Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[C:9](Cl)(=[O:11])[CH3:10]>C(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[N:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: Nc1cncc(Cl)n1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cncc(Cl)n1
Reaction time: 1 h
Yield: 52.8 %

Procedure:
To a solution of 6-chloropyrazin-2-amine (1.00 g, 7.72 mmol) in DCM (20 mL) was added acetyl chloride (0.659 mL, 9.26 mmol) at RT and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2×100 mL). The combined organic layer was dried over sodium sulfate, filtered and evaporated under reduced pressure to give a residue which was purified by CombiFlash (REDISEP®, silica gel, 12 g, 25% EtOAc/petroleum ether) to give N-(6-chloropyrazin-2-yl)acetamide (0.700 g, 52.9%). LCMS Condition B-39: retention time 1.67 min, [M+1]=170.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 3H), 8.47 (s, 1H), 9.29 (s, 1H), 11.09 (br s, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1.C=O.[BH3-][C:17]#N.[Na+]>C(O)(=O)C>[CH3:17][N:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][O:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1
Reactant: Brc1cncc(OC[C@@H]2CCN2)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CC[C@H]1COc1cncc(Br)c1

Procedure:
A 480 mg sample of the free base of 3-(2-(S)-azetidinylmethoxy)-5-bromopyridine, from Example 67 above, was dissolved in 4 mL of acetic acid treated with 1 mL of 37% HCHO and 500 mg of NaBH3CN at 0° C. for 4 hr. The solvents were removed under reduced pressure. The residue was basified with NaHCO3 solution. The mixture was extracted with methylene chloride, the extract was dried over MgSO4, and the solvent was removed. The residue was purified by chromatography on silica gel, eluting with 200:1 and 100:1 chloroform:methanol to give 68 mg of the title compound. MS (DCI/NH3) m/e: 257/259 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.28 (d, J=1.9 Hz, 1H), 8.26 (d, J=2.6 Hz, 1H), 7.38 (dd, J=1.9, 2.6 Hz, 1H), 4.02 (d, J=6.3 Hz, 2H), 3.51-3.44 (m, 1H), 3.43-3.37 (m, 1H), 2.93-2.84 (m, 1H), 2.41 (s, 3H), 2.13-2.03 (m, 2H).
Reaction SMILES: [NH:1]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[C@@H:2]([C:19]([NH:21][CH2:22][C:23]([NH:25][C@H](C(NNC(CC)=O)=O)CC1C=CC=CC=1)=[O:24])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][N:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH:5]=1.[OH-:49].[Na+]>CO>[NH:1]([C:42]([O:44][C:45]([CH3:46])([CH3:47])[CH3:48])=[O:43])[C@@H:2]([C:19]([NH:21][CH2:22][C:23]([NH:25][NH:1][C:2]([CH2:3][CH3:4])=[O:49])=[O:24])=[O:20])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: [OH-]
Reactant: CCC(=O)NNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](Cc1cn(S(=O)(=O)c2ccc(C)cc2)cn1)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CO
Product: CCC(=O)NNC(=O)CNC(=O)[C@@H](Cc1c[nH]cn1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
BOC-(D)-His(Tos)-Gly-Phe-NHNH-COCH2CH3 (0.55 g) is suspended in MeOH (15 ml) and to this is added 1 N-sodium hydroxide solution (1 ml) at 0° C. The mixture is stirred for 60 min. at room temperature and evaporated. The residue is treated with acetonitrile to give a powder, which is washed with water and dried; yield 0.29 g. m.p. 261°-263° C., [α]D23 +9.5°(c=0.40, DMF), Rf2 =0.38
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24](Cl)[C:23]4[C:18](=[C:19]([Br:29])[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH3:32]>O1CCCC1>[N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[CH:25]=[C:24]([N:31]([CH3:32])[CH3:30])[C:23]4[C:18](=[C:19]([Br:29])[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1cc(Br)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(Cl)c2c1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1cc(Br)c2nc(C(=O)Nc3ccc(N4CCOCC4)cc3)cc(N(C)C)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 8-bromo-4-chloro-6-methoxy-quinoline-2-carboxylic acid (4-morpholin-4-yl-phenyl)-amide (Reference Example 28a) (0.1512 g, 0.317 mmol) in 100 mL 2.0 M dimethyl amine in tetrahydrofuran was heated at 100° C. in a Parr bomb. The initial pressure was 75–80 psi and then remained at approximately 60 psi. After 18 hours, the reaction was cooled to room temperature, concentrated and dried to afford the crude product as a brown solid. Purification on silica gel using a gradient of 100:0 to 95:5 methylene chloride:methanol afforded the clean product (0.142 g; 92%). 1H NMR (300 MHz, DMSO, d6) δ 10.20 (s, 1 H, C(O)NH), 7.90 (d, 1 H, Jm=2.7 Hz, ArH5), 7.69 (d, 2 H, Jo=9.0 Hz, ArH2′ & H6′), 7.60 (s, 1 H, ArH3), 7.41 (d, 1 H, Jm=2.7 Hz, ArH7), 7.01 (d, 2 H, Jo=9.0 Hz, ArH3′ & H5′), 3.96 (s, 3 H, OCH3), 3.75 (t, 4 H, J=4.8 Hz, OCH2CH2N), 3.10 (t, 4 H, J=4.8 Hz, OCH2CH2N), 3.08 (s, 6 H, N(CH3)2); Mass Spec.: calc. for [C21H19BrClN3O3+H]+ Theor. m/z=485, 487; Obs.=485, 487
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].[SH:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:4][CH2:3][CH2:2][S:5][C:6]1[S:7][CH:8]=[CH:9][N:10]=1
Reactant: Sc1nccs1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCSc1nccs1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
1.2 cm3 of 1-bromo-2-chloroethane were run, at a temperature in the region of 20° C., into a stirred solution of 1.47 g of 2-mercaptothiazole and 1.95 g of potassium carbonate in 12.5 cm3 of dimethylformamide. The mixture was subsequently stirred for 2 hours at a temperature in the region of 20° C. The insoluble material was filtered off and washed with 2 times 5 cm3 of dimethylformamide. The filtrate was run onto a mixture of 50 g of crushed ice and 50 cm3 of distilled water, 50 cm3 of ethyl ether were then added and the mixture was stirred and then separated by settling. The aqueous phase was separated by settling and then extracted with 2 times 25 cm3 of ethyl ether. The combined ethereal phases were washed with 2 times 25 cm3 of water and then dried over magnesium sulfate. After filtering through paper, the organic solution was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 2.11 g of 2-(2-chloroethylthio)thiazole were obtained in the form of a mobile oil with a yellow color.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:22])[C:6]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=3[CH:12]=2)=[CH:7][CH:8]=1.[CH2:23](OC(OCC)OCC)C>C(O)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[N:9]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=4[CH:12]=3)[CH:23]=[N:22][C:5]=2[CH:4]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(NCc2ccc3nc(SC)oc3c2)c(N)c1
Solvent: O=CO
Product: COc1ccc2c(c1)ncn2Cc1ccc2nc(SC)oc2c1
Yield: 87.6 %

Procedure:
A solution of 4-methoxy-N1-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine (755 mg, 2.40 mmol) in triethoxymethane (8 mL) and HCOOH (0.2 mL) was stirred at 90° C. for 40 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:2 petroleum ether/ethyl acetate to give 6-((5-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole as a light brown solid (683 mg, 87.6%). 1H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.66 (s, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.43 (d, J=9.0 Hz, 1H), 7.30 (d, J=6.6 Hz, 1H), 7.16 (s, 1H), 6.82 (d, J=6.6 Hz, 1H), 5.54 (s, 2H), 3.75 (s, 3H), 2.73 (s, 3H). LCMS (ESI) m/z 326 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH2:10])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:11]1(=O)[CH2:15][CH2:14][CH2:13][CH2:12]1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C1CCCC1
Reactant: CCOC(=O)C1(CN)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1(CNC2CCCC2)CC1

Procedure:
Reaction of 1-aminomethyl-cyclopropanecarboxylic acid ethyl ester with cyclopentanone, sodium acetate and sodium triacetoxyborohydride in DCM gave 1-cyclopentylaminomethyl-cyclopropanecarboxylic acid ethyl ester
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:19]([F:22])([F:21])[F:20].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:19]([F:22])([F:20])[F:21]
Reactant: OCCc1ccc(CBr)cc1
Reactant: Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc(CCO)cc2)c1
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
To a stirred solution of 3-[3-Methyl-8-(trifluoromethyl)quinolin-4-yl]phenol (0.086 g, 0.28 mmol) and 2-(4-bromomethlyphenyl)ethanol (0.061 g, 0.28 mmol) in CH2Cl2 (5 mL) is added Cs2CO3 (0.365 g, 1.12 mmol). After 1.5 h, additional alkylating agent (0.015 g) is added and the reaction is stirred overnight. The reaction is neutralized with 2N aq HCl, extracted with ethyl acetate and dried (MgSO4). Chromatography eluting with 5:95 ethyl acetate:hexane afforded the title compound (0.092 g, 75%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][N:17]([C:24]4[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=4)[CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(N2CCc3c(ncnc3Nc3ccc(C(F)(F)F)cc3)C2)c1
Reaction time: 6 h
Yield: 4.7 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added m-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (6.2 mg, 5%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][NH2:25]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[CH:10]=[CH:11][C:2]([NH:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[O:21][CH3:20])=[N:3]3)=[CH:14][CH:15]=1
Reactant: COc1ccccc1CN
Reactant: Fc1ccc(Oc2cccc3nc(Cl)ccc23)cc1
Product: COc1ccccc1CNc1ccc2c(Oc3ccc(F)cc3)cccc2n1

