Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][C:6]([C:8]1[S:9][C:10]([C:15]2[CH:20]=[C:19]([C:21](=[O:26])[NH:22][CH:23]3[CH2:25][CH2:24]3)[CH:18]=[CH:17][C:16]=2[CH3:27])=[CH:11][C:12]=1[CH:13]=O)=[O:7])(C)(C)C.C(O)(=O)C.[NH2:32]N>>[CH:23]1([NH:22][C:21](=[O:26])[C:19]2[CH:18]=[CH:17][C:16]([CH3:27])=[C:15]([C:10]3[S:9][C:8]4[C:6](=[O:7])[NH:5][N:32]=[CH:13][C:12]=4[CH:11]=3)[CH:20]=2)[CH2:25][CH2:24]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1cc(C=O)c(C(=O)NC(C)(C)C)s1
Reactant: NN
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cn[nH]c(=O)c2s1
Temperature: 150 °C
Yield: 37.1 %

Procedure:
A 5 ml glass microwave reaction vessel was charged with N-tert-butyl-5-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-formylthiophene-2-carboxamide (0.350 g, 0.910 mmol), glacial acetic acid (2.63 ml, 45.5 mmol), hydrazine (0.0875 g, 2.73 mmol). The reaction mixture was heated in a Smith Synthesizer microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 150° C. for 20 min. The crude was concentrated and azeotropically dried with toluene, the residue was partioned between water and DCM, and the aqueous layer was extracted with DCM (2×25 ml). Combined organic solution was washed with saturated solution of NaHCO3(aq), and dried over MgSO4. The organic solutions were evaporated under reduced pressure and the crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 5% to 95% MeOH in DCM to provide N-Cyclopropyl-4-methyl-3-(7-oxo-6,7-dihydrothieno[2,3-d]pyridazin-2-yl)benzamide (0.110 g) MS (ES+): 328 (M+H)+
Reaction SMILES: [C:1]([O:4][CH:5]([O:7][C:8](SCC)=[O:9])[CH3:6])(=[O:3])[CH3:2].S(Cl)([Cl:16])(=O)=O>>[C:1]([O:4][CH:5]([O:7][C:8]([Cl:16])=[O:9])[CH3:6])(=[O:3])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCSC(=O)OC(C)OC(C)=O
Product: CC(=O)OC(C)OC(=O)Cl
Reaction time: 0.5 h

Procedure:
The compound (394 mg) obtained in Step 1 of this Example was cooled to −30° C. Sulfuryl chloride (175 μL) was added thereto, and the mixture was then stirred for 30 minutes. The solvent in the reaction solution was distilled off under reduced pressure to obtain a crude product of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.S(C1C=CC(C)=CC=1)(O)(=O)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:36][CH2:37][C:38]1[N:42]([C:43]2[S:44][C:45]([CH2:57][CH3:58])=[CH:46][C:47]=2[C:48](=[O:56])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:55])[C:41]([CH3:59])=[N:40][N:39]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[Cl:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[C:48]([C:47]1[CH:46]=[C:45]([CH2:57][CH3:58])[S:44][C:43]=1[N:42]1[C:41]([CH3:59])=[N:40][N:39]=[C:38]1[CH2:37][NH:36][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)=[O:13])=[O:56]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2cc3cc(F)ccc3[nH]2)s1
Reaction time: 4 h
Yield: 15.8 %

Procedure:
5-Fluoroindole-2-carboxylic acid (0.50 g) and 3-aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole ditosylate (2.07 g) were dissolved in dimethylformamide (40 ml). Triethylamine (1.6 ml) and 1-benzotriazolyloxytris(dimethylamino)phosphonium hexafluorophosphate (Bop reagent, 1.29 g) were added under ice-cooling, and the mixture was stirred for 4 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with an aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the obtained residue was crystallized from ethyl acetate to give 0.23 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-5-fluoroindole-2-carboxamide.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl.Cl[CH2:12][CH2:13][CH2:14][N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19]>O>[CH2:20]([N:15]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH2:13][CH2:12][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN(CCCC)CCCCl
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCN(CCCC)CCCOc1ccccc1
Yield: 91.4 %

