)cc1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 82.4 %

Procedure:
Under N2 protection, 352 mg (1 mmol) p-methoxyphenyliodonium diacetate was dissolved in 1.5 mL of dry acetonitrile. The solution was combined with a solution of 190 mg (1 mmol) tosylic acid monohydrate in 1.5 mL of dry acetonitrile. After addition of 0.11 mL (1 mmol) p-iodoanisole, the mixture was allowed to react at room temperature for 2 hours. The solvent was then removed and the remaining solid was recrystallized from diethylether/dichloromethane to give 422 mg bis(p-methoxyphenyl)iodonium tosylate (82%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[CH3:13][C:14]1N=CC(C=O)=CC=1.C(O)(=O)CC(O)=O.[H][H]>N1C=CC=CC=1.N1CCCCC1.[Pd]>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1ccc(C=CC(=O)O)cn1
Reactant: Cc1ccc(C=O)cn1
Agent: [Pd]
Agent: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)CCc1ccc(C)nc1

Procedure:
3-(6-Methyl-3-pyridyl)propenoic acid, m.p. 213.5-215.5°, was prepared by reacting 6-methylpyridine-3-carboxaldehyde with malonic acid in pyridine with piperidine catalyst, and was converted into the corresponding ethyl ester m.p. 36°-37° which was reduced with hydrogen and palladium-on-charcoal catalyst to give ethyl 3-(6-methyl-3-pyridyl)-propionate (oil). This ester was reacted with sodium and ethyl formate and the product treated with thiourea to give 5-(6-methyl-3-pyridylmethyl)-2-thiouracil m.p. 240°-241° which was alkylated with methyl iodide in the presence of sodium hydroxide at 70° to give 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone, m.p. 197°-198.5°.
Reaction SMILES: C([O:4][C@H:5]1[C@H:9]([O:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:8]([CH2:19][O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:7][C@@H:6]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][CH:32]=[N:33][C:34]=2[NH2:38])(=O)C.O.NN>N1C=CC=CC=1>[C:11]([O:10][C@@H:9]1[C@H:8]([CH2:19][O:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:7][C@H:6]([N:29]2[CH:37]=[N:36][C:35]3[C:30]2=[N:31][CH:32]=[N:33][C:34]=3[NH2:38])[C@H:5]1[OH:4])(=[O:18])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)O[C@H]1[C@H](OC(=O)c2ccccc2)[C@H](COC(=O)c2ccccc2)O[C@@H]1n1cnc2c(N)ncnc21
Agent: NN
Solvent: O
Solvent: c1ccncc1
Product: Nc1ncnc2c1ncn2[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@@H]1O
Temperature: 25 °C
Reaction time: 22 h
Yield: 68 %

Procedure:
A solution of 9-(2-O-acetyl-3,5-di-O-benzoyl-β-L-xylofuranosyl)adenine 2 [Ref.: Gosselin, G.; Bergogne, M.-C.; Imbach, J.-L., “Synthesis and Antiviral Evaluation of β-L-Xylofuranosyl Nucleosides of the Five Naturally Occurring Nucleic Acid Bases”, Journal of Heterocyclic Chemistry, 1993, 30 (October-November), 1229-1233] (8.30 g, 16.05 mmol) and hydrazine hydrate 98% (234 mL, 48.5 mmol) in a mixture of pyridine/glacial acetic acid (4/1, v/v, 170 mL) was stirred at room temperature for 22 h. The reaction was quenched by adding acetone (40 mL) and stirring was continued for one additional hour. The reaction mixture was reduced to one half of its volume, diluted with water (250 mL) and extracted with chloroform (2×150 mL). The organic layer was washed successively with an aqueous saturated solution of NaHCO3 (3×100 mL) and water (3×100 mL), dried, filtered, concentrated and co-evaporated with toluene and methanol. The residue was purified by silica gel column chromatography (0-3% MeOH in dichloromethane) to give 3 (5.2 g, 68%) precipitated from diisopropylic ether: 1H NMR (DMSO-d6): δ 4.5-4.9 (m, 4H, H-2′, H-4′, H-5′ and H-5″), 5.64 (t, 1H, H-3′, J2′,3′=J3′,4′=3.5 Hz), 6.3 (br s, 1H, OH-2′), 6.45 (d, 1H, H-1′, J1′,2′=4.6 Hz), 7.3 (br s, 2H, NH2-6), 7.4-7.9 (m, 10H, 2 benzoyls), 8.07 and 8.34 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 476 [M+H]+, 136 [BH2]+, (FAB−) m/z 474 [M−H]−, 134 [B]−; UV (95% ethanol): λmax 257 nm (ε 16400), 230 μm (ε 29300), λmin 246 nm (ε 14800); [α]D20=−64 (c 1.07, CHCl3). Anal. Calcd for C24H21N5O4 (M=475.45): C, 60.43; H, 4.45; N, 14.73. Found: C, 60.41; H, 4.68; N, 14.27.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][C:13]2[N:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[N:3]=1.Br[CH2:22][C:23](=O)[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][N:18]=2)[N:3]2[CH:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[N:1]=[C:2]2[CH:7]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: N#Cc1ccc(NCCNc2nc(N)cc(Cl)n2)nc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(NCCNc3ccc(C#N)cn3)nc(Cl)cc2n1
Temperature: 100 °C

