Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][C@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@@H:16]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:14][C@H:15]1[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:16]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:13])=[CH:5]2
Reactant: CC(C)(C)OC(=O)N[C@H]1c2ccccc2C[C@@H]1N
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.08 h
Yield: 95.6 %

Procedure:
5-Chloroindole-2-carboxylic acid (2.8 g, 14 mmol), tert-Butyl [(1S,2S)-2-amino-2,3-dihydro-1H-inden-1-yl]carbamate (3.47 g, 14 mmol), DIPEA (4.9 ml, 28 mmol) and HOBT (1.89 g, 14 mmol) were dissolved in DCM (100 mL), stirred for 5 mins, then EDCI (3.2 g, 16.7 mmol) was added and the reaction stirred for 3 hours. The volatiles were removed by evaporation under reduced pressure, EtOAc (125 mL) was added and the organic solution washed with water (2×50 mL), brine (50 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound (5.7 g, 93%) as a pale brown foam.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH:31]([CH3:33])[CH3:32]>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:30][CH:31]([CH3:33])[CH3:32])[C:5]=1[O:21][CH3:22]
Reactant: CC(C)CBr
Reactant: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1OCC(C)C
Temperature: 80 °C
Yield: 31.7 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (103 mg, 0.75 mmol) and isobutyl bromide (102 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (30 mg, 32%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([CH:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:22][CH2:23]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Reactant: CCC(Br)CC
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(C(CC)CC)CC3)c2n1

Procedure:
Prepared similarly to Example 35 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 3-bromopentane.
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:18]([N:25]1[CH2:29][C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][C@H:26]1[CH2:38][OH:39])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(N(CC)CC)C>ClCCl>[C:18]([N:25]1[CH2:29][C@H:28]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:27][C@H:26]1[CH:38]=[O:39])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.8 %

Procedure:
To a solution of 1 ml (14.1 mmol) of DMSO in 7 ml of dichloromethane were added 1.48 ml (10.4 mmol) of trifluoroacetic anhydride in 3.5 ml of dichloromethane at −78° C. under a slight stream of argon. After 10 min, 2.35 g (7 mmol) of (2S,4R)-1-Boc-4-[t-butyldimethylsilyloxy]-2-(hydroxymethyl)pyrrolidine, prepared as in Example 171A, in 7 ml of dichloromethane was added to this mixture at the same temperature. The reaction mixture was stirred for 1 hour. To this solution was added 3 ml (21.5 mmol) of triethylamine. The reaction mixture was stirred for 1 hour at −78° C., slowly warmed to room temperature, and concentrated. The residue was chromatographed on silica gel (9:1 hexanes-ethyl acetate to yield 1.08 g (47%) of (2S,4R)-1-Boc-4-[t-butyldimethylsilyloxy]-pyrrolidin-2-aldehyde as an oil:
Reaction SMILES: C[NH:2][C:3](=[NH:5])S.OS(O)(=O)=O.[OH-].[K+].[C:13]([CH2:21][C:22]([O:24]CC)=O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[NH2:5][C:3]1[O:20][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:21][C:22](=[O:24])[N:2]=1
Reactant: CNC(=N)S
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(=O)cc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.2 %

Procedure:
To 9.45 g (0.034M) of methylthiopseudourea H2SO4 is added 40.0 ml of H2O+8.0 g (0.142M) of KOH. With vigorous stirring, 12.0 g (0.0625M) of ethyl benzoylacetate (Aldrich) is also added and the heterogenous mixture allowed to stir at ambient temperature for 18 hours. The resulting solids are filtered and washed very well with H2O followed by ether. The solids are dried at 60° C. in a vacuum oven to yield 7.20 g (61.3 percent) of 2-amino-6-phenyl-1,3-oxazine-4-one. An analytical sample is recrystallized from 95 percent EtOH:DMF to yield 2-amino-6-phenyl-1,3-oxazine-4-one (m.p. 244-246 d).
Reaction SMILES: CN(C)[C:3]([C:5]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)=[O:4].C[Mg]Br.Cl.[O:21]1CC[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[C:10]1([C@@H:8]2[O:7][N:6]=[C:5]([C:3]([C:22](=[O:21])[CH3:23])=[O:4])[CH2:9]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCOC1
Reactant: CN(C)C(=O)C1=NO[C@@H](c2ccccc2)C1
Agent: C[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)C(=O)C1=NO[C@@H](c2ccccc2)C1
Temperature: -15 °C

