Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C.C(OCC)C>O1CCCC1>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:3]([F:10])[CH:4]=1
Reactant: Fc1cc(Br)c(F)cc1Cl
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc(F)c(Cl)cc2F)OC1(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
1-Bromo-4-chloro-2,5-difluorobenzene (1.11 g, 4.9 mmol) was dissolved in tetrahydrofuran (THF; 15 mL) and cooled to −10° C. A 2.0M solution of isopropyl-magnesium chloride (2.7 mL, 5.4 mmol) in THF was added dropwise via a syringe. The reaction mixture was stirred at −10° C. for 1 hour, allowed to warm toward 0° C. for 1 hour, then cooled to −10° C. again. A solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.0 g, 5.4 mmol) in THF (1.0 mL) was then added dropwise and the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to diethyl ether and extracted with 1N sodium hydroxide twice. The aqueous phases were combined, acidified to pH 3 with concentrated HCl, and extracted with dichloromethane twice. The organic phases were combined, dried, filtered and concentrated to give the title compound (0.97 g, 72.3% yield) that was used without further purification: 1H NMR (CDCl3): δ 7.45 (dd, 1H), 7.09 dd, 1H), 1.36 (s, 12H).
Reaction SMILES: Cl[Si:2]([CH3:8])([CH3:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[Br:9][C:10]1[CH:44]=[CH:43][C:13]([C:14]([CH:16]([N:18]2[C:22](=[O:23])[N:21]([C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][N:33]([C:36]5[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=5)[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[CH:20]=[N:19]2)[CH3:17])=[O:15])=[CH:12][CH:11]=1>ClCCl.N1C=CC=CC=1>[Br:9][C:10]1[CH:44]=[CH:43][C:13]([C:14]([CH:16]([N:18]2[C:22](=[O:23])[N:21]([C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH2:31][CH2:32][N:33]([C:36]5[CH:41]=[CH:40][C:39]([O:42][Si:2]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:8])[CH3:7])=[CH:38][CH:37]=5)[CH2:34][CH2:35]4)=[CH:28][CH:29]=3)[CH:20]=[N:19]2)[CH3:17])=[O:15])=[CH:12][CH:11]=1
Reactant: CC(C(=O)c1ccc(Br)cc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C(=O)c1ccc(Br)cc1)n1ncn(-c2ccc(N3CCN(c4ccc(O[Si](C)(C)C(C)(C)C)cc4)CC3)cc2)c1=O
Yield: 45.3 %

Procedure:
A solution of 2-(chlorodimethylsilyl)-2-methylpropane (0.011 mol) in dichloromethane (20 ml) was added to a stirred solution of 2-[1-(4-bromobenzoyl)ethyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.009 mol) in pyridine (20 ml) under a nitrogen atmosphere. Stirring was continued for 1 week at room temperature. The reaction mixture was evaporated and the residue was dissolved in dichloromethane. This solution was purified over silica gel on a glass filter (eluent: dichloromethane). The pure fractions were collected and the solvent was evaporated. The residue (3.5 g) was recrystallized from ethyl acetate. The product was filtered off and dried, yielding 2.7 g (45 %) of 2-[1-(4-bromobenzoyl)ethyl]-4-[4-[4-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; mp. 177.8° C. (comp. 47).
Reaction SMILES: C(O[C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(C)C.[CH3:19][C:20]([NH2:29])([CH3:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C>[CH3:28][C:20]([NH:29][C:5]1[C:6](=[O:18])[C:7](=[O:17])[C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)([CH3:19])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(-c2c(OC(C)C)c(=O)c2=O)cc1
Reactant: CC(C)(N)Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2c(NC(C)(C)Cc3ccccc3)c(=O)c2=O)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of 3-isopropoxy-4-(4-methoxy-phenyl)-cyclobut-3-ene-1,2-dione (0.150 g, 0.609 mmol) in ethanol (3 mL) was added 1,1-dimethyl-2-phenyl-ethylamine (0.182 g, 1.22 mnol). The mixture was stirred at 70° C. overnight then filtered hot through a pad of silica gel. The filtrate was concentrated and the resulting residue was recrystallized from ethyl acetate/hexanes to give 0.170 g (83%) of the title product as a tan solid: m.p. 150-151° C.; 1H NMR (DMSO-d6)δ8.28(s,1H), 8.00(m,2H), 7.28(m,2H), 7.26(m,1H), 7.13(m,2H), 7.09(m,2H), 3.82(s,3H), 3.10(s,2H), 1.42(s,6H); IR (KBr) 3420, 2950, 1775, 1715, 1650, 1570, 1410, 1252, 1200, 1045, 850, 740, 700, 602, 530 cm−1; MS (m/z) 335 [M+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][C@H:26]1[O:31][C:30]2([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[O:29][C@@H:28]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:23]([CH2:24][CH2:25][C@H:26]3[O:31][C:30]4([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[O:29][C@@H:28]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:27]3)[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:9]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC2(CCCCC2)O1
Reactant: CC(C)C(=O)CC(C(=O)c1ccc(F)cc1)c1ccccc1
Product: CC(C)c1cc(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@H](CC(=O)OC(C)(C)C)OC2(CCCCC2)O1

