Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][NH:11]1.O.[F:17][C:18]([F:42])([F:41])[CH2:19][O:20][C:21]1[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[CH:31][C:22]=1[C:23](OCC(F)(F)F)=[O:24]>CO>[CH:33]1[C:32]([O:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[CH:31][C:22]([C:23]([NH:8][CH2:9][CH:10]2[NH:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:24])=[C:21]([O:20][CH2:19][C:18]([F:17])([F:41])[F:42])[CH:34]=1
Reactant: NCC1CCCCN1
Reactant: O=C(OCC(F)(F)F)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(NCC1CCCCN1)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Temperature: 50 °C

Procedure:
Dissolve in 48 ml of toluene 12.0 g (0.03 mol) of trifluoroethanol 2,5-bis-trifluoroethoxybenzoate. Add 3.94 g (0.0345 mol) of 2-aminomethylpiperidine and heat the solution to a temperature of 80°±5° C. for 8 hours. Cool to 50° C. and add 36 ml of water. Carry out the separation at a temperature of 45°±5° C. Concentrate the organic phase under vacuum at a temperature of 35°±5° C. so as to eliminate as much toluene as possible. A semi-solid residue is obtained which is dissolved in 20 ml of methanol and concentrated again to a residue under vacuum. Methanol (40 ml) is then added and heated with refluxing until a yellow solution is obtained. Then cool until the crude base crystallizes, the precipitation is completed by adding 40 ml of water.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:20]([Cl:24])(Cl)(Cl)Cl.O[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][NH:35][C:36]2[C:49]3[C:48](=[O:50])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:41](=[O:51])[C:40]=3[C:39]([NH:52][CH2:53][CH2:54][N:55]3[CH2:60][CH2:59][CH2:58][CH:57](CO)[CH2:56]3)=[CH:38][CH:37]=2)[CH2:28]1.[ClH:63].P(C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)=O>C(Cl)Cl.CCOC(C)=O.CCO>[Cl:63][CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([CH2:33][CH2:34][NH:35][C:36]2[C:49]3[C:48](=[O:50])[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:41](=[O:51])[C:40]=3[C:39]([NH:52][CH2:53][CH2:54][N:55]3[CH2:60][CH2:59][CH2:58][CH:57]([CH2:20][Cl:24])[CH2:56]3)=[CH:38][CH:37]=2)[CH2:28]1
Reactant: Cl
Reactant: ClC(Cl)(Cl)Cl
Reactant: O=C1c2ccccc2C(=O)c2c(NCCN3CCCC(CO)C3)ccc(NCCN3CCCC(CO)C3)c21
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)c2c(NCCN3CCCC(CCl)C3)ccc(NCCN3CCCC(CCl)C3)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ph3P (377.7 mg, 1.44 mmol) and CCl4 (425 μL, 432 mmol) were stirred for 15 min. before it was added dropwise to a stirred solution of HAQ38 (125 mg, 0.24 mmol) in dry CH2Cl2 (5 mL) under N2 at reflux temperature. The reaction mixture was kept at reflux temperature for 4 h before it was cooled down to RT. Ethereal HCl was added to the solution and after 1 h of stirring, the precipitated solid was filtered off. To remove excess of Ph3P and Ph3PO, the precipitated solid was dissolved in warm CH3OH (10 mL). While stirring the dark blue solution at reflux, a mixture of EtOAc and EtOH (1:1) was added until precipitation of solid was observed. The solution was set aside for 1 h before the precipitated product was isolated by filtration; the excess Ph3P and Ph3PO remained in the EtOAc/EtOH solution. The title compound was afforded as a dark blue solid (98.3 mg, 65%). M.p. dec.>300° C.; δH (250 MHz; CDCl3); 1.1 (m, 2H, 2×CH2CHCH2Cl), 1.75 (m, 6H, CH2CH2CH and 2×CH2CH2CH2), 2.05 (m, 4H, ring-H), 2.18 (3×d, 2H, J=3 Hz and 10 Hz, 2×NCH2CH2), 2.73 (t, 4H, J=9 Hz, 2×HNCH2CH2N), 2.8 (m, 2H, ring-H), 2.96 (2×d, 2H, 2×NCH2CH), 3.5 (m, 8H, 2×CHCH2Cl and 2×HNCH2CH2N), 7.25 (s, 2H, C(2)H and C(3)H), 7.7 (m, 2H, C(6)H and C(7)H), 8.3 (m, 2H, C(5)H, C(8)H) and 10.75 (t, 2H, C(1)NH and C(4)NH); dC(62.9 MHz; CDCl3); 24.42, 28.34, 38.47, 40.56, 48.14, 54.22, 57.52, 57.60, 110.30, 123.52, 126.12, 132.01, 134.56, 145.82 and 182.65; FAB MS, m/z(M+H)+ 557; IR υmax/cm−1; 3400 (NH), 3090, 2960-2825 (CH2, CH3), 1650, 1600, 1585, 1525, 1275, 1025 and 740; Anal. calcd for C30H38Cl2N4O2.2HCl.2H2O: C, 54.06; H, 6.65; N, 8.41. Found: C, 54.07; H, 6.27; N, 8.14.