Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:11])[CH:3]=1.C(N(CC)CC)C.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:25][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCCCC1)c1ccc(Br)cc1F
Yield: 98.1 %

Procedure:
Dissolve 4-bromo-2-fluoro-benzoyl chloride (1 g, 4.21 mmol) in DCM and cool the solution in an ice bath. Add triethylamine (0.87 mL, 6.32 mmol) and cyclohexylamine (502 mg, 5.1 mmol) and stir the mixture at ambient temperature for 2 h. Partition the reaction mixture between brine and DCM. Dry the organic layer over Na2SO4, filter and concentrate in vacuo to give the desired intermediate as a white solid (1.24 g, 98%).
Reaction SMILES: Br[CH:2](Br)[CH2:3][C:4]12[CH2:14][C:8]3([CH3:15])[CH2:9][C:10]([CH3:13])([CH2:12][C:6]([C:16]45[CH2:26][C:20]6([CH3:27])[CH2:21][C:22]([CH3:25])([CH2:24][C:18]([CH2:28][CH:29](Br)Br)([CH2:19]6)[CH2:17]4)[CH2:23]5)([CH2:7]3)[CH2:5]1)[CH2:11]2.CC(C)([O-])C.[K+]>O>[C:3]([C:4]12[CH2:11][C:10]3([CH3:13])[CH2:9][C:8]([CH3:15])([CH2:7][C:6]([C:16]45[CH2:26][C:20]6([CH3:27])[CH2:21][C:22]([CH3:25])([CH2:24][C:18]([C:28]#[CH:29])([CH2:19]6)[CH2:17]4)[CH2:23]5)([CH2:12]3)[CH2:5]1)[CH2:14]2)#[CH:2]
Reactant: CC12CC3(C)CC(CC(Br)Br)(C1)CC(C14CC5(C)CC(C)(CC(CC(Br)Br)(C5)C1)C4)(C2)C3
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: C#CC12CC3(C)CC(C)(C1)CC(C14CC5(C)CC(C)(CC(C#C)(C5)C1)C4)(C3)C2
Temperature: 25 °C
Yield: 92.6 %

Procedure:
Next, 63.4 g of the 3,3′-bis(2,2′-dibromoethyl)-5,5′,7,7′-tetramethyl-1,1′-biadamantane obtained above (90.9 mmol), 200 ml of N,N-dimethylsulfoxide and a stirrer were charged in a 500 mL recovery flask. Under nitrogen flow, 28 g of potassium tert-butoxide (250 mmol) was added with agitating at room temperature. After the addition, the mixture was agitated at room temperature for 48 hours. Reaction solution was added to 400 mL of ion-exchange water. An aqueous layer was separated and removed therefrom, and solvent was removed under reduced pressure. Solid thus obtained was dried under reduced pressure, thus obtaining 31.5 g of 3,3′-diethynyl-5,5′,7,7′-tetramethyl-1,1′-biadamantane (84.1 mmol; yield: 92.5%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].[H-].[Na+].Br[CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH3:32]>CN(C)C=O>[CH3:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: COCCOCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCN1C(=O)[C@@]2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 86.7 %

Procedure:
To a solution of (8S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.27 g, 0.9 mmol) in dry N,N-dimethylformamide (15 mL) was added sodium hydride (60% w/w dispersion in mineral oil, 0.054 g, 1.4 mmol) at ambient temperature. The mixture was stirred at ambient temperature for 15 minutes and 1-bromo-2-(2-methoxyethoxy)ethane (0.33 g, 1.8 mmol) was added in one portion. The mixture was stirred at 60° C. for 6 h and concentrated in vacuo. Water (50 mL) was added to the residue and the mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with 40% ethyl acetate in hexanes to afford (8S)-1′-[2-(2-methoxyethoxy)ethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.31 g, 85%) as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.32-7.20 (m, 1H), 7.15-7.08 (m, 1H), 7.05-6.96 (m, 2H), 6.46 (s, 1H), 6.21 (s, 1H), 4.73 (ABq, 2H), 4.20-4.04 (m, 4H), 4.05-3.83 (m, 2H), 3.80-3.69 (m, 2H), 3.64-3.56 (m, 2H), 3.51-3.44 (m, 2H), 3.32 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 177.5, 155.1, 144.5, 142.5, 138.2, 132.3, 128.6, 123.7, 123.2, 121.2, 111.5, 109.2, 99.3, 80.0, 71.9, 70.4, 68.1, 64.5, 63.9, 59.0, 57.9, 40.2; MS (ES+) m/z 397.9 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[C:26]([O:30][C:31]([NH:33][C@H:34]([C:38](O)=[O:39])[CH2:35][S:36]C)=[O:32])([CH3:29])([CH3:28])[CH3:27].OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[C:26]([O:30][C:31]([NH:33][C@H:34]([C:38]([NH:1][C@@H:2]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]([NH:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])=[O:39])[CH2:35][SH:36])=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@@H](N)Cc1ccccc1
Reactant: CSC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)[C@@H]1CCCCN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
A solution of 1.02 g of 1-[3 (S)-amino-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-2(S)-piperidinecarboxamide and 685 mg of N-(tert.butoxycarbonyl)-S-methyl-L-cysteine in 7 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 394 mg of hydroxybenzotriazole , 335 mg of N-ethylmorpholine and 661 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 3 hours. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and with sodium chloride solution and then evaporated. The solvent was removed by evaporation and the residue was chromatographed on silica gel using dichloromethane/methanol (96:4) for the elution to give 630 mg of 1-[3(S)-[[N-(tert.butoxycarbonyl)-L-cysteinyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-2(S)-piperidinecarboxamide in the form of a white solid; MS: m/e 565 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:24][N:23]([C:25]([C@H:27]4[CH2:32][CH2:31][C@@H:30]([OH:33])[CH2:29][CH2:28]4)=[O:26])[CH2:22]3)[CH:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=2[N:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)(=O)C>C(Cl)Cl>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([O:20][CH:21]3[CH2:22][N:23]([C:25]([CH:27]4[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]4)=[O:26])[CH2:24]3)[CH:9]=2)[C:6]2[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=2[N:4]=1
Reactant: O=C([C@H]1CC[C@@H](O)CC1)N1CC(Oc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1CCC(C(=O)N2CC(Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.5 %

Procedure:
To a solution of [3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)azetidin-1-yl](cis-4-hydroxycyclohexyl)methanone (60 mg) in methylene chloride (1.2 mL) was added a Dess-Martin reagent (53 mg) under ice-cooling, followed by stirring at room temperature overnight. To the reaction mixture were added ethyl acetate and a saturated aqueous sodium bicarbonate solution, the organic layer was extracted, washed with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0-90:10) to obtain 4-{[3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)azetidin-1-yl]carbonyl}cyclohexanone (20 mg).
Reaction SMILES: C([O:4][C:5](=[O:77])[CH2:6][C@H:7]([OH:76])[C@H:8]([NH:16][C:17](=[O:75])[C@H:18]([NH:40][C:41](=[O:74])[C@H:42]([NH:44][C:45](=[O:73])[CH2:46][C@H:47]([OH:72])/[CH:48]=[CH:49]/[CH2:50][CH2:51][S:52][C:53]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[CH3:43])[CH2:19][S:20][C:21]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C=C.N1CCOCC1.CC(O)=O>CO.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>[OH:76][C@H:7]([C@H:8]([NH:16][C:17](=[O:75])[C@H:18]([NH:40][C:41](=[O:74])[C@H:42]([NH:44][C:45](=[O:73])[CH2:46][C@H:47]([OH:72])/[CH:48]=[CH:49]/[CH2:50][CH2:51][S:52][C:53]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[CH3:43])[CH2:19][S:20][C:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][C:5]([OH:77])=[O:4]
Reactant: C=CCOC(=O)C[C@H](O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)[C@@H](C)NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](NC(=O)C[C@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](Cc1ccccc1)[C@@H](O)CC(=O)O
Reaction time: 3 h
Yield: 81.8 %

Procedure:
To a solution of 4D (170 mg, 0.159 mmol), Pd(PPh3)4 (9 mg, 0.008 mmol) in dry methanol (6 mL) under argon was added morpholine (28 μL, 0.32 mmol) which was allowed to stir for 3 h. The reaction mixture was concentrated in vacuo, CH2Cl2 (20 mL) was then added before washing with 1M HCl (15 mL), sat. sodium hydrogen carbonate (15 mL), sat. brine (15 mL), dried over MgSO4 and concentrated in vacuo. Purification was then carried out by column chromatography on silica gel (5-8% MeOH/CH2Cl2 then +0.2% AcOH) to give 5D (130 mg, 0.13 mmol, 61%).
Reaction SMILES: C([O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([CH3:25])([CH3:24])[CH2:11][C:12]#[C:13][C:14]([C:20]([F:23])([F:22])[F:21])([OH:19])[C:15]([F:18])([F:17])[F:16])(C)(C)C.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OC)(C)(C)C>[F:16][C:15]([F:17])([F:18])[C:14]([C:20]([F:21])([F:22])[F:23])([OH:19])/[CH:13]=[CH:12]\[CH2:11][C:10]([CH3:25])([CH3:24])[CH2:9][CH2:8][CH2:7][CH2:6][OH:5]
Reactant: [H][H]
Reactant: CC(C)(CC#CC(O)(C(F)(F)F)C(F)(F)F)CCCCOC(C)(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: COC(C)(C)C
Product: CC(C)(C/C=C\C(O)(C(F)(F)F)C(F)(F)F)CCCCO
Yield: 94.8 %

Procedure:
A suspension of 22.13 g of 10-tert-butoxy-1,1,1 -trifluoro-6,6-dimethyl-2-trifluoromethyl-dec-3-yn-2-ol, 220 ml of tert-butylmethyl ether and 3.32 g of Lindlar catalyst was hydrogenated at 22° and 1 bar for 1.5 h after which time hydrogen up-take ceased. The suspension was filtered, the filtrate evaporated and the residue, containing pure (Z)-10-tert-butoxy-1,1,1-trifluoro-6,6-dimethyl-2-trifluoromethyl-dec-3-en-2-ol, was dissolved in 44 ml of isopropanol. The solution was treated with 22.8 g of 50% aqueous H2SO4 and the mixture was heated to 90° for 2 h after which time g.l.c. indicated completion of the reaction. The mixture was evaporated, the residue partitioned between dichloromethane and saturated NaHCO3 solution and the aqueous layer was extracted several times with dichloromethane. The combined organic layers were dried over MgSO4 and evaporated to give 17.97 g of the pure title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.[CH2:15]=O>C(O)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([CH3:15])[CH2:10]1
Reactant: C=O
Reactant: OC1(c2cccc(F)c2F)CCNC1
Solvent: O=CO
Product: CN1CCC(O)(c2cccc(F)c2F)C1

Procedure:
Preparation according to Example 11: Enantiomer E1 of 3-(2,3-difluorophenyl)-pyrrolidin-3-ol (0.15 g, 0.72 mmol), formic acid (1.95 mL), aqueous formaldehyde (40%, 2.17 mL). The mixture was stirred for 5 h after which additional aqueous formaldehyde (1.5 mL) was added and the mixture was refluxed overnight. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 10:1). Yield: 0.09 g. [α]D=+19.1°; The amine was converted to the oxalic acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether; M.p. 131-132° C.; MS m/z (relative intensity, 70 eV) 213 (M+, 15), 57 (bp), 58 (28), 141 (15), 127 (10), 113 (10).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][C@H:25]1[CH2:30][O:29][CH2:28][CH2:27][NH:26]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:24][C@H:25]1[CH2:30][O:29][CH2:28][CH2:27][N:26]1[C:21]([C@H:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:22]
Reactant: C[C@H]1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1COCCN1C(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.2 %

Procedure:
A 100-mL round-bottomed flask was charged with (R)-1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (2.04 g, 6.17 mmol, ASW MedChem. Inc., New Brunswick, N.J.), (S)-3-methylmorpholine (0.657 g, 6.50 mmol, Synthetech Inc., Albany, Oreg.), HATU (2.83 g, 7.45 mmol, ChemImpex International Inc., Wood Dale, Ill.), DIPEA (2.20 mL, 12.6 mmol) and DMF (12 mL). The reaction mixture was stirred at room temperature for 1 h. After this time, additional HATU (0.475 g) was added and the stirring at room temperature was resumed for 2 days. The reaction mixture was partitioned between water (120 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (2×40 mL). The combined organic phases were washed with water (50 mL), saturated aqueous NaHCO3 (50 mL), water (50 mL) and saturated aqueous NaCl (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to afford di-tert-butyl (2R)-2-(((3S)-3-methyl-4-morpholinyl)carbonyl)-1,4-piperazinedicarboxylate (2.71 g) as a light-brown solid.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[Cl:8][C:9]1[CH:21]=[CH:20][C:12]2[O:13][CH:14]([CH2:17][NH:18][CH3:19])[CH2:15][O:16][C:11]=2[CH:10]=1>>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][CH2:3][N:18]([CH2:17][CH:14]1[O:13][C:12]2[CH:20]=[CH:21][C:9]([Cl:8])=[CH:10][C:11]=2[O:16][CH2:15]1)[CH3:19])[CH3:7]
Reactant: CNCC1COc2cc(Cl)ccc2O1
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCN(C)CC1COc2cc(Cl)ccc2O1
Reaction time: 60 h

Procedure:
3.3 ml (0.03 mol) of ethyl acrylate are added to 5.0 g (0.023 mol) of 6-chloro-2-methylaminomethylbenzo-1,4-dioxane and the reaction mixture is allowed to stand for 60 hours at room temperature, yielding crude 3-[N-(6-chlorobenzo-1,4-dioxan-2-ylmethyl)-N-methylamino]-propionic acid ethyl ester which can be used without further purification.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]([F:21])([F:20])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][C:13]2=O)=[CH:8][CH:7]=1.Cl>N1C=CC=CC=1>[F:4][C:5]([F:21])([F:20])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[NH:17][C:16](=[O:18])[CH2:15][CH2:14][C:13]2=[N:2][OH:3])=[CH:8][CH:7]=1
Reactant: O=C1CCC(=O)C(c2ccc(C(F)(F)F)cc2)N1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: O=C1CCC(=NO)C(c2ccc(C(F)(F)F)cc2)N1
Temperature: 25 °C
Yield: 61.1 %

Procedure:
Pyridine (47 ml) and hydroxylamine hydrochloride (8.18 g) were added to a stirring solution of 6-(4-trifluoromethyl-phenyl)-piperidin-2,5-dione (5.04 g) under nitrogen. The mixture was heated at reflux for 21 h, cooled to room temperature, poured into aqueous hydrochloric acid (2M, 100 ml) and extracted with ethyl acetate (100 ml). The organic extract was washed with aqueous hydrochloric acid (3×100 ml) and the combined aqueous solution was extracted with ethyl acetate (2×50 ml). The combined organic solution was dried (MgSO4) and evaporated in vacuo to give the crude product (5.84 g) which was azeotroped with toluene (3×50 ml). FCC (dichloromethane: methanol, 12:1) gave the title compound (3.26 g) as an inseparable mixture of geometrical isomers (2:1). δ (d6 -DMSO) for the major isomer: 2.0-2.4 (m, 4H), 5.15 (d, 1H, J=3.5 Hz), 7.49 and 7.75 (2d, 4H, J=8 Hz for both). 8.39 (d, 1H, J=3.5 Hz), 11.08 (s, 1H). 1H-NMR signals for the minor isomer includes 5.77 (d, 1H, J=2.5 Hz), 7.59 and 7.72 (2d, 4H, J=8 Hz for both), 8.10 (d, 1H, J=2.5 Hz), 11.14 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:9]1[C:10]([C:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[N:17]=2)=[N:11][C:12](Br)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39]1([N:45]2[CH2:50][CH:49]=[C:48](B3OC(C)(C)C(C)(C)O3)[CH2:47][CH2:46]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)(C)C.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.C(Cl)Cl.Cl[Pd]Cl>[C:1]([O:5][C:6]([N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:9]1[C:10]([C:16]2[N:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:19]3[CH:28]=[CH:29][CH:30]=[CH:31][C:18]=3[N:17]=2)=[N:11][C:12]([C:48]2[CH2:49][CH2:50][N:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:46][CH:47]=2)=[CH:13][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCN(c3ccccc3)CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nc2ccccc2n1C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(C2=CCN(c3ccccc3)CC2)nc1-c1nc2ccccc2n1C(=O)OC(C)(C)C

Procedure:
A mixture of tert-butyl 2-[3-[bis(tert-butoxycarbonyl)amino]-6-bromo-pyrazin-2-yl]benzimidazole-1-carboxylate (100 mg, 0.1694 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine (58 mg, 0.2034 mmol), 4-ditert-butylphosphanyl-N,N-dimethyl-aniline; dichloropalladium (2 mg, 0.002825 mmol) and K2CO3 (28 mg, 0.2026 mmol) in toluene (1000 μL) and water (120 μL) were heated to 100° C. overnight. The reaction was diluted with DCM, washed with water followed by 1M NaOH, dried (MgSO4) and concentrated in vacuo. The material was used crude in the next step (quantitative yield assumed).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[CH:8]=[O:9])#[N:2].P([O-])(O)(O)=[O:13].[Na+].OO.Cl([O-])=O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([F:11])=[C:7]([CH:10]=1)[C:8]([OH:13])=[O:9])#[N:2]
Reactant: O=P([O-])(O)O
Reactant: N#Cc1ccc(F)c(C=O)c1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#Cc1ccc(F)c(C(=O)O)c1
Temperature: 25 °C
Yield: 432.8 %

Procedure:
To a solution of 5-cyano-2-fluorobenzaldehyde (145 mg) in acetonitrile (2 mL) were added a sodium dihydrogenphosphate aqueous solution (23 mg in 1 mL water) and 30% hydrogen peroxide (0.09 mL). To the resulting mixture was added dropwise a sodium chlorite aqueous solution (126mg in 1 mL water) for an hour at 0° C. The mixture was stirred for an hour at ambient temperature, then a small amount of sodium sulfite was added. The mixture was diluted with ethyl acetate and washed successively with 1N-hydrochloric acid and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 5-cyano-2-fluorobenzoic acid (137 mg) as a solid substance.
Reaction SMILES: COC1C=CC(N=[N:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[C:13]([S:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:23])=[O:22])[C:12]=2[OH:42])=CC=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[C:13]([S:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:23])=[O:22])[C:12]=1[OH:42]
Reactant: CCCCCCCCCCCCCCCCCCS(=O)(=O)c1cc2ccccc2c(N=Nc2ccc(OC)cc2)c1O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCS(=O)(=O)c1cc2ccccc2c(N)c1O
Yield: 96.3 %

Procedure:
To a suspension of 14 g (0.024 mole) 1-(p-methoxyphenylazo)-3-octadecanesulfonyl-2-naphthol in 500 ml hot ethanol was added a solution of 12 g (0.060 mole) sodium dithionite in 60 ml water. The mixture was stirred and refluxed for one hour, then cooled and filtered to give 11 g of solid, which can be recrystallized from hexane to give a solid, m.p. 84°-88° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]=[N:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C[O-].[Na+:14]>COCCOC>[C:9]([C:8]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=1[S-:11])#[N:10].[Na+:14]
Reactant: COc1cccc2sncc12
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cccc([S-])c1C#N
Temperature: 80 °C
Reaction time: 16 h

Procedure:
15.5 g (93.8 mmol) 4-Methoxy-benzo[d]isothiazole were dissolved in 200 ml ethylene glycol dimethyl ether at room temperature. 10.45 g (188 mmol) sodium methoxide were added. The mixture was heated to 80° C. for 8 h and stirring was continued at room temperature for 16 h. The mixture was divided and one quarter of the mixture was used in the subsequent synthesis without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][CH:11]=1.N1C=CC=CC=1.[CH3:26][O:27][C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)=[O:29].O>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH:17][C:34](=[O:35])[C:33]2[CH:32]=[CH:31][C:30]([C:28]([O:27][CH3:26])=[O:29])=[CH:38][CH:37]=2)=[O:15])=[CH:12][CH:11]=1
Reactant: COCCCCCCOc1ccc(C(=O)NN)cc1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COCCCCCCOc1ccc(C(=O)NNC(=O)c2ccc(C(=O)OC)cc2)cc1
Reaction time: 1 h
Yield: 99.5 %

Procedure:
A mixture of 4-(6-methoxy-n-hexyloxy)benzohydrazide (106.82 g) and pyridine (162 ml) in tetrahydrofuran (1 L) at 0°‥5° C. was treated portionwise with 4-methoxycarbonylbenzoyl chloride 83.75 g) over 30 minutes. After a further 1 hour at 0°-5° C., and 2 hours at room temperature, tlc indicated completed reaction and the reaction mixture was poured into water (7 L). The resulting precipitate was collected by filtration, washed thoroughly with water, and dried under hi-vacuum at 50° C. to give N-[4-(6-methoxy-n-hexyloxy)benzoyl]-N′-(4-methoxycarbonylbenzoyl)hydrazine (171.0 g) as a white solid.