Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:29])=[C:15]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[CH3:38][CH:39]([CH3:43])[C:40](=[S:42])[NH2:41]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:42][C:40]([CH:39]([CH3:43])[CH3:38])=[N:41][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([F:29])=[C:15]([NH:17][S:18]([C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])(=[O:20])=[O:19])[CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)C(N)=S
Reactant: O=C(Cc1ccnc(Cl)n1)c1ccc(F)c(NS(=O)(=O)c2c(F)cccc2F)c1
Agent: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 41 %

Procedure:
To a solution of N-{5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}-2,6-difluorobenzenesulfonamide (1.0 g, 2.3 mmol) in DMF (10 mL) was added NBS (0.49 g, 2.8 mmol). After stirring for 45 min at rt, 2-methylpropanethioamide (0.35 g, 3.4 mmol), was added and the reaction was stirred at rt. After 4 h, the reaction mixture was partitioned between ether and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over anhydrous NaSCO4, filtered, and concentrated to generate 0.49 g (41% yield) as a yellow powder. MS (ESI) 525 (M+H).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:24][CH:25]([CH3:27])[CH3:26])[CH:17]=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1.C(O)(C(F)(F)F)=O>>[F:42][C:2]([F:1])([F:41])[C@H:3]([N:28]1[CH2:32][CH2:31][C@H:30]([NH2:33])[CH2:29]1)[C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:10]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([O:24][CH:25]([CH3:27])[CH3:26])[CH:17]=[C:18]([F:23])[CH:19]=4)[N:14]=3)=[N:11][N:12]=2)[CH:9]=1
Reactant: CC(C)Oc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cc(F)cc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](N)C5)C(F)(F)F)cn34)nc12
Reaction time: 0.5 h
Yield: 105.4 %

Procedure:
To tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-8-isopropoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (120 mg, 0.204 mmol) was added TFA (2 mL) and the reaction was stirred for 30 minutes. After concentrating to dryness, the residue was dissolved in methanol and added to 2N HCl in ether. The resulting solid was filtered and dried under high vacuum to yield (S)-1-((R)-2,2,2-trifluoro-1-(3-(6-fluoro-8-isopropoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-amine (105 mg, 105% yield) hydrochloride as a beige solid. LCMS APCI (+) m/z 489 (M+H). Specific rotation: [α]26D=+1.43° (c=0.93, MeOH).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[C:27]1([C@H:33]([OH:35])[CH3:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:35][C@@H:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH3:34])[CH:7]=1
Reactant: C[C@@H](O)c1ccccc1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Product: C[C@@H](Oc1cc(F)ccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1)c1ccccc1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (110 mg; 0.289 mmol), intermediate 42.1, and (R)-(+)-1-phenylethanol (143 mg; 1.157 mmol), example 79 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])=O.[C:12]([NH2:20])(=[S:19])[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>>[CH3:11][C:10]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:3]1[N:20]=[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[S:19][CH:2]=1
Reactant: NC(=S)c1ccncc1
Reactant: Cc1ccncc1C(=O)CBr
Product: Cc1ccncc1-c1csc(-c2ccncc2)n1
Yield: 27.5 %

Procedure:
By the reaction in the same manner as in Example 25-iii) using 2-bromo-1-(4-methylpyridin-3-yl)ethanone hydrobromate (428 mg) and thioisonicotinamide (153 mg), the title compound (77 mg) was obtained as colorless powder crystals.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[F:22])[CH:6]=1)(=[O:4])=[O:3].[C:23]1([CH2:29][C:30]([N:32]=[C:33]=[S:34])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1.CO>[CH3:1][S:2]([C:5]1[S:13][C:12]2[C:7](=[N:8][CH:9]=[CH:10][C:11]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:33]([NH:32][C:30](=[O:31])[CH2:29][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[S:34])=[CH:17][C:16]=2[F:22])[CH:6]=1)(=[O:3])=[O:4]
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CS(=O)(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 2 h
Yield: 31.6 %

