Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:12])([CH3:11])[CH3:10])[CH2:5][CH2:4]1.[C:13](OC(=O)C)(=[O:15])[CH3:14].N1C=CC=CC=1>O>[C:13]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:12])([CH3:10])[CH3:11])[CH2:5][CH2:4]1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)C1CCC(CO)CC1
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OCC1CCC(C(C)(C)O)CC1
Reaction time: 0.75 h
Yield: 86 %

Procedure:
A mixture of 258 g (1.5M) of 7,8-dihydroxy-p-menthane, 2700 ml of acetic anhydride and 810 ml of pyridine was kept under stirring for 45 minutes, then it was poured onto ice (1 kg) and water (1000 ml). After its extraction with three fractions of 700 ml each of ether, the combined organic phases were washed with a 10% aqueous solution of NaOH (3×500 ml), water (2×500 ml) and a saturated aqueous solution of NaCl (500 ml). The solvent was evaporated and the residue (284 g) was distilled to give a colorless oil (276 g) having b.p. 108°-110°/0.133 Pa (yield 86%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:36]=[CH:35][CH:34]=[CH:33][C:14]=1[C:15]([C:17]1[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:18]=1[NH:24][C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=O>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:36]=[CH:35][CH:34]=[CH:33][C:14]=1[C:15]1[C:17]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:18]=2[NH:24][C:25](=[O:32])[C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CC(=O)Nc1sc(CC)cc1C(=O)c1ccccc1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2Cl)c2cc(CC)sc2[nH]c1=O
Yield: 33.1 %

Procedure:
To a solution of DBU (5.2 g) in toluene (50 ml) was added dropwise a solution of 3-(2-chlorobenzoyl)-2-ethoxycarbonylacetylamino-5-ethylthiophene (6.5 g) in toluene (30 ml) over one hour with stirring under reflux. After refluxing for 7 hours, the mixture was washed with water and dried over MgSO4, and then the solvent was distilled off. The residue was chromatographed on a silica gel column and eluted with hexane-acetone (5 : 1). The solvent was distilled off and hexane was added to obtain ethyl 4-(2-chlorophenyl)-6,7-dihydro-2-ethyl-6-oxothieno[2,3-b]pyridine-5-carboxylate as crystals 33.1%). The crystals were recrystallized from ethanol to obtain light yellow prisms, mp: 126°-127° C.
Reaction SMILES: [CH:1]([P:4]([CH:12]([CH3:14])[CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[OH:15]O>C(Cl)Cl>[CH:12]([P:4]([CH:1]([CH3:3])[CH3:2])([C:5]1[CH:6]=[CH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:15])([CH3:14])[CH3:13]
Reactant: OO
Reactant: Cc1ccc(P(C(C)C)C(C)C)cc1
Solvent: ClCCl
Product: Cc1ccc(P(=O)(C(C)C)C(C)C)cc1
Temperature: 25 °C

Procedure:
To a solution of diisopropyl-p-tolyl-phosphane (2.6 g, 12.48 mmol) in DCM (5 mL) at 0° C. was added hydrogen peroxide (4.08 mL, 13.31 mmol) dropwise. The reaction mixture was allowed to warm to RT. The reaction was diluted with DCM, washed with water, brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The material was used without further purification. MS: cal'd 225 (MH+), exp 225 (MH+).
