Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:12][O:11][CH2:10][CH2:9][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O[I:25](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.II.IC1C=CC=CC=1>C(Cl)Cl.CCCCC>[I:25][C:4]1[CH:3]=[CH:2][C:1]([C@@H:7]2[CH2:12][O:11][CH2:10][CH2:9][N:8]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccccc1
Agent: II
Solvent: ClCCl
Solvent: CCCCC
Solvent: Ic1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of (R)-tert-butyl 3-phenylmorpholine-4-carboxylate 7 (41.55 g, 157.66 mmol) in CH2Cl2 (400 mL) was added [bis(trifluoroacetoxy)-iodo]benzene (74.25 g, 172.7 mmol, 1.1 eq.) followed by I2 (40 g, 157.6 mmol, 1 eq.) at room temperature (The reaction was exothermic on this scale, the temperature was maintained at room temperature by means of a water bath!). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with CH2Cl2 (˜200 mL) and washed with sat. aq. NaHCO3 (2×750 mL), sat. aq. Na2S2O3 (2×500 mL) and brine (1 L). The organic layer was dried over Na2SO4 filtered and concentrated in vacuo leading to a brown oil containing the desired product. The residue was purified by automated column chromatography (silica column (1.6 kg); gradient heptanes/EtOAc 0 to 15%). The separation was not optimal, the product-containing fractions were concentrated affording a white solid contaminated with some (˜10%) iodobenzene and starting material. Trituration in pentane (2 mL/g) afforded material of sufficient purity (22.7 g, 58.3 mmol) was isolated in 37% yield.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:16][CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1>>[CH2:16]([C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)[CH2:31][CH2:30]2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:15])[CH3:17]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccccc21
Product: CCC1(CCCCN2CCN(c3ccc(OC)cc3)CC2)C(=O)Nc2ccccc21

Procedure:
The title compound is prepared according to process H by applying processing method 1 starting from 3-(4-chlorobutyl)-3-ethyl-1,3-dihydro-2H-indol-2-one and 1-(4-methoxyphenyl)-piperazine.
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[CH:8][N:7]=[N:6]1)[CH2:2][CH:3]=[CH2:4].C1COCC1.Br[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH2:25][C:26]2[N:27]=[C:28]([C:31]3[NH:32][C:33]4[C:38]([CH:39]=3)=[CH:37][C:36]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:35][CH:34]=4)[O:29][CH:30]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=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].O>[N:5]1([CH2:1][CH2:2][CH2:3][CH2:4][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][C:26]3[N:27]=[C:28]([C:31]4[NH:32][C:33]5[C:38]([CH:39]=4)=[CH:37][C:36]([O:40][C:41]([F:44])([F:42])[F:43])=[CH:35][CH:34]=5)[O:29][CH:30]=3)(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:9]=[CH:8][N:7]=[N:6]1
Reactant: C=CCCn1ccnn1
Reactant: O=S(=O)(Cc1coc(-c2cc3cc(OC(F)(F)F)ccc3[nH]2)n1)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S(=O)(Cc1coc(-c2cc3cc(OC(F)(F)F)ccc3[nH]2)n1)c1ccc(CCCCn2ccnn2)cc1
Reaction time: 2 h

Procedure:
To a solution of 1-but-3-enyl-1H-[1,2,3]triazole (69 mg, 0.56 mmol) in THF (5 ml) 9-borabicyclo[3.3.1]nonane (0.5 M in THF, 2.46 ml, 1.23 mmol) was added dropwise at 0° C. and stirring continued for 2 h. This mixture was then added to a solution of 2-[4-(4-bromo-benzenesulfonylmethyl)-oxazol-2-yl]-5-trifluoromethoxy-1H-indole (0.28 g, 0.56 mmol), Pd(dppf)Cl2 (49 mg, 0.06 mmol) and aqueous cesium carbonate (0.56 ml, 3M) in DMF (5 ml) and stirred for 3 h at 70° C. Water (10 ml) was added and the mixture extracted with ethyl acetate (3×20 ml). The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated. The crude product was purified on silica gel (ethyl acetate) to yield 2-{4-[4-(4-[1,2,3]Triazol-1-yl-butyl)-benzenesulfonylmethyl]-oxazol-2-yl}-5-trifluoromethoxy-1H-indole as light yellow solid. Yield 24 mg (8%)
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[C:5]([N:10]=1)=[N:6][CH:7]=[CH:8][CH:9]=2.Cl.[CH:12]1([NH:17][C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[CH2:20]Cl)[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[CH:12]1([NH:17][C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[CH2:20][S:1][C:2]2[NH:3][C:4]3[C:5]([N:10]=2)=[N:6][CH:7]=[CH:8][CH:9]=3)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Sc1nc2ncccc2[nH]1
Reactant: ClCc1ccccc1NC1CCCC1
Agent: Cl
Solvent: CCO
Product: c1ccc(NC2CCCC2)c(CSc2nc3ncccc3[nH]2)c1

