Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH:13]3[N:15](C(OC(C)(C)C)=O)[CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[ClH:23].CCOCC>>[ClH:23].[ClH:23].[ClH:23].[NH2:1][C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C2
Agent: Cl
Solvent: CCOCC
Product: Nc1ccc(N2CC3CCC(C2)N3)cn1
Yield: 72 %

Procedure:
The product from Example 11A was treated with 1M HCl/ether to provide the title compound (72% yield). 1H NMR (DMSO-d6, 300 MHz) δ 2.00 (s, 4H), 3.2 (d, J=11 Hz, 2H), 3.4 (s, J=11 Hz, 2H), 4.20 (br s, 2H), 5.80 (s, 2H, exchangeable), 7.00, (d, J=8.5 Hz, 1H), 7.40 (br s, 1H), 7.80 (br s, 2H, exchangeable), 7.9-8.0 (m, 1H), 9.10 (br s, 2H, exchangeable).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([F:47])([F:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C@@:22]([OH:29])([CH2:26][CH2:27][CH3:28])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].C(N(CC)CC)C.[Br-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C.O.C(OCC)(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:30]=[CH:31]/[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([F:46])([F:47])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C@@:22]([OH:29])([CH2:26][CH2:27][CH3:28])[C:23]([OH:25])=[O:24])=[O:20])[C:14]([OH:16])=[O:15])=[CH:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(F)(F)CCCCCCC)[C@@](O)(CCC)C(=O)O)C(=O)OC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(F)(F)CCCCCCC)[C@@](O)(CCC)C(=O)O)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
At room temperature, (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-propyl-nonadec-4-enoic acid (No. 5501824; 27.5 mg, 0.041 mmol) was dissolved in acetonitrile (0.55 mL) and water (22 μL), and triethylamine (34.6 μL, 0.249 mmol) and lithium bromide (72.0 mg, 0.829 mmol) were added in order. The mixture was stirred at 50° C. for 2.0 hours, and cooled to room temperature. The progress of the reaction was then stopped by adding an aqueous solution of 0.5 M citric acid. Ethyl acetate was added, and the mixture was extracted. The organic layer was washed with water, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The residue was then purified by preparative HPLC (water with 0.05% TFA-acetonitrile with 0.05% TFA) to obtain (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-carboxy-ethylcarbamoyl]-12,12-difluoro-2-hydroxy-2-propyl-nonadec-4-enoic acid (No. 5501825; 22.4 mg, 84% yield, white powder).
Reaction SMILES: [OH:1][CH2:2]/[C:3](/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:4]/[CH2:5][CH2:6]/[C:7](/[CH3:12])=[CH:8]\[C:9]([OH:11])=O.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C)C=O>[N:27]1([CH2:26][CH2:25][NH:24][C:9](=[O:11])/[CH:8]=[C:7](/[CH3:12])\[CH2:6][CH2:5]/[CH:4]=[C:3](/[CH2:2][OH:1])\[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C\C(=O)O)CO
Reactant: NCCN1CCCC1
Solvent: CN(C)C=O
Product: CC(C)=CCC/C(C)=C/CC/C(=C\CC/C(C)=C\C(=O)NCCN1CCCC1)CO

