Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][N:6]([C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]([O:13]CC)=[O:12])[C:5]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:4]=2[O:3]1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1([CH3:24])[CH2:7][N:6]([C:8](=[O:16])/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[C:5]2[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:4]=2[O:3]1
Reactant: CCOC(=O)/C=C/C(=O)N1CC(C)(C)Oc2ccc([N+](=O)[O-])cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CN(C(=O)/C=C/C(=O)O)c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
In 2 ml of ethanol was dissolved 0.5 g of ethyl trans-4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4yl)-4-oxo-2-butenoate followed by addition of 1.5ml of an aqueous solution of 0.06 g of sodium hydroxide. The mixture was stirred at room temperature for 2 hours. The ethanol was distilled off under reduced pressure and the residue was adjusted to pH 4 with 1N hydrochloric acid. The resulting precipitate was recovered by filtration and washed with water and ethanol to give 0.31 g of trans-4-(3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)-4-oxo-2-butenoic acid.
Reaction SMILES: [C:1]([CH:4]([C:10](=O)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:3])[CH3:2].[CH3:13][Mg]Br.C(OC(=O)C)(=O)C>CCOCC>[C:10](=[C:4]([C:1]([CH3:2])=[O:3])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:11])[CH3:13]
Reactant: C[Mg]Br
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Solvent: CCOCC
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C(C)=O)=C(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
To a solution of ethyl diacetyl-acetate maintained at 5°-10° [which can be prepared according to the method described in Helv. Chim. Acta, 35, 2280 (1952)] in 400 ml of anhydrous ether there were added 110 ml (0.33 mole) of a solution of 3 M methyl-magnesium bromide in ether. The reaction mixture was stirred for 24 hours at room temperature. After cooling, 50 ml of acetic acid anhydride were added and the whole was allowed to stand for 2 hours at room temperature, whereupon it was poured into ice-water. After separation, the organic phase was washed with a 5 % aqueous solution of NaOH, then with water, whereupon it was dried (Na2SO4) and concentrated. The subsequent distillation of the residue yielded 16.1 g (63 %) of ethyl α-isopropylidene-acetoacetate, b.p. 94°-98° /8 Torr. A pure sample was obtained by purification of the said product by chromatography on a colum (silica gel and benzene) followed by vapour phase chromatography.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.[CH:21]1[C:26](O)=[CH:25][CH:24]=[C:23]([CH3:28])[CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:1][C:26]3[CH:25]=[CH:24][C:23]([CH3:28])=[CH:22][CH:21]=3)[CH2:10][CH2:9][C:8]=2[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: Cc1ccc(O)cc1
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccc(C)cc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (103 mg), p-cresol (118 mg) and triphenylphosphine (121 mg) in THF (2 ml) was added a solution of diethyl azodicarboxylate (87 mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 hr and then concentrated in vacuo. The residue was purified by alumina column chromatography (ethyl acetate:hexane=1:10) and then with recrystallization from duisopropylether-hexane to obtain the entitled compound (80 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH2:12].[C:13](Cl)(=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1
Reactant: Cc1nc2c(Cl)c(N)ccc2s1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)Nc2ccc3sc(C)nc3c2Cl)c1
Yield: 84 %

