Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([C:15]#[N:16])[CH:12]=[CH:11][CH:10]=2)=[CH:5][C:4]=1[CH:17]1[C:30]2[C:29](=[O:31])[CH2:28][C:27]([CH3:33])([CH3:32])[CH2:26][C:25]=2[O:24][C:23]2[CH2:22][C:21]([CH3:35])([CH3:34])[CH2:20][C:19](=[O:36])[C:18]1=2.[N-:37]=[N+:38]=[N-:39].[Na+].[Cl-].[NH4+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:15]3[NH:39][N:38]=[N:37][N:16]=3)[N:14]=2)=[CH:5][C:4]=1[CH:17]1[C:30]2[C:29](=[O:31])[CH2:28][C:27]([CH3:32])([CH3:33])[CH2:26][C:25]=2[O:24][C:23]2[CH2:22][C:21]([CH3:35])([CH3:34])[CH2:20][C:19](=[O:36])[C:18]1=2
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2cccc(C#N)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2cccc(-c3nnn[nH]3)n2)cc1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Temperature: 80 °C
Reaction time: 4 h
Yield: 9.3 %

Procedure:
A suspension of the 6-[4-methoxy-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyridine-2-carbonitrile produced in Example 6 (500 mg, 1.04 mmol), sodium azide (76.4 mg, 1.14 mmol), and ammonium chloride (61.0 mg, 1.14 mmol) in DMF (10 ml) was prepared at room temperature, and the suspension thus prepared was then stirred at 80° C. for 4 hours. After air-cooling, water was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (ethyl acetate:hexane=66:34, v/v, methanol:dichloromethane=3:97 to 5:95, v/v). The solid thus obtained was washed with a mixed solution of diethyl ether and hexane, followed by collection by filtration and drying, to obtain the title compound (51 mg, yield: 9.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:18]=[CH2:19])[C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[NH2:10])[CH:5]=[CH:6][CH:7]=1.[CH:20]1([C:23]([CH:25]2[CH2:27][CH2:26]2)=O)[CH2:22][CH2:21]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([CH:18]=[CH2:19])[C@@H:9]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[NH:10][CH:23]([CH:25]2[CH2:27][CH2:26]2)[CH:20]2[CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C1CC1)C1CC1
Reactant: C=C[C@H](c1cccc(Cl)c1)[C@H](N)c1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: C=C[C@H](c1cccc(Cl)c1)[C@H](NC(C1CC1)C1CC1)c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
To a solution of 2.0 g (6.84 mmol) of (1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-en-1-amine (Example 115, Step E), dicyclopropyl ketone (7.54 mL, 68.4 mmol), and acetic acid (1.96 mL, 34.2 mmol) in methanol (25.0 mL) was added sodium cyanoborohydride (1.44 mL, 27.4 mmol) at rt. The resulting mixture was stirred at 50° C. for 2 days. Acetic acid (1.5 ml) and sodium cyanoborohydride (0.6 g) were added again and heating was continued overnight. 200 ml of ethyl acetate was added, and the organic layer was washed consecutively with K2CO3 solution and sat. NaCl solution, dried over K2CO3, filtered and the filtrate was concentrated under reduced pressure at 60° C. The mixture was purified by flash chromatography on silica gel (eluent: DCM/MeOH, 95/5) to give the title compound.