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH:20]=[C:19]1[CH3:40])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[C@H:21]([CH2:31][OH:32])[CH:20]=[C:19]1[CH3:40])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO[Si](C)(C)C(C)(C)C)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 90.6 %

Procedure:
To a solution of (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-((tert-butyldimethylsilyloxy)methyl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 10, 1 g, 1.67 mmol) in THF (11 mL) at 0° C. was added tetrabutylammonium fluoride (1M in THF) (2.175 mL, 2.17 mmol). After 90 minutes the reaction mixture was concentrated onto silica gel. Silica gel chromatography (0%-70% ethyl acetate/hexanes) afforded the desired product (0.732 g, 90%) as a tan foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10](Br)[CH:9]=1)([CH3:7])[CH3:6])[CH3:2].CC1(C)C(C)(C)OB([C:26]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:27]=2[CH:28]=[O:29])O1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:8]1[CH:9]=[C:10]([C:26]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:27]=2[CH:28]=[O:29])[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CC1(C)OB(c2ccc(C(F)(F)F)cc2C=O)OC1(C)C
Reactant: CCOC(=O)C(C)(C)c1ccc(OC)c(Br)c1
Product: CCOC(=O)C(C)(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: 2-(3-bromo-4-methoxy-phenyl)-2-methyl-propionic acid ethyl ester and 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[CH:4]([C:9]1[CH:10]=[C:11]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([C:37]([F:40])([F:39])[F:38])[CH:31]=2)[CH:12]=[C:13]([NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[CH3:42]C(C)([O-])C.[K+].CI.O1CCOCC1>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:41])[CH:4]([C:9]1[CH:10]=[C:11]([C:30]2[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([C:37]([F:38])([F:39])[F:40])[CH:31]=2)[CH:12]=[C:13]([N:15]([C:16]2[CH:17]=[C:18]([C:26]([F:29])([F:27])[F:28])[CH:19]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:21]=2)[CH3:42])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2cc(F)cc(C(F)(F)F)c2)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CI
Solvent: CN1CCCC1=O
Product: COC(=O)C(CC(C)C)c1cc(-c2cc(F)cc(C(F)(F)F)c2)cc(N(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 130 °C
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
A mixture of 2-[5′-fluoro-5-(3,5-bis-trifluoromethyl-phenylamino)-3′-trifluoromethyl-biphenyl-3-yl]-4-methyl-pentanoic acid methyl ester (57 mg, 0.096 mmol), potassium tert-butoxide (58 mg, 0.52 mmol), methyl iodide (60 μL, 0.11 mmol), dioxane (2 mL) and N-methylpyrrolidinone (0.2 mL) was stirred with microwave irradiation for 15 min at 130° C. The mixture was concentrated in vacuo, suspended in 1M HCl (20 mL) and extracted with diethyl ether (2×20 mL). The combined organic layer was washed with brine, dried (MgSO4), concentrated in vacuo and purified by flash column chromatography (silica, 0-5% diethyl ether in petroleum ether) to afford the title product as a colourless solid (33 mg, 56%). RT=5.24 min.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][OH:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[O:23][C:24]=3[CH3:25])=[C:14]([O:31][CH3:32])[CH:13]=2)=[N:4]1)[CH3:2]>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:3]1[CH:7]=[C:6]([CH:8]=[O:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[O:27][CH:28]=[CH:29][CH:30]=4)[O:23][C:24]=3[CH3:25])=[C:14]([O:31][CH3:32])[CH:13]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(CO)c(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCn1cc(C=O)c(OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.5 %

Procedure:
A mixture of {1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}methanol (2.19 g), activated manganese dioxide (6.0 g) and tetrahydrofuran (100 mL) was stirred at room temperature for 15 hrs. Manganese dioxide was removed by filtration and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-ethyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carbaldehyde (1.95 g, yield 89%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 103-104° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]([F:24])([F:23])[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N+:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:14]([F:13])([F:23])[F:24])=[CH:17][CH:18]=1)[C:6]#[N:7])([O-:12])=[O:11]
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1ccc(Nc2ccc(OC(F)(F)F)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
A solution of 4-fluoro-3-nitrobenzonitrile (500 mg, 3.01 mmol), 4-trifluoromethoxyaniline (404 μL, 3.01 mmol) and potassium carbonate (416 mg, 3.01 mmol) in DMSO (15.0 mL) were heated in a sealed tube within a microwave reactor at 120° C. for 10 min. The reaction mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0%-40% EtOAc/hexanes as eluent) afforded the title compound i-1a. m/z (ES) 324 (MH)+. 1H NMR (500 MHz, CDCl3): δ 9.81 (s, 1H), 8.60 (d, 1H, J=1.9 Hz), 7.58 (dd, 1H, J=1.8, 9.1 Hz), 7.29 (m, 4H), 7.16 (d, 1H, J=8.9 Hz).
