Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:35][NH:36][C:37](=O)[CH2:38][CH3:39])=[N:10][N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:37]([CH2:38][CH3:39])=[N:36][N:35]=3)[N:11]([CH2:23][C:24]3[C:25]([CH3:34])=[N:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=3)[C:12](=[O:22])[C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)NNc1nn(Cc2ccc(C(F)(F)F)nc2C)c(=O)c(-c2ccc(C#N)cc2)c1-c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCc1nnc2c(-c3ccc(Cl)cc3)c(-c3ccc(C#N)cc3)c(=O)n(Cc3ccc(C(F)(F)F)nc3C)n12
Temperature: 130 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a round bottom flask was added N′-(4-(4-chlorophenyl)-5-(4-cyanophenyl)-1-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-1,6-dihydropyridazin-3-yl)propionohydrazide (45 mg, 0.0794 mmol) and toluene (3 ml). The reaction was heated to 130° C. and stirred at this temperature for 1 hr. After this time, POCl3 (1 ml) was added and the reaction mixture was stirred at 130° C. for additional 4 hrs. The reaction was then cooled to rt and concentrated under reduced pressure. The residue was dissolved in EtOAc (30 ml) and the resulting solution was washed with 0.5N NaOH (10 ml), water (15 ml), saturated aqueous NaCl (10 mL). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was purified using an automated column chromatography system (ISCO, 4 gm silica gel) eluting with a gradient of 65%-100% EtOAc/Hex to give product 4-(8-(4-chlorophenyl)-3-ethyl-5-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-6-oxo-5,6-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-7-yl)benzonitrile (30 mg) as off-white solid. 69% yield. HPLC retention time (method A) 3.110 min; LCMS (M+H)=549.4. 1HNMR (CDCl3, 500 Hz): 7.49-7.53 (3H, m), 7.35-7.37 (1H, m), 7.22-7.24 (6H, m), 5.57 (2H, s), 2.73 (2H, q), 2.65 (3H, s), 1.38 (3H, t); 13CNMR (CDCl3, 500 Hz) 159.8, 155.7, 148.6, 147.5(q), 143.9, 138.0, 137.1, 136.6, 133.5, 131.9, 131.8, 128.9, 120.8(q), 118.6, 118.2, 112.6, 49.2, 22.2, 20.5, 12.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[C:9](/[CH2:31][CH3:32])=[C:10](\[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=1)/[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][N:15]=[CH:14]2.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:33]([N:16]1[C:17]2[C:13](=[CH:12][C:11](/[C:10](/[C:20]3[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=3)=[C:9](/[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[Cl:1])\[CH2:31][CH3:32])=[CH:19][CH:18]=2)[CH:14]=[N:15]1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1ccc(F)cc1Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2c(cnn2C(C)=O)c1)c1ccc(F)cc1Cl
Temperature: 25 °C

