Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[C:60]([F:62])[CH:59]=[C:58]([F:63])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:49]=[CH:50][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:57]=[C:58]([F:63])[CH:59]=[C:60]([F:62])[CH:61]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:64][CH:65]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cc(F)cc(F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(CCc2cc(F)cc(F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 72.4 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 91 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(3,5-difluoro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 4 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 97 mg off-white solid (71%). MS (ISP) 447.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:22]=1)[C:18]1[CH:17]=[C:16](O)[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](Br)=[CH:9][CH:10]=1.[C:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[N:30][CH:31]=1)#[C:24][CH3:25].[CH3:35][C:36]([OH:40])([C:38]#[CH:39])[CH3:37]>>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:22]=1)[C:6]1[CH:7]=[C:8]([C:28]3[CH:29]=[N:30][CH:31]=[C:26]([C:23]#[C:24][CH3:25])[CH:27]=3)[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:18]2=[CH:17][C:16]([C:39]#[C:38][C:36]([CH3:37])([OH:40])[CH3:35])=[CH:15][C:14]=1[F:20]
Reactant: CC#Cc1cncc(B(O)O)c1
Reactant: C#CC(C)(C)O
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c(F)cc(O)cc12
Product: CC#Cc1cncc(-c2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(C#CC(C)(C)O)cc(F)c2O3)c1

Procedure:
The titled compound was synthesized by steps analogous to those described in method AA21 above, but using (S)-2-amino-7′-bromo-4′-fluoro-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (prepared by steps analogous to those described in Method BB40 and Example 2), 5-(prop-1-ynyl)pyridin-3-ylboronic acid, and 2-methylbut-3-yn-2-ol.
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][O:36][C:35]1=[O:39]>C1C=CC=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:22]=[CH:21][C:5]2[S:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:32][CH2:33][N:34]4[CH2:38][CH2:37][O:36][C:35]4=[O:39])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1S2
Reactant: O=C1OCCN1CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Br)ccc3Sc3ccccc32)CC1
Temperature: 0 °C

Procedure:
12.5 g of 1-(2-bromo- 10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-piperazine are treated, together with 13 g of powdered potassium carbonate, 0.2 g of potassium iodide and 1 litre of toluene, with 13.2 g of N-(β-chloroethyl)-oxazolidinone and the mixture is heated under reflux for 25 hours. Then the mixture is poured on to ice-water and diluted with benzene. The benzene solution is washed neutral with water and extracted with 2-N hydrochloric acid. The aqueous phase is made alkaline with sodium hydroxide and extracted with benzene. The organic phase is washed with water, dried over magnesium sulphate and concentrated under reduced pressure. There is obtained crude 3-[2-[4-(2-bromo- 10,11-dihydro-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl]-2-oxazolidinone which is converted into the maleate of melting point 170°-172° C by treatment with maleic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[C:3]=1[C:12](=[O:14])[CH3:13].C([NH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)(=O)C.[OH-].[K+].O>C(O)C>[NH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[CH:13][C:12]([C:3]2[C:4]([O:10][CH3:11])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[OH:1])=[O:14])=[CH:21][CH:20]=1
Reactant: COc1cc(O)c(C(C)=O)c(OC)c1
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc(O)c(C(=O)C=Cc2ccc(N)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 8 %

Procedure:
A mixture of 98 mg of 2'-hydroxy-4',6'-dimethoxyacetophenone, 85 mg of 4-acetamidobenzaldehyde and 1 g of potassium hydroxide in 4 ml of 50% aqueous ethanol was stirred at room temperature for 3 days. The mixture was poured into 30 ml of cold water and then extracted with three 30 ml portions of ethyl acetate. The combined extracts were washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography using a silica gel plate (Kiesel gel 60 F254, Merck Co.) and cyclohexane/ethyl acetate (1:1, v/v) as the developing solvent, whereby 12 mg of 4-amino-2'-hydroxy-4',6'-dimethoxychalcone as a yellow powder were obtained: Rf value 0.22; 1H-nmr spectrum (in CDCl3): δ3.6(2H), 3.72(3H), 3.82(3H), 5.90(1H), 6.06(1H), 6.56(1H), 6.70(1H), 7.50(1H), 7.62(1H) and 14.4 ppm (1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7](/[CH:10]=[CH:11]\[S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:8][CH:9]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.O.Cl>ClCCl>[OH:2][CH2:3][C:5]1[N:6]=[C:7](/[CH:10]=[CH:11]\[S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:8][CH:9]=1
Reactant: COC(=O)c1csc(/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: OCc1csc(/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h
Yield: 88.3 %

Procedure:
A solution of 3.48 g of 4-methoxycarbonyl-2-((Z)-2-tritylthioethen-1-yl)thiazole in 70 ml of dichloromethane was cooled in ice, and 18.7 ml of a 1.0 M diisobutylaluminum hydride/toluene solution was added dropwise to the cooled solution under an argon atmosphere. The mixture was stirred at the same temperature for one hr. Water was then added to the reaction solution, and the mixture was adjusted to pH 2.5 by the addition of 1 N aqueous hydrochloric acid. The insolubles were removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 2.88 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.F[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)C=O>CN1CCCC1=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([O:25][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Reactant: Fc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccccn5)ccc(F)c43)ccc21
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
A microwave vial is charged with a stir bar, {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester (0.10 g), 2-fluoro-pyridine (27 mg), Cs2CO3 (91 mg) and N,N-dimethylformamide (2 mL; alternatively N-methyl-pyrrolidinone is used). The mixture is stirred at 130° C. for 30 min by irradiation in a microwave oven. After cooling to room temperature, the mixture is concentrated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→80:20) to give the title compound. LC (method 2): tR=1.15 min; Mass spectrum (ESI+): m/z=436 [M+H]+.
Reaction SMILES: [CH3:1][C@:2]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18]/[N:19]=[CH:20]/[C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[C:24]([O:31][CH:32]([CH3:34])[CH3:33])[CH:25]=[CH:26][CH:27]=4)[N:22]=3)=[CH:16][CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(Cl)Cl>[CH3:1][C@:2]1([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:17]=[CH:16][C:15]3[N:14]([C:20]([C:21]4[CH:30]=[CH:29][C:28]5[C:23](=[C:24]([O:31][CH:32]([CH3:34])[CH3:33])[CH:25]=[CH:26][CH:27]=5)[N:22]=4)=[N:19][N:18]=3)[CH:13]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1
Reactant: CC(C)Oc1cccc2ccc(/C=N/Nc3ccc([C@H](N4CC[C@](C)(NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc12
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: Ic1ccccc1
Product: CC(C)Oc1cccc2ccc(-c3nnc4ccc([C@H](N5CC[C@](C)(NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred solution of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-((E)-2-((8-isopropoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (1.33 g, 2.27 mmol) in DCM (20 mL) was added iodo benzene diacetate (0.949 g, 2.95 mmol). The reaction mixture was stirred at ambient temperature for 2 hours and then partitioned between ethyl acetate and saturated aqueous NaHCO3. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by chromatography (1:3 hexane/ethyl acetate) to give tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(3-(8-isopropoxyquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (1.30 g, 98%).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)[C@@H]([C@@H](CO)S)S.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH:19]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:14][N:15]=2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: ClCCN1CCOCC1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: OC[C@@H](S)[C@@H](S)CO
Product: O=C(Nc1ncc(SCCN2CCOCC2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithio-erythritol and N-(2-chloroethyl)-morpholine
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]1[C:14]([NH2:28])=[N:15][CH:16]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH:18]=1)[N:6]=[CH:7]2.C[O:30][C:31]([C@@H:33]1[CH2:37][C@H:36]([N:38]2[CH:42]=[C:41](I)[CH:40]=[N:39]2)[CH2:35][N:34]1C(OCC1C=CC=CC=1)=O)=[O:32].[F-].[K+].O1CCOCC1>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.O>[NH2:28][C:14]1[N:15]=[CH:16][C:17]([C:41]2[CH:40]=[N:39][N:38]([C@@H:36]3[CH2:35][NH:34][C@H:33]([C:31]([OH:32])=[O:30])[CH2:37]3)[CH:42]=2)=[CH:18][C:13]=1[C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([Cl:1])[CH:11]=[CH:10][C:9]=2[F:12]
Reactant: COC(=O)[C@@H]1C[C@H](n2cc(I)cn2)CN1C(=O)OCc1ccccc1
Reactant: CC1(C)OB(c2cnc(N)c(-c3cc4c(Cl)ccc(F)c4cn3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2cnn([C@@H]3CN[C@H](C(=O)O)C3)c2)cc1-c1cc2c(Cl)ccc(F)c2cn1
Temperature: 60 °C

Procedure:
A mixture of 3-(5-chloro-8-fluoroisoquinolin-3-yl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (100 mg, 0.250 mmol), (2S,4S)-4-(4-iodopyrazol-1-yl)-pyrrolidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (137.0 mg, 0.300 mmol), Pd(PPh3)4 (29 mg, 0.025 mmol), potassium fluoride (43.6 mg, 0.751 mmol) and 4:1 dioxane:water (3 mL) was heated in the microwave reactor to 85° C. for 30 min. The material was concentrated in vacuo, then dry-loaded onto silica gel for column chromatography. The product was eluted with 2→5% MeOH/DCM, and the fractions containing the product were concentrated in vacuo. The material was dissolved in conc. HCl, transferred to a sealed tube and heated at 60° C. for 2 h. The solvent was removed in vacuo to afford the title compound as a brown solid. MS (ES+): m/z=453.09/455.10 (100/37) [MH+]. HPLC: tR=1.94 min (ZQ2, polar—5 min).
Reaction SMILES: C(N[C@H](C(O)=O)CC(C)C)(OC(C)(C)C)=[O:2].[CH2:17]([O:24][C:25](=[O:42])[CH:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:28][CH:29]=[CH2:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Br)C=C>C1COCC1>[CH2:17]([O:24][C:25](=[O:42])[CH:26]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[N:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[CH2:28][CH2:29][CH2:30][OH:2])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CCN(C(C(=O)OCc1ccccc1)C(=O)OC(C)(C)C)C(C)(C)C
Solvent: C=CCBr
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C(=O)OCc1ccccc1)N(CCCO)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
BOC-L-leucine is converted to racemic BOC-(2-isobutyl)-allyl glycine benzyl ester using essentially the procedures of Example 20, Steps A and B, substituting allyl bromide in the alkylation step. The benzyl ester (2.07 g, 5.73 mmol) is dissolved in THF (40 ml), under nitrogen, 0.5M 9-borabicyclo[3.3.1]-nonane (9-BBN)in hexanes (46 ml, 23 mmol) is added and mixture stirred at room temperature for 16 hours. The reaction mixture is quenched with water (1 ml) and a mixture of 1N aqueous sodium hydroxide solution (51 ml) and 30% hydrogen peroxide solution (18 ml) is added dropwise. The mixture is stirred for 1 hour at room temperature, saturated with solid sodium chloride, then extracted with ether. The organic layer is washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography, eluting with 20% ethyl acetate/hexanes to give BOC-(2-isobutyl)-3-hydroxypropyl glycine benzyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[N:3]1.[Cl:12][C:13]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:14]=1[CH2:15][N:16]=[C:17]=[O:18]>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:14]=1[CH2:15][NH:16][C:17]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[N:3][N:2]2[CH3:1])=[O:18]
Reactant: Cn1ncc2c(N)cccc21
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: Cn1ncc2c(NC(=O)NCc3ccc(Cl)cc3Cl)cccc21
Temperature: 80 °C

Procedure:
1-Methyl-1H-indazol-4-amine (310 mg, 2.1 mmol) and 2,4-dichlorobenzyl isocyanate (0.3 mL, 2.06 mmol) were combined in toluene (10 mL) and heated for 2 hours at 80° C. The mixture was then allowed to cool to ambient temperature, filtered, and the filter cake was allowed to air-dry to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) δ 9.22 (s, 1H), 8.21 (d, J=1.0 Hz, 1H), 7.62-7.67 (m, 2H), 7.43-7.46 (m, 2H), 7.21-7.27 (m, 2H), 7.12 (m, 1H), 4.40 (d, J=5.5 Hz, 2H), 3.99 (s, 3H); MS (ESI+) m/z 349/351 (M+H, 35Cl/37CI)+.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.C.[H][H]>C(O)(=O)C.[Pd]>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[NH2:16])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1ccccc1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Nc1cccc(CCCc2ccccc2)c1
Yield: 71.1 %

Procedure:
253 g of 1-phenyl-3-(3'-nitrophenyl)-prop-2-en-1-one are suspended in 2.5 liters of glacial acetic acid. 196 g of concentrated sulfuric acid and 10 g of 10% strength Pd on animal charcoal are added and the mixture is hydrogenated under 1.1 bar hydrogen pressure, at 65°-70° C., until hydrogen is no longer absorbed. When the mixture has cooled, part of the acetic acid is distilled off, the residue is rendered alkaline with sodium hydroxide solution and extracted with ether, the organic phase is dried with sodium sulfate and filtered, the solvent is distilled off and the residue is then distilled. 150 g of 3-(3-phenylpropyl)-aniline, of boiling point 148° C./0.2 mbar, are obtained.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH:10]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH2:1]([N:10]1[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCCN(Cc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
6 mL benzyl bromide was added to 5 g azepane-4-one hydrochloride and 18.5 g potassium carbonate in 50 mL THF and 25 mL water. The mixture was stirred 5 h at 50° C., evaporated, diluted with water and extracted with ethyl acetate. The organic layer was evaporated. The residue was purified by chromatographie on silica gel (petrolether/ethyl acetate:8/2) to give 5 g of the desired product. Rf: 0.40 (hexane/ethyl acetate=1/1), (M+H)+=204
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][OH:12])=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:5][C:4]1[C:3]2[CH:6]=[C:7]3[C:8]([O:12][CH2:11][O:10]3)=[CH:9][C:2]=2[O:1][C:14]=1[C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])=[O:16]
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Reactant: N#Cc1cc(OCO)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3c(cc12)OCO3
Yield: 60.9 %

Procedure:
A solution of 2-hydroxy-5-hydroxymethoxy-benzonitrile (0.10 g, 0.61 mmol), 2,2′,4′-trichloroacetophenone (0.16 g, 0.74 mmol, 1.2 eq) and potassium carbonate (0.13 g, 0.92 mmol, 1.5 eq) in 1 mL DMF was stirred overnight at 80° C. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried with sodium sulfate and filtered through a plug of silica. Concentration in vacuo provided an orange solid, purification of which by RP-HPLC (H2O-MeCN gradient) provided 0.13 g (61%) of (7-amino-1,3,5-trioxa-s-indacen-6-yl)-(2,4-dichloro-phenyl)-methanone as a yellow solid. 1H-NMR (DMSO-d6) δ 7.70–7.69 (m, 1 H), 7.51–7.49, (m 2H), 7.42, (s, 1H) 7.30 (bs, 2H), 7.03 (s, 1H), 6.07 (s, 2H); MS LC-MS (MH+=350.2/352.1), LC-MS RT=3.21 min.
Reaction SMILES: C1COCC1.BrC1C=CC(C)=NC=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[C:22][Si](C)(C)C)=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C>[C:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:14])=[N:16][CH:17]=1)#[CH:22]
Reactant: Cc1ccc(C#C[Si](C)(C)C)cn1
Agent: Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: C#Cc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a NMP solution (20 mL) of 5-bromo-2-methyl-pyridine (1.0 g) were added trimethylsilylacetylene (1.2 mL), tetrakis(triphenylphosphine)palladium(0) (130 mg), copper(I) iodide (44 mg), and N,N-diisopropylethylamine (2.0 mL), which was stirred under a nitrogen atmosphere for 2 hours at 65° C. Water was added at room temperature to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated from the filtrate under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=5:1) to obtain a mixture (810 mg) of 5-bromo-2-methyl-pyridine and 2-methyl-5-trimethylsilanylethynyl-pyridine. Then, to a solution of THF (10 mL) and ethanol (5 mL) of the mixture (810 mg) of 5-bromo-2-methyl-pyridine and 2-methyl-5-trimethylsilanylethynyl-pyridine was added potassium carbonate (1.2 g) at room temperature, which was stirred for 2 hours and 30 minutes at room temperature. Water was added at room temperature to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated from the filtrate under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=5:1) to obtain the titled compound (55 mg).
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[C:25]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]=1[OH:30])(C1C=CC(C)=CC=1)(=O)=O.[H-].[Na+].O>C1COCC1.C(OCC)(=O)C>[C:27]([NH:26][C:25]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][O:30][C:17]=2[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1)(=[O:29])[CH3:28]
Reactant: COC(=O)c1ccc(NC(C)=O)c(CCCCOS(=O)(=O)c2ccc(C)cc2)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(NC(C)=O)c2c1OCCCC2
Reaction time: 24 h

Procedure:
To a solution of 5 g (14.6 mmol) of methyl 3-(4'-tosyloxybutyl)-4-acetylaminosalicylate in 50 ml of THF is added 0.64 g (16.1 mmol) of sodium hydride (60% dispersion in mineral oil) portionwise at room temperature. After addition is complete stirring is continued 24 hours at room temperature. Water is added dropwise to decompose excess NaH. The reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is dried over MgSO4, filtered and concentrated. Flash chromatography (5% EtOAc/hexanes) provides methyl 6-acetylamino-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylate.