Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:4]([Cl:27])[CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C(Cl)Cl>[Cl:27][C:4]1[CH:3]=[C:2]([NH:1][C:36]([O:38][CH3:39])=[O:37])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[O:18][CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21]
Reactant: COC(=O)Cl
Reactant: CC(C)(C)OC(=O)COc1ccc(C(F)(F)F)cc1-c1ccc(N)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1ccc(-c2cc(C(F)(F)F)ccc2OCC(=O)OC(C)(C)C)c(Cl)c1
Reaction time: 20 h

Procedure:
The product from step (iii) (0.07 g) was dissolved in DCM (5 ml), triethylamine (0.024 ml) added, followed by methyl chloroformate (0.013 ml) and stirred for 20 h. Further triethylamine (0.024 ml) and methyl chloroformate (0.013 ml) were added three times over to achieve complete reaction. The solvent was removed by evaporation to give the crude product which was carried forward to step (v) without characterisation.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:10][C:11]([F:36])([F:35])[C:12]1[CH:34]=[CH:33][CH:32]=[CH:31][C:13]=1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:22]2[N:27]=[N:26][C:25]([C:28](O)=O)=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)=[O:15]>O=P(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:28]([C:25]3[N:26]=[N:27][C:22]([N:19]4[CH2:18][CH2:17][N:16]([C:14]([C:13]5[CH:31]=[CH:32][CH:33]=[CH:34][C:12]=5[C:11]([F:36])([F:10])[F:35])=[O:15])[CH2:21][CH2:20]4)=[CH:23][CH:24]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=C(O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(-c3nc4cc(Br)cnc4[nH]3)nn2)CC1
Temperature: 12.5 °C
Yield: 74 %

Procedure:
A mixture of 5-bromopyridine-2,3-diamine (0.188 g, 1.000 mmol) and 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (0.380 g, 1.000 mmol) in POCl3 (7 mL) was heated to reflux for 24 hours. The solvent was evaporated in vacuo, and the dark residue was neutralized with ice-cold NaOH solution. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over MgSO4 and filtered through the short pad of silica gel. The filtrate was concentrated, ether was added. After cooling to 10-15° C. the white precipitation started to form. This was filtered off and dried in vacuo to yield {4-[6-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)pyridazin-3-yl]piperazin-1-yl}-(2-trifluoromethylphenyl)methanone in 74% yield (0.394 g, 0.810 mmol). 1H NMR (300 MHz, CDCl3) δ 13.64 (br., s, 1H), 8.40 (s, 1H), 8.17 (d, J=9.6 Hz, 1H), 8.03 (br, s, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.76 (t, J=7.4 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.43 (d, J=9.6 Hz, 1H), 3.90-3.20 (m, 8H13C NMR (75 MHz, CDCl3) δ 166.8, 159.9, 152.8, 144.9, 143.5, 135.0, 133.4, 130.1, 128.0, 127.1, 127.0, 126.9, 126.0, 125.9, 125.6, 122.4, 113.8, 46.4, 44.5, 44.3, 41.2. MS (ES+) m/z 532, 534 (M+1).
Reaction SMILES: C(OC(=O)N[N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]3[C:33]([CH3:34])=[C:32]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)(C)(C)C.C(OCC)(=O)C.Cl>C(OCC)(=O)C.C(O)C>[CH2:36]([O:35][C:32]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=[C:24]([CH2:23][O:22][C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:17]=2)[C:33]=1[CH3:34])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cc1c(COc2cccc(OCC3CCN(NC(=O)OC(C)(C)C)CC3)c2)nc2ccccc2c1OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1c(COc2cccc(OCC3CCNCC3)c2)nc2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
To an ice-cold solution of 4-[(3-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}phenoxy)methyl]piperidine-1-carbamic acid tert-butyl ester (735 mg) in ethyl acetate-ethanol (3:1, 20 mL) was added a 4M hydrogen chloride-ethyl acetate solution (15 mL), and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and then a 5% aqueous sodium hydrogen carbonate solution was added to the residue, followed by extraction with ethyl acetate (80 mL). The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1) to obtain 4-(benzyloxy)-3-methyl-2-{[3-(piperidin-4-ylmethoxy)phenoxy]methyl}quinoline (545 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:10][CH2:11][CH2:12][O:13]C.C[Si](I)(C)C.Cl>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: COCCCOc1c(Cl)ccnc1C
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClCCl
Product: Cc1nccc(Cl)c1OCCCO
Reaction time: 96 h