Procedure:
2-Mercaptoimidazo[4,5-b]pyridine and 2-(N-cyclopentylamino)benzyl chloride hydrochloride were reacted in an aqueous ethanol solution to obtain 2-[2-(N-cyclopentylamino)benzylthio]-imidazo[4,5-b]pyridine in the same manner as in Example 9-(2). The obtained 2-[2-(N-cyclopentylamino)benzylthio]imidazo[4,5-b]pyridine was oxidized by m-chloroperbenzoic acid in chloroform in the same manner as in Example 9-(3) to give 2-[2-(N-cyclopentylamino)benzylsulfinyl]imidazo[4,5-b]pyridine as a pale yellow crystalline product. m.p.: 134° C. (decompn.)
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:18][C@H:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][OH:21])=[N:4][C:5]([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[N:13]3)=[CH:6][N:7]=1.NC1C(N[C@H](C2C=CC=CC=2)[CH2:38][OH:39])=NC(Br)=CN=1.N1C2C=CC=C(B(O)O)C=2C=CC=1.C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O.O>[OH:21][CH2:20][C@H:19]([N:18]1[C:3]2=[N:4][C:5]([C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH:10]=[CH:11][CH:12]=[N:13]4)=[CH:6][N:7]=[C:2]2[NH:1][C:38]1=[O:39])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ncc(-c2cccc3ncccc23)nc1N[C@@H](CO)c1ccccc1
Reactant: Nc1ncc(Br)nc1N[C@@H](CO)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: OB(O)c1cccc2ncccc12
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2ncc(-c3cccc4ncccc34)nc2n1[C@@H](CO)c1ccccc1
Yield: 67 %

Procedure:
(R)-2-(3-Amino-6-(quinolin-5-yl)pyrazin-2-ylamino)-2-phenylethanol. (R)-2-(3-Amino-6-bromopyrazin-2-ylamino)-2-phenylethanol (0.700 g, 2.26 mmol), quinoline-5-boronic acid (0.431 g, 2.48 mmol), tetrakis(triphenylphosphine)-palladium (0.287 g, 0.226 mmol), potassium carbonate (1.24 g, 9.04 mmol), water (8 mL) and dimethylformamide (35 mL) were reacted according to General Procedure B. The crude material was purified via Biotage silica gel chromatography (40-100% ethyl acetate/hexanes, 40S column) to afford the title compound (0.546 g, 67% yield). MS (ESI) m/z 358.3 [M+1]+.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.C(N(CC)C(C)C)(C)C.[CH2:30]([NH:34][CH2:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:38]([CH3:49])[CH:37]=1)[CH2:31][CH2:32][CH3:33]>C(Cl)Cl>[CH2:30]([N:34]([CH2:35][C:36]1[CH:48]=[CH:47][C:39]([O:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:38]([CH3:49])[CH:37]=1)[C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1nccc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C
Yield: 21.9 %

