Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([O:20][C@H:21]2[CH2:54][N:24]3[C:25](=[O:53])[C@@H:26]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([F:44])([F:43])[CH2:33][C@@H:34]4[CH2:39][C@@:35]4([C:40](O)=[O:41])[NH:36][C:37](=[O:38])[C@@H:23]3[CH2:22]2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:67]1([S:70]([NH2:73])(=[O:72])=[O:71])[CH2:69][CH2:68]1.C1CCN2C(=NCCC2)CC1.Cl>ClCCl.ClCCCl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([O:20][C@H:21]2[CH2:54][N:24]3[C:25](=[O:53])[C@@H:26]([NH:45][C:46](=[O:47])[O:48][C:49]([CH3:51])([CH3:52])[CH3:50])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([F:44])([F:43])[CH2:33][C@@H:34]4[CH2:39][C@@:35]4([C:40](=[O:41])[NH:73][S:70]([CH:67]4[CH2:69][CH2:68]4)(=[O:72])=[O:71])[NH:36][C:37](=[O:38])[C@@H:23]3[CH2:22]2)=[N:12][C:13]2[C:18]([N:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)O)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3nc4ccccc4s3)CN2C1=O
Reactant: NS(=O)(=O)C1CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCCCC(F)(F)C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](Oc3nc4ccccc4nc3-c3nc4ccccc4s3)CN2C1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS)-2-(3-(benzo[d]thiazol-2-yl)quinoxalin-2-yloxy)-6-(tert-butoxycarbonylamino)-12,12-difluoro-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (Example 13d, 6.22 mg, 8.13 μmol) was added molecular sieves and DCE (81 μl). CDI (2.91 mg, 0.018 mmol) was added, and the mixture was stirred at 40° C. for 2 h. The reaction mixture was cooled to rt and cyclopropanesulfonamide (2.4 mg, 0.020 mmol) was added followed by DBU (3 μl, 0.020 mmol). The mixture was stirred at rt for 2.5 h, diluted with dichloromethane and cooled to 0° C. The mixture was neutralized with HCl (14 μl, 4 N in dioxane, diluted with EA) and stirred for 5 min at 0° C., and evaporated under reduced pressure. The residue was purified by silica gel prep-TLC (dichloromethane/EA =1/1) to provide the title compound as a yellow solid, (5.2 mg, 74% yield). MS (ESI): m/z=868.3 [M+H], 866.3 [M−H].
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].[CH2:12]([OH:16])[CH2:13]CC.[Br:17]Br.CC1C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1.C(O)CO>[Br:17][CH2:10][C:9]1([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=2[Cl:1])[O:16][CH2:12][CH2:13][O:11]1
Reactant: CCCCO
Reactant: CC(=O)c1cccc(Cl)c1Cl
Reactant: BrBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: OCCO
Product: Clc1cccc(C2(CBr)OCCO2)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a stirred solution of 120 parts of 1-(2,3-dichlorophenyl)-1-ethanone in 240 parts of butanol are added dropwise 101 parts of bromine at room temperature. After stirring for 1 hour at room temperature, there are added successively 42 parts of 1,2-ethanediol, 540 parts of anhydrous benzene and 4 parts of 4-methylbenzenesulfonic acid. The whole is stirred and refluxed overnight with water-separator. The reaction mixture is evaporated and the residue is dissolved in 2,2'-oxybispropane. The solution is washed with a diluted sodium hydroxide solution and three times with water, dried, filtered and evaporated. The residue is distilled, yielding 96.6 parts (49%) of 2-(bromomethyl)-2-(2,3-dichlorophenyl)-1,3-dioxolane; bp. 135°-137° C. at 0.1 mm. pressure.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:26]2[CH2:25][CH2:24][CH:23]([NH:22][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:28][CH2:27]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(S(C)(=O)=O)cc2[N+](=O)[O-])CC1

