Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH:5]([CH:12]1[O:17][CH2:16][C:15](=[O:18])[N:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N([O-])=[O:25].[Na+]>OS(O)(=O)=O.O>[OH:25][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH:5]([CH:12]1[O:17][CH2:16][C:15](=[O:18])[N:14]([CH3:19])[CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=N[O-]
Reactant: CN1CC(C(Oc2ccccc2N)c2ccccc2)OCC1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN1CC(C(Oc2ccccc2O)c2ccccc2)OCC1=O
Reaction time: 0.33 h
Yield: 59.8 %

Procedure:
10 g of 2-[α-(2-amino-phenoxy)-benzyl]-4-methyl-morpholin-5-one was dissolved at 0° C. in 32 ml of 35% H2SO4. At this temperature slow addition was made of 2.76 g of NaNO2 dissolved in 40 ml of H2O and the mixture was kept under stirring in cold conditions for 20 minutes. Still at 0° C. there was added 120 g of Cu(NO3)2 dissolved in 1000 ml of H2O and 4.2 g of Cu2O. After 5 minutes extraction was performed in cold conditions with ethyl acetate; the organic phase was washed to neutrality with a saturated aqueous solution of NaCl, dehydrated with sodium sulphate and evaporated to dryness. There was obtained a yellow oil which was separated by column chromatography on silica gel (phase: ethyl acetate/cyclohexane 2:1). There was obtained 6 g (Yield 60%) of 2-[α-(2-hydroxy-phenoxy)-benzyl]-4-methyl-morpholin-5 -one.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]#[C:6][C:7]([CH3:11])=[CH:8][CH2:9][OH:10])[CH3:2].N1C2C(=CC=CC=2)C=CC=1>[Pd]>[CH2:13]([O:12][CH:4]([O:3][CH2:1][CH3:2])[CH:5]=[CH:6][C:7]([CH3:11])=[CH:8][CH2:9][OH:10])[CH3:14]
Reactant: CCOC(C#CC(C)=CCO)OCC
Agent: [Pd]
Solvent: c1ccc2ncccc2c1
Product: CCOC(C=CC(C)=CCO)OCC

Procedure:
198 g. of 1,1-diethoxy-4-methyl-4-hexen-2-yn-6-ol are hydrogenated in the usual manner in the presence of 35 g. of a lead/palladium/calcium carbonate catalyst, 5 ml. of quinoline and 1500 ml. of high boiling petroleum ether. There is obtained 1,1-diethoxy-4-methyl-2,4-hexadien-6-ol of boiling point 96°-98° (0.01 mm.); nD20 = 1.4730 - 1.4760.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH:12]=O)[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.N1(C2C=C[C:22]([CH:23]=[O:24])=CC=2)C=CC=N1>>[N:1]1([C:6]2[N:11]=[C:10]([CH:12]=[CH:22][CH:23]=[O:24])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=Cc1cccc(-n2cccn2)n1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Product: O=CC=Cc1cccc(-n2cccn2)n1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 6-(1H-pyrazol-1-yl)-2-pyridinecarboxaldehyde (prepared as described in J. Med. Chem. 1998, 41, 5070) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 200 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:17]=[CH:16]C(F)=[CH:14][C:13]=1O[C@H](CC=C)C>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[O:10][C@H:17]([CH2:12][CH:13]=[CH2:14])[CH3:16]
Reactant: Cc1cc(O)c(Br)cc1C
Reactant: C=CC[C@H](C)Oc1cc(F)ccc1Br
Product: C=CC[C@H](C)Oc1cc(C)c(C)cc1Br
Yield: 59 %

Procedure:
Prepared in 59% yield from 2-bromo-4,5-dimethylphenol following the same procedure as (S)-1-bromo-4-fluoro-2-(pent-4-en-2-yloxy)benzene. 1H NMR (400 MHz, CDCl3) δ 7.30 (s, 1H), 6.73 (s, 1H), 5.92 (ddt, J=17.2, 10.1, 7.1 Hz, 1H), 5.19-5.09 (m, 2H), 4.44-4.33 (m, 1H), 2.59-2.49 (m, 1H), 2.45-2.37 (m, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 1.34 (d, J=6.0 Hz, 3H).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[CH2:5]1[C:14]2[C:13]3[CH:15]=[CH:16][C:17]([C:19]([C:21]4[N:22]=[CH:23][NH:24][CH:25]=4)=[O:20])=[CH:18][C:12]=3[CH:11]=[CH:10][C:9]=2[O:8][CH2:7][CH2:6]1.[Cl-].[NH4+]>C1COCC1>[CH2:5]1[C:14]2[C:13]3[CH:15]=[CH:16][C:17]([C:19]([C:21]4[N:22]=[CH:23][NH:24][CH:25]=4)([OH:20])[CH2:1][CH3:2])=[CH:18][C:12]=3[CH:11]=[CH:10][C:9]=2[O:8][CH2:7][CH2:6]1
Reactant: CC[Mg]Cl
Reactant: O=C(c1ccc2c3c(ccc2c1)OCCC3)c1c[nH]cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(c1ccc2c3c(ccc2c1)OCCC3)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethylmagnesium chloride in THF (3M; 3 mL) was added to a solution of (2,3-dihydro-1H-benzo[f]chromen-8-yl)(1H-imidazol-4-yl)ketone (0.523 g) in THF (20 ml) at 0° C. The mixture was stirred at room temperature for 2 h. Aqueous ammonium chloride solution was added to the mixture and extracted with ethyl acetate. The extract was dried and concentrated. The residue was chromatographed on silica gel (eluent; dichloromethane:methanol=20:1) to give the titled compound (0.512 g) as a colorless solid.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[C@@H:11]([N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:10]2)[CH2:7][CH2:6]3.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>>[N:44]1([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:26][CH2:25][CH2:24][CH2:23]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:1])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: C1COCCN1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@]12C[C@H](N3CCOCC3)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCC3)C[C@@H]12
Temperature: 105 °C

Procedure:
A suspension of 2α,3α-epoxy-16β-(1-pyrrolidinyl)-5α-androstan-17β-ol (1.80 Kg, 5.006 mol) in a mixture of morpholine (11.44 L) and purified water (1.144 L) was prepared at 20-24° C. and under N2 atmosphere. To the suspension was added p-toluenesulphonic acid (1.24 Kg, 6.508 mol) at 20-24° C. and under N2 atmosphere. The suspension was stirred in the darkness and heated to reflux (100-110° C.) for 40 h. After 40 h the reaction mixture was cooled to 20-24° C., and poured into a second vessel maintained at about 4° C. containing a 2% s solution of sodium carbonate (128 L), while stirred vigorously. The resulting suspension was stirred for 1 hour at about 4° C. The obtained solid was filtered off under vacuum, washed with cold purified water (100 L), and dried in a vacuum oven at about 40° C. for at least 48 hours, to give 2.07 Kg (4.49 mol) of a white solid. (89.7% molar yield and purity of 94.12% area by HPLC) m.p. 225° C.; [α]D20+82.00 (c=1.02 in CHCl3). The product could be used in the next stage without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[N:9][C:8]=1[C:18]([OH:20])=O.[CH3:21][CH:22]([CH3:46])[CH2:23][NH:24][C@H:25]1[CH2:30][C@@H:29]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:26]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.ClC(N(C)C)=[N+](C)C>ClCCCl.C(=O)([O-])O.[Na+]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[N:9][C:8]=1[C:18]([N:24]([CH2:23][CH:22]([CH3:46])[CH3:21])[C@H:25]1[CH2:30][C@@H:29]([C:31]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[O:32])[CH2:28][N:27]([C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])[CH2:26]1)=[O:20]
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCc1c(C(=O)O)nnn1-c1ccccc1
Agent: CN(C)C(Cl)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74.9 %

Procedure:
5-(4-Methoxybutyl)-1-phenyl-1H-1,2,3-triazole-4-carboxylic acid (138 mg), tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (185 mg) and N,N-diisopropylethylamine (345 μl) were dissolved in 1,2-dichloroethane (5 ml), chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (154 mg) was added and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (235 mg) as an amorphous compound.
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C:8]3[S:13][CH:14]=[CH:15][C:7]=3[C:6]=2[CH:5]=[C:4]([O:16][CH3:17])[CH:3]=1.[Br:18]N1C(=O)CCC1=O>>[Br:18][C:5]1[C:6]2[C:7]3[CH:15]=[CH:14][S:13][C:8]=3[C:9](=[O:12])[NH:10][C:11]=2[C:2]([F:1])=[CH:3][C:4]=1[O:16][CH3:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(F)c2[nH]c(=O)c3sccc3c2c1
Product: COc1cc(F)c2[nH]c(=O)c3sccc3c2c1Br
Yield: 60.9 %

