Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:23][CH2:22][C:5]2[N:6]=[C:7]([NH:9][C:10]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])=[O:11])[S:8][C:4]=2[CH2:3]1.O.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1([CH3:24])[CH2:23][CH2:22][C:5]2[N:6]=[C:7]([NH:9][C:10]([C:12]([OH:14])=[O:13])=[O:11])[S:8][C:4]=2[CH2:3]1
Reactant: [H][H]
Reactant: CC1(C)CCc2nc(NC(=O)C(=O)OCc3ccccc3)sc2C1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC1(C)CCc2nc(NC(=O)C(=O)O)sc2C1

Procedure:
The acids of Examples 26 to 37 are also prepared by hydrogenolysis of the corresponding benzyl esters, by adaptation of the following specific exemplary method. Benzyl 6,6-dimethyl-4,5,6,7-tetrahydrobenzthiazol-2-ylcarbamoylcarboxylate (1 g.) in 25 ml. of 50:50 water:ethanol in the presence of 5% palladium on carbon (300 mg.) is hydrogenated at atmospheric pressure and room temperature until uptake of hydrogen is complete (in small excess of one equivalent to account for reduction of the catalyst). The catalyst is removed by filtration and the filtrate evaporated to dryness to yield 6,6-dimethyl-4,5,6,7-tetrahydrobenzthiazol-2-ylcarbamoylcarboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:26])=[C:9]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)(=[O:14])=[O:13])[N:10]=2)[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][C:35]=1[C:42]([F:45])([F:44])[F:43]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:26])=[C:9]([N:11]([CH2:38][C:37]3[CH:40]=[CH:41][C:34]([F:33])=[C:35]([C:42]([F:45])([F:43])[F:44])[CH:36]=3)[S:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:19][CH:20]=3)(=[O:14])=[O:13])[N:10]=2)[CH:7]=1
Reactant: Cc1c(NS(=O)(=O)c2ccc(-n3cccn3)cc2)nc2ccc(Cl)cn12
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(N(Cc2ccc(F)c(C(F)(F)F)c2)S(=O)(=O)c2ccc(-n3cccn3)cc2)nc2ccc(Cl)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of compound 16-C (0.011 g, 0.27 mmol) in DMF (0.5 mL) was added Na2CO3 (0.0057 g, 0.054 mmol) and 4-fluoro-3-trifluoromethylbenzyl bromide (0.0077 g, 0.03 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give Compound 102 (0.011 g, 72%) as a white solid; MS m/z (M+H+) 564.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Li]CCCC.[C:17]1(=O)[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18]1.Cl>C1COCC1>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCc2ccccc21
Reactant: Brc1cccc2cccnc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C1=CC(c2cccc3cccnc23)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 54.3 %

Procedure:
10.4 g (50 mmol) of 8-bromoquinoline in 100 ml of THF were cooled to about −100° C. 20 ml of n-BuLi (2.5M in hexane, 50 mmol) were added dropwise within a period of 5 min while the internal temperature was held below −80° C. After this addition stirring was continued at −80° C. for a further 15 min, and 6.6 g of 1-indanone (50 mmol) dissolved in 30 ml of THF were then added dropwise within a period of 10 min. The reaction mixture was then allowed to reach room temperature gradually and was then heated for 3 b at reflux. Once the mixture had cooled to room temperature, ice was added, followed by hydrochloric acid until the pH was about 1, followed by stirring for 30 min. The aqueous and organic phase were separated. The aqueous phase was mixed with ammonia solution until the pH was about 9 and extracted with ether. The combined organic phases were then evaporated to dryness in vacuo. The resultant viscous oil (1-(8-quinolyl)indan-1-ol (8H2O)) vas mixed with hydrochloric acid until the pH was 0, heated at reflux for 2 hours and then neutralised. After work-up and drying it was possible to isolate 6.6 g of 1-(8-quinolyl)indene (55%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:3]=1.[CH:15](O)([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Br:1][C:2]1[S:6][C:5]([N:7]([CH:15]([CH3:17])[CH3:16])[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[N:4][CH:3]=1
Reactant: CC(C)O
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)s1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)N(C(=O)OC(C)(C)C)c1ncc(Br)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.2 %

Procedure:
Step 2 A solution of tert-butyl 5-bromothiazol-2-ylcarbamate (3 g, 10.7 mmol), isopropanol (6.40 g, 107.4 mmol) and triphenylphosphine (5.63 g, 21.5 mmol) in THF (30 mL) was treated with diethyl azodicarboxylate (3.74 g, 21.5 mmol) dropwise at 0° C. and was stirred overnight while warming slowly to rt. The mixture was concentrated and the residue was dissolved in DCM (20 mL), filtered to remove undissolved solid and concentrated. The residue was purified by column chromatography (eluting with hexane) to give tert-butyl 5-bromothiazol-2-yl(isopropyl)carbamate as a light yellow oil (3.10 g, 90%). 1H NMR (400 MHz, chloroform-d) δ 7.34 (s, 1H) 5.29 (m, 1H) 1.59 (s, 9H) 1.45 (d, 6.8 Hz, 6H). Mass spectrum m/z 265, 267 (M+H—C4H9)+.
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[O:17][CH:16]=1>[Cu]I>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:18]1[O:17][CH:16]=[C:15]([N:3]2[CH2:4][C@:5]3([CH:10]4[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]4)[CH2:6]3)[O:1][C:2]2=[O:13])[CH:19]=1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Reactant: Brc1coc(-c2ccccn2)c1
Agent: [Cu]I
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1coc(-c2ccccn2)c1

Procedure:
The title compound was prepared by a method analogous to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 3-bromo-5-(2-pyridyl)-furan with 2 equivalents of copper (I) iodide. The title compound (90 mg) was obtained as a pale yellow solid, m/z 342 (MH+).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:19])[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=CC=1)([O-])=O.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>O1CCCC1>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([NH:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[O:19])=[CH:17][CH:16]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1ccc(Cl)cc1
Reactant: NCCN1CCOCC1
Solvent: C1CCOC1
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
5.55 G. of p-chlorobenzoic acid p-nitrophenyl ester are added to a solution of 2.6 g. of N-(2-aminoethyl)-morpholine in 100 ml. of tetrahydrofuran and the mixture is allowed to stand overnight at room temperature. It is then evaporated to dryness and the residue is taken up in 200 ml. of methylene chloride. The methylene chloride solution is washed three times with 50 ml. of a 1% sodium hydroxide solution each time and twice with 50 ml. of water each time until neutral, dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from isopropanol, and 3.1 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1>>[CH2:35]([O:34][C:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([NH:24]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:30][CH:29]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Product: CCOC(=O)Cc1ccc(N/C(CC)=C2\C(=O)Nc3cc(OC)c(OC)cc32)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and ethyl 4-aminophenylacetate
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23](=O)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]1([N:31]2[C:43]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:37]3[C:32]2=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClCCl>[C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:40]5[CH:41]=[CH:42][C:43]6[N:31]([C:25]7[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=7)[C:32]7[C:37]([C:38]=6[CH:39]=5)=[CH:36][CH:35]=[CH:34][CH:33]=7)([C:40]5[CH:41]=[CH:42][C:43]6[N:31]([C:25]7[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=7)[C:32]7[C:37]([C:38]=6[CH:39]=5)=[CH:36][CH:35]=[CH:34][CH:33]=7)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2-c2nc3ccccc3c(-c3ccccc3)c21
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: c1ccc(-c2c3c(nc4ccccc24)-c2ccccc2C3(c2ccc3c(c2)c2ccccc2n3-c2ccccc2)c2ccc3c(c2)c2ccccc2n3-c2ccccc2)cc1
Yield: 83.8 %

Procedure:
The chemical compound can be obtained by performing nucleophilic addition reactions twice between starting materials and different aniline aromatic rings (e.g. carbazole or triphenylamine) along with using non-metal catalytic Eaton's reagents on different chemical equivalent basis. First, 10-phenyl-11H-indeno[1,2-b]quinolin-11-one (860 mg, 2.80 mmol) and 9-phenyl-9H-carbazole (1500 mg, 6.10 mmol) are placed in a round bottom flask and then dissolved in 5 ml of dichloromethane. Subsequently, 800 μl of Eaton's reagent is slowly dripped into the flask to promote reaction. After 12 hours of reaction at 100° C., the crude product is extracted with 20 ml of dichloromethane and sodium bicarbonate for three times. Finally, an organic layer of the crude product is dehydrated with magnesium sulfate and concentrated to be sublimated and purified to obtain 1820 mg of 10-phenyl-11,11-bis(9-phenyl-9H-carbazol-3-yl)-11H-indeno[1,2-b]quinoline. The percentage yield is 83.8%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]([CH3:26])=[C:17]([CH2:19][CH2:20]OS(C)(=O)=O)[N:18]=2)=[CH:10][CH:9]=1>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[O:15][C:16]([CH3:26])=[C:17]([CH2:19][CH2:20][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[N:18]=2)=[CH:12][CH:13]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCOS(C)(=O)=O
Reactant: C1CCNCC1
Solvent: C1CCOC1
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCCC1
Yield: 74.9 %

Procedure:
Add piperidine (3.04 g, 36.11 mmol) to a solution of Methanesulfonic acid 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl ester (See Intermediate 13) (1.3 g, 3.61 mmol) in anhydrous THF (15 mL). Reflux the reaction overnight and cool. Wash organic material with 1N HCl (50 mL) and extract aqueous layer with diethyl ether (2×50 mL). Add 5N NaOH to aqueous layer (pH>10) and extract with dichoromethane (2×50 mL). Dry organics over Na2SO4, filter and concentrate. Purify crude on silica gel, eluting with 5% 2N NH3 in methanol/dichloromethane to give 1-{2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethyl}-piperidine (0.944 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([CH3:11])=[O:10])[CH:3]=1.[CH2:12]([O:19][C:20]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[CH:24][C:21]=1[CH:22]=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:19][C:20]1[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=[CH:24][C:21]=1/[CH:22]=[CH:11]/[C:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[OH:8])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(C=O)c(OCc2ccccc2)c1OC
Reactant: CC(=O)c1cc(C)ccc1O
Product: COc1ccc(/C=C/C(=O)c2cc(C)ccc2O)c(OCc2ccccc2)c1OC
Yield: 72.3 %

Procedure:
2-Hydroxy-5-methylacetophenone (690 mg, 2.53 mmol) and 2-benzyloxy-3,4-dimethoxybenzaldehyde (460 mg, 3.03 mmol) was reacted according to the same procedure as Preparation 1 to give 740 mg (Yield 76%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C@@:7]([C:16]([NH:18][CH:19]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:20]([OH:33])[C:21]([F:32])([F:31])[CH:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:17])([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10].[C:41]([CH2:45][C:46](Cl)=[O:47])([CH3:44])([CH3:43])[CH3:42].C(N(CC)CC)C>ClCCl>[C:41]([CH2:45][C:46]([NH:30][CH:22]([C:21]([F:32])([F:31])[CH:20]([OH:33])[CH:19]([NH:18][C:16](=[O:17])[C@:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10])[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:47])([CH3:44])([CH3:43])[CH3:42]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: COC(=O)N[C@@](C(=O)NC(Cc1ccccc1)C(O)C(F)(F)C(N)Cc1ccccc1)(c1ccccn1)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N[C@@](C(=O)NC(Cc1ccccc1)C(O)C(F)(F)C(Cc1ccccc1)NC(=O)CC(C)(C)C)(c1ccccn1)C(C)C
Yield: 77 %

Procedure:
Reaction of the resultant compound from Example 269 with t-butylacetyl chloride in dichloromethane and 1.1 equivalent of triethylamine provided the desired compound in 77% yield. Mass spectrum: (M+H)+ =653. 1H NMR (CDCl3): 80.80 (s, 9H), 0.82 (d, 3H), 0.93 (d, 3H), 1.83 (q, 2H), 2.12 (m, 1H), 2.70-3.20 (m, 4H), 3.80 (m, 1H), 3.95 (m, 1H), 4.55 (m, 1H), 4.80 (m, 1H), 5.20 (s,0.2H), 5.35 (br d, 1H), 6.50 (br d, 1H), 7.10-7.35 (m, 13H), 7.70 (m, 1H), 8.60 (br d, 1H).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:37])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:36])([C:17]([NH:19][C:20]1[C:21](=[O:35])[N:22]([CH3:34])[C:23](=[O:33])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:25]=1[NH2:26])=O)[CH2:9][CH2:8]2)(=O)C.Cl>C1COCC1>[NH2:26][C:25]1[N:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:33])[N:22]([CH3:34])[C:21](=[O:35])[C:20]=1[NH:19][CH2:17][C:10]1([CH3:36])[CH2:9][CH2:8][C:7]2[C:12](=[C:13]([CH3:16])[C:14]([CH3:15])=[C:5]([OH:4])[C:6]=2[CH3:37])[O:11]1
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Nc1c(N)n(-c3ccccc3)c(=O)n(C)c1=O)O2
Agent: Cl
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CNc1c(N)n(-c3ccccc3)c(=O)n(C)c1=O)O2
Yield: 35 %

Procedure:
The compound of Example 14 (64 mg, 1.0 mmol) was dissolved in THF (10 mL). To the resultant solution was added borane-methyl sulfide complex (10 M, 0.24 mL, 2.4 mmol). The resultant reaction mixture was refluxed for 5 h. To the resultant was added 1N hydrochloric acid (2.4 mL) under ice-cooling. The resultant mixture was refluxed for 2 h, followed by concentration under reduced pressure. The residue was extracted with dichloromethane after addition of 1N aqueous solution of sodium hydroxide. The organic layer was washed with 10% aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was crystallized by addition of ethyl acetate and ether to give the title compound (yield 35%).
Reaction SMILES: C[O:2][C:3]1[C:8]([O:9]C)=[CH:7][CH:6]=[CH:5][C:4]=1[C:11](=[O:13])[CH3:12].B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11](=[O:13])[CH3:12]
Reactant: COc1cccc(C(C)=O)c1OC
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cccc(O)c1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 75.7 %

Procedure:
A solution of 2',3'-dimethoxyacetophenone (4.85 g, 26.9 mmol) in dichloromethane (100 ml) was added at -70° C. with a 1M boron tribromide solution in dichloromethane (68 ml). The mixture was left to cool, keeping stirring for 2.5 hours at room temperature, then added with methanol (70 ml), left under stirring for 1 h, thereafter evaporated to dryness. The residue was dissolved in ethyl acetate (250 ml), washed with 2% NaHCO3 (1×30 ml), dried and the solvent was evaporated off, to obtain a crude which was purified by crystallization in methanol, thereby obtaining 3.10 g of the title compound as a yellow solid (76% yield).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[CH:5][CH:4]=1.C(Cl)(=O)[C:13](Cl)=[O:14]>C(Cl)CCl>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:9]=[C:13]=[O:14])=[O:8])=[CH:5][CH:4]=1
Reactant: NC(=O)c1ccc(CBr)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1ccc(CBr)cc1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 4-(bromomethyl)benzamide (0.200 g), oxalyl chloride (0.012 mL) and EDC (15 mL) to afford 0.150 g of the desired product.
Reaction SMILES: N#N.C(O)C.[NH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1B(O)O.[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](Br)[CH:21]=1>C1(C)C=CC=CC=1.[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>[CH3:16][O:17][C:18](=[O:27])[CH2:19][C:20]1[CH:25]=[C:24]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH2:6])[CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1B(O)O
Reactant: COC(=O)Cc1cccc(Br)c1
Agent: [Pd]
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)Cc1cccc(-c2ccccc2N)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 106.8 %

Procedure:
(The following reaction is done in an oxygenfree N2 atmosphere.) Add ethanol (0.8 mL), Tetrakis-(triphenylphosphine)-palladium(0) (30 mg, 2.2 mol %) and Na2CO3 decahydrate (944 mg, 3.30 mmol; presolved in 1.2 mL H2O) subsequently to dissolved 2-Amino-benzeneboronic acid (70) (201 mg, 1.30 mmol) in toluene (6.0 mL). Degas the reaction mixture for 5 times and flood with N2 again. Add (3-Bromo-phenyl)-acetic acid methyl ester (69) (270 mg, 1.18 mmol) in toluene (6.0 mL), degas again (5 times) and stir the reaction solution overnight at 100° C. Partition the reaction solution between EtOAc and brine (1+1) and extract the separated aqueous layer 3 times with EtOAc. Wash combined organic layer with brine and dry with Na2SO4. Remove solvent under reduced pressure and purify the crude product by preparative radial chromatography (silica gel 60 PF, CyH/EtOAc 3+1) to obtain (2′-Amino-biphenyl-3-yl)-acetic acid methyl ester (71) as an orange oil (304 mg, 81%). 1H NMR (400 MHz, CDCl3): 3.66 (s, 2H); 3.69 (s, 3H); 3.62-3.86 (br.s, 2H); 6.75 (d, 1H, J=8.1 Hz); 6.80 (t, 1H, J=7.3 Hz); 7.11 (d, 1 H, J=7.3 Hz); 7.15 (d, 1H, J=8.1 Hz); 7.22-7.26 (br.m, 1H); 7.32-7.42 (m, 3H).
Reaction SMILES: [Cl:1][CH:2]([CH:7]=[C:8]([Cl:10])[Cl:9])[CH2:3][C:4](O)=[O:5].S(Cl)([Cl:13])=O>>[Cl:1][CH:2]([CH:7]=[C:8]([Cl:10])[Cl:9])[CH2:3][C:4]([Cl:13])=[O:5]
Reactant: O=C(O)CC(Cl)C=C(Cl)Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CC(Cl)C=C(Cl)Cl

Procedure:
205.6 g (1.19 mols) of 2,4,4-trichlorobut-3-enecarboxylic acid [produced according to Monateshefte d. Chemie, 98, 2138 (1967)] is heated with 290 ml of thionyl chloride for 5 hours at 85° C. The reaction solution is concentrated by evaporation and subsequently distilled to obtain 209.7 g of 2,4,4-trichlorobut-3-enecarboxylic acid chloride; b.p. 75°-76° C./20 mm Hg. The spectroscopic data of the substance obtained agree with those of the products obtained according to (a).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[C:27]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:37]2[CH2:36][CH2:35][N:34]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:39][CH2:38]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: CC(C)(C)OC(=O)N1CCN(CCCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and Boc-piperazine.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:11]([O:12]C(=O)C)[CH2:10][O:9][CH:7]([OH:8])[C@@H:6]1[F:16])(=O)C.C[O-].[Na+]>CO>[F:16][C@@H:6]1[C@@H:5]([OH:4])[C@@H:11]([OH:12])[CH2:10][O:9][CH:7]1[OH:8]
Reactant: CC(=O)O[C@H]1[C@@H](OC(C)=O)COC(O)[C@@H]1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: OC1OC[C@H](O)[C@H](O)[C@H]1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
A solution of 17 (5.7 g, 24.1 mmol) in dry methanol (220 mL) was treated with 0.1 N NaOMe in methanol (114 mL, 11.4 mmol) and stirred for 1 hour at room temperature. The solution was then neutralized with DOWEX 50W X8-100, filtered and evaporated to afford 18 (3.7 g, 24 mmol, 100%) as a yellow syrup: 13C-NMR (D2O) δ 94.19 (C-1α, d, JC-1,F=23.0), 92.24 (C-2α, d, JC-2,F=179.6), 90.10 (C-1β, d, JC-1,F=20.3), 88.60 (C-2β, d, JC-2,F=182.3), 70.77 (C-3α, d, JC-3,F=18.2), 69.03 (C-4β, d, JC-4,F=8.0), 68.90 (C4α, d, JC-4,F=10.2), 66.85 (C-3β, d, JC-3,F=18.2), 66.32 (C-5β).
Reaction SMILES: CO[C:3](=[O:23])[C:4]([OH:22])=[CH:5][C:6](=[O:21])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[O:8][CH2:9][CH:10]([CH3:12])[CH3:11].C=O.CN.ClC1C=C(C=CC=1Cl)[CH2:32][N:33](C)[C:34](C1CN(C)C(=O)C=1O)=O>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:7]([O:8][CH2:9][CH:10]([CH3:11])[CH3:12])[C:6]([C:5]2[CH2:32][N:33]([CH3:34])[C:3](=[O:23])[C:4]=2[OH:22])=[O:21])=[CH:19][CH:18]=1
Reactant: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)OCC(C)C
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Agent: CN
Product: CC(C)CON(Cc1ccc(F)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Yield: 40 %

Procedure:
3-[(4-Fluorobenzyl)-isobutoxy-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 58-D) was treated with paraformaldehyde and methylamine as described in the preparation of Compound 12 to give the title compound as a white solid (40% yield); mp 96–97° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 0.98 (6H, d, J=6.5 Hz, CH3), 1.96 (1H, m CH), 3.12 (3H, s, NCH3), 3.69 (2H, d, J=6.4 Hz, OCH2), 4.1 (2H, s, NCH2), 4.85 (2H, s, NCH2), 7.06 (2H, m, aromatics), 7.33 (2H, m, aromatics), 11.65 (1H, broad s, OH). HRMS (ES+) calculated for C17H22FN2O4, [M+H]+: 337.156361. found: 337.156153.
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]([CH3:21])([CH3:20])[CH2:10][N:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH3:22]>C(O)C>[NH2:22]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH2:8][C:9]([CH3:21])([CH3:20])[CH2:10][N:11]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:12])=[O:6]
Reactant: CC(=O)CC(=O)OCC(C)(C)CN(C)Cc1ccccc1
Reactant: N
Solvent: CCO
Product: C/C(N)=C/C(=O)OCC(C)(C)CN(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5.07 g of 3-(N-benzyl-N-methylamino)-2,2-dimethylpropyl acetoacetate in 15 ml of ethanol was cooled with ice-water. The solution was bubled gasous ammonia and then stirred at room temperature. The solution stood at room temperature overnight. To the solution was added ice-water, and then a precipitated white solid was removed. The solid was washed with water and dried under reduced pressure to yield 4.79 g of the desired compound.