Procedure:
A solution of (5R)-4,5-dihydro-N,N-dimethyl-5-phenyl-3-isoxazole-carboxamide (i.e. the product of Example 12, Step D) (3.5 g, 16.0 mmol) in a mixture of tetrahydrofuran (5 mL) and toluene (10 mL) was cooled to −15° C., and methyl magnesium bromide (3.0M solution in tetrahydrofuran, 8.8 mL, 26.4 mmol) was added over 1 h at −15° C. Then the reaction mixture was poured over a mixture of 20 g of concentrated hydrochloric acid and 80 g of ice, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 mL), and the combined extract was washed with brine (40 mL) and concentrated under reduced pressure to give 3.2 g of 1-[(5R)-4,5-dihydro-5-phenyl-3-isoxazoyl]ethanone.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5]C=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:28]=[N:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH:8]1([CH2:9][NH:10][C:29]([C:26]2[N:27]=[N:28][C:23]([NH:22][C:20]([N:12]3[CH2:11][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13]3)=[O:21])=[CH:24][CH:25]=2)=[O:31])[CH2:5][CH2:6][CH2:1][CH2:7]1
Reactant: NCCCc1ccccc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1
Agent: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: O=C(NCC1CCCC1)c1ccc(NC(=O)N2Cc3ccccc3C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting cyclopentylmethamine for 3-phenylpropan-1-amine and 6-(isoindoline-2-carboxamido)pyridazine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.00 (t, J=6.1 Hz, 1H), 8.31 (d, J=9.3 Hz, 1H), 8.11 (d, J=9.3 Hz, 1H), 7.41-7.28 (m, 4H), 5.13-4.72 (m, 4H), 3.31-3.16 (m, 2H), 2.22 (p, J=7.3 Hz, 1H), 1.70-1.45 (m, 6H), 1.38-1.20 (m, 2H); MS (ESI(+)) m/e 366 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:21][CH2:20][C:19]3[CH:23]=[CH:24][C:25]([F:27])=[CH:26][C:18]=3[F:17])[CH2:13][CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccc(Br)cc1)C1CCNCC1
Reactant: Fc1ccc(CCBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(c1ccc(Br)cc1)C1CCN(CCc2ccc(F)cc2F)CC1
Yield: 58.5 %

Procedure:
A mixture of 4-(4-bromophenylsulphonyl)piperidine (7.6 g, 0.025 mol), 2,4-difluorophenethyl bromide (8.3 g, 0.38 mol), potassium carbonate (7.5 g, 0.054 mol) and sodium iodide (5.6 g, 0.037 mol) in CH3CN (70 ml) was heated at reflux under nitrogen for 18 h. The reaction mixture was then concentrated and partitioned between water and EtOAc. The organic phase was washed with brine, dried (Na2SO4) and concentrated. Trituration with hexane gave 6.5 g of product as a colourless solid. δH (360 MHz, CDCl3) 1.55-1.75 (2H, m), 1.95-2.05 (4H, m), 2.45-2.55 (2H, m), 2.70-2.75 (2H, m), 2.85-2.95 (1H, m), 3.05-3.10 (2H, m), 6.70-6.85 (2H, m), 7.10-7.15 (1H, m), 7.72 (4H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([CH3:14])[CH:8]=1)[CH3:2].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)[S:24][CH:25]=1.C(C1C=CC(C(N)=S)=CC=1)(C)C.ClCC(CCl)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[S:24][CH:25]=2)=[C:9]([CH3:14])[CH:8]=1)[CH3:2]
Reactant: CC(C)c1ccc(-c2nc(CCl)cs2)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OCC
Agent: CC(C)c1ccc(C(N)=S)cc1
Agent: O=C(CCl)CCl
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(C(C)C)cc3)n2)c(C)c1)OCC

