Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=CN[C:6]=1[CH2:7]SCCN.CSC(SC)=C[N+]([O-])=O.[N+:21]([CH:24]=[C:25](SC)[NH:26][CH2:27][CH2:28][S:29][CH2:30][C:31]1[NH:35][CH:34]=[N:33][C:32]=1[Br:36])([O-:23])=[O:22].C(N)C#C>>[N+:21]([CH:24]=[C:25]([NH:3][CH2:2][C:6]#[CH:7])[NH:26][CH2:27][CH2:28][S:29][CH2:30][C:31]1[NH:35][CH:34]=[N:33][C:32]=1[Br:36])([O-:23])=[O:22]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1Br
Reactant: NCCSCc1[nH]cnc1Br
Agent: C#CCN
Agent: CSC(=C[N+](=O)[O-])SC
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1Br

Procedure:
When 2-[(4-bromo-1H-imidazol-5-yl)methylthio]ethylamine (prepared according to the procedure described in Belgian Patent 779,775) is reacted with 1,1-bis(methylthio)-2-nitroethylene according to the procedure of Example 6, Step A, and the resultant 1-nitro-2-methylthio-2-{2-[(4-bromo-1H-imidazol-5-yl)methylthio]ethylamino}ethylene is treated with propargylamine by the procedure of Example 6, Step B, the title compound is produced.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:11])[CH:3]=1.[CH2:12]([NH:14][CH2:15][CH3:16])[CH3:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:14]([CH2:15][CH3:16])[CH2:12][CH3:13])=[O:8])=[C:4]([F:11])[CH:3]=1
Reactant: CCNCC
Reactant: O=C(O)c1ccc(Br)cc1F
Product: CCN(CC)C(=O)c1ccc(Br)cc1F

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-fluorobenzoic acid and N-ethyl-ethanamine.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=CC=[C:12]([C:13]3[CH:18]=CC=CC=3OC)[N:6]2[N:5]=1)=O.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:40][CH3:41])=[C:26]([C:28]2[N:36]3[C:31]([CH:32]=[N:33][C:34](S(C)=O)=[N:35]3)=[CH:30][CH:29]=2)[CH:27]=1>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([O:40][CH3:41])=[C:26]([C:28]2[N:36]3[C:31]([CH:32]=[N:33][C:34]([N:5]4[C:18]5[CH:13]=[CH:12][N:6]=[CH:7][C:8]=5[N:9]=[CH:4]4)=[N:35]3)=[CH:30][CH:29]=2)[CH:27]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1ccc(Cl)cc1-c1ccc2cnc(S(C)=O)nn12
Product: COc1ccc(Cl)cc1-c1ccc2cnc(-n3cnc4cnccc43)nn12

Procedure:
The compound was made in an analogous fashion to Example 322 replacing 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine with 7-(5-Chloro-2-methoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine to afford 67.32 mg of 1-[7-(5-Chloro-2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-1H-imidazo[4,5-c]pyridine as a lyophilized powder. (M+H)=377.6. 1H NMR (400 MHz, DMSO, d6) δ 9.38 (s, 1H), 9.17 (s, 1H), 8.50 (m, 1H), 8.21 (m, 1H), 8.07 (m, 1H), 7.41 (m, 1H), 7.36 (m, 1H), 7.32 (m, 3H), 3.85 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[F:29][C:27]([F:28])([F:30])[C:23]1[CH:22]=[C:21]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][O:15][C:12]2[CH:13]=[C:14]3[C:9]([CH:8]=[CH:7][N:6]3[CH2:5][C:4]([OH:31])=[O:3])=[CH:10][CH:11]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)Cn1ccc2ccc(OCCCC#Cc3cccc(C(F)(F)F)c3)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCCCC#Cc3cccc(C(F)(F)F)c3)cc21

Procedure:
In analogy to the procedure described for example 1 e], {6-[5-(3-trifluoromethyl-phenyl)-pent-4-ynyloxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as off-white crystals.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([C:12]#[N:13])[CH:5]=1.[Li+].[BH4-]>C1COCC1>[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:8][CH:9]=1)[C:10]#[N:11]
Reactant: COC(=O)c1ccc(C#N)c(C#N)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CO)cc1C#N
Temperature: 70 °C

Procedure:
3,4-Dicyano-benzoic acid methyl ester from step 1 (2.4 g, 12.9 mmol ) was dissolved in THF (65 ml). LiBH4 in THF (2M, 12.9 ml, 25.8 mmol) was added. The reaction mixture was heated to 70° C. for 3 hours. The reaction was quenched carefully with 3N HCl and then extracted with EtOAc (3×20 mL). The organic layers were combined, washed with brine, dried (MgSO4), filtered and concentrated to yield the desired product. FAB MS: 159 m/z (M+ +H)
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:19][NH2:20]>O1CCCC1>[CH3:19][NH:20][S:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=2)=[CH:10][CH:11]=1)(=[O:17])=[O:16]
Reactant: CN
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccncc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(Oc2ccncc2)cc1

Procedure:
A suspension of 35 g of [4-(4-pyridinyloxy) benzenesulfonyl chloride hydrochloride in 800 ml of tetrahydrofuran was added slowly to 163 ml of 2 M methylamine in tetrahydrofuran. An additional 550 ml of tetrahydrofuran was added and the suspension refluxed for 3 hours. The solvent was removed under vacuum and the residue partitioned between CH2Cl2 and H2O. The organic layer was separated, washed with saturated NaHCO3, brine and dried (Na2SO4). The solvent was removed to give 13.11 g of N-methyl-4-(pyridin-4-yloxy)benzenesulfonamide, m.p. 125-127° C. The aqueous layer was neutralized with 1 N NaOH (solid precipitated) and extracted with CH2Cl2. The extract was washed with brine and dried (Na2SO4). The solvent was removed to give an additional 15.9 g of N-methyl-4-(pyridin-4-yloxy)benzenesulfonamide. A 2.80 g (10.6 mmol) portion of the preceding compound was added to a stirred suspension of 0.424 g (10.6 mmol) of sodium hydride (60% in oil) in 20 ml of dry 1-methylpyrrolidinone. The mixture was stirred until gas evolution ceased and 2.8 g (10.0 mmol) of ethyl 4-chloro-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate was added followed by the addition of 20 ml of dry 1-methylpyrrolidinone. The mixture was heated at 80-90° C. for 58 hours. The solvent was removed under vacuum and the residue extracted with ethyl acetate (100 ml) and the extract washed with 100 ml of H2O. The extract was stirred with 40 ml of 1 N HCl for 1 hour and the aqueous layer separated and neutralized (pH 6-7) with 1 N NaHCO3. The mixture was extracted with ethyl acetate and the extract washed with H2O, brine and dried (Na2SO4). The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with ethyl acetate. The filtrate was concentrated to dryness and the residue crystallized with ethyl acetate-hexane to give 3.43 g of ethyl 4-{methyl-[4-(4-pyridinyloxy)benzenesulfonyl] amino}-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate as pale yellow crystals, m.p. 117-119° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>O.ClCCCl>[CH3:30][N:31]1[CH2:36][CH2:35][CH:34]([N:27]2[CH2:28][CH2:29][CH:24]([N:16]3[C:17]4=[N:18][CH:19]=[N:20][C:21]([NH2:23])=[C:22]4[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)=[N:15]3)[CH2:25][CH2:26]2)[CH2:33][CH2:32]1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CN1CCC(N2CCC(n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
3-(4-phenoxyphenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 2) (199 mg, 0.515 mmol), 1-methyl-4-piperidone(70 ul, 0.566 mmol), sodium triacetoxyborohydride (163 mg, 0.772 mmol) and glacial acetic acid(34 mg, 0.566 mmol) were mixed with 3 ml of 1,2-dichloroethane. After stirring at room temperature overnight, 2 ml of water was added followed by solid sodium bicarbonate until the pH reached about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed, dried and evaporated. The residue was purified via flash column chromatography to give 92 mg of 1-[1-(1-methyl-4-piperidinyl)-4-piperidinyl](4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO) 1.47 (m, 2H), 1.72 (d, J=1 1.75 Hz, 2H), 1.88 (m, 4H), 2.14 (s, 3H), 2.35 (m, 5H), 2.81(d, J=11.32 Hz, 2H), 3.01(d, J=11.26 Hz, 2H), 4.62 (m, 1H), 7.16 (m, 5H), 7.44 (m, 2H), 7.67 (d, J=8.69 Hz, 2H), 8.23 (s, 1H); LC/MS (MH+32 484).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]([F:18])([F:17])[CH2:15][OH:16].[CH2:19]([N:26]1[CH:30]=[C:29]([CH2:31][C@@H:32]([C:41](O)=[O:42])[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:28]([N+:44]([O-:46])=[O:45])=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C1C=CN=CC=1.ClCCl>[CH2:19]([N:26]1[CH:30]=[C:29]([CH2:31][C@@H:32]([C:41]([O:16][CH2:15][C:14]([F:18])([F:17])[F:13])=[O:42])[NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C:28]([N+:44]([O-:46])=[O:45])=[N:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nc1[N+](=O)[O-])C(=O)O
Reactant: OCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cn(Cc2ccccc2)nc1[N+](=O)[O-])C(=O)OCC(F)(F)F
Reaction time: 18 h