Procedure:
To a solution of (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (0.25 g, 0.56 mmol; Compound 195) in DCM (5.6 mL) at room temperature, acetic anhydride (57 mg, 0.56 mmol) was added followed by N,N-dimethylpyridin-4-amine (6 mg, 0.056 mmol). The reaction was stirred at room temperature over the weekend, quenched with water, and then extracted with DCM (2×50 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered, and concentrated to give the crude product. This crude material was purified on a silica gel column using 0-20% ethyl acetate in hexanes to afford the title compound. 1H NMR (400 MHz, DMSO-d6): δ 12.34 (br, 1H), 8.52 (s, 1H), 8.30 (d, 1H), 7.80 (s, 1H), 7.50 (d, 1H), 7.45-7.40 (m, 5H), 7.20-7.10 (m, 1H), 6.94 (d, 2H), 6.39 (d, 1H), 2.77 (s, 3H), 2.34 (q, 2H), 0.87 (t, 3H); LCMS: 489 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][O:6][CH:7]1[CH2:14][CH:13]2[N:15](C(OCC3C=CC=CC=3)=O)[CH:9]([CH2:10][O:11][CH2:12]2)[CH2:8]1)[CH3:2]>CCO.[Pd]>[CH:13]12[NH:15][CH:9]([CH2:8][CH:7]([O:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:26])[CH2:14]1)[CH2:10][O:11][CH2:12]2
Reactant: CCOC(=O)COC1CC2COCC(C1)N2C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COC1CC2COCC(C1)N2
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
To a solution of intermediate benzyl 7-(2-ethoxy-2-oxo-ethoxy)-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate (144 mg, 0.40 mmol) in EtOH (10 mL) was added 10% Pd/C (20 mg). The mixture was charged with H2 and being stirred at room temperature for 2 h. The mixture was filtered through a pad of Celite and washed with EtOH. The resulting filtrate was concentrated in vacuo to give compound 46a (83 mg, 91%). LC/MS: calc'd 230 (MH+), exp 230 (MH+); 1H NMR (MeOD, 400 MHz): 4.18 (dd, J=14.0, 6.8 Hz, 2H), 4.13 (s, 2H), 3.74 (m, 1H), 3.68 (m, 4H), 2.98 (m, 2H), 2.27 (m, 2H), 1.77 (m, 2H), 1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][C:11]2[C:19]3[N:18]=[N:17][NH:16][C:15]=3[CH:14]=[CH:13][C:12]=2[Cl:20])=[CH:8][C:7]([Cl:21])=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[C:38]2[C:33](=[N:34][CH:35]=[CH:36][CH:37]=2)[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:31]=1>CN(C=O)C>[Cl:20][C:12]1[CH:13]=[CH:14][C:15]2=[N:16][N:17]([CH2:29][C:30]3[C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:31]=3)[N:18]=[C:19]2[C:11]=1[O:10][C:9]1[CH:8]=[C:7]([Cl:21])[CH:6]=[C:3]([C:4]#[N:5])[C:2]=1[Cl:1]
Reactant: CC(C)(C)OC(=O)n1nc(CBr)c2cccnc21
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)n1nc(Cn2nc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4Cl)c3n2)c2cccnc21
Reaction time: 1 h

Procedure:
2,5-dichloro-3-[(5-chloro-1H-1,2,3-benzotriazol-4-yl)oxy]benzonitrile (1.00 g, 2.94 mmol) and cesium carbonate (1.15 g, 3.53 mmol) were suspended in dry DMF (10 mL) under N2, and tert-butyl 3-(bromomethyl)-1H-pyrazolo[3,4-b]pyridine-1-carboxylate (0.965 g, 3.09 mmol) was added as a solution in DMF (5 mL) at room temperature. After 1 hour, the reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL), diluted with water (50 mL), and the mixture extracted with EtOAc (2×100 mL). The combined organic fractions were washed with water (3×100 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by automated column chromatography on silica gel (120 g) eluting with 25-50% EtOAc/hexanes. LRMS (M+1)=569.6.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].[CH:20]([O-])([O-])[O:21][CH2:22][CH3:23]>>[N+:1]([C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]3[N:15]=[C:16]([N:19]=[CH:20][O:21][CH2:22][CH3:23])[CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N)nn12
Reactant: CCOC([O-])[O-]
Product: CCOC=Nc1ccc2nnc(-c3ncc([N+](=O)[O-])n3C)n2n1

Procedure:
1.15 g. 3-(5-nitro-1-methyl-2-imidazolyl)-6-amino-s-triazolo[4,3-b]pyridazine was stirred with 15 ml. ethyl orthoformate and 7.5 m. acetic anhydride at a bath temperature of 130° C., then evaporated in a vacuum at 70° C. to give a residue of crude 3-(5-nitro-1-methyl-2-imidazolyl)-6-ethoxymethyleneamino-s-triazolo[4,3-b]pyridazine. A sample thereof, triturated with ethanol, melted at 134° - 135° C. The residue thus obtained was dissolved in 20 ml. of a mixture of isopropanol and dioxan (7:3) and 2.3 ml. 4-methylpiperazine added thereto at 20° C., while stirring. The crystals formed were filtered off with suction after about 15 minutes, washed with isopropanol and water and dried in a vacuum for 2 hours at 120° C. There was thus obtained 1.22 g. of the desired 3-(5-nitro-1-methyl-2-imidazolyl)-6-(4-methyl-piperazin-1-yl-methyleneamino)-s-triazolo[4,3-b]pyridazine which melts at 219° - 222° C.
Reaction SMILES: [CH2:1]([C@:3]1([CH:21]([CH3:25])[C:22](O)=[O:23])[C@@H:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH3:20])[C:11]=32)[CH2:6][CH2:5][CH2:4]1)[CH3:2].CN1CCOCC1.ClC(OCC)=O.[CH2:39]([NH2:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCCC1>[CH2:39]([NH:46][C:22](=[O:23])[CH:21]([C@@:3]1([CH2:4][CH3:5])[C@@H:12]2[N:7]([CH2:8][CH2:9][C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]([CH3:20])[C:11]=32)[CH2:6][CH2:2][CH2:1]1)[CH3:25])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC[C@@]1(C(C)C(=O)O)CCCN2CCc3c(n(C)c4ccccc34)[C@@H]21
Reactant: NCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC[C@@]1(C(C)C(=O)NCc2ccccc2)CCCN2CCc3c(n(C)c4ccccc34)[C@@H]21
Temperature: -5 °C
Yield: 78 %

Procedure:
3.40 g. (0.01 moles) of (-)-(1S,12bS)-1-ethyl-12-methyl-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-1-yl-propionic acid are added to a solution containing 2.04 g. (0.02 moles) of N-methylmorpholine (redistilled from sodium) in 20 ml. of dry tetrahydrofuran while stirring under nitrogen, then the solution is cooled to -5° C. and 1.10 g. (0.01 mole) of ethyl chloroformate are rapidly dropped in while stirring vigorously and keeping the inner temperature at or lower than 0° C. The mixture is stirred at 0° C. for 30 minutes, whereupon a solution containing 1.18 g. (0.011 moles) of benzylamine in 10 ml. of dry tetrahydrofuran is dropwise added at a temperature between -5° C. and 0° C. during 10 minutes. The mixture is stirred at 0° C. for 30 minutes, then during an additional stirring for 4 hours the mixture is allowed to warm to room temperature. The mixture is evaporated on a rotating evaporator and after shaking thoroughly the residue with 50 ml. of dichloromethane and 20 ml. of water, the phases are separated. The dichloromethane layer is washed at first with 20 ml. of 5% sodium carbonate solution, then three times with 20 ml. of water each, dried over anhydrous magnesium sulphate and evaporated. The residue which is the crude product, is purified by column chromatography on silica gel by using toluene containing 10% of diethylamine to give 3.36 g. (78% yield) of the title compound as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([CH:21]3[CH2:23][CH2:22]3)([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)O)[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)\[CH:21]=[CH:22]\[CH3:23])[C:6]3[CH2:24][CH2:25][N:26]([CH3:28])[CH2:27][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(O)(c2ccc(F)cc2)C2CC2)C1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: C/C=C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
2-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-1-cyclopropyl-1-(4-fluorophenyl)ethanol (398 g, 1 mmol) was dissolved thionyl chloride (3 mL) and stirred for 5 min. at RT. The solution was heated at 50° C. for 2 h. Excess thionyl chloride was removed under reduced pressure and the residue was dissolved in N-methyl-2-pyrrolidone (3 mL). KOH (472 mg, 8.4 mmol) was added and the reaction mixture was heated at 100° C. for 2 h. The reaction mixture was cooled to RT and diluted with ice-cold water. The aqueous layer was extracted with EtOAc, the organic layer was washed with water, dried over sodium sulfate, and concentrated, under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh) eluting with 2% MeOH-DCM followed by HPLC. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.58 (s, 1H), 7.48 (m, 2H), 7.20 (m, 4H), 6.60 (s, 1H), 6.0 (d, 1H), 5.80 (m, 1H), 4.75 (m, 2H), 4.40 (m, 1H), 3.82 (m, 1H), 3.58 (m, 1H), 3.20 (m, 1H), 3.10 (s, 3H), 2.0 (d, 3H).
Reaction SMILES: N1([C@]23CC[C@@H](C(C)=C)[C@@H]2[C@@H]2[C@@](C)(CC3)[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)C(=O)CC4)CC2)CC1.[CH3:34][S:35]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36].[N:44]1([C@:47]23[CH2:83][CH2:82][C@@H:81]([C:84]([CH3:86])=[CH2:85])[C@@H:48]2[C@@H:49]2[C@@:62]([CH3:65])([CH2:63][CH2:64]3)[C@@:61]3([CH3:66])[C@@H:52]([C@:53]4([CH3:80])[C@@H:58]([CH2:59][CH2:60]3)[C:57]([CH3:68])([CH3:67])[C:56]([C:69]3[CH2:74][CH:73]5[CH:71]([CH:72]5[C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH:70]=3)=[CH:55][CH2:54]4)[CH2:51][CH2:50]2)[CH2:46][CH2:45]1>>[CH3:65][C@:62]12[C@@:61]3([CH3:66])[C@@H:52]([C@:53]4([CH3:80])[C@@H:58]([CH2:59][CH2:60]3)[C:57]([CH3:67])([CH3:68])[C:56]([C:69]3[CH2:74][CH:73]5[CH:71]([CH:72]5[C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH:70]=3)=[CH:55][CH2:54]4)[CH2:51][CH2:50][C@@H:49]1[C@H:48]1[C@H:81]([C:84]([CH3:86])=[CH2:85])[CH2:82][CH2:83][C@:47]1([NH:44][CH2:45][CH2:46][N:41]1[CH2:42][CH2:43][CH:38]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:39][CH2:40]1)[CH2:64][CH2:63]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CS(=O)(=O)C1CCNCC1
Agent: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 33.2 %

Procedure:
The title compound was prepared following the method describe on step 1 for the preparation of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)octadecahydro-1H-cyclopenta[a]chrysen-9(5bH)-one using 4-(methylsulfonyl)piperidine and ethyl 3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylate as the reactants. The product was obtained as a mixture of diastereomers in 33.2% yield. MS: m/e 749.6 (M+H)+, 2.794 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.84-5.75 (m, 1H), 5.49-5.38 (m, 1H), 4.69 (br. s., 1H), 4.59 (br. s., 1H), 4.19-4.04 (m, 2H), 3.12 (dd, J=15.6, 12.8 Hz, 1H), 2.98-2.74 (m, 7H), 2.68-2.51 (m, 5H), 2.45 (d, J=7.5 Hz, 4H), 2.22-2.10 (m, 3H), 2.09-1.74 (m, 8H), 1.69 (s, 3H), 1.65-1.30 (m, 12H), 1.26 (m, 6H), 1.06 (br. s., 5.5H), 1.02 (s, 3H), 0.98-0.92 (m, 4.5H), 0.85-0.78 (m, 3H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].CC(C)=O.C1(O)C=CC=CC=1.[OH:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][C:20]=1[O:27][CH3:28].Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([O:39][CH3:40])=[O:38]>>[OH:24][CH2:23][C:22]1[CH:25]=[CH:26][C:19]([O:18][CH:36]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:30]=2)[C:37]([O:39][CH3:40])=[O:38])=[C:20]([O:27][CH3:28])[CH:21]=1
Reactant: COC(=O)Cc1ccccc1Br
Reactant: COc1cc(CO)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Oc1ccccc1
Solvent: CC(C)=O
Product: COC(=O)C(Oc1ccc(CO)cc1OC)c1ccccc1
Yield: 25.2 %

Procedure:
Using the K2CO3 /acetone conditions for phenol alkylation described in Step A of Example 30, 1.00 g (6.49 mmol) of 4-hydroxy-3-methoxybenzyl alcohol was alkylated with 1.64 g (7.14 mmol) of methyl 2-bromophenylacetate to afford 0.495 g (25%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CC1(C)[O:15][C:14](=O)[CH2:13][C:12](=[O:17])[O:11]1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[CH2:13][C:12]([OH:17])=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: O=C(O)CC(=O)Nc1ccc(Br)cc1
Temperature: 80 °C

Procedure:
According to the general method described in Synth. Commun. 2010, 40, 732, a mixture of 4-bromoaniline (10.0 g, 58.1 mmol) and 2,2-dimethyl-1,3-dioxan-4,6-dione (8.40 g, 58.1 mmol) was heated at 80° C. for 1 hour and cooled to room temperature to provide 3-((4-bromophenyl)amino)-3-oxopropanoic acid as a solid. A stream of nitrogen gas was passed over the solid product to remove liquid acetone formed as a by-product. To this solid was added Eaton's reagent (40 mL) and heated at 70° C. for 12 hours and cooled to room temperature. To the resulting mixture was added water and stirred vigorously to provide a suspension which was filtered. The solid residue was washed with water and dried in air to provide the title compound.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:33][C:32]([CH3:39])([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:31]3)[N:26]=[C:25]([CH3:40])[N:24]=2)=[O:20])[CH2:8][N:9]([O:12]C2CCCCO2)[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(O)=O>O>[CH:1]1([CH2:6][C@@H:7]([C:19]([NH:21][NH:22][C:23]2[C:28]([F:29])=[C:27]([N:30]3[CH2:31][C:32]([CH3:39])([N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)[CH2:33]3)[N:26]=[C:25]([CH3:40])[N:24]=2)=[O:20])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2CC(C)(N3CCCC3)C2)n1
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CC(C)(N3CCCC3)C2)n1
Yield: 64.8 %

Procedure:
A solution of [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}hydrazino)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (118 mg) in 4:1 AcOH:water (20 mL) was stirred at room temperature for 3 days. The solvents were removed in vacuo, and the resulting crude product was purified by RP-HPLC to provide [(2R)-2-(cyclopentylmethyl)-3-(2-{5-fluoro-2-methyl-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide (65 mg, 64%). LCMS: (M+H)+: 478.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=O)[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([F:21])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+].O1CCCC1>CO.C(#N)C>[Cl:1][C:2]1[CH:11]=[C:10]([CH:12]([NH2:28])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][CH:18]([F:21])[CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(F)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CC#N
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CCC(F)CC1
Temperature: 65 °C

Procedure:
A mixture of 1-[5-chloro-8-(4-fluoropiperidin-1-yl)quinolin-7-yl]ethanone (0.0364 g, 0.119 mmol) and ammonium acetate (0.0915 g, 1.19 mmol) in methanol (1.0 mL) and acetonitrile (1.0 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.297 mL, 0.297 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C16H20ClFN3 (M+H)+: m/z=308.1; Found: 308.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1.[Cl:26]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Cl:26][N:13]1[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:11]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:10]=[C:9]1[C:3]1[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: Clc1cccc(Cl)c1-c1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cccc(Cl)c1-c1nc(-c2ccccc2)c(-c2ccccc2)n1Cl

Procedure:
A mixture of 14.60 g. (0.04 mole) of the 2-(2',6'-dichlorophenyl)-4,5-diphenylimidazole, 5.34 g. (0.04 mole) of N-chlorosuccinimide, and 400 ml of carbon tetrachloride was heated at reflux temperature for 2 hours. The solution was cooled, filtered, and thefiltrate concentrated under vacuum. The resulting solid-oil mixture was triturated with 1-chlorobutane to give a residue of 16.68 g., m.p. 120°-140° C. (broad). The compound proved difficult to recrystallize from common solvents and only acetonitrile and nitromethane afforded reasonable recovery of crystals; from the latter solvents the crystals formed as large chunky aggregates. The best fraction 0.7664 g. has m.p. 125°-127° C.; an IR spectrum showed no NH absorption and a very strong 1620 cm-1 band.
Reaction SMILES: [CH2:1](O)[CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH:9]=[CH:10]\[CH2:11][CH3:12].N1C=CC=CC=1.CN(C)C=O.CS([Cl:29])(=O)=O>CCCCCC.O>[Cl:29][CH2:1][CH2:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH:9]=[CH:10]\[CH2:11][CH3:12]
Reactant: CC/C=C/C=C\CC/C=C\CCO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: O
Product: CC/C=C/C=C\CC/C=C\CCCl
Temperature: 7.5 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
(Z,Z,E)-3,7,9-Dodecatrien-1-ol (169.47 g, 0.94 mol), pyridine (134.2 g, 1.70 mol) and N,N-dimethylformamide (284 g) were placed in a reaction vessel, and stirred at 5 to 10° C. for 30 minutes. After stirring, methanesulfonyl chloride (151.2 g, 1.32 mol) was added dropwise thereto at 5 to 15° C. After completion of the dropwise addition, the reaction mixture was stirred at 60 to 65° C. for 2 hours. Then, water (471 g) was added to the reaction mixture to terminate the reaction. Hexane (471 g) was added thereto to separate the reaction mixture into phases. The organic phase was washed with hydrochloric acid and then with an aqueous sodium bicarbonate solution, and then concentrated by removal of the solvent under reduced pressure. The residue was distilled under reduced pressure to obtain (Z,Z,E)-1-chloro-3,7,9-dodecatriene (bp: 114 to 120° C./5 mmHg, 166.93 g, 0.84 mol) with a yield of 89.2%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([F:17])=[C:5]([C:14]([OH:16])=[O:15])[C:6](=[C:10]([F:13])[C:11]=1[F:12])C(O)=O.C(N(CCCCCCCC)CCCCCCCC)CCCCCCC.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[C:4]([F:17])=[C:5]([CH:6]=[C:10]([F:13])[C:11]=1[F:12])[C:14]([OH:16])=[O:15]
Reactant: COc1c(F)c(F)c(C(=O)O)c(C(=O)O)c1F
Agent: CCCCCCCCN(CCCCCCCC)CCCCCCCC
Agent: [Na+]
Agent: [OH-]
Product: COc1c(F)c(F)cc(C(=O)O)c1F
Yield: 87 %

Procedure:
Into a 100 ml three necked flask, 10 g (0.04 mol) of the 4-methoxy-3,5,6-trifluorophthalic acid prepared in Example 22 and 14.2 g (0.04 mol) of trioctylamine were charged, and the mixture was reacted at 140° C. for 4 hours with stirring. After completion of the reaction, 30 ml of a 20% sodium hydroxide aqueous solution was added thereto and stirred. The aqueous phase was separated and neutralized with a 10% hydrochloric acid aqueous solution and extracted with ethyl acetate. Then, the solvent was distilled off to obtain 7.17 g of 3-methoxy-2,4,5-triflourobenzoic acid. The yield was 87.0%
Reaction SMILES: CO[C:3](=O)[NH:4]/[C:5](/SC)=[N:6]/[C:7](=[O:10])[O:8][CH3:9].[Cl:14][C:15]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:16]=1[CH2:17][O:18][C:19]1[CH:20]=[C:21]([NH2:26])C(N)=[CH:23][CH:24]=1>CO.C(O)(=O)C>[Cl:14][C:15]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:16]=1[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:3]2[N:4]=[C:5]([NH:6][C:7](=[O:10])[O:8][CH3:9])[NH:26][C:21]=2[CH:20]=1
Reactant: COC(=O)/N=C(/NC(=O)OC)SC
Reactant: Nc1ccc(OCc2c(Cl)cccc2Cl)cc1N
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2ccc(OCc3c(Cl)cccc3Cl)cc2[nH]1
Yield: 64.5 %

Procedure:
add 728 mg of dimethyl[(Z)-(methylsulphanyl)methylylidene]biscarbamate to a solution of 1 g of 4-[(2,6-dichlorobenzyl)oxy]benzene-1,2-diamine in a mixture of 60 cm3 of methanol and 212 mg of glacial acetic acid. The mixture is refluxed for 5.5 hours then concentrated under reduced pressure (0.2 kPa). The residue is taken up in 80 cm3 of a saturated aqueous solution in sodium hydrogen carbonate and the mixture obtained is extracted five times with 150 cm3 of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue is taken up in 25 cm3 of acetonitrile, washed twice with 5 cm3 of acetonitrile, then dried under reduced pressure over sodium hydroxide. We obtain 834 mg of methyl {6-[(2,6-dichlorobenzyl)oxy]-1H-benzimidazol-2-yl}carbamate in the form of a white powder, which has the following characteristics: