Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH:9](=[O:12])[CH2:10][CH3:11]>CC(C)=O.CCCCCC>[CH3:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([C:9](=[O:12])[CH2:10][CH3:11])=[CH:4][N:3]=1
Reactant: Cc1nccnc1C
Reactant: CCC=O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCC(=O)c1cnc(C)c(C)n1
Yield: 25 %

Procedure:
The reaction of 2,3-dimethylpyrazine and freshly distilled propionaldehyde is carried out as described in Example I on the same molar scale. Preparative thick layer chromatography (2000μ silica gel GF, developed in 5% acetone/hexane) of the crude reaction product gives a 25% yield of 1-(2,3-dimethyl-5-pyrazinyl)-1-propanone.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]3[C:15]4[CH:21]=[CH:20][C:19]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=5)=[CH:18][C:16]=4[S:17][C:13]=3[C:12]([C:32]#[N:33])=[CH:11][N:10]=2)=CC=1.[OH:36]S(O)(=O)=O.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O>[NH2:8][C:9]1[C:14]2[C:15]3[CH:21]=[CH:20][C:19]([C:22]4[CH:23]=[CH:24][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:26][CH:27]=4)=[CH:18][C:16]=3[S:17][C:13]=2[C:12]([C:32]([NH2:33])=[O:36])=[CH:11][N:10]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(-c5ccc(S(C)(=O)=O)cc5)ccc4c23)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccc3c(c2)sc2c(C(N)=O)cnc(N)c23)cc1

Procedure:
A solution of 1-[(4-methoxybenzyl)amino]-7-[4-(methylsulfonyl)phenyl][1]benzothieno[3,2-c]pyridine-4-carbonitrile in conc. H2SO4 (45 equiv) was stirred at room temperature for 2 h and then poured into H2O. The mixture was neutralized with K3PO4, filtered, washed with H2O and dried. The crude product was purified by flash chromatography on silica gel, eluted with 10% MeOH in EtOAc to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH2:10])([CH3:4])([CH3:3])[CH3:2].Br[C:13]1[S:14][C:15]([C:22]2[C:23]([CH3:37])=[N:24][N:25]3[C:30]([CH:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:29][C:28]([CH3:36])=[N:27][C:26]=23)=[C:16]([C:18]([F:21])([F:20])[F:19])[N:17]=1.C(N(CC)CC)C>CO>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][NH:10][C:13]1[S:14][C:15]([C:22]2[C:23]([CH3:37])=[N:24][N:25]3[C:30]([CH:31]([CH2:32][CH3:33])[CH2:34][CH3:35])=[CH:29][C:28]([CH3:36])=[N:27][C:26]=23)=[C:16]([C:18]([F:19])([F:21])[F:20])[N:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Br)nc3C(F)(F)F)c(C)nn12
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC(CC)c1cc(C)nc2c(-c3sc(NCCNC(=O)OC(C)(C)C)nc3C(F)(F)F)c(C)nn12
Temperature: 80 °C
Yield: 94.9 %

