Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C(OC(=O)C)=C(I)C=CC=1)(=O)C.[CH3:16][C:17]([CH3:30])([CH:20]([OH:29])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:18][OH:19].O.C(=O)(O)[O-].[Na+]>ClCCl>[OH:29][CH:20]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]([CH3:16])([CH3:30])[CH:18]=[O:19]
Reactant: CC(C)(CO)C(O)CCc1ccccc1
Agent: CC(=O)Oc1cccc(I)c1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C=O)C(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
DMN-AZADO (2.00 mg, 0.012 mmol) and diacetoxyiodobenzene (117 mg, 0.362 mmol) were added to a dichloromethane solution (0.24 ml) of 2,2-dimethyl-5-phenylpentane-1,3-diol (50.2 mg, 0.241 mmol), and the mixture was stirred at room temperature for 15 min. This was followed by addition of saturated sodium bicarbonate water (1 ml) and a sodium thiosulfate solution (1 ml), and extraction with diethyl ether. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give 3-hydroxy-2,2-dimethyl-5-phenylpentanal (49.2 mg, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][O:16][C:15](=O)[CH:14]2[CH3:20])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH:14]2[CH:20]=[S:22])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(N2CCOC(=O)C2C)cc(OC)c1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: COc1cc(N2CCOCC2C=S)cc(OC)c1OC

Procedure:
28.1 g (0.1 mole) of 4-(3',4',5'-trimethoxyphenyl)-oxo-methylmorpholine, 100 ml of pyridine and 22.3 g (0.1 mole) of phosphorus pentasulfide are reacted at the boiling point of the reaction mixture for 5 hours. Then the solvent is distilled off and the product is precipitated with water.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:20][CH:21]1[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[S:31][CH:32]=[CH:33][C:23]=2[NH:22]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:22]2[C:23]3[CH:33]=[CH:32][S:31][C:24]=3[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:30]=3[CH:21]2[CH3:20])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1Nc2ccsc2-c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2c3ccsc3-c3ccccc3C2C)cc1
Yield: 55.9 %

Procedure:
A solution of 4-Methoxybenzenesulfonyl chloride (16 g, 77 mmol), triethylamine (25 mL, 180 mmol), and 4-dimethylaminopyridine (0.20 g, 1.6 mmol) in methylene chloride (100 mL) was de-gassed with nitrogen and treated with a de-gassed methylene chloride (100 mL) solution of 5-Methyl4,5-dihydrothieno[3,2-c]isoquinoline (16 g obtained above) at 23° C. After 21 h the reaction mixture was quenched with 1 N aqueous sodium hydroxide (200 mL). The organic layer was separated and the aqueous phase was extracted with methylene chloride (2×200 mL). The combined extracts were washed with 1 N aqueous sodium hydroxide, 1 N aqueous hydrochloric acid, and brine (200 mL each), dried (K2CO3), and concentrated in vacuo to give the crude product (21 g) as a dark oil. The oil was taken up in methylene chloride (ca. 80 mL) and pre-adsorbed on silica gel (80 g). Flash chromatography on silica gel (400 g) eluting 25-, then 50-, and then 75% methylene chloride-hexane gave the product (16 g) as a yellow solid. Further elution with methylene chloride, then 10-, and then 20% ethyl acetate-methylene chloride gave recovered 5-methylthieno[3,2-c]isoquinoline (1.7 g, 14%) from the previous step. Recrystallization of the product from hot ethyl acetate-hexane provided the title compound (15 g, 79% overall based on recovered starting material from Step 1, m.p. 135-36° C.) as shiny yellow-orange prisms.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24]C2C=CC=C3C=2C=C(S(O)(=O)=O)C=C3)[CH2:18][CH2:17]1>>[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][O:24][C:11]2[CH:2]=[CH:3][CH:4]=[C:5]3[C:10]=2[CH:9]=[C:8]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:7]=[CH:6]3)[CH2:18][CH2:17]1
Reactant: O=S(=O)(O)c1ccc2cccc(OCCN3CCOCC3)c2c1
Reactant: NS(=O)(=O)c1ccc2ccc(I)cc2c1
Product: NS(=O)(=O)c1ccc2cccc(OCCN3CCOCC3)c2c1
Yield: 27 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 11, 8-(2-morpholinoethoxy)naphthalene-2-sulfonic acid (100 mg, 0.30 mmol) was converted to the title compound (27 mg, 27%). 1H NMR (CD3OD) δ 8.82 (d, J=1.8 Hz, 1H), 8.05-8.01 (m, 1H), 7.99-7.94 (m, 1H), 7.63-7.60 (m, 2H), 7.16 (dd, J=5.3, 3.3 Hz, 1H), 4.70-4.65 (m, 2H), 4.00 (t, J=4.7 Hz, 4H), 3.79-3.74 (m, 2H), 3.49 (d, J=4.2 Hz, 2H), 3.33 (ddd, J=3.2, 1.8, 1.7 Hz, 2H); MS(ESI−) m/z 335.3 (M−H)−.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)[C:9](=[O:11])[CH:10]=1.[C:24]1([CH3:33])[C:25]([C:30](Cl)=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1.C1(C2C=CC=CC=2C(Cl)=O)C=CC=CC=1>>[OH:1][CH2:2][CH2:3][C:4]1[S:5][C:6]2[CH:23]=[CH:22][CH:21]=[CH:20][C:7]=2[N:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][C:30](=[O:31])[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:33])=[CH:17][CH:18]=2)[C:9](=[O:11])[CH:10]=1
Reactant: Nc1ccc(CN2C(=O)C=C(CCO)Sc3ccccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: O=C(Cl)c1ccccc1-c1ccccc1
Product: Cc1ccccc1C(=O)Nc1ccc(CN2C(=O)C=C(CCO)Sc3ccccc32)cc1
Yield: 64 %

