Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[O:7])=[CH:4][CH:3]=1>C(O)=O>[ClH:1].[NH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(Cl)cc1
Solvent: O=CO
Product: Cl
Product: NCCNC(=O)c1ccc(Cl)cc1
Reaction time: 1.5 h
Yield: 190.6 %

Procedure:
A solution of 2.8 g of t-butyl [2-(4-chlorobenzamido)ethyl]carbamate in 50 ml of formic acid is left to stand at room temperature for 1.5 hours. The mixture is then concentrated to dryness, and the residue is dissolved in 50 ml of hydrochloric acid(l:l; volume/volume). The solution is concentrated, the residue is evaporated twice with ethanol/benzene and then recrystallized from ethanol. There are obtained 2.1 g of N-(2-aminoethyl)-4-chlorobenzamide hydrochloride which is identical with the product obtained in Example 1.
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[O:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][O:11]2)=[CH:6][CH:5]=1.C([Li])CCC.C1(O[C:33]#[N:34])C=CC=CC=1.O>O1CCCC1.CCCCCC>[CH2:16]([C@@H:13]1[CH2:14][O:15][C@@H:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]#[C:2][C:33]#[N:34])=[CH:5][CH:6]=2)[O:11][CH2:12]1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCC[C@H]1CO[C@H](c2ccc(C=C(Br)Br)cc2)OC1
Reactant: N#COc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@H]1CO[C@H](c2ccc(C#CC#N)cc2)OC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 3.5 g of trans-2-[p-(2,2-dibromovinyl)phenyl]-5-butyl-1,3-dioxane in 80 ml of absolute tetrahydrofuran was placed at -78° C. in a sulphonation flask under argon gasification and treated within 5 minutes with 13.4 ml of a 1.2N solution of butyl lithium in hexane. After completion of the addition, the mixture was held at -10° C. for 1 hour, then again cooled to -78° C. and treated with 1.2 ml of phenyl cyanate within 5 minutes. The mixture was stirred at -78° C. for a further 30 minutes, then poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed with 100 ml of water and 100 ml of saturated sodium chloride solution, dried over potassium carbonate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (3.26 g) on silica gel with petroleum ether/ethyl acetate/triethylamine (97:3:0.2) gave 1.18 g (50%) of p-(trans-5-butyl-1,3-dioxan-2-yl)phenylpropiolonitrile (purity 98.7%). A recrystallization from 50 ml of hexane yielded 1.03 g of the nitrile as colourless crystals (purity 99.7%); m.p. (C-N) 54.3° C., cl.p. (N-I) 108.7° C.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:5]=1[C:6](Cl)=[O:7]>C(Cl)(Cl)Cl>[Cl:3][C:4]1[C:12]([Cl:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:5]=1[C:6]([NH:1][NH2:2])=[O:7]
Reactant: O=C(Cl)c1c(Cl)ccc(Cl)c1Cl
Reactant: NN
Solvent: ClC(Cl)Cl
Product: NNC(=O)c1c(Cl)ccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.22 mol. hydrazine in 100 ml. chloroform at -10° C. was added 0.1 mol of 2,3,6-trichlorobenzoyl chloride. The mixture was stirred at ambient temperature for 2 hours, filtered, and the filtrate evaporated in vacuo. The residue was crystallized from methanol and water, then recrystallized from chloroform and hexane to obtain the titled product.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].C(OCC)(=O)C.[CH2:15]([O:22][C:23]([N:25]1[CH2:29][C:28](O)=[CH:27][C:26]1=[O:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[ClH:32]>C(O)C>[ClH:32].[CH2:15]([O:22][C:23]([N:25]1[CH2:29][C:28]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH2:8])=[CH:27][C:26]1=[O:31])=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: O=C1C=C(O)CN1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: N[C@@H]1CCCC[C@H]1NC1=CC(=O)N(C(=O)OCc2ccccc2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
(1R,2R)-1,2-diaminocyclohexane 2294 g (20.09 mol) was dissolved in 3.1 L of ethanol to make a solution. To a 100 L glass lined reactor equipped with a stirrer, were added 26.8 L of ethyl acetate, 4635 g of 4-hydroxy-2-oxo-3-pyrroline-1-carboxylic acid benzyl ester (content: 96.2%, 19.12 mol) synthesized according to the methods of Non-Patent Reference 9 and 12.5 L of ethanol, furthermore, a previously prepared ethanol solution of (1R,2R)-1,2-diaminocyclohexane was added at 15 to 21° C. For washing, 2.2 L of ethanol was used. Next, 3.35 L of 6M hydrochloric acid (20.1 mol) was added at 19 to 25° C. For washing, 0.3 L of water was used. The reaction mixture was heated to 60° C., and reacted at the same temperature for 3 hours. While holding the temperature at approximately 60° C., 4.4 L of ethyl acetate was added, the mixture was cooled to 50° C., 2.4 g of seed crystal was added, and the solution was kept at 50° C. for one hour. While holding the temperature at approximately 50° C., 22.3 L of ethyl acetate was added over one hour, the solution was kept at 50° C. for one hour, cooling to 10° C. over 4.6 hours, and kept at 10° C. for another 10 hours. The deposited solid was separated with a centrifuge, and washed with 17.8 L of a cooled mixed solution of ethyl acetate-ethanol (volume ratio: 75:25). The obtained wet solid was dried under reduced pressure at 50° C. for 19 hours to obtain 6342 g of 4-[(1R,2R)-2-aminocyclohexylamino]-2-oxo-3-pyrroline-1-carboxylic acid benzyl ester hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C@H:9]([NH:14][C:15](=O)[C:16](F)(F)F)[C:10]2=[O:13])=[CH:6][CH:5]=1)[CH3:2].[BH4-].[Na+].[O-]P([O-])([O-])=O.[Na+].[Na+].[Na+].[CH2:31](Br)[CH2:32][CH3:33].[CH2:35](O)C>>[CH2:15]([N:14]([CH2:31][CH2:32][CH3:33])[C@H:9]1[CH2:8][C:7]2[C:11](=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[C@@H:10]1[OH:13])[CH2:16][CH3:35]
Reactant: CCOc1ccc2c(c1)C(=O)[C@@H](NC(=O)C(F)(F)F)C2
Reactant: CCCBr
Reactant: CCO
Agent: O=P([O-])([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Product: CCCN(CCC)[C@H]1Cc2ccc(OCC)cc2[C@@H]1O
Reaction time: 48 h

Procedure:
N-[(2S)-6-Ethoxy-2,3-dihydro-1-oxo-1H-inden-2-yl]-2,2,2-trifluoroacetamide (V, EXAMPLE 4, 4.13 g, 15 mmol) is suspended in ethanol (45 ml) and cooled to −15°. Sodium borohydride (2.83 g, 75 mmol, 5 equiv.) is added and the reaction mixture gradually warmed to 20-25° overnight. The reaction mixture is concentrated to dryness and then suspended in acetonitrile (105 ml). Sodium phosphate tribasic (8.12 g, 49.5 mmol, 3.3 equivalents) is added and the mixture heated to 40°. n-Propylbromide (12.26 ml, 135 mmol, 9 equivalents) is added and reaction is heated to 65°. Heating is continued for 48 hr. The reaction mixture is filtered and the filtrate concentrated. The concentrate is partitioned in methyl t-butyl ether (100 ml) and sodium hydroxide (1 M, 50 ml). The organic layer is collected and acidified with hydrochloric acid (3 M, 50 ml). The aqueous phase is collected and the pH is adjusted to 13 using sodium hydroxide (50%, 25 ml). The product is extracted into methyl t-butyl ether (100 ml) and concentrated to give the title compound. TLC Rf=0.9 (ammonium hydroxide/methanolnmethylene chloride. 1.5/13.5/85); NMR δ7.04, 6.90, 6.79, 5.04, 4.01, 3.39, 2.87, 2.72, 2.59-2.48, 1.54-1.48, 1.39 and 0.90; CMR δ158.4, 144.2, 131.5, 125.6, 115.4, 109.2, 77.3, 73.2, 63.6, 53.6, 29.9, 21.1, 14.8, 11.9; MS (CI, NH3) m/z (relative intensity) 278 (100), 248 (70), 236 (20).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]#[C:13][C:14]([OH:16])=[O:15].[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][N:18]1[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][C:31]=1[O:37][CH3:38]>ClCCl.CO>[CH:14]([OH:16])=[O:15].[CH2:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][N:18]1[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:14](=[O:16])[C:13]#[C:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])=[CH:32][C:31]=1[O:37][CH3:38]
Reactant: O=C(O)C#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1cc(N)ccc1OCCN1CCc2ccccc2C1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(NC(=O)C#Cc2ccc(C(F)(F)F)cc2Cl)ccc1OCCN1CCc2ccccc2C1
Product: O=CO

Procedure:
Prepared analogously to Example 2.3.f. from 150 mg (0.6 mmol) of (2-chloro-4-trifluoromethylphenyl)propynoic acid and 304 mg (0.66 mmol) of 4-[2-(3,4-dihydro-1H-isoquinolin-2-yl)ethoxy]-3-methoxyphenylamine (65%). Yield: 17 mg (5% of theory); melting point: 92° C.-95° C.; C28H24ClF3N2O3 (M=528.96)*CH2O2; calc.: molecular ion peak (M+H)+: 529/531 (Cl); found: molecular ion peak (M+H)+: 529/531 (Cl); Rf value: 0.55 (silica gel, dichloromethane/methanol (9:1)).
Reaction SMILES: [CH2:1]([C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[CH:28]=[C:29](I)[S:30][C:23]=34)=[C:17]([F:32])[CH:16]=2)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]#[CH:42])[CH2:36][CH2:35]1.C(N(CC)CC)C>C1COCC1.[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>[CH2:1]([C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[CH:28]=[C:29]([C:42]#[C:41][CH2:40][N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)[S:30][C:23]=34)=[C:17]([F:32])[CH:16]=2)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(Cc2ccccc2)ncc1-c1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CCN1CCN(C)CC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(-c5cnc(Cc6ccccc6)[nH]c5=O)cc4F)c3s2)CC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 83.3 %

Procedure:
A mixture of 2-benzyl-5-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)pyrimidin-4(3H)-one (8.0 mg, 0.014 mmol), 1-methyl-4-(prop-2-ynyl)piperazine (Example 17, Step A; 5.0 mg, 0.036 mmol), copper(I) iodide (0.1 mg, 0.0007 mmol), and triethylamine (0.020 ml, 0.14 mmol) in THF (0.5 mL) was sparged with N2 for 5 minutes, and then Pd(PPh3)4 (1.0 mg, 0.0007 mmol) was added. The sealed reaction was stirred at 50° C. for 3 hours. The reaction mixture was purified directly by silica gel chromatography, eluting with 10:1 dichloromethane/methanol. The desired product (6.6 mg, 81%) was obtained as a pale yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 8.58 (d, J=5.5 Hz, 1H), 8.29 (s, 1H), 7.93 (dd, J=1.9, 12.5 Hz, 1H), 7.81 (s, 1H), 7.74 (m, 1H), 7.54 (t, J=8.6 Hz, 1H), 7.39-7.32 (m, 4H), 7.29-7.24 (m, 1H), 6.76 (d, J=5.1 Hz, 1H), 3.94 (s, 2H), 3.68 (s, 2H), 2.55-2.46 (m, 8H), 1.23 (s, 3H). LRMS (ESI pos) m/e 566 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=O)[CH:3]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.CC(OO)=O.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:10])[CH:3]=1
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(=O)OO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: N#Cc1cc(Cl)ccn1
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
4-Chloro-2-pyridinecarboxamide (93.9 g, 0.6 moles) and TEA (125′ mL, 0.9 moles) in EtOAc (500 mL) was cooled to 0.2° C. via an external chiller unit. TFAA (92 mL, 0.66 moles) was added via addition funnel over 40 min. The internal temperature rose to 10° C. during the addition. The temperature at the completion of the addition was 0.0° C. After addition, the chiller was turned off. After an additional 30 min, HPLC analysis showed 4.3% (LCAP) of the starting material. An additional 8.3 mL (0.06 moles) of TFAA was added. After stirring the reaction mixture for an additional 20 min, HPLC analysis indicated complete conversion. 10% Aqueous K2CO3 (w/v, 500 mL) was added. The internal temperature rose from 13.7 to 22.0° C. The mixture was transferred to a separatory funnel after stirring for 20 min. The layers were separated and the aqueous layer extracted with EtOAc (150 mL). The combined organic layers were washed with 10% aqueous citric acid (w/v, 300 mL), dried (Na2SO4), filtered, and concentrated. The crude product was dried in a vacuum oven at 50° C. for 16 h to afford 72.85 g (87%) of the title compound: 1H NMR (400 MHz, CDCl3) δ 8.6 (m, 1H), 7.7 (m, 1H), 7.5 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 151.8, 145.3, 134.9, 128.7, 127.4, 116.1; HPLC>99% (LCAP).
Reaction SMILES: [C:1]1([C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].[H-].[Na+].Cl>COCCOC.O>[C:1]1([C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH2:14][C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(=O)c1cccc2ccccc12
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(=O)CC(=O)CC(=O)c1cccc2ccccc12

Procedure:
A solution of 1-(1-naphthalenyl)-1,3-butanedione (5.3 g) and diethyl oxalate (6.75 ml) in 1,2-dimethoxyethane (10 ml) was added dropwise to a stirred suspension of sodium hydride (3.6 g, 50% dispersion in mineral oil, washed with petrol 40°-60° C.) in 1,2-dimethoxyethane (40 ml) under nitrogen. The stirred mixture was heated under reflux for 5 minutes, cooled, acidified with 2M hydrochloric acid (50 ml), diluted with water (50 ml) and filtered. The filtrate was extracted with ethyl acetate and the extract was dried and evaporated to yield ethyl 6-(1-naphthalenyl)-2,4,6-trioxohexanoate as a dark oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=1[O:10][CH3:11].Cl.Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[N:14]1[CH:19]=[CH:18][CH:17]=[N:16][C:15]=1[N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:4]=2[O:10][CH3:11])[CH2:22][CH2:21]1
Reactant: COc1ccc(Br)cc1CCl
Reactant: c1cnc(N2CCNCC2)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)cc1CN1CCN(c2ncccn2)CC1
Temperature: 25 °C
Yield: 235 %

Procedure:
A mixture of 1.1 g of 2-(chloromethyl)-4-bromoanisole, 1 g of 1-(2-pyrimidyl)piperazine dihydrochloride and 2.0 mL N,N-diisopropylethylamine in 10 mL chloroform was heated at reflux temperature for 2 hr, cooled to room temperature, washed with 1N NaOH and water. The solvent was removed by evaporation under reduced pressure to yield 3.6 g of 2-[(4-(2-pyrimidinyl)-piperazinyl)methyl]-4-bromoanisole as a white solid which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:21][C:22]([F:25])([F:24])[F:23])[S:10]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])(=[O:12])=[O:11])=[C:4]([F:26])[CH:3]=1.[H-].[Na+].I[CH3:30].O>CN(C)C(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:21][C:22]([F:23])([F:24])[F:25])[S:10]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH3:30])[CH3:14])(=[O:12])=[O:11])=[C:4]([F:26])[CH:3]=1
Reactant: CI
Reactant: CC(c1ccccc1)S(=O)(=O)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(c1ccccc1)S(=O)(=O)N(Cc1ccc(Br)cc1F)CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.4 %

Procedure:
To a solution of N-[(4-bromo-2-fluoro-phenyl)methyl]-1-phenyl-N-(2,2,2-trifluoroethyl)ethanesulfonamide (307 mg, 0.67 mmol) in N,N-dimethylacetamide (5 mL) was added sodium hydride (60% in mineral oil) (33 mg, 0.81 mmol) and the reaction was stirred at ambient temperature for 1 hour. Iodomethane (0.063 mL, 1.0 mmol) was then added and the reaction was stirred at 75° C. for 16 hours. LCMS analysis showed a 1:1 mixture of starting material and product. Water was added and the reaction was diluted with EtOAc, washed with brine (×2), dried with MgSO4, concentrated an purified by silica gel column chromatography (0-10% EtOAc in heptane) to give 249 mg of an inseparable mixture of starting material and product. The mixture was used for the next step. LCMS (m/z) ES+ 471 [M+18]+ (starting material); LCMS (m/z) ES+ 485 [M+18]+ (product).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19]Cl)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[N:22]1.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]([C:30]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[O:31])=[N:22]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][N:22]4[C:23]([C:30]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[O:31])=[C:24]5[C:29]([CH:28]=[CH:27][CH:26]=[CH:25]5)=[N:21]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCl)ccc3o2)n1
Reactant: O=C(OCc1ccccc1)c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4nc(C(=O)OCc5ccccc5)c5ccccc54)ccc3o2)n1
Product: CC(C)(C)c1csc(-c2cc3cc(Cn4nc5ccccc5c4C(=O)OCc4ccccc4)ccc3o2)n1
Temperature: 25 °C

Procedure:
A mixture of 4-tert-butyl-2-[5-(chloromethyl)benzofuran-2-yl]thiazole (0.36 g), benzyl indazole-3-carboxylate (0.30 g) and potassium carbonate (0.33 g) in methylethylketone (20 ml) was stirred under reflux for 7 hours. After being cooled to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing the objective compounds were combined and concentrated under reduced pressure to give benzyl 1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-1H-indazole-3-carboxylate (0.40 g) and benzyl 2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}-2H-indazole-3-carboxylate (0.12 g).
Reaction SMILES: [H-].[Na+].CN1C(=O)N(C)CCC1.[CH2:12]([OH:17])[C:13]#[C:14][CH2:15][OH:16].[CH:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:31]2[C:36]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)=[C:35](Cl)[N:34]=[C:33]([C:45]3[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=3)[N:32]=2)(=[O:29])=[O:28])=[N:25][CH:26]=1)([CH3:20])[CH3:19]>CN(C=O)C>[CH:18]([C:21]1[CH:22]=[CH:23][C:24]([S:27]([NH:30][C:31]2[C:36]([C:37]3[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=3)=[C:35]([O:16][CH2:15][C:14]#[C:13][CH2:12][OH:17])[N:34]=[C:33]([C:45]3[CH:46]=[CH:47][N:48]=[CH:49][CH:50]=3)[N:32]=2)(=[O:28])=[O:29])=[N:25][CH:26]=1)([CH3:20])[CH3:19]
Reactant: Cc1ccc(-c2c(Cl)nc(-c3ccncc3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)cc1
Reactant: OCC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)C)cn3)nc(-c3ccncc3)nc2OCC#CCO)cc1

Procedure:
To a slurry of 0.34 g of sodium hydride in 15 ml of DMF and 4 ml of DMPU 2.4 g of 2-butyne-1,4-diol was added at room temperature. The mixture was stirred until no more gas evolved. Then 0.67 g of 5-isopropyl-N-[6-chloro-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was added and the mixture was stirred at 90° C. for 48 h. The solvent was removed in vacuo and the residue was taken up in 100 ml of 10% aqueous acetic acid. The mixture was extracted three times with 100 ml of ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSO4 and evaporated. The resulting brown oil was purified by column chromatography on silica gel eluting with DCM containing 4-10% of methanol. This furnished a fraction which after recrystallisation from DCM: ethyl acetate gave 43 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide as pale yellow crystals. A second fraction gave 456 mg of 5-isopropyl-N-[6-(4-hydroxy-2-butynyloxy)-5-(p-tolyl)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide with about 90% purity as a brown oil. LC-MS: tR=4.53 min, [M+1]+=530.23, [M−1]−=528.21.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]([F:40])([F:39])[C:15]1[CH:16]=[C:17]([C:25]#[C:26][CH2:27][N:28]2[CH2:33][CH2:32][CH:31]([C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])[CH2:30][CH2:29]2)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1>O1CCCC1>[F:22][C:21]([F:24])([F:23])[C:19]1[CH:18]=[C:17]([C:25]#[C:26][CH2:27][N:28]2[CH2:29][CH2:30][CH:31]([C:34]([CH3:37])([CH3:38])[CH2:35][O:36][S:9]([CH3:8])(=[O:11])=[O:10])[CH2:32][CH2:33]2)[CH:16]=[C:15]([C:14]([F:39])([F:13])[F:40])[CH:20]=1
Reactant: CC(C)(CO)C1CCN(CC#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(COS(C)(=O)=O)C1CCN(CC#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reaction time: 5 h
Yield: 67.1 %