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:30]C(OCC1C=CC=CC=1)=O)[C:10](=[O:29])[C@H:11]([NH:21][C:22]([O:24]C(C)(C)C)=O)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]1C=C[CH:6]=[CH:5][CH:4]=1.O1CCO[CH2:43][CH2:42]1>ClCCl>[CH2:2]([N:9]1[CH2:30][C:22](=[O:24])[NH:21][C@H:11]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)[C:10]1=[O:29])[C:3]1[CH:43]=[CH:42][CH:6]=[CH:5][CH:4]=1
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)OCc2ccccc2)Cc2ccccc2)cc1
Reactant: C1COCCO1
Agent: Cl
Solvent: ClCCl
Product: COc1ccc(C[C@H]2NC(=O)CN(Cc3ccccc3)C2=O)cc1
Reaction time: 2 h

Procedure:
4N Hydrogen chloride in 1,4-dioxane solution (48 ml) was added dropwise to a solution of N-benzyl-N-benzyloxycarbonylmethyl-(2R)-2-(tert-butoxycarbonylamino)-3-(4-methoxyphenyl)propionamide (8.48 g) in dichloromethane (48 ml) under ice-bath cooling. After being stirred for 2 hours at the same temperature, the reaction mixture was concentrated under reduced pressure. The residue was added to aqueous sodium bicarbonate solution (50 ml) and dichloromethane (50 ml), and the organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated under reduced pressure to give a powder of (3R)-1-benzyl-3-(4-methoxybenzyl)piperazine-2,5-dione (3.65 g).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:17])[CH2:4][CH2:3]1.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCCl>[CH2:28]([O:27][C:25]([N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C@H:2]2[CH2:7][CH2:6][C@H:5]([N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[NH:10][C:9]3=[O:17])[CH2:4][CH2:3]2)[CH2:24][CH2:23]1)=[O:26])[CH3:29]
Reactant: O=C1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: CCOC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)N1CCC(N[C@H]2CC[C@H](n3c(=O)[nH]c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 1.5 g of 1,3-dihydro-1-(4-oxocyclohexyl)-2H-benzimidazol-2-one, 1.12 g of ethyl 4-amino-1-piperidinecarboxylate, 20 mL of 1,2-dichloroethane, 0.40 mL of glacial acetic acid and 1.79 g of sodium triacetoxyborohydride was stirred at room temperature for 48 h. The reaction mixture was poured into 50 mL chloroform and 50 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over MgSO4 and concentrated under reduced pressure. Chromatography of the crude product on silica gel, eluting with 10% methanol in ethyl acetate gave 1.3 g of 1,3-dihydro-1-{trans-4-[1-ethoxycarbonyl-4-piperidinylamino]-1-cyclohexyl}-2H-benzimidazol-2-one as a white solid: 1H NMR (400 MHz, CDCl3) 9.8-9.9 (br m, 1H), 7.30 (m, 1H), 7.11-7.02 (m, 4H), 4.37 (m, 1H), 4.17-4.06 (m, 4H), 3.15 (m, 1H), 2.88 (t, 2H), 2.7 (m, 1H), 2.55 (m, 2H), 1.97 (d, 2H), 1.86 (d, 2H), 1.65 (q, 4H), 1.25 (m, 5H). Analysis calculated for C21H30N4O3C: 65.26, H: 7.82, N: 14.46 found C: 65.20, H: 7.57, N: 14.15.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]2[CH:10]3[CH:6]2[CH2:7][CH2:8][CH:9]3[OH:11])[CH2:3][CH2:2]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[CH:1]1([CH2:4][CH:5]2[CH:10]3[CH:6]2[CH2:7][CH2:8][C:9]3=[O:11])[CH2:2][CH2:3]1
