Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12])=[CH:5][N:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:3]=1.[H-].[Na+].Br[CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]>CN(C)C=O>[Si:27]([O:26][CH2:25][CH2:24][N:7]([C:6]1[C:2]([Cl:1])=[N:3][N:4]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:5]=1)[C:8](=[O:14])[CH:9]([CH3:13])[CH2:10][S:11][CH3:12])([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CSCC(C)C(=O)Nc1cn(-c2cccnc2)nc1Cl
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCC(C)C(=O)N(CCO[Si](C)(C)C(C)(C)C)c1cn(-c2cccnc2)nc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
A solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)propanamide (0.150 g, 0.483 mmol) in N,N-dimethylformamide (2.413 ml) was cooled to 0° C. Sodium hydride (0.039 g, 0.965 mmol, 60% dispersion) was added at and the reaction was stirred at 0° C. for 30 minutes. (2-Bromoethoxy)(tert-butyl)dimethylsilane (0.231 g, 0.965 mmol) was added, the ice bath was removed, and the reaction was stirred at room temperature for 2 hours. The reaction was heated at 65° C. for 1.5 hours and then cooled to room temperature. Brine was added and the mixture was extracted with dichloromethane. The combined organic phases were concentrated and chromatographed (0-100% ethyl acetate/hexanes) to give N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-3-(methylthio)propanamide (0.120 g, 0.243 mmol, 50.4%) as an orange oil: IR (thin film) 1669 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J=2.5 Hz, 1H), 8.55 (dd, J=4.7, 1.4 Hz, 1H), 8.05 (s, 1H), 7.98 (ddd, J=8.3, 2.6, 1.4 Hz, 1H), 7.41 (ddd, J=8.4, 4.8, 0.5 Hz, 1H), 4.35-3.06 (m, 4H), 2.86-2.73 (m, 1H), 2.73-2.59 (m, 1H), 2.41 (dd, J=12.8, 5.7 Hz, 1H), 1.94 (s, 3H), 1.11 (d, J=6.7 Hz, 3H), 0.80 (s, 9H), 0.00 (s, 3H), −0.01 (s, 3H); ESIMS m/z 470 ([M+H]+).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH2:11]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1)[CH3:12]>>[CH2:11]([C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:15][CH:14]=1)[CH3:12]
Reactant: CCc1ccc(N)cc1
Reactant: CSc1ccc(C#N)cc1
Product: CCc1ccc(NC(=N)c2ccc(SC)cc2)cc1
Yield: 81.1 %

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (1.23 g, 8.2 mmol) and 4-ethylaniline (1 g, 8.2 mmol) by following the procedure described in preparation 10 (1.81 g, yield 81.1%, mp 156-158° C., purity 98.6% by HPLC). 1H-NMR (CDCl3): δ 1.22-1.26 (t, 3H), 2.51 (s, 3H), 2.60-2.66 (q, 2H), 4.70 (bs, 2H, D2O exchangeable), 6.89-6.91 (d, 2H), 7.17-7.19 (d, 2H), 7.26-7.29 (m, 2H), 7.79-7.81 (d, 2H). MS m/z:271.3 (M+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:60])[N:7]([CH2:34][CH2:35][O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[C:40]([C:45]([N:47]2[CH2:51][C:50](=[CH2:52])[CH2:49][C@H:48]2[C:53](OC)=[O:54])=[O:46])=[CH:39][C:38]=1[N+:57]([O-:59])=[O:58])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([C:19]([N:21]2[CH2:25][C:24](=[CH2:26])[CH2:23][C@H:22]2[C:27](OC)=[O:28])=[O:20])=[CH:13][C:12]=1[N+:31]([O-:33])=[O:32])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.Cl>C1(C)C=CC=CC=1.CO>[C:1]([O:5][C:6](=[O:60])[N:7]([CH2:34][CH2:35][O:36][C:37]1[CH:42]=[C:41]([O:43][CH3:44])[C:40]([C:45]([N:47]2[CH2:51][C:50](=[CH2:52])[CH2:49][C@H:48]2[CH:53]=[O:54])=[O:46])=[CH:39][C:38]=1[N+:57]([O-:59])=[O:58])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([C:19]([N:21]2[CH2:25][C:24](=[CH2:26])[CH2:23][C@H:22]2[CH:27]=[O:28])=[O:20])=[CH:13][C:12]=1[N+:31]([O-:33])=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C1C[C@@H](C(=O)OC)N(C(=O)c2cc([N+](=O)[O-])c(OCCN(CCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4C(=O)OC)cc3[N+](=O)[O-])C(=O)OC(C)(C)C)cc2OC)C1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: C=C1C[C@@H](C=O)N(C(=O)c2cc([N+](=O)[O-])c(OCCN(CCOc3cc(OC)c(C(=O)N4CC(=C)C[C@H]4C=O)cc3[N+](=O)[O-])C(=O)OC(C)(C)C)cc2OC)C1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 89.5 %

Procedure:
To a vigorously stirred solution of bis{2-[5-methoxy-2-nitro-4-[(S)-4-methylene-2-methoxycarbonyl-1-pyrrolidinylcarbonyl]phenyloxy]-ethyl}-carbamic acid tert-butyl ester 12 (100 mg, 0.12 mmol) in anhydrous toluene (2.4 mL) was added dropwise solution of DIBAL-H (480 μL of a 1M solution in toluene) at −78° C. under argon atmosphere. After the mixture was stirred for an additional 45 min, excess reagent was decomposed by addition of five drops of methanol followed by 5% HCl (4 mL). The resulting mixture was allowed to warm to 0° C. Layers were separated and the aqueous layer was further extracted with CH2Cl2 (3×3 mL). Combined organic layers were washed with brine, dried (MgSO4) and concentrated. Purification of the residue by flash chromatography (silica gel, 95:5 CHCl3/MeOH) yielded bis{2-[5-methoxy-2-nitro-4-[(S)-4-methylene-2-formyl-1-pyrrolidinylcarbonyl]phenyloxy]-ethyl}-carbamic acid tert-butyl ester 13 as light yellow oil (84 mg, 91%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([F:12])[C:6]([S:10][CH3:11])=[C:7]([F:9])[CH:8]=1.[Br-:13].[Li+].CC(C)=O.[Br-].[Na+]>O>[Br:13][CH2:2][C:3]1[CH:4]=[C:5]([F:12])[C:6]([S:10][CH3:11])=[C:7]([F:9])[CH:8]=1
Reactant: CSc1c(F)cc(CCl)cc1F
Reactant: [Br-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CSc1c(F)cc(CBr)cc1F

Procedure:
A mixture of 5-(chloromethyl)-1,3-difluoro-2-(methylthio)benzene (21.3 g, 0.10 mol), lithium bromide (15 g, 0.17 mol), and acetone (200 mL) was heated and held at reflux for 18 hours. The cool mixture was poured into water and extracted with dichloromethane (1×200 mL, 2×50 mL). The combined extracts were dried using magnesium sulfate, and concentrated. The residue was dissolved in acetone (200 mL), lithium bromide (30 g, 0.34 mol) and sodium bromide (20 g, 0.19 mol) were added and the mixture heated and held at 5 reflux for 42 hours. The mixture was cooled, added to water, and extracted with dichloromethane (1×150 mL, 1×50 mL). The combined extracts were washed with dilute sodium chloride, dried with magnesium sulfate, and concentrated. The 5-(bromomethyl)-1,3-difluoro-2-(methylthio)benzene was purified using silica gel chromatography using hexanes as a yellow solid (20.5 g, 80%). 1H NMR (CDCl3/400 MHz) 6.92-6.95 (m, 2H), 4.37 (s, 2H), 2.45 (s, 3H). HRMS m/z 251.9432 (M+, calcd 251.9420).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>N.CCO.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:22][NH2:23])[CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2CN(c3ccccc3C#N)CC2C1
Reactant: [H][H]
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CN(c3ccccc3CN)CC2C1
Reaction time: 2.5 h
Yield: 91.9 %

Procedure:
To a solution of 5-(2-cyano-phenyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (150 mg, 0.48 mmol) in NH3/EtOH (2M, 10 mL) was added Raney Nickel (3 mL slurry in water). The atmosphere was exchanged with hydrogen via balloon and the mixture was allowed to stir for 2.5 h. After this time the mixture was filtered through celite and concentrated to yield the title compound (140 mg). m/z (M+1) 318.29.
Reaction SMILES: F[C:2]1[C:7]([C:8](=O)[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][NH2:12].C(Cl)Cl>C(O)CO>[CH3:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:12][N:11]=1
Reactant: CC(=O)c1cccnc1F
Reactant: NN
Solvent: OCCO
Solvent: ClCCl
Product: Cc1n[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred solution of 1.10 g (7.91 mmol) of 1-(2-fluoropyridin-3-yl)ethanone in 5 mL of ethylene glycol under nitrogen was treated with 265 μL (8.31 mmol) of hydrazine. This solution was stirred for 2 hours at room temperature and then heated at 165° C. for 1.5 hours. The solution was cooled to room temperature, poured into CH2Cl2 (25 mL), and extracted with H2O (2×50 mL). The organic portions were combined, dried (MgSO4), filtered and concentrated in vacuo to give the title product as a fluffy off-white solid. 1H NMR (CDCl3): 2.61 (s, 3H), 7.14 (m, 1H), 8.06 (dd, 1H), 8.58 (dd, 1H), 11.18 (br s, 1H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].Br[CH2:39][C:40]([O:42][CH3:43])=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:43][O:42][C:40](=[O:41])[CH2:39][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1)=[O:11]
Reactant: COC(=O)CBr
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 55 °C
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-{(1H-benzimidazol-2-ylcarbonyl)(2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (1.06 g) was dissolved in dimethylformamide (20 ml), methyl bromoacetate (390 μl) and cesium carbonate (2.02 g) were added and the mixture was stirred at 55° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (1:9)-ethyl acetate was concentrated under reduced pressure to give the object product (1.19 g).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[CH:17][N:18]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].[B:30](OC(C)C)([O:35]C(C)C)[O:31]C(C)C>C1COCC1>[C:26]([O:25][C:23]([N:18]1[C:19]2[C:15](=[C:14]([F:13])[CH:22]=[CH:21][CH:20]=2)[CH:16]=[C:17]1[B:30]([OH:35])[OH:31])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)n1ccc2c(F)cccc21
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(B(O)O)cc2c(F)cccc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 66.6 %

Procedure:
To a solution of diisopropylamine (175 mL, 1.25 mol) in THF (800 mL) at 0° C. was added n-BuLi (500 mL, 1.25 mol, 2.5 M in hexane) dropwise. The mixture was stirred at 0° C. for 40 min. Then the mixture was cooled to −78° C. Tert-butyl 4-fluoro-1H-indole-1-carboxylate (118 g, 0.50 mol) in THF (300 mL) was added dropwise slowly, followed by triisopropyl borate (231 mL, 1.00 mol). The mixture was stirred at −78° C. for another 40 min. The reaction was monitored by HPLC. When the reaction was completed, the reaction was quenched with NH4Cl (sat. 500 mL). Then the mixture was adjusted to pH=6 with 1 N HCl. Extracted with EtOAc (2000 mL) and the combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated. The obtained solid was recrystallized with EtOAc and PE to give (1-(tert-butoxycarbonyl)-4-fluoro-1H-indol-2-yl)boronic acid (93 g, yield: 64%, store in fridge). 1H-NMR (CDCl3, 400 MHz) δ 7.77 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (s, 2H), 7.24 (m, 1H), 6.90 (m, 1H), 1.66 (s, 9H). MS (M+H)+: 280.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:20]3[CH:21]=[N:22][C:23]([CH2:25][OH:26])=[CH:24][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:27]([NH2:29])=[O:28])[CH3:9].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[CH3:30][S:31]([O:26][CH2:25][C:23]1[N:22]=[CH:21][C:20]2[N:16]([C:14]3[S:13][C:12]([C:27](=[O:28])[NH2:29])=[C:11]([O:10][CH:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH3:9])[CH:15]=3)[CH:17]=[N:18][C:19]=2[CH:24]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)Cl
Reactant: CC(Oc1cc(-n2cnc3cc(CO)ncc32)sc1C(N)=O)c1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Oc1cc(-n2cnc3cc(COS(C)(=O)=O)ncc32)sc1C(N)=O)c1ccccc1F

Procedure:
In a similar manner as described for example 49 (step 1), 2.9 g of 3-[-1-(2-fluorophenyl)ethoxy]-5-[6-(hydroxymethyl)-3H-imidazo[4,5-c]pyridin-3-yl]thiophene-2-carboxamide, 1.53 g of methanesulfonyl chloride, and 1.42 g of triethylamine in 70 ml dichloromethane give (3-{5-carbamoyl-4-[-1-(2-fluorophenyl)ethoxy]-2-thienyl}-3H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14]Br)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[F:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:11][CH2:12][CH2:13][CH2:14][O:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:6]1(=[O:23])=[O:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(NCCCBr)=C(c2ccccc2)S1(=O)=O
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)N1C(=O)C(NCCCOc2ccc(F)cc2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 31 %

Procedure:
The title compound was prepared as described for Example 5 from 2-tert-butyl-4-[(3-bromopropyl)amino]-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-fluorophenol using 3 equivalents of K2CO3 and with heating at 80° C. for 15 mins, 100° C. for 1 h and 120° C. for 1 h. The reaction mixture was evaporated to dryness and the residue was purified by silica gel column chromatography (Horizons Biotage) using 12-20% EtOAc in petroleum ether 40-60° C. as eluent to give the title compound (0.007 g, 31%). 1H NMR (500 MHz CDCl3): δ 7.54-7.50 (m, 2H), 7.45-7.40 (m, 3H), 7.00-6.96 (m, 2H), 6.82-6.78 (m, 2H), 5.76 (t, 1H), 3.86 (t, 2H), 3.11-3.02 (m, 2H), 1.88-1.80 (m, 2H), 1.75 (s, 9H); 13C NMR (125 MHz CDCl3): δ 159.8, 158, 154.7, 156.7, 135.3, 131.8, 129.7, 128.8, 125.3, 116.2, 160.0, 115.6, 115.5, 107.2, 66.7, 61.7, 42.5, 28.9, 27.8; Mass Spectrum: M+H+ 433.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH:24](OCC)[C:23]3[CH:22]=[C:21]4[CH:28]=[CH:29][CH:30]=[CH:31][C:20]4=[CH:19][C:18]=3[C:17]2=[O:32])=[O:8])=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[C:17](=[O:32])[C:18]3[CH:19]=[C:20]4[CH:31]=[CH:30][CH:29]=[CH:28][C:21]4=[CH:22][C:23]=3[CH2:24]2)=[O:8])=[CH:33][CH:34]=1
Reactant: CCOC1c2cc3ccccc3cc2C(=O)N1c1ccccc1NC(=O)c1ccc(OC)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)Nc2ccccc2N2Cc3cc4ccccc4cc3C2=O)cc1
Reaction time: 16 h
Yield: 94.8 %

Procedure:
To a solution of N-(4-methoxybenzoyl)-2-(1-ethoxy-1,3-dihydro-3-oxo-2H-benz[f]isoindol-2-yl)benzeneamine (140 mg, 0.31 mmol) in methylene chloride (2 mL) was added triethylsilane (0.5 mL) and trifluoroacetic acid (0.5 mL). After standing at room temperature for 16 h, the mixture was concentrated in vacuo. The residue was dissolved in methylene chloride and washed with saturated aqueous sodium bicarbonate solution, dried (magnesium sulfate), filtered, and concentrated in vacuo to yield 120 mg (95%) of the title compound.
Reaction SMILES: [C:1]1([S:7]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH:17]=O.N1CCCCC1>C(#N)C>[CH3:14][O:15][CH:16]([O:19][CH3:20])/[CH:17]=[C:9](/[S:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:8])\[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)CS(=O)c1ccccc1
Reactant: COC(C=O)OC
Solvent: C1CCNCC1
Solvent: CC#N
Product: COC(=O)/C(=C\C(OC)OC)S(=O)c1ccccc1
Temperature: 60 °C
Yield: 99 %

Procedure:
A mixture of methyl 2-(phenylsulfinyl)acetate (1 g, 5.04 mmol), 2,2-dimethoxyacetaldehyde (3.15 ml, 10.09 mmol) and piperidine (0.999 ml, 10.09 mmol) in acetonitrile (20 ml) was heated to 60° C. for 18 hr. After cooling to rt, the volatiles were removed in vacuo and the residue was chromatographed on a 5×12 cm silica gel column, eluting with a 0-40% EtOAc/Hex gradient. The pure fractions were concentrated to afford (E)-methyl 4,4-dimethoxy-2-(phenylsulfinyl)but-2-enoate (1.42 g, 4.99 mmol, 99% yield) as a light yellow oil. HPLC retention time=1.23 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS: (M+Na)=307.06. 1H NMR (500 MHz, chloroform-d) δ ppm 3.40 (s, 3H), 3.41 (s, 3H), 3.69 (s, 3H), 5.71 (d, J=7.2 Hz, 1H), 7.07 (d, J=6.6 Hz, 1H), 7.48 (m, 3H), 7.66 (m, 2H).
Reaction SMILES: Br[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:17]1[CH2:20][CH:19]([OH:21])[CH2:18]1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:17]2[CH2:20][CH:19]([OH:21])[CH2:18]2)=[CH:4][CH:5]=1
Reactant: Clc1ccc(C(Br)c2ccc(Cl)cc2)cc1
Reactant: OC1CNC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Reaction time: 1.5 h

Procedure:
The reaction mixture of 22.30 g (70.5 mmol) of 1-[bromo(4-chlorophenyl)methyl]-4-chlorobenzene, 5.67 g (77.6 mmol) of azetidin-3-ol (2) and 18.4 mL (105.75 mmol) of N,N-diisopropylethylamine in 250 mL of acetonitrile was rapidly stirred for 1.5 h at rt to 91° C. Reaction mixture was concentrated to remove solvents and residue was purified by silica gel chromatography with hexanes/ethyl acetate/ammonia (2M in MeOH)=100/30/0.5 to afford the title compound; 1NMR (CDCl3) δ 2.03 (br s, 1H), 2.81 (m, 2H), 3.55 (m, 2H), 4.34 (s, 1H), 4.50 (m, 1H), 7.29 (m, 4H), 7.34 (m, 4H).
Reaction SMILES: C([NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:12]([F:20])=[CH:11][N:10]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[NH2:8][C:9]1[N:14]=[C:13]([NH:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:12]([F:20])=[CH:11][N:10]=1
Reactant: CC(C)(C)Nc1nc(NCc2ccccc2)ncc1F
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(C)Nc1nc(N)ncc1F
Yield: 53.6 %

Procedure:
To 8 ml of acetic acid were added 1.00 g of 2-benzylamino-4-(t-butylamino)-5-fluoropyrimidine together with 215 mg of 10% palladium on carbon, and the mixture was hydrogenated at 60° C. for ten days. The catalyst was separated by filtration, and the solvent and the like were distilled off under reduced pressure. The procedure of adding 10 ml of ethanol and concentrating under reduced pressure was repeated three times, and the residue was separated by column chromatography (silica gel, 25 g; eluent: chloroform, and then, chloroform:methanol, 200:1), and the corresponding fractions were collected and concentrated under reduced pressure to obtain 360 mg of the title compound as a pale gray solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH:9]=[CH2:10])[CH:3]=1.[H][H]>CCOC(C)=O.[Pd]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: C=Cc1cc(Br)ccc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(Br)ccc1F
Yield: 61.1 %

Procedure:
4-Bromo-1-fluoro-2-vinylbenzene (470 mg) was hydrogenated in EtOAc with 10% Pd/C (100 mg) with a hydrogen balloon for 2.0 h. The Pd/C was removed by filtration. The filtrate was condensed to give 95A (290 mg, 62% yield) as an orange oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.22 (t, J=6.81 Hz, 3H) 2.63 (d, J=7.03 Hz, 2H) 6.88 (t, J=8.57 Hz, 1H) 7.25 (s, 1H) 7.32 (d, J=4.39 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.[H][H]>C1C=CC=CC=1.C(O)C.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[NH2:19]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3ccccc3c2)c(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: c1ccccc1
Solvent: CCO
Product: Nc1ccc(Oc2ccc3ccccc3c2)c(Cl)c1
Yield: 60.1 %

Procedure:
3-Chloro-4-(2-naphthyloxy)nitrobenzene (14.8 g) and platinum dioxide (0.1 g) were suspended in a mixture of benzene and ethanol (1:1) (200 ml), and hydrogenation was carried out until 3.2 liters of hydrogen were absorbed. After removal of the solvent from the reaction mixture by distillation under reduced pressure, the residue was distilled in vacuo to give 3-chloro-4-(2-naphthyloxy)aniline (8 g) as a fraction boiling at 173° to 198° C./0.2 to 0.3 mmHg. M.P., 67°-69° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7]2)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:30]([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31])[CH2:7]2)([O-:3])=[O:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNC2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-nitroisoindoline (1.16 g, 7.79 mmol) in CH2Cl2 (100 mL), was added diisopropylethylamine (2.7 mL, 15.6 mmol) followed by benzylchloroformate (1.2 mL, 8.56 mmol). The mixture was stirred at room temperature under N2 for 1 h. The reaction mixture was diluted with CH2Cl2 and washed with 1N HCl. The organic layer was dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to provide benzyl 5-nitro-1,3-dihydro-2H-isoindole-2-carboxylate. LCMS calc.=321.1; found=320.8 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 8.22-8.14 (m, 2H); 7.49-7.37 (m, 6H); 5.27 (s, 2H); 4.89 (s, 2H); 4.87 (s, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7].Cl[C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][N:14]=1>CN(C)C=O>[N+:19]([C:18]1[C:13]([O:3][C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=2[CH:6]=[O:7])=[N:14][CH:15]=[CH:16][CH:17]=1)([O-:21])=[O:20]
Reactant: O=Cc1ccccc1O
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Oc1ncccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 22.5 %

Procedure:
Sodium hydride (60%) (0.0899 mol) was added portionwise under N2 at room temperature to a mixture of 2-hydroxybenzaldehyde (0.0818 mol) in N,N-dimethyl-formamide and the mixture was stirred under N2 for 15 minutes. 2-Chloro-3-nitro-pyridine (0.0818 mol) in N,N-dimethylformamide was added and the mixture was stirred at 100° C. for 2 hours. The mixture was poured into ice/water, extracted with diethylether and the solvent was evaporated, yielding 4.5 g (23%) of 2-[(3-nitro-2-pyridinyl)oxy]benzaldehyde (interm. 1).