Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH2:39][C:40](O)=[O:41])=[CH:31]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[CH2:1]([C@@H:8]1[CH2:13][N:12]([C:40](=[O:41])[CH2:39][C:32]2[C:33]3[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=3)[NH:30][CH:31]=2)[CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccccc1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1c[nH]c2ccccc12)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccccc2)C1
Reaction time: 5 h
Yield: 82.3 %

Procedure:
To a stirred mixture of (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]piperazine (0.3 g) and 2-(1H-indol-3-yl)acetic acid (0.13 g) in dichloromethane (8 ml) containing triethylamine (0.25 ml) was added 2-chloro-1-methylpyridinium iodide (0.22 g) at room temperature under nitrogen atmosphere. After being stirred for 5 hours, the reaction mixture was diluted with dichloromethane and washed with 0.1N hydrochloric acid, aqueous saturated sodium bicarbonate solution and brine, and dried over magnesium sulfate. After removal of the solvent, the residue was purified by column chromatography on silica gel using chloroform-methanol (50:1) as eluent to give (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[2-(1H-indol-3-yl)acetyl]piperazine (0.34 g) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C.[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)ccc1-c1ccccc1
Yield: 95.4 %

Procedure:
2-Methyl-4-nitro-1-phenylbenzene (12.7 gm, 60 mmol) was dissolved in ethanol (260 mL) and hydrogenated over 10% palladium on charcoal (1.27gm) at 3 bar and 20° C. for 2 h. The mixture was filtered through Arbocel filter aid, washing with ethyl acetate. The filtrate was concentrated under reduced pressure to give 4-amino-2-methyl-1-phenylbenzene (10.49 gm, 95%) as a pinkish brown oil.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[C:14](=[O:27])[CH2:15][C@H:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[C:17]([OH:19])=[O:18].C(N1C=CN=C1)(N1C=CN=C1)=O.N12CCCN=C1CCCCC2.[C:51](O)([CH3:54])([CH3:53])[CH3:52]>CCOCC.CN(C=O)C>[C:51]([O:18][C:17](=[O:19])[C@@H:16]([NH:20][C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:15][C:14]([C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[C:9]=2[CH:1]=1)=[O:27])([CH3:54])([CH3:53])[CH3:52]
Reactant: O=C(C[C@H](NC(=O)C(F)(F)F)C(=O)O)c1ccc2oc3ccccc3c2c1
Reactant: CC(C)(C)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)[C@H](CC(=O)c1ccc2oc3ccccc3c2c1)NC(=O)C(F)(F)F
Temperature: 24 °C
Reaction time: 1 h

Procedure:
To a DMF solution (10 mL) of (S)-4-dibenzofuran-2-yl-4-oxo-2-(2,2,2-trifluoroacetylamino)-butyric acid (0.3 g, 0.00079 mol) at 40° C. was added carbonyldimidazole (0.13 g, 0.00079 mol). This mixture was stirred for 1 hour and then 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU, 0.12 mL, 0.00079 mol) and t-butanol (0.15 mL, 0.00158 mol) were added. The reaction mixture was stirred for 24 hours at 40° C., cooled to 24° C., and then diluted with ether (20 mL). The solution was washed with water (2×10 mL), brine (2×10 mL), and dried over anhydrous magnesium sulfate. The mixture was filtered and the filtrate was concentrated to an oil by evaporation of the solvent in vacuo. The oil was flash chromatographed on silica gel eluting with 20% ethyl acetate/hexane (v/v) to yield the title compound; mp 92-94° C.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.[N-:12]=[N+]=[N-].[Na+]>OS(O)(=O)=O.C(Cl)Cl>[NH:12]1[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:2][CH2:1][CH2:11][C:9]1=[O:10]
Reactant: O=C1CCCc2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C1CCCc2ccccc2N1