Procedure:
Following Step 4 from General Procedure A, 6-fluoro-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.0 g, 4.0 mmol) was reacted with N-bromosuccinimide (570 mg, 4.8 mmol) to afford the desired product (800 mg, 61%) as a brown solid: ESI MS m/z 329 [C12H7BrFNO2S+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][CH3:14])[N:12]=1)[C:5]([O:7]CC)=[O:6].[CH3:15][N:16](C)C(=O)C>[C-]#N.[Zn+2].[C-]#N.[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:15]([C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([O:13][CH3:14])[N:12]=1)[C:5]([OH:7])=[O:6])#[N:16]
Reactant: CC(=O)N(C)C
Reactant: CCOC(=O)c1cc(Cl)nc(OC)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: COc1cc(C(=O)O)cc(C#N)n1
Temperature: 95 °C
Reaction time: 18 h
Yield: 45.3 %

Procedure:
Into an oven-dried microwave vial was added ethyl 2-chloro-6-methoxyisonicotinate (0.6 g, 2.78 mmol), zinc cyanide (392 mg, 3.34 mmol), zinc dust (36.4 mg, 0.2 mmol) and N,N-dimethylacetamide (10 mL). The vial was capped, evacuated, and filled with nitrogen. This process was repeated 3 times. Then the cap of the vial was removed and bis(tri-t-butylphosphine)palladium(0) (142 mg, 0.278 mmol) was added. The vial was capped again, evacuated, and filled with nitrogen (3×). The reaction mixture was heated to 95° C. and left stirring for 18 h. The reaction mixture was diluted with ethyl acetate (100 mL) and filtered through Celite. The filtrate was poured into a saturated aqueous solution of sodium bicarbonate (100 mL). Then the mixture was extracted with ethyl acetate (50 mL×3). The combined organics were washed with a saturated aqueous solution of ammonium chloride, washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified via flash chromatography to afford 2-cyano-6-methoxyisonicotinic acid (260 mg, 45.3%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.42 (s, 3H), 4.01 (s, 3H), 4.43 (s, 2H), 7.53 (s, 1H), 7.82 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].S(Cl)(Cl)=O.[Cl:20][S:21](O)(=[O:23])=[O:22]>>[F:15][C:2]([F:1])([F:14])[C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([S:21]([Cl:20])(=[O:23])=[O:22])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N1CCc2ccccc21)C(F)(F)F
Reactant: O=S(=O)(O)Cl
Solvent: O=S(Cl)Cl
Product: O=C(N1CCc2cc(S(=O)(=O)Cl)ccc21)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
A solution of the 1-(trifluoroacetyl)indoline (2-1, 21.5 g), neat in thionyl chloride (65.59 mL, 899.24 mmol), was cooled to 0° C. and treated with chlorosulfonic acid (13.28 mL, 199.83 mmol). The solution was stirred for 50 minutes, then poured directly into a beaker of ice (3 L). The precipitate was filtered and vacuum dried to afford 1-(trifluoroacetyl)indoline-5-sulfonyl chloride (2-2) as an orange solid; 1H NMR (500 MHz, CDCl3) δ 8.42 (d, 1H, J=8.5 Hz), 8.00 (d, 1H, J=6.7 Hz), 7.92 (s, 1H), 4.43 (t, 2H, J=8.2 Hz), 3.41 (t, 2H, J=8.2 Hz).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:17]1([CH2:20][NH2:21])[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][NH:21][C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:19][CH2:18]1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Reactant: NCC1CC1
Product: O=C(NCC1CC1)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 130° C. and MS: m/e=265 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and cyclopropylmethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH2:12][C:11](=[O:28])[NH:10]1.[H-].[Na+].[CH3:31]I>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[C:18]=3[N:14]2[CH2:13][CH2:12][C:11](=[O:28])[N:10]1[CH3:31]
Reactant: CI
Reactant: CCN(CC)c1cccc2nc3n(c12)CCC(=O)NC3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC)c1cccc2nc3n(c12)CCC(=O)N(C)C3c1ccc(Cl)cc1Cl
Reaction time: 0.25 h
Yield: 5.8 %

Procedure:
To a stirred solution of 1-(2,4-dichlorophenyl)-7-(diethylamino)-1,2,4,5-tetrahydro-3H-[1,4]diazepino[1,2-a]benzimidazol-3-one (83.5 mg, 0.200 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (60%, 20.0 mg, 0.500 mmol) at room temperature. After 15 min, methyl iodide (62.3 μL, 1.00 mmol) was added. After 1 h, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-50% ethyl acetate/n-hexane gradient mixture and by preparative NH TLC eluting with a 33% ethyl acetate/n-hexane mixture to give the title compound as a colorless solid (5.0 mg, 0.0115 mmol, 5.7%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH2:13][NH2:14]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:13][NH2:14]
Reactant: NN
Reactant: NS(=O)(=O)c1ccc(F)c(F)c1
Solvent: CC#N
Product: NNc1ccc(S(N)(=O)=O)cc1F

Procedure:
In a 500 mL round-bottomed flask fitted with a condenser and N2 inlet septum was placed a stir bar, 3,4-difluoro-benzenesulfonamide (10 g, 52 mmol), anhydrous hydrazine (10.56 mL, 336 mmol), and acetonitrile (180 mL). The mixture was refluxed for 6 h under N2. The solvent was then removed under vacuum and the residue was treated with H2O. The separated solid was filtered and washed with H2O to give the desired product. Exact mass calculated for C6H8FN3O2S 205.03, found 206.1 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[C:6]=1[C:7](O)=[O:8].C1C=CC2N(O)N=NC=2C=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[N+:14]([C:10]1[C:6]2[C:7](=[O:8])[NH:1][CH2:2][CH2:3][NH:4][C:5]=2[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: NCCNc1cccc([N+](=O)[O-])c1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1NCCNc2cccc([N+](=O)[O-])c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a stirred solution of 2-(2-amino-ethylamino)-6-nitro-benzoic acid (0.35 g, 0.0013 mol) in DMF (10 mL) was added HOBt (0.22 g, 0.0016 mol), BOP (0.71 g, 0.0016 mol) and N-methylmorpholine (0.18 mL, 0.0016 mol) at 0° C. under nitrogen. The reaction was stirred for at 0° C. for 1 h then warmed to room temperature overnight. The reaction was diluted with ethyl acetate (20 mL) and washed with water, 10% aqueous HCl, water and brine. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by ISCO purification using 5-15% methanol-methylene chloride to give desired 6-Nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (0.22 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ 9.9 (s, 1H), 7.41 (t, 1H, J=7.6 Hz), 7.12 (d, 1H, J=7.6 Hz), 6.95 (d, 1H, J=7.6 Hz), 3.92 (broad s, 1H), 3.25 (m, 2H), 2.73 (m, 2H); MS (m/e) 208 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13][S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1.Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:14]([C:17]2[S:18][CH:19]=[CH:20][CH:21]=2)(=[O:16])=[O:15])[CH:6]=[C:5]1[C:22]1[S:23][CH:24]=[CH:25][N:26]=1
Reactant: CCOC(=O)CBr
Reactant: COCn1c(-c2nccs2)cc2cccc(NS(=O)(=O)c3cccs3)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(c1cccc2cc(-c3nccs3)n(COC)c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of N-[1-(methoxymethyl)-2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (0.68 g), ethyl bromoacetate (0.23 mL), potassium carbonate (0.35 g) and N,N-dimethylformamide (6 mL) was stirred at room temperature for 4 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.82 g, quantitative) was obtained as pale-yellow crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 124-125° C.
Reaction SMILES: [CH2:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]4[CH:23]=[C:24]([C:32]([O:34][CH3:35])=[O:33])[C:25](=[CH:30][CH:31]=4)[C:26]([O:28][CH3:29])=[O:27])[CH:15]=3)=[C:10]([CH3:36])[CH:9]=2)OCC[O:4]1)[CH3:2].S(=O)(=O)(O)O>CO.O>[CH3:36][C:10]1[CH:9]=[C:8]([C:3](=[O:4])[CH2:1][CH3:2])[CH:13]=[CH:12][C:11]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:32]([O:34][CH3:35])=[O:33])[C:25](=[CH:30][CH:31]=2)[C:26]([O:28][CH3:29])=[O:27])[CH:15]=1
Reactant: CCC1(c2ccc(-c3cccc(COc4ccc(C(=O)OC)c(C(=O)OC)c4)c3)c(C)c2)OCCO1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: CCC(=O)c1ccc(-c2cccc(COc3ccc(C(=O)OC)c(C(=O)OC)c3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
6.8 g (14 mmol) of dimethyl 4-[4′-(2-ethyl-[1,3]dioxolan-2-yl)-2′-methylbiphenyl-3-ylmethoxy]-phthalate are dissolved in 200 mL of methanol and 50 mL of water. 0.5 mL of sulphuric acid is added and the reaction medium is stirred at room temperature for 10 hours. After the usual treatment, the desired product is obtained, without purification, in the form of a colourless oil (m=6.05 g; Y=97%).
Reaction SMILES: [F:1][C:2]([F:9])([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.Cl.Cl.[CH3:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)[CH:20]=1.C(N(C(C)C)C(C)C)C>ClCCl.CN(C=O)C>[F:9][C:2]([F:1])([CH3:8])/[CH:3]=[CH:4]/[C:5]([N:28]1[CH2:29][CH2:30][CH2:31][C@@H:26]([NH:25][C:21]2[CH:20]=[C:19]([CH3:18])[CH:24]=[CH:23][N:22]=2)[CH2:27]1)=[O:7]
Reactant: CC(F)(F)/C=C/C(=O)O
Reactant: Cc1ccnc(N[C@@H]2CCCNC2)c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(N[C@@H]2CCCN(C(=O)/C=C/C(C)(F)F)C2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
(E)-4,4-Difluoropent-2-enoic acid (22 mg, 0.16 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (14 μl, 0.16 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 15 minutes. This solution was added to a solution of 4-methyl-N-[(3R)-3-piperidyl]pyridin-2-amine dihydrochloride (23 mg, 0.087 mmol) in DCM (2 ml). Ethyl-N,N-diisopropylamine (DIPEA, 70 μl, 0.4 mmol) was added and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters X-bridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 13 mg of a solid (0.042 mmol, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[C:9]1([C:15]2[CH:33]=[C:32](B(O)O)[C:18]3[O:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)=[CH:22][C:21]=4[C:17]=3[CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=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>[Br:1][C:2]1[CH:3]=[C:4]([C:25]2[C:20]3[O:19][C:18]4[CH:32]=[CH:33][C:15]([C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=5)=[CH:16][C:17]=4[C:21]=3[CH:22]=[C:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:24]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cc(-c2ccccc2)cc2c1oc1ccc(-c3ccccc3)cc12
Reactant: Brc1cccc(I)c1
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: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cc(-c3ccccc3)cc3c2oc2ccc(-c4ccccc4)cc23)c1
Temperature: 110 °C
Yield: 42.1 %