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:5])[CH3:4].C([Si](C)(C)[O:11][CH:12]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:26]2[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[C:28]([CH3:35])[CH:27]=2)([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:17][C:16]=1[CH3:36])(C)(C)C.F>C(#N)C>[CH3:1][O:2][C:3](=[O:5])[CH3:4].[CH2:22]([C:21]([C:26]1[S:30][C:29]([S:31]([NH2:34])(=[O:33])=[O:32])=[C:28]([CH3:35])[CH:27]=1)([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][CH:12]([OH:11])[C:37]([CH3:39])([CH3:40])[CH3:38])=[C:16]([CH3:36])[CH:17]=1)[CH2:24][CH3:25])[CH3:23]
Reactant: CCC(CC)(c1ccc(OCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Agent: F
Solvent: COC(C)=O
Solvent: CC#N
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc(C)c(S(N)(=O)=O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To a solution of [5-(1-{4-[2-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-butoxy]-3-methyl-phenyl}-1-ethyl-propyl)-3-methyl-thiophene-2-sulfonylamine]-acetic acid methyl ester (380 mg, 0.59 mmol) in acetonitrile (10 ml) at 0° C. is added hydrofluoride solution (3 ml, 48% in water). After stirring at RT for 2 h, the reaction is concentrated and partitioned between EtOAc and 1N HCl. The organic layer is washed successively with 1N HCl and brine. Tle organic layer is concentrated and chromatographed (Hex to 25% EtOAc/Hex) to give the title compound (250 mg, 82%).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([OH:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]1=2.C(=O)([O-])[O-].[K+].[K+].[CH:17]([N:30]1[CH2:33][CH:32](I)[CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(OCC)(=O)C>COCCOC.O>[CH:17]([N:30]1[CH2:33][CH:32]([O:6][C:4]2[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[S:1][CH:5]=2)[CH2:31]1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Oc1csc2ccccc12
Reactant: IC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: c1ccc(C(c2ccccc2)N2CC(Oc3csc4ccccc34)C2)cc1
Temperature: 95 °C
Reaction time: 3 h

Procedure:
Benzo[b]thiophen-3-ol (215 mg, 1.43 mmol) and potassium carbonate (237 mg, 1.72 mmol) were successively added to a solution of 1-benzhydryl-3-iodoazetidine (500 mg, 1.43 mmol) in a mixture of 1,2-dimethoxyethane (12 mL) and water (6 mL) at room temperature. The reaction mixture was then heated up to 95° C. and stirred for 3 hours. After cooling down to room temperature, the reaction mixture was diluted by addition of water (50 mL) and ethyl acetate (50 mL). The aqueous phase was separated and extracted with ethyl acetate (5×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (2×50 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using petroleum ether/ethyl acetate (1:0 to 9:1) as eluent. The title compound was obtained as a yellow oil (220 mg, 21%).
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH:10]([CH3:21])[CH:9]([OH:8])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)=[CH:33][CH:32]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: Clc1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(Oc1ccc(-c2ccc(Cl)cc2)cc1)C(O)CCc1cccnc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11)), 4-chloro-iodobenzene (0.24 g), 2M aqueous sodium carbonate (0.5 ml) and tetrakis(triphenylphosphine)palladium (0) (0.1 g) in toluene (4 ml) and ethanol (1 ml). The reaction mixture was heated at 100° C. for 4 hours. After cooling, the solution was concentrated under reduced pressure. Concentrated hydrochloric acid (1 ml) was added to a solution of the residue in methanol (5 ml) and the suspension was stirred at room temperature for 3 hours. After work up, the residue was purified by normal-phase HPLC eluting with a gradient of 0-25% ethanol in dichloromethane to give a gum, from which the oxalate salt was made (0.11 g).