Procedure:
2-(2-Hydroxyethyl)-5-(4-aminobenzyl)-1,5-benzothiazepine-4-one as prepared in Example 21 (0.105 g, 0.31 mM) was treated using the procedure described in Example 22, with o-toluoyl chloride (0.04 ml, 0.33 mM) substituted for 2-phenylbenzoyl chloride, to yield the title product as a white solid (0.086 g, 64%) m/z (MH+) 447
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6](I)[C:5]([CH2:10][CH3:11])=[N:4]1)[CH3:2].[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.CC(C)([O-])C.[K+]>O1CCOCC1.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>[CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([C:15]2[CH:16]=[CH:17][N:12]=[CH:13][CH:14]=2)[C:5]([CH2:10][CH3:11])=[N:4]1)[CH3:2]
Reactant: CCc1nn(CC)c(C)c1I
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nn(CC)c(C)c1-c1ccncc1
Temperature: 100 °C

Procedure:
A mixture of 17.05 g (64.6 mmol) of 1,3-diethyl-4-iodo-5-methylpyrazole (from Step D) and 11.9 g (105.4 mmol) of pyridine 4-boronic acid in 300 mL of dioxane was treated with a solution of 44 g (392 mmol) of potassium tert-butoxide in 100 mL of water. The resulting mixture was treated with 3.75 g (3.2 mmol) of tetrakis(triphenylphosphine)palladium(0), put under an argon atmosphere and heated at 100° C. for 18 h. The mixture was cooled and partitioned between 1 L of ether and 500 mL of water. The organic layer was separated, dried over MgSO4 and concentrated. Flash chromtography on a Biotage 75S afforded of the title compound. 1H-NMR (500 MHz) δ 1.19 (t, J=7.5, 3H), 1.48 (t, J=7.5, 3H), 2.27 (s, 3H), 2.67 (q, J=7.5, 2H), 4.09 (q, J=7.5, 2H), 7.18 (dd, J=2.0, 4.5, 2H), 8.60 (dd, J=2.0, 4.5, 2H).
Reaction SMILES: [Br:1]Br.[O:3]=[C:4]([CH2:10][CH2:11][CH3:12])[CH2:5][C:6]([O:8][CH3:9])=[O:7]>C(Cl)(Cl)Cl>[Br:1][CH:10]([CH2:11][CH3:12])[C:4](=[O:3])[CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: BrBr
Reactant: CCCC(=O)CC(=O)OC
Solvent: ClC(Cl)Cl
Product: CCC(Br)C(=O)CC(=O)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a solution of bromine (8.61 mL, 167 mmol) in chloroform (20 mL) was added drop-wise over a period of 2 h to a solution of methyl 3-oxohexanoate (Fluka, 24.1 g, 167 mmol) in chloroform (147 mL), at 0° C. (ice bath). The reaction mixture was stirred for 30 min at 0° C. and then allowed to warm to room temperature overnight. While stirring, a stream of air was bubbled through the solution for 1 hour. The reaction mixture was dried over sodium sulfate and the solvent evaporated under reduced pressure to provide the desired compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21].C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)=[O:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc2ccc(-c3cccc(NC(=O)C(C)(C)C)c3)nn12
Reaction time: 3 h

Procedure:
To solution of 8.0 g of 3-methyl-6-[3-(amino)phenyl]-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liters of dichloromethane was added 4.6 ml of trimethylacetyl chloride and 6.8 ml of diisopropylethylamine. The mixture was stirred for 3 hours and then poured into 200 ml of aqueous saturated sodium bicarbonate. The organic layer was separated, dried, and the solvent was removed in vacuo. The residue was recrystallized from dichloromethane-hexane to give 9.2 g of white crystals, mp 256°-258° C.
Reaction SMILES: [N+:1]([C:4]1[CH:32]=[CH:31][C:7]2[S:8][C:9]3[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=3[CH:11]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][O:23][C:22]4=[O:26])[CH2:15][CH2:14]3)[CH2:12][C:6]=2[CH:5]=1)([O-])=O.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:32]=[CH:31][C:7]2[S:8][C:9]3[CH:30]=[CH:29][CH:28]=[CH:27][C:10]=3[CH:11]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][O:23][C:22]4=[O:26])[CH2:17][CH2:18]3)[CH2:12][C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=C1OCCN1CCN1CCN(C2Cc3cc([N+](=O)[O-])ccc3Sc3ccccc32)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1ccccc1S2

Procedure:
24.1 g of 3-[2-[4-(10,11-dihydro-2-nitro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone in 2000 ml of ethyl acetate are hydrogenated in the presence of 5.7 g of palladium/carbon (5%) at 70° C and 10 atmospheres of hydrogen. After filtration, the filtrate is concentrated under reduced pressure. There is obtained 3-[2-[4-(2-amino-10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone which melts at 193°-196° C. After chromatographic purification over aluminium oxide using acetone/hexane as the elution agent, there is obtained a pure product which melts at 195.5°-196.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([C:25]([NH:27][CH:28]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:29][CH3:30])=[O:26])=[CH:22][CH:23]=3)[C:18]([CH3:37])=[C:17]2[CH3:38])=[CH:11][CH:10]=1)#[N:2].[Si]([N:43]=[N+:44]=[N-:45])(C)(C)C>C1(C)C=CC=CC=1>[NH:43]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[CH:10]=[CH:11][C:12]([CH2:15][N:16]3[C:24]4[C:19](=[CH:20][C:21]([C:25]([NH:27][CH:28]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[CH2:29][CH3:30])=[O:26])=[CH:22][CH:23]=4)[C:18]([CH3:37])=[C:17]3[CH3:38])=[CH:13][CH:14]=2)=[N:2][N:45]=[N:44]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCC(NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C#N)cc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCC(NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)c1ccccc1