Procedure:
Reaction of 4-chloro-2-methyl-benzothiazol-5-ylamine (50 mg, 0.25 mmol) in THF (1.5 mL) with m-anisoyl chloride (41 μL, 0.30 mmol) in presence of triethylamine (42 μL, 0.30 mmol) according to method A gave N-(4-chloro-2-methyl-benzothiazol-5-yl)-3-methoxy-benzamide (70 mg, 0.21 mmol, 84% yield) as a orange powder after crystallisation in hexane/DCM.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[N:18]([CH3:24])[N:17]=2)=[CH:12][CH:11]=1>CCOCC.CO.C(Cl)Cl>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:20]=[C:19]([C:21]([O:23][CH3:1])=[O:22])[N:18]([CH3:24])[N:17]=2)=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ccc(-c2cc(C(=O)O)n(C)n2)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nn1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Trimethylsilyldiazomethane (1.75 mL of a 2 M soln in Et2O, 3.49 mmol) was added to a stirred solution of 3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylic acid (0.507 g, 2.182 mmol) in dry MeOH (2.2 mL) and dry CH2Cl2 (19.6 mL) at 25° C. under N2. The reaction was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo to afford methyl 3-(4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carboxylate, as a colorless solid. LCMS calc.=247.11. found=247.03 (M+H)+. 1H NMR (600 MHz, CDCl3): δ 7.71 (d, J=8.5 Hz, 2H); 7.04 (s, 1H); 6.93 (d, J=8.5 Hz, 2H); 4.21 (s, 3H); 3.90 (s, 3H); 3.83 (s, 3H).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([O:7][C:8]([C:10]1[CH:27]=[CH:26][C:13]2[S:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][C:18]=3[CH3:25])=[CH:16][C:12]=2[CH:11]=1)=[O:9])[CH3:6].O.C(Cl)(=O)C>ClCCl.C(OCC)(=O)C>[CH2:5]([O:7][C:8]([C:10]1[CH:27]=[CH:26][C:13]2[S:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=3[CH3:25])=[CH:16][C:12]=2[CH:11]=1)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1ccc2sc(-c3ccc(OC)cc3C)cc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2sc(-c3ccc(O)cc3C)cc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 43.4 %

Procedure:
A 0° C. solution of boron tribromide (1M in dichloromethane, 1.29 mmol; 1.29 mL) is added under nitrogen atmosphere to a solution of 2-(4-methoxy-2-methyl-phenyl)-benzo[b]thiophene-5-carboxylic acid ethyl ester (1.07 mmol; 350 mg) in anhydrous dichloromethane (4.00 mL) and the mixture is stirred at room temperature for 4 h. Water and ethyl acetate are added. The aqueous layer is separated and the organic layer is dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue is dissolved in ethanol (5 mL) and acetyl chloride (3.48 mmol, 0.25 mL) is added. The mixture is stirred at reflux for 5 h. The solvent is removed and the residue is chromatographed (5-20% EtOAc in hexanes) to yield the title compound (145 mg, 40%) as a white solid. LC-ES/MS m/e 313 (M+1).
Reaction SMILES: BrCCBr.[Mg].[CH3:6][N:7]1[CH2:12][CH2:11][CH:10](Cl)[CH2:9][CH2:8]1.[F:14][C:15]1[CH:31]=[CH:30][C:18]2[N:19]3[CH2:29][CH2:28][C:27]4[C:20]3=[C:21]([CH:24]=[CH:25][CH:26]=4)[CH:22]=[N:23][C:17]=2[CH:16]=1>O1CCCC1>[F:14][C:15]1[CH:31]=[CH:30][C:18]2[N:19]3[CH2:29][CH2:28][C:27]4[C:20]3=[C:21]([CH:24]=[CH:25][CH:26]=4)[CH:22]([CH:10]3[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]3)[NH:23][C:17]=2[CH:16]=1
Reactant: CN1CCC(Cl)CC1
Reactant: Fc1ccc2c(c1)N=Cc1cccc3c1N2CC3
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CN1CCC(C2Nc3cc(F)ccc3N3CCc4cccc2c43)CC1
Temperature: 5 °C
Reaction time: 0.67 h

Procedure:
In a dried 1 L three-necked flask, 1,2-dibromoethane (0.5 ml) was added to a refluxing slurry of magnesium chips (6.3 gm) in tetrahydrofuran (50 ml) to initiate a Grignard reaction. The mixture became cloudy and a vigorous reaction ensued. A solution of N-methyl-4-chloropiperidine (37 ml) in tetrahydrofuran (40 ml) was added in portions to maintain a fast reflux over a period of 10 minutes. The resultant slurry was refluxed for 1.5 hours and thereafter cooled to about 5° C. with an ice-water bath. A solution of 9-fluoro-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepine (15.7 gm) in tetrahydrofuran (70 ml) was added in 5 minutes. The mixture was stirred for 40 minutes.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[Li+].[Cl-].[CH2:13]([Sn](CCCC)(CCCC)CCCC)[CH:14]=[CH2:15]>C1(C)C=CC=CC=1.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>[CH2:15]([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1)[CH:14]=[CH2:13]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: N#Cc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCc1ccc(C#N)c(F)c1

