Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([N:9]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].C[Al](C)C.[N:22]1([C:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:38])[C:32]=2[C:33](OCC)=[O:34])=[O:27])[CH2:25][CH2:24][CH2:23]1>O1CCOCC1>[N:22]1([C:26]([C:28]2[CH:29]=[N:30][N:31]([CH3:38])[C:32]=2[C:33]([NH:8][C:7]2[CH:6]=[CH:5][N:4]3[N:9]=[C:10]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:11]=[C:3]3[C:2]=2[CH3:1])=[O:34])=[O:27])[CH2:23][CH2:24][CH2:25]1
Reactant: CCOC(=O)c1c(C(=O)N2CCC2)cnn1C
Reactant: Cc1c(N)ccn2nc(-c3ccccc3)nc12
Agent: C[Al](C)C
Solvent: C1COCCO1
Product: Cc1c(NC(=O)c2c(C(=O)N3CCC3)cnn2C)ccn2nc(-c3ccccc3)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To an argon purged solution of 8-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-amine (60 mg, 268 μmol) in dioxane (5 ml) is added trimethylaluminum (2M solution in toluene, 401 μl, 803 μmol). The resulting mixture is stirred for 1 hour at 25° C., then ethyl 4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxylate (63.5 mg, 268 μmol) is added, the mixture is heated to 100° C. and stirred for 72 hours. The crude material is loaded on silica and purified by flash chromatography on a 20 g silica column using heptane/ethyl acetate 50-100% as eluent affording 4-(azetidine-1-carbonyl)-1-methyl-N-(8-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (77 mg, 69.3%) as a white solid. mp.: 243-5° C. MS: m/z=416.2 (M+H+).
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14].N([O-])=O.[Na+].[F:19][B-](F)(F)F.[H+]>O>[F:19][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:14]
Reactant: F[B-](F)(F)F
Reactant: Cc1c(N)ccc(C#N)c1C(F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: Cc1c(F)ccc(C#N)c1C(F)(F)F
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
4-amino-3-methyl-2-(trifluoromethyl)benzonitrile (CAS 573764-86-0, 2.0 g, 9.99 mmol) was dissolved in fluoroboric acid, HBF4 solution (15 mL) at −10° C. (ice/MeOH). To the pre-cooled solution was added NaNO2(689 mg, 9.992 mmol) in 2 mL H2O drop by drop under constant stirring. The reaction mixture was allowed to stir for 15 min at −10° C. and filtered off. The white residue was washed with cold EtOH and cold ether to get the diazosalt as a white crystalline solid. The salt is dried over high vacuum for 4-5 h. to provide 1.9 g. The salt was heated up (>250° C.) and sublimed under reduced pressure to get the crude fluoro compound as an oil. The oil is chromatographed to get the pure 4-fluoro-3-methyl-2-(trifluoromethyl)benzonitrile as a clear oil (700 mg): 1H NMR (400 MHz, CDCl3, δ in ppm) 7.68 (dd, J=5.0, 9.0 Hz, 1H), 7.33 (t, J=9 Hz, 1H), 2.43 (quin, J=2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([Cl:16])=[CH:11][N:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:8][C:9]1[N:14]=[C:13]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)[C:12]([Cl:16])=[CH:11][N:10]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: Cc1cc(N)no1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)ncc2Cl)no1

Procedure:
The mixture 5-methylisoxazol-3-amine (98 mg, 1.0 mmol), 2,4,5-trichloropyrimidine (344 μL, 3.0 mmol), and sodium carbonate (106 mg, 1.0 mmol) in 3 mL of EtOH was heated at 60° C. overnight. The reaction mixture was concentrated and then partitioned between EtOAc and brine. The collected organic extracts were dried (Na2SO4), concentrated in vacuo, and purified with silica gel chromatography (MeOH/DCM: 1/9) to afford N-(2,5-dichloropyrimidin-4-yl)-5-methylisoxazol-3-amine; ESMS m/z 245.0 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:3]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH2:22])[CH:16]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:22][CH2:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[N:3]=[C:4]([NH:11][CH2:12][CH2:13][OH:14])[N:5]=1
Reactant: NCc1cccnc1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(Cl)nc(NCCO)nc1NCc1cccnc1

