Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([CH2:44][C:45]([NH2:47])=[O:46])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:38]3[CH2:43][CH2:42][CH:41]([CH2:44][C:45]([NH2:47])=[O:46])[CH2:40][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NC(=O)CC1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 2-piperidin-4-yl-acetamide (ChemBridge) to give the title compound. HR-MS (ES, m/z) calculated for C36H44Cl2N5O3 [(M+H)+] 664.2816, observed 664.2818.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:14]([O:16]CC)=O)[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.[C:20]([NH:29][NH2:30])(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:14]([NH:30][NH:29][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:16])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2ccc(Cl)cc2n(C)c1=O
Product: CCCCCCCC(=O)NNC(=O)c1c(O)c2ccc(Cl)cc2n(C)c1=O

Procedure:
Reagents: Comp 39 (0.36 mmols, 0.1 g); octanoyl hydrazine (0.39 mmols, 0.063 g). Yield: 0.07 g (50%), white solid, m.p.=164° C.-165° C.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C=O)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[S:21]([C:24]1[CH:25]=[C:26]([CH2:33]O)[C:27]2[O:31][CH:30]=[CH:29][C:28]=2[CH:32]=1)(=[O:23])=[O:22]>C(Cl)Cl>[Cl:4][CH2:33][C:26]1[C:27]2[O:31][CH:30]=[CH:29][C:28]=2[CH:32]=[C:24]([S:21]([C:15]2[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=2[O:13][CH3:12])(=[O:23])=[O:22])[CH:25]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C)cc1S(=O)(=O)c1cc(CO)c2occc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C)cc1S(=O)(=O)c1cc(CCl)c2occc2c1

Procedure:
Oxalyl chloride (0.1 mL, 1.1 mmol) was dissolved in dry DCM (2 mL) and DMF (0.9 mL, 1.1 mmol) was added (very exothermic reaction). {5-[(2-Methoxy-5-methylphenyl)sulfonyl]-1-benzofuran-7-yl}methanol (370 mg, 1.1 mmol; Intermediate 68)
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[C:8]([OH:10])=[O:9].Cl.[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1>>[CH3:12][C:13]1[CH:22]=[C:21]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH:2][C@@H:3]3[CH2:7][CH2:6][CH2:5][C@@H:4]3[C:8]([OH:10])=[O:9])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: N[C@@H]1CCC[C@@H]1C(=O)O
Agent: Cl
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCC[C@@H]3C(=O)O)cc2)c2ccccc2n1
Yield: 87.6 %

Procedure:
According to the procedure of Example 10, Step 1, the reaction of 141 mg (0.85 mmol) of (+)-(1S,2R)-2-amino-1-cyclopentane-carboxylic acid hydrochloride with 400 mg (1.04 mmol) of 4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl chloride hydrochloride provided 327.9 mg of (1S,2R)-2-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]cyclopentanecarboxylic acid in 86% yield. MS: 441.1 (M+H)+
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[CH2:21]([NH:25][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH2:22][CH2:23][CH3:24]
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: CCCCN
Product: CCCCNCc1ccc(Oc2ccc(C(N)=O)cn2)c(OC)c1
Yield: 75.6 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and n-butylamine (0.0134 g, 0.184 mmol) gives the title compound (0.0458 g, 75.7%): TOF MS ES+ 330.2 (M+H)+, HRMS calcd for C18H24N3O3 330.1818 (M+H)+, found 330.1802, time 0.39 min, HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=4.9 min, 100% purity.