Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH2:19][C:20]([CH3:22])=[CH2:21])[CH2:3][CH2:4][NH:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.C(N(CC)CC)C.N1C=CC=CC=1.Cl[C:43]([O:45][CH3:46])=[O:44]>ClCCl.CCOCC>[OH:1][C:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([CH2:19][C:20]([CH3:22])=[CH2:21])[CH2:3][CH2:4][N:5]([C:43]([O:45][CH3:46])=[O:44])[C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]1
Reactant: C=C(C)CC(O)(CCN[C@H]1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: C=C(C)CC(O)(CCN(C(=O)OC)[C@H]1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Reaction time: 0.25 h
Yield: 60 %

Procedure:
A solution of (3S)-tert-butyl 3-(3-hydroxy-5-methyl-3-phenylhex-5-enylamino)piperidine-1-carboxylate (8.41 g, 21.65 mmol), triethylamine (4.53 mL, 1.5 equiv), pyridine (1.75 mL, 1 equiv) in dichloromethane (250 mL) was cooled to 0° C. Methyl chloroformate (3.35 mL, 2 equiv) was added slowly during a 10 min period. After 15 min, the mixture was warmed to it slowly and stirred 3 h. The mixture was diluted with ether (350 mL), washed with 5% aq HCl solution (2×30 mL), satd aq NaHCO3 solution (25 mL), brine (25 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 120 g silica gel column, eluted with a 30-85% EtOAc in hexanes gradient, to afford (3S)-tert-butyl 3-((3-hydroxy-5-methyl-3-phenylhex-5-enyl)(methoxycarbonyl)amino)piperidine-1-carboxylate (5.80 g, 60%). LC-MS Method 1 tR=2.08 min., m/z 447 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[S:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22]Cl)=[CH:14]1)(=[O:12])=[O:11].[NH:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[S:10]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][N:24]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:14]1)(=[O:12])=[O:11]
Reactant: COc1ccc(S(=O)(=O)n2cc(CCl)c3ccccc32)c(Br)c1
Reactant: C1CNCCNC1
Product: COc1ccc(S(=O)(=O)n2cc(CN3CCCNCC3)c3ccccc32)c(Br)c1

Procedure:
Using essentially the same procedure as described in example 127, 1-(2-Bromo-4-methoxybenzenesulfonyl)-3-chloromethyl-1H-indole was reacted with homopiperazine to obtain the above derivative.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([OH:30])=[CH:25][C:24]=3[Cl:31])=[O:15])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH2:32]([O:34][C:35](=[O:40])[C:36](Br)([CH3:38])[CH3:37])[CH3:33]>CCCCCCC.C(OCC)(=O)C>[CH2:32]([O:34][C:35](=[O:40])[C:36]([O:30][C:26]1[CH:25]=[C:24]([Cl:31])[C:23]([O:22][C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:14]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:4]([CH:1]3[CH2:2][CH2:3]3)[CH2:5][CH2:6]2)=[O:15])=[CH:28][C:27]=1[Cl:29])([CH3:38])[CH3:37])[CH3:33]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(O)cc1Cl)N1CCN(C2CC2)c2ccccc21
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl

Procedure:
The title compound was prepared in analogy to Example 58, from (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone (Example 57) and 2-bromo-2-methyl-propionic acid ethyl ester (commercially available, CAS RN 600-00-0) after a reaction time of 23 hours at room temperature and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light brown foam (30%). MS (ESI): m/z=570.156 [M+H]+.
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH:7]1[C@@H:11]2[CH2:12][N:13]([C:15]3[N:20]=[C:19]([C:21]4[O:25][C:24]([C:26]5[CH:31]=[CH:30][C:29]([CH2:32][N:33](C)[C:34](=O)OC(C)(C)C)=[CH:28][CH:27]=5)=[N:23][N:22]=4)[C:18]([N:42](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:17][CH:16]=3)[CH2:14][C@@H:10]2[CH2:9][CH2:8]1)(=[O:5])=[O:4])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:42][C:18]1[N:17]=[CH:16][C:15]([N:13]2[CH2:14][C@@H:10]3[CH2:9][CH2:8][CH:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[C@@H:11]3[CH2:12]2)=[N:20][C:19]=1[C:21]1[O:25][C:24]([C:26]2[CH:27]=[CH:28][C:29]([CH2:32][NH:33][CH3:34])=[CH:30][CH:31]=2)=[N:23][N:22]=1
Reactant: CCS(=O)(=O)NC1CC[C@H]2CN(c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nnc(-c5ccc(CN(C)C(=O)OC(C)(C)C)cc5)o4)n3)C[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)NC1CC[C@H]2CN(c3cnc(N)c(-c4nnc(-c5ccc(CNC)cc5)o4)n3)C[C@@H]12
Reaction time: 1 h