Procedure:
In analogy to the procedure described in example 38b, 4,6-dichloro-2-(2-hydroxy-ethyl-amino)-pyrimidine-5-carbonitrile was treated with 3-picolylamine in dioxane in the presence of N-ethyl-diisopropylamine at room temperature to yield 4-chloro-2-(2-hydroxy-ethylamino)-6-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as a colorless foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)[CH2:9][C:8]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:7]1)[CH3:2].[CH:27]1[C:35]2[C:34]3[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=3[O:32][C:31]=2[C:30](B(O)O)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([C:39]3[C:33]4[O:32][C:31]5[CH:30]=[CH:29][CH:28]=[CH:27][C:35]=5[C:34]=4[CH:36]=[CH:37][CH:38]=3)=[CH:13][CH:12]=2)[CH2:9][C:8]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:7]1)[CH3:2]
Reactant: OB(O)c1cccc2c1oc1ccccc12
Reactant: CCOC(=O)CN1N=C(c2ccc(OC)cc2)CC1c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CN1N=C(c2ccc(OC)cc2)CC1c1ccc(-c2cccc3c2oc2ccccc23)cc1
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A solution of [5-(4-bromo-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-acetic acid ethyl ester (0.417 g, 1.0 mmol) and 4-dibenzofuranboronic acid (0.233 g, 1.1 mmol) in toluene (15 mL, X M) was treated with 2 N aq K2CO3 (1.5 mL, xx mmol) and Pd[PPh3]4 (0.058 g, 0.05 mmol). The resulting solution was heated to reflux for 2 h, cooled to room temperature, diluted with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over MgSO4, filtered and concentrated. Purification by flash column chromatography (10% ethyl acetate in heptane) provided [5-(4-Dibenzofuran-4-yl-phenyl)-3-(4-methoxy-phenyl)-4,5-dihydro-pyrazol-1-yl]-acetic acid ethyl ester (0.394 g, 78%) as a white crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH3:16])[CH:11]=1.CC(C)([O-])C.[K+].O>CN1C(=O)N(C)CCC1>[CH3:16][C:12]1[CH:11]=[C:10]([O:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Nc1ccc(O)cc1
Reactant: Cc1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Product: Cc1cc(Oc2ccc(N)cc2)ccn1
Temperature: 100 °C
Reaction time: 18 h
Yield: 10.7 %

Procedure:
To a solution of 4-aminophenol (3.6 g, 32.8 mmol) and 4-chloropicoline (5.0 g, 39.3 mmol) in anh DMPU (50 mL) was added potassium tert-butoxide (7.4 g, 65.6 mmol) in one portion. The reaction mixture was heated at 100° C. with stirring for 18 h, then was allowed to cool to room temp. The resulting mixture was poured into water (200 mL) and extracted with EtOAc (3×150 mL). The combined extracts were sequentially washed with water (3×100 mL) and a saturated NaCl solution (2×100 mL), dried (Na2SO4), and concentrated in vacuo. The resulting oil was purified by flash chromatography (50% EtOAc/50% hexane) to afford the desired product as a yellow oil (0.7 g, 9%): CI-MS m/z 201 ((M+H)+). A14c. General Method for Substituted Aniline Synthesis via Nucleophilic Aromatic Substitution using a Halopyridine
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)COc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (4.4 g) obtained in Example 2 was suspended in dimethyl sulfoxide (250 ml), and to the suspension was added potassium carbonate (4.5 g). The mixture was stirred at room temperature for 30 minutes, and t-butyl bromoacetate (2.1 ml) was added. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice water (300 ml) and extracted with methylene chloride. The methylene chloride layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: methylene chloride containing 3% methanol) to produce the title compound (3.4 g, 63%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.C([O-])([O-])=O.[K+].[K+].[F:17][C:18]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:19]=1[NH2:20]>C(#N)C>[F:17][C:18]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:19]=1[NH:20][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: ClCCCN1CCOCC1
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(NCCCN2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.8 %