Procedure:
To a solution of 4-chloro-3-(3-methoxy-1-propoxy)-2-methylpyridine (120 mg, 0.56 mmol) in 2 ml of CDCl3 was added trimethylsilyl iodide (0.16 ml, 1.3 mmol), this was done in a NMR tube. The reaction was complete after four days as indicated by the absence of a signal for the OCH3 protons at 3.3 ppm in the NMR spectrum. The solution was poured over 10 ml of 1M HCl whereupon the mixture was stirred for 5 minutes with 10 ml of methylene chloride. The aqueous layer was separated, treated with K2CO3 until pH=10 and extracted with methylene chloride. The organic phase was dried over Na2SO4 and evaporated. This afforded 0.049 g (43%) of the desired product as a yellow oily film.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[N:18]=2)[CH:12]=1)[S:6]([CH3:9])(=[O:8])=[O:7].[C:33]1([CH2:39][S:40](Cl)(=[O:42])=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[OH:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=3)[CH2:10][N:5]([S:6]([CH3:9])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2][NH:1][S:40]([CH2:39][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)(=[O:42])=[O:41])[CH:22]=[CH:21][N:20]=2)=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1
Product: CS(=O)(=O)N(CCCNS(=O)(=O)Cc1ccccc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Compound 2 was coupled with phenyl-methanesulfonyl chloride following procedure D. LC-MS showed the product had the expected M+H+ of 610. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.3 (d, 1H), 8.0 (d, 1H) 7.5 (m, 3H) 7.3 (d, 2H), 7.2 (m, 4H), 6.7 (d, 4H), 4.4 (s, 2H), 4.2 (s, 2H), 3.6 (t, 2H), 3.2 (t, 2H), δ 2.9 (s, 3H), 2.7 (t, 2H), 2.7 (t, 2H), δ 1.6 (m, 2H).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 4-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H11FN4, 279. Found, 279.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:6](=[CH:7][S:8][N:9]=2)[CH:5]=[CH:4][CH:3]=1.C1N2CCN(CC2)C1.CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2].[CH3:40][N:41]=[C:42]=[O:43]>C1C=CC=CC=1>[N:9]1[S:8][CH:7]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([O:1][C:42](=[O:43])[NH:41][CH3:40])[C:10]=12
Reactant: Oc1cccc2csnc12
Reactant: CN=C=O
Agent: C1CN2CCN1CC2
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Sn+2]
Solvent: c1ccccc1
Product: CNC(=O)Oc1cccc2csnc12
Reaction time: 0.08 h

Procedure:
To a solution of 2.0 g. 7-hydroxy-2,1-benzisothiazole, 40 ml. dry benzene, and catalytic amounts of triethylenediamine and stannous octoate was added 2.5 g. methylisocyanate. After about five minutes at room temperature, yellow solid carbamate product crystallized from solution. The mixture was allowed to stand at room temperature overnight, then solvent and excess methylisocyanate were removed by evaporation on a rotatory evaporator. The solid residue was washed with hot hexane and isolated by suction filtration to give 2.6 g. yellow, microcrystalline 2,1-benzisothiazol-7-yl N-methylcarbamate, mp. 145°-148° (dec.) after recrystallization from benzene. This structure was confirmed by ir and nmr. The insecticidal activity of this material was determined exactly as described in Example 12, whereby 2,1-benzisothiazol-7-yl N-methylcarbamate (500 ppm. concentration) destroyed 100 percent of Mexican bean beetle larvae and bean aphids, four of five southern armyworms, and had no effect on two-spotted mites.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:20]([O-])=O)[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH4+].[Cl-].O>CCO.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=[N+]([O-])c1cc(F)c(Oc2cnc3ccccc3c2)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cc(F)c(Oc2cnc3ccccc3c2)c(Cl)c1
Yield: 47.3 %

Procedure:
To a solution of 3-chloro-5-fluoro-4-(quinolin-3-yloxy)nitrobenzene (50.1) (0.980 g) and NH4Cl (1.64 g) in EtOH (50 mL)-H2O (5 mL), was added iron powder (1.92 g). The mixture was heated to reflux for 1 h. After cooling the reaction mixture was filtered through short celite pad. The filtrate was concentrated, diluted with sat.NaHCO3 and extracted with AcOEt (30 mLx3). The combined organic layers were washed with brine and dried over Na2SO4. Concentration of solvent afford crude product, which was purified by column chromatography (silica gel, AcOEt:hexane=1:3) to provide aniline 50.2 (0.420 g) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=1.C([Mg]Cl)(C)C.[Li]CCCC.CN([CH:26]=[O:27])C>C1COCC1>[C:9]([C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([F:8])[CH:5]=1)[CH:26]=[O:27])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1cc(F)cc(Br)c1
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(F)cc(C=O)c1
Reaction time: 0.75 h