Reaction SMILES: C([O:8][C@@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@H:10]1[O:32][C@@H:33]1[C@@H:42]([O:43][C@H:44]2[O:73][C@H:72]([CH2:74][O:75][CH2:76][C:77]3[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=3)[C@@H:63]([O:64][CH2:65][C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[C@H:54]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C@H:45]2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:41]([CH3:83])[O:40][C@@H:35]([O:36][CH2:37][CH:38]=[CH2:39])[C@@H:34]1[O:84][C:85](=[O:92])[C:86]1[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=1)(=O)CCC(C)=O.NN.CC(C)=O>N1C=CC=CC=1.C(O)(=O)C>[CH2:16]([O:15][C@@H:14]1[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([CH3:31])[O:11][C@@H:10]([O:32][C@@H:33]2[C@@H:42]([O:43][C@H:44]3[O:73][C@H:72]([CH2:74][O:75][CH2:76][C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)[C@@H:63]([O:64][CH2:65][C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)[C@H:54]([O:55][CH2:56][C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C@H:45]3[O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:41]([CH3:83])[O:40][C@@H:35]([O:36][CH2:37][CH:38]=[CH2:39])[C@@H:34]2[O:84][C:85](=[O:92])[C:86]2[CH:91]=[CH:90][CH:89]=[CH:88][CH:87]=2)[C@@H:9]1[OH:8])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C=CCO[C@@H]1O[C@@H](C)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](O[C@@H]2O[C@@H](C)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2OC(=O)CCC(C)=O)[C@H]1OC(=O)c1ccccc1
Agent: NN
Solvent: c1ccncc1
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: C=CCO[C@@H]1O[C@@H](C)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@@H](O[C@@H]2O[C@@H](C)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)[C@H]1OC(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 94 %

Procedure:
The trisaccharide 215 (200 mg, 0.16 mmol) was treated with 0.4 mL of a solution 1 M of hydrazine (100 mg) diluted in a mixture of pyridine (1.6 mL) and acetic acid (0.4 mL) at rt. The solution was stirred during 20 min. Acetone (1.2 mL) was added and the solution was concentrated. The residue was eluted from a column of silica gel with 98.5:1.5 DCM-EtOAc to give 216 (174 mg) as a foam. Although, contaminated with hydrazine salts, the 1H NMR spectrum showed that compound 216 had NMR data identical to that of a reference compound. (F. Bélot, K. Wright, C. Costachel, A. Phalipon, L. A. Mulard, J. Org. Chem. 2004, 69, 1060-1074)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:11]1([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:25]=2[NH:24][C:23](=[O:26])[C:22]3=[O:27])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:2]([N:24]1[C:25]2[C:21](=[CH:20][CH:19]=[CH:18][C:17]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:22](=[O:27])[C:23]1=[O:26])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCBr
Reactant: O=C1Nc2c(cccc2-c2ccccc2)C1=O
Product: CCCCCCCCCN1C(=O)C(=O)c2cccc(-c3ccccc3)c21

Procedure:
The title compound was prepared in a manner similar to the process step described in the text from Page 7, line 34 to Page 8, line 5 of WO 94/29272 but using a haloalkane such as 1-bromononane together with 7-phenyl-1H-indole-2,3-dione.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[O:19])=[C:15]([O:28][CH3:29])[C:14]([O:30][CH3:31])=[C:13]([O:32][CH3:33])[CH:12]=2)=[O:10])=[N:6][CH:7]=1.Cl.[CH3:35][NH:36][CH2:37][CH2:38]N>CO.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[N:36]([CH3:35])[CH2:37][CH2:38][N:27]=4)=[CH:22][CH:21]=3)=[O:19])=[C:15]([O:28][CH3:29])[C:14]([O:30][CH3:31])=[C:13]([O:32][CH3:33])[CH:12]=2)=[O:10])=[N:6][CH:7]=1
Reactant: CNCCN
Reactant: COc1cc(C(=O)Nc2ccc(Br)cn2)c(NC(=O)c2ccc(C#N)cc2)c(OC)c1OC
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)Nc2ccc(Br)cn2)c(NC(=O)c2ccc(C3=NCCN3C)cc2)c(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
To a solution of the compound of N-{6-[N-(5-bromo(2-pyridyl))carbamoyl]-2,3,4-trimethoxyphenyl}(4-cyanophenyl)carboxamide (680 mg, 1.33 mmol) in anhydrous methanol (5 ml) and ethyl acetate (10 ml) was saturated with hydrogen chloride gas at 0° C. The mixture was stirred at r.t. overnight. After the evaporated the solvent, the residue was dissolved in anhydrous methanol (5 ml) and N-methylethylenediamine (0.586 ml, 6.65 mmol) was added. The mixture was stirred under reflux condition for 2 hrs. After the evaporation of solvent, the crude residue was purified by RP-HPLC to give N-{6-[N-(5-bromo(2-pyridyl))carbamoyl]-2,3,4-trimethoxyphenyl}[4-(1-methyl(2-imidazolin-2-yl))phenyl]carboxamide as a white powder (240 mg, 32%). MS found for C26H26BrN5O5 M+=568, (M+2)+=570.
Reaction SMILES: CC([O-])(C)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].[CH3:25][C:26]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:27]=1[NH2:28]>COCCOC.CCOCC.CCCCCCCCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:25][C:26]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:27]=1[NH:28][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]
Reactant: Cc1cccc(C)c1N
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Solvent: CCCCCCCCCCCC
Solvent: CCOCC
Product: Cc1cccc(C)c1Nc1ccccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
A solution of ligand 1 (see FIG. 1) [42 mg, 0.1 mmol (8.4 mg, 0.02 mmol, 4 mol % per reaction)] and NaOt-Bu [10 mg, 0.1 mmol (2 mg, 0.02 mmol, 4 mol % per reaction)] were stirred in 5 mL DME (anhy). After 10 minutes, 1 mL of the solution was added via syringe to a test tube containing (under an Argon atmosphere) Pd2(dba)3 (4.6 mg, 0.005 mmol, 2 mol % Pd), K3PO4 (148 mg, 0.7 mmol), 2-chloronitrobenzene (79 mg, 0.5 mmol), and 2,6-dimethylaniline (74 μL, 0.6 mmol). The test tube was capped (with a proper cap-no rubber septa) and heated at 100° C. for 18 hours. The reaction mixture was allowed to cool to r.t., diluted with ether and dodecane was added as an internal standard. The reaction mixture was purified by column chromatography (5% EtOAc/hexanes) to yield 110 mg (91% yield) of the product.
Reaction SMILES: C(O)CCC#C.BrC1C=CC(C2C=CC=CC=2)=CC=1.[C:20]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[C:33][CH2:34][CH2:35][CH:36]=[O:37])=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(NC(=O)/C=C/CCC#CC1C=CC(C2C=CC=CC=2)=CC=1)C(C)C>>[C:20]1([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[C:33][CH2:34][CH2:35][CH2:36][OH:37])=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=CCCC#Cc1ccc(-c2ccccc2)cc1
Agent: Brc1ccc(-c2ccccc2)cc1
Agent: C#CCCCO
Agent: CC(C)CNC(=O)/C=C/CCC#Cc1ccc(-c2ccccc2)cc1
Product: OCCCC#Cc1ccc(-c2ccccc2)cc1

Procedure:
5-(4'-phenylphenyl)-4-pentyn-1-ol was prepared from 4-pentyn-1-ol and 4'-bromobiphenyl as in Example 15, and converted into 5-(4'-phenylphenyl)-4-pentyn-1-al by the method of Example 9. N-isobutyl 7-(4'-phenylphenyl)-(2E)-hepten-6-ynamide was then prepared from 5-(4'-phenylphenyl)-4-pentyn-1-pentyn-1-al and N-isobutylacetamidotriphenylphosphonium chloride as in Example 9 and semi-hydrogenated as in Example 9 to give N-isobutyl 7-(4'-phenylphenyl)-(2E,6Z)-heptadienamide.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][N:8]([C:15]4[C:20]([CH:21]=[O:22])=[C:19]([C:23]5[CH:28]=[C:27]([NH:29][C:30]6[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([CH3:37])[N:31]=6)[C:26](=[O:38])[N:25]([CH3:39])[CH:24]=5)[CH:18]=[CH:17][N:16]=4)[C:9]3=[O:14])[C:4]=2[CH2:3]1.[BH4-].[Na+]>CO>[CH3:37][C:32]1[N:31]=[C:30]([NH:29][C:27]2[C:26](=[O:38])[N:25]([CH3:39])[CH:24]=[C:23]([C:19]3[CH:18]=[CH:17][N:16]=[C:15]([N:8]4[CH2:7][CH2:6][N:5]5[C:4]6[CH2:3][C:2]([CH3:40])([CH3:1])[CH2:13][C:12]=6[CH:11]=[C:10]5[C:9]4=[O:14])[C:20]=3[CH2:21][OH:22])[CH:28]=2)[CH:35]=[C:34]([CH3:36])[N:33]=1
Reactant: Cc1cc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3C=O)cn(C)c2=O)nc(C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3CO)cn(C)c2=O)nc(C)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 17.2 %

Procedure:
At 0° C., to a solution of 173c (290 mg, 0.54 mmol) in methanol (5 mL) was added sodium borohydride (62 mg, 1.62 mmol). The reaction mixture was stirred at room temperature for 20 minutes and quenched with water (1 mL). It was then concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 173 as white solid (50 mg, 17%). MS-ESI: [M+H]+ 540.3. 1H NMR (500 MHz, CDCl3) δ 8.90 (d, J=2.5 Hz, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 8.00 (s, 1H), 7.35 (d, J=5.5 Hz, 1H), 6.85 (s, 1H), 6.45 (s, 1H), 5.16-5.13 (m, 1H), 4.67-4.52 (m, 2H), 4.33-4.29 (m, 1H), 4.16 (d, J=5.0 Hz, 2H), 3.90-3.86 (m, 1H), 3.72 (s, 3H), 2.58-2.56 (m, overlap, 5H), 2.51 (s, 2H), 2.40 (s, 3H), 2.02 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35](C4C=CC([N+]([O-])=O)=CC=4)[CH2:34][CH2:33]3)[N:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:21]2[C@@H:30]3[C@@H:25]([CH2:26][CH:27]=[CH:28][CH2:29]3)[C:24](=[O:31])[N:23]([CH:32]3[CH2:37][CH2:36][N:35]([C:2]4[C:3]5[CH:10]=[CH:9][S:8][C:4]=5[N:5]=[CH:6][N:7]=4)[CH2:34][CH2:33]3)[N:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: Clc1ncnc2sccc12
Reactant: COc1ccc(C2=NN(C3CCN(c4ccc([N+](=O)[O-])cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC
Solvent: O
Product: COc1ccc(C2=NN(C3CCN(c4ncnc5sccc45)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OC

Procedure:
Prepared from 4-Chloro-thieno[2,3-d]pyrimidine and starting compound A1 as described for compound 11. After the addition of water, the mixture is extracted with diethyl ether. The ether solution is dried over magnesium sulfate. After the addition of a saturated solution of hydrochloric acid in ether, the compound precipitates. M. p. 219-220° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH2:12]([C:19]#[N:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>O1CCOCC1>[C:19]([CH:12]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:20]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N#CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: N#CC(c1ccccc1)c1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
There were gradually added to a cooled and stirred solution of 190 grams of 2,6-dichloro-3-nitropyridine and 117 grams of benzyl cyanide in 2 liters of dioxane under a nitrogen atmosphere 64 grams of sodium hydride (80% in white oil). The reaction mixture immediately turned a deep dark blue color, gradually a finely divided precipitate began to separate out, the temperature rose (with cooling with ice water) to 30° C. After 3 hours the mixture was treated with about 20 ml of ethyl alcohol, stirred for another 20 minutes, then filtered with suction. The deep blue sodium salt was dissolved in 1 liter of water, treated with dilute acetic acid until the color changed. The 2-(α-cyanobenzyl)-3-nitro-6-chloropyridine formed crystallized out in pure form. M.P. 165° C.; Yield 146 grams.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:20]=1[N:27]=[C:28]=[S:29]>>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:28](=[S:29])[NH:27][C:20]1[C:21]([Cl:26])=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=1[Cl:18]
Reactant: S=C=Nc1c(Cl)cc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2c(Cl)cc(Cl)cc2Cl)c1NCCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.3 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (200 mg, 0.773 mmol) and 2,4,6-trichlorophenyl isothiocyanate (406 mg, 1.70 mmol) was stirred at room temperature for 2 days and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a red oil (285 mg, 0.574 mmol, 74%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12]Br)=[CH:4][N:3]=1.C([C:16](CC)([C:20]([O-])=[O:21])[C:17]([O-])=[O:18])C.C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+].Cl>CS(C)=O.CO.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:16]([CH2:20][OH:21])[CH2:17][OH:18])=[CH:4][N:3]=1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: Nc1ncc2ncn(CCBr)c2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CO
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncc2ncn(CCC(CO)CO)c2n1
Temperature: 45 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
24.21 g (0.1 mole) of 2-amino-9-(2-bromoethyl)purine was completely dissolved in 120 ml of dimethylsulfoxide, to which 48.05 g (0.3 mole) of diethylmalonate and 41.46 g (03 mole) of potassium carbonate were then added. The mixture was stirred at a temperature of 40-50° C. for 4 hours. After completion of the reaction, the reaction product was cooled to room temperature, to which 300 ml of water was then added. The solution was then extracted three times with 400 ml portions of dichloromethane. The organic layer was collected, and dried with anhydrous magnesium sulfate, followed by filtration and washing. The filtrate was concentrated under reduced pressure. The remaining concentrate was added to 300 ml of t-butanol and then warmed to 60° C., followed by the addition of 21.06 g (0.61 mole) of sodium borohydride. To the resulting mixture, 30 ml of methanol was added slowly, followed by stirring for five hours. After completion of the reaction, the reaction product was cooled to room temperature, neutralized with diluted hydrochloric acid, and then concentrated. The remaining concentrate was added to 100 ml of methanol and then stirred for two hours at room temperature, followed by filtration. The filtrate was concentrated under reduced pressure and crystallized from butanol, thereby giving 13.05 g (55% yield) of light yellow-colored 2-amino-9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purine.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:11][C:12]1[CH:25]=[CH:24][C:15]([O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=1>C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][C:12]2[CH:25]=[CH:24][C:15]([O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)Oc1ccc(CBr)cc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of 2.3 gm (0.1 mol) of sodium in 100 ml of ethanol was admixed at room temperature with 12.8 gm (0.1 mol) of 4-chloro-phenol, and the resulting solution was heated to its boiling point for a short time and then allowed to cool to room temperature. A solution of 28.7 gm (0.1 mol) of ethyl 2-(4-bromomethyl-phenoxy)-propionate in 20 ml of ethanol was now added while thoroughly stirring, and the mixture was boiled for a few hours, then cooled to room temperature and suction-filtered through diatomaceous earth. The filtrate was evaporated, the viscous residue was suspended in 100 ml of isopropyl ether, the suspension was suction-filtered through diatomaceous earth, and the filtrate was evaporated. The oily residue was fractionally distilled in an oil pump vacuum, yielding 71% of theory of ethyl 2-[4-(4-chlorophenoxy-methyl)-phenoxy]-propionate, b.p. 185°-190° C. at 0.1 mm Hg.
Reaction SMILES: [BH4-].[Na+].[C:3]([C:6]1[CH:16]=[CH:15][C:9]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH:7]=1)(=[O:5])[CH3:4].C(O)(=O)C>CO>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[S:17][C:8]1[CH:7]=[C:6]([CH:3]([OH:5])[CH3:4])[CH:16]=[CH:15][C:9]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CC(=O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(O)c1ccc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
Sodium borohydride (0.2 g) was added portionwise to a solution of 4'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide (1.55 g) in methanol (30 ml) at 15° C. The mixture was stirred overnight at room temperature, treated with acetic acid, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate, dried, and concentrated. The residual oil (1.6 g) was purified by column chromatography on silica gel (50 g) eluting with a mixture of toluene and ethyl acetate (4:1). The purified product was recrystallized from a mixture of ethanol and water (2:1) to give crystals of 2'-(2,4-difluorophenylthio)-4'-(1-hydroxyethyl)methanesulfonanilide (1.03 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:23])[NH:15][CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][C:19]=4[N:20]=3)[C:6]=2[CH:24]=1.C(=[NH:38])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1COCC1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:38][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:23])[NH:15][CH2:16][C:17]([CH3:22])([CH3:21])[CH2:18][C:19]=4[N:20]=3)[C:6]=2[CH:24]=1
Reactant: CC1(C)CNC(=O)c2sc(N3CCOc4ccc(Br)cc43)nc2C1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1CCOC1
Product: CC1(C)CNC(=O)c2sc(N3CCOc4ccc(N)cc43)nc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.9 %

Procedure:
A mixture of Example 67 (0.48 g, 0.98 mmol), benzophenone imine (0.356 g, 1.96 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (40 mg, 0.06 mmol), sodium tert-butoxide (0.192 g, 2.0 mmol) and tris(dibenzylidineacetone)dipalladium(0) (29 mg, catalytic) in THF (10 mL) was heated to 120° C. for 2 h. The reaction mixture was cooled to r.t., concentrated in vacuo, and the residue dissolved in methanol (2 mL). 2N Hydrochloric acid (10 mL) was added and the mixture stirred overnight. It was basified with aqueous sodium carbonate and extracted with DCM (3×25 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo. The residue was triturated with Et2O to give the title compound (0.30 g, 89%) as a beige solid. δH (CDCl3) 1.11 (6H, s), 2.85 (2H, s), 3.12 (2H, d, J 5.3 Hz), 3.52 (2H, br.s), 4.07-4.13 (2H, m), 4.19-4.26 (2H, m), 5.93 (1H, br.s), 6.40 (1H, dd, J 8.5, 2.6 Hz), 6.75 (1H, d, J 8.7 Hz), 7.29 (1H, d, J 2.6 Hz). LCMS (ES+) 345 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:15]C(=O)OC(C)(C)C)[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[NH2:15][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: CC(C)(C)OC(=O)NC(CNS(C)(=O)=O)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCC(N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
tert-butyl 1-(4-chlorophenyl)-2-(methylsulfonamido)ethylcarbamate (Intermediate 74) (151 mg, 0.43 mmol) was treated with trifluoroacetic acid (2 mL). The solution was stirred for 1 hour at room temperature. The mixture was concentrated under reduced pressure. The crude product was purified by ion exchange chromatography, using an SCX column. The residue was loaded onto the column in methanol and washed with methanol. The desired product was eluted from the column using 2M ammonia in methanol and pure fractions were evaporated to dryness to afford N-(2-amino-2-(4-chlorophenyl)ethyl)methanesulfonamide (93 mg, 86%) as a colourless crystalline solid.