Procedure:
Method 1 was followed using 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (1.0 eq), 4-(N-Boc-amino) piperidine (1.1 eq), and TEA (2.0 eq) at 55° C. for 24 hours yielding tert-butyl 1-(4-(methylsulfonyl)-2-nitrophenyl)piperidin-4-ylcarbamate. LCMS (m/z): 400.1 (MH+); LC Rt=2.83 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][C:43]([C:46]#[N:47])=[N:44][CH:45]=2)O1>>[C:46]([C:43]1[N:44]=[CH:45][C:40]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:22][CH2:23]2)=[CH:41][N:42]=1)#[N:47]
Reactant: CC1(C)OB(c2cnc(C#N)nc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cnc(C#N)nc4)cc23)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-carbonitrile (46 mg, 0.200 mmol) to afford the crude product (52 mg): ESI MS m/z 513 [C29H32N6O3+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2.[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1.C1CCN2C(=NCCC2)CC1>C(O)(C)C>[CH3:17][C:18]1[N:19]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]3)[CH:20]=[CH:21][N:22]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C1CCc2cc(OCCCBr)ccc2N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)O
Product: Cc1nccn1CCCOc1ccc2c(c1)CCC(=O)N2

Procedure:
2.0 Grams (7.0 mM) of 6-(3-bromopropoxy)-3,4-dihydrocarbostyril, 2.2 g (7.7 mM) of 2-methylimidazol and 1.3 ml (8.4 mM) of DBU were dissolved in 80 ml of isopropanol, and the resulting solution was refluxed by heating for 20 hours. The reaction mixture was concentrated, and to the resulting residue was added water, then extracted with chloroform. The chloroform extract was washed with water, dried with anhydrous sodium sulfate, then concentrated. The resulting residue was purified by means of a silica gel column chromatography (eluent: dichloromethane:methanol=20:1), and recrystallized from ethanol-n-hexane to yield 1.0 g of 6-[3-(2-methyl-1-imidazolyl)propoxy]-3,4-dihydrocarbostyril. White powdery substance.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:38]4[CH2:39][CH:36]([NH:35][CH3:34])[CH2:37]4)[C:21]=3[Br:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: CNC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Br)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Br)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To 800 mg of N,N-dimethylformamide were added 260 mg of 1-(6-amino-3,5-difluoropyridine-2-yl)-8-bromo-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 130 mg of 3-methylaminoazetidine dihydrochloride, and 300 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 247 mg of the title compound as a pale yellow powder.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][NH2:54])[CH:48]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:53]([C:49]3[CH:48]=[N:47][CH:52]=[CH:51][CH:50]=3)[N:54]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Reactant: NNc1cccnc1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cccnc2)n1

Procedure:
600 mg (1.39 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 303 mg (2.08 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 355 mg (60% of theory) of the title compound is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])#[N:2].O[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14].C(O)C>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]1[CH2:12][C:13](=[O:14])[C:15]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[O:7]1)#[N:2]
Reactant: O=C(CO)c1ccccc1
Reactant: N#Cc1cccc(C=O)c1
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(C2CC(=O)c3ccccc3O2)c1
Yield: 10.6 %

Procedure:
A mixture of 3-cyanobenzaldehyde (25 g, 0.19 mol), 2-hydroxyacetophenone (25.9 g. 0.19 mol), 38.1 g (0.1 mol) of borax, 250 ml of ethanol, and 250 ml of H2O was refluxed for four days. When cool the reaction mixture was diluted with H2O and extracted with ethyl acetate. The ethyl acetate was dried over anhydrous Na2SO4, filtered, and evaporated to give a dark, tarry residue. The residue was chromatographed on 1 kg of silica gel, eluting with benzene. From this was isolated 5 g of 3'-cyano flavanone as an oil.
Reaction SMILES: C(OC([NH:8][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH3:36])[CH:34]=2)[N:29]=[C:28]([C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)=[O:38])[N:27]=1)=[N:10]C(OC(C)(C)C)=O)=O)(C)(C)C.C(OCC)(=O)C.[ClH:54]>CO.C(Cl)(Cl)Cl>[ClH:54].[ClH:54].[NH2:10][C:9]([NH:18][C@@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][C@@H:20]1[NH:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH3:36])[CH:34]=2)[N:29]=[C:28]([C:37]([NH:39][C:40]2[CH:41]=[CH:42][C:43]([O:46][CH3:47])=[CH:44][CH:45]=2)=[O:38])[N:27]=1)=[NH:8]
Reactant: COc1ccc(NC(=O)c2nc(N[C@H]3CCCC[C@H]3NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c3cc(C)ccc3n2)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(NC(=O)c2nc(N[C@H]3CCCC[C@H]3NC(=N)N)c3cc(C)ccc3n2)cc1

Procedure:
To a solution of 2.07 g of 4-{[(1S,2R)-2-({(tert-butoxycarbonyl)amino[(tert-butoxycarbonyl)imino]methyl}amino)cyclohexyl]amino}-N-(4-methoxyphenyl)-6-methylquinazoline-2-carboxamide in 10 ml of methanol and 10 ml of chloroform, 40 ml of a 4N-hydrogen chloride-ethyl acetate solution was added, and then the mixture was reacted at 50° C. for 15 hours. The reaction solution was concentrated and recrystallized from methanol-diisopropyl ether to obtain 952 mg of the desirable compound as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:24][C:25](=[O:27])[NH2:26])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:35][C:36]([CH3:41])([CH3:40])[C:37](Cl)=[O:38]>CC(C)=O.O>[C:25](=[O:27])([O:24][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:37](=[O:38])[C:36]([CH3:41])([CH3:40])[CH3:35])=[CH:19][CH:18]=2)[CH2:13][CH2:12]1)[NH2:26]
Reactant: NC(=O)OC(CCN1CCN(c2ccc(O)cc2)CC1)c1ccc(F)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)Oc1ccc(N2CCN(CCC(OC(N)=O)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The compound ‘carbamic acid 1-(4-fluoro-phenyl)-3-[4-(4-hydroxy-phenyl)-piperazin-1-yl]-propyl ester (2 mmol) prepared in Example 88 was dissolved in acetone (15 mL), and triethylamine (2.4 mmol) was added and trimethyl acetylchloride (2.4 mmol) was added dropwise, and the resulting mixture was then stirred at a room temperature for 5 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate to obtain an organic phase. The prepared organic phase was dried over magnesium sulfate, and concentrated under a reduced pressure. The resulting pellet was purified with column chromatography (hexane:ethyl acetate=1:1) to obtain a title compound.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8](OC)[CH:7]=1.Cl[C:16]1[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=1.[C:24]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:16]2[N:17]=[CH:18][C:19]([C:22]#[N:23])=[N:20][CH:21]=2)=[C:8]([CH3:24])[CH:7]=1
Reactant: COc1cc(C2OCCO2)ccc1O
Reactant: N#Cc1cnc(Cl)cn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C2OCCO2)ccc1Oc1cnc(C#N)cn1
Temperature: 100 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Take up 4-[1,3]dioxolan-2-yl-2-methylphenol (Example 388, Part C2) (0.288 g, 2.06 mmol), 5-chloropyrazine-2-carbonitrile (0.372 g, 2.06 mmol) and K2CO3 (0.428 g 3.10 mmol) in DMF (13.8 mL). Heat at 100° C. for 45 minutes. Cool to 80° C. and stir overnight. Dilute the reaction mixture with dichloromethane (100 mL). Wash the organic layer with saturated aqueous NaBCO3 (2×25 mL) and brine (1×25 mL). Dry over Na2CO3, filter and concentrate. Purify by flash chromatography, eluting with 30% ethyl acetate in hexanes to give the title compound (0.560 g, 95.58%): TLC [silica gel 60 F254, 30% ethyl acetate in hexanes] Rf=0.52.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:8][C:9](=[O:10])[C:2]1=2)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:6]([C:3]1[CH:4]=[CH:5][S:1][C:2]=1[C:9]([OH:8])=[O:10])(=[O:7])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1OC(=O)c2sccc21
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1ccsc1C(=O)O