Procedure:
Add (2-amino-ethyl)-carbamic acid tert-butyl ester (0.5 mL, 506 mg, 3.2 mmol) to a solution of 3-(2-bromo-4-trifluoromethyl-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (100 mg, 0.22 mmol) and triethylamine (0.3 mL, 222 mg, 2.2 mmol) in methanol (1 mL). Evaporate off the methanol and heat to 80° C. overnight. Cool the reaction to room temperature and concentrate under vacuum. Purify the resulting residue by column chromatography, eluting with 10-50% ethyl acetate in CH2Cl2, to give the title compound (0.11 g, 97%). ES/MS m/z 527.2 (M+1)+.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)=[O:28]>>[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:23](=[O:24])[CH2:22][C:20]2[N:21]=[C:17]([C:8]3[CH:7]=[N:6][N:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[C:9]=3[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)[S:18][CH:19]=2)=[CH:32][CH:31]=1)(=[O:28])[CH3:26]
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(=O)Nc1ccc(NC(=O)Cc2csc(-c3cnn(C(C)(C)C)c3-c3ccc(F)cc3)n2)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 4-aminoacetanilide and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[N:13]=[CH:14][C:15]([NH:18]C(=O)OC(C)(C)C)=[N:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[N:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cnc(OCCOCc2ccccc2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnc(OCCOCc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of tert-butyl {5-[2-(benzyloxy)ethoxy]pyrazin-2-yl}carbamate (614 mg) in dichloromethane (10 mL) was added trifluoroacetic acid (0.68 mL) at room temperature, followed by stirring at room temperature overnight. After concentration, saturated aqueous sodium bicarbonate was added thereto. After extraction with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate. The crude product obtained by concentration was purified by basic silica gel column chromatography (hexane:ethyl acetate=5:1-1:1) to obtain 5-[2-(benzyloxy)ethoxy]pyrazin-2-amine (269 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C@@:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])[OH:3].S(Cl)(Cl)=O.[CH3:17]O>>[C:1]([O:12][CH3:17])(=[O:11])[C@@:2]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([CH3:4])[OH:3]
Reactant: C[C@@](O)(C(=O)O)c1ccccc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@](C)(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.0 g (6.0 mmol) of (S)-atrolactic acid in 7 mL of methanol was cooled in an ice-water bath and stirred while 0.70 mL (1.15 g, 9,6 mmol) of thionyl chloride was added dropwise. The resulting mixture was stirred at room temperature for one hour, then concentrated under reduced pressure to give 1.1 g of methyl (S)-atrolactate, nD 25 1.5096.
Reaction SMILES: Br.[OH:2][CH2:3][C:4]1[NH:5][CH:6]=[C:7]([C:9](=O)[CH2:10][Br:11])[N:8]=1.C(=O)(O)[O-].[Na+].[C:18]([NH:21][C:22]([NH2:24])=[S:23])(=[NH:20])[NH2:19]>O.CC(C)=O>[BrH:11].[NH:21]([C:22]1[S:23][CH:10]=[C:9]([C:7]2[N:8]=[C:4]([CH2:3][OH:2])[NH:5][CH:6]=2)[N:24]=1)[C:18]([NH2:20])=[NH:19]
Reactant: N=C(N)NC(N)=S
Reactant: O=C(CBr)c1c[nH]c(CO)n1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: N=C(N)Nc1nc(-c2c[nH]c(CO)n2)cs1
Yield: 87.6 %

Procedure:
1.78 g (0.0059 mol) of 2-hydroxymethyl-4-bromoacetylimidazole hydrobromide was dissolved in water and saturated sodium bicarbonate solution was added to precipitate the free base. This material was collected by filtration and dried and combined with 956 mg (0.0081 mol) of amidinothiourea in 60 ml acetone and heated to 70°. After 15 minutes heating a solid formed. The reaction mixture was cooled and the resultant solid was collected by filtration to give 1.65 g (87%) 2-guanidino-4-(2-hydroxymethyl-4-imidazolyl)thiazole hydrobromide, mp>310°. A sample was converted to the free base by dissolving in hot water and adding sodium bicarbonate solid to pH 10 to precipitate 2-guanidino-4-(2-hydroxymethyl-4-imidazolyl)thiazole free base. This material was dried over toluene at high vacuum to give a light tan solid, mp 208°-209° with decomposition. nmr (DMSO-d6) (δ): 7.16 (s, 1H); 6.83 (broad s, 4H) 6.68 (s, 1H); 4.45 (s, 2H); 3.46 (very broad s, 1H). High resolution mass spectrum, calcd for C8H10N6OS: 238.0638; found: 238.0654.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])([O-:3])=[O:2].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1)#[N:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:30]=[CH:31][C:32]([CH2:33][N:14]([C:5]2[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])[C:8]([O:10][CH3:11])=[O:9])[C:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:35][CH:36]=1)#[N:22]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCCCC(=O)Nc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)c1cc(C(=O)OC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.8 %

Procedure:
A mixture of methyl 4-nitro-3-valerylaminobenzoate (1.0 g), 4-(2-cyanophenyl)benzyl bromide (0.97 g) and potassium carbonate (0.55 g) in DMF (10 ml) was stirred for two days at room temperature. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried. The solvent was distilled off, and the residue was purified by column chromatography on silica gel to afford a pale yellow oil (1.24 g, 73%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][N:6]([C@@H:8]([CH2:16][CH3:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:5](=[O:18])[CH2:4]1>C(Cl)Cl.N1C=CC=CC=1>[C:12]([O:11][C:9]([C@@H:8]([N:6]1[C:5](=[O:18])[CH2:4][CH:3]([CH:2]=[O:1])[CH2:7]1)[CH2:16][CH3:17])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1CC(CO)CC1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC[C@@H](C(=O)OC(C)(C)C)N1CC(C=O)CC1=O
Temperature: 25 °C
Yield: 49.7 %

