Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[C:3]=1[N+:19]([O-:21])=[O:20].[H-].[Na+].[C:24]([C:28]1[CH:29]=[C:30]([C:34](Cl)=[O:35])[N:31]([CH3:33])[N:32]=1)([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])[N:5]=[C:4]([NH:18][C:34]([C:30]2[N:31]([CH3:33])[N:32]=[C:28]([C:24]([CH3:26])([CH3:25])[CH3:27])[CH:29]=2)=[O:35])[C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: Cc1nc(-c2ccccc2C(F)(F)F)nc(N)c1[N+](=O)[O-]
Reactant: Cn1nc(C(C)(C)C)cc1C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2C(F)(F)F)nc(NC(=O)c2cc(C(C)(C)C)nn2C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-methyl-5-nitro-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-ylamine (150 mg, 0.503 mmol, prepared as described in Example 2, STEP A) in THF (10 mL) was treated with NaH (60.4 mg, 1.51 mmol, 60% dispersion in oil), and the resulting mixture was allowed to stir for 30 min at room temperature. 5-tert-Butyl-2-methyl-2H-pyrazole-3-carbonyl chloride (131 mg, 0.654 mmol) was added as a solution in THF (3 mL). After 15 min, the mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted twice with EtOAc (25 mL). The combined extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 12-g SEPRA Si 50 SPE column (Isco system: Flow rate=15 mL/min; Eluent=EtOAc/hexanes, 1:99 v/v for 10 min, then 1:99 to 1:4 v/v over 40 min) to yield 5-tert-butyl-2-methyl-2H-pyrazole-3-carboxylic acid [6-methyl-5-nitro-2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amide as a colorless glassy solid. 1H-NMR (400 MHz, CDCl3) δ: 9.10 (s, 1H), 7.79-7.86 (m, 2H), 7.60-7.72 (m, 2H), 6.64 (s, 1H), 4.14 (s, 3H), 2.83 (s, 3H), 1.33 (s, 9H). Mass Spectrum (LCMS, APCI pos.): Calculated for C21H21F3N6O3: 463.2 (M+H); Measured: 463.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([CH3:11])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(Br)C=C.C12BC(CCC1)CCC2.[CH2:26]1C[O:29][CH2:28][CH2:27]1.OO>[OH-].[Na+].S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:1]([O:5][C:6](=[O:12])[NH:7][C@H:8]([CH3:11])[CH2:9][O:10][CH2:26][CH2:27][CH2:28][OH:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: C=CCBr
Solvent: O
Product: C[C@H](COCCCO)NC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 4 h
Yield: 56.6 %

Procedure:
(R)-(2-Hydroxy-1-methyl-ethyl)-carbamic acid tert-butyl ester (4.0 g, 22.8 mmol) was dissolved in 50% aqueous sodium hydroxide solution (15 mL) at 0° C. and to the resulting solution was added allylbromide (2.2 mL, 25 mmol) and catalytic amount of tetrabutylammonium hydrogensulfate (0.85 g, 2.5 mmol) at room temperature and stirred for 4 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The organic extracts were dried over anhydrous sodium sulfate and concentrated. The resulting crude allyl ether was dissolved in THF (75 mL) at room temperature and to the resulting solution was added a solution of 9-borabicyclo[3,3,1]nonane in THF (0.5 M, 100 mL, 50 mmol). After 5 hour-stirring, to the resulting solution was added water (8 mL), 3N aqueous sodium hydroxide solution (8.1 mL) and 30% aqueous hydrogen peroxide solution (8.2 mL) at room temperature and warmed to 40° C. followed by stirring for 30 minutes. The organic solvent was removed under reduced pressure and the residue was diluted with brine. Extraction was performed with ethyl acetate and the extracts were dried over magnesium sulfate. After concentration, the residual materials were purified by flash column chromatography on silica gel to afford (R)-[2-(3-hydroxypropoxy)-1-methyl-ethyl]carbamic acid tert-butyl ester (3.0 g, 12.9 mmol, 56%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]([F:6])=[C:3]([F:5])[F:4].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].[OH-].[K+]>CC(C)=O>[F:4][C:3]([F:5])([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH:2]([F:6])[Cl:1]
Reactant: FC(F)=C(F)Cl
Reactant: COC(=O)c1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC(=O)c1cccc(OC(F)(F)C(F)Cl)c1

