Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[NH2:19][C:20]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:30][C:27]1[CH:28]=[CH:29][C:20]([NH:19][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COC(=O)c1cc(F)ccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COC(=O)c1cc(F)ccc1NC(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 69.1 %

Procedure:
The product is prepared according to the procedure described in example 5, using 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 303 mg of methyl 2-amino-5-fluorobenzoate and 308 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of dimethylformamide. 310 mg of methyl 5-fluoro-2-({[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetyl}amino)benzoate are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:13][CH:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:15]([OH:19])[C:16](O)=[O:17])=[O:12].[CH3:31][O:32][NH2:33]>>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9](=[O:10])[CH2:8][CH2:7][C@@H:6]1[C:11]([NH:13][CH:14]([CH:15]([OH:19])[C:16]([NH:33][O:32][CH3:31])=[O:17])[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:12]
Reactant: O=C(O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1Cl
Reactant: CON
Product: CONC(=O)C(O)C(Cc1ccccc1)NC(=O)[C@H]1CCC(=O)N1Cc1ccccc1Cl

Procedure:
The reaction can be carried out in analogy to reaction step 1.3 by reacting 3-((R)-1-(2-chlorobenzyl)-5-oxopyrrolidine-2-carboxamido)-2-hydroxy-4-phenylbutanoic acid with O-methylhydroxylamine.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH2:64])[S:61][C:51]=2[C:52]([N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[N:53][CH:54]=1>C1COCC1>[CH3:47][O:48][C:49]1[C:50]2[N:63]=[C:62]([NH:64][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:8]=3)[S:61][C:51]=2[C:52]([N:55]2[CH2:56][CH2:57][O:58][CH2:59][CH2:60]2)=[N:53][CH:54]=1
Reactant: O=C(O)c1cccc(N2CCOCC2)c1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)c3cccc(N4CCOCC4)c3)nc12

Procedure:
From 3-morpholin-4-yl-benzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 456 (M+H+, 100).
Reaction SMILES: [CH2:1]([C@H:8]1[NH:12][C:11](=[O:13])[C@@H:10]([CH2:14][CH2:15][C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CCOC(C)=O>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][N:12]1[C@H:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C@H:10]([CH2:14][CH2:15][C:16]2([CH3:21])[O:20][CH2:19][CH2:18][O:17]2)[C:11]1=[O:13])[CH3:43]
Reactant: CCOC(=O)CBr
Reactant: CC1(CC[C@H]2C[C@@H](Cc3ccccc3)NC2=O)OCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CN1C(=O)[C@@H](CCC2(C)OCCO2)C[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 12-3 (210 mg, 0.7257 mmol) and THF (5 mL) at −78° C. was added NaN(TMS)2 (0.943 mL, 0.943 mmol, 1.0 M in THF). After 30 min, ethyl bromoacetate (0.104 mL, 0.9434 mmol) was added and the reaction was warmed to 0° C. After 1.0 hour, the reaction mixture was diluted with EtOAc and then washed with sat NaHCO3, brine, dried (MgSO4), and concentrated to give 12-4 as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:16])[NH:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:16])[N:11]([CH3:17])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]cc(Br)cc1OCc1ccccc1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(Br)cc(OCc2ccccc2)c1=O
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 3-(benzyloxy)-5-bromopyridin-2(1H)-one (4.4 g, 15.71 mmol) in DMF (50 mL) was added Cs2CO3 (6.65 g, 20.42 mmol) then iodomethane (1.2 mL, 19.19 mmol) at RT. After stirring overnight the mixture was concentrated. The residue was taken up in H2O and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column (Biotage-SNAP-100 g, 50% EtOAc/hexanes) gave the title compound (3.61 g, 78%) as a white solid. 1H NMR (500 MHz, CDCl3): δ 7.43-7.30 (m, 5 H); 7.05 (d, J=2.4 Hz, 1 H); 6.69 (d, J=2.4 Hz, 1 H); 5.24 (s, 0 H); 5.10 (s, 2 H); 3.55 (s, 3 H). LC/MS (M+H)+ 294/296.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][C:11]([CH3:13])=[CH:10][C:9]=2[CH:14]=1)=[NH:4].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21](O)=O)[CH3:16].ONC(=N)C1C=CC(OC(C)C)=C(I)C=1.ClC1C=C(C=CC=1OCCC)C(O)=O>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]4[O:12][C:11]([CH3:13])=[CH:10][C:9]=4[CH:14]=3)[N:4]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Reactant: Cc1cc2cc(C(=N)NO)ccc2o1
Agent: CC(C)Oc1ccc(C(=N)NO)cc1I
Agent: CCCOc1ccc(C(=O)O)cc1Cl
Product: CCOc1ccc(-c2nc(-c3ccc4oc(C)cc4c3)no2)cc1OCC
Yield: 6 %

