Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH3:25])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:25][NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1
Reactant: Nc1ccccc1
Reactant: CSc1nccc(-c2cnc3c(N(C)C(=O)OC(C)(C)C)nccn23)n1
Product: CNc1nccn2c(-c3ccnc(Nc4ccccc4)n3)cnc12

Procedure:
Methyl-[3-(2-phenylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine was prepared by a process analogous to that described in Example 12 starting from methyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 8 supra), and aniline. LC-MS: [M+H]+ 318.2.
Reaction SMILES: [CH2:1]([CH:3]([CH2:19][CH3:20])[CH:4]([NH2:18])[C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:8]=[CH:7][N:6]=1)[CH3:2].CCN(CC)CC.[Cl:28][C:29]1[S:33][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:31][CH:30]=1>C(Cl)Cl>[Cl:28][C:29]1[S:33][C:32]([S:34]([NH:18][CH:4]([C:5]2[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:8]=[CH:7][N:6]=2)[CH:3]([CH2:1][CH3:2])[CH2:19][CH3:20])(=[O:36])=[O:35])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CCC(CC)C(N)c1ncnn1Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(CC)C(NS(=O)(=O)c1ccc(Cl)s1)c1ncnn1Cc1ccc(F)cc1
Reaction time: 18 h
Yield: 60 %

Procedure:
To a stirred solution of the {2-ethyl-1-[1-(4-fluorobenzyl)-1H-1,2,4-triazol-5-yl]butyl}amine (0.133 g, 0.481 mmol) in CH2Cl2 (10 mL) was added Et3N (0.10 mL, 0.72 mmol) followed by 5-chlorothiophene-2-sulfonyl chloride (0.115 g, 0.529 mmol). The reaction mixture was stirred for 18 h, concentrated in vacuo, partitioned between 0.1N HCl and EtOAc. The organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Column chromatography (SiO2, EtOAc/hexane, 3:7) provided pure material as a yellow solid in 60% yield.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][C:10]=2[O:17]C)=[C:4]([F:22])[CH:3]=1>Br.C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][NH:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[C:4]([F:22])[CH:3]=1
Reactant: COc1cc(SC)ccc1C(=O)NCc1ccc(Br)cc1F
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(=O)NCc2ccc(Br)cc2F)c(O)c1
Temperature: 100 °C
Yield: 47.2 %

Procedure:
A solution of N-(4-bromo-2-fluoro-benzyl)-2-methoxy-4-methylsulfanyl-benzamide (11 g crude, from step 1) was dissolved in a 25% HBr in glacial acetic acid solution (400 mL) and heated to 100° C. for 4 h. The solution was diluted with ethyl acetate (750 mL) and washed with saturated NaCl (500 mL). The organic layer was dried over MgSO4, filtered and concentrated. Purification by MPLC (10–100% ethyl acetate in heptane, 23 mL/min, 75 min) gave N-(4-bromo-2-fluoro-benzyl)-2-hydroxy-4-methylsulfanyl-benzamide (5.0 g, 50%). Rf 0.57 (40% ethyl acetate in heptane); 1H NMR (DMSO-d6 300 MHz) δ 12.57 (s, 1 H), 9.22 (t, J=5.4 Hz, 1 H), 7.78 (d, J=8.4 Hz, 1 H), 7.52 (dd, J, =9.8 Hz, J2=1.7 Hz, 1 H), 7.40–7.27 (m, 2 H), 6.77–6.71 (m, 2 H), 4.46 (d, J=5.7 Hz, 2 H), 2.46 (s, 3 H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14](Cl)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([O:29][CH3:30])[CH:23]=1>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([O:29][CH3:30])[CH:23]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cccc(-c2ccnc(Cl)n2)c1
Reactant: COc1cc(CCN)ccc1O
Product: CCCCOc1cccc(-c2ccnc(NCCc3ccc(O)c(OC)c3)n2)c1

