Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH2:27][CH2:28][O:29][CH3:30])[N:17]=[C:16]([CH3:31])[N:15]=1>CN(C=O)C>[CH3:30][O:29][CH2:28][CH2:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[N:17]=[C:16]([CH3:31])[N:15]=[C:14]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:19]=1
Reactant: Nc1cccc(CS(N)(=O)=O)c1
Reactant: COCCOc1ccccc1-c1cc(Cl)nc(C)n1
Solvent: CN(C)C=O
Product: COCCOc1ccccc1-c1cc(Nc2cccc(CS(N)(=O)=O)c2)nc(C)n1
Temperature: 90 °C

Procedure:
A mixture of (3-amino-phenyl)-methanesulfonamide (0.1 g, 0.54 mmol) and 4-chloro-6-[2-(2-methoxy-ethoxy)-phenyl]-2-methyl-pyrimidine (0.16 g, 0.0.57 mmol) in DMF (3 mL) was stirred at 90° C. till the reaction completion (TLC control), then evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel yielding (3-{6-[2-(2-methoxy-ethoxy)-phenyl]-2-methyl-pyrimidin-4-ylamino}-phenyl)-methanesulfonamide (Compound 83) as beige powder.
Reaction SMILES: C(N([CH2:10][C:11]1[C:19]2[C:18](=[O:20])[N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:27])[N:15]([CH2:28][C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:14]=2[S:13][C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][O:47][CH3:48])=[O:45])=[CH:39][CH:38]=1)C)C1C=CC=CC=1.[Cl:49]C([O-])=O>C1COCC1.C(=O)(O)[O-].[Na+]>[Cl:49][CH2:10][C:11]1[C:19]2[C:18](=[O:20])[N:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16](=[O:27])[N:15]([CH2:28][C:29]3[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:30]=3[F:36])[C:14]=2[S:13][C:12]=1[C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][O:47][CH3:48])=[O:45])=[CH:39][CH:38]=1
Reactant: O=C([O-])Cl
Reactant: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CCl)c(=O)n(-c2ccccc2)c(=O)n3Cc2c(F)cccc2F)cc1
Reaction time: 2.5 h

Procedure:
Into a solution of N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxo-3-phenylthieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea (7.7 g, 11.53 mmol) in THF (200 ml) which was cooled with a dry ice-acetone bath was added α-choloroethyl chloroformate (1.7 ml, 11.64 mmol). The temperature of the mixture was elevated up to room temperature, and the mixture was stirred for 2.5 hours. The reaction mixture was diluted with saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure.
Reaction SMILES: [C:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[N:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1)#[N:2].[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[CH:30]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]([C:3]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][CH2:30][CH:22]3[CH2:21][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:23]3)=[CH:12][CH:13]=2)[N:6]=[C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:4]=1)#[N:2]
Reactant: N#Cc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: O=CC1Cc2ccccc2C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1cc(-c2cccnc2)nn1-c1ccc(NCC2Cc3ccccc3C2)cc1

