Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]#[C:6][C:7]1[CH:8]=[CH:9][C:10]2[O:14][CH2:13][CH2:12][C:11]=2[CH:15]=1)[CH3:2].[C:17]([O:21][C:22]([N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[NH:42][CH:41]=[CH:40]4)[N:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[N:42]([C:6]([C:7]3[CH:8]=[CH:9][C:10]5[O:14][CH2:13][CH2:12][C:11]=5[CH:15]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH:41]=[CH:40]4)[N:32]=2)[CH2:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: CCOC(=O)C#Cc1ccc2c(c1)CCO2
Product: CCOC(=O)C=C(c1ccc2c(c1)CCO2)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 52 %

Procedure:
The title compound was synthesized from (2,3-dihydro-benzofuran-5-yl)-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (c1), in 52% yield as an E/Z mixture. 1H NMR (CDCl3) δ 7.31 (d, 1H, J=7.6 Hz), 7.18–7.01 (m, 4H), 6.94(dd, 1H, J=3.5, 7.6 Hz), 6.82–6.71 (m, 3H), 6.56–6.48 (m, 1H), 6.10 (s, 0.6H), 6.00 (s, 0.4H), 4.62 (q, 2H, J=8.8 Hz), 4.39–4.35 (m, 2H), 4.13 (q, 0.8H, J=7.1 Hz), 3.98 (q, 1.2H. J=7.1 Hz), 3.76 (t, 2H, J=5.9 Hz), 3.23–3.14 (m, 4H), 2.73 (t, 2H, J=6.64 Hz), 1.95–1.89 (m, 2H), 1.52 (s, 9H), 1.21 (t, 1.2H, J=7.1 Hz), 1.00 (t, 1.8 Hz, J=7.1 Hz).
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.O1CCCC1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:36]([CH:37]([OH:48])[C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)=[C:35]([CH:49]([CH3:51])[CH3:50])[CH:34]=[C:33]3[C:25]=2[C:26](=[O:52])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:20][CH:19]=1>CO>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[C:36]([C@H:37]([OH:48])[C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:46])([F:47])[F:45])=[CH:40][CH:39]=3)=[C:35]([CH:49]([CH3:50])[CH3:51])[CH:34]=[C:33]3[C:25]=2[C@@H:26]([OH:52])[CH2:27][C:28]2([O:32]3)[CH2:31][CH2:30][CH2:29]2)=[CH:22][CH:23]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC1(CCC1)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under argon, 1.6 mg (0.011 mmol) of (1R,2S)-1-aminoindan-2-ol are dissolved in 1 ml of abs. tetrahydrofuran, 77 μl (0.43 mmol) of borane/N,N-diethylaniline complex are added and the mixture is stirred at room temperature for 30 min. After this time, 60 mg (0.108 mmol) of 5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethyl)phenyl]methyl}-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 52A), dissolved in 2 ml of abs. tetrahydrofuran, are added at room temperature over a period of 10 min, and the mixture is then stirred at room temperature for 18 h. 2 ml of methanol are added and the mixture is stirred for 15 min and then concentrated to dryness. The residue is taken up in ethyl acetate and washed twice with 1 N hydrochloric acid, twice with saturated sodium bicarbonate solution and twice with saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The crude product obtained is purified by preparative thick-layer chromatography (mobile phase: cyclohexane/ethyl acetate 4:1), resulting in the separation of the diastereomers.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH:7]=[CH:6][C:5]=1[O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[O:3].[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1>>[F:21][C:18]([F:19])([F:20])[CH2:17][O:16][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])=[CH:9][C:4]=1[C:2](=[O:3])[CH:1]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1
Reactant: COc1cccc(C=O)c1
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Product: COc1cccc(C=CC(=O)c2cc(OCC(F)(F)F)ccc2OCC(F)(F)F)c1