Procedure:
480 mg (1.66 mmol) of 6-({2-[(4-amino-6-chloropyrimidin-2-yl)amino]ethyl}amino)pyridine-3-carbonitrile and 538 mg (2.49 mmol) of ethyl bromopyruvate are dissolved in 8 ml of DMF and heated at 100° C. for 16 h. After the reaction is complete, the crude mixture is purified by preparative HPLC. 190 mg (27% of theory) of the product are obtained as a solid.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)#[N:6].[CH2:15]([NH2:19])[CH:16]([CH3:18])[CH3:17].C(O)(=O)C>CO>[CH2:15]([NH:19][CH2:11][C:10]1[CH:13]=[CH:14][C:7]([C:5]#[N:6])=[CH:8][CH:9]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(C)CN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)CNCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.2 %

Procedure:
Under a nitrogen atmosphere add sodium cyanoborohydride (5.77 g, 91.6 mmol) to 4-cyanobenzaldehyde (3 g, 22.9 mmol), iso-butylamine (3.34 g, 45.8 mmol) and acetic acid (1.37 g, 22.9 mmol) in methanol (30 mL) at 0° C. Warm the mixture to room temperature and stir overnight. Add water (40 mL), saturated aqueous K2CO3 (30 mL) and extract with DCM. Wash the combined organic extracts with water and brine. Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Purify the residue by chromatography on silica gel (500 g) eluting with 9:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the desired intermediate (3.63 g, 84%). MS (APCI+) m/z: 189 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[S:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.O1CCOCC1>CO.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]>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([C:26]3[CH:27]=[CH:28][S:24][CH:25]=3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: OB(O)c1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(-c3ccsc3)n3nccc3n2)cc1
Temperature: 110 °C
Yield: 0 %

Procedure:
A suspension of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 151 mmol), thiophen-3-ylboronic acid (64 mg, 302 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9 mg, 12 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (670 microliters of 1,4-dioxane and 330 microliters of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC, 40-70% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (6.4 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46 (s, 6 H) 6.61 (d, 1 H) 7.63 (d, J=8.34 Hz, 2 H) 7.84 (dd, J=5.18, 2.91 Hz, 1 H) 7.93 (dd, J=5.18, 1.14 Hz, 1 H) 8.04 (d, J=8.34 Hz, 2 H) 8.23-8.40 (m, 2 H) 9.12 (dd, J=3.03, 1.26 Hz, 1 H) 11.24 (s, 1 H). ESI-MS: m/z 379.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH:9]=O)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:5]=[CH:4][N:3]=1.[CH3:17][NH:18][NH2:19].C([O-])(=O)C.[Na+]>CC#N>[CH3:17][N:18]1[C:2]2[N:3]=[CH:4][N:5]=[C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:7]=2[CH2:8][CH:9]=[N:19]1
Reactant: O=CCc1c(Cl)ncnc1-c1ccccn1
Reactant: CNN
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Product: CN1N=CCc2c(-c3ccccn3)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.5 %

Procedure:
To a stirred solution of 2-(4-chloro-6-(pyridin-2-yl)pyrimidin-5-yl)acetaldehyde (600 mg) in dry MeCN (10 mL), methyl hydrazine (181 mg) and sodium acetate (422 mg) were added. The reaction mixture was stirred at room temperature for 3 hours and solvents were removed under reduced pressure. The resulting crude was purified by column chromatography using MeOH/CHCl3 (0.5:9.5) as eluent to afford 1-methyl-5-(pyridin-2-yl)-1,4-dihydropyrimido[4,5-c]pyridazine (350 mg) as white solid. 1H NMR (DMSO-d6): δ 3.41 (s, 3H), 3.93-3.94 (d, 2H), 6.92-6.94 (t, 1H), 7.47-7.51 (m, 1H), 7.94-7.99 (m, 1H), 8.00-8.10 (m, 1H), 8.67-8.69 (d, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.C([Mg]Cl)C.[Cl:18][CH2:19][C:20](Cl)=[O:21].C1COCC1>C(OCC)C.C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:13][O:12][C:10]([C:7]1[CH:8]=[C:9]2[C:4]([C:3]([C:20](=[O:21])[CH2:19][Cl:18])=[CH:2][NH:1]2)=[CH:5][CH:6]=1)=[O:11]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=C(Cl)CCl
Agent: CC[Mg]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C(=O)CCl)c[nH]c2c1
Yield: 19.9 %

