Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[F:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1>CC(C)=O>[F:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Oc1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1ccc(COc2cccc(F)c2)cc1
Yield: 87.2 %

Procedure:
A mixture of 4-(bromomethyl)benzonitrile (23.50 g, 120.0 mmol), K2CO3 (55.20 g, 400.0 mmol) and 3-fluorophenol (11.21 g, 100.0 mmol) were heated at reflux in acetone (400 mL) (16 h). The volatiles were evaporated and the residue was diluted with CH2Cl2 (300 mL). The organic layer was washed with H2O (300 mL), dried (MgSO4) and concentrated in vacuo to give white needles (19.81 g, 87%): Rf=0.40 (9/1 hexanes/ethyl acetate); mp 69-70° C.; 1H NMR (CDCl3) δ 5.02 (s, CH2O), 6.56-6.67 (m, 3 ArH), 7.16 (q, J=7.7 Hz, 1 ArH), 7.45 (d, J=7.1 Hz, 2 ArH), 7.59 (d, J=8.1 Hz, 2 ArH); 13C NMR (CDCl3) δ 60.1 (CH2O), 102.8 (d, J=24.4 Hz, C2′ or C4′), 108.3 (d, J=21.1 Hz, C4′ or C2′), 110.4 (d, J=2.8 Hz, C6′), 111.9 (ArC), 118.6 (CN), 127.5 (ArC), 130.4 (d, J=9.7 Hz, C5′), 132.4, 141.9 (2 ArC), 159.4 (d, J=10.8 Hz, C1′), 163.6 (d, J=244.2 Hz, C3′); LRMS (M+Na+) (ESI+) 250.0 [M+Na+] (calcd for C14H10NONa+ 250.0).
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:12](OC(=O)C)(=[O:14])[CH3:13].Cl>C(O)(=O)C>[C:12]([S:11][C:3]1[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])(=[O:14])[CH3:13]
Reactant: O=C(O)c1cccc(Cl)c1S
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Sc1c(Cl)cccc1C(=O)O

Procedure:
3-Chloro-2-mercaptobenzoic acid (9.8 g, 52 mmol), acetic anhydride (6.3 g, 62 mmol) and glacial acetic acid (22 ml) were heated at 80° C. for 4 hours, then cooled and mixed with dilute hydrochloric acid.
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl>C(O)(CC)C>[CH:2]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])([CH2:6][CH3:7])[CH3:3]
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Agent: Cl
Solvent: CCC(C)O
Product: CCC(C)OC(=O)C(N)/C=C/CP(=O)(O)O

Procedure:
1.5 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of sec.-butanol and the suspension is saturated with hydrogen chloride gas for 4 hours at 75°. After concentration, the residue is dissolved in 10 ml of 2-butanol, 10 ml of propylene oxide are added and the precipitate is filtered off. Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphono-3-pentenoic acid sec.-butyl ester, m.p. 169°-170°.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=O.[NH2:16][C:17]1[NH:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1>C(O)(=O)C>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([C:5]2[CH:4]=[CH:3][N:21]3[C:17](=[N:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=43)[N:16]=2)=[CH:8][CH:9]=1)#[N:12]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CN(C)/C=C/C(=O)c1ccc(C#N)cc1
Solvent: CC(=O)O
Product: N#Cc1ccc(-c2ccn3c(n2)nc2ccccc23)cc1

Procedure:
To a solution of (E)-4-(3-(dimethylamino)acryloyl)benzonitrile (2.0 g, 10.0 mmol) and 2-aminobenzimidazole (1.33 g, 10 mmol) in acetic acid (15 mL) was heated at 120° C. for 16 hours. The mixture was concentrated to a residue and treated with sodium bicarbonate solution to neutralize the residual acetic acid. The resulting suspension was added EtOAc, sonicated, and filtered. The solid collected was washed with water, ether, and dried under high vacuum to give 630 mg (23%) of T709 as yellow solid. A small amount was purified by HPLC (acetonitrile/H2O) for NMR and bioassay. 1H NMR (CD3OD): δ 9.83 (1H, d, J=8.4 Hz), 8.59 (2H, m), 8.46 (1H, d, J=8.4 Hz), 8.36 (1H, d, J=6.8 Hz), 8.01 (2H, m), 7.93 (1H, m), 7.87 (1H, m), 7.74 (1H, m); MS: 271 (M+H+).
Reaction SMILES: N12CCCN=C1CCCCC2.[C:12]([O:16][C:17]([N:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=[C:20]1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]#[C:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][C:43]=2[NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:31][C:30]1=[O:52])=[O:18])([CH3:15])([CH3:14])[CH3:13]>CC#N>[C:12]([O:16][C:17]([N:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=[C:20]1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:43]3[CH:42]=[CH:41][N:40]=[CH:39][C:38]=3[CH:37]=2)[CH2:31][C:30]1=[O:52])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C#CCN1CCN(Cc2cc3cnccc3n2C(=O)OC(C)(C)C)C(=O)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(CN2CCN(Cc3cc4cnccc4n3C(=O)OC(C)(C)C)C(=O)C2)cc2cnccc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 108.3 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (42 mg, 0.27 mmol) is added to a suspension containing 2-{4-[3-(4-tert-butoxycarbonylamino-pyridin-3-yl)-prop-2-ynyl]-2-oxo-piperazin-1-ylmethyl}-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (77 mg, 0.14 mmol) in anhydrous CH3CN (10 mL) and the mixture is warmed to 50° C. After 4 h, the reaction mixture is concentrated to dryness and the residue is partitioned between CH2Cl2 (50 mL) and water (50 mL) and the layers are separated. The aqueous layer is extracted twice with CH2Cl2 (25 mL) and the combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to provide 85 mg of the title compound as a crude solid which is used directly without further purification. 1H NMR (300 MHz, CDCl3) δ1.68 (s, 9H), 1.70 (s, 9H), 2.91 (m, 2H), 3.41 (s, 2H), 3.49 (m, 2H), 4.26 (s, 2H), 4.95 (d, J=1.1 Hz, 2H), 6.39 (d, J=0.7 Hz, 1H), (d, J=0.7 Hz, 1H), 7.86 (m, 1H), 8.41 (m, 1H), 8.76 (br s, 1H), 8.82 (br s, 1H) ppm; MS (EI): m/z 561 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>>[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC(C)=O)cc3)ccn2c1=O
Yield: 91.6 %

Procedure:
Methyl 8-(4-acetamido-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (77 mg, 0.26 mmol) and (4-acetamido-phenyl)-boronic acid (56 mg, 0.31 mmol). Purification by flash silica column chromatography (CH2Cl2:MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (93 mg, 90%). ESI-MS m/z: 391 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]#[N:20])[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][CH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CCC#N)NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCc1nnn[nH]1)NC(=O)OCc1ccccc1
Temperature: 82.5 °C
Yield: 75 %

Procedure:
Into the same device as used in Example 1 were placed 77.3 g (0.28 mole) of methyl (2S)-2-benzyloxycarbonylamino-4-cyanobutyrate, 27.3 g (0.42 mole) of sodium azide, 57.7 g (0.42 mole) of triethylamine hydrochloride and 280 ml of toluene. Thereafter, the mixture was heated to a temperature of 82 to 83° C. to undergo a reaction for 24 hours. Subsequently the same procedure as in Example 1 was repeated, and crystals were collected by filtration. Further, the crystals were recrystallized from methanol and water, filtered and dried, giving 67.7 g (0.21 mole) of methyl (2S)-2-benzyloxycarbonylamino-4-(tetrazole-5-yl)butyrate (yield 75.8% based on methyl (2S)-2-benzyloxycarbonylamino-4-cyanobutyrate). The reaction is illustrated below with chemical formulas: ##STR27##
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:24]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.5 %

Procedure:
To a solution of the product of Example 126A (0.20 g, 1.1 mmol) and Et3N (0.3 mL, 2.2 mmol) in 25 mL THF was added 2-bromobenzoyl chloride (Aldrich, 0.18 mL, 1.4 mmol). This mixture stirred at ambient temperature for 20 hours then was concentrated under reduced pressure and the residue was diluted with 10 mL EtOAc and washed with 5 mL NH4Cl. The layers were separated and the aqueous layer was extracted (2×5 mL EtOAc). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via recrystallization with 50% hexanes/EtOAc to afford 0.18 g of the title compound (0.49 mmol, 46% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.26 (s, 3H), 2.28 (s, 3H), 3.30 (s, 3H), 3.78 (t, J=5.1 Hz, 2H), 4.42 (t, J=5.1 Hz, 2H), 7.22 (dt, J=7.8, 1.7 Hz, 1H), 7.34 (dt, J=7.5, 1.4 Hz, 1H), 7.63 (dd, J=8.0, 1.2 Hz, 1H), 7.90 (dd, J=7.6, 1.9 Hz, 1H); MS (DCI/NH3) m/z 369, 371 (M+H)+; Anal. calculated for C15H17BrN2O2S: C, 48.79; H, 4.64; N, 7.59. Found: C, 48.84; H, 4.49; N, 7.40.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:18])OCC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[N:19]#[C:20][NH2:21]>C(O)C>[C:20]([NH:21][C:14](=[NH:18])[CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)#[N:19]
Reactant: N#CN
Reactant: CCOC(=N)CCSCc1csc(NC(=N)N)n1
Solvent: CCO
Product: N#CNC(=N)CCSCc1csc(NC(=N)N)n1
Reaction time: 8 h
Yield: 72.1 %

