Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[O:12])=[N:9][CH:10]=1)[CH3:2].C1(C)C=CC(S([CH2:25][N+:26]#[C-:27])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:14]([O:13][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:12][CH:27]=[N:26][CH:25]=2)=[N:9][CH:10]=1)[CH3:15]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(OCC)c1ccc(C=O)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCOC(OCC)c1ccc(-c2cnco2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
In methanol (5 mL) was dissolved 5-(diethoxymethyl)picolinaldehyde (148 mg, 0.707 mmol) obtained in Step 1. To the solution were added toluene-4-sulfonylmethylisocyanide (345 mg, 1.77 mmol) and potassium carbonate (244 mg, 1.77 mmol) and the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture. Extraction with ethyl acetate, washing with saturated brine and drying over anhydrous sodium sulfate were performed. After filtration, the solvent in the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to give 5-(5-(diethoxymethyl)pyridin-2-yl)oxazole (161 mg, 92% yield).
Reaction SMILES: CN(C)C1C=CC=CC=1.[C:10]([O:13][CH2:14][C:15]1[N:29]=[C:18]2[N:19]=[C:20]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:21]=[C:22](O)[N:17]2[N:16]=1)(=[O:12])[CH3:11].C(Cl)(Cl)[Cl:31]>P(Cl)(Cl)(Cl)=O>[Cl:31][C:22]1[N:17]2[N:16]=[C:15]([CH2:14][O:13][C:10](=[O:12])[CH3:11])[N:29]=[C:18]2[N:19]=[C:20]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:21]=1
Reactant: CC(=O)OCc1cc(O)n2nc(COC(C)=O)nc2n1
Reactant: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)OCc1cc(Cl)n2nc(COC(C)=O)nc2n1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
In 300 ml of phosphorus oxychloride was added dropwise 28 ml of N,N-dimethylaniline, and 30.5 g of 2,5-bis(acetoxymethyl)-7-hydroxy-s-triazolo[1,5-a]pyrimidine was added to the mixture and the mixture was stirred at 50° C. for 1.5 hours. An oily residue obtained by removing phosphorus oxychloride was dissolved in 500 ml of chloroform and ice-cooled. After addition of crushed ice and water to the mixture and stirring thereof, a chloroform layer was separated, washed with water and dried over anhydrous magnesium sulfate. Then, the mixture was condensed. This was applied to a silica gel column chromatography (eluent: chloroform) and fractions containing the title compound were condensed to obtain 14 g of the title compound as an oily product.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5](Cl)=[CH:4][CH:3]=1>C(O)(=O)C.CO.[Pd]>[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCc2c(N)ccc(Cl)c2CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCc2cccc(N)c2CC1

Procedure:
9-Amino-6-chloro-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, prepared according to R. M. DeMarinis et al, J. Med. Chem., 1984, 27, 918, (0.190 g, 0.90 mmol) was dissolved in 10% acetic acid in methanol (50 ml) and 10% Pd/C (150 mg) added. The mixture was stirred at room temperature, under hydrogen/atmos pressure for 4h, then filtered through Kieselguhr and evaporated in vacuo. Residual material was taken up into dichloromethane and 5% NaHCO3 solution; the organic layer was washed with brine, dried (Na2SO4) and evaporated in vacuo to afford the title compound as a colourless oil (133 mg).
Reaction SMILES: [Cl:1][CH:2]([Cl:7])[C:3]([O:5][CH3:6])=[O:4].[CH3:8][O:9][C:10](=[O:13])[CH:11]=[CH2:12].C[O-].[Na+]>O>[Cl:1][C:2]([Cl:7])([CH2:12][CH2:11][C:10]([O:9][CH3:8])=[O:13])[C:3]([O:5][CH3:6])=[O:4]
Reactant: C=CC(=O)OC
Reactant: COC(=O)C(Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)CCC(Cl)(Cl)C(=O)OC
Reaction time: 2.5 h

Procedure:
In a 3000 liter reactor, methyl dichloroacetate and acrylic acid methyl ester are added. The stirring is controlled to start and a first controlled temperature is adjusted to 0-60° C. Then, sodium methoxide is added slowly to form a first reaction mixture. After the sodium methoxide is added, the first reaction mixture is stirred at the first controlled temperature for 1-4 hours. Subsequently, 100-300 liter of water is added to wash the first reaction mixture. The first reaction mixture is washed with water twice. The organic phase is then separated and distillation under reduced pressure is set to obtain dimethyl 2,2-dichloroglutarate.
Reaction SMILES: [F:1][C:2]1([F:34])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]([C:22]3[C:30]4[C:25](=[C:26]([CH2:31][S:32][CH3:33])[CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH:12]3C(=O)O[C:15](C)([CH3:19])[O:14][C:13]3=[O:21])=[CH:10][C:4]=2[O:3]1>N1C=CC=CC=1.C(O)C.[Cu]>[F:34][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]([C:22]3[C:30]4[C:25](=[C:26]([CH2:31][S:32][CH3:33])[CH:27]=[CH:28][CH:29]=4)[NH:24][CH:23]=3)[CH2:12][C:13]([O:14][CH2:15][CH3:19])=[O:21])=[CH:10][C:4]=2[O:3]1
Reactant: CSCc1cccc2c(C(c3ccc4c(c3)OC(F)(F)O4)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc2c(c1)OC(F)(F)O2)c1c[nH]c2c(CSC)cccc12

Procedure:
17 mg (271 μmol) of copper powder were added to a solution of 2.66 g (5.43 mmol) of the compound from Example 97A in 10 ml of pyridine and 2 ml of ethanol. The reaction mixture was heated under reflux for 4 h. It was concentrated, and the crude product was purified firstly by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) and then by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.73 g (74% of theory) of the title compound were obtained.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[C:12]([NH2:17])[CH:13]=[C:14]([CH3:16])[CH:15]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>ClCCl>[NH2:17][C:12]1[CH:11]=[C:10]([S:9][C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[CH:15]=[C:14]([CH3:16])[CH:13]=1
Reactant: COc1ccc(Sc2cc(C)cc(N)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(N)cc(Sc2ccc(O)cc2)c1

Procedure:
To the product from Example 181B (0.5 g, 2.0 mmol) in dichloromethane was treated with boron tribromide (10 mmol) at room temperature for 1 hour. The solution was the extracted with water, then the organic solution dried and concentrated to provide the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].Br[C:13]1[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=1>>[CH3:19][C:15]1[CH:14]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Cc1cccc(Br)c1
Product: Cc1cccc(-c2ccc(C=O)cc2)c1

Procedure:
Scheme 43, Example 1 depicts the coupling reaction of 4-formylbenzeneboronic acid 43.1 with 3-bromotoluene 43.9 to afford 3′-methylbiphenyl-4-aldehyde 43.10. The product is then reacted with N-bromosuccinimide, as described above, to afford the bromomethyl product 43.11. This material is reacted with a sodium dialkyl phosphonate 43.5 to afford the phosphonate ester 43.12.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][O:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.N[C:22]1C=CC=C(C(OC)=O)C=1OC[C@H](NC(OC(C)(C)C)=O)C(O)=O>>[CH3:22][C@H:7]1[O:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3][C:2](=[O:1])[C@H:8]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Reactant: COC(=O)c1cccc(N)c1OC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C[C@H]1Oc2ccccc2NC(=O)[C@H]1NC(=O)OC(C)(C)C
Yield: 46 %

Procedure:
In a similar manner to that described for the preparation of (S)-tert-butyl 4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-ylcarbamate except the crude product was purified by silica gel chromatography, (S)-3-(2-amino-6-(methoxycarbonyl)phenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (1.5 g, 4.83 mmol) was converted to the title compound (0.65 g, 46%) as a white solid.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C@:19]1([CH3:25])[CH2:23][O:22]C(=O)[NH:20]1)[CH:13]=[CH:12]2.C(O)C.O.[OH-].[Li+].O>>[NH2:20][C@@:19]([C:14]1[CH:13]=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][C@@H:2]3[CH2:3][C@@H:4]4[CH2:7][C@H:1]3[CH2:6][CH2:5]4)[CH:10]=2)[CH:15]=1)([CH3:25])[CH2:23][OH:22]
Reactant: C[C@@]1(c2ccc3cc(O[C@@H]4C[C@H]5CC[C@@H]4C5)ccc3c2)COC(=O)N1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[C@](N)(CO)c1ccc2cc(O[C@@H]3C[C@H]4CC[C@@H]3C4)ccc2c1
Yield: 34.3 %

Procedure:
The compound was prepared in a manner similar as to that described (R)-4-(6-((1R,2R,4S)-bicyclo[2.2.1]heptan-2-yloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (100 mg, 0.0003 mol), ethanol (2.2 g, 0.049 mol), 4.2 M lithium hydroxide, monohydrate in water (2.1 mL, 0.0090 mol) to give 32 mg of the desired product as a white solid (32%). ESI-MS: 339 (M−16)+. NMR (400 MHz, CDCl3) δ=7.94-7.61 (m, 3H), 7.50 (d, J=8.5 Hz, 1H), 7.23-7.05 (m, 2H), 4.33-4.17 (m, 1H), 3.84-3.51 (m, 2H), 2.49-0.78 (m, 13H).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[NH2:5].[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+].O>C(OCC)(=O)C>[Cl:2][CH2:3][CH:4]([NH:5][C:25](=[O:26])[C:24]1[C:23]([F:22])=[CH:31][CH:30]=[CH:29][C:28]=1[F:32])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: NC(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(CCl)c1ccc(-c2ccc(SC(F)F)cc2)cc1)c1c(F)cccc1F
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a slurry of 1.1 g of (+/-)-α-(chloromethyl)-4'-[(difluoromethyl)thio][1,1'-biphenyl]-4-methanamine hydrochloride in 13 mL of ethyl acetate was added 0.60 g of 2.6-difluorobenzoyl chloride. 0.60 g of sodium bicarbonate, and 3 mL of water. After 15 min, ethyl acetate was added and the organic phase was washed with aqueous NaCl, dried (MgSO4), filtered, and concentrated to dryness. The residue was triturated with toluene/hexanes, filtered, washed with hexanes, and suction-dried to afford 1.22 g of product, m.p. 148-150° C. 1H-NMR (CDCl3): δ4.0 (dq, 2H), 5.6 (m, 1H), 6.75 (br d, 1H), 6.85 (t, 1H, J=60 Hz), 7.0 (t, 2H), 7.4 (m, 1H), 7.5 (d, 2H), 7.6 (m, 6H).
Reaction SMILES: [H][H].[CH3:3][CH:4]([C:7]([CH3:12])([CH3:11])[CH2:8][C:9]#[N:10])[C:5]#[N:6].N>C(O)C>[CH3:3][CH:4]([C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][NH2:10])[CH2:5][NH2:6]
Reactant: [H][H]
Reactant: CC(C#N)C(C)(C)CC#N
Agent: N
Solvent: CCO
Product: CC(CN)C(C)(C)CCN
Temperature: 105 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
After scavenging with nitrogen and then with hydrogen, commercial hydrogen is introduced under a pressure of 170 atm and then the autoclave is heated to about 105° C. for six hours. Thereafter the autoclave is cooled, the pressure is released and the autoclave is charged with a solution of 68 grams of 2,3,3-trimethylglutaronitrile dissolved in 30 mls abs.ethanol, the scavenging with nitrogen is repeated, there are charged 160 grams of anhydrous ammonia and finally commercial hydrogen is introduced under a pressure of 165 atm approx. The autoclave, which is fitted with a magnetic stirrer, is heated to about 105° C.-108° C. the hydrogen pressure being restored as hydrogen is gradually being absorbed. After about 2 hrs. the pressure does not decrease any more and the above specified temperature is maintained for three additional hours, whereafter the autoclave is allowed to cool. The catalyst is filtered off, the solvent is distilled off and, on the raw production of the reaction, the yield in terms of 2,3,3-trimethyl pentamethylene diamine is determined by gaschromatographic methods in the presence of an internal standard (yield 65%-70%). The diamine is then purified by fractionation and, under a pressure of about 12 Torr. it boils at 105° C.-106° C.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([C:14]([NH2:16])=[O:15])=[CH:8][NH:9]2.[CH2:17]([S:21][C:22]1[N:27]=[C:26](Cl)[CH:25]=[CH:24][N:23]=1)[CH2:18][CH2:19][CH3:20]>CN(C=O)C>[CH2:17]([S:21][C:22]1[N:23]=[C:24]([N:9]2[C:10]3[C:6](=[C:5]([O:4][CH3:3])[CH:13]=[CH:12][CH:11]=3)[C:7]([C:14]([NH2:16])=[O:15])=[CH:8]2)[CH:25]=[CH:26][N:27]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCSc1nccc(Cl)n1
Reactant: COc1cccc2[nH]cc(C(N)=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCSc1nccc(-n2cc(C(N)=O)c3c(OC)cccc32)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
NaH (397 mg, 9.94 mmol, 60% dispersion) was added to a solution of 4-methoxy-1H-indole-3-carboxylic acid amide (1.575 g, 8.28 mmol) in dry DMF (5 mL) at 0° C., stirred for 20 min, and a solution of 2-butylsulfanyl-4-chloro-pyrimidine (1.846 g, 9.108 mmol) in DMF (4 mL) added at 0° C. The mixture was allowed to warm up to RT without stirring, whereupon a solid precipitated. Dry THF (20 mL) was added, and the mixture stirred overnight. Water was added to the mixture, and the resulting white solid was filtered off, washed with water (20 mL) and DCM (20 mL), and air-dried for 3 h to provide 1-(2-butylsulfanyl-pyrimidin-4-yl)-4-methoxy-1H-indole-3-carboxylic acid amide (2.916 g, 98.8% yield) as a crude solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=2)[NH:7][C:6](=[O:17])[CH:5]=1.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:26][CH:25]=2)[CH2:20][CH2:19]1.C(=O)([O-])O.[Na+].O>CN(C)C=O>[NH:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:2][CH2:3][C:4]3[C:13]4[C:8](=[CH:9][CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=4)[NH:7][C:6](=[O:17])[CH:5]=3)[CH2:19][CH2:20]2)=[CH:25]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=c1cc(CCBr)c2cc([N+](=O)[O-])ccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(CCN2CCC(c3c[nH]c4ccccc34)CC2)c2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 50 °C
Reaction time: 30 h
Yield: 51.2 %

Procedure:
A suspension of 4-(2-bromoethyl)-6-nitro-2(1H)-quinolinone (II-9) (891 mg, 3.0 mmol), 3-(4-piperidinyl)-1H-indol (600 mg, 3.0 mmol) and sodium hydrogen carbonate (378 mg, 4.5 mmol) in dimethylformamide (9 ml) was stirred at 50 ° C. for 30 hours. Then the reaction mixture was poured into water. The precipitated solid was filtered, washed with water, dried and recrystallized from a mixed solvent consisting of methanol, tetrahydrofuran and water to give the desired compound (III-19) (640 mg, yield 51.2%) as pale yellow crystals, mp 251°-253 ° C. (recrystallized from a mixture of methanol, tetrahydrofuran and water).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:17](I)[CH3:18]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:17][CH3:18])[C@@H:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCI
Reactant: COC(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN(C(=O)OC(C)(C)C)[C@@H](C)C(=O)OC
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 38.7 %

Procedure:
(S)-methyl 2-(tert-butoxycarbonylamino)propanoate (10.0 g, 49.2 mmol) was dissolved in THF (100 mL) and cooled to 0° C. under nitrogen. Sodium hydride (60% susp. in mineral oil, 3.00 g, 75.1 mmol) was added in portions over 2 min. The reaction mixture was stirred for 5 min at 0° C. and EtI (4.80 mL, 59.5 mmol) was added. It was allowed to warm to room temperature over the period of 1 h, stirred at room temperature overnight and at 70° C. for 7 d. The reaction mixture was cooled, filtered and concentrated in vacuo. The solid was triturated with hexanes (2×70 mL), the triturates were concentrated in vacuo and the residue was purified using flash column chromatography on silica gel (330 g SiO2, hexanes:ethyl acetate 19:1-9:1) to afford the title compounds as an oil (4.40 g, 39%). [M+H] calc'd for C11H21NO4, 232. found, 232.
Reaction SMILES: Br[C:2]1[C:11]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][C@@H:13]2[CH3:24])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:25]([O:27][CH3:28])=[O:26])[CH:8]=2)[N:3]=1.[CH3:29][C:30]1[NH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][C:35](B1OC(C)(C)C(C)(C)O1)=[CH:34][CH:33]=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:29][C:30]1[NH:31][C:32]2[C:37]([CH:38]=1)=[CH:36][C:35]([C:2]1[C:11]([N:12]3[CH2:17][CH2:16][N:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:14][C@@H:13]3[CH3:24])=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:25]([O:27][CH3:28])=[O:26])[CH:8]=3)[N:3]=1)=[CH:34][CH:33]=2
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Reactant: COC(=O)c1ccc2nc(Br)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4[nH]c(C)cc4c3)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To a solution of (S)-methyl 2-bromo-3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate (200 mg, 0.45 mmol) in dioxane (7 ml) was added 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (140 mg, 0.54 mmol), K3PO4 (190 mg, 0.90 mmol), and Pd(PPh3)4 (26 mg, 0.02 mmol). The resulting solution was stirred for 2 h at 90° C. Then the mixture was concentrated under vacuum, and the residue was purified via silica gel column chromatography (5% ethyl acetate in petroleum ether) to afford (S)-methyl 2-(2-methyl-1H-indol-5-yl)-3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate as a yellow solid (202 mg, 91%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([C:28]2[CH:45]=[CH:44][C:31]([O:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41](O)=[O:42])=[CH:35][CH:34]=3)=[CH:30][CH:29]=2)[C:23](=[O:27])[N:24]([CH3:26])[CH3:25])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([C:28]2[CH:45]=[CH:44][C:31]([O:32][C:33]3[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][C:41](=[O:42])[NH:1][CH2:2][C:3]([N:5]4[CH2:10][CH2:9][O:8][CH2:7][CH2:6]4)=[O:4])=[CH:35][CH:34]=3)=[CH:30][CH:29]=2)[C:23]([N:24]([CH3:26])[CH3:25])=[O:27])[CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1
Reactant: NCC(=O)N1CCOCC1
Reactant: COc1cc(C=C(C(=O)N(C)C)c2ccc(Oc3ccc(CCC(=O)O)cc3)cc2)cc(OC)c1
Product: COc1cc(C=C(C(=O)N(C)C)c2ccc(Oc3ccc(CCC(=O)NCC(=O)N4CCOCC4)cc3)cc2)cc(OC)c1

Procedure:
Following the general procedure for conversion of carboxylic acids to amides mentioned above and using 2-amino-1-morpholin-4-yl-ethanone as amine, 3-(4-{4-[2-(3,5-dimethoxyphenyl)-1-dimethylcarbamoylvinyl]-phenoxy}-phenyl)-propionic acid, 38, was converted to 63.
Reaction SMILES: Cl.C(OC([N:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[S:10]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:12])=[O:11])=O)CCC>CO>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][NH:9][S:10]([NH:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:11])=[O:12])=[CH:26][CH:25]=1
Reactant: CCCCOC(=O)N(Cc1ccc(OC)cc1)S(=O)(=O)NCC(=O)OCC
Agent: Cl
Solvent: CO
Product: CCOC(=O)CNS(=O)(=O)NCc1ccc(OC)cc1
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of HCl in methanol (2 M) was added ethyl 2-((N-(butyloxycarbonyl)-N-(p-methoxybenzyl)sulfamoyl)amino)acetate from the previous step (2.0 g, 5.0 mmol) in portions at RT and the mixture was stirred for 3 h. After the solvent was removed in vacuo, the residue was washed with diethyl ether to afford ethyl 2-((N-(p-methoxybenzyl)sulfamoyl)amino)acetate (1.0 g, 70%). 1H-NMR (DMSO-d6): δ 7.43 (t, J=6.0 Hz, 1H), 7.287 (t, J=6.4 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 3.94 (d, J=4.8 Hz, 2H), 3.71 (s, 3H), 3.64 (d, J=6.0 Hz, 2H), 3.62 (s, 3H),
Reaction SMILES: CS([O:5][C@@:6]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[NH2:23])([C:11]#[C:12][CH:13]1[CH2:15][CH2:14]1)[C:7]([F:10])([F:9])[F:8])(=O)=O.[OH-].[Na+].[C:26]([O-])([O-])=[O:27].[Na+].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>>[CH:13]1([C:12]#[C:11][C@:6]2([C:7]([F:10])([F:9])[F:8])[C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[NH:23][C:26](=[O:27])[O:5]2)[CH2:15][CH2:14]1
Reactant: CS(=O)(=O)O[C@](C#CC1CC1)(c1cc(F)ccc1N)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1Nc2ccc(F)cc2[C@](C#CC2CC2)(C(F)(F)F)O1
Temperature: 15 °C
Reaction time: 0.08 h

Procedure:
(R)-2-(2-Amino-5-fluorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol methanesulfonate (CN46619-MSA) of example 4 (14.0 g, 33.5 mmol) in ethyl acetate/heptanes (40 g, 6/4 v/v) was charged to a jacketed 150 mL-reactor with agitator and off-gas scrubber with caustic soda. After addition of aqueous Na2CO3 (12%-w/w, 26.9 g, 30.3 mmol) the mixture was stirred for 5 min at 15° C. The aqueous phase was separated and discarded. Aqueous Na2CO3 (12%-w/w, 34.1 g, 38.4 mmol) was charged to the organic phase, then triphosgene (3.73 g, 12.6 mmol) was added in portions over a period of 25 min at 10° C. The reaction mixture was stirred for 2 h at 8° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCOc1cccc2nccn12
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCOc1cccc2nccn12

Procedure:
Using 1.65 g (8.0 mmol) of 5-(4-hydroxybutyloxy)-imidazo[1,2-a]pyridine, 1.23 ml (8.8 mmol) of triethylamine and 0.68 ml (8.8 mmol) of methanesulfonyl chloride, the same procedure as in Reference Example 8 was followed, to yield 5-(4-methanesulfonyloxybutyloxy)imidazo[1,2-a]pyridine.
Reaction SMILES: [F:1][C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]2[S:9][C:8]([NH2:10])=[N:7][C:6]=2[CH:11]=1.Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH:16]1([CH2:15][NH:10][C:8]2[S:9][C:5]3[CH:4]=[C:3]([O:12][CH3:13])[C:2]([F:1])=[CH:11][C:6]=3[N:7]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: BrCC1CCCCC1
Reactant: COc1cc2sc(N)nc2cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc2sc(NCC3CCCCC3)nc2cc1F
Temperature: 80 °C
Reaction time: 24 h
Yield: 59.8 %

Procedure:
To the solution of 5-fluoro-6-methoxybenzo[d]thiazol-2-amine (350 mg, 1.76 mmol, 1.0 eq) in 2 mL of NMP was added bromomethyl cyclohexane (370 μL, 2.65 mmol, 1.5 eq) and potassium carbonate (366 mg, 2.65 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred at 80° C. for 24 hours with subsequent addition of reagents till reaction completion and thereafter quenched with saturated sodium bicarbonate solution (100 mL) which was then extracted with ethyl acetate (125 mL×3), combined organic layers dried over sodium sulfate, filtered and condensed under reduced pressure. Purification of the crude over ISCO using slow gradient of 0%-50% ethyl acetate-hexane gave 310 mg of product in 60% yield. LC/MS (m/z) [295.1] (MH+)