Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[C:21]([O:23][CH3:24])=[O:22])[C:15]([OH:17])=O.[C:25]1([C@H:35]([NH2:37])[CH3:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:14]([C:15]([NH:37][C@@H:35]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH3:36])=[O:17])=[CH:13][C:12]=1[Cl:11]
Reactant: C[C@@H](N)c1cccc2ccccc12
Reactant: COC(=O)c1ccc(C(=O)O)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 116.2 %

Procedure:
N,N-dicyclohexylcarbodiimide (5.12 g, 24.84 mmol) and 1-hydroxybenzotriazole (3.08 g, 24.84 mol) were added to a solution of 3-chloro-4-(methoxycarbonyl)benzoic acid (Example 72; 5.0 g, 23.7 mmol) and (R)-(+)-1-(naphthalen-1-yl)ethylamine (3.45 g, 20.7 mmol) in N,N-dimethylformamide (10 mL). The solution was stirred for 6 h at room temperature, then after the volatiles were removed in vacuo, the residual material was partitioned between ethyl acetate and water. The separated aqueous phase was extracted with three portions of ethyl acetate , then the combined ethyl acetate layers were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The resulting colorless solid was crystallized from dichloromethane/hexane to yield 8.85 g of (R)-2-chloro-4-[[1-(naphthalen-1-yl)ethylamino]carbonyl]benzoic acid methyl ester (over theory; material 94% pure by analytical HPLC).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][N:5]=[C:6]=[O:7].[NH2:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)[N:16]=[CH:15][N:14]=[C:13]2[NH:12][C:6]([NH:5][CH2:4][C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[CH3:1])=[O:7]
Reactant: Cc1ccccc1CN=C=O
Reactant: COc1cc2c(N)ncnc2cc1OCC1CCN(C)CC1
Product: COc1cc2c(NC(=O)NCc3ccccc3C)ncnc2cc1OCC1CCN(C)CC1

Procedure:
Using an analogous procedure to that described in Example 3, 2-methylbenzyl isocyanate was reacted with 4-amino-6-methoxy-7-(N-methylpiperidin-4-ylmethoxy)quinazoline. The resultant solid was purified by column chromatography on silica using increasingly polar mixtures of methylene chloride, methanol and a 1% aqueous ammonium hydroxide solution as eluent. There was thus obtained the title compound; NMR Spectrum: (CDCl3) 1.39-1.56 (m, 2H), 1.84-2.04 (m, 5H), 2.29 (s, 3H), 2.39 (s, 3H), 2.9 (d, 2H), 3.92 (s, 3H), 4.03 (d, 2H), 4.66 (d, 2H), 7.21 (m, 4H), 7.34 (m, 2H), 8.6 (s, 1H), 8.74 (s, 1H), 10.44 (t, 1H); Mass Spectrum: M+H+ 450.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([S:12]([C:14]2[CH:15]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=O.[CH2:30]([NH2:33])[CH2:31][CH3:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[N+:9]([C:8]1[CH:7]=[CH:6][C:5]([S:12]([C:14]2[CH:15]=[C:16]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:22])=[O:23])[CH:17]=[CH:18][CH:19]=2)=[O:13])=[CH:4][C:3]=1[CH2:1][NH:33][CH2:30][CH2:31][CH3:32])([O-:11])=[O:10]
Reactant: O=Cc1cc(S(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNCc1cc(S(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
The following reaction was run under N2. A mixture of N-[3-(3-formyl-4-nitro-benzenesulfinyl)-phenyl]-benzenesulfonamide (0.0023 mol) and propylamine (0.0025 mol) in DCE (50 mL) was stirred at room temperature and NaBH(OAc)3 (0.8 g) was added. The reaction mixture was stirred overnight at room temperature, and then a NaHCO3 solution was added. The organic layer was separated, dried, and filtered, and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([Mg]Br)[CH:15]=[CH:16][CH:17]=1.C(=O)(O)[O-].[Na+].O>C1COCC1.C(Cl)(Cl)Cl>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([O:11][CH3:10])[CH:17]=2)[N:1]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: COc1cccc([Mg]Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1cccc(-c2nc(Cl)nc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of cyanuric chloride (3.69 g, 20 mmol) in dry THF (20 mL) under nitrogen was treated dropwise with a solution of 3-methoxyphenylmagnesium bromide in THF (20 mL, 1M, 20 mmol). The solution became warm and was stirred for 30 minutes at room temperature followed by stirring overnight at ˜40° C. The reaction was poured into a mixture of saturated sodium bicarbonate (50 mL) and water (50 mL) forming a solid. The mixture was stirred for 20 minutes and separated layers. The aqueous layer was extracted with ethyl acetate (EtOAc) twice. The combined organic layers was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to yield a tan solid. The solid was dissolved in chloroform and loaded onto 100 g of silica gel. The silica gel was eluted with 10% ethyl acetate/hexanes followed by 20% ethyl acetate/hexanes. The appropriate fractions were concentrated on a rotary evaporator to yield 2,4-dichloro-6-(3-methoxyphenyl)-1,3,5-triazine (VIII) as a white solid (0.52 g, 4.50 g). ESI/MS 256.1, 258.1, 260.1 (M+H).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([NH:44][CH:45]([CH3:47])[CH3:46])=[O:43])[CH:37]=2)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Cl.N1C=CC=CC=1>>[OH:1][C:2]([C:30]1[CH:31]=[CH:32][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([NH:44][CH:45]([CH3:47])[CH3:46])=[O:43])[CH:37]=2)=[CH:34][CH:35]=1)([C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)NC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)NC(=O)c1cccc(-c2ccc(C(O)(c3c[nH]cn3)C(C)C)cc2)c1
Yield: 47.2 %

Procedure:
By the reaction in the same manner as in Example 4-(iii) using 4′-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-N-isopropyl[1,1′-biphenyl]-3-carboxamide (1.67 g) and pyridine hydrochloride (490 mg), the title compound (480 mg) was obtained as colorless powder crystals.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3([OH:24])[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)=[CH:11][C:10]=2[CH3:25])[CH:6]=[CH:7][CH:8]=1.[F:26][C:27]1[CH:32]=[C:31]([NH:33][S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[N+:43]([O-:45])=[O:44])(=[O:36])=[O:35])[CH:30]=[CH:29][C:28]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:26][C:27]1[CH:32]=[C:31]([N:33]([CH2:2][C:3]2[CH:4]=[C:5]([C:9]3[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]4([OH:24])[CH2:19][CH2:20][S:21][CH2:22][CH2:23]4)=[CH:11][C:10]=3[CH3:25])[CH:6]=[CH:7][CH:8]=2)[S:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[N+:43]([O-:45])=[O:44])(=[O:35])=[O:36])[CH:30]=[CH:29][C:28]=1[CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49]
Reactant: CCOC(=O)CCc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Reactant: Cc1cc(OCC2(O)CCSCC2)cc(C)c1-c1cccc(CO)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(N(Cc2cccc(-c3c(C)cc(OCC4(O)CCSCC4)cc3C)c2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1F
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To a solution of 4-({[3′-(hydroxymethyl)-2,6-dimethylbiphenyl-4-yl]oxy}methyl)tetrahydro-2H-thiopyran-4-ol (0.90 g, 2.51 mmol), ethyl 3-(2-fluoro-4-{[(2-nitrophenyl)sulfonyl]amino}phenyl)propanoate (1.05 g, 2.64 mmol) and tributylphosphine (0.86 mL, 3.26 mmol) in tetrahydrofuran (15 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.85 g, 3.26 mmol) under stirring at room temperature, and the mixture was stirred for 10 hr. The resulting precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=2/1) to give the title compound (1.71 g, yield 92%) as a pale-yellow amorphous powder.
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH2:13][OH:14])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][C:23](Cl)=[O:24].[OH-].[Na+]>O1CCCC1.C(OCC)C>[CH2:1]([N:8]1[C:23](=[O:24])[CH2:22][O:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: O=C(O)[C@H](CO)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)[C@@H]1COCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of (S)-2-(benzylamino)-3-hydroxypropanoic acid (40.0 g, 205 mmol) in tetrahydrofuran (600 mL) was added aqueous potassium carbonate solution (85.0 g, 600 mL) at 0° C. under nitrogen atmosphere, and additionally, chloroacetylchloride (29.0 mL, 369 mmol) was added. After stirring for 2 hours at room temperature, to the mixture was added 30% aqueous sodium hydroxide solution to adjust to pH 13. To the mixture was added diethyl ether, and the organic layer was separated, and then concentrated hydrochloric acid was added to adjust to pH 1, and cooled to 0° C. The precipitated crystal was collected by filtration to give the title compound (29.0 g, 123 mmol, 60%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.Cl.[Pd]>[F:21][C:17]1([F:20])[CH2:18][CH2:19][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:15][CH2:16]1
Reactant: FC1(F)CCN(C2CCN(Cc3ccccc3)CC2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: FC1(F)CCN(C2CCNCC2)CC1

Procedure:
A solution of 2.8 g (9.5 mmol) 1′-benzyl-4,4-difluoro-[1,4′]bipiperidinyl in 300 mL MeOH was hydrogenated in the presence of 1.2 g Pd/C (10%) at 50° C. and 50 psi hydrogen pressure with the addition of a few drops of 1 M HCl until the calculated volume of hydrogen had been taken up. The catalyst was filtered off and the filtrate was evaporated down under reduced pressure. The residue was triturated with diisopropylether, suction filtered and dried.
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([F:32])=[C:17]2[C:22]=1[NH:21][CH:20]=[C:19]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)[C:18]2=[O:31])C1C=CC=CC=1>[C].[Pd].C(O)C>[F:32][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])=[C:22]2[C:17]=1[C:18](=[O:31])[C:19]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[CH:20][NH:21]2
Reactant: COc1ccc(-c2c[nH]c3c(OCCCOCc4ccccc4)ccc(F)c3c2=O)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(-c2c[nH]c3c(OCCCO)ccc(F)c3c2=O)cc1
Temperature: 50 °C
Reaction time: 7.5 h
Yield: 53 %

Procedure:
8-(3-Benzyloxypropoxy)-5-fluoro-3-(4-methoxyphenyl)-1H-quinolin -4-one (1.95 g, 4.49 mmol) and a 10% palladium carbon (720 mg) were added to ethanol (50 ml). The mixture was stirred at 50° C. for 7.5 hours under a hydrogen atmosphere (1 atmosphere) and subjected to a catalytic reduction. The reaction mixture was cooled to room temperature, and filtration with Celite was conducted to remove the solvent. The filtrate was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (dichloromethane:methanol=80:1→20:1). The purified product was concentrated under reduced pressure, and the residue was concentrated to dryness to thereby obtain 820 mg of pale dark brown amorphous solid 5-fluoro-8-(3-hydroxypropoxy)-3-(4-methoxyphenyl)-1H-quinolin-4-one (yield: 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[C-:12]#[N:13].[K+]>[C-]#N.[Zn+2].[C-]#N>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([C:12]#[N:13])=[O:8])=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: [K+]
Agent: [Zn+2]
Product: COc1ccc(C(=O)C#N)cc1
Temperature: 210 °C
Yield: 86.5 %

Procedure:
In the manner described above, 170 g (1 mol) of p-methoxybenzoyl chloride and 64.5 g (0.99 mol) of potassium cyanide and 1.17 g (0.1 mol) of zinc cyanide were mixed, whilst stirring, and the mixture was heated to 210° C. for 1 hour. A distillation bridge was then connected and the reaction product was separated from the residue direct. On subsequent fractionation, 138 g (86% of theory) of p-methoxybenzoyl cyanide with a melting point of 63° C. were obtained.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[C:12]([NH:13][C:14](=O)[C:5]2=[N:4][CH:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:14]2[C:5]3[N:6]([C:2]([CH3:1])=[CH:3][N:4]=3)[C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cnc2c(=O)[nH]c3ccccc3n12
Reactant: NC1CCCCC1
Product: Cc1cnc2c(NC3CCCCC3)nc3ccccc3n12

Procedure:
By reaction of 1-methylimidazo[1,2-a]quinoxaline-4(5H)-one (example 2) with cyclohexylamine, according to a procedure that is similar to that followed in example 9, there is obtained 4-cyclohexylamino-1-methyl imidazo [1,2-a]quinoxaline. m.p. (DSC)=126.5° C. (onset); IR (KBr): 3345, 2938, 1546 cm-1 ; 1H-NMR (CDCl3): δ8.0 (1H,dd), 7.7 (1H,dd), 7.5÷7.1 (3H,m), 6.0 (1H,d), 4.2 (1H,m), 2.85 (3H,s), 2.3÷1.95 (4H,m), 1.95÷0.9 (6H,m); UV (EtOH): λmax =225, 243, 272, 301, 316, 329 nm. Elementary analysis for C17H20N4 (m.w.280.37): calcd. C 72.83, H 7.19, N 19.98%; found C 72.21, H 7.54, N 20.14%.
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12](I)[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2].C([O-])(O)=O.[Na+].[CH3:39][N:40](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[CH2:1]([N:3]([CH2:32][CH3:33])[CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=[C:12]([C:39]#[N:40])[CH:13]=2)[C:8]([OH:30])([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[C:7]1=[O:31])[CH3:2]
Reactant: CN(C)C=O
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(I)cc2C(F)(F)F
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: [C-]#N
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c1cc(C#N)cc2C(F)(F)F
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 66 %

