Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1([NH:15][C:16]([C:18]2([NH:21][C:22]([C:24]3[N:28]4[C@@:29]([CH2:42][C:43]5[CH:48]=[CH:47][C:46]([C:49]#[N:50])=[CH:45][CH:44]=5)([CH3:41])[C:30](=[O:40])[N:31]([C:32]5[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=5)[C:27]4=[N:26][CH:25]=3)=[O:23])[CH2:20][CH2:19]2)=[O:17])[CH2:14][CH2:13]1)=[O:11])=O)(C)(C)C>Cl.O1CCOCC1.CCOCC>[ClH:38].[NH:9]([C:10]([C:12]1([NH:15][C:16]([C:18]2([NH:21][C:22]([C:24]3[N:28]4[C@@:29]([CH2:42][C:43]5[CH:44]=[CH:45][C:46]([C:49]#[N:50])=[CH:47][CH:48]=5)([CH3:41])[C:30](=[O:40])[N:31]([C:32]5[CH:37]=[C:36]([Cl:38])[CH:35]=[C:34]([Cl:39])[CH:33]=5)[C:27]4=[N:26][CH:25]=3)=[O:23])[CH2:20][CH2:19]2)=[O:17])[CH2:14][CH2:13]1)=[O:11])[NH2:8]
Reactant: CC(C)(C)OC(=O)NNC(=O)C1(NC(=O)C2(NC(=O)c3cnc4n3[C@](C)(Cc3ccc(C#N)cc3)C(=O)N4c3cc(Cl)cc(Cl)c3)CC2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(C(=O)NN)CC4)CC3)n21
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 108.6 %

Procedure:
N′-{1-[(1-{[(R)-5-(4-Cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-cyclopropanecarbonyl)-amino]-cyclopropanecarbonyl}-hydrazinecarboxylic acid tert-butyl ester (0.30 g, 0.42 mmol) was dissolved in 4 N HCl in dioxane (3 mL) and allowed to stir at room temperature for 40 min. The resulting white suspension was diluted with Et2O and the precipitate was collected by filtration. The solid was washed twice with Et2O to give (R)-5-(4-cyano-benzyl)-7-(3,5-dichloro-phenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo-[1,2-a]imidazole-3-carboxylic acid [1-(1-hydrazinocarbonyl-cyclopropylcarbamoyl)-cyclopropyl]-amide hydrochloride (0.15 g, 52%) as a white powder, m/z 621.7 [M+1]+.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=1.IC>O1CCCC1>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([CH:16]([CH3:1])[C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1ccc(Br)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
To a solution of lithium diisopropylamide (2 mol/L, 22 mL, 44 mmol) in tetrahydrofuran (80 mL) was dropwise a solution of methyl 2-(4-bromophenyl)acetate (10 g, 44 mmol) in tetrahydrofuran (20 mL) at −78° C. The mixture solution was stirred for 0.5 hour at that temperature, then iodomethane (8 g, 56 mmol) was added. The mixture was stirred for 10 minutes at −78° C., then was removed from the cooling bath and stirred for 0.5 hour. The reaction was quenched with sat. ammonium chloride, then diluted with ethyl acetate, washed with water, The organic layer concentrated to dry, purified by column chromatography (silica-gel, petroleum:ethyl acetate=20:1) to give methyl 2-(4-bromophenyl)propanoate as a colorless oil (10 g, 91%). 1H NMR (300 MHz, CDCl3): δ 7.44 (d, J=9 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 3.65-3.70 (m, 4H), 1.48 (d, J=6 Hz, 3H).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])([CH3:57])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:65][C:66]1[S:67][C:68]2[C:69]([N:74]=1)=[N:70][CH:71]=[CH:72][CH:73]=2.SC1SC2C=CN=CC=2N=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C:55]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])([CH3:57])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:65][C:66]4[S:67][C:68]5[C:69]([N:74]=4)=[N:70][CH:71]=[CH:72][CH:73]=5)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1nc2ncccc2s1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Agent: Sc1nc2cnccc2s1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4ncccc4s3)CS[C@@H]3C(NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 60.6 %

Procedure:
Using 276 mg of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido}-3-chloromethyl-3-cephem-4-carboxylate and 60 mg of 2-mercaptothiazolo[4,5-b]pyridine in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 2-mercaptothiazolo[4,5-c]pyridine, respectively, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 191 mg of the title compound in a yield of 61%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:18](O)=O)[C:5]([C:8]2[C:9](=[CH:13][C:14]([Br:17])=[CH:15][CH:16]=2)[C:10](O)=O)=[CH:6][CH:7]=1.[C:21]1([NH2:28])[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27].O>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:9]=2[C:10]2[NH:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:28]=2)=[C:4]([C:18]2[NH:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:28]=2)[CH:3]=1
Reactant: O=C(O)c1cc(Br)ccc1-c1ccc(Br)cc1C(=O)O
Reactant: Nc1ccccc1N
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Brc1ccc(-c2ccc(Br)cc2-c2nc3ccccc3[nH]2)c(-c2nc3ccccc3[nH]2)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a mixture containing 3.0 g of 4,4'-dibromodiphenic acid and 1.8 g of o-phenylene diamine was added 100 g of polyphosphoric acid (85%). The mixture was stirred and heated at 60° C. for 1 hour, 100° C. for 1 hour, and finally at 160° C. for 24 hours. The cooled heterogenous mixture was poured into 2L of distilled water. The procedure was not successful in that the product was identified as an anhydride (IR, MS and elemental analysis). This procedure was repeated using methanesulfonic acid/phosphorus pentoxide and polyphosphoric acid/sulfolane as solvents. The same result was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.CCN(CC)CC.[NH2:18][CH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>O1CCOCC1>[O:22]1[CH2:23][CH2:24][CH:19]([NH:18][C:2]2[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][CH2:21]1
Reactant: NC1CCOCC1
Reactant: O=C(O)c1cnc(Cl)nc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(O)c1cnc(NC2CCOCC2)nc1
Temperature: 150 °C
Yield: 99.7 %

Procedure:
2-Chloropyrimidine-5-carboxylic acid (500 mg, 3.15 mmol), Et3N (1.15 mL, 8.20 mmol) and 4-aminotetrahydropyran (335 mg, 3.31 mmol) were dissolved in dioxane (10 mL) and heated in a microwave reactor at 150° C. for 30 min. The reaction mixture was concentrated in vacuo to give the crude title compound (701 mg) as a beige solid. LCMS (ES+): 224.1 [MH]+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([O:10][C:11]3[CH:12]=[C:13]([NH2:18])[C:14]([NH2:17])=[CH:15][CH:16]=3)=[C:4]2[CH:3]=[CH:2]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=S)=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[NH:18][C:13]3[CH:12]=[C:11]([O:10][C:9]4[CH:8]=[CH:7][N:6]=[C:5]5[NH:1][CH:2]=[CH:3][C:4]=45)[CH:16]=[CH:15][C:14]=3[N:17]=2)=[CH:22][C:21]=1[C:29]([F:30])([F:31])[F:32]
Reactant: Nc1ccc(Oc2ccnc3[nH]ccc23)cc1N
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(Nc2nc3ccc(Oc4ccnc5[nH]ccc45)cc3[nH]2)ccc1Cl

Procedure:
The title compound was prepared by the method described in Example 1, using 4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-benzene-1,2-diamine (Step D, 0.082 g, 0.34 mmol) and 1-chloro-4-isothiocyanato-2-trifluoromethyl-benzene (0.081 g, 0.34 mmol). MS (MH+)=444.1, MW: 443.08 Calc'd for: C21H13ClF3N5O.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:9]([CH3:20])=[C:8]([C:21]([O:23]CC2C=CC=CC=2)=[O:22])[CH:7]=1>C(O)C.O1CCCC1.[Pd]>[CH3:31][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:9]([CH3:20])=[C:8]([C:21]([OH:23])=[O:22])[CH:7]=1
Reactant: Cc1c(C(=O)OCc2ccccc2)cc(CCCN(C)C)n1CCc1ccc(F)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cc(CCCN(C)C)n1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 501 mg portion of benzyl 5-[3-(dimethylamino)propyl]-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate was dissolved in a mixed solvent of 1 ml ethanol and 5 ml tetrahydrofuran, and 119 mg of 10% palladium-activated carbon was added, followed by stirring at room temperature for 15 hours under an atmosphere of hydrogen. The reaction liquid was filtered through celite, and the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (methanol:chloroform=10:90-15:85-20:80), to obtain 342 mg of 5-[3-(dimethylamino)propyl]-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylic acid as a colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)([O-])=O.O>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: N#CC=Cc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CCO
Product: N#CC=Cc1ccc(N)cc1
Yield: 76 %

Procedure:
A mixture of 120 parts of acrylonitrile and 1000 parts of acetone is introduced into the solution of the diazo derivative obtained from 276 parts of p-nitroaniline. Then, 40 parts of cupric chloride crystallised with 2 molecules of water are added and the mixture is stirred vigorously. The evolution of nitrogen is exothermic and the temperature should be kept at 30°-32° C. by means of a cooling bath. When the diazonium chloride has disappeared (6 hours), yellow leaflets melting at 108° C. are filtered off. After recrystallisation from methanol, one obtains 330 parts of 2-chloro-3-(4-nitrophenyl) propionitrile which melts at 112° C. This product is then dehydrohalogenated by means of 200 parts of crystallised sodium acetate in a mixture of 340 parts of water and 800 parts of ethyl alcohol. The mixture is refluxed for 12 hours and 225 parts of 4-nitrocinnamonitrile are isolated in the cold. Melting point: 202° C. The 4-nitro-cinnamonitrile thus obtained is then reduced by the Bechamp method in 2000 parts of water and 800 parts of ethyl alcohol. The 4-aminocinnamonitrile is obtained which melts at 109°-110° C. Yield: 76%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=2)[N:32]=[CH:31][CH:30]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][C:29]4[C:38]5[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=5)[N:32]=[CH:31][CH:30]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:6][CH:7]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(Nc1ccc(Cl)cc1)c1cccc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc4c(C(=O)Nc5ccc(Cl)cc5)cccc4c3)c2cc1OC
Temperature: 100 °C
Reaction time: 60 h

Procedure:
The 6-hydroxy-naphthalene-1-carboxylic acid(4-chlorophenyl)-amide (Step a, 0.076 g, 0.254 mmol), Cs2CO3 (0.248 g, 0.762 mmol), 4-chloro-6,7-dimethoxy-quinoline (0.114 g, 0.508 mmol) and DMF (0.250 mL) were combined in a screw-cap test tube under N2. The tube was sealed and heated to 100° C. After 60 h at 100° C., the reaction was cooled to RT. The solvent was removed in vacuo, dissolved in EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and concentrated. The residue remaining after concentration was dissolved in MeOH and purified by reverse-phase HPLC (pH 10 buffer solvent system). The fractions containing the desired product were concentrated, dissolved in EtOAc, and washed with brine. The organic layer was dried (Na2SO4), filtered and concentrated to afford the title compound as a tan solid. M+H-485.1. Calc'd for C28H31N2O4-484.12.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].C([O:18][C:19](=O)[C:20](Br)([CH3:22])[CH3:21])C>CC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:19](=[O:18])[C:20]([CH3:22])([CH3:21])[O:9][C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C)Oc2cc(Br)ccc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.5 %

Procedure:
5.0 g 2-Amino-5-bromophenol were dissolved in 100 ml acetone. Then 11.0 g potassium carbonate and 6.74 g ethyl-2-bromoisobutyrate were added. The reaction mixture was stirred at room temperature overnight and refluxed overnight. The cooled reaction mixture was then filtrated and the filtrate concentrated in vacuo. The resulting residue was purified by chromatography on silica gel to obtain 4.6 g 7-Bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:9]=2NC1=O)=[O:5])[CH3:2].[H-].[Na+].[ClH:27].[CH2:28]([N:30]([CH2:34][CH3:35])[CH2:31][CH2:32]Cl)[CH3:29].[Cl-].[Na+]>CN(C)C=O>[ClH:23].[CH2:1]([O:3][C:4]([C:6]1[N:12]([CH2:29][CH2:28][N:30]([CH2:34][CH3:35])[CH2:31][CH3:32])[C:11]([C:10]2[CH:9]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:13]2[C:18]=1[CH:17]=[CH:16][C:15]([Cl:27])=[CH:14]2)=[O:5])[CH3:2]
Reactant: CCN(CC)CCCl
Reactant: CCOC(=O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCN(CC)CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 27.2 g. of 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid ethyl ester in 480 ml. of dimethylformamide is treated under nitrogen at -10° C. with 0.33 mol. of sodium hydride (14.4 g. of a 5 55% dispersion in mineral oil) and stirred at the same temperature for 15 minutes. To this mixture, there are added at -10° C. to -5° C. 27.2 g. of 2-diethylaminoethyl chloride hydrochloride; the mixture is then stirred at room temperature for 1 hour and subsequently heated for 3 hours at 60° C. After cooling, the mixture is poured into 4 liters of ice-water with stirring; 200 g. of sodium chloride are added and the oily precipitate is separated by decantation. The latter is immediately dissolved in methylene chloride and the organic solution, shielded from daylight, is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated to dryness. The resulting oil is dissolved in 100 ml. of ether and filtered; the filtrate is treated with 180 ml. of 0.5-N hydrochloric acid and thoroughly shaken. After cooling in an ice-bath, the crystallized hydrochloride is removed by filtration, washed with water and ether and then dissolved in 200 ml. of methylene chloride. After separation of the aqueous layer, the methylene chloride solution is dried over sodium sulfate, filtered and treated portionwise with 150 ml. of ether, whereby there is obtained 5-chloro-2-[2-(diethylamino)ethyl]-3-phenylisoindole-1-carboxylic acid ethyl ester hydrochloride; melting point 248°-250° C. (decomposition).
Reaction SMILES: [Na+].[C:2]1([CH:8]([N:10]2[C:14]([C:15]([O-:17])=[O:16])=[CH:13][N:12]=[CH:11]2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C)P(=O)(N(C)C)N(C)C>O>[C:2]1([CH:8]([N:10]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[CH:11]2)[CH3:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(c1ccccc1)n1cncc1C(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(c1ccccc1)n1cncc1C(=O)O
Temperature: 100 °C
Reaction time: 20 h