Procedure:
A sample of alpha tetralone (Aldrich, 36.5 g, 0.25 mol) was converted to the title material by the method of EXAMPLE 50 using 19.5 g (0.3 mol) of sodium azide in a mixture of 300 mL of conc H2SO4 and 100 mL of CH2Cl2. This procedure yielded after recrystalization from EtOH 12.1 g (30%) of the title product.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[C@H:69]12[CH2:75][C@H:72]([CH2:73][CH2:74]1)[C@@H:71]([C:76]1[NH:77][C:78]([C:81]3[CH:82]=[C:83]4[C:88](=[CH:89][CH:90]=3)[CH:87]=[C:86]([C:91]3[CH:92]=[C:93]5[C:118](=[CH:119][CH:120]=3)[C:97]3[NH:98][C:99]([C@@H:101]6[CH2:105][CH2:104][CH2:103][N:102]6[C:106](=[O:117])[C@@H:107]([NH:112][C:113](=[O:116])[O:114][CH3:115])[C@H:108]([O:110][CH3:111])[CH3:109])=[N:100][C:96]=3[CH:95]=[CH:94]5)[CH:85]=[CH:84]4)=[CH:79][N:80]=1)[NH:70]2>>[CH3:115][O:114][C:113](=[O:116])[NH:112][C@@H:107]([C@H:108]([O:110][CH3:111])[CH3:109])[C:106]([N:102]1[CH2:103][CH2:104][CH2:105][C@H:101]1[C:99]1[NH:98][C:97]2[C:118]3[C:93]([CH:94]=[CH:95][C:96]=2[N:100]=1)=[CH:92][C:91]([C:86]1[CH:85]=[CH:84][C:83]2[C:88](=[CH:89][CH:90]=[C:81]([C:78]4[NH:77][C:76]([C@@H:71]5[C@@H:72]6[CH2:75][C@@H:69]([CH2:74][CH2:73]6)[N:70]5[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)=[N:80][CH:79]=4)[CH:82]=2)[CH:87]=1)=[CH:120][CH:119]=3)=[O:117]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5cc(-c6cnc([C@H]7N[C@@H]8CC[C@H]7C8)[nH]6)ccc5c4)ccc3c2[nH]1)[C@@H](C)OC
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5cc(-c6cnc([C@@H]7[C@H]8CC[C@H](C8)N7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)ccc3c2[nH]1)[C@@H](C)OC

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (2S,3R)-1-((S)-2-(7-(6-(2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 889.43 [M+H]+. (100 mg, 43%).
Reaction SMILES: N.C([N:9]1[C@H:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][C@H:11]([CH2:21][CH2:22][C:23]2([CH3:28])[O:27][CH2:26][CH2:25][O:24]2)[C:10]1=[O:29])C1C=CC=CC=1.[Li]>C1COCC1.CO>[CH2:14]([C@H:13]1[NH:9][C:10](=[O:29])[C@@H:11]([CH2:21][CH2:22][C:23]2([CH3:28])[O:27][CH2:26][CH2:25][O:24]2)[CH2:12]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC1(CC[C@H]2C[C@@H](Cc3ccccc3)N(Cc3ccccc3)C2=O)OCCO1
Agent: N
Agent: [Li]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(CC[C@H]2C[C@@H](Cc3ccccc3)NC2=O)OCCO1
Reaction time: 0.33 h

Procedure:
Into a 3-necked 500 mL flask at −78° C. was condensed 100 mL of ammonia. Next, 12-2 (470 mg, 1.24 mmol), dissolved in 20 mL of THF, was added. Lithium (19 mg, 2.48 mmol) was washed with MeOH, then THF and then added to the ammonia. After 20 minutes, the reaction was quenched with NH4Cl; 200 mL of THF was added, the cooling bath was removed and the solution purged with argon for 30 minutes to remove the ammonia. The solution was dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc) gave 12-3 as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([OH:10])[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl>CC(C)=O>[Br:1][C:2]1[C:3]([O:11][CH2:18][O:19][CH3:20])=[C:4]([OH:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1
Reactant: COc1ccc(Br)c(O)c1O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1c(Br)ccc(OC)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.5 %

Procedure:
To a stirring solution of 3-bromo-6-methoxybenzene-1,2-diol (500 mg, 2.27 mmol) in acetone (40 mL) at 0° C. was added potassium carbonate (313 mg, 2.27 mmol) and methoxymethyl chloride (183 mg, 2.27 mmol) and the resultant reaction mixture was stirred at RT for 2 h. The reaction mixture was filtered and filtrate was concentrated under reduced pressure. Purification of the residue by column chromatography (silica gel, 0-8% ethyl acetate in pet ether) afforded 3-Bromo-6-methoxy-2-(methoxymethoxy)phenol as a liquid (230 mg, 38%).
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][CH:27]([CH3:31])[CH2:28][CH2:29]N.S>C(O)C>[CH3:26][CH:27]([CH3:31])[CH2:28][CH2:29][NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25]
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Reactant: CC(C)CCN
Agent: S
Solvent: CCO
Product: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reaction time: 16 h

Procedure:
A solution of 10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (6 g) and 3-methylbutylamine (18.9 cc) in absolute ethanol (90 cc) is saturated with hydrogen sulphide and brought for 16 hours to a temperature in the region of 105° C. After being cooled, the reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The oily brown residue is purified by chromatography on a column (height: 40 cm; diameter: 4 cm) of silica gel (0.02-0.063 mm), eluting with methylene chloride (1 liter) and then with a mixture (95:5 by volume) (1.5 liters) of methylene chloride and methanol and collecting 80-cc fractions. Fractions 23 to 36 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-(3-Methylbutyl)-10-[1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide, L series (6.76 g) is thereby obtained in the form of an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:20]=1[C:21](O)=[O:22]>>[Cl:18][C:19]1[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][C:20]=1[C:21]([NH:15][CH2:14][C:13]([C:11]1[N:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[O:9][CH:10]=1)([CH3:17])[CH3:16])=[O:22]
Reactant: N#Cc1ccc(Cl)c(C(=O)O)c1
Reactant: CC(C)(CN)c1coc(-c2ccc(F)cc2)n1
Product: CC(C)(CNC(=O)c1cc(C#N)ccc1Cl)c1coc(-c2ccc(F)cc2)n1
Yield: 44 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)oxazol-4-yl)-2-methylpropan-1-amine and 2-chloro-5-cyanobenzoic acid as described in example 8 step 6 (300 mg, yield 44%). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J=2.0 Hz, 1H), 7.98-7.95 (m, 2H), 7.66-7.63 (m, 1H), 7.56-7.54 (d, J=8.3 Hz, 1H), 7.48 (s, 1H), 7.39 (m, 1H), 7.17-7.13 (t, J=8.8 Hz, 2H), 3.68-3.66 (d, J=5.8 Hz, 2H), 1.41 (s, 6H). MS (ESI) m/z: Calculated for C21H17ClFN3O2: 397.10. found: 396.4 (M−H)−.
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]1[C:45]([O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46].C(=O)([O-])[O-].[Na+].[Na+].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.O>[Cl:9][C:6]1[C:7]([CH3:8])=[C:2]([C:34]2[CH:33]=[C:32]([C:45]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:46])[N:31]([CH3:30])[CH:35]=2)[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:11])[CH:5]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(C)c1-c1cc(C(=O)OCc2ccccc2)n(C)c1
Temperature: 95 °C

Procedure:
A mixture of N-[1-(3-bromo-5-chloro-2-methoxy-4-methylphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (0.032 g, 0.066 mmol, from Example 113, Step 2, Chiral intermediate), benzyl 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-2-carboxylate (0.027 g, 0.080 mmol), sodium carbonate (0.16 mL, 0.17 mmol), 1,4-dioxane (0.6 mL)/water (0.2 mL) and tetrakis(triphenylphosphine)palladium(0) (4.6 mg, 0.0040 mmol) was degassed with N2 for 5 minutes, then heated at 95° C. overnight. The mixture was diluted with EtOAc, washed with sat. NaHCO3, water, brine, and dried over Na2SO4 and concentrated. The crude product (20 mg, 50%) was purified by chromatography eluting with 0 to 40% EtOAc in CH2Cl2. LCMS calculated for C33H36ClN6O4 (M+H)+: m/z=615.2. found: 615.2.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].CC(O)=O>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=2)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4.8 g of 2-butyl-4-chloro-5-formyl-1-[(2'-methoxycarbonyl-1,1'-biphenyl-4-yl)methyl]-1H-imidazole in 100 ml of absolute ethanol is added with a solution of 0.44 g of NaBH4 in 10 ml of ethanol. The mixture is stirred at room temperature for 1 hour then is acidified with glacial CH3COOH to pH 4. The resulting solution is evaporated to dryness under reduced pressure and the residue is taken up into ether. The in soluble part is filtered, the ether solution is evaporated to dryness and the residue is stripped more times with toluene.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[C:14](Cl)(=[O:23])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C1COCC1.O>[CH2:16]([O:15][C:14]([N:2]([CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[CH3:1])=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCc1ccc(C(=O)OC)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CN(C)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
Methyl 4-((methylamino)methyl)benzoate was dissolved in the mixed solution of THF (12 mL) and water (12 mL), then benzyl carbonochloridate (2.57 g, 15.0 mmol) was dropped into it. To the mixture sodium bicarbonate (1.7 g, 20.5 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was poured into ethyl acetate (50 mL×3) and the organic layer was washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate and condensed to get methyl 4-(((benzyloxycarbonyl)(methyl)amino)methyl)benzoate (2.3 g, 53.5%), LC-MS (ESI) m/z 314 [M+1]+.
Reaction SMILES: [OH:1][C:2]([CH:5]1[CH2:9][CH2:8][CH:7]([CH3:10])[CH:6]1[OH:11])([CH3:4])[CH3:3].ClCCl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(OCC)C>[OH:1][C:2]([CH:5]1[CH2:9][CH2:8][CH:7]([CH3:10])[C:6]1=[O:11])([CH3:4])[CH3:3]
Reactant: CC1CCC(C(C)(C)O)C1O
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1CCC(C(C)(C)O)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
7.9 g of 2-(1-hydroxyisopropyl)-5-methyl-cyclopentanol was added dropwise to 100 ml of a dichloromethane suspension containing 16.2 g pyridinium chlorochromate and the mixture was stirred for 5 hours at room temperature. The reaction solution was admixed with diethylether and stirred. Then, the chromate was filtered out and the filtrate was condensed under a vacuum. The residue was purified by means of silica gel column chromatography (eluent: hexane/ethylacetate=7/3) and 6.6 g of 2-(1-hydroxyisopropyl)-5-methyl-cyclopentanone was obtained as an oily substance (yield: 86%).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3S(C2C=CC=CC=2)(=O)=O)=[N:5][N:4]=1.[NH2:35][CH2:36][CH:37]([OH:45])[CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.[OH-].[Na+].Cl>C(#N)C.CS(C)=O>[NH:21]1[C:22]2[C:18](=[C:17]([C:15]3[CH:14]=[C:13]4[C:9]([CH:10]=[N:11][NH:12]4)=[C:8]([C:6]4[O:7][C:3]([CH2:2][NH:35][CH2:36][CH:37]([OH:45])[CH2:38][N:39]5[CH2:40][CH2:41][O:42][CH2:43][CH2:44]5)=[N:4][N:5]=4)[CH:16]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: NCC(O)CN1CCOCC1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CS(C)=O
Product: OC(CNCc1nnc(-c2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)o1)CN1CCOCC1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
4-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (100 mg, 0.184 mmol) in acetonitrile (2 ml) was treated with 1-amino-3-(4-morpholinyl)-2-propanol (147 mg, 0.918 mmol, available from Enamine Ltd) and heated in a microwave at 100° C. for 30 mins. The solution was pipetted off the solid, then the solid was dissolved in DMSO (ml) and loaded onto a 5 g SCX cartridge. Methanol was eluted, then 2M ammonia in ethanol. Basic fractions were blown to dryness. The fully-protected intermediate was treated with isopropanol (1.000 ml) followed by 2M aqueous sodium hydroxide (1.001 ml, 2.002 mmol) and stirred for 20 h at 20° C. The solution was neutralised by addition of 2M hydrochloric acid then blown to dryness to give a brown solid. The material was purified MDAP (Method E). The appropriate fraction was blown to dryness to give the title compound as a brown film (27 mg).
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.C1(S(O)(=O)=O)C=CC=CC=1.[NH2:21][C:22]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.Cl.[C:35]([N:43]1[CH2:48][CH2:47][CH2:46][C:45]([C:65]2[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=2)([CH2:49][CH2:50][CH2:51]N2CCC(C(N3CCCC3)=O)CC2)[CH2:44]1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(#N)C>[NH2:21][C:22]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:27][CH2:26][N:25]([CH2:51][CH2:50][CH2:49][C:45]2([C:65]3[CH:70]=[CH:69][C:68]([Cl:71])=[C:67]([Cl:72])[CH:66]=3)[CH2:46][CH2:47][CH2:48][N:43]([C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:44]2)[CH2:24][CH2:23]1
Reactant: NC1(c2ccccc2)CCNCC1
Reactant: O=C(c1ccccc1)N1CCCC(CCCN2CCC(C(=O)N3CCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)c1ccccc1
Solvent: CC#N
Solvent: CN(C)C=O
Product: NC1(c2ccccc2)CCN(CCCC2(c3ccc(Cl)c(Cl)c3)CCCN(C(=O)c3ccccc3)C2)CC1
Temperature: 100 °C
Yield: 74.6 %