Procedure:
52.4 Parts by weight of chlorotrifluoroethylene are introduced, over 10 hours, into a mixture of 46.5 parts by weight of methyl 3-hydroxybenzoate and 9.5 parts by weight of potassium hydroxide powder in 50 parts by weight of acetone, refluxing at 45°-52° C. After concentrating the reaction mixture on a rotary evaporator under reduced pressure, the residue is taken up in methylene chloride and the solution is extracted with sodium bicarbonate solution, dried and evaporated, giving 69.5 parts by weight of methyl 3-(1',1',2'-trifluoro-2'-chloroethoxy)-benzoate of nD25 =1.4710.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:12]3)O1.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[N:29]([CH:37]([CH3:39])[CH3:38])[N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([CH:37]([CH3:39])[CH3:38])[N:28]=[C:27]([C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[N:14]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[CH:13]=[CH:12]4)[C:35]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)c2c(N)ncnc21
Temperature: 80 °C
Yield: 9.5 %

Procedure:
A solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (212 mg, 0.61 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (75 mg, 0.25 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O) to yield BA86 (9.3 mg, 9% yield). ESI-MS (M+H)+ m/z calcd 362.1, found 362.0.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]2([CH3:26])[CH2:21][CH2:20][C:19]3[C:14](=[C:15]([CH3:25])[C:16]([CH3:24])=[C:17]([OH:23])[C:18]=3[CH3:22])[O:13]2)=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1.[O:27]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].CCOC(C)=O>C(C#N)(C)=O.C(Cl)Cl.O>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:11])[C:12]([OH:27])([CH3:26])[CH2:21][CH2:20][C:19]2[C:14](=[O:13])[C:15]([CH3:25])=[C:16]([CH3:24])[C:17](=[O:23])[C:18]=2[CH3:22])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCn1ccnc1)O2
Agent: CC(=O)C#N
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCCn2ccnc2)=C(C)C1=O
Reaction time: 0.08 h
Yield: 93.2 %

Procedure:
To a solution of N-(3-(1H-imidazol-1-yl)propyl)-6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamide (100.7 mg, 0.282 mmol) in 6 mL AcCN and 6 mL CH2Cl2, cooled to 0° C., was added a cooled solution of CAN (340 mg, 0.620 mmol) in 2 mL H2O, dropwise over 5 minutes. The reaction was immediately treated with 5 mL EtOAc and washed 3×3 mL H2O. The aqueous layer was basified with 6 mL saturated NaHCO3 solution and extracted 6×3 mL EtOAc. The combined organics were dried over Na2SO4 and concentrated to a yellow oil. Flash chromatography yielded 98.1 mg of N-(3-(1H-imidazol-1-yl)propyl)-2-hydroxy-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6](Cl)=O.[NH2:10][NH:11][C:12]([NH2:14])=[S:13].CS(O)(=O)=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:9])[CH2:4][CH2:5][C:6]1[S:13][C:12]([NH2:14])=[N:11][N:10]=1
Reactant: NNC(N)=S
Reactant: COC(=O)CCC(=O)Cl
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CCc1nnc(N)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Chlorocarbonyl-propionic acid methyl ester (4.4 g, 21 mmol) is added dropwise to a stirred suspension of thiosemicarbazide (4.0 g, 44 mmol) in THF (25 ml) at 0° C. After stirring at room temperature for 18 h the product which precipitates is removed by filtration and washed with diethyl ether. This product (7.1 g, 34 mmol) is suspended in toluene (30 ml) at 0° C. and methane sulfonic acid (3.37 ml, 52 mmol) is added dropwise to the stirred reaction. The reaction is heated at 70° C. for 3 hours then concentrated at reduced pressure. Methanol (30 ml) is added followed by slow addition of aqueous ammonia, with stirring, until the solution is basic. The titled compound which precipitates is removed by filtration and purified by chromatography on silica, eluting with chloroform-methanol (10:1).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=2)[CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=3[S:14][C:13]2=[O:25])=[N:6][CH:7]=1.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.O>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C:2]2[CH:3]=[N:4][C:5]([C:8]3[CH:9]=[C:10]([CH:26]=[CH:27][CH:28]=3)[CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([C:21]([F:24])([F:23])[F:22])[CH:19]=[CH:20][C:15]=4[S:14][C:13]3=[O:25])=[N:6][CH:7]=2)[CH2:32][CH2:31]1
Reactant: CN1CCNCC1
Reactant: O=c1sc2ccc(C(F)(F)F)cc2n1Cc1cccc(-c2ncc(I)cn2)c1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CN1CCN(c2cnc(-c3cccc(Cn4c(=O)sc5ccc(C(F)(F)F)cc54)c3)nc2)CC1
Temperature: 100 °C