Procedure:
To a solution of 4-bromo-2-fluorobenzonitrile (5.0 g, 13 mmol) in 100 ml of toluene was added LiCl (1.7 g, 39 mmol), Pd(PPh3)4 (400 mg), Allyl tributyltin (5.2 g, 16 mmol), and then the mixture was heated to reflux overnight. After the reaction was completed, the reaction solution was diluted with EtOAc and filtered. The filtrate was concentrated and purified with silica gel column chromatograph to give crude 4-allyl-2-fluorobenzonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Oc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Oc2ccc(F)cc2)cc1
Yield: 140.3 %

Procedure:
To a solution of 6.0 g of 4-fluorophenol (manufactured by TOKYO CHEMICAL INDUSTRIES, LTD.) in 60 ml of chloroform were added 6 ml of triethylamine and a solution of 4.0 g of 4-methoxybenzoyl chloride (manufactured by TOKYO CHEMICAL INDUSTRIES, LTD.) in 40 ml of chloroform, and the mixture was stirred at 55° C for 1 hour. The reaction solution was separated by adding to it 100 ml of dichloromethane, 200 ml of water, and 25 ml of a 1N aqueous solution of sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and then concentrated to obtain 8.1 g of the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11](O)=O)=[CH:2]1.[CH3:14][N:15]1[CH:19]=[C:18]([C:20]2[N:25]=[N:24][C:23]([NH:26][NH2:27])=[CH:22][CH:21]=2)[CH:17]=[N:16]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:14][N:15]1[CH:19]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]3[N:24]([C:11]([CH2:10][C:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:1][CH:2]=4)=[N:27][N:26]=3)[N:25]=2)[CH:17]=[N:16]1
Reactant: Cn1cc(-c2ccc(NN)nn2)cn1
Reactant: O=C(O)Cc1c[nH]c2ncccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1cc(-c2ccc3nnc(Cc4c[nH]c5ncccc45)n3n2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 3.1 %

Procedure:
To a 20 ml vial 52 mgs (0.295 mmol) of (1H-pyrrolo[2,3-b]pyridine-3-yl)-acetic acid, 1.2 eq. (0.354 mmol) of 0-(7-azabenzotriazole-1-yl)-N,N,N,N′-tetramethyluroniumhexafluoro-phosphate, 1.5 eq. (0.443 mmol) [6-(1-methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-hydrazine and 4 eq. (1.18 mmol) N,N-diisopropylethylamine were added and dissolved in 4 mls of dimethyl-formamide. The reaction mixture was stirred at room temperature for 18 h. After such time the dimethylformamide was removed in vacuo and acetic acid (4 mls) was added to the residue and heated to 60° C. for 4 hours. The solvent was removed in vacuo purification via preparative HPLC eluting with dichloromethane:methanol 95:5 returned the title compound (3 mgs, 3% yield) as an off white solid. Analytical data presented in Table 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:43])[CH2:42][C:5]2[C:6]3[CH2:11][CH2:10][NH:9][CH:8]([C:12]4[C:13]([CH2:39][OH:40])=[C:14]([C:19]5[CH:20]=[C:21]([NH:27][C:28]6[CH:37]=[CH:36][C:35]7[CH2:34][N:33]([CH3:38])[CH2:32][CH2:31][C:30]=7[N:29]=6)[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=5)[CH:15]=[C:16]([F:18])[CH:17]=4)[C:7]=3[S:41][C:4]=2[CH2:3]1.Br[C:45]1C=C(NC2C=CC3CN(CC)CCC=3N=2)C(=O)N(C)C=1>>[CH3:1][C:2]1([CH3:43])[CH2:42][C:5]2[C:6]3[CH2:11][CH2:10][NH:9][CH:8]([C:12]4[C:13]([CH2:39][OH:40])=[C:14]([C:19]5[CH:20]=[C:21]([NH:27][C:28]6[CH:37]=[CH:36][C:35]7[CH2:34][N:33]([CH2:38][CH3:45])[CH2:32][CH2:31][C:30]=7[N:29]=6)[C:22](=[O:26])[N:23]([CH3:25])[CH:24]=5)[CH:15]=[C:16]([F:18])[CH:17]=4)[C:7]=3[S:41][C:4]=2[CH2:3]1
Reactant: CN1CCc2nc(Nc3cc(-c4cc(F)cc(C5NCCc6c5sc5c6CC(C)(C)C5)c4CO)cn(C)c3=O)ccc2C1
Reactant: CCN1CCc2nc(Nc3cc(Br)cn(C)c3=O)ccc2C1
Product: CCN1CCc2nc(Nc3cc(-c4cc(F)cc(C5NCCc6c5sc5c6CC(C)(C)C5)c4CO)cn(C)c3=O)ccc2C1
Yield: 28 %

