Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:26][C:27]1[CH:28]=[CH:29][C:30](F)=[N:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:30]2[CH:29]=[CH:28][C:27]([Br:26])=[CH:32][N:31]=2)([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: Fc1ccc(Br)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccc(Br)cn2)CC1
Reaction time: 0.75 h
Yield: 123.6 %

Procedure:
To a solution of 4-cyanopiperidine-1-carboxylic acid tert-butyl ester (6.24 g) described in Reference Example 88 (1) in tetrahydrofuran (20 ml) was added a 1.9 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (21.2 ml) at 0° C., stirred for 45 minutes, then a solution of 5-bromo-2-fluoropyridine (2.76 g) in tetrahydrofuran (10 ml) was added thereto, and stirred at room temperature for 5 hours. To the reaction solution was added 10% potassium carbonate aqueous solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated in vacuo. The obtained residue was purified with silica gel chromatography (n-hexane/ethyl acetate) to give 4-(5-bromopyridin-2-yl)-4-cyanopiperidine-1-carboxylic acid tert-butyl ester (7.1 g) as a pale yellow oil.
Reaction SMILES: [Br-].[Li+].[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][C:28]2[C@H:23]([CH2:24][CH2:25][C:26](=[O:30])[CH:27]=2)[C@@H:22]2[C@@H:13]1[C@H:14]1[C@@:18]([CH2:20][C@@H:21]2[F:31])([CH3:19])[C:17](=[O:32])[CH2:16][CH2:15]1)(=[O:5])[CH3:4].C(=O)(O)[O-].[Na+]>C(#N)C.C(OCC)(=O)C.[Cu](Br)Br>[C:3]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@@H:12]1[CH2:29][C:28]2[CH:27]=[C:26]([OH:30])[CH:25]=[CH:24][C:23]=2[C@@H:22]2[C@@H:13]1[C@H:14]1[C@@:18]([CH2:20][C@@H:21]2[F:31])([CH3:19])[C:17](=[O:32])[CH2:16][CH2:15]1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCCCCC[C@@H]1CC2=CC(=O)CC[C@@H]2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Agent: Br[Cu]Br
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)OCCCCC[C@@H]1Cc2cc(O)ccc2[C@@H]2[C@@H]1[C@@H]1CCC(=O)[C@@]1(C)C[C@@H]2F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.8 %

Procedure:
18.6 of copper(II) bromide and 3.6 g of lithium bromide are added to 16.5 g of 7α-(5-acetoxypentyl)-11β-fluoro-estr-4-ene-3,17-dione in 190 ml of acetonitrile at 80° C. After 15 minutes, the reaction mixture is stirred into sodium bicarbonate-containing ice water. The precipitated product is suctioned off, dissolved in ethyl acetate, washed with water, dried and concentrated by evaporation in a vacuum. After the crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, 8.5 g of 7α-(5-acetoxypentyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained as foam.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.Cl.O1CCOCC1>C(O)(C)C>[CH3:1][C:2]1[C:10]([O:11][C@H:12]2[CH2:17][CH2:16][CH2:15][C@@H:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(O[C@H]2CCC[C@@H](N3CCOCC3)C2)ccc2c1cnn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cc1c(O[C@H]2CCC[C@@H](N3CCOCC3)C2)ccc2[nH]ncc12
Yield: 87.2 %