Procedure:
To a suspension of 237 (20 mg, 0.059 mmol) in THF (10 mL) was added 2-phenylacetyl isothiocyanate (26 mg, 0.146 mmol). The reaction mixture was stirred for 2 hours, concentrated under reduced pressure and the residue was purified by column chromatography, eluent EtOAc/MeOH (19:1), to afford a solid material that was dissolved in a minimum MeOH and precipitated with hexane to afford title compound 238 (9.6 mg, 31%) as a white solid. 1HNMR: (DMSO-d6) δ (ppm): 12.48(s, 1H), 11.81(s, 1H), 8.69(d, J=5.5 Hz, 1H), 8.36(s, 1H), 8.03(d, J=12.13 Hz, 1H), 7.55(s, 2H), 7.36-7.30(m, 2H), 7.30-7.24(m, 3H), 6.86(d, J=5.5 Hz, 1H), 3.83(s, 2H), 3.54(s, 3H). MS (m/z): 516.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ncccn1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ncccn1)c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 17 h
Yield: 80 %

Procedure:
A mixture of 4-bromobenzene sulfonyl chloride (3.0 g, 11.74 mmol) and 2-aminopyrimidine (1.17 g, 12.3 mmol, 1.05 eq) in anhydrous pyridine (23 mL) was stirred at 50° C. for 17 hours. The reaction was quenched with 2N aqueous hydrochloric acid (100 mL) and the resultant reaction mixture was extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (1×100 mL) and brine (1×100 mL), dried (Na2SO4), filtered, and evaporated under reduced pressure. Recrystallization from ethyl acetate-dichloromethane gave the desired product as a white solid (2.95 g, 80%). LC-MS (ES MH+=314/316); TLC (Rf=0.42, 75% ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:31])[C:10]2[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][C:11]=2[NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]2)=[N:6][CH:7]=1.CO.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].[ClH:45]>O.C1COCC1>[ClH:1].[ClH:45].[ClH:1].[C:16]([C:14]1[CH:13]=[CH:12][C:11]([NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]2)=[C:10]([CH:15]=1)[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:31])([OH:18])=[O:17]
Reactant: COC(=O)c1ccc(NCC2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)N1CCC(CNc2ccc(C(=O)O)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reaction time: 72 h
Yield: 52 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-[(1-isopropylpiperidin-4-ylmethyl)amino]-5-methoxycarbonylbenzamide (0.50 g, 1.1 mmol) in 1:1:1 methanol:THF:water was treated with barium hydroxide octahydrate (3.6 g, 11 mmol). After 3 days, the mixture was treated with 5 N HCl and concentrated under reduced pressure until precipitation resulted. The mixture was filtered affording 250 mg (52%) of the title compound as a hydrochloride salt.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2.[N+:27]([O-])([O-:29])=[O:28].[K+]>OS(O)(=O)=O>[N+:27]([C:5]1[C:6]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=2)=[O:15])=[CH:7][C:8]2[C:9]([CH3:12])([CH3:13])[CH2:10][CH2:11][C:2]([CH3:26])([CH3:1])[C:3]=2[CH:4]=1)([O-:29])=[O:28]
Reactant: COC(=O)c1ccc(C(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1ccc(C(=O)c2cc3c(cc2[N+](=O)[O-])C(C)(C)CCC3(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Compound 43 (693 mg, 1.98 mmol) was dissolved in concentrated H2SO4 (5 ml) and the mixture was added with KNO3 (240 mg, 2.37 mmol) under ice cooling. After 1 hour, the reaction mixture was poured into ice water and extracted with dichloromethane. The organic phase was washed with saturated aqueous solution of sodium hydrogen carbonate, water and saturated brine, and then concentrated after dryness. The residue was recrystallized from ethyl acetate to give methyl 4-[3-nitro-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylcarbonyl]benzoate as colorless needles (Compound 44, 414 mg, 53%).
Reaction SMILES: [OH-:1].[K+].Cl.[NH2:4]O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]([C@@H:17]1[O:23][C@H:22]([CH2:24][O:25]C(=O)C)[C@@H:20]([OH:21])[C@H:18]1[OH:19])[C:11]([Br:29])=[C:10]2[C:30]#[N:31].CO.C(Cl)(Cl)Cl>CO.NO.CO.O>[NH2:4][OH:1].[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]([C@@H:17]1[O:23][C@H:22]([CH2:24][OH:25])[C@@H:20]([OH:21])[C@H:18]1[OH:19])[C:11]([Br:29])=[C:10]2[C:30](=[N:31][OH:1])[NH2:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Br)c(C#N)c3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Reactant: [OH-]
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=NO)c1c(Br)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2cc(Cl)c(Cl)cc12
Reaction time: 0.17 h
Yield: 40.9 %

Procedure:
A solution of hydroxylamine in absolute MeOH was prepared by adding potassium hydroxide (1.83 g, 33 mmol) to hydroxylamine hydrochloride (2.50 g, 36 mmol) dissolved in absolute MeOH (20 mL) and stirring for 10 min. The resulting solids were filtered and rinsed with cold absolute MeOH (10 mL), and the filtrate used without further purification. 5,6-Dichloro-2-bromo-3-cyano-1-(5-O-acetyl-β-D-ribofuranosyl)indole (4.139, 133 mg, 0.29 mmol) was dissolved in the crude solution of hydroxylamine in MeOH and stirred at room temperature for 4 days. The solvent was then removed under vacuum, and the residual solid dissolved in brine (40 mL). The aqueous suspension was extracted with EtOAc (2×50 mL), and the combined organic extracts dried over MgSO4, filtered and evaporated to yield a pale yellow solid. The solid was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 20% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a pale yellow solid. The solid was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield a pale yellow solid which was recrystallized from MeOH/H2O to yield 54 mg (41%) of 4.140 as a pale yellow powder: mp slow dec >170° C.; Rf0.5 (20% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 9.66 (s, 1H, D2O exch.), 8.48 (s, 1H), 7.89 (s, 1H), 5.99 (d, 1H), 5.76 (s, 2H, D2O exch.), 5.35 (t, 1H, D2O exch.), 5.31 (d, 1H, D2O exch.), 5.22 (d, 1H, D2O exch.), 4.45 (q, 1H), 4.15 (t, 1H), 3.96 (d, 1H), 3.72 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 146.18, 133.16, 127.04, 124.88, 123.77, 120.74, 115.72, 114.86, 110.61, 90.17, 85.68, 71.21, 69.55, 61.07. HRMS (ES) m/z calcd. for C14H14BrCl2N3O5+H 453.9572, found 453.9570. Anal calcd for C14H14BrCl2N3O5.¼MeOH: C, 36.96; H, 3.26; N, 9.07. Found: C, 37.11; H, 3.22; N, 8.85.
Reaction SMILES: [NH2:1][C@@H:2]([CH:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)[CH3:3].CN(C=O)C.C(N(C(C)C)CC)(C)C.Cl[C:26]1[N:31]=[C:30]([C:32]2[C:40]3[C:35](=[N:36][CH:37]=[C:38]([C:41]([F:44])([F:43])[F:42])[CH:39]=3)[N:34]([S:45]([C:48]3[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=3)(=[O:47])=[O:46])[CH:33]=2)[C:29]([C:55]#[N:56])=[CH:28][N:27]=1>C1COCC1>[OH:10][CH:7]1[CH2:8][CH2:9][CH:4]([C@H:2]([NH:1][C:26]2[N:31]=[C:30]([C:32]3[C:40]4[C:35](=[N:36][CH:37]=[C:38]([C:41]([F:43])([F:44])[F:42])[CH:39]=4)[N:34]([S:45]([C:48]4[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=4)(=[O:46])=[O:47])[CH:33]=3)[C:29]([C:55]#[N:56])=[CH:28][N:27]=2)[CH3:3])[CH2:5][CH2:6]1
Reactant: C[C@@H](N)C1CCC(O)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(Cl)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCC(O)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-((R)-1-aminoethyl)cyclohexanol (309.4 mg, 2.16 mmol) was dissolved in THF (10 mL) and DMF (4 mL) and stirred over molecular sieves for 10 minutes. Diisopropylethylamine (376.3 μL, 2.160 mmol) was added, followed by 2-chloro-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (516.1 mg, 1.080 mmol). The reaction mixture was stirred under nitrogen at ambient temperature for 18 hours. The molecular sieves was removed by filtration and washed with EtOAc. The filtrate was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on silica gel by flash column chromatography (ISCO Companion|, 80 g column, 0-100% EtOAc/DCM) to afford the title compound as a yelow solid (558 mg, 88% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]=[S:27]>CS(C)=O.O>[CH3:24][C:23]1[C:18]([C:16]([NH:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:26]([NH:25][C:28](=[O:29])[O:30][CH2:31][CH3:32])=[S:27])=[N:7][CH:6]=2)=[O:17])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cccnc1C(=O)Nc1cccc(Oc2ccc(N)nc2)c1
Reactant: CCOC(=O)N=C=S
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)NC(=S)Nc1ccc(Oc2cccc(NC(=O)c3ncccc3C)c2)cn1
Yield: 77 %

Procedure:
To a solution of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-3-methylpyridine-2-carboxamide (1.84 g, 5.75 mmol) in DMSO (20 mL) was added dropwise with stirring under ice-cooling ethyl isothiocyanatoformate (0.75 mL, 6.35 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (25%→40% ethyl acetate-hexane) to give the title compound (2.00 g, 77%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:11][CH:10]=2)[C:5](=[O:28])[N:4]([CH3:29])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:13][CH:14]=2)[C:5](=[O:28])[N:4]([CH3:29])[CH:3]=1
Reactant: Cn1cc(Br)nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(Br)nc(Nc2ccc(C3CCNCC3)cc2)c1=O
Yield: 99.4 %

Procedure:
Compound 214a was synthesized using the same procedure as for 121c, except using tert-butyl 4-(4-(6-bromo-4-methyl-3-oxo-3,4-dihydropyrazin-2-ylamino)phenyl)-piperidine-1-carboxylate (121a) (0.53 g, 1.08 mmol), trifluoroacetic acid (0.9 mL, 10.8 mmol) and methylene chloride (20 mL). Work-up and concentration afforded a quantitative yield of 214a (390 mg) as yellow oil, which was used without purification in the next step.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[N:17]=[C:16]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][NH:25][C:26](=[O:43])[C:27]5[CH:32]=[C:31]([O:33]C)[CH:30]=[C:29]([O:35][CH2:36]C6C=CC=CC=6)[CH:28]=5)[CH2:20][CH2:19]4)[CH:15]=[CH:14][N:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])=O.[NH4+]>[Pd].CO>[N:1]1([C:6]2[CH:7]=[C:8]([C:12]3[N:17]=[C:16]([N:18]4[CH2:19][CH2:20][CH:21]([CH2:24][NH:25][C:26](=[O:43])[C:27]5[CH:28]=[C:29]([O:35][CH3:36])[CH:30]=[C:31]([OH:33])[CH:32]=5)[CH2:22][CH2:23]4)[CH:15]=[CH:14][N:13]=3)[CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1cc(OCc2ccccc2)cc(C(=O)NCC2CCN(c3ccnc(-c4cccc(-n5cccn5)c4)n3)CC2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cc(O)cc(C(=O)NCC2CCN(c3ccnc(-c4cccc(-n5cccn5)c4)n3)CC2)c1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A solution of N-((1-(2-(3-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)-3-(benzoxy)-5-methoxybenzamide (Example 11, step iv, 1.45 g, 2.5 mmol), ammonium formate (0.70 g, 11.1 mmol) and 10% palladium on carbon (0.15 g) in methanol (30 ml) was heated to reflux temperature for 18 hours. The reaction mixture was cooled to ambient temperature and filtered through celite. The filtrate was concentrated under reduced pressure and the residue obtained was partitioned between CH2Cl2 and water. The organic phase was passed through a hydrophobic frit and concentrated under reduced pressure to give N-((1-(2-(3-(1H-pyrazol-1-yl)phenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)-3-hydroxy-5-methoxybenzamide as a pale yellow foam (1.16 g). MS (ESI) me: 485.6 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CCN(C(C)C)C(C)C>CN(C)C=O>[CH3:22][N:23]1[CH2:29][CH2:28][CH2:27][N:26]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=3)[CH2:25][CH2:24]1
Reactant: CN1CCCNCC1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCCN(C)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) in N,N-dimethylformamide (4 mL), 1-methyl-1,4-diazepane (100.3 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 126.6 mg (77%) of methyl 3-(4-methyl-1,4-diazepan-1-yl)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10].[CH3:28][C@@H:29]1[CH2:33][CH2:32][S:31](=[O:35])(=[O:34])[NH:30]1>>[F:1][C:2]1[CH:7]=[C:6]([N:30]2[C@H:29]([CH3:28])[CH2:33][CH2:32][S:31]2(=[O:35])=[O:34])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10]
Reactant: C[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(I)cc2F)CC1
Product: Cc1cc(C(F)(F)F)cnc1N1CCN(C(=O)c2ccc(N3[C@H](C)CCS3(=O)=O)cc2F)CC1
Yield: 5.6 %

Procedure:
Using (2-fluoro-4-iodophenyl)[4-(3-methyl-5-trifluoromethylpyridin-2-yl)piperazin-1-yl]methanone (507 mg) described in Preparation Example 161 and (R)-3-methylisothiazolidine 1,1-dioxide (139 mg) described in Preparation Example 2 and by the reaction and treatment in the same manner as in Example 1, the title compound (29 mg) was obtained.
Reaction SMILES: Br[C:2]1[C:10]2[CH:9]=[CH:8][S:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Mg].II.CON(C)[C:17](=[O:22])[CH2:18][CH:19]1[CH2:21][CH2:20]1>O1CCCC1>[S:7]1[CH:8]=[CH:9][C:10]2[C:2]([C:17](=[O:22])[CH2:18][CH:19]3[CH2:21][CH2:20]3)=[CH:3][CH:4]=[CH:5][C:6]1=2
Reactant: Brc1cccc2sccc12
Reactant: CON(C)C(=O)CC1CC1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: O=C(CC1CC1)c1cccc2sccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A few drops of a solution of 4-bromobenzo[b]thiophene (2.84 g; prepared in a manner similar to that described in Example 9 Method A) in tetrahydrofuran (20 ml) was added under nitrogen to magnesium turnings (0.4 g). Two crystals of iodine were added and heat was applied to initiate the reaction. The remainder of the 4-bromobenzo[b]thiophene solution was added at reflux temperature over 20 minutes, then the mixture was heated under reflux for 2 hours. A solution of N-methoxy-N-methylcyclopropaneacetamide (2.0 g) in tetrahydrofuran (10 ml) was added, the mixture was heated under reflux for 2.5 hours, then it was stirred at ambient temperature for 18 hours and quenched by the addition of 2M hydrochloric acid (40 ml). The mixture was stirred at ambient temperature for 1 hour, then the product was extracted into ethyl acetate (3×30 ml). The combined extracts were washed with water (30 ml) and saturated aqueous sodium chloride solution (20 ml), dried (MgSO4), and the solvents were removed in vacuo. The residue was purified by flash chromatography over silica using petroleum ether (b.p. 60-80° C.) followed by a 95:5 mixture of petroleum ether (b.p. 60-80° C.) and ethyl acetate as eluants. Appropriate fractions were combined and the solvents removed in vacuo to give 1-(benzo[b]thiophen-4-yl)-2-cyclopropylethan-1-one (1.2 g) as a colourless oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:3]=1[C:4](O)=[O:5].[NH2:13][C:14](N)=[O:15].[OH-].[Na+].Cl>O>[Cl:12][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[Cl:11])[NH:1][C:14](=[O:15])[NH:13][C:4]2=[O:5]
Reactant: Nc1cc(Cl)c(Cl)cc1C(=O)O
Reactant: NC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(=O)c2cc(Cl)c(Cl)cc2[nH]1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 96.3 %

Procedure:
2-Amino-4,5-dichlorobenzoic acid (920 mg) and urea (2.75 g) were stirred at 160° C. After 6 hours the mixture was cooled to 100° C. and an equivalent volume of water was added while stirring was continued for 5 minutes. The formed precipitate was filtered off and washed with water to yield a solid cake that was suspended in a solution of 0.5 N NaOH in water. The suspension was heated to boil for 5 minutes and then cooled to r.t. The pH was adjusted to about 2 with HCl and the quinazoline-dione was filtered off. After washing with a mixture of water and methanol the product was dried in vacuo to yield 994 mg (94%) of a solid. 1H-NMR (DMSO-δ6) δ (ppm) 7.89 (s, 1H), 7.33 (s, 1H).
Reaction SMILES: [P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH:19]=[C:18]([NH2:20])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][C@@H:8]1[OH:21])([OH:4])([OH:3])=[O:2].[N:22]([O-])=O.[Na+]>>[P:1]([O:5][CH2:6][C@H:7]1[O:11][C@@H:10]([N:12]2[CH2:19][C:18](=[N+:20]=[N-:22])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:9][C@@H:8]1[OH:21])([OH:3])([OH:4])=[O:2]
Reactant: Nc1cn([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)c(=O)[nH]c1=O
Reactant: O=N[O-]
Agent: [Na+]
Product: [N-]=[N+]=C1CN([C@H]2C[C@H](O)[C@@H](COP(=O)(O)O)O2)C(=O)NC1=O

Procedure:
acidifying said 5-amino-2'-deoxyuridine-5'-monophosphate and reacting the acidified product with sodium nitrite to produce 5-diazo-2'-deoxyuridine-5'-monophosphate; and