Procedure:
Bromo-3-tert-butyl-5-fluorobenzene (323.2 g, 1.4 moles) was dissolved in THF (3.3 L) and cooled −10° C. iPrMgCl (2M solution in THF, 0.5 eq, 350 mL) was added over 20 min, followed by nBuLi (2.5M solution in hexanes, 1.0 eq, 560 mL) over two hours. DMF (4 eq, 450 mL) was added over one hour then stirred for 45 minutes and quenched with 3M HCl (1000 mL). The layers were separated and the aqueous fraction was diluted with water (1 L) and extracted with ethyl acetate (1 L). The organic fractions were combined and washed with water (2×2 L). The organic fraction was concentrated to provide an orange oil (252 g, quant), used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=2)=[O:29])[CH:25]=[C:24]([CH3:39])[C:3]=1[C:4]([NH:6][C@H:7]([C:20]([O:22]C)=[O:21])[CH2:8][NH:9][C:10](=[O:19])[C:11]1[CH:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[CH:12]=1)=[O:5].O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:1][C:2]1[CH:27]=[C:26]([C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=2)=[O:29])[CH:25]=[C:24]([CH3:39])[C:3]=1[C:4]([NH:6][C@H:7]([C:20]([OH:22])=[O:21])[CH2:8][NH:9][C:10](=[O:19])[C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([OH:17])[CH:16]=1)=[O:5]
Reactant: COC(=O)[C@H](CNC(=O)c1cc(O)cc(O)c1)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(=O)NCc2cccc(O)c2)cc(Cl)c1C(=O)N[C@@H](CNC(=O)c1cc(O)cc(O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
A solution of N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-(3,5-dihydroxybenzoylamino)-L-alanine, methyl ester (790 mg, 0.87 mmol) in tetrahydrofuran/methanol (1:1; 8 mL) was added to a solution of lithium hydroxide monohydrate (183 mg, 4.4 mmol) in water (4 mL). The solution was stirred at room temperature overnight and then the solvents were evaporated. Water (15 mL) was added and the solution was acidified with 3 M HCl. The mixture was extracted with ethyl acetate (3×20 mL) and the combined extracts were washed with brine and evaporated. The residue was dissolved in methanol (14 mL) and purified in two portions by HPLC to give N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-6-methylbenzoyl]-3-(3,5-dihydroxybenzoylamino)-L-alanine (65 mg, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([O:18]CC)=[O:17])[CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>C(O)C>[C:16]([CH:14]([O:13][C:10]1[N:11]=[CH:12][N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:9]=1)[CH3:15])([OH:18])=[O:17]
Reactant: CCOC(=O)C(C)Oc1ncn(-c2cccc(Cl)c2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ncn(-c2cccc(Cl)c2)n1)C(=O)O

Procedure:
A 6.7 g portion of the compound of Example 5 was refluxed for 3 hours with 2.5 g of potassium hydroxide in 100 ml of ethanol and the product was collected as shown in Example 22 and recrystallized from ethanol to obtain 5.2 g of the desired product, m.p. 197°-199°.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([NH:6][C:7]2[CH:19]=[C:18]([CH:20]=[CH2:21])[CH:17]=[CH:16][C:8]=2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.I[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=1.C1(CNCC2CCCCC2)CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25](/[CH:21]=[CH:20]/[C:18]2[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:13])[CH3:14])=[O:10])=[C:7]([NH:6][C:5]3[CH:22]=[CH:23][C:2]([F:1])=[CH:3][CH:4]=3)[CH:19]=2)=[CH:26][CH:27]=1)(=[O:34])[CH3:33]
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(Nc2ccc(F)cc2)c1
Reactant: CC(=O)Nc1ccc(I)cc1
Agent: [Pd+2]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1ccc(/C=C/c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc(F)cc3)c2)cc1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
To N,N-dimethylacetamide 3.0 mL solution of tert-butyl 2-(4-fluoroanilino)-4-vinylbenzoate 0.15 g were added N-(4-iodophenyl)acetamide 0.37 g, N,N-dicyclohexylmethylamine 0.41 mL and palladium acetate 5.4 mg at room temperature, and it was stirred at 130° C. for 4 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and 10% citric acid aqueous solution were added to it. The organic layer was separated and collected, and the solvent was removed under reduced pressure after sequential washing with 10% citric acid aqueous solution, saturated sodium thiosulfate aqueous solution and saturated sodium chloride aqueous solution. The obtained residue was refined by silica gel column chromatography [Trikonex company, Flash Tube 2008, eluent; hexane:ethyl acetate=1:1] to give tert-butyl 4-((E)-2-(4-(acetamido)phenyl)vinyl)-2-(4-fluoroanilino)benzoate.
Reaction SMILES: F[C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[CH:5][C:3]=1[NH2:4].[I:19]C1C=C(Br)C=CC=1N.FC1C=C(Br)C=CC=1N>>[I:19][C:2]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Reactant: Nc1ccc(Br)cc1I
Agent: Nc1ccc(Br)cc1F
Product: Nc1ccc(-c2ccccc2S(N)(=O)=O)cc1I