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([CH3:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:64][N:65]1[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]([CH3:13])([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:64][N:65]5[CH2:70][CH2:69][N:68]([CH3:71])[CH2:67][CH2:66]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NN2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(9-Cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (Intermediate 6) (20 mg, 0.046 mmol, 1 eq), DIPEA (16 μl, 0.091 mmol, 2 eq) and TBTU (16 mg, 0.05 mmol, 1.1 eq) were added to 0.5 mL DMF and the resulting solution stirred at rt for 5 min before the addition of 1-amino-4-methylpiperazine (7 mg). The RM was then stirred at rt for 16 hours before purifying by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9-cyclopentyl-5,7,7-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(4-methyl-piperazin-1-yl)-benzamide.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH:16]=[O:17])[C:11](Cl)=[N:12]2)=[CH:7][CH:6]=1)(=O)C.CCN(CC)CC.C(O)=O.O>CN(C=O)C.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>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH:16]=[O:17])[CH:11]=[N:12]2)=[CH:7][CH:6]=1
Reactant: CC(=O)Oc1ccc2cc(C=O)c(Cl)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=Cc1cnc2cc(O)ccc2c1
Temperature: 110 °C
Yield: 59.8 %

Procedure:
To a solution of 2-chloro-3-formylquinolin-7-yl acetate (2.9 g, 14 mmol) and Pd(PPh3)4 (1.6 g, 1.4 mmol, 0.1 eq.), Et3N (17 g, 168 mmol, 16 eq.) in DMF (100 mL) was added formic acid (3.48 g, 75.6 mmol, 5.4 eq.) dropwise over 5 min. The mixture was warmed to 110° C. over 2 h. Then, the reaction mixture was diluted (water), extracted (ethyl acetate), washed (brine), dried (Na2SO4), filtered and evaporated to dryness to give the crude product, which was purified by silica gel column chromatography (pet. ether:ethyl acetate, 1:1) to give 7-hydroxyquinoline-3-carbaldehyde as yellow solid (1.45 g, yield 60%). ESI-MS: 216 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[N:18]1[C:22](=[O:23])[NH:21][N:20]=[C:19]1[CH2:24][C@@H:25]1[CH2:29][CH2:28][N:27]([C:30](OC(C)(C)C)=[O:31])[CH2:26]1.[CH3:37][C:38]1(C(O)=O)[CH2:40][CH2:39]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[CH:13][CH:14]=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[N:18]1[C:19]([CH2:24][C@@H:25]2[CH2:29][CH2:28][N:27]([C:30]([C:38]3([CH3:37])[CH2:40][CH2:39]3)=[O:31])[CH2:26]2)=[N:20][NH:21][C:22]1=[O:23]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cccnc4c3)cc2F)C1
Reactant: CC1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C(=O)N2CC[C@@H](Cc3n[nH]c(=O)n3-c3ccc(-c4ccc5cccnc5c4)cc3F)C2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
Into a 50 mL round bottom flask was placed 1,1-dimethylethyl (3S)-3-({4-[2-fluoro-4-(7-quinolinyl)phenyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl}methyl)-1-pyrrolidinecarboxylate (0.082 mmol). Added was 4N HCL in dioxane (1.0 mL). The solution was stirred at room temperature for 1 h and then was concentrated in vacuo. The solid was taken up in N,N-dimethylformamide (1 mL). Added to flask was 1-methylcyclopropanecarboxylic acid (0.100 mmol), 1-hydroxybenzotriazole (0.196 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.183 mmol), and N,N-diisopropylethylamine (0.286 mmol). The flask was capped and stirred at room temperature for 1 h. Purification of the crude material was performed by injecting the solution directly onto a reverse phase HPLC (10-40% acetonitrile w/0.1% TFA/water w/0.1% TFA). The desired fractions were combined and concentrated in vacuo. The recovered material was taken up in 1 mL dichloromethane and 1 mL acetonitrile. A 6 mL tube packed with PL-HCO3 (Stratospheres Solid Phase Extraction macroporous resin for Acid Removal, Varian Industries) was pretreated with 2 mL of dichloromethane. The product solution was added to the top of the resin via pipette and was allowed to freely pass through the column via gravity. The column was rinsed with dichloromethane (2 mL) and acetonitrile (2 mL). The recovered filtrate was concentrated in vacuo to afford the title compound (23 mg, 59%). MS(ES)+ m/e 472.2 [M+H]+.