Procedure:
Intermediate 46 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 394. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.3 (m, 1H) 7.6 (m, 2H) 7.35 (m, 1H) 7.0 (m, 2H) 6.85 (m, 1H) 672 (m, 2H) 5.51 (br s, 1H) 4.0 (t, 2H) 3.75 (s, 3H) 3.7 (m, 2H) 2.89 (t, 2H) 1.78 (d, 2H) 1.5 (d, 2H) (t, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([NH:19][CH:20]([CH3:22])[CH3:21])=[N:15]2)[CH:3]=1.O.C([O-])(=[O:26])C.[Na+]>C(O)(=O)C>[OH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([N:14]2[CH:18]=[CH:17][C:16]([NH:19][CH:20]([CH3:22])[CH3:21])=[N:15]2)[CH:3]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(Cl)cc(-n3ccc(NC(C)C)n3)nc2c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(O)cc(-n3ccc(NC(C)C)n3)nc2c1
Temperature: 130 °C
Reaction time: 48 h
Yield: 18.9 %

Procedure:
A mixture of [1-(4-chloro-7-methoxy-quinolin-2-yl)-1H-pyrazol-3-yl]-isopropyl-amine (0.52 g, 1.6 mmol) and sodium acetate monohydrate (1.0 g) in acetic acid (5 mL) was stirred at 130° C. for 2 d. The mixture was concentrated and then partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexanes), affording [1-(4-hydroxy-7-methoxy-quinolin-2-yl)-1H-pyrazol-3-yl]-isopropyl-amine (0.09 g, 19%). LC/MS=299.1 (M++1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([NH:9][C:10]2[CH:11]=[C:12]([C:16]3[N:25]=[C:24]([NH:26][C:27]4[CH:28]=[C:29]5[C:33](=[CH:34][CH:35]=4)[N:32](C(OC(C)(C)C)=O)[N:31]=[CH:30]5)[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:32]1[C:33]2[C:29](=[CH:28][C:27]([NH:26][C:24]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]([C:12]4[CH:11]=[C:10]([NH:9][C:7]([CH:4]5[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]5)=[O:8])[CH:15]=[CH:14][CH:13]=4)[N:25]=3)=[CH:35][CH:34]=2)[CH:30]=[N:31]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)C5CCNCC5)c4)nc4ccccc34)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1)C1CCNCC1

Procedure:
To tert-butyl 5-(2-(3-(piperidine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (mg, mmol) was added a solution of 1:1 TFA:CH2Cl2 (4 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and left under high vacuum for several hours. The crude product was triturated with ethyl ether to afford N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)piperidine-4-carboxamide. (97 mg, 0.21 mmol, 75% over two steps)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1C(N)=CS[CH:6]=1)=[O:4].[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].C(OC)(=O)C=C>>[CH3:1][O:2][C:3](=[O:4])[CH2:5][CH2:6][S:13][CH2:12][C:11]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cscc1N
Reactant: COC(=O)CS
Solvent: C=CC(=O)OC
Product: COC(=O)CCSCC(=O)OC