Procedure:
A solution of 5-cyano-3-(3-pyridyl)-1-(4′-aminophenyl)pyrazole (185 mg, 0.7 mmol) and indane 2-carboxaldehyde (0.96 mmol, 140 mg) in methanol (9 mL) and acetic acid (1 mL) was stirred at room temp for 30 min. Sodium cyanoborohydride (124 mg, 2 mmol) was added and stirring continued at room temperature. After 3 h the solvent was evaporated under vacuum, and the residue was taken up in sodium bicarbonate solution (50 mL) and extracted with methylene chloride (3×50 mL). The combined extract was washed with water, dried over anhydrous sodium sulfate and evaporated. Chromatography of the residue over silica gel (eluant, 15% ethyl acetate in methylene chloride) gave the title compound as a cream colored solid, m.p. 156-158° C. 1H NMR (DMSO-d6): δ 2.68-2.82 (3H, m), 3.05-3.15 (4H, m), 6.36-6.42 (1H, br. t), 6.75-6.77 (2H, d, J=8.9 Hz), 7.09-7.15 (2H, m), 7.21-7.24 (4H, m), 7.45-7.47 (2H, d, J=8.8 Hz), 7.51-7.54 (1H, m), 7.98 (1H, s), 8.21-8.28 (1H, br. d.), 8.6-8.62 (1H, br. d.), 9.1 (1H, d, J=1.9 Hz).
Reaction SMILES: [C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@@H:10]1[CH2:12][O:11]1)([CH3:4])([CH3:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1>CCO.O>[C:1]([Si:5]([CH3:14])([CH3:13])[O:6][CH2:7][CH2:8][CH2:9][C@@H:10]([OH:11])[CH2:12][NH:15][C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[NH:21][C:20]=2[CH:26]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: CC(C)(C)[Si](C)(C)OCCC[C@@H]1CO1
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCCC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2
Yield: 39 %

Procedure:
A mixture of (R)-tert-butyl-dimethyl-(3-oxiranyl-propoxy)-silane (13 g, 60 mmol; prepared according to Org. Lett. (2005), 7, 3997) and 6-amino-4H-benzo[1,4]oxazin-3-one (9.9 g) in EtOH/H2O (9:1, 325 mL) was heated at reflux overnight. The volatiles were removed under reduced pressure and the residue purified by CC (Hept/EA 1:1) to give the desired intermediate as a brown oil (8.9 g, 39% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1.O=C1CCC(=O)N1[O:41][C:42](=O)[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][NH:57][C:58](=[O:68])[CH2:59][CH2:60][N:61]1[C:65](=[O:66])[CH:64]=[CH:63][C:62]1=[O:67].CCN(C(C)C)C(C)C>CS(C)=O>[Cl:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:32])[C:25]=1[C:24]([NH:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@H:12]([NH:11][C:9]([C:4]2([CH2:3][CH2:2][NH:1][C:42](=[O:41])[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][NH:57][C:58](=[O:68])[CH2:59][CH2:60][N:61]3[C:65](=[O:66])[CH:64]=[CH:63][C:62]3=[O:67])[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:10])[C:13]([OH:15])=[O:14])=[CH:22][CH:21]=1)=[O:33]
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Reactant: NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(CCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O)NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Reaction time: 1 h

Procedure:
To a solution of (S)-2-[[1-(2-aminoethyl)cyclopentanecarbonyl]amino]3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid (191.5 mg, 0.39 mmol) and 3-[2-[2-[2-[[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]-ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (200 mg, 0.39 mmol) in DMSO (2 mL) was added an excess of DIPEA (151 mg, 203 uL, 1.17 mmol) at room temperature under nitrogen atmosphere. The resulting light yellow solution was stirred for 1 h at which time LCMS analysis indicated the absence of starting material. Then, the excess DIPEA was removed under vacuum and the desired product was isolated by purification using an HPLC method to obtain 90 mg (26% yield) of (S)-3-[4-(2,6-dichlorobenzoylamino)phenyl]-2-[[1-[2-[3-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydropyrrol-1-yl)propionylamino]ethoxy]ethoxy]ethoxy]ethoxy]propionylamino]ethyl]cyclopentanecarbonyl]amino]propionic acid as a white solid. ES(+)-HRMS m/e calcd. for C42H53Cl2N5O12 (M+H)+ 890.3141, obsd. 890.3140.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:11]=1)[CH:7]([CH3:9])[CH3:8].[C:28]([O:32][CH3:33])(=[O:31])[CH2:29][SH:30].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:33][O:32][C:28](=[O:31])[CH2:29][S:30][CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:11]=1)[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)N(CCCCBr)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CSCCCCN(c1cnc(-c2ccccc2)c(-c2ccccc2)n1)C(C)C
Yield: 96.9 %

Procedure:
1.17 g of 1-bromo-4-[N-(5,6-diphenylpyrazin-2-yl)-N-isopropylamino]butane, 0.29 g of methyl thioglycolate, 0.46 g of potassium carbonate, a catalytic amount of potassium iodide and 27 ml of acetonitrile were mixed and the mixture was refluxed for 4 hours. The insoluble matter was removed by filtration and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.19 g of the desired compound as a pale yellow crystal having a melting point of 64 to 67° C.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:7]2[CH:6]=[CH:5][CH2:4]1.[C:15](OC(N[C@@H](CCC=C)C(O)=O)=O)(C)(C)C>>[ClH:1].[NH2:2][C@@H:3]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:7]2[CH:6]=[CH:5][CH2:4][CH2:15]1
Reactant: C=CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N[C@H]1CC=C[C@H]2CCCCN2C1=O
Agent: Cl
Agent: N[C@H]1CC/C=C\[C@H]2CCCCN2C1=O
Product: N[C@H]1CCC=C[C@H]2CCCCN2C1=O

Procedure:
(7S,11aR,Z)-7-Amino-3,4,7,8,9,11a-hexahydro-1H-pyrido[1,2-a]azocin-6(2H)-one hydrochloride (538 mg, 2.332 mmol) was synthesized as described for the preparation of Intermediate 53 using (S)-2-(tert-butoxycarbonylamino)hex-5-enoic acid in step E. Anal. Calcd. for C11H18N2O m/z 194.2. found: 195.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH:14]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:15]([N:25]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([OH:48])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:49][CH2:50][C:51]1([CH2:56]OS(C(F)(F)F)(=O)=O)[CH2:55][CH2:54][CH2:53][CH2:52]1>>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:15]([N:25]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C@@H:10]([O:48][CH2:56][C:51]2([CH2:50][F:49])[CH2:55][CH2:54][CH2:53][CH2:52]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(OCC1(CF)CCCC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)OCC1C(OCc1ccccc1)C(Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C[C@H](OCC2(CF)CCCC2)OC[C@@H]1[C@@H](OCc1ccccc1)[C@H](Cc1cc(F)cc(F)c1)N(Cc1ccccc1)Cc1ccccc1

Procedure:
Beginning with (R)-5-[1-benzyloxy-2-dibenzylamino-3-(3,5-difluorophenyl)-propyl]-2-hydroxymorpholine-4-carboxylic acid tert-butyl ester and trifluoromethane-sulfonic acid 1-fluoromethyl-cyclopentylmethyl ester, the desired compound may be prepared essentially as described in Preparation 306.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[O:15][C:16]3[C:21]([N:22]=2)=[CH:20][CH:19]=[CH:18][N:17]=3)[C@@H:10]([CH3:23])[CH2:9]1)C1C=CC=CC=1.Cl.C([O-])=O.[NH4+]>CO.[Pd]>[CH3:23][C@H:10]1[CH2:9][NH:8][CH2:13][CH2:12][N:11]1[C:14]1[O:15][C:16]2[C:21]([N:22]=1)=[CH:20][CH:19]=[CH:18][N:17]=2
Reactant: C[C@H]1CN(Cc2ccccc2)CCN1c1nc2cccnc2o1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Product: C[C@H]1CNCCN1c1nc2cccnc2o1
Yield: 76 %