Procedure:
A solution of tert-butyl N-[[4-[5-[6-[(3aR,6aS)-6-(ethylsulfonylamino)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-3-[bis(tert-butoxycarbonyl)amino]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (110 mg, 0.14 mmol) in DCM (1 mL) was treated with TFA (1.0 g, 676 μL, 8.8 mmol). The reaction mixture was stirred for 1 hour. The solvent was evaporated and the residue was purified via reverse phase HPLC using 10 to 99% ACN in water (5 mM HCl modifier) to obtain N-[(3aR,6aS)-2-[5-amino-6-[5-[4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-6-yl]ethanesulfonamide. LC/MS m/z 499.2 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12]O)[CH:8]=2)[N:3]=1.C1CCN2C(=NCCC2)CC1.C1C=CC(P([N:39]=[N+:40]=[N-:41])(C2C=CC=CC=2)=O)=CC=1.O>CN(C=O)C>[N:39]([CH2:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)=[N+:40]=[N-:41]
Reactant: Cc1ccc2cc(CO)ccc2n1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2cc(CN=[N+]=[N-])ccc2n1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of (2-methyl-6-quinolinyl)methanol (100 mg, 0.560 mmol) and DBU (0.152 ml, 1.008 mmol) in DMF (4 ml) was added DPPA (0.205 ml, 0.952 mmol). The reaction mixture was stirred overnight at 23° C. Reaction mixture was poured into water and extracted twice with ethyl acetate. Organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to afford a crude material, which was purified by silicagel chromatography (cyclohexane:ethyl acetate from 100:0 to 0:100) to afford the title compound. HPLC (Method G) Rt=1.048 min; MS (Method F) [M+H]+=199.2
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)[OH:33])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]([O:29]C)=[O:28])[CH:21]=[CH:20]3)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.C(Cl)(Cl)Cl.CO>O1CCOCC1>[C:1]([O:5][C:6]([N:8]([CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)[OH:33])[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]([OH:29])=[O:28])[CH:21]=[CH:20]3)=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2cc(-c3ccc(CCN(C[C@H](O)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)ccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc3cc(C(=O)O)ccc3c2)cc1)C[C@H](O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.7 %

Procedure:
A mixture of methyl 6-[4-[2-[(tert-butoxycarbonyl)-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-phenyl]-2-naphthoate (105 mg) and 1N sodium hydroxide (0.375 ml) in 1,4-dioxane (1 ml) was stirred at room temperature for 12 hours. To the resulting mixture were added 1N hydrochloric acid (0.375 ml) and chloroform-methanol (5:1). After separation, the organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chlorofom/methanol=10/1) to give 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl]-2-naphthoic acid (100 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][OH:22])[CH:18]=2)[NH:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][O:22][S:32]([CH3:31])(=[O:34])=[O:33])[CH:18]=2)[NH:13][C:12]=1[CH3:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1[nH]c2ccc(CCO)cc2c1C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1[nH]c2ccc(CCOS(C)(=O)=O)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a mixture of 5-(2-hydroxy-ethyl)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (1.02 g, 3.3 mmol) and triethylamine (0.92 mL, 6.6 mmol) in dry THF (10 mL) was added methanesulfonyl chloride (0.26 mL, 3.3 mmol) under nitrogen atmosphere at room temperature. The mixture was stirred at room temperature for 3 hours and then partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give 1.27 g (99%) of the desired product as a white solid: mp 122-124° C.; MS(APCI−): m/z 386.0 (M−H); Anal. Calcd for C20H21N1O5S1: C, 62.00; H, 5.46; N, 3.62; S, 8.28. Found: C, 61.95; H, 5.61; N, 3.54; S, 8.32.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]([F:11])[F:10])=[C:4]([O:12][CH3:13])[C:3]=1[O:14]COC.Cl>CO>[Br:1][C:2]1[C:3]([OH:14])=[C:4]([O:12][CH3:13])[C:5]([O:8][CH:9]([F:10])[F:11])=[CH:6][CH:7]=1
Reactant: COCOc1c(Br)ccc(OC(F)F)c1OC
Agent: Cl
Solvent: CO
Product: COc1c(OC(F)F)ccc(Br)c1O
Temperature: 50 °C
Yield: 93.2 %

Procedure:
To a stirring solution of 1-bromo-4-(difluoromethoxy)-3-methoxy-2-(methoxymethoxy)benzene (1 g, 3.19 mmol) in methanol (15 mL) was added concentrated hydrochloride (2 mL) and the reaction mixture was heated to 50° C. for 1 h. The reaction mixture was cooled to RT, concentrated under reduced pressure and the obtained residue was basified with sodium bicarbonate solution and extracted with dichloromethane (3×). The combined dichloromethane layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford the title compound as a solid (800 mg, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][O:11][CH3:12])[C:6]([O:13][CH3:14])=[C:5]([S:15][CH3:16])[C:4]=1[O:17][CH2:18][O:19][CH3:20].CN(C)CCN(C)C.C([Li])CCC.I[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]1[C:45]([O:46][CH2:47][O:48][CH3:49])=[C:44]([O:50][CH3:51])[CH:43]=[C:42]([O:52][CH2:53][O:54][CH3:55])[C:41]=1[O:56][CH3:57]>C1(C)C=CC=CC=1.CN(C)P(=O)(N(C)C)N(C)C.C(OCC)C>[CH3:57][O:56][C:41]1[C:42]([O:52][CH2:53][O:54][CH3:55])=[CH:43][C:44]([O:50][CH3:51])=[C:45]([O:46][CH2:47][O:48][CH3:49])[C:40]=1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][C:8]1[C:7]([O:9][CH2:10][O:11][CH3:12])=[C:6]([O:13][CH3:14])[C:5]([S:15][CH3:16])=[C:4]([O:17][CH2:18][O:19][CH3:20])[C:3]=1[O:2][CH3:1]
Reactant: COCOc1cc(OC)c(OCOC)c(SC)c1OC
Reactant: COCOc1cc(OC)c(OCOC)c(CCCCCI)c1OC
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COCOc1cc(OC)c(OCOC)c(CCCCCc2c(OCOC)c(OC)c(SC)c(OCOC)c2OC)c1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
150 Milligrams of 1,4-dimethoxy-2,5-bis(methoxymethoxy)-3-(methylthio)benzene was dissolved in a mixed solvent of 4 ml of toluene with 1 ml of hexamethylphosphoric triamide, to this solution was added 0.104 ml of N,N,N',N'-tetramethylethylenediamine was added, then the whole mixture was cooled to -78° C. on a dry ice-acetone bath. 0.466 Milliliter of n-butyllithium (1.6 M, n-hexane solution) was added dropwise thereto and stirred for 30 minutes. Next, 8 ml of toluene solution containing 269 mg of 1-(5-iodopent-1-yl)-2,5-dimethoxy-3,6-bis(methoxymethoxy)benzene was added dropwise and the reaction mixture was stirred overnight. The reaction mixture was warmed to room temperature, then 30 ml of diethyl ether was added thereto, the organic layer was washed three times with 20 ml of water then washed twice with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. The diethyl ether solution was concentrated under reduced pressure, the residue obtained was purified by means of a preparative thin layer chromatography (thickness: 2 mm, adsorbent: Merck Art 5717 silica gel, developing solvent: 40% ethyl acetate-n-hexane). There was obtained 120 mg of 1-[2,5-dimethoxy3,6-bis(methoxymethoxy)phenyl]-5-[2,5-dimethoxy-3,6-bis(methoxymethoxy)-4-(methylthio)phenyl]pentane as in the form of colorless oily substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][C@H:9]([C:11](=O)[NH2:12])[CH3:10])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][C@H:9]([C:11]#[N:12])[CH3:10])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](CNC(=O)OC(C)(C)C)C(N)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](C#N)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
((R)-2-Carbamoyl-propyl)-carbamic acid tert-butyl ester (50 mg, 0.247 mmol) was dissolved in THF (1.4 ml). Pyridine (40 ul, 0.49 mmol) and then trifluoroacetic anhydride (42 ul, 0.30 mmol) were added dropwise. The reaction was stirred at room temperature for 1 h and then additional pyridine (40 ul, 0.49 mmol) and trifluoroacetic anhydride (42 ul, 0.30 mmol) were added. The reaction was stirred at room temperature for 16 h then water, sodium carbonate solution and ethyl acetate were added. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and sodium chloride solution, and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to give 40 mg (87%) of ((R)-2-cyano-2-methyl-ethyl)-carbamic acid tert-butyl ester. (M+Na)+=207.
Reaction SMILES: [CH2:1](P(CCCC)CCCC)[CH2:2][CH2:3]C.ClCCCCl.[Cl:19][SiH:20]([Cl:22])[Cl:21]>>[Cl:19][Si:20]([Cl:22])([Cl:21])[CH2:1][CH2:2][CH2:3][Si:20]([Cl:22])([Cl:21])[Cl:19]
Reactant: CCCCP(CCCC)CCCC
Reactant: Cl[SiH](Cl)Cl
Solvent: ClCCCCl
Product: Cl[Si](Cl)(Cl)CCC[Si](Cl)(Cl)Cl
Yield: 343 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.30 g (1.5 mmol) of tri-n-butylphosphine, 0.85 g (7.5 mmol) of 1,3-dichloropropane, and 10.2 g (75.0 mmol) of trichlorosilane were reacted at 150° C. for 12 hrs. The resulting mixture was distilled to give 1.6 g of 1,3-bis(trichlorosilyl)propane (bp; 104° C./12.5 mmHg, yield; 70%) and 0.3 g of 3-(chloropropyl)trichlorosilane (bp; 88-90° C./12.5 mmHg, yield; 20%).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH2:3][CH2:4][CH:5]=[CH2:6].[CH:15]1[CH:20]=[CH:19][C:18]([CH2:21][O:22][C:23](Cl)=[O:24])=[CH:17][CH:16]=1.CCOCC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]([NH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])[CH2:3][CH2:4][CH:5]=[CH2:6])([O:22][CH2:21][C:18]1[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=1)=[O:24]
Reactant: C=CCCC(N)c1ccccc1OC
Reactant: O=C(Cl)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: C=CCCC(NC(=O)OCc1ccccc1)c1ccccc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a solution of crude 5-amino-5-(2-methoxyphenyl)-1-pentene (1.63 g) in CH2Cl2 (10 mL) at 0° C. was added DMAP (1.15 g, 9.38 mmol) followed by Cbz-Cl (1.34 mL, 9.38 mmol) and the resulting solution was stirred at room temperature overnight. Ether was added, the aqueous layer was extracted with diethyl ether (x4), and the combined organic layers was washed with brine, dried over MgSO4 and evaporated in vacuo. The crude product was purified by silica gel flash chromatography (5% EtOAc-95% hexanes) to provide the title compound as a white solid (1.84 g). 1H NMR (CDCl3, 400 MHz) δ: 3.82 (3H, s, OMe), 2.0 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[C:11](=[O:21])[C:12]([C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=1)=[CH2:13].S(=O)(=O)(O)O>ClCCl>[Br:20][C:17]1[CH:16]=[CH:15][C:14]([CH:12]2[CH2:13][C:4]3[C:3](=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([O:9][CH3:10])[CH:5]=3)[C:11]2=[O:21])=[CH:19][CH:18]=1
Reactant: C=C(C(=O)c1ccc(OC)c(Cl)c1Cl)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccc(Br)cc1)C2
Reaction time: 0.5 h

Procedure:
2',3'-Dichloro-4'-methoxy-2-(4-bromophenyl)acrylophenone (143 g., 0.37 mole) dissolved in dichloromethane (2 l.) is drizzled into cold 36N sulfuric acid (1 l.)-dichloromethane (1 l.) in an ice bath over 4 hours. After stirring for an additional half hour, the reaction mixture is slowly added to crushed ice, the dichloromethane layer separated, washed with saturated salt solution, concentrated in vacuo to give 134.8 g. of 2-(4-bromophenyl)-5-methoxy-6,7-dichloro-1-indanone which melts at 202°-203° C. after trituration with water followed by crystallization from benzene:hexane, 1:1.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[Cl:47][C:48]1[CH:56]=[CH:55][C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=1.O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:52]([C:51]3[CH:55]=[CH:56][C:48]([Cl:47])=[CH:49][CH:50]=3)=[O:53])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.210 g, 0.35 mmol) in pyridine (2 mL) was added 4-chlorobenzoyl chloride (0.051 mL, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.090 g, 62% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 14.20 (br s, 1H), 13.45 (br s, 1H), 10.54 (s, 1H), 8.73 (s, 1H), 8.44 (s, 1H), 8.10 (d, 1H), 8.04 (d, 2H), 7.93 (d, 1H), 7.76 (d, 1H), 7.71 (d, 1H), 7.64 (d, 2H), 7.56 (t, 1H); ES-MS (m/z) 415 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:2]=1.[H][H]>[Pd].C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH:2]=1
Reactant: O=C(O)C=Cc1cccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)CCc1cccnc1

Procedure:
A mixture of 3 g (20 mmol) of 3-(3-pyridinyl)acrylic acid and 0.3 g of 10% palladium on carbon in 150 ml of ethyl acetate was shaken under 4 atmospheres of hydrogen for 24 h. After filtration, the resulting solution was concentrated in vacuo to provide the desired compound.
Reaction SMILES: [I:1][C:2]1[C:3]2[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][C:4]=2[NH:5][N:6]=1.C(N=C=NCCCN(C)C)C.O[N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=N1.C(N(C(C)C)CC)(C)C.NCC1C=CC=CN=1>CN(C)C=O.C(OCC)(=O)C>[N:27]1[CH:28]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:29][NH:25][C:10]([C:8]1[S:9][C:3]2[C:2]([I:1])=[N:6][NH:5][C:4]=2[CH:7]=1)=[O:12]
Reactant: O=C(O)c1cc2[nH]nc(I)c2s1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccn1)c1cc2[nH]nc(I)c2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
A mixture of 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylic acid [1.05 g, 3.57 mmol, Intermediate (29)], 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (821 mg, 4.28 mmol), 1-hydroxybenzotriazole (482 mg, 3.57 mmol) in dimethyl formamide (45 mL) is stirred at room temperature for 10 minutes. To it is added diisopropylethylamine (1.3 mL, 7.46 mmol) followed by a solution of 2-(aminomethyl)pyridine (425 mg, 3.93 mmol) in dimethyl formamide (2 mL). After stirring overnight, the reaction mixture is diluted with ethyl acetate (200 mL) and washed water, brine and dried over sodium sulfate. The residue is chromatographed on 35 g silica gel cartridge (ethyl acetate and 10% methanol in ethyl acetate) to give 3-iodo-1H-thieno[3,2-c]pyrazole-5-carboxylic acid (pyridin-2-ylmethyl)-amide [1.08 g, 79%, Intermediate (30)] as a light yellow solid; LC/MS: 385 (M+H); 1H NMR [(CD3)2SO)]: δ 13.67 (1H, s), 9.35 (1H, t), 8.53 (1H), 8.01 (1H), 7.80 (1H), 7.36 (1H, d), 7.28 (1H), 4.58 (2H, d).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]2[CH:37]=[CH:36][C:33]([C:34]#N)=[CH:32][CH:31]=2)=[CH:15][CH:14]=1.C[OH:39]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]2[CH:37]=[CH:36][C:33]([CH:34]=[O:39])=[CH:32][CH:31]=2)=[CH:15][CH:14]=1
Reactant: CO
Reactant: COc1ccc(CCCCCCCCCCNc2ccc(C#N)cc2)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: COc1ccc(CCCCCCCCCCNc2ccc(C=O)cc2)cc1
Temperature: 0 °C

Procedure:
Di-isobutylaluminum hydride (54 ml., 25% solution in toluene) is added with stirring to a solution of 12.1 g. of 4-[10-(4-methoxyphenyl)decylamino]benzonitrile under a nitrogen atmosphere. After addition is completed, the solution stirred for one hour. A solution of methanol in toluene (50 ml., 1:1) is added over 30 minutes and the mixture is poured into 500 ml. vigorously stirred ice-cold 50% aqueous sulfuric acid. The mixture is filtered and the organic layer separted. The aqueous solution is extracted twice with toluene (100 ml.) and the combined organic layers are washed with aqueous sodium bicarbonate, dried over magnesium sulfate, decolorized with charcoal, filtered and evaporated in vacuo to give a light yellow crystalline solid. The product is recrystallized from dichloromethane/hexanes giving colorless needles.