Reaction SMILES: Cl[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].[CH:28]1([NH2:31])[CH2:30][CH2:29]1.C([Mg]Cl)(C)C.[NH4+].[Cl-]>O1CCCC1>[Cl:8][C:6]1[N:7]=[C:2]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:31][CH:28]2[CH2:30][CH2:29]2)=[O:14])[CH:5]=1
Reactant: CN(C)CCCN
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Cl)nc(Cl)c2=O)c1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(Cl)nc(NCCCN(C)C)c1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 3-(3,5-dichloro-2-oxo-1(2H)-pyrazinyl)-4-methyl-benzoic acid, methyl ester (Example 107a, 200 mg) in tetrahydrofuran (3 mL) was added N,N-dimethyl-1,3-propanediamine (90 μL) and the mixture was stirred at room temperature for 12 h. Cyclopropylamine (220 μL) was added followed by the addition of iso-propylmagnesium chloride (2M in tetrahydrofuran, 1 mL) portionwise. The reaction mixture was stirred for 60 minutes and iso-propylmagnesium chloride (2M in tetrahydrofuran, 1 mL) was added. The mixture was stirred for an additional 30 minutes and sat. aqueous NH4Cl was added. The aqueous solution was extracted with ethyl acetate. The pooled organic was washed with brine and dried (MgSO4), filtered and the solvent removed. Purification by preparative HPLC (Gemini column, 0.1% ammonia:acetonitrile eluent) gave the title compound (149 mg).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][CH:25]([C:28]5[CH:32]=[C:31]([C:33]6[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=6)[NH:30][N:29]=5)[CH2:24][CH2:23]4)=[CH:17][CH:16]=3)=[N:9][CH:10]=[C:11]([CH:14]=2)[C:12]#[N:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[NH:40][C:41]([NH2:43])=[S:42].C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O>[C:1]1([C:7]2[CH:14]=[C:11]([C:12]3[S:42][C:41]([NH2:43])=[N:40][N:13]=3)[CH:10]=[N:9][C:8]=2[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:32]=[C:31]([C:33]5[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=5)[NH:30][N:29]=4)[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1cnc(-c2ccc(CN3CCC(c4cc(-c5ccncc5)[nH]n4)CC3)cc2)c(-c2ccccc2)c1
Reactant: NNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2cnc(-c3ccc(CN4CCC(c5cc(-c6ccncc6)[nH]n5)CC4)cc3)c(-c3ccccc3)c2)s1

Procedure:
A solution of 5-phenyl-6-(4-{[4-(5-pyridin-4-yl-1H-pyrazol-3-yl)piperidin-1-yl]methyl}phenyl)nicotinonitrile (4B-5; 0.030 g, 0.060 mmol) and thiosemicarbazide (0.006 g, 0.066 mmol) in TFA (1.5 mL) were heated to 60° C. for 16 hr. The reaction was then cooled, poured onto ice and basified with saturated aqueous sodium bicarbonate. The resulting precipitate (4B-6) was filtered, taken up in DMF and purified by reverse phase HPLC (5% CH3CN: 95% H2O+0.1% TFA to 95% CH3—CN: 5% H2O+0.01% TFA). 1H-NMR (500 MHz, d6 DMSO) δ 13.54 (bs, 1H), 9.64 (s, 1H), 9.07 (d, J=1.96, 1H), 8.81 (d, J=6.11, 2H), 8.21 (s, 2H), 8.10 (d, J=2.2, 1H), 7.65 (s, 2H), 7.23-7.49 (m, 9H), 7.00 (s, 1H), 4.33 (d, 2H), 3.45 (d, J=10.5, 2H), 2.95-3.15 (m, 3H), 2.21 (d, J=12.69, 2H), 1.76-1.90 (m 2H). HRMS m/z (M+H) Calcd: 571.2387, found: 571.2359.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[CH:4][C:5]([Cl:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)[CH:7]=1.CCO[C:23]([S-:25])=[S:24].[K+].Cl>CN(C)C=O>[Cl:18][C:5]1[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[CH:7][C:2]2[N:1]=[C:23]([SH:25])[S:24][C:3]=2[CH:4]=1
Reactant: CCOC(=S)[S-]
Reactant: Cc1nn(-c2cc(N)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc3nc(S)sc3cc2Cl)c(=O)n1C(F)F
Temperature: 140 °C
Yield: 68 %

Procedure:
30 mL N,N-dimethylformamide was charged with 0.01 mol 1-(5-amino-2,4-dichlorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred until it became clear. Then, 0.02 mol potassium ethyl xanthogenate was added to the mixture in two portions. The mixture was refluxed at 140° C. for 5 h, cooled, and poured into 100 mL ice water. Then, the mixture was acidified with 6 mol/L hydrochloric acid, and a large amount of solids crushed out. The title compound was obtained in a 68% yield as a white solid after filtration.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:22][CH:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:30])[CH2:25][CH2:24]2)=[N:4][CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][O:19][S:18](=[O:21])[O:17][CH2:16]2)=[CH:11][CH:10]=1.C([O:38]CC)C>C(#N)C.O>[O:21]=[S:18]1(=[O:38])[O:19][CH2:20][CH:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][C:7]3[N:6]=[CH:5][N:4]=[C:3]([O:22][CH:23]4[CH2:24][CH2:25][N:26]([C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:30])[CH2:27][CH2:28]4)[C:2]=3[CH3:1])=[CH:10][CH:11]=2)[CH2:16][O:17]1
Reactant: Cc1c(Oc2ccc(C3COS(=O)OC3)cc2)ncnc1OC1CCN(C(=O)OCC(C)C)CC1
Reactant: CCOCC
Solvent: CC#N
Solvent: O
Product: Cc1c(Oc2ccc(C3COS(=O)(=O)OC3)cc2)ncnc1OC1CCN(C(=O)OCC(C)C)CC1
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
To a solution of iso-butyl 4-((5-methyl-6-(4-(2-oxido-1,3,2-dioxathian-5-yl)phenoxy)pyrimidin-4-yl)oxy)piperidine-1-carboxylate (100 mg, 0.000198 mole) in acetonitrile (1.2 mL) were added NaIO4 (59 mg, 0.000277 mole) and RuCl3.3H2O (0.5 mg, 0.0000198 mole) in 0.2 mL water. After stirring the suspension at 30° C. for 30 minutes, 0.8 mL water and 1.2 mL diethyl ether were added. The layers were separated, and the aqueous layer was extracted with diethyl ether. The combined ether layer was dried over sodium sulfate, the solvents were evaporated to yield 50 mg product as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10](C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2].C1(C(C2C=CC=CC=2)CC(O)=O)C=CC=CC=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(c2ccccc2)c2ccccc2)CCN1
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCOC(=O)C1CNCCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
To a solution of 4-Benzhydryl-piperazine-2-carboxylic acid ethyl ester (0.5 g, 1.54 mmol) in dry CH2Cl2 (25 ml) was added 3,3-diphenylpropanoic acid (0.35 g, 1.54 mmol) under nitrogen. To the reaction was added EDC (0.59 g, 3.08 mmol) and DMAP (cat) and the reaction mixture stirred under nitrogen at room temperature overnight. The reaction was then concentrated under reduced pressure. The residue dissolved in ethyl acetate: water (10:1) (100 ml). The organic was washed with water (20 ml, 2×) and 10% NaOH (20 ml) and dried over MgSO4 and evaporated to dryness. The resulting residue was purified by column chromatography using hexane: ethyl acetate (3:1) to give title compound in 73% yield.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:17][C:18]1[C:19]([OH:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O>>[F:17][C:18]1[C:19]([OH:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[C:11]1[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13][C:12]1=[O:16]
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Reactant: O=Cc1cccc(F)c1O
Product: O=C1Nc2cc(-c3ccccc3)ccc2C1=Cc1cccc(F)c1O
Yield: 52.3 %

Procedure:
6-phenyl-2-oxindole (50 mg, 0.3 mmol) was condensed with 3-fluoro-2-hydroxybenzaldehyde (50 mg, 0.36 mmol) using method B to give 52 mg (53%) of 3-(3-fluoro-2-hydroxybenzylidene)-6-phenyl-1,3-dihydroindol-2-one as a yellow/orange solid.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH2:33]I)[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)C.[NH:39]1[CH:43]=[CH:42][N:41]=[CH:40]1.C(OC(C)C)(C)C>CC(N(C)C)=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[N:30][O:31][CH2:32][CH2:33][N:39]2[CH:43]=[CH:42][N:41]=[CH:40]2)[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1c[nH]cn1
Reactant: O=C(O)C(=NOCCI)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CC(=O)N(C)C
Solvent: CC(Cl)Cl
Solvent: CC(C)OC(C)C
Product: O=C(O)C(=NOCCn1ccnc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3 g of the syn isomer of 2-(2-tritylamino-4-thiazolyl)-2-(2-iodoethoxyimino)-acetic acid solvated with dichloroethane (=2.56 g of pure acid), 4.2 g of imidazole and 10 ml of dimethylacetamide was stirred for 3 hours at room temperature and after addition of another 10 ml of dimethylacetamide, the mixture was stirred for 40 hours at room temperature. The mixture was poured into 200 ml of isopropyl ether and the mixture was stirred for 30 minutes and was then decanted. The gummy residue was triturated in 200 ml of isopropyl ether and then treated with 300 ml of ether. The mixture was stirred for 30 minutes and was vacuum filtered. The product was rinsed with ether and was then taken up in 30 ml of acetone. The solution was stirred for one hour and was vacuum filtered and the recovered product was rinsed with acetone, with ether and dried to obtain 1.243 g of the syn isomer of 2-(2 -tritylamino-4-thiazolyl)-2-(2-imidazol-1-yl-ethoxyimino)-acetic acid (internal imidazolium salt) melting at 280° C. (decomposition).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:12][SiH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:10]=1)=[O:5])[CH3:2].Br[CH2:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=1)=[O:33].O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:12][SiH2:13][C:14]([CH3:17])([CH3:15])[CH3:16])[N:8]([CH2:31][C:32](=[O:33])[NH:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][N:36]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)n[nH]1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(O[SiH2]C(C)(C)C)(c2ccccc2)c2ccccc2)n(CC(=O)Nc2ccc(Cl)cn2)n1
Reaction time: 3 h

Procedure:
To a solution of 5 g 5-(tert-Butyl-diphenyl-silanyloxymethyl)-2H-pyrazole-3-carboxylic acid ethyl ester in 10 ml DMF 4 g Cs2CO3 and 3 g 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide were added and the mixture was stirred for 3 h. Then 10 ml of water were added and the mixture was extracted with ethyl acetate (2×50 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Inspection of the TLC and HPLC/MS indicated that a 1:1 mixture of the desired product together with the regioisomeric 5-(tert-Butyl-diphenyl-silanyloxymethyl)-2-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-2H-pyrazole-3-carboxylic acid ethyl ester was present. Purification of this mixture on silica gel eluting with a gradient on n-heptane/ethylacetate yielded the desired product as the faster eluting less polar isomer.
Reaction SMILES: [CH3:1][Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH:11]1([C:14]2[C:15]([O:28][CH2:29][C:30]3([CH3:37])[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]3)=[CH:16][C:17]([F:27])=[C:18]([CH:26]=2)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][CH2:12]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[CH:11]1([C:14]2[C:15]([O:28][CH2:29][C:30]3([CH3:37])[CH2:35][CH2:34][C:33](=[CH2:1])[CH2:32][CH2:31]3)=[CH:16][C:17]([F:27])=[C:18]([CH:26]=2)[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:13][CH2:12]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC1(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CCC(=O)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C1CCC(C)(COc2cc(F)c(C(=O)OC(C)(C)C)cc2C2CC2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
To a cooled (−20° C.) suspension of methyltriphenylphosphonium bromide (1.44 g, 4.02 mmol) in tetrahydrofuran (12 mL) was added lithium hexamethyldisilazide (1M solution in tetrahydrofuran, 4.0 mL, 4.00 mmol). After 90 minutes, a solution of tert-butyl 5-cyclopropyl-2-fluoro-4-((1-methyl-4-oxocyclohexyl)methoxy)benzoate (1.00 g, 2.68 mmol) in tetrahydrofuran (6 mL) was added. The reaction mixture was slowly warmed to ambient temperature and stirred for 12 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (20 mL) and diluted with ethyl acetate (100 mL). The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (0% to 5% ethyl acetate in hexanes) afforded the title compound (0.83 g, 82%) as a colourless oil: MS (ES+) m/z 319.1 (M−55).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1.[CH2:15]([S:18](Cl)(=[O:20])=[O:19])[CH2:16][CH3:17].C(N(CC)C(C)C)(C)C>ClC(Cl)C>[CH3:2][O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][S:18]([CH2:15][CH2:16][CH3:17])(=[O:20])=[O:19])[CH:7]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: COC(=O)Cc1cccc(CN)c1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)NCc1cccc(CC(=O)OC)c1

Procedure:
Following the procedure described in Preparation 8, (3-aminomethyl-phenyl)-acetic acid methyl ester hydrochloride (603 mg, 2.80 mmol) was converted to the title sulfonamide by reaction with 1-propanesulfonyl chloride (0.375 mL) and N,N-diisopropylethylamine (2.0 mL) in dichloroethane (10 mL). 1H NMR (400 MHz, CDCl3) δ 7.35-7.22 (m, 4H), 4.60 (bs, 1H), 4.29 (s, 2H), 3.70 (s, 3H), 3.63 (s, 2H), 2.92 (t, 2H), 1.79 (m, 2H), 0.99 (t, 3H).