Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:33]2[CH:41]=[CH:40][CH:39]=[C:38]3[C:34]=2[CH:35]=[N:36][NH:37]3)O1>>[NH:37]1[C:38]2[C:34](=[C:33]([C:2]3[N:3]=[C:4]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5]4[S:10][C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=5)=[CH:8][C:6]=4[N:7]=3)[CH:41]=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: COc1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: COc1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1

Procedure:
2-Chloro-6-(3-methoxyphenyl)-4-morpholinothieno[3,2-d]pyrimidine (94 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 8.1 mg of 335. MS (Q1) 444.2 (M)+
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.C1CCCCC1.[CH3:18][CH:19]([SH:23])[CH:20]([SH:22])[CH3:21].C(=O)C1C=CC=CC=1>O>[CH3:21][CH:20]1[CH:19]([CH3:18])[S:23][CH:11]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[S:22]1
Reactant: CC(S)C(C)S
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: O=Cc1ccccc1
Solvent: C1CCCCC1
Product: CC1SC(c2ccccc2)SC1C
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Into a 100 ml reaction flask equipped with thermometer, reflux condenser and magnetic stirring bar and hot plate with magnetic stirring apparatus is placed 0.5 grams of para-toluenesulfonic acid, 5.0 ml cyclohexane and 6.1 grams (0.05 moles) of 2,3-butanedithiol. Over a period of 25 minutes, 5.3 grams (0.05 moles) of benzaldehyde is added to the reaction mass with stirring. The reaction mass is then heated to reflux with stirring and refluxed for a period of 9.5 hours while taking off water of reaction. At the end of the refluxing period, the reaction mass is cooled to room temperature and transferred to a separatory funnel. The reaction mass is then washed with one 50 ml portion of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The resulting filtrate is distilled on a Microvigreux column yielding the following three fractions:
Reaction SMILES: [CH2:1]([N:3]([CH2:22]C)[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17]C)[CH:13]=[C:12](OCC)[CH:11]=1)C.C(OC1C=C(CCCC#C)C=C(OCC)C=1)C>>[CH3:22][N:3]([CH3:1])[CH2:4][C:5]#[C:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1
Reactant: CCOc1cc(CCCC#CCN(CC)CC)cc(OCC)c1
Agent: C#CCCCc1cc(OCC)cc(OCC)c1
Product: COc1cccc(CCCC#CCN(C)C)c1

Procedure:
To prepare 1-diethylamino-6-(3,5-diethoxyphenyl)-hex-2-yne treat 5-(3,5-diethoxyphenyl)pent-1-yne (ca. 8 g) according to the manipulative procedure described above.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:33])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1.Cl.CCOCC>C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][N:10]([C:24]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)=[O:33])[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Agent: Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2CCc3[nH]c4ncc(Cl)cc4c3C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 108 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2 mL). p-Anisoyl chloride (0.04 mL, 0.29 mmol) was added dropwise, and the reaction solution was stirred at room temperature for 1 h The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 ml) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 26 (49 mg, 54% yield) as an off white solid. LC-MS (M+H=342, obsd.=342).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([N:18]=2)[C:16]2[CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=[CH:22][C:15]=2[O:14][CH2:13][CH2:12]3)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]3[N:17]([C:16]4[CH:19]=[C:20]([C:23]([NH:32][C:33]5[CH:37]=[CH:36][O:35][N:34]=5)=[O:24])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12]3)[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: Nc1ccon1
Reactant: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)O)ccc1OCC2
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cc2n(n1)-c1cc(C(=O)Nc3ccon3)ccc1OCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an ice-cooled suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,10b-diaza-benzo[e]azulene-9-carboxylic acid (0.15 g, 0.44 mmol) in DCM (3.5 mL) was added oxalyl chloride (79 L, 0.93 mmol) and DMF (25 L) and the mixture stirred at RT for 2 h. 3-Amino-isoxazole (185 mg, 2.2 mmol) and triethylamine (0.12 mL, 0.88 mmol) were added and the mixture stirred at RT for 18 h before the addition of saturated aqueous sodium hydrogen carbonate. The resultant mixture was extracted with DCM then 5% MeOH in DCM and the combined extracts dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% MeOH in DCM) followed by trituration in diethyl ether to give 126 as a white solid. 1H NMR (CDCl3, 400 MHz): δ 9.49 (s, 1H); 8.65 (d, J=2.3 Hz, 1H); 8.30 (d, J=1.8 Hz, 1H); 7.96 (d, J=0.7 Hz, 1H); 7.86 (dd, J=8.5, 2.3 Hz, 1H); 7.30 (d, J=8.5 Hz, 1H); 7.23 (d, J=1.8 Hz, 1H); 6.88 (s, 1H); 5.72-5.59 (m, 1H); 4.61 (t, J=5.6 Hz, 2H); 3.25 (t, J=5.6 Hz, 2H); 1.58 (d, J=6.6 Hz, 6H). LCMS: RT=10.24 min, M+H+=406
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH:7]=1.ClC1CCC(C(OCC)=O)=C(C2C=CC=CC=2)C=1.C(O[K])(C)(C)C.O>C(O)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1
Reactant: CCOC(=O)C1CC=C(Cl)C=C1c1ccccc1
Agent: CC(C)(C)O[K]
Agent: CCOC(=O)C1=C(c2ccccc2)C=C(Cl)CC1
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)c1ccc(Cl)cc1-c1ccccc1
Reaction time: 48 h

Procedure:
To a stirred solution of ethyl 4-chloro-2-phenylcyclohexa-2,4-dienecarboxylate and ethyl 4-chloro-2-phenylcyclohexa-1,3-dienecarboxylate(200 mg, 0.762 mmol) in tert-BuOH(3 ml), tert-BuOK(103 mg, 0.914 mmol) was added by portion on a water bath. After stirring for 2 days, water was added to the reaction mixture and it was acidified with dil. HCI aq., extracted with AcOEt. The organic layer was washed with brine and dried over MgSO4. Concentration of the organic layer afford a mixture(200 mg) of ethyl 4-chloro-2-phenylbenzoate and 4-chloro-2-phenylbenzoic acid. 1H-NMR(ppm, 300 MHz, CDCl3) δ ester 7.79(1H, d, J=8.0 Hz), 7.10-7.50(7H), 4.07(2H, d, J=6.9 Hz), 0.98(3H, t, J=6.9 Hz); acid 7.91(1H, d, J=8.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH:6]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH2:21])[CH2:15][CH2:14]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:24]1([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[N:40]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[N:39]=[C:38]([CH:47]=O)[CH:37]=3)=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([N:13]2[CH2:14][CH2:15][N:16]([CH2:19][CH2:20][NH:21][CH2:47][C:38]3[CH:37]=[C:36]([C:33]4[CH:34]=[CH:35][C:30]([CH:24]5[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]5)=[CH:31][CH:32]=4)[N:40]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[N:39]=3)[CH2:17][CH2:18]2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:22][CH:23]=1
Reactant: NCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reactant: O=Cc1cc(-c2ccc(C3CCCCC3)cc2)n(-c2ccccc2)n1
Product: Clc1ccc(C(c2ccccc2)N2CCN(CCNCc3cc(-c4ccc(C5CCCCC5)cc4)n(-c4ccccc4)n3)CC2)cc1
Yield: 31 %

Procedure:
Compound 101 was prepared using the same method as that of Example 1 except that 4-(4-chlorobenzhydryl)piperazin-1-ylethylamine and 5-(4-cyclohexyl phenyl)-1-phenyl pyrazole-3-carbaldehyde were used.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]([OH:13])[CH3:12])[O:10][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[C:11]([C:9]1[O:10][C:6]2[C:5]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]3=[O:26])=[C:4]([F:27])[CH:3]=[C:2]([Cl:1])[C:7]=2[CH:8]=1)(=[O:13])[CH3:12]
Reactant: CC(O)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1

Procedure:
1.5 g (3.7 mmol) of 3-[4-chloro-6-fluoro-2-(1-hydroxyethyl) benzofuran-7-yl]-1-methyl-6-trifluoromethyluracil was dissolved in 20 ml of acetone, and a Jones' reagent was dropwise added thereto at 5° C. until the orange color no longer disappeared. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to quantitatively obtain the desired product as pale orange crystals. Melting point: 193-194° C.
Reaction SMILES: [CH:1](=O)[CH3:2].C=O.[C:6]1([S:12]([CH2:15][C@@H:16]2[CH2:21][C@H:20]([NH:22][CH:23]([CH3:25])[CH3:24])[CH2:19][CH2:18][C@@H:17]2[N:26]2[CH2:31][CH2:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)=[CH:28][C:27]2=[O:42])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[C:6]1([S:12]([CH2:15][C@@H:16]2[CH2:21][C@H:20]([N:22]([CH:23]([CH3:25])[CH3:24])[CH2:1][CH3:2])[CH2:19][CH2:18][C@@H:17]2[N:26]2[CH2:31][CH2:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:39])[F:40])[CH:33]=3)=[CH:28][C:27]2=[O:42])(=[O:13])=[O:14])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC=O
Reactant: CC(C)N[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Agent: C=O
Product: CCN(C(C)C)[C@@H]1CC[C@H](N2CCC(c3cccc(C(F)(F)F)c3)=CC2=O)[C@H](CS(=O)(=O)c2ccccc2)C1

Procedure:
Following the procedure of Example 104 but substituting acetaldehyde for aqueous formaldehyde, 1-([(1S, 2R, 4R)-2-benzenesulfonylmethyl-4-isopropylamino-cyclohexyl)-4-(3-trifluoromethylphenyl)-5,6-dihydro-1H-pyridin-2-one (43 mg, 0.08 mmol) was converted to the title product (45 mg) as a white glassy solid. MS found: (M+H)+=563.29.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([NH2:40])[CH2:35]1)(=[O:33])=[O:32]>>[NH2:40][CH:36]1[CH2:37][CH2:38][CH2:39][N:34]([S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:35]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: NC1CCCN(S(=O)(=O)c2ccccc2Br)C1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCCC(N)C3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and racemic-1-((2-bromophenyl)sulfonyl)piperidin-3-amine. MS (ESI): mass calcd. for C26H30FN5O4S, 427.15; m/z found, 428.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H), 8.33 (s, 1H), 8.11-8.07 (m, 1H), 8.03 (m, 1H), 7.76-7.70 (m, 1H), 7.67-7.62 (m, 1H), 7.46-7.42 (m, 1H), 7.36-7.29 (m, 2H), 3.40-3.41 (m, 1H), 3.13-3.02 (m, 2H), 2.66-2.60 (m, 2H), 2.01-1.92 (m, 1H), 1.78-1.67 (m, 1H), 1.55-1.42 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[N:9]=2)[CH:7]=1.[Cl:28][C:29]1[C:30](F)=[CH:31][C:32]([F:55])=[C:33]([S:35]([N:38](CC2C=CC(OC)=CC=2OC)[C:39]2[S:40][CH:41]=[N:42][N:43]=2)(=[O:37])=[O:36])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].[F:63][C:64]([F:69])([F:68])[C:65]([OH:67])=[O:66]>CS(C)=O.O>[F:63][C:64]([F:69])([F:68])[C:65]([OH:67])=[O:66].[Cl:28][C:29]1[C:30]([O:27][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=2[C:8]2[CH:13]=[CH:12][N:11]=[C:10]([N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[N:9]=2)=[CH:31][C:32]([F:55])=[C:33]([S:35]([NH:38][C:39]2[S:40][CH:41]=[N:42][N:43]=2)(=[O:36])=[O:37])[CH:34]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3cc(Cl)ccc3O)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CS(C)=O
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Oc2ccc(Cl)cc2-c2ccnc(N3CCNCC3)n2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.3 %

Procedure:
tert-Butyl 4-[4-(5-chloro-2-hydroxyphenyl)pyrimidin-2-yl]piperazine-1-carboxylate (Preparation 2, 48.6 mg, 0.11 mmol), 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 6, 49.1 mg, 0.11 mmol) and potassium carbonate (21.9 mg, 0.16 mmol) were mixed in dimethylsulfoxide (1 mL) and shaken at ambient temperature for 18 hours. The reaction mixture was diluted with water and the precipitate collected by filtration. The solid was dissolved in dichloromethane (2.0 mL) and dried over anhydrous magnesium sulfate. The mixture was filtered and trifluoroacetic acid (0.060 mL, 0.78 mmol) was added to the filtrate. After 2 hours the reaction mixture was concentrated in vacuo to a residue and purified by reverse phase HPLC to afford the title compound as a tan glass (35.5 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-])=O.S.[Na].O>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]=[N:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1
Reactant: CN(C)c1ccc(N=Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: S
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CN(C)c1ccc(N=Nc2ccc(N)cc2)cc1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
A suspension of 88.1 g of 4-nitro-4'-(dimethylamino)azobenzene in 1080 ml of ethanol was heated to slight reflux while stirring, treated dropwise within 35 minutes with 1017 g of 25% sodium hydrogen sulphide solution and then stirred at slight reflux for another 1 hour. The mixture was cooled to room temperature, treated with 2120 ml of water and suction filtered. The residue was washed with water/ethanol (vol. 3:1) and dried at 50° C. in vacuo, yielding 55.7 g of 4-amino-4'-(dimethylamino)azobenzene; m.p. 182.5°-187.4° C.
Reaction SMILES: C([O:5][C:6]([CH:8]1[C:13]([OH:15])([CH3:14])[CH2:12][CH2:11][CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][O:25][C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:9]3[CH2:10][CH2:11][CH2:12][C:13]([OH:15])([CH3:14])[CH:8]3[C:6]([OH:7])=[O:5])(=[O:17])=[O:18])=[CH:24][CH:23]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)C1N(S(=O)(=O)c2ccc(OCc3ccc(F)cc3)cc2)CCCC1(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(O)CCCN(S(=O)(=O)c2ccc(OCc3ccc(F)cc3)cc2)C1C(=O)O

Procedure:
A solution of 1-[4-(4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid tert-butyl ester in 2 mL of 1:1 trifluoroacetic acid-CH2Cl2 was stirred for 15 min-2 h at room temperature. Concentration in vacuo afforded 1-[4-(4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic acid as a colorless syrup:
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[C:4]=1[CH:15]=[O:16].C(=O)([O-])O.[Na+]>ClCCl>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[C:4]=1[CH:15]=[O:16]
Reactant: COc1ccc2ccc(OC)c(C=O)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2ccc(O)c(C=O)c2c1
Reaction time: 0.58 h

Procedure:
After the dimethoxylated product obtained in Step B (2 g:9.25 mmol) has been dissolved in anhydrous dichloromethane, 97% BBr3Me2S complex (2.98 g:9.25 mmol:1 eq.) is introduced at ambient temperature. After 35 minutes of stirring, hydrolysis is carried out with a saturated solution of sodium hydrogen carbonate (pH=8). The product is extracted with dichloromethane and then purified on a silica column AcOEt/PE (3/7).
Reaction SMILES: Br[C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[N:5]=2.[CH3:23][O-:24].[Na+]>CO>[CH3:23][O:24][C:2]1[N:3]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[N:5]=2
Reactant: C[O-]
Reactant: CC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Reaction time: 8 h

Procedure:
8-Bromo-2-{[(1S)-1-methylpropyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.79 g, 4.83 mmol) was dissolved in methanol (15 ml) and 25% sodium methoxide in methanol (3.2 ml, 4.83 mmol) was added and the mixture heated to reflux for 2.5 hours. The reaction mixture was left standing at room temperature overnight and then concentrated in vacuo and the residue partitioned between dichloromethane (40 ml) and saturated ammonium chloride solution (40 ml). The layers were separated using a hydrophobic frit and the aqueous phase was re-extracted with dichloromethane (40 ml). The combined organic extracts were concentrated in vacuo to give the title compound as a yellow foam (1.65 g).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH:11]1([CH2:14][OH:15])[CH2:13][CH2:12]1.CC(C)([O-])C.[K+]>CN(C)C=O>[CH:11]1([CH2:14][O:15][C:2]2[N:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=2)[CH2:13][CH2:12]1
Reactant: O=C(O)c1cnc(Cl)cn1
Reactant: OCC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1cnc(OCC2CC2)cn1
Temperature: 25 °C
Yield: 89.8 %

Procedure:
A solution of 5-chloropyrazine-2-carboxylic acid (1.00 g, 6.31 mmol), cyclopropyl carbinol (1.00 mL, 12.4 mmol) and potassium tert-butoxide (2.00 g, 17.8 mmol) in dimethylformamide (20.0 mL) is heated at 100° C. for 3 hours. The reaction is cooled to room temperature, quenched with 1 M hydrochloric acid. The mixture is extracted with ethyl acetate and isopropyl alcohol/chloroform (1/10), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound (1.10 g, 90%) as a grayish solid. This acid is used directly without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:21]=[C:20]([CH2:22][O:23][CH3:24])[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:11]=2[CH:12]=1)=[O:5].O[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[NH2:1][C:2]1[N:21]=[C:20]([CH2:22][O:23][CH3:24])[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[C:15]([O:17][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:14]=[CH:13][C:11]=2[CH:12]=1)=[O:5]
Reactant: OCc1ccccn1
Reactant: COCc1ccc(C(=O)NCc2cc3ccc(O)cc3o2)c(N)n1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCc1ccc(C(=O)NCc2cc3ccc(OCc4ccccn4)cc3o2)c(N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a tetrahydrofuran (2 mL) solution of 2-amino-N-(6-hydroxy-benzofuran-2-ylmethyl)-6-methoxymethyl-nicotinamide (20 mg, 61 μmol) described in Production Example 5-1 were added 2-(hydroxymethyl)pyridine (6.5 μL, 67 μmol), triphenylphosphine (19.2 mg, 73 μmol) and diethylazodicarboxylate (33 μL, 73 μmol) at room temperature, which was stirred at room temperature for 30 minutes. After filtering the reaction solution, the filtrate was purified by reverse phase high-performance liquid chromatography (using an acetonitrile-aqueous mobile phase (containing 0.1% trifluoroacetic acid)) to obtain a mixture of the title compound and 2-amino-N-(6-hydroxy-benzofuran-2-ylmethyl)-6-methoxymethyl-nicotinamide. Then, this mixture was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to obtain the title compound (6 mg, 24%) as a white solid.
Reaction SMILES: [Li]C(C)(C)C.[Si:6]([C:10]#[CH:11])([CH3:9])([CH3:8])[CH3:7].[C:12]([Si:16]([CH3:23])([CH3:22])[O:17][CH2:18][C@H:19]1[CH2:21][O:20]1)([CH3:15])([CH3:14])[CH3:13].B(F)(F)F>C1COCC1>[Si:16]([O:17][CH2:18][C@H:19]([OH:20])[CH2:21][C:11]#[C:10][Si:6]([CH3:9])([CH3:8])[CH3:7])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CO1
Reactant: C#C[Si](C)(C)C
Agent: FB(F)F
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC[C@H](O)CC#C[Si](C)(C)C
Temperature: -78 °C
Reaction time: 4.5 h

Procedure:
tert-BuLi (12.4 ml, 1.7M, 21.1 mmol) was added to a solution of TMS-acetylene (2.12 g, 21.7 mmol) in THF (40 ml) at −78° C. and the reaction mixture was stirred for an additional 30 min. (R)-tert-butyldimethyl(oxiran-2-ylmethoxy)silane (2 g, 10.6 mmol) and BF3.EtO2 (3 g, 21.1 mmol) were added and stirred at −78° C. for 4.5 hours. The reaction was then quenched by addition of aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated under reduced pressure to afford the desired material in a quantitative yield. The material was used in the next step with no further purification.
Reaction SMILES: CON(C)[C:4](=[O:18])[C@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:6].[CH3:20][Mg]Br.C1COCC1.C1(C)C=CC=CC=1.O>C1COCC1>[O:18]=[C:4]([CH3:20])[C@H:5]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH3:6]
Reactant: CON(C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)[C@@H](C)NC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under argon, 1000 mg of benzyl {(2R)-1-[methoxy(methyl)amino]-1-oxopropan-2-yl}carbamate (Example 149A, 3.8 mmol, 1 equivalent) were dissolved in 19.5 ml of THF and cooled to −78° C. At this temperature, 4 ml of 1.4 M methylmagnesium bromide solution in 1:3 THF/toluene (6 mmol, 1.5 equivalents) were added slowly. The mixture was then stirred at −78° C. for 5 min and at RT for 1 h and then allowed to stand at RT overnight. 0.27 ml of water was then added with ice cooling, and the mixture was then concentrated. The residue was diluted with water and 1 N aqueous hydrochloric acid solution and extracted four times with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate solution and with saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated. This gave 888 mg (97% of theory) of the title compound as a colourless oil.