Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18]>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:6]1[CH:5]=[CH:4][C:3]2[C:2]([NH:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[O:14][CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: Clc1ccc2c(Br)cccc2n1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2c(NCc3ccccc3OC)cccc2n1

Procedure:
The title compound, MS: m/e=400.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-bromo-2-chloroquinoline and 2-methoxybenzylamine in step A and step B.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11](Cl)(=[O:13])=[O:12].C1OC(C2C=CSC=2)OC1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1.C(N(CC)CC)C>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[S:11]([NH:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1sccc1C1OCCO1
Reactant: COc1ccc(N)cc1
Agent: c1cc(C2OCCO2)cs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NS(=O)(=O)c2sccc2C2OCCO2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
A solution of 3-(1,3-dioxolan-2-yl)-thiophene-2-sulfonyl chloride (11.16 g), prepared from thiophene-3-carboxaldehyde ethylene acetal as described in Example 6, Step A, in THF (100 mL) at 0° C. was combined with p-anisidine (7.87 g, 63.9 mmol) and triethylamine (4.04 g, 40 mmol). After stirring for 4 hr at ambient temperature, the mixture was evaporated to a residue which was extracted with ethyl acetate (2×150 mL). The combined extracts were dried (MgSO4) and evaporated to a residue which was purified by column chromatography (silica, 40% ethyl acetate/hexane) to give an oil (10.21 g, 75%).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][O:15][C:16]([C:18]2([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[C:8]1([CH2:14][O:15][C:16]([C:18]2([NH:24][C:32](=[O:33])[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[O:17])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)NC1(C(=O)OCc2ccccc2)CCCCC1
Reaction time: 8 h
Yield: 91.3 %

Procedure:
1.21 g (12 mmol) of triethylamine was added to a solution of 2.33 g (10 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester in 100 ml of tetrahydrofuran, 1.55 g (10 mmol) of phenylacetyl chloride was added dropwise thereto under ice-cooling, and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, the mixture was successively washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography to obtain 3.21 g (91%) of the title compound.
Reaction SMILES: [NH:1]([C:3]([C:5]1[N:10]=[C:9]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[CH:7][CH:6]=1)=O)[NH2:2].[CH:22]1([NH:25][CH:26]=O)[CH2:24][CH2:23]1.C1(N)CC1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[CH:22]1([N:25]2[CH:26]=[N:2][N:1]=[C:3]2[C:5]2[N:10]=[C:9]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=[CH:7][CH:6]=2)[CH2:24][CH2:23]1
Reactant: NNC(=O)c1cccc(NC(=O)OCc2ccccc2)n1
Reactant: O=CNC1CC1
Agent: NC1CC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(-c2nncn2C2CC2)n1)OCc1ccccc1
Temperature: 100 °C
Yield: 29.4 %

Procedure:
To a sealable flask containing benzyl 6-(hydrazinecarbonyl)pyridin-2-ylcarbamate (1.97 g, 6.89 mmol, 1.0 eq) was added N-cyclopropyl formamide (1.8 mL, 20.7 mmol, 3.0 eq), cyclopropylamine (1.4 mL, 20.7 mmol, 3.0 eq), toluene (0.2 M), and trifluoracetic acid (0.511 mL, 6.89 mmol, 1.0 eq). The flask was sealed and heated to 100° C. for 24 hours. The reaction mixture was concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography (Rf=0.44 in 10% methanol/ethyl acetate, gradient flash: 3%→10% methanol in ethyl acetate). The product, which consisted of a mixture of the desired compound with cyclopropyl formamide, was suspended in acetonitrile, sonicated, and the resultant suspension filtered to provide benzyl 6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-ylcarbamate (680 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([NH2:11])[CH2:6][CH2:5]2.[F:12][C:13]([F:24])([F:23])[C:14]([NH:16][C:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1)=[O:15]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([NH:11][C:20]([C:17]1([NH:16][C:14](=[O:15])[C:13]([F:12])([F:23])[F:24])[CH2:18][CH2:19]1)=[O:21])[CH2:6][CH2:5]2
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Reactant: N[C@H]1CCc2cc(Br)ccc21
Product: O=C(NC1(C(=O)N[C@H]2CCc3cc(Br)ccc32)CC1)C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B] and A-1 [C], (S)-5-bromo-indan-1-ylamine has been coupled with 1-(2,2,2-trifluoroacetamido)cyclopropanecarboxylic acid (intermediate A-1 [A]) to give 1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid ((S)-5-bromo-indan-1-yl)-amide, which was subsequently reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to yield the title compound as light brown solid. MS: 439.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[N:14]2[C:9]([C:10]([CH3:18])=[C:11](Cl)[CH:12]=[CH:13]2)=[C:8]([CH:19]2[CH2:21][CH2:20]2)[CH:7]=1)=[O:5])[CH3:2].[CH3:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:19]1([C:8]2[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:15](=[O:16])[N:14]3[C:9]=2[C:10]([CH3:18])=[C:11]([C:26]2[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=2)[CH:12]=[CH:13]3)[CH2:21][CH2:20]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(C)cc3)ccn2c1=O
Temperature: 80 °C
Yield: 62.3 %