Procedure:
A mixture of 1-(2-diethylaminoethyl)-4-trifluoromethyl-6-iodo-3-hydroxy-3-(2-naphthyl)oxindole of Example 48 (582 mg, 1, 24 mmol), 60% Zn(CN)2 (172 mg, 0.879 mmol), and (PPh3)4Pd (177 mg, 0.153 mmol) in DMF (6 mL) was stirred for 2.5 h at 80° C. Sat. aqueous NaHCO3 was added. The mixture was extracted with toluene-ethyl acetate, and the extracts were washed with sat. aq. NaHCO3, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography with 80:1 to 50:1 chloroform/methanol to give the title compound (382 mg, 66%).
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])[C:22]([Cl:37])=[CH:21][N:20]=1>>[Cl:37][C:22]1[C:23]([NH:25][C:26]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:24][C:19]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:17])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:20][CH:21]=1
Reactant: Nc1ccc2c(c1)CCC(NCC(F)F)CC2
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)F)CC3)ncc1Cl
Yield: 14.3 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide to yield 2-{5-Chloro-2-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-methyl-benzamide (15.43 mg, 14.3% yield) as a off white foam. 1H-NMR (CDCl3) δ 8.69 (s, 1H), 8.05 (s, 1H), 7.24 (m, 2H), 7.14 (s, 1H), 7.09 (d, J=8.1 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.83 (s, 1H), 6.05 (m, 1H), 5.83 (m, 1H), 5.83 (m, 1H), 3.01 (t, J=4.3 Hz, 1H), 2.90 (d, J=4.9 Hz, 1H), 2.77 (m, 2H), 2.60 (m, 3H), 2.02 (m, 2H), 1.25 (m, 2H). LC/MS (ESI+)=519 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[C:5]2[Cl:16]
Reactant: O=c1[nH][nH]c(=O)c2cc(Br)ccc12
Reactant: O=P(Cl)(Cl)Cl
Product: O=c1[nH]nc(Cl)c2cc(Br)ccc12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 24.3 %

Procedure:
A mixture of 6-bromo-2,3-dihydro-phthalazine-1,4-dione (42.8 g, 178 mmol) in POCl3 (300 mL) was heated at reflux for 3 h. The mixture was allowed to cool and concentrated. The residue was taken up in EtOAc (400 mL) and water (200 mL), and neutralized with sodium bicarbonate. The layers were separated, aqueous layer was extracted with EtOAc (3×200 mL), and combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in dioxane (300 mL) and 2N NaOH (250 mL). The mixture was heated at 50° C. for 30 min, poured into water (3 L), and stirred for 15 min. Solid was filtered and dried in vacuum at room temperature to give title compound as a greenish solid (12.0 g, 24.3%). M/z (M+1)=259.32.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)=[O:3].[C:12](=O)([O:16]CC)[O:13][CH2:14][CH3:15]>C1(C)C=CC=CC=1>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([CH2:1][C:12]([O:13][CH2:14][CH3:15])=[O:16])=[O:3])=[CH:5][CH:6]=1
Reactant: CCOC(=O)OCC
Reactant: COc1ccc(C(C)=O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1ccc(OC)cc1
Temperature: 20 °C

Procedure:
To potassium t-amylate (25 wt %, 50.8 kg, 99.26 mol) in toluene (15.2 kg) cooled to 5° C. under mechanical stirring and under nitrogen was added a mixture of 4-methoxyacetophenone (6.755 kg, 44.98 mol) and diethyl carbonate (6.40 kg, 54.18 mol) in toluene over 1 hour maintaining the temperature below 10° C. The reaction mixture was heated to 60° C. for 8 hours until no 4-methoxyacetophenone was detected by HPLC. The mixture was cooled to 20° C. and quenched by adding to a mixture of acetic acid (8 kg) and water (90 kg) over 30 minutes while maintaining the temperature at <20° C. The layers were separated, and the organic layer was washed with 5% sodium bicarbonate solution (41 kg) and concentrated to 14.65 kg. The temperature is maintained below 50° C. during the distillation. The yellow product concentrate was assayed by HPLC against an external standard and the yield was found to be 9.40 kg (94%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([O:24]C)=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1.Cl>COCCOC>[F:28][C:2]([F:1])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)C1=Cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2S(=O)(=O)CC1
Agent: Cl
Solvent: COCCOC
Product: O=C(O)C1=Cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
To a solution of methyl 7-(4-trifluoromethoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (450 mg) in 1,2-dimethoxyethane (10 ml) was added at room temperature 6N hydrochloric acid (5 ml), and the mixture was refluxed for 24 hours, cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration. The crystals were washed with hexane to give colorless crystals of 7-(4-trifluoromethoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (390.3 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([Li])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:21][C:22]([NH:25][Si:26](Cl)([CH3:28])[CH3:27])([CH3:24])[CH3:23]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([Si:26]([CH3:28])([CH3:27])[NH:25][C:22]([CH3:24])([CH3:23])[CH3:21])[CH:7]=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [Li]C1C=C(c2ccccc2)c2cc(OC)c(OC)cc21
Reactant: CC(C)(C)N[Si](C)(C)Cl
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C([Si](C)(C)NC(C)(C)C)C=C2c1ccccc1
Reaction time: 20 h

Procedure:
(5,6-dimethoxy-3-phenyl-1H-inden-1-yl)lithium (1.24 g, 4.8 mmol) was dissolved in 20 mL of THF and added to a solution of N-(tert-butyl)-N-(1-chloro-1,1-dimethylsilyl)amine (1.035 g, 6.24 mmol) in 50 mL of THF over a 25 min period, with stirring continued for 20 h. The solution was then evaporated under reduced pressure and the residue was extracted with hexane (50 mL). After filtration, the solvent was removed under reduced pressure. To this residue, 30 mL of hexane was added and the flask was put aside into a freezer (−27° C.) for 2 days. After that time the crystallized solid was filtered off and the solvent was removed leaving 1.68 of the product as a yellow oil.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[N:16]2[N:17]=[CH:18][C:19]([C:20]3[CH:21]=[N:22][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:24][CH:25]=3)=[C:15]2[N:14]=[C:13]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[C:12]=1[C:38](=[O:40])[CH3:39].[N:41]1([S:47](Cl)(=[O:49])=[O:48])[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>CN(C=O)C>[NH2:10][C:11]1[N:16]2[N:17]=[CH:18][C:19]([C:20]3[CH:21]=[N:22][C:23]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:24][CH:25]=3)=[C:15]2[N:14]=[C:13]([CH:32]2[CH2:33][CH2:34][N:35]([S:47]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)(=[O:49])=[O:48])[CH2:36][CH2:37]2)[C:12]=1[C:38](=[O:40])[CH3:39]
Reactant: CC(=O)c1c(C2CCNCC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Reactant: O=S(=O)(Cl)N1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1c(C2CCN(S(=O)(=O)N3CCOCC3)CC2)nc2c(-c3ccc(-c4ccccc4)nc3)cnn2c1N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
DIEA (121 mg, 0.94 mmoL) was added to at 0° C. a mixture of 1-(7-amino-3-(6-phenylpyridin-3-yl)-5-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone (64.3 mg, 0.15 mmoL) and morpholine-4-sulfonyl chloride (28.9 mg, 0.15 mmol) in DMF (3 mL). After stirring at 0° C. for 0.5 h and then room temperature for 2 h, the mixture was purified by prep-LC to afford 1-(7-amino-5-(1-(morpholinosulfonyl)piperidin-4-yl)-3-(6-phenylpyridin-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone, LCMS tR=3.83 Min (5 min run, UV254nm). Mass calculated for, M+ 561.66, observed LC/MS m/z 567.66 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[N:10])[N:4]=1>CO.[OH-].[NH4+].[Ni]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][NH2:10])[N:4]=1
Reactant: COc1ccnc(C#N)n1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1ccnc(CN)n1
Reaction time: 2 h

Procedure:
To 4-methoxypyrimidine-2-carbonitrile (370 mg) in MeOH (5 mL), aqueous ammonium hydroxide (1 mL) and Raney Nickel (catalytic) were added and the reaction mixture was hydrogenated at 55 psi for 2 h. Then the reaction mixture was filtered and solvent evaporated to afford (4-methoxypyrimidin-2-yl)methanamine, which was carried to next step without purification.