Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([S:13](Cl)(=[O:15])=[O:14])[CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.N1C=CC=CC=1>C1COCC1>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([S:13]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=3)(=[O:15])=[O:14])[CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1
Reactant: Nc1ccc2cc(Cl)cc(S(=O)(=O)Cl)c2n1
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Nc1ccc2cc(Cl)cc(S(=O)(=O)Nc3ccc(C(=O)O)cc3)c2n1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
A mixture of 2-amino-6-chloroquinoline-8-sulfonyl chloride (500 mg, 1.8 mmol), 4-aminobenzoic acid (300 mg, 2.2 mmol) and pyridine (1 mL) in 10 mL of THF was stirred at 30° C. overnight, when LCMS indicated that the reaction was complete. The resulting mixture was concentrated, and the residue was purified by a standard method to yield the title compound. LCMS (m/z): 378.8 (M+1)+
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1.N1C=CC=CC=1.O.[NH2:21][NH2:22]>O>[NH:21]([C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][N:3]=1)[NH2:22]
Reactant: NN
Reactant: Clc1cnc(-c2ccccc2)cn1
Solvent: c1ccncc1
Solvent: O
Product: NNc1cnc(-c2ccccc2)cn1

Procedure:
A mixture of 1.0 g. of 2-chloro-5-phenylpyrazine, m.p. 98°-99° C., 5.0 ml. of pyridine and 5.0 ml. of hydrazine hydrate is heated at reflux for 1.5 hours. The solution is cooled, and 20 ml. of water is added. The colorless crystalline product is collected and air dried. The crude product is recrystallized from aqueous ethanol to yield 0.35 g. of the product of the example as colorless needles, m.p. 128°-130° C.
Reaction SMILES: [OH2:1].[C:2](#[N:5])[CH:3]=[CH2:4]>CC(C)=O>[N+:5]([C:2]1[CH:4]=[CH:3][C:2]([NH2:5])=[CH:4][CH:3]=1)([O-:1])=[O:1]
Reactant: C=CC#N
Reactant: O
Solvent: CC(C)=O
Product: Nc1ccc([N+](=O)[O-])cc1

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-nitrocinnamonitrile thus obained 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: C(O)C.[C:4]1([S:14]([CH2:17][C:18]2[CH:19]=[C:20]([CH:35]=[CH:36][C:37]=2[N+:38]([O-])=O)[O:21][CH2:22][CH2:23][O:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])(=[O:16])=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1>[Pd].C1COCC1>[NH2:38][C:37]1[CH:36]=[CH:35][C:20]([O:21][CH2:22][CH2:23][O:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:26])=[O:27])=[CH:19][C:18]=1[CH2:17][S:14]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:15])=[O:16]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3cccc4ccccc34)c2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(N)c(CS(=O)(=O)c3cccc4ccccc34)c2)cc1
Reaction time: 5 h
Yield: 87.6 %

Procedure:
Ethanol (180 mL) and 10% palladium on carbon (5.2 g) were added to a hot solution of toluene-4-sulfonic acid 2-[3-(naphthalene-1-sulfonylmethyl)-4-nitro-phenoxy]-ethyl ester (11.5 g, 21.2 mmol) in THF (180 mL). This mixture was shaken on the Parr hydrogenation apparatus for 5 hours, with a starting pressure of 47 psi. It was then filtered over Celite, concentrated and dried in vacuo at 80° C. for 30 minutes to give toluene-4-sulfonic acid 2-[4-amino-3-(naphthalene-1-sulfonylmethyl)-phenoxy]-ethyl ester as a dark brown gum (9.5 g, 88.0%). Mass Spectrum (+EI, [M+H]+) m/z 512. 1HNMR (500 MHz, DMSO-d6): 88.61 (d, 1H, J=8.41 Hz), 8.25 (d, 1H, J=8.30 Hz), 8.03-8.08 (m, 2H), 7.59-7.75 (m, 5H), 7.43 (d, 2H, J=7.93 Hz), 6.49-6.53 (m, 2H), 6.11 (d, 1H, J=2.68 Hz), 4.65-4.77 (br, 2H), 4.59 (s, 2H), 4.09-4.11 (m, 2H), 3.63-3.65 (m, 2H), 2.38 ppm (s, 3H).
Reaction SMILES: [NH:1]([C:3]([O:5][CH3:6])=[O:4])[NH2:2].N1C=CC=CC=1.[C:13]([CH2:17][C:18](Cl)=[O:19])([CH3:16])([CH3:15])[CH3:14]>ClCCl>[CH3:14][C:13]([CH3:16])([CH3:15])[CH2:17][C:18]([NH:2][NH:1][C:3]([O:5][CH3:6])=[O:4])=[O:19]
Reactant: COC(=O)NN
Reactant: CC(C)(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)NNC(=O)CC(C)(C)C
Yield: 95 %

Procedure:
A solution of 65.5 g of hydrazinecarboxylic acid, methyl ester, 150 ml of dry pyridine and 500 ml of dry dichloromethane was stirred at 0° C. and 100 g of distilled t-butylacetyl chloride was added dropwise. After 2 hours at 0°-5° C. the solvent was removed in vacuo. The residue was taken up in 1.2 liters of ethyl acetate, washed with saturated sodium chloride and filtered through a bed of hydrous magnesium silicate with additional ethyl acetate. The filtrate was concentrated and the solid recrystallized from diisopropyl ether, giving 130 g of 2-(3,3-dimethyl-1-oxobutyl)hydrazinecarboxylic acid, methyl ester as white platelets, mp 83°-84.5° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[CH2:10][CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[Li+].CC([N-]C(C)C)C.Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[Cl:35]>>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[CH2:27][CH:14]1[CH2:15][CH2:16][N:12]([C@H:11]2[CH2:10][CH2:9][C:4]3([O:5][CH2:6][CH2:7][O:8]3)[CH2:3][C@H:2]2[CH3:1])[C:13]1=[O:17]
Reactant: C[C@@H]1CC2(CC[C@@H]1N1CCCC1=O)OCCO2
Reactant: Clc1ccc(CBr)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: C[C@@H]1CC2(CC[C@@H]1N1CCC(Cc3ccc(Cl)cc3Cl)C1=O)OCCO2
Yield: 56.5 %

Procedure:
Using the procedure to synthesize Example 1 and using reagent 1-(cis-7-methyl-1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one (Preparation 45) (2.49 g, 10.4 mmol), LDA (1.5M, 8.3 mL, 12.5 mmol) and 1-(bromomethyl)-2,4-dichlorobenzene (4.07 g, 20.8 mmol) yields 2.34 g (56%) of 3-(2,4-dichloro-benzyl)-1-(cis-7-methyl-1,4-dioxa-spiro[4.5]dec-8-yl)-pyrrolidin-2-one as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]=[C:20]=[O:21])=[CH:14][C:13]=1[Cl:22].CCCCCC>C1COCC1>[Cl:22][C:13]1[CH:14]=[C:15]([CH:16]=[CH:17][C:12]=1[Cl:11])[CH2:18][NH:19][C:20]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2)=[O:21]
Reactant: Nc1cccc2[nH]ccc12
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1cccc2[nH]ccc12

Procedure:
4-Aminoindole (0.13 g, 1 mmol) in THF (3 mL) was treated with 1,2-dichloro-4-(isocyanatomethyl)benzene (0.22 g, 1.1 mmol) for 3 h at ambient temperature. Hexane was added to the reaction mixture to precipitate 0.25 g of the title compound as a tan solid. mp 201° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.23 (d, 2H), 6.36 (s, 1H), 6.54 (t, 1H), 7.0 (dd, 1H), 7.25 (m, 2H), 7.30 (d, 2H), 7.45 (d, 1H), 7.6 (m, 2H), 8.31 (s, 1H), 10.87 (s, 1H) MS (DCI+) m/z 336 (M+H); Anal. Calcd. For C16H13N3Cl2O: C, 57.50; H, 3.92; N, 12.57. Found: C, 56.94, H, 3.68; N, 11.97.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[O:9])=[C:6]([CH3:19])[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1.[CH:26]([Mg]Cl)([CH3:28])[CH3:27].[NH4+].[Cl-]>C1COCC1.CN1C(=O)CCC1>[F:18][C:14]1[CH:13]=[C:12]([CH2:11][NH:10][C:8]([C:7]2[C:2]([CH:26]([CH3:28])[CH3:27])=[N:3][C:4]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:5][C:6]=2[CH3:19])=[O:9])[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Reactant: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)nc(C(C)C)c1C(=O)NCc1cccc(F)c1
Temperature: -30 °C
Yield: 36.1 %