Procedure:
Following the same manner as in Example 9, the reaction was conducted using 1.0 g of (E,Z,E), (E,E,E), (Z,Z,E) and (Z,E,E)-7-hydroxymethyl-3,11,15-trimethyl-2,6,10,14-hexadecatetraenoic acid and 450 mg of 1-(2-aminoethyl)pyrrolidine in 6.0 ml of N,N-dimethylformamide and the reaction mixture was extracted with chloroform. The chloroform layer was washed with aqueous sodium hydrogencarbonate and extracted with dilute hydrochloric acid. The hydrochloric acid layer was neutralized with sodium hydrogencarbonate and extracted with chloroform. The chloroform layer was washed with water, dried and the solvent was distilled off. The residue was purified by a column chromatography using alumina (20 g) to afford 1.0 g of the end product.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[C:5]([O:9][C:10]([NH:12][C@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][C:20]1[N:25]=[C:24]([C:26]#[N:27])[C:23]([C:28](OC)=[O:29])=[C:22]([NH:32][C:33]2[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=2)[N:21]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6]>CCOCC.CCOC(C)=O>[O:29]=[C:28]1[C:23]2[C:22]([NH:32][C:33]3[CH:34]=[C:35]([CH3:39])[CH:36]=[CH:37][CH:38]=3)=[N:21][C:20]([NH:19][C@@H:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C@@H:13]3[NH:12][C:10](=[O:11])[O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[N:25][C:24]=2[C:26]2([CH2:2][CH2:1]2)[NH:27]1
Reactant: CC[Mg]Br
Reactant: COC(=O)c1c(C#N)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1cccc(C)c1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nc3c2C(=O)NC32CC2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Ethylmagnesium bromide (0.069 mL, 0.208 mmol) was added at RT to a solution of methyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-cyano-6-(m-tolylamino)pyrimidine-5-carboxylate (50 mg, 0.104 mmol) and tetraisopropylorthotitanate (0.091 mL, 0.312 mmol) in Et2O (5 mL). The reaction mixture was stirred at RT for 20 h and was subsequently diluted with EtOAc. The organic phase was washed with saturated aq NaHCO3, brine and water, was dried then concentrated to give a pink residue, which was purified by reverse phase preparative HPLC. The fractions were collected and concentrated to a residue, which was used in next step. [M+H] calc'd for C26H34N6O3, 479; found, 479.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5].IC.[C:36](=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)C>[CH3:36][O:1]/[N:2]=[C:3](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)/C(=N\OC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
To ethyl (Z)-2-(hydroxyimino)-2-[2-(triphenylmethyl)aminothiazol-4-yl]acetate(46 g) were added iodo methane(28.4 g), potassium carbonate (27.6 g) and dimethylsulfoxide(500 ml), and the mixture was stirred for 5 hours at room temperature. After ethyl ether(2 l) was added to the reaction mixture, the mixture was washed 5 times with distilled water(500 ml). The separated organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated. The residue was chromatographed over silica gel to give the above-indicated compound (35.2 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:15]([O-])([OH:17])=[O:16]>>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[CH:4][C:5]([CH2:11][C:12]([OH:14])=[O:13])=[C:6]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: COc1ccc(CC(=O)O)cc1OC
Reactant: O=[N+]([O-])O
Product: COc1cc(CC(=O)O)c([N+](=O)[O-])cc1OC
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
First, 3,4-dimethoxyphenylacetic acid (49.05 g, 0.25 mol) is added in batches to concentrated nitric acid (500 ml), with cooling, at 30° C. and stirred for a further 15 minutes with cooling. The reaction mixture is poured onto ice water (1.5 liters), the precipitate obtained is suction filtered, washed with ice water until neutral and dried. Yield: 56.4 g. Mp: 209°-211° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][CH2:11][CH2:12][Cl:13])=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: ClCCCBr
Product: Fc1ccc(SCCCCl)cc1

Procedure:
Prepared by Procedure R and Scheme Z using 4-fluorobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:23][CH:22]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([O:34][CH3:35])[N:32]=3)[N:27]=[CH:26][CH:25]=2)[O:21][C:20]1=[O:36].C(N(CC)CC)C.[O:44]=[C:45]1[CH2:50][S:49][C:48]2[CH:51]=[CH:52][C:53]([CH:55]=O)=[N:54][C:47]=2[NH:46]1.[BH4-].[Na+]>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[CH3:35][O:34][C:31]1[N:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[C:24]2[CH:22]1[O:21][C:20](=[O:36])[N:19]([CH2:18][CH2:17][CH2:16][NH:15][CH2:55][C:53]2[CH:52]=[CH:51][C:48]3[S:49][CH2:50][C:45](=[O:44])[NH:46][C:47]=3[N:54]=2)[CH2:23]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2nccc(C3CN(CCCN)C(=O)O3)c2n1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [BH4-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1ccc2nccc(C3CN(CCCNCc4ccc5c(n4)NC(=O)CS5)C(=O)O3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To the dihydrochloride salt of 3-(3-Amino-propyl)-5-(6-methoxy-[1,5]naphthyridin-4-yl)-oxazolidin-2-one (previous patent) (0.47 g, 1.25 mmol) in CH2Cl2 (14 mL) and MeOH (3.5 mL) was added triethylamine (1.0 mL, 7.2 mmol) and the mixture was stirred at room temperature until all the solid went into solution. 3-Oxo-3,4-dihydro-2H-pyrido[3,2,b][1,4]thiazine-6-carbaldehyde (SB-735214, 0.24 g, 1.24 mmol) was added and the reaction mixture was stirred for 15 hours. Sodium borohydride (0.0519, 1.35 mmol) was added followed by methanol (10 mL). After 30 minutes, the reaction mixture was diluted with chloroform and washed with saturated aqueous NaHCO3 solution, dried (MgSO4), filtered and concentrated. Flash chromatography on silica gel using a gradient of 0-10% MeOH/CHCl3 afforded the product as a white solid (0.32 g, 53%) 1H NMR (400 MHz, CDCl3): δ8.80 (d, J=4.6 Hz, 1H); 8.36 (d, J=9.1 Hz, 1H); 7.70 (d, J=4.5 Hz, 1H); 7.56 (d, J=7.8 Hz, 1H); 7.17 (d, J=9.1 Hz, 1H); 6.92 (d, J=7.8 Hz, 1H); 6.31 (dd, J=8.6, 6.9 Hz, 1H); 4.35 (t, J=9.3 Hz, 1H); 4.04 (s, 3H); 3.75 (s, 2H); 3.48 (s, 2H); 3.47 (dd, J=8.9, 6.9 Hz, 1H); 3.41 (m, 2H); 2.63 (m, 2H), 1.75 (m, 2H). MS (ES) m/e 481 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][NH:4][CH:5]=[C:6]([C:12](=[O:23])[C:13]1[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=1F)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C>[F:21][C:15]1[CH:14]=[C:13]2[C:18](=[C:17]([F:19])[C:16]=1[F:20])[N:4]([CH2:3][CH2:2][F:1])[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]2=[O:23]
Reactant: CCOC(=O)C(=CNCCF)C(=O)c1cc(F)c(F)c(F)c1F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
8.0 g of ethyl 3-(2-fluoroethylamino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylate was dissolved in 64 ml of acetonitrile under heating to 75˜80° C. 9.06 g (1.8 eq.) of K3PO4 was added in portions to the reaction mixture, which was then stirred at the same temperature for 1.5 hours. The reaction mixture was filtered under a reduced pressure and washed with 80 ml of dichloromethane. The filtrate was concentrated under a reduced pressure. The resulting residue was dissolved in 48 ml of dichloromethane and then washed with water. The organic layer was concentrated under a reduced pressure to give 7.29 g of ethyl 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate (Yield: 96.9%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40][CH2:41][NH2:42]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:42][CH2:41][CH2:40][CH2:39][O:38][CH3:37])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][N:22]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]3=[O:29])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O
Reactant: COCCCN
Product: COCCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2CCCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(2-oxohexahydro-1H-azepin-1-yl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and [3-(methyloxy)propyl]amine using methods similar to Example 563 to provide an orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (d, J=3.58 Hz, 4 H), 1.64 (d, J=7.16 Hz, 2 H), 1.69-1.75 (m, 2 H), 1.77-1.82 (m, 2 H), 2.38-2.44 (m, 2 H), 3.24-3.26 (m, 3 H), 3.34-3.47 (m, 8 H), 4.15-4.25 (m, 4 H), 7.11-7.18 (m, 2 H), 7.40 (dd, J=8.63, 5.69 Hz, 2 H), 8.00 (s, 1 H), 8.56 (d, J=1.26 Hz, 1 H), 10.34 (t, J=5.90 Hz, 1 H), 17.19 (s, 1 H); ES+ MS: 539 (M+H+).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]2[C:8]=1[N:9]=[C:10]([O:20][CH3:21])[C:11]([O:18][CH3:19])=[N:12]2>CN(C)C=O>[N:1]([CH2:6][C:7]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]2[C:8]=1[N:9]=[C:10]([O:20][CH3:21])[C:11]([O:18][CH3:19])=[N:12]2)=[N+:2]=[N-:3]
Reactant: COc1nc2cc(F)cc(CBr)c2nc1OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc2cc(F)cc(CN=[N+]=[N-])c2nc1OC
Reaction time: 5 h

Procedure:
1.73 g (26.6 mmol) of sodium azide are added at room temperature to 4.0 g (13.3 mmol) of 5-bromomethyl-2,3-dimethoxy-7-fluoroquinoxaline in 50 ml of dimethylformamide and stirred for 5 h. The reaction mixture is poured onto water, extracted with diethyl ether and washed with water and brine. The organic phase is dried using Na2SO4, filtered off on a suction filter and concentrated. The title compound is obtained as white crystals of m.p. 75-78° C.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH3+:16].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH:16][CH2:22][C:18]1[S:17][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1cccs1
Reactant: [NH3+]CCNc1ccc2ccccc2c1Cl
Agent: [Cl-]
Product: Clc1c(NCCNCc2cccs2)ccc2ccccc12
Yield: 59 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)amino]ethanaminium chloride and thiophene-2-carbaldehyde in 59% yield as a white oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][NH:22][S:23]([C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=4)[C:29](O)=[O:30])(=[O:25])=[O:24])[CH:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl.[NH2:36][CH2:37][C:38]1[C:43]([CH2:44][CH3:45])=[N:42][C:41]2[N:46]([CH2:49][CH3:50])[N:47]=[CH:48][C:40]=2[C:39]=1[NH:51][CH:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH2:49]([N:46]1[C:41]2=[N:42][C:43]([CH2:44][CH3:45])=[C:38]([CH2:37][NH:36][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([S:23]([NH:22][CH2:21][C:17]4[CH:16]=[C:15]([C:11]5[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][CH:5]6[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]6)[CH:10]=5)[CH:20]=[CH:19][CH:18]=4)(=[O:25])=[O:24])[CH:27]=3)[C:39]([NH:51][CH:52]3[CH2:53][CH2:54][O:55][CH2:56][CH2:57]3)=[C:40]2[CH:48]=[N:47]1)[CH3:50]
Reactant: CN1CCC(Cc2cccc(-c3cccc(CNS(=O)(=O)c4cccc(C(=O)O)c4)c3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(S(=O)(=O)NCc2cccc(-c3cccc(CC4CCN(C)CC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.8 %

Procedure:
To a solution of 3-{[({3′-[(1-methyl-4-piperidinyl)methyl]-3-biphenylyl}methyl)amino]sulfonyl}benzoic acid (0.086 g, 0.102 mmol) in THF (1 mL) was added 5-(aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine hydrochloride (0.042 g, 0.122 mmol), HBTU (0.048 g, 0.133 mmol), and TEA (0.036 mL, 0.255 mmol) and the reaction was stirred at room temperature for 18 h. The reaction mixture was concentrated on Glas-Col evaporator, purified using a Gilson HPLC (with 0.1% TFA), concentrated, basified with amino cartridge to afford 0.0458 g (59%) of the title compound. LC-MS m/z 764 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1.[OH:15][CH2:16][CH2:17][NH:18][NH2:19].Cl>C(O)C>[OH:15][CH2:16][CH2:17][NH:18][NH:19][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)=[CH:6][CH:7]=1
Reactant: NNCCO
Reactant: Cc1cc(C)n(-c2ccc(Cl)nn2)n1
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)n(-c2ccc(NNCCO)nn2)n1

Procedure:
A mixture of 2.09 g (0.01 moles) of 3-chloro-6-(3,5-dimethyl-1-pyrazolyl)-pyridazine, 30 ml of ethanol and 1.52 g (0.02 moles) of hydroxyethyl hydrazine is reacted and worked up in the same way as described in Example 42. Yield: 0.3 g (10.5%); the hydrochloride melts at 302°-305° C.
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]2[CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][C:16](=[O:22])[CH:15]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.O[C:36]([CH3:41])([CH3:40])[C:37]([OH:39])=[O:38]>O1CCCC1>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]2[CH:19]([CH2:20][CH3:21])[CH2:18][CH2:17][C:16](=[O:22])[CH:15]=2)[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([O:8][C:36]([C:37]([OH:39])=[O:38])([CH3:41])[CH3:40])=[O:7]
Reactant: CC(C)(O)C(=O)O
Reactant: CCC1CCC(=O)C=C1c1ccc(OCC(=O)O)c(Cl)c1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCC1CCC(=O)C=C1c1ccc(OCC(=O)OC(C)(C)C(=O)O)c(Cl)c1Cl
Reaction time: 1 h

Procedure:
To a stirred solution of [2,3-dichloro-4-(6-ethyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetic acid (2.06 g, 0.006 mole) under nitrogen in tetrahydrofuran (THF) (50 ml) was added 1,1'-carbonyldiimidazole (0.97 g, 0.006 mole). The solution was stirred for 1 hour then 2-hydroxy-2-methylpropanoic acid (0.62 g, 0.006 mole) in THF (25 ml) was added and stirring was continued overnight. The THF was evaporated in vacuo and the residue chromatographed on silica (300 g) eluting with CH2Cl2 -THF-AcOH (100:2:1). Evaporation of the pertinent fractions gave 1-carboxy-1-methylethyl [2,3-dichloro-4-(6-ethyl-3-oxo-1-cyclohexen-1-yl)phenoxy]acetate which melted at 167°-168° C.
Reaction SMILES: CN(C=O)C.C([N:9]1[CH2:14][C:13](=[O:15])[N:12]([C:16](=[O:18])[CH3:17])[CH2:11][C:10]1=[O:19])(=O)C.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1.CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[C:16]([N:12]1[CH2:11][C:10](=[O:19])[NH:9][C:14](=[CH:26][C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)[C:13]1=[O:15])(=[O:18])[CH3:17]
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Reactant: O=Cc1cccnc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)N1CC(=O)NC(=Cc2cccnc2)C1=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 54.4 %

Procedure:
Add DMF (60 mL) to a mixture of 1,4-diacetyl-piperazine-2,5-dione (5.94 g, 30 mmol) and 3-pyridinecarboxaldehyde (12.84 g, 120 mmol). Cool to 0° C. Add portionwise over 20 min a solution of potassium tert-butoxide (3.36 g, 30 mmol) in tert-butanol (60 mL) to this solution. Warm to room temperature and stir for 2 h. Pour the mixture into water (400 mL) and filter. Wash with water three times, then with hexanes to obtain the title compound as a yellow powder (4.0 g, 54%): 1H NMR (DMSO-d6) δ 2.51 (s, 3H), 4.37 (s, 2H), 6.95 (s, 1H), 7.43 (dd, 1H), 7.96 (d, 1H1), 8.50 (d, 1H), 8.73 (s, 1H), 10.64 (bs, 1H).
Reaction SMILES: CN(C)C(=CC=C(C1C=CC=CC=1)C(OCC)=O)C(OCC)=S.F[B-](F)(F)F.[CH3:29][N:30]([CH3:42])[C:31]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=[N+](C)C.CC[O-].[Na+].[CH:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][C:48]=1[S:57][CH2:58][C:59]([O:61][CH2:62][CH3:63])=[O:60]>C(O)C>[CH3:29][N:30]([CH3:42])[C:31](=[CH:32][CH:33]=[C:58]([S:57][C:48]1[CH:49]=[CH:50][C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:47]=1)[C:59]([O:61][CH2:62][CH3:63])=[O:60])[C:37]([O:39][CH2:40][CH3:41])=[O:38]
Reactant: CCOC(=O)CSc1ccc2ccccc2c1
Reactant: CCOC(=O)C(=CC=[N+](C)C)N(C)C
Agent: CCOC(=O)C(=CC=C(C(=S)OCC)N(C)C)c1ccccc1
Agent: CC[O-]
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C(=CC=C(C(=O)OCC)N(C)C)Sc1ccc2ccccc2c1
Yield: 82.3 %

