Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[Br:16][C:17]1[C:18](O)=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.C(=O)([O-])O.[Na+]>O>[Cl:3][C:18]1[C:17]([Br:16])=[CH:22][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:20][N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc(C(F)(F)F)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccc2ncccc2c1
Solvent: O
Product: FC(F)(F)c1cnc(Cl)c(Br)c1
Temperature: 120 °C
Yield: 75.1 %

Procedure:
To phosphorous oxychloride (2.02 ml, 21.6 mmol) was added quinoline (1.34 ml, 11.2 mmol) followed by 3-bromo-2-hydroxy-5-trifluoromethylpyridine (5.0 g, 20.7 mmol), and the mixture formed heated at 120° C. for 3 hrs. It was then cooled to 100° C. and water (10 ml) added. After cooling to 22° C., sodium hydrogen carbonate solution (100 ml) was added and the mixture extracted with ethyl acetate (2×100 ml). The extracts were dried (MgSO4) and concentrated, and the residue purified by silica chromatography to give the product as an oil (4.05 g, 75% yield).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:5]=[C:6]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[S:7][C:8]=1[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].C(N(CC)CC)C.Cl[S:31]([C:34]1[CH:42]=[CH:41][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>ClCCl>[C:38]([C:37]1[CH:36]=[CH:35][C:34]([S:31]([N:14]2[CH2:15][CH2:16][N:11]([C:9]([C:8]3[S:7][C:6]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)=[N:5][C:4]=3[CH3:3])=[O:10])[CH2:12][CH2:13]2)(=[O:33])=[O:32])=[CH:42][CH:41]=1)([OH:40])=[O:39]
Reactant: Cc1nc(-c2ccncc2)sc1C(=O)N1CCNCC1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccncc2)sc1C(=O)N1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.2 %

Procedure:
To a solution of 1-[4-methyl-2-(4-pyridyl)-5-thiazolecarbonyl]piperazine dihydrochloride (180 mg) and triethylamine (253 mg) in dichloromethane (20 ml) was added 4-chlorosulfonylbenzoic acid (108 mg), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was dissolved in water and neutralized with 1 N hydrochloric acid. The precipitate was filtered, washed with water and dried to give a colorless solid of the title compound (174 mg).
Reaction SMILES: [OH-].[K+].C(O)(C)C.Cl[CH2:8][C:9]([N:11]([CH2:15][CH:16]([OH:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1)[CH2:12][CH2:13][CH3:14])=[O:10]>O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH:16]2[CH2:15][N:11]([CH2:12][CH2:13][CH3:14])[C:9](=[O:10])[CH2:8][O:25]2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCCN(CC(O)c1cccc(OC)c1)C(=O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CCCN1CC(c2cccc(OC)c2)OCC1=O
Yield: 100 %

Procedure:
Potassium hydroxide (4.2 g, 0.07 mol), isopropyl alcohol (500 ml) and the amide from example 4 (17.8 g, 0.06 mol) were stirred together as an opaque solution with water (15 ml) for 2 hours. The reaction mixture was concentrated in vacuo and the yellow residue dissolved in ethyl acetate (200 ml. This was partitioned with water (200 ml) then brine (200 ml). The organic fraction was dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the title compound as a yellow oil (15.8 g, 0.06 mol, 100%). 1H NMR (CDCl3, 400 MHz) δ: 0.96 (t, 3H), 1.62 (m, 2H), 3.36 (m, 2H), 3.51 (q, 2H), 3.81 (s, 3H), 4.30-4.62 (bq, 2H), 4.79 (d, 1H), 6.85 (d, 1H), 6.91 (d, 1H), 6.95 (s, 1H), 7.29 (t, 1H). LRMS: m/z 272. Analysis found C, 66.80; H, 7.78; N, 5.52%. C14H19NO3.0.1H2O requires C, 66.96; H, 7.71; N, 5.58%.
Reaction SMILES: [CH2:1](N1CCCC(CCN2C(OC)=NC3C2=NC(O[C@@H](C)CCC)=NC=3N)C1)[CH3:2].[CH3:29][C@H:30]([O:34][C:35]1[N:43]=[C:42]2[C:38]([N:39]=[C:40]([O:54][CH3:55])[N:41]2[CH2:44][CH2:45][CH2:46][CH2:47][CH:48]2[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]2)=[C:37]([NH2:56])[N:36]=1)[CH2:31][CH2:32][CH3:33].ICC>>[CH2:1]([N:50]1[CH2:51][CH2:52][CH2:53][CH:48]([CH2:47][CH2:46][CH2:45][CH2:44][N:41]2[C:40]([O:54][CH3:55])=[N:39][C:38]3[C:42]2=[N:43][C:35]([O:34][C@@H:30]([CH3:29])[CH2:31][CH2:32][CH3:33])=[N:36][C:37]=3[NH2:56])[CH2:49]1)[CH3:2]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCC3CCCN(CC)C3)c2n1
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCCNC3)c2n1
Solvent: CCI
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCCN(CC)C3)c2n1

Procedure:
Prepared similarly to Intermediate 46 from 2-{[(1S)-1-methylbutyl]oxy}-8-(methyloxy)-9-[4-(3-piperidinyl)butyl]-9H-purin-6-amine and 2-iodoethane.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[CH:11]([N:15]([CH:17]3[CH2:19][CH2:18]3)[CH3:16])[CH2:10][CH2:9][C:8]([CH3:21])([CH3:20])[C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO.O1CCCC1>[CH:17]1([N:15]([CH3:16])[CH:11]2[CH2:10][CH2:9][C:8]([CH3:20])([CH3:21])[C:7]3[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13][C:12]2=3)[CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CCC2N(C)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C1CC1)C1CCC(C)(C)c2cc(C(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A solution of 5-(cyclopropyl-methyl-amino)-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (Intermediate 55, 0.236 g, 0.83 mmol) in methanol (4 mL) and tetrahydrofuran (4 mL) was treated with a 2M solution of sodium hydroxide (4 mL, 8 mmol) and the resulting reaction mixture was stirred at ambient temperature overnight. The volatiles were evaporated in vacuo to a residue that was neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title compound as a solid (0.22 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH:6]=[C:5]2[C:19]([OH:21])=O.S(Cl)([Cl:24])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH:6]=[C:5]2[C:19]([Cl:24])=[O:21]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(-c2cc(C(=O)O)c3cc(Cl)ccc3n2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2cc(C(=O)Cl)c3cc(Cl)ccc3n2)cc1

Procedure:
A mixture of 28.4 g of 6-chloro-2-(4-methylphenyl)-4-quinolinecarboxylic acid, 100 ml of thionyl chloride, and 200 ml of toluene was stirred and heated under reflux for 1.5 hr. The reaction mixture was then concentrated in vacuo, the residue was treated with more toluene, and the mixture again concentrated in vacuo. The residue was recrystallized from 300 ml of heptane to give 17.7 g of the above-named compound as a yellow solid.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:12]2[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[NH:15]1[CH2:16][CH2:17][CH2:18][CH:12]([CH2:11][NH:10][C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: c1ccc([C@@H]2C[C@H]2NCC2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
Chloroform (50 mL) was added to a 200 mL round-bottomed flask containing tert-butyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)azepane-1-carboxylate (49.4 mg, 0.143 mmol) to give a suspension. HCl/1,4-Dioxane (12 mL, 48.0 mmol) was added and the mixture stirred 18 hour at room temperature. Upon completion, the residue was adsorbed directly onto silica and purified via column chromatography on the ISCO Companion (gradient 0-100% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 4 g column). Fractions were collected, solvents removed and the resulting residue was taken up in MeOH (2 mL). Excess 2M HCl in Et2O and stirred for 10 minutes. The solvent was removed to yield the 2HCl salt of the desired product (28 mg, 59% yield) as a yellow solid: LC-MS (ES) m/z=245 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.32 (m, 1H) 1.36 (d, J=11.37 Hz, 1H) 1.54-1.79 (m, 3H) 1.80-1.96 (m, 2H) 2.06 (br. s., 2H) 2.54-2.64 (m, 1H) 2.97 (br. s., 5H) 3.06-3.27 (m, 2H) 7.14-7.26 (m, 3H) 7.27-7.35 (m, 2H) 9.03 (br. s., 2H) 9.38-9.62 (m, 2H).
Reaction SMILES: C1(S([N:10]2[CH:14]=[C:13]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])[N:12]=[C:11]2[C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31](S(C3C=CC=CC=3)(=O)=O)[CH:30]=2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O>[NH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([C:11]2[NH:10][CH:14]=[C:13]([C:15]([C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[O:16])[N:12]=2)=[CH:30]1
Reactant: COc1cc(C(=O)c2cn(S(=O)(=O)c3ccccc3)c(-c3cn(S(=O)(=O)c4ccccc4)c4ccccc34)n2)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)c2c[nH]c(-c3c[nH]c4ccccc34)n2)cc(OC)c1OC
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of (1-(phenylsulfonyl)-2-(1-(phenylsulfonyl)-1H-indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl)methanone (17yaa) (1 mmol) in ethanol (40 mL) and water (4 mL) was added sodium hydroxide (10 equiv, 10 mmol) and stirred overnight under refluxing condition in darkness. The reaction mixture was diluted by 50 mL of water and extracted by ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified by flash column chromatography (hexane:ethyl acetate 1:1) to give a yellow solid. Yield: 60%. 1H NMR (500 MHz, CD3OD) δ 8.31 (d, J=6.5 Hz, 1H), 7.99 (s, 1H), 7.90 (s, 1H), 7.48-7.52 (m, 3H), 7.24-7.28 (m, 2H), 4.00 (s, 6H), 3.93 (s, 3H). MS (ESI) calcd for C21H19N3O4 377.1. found 400.1 [M+Na]+. Mp 208-210° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([CH:14]=2)[NH2:13])[CH2:4][CH2:3]1.Cl.C(O[C:22](=N)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])C.Cl.[OH-].[Na+]>>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:22]1[NH:13][C:12]2[CH:14]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:9]=[CH:10][C:11]=2[N:15]=1)[CH3:28]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)Cc1nc2ccc(N3CCN(C)CC3)cc2[nH]1
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 74.1 %

Procedure:
After all the 5-(4-methyl-piperazin-1-yl)-2-nitroaniline had disappeared from the reaction, the solution was purged with N2 for 15 minutes. Next, 440.0 g (2.25 mol) of ethyl 3-ethoxy-3-iminopropanoate hydrochloride was added as a solid. The reaction was stirred at 40-50° C. (internal temperature) until the reaction was complete. The reaction was monitored by following the disappearance of the diamino compound by HPLC. The typical reaction time was 1-2 hours. After the reaction was complete, it was cooled to room temperature and filtered through a pad of Celite filtering material. The Celite filtering material was washed with absolute EtOH (2×250 mL), and the filtrate was concentrated under reduced pressure providing a thick brown/orange oil. The resulting oil was taken up in 850 mL of a 0.37% HCl solution. Solid NaOH (25 g) was then added in one portion, and a precipitate formed. The resulting mixture was stirred for 1 hour and then filtered. The solid was washed with H2O (2×400 mL) and dried at 50° C. in a vacuum oven providing 251.7 g (74.1%) of [6-(4-methyl-piperazin-1-yl)-1H-benzoimidazol-2-yl]-acetic acid ethyl ester as a pale yellow powder.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1.O>CC(N(C)C)=O>[CH:12]1([NH:17][C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: NC1CCCC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc2cccc(NC3CCCC3)n2n1
Temperature: 180 °C

Procedure:
To a solution of 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (0.5 g, 2.35 mmol) in dimethylacetamide (2 mL), cyclopentylamine (2.3 mL, 23.5 mmol) was added and the solution was heated under microwave irradiation (180° C., 180 min). The resulting mixture was dilluted with water and extracted into ethyl acetate. The organics were washed with water then brine, and dried over magnesium sulfate. The solid (0.5 g) was used without further purification. LCMS1: 2.84 min, 218 [M+1].
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:25]=[CH:24][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](/[C:17](=[N:19]/[N:20]=[C:21]([NH2:23])[NH2:22])/[CH3:18])[CH:12]=2)=[O:9])=[CH:6][CH:5]=1.CCO.[CH3:29][N:30]([CH3:42])[C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[CH:36][CH:35]=[C:34]2[Cl:41].Cl>O>[ClH:41].[ClH:1].[NH2:22][C:21](=[N:20]/[N:19]=[C:17](/[C:13]1[CH:12]=[C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:6]=[CH:5][C:4]([NH:3][C:34]3[C:33]4[C:38](=[CH:39][CH:40]=[C:31]([N:30]([CH3:42])[CH3:29])[CH:32]=4)[N:37]=[CH:36][CH:35]=3)=[CH:25][CH:24]=2)[CH:16]=[CH:15][CH:14]=1)\[CH3:18])[NH2:23]
Reactant: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(N)cc2)c1
Reactant: CN(C)c1ccc2nccc(Cl)c2c1
Agent: Cl
Solvent: O
Solvent: CCO
Product: C/C(=N\N=C(N)N)c1cccc(NC(=O)c2ccc(Nc3ccnc4ccc(N(C)C)cc34)cc2)c1

Procedure:
To a solution of triamine F5 (0.22 g, 0.59 mmol) in 1:2 EtOH:H2O (60 mL) were sequentially added 6-dimethylamino-4-chloroquinoline (0.13 g, 0.64 mmol) and c.HCl (0.16 mL, 5.32 mmol), and the resulting solution was refluxed for 20 h (reaction progress followed by TLC, eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:acetic acid). After this time, solvent was removed under reduced pressure, and the residue dried via two MeOH-azeotrope cycles. The residue was re-precipitated from MeOH:EtOAc to give Cpd. JJ1 (61 mg, 19%) as an amorphous dark brown solid; mp 239-243° C. (powder-glue), 278-282° C. (glue-liquid); 1H NMR (400 MHz, DMSO): δ 14.44 (s, 1H, quinolinyl-N+—H), 11.20 (s, 1H, hydrazonyl-N+—H), 10.58 (s, 1H, ArC(O)NHAr), 10.46 (s, 1H, ArNHAr), 8.35 (d, J=6.71 Hz, 1H, ArH), 8.26 (t, J=1.73 Hz, 1H, ArH), 8.22 (d, J=8.61 Hz, 3H, ArH), 7.95 (m, 2H, ArH), 7.79 (m, 5H, ArH & ═C(NH2)2), 7.69 (d, J=2.52 Hz, 1H, ArH), 7.66 (d, J=8.61 Hz, 2H, ArH), 7.58 (d, J=2.43 Hz, 1H, ArH), 7.43 (t, J=7.98 Hz, 1H, ArH), 6.95 (d, J=6.71 Hz, 1H, ArH), 3.15 (s, 6H, ArN(CH3)2), 2.37 (s, 3H, Ar(CH3)═N—); LCMS (APCI+): 482 (100%); HPLC: 95.8%.
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[NH:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=O.[H-].[Na+].[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25]>O1CCCC1.CC(C)=O>[C:1]1([C:7]2[N:12]3[C:11]4[N:10]([C:24](=[S:25])[NH:18][C:16](=[O:17])[C:15]=4[CH:14]=[N:13]3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)c1cnn2c1NCC=C2c1ccccc1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=c1[nH]c(=S)n2c3c1cnn3C(c1ccccc1)=CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.7 %

Procedure:
A mixture of 7.6 g of 4,5-dihydro-7-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide (prepared as described in Example 3) in 304 ml of dry tetrahydrofuran was stirred and cooled at -78° C. (dry-ice, acetone), under nitrogen and 2.17 g of sodium hydride (60% dispersion in mineral oil) was added. The mixture was stirred at -78° C. for 30 minutes, then 4.84 g of 1,1'-thiocarbonyldiimidazole was added in one portion. The temperature was kept at -78° C. for 2 hours, then was allowed to warm slowly to room temperature while stirring was continued for 48 hours. The reaction mixture was quenched with 500 ml of water and neutralized to pH 6-7 with 5% aqueous hydrochloric acid. A crystalline solid formed which was collected by filtration, triturated with ether, filtered and dried to give 3.2 g of the desired product as white crystals, m.p. 289°-291° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[C:17]1([NH:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>COCCOC>[Cl:1][C:2]1[C:7]([NH:26][CH2:25][CH2:24][NH:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:6][C:5]([NH2:11])=[N:4][C:3]=1[C:12]1[O:13][CH:14]=[CH:15][CH:16]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Cl
Reactant: NCCNc1ccccc1
Solvent: COCCOC
Product: Nc1nc(NCCNc2ccccc2)c(Cl)c(-c2ccco2)n1

Procedure:
From 5-chloro-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl-amine and N-phenylethylenediamine in DME. ES-MS m/e (%): 332 (M{37Cl}+H+, 40), 330 (M{35Cl}+H+, 100).
Reaction SMILES: [C:1]([CH2:3][N:4]([C:16]1[CH:21]=[CH:20][N:19]=[C:18](F)[N:17]=1)[C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])#[N:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([C:18]3[N:17]=[C:16]([N:4]([CH2:3][C:1]#[N:2])[C:5](=[O:15])[C@H:6]([CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[NH2:7])[CH:21]=[CH:20][N:19]=3)[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: N#CCN(C(=O)[C@@H](N)Cc1ccccc1)c1ccnc(F)n1
Product: N#CCN(C(=O)[C@@H](N)Cc1ccccc1)c1ccnc(N2CCN(c3ccc(Cl)cc3)CC2)n1

Procedure:
The title compound was prepared from the product of example 5 step (ii) (0.2 g) and 4(4-chlorophenyl)piperazine by the method of example 1 step (iv). Yield 0.18 g.
Reaction SMILES: [Cl:1][C:2]1[S:12][C:5]2[NH:6][C:7]([C:9]([OH:11])=O)=[CH:8][C:4]=2[CH:3]=1.Cl.[NH2:14][C@@H:15]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17].O.[O-]S([O-])(=O)=O.[Mg+2]>C(OCC)(=O)C>[CH2:24]([C@H:15]([NH:14][C:9]([C:7]1[NH:6][C:5]2[S:12][C:2]([Cl:1])=[CH:3][C:4]=2[CH:8]=1)=[O:11])[C:16]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(O)c1cc2cc(Cl)sc2[nH]1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCOCC1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCOCC1)c1cc2cc(Cl)sc2[nH]1

Procedure:
2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid and (2S)-amino-1-morpholin-4-yl-3-phenyl-propan-1-one hydrochloride (See, for example, Suzuki, K.; Fujita, H.; Sasaki, Y.; Shiratori, M.; Sakurada, S.; Kisara, K., Chem. Pharm. Bull., 36, 4834-40 (1988)) were coupled according to Procedure C (solution of product in ethyl acetate washed with water, dried over MgSO4, concentrated).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:9][C:10]=2[C:11]2[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][N:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:32][CH:31]=1>CN(C=O)C>[C:37]([O:36][C:33]1[CH:32]=[CH:31][C:30]([CH2:29][O:17][C:13]2[CH:12]=[C:11]([C:10]3[N:9]=[C:8]([CH:18]4[CH2:21][CH2:20][CH2:19]4)[N:4]4[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=34)[CH:16]=[CH:15][CH:14]=2)=[CH:35][CH:34]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)Oc1ccc(CBr)cc1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3cccc(O)c3)c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)Oc1ccc(COc2cccc(-c3nc(C4CCC4)n4ccnc(N)c34)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-(8-Amino-3-cyclobutyl-imidazo[1,5-a]pyrazin-1-yl)-phenol (200 mg, 0.71 mmol) in DMF (3.5 mL) was charged with Cs2CO3 (348 mg, 1.07 mmol) and stirred at rt for 30 min. A solution of 1-bromomethyl-4-tert-butoxy-benzene (162 mg, 0.71 mmole) in 0.5 mL of DMF, was added to the reaction mixture. After 15 h, the reaction was complete by LC/MS analysis. The product was an orange/brown solid. The crude product was chromatographed on silica gel [Jones Flashmaster, 5 g cartridge, eluting with 10% ethyl acetate]. The product was then recrystalized with ethyl acetate and hexanes yielding the title compound as a white solid; 1H NMR (CDCl3, 400 MHz) δ 1.36 (s, 9H), 2.11-2.23 (m, 2H), 2.45-2.52 (m, 2H), 2.59-2.69 (m, 2H), 3.77-3.85 (m, 1H), 5.08 (s, 2H), 5.49 (brs, 2H), 7.01-7.04 (m, 3H), 7.05 (dd, J=4.00 Hz, 1H), 7.10 (d, J=5.02 Hz, 1H), 7.23-7.25 (m, 1H), 7.29 (q, J=40 Hz, 1H), 7.34-7.36 (m, 2H), 7.41 (t, J=16 Hz, 1H); MS (ES+): m/z 443.04 (100) [MH+].
Reaction SMILES: Br[C:2]12[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1.[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>[Ag]=O>[CH2:13]([O:17][C:2]12[CH2:11][CH:7]([CH2:8][CH2:9][CH2:10]1)[CH:6]1[CH2:12][CH:3]2[CH2:4][CH2:5]1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCO
Reactant: BrC12CCCC(C1)C1CCC2C1
Agent: O=[Ag]
Product: CCCCOC12CCCC(C1)C1CCC2C1
Yield: 65.3 %

Procedure:
A mixture of 3.0 g of 1-bromotricyclo[4.3.1.12,5 ]undecane, 2.0 g of silver oxide and 30 ml of anhydrous n-butanol was refluxed for 6 hours. Thereafter, the mixture was treated in the same manner as described in Example 1, and there was obtained 1.9 g (yield, 65.3%) of 1-n-butoxytricyclo[4.3.1.12,5 ]undecane having a boiling point of 97° to 98° C./1 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[CH:6]=[CH:5][CH:4]=1.C1C(=O)N([I:18])C(=O)C1>CN(C=O)C>[I:18][C:4]1[CH:5]=[CH:6][C:7]([NH:9][CH3:10])=[N:8][C:3]=1[O:2][CH3:1]
Reactant: CNc1cccc(OC)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CNc1ccc(I)c(OC)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
6-Methoxy-N-methyl-2-pyridinamine (17.24 g, 124 mmol) is dissolved in DMF (160 mL) and cooled to 0° C. followed by the addition of NIS (28 g, 124 mmol, 1 equiv), at a rate which keeps the reaction temperature below 10° C. The reaction is then allowed to warm to room temperature and stirred for 1 h. The reaction is distilled to dryness in vacuo and the residue is dissolved in CH2Cl2 and passed through a silica plug eluting with heptane/EtOAc (9/1) affording 32 g of crude 5-iodo-6-methoxy-N-methyl-2-pyridinamine. The crude 5-iodo-6-methoxy-N-methyl-2-pyridinamine is dissolved in diethyl ethoxymethylenemalonate (32 mL) and the mixture is heated at 140° C. for 2 h, then cooled to room temperature and passed through a silica plug eluting with heptane/EtOAc (19/1, 0/1). The product is then dissolved in Eaton's reagent (132 mL) and heated at 100° C. for 40 min, cooled to rt and poured into Na2CO3. The basic aqueous layer is then extracted with CH2Cl2 (3×), washed with water, and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (heptane/EtOAc, 4/1, 1/1, CH2Cl2/MeOH 19/1) the desired product is then triturated with MeOH to afford 7.9 g (16%) of ethyl 6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate. Physical characteristics are as follows: 1H NMR (CDCl3) δ 9.04, 8.52, 4.41, 4.13, 3.91, 1.43; IR (diffuse reflectance) 2491, 2427, 2350, 2282, 2242, 1678, 1632, 1613, 1579, 1384, 1309, 1275, 1227, 1106, 804, cm−1; MS (EI) m/z 388, 344, 343, 317, 316, 185, 159, 86, 84, 51; Anal calcd for C13H13IN2O4: C, 40.23; H, 3.38; N, 7.22. Found: C, 40.20; H, 3.40; N, 7.16.
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]([C:15](=[O:25])[NH:16][C:17]([C:22](=[O:24])[NH2:23])([CH3:21])[CH:18]([CH3:20])[CH3:19])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:4])[CH3:3].[CH3:27]O>>[CH3:27][O:12][C:11](=[O:13])[C:10]1[CH:14]=[C:6]([O:5][C:2](=[O:4])[CH3:3])[C:7]([CH3:26])=[N:8][C:9]=1[C:15](=[O:25])[NH:16][C:17]([C:22](=[O:24])[NH2:23])([CH3:21])[CH:18]([CH3:19])[CH3:20]
Reactant: CO
Reactant: CC(=O)Oc1cc(C(=O)O)c(C(=O)NC(C)(C(N)=O)C(C)C)nc1C
Agent: Cl
Product: COC(=O)c1cc(OC(C)=O)c(C)nc1C(=O)NC(C)(C(N)=O)C(C)C

Procedure:
Hydrochloric acid gas is led for 3 hours through a solution of 53 g (0.151 mol) 5-acetoxy-2-(1-carbamoyl-1,2-dimethylpropyl-carbamoyl)-6-methyl-nicotinic acid in 500 ml absolute methanol boiling under reflux. Then, the solvent is evaporated and the product is dried in a vacuum.