Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20](=[O:29])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=O)C=1.[NH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1.C(OCC)(=O)C>C(Cl)(Cl)Cl>[N:41]1([C:3]2[N:8]=[C:7]([NH:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=3)[C:6]([C:20](=[O:29])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[CH:5][N:4]=2)[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1
Reactant: C1CNCCN1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)NCc2ccccn2)cc1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(CNc2nc(N3CCNCC3)ncc2C(=O)NCc2ccccn2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyridylmethyl)carbamoyl]pyrimidine (prepared in Example 80) 150.0 mg in chloroform 5.0 ml is treated with m-chloroperbenzoic acid (80%) 85.6 mg at 0° C. for 30 minites. Piperazine 0.263 g is added thereto and the mixture is stirred at room temperature overnight. To the reaction mixture is added ethyl acetate and an aqueous saturated sodium hydrogen carbonate solution, and the organic layer is separated. The organic layer is washed with an aqueous saturated sodium hydrogen carbonate solution, water and a saturated brine, dried over anhydrous sodium sulfate, filtered and then concentrated in vacuo. The residue is purified with silica gel chromatography (solvent; ethyl acetate) to give 2-(1-pyperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyridylmethyl)carbamoyl]pyrimidine as a colorless amorphous solid, 128.4 mg.
Reaction SMILES: C(OC([N:8]1[CH2:38][CH2:37][CH2:36][C@H:9]1[C:10]([O:12][CH2:13][C@H:14]1[O:18][C@@H:17]([N:19]2[CH:26]=[C:25]([F:27])[C:23](=[O:24])[NH:22][C:20]2=[O:21])[CH2:16][C@@H:15]1[O:28][CH2:29][C:30]1[S:34][C:33]([Cl:35])=[CH:32][CH:31]=1)=[O:11])=O)(C)(C)C>Cl.O1CCOCC1>[ClH:35].[Cl:35][C:33]1[S:34][C:30]([CH2:29][O:28][C@@H:15]2[C@@H:14]([CH2:13][O:12][C:10](=[O:11])[C@@H:9]3[CH2:36][CH2:37][CH2:38][NH:8]3)[O:18][C@@H:17]([N:19]3[CH:26]=[C:25]([F:27])[C:23](=[O:24])[NH:22][C:20]3=[O:21])[CH2:16]2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccc(Cl)s1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OCc1ccc(Cl)s1)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1.21 g of 5'-O-[N-(t-butoxycarbonyl)-L- prolyl]-3'-O-(5-chloro-2-thenyl)-2'-deoxy-5-fluorouridine prepared in Example 27 was added 20 ml of 4N hydrochloric acid-dioxane, and the mixture was stirred at room temperature for 30 minutes.
Reaction SMILES: C(C1C=CC(S([N:14]2[C:18]3=[N:19][CH:20]=[C:21]([NH:23][NH2:24])[N:22]=[C:17]3[CH:16]=[CH:15]2)(=O)=O)=CC=1)(C)(C)C.CCN(C(C)C)C(C)C.[CH:34]1([C:40](Cl)=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.O=S(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH:34]1([C:40]2[N:22]3[C:17]4[CH:16]=[CH:15][NH:14][C:18]=4[N:19]=[CH:20][C:21]3=[N:23][N:24]=2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)n2ccc3nc(NN)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: c1cc2c(ncc3nnc(C4CCCCC4)n32)[nH]1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
To a solution of 5-(4-tert-butylphenylsulfonyl)-2-hydrazinyl-5H-pyrrolo[2,3-b]pyrazine (0.39 g, 1.1 mmol; Preparation #3) and DIEA (0.20 mL, 1.1 mmol) in 1,4-dioxane (12 mL) at about 0° C. was added cyclohexanecarbonyl chloride (0.17 g, 1.1 mmol). The reaction was then warmed to ambient temperature for about 1 h. SOCl2 (0.41 mL, 5.6 mmol) was added and the reaction was heated to about 90° C. for about 1 h. The reaction was cooled to ambient temperature and aqueous Na2CO3 (2 M, 12 mL, 24 mmol) was added slowly followed by 1,4-dioxane (5 mL). The reaction was heated at about 60° C. for about 72 h. The reaction was cooled to ambient temperature and concentrated under reduced pressure. The crude product was diluted with EtOAc (40 mL) and washed with saturated aqueous NaHCO3 (40 mL) and brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with a gradient of 0-100% heptane/EtOAc (12 g column) and dried in a vacuum oven at about 55° C. for about 18 h to give 1-cyclohexyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (0.109 g, 40%): LC/MS (Table 2, Method a) Rt=1.66 min; MS m/z: 242 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([C:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].[CH3:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CN(C)C=O>[CH3:3][C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:7]([CH:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:24][C:25]2[CH:32]=[CH:31][CH:30]=[C:27]([CH3:28])[CH:26]=2)[CH2:10]1)=[O:8]