Procedure:
The procedure is as in Example 2 for the preparation of diethyl 2-dimethylamino-5-phenylthio-2,4-hexadienedioate, starting with N-(3-dimethylamino-3-ethoxycarbonylpropenylidene)-N-methylmethanaminium tetrafluoroborate (10 g), a 2M ethanolic solution of sodium ethylate (21 cc) and ethyl (2-naphthylthio)acetate (12.9 g) in ethanol (100 cc). After purification by chromatography on a silica column with a mixture of cyclohexane and ethyl acetate (50:50 by volume) as eluent, diethyl 2-dimethylamino-5-(2-naphthylthio)-2,4-hexadienedioate (11.5 g) is obtained in the form of a yellow oil, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1)([O-])=O>CCO.[Pd]>[F:15][C:12]([F:13])([F:14])[CH2:11][O:10][C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1ccnc(OCC(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccnc(OCC(F)(F)F)c1
Yield: 93.7 %

Procedure:
4-Nitro-2-(2,2,2-trifluoro-ethoxy)-pyridine (1.11 g, 5 mmol) in 40 mL EtOH and 50 mg 10% Pd/C is placed under hydrogen atmosphere at room temp for 16 h. The solvent is removed under reduced pressure to give 0.9 g, 100% yield of 2-(2,2,2-trifluoro-ethoxy)-pyridin-4-ylamine.
Reaction SMILES: [Cl:1][SiH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:7]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:12])[CH2:8][CH2:9][CH:10]=[CH2:11]>>[Cl:1][Si:2]1([CH2:11][CH2:10][CH2:9][CH2:8][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cl[SiH]1CCCC1
Reactant: C=CCCC(=O)OCc1ccccc1
Product: O=C(CCCC[Si]1(Cl)CCCC1)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a mixture of crude 1-chlorosilolane (0.317 g) and benzyl pent-4-enoate (0.50 g; 2.63 mmol) under argon was added two drops of Karstedt's catalyst solution (in xylenes; ˜2% Pt). The reaction vessel was sealed and the mixture was heated to 60° C. for 18 hours. The crude liquid was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[C:28]([F:31])([F:30])[F:29])[CH:23]=O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[C:28]([F:29])([F:30])[F:31])/[CH:23]=[C:8]1/[C:9](=[O:12])[C:10]2[C:6]([CH2:7]/1)=[CH:5][C:4]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[C:3]([O:2][CH3:1])[CH:11]=2
Reactant: COc1cc2c(cc1N1CCOCC1)CCC2=O
Reactant: O=Cc1ccc(C(F)(F)F)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1N1CCOCC1)C/C(=C\c1ccc(C(F)(F)F)c(Cl)c1)C2=O
Temperature: 120 °C
Reaction time: 6 h

Procedure:
To a solution of 13 (550 mg, 2.226 mmol) in toluene 25 mL was added 3-chloro-4-(trifluoromethyl)benzaldehyde 90 (464.2 mg, 2.226 mmol). PTSA (846.7 mg, 4.452 mmol) was added to the reaction, and stirred at 120° C. for 6 h, then diluted with ethyl acetate and washed with water (3×25 mL). The organic layer was dried over sodium sulphate and concentrated to get the crude compound 91 which was purified through flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 30% ethyl acetate in hexane to afford yellow coloured solid compound (E)-2-(3-chloro-4-(trifluoromethyl)benzylidene)-6-methoxy-5-morpholino-2,3-dihydro-1H-inden-1-one 91.