Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:28]I>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:28])[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)c(C)c1
Reactant: CI
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N(C)S(C)(=O)=O)cc3)CC2)c(C)c1

Procedure:
Using N-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}methanesulfonamide (259.2 mg) described in Example 465 and methyl iodide (65 μL) and by the reaction and treatment in the same manner as in Example 36, the title compound (187 mg) was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20]>C(O)C>[ClH:2].[Br:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH:20][C:3]1[C:4]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: Clc1ncnc2[nH]c3ccccc3c12
Reactant: Nc1cccc(Br)c1
Agent: Cl
Solvent: CCO
Product: Brc1cccc(Nc2ncnc3[nH]c4ccccc4c23)c1
Yield: 66 %

Procedure:
4-Chloroindolo[2,3-d]pyrimidine hydrochloride (240 mg, 1 mmol) and 3-bromoaniline (0.33 mL, 3 mmol) in ethanol (3 mL) are heated under reflux for 2h. The solids are collected by suction filtration, washed with ethanol and dried to give 4-(3-bromoanilino)indolo[2,3-d]pyrimidine hydrochloride (248 mg, 73%). 1H NMR (DMSO) δ1H, s), 9.02 (1H, s),8.51 (1H, s), 8.42 (1H, d, J=7.7 Hz), 8.08 (1H, t, J=1.9 Hz), 7.82 (1H, d, J=8.0 Hz), 7.53 (1H, d, J=7.9 Hz), 7.46 (1H, dr, Jd =1.0 Hz, Jt =7.6 Hz), 7.36-7.27 (3H, m). ##STR29##
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][NH:7][NH2:8].C(N(CC)CC)C.Cl[C:17](=[N:25][N:26]=[C:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24]>C(O)C>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[NH:8][N:7]([CH3:6])[C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[N:26][N:25]=1
Reactant: ClC(=NN=C(Cl)c1ccccc1Cl)c1ccccc1Cl
Reactant: CNN
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1NC(c2ccccc2Cl)=NN=C1c1ccccc1Cl

Procedure:
The suspension containing 3.74 g (0.026 mol) of methylhydrazine sulfate, 11.9 ml (0.086 mol) of triethylamine in 11.2 ml of abs. ethanol is boiled under reflux while portionwise adding 1.12 g (0.0032 mol) of bis(alpha,2-dichlorobenzylidene)hydrazine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][OH:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].CS(C)=O.[CH2:26]1[O:34][CH:27]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)C>[C:28]1([CH:27]([OH:34])[CH2:26][O:15][CH2:14][CH:10]2[O:11][CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:9]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: OCC1CN(Cc2ccccc2)CCO1
Reactant: c1ccc(C2CO2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Product: OC(COCC1CN(Cc2ccccc2)CCO1)c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of 4.30 g of 4-benzyl-2-hydroxymethylmorpholine, 930 mg of potassium tert-butoxide and 4 ml of dimethyl sulfoxide was heated to 80° C. Thereto was dropwise added 2.50 g of styrene oxide over 20 minutes. The resulting mixture was stirred for 2 hours at the same temperature. The reaction mixture was added to a mixture of 30 ml of diethyl ether and 30 ml of ice water. The organic layer was separated and mixed with 10 ml of water. The mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The aqueous layer was separated and mixed with 30 ml of diethyl ether. The mixture was adjusted to pH 11 with a 2N aqueous sodium hydroxide solution. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=1/1) to obtain 2.00 g of oily 1-phenyl-2-[(4-benzylmorpholin-2-yl)methoxy]ethanol (compound No. 144).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)(=[O:3])[CH3:2].C([Li])CCC.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][C@H:25]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:26]2[O:31][C:30](=[O:32])[C:29]3[CH:33]=[CH:34][CH:35]=[C:36]([C:37]([F:40])([F:39])[F:38])[C:28]=3[N:27]=2)=[CH:16]1>O1CCCC1.CCCCCC>[O:32]=[C:30]([C:29]1[CH:33]=[CH:34][CH:35]=[C:36]([C:37]([F:38])([F:39])[F:40])[C:28]=1[NH:27][C:26]([C@@H:25]([NH:41][C:42](=[O:48])[O:43][C:44]([CH3:46])([CH3:45])[CH3:47])[CH2:24][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][CH:16]=1)=[O:31])[CH2:2][C:1](=[O:3])[NH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1
Reactant: CC(=O)Nc1nccs1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)c1nc2c(C(F)(F)F)cccc2c(=O)o1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)Nc1c(C(=O)CC(=O)Nc2nccs2)cccc1C(F)(F)F
Yield: 106.1 %

Procedure:
Using the procedure of Step B of Example 7, a solution of 18.34 g of 2-acetylaminothiazole in 565 ml of tetrahydrofuran, 184 ml of a solution of n-butyllithium in hexane and 20.3 g of the product of Step A in 150 ml of tetrahydrofuran were reacted to obtain 28 g of 1,1-dimethylethyl N-[(S) 1-[[2-[1,3-dioxo-3-(2-thiazolylamino)-propyl]-6-(trifluoromethyl)-phenyl]-aminocarbonyl]-2-(1H-indol-3-yl)-ethyl]-carbamate as an orange oil which was used as is in the following step.
Reaction SMILES: [N+:1]([C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[CH2:5][NH:6][C:7]([NH:9][CH3:10])=[O:8])#[C-:2].[C:15]([OH:21])(=O)[CH2:16][C:17]([OH:19])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:1]([C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[CH2:5][N:6]1[C:15](=[O:21])[CH2:16][C:17](=[O:19])[N:9]([CH3:10])[C:7]1=[O:8])#[C-:2]
Reactant: O=C(O)CC(=O)O
Reactant: [C-]#[N+]c1ccccc1CNC(=O)NC
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: [C-]#[N+]c1ccccc1CN1C(=O)CC(=O)N(C)C1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
In an alternate embodiment, 1-(2-isocyanobenzyl)-3-methylurea (30 g), acetic acid (105 ml) and malonic acid (18 g) were mixed and heated to 60° C. Acetic anhydride (60 ml) was added at 60° C. and heating was continued for two hours at 80° C. The reaction mixture was poured over ice water (300 ml) and the obtained solid was filtered, washed with water (1×500 ml) and methyl-tert-butylether (100 ml). The yield is 60% with 93.4% purity.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][CH2:34][CH:35]([OH:37])[CH3:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][CH2:34][CH:35]([OH:37])[CH3:36])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CC(O)CN
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCNCC(C)O)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and 1-amino-2-propanol (Eastman Kodak) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C23H34N6O5SF [(M+H)+] 525.2290, observed 525.2295.
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.C(N(CC)CC)C.[C:16]([C:18]1[C:23]2[N:24]=[C:25]([C:27]3[S:28][CH:29]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:31]=3)[O:26][C:22]=2[C:21](F)=[C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:19]=1[CH3:44])#[N:17]>CS(C)=O>[C:16]([C:18]1[C:23]2[N:24]=[C:25]([C:27]3[S:28][CH:29]=[C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[N:31]=3)[O:26][C:22]=2[C:21]([N:5]2[CH2:6][CH2:7][C@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]2)=[C:20]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:19]=1[CH3:44])#[N:17]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCOC(=O)c1csc(-c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)n1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1csc(-c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.3 %

Procedure:
(3S)-3-(Dimethylamino)pyrrolidine (91.6 μl, 0.722 mmol) and triethylamine (101 μl, 0.722 mmol) were added to a dimethyl sulfoxide (2 ml) solution of ethyl 2-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)-1,3-thiazole-4-carboxylate (I-197) (147 mg, 0.361 mmol), followed by stirring in an oil bath at 100° C. for 3 hours. The reaction liquid was concentrated under reduced pressure, the residue was dissolved in chloroform (100 ml) and washed with water (50 ml) and saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration, the resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=100:1→100:3), and the obtained yellow solid was purified in slurry with isopropanol (3 ml) to obtain the entitled compound (120 mg, 66.3%) as a pale yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:21][N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][C:28](O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[CH3:20][N:12]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([NH2:19])=[C:18]2[C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:28](=[O:29])[CH2:27][C:23]2[N:22]([CH3:21])[CH:26]=[CH:25][CH:24]=2)[CH2:2][CH2:3]3)=[N:11]1
Reactant: Cn1cccc1CC(=O)O
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cccc1CC(=O)N1CCc2cc(-c3nn(C)c4ncnc(N)c34)ccc21
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.330 mmol), (1-methyl-1H-pyrrol-2-yl)acetic acid (46 mg, 0.33 mmol), HATU (126 mg, 0.330 mmol), and DIEA (0.231 mL, 1.321 mmol) was stirred at room temperature overnight. LCMS indicated good converison, so the crude was poured into water and stirred for 30 minutes. The precipitate that formed was collected by filtration, washed with water and dried at the pump for 30 minutes. The crude was adsorbed onto silica and purified by flash chromatography (0-10% methanol in DCM) to afford 1-methyl-3-{1-[(1-methyl-1H-pyrrol-2-yl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (57.9 mg, 0.149 mmol, 45.2% yield) as a white solid. LC-MS (ES) m/z=388 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 3.25 (m, 2H), 3.55 (s, 3H), 3.86-3.90 (m, 2H), 3.94 (s, 3H), 4.21-4.32 (m, 2H), 5.86-5.93 (m, 2H), 6.66-6.71 (m, 1H), 7.41-7.48 (m, 1H), 7.49-7.53 (m, 1H), 8.13-8.22 (m, 1H), 8.23-8.27 (m, 1H). Note: NH's are not observed in the NMR spectrum.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:19]([NH:21][NH2:22])=O)[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]=1>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2([C:19]3[N:32]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:25]4=[N:22][N:21]=3)[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC1=NCCCCCC1
Reactant: NNC(=O)C1(C2CCN(Cc3ccccc3)CC2)CCCC1
Solvent: Cc1ccccc1
Product: c1ccc(CN2CCC(C3(c4nnc5n4CCCCCC5)CCCC3)CC2)cc1
Yield: 50.6 %

Procedure:
1-(1-Benzylpiperidin-4-yl)cyclopentane-1-carbohydrazide (1.04 g) and 8-methoxy-2,3,4,5,6,7-hexahydroazocine (1.46 g) were reacted in toluene (10 ml) under heating to obtain 3-[1-(1-benzyl-4-piperidinyl)cyclopentyl]-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (0.686 g). The resulting compound was reacted in ethanol under a hydrogen atmosphere using 10% palladium-active carbon (0.14 g) as a catalyst and, after filtration through celite, the resulting solution was concentrated to obtain 3-(1-piperidin-4-ylcyclopentyl)-5,6,7,8,9,10-hexahydro[1,2,4]triazolo[4,3-a]azocine (0.610 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CN(C=O)C>[F:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: Cc1nc(NC(=O)CCBr)sc1-c1ccnc(Nc2ccc(F)cc2)n1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)CCN2CCOCC2)sc1-c1ccnc(Nc2ccc(F)cc2)n1

Procedure:
A solution of 3-bromo-N-{5-[2-(4-fluoro-phenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide (20 mg, 0.046 mmol) and morpholine (8 μL, 0.092 mmol,) in DMF (2 mL) was stirred at room temperature for 2 h. The reaction mixture was purified by preparative RP-HPLC (0-60% MeCN in 0.1% aq CF3COOH over 40 min, 9 mL/min) to afford the title compound as a pale solid. Anal. RP-HPLC: tR=13.3 min (0-60% MeCN in 0.1% aq CF3COOH over 20 min, 1 mL/min, purity>93%). 1H-NMR (CD3OD) δ: 2.66 (s, 3H, CH3), 3.23 (m, 2H, CH2), 3.33 (m, 2H, CH2), 3.41 (m, 4H, CH2), 3.87 (m, 2H, CH2), 4.13 (m, 2H, CH2), 7.04-7.09 (m, 3H, pyrimidinyl-H & Ph-H), 7.68 (m, 2H, Ph-H), 8.39 (d, 1H, J=5.5 Hz, pyrimidinyl-H). MS (ESI+) m/z 443.3 (C21H23FN6O2S requires 442.5).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[N:10][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:22][Si:23]([CH3:37])([CH3:36])[CH2:24][CH2:25][O:26][CH2:27][N:28]1[C:32](B(O)O)=[CH:31][CH:30]=[N:29]1.C([O-])(O)=O.[Na+]>C1COCC1.O.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>[N+:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][N:9]1[C:4]2[N:5]=[C:6]([NH2:8])[N:7]=[C:2]([C:32]3[N:28]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:37])([CH3:36])[CH3:22])[N:29]=[CH:30][CH:31]=3)[C:3]=2[N:11]=[N:10]1)([O-:21])=[O:20]
Reactant: C[Si](C)(C)CCOCn1nccc1B(O)O
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc([N+](=O)[O-])c3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1nccc1-c1nc(N)nc2c1nnn2Cc1cccc([N+](=O)[O-])c1
Yield: 33.4 %

Procedure:
A solution of 7-chloro-3-(3-nitrobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (306 mg, 1 mmol), 1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-ylboronic acid (2 mmol), Pd(PPh3)4 (100 mg) and saturated NaHCO3 (5 mL) in THF (20 mL) was refluxed for 2 h, diluted with water (20 mL), extracted with EtOAc (2×20 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; CH2Cl2:EtOAc (6:1)] to give 3-(3-nitrobenzyl)-7-(1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrazol-5-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (156 mg, 34%) as a pale yellow syrup.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[C:10](I)[C:5]=2[S:4][CH:3]=1.[CH2:13]([O:15][CH:16]([O:28][CH2:29][CH3:30])/[CH:17]=[CH:18]/B1OC(C)(C)C(C)(C)O1)[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[C:10](/[CH:18]=[CH:17]/[CH:16]([O:28][CH2:29][CH3:30])[O:15][CH2:13][CH3:14])[C:5]=2[S:4][CH:3]=1
Reactant: CCOC(/C=C/B1OC(C)(C)C(C)(C)O1)OCC
Reactant: Nc1ncc(I)c2scc(Br)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(/C=C/c1cnc(N)c2c(Br)csc12)OCC
Temperature: 25 °C
Yield: 75 %

Procedure:
A mixture of Example 21A (200 mg, 0.56 mmol), 2-[(1E)-3,3-diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (175 mg, 0.67 mmol), Pd(PPh3)4 (40 mg, 0.03 mmol) and Na2CO3 (120 mg, 1.13 mmol) in 1,2-dimethoxyethane (10 mL) and water (5 mL) was heated in an 85° C. oil bath for 15 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was extracted with dichloromethane and the extract was dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel to provide the desired product (150 mg, 75%). 1H NMR (DMSO-d6, 400 MHz) δ 8.02 (s, 1H), 7.88 (s, 1H), 6.74 (d, 1H), 6.09 (dd, 1H), 5.09 (d, 1H), 3.62 (m, 2H), 3.48 (m, 2H), 1.15 (t, 6H); MS m/e 357.1, 359.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(N(CC)C(C)C)(C)C>CC(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)C1
Reactant: Brc1ncccn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)N1CCC(CNc2ncccn2)C1

Procedure:
A mixture of 3-aminomethyl-pyrrolidine-1-carboxylic acid benzyl ester (0.15 g), 2-bromopyrimidine (0.25 g), 2-propanol (10 mL), and of N,N-diisopropylethylamine (0.1 mL) was heated to reflux overnight. Purification of the residue obtained after concentration under reduced pressure by preparative chromatography, and eluting with ethyl acetate, gave 3-(pyrimidin-2-ylaminomethyl)-pyrrolidine-1-carboxylic acid benzyl ester as a solid:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]2)[N:3]=1.C(N(CC)CC)C.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[CH:6][N:5]=[C:4]([NH:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39])[CH2:23][CH2:22]2)[N:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](N)CC2)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(N[C@H]2CC[C@H](NC(=O)CCC(=O)O)CC2)nc1N

Procedure:
To a stirred solution of trans-[4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone (100 mg, 0.27 mmol, Example 120) and triethylamine (125 mg, 0.33 mmol) in tetrahydrofuran (5 mL), succinic anhydride (35 mg, 0.35 mmol, Aldrich,) was added and the mixture was refluxed for 2 hours. The mixture was cooled and the solid was filtered and dried to yield a white powder. 130 mg, 100%. MS (ES) MH+=478.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:31])([F:30])[CH2:4][N:5]=[C:6]([NH2:29])[NH:7][C:8]1[S:9][C:10]([CH3:28])=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[N:12]=1.[OH-].[Na+].Cl>O.C(O)C>[ClH:1].[ClH:1].[F:31][C:3]([F:2])([F:30])[CH2:4][N:5]=[C:6]([NH2:29])[NH:7][C:8]1[S:9][C:10]([CH3:28])=[C:11]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:12]=1
Reactant: Cc1sc(NC(N)=NCC(F)(F)F)nc1CCCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1sc(NC(N)=NCC(F)(F)F)nc1CCCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 128.6 %

Procedure:
To a mixture of 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-phthalimidobutyl)-5-methylthiazole hydrochloride (0.60 g.) in water (2 ml.) and ethanol (2 ml.) was added sodium hydroxide pellets (0.2 g.). The resulting yellow solution was heated on a steam bath for 10 minutes and then allowed to cool to ambient temperature. The reaction mixture was adjusted to pH3 by addition of 2N hydrochloric acid and then reheated on a steam bath for 1 hour. After cooling to ambient temperature the mixture was extracted three times with equal volumes of ethyl acetate. The aqueous layer was evaporated to dryness, azeotroped twice with toluene, the residue dissolved in methanol (10 ml.) and the solution filtered. The filtrate was evaporated to dryness to give 2-[2-(2,2,2-trifluoroethyl)guanidino]-4-(4-aminobutyl)-5-methylthiazole dihydrochloride (0.31 g.) as an oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O.S(Cl)(Cl)=O.[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].[Mg+2].[Cl-].[Cl-]>C(#N)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:13])([CH3:12])[C:9]([CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([O:26][CH2:27][CH3:28])=[O:25])=[O:11]
Reactant: CC(C)(C(=O)O)c1ccccc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A solution of 2-(2-chlorophenyl)-2-methylpropanoic acid (2.55 g, 12.8 mmol) in thionyl chloride (50.0 mL, 685 mmol) was heated at 95° C. for 2 hours. The solution was concentrated in vacuo, azeotroped using toluene (2×100 mL), and dried in vacuo to give the crude acid chloride. A mixture of diethyl malonate (1.94 mL, 12.8 mmol) and MgCl2 (1.22 g, 12.8 mmol) in ACN (50 mL) was cooled to 0° C. TEA (3.75 mL, 27.0 mmol) was added slowly, and the mixture was stirred at 25° C. for 2 hours. A solution of the acid chloride in ACN (50 mL) was added, and the mixture was heated at 50° C. for 2 days. The solution was diluted with 10% HCl (aq) (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with 2N NaOH (aq) (3×200 mL) and then with brine (75 mL). The organic layer was dried over MgSO4, concentrated, and purified by flash column chromatography (silica, 0-100% DCM in hexane) to give diethyl 2-(2-(2-chlorophenyl)-2-methylpropanoyl)malonate (3.25 g). MS m/e=341 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:31])[N:6]2[CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([O:29]C)=[O:28])[CH:23]=[CH:24][CH:25]=1.[OH-].[Li+]>CO.O>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:31])[N:6]2[CH2:16][CH2:17][CH2:18][NH:19][C:20]1[CH:21]=[C:22]([CH2:26][C:27]([OH:29])=[O:28])[CH:23]=[CH:24][CH:25]=1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNc3cccc(CC(=O)OC)c3)c2n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNc3cccc(CC(=O)O)c3)c2n1

Procedure:
The compound obtained in Example 2-42 (70 mg) was dissolved in methanol (5 ml) and a lithium hydroxide solution (45 mg) in water (5 ml) was added thereto. The same manner to Example 2-12 was conducted to give the titled compound as a colorless solid. Yield: 14 mg (21%); mp 247° C., MS APCI-ve 413 (M−H).