Procedure:
A mixture of 6.81 g of 4-amino-4-phenylpiperidine dibenzenesulfonate, 5.2 g of the compound obtained in step B of EXAMPLE 1 and 6.1 g of K2CO3 in 30 ml of a DMF/acetonitrile mixture (50/50; v/v) is heated at 100° C. for 5 hours. It is concentrated under vacuum, the residue is taken up with water and extracted with AcOEt, the organic phase is washed with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using a DCM/MeOH mixture (from 99/1; v/v to 85/15; v/v) as the eluent to give 3.6 g of the expected product.
Reaction SMILES: [CH2:1]=[C:2]([CH2:15][CH2:16][CH3:17])[CH:3]([O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH2:4][C:5]#[CH:6].[CH2:18]([SnH:22]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21]>>[CH2:1]=[C:2]([CH2:15][CH2:16][CH3:17])[CH:3]([O:7][Si:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[CH2:9][CH3:10])[CH2:4][CH:5]=[CH:6][Sn:22]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(O[Si](CC)(CC)CC)C(=C)CCC
Product: C=C(CCC)C(CC=C[Sn](CCCC)(CCCC)CCCC)O[Si](CC)(CC)CC
Temperature: 150 °C

Procedure:
A mixture of 20 g. of 5-methylene-4-triethylsilyloxy-1-octyne, 25.36 g. of tri-n-butylstannane and 0.1 g. of azobisisobutyrylnitrile is placed in an oil bath at 100° C. After 10 minutes an exotherm raises the temperature to 150° C. The mixture is then heated at 130°-140° C. for 1.5 hours. The excess tri-n-butylstannane is distilled off at 130° C. (1 mm.) and the residue is distilled in a Kugelrohr at 120°-140° C., 0.15-0.05 mm., giving the product as a colorless liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[NH2:10][NH2:11].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:9][S:8][C:4]1[N:3]=[C:2]([NH:10][NH2:11])[CH:7]=[CH:6][N:5]=1
Reactant: NN
Reactant: CSc1nccc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CSc1nccc(NN)n1
Yield: 57.6 %

Procedure:
In a 250 mL round bottom flask, 4-chloro-2-methylsulfanyl-pyrimidine (5 g, 31.1 mmol), hydrazine (4.5 g, 140 mmol) and potassium carbonate (6.45 g, 46.7 mmol) were combined with ethanol (50 mL). The mixture was refluxed for 3 hrs and filtered. The filtered solid was rinsed with ethanol (30 mL). The combined ethanol solution was evaporated to give a crude oily mixture which was purified by ISCO flash column chromatography (30% to 100% ethyl acetate in hexanes) to give N-(2-methylsulfanyl-pyrimidin-4-yl)-hydrazine as a white solid (2.8 g, 57.6% yield).