Procedure:
The product Step A was converted to N-hydroxy-2-methylbenzofuran-5-carboximidamide by method described for Example 36, Step A. When N-hydroxy-2-methylbenzofuran-5-carboximidamide and 3,4-diethoxybenzoic acid were substituted for N-hydroxy-3-iodo-4-isopropoxybenzimidamide and 3-chloro-4-propoxybenzoic acid, respectively, in Example 36, Step B, the similar procedure afforded the title compound in 6% yield, as colourless solid. 1H-NMR (CDCl3) 8.28 (bs, 1H); 8.00 (dd, 1H, J=8.55, 1.68 Hz); 7.8 (dd, 1H, J=8.4, 1.98 Hz); 7.68 (d, 1H, J=1.92 Hz); 7.47 (d, 1H, J=8.58 Hz); 6.97 (d, 1H, J=8.46 Hz); 6.45 (s, 1H); 4.23-4.16 (m, 4H); 2.48 (3H); 1.52-1.47 (m, 6H).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:11](=[O:14])([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[C:2]1([C:1]2[S:8][C:2]([CH2:3][CH2:4][CH:11]=[O:14])=[CH:1][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: NC(=S)c1ccccc1
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: O=CCCc1cnc(-c2ccccc2)s1

Procedure:
A solution of ethyl formyl β chloracetate in 240 ml of benzene was added to a suspension of 78 g of thiobenzamide in 200 ml of benzene and the mixture was refluxed for 3 hours 30 minutes while eliminating the water formed. The reaction medium was cooled and 320 ml of a 20% solution of potassium carbonate and 220 ml of water were added slowly. Extraction was carried out with ether, followed by washing, drying and distillation under reduced pressure to obtain 75.5 g of the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].C(N(CC)CC)C.[CH3:35][O:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:35][O:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41][C:1]([C:4]2[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]3[N:18]=[C:17]([N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[N:21]=[CH:20]4)[CH:16]=[CH:15][N:14]=3)[CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:2])=[CH:39][CH:38]=1
Reactant: COc1ccc(N)cc1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2cccc([C@H](C)Nc3nccc(-n4cnc5ccccc54)n3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.7 %

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (28.9 mg) was dissolved in CH2Cl2 (2 mL), then triethylamine (55 μL) was added followed by 4-methoxyaniline (62 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53.4 mg) and 4-dimethylaminopyridine (˜1 mg). The mixture was stirred at room temperature for 18 h then directly eluted on silica gel column (1-4% MeOH:CH2Cl2) to yield 19.7 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.45 (br s, 1H); 8.37 (d, J=5.5 Hz, 1H); 7.99 (s, 1H); 7.88 (s, 1H); 7.80 (d, J=6.2 Hz, 1H); 7.75 (d, J=7.5 Hz, 1H); 7.62 (d, J=7.8 Hz, 1H); 7.49 (m, 3H); 7.33 (m, 2H); 6.90 (d, J=8.9 Hz, 2H); 6.77 (d, J=5.5 Hz, 1H); 5.87 (br s, 1H); 5.26 (br s, 1H); 3.81 (s, 3H); 1.65 (d, J=6.8 Hz, 3H). Mass Spectrum (ESI): m/e 465.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:35])=O.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([Cl:35])=[O:5]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)ccc1-c1ccccc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCc1cc(-c2nc(-c3ccc(C(=O)Cl)c(F)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.2 %

Procedure:
To a solution of example 35 (2 170 mg; 5.2 mmol) in dry DCM (40 mL), oxalyl chloride (1 316 μl; 15.6 mmol) was added followed by dry DMF (40 μl). The reaction mixture was stirred at RT for 2 h and concentrated to afford 2-fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride as a white powder (2300 mg, 100%). In dry THF (1 mL) with a catalytic amount of DMF was swelled morpholinomethyl polystyrene high loading resin (NovaBiochem; 35.77 mg; 0.14 mmol), 3.9 mmol/g). 2-Fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride (25 mg; 0.06 mmol) was added followed by sarcosine methyl ester hydrochloride (15.98 mg; 0.11 mmol). The mixture was stirred overnight at rt. Isocyanate resin Si—NCO (Argonaut, 97 mg; 1.5 eq; 1.7 mmol/g) was added and the mixture stirred for 2 h. It was filtered through a SAX column (2 g) to obtain the title compound as a colorless oil. LC/MS (Method B): 504.2 (M+H)+ HPLC (Method A) Rt: 5.39 min (purity: 97%).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=1.C(N(CC)CC)C>ClCCl>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([NH:14][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH:1]([CH3:3])[CH3:2])=[CH:16][C:17]=1[C:23]([F:24])([F:25])[F:26])#[N:20]
Reactant: CC(C)Oc1ccccc1C(=O)Cl
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)Oc1ccccc1C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
2-Isopropoxy-benzoyl chloride was condensed with 4-Amino-2-trifluoromethyl benzonitrile in dichloromethane in presence of triethylamine as acid scavenger to yield N-(4-Cyano-3-trifluoromethyl-phenyl)-2-Isopropoxy-benzamide. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:23]([OH:25])=O)=[CH:17]2.[CH2:26]([NH:29][C:30]1[C:31]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[N:32][CH:33]=[CH:34][CH:35]=1)[CH2:27]C>C1COCC1.ClCCl>[CH3:27][CH2:26][NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[N:36]1[CH2:41][CH2:40][N:39]([C:23]([C:18]2[NH:19][C:20]3[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][C:16]=3[CH:17]=2)=[O:25])[CH2:38][CH2:37]1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CCCNc1cccnc1N1CCNCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNc1cccnc1N1CCN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reaction time: 1 h

Procedure:
1,1'-carbonyldiimidazole (0.42 g) is added to a 20°-25° solution of 5-chloroindole-2-carboxylic acid (I, 0.5 g) in THF (5 ml). After 1 hour of stirring at 20°-25°, the above reaction is added dropwise over 10 minutes via cannula to a -10° (ice/acetone bath) solution of [3-(ethylamino)-2-pyridinyl]piperazine (II, 0.58 g) in THF (5 ml). After 30 minutes of stirring at -10°, the reaction is warmed to 20°-25° and stirring is continued for 5 hours. The reaction is diluted with dichloromethane (50 ml), washed with saturated aqueous sodium bicarbonate (40 ml), water (40 ml) and saline (40 ml). The organic layers are dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by flash column chromatography (50 g silica gel), eluting with ethyl acetate/hexane (1/1). The appropriate fractions are pooled and concentrated to give the title compound, mp 208°-209°; IR (mineral oil) 3200, 2920-3000, 1632, and 1425 cm-1 ; NMR (300 MHz, CDCl3) 9.77, 7.72, 7.60, 7.36, 7.22, 6.97, 6.86, 6.75, 4.23, 4.09, 3.23-3.15, and 1.33 δ; MS (m/e) 383, 178, 176, 162, 150, 148, 137, 134, and 120.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:10][CH:9]=[CH:8][C:7]=1[OH:25].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][CH2:29][CH2:28][O:25][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:26])[CH3:35]
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCOc1cccc(C#CCCCCOC2CCCCO2)c1/C=C/C(=O)OC

Procedure:
Using the procedure of example 122, rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester (example 121), was alkylated with ethyl 4-bromobutyrate giving the title compound as a pale-yellow oil, in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[NH:8][C:7](=[S:11])[NH:6][C:5]2=[O:12].[CH3:13]I>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[N:8]=[C:7]([S:11][CH3:13])[NH:6][C:5]2=[O:12]
Reactant: O=c1[nH]c(=S)[nH]n2cc(Br)cc12
Reactant: CI
Solvent: C1CCOC1
Product: CSc1nn2cc(Br)cc2c(=O)[nH]1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Into a round bottom flask, 6-Bromo-2-thioxo-2,3-dihydro-1H-pyrrolo[2,1-f][1,2,4]triazin-4-one (11.20 g, 0.04551 mol), Tetrahydrofuran (200 mL) and Methyl iodide (6.517 mL, 0.1047 mol) were added, respectively. The reaction was stirred at 45° C. for one hour. The solid was filtered. The solvent was removed under vacuum to give a solid. The combined solid was partitioned with water (500 mL) and saturated NaHCO3 (500 mL). The mixture was stirred for 30 minutes. The solid was filtered and washed with water to give 6-Bromo-2-methylsulfanyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one as a white solid (5.80, 49%).
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](O)(=O)[CH3:28].C(=O)C>C1COCC1>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:27][CH3:28])[CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nnc2c(NC3CCNCC3)cc(N(C)Cc3ccccc3)nn12
Reactant: CC(=O)O
Agent: CC=O
Solvent: C1CCOC1
Product: CCN1CCC(Nc2cc(N(C)Cc3ccccc3)nn3c(C)nnc23)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N6-Benzyl-3,N6-dimethyl-N8-piperidin-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (0.05 g; 0.11 mmol) was dissolved in 0.5 ml THF. Acetic acid (0.01 ml; 0.23 mmol), acetaldehyde (0.03 ml; 0.46 mmol) and STAB (0.03 g; 0.15 mmol) were added and stirred at ambient temperature for 3 hours. The crude material was purified by using reversed phase chromatography under basic conditions and afterwards by TLC.
Reaction SMILES: [CH2:1]([N:4]([C:11]1[N:19]=[C:18](Cl)[N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH:21]1[CH2:25][CH2:24][CH2:23][O:22]1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:26][NH2:27]>CO>[CH2:1]([N:4]([C:11]1[N:19]=[C:18]([NH:27][CH3:26])[N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH:21]1[CH2:25][CH2:24][CH2:23][O:22]1)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: CN
Reactant: C=CCN(c1nc(Cl)nc2c1ncn2C1CCCO1)C1CCCCC1
Solvent: CO
Product: C=CCN(c1nc(NC)nc2c1ncn2C1CCCO1)C1CCCCC1
Temperature: 100 °C
Yield: 82 %

Procedure:
A mixture of 8.5 g. (22 mmole) 6-(N-allyl-N-cyclohexylamino)-2-chloro-9-tetrahydrofuran-2-ylpurine and 150 ml. methanol, which has been saturated with methylamine, is heated to 100° C. in an autoclave for 48 hours. The reaction mixture is then evaporated, the residue is taken up in dichloromethane, washed with water, dried and evaporated. After chromatography with dichloromethane, there are obtained 6.4 g. of the title compound (82% of theory) in the form of an oil.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1[CH:7]=[CH:6][N:5]=C1)=[O:2].[NH2:13][C:14]1[N:23]=[C:22]([C:24]([N:26]2[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:27]2)=[O:25])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:35]3[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=3[CH2:43][OH:44])[CH:20]=2)[N:15]=1.C(NCCN)(OC(C)(C)C)=O.Cl.C(=O)(O)[O-]>N1C=CC=CC=1>[NH2:5][CH2:6][CH2:7][NH:3][C:1](=[O:2])[O:44][CH2:43][C:36]1[CH:37]=[C:38]([F:42])[C:39]([F:41])=[CH:40][C:35]=1[C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([NH2:13])[N:23]=[C:22]2[C:24]([N:26]1[CH2:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34]1)=[O:25]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CO)ccc2n1
Agent: CC(C)(C)OC(=O)NCCN
Agent: Cl
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: NCCNC(=O)OCc1cc(F)c(F)cc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
400 mg of 1,1′-carbonyldiimidazole are dissolved in 10 ml of pyridine and cooled to 0° C. A solution of 1.0 g of [2-amino-6-(4,5-difluoro-2-hydroxymethylphenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone dissolved in 10 ml of pyridine is added. The mixture is subsequently stirred at 0° C. for 2 h and at 25° C. for 2 h. 400 mg of N-Boc-ethylenediamine are then added, and the mixture is stirred at 25° C. for a further 18 h. The mixture is added to 250 ml of 1 N HCl and stirred at 25° C. for 3 h, neutralised using bicarbonate solution and washed 3 times with 150 ml of dichloromethane each time. The organic phases are washed twice with 50 ml of water each time, dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue is dissolved in 1 ml of dimethyl sulfoxide and purified by chromatography (reversed phase).
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1.C([O:21]B(OC(C)C)OC(C)C)(C)C.C(O)(=O)C.OO>C1COCC1>[C:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([OH:21])=[CH:8][CH:9]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)Oc1ccc(Br)cc1
Agent: OO
Agent: [Li]C(C)CC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ccc(O)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
Sec-butyllithium (53.2 mmoles, 41 ml of 1.3M in hexane) was added dropwise at -78° C. to 4-bromo-t-butoxybenzene (53.2 mmoles, 12.2 g) in 200 ml THF, stirred at -78° C. for 1 hour, and added slowly to a solution of triisopropylborate (58.5 mmoles, 11.0 g) in 50 ml THF while maintaining the temperature below -60° C. The mixture was allowed to warm gradually to -20° C. Chilled acetic acid (80 mmoles,9.6 ml) was added. Hydrogen peroxide (58.5 mmoles, 5.9 ml of 30% diluted with 5 ml water) was added dropwise over 15 minutes while maintaining the temperature below 0° C. After stirring 10 minutes, the solution was washed with ammonium sulfate solution, dried, and concentrated. The residue was triturated with hexane and filtered to yield 4.2 g of 4-t-butoxyphenol. (MS).
Reaction SMILES: [F-].[K+].C(O[C:6](=[O:15])[C:7](Br)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])C.[SH:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].O>CN(C)C=O>[CH2:11]([O:10][C:8]([C:7]1([CH3:13])[C:6](=[O:15])[NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=2[S:16]1)=[O:9])[CH3:12]
Reactant: Nc1ccccc1S
Reactant: CCOC(=O)C(C)(Br)C(=O)OCC
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1(C)Sc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.6 %