Procedure:
This compound was prepared by the method described for 2-fluoro-4-(2-aminosulfonylphenyl)aniline described in EXAMPLE 8 by starting with 2-iodo-4-bromoaniline rather than 2-fluoro-4-bromoaniline.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[C:22]([C:25]([O:27]CC)=[O:26])=[CH:21][N:20]([CH2:30][CH3:31])[C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[C:22]([C:25]([OH:27])=[O:26])=[CH:21][N:20]([CH2:30][CH3:31])[C:18]=3[N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(CC)c2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O
Agent: [Na+]
Agent: [OH-]
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(Cc4ccccc4)CC3)nc21

Procedure:
Saponification of 9.5 g. of this ester with an aqueous-alcoholic solution of sodium hydroxide (N NaOH, 15 cm3 + water, 30 cm3 + ethanol, 30 cm3) is complete in 1 hour at ordinary temperature. After acidification, the precipitate is filtered off and recrystallised from 160 cm3 of a mixture of dimethylformamide (1 volume) and ethanol (1 volume). 6.8 g. of 2-(4'-benzyl-piperazino)-5-oxo-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine-6-carboxylic acid are obtained; melting point 207°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH2:10]1[CH2:14][O:13][CH2:12][CH2:11]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:12]([OH:13])[C:11]2[CH:10]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:14]=2)=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Fc1ccc([Mg]Br)cc1
Product: O=Cc1ccc(C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27 %

Procedure:
To a stirred solution of terepathaldehyde (0.5 g, 3.7 mmol) in anhydrous THF (8 ml) at 0° C. was added 2M THF solution of 4-fluorophenyl magnesium bromide (1.86 ml; 3.72 mmol) drop wise and the mixture was allowed to warm up to room temperature and stirred for 4 h. The mixture was then quenched with NH4Cl solution and diluted with to 100 ml with EtOAc. The organic layer was washed with H2O, dried over MgSO4, filtered and the filtrate evaporated to dryness. The residue was purified by FCC (SiO2) to give the desired product (0.23 g; 27%) as creamy paste. 1H-NMR (CDCl3) 2.57 (s, 1H); 5.86 (s, 1H); 7.0 (tr, 2H, J=8.58 Hz); 7.28-7.33 (m, 2H); 7.51 (d, 2H, J=7.98 Hz); 7.81 (d, 2H, J=8.1 Hz); 9.95 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:18]2[O:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:19])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+]>CO>[O:19]=[C:10]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:18]=2[O:17][C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: COC(=O)c1cccc2c(=O)c3ccccc3oc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc2c(=O)c3ccccc3oc12

Procedure:
To a suspension of 9-oxo-9H-xanthene-4-carboxylic acid methyl ester 4j (2.0 g, 7.87 mmol) in methanol (30 mL) was added a 3N sodium hydroxide solution (3.2 mL), and the mixture was heated to reflux for 2 h. The solvent was evaporated and the residue was dissolved in water (50 mL). The solution was filtered, acidified with concentrated hydrochloric acid, and a precipitate formed. The solid was separated via filtration, washed with water, and air-dried to yield 1.9 g (quant.) of title compound 5j.
Reaction SMILES: [Cl-].C([N+:5](CCC)(CCC)[NH2:6])CC.[NH2-].[Na+].[CH2:15]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:16][CH3:17]>>[NH2:5][NH2:6].[CH2:15]([N:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21])[CH2:16][CH3:17]
Reactant: CCC[N+](N)(CCC)CCC
Agent: CCCN(CCC)CCC
Agent: [Cl-]
Agent: [NH2-]
Product: NN
Temperature: 156 °C