Procedure:
A mixture of 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (120 mg, 0.400 mmol), 4-methyl-phenyl boronic acid (65 mg, 0.48 mmol), (Ph3P)2PdCl2 (28 mg, 0.040 mmol), and Na2CO3 (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N2 and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with water (2×20 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 1:2) to afford the title compound as a yellow solid (90 mg, 62%). ESI-MS m/z: 362 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C@H:11]2[CH2:16][CH2:15][CH2:14][N:13]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH2:12]2)=[O:10])[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:20]1([S:17]([N:13]2[CH2:14][CH2:15][CH2:16][C@H:11]([C:9]([NH:8][CH:5]3[CH2:6][CH2:7][CH:2]([O:1][C:29]4[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=4)[CH2:3][CH2:4]3)=[O:10])[CH2:12]2)(=[O:19])=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Oc1ccncc1
Reactant: O=C(N[C@H]1CC[C@H](O)CC1)[C@H]1CCCN(S(=O)(=O)c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(NC1CCC(Oc2ccncc2)CC1)[C@H]1CCCN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.3 %

Procedure:
Under a nitrogen atmosphere, to a mixture of (3S)—N-(trans-4-hydroxycyclohexyl)-1-(phenylsulfonyl)piperidine-3-carboxamide (25 mg, 0.068 mmol), 4-pyridinol (9.7 mg, 0.10 mmol), and triphenylphosphine (26.8 mg, 0.10 mmol) in tetrahydrofuran (0.5 mL) was added a solution of diethyl azodicarboxylate (16 μL, 0.10 mmol) in tetrahydrofuran (0.1 mL). The mixture was stirred at r.t. overnight. The product was purified with prep. HPLC. 1.9 mg product was obtained, yield: 6.3%. LCMS: m/z 444.2 (M+H)+; 887.2 (2M+Na)+.
Reaction SMILES: O.[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH3:13].Br[CH:15]1[CH2:20][CH2:19][O:18][C:16]1=[O:17].CC1C=CC=C(C)N=1>CC(C)=O>[CH3:13][C:4]1[CH:5]=[CH:6][C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[NH:2][CH:20]1[CH2:19][O:18][C:16](=[O:17])[CH2:15]1
Reactant: Cc1ccc2ccccc2c1N
Reactant: O=C1OCCC1Br
Solvent: O
Solvent: CC(C)=O
Solvent: Cc1cccc(C)n1
Product: Cc1ccc2ccccc2c1NC1COC(=O)C1
Reaction time: 7 h
Yield: 63.4 %

Procedure:
A 200-ml round-bottom flask equipped with a heating mantle and connected to a water aspirator vacuum system was charged with 15.0 g (0.1 mcl) 1-amino-2-methylnaphthalene, 16.4 g (0.1 mol) alpha-bromo-gamma-butyrolactone and 10.7 g (0.1 mol) 2,6-dimethylpyridine. The reaction mixture was maintained at about 94°-101° C. and 160 mm of Hg for about 7 hours. The reaction mixture was cooled, diluted with 100 ml acetone and filtered. The filtrate was evaporated under reduced pressure to give an oily residue which was eluted through a silica gel column with 15% acetone/85% petroleum ether to give 14.6 g of 3-(N-2-methylnaphth-1-ylamino)-gamma-butyrolactone, m.p. 92°-94° C. Elemental analysis for C15H15NO2 showed: %C, calc. 75.0, found 74.5; %H, calc. 5.9, found 5.6; %N, calc. 5.8, found 5.6.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:18][CH:17]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C(O[C:35]1(O[Si](C)(C)C)[CH2:37][CH2:36]1)C.C([BH3-])#N.[Na+]>CO>[CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][N:25]([CH:35]5[CH2:37][CH2:36]5)[CH2:24][CH2:23]4)=[CH:20][CH:21]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: c1ccc2c(Nc3ccc(N4CCNCC4)cc3)c3ccccc3nc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc2c(Nc3ccc(N4CCN(C5CC5)CC4)cc3)c3ccccc3nc2c1
Temperature: 25 °C
Yield: 2 %

Procedure:
35 mg (0.10 mmol) of 9-[4-(piperazin-1-yl)phenyl]aminoacridine (Example 16) was dissolved in 1 ml of methanol. 57 μl (1.0 mmol) of acetic acid, 22 μl (0.11 mmol) of (1-ethoxycyclopropyloxy)-trimethylsilane and a small amount of 3 Å molecular sieves were added. The reaction mixture was stirred at room temperature under nitrogen atmosphere. After 30 min 28 mg (0.45 mmol) of sodium cyanoborohydride was added and the reaction mixture was heated at 50° C. over night. The solvents were removed under vacuum, and the residue was purified by chromatography (silica gel column, eluent chloroform/methanol 6:1) to obtain 3.8 mg (10%, overall yield 2%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[N:18][CH:19]=[C:20](Cl)[N:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)(=[O:27])=[O:26].C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:23][C:17]3=[N:18][CH:19]=[C:20]([C:31]4[CH:32]=[CH:33][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:29][CH:30]=4)[N:21]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3nc(Cl)cnc3o2)CC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc3nc(-c4ccc(S(C)(=O)=O)cc4)cnc3o2)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 4-(2-chloro-furo[2,3-b]pyrazin-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (200 mg), 4-(methanesulfonyl)phenyl boronic acid (140 mg), Na2CO3 (126 mg), water (2.5 mL), and N,N-dimethylformamide (2.5 mL) is sparged with argon for 10 min and Pd(PPh3)4 (15 mg) is added. The resulting mixture is stirred at 100° C. for 1.5 h. After cooling to room temperature, water and ethyl acetate are added. The organic phase is washed with brine, dried (MgSO4), and the solvent is evaporated. The residue is chromatographed on silica gel (ethyl acetate/cyclohexane 60:40) to give an oily residue that is triturated with diethyl ether and dried to afford the title compound as a colorless solid. Yield: 175 mg (65% of theory); LC (method 2): tR=1.35 min; Mass spectrum (ESI+): m/z=458 [M+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][N:6]=1)=[O:4].Br[C:21]1[N:26]=[N:25][C:24]([NH2:27])=[N:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[NH2:27][C:24]1[N:25]=[N:26][C:21]([C:8]2[CH:9]=[CH:10][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[N:6][CH:7]=2)=[CH:22][N:23]=1
Reactant: Nc1ncc(Br)nn1
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CNC(=O)c1ccc(-c2cnc(N)nn2)cn1
Temperature: 120 °C
Yield: 45.7 %

Procedure:
A mixture of N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxamide (200 mg, 0.80 mmol) (VWR, Cat. #200068-640), 6-bromo-1,2,4-triazin-3-amine (130 mg, 0.76 mmol, Example 2, Step 1), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.04 mmol) and potassium carbonate (0.32 g, 2.3 mmol) in toluene (1.3 mL), ethanol (0.66 mL) and water (0.66 mL) was heated at 120° C. for 1.5 h. The mixture was filtered and washed with methanol. The filtrate was purified by RP-HPLC (pH=10) to afford the desired product (80 mg, 45.54%). LCMS (M+H)+: m/z=231.4; LCMS (M+H+H2O)+: m/z=249.3.
Reaction SMILES: C1O[C:4]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:7]=2)([CH3:5])[O:3]C1.C(O)(=O)C.O.[OH-].[Na+]>CO>[C:14]([NH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:3])[CH3:5])=[CH:7][CH:8]=1)([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C2(C)OCCO2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1