Procedure:
A mixture of 14.3 parts of (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid sodium salt, 1.9 parts of a 61.8% suspension of sodium hydride in mineral oil and 60 parts of hexamethylphosphoric triamide is stirred for 20 hours at 100° C. under Argon atmosphere. The mixture is allowed to cool to room temperature and poured onto 150 parts of water. The whole is washed three times with 200 parts of dichloromethane. The aqueous phase is neutralized (pH 7) with acetic acid and the product is allowed to crystallize. The product is filtered off, dried and recrystallized from ethanol, yielding (±)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid; m.p. 188° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=2)[N:3]=1.[NH2:21][CH2:22][CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[NH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([CH2:23][CH2:22][NH:21][C:2]2[CH:7]=[C:6]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[N:15]=3)[N:3]=2)=[CH:25]1
Reactant: Cc1cccc(-c2nc(Cl)cc(-c3cccnc3)n2)n1
Reactant: NCCc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cccc(-c2nc(NCCc3c[nH]c4ccccc34)cc(-c3cccnc3)n2)n1
Temperature: 25 °C

Procedure:
A solution of 4-chloro-2-(6-methyl-pyridin-2-yl)-6-pyridin-3-yl-pyrimidine (Intermediate D) (1 eq, 50 mg), 3-(2-aminoethyl)indole (1.0 eq, 28.3 mg) and K2CO3 (1.0 eq, 24.4 mg) in NMP (1 ml) is heated using microwave radiation at 120° C. for 1 hour. After cooling to room temperature, the mixture is partitioned between EtOAc/water and the organic portion is separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue is purified by flash chromatography on silica eluting with 0-5% MeOH in DCM and the appropriate fractions are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and the residue is dissolved in DCM and concentrated in vacuo once again. The resulting solid is dried under vacuum to afford the title compound [M+H]+=407.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[N:3]=1.Cl.[CH:18]1([N:22]([CH3:29])[CH2:23]/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH2:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:26](=[O:27])/[CH:25]=[CH:24]/[CH2:23][N:22]([CH:18]4[CH2:21][CH2:20][CH2:19]4)[CH3:29])[CH2:13]3)[N:3]=[C:2]([I:1])[C:10]=12
Reactant: CN(C/C=C/C(=O)O)C1CCC1
Reactant: Nc1ncnc2c1c(I)nn2[C@@H]1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C/C=C/C(=O)N1CC[C@@H](n2nc(I)c3c(N)ncnc32)C1)C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 118.4 %

Procedure:
To a cooled solution of (R)-3-iodo-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (4) (990 mg, 3.0 mmol), (E)-4-(cyclobutyl(methyl)amino)but-2-enoic acid (21) (871 mg, 3.0 mmol) and DIPEA (3.1 mL, 18 mmol) in DMF (15 mL) was added HBTU (1.74 g, 4.5 mmol). The resulting solution was stirred at RT overnight, then quenched with water. The layers were separated and the aqueous layer was extracted with 85% DCM/IPA(3×). The combined organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography to provided (R,E)-1-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one (22) (1.71 g, quant. yield) as a white solid. LC-MS (ESI): m/z (M+1) 482.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:27]=[CH:26][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=1.[Cl:28][C:29]1[CH:30]=[C:31]2[C:36](=[O:37])[O:35][C:33](=[O:34])[C:32]2=[CH:38][C:39]=1[Cl:40]>C(Cl)(Cl)Cl>[C:21]([O:20][C:19]([NH:18][CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[NH:1][C:33]([C:32]2[CH:38]=[C:39]([Cl:40])[C:29]([Cl:28])=[CH:30][C:31]=2[C:36]([OH:37])=[O:35])=[O:34])=[CH:14][CH:15]=1)=[O:25])([CH3:23])([CH3:24])[CH3:22]
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2ccc(C(F)(F)F)cc2NC(=O)c2cc(Cl)c(Cl)cc2C(=O)O)cc1
Reaction time: 18 h

Procedure:
Tert-butyl 4-{[2-amino-4-(trifluoromethyl)phenyl]amino}benzylcarbamate (216 mg, 0.56 mmol), and 4,5-dichlorophthalic anhydride (110 mg, 0.51 mmol) are added to a 7 ml vial. After diluting with chloroform (4 mL), the reaction vial is placed on an orbit shaker at 40° C. After 18 hr, the reaction mixture is concentrated. Recrystallization gives 2-({[2-[(4-{[(tert-butoxycarbonyl)amino]methyl}phenyl)amino]-5-(trifluoromethyl)phenyl]amino}carbonyl)-4,5-dichlorobenzoic acid, which is dissolved in ethyl acetate (10 mL). After cooling to 0° C., ethyl acetate saturated with HCl (10 mL) is added. After 2 hr the reaction mixture is concentrated and purified by recrystallization to give 2-({[2-{[4-(aminomethyl)phenyl]amino}-5-(trifluoromethyl)phenyl]amino}carbonyl)-4,5-dichlorobenzoic acid hydrochloride. The yield is 92 mg (34%). 1H NMR (400 MHz, DMSO-d6) 13.91 (s, 1H), 10.24 (s, 1H), 8.25 (s, 3H), 8.09 (s, 1H), 8.02 (s, 1H), 7.95, (s, 1H), 7.83 (m, 1H), 7.49 (m, 1 H), 7.43 (d, 2H), 7.36 (m, 1H), 7.21 (d, 2H), 3.97 (m, 2H); HRMS for C22H16Cl2F3N3O3 498.0584 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)[CH:5]=[N:4]1)[CH3:2].Br[C:18]1C=NN(C2CC2)C=1>>[CH3:16][C:10]1([CH3:15])[C:11]([CH3:14])([CH3:13])[O:12][B:8]([C:6]2[CH:5]=[N:4][N:3]([CH:1]3[CH2:18][CH2:2]3)[CH:7]=2)[O:9]1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cnn(C2CC2)c1
Product: CC1(C)OB(c2cnn(C3CC3)c2)OC1(C)C

Procedure:
The title compound was prepared in the same manner as 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole starting with 4-bromo-1-cyclopropyl-1H-pyrazole.
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH3:19][NH:20][CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C([O-])(O)=O.[Na+]>[CH3:19][N:20]([CH3:21])[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CCC2=O
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)C1CCc2cc(NC(=O)OC(C)(C)C)ccc21
Yield: 54.3 %

Procedure:
To a solution of tert-butyl (1-oxo-2,3-dihydro-1H-inden-5-yl)carbamate (371 mg, 1.5 mmol) in dimethylamine (2.0 M solution in THF, 5 mL, 10 mmol) was added sodium triacetoxyborohydride (636 mg, 3.0 mmol). The resultant suspension was stirred at room temperature for 16 h, diluted with a saturated NaHCO3 solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded the desired product (225 mg, 54%) as an off-white solid. ESI MS m/z 277 [C16H24N2O2+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([O:13]CC)=O)[CH2:8][NH:7][C:6]=2[CH:16]=1.[CH2:17]([NH2:20])[CH:18]=[CH2:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11]([NH:20][CH2:17][CH:18]=[CH2:19])=[O:13])[CH2:8][NH:7][C:6]=2[CH:16]=1
Reactant: CCOC(=O)C1CNc2cc(Cl)ccc2O1
Reactant: C=CCN
Product: C=CCNC(=O)C1CNc2cc(Cl)ccc2O1

Procedure:
3 was prepared as white platelets, mp: 114°-114.5° C., by treating 3A with 2-propenamine by the procedure of Example 1.