Procedure:
According to the same method as in Example 4-1, the title compound was synthesized using 1-(4-fluorophenyl)-5-methyl-2-phenyl-1,4-hexanedione and t-butyl 2-((2R,4R)-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[C:26]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([S:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:7])[N:9]=1)#[N:27]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Sc3ccccc3)cc2c1O
Reactant: NCC(=O)O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Sc3ccccc3)ccc12

Procedure:
The title compound was synthesized from 1-Cyano-4-hydroxy-6-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=377.9.
Reaction SMILES: [C:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]([C:15]1[S:16][CH:17]=[C:18]([CH2:20]SCCC(=N)OC)[N:19]=1)[C:12]([NH2:14])=[NH:13]>CO>[C:1]1([S:7]([NH:10][C:1](=[S:7])[CH2:2][CH2:3][CH2:20][C:18]2[N:19]=[C:15]([NH:11][C:12]([NH2:14])=[NH:13])[S:16][CH:17]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Reactant: NS(=O)(=O)c1ccccc1
Solvent: CO
Product: N=C(N)Nc1nc(CCCC(=S)NS(=O)(=O)c2ccccc2)cs1

Procedure:
In 8 ml of methanol were dissolved 800 ml of methyl 3-[(2-guanidinothiazol-4-yl)methylthio]propionimidate and 590 mg of benzenesulfonamide and after causing reaction for 24 hours at room temperature, the solvent was distilled off under reduced pressure. The residue formed was purified by a silica gel column chromatography using a mixture of chloroform and methanol (20:1→10:1) to provide 855 mg of amorphous N-benzenesulfonyl-3-(2-guanidinothiazol-4-yl)methylthio propionamide. The product shows the following physicochemical properties:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)[CH:18]=[CH:17][N:16]=1>CN(C=O)C>[F:30][C:27]([F:28])([F:29])[C:24]1[CH:23]=[CH:22][C:21]([C:19]2[CH:20]=[CH:15][N:16]=[C:17]([O:1][C:2]3[CH:11]=[C:10]4[C:5]([CH:6]=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)[CH:18]=2)=[CH:26][CH:25]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2ccnc(Oc3ccc4cccnc4c3)c2)cc1
Temperature: 155 °C
Reaction time: 0.17 h

