Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:39])[C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:25][CH:24]=3)[C@@H:14]([CH3:40])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[C:41](Cl)(=[O:43])[CH3:42].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:41]([N:36]1[CH2:35][CH2:34][N:33]([CH2:32][CH2:31][CH2:30][O:29][C:26]2[CH:27]=[CH:28][C:23]([C:22]([N:15]3[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C@H:12]([N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:9](=[O:11])[CH3:10])[CH2:13][C@@H:14]3[CH3:40])=[O:39])=[CH:24][CH:25]=2)[CH2:38][CH2:37]1)(=[O:43])[CH3:42]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCN3CCNCC3)cc2)c2ccccc21
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(CCCOc2ccc(C(=O)N3c4ccccc4[C@H](N(C(C)=O)c4ccc(Cl)cc4)C[C@@H]3C)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.4 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-{2-methyl-1-[4-(3-piperazin-1-yl-propoxy)-benzoyl]-1,2,3,4-tetrahydro-quinolin-4-yl}-acetamide (168 mg) was dissolved in CH2Cl2 (2 mL). Acetic chloride (47 mg) and DIEA (52 uL) were added. The reaction mixture was stirred at room temperature overnight. The organic phase was washed with sat. NaHCO3 (2×5 mL), dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (EtOAc) to afford pure (2S,4R)-N-(1-{4-[3-(4-acetyl-piperazin-1-yl)-propoxy]-benzoyl}-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-N-(4-chloro-phenyl)-acetamide (100 mg, 57%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH3:9][NH:10][CH:11]([CH2:13][CH3:14])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[Cl:8][C:4]1[N:3]=[C:2]([N:10]([CH3:9])[CH:11]([CH3:12])[CH2:13][CH3:14])[CH:7]=[N:6][CH:5]=1
Reactant: CCC(C)NC
Reactant: Clc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(C)N(C)c1cncc(Cl)n1
Temperature: 80 °C
Reaction time: 40 h
Yield: 72 %

Procedure:
A mixture of 2,6-dichloropyrazine (1.49 g), N-methylbutan-2-amine (1.31 mL), potassium carbonate (2.07 g) and DMA (10 mL) was stirred at 80° C. for 40 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 5→20% ethyl acetate/hexane) to give the title compound (1.43 g, 72%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[N:7]=1)#[N:5]>CO>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:8]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:14]2[C:6]([C:4](=[NH:5])[O:2][CH3:1])=[N:7]1
Reactant: N#Cc1nn(Cc2ccccc2F)c2ncccc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1nn(Cc2ccccc2F)c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30.37 g (562 mmol) of sodium methoxide are dissolved in 1.5 l of methanol and 36.45 g (144.5 mmol) of 3-cyano-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (from Example 3D) are added. The mixture is stirred at room temperature for 2 hours and the solution obtained is employed directly for the next step.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1>>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][CH3:24])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[CH:28][CH:29]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COc1ccccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Product: COc1ccccc1-c1cccc(-n2cnc(C(=O)c3ccc(F)cc3)c2)c1

Procedure:
This compound is prepared by method C using compound 12c and 1-bromo-4-fluorobenzene
Reaction SMILES: F[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1(C)CCC2C(=CC=CC=2)C1=O>>[CH2:14]([C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]([CH3:13])([CH3:12])[C:8]2=[O:11])=[CH:4][CH:3]=1)[CH3:15]
Reactant: CC1(C)CCc2ccccc2C1=O
Reactant: CC1(C)Cc2ccc(F)cc2C1=O
Product: CCc1ccc2c(c1)C(=O)C(C)(C)C2

Procedure:
6-Fluoro-2,2-dimethyl-1-indanone, a white crystalline solid melting at 64.5°-66.5° C. and 2,2-dimethyl-1-tetralone, a colorless liquid boiling at 88°-89° C. under 0.75 mm Hg (100 Pascals) pressure were prepared similarly.
Reaction SMILES: N[C:2]1[S:3][C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:6]=1.N(OCCC(C)C)=O>CN(C=O)C.C1COCC1>[CH2:10]([O:9][C:7]([C:4]1[S:3][CH:2]=[N:6][CH:5]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1cnc(N)s1
Agent: CC(C)CCON=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cncs1
Temperature: 25 °C