Reaction SMILES: C1(C[O:8][CH2:9][C@H:10]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:20]([O:21]CC3C=CC=CC=3)[C@@H:11]2[O:12]CC2C=CC=CC=2)C=CC=CC=1>CO.C(O)(=O)C.[Pd]>[CH2:31]([OH:32])[C@H:29]1[O:30][C@H:10]([CH2:9][OH:8])[C@@H:11]([OH:12])[C@@H:20]1[OH:21]
Reactant: OC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: OC[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
In accordance with Flowchart E, 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-mannose 29 is reacted with lithium aluminum hydride in ether at reflux temperature under argon, giving 2,5-anhydro-1,3,4-tris-O-(phenylmethyl)-D-mannitol 38. Compound 38 is hydrogenated in methanol/acetic acid over palladium on carbon, giving 2,5-anhydro-D-mannitol 39, which is then reacted with diphenyl phosphorochloridate in pyridine at reduced temperature, giving the product of Formula I where R', R",R'" and R"" are phenyl, 2,5-anhydro-D-mannitol, 1,6-bis(diphenyl phosphate) 40. Compound 40 is hydrogenated in methanol over platinum oxide, giving the product of Formula I where R', R",R'" and R"" are hydrogen, 2,5-anhydro-D-mannitol, 1,6-bis(dihydrogen phosphate) 41. Compounds 40 and 41 are disclosed in Voll et al., Carbohydrate Research, 95, 145-154 (1981), but are prepared by a different process. Substituting other phosphorylating agents in the reaction from 39 to 40, as described in Flowchart A, will result in the corresponding tetraesters and mixed tetraesters. ##STR18##
Reaction SMILES: Cl[Si](C)(C)C=C[Si](Cl)(C)C.[Cl:11][CH:12]([Cl:22])[CH2:13][SiH2:14][CH:15]=[CH:16][SiH2:17][CH2:18][CH:19]([Cl:21])[Cl:20]>>[Cl:21][CH:19]([Cl:20])[CH2:18][SiH2:17][CH2:16][CH2:15][SiH2:14][CH2:13][CH:12]([Cl:11])[Cl:22]
Reactant: ClC(Cl)C[SiH2]C=C[SiH2]CC(Cl)Cl
Agent: C[Si](C)(Cl)C=C[Si](C)(C)Cl
Product: ClC(Cl)C[SiH2]CC[SiH2]CC(Cl)Cl

Procedure:
Example 1 was repeated with the modification that, instead of 300.0 g (1.41 mol) of 1,2-bis(chlorodimethylsilyl)ethene, 300.0 g (1.06 mol) of 1,2-bis(dichloroethylsilyl)ethene were used. The results are summarized in Table 1.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1.[NH:9]1[C:17]2[C:12](=[C:13]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)[CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[CH3:35][CH:33]([CH3:34])[C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([CH:22]2[CH2:23][CH2:24][N:19]([CH2:18][C:13]3[CH:14]=[CH:15][CH:16]=[C:17]4[C:12]=3[CH:11]=[CH:10][N:9]4[C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=3)[CH2:20][CH2:21]2)[CH:26]=1)=[O:36]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Cc1cccc(I)c1
Product: Cc1cccc(-n2ccc3c(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)cccc32)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-iodo-3-methylbenzene and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 466.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]([CH3:16])([CH3:15])[CH2:13]O>ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH2:13][C:12]([CH3:16])([CH3:15])[N:11]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Product: CC1(C)COC(c2ccc(Br)cc2)=N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-Bromobenzoyl chloride (20.02 g, 91 mmol) was dissolved in dichloromethane (180 ml) and added dropwise to a solution of 2-amino-2-methyl-1-propanol (19.20 g, 216 mmol) in dichloromethane (90 ml) at ambient temperature. The mixture was stirred for 24 hours at ambient temperature, followed by filtration and removal of the solvent at reduced pressure. Thionyl chloride (90 ml) was added dropwise and the mixture was stirred for 30 minutes at ambient temperature. Excess thionyl chloride was removed at reduced pressure and the residue was added to an aqueous HCl-solution (5%, 500 ml). The solution was washed with ether (2×100 ml) and aqueous NaOH (50%) was added to pH 9. The basic solution was extracted with ether (3×100 ml), and the combined ether solution was washed with water (50 ml) and saturated aqueous NaCl-solution. The dried (MgSO4) ether solution was evaporated and the title compound isolated by distillation. Yield 14.14 g (61%), b.p. 128-130° C. (1 mm Hg).