Procedure:
To a suspension of 4-(3-chloropropyl)morpholine (1.64 g, 10 mmol) and K2CO3 (4.14 g, 30 mmol) in acetonitrile (20 mL) was added 2-fluoro-4-nitroaniline (1.56 g, 10 mmol) dropwise. The mixture was stirred at rt for 24 h, then filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=1:1) to give the title compound as yellow oil (1.78 g, 63%).
Reaction SMILES: Cl[CH2:2][CH2:3][S:4][CH3:5].[C:6]([C:10]1[N:14]=[C:13]([SH:15])[NH:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]>CC[O-].[Na+]>[C:6]([C:10]1[N:14]=[C:13]([S:15][CH2:2][CH2:3][S:4][CH3:5])[NH:12][N:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1n[nH]c(S)n1
Reactant: CSCCCl
Agent: CC[O-]
Agent: [Na+]
Product: CSCCSc1nc(C(C)(C)C)n[nH]1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
15 g of 2-chloroethyl-methylsulfide are added dropwise to a solution of 15.7 g of 3-tert-butyl-5-mercapto-1,2,4-triazole in ethanolic sodium ethylate (2.3 g of sodium in 300 ml of ethanol). The reaction mixture is stirred for 2 hours at 80° C., then cooled and filtered. The solvent is removed in vacuo and the residue is taken up in 300 ml of chloroform and extracted with 100 ml of water. The solvent is removed by distillation and the crude product is washed with cold petroleum ether, yielding 3-tert-butyl-5-(2-methylthioethylthio)-1,2,4-triazole of the formula ##STR5## with a melting point of 114°-116° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH2:14])[CH:5]=[CH:4][C:3]1=2.C(N(CC)CC)C.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([NH:14][C:30](=[O:31])[CH2:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC1(C)CCC(C)(C)c2cc(N)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CCC(C)(C)c2cc(NC(=O)Cc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
A solution of 5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine (1) (0.5 g, 2.46 mmole) in 20 mL of dicloromethane was treated successively with 0.51 mL of triethylamine (1.5 eq.) and 0.33 mL of phenylacetyl chloride (1 eq.), stirred at room temperature for two hours and then diluted with an additional 20 mL of dichloromethane. The organic solution was washed with two 50 mL portions of water and one 50 mL portion of saturated aqueous sodium chloride solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give 790 mg (100%) of phenylacetic acid (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-amide (7) as a pale yellow foam.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([P:14]([OH:16])[OH:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:19])=[N-]>CCOCC>[CH3:19][O:16][P:14]([CH:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:13])[OH:15]
Reactant: CC(NC(=O)OCc1ccccc1)P(O)O
Reactant: C=[N+]=[N-]
Solvent: CCOCC
Product: COP(O)C(C)NC(=O)OCc1ccccc1

Procedure:
1-Benzyloxycarbonylaminoethylphosphonous acid, prepared by the method of E. K. Baylis et al. [J. Chem. Soc., Perkin Trans, 2845-2853 (1984)] was esterified with diazomethane in an ether solution prepared by a method of F. Arndt [organic Syn. Coll. V. II 165-167 (1943)]. The compound was purified by standard chromatography on silica gel. TLC (silica, 9:1, ethyl acetate:acetonitrile) Rf =0.51 NMR (CDCl3, TMS) & 1.2 and 1.5 (2d, 3H); 2.2 and 10.1 (d, 1H); 3.6 (d, 3H); 3.9 (m, 1H); 5.0 (s, 2H); 6.0-6.6 (overlapping doublets, 1H); 7.2 (s, 5H).
Reaction SMILES: [C:1]1(OC2C=CC=CC=2)C=CC=C[CH:2]=1.[C:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[C:27]([NH:29][CH:30]=[C:31]([C:35]([O-:37])=[O:36])[C:32]([O-])=[O:33])[CH:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15]>CCCCCC>[C:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[N:24]=[CH:25][C:26]3[C:32](=[O:33])[C:31]([C:35]([O:37][CH2:1][CH3:2])=[O:36])=[CH:30][NH:29][C:27]=3[N:28]=2)[CH2:19][CH2:18]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1CCN(c2nccc(NC=C(C(=O)[O-])C(=O)[O-])n2)CC1
Reactant: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCOC(=O)c1c[nH]c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 16 ml of diphenyl ether heated at 250° - 255°C was added with stirring 2.0 g of diethyl, N-[2-(4-acetyl-1-piperazinyl)-4-pyrimidinyl]-aminomethylenemalonate, gentle refluxing was continuted for 10 minutes, and then the mixture allowed to cool to room temperature. To the mixture was added 12 ml of n-hexane and the resulting precipitate was collected, washed with ethanol, and recrystallized from ethanol to yield 1.52 g of the product, m.p. 300° - 302°C with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C)C=O>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([O:14][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)c(OCc3ccccc3)nc2-c2ccc(F)cc2)cc1

