Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Br[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:12][C:11]1[C:6]([CH:4]2[CH2:5][N:2]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:3]2)=[N:7][CH:8]=[CH:9][N:10]=1
Reactant: Brc1ccc2ccccc2n1
Reactant: Clc1nccnc1C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nccnc1C1CN(c2ccc3ccccc3n2)C1
Temperature: 110 °C
Reaction time: 19 h
Yield: 42.7 %

Procedure:
A mixture of 2-(azetidin-3-yl)-3-chloropyrazine hydrochloride (8) (163 g, 0.79 mol), 2-bromoquinoline (164 g, 0.79 mol, 1 eq., Combi-Blocks) and cesium carbonate (772 g, 2.37 mol, 3 eq., Aldrich) in anhydrous DMF (6.5 L) was heated to 110° C. and stirred for 19 h. After cooling to RT, the mixture was transferred to 50 L separatory funnel and diluted with water (13 L). Then it was extracted with ethyl acetate (20 L×2) and the organic extracts were combined, washed with water (8 L), brine (8 L), dried and concentrated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=9:1 to 3:1). All fractions containing desired compound were combined and concentrated. The obtained solid was triturated with MTBE (250 mL), washed with MTBE (100 mL×2) and dried to obtain 100 g of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (9) with >99% purity. The mother liquor was concentrated and purified by column chromatography and trituration with MTBE again to give 4.5 g of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (9) with >99% purity. Yield: 45% for two steps.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[C:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=1)=[O:6].Br[CH:28]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH:41]([CH3:43])[CH3:42])=[CH:36][CH:35]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>ClCCl.O>[CH2:40]([C:37]1[CH:36]=[CH:35][C:34]([CH:28]([NH:1][C:2]2[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=2)[C:5]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:8]=2)=[O:6])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:39][CH:38]=1)[CH:41]([CH3:43])[CH3:42]
Reactant: CCCCCC(Br)c1ccc(CC(C)C)cc1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc(N)c2)c2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCC(Nc1cccc(C(=O)c2cn(CCCC(=O)OCC)c3ccccc23)c1)c1ccc(CC(C)C)cc1
Yield: 54.4 %

Procedure:
A mixture of ethyl 4-[3-(3-aminobenzoyl)indol-1-yl]butyrate (176 mg), 1-(1-bromohexyl)-4-isobutylbenzene (233 mg) and diisopropylethylamine (194 mg) in dichloromethane (5 ml) was refluxed for 20 hours. The reaction mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated and washed with water and brine, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel column eluting with a mixture of n-hexane and ethyl acetate (3:1) to give ethyl 4-[3-[3-[1-(4-isobutylphenyl)hexylamino]benzoyl]indol-1-yl]butyrate (155 mg) as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=O)=[C:9]([O:16][CH3:17])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:18].[H-].[Na+].[CH3:21][N:22]1[CH:26]=[C:25]([C:27]2[C:32]3[N:33]=C(S(C)(=O)=O)[N:35]=[CH:36][C:31]=3[CH:30]=[CH:29][N:28]=2)[CH:24]=[N:23]1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:35]=[CH:36][C:31]4[CH:30]=[CH:29][N:28]=[C:27]([C:25]5[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=5)[C:32]=4[N:33]=3)=[C:9]([O:16][CH3:17])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:18]
Reactant: Cn1cc(-c2nccc3cnc(S(C)(=O)=O)nc23)cn1
Reactant: COc1cc(-c2cnc(C)n2C)ccc1NC=O
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2cnc(C)n2C)ccc1Nc1ncc2ccnc(-c3cnn(C)c3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 14 %

Procedure:
A solution of N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)formamide (Preparation 55, 37 mg, 0.151 mmol) in THF (1 mL) was treated with sodium hydride (10 mg, 0.250 mmol) at 0° C. After stirring for 20 minutes at room temperature, the mixture was cooled to 0° C. and 8-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 35, 50 mg, 0.173 mmol) was added. The reaction was allowed to reach room temperature and stirred for 18 hours. Aqueous NaOH (2M, 0.5 mL) and MeOH (0.5 mL) were added and the resulting mixture stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine, dried and evaporated. The residue was purified by silica gel column chromatography eluting with 0 to 10% MeOH in EtOAc to give the title compound (9 mg, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13](Br)[C:12]([NH:17][C:18](=[O:48])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:47])[CH:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])=[CH:33][C:32]=3[C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])[CH2:28][CH3:29])[CH:20]=2)=[N:11]1.[C:49]([NH:52][C:53]1[CH:54]=[N:55][NH:56][CH:57]=1)(=[O:51])[CH3:50]>C(OCC)(=O)C>[C:49]([NH:52][C:53]1[CH:54]=[N:55][N:56]([CH:13]2[C:14](=[O:15])[N:10]([C:3]3[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=3[Cl:9])[N:11]=[C:12]2[NH:17][C:18](=[O:48])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:47])[CH:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])=[CH:33][C:32]=3[C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])[CH2:28][CH3:29])[CH:20]=2)[CH:57]=1)(=[O:51])[CH3:50]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2Br)c1
Reactant: CC(=O)Nc1cn[nH]c1
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2n2cc(NC(C)=O)cn2)c1
Temperature: 100 °C

Procedure:
17.8 g of 1-(2,4,6-trichlorophenyl)-3-{3-[2-(2,4-di-tert-amylphenoxy)butyramido]benzamido}-4-bromo-5-oxo-2-pyrazoline and 10 g of 4-acetamidopyrazole were well mixed in a mortar and heated at 100° C. for 2 hours. To the reaction mixture, 200 cc of ethyl acetate was added and the mixture was washed several times with water. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated. Upon crystallization of the residue from a solvent mixture of acetonitrile and ethyl acetate, 12.1 g of Coupler (1) was obtained. The melting point of the coupler was 135° to 141° C.
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].Br[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>>[CH2:1]([C:3]1[N:12]([CH2:15][CH2:16][O:17][C:18]2[CH:19]=[CH:20][C:21]([N+:24]([O-:26])=[O:25])=[CH:22][CH:23]=2)[C:11](=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Reactant: CCc1nc2ccccc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1nc2ccccc2c(=O)n1CCOc1ccc([N+](=O)[O-])cc1
Yield: 64.4 %

Procedure:
The title compound (1.246 g, 64%) was prepared from 2-ethyl-4-oxo-3,4-dihyroquinazoline (1.0 g, 5.7 mmol) and 4-[2-bromoethoxy]nitrobenzene (1.696 g, 6.8 mmol) and K2CO3 (1.58 g, 11.49 mmol) as a base by a similar procedure to that described in preparation 1.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([CH3:25])[CH:16]=3)=[N:7][C:6]=12.[C:26]([C:28]1[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=1)#[CH:27]>>[CH3:25][C:17]1[CH:16]=[C:15]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:5]3[N:4]=[CH:3][C:2]([C:27]#[C:26][C:28]4[CH:29]=[N:30][C:31]([NH2:34])=[N:32][CH:33]=4)=[C:6]3[N:7]=2)[CH:20]=[CH:19][C:18]=1[C:21]([F:24])([F:23])[F:22]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(I)c3n2)ccc1C(F)(F)F
Reactant: C#Cc1cnc(N)nc1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cnc(N)nc4)c3n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 3-iodo-5-(3-methyl-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.32) (236 mg, 0.5 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2) (60 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (139 mg, 60%). MS (EI) 462.1 [(M)+]; mp 240° C.
Reaction SMILES: C[C:2]1[C:6]2[N:7]=[CH:8][NH:9][C:10](=O)[C:5]=2[S:4][CH:3]=1.C(=O)(O)[O-].[Na+].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:10]1[C:5]2[S:4][CH:3]=[CH:2][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1csc2c(=O)[nH]cnc12
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1ncnc2ccsc12
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 3H-thieno[3,2-d]pyrimid-4-one (3, 2.7 g, 18 mmol) in phosphorus oxychloride (18 mL) under N2 was heated at reflux for 1 hour. The resulting solution was allowed to cool to room temperature and then poured into a saturated aqueous solution of sodium bicarbonate to neutralize. The aqueous mixture was extracted with diethyl ether. The organic layer was washed with water followed by saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to yield 4-chlorothieno[3,2-d]pyrimidine (2.9 g, 97% yield) as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1.C(N(CC)CC)C.CS([Cl:26])(=O)=O>C(Cl)Cl>[Cl:26][CH2:2][C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C=Cc1ccc(CO)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C=Cc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of methyl 4-(hydroxymethyl)cinnamate (4.1 g), triethylamine (3.1 ml) and methylene chloride (50 ml) was added dropwise under ice cooling methanesulfonyl chloride (1.7 ml), and the mixture was stirred at room temperature for 1.5 hours. Evaporation of the reaction solution gave a residue, which was then chromatographed on silica gel column (eluent: methylene chloride) to give methyl 4-(chloromethyl)cinnamate (2.57 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.CO.C(=O)(O)[O-].[Na+]>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>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[C:3]([C:11](=[O:13])[CH3:12])=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=2)=[CH:17][CH:16]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(=O)c1cc([N+](=O)[O-])ccc1-c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
1-(2-Bromo-5-nitro-phenyl)-ethanone (1 g, 4 mmol; prepared similarly to the procedure described in Meisenheimer, J., Zimmermann P., and v. Kummer, U. Ann. der. Chem. 446, pp. 205-228), p-Chlorophenylboronic acid (768 mg, 1.2 eq.), and tetrakis(triphenylphosphine)-palladium(0) (473 mg, 0.1 eq.), were dissolved in 25 mL toluene, 6 mL methanol and 2.5 mL sat. sodium bicarbonate solution. After degassing/sonicating the solution, the sealed reaction vessel was heated to 80° C. overnight. The cooled solution was separated between ethyl acetate and water; the aqueous phase extracted two more times with ethyl acetate, and the organic fractions were combined, dried with sodium sulfate and evaporated. Silica gel chromatography (4:1 hexanes/ethyl acetate) gave 1-(4′-chloro-4-nitro-biphen-2-yl)-ethanone (962 mg).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([P:10](=[S:12])=[S:11])[CH3:9].[CH:13]([SH:17])([CH2:15][CH3:16])[CH3:14]>O1CCCC1>[CH:13]([S:17][P:10]([CH2:8][CH3:9])([SH:12])=[S:11])([CH2:15][CH3:16])[CH3:14]
Reactant: CCC(C)S
Reactant: CCP(=S)=S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(C)SP(=S)(S)CC
Temperature: 25 °C

Procedure:
The triethylamine salt of S-(sec-butyl)ethylphosphonotrithioic acid was prepared as follows: 14.0 g (0.056 mole) of ethyl thionophosphine sulfide was dissolved in tetrahydrofuran; then 11.2 g (0.124 mole) of sec-butyl mercaptan was added, all at once. Then, 11.3 g (0.112 mole) triethylamine was added dropwise. The mixture was stirred at room temperature, then refluxed for 15 minutes. The solvent was removed in vacuo, leaving the acid salt (24.1 g, 68% of theoretical yield) as a semi-solid.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.O.[F:10][C:11]1[C:12]([N+:19]([O-:21])=[O:20])=[C:13](O)[CH:14]=[C:15]([F:17])[CH:16]=1>CN(C=O)C>[F:10][C:11]1[C:12]([N+:19]([O-:21])=[O:20])=[C:13]([O:4][CH3:1])[CH:14]=[C:15]([F:17])[CH:16]=1
Reactant: O=[N+]([O-])c1c(O)cc(F)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1cc(F)cc(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In DMF (50 ml) was dissolved 3,5-difluoro-2-nitrophenol. Potassium carbonate (10.4 g, 75.5 mmol) and methyl iodide (6.3 ml, 100.6 mmol) were added and the mixture was stirred for 15 hours at room temperature. Water (300 ml) was added, followed by extraction with ether (500 ml). The extract was washed with saturated brine (2×200 ml), dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, whereby the title compound (8.29 g, 87%) was obtained as a yellow crystalline powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[C@H:9](O)[CH3:10])[CH:5]=[CH:6][CH:7]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:44][C:45]([CH3:49])([CH3:48])[CH2:46][OH:47]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C@:8]2([OH:12])[O:47][CH2:46][C:45]([CH3:49])([CH3:48])[NH:44][C@H:9]2[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](O)C(=O)c1cccc(F)c1
Reactant: CC(C)(N)CO
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1cccc(F)c1
Yield: 38.3 %

Procedure:
Compound 4c was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-1-(3-fluorophenyl)-2-hydroxypropan-1-one (10c, 3.94 g, 0.024 mol), Proton sponge (6.0 g), triflic anhydride (4.6 mL, 25.8 mmol), and 2-amino-2-methyl-1-propanol (4.6 g, 0.052 mol) in acetonitrile (50 mL). After purification, 2.2 g (39%) of the free base 4c was isolated and converted to the hemi-D-tartrate salt, which had >99% ee: mp 131-132° C.; [α]20D +20.4° (c 1.0, CH3OH); 1H NMR (methanol-d4) δ 7.45-7.41 (m, 2H), 7.35-7.31 (m, 1H), 7.11-7.09 (m, 1H), 4.33 (s, 1H), 4.26 (d, 1H, J=12.0 Hz), 3.56-3.45 (m, 2H), 1.59 (s, 3H), 1.34 (s, 3H), 1.06 (d, 3H, J=6.6 Hz); 13C NMR (methanol-d4) δ 178.1, 165.4, 162.1, 144.8, 130.8, 123.2, 116.3 (d), 114.3 (d), 96.2, 74.5, 67.0, 54.3, 23.6, 20.8, 13.7; LCMS (ESI) m/z 240.0 [(M-tartrate)+, M=C15H21FNO5]; Anal. (C15H21FNO5.0.5H2O) calcd: C, 55.72; H, 6.86; N, 4.33. found: C, 55.61; H, 6.89; N, 4.33.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[C:9]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([OH:30])[C:22]=2[CH2:31][CH2:32][CH3:33])[C:8]=1[CH2:34][CH2:35][CH3:36])C>C(O)C.[OH-].[Na+]>[C:13]([C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:37])=[O:3])=[C:8]([CH2:34][CH2:35][CH3:36])[C:9]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([OH:30])[C:22]=1[CH2:31][CH2:32][CH3:33])(=[O:15])[CH3:14]
Reactant: CCCc1c(OCCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1c(OCCCOc2c(C(C)=O)ccc(OCC(=O)O)c2CCC)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 71 %

Procedure:
A suspension of 1.94 g of [4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid ethyl ester in 5 ml of ethanol and 20 ml of 1.0N sodium hydroxide was refluxed for 1 hour. After cooling, ice water was added and the mixture was acidified. The precipitate was extracted with methylene chloride. The dried, over magnesium sulfate, extract was concentrated in vacuo to an oil. Crystallization from ether-hexane gave 1.29 g, mp 124°-125°, (71% yield) of [4-acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-2-propylphenoxy]acetic acid.
Reaction SMILES: [C:1]([C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([O:32][CH2:33][CH3:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37]([O:44][NH2:45])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH2:37]([O:44][N:45]=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][CH:27]([O:32][CH2:33][CH3:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:24][CH:25]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NOCc1ccccc1
Reactant: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)C(=O)OC
Product: CCOC(Cc1ccc(OCCn2c(=O)sc3cc(C(=NOCc4ccccc4)c4ccccc4)ccc32)cc1)C(=O)OC

Procedure:
Starting from the compound obtained in Step C of Example 1, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-benzylhydroxylamine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[O:16][CH3:17])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:20][C:21]1[C:22]([CH3:37])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:20][C:21]2[C:22]([CH3:37])=[N:23][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)=[CH:11][C:10]=1[O:16][CH3:17])([CH3:6])[CH3:7])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1OC
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1OC

Procedure:
In analogy to the procedures described in examples 8A] and 31B], 2-(4-hydroxy-2-methoxy-phenoxy)-2-methyl-propionic acid ethyl ester was reacted with 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 1N]) to give 2-{2-methoxy-4-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester, which was subsequently saponified to yield the title compound as light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:14]=1[CH2:15][N:16]([C:30]1[S:31][CH:32]=[N:33][N:34]=1)[S:17]([C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[O:26][C:22]=2[CH:21]=1)(=[O:19])=[O:18].C(N(CC)CC)C.[NH4+].[OH-]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CCOC(C)=O.O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:24]2[C:23]3[CH:28]=[CH:29][C:20]([S:17]([N:16]([CH2:15][C:14]4[CH:35]=[CH:36][C:37]([O:39][CH3:40])=[CH:38][C:13]=4[O:12][CH3:11])[C:30]4[S:31][CH:32]=[N:33][N:34]=4)(=[O:19])=[O:18])=[CH:21][C:22]=3[O:26][C:25]2=[O:27])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2ccc3[nH]c(=O)oc3c2)c(OC)c1
Reactant: OB(O)c1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2ccc3c(c2)oc(=O)n3-c2cccc(Cl)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62.4 %

Procedure:
A sealable vial was charged with (3-chlorophenyl)boronic acid (25.6 mg, 0.164 mmol), N-(2,4-dimethoxybenzyl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (48.9 mg, 0.109 mmol), 3 Å molecular sieves (powdered, 60 mg), DCM (545 μl), and triethylamine (45.6 μl, 0.327 mmol). Copper (II) acetate (39.6 mg, 0.218 mmol) was added as a solid in a single portion. The mixture was stirred at rt for 48 h. The reaction mixture was poured into a mixture of NH4OH and water (10% NH4OH in H2O), extracted with DCM (2×10 mL), organic layers (which were an emulsion) were combined and washed with water (10 mL) then brine (20 mL), the emulsion resolved upon brine wash. The organic layers were dried (Na2SO4) and concentrated for purification by silica gel MPLC. The residue was taken up in minimal DCM and absorbed onto a 5 g loading cartridge and passed through a silica gel column (12 g) using 98:2 Heptane:EtOAc to 100% EtOAc gradient to afford 3-(3-chlorophenyl)-N-(2,4-dimethoxybenzyl)-2-oxo-N-(1,3,4-thiadiazol-2-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (38.0 mg, 0.068 mmol) as a white amorphous solid. m/z (ESI) 559.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[S:20]1[CH2:24][C:23](=[O:25])[NH:22][C:21]1=[O:26].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:24]4[S:20][C:21](=[O:26])[NH:22][C:23]4=[O:25])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: O=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=O)C(=Cc2cnn3ccc(Nc4cccc(Cl)c4)nc23)S1
Temperature: 80 °C

Procedure:
To 5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.184 mmol) in 1 mL EtOH was added 2,4-thiazolidinedione (22 mg, 0.184 mmol) and piperidine (18 μL, 0.184 mmol). The mixture was heated in microwave for 20 minutes at 80° C. The solid formed was isolated by filtration and air dried to give 5-((5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione. LCMS (M+1=372)
Reaction SMILES: [F:1][C:2]1[C:11]2[N:10]3[CH2:12][CH2:13][CH2:14][CH:9]3[CH2:8][O:7][C:6]=2[CH:5]=[C:4]([N+:15]([O-])=O)[CH:3]=1>C1COCC1.[Pd]>[F:1][C:2]1[C:11]2[N:10]3[CH2:12][CH2:13][CH2:14][CH:9]3[CH2:8][O:7][C:6]=2[CH:5]=[C:4]([NH2:15])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)c2c(c1)OCC1CCCN21
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cc(F)c2c(c1)OCC1CCCN21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 9-fluoro-7-nitro-2,3,3a,4-tetrahydro-1H-benzo[b]pyrrolo[1,2-d][1,4]oxazine (4.00 g, 16.79 mmol) in THF (40 mL) was added Pd/C (1.50 g). The reaction mixture was stirred at rt under H2 for 12 h. The mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo to give the title compound as an offwhite solid (3.00 g, 85%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([C@H:16]([NH:18]C(=O)OC(C)(C)C)[CH3:17])([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[ClH:35]>CO>[ClH:35].[NH2:18][C@@H:16]([C:13]1([OH:15])[CH2:14][N:11]([C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[C:3]=2[NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[O:10])[CH2:12]1)[CH3:17]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: Cl
Solvent: CO
Product: C[C@@H](N)C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Yield: 96.4 %

Procedure:
A solution of 1,1-dimethylethyl {(1R)-1-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]ethyl}carbamate (333 mg, 0.56 mmol) in methanol (10 mL) was treated with hydrochloric acid (4 N in dioxane, 1.4 mL, 5.6 mmol) at 60° C. for 30 min. After cooling, the volatile materials were removed in vacuo to provide 3-[(1R)-1-aminoethyl]-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol hydrochloride as a white solid (285 mg, 0.54 mmol, 97% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.83 (br s, 3H), 7.59 (dd, 1H), 7.39 (d, 1H), 7.34 (m, 1H), 7.21 (q, 1H), 6.69 (m, 1H), 6.65 (s, 1H), 4.25 (dd, 1H), 4.10 (dd, 1H), 3.98 (dd, 1H), 3.80 (m, 1H), 3.48 (m, 1H), 1.11 (dd, 3H); MS (EI) for C18H17F3IN3O2: 492 (MH+)