Procedure:
In analogy to the procedure described in example 4 d], [rac]-2-ethoxy-3-(4-hydroxy-3-methyl-phenyl)-propionic acid ethyl ester (example 4 c]) was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-thiazole (prepared from 4-isopropyl-thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in acetonitrile in the presence of cesium carbonate to yield [rac]-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-thiazol-4-ylmethoxy]-3-methyl-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 4 e], to yield [rac]-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-thiazol-4-ylmethoxy]-3-methyl-phenyl}-propionic acid as colorless gum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P].[CH3:9][O:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]([NH:17][NH:18][C:19](=O)[CH3:20])=O)=[CH:13][CH:12]=1>ClC1C=CC=CC=1Cl>[CH3:9][O:10][C:11]1[CH:23]=[CH:22][C:14]([C:15]2[N:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:19]([CH3:20])=[N:18][N:17]=2)=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc(C(=O)NNC(C)=O)cc1
Agent: [P]
Solvent: Clc1ccccc1Cl
Product: COc1ccc(-c2nnc(C)n2-c2ccccc2)cc1

Procedure:
Using the procedure of Step B in Example 1, 26.3 ml of aniline, 150 ml of o-dichlorobenzene, 4.65 ml of phosphorus trichlorode and 10 g of N-(4-methoxybenzoyl)-N'-acetyl-hydrazine [prepared by process of J. Org., Vol. 19 (1954), p. 194-201] were reacted to obtain 7.1 g of 3-(4-methoxyphenyl)-4-phenyl-5-methyl -4H-1,2,4-triazole melting at 140°-141° C.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[C:8]([N:11]3[C:16](=[O:17])[CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[N:13]([CH3:22])[C:12]3=[O:23])[CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.[C:24](#[N:28])[CH2:25][C:26]#[N:27].C(N(CC)CC)C.Cl>CS(C)=O.O.[Cl-].[Na+].O>[CH3:22][N:13]1[C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][C:16](=[O:17])[N:11]([C:8]2[CH:9]=[CH:10][C:5]3[S:4][N:3]=[C:2]([CH:25]([C:24]#[N:28])[C:26]#[N:27])[C:6]=3[CH:7]=2)[C:12]1=[O:23]
Reactant: N#CCC#N
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(Cl)c3c2)c1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(C#N)C#N)c3c2)c1=O
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
A mixture of 3-(3-chloro-1,2-benzisothiazol-5-yl)-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (0.500 g), malononitrile (0.270 g) and triethylamine (1.50 g) in methyl sulfoxide is stirred at 60° C. for 15 minutes, cooled to room temperature, and diluted with water. The resultant aqueous mixture is extracted with ethyl acetate. The organic extract is washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a brown oil. The extracted aqueous phase is diluted with brine, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic extract is dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a brown oil. Flash column chromatography of the combined oils using silica gel and an ethyl acetate/hexanes/methanol/acetic acid solution (10:10:4:1) gives the title product as an oil which is identified by NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.CC(C)([O-])C.[K+].Br[C:16]1[C:17]([CH3:25])=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:16]2[CH:21]=[N:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2[CH3:25])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])ncc1Br
Reactant: Oc1ccnc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])ncc1Oc1ccnc(Cl)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 17.8 %

Procedure:
2-Chloro-4-hydroxypyridine (0.239 g, 1.843 mmol) was dissolved in DMF (18.43 ml) and potassium t-butoxide (0.290 g, 2.58 mmol) was added. The solution was degassed for several minutes, and then 5-bromo-4-methyl-2-nitropyridine (0.4 g, 1.843 mmol) was added. The mixture was heated at 65° C. for 70 hours under argon and then at 80° C. for 24 hours. The reaction mixture was cooled to RT, diluted with ethyl acetate (150 mL), washed with water (75 mL), 10% aqueous LiCl (2×75 mL), saturated aqueous bicarbonate (75 mL) and brine (75 mL), dried (MgSO4), evaporated and purified via silica gel chromatography (ethyl acetate/hexanes) to yield 2-chloro-4-(4-methyl-6-nitropyridin-3-yloxy)pyridine as a yellow solid (0.087 g, 18% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.49 (s, 1H), 8.47 (s, 1H), 8.35 (d, 1H), 7.24 (d, 1H), 7.12 (dd, 1H), 2.31 (s, 3H); MS (ESI) m/z: 266.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[N:11]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH3:23])=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[NH2:11]
Reactant: COc1ccc(F)c2[nH]nc(N3C(=O)c4ccccc4C3=O)c12
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(F)c2[nH]nc(N)c12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 60 %