Procedure:
2-Chloro-5-(4-fluoro-phenoxy)-quinoline (60 mg, 0.22 mmol) and 2-methoxybenzylamine (90 mg, 0.66 mmol) were stirred in a sealed tube at 150° C. for 16 hours. The reaction mixture was purified by flash chromatography on silica gel (heptane/ethyl acetate 100:0->75:25 gradient). (5-(4-Fluoro-phenoxy)-quinolin-2-yl)-(2-methoxy-benzyl)-amine was obtained as a yellow oil (56 mg, 68%), MS: m/e=375.4 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[CH:5]=[CH:4][N:3]=1.Cl.[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH:26]2[CH2:29][NH:28][CH2:27]2)=[CH:23][CH:22]=1.C(N(C(C)C)C(C)C)C>CC(O)C>[F:20][C:21]1[CH:31]=[CH:30][C:24]([O:25][CH:26]2[CH2:27][N:28]([C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=4)[C:12]([NH:14][CH3:15])=[O:13])[CH:5]=[CH:4][N:3]=3)[CH2:29]2)=[CH:23][CH:22]=1
Reactant: CNC(=O)c1cccc(Nc2ccnc(Cl)n2)c1
Reactant: Fc1ccc(OC2CNC2)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cccc(Nc2ccnc(N3CC(Oc4ccc(F)cc4)C3)n2)c1
Temperature: 84 °C
Yield: 75.8 %

Procedure:
To 3-(2-chloropyrimidin-4-ylamino)-N-methylbenzamide (90.0 mg, 0.343 mmol) and 3-(4-fluorophenoxy)azetidine hydrochloride (73.3 mg, 0.360 mmol) in a disposable sealed tube in 2-propanol (2.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.179 mL, 1.028 mmol). The resulting reaction mixture was heated at 84° C. for 48 h, cooled to RT, filtered, rinsed with IPA, and concentrated under reduced pressure to afford 3-(2-(3-(4-fluorophenoxy)azetidin-1-yl)pyrimidin-4-ylamino)-N-methylbenzamide (102.3 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-])=O.[H][H]>[Pd].C(O)C>[NH:8]1[C:9]2[C:5](=[C:4]([NH2:1])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2[nH]ncc12

Procedure:
A mixture of 4-nitro-1H-indazole C (760 mg, 4.68 mmol), palladium on charcoal (10%, cat.) and ethanol (30 mL) was stirred under a balloon of hydrogen for 4 h. The reaction mixture was then filtered through celite, and the solvent removed in vacuo to yield 1H-indazol-4-ylamine D (631 mg, 100%).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH2:9]([O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[O:17][CH2:18][C:19](O)=O)[CH:10]([CH3:12])[CH3:11]>Cl>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:19]=1[CH2:18][O:17][C:16]1[CH:22]=[CH:23][CH:24]=[C:14]([O:13][CH2:9][CH:10]([CH3:11])[CH3:12])[CH:15]=1
Reactant: Nc1ccccc1N
Reactant: CC(C)COc1cccc(OCC(=O)O)c1
Agent: Cl
Product: CC(C)COc1cccc(OCc2nc3ccccc3[nH]2)c1
Yield: 58.7 %

Procedure:
A 250 mL flask fitted with a stir-bar and condenser was charged with 1,2-phenylenediamine (2.46 g, 22.7 mmol), acid 72 (5.10 g, 22.7 mmol), and 4M HCl (50 mL). The resultant suspension was heated in a 125° C. bath for 72 hr. The mixture was cooled, and concentrated in vacuo to a green solid. The solid was triturated with acetone (50 mL), filtered, and rinsed with acetone (2×20 mL). The solid was then triturated with H2O (50 mL) and filtered. The material was next taken up in MeOH:H2O 1:1 (75 mL), and the pH was adjusted to 11 with 2M NaOH (10 mL). The mixture was then extracted with EtOAc (100 mL). The organic phase was washed with saturated aqueous NH4Cl (50 mL) and brine (50 mL), filtered through phase separation paper, and concentrated in vacuo to a light pink glass. The material crystallized to give 3.95 g of 73 as a white solid (59%). 1H NMR (60 MHz, CDCl3): δ 7.8-7.6 (m, 2H), 7.5-7.0 (m, 3H), 6.6-6.4 (m, 3H), 5.4 (s, 2H), 3.5 (d, 2H), 1.9 (nonet, 1H), 0.9 (d, 6H) ppm. HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 99% with a retention time of 8.5 min.
Reaction SMILES: [OH-].[Na+].Cl.[N+:4]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[NH:12])=[CH:9][CH:8]=1)([O-:6])=[O:5].[Cl:16][C:17]([SH:20])(Cl)Cl.ClCCl>O>[Cl:16][C:17]1[S:20][N:13]=[C:11]([C:10]2[CH:9]=[CH:8][C:7]([N+:4]([O-:6])=[O:5])=[CH:15][CH:14]=2)[N:12]=1
Reactant: SC(Cl)(Cl)Cl
Reactant: N=C(N)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2nsc(Cl)n2)cc1
Reaction time: 2 h
Yield: 40.3 %

Procedure:
A solution of 75.6 gm of sodium hydroxide in 100 ml of water was added to a stirred mixture of 101.4 gm of p-nitrobenzamidine hydrochloride, 70 gm of perchloromethyl mercaptan and 760 ml of dichloromethane, while keeping the temperature below -5° C. After additional 2 hours at -5° C., the resulting suspension was filtered, and the organic phase was separated, evaporated to dryness, and the residual solid was recrystallized from 95% ethanol, yielding 45 gm of the title compound, m.p. 143°-145° C.
Reaction SMILES: O=S(Cl)[Cl:3].[CH2:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:6][CH3:7]>>[CH2:5]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([Cl:3])=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)[CH2:6][CH3:7]
Reactant: O=S(Cl)Cl
Reactant: CCC[C@H]1CC[C@H](c2ccc(C(=O)O)cc2)CC1
Product: CCC[C@H]1CC[C@H](c2ccc(C(=O)Cl)cc2)CC1

Procedure:
In 75 cm3 (1.0 mol) of SOCl2, 128 g (0.52 mol) of 4-(trans-4'-propylcyclohexyl) benzoic acid was refluxed for 3 hours. The excess SOCl2 was distilled off under a reduced pressure and the residue was distilled under reduced pressure (158° C./3.0 mmHg) to yield 133 g (0.50 mol) of 4-(trans-4'-propylcyclohexyl) benzoic acid chloride.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5](C(OC(C)(C)C)=O)[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[C:18]([OH:24])([C:20]([F:23])([F:22])[F:21])=[O:19]>C(Cl)(Cl)Cl>[F:21][C:20]([F:23])([F:22])[C:18]([OH:24])=[O:19].[OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](O)CN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2.00 g of 1-tert-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate in CHCl3 (20 ml) was added TFA (10 ml) under ice cooling, the reaction mixture was warmed to room temperature, then was stirred for 3 hours at the same temperature. Thereafter, the reaction solution was concentrated under reduced pressure to obtain 3.82 g of the title compound (crude form, colorless oil). The present compound was used in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].Cl[CH2:11][CH2:12][C:13](Cl)=[O:14].[Al+3].[Cl-].[Cl-].[Cl-].S(=O)(=O)(O)O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:11][CH2:12][C:13]2=[O:14])=[CH:4][C:3]=1[O:8][CH3:9]
Reactant: O=C(Cl)CCCl
Reactant: COc1ccccc1Cl
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(cc1Cl)C(=O)CC2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-chloro-2-methoxybenzene (12.8 mL, 100 mmol) and 3-chloropropanoyl chloride (10.5 mL, 110 mmol) in CH2Cl2 (100 mL) at 0° C. was added AlCl3 (14.6 g, 110 mmol) portionwise during about 1 minute. After 30 minutes, sulfuric acid (300 mL) was poured slowly into the reaction mixture during about 3 minutes. The CH2Cl2 was removed by rotary evaporation under reduced pressure and the viscous residue was stirred at 100° C. for 2 hours. After cooling to −50° C., the viscous reaction mixture was poured cautiously onto 1.5 L of ice and allowed to stand overnight. The mixture was filtered and the cake of crude product was washed with water. The crude product was dissolved in 500 mL of 2% MeOH in CH2Cl2, dried over a mixture of Na2CO3 (˜10 g) and Na2SO4 (˜20 g), filtered and concentrated under vacuum to give 6-chloro-5-methoxyindan-1-one as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[Cl:14]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CC#N.O>[Cl:14][C:7]1[C:6]2[C:10](=[C:2]([CH3:1])[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(C(=O)O)cc2cn[nH]c12
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: Cc1cc(C(=O)O)cc2c(Cl)n[nH]c12
Yield: 97.8 %

Procedure:
To a suspension of 7-methyl-1H-indazole-5-carboxylic acid (180 mg, 1.01 mmol) in CH3CN (10 mL) was added N-chlorosuccinimide (150 mg, 1.12 mmol). The mixture was heated at reflux overnight before concentration. The solid was suspended in water and aqueous sodium thiosulfate solution, acidified with 1 N HCl and the solids were isolated by filtration. The solids were then washed with water and dried to provide the title compound as a tan solid (208 mg, 98%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[N:8]=[N:7][C:6]([CH2:9][O:10][CH2:11][C:12]2[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])[C:17]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:5]1.C(N(CC)CC)C.[Cl:43][C:44]1[CH:49]=[C:48](Cl)[N:47]=[CH:46][N:45]=1>C(O)C>[Cl:43][C:44]1[N:45]=[CH:46][N:47]=[C:48]([NH:1][CH2:2][CH2:3][N:4]2[N:8]=[N:7][C:6]([CH2:9][O:10][CH2:11][C:12]3[NH:13][C:14]([CH3:35])=[C:15]([C:31]([O:33][CH3:34])=[O:32])[CH:16]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[Cl:30])[C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:5]2)[CH:49]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCOC(=O)C1=C(COCc2nnn(CCN)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1=C(COCc2nnn(CCNc3cc(Cl)ncn3)n2)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Yield: 80.8 %

Procedure:
A solution of 2-(2-aminoethyl)-5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}tetrazole (0.52 g), triethylamine (0.5 ml) and 4,6-dichloropyrimidine (0.16 g) in ethanol (20 ml) was heated under reflux for 23 hours and then evaporated. The residue was purified by chromatography on silica (8 g) using dichloromethane plus from 0 to 100% by volume of ethyl acetate as eluant. Appropriate fractions were combined and evaporated to give 2-{[(6-chloro-4-pyrimidinyl)amino]ethyl}-5-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridin-2-yl]methoxymethyl}tetrazole (0.51 g) as a colourless foam. A solution of this crude product in morpholine (3 ml) was heated on a steam-bath for 90 minutes and then partitioned between 2M hydrochloric acid and dichloromethane. The acidic layer was extracted into dichloromethane and the combined organic layers were washed with water and 10% aqueous sodium carbonate solution, dried over anhydrous sodium sulphate and evaporated. The residue was purified by chromatography on silica (10 g) using dichloromethane plus from 0 to 50% by volume of ethyl acetate followed by dichloromethane plus from 1 to 5% by volume of methanol as eluant. Appropriate fractions were combined and evaporated. The residual oil was triturated with diethyl ether and the resulting solid collected, washed with diethyl ether and dried to give the title compound (0.51 g), m.p. 160°-162° C. Found: C,52.24; H,5.20; N,18.24. C30H35Cl2N9O6 requires: C,52.33; H,5.09; N,18.31%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]([CH2:33][C:34]#[C:35][CH3:36])[C:17](=[O:32])[N:18]3COC(=O)C(C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]([CH2:33][C:34]#[C:35][CH3:36])[C:17](=[O:32])[NH:18]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC#CCn1c(=O)n(COC(=O)C(C)(C)C)c2nc(Cl)nc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC#CCn1c(=O)[nH]c2nc(Cl)nc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
4-[7-(2-Butynyl)-2-chloro-9-(2,2-dimethylpropionyloxymethyl)-8-oxo-8,9-dihydro-7H-purin-6-yl]piperazine-1-carboxylic acid t-butyl ester (665 mg) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (3 mL), and then sodium hydride (60-72% in oil) (61 mg) was added to this solution. The reaction solution was stirred at room temperature for three hours. 1 N aqueous hydrochloric acid (3 mL) was then added to the reaction solution, which was extracted using ethyl acetate. The obtained organic layer was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (294 mg).