Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].Br[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[CH:6][C:5]=1[Cl:14].[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O.[OH-].[Na+]>C(O)C.O.O1CCOCC1>[C:19]([O:18][C:16]([NH:1][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[CH:6][C:5]=1[Cl:14])=[O:15])([CH3:22])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(CBr)c(Cl)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a saturated solution of ammonia in ethanol (170 ml) was added methyl 4-bromomethyl-3-chlorobenzoate from Example A1 (5.5 g, 20.9 mmol). The mixture was stirred at room temperature for 1 hr and then concentrated in vacuo. The residue was triturated with diethyl ether and the resultant white crystals were filtered off and washed with more diethyl ether. To a solution of this solid in water (100 ml) were added solutions of (BOC)2O (5.0 g, 23.0 mmol) in dioxan (100 ml) and sodium hydroxide (1.86 g, 46.0 mmol) in water (100 ml). The mixture was stirred at room temperature for 18 h and then concentrated in vacuo. The aqueous residue was acidified with citric acid and extracted with chloroform/IPA. The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 2.8 g (67%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:8][CH2:9][CH2:10][CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:22].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O.Cl>CN(C)C=O>[CH2:13]([N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:20])[CH2:8][CH2:9][CH2:10][C:11]([OH:22])=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N(CCCCO)Cc1ccccc1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCC(=O)O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.5 %

Procedure:
A solution of benzyl-(4-hydroxy-butyl)-carbamic acid tert butyl ester (9.4 g, 33.7 mmol) in anhydrous dimethyl formamide “DMF” (40 mL) was cooled in an ice bath. Pyridinium dichromate (44 g, 117 mmol) was added in 4 portions of with 15 min intervals. The reaction mixture was allowed to stir overnight at room temperature resulting in a viscous black slurry. The slurry was poured into water (400 mL), acidified to pH 1 with concentrated HCl and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with, 5% NaHSO4 (100 mL), water (4×300 mL). Subsequently, the organic layer was extracted with 1M NaOH (150, 75, and 50 mL). The combined aqueous layers were cooled with an ice bath and the pH was adjusted to 3 with concentrated HCl. The resulting white suspension was extracted three times with ethyl acetate (3×200 mL) and the combined organic layers were dried over Na2SO4, filtered, and the solvent was evaporated in vacuo to give N-benzyl-N-(t-butoxy-carbonyl)-4-amino-1-butanoic acid (4.0 g, 40%) as viscous oil. 1H NMR (CDCl3): δ 7.23-7.35 (m, 5H); 4.41 (bs, 2H); 3.29 (bs, 1H); 3.19 (bs, 1H); 2.33 (bs, 2H); 1.82 (bs, 2H); 1.46 (bs, 9H).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=2)[CH2:3]1.[N:17]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[CH:25]2)=[C:18]=[O:19]>>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:18]([NH:17][C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][N:24]=[CH:25]4)=[O:19])=[CH:11][CH:10]=2)[CH2:5]1
Reactant: O=C=Nc1cccc2cnccc12
Reactant: CC1CN(c2ccc(CN)cc2)CC(C)O1
Product: CC1CN(c2ccc(CNC(=O)Nc3cccc4cnccc34)cc2)CC(C)O1

Procedure:
The product from Example 67A and the product from Example 61A were processed as described in Example 66C to provide a waxy material which was purified by chromatography (95:5 CH2Cl2-MeOH, eluant) to provide the title compound as a white solid. The corresponding di-hydrochloride salt was prepared using methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.67 (s, 1H), 8.53 (d, J=6.1 Hz, 1H), 8.31 (dd, J=7.6 Hz, 1.1 Hz, 1H), 7.92 (d, J=6.1 Hz, 1H), 7.73 (d, J=8.1 Hz, 1H), 7.57-7.62 (m, 1H), 7.22 (d, J=8.8 Hz, 2H), 6.92-6.95 (m, 3H), 4.26 (d, J=5.7 Hz, 2H), 3.68 (m, 2H), 3.54-3.57 (m, 2H), 2.21 (m, 2H), 1.16 (s, 3H), 1.14 (s, 3H); MS (ESI+) m/z 391 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]([OH:21])=O.[CH:25]([N:28](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN.C1COCC1>CN(C=O)C.CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:15]([CH3:18])=[N:16][N:17]=3)[C:9]=2[CH:8]=[C:7]1[C:19]([NH:28][CH3:25])=[O:21]
Reactant: Cc1nnc2ccc3c(cc(C(=O)O)n3Cc3cccc(Cl)c3)n12
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CNC(=O)c1cc2c(ccc3nnc(C)n32)n1Cc1cccc(Cl)c1
Reaction time: 0.25 h

Procedure:
To a solution of 6-(3-chlorobenzyl)-1-methyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (0.034 g, 0.10 mmol, from Step 4) in DMF (2 mL) was added N,N-diisopropylethylamine (0.16 mL, 0.93 mmol, Aldrich) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.12 g, 0.32 mmol, Aldrich) and then by 2.0 M methylamine in THF (0.40 mL, 0.80 mmol, Aldrich). After stirring for 15 minutes, the reaction mixture was diluted with MeCN and purified via preparative HPLC-MS (C18 eluting with a gradient of MeCN and H2O containing 0.15% NH4OH). Yield: (25 mg, 71%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[CH3:33][N:34]([CH3:44])[CH2:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:41]3[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][CH2:35][N:34]([CH3:33])[CH3:44])[CH2:39][CH2:40]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: CN(C)CCCN1CCNCC1
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCN(CCCN(C)C)CC3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 1-(3-dimethylaminopropyl)piperazine. A yellow solid 113 was obtained (0.0414 g, 79%). 1H NMR (CDCl3, 400 MHz) δ 2.20-2.50 (br, 6H), 2.42-2.50 (m, 2H), 2.86 (s, 6H), 3.21-3.28 (m, 2H), 3.32-3.38 (br, 2H), 3.83 (s, 3H), 4.05-4.10 (br, 2H), 6.88 (s, 1H), 6.99-7.06 (m, 3H), 7.10 (d, J=8.2 Hz, 1H), 7.43-7.52 (m, 3H), 7.85 (s, 1H), 8.25 (d, J=5.5 Hz, 1H); MS (APCI) m/z 531 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.Cl[CH2:9][C:10]1[N:11]=[C:12]([NH2:15])[S:13][CH:14]=1>CN(C=O)C.C(OCC)(=O)C>[O:4]1[CH2:5][CH2:6][N:1]([CH2:9][C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)[CH2:2][CH2:3]1
Reactant: Nc1nc(CCl)cs1
Reactant: C1COCCN1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nc(CN2CCOCC2)cs1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
Morpholine (350 μL, 4.00 mmol) is added to a solution of 4-chloromethyl-thiazol-2-ylamine hydrochloride (368 mg, 2.00 mmol) in DMF (7 mL). The reaction is stirred at 90° C. for 16 h. The reaction is diluted with ethyl acetate and washed with water. The aqueous layer is concentrated in vacuo and extracted with ethyl acetate. The combined organic layers are dried over MgSO4 and evaporated to give brown crystals which are used without further purification. 1H-NMR (400 MHz, d6-DMSO) δ=2.41-2.42 (m, 4H, CH2CH2), 3.30 (s, 2H, CH2), 3.55-3.60 (m, 4H, CH2CH2), 6.33 (s, 1H, Har), 6.85 (bs, 2H, NH2).
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].O.O.O.C([O-])(=O)C.[Na+].Br[CH2:21][C:22]1[CH:35]=[CH:34][C:25]([C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>C(#N)C.O.CO>[C:26]([C:25]1[CH:24]=[CH:23][C:22]([CH2:21][NH:9][C:6]2[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=2)=[CH:35][CH:34]=1)(=[O:27])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(c1ccccc1)c1ccc(CBr)cc1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: O=C(c1ccccc1)c1ccc(CNc2ccc(S(=O)(=O)O)cc2)cc1
Temperature: 70 °C
Yield: 54.2 %

Procedure:
To a 1-liter 3-necked round-bottomed flask equipped with overhead stirrer, reflux condenser, dropping funnel and thermometer and containing a stirred slurry of 33.8 g (0.195 mole) of sulfanilic acid in 150 ml of warm (60° C.) water was added 55 g (0.404 mole) of sodium acetate trihydrate and 50 ml of acetonitrile. The resulting yellow solution was heated to 70° C. and a solution of 35 g (0.127 mole) of the 4-(bromomethyl)benzophenone prepared above in 80 ml of acetonitrile was added dropwise over 11/2 hrs. The resulting solution was then refluxed for 5 hrs. Approximately 75 ml of acetonitrile was then removed by distillation at the same time that a dropwise addition of 32 ml of conc. HCl (over a 20 minute period) was made. The mixture was then vacuum filtered at 80° C. which gave a pale yellow powder. The powder was then slurried in 250 ml of water for 15 minutes and again isolated by vacuum filtration. The resulting solids were reslurried in 250 ml of methanol and isolated by vacuum filtration which afforded 25.28 g (54.2%) of purified 4-(((4-benzoylphenyl)methyl)amino)benzenesulfonic acid as a pale yellow powder, which decomposed at 257°-259° C.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[C:12]([F:21])[C:13]([F:20])=[C:14]([OH:19])[CH:15]=3)[O:10]2)[CH2:5][CH2:4]1)[CH3:2].I[CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[CH2:23]([O:19][C:14]1[CH:15]=[C:16]2[C:11](=[C:12]([F:21])[C:13]=1[F:20])[O:10][CH:9]([C@H:6]1[CH2:5][CH2:4][C@H:3]([CH2:1][CH3:2])[CH2:8][CH2:7]1)[CH2:18][CH2:17]2)[CH3:24]
Reactant: CC[C@H]1CC[C@H](C2CCc3cc(O)c(F)c(F)c3O2)CC1
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc2c(c(F)c1F)OC([C@H]1CC[C@H](CC)CC1)CC2

Procedure:
The DMF (100 ml) suspension containing 2-(trans-4-ethylcyclohexyl)-7,8-difluoro-6-hydroxychroman (28 g), iodoethane (25 g), and anhydrous potassium carbonate (15 g) was heated to reflux for 2 hours. The reaction solution was poured into 5% hydrochloric acid, extracted with toluene, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain 6-ethoxy-2-(trans-4-ethylcyclohexyl)-7,8-difluorochroman (30 g). Moreover, this was recrystallized using acetone to obtain 26 g of a pure substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[Cl:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH:29][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:16])=[CH:24][CH:23]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1ccc(Cl)nc1
Product: O=C(NCc1ccc(Cl)nc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (1.0 g, 2.85 mmol) and (6-chloropyridin-3-yl)methylamine (488 mg, 3.42 mmol). The title compound was obtained as a solid (500 mg, 37% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.43 (1H, m), 9.00 (2H, s), 8.44 (1H, s), 8.34 (1H, s), 7.77 (1H, dd), 7.49 (1H, dd), 4.23 (2H, m). MS m/z: 473.05, 475.03 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]([C:13]2[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=2[N:19]=1)[C@@H:4]1[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]1[OH:6].[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[CH:37][CH:36]=2)[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>C(O)CC>[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:36]=[CH:37][C:38]([CH2:41][NH:42][C:2]3[N:3]([C:13]4[N:14]=[CH:15][N:16]=[C:17]([NH2:20])[C:18]=4[N:19]=3)[C@@H:4]3[O:12][C@H:9]([CH2:10][OH:11])[C@@H:7]([OH:8])[C@H:5]3[OH:6])=[CH:39][CH:40]=2)[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCc1ccc(-c2cccc(OCc3ccccc3)c2)cc1
Reactant: Nc1ncnc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncnc2c1nc(NCc1ccc(-c3cccc(OCc4ccccc4)c3)cc1)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A mixture of a 8-bromoadenosine (0.130 g), 3′-benzyloxy-biphenyl-4-ylmethylamine (0.326 g) and N,N-diisopropyl-ethylamine (0.262 mL) in 1-propanol (3.8 mL) was stirred under reflux for 24 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography on amino-propylated silica gel (eluent: dichloromethane/methanol=12/1) to give the title compound (0.120 g).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]>C(Cl)CCC>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:6][CH2:5][CH2:10][CH3:9])[CH2:13][CH2:12]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cccc(C2CCNCC2)c1
Solvent: CCCCCl
Product: CCCCN1CCC(c2cccc(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 4-(3-methanesulfonyl-phenyl)-piperidine and n-BuCl. MS m/z (rel. intensity, 70 eV) 295 (M+, 3), 252 (bp), 130 (5), 115 (3), 70 (8).
Reaction SMILES: [C:1]([SH:5])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br.C1(C)C=CC=CC=1>CO.O>[Br:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][S:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1Br
Reactant: CC(C)(C)S
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CC(C)(C)SCc1ccccc1Br
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
36.6 g (406 mmol) of tert-butylmercaptan were added to a mixed solution of 36.5 g (438 mmol) of 48% aqueous sodium hydroxide solution and 400 ml of methanol under a nitrogen atmosphere at room temperature. A solution of 99.5 g (398 mmol) of 2-bromobenzylbromide in 100 ml of methanol were dropped into this solution below 40° C. After stirring for 30 minutes at 40° C. 1000 ml of toluene and 500 ml of water were sequentially added to the reaction solution. The aqueous layer was separated, and the organic layer was sequentially washed with 500 ml of 5% aqueous sodium hydroxide solution and 500 ml of water. After drying the organic layer with magnesium sulfate, the solvent was distilled off to obtain 300 ml of residue, which was used in the next step.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1)=O)(C)(C)C.C(OC(N1CCC[C@@H]1CO)=O)(C)(C)C.C=O>C(O)=O>[CH3:6][N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:21])=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cl)nc1
Agent: C=O
Agent: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Solvent: O=CO
Product: CN1CCC[C@@H]1COc1ccc(Cl)nc1

Procedure:
A 376 mg (1.2 mmol) sample of 3-((1-t-butoxycarbonyl-2-(R)-pyrrolidinyl)methoxy)-6-chloropyridine, prepared from (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol by the procedure described in Example 45a above, was treated with paraformaldehyde and formic acid for 2 hours as described in Example 16a above. The crude material was purified by column chromatography on silica gel, eluting with 20:1 chloroform:methanol to afford 219 mg of the title compound. MS (DCI/NH3) m/e: 225/227 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.07 (s, 1H), 7.25-7.18 (m, 2H), 4.02 (dd, J=9.1, 5.4 Hz, 1H), 3.93 (dd, J=9.1, 5.4 Hz, 1H), 3.17-3.11 (m, 1H), 2.71-2.67 (m, 1H), 2.49 (s, 3H), 2.38-2.29 (m, 1H), 2.10-1.98 (m, 1H), 1.91-1.68 (m, 3H). [α]25D =+64.5° (c=1.1, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[O:15][C:14]([CH:16]=[N:17][OH:18])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:19][N:20]([CH:22]=[O:23])C.CN=C=O>O>[CH3:19][NH:20][C:22]([O:18][N:17]=[CH:16][C:14]1[O:15][C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:12][CH:13]=1)=[O:23]
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2ccc(C=NO)o2)cc1OC
Agent: CN=C=O
Solvent: O
Product: CNC(=O)ON=Cc1ccc(-c2ccc(OC)c(OC)c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
5-(3,4-Dimethoxyphenyl)furylformaldoxime (9.5 g, 0.038 mole) and DMF (500 ml) was treated with methyl isocyanate (16 ml, 0.27 mole). The solution was stirred at room temperature for 4 hours and at steam bath temperature for 1 hour. The reaction solution was poured into 3 liters of water. The tan precipitate was collected to give 6 g (51%) of product.
Reaction SMILES: O[C:2]1[CH:3]=[N:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[CH:3]=[N:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cnc2ccccc2n1
Solvent: CN(C)c1ccccc1
Product: Clc1cnc2ccccc2n1
Yield: 87.5 %

Procedure:
A mixture of 74 g (0.5 mole) of 2-hydroxy-benzopyrazine, 12 g of dimethylaniline and 250 ml of phosphorus oxychloride was heated under reflux for 10 minutes. At about 80° C, all the material had dissolved; the reaction solution was cooled and poured onto ice, and the product was filtered off. The residue was dried on clay and was then taken up in petroleum ether, and the solution was filtered through active charcoal. The reaction solution was evaporated and 78 g (87.5% of theory) of 2-chloro-benzopyrazine of melting point 48°-49° C, were obtained. ##STR33##
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([CH2:17][C:18]([OH:20])=O)=[CH:11][C:12]([O:15][CH3:16])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:9]2=[CH:14][N:13]=[C:12]([O:15][CH3:16])[CH:11]=[C:10]2[CH2:17][C:18]1=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(CC(=O)O)c(NC(=O)OC(C)(C)C)cn1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc2c(cn1)N(C(=O)OC(C)(C)C)C(=O)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
(5-tert-Butoxycarbonylamino-2-methoxy-pyridin-4-yl)-acetic acid (10 g, 35.4 mmol) was dissovled in DCM (142 mL) and EDC (7.5 g, 39 mmol), HOAt (5.4 g, 39 mmol) and DIPEA (15 mL, 85.7 mmol) were sequentially added, under N2. The reaction was stirred for 2 h at ambient temperature then quenched by addition of saturated aqueous NaHCO3 and extracted with DCM (×3). The combined organic extracts were washed with water and brine then dried over MgSO4 and concentrated in vacuo. The product was purified by column chromatography to yield the title compound (9.5 g) as a pale brown solid. 1H NMR (DMSO-c/6): 8.38 (1H, s), 6.83 (1H, s), 3.84 (3H, s), 3.77 (2H, s), 1.57 (9H, s). MS: [M+H]+=265.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]5[N:21]([C:23]([C:26](=[O:28])[CH3:27])=[CH:24][N:25]=5)[CH:22]=4)=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.O.[BH4-].[Na+].O1CCOCC1>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]5[N:21]([C:23]([CH:26]([OH:28])[CH3:27])=[CH:24][N:25]=5)[CH:22]=4)=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1
Reactant: CC(=O)c1cnc2ccc(Cc3cnc4ccc(-c5cnn(C)c5)nn34)cn12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(O)c1cnc2ccc(Cc3cnc4ccc(-c5cnn(C)c5)nn34)cn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-{6-[6-(1-Methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-ylmethyl]-imidazo[1,2-a]pyridin-3-yl}-ethanone (Example 301, 50 mg, 0.135 mmol) was dissolved in MeOH (3 mL) and water (1 mL) then NaBH4 (3.1 mg, 0.081 mmol) was added. The RM was stirred at rt for 2 h. More equivalents of NaBH4 (3 times 5.1 mg, 0.135 mmol) were added to RM over 18 h. Then dioxane was added and it was stirred at 60° C. for 2 h. It was quenched with EtOAc and solvents were removed. The residue was purified by preparative HPLC with acetonitrile and water (+0.1% TFA). The fractions were joined and lyophilized. The residue was dissolved in MeOH and it was passed through an SPE cartridge of HCO3− to remove the TFA salt. The filtrate was evaporated to give the free salt compound of the title compound as a white solid (tR 0.6 min (conditions 2), MH+=374).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[I:8][C:4]1[CH:3]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Ic1cccc(I)c1
Reactant: C1COCCN1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Ic1cccc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 40.9 %

Procedure:
To a solution of 1,3-diiodobenzene (5.05 g, 15.3 mmol) in isopropanol (16 mL) under nitrogen was added morpholine (1.33 g, 1.33 mL, 15.3 mmol), potassium phosphate (6.50 g, 30.6 mmol), ethylene glycol (1.90 g, 1.70 mL, 30.6 mmol) and copper (I) iodide (146 mg, 0.765 mmol). The mixture was heated at 80° C. for 15 h, and then cooled to room temperature. The solids were removed by filtration and the solution was concentrated. The residue was purified by silica gel column chromatograghy eluted with EtOAc:hexanes (5 to 25% EtOAc) to give 4-(3-iodo-phenyl)-morpholine (1.81 g, 41%) as a colorless oil. MS (ES+): m/z=290.0; 1H NMR (CDCl3, 500 MHz): δ 3.15 (t, 4H), 3.85 (t, 4H), 6.87 (dd, 1H), 6.96-7.00 (m, 1H), 7.20 (d, 1H), 7.22-7.25 (m, 1H).
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:12][CH2:13][CH3:14])(=[O:11])[C:6]([O:8]CC)=O.[C:15]([C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])[CH3:26])=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>C(O)C.C1(C)C=CC=CC=1>[C:15]([C:19]1[CH:20]=[CH:21][C:22]([C:25](=[O:27])[CH2:26][C:6](=[O:8])[C:5]([O:12][CH2:13][CH3:14])=[O:11])=[CH:23][CH:24]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(=O)c1ccc(C(C)(C)C)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)c1ccc(C(C)(C)C)cc1
Yield: 100 %

Procedure:
To a cooled solution, <5° C., of sodium ethoxide (4.4 g, 64.6 mmol) in ethanol, diethyl oxalate (7.71 mL, 56.7 mmol) in toluene (150 mL) was added. The reaction mixture was stirred for 30 min, before the addition of 1-(4-tert-butylphenyl)ethanone (56.7 mmol, 10 g) dropwise in toluene (20 mL) (via pressurised dropping funnel). The reaction mixture was stirred overnight to room temperature and then evaporated to low volume. Acetic acid was added and the resultant precipitate was filtered and washed with heptane to obtain ethyl 4-(4-tert-butylphenyl)-2,4-dioxobutanoate (15.68 g, 56.7 mmol).