Procedure:
A mixture of 2-(methylsulfonyl)-4-[4-(trifluoromethyl)phenyl]pyrimidine (0.3 g, 1 mmol), N,N-diisopropylethylamine (0.18 mL, 1 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.424 g, 1.53 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The residue was dissolved in CH2Cl2 and purified by Biotage™ chromatography (Silica, 40 g) eluting 3:97 EtOAc:cyclohexane to afford the title compound as a pale yellow oil (110 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C1(C)C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4ccc(Cl)cc4Cl)cc3)c2cc1OC
Yield: 85.4 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (53 mg) was dissolved in toluene (5 ml) with heat, 2,4-dichlorophenyl isocyanate (115 mg) was added, and the admixture was refluxed with heat for 20 minutes. The separated crystals were filtered and then washed with toluene to obtain 74 mg of the title compound (yield: 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=[CH:13][C:12]=2[CH2:21][C:22]#[N:23])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[K+].[K+].C(Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl.CN(C)C=O>[C:3]1([CH2:1][O:2][C:3]2[CH:4]=[C:5]([CH2:9][CH2:10][C:11]3[C:16]([O:17][CH2:18][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:15]([O:19][CH2:20][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH:14]=[CH:13][C:12]=3[CH2:21][C:22]#[N:23])[CH:6]=[CH:7][CH:8]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCc2c(CC#N)ccc(OC)c2OC)c1
Reactant: BrCc1ccccc1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1CCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To the 2-[2-[(3-methoxyphenyl)ethyl]-3,4-dimethoxybenzeneacetonitrile (5 g) in dichloromethane (100 ml) at -78°, under nitrogen was added 1M boron tribromide (80 ml) in dichloromethane. The reaction was then stirred at room temperature for 4 hours. Ice/water (50 ml) was added and the aqueous extracted with ether. The ethereal layer was dried (MgSO4) and concentrated to give a purple oil. This oil was dissolved in dry dimethylformamide (100 ml) and then potassium carbonate (22.18 g) followed by benzyl bromide (16.5 g) were added. The reaction was stoppered and stirred at room temperature for 14 hours. Ice/water was added, the aqueous layer extracted with ether, the ethereal layer washed with brine, dried (MgSO4) and concentrated to give a yellow oil. This was purified by flash column chromatography on silica gel using ether:petroleum ether 40°-60°; 1:2; v/v to give 2.6 g of the sub-title compound as a white solid, mp 90° (softens) -95° -97° melts.
Reaction SMILES: [CH2:1]([C:3]1([C:40]2[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][CH:41]=2)[CH:12]([CH2:13]CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2].[F:47][C:48]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH:66]=[CH2:67])[C:55]([O:57]CC)=[O:56]>>[CH2:1]([C:3]1([C:40]2[CH:41]=[CH:42][C:43]([OH:46])=[CH:44][CH:45]=2)[CH:12]([CH2:13][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH:54]([CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][C:48]([F:47])([F:72])[C:68]([F:69])([F:70])[F:71])[C:55]([OH:57])=[O:56])[C:11]2[C:6](=[CH:7][C:8]([OH:39])=[CH:9][CH:10]=2)[O:5][CH2:4]1)[CH3:2]
Reactant: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)OCC
Product: CCC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCC(CCCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 21 and the ethyl 2-(6,6,7,7,7-pentafluoroheptyl)-9-decenoate prepared in Example 7, the same procedure as shown in Example 21 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)chroman-4-yl]-2-(6,6,7,7,7-pentafluoroheptyl)undecanoic acid.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][CH2:22][C@@H:23]([C:25]4[CH:34]=[CH:33][C:32]([O:35]CC5C=CC=CC=5)=[C:31]5[C:26]=4[CH:27]=[CH:28][C:29](=[O:43])[NH:30]5)[OH:24])[CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl>CO.O1CCCC1.[Pd]>[C:1]12([CH2:11][O:12][C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][NH:21][CH2:22][C@@H:23]([C:25]4[CH:34]=[CH:33][C:32]([OH:35])=[C:31]5[C:26]=4[CH:27]=[CH:28][C:29](=[O:43])[NH:30]5)[OH:24])[CH:16]=[CH:17][CH:18]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: O=c1ccc2c([C@@H](O)CNCCc3cccc(OCC45CC6CC(CC(C6)C4)C5)c3)ccc(OCc3ccccc3)c2[nH]1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=c1ccc2c([C@@H](O)CNCCc3cccc(OCC45CC6CC(CC(C6)C4)C5)c3)ccc(O)c2[nH]1
Yield: 86.6 %