Procedure:
The title compound was prepared from a mixture of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone (200 mg, 0.633 mmol) and m-anisaldehyde (77 ul, 0.633 mmol) similar to Example 6 and isolated as a light yellow solid (74 mg, 27%). 1H NMR (CDCl3): 7.67 (d, J=15.6 Hz, 1H), 7.44 (d, J=15.6 Hz, 1H), 7.34 (s, 1H), 7.30 (dd, J=2.4, 5.7 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H), 7.11 (dd, J=3.2, 8.9 Hz, 2H), 6.97 (dd, J=0.9, 2.7 Hz, 1H), 6.93 (d, J=9.0 Hz, 1H), 4.44-4.33 (m, 4H), 3.83 (s, 3H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[F:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:31]2[CH:32]=[N:33][C:28]([F:27])=[CH:29][CH:30]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccc(F)nc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(-c2ccc(F)nc2)c1

Procedure:
By carrying out the operation analogously to example 1, starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IX, and 6-fluoro-3-pyridineboronic acid, the desired product is obtained in the form of a cream solid (yield=56%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5](I)=[CH:4][N:3]=1.[B-](F)(F)(F)[C:12]1[CH:16]=[CH:15][S:14][CH:13]=1.[K+].C(N(CC)CC)C>C(O)C.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(I)cc1C=O
Reactant: F[B-](F)(F)c1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2ccsc2)cc1C=O
Temperature: 80 °C
Reaction time: 14 h

Procedure:
150 mg (0.605 mmol) of 2-amino-5-iodopyridine-3-carbaldehyde and 115 mg (0.605 mmol) of potassium 3-thiophenetrifluoroborate are suspended in 4 ml of ethanol in a nitrogen-filled reaction vessel, and 251 μl (1.814 mmol) of triethylamine and 22.1 mg (0.030 mmol) of [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride are added. The reaction mixture is stirred at 80° C. for 14 h under a nitrogen protective atmosphere. The reaction mixture is cooled to room temperature and diluted with water/ethyl acetate and filtered off. The organic phase is separated, and the aqueous phase is extracted a further 2× with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered, and the solvent is removed, giving 2-amino-5-thiophen-3-ylpyridine-3-carbaldehyde; HPLC-MS [M+H]+ 205.2.
Reaction SMILES: C[O:2][CH:3](OC)[CH:4]([CH3:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.O.S(=O)(=O)(O)O>C1COCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][O:5][CH:4]([CH3:13])[CH:3]=[O:2]
Reactant: COC(OC)C(C)OCc1ccccn1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C=O)OCc1ccccn1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To a solution of 2-[(2,2-dimethoxy-1-methylethoxy)methyl]pyridine (1.66 g, 7.85 mmol, obtained from Example 20(a)) in THF (30 mL) was added water (10 mL) and concentrated sulfuric acid (1 mL) and the resulting solution was refluxed for 12 h. After cooling to r.t., the volatile components were removed in vacuo and dichloromethane was added followed by saturated sodium bicarbonate solution until the aqueous layer was pH 7. The layers were separated and the aqueous phase was extracted with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated yielding 0.875 g (68% yield) of the title compound. This material was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:9](Br)[N:8]([CH2:22][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:24]=[CH2:25])[C:4]=2[N:5]=[CH:6][N:7]=1.NC1C2C(C3C=NC4C(C=3)=CC=CC=4)=C3N(C=2N=CN=1)C[C@@H](NC(=O)OC(C)(C)C)CC3>>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:9]3[N:8]([C:4]=2[N:5]=[CH:6][N:7]=1)[CH2:22][C@H:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][CH2:25]3
Reactant: C=C[C@H](Cn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2C1
Yield: 84.1 %

Procedure:
In accordance with Example 10, except that the (R)-tert-butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate (6.70 g) obtained in Reference Example 2 was used in place of the (S)-tert-butyl (1-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)but-3-en-2-yl)carbamate obtained in Example 10, (R)-tert-butyl (4-amino-5-(quinolin-3-yl)-6,7,8,9-tetrahydropyrimido[5,4-b]indolizin-8-yl)carbamate (4.76 g) (yield: 84%) was obtained as a light-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[NH2:21][CH:22]([CH2:26][CH3:27])[CH2:23][O:24][CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=2[O:19][CH3:20])[C:13]([NH:21][CH:22]([CH2:23][O:24][CH3:25])[CH2:26][CH3:27])=[O:15])=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(Cl)cc1
Reactant: CCC(N)COC
Product: CCC(COC)NC(=O)c1ccc(OC)c(/C=C/c2ccc(Cl)cc2)c1

Procedure:
The captioned compound was synthesized from 3-[(E)-2-(4-chlorophenyl)vinyl]-4-methoxy-benzoic acid and 2-amino-1-methoxybutane in accordance with the same procedure as in the manufacturing method described in step C of Example 1-2-3.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([O:15]CC)=O.[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>C(Cl)Cl>[Cl:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:13]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=3)=[O:15])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnc2ccc(O)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(O)cc2c1O
Temperature: 180 °C
Yield: 52.8 %

Procedure:
A mixture of 4-aminophenol (5.457 g) and diethyl ethoxymethylenemalonate (10.81 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature. Diphenyl ether (50 mL) is added and the mixture is heated to 250° C. for 45 min with removal of ethanol by a Dean-Stark trap. The solution is cooled to 80° C. and the resulting solid is collected and washed with hexanes. The solid is suspended in 250 mL MeOH and brought to a boil. The insoluble material is filtered and the filtrate is adsorbed onto silica and chromatographed, eluting with 5% MeOH/CH2Cl2 then with 10% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.644 g of ethyl 4,6-dihydroxyquinoline-3-carboxylate. A mixture of this ester (0.500 g) and 4-chlorobenzylamine (1.518 g) are heated to 180° C. for 1 h. The solution is cooled to room temperature and diluted with CH2Cl2. The resulting solid is collected and chromatographed on silica, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo. The residue is sonicated with CH2Cl2 /hexanes. The resulting solid is collected and dried to afford 0.372 g of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.C([O-])=O.[Na+].Cl.[NH2:15]O>C(O)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:15])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1ccc(Cl)cc1

Procedure:
The Compound (I) may be synthesized by reacting 4-chlorobenzaldehyde, sodium formate, hydroxylamine hydrochloride and formic acid to form 4-chlorobenzonitrile, which may be nitrated to form 4-chloro-3-nitrobenzonitrile. Finally, this compound is reacted with the appropriate amine to obtain the desired compound (I) of the present invention.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13](I)=[CH:12][N:11]=[CH:10][N:9]=1)(C)(C)C.[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][CH:20]=1.N12CCCN=C1CCCCC2>CN(C=O)C.C(OCC)(=O)C.[Cu](I)I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:16][O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[NH:7][C:8]3[N:9]=[CH:10][N:11]=[CH:12][C:13]=3[CH:26]=2)=[CH:21][CH:20]=1
Reactant: C#Cc1ccc(C(=O)OC)cc1
Reactant: CC(C)(C)OC(=O)Nc1ncncc1I
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2cc3cncnc3[nH]2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
To a solution of (5-iodo-pyrimidin-4-yl)carbamic acid tert-butyl ester (1.46 g, 4.55 mmol) (reference example 44a) in DMF (15 mL) is added 4-ethynyl-benzoic acid methyl ester (0.721 g, 4.5 mmol)(reference example 46), copper iodide 99.999% (21 mg, 0.112 mmol), bis(triphenylphosphine)palladium(II)chloride (158 mg, 0.225 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.5 mL, 10 mmol). The resulting solution is heated to 100° C. and stirred for 1 hour then cooled to 20° C. The solution is diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 50% ethyl acetate, 5% methanol in hexanes) to give 601 mg of title compound as a yellow crystalline solid. 1H NMR (DMSO) δ 3.89 (s, 3H), 7.24 (s, 1H), 8.06 (d, J=8 Hz, 2H), 8.14 (d, J=8 Hz, 2H), 8.81 (bs, 1H), 9.05 (bs, 1H), 12.79 (bs, 1H). MS (ion spray) m/z 254 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:17]=[C:18]([O:25][C:26]4[CH:27]=[C:28]([NH:32]C(=O)C=C)[CH:29]=[CH:30][CH:31]=4)[C:19]4[S:24][CH:23]=[CH:22][C:20]=4[N:21]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1>C(O)C.[Fe]>[NH2:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[O:25][C:18]1[C:19]2[S:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:6]3[CH2:5][CH2:4][N:3]([CH3:2])[CH2:8][CH2:7]3)=[CH:14][CH:13]=2)[N:17]=1
Reactant: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc3ccsc23)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc(N)c4)c4sccc4n3)cc2)CC1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 67.8 %