Procedure:
1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (98%, 361 mg, 1.85 mmol), 4-(dimethylamino)pyridine (97%, 116 mg, 0.921 mmol) and 2,2,2-trifluoroethanol (99%, 1.36 mL, 18.5 mmol) were added to a solution of C7 (0.36 g, 0.92 mmol) in dichloromethane (30 mL), and the reaction mixture was allowed to stir for 18 hours. The reaction was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% EtOAc in heptane) afforded C8 as a solid. Yield: 223 mg, 0.472 mmol, 51%. LCMS m/z 471.1 (M−1). 1H NMR (400 MHz, CDCl3) δ 1.37 (s, 9H), 3.24 (br dd, half of ABX pattern, J=14.7, 7.9 Hz, 1H), 3.35 (dd, half of ABX system, J=15.0, 5.7 Hz, 1H), 4.42-4.52 (m, 2H), 4.59 (br ddd, J=8, 8, 6 Hz, 1H), 5.13 (br d, J=8 Hz, 1H), 5.31 (s, 2H), 7.26-7.32 (m, 3H), 7.36-7.42 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:25]([N:32]1[CH2:37][CH2:36][CH:35](O)[CH2:34][CH2:33]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:12][CH:35]2[CH2:34][CH2:33][N:32]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:37][CH2:36]2)=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(OC1CCN(Cc2ccccc2)CC1)c1ccc([N+](=O)[O-])cn1
Reaction time: 3 h
Yield: 41 %

Procedure:
5.0 g (0.03 mol) of 5-nitro-picolinic acid (Pharmazie 38 (1983), p. 593) and 4.87 g (0.03 mol) of carbonyidiimidazole were dissolved in 250 ml of THF and stirred at 60° for 3 hours. The mixture was subsequently treated with 5.75 g (0.03 mol) of 1-benzyl-4-hydroxy-piperidine, stirred at 0°-5° for 18 hrs., at room temperature for 3 hrs. and subsequently at 40° for 2 hrs. The reaction mixture was completely freed from solvent and the residue was chromatographed over neutral Alox (grade II) with dichloromethane as the eluent and recrystallized from ethyl acetate. 4.2 g (41%) of 1-benzyl-piperidin-4-yl 5-nitro-picolinate were obtained as yellow crystals; m.p. 175°-176°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])=[CH:3][CH:2]=1.C(C1C=CN=CC=1)(=O)C.[NH2:25][C:26]1[C:30]([C:31]#[N:32])=[CH:29][NH:28][N:27]=1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[N:27]3[N:28]=[CH:29][C:30]([C:31]#[N:32])=[C:26]3[N:25]=2)=[CH:3][CH:2]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccncc1
Reactant: N#Cc1c[nH]nc1N
Agent: CC(=O)c1ccncc1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccncc3)nc12
Yield: 38 %

Procedure:
Reaction of 1-pyridin-4-yl-4,4,4-trifluoro-butane-1,3-dione (217 mg, 1.0 mmol), prepared from commercially available 4-acetylpyridine according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (110 mg, 38%). MS (ISP) 289.8 [(M+H)+]; mp 233° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2=[N:8][C:9]3[CH2:15][CH2:14][CH2:13][C:10]=3[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(CC)=O>[C:22]1([CH2:21][O:1][C:2]2[C:7]3=[N:8][C:9]4[CH2:15][CH2:14][CH2:13][C:10]=4[C:11](=[O:12])[N:6]3[CH:5]=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: O=c1c2c(nc3c(O)cccn13)CCC2
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCC(C)=O
Product: O=c1c2c(nc3c(OCc4ccccc4)cccn13)CCC2
Reaction time: 18 h

Procedure:
A suspension of 2,3-dihydro-5-hydroxycyclopenta[d]pyrido[1,2-a]pyrimidin-10(1H)-one prepared as described in Example 1, (6.1 g), 9.9 g of anhydrous potassium bicarbonate, 6.2 g of benzyl bromide, and 300 ml of ethyl methyl ketone is stirred and slowly heated to reflux. Stirring and heating under reflux is continued for 18 hours. The hot solution is filtered to remove inorganic salts and the ethyl methyl ketone filtrate is concentrated in vacuo to give 10.0 g of crude product; this, when recrystallized from 1000 ml of cyclohexane, and the crystalline solid dried at 78° for 2 hours, gives 6.0 g of product, mp 150°-152°.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]([CH3:68])([O:10]/[N:11]=[C:12](/[C:43]1[N:44]=[C:45]([NH:48][C:49]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=2)([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[S:46][CH:47]=1)\[C:13]([NH:15][CH:16]1[C:41](=[O:42])[N:18]2[C:19]([C:25]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])=[C:20]([CH2:23][Cl:24])[CH2:21][S:22][C@H:17]12)=[O:14])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:77])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([C:8]([CH3:68])([O:10]/[N:11]=[C:12](/[C:43]1[N:44]=[C:45]([NH:48][C:49]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[S:46][CH:47]=1)\[C:13]([NH:15][CH:16]1[C:41](=[O:42])[N:18]2[C:19]([C:25]([O:27][CH:28]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:26])=[C:20]([CH2:23][Cl:24])[CH2:21][S:22](=[O:77])[C@H:17]12)=[O:14])[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 0.33 h

Procedure:
10 g (10.3 mmol) of benzhydryl 7-[(Z)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem- 4-carboxylate was dissolved in 200 ml of methylene chloride, and 1.78 g (10.3 mmol) of m-chloroperbenzoic acid was added under cooling with ice in 10 minutes. The mixture was further stirred for 20 minutes. To the reaction solution, 40 ml of a 10% sodium thiosulfate aqueous solution was added for extraction. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a powder of the above-identified compound.
Reaction SMILES: [Cl:1][C:2]1[C:46]([Cl:47])=[CH:45][CH:44]=[CH:43][C:3]=1[CH2:4][N:5]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:6](=[O:37])[CH:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]2[C:33]([Cl:34])=[CH:32][C:31]([CH3:35])=[CH:30][C:29]=2[Cl:36])=[CH:20][CH:19]=1)[CH2:8][NH:9]C(=O)OC(C)(C)C.Cl>C(Cl)Cl>[NH2:9][CH2:8][CH:7]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][C:28]2[C:29]([Cl:36])=[CH:30][C:31]([CH3:35])=[CH:32][C:33]=2[Cl:34])=[CH:20][CH:19]=1)[C:6]([N:5]([CH2:4][C:3]1[CH:43]=[CH:44][CH:45]=[C:46]([Cl:47])[C:2]=1[Cl:1])[CH2:38][C:39]([F:42])([F:41])[F:40])=[O:37]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)C(=O)N(Cc3cccc(Cl)c3Cl)CC(F)(F)F)cc2)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CN)C(=O)N(Cc3cccc(Cl)c3Cl)CC(F)(F)F)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a CH2Cl2 solution (0.05 M) of tert-butyl (3-[(2,3-dichlorobenzyl)(2,2,2-trifluoroethyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (1 eq.) was added HCl (4 M dioxane solution, 20 eq.). The resulting solution was stirred at RT for 13 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 95:5 (v/v) CH2Cl2: 2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound as a colorless oil. MS (ESI+): 638.2.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3(O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:5]([CH3:24])[O:4][N:3]=1.N1C=CC=CC=1.O=S(Cl)[Cl:33]>C1COCC1>[Cl:33][C:10]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:24])[CH:8]=2)[NH:12][C:11]1=[O:16]
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccccc1)C(=O)N2
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1noc(C)c1-c1ccc2c(c1)C(Cl)(c1ccccc1)C(=O)N2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 5-(3,5-dimethylisoxazol-4-yl)-3-hydroxy-3-phenylindolin-2-one (30 g, 0.094 mol) in THF (300 mL) was added pyridine (40 mL) followed by SOCl2 (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h and quenched by the addition of saturated ammonium chloride solution (50 mL). The organic layer was washed with saturated ammonium chloride (2×50 mL). The combined aqueous layers were extracted with CH2Cl2 (200 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford target compound (25 g, 79%). 1H NMR (400 MHz, DMSO-d6): δ 11.11 (s, 1H), 7.37-7.53 (m, 6H), 7.08 (d, J=8.0 Hz, 1H), 2.30 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=2)=[CH:14][CH:15]=1
Reactant: CN(CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (300 mg, 0.759 mmol, 1 eq) was dissolved in dry DCM (3 ml) under argon atmosphere and TFA (290.6 μl, 5 eq) was added. Reaction mixture was stirred for overnight. In the reaction mixture was added more DCM (15 ml) and was extracted with saturated NaHCO3 (3×15 ml) and brine. Organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give a product methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-amine (211.5 mg, yield=82.1%, purity=87%). [M+H]+=296.31 1H NMR (300 MHz; CDCl3) δ/ppm 2.44 (s, 3H), 2.74-2.89 (m, 4H), 6.90-6.98 (m, 2H), 7.09-7.22 (m, 4H), 7.27-7.33 (m, 1H), 7.35-7.45 (m, 1H)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:16][O:17][C:18](=[O:34])[CH:19]([CH:29]1[CH2:33][CH2:32][CH2:31][NH:30]1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=1>>[CH3:16][O:17][C:18](=[O:34])[CH:19]([CH:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:15][CH:14]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[N:28])[CH:22]=1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: COC(=O)C(Cc1cccc(C#N)c1)C1CCCN1
Product: COC(=O)C(Cc1cccc(C#N)c1)C1CCCN1C(=O)c1ccc(-c2cccnc2)cc1
Yield: 80 %

Procedure:
4-Pyridin-3-ylbenzoic acid (0.83 g, 3.5 mmol) and 3-(3-cyanophenyl)-2-(pyrrolidin-2-yl)-propionic acid methyl ester (0.91 g, 3.5 mmol) are coupled as described in EXAMPLE 1B to give the title compound (1.22 g, 2.8 mmol). 1H NMR (CDCl3, 300 MHz) □ 8.98(s, 1H), 8.75(d, 1H), 8.58(d, 1H), 8.03(m, 1H), 7.85-7.60(m, 4H), 4.72-4.45(two m, 1H), 3.80-3.71(m, 1H), 3.68, 3.62(two s, 3H), 3.63-3.40(m, 2H), 3.21-3.10(m, 1H), 2.90-2.78(m, 1H), 2.20-2.05(m, 1H), 2.02-1.50(m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Li+].[CH3:11]C([N-]C(C)C)C.IC>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][CH3:11])[N:3]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of 2,4-dichloro-6-methylpyrimidine (4.0 g) in 90 mL THF was cooled to −78 C and treated dropwise with LDA (2 M, 14.7 mL). After 35 min, iodomethane (1.55 mL) was added and the reaction was stirred for 3 more hours at −78 C. The reaction was allowed to slowly warm to room temperature, then quenched with 0.5 mL of water. The mixture was dissolved in water and extracted with ethyl acetate. Chromatography (30% ethyl acetate in hexanes) provided 1.64 g of 2,4-Dichloro-6-ethylpyrimidine.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH:10]([Cl:13])(Cl)[Cl:11].[OH-].[Na+]>[Cl-].C[N+](C)(C)C.O>[Cl:11][C:10]1([Cl:13])[CH2:3][CH:2]1[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: ClC(Cl)Cl
Reactant: C=CC(=O)OC(C)(C)C
Agent: C[N+](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)C1CC1(Cl)Cl
Yield: 30.3 %

Procedure:
Tert-butyl acrylate (32 g, 0.25 mol), CHCl3 (318 g, 3 mol), tetramethyl ammonium chloride (0.75 g, 0.0050 mol) and 50% aqueous NaOH (300 mL) were stirred at 45-50° C. for 8 hours. The mixture was diluted with water (400 mL) and the organic layer was separated. The aqueous layer was extracted with CHCl3 (75 mL). The combined organic extracts were washed with 1N HCl (200 mL) and water (250 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was distilled to give tert-butyl 2,2-dichlorocyclopropanecarboxylate as colorless oil (16 g, yield: 30%). 1H-NMR (500 MHz, CDCl3,): δ 2.48 (m, 1H), 2.00 (m, 1H), 1.81 (m, 1H), 1.52 (s, 9H).