Procedure:
To 1.9 g of ethyl 3-[(2-guanidinothiazol-4-yl)methylthio]-propionimidate was added 10 ml of an ethanol solution of 0.28 g of cyanamide and the mixture was allowed to stand overnight at room temperature. Then, the solvent was distilled off from the reaction mixture under reduced pressure and the residue obtained was purified by a silica gel column chromatography using a solvent mixture of chloroform and methanol as a developing solvent to provide 1.35 g of N-cyano-3-[(2-guanidinothiazol-4-yl)methylthio]propionamidine. The product shows the following physicochemical properties:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[CH:17][C:18]=3[O:23][CH3:24])[N:13]=2)=[CH:7][C:6]=1[CH3:27].[CH3:28][N:29]=[C:30]=[O:31].CCN(CC)CC>C1COCC1>[CH3:24][O:23][C:18]1[CH:17]=[C:16]([O:25][CH3:26])[CH:15]=[C:14]2[C:19]=1[C:20](=[O:22])[NH:21][C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([O:4][CH2:3][CH2:2][NH:1][C:30]([NH:29][CH3:28])=[O:31])=[C:6]([CH3:27])[CH:7]=1)=[N:13]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN)c(C)c3)nc2c1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)NCCOc1c(C)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.2 %

Procedure:
A mixture of compound 2-(4-(2-aminoethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.10 g, 0.27 mmol), methylisocyanate (0.020 g, 0.35 mmol), and Et3N (0.034 g, 0.35 mmol) in THF (4.0 mL) was stirred at room temperature for 16 hours. The mixture was filtered, washed with CH2Cl2 and the solvent was removed under reduced pressure. The resulting residue was chromatographed on silica gel to yield the title compound (0.082 g, 71%) as a white solid: MS (APCI) m/z 449 [M+Na]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].Cl[C:6]([CH3:14])([CH2:8][CH2:9][C:10](Cl)([CH3:12])[CH3:11])[CH3:7].[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCOCC.CCCCCC>[Br:15][C:16]1[CH:21]=[C:20]2[C:19](=[CH:18][CH:17]=1)[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][C:6]2([CH3:14])[CH3:7]
Reactant: Brc1ccccc1
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: CCOCC
Product: CC1(C)CCC(C)(C)c2cc(Br)ccc21
Reaction time: 0.33 h
Yield: 83 %

Procedure:
Aluminum chloride (700 mg, 5.25 mmol) was added slowly to a solution of 2,5-dichloro-2,5-dimethylhexane (11 g, 60 mmol) in bromobenzene (90 mL) at 0° C. After stirred for 20 min, the mixture was diluted with 100 mL of ether:hexane (1:1), washed with ice-water (1×10 mL), 10% HCl (1×10 mL) and brine (1×10 mL), dried (MgSO4) and concentrated to afford a brown oil. The crude was then distilled using Coughler distillation to yield the title compound (13.2 g, 83% yield) as a white solid:
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13](Cl)[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)[N:10]=1)[CH2:2]2.CC1(C)C(C)(C)OB([C:35]2[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=2)O1>>[NH2:39][C:38]1[CH:40]=[CH:41][C:35]([C:13]2[N:14]=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:10]=[C:11]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][CH3:26])=[O:24])=[CH:18][CH:17]=3)[N:12]=2)=[CH:36][CH:37]=1
Reactant: CNC(=O)Nc1ccc(-c2nc(Cl)nc(N3CC4CCC(C3)O4)n2)cc1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Product: CNC(=O)Nc1ccc(-c2nc(-c3ccc(N)cc3)nc(N3CC4CCC(C3)O4)n2)cc1
Yield: 49 %