Reactant: Cc1cccc(CBr)c1
Reactant: Cc1ccc(C(=O)c2c[nH]c3ccccc3c2=O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(CN2CC(C(=O)c3ccc(C)c(C)c3)C(=O)c3ccccc32)c1

Procedure:
Compound 4m was prepared following the procedure outlined in Step 3 of Example 1 using 16 mg (0.4 mmol) of sodium hydride (60%), 86 mg (0.31 mmol) of 3-(3,4-dimethyl-benzoyl)-2,3-dihydro-1H-quinolin-4-one 3a, 3 mL of anhydrous dimethylformamide, and 74.0 mg (0.40 mmol) of 3-methylbenzylbromide. The crude product 4m was purified by flash chromatograph to yield 55 mg of colorless solid: LC-MSD, m/z for C26H23NO2, [M+H]+: 382.5, [M+H]+: 383.5; Reverse phase HPLC (gradient acetonitrile 0.1% TFA 20-95% in 4 min) retention time=2.628 min; 1H NMR (400 MHz, CDCl3/HCl): δ 2.3-2.4 (t, 9H), 5.4 (s, 2H), 7.0 (d, 2H), 7.12 (d, 1H), 7.18 (d, 1H), 7.25 (d, 1H), 7.4 (t, 2H), 7.58 (m, 2H), 7.65 (s, 1H), 8.26 (s, 1H), 7.48 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[N:25]1>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][N:25]=2)=[O:34])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2n[nH]c3ccccc23)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1H-Indazole-3-carboxylic acid. LC-MS (basic): tR=0.87 min; [M+H]+=492.3.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:9]=1)[CH2:3][OH:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH3:1][C:2]([CH3:22])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:9]=1)[CH:3]=[O:4]
Reactant: CC(C)(CO)COCc1ccc(F)c(Cc2ccccc2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C=O)COCc1ccc(F)c(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 2,2-dimethyl-3-(3-benzyl-4-fluorobenzyloxy)-propan-1-ol (from the previous Example) in dichloromethane (15 cm3) was added dropwise to a stirred suspension of pyridinium chlorochromate (5.13 g) in dichloromethane (40 cm3) whilst the reaction temperature was maintained within the range 0°-5° C. When the addition was complete the mixture was allowed to warm to the ambient temperature (ca 25° C.) over a period of two hours, and left to stir for 14 hours. Diethyl ether was then added to the reaction mixture, and the whole was flushed through a plug of silica gel using diethyl ether as eluent. Evaporation of the solvent under reduced pressure gave a green oil which was subjected to column chromatography through silica gel using petroleum ether (boiling range 40°-60° C.) containing diethyl ether (10% by volume) as eluent, to give 2,2-dimethyl-3-(3-benzyl-4-fluorobenzyloxy)propan-1-al (1.40 g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:11]([C:12]2[S:13][C:14]3[CH2:15][N:16]([CH3:21])[CH2:17][CH2:18][C:19]=3[N:20]=2)[N:10]=[C:9]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[S:8]1)=[N+]=[N-].Cl.CO>CO.[Pd]>[F:29][C:23]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=1[C:9]1[S:8][C:7]([CH2:6][CH2:5][CH2:4][NH2:1])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:11]([C:12]2[S:13][C:14]3[CH2:15][N:16]([CH3:21])[CH2:17][CH2:18][C:19]=3[N:20]=2)[N:10]=1
Reactant: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN=[N+]=[N-])c3ccccc3)sc2C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCCN)c3ccccc3)sc2C1
Reaction time: 1 h

Procedure:
To a solution of 2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (0.046 g, 0.090 mmol) in 2 mL of methanol was added 1N HCl/MeOH (0.27 mL, 0.27 mmol) followed by 10% Pd/C (10 mg). The mixture was hydrogenated under a balloon atmosphere for 1 hour then filtered through GF paper, and the filtrate concentrated in vacuo. The residue was triturated with diethyl ether, filtered, washed with ether and dried in vacuo to afford the desired product as a bright yellow solid, 0.027 g, 50%. MS ESI (+) m/z 486 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.59 (m, 1H), 7.45 (d, 2H, J=7.6 Hz), 7.32 (m, 2H), 7.26 (m, 1H), 7.06 (m, 2H), 3.50 (m, 2H), 3.43 (m, 1H), 2.77 (t, 2H, J=6.9 Hz), 2.68 (m, 2H), 2.56 (m, 2H), 2.46 (s, 3H), 2.41 (m, 1H), 1.99 (m, 1H), 1.55 (m, 1H) ppm.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])=[C:4]([CH3:17])[CH:3]=1.[OH-].[Na+].Cl[C:21]([F:26])([F:25])C(O)=O>CN(C=O)C.O.C(OCC)(=O)C>[F:25][CH:21]([F:26])[O:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:12])=[O:13])=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Reactant: O=C(O)C(F)(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(OC(F)F)c([N+](=O)[O-])cc1S(=O)(=O)N(C)C
Temperature: 120 °C
Reaction time: 18 h
Yield: 21.3 %

Procedure:
To a solution of 4-hydroxy-2-methyl-5-nitro(N,N-dimethyl)benzenesulfonamide (200 mg, 0.77 mmol) in dry DMF (2 mL) was added sodium hydroxide (74 mg, 1.85 mmol) and chlorodifluoroacetic acid (120 mg, 0.92 mmol). The resulting reaction mixture was stirred at 120° C. for 18 h. After cooling, the reaction was diluted with water and ethyl acetate, and the layers were separated. The organics were washed three times with 1 N NaOH, dried and concentrated. The residue was purified by flash chromatography (20% ethyl acetate/hexanes) to provide 4-difluoromethoxy-2-methyl-5-nitro (N,N-dimethyl)-benzenesulfonamide (51 mg, 21%) as a yellow solid, mp 125-126° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:14]=[C:13]3[C:9]([N:10]=[CH:11][N:12]3[CH:15]([CH3:17])[CH3:16])=[C:8](Cl)[N:7]=2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[NH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>CC(O)C>[S:1]1[CH:5]=[C:4]([C:6]2[N:14]=[C:13]3[C:9]([N:10]=[CH:11][N:12]3[CH:15]([CH3:17])[CH3:16])=[C:8]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:7]=2)[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: NCCc1ccc(O)cc1
Reactant: CC(C)n1cnc2c(Cl)nc(-c3csc4ccccc34)nc21
Solvent: CC(C)O
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(-c3csc4ccccc34)nc21
Temperature: 85 °C

Procedure:
2-(benzo[b]thiophen-3-yl)-6-chloro-9-isopropyl-9H-purine (2.2 g, 0.0067 mol) was suspended in anhydrous 2-propanol (70 mL) in a pressure tube. Tyramine (1.01 g, 0.0074 mol) was added. The tube was sealed and heated at 85° C. for 16 hr. Additional tyramine (0.50 g, 0.0037 mol) was added and the mixture was heated at 85° C. for 48 hr. The reaction was concentrated. Aqueous sodium bicarbonate solution was added to the residue, which was extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with 50 to 85% EtOAc in hexane to afford a solid. The solid was triturated with methanol to provide the title compound as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)C(=O)C1.[NH2:36][C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][N:38]=1.CCOCC>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:38]3[CH:39]=[CH:40][CH:41]=[C:42]([F:43])[C:37]3=[N:36][C:9]=2[C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cc1ccnc(Cl)n1)c1cccc(C(=O)Nc2c(F)cccc2F)c1
Reactant: Nc1ncccc1F
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3c(F)cccn3c2-c2ccnc(Cl)n2)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
To a stirred solution of 3-[(2-chloro-4-pyrimidinyl)acetyl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1, step B) (4.0 g, 10.34 mmol) in DCM (103 mL) at rt under N2 was added NBS (1.84 g, 10.34 mmol). The reaction was stirred approximately 30 min, then concentrated under vacuum to a foam like solid. The solid was dissolved in dioxane (103 mL) and 2-amino-3-fluoropyridine (3.47 g, 31.0 mmol) was added. The reaction was stirred under N2, heated to 80° C., and stirred for approximately 40 h, then cooled to rt. The reaction was diluted with EtOAc (200 mL) and half-saturated aqueous NaHCO3 (150 mL). The organic layer was separated and washed with brine. The combined aqueous layers were extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give a yellow solid. The solid was dissolved in minimal DCM and ether was added until a precipitate formed. The slurry was filtered, washing the solids with cold ether. The solids were dried under vacuum to give the title compound of step A (1.58 g, 3.29 mmol, 32%) as a white solid. MS (ESI): 480 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:8])([F:9])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)[C:14]([C:17]([NH2:18])=[O:34])=[N:15][CH:16]=1
Reactant: CC(=O)O
Reactant: COc1ccc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C#N)cc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: COc1ccc(Nc2nc(N[C@@H]3CCCC(F)(F)[C@@H]3N)cnc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(4-methoxyphenylamino)pyrazine-2-carbonitrile (43 mg, 0.115 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (32 mg). MS 393.3 (M+H); UV 206.0, 251.1, 297.8 nm; t 0.471 min.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].CS(O[CH:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:23]3[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(Cc2ccc(O)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(Cc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc2)CC1
Temperature: 140 °C
Yield: 96.3 %

Procedure:
In a microwave vial, 4-[(4-acetylpiperazin-1-yl)methyl]phenol (1.0 g, 4.3 mmol)—see EP 50298—, tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.0 g, 4.0 mmol) and Cs2CO3 (1.5 g, 4.6 mmol) together with DMF (10 mL) was added. The mixture was heated in a microwave oven at 140° C. for 60 minutes. Water (40 mL) was added and the suspension was extracted with twice with EtOAc (50 mL). The combined organic phases were washed with brine, dried (Na2CO3) and the solvent was removed by evaporation. The residue was co-evaporated with toluene. There was obtained 1.5 g (68%) of 23A.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]3=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[F:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[CH:31][C:32]=1[F:33]>>[F:26][C:27]1[CH:28]=[C:29]([NH:34][C:35](=[O:36])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[C:15]4[C:11]([CH2:12][N:13]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[C:14]4=[O:17])=[CH:10][CH:9]=3)=[CH:6][CH:7]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: O=C=Nc1ccc(F)c(F)c1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)c(F)c4)cc3)cc2C1=O

Procedure:
The compound of example 31 was prepared analogous to compound of example 7 by reaction of compound of example 6 with 3,4-difluorophenyl isocyanate. The compound of example 31 was used directly without isolation for the preparation of compound of example 32.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:37])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:31](=[C:32]([F:36])[CH:33]=[CH:34][CH:35]=3)/[C:21](=[C:22](\[C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: Clc1ccc(I)cc1
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2cccc(F)c2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccc(Cl)cc3)c3c(F)cccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-4-iodo-benzene (commercially available) and 3-{[(3-fluoro-phenyl)-(3-phenyl-propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (300 Hz, CDCl3): δppm 4.97 (s, 2H), 6.39-6.51 (m, 2H), 7.25-7.45 (m, 11H), 7.53 (d, 1H), 7.99 (d, 1H), 8.00 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>CN(C)C=O.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:29][C:30](=[O:31])[N:32]([CH3:34])[CH3:33])[C:8]2[C:13]([C:14]=1[CH2:15][C:16]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccccc2c1Cc1cccc2ccccc12
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Cc2cccc3ccccc23)c2ccccc2n1CC(=O)N(C)C
Reaction time: 1 h

Procedure:
To as solution of 3-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (46 mg, from Example 64.2.) in dimethylformamide (1 ml) was added 8 mg of NaH (55% in oil) and stirring was continued at 22° C. for 1 h. The mixture was treated with a solution of 2-chloro-N,N-dimethylacetamide (18 mg) in dimethylformamide (0.5 ml) and stirring was continued for 16 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with ethylacetate. The organic layer was washed with brine, dried, evaporated and the residue chromatographed on silica (n-heptane/AcOEt, 3:2) to give 1-dimethylcarbamoylmethyl-3-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester as a colorless solid, MS: 415.4 ([M+H]+), which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless solid. MS: 385.4 ([M−H]−).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][CH2:12][C:13]([C:28]([F:31])([F:30])[F:29])([OH:27])[CH2:14][C:15]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[O:25]C)([CH3:17])[CH3:16])=[CH:3][CH:2]=1.B(Br)(Br)Br.C(Cl)Cl>C(Cl)Cl.CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([NH:11][CH2:12][C:13]([C:28]([F:30])([F:29])[F:31])([OH:27])[CH2:14][C:15]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[OH:25])([CH3:17])[CH3:16])=[CH:3][CH:2]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1ccnc2ccccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(C)(CC(O)(CNc1ccnc2ccccc12)C(F)(F)F)c1cc(F)ccc1O
Yield: 71 %

Procedure:
Analogously to Example 2, 200 mg (0.46 mmol) of 1-(quinolin-4-ylamino)-4-(5-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)pentan-2-ol and 9 ml of 1 M boron tribromide-CH2Cl2 solution are reacted. After chromatography on silica gel with CH2Cl2-methanol (0–15%), 138 mg of product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1N.N([O-])=O.[Na+].C(OC([S-])=[S:18])C.[K+].[N+](=S=C([S-])O)=[N-]>Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[SH:18]
Reactant: Nc1cc(F)ccc1Br
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: Fc1ccc(Br)c(S)c1
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
325 grams of 2-bromo-5-fluoroaniline were dissolved in 300 milliliters of concentrated hydrochloride acid (d = 1.2 grams/ml) and 350 milliliters of water. The mixture was heated to 60° Centigrade and cooled again to 0° Centigrade, whereupon 130 grams of sodium nitrite dissolved in 330 milliliters of water were added dropwise while the temperature was kept below 4° Centigrade. The reaction mixture was then left standing for 30 minutes while stirring and keeping the temperature at 0° centigrade. Then the mixture containing the diazonium compound formed was added at 60° Centigrade to a solution of 330 grams of potassium ethylxanthate in 400 milliliters of water. CAUTION ! At temperature below 60° Centigrade there may be risk of violent explosions due to accumulation of a diazoxanthate. After the addition has been completed the mixture was stirred for 30 minutes at 60° Centigrade, cooled and extracted with ether. The ether phase was separated and washed successively with 2N sodium hydroxide solution and water and evaporated. The residue was dissolved in 1 liter of 96% ethanol, and 400 grams of potassium hydroxide were added cautiously under reflux, whereupon the reaction mixture was refluxed for 18 hours. Water was added and the ethanol evaporated. 600 milliliters of concentrated hydrochloric acid and 50 grams of zink were added and the mixture steam distilled. The distillate was extracted with ether, the ether phase separated, washed with water, dried over anhydrous magnesium sulphate and evaporated. The residue was distilled at 35 mm Hg, whereby 160 grams of 2-bromo-5-fluorothiophenol boiling at 112°-116° Centigrade was obtained.