Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:25]([C:29]1[CH:30]=[C:31]([CH3:55])[C:32](=[C:34]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:44])([F:43])[F:42])[CH:36]=2)[CH:33]=1)([CH3:28])([CH3:27])[CH3:26].Cl>C(OCC)C>[C:25]([C:29]1[CH:30]=[C:31]([CH3:55])[CH:32]([C:34]([C:1]2[C:13]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[CH:4]=[CH:3][CH:2]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([F:42])([F:43])[F:44])[CH:36]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[CH:33]=1)([CH3:26])([CH3:27])[CH3:28]
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1cccc(C(F)(F)F)c1)c1cccc(C(F)(F)F)c1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1=CC(C(C)(C)C)=CC1C(c1cccc(C(F)(F)F)c1)(c1cccc(C(F)(F)F)c1)c1cccc2c1Cc1ccccc1-2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 1.44 g of fluorene (8.69 mmol) was dissolved in 60 ml of dehydrated diethylether in a nitrogen atmosphere. To the solution, 5.8 ml of n-butyl lithium/hexane solution (1.58M: 9.16 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, 4.15 g of 3-tert-butyl-1-methyl-6,6-di(3-trifluoromethyl-phenyl)fulvene (9.50 mmol) was added and stirred under reflux for several days. The reaction mixture was gradually added dropwise to 30 ml of a hydrochloric acid aqueous solution set (1N) in an ice bath, and stirred at room temperature briefly. Therein, diethyl ether was added to separate an organic phase. The organic phase was washed with distilled water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give a dark red solid. The solid was purified with a column chromatography using 220 g of silica gel (developing solvent: n-hexane) and the developing solvent was distilled off under reduced pressure. Thereafter, the remaining product was re-crystallized using hexane and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 1.69 g (2.72 mmol) as a white solid (yield: 31%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10]#[CH:11])([CH3:4])([CH3:3])[CH3:2].I[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][C:10]#[C:11][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(I)cc1
Reactant: C#CCCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC#Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
But-3-ynylcarbamic acid tert-butyl ester (3.66 g, 22 mmol) was added dropwise to an ice cooled, stirring, argon purged mixture of 4-iodobenzonitrile (4.5 g, 19.6 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.69 g, 0.98 mmol), copper (I) iodide (0.19 g, 0.98 mmol), triethylamine (11 mL, 78.4 mmol), and THF (24 mL). After stirring for 10 min, the ice bath was removed, and the reaction was allowed to stir for an additional 2 h. The reaction mixture was passed through a pad of silica gel with methylene chloride/ethyl acetate (5:1) as eluant. After evaporating the solvent, the crude product was chromatographed with methylene chloride/ethyl acetate (20:1) as eluant. Evaporation of the solvent, followed by placement under vacuum for 1 h, afforded the pure product 56 (5.2 g, 99%) as an oil. 1H NMR (300 MHz, CDCl3) δ 1.46 (s, 9H), 2.64 (t, 2H), 3.37 (m, 2H), 4.85 (br s, 1H), 7.47 (d, 2H), 7.58 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:40]=[CH:39][C:5]2[N:6](CC3C=CC(OC)=CC=3)[C:7](=[O:29])[CH:8]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[N:15][CH:16]=3)[C:4]=2[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(OCC)(=O)C>C1(OC)C=CC=CC=1>[Cl:1][C:2]1[CH:40]=[CH:39][C:5]2[NH:6][C:7](=[O:29])[CH:8]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:20])[CH3:19])=[N:15][CH:16]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3ccc(NC(C)=O)nc3)c3cc(Cl)ccc32)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Product: CC(=O)Nc1ccc(C2=NC(Cc3ccccc3Cl)C(=O)Nc3ccc(Cl)cc32)cn1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
N-(5-(7-Chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)pyridin-2-yl)acetamide (210 mg, 0.366 mmol) was dissolved in anisole (1 mL) under nitrogen and AlCl3 (195 mg, 1.465 mmol) was added in one portion. The resulting orange solution was heated to 85° C. for 2 h then allowed to cool. Ice and ethyl acetate were added and the mixture was stirred for 30 min then partitioned and the organic layer was washed with water then brine and dried (MgSO4). Chromatography on silica gel eluting with 10%-50%-70% ethyl acetate in hexanes gave the product (120 mg, 72% yield). 1H-NMR (300 MHz, CDCl3) δ 7.62-7.5 (m, 3H), 7.5-7.20 (m, 7H), 6.49 (s, 1H), 6.47 (s, 1H), 4.31 (dd, 1H), 4.25-4.17 (m, 2H), 3.59 (dd, 1H), 3.35 (dd, 1H). HRMS (ES+) m/z calcd for C23H18Cl2N4O2 [M+H]+, 453.0885. found, 453.0872.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:21])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[CH:10]=[CH:9][C:8]=2[F:20])(=[O:3])[CH3:2].[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[NH2:29]>>[C:1]([C:4]1[C:5](=[O:21])[NH:6][C:7]2[C:12]([C:13]=1[NH:29][CH:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[CH3:22])=[CH:11][CH:10]=[CH:9][C:8]=2[F:20])(=[O:3])[CH3:2]
Reactant: CC1CCCCC1N
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)ccc(F)c2[nH]c1=O
Product: CC(=O)c1c(NC2CCCCC2C)c2cccc(F)c2[nH]c1=O
Yield: 66.4 %