Procedure:
Employing 2,3-thiophene dicarboxylic anhydride and benzene, substantially the same reaction and work-up as in Reference Example 8 Step 1 in the presence of aluminum chloride were conducted to give 3-benzoyl-2-thiophenecarboxylic acid as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH:16]=O)=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.NO.C([N:23](CC)CC)C.[N+](C1C=C2C(=O)OC(=O)C2=CC=1)([O-])=O>C(#N)C.O>[CH2:1]([O:8][C:9]1[C:10]([C:16]#[N:23])=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccc(OCc2ccccc2)c(C=O)n1
Agent: Cl
Agent: NO
Agent: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: O
Solvent: CC#N
Product: Cc1ccc(OCc2ccccc2)c(C#N)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
3-Benzyloxy-6-methyl-pyridine-2-carbaldehyde (100 mg) was dissolved in acetonitrile (5 ml) to prepare a solution. Hydroxylamine hydrochloride (72 mg) and triethylamine (0.25 ml) were added to the solution, and the mixture was stirred at room temperature for one hr. 4-Nitrophthalic anhydride was added to the reaction solution, and the mixture was stirred at 100° C. overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using ethyl acetate-hexane to give 3-benzyloxy-6-methylpyridine-2-carbonitrile (53 mg, yield 54%).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[B:9]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[CH3:19])F.[C:21]1([B:27]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)OC(C)C)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]1([CH3:20])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[B:9]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=1[CH3:19])[C:1]1[CH:6]=[CH:5][C:4]([B:27]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[CH:3][CH:2]=1
Reactant: CC(C)OB(c1ccccc1)c1ccccc1
Reactant: Cc1cc(C)c(B(F)c2c(C)cc(C)cc2C)c(C)c1
Product: Cc1cc(C)c(B(c2ccc(B(c3ccccc3)c3ccccc3)cc2)c2c(C)cc(C)cc2C)c(C)c1

Procedure:
The compound is prepared in accordance with Method B described above, using 1 equivalent of dimesitylfluoroborane and 1 equivalent of diphenylisopropoxyborane. The crude product is obtained by concentrating the reaction mixture under a high vacuum and treating the solid residue, under argon, with hexane. Filtration, concentration of the filtrate and recrystallization of the residue from acetonitrile give 3.0 g (61% of theory) of the pale yellow title product, which is sensitive to air. Physical data are given in Tabelle 1.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].Cl.[CH:20](=O)[CH3:21]>CO>[CH2:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)[CH3:21]
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: CC=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNc1ccc(C=CC(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5 g of ethyl 4-aminocinnamate in 100 ml of methanol, 0.1 ml of acetaldehyde, 1.256 g of sodium cyanoborohydride and 2.15 ml of hydrochloric acid 23% were added. The solution was stirred at room temperature for one day, then the solvent evaporated in vacuum and the crude residue purified by flash chromatography (n-exane/ethyl acetate 9/1) to yield 2.1 g of intermediate as a yellow solid.
Reaction SMILES: [CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:22])=[C:18]([Cl:21])[CH:19]=2)[N:14](C(OC(C)(C)C)=O)[C:13]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([CH2:10][NH:11][C:12]1[C:20]2[C:15](=[CH:16][C:17]([Cl:22])=[C:18]([Cl:21])[CH:19]=2)[NH:14][C:13]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CCOC(=O)c1c(NCCC(=O)c2ccccc2)c2cc(Cl)c(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2cc(Cl)c(Cl)cc2c1NCCC(=O)c1ccccc1

Procedure:
Dissolve 3-[(phenacyl)methylamino]-2-carbethoxy-5,6-dichloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (15 mL). Add trifluoracetic acid (5 mL) and stir for 5 hours. Concentrate the reaction in vacuo, dilute with ethyl acetate (100 mL), wash with saturated sodium carbonate, dry over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue from ethyl acetate/hexane to yield the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26])([CH3:19])[CH3:18].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1)([CH3:19])[CH3:18]
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Reactant: CC(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)c1ccccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 77.8 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2-isopropylphenol (25 μL, 0.185 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-isopropyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (28 mg, 78%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (br. s., 1H), 8.01 (br. s., 1H), 7.93 (d, J=8.1 Hz, 2H), 7.55-7.65 (m, 3H), 7.21 (dd, J=7.5, 1.6 Hz, 1H), 7.06-7.17 (m, 1H), 7.01 (d, J=7.3 Hz, 1H), 6.84-6.96 (m, 1H), 5.18 (s, 2H), 3.22-3.39 (m, 3H, including water peak), 1.18 (d, J=7.0 Hz, 6H).
Reaction SMILES: [C:1]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=[O:2].N1CCCCC1.[CH:30]1[C:42]2[CH:41]([CH2:43][O:44][C:45]([NH:47][CH2:48][C:49]3[CH:57]=[CH:56][C:52](C(O)=O)=[CH:51][CH:50]=3)=[O:46])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C=O)C.C(N(CC)C(C)C)C>[CH:30]1[C:42]2[CH:41]([CH2:43][O:44][C:45]([NH:47][CH2:48][C:49]3[CH:50]=[CH:51][C:52]([C:1]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:2])=[CH:56][CH:57]=3)=[O:46])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]=2[CH:33]=[CH:32][CH:31]=1
Reactant: O=C(NCc1ccc(C(=O)O)cc1)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CCN(CC)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: O=C(O)CCNC(=O)c1ccc(CNC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
To the above resin bound Fmoc β-alanine was added 500 μL of a 20% solution of piperidine in DMF. Upon shaking for 30 min, the resin was drained and washed with 1 mL DMF containing 1-hydroxybenzotriazole (50 mg/mL) and DMF (2×1 mL). Then 200 μmol 4-[(9H-fluoren-9-ylmethoxycarbonylamino)methyl]benzoic acid (74.2 mg) dissolved in a mixture of 430 μL DMF and 70 μL diethylisopropylamine was added followed by 200 μmol bromo-tris-pyrrolidinophosphonium hexafluorophosphate (PyBrOP, 93 mg) dissolved in 500 μL DMF. The mixture was shaken for 4 hours at 25° C. followed by filtration and washing of the resin with 3×1 mL DMF.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:23][CH3:24])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([Cl:39])[C:31]=1[C:32](=O)[C:33]([O:35]CC)=O.CC(O)=O>COCCO>[Cl:39][C:30]1[CH:29]=[N:28][CH:27]=[C:26]([Cl:25])[C:31]=1[C:32]1[C:33](=[O:35])[N:23]([CH3:24])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][N:18]([CH2:19][CH3:20])[CH2:21][CH3:22])=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=O)C(=O)c1c(Cl)cncc1Cl
Reactant: CCN(CC)CCOc1ccc(Nc2ncc(N)c(NC)n2)cc1
Solvent: CC(=O)O
Solvent: COCCO
Product: CCN(CC)CCOc1ccc(Nc2ncc3nc(-c4c(Cl)cncc4Cl)c(=O)n(C)c3n2)cc1
Yield: 15.3 %

Procedure:
A mixture of 0.465 g (1.4 mmol) of 5-amino-2-[[4-[2-(diethylamino)-ethoxy]-phenyl]amino]-4-(methylamino)pyrimidine, 0.69 g (2.8 mmol) of ethyl 2-(3,5-dichloropyridin-4-yl)-2-oxoacetate, and 0.5 mL of HOAc in 15 mL of 2-methoxyethanol is heated under reflux for 18 hours, and the reaction is worked up as above in 6 to give 0.11 g (15%) of the title compound (Compound 20): mp (MeOH) 179–180.5° C.