Procedure:
To an oven-dried, 50-mL, round-bottomed flask-were added 7-hydroxyquinoline (Aldrich) (87 mg, 0.6 mmol) and DMF (1 mL). The solution was place under nitrogen, and NaH (24 mg, 0.6 mmol) was added in one portion. After stirring for 10 min, 2-chloro-4-(4-trifluoromethylphenyl) pyridine (Example 410 (c), 129 mg, 0.5 mmol) was added. The reaction mixture was heated in a 155° C. oil bath for 72 h. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and brine. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, concentrated in vacuo. The crude material was purified on a Biotage 40 S column (3:1 hexanes: EtOAc) to give the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 367 (M+1). Mp: 156.5-158.5° C.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([CH:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[N:5][CH:4]=1)=[O:2].P([O-])(O)(O)=[O:21].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[C:16]([O:15][C:13]([N:10]1[CH2:11][CH2:12][CH:8]([C:6]2[S:7][C:3]([C:1]([OH:21])=[O:2])=[CH:4][N:5]=2)[CH2:9]1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc(C=O)s2)C1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ncc(C(=O)O)s2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
tert-Butyl 3-(5-formylthiazol-2-yl)pyrrolidine-1-carboxylate (3.65 g, 12.93 mmol) was suspended in water (35 ml) and t-butanol (60 ml). Sodium dihydrogenphosphate (2.094 g, 17.45 mmol) was added, followed by 2-methylbut-2-ene (5.34 ml, 50.4 mmol). After 5 minutes, sodium chlorite (2.92 g, 32.3 mmol) was added in portions over about 5 minutes (mildly exothermic). The reaction was stirred for 1 hour at room temperature, then additional 2-methyl-2-butene (2 mL) was added. After stirring for 2 hours at room temperature, the reaction was concentrated and water (100 mL) was added. The mixture was adjusted to pH 2 by addition of 1N hydrochloric acid, then extracted dichloromethane. The organic extracts were dried over sodium sulfate, filtered and concentrated to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[O:5][C@@H:6]1[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[C@H:9]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[O:17])[C@@H:8]([C:30]([O:32]C)=O)[CH2:7]1.[OH:37][NH2:38].Cl.C[O-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[O:5][C@@H:6]1[CH2:11][N:10]([C:12]([O:14][CH3:15])=[O:13])[C@H:9]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[O:17])[C@@H:8]([C:30]([NH:38][OH:37])=[O:32])[CH2:7]1
Reactant: COC(=O)[C@H]1C[C@H](Oc2cccc(F)c2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1C[C@@H](Oc2cccc(F)c2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
To a solution of dimethyl(2S,3S,5S)-5-(3-fluorophenoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (27 mg, 0.000054 mol) in methanol (0.2189 mL, 0.005405 mol) was added 1.640 M of N-hydroxyamine in Methanol (0.659 mL) made from the corresponding HCl salt and sodium methoxide. After stirred at rt for 1 h, the mixture was acidified with 1N HCl. The resultant mixture was applied directly on RP-HPLC to afford the product as a TFA salt (18 mg 54.5%). MS (ESI): (M+H)+=501.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1.[CH:18]([C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=1)=[O:19].C1CCN2C(=NCCC2)CC1>ClCCl>[OH:19][CH:18]([C:7]1[C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[NH:9][C:8]=1[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1)[C:20]1[N:25]=[C:24]([C:26]([O:28][CH3:29])=[O:27])[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc2cc(-c3cncnc3)[nH]c2c1
Reactant: COC(=O)c1cccc(C=O)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COC(=O)c1cccc(C(O)c2c(-c3cncnc3)[nH]c3cc(OC)ccc23)n1
Temperature: 30 °C
Reaction time: 76 h
Yield: 61.4 %

Procedure:
To a suspension of 6-methoxy-2-pyrimidin-5-yl-1H-indole (779 mg) and methyl 6-formylpyridine-2-carboxylate (628 mg) in dichloromethane (17.3 mL) was added 1,8-diazabicyclo[5,4,0]-7-undecene (0.052 mL), and the mixture was stirred at 30° C. for 76 hours. The reaction mixture was purified by aminopropylated silica gel column chromatography (eluting solvent: methanol-ethyl acetate) to obtain the title compound (829 mg). 1H-NMR (DMSO-d6) δ ppm: 3.75 (3H, s), 3.82 (3H, s), 5.99 (1H, d, J=3.5 Hz), 6.16 (1H, d, J=3.5 Hz), 6.61 (1H, dd, J=2.3, 8.8 Hz), 6.84 (1H, d, J=2.3 Hz), 7.49 (1H, d, J=8.8 Hz), 7.86-7.92 (1H, m), 8.06 (1H, t, J=7.8 Hz), 8.18-8.26 (1H, m), 9.23 (1H, s), 9.55 (2H, s), 11.40 (1H, br s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([C:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=3)=[CH:9]2)=[O:23])=[CH:20][CH:19]=1
Reactant: CN1CC=C(c2c[nH]c3ccccc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CN1CC=C(c2cn(C(=O)c3ccc(F)cc3)c3ccccc23)CC1

Procedure:
(8.7 mg, 22%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (Example 4e, 24.8 mg, 0.12 mmol) and 4-fluorobenzoyl chloride (28 uL, 0.24 mmol); HRMS-FAB+ for C21H19N2O2F: calculated MH+ : 335.15598; found: 335.15560.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][N:3]=1.BrC1C=CC(S(C)=[O:18])=NC=1>>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:9])=[O:18])[CH:5]=[CH:4][N:3]=1
Reactant: CSc1ccnc(Br)c1
Reactant: CS(=O)c1ccc(Br)cn1
Product: CS(=O)c1ccnc(Br)c1