Procedure:
A solution of 2-amino-5-(ethoxycarbonyl)thiazole (50 9, 0.29 mmol) in a mixture of DMF (83 mL) and THF (317 mL) was added dropwise over 87 minutes to a stirred 41° C. solution of isoamyl nitrite (59 mL, 0.44 mol) in DMF (130 mL). A maximum temperature of 60° C. was observed during the exothermic addition. After another 40 minutes the THF was removed under vacuum at 45° C. The concentrated DMF solution was cooled to 25° C. and diluted with toluene (420 mL) and water (440 mL). The toluene layer was extracted with 3×120 mL water, then dried with Na2SO4 (50 g) for 1 hour. After filtration the toluene layer was stripped on a rotary evaporater at 50° C. bath temperature, then on a vacuum pump at 21° C. The crude residue containing the title compound weighed 65.6 g. This material was used directly in the next step. A sample of similarly prepared material was purified by column chromatography to give a yellow oil. 1H NMR (CDCl3) δ 8.95 (s, 1H), 8.51 (s, 1H), 4.39 (q, 2H), 1.40 (t, 3H). 13C NMR (CDCl3) δ 161.0, 157.9, 148.6, 129.8, 61.6, 14.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]([CH3:17])[C:10]1=[O:18].Cl[C:20]1[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:29])[F:28])=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[C:25]([Cl:26])=[CH:24][C:23]([C:27]([F:30])([F:28])[F:29])=[CH:22][N:21]=2)=[CH:4][C:3]=1[N:9]1[C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]([CH3:17])[C:10]1=[O:18]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: Cn1c(=O)[nH]c(=O)n(-c2cc(O)ccc2Br)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)n(-c2cc(Oc3ncc(C(F)(F)F)cc3Cl)ccc2Br)c1=O
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(2-bromo-5-hydroxyphenyl)-3-methyl-s-triazine-2,4,6(1H,3H,5H)-trione (5.29 g, 0.0168 mol), 2,3-dichloro-5-trifluoromethylpyridine (5.44 g, 0.025 mol) and potassium carbonate (3.45 g, 0.025 mol) in N,N-dimethylformamide is stirred at 80° C. for 18 hours, cooled to room temperature and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. The solid is recrystallized from an ether/hexanes solution to give the title product as a yellow solid, mp 97°-110° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[CH2:32]1[CH2:36]OC[CH2:33]1.CO>[OH-].[Na+]>[CH2:31]([O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:6]2([C:4]([OH:3])=[O:5])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH2:8][CH2:7]2)(=[O:22])=[O:23])=[CH:29][CH:28]=1)[CH2:33][CH2:32][CH3:36]
Reactant: C1CCOC1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2cccc(OC)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3cccc(OC)c3)CC2)cc1

Procedure:
4-(4-Butoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid ethyl ester (2.61 g, 5.34 mmol) dissolved in THF:methanol (3:1 150 ml) and 10 N NaOH (15 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1 g (41%); brown solid; mp 175° C.; MS: 462.0 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[C:28]([Cl:30])[CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:25]=[C:24]([Cl:23])[CH:29]=[C:28]([Cl:30])[CH:27]=3)[CH2:36][CH2:35]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: COc1cc2ccccc2cc1NC(=O)Oc1ccccc1
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Product: COc1cc2ccccc2cc1NC(=O)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 76.7 %

Procedure:
Phenyl N-(2-methoxynaphth-3-yl)carbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 86 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.O[CH:11]1[CH2:15][CH2:14][O:13][CH2:12]1>>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([O:8][CH:11]2[CH2:15][CH2:14][O:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: OC1CCOC1
Reactant: Cc1cc(O)ncc1Br
Product: Cc1cc(OC2CCOC2)ncc1Br

Procedure:
The title compound was prepared from 5-bromo-2-hydroxy-4-methylpyridine and rac-3-hydroxy-tetrahydrofuran in analogy to Example 9c): colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](Cl)[CH:6]=[CH:5][CH:4]=1.O.[NH2:11][NH2:12]>>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:11][NH2:12])[CH:6]=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1cccc(Cl)n1
Solvent: O
Product: COc1cccc(NN)n1
Yield: 25.5 %

Procedure:
90 g (0.626 mol) of 6-methoxy-2-chloropyridine and 313.4 g of hydrazine hydrate were refluxed for 18 hours with stirring. The reaction mixture was cooled and the oil of the bottom layer was separated. The top layer was extracted three times with diethyl ether (total volume of 450 ml). The oil and the bottom layer left after extraction with diethyl ether were distilled under reduced pressure to remove the hydrazine hydrate. The residue was dissolved in 150 ml of a 20% aqueous solution of potassium hydroxide and extracted twice with diethyl ether (total volume 300 ml). The ether extract was dried with potassium hydroxide and combined with the ether solution. The mixture was distilled to afford 22.2 g of the desired product having a boiling point of 144° to 150° C./19-20 mmHg (yield 25%). Upon cooling, the product crystallized providing crystals having a melting point of about 30° to 40° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[O:1]=[CH:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (0.6 g, 2.6 mmol) in dichloromethane (30 mL) was added Dess-Martin-periodinane (1.2 g, 2.8 mmol), and the mixture was stirred at room temperature for 90 min. A 10% aqueous solution of sodium thiosulfate (15 mL) was added followed by saturated sodium bicarbonate (15 mL), and the biphasic mixture was stirred at room temperature for 1 h. The layers were separated, the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate, and brine, dried over sodium sulfate, filtered and concentrated to afford tert-butyl 4-(oxoethyl)piperidine-1-carboxylate that was used directly without further purification.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][C:10](=[O:13])[CH2:11]I)=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:24][O:25][C@@H:26]1[CH2:31][CH2:30][C@H:29]([NH2:32])[CH2:28][CH2:27]1>C(#N)C>[Br:8][C:6]1[N:7]=[C:2]2[N:32]([C@H:29]3[CH2:30][CH2:31][C@@H:26]([O:25][CH3:24])[CH2:27][CH2:28]3)[CH2:11][C:10](=[O:13])[NH:9][C:3]2=[N:4][CH:5]=1
Reactant: O=C(CI)Nc1ncc(Br)nc1Br
Reactant: CO[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@H]1CC[C@@H](N2CC(=O)Nc3ncc(Br)nc32)CC1
Temperature: 55 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a solution of N-(3,5-dibromopyrazin-2-yl)-2-iodoacetamide (See Example 5.B) (1.0 g, 2.376 mmol) and diisopropylethylamine (1.038 mL, 5.94 mmol) in acetonitrile (10 mL) was added (cis)-4-methoxycyclohexanamine hydrochloride (0.413 g, 2.495 mmol). The solution was stirred at 55° C. for 3 h. The resulting precipitate was filtered and washed with acetonitrile and dried under reduced pressure to afford the title compound (0.442 g, 1.29 mmol, 55% yield). MS (ESI) m/z 341.3 [M]+, 343.3 [M+2]+.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[NH:11]([CH2:13][CH2:14][OH:15])[NH2:12]>C(O)C>[NH2:6][C:5]1[N:11]([CH2:13][CH2:14][OH:15])[N:12]=[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])[CH:4]=1
Reactant: NNCCO
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(CCO)n1
Yield: 97.3 %

Procedure:
A solution of 4,4-dimethyl-3-oxo-pentanenitrile (5.00 g, 40.0 mmol), concentrated HCl (0.1 mL), and 2-hydrazino ethanol (2.98 mL, 44.0 mmol) in ethanol (40 mL) was refluxed for 20 h. The reaction mixture was then concentrated in vacuo. The resulting oily solid was washed with cyclohexane (30 mL), and dissolved in MeOH (5 mL) and H2O (5 mL) and lyophilised to give the title compound as a white powder (7.13 g, 97%). LCMS (Method 3): Rt 0.43 min, m/z 184 [MH+].
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:14]2([C:18](=[O:19])[N:17]([OH:20])[C:16](=[O:21])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:27][C:28]#[N:29]>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:14]2([C:18](=[O:19])[N:17]([O:20][CH2:27][C:28]#[N:29])[C:16](=[O:21])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CC(=O)N(O)C2=O
Reactant: N#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCON1C(=O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-benzyloxycarbonyl-2-hydroxy-2,8-diazaspiro[4,5]decane-1,3-dione (0.96 g) in dimethylformamide (5 ml) was added 132 mg of sodium hydride (60% in oil), and the mixture was stirred for one hour at room temperature. To the reaction mixture was added 210 μl of chloroacetonitrile, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was treated in the same manner as in Example 40 to obtain 1.0 g of a non-crystalline solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)([CH3:25])=[O:24].Cl.C(=O)(O)[O-].[Na+]>COCCO.CCO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([P:23]([CH3:25])([CH3:22])=[O:24])=[CH:32][CH:31]=2)=[N:3][CH:4]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CP(C)(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: COCCO
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc(P(C)(C)=O)cc2)ncc1Cl
Temperature: 140 °C
Yield: 149.1 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (prepared as in Example 17: 50 mg, 0.14 mmol) in 1 mL of 2-methoxyethanol was added 4-(dimethylphosphoryl)-aniline (0.025 g, 0.14 mmol) and 0.12 ml of 2.5M HCl in EtOH. The mixture was heated in a sealed tube at 140° C. for 1 h. The mixture was basified with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was purified by prep-HPLC to give the final product (0.100 g, 15% yield). MS/ES+: m/z=478.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[N:6]=[C:5]2[NH:23][C:24]1[N:25](C(C)(C)C)[N:26]=[C:27]([CH3:29])[CH:28]=1.Cl>CO>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1)[N:6]=[C:5]2[NH:23][C:24]1[NH:25][N:26]=[C:27]([CH3:29])[CH:28]=1
Reactant: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3ccc(N)cc23)n(C(C)(C)C)n1
Agent: Cl
Solvent: CO
Product: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3ccc(N)cc23)[nH]n1
Temperature: 80 °C
Yield: 45.8 %

Procedure:
30 mg 6-amino-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one were dissolved in 0.5 ml MeOH. 2 ml conc. HCl were added and the mixture was heated to 80° C. for 7 hrs. The mixture was evaporated under vacuum, the residue dissolved in DCM and washed with sodium bicarbonate solution. Removal of the DCM yielded 12 mg of the title product. 1H-NMR: (400 MHz, D6-DMSO) 11.75 (1H, br s), 8.75 (1H, br s), 8.00 (1H, d), 7.59 (2H, d), 7.46 (2H, d), 7.27 (1H, s), 7.05 (1H, d), 6.16 (br s, 2H), 2.17 (3H, s), 1.33 (9H, s); MS (ESI+)=389.22 (M+H)+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:10][CH:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([NH:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH:7]=1)[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CC(C)Oc1ccc([N+](=O)[O-])c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 80 °C
Reaction time: 17 h
Yield: 97.5 %

Procedure:
A solution of 2-fluoro-4-[(1-methylethyl)oxy]-1-nitrobenzene (D46, 276 mg, 1.39 mmol) in dimethylformamide (10 ml) was treated with 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (278 mg, 1.39 mmol) and diisopropylethylamine (0.241 ml, 1.39 mmol) and stirred at approx. 80° C. for 17 hrs. The mixture was concentrated under vacuum and the residue treated with water and extracted with a mixture of ethyl acetate/diethyl ether (×2). The combined extract was dried and concentrated under vacuum to afford the title compound as a yellow oil/solid (514 mg, 97%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:14]=[C:13]3B2OC(C)(C)C(C)(C)O2)=[N:8][N:9]=1)([CH3:3])[CH3:2].Br[C:39]1[N:44]=[C:43]([C:45]([OH:47])=[O:46])[CH:42]=[CH:41][CH:40]=1.O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]([NH:4][C:5]1[O:6][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:20])=[O:21])[CH:14]=[C:13]3[C:39]2[N:44]=[C:43]([C:45]([OH:47])=[O:46])[CH:42]=[CH:41][CH:40]=2)=[N:8][N:9]=1)([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Reactant: O=C(O)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cccc(C(=O)O)n3)c3cc(-c4nnc(NC(C)C)o4)ccc32)cc1
Temperature: 90 °C

Procedure:
To a solution of N-isopropyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (500 mg, 0.957 mmol) and 6-bromopicolinic acid (280 mg, 1.436 mmol, Sigma-Aldrich) in DME (10 mL)/water (2.5 mL) was added Na2CO3 (304 mg, 2.871 mmol) and Pd(PPh3)4 (111 mg, 0.096 mmol) and Ar gas was bubbled for 5 min. The reaction mixture was heated at 90° C. for 4 h. The reaction was quenched with water (200 mL) to get a brown precipitate. The precipitate was filtered, washed with water (2×100 mL) and dried to give crude product, which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 518.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([OH:19])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4].[C:23](N=P(N(C)C)(N(C)C)N(C)C)(C)([CH3:25])[CH3:24].C(Br)C=C>ClCCl.Cl>[F:22][C:2]([F:1])([F:21])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:20])[C:17]([O:19][CH2:25][CH:23]=[CH2:24])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)C1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Reactant: CN(C)P(=NC(C)(C)C)(N(C)C)N(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C=CCBr
Product: C=CCOc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 3 h
Yield: 58.2 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-7-hydroxy-1-isopropyl-2,3,4,5-tetrahydro-1H-3-benzazepine (0.017 g, 0.045 mmol) in dichloromethane (1 mL) was treated with N′″-tert-butyl-N,N,N′,N′,N″,N″-hexamethylphosphorimidic triamide (0.016 g, 0.068 mmol), allyl bromide (0.011 g, 0.09 mmol) and stirred for 3 hours at 20 C. The product mixture was diluted with 10% aqueous HCl, extracted twice with dichloromethane (20 mL), and concentrated. Flash chromatography (10% EtOAc in hexanes, silica) resulted in 0.011 g of a clear oil. MS calculated for C18H21BrF3NO2+H: 420, observed: 420.
Reaction SMILES: CS([CH2:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:13]([C:14]#[N:15])[C:12]=2[C:19]#[N:20])=[CH:8][CH:7]=1)(=O)=O.[Li+].[Br-:24]>C1COCC1>[Br:24][CH2:5][C:6]1[CH:22]=[CH:21][C:9]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[C:13]([C:14]#[N:15])[C:12]=2[C:19]#[N:20])=[CH:8][CH:7]=1
Reactant: [Br-]
Reactant: CS(=O)(=O)Cc1ccc(Oc2cccc(C#N)c2C#N)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1cccc(Oc2ccc(CBr)cc2)c1C#N
Temperature: 25 °C

Procedure:
To a solution of 3-[4-(methansulfonylmethyl)phenoxy]phthalonitrile (1.1 g, 3.1 mmol) prepared according to Example 2, in anhydrous THF (15 ml) kept in an inert atmosphere, LiBr (0.4 g, 4.6 mmol) was added. The solution was refluxed for 1 hour, during which a white precipitate formed, then it was allowed to cool at room temperature. The white precipitate was filtered off and the solvent was evaporated. From the crude mixture the desired product was isolated by filtration on silica gel (eluent: chloroform). (900 mg, 93%).
Reaction SMILES: N[CH:2]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:3](O)=[O:4].[CH:10]1([NH:17][C:18]([NH2:20])=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[C:6]([CH:2]1[S:19][C:18]([NH:17][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)=[N:20][C:3]1=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C(N)C(=O)O
Reactant: NC(=S)NC1CCCCCC1
Product: CC(C)(C)C1SC(NC2CCCCCC2)=NC1=O

Procedure:
Synthesis was performed from 2-amino-3,3-dimethylbutanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Br[CH:12]([CH3:20])[C:13]([O:15]C(C)(C)C)=[O:14]>>[CH2:9]([O:8][C:6]([C:4]1[CH:5]=[N:1][N:2]([CH:12]([CH3:20])[C:13]([OH:15])=[O:14])[CH:3]=1)=[O:7])[CH3:10]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cn[nH]c1
Product: CCOC(=O)c1cnn(C(C)C(=O)O)c1
Yield: 87.2 %

Procedure:
By a reaction in the same manner as in Example 10a and using ethyl 1H-pyrazole-4-carboxylate (1.40 g, 10.0 mmol) and tert-butyl 2-bromopropanate (3.14 g, 15.0 mmol), the title compound (1.85 g, 87%) was obtained as a colorless oil.