Reactant: OC1CCC2C(CC3CC3)C12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=C1CCC2C(CC3CC3)C12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-cyclopropylmethyl-bicyclo[3.1.0]hexan-2-ol (220 mg, 1.45 mmol) in 10 mL DCM was added sequentially 4 A Molecular sieves (200 mg), NMO (N-Methyl morpholine N-oxide) (339 mg, 2.90 mmol), TPAP label (25.448 mg, 0.0725 mmol). The mixture was stirred overnight at room temperature and plugged through silica gel (3:1 DCM: Et2O) to give 6-cyclopropylmethyl-bicyclo[3.1.0]hexan-2-one as a clear oil; 1H NMR (400 MHz, CDCl3): δ 2.32–2.21 (m, 2H), 2.16 (dd, 1H, J1=13.4 Hz, J2=5.4 Hz), 1.97–1.86 (m, 3H), 1.61–1.53 (m, 1H), 1.38–1.28 (m, 2H), 0.82–0.73 (m, 1H), 0.49–0.44 (m, 2H), 0.09–0.05 (m, 2H).
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:9]([C:19]#[N:20])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[ClH:26].N([O-])=O.[Na+]>[Cu]Cl.C(OCC)(=O)C>[Cl:26][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[C:9]([C:19]#[N:20])[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Cl
Reactant: CCOC(=O)c1cnn(-c2ccc(OCC(C)(C)C)c(C#N)c2)c1N
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2ccc(OCC(C)(C)C)c(C#N)c2)c1Cl
Temperature: 60 °C

Procedure:
To a solution (15 ml) of ethyl 5-amino-1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylate (2.09 g) obtained in Example 31 in con. hydrochloric acid was added an aqueous solution (4 ml) of sodium nitrite (0.62 g) with stirring under ice-cooling. To this diazonium salt solution was gradually added copper (I) chloride (1.49 g) under ice-cooling. After the dropwise addition, the reaction mixture was heated at 60° C. for 1 hour. After the completion of the reaction, the reaction mix was enacted with ethyl acetate, washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was applied to silica gel column chromatography to give 0.74 g of ethyl 5chloro-1-(3-cyano-4-neopentyloxyphenyl)pyrazole-4-carboxylate, melting point 90-92° C.
Reaction SMILES: [CH2:1]1[O:32][C:31]2[CH:30]=[CH:29][C:5]([CH2:6][O:7][C:8](=[O:28])[C@H:9]([NH:13][S:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH3:25])=[C:19]([CH3:26])[C:18]=3[CH3:27])(=[O:16])=[O:15])[C@@H:10]([OH:12])[CH3:11])=[CH:4][C:3]=2[O:2]1.N1C=CN=C1.[CH2:38]([Si:40](Cl)([CH2:43][CH3:44])[CH2:41][CH3:42])[CH3:39]>O1CCCC1>[CH2:1]1[O:32][C:31]2[CH:30]=[CH:29][C:5]([CH2:6][O:7][C:8](=[O:28])[C@H:9]([NH:13][S:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([O:24][CH3:25])=[C:19]([CH3:26])[C:18]=3[CH3:27])(=[O:16])=[O:15])[C@@H:10]([O:12][Si:40]([CH2:43][CH3:44])([CH2:41][CH3:42])[CH2:38][CH3:39])[CH3:11])=[CH:4][C:3]=2[O:2]1
Reactant: CC[Si](Cl)(CC)CC
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](C(=O)OCc2ccc3c(c2)OCO3)[C@H](C)O)c(C)c1C
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)O[C@@H](C)[C@@H](NS(=O)(=O)c1c(C)cc(OC)c(C)c1C)C(=O)OCc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3(S)-hydroxybutyric acid 3,4-methylenedioxybenzyl ester (10.9 g, 23.41 mmol) and imidazole (2.07 g, 30.43 mmol was dissolved in tetrahydrofuran (28 mL). The reaction mixture was cooled to 0° C. and 1 M triethylsilyl chloride in tetrahydrofuran (28 mL, 28 mmol) was added. After 1 h, the reaction mixture was concentrated and chromatographed over a Biotage 40L column (eluted with 10% ethyl acetate-hexanes) to afford 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl-amino)-3(S)-(triethylsilyloxy)butyric acid 3,4-methylenedioxybenzyl ester (13.5 g).
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1.N1C=CC=CC=1>ClCCl>[CH2:4]([O:3][C:1](=[O:2])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1)[CH:5]=[CH2:6]
Reactant: C=CCOC(=O)Cl
Reactant: Nc1ccc(CO)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)Nc1ccc(CO)cc1
Reaction time: 2 h
Yield: 28.9 %

Procedure:
Alloc-Cl (537 g) in dichloromethane (5 ml) was added dropwise to a solution of (4-amino-phenyl)-methanol (500 mg) and pyridine (5 ml) in dichloromethane (5 ml). After stirring for 2 h, the reaction mixture was diluted with dichloromethane and washed with water. The organic layer was separated, dried (MgSO4), filtered and concentrated in vacuo. The title compound (243 mg) was obtained by recrystallization from dichloromethane. The mother liquor was chromatographed on silica gel in heptane/ethyl acetate=1/1 (v/v) as eluent which yielded another 245 mg of the title compound. Yield: 488 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-])=O)[C:3]=1[F:12].O.O.Cl[Sn]Cl>CCO>[Br:1][C:2]1[C:3]([F:12])=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)c(F)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(Br)c(F)c1N
Yield: 84.7 %

Procedure:
To a solution of 140 (34 g, 0.144 mol) and EtOH (510 mL) was added SnCl2.2H2O (130.1 g, 0.576 mol) and the resulting mixture was heated to reflux for 4 h. After the completion of the reaction, the solvent was removed in vacuo. The residue was taken up in water and made slightly basic with 10% NaHCO3. The resulting solid was filtered and washed well with EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo to afford 25 g (84%) of 4-bromo-3-fluoro-benzene-1,2-diamine (142) as yellow solid which was used without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([F:8])[CH:3]=1.C(N(CC)CC)C.[C:16]([C:18]1[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=1)#[CH:17]>O1CCCC1.[Cu]I>[F:8][C:4]1[CH:3]=[C:2]([C:17]#[C:16][C:18]2[CH:23]=[CH:22][N:21]=[C:20]([S:24][CH3:25])[N:19]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Fc1cc(I)ccn1
Reactant: C#Cc1ccnc(SC)n1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1nccc(C#Cc2ccnc(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Iodo-2-fluoropyridine (1.09 g, 4.9 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). To this solution was added triethylamine (0.9 mL, 6.5 mmol), copper (I) iodide (80 mg, 0.4 mmol) and dichlorobis(triphenylphosphine) palladium (II) (60 mg, 0.32 mmol). 4-Ethynyl-2-(methylsulfanyl)pyrimidine (example 4, 0.75 g, 4.9 mmol) in tetrahydrofuran was added dropwise to the resulting solution. After the addition was complete the reaction was stirred at room temperature overnight. The mixture was concentrated to give a syrup, that was purified by silica gel chromatography (1:1 ethyl acetate:hexane) to give after removal of solvents 0.84 g (70%) of 4-[(2-fluoro-4-pyridinyl)ethynyl]-2-(methylsulfanyl)pyrimidine as a white solid. 1H NMR (CDCl3): δ 8.61 (d, 1H), 8.32 (d, 1H), 7.39 (d, 1H), 7.17 (m, 2H), 2.64 (s, 3H); 19F NMR (CDCl3): 8–66.82; MS m/z 246 (M+1).
Reaction SMILES: [ClH:1].[NH2:2][N:3]=[CH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.Cl.Cl.[CH3:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[C:20]([O:27][CH2:28][C:29]3[C:30]([Cl:54])=[C:31]([S:36]([N:39]4[CH2:43][CH2:42][CH2:41][C@H:40]4[C:44]([NH:46][CH2:47][CH:48]4[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]4)=[O:45])(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=3[Cl:35])[CH:21]=[CH:22][CH:23]=2)[N:18]=1>>[ClH:35].[ClH:1].[CH3:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[C:20]([O:27][CH2:28][C:29]3[C:30]([Cl:54])=[C:31]([S:36]([N:39]4[CH2:43][CH2:42][CH2:41][C@H:40]4[C:44]([NH:46][CH2:47][CH:48]4[CH2:49][CH2:50][N:51]([C:9](=[O:11])[C:8]5[CH:7]=[CH:6][C:5]([CH:4]=[N:3][NH2:2])=[CH:13][CH:12]=5)[CH2:52][CH2:53]4)=[O:45])(=[O:38])=[O:37])[CH:32]=[CH:33][C:34]=3[Cl:35])[CH:21]=[CH:22][CH:23]=2)[N:18]=1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(S(=O)(=O)N4CCC[C@H]4C(=O)NCC4CCNCC4)c3Cl)c2n1
Reactant: NN=Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(S(=O)(=O)N4CCC[C@H]4C(=O)NCC4CCN(C(=O)c5ccc(C=NN)cc5)CC4)c3Cl)c2n1

Procedure:
By following a procedure analogous to Example 23, starting from 4-(aminoiminomethyl)benzoic acid hydrochloride and 1-[[3-[(2-methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[(piperidin-4-yl)methyl]-2(S)-pyrrolidinecarboxamide dihydrochloride, the expected product is obtained in the form of a powdery white solid (yield=39%) after purification by means of reversed phase chromatography on RP18-grafted silica gel using a water/acetonitrile/hydrochloric acid mixture (63/32/1; v/v/v) as the eluent.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[O:37]1C2C=CC(C(=O)C)=CC=2[O:39][CH2:38]1.[OH-].[K+]>C(O)C>[O:37]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)=[CH:7][C:2]=2[O:39][CH2:38]1
Reactant: CC(=O)c1ccc2c(c1)OCO2
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccc5c(c4)OCO5)ccc3c1)n2C1CCCCC1
Yield: 24 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-benzo[1,3]dioxol-5-yl-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (30 mg, 24% yield).
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][C:14]=1[CH2:27][CH3:28].CN(C)[CH:31]=[O:32].[NH4+].[Cl-]>C1COCC1>[CH2:20]([O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:31]=[O:32])=[C:14]([CH2:27][CH3:28])[CH:15]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCc1cc(OCc2ccccc2)ccc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1cc(OCc2ccccc2)ccc1C=O
Temperature: -85 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A 1.6 M solution of n-BuLi in hexane (44.4 ml, 69.9 mmol) was added within 10 min to a stirred cooled (−85° C.) solution of 1-bromo-2-ethyl-4-(phenylmethoxy)-benzene (18.5 g, 63.5 mmol) in dry THF (22 ml). The mixture was stirred for 1 h at −85° C. under an argon atmosphere. N,N-Dimethylformamide (25.5 ml, 330.4 mmol) was added and the temperature was allowed to rise slowly to room temperature. An aqueous saturated NH4Cl solution (70 ml) was added under ice cooling. The mixture was extracted two times with dichloromethane, the combined extracts were washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a yellow oil which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to yield 11.9 g (49.5 mmol, 78%) of the title compound as yellow oil.