Procedure:
Compounds of structure (II) were prepared by using 4-amino-thiophene-3-carboxylic acid methyl ester, as depicted by formula (21), as a starting material. To make this compound, methyl thioglycolate was reacted with methyl acrylate to yield intermediate 3-methoxycarbonylmethylsulfanyl-propionic acid methyl ester, depicted by formula (18), which was cyclized to 4-oxo-tetrahydro-thiophene-3-carboxylic acid methyl ester, depicted by formula (19). This intermediate was reacted with hydroxylamine hydrochloride to yield 4-hydroxyimino-tetrahydro-thiophene-3-carboxylic acid methyl ester, depicted by formula (20), which yielded 4-amino-thiophene-3-carboxylic acid methyl ester hydrochloride, depicted by formula (21), as shown in Scheme 10.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.Br[CH2:14][CH2:15][CH2:16][Cl:17].O>CN(C)C=O>[Cl:17][CH2:16][CH2:15][CH2:14][O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2
Reactant: ClCCCBr
Reactant: Oc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCOc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (0.8 g, 17 mmol of a 50% oil dispersion) in dimethylformamide (20 ml), under nitrogen, was added dropwise 7-hydroxyindole (2.1 g, 15.7 mmol) in dimethylformamide (20 ml). After complete addition, the reaction was stirred at ambient temperature for 0.5 hour and then cooled to 15° C. To this cooled solution was added, dropwise, 1-bromo-3-chloropropane (2.5 g, 15.7 mmol) in dimethylformamide (5 ml). The reaction was then stirred at ambient temperature for 16 hours. The reaction was poured into water, and the aqueous suspension extracted with ethyl acetate. The ethyl acetate was washed with water, dried (MgSO4), and the solvent was concentrated to afford a dark brown oil. Following flash chromatography on silica gel, 7-(3chloropropoxy)indole was obtained as a colorless oil, 1.0 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[Br:12].Cl[C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][N:15]=1.CN(C)C=O.[CH3:29][S-:30].[Na+]>[Cl-].[Na+].O.N1C=CC=CC=1>[Br:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[N:4]=[CH:3][C:2]([NH:1][S:20]([C:17]1[CH:18]=[CH:19][C:14]([S:30][CH3:29])=[N:15][CH:16]=1)(=[O:22])=[O:21])=[CH:11]2
Reactant: C[S-]
Reactant: Nc1cnc2c(Br)cccc2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CSc1ccc(S(=O)(=O)Nc2cnc3c(Br)cccc3c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
197 mg (0.556 mmol) of white crystals were obtained using 100 mg (0.56 mmol, Production Example 5b) of 3-amino-8-bromoquinoline and 142 mg (0.67 mmol) of 2-chloro-5-pyridinesulfonyl chloride in the same manner as in Synthetic Example 1b. Dimethylformamide (1 ml), pyridine (1 ml) and 111 mg (1.6 mmol) of sodium thiomethoxide were added to 60 mg (0.17 mmol) of the crystals, followed by stirring at room temperature for 3 hours. Brine was added to the reaction solution, followed by extracting with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated, to give the residue. The residue was purified by silica gel chromatography, to give 62 mg of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([O:29][C:30]3[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=3)[C:23]=1[F:39])=[O:19])=[CH:12]2.[N:40]1[CH:45]=[CH:44][C:43]([C:46](O)=[O:47])=[CH:42][CH:41]=1.CCN(C(C)C)C(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([NH:8][C:46]([C:43]2[CH:44]=[CH:45][N:40]=[CH:41][CH:42]=2)=[O:47])=[CH:17][CH:16]=3)=[O:19])=[C:23]([F:39])[C:24]=1[O:29][C:30]1[CH:35]=[C:34]([C:36]#[N:37])[CH:33]=[C:32]([Cl:38])[CH:31]=1
Reactant: O=C(O)c1ccncc1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(N)ccc4[nH]3)c2F)c1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3cc4cc(NC(=O)c5ccncc5)ccc4[nH]3)c2F)c1
Yield: 33.8 %

