Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[S:11][C:12]([C:15]#[N:16])=[CH:13][N:14]=2)[CH:4]=1.[CH3:17][N:18]([CH3:27])[C:19]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20]>CS(C)=O.O>[C:15]([C:12]1[S:11][C:10]([NH:9][C:5]2[CH:4]=[C:3]([CH2:2][N:24]3[CH2:23][CH2:22][N:21]([C:19]([N:18]([CH3:27])[CH3:17])=[O:20])[CH2:26][CH2:25]3)[CH:8]=[CH:7][N:6]=2)=[N:14][CH:13]=1)#[N:16]
Reactant: N#Cc1cnc(Nc2cc(CCl)ccn2)s1
Reactant: CN(C)C(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CN(C)C(=O)N1CCN(Cc2ccnc(Nc3ncc(C#N)s3)c2)CC1
Reaction time: 3.5 h

Procedure:
2-(4-Chloromethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.119 g, 0.47 mmol) was dissolved in 1 mL DMSO. N,N-Dimethyl-1-piperazinecarboxamide (0.149 g, 0.95 mmol) was added and the solution was stirred for 3.5 hr. Additional N,N-dimethyl-1-piperazinecarboxamide (0.149 g, 0.95 mmol) was added and the solution was stirred for 1.5 hr. The reaction was diluted with water and the resulting precipitate collected by filtration. The solid was washed with water and hexanes then air dried overnight to afford the free base. Free base: 1H NMR (CD3OD) δ 8.33 (d, 1H, J=5.0 Hz), 8.03 (s, 1H), 7.08 (s, 1H), 7.04 (d, 1H, J=5.0 Hz), 3.58 (s, 1H), 3.29 (t, 4H, J=6.0 Hz), 2.84 (s, 6H), 2.49 (t, 4H, J=Hz). MS [M+H]+=372.1611.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:11][NH:10][C:9]1=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:23]I>C(O)C>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9](=[O:20])[N:10]([CH3:23])[N:11]=2)=[CH:14][CH:15]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1Cc1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(-c2ccc(Cl)cc2)n(Cc2ccccc2)c1=O
Reaction time: 8 h

Procedure:
To a stirred, room temperature, suspension of 4-benzyl-5-(4-chlorophenyl)-3H-1,2,4-triazol-3-one (10.85 g, 3.797×10-2 mole), 1 molar aqueous NaOH (42 ml, 4.2×10-2 mole), and ethanol (15 ml) was added methyl iodide (3.6 ml, 5.8×10-2 mole). After stirring overnight, the reaction was transferred to a separatory funnel where it was extracted with EtOAc (3x). The EtOAc extracts were combined, washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving a yellowish foam. Purification of this foam by a combination of flash chromatography (20% EtOAc/CH2Cl2) and crystallization from cyclohexane afforded colorless crystals 5.92 g (52%), mp 90°-91° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH2:8][CH2:9][CH2:10][CH:11]=O)[CH:7]=1.OS(O)(=O)=O.C[C:21](C)=[O:22]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH3:14])=[C:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH:21]=[O:22])[CH:7]=1
Reactant: CC(C)=O
Reactant: COc1ccc(F)cc1CCCC=O
Agent: O=S(=O)(O)O
Product: COc1ccc(F)cc1CCCCC=O
Temperature: 25 °C
Yield: 50 %

Procedure:
To a solution of 9 (0.46 g, 2.0 mmol) in acetone (20 mL) was added H2SO4 (5%, 2 mL) and the reaction was heated to reflux for 1.6 h. After the reaction was cooled to room temperature, most of the solvent was then removed in vacuo. A solution of NaHCO3 (sat. 40 mL) was added and the organics were extracted with EtOAc (3×40 mL) and the combined organic layers were washed with brine (30 mL) and dried over Na2SO4. The crude product obtained by removal of the solvent in vacuo was purified by flash column chromatography on silica (Rf=0.10, EtOAc/Hexane, 10:90, v:v) to give the product (0.20 g, 50%) as oil; 1H NMR (CDCl3, 500 MHz): δ 9.76 (s, 1 H), 6.88-6.82 (m, 2 H), 6.74 (dd, J=4.6, 8.6 Hz, 1 H), 3.79 (s, 3 H), 2.61 (t, J=7.3 Hz, 2 H), 2.45 (m, 2 H), 1.69-1.60 (m, 4 H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[I-].[Na+].Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[O:25])[CH2:18]1>O1CCCC1>[C:3]([CH:2]([CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH2:20][CH:19]([CH2:23][C:24]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[O:25])[CH2:18]1)[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=C(CC1CCCN(CCCl)C1)c1ccc(F)cc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCN1CCCC(CC(=O)c2ccc(F)cc2)C1)C(C)=O
Yield: 45 %