Procedure:
513 mg (1 mmol) of 3-[3-(5-iodopyrimidin-2-yl)benzyl]-5-trifluoromethyl-3H-benzothiazol-2-one is suspended in toluene, briefly heated to 100° C. and cooled to room temperature. 134 μl (1.2 mmol) of methylpiperazine, 297 mg (1.4 mmol) of potassium phosphate trihydrate, and 33 mg (0.08 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and 18 mg (0.02 mmol) of tris(benzylideneacetone)dipalladium are subsequently added and stirred at 100° C. under an argon atmosphere. 33 mg (0.08 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl and 18 mg (0.02 mmol) of tris(benzylideneacetone)dipalladium are subsequently again added and stirred at 100° C. for a further 24 h under an argon atmosphere. Water is added to the reaction mixture, which is then extracted with ethyl acetate and dried. The crude product is purified by means of preparative HPLC. The product is in the form of the trifluoroacetate.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([Cl:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1=O>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:38]4[CH2:39][CH:36]([NH:35][CH3:34])[CH2:37]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([Cl:30])=[CH:9][C:8]=1[F:31]
Reactant: CNC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(Cl)cc1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4Cl)c3c2Cl)C1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
To 300 mg of N,N-dimethylformamide were added 103 mg of 1-(6-amino-3-chloro-5-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 85 mg of 3-methylaminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidone, and the mixture was stirred at 85° C. for 30 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 98 mg of the title compound as a colorless powder.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[S:6][CH3:7])([O-:3])=[O:2].[CH2:10]([NH:14][CH3:15])[CH2:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[CH2:10]([N:14]([C:5]([S:6][CH3:7])=[CH:4][N+:1]([O-:3])=[O:2])[CH3:15])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNC
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: Cc1ccccc1
Product: CCCCN(C)C(=C[N+](=O)[O-])SC

Procedure:
A solution of 8.26 g (0.05 mol) of 1-nitro-2,2-di(methylthio)ethylene and 5.25 g (0.06 mol) of N-n-butyl-N-methylamine in toluene is refluxed for 2 hours. After evaporation of the toluene under vacuum, 10.2 g of 2-(N-butyl-N-methylamino)-2-methylthio-1-nitroethylene are isolated as an oil (nD21 =1.584). (Compound 2.1, Table 2).
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](/[CH3:25])=[CH:15]/[C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]O)[CH3:28]>>[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][O:21][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][C:16](/[CH:15]=[C:14](/[C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:26])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=3[CH:7]=2)\[CH3:25])=[CH:17][CH:18]=1)[CH3:28]
Reactant: C/C(=C\c1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCN(CC)CCO
Product: CCN(CC)CCOC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner analogous to that described in Example 11, from p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid and 2-diethylamino-ethanol there can be obtained p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-benzoic acid 2-diethylamino-ethyl ester of melting point 65°-66° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH:27]=O)=[CH:26][C:4]=2[N:3]=1.C(OP([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])(OCC)=O)C>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=3[CH3:22])=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25](/[CH:27]=[CH:37]/[C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:26][C:4]=2[N:3]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc(CCc2cnc3c(N)nc4cc(C=O)ccc4c3c2)c(C)c1
Product: CCOC(=O)/C=C/c1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC)cc3C)cc12

Procedure:
(E)-ethyl 3-(5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)acrylate was prepared from 5-amino-2-(4-methoxy-2-methylphenethyl)benzo[f][1,7]naphthyridine-8-carbaldehyde (from Example 69) and ethyl 2-(diethoxyphosphoryl)acetate (commercially available) following the procedures described for Example 65/Step 3. LRMS [M+H]=442.2
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[CH2:15][C:16]([OH:18])=[O:17].[CH3:19][CH2:20]O>>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCO
Reactant: O=C(O)Cc1cc([N+](=O)[O-])ccc1Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)Cc1cc([N+](=O)[O-])ccc1Cl
Yield: 99 %

Procedure:
Thionyl chloride (16.7 g, 0.14 mol) was added dropwise to a 0° C. solution of (2-chloro-5-nitro-phenyl)acetic acid (15 g, 0.07 mol) in EtOH (300 mL) and the resultant mixture was heated at reflux overnight. The reaction mixture was concentrated under reduced pressure and the residue was poured into ice water, and extracted with EtOAc (2×300 mL). The combined organics were washed with brine and saturated NaHCO3 solution, were dried over Na2SO4, and were concentrated in vacuo to give ethyl 2-(2-chloro-5-nitrophenyl)acetate (17 g, 99% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.35 (d, J= 2.8 Hz, 1 H), 8.12 (dd, J=8.4, 2.8 Hz, 1 H), 7.72 (d, J=8.4 Hz, 1 H), 4.10 (q, J=7.2 Hz, 2 H), 3.96 (s, 2 H), 1.15 (t, J=7.2 Hz, 3 H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]2)=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:20][S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOCC>[CH:17]([N:14]1[CH2:15][CH2:16][N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:2]([O:28][C:25]3[CH:26]=[CH:27][C:22]([S:21][CH3:20])=[CH:23][CH:24]=3)=[C:3]([CH:6]=2)[CH:4]=[O:5])[CH2:12][CH2:13]1)([CH3:19])[CH3:18]
Reactant: CSc1ccc(O)cc1
Reactant: CC(C)N1CCN(Cc2ccc(F)c(C=O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CSc1ccc(Oc2ccc(CN3CCN(C(C)C)CC3)cc2C=O)cc1
Temperature: 90 °C
Yield: 107.7 %

Procedure:
A mixture of 2-fluoro-5-(4-isopropyl-piperazin-1-ylmethyl)-benzaldehyde (513.7 mg, 1.943 mmol), 4-methylsulfanyl-phenol (326.8 mg, 2.138 mmol), and K2CO3 (845.2 mg, 5.829 mmol) in DMF (9.0 mL) was heated at 90° C. for 3 days. After cooling to rt, the mixture was diluted with Et2O, washed with 1 N NaOH and brine, dried (Na2SO4), and concentrated. Purification by FCC followed by reverse phase chromatography gave the desired product (804.5 mg, >100%). MS (ESI): mass calcd. for C22H28N2O2S, 384.19; m/z found, 385.3 [M+H]+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][C:20](=[O:35])[N:21]2[C@H:24]2[C:33]3[C:28](=[C:29]([F:34])[CH:30]=[CH:31][CH:32]=3)[O:27][CH2:26][CH2:25]2)=[CH:17][N:16]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>>[NH2:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[NH:14][C:15]1[N:23]=[C:22]2[C:18]([NH:19][C:20](=[O:35])[N:21]2[C@H:24]2[C:33]3[C:28](=[C:29]([F:34])[CH:30]=[CH:31][CH:32]=3)[O:27][CH2:26][CH2:25]2)=[CH:17][N:16]=1
Reactant: COc1ccc(CNc2cc(F)ccc2Nc2ncc3[nH]c(=O)n([C@@H]4CCOc5c(F)cccc54)c3n2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(F)ccc1Nc1ncc2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-2-(2-(2,4-dimethoxybenzylamino)-4-fluorophenylamino)-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-one (14 mg) and TFA (1 mL) was stirred for 60 min when triethyl silane (0.5 mL) was added. The resulting solution was stirred at RT for 16 hr, then the solvents were reduced in vacuo to yield (R)-2-(2-amino-4-fluorophenylamino)-9-(8-fluorochroman-4-yl)-7H-purin-8(9H)-one that was used as such.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[C:21]([Zn]C#N)#[N:22]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([C:14]#[N:15])[CH:16]=[C:17]([C:21]#[N:22])[CH:18]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: N#C[Zn]C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 120 °C
Yield: 77.8 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.355 g, 0.998 mmol) was combined with dicyanozinc (0.100 g, 0.852 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.115 g, 0.100 mmol) in DMF (3 mL) and heated at 120° C. for 25 min in a microwave reactor under an inert atmosphere. The reaction mixture was diluted with EtOAc, washed twice with saturated aqueous NaHCO3 and twice with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in CH3OH and gravity filtered through a StratoSpheres™ PL-Thiol MP SPE+ cartridge. The filtrate was concentrated to dryness and purified on 40 g silica gel eluted successively with EtOAc and 10% CH3OH/DCM to give 5-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-1,3-benzenedicarbonitrile (0.200 g, 0.663 mmol, 66.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (s, 1H), 7.91 (s, 2H), 7.46-7.57 (m, 2H), 3.77 (s, 2H), 1.90 (br. s., 2H). LC-MS (ES+) m/z 302.27, 304.19 [M+H].
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].C(N(CC)CC)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>ClCCl>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH:1][C@@H:2]2[C:7]3[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=3[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]2[OH:16])=[O:30])=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=O)c2ccc(Cl)cc2)[C@@H]1O
Reaction time: 1.5 h

Procedure:
To a stirred solution of trans-4-amino-6cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-ol (1.0 g), triethylamine (0.64 mL) and dichloromethane was added 4-chlorobenzoyl chloride (0.55 mL). The solution was stirred for a further 1.5 hours. The solution was washed with water and brine and dried over anhydrous magnesium sulphate. The solution was filtered and evaporated and recrystallised from ethyl acetate--60-80° petroleum ether as a white solid of mp 226-229° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8].Br[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10]([C:12]2[C:17]([NH:18][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:16][CH:15]=[C:14]([CH3:19])[N:13]=2)=[O:11])=[N:6][C:7]=1[CH3:8]
Reactant: Brc1cccnc1
Reactant: Cc1ccc(N)c(C(=O)Nc2ccc(F)c(C)n2)n1
Agent: [Pd]
Product: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ccc(F)c(C)n2)n1

Procedure:
The title compound was prepared from 3-tert-Butoxy-carbonylamino-6-methyl-pyridine-2-carboxylic acid methyl ester in accordance with the general method of example 4; step 2 using 2-amino-5-fluoro-6-methylpyridine (Sanchez & al., J. Heterocycl. Chem. 24, 215(1987); CAS:[110919-71-6]) instead of 2-chloro-4-aminopyridine to yield [2-(5-Fluoro-6-methyl-pyridin-2-ylcarbamoyl)-6-methyl-pyridin-3-yl]-carbamic acid tert-butyl ester, white solid, MS (ISP): m/e=361.0 (M+H+). Boc-deprotection as described in example 4 step 3 yielded 3-Amino-6-methyl-pyridine-2-carboxylic acid (5-fluoro-6-methyl-pyridin-2-yl)-amide, white solid, MS (ISP): m/e=261.3 (M+H+). Palladium catalysed arylation with 3-Bromopyridine as described in example 4 step 4 yielded the final product as a yellow solid, (ISP): m/e=338.1 (M+H+).
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][N:8]([S:20](=[O:30])(=[O:29])[NH:21]C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[S:20]([N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:7][C:6]([OH:31])=[O:5])(=[O:30])(=[O:29])[NH2:21]
Reactant: COC(=O)Cc1ccccc1N(CC(=O)OC(C)(C)C)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccccc1N(CC(=O)O)S(N)(=O)=O
Reaction time: 0.5 h

Procedure:
The title D compound, N-(t-butoxycarbonyl-sulfamoyl)-N-[2-(methoxycarbonyl-methyl)-phenyl]-glycine t-butyl ester (1.87 g, 4.07 mmol) is dissolved in a mixture of TFA (35 mL) and CH2Cl2 (35 mL) and stirred for 30 min. The reaction is concentrated in vacuo, then triturated with diethyl ether to yield N-sulfamoyl-N-[2-(methoxycarbonylmethyl)-phenyl]glycine as a clear glass.