Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[F:16][C:17]([F:21])([F:20])[CH2:18][OH:19].[OH-].[K+].Cl>CS(C)=O.O>[N+:9]([C:5]1[CH:4]=[C:3]([C:12]([F:15])([F:14])[F:13])[C:2]([O:19][CH2:18][C:17]([F:21])([F:20])[F:16])=[CH:7][C:6]=1[NH2:8])([O-:11])=[O:10]
Reactant: OCC(F)(F)F
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 96 h
Yield: 98 %

Procedure:
Commercially available 5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7] (72.2 g, 300 mmol) was dissolved in DMSO (600 mL) and 2,2,2-trifluoroethanol (270 mL) were added at 23° C., the slightly exothermic reaction was cooled with a ice bath. KOH (85%, 99.0 g, 1500 mmol) were added slowly and the dark red reaction mixture was stirred at 23° C. for 4 days. Transferred into a 3 L flask and 1500 ml H2O were added under ice bath cooling, acidified with 3 N HCl and stirred at 23° C. for 3 h, filtered off the yellow precipitate, washed with H2O and dried in air at 60° C. to give the title compound as a yellow solid (89.47 g, 98%). MS (ISN) 303.1 [M−H].
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([NH:13][C:14](=[O:28])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:17][CH:16]=1)[CH2:6][CH2:7][C:8]([O:10]CC)=[O:9])C.CO.[OH-].[Na+]>C1COCC1>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[NH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([NH:13][C@H:5]([C:4]([OH:29])=[O:3])[CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:28])=[CH:20][CH:19]=1
Reactant: CCOC(=O)CCC(NC(=O)c1ccc(Nc2ncccn2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC[C@H](NC(=O)c1ccc(Nc2ncccn2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
A solution of 2-[4-(pyrimidin-2-ylamino)-benzoylamino]-pentanedioic acid diethyl ester (250 mg, 0.62 mmol) in THF (4 mL) was added to MeOH (4 mL), followed by the addition of 1N NaOH solution (5 mL, 5 mmol, 8 equiv.). The mixture was stirred at room temperature overnight. Reaction was complete as determined by HPLC. Solvents were removed by rotavap and a small amount of water (5 mL) was added to make a homogeneous solution. 1N HCl was added dropwise until the solution reached a pH of 4. The solid precipitate was collected by filtration, washed with EtOAc, and dried in vacuum oven. The product N-[4-(pyrimidin-2-ylamino)benzoyl]-L-glutamic acid (120 mg) was isolated in 45% yield. MS (ESI) m/z 343.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([N:10]1[CH2:14][CH2:13][N:12]=[CH:11]1)[OH:9]>CC(C)=O.O>[N:10]1([C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[O:9])[CH2:14][CH2:13][N:12]=[CH:11]1
Reactant: OC(c1ccccc1Br)N1C=NCC1
Solvent: CC(C)=O
Solvent: O
Product: O=C(c1ccccc1Br)N1C=NCC1
Reaction time: 1 h
Yield: 72.4 %

Procedure:
A solution of α-(o-bromophenyl)-2-imidazoline-methanol (16.0 g.) in acetone (600 ml.) and water (150 ml.) was stirred with deactivated precipitated manganese dioxide (100 g.) for 24 hours. [The commerical precipitated manganese dioxide was deactivated by stirring with water for 1 hour. and drying in a vacuum oven at ca.65°-70°C for 5 hours]. After filtering and washing the manganese dioxide with acetone, the solution was evaporated to a small volume under reduced pressure, diluted with water and extracted with chloroform. The combined extracts were dried (MgSO4), the solvent removed and the residue allowed to crystallise from a small volume of ether to yield crude o-bromophenyl 2-imidazolinyl ketone (11.5 g.). A sample recrystallised from benzene petroleum (b.p. 60°-80°) had m.p. 149°-151°. [Found: C, 47.9; H, 3.7; N, 11.1%; C10H9BrN2O requires C, 47.5; H, 3.6; N, 11.1%] .
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[NH2:16][C:17]1[CH:18]=[C:19]([C:24]([Br:27])=[CH:25][N:26]=1)[C:20]([O:22][CH3:23])=[O:21].O>CO>[CH3:23][O:22][C:20]([C:19]1[C:24]([Br:27])=[CH:25][N:26]2[CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:16]=[C:17]2[CH:18]=1)=[O:21]
Reactant: COC(=O)c1cc(N)ncc1Br
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2nc(-c3ccccc3)cn2cc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2-Bromoacetophenone (17.29 g, 87 mmol) and NaHCO3 (8.03 g, 96 mmol) were added to a solution of methyl 2-amino-5-bromoisonicotinate (20.07 g, 87 mmol) in methanol (240 ml), and the mixture was heated to reflux (5 h). After cooling to r.t., water (75 ml) was added, and the brown suspension was stirred (15 min) and filtered. The precipitate was washed with a small amount of methanol. The title compound (10.11 g, 35%) was dried under vacuum and was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[C:9]([O:8][C:7]([NH:6][C@H:3]1[CH2:4][CH2:5][N:1]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:2]1)=[O:13])([CH3:10])([CH3:12])[CH3:11]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (6.0 g, 32.2 mmol) and DIEA (12.5 g, 16.8 mL, 96.6 mmol) in dichloromethane (60 mL) cooled to 0° C. on an ice-bath was added benzyl chloroformate (8.7 g, 7.2 mL, 48.3 mmol), and the resulting mixture stirred at 0° C. for 2 hours. The mixture was diluted with dichloromethane (30 mL) and washed successively with cold aqueous 10% HCl, water, saturated sodium bicarbonate solution and brine. The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography silica gel (Biotage, 65M; 20% ethyl acetate/hexanes) to afford (S)-benzyl 3-(tert-butoxycarbonylamino)pyrrolidine-1-carboxylate (10 g, 97%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[C:9]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:10]=2[S:11][C:12]=1[CH:13]([O:19][CH3:20])[CH:14]([N+:16]([O-])=O)[CH3:15].O>C(OCC)C>[Cl:7][C:8]1[C:9]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:10]=2[S:11][C:12]=1[CH:13]([O:19][CH3:20])[CH:14]([NH2:16])[CH3:15]
Reactant: COC(c1sc2ccc(Cl)cc2c1Cl)C(C)[N+](=O)[O-]
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: COC(c1sc2ccc(Cl)cc2c1Cl)C(C)N
Reaction time: 5 h

Procedure:
In a sulfonation flask 15 ml (0.015 mol) of an etheral 1 molar LiAlH4 solution is diluted with 40 ml of diethylether. A solution of 0.97 g (0.003 mol) 3,5-dichloro-2-(1-methoxy-2-nitropropyl)benzo[b]thiophene and 30 ml diethylether is added under stirring in such a manner that the internal temperature remains constant at 0-5° C. Then the mixture is warmed up to it and stirring continued for 5 h. Then the reaction mixture is cooled again and water added slowly. After quenching sodium sulphate is added. Filtration and distilling off the solvent in a water jet vacuum, the raw material is obtained. Purification is achieved by column chromatography (eluent: tert. butylmethylether/EtOH 3:1). Yield: 0.62 g (87% of theory) yellowish oil consisting of a diastereoisomeric mixture (ratio:ca. 2:1). 1H-NMR: 1.05/d/3H-DS1 (minor isomer), 1.13/d/3H, DS2 (major isomer), 3.2/m/1H-DS1, 3.35/s/6H-DS1+DS2, 3.39/m/1H-DS2, 4.45/d/1H-DS1, 4.52/d/1H-DS2, 7.38/m/2H-DS1+DS2, 7.72/d/2H-DS1+DS2, 7.8/2 s/DS1+DS2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]2[CH2:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16]2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]4[CH2:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[CH2:16]4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC1Cc2ccccc2C1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC4Cc5ccccc5C4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 108, Step 2, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-indan-2-yl-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][CH:2]([C:8]([CH3:10])=[O:9])[C:3](OCC)=[O:4].C(O)C.[CH3:14][NH:15][CH3:16]>>[F:1][CH:2]([C:8](=[O:9])[CH3:10])[C:3]([N:15]([CH3:16])[CH3:14])=[O:4]
Reactant: CNC
Reactant: CCOC(=O)C(F)C(C)=O
Solvent: CCO
Product: CC(=O)C(F)C(=O)N(C)C

Procedure:
0.2 mol (25 ml) of ethyl 2-fluoroacetoacetat and 107 ml 33% dimethylamine in ethanol (0.6 mol dimethylamine) were stirred for 3 h at 70° C. The reaction mixture was evaporated to dryness and 27 g of crude product chromatographed over 350 g silica gel with ethyl acetate/methanol 9/1. 13.4 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][S:23][CH3:24])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:27])[CH:3]=1.[OH:28]OS([O-])=O.[K+]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][S:23]([CH3:24])=[O:28])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:27])[CH:3]=1
Reactant: O=S([O-])OO
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCSC
Agent: [K+]
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCCS(C)=O
Yield: 29.5 %