Procedure:
The title compound (0.020 g, 34% yield) was prepared from 5-amino-N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1H-indole-2-carboxamide trifluoroacetate (0.060 g, 0.103 mmol), 4-pyridinecarboxylic acid (0.013 g, 0.103 mmol), DIPEA (0.090 ml, 0.514 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.079 g, 0.309 mmol) in a similar manner as described in the general procedure. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.64 (s, 1H), 10.39 (s, 1H), 8.90-9.22 (m, 1H), 8.76 (d, 8.09 (s, 1H), 7.86 (d, 2H), 7.81 (s, 1H), 7.52 (s, 1H), 7.43-7.51 (m, 3H), 7.36-7.43 (m, 2H), 7.16 (d, 1H), 4.56 (d, 2H). MS: m/z 574 (M+1).
Reaction SMILES: [C:1]([Si:5]([CH3:32])([CH3:31])[O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH:10]=[CH:9][C:8]=1[C:23]([OH:30])=[CH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])([CH3:4])([CH3:3])[CH3:2].[Br:33]N1C(=O)CCC1=O.O>ClCCl>[Br:33][CH:24]([C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[C:23]([C:8]1[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:12][C:7]=1[O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:32])[CH3:31])=[O:30]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc(COc2ccc(C(O)=CC(=O)C(C)C)c(O[Si](C)(C)C(C)(C)C)c2)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(COc2ccc(C(=O)C(Br)C(=O)C(C)C)c(O[Si](C)(C)C(C)(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-[2-(tert-Butyl-dimethyl-silanyloxy)-4-(4-methoxy-benzyloxy)-phenyl]-1-hydroxy-4-methyl-pent-1-en-3-one (5.81 g, 12.72 mmol) is dissolved in dry dichloromethane (100 ml) at room temperature. N-bromosuccinimide (2.38 g, 13.36 mmol) is added portionwise. The reaction mixture is stirred at room temperature for 30 minutes, poured into water (200 ml) and extracted with dichloromethane (3×75 ml). The dichloromethane extracts are combined, washed with saturated brine (100 ml), dried (MgSO4), filtered and evaporated to give a pale yellow solid.
Reaction SMILES: O.O.Cl[Sn]Cl.C(OC([N:13]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-])=O)=[CH:29][CH:28]=3)(=[O:26])=[O:25])=[CH:20][C:19]=2[CH3:36])[CH2:14]1)=O)(C)(C)C.C([O-])(O)=O.[Na+]>C(O)(C)C>[CH3:36][C:19]1[CH:20]=[C:21]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH:22]=[CH:23][C:18]=1[CH:15]1[CH2:16][CH2:17][NH:13][CH2:14]1
Reactant: Cc1cc(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)ccc1C1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Cc1cc(S(=O)(=O)c2ccc(N)cc2)ccc1C1CCNC1
Temperature: 75 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
SnCl2.2H2O (1.74 g, 7.726 mmol) was added to a solution of 3-[2-methyl-4-(4-nitro-benzenesulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.69 g, 1.545 mmol) (prepared following the procedure described in Example 3) in isopropanol (20 mL) and the mixture was stirred at 75° C. for 2 hours. The reaction mixture was then cooled to 0° C. and a saturated solution of NaHCO3 was added. The gelatinous material obtained was filtered and the solvent was evaporated under reduced pressure. The crude material was purified via flash chromatography (DCM/MeOH/NH4OH) to give 0.407 g (83% yield) of 4-(3-methyl-4-pyrrolidin-3-yl-benzenesulfonyl)-phenylamine as a white foam: MS (M+H)=317.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][CH2:6][C:7]1[C:8]2[CH:23]=[C:22]([OH:24])[C:21]([OH:25])=[CH:20][C:9]=2[S:10][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13]>ClCCl.C(OCC)(=O)C>[Br:5][CH2:6][C:7]1[C:8]2[CH:23]=[C:22]([OH:24])[C:21]([OH:25])=[C:20]([N+:1]([O-:4])=[O:2])[C:9]=2[S:10][C:11]=1[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13]
Reactant: O=C(c1sc2cc(O)c(O)cc2c1CBr)N1CCOCC1
Reactant: O=[N+]([O-])O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1sc2c([N+](=O)[O-])c(O)c(O)cc2c1CBr)N1CCOCC1
Reaction time: 2 h