Procedure:
A solution of 300 mg (0.83 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 9) in THF/NMP (6:1 v/v, 14 ml) was cooled to −30° C. At this temperature were successively added 58 mg (0.16 mmol) Fe(acac)3 and 6 ml (12.0 mmol, 2M in THF) iso-propyl-magnesium-chloride. The RM was then allowed to warm to 0° C. within 1 h. Then sat. aq. NH4Cl sol. was added the mixture was extracted with EtOAc (3×20 ml). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 110 mg (0.30 mmol, 36%) N-[(3-Fluorophenyl)-methyl]-2-isopropyl-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (example 23). [M+H]+372.2.
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH2:29]([CH2:31][NH2:32])[OH:30]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C@:13]1([CH3:23])[CH2:17][CH2:16][C@H:15]([C:18]([NH:32][CH2:31][CH2:29][OH:30])=[O:20])[C:14]1([CH3:21])[CH3:22])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: NCCO
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)[C@]1(C)CC[C@H](C(=O)NCCO)C1(C)C

Procedure:
The product from Example 173 and ethanolamine hydrochloride (Aldrich) were processed using the method described in Example 178 to afford the title compound. 1H NMR (DMSO-d6) δ 0.47 (s, 3H), 0.90 (t. J=7.0 Hz, 3H), 1.19 (s, 3H), 1.23 (s, 3H), 1.26-1.48 (m, 4H), 1.57 (s, 9H), 1.57-1.67 (m, 3H), 1.96-2.08 (m, 1H), 2.62-2.68 (m, 2H), 2.71-2.82 (m, 1H), 3.00-3.10 (m, 1H), 3.14-2.25 (m, 1H), 3.33-3.39 (m, 2H), 4.62 (t, J=4.6 Hz, 1H), 7.52 (t, J=5.7 Hz, 1H), 8.50 (s, 1H). MS (ESI+) m/z 438 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH3:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([N:10]2[C:14]([CH2:15][Br:27])=[CH:13][C:12]([C:16]([F:18])([F:19])[F:17])=[N:11]2)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(F)(F)F)nn1-c1ccc(F)c(C#N)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2CBr)ccc1F
Yield: 48.3 %

Procedure:
To a solution of 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-methyl pyrazole(4.0 g, 14.87 mmol) in carbon tetrachloride(50 mL) was added NBS (2.65 g, 14.87 mmol) and benzoyl peroxide (0.36 g, 1.48 mmol). The reaction mixture was brought to reflux overnight. Solvent was removed on rotary evaporator under reduced pressure. Residue was partitioned between ethyl acetate (80 mL) and sodium bicarbonate (sat. 80 mL). Organic phase was separated and washed with water (60 mL); dried over sodium sulfate; filtered, concentrated and subjected to silica-gel flash chromatography (ethyl acetate:hexane, 1:10) to afford 1-(3-cyano-4-fluorophenyl)-3-trifluoromethyl-5-bromomethyl pyrazole (2.5 g). CI mass spectrum m/z (rel. intensity) 348 (M+H, 100).
Reaction SMILES: Cl.[F:2][C:3]([F:16])([F:15])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([CH:12]([NH2:14])[CH3:13])=[CH:8][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][N:26]=1)[C:21](O)=[O:22].C(N(CC)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)C=O>[NH2:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][N:26]=1)[C:21]([NH:14][CH:12]([C:9]1[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([F:2])([F:15])[F:16])=[CH:7][CH:8]=1)[CH3:13])=[O:22]
Reactant: Nc1cc(C(=O)O)ccn1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
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: CC(NC(=O)c1ccnc(N)c1)c1ccc(OCC(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a mixture of (−)-1-(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (300 mg, 1.17 mmol, Amine-1, single enantiomer), 2-aminoisonicotinic acid (161 mg, 1.17 mmol), and N,N-diisopropylethylamine (0.82 mL, 4.68 mmol) in N,N-dimethylformamide (12 mL) is added HBTU (665 mg, 1.75 mmol) at room temperature. After stirring at room temperature for 1 hour, the mixture is poured onto water (20 mL), and the mixture is extracted with ethyl acetate (20 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel eluting with dichloromethane/methanol (10:1) to give 252 mg (63% yield) of the title compound as a slight brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH2:17]([NH:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[CH2:17]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:37])=[CH:39][CH:40]=1)[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 6.4 g. 4-chlorophenol and 7.6 g. triethylamine in 500 ml. methylene chloride is added 10.4 g. 4(4-tetradecenylamino)benzoyl chloride hydrochloride in 250 ml. methylene chloride. After four hours at reflux, the solution is cooled, washed with water and dilute phosphoric acid, and dried. After passing the solution through a column of alumina, the solvent is evaporated and the residue is crystallized from diisopropyl ether.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][CH:5]([C:7]2[N:11]3[CH:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]3=[C:9]([C:17]3[CH:26]=[C:25]4[C:20]([CH:21]=[CH:22][C:23]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)=[N:24]4)=[CH:19][CH:18]=3)[N:8]=2)[CH2:4]1.CCN(C(C)C)C(C)C.[CH3:42][C:43](OC(C)=O)=[O:44]>C(Cl)Cl>[NH2:16][C:15]1[C:10]2[N:11]([C:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:43](=[O:44])[CH3:42])[CH2:6]3)=[N:8][C:9]=2[C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[CH:22][C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[N:24]3)=[CH:19][CH:18]=2)[CH:12]=[CH:13][N:14]=1
Reactant: NCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn23)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NC[C@H]1C[C@@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(N)nccn32)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 3-[3-(aminomethyl)cyclobutyl]-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-amine (0.237 mmol, 100 mg) in DCM (6 mL) was charged with DIEA (0.475 mmol, 83 μL) and Ac2O (0.237 mmol, 22.43 μL) at −40° C. The reaction solution was warmed to rt slowly and stirred under N2 for 1.5 h. The reaction was quenched with water (3 mL), diluted with methylene chloride (20 mL), washed with water (30 mL) and brine (30 mL), and dried (Na2SO4). The filtrate was concentrated under reduced pressure, and the crude material was purified by silica gel flush column chromatography (Jones Flashmaster, 10 g/70 mL cartridge), eluting with 3% MeOH (7 N NH3) in DCM, yielding the title compound as a light yellow solid. The sample was recrystallized from DCM (minimal amount) and EtOAc. The final product was obtained as an off-white solid; 1H NMR (400 MHz, CDCl3) δ 8.43-8.42 (m, 1H), 8.28 (dd, J=8.0 Hz, 0.4 Hz, 1H), 8.20-8.18 (m, 2H), 7.97-7.92 (m, 3H), 7.57-7.48 (m, 3H), 7.15 (d, J=4.8 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 5.19 (b, 2H), 3.78-3.70 (m, 1H), 3.38 (t, J=5.6 Hz, 2H), 2.77-2.66 (m, 3H), 2.42-2.34 (m, 2H), 1.87 (s, 3H); MS (ES+): m/z 463 (100) [MH+]; HPLC: tR=2.06 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-:17])=[CH:4][CH:3]=1
Reactant: Cc1ccc2cccnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc2ccc[n+]([O-])c2c1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
7-Methylquinoline (1-1, 240 g, 1.7 mol, 1.0 equiv) was dissolved in methylene chloride (5 L, 0.34 M). 3-Chloroperoxybenzoic acid (488 g, 2.2 mol, 1.3 equiv) was added portionwise with cooling so that the reaction temperature did not rise above 34° C. After stirring for 1 h, the reaction mixture was quenched with 2 L of 1N aqueous NaOH and the product was extracted with methylene chloride. The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and filtered. Heptane was added and the organic layer was evaporated to dryness, giving 246 g of 7-methylquinoline N-oxide (1-2) as a pink solid that was carried on without further purification. LRMS m/z (M+H)+ 160.1 found, 160.2 required.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(Cl)(Cl)Cl.[CH3:16][S:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:16][S:17]([CH:18]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CS(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A solution of 10.7 grams (0.0525 mole) of m-chloroperbenzoic acid in 150 ml. of chloroform was slowly added to a cool solution (5°-7° C.) of 14.1 grams (0.050 mole) of bis(p-chlorophenyl)methyl methyl sulfide in 500 ml. of chloroform, and the resulting solution stirred for two hours at a temperature of 5° C., while a white precipitate formed. The mixture after warming to ambient temperature and holding at this temperature for a two hour period was then mixed with a solution having 20 grams of potassium carbonate in 200 ml. of water. The chloroform phase was then removed and washed with 100 ml. of water, and the chloroform distilled off; the vacuum distillation leaving 14.7 grams of a crude product which was recrystallized twice from 2,2,4-trimethylpentane-benzene (2:1) mixture to yield 11.7 grams (78 percent) of the white colored solid of bis(p-chlorophenyl)methyl methyl sulfoxide with a melting point of 109.5°-110.5° C.
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[F:14][C:15]([F:30])([F:29])[C:16]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:17]=1[C:18](Cl)=[O:19]>CN(C1C=CN=CC=1)C>[F:14][C:15]([F:29])([F:30])[C:16]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:17]=1[C:18](=[O:19])/[CH:13]=[C:7]1\[S:8][C:9]([CH3:12])=[C:10]([CH3:11])[N:6]\1[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(C(F)(F)F)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by 2,5-bis(trifluoromethyl)benzoyl chloride (0.9 mL of 0.2M in DMA, 1.2 equiv). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.89 (t, 3 H) 1.28-1.38 (m, 2 H) 1.56-1.64 (m, 2 H) 2.19 (s, 3 H) 2.23 (s, 3 H) 3.92-3.98 (m, 2 H) 6.02 (s, 1 H) 7.82-7.84 (m, 1 H) 7.93-7.97 (m, 1 H) 7.98-8.02 (m, 1 H); MS (ESI) m/z 424 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=2[CH:17]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:6]=3[CH:17]=2)[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: CCC1(CC)OC(=O)N(C)c2ccc(N)cc21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CCC1(CC)OC(=O)N(C)c2ccc(Nc3ccc(F)c(Cl)c3)cc21

Procedure:
Prepared from 6-amino-4,4-diethyl-1-methyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 3-chloro-4-fluorophenylboronic acid according to the coupling procedure described in example 1. 1H NMR (DMSO-d6): δ 8.22 (s, 1H), 7.26 (t, J=9.1 Hz, 1H), 7.09 (dd, J=8.7, 2.3 Hz, 1H), 7.03 (m, 2H), 6.91 (m, 1H), 6.88 (d, J=2.3 Hz, 1H), 3.26 (s, 3H), 1.97 (m, 4H), 0.82 (t, J=7.2 Hz, 6H); MS (ESI) m/z 363/365 ([M+H]+); MS (ESI) m/z 361/363 ([M−H]−); Anal. calcd for C19H20ClFN2O2: C, 62.90H, 5.56; N, 7.72. Found: C, 62.65; H, 5.53; N, 7.58.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](I)[CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:13].[CH3:14][N:15](C)C=O>ClCCl.O.[C-]#N.[Zn+2].[C-]#N.[Pd]>[NH2:13][C:5]1[C:4]2[C:9](=[C:10]([C:14]#[N:15])[CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: CN(C)C=O
Reactant: Nc1ncnc2c(I)cc(Cl)cc12
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc2c(N)ncnc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To an 8 mL screw-cap vial was added 6-chloro-8-iodo-quinazolin-4-amine (450 mg, 1.47 mmol), dimethylformamide (2 mL), zinc cyanide (0.65 equiv., 1.0 mmol, 115 mg), and palladium tetra is(triphenylphosphine), (0.1 equiv., 0.15 mmol), 179 mg). The reaction was capped and shaken at 110° C. overnight. The reaction was cooled to room temperature, diluted with 3 mL of dichloromethane, and 2 mL of water was added. The precipitate that followed was collected by filtration, and washed with water, then dichloromethane yielding 240 mg of 4-amino-6-chloro-quinazoline-8-carbonitrile as a light yellow solid. 1H NMR (400 MHz, DMSO) δ 8.72-8.67 (d, J=2.2 Hz, 1H), 8.54-8.50 (s, 1H), 8.50-8.46 (d, J=2.1 Hz, 1H), 8.29-8.22 (bs, 2H). LCMS M/Z (M+H)=205.