Procedure:
Under nitrogen, the 4-methyl-5-[(cis-3-morpholin-4-ylcyclohexyl)oxy]-1-tetrahydro-2H-pyran-2-yl-1H-indazole (80 mg, 0.200 mmol) obtained in Example 727 was dissolved in isopropyl alcohol (3 ml), followed by adding thereto 4N-hydrochloric acid/1,4-dioxane (3 ml), and the resulting mixture was stirred at room temperature for 19 hours. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: acetonitrile/aqueous ammonia=100/0, 100/1, 100/2) to obtain 4-methyl-5-[(cis-3-morpholin-4-ylcyclohexyl)oxy]-1H-indazole (55 mg, yield 87.1%) as a white amorphous substance.
Reaction SMILES: [Na].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]#[N:9].C([O:14][N:15]=O)CCC>C(O)C>[N:15](=[C:7]([C:3]1[S:2][CH:6]=[CH:5][CH:4]=1)[C:8]#[N:9])[OH:14]
Reactant: N#CCc1cccs1
Reactant: CCCCON=O
Agent: [Na]
Solvent: CCO
Product: N#CC(=NO)c1cccs1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2.3 g. (0.10 mole) of sodium metal dissolved in 50 ml. ethanol and cooled to 0° C. in an ice bath was added 12.3 g. (0.10 mole) of 2-thienylacetonitrile. After the addition was complete 10.3 g. (0.10 mole) of butylnitrite was added. The reaction was stirred 1 hour at 0° C. and 3 hours at room temperature before the mixture was concentrated to dryness in vacuo. The residue was washed with ether. The sodium salt of the product was dissolved in water and acidified with concentrated hydrochloric acid to a pH of 3. The solid was filtered, washed with water, dried and recrystallized from chloroform to give 6.6 g. of final product which melted at 135°-137° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.C(N(CC)CC)C.[C:35]1(=O)[CH2:39][CH2:38][CH2:37][CH2:36]1>ClC(Cl)C>[CH:35]1([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C1CCCC1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: c1cc(C2(CNC3CCCC3)CCOCC2)ccc1OCCCN1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of (4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (254 mg, 0.798 mmol) in dichloroethane (5 mL) under nitrogen atmosphere were added acetic acid (37 mg, 1.6 mmol), triethylamine (97 mg, 1.6 mmol) and cyclopentanone (10 mg, 1.19 mmol). The mixture was stirred for 30 min at ambient temperature and NaHB(OAc)3 (204 mg, 1.6 mmol) was added at 0° C. After stirring overnight, the reaction mixture was filtered over celite, concentrated in vacuo and purified by column chromatography on silica gel eluting with DCM:MeOH:NH3 (89:10:1) to give the title compound (226 mg, 58%). 1H NMR (400 MHz, CDCl3) δ 7.20 (d, 2H), 6.88H), 4.03 (t, 2H), 3.78-3.73 (m, 2H), 3.59-3.53 (m, 2H), 2.84 (q, 1H), 2.73 (t, 2H), 2.65-2.68 (m, 6H), 2.03-2.12 (m, 4H), 1.84-1.94 (m, 6H), 1.65-1.72 (m, 2H), 1.51-1.58 (m, 2H), 1.41-1.46 (m, 2H), 1.07-1.16 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[O:27][CH:28]=[C:29]([CH2:31][CH3:32])[N:30]=4)=[CH:22][C:21]=3[O:33][CH3:34])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)[CH3:5].[OH-].[Li+]>O1CCCC1.CO.O>[CH2:31]([C:29]1[N:30]=[C:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH2:18][CH2:17][CH2:16][O:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH:4]([CH3:5])[C:3]([OH:35])=[O:2])[CH:7]=[CH:8]4)=[C:21]([O:33][CH3:34])[CH:22]=2)[O:27][CH:28]=1)[CH3:32]
Reactant: CCc1coc(-c2ccc(OCCCOc3ccc4c(ccn4C(C)C(=O)OC)c3)c(OC)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCc1coc(-c2ccc(OCCCOc3ccc4c(ccn4C(C)C(=O)O)c3)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
2-(5-{3-[4-(4-Ethyl-oxazol-2-yl)-2-methoxy-phenoxy]-propoxy}-indol-1-yl)-propionic acid methyl ester (Example 62, 129.7 mg, 0.27 mmol) was dissolved in a solution of tetrahydrofuran (2 mL), methanol (1 mL), and water (2 mL). Lithium hydroxide (32.45 mg, 1.36 mmol) was added and the mixture was stirred at rt for 2 h. The solution was concentrated, diluted with water (5 mL), and acidified with 1N HCl. The resulting white precipitate was collected by filtration and dried to give the title compound (100.1 mg, 79.5%). LC/MS m/z 465.1 (M+H)+; RT 3.25 min. 1H NMR (400 MHz, DMSO-d6) δ 7.82 (s, 1H), 7.47 (dd, 1H), 7.42 (d, 1H), 7.37 (d, 1H), 7.28 (d, 1H), 7.11 (d, 1H), 7.06 (d, 1H), 6.77 (dd, 1H), 6.34 (d, 1H), 5.24 (q, 1H), 4.19 (t, 2H), 4.12 (t, 2H), 3.82 (s, 3H), 2.52 (m, 2H), 2.20 (m, 2H), 1.68 (d, 3H), 1.19 (t, 3H).
Reaction SMILES: [OH:1][N:2]1C(=O)C2=CC=CC=C2C1=O.Cl.[Cl:14][CH2:15][C:16]1[N:17]=[CH:18][S:19][CH:20]=1>>[ClH:14].[S:19]1[CH:20]=[C:16]([CH2:15][O:1][NH2:2])[N:17]=[CH:18]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: ClCc1cscn1
Agent: Cl
Product: NOCc1cscn1