Reaction SMILES: [NH2:1][C:2](=[S:16])[C:3]1[CH:4]=[C:5]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[S:6][C:7]=1[CH2:8][CH3:9].[C:17]([C:19]1C=C(C(OC(C)C)=O)SC=1CC)#N>>[CH2:8]([C:7]1([CH2:17][CH3:19])[S:6][CH:5]([C:10]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11])[CH:4]=[C:3]1[C:2]([NH2:1])=[S:16])[CH3:9]
Reactant: CCc1sc(C(=O)OC(C)C)cc1C#N
Reactant: CCc1sc(C(=O)OC(C)C)cc1C(N)=S
Product: CCC1(CC)SC(C(=O)OC(C)C)C=C1C(N)=S
Yield: 74 %

Procedure:
Isopropyl 4-(aminothioxomethyl)-5-ethylthiophene-2-carboxylate: A stirred solution of 1.7 g (7.6 mmol) of isopropyl 4-cyano-5-ethylthiophene-2-carboxylate was treated as in Example 139, step (c) to give isopropyl 5-ethyl-4-(aminothioxomethyl)-5-ethylthiophene-2-carboxylate (1.45 g, 74%) as a yellow solid. 1H-NMR (DMSO-d6; 300 MHz) δ 9.93 (br s, 1H), 9.39 (br s, 1H), 8.04 (s, 1H), 5.08 (septet, 1H, J=6.2 Hz), 3.08 (q, 2H, J=7.5 Hz), 1.29 (d, 6H, J=6.2 Hz), 1.24 (t, 3H, J=7.5 Hz).
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.Cl[Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)C.O>[Cl:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])=[CH:5][CH:4]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: C[Si](C)(Cl)CCCCCl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: C[Si](C)(CCCCCl)Cc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
In a 500 ml glass reactor fitted with a mechanically driven stirrer, thermometer, nitrogen inlet, dropping funnel and water-cooled reflux condenser was charged 7.9 g magnesium chip. Via the dropping funnel was added a solution of 47.5 g 4-chlorobenzyl chloride in 200 ml diethyl ether with stirring over a period of 1/2 an hour. After the addition was complete, the reaction was refluxed for 1/2 hour, then cooled to room temperature. To the Grignard reagent was added a solution of 31.0 g chlorodimethyl-4-chloro-n-butylsilane (Petrarch Systems Inc., Bristol, PA) in 50 ml ether. The reaction mixture was refluxed for 1 hour after the addition was complete, then cooled to room temperature. A solution of 10 g citric acid in 200 ml water was added to hydrolyze the reaction. The organic layer was separated, dried over magnesium sulfate and the solvent removed at room temperature under vacuum. Low boiling impurities were removed by distillation at 150° C. under 15 mm vacuum. The residue was a yellow oil. Vapor phase chromatography showed the compound to be about 95 percent pure. Its NMR spectrum was consistent with the expected compound.
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[C:7]([F:26])=[CH:8][C:9](N)=[C:10]([CH:24]=1)[O:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:4])[CH3:3].N([O-])=O.[Na+]>[Cu]Cl.O.COC(C)(C)C>[C:2]([NH:5][C:6]1[C:7]([F:26])=[CH:8][C:9]([Cl:1])=[C:10]([CH:24]=1)[O:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:4])[CH3:3]
Reactant: Cl
Reactant: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1N
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)COc1ccccc1Oc1cc(NC(C)=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 30 ml of conc. hydrochloric acid was added 2.0 g of methyl [2-(5-acetylamino-2-amino-4-fluorophenoxy)phenoxy]acetate, and the mixture was stirred for 1 hour at room temperature. Thereafter, a mixture of 0.42 g of sodium nitrite and 3 ml of water was added under ice cool. The mixture was stirred for 1 hour under the same condition, then, 40 ml of t-butyl methyl ether was added, then, 0.85 g of copper (I) chloride was added. The mixture was stirred for 30 minutes, then, water was added to this, and extracted with t-butyl methyl ether, and the organic layer was washed with water, dried over magnesium sulfate and concentrated, and the resulted residue was purified by column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain 0.52 g of methyl [2-(5-acetylamino-2-chloro-4-fluorophenoxy)phenoxy]acetate.
Reaction SMILES: [NH2:1][C:2]([CH3:15])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[S:23])=[CH:20][CH:19]=1>>[N:7]1[N:6]([CH2:5][C:2]([NH:1][C:22](=[S:23])[C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:27])[F:28])=[CH:26][CH:25]=2)([C:3]#[N:4])[CH3:15])[N:10]=[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=12
Reactant: CC(N)(C#N)Cn1nc2ccccc2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1nc2ccccc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 5, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (0.12 g, 59%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=406. 1H NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 5.39-5.50 (m, 2H), 7.46 (dd, J=6.6, 3.1 Hz, 2H), 7.85-7.95 (m, 6H) and 9.01 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][C:24]=1[NH:25][CH3:26])[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].[C:27]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=O)=[CH:31][CH:30]=1)#[N:28]>O1CCCC1.C(O)(=O)C>[CH2:20]([O:19][C:17]([CH2:16][CH2:15][C:7]1[N:6]([CH2:5][C:4]2[CH:22]=[CH:23][C:24]3[N:25]([CH3:26])[C:36]([CH2:35][C:32]4[CH:31]=[CH:30][C:29]([C:27]#[N:28])=[CH:34][CH:33]=4)=[N:1][C:2]=3[CH:3]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=1)=[O:18])[CH3:21]
Reactant: N#Cc1ccc(CC(=O)O)cc1
Reactant: CCOC(=O)CCc1nc2ccccc2n1Cc1ccc(NC)c(N)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1nc2ccccc2n1Cc1ccc2c(c1)nc(Cc1ccc(C#N)cc1)n2C

Procedure:
Prepared analogously to Example 24f from ethyl 3-[1-(3-amino-4-methylamino-benzyl)-1H-benzimidazol-2-yl]-propionate, 4-cyanophenylacetic acid and N,N'-carbonyldiimidazole in tetrahydrofuran, glacial acetic acid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](I)[CH:7]=1.[Cl-].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][Zn+])=[CH:15][CH:14]=1.O.C(OCC)(=O)C>C1COCC1.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>[F:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: N#Cc1ncc(I)cc1F
Reactant: Fc1ccc(C[Zn+])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ncc(Cc2ccc(F)cc2)cc1F
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a solution of 3-fluoro-5-iodo-2-pyridinecarbonitrile(2.31 g, 9.3 mmol) in THF (100 mL) was added 4-fluorobenzyl zinc chloride (27.9 mL, 0.5 M in THF, 14.0 mmol) followed by Pd(PPh3)4 (538 mg, 0.47 mmol). The resultant solution was heated at 75° C. (bath temperature) for 3 hours. After cooling to room temperature, water and ethyl acetate were added. The layers were separated and the organic layer was washed with brine. The aqueous layer was acidified with 1 N HCl until it cleared and extracted with ethyl acetate. The combined organics were dried over sodium sulphate. Filtration and concentration followed by purification by silica gel chromatography provided 3-fluoro-5-[(4-fluorophenyl)methyl]-2-pyridinecarbonitrile (1.6 g, 75%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1 H), 7.28 (d, J=8.8 Hz, 1 H), 7.12 (dd, J=8.4, 5.2 Hz, 2 H), 7.03 (t, J=8.4 Hz, 2 H), 4.04 (s, 2 H). MS m/z 231 (M+1).