Procedure:
To a suspension of 2-[7-fluoro-4-(methyloxy)-1H-indazol-3-yl]-1H-isoindole-1,3(2H)-dione (for a preparation see Intermediate 13) (1.36 g, 4.37 mmol) in ethanol (15 mL) at 0° C. (ice/water bath) was added hydrazine hydrate (0.638 mL, 13.11 mmol) dropwise. The ice/water bath was removed and the reaction mixture was allowed to warm to room temperature. Stirring was continued for a further 40 min. During this time the reaction mixture became very viscous. Acetone (10 mL) was added to the reaction and the resultant reaction mixture was allowed to stand at room temperature overnight. The solid was removed by filtration and washed with acetone (×2). The combined filtrates were concentrated in vacuo. The solid was triturated in cyclohexane-ethyl acetate (2:1; ˜25 mL) and then collected by filtration to give the title compound (479 mg, 60%) as a light brown powder. LCMS (System A) RT=0.69 min, ES+ve m/z 182 (M+H)+. The filtrate was concentrated and the resultant oil was loaded in dichloromethane (and minimum amount of methanol) to a silica cartridge 70 g and purified by chromatography on Flashmaster eluting with a 0-50% ethyl acetate-cyclohexane over 30 min. The appropriate fractions were combined and evaporated in vacuo to give another batch of the required product (316 mg, 40%) as a brown oil. LCMS (System A) RT=0.62 min, ES+ve m/z 182 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH2:36]([N:38]([C:46]([CH3:50])([CH3:49])[CH:47]=O)[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH3:37].N1CCCCC1>O1CCOCC1.CC(O)=O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:50][C:46]([N:38]([CH2:36][CH3:37])[C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:47])[CH3:49])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: CCN(C(=O)OC(C)(C)C)C(C)(C)C=O
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: C1COCCO1
Product: CCN(C(=O)OC(C)(C)C)C(C)(C)C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a solution of 3-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (236 mg, 0.5 mmol, 1 equiv) and tert-butyl ethyl(2-methyl-1-oxopropan-2-yl)carbamate (2.15 g, 10 mmol, 20 equiv) in dioxane (30 mL) was added 0.5 mL piperidine, 1 drop AcOH and 2 g of 4A molecular sieves. The resulting mixture was stirred for 2 h at 110° C. The solids was filtered out, the filtrate was diluted with 200 mL of ethyl acetate, washed with brine, dried over Na2SO4, concentrated and purified by silica gel column (ethyl acetate/MeOH 10/1) to give 60 mg (19%) of tert-butyl 5-((S)-2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-4-cyano-2-methyl-5-oxopent-3-en-2-yl(ethyl)carbamate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[NH:14][CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1.[C:20]([C:24]1[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN1C(=O)CCC1.[Cu]I>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[C:13](=[O:19])[N:14]([C:27]4[CH:28]=[CH:29][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:25][CH:26]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)c1ccc(I)cc1
Reactant: Cc1cc[nH]c(=O)c1N1CCc2nc(N)ncc2C1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: CN1CCCC1=O
Product: Cc1ccn(-c2ccc(C(C)(C)C)cc2)c(=O)c1N1CCc2nc(N)ncc2C1
Temperature: 70 °C
Yield: 57 %

Procedure:
A mixture of 3-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methylpyridin-2(1H)-one, 1-tert-butyl-4-iodobenzene (0.071 mL, 0.40 mmol), N,N′-dimethylethylenediamine (0.022 mL, 0.20 mmol), potassium phosphate tribasic (170 mg, 0.80 mmol), copper (I) iodide (15 mg, 0.080 mmol) in 1.0 mL NMP was heated at 70° C. for 17 hours. The reaction mixture was partitioned between EtOAc and aqueous NaHCO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting oil was chromatographed eluting with CHCl3, then CHCl3/EtOAc (1:1), and then gradient 3% to 6% MeOH in CHCl3/EtOAc (1:1). The solid obtained was then precipitated from an EtOAc/hexane mixture to give a pale yellow solid (44 mg, 57%). 1H NMR (DMSO) δ: 7.94 (s, 1H), 7.48-7.53 (m, 2H), 7.43 (d, J=6.7 Hz, 1H), 7.27-7.33 (m, 2H), 6.30 (s, 2H), 6.19 (d, J=7.0 Hz, 1H), 3.98 (br. s, 2H), 3.31 (br. s, 2H), 2.68 (t, J=5.3 Hz, 2H), 2.19 (s, 3H), 1.32 (s, 9H)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH3:8])[CH:7]=1.[Br:10]N1C(=O)CCC1=O.C(OOCC1C=CC=CC=1)C1C=CC=CC=1.C1(=O)NC(=O)CC1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH2:8][Br:10])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccc1F
Agent: O=C1CCC(=O)N1
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)cc1CBr
Temperature: 79 °C

Procedure:
5-bromo-2-fluorotoluene (5.00 g, 26.5 mmol), N-bromosuccinimide (5.18 g, 29.1 mmol), benzyl peroxide (0.205 g, 0.850 mmol) and carbon tetrachloride (50 mL) were loaded to a r.b. flask and set to reflux (79° C.) for 2 h. Once cooled the succinimide was filtered off and carbon tetrachloride removed via a dry ice-acetone cooled rotary evaporator. The residues were dissolved in dichloromethane (100 mL) and washed with distilled H2O (50 mL×3) and brine (50 mL). Dried over MgSO4 and solvent removed in vacuo to yield the title compound as a colourless liquid yellow (6.80 g, 96%),
Reaction SMILES: [O:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[N:9][NH:8][C:7]=2[CH:11]=1)[CH3:2].[OH-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:14][CH2:15][CH2:16][CH2:17][N:8]1[C:7]2[CH:11]=[C:3]([O:1][CH3:2])[CH:4]=[CH:5][C:6]=2[N:10]=[N:9]1
Reactant: COc1ccc2nn[nH]c2c1
Reactant: ClCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: COc1ccc2nnn(CCCCl)c2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 34.1 %

Procedure:
6-methoxyl-1H-benzotriazole (14.9 g, 0.10 mol) is dissolved into 100 ml of 30% wt. sodium hydroxide, 3-chlorobromopropane (31.4 g, 0.10 mol), tetrabutyl ammonium bromide (0.8 g) are added, and mixed for 5 min. The reaction solution is gradually heated to 60° C., stirred for reaction for 2 hours. Post treatment was performed based on common method two for synthesis. The solution was separated and purified by HPLC to produce 7.7 g of N-(3-chloropropyl)-6-methoxyl-benzotriazole, with a yield of 34.1%.
Reaction SMILES: C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[O:18]=[C:19]1[NH:23][C@H:22]([C:24]([OH:26])=O)[CH2:21][O:20]1.[N+]([O-])(O)=O.[N+:31]([O:34][CH2:35][CH2:36][NH2:37])([O-:33])=[O:32]>O1CCCC1>[N+:31]([O:34][CH2:35][CH2:36][NH:37][C:24]([C@@H:22]1[CH2:21][O:20][C:19](=[O:18])[NH:23]1)=[O:26])([O-:33])=[O:32]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1N[C@H](C(=O)O)CO1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Solvent: C1CCOC1
Product: O=C1N[C@H](C(=O)NCCO[N+](=O)[O-])CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.2 ml of triethylamine and 1.5 ml of diethyl cyanophosphonate were added, whilst ice-cooling, to a suspension of 1.0 g of (4S)-2-oxooxazolidine-4-carboxylic acid and 1.55 g of N-(2-nitrooxyethyl)amine nitrate in 20 ml of dry tetrahydrofuran, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was diluted with ethyl acetate; the mixture was then washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residual brown oil thus obtained was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give the title compound as yellowish brown crystals. These crude crystals were recrystallized from ethyl acetate, to give 0.25 g of the title compound as colorless needles, melting at 102°-103° C.