Procedure:
A solution of 1 M HNO3 in dichloromethane (1.02 ml) was added to a solution of (3-bromomethyl-5,6-dihydroxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone (0.35 g) in ethyl acetate (50 ml) and stirring continued at 60° C. for 2 hours. The cooled mixture was washed with water, dried and evaporated to dryness. The product was recrystallized from acetone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[N:9]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][NH2:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(Br)c1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: NNc1cccc(Br)c1
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-phenylamine (17 g, 0.1 mol) in concentrated HCl (200 mL) was added an aqueous solution (20 mL) of NaNO2 (7 g, 0.1 mol) at 0° C. and the resulting mixture was stirred for 1 h. A solution of SnCl2.2H2O (45 g, 0.2 mmol) in concentrated HCl (500 mL) was then added at 0° C. The reaction solution was stirred for an additional 2 h at RT. The precipitate was filtered and washed with ethanol and ether to give (3-bromo-phenyl)-hydrazine as a white solid, which was used for the next reaction without further purification
Reaction SMILES: C(N(CC)[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12])C.C([Li])(CC)C.CN([CH:26]=[O:27])C.C1C[O:31]CC1>>[OH:31][CH:26]1[C:10]2[C:5](=[C:6]([C:11]([F:12])([F:13])[F:14])[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:15])[O:27]1
Reactant: CN(C)C=O
Reactant: C1CCOC1
Reactant: CCN(CC)C(=O)c1ccccc1C(F)(F)F
Agent: [Li]C(C)CC
Product: O=C1OC(O)c2cccc(C(F)(F)F)c21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N,N-diethyl-2-(trifluoromethyl)benzamide (8.0 g, 32.6 mmol) and N,N,N′N′-tetramethylethylenediamine (5.4 mL, 35.9 mmol) in 100 mL of anhydrous THF at −78° C. was added sec-butyllithium (35.9 mL of a 1.0 M solution in hexanes, 35.9 mmol) dropwise over 30 min. The reaction was stirred at −78° C. for 1 h and then there was added DMF (7.6 mL, 97.8 mmol). The reaction was stirred at −78° C. for 1 h and then was quenched with 1N HCl (25 mL). The reaction mixture was concentrated in vacuo. The residue was taken up in 6N HCl (100 mL) and stirred at 100° C. for 18 h. The reaction mixture was allowed to cool, was diluted with water and extracted with EtOAc. The organics were washed with brine, dried (MgSO4) and concentrated to afford 8.5 g of a tan solid. This material was purified by acid-base extraction as follows. The solid was dissolved in 1:1 hexane/EtOAc and extracted twice with sat'd aq NaHCO3/sat'd aq Na2CO3. The organics were discarded. The combined aqueous extracts were acidified with 12 N HCl and extracted with EtOAc. The EtOAc extracts were washed with brine, dried (MgSO4), and concentrated to afford 6.3 g (88%) of the title compound as a pale yellow powder. LRMS (ESI): 219.02 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[C:13]([C:16]1[S:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].O>CN(C=O)C>[CH2:9]([O:8][C:6]1[N:5]=[C:4]([S:11][CH3:12])[N:3]=[C:2]([C:19]2[S:20][C:16]([C:13](=[O:15])[CH3:14])=[CH:17][CH:18]=2)[CH:7]=1)[CH3:10]
Reactant: CCOc1cc(Cl)nc(SC)n1
Reactant: CC(=O)c1ccc(B(O)O)s1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ccc(C(C)=O)s2)nc(SC)n1
Temperature: 80 °C
Yield: 27.9 %