Procedure:
3-Acetyl-8-fiuoro-4-methylsulfoxy-2-quinolinone (2.67g, 0.01 mol) and 2methylcyclohexylamine(1.13g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.1g, yield: 66%).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:10]([OH:12])=O)[C@H:6]([CH2:8][CH3:9])[CH3:7])(=[O:3])[CH3:2].C([O:20][C:21]1[CH:52]=[CH:51][C:24]([CH2:25][C@@H:26]([C:28]([NH:30][C@H:31]([P:47](=[O:50])([OH:49])[OH:48])[CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39]CC3C=CC=CC=3)=[CH:35][CH:34]=2)=[O:29])[NH2:27])=[CH:23][CH:22]=1)C1C=CC=CC=1>>[C:1]([NH:4][C@H:5]([C:10]([NH:27][C@H:26]([C:28]([NH:30][C@H:31]([P:47](=[O:48])([OH:50])[OH:49])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)=[O:29])[CH2:25][C:24]1[CH:23]=[CH:22][C:21]([OH:20])=[CH:52][CH:51]=1)=[O:12])[C@H:6]([CH2:8][CH3:9])[CH3:7])(=[O:3])[CH3:2]
Reactant: CC[C@H](C)[C@H](NC(C)=O)C(=O)O
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)P(=O)(O)O
Product: CC[C@H](C)[C@H](NC(C)=O)C(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@@H](Cc1ccc(O)cc1)P(=O)(O)O

Procedure:
Diethyl ester of N-(N-acetyl-L-isoleucyl-L-tyrosyl)-(R)-(-)-1-amino-2-(4-hydroxyphenyl)ethylphosphonic acid was synthesized from N-acetyl-L-isoleucine and the compound 46a in the same condensation procedure as in Example 1 and then through the same reaction and treatment as in Example 8.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH3:51]>>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][N:30]1[C:31]2[C:26](=[CH:25][CH:24]=[C:23]([CH2:22][O:21][CH:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([O:1][CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=5[CH3:51])=[CH:3][CH:4]=4)[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10]3)[CH:32]=2)[CH2:27][CH2:28][C:29]1=[O:38]
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: Cc1ccccc1OCCCCBr
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4ccccc4C)cc3)cc21

Procedure:
Analogously to Method I, 0.160 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.099 g of 1-(4-bromobutoxy)-2-methylbenzene are reacted. The title compound is obtained as a colourless oil. Rf=0.33 (2:1 EtOAc-heptane); Rt=6.34.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[F:31][C:32]1[CH:33]=[N:34][C:35]([C:38]2([NH2:41])[CH2:40][CH2:39]2)=[N:36][CH:37]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:41][C:38]5([C:35]6[N:36]=[CH:37][C:32]([F:31])=[CH:33][N:34]=6)[CH2:40][CH2:39]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2ncc(F)cn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(F)cn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.04 g, 0.099 mmol, 1 eq), 1-(5-fluoropyrimidin-2-yl)cyclopropanamine (125 mg, crude), Py-Bop (0.067 g, 0.13 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.026 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative TLC (Eluent Chloroform: Methanol 9.5:0.5 200 ml. Yield: 32 mg (55%). 1H NMR (400 MHz, CD3OD): δ 8.58 (d, J=0.5 Hz, 2H), 8.05-7.93 (m, 2H), 7.89-7.79 (m, 2H), 7.68 (s, 2H), 7.49-7.36 (m, 2H), 7.34-7.23 (m, 2H), 2.96 (s, 3H), 2.36 (s, 3H), 1.83-1.68 (m, 2H), 1.55-1.38 (m, 2H). LCMS: (ES+) m/z=539.2 (M+H)+
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:5]=1)([OH:3])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.O[NH:35][C:36](=[NH:38])[CH3:37].ClCCCl.C(O)C>CN(C=O)C>[CH3:37][C:36]1[N:38]=[C:1]([C:4]2[S:8][C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)=[N:6][CH:5]=2)[O:3][N:35]=1
Reactant: CC(=N)NO
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)s2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1noc(-c2cnc(N3CCN(C(=O)OC(C)(C)C)CC3)s2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21 %

Procedure:
939 mg (3.0 mmol) of tert-butyl 4-(5-carboxythiazol-2-yl)piperazine-1-carboxylate [Precursor BBB61] were dissolved in DMF (15 ml) together with 534 mg (3.3 mmol) of CDI and the solution was stirred at RT 4 h. Subsequently, 243 mg (3.3 mmol) of N-hydroxyacetamidine were added and the mixture was stirred at 120° C. a further 4 h. The reaction solution was then poured onto water and the resulting precipitate was filtered off and washed with water. By means of CC (DCE/ethanol mixture) of the residue, 220 mg (0.63 mmol, 21%) of tert-butyl 4-[5-(3-methyl-[1,2,4]-oxadiazol-5-yl)-thiazol-2-yl]piperazine-1-carboxylate were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][C:3]=1[F:22].[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:31][CH2:30][C:28]2[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=2)=[O:14])=[CH:4][C:3]=1[F:22]
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1cnc(OC2CCC2)c(-c2ccc(Cl)c(F)c2)c1
Product: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OC2CCC2)c(-c2ccc(Cl)c(F)c2)c1

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-3-fluorophenyl)-6-cyclobutoxy-nicotinic acid (example CB) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 90.1%, 471.1 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:7]1[N:8]=[C:9]([CH2:51][CH2:52][CH3:53])[N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:11]=1[C:12]#[N:13])[C:3]([CH3:6])([CH3:5])[CH3:4].C(O)(=O)C>O>[OH:1][CH:2]([C:7]1[N:8]=[C:9]([CH2:51][CH2:52][CH3:53])[N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:11]=1[C:12]#[N:13])[C:3]([CH3:6])([CH3:4])[CH3:5]
Reactant: CCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCc1nc(C(O)C(C)(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A suspension of 1.65 g of 4-(1-hydroxy-2,2-dimethyl propyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (b) above] in 24 ml of 75% v/v aqueous acetic acid was stirred at 60° C. for 2 hours. At the end of this time, 6 ml of water was added to the reaction mixture, which was then cooled with ice. The trityl alcohol which precipitated was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure, to give 1.07 g of the title compound as a glass.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18].[OH-].[Na+]>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:6]([CH3:7])[C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:19])=[O:18]
Reactant: CNc1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Product: CN(c1ccc(Cl)cc1)S(=O)(=O)c1ccccc1Br
Yield: 69 %

