Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][C:6]1[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=12)C.[OH-].[Na+].O>C(O)C>[C:15]1([C:7]2[C:6]([CH2:5][C:4]([OH:21])=[O:3])=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)Cc1c(-c2ccccc2)nn2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1c(-c2ccccc2)nn2cccnc12
Yield: 75.8 %

Procedure:
A solution of 12.25 g (0.043 mole) of 2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid ethyl ester in 100 ml of absolute ethanol was treated with 6.9 g (0.087 mole) of 50% sodium hydroxide and 35 ml of water and refluxed for 4 hours under a nitrogen atmosphere. The solvent was evaporated under reduced pressure and the residue was dissolved in water (100 ml). Acidification with glacial acetic acid produced a solid precipitate. The solid was collected by filtration to yield 10.8 g of crude product, mp 78°-90° C. Recrystallization from acetone-water, and then from toluene provided 8.25 g (75%) of product, mp 153°-156° C.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][O:5][C:6]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27]Br)([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:19]([O:23][C:24](=[O:29])[NH:25][CH2:26][CH2:27][O:14][C:12]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:5][CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[Br:1])[CH:13]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: O=Cc1ccc(O)cc1OCc1ccccc1Br
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1ccc(C=O)c(OCc2ccccc2Br)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-bromobenzyloxy)-4-hydroxybenzaldehyde (60 mg, 020 mmol) in DMF (10 ml) were added t-butyl-2-bromoethylcarbamate (43.70 g, 0.20 mmol) and K2CO3 (54.18 mg, 0.39 mmol), followed by stirring at 100° C. for 3 hours. After completion of the reaction, the solution was extracted with a saturated aqueous NH4Cl solution and ethyl acetate. The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated in a vacuum. The residue was purified through column chromatography (ethyl acetate/n-hexane=1/9→1/5) to afford the object compound (pale yellowish solid, 69 mg, 79.3%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[O:15]=[C:16]1[C:25]2([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:28]3[CH2:27][CH2:26][C:25]4([C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[CH2:18][CH2:17][C:16]4=[O:15])[CH2:30][CH2:29]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: O=C1CCc2ccccc2C12CCNCC2
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C1CCc2ccccc2C12CCN(C[C@H](O)COc1cccc3[nH]ccc13)CC2

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 3,4-dihydro-2-oxospiro[naphthalene-1(2H),4'-piperidine]. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 68% overall yield. FDMS m/e=404 (M+ of free base). α[D]589 =-15.81 c=0.51, methanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:51])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:51])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH:38]=2)[CH:32]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (320 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionic acid tert-butyl ester (Example K40) (412 mg, 1.0 mmol) according to the general procedure M. Obtained as an off-white solid (500 mg, 76%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=1B(O)O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1.[OH-].[Na+].CCO>C1(C)C=CC=CC=1.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>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][C:10]=1[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccc(Br)cc1
Reactant: CCCc1ccc(S(=O)(=O)NC(C)(C)C)c(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCc1ccc(S(=O)(=O)NC(C)(C)C)c(-c2ccc(CO)cc2)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of 2.80 g (9.36 mmol) of 2-(N-t-butylsulfamoyl)-5-n-propylphenylboronic acid (from Step B) and 4-bromobenzyl alcohol (5.25 g, 3 equiv) in toluene (125 mL) was added 1.25N NaOH (32 mL), EtOH (86 mL) and tetrakis(triphenylphosphine)palladium(0) (325 mg, 3 mol %). The mixture was stirred at 100° C. under N2 for 3 hours. The reaction was concentrated and the residue was extracted with ethyl acetate. The organic solution was washed with 1N NaOH, H2O and brine. Next, the organic phase was dried over anhydrous MgSO4 and concentrated in vacuo. The product was purified by flash chromatography, eluting with 2:1 hexane-EtOAc, to provide the titled compound; Rf =0.42 (1:1 EtOAc-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:19]#[N:20])=[C:10]([N+:16]([O-])=O)[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[NH2:16][C:10]1[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]=1[C:19]#[N:20]
Reactant: COc1cc(-c2ccccc2Cl)c(C#N)c([N+](=O)[O-])c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(N)c(C#N)c(-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
The product of step (a) (300 mg, 1.0 mmol) was dissolved in DMF (3 ml) and a solution of sodium dithionite hydrate added (500 mg, 2.9 mmol in 6 ml of H2O). The solution became warm and some solid precipitated out of solution. After stirring for 30 min at room temperature, 15 ml of H2O and 2N HCl were added. This mixture was extracted with EtOAc (2×30 ml), neutralised using 2N NaOH and re-extracted with EtOAc (2×30 ml). The combined EtOAc extracts were dried over MgSO4 and the solvent removed to give the crude product. This was purified on silica gel, eluting with CH2Cl2 /MeOH (98/2, v/v) to give the subtitle compound as colourless gum (190 mg, 74%). Rf 0.29 (hexane/ether 1/1, v/v). MS m/e 276 and 278 (MNH4+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:10][C:11](=[O:12])[CH:13]=[CH:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)=O
Reactant: O=Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(C=Cc1cccc(Cl)c1)C=Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
3-Chlorobenzaldehyde (1y, 2.00 ml, 17.7 mmol) and acetone (19, 0.65 ml, 8.8 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (1.00 g, 25.0 mmol) and water (20 ml) was added and the mixture stirred for 2 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethyl acetate to give 2.41 g (90%) of a yellow solid: mp 125-127° C. [expected mp 120-121° C.]; 1H NMR: δ 7.03 (d, 2H, J=15.9 Hz), 7.33 (m, 4H), 7.45 (d, 2H, J=6.6 Hz), 7.58 (m, 2H), 7.64 (d, 2H, J=15.9 Hz); 13C NMR: δ 126.3, 126.6, 127.9, 130.1, 130.3, 134.9, 136.5, 141.8, 188.0.
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[OH-].[Na+].[S:11](=O)([OH:13])[O-:12].[Na+]>>[CH2:6]([CH:2]1[C:3](=[O:5])[O:4][S:11](=[O:13])(=[O:12])[CH2:1]1)[CH2:7][CH3:8]
Reactant: C=C(CCC)C(=O)O
Reactant: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Product: CCCC1CS(=O)(=O)OC1=O

Procedure:
114 g. of α-methylene-pentanoic acid is reacted with sodium hydroxide to neutralize the carboxyl group. Sodium bisulfite (1 mol) solution is added and the reaction carried out as described in procedure (10) (b) to obtain 4-n-propyl-1,2-oxathiolane-5-one-2,2-dioxide of an equivalent weight of 93.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:35]4[CH:36]=[CH:37][CH:38]=[C:33]([CH3:32])[CH:34]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cccc(C)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3-methyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=575.7)=93%.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=4)[CH2:23][C@H:22]3[OH:32])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=O)C.Cl[C:34]([O:36][CH3:37])=[O:35].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:37][O:36][C:34]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([C@@H:21]3[C:29]4[C:24](=[C:25]([F:31])[CH:26]=[C:27]([F:30])[CH:28]=4)[CH2:23][C@H:22]3[OH:32])[N:11]=[C:12]([C:13]3[CH:20]=[CH:19][CH:18]=[C:15]([C:16]#[N:17])[CH:14]=3)[C:6]=2[CH2:5]1)=[O:35]
Reactant: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(F)c3C[C@H]2O)C1
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2[C@@H]2c3cc(F)cc(F)c3C[C@H]2O)C1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
According to Scheme 11: To a solution of 3-[1-((1R,2R)-4,6-difluoro-2-hydroxy-indan-1-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (11t) (0.05 g, 0.123 mmol) in dry CH2Cl2 (2 ml) at 0° C. methyl chloroformate (12 mg, 0.13 mmol) and NEt3 (19 mg, 0.191 mmol) was added, the mixture was stirred at 0-5° C. for 60 min, then at 25° C. for 18 h. After addition of aqueous saturated NaHCO3 (2 ml), the mixture was extracted with CH2Cl2 (10 ml), the organic layer was dried over Na2SO4, solvents were evaporated in vacuo and the crude product was purified by purified by reverse phase HPLC (CH3CN/water gradient with 0.1% trifluoroacetic acid) to give 31 mg of 3-(3-cyano-phenyl)-1-((1R,2R)-4,6-difluoro-2-hydroxy-indan-1-yl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid methyl ester (17a).
Reaction SMILES: C[O:2][C:3](=[O:28])[CH2:4][NH:5][C:6]1[CH:27]=[CH:26][C:9]2[C:10]3[N:14]([CH2:15][CH2:16][O:17][C:8]=2[CH:7]=1)[CH:13]=[C:12]([C:18]1[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=1)[N:11]=3.O.[OH-].[Li+:31]>O1CCOCC1.O>[Li+:31].[CH:23]([N:19]1[C:18]([C:12]2[N:11]=[C:10]3[N:14]([CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([NH:5][CH2:4][C:3]([O-:28])=[O:2])[CH:27]=[CH:26][C:9]=43)[CH:13]=2)=[N:22][CH:21]=[N:20]1)([CH3:25])[CH3:24]
Reactant: COC(=O)CNc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(NCC(=O)[O-])cc1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a solution of [2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-acetic acid methyl ester (407 mg, 0.43 mmol) in dioxane (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (36 mg, 0.86 mmol) and the reaction mixture stirred at RT for 18 h. Water was added and the reaction mixture extracted with DCM. The aqueous phase was filtered and concentrated in vacuo to give [2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ylamino]-acetic acid lithium salt (130 mg, 81%). LCMS: RT=2.30 min, [M+H]+=369.
Reaction SMILES: Cl[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[N:16]3)=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[F:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:20]=[CH:19][C:5]([C:6]([NH:8][C:9]3[CH:18]=[C:17]4[C:12]([CH:13]=[CH:14][CH:15]=[N:16]4)=[CH:11][CH:10]=3)=[O:7])=[CH:4][N:3]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: O=C(Nc1ccc2cccnc2c1)c1ccc(Cl)nc1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(-c2ccc(F)c(F)c2)nc1

Procedure:
Using the procedure outlined in Example 100, the title compound was prepared from 6-chloro-N-quinolin-7-yl-nicotinamide (D70) (40 mg, 0.14 mmol) and 3,4-difluorophenylboronic acid (27 mg, 0.17 mmol) as a cream solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 9.24 (dd, 1H), 8.86 (dd, 1H), 8.39 (dd, 1H), 8.28 (dd, 1H), 8.14 (br.d, 1H), 8.13 (d, 1H), 7.97 (ddd, 1H), 7.85 (m, 3H), 7.39 (dd, 1H), 7.28 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH:9]=[CH:10][CH3:11])=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH2:22])[CH3:21])=[CH:16][CH:15]=1>CCO>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][CH:10]([CH3:11])[CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:12])[CH3:21])=[CH:16][CH:15]=1
Reactant: CC=CC(=O)c1ccc(F)cc1
Reactant: C[C@H](N)c1ccc(Br)cc1
Solvent: CCO
Product: CC(CC(=O)c1ccc(F)cc1)N[C@@H](C)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
A solution of 1-(4-fluorophenyl)but-2-en-1-one (13 g, 79.2 mmol) in EtOH (150 mL) was added (S)-1-(4-bromophenyl)ethanamine (32 g, 158 mmol), and the resulting mixture was stirred overnight. The solvent was removed in vacuo to give the crude 3-((S)-1-(4-bromophenyl)ethylamino)-1-(4-fluorophenyl)butan-1-one which was used for the next step without purification.
Reaction SMILES: [CH3:1][C@@:2]1([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@H:19]4[CH2:24][CH2:23][C@@H:22]([CH3:25])[CH2:21][CH2:20]4)[CH:14]=3)[CH:9]=2)[CH2:6][O:5]C(=O)[NH:3]1.C(O)C.O.[OH-].[Li+]>O>[NH2:3][C@@:2]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][C@H:19]3[CH2:20][CH2:21][C@@H:22]([CH3:25])[CH2:23][CH2:24]3)[CH:14]=2)[CH:9]=1)([CH3:1])[CH2:6][OH:5]
Reactant: C[C@@]1(c2ccc3cc(O[C@H]4CC[C@@H](C)CC4)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@](N)(CO)c1ccc2cc(O[C@H]3CC[C@@H](C)CC3)ccc2c1
Temperature: 80 °C

Procedure:
To a solution of (R)-4-Methyl-4-[6-(cis4-methyl-cyclohexyloxy)-naphthalen-2-yl]-oxazolidin-2-one (0.4420 g, 0.001302 mol) in ethanol (5.00 mL, 0.0856 mol) in a capped 40 mL vial was added 4.2 M Lithium hydroxide, monohydrate in water (2.8 mL). The mixture was heated overnight at 80° C. TLC analysis showed the reaction was complete. The mixture was concentrated to dryness under vacuum. Methylene chloride (5 mL) and water (5 mL) were added and the layers were separated (2×). The organic layer was concentrated under vacuum and purified by HPLC to give 0.0233 g of the title compound (6% yield). MS: m/z=297.29 [M-NH2]+. 1H NMR (400 MHz, MeOD) δ 0.98 (d, J=6.02 Hz, 3 H), 1.40-1.51 (m, 2 H), 1.51-1.60 (m, 3 H), 1.64-1.74 (m, 2 H), 1.79 (s, 3 H), 2.03-2.14 (m, 2 H), 3.83 (d, J=11.55 Hz, 1 H), 3.93 (d, J=11.55 Hz, 1 H), 4.69-4.77 (m, 1 H), 7.23 (dd, J=8.91, 2.38 Hz, 1 H), 7.27 (d, J=2.51 Hz, 1 H), 7.53 (dd, J=8.78, 2.01 Hz, 1 H), 7.79-7.89 (m, 3 H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[F:15][C:16]1[CH:17]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35](Cl)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:19]=[C:20]([F:27])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:27][C:20]1[CH:19]=[C:18]([CH:28]([NH:30][C:31]([C:33]2[N:34]=[C:35]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]([F:14])([F:13])[F:12])[CH:4]=3)[O:36][CH:37]=2)=[O:32])[CH3:29])[CH:17]=[C:16]([F:15])[C:21]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24]
Reactant: OB(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(NC(=O)c1coc(-c2ccc(Cl)c(C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 25 %

Procedure:
4-Chloro-3-trifluoromethylphenylboronic acid (58.3 mg, 0.26 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted using Pd(PPh3)2Cl2 (7 mg, 0.01 mmol), Cs2CO3 (127 mg, 0.39 mmol) as described above to give the title compound (17 mg, 25%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:12]([O-])=O.[Na+].[ClH:16]>O>[ClH:16].[Br:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][NH2:12])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Br)cc1C(=O)O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(Br)cc1C(=O)O
Reaction time: 2 h

Procedure:
To a suspension of 2-amino-5-bromobenzoic acid (50.0 g, 231.5 mmol) in conc. HCl (250 mL) at −10° C. was added a solution of sodium nitrite (23.92 g, 347.2 mmol) in water (250 mL), slowly, followed by stirring for 2 h. To this reaction mixture was slowly added a solution of stannous chloride (130.50 g, 225.6 mmol) in conc. HCl (125 mL) with continued stirring at RT for 12 h. The reaction mixture was filtered, the residue washed with the minimum amount of water and vacuum dried to afford the title compound as and ‘off white’ solid 61 g (100%), which was used for next step without further purification. Rf=0.10 (ethyl acetate); 1H NMR (400 MHz, DMSO-d6): δ 11.60-9.60 (brs, 3H), 7.93 (d, J=2.4 Hz, 1H), 7.72 (dd, J=2.4 & 8.8 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H); ES-MS: m/z 229.1 (M−H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>CS(C)=O.[I-].[Na+]>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][CH2:12][N:25]2[CH2:24][CH2:23][N:22]([CH:21]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[C:18]3[CH:17]=[CH:16][C:15]([F:14])=[CH:20][CH:19]=3)[CH2:27][CH2:26]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(C=CCCl)cc1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(C=CCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
A solution of 0.5 gram (0.002 mole) of 3-(4-nitrophenyl)-2-propenyl chloride in 5 mL of dimethyl sulfoxide was added to a solution of 0.7 gram (0.002 mole) of N-[bis(4-fluorophenyl)methyl]piperazine in 10 mL of dimethyl sulfoxide. To this was added 0.1 gram (0.0005 mole) of sodium iodide as a catalyst. Upon completion of the addition 1.2 grams (0.010 mole) of N,N-diisopropylethylamine was added dropwise. To effect solution the reaction mixture was then warmed to 50-80° C., where it stirred for four hours . After this time the reaction mixture was cooled to ambient temperature, where it stirred for about 18 hours. The reaction mixture was then poured into 50 mL of aqueous saturated sodium bicarbonate solution and then extracted with three 50 mL portions of diethyl ether. The combined extracts were washed with 75 mL of aqueous saturated sodium chloride solution, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding a crude oil, which was subjected to column chromatography on silica gel. Elution was accomplished with 1:1 ethyl acetate:heptane. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.5 gram of of N-[3-(4-nitrophenyl)-2-propenyl]-N′-[bis(4-fluorophenyl)methyl]piperazine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[NH2:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:33][CH2:34][CH2:35][N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: O=C(NCCN1CCOCC1)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 67 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 4-(2-aminoethyl)morpholine (available from Aldrich Chemical Company, Inc.; 81 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(2-morpholin-4-yl-ethylcarbamoyl)-biphenyl-2-carboxylic acid (82 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (br s, 1H), 8.47 (s, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 1.8 Hz, 1H), 8.09 (dd, J=8.3, 2.0 Hz, 1H), 7.94 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 2H), 3.90-4.10 (m, 2H), 3.50-3.72 (m, 4H), 3.27-3.44 (m, 4H), 3.08-3.23 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:11][CH:10]2[CH2:12]O)[CH:6]=[CH:7][CH:8]=1.[Br:16]P(Br)Br>C(OCC)C>[Br:16][CH2:12][CH:10]1[CH2:11][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=1
Reactant: BrP(Br)Br
Reactant: OCC1CC1c1cccc(C(F)(F)F)c1
Solvent: CCOCC
Product: FC(F)(F)c1cccc(C2CC2CBr)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 145.6 %

Procedure:
[2-(3-Trifluoromethyl-phenyl)-cyclopropyl]-methanol obtained in step 1 (0.250 g, 1.15 mmol) was taken in diethyl ether (4 ml) and cooled to 0° C. Tribromo phosphine (0.06 ml, 0.64 mmol) in diethyl ether (4 ml) was added slowly at 0° C. and stirred at 15-20° C. for 2 hrs. Reaction mixture was quenched with saturated NaHCO3 solution (20 ml) and extracted with diethyl ether. Organic layer was washed with saturated brine solution, dried over Na2SO4, and evaporated under vacuum to get 1-(2-bromomethyl-cyclopropyl)-3-trifluoromethyl-benzene (0.26 g, 80%) as a sticky mass.