Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([N:20]([CH3:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:28])=[CH:4][N:3]=1.[CH3:29][N:30]([CH3:39])[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:28][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C:18]([N:20]([CH3:27])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:19])[CH2:15][CH2:16]2)=[C:7]2[N:8]=[C:35]([C:34]3[CH:37]=[CH:38][C:31]([N:30]([CH3:39])[CH3:29])=[CH:32][CH:33]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CN(C(=O)CN1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1)c1ccccc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc(-c2nc3c(N4CCN(CC(=O)N(C)c5ccccc5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C

Procedure:
To a mixture of 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-methyl-N-phenyl-acetamide (0.037 g, 0.09 mmol), ethanol (3 ml), and 4-dimethylamino-benzaldehyde (0.019 g, 0.13 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.4 ml, 0.4 mmol). The reaction mixture was heated at 70° C. for 6 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column which was eluted first with ethyl acetate/dichloromethane (v/v; 1:1), and then 1-2% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained after trituration with diethyl ether as a pale yellow solid (0.008 g, 18%); 1H-NMR (500 Mz, DMSO-d6) 2.58 (br s, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.21 (s, 3H, NCH3), 3.61 (br s, 4H, piperazine N(CH2)2), 6.82 (d, J=9.87 Hz, 2H, 3,5-C6H4—NMe2 or 2,6-C6H4—NMe2), 7.30-7.50 (m, 5H, N-Ph), 8.00 (m, 3H, 3,5-C6H4—NMe2 or 2,6-C6H4—NMe2 and imidazo[4,5-b]pyridine 5-H); 13.09 (s, 1H, imidazo[4,5-b]pyridine N—H); LC-MS (ESI, m/z) 5.10 min—504, 506 [(M+H)+, Cl isotopic pattern]; ESI-HRMS Found: 504.2278, calculated for C27H31N7ClO (M+H)+: 504.2279.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](/[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)=[CH:10]/[CH:11]=O.[C:21]([CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:23][CH3:24])=[O:22]>C(Cl)(Cl)(Cl)Cl.ClCCl>[CH3:24][O:23][C:21](=[O:22])/[CH:25]=[CH:11]/[CH:10]=[C:9](/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])\[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc(/C(=C\C=O)c2ccccc2OC)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C/C=C(\c1ccc(OC)cc1)c1ccccc1OC
Yield: 76.1 %

Procedure:
As described in Example 99, (E)-3-(2-methoxyphenyl)-3-(4-methoxyphenyl)-2-propenal (5 g) was reacted with (carbomethoxymethylene)triphenylphosphorane (6.83 g) in a mixture of carbon tetrachloride (50 ml) and dichloromethane (25 mL) for 4 days at room temperature. The crude ester was isolated in the usual way and was crystallized from 2-propanol-hexane to provide 4.6 g of (E,E)-5-(2-methoxyphenyl)-5-(4-methoxyphenyl)-2,4-pentadienoic acid methyl ester. Recrystallization of a sample from the same solvents gave the analytical specimen, mp 99.5°-102.5° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[CH2:4][CH2:5][CH:6]=[O:7].[O:12]=[C:13]([CH3:20])/[CH:14]=[CH:15]/[C:16]([O:18][CH3:19])=[O:17]>C(Cl)(Cl)Cl>[CH2:4]([C@H:5]1[C@@H:15]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[C:13]([CH3:20])[O:12][C:6]1=[O:7])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: COC(=O)/C=C/C(C)=O
Reactant: O=CCCc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1C=C(C)OC(=O)[C@H]1Cc1ccccc1
Yield: 88 %

Procedure:
Prepared according to the general procedure from 2-chloro-hydrocinnamaldehyde and (E)-methyl 4-oxopent-2-enoate using 0.5 mol % 1 as the catalyst in 88% yield as a single diasteromer (colorless oil). [α]D20 (c 1.10, CHCl3)=+218.7; 1H NMR (400 MHz, CDCl3) δ 7.32-7.23 (m, 3H), 7.12 (d, 2H, J=7.2 Hz), 5.02 (d, 1H, J=7.2 Hz), 3.73 (s, 3H), 3.48 (dd, 1H, J=14.3, 4.6 Hz), 3.02 (t, 1H, J=6.0 Hz), 2.89-2.84 (m, 1H), 2.66 (dd, 1H, J=14.3, 10.1 Hz), 1.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 171.3, 169.3, 152.6, 138.3, 129.2, 129.0, 127.0, 98.7, 52.6, 42.8, 40.3, 33.4, 19.0; IR (thin film) ν 3062, 2954, 1780, 1732, 1496, 1435, 1362, 1164 cm−1; HRMS (ESI) calcd for C15H16O4 [M+Na]+ 283.0940, found 283.0944; 99% ee (3S,4S)-isomer as determined by HPLC (AD-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=12.0 min, tr (3R,4R)=9.40 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[CH2:13]([NH2:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH:23][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCCCCCCCCCN
Product: CCCCCCCCCCNC(=O)c1cccc([N+](=O)[O-])c1

Procedure:
Using this procedure 3-nitrobenzoyl chloride was treated with decylamine to give 3-nitro-N-decylbenzamide, mp 86°-88°, which was hydrogenated to give 3-amino-N-decylbenzamide, mp 56°-58°, which gave nmr and mass spectra consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:16]([OH:18])=O)[C:6](=[O:15])[N:7]2[CH:12]([CH3:14])[CH3:13].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2([OH:45])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH2:34][CH2:33]1>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:16]([NH:30][CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]3([OH:45])[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[CH2:34][CH2:33]1)=[O:18])[C:6](=[O:15])[N:7]2[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)n1c(=O)c(C(=O)O)cc2c(Cl)cccc21
Reactant: NCC1CCN(CC2(O)CCOCC2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)n1c(=O)c(C(=O)NCC2CCN(CC3(O)CCOCC3)CC2)cc2c(Cl)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a solution of 5-chloro-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (111 mg, 0.418 mmol, step 4 in preparation 1) in dichloromethane (1 mL) was added oxalyl chloride (0.11 mL, 1.26 mmol) and a drop of N,N-dimethylformamide at 0° C. The mixture was stirred at room temperature for 0.5 h. The solvent and excess amount of oxalyl chloride was removed in vacuo. The residue was dissolved in dichloromethane (1 mL), 4-{[4-(aminomethyl)piperidin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (191 mg, 0.837 mmol, step 2) was added at 0° C. and the mixture was stirred at room temperature for 1 h. Then, the mixture was quenched with water (10 mL), and the aqueous layer was extracted with dichloromethane (20 mL×2). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from isopropanol to give 156 mg (78%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27](=[N:30]O)([NH2:29])[CH3:28]>CN(C=O)C>[CH3:28][C:27]1[N:30]=[C:12]([CH2:11][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)[O:14][N:29]=1
Reactant: CC(N)=NO
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1noc(Cc2ccc(S(C)(=O)=O)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(methylsulfonyl)phenylacetic acid (15 g, 70 mmol) in DMF (300 mL) at r.t., was added carbonyldiimidazole (12.5 g, 77 mmol). After 0.5 h at r.t., acetamide oxime (5.7 g, 77 mmol) was added. After stirring the resulting mixture overnight at r.t., the mixture was heated to 120° C. for 6 h. After cooling to r.t., the mixture was quenched with H2O, and extracted with EtOAc. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (Hex:EtOAc, 1:1) yielded (3-Methyl-1,2,4-oxadiazol-5-yl) [4-(methylsulfonyl)phenyl]methane.
Reaction SMILES: Br.COC([N:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:15])[CH3:14])[CH2:8][C@H:7]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O.O>C(O)(=O)C>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:7]2[CH2:8][C@@H:9]([NH:12][C:13](=[O:15])[CH3:14])[CH2:10][CH2:11][NH:6]2)=[CH:22][CH:21]=1
Reactant: COC(=O)N1CC[C@H](NC(C)=O)C[C@H]1Cc1ccc(Cl)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)N[C@H]1CCN[C@H](Cc2ccc(Cl)cc2)C1
Reaction time: 16 h

Procedure:
51.8 ml of 33% hydrogen bromide in acetic acid are added to (2R*,4S*)-4-acetylamino-2-(4-chloro-benzyl)-piperidine-1-carboxylic acid methyl ester (30.0 g, 92.3 mmol). After 16 hours, 200 ml of water are added to the mixture which is then washed twice with toluene. The aqueous phase is rendered basic and extracted twice with ethyl acetate. The organic phases are dried on potassium carbonate and concentrated by evaporation using a rotary evaporator. The title compound crystallises in the form of a hydrochloride from EtOH/ethyl acetate. M.p.: 288-289° C. TLC: methylene chloride/methanol/conc. ammonia (90:9:1) Rf =0.17, FD-MS: (M+1)+ =267.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1=[N:11][C:12]([CH3:14])=[N:13][N:6]1[C:5]2([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)N.C(O)(=[O:24])C>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:7]2[N:11]=[C:12]([CH3:14])[NH:13][N:6]=2)=[C:4]([CH:3]=1)[C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: Cc1nc2n(n1)C(N)(c1ccccc1)c1cc(Cl)ccc1-2
Reactant: CC(=O)O
Solvent: CO
Product: Cc1nc(-c2ccc(Cl)cc2C(=O)c2ccccc2)n[nH]1

Procedure:
Ten milligrams of 7-chloro-2-methyl-5-phenyl-5H-[1,2,4]triazolo-[5,1-a]-isoindol-5-amine (as prepared in Example 1) are refluxed for 10 minutes in 2 ml of 50% aqueous methanol containing a drop of acetic acid. The methanol is removed under vacuum and the aqueous residue made basic with 10% NaOH. The aqueous solution is washed with chloroform, neutralized with 10% HCl and extracted with chloroform. The chloroform solution is evaporated to dryness and the residue is recrystallized from a water-ethanol mixture, m.p. 149° to 150°.
Reaction SMILES: [CH3:1][C:2]1[C:30]([CH3:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[NH:12][N:13]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl>CN(C)C=O.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[C:30]([CH3:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[N:12]([CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[N:13]=3)[C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1C)-n1c(n[nH]c1=O)-c1cccnc1N2C(=O)CN1CCN(C)CC1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C)-n1c(nn(CCCN(C)C)c1=O)-c1cccnc1N2C(=O)CN1CCN(C)CC1
Reaction time: 22 h

Procedure:
In the manner given in Example 21, to 6,7-dimethyl-2,9-dihydro-9-[(4-methylpiperazino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling [3-(dimethylamino)propyl]chloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 6,7-dimethyl-2,9-dihydro-2-[3-(dimethylamino)propyl]-9-[(4-methylpiperazino)-acetyl]-3-H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepin-3-one.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:22][CH2:23][CH2:24][NH2:25]>>[OH:22][CH2:23][CH2:24][NH:25][C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: NCCO
Product: COc1ccc(N(C)c2nc(NCCO)nc3ccccc23)cc1

Procedure:
The title compound was prepared from (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine (15 mg, 0.050 mmol) and 2-hydroxylethylamine (20 μL) by a procedure similar to example 10 and was isolated as white solid (12 mg, 80%). 1H NMR (CDCl3): 7.43 (ddd, J=8.4, 1.5 and 0.9 Hz, 1H), 7.35 (ddd, J=7.8, 3.3 and 1.5 Hz, 1H), 7.12-7.06 (m, 2H), 6.92-6.90 (m, 2H), 6.84 (dd, J=8.4 and 1.5 Hz, 1H), 6.66 (ddd, J=7.2, 6.3 and 1.5 Hz, 1H), 3.91-3.89 (m, 2H), 3.83 (s, 3H), 3.69-3.65 (m, 2H), 3.48 (s, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([O:21][CH2:22][CH:23]([CH2:41][O:42][CH2:43][CH:44]1[O:46][CH2:45]1)[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O.O1CCOCC1>[CH2:5]([O:21][CH2:22][CH:23]([CH2:41][O:42][CH2:43][CH:44]([OH:46])[CH2:45][N:1]=[N+:2]=[N-:3])[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCCOCC(COCC1CO1)OCCCCCCCCCCCCCCCC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(COCC(O)CN=[N+]=[N-])OCCCCCCCCCCCCCCCC
Yield: 62 %

Procedure:
A solution of sodium azide (0.5 g., 7.7 mmoles) in water (5 ml.) was added to a refluxing solution of 1,2-di-O-(n-hexadecyl)-3-O-(2,3-epoxypropyl)-glycerol (3.3 g., 5.5 mmoles) in 1,4-dioxane (100 ml.), and the resulting solution stirred at reflux for 16 hours. Since the reaction was not yet complete, additional sodium azide (0.5 g., 7.7 mmoles) was added and the reaction stirred at reflux for another 16 hours. The reaction solution was then cooled, concentrated in vacuo, diluted with water (100 ml.) and extracted with ether (3×100 ml.). The combined ether extract was washed with water (100 ml.), dried (MgSO4), filtered and evaporated in vacuo to an oil which solidified on standing [2.2 g., 62% yield, ir (CHCl3) 2105 cm-1 ].
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:10][C:9]=2[O:19][CH3:20])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][CH:3]=1.Cl[C:31]1[C:32]2[N:39]=[CH:38][N:37]([CH2:40][CH3:41])[C:33]=2[N:34]=[N:35][CH:36]=1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH3:18])(=[O:15])=[O:16])=[CH:10][C:9]=2[O:19][CH3:20])=[CH:6][C:5]([C:31]2[C:32]3[N:39]=[CH:38][N:37]([CH2:40][CH3:41])[C:33]=3[N:34]=[N:35][CH:36]=2)=[CH:4][CH:3]=1
Reactant: CCS(=O)(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)ccc2Cl)c(OC)c1
Reactant: CCn1cnc2c(Cl)cnnc21
Product: CCn1cnc2c(-c3ccc(Cl)c(-c4ccc(S(=O)(=O)CC)cc4OC)c3)cnnc21
Yield: 19 %

Procedure:
Prepared according to the method described for Example 45 using 2-(6-chloro-4′-(ethylsulfonyl)-2′-methoxy-[1,1′-biphenyl]-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 56) and 4-chloro-7-ethyl-7H-imidazo[4,5-c]pyridazine (Preparation 8) to afford the title compound as an off white solid in 19% yield, 9.9 mg.
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17]>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:11]([NH:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])=[O:12])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NS(=O)(=O)c1ccccc1
Yield: 83.5 %

Procedure:
The title compound was prepared in 83.5% yield from benzenesulfonyl isocyanate and 3,4-dichloroaniline following the procedure of Example 1, m.p. 194-195° C.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5][C:6]2[CH:17]=[CH:16][C:9]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=2)[CH2:2]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:30][C:29]([C:31](OCC)=[O:32])=[N:28][N:27]=2)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[O:30][C:29]([C:31]([N:1]3[CH2:2][CH:3]([S:5][C:6]4[CH:17]=[CH:16][C:9]([CH2:10][N:11]5[CH2:12][CH2:13][CH2:14][CH2:15]5)=[CH:8][CH:7]=4)[CH2:4]3)=[O:32])=[N:28][N:27]=2)=[CH:24][CH:25]=1
Reactant: c1cc(SC2CNC2)ccc1CN1CCCC1
Reactant: CCOC(=O)c1nnc(-c2ccc(OC)cc2)o1
Product: COc1ccc(-c2nnc(C(=O)N3CC(Sc4ccc(CN5CCCC5)cc4)C3)o2)cc1
Temperature: 120 °C
Yield: 23.7 %

Procedure:
Intermediate 59E (0.37 g, 1.5 mmol) and ethyl 5-(4-methoxyphenyl)-1,3,4-oxadiazole-2-carboxylate (0.48 g, 1.9 mmol) were mixed and heated to 120° C. for 2 h using an oil-bath. The product was purified by flash-chromatography using 1-5% methanol/DCM where the methanol contained ammonia (2M). The product crystallised when adding ether and the solid was dried in vacuo. There was obtained 0.16 g (24%) of 59 as a solid. 1H NMR (500 MHz, CDCl3): δ 1.81 (m, 4H), 2.51 (m, 4H), 3.62 (m, 2H), 3.89 (s, 3H), 4.18 (m, 2H), 4.63 (m, 2H), 5.11 (m, 1H), 7.02 (d, 2H), 7.27 (m, 4H), 8.09 (d, 2H), MS (APCI+) m/z 451 [M+H]+, LC purity: 97%.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[C:4]#[N:5].O=[C:13]([CH3:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[CH2:18]([O:17][C:15]([C:14]1[C:13]([CH3:20])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH3:11])[CH:7]=[CH:8][CH:9]=2)=[O:16])[CH3:19]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cccc(N)c1C#N
Product: CCOC(=O)c1c(C)nc2cccc(OC)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-methoxybenzonitrile and ethyl 3-oxobutanoate as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=7.2 Hz, 3H), 2.55 (s, 3H), 3.96 (s, 3H), 4.30 (q, J=7.2 Hz, 2H), 6.88 (d, J=8.4 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.52 (t, J=8.0 Hz, 1H), 8.15 (s, 2H). MS 261 (MH+).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([N:8]([CH3:31])[C@@H:9]2[CH2:13][CH2:12][N:11]([C:14]3[C:15]4[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:10]2)=[N:6][CH:7]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.O>CN1C(=O)CCC1>[CH3:31][N:8]([C@@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10]1)[C:5]1[CH:4]=[N:3][C:2]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[CH:7][N:6]=1
Reactant: CN(c1cnc(Br)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Reactant: C1COCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: CN(c1cnc(N2CCOCC2)cn1)[C@@H]1CCN(c2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C

Procedure:
A solution of (R)-5-bromo-N-methyl-N-(1-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)pyrazin-2-amine (0.099 mmol) and morpholine (1.5 mL) in NMP (0.5 mL) was stirred at 195° C. for 2 hours in a microwave reactor. After cooling to the ambient temperature, it was poured into water, and extracted with EtOAc. The combined organic extracts were concentrated and the residue was purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[S:10][C:9]=1[C:16]([O:18]C)=O)[CH3:5].O>C1COCC1>[CH3:3][N:4]([N:6]=[N:7][C:8]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[S:10][C:9]=1[C:16]([NH2:2])=[O:18])[CH3:5]
Reactant: [NH4+]
Reactant: COC(=O)c1sc([N+](=O)[O-])cc1N=NN(C)C
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)N=Nc1cc([N+](=O)[O-])sc1C(N)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
To an ice cold (0-5° C.) solution of ammonium hydroxide (35 mL) was added a solution of methyl 3-[(dimethylamino)diazenyl]-5-nitrothiophene-2-carboxylate (400 mg) in THF (10 mL) for 5 min and stirred at rt for 20 h. The solution was poured into ice cooled water and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (50:50) as eluents to give the product as a yellow color solid (90 mg, 26%), mp 240-246° C. 1H NMR (400 MHz, DMSO-d6): δ 8.22 (1H, s), 8.05 (1H, s), 7.91 (1H, s), 3.63 (3H, s), 3.26 (3H, s); LC-MS (positive ion mode): m/z 266 (M+Na)+.
Reaction SMILES: [NH2:1][C@:2]([CH3:13])([CH2:5][CH2:6][C:7]1[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1)[CH2:3][OH:4].[C:14](OC(OC(C)(C)C)=O)(OC(C)(C)C)=[O:15].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:13][C@@:2]1([CH2:5][CH2:6][C:7]2[N:8]([CH3:12])[CH:9]=[CH:10][CH:11]=2)[CH2:3][O:4][C:14](=[O:15])[NH:1]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cn1cccc1CC[C@@](C)(N)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cccc1CC[C@]1(C)COC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
The obtained (2R)-2-amino-2-methyl-4-(1-methylpyrrol-2-yl)butan-1-ol 1/2 D-(−)-tartrate (41.4 mg, 0.16 mmol) was suspended in methylene chloride (1.6 mL) and di-t-butyl dicarbonate (0.176 g, 0.810 mmol), triethylamine (0.225 mL, 1.62 mmol) and 4-dimethylaminopyridine (2.0 mg, 0.016 mmol) were added thereto, followed by stirring of the mixture at room temperature for 30 minutes. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane:ethyl acetate 3:2-2:1) to obtain (4R)-4-methyl-4-[2-(1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (17.7 mg, yield: 53%).
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=O)[CH2:17]Br)=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]2[C:9]3=[C:10]4[C:5]([CH2:6][CH2:7][CH2:8]3)=[CH:4][CH:3]=[CH:2][N:1]4[CH:17]=2)=[CH:14][CH:13]=1
Reactant: c1cnc2c(c1)CCCC2
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2cn3cccc4c3c2CCC4)cc1
Temperature: 25 °C

Procedure:
5,6,7,8-Tetrahydroquinoline (35 g) was dissolved in 500 ml of toluene. To this solution was added 4-chlorophenacyl bromide (61.4 g) gradually and refluxed for 1 hour. The reaction mixture was cooled to room temperature, and depositing crystals were collected by filtration (86 g). These solids were dissolved in 500 ml of N,N-dimethylformamide. To this solution was added, molecular sieves 3A (50 g) and triethylamine (44 ml), then the reaction mixture was heated at 100° C. for 1 hour. The reaction mixture became dark brown. The dark brown solution that obtained after removing insoluble matter by filtration was concentrated under reduced pressure. The resultant brown solids were recrystallized from ethanol (300 ml), and the title compound was obtained as colorless leaflets (50 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:23](Cl)(=[O:25])[CH3:24].C(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([O:16][C:23](=[O:25])[CH3:24])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2O)cc1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3NC(=O)[C@@H]2OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
3.36 g of (-)-cis-2-(4-methoxyphenyl)-3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are dissolved in 10 ml of pyridine, and 0.87 g of acetyl chloride is added dropwise thereto under ice-cooling. The mixture is stirred at room temperature for one hour. Then, the mixture is diluted by addition of chloroform. The diluted mixture is washed with 10% hydrochloric acid and water, and then evaporated under reduced pressure to remove solvent. The residue is recrystallized from a mixture of ether and n-hexane, whereby 3.37 g of (-)-cis-2-(4-methoxyphenyl)-3-acetoxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained as needles.