Procedure:
125 g of N-BOC-p-aminomethylacetophenone ethylene ketal are heated for 15 minutes at 65° in 250 ml of methanol and 250 ml of acetic acid as well as 50 ml of water. The reaction mixture is cooled to 0°, adjusted to a pH of 10 with 10N aqueous NaOH, extracted with ethyl acetate and washed neutral with saturated aqueous NaCl solution. The crude product obtained after drying and concentrating by evaporation is crystallised from hexane. N-BOC-p-aminomethylacetophenone having a melting point of 73°-75° is obtained. IR: 3420, 1707, 1680, 1607, 1500 cm-1 (CH2Cl2). UV: 250 nm (15700) in C2H5OH.
Reaction SMILES: [CH2:1]([C:3]([CH3:9])([CH2:7][CH3:8])[C:4](O)=O)[CH3:2].[NH2:10][NH:11][C:12]([NH2:14])=[S:13].P(Cl)(Cl)(Cl)=O.[OH-].[NH4+]>O1CCOCC1>[NH2:14][C:12]1[S:13][C:4]([C:3]([CH2:7][CH3:8])([CH3:9])[CH2:1][CH3:2])=[N:10][N:11]=1
Reactant: NNC(N)=S
Reactant: CCC(C)(CC)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CCC(C)(CC)c1nnc(N)s1
Temperature: 90 °C
Yield: 91.9 %

Procedure:
A solution containing 13.0 g of 2-ethyl-2-methylbutyric acid and 9.1 g of thiosemicarbazide in 125 ml of dioxane was stirred and heated to 90° C. To the stirred reaction mixture was added dropwise over thirty minutes 15.3 g of phosphorous oxychloride. Following complete addition, the reaction mixture was heated at 90° C. for six hours. The mixture was then cooled to abiout 30° C. and added to 100 g of ice. The aqueous mixture was made alkaline by the addition of ammonium hydroxide, and the alkaline solution was extracted several times with ethyl acetate. The extracts were combined, washed with water, dried, and the solvent was removed by evaporation under reduced pressure to afford 17.0 g of 2-amino-5-(1-ethyl-1-methylpropyl)-1,3,4-thiadiazole.
Reaction SMILES: Cl[C:2]1(Cl)[CH2:7][CH2:6]CC(Cl)(Cl)[C:3]1=[O:10].[C:12]([O-:15])(=O)[CH3:13].[Na+].C(=O)(O)[O-:18].[Na+]>O>[C:12]1([CH:13]=[CH:6][CH:7]=[C:2]([OH:18])[C:3]=1[OH:10])[OH:15]
Reactant: O=C1C(Cl)(Cl)CCCC1(Cl)Cl
Reactant: O=C([O-])O
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Oc1cccc(O)c1O
Yield: 28.5 %

Procedure:
Under a blanket of nitrogen were mixed 2,2,6,6-tetrachlorocyclohexanone (100 parts), sodium acetate (424 parts) and water (1,059 parts), and the mixture refluxed for 10 minutes. The mixture was then cooled to 50° C. when sodium bicarbonate (318 parts) was added giving severe foaming. The mixture was then extracted continuously with ether, the extract dried over magnesium sulphate and evaporated to give a residue (39 parts). The residue was triturated with chloroform (39 parts) to give after filtering and drying in air 15.2 parts of pyrogallol (28.5% yield) as a tan solid, m.pt. 130.5°-133.5° C.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[C:15]([C:16](=O)/[CH:17]=[CH:18]/N(C)C)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+]([O-])([O-])=O.[C:35]([C:43]1C=[C:45]([NH:49][C:50]([NH2:52])=[NH2+:51])[CH:46]=[CH:47][CH:48]=1)(=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[C:53](=O)([O-])[O-:54].[K+].[K+].CCOCC>CN(C)C=O.O>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:23]4[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=4)[C:15]([C:16]4[CH:17]=[CH:18][N:51]=[C:50]([NH:49][C:45]5[CH:46]=[CH:47][CH:48]=[CH:43][C:35]=5[C:36]5[CH:37]=[C:38]([CH:53]=[O:54])[CH:39]=[CH:40][CH:41]=5)[N:52]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: NC(=[NH2+])Nc1cccc(C(=O)c2ccccc2)c1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2C(=O)/C=C/N(C)C)cc1
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(Nc3ccccc3-c3cccc(C=O)c3)n2)cc1
Temperature: 140 °C
Yield: 62 %