Procedure:
Prepared by a similar procedure as described for preparation 18. Starting materials: N-hydroxyphthalimide and 4-(chloromethyl)thiazole hydrochloride (TCl). 13C-NMR (DMSO-d6) δ 155.1, 149.2, 121.4, 70.3.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:8]([C:9]([O:11]C)=O)=[N:7][N:6]2[C:13]([NH:16][CH3:17])=[N:14][N:15]=[C:5]2[C:4]=1[CH3:18].[CH2:19]([NH2:21])[CH3:20]>CO>[CH2:19]([NH:21][C:9]([C:8]1[C:3]([CH3:2])=[C:4]([CH3:18])[C:5]2[N:6]([C:13]([NH:16][CH3:17])=[N:14][N:15]=2)[N:7]=1)=[O:11])[CH3:20]
Reactant: CNc1nnc2c(C)c(C)c(C(=O)OC)nn12
Reactant: CCN
Agent: Cl
Solvent: CO
Product: CCNC(=O)c1nn2c(NC)nnc2c(C)c1C
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Methyl 7,8-dimethyl-3-methylamino-[1,2,4]triazolo[4,3-b]pyridazine-6-carboxylate hydrochloride (W1.220; 1.3 g) was dissolved in methanol (30 ml), cooled to 0° C., slowly admixed dropwise with ethylamine (11.44 ml; 2 M in THF) and stirred at 0° C. for 6 h. Then four further equivalents ethylamine were added and the mixture was left to stand at RT over the weekend. Subsequently, the mixture was concentrated and purified using silica gel (40 g cartridge, dichloromethane/methanol gradient of 0-20% in 60 min). 1.12 g of the title compound were obtained. LC-MS rt: 0.81 min [M+H]+: 249.1 (met. b)
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:11]2[C:10]=1[C:2]([CH3:1])=[C:3]([CH3:4])[NH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(OCc2ccccc2)cc1N
Solvent: CN(C)C=O
Product: COc1ccc(OCc2ccccc2)c2c(C)c(C)[nH]c12
Temperature: 40 °C

Procedure:
1 mole (229 g) of 3-benzyloxy-6-methoxyaniline is added to 700 ml of dimethylformamide and 0.5 mole (76 g) of 2-bromobutanone. The reaction medium is heated to 40° C. for 2 hours 30 minutes and then to 120° C. for three quarters of an hour. By adding ice and then cooling, an oil is obtained which is decanted and then dissolved in ethyl acetate. After washing with a 2N solution of hydrochloric acid, then with water and evaporation of the ethyl acetate, the desired product is obtained in the form of a dry extract which is recrystallized from cyclohexane under reflux. The desired product melts at 100° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:45]1[CH2:50][CH2:49][CH2:48][CH:47](O)[CH2:46]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:47]2[CH2:48][CH2:49][CH2:50][O:45][CH2:46]2)=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCCOC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCCOC2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 250 mg (0.691 mmol) rac-[1-(4-chloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester, 257 mg (0.864 mmol) triphenylphosphine and 84.7 mg (0.829 mmol) tetrahydro-pyran-3-ol in 8.5 ml tetrahydrofuran were added 191 mg (0.829 mmol) di-tert-butyl azodicarboxylate and the reaction mixture stirred at ambient temperature for 2 hours. Then the reaction mixture was evaporated and purified by flash chromatography on silica gel with a heptane/ethyl acetate gradient of 0-30% ethyl acetate. The title compound was obtained as colorless solid: MS (ISN): 444.2 (M−H)−.
Reaction SMILES: [NH:1]([C:13]([CH3:15])=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:16](O)(=O)[CH:17]=C.N(C(C)=O)[C@H](C(O)=O)CC1C=CC=CC=1>C(O)C.Cl>[NH:1]([C:13]([CH3:15])=[O:14])[C@H:2]([C:10]([O:12][CH2:16][CH3:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(=O)O
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(C)=O

Procedure:
The synthesis of N-Ac-L-Phe-acrylic acid is shown below in Scheme B. To a solution of N-Ac-L-Phe (5.0 g, 24.1 mmol) in 120 ml of ethanol was added a few drops of concentrated HCl. The reaction mixture was refluxed overnight, then concentrated under reduced pressure. The residual solid was dissolved in ethyl acetate, washed twice with dilute NaHCO3, then once with water. The organic phase was dried over MgSO4, concentrated under reduced pressure, and dried under vacuum, to give N-Ac-Phe-OEt (7) as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([N:10]([CH2:29][C:30]([O:32]CC)=[O:31])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3].[OH-].[K+]>C(O)C.O>[CH2:1]([C:4]1[C:9]([N:10]([CH2:29][C:30]([OH:32])=[O:31])[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[NH:28][N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ncccc1N(CC(=O)OCC)Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCc1ncccc1N(CC(=O)O)Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
The compound resulting from Example 153E is dissolved in 1 part methylene chloride and 1.5 parts formic acid and stirred at ambient temperature to give 2-propyl-3-{N-ethoxycarbonylmethyl-N-[(2'-[1H-tetrazol-5-yl]biphenyl-4-yl)methyl]amino}pyridine. This ester is hydrolyzed with potassium hydroxide in ethanol/water to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[NH2:25][C:26]1[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:25][C:26]4[CH:27]=[N:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: COC(=O)CC1CCC(c2ccc(-c3ccc(Br)cn3)cc2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: COC(=O)CC1CCC(c2ccc(-c3ccc(Nc4ccc(C(F)(F)F)nc4)cn3)cc2)CC1
Temperature: 150 °C

Procedure:
A microwave vial was charged with {4-[4-(5-bromo-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (3.4 g, 8.8 mmol, 1.0 equiv), 3-amino-6-trifluoromethyl pyridine (2.1 g, 13.1 mmol, 1.2 equiv), cesium carbonate (7.1 g, 21.9 mmol, 2.5 equiv), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos, 0.42 g, 0.88 mmol, 0.1 equiv) and palladium acetate (0.30 g, 0.44 mmol, 0.05 equiv) in 20 Ml of toluene/t-butanol (9:1). The suspension was sparged with nitrogen for 10 min, then heated to 150° C. under microwave heating for 45 min. The reaction was cooled to room temperature, partitioned between ethyl acetate and water. The organic extracts were washed with brine, then dried over sodium sulphate and concentrated in vacuo. Purification by silica gel chromatography afforded the title compound: 1H NMR (400 MHz, DMSO-d6) 1.10-1.21 (m, 1 H) 1.51 (qd, J=12.72, 2.78 Hz, 2 H) 1.70-1.87 (m, 5 H) 2.26 (d, J=6.57 Hz, 2 H) 2.50 (m, 1 H) 3.61 (s, 3 H) 7.33 (d, J=8.34 Hz, 2 H) 7.65 (d, J=2.53 Hz, 1 H) 7.67-7.74 (m, 2 H) 7.89 (d, J=8.59 Hz, 1 H) 7.95 (d, J=8.34 Hz, 2 H) 8.46 (d, J=2.53 Hz, 1 H) 8.54 (d, J=2.53 Hz, 1 H) 9.18 (s, 1 H); (M+H)+ 427.3.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[C:8](=[N:13][NH:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)N=CC=C3)[C:9]([NH2:12])=[N:10][N:11]=1.NC1C=C2C(=CC=1)N=CC=C2>>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[C:8](=[N:13][NH:14][C:15]2[CH:16]=[CH:17][CH:22]=[CH:23][CH:24]=2)[C:9]([NH2:12])=[N:10][N:11]=1
Reactant: Cn1cccc1C1=NN=C(N)C1=NNc1ccc2ncccc2c1
Agent: Nc1ccc2ncccc2c1
Product: Cn1cccc1C1=NN=C(N)C1=NNc1ccccc1

Procedure:
In a similar manner, 5-(1-methyl-1H-pyrrol-2-yl)-4-(quinolin-6-ylhydrazono)-4H-pyrazol-3-ylamine was prepared from 6-aminoquinoline (0.25 g, 1.73 mmol) to yield 85 mg of the product. MS (m/z, ES+): 318.3 (M+1, 100%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:4])=[O:3].S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[N:34]=[C:33]([NH:35][CH2:36][CH2:37][C:38]3[NH:39][CH:40]=[N:41][CH:42]=3)[C:32]([Br:43])=[CH:31][N:30]=2)=[CH:24][CH:23]=1>CC(N(C)C)=O>[Br:43][C:32]1[C:33]([NH:35][CH2:36][CH2:37][C:38]2[NH:39][CH:40]=[N:41][CH:42]=2)=[N:34][C:29]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([NH:21][C:9](=[O:11])[C:8]3[CH:12]=[CH:13][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=3)=[CH:27][CH:26]=2)=[N:30][CH:31]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccc(Nc2ncc(Br)c(NCCc3cnc[nH]3)n2)cc1
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Nc3ncc(Br)c(NCCc4cnc[nH]4)n3)cc2)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 23.7 %

Procedure:
4-Methanesulfonyl-3-nitro-benzoic acid (72 mg, 0.29 mmole) was dissolved in DMA (3 ml) and thionyl chloride (0.29 mmole) was added at ambient temperature. After the mixture was stirred for 5 minutes N2-(4-Amino-phenyl)-5-bromo-N4-[2-(3H-imidazol-4-yl)-ethyl]-pyrimidine-2,4-diamine (100 mg, 0.26 mmole, prepared according to procedure 21) was added and the reaction was allowed to stir overnight. After extraction with bicarbonate solution and ethyl acetate (3×) the combined organic layers were dried over magnesium sulfate and the solvent was removed under reduced pressure. The crude product was purified by flashmaster chromatography on silica gel to provide 37 mg of N-(4-{5-Bromo-4-[2-(3H-imidazol-4-yl)-ethylamino]-pyrimidin-2-ylamino}-phenyl}-4-methanesulfonyl-3-nitro-benzamide (23% yield). ESI-MS: 602.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][C:21]=3[N:22]([CH3:25])[C:23]=2[CH:24]=1>>[CH3:25][N:22]1[C:23]2[CH:24]=[C:16]([N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=[O:14])[CH:17]=[CH:18][C:19]=2[C:20]2[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][C:21]1=2
Reactant: Cc1ccc(-c2cc[nH]c(=O)c2)cn1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)cn1
Yield: 58.1 %

Procedure:
4-(6-Methylpyridin-3-yl)pyridin-2(1H)-one (150 mg, 0.81 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (294 mg, 0.805 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (220 mg, 58%) as a yellow/green solid: 1H NMR (500 MHz, CDCl3) δ 8.79 (d, J=8.2 Hz, 1H), 7.83 (dd, J=8.1, 2.4 Hz, 1H), 7.56-7.51 (m, 2H), 7.37 (d, J=1.4 Hz, 1H), 7.30 (1H, partially under solvent), 7.08 (d, J=8.7 Hz, 1H), 6.90 (d, J=1.6 Hz, 1H), 6.50 (dd, J=7.1, 1.9 Hz, 1H), 4.66 (br s, 2H), 3.85 (br m, 2H), 3.65 (s, 3H), 2.84 (br m, 2H), 2.64 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])[CH:16]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C)nc1OCc1ccnc(OCc2nc(-c3ccccc3)oc2C)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 87.8 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (298 mg), 4-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (551 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [1-methyl-3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (689 mg, yield 88%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32].[H-].[Na+].I[CH3:36].[NH4+].[Cl-]>CN(C=O)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:27]([CH3:36])[S:28]([CH3:31])(=[O:30])=[O:29])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32]
Reactant: CI
Reactant: Cc1cc(F)ccc1-c1nc(NS(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1-c1nc(N(C)S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To the solution of N-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]-methanesulfonamide (92 mg, 0.2 mmol) in anhydrous DMF (2 mL) was added NaH (80 mg of 60% dispersion in mineral oil, 2 mmol, 10 eq) and the reaction mixture was stirred for 30 minutes at 23°. Iodomethane (280 mg, 2 mmol, 10 eq) was added and the reaction mixture was stirred 1 h at 23°. Saturated aq NH4Cl (5 mL) was added and the reaction mixture was extracted with EtOAc (2×20 mL). Organic layers were combined, washed with satd aq NaCl, dried (MgSO4), filtered and solvent was evaporated. The yellow residue was then purified by Flash chromatography to give 80 mg of pure N-[8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-yl]-N-methyl-methanesulfonamide. 1H-NMR (CDCl3): δ 2.22 (s, 3H), 2.96 (s, 3H), 3.30 (s, 3H), 6.68 (d, 1H, J=9.8 Hz), 7.02 (m, 4H). 7.213 (m, 1H), 7.42 (m, 2H), LC MS (m/e)=475.4 (MH+). Rt=2.25 min.