Procedure:
To 2.51 g (~0.017 mole) of freshly distilled 4-chloro-N-methylaniline (b.p. 102-103° C.) is added 4.26 g (~0.017 mole) of 2-bromo-benzenesulfonyl chloride (98 w/w %). The mixture is stirred until hot. Ten percent sodium hydroxide is added dropwise with stirring until the solution is slightly alkaline. The 2-bromo-4'-chloro-N-methylbenzene-sulfonanilide is formed as viscous liquid. It is washed with water several times until the wash water is neutral. The compound is dried overnight at room temperature. The yield is 4.2 g (69% yield). 1H NMR (deuterioacetone): δ6.8-7.9 (m, 8 ArH), 3.2 (s, 3H, N--CH3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[CH:6]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)#[CH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(O)=O.[Na+]>CCN(CC)CC.O1CCOCC1.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:14]#[C:13][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)[CH:6]=1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)Cc1ccnc(Cl)c1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccnc(C#Cc2ccc(C(F)(F)F)cc2)c1
Temperature: 150 °C
Yield: 17.3 %

Procedure:
A mixture of methyl(2-chloropyridin-4-yl)acetate (1 g, 5.4 mmol), 1-ethynyl-4-(trifluoromethyl)benzene (3.6 ml, 22 mmol), triphenylphosphine (141 mg, 0.54 mmol), CuI (105 mg, 0.54 mmol), and tetrakis(triphenylphosphine) palladium (0) (312 mg, 0.54 mmol) in Et3N (5 ml) and dioxane (5 ml) in a sealed microwave vial was heated, under microwave irradiation at 150° C. for 15 minutes. The reaction was treated with NaHCO3 (half saturated and extracted with EtOAc (×2). The extracts were washed with brine dried (MgSO4) and evaporated in vacuo to a brown gum which was purified by chromatography (silica, 25% EtOAc/isohexane) to give the acetylene (298 mg, 17%). M/Z (ES+) 320 (MH+).
Reaction SMILES: Br[C:2]1[C:7]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][N:5]=[C:4]([C:13]2[CH2:17][CH2:16][C:15]3([CH2:21][CH2:20][N:19]([CH3:22])[C:18]3=[O:23])[N:14]=2)[CH:3]=1.O.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(Cl)Cl.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[C:9]([O:8][C:7]1[C:2]([C:30]2[CH:31]=[CH:32][C:27]([C:26]([F:37])([F:36])[F:25])=[CH:28][CH:29]=2)=[CH:3][C:4]([C:13]2[CH2:17][CH2:16][C:15]3([CH2:21][CH2:20][N:19]([CH3:22])[C:18]3=[O:23])[N:14]=2)=[N:5][CH:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CN1CCC2(CCC(c3cc(Br)c(OC(C)(C)C)cn3)=N2)C1=O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CN1CCC2(CCC(c3cc(-c4ccc(C(F)(F)F)cc4)c(OC(C)(C)C)cn3)=N2)C1=O
Temperature: 120 °C
Yield: 37.1 %

Procedure:
To a solution of 2-(4-bromo-5-tert-butoxy-2-pyridyl)-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (which may be prepared as described in Description 36) (605 mg, 1.59 mmol) in 1,2-dimethoxyethane (16 mL) was added water (4 mL), [4-(trifluoromethyl)phenyl]boronic acid (332.38 mg, 1.75 mmol) and sodium carbonate (505.87 mg, 4.77 mmol). The mixture was degassed with a stream of nitrogen and bis(triphenylphosphine)-palladium (II) dichloride (55.83 mg, 0.0800 mmol) was added. The mixture was heated to 120° C. over 15 minutes in a microwave. The reaction mixture was diluted with DCM and a little water and the phases separated with a hydrophobic frit. The organic filtrate was evaporated to yield a brown gum, (798 mg). Column chromatography (0-10% MeOH in EtOAc) yielded 2-[5-tert-butoxy-4-[4-(trifluoro-methyl)-phenyl]-2-pyridyl]-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (263 mg, 0.5904 mmol, 37.1% yield) as a yellow foam;
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH3:27][S:28]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:30])=[O:29]
Reactant: OCCCCCCCCCCCOc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCCCCCCOc1ccccc1
Temperature: -8 °C
Reaction time: 0.5 h

