Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C([O-])(=O)C.[K+].ClCC1[C:13]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[N:14][CH:15]=[C:16]([CH:18]([Cl:20])[Cl:19])[N:17]=1.ClCCl>CS(C)=O.O>[Cl:20][CH:18]([Cl:19])[C:16]1[N:17]=[C:2]([CH2:1][OH:4])[C:13]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[N:14][CH:15]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ncc(C(Cl)Cl)nc1CCl
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1c1ncc(C(Cl)Cl)nc1CO
Temperature: 25 °C
Reaction time: 72 h
Yield: 47 %

Procedure:
50 ml of glacial acetic acid and 35 g of potassium acetate were added to a solution of 57.7 g (0.16 mole) of 65% strength 3-chloromethyl-5-dichloromethyl-2-phthalimidopyrazine in 1,000 ml of a 95:5 dimethyl sulfoxide/water mixture. The mixture was stirred for three days at room temperature, after which 1,000 ml of dichloromethane and 1,000 ml of ice-water were added, the resulting mixture was mixed thoroughly and phase separation was effected. The aqueous phase was washed once with 500 ml of dichloromethane and once with 250 ml of dichloromethane, and the combined organic phases were washed twice with 1,000 ml of water, dried over sodium sulfate and evaporated down. The resulting black oil was brought to crystallization with 50 ml of methanol, and then recrystallized from 700 ml of methanol. 16.6 g (47%) of 5-dichloromethyl-3-hydroxymethyl-2-phthalimidopyrazine of melting point 191°-192° C. (sublimation with decomposition) were obtained. 1H-NMR (200 MHz, CDCl3): δ3.3 (t, OH), 4.8 (d, 2H), 6.9 (s, 1H), 8.0 (m, 4H), 9.1 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:7]([O-:9])=[O:8])=[CH:4][S:5][CH:6]=1.[Li+].[Cl:11]N1C(=O)CCC1=O>O.CC(O)C>[CH3:1][C:2]1[C:3]([S:7]([Cl:11])(=[O:9])=[O:8])=[CH:4][S:5][CH:6]=1
Reactant: Cc1cscc1S(=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Agent: [Li+]
Solvent: O
Solvent: CC(C)O
Product: Cc1cscc1S(=O)(=O)Cl
Temperature: 20 °C
Reaction time: 1.17 h

Procedure:
To 34 g of lithium 4-methyl-3-thiophenesulfinate in 220 ml of water cooled to 10° C. was added a suspension of 26.7 g of N-chlorosuccinimide in 80 ml of 2-propanol portionwise during 5 minutes. An additional 75 ml of 2-propanol was added to dissolve the reagents and the mixture was stirred for 70 minutes at 20° C. A large excess (1 liter) of water was then added and the mixture was extracted with methylene chloride 3 times. The methylene chloride portions were combined, dried over sodium sulfate and the solvent removed in vacuo to yield 4-methyl-3-thiophenesulfonyl chloride. This product was dissolved in 100 ml of tetrahydrofuran and 70 ml of concentrated aqueous ammonia was then added, and the mixture stirred overnight. Concentration of the resultant solution in vacuo and dilution of the residue with water yielded a solid which was filtered, washed with water and stirred with hot 1-chlorobutane, cooled and filtered to yield 14 g of the desired solid compound, m.p. 73°-85°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:18]=[O:19])[CH:14]=2)[N:9]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:8]1=[O:26].[BH4-].[Na+]>CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][OH:19])[CH:14]=2)[N:9]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:8]1=[O:26]
Reactant: COc1ccc(Cn2c(=O)c3cc(C=O)ccc3n(C3CCOCC3)c2=O)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cn2c(=O)c3cc(CO)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
A mixture of 0.575 g of the compound obtained in Step 14.2 and 0.077 g of NaBH4 in a mixture of 20 ml of MeOH and 10 ml of THF is stirred for 30 minutes at room temperature. The reaction medium is evaporated under reduced pressure. The residue is taken up in DCM. This solution is washed with saturated NH4Cl solution. The organic phase is dried over Na2SO4, filtered and evaporated under reduced pressure to give 0.554 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[S:22](Cl)(=[O:24])=[O:23].C(Cl)Cl>O>[CH3:5][N:9]([CH3:10])[S:22]([C:3]1[CH:4]=[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:17])([F:18])[F:19])[N:11]([CH3:20])[C:10]2=[O:21])[C:6]([N:11]([CH3:20])[CH3:12])=[CH:7][C:2]=1[F:1])(=[O:23])=[O:24]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(S(=O)(=O)Cl)c(F)cc2F)c1=O
Solvent: ClCCl
Solvent: O
Product: CN(C)c1cc(F)c(S(=O)(=O)N(C)C)cc1-n1c(=O)cc(C(F)(F)F)n(C)c1=O
Reaction time: 2 h
Yield: 129.2 %

Procedure:
To a solution of 2.0 g of 2,4,-difluoro-5-(3,6-dihydro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H) pyrimidinyl)benzenesulfonyl chloride and 30 ml of methylene chloride cooled to 5° C. was added 1.9 ml of a 40% solution of dimethylaminein water over 15 minutes. Analysis of the reaction mixture by TLC after 2 hours of stirring showed a single component. Work up was carried out as described in Example B-4. Two grams of crude solid was obtained and recrystallized from ethanol giving 1.7 g of a white solid, melting point 185°-194° C. NMR analysis of the product showed a 2:1 mixture of N,N-dimethyl-2,4-difluoro-5-(3,6-dihydro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H)-pyrimidinyl)benzenesulfonamide (Compound #49) and the title compound. A mixture of 1.6 g of the product, 30 ml of methylene chloride and 3.8 ml of a 40% solution of dimethylamine in water was stirred at roomtemperature for 21 hours. The organic layer was separated, washed with water and dried over magnesium sulfate. After removal of volatiles using arotary evaporator there remained 1.6 g of a solid. Recrystallization of theproduct from ethanol gave 1.4 g of the title compound as fine white crystals, m.p. 223.5°-225° C. Spectral data for this compound is found in Table I.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[C:12]([CH3:21])[C:11]([C:22](O)=[O:23])=[N:10]1.[NH2:25][N:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=2)=[C:12]([CH3:21])[C:11]([C:22]([NH:25][N:26]2[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]2)=[O:23])=[N:10]1
Reactant: NN1CCS(=O)(=O)CC1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(I)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)NN2CCS(=O)(=O)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(I)cc1
Reaction time: 1 h
Yield: 31.4 %

Procedure:
The acid (7.5 g, 15.8 mmol) obtained from step D was taken in a 500 ml 1 neck flask equipped with a nitrogen inlet and to it 200 ml of DCM, 4-aminothiomorpholine-1,1-dioxide (2.61 g, 17.4 mmol), TBTU (5.59 g, 17.4 mmol) and DIPEA (2.25 g, 17.4 mmol) were added and the contents were stirred for 1 hour. To the reaction mixture, 100 ml of water was added and the contents were acidified to pH ˜2 using concentrated HCl. The organic layer was separated, washed with brine, dried over sodium sulphate and concentrated to give the amide (3 g, 31.2%).
Reaction SMILES: B(F)(F)F.C(O)(=O)C.[CH2:9]([SH:12])[CH2:10][SH:11].[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][C:31](=O)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)Cl.CCOCC>[CH2:13]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][C:31]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[S:12][CH2:9][CH2:10][S:11]2)[CH2:25][CH2:24]1)=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CCC1CCN(C(=O)OCc2ccccc2)CC1)c1ccccc1
Reactant: SCCS
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(CCC2(c3ccccc3)SCCS2)CC1
Reaction time: 6 h
Yield: 92.7 %

Procedure:
Boron trifluoride-acetic acid complex (BF3.2-CH3CO2H, 0.370 mL, 501 mg, 2.67 mmol) was added to a solution of 1,2-ethanedithiol (0.440 mL, 494 mg, 5.25 mmol) and (1-(benzyloxycarbonyl)-4-(3-oxo-3-phenylprop-1-yl)piperidine (930 mg, 2.65 mmol) in methylene chloride (4.0 mL), at rt. After 6 h, the mixture was diluted with ether 50 mL) and washed with saturated aq. sodium bicarbonate (2×25 mL), 2.5 N aq. NaOH (25 mL), and saturated aq. brine (25 mL). The organic layer was dried (sodium sulfate), decanted, and evaporated. The crude product was purified by FC, eluting with 10% ethyl acetate in hexane, to give 1.05 g of the title compound as a colorless liquid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:19]1([NH:18][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]4[CH2:17][CH2:16]4)=[O:14])[N:8]=[CH:9]3)=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Reactant: Nc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: COCCOC
Product: O=C(Nc1cc2ccc(Nc3ccccc3)cc2cn1)C1CC1
Temperature: 100 °C
Reaction time: 3 h
Yield: 44.5 %

Procedure:
N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (200 mg, 0.69 mmol), aniline (76 mg, 0.83 mmol), palladium(II) acetate (30 mg, 0.15 mmol), X-Phos (66 mg, 0.15 mmol) and cesium carbonate (450 mg, 1.4 mmol) were mixed in 1,2-dimethoxyethane (50 mL). After the reaction mixture was stirred at 100° C. under nitrogen for 3 hours, it was concentrated, washed with water and extracted with ethyl acetate, and purified by prep-HPLC to give the desired product (93.2 mg, 44.5%). LCMS (ESI): RT (min)=1.018, M+H+=303.8, Method=A; 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.89 (s, 1H), 8.51 (s, 1H), 8.29 (s, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.56 (s, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.30-7.20 (m, 2H), 7.20-7.18 (m, 2H), 6.90-6.89 (m, 1H), 2.05-2.01 (m, 1H), 0.82-0.76 (m, 4H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][C:11]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:8][C:11]3[CH:12]=[C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:15][C:10]=3[N:9]=2)[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Solvent: CCO
Product: COC(=O)Cc1ccc2nc(-c3cccnc3)oc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 22.9 %

Procedure:
In EtOH (15 ml), pyridine-3-aldehyde (0.63 g, 5.89 mmol) and methyl 4-amino-3-hydroxyphenylacetate (1.06 g, 5.85 mmol) were stirred at room temperature for 20 hours. To the reaction mixture was added iodobenzene diacetate (2.26 g, 7.02 mmol), followed by stirring at room temperature for 20 minutes. The reaction mixture was distilled under reduced pressure to remove the solvent and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (1:1, v/v) eluate fractions, methyl (2-(3-pyridyl)-6-benzoxazolyl)acetate (360 mg, 23%) was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][N:10]=[N:9]2)=[C:4]([F:14])[CH:3]=1.[F:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:18][CH2:17][CH2:16][F:15])[N:10]=[N:9]2)=[C:4]([F:14])[CH:3]=1
Reactant: O=c1[nH]nnn1-c1ccc(Cl)cc1F
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1n(CCCF)nnn1-c1ccc(Cl)cc1F
Yield: 57.9 %

Procedure:
A stirred solution of 4.7 g (0.022 mole) of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-one, 4.0 g (0.028 mole) of 3-fluoropropyl bromide and 4.0 g (0.028 mole) of potassium carbonate in 60 ml of dimethylformamide was heated at 60° C. for 16 hours. The reaction mixture was poured into water and the mixture extracted with diethyl ether. The combined ether extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was dissolved in methylene chloride and passed through a pad of silica gel. The eluate was concentrated under reduced pressure to yield 3.5 g of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-4-(3-fluoropropyl)-5H-tetrazol-5-one; m.p. 62°-63° C. The reaction was repeated several times.
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[C:8]([Br:10])[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]=1[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([F:24])[CH:17]=1)O)=[O:4].[NH2:25][C:26]1[CH:27]=[C:28]([Cl:34])[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=1.COC(C1C=C(Br)N(C(C)C)C=1C(C1C=CC(C#N)=CC=1)O)=O.CN1C(N)=CC(C)=N1.ClC(N(C)C)=C(C)C>CCOC(C)=O.CCN(CC)CC>[Br:10][C:8]1[N:7]([CH:11]([CH3:13])[CH3:12])[C:6]2[CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([F:24])[CH:17]=3)[N:25]([C:26]3[CH:27]=[C:28]([Cl:34])[C:29](=[O:33])[N:30]([CH3:32])[CH:31]=3)[C:3](=[O:4])[C:5]=2[CH:9]=1
Reactant: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(C#N)c(F)c1
Reactant: Cn1cc(N)cc(Cl)c1=O
Agent: CC(C)=C(Cl)N(C)C
Agent: COC(=O)c1cc(Br)n(C(C)C)c1C(O)c1ccc(C#N)cc1
Agent: Cc1cc(N)n(C)n1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)n1c(Br)cc2c1C(c1ccc(C#N)c(F)c1)N(c1cc(Cl)c(=O)n(C)c1)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Intermediate AX but in the step corresponding to Step AX1, 5-bromo-2-[(4-cyano-3-fluoro-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester (Step BC1) and 5-amino-3-chloro-1-methyl-1H-pyridin-2-one (Step E5) were used instead of 5-bromo-2-[(4-cyano-phenyl)-hydroxy-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid methyl ester and 2,5-dimethyl-2H-pyrazol-3-ylamine respectively. Moreover, in this step, the procedures described for Steps H3 and H2 using 1-chloro-N,N,2-trimethylpropenylamine and Et3N were used. The title compound (containing some of the corresponding 2-chloro analog) was obtained as a yellow solid. tR: 1.08 min (HPLC 3); ESI-MS: tR=0.99 min, [M+H]+ 503/505/507 (LC-MS 1); TLC: Rf=0.18 (EtOAc).
Reaction SMILES: [CH3:1][CH:2]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:15]=1)[CH2:3][NH:4][C:5]([NH:7][NH:8][C:9]([NH2:11])=[O:10])=O.N>P(Cl)(Cl)(Cl)=O>[CH3:1][CH:2]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:15]=1)[CH2:3][NH:4][C:5]1[O:10][C:9]([NH2:11])=[N:8][N:7]=1
Reactant: CC(CNC(=O)NNC(N)=O)COc1cccc(CN2CCCCC2)c1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(CNc1nnc(N)o1)COc1cccc(CN2CCCCC2)c1
Temperature: 0 °C

Procedure:
7 mmol of N-[2-Methyl-3-[3-(1-piperidinylmethyl)phenoxy]propyl]-1,2-hydrazine dicarboxamide in 30 ml of phosphorus oxychloride are stirred for 6 hours at 50°-60° C. When cooled, the reaction mixture is poured out on 300 ml of ice water and neutralized by the addition of concentrated ammonia solution with cooling. The product is extracted with ether and the combined ether extracts are washed, dehydrated and concentrated by evaporation. The solid residue is recrystallised from ether.
Reaction SMILES: I[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].C([C:14]1[S:18][C:17](C2SC(NC(=O)C)=NC=2C)=[CH:16][CH:15]=1)=O.[F-].[K+].CC1(C)C(C)(C)OB(C2C=CSC=2)O1>C1(C)C=CC=CC=1.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]>[CH3:11][C:3]1[N:4]=[C:5]([NH:7][C:8](=[O:10])[CH3:9])[S:6][C:2]=1[C:16]1[CH:15]=[CH:14][S:18][CH:17]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C=O)s2)s1
Reactant: CC(=O)Nc1nc(C)c(I)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC1(C)OB(c2ccsc2)OC1(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nc(C)c(-c2ccsc2)s1
Temperature: 120 °C
Yield: 66 %

Procedure:
In a microwave tube, N-(5-iodo-4-methyl-1,3-thiazol-2-yl)acetamide, Intermediate 1 (564.2 mg; 2 mmol; 1 eq.) and Pd(dppf)Cl2 (73.2 mg; 0.10 mmol; 0.05 eq.) are suspended in Toluene (7 ml). A solution of potassium fluoride (464.8 mg; 8 mmol; 4 eq.) in MeOH (7 ml) is added. 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene (630.3 mg; 3 mmol; 1.50 eq.) is finally added as a solid. The resulting solution is flushed with argon, the tube is closed and heated under microwave action at 120° C. for 15 minutes. The reaction mixture is filtered over Celite and the solvents are evaporated. The resulting crude product is dissolved in EtOAc, washed with water and brine and dried over MgSO4. It is then purified by preparative HPLC, affording Compound (19) as white-off solid (316.7 mg; 66% yield). 1H NMR (DMSO-d6) δ 2.12 (s, 3H), 2.35 (s, 3H), 7.28 (dd, J=1.5, 4.9 Hz, 1H), 7.58 (dd, J=1.5, 3.0 Hz, 1H), 7.67 (dd, J=3.0, 4.9 Hz, 1H), 12.09 (s, 1H). M−(ESI): 237.03; M+(ESI): 239.03. HPLC, Rt: 2.92 min (purity: 99.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[CH:17][CH:16]=1.[OH-].[Na+].Cl>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)=[CH:19][CH:20]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCOCC4)cc3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCN4CCOCC4)cc3)cc12

Procedure:
A solution of methyl 6-chloro-5-{4-[3-(morpholin-4-yl)propoxy]phenyl}-1H-indole-3-carboxylate (24 mg, 0.056 mmol) in methanol (0.5 mL) and 1M sodium hydroxide (0.17 mL, 0.17 mmol) was heated at 75° C. for 24 hours. The reaction was acidified with 1M HCl to pH=2 then diluted with ethyl acetate. The layers were separated and the aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using reverse-phase chromatography to give the title compound as the formic acid salt. MS (ES+) 415.129 (M+H)±Retention time: 2.2 min; Waters Atlantis dC18 5 μm 4.6×50 mm, 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. (0.05% TFA) Flow: 2.0 mL/min.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:23][CH2:24][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:27])[CH3:26])=[C:15]([N+:20]([O-])=O)[CH:16]=[N:17]2)=[CH:12][CH:11]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pt].C(#N)C>[NH2:20][C:15]1[CH:16]=[N:17][C:18]2[C:13]([C:14]=1[NH:23][CH2:24][C:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:26])[CH3:27])=[CH:12][CH:11]=[C:10]([O:9][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:19]=2
Reactant: CC(C)(CNc1c([N+](=O)[O-])cnc2cc(OC(=O)c3ccccc3)ccc12)NC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(CNc1c(N)cnc2cc(OCc3ccccc3)ccc12)NC(=O)OC(C)(C)C
Yield: 98.6 %

Procedure:
tert-Butyl [2-(7-benzoyloxy-3-nitroquinolin-4-ylamino)-1,1-dimethylethyl]carbamate (6.74 g), 5% platinum on carbon (1.02 g), and acetonitrile (125 mL) were combined. The mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen. The reaction was filtered through CELITE filter agent and the filtrate was concentrated under reduced pressure to give 6.04 g of tert-butyl [2-(3-amino-7-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]carbamate as an orange foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]#[N:11].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1>>[Cl:12][C:13]1[N:18]=[C:17]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]#[N:11])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: N#CCCc1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Product: N#CCCc1ccccc1Nc1nc(Cl)ncc1Cl

Procedure:
3-[2-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-propionitrile was prepared from 3-(2-Amino-phenyl)-propionitrile and 2,4,5-Trichloro-pyrimidine in an analogous manner to Example 1230a. Title product was isolated as an off white solid (554 mg, 94%), MP: 115-116, LCMS 293.10 (M+H), HPLC purity: 92%, 1H-NMR (CDCl3, 400 MHz) δ:8.24 (s, 1H), 7.48-7.45 (m, 1H), 7.39-7.36 (m, 3H), 7.19 (bs, 1H), 2.98 (t, J=7.2 Hz, 2H), 2.71 (t, J=7.2 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[O:12])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:25])[N:6]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[OH2:33]>C(Cl)Cl>[CH2:14]([NH:13][C:11](=[O:33])[OH:12])[CH3:15].[NH2:1][C:2]1[N:10]=[C:9]([C:11]([NH:13][CH2:14][CH:15]2[CH2:17][CH2:16]2)=[O:12])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:25])[N:6]2[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O
Agent: Nc1nc(C(=O)NCC2CC2)nc2c1[nH]c(=O)n2Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6-Amino-9-benzyl-N-(cyclopropylmethyl)-8-oxo-8,9-dihydro-7H-purine-2-carboxamide (Example 1, 50 mg, 0.15 mmol) was taken up in 2 ml DCM under a nitrogen atmosphere at room temperature and firstly triethylamine (103 μl, 0.74 mmol) and then N-ethyl isocyanate (47 μl, 0.59 mmol) were added in one portion each and the whole stirred at room temperature for 24 h. The mixture was poured into water (5 ml) and extracted with DCM (3×2 ml). The combined organics were dried over MgSO4 and concentrated in vacuo to a yellow residue which was purified by column chromatography using a gradient of 1:1 DCM:EtOAc→EtOAc as the eluant. Combination and evaporation of the appropriate fractions provided the title compound as a white solid (16 mg).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([F:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.FC1C(F)=C(F)C(F)=CC=1C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][C:51]([CH3:54])([CH3:53])[CH3:52])[N:43]=1.NC(=C)C([O-])=O>C(Cl)(Cl)Cl>[C:51]([NH:50][C:44]1[N:43]=[C:42]([N:41]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[F:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[C:47]([F:48])=[CH:46][C:45]=1[F:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC(C)(C)Nc1nc(N)c(F)cc1F
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Agent: C=C(N)C(=O)[O-]
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2F)c2c(F)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To 1 ml chloroform solution of ethyl 3-ethoxy-2-(2,3,4,5-tetrafluorobenzoyl)acrylate prepared from 0.27 g of ethyl 2,3,4,5-tetrafluorobenzoylacetate by normal process was added 2-amino-6-(t-butylamino)-3,5-difluoropyridine until completion of the conversion into the aminoacrylate form was confirmed by monitoring the reaction by TLC. The solution was concentrated under reduced pressure. To the residue were added 0.6 g of anhydrous potassium carbonate and 1 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 0.15 g of the title compound as a colorless powder.