Procedure:
The title compound was prepared by following the procedure of example 462 step 4 using 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-chloro-1,3,5-triazin-2-yl)phenyl)-3-methylurea and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Yield 2.8 g, 49% yield.
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2].Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:26])([CH3:25])[C:23]#[CH:24]>>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:26])([CH3:25])[C:23]#[CH:24])[C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH3:2]
Reactant: C#CC(C)(O)CCCCCl
Reactant: CCOCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: C#CC(C)(O)CCCCn1c(=O)c2c(ncn2COCC)n(C)c1=O

Procedure:
44.84 g (0.2 mol) of 7-ethoxymethyl-3-methylxanthine were reacted with 32.13 g (0.2 mol) of 1-chloro-5-hydroxy-5-methyl-6-heptyne from Example 1B1), and worked up in analogy to Example 1B2).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].OOS([O-])=O.[K+].[CH:25](=O)[CH:26]([CH3:28])[CH3:27]>CN(C=O)C.O>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[C:25]1[CH:26]([CH3:28])[CH3:27]
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Reactant: CC(C)C=O
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2nc(C(C)C)n(CC(OC)OC)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a stirred solution of methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (0.5 g, 2.0 mmol) from Step C of Example 13 in DMF (15 mL) and H2O (0.5 mL) were added oxone (0.8 g, 1.3 mmol) and iso-butyraldehyde (0.2 mL, 2.2 mmol) and the reaction was stirred overnight at room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 0% to 30% ethyl acetate in hexanes) to afford methyl 1-(2,2-dimethoxyethyl)-2-isopropyl-1H-benzo[d]imidazole-7-carboxylate (0.5 g, 85%): 1H NMR (500 MHz, DMSO-d6) δ 7.79 (dd, J=8.0, 1.0 Hz, 1H), 7.56 (dd, J=7.5, 1.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 4.61 (d, J=5.0 Hz, 2H), 4.38 (t, J=5.0 Hz, 1H), 3.90 (s, 3H), 3.38-3.33 (m, 1H), 3.19 (s, 6H), 1.32 (d, J=7.0 Hz, 6H); MS (ESI+) m/z 306 (M+H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:14][CH2:15][C:16](O)=[O:17]>O>[CH3:6][N:7]([C:16](=[O:17])[CH2:15][Cl:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNc1ccccc1
Reactant: O=C(O)CCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CN(C(=O)CCl)c1ccccc1
Reaction time: 1.25 h
Yield: 85.5 %

Procedure:
76.75g (0.50 moles) of phosphoryl chloride and 107g (1.00 moles) of N-methyl aniline were added to 99.2g (1.05 moles) of monochloracetic acid. Alternate additions of 10% of the total amount of each of the N-methyl aniline and of the phosphoryl chloride were made with stirring at a temperature of 60° to 70°C over a period of 75 minutes. The reaction mixture was then stirred at 100° to 110°C for 4 hours, after which the reaction mixture was cooled to 70° to 80°C and then poured into warm water. The aqueous suspension was stirred vigorously whilst cooling until the product crystallised and then cooled further until the temperature reached 30° to 35°C. The precipitated crystalline product was separated from the aqueous phase by filtration and then washed with water. The washed product was dried in an oven at a temperature of 50° to 60°C. 157g of dry off-white crystals of N-methyl chloro acetanilide having a melting point of 69°C were obtained. The yield was 85.5% based on the theoretical yield from the N-methyl aniline in the starting material.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:11][S:12](O)(=[O:14])=[O:13].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[F:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][CH:6]=1
Reactant: O=S(=O)(O)Cl
Reactant: FCCCc1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(CCCF)cc1
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 78.3 %

Procedure:
4.1 g of (3-fluoro-propyl)-benzene (29.67 mmol) were dissolved in 40 ml of dichloromethane. At 0-5° C., 6.91 g of chlorosulfonic acid (59.34 mmol), dissolved in 10 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 45 min at 0-5° C. and then added to a solution of 6.8 g of phosphorous pentachloride (32.63 mmol) dissolved in 50 ml of dichloromethane. The reaction mixture was stirred for 1 h at 5-10° C. The solvent was evaporated, 150 ml of diethyl ether added, washed once with 150 ml of ice water, and the organic layer dried over magnesium sulfate, filtered, and the solvent evaporated under reduced pressure. The crude product was purified via silica gel chromatography with n-heptane-dichloromethane (11:9) as eluent to give 5.5 g of the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10](O)([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:29])CC>ClCCl>[CH2:1]([N:8]([CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:9][C:10]([F:29])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)C(C)(O)CN(Cc1ccccc1)C1CCCC1
Solvent: ClCCl
Product: CCOC(=O)C(C)(F)CN(Cc1ccccc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To ethyl 3-(benzyl(cyclopentyl)amino)-2-hydroxy-2-methylpropanoate (4.2 g, 14 mmol) in 50 ml of dichlormethane at −78° C., was added DAST (2.7 ml, 21 mmol) dropwise. The reaction mixture was gradually warmed up to room temperature and stirred for 2 h. It was then diluted to dichloromethane, washed by NaHCO3, brine and water. Organic extract dried and concentrated to a residue, which was purified on silica gel column chromatographically (Hex/EtOAc=40:1 to 20:1) to give 3.5 g product (83%) as light yellow liquid. [M+H] calc'd for C18H26FNO2, 308; found 308.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9](=[N:13]O)[C:10](=O)[CH3:11])[CH:5]=[CH:6][CH:7]=1.[NH2:16][NH2:17]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:17][N:16]=[C:10]([CH3:11])[C:9]=2[NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(=NO)C(=O)c1cccc(Cl)c1
Reactant: NN
Solvent: CCO
Product: Cc1n[nH]c(-c2cccc(Cl)c2)c1N
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.8 %

Procedure:
To a 0° C. solution of 1-(3-chlorophenyl)-2-(hydroxyimino)butane-1,3-dione (224.8 mg, 0.996 mmol) in 5 mL ethanol was dropwise added hydrazine (0.30 mL, 9.6 mmol). The reaction was warmed to room temperature and stirred for 15 hours. The crude reaction mixture was concentrated and purified by flash chromatography on silica gel (20 to 100% ethyl acetate in dichloromethane) to yield 113.3 mg (55%) of 5-(3-chlorophenyl)-3-methyl-1H-pyrazol-4-amine. LCMS (ESI) m+H=208.2; 1H NMR (400 MHz, DMSO-d6) δ: 12.20 (s, 1H), 7.94-7.57 (m, 2H), 7.40 (s, 1H), 7.27 (d, J=9.1, 1H), 2.12 (s, 3H).
Reaction SMILES: [NH3:1].[Cl:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1>C1(C)C=CC=CC=1>[Cl:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:1])=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: N
Solvent: Cc1ccccc1
Product: NC(=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
To a mixture of 28% aqueous ammonia (19.3 g, 317 mmol, 4.0 eq) and toluene (30 mL) was dropwise added a 4-chloromethylbenzoyl chloride. (15.0 g, 79.3 mmol)/toluene (30 mL) solution under ice-cooling. The mixture was stirred at room temperature for 1 hr. and under ice-cooling for 1 hr. The crystals were collected by filtration, washed with water (9 mL) and toluene (9 mL), and dried in vacuo at 40° C. to give the title compound (13.36 g, yield 99.3%) as white crystals.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=2)[N:10]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]1=[O:31])(C)(C)C.C(N1C2C(=CC(Br)=CC=2)CC(N[S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=[O:54])=[O:53])C1=O)C1C=CC=CC=1>>[CH2:24]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=2)[CH2:17][CH:8]([NH:7][S:52]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)(=[O:54])=[O:53])[C:9]1=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2cc(-c3ccccc3)ccc2N(Cc2ccccc2)C1=O
Reactant: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cc(Br)ccc2N1Cc1ccccc1
Product: O=C1C(NS(=O)(=O)c2ccccc2)Cc2cc(-c3ccccc3)ccc2N1Cc1ccccc1

Procedure:
The title compound (15 mg) was prepared from 4B (22 mg) according to the procedures described in 3D and 3E. HPLC/MS retention time=4.0 min (Phenomenex Luna 5 micron C18 4.6 mm×50 mm column eluted with a 0% to 100% B solvent gradient over 4 min; solvent A=90% H2O, 10% MeOH, 0.1% TFA and solvent B=10% H2O, 90% MeOH, 0.1% TFA; flow rate=4.0 mL/min; UV detection at 220 nm); m/z=469 [M+H]+, 491 [M+Na]+.