Procedure:
To a solution of (S)-2-(4-benzyl-2-methyl-piperazin-1-yl)-oxazolo[5,4-b]pyridine (prepared according to the method of Example 16, Step A, 30 g, 97 mmol) in methanol (970 mL) was added hydrogen chloride (5.85 M in methanol, 20 mL, 116 mmol), ammonium formate (122 g, 1.95 mol), and 10% palladium on carbon (60 g, 200 wt %). This mixture was stirred at reflux for 50 min, cooled, and filtered through Celite. The filtrate was concentrated, diluted with saturated aqueous sodium bicarbonate, and extracted with chloroform (1×) followed by 10% isopropanol/chloroform (4×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give 16 g (76%) of the title compound of Example 16, Step B as a green oil. 1H NMR (CDCl3, 400 MHz) δ 7.89 (m, 1H), 7.53 (m, 1H), 7.09 (m, 1H), 4.42 (m, 1H), 4.11 (d, 1H), 3.35 (td, 1H), 3.09-3.03 (c, 2H), 2.85 (d, 1H), 2.82 (td, 1H), 1.38 (d, 3H); MS (APCI) 219 (MH+).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][C:14]3[N:13]=[CH:12][C:11]4[N:17]=[CH:18][N:19]([C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[C:22]#[N:23])[C:10]=4[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:29][OH:30].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[OH:30][NH:29][C:22](=[NH:23])[C:21]1[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=1[N:19]1[C:10]2[C:9]3[CH:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:17]=[CH:18]1
Reactant: N#Cc1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N=C(NO)c1ccccc1-n1cnc2cnc3ccc(-c4ccccc4)cc3c21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 300 mg (0.832 mmol) of 2-(8-phenyl-imidazo[4,5-c]quinolin-1-yl)-benzonitrile (Example 63) and 360 mg (5.19 mmol) hydroxylamine hydrochloride in 7 ml DMF, a solution of 490 mg (4.61 mmol) sodium carbonate in 2.6 ml water is added using a syringe within 3 min. After a few minutes, a precipitate starts to appear. Stirring is continued for 4 h at 70° C. (tlc-control). The reaction mixture is cooled to 0° C. and is poured into 100 ml ice-water. The compound is filtered off, washed with water and hexane, and dried at 65° C. for 16 h (high-vacuum). mp: 249-251° C. MS: 380 (M+1); HPLC: tret=6.91 min (Grad 1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:33]=[CH:32][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1)[CH3:2].[CH3:34][C:35]([NH2:39])([CH3:38])[CH2:36][CH3:37].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:11]1([N:10]2[C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:33]=[CH:32][C:7]=3[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:28])[NH:39][C:35]([CH3:38])([CH3:34])[CH2:36][CH3:37])=[CH:23][C:22]=3[O:30][CH3:31])(=[O:20])=[O:19])[C:9]2=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)O)cc1OC
Reactant: CCC(C)(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2S(=O)(=O)c1ccc(C(=O)NC(C)(C)CC)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1.09 g of the compound obtained in EXAMPLE 13, 1 ml of 1,1-dimethylpropylamine, 1.2 g of BOP, 1 ml of DIPEA and 20 ml of DCM is stirred for 2 hours at RT. The reaction mixture is evaporated under vacuum, the residue is extracted with AcOEt, washed with a 1N solution of HCl, with a 1N solution of NaOH and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/AcOEt mixture (99/1; v/v) as the eluent to give 0.88 g of the expected product in the form of white crystals. M.p.=219° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2].[N+:13]([O-])([O-:15])=[O:14].[K+].OS(O)(=O)=O>>[CH2:1]([C:3]1[C:12]([N+:13]([O-:15])=[O:14])=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CCc1ccc2cccnc2c1
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCc1ccc2cccnc2c1[N+](=O)[O-]
Yield: 10.9 %

Procedure:
In a similar fashion using route 7 general procedure 15, 7-ethylquinoline (Intermediate 57) (1.21 g, 7.7 mmol), potassium nitrate (1.01 g, 10.0 mmol) and H2SO4 (3.6 ml) gave the title compound (170 mg, 12%) after purification by column chromatography with n-hexane/EtOAc (23:2-17:3) gradient elution.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH3:22])=[C:12]([F:23])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)=O.O.[NH2:25][NH2:26]>CCO>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]2[C:5]([C:3]([NH:25][NH2:26])=[O:2])=[CH:6][C:7]3[NH:11][CH:10]=[N:9][C:8]=3[C:12]=2[F:23])=[C:16]([CH3:22])[CH:17]=1
Reactant: NN
Reactant: COC(=O)c1cc2nc[nH]c2c(F)c1Nc1ccc(Br)cc1C
Solvent: CCO
Solvent: O
Product: Cc1cc(Br)ccc1Nc1c(C(=O)NN)cc2[nH]cnc2c1F
Yield: 80.3 %

Procedure:
6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid methyl ester 8a (0.051 g, 0.135 mmol) is suspended in EtOH (5 mL) and hydrazine hydrate (0.118 g, 2.023 mmol) is added. The reaction mixture is heated at reflux for 16 hours. The reaction mixture is concentrated under reduced pressure and purified by FCC eluted with 97:3 ethyl acetate:MeOH to give 0.041 g (81%) of clean desired product: LC/MS ESI (+) m/z 378, 380 (M+Br pattern) detected.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([CH2:10][C:11]([O:13]CC)=O)=O)=[C:6]([F:16])[C:5]([F:17])=[C:4]([F:18])[C:3]=1[F:19].[C:20]1([NH:26][NH2:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>CO>[C:20]1([N:26]2[C:11]([OH:13])=[CH:10][C:8]([C:7]3[C:6]([F:16])=[C:5]([F:17])[C:4]([F:18])=[C:3]([F:19])[C:2]=3[F:1])=[N:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)CC(=O)c1c(F)c(F)c(F)c(F)c1F
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CO
Product: Oc1cc(-c2c(F)c(F)c(F)c(F)c2F)nn1-c1ccccc1
Temperature: 110 °C
Yield: 54 %

Procedure:
A mixture of 2.82 g (10 mmol) of ethyl pentafluorobenzoylacetate, phenylhydrazine (1.08 g; 10 mmol), and 0.33 ml of conc. HCl in 10 ml of methanol was refluxed for 18 hours. The mixture was concentrated in vacuo, the residue was diluted with toluene and heated at 110° C. for 20 hours and cooled. The mixture was diluted with sodium bicarbonate solution and extracted with ethyl acetate (3×). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel; 20-50% ethyl acetate/hexane) and recrystallized from ethyl acetate/hexane to afford 1.76 g (54%) of 1-phenyl-3-(pentafluorophenyl)-5-hydroxypyrazole as a white solid, mp 149-151° C.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[N:16]\[O:17][CH3:18])/[C:13]([NH2:15])=[O:14])(=O)C.[CH3:19]N.CO>CO>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[N:16][O:17][CH3:18])[C:13]([NH:15][CH3:19])=[O:14]
Reactant: CO/N=C(/C(N)=O)c1ccccc1COC(C)=O
Reactant: CN
Solvent: CO
Product: CNC(=O)C(=NOC)c1ccccc1CO
Temperature: 60 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
A mixture of (E)-2-(2-acetoxymethylphenyl)-2-methoxyiminoacetamide (432 mg), 40% methylamine/methanol solution (5 ml) and methanol (5 ml) was stirred at 60° C. for 16 hours in a sealed tube. After the mixture was cooled by allowing it to stand, the solvent was evaporated under reduced pressure. The resulting residue was crystallized from ethyl acetate-hexane. The crystallization mother liquor was concentrated under reduced pressure and purified by column chromatography on silica gel (ethyl acetate:hexane=4:1) to obtain the title compound (379 mg, yield: 98.3%, white crystals) as a mixture of the E- and Z-isomers (E/Z≠93/7 determined by 1H-NMR analysis).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([N:8]([CH2:29][CH3:30])[CH2:9][CH2:10][CH2:11][CH:12]([NH:14][C:15](=[O:28])[CH2:16][CH2:17][N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1)[CH3:13])[CH3:7].CN([CH:34]=[O:35])C>>[CH2:29]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][CH2:11][CH:12]([NH:14][C:15](=[O:28])[CH2:16][CH2:17][N:18]1[C:27]2[C:22](=[CH:23][C:24]([CH:34]=[O:35])=[CH:25][CH:26]=2)[CH2:21][CH2:20][CH2:19]1)[CH3:13])[CH3:30]
Reactant: CCN(CC)CCCC(C)NC(=O)CCN1CCCc2ccccc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)CCCC(C)NC(=O)CCN1CCCc2cc(C=O)ccc21
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
POCl3 (2.37 g, 15.3 mmol) was added dropwise to DMF (1.8 mL) which was cooled in an ice bath. The combined mixture was stirred for 30 minutes and to this a solution of Compound 5 (2.64 g, 7.6 mmol) in DMF (25 mL) was added dropwise over a period of 20 min. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature for 17 hour. An aqueous solution of sodium acetate (25% w/w, 25 mL) was then added to the reaction mixture and it was heated in an oil bath (T=110° C.) for 15 min. The reaction mixture was cooled and pH was adjusted with 10 N NaOH to ˜11. It was diluted with water (100 mL) and extracted with ethyl acetate. The organic layer was washed twice with water (75 mL) followed by brine (3×50 mL), dried over magnesium sulfate and then evaporated to dryness to yield 1.44 g of an orange viscous liquid which was used without any further purification. The structure of Compound 6 is given below:
Reaction SMILES: C1(P(C2CCCCC2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2C(OC)=CC=CC=2OC)CCCCC1.C1(C)C=CC=CC=1B(O)O.[C:40]([O:44][C@@H:45]([C:50]1[C:51]([CH3:78])=[N:52][C:53]2[N:54]([N:68]=[C:69]([C:71]3[CH:76]=[CH:75][CH:74]=[C:73](Cl)[CH:72]=3)[CH:70]=2)[C:55]=1[C:56]1[C:57]([CH3:67])=[C:58]2[C:63](=[C:64]([F:66])[CH:65]=1)[O:62][CH2:61][CH2:60][CH2:59]2)[C:46]([O:48][CH3:49])=[O:47])([CH3:43])([CH3:42])[CH3:41].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:40]([O:44][C@@H:45]([C:50]1[C:51]([CH3:78])=[N:52][C:53]2[N:54]([N:68]=[C:69]([C:71]3[CH:72]=[C:73]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[CH3:14])[CH:74]=[CH:75][CH:76]=3)[CH:70]=2)[C:55]=1[C:56]1[C:57]([CH3:67])=[C:58]2[C:63](=[C:64]([F:66])[CH:65]=1)[O:62][CH2:61][CH2:60][CH2:59]2)[C:46]([O:48][CH3:49])=[O:47])([CH3:43])([CH3:42])[CH3:41]
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(Cl)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1B(O)O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(-c3cccc(-c4ccccc4C)c3)nn2c1-c1cc(F)c2c(c1C)CCCO2
Temperature: 130 °C
Yield: 51.2 %

Procedure:
To a 2-5 ml microwave tube was added dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (595 mg, 1.449 mmol), PALLADIUM(II) ACETATE (163 mg, 0.725 mmol), o-tolylboronic acid (296 mg, 2.174 mmol) and (2S)-methyl 2-(tert-butoxy)-2-(2-(3-chlorophenyl)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (400 mg, 0.725 mmol) in DMF (1.5 mL), followed by 2M K3PO4 solution (200 μl). The reaction mixture was heated in a microwave reactor at 130° C. for 30 min. The reaction mixture was filtered and the filtrate was purified by silica gel chromatography to afford (225.6 mg, 51.2%) of the title compound. 1H NMR (500 MHz, CHLOROFORM-d) δ 7.86-7.76 (m, 2H), 7.42 (t, J=7.8 Hz, 1H), 7.29-7.26 (m, 5H), 6.88-6.86 (m, 2H), 4.99 (s, 1H), 4.39-4.27 (m, 2H), 3.64 (s, 3H), 2.83-2.70 (m, 5H), 2.26 (s, 3H), 2.22-2.13 (m, 2H), 1.84 (s, 3H), 1.16 (s, 9H).