Procedure:
Using a method analogous to that in Example 25, 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-methylthiopropoxy)quinazoline (250 mg, 0.6 mmol), (prepared as described in Example 21), was treated with OXONE, (trade mark of E.I. du Pont de Nemours & Co., Inc), (84 mg) and the product was pied and isolated to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-methylsulphinylpropoxy)quinazoline (75 mg, 29%).
Reaction SMILES: CO[C:3](=[O:14])[C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Br:11])=[CH:6][C:5]=1[CH2:12]Br.[F:15][C:16]1([F:24])[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[Br:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([Cl:10])[CH:8]=1)[C:3](=[O:14])[N:23]([CH2:22][CH:19]1[CH2:20][CH2:21][C:16]([F:24])([F:15])[CH2:17][CH2:18]1)[CH2:12]2
Reactant: NCC1CCC(F)(F)CC1
Reactant: COC(=O)c1c(Cl)cc(Br)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2c(Cl)cc(Br)cc2CN1CC1CCC(F)(F)CC1
Yield: 62.1 %

Procedure:
4-Bromo-2-bromomethyl-6-chlorobenzoic acid methyl ester (3.5 g, 9.35 mmol), (4,4-difluorocyclohexyl)methylamine (1.7 g, 11.39 mmol) and K2CO3 (3.15 g, 22.78 mmol) were stirred in toluene (10 mL) at 95° C. for 12 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2—SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (10-25% EtOAc/Hexanes) to afford the title compound as a yellow foam (2.2 g, 45%), 1H NMR (300 MHz, CDCl3): 7.58 (s, 1H), 7.50 (s, 1H), 4.36 (s, 2H), 3.48 (d, 2H), 2.10-2.14 (m, 2H), 1.64-1.82 (m, 5H), 1.35-1.447 (m, 2H)
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][S:23][CH2:22][CH2:21]2)=[C:12]([NH2:26])[CH:11]=1)=[O:5].[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=O)=[CH:32][CH:31]=1)#[N:29]>C(O)(=O)C>[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34]2[N:16]([CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][S:23][CH2:22][CH2:21]3)[C:13]3[CH:14]=[CH:15][C:10]([C:9]([NH:8][CH2:7][CH2:6][C:4]([O:3][CH3:2])=[O:5])=[O:27])=[CH:11][C:12]=3[N:26]=2)=[CH:32][CH:31]=1)#[N:29]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c(N)c1
Agent: Cl
Solvent: CC(=O)O
Product: COC(=O)CCNC(=O)c1ccc2c(c1)nc(-c1ccc(C#N)cc1)n2CCCN1CCSCC1
Temperature: 120 °C

Procedure:
48.6 g of 3-amino-4-(3-thiomorpholino-propylamino)-benzoic acid-[N-(2-methoxycarbonyl-ethyl)-amide]-hydrochloride are dissolved in 500 ml of glacial acetic acid with heating, 19.5 g of 4-cyano-benzoylchloride are added, the mixture is heated for one hour over a steam bath and a further 2 hours at a bath temperature of 120° C. The mixture is evaporated down in vacuo and the residue is purified by chromatography on silica gel (eluant:methylene chloride/methanol/conc. ammonia=9:1:0 to 8:2:0.2). Yield: 33.7 g (58% of theory), Rf value: 0.84 (silica gel; methylene chloride/methanol/conc. ammonia=19:1:0.1, after developing three times)
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:20])[C:12](C(O)=O)=[CH:13][NH:14]3)=[CH:9][C:8]=2[O:21][CH3:22])=[C:5]([CH3:23])[O:4][N:3]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11](=[O:20])[CH:12]=[CH:13][NH:14]3)=[CH:9][C:8]=2[O:21][CH3:22])=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: COc1cc2c(=O)c(C(=O)O)c[nH]c2cc1-c1c(C)noc1C
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Product: COc1cc2c(=O)cc[nH]c2cc1-c1c(C)noc1C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
7-(3,5-Dimethyl-4-isoxazolyl)-6-(methyloxy)-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (for a preparation see Intermediate 5) (8 g, 25.5 mmol) was added in small portions to refluxing diphenyl ether (150 ml) and the resulting solution was stirred for 30 min, then allowed to cool to 35° C. before addition of diethyl ether (200 ml). The resulting suspension was filtered and the solid product washed with ether (100 ml) to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-4(1H)-quinolinone (6.9 g, 25.5 mmol, 100% yield) as a beige solid. LCMS (formate) Rt 0.61, MH+ 271.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:6][C:3]=1[C:4]#[N:5].Cl.Cl[C:19]([NH2:21])=[NH:20].Cl>>[NH2:21][C:19]1[N:20]=[C:4]([NH2:5])[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:6]=2)[N:1]=1
Reactant: N#Cc1cc(Cc2ccccc2)ccc1N
Reactant: N=C(N)Cl
Agent: Cl
Product: Nc1nc(N)c2cc(Cc3ccccc3)ccc2n1
Temperature: 120 °C

Procedure:
A finely ground mixture of amino nitrile 10a (60 mg, 0.29 mmol) and chloroformamidine hydrochloride (132 mg, 1.16 mmol) was placed in a 10 mL pear-shaped flack, which was immersed in an oil bath and triturated continuously with a glass rod while being heated to 120° C. (internal temperature) under a gentle stream of N2 as described (Rosowsky, A. et al.; J. Med Chem. 1993; 36, 3103-3112). After 20 min the reaction mixture was cooled to room temperature, the resulting glassy solid was dissolved in MeOH (0.75 mL), and the solution was diluted with CHCl3 (12 mL) and chilled at 0° C. for 1 h. The solid precipitate was collected, washed with CHCl3, and discarded. This solid consists mainly of by-products arising from the self-condensation of chloroformamidine, whereas the pooled filtrates contain the HCl salt of the desired product, along with a variable amount of the salt of what is presumed to an intermediate non-cyclized amidinonitrile of the type previously observed (Rosowsky, A. et al.; J. Med Chem. 1993; 36, 3103-3112). To ensure complete ring closure, excess i-Pr2NH (0.5 mL) was added to the filtrate to neutralize the acid, the mixture was concentrated dryness on a rotary evaporator, and the solid residue was heated for 1.5 h at 70° C. under high vacuum (0.1 Torr). The crude product was then dissolved in boiling MeOH, and the solution treated with a little decolorizing carbon (Darco) and hot-filtered through a bed of Celite. When the filtrate became cool it was basified to pH 10 with ammonia, and the precipitate was collected. Recrystallization from MeOH—H2O afforded 8a as a white crystalline solid (32 mg, 44%): mp 220-222° C.; MS: m/z 251.4, calcd 251.3 (M+1); IR (KBr) v 3340, 3170, 1620, 1570, 1510, 1450, 1400 cm−1; 1H NMR (DMSO-d6) δ 3.92 (s, 2H, CH2), 5.84 (br s, 2H, 2-NH2), 7.13 (d, J=8.6 Hz, 1H, H-8), 7.16-7.35 (m, ca. 6H, H-7 and other aromatic protons), 7.89 (s, 1H, H-5). In contrast to the majority of the other diaminoquinazolines described below, the hydrogens on the 4-NH2 group apparently gave a signal at around δ 7.2 which was too broad to be observed. Anal. Calcd. for C15H15N4-0.3H2O: C, 70.46, H, 5.75, N, 22.16. Found: C, 70.20; H, 5.42; N, 22.28.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH2:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[O:17][CH2:16][CH2:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][NH:9]2)=[CH:31][CH:30]=1)[CH3:33]
Reactant: CCc1ccc(CCc2ccccc2OCCC2CCCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1ccc(CCc2ccccc2OCCC2CCCCN2)cc1
Reaction time: 1 h
Yield: 88 %

Procedure:
5 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 0.91 g of 1-t-butoxycarbonyl-2-(2-{2-[2-(4-ethylphenyl)ethyl]phenoxy}ethyl)piperidine [prepared as described in step (a) above] in 5 ml of dioxane, and the resulting solution was allowed to stand at room temperature for 1 hour. At the end of this time, the mixture was concentrated by distillation under reduced pressure, and the resulting oily residue was dissolved in a small amount of ethyl acetate. Diethyl ether was added to the solution, which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 687 mg (yield 88%) of the title compound as colorless crystals, melting at 74°-76° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:48])([CH3:47])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:17]3[CH:18]=[N:19][C:20](Cl)=[CH:21][CH:22]=3)=[C:12]2[N:11]=[C:10]([CH:24]2[CH2:30][CH:29]3[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:26]([CH2:27][CH2:28]3)[CH2:25]2)[CH:9]=1.C([Sn](CCCC)(CCCC)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1)CCC>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.CC#N>[N:19]1[CH:18]=[C:17]([C:16]2[CH:15]=[N:14][N:13]3[C:8]([N:7]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:48])([CH3:47])[CH3:1])=[CH:9][C:10]([CH:24]4[CH2:30][CH:29]5[N:31]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH:26]([CH2:27][CH2:28]5)[CH2:25]4)=[N:11][C:12]=23)[CH:22]=[CH:21][C:20]=1[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(Cl)nc4)c3n1)C2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(-c5ccccn5)nc4)c3n1)C2
Reaction time: 0.75 h

Procedure:
To tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(6-chloropyridin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (Int-2a) (2.66 mmol, 1904 mg) and Pd(PPh3)4 (0.27 mmol, 307 mg) in a 20 mL microwave vial was added 2-(Tributylstannyl)pyridine (5.25 mmol, 1.7 mL) and CH3CN (12 mL). The reaction was run in the microwave at 150° C. for 45 mins. The reaction was filtered through a pad of KF (˜7 g) and SiO2 (˜7 g) with the aid of EtOAc and fractions containing product were combined and concentrated to give a brown oil. Gradient column chromatography on silica (80 g) eluting with 5%-40% EtOAc/hexanes gave tert-butyl 3-(3-(2,2′-bipyridin-5-yl)-7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate, LCMS tR=2.1 Min (5 min run, UV254nm). Mass calculated for, M+H 758.4, observed LC/MS m/z 758.3 (M+H).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:13])[CH:9]=2)[N:4]=[CH:3]1.[C:14]12([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[C:14]12([CH2:24][C:25]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([Br:13])[CH:9]=4)[N:4]=[CH:3]3)=[O:26])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1cnc2ccc(Br)cc2c1=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1cnc2ccc(Br)cc2c1=O

Procedure:
3-Amino-6-bromo-quinazolin-4(3H)-one and 1-adamantaneacetyl chloride were reacted as described in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 11.60-1.70 (m, 12H), 1.93-1.98 (m, 3H), 2.10 (s, 2H), 7.71 (d, J=8.7 Hz, 1H), 8.05 (dd, J=8.7, 2.4 Hz, 1H), 8.27 (s, 1H), 8.29 (d, J=2.4 Hz, 1H), 11.21 (s, 1H); MS (DCI/NH3) m/z 416 (M+H)+; Elemental Analysis: Calculated for C20H22BrN3O2: C, 57.70; H, 5.33; N, 10.09. Found: C, 57.63; H, 5.28; N, 10.06.
Reaction SMILES: [Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][O:4][C:5]([NH:7][CH2:8][C:9](O)=[O:10])=[O:6].S(Cl)([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:13])([Cl:12])[CH2:3][O:4][C:5]([NH:7][CH2:8][C:9]([Cl:16])=[O:10])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CNC(=O)OCC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)CNC(=O)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 25 parts of N-[(2,2,2-trichloroethoxy)carbonyl]glycine in 250 parts by volume of toluene is added dropwise with stirring 20 parts of thionyl chloride. The resultant reaction mixture is heated on a steam bath for about 2 hours, then the solvent and excess of thionyl chloride are removed by distillation to afford {[(2,2,2-trichloroethoxy)carbonyl]amino} acetyl chloride represented by the following formula
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=2)=[C:4]([O:21][CH3:22])[CH:3]=1.C([Sn](CCCC)(CCCC)[C:28]1[S:32][CH:31]=[N:30][CH:29]=1)CCC>>[CH3:22][O:21][C:4]1[CH:3]=[C:2]([C:28]2[S:32][CH:31]=[N:30][CH:29]=2)[N:7]=[CH:6][C:5]=1[NH:8][C:9]1[N:14]=[C:13]([NH:15][CH3:16])[C:12]([C:17]([F:20])([F:19])[F:18])=[CH:11][N:10]=1
Reactant: CNc1nc(Nc2cnc(Cl)cc2OC)ncc1C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Product: CNc1nc(Nc2cnc(-c3cncs3)cc2OC)ncc1C(F)(F)F

Procedure:
N2-(4-Methoxy-6-(thiazol-5-yl)pyridin-3-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine was prepared by the procedure described in Example 7, using N2-(6-chloro-4-methoxypyridin-3-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine and 5-(tributylstannyl)thiazole. LCMS (10 cm_ESCI_Formic_MeCN): [MH+]=383 at 2.60 min. 1H NMR δ (ppm) (CDCl3): 9.65 (1H, s), 8.9 (1H, d, J=2.1), 8.2 (1H, d, J=1.1), 8.1 (1H, d, J=2.1), 7.75 (1H, s), 7.55 (1H, s), 5.27 (1H, s), 4.1 (3H, s), 3.2 (3H, d, J=4.7).