Procedure:
The crude product of Preparation 27, 4-chloro-6-ethoxy-2-methylsulfanylpyrimidine, (525 mg, 2.56 mmol) was dissolved in DMF (4 mL). To this solution was added 5-acetyl-2-thiopheneboronic acid (523 mg, 3.08 mmol), PdCl2dppf (209 mg, 0.26 mmol), potassim carbonate (1.06 g, 7.69 mmol) and water (0.4 mL). The reaction mixture was heated at 80° C. under nitrogen atmosphere for overnight. The reaction mixture was cooled and poured into 30 mL of water and was then extracted with diethyl ether (20 mL×3) three times. The ether layer was separated and dried with anhydrous MgSO4 and concentrated in vacuo. The resulting crude product was purified by flash silica column chromatography (20% ethyl acetate in hexane) to give product 1-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-ethanone (210 mg, 28% yield over two steps). 1H-NMR (CDCl3): δ 7.67 (m, 2 H), 6.68 (s, 1 H), 4.46 (q, J=7.1 Hz, 2 H), 2.60 (s, 3 H), 2.59 (s, 3 H), 1.40 (t, J=7.1 Hz, 3 H).
Reaction SMILES: C(Cl)Cl.[NH:4]1[CH:12]=[C:10]([CH3:11])[C:8](=[O:9])[NH:7][C:5]1=[O:6].C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH3:25][O:26][CH2:27]Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O.CO>[CH3:25][O:26][CH2:27][N:4]1[CH:12]=[C:10]([CH3:11])[C:8](=[O:9])[NH:7][C:5]1=[O:6]
Reactant: COCCl
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [I-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COCn1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To 250 ml of methylene chloride, 25 g (0.20 mol) of thymine and 109 ml (0.44 mol) of bistrimethylsilylacetamide were added under a nitrogen flow, and stirred for 2.5 hours at room temperature. To this mixture, 24 g (0.30 mole) of chloromethyl methyl ether and 0.59 g (1.6 mmol) of tetrabutylammonium iodide were added and heated under reflux for 1.5 hours. Then, the reaction mixture was added with 400 ml of methanol and 100 ml of water slowly and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to obtain 1-(methoxymethyl)-thymine. Then, 119 ml of lithium diisopropylamide (0.25 mol) solution in tetrahydrofuran (2.1M) was added to 335 ml of tetrahydrofuran under a nitrogen flow at −70° C., to which a suspension of 17.0 g (0.10 mol) 1-(methoxymethyl)thymine in 107 ml of tetrahydrofuran added dropwise over 30 minutes. After stirring for 2.5 hours at −70° C., the reaction mixture was with a solution of 43.6 g of diphenyl disulfide in 49 ml of tetrahydrofuran dropwise over 20 minutes and allowed to react for 20 minutes. The reaction mixture was added with 35 ml of acetic acid, brought to room temperature and then added with 1 l of ethyl acetate. The mixture was washed with water (100 ml×5) and saturated solution of sodium hydrogencarbonate (twice), dried on magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethanol to obtain 20 g of the target compound (Yield: 73%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]=[C:7]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:6]=2.[CH:18]1([C:21]([NH2:23])=[O:22])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[CH:12]1([C:7]2[CH:6]=[C:5]3[C:10]([CH:11]=[C:2]([NH:23][C:21]([CH:18]4[CH2:20][CH2:19]4)=[O:22])[N:3]=[CH:4]3)=[CH:9][N:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Clc1cc2cnc(C3CCCCC3)cc2cn1
Reactant: NC(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(Nc1cc2cnc(C3CCCCC3)cc2cn1)C1CC1
Temperature: 90 °C
Yield: 66 %

Procedure:
A mixture of 3-chloro-7-cyclohexyl-2,6-naphthyridine (80.0 mg, 0.324 mmol), cyclopropanecarboxamide (47.7 mg, 0.560 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-1-propyl-1,1′-biphenyl (6.0 mg, 0.011 mmol), chloro[2-(dicyclohexylphosphino)-3-,6-dimethoxy-2-4′-6′-tri-i-pr-1,1′-biphenyl)][2-(2-aminoethyl)Ph]Pd(II) (9.2 mg, 0.012 mmol), and cesium carbonate (240.1 mg, 0.7369 mmol) in 1,4-dioxane (2 mL, 20 mmol) was heated at 90° C. for 2 hours. The reaction mixture was cooled to room temperature, diluted in ethyl acetate, washed with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 63.2 mg (66%) of N-(7-cyclohexyl-2,6-naphthyridin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (Min)=4.090, M+H=296.1, method=E; 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 9.28 (s, 1H), 9.19 (s, 1H), 8.55 (s, 1H), 7.72 (s, 1H), 2.89-2.73 (m, 1H), 2.14-2.03 (m, 1H), 1.96 (d, J=11.6 Hz, 2H), 1.84 (d, J=12.8 Hz, 2H), 1.74 (d, J=12.6 Hz, 1H), 1.63-1.51 (m, 2H), 1.43 (dd, J=25.4, 12.6 Hz, 2H), 1.34-1.18 (m, 1H), 0.85 (dd, J=8.3, 6.5 Hz, 4H).