Procedure:
To a solution of Intermediate 43 (0.075 g, 0.13 mmol) in a mixture of methanol (3 mL) and tetrahydrofuran (1 mL) was added some drops of hydrogen chloride 1.25M in methanol and palladium on charcoal (10%, 0.015 g). The reaction mixture was hydrogenated under a balloon pressure overnight. The catalyst was filtered through Celite® and the solvent removed under reduced pressure. The crude was treated with ether and collected by filtration to obtain the title compound as a yellow solid (0.055 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[C:17]([O:22][CH3:23])=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:32])C=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]3[C:17]([O:22][CH3:23])=[N+:18]([O-:32])[CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: COc1ncccc1COc1ccc(-c2ccc(Br)cc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1c(COc2ccc(-c3ccc(Br)cc3)cc2)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 3-(4′-bromo-biphenyl-4-yloxymethyl)-2-methoxy-pyridine (0.19 g, 0.51 mmol) from Step B and mCPBA (77% max., 0.25 g, 1.13 mmol) in dichloromethane (5 mL) was stirred at room temperature for 3 days. The reaction was diluted with dichloromethane and washed with aqueous Na2SO3 solution, 1N NaOH solution, water and brine. The organic layer was dried over anhydrous K2CO3 and filtered through Celite. The filtrate was concentrated under vacuo and the residue was purified by chromatography (silica gel, 10% MeOH/EtOAc) to give the desired product. MS: 386, 388 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][CH:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN1CCCC1=O.O>[N+:11]([C:10]1[C:4]2[S:3][C:2]([NH:22][CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:14])=[N:6][C:5]=2[CH:7]=[CH:8][CH:9]=1)([O-:13])=[O:12]
Reactant: CC(N)c1ccccc1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)sc12
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(Nc1nc2cccc([N+](=O)[O-])c2s1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
To 0.160 g (0.75 mmol) of 2-chloro-7-nitro-1,3-benzothiazole in 2 mL of 1-methyl-2-pyrrolidinone (NMP) was added 0.29 μL (2.2 mmol) of racemic α-methylbenzylamine. The reaction was stirred at room temperature for 18 h, diluted with water and extracted with dichloromethane. The organic layer was concentrated in vacuo and purified by flash chromatography eluting with a 25% ethyl acetate/hexanes mixture to give 0.165 g (74%) of the title compound as a light yellow solid which was used without further analysis in the subsequent step.
Reaction SMILES: CO[C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[N:6][CH:5]=1.[CH3:30][O:31][CH2:32][CH2:33][CH2:34][NH2:35]>>[CH2:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3](=[O:29])[NH:35][CH2:34][CH2:33][CH2:32][O:31][CH3:30])=[CH:5][N:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)[CH:26]([CH3:27])[CH3:28]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NCC(C)C)CC2)nc1
Reactant: COCCCN
Product: COCCCNC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NCC(C)C)CC2)nc1
Yield: 64 %

Procedure:
By the same procedure as described in the example 25, the synthesis was carried out starting with 6-[1-[3-(isobutylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid methyl ester and using 3-methoxypropylamine. And then, the product was recrystallized with methanol and isopropyl ether to give a desired compound.
Reaction SMILES: [Br:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6](C(=O)C(F)(F)F)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[CH:3]=1>CO.[OH-].[Na+].O>[Br:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[CH:3]=1
Reactant: O=C(N1c2ccccc2C=C(Br)c2ccccc21)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: BrC1=Cc2ccccc2Nc2ccccc21