Procedure:
The title compound was prepared from 2-bromo-4-methylsulfanyl-pyridine following a procedure analogous to that described for 5-bromo-2-methanesulfinyl-pyridine in Example 182. Mass spectrum (ESI+): m/z=220/222 (Br) [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:47][C:48]1[CH:54]=[CH:53][C:51]([NH2:52])=[CH:50][C:49]=1[N+:55]([O-:57])=[O:56]>CN(C=O)C>[CH3:47][C:48]1[CH:54]=[CH:53][C:51]([NH:52][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=2)=[CH:50][C:49]=1[N+:55]([O-:57])=[O:56]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
A solution of 3-(trifluoromethyl)benzoic acid (8 g, 42.1 mmol), HATU (19.20 g, 50.5 mmol) and DIPEA (13.91 mL, 84 mmol) in DMF (350 mL) was stirred for 15 min at rt. 4-methyl-3-nitroaniline (6.40 g, 42.1 mmol) was added and stirred overnight at 60° C. After cooling to room temperature the reaction was quenched with H2O. After stirring for 10 minutes the resulting precipitate was collected and washed with water to give compound N-(4-methyl-3-nitrophenyl)-3-(trifluoromethyl)benzamide 66 (12 g, 88%). (m/z)=325 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[N:13][N+:14]([O-:16])=[O:15])SC)=[CH:4][N:3]=1.[CH3:17][NH:18][CH3:19]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[N:13][N+:14]([O-:16])=[O:15])[N:18]([CH3:19])[CH3:17])=[CH:4][N:3]=1
Reactant: CNC
Reactant: CSC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Solvent: CCO
Product: CN(C)C(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Temperature: 30 °C
Yield: 93.4 %

Procedure:
1-(2-chloro-5-pyridylmethyl)-2-methyl-3-nitroisothiourea (1.3 g) was dissolved in ethanol (20 ml) and to the solution was added an aqueous solution (50%) of dimethylamine (0.5 g) at room temperature, followed by one-day stirring at 30° C. The ethanol in the solution was distilled off under reduced pressure and it was purified on a chromatographic column (the eluent was a mixture of methanol and chloroform) so as to obtain the desired 3-(2-chloro-5-pyridylmethyl)-1,1-dimethyl-2-nitroguanidine (1.2 g) having a melting point in the range of from 158° to 160° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>C(#N)C.CCOC(C)=O.[Cu]I>[CH3:16][N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:3]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: C#C[Si](C)(C)C
Reactant: CN1CCN(C(=O)c2cccc(I)c2)CC1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN1CCN(C(=O)c2cccc(C#C[Si](C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
(3-Iodophenyl)(4-methylpiperazin-1-yl)methanone (1.15 g, 3.5 mmol) and ethynyl-trimethyl-silane (0.58 mL, 4.2 mmol) in dry acetonitrile (30 mL) were purged with nitrogen and treated with TEA (0.97 mL, 7.0 mmol, 2 eq.), CuI (0.033 g, 0.17 mmol) and Pd (Ph3P)2Cl2 (0.120 g, 0.17 mmol). The reaction was stirred at room temperature for 2 h, then was diluted with EtOAc (30 mL), washed with water (2×20 mL), brine, dried over sodium sulphate, and evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH 95/5) to afford the title compound (0.95 g, 91%).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][OH:14])C(O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:15]([O-])=O.[Na+]>OS(O)(=O)=O>[CH2:1]([C@H:8]([NH2:15])[CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H](CCO)Cc1ccccc1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@H](CCO)Cc1ccccc1
Temperature: 2.5 °C

Procedure:
The hydrazide of (S)-2-benzyl-4-hydroxybutanoic acid (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (S)-1-benzyl-3-hydroxypropylamine is isolated as a light yellow oil.
Reaction SMILES: Cl.[F:2][CH2:3][C:4]([NH2:6])=[NH:5].[F:7][CH:8]([C:13](OC)=[O:14])[C:9](OC)=[O:10].C[O-].[Na+]>CO>[F:7][C:8]1[C:9](=[O:10])[N:5]=[C:4]([CH2:3][F:2])[NH:6][C:13]=1[OH:14]
Reactant: N=C(N)CF
Reactant: COC(=O)C(F)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=c1nc(CF)[nH]c(O)c1F
Temperature: 50 °C