Procedure:
Iron (27.1 mmol) and 12 N HCl aqueous solution (2.17 mmol) were diluted with 50% ethanol aqueous solution (30 mL), followed by stirring at 100° C. for 10 min. The compound (5.42 mmol) obtained in Step 4 was dissolved in 50% ethanol aqueous solution (30 mL) and then added to the reaction flask in which iron was activated, followed by stirring at 100° C. for 1 hour. After the reaction was complete, the reaction mixture was filtered with celite to remove iron, and the filtrate was distilled under a reduced pressure. The residue was distilled with dichloromethane and washed with sat. NaHCO3 aqueous solution. The organic layer was dried with anhydrous sodium sulfate and then filtered and distilled under a reduced pressure. The residue was separated by column chromatography (dichloromethane:methanol=10:1 (volume ratio)) to obtain the title compound (yield: 67.8%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14]O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:36]>>[Cl:36][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1
Reactant: OCc1ccc(Oc2ccccc2)cc1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of (4-phenoxy-phenyl)-methanol (408 mg, 2.04 mmol) in carbon tetrachloride (8.2 mL) was added triphenylphosphine (642 mg, 2.45 mmol) under nitrogen atmosphere at room temperature, and the reaction solution was stirred under reflux for 7 hours and 40 minutes. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (409 mg, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[NH4+:14]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Product: COc1ccc(S(N)(=O)=O)cc1

Procedure:
Proceeding in a manner similar to that described in Example 1, part B above, 100.42 g (0.486 m) of 4-methoxybenzenesulfonyl chloride from part A above was interacted with ammonium hydroxide and acidified to obtain 69.25 g of 4-methoxybenzenesulfonamide, a white solid which melted at 111.5°-112.5° C. The nuclear magnetic resonance spectrum was in accord with the assigned structure.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[C:10]2[C:14]1[C:15](=[O:30])[NH:16][C:17](=[O:29])[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[N:26]([CH3:28])[CH:25]=[CH:24]2.O1CCCC1.C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:59]>C(Cl)Cl>[Br:59][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][CH:11]=[C:10]2[C:14]1[C:15](=[O:30])[NH:16][C:17](=[O:29])[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:27]=1[N:26]([CH3:28])[CH:25]=[CH:24]2
Reactant: BrC(Br)(Br)Br
Reactant: Cn1ccc2cccc(C3=C(c4c[nH]c5c(CCCO)cccc45)C(=O)NC3=O)c21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1ccc2cccc(C3=C(c4c[nH]c5c(CCCBr)cccc45)C(=O)NC3=O)c21
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To a solution of 3-[7-(3-hydroxypropyl)-1H-indol-3-yl]-4-(1-methyl-1H-indol-7-yl)pyrrole-2,5-dione (505 mg, 1.27 mmol) in 1:1 tetrahydrofuran/methylene chloride (60 mL) was added triphenylphosphine (330 mg, 1.25 mmol) followed by carbon tetrabromide (418 mg, 1.26 mmol). After one hour, additional triphenylphosphine (332 mg, 1.27 mmol) and carbon tetrabromide (414 mg, 1.25 mmol) was added. After 1 h, triphenylphosphine (330 mg, 1.26 mmol) and carbon tetrabromide (430 mg, 1.30 mmol) was added and stirred for 1 h. The reaction mixture was diluted with methylene chloride (100 mL), washed with saturated aq NaHCO3 (100 mL), brine (100 mL), dried (MgSO4) and concentrated. Flash chromatography (SiO2, 30% EtOAc/hexanes) gave the title compound (462 mg, 91%) as a red solid. 1H NMR (CDCl3) 8.93 (m, 1H), 8.66 (m, 1H), 8.07–7.87 (m, 4H), 6.64 (m, 1H), 6.49 (m, 2H), 3.72 (s, 3H), 3.41 (m, 2H), 2.96 (m, 2H), 2.21 (m, 2H). MS (electrospray, m/z) 464/462 (C24H20BrN3O2+H)+.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:14]=[O:15])C1C=CC=CC=1.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20]2>ClCCCl>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:20]2[CH:14]=[O:15]
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: CN(C=O)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)c1[nH]c2ccc(Br)cc2c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
In a 1 L round bottom flask 10.5 mL of phosphorus oxychloride was added to 15.5 g of N-methylformanilide at room temperature that resulted in a yellow solid after 15 min. At this time, 170 mL of 1,2-dichloroethane and 20.1 g of ethyl 5-bromoindole-2-carboxylate were added. The resulting suspension was heated under reflux for 4 hours and then concentrated to remove the organic solvent. 75 g of sodium acetate in 750 mL of water were added and the solid suspension was stirred for 30 min at room temperature, filtered and washed 3 times with water. The crude material was dried under vacuum for 1 hour and swished with 500 mL of EtOH to yield 21.2 g of the title compound as off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[I-].[K+].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: C1COCCN1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CN3CCOCC3)n1-2