Procedure:
To a suspension of KF (3.016 g, 52 mmoles) in anhydrous dimethyl formamide (14 ml), diethyl-2-bromo-2-methyl-malonate (3.90 ml, 20 mmoles) was added and the mixture was stirred for 15 minutes at room temperature. Subsequently, 2-mercaptoaniline (2.50 g, 20 mmoles) was added and the mixture was stirred for 6 hours at the temperature of 60° C. and overnight at room temperature. The reaction mixture was admixed with a mixture of water and ice (80 ml), the product which separated was filtered off by suction and recrystallized from absolute ethanol. Thus there were obtained 3.80 g (75.7%) of the title product in the form of white crystals, m.p. 109°-111° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([CH3:13])[CH:7]=1.CC(OC(C)=O)=O.C([O-])(=O)C.[K+].[N:29](OC(C)(C)C)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][C:6]1[CH:7]=[C:8]2[C:9](=[CH:10][CH:11]=1)[NH:12][N:29]=[CH:13]2
Reactant: CC(C)(C)ON=O
Reactant: Cc1cc(Oc2cccc(Cl)c2)ccc1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: Clc1cccc(Oc2ccc3[nH]ncc3c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.6 %

Procedure:
4-(3-Chloro-phenoxy)-2-methyl-phenylamine (0.87 g, 3.74 mmol) was dissolved in chloroform. Ac2O (0.878 g, 8.61 mmol) was then added dropwise over 10 min at 0° C. and the mixture was stirred for 1 h at 25° C. Potassium acetate (110 mg, 1.12 mmol) and t-butyl nitrite (829 mg, 8.05 mmol) were added to the reaction mixture and the mixture was heated at 80° C. for 16 h. This mixture was then concentrated, conc. HBr was added and the mixture was stirred for 16 h at 25° C. The pH of the mixture was adjusted to pH 7 using KOH solution and the resulting mixture was extracted with EtOAc (3×50 mL). The organic phase was washed with brine (3×10 mL), dried over sodium sulfate and concentrated. The residue was purified by column chromatography (11% EtOAc in hexanes) to afford 5-(3-chloro-phenoxy)-1H-indazole (152 mg, 17%). MS (M+H)+=245; 1H NMR (CDCl3) δ: 8.03 (s, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.37 (br.s., 1H), 7.21 (d, J=6.18 Hz, 1H), 7.16 (dd, J=6.5, 1.1 Hz, 1H); 7.08 (d, J=5.8 Hz, 1H), 6.93 (br.s., 1H), 6.86 (d, J=6.0 Hz, 1H).