Procedure:
2-Fluoro-acetamidine hydrochloride salt (11.2 g, 100 mmol) and dimethyl fluoromalonate (15 g, 100 mmol) in anhydrous methanol (300 mL) were treated with solid NaOMe (16.2 g, 300 mmol) and heated to 50° C. with stirring. When LCMS showed formation of the desired product, the solvent was evaporated to dryness, and the residue was neutralized with concentrated HCl (20 mL). The white precipitate was collected by filtration to give 5-fluoro-2-(fluoromethyl)-6-hydroxy-4(1H)-pyrimidinone (100% yield). LCMS: (M+H)+: 163.1.
Reaction SMILES: C([O-])(O)=O.[Na+].[NH:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[CH2:11][OH:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C(Cl)Cl>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:6]2[CH2:10][CH2:9][CH2:8][C@@H:7]2[CH2:11][OH:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: OC[C@H]1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC[C@@H]1CO
Temperature: 20 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To a mixture of sat aq. NaHCO3 (44 g, 0.53 mol), CH2Cl2 (400 mL) and (R)-pyrolidin-2-yl-methanol (53 g, 0.53 mol) was added 4-bromo-benzenesulfonyl chloride (130 g, 0.50 mol) in CH2Cl2 (100 mL). The reaction was stirred at 20° C. overnight. The organic phase was separated and dried over Na2SO4. Evaporation of the solvent under reduced pressure provided (R)-[1-(4-bromo-benzenesulfonyl)-pyrrolidin-2-yl]-methanol (145 g, crude), which was used in the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ 7.66-7.73 (m, 4 H), 3.59-3.71 (m, 3 H), 3.43-3.51 (m, 1 H), 3.18-3.26 (m, 1 H), 1.680-1.88 (m, 3 H), 1.45-1.53 (m, 1 H).
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([CH2:13][CH2:14][C:15](O)=[O:16])=O)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].O.[NH2:22][NH2:23]>C(O)(=O)C.O>[C:1]([O:4][CH:5]([CH3:20])[CH2:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]2[CH2:13][CH2:14][C:15](=[O:16])[NH:22][N:23]=2)=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)Cc1ccc(C(=O)CCC(=O)O)cc1
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)OC(C)Cc1ccc(C2=NNC(=O)CC2)cc1

Procedure:
A solution of 3-[4-(2-acetoxypropyl)benzoyl]propionic acid (0.8 g) in glacial acetic acid (10 ml) was treated with hydrazine hydrate (1 ml). The resulting solution was stirred and heated under reflux for 1 hr., cooled, diluted with water, and extracted into ethyl acetate. The organic layer was washed with NaHCO3 solution, dried (MgSO4) and evaporated to give 4,5-dihydro-6-[4-(2-acetoxypropyl)phenyl]-3(2H)-pyridazinone as a colourless oil.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[C:17]([CH:22]=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C1COCC1>[Br:13][C:9]1[CH:8]=[C:7]([CH:22]([C:17]2[C:16]([C:15]([F:25])([F:14])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[OH:23])[CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ncccc1C(F)(F)F
Reactant: Brc1cccc(Br)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: OC(c1cccc(Br)c1)c1ncccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 55.5 %

Procedure:
25 mL of anhydrous THF was placed under nitrogen and cooled to −78° C. 2.2 ml (5.5 mmol) of a 2.5 M solution of n-butyl lithium in hexanes were added. To the resulting solution was slowly added 0.7 mL (1.4 g, 5.8 mmol) of 1,3-dibromobenzene. Upon complete addition the resulting solution was stirred at −78° C. for 90 min. 1.00 g (5.71 mmol) of 3-trifluoromethyl-pyridine-2-carbaldehyde was added rapidly. The dark solution was warmed to −20° C. and stirred for 20 min at that temperature. The resulting mixture was distributed between 10% aqueous citric acid and dichloromethane. The phases were separated and the aqueous layer extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent completely evaporated. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 1.053 g (3.171 mmol, 58%) of (3-bromo-phenyl)-(3-trifluoromethyl-pyridin-2-yl)-methanol as a yellow oil. 1H NMR (500 MHz, DMSO-d6) δ 8.84 (m, 1H), 8.18 (dd, 1H), 7.63 (m, 1H), 7.53 (dd, 1H), 7.42 (m, 1H), 7.26-7.24 (m, 2H), 6.31 (d, 1H), 6.02 (d, 1H); MS: m/z 332.0+334.0 (M+H+).