Procedure:
To a solution of 10.6 g of 11-phenoxy-1-undecanol, 200 ml of dichloromethane and 8.4 ml of triethylamine chilled to -8° C. in an ice-salt bath is added dropwise over 10 minutes, a solution of 3.38 ml of methanesulfonyl chloride in 10 ml of dichloromethane. The solution is stirred for 30 minutes at -8° C., washed with 150 ml of ice-cold water, 75 ml of cold 10% hydrochloric acid, 75 ml of cold saturated sodium bicarbonate, 75 ml of cold saturated sodium chloride solution and dried over magnesium sulfate. The solvent is removed in vacuo to give off-white crystals, mp 54°-58° C.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:32])[C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10]([C:21](=O)[CH2:22][S:23](=[O:28])(=[O:27])[NH:24][CH2:25][CH3:26])=[C:9]([CH3:30])[NH:8][C:7]=1[CH3:31])([CH3:3])[CH3:2].[BH4-].[Na+].C(Cl)Cl.C(OCC)(=O)C>C(O)(C)C.CN(C)C=O>[CH:1]([O:4][C:5](=[O:32])[C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:10](/[CH:21]=[CH:22]/[S:23](=[O:27])(=[O:28])[NH:24][CH2:25][CH3:26])=[C:9]([CH3:30])[NH:8][C:7]=1[CH3:31])([CH3:3])[CH3:2]
Reactant: CCNS(=O)(=O)CC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCNS(=O)(=O)/C=C/C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+](=O)[O-])c1
Yield: 83.5 %

Procedure:
Analogously to Example 18, 1.86 g of 5-[(ethylsulfamoyl)acetyl]-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid isopropyl ester were treated with 0.16 g of sodium borohydride in a mixture of 20 ml of isopropanol and 4 ml of dimethylformamide. After chromatography with methylene chloride/ethyl acetate (4:1) as the elution agent there were obtained 1.5 g of 5-[(E)-2-(ethylsulfamoyl)vinyl]-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)nicotinic acid isopropyl ester in the form of yellow crystals, m.p. 187°-189°. Recrystallization from methylene chloride/ether did not increase the melting point.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[NH2:53][C@H:54]1[CH2:59][CH2:58][CH2:57][CH2:56][C@H:55]1[OH:60]>CN(C=O)C>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:53][CH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH:55]1[OH:60])=[O:9]
Reactant: O=C(O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Reactant: N[C@H]1CCCC[C@H]1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Reaction time: 3 h

Procedure:
To a solution of 5-bromo-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinic acid (94.0 g, 0.255 mol) in DMF (900 mL) was added with stirring TBTU (90.2 g, 0.28 mol), N,N-diisopropyl ethylamine (219 mL) and cis-2-aminocyclohexanol hydrochloride (42.6 g, 0.28 mol). The temperature rose to 35° C. After stirring was for 3 h the mixture was concentrated in high vacuo at 45° C. The residue was extracted with cold 1N—NaOH (2 L) and ethylacetate (1×2.5 L, 1×1.5 L). Organic phases were washed with water (2×1.5 L). The organic phases were combined, dried with MgSO4 and concentrated in vacuo to ˜800-900ml volume. The product precipitated and the mixture was stirred at 0° C. for about 30 min. Filtration, washing with ethyl acetate/n-heptane 1:1 (4×50 mL) and drying in vacuo at 40° C. for 18 h yielded the title compound (75.8 g as a white solid); MS (ISP) 465.0, 467.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>>[Cl:1][C:2]1[N:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: O=C(O)c1cc(F)cnc1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(F)cnc1Cl
Temperature: 0 °C
Yield: 25 %

Procedure:
To a solution of 2-chloro-5-fluoronicotinic acid (5.2 g, 30 mmol) in methanol (20 ml) was added conc. sulfuric acid (0.5 ml) and the reaction mixture was stirred at reflux for 30 hours. The reaction mixture was cooled to 0° C. and 0.5 N sodium hydroxide solution was added to the mixture. The whole was extracted with diethylether. The organic phase was washed with brine, dried (sodium sulfate), and concentrated to afford 3.2 g (25%) of the title compound: