Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]([CH2:44][CH2:45][O:46][CH3:47])[CH3:43])=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: COCCN(C)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)CCOC)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(O)ccc2C1
Yield: 36.3 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N-(2-methoxyethyl)-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (7.5 mg) was obtained.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1)([O-:23])=[O:22]>O1CCCC1>[N+:21]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28][N:1]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[N:2]2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: COC(=O)Cc1n[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.5 %

Procedure:
Methyl 2-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetate (250 mg, 1.31 mmol), cesium carbonate (850 mg, 2.61 mmol), were added into 30 mL tetrahydrofuran, and stirred at room temperature for 15 minutes. Then 4-nitrobenzyl bromide (283 mg, 1.31 mmol) was added, and reacted at room temperature for 12 hours. It was filtered to remove the solid. The filtrate was rotate evaporated to dryness, and chromatographed on a column (PE:EA=10:1) to obtain a light yellow solid 75 mg, at a yield of 17.6%.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:7][C:6]=1[N+:20]([O-:22])=[O:21])(=O)C.[OH-].[Na+].CO>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])=[CH:7][C:6]=1[N+:20]([O-:22])=[O:21]
Reactant: CC(=O)Nc1ccc(S(=O)Cc2ccccc2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(S(=O)Cc2ccccc2)cc1[N+](=O)[O-]

Procedure:
2.42 G. 1-acetamido-2-nitro-4-benzylthiobenzene in 25 ml. chloroform is treated at -20 to -15° C with 1.6 g. 40% peracetic acid in 2 ml. methanol. The mixture is allowed to warm slowly to room temperature, held for 6 hours and washed with sodium bisulfite solution and sodium bicarbonate solution, dried and stripped. The residue is recrystallized from methanol giving 1-acetamido-2-nitro-4-benzylsulfinylbenzene. 2.14 G. 1-acetamido-2-nitro-4-benzylsulfinylbenzene is treated with 4 ml. 5N sodium hydroxide and 12 ml. methanol, on steam bath for 30 minutes, diluted with water, and filtered to give 1-amino-2-nitro-4-benzylsulfinylbenzene.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([OH:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCOCC>[CH3:21][N:2]([CH3:1])[C:3](=[O:20])[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([O:14][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13]
Reactant: CCOC(=O)C(C(=O)N(C)C)=C(O)c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)N(C)C)=C(OC(=O)c1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a well stirred mixture of 12.4 g of N,N-dimethylalphaethoxycarbonyl-beta-hydroxy-2,4-dichlorocinnamamide, 4.0 g of triethylamine and 150 ml of dry ether at 4° C. was added dropwise benzoyl chloride at such a rate that the temperature did not exceed 5° C. The reaction was allowed to warm up to room temperature, stirred at this temperature for 2 hours, the cooled again to 4° C. The solids were filtered off and the filtrate concentrated under reduced pressure to yield 12.0 g of a white solid. The solid was crystallized from ether/hexane to yield 8.0 g of the desired product, m.p. 106° C.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[N:4]=1.[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]3[CH2:27][CH2:28][CH2:29][NH:30][C:25]3=[N:24][N:23]=2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(O)(C)C>[N:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]3[CH2:27][CH2:28][CH2:29][N:30]([CH2:2][C:3]4[O:7][N:6]=[C:5]([C:8]5[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=5)[C:11]#[N:12])[N:4]=4)[C:25]3=[N:24][N:23]=2)=[CH:18][CH:17]=1
Reactant: N#Cc1cccc(-c2noc(CCl)n2)c1
Reactant: c1cc(-c2nnc3n2CCCN3)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CC#N
Product: N#Cc1cccc(-c2noc(CN3CCCn4c(-c5ccncc5)nnc43)n2)c1
Temperature: 130 °C
Yield: 24.4 %

Procedure:
3-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]benzonitrile (98.2 mg, 0.447 mmol), and 3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine (62.2 mg, 0.309 mmol) were suspended in acetonitrile (2 ml) and isopropanol (2.4 ml). After stirring for 45 min. potassium carbonate (88.1 mg, 0.637 mmole) was added. The mixture was heated in a microwave oven (130° C.) for 30 min. The product was filtered and then purified on prep. HPLC to give 29 mg of the title compound. 1H NMR(DMSO-d6): 8.72 (dd, 2H), 8.36 (br t, 1H), 8.30 (dt, 1H), 8.08 (dt, 1H), 7.79 (t, 1H), 7.68 (dd, 2H), 5.49 (s, 2H), 4.02(t, 2H), 3.3 (m, 1H), 2.36 (s, 3H), 1.71 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: Clc1cccc(I)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4cccc(Cl)c4)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-chloro-3-iodobenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 486.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C@@H:22]([C:25]1[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1)[CH2:23][OH:24].C(N(CC)C(C)C)(C)C>C(#N)C>[OH:24][CH2:23][C@@H:22]([NH:21][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:25]1[CH:26]=[N:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=1
Reactant: N[C@H](CO)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CO)c4ccc(C(F)(F)F)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (160 mg, 0.56 mmol) and (S)-2-amino-2-(6-(trifluoromethyl)pyridin-3-yl)ethanol (118 mg, 0.57 mmol) (prepared similarly according to the method for Intermediate 10) in acetonitrile (2 mL) and N,N-diisopropylethylamine (0.4 mL) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 40-60% acetonitrile-water [10 mM diethylamine]) to yield a light brown solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[C:19]([C:30](O)=[O:31])[N:20]=[C:21]3[CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[CH:16][CH:15]=2)=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:34][O:35][C:36](=[O:43])[C@@H:37]([NH2:42])[C:38]([CH3:41])([CH3:40])[CH3:39].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][O:35][C:36](=[O:43])[C@@H:37]([NH:42][C:30]([C:19]1[N:20]=[C:21]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:22]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([C:12](=[O:13])[NH:11][CH:8]1[CH2:9][CH2:10][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1)[CH:23]=2)=[O:31])[C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: CC(C)(C)C1CCC(NC(=O)c2ccc3cc(C(=O)O)nc(CC4CCCC4)c3c2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1cc2ccc(C(=O)NC3CCC(C(C)(C)C)CC3)cc2c(CC2CCCC2)n1)C(C)(C)C
Yield: 21.6 %

Procedure:
A solution of 7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid (65 mg, 0.148 mmol) in DMF(1.5 mL) was treated with (2S)-amino-3,3-dimethyl-butyric acid methyl ester HCL (35 mg, 0.193 mmol), HBTU (73 mg), and DIEA (0.106 mL) by the General Procedure A. The crude product was purified by flash column chromatography on silica gel using 88:12 Hexanes/EtOAc to give 18 mg of 2(S)-{[7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carbonyl]-amino}3,3-dimethylbutyric acid methyl ester as a colorless oil. This was used for the next step.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8]([Cl:12])[CH:9]=[C:10](Br)[C:5]2=[N:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=1.CC(C)([O-])C.[K+]>C1COCC1>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([Cl:12])[CH:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:23][CH3:24])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[C:5]2=[N:4][CH:3]=1
Reactant: Clc1cc(Br)c2ncc(Br)n2n1
Reactant: CNS(=O)(=O)c1ccc(N)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Nc2cc(Cl)nn3c(Br)cnc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
In a 100 ml round bottom flask was added 3,8-dibromo-6-chloroimidazo[1,2-b]pyridazine (0.122 g, 0.391 mmol) from Example XXIV, step (1a), 4-amino-N-methylbenzenesulfonamide (0.080 g, 0.430 mmol), and THF (3.9 ml, 0.1 M). Potassium tert-butoxide (0.976 mL, 0.976 mmol) was added drop-wise and the reaction was stirred at 25° C. overnight. The mixture was concentrated and diluted with ethyl acetate and water. The layers were separated and the organic was washed water (20 ml), then brine (10 ml), dried over Na2SO4, filtered and concentrated to provide 4-(3-bromo-6-chloroimidazo[1,2-b]pyridazin-8-ylamino)-N-methylbenzenesulfonamide (0.090 g, 55.3% yield) as a brownish solid. m/z=(417, M+1).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH:2]=1.Cl.[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[C:30]([CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31]>>[CH3:22][C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][C:24]=1[C:30]([CH:32]1[CH2:37][CH2:36][N:35]([C:14]([C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:20][CH:19]=2)=[O:16])[CH2:34][CH2:33]1)=[O:31]
Reactant: Cc1ccc(C(=O)C2CCNCC2)c(C)c1
Reactant: CCOC(=O)c1ccc(-n2cnc3cccnc32)cc1
Agent: Cl
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(-n4cnc5cccnc54)cc3)CC2)c(C)c1
Yield: 63.4 %

Procedure:
Using ethyl 4-(imidazo[4,5-b]pyridin-3-yl)benzoate (300 mg) described in Preparation Example 77 and (2,4-dimethylphenyl)(piperidin-4-yl)methanone hydrochloride (285 mg) and by the reaction and treatment in the same manner as in Example 170, the title compound (312 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.[CH3:10][C:11]1[C:15]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=2)=[C:14]([CH3:28])[O:13][N:12]=1>N1C=CC=CC=1>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:24]([C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][C:15]3[C:11]([CH3:10])=[N:12][O:13][C:14]=3[CH3:28])=[CH:23][CH:22]=2)(=[O:25])=[O:26])=[N:7][CH:6]=1)#[N:9]
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(N)nc1
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C#N)cn2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
To a solution of 6-amino-3-pyridinecarbonitrile (30 mg, 0.252 mmol) in pyridine (1 mL) at room temperature, was added 4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (84 mg, 0.277 mmol). The reaction mixture was stirred at 20° C. for 30 minutes, then left to stand overnight. The solvent was evaporated in vacuo. The sample was purified by passing through an aminopropyl (NH2) solid phase extraction (SPE) cartridge eluting with methanol, followed by a sulphonic acid (SCX) SPE cartridge eluting with methanol then 2M ammonia/methanol. The product-containing fractions were concentrated to give the title compound (23 mg) as an off-white solid. LCMS (2 min, formic) Rt 0.88 min, m/z (ES+) 385 (M+H)
Reaction SMILES: Br.[Br-].[NH2:3][CH2:4][CH2:5][N+:6]12[CH2:13][CH2:12][CH:9]([CH2:10][CH2:11]1)[C@@H:8]([O:14][C:15](=[O:30])[C:16]([OH:29])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:7]2.C(N(CC)CC)C.[C:38]([Br:46])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[Br-:46].[C:38]([NH:3][CH2:4][CH2:5][N+:6]12[CH2:13][CH2:12][CH:9]([CH2:10][CH2:11]1)[C@@H:8]([O:14][C:15](=[O:30])[C:16]([OH:29])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:7]2)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2
Reactant: O=C(Br)c1ccccc1
Agent: Br
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC[N+]12CCC(CC1)[C@@H](OC(=O)C(O)(c1ccccc1)c1ccccc1)C2)c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of (R)-1-(2-Amino-ethyl)-3-(2-hydroxy-2,2-diphenyl-acetoxy)-1-azonia-bicyclo[2.2.2]octane bromide hydrobromide [50(H)] (0.28 g, 0.517 mmol) in DCM at 0° C. is added triethylamine (0.216 ml, 1.552 mmol) followed by benzoyl bromide (0.122 ml, 1.03 mmol). The reaction mixture is stirred at 0° C. for 1.5 hours and the solvent was removed in vacuo. Purification of the crude residue by chromatography on C18 silica, eluting with water:acetonitrile affords the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[N:3]=1.[C-:34]#[N:35].[Na+].[I-].[K+]>CC(N(C)C)=O.O>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][C:2]([C:34]#[N:35])=[N:3][C:4]=3[NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: [C-]#N
Reactant: CN1CCN(CCCOc2ccccc2Nc2nc(Cl)nc3c2ncn3C2CCCC2)CC1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN1CCN(CCCOc2ccccc2Nc2nc(C#N)nc3c2ncn3C2CCCC2)CC1
Temperature: 160 °C
Reaction time: 24 h

Procedure:
(2-Chloro-9-cyclopentyl-purin-6-yl)-{2-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-amine (0.1 mmol), sodium cyanide (50 mg), potassium iodide (5 mg) are suspended in DMA (2 ml) and heated up to 160° C. and the mixture is stirred at this temperature for 24 hours. The mixture is diluted with water and extracted 3 times with ethyl acetate. The combined organic phases are washed with brine and the extract is dried over sodium sulfate and evaporated. The residue is dissolved in diethylether, filtered over powdered charcoal and cooled to 4° C. The solid material formed is filtered of and dried (vacuum). A white powder with mp. 136-138° C. is obtained.
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=CC=2)=[N:8][NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:6]=CC=CC=1.C1(C(=O)CC#[N:33])CCC1>>[CH:20]1([C:7]2[CH:1]=[C:6]([NH2:33])[N:9]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[N:8]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: c1ccc(C(=NNc2ccc3ncccc3c2)c2ccccc2)cc1
Reactant: N#CCC(=O)C1CCC1
Product: Nc1cc(C2CCC2)nn1-c1ccc2ncccc2c1
Yield: 40 %

Procedure:
Using a procedure analogous to Example B3, 6-(2-(diphenylmethylene)hydrazinyl)quinoline (4.0 g, 12.3 mmol) and 3-cyclobutyl-3-oxo-propionitrile (1.7 g, 1.1 eq) were combined to provide 5-cyclobutyl-2-quinolin-6-yl-2H-pyrazol-3-ylamine (1.3 g, 40% yield). 1H NMR (300 MHz, CDCl3) δ 8.92 (dd, J=4.5, 1.2 Hz, 1H), 8.16-8.20 (m, 2H), 8.00-8.04 (m, 2H), 7.43 (dd, J=8.4, 1.2 Hz, 1H), 5.64 (s, 1H), 3.83 (br s, 2H), 3.53 (m, 1H), 2.40-2.20 (m, 4H), 2.08-1.92 (m, 2H); MS (ESI) m/z: 265.1 (M+H+).
Reaction SMILES: Br[C:2]1[O:11][CH2:10][C:9]2[CH:8]([N:12]([CH3:14])[CH3:13])[CH2:7][C:6]3=[CH:15][N:16]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:17]=[C:4]([C:5]=23)[CH:3]=1.[Li]CCCC.CN(C)[CH:35]=[O:36]>O1CCCC1.[Cl-].[NH4+]>[CH3:13][N:12]([CH3:14])[CH:8]1[C:9]2[CH2:10][O:11][C:2]([CH:35]=[O:36])=[CH:3][C:4]3=[CH:17][N:16]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:26])[CH3:27])[CH:19]([CH3:20])[CH3:21])[CH:15]=[C:6]([C:5]=23)[CH2:7]1
Reactant: CN(C)C=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1C=C2C=C(Br)OCC3=C2C(=C1)CC3N(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)N1C=C2C=C(C=O)OCC3=C2C(=C1)CC3N(C)C
Reaction time: 1 h
Yield: 59 %

Procedure:
A solution of compound (42) 750 mg in dry tetrahydrofuran 7 ml was cooled at −70° C. and n-BuLi (1.56 mol/l hexane solution) 2.2 ml was added dropwise to the solution. The mixture was stirred for 1 h. Dimethylformamide 257 μl was added and the mixture was stirred for 2 h. The reaction mixtures was diluted with an aqueous ammonium chloride solution and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:4) to give the titled compound as yellow oil, 556 mg. This was recrystallized from hexane to give the titled compound as colorless crystals, m.p. 104-106° C., 395 mg. Yield 59%
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1C=CC=CC=1>[NH:11]([C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[N:10][C:3]=12)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1ccnc2[nH]cnc12
Reactant: Nc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(Nc2ccnc3[nH]cnc23)cc1
Temperature: 130 °C
Yield: 35.3 %

Procedure:
To 7-chloro-3H-imidazo(4,5-b)pyridine (16 g, 97 mmol) was added aniline (200 mL, 2.1 mol). The resulting mixture was heated under a nitrogen atmosphere at 130° C. for 24 hours. Benzene was added to the cooled mixture and the precipitate was filtered. The solid was dissolved in water and 1N NaOH was added to give a pH reading of 9. The precipitate was filtered and recrystallized from EtOH (decolorized by charcoal) to give 7.2 g (35%) of the 7-anilino-3H-imidazo[4,5-b]pyridine, m.p. 251°-252° C.
Reaction SMILES: [CH2:1]([NH:6][C:7](=S)[NH:8][NH2:9])[CH2:2][CH2:3][CH2:4][CH3:5].Cl[CH:12]([C:18]([CH3:20])=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCCC1>[CH3:20][C:18]1[NH:9][N:8]=[C:7]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CCCCCNC(=S)NN
Solvent: C1CCOC1
Product: CCCCCNc1n[nH]c(C)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
A stirred solution of 25.8 g (0.16 mole) of 4-pentyl-3-thiosemicarbazide in 150 mL of tetrahydrofuran was treated with 26.4 g (0.16 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for 2 hr, heated at reflux for 4 hr, and stirred for ~16 hr at ambient temperature. The reaction mixture contained amorphous material and large yellow crystals, which dissolved on heating at reflux for 1 hr. Upon cooling, large yellow crystals separated and were removed by filtration (sulfur). The filtrate was diluted with ice water, made acidic with 6N sulfuric acid and filtered to remove additional sulfur. The filtrate was adjusted to pH 6 with sodium carbonate and a total of 32.2 g of precipitated product was collected in 3 fractions. All the material was chromatographed twice on silica gel without purification, first by eluting with methylene chloride and the second time by eluting with benzene. A third column of 800 g of silica gel was eluted with isopropyl ether to give an orange oil which was not the product, then eluted with 50/50 isopropyl ether/methylene chloride. The product crystallized from the second eluent to give 7.8 g of white crystalline product after washing with isopropyl ether to remove a yellow color, mp 117°-119° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]([NH2:11])=[S:10])=[N:6][CH:7]=1.Br[CH2:21][C:22](=O)[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>>[Br:1][C:2]1[CH:3]=[C:4]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:5]([NH:8][C:9]2[S:10][CH:21]=[C:22]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:11]=2)=[N:6][CH:7]=1
Reactant: O=C(CBr)CCc1ccccc1
Reactant: NC(=S)Nc1ncc(Br)cc1Oc1ccc(F)cc1
Solvent: CCN(CC)CC
Product: Fc1ccc(Oc2cc(Br)cnc2Nc2nc(CCc3ccccc3)cs2)cc1
Yield: 102.2 %

Procedure:
Following the procedure in Example 7 Step E, 1-(5-bromo-3-(4-fluorophenoxy)pyridin-2-yl)thiourea (740 mg, 2.163 mmol), 1-bromo-4-phenylbutan-2-one (687.6 mg, 3.028 mmol) and triethylamine (0.5014 mL, 3.676 mmol) afforded 5-bromo-3-(4-fluorophenoxy)-N-(4-phenethylthiazol-2-yl)pyridin-2-amine (1040 mg, 102.2% yield) as a white solid after drying. 1H NMR (CDCl3) δ 8.71 (bs, 1H), 8.13 (d, 1H), 7.28 (m, 2H), 7.20 (m, 3H), 7.13 (m, 2H), 7.06 (m, 3H), 6.43 (s, 1H), 3.05-2.92 (m, 4H), Mass spectrum (apci) m/z=470.2, 472.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][C:16]2[S:17][C:18](Br)=[CH:19][N:20]=2)=[O:14])=[C:8]([C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:7]=1)[CH3:2].[SH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([NH:15][C:16]2[S:17][C:18]([S:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:19][N:20]=2)=[O:14])=[C:8]([C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:7]=1)[CH3:2]
Reactant: Sc1ccccn1
Reactant: CCOC(=O)Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Product: CCOC(=O)Cc1ccc(NC(=O)Nc2ncc(Sc3ccccn3)s2)c(C(=O)C2CCCC2)c1
Yield: 30 %

Procedure:
(3-Cyclopentanecarbonyl-4-{3-[5-(pyridin-2-ylsulfanyl)-thiazol-2-yl]-ureido}-phenyl)-acetic acid ethyl ester (153 mg, 30%) was prepared from {4-[3-(5-bromo-thiazol-2-yl)-ureido]-3-cyclopentanecarbonyl-phenyl}-acetic acid ethyl ester (480 mg, 1 mmol) and 2-mercapto-pyridine (222 mg, 2 mmol) following the general procedure Q.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[C:3]=1[Cl:11].[C:12]1([CH:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:11][C:3]1[C:4]([CH:8]([CH3:9])[CH3:10])=[N:5][CH:6]=[CH:7][C:2]=1[NH:1][C@H:21]1[CH2:20][CH2:19][C@@H:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:23][CH2:22]1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CC(C)c1nccc(N)c1Cl
Product: CC(C)c1nccc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1Cl
Yield: 26.6 %

Procedure:
Was prepared analogously to Example 75 starting from 4-amino-3-chloro-2-isopropylpyridine and 4-phenylcyclohexanone. Yield: 26.6%