Procedure:
The process is performed in the same manner as previously (Example 13), starting with 138 g (1.466 mol; 1.15 eq.) of phenol, 109.5 g (2.738 mol; 2.15 eq.) of NaOH, 530 ml of distilled water and 308.9 g (1.275 mol; 1 eq.) of N-(3-chloropropyl)-N,N-dibutylamine hydrochloride. The mixture is refluxed for 16 hours. The oil formed is separated out by settling and washed with 500 ml of water and then diluted with 500 ml of MTBE and washed with 500 ml of 2% HCl. The MTBE phase is concentrated under vacuum and the oil is dried by azeotropic distillation with DCM. 307.1 g of the crude derivative N,N-dibutyl-N-(3-phenoxypropyl)amine are obtained.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)[CH:9]=[CH:10][CH:11]=1)=[C:2]=[O:3].[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[NH:38][C:39]([NH2:41])=[S:40])([CH3:30])[CH3:29]>>[CH:28]([C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[NH:38][C:39]([NH:41][C:2]([NH:1][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:3])=[S:40])([CH3:30])[CH3:29]
Reactant: Cc1ccc(C(C)C)c(NC(N)=S)c1
Reactant: O=C=NCCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Product: Cc1ccc(C(C)C)c(NC(=S)NC(=O)NCCc2cccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)c2)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(2-isocyanatoethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CA44) and 1-(2-isopropyl-5-methylphenyl)thiourea isolated as an off-white solid (0.019 g, 6%): 1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 10.12 (s, 1H), 9.42 (s, 1H), 8.14-8.05 (m, 2H), 8.05-7.96 (m, 2H), 7.62 (ddd, J=7.8, 1.9, 0.9 Hz, 2H), 7.49 (t, J=7.6 Hz, 1H), 7.39 (dt, J=7.7, 1.5 Hz, 1H), 7.24-7.17 (m, 2H), 7.12-7.05 (m, 1H), 7.02 (t, J=5.8 Hz, 1H), 3.52-3.42 (m, 2H), 2.91 (dt, J=14.1, 6.9 Hz, 3H), 2.25 (s, 3H), 1.13 (d, J=6.8 Hz, 6H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 583 ([M+H]+), 581 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([NH2:12])[CH:3]=1.BrC1C=C(N2[C:24]([C:25]([F:28])([F:27])[F:26])=[N:23][N:22]=[N:21]2)C=CC=1OC>>[Br:1][C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([N:12]2[C:24]([C:25]([F:28])([F:27])[F:26])=[N:23][N:22]=[N:21]2)[CH:3]=1
Reactant: COc1ccc(-n2nnnc2C(F)(F)F)cc1Br
Reactant: Cc1nc2c(Br)cc(N)cc2o1
Product: Cc1nc2c(Br)cc(-n3nnnc3C(F)(F)F)cc2o1

Procedure:
Compound was prepared according to the procedure given in Example 6, Step F (b & c) using 4-bromo-2-methyl-6-amino-benzooxazole in place of 2-Bromo-4-(trifluoroacetamido)anisole and 2-Bromo-4-(5-(trifluoromethyl)tetrazol-1-yl)anisole.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[C:7]#[N:8].[C:9](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:9][C:3]1([C:7]#[N:8])[C:2](=[O:1])[CH2:6][S:5][CH2:4]1
Reactant: O=C([O-])[O-]
Reactant: N#CC1CSCC1=O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CC1(C#N)CSCC1=O
Temperature: 35 °C
Reaction time: 1 h

Procedure:
To a solution of 4-oxotetrahydrothiophene-3-carbonitrile (0.50 g, 3.9 mmol) in anhydrous acetone (7.8 mL) was added potassium carbonate (1.63 g, 11.8 mmol), followed by iodomethane (0.56 g, 3.9 mmol). The resulting mixture was stirred at 35° C. for 1 hour. The mixture was cooled to ambient temperature, filtered, and carefully concentrated in vacuo to afford the title compound. The residue was carried forward without further purification.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[Na+].[Na+].C(=O)=O.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[O-:20].[Na+]>>[OH:20][C:11]1[C:12]([C:1]([OH:2])=[O:4])=[CH:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:10]=1
Reactant: [O-]c1ccc2ccccc2c1
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [Na+]
Product: O=C(O)c1cc2ccccc2cc1O
Temperature: 240 °C
Yield: 65 %

Procedure:
A stainless steel pressure autoclave is charged with 150 parts of kerosene and 32 parts of sodium carbonate and heated to 240° C. It is then pressurized with 10 bar of carbon dioxide. Over the course of 6 hours, 50 parts of sodium β-naphtholate are metered in as a suspension in kerosene via a metering pump, part of the kerosene being distilled off, condensed and transferred out of the reaction vessel at reduced pressure. After the usual workup, the 2-hydroxynaphthalene-3-carboxylic acid is obtained in a yield of 65% based on sodium β-naphtholate used. In addition, 23% of unreacted β-naphthol and small amounts of 2-hydroxynaphthalene-6-carboxylic acid and 2-hydroxynaphthalene-3,6-dicarboxylic acid are obtained.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]N)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:1][C:2]2[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=2)=[CH:14][CH:13]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CC(C)C1OC(N)=NC1=O
Product: CC(C)C1OC(NCc2ccc(Cl)cc2)=NC1=O

Procedure:
Synthesis was performed from 2-amino-5-isopropyl-1,3-oxazol-4(5H)-one and 4-Chlorobenzylamine according to Method G+H.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1B(O)O>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1
Reactant: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2c1
Reactant: OB(O)c1ccccc1F
Product: COc1ccc2cc(Nc3cc(C)[nH]n3)nc(-c3ccccc3F)c2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-7-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-fluoro-phenyl)-7-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 349(MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH:10]1[NH:17][CH:13]2[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18]I>CN(C=O)C>[CH2:1]([N:8]1[CH:9]2[CH2:16][CH2:15][CH:14]1[CH:13]1[N:17]([CH3:18])[CH:10]2[CH2:11][CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: c1ccc(CN2C3CCC2C2CCC3N2)cc1
Solvent: CN(C)C=O
Product: CN1C2CCC1C1CCC2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a cold (0° C.) solution of 9-benzyl-9,10-diazatricyclo[4.2.1.12,5]decane (J. Med. Chem. 2000, 43, 2115-2123) and TEA in an DMF (1-2 ml) was added MeI. The mixture was allowed to warm to rt and stirred for 2-3 h. The rxn mixture was evaporated to dryness and partitioned between ether and satd. NaHCO3 and ether layer separated, washed with brine and dried (Na2SO4). Evaporation of ether afforded 9-benzyl-10-methyl-9,10-diazatricyclo[4.2.1.12,5]decane as a light-brown oil. A stirred suspension of 9-benzyl-10-methyl-9,10-diazatricyclo[4.2.1.12,5]decane in EtOH containing conc. HCl (0.5 ml) and 10% Pd—C was hydrogenated under balloon pressure of hydrogen overnight. The suspension was filtered and filtrate was added dry toluene (10-15 ml) and evaporated to dryness to afford the 9-methyl-9,10-diazatricyclo[4.2.1.12,5]decane and isolated as bis-HCl salt.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)[CH2:23][CH2:22]1>>[C:31]([N:28]1[CH2:27][CH2:26][CH:25]([N:24]([CH:21]2[CH2:23][CH2:22]2)[C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:30][CH2:29]1)(=[O:33])[CH3:32]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(=O)N1CCC(NC2CC2)CC1
Product: CC(=O)N1CCC(N(C(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C2CC2)CC1

Procedure:
The title compound was synthesized in analogy to Example 47 b), using 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid and 1-(4-(cyclopropylamino)piperidin-1-yl)ethanone (CAS 387358-46-5) as starting materials and isolated as colorless oil. MS (EI): m/e=449.6 [MH+].
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][CH3:11].II.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20](=[O:25])[C:19]2=[O:26]>C(OCC)C.C1COCC1>[CH2:10]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:19]1([OH:26])[C:18]2[C:22](=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=2)[NH:21][C:20]1=[O:25])[CH3:11]
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Reactant: CCOc1ccccc1Br
Agent: II
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOc1ccccc1C1(O)C(=O)Nc2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
40 g (1.65 mol) of magnesium chips and 5% of the total amount of the 2-bromo-1-ethoxy benzene were added to 100 ml diethyl ether and after adding a few crystals iodine the mixture was carefully heated to initiate the reaction. To the refluxing mixture the remaining amount of 203 ml (1.65 mol) 2-bromo-1-ethoxy benzene, dissolved in 450 ml diethyl ether, was added slowly to maintain the reaction. Then 75 g (0.41 mol) of 5-methoxyisatine, suspended in 750 ml THF, were added to the cooled reaction mixture. After stirring the reaction mixture for 30 minutes at ambient temperature, the mixture was poured into an ice/aqueous NH4Cl mixture. The aqueous phase was extracted with ethyl acetate several times and the combined organic phase was washed with H2O, dried over magnesium sulfate and the solvent was removed in vacuo.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[C:14]1([CH2:20][N:21]2[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:3][C:2]([CH3:13])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([CH:24]2[CH2:23][CH2:22][N:21]([CH2:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:26][CH2:25]2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C2CCN(Cc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 15.0 g ( 0.8054 mol) of 1-(1,1-dimethylethoxycarbonyl)piperazine and 14.26 ml (0.08053 mol) of 1-(phenylmethyl)-4-piperidinone in 250 ml of methanol was adjusted to a pH of between 5 and 6 by dropwise addition of acetic acid and mixed in batches with a total of 4.13 g ( 0.0624 mol) of 95% sodium cyanoborohydride, whilst taking care to maintain a pH of 5 to 6 by further dropwise addition of acetic acid. After stirring for 18 hours at room temperature the mixture was evaporated down in vacuo, the residue was made alkaline with soda and divided between water and ethyl acetate. After working up the ethyl acetate phase in the usual way 21.76 g (75.2% of theory) of a highly viscous colourless oil were obtained, Rf 0.66 (FM1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([S:12][CH3:13])=[N:10][CH:11]=1)=[O:5])[CH3:2].C[CH2:16][N:17](C(C)C)C(C)C.Cl.CN>C(#N)C>[CH3:16][NH:17][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH3:13])[N:8]=1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)c1cnc(SC)nc1NC
Temperature: 100 °C
Reaction time: 3 h
Yield: 11.3 %

Procedure:
4-Chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (10 g, 429 mmol) was dissolved in acetonitrile to which DIPEA (4.34 g, 642 mmol) and methylamine hydrochloride (11.10 g, 858 mmol) was added. The reaction mixture was stirred at 100° C. for 3 hours, then cooled to room temperature and poured in to ice water. Off-white crystalline solid precipitated out. The solid was collected by filtration on a Buchner funnel and dried under vacuum to give the desired product (11 g). 1H NMR (DMSO-d6): δ 1.30 (t, J=7 Hz, 3H), δ 2.46 (s, 3H), δ 2.99 (d, J=5 Hz, 3H), δ 4.29 (q, J=7 Hz, 2H), δ 8.09 (br, s, 1H), δ 8.53 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[NH2:23].[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:23][C:22]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[CH3:16])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cnccc1N
Reactant: O=C(O)c1ccc(Br)s1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cnccc1NC(=O)c1ccc(Br)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
To a (0° C.) cooled and stirred solution of 5-bromothiophene-2-carboxylic acid (1.91 g, 9.25 mmol) in DCM (20 mL) was added oxalyl chloride (4.05 mL, 46.2 mmol) followed by the addition of catalytic amount of DMF. Reaction was allowed to stir at 0° C. for 2 h. The resulting reaction mixture was then concentrated under vacuum, obtained residue was dissolved in DMF (2 mL) and added to a separately prepared (0° C.) cooled mixture containing 3-methylpyridin-4-amine (1.23 g, 11.37 mmol) and sodium hydride (0.444 g, 18.49 mmol) in DMF (10 mL). After stirring the reaction at RT overnight, quenched with ice cold water (20 mL), followed by the addition of ethyl acetate (30 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (2×50 mL), brine (20 mL), dried (Na2SO4) and filtered. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography (silica gel, DCM-methanol system as eluent) to afford 1.10 g (40%) of the title product as a white solid. 1HNMR (400 MHz, CDCl3) δ 8.44 (d, J=5.5 Hz, 1H), 8.40 (s, 1H), 8.14 (d, J=5.5 Hz, 1H), 7.70 (s, 1H), 7.40 (d, J=4.0 Hz, 1H), 7.13 (d, J=4.0 Hz, 1H), ESI-MS (m/z) 297, 298 [(MH)+ Br79,81].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][CH:21]1[CH2:26][C:25](=[O:27])[CH2:24][CH2:23][O:22]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:25]2([OH:27])[CH2:24][CH2:23][O:22][CH:21]([CH3:20])[CH2:26]2)[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CC(=O)CCO1
Reactant: FC(F)(F)c1cc(Br)cc(OCc2ccccc2)c1
Product: CC1CC(O)(c2cc(OCc3ccccc3)cc(C(F)(F)F)c2)CCO1
Yield: 16 %

Procedure:
The procedure described in the second paragraph of Note e. below Table IV in Example 15 was repeated, except that 3-benzyloxy-5-trifluoromethylbromobenzene (8.3 g) was used and 2-methyltetrahydropyran-4-one was used in place of tetrahydropyran-4-one. There were thus obtained a less polar isomer, (2RS,4SR)-4-(3-benzyloxy-5-trifluoromethylphenyl)-4-hydroxy-2-methyltetrahydropyran (1.44 g, 16%), as an oil,
Reaction SMILES: [C:1]([NH:9][C:10]1[C:30]([C:31]#[C:32][CH2:33][NH:34][C:35](=[O:40])[C:36]([F:39])([F:38])[F:37])=[CH:29][N:13]([C@@H:14]2[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C@@H:16]([OH:17])[CH2:15]2)[C:12](=[O:41])[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+].[CH3:58][S:59]([CH3:61])=O>>[C:1]([NH:9][C:10]1[C:30]([C:31]#[C:32][CH2:33][NH:34][C:35](=[O:40])[C:36]([F:37])([F:38])[F:39])=[CH:29][N:13]([C@@H:14]2[O:28][C@H:18]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[C@@H:16]([O:17][CH2:58][S:59][CH3:61])[CH2:15]2)[C:12](=[O:41])[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)C[C@@H]1O
Reactant: CS(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CSCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(NC(=O)c3ccccc3)nc2=O)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
The starting material (13) (2.85 g, 4.79 mmol) was dissolved in dry DMSO (40 ml) under N2 atmosphere. Acetic acid (2.7 ml, 47.9 mmol) and acetic anhydride (14.4 ml, 143.7 mmol) were added sequentially and slowly to the starting material, which was then stirred for 18 h at room temperature. Saturated NaHCO3 (150 ml) solution was carefully added to the reaction mixture. The aqueous layer was extracted with EtOAc (3×150 ml). The organic layers were combined, dried (MgSO4), filtered and evaporated to yield an orange liquid that was subsequently azeotroped with toluene (4×150 ml) until material solidified. Crude residue purified on silica gel (petroleum ether:EtOAc 3:1 to 2:1) to yield a yellow crystalline solid (14) (1.58 g, 50%). 1H NMR (d6 DMSO): δ 0.00 (s, 6H, CH3), 0.78 (s, 9H, tBu), 1.99 (s, 3H, CH3), 2.09 (m, 1H, H-2′), 2.28 (m, 1H, H-2′), 3.66 (d, 1H, J=11.5, 2.9 Hz, H-5′), 3.74 (dd, 1H, J=11.3, 2.9 Hz, H-5′), 3.99 (m, 1H, H-4′), 4.09 (m, 1H, CH2NH), 4.29 (m, 1H, H-3′), 4.61 (s, 2H, CH2S), 6.00 (m, 1H, H-1′), 7.37 (m, 2H, Ph), 7.50 (m, 2H, Ph), 7.80 (d, 1H, J=7.55 Hz, HAr), 7.97 (s, 1H, H-6), 9.79 (br t, 1H, NHCH2), 12.64 (br s, 1H, NH). Mass (−ve electrospray) calcd for C29H37F3N4O6SSi, 654.79. found 653.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:37]1[CH2:41][CH2:40][N:39]=[C:38]1[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][CH2:49][NH:50][CH3:51])=[CH:44][CH:43]=1>ClCCCl>[NH:39]1[CH2:40][CH2:41][N:37]=[C:38]1[C:42]1[CH:43]=[CH:44][C:45]([CH2:48][CH2:49][N:50]([CH3:51])[C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=3[CH3:9])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=2)=[O:22])=[CH:46][CH:47]=1
Reactant: CNCCc1ccc(C2=NCCN2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N(C)CCc3ccc(C4=NCCN4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (150 mg, 0.42 mmol), CDI (276 mg, 0.84 mmol) and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]-N-methylethanamine (80 mg, 0.42 mmol) in DCE (8 mL).