Procedure:
To a solution of (2E)-1-[7-(cyclopentylamino)-2-(4-methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-3-(dimethylamino)-2-propen-1-one (100 mg, 0.25 mmol) in N,N-dimethylformamide (5 mL) was added N-(3-benzoylphenyl)guanidinium nitrate (223 mg, 0.74 mmol) and potassium carbonate (102 mg, 0.74 mmol). The suspension was heated at 140 ° C. (bath temperature) for 18 hours. The mixture was cooled to room temperature, ether was added followed by water. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed by flash chromatography (4:1 to 2:1 hexanes-ethyl acetate) provided [3-({(4-[7-(Cyclopentylamino)-2-(4methoxyphenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-pyrimidinyl}amino)phenyl](phenyl)methanone (90 mg, 76%) as a yellow solid. 1H NMR (CDCl3): δ 8.10 (d, 1 H), 8.04 (s, 1 H), 7.95 (d, 1 H), 7.81 (d, 2 H), 7.64 (d 1 H), 7.57 (d, 2 H), 7.53–7.38 (m, 6 H), 7.22 (t, 1 H), 6.98 (d, 2 H), 6.53 (d, 1 H), 6.04–5.99 (m, 2 H); 4.00 (m, 1 H), 3.86 (s,3 H), 2.12 (m, 2 H), 1.81–1.67 (m, 6 H); MS m/z581 (M+1).
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[C:14]#[N:15].O.O.O.C([O-])(=O)C.[Na+]>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C>[NH2:3][C:4]1[C:5]([C:14]#[N:15])=[CH:6][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:8][C:9]=1[Br:1]
Reactant: BrBr
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)cc(Br)c1N
Temperature: 80 °C

Procedure:
Bromine (a total of 4.9g) was added in two portions to a stirred suspension of 4-amino-3-cyano-benzotrifluoride (3g) and sodium acetate trihydrate (1g) in carbon tetrachloride (65ml). The mixture was heated to 80° C. until the absence of starting material was confirmed by gas liquid chromatography. Evaporation of the solvent under reduced pressure gave a pale green solid, which was dissolved in ethyl acetate, and washed with water and brine. After drying over anhydrous magnesium sulphate, the solvent was removed to give 4-amino-3-bromo-5-cyano-trifluoromethylbenzene (3.63g) as an oil which solidified on standing.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26](I)=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][SH:35].CC(C)([O-])C.[Na+]>CS(C)=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([C:20]#[N:21])=[C:18]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])=[CH:25][C:24]=3[F:30])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CN(C)CCS
Reactant: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(I)cc3F)c2C#N)CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(SCCN(C)C)cc3F)c2C#N)CC1
Temperature: 120 °C

Procedure:
In a microwave reaction tube was placed 4-[5-cyano-6-(2-fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (10 mg, 0.19 mmol), 2-dimethylamino-ethanethiol (27 mg, 0.19 mmol), di-m-bromobis (tri-t-butylphosphino)dipalladium (I) (8 mg, 0.0095 mmol), sodium t-butoxide (55 mg, 0.57 mmol), and DMSO (0.5 mL). The reaction mixture was heated at 120° C. under microwave for 4 hours. The resulting mixture was filtered through a syringe filter and purified by preparative HPLC. 1H NMR (CDCl3, 400 MHz) δ 1.26 (d, 6H), 1.86 (m, 2H), 2.00 (m, 2H), 2.86 (s, 6H), 3.20 (m, 2H), 3.30 (m, 2H), 3.43 (m, 2H), 3.78 (m, 2H), 4.94 (m, 1H), 5.44 (m, 1H), 7.22 (s, 1H), 7.24 (s, 1H), 7.35 (s, 1H), 8.11 (t, 1H), 8.45 (s, 1H). Exact mass calculated for C24H31FN6O3S 502.22, found 503.2 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[O:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].CC1OC=CC=1CCO.Cl[Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24].N1C=CN=C1>ClCCl.O>[CH:23]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[O:9][CH2:8][C:7]1[CH:6]=[CH:5][O:4][C:3]=1[C:2]([F:1])([F:10])[F:11])([CH3:25])[CH3:24]
Reactant: OCc1ccoc1C(F)(F)F
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: Cc1occc1CCO
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)[Si](OCc1ccoc1C(F)(F)F)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the (2-trifluoromethyl-furan-3-yl)-methanol from (i) in dry dichloromethane (180 ml) was treated with chloro-tri-isopropyl-silane (2.6 g, 13.4 mmoles) and imidazole (1.45 g, 21.3 mmoles) and the mixture was stirred overnight at room temperature. Further aliquots of chloro-tri-isopropyl-silane (0.9 g, 4.64 mmoles) and imidazole (0.5 g, 7.34 mmoles) were added and the mixture was stirred for 3 h. The reaction mixture was diluted with water, the organic phase separated and washed sequentially with 0.1M aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, water and brine. After drying, evaporation of the solvents afforded a colourless oil. The oil was distilled under reduced pressure (0.05 torr) in a Kugelruhr apparatus collecting the fraction boiling at an oven temperature of 125±20° C. to afford compound 88 as a colourless oil.