Procedure:
Using the same general procedure as described for the preparation of 240, reaction of 5-bromo-3-(6-ethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ylamino)-1-methylpyridin-2(1H)-one (143 mg, 0.394 mmol) with 182c (300 mg, 0.513 mmol) gave a 28% yield (70 mg) of 241 as a yellow solid: mp 134-135° C.; 1H NMR (500 MHz, DMSO-d6) d 8.78 (d, 1H, J=2.0 Hz), 8.43 (s, 1H), 7.44 (d, 1H, J=2.0 Hz), 7.31 (dd, 1H, J=9.5, 2.5 Hz), 7.28 (d, 1H, J=8.0 Hz), 7.18 (dd, 1H, J=9.5, 2.5 Hz), 7.06 (d, 1H, J=8.0 Hz), 4.86 (m, 1H), 4.38 (m, 2H), 4.04 (m, 1H), 3.84 (m, 1H), 3.59 (s, 3H), 3.43 (s, 2H), 3.03 (m, 1H), 2.89 (m, 1H), 2.75 (s, 4H), 2.62 (m, 2H), 2.53 (m, 2H), 2.50 (m, 2H), 1.23 (s, 6H), 1.08 (t, 3H, J=7.0 Hz); MS (ESI+) m/z 628 (M+H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[N:13](COCC[Si](C)(C)C)[CH:12]=1)=[O:10])[CH2:5][O:6][CH3:7].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][CH:4]([NH:8][C:9]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[N:22]([CH3:30])[N:21]=3)[N:18]=2)[NH:13][CH:12]=1)=[O:10])[CH2:5][O:6][CH3:7]
Reactant: COCC(COC)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Product: COCC(COC)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 62.4 %

Procedure:
In a sealed 25 mL round-bottom flask, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-methoxy-1-methoxymethyl-ethyl)-amide (40 mg, 0.071 mmol) and TFA (0.6 ml, 7.8 mmol) were combined with dichloromethane (2 ml) to give an orange solution. The reaction mixture was stirred at room temperature until the consumption of starting material (2.5 h). The reaction mixture was then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (2 mL) and ethylenediamine (400 μl, 5.9 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (hexanes/dichloromethane/EtOAc) to afford 19 mg (62%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-methoxy-1-methoxymethyl-ethyl)-amide as an off-white solid. MS: [M+H]+=429; 1H NMR (300 MHz, DMSO-d6) δ: 12.88 (br. s., 1H), 9.13 (s, 1H), 8.55 (d, J=8.7 Hz, 1H), 8.46 (s, 1H), 8.30 (d, J=9.1 Hz, 1H), 8.01 (s, 1H), 7.25 (dd, J=8.7, 1.1 Hz, 1H), 4.33-4.67 (m, 1H), 4.18 (s, 3H), 3.61 (dd, J=9.8, 5.3 Hz, 2H), 3.56 (dd, J=9.4, 5.3 Hz, 1H), 3.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[N:7]=[C:8]([C:10](=[O:21])[NH:11][C:12]([CH3:20])([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[S:9][C:5]=2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=1.[S:29]1[CH:33]=[CH:32][C:31]([C:34](Cl)=[O:35])=[CH:30]1.[Cl-].[Na+]>N1C=CC=CC=1.O1CCCC1>[CH3:13][C:12]([NH:11][C:10]([C:8]1[S:9][C:5]2[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[N:3]=[C:2]([NH:1][C:34]([C:31]3[CH:32]=[CH:33][S:29][CH:30]=3)=[O:35])[C:6]=2[N:7]=1)=[O:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:20]
Reactant: O=C(Cl)c1ccsc1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)n1nc(NC(=O)c2ccsc2)c2nc(C(=O)NC(C)(C)c3ccccc3)sc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 28.9 %

Procedure:
0.20 g (0.50 mmol) of tert-butyl 3-amino-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate dissolved in 5 ml of pyridine is placed in a 50 ml round-bottomed flask under argon. A solution of 0.07 g (0.50 mmol) of thiophene-3-carbonyl chloride (prepared according to FR 2 411 188) in 2.0 ml of tetrahydrofuran is then added dropwise and the mixture is stirred for 15 hours at 25° C. The reaction medium is then concentrated to dryness under reduced pressure (40° C.) and the residue is taken up in 30 ml of dichloromethane and 30 ml of water, and basified with 0.1N sodium hydroxide solution. The emulsion obtained is resorbed by saturation with sodium chloride. After separation of the phases by settling, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is purified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.074 g of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-[(thiophene-3-carbonyl)amino]-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a cream-coloured foam. 0.14 g of an impure batch is also obtained, and is repurified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.013 g of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-[(thiophene-3-carbonyl)amino]-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a cream-coloured foam, along with 0.11 g of an impure batch, which is repurified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.04 g of tert-butyl 5-(1-methyl-1-phenylethylcarbamoyl)-3-[(thiophene-3-carbonyl)amino]-1H-pyrazolo[4,3-d]thiazole-1-carboxylate is thus obtained in the form of a cream-coloured foam. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.62 (s, 9H); 1.71 (s, 6H); 7.20 (t, J=7.5 Hz, 1H); 7.30 (t, J=7.5 Hz, 2H); 7.41 (d, J=7.5 Hz, 2H); 7.70 (d, J=2.0 Hz, 2H); 8.50 (t, J=2.0 Hz, 1H); 8.70 (s, 1H); 11.25 (s, 1H). LC-MS-DAD-ELSD: 510(−)=(M−H)(−); 512(+)=(M+H)(+).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([C:12]2[N:17]=[N:16][C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:14][CH:13]=2)[CH3:11])=[O:8])=[CH:4][CH:3]=1.NC(C1N=NC(NC2C=CC(OC)=CC=2)=NC=1)C.[Br:45]C1C=CSC=1C(O)=O>>[Br:45][C:4]1[CH:3]=[CH:2][S:6][C:5]=1[C:7]([NH:9][CH:10]([C:12]1[N:17]=[N:16][C:15]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[N:14][CH:13]=1)[CH3:11])=[O:8]
Reactant: COc1ccc(Nc2ncc(C(C)NC(=O)c3ccc(Br)s3)nn2)cc1
Reactant: O=C(O)c1sccc1Br
Agent: COc1ccc(Nc2ncc(C(C)N)nn2)cc1
Product: COc1ccc(Nc2ncc(C(C)NC(=O)c3sccc3Br)nn2)cc1
Reaction time: 6.5 h