Procedure:
Triethylamine (0.75 g), followed by methylsulphonyl chloride (0.85 g) were added to a solution of 1-(3,5-bistrifluoromethylphenyl)-3-[4-(1,1-dimethyl-2-hydroxyethyl)piperidino]-prop-1-yne (3.0 g) in tetrahydrofuran (50 ml). After stirring for 5 hours, the precipitate of triethylamine hydrochloride was filtered off, and the filtrate was evaporated in vacuo to give a brown gum. This gum was purified by medium pressure chromatography using a mixture of dichloromethane and ethyl acetate (85:15) as eluent to give 1-(3,5-bistrifluoromethylphenyl)-3-[4-(1,1-dimethyl-2-methylsulphonyloxyethyl)piperidino]prop-1-yne (2.4 g) as a colourless gum.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9]C(=O)OCC2C=CC=CC=2)=[N:7][CH:8]=1)[CH3:2].[H][H]>C(O)C.[Pd]>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][N:7]=1
Reactant: [H][H]
Reactant: CCc1ccc(NC(=O)OCc2ccccc2)nc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(N)nc1
Reaction time: 2 h
Yield: 99.2 %

Procedure:
A suspension of benzyl (5-ethyl-2-pyridyl)carbamate (1.9 g., 7.43 mmoles) and 10% palladium-on-carbon (0.4 g.) in ethanol (100 ml.) was shaken with hydrogen at a pressure of 3.5 kg./cm2 for 2 hours. The catalyst was removed by filtration and the filtrate concentrated to yield 2-amino-5-ethylpyridine (0.9 g., 99.4%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][CH2:18][CH:17]3[C:23]([O:25]CC2C=CC([N+]([O-])=O)=CC=2)=[O:24])(=[O:13])=[O:12])[CH2:8][CH2:7][N:6]1[C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][N:37]=1)=[O:4].C1CCC=CC=1.C(O)C>[Pd].CO>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][N:9]([S:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[CH2:19][CH2:18][CH:17]3[C:23]([OH:25])=[O:24])(=[O:13])=[O:12])[CH2:8][CH2:7][N:6]1[C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:44])([F:43])[F:45])=[CH:38][N:37]=1)=[O:4]
Reactant: COC(=O)C1CN(S(=O)(=O)c2ccc3c(c2)C(C(=O)OCc2ccc([N+](=O)[O-])cc2)CC3)CCN1c1ccc(C(F)(F)F)cn1
Agent: [Pd]
Solvent: CO
Solvent: C1=CCCC=C1
Solvent: CCO
Product: COC(=O)[C@H]1CN(S(=O)(=O)c2ccc3c(c2)C(C(=O)O)CC3)CCN1c1ccc(C(F)(F)F)cn1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
4-[3-(4-Nitro-benzyloxycarbonyl)-indane-5-sulfonyl]-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylic acid methyl ester (87 mg, 0.14 mmol) obtained from step 4 was combined with 10% Pd/C (75 mg), cyclohexadiene (260 μL, 2.8 mmol) and 2.0 mL of ethanol within an 8 mL Teflon-capped vial. This mixture was stirred at 70° C. for 6 h and then passed through a Celite plug (with MeOH washings). The resulting filtrate was evaporated in vacuo, and the crude residue was purified using flash silica chromatography (0-10% MeOH/CH2Cl2) to yield (R)-4-(3-Carboxy-indane-5-sulfonyl)-1-(5-trifluoromethyl-pyridin-2-yl)-piperazine-2-carboxylic acid methyl ester. 1H NMR (400 MHz, CD3OD) δ 8.37 (m, 1H), 7.85 (s, 1H), 7.80 (d, 1H), 7.69 (d, 1H), 7.52 (d, 1H), 6.94 (d, 1H), 5.55 (m, 1H), 4.33-4.29 (m, 1H), 4.20-4.11 (m, 2H), 3.84-3.81 (m, 1H), 3.74 (s, 3H), 3.47-3.41 (m, 1H), 3.20-3.14 (m, 1H), 3.07-2.99 (m, 1H), 2.65-2.61 (m, 1H), 2.51-2.42 (m, 3H). ESMS (M+H): 514.0