Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[Cl:17][S:18](O)(=[O:20])=[O:19]>>[C:1]([C:4]1[O:5][C:6]2[C:12]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:11][CH:10]=[C:9]([S:18]([Cl:17])(=[O:20])=[O:19])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCC(C)c1cccc2cc(C(C)=O)oc12
Product: CCC(C)c1ccc(S(=O)(=O)Cl)c2cc(C(C)=O)oc12
Yield: 67 %

Procedure:
There was reacted 1 g (4.6 mmole) of 2-acetyl-7-sec-butylbenzofuran with chlorosulfonic acid as in Example 1, yielding 0.97 g of 2-acetyl-4-chlorosulfonyl-7-sec-butylbenzofuran (yield: 67%, MS (m/z): 314 (M+), 285 and 186). The obtained chlorosulfonyl compound was reacted with glycine ethyl ester hyrochloride as in Example 1 to give an ester compound (yield: 82%, MS (m/z): 381 (M+), 352, 308 and 279), which was then hydrolyzed to give 2-acetyl-4-(N-carboxymethylsulfamoyl)-7-sec-butylbenzofuran (light yellow plates, yield: 73%). The physical constants are shown in Table 4.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[N:9][CH:10]=1)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([I:23])=[CH:19][N:18]=1>C(#N)C>[I:23][C:20]1[CH:21]=[CH:22][C:17]2[N:18]([CH:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([N:11]4[N:15]=[CH:14][CH:13]=[N:12]4)=[N:9][CH:10]=3)[N:16]=2)[CH:19]=1
Reactant: O=C(CBr)c1ccc(-n2nccn2)nc1
Reactant: Nc1ccc(I)cn1
Solvent: CC#N
Product: Ic1ccc2nc(-c3ccc(-n4nccn4)nc3)cn2c1
Temperature: 100 °C
Yield: 35.3 %

Procedure:
20.4 mg (corresponding to 0.0764 mmol) of 5-(2-bromoacetyl)-2-(2H-1,2,3-triazole-2-yl)pyridine and 16.8 mg (corresponding to 0.0764 mmol) of 2-amino-5-iodopyridine were dissolved in 2.0 mL of acetonitrile. The resulting solution was heated under reflux for 1.5 hours in an oil bath at 100° C. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered. The precipitates were washed with acetonitrile and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 2 mL of water and 2 mL of methanol. Then, about 1 mL of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was sonicated for 10 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 10.4 mg (corresponding to 0.027 mmol) of 6-iodo-2-[2-(2H-1,2,3-triazole-2-yl)pyridine-5-yl]imidazo[1,2-a]pyridine (FIG. 2, step 3).
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:14])=[C:6]([CH:10]=[C:11](Br)[CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]>C(O)C.[Pd]>[C:1]([C:4]1[C:5]([OH:14])=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(Br)cc(C(=O)O)c1O
Agent: [Pd]
Solvent: CCO
Product: CC(=O)c1cccc(C(=O)O)c1O
Reaction time: 6 h
Yield: 81.8 %

Procedure:
3-acetyl-5-bromo-2-hydroxybenzoic acid 31 (50 g, 0.19 mol) was dissolved in 250 mL ethanol. After addition of 5.0 g 10% Pd/C the reaction mixture was hydrogenated under 15 atm H2-pressure at room temperature for 6 h. The catalyst was filtered and the solvent was evaporated. The residue was poured into H2O and extracted with CH2Cl2. The combined organic phase was dried and the solvent was removed to give 32 (28 g, 85% yield)
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: OB(O)c1ccccc1Cl
Product: Nc1c(F)cc(-c2ccccc2Cl)cc1Cl
Yield: 42.3 %

Procedure:
The title compound (0.260 g) was prepared from 4-bromo-2-chloro-6-fluoroaniline (0.5 g, 2.4 mmol) and 2-chlorophenylboronic acid (0.453 g, 2.9 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.60 (d, J 7.3, 1H), 7.42-7.31 (m, 3H), 7.18-7.11 (m, 2H), 5.6 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].Cl.[CH3:15][NH:16][CH3:17].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:15][N:16]([CH3:17])[C:11]([C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]1)=[O:13]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](C(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Trans-4-(methoxycarbonyl)cyclohexanecarboxylic acid (20.0 g) obtained in Reference Example 1(2) is dissolved in chloroform (200 ml), and thereto are added dimethylamine hydrochloride (10.5 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (24.7 g) and triethylamine (26.0 g) under ice-cooling. The mixture is then stirred at room temperature for 17 hours. Ice-water is poured to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine successively and dried over sodium sulfate. The solvent is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography (eluent: chloroform, followed by chloroform/methanol=20/1) to give methyl trans-4-[(dimethylamino)carbonyl]-cyclohexanecarboxylate (20.1 g).
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[CH2:8]([SH:12])[CH:9]([SH:11])[CH3:10]>>[CH3:10][CH:9]1[S:11][C:3]2[CH2:4][CH2:5][CH2:6][C:2]=2[S:12][CH2:8]1
Reactant: O=C1CCCC1Br
Reactant: CC(S)CS
Product: CC1CSC2=C(CCC2)S1
Yield: 69 %

Procedure:
The procedure of Example 1(a) is followed using 2-bromocyclopentanone and 1,2-propanedithiol to give 2,3,6,7-tetrahydro-2-methyl-5H-cyclopenta-1,4-dithiin as a greenish oil, bp 92.5°-93°/1 mm, Yield 69%. NMR, 1.42 (3d), 1.6-2.2 (2m), 2.2-2.65 (4m), 2.5-3.7 (3m) (CDCl3) IR 2920, 1605, 1420, 1310, 1260, 1125, 870, 720.
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=2)=[CH:6][C:5]=1[NH:27][C:28]([C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1)=[O:29].[OH-].[K+]>C1COCC1.CO>[C:33]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:35][C:30]([C:28]([NH:27][C:5]2[CH:6]=[C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:16]/[C:17]3[CH:18]=[CH:19][C:20]([C:23]([CH3:26])([CH3:24])[CH3:25])=[CH:21][CH:22]=3)[CH:8]=[CH:9][C:4]=2[C:3]([OH:42])=[O:2])=[O:29])=[CH:31][CH:32]=1
Reactant: COC(=O)c1ccc(OCCCO/N=C/c2ccc(C(C)(C)C)cc2)cc1NC(=O)c1ccc(-c2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(/C=N/OCCCOc2ccc(C(=O)O)c(NC(=O)c3ccc(-c4ccccc4)cc3)c2)cc1
Yield: 63616.1 %

Procedure:
The desired product was prepared using a procedure similar to Step 7 of example 34. Thus, 2-[(1,1′-biphenyl-4-ylcarbonyl)amino]4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid methyl ester (0.253 g, 0.448 mmol) was reacted with 1N KOH (0.90 ml) in THF/MeOH (6 ml/4 ml) to give 2-[(1,1′-biphenyl-4-ylcarbonyl)amino]-4-[3-({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)propoxy]benzoic acid (0.157 g, 0.285 mol, 64%) as a white solid, mp 155-158.5° C. 1H NMR (DMSO-d6) δ 1.25 (s, 9H), 2.14-2.18 (m, 2H), 4.21 (t, J=6.3 Hz, 2H), 4.28 (t, J=6.3 Hz, 2H), 6.78 (dd, J=2.4, 8.9 Hz, 1H), 7.38-7.45 (m, 3H), 7.49-7.54 (m, 4H), 7.77 (d, J=8.3 Hz, 2H), 7.90 (d, J=8.2 Hz, 2H), 7.98-8.06 (m, 3H), 8.22 (s, 1H), 8.46 (d, 2.4 Hz, 1H) 12.60 (s, 1H); IR (solid) 3120, 2960, 1620, 1580, 1220 and 1140 cm−1; [ES(+)], m/z 551 (M+H)+; Anal. Calcd. for C34H34N2O5: C, 74.16; H, 6.22; N, 5.09, Found: C, 73.94; H, 5.91; N, 4.93.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[C:4]([F:14])[C:3]=1[CH2:15][CH:16]1[CH2:20][CH2:19][N:18]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:17]1=[O:27].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:56][N:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1>C1COCC1>[Cl:1][C:2]1[C:3]([CH2:15][CH:16]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[C:17]2=[O:27])=[C:4]([F:14])[C:5]([CH2:8][CH2:9][CH2:10][C:11]([N:60]2[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]2)=[O:13])=[CH:6][CH:7]=1
Reactant: O=C(O)CCCc1ccc(Cl)c(CC2CCN(C3CCCCC3)C2=O)c1F
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)CCCc2ccc(Cl)c(CC3CCN(C4CCCCC4)C3=O)c2F)CC1
Temperature: 80 °C

Procedure:
Add 4-[4-chloro-3-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-2-fluoro-phenyl]-butyric acid (Preparation 80) (200 mg, 0.22 mmol), EDAC (63 mg, 0.33 mmol), HOBT (45, mg, 0.33 mmol), triethylamine (0.1 mL, 0.7 mmol) and 1-methylpiperazine (0.1 mL, 0.9 mmol) in THF (5 mL). Heat the mixture at 80° C. for 3 hours. Evaporate solvent and purify the residue by column chromatography to give the title product as white solid: Mass spectrum (ion spray): m/z=478.3 (M+H).
Reaction SMILES: [C:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)(=O)[CH3:2].[CH:16]([NH2:18])=[O:17]>C(O)=O>[CH:16]([NH:18][CH:1]([C:4]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:7][CH2:6][CH2:5]1)[CH3:2])=[O:17]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: NC=O
Solvent: O=CO
Product: CC(NC=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 180 °C

Procedure:
1-Acetyl-1-(3,4-dichlorophenyl)cyclobutane (9.1 g) prepared as above, formamide (6.5 ml) and 98% formic acid (3 ml) were heated at 180° C. for sixteen hours to give N-formyl-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethlyamine. Concentrated hydrochloric acid (20 ml) was added and the mixture heated under reflux for three hours. The solution was then cooled, washed with ether and sodium hydroxide solution added. The product was extracted with ether, and the ether extract washed with water, dried and evaporated. 1-[1-(3,4-Dichlorophenyl)cyclobutyl]ethylamine (b.p. 112°-118° at 0.2 mm Hg) was isolated by distillation. The amine was dissolved in propan-2-ol and concentrated hydrochloric acid and the solution evaporated to dryness to give 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethylamine hydrochloride (m.p. 185°-195° C.). (Formula I R1 =M3; R2,R3 and R4 =H; R5 =4-Cl; R6 =3-Cl).
Reaction SMILES: [NH2:1][C@H:2]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:3]([NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28])=[O:4].[C:33]([O:37][C:38]([NH:40][C@@H:41]([CH3:45])[C:42](O)=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34]>>[CH3:31][CH:30]([CH3:32])[CH2:29][C@@H:2]([NH:1][C:42](=[O:43])[C@@H:41]([NH:40][C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])[CH3:45])[C:3](=[O:4])[NH:5][CH:6]1[CH2:15][C:14]2[C:9](=[C:10]([N:16]3[CH2:20][CH2:19][CH2:18][C:17]3=[O:21])[CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:22][C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:7]1=[O:28]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@@H](N)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Product: CC(C)C[C@@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3CCCC3=O)c2N(Cc2ccsc2)C1=O
Yield: 83.3 %

Procedure:
The procedure of Example 14(a) was repeated, except that (2R)-2-amino-4-methyl-N-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-yl]pentanamide (600 mg) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (279 mg) were used, whereby tert-butyl (2S)-1-[(2R)-4-methyl-1-oxo-1-[2-oxo-8-(2-oxopyrrolidin-1-yl)-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino]pentan-2-ylamino]-1-oxopropan-2-ylcarbamate (688 mg) was yielded. Subsequently, the procedure of Example 25(a) was repeated, except that the compound prepared as described above was used, whereby the title compound (455 mg) was yielded.
Reaction SMILES: [CH3:1][Mg]Br.[NH2:4][C:5]1[C:10]2=[C:11]([C:28]3[CH:33]=[CH:32][C:31]([NH:34][C:35]([NH:37][C:38]4[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][N:39]=4)=[O:36])=[CH:30][CH:29]=3)[C:12]([C:22](N(OC)C)=[O:23])=[C:13]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[N:9]2[N:8]=[CH:7][N:6]=1>C1COCC1>[C:22]([C:12]1[C:11]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:35]([NH:37][C:38]3[CH:43]=[C:42]([C:44]([F:45])([F:47])[F:46])[CH:41]=[CH:40][N:39]=3)=[O:36])=[CH:32][CH:33]=2)=[C:10]2[N:9]([C:13]=1[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:4])(=[O:23])[CH3:1]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)ncnn2c1CN1CCN(C)CC1
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)ncnn2c1CN1CCN(C)CC1
Temperature: 60 °C
Reaction time: 15 h
Yield: 42.9 %

Procedure:
Methyl magnesium bromide (0.54 mL, 1.63 mmol, in 3.0 M in diethyl ether) was added dropwise to a stirring solution of Example 94 (100.0 mg, 0.163 mmol) in THF (2 mL) at rt. The reaction was heated to 60° C. and allowed to stir overnight (15 hrs) or until all starting material had been consumed as seen by HPLC. After cooling to rt, the reaction was quenched with methanol and diluted with 100 mL of EtOAc and washed 3× with saturated NH4Cl solution. The organic layer was dried over Na2SO4, concentrated and purified by HPLC (10-70% ACN/H2O) to give 37.9 mg (0.07 mmol, 40.9%) of the title compound. 1H-NMR (DMSO-d6). δ 10.88 (s, 1H), 10.19 (s, 1H), 8.57 (d, J=5.4 Hz, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.40-7.35 (m, 3H), 4.17 (s, 2H), 3.08-3.04 (m, 4H), 2.73-2.65 (m, 7H), 2.06 (s, 3H). MS [M+H]+=568; LCMS RT=2.31 min.
Reaction SMILES: [NH:1]([C:5]1[CH:13]=[CH:12][C:8]([NH:9][CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3].[CH3:15][S:16]([NH:19][CH2:20][CH2:21]Cl)(=[O:18])=[O:17].C(=O)([O-])O.[Na+].O>CO>[NH:1]([C:5]1[CH:13]=[CH:12][C:8]([N:9]([CH2:21][CH2:20][NH:19][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:10][CH3:11])=[CH:7][C:6]=1[CH3:14])[C:2]([CH3:4])=[O:3]
Reactant: CS(=O)(=O)NCCCl
Reactant: CCNc1ccc(NC(C)=O)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN(CCNS(C)(=O)=O)c1ccc(NC(C)=O)c(C)c1

Procedure:
A mixture of 57.6g of 4-acetamino-3-methyl-N-ethylaniline, 52g of βmethanesulfonamidoethyl chloride, 27.7g of sodium hydrogen carbonate, 70g of water and 70ml of methanol were refluxed for 5 hours, and thereafter the methanol was distilled out under reduced pressure. Water was added to the reaction system and an oily product separated out. This oily product was poured into ethyl acetate and cooled to obtain white 4-acetamino-3-methyl-N-(β-methanesulfonamidoethyl)-N-ethylaniline.
Reaction SMILES: Cl[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[NH:22][C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=1)=[O:24].C([O-])(O)=O.[Na+]>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>[Cl:10][C:6]1[C:3]([C:4]#[N:5])=[C:2]([C:29]2[CH:28]=[CH:27][C:26]([NH:25][C:23]([NH:22][C:13]3[CH:14]=[C:15]([C:18]([F:19])([F:21])[F:20])[CH:16]=[CH:17][C:12]=3[F:11])=[O:24])=[CH:31][CH:30]=2)[CH:9]=[N:8][CH:7]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Reactant: N#Cc1c(Cl)cncc1Cl
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1c(Cl)cncc1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To a solution of 346 mg of 3,5-dichloroisonicotinonitrile and 959 mg of 1-(2-fluoro-5-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea in 24 mL of dioxane are added 462 mg of NaHCO3 in 14.4 mL of water. 462 mg of tetrakis(triphenylphosphine)palladium are then added and the reaction is refluxed for 5 hours and then left overnight at 20° C. 20 mL of water are then added and the mixture is extracted with 2×60 mL of ethyl acetate. The organic phase is dried over magnesium sulfate and then concentrated under reduced pressure. The brown oil is purified on a prepacked Merck cartridge of 30 g of SiO2 15-40 μm (dichloromethane and then 99/1 dichloromethane/methanol). 290 mg of yellow crystals of 1-[4-(5-chloro-4-cyanopyrid-3-yl)phenyl]-3-(2-fluoro-5-trifluoromethylphenyl)urea are obtained.
Reaction SMILES: [N:1]1[NH:2][N:3]=[CH:4][CH:5]=1.Cl[Si:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:8][Si:7]([CH3:10])([CH3:9])[N:2]1[N:3]=[CH:4][CH:5]=[N:1]1
Reactant: c1cn[nH]n1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: C[Si](C)(C)n1nccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
A 1000-mL 4-necked round-bottomed flask was charged with a solution of 2H-1,2,3-triazole (30 g, 434.78 mmol, 1.00 equiv) in benzene (500 mL). To this solution was added chlorotrimethylsilane (49.3 g, 456.48 mmol, 1.05 equiv) drop wise 0° C. followed by addition of triethylamine (48.3 g, 478.22 mmol, 1.10 equiv). The resulting solution was stirred for 16 hours at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The crude product was purified by distillation and the fraction was collected at 140-150° C. affording 2-(trimethylsilyl)-2H-1,2,3-triazole as colorless oil (11 g, 18%). To a solution of 2-(trimethylsilyl)-2H-1,2,3-triazole (6.2 g, 43.97 mmol, 2.74 equiv) in DMF (100 mL) was added tert-butyl 3-(4-nitrophenylsulfonyloxy)piperidine-1-carboxylate (6.2 g, 16.06 mmol, 1.00 equiv). The resulting solution was refluxed for 3 hours. Upon completion, the mixture was cooled down to room temperature and concentrated on a rotary evaporator affording tert-butyl 3-(1H-1,2,3-triazol-1-yl)piperidine-1-carboxylate as brown solid (2.3 g).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH:28]([C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:34][CH:35]=1)=[O:29]>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:32]3[CH:31]=[C:30]([CH:28]=[O:29])[CH:35]=[N:34][CH:33]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cncc(C=O)c4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 5-formylpyridine-3-boronic acid pinacol ester in General Procedure A. Purification on silica and ether trituration gave 241. NMR (CDCl3): 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 7.38 (1H, s), 9.18 (2H, m), 9.37 (1H, s), 10.25 (1H, s). MS (ESI+): MH+503.17 (100%)
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]1([C:15]2[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=2[NH2:20])[CH2:14][CH2:13][CH2:12][CH:11]=1>C1C=CC=CC=1>[C:10]1([C:15]2[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=2[NH:20][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH2:14][CH2:13][CH2:12][CH:11]=1
Reactant: Cc1nn(C)c(N)c1C1=CCCC1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: Cc1nn(C)c(NC(=O)Nc2ccccc2)c1C1=CCCC1
Temperature: 25 °C

Procedure:
Phenylisocyanate (0.176 mol) is added to 4-(1-cyclopenten-1-yl)-1,3-dimethyl-1H-pyrazol-5-amine (0.16 mol) in benzene (800 ml). The reaction mixture is stirred at room temperature and then at a temperature between 50° and 70° C. After distillation under vacuum, the product of the title is recovered by usual procedures. M.p. 204° C.
Reaction SMILES: CC(C)(S([NH:6][CH:7]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[O:23][CH2:24][CH3:25])[CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)C.Cl.O1CCOCC1>CCO>[NH2:6][CH:7]([C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[O:23][CH2:24][CH3:25])[CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1c(F)cccc1OCC
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) solution of ethyl 4-(1,1-dimethylethylsulfinamido)-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate (1.550 g; 4.00 mmol) in EtOH (20 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (2.0 ml; 8.00 mmol). The resulting mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 30 min. The reaction mixture was then concentrated to dryness under reduced pressure and the oily residue was further dried under HV to give the chlorhydrate salt of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate. LC-MS (conditions A): tR=0.55 min. and [M+H]+: 284.07 g/mol; tR=0.57 min. and [M+H]+: 284.07 g/mol (mixture of diastereoisomers).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH:12]=O)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH2:20][N:19]1[C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH2:12][N:22]2[CH2:21][CH2:20][N:19]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[CH:18]([CH3:17])[CH2:23]2)=[CH:8][C:7]([CH2:14][CH2:15][CH3:16])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)n(C(C)(C)C)n1
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3)C(C)C2)n(C(C)(C)C)n1

Procedure:
190 mg (98%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-3-propyl-1H-pyrazol-5-yl)propanal (100 mg, 0.450 mmol), 2-methyl-1-m-tolylpiperazine (86 mg, 0.450 mmol), DIPEA (0.118 mL, 0.675 mmol) and NaBH(OAc)3 (286 mg, 1.350 mmol).
Reaction SMILES: Br[CH:2]([C:4]1[S:8][C:7]([S:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=1)[CH3:3].[CH3:21][NH2:22]>O1CCCC1>[Cl:17][C:11]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=1[S:9][C:7]1[S:8][C:4]([CH:2]([NH:22][CH3:21])[CH3:3])=[CH:5][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(Br)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(C)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1
Temperature: 80 °C
Yield: 34 %

Procedure:
To a solution of 5-(1-bromoethyl)-2-(2,4-dichlorophenyl)sulfanyl-3-nitro-thiophene (0.1 g, 0.243 mmol) in tetrahydrofuran (5 mL), was added N-methylamine (0.012 mL, 0.29 mmol). The resulting reaction mixture was heated at 80° C. under microwave irradiation (200 W) on a CEM Discovery™ microwave machine for 50 minutes. The reaction mixture was concentrated and the crude was purified by silica gel chromatography to afford the title compound as a yellow solid (30 mg, 33% yield). 1H NMR (400 MHz, d6-DMSO) δ: 7.83 (2H, m), 7.54 (1H, m), 7.49 (1H, s), 3.83 (1H, q), 2.44 (3H, s), 1.32 (3H, d). MS m/z: 376.8 [M+H]+.