Procedure:
To a solution of 1-((2′-cyano-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-N-(1-phenylpropyl)-1H-indole-5-carboxamide (27 mg, 0.05 mmol, 1 equiv) in toluene (0.6 mL) in a high-pressure vial were added TMSN3 (14 μL, 0.05 mmol, 2 equiv) and Bu2SnO (2 mg, 0.005 mmol, 0.1 equiv). The vial was sealed and the reaction mixture was heated at reflux for 2 h. After concentration, the residue was purified by preparative HPLC to afford a beige powder. ESI-MS (m/z): 541 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:13]([CH3:14])[C:12](=[O:15])[C:9]3([CH2:11][CH2:10]3)[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[CH3:32].C(O)C>Cl.O>[CH:16]1([N:7]2[CH2:8][C:9]3([CH2:11][CH2:10]3)[C:12](=[O:15])[N:13]([CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[CH3:32])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C2(CC2)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Yield: 41 %

Procedure:
A mixture of 0.0515 g (0.000168 mole) of 2-chloro-9-cyclopentyl-8,9-dihydro-5-methylspiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-6(7H)-one (VII-53), 0.0283 g (0.000183 mole) of 4-amino-3-methylbenzoic acid, 1 mL of ethanol, 4 mL of water and 4 drops of hydrochloric acid was heated at reflux for 17 hours. The mixture was cooled, and the precipitate which formed was collected by filtration to give 0.029 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methylbenzoic acid (I-60) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].[CH:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]>>[F:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCC=O
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Product: CCCCC(=O)c1ccc(C(F)(F)F)cc1F

Procedure:
The titled compound was prepared from 1-bromo-2-fluoro-4-(trifluoromethyl)benzene (200 mg, 0.823 mmol) and valeraldehyde (0.05 mL, 0.8 mmol) in a procedure similar to that of Example 9 (1) as a pale yellow oil (114 mg, yield 97%).
Reaction SMILES: [C:1]1([C:7]2[C:18]3[CH:17]=[C:16]4[C:12]([CH2:13][CH2:14][CH2:15]4)=[CH:11][C:10]=3[CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][Li].[Si:21]([CH3:25])([CH3:24])(Cl)[Cl:22]>C1COCC1>[Cl:22][Si:21]([CH3:25])([CH3:24])[CH:9]1[C:10]2[C:18](=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][C:12]=3[CH:11]=2)[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8]1
Reactant: C[Si](C)(Cl)Cl
Reactant: C1=C(c2ccccc2)c2cc3c(cc2C1)CCC3
Agent: [Li][Li]
Solvent: C1CCOC1
Product: C[Si](C)(Cl)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
1,2,3,5-Tetrahydro-7-phenyl-s-indacene, dilithium salt (12.2075 g, 0.05102 moles) in THF (50 mL) was added dropwise to a solution of Me2SiCl2 (19.5010 g, 0.1511 moles) in THF (100 mL) at 0° C. This mixture was then allowed to stir at room temperature overnight. After the reaction period the volatiles were removed and the residue extracted and filtered using hexane. The removal of the hexane resulted in the isolation of the desired product as a yellow oil (15.1492 g, 91.1% yield).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.C[NH:12][CH2:13][C:14]1[N:15]=[C:16]([NH2:19])[S:17][CH:18]=1.C(N(CC)CC)C>C1COCC1>[NH2:19][C:16]1[S:17][CH:18]=[C:14]([CH2:13][NH:12][C:2]2[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=2)[N:15]=1
Reactant: CNCc1csc(N)n1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c(F)c(NCc2csc(N)n2)n1
Temperature: 25 °C
Yield: 62 %

Procedure:
4,6-Dichloro-5-fluoro-2-methylpyrimidine (480 mg, 2.65 mmol) was dissolved in 20 mL of THF and stirred at room temperature. (4-[(Methylamino)methyl]-1,3-thiazol-2-amine (2.65 mmol, theoretical) was added, followed by triethylamine (400 μL, 2.92 mmol). The resulting reaction mixture was stirred overnight and evaporated. The residue was stirred in water and the solid precipitate was collected by filtration and was dried in vacuo to provide N-[(2-amino-1,3-thiazol-4-yl)methyl]-6-chloro-5-fluoro-2-methyl-4-pyrimidinamine (450 mg, 59%) that was used without further purification. LCMS: (M+H)+: 288.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[C@@H:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH2:35][CH2:34][N:33]2C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)=[O:31])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(S)CCCCCCC.N12CCCN=C1CCCCC2>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:29][C:30]([C@@H:32]2[C@@H:36]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:35][CH2:34][NH:33]2)=[O:31])[C:10]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH2:16][CH2:17]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@@H]2[C@@H](c3ccccc3)CCN2C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: CCCCCCCCS
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)[C@H]2NCC[C@@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The title compound was prepared according to the procedure of Sheppeck, J. E., et al. (Tetrahedron Lett. 2000, 41, 5329-5333) using fluoren-9-ylmethyl 2-{N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(methylsulfonyl)amino]phenyl)piperidyl)-2-oxoethyl]carbamoyl}(2S, 3R)-3-phenylpyrrolidine carboxylate (Step a) (415 mg, 0.5 mmol), THF (10 mL), n-octanethiol (Aldrich) (876 mg, 6 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (Aldrich) (5 mg, 0.03 mmol). The reaction mixture was stirred for 5 h at 25° C. and the organic solvent was removed in vacuo. To the residue was added Et2O (20 mL) resulting in precipitation of the compound. The precipitate was collected by filtration and washed with hexane to provide a yellow solid. Purification by preparative reverse phase HPLC [Phenomenex; 5 μm 250×21.2 mm, 5% to 95% CH3CN (0.1% TFA) in H2O (0.1% TFA) over 30 min, then 100% CH3CN (0.1% TFA) for 2 min] provided the title compound (TFA salt) as a white foam (187 mg). MS (ESI, pos. ion) m/z: 609 (M+1); (ESI, neg. ion) m/z: 607 (M−1). Calc'd for C32H37ClN4O4S: 608.22. Anal. Calcd for C32H37ClN4O4S.1.4C2HF3O2: C, 54.37; H, 5.03; N, 7.29. Found: C, 54.26; H, 5.19; N, 7.41.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][C:6]3[CH:12]=[C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[CH3:18])=[O:16])[S:14][C:5]=3[C:4]=2[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:14][C:5]2[C:4]3[CH:3]=[C:2]([N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH:11]=[CH:10][C:9]=3[O:8][CH2:7][C:6]=2[CH:12]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(Br)ccc1OC2)c1ccc(F)cc1F
Reactant: CN1CCNCC1
Product: CN1CCN(c2ccc3c(c2)-c2sc(C(=O)N(C)c4ccc(F)cc4F)cc2CO3)CC1

Procedure:
Following Example 70 and General Procedure D, 8-bromo-N-(2,4-difluorophenyl)-N-methyl-4H-thieno[3,2-c]chromene-2-carboxamide 160bp and N-methylpiperazine were reacted to give 128bp. 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 1 H), 6.94-7.00 (m, 2 H), 6.85 (m, 1 H), 6.75-6.82 (m, 2 H), 6.68 (s, 1 H), 5.03 (s, 2 H), 3.69 (m, 2 H), 3.46 (m, 2 H), 3.39 (s, 3 H), 3.30 (m, 2 H), 3.07 (m, 2 H), 2.90 (s, 3 H). LCMS (ESI) m/z: 456.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[I:21]N1C(=O)CCC1=O>ClCCl.C(O)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)=[CH:6][C:7]=1[I:21]
Reactant: N#Cc1cccc(-c2ccc(O)cc2)c1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1cccc(-c2ccc(O)c(I)c2)c1
Temperature: 25 °C
Yield: 76.8 %

Procedure:
4′-Hydroxybiphenyl-3-carbonitrile (Preparation 121, 570 mg, 2.92 mmol) was dissolved in dichloromethane (10 mL) and acetic acid (10 mL). Then concentrated sulfuric acid (0.30 mL) and N-iodosuccinimide (657 mg, 2.92 mmol) were added at 0° C. (ice-bath cooling) and the reaction was allowed to warm to room temperature over 2 hours. The mixture was partitioned between ethyl acetate (30 mL) and water (15 mL). The organic layer was separated and dried over anhydrous MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 50% ethyl acetate in heptane to give the title compound (720 mg, 77%).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)(C)C.Cl[C:14]1[N:15]=[N:16][C:17]([CH3:20])=[CH:18][CH:19]=1.[I-].C(N(CC)CC)C>COCCOC>[CH3:20][C:17]1[N:16]=[N:15][C:14]([C:5]#[C:6][C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:18]=1
Reactant: C[Si](C)(C)C#Cc1cccnc1
Reactant: Cc1ccc(Cl)nn1
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Cc1ccc(C#Cc2cccnc2)nn1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
To the solution of 3-[(trimethylsilyl)ethynyl]pyridine (0.175g, 1.0 mmol), 3-chloro-6-methylpyridazine (0.128 g, 1.0 mmol), cupper (I) iodide (0.019 g, 0.1 mmol), triethylamine (0.202 g, 2.1 mmol), in 20 ml Ethylene glycol dimethyl ether was added tetrakis(triphenlyphosphine)palladium (0) (60 mg, 0.052 mmol). The result solution was heated to 80° C. after degasing by argon for 5 minute, and then Tetrabutylammonium fluoride (2.1 ml, 1M/THF) was added dropwise. After stirring at 80° C. for 12 hour, the reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (Hexane/EtOAc: 9/1 to 1/9) to give 3-methyl-6-(pyridin-3-ylethynyl)pyridazine as brown solid. 1H NMR (CDCl3 300 MHz) δ 8.875-8.87 (m, 1H), 8.65-8.63 (d, 1H), 7.95-7.93 (d, 1H), 7.60-7.58 (dd, 1H), 7.39-7.36 (m, 2H), 2.80 (s, 3H). MS (ESI) 196.10 (M++H).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([OH:13])(=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[C:5]([Cl:3])(=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ccccc1
Reaction time: 8 h

Procedure:
Benzoyl chloride was synthesized by refluxing 5 ml of 2 M thionyl chloride in 10 ml of toluene with benzoic acid for 30 minutes. The residual thionyl chloride and toluene were removed by distillation. 2 gm of the 3-amino-propyl resin was then incubated at room temperature overnight with the fresh benzoyl chloride in pyridine. The next day, the resin was washed with methanol and dried.
Reaction SMILES: [F:1][C:2]1([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH:7]([O:8]C(=O)C)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13].[CH:21](=[N:27]/O)/[C:22]1[O:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.CC(C)=O>[F:1][C:2]1([C:14]([O:16][CH2:17][CH:18]([CH3:19])[CH3:20])=[O:15])[CH:7]([O:8]/[N:27]=[CH:21]\[C:22]2[O:26][CH:25]=[CH:24][CH:23]=2)[NH:6][C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: CC(=O)OC1NC(=O)NC(=O)C1(F)C(=O)OCC(C)C
Reactant: O/N=C\c1ccco1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)COC(=O)C1(F)C(=O)NC(=O)NC1O/N=C\c1ccco1
Temperature: 60 °C
Reaction time: 16 h
Yield: 40.3 %

Procedure:
In 45 ml of pyridine-acetone (pyridine:acetone=2:1) were dissolved 11.6 g (40 mmol) of isobutyl 5-fluoro-6-acetoxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate and 6.1 g (54.9 mmol) of (Z)-furfuraldoxime, and the solution was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 150 ml of ethyl acetate. The solution was washed three times with 50-ml portions of water, and the ethyl acetate layer was dried and the solvent was evaporated under reduced pressure. The residue was recrystallized three times from ethyl acetate-hexane to give 5.5 g of isobutyl 5-fluoro-6-(Z)-furfurylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate. m.p. 159°-160° C.