Procedure:
A mixture of 14 g (80 mmol) methyl indole-6-carboxylate, 40 mL (84 mmol) ethylmagnesium chloride (2M) in diethyl ether, 240 mL (240 mmol) zinc chloride (1M) in diethyl ether, 9.5 g (84 mmol) chloroacetyl chloride in 680 mL DCM was stirred at room temperature for 19 h. THF was added and diethyl ether and DCM were removed by evaporation. The mixture was treated with NH4Cl aq. and ethyl acetate. The aqueous phase was extracted with THF/ethyl acetate and the combined organic layers were washed with NaCl aq., dried with Na2SO4 and evaporated. The residue was washed with ethyl acetate and dried under vacuum at 50° C. to yield 4 g (20%) of the title compound as light yellow solid. MS (m/e): 250.1 (M−H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2/[C:11](=[CH:19]/[C:20]2[NH:21][CH:22]=[CH:23][CH:24]=2)/[C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[F:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl>[O:18]=[C:12]1[NH:13][C:14]2[C:10](/[C:11]/1=[CH:19]/[C:20]1[NH:21][CH:22]=[CH:23][CH:24]=1)=[C:9]([C:5]1[CH:4]=[C:3]([NH:2][C:37](=[O:38])[C:36]3[CH:40]=[CH:41][C:33]([F:32])=[CH:34][CH:35]=3)[CH:8]=[CH:7][CH:6]=1)[CH:17]=[CH:16][CH:15]=2
Reactant: Nc1cccc(-c2cccc3c2/C(=C/c2ccc[nH]2)C(=O)N3)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4ccc(F)cc4)c3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A solution of (Z)-4-(3-aminophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one hydrochloride (25 mg, 0.074 mmol) (from Example 5 supra) and Et3N (21 μL , 0.148 mmol) in 3 mL of chloroform was treated with 4-fluorobenzoyl chloride (10.5 μL , 0.088 mmol) (Aldrich). The resulting reaction mixture was stirred at room temperature for 8 h and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 50% ethyl acetate-hexanes elution) to provide pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-4-fluorobenzamide (yield: 26 mg, 83%) as a yellow solid (mp 130-131° C.).
Reaction SMILES: ClC1C=C([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:45])CCC(O)=O)=[CH:35][CH:34]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]([OH:45])[CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:35][CH:34]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCC(O)c2ccc(F)cc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(4-fluoro-phenyl)-4-oxo-butyric acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[C:5](F)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C([O-])([O-])=O.[K+].[K+].OC(C(F)(F)F)=O.FC1C=C(CN)C=[N:31]C=1>C1COCC1.CCOC(C)=O>[N+:10]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH2:31])([O-:12])=[O:11]
Reactant: NCc1cncc(F)c1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,4,5-tri-fluoronitrobenzene (2.864 g, 0.016 mol), K2CO3 (2.236 g, 0.0161 mol) and (5-fluoropyridin-3yl)methanamine TFA salt (1.02 g, 50% LC-MS) were dissolved in THF (25 mL) and stirred at room temperature for 16 hours. The reaction mixture was then diluted with EtOAc (100 mL) and washed with H2O. The organic phase was dried and concentrated under vacuum to give the ortho-substitution product, 4,5-difluoro-N-(5-fluoropyridin-3-yl) methyl)-2-nitroaniline as a yellow solid. 1H NMR (400 MHz, DMSO-d6), δ: 8.72 (br, 1H), 8.43 (s, 1H), 8.39 (s, 1H), 8.15 (dd, J=10 Hz, 8.8 Hz, 1H), 7.65 (d, J=9.2 Hz, 1H), 6.83 (dd, J=12.8 Hz, 7.8 Hz, 1H), 4.71 (s, 2H). MS (M+1): 284
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]([CH2:9][CH:10]([CH3:12])[CH3:11])=O)=[CH:3][CH:2]=1.[O:13]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([NH:24][NH2:25])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)(=O)C>[CH3:11][CH:10]([CH3:12])[CH2:9][C:7](=[N:25][NH:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: CC(C)CC(=O)c1ccncc1
Reactant: NNC(=O)c1ccccc1Oc1ccccc1
Solvent: CC(=O)O
Product: CC(C)CC(=NNC(=O)c1ccccc1Oc1ccccc1)c1ccncc1

Procedure:
Following the general method of procedure 4 and making noncritical variations, except 12 drops of glacial acetic acid is added as a catalyst, 9.00 gm (0.055 mole) of isobutyl 4-pyridyl ketone and 12.59 gm (0.055 mole) of 2-phenoxybenzhydrazide yield 13.89 gm (67%) of the title compound having a melting point of 137.6° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:4]=[C:5]([Sn](CCCC)(CCCC)CCCC)[N:6]=1.Cl[C:40]1[S:41][CH:42]=[CH:43][C:44]=1[N+:45]([O-:47])=[O:46]>>[CH3:1][C:2]1[N:3]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:4]=[C:5]([C:40]2[S:41][CH:42]=[CH:43][C:44]=2[N+:45]([O-:47])=[O:46])[N:6]=1
Reactant: O=[N+]([O-])c1ccsc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)n1
Product: Cc1nc(-c2sccc2[N+](=O)[O-])cn1C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared from 2-methyl-4-(tributylstannyl)-1-trityl-1H-imidazole and 2-chloro-3-nitrothiophene using protocol E (3.43 g, 76% over 2 steps). Method [7] Retention time 8.87 min by HPLC (M+Na=474).