Procedure:
In the manner given in Preparation 48, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, potassium iodide, and morpholine in tetrahydrofuran are reacted to give 8-chloro-1-(morpholinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([C:8]1([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)C#N)C.[OH-].[K+]>C(O)CO.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2([CH2:5][C:4]([OH:21])=[O:3])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]2)=[CH:15][CH:16]=1
Reactant: CCOC(=O)C(C#N)C1(c2ccc(Cl)cc2)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: O=C(O)CC1(c2ccc(Cl)cc2)CCOCC1
Yield: 125.2 %

Procedure:
A stirred solution of (4-{4-chloro-phenyl}-tetrahydro-pyran-4-yl)-cyano-acetic acid ethyl ester (3.3 g, Reference Example 22) in ethylene glycol (50 mL) was treated with a solution of potassium hydroxide (5 g) in water (10 mL) in one portion and then heated at reflux temperature for 23 hours. The resultant pale amber solution was evaporated and the oily residue was treated with water (50 mL). The mixture was washed with diethyl ether (20 mL), then ice-cooled, then acidified to pH 1 by addition of concentrated hydrochloric acid (3 mL) and then extracted with diethyl ether (50 mL). The organic extract was washed with water (25 mL) then dried over magnesium sulfate and then evaporated to give the title compound (3.42 g) as a colourless oil, which slowly crystallised on standing. LC-MS: RT=2.92 minutes, MS(ES+): 253 and 255(M+H)+.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[C:7]([CH:9]=[N:10][OH:11])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[O-]Cl.[Na+].[C:23]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)#[CH:24]>C(Cl)Cl>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:8]=[C:7]([C:9]2[CH:24]=[C:23]([C:25]3[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=3)[O:11][N:10]=2)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(N)cc1
Reactant: ON=Cc1ccc(-c2ccccc2)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: Nc1ccc(-c2cc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)no2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-trifluoromethyl-biphenyl-4-carbaldehyde oxime (1 eq) in CH2Cl2 a 10% aqueous solution of NaOCl is added at 0° C. Thereafter a solution of 4-ethynylaniline (1.1 eq) is added and then the reaction mixture is stirred at room temperature for 16 hours. The reaction mixture is diluted with CH2Cl2 and 3 times extracted with water. The combined organic layers are dried over Na2SO4, filtered and concentrated. Purification is achieved, after drying over Na2SO4, over silica gel using c-hexane/ethyl acetate 9/1→7/3 as mobile phase.