Procedure:
In a similar manner as described for Intermediate 48, using 6-(1-aminoethyl)-N-[4-(methyloxy)phenyl]-1,2,4-triazin-3-amine (Intermediate 47) (100 mg, 0.41 mmol), and 3-bromothiophene-2-carboxylic acid (93 mg, 0.45 mmol), except the reaction was stirred for 6.5 h and purification using silica SPE was omitted, to give 3-bromo-N-[1-(3-{[4-(methyloxy)phenyl]amino}1,2,4-triazin-6-yl)ethyl]-2-thiophenecarboxamide (162 mg) as a yellow solid. MS m/z 434/436 (M+1).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([O:15][CH3:16])=[CH:7][CH:6]=1)=[NH:4].[C:17]([C:21]1[O:25][N:24]=[C:23]([NH:26][C:27](=[O:38])[NH:28][C:29]2[CH:37]=[CH:36][C:32]([C:33](O)=O)=[CH:31][CH:30]=2)[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>COCCOCCOC>[C:17]([C:21]1[O:25][N:24]=[C:23]([NH:26][C:27]([NH:28][C:29]2[CH:37]=[CH:36][C:32]([C:33]3[O:1][N:2]=[C:3]([C:5]4[C:14]5[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=5)[C:8]([O:15][CH3:16])=[CH:7][CH:6]=4)[N:4]=3)=[CH:31][CH:30]=2)=[O:38])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(C(=O)O)cc2)no1
Reactant: COc1ccc(C(=N)NO)c2ccccc12
Solvent: COCCOCCOC
Product: COc1ccc(-c2noc(-c3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)n2)c2ccccc12

Procedure:
N-Hydroxy-4-methoxy-naphthalene-1-carboxamidine (1 g) and 4-[3-(5-tert-Butyl-isoxazol-3-yl)-ureido]-benzoic acid (1 eq) were reflued in diglyme (5 mL) for 24 h and then purified to give 100 mg of 1-(5-tert-Butyl-isoxazol-3-yl)-3-{4-[3-(4-methoxy-naphthalen-1-yl)-[1,2,4]oxadiazol-5-yl]-phenyl}-urea.
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[C:19]2[CH:20]=[C:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][N:28]=[C:27]([NH:32][C:33]4[CH:38]=[C:37]([CH3:39])[C:36]([F:40])=[C:35]([O:41][CH3:42])[CH:34]=4)[N:26]=3)[CH:22]=[CH:23][C:18]=2[O:17][C:16]1=[O:43])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].CC(O)=O>O>[P:1]([OH:8])([OH:3])([O:13][CH2:14][N:15]1[C:19]2[CH:20]=[C:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][N:28]=[C:27]([NH:32][C:33]4[CH:38]=[C:37]([CH3:39])[C:36]([F:40])=[C:35]([O:41][CH3:42])[CH:34]=4)[N:26]=3)[CH:22]=[CH:23][C:18]=2[O:17][C:16]1=[O:43])=[O:2]
Reactant: COc1cc(Nc2ncc(C)c(Nc3ccc4oc(=O)n(COP(=O)(OC(C)(C)C)OC(C)(C)C)c4c3)n2)cc(C)c1F
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(Nc2ncc(C)c(Nc3ccc4oc(=O)n(COP(=O)(O)O)c4c3)n2)cc(C)c1F
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To the crude di-tert-butyl (5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl phosphate, was added HOAc (280 mL) and H2O (70 mL), the resultant light brown homogeneous solution was stirred at 65° C. (note: a lighter color ppt was formed between 15-45 min). The reaction was monitored by LC-MS. After 1 h, the mixture was cooled to rt, ppt was collected by filtration, washing with H2O (˜50 mL×2). Product (5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)-2-oxobenzo[d]oxazol-3(2H)-yl)methyl dihydrogen phosphate was obtained as a light pinkish beige color solid and was used directly in salt formation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18]CC4C=CC=CC=4)[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][N:37]3[CH3:42])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1>C(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][N:37]3[CH3:42])=[CH:29][CH:28]=2)=[CH:4][CH:3]=1
Reactant: CN1CCCCC1CCOc1ccc(CC2c3ccc(OCc4ccccc4)cc3CCN2c2ccc(F)cc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CN1CCCCC1CCOc1ccc(CC2c3ccc(O)cc3CCN2c2ccc(F)cc2)cc1
Yield: 13.9 %

Procedure:
The title compound was prepared as described in Example 44.G, using 2-(4-fluorophenyl)-1-(4-[2-(1-methyl(2-piperidyl))ethoxy]benzyl)-6-(phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline (0.043 g, 0.076 mmol). The product was purified by radial chromatography (100% CH2Cl2, then CH2Cl2/MeOH, 95:5) to yield the title compound (0.005 g, 14 % yield): ES-MS (m/z) 475 [M+H]+.