Procedure:
In a 100 mL three-neck flask were put 1.7 g (6.0 mmol) of 3-bromoiodobenzene and 2.2 g (6.0 mmol) of 2,8-diphenyldibenzofuran-4-boronic acid. The air in the flask was replaced with nitrogen. To this mixture were added 30 mL of toluene and 6.0 mL of an aqueous solution of sodium carbonate (2.0 mol/L). While the pressure was reduced, this mixture was stirred to be degassed. To this mixture was added 0.35 g (0.30 mmol) of tetrakis(triphenylphosphine)palladium(0), and the mixture was refluxed at 110° C. for 4 hours. After reaction, the aqueous layer was extracted with ethyl acetate, and the ethyl acetate solution and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate. Then, this mixture was gravity filtered. The resulting filtrate was concentrated to give an oily substance, and the oily substance was dissolved in about 10 mL of toluene. This solution was suction-filtered through Celite (manufactured by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855), alumina, and Florisil (manufactured by Wako Pure Chemical Industries, Ltd., Catalog No. 540-00135). The resulting filtrate was concentrated to give an oily substance, and hexane was added to the oily substance. The mixture was irradiated with ultrasonic waves, whereby a solid was precipitated. This solid was collected by suction filtration to give 1.2 g of a white powder in 44% yield, which was the substance to be produced.