Procedure:
In a three necked flask, under argon, a solution of tert-butyl (2S)-2-[4-(hydroxymethyl)-2-oxo-1-pyrrolidinyl]butanoate 398 (4.0 g, 0.016 mol.) in CH2Cl2 (8 ml) is added to a suspension of CrO3 (6.2 g, 0.062 mol.) in pyridine (11.3 ml)/CH2Cl2 (80 ml) stirred at room temperature. The temperature increases to 30° C. and the suspension is stirred for 0.2 h. The suspension is filtered through celite and the filtrate is washed successively with HCl 1N, brine, dried over magnesium sulfate and concentrated in vacuo to afford the crude aldehyde which is purified by column chromatography on silicagel (hexane/acetone 70/30 (v/v)) to afford 2.03 g of 1-[(1S)-1-(tertbutoxycarbonyl)propyl]-5-oxo-3-pyrrolidinecaboxaldehyde 396 (41%).
Reaction SMILES: C[O:2][C:3]1[C:12]([O:13]C)=[C:11]2[C:6]([CH:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[C:17]([O:23]C)[CH:16]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[BrH:25]>>[BrH:25].[OH:2][C:3]1[C:12]([OH:13])=[C:11]2[C:6]([CH:7]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([OH:23])[CH:16]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2CNCc3c2ccc(OC)c3OC)cc1OC
Agent: Br
Product: Oc1ccc(C2CNCc3c2ccc(O)c3O)cc1O

Procedure:
To 700 mg of 7,8-dimethoxy-4-(3,4-dimethoxyphenyl)-1,2,3,4-tetrahydroisoquinoline, was added 14 ml of 48% hydrobromic acid, and the mixture was heated under reflux for 3 hours under an argon gas stream. The reaction mixture was cooled, and the crystals which separated ount were collected by filtration, giving 540 mg of 7,8-dihydroxy-4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline hydrobromide.
Reaction SMILES: [SnH3][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:13]1[C:17]2([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>C1COCC1>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:20]1([OH:23])[CH2:21][CH2:22][C:17]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:18][CH2:19]1
Reactant: [SnH3]c1ncccn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2ncccn2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-stannyl pyrimidine (200 mmol, 80 g), prepared as previously described in the literature (Tetrahedron, 1994, 50, 275-284), in THF (1 L) was added n-butyllithium (240 mmol, 150 mL) at −78° C. The reaction was stirred for 30 min at −78° C. and 1,4-dioxa-spiro[4.5]decan-8-one (200 mmol, 30 g) was added. The reaction was allowed to stir overnight while warming to ambient temperature. The reaction was then quenched using NH4Cl and extracted using EtOAc (3×400 mL). The organic layers were combined and dried over MgSO4 and concentrated in vacuo. The crude was taken to the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][O:10]COC.FC1C=CC2[B:22](O)[O:21]CC=2C=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[B:22]([OH:21])[O:10][CH2:9][C:3]=2[CH:4]=1
Reactant: OB1OCc2cc(F)ccc21
Reactant: COCOCc1cc(Cl)ccc1Br
Product: OB1OCc2cc(Cl)ccc21

Procedure:
This compound was made from 18d in the same manner as compound 19b: mp 142-144° C. 1H NMR (300 MHz, DMSO-d6) δ (ppm) 4.96 (s, 2H), 7.38 (d, J=7.8 Hz, 1H), 7.49 (s, 1H), 7.71 (d, J=7.8 Hz, 1H), 9.30 (s, 1H); ESI-MS m/z 167 (M−H)−; HPLC purity 99.0%; Anal (C7H6ClO2.0.1H2O)C, H.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([N:6]1[CH2:34][CH2:33][CH2:32][C@H:7]1[C:8]([NH:10][C@H:11]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:21])[NH:17][N+:18]([O-:20])=[O:19])=[O:9])=[O:5])[CH3:3].Cl.CCOC(C)=O.[NH:49]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[C@H:50]([C:55]([OH:57])=O)[CH2:51][C:52](=[O:54])[NH2:53].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:49]([C:58]([O:60][CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)=[O:59])[C@H:50]([C:55]([NH:1][C@H:2]([C:4]([N:6]1[CH2:34][CH2:33][CH2:32][C@H:7]1[C:8]([NH:10][C@H:11]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[NH:21])[NH:17][N+:18]([O-:20])=[O:19])=[O:9])=[O:5])[CH3:3])=[O:57])[CH2:51][C:52](=[O:54])[NH2:53]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1

Procedure:
The desired compound was prepared from 2.9 g of Boc-Ala-Pro-Arg(NO2)-OBzl, 15 ml of 4N HCl-AcOEt, 1.4 g of Z-Asn-OH, 1.0 g of HOBt and 1.1 g of DCC in the same manner as in Example 7-(3).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#[N:11])[C:5](=[O:9])[NH:6][C:7]=1[CH3:8]>N.CO>[NH2:11][CH2:10][C:4]1[C:5](=[O:9])[NH:6][C:7]([CH3:8])=[C:2]([F:1])[C:3]=1[CH3:12]
Reactant: Cc1[nH]c(=O)c(C#N)c(C)c1F
Agent: N
Solvent: CO
Product: Cc1[nH]c(=O)c(CN)c(C)c1F
Yield: 41 %

Procedure:
A solution of 0.05M 5-fluoro-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (731 mg, 4.4 mmol) in 1.75M NH3/MeOH (87 ml) was passed through the H-Cube at 80° C. and 50 bar at a flow rate of 1 ml/min. The resulting solution was concentrated in-vacuo. The resulting solid was split into 2 batches and 350 mg of the crude product was purified by column chromatography (25 g SNAP cartridge, Isolera, 0-25% MeOH (containing 10% NH4OH):CH2Cl2) to give the title compound (307 mg, 20%) as an off white solid and a 1:1 mixture of product: starting material. LC-MS (ELS) 100%, 0.23 min (3.5 minute LC-MS method), m/z=170.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 3.79 (s, 2H) 2.31 (d, J=2.84 Hz, 3H) 2.25 (d, J=2.05 Hz, 3H).
Reaction SMILES: [C:1]12([CH2:11][C:12](Cl)=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:15][N:16]1[C:21](=[O:22])[C:20]2[C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[C:24]([CH3:26])[S:25][C:19]=2[N:18]=[C:17]1[CH3:33]>>[C:1]12([CH2:11][C:12]([NH:15][N:16]3[C:21](=[O:22])[C:20]4[C:23]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)=[C:24]([CH3:26])[S:25][C:19]=4[N:18]=[C:17]3[CH3:33])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Reactant: Cc1sc2nc(C)n(N)c(=O)c2c1-c1ccccc1
Product: Cc1sc2nc(C)n(NC(=O)CC34CC5CC(CC(C5)C3)C4)c(=O)c2c1-c1ccccc1

Procedure:
1-Adamantaneacetyl chloride and 3-amino-2,6-dimethyl-5-phenylthieno[2,3-d]pyrimidin-4(3H)-one (Matrix) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87-1.08 (m, 6 H) 1.08 (s, 3 H) 1.19 (d, 3 H) 1.46-1.69 (m, 1 H) 1.75-2.06 (m, 7 H) 2.10-2.25 (m, 1 H) 2.27-2.44 (m, 2 H) 7.43-7.51 (m, 3 H) 7.54 (d, J=7.8 Hz, 1 H) 7.75-7.84 (m, 1 H) 8.08 (dd, J=7.9, 1.19 Hz, 1 H); MS (ESI+) m/z 448 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[O:12])=[CH:6][CH:5]=1.[NH2:15][CH:16]([CH:32]([CH3:34])[CH3:33])[C:17]([N:19]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[O:18]>ClCCl>[CH2:25]([N:19]([CH2:20][CH2:21][N:22]([CH3:23])[CH3:24])[C:17](=[O:18])[C@@H:16]([NH:15][C:11]([NH:10][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)=[O:12])[CH:32]([CH3:33])[CH3:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)C(N)C(=O)N(CCN(C)C)Cc1ccccc1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: ClCCl
Product: CC(C)[C@H](NC(=O)Nc1ccc(OC(F)(F)F)cc1)C(=O)N(CCN(C)C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
4-(Trifluoromethoxy)phenyl isocyanate (0.18 g, 0.86 mmole) was slowly added to a solution of 13 (0.20 g, 0.72 mmole) in dichloromethane (20 mL) at 0° C. The solution was allowed to warm to room temperature and stirred for 18 h. The reaction was then quenched with water (20 mL), and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The organic residue was purified by flash chromatographey on silica gel, eluting with dichloromethane/2.0 M ammonia in ethyl alcohol (96:4) to give 14a (0.24 g, 69%) as a white solid; MS (EI)=480 (M+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N+:15]([O-])=[CH:14][C:13]3[N:20]=[C:21]([CH2:27][O:28][CH2:29][CH3:30])[N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)(Cl)C([N:35]=C=O)=O.C[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[C:14]([NH2:35])[C:13]3[N:20]=[C:21]([CH2:27][O:28][CH2:29][CH3:30])[N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CCOCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Reaction time: 1 h

Procedure:
A modification of the general method described in Part C of Example 3 was followed using 8-benzyloxy-2-ethoxymethyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c]quinoline (2.6 g, 6.4 mmol) as the starting material and chloroform as the solvent. The reaction with trichloroacetyl isocyanate was not complete after one hour as evidenced by a TLC analysis. Additional trichloroacetyl isocyanate was added, and the reaction was stirred overnight. Following the reaction with sodium methoxide, the solid product was isolated by filtration and washed with methanol and a mixture of dichloromethane and water. The solid was isolated by filtration and recrystallized from 2-methoxyethyl ether. The crystals were dried under high vacuum to provide 8-benzyloxy-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 183-184° C.
Reaction SMILES: CS(O)(=O)=O.C(OC([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16])=O)(C)(C)C.C(N(CC)CC)C>C(Cl)Cl>[NH2:13][C@H:14]([C:19]([OH:21])=[O:20])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonic acid (576 mg, 6 mmol) was added to a solution of (S)—N-(tert-butoxycarbonyl)-tert-leucine (1155 mg, 5 mmol) and methylene chloride (5 mL), and the mixture was stirred at 25° C. for 3 hours. When triethylamine (708 mg, 7 mmol) was added thereto, a solid was precipitated. The solid was sufficiently precipitated, and then the solution was stirred at 25° C. for 30 minutes and further stirred at 25° C. for 30 minutes. Thereafter, the solid was separated by filtration under reduced pressure. The solid was washed with methylene chloride (5 mL), and then was subjected to vacuum drying. Thereby, the titled compound was produced as a white solid (514 mg, yield of 75%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.CCN(CC)CC.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>C1COCC1.CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+]>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: C=C(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Yield: 32 %

Procedure:
To a stirred solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (J Med Chem, 1995;38:3482) (0.50 g, 1.59 mmol) in THF (20 mL) under nitrogen was added Et3N (excess, 1.0 mL), a catalytic amount of DMAP and methacryloyl chloride (1.1 mol eq., 1.75 mmol, 171 μL) dropwise. The reaction was stirred at 25° C. for 1.5 hours over which time two further amounts (50 μL) of methacryloyl chloride were added. The reaction was then diluted with saturated NaHCO3 and extracted with EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, concentrated under reduced pressure and chromatographed on silica gel eluting with CH2Cl2/EtOAc (1:1) to MeOH/CH2Cl2/EtOAc (5:45:50). Recrystallization from EtOAc gave N-[4-[(3-bromophenyl)amino]quinazolin-6-yl]-2-methylacrylamide (195 mg, 32%) as a cream powder, mp 244-245° C.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:20].[F:21][C:22]([F:34])([F:33])[C:23]1[CH:24]=[C:25]([N:30]=[C:31]=[O:32])[CH:26]=[CH:27][C:28]=1[Cl:29]>>[Cl:29][C:28]1[CH:27]=[CH:26][C:25]([NH:30][C:31]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[C:16]4[NH:15][C:14](=[O:17])[CH:13]=[N:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[F:20])=[O:32])=[CH:24][C:23]=1[C:22]([F:21])([F:33])[F:34]
Reactant: Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)cc1F
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Nc1ccc(Oc2ccnc3ncc(=O)[nH]c23)cc1F

Procedure:
Method F2 was used with 8-(4-amino-3-fluorophenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-trifluoromethyl-4-chloro-phenylisocyanate to afford the title compound as a beige powder. Yield: 60 mg (79%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[N:36][NH:37]3)O1>>[NH:37]1[C:38]2[C:34](=[C:33]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[S:10][C:9]([CH2:11][NH:12][CH2:13][CH2:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][C:6]=4[N:7]=3)[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: CS(=O)(=O)CCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: CS(=O)(=O)CCNCc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-(2-methanesulfonyl-ethyl)-amine was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole in General Procedure A. Purification by column chromatography yielded 383. NMR: CDCl3: 2.95 (3 H, s, Me), 3.18-3.21 (4 H, m, CH2), 3.82-3.85 (4 H, m, CH2), 4.01-4.04 (4 H, m, CH2), 4.12 (2 H, s, CH2), 7.45 (1 H, s, Ar), 7.50 (1 H, apparent triplet, J 8.2, Ar), 7.61 (1 H, d, J 8.2, Ar), 8.28 (1 H, d, J 7.5, Ar) and 9.03 (1 H, s, Ar). MS: (ESI+): MH+ 473.22