Procedure:
6-(4-Fluorophenyl)-1,2-dihydro-5-[4-(methylsulfonyl)phenyl]-2-oxo-pyridine-3-carbonitrile (Example 1, Step 6) (200 mg, 0.54 mMol), silver carbonate (150 mg, 0.54 mMol) and benzyl chloride (1 ml) were stirred in acetone (100 ml) and dimethylformamide (25 ml) at room temperature for 48 hours. The mixture was filtered and the filtrate was concentrated to a white solid which was recrystallized from chloroform-methanol: m.p. (DSC): 204.81° C. Anal. Calc'd. for C26H19N2O3SF (458.52): C, 68.11; H, 4.18; N, 6.11. Found: C, 67.81; H, 4.16; N, 6.04.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]2[C:12]([CH3:17])=[N:13][O:14][C:15]=2[CH3:16])=[CH:4][C:3]=1[I:18].[CH:19]1([NH2:22])[CH2:21][CH2:20]1>CN1C(=O)CCC1>[CH:19]1([NH:22][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]3[C:12]([CH3:17])=[N:13][O:14][C:15]=3[CH3:16])=[CH:4][C:3]=2[I:18])[CH2:21][CH2:20]1
Reactant: Cc1noc(C)c1-c1cc(I)c(Br)c([N+](=O)[O-])c1
Reactant: NC1CC1
Solvent: CN1CCCC1=O
Product: Cc1noc(C)c1-c1cc(I)c(NC2CC2)c([N+](=O)[O-])c1
Temperature: 130 °C

Procedure:
To a mixture of 4-(4-bromo-3-iodo-5-nitrophenyl)-3,5-dimethylisoxazole (1 g, 2.36 mmol, 1 equiv.) in a pressure tube was added NMP (10 mL) and cyclopropylamine (982 μL, 14.2 mmol, 6 equiv.). The mixture was heated to 130° C. for 60 minutes in a microwave reactor. The reaction was concentrated under reduced pressure and purified by flash column chromatography to provide N-cyclopropyl-4-(3,5-dimethylisoxazol-4-yl)-2-iodo-6-nitroaniline.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][C@@:5]1([C:20]([O:22][CH3:23])=[O:21])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[CH3:24][C:25]([S@@:28]([NH2:30])=[O:29])([CH3:27])[CH3:26]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[C:25]([S@@:28](/[N:30]=[CH:2]/[CH2:3][CH2:4][C@@:5]1([C:20]([O:22][CH3:23])=[O:21])[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:29])([CH3:27])([CH3:26])[CH3:24]
Reactant: COC(=O)[C@]1(CCC=O)CCCN1C(=O)OCc1ccccc1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: COC(=O)[C@]1(CC/C=N/[S@@](=O)C(C)(C)C)CCCN1C(=O)OCc1ccccc1
Reaction time: 25 h

Procedure:
To a mixture of 1-benzyl 2-methyl (2R)-2-(3-oxopropyl)pyrrolidine-1,2-dicarboxylate from Step A (1.69 g, 5.29 mmol) and anhydrous CuSO4 (2.36 g, 10.6 mmol) in CH2Cl2 (10 mL) was added (S)-2-methylpropane-2-sulfinamide (0.641 g, 5.29 mmol). This mixture was stirred for 25 h before being filtered through a pad of celite. Additional CH2Cl2 was used to wash the celite. The combined organics were concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc-95:5 to 0:100, to give the title compound. MS: m/z=423 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[C:11]([CH2:14][C:15](=[O:17])[CH3:16])(=[O:13])[CH3:12].N1CCCCC1>C1CCCCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:14]([C:15](=[O:17])[CH3:16])[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: CC(=O)CC(C)=O
Reactant: COc1ccc(C=O)cc1
Solvent: C1CCCCC1
Solvent: C1CCNCC1
Product: COc1ccc(C=C(C(C)=O)C(C)=O)cc1
Reaction time: 8 h
Yield: 70 %

Procedure:
3-(4-methoxybenzylidene)-2,4-pentanedione was prepared by the condensation of 4-methoxy benzaldehyde with acetyl acetone in the presence of piperidine and cyclohexane as the reaction medium at reflux temperature under continuous azeotropic water removal. The reaction takes about eight hours to complete. The reaction product was purified by crystallization with methanol and yields about 70% 3-(4-methoxybenzylidene)-2,4-pentanedione (hereinafter “Compound 3”) with a purity, as determined by GC, of about 99.6%. Compound 3 is an off-white free-flowing powder having a melting point of 82-84° C. with a λmax at 319 nm.
Reaction SMILES: [CH:1]1([C:6]2[NH:10][N:9]=[C:8]([C:11]([OH:13])=[O:12])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[N+:19]([O-])([OH:21])=[O:20]>>[CH:1]1([C:6]2[NH:10][N:9]=[C:8]([C:11]([OH:13])=[O:12])[C:7]=2[N+:19]([O-:21])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cc(C2CCCC2)[nH]n1
Agent: O=S(=O)(O)O
Product: O=C(O)c1n[nH]c(C2CCCC2)c1[N+](=O)[O-]
Temperature: 60 °C
Yield: 43.7 %

Procedure:
5-Cyclopentyl-1H-pyrazol-3-carboxylic acid (13 g, 72.1 mmol) was added portionwise to concentrated sulfuric acid (75 ml) at room temperature with stirring. The reaction mixture was then heated to 60° C. and concentrated nitric acid (70%, 12.7 ml, 202 mmol) was added dropwise, keeping the temperature at 60° C. The reaction was then stirred at 60° C. for 3 hours, cooled to room temperature and poured onto 50 ml of ice with stirring. After 15 minutes the precipitate was isolated by filtration, washed with water and dried under reduced pressure to give 5-cyclopentyl-4-nitro-1H-pyrazol-3-carboxylic acid (7.1 g) as a yellow solid. 1H NMR (400 MHz, DMSO-D6): δ=14.00-14.41 (1H, brs), 13.28-13.85 (1H, brs), 3.20-3.56 (1H, brs, partially masked by solvent), 1.96-2.10 (2H, m), 1.54-1.80 (6H, 2×m) ppm. LRMS (electrospray): m/z [M−H]+ 224, [2M−H]+ 449. Anal. Found C, 43.83; H, 5.35; N, 16.94. C9H11N3O4. 1.2 mol H2O requires C, 43.80; H, 5.47; N, 17.02%.
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.[CH3:36][C:37]([N:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1)([CH3:40])[CH:38]=O.N1CCCC1.Cl[Si](C)(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[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]([C:32](=[CH:36][C:37]([CH3:40])([N:41]3[CH2:45][CH2:44][CH2:43][CH2:42]3)[CH3:38])[C:33]#[N:34])=[O:35])[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: CC(C)(C=O)N1CCCC1
Reactant: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCNC1
Solvent: ClCCl
Product: CC(C)(C=C(C#N)C(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21)N1CCCC1
Reaction time: 1.5 h
Yield: 75.7 %

Procedure:
To a mixture of (S)-3-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile (285 mg, 0.60 mmol), 2-methyl-2-pyrrolidin-1-yl-propanal (719 mg, 5.1 mmol) and pyrrolidine (0.23 mL, 2.8 mmol) in DCM (6 mL) at room temperature was added chloro(trimethyl)silane (0.23 mL, 1.8 mmol). After stirring 90 min, the solution was diluted with sat. NaHCO3 and extracted with DCM. The organic layers were combined, dried (MgSO4), filtered and concentrated. The crude material was purified by Isolera (10 g column:0%-15% iPrOH/DCM) to obtain 270 mg of (S)-2-(2-((4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidine-1-carbonyl)-4-methyl-4-(pyrrolidin-1-yl)pent-2-enenitrile. MS (pos. ion) m/z: 595 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10](Cl)=[O:11].[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>O1CCCC1>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]([NH:13][NH:14][C:15]([NH2:17])=[S:16])=[O:11]
Reactant: NNC(N)=S
Reactant: Cn1c([N+](=O)[O-])cnc1C(=O)Cl
Solvent: C1CCOC1
Product: Cn1c([N+](=O)[O-])cnc1C(=O)NNC(N)=S
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 1-methyl-5-nitro-2-imidazolecarboxylic acid chloride (1.1 g.) in 25 ml. of dry tetrahydrofuran is added 0.55 g. powdered thiosemicarbazide and the mixture is stirred at room temperature for 24 hours. The reaction mixture is evaporated to dryness and water is added. The solution is made basic with sodium hydroxide and the solid is filtered, washed with water and dried affording 1-(1-methyl-5-nitro-2-imidazolecarbonyl)-3-thiosemicarbazide.