Procedure:
1,1,1-Tripropylhydrazinium chloride (19.4 g, 0.1 mole) is reacted with dry, powdered sodamide (4.0 g, 0.102 mole) in the presence of excess tripropylamine as the reaction medium. The mixture is degassed, then heated rapidly to reflux temperature (156° C.) in a stream of dry nitrogen, and the refluxing vapors are led into a glass fractionating column to yield hydrazine (bp 113°) as the distillate, tripropylamine remaining in the reaction vessel for reuse.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH:26]=4)=[CH:17][CH:16]=3)[CH:14]=2)=[N:2]1.C([O-])=O.[NH4+]>C1COCC1.[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[N:11]=[N:12][N:13]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]4)=[CH:19][CH:20]=3)[CH:14]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(-n3cc(-c4n[nH]c5ccccc45)nn3)cc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-n3cc(-c4n[nH]c5ccccc45)nn3)cc2)CC1
Temperature: 70 °C
Reaction time: 48 h
Yield: 94.6 %

Procedure:
In a Parr reactor, Pd/C (10% Pd moistened, 50% water, 24 mg, 0.23 mmol, 0.1 eq.) was suspended in a solution of tert-butyl 4-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}-3,6-dihydropyridine-1(2H)-carboxylate (1.0 g; 2.26 mmol; 1.0 eq.) and ammonium formate (2.85 g; 45.2 mmol; 20 eq.) in THF (55 mL). The reaction mixture was stirred for 48 h at 70° C. It was then filtered through a celite pad, the cake was rinsed several times with THF and the filtrate was concentrated to dryness. The resulting residue was partitioned between DCM and water. Organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM:MeOH, gradient from 100:0 to 95:5) gave the title compound as a white foam (950 mg g; 94.5%). 1H NMR (300 MHz, DMSO-d6) δ 13.36 (brs, 1H), 9.27 (s, 1H), 8.36 (d, J=8.2 Hz, 1H), 8.01-7.93 (m, 2H), 7.61 (d, J=8.4 Hz, 1H), 7.56-7.39 (m, 3H), 7.30-7.20 (m, 1H), 4.27-3.94 (m, 2H), 3.01-2.63 (m, 3H), 1.96-1.70 (m, 2H), 1.69-1.47 (m, 2H), 1.43 (s, 9H). 1H HPLC (max plot) 97.2%; Rt 5.33 min. UPLC/MS: (MS+) 445.2, (MS−) 443.2.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[C:14]1([C:20]2[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl:28][SiH:29]([Cl:31])[Cl:30]>>[C:14]1([C:20]2[CH:27]=[CH:26][C:23]([CH2:24][Si:29]([Cl:31])([Cl:30])[Cl:28])=[CH:22][CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Reactant: Cl[SiH](Cl)Cl
Agent: CCCCP(CCCC)CCCC
Product: Cl[Si](Cl)(Cl)Cc1ccc(-c2ccccc2)cc1
Yield: 88.4 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.15 g (0.75 mmol) of tri-n-butylphosphine, 1.52 g (7.5 mmol) of 4-phenylbenzyl chloride, and 5.08 g (37.5 mmol) of trichlorosilane were reacted at 150° C. for 2 hrs. The resulting mixture was distilled to give 2.0 g of (4-phenylbenzyl)trichlorosilane (mp; 60-65° C., yield; 90%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[N:10]=[C:11]=[N:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[CH2:37][CH2:36][N:35]([C:11]3[N:10]([C:4]4[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH:19]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:14]4[CH:15]=[N:16][CH:17]=[CH:18][C:13]=4[N:12]=3)[CH2:34][CH2:33]2)=[CH:30][CH:31]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)/C=C/c1cnccc1N=C=Nc1cc(C)ccc1OC
Product: COC(=O)CC1c2cnccc2N=C(N2CCN(c3ccc(F)cc3)CC2)N1c1cc(C)ccc1OC

Procedure:
Starting from 91 mg (0.28 mmol) of the carbodiimide from Example 16A and 76 mg (0.42 mmol) of 4-fluorophenylpiperazine, general procedure [C] and purification by preparative HPLC result in 14 mg (9% of theory) of product.