Procedure:
A solution of 85.9 g of 10-bromo-5-(trifluoroacetyl)-5H-dibenz[b,f]azepine in 500 ml of methanol and 233 ml of normal sodium hydroxide solution is refluxed for 2 hours. The methanol is evaporated off, the concentrated reaction mixture diluted with water and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation. The residue is purified by chromatography over 380 g of silica gel with benzene/petroleum ether (1:1) as eluant. The fraction containing pure 10-bromo-5H-dibenz[b,f]azepine are combined and concentrated by evaporation. The residue is crystallised from cyclohexane to yield 10-bromo-5H-dibenz[b,f]azepine which melts at 65°-69° C.
Reaction SMILES: [Cs].Cl.[Cl:3][C:4]1[S:8][C:7]([C:9]([N:11]([CH2:22][C@@H:23]2[O:27][C:26](=[O:28])[N:25]([C:29]3[CH:34]=[CH:33][C:32]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][C:36]4=[O:41])=[CH:31][CH:30]=3)[CH2:24]2)[CH:12]([C:19]([OH:21])=[O:20])[NH:13][CH2:14][CH2:15]CC=O)=[O:10])=[CH:6][CH:5]=1>CN(C=O)C>[ClH:3].[Cl:3][C:4]1[S:8][C:7]([C:9]([N:11]([CH2:22][C@@H:23]2[O:27][C:26](=[O:28])[N:25]([C:29]3[CH:30]=[CH:31][C:32]([N:35]4[CH2:40][CH2:39][O:38][CH2:37][C:36]4=[O:41])=[CH:33][CH:34]=3)[CH2:24]2)[CH:12]([C:19]([OH:21])=[O:20])[NH:13][CH2:14][CH2:15][CH2:6][CH2:7][CH:9]=[O:10])=[O:10])=[CH:6][CH:5]=1
Reactant: O=CCCCNC(C(=O)O)N(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Agent: Cl
Agent: [Cs]
Solvent: CN(C)C=O
Product: O=CCCCCNC(C(=O)O)N(C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1)C(=O)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
59 mg (106 μmol) of Example 2A are dissolved with 43 mg (138.4 μmol) of the caesium salt of Boc-glycine (prepared from Boc-glycine by General Procedure 1) in 10 ml of DMF. Stirring at 50° C. for 16 h is followed by concentrating and the residue is purified by preparative HPLC (method 1a). The appropriate fractions are concentrated and dried under high vacuum to obtain 26 mg (35% of theory) of the protected title compound.
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[NH:12][C:11](=O)[C:10]2[C:5](=[C:6]([F:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.CCN(C(C)C)C(C)C.P(Cl)(Cl)([Cl:34])=O>>[Cl:34][C:11]1[C:10]2[C:5](=[C:6]([F:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:22])([F:1])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:12]=1
Reactant: O=c1[nH]c(C(F)(F)c2ccc(F)cn2)nc2c(F)cccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(F)c3n2)nc1
Temperature: 115 °C

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoroquinazolin-4(3H)-one (309 mg, 1.0 mmol) were added DIEA (0.36 mL, 2.0 mmol) and phosphorous oxychloride (7.0 mL, 76 mmol, and the mixture was heated at 115° C. for 6 h. The mixture was allowed to cool to rt and then was concentrated under reduced pressure. Toluene was added and evaporated twice to remove residual phosphorous oxychloride. The residue was partitioned between EtOAc (20 mL) and cold saturated aq NaHCO3 (10 mL). The separated EtOAc layer was diluted with EtOAc (60 mL) and washed with saturated aq NaHCO3 (10 mL) and brine (2×10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoroquinazoline as a brown viscous oil (222 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](O)=[C:8]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:9]2=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2].P(Cl)(Cl)([Cl:21])=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:21])=[C:8]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:9]2=[N:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)nc2c(cnn2CC)c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C)nc2c(cnn2CC)c1Cl

Procedure:
A mixture of 49.1 g of 1-ethyl-6-methyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.197 mole) and 250 ml of phosphorus oxychloride is refluxed for 4 hours. Then the excess phosphorus oxychloride is removed by vacuum distillation and the residue is treated with water. The 4-chloro compound (42 g) is filtered under suction and recrystallized from n-hexane, mp 54°-56° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5](Cl)=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10].ClC1C=CC(Cl)=CC=1S(Cl)(=O)=O>>[CH2:41]([S:38]([N:35]1[CH2:34][CH2:33][CH:32]([C:23]2[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=[C:20]([C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][NH:12][S:9]([C:3]5[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=5)(=[O:11])=[O:10])[CH:15]=4)[CH:21]=3)[NH:25][CH:24]=2)[CH2:37][CH2:36]1)(=[O:39])=[O:40])[CH3:42]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5cc(Cl)ccc5Cl)c4)cc23)CC1
Agent: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5ccccc5)c4)cc23)CC1
Yield: 24 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide substituting benzenesulfonyl chloride (62 mg, 0.352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 13.4 mg the title compound (24%).