Procedure:
A solution of 6.2 g of ethyl acetoacetate is added at 0° C. to a suspension of 1.13 g of sodium hydride in 150 ml of tetrahydrofuran. After 15 minutes at this temperature, 7.1 g of anhydrous sodium iodide are added, followed by the addition at 0° C. of l3.5g of the product obtained in Stage B. The mixture is then brought to reflux for 12 hours and the whole is thereafter concentrated, the residue is taken up in water and the product is extracted with dichloromethane. The 16.9 g of oil obtained are purified by chromatography on 900 g of silica (70-230 mesh), using a mixture of dichloromethane and methanol (98:2 V/V) as eluant.
Reaction SMILES: B(Br)(Br)Br.C([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[S:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][N:18]=2)=[CH:10][CH:9]=1)C.O>ClCCl>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[S:15][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:17][N:18]=2)=[CH:12][CH:13]=1
Reactant: CCCCCCCCc1cnc(-c2ccc(OCC)cc2)s1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCc1cnc(-c2ccc(O)cc2)s1
Reaction time: 8 h

Procedure:
A 1M solution of boron tribromide in dichloromethane (50 cm3) is added dropwise to a solution of 2-(4-ethoxyphenyl)-5-octylthiazole [J. prakt. Chem., (1979) Vol. 321, pp 643](2.0 g) and dichloromethane (50 cm3) at 0° C. under an atmosphere of nitrogen. The reaction solution is stirred overnight and water (100 cm3) added. The organic layer is separated off and the aqueous layer extracted with dichloromethane (2×100 cm3). The combined organic layers are washed with brine (2×100 cm3) and then dried (MgSO4), filtered and evaporated down. The residue is purified by column chromatography on silica gel using a 9:1 hexane/ethyl acetate mixture as eluent and recrystallisation from ethanol to yield 1.0 9 of g 2-(4-hydroxyphenyl)-5-octylthiazole.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][C@@H:13](Cl)[C@@H:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[C:1]([O:4][C@H:5]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:21]2[CH2:20][CH2:19][C@@:18]2([CH3:26])[C@H:11]3[CH2:12][CH:13]=[C:14]2[C:15](=[O:17])[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4C[C@@H](Cl)[C@H](C(C)=O)[C@@]4(C)CC[C@@H]32)C1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(C(C)=O)=CC[C@@H]32)C1
Yield: 44.1 %

Procedure:
One gram of 3β-acetoxy-16α-chloro-5-pregnen-20-one is treated analogously to Example 1 in "Dowtherm" for 6 hours at 240° C. and worked up. Recrystallization from isopropyl ether yields 400 mg of 3β-acetoxy-5,16-pregnadien-20-one (56% of theory).
Reaction SMILES: Br[C:2]1[C:3](Br)=[C:4](Br)[C:5](Br)=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[OH-:16].[Na+]>[Zn]>[C:8]([OH:16])(=[O:9])[C:7]1[C:6](=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11]([OH:10])=[O:12]
Reactant: [OH-]
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Agent: [Na+]
Agent: [Zn]
Product: O=C(O)c1ccccc1C(=O)O
Reaction time: 1 h
Yield: 97 %

Procedure:
Example 1 was repeated using tetrabromophthalic anhydride with 72 wt % zinc and 20% aqueous NaOH. After one hour at 60° C., 97% phthalic acid was produced. This example shows that the process of this invention is ineffective in selectively removing bromine.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(OC(=O)[NH:35][C:36]1([CH2:41][O:42][C:43]2[CH:48]=[CH:47][C:46]([CH:49]=O)=[CH:45][CH:44]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1)(C)(C)C>>[NH2:35][C:36]1([CH2:41][O:42][C:43]2[CH:44]=[CH:45][C:46]([CH2:49][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:47][CH:48]=2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)NC1(COc2ccc(C=O)cc2)CCCC1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCC3(N)CCCC3)cc2)c1
Yield: 61 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and tert-butyl[1-(4-formylphenoxymethyl)cyclopentyl]carbamate (74 mg) according to an analogous synthetic method to Example 238 and purified by LC-MS, the title compound (16 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.[CH3:25][O:26][C:27](OC)(OC)OC.[OH-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[N:16]=[C:25]([O:26][CH3:27])[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]=2[CH:11]=1
Reactant: COC(OC)(OC)OC
Reactant: COC(=O)CCCCCOc1ccc(N)c(Nc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COC(=O)CCCCCOc1ccc2nc(OC)n(-c3ccccc3)c2c1

Procedure:
200 mg of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester was mixed with 0.12 ml of tetramethylorthocarbonate and 40 μl of acetic acid, and the mixture was heated for 4 hours to 80° C. After cooling, it was mixed with 1N sodium hydroxide solution, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was purified by column chromatography on silica gel. 104 mg was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:34]=[CH:35][N:36]([CH:38]([CH3:40])[CH3:39])[CH:37]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:34]=[CH:35][N:36]([CH:38]([CH3:39])[CH3:40])[CH:37]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2ccc(-c3cn(C(C)C)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1nc2ccc(-c3cn(C(C)C)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-ethoxy-6-(1-isopropyl-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[S:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[N:14][N:15]=3)[CH:9]=2)[N:4]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Sn](CCCC)(CCCC)CCCC)[N:35]=2)[CH2:30][CH2:29]1>[Cu]I.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>[CH3:27][N:28]1[CH2:29][CH2:30][N:31]([C:34]2[N:35]=[C:36]([C:2]3[C:10]4[C:5](=[CH:6][CH:7]=[C:8]([C:11]5[S:12][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[N:14][N:15]=5)[CH:9]=4)[N:4]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH:3]=3)[CH:37]=[CH:38][CH:39]=2)[CH2:32][CH2:33]1
Reactant: CC(C)(C)OC(=O)n1cc(I)c2cc(-c3nnc(S(C)(=O)=O)s3)ccc21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(N2CCN(C)CC2)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CN1CCN(c2cccc(-c3cn(C(=O)OC(C)(C)C)c4ccc(-c5nnc(S(C)(=O)=O)s5)cc34)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
A solution of tert-butyl 3-iodo-5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-1H-indole-1-carboxylate (650 mg, 1.146 mmol) and 1-methyl-4-(6-(tributylstannyl)pyridin-2-yl)piperazine (596 mg, 1.146 mmol) DMF (10 mL) was purged the Argon gas for 5 min. To the solution was added CuI (327.5 mg, 1.71 mmol), Pd(PPh3)4 (159 mg, 0.137 mmol) and again the mixture was purged the Argon gas for 5 min. The mixture was stirred at RT for 2 h, then at 90° C. for 1 h. The mixture was poured into H2O and was extracted with EtOAc. The combined organic layer was dried, filtered and concentrated. The residue was purified with silica gel chromatography to give tert-butyl 3-(6-(4-methylpiperazin-1-yl)pyridin-2-yl)-5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-1H-indole-1-carboxylate (400 mg, 53.5%). MS (ESI, pos. ion) m/z: 555.1 (M+1); 1H-NMR (DMSO-d6, 300 MHz) δ: 9.245 (1H, s), 8.45 (1H, s), 8.35 (1H, d), 8.07 (1H, d), 7.65 (1H, m), 7.4 (1H, d), 6.85 (1H, d), 3.7-3.8 (3H, s), 3.7 (2H, brs), 2.3 (3H, s), 1.75 (9H, s), 1.2-1.3 (6H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:9]=2[C:10]=1[CH:11]([CH3:13])[CH3:12])=[O:5])[CH3:2].[CH:19]([N:22]1[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]1)([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[C:16]([O:18][CH:25]3[CH2:26][CH2:27][N:22]([CH:19]([CH3:21])[CH3:20])[CH2:23][CH2:24]3)[CH:15]=[CH:14][C:9]=2[C:10]=1[CH:11]([CH3:13])[CH3:12])=[O:5])[CH3:2]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CCOC(=O)c1oc2cc(O)ccc2c1C(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cc(OC3CCN(C(C)C)CC3)ccc2c1C(C)C
Reaction time: 1 h
Yield: 119.7 %

Procedure:
The above prepared 6-hydroxy-3-isopropyl-benzofuran-2-carboxylic acid ethyl ester (0.400 g, 1.61 mmol) was dissolved in 8 mL of THF and treated successively at 0° C. with 1-isopropyl-piperidin-4-ol (0.461 g, 2 eq.), triphenylphosphine (0.845 g, 2 eq.) and DIAD (0.630 mL, 2 eq.), and the mixture then kept at ambient temperature for another 1 h. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=5/95), yielded 0.720 g of the title compound as light yellow oil, contaminated with tiny amounts of reduced DIAD.
Reaction SMILES: [CH2:1]([C:12]1[NH:13][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:21]([OH:23])=[O:22])[C:19]=2[CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].Cl(O)(=O)(=O)=O.[H][H]>[Pd].C(O)(=O)C>[CH2:1]([CH:12]1[CH2:20][C:19]2[C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=[CH:15][C:14]=2[NH:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: [H][H]
Reactant: CCCCCCCCCCCc1cc2c(C(=O)O)cccc2[nH]1
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Product: CCCCCCCCCCCC1Cc2c(cccc2C(=O)O)N1
Yield: 73.6 %

Procedure:
A mixture containing 2-(n-undecyl)indole-4-carboxylic acid (25.8 g), palladium on charcoal (5% w/w, 5.2 g), 72% w/v aqueous perchloric acid (26 ml) and glacial acetic acid (200 ml) was heated by external application of steam while being shaken under an atmosphere of hydrogen. When the required hydrogen had been taken up, the hot mixture was filtered through diatomaceous earth, the residue was washed with fresh hot glacial acetic acid (200 ml), and the combined filtrates were concentrated in vacuo to about 75 ml. The residue was poured onto crushed ice and water, and 50% w/v aqueous sodium hydroxide was added to pH 12. Acetic acid was added to pH B 4-5 and the product was collected by filtration and washed with water. Recrystallisation from methanol yielded (RS)-2-(n-undecyl)indoline-4-carboxylic acid (19.1 g) in the form of a buff solid, m.p. 105°-108° C.
Reaction SMILES: [F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[N:14]([C@H:17]([CH3:21])[C:18](O)=[O:19])[N:13]=[CH:12]2)=[CH:7][CH:6]=1.C(Cl)(=O)C([Cl:29])=O>CN(C)C=O.ClCCl>[F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[N:14]([C@H:17]([CH3:21])[C:18]([Cl:29])=[O:19])[N:13]=[CH:12]2)=[CH:7][CH:6]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H](C(=O)O)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H](C(=O)Cl)n1ncn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2R)-2-[4-[4-(2,2,3,3-Tetrafluoropropoxy)phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]propanoic acid (1.0 g) and 2.5 ml of oxalyl chloride were added to 20 ml of dichloromethane, to which dimethylformamide (5 drops) was added dropwise at room temperature. After the reaction solution was stirred at room temperature for 2 hours, the solvent was distilled off under reduced pressure to give 1 g of (2R)-2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-4,5-dihydro-5-oxo-1H-1,2,4-triazol-1-yl]propanoyl chloride as a pale yellow oil. This product was used for the next step without purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH2:8]Cl)=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:8][CH:7]=[CH:6][C:5]3[CH:10]=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Fc1ccc(C=CCCl)cc1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CC=Cc1ccc(F)cc1)CC2
Yield: 13 %

Procedure:
Prepared from 4-fluoro-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 13% of theory, Melting point: 142°-146° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:32])=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][C:11]([C:18]([F:27])([C:23]([F:26])([F:25])[F:24])[C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[Br:28])=[O:6].S(=O)(=O)(O)O.[CH2:38]=O.[OH-].[Na+]>>[Br:28][C:9]1[CH:10]=[C:11]([C:18]([F:27])([C:19]([F:20])([F:21])[F:22])[C:23]([F:24])([F:25])[F:26])[CH:12]=[C:13]([C:14]([F:16])([F:17])[F:15])[C:8]=1[NH:7][C:5](=[O:6])[C:4]1[CH:29]=[CH:30][CH:31]=[C:2]([NH:1][CH3:38])[C:3]=1[F:32]
Reactant: Nc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c1F
Reactant: C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CNc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2C(F)(F)F)c1F
Temperature: 0 °C
Yield: 72 %

Procedure:
0.930 g (1.71 mmol) of 3-amino-N-(2-bromo-4-(heptafluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-2-fluorobenzamide was added to 5 ml of concentrated sulfuric acid, and 10 ml of a 37% aqueous formaldehyde solution was charged dropwise thereto at 40° C. The reaction mixture was poured into ice-water, adjusted to pH 10 using an aqueous sodium hydroxide solution, and extracted with the addition of ethyl acetate. The organic layer was washed with a 20% aqueous sodium hydroxide solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent solvent; hexane:ethyl acetate=8:1) to prepare 0.690 g (yield 72%) of a target compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].Br[C:13]1[C:14]([CH3:38])=[C:15]([N:19]([CH2:23][C:24]2[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[C:26]([CH3:37])[CH:25]=2)[CH2:20][CH2:21][CH3:22])[CH:16]=[CH:17][CH:18]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N:19]([CH2:23][C:24]3[CH:36]=[CH:35][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[C:26]([CH3:37])[CH:25]=3)[CH2:20][CH2:21][CH3:22])[C:14]=2[CH3:38])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Product: CCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C#N)cc2)c1C

Procedure:
Prepared from 4-cyanophenylboronic acid and ethyl (4-{[(3-bromo-2-methylphenyl)(propyl)amino]methyl}-2-methylphenoxy)acetate using the procedure described for Example 25 (Method A).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([OH:24])[C@@H:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].[Br:31][C:32]1[CH:33]=[C:34]([CH2:41]Br)[C:35]2[O:39][CH:38]=[CH:37][C:36]=2[CH:40]=1>COCCOC.O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C@H:20]([O:24][CH2:41][C:34]2[C:35]3[O:39][CH:38]=[CH:37][C:36]=3[CH:40]=[C:32]([Br:31])[CH:33]=2)[C@@H:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: BrCc1cc(Br)cc2ccoc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)[C@@H]1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC[C@H](OCc2cc(Br)cc3ccoc23)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 48.5 %

Procedure:
Potassium bis(trimethylsilyl)amide (300 mg) was added to a stirred solution of [2S,3S]-N-tert-butoxycarbonyl-2-phenylpiperidine-3-ol (160 mg) in dry 1,2-dimethoxyethane (3.0 ml) under a dry nitrogen atmosphere. After 30 minutes 5-bromo-7-bromomethylbenzofuran (290 mg) was added, and the reaction stirred for 18 hours at room temperature. The resulting mixture was then diluted with water (50 ml), and extracted into ethyl acetate (2×50 ml). The organic layers were separated and washed with brine (20 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by MPLC (20% ethyl acetate/n-hexane), afforded [2S,3S]-1-tert-butoxycarbonyl-2-phenyl-3-[(5-bromobenzofuran-7-yl)methyloxy]piperidine as a yellow gum (136 mg). 1H NMR (360 MHz,CDCl3)δ1.43 (9H, s), 1.65 (2H, m), 1.92 (2H, m), 2.70 (1H, t d, J=7.2, 3.0 Hz), 3.74 (2H,m), 4.90 (2H, d, J=5.0 Hz), 5.74 (1H, br s), 6.71 (1H, d, J=1.0 Hz), 7.30-7.42 (4H, m), 7.58 (3H, m), 7.75 (1H, d, J=1.0 Hz); MS m/z CI+ 487 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:22]([C:24]1[N:29]=[C:28]2[CH2:30][O:31][C:32](=O)[C:27]2=[CH:26][CH:25]=1)=C.Cl>C1COCC1>[CH2:6]([N:7]([CH2:22][C:24]1[N:29]=[C:28]2[CH2:30][O:31][C:32](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:27]2=[CH:26][CH:25]=1)[CH2:8][CH3:4])[CH3:5]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: C=Cc1ccc2c(n1)COC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.1 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (3.38 g, 22.4 mmol.) in THF (100 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (45 mL of a 1 M solution in THF, 45 mmol) dropwise. The resulting solution is stirred at room temperature for 15 min and then treated with 2-vinyl-7H-furo[3,4-b]pyridin-5-one (1.2 g, 7.45 mmol) in one portion. The reaction mixture is stirred at room temperature for 2 h. The reaction mixture is poured into a cold aqueous 2 N HCl solution (200 mL). The ice bath is removed and the reaction mixture is heated at 50° C. for 2 h and then stirred at room temperature overnight. The reaction mixture is treated with 100 mL ice water and stirred for 30 min. The yellow solid is collected by filtration and dried. The solid is purified by chromatography (silica gel, MeOH-Chloroform) and the product containing fractions concentrated. The residue is triturated with MeOH and the solid is collected by filtration and dried to give 5-Fluoro-3-(2-vinyl-7H-furo[3,4-b]pyridin-5-ylidene)-1,3-dihydro-indol-2-one (Example 6) as an orange solid (0.82 g, 37%). The filtrate is absorbed to silica gel and subjected to chromatography (silica gel, EtOAc-hexane) to afford (Example 28) as a yellow solid (50 mg, 1.5%).