Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C:11]([NH:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH3:38])=[O:12].[CH2:39]([N:41]([CH2:80][CH3:81])[C:42]1[CH:47]=[CH:46][C:45]([NH:48][C:49]([C:51]2[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=2)[C:54]([OH:56])=O)=[O:50])=[C:44]([C:60]2[CH:65]=[C:64]([C:66](=[O:79])[NH:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:78])([F:77])[F:76])[CH:70]=3)[CH:63]=[CH:62][N:61]=2)[CH:43]=1)[CH3:40].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:38][O:37][CH2:36][CH2:35][O:34][CH2:33][CH2:32][O:31][CH2:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][NH:13][C:11]([C@@H:6]1[CH2:7][CH2:8][CH2:9][CH2:10][N:5]1[CH2:4][CH2:3][N:2]([CH3:1])[C:54](=[O:56])[C:53]1[CH:57]=[CH:58][CH:59]=[C:51]([C:49]([NH:48][C:45]2[CH:46]=[CH:47][C:42]([N:41]([CH2:39][CH3:40])[CH2:80][CH3:81])=[CH:43][C:44]=2[C:60]2[CH:65]=[C:64]([C:66](=[O:79])[NH:67][CH2:68][C:69]3[CH:74]=[CH:73][CH:72]=[C:71]([C:75]([F:76])([F:77])[F:78])[CH:70]=3)[CH:63]=[CH:62][N:61]=2)=[O:50])[CH:52]=1)=[O:12]
Reactant: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)O)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CNCCN1CCCC[C@H]1C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(NC(=O)c2cccc(C(=O)N(C)CCN3CCCC[C@H]3C(=O)NCCOCCOCCOCCOCCOCCOCCOCCOC)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
To a mixture of (S)-1-(2-(methylamino)ethyl)-N-(2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)piperidine-2-carboxamide (0.145 mmol), 3-((4-(diethylamino)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)benzoic acid (0.12 mmol, 80 mg) and DIEA (0.6 mmol, 78 mg) in DMF (0.4 mL) was added HATU (0.145 mmol, 55 mg). The mixture was stirred at 60° C. for 1 h and purified by prep. HPLC to give a yellow solid (91 mg, 52%). MS (ES, m/z): 1124.38 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]=O)[C:3]=1F.[NH2:12][NH2:13]>CCCCO>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[CH:9]=[N:12][NH:13][C:3]=12
Reactant: O=Cc1ncc(F)c(Cl)c1F
Reactant: NN
Solvent: CCCCO
Product: Fc1cnc2cn[nH]c2c1Cl
Temperature: 110 °C

Procedure:
To a solution of 4-chloro-3,5-difluoropicolinaldehyde (533 mg, 3.0 mmol) in n-BuOH (15 mL) was added hydrazine (0.113 mL, 3.60 mmol) and the reaction was heated at 110° C. for 22 hours. The reaction mixture was cooled, concentrated and the residue was dissolved in EtOAc (100 mL) and washed with saturated Na2CO3 solution, dried over Na2SO4, and evaporated to give a residue which was purified by silica gel column chromatography eluted with hexanes/EtOAc (0-100%) to give the title compound. MS [M+H] found 172.0.
Reaction SMILES: [Si]([O:8][C:9]1[CH:47]=[CH:46][C:12]([O:13][C:14]([C:16]2[CH:17]=[C:18]([N:39]3[C:43](=[O:44])[CH:42]=[CH:41][C:40]3=[O:45])[CH:19]=[C:20]([C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][Si](C(C)(C)C)(C)C)=[CH:27][CH:26]=3)=[O:23])[CH:21]=2)=[O:15])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.F.[F-].[Na+].O>C1COCC1>[OH:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22]([C:20]2[CH:19]=[C:18]([N:39]3[C:43](=[O:44])[CH:42]=[CH:41][C:40]3=[O:45])[CH:17]=[C:16]([C:14]([O:13][C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:47][CH:46]=3)=[O:15])[CH:21]=2)=[O:23])=[CH:26][CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OC(=O)c2cc(C(=O)Oc3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc(N3C(=O)C=CC3=O)c2)cc1
Agent: F
Agent: [F-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Oc1ccc(O)cc1)c1cc(C(=O)Oc2ccc(O)cc2)cc(N2C(=O)C=CC2=O)c1
Reaction time: 8 h
Yield: 95.9 %

Procedure:
N-[3,5-di-(4-(tert-butyldimethylsilyloxy)phenoxycarbonyl)phenyl]maleimide (35 g 0.052 mole) was dissolved in THF (500 ml). Hydrogen fluoride (2.5 M, 70 ml), sodium fluoride (3 g) and water (280 ml) were added. The reaction mixture was stirred overnight and most of the solvent was removed. Filtration of the product over a silica bed and concentration in vacuo afforded N-[3,5-di-(4-hydroxyphenoxycarbonyl)phenyl]maleimide (22.2 g, 96%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1F)[CH:16]=[O:17]>>[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:9][C:6]1[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=1)[CH:16]=[O:17]
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: Oc1ccc(C(F)(F)F)nc1
Product: O=Cc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to those described for D4 starting from 6-(trifluoromethyl) 3-pyridinol and 3,4-difluorobenzaldehyde.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH2:12]O)=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:23].C(N(S(F)(F)[F:30])CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:11]([CH2:12][F:30])=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:23]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCOC(=O)c1cn(C2CC2)c2c(CO)c(Br)c(F)cc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(C2CC2)c2c(CF)c(Br)c(F)cc2c1=O
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In 127 ml of methylene chloride was suspended 1.27 g of ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-hydroxymethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate, and 1.33 g of diethylaminosulfur trifluoride was dropwise added to the suspension at -40° C., after which the resulting mixture was stirred at -20° C. for one hour and then at 0° C. for three hours. The reaction mixture was added to 120 ml of ice water and the pH was adjusted to 8 with a saturated aqueous sodium hydrogencarbonate solution. Thereafter, the organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluent: chloroform:ethanol=100:1), to obtain 1.05 g of colorless, crystalline ethyl 7-bromo-1-cyclopropyl-6-fluoro-8-fluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.[CH:6]1([CH2:12][CH:13]=O)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:13][CH2:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=CCC1CCCCC1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=CCC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
A solution of 76.36 g of tetrabromomethane in 100 ml of CH2Cl2 is added dropwise at -10° C. to a solution of 0.2 mol of cyclohexylacetaldehyde and 104.8 g of triphenylphosphine in 150 ml of CH2Cl2. After stirring at room temperature for 30 min, the mixture is filtered with suction, concentrated and purified on silica gel using petroleum ether as the eluent. 48 g of the title compound are obtained as an oil.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)(=O)[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[K+].O.NN>C(O)COCCO>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)c1ccc(-c2ccccc2)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCCc1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Yield: 70 %

Procedure:
Thousand gram of 4-n-pentanoylbiphenyl, 2 l of diethylene glycol and 564 g of potassium hydroxide were introduced into a 5 l three neck flask and warmed with stirring to give a uniform solution at about 80° C, which was then cooled to about 50° C, followed by adding 738 ml of hydrazine hydrate, heating with stirring, distilling off low boiling fractions (mainly water) until the temperature of the reaction mixture reached 185° C, heating under reflux at 185°-190° C for 4 hours, cooling to room temperature, adding 1.5 l of water and 400 ml of hexane, stirring, washing hexane layer with aqueous solution of sodium chloride, and distilling, to give 659 g of 4-n-pentylbiphenyl (b.p. 166°-167°/6 mmHg) (Yield 70%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH2:10][C:11]([C:34](=[O:50])[N:35]([CH2:39][CH2:40][CH2:41][O:42][Si](C(C)(C)C)(C)C)[CH2:36][CH2:37][CH3:38])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=O)(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[CH2:10][C:11]([C:34](=[O:50])[N:35]([CH2:39][CH2:40][CH2:41][OH:42])[CH2:36][CH2:37][CH3:38])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[O:28])=[CH:24][CH:25]=3)=[CH:16][C:14]=2[N:15]=1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCC(C)C)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCCO)C(=O)C1=Cc2ccc(-c3ccc(CC(=O)OCC(C)C)cc3)cc2N=C(N)C1
Reaction time: 1 h

Procedure:
Isobutyl 2-(4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate) was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then re-dissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2×), extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 10% MeOH/DCM/0.5% NH4OH) afforded isobutyl 2-(4-((1E,4E)-2-amino-4-((3-hydroxypropyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)phenyl)acetate. 1H NMR (400 MHz, CDCl3) δ 7.27-7.39 (m, 5H), 7.19-7.21 (m, 1H), 7.01-7.06 (m, 1H), 6.87 (s, 1H), 3.80-3.85 (m, 2H), 3.58-3.69 (m, 6H), 3.46-3.53 (m, 2H), 2.82 (s, 2H), 1.80-1.89 (m, 3H), 1.66-1.75 (m, 2H), 0.90-0.98 (m, 3H), 0.81-0.87 (m, 6H); m/z (APCI-pos) M+1=492.3.
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15](=O)[CH2:16][CH2:17][CH3:18])[CH:10]=1.Cl>CCO>[CH2:17]([C:16]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[NH:7][C:15]=1[C:11]1[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=1)[CH3:18]
Reactant: CCCC(=O)c1cccnc1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: CCc1c(-c2cccnc2)[nH]c2ccccc12
Temperature: 25 °C

Procedure:
A flask is charged with phenylhydrazine (0.873 g, 6.46 mmol) and EtOH (14 mL). 1-Pyridin-3-yl-butan-1-one (0.914 g, 6.13 mmol) is added and the reaction is refluxed for 1 h. After cooling to room temperature, HCl (4M in 1,4-dioxane, 6.45 mL, 25.83 mmol) is added. The reaction mixture is refluxed for 4 h. After cooling to room temperature, the precipitate formed is filtered to afford 3-ethyl-2-pyridin-3-yl-1H-indole as a yellow solid. MS (ESI) m/z 223.0 (M+H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:38])[CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]([C:31]4[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=4)[C:26]=3[C:27]([F:30])([F:29])[F:28])=[O:21])[CH:14]=2)[CH:9]=1.O.Cl>CO>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([N:25]2[C:26]([C:27]([F:30])([F:29])[F:28])=[C:22]([C:20]([NH:19][CH2:18][C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH:9]=[C:8]([O:7][CH2:6][C:5]([OH:38])=[O:4])[CH:17]=[CH:16]4)=[O:21])[CH:23]=[N:24]2)=[CH:32][CH:33]=1
Reactant: COC(=O)COc1ccc2cc(CNC(=O)c3cnn(-c4ccc(Cl)cc4)c3C(F)(F)F)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)COc1ccc2cc(CNC(=O)c3cnn(-c4ccc(Cl)cc4)c3C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
1 N NaOH (563 μL, 0.563 mmol) was added under nitrogen to [6-({[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester (243 mg, 0.469 mmol), prepared in the previous step, in 100 mL of MeOH plus 25 mL of water at room temperature. After the addition the reaction was stirred at room temperature overnight. The reaction was acidified by the addition of 1 N HCl and then concentrated under reduced pressure to remove the MeOH. The solid present was collected by filtration and dried under reduced pressure to give the title compound (210 mg, 89%) as a pink solid, mp 189-191° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9](=[O:18])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)(C)(C)C>Cl.O1CCOCC1>[NH2:7][CH2:8][C:9]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1cccc(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To [(3-chloro-phenylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (0.7 g, 2.46 mmol) at rt was added 1,4-dioxane HCl (10 ml). The reaction was stirred for 16 h at rt and then filtered. The collected solid was 2-amino-N-(3-chloro-phenyl)-acetamide hydrochloride salt (0.6 g, 100%). HPLC-MS 184, 186 [M+1]+.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1CCCC([O:24][C@H:25]2[CH2:51][CH2:50][C@@:49]3([CH3:52])[C:27](=[CH:28][CH:29]=[C:30]4[C@@H:48]3[CH2:47][CH2:46][C@@:45]3([CH3:53])[C@H:31]4[CH2:32][CH2:33][C@@H:34]3[C@H:35]([CH3:44])[CH2:36][CH2:37][C@@H:38]([OH:43])[C:39]([OH:42])([CH3:41])[CH3:40])[CH2:26]2)C1>C(O)C>[CH3:40][C:39]([OH:42])([C@H:38]([OH:43])[CH2:37][CH2:36][C@H:35]([C@@H:34]1[C@:45]2([CH3:53])[C@H:31]([C:30]3[C@H:48]([CH2:47][CH2:46]2)[C@:49]2([CH3:52])[C:27]([CH2:26][C@@H:25]([OH:24])[CH2:51][CH2:50]2)=[CH:28][CH:29]=3)[CH2:32][CH2:33]1)[CH3:44])[CH3:41]
Reactant: C[C@H](CC[C@@H](O)C(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC5CCCOC5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@H](CC[C@@H](O)C(C)(C)O)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 48 h
Yield: 67.3 %

Procedure:
Pyridinium p-toluenesulfonate (12.5 mg) was added to a solution of (24R)-5,7-cholestadiene-3β,24,25-triol 3-tetrahydropyranyl ether (25 mg) in 2 ml of ethanol in an argon stream under stirring, and the mixture was left to stand at room temperature for 2 days. The reaction mixture was evaporated with 40 ml of ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give 14 mg (67%) of (24R)-5,7-cholestadiene-3β,24,25-triol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:21]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH3:21])[C:13](=[O:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCN(C(=O)OCc2ccccc2)CC1=O
Yield: 79.6 %

Procedure:
Dissolve 4-benzyloxycarbonylpiperazin-2-one (2 g, 8.6 mmol) in THF (10 mL). Add sodium hydride (236 mg, 9.4 mmol, 60% dispersion in mineral oil) in one portion and stir at room temperature for 30 min. Add iodomethane (0.8 mL, 13 mmol) and stir at room temperature overnight. Concentrate, add ethyl acetate and wash with water. Separate organic layer, wash with saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with ethyl acetate) to give the title compound as a yellow oil (1.7 g, 82%).
Reaction SMILES: Br[C:2]1[C:16]([CH3:17])=[CH:15][C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([Cl:18])[CH:3]=1.COC1C=CC(C)=C([B:27]([OH:38])[O:28]OCOCC[Si](C)(C)C)C=1>>[Cl:18][C:4]1[C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:15][C:16]([CH3:17])=[C:2]([B:27]([OH:38])[OH:28])[CH:3]=1
Reactant: COc1ccc(C)c(B(O)OOCOCC[Si](C)(C)C)c1
Reactant: Cc1cc(OCOCC[Si](C)(C)C)c(Cl)cc1Br
Product: Cc1cc(OCOCC[Si](C)(C)C)c(Cl)cc1B(O)O
Yield: 54 %

Procedure:
5-Chloro-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid was prepared in 54% yield from [2-(4-bromo-2-chloro-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane according to the procedure for 5-methoxy-2-methyl-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid. 1H NMR (300 MHz, CDCl3) δ 8.11 (s. 1H), 7.09 (s, 1H), 5.37 (s, 2H), 3.84 (t, 2H, J=8.4 Hz), 2.76 (s, 3H), 0.98 (t, 2H, J=8.4 Hz), 0.01 (s, 9H). Anal. (C13H22BClO4Si—H2O)C, H. Calculated: C, 52.28; H, 6.75. Found: C, 51.98; H. 6.84.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:34]([O:36]CC)=O)=[C:4]([CH2:16][N:17]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])S(C2C=CC(C)=CC=2)(=O)=O)[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:6]=1[Br:7].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:7][C:6]1[N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:4]2=[CH:16][N:17]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:34]([OH:36])=[C:3]2[C:2]=1[Br:1]
Reactant: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(Br)n1Cc1ccc(F)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2Cc1ccc(F)cc1
Yield: 0.1 %

Procedure:
To a stirring solution of ethyl 4,5-dibromo-1-(4-fluorobenzyl)-2-({(2-ethoxy-2-oxoethyl)[(4-methylphenyl) sulfonyl]amino}methyl)-1H-pyrrole-3-carboxylate (124.2 g, 184.3 mol) in anhydrous THF (1.0 L) was added LiHMDS (405 mL, 1.0M in THF, 0.405 mol) at −78° C. over 1 h. The mixture was quenched with aq. NH4Cl, extracted with ethyl acetate. The organic layer was dried over Na2SO4, and concentrated. The residue was purified by column chromatography with etyl acetate/hexane (1/1, v:v) to ethyl acetate/dichloromethane (9/1) to give the title product (52.0 g 60% yield). 1H NMR (DMSO-d6) δ ppm. 11.50 (s, 1H), 8.63 (s, 1H), 7.16 (d, J=7.2 Hz, 4H), 5.60 (s, 2H), 5.67 (s, 2H), 4.39 (q, J=7.1 Hz, 2H,), 1.33 (t, J=7.2 Hz, 3H). LC/MS (API-ES, M+H+): 473.0.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][NH:4][C:3]=1[N:9]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:29][C:30]1[C:31](F)=[C:32]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>CN(C=O)C>[Cl:1][C:2]1[C:3]([N:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:35]1[CH:34]=[CH:33][C:32]([N+:36]([O-:38])=[O:37])=[CH:31][C:30]=1[F:29]
Reactant: O=[N+]([O-])c1cccc(F)c1F
Reactant: O=c1cc[nH]c(N=C(c2ccccc2)c2ccccc2)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccnc(N=C(c3ccccc3)c3ccccc3)c2Cl)c(F)c1
Temperature: 95 °C
Reaction time: 3 h
Yield: 67 %

Procedure:
To a reactor was added 24 g of 3-chloro-2-(diphenylmethyleneamino) pyridin-4(1H)-one, DMF (100 mL), cesium carbonate (12.7 g; 0.5 eq) and difluoronitrobenzene (9.3 mL; 1.1 eq). The reaction mixture was heated to 95° C. and stirred for three hours. After the reaction was complete, the reaction mixture was poured onto crushed ice and the solids were filtered off and washed with water. The crude solids were charged back to the reactor and dissolved in THF (200 mL). Methanol was added and the mixture was distilled at a constant volume of 350 mL, until THF had been azeotropically removed. Additional methanol (100 mL) was added and the suspension was cooled to room temperature. The solids were filtered and dried under vacuum to yield 3-Chloro-N-(diphenylmethylene)-4-(2-fluoro-4-nitrophenoxy)pyridin-2-amine (23.3 g; 67% yield).
Reaction SMILES: [F:1][C:2]1[C:3](B(O)O)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)C.C([O-])([O-])=O.[K+].[K+].Br[C:21]1[S:22][C:23]([N:26]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:24][N:25]=1>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.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([C:21]2[S:22][C:23]([N:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])=[CH:24][N:25]=2)[CH:5]=[N:4][CH:3]=1
Reactant: OB(O)c1ncccc1F
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(Br)s1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1cnc(-c2cncc(F)c2)s1
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
To a 3-neck round bottom flask was added fluoropyridine boronic acid (4.55 g, 32.3 mmol), ethanol (54 mL), and aqueous K2CO3 solution (27 mL, 2.0 M, 53.8 mmol), followed by 50 mL toluene. To this mixture was added di(tert-butyl) 2-bromo-1,3-thiazol-5-ylimidodicarbonate (10.2 g, 26.9 mmol). Next, tetrakis(triphenylphosphine)palladium(0) (6.2 g, 5.4 mmol) was added in one portion. The flask was fitted with a reflux condenser and was heated to reflux. After 45 minutes, the reaction was cooled in an ice bath and partitioned between aqueous saturated NaHCO3 and ethyl acetate. The layers were separated and the aqueous layer was extracted once with ethyl acetate. The combined organics were washed once with brine, dried over MgSO4, filtered, and then concentrated. This solid was triturated with 20% ethyl acetate/hexanes. The solids were filtered off and the filtrate evaporated to provide a residue which was purified via silica gel column chromatography (0 to 100% ethyl acetate/hexanes) to afford the desired product as an off-white solid (7.74 g, 73% yield): mp 94-96° C.; 1H NMR (300 MHz, CDCl3) δ 8.91 (app t, J=1.3 Hz, 1H), 8.52 (d, J=3.0 Hz, 1H), 7.96 (ddd, J=9.2, 3.0, 1.8 Hz, 1H), 7.66 (s, 1H), 1.48 (s, 18H); ESIMS m/z 396 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15]1[O:18][C@@H:16]1[CH3:17]>>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:15][C@H:16]([OH:18])[CH3:17])[CH:8]=1
Reactant: C[C@@H]1CO1
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@H](O)Cn1cc(N)cn1
Reaction time: 64 h

Procedure:
To a solution of 4-nitropyrazole (44.7 mg, 0.395 mmol, 1 equiv) in (R)-propylene oxide (1 mL) was added cesium carbonate (78 mg, 0.24 mmol, 0.61 equiv) at 24° C. After 64 h, the reaction mixture was partitioned between ethyl acetate (3 mL) and half-saturated aqueous sodium chloride solution (3 mL). The organic was separated, and the remaining aqueous phase was extracted with ethyl acetate (2×3 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in methanol (4 mL) and circulated through a H-Cube® continuous-flow hydrogenation reactor (ThalesNano) fitted with a palladium on carbon catalyst cartridge at 30° C. The resulting solution was concentrated in vacuo to provide product as a pink oil, which was used without further purification. 1H NMR (500 MHz, CDCl3), δ: 7.17 (s, 1 H), 7.01 (s, 1 H), 4.13 (m, 1 H), 4.00 (dd, J=13.8, 2.7 Hz, 1 H), 3.84 (dd, J=13.8, 7.9 Hz, 1 H), 3.47 (s, 1 H), 3.15 (br s, 2 H), 1.18 (d, J=6.3 Hz, 3 H).